Comprehensive Organic Functional Group Transformations II - V 1 (Carbon With No Attached Heteroatoms)

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Editors-in-Chief
Professor Alan R. Katritzky, FRS
University of Florida, Gainesville, FL, USA
Professor Richard J. K. Taylor

University of York, York, UK
Editors-in-Chief
Alan Katritzky, educated at Oxford, held faculty positions at
Cambridge and East Anglia before migrating in 1980 to the
University of Florida, where he is Kenan Professor and Director
of the Center for Heterocyclic Compounds. He has trained some
800 graduate students and postdocs, and lectured and consulted
worldwide. He led the team which produced Comprehensive
Heterocyclic Chemistry and its sequel CHECII, has edited Advances
in Heterocyclic Chemistry, Vols. 1 through 86 and conceived the plan
for Comprehensive Organic Functional Group Transformations. He
founded Arkat-USA, a nonprofit organization which publishes
Archive for Organic Chemistry (ARKIVOC) electronic journal
completely free to authors and readers at (www.arkat-usa.org).
Honors include 11 honorary doctorates from eight countries and
membership or foreign membership of the National Academies of
Britain, Catalonia, India, Poland, Russia, and Slovenia.
Richard Taylor is currently Professor of Organic Chemistry at the

University of York, where his research focuses on the development
of novel synthetic methodology and the synthesis of natural
products and related compounds of biological/medicinal interest.
The methodology is concentrated primarily on organometallic,
organosulfur, and oxidation processes, and the targets include
amino acids, carbohydrates, prostaglandins, and polyene and
polyoxygenated natural products, particularly with activity as
antibiotics and anti-cancer agents.
Richard Taylor is a graduate and postgraduate of the University
of Sheffield. After his studies at Sheffield, he carried out postdoctoral
research at Syntex, California (Dr. I. T. Harrison) and University
College London (Professor F. Sondheimer). His first academic
appointment was at the Open University in Milton Keynes. This
post gave Professor Taylor the opportunity to contribute to Open
University textbooks, radio programs and television productions on
various aspects of organic chemistry. Professor Taylor then moved to UEA, Norwich, where he
established his independent research program, before taking up his present position in York in 1993.
Richard Taylor has just finished his term as President of the Organic Division of the Royal Society
of Chemistry and was awarded the 1999 RSC Tilden Lectureship and the 1999 RSC Heterocyclic
Prize. He is currently the UK Regional Editor of the international journal Tetrahedron.
Volume Editors
EDITOR OF VOLUME 1
Janine Cossy did her undergraduate and graduate studies at the

University of Reims. After a postdoctoral stay with Barry Trost, for
two years (1980–1982) at the University of Wisconsin, she returned to
Reims, where she became a Director of Research of the CNRS in
1990. In the same year she moved to Paris to become Professor of
Organic Chemistry at the ESPCI (Ecole Supérieure de Physique et
de Chimie Industrielles de la Ville de Paris). She is interested in
synthetic methodologies (radicals, organometallics, photochemistry,
thermal reactions, ring expansions, enantioselectivity, synthesis of
heterocycles, synthesis of solid support) and in their applications to
the synthesis of natural products and biologically active molecules.
EDITOR OF VOLUME 2
Chris Ramsden was born in Manchester, UK in 1946. He is

a graduate of Sheffield University and received his Ph.D.
(W. D. Ollis) in 1970 and D.Sc. in 1990. After postdoctoral work
at the University of Texas (M. J. S. Dewar)(1971–1973) and
University of East Anglia (A. R. Katritzky)(1973–1976), he worked
in the pharmaceutical industry. He moved to Keele University as
Professor of Organic Chemistry in 1992. His research interests are
heterocycles and three-center bonds and applications of their
chemistry to biological problems.
EDITOR OF VOLUME 3
Keith Jones was born in Manchester. He studied at Cambridge

University for his B.A. in Natural Sciences (1976) and stayed to
carry out research with Professor Sir Alan Battersby obtaining his
Ph.D. in 1979. In 1979, he moved to a lectureship at King’s College
London. In 1984, he caught up with his postdoctoral research by
spending a year working with Professor Gilbert Stork at Columbia
University, New York. After returning to King’s College, he
became a reader in 1995. In 1998, he moved to a chair in organic
and medicinal chemistry at Kingston University. His research
interests cover natural product synthesis, heterocyclic chemistry
and the use of radicals in synthesis. He has been a visiting
professor at Neuchatel and Barcelona Universities as well as the
Australian National University.
EDITOR OF VOLUME 4
Professor Gary Molander was born in Cedar Rapids, Iowa. He

received his B.S. degree at Iowa State University and subsequently
entered the graduate chemistry program at Purdue University in
1975, obtaining his Ph.D. degree in 1979 under the direction of
Professor Herbert C. Brown. He joined Professor Barry Trost’s
group at the University of Wisconsin, Madison 1980 as a
postdoctoral research associate, and in 1981 he accepted an
appointment at the University of Colorado, Boulder, as an
Assistant Professor of chemistry, where he rose through the
academic ranks. In 1999 he joined the faculty at the University of
Pennsylvania, and in 2001 was appointed Allan Day Professor of
Chemistry. Professor Molander’s research interests focus on the
development of new synthetic methods for organic synthesis and
natural product synthesis. A major focus of his research has been
the application of organolanthanide reagents and catalysts to
selective organic synthesis.
EDITOR OF VOLUME 5
Ray Jones started his chemistry career as an undergraduate

and then completing a Ph.D. at Cambridge University under the
supervision of Professor Sir Alan Battersby, in the area of alkaloid
biosynthesis. After a year as an ICI Postdoctoral Fellow in the
laboratories of Professor Albert Eschenmoser at the ETH Zurich,
he was appointed as Lecturer in Organic Chemistry at University
of Nottingham in 1974. He progressed to Senior Lecturer at
Nottingham and then took up the Chair of Organic Chemistry
at the Open University in 1995, before moving to the Chair of
Organic and Biological Chemistry at Loughborough University in
2000.
His research interests span heterocyclic and natural product
chemistry, with over 100 publications. Example topics include
the acyltetramic acids and pyridones, Mammea coumarins, spermine
and spermidine alkaloids, imidazolines as templates for (asymmetric)
synthesis, dipolar cycloadditions, and unusual amino acids and
peptide mimetics.
EDITOR OF VOLUME 6
Eric F. V. Scriven is a native of Wales, UK. After working at

BISRA and ESSO Ltd, he attended the University of Salford and
graduated in 1965. He obtained his M.Sc. from the University of
Guelph, and his Ph.D. from the University of East Anglia (with
Professor A. R. Katritzky) in 1969. After postdoctoral years at the
University of Alabama and University College London, he was
appointed Lecturer in organic chemistry at the University of
Salford. There, his research interests centered on the reactivity of
azides and nitrenes. While at Salford, he spent two semesters on
secondment at the University of Benin in Nigeria. He joined Reilly
Industries Inc. in 1979 and was director of Research from 1991
to 2003. He is currently at the University of Florida. He edited
Azides & Nitrenes (1984), and he and Professor H. Suschitzky were
founding editors of Progress in Heterocyclic Chemistry, which has
been published annually since 1989 by the International Society of
Heterocyclic Chemistry. He also collaborated with Professors
A. R. Katritzky and C. W. Rees as Editors-in-Chief of Comprehensive Heterocyclic Chemistry II
(1997). His current research interests are in novel nitration reactions, ionic liquids, and
applications of polymers in organic synthesis.
Preface
Comprehensive Organic Functional Group Transformations (COFGT 1995) presented the vast
subject of organic synthesis in terms of the introduction and interconversion of functional groups,
according to a rigorous system, designed to cover all known and as yet unknown functional
groups.
Comprehensive Organic Functional Group Transformations II (COFGT-II), designed for specia-
list and nonspecialist chemists, active in academic, industrial, and government laboratories, now
updates the developments of functional group transformations since the publication of the
COFGT 1995. COFGT-II is structured in precisely the same manner as the original COFGT
work, allowing truly comprehensive coverage of all organic functional group transformations.
COFGT-II, in combination with COFGT 1995, provides an essential reference source for the
all-important topic of methodologies for the interconversion of functional groups in organic
compounds, and provides an efficient first point of entry into the key literature and background
material for those planning any research involving the synthesis of new organic compounds. With
the increase in our understanding of the way in which the chemical structure of compounds
determines all physical, chemical, biological, and technological properties, targeted synthesis
becomes ever more important. The making of compounds is germane not only to organic
chemistry but also to future developments in all biological, medical, and materials sciences.
The availability of the work in electronic format through ScienceDirect will greatly enhance its
utility.
The Editors-in-Chief would like to extend their warm thanks to the Volume Editors, the
chapter authors, and the Elsevier staff for operating in such an efficient and professional manner.
A. R. Katritzky
R. J. K. Taylor
Introduction to Volume 1
Since 1995, there has been great activity in organic synthesis, particularly concerning the forma-
tion of carbon–hydrogen and carbon–carbon bonds. This volume deals with synthetic reactions
which result in the alteration of bonding at carbon atoms which are left with no attached
heteroatoms. All the major structural influences are treated in this volume, such as the effects
of configuration, remote substituents, ring stereochemistry, strain, kinetic or thermodynamic
factors, solvation, etc.
This volume is divided into three parts. Part I deals with the formation of tetracoordinated
carbon by reduction of heteroatomic bonds and by addition to carbon–carbon bonds. In Part II,
the formation of tricoordinated carbons such as ¼CH, C¼CC, C¼C bonds are covered,
i.e., involving substitution, addition, elimination, condensation, pericyclic processes, and rearrange-
ments. In this part, tricoordinate anions, cations, and radicals are also discussed. In Part III, allenes,
cumulenes, alkynes as well as ions, radicals carbenes, and other monocoordinated systems are
examined.
The philosophy of this volume has been to rationalize the enormous amount of information
within a logical framework and in a critical fashion. This volume is designed to provide a fast
entry to the literature for synthetic organic chemists, and could also stimulate new research areas.
Janine Cossy
Paris, France
August 2004
Explanation of the reference
system
Throughout this work, references are designated by a number-lettering coding of which the first
four numbers denote the year of publication, the next one to three letters denote the journal, and
the final numbers denote the page. This code appears in the text each time a reference is quoted.
This system has been used successfully in previous publications and enables the reader to go
directly to the literature reference cited, without first having to consult the bibliography at the end
of each chapter.
The following additional notes apply:

1. A list of journal codes in alphabetical order, together with the journals to which they refer
is given immediately following these notes. Journal names are abbreviated throughout
using the CASSI ‘‘Chemical Abstracts Service Source Index’’ system.
2. The references cited in each chapter are given at the end of the individual chapters.
3. The list of references is arranged in order of (a) year, (b) journal in alphabetical order
of journal code, (c) part letter or number if relevant, (d) volume number if relevant, and
(e) page number.
4. In the reference list the code is followed by (a) the complete literature citation in the
conventional manner and (b) the number(s) of the page(s) on which the reference appears,
whether in the text or in tables, schemes, etc.
5. For non-twentieth-century references, the year is given in full in the code.
6. For journals which are published in separate parts, the part letter or number is given (when
necessary) in parentheses immediately after the journal code letters.
7. Journal volume numbers are not included in the code numbers unless more than one
volume was published in the year in question, in which case the volume number is included
in parentheses immediately after the journal code letters.
8. Patents are assigned appropriate three-letter codes.
9. Frequently cited books are assigned codes.
10. Less common journals and books are given the code ‘‘MI’’ for miscellaneous with the
whole code for books prefixed by the letter ‘‘B-’’.
11. Where journals have changed names, the same code is used throughout, e.g., CB refers to
both Chem. Ber. and to Ber. Dtsch. Chem. Ges.
JOURNAL ABBREVIATIONS
AAC Antimicrob. Agents Chemother. CLY Chem. Listy
ABC Agric. Biol. Chem. CM Chem. Mater.
AC Appl. Catal. CMC Comp. Med. Chem.
ACA Aldrichim. Acta COC Comp. Org. Chem.
AC(P) Ann. Chim. (Paris) COFGT Comp. Org. Func. Group Transformations
AC(R) Ann. Chim. (Rome) COMCI Comp. Organomet. Chem., 1st edn.
ACH Acta Chim. Acad. Sci. Hung. CONAP Comp. Natural Products Chem.
ACR Acc. Chem. Res. COS Comp. Org. Synth.
ACS Acta Chem. Scand. CP Can. Pat.
ACS(A) Acta Chem. Scand., Ser. A CPB Chem. Pharm. Bull.
ACS(B) Acta Chem. Scand., Ser. B CPH Chem. Phys.
AF Arzneim.-Forsch. CPL Chem. Phys. Lett.
AFC Adv. Fluorine Chem. CR C.R. Hebd. Seances Acad. Sci.
AG Angew. Chem. CR(A) C.R. Hebd. Seances Acad. Sci., Ser. A
AG(E) Angew. Chem., Int. Ed. Engl. CR(B) C.R. Hebd. Seances Acad. Sci., Ser. B
AHC Adv. Heterocycl. Chem. CR(C) C.R. Hebd. Seances Acad. Sci., Ser. C.
AHCS Adv. Heterocycl. Chem. Supplement CRAC Crit. Rev. Anal. Chem.
AI Anal. Instrum. CRV Chem. Rev.
AJC Aust. J. Chem. CS Chem. Scr.
AK Ark. Kemi CSC Cryst. Struct. Commun.
AKZ Arm. Khim. Zh. CSR Chem. Soc. Rev.
AM Adv. Mater. (Weinheim, Ger.) CT Chem. Tech.
AMLS Adv. Mol. Spectrosc. CUOC Curr. Org. Chem.
AMS Adv. Mass Spectrom. CZ Chem.-Ztg.
ANC Anal. Chem. CZP Czech. Pat.
ANL Acad. Naz. Lincei DIS Diss. Abstr.
ANY Ann. N. Y. Acad. Sci. DIS(B) Diss. Abstr. Int. B
AOC Adv. Organomet. Chem. DOK Dokl. Akad. Nauk SSSR
AP Arch. Pharm. (Weinheim, Ger.) DOKC Dokl. Chem. (Engl. Transl.)
APO Adv. Phys. Org. Chem. DP Dyes Pigm.
APOC Appl. Organomet. Chem. E Experientia
APS Adv. Polym. Sci. EC Educ. Chem.
AQ An. Quim. EF Energy Fuels
AR Annu. Rep. Prog. Chem. EGP Ger. (East) Pat.
AR(A) Annu. Rep. Prog. Chem., Sect. A EJI Eur. J. Inorg. Chem.
AR(B) Annu. Rep. Prog. Chem., Sect. B EJM Eur. J. Med. Chem.
ARP Annu. Rev. Phys. Chem. EJO Eur. J. Org. Chem.
ASI Acta Chim. Sin. Engl. Ed. EUP Eur. Pat.
ASIN Acta Chim. Sin. FCF Fortschr. Chem. Forsch.
AX Acta Crystallogr. FCR Fluorine Chem. Rev.
AX(A) Acta Crystallogr., Part A FES Farmaco Ed. Sci.
AX(B) Acta Crystallogr., Part B FOR Fortschr. Chem. Org. Naturst.
B Biochemistry FRP Fr. Pat.
BAP Bull. Acad. Pol. Sci., Ser. Sci. Chim. G Gazz. Chim. Ital.
BAU Bull. Acad. Sci. USSR, Div. Chem. Sci. GAK Gummi Asbest Kunstst.
BBA Biochim. Biophys. Acta GC Green Chem.
BBR Biochem. Biophys. Res. Commun. GEP Ger. Pat.
BCJ Bull. Chem. Soc. Jpn. GSM Gen. Synth. Methods
BEP Belg. Pat. H Heterocycles
BJ Biochem. J. HAC Heteroatom Chem.
BJP Br. J. Pharmacol. HC Chem. Heterocycl. Compd. [Weissberger-Taylor series]
BMC Biorg. Med. Chem. HCA Helv. Chim. Acta
BMCL Biorg. Med. Chem. Lett. HCO Heterocycl. Commun.
BOC Bioorg. Chem. HOU Methoden Org. Chem. (Houben-Weyl)
BP Biochem. Biopharmacol. HP Hydrocarbon Process
BPJ Br. Polym. J. IC Inorg. Chem.
BRP Br. Pat. ICA Inorg. Chim. Acta
BSB Bull. Soc. Chim. Belg. IEC Ind. Eng. Chem. Res.
BSF Bull. Soc. Chim. Fr. IJ Isr. J. Chem.
BSF(2) Bull. Soc. Chim. Fr., Part 2 IJC Indian J. Chem.
BSM Best Synthetic Methods IJC(A) Indian J. Chem., Sect. A
C Chimia IJC(B) Indian J. Chem., Sect. B
CA Chem. Abstr. IJM Int. J. Mass Spectrom. Ion Phys.
CAN Cancer IJQ Int. J. Quantum Chem.
CAR Carbohydr. Res. IJS Int. J. Sulfur Chem.
CAT Chim. Acta Turc. IJS(A) Int. J. Sulfur Chem., Part A
CB Chem. Ber. IJS(B) Int. J. Sulfur Chem., Part B
CBR Chem. Br. IS Inorg. Synth.
CC J. Chem. Soc., Chem. Commun. IZV Izv. Akad. Nauk SSSR, Ser. Khim.
CCA Croat. Chem. Acta JA J. Am. Chem. Soc.
CCC Collect. Czech. Chem. Commun. JAN J. Antibiot.
CCHT Comb. Chem. High T. Scr. JAP Jpn. Pat.
CCR Coord. Chem. Rev. JAP(K) Jpn. Kokai
CE Chem. Express JBC J. Biol. Chem.
CEJ Chem. -Eur. J. JC J. Chromatogr.
CEN Chem. Eng. News JCA J. Catal.
CHE Chem. Heterocycl. Compd. (Engl. Transl.) JCC J. Coord. Chem.
CHECI Comp. Heterocycl. Chem., 1st edn. JCO J. Comb. Chem.
CHECII Comp. Heterocycl. Chem., 2nd edn. JCE J. Chem. Ed.
CHIR Chirality JCED J. Chem. Eng. Data
CI(L) Chem. Ind. (London) JCI J. Chem. Inf. Comput. Sci.
CI(M) Chem. Ind. (Milan) JCP J. Chem. Phys.
CJC Can. J. Chem. JCPB J. Chim. Phys. Physico-Chim. Biol.
CJS Canadian J. Spectrosc. JCR(M) J. Chem. Res. (M)
CL Chem. Lett. JCR(S) J. Chem. Res. (S)
JCS J. Chem. Soc. PB Polym. Bull.
JCS(A) J. Chem. Soc. (A) PC Personal Communication
JCS(B) J. Chem. Soc. (B) PCS Proc. Chem. Soc.
JCS(C) J. Chem. Soc. (C) PH ‘Photochemistry of Heterocyclic Compounds’, O.
JCS(D) J. Chem. Soc., Dalton Trans. Buchardt, Ed.; Wiley, New York, 1976
JCS(F1) J. Chem. Soc., Faraday Trans. 1 PHA Pharmazi
JCS(F2) J. Chem. Soc., Faraday Trans. 2 PHC Prog. Heterocycl. Chem.
JCS(P1) J. Chem. Soc., Perkin Trans. 1 PIA Proc. Indian Acad. Sci.
JCS(P2) J. Chem. Soc., Perkin Trans. 2 PIA(A) Proc. Indian Acad. Sci., Sect. A
JCS(S2) J. Chem. Soc., (Suppl. 2) PJC Pol. J. Chem.
JEC J. Electroanal. Chem. Interfacial Electrochem. PJS Pak. J. Sci. Ind. Res.
JEM J. Energ. Mater. PMH Phys. Methods Heterocycl. Chem.
JES J. Electron Spectrosc. PNA Proc. Natl. Acad. Sci. USA
JFA J. Sci. Food Agri. POL Polyhedron
JFC J. Fluorine Chem. PP Polym. Prepr.
JGU J. Gen. Chem. USSR (Engl. Transl.) PRS Proceed. Roy. Soc.
JHC J. Heterocycl. Chem. PS Phosphorus Sulfur (formerly); Phosphorus Sulfur Silicon
JIC J. Indian Chem. Soc. (currently)
JINC J. Inorg. Nucl. Chem. QR Q. Rev., Chem. Soc.
JLC J. Liq. Chromatogr. QRS Quart. Rep. Sulfur Chem.
JMAC J. Mater. Chem. QSAR Quant. Struct. Act. Relat.
JMAS J. Mater. Sci. RC Rubber Chem. Technol.
JMC J. Med. Chem. RCB Russian Chemical Bull.
JMOC J. Mol. Catal. RCC Rodd’s Chemistry of Carbon Compounds
JMR J. Magn. Reson. RCM Rapid Commun. Mass Spectrom.
JMS J. Mol. Sci. RCP Rec. Chem. Prog.
JNP J. Nat. Prod. RCR Russ. Chem. Rev. (Engl. Transl.)
JOC J. Org. Chem. RHA Rev. Heteroatom. Chem.
JOM J. Organomet. Chem. RJ Rubber J.
JOU J. Org. Chem. USSR (Engl. Transl.) RJGC Russ. J. Gen. Chem. (Engl. Transl.)
JPC J. Phys. Chem. RJOC Russ. J. Org. Chem. (Engl. Transl.)
JPJ J. Pharm. Soc. Jpn. RP Rev. Polarogr.
JPO J. Phys. Org. Chem. RRC Rev. Roum. Chim.
JPP J. Pharm. Pharmacol. RS Ric. Sci.
JPR J. Prakt. Chem. RTC Recl. Trav. Chim. Pays-Bas
JPS J. Pharm. Sci. RZC Rocz. Chem.
JPS(A) J. Polym. Sci., Polym. Chem., Part A S Synthesis
JPU J. Phys. Chem. USSR (Engl. Transl.) SA Spectrochim. Acta
JSC J. Serbochem. Soc. SA(A) Spectrochim. Acta, Part A
JSP J. Mol. Spectrosc. SAP S. Afr. Pat.
JST J. Mol. Struct. SC Synth. Commun.
K Kristallografiya SCI Science
KFZ Khim. Farm. Zh. SH W. L. F. Armarego, ‘Stereochemistry of Heterocyclic
KGS Khim. Geterotsikl. Soedin. Compounds’, Wiley, New York, 1977, parts 1 and 2.
KO Kirk-Othmer Encyc. SL Synlett
KPS Khim. Prir. Soedin. SM Synth. Met.
L Langmuir SR Sulfur Reports
LA Liebigs Ann. Chem. SRC Supplements to Rodd’s Chemistry of Carbon Compounds
LC Liq. Cryst. SRI Synth. React. Inorg. Metal-Org. Chem.
LS Life. Sci. SS Sch. Sci. Rev.
M Monatsh. Chem. SSR Second Supplements to Rodd’s Chemistry of Carbon Com-
MC Mendeleev Communications pounds
MCLC Mol. Cryst. Liq. Cryst. SST Org. Compd. Sulphur, Selenium, Tellurium [R. Soc.
MI Miscellaneous [journal or B-yyyyMI for book] Chem. series]
MIP Miscellaneous Pat. SUL Sulfur Letters
MM Macromolecules SZP Swiss Pat.
MP Mol. Phys. T Tetrahedron
MRC Magn. Reson. Chem. T(S) Tetrahedron, Suppl.
MS Q. N. Porter and J. Baldas, ‘Mass Spectrometry of TA Tetrahedron Asymmetry
Heterocyclic Compounds’, Wiley, New York, 1971 TAL Talanta
N Naturwissenschaften TCA Theor. Chim. Acta
NAT Nature TCC Top. Curr. Chem.
NEP Neth. Pat. TCM Tetrahedron, Comp. Method
NJC Nouv. J. Chim. TFS Trans. Faraday Soc.
NJC New J. Chem. TH Thesis
NKK Nippon Kagaku Kaishi (J. Chem. Soc. Jpn.) TL Tetrahedron Lett.
NKZ Nippon Kagaku Zasshi TS Top. Stereochem.
NMR T. J. Batterham, ‘NMR Spectra of Simple Heterocycles’, UK Usp. Khim.
Wiley, New York, 1973 UKZ Ukr. Khim. Zh. (Russ. Ed.)
NN Nucleosides & Nucleotides UP Unpublished Results
NZJ N. Z. J. Sci. Technol. URP USSR Pat.
OBC Organic and Biomolecular Chemistry USP U.S. Pat.
OCS Organomet. Synth. WOP PCT Int. Appl. WO (World Intellectual Property
OL Org. Lett. Organization Pat. Appl.)
OM Organometallics YGK Yuki Gosei Kagaku Kyokaishi
OMR Org. Magn. Reson. YZ Yakugaku Zasshi
OMS Org. Mass Spectrom. ZAAC Z. Anorg. Allg. Chem.
OPP Org. Prep. Proced. lnt. ZAK Zh. Anal. Khim.
OPRD Org. Process Res. Dev. ZC Z. Chem.
OR Org. React. ZN Z. Naturforsch.
OS Org. Synth. ZN(A) Z. Naturforsch., Teil A
OSC Org. Synth., Coll. Vol. ZN(B) Z. Naturforsch., Teil B
P Phytochemistry ZOB Zh. Obshch. Khim.
PA Polym. Age ZOR Zh. Org. Khim.
PAC Pure Appl. Chem. ZPC Hoppe-Seyler’s Z. Physiol. Chem.
PAS Pol. Acad. Sci. ZPK Zh. Prikl. Khim.
List of Abbreviations
TECHNIQUES/CONDITIONS
18-C-6 18-crown-6
))))) ultrasonic (sonochemistry)
heat, reflux
AAS atomic absorption spectroscopy
AES atomic emission spectroscopy
AFM atomic force microscopy
approx. approximately
aq. aqueous
b.p. boiling point
CD circular dichroism
CIDNP chemically induced dynamic nuclear polarization
CNDO complete neglect of differential overlap
conc. concentrated
CT charge transfer
ee enantiomeric excess
equiv. equivalent(s)
ESR electron spin resonance
EXAFS extended X-ray absorption fine structure
FVP flash vacuum pyrolysis
g gaseous
GC gas chromatography
GLC gas–liquid chromatography
h Planck’s constant
h hour
HOMO highest occupied molecular orbital
HPLC high-performance liquid chromatography
h light (photochemistry)
ICR ion cyclotron resonance
INDO incomplete neglect of differential overlap
IR infrared
l liquid
LCAO linear combination of atomic orbitals
LUMO lowest unoccupied molecular orbital
MCD magnetic circular dichroism
MD molecular dynamics
min minute(s)
MM molecular mechanics
MO molecular orbital
MOCVD metal organic chemical vapor deposition
m.p. melting point
MS mass spectrometry
MW molecular weight
NMR nuclear magnetic resonance
NQR nuclear quadrupole resonance
ORD optical rotatory dispersion
PE photoelectron
ppm parts per million
rt room temperature
s solid
SCF self-consistent field
SET single electron transfer
SN1 first-order nucleophilic substitution
SN2 second-order nucleophilic substitution
SNi internal nucleophilic substitution
STM scanning tunneling microscopy
TLC thin-layer chromatography
UV ultraviolet
vol. volume
wt. weight
REAGENTS, SOLVENTS, ETC.

Ac acetyl CH3CO-
acac acetylacetonato
acam acetamide
AcO acetate
AcOH acetic acid
AIBN 2,20 -azobisisobutyronitrile
Ans ansyl
Ar aryl
ATP adenosine 50 -triphosphate
9-BBN 9-borabicyclo[3.3.1]nonyl
9-BBN-H 9-borabicyclo[3.3.1]nonane
BEHP bis (2-ethylhexyl) phthalate
BHT 2,6-di-t-butyl-4-methylphenol (butyrated hydroxytoluene)
binap 2,20 -bis(diphenylphosphino)-1,10 -binaphthyl
bipy 2,20 -bipyridyl
Bn benzyl C6H5CH2- (NB avoid confusion with Bz)
t-BOC t-butoxycarbonyl
bpy 2,20 -bipyridyl
BSA N,O-bis(trimethylsilyl)acetamide
BSTFA N,O-bis(trimethylsilyl)trifluoroacetamide
Bt benzotriazole
BTAF benzyltrimethylammonium fluoride
Bz benzoyl C6H5CO- (NB avoid confusion with Bn)
Bzac benzoylacetone
CAN ceric ammonium nitrate
Cbz carbobenzoxy
chalcogens oxygen, sulfur, selenium, tellurium
CH2Cl2 dichloromethane
COD 1,5-cyclooctadiene
COT cyclooctatetraene
Cp cyclopentadienyl
Cp* pentamethylcyclopentadienyl
18-crown-6 1,4,7,10,13,16-hexaoxacyclooctadecane
CSA camphorsulfonic acid
CSI chlorosulfonyl isocyanate
CTAB cetyl trimethyl ammonium bromide
DABCO 1,4-diazabicyclo[2.2.2]octane
DBA dibenzylideneacetone
DBN 1,5-diazabicyclo[4.3.0]non-5-ene
DBU 1,5-diazabicyclo[5.4.0]undec-5-ene
DCC dicyclohexylcarbodiimide
DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
DEAC diethylaluminum chloride
DEAD diethyl azodicarboxylate
DET diethyl tartrate (þ or )
DHP dihydropyran
DIBAL-H diisobutylaluminum hydride
diglyme diethylene glycol dimethyl ether
dimsyl Na sodium methylsulfinylmethide
DIOP 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane
DIPT diisopropyl tartrate (þ or )
DMA dimethylacetamide
DMAC dimethylaluminium chloride
DMAD dimethyl acetylenedicarboxylate
DMAP 4-dimethylaminopyridine
DME dimethoxyethane
DMF dimethylformamide
DMI N,N0 -dimethylimidazolidinone
DMN diaminomaleonitrile
DMSO dimethyl sulfoxide
DMTSF dimethyl(methylthio)sulfonium fluoroborate
DPPB 1,2-bis(diphenylphosphino)butane
DPPE 1,2-bis(diphenylphosphino)ethane
DPPF 1,10 -bis(diphenylphosphino)ferrocene
DPPP 1,2-bis(diphenylphosphino)propane
Eþ electrophile
EADC ethylaluminium dichloride
EDG electron-donating group
EDTA ethylenediaminetetraacetate
EEDQ N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline
Et ethyl
Et2O diethyl ether
EtOH ethanol
EtOAc ethyl acetate
EWG electron-withdrawing group
HMPA hexamethyl phosphoramide
HMPT hexamethylphosphoric triamide
IpcBH2 isopinocampheylborane
Ipc2BH diisopinocampheylborane
KAPA potassium 3-aminopropylamide
K-selectride potassium tri-s-butylborohydride
LAH lithium aluminium hydride
LDA lithium diisopropylamide
LICA lithium isopropyl cyclohexylamide
LITMP lithium tetramethyl piperidide
L-selectride lithium tri-s-butyl borohydride
LTA lead tetraacetate
MAO monoamine oxidase
MCPBA 3-chloroperoxybenzoic acid
MCT mercury cadmium telluride
Me methyl
MEM methoxyethoxymethyl
MEM-Cl methoxyethoxymethyl chloride
MeOH methanol
MMA methyl methacrylate
MMC methylmagnesium carbonate
MOM methoxymethyl
Ms methanesulfonyl (mesylate)
MSA methanesulfonic acid
MsCl methanesulfonyl chloride
MVK methyl vinyl ketone
NBS N-bromosuccinimide
NCS N-chlorosuccinimide
NMO N-methylmorpholine N-oxide
NMP N-methyl-2-pyrrolidone
Nu nucleophile
PPA polyphosphoric acid
PCC pyridinium chlorochromate
PDC pyridinium dichromate
Ph phenyl
phen 1,10-phenanthroline
Phth phthaloyl
PPE polyphosphate ester
PPO 2,5-diphenyloxazole
PPTS pyridinium p-toluenesulfonate
Pr propyl
Pyr pyridine
Red-Al sodium bis(methoxyethoxy)aluminum dihydride
SDS sodium dodecyl sulfate
SEM trimethylsilylethoxymethyl
Sia2BH disiamylborane
SM starting material
TAS tris(diethylamino)sulfonium
TBAF tetra-n-butylammonium fluoride
TBDMS t-butyldimethylsilyl
TBDMS-Cl t-butyldimethylsilyl chloride
TBDPS t-butyldiphenylsilyl
TBHP t-butyl hydroperoxide
TCE 2,2,2-trichloroethanol
TCNE tetracyanoethylene
TEA tetraethylammonium
TES triethylsilyl
Tf triflyl (trifluoromethanesulfonyl)
TFA trifluoroacetyl
TFAA trifluoroacetic anhydride
THF tetrahydrofuran
THP tetrahydropyranyl
TIPBSCl 2,4,6-triisopropylbenzenesulfonyl chloride
TIPSCl triisopropylsilyl chloride
TMEDA tetramethylethylenediamine [1,2-bis(dimethylamino)ethane]
TMS trimethylsilyl
TMSCl trimethylsilyl chloride
TMSCN trimethylsilyl cyanide
Tol tolyl C6H4(CH3)–
TosMIC tosylmethyl isocyanide
TPP meso-tetraphenylporphyrin
Tr trityl (triphenylmethyl)
Tris tris(hydroxymethyl)aminomethane
Ts 4-toluenesulfonyl (tosyl)
TTFA thallium trifluroacetate
TTMSS tris(trimethylsilyl)silane
TTN thallium(III) nitrate
X halogen or leaving group
Volume 1 - Synthesis: Carbon With No Attached Heteroatoms
Part I: Tetracoordinated Carbon with No Attached Heteroatoms
1.01 One or More CH Bond(s) Formed by Substitution:

Reduction of C---Halogen and C---Chalcogen Bonds,
Pages 1-30, A. G. Sutherland
1.02 One or More C---H Bond(s) Formed by Substitution:

Reduction of Carbon---Nitrogen, ---Phosphorus, ---
Arsenic, ---Antimony, ---Bismuth, ---Carbon, ---Boron, and
---Metal Bonds, Pages 31-78, J. Blanchet, Yanxing Jia and
Jieping Zhu
1.03 Two or More CH Bond(s) Formed by Addition to CC

Multiple Bonds, Pages 79-119, L. Micouin
1.04 One or More CC Bond(s) Formed by Substitution:

Substitution of Halogen, Pages 121-199, M. Santelli and C.
Ollivier

Substitution of Chalcogen, Pages 201-230, N. Hoffmann

Substitution of Carbon–Nitrogen, –Phosphorus, –Arsenic, –
Antimony, –Boron, –Silicon, –Germanium, and –Metal
Functions, Pages 231-285, C. Kouklovsky
1.07 One or More CC Bonds Formed by Addition:

Addition of Carbon Electrophiles and Nucleophiles to CC
Multiple Bonds, Pages 287-311, A. Armstrong and N. J.
Convine
1.08 One or More CC Bond(s) Formed by Addition:

Addition of Carbon Radicals and Electrocyclic Additions
to CC Multiple Bonds, Pages 313-374, G. Balme, D.
Bouyssi and N. Monteiro
1.09 One or More CH and/or CC Bond(s) Formed by

Rearrangement, Pages 375-426, P. H. Ducrot
Part II: Tricoordinated Carbon with No Attached Heteroatoms
1.10 One or More =CH Bond(s) Formed by Substitution

or Addition, Pages 427-462, G. Rousseau
1.11 One or More =C---C Bond(s) Formed by Substitution

or Addition, Pages 463-531, D. J. Aitken and S. Faure
1.12 One or More C=C Bond(s) Formed by Addition,

Pages 533-580, A. C. Regan
1.13 One or More C=C Bond(s) by Elimination of

Hydrogen, Carbon, Halogen, or Oxygen Functions, Pages
581-600, O. Piva
1.14 One or More C=C Bond(s) by Elimination of S, Se,

Te, N, P, As, Sb, Bi, Si, Ge, B, or Metal Functions, Pages
601-668, J. Eustache, P. Bisseret and P. Van de Weghe
1.15 One or More C=C Bond(s) Formed by Condensation:

Condensation of Nonheteroatom-linked Functions,
Halides, Chalcogen, or Nitrogen Functions, Pages 669-722,
J. Prunet and L. Grimaud
1.16 One or More C=C Bond(s) Formed by Condensation:

Condensation of P, As, Sb, Bi, Si, Ge, B, or Metal
Functions, Pages 723-759, P. Savignac, B. Iorga and M.
Savignac
1.17 One or More C=C Bond(s) by Pericyclic Processes,

Pages 761-795, J. Lebreton and A. Guingant
1.18 One or More =CH, =CC, and/or C=C Bond(s)

Formed by Rearrangement, Pages 797-888, M. T. Molina
and J. L. Marco-Contelles
1.19 Tricoordinate Carbanions, Cations, and Radicals,

Pages 889-1017, P. Pale and P. Vogel
Part III: Dicoordinate and Monocoordinate Carbon with No Attached Heteroatoms
1.20 Allenes and Cumulenes, Pages 1019-1081, C. Bruneau

and J. -L. Renaud
1.21 Alkynes, Pages 1083-1176, E. Tyrrell
1.22 Ions, Radicals, Carbenes, and Other

Monocoordinated Systems, Pages 1177-1259, I. J. S.
Fairlamb and J. M. Dickinson
1.01
One or More CH Bond(s) Formed
by Substitution: Reduction of
CHalogen and CChalcogen Bonds
A. G. SUTHERLAND
Wyeth Research, Pearl River, NY, USA
1.01.1 REDUCTION OF CHALOGEN BONDS TO CH 1

1.01.1.1 General Methods 1
1.01.1.2 Reduction of Fluoroalkanes 2
1.01.1.3 Reduction of Chloroalkanes 3
1.01.1.4 Reduction of Bromoalkanes 7
1.01.1.5 Reduction of Iodoalkanes 10
1.01.1.6 Reduction of Hypervalent Haloalkanes 12
1.01.2 REDUCTION OF COXYGEN BONDS TO CH 12
1.01.2.2 Reduction of COX Bonds 13
1.01.2.2.1 Reduction of COH bonds 13
1.01.2.2.2 Reduction of COC bonds 14
1.01.2.2.3 Reduction of COheteroatom bonds 17
1.01.2.3 Reduction of C¼O Bonds to CH2 17
1.01.2.3.1 Reduction of aldehydes 17
1.01.2.3.2 Reduction of ketones 18
1.01.2.4 Reduction of C(¼O)X to CH3 19
1.01.2.5 Reduction of C(OX)n Systems 20
1.01.3 REDUCTION OF CSULFUR, CSELENIUM, AND CTELLURIUM BONDS TO CH 21
1.01.3.2 Reduction of CSX Bonds 21
1.01.3.3 Reduction of C¼S to CH2 22
1.01.3.4 Reduction of C(¼S)X to CH3 22
1.01.3.5 Reduction of C(SX)n Systems 22
1.01.3.6 Reduction of CSe Systems 23
1.01.3.7 Reduction of CTe Systems 24
1.01.1 REDUCTION OF CHALOGEN BONDS TO CH
1.01.1.1 General Methods

There are four common general methods for the reduction of alkyl halides to the corresponding
alkanes: radical reduction (typically employing a tin or silicon hydride reagent); catalytic hydro-
genation with transition metal catalysis; low-valent metal reduction and metal hydride reduction
(by an ionic mechanism such as with lithium aluminum hydride).
1
2 One or More CH Bond(s) Formed by Substitution
The radical reduction methods came to the fore in the 1980s and 1990s and continue to be
dominant, with the caveat that these cannot be used for fluoroalkanes. It is interesting to note that
although more environmentally friendly alternatives to tin hydrides continue to be mooted most
chemists tend not to be swayed and opt for the reliability and selectivity of these reagents!
Hydrogenation remains a distant second in popularity with the sometime need for high
pressures and catalyst poisoning issues tending to weigh against their selection. Low-valent
metal reductions and metal hydride reductions often suffer from chemoselectivity problems but
when such factors are less relevant these can often be the method of choice.
1.01.1.2 Reduction of Fluoroalkanes

As fluoroalkanes are inert to radical reagents, the most common method for their reduction is by
hydrogenolysis over a transition metal catalyst, although often relatively forcing conditions are
required. Thus, while the reduction of an azido fluoride by hydrogen over palladium-on-carbon
(Equation (1)) is reported to proceed in high yields at relatively high pressure, only the azide is
reduced under 1 atm <2001JOC4687>. Allylic fluorides are relatively reactive and can be reduced
to the corresponding alkane although generally alkyl fluoride products are also found (Equation
(2)) <1999T13819>. These reactions can be sensitive to steric effects as illustrated in the given
example where the epimeric fluoride was resistant to reduction.
F N3 NH2
Pd/C, H2 (40 psi), MeOH
ð1Þ
97%
N N N N
Tr Tr
Pd/C, H2 (1 atm), EtOH

ð2Þ
CO2Me 99% (1:1) CO2Me
BocHN CO2Me BocHN
BocHN
F F
Low-valent metal-mediated reductions are also of utility. Sodium–potassium alloy, in the presence
of a crown ether, was used to remove a fluorine from a steroidal skeleton, the subsequent protonation
of the intermediate organometallic species being stereoselective <1999JOC9587> (Equation (3)).
F H
H H
Na/K alloy, PhCH3
Dicyclohexano-18-crown-6 ð3Þ
H H
74%
H H
While fluoroalkanes are largely inert to reduction by either reagents such as lithium–aluminum
hydride or photochemical means, it has been reported that the combination of these two conditions
has a synergistic effect and, although competing elimination reactions are not entirely avoided,
reasonably clean conversions to the alkane are observed <1995TL7921> (Equation (4)). Zirconium
hydrides have been reported to effect quantitative reductions of simple primary, secondary, and
tertiary fluoroalkanes under increasingly forcing conditions <2000JA8559> (Equation (5))
although little information on the chemoselectivity of this methodology is yet available.
LiAlH4, hν, THF

ð4Þ
39% (+34% SM)
F
Cp2ZrH2, H2
Cyclohexane ð5Þ
F
100%
One or More CH Bond(s) Formed by Substitution 3
A detailed study suggests that there is considerable scope for the use of electrochemical
reduction, at least for benzylic fluorides. Although no specific isolated yields are discussed, the
reaction appears to proceed cleanly for mono-, di-, and trifluorides while other potentially
sensitive groups such as nitriles or t-butylesters are untouched <1997JA9527> (Scheme 1).
CH2F Electrochemical reduction

DMF, 20 °C
CN CN
CHF2 Electrochemical reduction

DMF, 20 °C
CN CN
CF3 Electrochemical reduction

DMF, 20 °C
CO2But CO2But
Scheme 1
A rather unusual rearrangement, which involves a formal fluoride reduction (with a concomi-
tant oxidation at a nearby carbon), has been reported where -amino-0 -fluoroketones are
converted to -amino--alkoxyketones <2001OL425> (Equation (6)). A body of evidence was
amassed that suggests that this reaction proceeds via a hydroxyvinyliminium ion intermediate and
the authors did not seek to investigate this transformation on a preparative scale.
H CD3OD, NEt3 H
N O H N O H ð6Þ
N N O N N O
F O OCD3 O
ButHN O ButHN O
1.01.1.3 Reduction of Chloroalkanes

A wide range of methods are available for the reduction of chloroalkanes but it is worth noting at
this point that, particularly in the case of primary systems, many investigators take the option of
using the simple Finkelstein procedure to convert the chloroalkane to the corresponding iodoalk-
ane which can then be reduced more easily <1999CPB1380, 2002JOC3861>.
Radical reduction methods, predominantly using tin hydrides and an appropriate radical
chain initiator (although photochemical activation is still occasionally seen
<2001JCS(P1)891>), offer excellent chemoselectivity. Thus, chloroalkanes are cleanly reduced
in the presence of N-methoxyindoles <1999H1949> (Equation (7)), -acetoxyesters
<1995TA961> (Equation (8)), N-acylcarbamates <2002JOC1738> (Equation (9)), enones, ben-
zylethers <2002T3535> (Equation (10)), and vinyl chlorides <1999TL9289> (Equation (11))
inter alia. Methodology that is catalytic in tin reagents (and stoichiometric in polymethylhydro-
siloxane) has also been suggested, although incomplete reactions do seem to be an issue in the
reduction of chloroalkanes <1999JOC342>.
Cl
O O
Bu3SnH, C6H6, AIBN, ∆
ð7Þ
95%
N N
OMe OMe
Cl
n-C11H23 OBut Bu3SnH, C6H6, AIBN, ∆ n-C11H23 OBut ð8Þ
OAc O 99% OAc O
Cl
O O O O
OEt Bu3SnH, PhCH3, AIBN, ∆ OEt
O N O N ð9Þ
O 76% O
Ph Ph
Ph Ph
Bu3SnH, PhCH3, ∆
CN
N
Cl N ð10Þ
OBn CN OBn
BnO BnO
50%
OAc O OAc O
MeO OMe MeO OMe

Cl
Cl Cl ð11Þ
CO2Me 97% CO2Me
Cl Cl Cl
CO2Me CO2Me
Silicon hydrides are an attractive alternative to tin hydride reagents in these reactions and can
offer selectivity advantages as well as circumventing toxicity issues. Thus tris(trimethylsilyl)silane
gives a diastereoselective reduction of a complex macrocycle where tributyltin hydride gave poor
selectivity <1998TL7131> (Equation (12)).
O O O O
Cl
OMe O OMe O
(Me3Si)3SiH, Et3B, PhCH3
BnO BnO ð12Þ
O N >99% O N
O O O O
Hydrogenation over palladium on carbon, typically in the presence of a base, remains a useful
and quite general method for chloroalkane reduction. Primary <1995S1427> (Equation (13)),
secondary (Equations (14)–(16)), and tertiary systems <1998JOC8155> are all reduced cleanly
and it is notable that strained ring systems neighboring the chloro moiety, which might be sensitive to
radical reduction conditions, are unaffected <1998JOC2469, 1999EJO3105> (Equations (15) and (16)).
It is notable, however, that benzylic esters are also reduced under these conditions although this was by
design in the given instances.
+ –
OH Pd/C, NH4HCO2, MeOH OH
ð13Þ
But Cl 85% But
Cl
Ph
Ph Pd/C, H2, NaOMe, MeOH
N ð14Þ
N 78%
O OH
O OH
O Pd/C, H2, NEt3, MeOH O

OBn OH
ð15Þ
BocHN N 40% BocHN N
Cl H O H O
Ph
Ph
NH2
O Pd/C, H2, MeOH
N ð16Þ
86%
O CO2Me
Cl CO2Me
Low-valent metal methods remain very popular for the reduction of -chlorocarbonyl com-
pounds. The ‘‘classic’’ combination of zinc in acetic acid remains justifiably popular through its
excellent chemoselectivity <1998JOC7213, 1999JOC659> (Equations (17) and (18)), and the
replacement of this solvent system with methanol and use of ammonium chloride has been
shown to allow clean reductions in the presence of acid-sensitive functional groups
<1996JOC3677> (Equation (19)). Other metals have also been used where indium in water
shows promise <2000JCS(P1)4462> (Equation (20)) while Raney nickel is effective in scenarios
where multiple functional group reductions are required <2000JOC6249> (Equation (21)).
CO2Me CO2Me
H Cl H
O O
Zn, AcOH, rt
H H H H ð17Þ
96%
CN CN
Cl H H
Zn, AcOH, rt
O O
83% ð18Þ
H OAc H OAc
80% de
O O
Zn, NH4Cl, MeOH
O O ð19Þ
N 98% N
Cl H O
H
O
O
In, Na dodecylsulfate, H2O O
OBn ð20Þ
88% OBn
Cl
O O
Cl Ni, EtOH
N NMe2 NH ð21Þ
98%
Cl
The dechlorination of -chloro--hydroxy esters presents a range of chemoselectivity issues including

eliminations and oxirane formation but in fact either zinc/acetic acid <2000JA10033> or aluminum
amalgam in aqueous acetonitrile <2000CC545> selectively reduce the chloro moiety, whereas samarium
iodide in THF removes both the chloro- and hydroxy-functionalities <2001CEJ4266> (Scheme 2).
O O OH O O OH
N SiPr i3 N SiPr3i
N O Zn, AcOH, rt N O
Cl O 91% O
Ph Ph
O OH O OH
Al–Hg, MeCN, H2O
BnO 90% BnO
Cl
O OH O
SmI2, THF
EtO EtO
Cl 84%
OMe OMe
Scheme 2
Low-valent metal methods can, of course, be applied to the reductions of other classes of
chloroalkanes—although the mechanism is more typically an electron-transfer process rather than
the radical anion chemistry seen with -chlorocarbonyl compounds—and the use of lithium
<2002JA9199, 1995SC2091> or sodium <1995T7777, 1995LA351, 1997JOC3355> in the reduc-
tion of polycyclic, often polychlorinated, systems is particularly effective (Scheme 3). As is
O H H O H H
Li/NH3, THF
O O
Cl H 72% H H
O O O O
Cl
H H
Cl
Li, ButOH, THF
Cl Cl
80%
Cl
H H
Cl
Cl Cl
Cl Cl
Na, ButOH, THF
MeO OMe MeO OMe
66%
Cl Cl
Cl Cl
Cl
H H
Cl
N Na, PriOH, THF N
Cl Cl
N 37% N
Cl
H H
Cl
Br
Na/NH3, Et2O
95%
Cl
Scheme 3
already seen (Equation (21)), Raney nickel is also an attractive option here—although sulfides
are, unsurprisingly, reduced concomitantly <1998TL147> (Equation (22)), significant selectivity
over a range of other functional groups has been demonstrated <2001SL485> (Equations (23)
and (24)). The recent discovery that the combination of samarium bromide and HMPA also
provides clean chloroalkane reductions also merits further investigation <2001OL2321>.
Cl
Ni, EtOH SO2Tol
SO2Tol Ph N
Ph N ð22Þ
96% Ph
Ph
S
O O
Cl Ni, THF
ð23Þ
95%
F F
Ni, THF
NC Cl NC ð24Þ
75%
Ionic metal hydride chemistry sees some use here, although less so than with the more reactive
bromo- and iodoalkanes, and tends to be used to reduce more reactive systems. Thus, sodium
borohydride has been shown to reduce a range of phenolic benzylic chlorides via quinomethane
intermediates <2002SL431> (Equation (25)), whereas lithium triethylborohydride has seen utility
in the conversion of primary allylic chloroalkanes <1999CC519, 2001OL2221> (Equation (26)).
Lithium aluminum hydride has also been employed in the reduction of primary chloroalkane
systems <1998JOC7505> (Equation (27)).
OH
OH
NaBH4, THF
CF3 ð25Þ
N 95% CF3
N
Cl
OTBDMS OTBDMS
N N
Cl
LiEt3BH, THF
S S ð26Þ
92%
TBDMSO TBDMSO
OH OH
LiAlH4, THF
O Cl O ð27Þ
93%
1.01.1.4 Reduction of Bromoalkanes

The reduction of bromoalkanes is dominated by radical reduction methods, in particular, using tin
hydrides. The popularity is justified as this methodology tends to be chemoselective and high yielding.
Examples include reduction in the presence of ketones <2001JA8612>, enoates <1997TL6521>,
alkynes <2001H747>, -carbamoylesters <1997TA903>, -lactams <2001JCR(S)166>, benzyloxy
moieties <2000TA3985>, and sulfoxides <2002JOC5838> (Scheme 4).
O
O
CO2Et Bu3SnH, C6H6, Et3B, ∆ CO2Et
92%
Br

Br CO2Et CO2Et
100%
t-BOC t-BOC
Br N Bu3SnH, PhCH3, AIBN, ∆ N
75%
TMS TMS
Br
Bu3SnH, C6H6, AIBN, ∆ CO2Me
CO2Me
80% NH
NH EtO2C
EtO2C
CO2Me CO2Me
O O
Br N Bu3SnH, C6H6, AIBN, ∆ N
76%
HO H O HO H O
O O
O O
BnO BnO
N Bu3SnH, C6H6, AIBN, ∆ N
Br O 95% O
H H
O O
OH OH
Ph Ph
TBDPSO S TBDPSO S
80%
Br O O
Scheme 4
While these radical reductions are typically initiated by the use of AIBN (or analogs thereof) or
by the triethylborane/oxygen combination, other initiators have also been advocated, including
trialkylaluminums <1995SL1045>, diethylzinc/air <1998TL6335>, and indium <1998TL1929,
2001TL4661> and cupric chlorides <1999TL2133>. However, these methods do not yet seem to
have been adopted widely, at least in this application.
Given the toxicity and purification issues that are associated with trialkyltin hydrides, a number of
researchers have sought alternatives. While Enholm and co-workers report methodology which is
catalytic in a polymer-bound trialkyltin hydride <1999OL1275>, silicon hydrides appear the main
alternative of choice. While tris(trimethylsilyl)silane is a clear favorite here <1998TL2385,
1999JA5155>, phenyl silane <1997SC1023> and poly(phenyl silane) <1997JOM475> have also
been advocated. Phosphinic acid has also been reported to be an efficient radical-reducing reagent
<1996TL5367> and now that conditions have been reported that allow the transformation of less
water-soluble substrates <2001BCSJ225>, perhaps this methodology will become increasingly popular.
An alternative approach, which completely avoids the use of tin hydrides, etc., is to generate
the radical by photochemical means in the presence of triethylamine. This does provide clean
reduction chemistry <2001T5173>; however, over the review period this methodology has
typically seen more use in carbon–carbon bond-forming processes.
There has been considerable study into the stereoselective radical reduction of -bromo-
-alkyl--oxyesters as a means of entry to the synthesis of polypropionate natural products and
analogs. Performing the reduction using tributyltin hydride in the presence of magnesium
bromide has been demonstrated to give excellent syn-stereoselectivity with high tolerance for
different functionality along the carbon backbone <1998JOC6554, 2001JA8496, 2002TL5377,
2002TL6373> (Scheme 5). Furthermore, it has also been discovered that conversion of a
-hydroxy functionality into a boronate ester prior to reduction, without the presence of magne-
sium bromide, affords very high anti-selectivity <2002TL7067> (Equation (28)).
OMe O MgBr2, Bu3SnH OMe O

CH2Cl2, Et3B, ∆
Ph OMe Ph OMe
Br
71%
84 /1 syn /anti
OH O MgBr2, Bu3SnH OH O
CH2Cl2, Et3B, ∆
TBDMSO OEt TBDMSO OEt
Br 80%
10 /1 syn /anti
OH O MgBr2, Bu3SnH OH O
CH2Cl2, Et3B, ∆
BnO OMe BnO OMe
Br 83%
>50 /1 syn /anti
OMe OMe
MgBr2, Bu3SnH
OMe O O CH2Cl2, Et3B, ∆ OMe O O
Ph OEt 95% Ph OEt

Br
>30 /1 syn /anti
Scheme 5
i. Et 2BOTf, iPr2NEt
ii. Bu3SnH, CH2Cl2
Et3B, ∆
BnO OH O BnO OH O ð28Þ
iii. aq. NH4Cl
BnO OMe 85% BnO OMe
Br
>20/1 anti /syn
There have been surprisingly few examples of the reduction of bromoalkanes by hydrogenation
in the review period. The use of Raney nickel as a catalyst in this process proved effective in the
reduction of a dioxolane derivative <1997TL13883> (Equation (29)) while the merits of triethyl-
silane <2000JCR(S)432> and of decaborane <2001SC2251> as hydrogen sources in palladium-
catalyzed reductions have also been espoused.
OH OH
O Ni, H2, Et3N, aq. MeOH O
Br ð29Þ
O 85% O
CO2Me CO2Me
In a parallel with the chloroalkanes, low-valent metal reduction methods are popular in the
conversion of -bromocarbonyl compounds. Notably, the ‘‘classical’’ conditions of zinc powder in
acetic acid offer excellent selectivity, the generation and quenching of a radical anion being
sufficiently facile that aryl and even primary alkyl bromides are unaffected <1997S1085,
2000S1259> (Scheme 6). In the reduction of -hydroxy--bromoesters aluminum amalgam has
been mooted for the reduction of only the halogen <2000CC545, 2000JOC6752> while samarium
iodide offers removal of both the bromo- and hydroxy-functionalities <2001CEJ4266>. The closely
related reductions of -bromoimines have been demonstrated to proceed cleanly using tin chloride
<2000SL1283, 2001JOC53>.
Br Br
CO2Me Zn, AcOH CO2Me
Br 90%
Br Br
O Ph OH
Zn, AcOH O Ph OH
Br
Ph Br
80% Ph
Br
Scheme 6
There are occasional reports of the use of low-valent metal methods for the reduction of
bromoalkanes other than those contiguous with a carbonyl group where the use of sodium in
ammonia <1997JOC3355> (Scheme 3) and of Raney nickel <1998BCJ1939, 2001SL485> have
met with success.
Ionic metal hydride chemistry is employed relatively sparingly for this transformation but is
nonetheless often very useful, particularly in the reduction of primary or benzylic systems. Where
over-reduction is either not an issue or a concern, lithium aluminum hydride <2000EJO257,
2001JMC1099> can be employed (Scheme 7). Where chemoselectivity is more important, sodium
borohydride <1997BMCL573, 2000JOC7634> and L-Selectride can be very effective
<1999TL3037> (Scheme 8).
Br
LiAlH4, Et2O
Ph Ph
Ph Ph
97% Ph
Ph 95 /5 (Z )/(E )
CO2But LiAlH4, THF

Br OH
F F 49% F F
Scheme 7
H H
O N Br NaBH4, aq. HMPA O N
O 80% O
n n
C13H27 C13H27
Br
NaBH4, DMSO Br N n
Br N n C11H23
C11H23
90%
Br Br
Br L-Selectride, CH2Cl2
100%
OPri OMe OPri OMe
Scheme 8
1.01.1.5 Reduction of Iodoalkanes

Radical reduction methods, largely through the use of tributyltin hydride, dominate the reduction
of iodoalkanes to a greater extent that even the chloro- and bromoalkanes. While alternative
reductants, such as polymer-supported trialkyltin hydrides (used catalytically with sodium
borohydride as co-reductant) <1999OL1275>, poly(phenyl silane) <1997JOM475>, phenyl

silane <1997SC1023>, and even phosphinic acid <2001BCSJ225> have their advocates, few
chemists seem to be willing to diverge from the time-tested methodology. This is not unreasonable
given the steady flow of examples of highly selective reductions in the presence of a range of other
functional groups which might also be reduced by other methods, including polyfluoroalkanes
<2000EJI1975>, alkynes <1997JOC4349>, ketones <1999CPB1380>, lactones <1997SL387>,
benzyl- and silyl-protected alcohols <2000SL1733>, and nitriles <1997T16489> (Scheme 9).
Diastereoselective reductions of tertiary iodoalkanes using this methodology have also been
reported and are often very successful <2000JA12458, 2001OL1391>.
OH Bu3SnH, PhCH3, AIBN, ∆

n-C8F17 OH
n-C8F17
I 87%

OH OH
74%
I OH OH
O O
Bu3SnH, PhCH3, AIBN, ∆
I
84%
MeO MeO
H O H O
O O
O O
98%
H H
n-C7F15 n-C7F15
I
O O
O O Bu3SnH, C6H6, BEt3 O O
TBDMSO OTBDPS 88% TBDMSO OTBDPS

I OBn OBn
O O Bu3SnH, C6H6, AIBN, ∆ O O

81%
I
CN CN
Scheme 9
Reduction by catalytic hydrogenation, typically over palladium, is still occasionally seen

<1996LA693, 1996OM1508, 2001MI227> (Equation (30)). Yields are often high and, given the
selectivity that this technique offers, it is surprising that it is not employed more frequently.
MeO2C OMe MeO2C OMe

O OH H2, Pd/C, MeOH, AcOH O OH
ð30Þ
I 99%
HO HO
H H
OH OH OH OH
Low-valent metal reduction methodology is similarly underutilized. Raney nickel reduces a

wide variety of iodoalkanes <2001SL485> while the combination of zinc and nickel chloride is
also very effective, e.g., reducing the iodo moiety in the presence of -fluoroesters
<1995JOC6798, 1996JCS(P1)1741> (Scheme 10). Similarly aluminum amalgam can be used to
good effect in the reduction of -iodoesters <2000CC545> (Equation (31)).
Ni, THF
I
I
92%
O O
NiCl2, Zn, aq. THF
CO2Et CO2Et
Ph Ph
81%
F F I F F
CO2Et NiCl2, Zn, aq. THF CO2Et
I F 86% F
Scheme 10
OH O OH O
Al–Hg, aq. MeCN
OBn ð31Þ
93% OBn
I
The above pattern is repeated in the case of ionic metal-hydride-mediated reductions where the few
examples indicate that this is a perfectly viable technique for this transformation. Thus, selective
reductions of a range of iodoalkanes in the presence of other, potentially reactive, functionality using
sodium borohydride/indium chloride <2001JOC4463> (Equation (32)), sodium cyanoborohydride
<2002AG(E)1381> (Equation (33)), lithium aluminum hydride <1998JMC3596> (Equation (34)),
and N-Selectride <2000JOC5037> are displayed (Equation (35)).
I
NaBH4, InCl3, H2O CO2H
CO2H ð32Þ
60% OH
OH
TBDMSO O TBDMSO O
NaBH3CN, HMPA
N N ð33Þ
I 65%
S S
HO HO
H H
LiAlH4, THF
HO HO ð34Þ
O 71% O
H H
I
NHt-BOC N-Selectride, THF

Ph NHt-BOC
Ph ð35Þ
94%
I
1.01.1.6 Reduction of Hypervalent Haloalkanes

No further advances have occurred in this area since the publication of chapter 1.01.1.6 in
COFGT (1995) <1995COFGT(1)1>.
1.01.2 REDUCTION OF COXYGEN BONDS TO CH

The diverse chemical nature of the carbonoxygen bond mitigates against there being an all-
encompassing method for the reduction of all the different classes. Indeed some of the reduction
chemistry is orthogonal in nature—such as the radical methods used to convert thionoethers

compared to the metal hydride reduction of sulfonates. Some generalities can be observed; thus,
almost any benzylic oxygenation can be removed by hydrogenation over palladium or platinum
given sufficiently forcing conditions. Meanwhile, Gevorgyan’s recent discovery (and minor adap-
tation by others) of the reduction chemistry of silanes in the presence of catalytic amounts of
tris(pentafluoro)borane—which offers the conversion of many aldehydes, carboxylic acids, acid
chlorides, carboxylic esters, alcohols, and ethers to the alkane oxidation state—begins to threaten
the validity of the opening sentence of this paragraph!
1.01.2.2 Reduction of COX Bonds
1.01.2.2.1 Reduction of COH bonds

The direct reduction of an alcohol to the corresponding alkane remains relatively uncommon—
typically the alcohol is first converted to a more labile group. The exception to this is the
reduction of benzylic alcohols which—depending to some extent on how electron rich the arene
is—have been reduced by a wide range of reagents and catalysts including sodium cyanoborohy-
dride/zinc iodide <1995TL3299>, lithium aluminum hydride <1998TL8125>, samarium iodide
<1999TL8823>, triethylsilane/trifluoroacetic acid <2001TL7333>, and hydrogenation over pal-
ladium oxide <1997SC2087> (Scheme 11).
Ph Ph
OH NaBH3CN, ZnI2
Ph ClCH2CH2Cl
Ph
80–90%
Ph Ph
84% de
But But
OH LiAlH4, PhCl OH
77%
HO
But But
OH SmI2, HMPA, THF

Me3CCO2H
N
N 63%
HO O2N
O2N
Et3SiH, TFA, CH2Cl2
N N
78%
N N
H H
HO OH
PdO, H2, THF, CHCl3
MeO OMe MeO OMe
O O
85%
MeO OMe MeO OMe
Scheme 11
Gevorgyan and co-workers <2000JOC6179> have reported that the use of triethylsilane in the
presence of a catalytic amount of tris(pentafluorophenyl)borane reduces primary alcohols in high
yield—benzhydryl and trityl systems are also converted (Equation (36)). While this methodology
has yet to be widely adopted and the chemoselectivity of the process has yet to be fully delineated,
there does seem to be considerable potential here.
Et3SiH, (C6F5)3B (cat.)

OH CH2Cl2 ð36Þ
>95%
1.01.2.2.2 Reduction of COC bonds
(i) Reduction of oxiranes

The complete deoxygenation of benzylic oxiranes using polymer-supported borohydride in the
presence of copper sulfate has been reported <1997BCJ1101> (Equation (37)). It is interesting to
note that nonbenzylic epoxides are essentially unreactive under the same conditions, perhaps
suggesting a deceptively complex mechanism.
O Amberlite (B H4– )
CO2Et CO2Et
CuSO4 (cat.), MeOH ð37Þ
74%
The reagent of choice for the reduction of oxiranes at the less sterically hindered position
remains lithium aluminum hydride, which offers good regioselectivity and high yields in the
reduction of terminal <2002T183>, 2,3-disubstituted systems <2001TL4001, 2002JOC2435> (at
least in examples where there is a reasonable steric difference in the substituents
<1998EJO1675>) and 2,2,3-trisubstituted systems <1999JOC8965> (Scheme 12). This holds
true even when the more hindered position is benzylic <1997T6337, 2002JOC2435>, allylic
<1996TA1683>, or propargylic <2002JOC2435>. Where chemoselectivity is an issue, reagents
such as DIBAL-H <1998JA10326> (Equation (38)) and lithium triethylborohydride
<1996T3905> (Equation (39)) have a widely demonstrated utility, while sodium borohydride
<2001CC1040> and hydrogenation over ethylenediamine-doped palladium on carbon
<1999CC1041> have also been used with success.
OMe OMe
Br LiAlH4, Et2O, 0 °C Br
OH
O
81%
OMe OMe
AcO O HO O
LiAlH4, Et2O, 0 °C
81%
O OH
LiAlH4, Et2O, ∆
O 62% OH
O OH
Scheme 12
OBn OBn
BnO DIBAL-H, BunLi, THF BnO

O O OH ð38Þ
O
78%
BnO BnO
OBn OBn
LiBHEt3, THF
N Cl N Cl ð39Þ
79%
O HO
Oxiranes bearing aryl or vinyl substituents can be reduced at the benzylic positions
<2001BMCL2597, 2002JA14544> and allylic positions <1998CL109, 2000TL3335> (Equation (40)),
respectively, by a variety of reducing agents (hydrogen, formate, borane inter alia) under palladium(0)
catalysis, regardless of steric influences. DIBAL-H has also been utilized for the reduction of an aryl
oxirane at the benzylic position <1998JOC6914>.
Me2NH·BH3, CH2Cl2
CO2Bn Pd(PPh ) (cat.) CO2Bn ð40Þ
3 4
O HO
74%
Steric factors can also be subverted when an alcohol functionality is close to the oxirane
(typically in a glycidol-like system). Here reduction is then directed to the proximal oxirane
carbon <2001JCS(P1)2356, 2001TL9065, 2002SL239> (Equation (41)).
NaBH3CN, BF3, THF

OH
ð41Þ
79% OH
OH
O
(ii) Reduction of other ethers

Hydrogenation over palladium remains the method of choice for the reduction of benzylic ethers. While
the reduction of simple benzyl ethers of complex molecules to give toluene (and a complex alcohol) is
not considered in detail, it is worth noting that Spencer and co-workers <1998JOC4172> have
reported that 2-methylnaphthyl ethers can be reduced in the presence of benzyl ethers, allowing easy
differentiation of these otherwise relatively inert protecting groups (Equation (42)). Examples where
complexity is retained in the reduced aryl alkane continue to appear <1995JOC1727, 2000SL1461>
(Equation (43)). Electron-rich benzylic ethers have also been reduced by sodium in liquid ammonia
<2000JHC751> and sodium cyanoborohydride/chlorotrimethylsilane <1998TL7059>, while arylox-
etanes have been reduced with lithium aluminum hydride <1996TL4363>. Among other ethers the
recent report that prenyl ethers are reductively cleaved by zirconium chloride/sodium borohydride in
the presence of a range of other similar systems (including benzyl ethers and prenyl esters) merits further
study <2003TL2525>, while examples of the reduction of -alkoxyketones by samarium iodide
continue to be reported <1995JOC1110, 2000T351>.
OH
O
Pd/C, H2, EtOH BnO
BnO O ð42Þ
O 89%
BnO OMe
BnO OMe
OBn
OBn
Boc Boc
N N
Pd/C or Pd(OH)2, H2
ð43Þ
90–100%
Ph OBn Ph
The use of triethylsilane in the presence of catalytic amounts of tri(pentafluorophenyl)borane

shows promise in the reduction of alkyl ethers <2000JOC6179>. A wide range of primary and
secondary ethers are reduced, the only caveat is that a number of other functional groups (e.g.,
aldehydes and primary alcohols) are also reduced under these conditions (Equation (44)).

CH2Cl2 OSiEt3
ð44Þ
O 97%
(iii) Reduction of oxycarbonyls

As was the case with benzylic ethers, the bulk of the examples in the literature of reductions of
benzylic esters involve hydrogenation over palladium(0) and give trivial products such as toluene
(and a more complex carboxylic acid) <1998JOC2469, 1999EJO3105> (Equations (15) and (16)).
Again there are examples where more complex arylalkanes are generated by this type of metho-
dology <2001T4817>, but these are relatively rare.
The situation is broadly similar with allylic systems where, at least from the perspective of this
chapter, the reaction product is propene—together with a more complex carboxylic acid. Again
there are examples of more complex reduced products where a series of selective reductions of
allylic carbonates merits attention <1995SC203> (Equation (45)). Similar reductions via allyl-
titanium species have also been advocated <1998TL7513>.
O
cat. Pd(PPh3)4,
O OH
NH4CO2H, THF ð45Þ
BnO O BnO
95%
Zinc in acetic acid effects a clean reductive cleavage of -oxycarbonyl ketones <1995TL2971>
(and -oxycarbonyl enoates <1995TL8469>). Occasionally further reduction chemistry is then
seen under these conditions—in the cited example, after decarboxylation of the carboxyamine, an
intramolecular reductive amination takes place (Scheme 13).
H H
Zn, AcOH H
N O 75% N
O
O H
H Zn, aq. AcOH

H
O CO2H
H 80% O
O
O
Scheme 13
(iv) Reduction of thionoethers

The net reduction of alcohols by first converting them to a thionoether derivative (typically a thiocar-
bonate or xanthate) then utilizing radical reduction methods remains an important method. The
selectivity that can be afforded by these techniques is illustrated by the regioselective reduction of a
cyclic thiocarbonate <1997SC3887> (Equation (46)). Interestingly, the avoidance of the use of stoi-
chiometric amounts of the ubiquitous tributyltin hydride seems to have received more attention here than
in the case of haloalkanes. Examples include polymethyl hydrosilane <1997JA6949> or trimethoxysi-
lane <2000TL3377> in the presence of catalytic amounts of tributyltin hydride, phosphinic acid
<2000TL247>, dibutylphosphine oxide <1998SL39>, and diphenylphosphine oxide <2000S1917>.
S
Bu3SnH, PhCH3 OH
O O ð46Þ
85% CO2Me
CO2Me
Cyclic thiocarbonates can also be reduced using magnesium in methanol—this has the advantage
of showing opposite regioselectivity to the radical method above <1999SC2875> (Equation (47)).
S
Mg, MeOH CO2Me
O O ð47Þ
65% OH
CO2Me
1.01.2.2.3 Reduction of COheteroatom bonds

The strategy of converting alcohols (particularly primary systems) to sulfonates prior to reduction
offers useful complementarity to the thionoether methodology above as orthogonal reducing
chemistry is employed. The most frequently employed reagents for sulfonate reduction are lithium
aluminum hydride followed by lithium triethyl borohydride <2001JOC4870, 2002JOC5124,
2002TA339>, although sodium borohydride <2002BMC2583> and low-valent metal methods
are occasionally seen <1998TL6341, 1999T14479, 2000JCS(P1)1919>.
Primary sulfonates are sufficiently reactive that rather good chemoselectivity is observed even
when reducing these systems with lithium aluminum hydride. Thus, primary sulfonates can be
reduced selectively in the presence of secondary <2002BMCL715> and tertiary <2002EJO2160>
sulfonates as well as a range of other potentially sensitive functional groups <2002BMCL633,
2001AG(E)1128, 2002AG(E)1404> (Scheme 14).
OSO2Me LiAlH4, THF OSO2Me
OSO2Me 97%
Cl Cl
MeO2SO N N
N LiAlH4, THF N
47%
N N N N
O S LiAlH4, THF O S
MeO2SO
86%
HO HO
O O
LiAlH4, THF
O O
H 88% H
MeO OSO2Me MeO
Scheme 14
There are occasional reports of the reduction of other C–Oheteroatom systems; thus, a wide
range of phosphoramidites have been reduced by lithium naphthalenide <1998TL367> while the
combination of chlorotrimethylsilane and sodium iodide in acetonitrile has been utilized to reduce
some benzylic silylethers <2000SC2873>.
1.01.2.3 Reduction of C¼O Bonds to CH2
1.01.2.3.1 Reduction of aldehydes

While the Wolff–Kischner procedure still sees some use for the reduction of aldehydes
<2002JOC4821> and has been examined in fluorous solvents <2002T4071>, other methods
have tended to predominate of late. The caveat here is that the bulk of these syntheses reported
in the review period generally involves electron-rich benzaldehydes which are more prone to
reduction by these alternatives.
Hydrogenation over palladium remains a popular approach to the reduction of benzaldehydes

<1996JMC46, 1997JCS(P1)1421>. The reduction of a benzaldehyde to the corresponding methyl
group in the presence of a benzylic chloride illustrates the advantages that can be obtained using
platinum catalysis <1995JOC5717> (Equation (48)).
OMe O OMe
H2, Pt /C, CCl4
ð48Þ
87%
Cl Cl
MeO MeO
Low-valent metal methods akin to the Clemmensen procedure are also useful for the reduction
of electron-rich benzaldehydes and both zinc <1996JMC4181> and Raney nickel
<1998JCS(P1)2939> have been utilized. The report of zinc-amalgam-mediated reduction of an
aldehyde in the presence of a ketone is notable <1995P491> (Equation (49)).
O OH O O OH
Zn–Hg, HCl, aq. MeOH
Ph Ph ð49Þ
73%
HO OH HO OH
The combination of a silane and either a protic acid (such as trifluoroacetic acid
<2001JA11381>) or a Lewis acid shows considerable promise in this area as, in particular
when tris(pentafluorophenyl)borane is employed as catalyst, a wide range of aldehydes, including
aliphatic systems can be reduced. Initial work using triethylsilane reduced aliphatic systems but
was found to arrest at the silyl ether oxidation state with benzaldehydes <2001JOC1672>.
However, the recent modification of this procedure using polymethyl hydrosiloxane as the
reducing agent extended the scope to include aromatic systems <2002JOC9080> (Scheme 15).

O CH2Cl2
96%
O
Polymethylhydrosiloxane
(C6F5)3B (cat.), CH2Cl2
65%
MeO MeO
Scheme 15
1.01.2.3.2 Reduction of ketones

In a parallel with aldehydes, the more traditional reductions such as the Wolf–Kischner
<1999T7441, 2001EJO1663, 2002BMCL533> and Clemmensen procedures <1995T12923>
seem to be seeing less use than emerging methods, despite the high yields that can also be
obtained from these methodologies. Similarly, while the reduction of benzylic ketones by hydro-
genation over palladium is often an efficient procedure <1996JMC3951, 2001JMC3424>, it again
sees limited use. An isolated report of the reduction of aliphatic ketones by hydrogenation over
platinum on Montmorillonite K-10 merits both attention here and further study <2000SL631>.
The most popular reagent for this transformation of late is the combination of a formal hydride
source—typically a borohydride or silane—with an acid. Among the borohydride-mediated
reductions the combination of either sodium borohydride <2000OPP481> (Equation (50)) or
sodium cyanoborohydride <1995TL2347> (Equation (51)) with boron trifluoride appears parti-
cularly effective although both hydrochloric acid <1998TL7059> and chlorotrimethylsilane
<2001SL1391> have also been used with success.
O Cl
Cl
NaBH4, BF3.OEt2, THF
ð50Þ
99% EtO2C
EtO2C N N
H H
O
NaBH3CN, BF3·OEt 2, THF
ð51Þ
75%
The use of triethyl silane in combination with trifluoroacetic acid provides efficient reductions
of electron-rich aryl ketones <1995JMC4411, 2000BCJ747> (Equation (52)). Lewis acids (e.g.,
titanium tetrachloride and trimethylsilyltrifluorosulfonate <2001T5353>) are also employed in
tandem with silanes where the use of only catalytic amounts of tris(pentafluoro)borane together
with polymethyl hydrosiloxane reduces a wide range of aromatic and aliphatic ketones in high
yields <2002JOC9080> (Equation (53)).
O
Et3SiH, CF3CO2H, CCl4
ð52Þ
79% Cl
Cl BnO O
BnO O
O Polymethylhydrosiloxane
(C6F5)3B (cat.), CH2Cl2 ð53Þ
88%
1.01.2.4 Reduction of C(¼O)X to CH3

A number of electron-rich arylcarboxylic esters such as azulenes <1996BCJ1645> (Equation
(54)), anilines <2002EJO2094> (Equation (55)), (aza)carbazoles <1996T3029, 1999JNP976>
(Equations (56)–(57)), pyrroles <1997JHC13> (Equation (58)), and imidazoles <2001CEJ721>
(Equation (59)) have been reduced to the corresponding aryl methyl system by metal hydride
reagents. Typically—although not exclusively—aluminum hydrides are employed and the reac-
tions are often high yielding.
O
OMe
DIBAL-H, Et2O
82%
ð54Þ
F
F
NH2 O NH2
(Pri)3Si Red-Al, PhCH3 (Pri)3Si
OMe ð55Þ
83%
HO
O HO O
O Red-Al, Dioxane
ð56Þ
75%
N OMe
H N
OH
O H
N
N
LiAlH4, THF
ð57Þ
N 63%
H OMe N
O H
Cl Cl
NaBH4, MeOH
ð58Þ
NO2 51%
NO2
OEt
N N
H O H
O
H H
N N LiAlH4, THF N N
OEt
ð59Þ
EtO 92%
N N N N
H H
O
Gevorgyan and co-workers report a remarkable new method where, apparently for the first
time, aliphatic acid chlorides, carboxylic acids, and esters are fully reduced to the corresponding
alkane. The reduction is effected by triethylsilane in the presence of only catalytic amounts of
tris(pentafluorophenyl)borane <2001JOC1672> (Scheme 16). Although the reduction of arylcar-
boxylic ester substrates stops at the aryl methyl silyl ether, the methodology is clearly a break-
through for the reduction of the aliphatic systems.
O HSiEt3, (C6F5)3B (cat.)

CH2Cl2 n-C16H34
C15H31 Cl 97%
O HSiEt3, (C6F5)3B (cat.)

CH2Cl2 n-C18H38
C17H35 OMe 96%
HSiEt3, (C6F5)3B (cat.)

CH2Cl2
O O 99% OSiEt3
Scheme 16
No examples of the reduction of thioesters, acid bromides, or acid iodides were reported since
the publication of COFGT (1995).
1.01.2.5 Reduction of C(OX)n Systems

Examples of the reduction of acetals and orthoesters to the corresponding alkanes have histori-
cally been somewhat rare, perhaps due to the many methods for the reduction of aldehydes and
ketones in the former case and indeed there has only been one example in this class of reaction in
the review period i.e., since the publication of COFGT (1995). Thus, treatment of the dimethyl
acetal of p-anisaldehyde with sodium cyanoborohydride and chlorotrimethyl silane gives the
correponding toluene in good yield <1998TL7059> (Equation (60)). The reduction of less
electron-rich systems halted at the benzyl methyl ether.
OMe
NaBH3CN, Me3SiCl
OMe MeCN ð60Þ
84% MeO
MeO
1.01.3 REDUCTION OF CSULFUR, CSELENIUM, AND CTELLURIUM

BONDS TO CH

Sulfur-containing compounds are almost universally reduced by Raney nickel and this chemistry
is sufficiently selective that it is unlikely ever to be threatened as the method of choice. Although
this reagent can also be used to reduce organoselenium compounds, there is a dramatic shift to
the use of tin hydride radical chemistry for these transformations, a trend which carries into the
reduction of tellurides.
1.01.3.2 Reduction of CSX Bonds

Raney nickel remains the stock reagent for the reduction of sulfides <1997TL6759> (Equation (61)).
Chemoselectivity can be an issue here; for example, benzylic chloroalkanes are concomitantly
reduced <1998TL147> (Equation (22)), but there are many examples such as benzylic alcohols and
ethers where functional groups that might prove reactive under forcing conditions are unaffected
<1995TL6755, 1996JA13103, 1997T12883>. Raney nickel reduction of sulfides has also been mooted
in the cleavage of alkyl groups from arylthiol-modified polyethylene glycol supports as an alternative
to other ‘‘traceless’’ cleavage methodologies <1997T6645>.
O O
Raney nickel, EtOH
PhS ð61Þ
72%
Other reduction methods see occasional use: radical reduction has been utilized to cleave
benzylic sulfides <1996T13867>, while low-valent metal methods can also be very effective
<1995JA5757, 1995TL7243> (Equation (62)).
SO2Ph
SO2Ph S
Zn, AcOH
O ð62Þ
O 98% O
O
Sulfoxides are also typically reduced by Raney nickel <2000TA3079>, although it has been
suggested that nickel boride is superior for this transformation <2000SL1725>.
Sulfones are commonly reduced by low-valent metal methods, although a tin hydride radical
procedure met with success in the reduction of an -sulfonyl ketone <1995SL973>. While both
magnesium <1995TL5691> and samarium <2000SC2559> in the presence of a catalytic amount
of mercuric chloride have been used with success, the classical choice of sodium amalgam is
generally preferred <1995JOC4978> (Equation (63)) and has even been applied as a method of
cleaving compounds from polymeric supports <1997TL977>.
Ph Ph
H H
EtO N SO2Ph Na–Hg, THF, MeOH EtO N
ð63Þ
82%
N OEt N OEt
S-Alkyl xanthates, in common with the O-alkyl thionoethers above, are readily reduced by radical
means. While tin hydride chemistry is efficient for this transformation <2000CC535, 2001CC1304>,
dilauroyl peroxide has also been used with success <1996TL5877> (see Chapter 1.05).
1.01.3.3 Reduction of C¼S to CH2

In contrast to the received wisdom that Raney nickel is of little utility in the reduction of
thioketones <1995COFGT(1)1>, the complete reduction of an ,-unsaturated system to the
corresponding alkane in reasonable yield has been reported using this reagent <1999JA2762>
(Equation (64)). Ytterbium metal has also been mooted for thioketone reductions. Although a
range of reactions is possible depending on the solvent, temperature, and ratio of metal to
substrate, the authors identified conditions which were very selective for the reduction of diaryl
thioketones <1996JOC372> (Equation (65)).
O O
O Raney nickel, H2, EtOH O
58%
ð64Þ
S
S
Yb (2 equiv.), Benzene, rt
ð65Þ
80%
The reduction of dimethylsulfonium ylides to the corresponding alkanes by zinc in acetic acid
in often excellent yields has been described <1996JOC8604> (Equation (66)). The conditions are
sufficiently mild that a nascent 1,3-diketone functionality is not reduced.
O O
R1 R2 Zn, AcOH, CH2Cl2, rt O O
ð66Þ
R1 R2
S R1, R2 = aryl 68–93%
1.01.3.4 Reduction of C(¼S)X to CH3

Huisgen and co-workers <1997LA1517> have reported the successful reduction of a thiolactone
using Raney nickel (Equation (67)). Although only a modest yield was reported, this must at least,
in part, be due to the volatile product being isolated by distillation on a very small scale, so the
method should not be dismissed for other synthetic applications.
S
Raney nickel, EtOH, ∆
S
ð67Þ
53% O
O
1.01.3.5 Reduction of C(SX)n Systems

As was observed in the case of sulfides, Raney nickel is a largely universal choice for the reduction
of thioacetals to alkanes, although nickel boride <1996TA2181> and sodium in i-propanol
<1998TL9609> have been utilized for this application. Raney nickel has sufficient versatility
that it can be employed to perform selective reductions of relatively sensitive molecules
<1995JOC4359> or, if desired, can be used under more forcing conditions to reduce other groups
at the same time <1995T1337> (Scheme 17).
H H
O O
S Raney nickel, aq. EtOH
N N
62%
Ph H S Ph H
O O
O OH
Raney nickel, EtOH
85%
N OBn N O
MeS SMe H
Scheme 17
1.01.3.6 Reduction of CSe Systems

The much greater propensity of the carbonselenium bond, relative to the carbonsulfur bond,
to undergo homolytic cleavage results in a dramatic, though not absolute, shift away from the use
of Raney nickel to radical reduction chemistry.
As was seen above, most of the radical reductions are performed with tributyltin hydride and
triphenyltin hydride—while alternatives such as tris(trimethylsilyl)silane <1995TL6781>, tetra-
phenyldisilane <1999JCS(P1)2891>, silyl-1,4-hexadienes <2000AG(E)3080>, and even acid solu-
ble tin hydrides <1995JOC2607> have all been advocated, they see little general use. The case for
the classical tin hydride approach is again easily made—selectivity over a wide range of other
functionality is excellent and the yields of these processes are frequently high <1997JOC9089,
1999JOC1375, 1999JOC7218, 2001JOC4187, 2001T7035, 2002EJO1776> (Scheme 18).
O O
Bu3SnH, AIBN, C6H6
Si SePh 79% Si
Ph Ph Ph Ph
Cl Cl
N N N N
Bu3SnH, AIBN, PhCH3
BnO N BnO N
O N O N
94%
F SePh F
SePh H
Bu3SnH, AIBN, PhCH3
CO2Me CO2Me
N N 90% N N
MeO2C H CO Me MeO2C H CO Me
2 2
TolO2S Bu3SnH, AIBN, PhCH3 TolO2S

N N
PhSe
OAc 77% OAc
H H
O H O H
Bu3SnH, AIBN, PhCH3
N N 79% N N
O H SePh O H
O O
SePh Bu3SnH, AIBN, PhCH3
SOPh 88% SOPh

MeO MeO2C CO2Me MeO MeO2C CO2Me
Scheme 18
These reductions, at least in the case of -selenoesters, can be performed with high diastereo-
selectivity. It is striking that subtle variation in nearby functionality and reaction additives give
opposite selectivity <2001JOC5427, 2002OL1019> (Scheme 19).
O O
O O O Bu3SnH, Et3B, THF

O O O
90%
OBut OBut
SePh
>30 /1 anti /syn
OH OH O Bu3SnH, Et3B, OH OH O
MgBr2.OEt2, THF
OBut OBut
SePh 94%
>30 /1 syn /anti
Scheme 19
The bulk of the remaining reductions of selenides is split relatively evenly between the use of Raney
nickel <1996JHC169, 1997SL123, 2000JOC6703> (Equations (68)–(70)) and of the combination of
nickel chloride and sodium borohydride <1998JCS(P1)969, 1999T12387> (Equations (71)–(72)). The
yields for these reactions are typically comparable to the radical processes above with potential over
reduction either not being an issue or being advantageously exploited (Equation (69)).
N N N Raney nickel, EtOH N N N

N N
ð68Þ
61%
N N
O SePh O
O H O H
Raney nickel, EtOH
O O ð69Þ
OH
N O 65% N
OSO2Me
PhSe
OAc OAc
H H
H H
O Raney nickel, EtOH O ð70Þ
PhSe
HO O 99% HO O
H H
O O
H NH NiCl2, NaBH4 H NH
Ph MeOH, THF Ph
ð71Þ
N N
SePh 87%
O O
PhSe O O
NiCl2, NaBH4, THF
Ph Ph
O 90% O ð72Þ
Ph Ph
>10/1 trans /cis
1.01.3.7 Reduction of CTe Systems

New examples of telluride reductions are unsurprisingly somewhat sparse. Tin-hydride-mediated
radical reduction <1999SL567> seems to remain the method of choice (Equation (73)), although
the use of ytterbium diiodide in combination with near-UV light has also been advocated
<1997TL9017> (Equation (74))—it remains to be seen how popular the latter reagent system will
become for this application.
MeO
Bu3SnH, PhCH3, ∆ O
O CO2Et ð73Þ
Te CO2Et 88%
YbI2, hν, THF, 60 °C

ð74Þ
40%
Te
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Biographical sketch
Alan G. Sutherland hails from the seaside town of Grangemouth in

Stirlingshire, Scotland. He received his B.Sc. in chemistry from the
University of Edinburgh. Then he moved to the University of East
Anglia where he obtained a Ph.D. working with Professor Richard J.
K. Taylor in 1989. He undertook postdoctoral research with Professor
Stanley M. Roberts at the University of Exeter. Then he took up the
Enzymatix Lectureship at the same institution in 1991. In 1992 he
moved to a Senior Lectureship at the University of North London. In
1995 he turned to an industry-based career in medicinal chemistry by
joining Wyeth Research at their Pearl River site near New York City.
# 2005, Elsevier Ltd. All Rights Reserved Comprehensive Organic Functional Group Transformations 2
No part of this publication may be reproduced, stored in any retrieval system ISBN (set): 0-08-044256-0
or transmitted in any form or by any means electronic, electrostatic, magnetic
tape, mechanical, photocopying, recording or otherwise, without permission Volume 1, (ISBN 0-08-044252-8); pp 1–30
in writing from the publishers
1.02
One or More CH Bond(s) Formed
by Substitution: Reduction of
CarbonNitrogen, Phosphorus,
Arsenic, Antimony, Bismuth,
Carbon, Boron, and Metal
Bonds
J. BLANCHET, YANXING JIA, and JIEPING ZHU
Institut de Chimie des Substances Naturelles, Gif-sur-Yvette,
France
1.02.1 REDUCTION OF CN BONDS TO CH BONDS 32

1.02.1.1 Reduction of CN Single Bonds 32
1.02.1.1.1 Reductive cleavage of sulfonimides 32
1.02.1.1.2 Deamination using pyridinium salts as intermediates 33
1.02.1.1.3 Direct reduction of amines or ammonium salts 33
1.02.1.1.4 Deamination using diazenes as intermediates 34
1.02.1.1.5 Reductive cleavage of nitro groups 35
1.02.1.1.6 Reductive cleavage of isonitrile groups 37
1.02.1.1.7 Reductive cleavage of azido groups 38
1.02.1.1.8 Reductive ring cleavage of aziridines 39
1.02.1.2 Reduction of CN Double Bonds to Methylene and Methyl Groups 41
1.02.1.2.1 Reduction of tosylhydrazones 41
1.02.1.2.2 Reduction of C¼NNR1R2 systems where R1 or R2 is alkyl, acyl, aryl, or hydrogen 43
1.02.1.2.3 Reduction of N-alkylimine type systems 45
1.02.1.2.4 Reduction of diazo compounds 46
1.02.1.3 Reduction of CN Triple Bonds to the Methyl Group 47
1.02.1.3.1 Reduction of nitriles using hydrogenolysis conditions 48
1.02.1.3.2 Reduction of nitriles to methyl groups using hydride reagents 49
1.02.2 REDUCTION OF CARBONPHOSPHORUS, ANTIMONY, AND BISMUTH BONDS
TO CARBONHYDROGEN BONDS 49
1.02.2.1 Reduction of CarbonPhosphorus Bonds 49
1.02.2.1.1 Cleavage of CP bonds under basic conditions 49
1.02.2.1.2 Cleavage of CP bonds under acidic conditions 51
1.02.2.1.3 Cleavage of CP bonds under neutral conditions 51
1.02.2.1.4 Cleavage of CP bonds with hydride 51
1.02.2.1.5 Miscellaneous methods 52
1.02.2.2 Reduction of CAs Bonds 52
1.02.2.3 Reduction of CSb Bonds 52
31
1.02.2.4 Reduction of CBi Bonds 53

1.02.3 REDUCTIVE CLEAVAGE OF CC BONDS TO CH BONDS 53
1.02.3.1 Reductive Decyanation 53
1.02.3.1.1 Use of dissolving metals 53
1.02.3.1.2 Use of radical conditions 54
1.02.3.1.3 Miscellaneous methods for reductive decyanation 54
1.02.3.2 Cleavage of CC Bonds Where Both Products are Hydrocarbons 55
1.02.3.2.1 Dealkylation of alkylbenzenes 55
1.02.3.2.2 Reductive cleavage of cyclopropylketones 55
1.02.3.2.3 Reductive cleavage of other constrained cycloalkanes 56
1.02.3.3 Reductive Decarboxylation of Aliphatic Carboxylic Acids, Esters, and Aldehydes 57
1.02.3.3.1 Decarboxylation of aliphatic carboxylic acids and esters 57
1.02.3.3.2 Reductive decarbonylation of aldehydes and acyl halides 58
1.02.3.3.3 Reductive cleavage of nonenolizables ketones 59
1.02.3.4 Reductive Decarboxylation of Activated Carboxylic Acids and Esters 60
1.02.3.4.1 Thermal decarboxylation of disubstituted malonic acids 60
1.02.3.4.2 Nucleophile-mediated decarboxylation of malono esters 61
1.02.3.4.3 Metal-mediated decarboxylation of activated acids and esters 62
1.02.4 REDUCTION OF CARBONBORON, SILICON, AND GERMANIUM BONDS
TO CARBONHYDROGEN BONDS 63
1.02.4.1 Reduction of CarbonBoron Bonds to Hydrocarbons 63
1.02.4.1.1 Cleavage of carbonboron bonds under acidic conditions 63
1.02.4.1.2 Cleavage of carbonboron bonds under neutral conditions 64
1.02.4.1.3 Cleavage of carbonboron bonds with base 64
1.02.4.2 Reduction of CarbonSilicon Bonds 65
1.02.4.2.1 Cleavage by acid 65
1.02.4.2.2 Cleavage by base 65
1.02.4.2.3 Desilylation by miscellaneous methods 67
1.02.4.3 Cleavage of CarbonGermanium Bonds to CarbonHydrogen Bonds 67
1.02.5 REDUCTION OF CARBONMETAL BONDS TO CARBONHYDROGEN BONDS 67
1.02.5.1 Reduction of CHg Bonds 68
1.02.5.1.1 Protonolysis 68
1.02.5.1.2 Metal hydride demercuration 68
1.02.5.2 Cleavage of Other Metals from Carbon to Give a CH Bond 71
1.02.5.2.1 Protonolysis 71
1.02.1 REDUCTION OF CN BONDS TO CH BONDS
1.02.1.1 Reduction of CN Single Bonds

Reductive deaminations have been the subject of many reviews <B-1982MI931, B-1956MI001,
1995COFGT(1)27>. The following sections are categorized according to the type of nitrogen
moiety lost during deamination.
1.02.1.1.1 Reductive cleavage of sulfonimides

Sodium borohydride in polar aprotic solvents (HMPA, DMSO) is used for the reductive dis-
placement of disulfonimides (Equation (1)) <1978JOC2259>. The incorporation of two electron-
withdrawing sulfonyl groups on nitrogen stabilizes the sulfonimide anion and allows the reaction
to proceed efficiently. The synthesis of disulfonimides from primary amines <1974JOC3525,
1998TL1799> is easy but the preparation of sulfonimides from hindered amines remains proble-
matic, restricting the scope of this deamination.
NaBH4, HMPA
SO2R2 150–175 °C SO2R2
R1 N R1 H + Na N ð1Þ
SO2R2 22–91% SO2R2
R1 = Bn, alkyl; R2 = 4-(Me)-C6H4, 4-(Br)-C6H4, CF3

1.02.1.1.2 Deamination using pyridinium salts as intermediates

This method of reduction has been thoroughly investigated <1980T679>. Highly substituted
pyrylium salts are used for a two-step conversion of the amino group into numerous other
functionalities. The first step involves the reaction between the pyrylium salt and the amine to
produce an N-substituted pyridinium salt. This pyridinium salt is then reacted with a nucleophile
and, in the case of reduction, the nucleophile is a hydride donor. Depending on the amine the
substituted pyrylium salt required to perform the deamination will be different.
With allylic, benzylic, or heteroarylmethyl amines <1979JCS(P1)442>, N-substituted 2,4,6-
triphenylpyridinium salts are synthesized. They are reduced with sodium borohydride in good
yields to the 1,2-dihydro derivatives, and the corresponding dihydropyridines decompose around
200 C to give 2,4,6-triphenylpyridines and hydrocarbons in good yields (Scheme 1).
Ph Ph
R NH2 NaBH4, CH3CN
Ph
EtOH, rt MeOH, 0 °C 200–220 °C
R–Me
45–87% Ph N Ph 75–86% Ph N Ph 75–82%
Ph O Ph
R R
BF4 BF4
R = CH=CH2, Ph, 2-furyl, 2-pyridyl, 4-pyridyl
Scheme 1
2,3,5,6-Tetraphenylpyrylium cations are transformed to the corresponding pyridinium salts

using nonactivated primary alkylamines <1980JCS(P1)2554>. Steric hindrance directs the attack
of sodium borohydride leading to 1,4-dihydropyridines, which decompose at 180 C to produce
the corresponding alkane (Scheme 2). NMR studies have suggested that a radical mechanism may
be involved in this type of reaction.
RNH2 NaBH4, CH3CN

Ph Ph Ph Ph
Ph Ph MeOH, 0 °C
EtOH, rt 180 °C
R–H
82–95% Ph N Ph 60–83% Ph N Ph 58–88%
Ph O Ph
R R
BF4 BF4
R = Hexn, Octn, CH2CH2Ph
Scheme 2
The method described above can be applied to anilines, but the temperature required for
decomposition is higher (300 C) and the reaction suffers from low reproducibility <1980T679>.
1.02.1.1.3 Direct reduction of amines or ammonium salts

Methods for the direct reduction of amines or ammonium salts exist. Such transformations
involving catalytic hydrogenation, metal reductions, and various hydrides are well known and
have been extensively reviewed <B-1956MI001, 1966JCE398, B-1985MI005>. In addition, elec-
trolytic reductions have also been reviewed.
Catalytic hydrogenation using palladium on carbon (Pd/C) and formic acid has been reported
to reduce allylic amines <1980JOC4926>. Essentially the corresponding alkenes are formed but
rearrangement or over-reduction are common side reactions. However, hydrogenolysis using
palladium on carbon is a well-known method to reduce Mannich bases derived from benzalde-
hyde derivatives to the corresponding methyl derivatives <1973S703>. The selective cleavage of
benzylic amines to the corresponding hydrocarbons has also been reported using low-valent
titanium reagent in modest yields (46–67%) <1996SC1051>.
Reduction of a range of aliphatic amines to the corresponding hydrocarbons and ammonia using
a platinum catalyst at high temperature has been investigated (Equation (2)) <1984JOC2875>. The
reaction system also reduces nitrogen heterocycles to cycloalkanes and ammonia.
NH2 Pt/H2, 45 °C
Cyclohexane ð2Þ
99%
Tributyltin hydride was also employed to reduce a series of arylmethyl and heteroarylmethyl
amines (Equation (3)) <1988SC1207> but temperatures of 200 C were required to effect the
reactions. The method can also be used to reduce N-oxides and amine salts.
NMe2
Me
OH Bu3SnH, 200 °C OH ð3Þ
89%
Sodium cyanoborohydride has been successfully used in the high-yield reduction of quaternary
ammonium salts (Equation (4)) <1978CC1089>. The reduction tolerates a large range of func-
tionalities (halogen, ester, nitrile, and nitro groups), and the authors claimed this method to be
superior to the sodium borohydride–dimethyl sulfoxide system.
Me2SO4 NaBH3CN
THF HMPA ð4Þ
Ar NMe2 Ar Me
Ar NMe3 + MeSO4
71–91%
Early methods for reducing amines to the corresponding alkanes commonly required zinc in
refluxing acetic acid <1958JA1654>, Raney-nickel hydrogenolysis <1953JA1128>, sodium meth-
oxide at 180 C <1951JA2718>, and tin chloride <1983SC677>. In these methods harsh condi-
tions are used, and since more selective methods for functional group manipulation have been
developed, the tendency to apply these methods has decreased.
Cleavage of tetraalkylammonium halides with sodium in liquid ammonia has been carried out
on a large number of substrates and results in hydrocarbons in good yields in almost every case
(Equation (5)) <1959JA4850>. This is a mild way of reducing amines, as long as the molecule
tolerates the conditions of dissolving metal reductions.
Na/NH3, –78 °C
Bu4n N Br BunH + Bun3N + NaBr + NaNH2 ð5Þ
89%
Reduction of -amino esters to the corresponding -keto esters has been carried out under
electrolytic conditions (Equation (6)) <1973JOC2731>.
O
2e + 2H O
NH2.HCl ð6Þ
Ph CO2Et
90% Ph
CO2Et
1.02.1.1.4 Deamination using diazenes as intermediates

Amine reductions, which result in the formation of a nitrogen molecule, are in most cases believed
to proceed via a diimide intermediate <1963JA1108>. For example, primary amines react with
difluoroamine to yield hydrocarbon, albeit in modest yields (Equation (7)). This conversion and
its mechanism have been previously reviewed <1963JA97, 1964JA2233>.
RNH2 + HNF2 R RH + N2
N NH ð7Þ
22–77%
A direct and selective method for the deamination of primary amines with hydroxylamine-
O-sulfonic acid has been reported (Equations (8) and (9)) but the scope of the reaction is rather
limited <1964JA1152, 1978JA341>.
NH2OSO3H
NaOH, 0 °C ð8Þ
PhCH2NH2 PhMe
65%
NH2OSO3H
O
OH NaOH, 0 °C O ð9Þ
50% OH
NH2
1.02.1.1.5 Reductive cleavage of nitro groups

In the last decades, the nitro group has found wide applications in organic synthesis, and as a
consequence it appears that a clean removal of such a useful group is of interest. The synthetic
utility of such a transformation has been reviewed <1986S693>.
Kornblum, in 1979, reported a general method for the replacement of a nitro group by a
hydrogen atom <1979JA647>. A large range of tertiary nitro groups was removed using sodium
thiolate in a nonprotic polar solvent upon exposure to fluorescent light (Equation (10)). The
solvent of choice is HMPA but can be replaced by DMF or DMSO if nucleophilic attacks of the
thiolate compete with the desired process.
MeSNa, hν
R Me solvent, rt R Me
NO2 H ð10Þ
Me 55–95% Me
Solvent: HMPA, DMF, DMSO
Tributyltin hydride was reported independently by two groups to be an efficient reagent for the
reduction of nitro groups <1981JA1557, 1981TL1705>. Countless applications witness the
importance of such a transformation. Selected examples are shown in Equations (11)–(14)
<1997JOC4002, 1996T6139, 2000H1011, 1997TA2579>.
Bu3SnH, AIBN
O O
O toluene, reflux
O ð11Þ
CO2Et CO2Et
65%
Me NO Me Me
Me 2
Bu3SnH, AIBN
OTBDMS O
benzene, reflux OTBDMS O ð12Þ
NO2 55%
Me Me
Bu3SnH, AIBN
Me Me
toluene, reflux
O N O N
ð13Þ
NO2
O 83%
O
Ph Ph
OH OH
Bu3SnH, AIBN
NO2 benzene, reflux H
ð14Þ
70%
OCOPh OCOPh
Recently, Fu <1998JOC5296> reported an improved procedure using a catalytic amount of

tributyltin hydride and triphenylsilane as the stoichiometric reducing agent. The reaction is extre-
mely versatile and tolerates a broad range of functionalities as shown in Equations (15) and (16).
10% Bu3SnH, Ph3SiH

O O
NO2 ACHN, toluene, 110 °C H
CO2Et CO2Et
ð15Þ
76%
ACHN: 1,1'-azobis(cyclohexanecarbonitrile)
10% Bu3SnH, Ph3SiH

ACHN, toluene, 110 °C ð16Þ
(MsOCH2CH2CH2)3C-NO2 (MsOCH2CH2CH2)3C-H
61%
Reduction of the nitro group can be highly stereoselective if the substrate allows an important
facial differentiation during the quenching of the intermediate radical (Equation (17))
<2001TA1673, 2003S1419>.
Bu3SnH, AIBN
CN CN
benzene, reflux
NO2
65%
ð17Þ
R R
R = D-manno-(CHOAc)4-CH2OAc Single stereoisomer
Other hydrides such as sodium hydrogen telluride have been used to remove the tertiary nitro
group in high yields under very mild conditions (Equations (18) and (19)) <1985BCJ1067>. The
authors claimed that this reaction overcomes drawbacks associated with other methods (high
temperature, purification).
NaHTe
NO2
EtO2C EtOH, rt EtO2C Me
Me ð18Þ
Me O 100% Me O
NC NaHTe
NC
NO2 EtOH, rt
Me Me ð19Þ
80%
Me Me
A general procedure for the reductive denitration of -nitro ketones using sodium dithionite
and triethylsilane has been reported <1989TL4819> (Equation (20)).
O Na2S2O4, Et3SiH O
NO2
HMPA, H2O, rt
ð20Þ
Cl 86% Cl
Me Br Me Br
Lithium aluminum hydride (LAH) has also been used as a reductant of the nitro group
(Equation (21)) <1983S137>. It is interesting to note that although LAH can reduce tosylhy-
drazones in refluxing THF (see Section 1.02.1.2.1), this reagent is chemoselective at 0 C and
tosylhydrazones are not reduced at this temperature.
NHTos LiAlH4 NHTos

N THF, 0 °C N
R3 R3
R1 R1
2 NO2
81–94% 2H ð21Þ
R R
R1 = alkyl, R2 = alkyl, R3 = H, Me
Removal of an allylic nitro group using radical conditions generally leads to the migration of
the double bond. However, a palladium-catalyzed hydride transfer has been shown to be highly
regioselective as shown in Equation (22) <1986JOC3734>.
Pd(PPh3)4, HCO2NH4
Me Me Me
THF, 60 °C
Ph Ph + Ph ð22Þ
NO2 55%
92:8
An isolated example of selective removal of a benzylic nitro group using hydrogenolysis

conditions (Pd/C, H2) has been reported (Equation (23)) <1996T6373>.
O2N Pd/C, H2 (15 bar) CH3 OH

OH
EtOH CH3
CH3 ð23Þ
47% N
N
OMe Bz OMe Bz
Other methods for the reduction of nitro groups to the corresponding alkanes involve 1-benzyl-
1,4-dihydronicotinamide <1983JA4017>, potassium hydroxide in ethylene glycol
<1979TL1243>, or triethylsilane with a Lewis acid (SnCl4 or AlCl3) <1987TL2277>.
1.02.1.1.6 Reductive cleavage of isonitrile groups

Because isonitriles can behave as an activating group for the selective introduction of electrophilic
species, its mild reductive cleavage to a CH bond has become a challenging area of research in
the last decades.
The main procedure uses tributyltin hydride as the reductant. This radical-induced deamination
of isonitriles was first reported in 1968 <1968JA4182> and has been thoroughly reviewed
<1987S665>. Further developments were achieved by Barton using AIBN as the radical initiator
(Equations (24)–(26)) <1979TL2291, 1980S68>.
H Bu3SnH, AIBN H
O benzene, reflux O
O O
H H ð24Þ
H 89% H
H H H H
CN
H H
OAc Bu3SnH, AIBN

OAc
benzene, reflux
O ð25Þ
AcO OAc O
72% AcO OAc
NC AcO
AcO
Bu3SnH, AIBN
NC H H
benzene, reflux N
N CO2Et CO2Et ð26Þ
71% O
O
Triethylborane as initiator and triphenyltin hydride as hydride donor have been reported as a
good system for such transformations (Equation (27)) <1989TL1257>.
Ph3SnH, Et3B
OTMS OTMS
toluene, rt
ð27Þ
CO2Me CO2Me
83%
Me NC Me H
The use of a recyclable polymer-supported tin hydride has been proposed to overcome the
toxicity generally associated with tin reagents <1991JOC5971>.
Barton <1993JOC6838> introduced hypophosphorous acid and dimethylphosphite as alterna-
tive hydride donors (Equation (28)). This method has been applied in a recent synthesis of
sorgolactone <1996TL3491>.
NC H3PO2, Et3N, AIBN H
dioxane, reflux ð28Þ
97%
Tris(trimethylsilyl)silane has been used as a more acceptable reducing agent than triorganotin com-
pounds from toxicological and ecological perspectives (Equation (29)) <1991JOC678>. Such a system
has been reported to be effective for the deamination of a more elaborate structure (Equation (30)),
whereas tributyltin hydride and other hydride donors failed to give good yields <1993JOC1646>.
(TMS)3SiH, AIBN
toluene, 80 °C Me ð29Þ
N NC N
O 96% O
(TMS)3SiH, AIBN
OBn OBn toluene, reflux OBn OBn
ð30Þ
MeO2C Me 80% MeO2C Me
NC
Another method for the reduction of isonitriles to the corresponding hydrocarbons utilizes a
dissolving metal reduction. Several isonitriles have been reduced by sodium or lithium in liquid
ammonia <1961CB1157, 1966HCA1145, 1974T1341>. For sensitive substrates prone to rearran-
gement, a milder procedure using sodium naphthalenide has been reported (Equation (31))
<1978JOC2396>.
Na, naphthalene
Ph Me DME, –10 °C Ph Me ð31Þ
Ph NC 95% Ph
Finally, the use of excess potassium and crown ether in toluene has been used to selectively reduce
a wide range of simple alkyl isonitriles in excellent yields (90–96%) (Equation (32)) <1989TL845>.
Dicyclohexano-18-crown-6
K, toluene
ð32Þ
97%
NC
1.02.1.1.7 Reductive cleavage of azido groups

The reduction of an azide derivative to the corresponding hydrocarbon has been neglected in the
literature. Isolated examples have been reported: when 2-azido-1-phenyl-propan-1-one reacted
with samarium(II) iodide (Equation (33)), the reduced compound was selectively obtained instead
of the desired 2,4-diphenylpyrrole <2002TL1863>.
O
SmI2, THF O
Me ð33Þ
Ph Me
N3 78% Ph
Some other research suggests that such deazidation of an alkyl azide by stannyl radicals can be
feasible <1999JOC7836>. As a primary amine can be readily transformed into an azide, the
development of a selective method for the reductive cleavage of alkyl azides would become a
useful deamination strategy.
1.02.1.1.8 Reductive ring cleavage of aziridines

Due to the strained nature of aziridines, ring-opening reactions are a dominant feature of this class
of compounds. The regioselective reductive opening of aziridines has been widely investigated since
the 1990s using hydride reagents, hydrogenolysis conditions, or single-electron transfer agents.
(i) Use of hydride reagents

Some reports deal with the opening of aziridines with a hydride source such as LAH, diisobutyl-
aluminum hydride, or Red-Al <1987TL1211, 1992T6069, 1994AG(E)599>. The regiocontrol of
the reaction relies on the neighboring group assistance of a hydroxyl group (Equation (34)). When
hydride reagents such as LAH or Red-Al are used, a complete regioselective ring opening is
observed while the use of diisobutylaluminum hydride gave less coherent results and incomplete
conversion.
Red-Al, THF, –78 °C
or
NHTs
LiAlH4, THF, –20 °C
HO OBn HO + HO ð34Þ
OBn OBn
N 80–86%
Ts NHTs
>100:1
Even aziridines derived from homoallylic alcohols have shown a good regioselectivity during
their reductive ring opening (Equation (35)) <1997T16139>. A cyclic six-membered transition
state was invoked to explain such selectivity. When R = Ph, the reagent of choice is Red-Al.
When LAH is used, the electronic effect of a phenyl group can interfere to afford mainly the
undesired 1,3-amino alcohol.
Red-Al, THF
–78 °C or rt NHTs
R R R
OH OH + OH ð35Þ
NTs 70–95%
NHTs
up to >95:5
R = Et (trans), c-Hex (trans or cis), Ph
(ii) Use of palladium-mediated hydrogenolysis

Evans <1993JA5328, 1994JOC3243, 1996TL5473> has reported that the regiospecific reductive
ring opening of a tosyl aziridine ester can be achieved by transfer hydrogenation (Equation (36)).
Pd/C, HCO2H
Ts MeOH, rt MeO2C
Ph N Ph ð36Þ
82% NHTs
CO2Me
Prolonged hydrogenolysis of aziridino esters yields the corresponding -amino ester via a
selective C(2)N bond cleavage (Equation (37)) <1994TL7613>.
Pd/C, H2
O EtOH, rt O
O O ð37Þ
CO2Et CO2Et
N
Bzl NH2
This methodology has been extended with Pearlman’s catalyst to the reductive ring opening of
an N-alkyl chiral aziridino alcohol (Equation (38)) <1995TL8431, 2001T8267>. Interestingly,
exclusive C(3)N bond cleavage occurred leading to the formation of the -amino alcohol in
excellent yield (Equation (39)). The corresponding aziridino esters were converted into the
-amino esters in 80% yield when submitted to hydrogenolysis in acetic acid.
Ph Pd(OH)2, H2
EtOH, rt
N Ph NH ð38Þ
95% OH
CH2OH
Pd(OH)2, H2
Ph
AcOH, rt ð39Þ
N Ph NH
80% CO2Et
CO2Et
This reaction seems to be sensitive to the nitrogen-protecting group since the authors reported
that the cleavage of the CN bond failed when protecting groups other than methylbenzylamine
are present (tosyl, benzyl, or trityl).
The benzylic character of the CN bond is obviously at the origin of the observed selectivity in
the reductive opening of aziridines. A similar approach has been employed using polymethyl-
hydroxysiloxane (PMHS) as a soluble hydrogen source (Equations (40) and (41)) <1999TL9325>.
The benzylic-substituted aziridine shown in Equation (41) reacted similarly when a phenyl
substituent is present, but in lower yield.
Ts Pd/C, PMHS
N EtOH, rt O CO2Et
O ð40Þ
CO2Et 80% NHTs
O
O
Pd/C, PMHS
Ts
EtOH, rt ð41Þ
N
Ph NHTs
PhCH2 60%
The use of Raney-nickel has been reported to be effective for the stereoselective reductive
opening of trisubstituted aziridines (Equation (42)) <2002T7135>. Interestingly, retention/inver-
sion of configuration was observed and the reaction was solvent dependent. The best selectivity
was observed when t-butanol was used as the solvent (71% de).
Raney-Ni, H2
Ph Me NHR
ButOH, rt
3 CO2Me CO2Me
N Ph ð42Þ
R 77–89% Me
R = Ts or H 70–71% de
(iii) Use of single electron-transfer reagents

Samarium(II) iodide is known to effect the reductive cleavage of -heterosubstituted carbonyl
substrates such as epoxy- or cyclopropyl ketones. Recently, this reagent has been applied to
aziridino ketones and satisfactory yields of the corresponding -amino ketones were obtained
(Equation (43)) <1995JOC6660, 1997T8887>. Similar behavior for aziridine esters and aziridine
amides has been reported (N,N-dimethylethanolamine was used as proton source to prevent
regioselectivity problems). Amino protecting group tolerance has also been demonstrated for a
wide range of protection and even unprotected aziridines have been successfully reduced.
SmI2, MeOH
R3 O THF, 0 °C TsNH O
R2
R1 R2 R1 ð43Þ
TsN 78–95% R3
R1 = alkyl, R2, R3 = alkyl, Ph
More recently, the same transformation was realized using magnesium in methanol as a synthetically
useful and economic single-electron-transfer reagent (Equations (44) and (45)) <1998JOC10006>.
Mg, MeOH
Ph COMe –23 °C TsNH O
ð44Þ
Me Ph Me
N 98%
Ts Me
Mg, MeOH
Ph CN –23 °C TsNH
CN ð45Þ
N Ph
80%
Ts
1.02.1.2 Reduction of CN Double Bonds to Methylene and Methyl Groups

This section considers the reduction of systems (C¼N)X to methylene or methyl groups, where X
is carbon or nitrogen. Four distinct groups of substrates can be considered for the reduction of
double bonds: (a) tosylhydrazones derived from an aldehyde or a ketone, (b) hydrazones of
general formula C¼NNR1R2 where R1 or R2 are not arylsulfonyl groups, (c) imino com-
pounds of general formula C¼NR1R2, and (d) diazo compounds.
1.02.1.2.1 Reduction of tosylhydrazones

The conversion of tosylhydrazones into methylene groups has been investigated in a very detailed
fashion. Alkyl tosylhydrazides can undergo thermal decomposition, with or without basic cata-
lysis, through an alkyl diimide intermediate <1963JA1108>. Since alkyl tosylhydrazones are
easily obtained from the corresponding ketones or aldehydes, it has been proposed that a clean
reduction of the CN double bond would lead to the corresponding tosylhydrazides, and then
the decomposition of the latter should lead to the formation of a methylene group. In the absence
of a strong base, diimide represents the key intermediate rather than the diimide anion involved in
the Wolff–Kishner reaction (Scheme 3, path A). Reduction with LAH probably follows a
different pathway due to its highly basic character and the diimide anion should then be
considered as the key intermediate (Scheme 3, path B).
R R
NHTs NH
R N –MTs R N –N2
M–H
M path A
R R
NHTs R H
R N H
LAH R R H2O
R M N
R N –N2 R
N
R N Ts path B
H
Scheme 3
A whole series of tosylhydrazones—derived from both ketones and aldehydes (Equations (46)
and (47))—was reduced with sodium borohydride <1966T487>.
O NaBH4 O
O O
dioxane, reflux
H H ð46Þ
80%
H H H H
TsHNN
H H
NaBH4
dioxane, reflux ð47Þ
CH=NNHTs
Dodecane
9
70%
The reduction of tosylhydrazones can also be achieved with LAH and this reducing agent has been
used successfully in some natural product syntheses. A particular example is the tandem denitration/
deoxygenation of -nitroketones, which have been used for the synthesis of cis-9-tricosene, the sex
pheromone of the domestic housefly (Equations (48) and (49)) <1990JOC5159>.
TsHN LiAlH4
N
THF, 60 °C
n-C8H17 n-C8H17 ð48Þ
Ph(CH2)2 Ph(CH2)2
61%
NO2
TsHN LiAlH4
N
THF, 60 °C
Me 7 7 65% Me 7 7
NO2
Other reducing agents have been used to effect this transformation. One of them is a combina-
tion of sodium cyanoborohydride and zinc chloride (2:1), which has been utilized in the reduction
of various tosylhydrazones (Equation (50)) <1985JOC1927>. The same method was used to
produce disubstituted cyclohexanes with the aim of synthesizing aliphatic liquid crystals
(Equation (51)) <1988CB1039>.
NaBH3CN, ZnCl2
N NHTs MeOH, rt ð50Þ
Undecane
7
78%
Tos
HN NaBH3CN, ZnCl2
N MeOH, rt ð51Þ
Ph Ph
85%
A modification of the Wolff–Kishner reaction involving catecholborane as a mild reducing agent

for tosylhydrazones has been reported (Equation (52)) <1975JOC1834, 1979SC275>, and bis(ben-
zyloxy)borane has also been employed with some success (Equation (53)) <1981JOC1217>.
TsHN Catecholborane
N
Bu4NOAc, CHCl3, rt ð52Þ
94%
Ph(CO2)2BH
TsHN
N NaOAc, CHCl3, rt ð53Þ
CO2H 12
CO2H
96%
8 4
A modified copper borohydride, bis(triphenylphosphine)copper(I) tetrahydroborate, has been

reported to reduce efficiently a wide range of tosylhydrazones derived from ketones. Interestingly,
a modest conversion has been obtained with tosylhydrazones derived from aldehydes (Equation
(54)) <1980TL4031>.
Cu(PPH3)2BH4
CHCl3, reflux
ð54Þ
H 70%
H
H H H H
TsHN
N
1.02.1.2.2 Reduction of C¼NNR1R2 systems where R1 or R2 is alkyl, acyl, aryl, or hydrogen

This second type of reduction of CN double bonds is dominated by the Wolff–Kishner reaction
(Scheme 4). A ketone is transformed to the hydrazone and treated in situ with a strong base to
form an alkane and evolution of nitrogen is observed. The reaction was originally discovered in
1912 and has been comprehensively reviewed <1948OR(4)378, 1968AG(E)120>. Experimental
evidence for an sp3-hybridized carbanion intermediate has been reported <1992TL903>.
R OH R OH R –N2 R H2O R
NH2 NH N
R N R N R N R R
Scheme 4
The original reaction conditions have almost entirely been replaced by the Huang–Minlon
modification <1946JA2487> in which the reaction is carried out in diethylene glycol at reflux.
The method is not suitable for ,-unsaturated aldehydes or ketones (pyrazoline formation). For
sterically hindered ketones, a vigorous treatment with anhydrous hydrazine is required, which is
known as the Barton modification of the Wolff–Kishner reaction <1955JCS2056>.
This reaction is very useful and has been used in a great number of syntheses <2001S364,
1999JCS(P1)1265, 1993T2613> such as (–)-methyl kaur-16-en-19-oate (Equation (55))
<2000JOC4565> and in the synthesis of (+)-vincamine (Equation (56)) <1997JOC3890>. In
this latter example, and after extensive experimentations, the authors claimed that the best way to
reduce the ketone is the Wolff–Kishner reaction.
i. NH2NH2.H2O
diethylene glycol, 135 °C
O
ii. KOH, 200 °C
iii. HCl Me
Me
iv. CH2N2 ð55Þ
Me
Me
59%
H
H MeO2C
MeO2C
(–)-Methyl kaur-16-en-19-oate
i. NH2NH2.H2O
ethylene glycol, 160 °C
ii. KOH, 220 °C
O N iii. HCl O N ð56Þ
N N
H iv. CH2N2 H Vincamine
HO2C MeO2C
55%
O
In some cases, double-bond isomerization has been reported, but the use of additives such as
silver(I) carbonate completely suppresses such side reactions <1986TL4111>.
Microwave irradiation has been recommended to effect the reduction of a range of acetophe-
none and benzophenone derivatives in the presence of potassium hydroxide <1999SL1573>. The
reaction proceeds efficiently in excellent yields (75–97%) at atmospheric pressure within minutes
and in the absence of solvent. It is worth noting that under such conditions, methoxy, chloro, and
carbomethoxy groups are not affected.
In some specific cases, it has been shown that -keto-carbonyl compounds can be reduced
under milder conditions <1983JOC3866> or even without base <1994SC2835>. For the devel-
opment of a new synthesis of 2-oxindoles <1994SC2835>, an intramolecular deprotonation of the
intermediate hydrazone was invoked. Interestingly, very short reaction times are reported for this
transformation (15–30 min) (Equation (57)).
O NH2NH2.H2O
R1 R1
reflux
O O
N 92–76% N ð57Þ
R2 R2
R1 = H, OMe; R2 = Bn, H, Ph, Me
Several hydrazones derived from heterocyclic aldehydes (pyrrole, furan, and thiophene) have
been transformed to the corresponding methyl analogs by initial conversion into the semicarba-
zone followed by reduction using a strong base <1951JA4033, 1956JOC918, 1976T829>. Another
cyclic semicarbazone, which has been reduced to the corresponding alkane, is displayed in
Equation (58) <1959CB916>.
H
N N KOH HO ð58Þ
O O
88%
A further modification of the Wolff–Kishner reaction, named the Cram modification, involves
the slow addition of hydrazones to a solution of potassium t-butoxide in anhydrous dimethyl
sulfoxide at room temperature (Equation (59)) <1962JA1734> and the reduction of carbonyl
hydrazones in refluxing toluene with potassium t-butoxide is called the Henbest modification of
the Wolff–Kishner reaction <1963JCS1855>.
H2N
N KOBut
DMSO, rt ð59Þ
72%
An alternative method is the reduction of hydrazones derived from N-aminoaziridine with

LAH (Equations (60) and (61)). Unlike most other hydrazone reductions, this reaction proceeds
at room temperature under mild conditions, thus furnishing a mild pathway to the methylene
group <1991TL1691>. Several substrates have been examined and the reaction gives similar
yields to those reported when tosylhydrazones are employed.
Ph LiAlH4
THF, rt
Ph But ð60Þ
N
But N 81%
Ph LiAlH4
THF, rt O
Ph ð61Þ
O N
N 48% O
O
Another efficient method is the hydrogenation of benzylic hydrazones in the presence of

palladium on carbon (Pd/C) (Equations (62) and (63)) <1971JOC737>.
Pd/C, H2
H
N NH2 MeCO2H
N ð62Þ
Ph Ph
O 93%
Ph Ph
Pd/C, H2
H
N MeCO2H
N ð63Þ
Ph Me
94%
Ph Me
This method has also been used to reduce arylhydrazones derived from aldehydes to the
corresponding methyl compound <1958CB2383>.
1.02.1.2.3 Reduction of N-alkylimine type systems

Several methods for the deamination of N-alkylimines have been reported. The first one is an
extension of the Wolff–Kishner reduction mentioned in Section 1.02.1.2.2 (Equation (64))
<1966JCS(C)425>.
KOH, NH2NH2.H2O
N NH2
diethylene glycol, reflux
R ð64Þ
N 71–92% N R
H H
R = H, Me, Ph
Sodium borohydride in ethanol has also been used in the reduction of 2-hydroxydiarylimines to
the corresponding diarylmethanes (Equation (65)) <1985IJC(B)59>.
OH OH
NaBH4
ð65Þ
EtOH
Ph
N
74%
MeO OH MeO OH
Methyl-substituted resorcinols can be prepared by hydrogenation of arylimines in the presence

of a palladium catalyst (Equation (66)). However, the conditions employed are rather drastic
<1943HCA800>.
HO OH Pd/C, H2 (20 atm) HO OH

120 °C ð66Þ
N
Ph 62%
One isolated case has been reported where an imine was reduced to the corresponding
methylene compound by hydrogen sulfide in dimethylformamide at 20–65 C (Equation (67))
<1969M724>.
Bun H 2S, DMF

N H
H 65 °C N
N Ph Bun ð67Þ
Ph Bun
S
S
The methylimine of anisaldehyde was reduced to 1-methoxy-4-methylbenzene using

sodium telluride, but competitive reduction to the amine also occurred (Equation (68))
<1988TL2571>.
TeNaH, EtOH
Me Me Me
N reflux N
+ H ð68Þ
MeO MeO MeO
25%
75%
1.02.1.2.4 Reduction of diazo compounds

The reduction of the diazo group to the corresponding methylene group has been the subject of
scattered studies. The first reduction of ethyl diazoacetate with zinc in acetic acid was described
by Curtius in 1883, and in 1912 Wolff observed an indirect reduction of diazoacetophenone when
subjected to basic conditions <1943JA1516>.
In 1943, Wolfrom found that treatment of a diazomethyl ketone derivative of galactose with
aqueous hydrogen iodide led to the corresponding methyl ketone <1943JA1516>. Presumably,
the initially formed iodomethyl ketone is reduced to the saturated ketone under the reaction
conditions. This reaction is illustrated in Equation (69) <1999TA4745> and Equation (70)
<1986JOC2405>.
O Aq. HI O
50 °C
ð69Þ
O N2 89% O
O O
Z 48% HI Z
N O CHCl3, rt N O
O O ð70Þ
N2
O O
R R
R = H, Me, Prn, Ph
The reduction of diazoacetates has been reported using a catalytic amount of diethyl peroxy-
carbonate in isopropanol (Equation (71)) <1966TL3579>, or under hydrogenolysis conditions in
an autoclave at room temperature <1985JCS(P1)493>. Recently, these conditions have been
reported for the reduction of a diazoketone in order to correlate its absolute configuration with
a known -hydroxy ketone (Equation (72)) <1998T6867>.
CO2Et
O O
EtO2C
O PriOH, 50 °C O ð71Þ
N2
R 83–96% R Me
R = Ph, 4-(NO2)-C6H4, 4-(MeO)-C6H4
Pd/C, H2
O N2 EtOAc, rt O
O CH3 O CH3 ð72Þ
90%
OH O OH O
A better reducing system (in terms of yields) involving rhodium(II) acetate as the catalyst has
been reported <1979CC959>. This reagent is particularly useful for the synthesis of -keto esters
since it also catalyzes the oxidation of a neighboring hydroxyl group (Equations (73) and (74)).
The conditions are milder than the usual conditions employed for such a transformation (heating
in the presence of hydrogen chloride or vacuum pyrolysis) <1978JOC3983>.
Rh2(OAc)4
OH
DME, rt O ð73Þ
CO2Et
CO2Et
100%
N2
Rh2(OAc)4
OH
DME, rt O
CO2Et ð74Þ
Ph CO2Et
90% Ph
N2
This reaction has found widespread applications in the synthesis of -diketones

<1981JCS(P1)2566, 1992T8007>, particularly in the efficient synthesis of a precursor of tsuku-
baenolide (Equation (75)) <1988TL4481>.
N CO2Me Rh2(OAc)4 N CO2Me

N2 DME, rt
O O Tsukubaenolide ð75Þ
OH 100% O
OTBS OTBS
OMe OMe OMe OMe
Tributyltin hydride in the presence of copper(II) acetylacetonate has also been used to
reduce efficiently -diazoketones to the corresponding ketones (Equations (76) and (77))
<2000T7457>.
Bu3SnH, Cu(acac)2
O benzene, reflux O ð76Þ
N2
PhCH2 PhCH2
93%
Bu3SnH, Cu(acac)2
O hν, benzene, rt O ð77Þ
TsHN N2 TsHN
51%
Other reagents such as activated titanium, zirconium, or niobium metallocenes have

been shown to be effective catalysts for the reduction of -diazoketones (Equation (78))
<1990SL465>.
ML2
O
THF, rt O
N2
R1 R2
90–95% R1
R 2 ð78Þ
M = Ti, Zr, Nb R1 = Ph, Me

L = Cp, Cp* R2 = H, Me, Ph, MeCO, PhCO, CO2Et
1.02.1.3 Reduction of CN Triple Bonds to the Methyl Group

The direct substitution of a nitrile by a methyl group can be accomplished under different
conditions (e.g., an -amino nitrile treated with a methyl Grignard reagent). This transformation
related to a CC bond formation will not be discussed here.
Indeed, there are few conditions allowing the direct reduction of a nitrile to a methyl group.
The first one is a metal-mediated hydrogenolysis of aromatic nitriles and the second method is a
sequence including the partial reduction of a nitrile to an aldehyde followed by a Wolff–Kishner
reaction.
1.02.1.3.1 Reduction of nitriles using hydrogenolysis conditions

The direct reduction of a nitrile to the corresponding hydrocarbon is only observed with
arylcyanides under prolonged hydrogenation.
In one of the first examples, 4-aminobenzonitrile was heated under hydrogen at 330 C in the
presence of nickel oxide on a copper/silica support, to produce 4-aminotoluene <1959BCJ861>.
Using the same catalyst, the reduction of cinnamonitrile afforded propenylbenzene chemoselectively.
Some years later, several nitriles were reduced over a platinum/silica catalyst (Equation (79))
<1984JOC2875>. This method is the most powerful method for the NC bond cleavage since it
also reduces alkylnitriles to hydrocarbons while minimizing direct defunctionalization through
CC bond cleavage (see Section 1.02.3.1).
Pt /SiO2, H2
150 °C ð79Þ
CN Me
99%
Although the yields for this method were excellent in most cases, there are two major draw-
backs: (i) it requires a special flow apparatus, which for a one-off experiment would be prohibitive
and (ii) the catalyst requires a high percentage of platinum, thus making the method costly.
Sometimes, chemoselectivity is lost as illustrated by the reduction of benzonitrile that affords
mainly methylcyclohexane (Equation (80)). Another flow method was devised to reduce 1-cyano-
adamantane with aluminum oxide as support <1979AG(E)939>.
Pt /SiO2, H2
150 °C
CN Me + Me ð80Þ
75% 20%
The reduction of several nitriles using Raney-nickel has been also achieved (Equation (81))
<1980S802>. A dramatic decrease of chemoselectivity was observed when alkylnitriles were
tested: CC bond cleavage became the main pathway (as mentioned in Section 1.02.3.1.) except
for 1-adamantanecarbonitrile.
Ni/Al2O3, H2
Me 150 °C Me
ð81Þ
CN 92% Me
Similarly, various 2-cyanotriazines have been successfully reduced to the 2-methyltriazines

using Raney-nickel in acetic anhydride under 1 atm of hydrogen <1962JA3744>. When
3-cyano-2-(methylthioindole) was subjected to Raney-nickel in ethanol under reflux, it has been
reported that desulfurization accompanied the reduction of the nitrile group (65–89% yield)
<1987S846>.
Various cyanopyridines have been inadvertently reduced to the corresponding methylpyridine
using zirconium oxide in 2-propanol. The method requires high temperature (300 C) and the
yields are modest (30–50%) <1990CL311>.
Pioneering investigations examined the use of palladium with cyclic terpenes that functioned
both as solvent and hydrogen donor <1966CB227>. It was observed that aromatic nitriles were
readily reduced to the corresponding methyl compounds. Applications to multifunctional systems
have been reported (Equation (82)) <1974JMC434>.
NC Pd/C Me
p-Cymene
MeO O MeO O ð82Þ
CO2Et 87% CO2Et
NC AcHN Me AcHN
Ammonium formate has been employed as the source of hydrogen, using Pd/C as the catalyst
<1982S1036>. This represents a very useful reaction for the reduction of aromatic nitrile groups
to methyl groups (Equation (83)). Alkylnitriles were not reduced under these conditions.
Pd/C, HCO2NH4
MeOH, rt
Ar CN Ar Me
20–100% ð83Þ
Ar = 4-(MeO)-C6H4, 4-(OH)-C6H4, 3-(OH)-C6H4, 1-napthyl

2-naphthyl, 1-(4-(MeO)-naphthyl), 5-indolyl
1.02.1.3.2 Reduction of nitriles to methyl groups using hydride reagents

The direct reduction of an alkylnitrile to the corresponding hydrocarbon with a hydride reagent has
not been reported as of early 2000. However, it is possible to achieve such a transformation through
a two-step sequence. The first step is the partial reduction of the nitrile with an appropriate hydride
reagent into an aldehyde, and the second step is a Wolff–Kishner reduction of the aldehyde.
Such a process has been reported rarely but two selected examples are shown in Equation (84)
<1986T2429> and Equation (85) <1988JOC477>.
i. Red-Al, toluene
ii. NH2NH2.H2O, KOH
ð84Þ
82%
NC O OEt Me O OEt
i. DIBAL-H, benzene
ii. N2H4, K2CO3
CN OTMS Triethylene glycol OTMS ð85Þ
65%
1.02.2 REDUCTION OF CARBONPHOSPHORUS, ANTIMONY, AND BISMUTH

BONDS TO CARBONHYDROGEN BONDS
1.02.2.1 Reduction of CarbonPhosphorus Bonds

The reduction of CP bonds to one or two CH bonds can be achieved under basic or acidic
conditions, or by using hydride reagents.
1.02.2.1.1 Cleavage of CP bonds under basic conditions

The alkaline cleavage of quaternary phosphonium salts is a well-documented reaction, which repre-
sents one of the most important methods for preparing phosphine oxides. Hydrocarbons are the other
products of this reaction. The generally agreed mechanism is indicated in Scheme 5 based on
numerous investigations <B-1973MI003, 1978CJC1933, 1978JA7312, 1983JCS(P2)1923,
1986TL1209>. The order of displacement of groups attached to the phosphonium salt is allyl, benzyl
> phenyl > methyl > 2-phenylethyl > ethyl, higher alkyls <1991COS(8)858>.
Et Et OH Et
OH + Me P HO P O P
Ph Ph Ph Me Ph H2O Ph Me Ph
Et H2O
O P Me + CH2Ph PhMe + OH
Ph
Scheme 5
Interesting effects on the rate and the regioselectivity of the alkaline cleavage of quaternary
phosphonium salts are observed when o- or p-methoxy- or o- or p-dimethylamino-phenyl groups
are present in the molecule. For example, benzyl[2-(N,N-dimethylamino)phenyl]diphenylphospho-
nium bromide undergoes alkaline cleavage in dioxane/water (1/1) to give N,N-dimethylaniline
(96.5%), benzene (3.5%), and benzyldiphenylphosphine oxide (96%) 103 times more rapidly at
38 C than benzyl[4-(N,N-dimethylamino)phenyl]diphenylphosphonium bromide, which gives
only toluene as the hydrocarbon product (Equations (86) and (87)) <1987JOC4829>.
Ph Ph KOH, dioxane, H2O NMe2
P Ph 38 °C
Br + Ph POPh2 ð86Þ
NMe2 96%
KOH, dioxane, H2O NMe2

Ph Ph
P Ph 38 °C
Br + PhMe ð87Þ
100%
Me2N
POPh2
The cleavage of an allylphosphonium bromide with hydroxide or t-butoxide resulted in a 3:1

mixture of two triene isomers (Equation (88)) <1970JA2139>. A significant competition between
allyl and phenyl group as the leaving group is described.
Aq. NaOH or KOBut

+
ð88Þ
PPh3 Br
3:1
Alkaline hydrolysis of phosphorus ylides is a general method for the reductive cleavage of the
CP bond. Protonation of ylides affords a phosphonium hydroxide, which can react with
hydroxide and then decomposes into hydrocarbon and phosphine oxide. Among the four ligands
of the ylide, the ligand that is the most electronegative or the best stabilized as an anion is the best
leaving group (Equation (89)) <1991COS(8)858>.
R1 H2O R1 R1
PR33 PR33 OH R33P O + ð89Þ
R2 R2 R2
The hydrolysis of acetate 1 under basic conditions (KOH or NH4OH or KCN/alcoholic

solution) led to the quantitative formation of the phosphate 4. The sequence of reactions which
explain the formation of 4 involves: (a) hydrolysis of acetate 1 by hydroxide, (b) intramolecular
attack of alkoxide 2 onto the phosphonate, (c) fragmentation and formation of phosphate 3, and
(d) protonation (Scheme 6) <1997T2199, 1988JCS(P1)2971, 1985TL5713>.
O O O O O O
(EtO)2P (EtO)2P (EtO)2P
OAc O O
1 2
O O
P(OEt)2 H 2O P(OEt)2
O O
O O
4
3
Scheme 6
1.02.2.1.2 Cleavage of CP bonds under acidic conditions

The CP bond of simple phosphines is known to withstand the conditions of common organic
reactions. However, it was found that the CP bond to a carbonyl group is sensitive to cleavage
when treated in acidic conditions (Equation (90)) <1974JOC3423>. The mechanism of the cleavage
of these -carbonylphosphines presumably involves the attack of water on the protonated phosphine.
HCl, HCO2H
CO2Me reflux CO2H
P P ð90Þ
H3C H
CH3 71% O
1.02.2.1.3 Cleavage of CP bonds under neutral conditions

The reaction of a methylenetrimethylphosphorane with 1-t-butyl-2-vinylphosphirane produces
two phosphino-substituted phosphorus ylides in a ratio of 2:3 resulting from a ring-opening
and a proton transfer (Equation (91)) <1984T3273>.
Pentane, rt
P + H2C=PMe3 P + P
85% ð91Þ
Me3P Me3P
2:3
1.02.2.1.4 Cleavage of CP bonds with hydride

LAH has been employed for the cleavage of the CP bond <1957JA3567>. Dephosphonylation
of -ketophosphonates using LAH has recently been accomplished to afford the corresponding
ketones (Scheme 7) <1996JOC2199>. During the cleavage of the CP bond the hydride does not
attack the carbon linked to the phosphorus atom, as shown by the deuterium labeling but it seems
that an intermediate with a dianion character might be involved.
i. LiAlD4 O
Na ii. H3O
O O
O O 96%
(EtO)2P NaH, rt (EtO)2P
O
i. LiAlH4
ii. D3O
D D
Scheme 7
Lithium tri-t-butoxyaluminohydride (LiAl(OBut)3H) selectively cleaves the CP bond in the

presence of keto or ester functional groups (Equation (92)). It is worth noting that reduction of
the same type of compounds with sodium borohydride leads to the corresponding -hydroxyphos-
phonates and does not cleave the CP bond <1972JCS(P1)2582>.
LiAl(OBut)3H
O
CO2Et THF O
R
ð92Þ
CO2Et
P(OEt)2 R
O
1.02.2.1.5 Miscellaneous methods

Acylylides have been reduced successfully by aluminum amalgam with excellent yields <1964JA1639,
1982JOC4963>. The reductions were conducted typically with an excess of aluminum amalgam with
a periodical addition of either trifluoroacetic acid or hydrochloric acid (Equation (93)).
Al–Hg, wet THF
O O HCl or CF3CO2H
15–25 °C O O ð93Þ
O
O
PPh3 81%
1,5-Dienes can be prepared by reduction of substituted allylphosphonium salts by using

lithium–ethylamine (Equation (94)) <1970JA2139>. Tri-n-butylphosphonium salts were used
instead of triphenylphosphonium salts in order to avoid other competitive side reactions.
Bun3P Br
Li, ethylamine
–76 °C ð94Þ
65%
Zinc in the presence of acid has also been utilized for the reduction of phosphoranes <1955JA3230,
B1979MI102-01>. Photolysis has also been employed for the cleavage of CP bonds. Thus, under
photolysis p-nitrophenylmethylphosphonic acid undergoes CP bond scission in alkaline ethanol to
produce p-nitrotoluene, orthophosphate, and ethyl phosphate <1986BCJ1505, 986CC1516>.
1.02.2.2 Reduction of CAs Bonds

When compared with phosphorus, the reduction of CAs bonds to CH bonds has been severely
neglected. There are few examples of this type of reaction in the literature. An alkyl substituent on
the arsenic atom can be removed by addition of sodium in ammonia <1988JA4346>. The
example given in Equation (95) was carried out in an attempt to produce optically active
arsenic-containing macrocycles.
i. BunLi
OH ii. Na/NH3 OLi H OH ð95Þ
AsMe2 AsMeNa 93% AsMeH
A further example of the cleavage of a CAs bond is where an arsonium chloride derivative is
treated with hydrogen chloride to form -keto esters (Equation (96)) <1986MI261>.
O HCl O
Cl
Ph3As CH2Cl2, rt
OEt OEt ð96Þ
Ph O Ph O
1.02.2.3 Reduction of CSb Bonds

Stilbonium ylides having -electron-withdrawing groups have been prepared under mild condi-
tions by reaction between triphenylantimony and an appropriate diazo compound in the presence
of homogeneous copper catalyst <1986T3887>. These stilbonium ylides are stable in a dry
atmosphere but slowly decompose to give triphenylantimony oxide and the corresponding methy-
lene compound in protic solvents (Equation (97)) <1986T3887>.
O O
H2O
SbPh3 + O=SbPh3 ð97Þ
O O
Antimony compounds containing the Sb(CF3)2 group can lose this moiety on photolysis over
100 h <1988ZAAC(560)141>. As shown in Equation (98), trifluoromethylcyclohexane is formed
resulting from the simple replacement of Sb(CF3)2 by hydrogen.
Sb(CF3)2 hν , 100 h
ð98Þ
CF3 CF3
1.02.2.4 Reduction of CBi Bonds

Only one example of a CBi bond cleavage to give the corresponding hydrocarbon has been
described. Bis(diphenylbismutino)methane was synthesized in 1985 <1985CB1039>. It is possible
to remove one of the diphenylbismuth groups using phenyllithium. This leads to an anion which
produces the methyldiphenyl bismuthine after addition of methanol (Scheme 8).
PhLi
Ph2Bi BiPh2 Ph2Bi Li + BiPh3
–78 °C
MeOH, –78 °C
72%
Ph2BiMe
Scheme 8
1.02.3 REDUCTIVE CLEAVAGE OF CC BONDS TO CH BONDS

There are four types of reaction devoted to the reductive cleavage of a CC bond to a CH bond:
(a) the reductive cleavage of a nitrile, (b) the direct cleavage of an alkyl CC bond to give two
distinct hydrocarbons, (c) the decarboxylation of aliphatic carboxylic acids and derivatives, and
(d) the decarboxylation of carboxylic acids with electron-withdrawing groups at the -position.
1.02.3.1 Reductive Decyanation

There are two main methods for the cleavage of a nitrile to give the corresponding CH bond, namely
dissolving metals and radical conditions, which are accompanied by various miscellaneous methods.
1.02.3.1.1 Use of dissolving metals

The reduction of nitriles occurs with dissolved alkali metals in HMPA with t-butanol as the
proton source <1973BSF1174, 1975TL3851> or with sodium or lithium in ammonia
<1967JA6794, 1975JOC1162>. Such conditions have found wide synthetic applications as illu-
strated by the decyanation of an intermediate used in the synthesis of dihydroxyvitamin D3
(Equation (99)) <1997T4703> as well as an intermediate used in the synthesis of a galbulimima
alkaloid <2003JA2400> (Equation (100)).
CN Me OH
Me OH K, ButOH
Me Me
HMPA, Et2O, 0 °C
ð99Þ
94%
TBSO TBSO
MeO CN i. Li, NH3, –78 °C O

H
H ii. HCl, MeOH, THF H H
H H
ð100Þ
MOMO H 55% MOMO H
OMOM OMOM
A crown ether in combination with potassium in toluene has been reported to be an efficient
system for the reductive decyanation of alkylnitriles and disubstituted malononitriles (76–96%
yields) <1985TL6103>. However, excess potassium and crown ether are required for this
reaction.
1.02.3.1.2 Use of radical conditions

The discovery by accident of the reductive decyanation of malononitriles promoted by tributyltin
hydride has been reported <1990JA9401, 1991SL107>, but the scope of the reaction is restricted
to malononitriles. A mechanism was proposed where the tin radical adds first to the nitrogen
atom prior to fragmentation (Scheme 9).
SnBun3
NC N NC Bun3 SnH NC
CN + Bun Sn NC H
3 C
R1 R2 R1 R2 –Bu n3Sn 1
R R2
R1 R2
Scheme 9
After this report, a milder method using SmI2 has been described <1995TL7661> (Equation (101))
and applied to the decyanation of malononitriles and -cyano esters.
SmI2
R1 EWG THF/HMPA 0 °C or rt R1 EWG
CN ð101Þ
R2 51–99% R2
EWG = CN or CO2Et; R1 = Alkyl, ArCH2; R2 = H, Alkyl, ArCH2
1.02.3.1.3 Miscellaneous methods for reductive decyanation

More drastic conditions such as alkali fusion (KOH, 150 C, 55–95% yields) have been reported
to reduce CC bonds to CH bonds <1980SC939>. Although the method is absolutely cost
effective, the substrates that can stand these drastic conditions are limited to unfunctionalized
benzylic nitriles.
Potassium on alumina has been successfully evaluated as a reagent for the reductive cleavage of
alkylnitriles but the tedious preparation of the reagent restricts its utility (Equation (102))
<1980JOC3227>.
K/Al2O3
hexane, rt
R CN R H ð102Þ
70–91%
R = Functionalized primary, secondary, tertiary alkanes
More recently, a method involving electroreductive decyanation of alkylnitriles has been

devised and has led to efficient syntheses of the corresponding hydrocarbons (Equation (103))
<1992T8253>.
Zn cathode
Et4NOTs, DMF
+e ð103Þ
72%
CN
While nitriles can react with alkyllithium reagents to form ketones, decyanation of tertiary nitriles has
been observed in some cases in quantitative yields (Equation (104)) <1990JOC1479>. A strong solvent
effect is observed: in diethyl ether, the addition of methyllithium affords mainly the corresponding
methyl ketones. The authors invoked a four-membered transition state accompanied by an internal
hydride capture. Similar behavior has been noticed previously with a Grignard reagent <1952JA5793>.
Ar(CH2)n CN (CH2)n Ar
MeLi or BunLi
THF
100% ð104Þ
OMe OMe
n = 1,3
Ar = C6H4, 4-(C6H4)-C6H4, 4-(C6H4CH2O)-C6H4
Finally, malononitriles are prone to decarboxylation and are easily transformed into the
corresponding carboxylic acid when they are treated with potassium hydroxide in refluxing
ethylene glycol (Equation (105)) <2000AG(E)758>.
NC CN CO2H
KOH, ethylene glycol
reflux
ð105Þ
1.02.3.2 Cleavage of CC Bonds Where Both Products are Hydrocarbons
1.02.3.2.1 Dealkylation of alkylbenzenes

In general, reaction conditions are drastic and the molecules involved are simple. The dealkyla-
tion of xylene using alumina-supported rhodium is extremely efficient, giving toluene in 93% yield
(Equation (106)) <1971MI1567>.
Me Rh/Al2O3 Me
Me 430 °C ð106Þ
+ MeH
93%
Under rather drastic reaction conditions, toluene was converted into benzene (95%) using a cobalt/
molybdenum/alumina catalyst in the presence of sodium hydroxide at 560–600 C <1958IEC1677>.
A similar catalytic system, nickel/aluminum oxide, has been studied and various isomers of picoline,
cresol, and xylene were demethylated when heated around 400 C <1965MI39>.
1.02.3.2.2 Reductive cleavage of cyclopropylketones

Cyclopropanes are important synthetic intermediates due to their exceptional reactivity related to the
strained nature of such cyclic hydrocarbons. A variety of methods exist for the reductive cleavage of
cyclopropane conjugated to a ketone and the earlier approaches have been reviewed <1979AG(E)809>.
The palladium-catalyzed reductive cleavage of cyclopropylketones afforded the compound,
which results from preferential cleavage of the least substituted bond <1983TL681>. Such a
strategy has been used in a synthesis of clavukerin (Equation (107)) <1994TL1905>.
Me Pd2(dba)3CHCl3, Bun3P, Et3N Me

H H
CO2Me HCO2H, dioxane, rt
CO2Me
CO2Me
ð107Þ
CO2Me 95%
O O
90% de
Lithium in liquid ammonia results in the cleavage of the bond that overlaps most efficiently
with the -orbital of the carbonyl group and chromium(II)-induced cleavage is subject to subtle
stereoelectronic effects. Such conditions have been used to effect selective cleavage of bridged-ring
cyclopropyl ketones (Equations (108) and (109)) <1983TL681>.
O O
i. Li/NH3, ButOH
Me
ii. Pd/C, H2
ð108Þ
70%
CO2Me CO2Me
O O
CrSO4
DMF, H2O, rt
ð109Þ
84%
O O
Prolonged treatment of such cyclopropyl ketones with excess zinc and zinc chloride has been found
to be another important system for their reductive ring opening <1986JCS(P1)1445, 1975TL2489>.
In cyclopropylketones, samarium(II) iodide has been reported to promote reductive ring opening
of the cyclopropane under mild conditions in modest yields (39–49%) <1991TL6211>. Photoche-
mical electron transfer has also been reported to efficiently induce such ring opening. The reaction
proceeds cleanly for a wide range of substrates (Equation (110)) <1995T11751>.
CH3CN, Et3N O
O
CO2Me LiClO4, hν
CO2Me ð110Þ
80%
1.02.3.2.3 Reductive cleavage of other constrained cycloalkanes

1,2-Dibenzoyl cyclobutanes have been reported to undergo facile ring cleavage when treated with
zinc and zinc chloride in a protic solvent (Equation (111)) <1975TL2489>.
Zn, ZnCl2
COPh O
ethanol, reflux
Ph ð111Þ
Ph
COPh 80%
O
Similarly, strained cyclobutanes and cyclopentanes involved in a norbornyl system can be

reductively cleaved by using zinc in acetic acid or dissolving metals. This interesting reactivity
has been exploited in a synthetic approach to triquinanes (Equation (112)) <1985JOC5537> and
in a synthesis of vitamin D3 ring synthons (Equation (113)) <1990TL4899>.
i. Na–K alloy, toluene
Zn, AcOH ii. TMSCl, heat
))) iii. ButOH ð112Þ
90% 50% O O
O O
O O
Li/NH3 Me
Me CO2Me
THF, –78 °C Me
Me
Vitamine D3 ð113Þ
71%
MeO2C O
O
1.02.3.3 Reductive Decarboxylation of Aliphatic Carboxylic Acids, Esters, and Aldehydes

Unactivated aliphatic carboxylic acids generally undergo decarboxylation at a temperature
greater than 300 C. Many procedures have been developed to render this interesting reaction
more synthetically useful and to extend it to other carbonylated functionalities.
1.02.3.3.1 Decarboxylation of aliphatic carboxylic acids and esters
(i) Barton reductive decarboxylation of carboxylic acids

The Barton decarboxylation is a well-established reaction for the radical decarboxylation of
carboxylic acids to the corresponding nor-hydrocarbons under mild conditions (Equation (114))
<1983CC939, 1985T3901, 1992T2529>. In this radical process tributyltin hydride or t-butylthiol
as hydride donor can be used. The mechanism is described in Scheme 10.
i. DMAP (cat.) N
benzene NaO
ð114Þ
ii. Bu n3 SnH S
R COCl RH
44–95% overall
O
Bun3 SnH
R CO2H N R RH
R O –CO2 –Bun3Sn
S
Bun3Sn - N
S
SnBun3
Scheme 10
Such conditions have been utilized for a clean preparation of cubane (Equation (115))
<1995S501>, for a synthesis of complex 1-methylcarbapenem antibiotic precursor (Equation
(116)) <1994TA2137> and for a synthesis of sphingosines (Equation (117)) <1995S868>.
CO2H i, ii
HO2C 77%
ð115Þ
i. SOCl2, reflux
ii. 2-Mercaptopyridine N-oxide sodium salt, DMAP
THF, t-butylthiol, hν (250 W), reflux
CO2H Me
MeO MeO
SPr SPr
N N
O O O O
O i, ii O
58–60% ð116Þ
O O
O O
i. 2,2'-dithiopyridine-1,1'-di-N-oxide, PPh3, CH2Cl2, rt

ii. t-Butylthiol, hν (Xe lamp, 150 W)
OMs
O OMs
Ph O i, ii
O
Ph O
Me 82%
Me ð117Þ
HO2C
i. (COCl)2, Pyr., toluene, rt

ii. 2-Mercaptopyridine N-oxide sodium salt, DMAP, t-butylthiol, AIBN, toluene, 60–110 °C
(ii) Metal-mediated reductive decarboxylation of unactivated acids and esters

Photochemical decarboxylation of thallium(III) or lead(III) carboxylates has been reported, but invari-
ably a mixture of alkanes and alkenes was obtained <1968JOC75>. More recently, Ru3(CO)12 has been
found to be a more general catalyst (5 mol.%) for the decarboxylation of a broad range of
2-pyridylmethyl esters in good yields and especially aliphatic esters (76–78%) (Equation (118))
<2001JA4849>. A wide variety of functional groups is tolerated, thus making this reagent versatile.
Ru(CO)12
HCO2NH4
O
dioxane, 160 °C ð118Þ
O
N 76%
1.02.3.3.2 Reductive decarbonylation of aldehydes and acyl halides
(i) Metal-mediated decarbonylation of aldehydes

Decarbonylation of aldehydes to produce the corresponding hydrocarbon is a synthetically useful
reaction that can be achieved at high temperature by a free-radical chain reaction initiated
by peroxides <1963JA4010>. Alternatively, photochemical conditions can be employed
<1970JA4906, 1995JA10391>. However, the transition metal-catalyzed processes dominate the
recent developments in this area.
A palladium/polystyrene catalyst has been shown to be an effective catalyst for the decarbo-
nylation of docecanal to undecane (77%), but the reaction requires extended reaction time (60 h)
in refluxing toluene <1983JOC4179>.
Wilkinson’s catalyst RhCl(PPh3)3, was demonstrated to be an effective catalyst for the dec-
arbonylation of aliphatic aldehydes to the corresponding nor-hydrocarbons (Equations (119) and
(120)) <1965TL3969, 1968JA99>. However, the reaction is catalytic in rhodium only at high
temperature and thermal decomposition of the substrate can compete with the desired process.
RhCl(PPh3)3
benzene, rt ð119Þ
PriCHO Propane
83%
RhCl(PPh3)3
benzene, reflux ð120Þ
PhCH2CH2CHO PhCH2CH3
90%
The impossibility to regenerate the active species RhCl(PPh3)2 at lower temperature made it an
expensive process and led to the development of many other catalysts such as [Rh(dppe)2]Cl or
[Rh(dppp)2]Cl with improved catalytic activity at reasonable temperatures <1978JA7083>. Other
rhodium-based catalysts have been reported <1992JA2520>. A ruthenium–porphyrin complex
and an iron analog have been described as alternatives to the costly rhodium catalysts but these
catalysts involve radical mechanisms and thus suffer from substrate rearrangement and low
reproducibility <1980CC939>.
The decarbonylation of aldehydes was recently achieved at room temperature in THF with a
catalytic amount of Wilkinson’s catalyst (Equations (121) and (122)) <1992JOC5075>. The
process involves stoichiometric amount of diphenylphosphoryl azide (DPPA, a readily available,
nonexplosive azide used in peptide synthesis) to regenerate active rhodium species by carbon
monoxide abstraction from inactive RhCl(PPh3)2(CO).
Me Rh(PPh3)3Cl (5 mol.%) Me
CH2CHO DPPA, THF, rt Me

ð121Þ
99%
Me Me Me Me
Rh(PPh3)3Cl (5 mol.%)
CH2CHO Me
Me DPPA, THF, rt Me
Me Me ð122Þ
Me Me
90%
(ii) Free-radical decarbonylation

Direct free-radical decarbonylation of aldehydes was first developed by Berman <1963JA4010>, but
the conditions employed (high temperature, UV irradiation) limit the reaction to aldehydes that
decarbonylate faster than they react by alternative pathways. Specific photodecarbonylation of
,-unsaturated aldehydes has also been reported <1970JA4906>. Milder conditions involve the
decomposition of peroxides derived from aldehydes (Equation (123)) <1999CC139, 2000JOC3961>.
MeO
i, ii O iii
Alkyl-CHO Alkyl-H
Alkyl O 75%
ð123Þ
i. HC(OMe)3, PTSA; ii. CH2=CMeCMe2OOH, PTSA
iii. n-C12H25SH, BEt3/O2, cyclohexane, 80 °C
Alkyl = n-C11H23 or n-C9H19CHCH3
This process is particularly recommended when standard free-radical conditions led to side
reactions. As shown in Scheme 11, homolytic cleavage of the peroxide 5 affords deformylated
compound in 75% yield, while direct free-radical conditions used with the starting aldehyde are
known to afford a cyclized ketone.
1.02.3.3.3 Reductive cleavage of nonenolizables ketones

The base-induced CC bond cleavage of nonenolizable ketones to give a carboxylic acid deriva-
tive and a hydrocarbon is known as the Haller–Bauer reaction (Scheme 12). The direction of
cleavage is determined by the carbanion-stabilizing abilities of R1 and R2. The initial reaction
conditions involve sodium amide in boiling benzene or toluene, but other bases such as
n-C12H25SH
OMe Bz2O2
O cyclohexane, 80 °C CH3
O
O
75%
Scheme 11
hydroxides can be equally efficiently employed (sodium hydroxide, sodium methoxide, potassium
t-butoxide). The steric course of this reaction and recent synthetic applications have been
reviewed <1990OPP169, 2000T1399>.
O O NH2 O O
NH2
R1 R2 R1 + R1H +
R1 R2 H2N R2 H2N R2
Scheme 12
The synthetic utility of this transformation was illustrated in the synthesis of pumiliotoxin C where
norbornenone was selectively cleaved to produce a key intermediate (Equation (124)) <1995JOC279>.
Optimized conditions have been reported to prevent the isomerization of double bonds. Other applica-
tions are related to the controlled ring opening of bicyclo[2.2.2]octenones <2001TL1287>.
i. 1% aq. NaOH
O
benzene, rt MeO2C
H
H ii. CH2N2
ð124Þ
H
65%
H O
O
1.02.3.4 Reductive Decarboxylation of Activated Carboxylic Acids and Esters

The presence of an electron-withdrawing group at the -position of an acid or an ester drama-
tically enhances the ability for decarboxylation as shown by the Van der Baan method for the
homologation of carboxylic acids (Scheme 13) <1979S787, 1999JA7425>.
CO2TMS
Li
O CO2TMS O CO2TMS H2O O CO2H
R
Cl R CO2TMS 63–92% R
R = Alkyl, Bn, Ar
Scheme 13
1.02.3.4.1 Thermal decarboxylation of disubstituted malonic acids

Refluxing disubstituted malonic acids in aprotic solvent is a convenient procedure to achieve
decarboxylation. Simple reflux in dioxane <1999SL1371> or toluene <2001TL6015> generally
provides high yields of the corresponding carboxylic acid. Microwave heating was found to effect
rapid decarboxylation of malonic acids in water (190 C, 800 W, 15 min, 80–98%) <2000SC2099>.
Similarly, heating malonic acid derivatives in acetic acid <1995SC521, 2000JMC4868> led to
high yields of the corresponding acids. These conditions have found broad utility in organic
synthesis. It is worth noting that unusual stereoselective decarboxylation has been reported as a
key reaction in an industrial synthesis of carbapenem antibiotic (Equation (125)) <1995JOC8367>.
TBDMSO Me HCO2H, EtOAc TBDMSO Me

H CO2H HH
Me CO2H 80 °C Me CO2H
N N ð125Þ
O TBDMS O TBDMS
88% de
From extensive computational studies, the authors concluded that the selectivity observed was
derived from a kinetically controlled protonation of the intermediate ketene acetal.
1.02.3.4.2 Nucleophile-mediated decarboxylation of malono esters

The decarboxylation of an activated ester (malonates, -keto esters, -cyano esters, -sulfonyl esters)
usually involves heating of the substrate in a dipolar aprotic solvent at high temperature in the
presence of nucleophiles such as water, halides, cyanides, acetates, t-butoxides, thiocyanates, amines,
or thiolates. Reports in the literature describe countless examples of such useful transformations.
(i) Use of cyanide or halide nucleophiles

The use of nucleophiles such as cyanides or halides in hot dimethyl sulfoxide to decarboxylate an
activated ester is named the Krapcho reaction. This well-known reaction has been widely exploited.
The scope and limitations have been reported by Krapcho <1978JOC138> and a review covering the
range of synthetic applications of this useful reaction has been published <1982S805, 1982S893>.
Recent applications are illustrated by a successful decarboxylation leading to a synthesis of
methyl ()-jasmonate (Equation (126)) <1992SC1283> and an efficient preparation of an inter-
mediate involved in a synthesis of a chiral bicyclic amidine (Equation (127)) <1995TL4279>.
O NaCl, wet DMSO O
CO2Me
180 °C
ð126Þ
78%
CO2Me CO2Me
Methyl (±)-jasmonate
NaCN, DMSO
N CN 160 °C N
ð127Þ
Ph Ph
CO2Et 72% CN
Ph Ph
(ii) Use of other nucleophiles

Other weak nucleophiles catalyze the decarboxylation reaction of activated esters such as
N-methylmorpholine <1997BMCL2299>, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), or diazabicy-
clooctane (DABCO) <1976JOC208>. Recently, the use of Triton B has been described to be
an efficient reagent for the mild decarboxylation of malonates (Equation (128)) <1998SC4179>.
Triton B
DMSO, 50–80 °C
R CO2Et R CO2H
ð128Þ
CO2Et 65–81%
R = H, Alkyl, Ph, Bz
Naproxen has been prepared enantioselectively using a cinchona-alkaloid-mediated enantio-

selective decarboxylation as the key step (Equation (129)) <2000EJO2119, 2002EJO2405>.
Cinchona alkaloid
CN 10 mol.% CN
Me THF, rt
CO2Et Me ð129Þ
MeO MeO
(±) (+)
70% ee
The use of p-aminothiophenolate (PATP) and catalytic quantities of caesium carbonate in DMF
has been described to afford better yields than Krapcho procedure for the decarboxylation of
activated methyl esters. The reported process uses shorter reaction time and lower temperatures
relative to the original Krapcho conditions (Equations (130) and (131)) <1986JOC3165>.
PATP, Cs2CO3
O O
Me DMF, 85 °C ð130Þ
Ph CH2Ph Ph Me
CO2Me 100% CH2Ph
PATP, Cs2CO3
CN DMF, 85 °C CN ð131Þ
Ph Ph
CO2Me 86%
1.02.3.4.3 Metal-mediated decarboxylation of activated acids and esters

Quinoline/copper is a classical system for the decarboxylation of ,-unsaturated acids and
malonic acids and have found some recent applications <1995JMC923>. An optimized copper
catalyst has been reported to afford a mild and quantitative process for the selective decarbox-
ylation of malonic acids. The low temperatures employed improve the yields (Equation (132))
<1984T3229, 1986S1029>. Some transfer of chirality (ee up to 31%) has been observed when
such conditions have been used in the presence of cinchona alkaloid <1987TL539>.
Cu2O 5%
CH3CN
R1 65 °C, reflux R1
CO2H CO2H ð132Þ
CO2H
95–98%
R2 R2
1 2
R = alkyl, H; R = alkyl, Ar
Recently, a tungsten-based complex <1993JA4675> was found to be an effective catalyst for

the decarboxylation of cyanoacetic acid under mild conditions but shows little improvement
against the former copper catalyst.
Palladium-catalyzed deprotection–decarboxylation is a mild and nearly neutral method for the
decarboxylation of activated allyl esters as illustrated by Equation (133) <1985JOC3416>.
Pd(OAc)2, PPh3
O O
CO2 HCO2HNEt3, THF, rt
CO2Me CO2Me ð133Þ
92%
Decarboxylation followed by asymmetric protonation of the intermediate enol has been

observed when subjecting an -keto ester to hydrogenolysis conditions in the presence of a
Cinchona alkaloid (Equation (134)) <2001CC533>.
Pd/C, H2
Cinchona alkaloid
O O O
MeCN or AcOEt
Ph ð134Þ
Ph O Ph Ph *
Me Ph 100%
Me
ee up to 71%

Decarboxylation is a well-known metabolic process for activated carboxylic acid derivatives such
as amino acids. Interestingly, this reaction has been successfully applied to the enantioselective
decarboxylation of malonates (Equation (135)) <1990JA4077>. This procedure is a useful new
entry for the preparation of chiral-substituted benzylic esters.
i. Alcaligenes
bronchisepticus
CO2H ii. CH2N2 Me
CO2H ð135Þ
Ar Ar CO2Me
Me 48–98%
91–99% ee
1.02.4 REDUCTION OF CARBONBORON, SILICON, AND GERMANIUM BONDS

TO CARBONHYDROGEN BONDS
1.02.4.1 Reduction of CarbonBoron Bonds to Hydrocarbons

The cleavage of CB bonds can be effected under various conditions, namely acidic, neutral, or
basic conditions.
1.02.4.1.1 Cleavage of carbonboron bonds under acidic conditions

The use of acids in CB bond cleavage was systematically studied in 1986 <1986T5497>. Trialkylbor-
anes are inert toward water or strong mineral acids with the exception of anhydrous hydrogen fluoride
(Equation (136)). For example, hydrogen bromide reacts slowly and incompletely (Equation (137)).
rt
R3B + 3HF 3RH + BF3
ð136Þ
R = Me, Et, Pri
55–60 °C
Bun3B + HBr Bun3H + Bun2BBr ð137Þ
Organoboranes react readily with carboxylic acids to liberate the corresponding alkanes
(Equation (138)) <1986T5497, 1984JOM(260)17, 1984JOM(270)9>. The steric requirements of
the alkyl groups attached to boron play an important role in the rates of protonolysis. The first
alkyl group of a trialkylborane is protonolyzed easily, followed by increased difficulty in the
removal of the second and third alkyl groups.
Me 225 °C
CO2H ð138Þ
Me +
B 16
MeO 71%
This property has been successfully used in the preparation of a secondary alcohol through the
selective protonolysis of a primary CB bond with acetic acid, followed by an oxidation step
(Equation (139)) <1998JOC8276>.
H
H
i. CH3COOH
B ð139Þ
H
ii. [O] OH
H
Protonolysis of the organoboranes with carboxylic acids involves coordination of the carbonyl
oxygen atom to the boron atom, followed by an easy intramolecular proton transfer (Equation
(140)) <1986T5497>.
R
R2B
H O
O O RH + R 2B ð140Þ
O R1
R1
Replacement of an alkyl group by an acyloxy group renders the boron atom less electrophilic,
and explains why the acyloxyboron intermediates become progressively less reactive toward
acidolysis <1986T5497>.
The stereochemistry of the protonolysis was established via deuterioboration of norbornene
and deuterolysis of the product. Protonolysis occurs with retention of configuration at the carbon
atom originally attached to boron (Equation (141)) <1986T5497>.
i. BD3
ii. EtCO2D ð141Þ
D
42% D
The protonolysis reaction tolerates functionalities such as halides or ether groups in the
alkylboranes <1986T5497>. However, systems that are intrinsically labile to either acid or heat
may be problematic. For example, enantiomerically pure d-limonene produces the racemic
1-menthene under hydroboration–protonolysis (Scheme 14) <1986T5497>.
MeCO2H
Sia2BH 100 °C
68%
Sia2B
(+)-Limonene (±)-1-Menthene
Scheme 14
1.02.4.1.2 Cleavage of carbonboron bonds under neutral conditions

Several organoboranes have been cleaved by alcohols. An interesting example of this process is
the use of the cyclic polyol octahydroxycyclobutane <1983CB1336>. When a suspension of the
cyclic polyol in mesitylene reacted with triethylborane (activated with diethylboryl pivalate),
8 equiv. of ethane were released and the product was formed (Equation (142)).
Et Et
B B
O O
HO OH BEt3, toluene
reflux O O O O
HO OHHO OH + 8EtH ð142Þ
90% B
O O
HO OH Et
B
Et
1.02.4.1.3 Cleavage of carbonboron bonds with base

Cleavage of organoboranes can also be achieved with potassium hydroxide. An example is given
below (Equation (143)) <1982JOM(226)115>.
KOH, 180 °C
MeO B ð143Þ
75%
1.02.4.2 Reduction of CarbonSilicon Bonds

There are a plethora of methods for the cleavage of CSi bonds to give CH bonds, ranging
from the use of acid or base to thermolysis.
1.02.4.2.1 Cleavage by acid

Acids have been used on several occasions for desilylation. Cleavage of an alkyl silicon bond
using concentrated sulfuric acid was first reported in 1910 <1980JPR503> and has since been
used with functionalized organosilicon compounds (Equation (144)).
Et
H2SO4, H2O Si Prn
Et
Si Prn O + MeH ð144Þ
Me Si Prn
Et
Trifluoroacetic acid has also been used to cleave CSi bonds. Trifluoroacetic acid selectively
cleaves specifically the alkyl silicon bond in preference to the vinylsilicon bond, but the yield is
very poor (Equation (145)) <1981ZOB420>.
CF3CO2H
Si Si Si ð145Þ
14%
The cleavage of the CSi bond by electrophilic reagents such as Lewis acids is well established
in organosilicon chemistry (Equation (146)) <1983ZOB806>. In some cases a Lewis acid is used
in conjunction with hydrogen halides (Equation (147)) <1980JPR503>.
AlBr3 ð146Þ
Et3SiH EtH
AlCl3 ð147Þ
Me4Si + HCl TMS-Cl + MeH
Simple -trimethylsilylketones can be desilylated in ethanol to give the corresponding ketone

(Equation (148)) <1970MI355>. Hydrogen chloride was required for the cleavage of
-trimethylsilyl esters (Equation (149)).
TMS EtOH
+ TMS-OEt ð148Þ
O O
OEt HCl OEt

TMS + TMS-Cl ð149Þ
O O
1.02.4.2.2 Cleavage by base

There have been several reports that show the cleavage of a CSi bond to give a CH bond
using a base. One of the earliest of these reports showed that tetramethylsilane could be cleaved
by potassium t-butoxide in dimethyl sulfoxide (Equation 150) <1967JOC4126>.
DMSO, rt ð150Þ
Me4Si + ButOK ButOSiMe3 + CH4
Unactivated hydroxysilanes can undergo protodesilylation when treated with potassium

t-butoxide in aqueous DMSO. Water was used as the proton source to favor formation of the
protodesilylation product. Under these conditions, no racemization is observed (Equation (151))
<1986JA6826, 1982JA6809>.
OBut
OBut
KOBut, DMSO
ð151Þ
O H 70% HO H
Si
Fluoride-induced hydrodesilylations presumably involve carbanion or radical intermediates and

have been widely used (Equations (152) and (153)) <2000JOC7033, 1999JOC2776, 2001JOC4841,
1992JA7578, 1999EJO1939, 1995CRV1253>.
N N
TBAF, THF, rt
O SiMe3 O ð152Þ
Me 99% Me
But
But HO
O Si OBn
H TBAF, DMF, 60 °C
ð153Þ
H OBn
OH
OH
Protodesilylation is sensitive to subtle structural variations. When a neighboring hydroxyl

group is not protected, no reaction takes place even when the mixture is stirred at 25 C. This
may be attributed to a facile equilibrium between the two corresponding siloxanes, which on
average could be viewed as a hypervalent siloxane complex (Equation (154)). When the alcohol is
protected, TBAF-mediated protodesilylation occurs readily (Equation (155)) <1992JOC1643>.
O Si TBAF
O
OH HO Si
H H ð154Þ
Fast
Me Me Me Me
Me
O Si Me TBAF, DMF, 25 °C
OH
OBn ð155Þ
OBn 95%
Me Me Me
Me
The desilylation of -silylcarbonyl compounds can be achieved at room temperature by treat-

ment with tetrabutylammonium fluoride in THF, since the intermediate carbanion is stabilized as
an enolate (Equation (156)) <1998JCS(P1)1373, 1995JOC7334>. However, sometimes this desi-
lylation is accompanied by racemization, due to the formation of basic Bun4NOH. This problem
was solved by the addition of solid ammonium fluoride used as a buffer and by carrying out the
reaction at low temperature to control the rate of formation of the base (Equation (157))
<1996AG(E)981, 1997AG(E)2362, 2000SL644>.
O TBAF, THF O
OH O OH O
–90 °C
R R
CH3(CH2)6 CH3(CH2)6 ð156Þ
H SiMe3 56–93% H H
R = (CH2)7CH(CH3)2, (CH2)9CH3, (CH2)11CH3
O TBAF, NH4F, THF O

R –70 °C to rt R ð157Þ
NBn2 NBn2
t-HexMe2Si CH3 98% CH3
Desilylation of 6 could be achieved with caesium fluoride in wet THF (Equation (158)), but
potassium hydrogen fluoride in DMF was required for 7 (Equation (159)). Other methods, such
as KF/18-crown-6 or tetrabutylammonium fluoride in THF, were unsuccessful <1999EJO1939>.
CsF, THF
COOMe
Si H2O, 40 °C HO
O
COOMe ð158Þ
H 79% H Me
Me
6
KHF2, DMF
COOMe
Si 70 °C HO
O
COOMe ð159Þ
Me 63% Me Me
Me
7
1.02.4.2.3 Desilylation by miscellaneous methods

Supercritical water (scH2O), the critical temperature and pressure of which are 374 C and 22.1
MPa, respectively, has recently been used to cleave the CSi bond of a wide range of organo-
silicon compounds (Equation (160)) <2003JA6058>.
Supercritical water
R SiMe2X R H
ð160Þ
R = aryl, alkenyl, allyl, and alkyl
X = OH, Cl, OEt, OSiR3, SiMe3, Me
When a benzene solution of cyclopentadienyl t-butoxydimethylsilane was heated in a sealed

tube at 100 C in the presence of a catalytic amount of anhydrous cupric sulfate, the correspond-
ing cyclopentadiene was obtained in 96% yield (Equation (161)) <1985OM584>.
Ph MeOH, CuSO4 Ph
Ph Ph
H 100 °C H
ð161Þ
SiMe2 H
Ph t 96% Ph
Ph OBu Ph
1.02.4.3 Cleavage of CarbonGermanium Bonds to CarbonHydrogen Bonds

Some work has been carried out to investigate the addition of alkoxides to carbon suboxide
<1988G577>. When germanium alkoxides are exposed to carbon suboxide, a germanium mal-
onate is formed. The CGe bond is cleaved by addition of water to form dimethyl malonate and
BunGeOH (Scheme 15).
C3O2 + 2Bun3GeOMe (Bun3Ge)2C(CO2Me)2
(Bun3Ge)2C(CO2Me)2 + 2H2O H2C(CO2Me)2 + 2BunGeOH
Scheme 15
1.02.5 REDUCTION OF CARBONMETAL BONDS TO CARBONHYDROGEN BONDS

The reduction of CHg bonds is the most common process. The reduction of other
carbonmetal bonds (where the metal is an alkali or alkali earth metal) to a CH bond usually
involves the reaction with a proton donor, such as water or acid.
1.02.5.1 Reduction of CHg Bonds

The reduction of CHg bond consists mainly in protonolysis and metal hydride reductive
demercuration. In addition, a few miscellaneous reactions will be discussed.
1.02.5.1.1 Protonolysis
The protonolysis of organomercurials has been studied extensively. The organomercurials are
easy to prepare in high purity and easy to handle. These properties make them ideal candidates
for mechanistic studies on the protonolysis of carbonmetal bonds, and several reviews
<1968PAC79, 1978T2827> and an article <1984JA3703> have been written on this topic.
As one could expect there are several mechanisms for the protonolysis reaction. The proto-
nolysis reaction of an alkyl mercury halide with hydrochloric acid proceeds through a four-center
transition state according to Scheme 16 <1968PAC79>.
R Hg X R Hg X
RHgX + HCl RH + HgXCl
H Cl
H Cl
Scheme 16
The intramolecular nucleophilic participation of the chloride conjugate base is arguable. There
is evidence, based on studies of protonolysis of unsymmetrical alkyl mercurials, which suggests a
three-center transition state <1969JCS(B)1071>. Whatever the transition state, further reaction
occurs by front side attack on the carbon center, forming a transition state containing a
pentacoordinate carbon atom <1984JA3703>. There are some reports on unimolecular SE1
reactions <1968PAC79, 1969JCS(B)1071>.
The CHg bonds are generally stable to water and alcohols, and thus the protonolysis of these
bonds requires stronger acids such as hydrochloric acid or sulfuric acid. Carboxylic acids are
much less effective. In general the acid cleavage of dialkylmercurials is much easier than that of
alkylmercuric salts. Alkyl–mercury bonds are cleaved less readily than aryl–mercury bonds
<B-1980MI004>.
1.02.5.1.2 Metal hydride demercuration

Sodium borohydride has been widely used to reduce organomercurials to produce the correspond-
ing hydrocarbons. The mechanism involving the reduction of the organomercurials with sodium
borohydride is believed to be a free radical process as shown in Scheme 17 <1976JA5973,
1984TL5239, B-1985MI006, 1991COS(8)850>.
NaBH4
RHgX RHgH + NaBH3X
R + RHgH RH + RHg
RHg R + Hg
Scheme 17
Reduction of exo- and endo-norbornylmercury(II) bromide with sodium borodeuteride pro-

vides exo-[2-D]norbornane as the major product (Equation (162)) <1970JA6611>. Other exam-
ples of this phenomenon can be found in the literature <1981JOC563>.
NaBD4
+
96% D ð162Þ
HgBr D
endo or exo 10:90
The diastereoselectivity in metal hydride demercuration of -mercury(II) carbonyl com-

pounds depends on the nature of the solvent, the amount of hydride used, the mode of
addition, the nature of the hydride source, and the ligand on mercury (Equation (163))
<1986JOC2024>.
HS(CH2)2SH
Me Me Me
HgOAc EtOH, 0 °C
Me Me Me
CO2Me CO2Me + CO2Me ð163Þ
OMe 99% OMe OMe
95:5
A frequent problem associated with the reductive demercuration of organomercurial com-

pounds is deoxymercuration, which would result in the isolation of alkenes. This is often
minimized by using alkaline borohydride (Equation (164)) <1984T2317, 1966JA993,
1983TL4923, 1997T2835, 2001T9915>. Alkaline borohydride in the demercuration of peroxy-
mercurials has also been accomplished (Equation (165)) <1992CC428, 1992CC926, 1992T3835,
1993T2729>.
O NaBH4, MeOH O
O NaOH, 0 °C HO2C
O +
ð164Þ
H H
HgOAc
85% 15%
R H R H
NaBH4, NaOH
O O O O ð165Þ
O 50–75% O
BrHg
Phase-transfer reagents are sometimes used to avoid deoxymercuration and other side reactions
(Equation (166)) <1986CC855, 1979S891, 1984JOC2838>.
HgCl NaBH4, PhNEt3Cl

O H2O, CH2Cl2 O
ClHg ð166Þ
O >90% O
Reductive demercurations using an excess of sodium borohydride in DMF without sodium

hydroxide have been reported to give good results (Equation (167)) <1997JOC5267>. However,
it seems that it is not a general method for the reduction of CHg bonds.
O Excess NaBH4 O
O O O O O O
HO DMF HO
ClHgCH2 AcHN AcHN ð167Þ
OBn OBn
O 79% O
OBn OBn
BnO OBn BnO OBn
Zinc borohydride has been successfully used for reductive demercuration to give desired
product as a milder reducing agent compared to alkaline borohydride, which resulted in
the isolation of the starting alkenes used prior to mercury addition (Equation (168))
<1992SC3013>.
HgOAc
H Zn(BH4)2, DME, rt H H
H
O O ð168Þ
71%
O O O O
A number of demercurations also use tributyltin hydride (Equation (169)) <2002AG(E)2144,

2001TA597, 2001OL2567, 1996JOC2109, 1984T2317, 1983JA6882>, or triphenyltin hydride
<1984JA8313, 1996CAR69>, but complete removal of tin residues can be difficult. As with
sodium borohydride, there is also a problem with competitive deoxymercuration when tin
hydrides are used <1984T2317>. The presence of sodium acetate prevents this problem if
triphenyltin hydride is employed (Equation (170)) <1984JA8313, 1996CAR69>.
Bu3SnH, toluene, THF

O
rt to 60 °C then CCl4 O
BzO ð169Þ
O OH BzO
H H O OH
85% H H
HgBr
OMe Ph3SnH, AcONa OMe

HO OH BnO HO OH BnO
BnO BnO BnO BnO
Toluene, rt, 3 h
BnO O BnO O
O O ð170Þ
BnO O 90% BnO O
ClHg
CO2Me CO2Me
LAH has been used as the reducing agent in demercuration (Equation (171)) <1999JOC101,
1983JA6882, 1986JA2094, 1997JOC4653>. Methylmercurio derivatives RHgMe are stable
toward a number of hydrides (NaBH4, LiAl(OBut)3H, L-selectride, or superhydride) and the
halomercurio functionality can be regenerated by treatment with HgCl2 or HgBr2. Alternatively,
LAH gave the fully reduced product (Scheme 18) <1999JOC101>.
HgCl
LiAlH4, THF, 0 °C
OH ð171Þ
OH HO
HO
86% OBn
OBn
“H ” MeHg HO
see text
H
MeHg O LiAlH4
HO
Scheme 18
The reduction of organomercury(II) halides with LAH has been investigated and the findings
suggest an electron-transfer mechanism involving attack of the alkyl radical on the metal hydride
(Scheme 19) <1983TL1411>.
R + AlH4 RH + AlH3
AlH3 + RHgX AlH3 + R + Hg + X
Scheme 19

Although sodium borohydride is most often employed for the reduction of CHg bonds, there
has been a significant increase in the use of other reducing reagents such as thiols and sodium
amalgam (vide infra). Reduction with hydrogen sulfide <1984JCS(P1)1689>, sodium dithionite
<1979JOC228>, metals <1980JA337, 1992CC1086>, Wilkinson’s catalyst <1980JA337>, and
electrochemical reductions have also been reported <1985JOC673>.
Organomercurials react with thiols by a free-radical substitution mechanism <1983JA1398>. A
limitation in the use of certain thiol reagents is, as for most reagents used for demercuration,
competitive deoxymercuration.
The sodium amalgam cleavage of alkylmercurials involves an ionic mechanism
<1972JOC4341>. The reaction is also stereospecific with retention of configuration at the carbon
center. No rearrangement was observed in the rearrangement-prone nortricyclyl–norbornenyl
system (Equation (172)) <1981JOC563>.
AcO Na–Hg HO
HgCl D ð172Þ
D2O, NaOD
The latest addition to the numerous reagents for reduction of mercurials is N-benzyl-1,4-
dihydronicotinamide (BNAH), which is proposed to reduce CHg bonds via an electron-transfer
chain substitution mechanism <1981TL4495>.
1.02.5.2 Cleavage of Other Metals from Carbon to Give a CH Bond
1.02.5.2.1 Protonolysis
There are many carbonmetal bonds, which can be reduced on addition of a proton donor to the
reaction. The CAl bond can be readily cleaved on addition of HX (where X is a hydroxyl or
alkoxyl group, etc.) to give the corresponding hydrocarbon <B-1972MI002>.
In general, all organometallic compounds of type RM (where R is lithium, sodium, or
potassium) and of type RMgX (where X is halogen) will undergo protonolysis readily, if not
violently, when they come into contact with a proton donor <B-80MI004>.
The CSn bond is very susceptible to protonolysis. Water and aliphatic alcohols are generally
inert, but phenols, mercaptans, and carboxylic acids readily cleave the CSn bond to give a CH
bond (Equation (173)) <B-80MI004>.
HX
R1 SnR23 R1H + XSnR23 ð173Þ
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Biographical sketch
Jérôme Blanchet was born in Versailles in Yanxing Jia was born in Baoding, People’s
1975. He studied chemistry at the Ecole Republic of China, in 1975. He received his
Nationale Supérieure de Chimie de Cler- B.Sc. from Lanzhou University in 1997. He
mont-Ferrand. He joined the research group subsequently joined the research group of
of Professor Henri-Philippe Husson (Univer- Professor Yongqiang Tu (Lanzhou Univer-
sity Paris-V) where he obtained his Ph.D. in sity) where he obtained his Ph.D. in 2002.
2001 under the guidance of Dr. Martine Now he is a postdoctoral fellow in the Jieping
Bonin and Dr. Laurent Micouin. He was a Zhu research group at the Institut de Chimie
one-year postdoctoral fellow in the Victor des Substances Naturelles (Gif sur Yvette,
Snieckus Group at Queens University (King- France). His research interests include natural
ston, ON), in the Jean-Charles Quirion Group products synthesis and synthesis of biologi-
at the Institut de Recherche en Chimie Orga- cally active compounds.
nique Fine (Rouen, France), and in the Jiep-
ing Zhu research group at the Institut de
Chimie des Substances Naturelles (Gif sur
Yvette, France). He obtained a permanent
position at CNRS in 2004 as Chargé de
Recherche. His research interest encompasses
the development of methodology including
the organoaluminum chemistry and the direc-
ted ortho-metallation (DoM) of aromatic
compounds.
Jieping Zhu, Director of Research at CNRS, was born in 1965 in

Hangzhou, People’s Republic of China. He received his B.Sc. degree
from Hanzhou Normal University in 1984 and M.Sc. degree from
Lanzhou University in 1987 under the supervision of Professor Y.-L.
Li. In 1988, he moved to France and obtained his Ph.D. degree in 1991
from Université Paris XI under the supervision of Professor H.-P.
Husson. After one and half year postdoctoral stay with Professor Sir
D. H. R. Barton at Texas A&M University in USA, he joined Institut de
Chimie des Substances Naturelles, CNRS in December 1992. His work
has been recognized with the award of the CNRS bronze medal (1996),
the French Chemical Society SFC-Across award (1999), the AstraZeneca
Award in Organic Chemistry (UK, 2002), the Japan Society for Promo-
tion of Science (JSPS) Senior Research Fellow (2002), Prix ‘‘EMILE
JUNGFLEISCH’’ of French Academy of Sciences (2003), National
Science Foundation Outstanding Young Overseas Scientist award
(China, 2003), and the Liebig Lectureship of the German Chemical
Society (2004).
1.03
Two or More CH Bond(s) Formed
by Addition to CC Multiple Bonds
L. MICOUIN
CNRS, Paris, France
1.03.1 REDUCTION OF ALKENES 79

1.03.1.1 General Methods for Alkene Reduction 79
1.03.1.2 Reduction of Alkyl-substituted Alkenes 85
1.03.1.3 Reduction of Alkenyl-, Aryl-, Heteroaryl-, and Alkynyl-substituted Alkenes 87
1.03.1.4 Reduction of Heteroalkyl-substituted Alkenes 91
1.03.1.5 Reduction of Remotely Substituted Alkenes 95
1.03.2 REDUCTION OF ARENES AND HETEROARENES 99
1.03.2.1 Types of Reactions 99
1.03.2.2 Heterogeneous Hydrogenation 99
1.03.2.3 Homogeneous Hydrogenation of Arenes 106
1.03.2.4 Dissolving Metal Reductions 107
1.03.2.5 Hydride Reductions 109
1.03.2.6 Electrochemical Reductions 110
1.03.3 REDUCTION OF ALKYNES AND ALLENES 110
1.03.1 REDUCTION OF ALKENES
1.03.1.1 General Methods for Alkene Reduction

Since the very first report of ethene reduction in 1874 <1874CB352> and the first extensive
developments of the reaction between hydrogen and organic compounds by Sabatier and his
group <1897CR1358>, heterogeneous catalytic hydrogenation continues to be one of the most
useful techniques for the addition of hydrogen to CC multiple bonds and to the aromatic
nucleus. As a clean, scalable process, this reaction has major applications both on the laboratory
and industrial scale and has been regularly reviewed <1985CRV129, 1995HOU(E21d)4239,
B-1998MI001, 2001AC(221)93, B-2001MI001, 2003MI103>. The performance of catalysts used
in such a reaction can be influenced by numerous parameters, sometimes difficult to control in a
reproducible manner. The characteristic of the metal is usually dominant: in the hydrogenation of
propene, the catalytic activities of the metals decrease in the following sequence: Rh > Ir > Ru >
Pt > Pd > Ni > Fe > Co > Os <B-1996MI001>. Among them, Pd, Pt, Rh, Ru, Ni, and Cu
are often used. The structure and morphology of metal particles exert an influence on the
macroscopic catalytic behavior, which can also be tuned by a second metal. The type of support
(usually charcoal, alumina, silica as well as CaCO3, BaSO4, or SrCO3 to a lesser extent
<1996T4495>), the particle size, the pore structure, and acid–base properties are also important
parameters for catalyst activity. Theoretical and practical aspects of the hydrogenation process
from an industrial point of view have been reviewed <B-1994MI001>. The mechanism of the
79
80 Two or More CH Bond(s) Formed by Addition to CC Multiple Bonds
reaction is complicated. The initial Horiuti–Polanyi proposal <1934TFS1164> has been investi-
gated in detail when techniques of molecular surface science became available <2001AC(222)3>.
Ethene hydrogenation has been studied on single-crystal Pt surfaces (Figure 1).
H H H H H H H H
H H H H
H2 H H
Dissociative
adsorption
H H H H
H H H-Addition
Adsorption
H H Desorption H H
H H H H H H H H
H H H H
H H H
H H
H-Addition HH
HH H HH
Figure 1 Mechanism of ethene heterogeneous hydrogenation.
Ethene is adsorbed in the form of unreactive ethylidyne at room temperature. This does not
prevent the reversible dissociative adsorption of hydrogen, but strong adsorption of additional
ethene in a -bonded fashion occurs only after the diffusion of an ethylidyne species and opening
of a vacant site <2002JA10982>. Sequential hydrogen transfers from adjacent sites give a mono-
absorbed ethyl and ethane, which is then desorbed from the metal. Recent studies on Ni surfaces
indicate that unbonded energetic bulk H atoms might also be reactive species in this process
<2001ACR737>. The major side reaction that can occur during heterogeneous hydrogenations is
isomerization and double bond migration. This of course goes unnoticed unless the isomer shows
an appreciably different reactivity or hydrogenation results in stereochemical scrambling. Two
mechanisms have been proposed for the double bond migration. First, the ‘‘associative’’ pathway is
based on the reversibility of the first H addition step in the Horiuti–Polanyi proposal (Figure 1).
This can happen only if two vacant sites are able to accept the leaving hydride and the alkene
near the -bonded intermediate. Second, the ‘‘dissociative’’ pathway, proposed by Farkas and co-
workers <1934MI630>, involves an allylic intermediate. This mechanism requires at least three
vacant coordination sites to bind the alkene and the hydrido group <1991COS(8)417>. Since the
surface of a metal might provide several coordinating sites, both mechanisms may operate. A
decreasing order of activity in the double bond migration is Pd > Ni >> Rh >> Ru¼Os > Ir¼Pt
<1991COS(8)417>. In a comparative study, an associative pathway has been proposed for Pt-,
Ir-, and Rh-catalyzed isomerizations, whereas a -allyl species is involved in Pd-catalyzed migra-
tions <1984JOC1845>. Besides the choice of the metal, several parameters can be optimized to
favor the addition of hydrogen over isomerization. Since, for both pathways, double bond
migration requires a vacant site to accept a hydride, decreasing the number of vacant sites by
increasing the hydrogen availability (pressure, solubility, etc.) or by adsorption of bases (tertiary
amines, phosphines, or CO groups) can prevent this isomerization. The use of benzene as a
solvent with Pt and Rh catalysts is known to lower the isomerization rate <1991COS(8)417>,
which has also been correlated with the polarity of the substrate to be hydrogenated
<1997JMOC(118)255>. The addition of two hydrogen atoms on a CC double bond occurs in
a syn-manner. Thus, hydrogenation of (Z)-2,3-diphenyl-2-butene leads to the meso-isomer (98%)
of 2,3-diphenylbutane (Equation (1)), whereas the (E)-isomer leads to a racemic mixture of
2,3-diphenylbutane (Equation (2)) <1991COS(8)417>.
Ph Ph Ph Ph
Pd, AcOH, H2, 1 atm
H H
ð1Þ
98%
Ph Ph Ph
Pd, AcOH, H2, 1 atm
H ð2Þ
Ph 98% H
Two or More CH Bond(s) Formed by Addition to CC Multiple Bonds 81
Apparent anti-addition might be obtained in some cases, and is the result of a syn-hydrogena-
tion of an isomerized intermediate <1973CL855>. The stereochemistry of hydrogenation of
alkenes generally involves a cis-addition of hydrogen to the least hindered face of the olefin. A
model of the mode of adsorption on active sites provides a good estimation of the outcome of
hydrogenation of 4-alkyl methylenecyclohexanes, leading to the predominant formation of 1,4-
cis-disubstituted cyclohexanes (Figure 2) <1997MI419>.
R H
H
CH2 CH2
H H H
H R H H Me
H
R Me R H
Trans Cis
Figure 2 Stereoselectivity in the hydrogenation of 4-alkymethylenecyclohexanes.
The preferred direction of adsorption can also be influenced by the presence of substituents
other than alkyl groups. -Electrons of phenyl groups can promote attractive interactions with
the surface, and the location of hydroxyl groups near the double bond can strongly influence the
facial selectivity of hydrogen addition. The relative importance of this phenomenon, called
haptophilicity <1973JA6379>, is sometimes difficult to predict, and might vary with the nature
of the catalyst <1997MI419>. A comparative hydrogenation (5% Pd/C catalyst) study performed
on alkenes incapable of isomerizing led to the following order of haptophilicity for the groups
studied (Equation (3) and Table 1): R = CH2NH2 > CH2NMe2 > CH2OH > CHNOH >
CH2OMe > CHO > CONH2¼CH2NHCOMe > COOK > COMe > CN > CONHOH > COOH >
COOMe >COONa > COOLi <2002JOC2813>.
R H R Me R
Me Me Me H Me
H2,Pd/C (5%)
+
EtOH ð3Þ
Proximofacial Distofacial
reduction reduction
Table 1 Percent proximofacial product <2002JOC2813>

R Proximofacial product (%) R Proximofacial product (%)
CH2NH2 87 COOK 30
CH2NMe2 62 COMe 22
CH2OH 48 CN 20
CHNHOH 45 CONHOH 18
CH2OMe 44 COOH 17
CHO 42 COOMe 16
CONH2 33 COONa 10
CH2NHAc 33 COOLi 7
This phenomenon is sometimes markedly influenced by the solvent, with an increase of

haptophilic effectiveness accompanied by a lowering of the dielectric constant. The use of chiral
modifiers for enantioselective transformations has been reviewed <2003MI45>. Only modest
(when compared to the classical standards of homogeneous catalysis) enantioselectivities could
be obtained on selected substrates.
Although heterogeneous catalysts offer an excellent method for the reduction of alkenes,
especially for large-scale transformations, the development of homogeneous catalysis, based on
soluble reducing species, was in recent years very spectacular and led to important results in the
field of asymmetric transformations, as recognized by the 2001 Nobel prize to W. S. Knowles and
R. Noyori for enantioselective hydrogenation (with K. B. Sharpless for enantioselective oxidation)

<2002AG(E)1998>. The attractiveness of homogeneous hydrogenation relies on a versatile hydro-
gen activation by numerous transition metals <B-1994MI002>, and the tuning of the complexes
reactivity by the electronic and steric properties of the ligands, and, with cationic species, the
counter-anion. Despite their lower activities, heterogeneous catalysts are more selective, not suscep-
tible to poisoning, and also enable enantioselective hydrogenations. They also cause fewer rearran-
gements and less isotope exchanges and are therefore suitable for deuteration, although in some
cases a mixture of partially deuterated products can be obtained with the Wilkinson catalyst
RhCl(PPh3)3 <1965CC131> in chlorinated or alcoholic solvents <1970CC495, 1970CC497,
1970CC571>. The Wilkinson catalyst and, to a lesser extent, Crabtree’s catalyst [Ir(cod)(py)
(PCy3)]PF6 <1979ACR331> are most widely used for olefins lacking coordinating functionalities.
Most of the other functional groups are tolerated by the Wilkinson catalyst with the exception of
aldehydes, which lead to decarbonylation. This side reaction can be avoided by increasing the
catalyst loading and hydrogen concentration <1966TL1605>. The rates of hydrogenation generally
depend on steric effects, with the following order of reactivity: terminal alkenes > cis-alkenes >
trans-alkenes <1991COS(8)443>. When applicable, functional groups such as hydroxyl, ester, and
amide can direct the stereochemistry of hydrogenation <1993CRV1307>. This directing effect,
however, is not necessary since significant stereocontrol can also arise from the intrinsic conforma-
tional preferences of the reactant <1998CC277>.
Although the real catalytic species is often short-lived and present at a very low level, the initial
or intermediate complexes can be isolated or characterized by spectroscopic methods, leading to a
good understanding of the catalytic cycle. Most of the mechanistic investigations have been
performed with the Wilkinson catalyst and have been reviewed <2000CRV439>. Even if pro-
posed classical mechanisms for Rh and Ru are taught in textbooks, such a reaction involving
widely different metals, ligands, and substrates cannot be described by a single mechanism, as
recently highlighted <2001AG(E)4611>. Low-valent Ru, Rh, and Ir complexes stabilized by
tertiary phosphorus ligands are the most versatile catalysts for homogeneous hydrogenation,
although hydrogenation of octene has been reported with nickel phosphane complexes
<1998CC2689>, and Ti-based <1993JA12569> and Zr-based catalysts <1999JA4916> gave
good results in the enantio- and diastereoselective reduction of olefins. Despite an impressively
large number of chiral ligands recorded for this reaction <2003MI103>, this field is still very
active with the recent revival of chiral monodentate phosphorus ligands <2001AG(E)1197,
2003MI308>, or the discovery of secondary phosphines <2002AG(E)612> and carbenes
<2002AG(E)1290, 2001OM1255>, as valuable stabilizing ligands in such a reductive system.
The use of homogeneous catalysis for the enantioselective reduction of olefins has been regularly
reviewed <2003MI45, B-1999MI001>.
Although several industrial applications are well established already for the preparation of
enantiomerically enriched chiral fine chemicals, at production, pilot, or bench stage
<2001AC(221)119>, new reaction conditions have been investigated, mainly with the aim of
addressing the immobilization or the recycling problem of the catalyst, and to get cleaner
processes. The general strategy is to have the substrate and the catalyst in two different phases.
For instance, hydrogenations have been carried out in biphasic aqueous medium <2002ACR738,
2002MI221, 2002MI239>, using mainly rhodium or ruthenium complexes, generally associated
with water-soluble ligands. In some cases, it has been shown that colloidal rhodium, stabilized by
oxidized phosphines, was the real catalytic species <B-1998MI002>. The substrate can be
hydrogenated in solution or in dispersion. Addition of a surfactant, leading to a micellar system,
can significantly enhance both activity and, with chiral catalysts, enantioselectivity in the hydro-
genation reaction, provided its concentration is above the critical micellar concentration
<1999CCR(185-186)585>. The influence of pH in such systems has been investigated
<2002MI312>. Water-soluble catalysts can also be dissolved in a film of water supported on a
high surface-area hydrophilic solid. This concept of supported aqueous phase catalyst (SAPC)
<1989NAT(339)454> has been extended to its asymmetric version <1994NAT(370)449>.
Although water is a ‘‘simple’’ solvent for chemical reactions, its reactivity can interfere with
hydrogenation processes. Furthermore, the solubility of hydrogen is low in such a medium. The
complete miscibility between hydrogen and supercritical fluids such as scCO2 is particularly
attractive for hydrogenation reactions, which are sometimes limited by the rate of diffusion of
H2 from the gas to the liquid phase. Furthermore, the pressure/solvation tuning enables the
recovery of homogeneous catalyst by preferential precipitation. The use of these reaction condi-
tions has been investigated both with homogeneous <1999CRV475> and heterogeneous
<1999CRV453> catalysts. Addition of co-solvents or counter-anion modifications
<1995JA8277> can improve the solubility of the charged complexes involved in the catalytic
cycle. The addition of water, leading to microemulsions, enables the solubilization of Pd nano-
particles, which catalyze the hydrogenation of hydrophilic as well as hydrophobic alkenes
<2002JA4540>. It must be noted that scCO2 is not inert and might interfere with hydrogenation
processes by insertion into the metal–hydride bond, or by reduction to CO on the surface of
heterogeneous catalysts. Hydrogenation can be conducted using fluorous biphasic catalysis
<1998ACR641, 1999CEJ1677>. The low miscibility of the cold fluorous phase with organic
solvents allows the recycling of the fluorocarbon soluble catalysts for several catalytic runs. A
suitable design of fluoroponytailed ligands <2002T3911> and weakly coordinating counter-
anions <2003MI625> enables catalytic activities of ionic rhodium complexes close to that of
Wilkinson catalyst, with low rhodium or phosphane leaching <2003MI603>. Catalytic hydro-
genation of various alkenes has been performed in ionic liquids <2002MI495>. The good
solubility of hydrogen in such a reaction medium contributes to the overall good catalytic activity,
although the reaction is not truly homogeneous. The use of imidazolium ionic liquids for the
formation and stabilization of iridium nanoparticles has been reported. These nanoclusters
proved to be as active as Crabtree’s catalyst in the hydrogenation of 1-decene, and could be
recycled several times without significant decrease of activity <2002JA4228>. The recycling of the
catalyst has been obtained by different immobilization techniques. Ligands can be functionalized
and grafted to various supports such as polymers (soluble and insoluble) <2002CRV3345,
2002CRV3217, 2002CRV3275, 2001T4637>, dendrimers <2001ACR181, 2002CRV3717>, or
inorganic oxide supports <2003MI584>, included in the soluble or insoluble support at the
polymerization <2003TL2703> or co-polymerization step <1999JA7407>. The use of chiral-
nonracemic ligands enables asymmetric reduction under heterogeneous conditions
<2003HCA1753>. Bimetallic nanoparticles anchored within silica nanopores (nanocatalysts)
have shown good performances in the hydrogenation of various substrates <2003ACR20>.
Homogeneous catalysts can also be entrapped in sol–gel matrices <2002CRV3543> or in poly-
mers <2003MI202> and recycled by ultrafiltration processes.
The reduction of alkenes using catalytic transfer hydrogenation can be a practical way at the
laboratory level, since this method uses solids or liquids as hydrogen donors, and does not require
special equipments such as hydrogenators. Furthermore, they can lead to more selective reduc-
tions than with the use of molecular hydrogen. Both homogeneous and heterogeneous catalysts
can be used in conjunction with a wide range of donors <1985CRV129>. The most common
donors are ammonium or trialkylammonium formates, formic acid, cyclohexene, cyclohexadiene,
indoline, tetralin, pyrrolidine, hydrazine, and triethyl silane <B-1996MI001>. An ion-exchange
resin-supported formate has been described as a recyclable hydrogen donor source
<2001TL5963>. Among the heterogeneous catalysts, the most commonly used is palladium
<B-2002MI001>, and platinum, rhodium, and Raney nickel to a lesser extent, whereas homo-
geneous catalysts based on Pd, Pt, Ru, Ir, Fe, and Ni have been reported. Although hydrogen
donors are usually simple hydrogen precursors by an oxidative process, generally obtained by
heating, other mechanisms, involving different rates of the individual steps within the catalytic
cycle, might take place with homogeneous catalysts and hydride donors such as formate deriva-
tives <2002JCS(D)752> and alcohols. In the latter case, the choice of suitable ligands for Ir-
catalyzed transfer hydrogenation of ,-unsaturated ketones enables a chemoselective alkene
reduction, whereas over-reduction to aliphatic alcohols occurs with PPh3 <2001JOC4710> and
allylic alcohols are obtained with diamines or amino alcohols (Scheme 1) <1997ACR97>.
[Ir(cod)Cl]2 (2 mol.%) [Ir(cod)Cl]2 (2 mol.%)

PPh3 (4 mol.%) DPPP (2 mol.%)
OH Cs2CO3 (2 mol.%) Cs2CO3 (2 mol.%) O
O
PriOH (10 equiv.) PriOH (10 equiv.)
Ph Ph Ph
Toluene, 80 °C, 4 h Toluene, 80 °C, 4 h
60% 93%
Scheme 1
In some cases, the use of transfer hydrogenation might cause some chemoselectivity problems,
since hydrogen donors are known to be particularly useful in benzylic bond hydrogenolysis
<B-1999MI003>.
Not only catalytic methods, but also several stoichiometric methods are valuable for the reduc-
tion of alkenes. Among them, the reduction by diimide (sometimes called diimine or diazene)
appears to be the most versatile <B-1996MI001, 1991COS(8)471>. This reactive species can be
generated from hydrazine with oxygen or hydrogen peroxide in the presence of a small quantity of
Cu(II) salt and/or a carboxylic acid in a wide range of solvents, or by the acid-catalyzed hydrolysis
of the commercially available dipotassium or disodium salt of azodiformate <1965JOC3985>. It
can also be obtained by thermal decomposition of anthracene-9,10-diimine <1962JA685> or
various aromatic sulfonylhydrazides. The reaction with diimide is a concerted addition, proceeding
through a six-membered transition state, and results in complete stereospecific syn-addition. The
main side reaction observed during diimide reduction is the formation of nitrogen gas by the
disproportionation of the reducing agent. A large excess of diimide precursor is, therefore, generally
required for the completion of the reaction, which has to be faster than the disproportionation. The
relative rate of reduction of various alkenes has been established <1991COS(8)471>. For nonfunc-
tional alkenes, reactivity decreases with alkyl substitution, increases with bond angle bending strain,
and trans-double bonds are generally more reactive than cis-double bonds. Substitution with an
electron-withdrawing group enhances the alkene reactivity <1962AG215> as well as the conjuga-
tion with another unsaturated bond <1975JOC3599>. This reactivity pattern enables very inter-
esting chemoselective reductions of double bonds in the presence of sensitive functions such as
peroxides <1987JMC1505>, or more generally in polyfunctionalized systems <2002JA9825>.
Furthermore, as a soluble reducing agent, diimide is particularly well suited for the reduction of
solid-supported alkenes (Equation (4)) <1998TL6785>.
O
O
3 equiv. TsNHNH2 O
O ð4Þ
DMF, 100 °C Br
Br
95%
Metal hydrides are useful reducing agents, but they generally do not reduce simple alkenes
<B-1997MI>. Addition of transition metal salts into the reaction medium enables the reduction
of alkenes, via the formation of transition metal hydrides as hydrometallation species. In a
comparative study, the ability of alkenes to be reduced by LiAlH4 in the presence of first-row
transition metal salts has been found to follow the order: Co(II) > Ni(II) > Fe(II) > Fe(III) >
Ti(III) > Cr(III) > V(III) > Mn(II) > Cu(I) > Zn(II). The addition of the transition metal hydride is
in this case supposed to be due to the d orbital overlap between the metal and the double bond,
explaining why d 10 Cu(I) and Zn(II) and d5 Mn(II) are less active in the series <1978JOC2567>.
Partial or polydeuteration is generally observed with deuterated metals, indicating that several steps
in the reduction are reversible. Transition metal salts and LiAlH4 are usually mixed in equimolar
quantities, except with CoCl2, NiCl2 and TiCl3, which are used in substoichiometric amounts.
Catalysis is slower for di- and trisubstituted alkenes. Sodium hydride <1976CL581> as well as
NaBH4 <1979JOC1014> can also serve as the hydride source in such systems. Aliphatic and
aromatic alkenes have been reported to be reduced by NaBH4 in the presence of a catalytic amount
of nickel chloride and moist alumina <2000TL6795>. The reaction is believed to involve the
formation of a nickel boride, and to take place at the alumina surface (Equation (5)).
NaBH4 (0.8 equiv.), NiCl2·6H2O (0.05 equiv.),

moist alumina
C8H17 C8H17 ð5Þ
Hexane, 30 °C, 3 h
91%
A two-stage reduction can also be performed by hydrometallation, followed by protonolysis of

the transient Cmetal bond. With boranes, the final alkylborane can be hydrolyzed with reten-
tion of configuration under acidic conditions <B-1997MI>. Hydrozirconation of alkenes with
i-BuZrCp2Cl can be accelerated by a catalytic amount of various Lewis acids, leading to alkanes
after acidic treatment <1999EJO969>.
Numerous metal hydrides have been described in the conjugate reduction of unsaturated
double bonds (see Section 1.03.1.5). A comprehensive comparative study on the elaboration of
the trans-hydrindane portion in steroids or related natural products by reduction has been
reported <1998T12071>. This field is growing with the development of new reagents
<2001JOC8692> and catalysts for asymmetric conjugate reductions <1999JA9473>.
Although the reduction of alkenes to alkanes has been reported to proceed stereoselectively
with sodium in HMPA in the presence of ButOH <1970JOC3565>, the use of dissolving metals in
such reactions has been mainly limited to the reduction of ,-unsaturated ketones
<1996JA8765>. The reduction of bis-cyclopropylated alkenes with lithium in ammonia has
been reported to proceed in a stereoselective manner (Equation (6)) <2000EJO2979>.
i. Li, NH3, –78 °C H

O
O ii. MeOH, Et2O
H ð6Þ
O
O 63%
19:1
The use of strong acidic media enables the reduction of hindered double bonds in the presence
of hydrides. Ionic hydrogenation has been described at low temperature in dichloromethane using
triflic acid and several transition metal carbonyl hydrides or triethyl silane (Equation (7))
<1994JA8602>. In some cases, the secondary carbenium ion formed by protonation can undergo
alkyl migration or hydride shift. The intermediacy of both olefin cation radicals and carbocations
in ionic hydrogenation with borane–dimethyl sulfide complex has been discussed
<1996JOC5246>.
CpW(CO)3H (2 equiv.), TfOH (1.8 equiv.)

CH2Cl2, –50 °C, 5 min ð7Þ
95%
Enzymes can also catalyze hydrogenations. Although the biohydrogenation of double bonds
represents a relatively small area within the field of biotransformations, interesting selectivity can
be obtained in such reductions <1995HOU(E21d)4364>. If isolated and purified enzymes are
used, a coenzyme must be added and recycled. With whole cells as catalysts, all the cofactors are
present and readily regenerated <1999OL1839> (Equation (8)).
O
O O
O
Baker’s yeast
Buffer (pH 7.2) ð8Þ
Glucose, 40 °C
O
O 65%
O
O
>99% ee
Besides carbohydrates, hydrogen gas or a cathode can serve as electron donors. Investigations
into the stereoselective reduction of nitro olefins have been reported, showing that nonredox
reactions can explain the stereochemical outcome of the reduction <2000PNA10733>. Since most
of the reductions occur by hydride transfer from reduced NADH or NADPH coenzymes, several
biomimetic hydride donors have been prepared and used in the reduction of alkenes
<1998SL1144>.
1.03.1.2 Reduction of Alkyl-substituted Alkenes

Isolated double bonds are best reduced by catalytic hydrogenation. Heterogeneous catalysis is
generally the method of choice, either with hydrogen or hydrogen donors, although the reduction
becomes more difficult as the number of alkyl substituents increases. Some selectivity can be
observed with substrates bearing several double bonds <2001TA29, 2001AG(E)1211>. A combi-
nation of 5% Pd/C–ethylenediamine [5% Pd/C(en)] in THF or dioxane as solvent enables the
selective reduction of double bonds in the presence of sensitive N-benzyloxycarbonyl protective
groups (Equation (9)) <2000T8433>. Hydrogenolysis-free hydrogenation has also been reported
with Pd-black powder as a catalyst in benzene or toluene <2001SL1590>.
5% Pd/C(en), H2 (5 atm)
NHCO2Bn 7 NHCO2Bn
7
THF, 18 h ð9Þ
99%
The catalytic mixture NiCl2–Li–naphthalene has been proposed as an alternative to Raney

nickel in alkene reductions, with similar activity and better handling conditions <2001MI188>.
The use of polymer-supported naphthalene enables its easy recovery by filtration and reusability
<2003MI275> (Equation (10)). Oct-1-ene can be reduced by transfer hydrogenation using NiBr2
in alkaline isopropanol <2000CC1647>.
NiCl2, Li, polymer-supported naphthalene

ð10Þ
H2, 1 h
99%
The reduction of simple alkenes with homogeneous catalysts can also proceed efficiently. A selective
tritiation of a linear alkene, without scrambling along the chain, can be achieved with the Wilkinson
catalyst (Equation (11)) <2000T5493>. The same catalyst enables the chemoselective reduction of a
terminal double bond in the presence of several unsaturations (Equation (12)) <1996JCS(P1)57>. The
use of borohydride exchange resin–nickel boride has been described as a catalyst for the hydrogenation
of monosubstituted alkenes <1996S597>. Triethyl silane in ethanol in the presence of PdCl2 can lead
to the reduction of 1-alkenes in excellent yields (Equation (13)) <2003TL4579>.
C10H21 C14H29
C10H21 C14H29 3
H2, Rh(PPh3)3Cl
ð11Þ
Ether, 16 h
3H 3
H
89%
H2, Rh(PPh3)3Cl
ð12Þ
EtOH, benzene 1/1
69%
Et3SiH (2 equiv.), 10% PdCl2

C15H31
C15H31 ð13Þ
EtOH, 1 day
96%
Unlike some transition metal-catalyzed reductions, organolanthanide-catalyzed processes are

usually not directed by polar groups, but appear purely steric in their selectivity patterns. They are
therefore attractive for the stereoselective reduction of nonfunctional alkyl-substituted alkenes
<1996JOM(524)275, 2002CRV2161>. Intramolecular complexation of the electrophilic center with
a -system or a heteroatom might be responsible for the lower reactivity (Equation (14), Table 2).
R R
Cp*2SmCH(SiMe3)2 ð14Þ
H2
Table 2 Stereoselective reduction of methylenecyclohexanes <1996JOM(524)275>

R Mol.% cat./reaction temp (C) Yield (%) cis:trans
Me 3/20 77 93:3
Bui 3/20 90 95:5
But 5/rt 95 100:0
Bn 3/20 95 93:7
Ph 5/50 96 100:0
(CH2)3NMe2 3/50 76 91:9
OMe 5/70 0
The enantioselective reduction of alkyl-substituted alkenes still remains a challenge. The lack of
a coordinating group on the substrate is a problem for strategies involving transition metal
catalysis. Furthermore, a reproducible, simple, and general method for enantiomeric excess
determination of alkanes is still necessary <B-1999MI002>.
1.03.1.3 Reduction of Alkenyl-, Aryl-, Heteroaryl-, and Alkynyl-substituted Alkenes

Partial reduction of conjugated dienes or polyenes is a complex reaction. Besides over-reduction,
heterogeneous hydrogenation of butadiene can lead to three different alkenes
<2001JMOC(173)185>. The product distribution of this reduction catalyzed by evaporated films
of the majority of the elements in groups 3–11 on the periodic table has been investigated
<2002AC(229)251>. According to this study, the butadiene hydrogenation can be interpreted by
processes involving - and -adsorbed half hydrogenated states (Figure 3) with all transition metals
except Pd, for which the trans:cis ratio of but-2-ene is up to 20, which can be interpreted as the result of
an anti:syn preference of butadiene in the gas phase and a 1,4-addition via noninterconvertible -
allylic intermediates (Figure 4). Correlation of but-1-ene yield with the Pauling electronegativity scale
indicates that an electronic effect governs the extent of overall 1,2-addition for all metals.
+H +H
–H
+H
+H
+
–H
Low trans:cis ratio
+H
+H
+
–H
Figure 3 Hydrogenation of butadiene leading to a low trans:cis ratio.
+H +H
+
–H
High trans:cis ratio
+H
+H
+
–H
Figure 4 Hydrogenation of butadiene leading to a high trans:cis ratio.
Unless there is an important difference between the two double bonds in terms of substitution
patterns and/or electron density, selectivity of heterogeneous reduction is generally difficult to
achieve (Equation (15)) <1991COS(8)523, 1998JCS(P1)2473>.
t
t H OCOBu
t H OCOBu
H OCOBu HO
HO
HO
H2, Ir black H ð15Þ

H
H
ButOH, 20 h
67% 27%
With several conjugated systems, however, selective mono-hydrogenation could be performed

on dienes (Equation (16)) <1998TL5675> or polyenes (Equation (17)) <1997T13703>. A good
chemoselectivity could be obtained in the hydrogenation of 2-pyrone derivatives with cinchona-
modified Pd/TiO2. Furthermore, enantioselectivity up to 94% could be obtained under high
dilution conditions (Equation (18)) <2002NJC6>.
CN Me
CN Me
H2, Pd/C (10%)
OSiPr3i ð16Þ
OSiPri3
25:1 cyclohexane/EtOAc
93%
O
O
H2, Pd/C (10%) CO2Me ð17Þ
CO2Me
AcOEt, 4 h
CO2Me
CO2Me 53%
OMe OMe OMe

H2, Pd/ TiO2 (5 wt.%), cinchonine
+
O O
i
Pr OH, 26 °C O O O O ð18Þ
80% 9%
90% ee 98% de
89% ee
A wide range of homogeneous catalysts can selectively lead to a 1,2-reduction of linear or cyclic
dienes <1991COS(8)443>. The less-substituted exocyclic double bonds are generally selectively
reduced with the Wilkinson catalyst <1995TL4039>. The binuclear palladium complex
[(But2PH)PdPBut2]2 pretreated with oxygen can catalyze the 1,2-hydrogenation of simple and
functionalized dienes, under mild conditions (Equation (19)) <1995TL5673>. Di- or polynuclear
palladium clusters <1998NJC1217> or tungsten complexes <1995CC1599> are also efficient
catalysts in the monohydrogenation of dienes. Several complexes, having arenes or cyclohepta-
triene ligands, are good catalysts for selective 1,4-hydrogen addition (Equation (20))
<2000JCS(P1)2211>. Thus, (6-naphthalene)chromium tricarbonyl enables the reduction of a
mixture of (Z)- and (E)-isomers to (E)-alkenes in the presence of a nonconjugated double bond
(Equation (21)) <2000JCS(P1)2211>. A less toxic Cp*Ru complex (Equation (22)) has been
proposed as an effective catalyst for the hydrogenation of sorbic alcohol into cis-hex-3-en-1-ol
(leaf alcohol, commercial fragrance) <2000CC217>.
[(Bu2t PH)PdPBu2t ]2 (1 mol.%)* CO2Et

CO2Et
H2 (1 atm), THF, rt, 2 h ð19Þ
95%
* Pretreated with oxygen
6 CO2Et
Cr(CO)3 (η -Naphthalene)
CO2Et
ð20Þ
H2 (50 atm), THF, 70 °C, 4 h
80%
6
Cr(CO)3 (η -Naphthalene)
OH
OH
H2 (50 atm), THF, ð21Þ
50 °C, 3 h
76%
Tf
Ru
CO2H OH ð22Þ
OH
H2 (20 atm), ethylene glycol–ButOMe
–1
60 °C, 0.4 h, TOF = 2495 h
Conversion = 88%
Diene systems can be reduced under the general conditions of the Birch reduction (Equation (23)),
leading to the corresponding (E)-alkene exclusively <1996JOC6454>. In selected cases, stoichio-
metric reducing agents may also provide a way to control the reduction of polyene systems
(Equation (24)–(27), Scheme 2) <1998TL677, 1997TL7463, 1996JOC2928, 1995TL8359>.
OH
OH
Li, NH3, MeOH ð23Þ
OH
OH 67%
O
O
O O
O NaBH4/I2 O
N N ð24Þ
THF, 0 °C O
O 74%
LiBH(Bus)3
ð25Þ
DMPU O
O
58%
ButLi
Al(2,6-Ph2-Phenoxy)3,
O Bu2i AlH O ð26Þ
Toluene, THF, hexane
87%
O Ph
O Ph
H
Zn–ZnCl2 ð27Þ
THF, H2O H Ph O
Ph O 45%
Bu2i AlH Dissolving metals

HO HO HO
H
Scheme 2
The enantioselective reduction of dienes has been reported <1998JA657>. Chelation through
the N-acetyl group ensures a high regioselectivity, even with tetra-substituted double bonds
<1999TL3093>. Stopping the reaction before over-reduction is critical for obtaining products
of high enantiomeric purity (Equation (28)). Diene esters (Equation (29)) <1998AG(E)1931> or
enol esters (Equation (30)) <1998TL5505> are reduced in a similar way, as well as pyrones with
ruthenium catalysts <1999JOC5768>.
Et CO2Me H2, ((R ),(R ))-MeBPE-Rh Et H H CO Me
2
NHAc MeOH, 20 °C, 24–48 h NHAc

Ph Ph ð28Þ
Conversion: 100% 93% ee
((R ),(R ))-MeBPE: 1,2-Bis((2(R ),5(R ))-2,5-dimethylphospholano)ethane
H2 (5 atm), ((S ),(S ))-Et-DUPHOS-Rh

+ CO2H ð29Þ
CO–2ButNH3 MeOH MeO2C
MeO2C
Conversion: 100%
99% ee
((S ),(S ))-Et-DUPHOS: 1,2-Bis((2S,5S)-2,5-diethyl-phospholano)benzene
AcO
AcO H2, ((R ),(R ))-MeDUPHOS-Rh
ð30Þ
MeOH or THF
Ph
Ph 97% 94% ee
The selective reduction of alkynyl-substituted double bonds is generally problematic using

standard hydrogenation conditions. A regio- and stereoselective ionic hydrogenation of enam-
ino-1-yne has been reported <1999JA10012>. An acyliminium reactive species is probably
involved in this selective reduction (Equation (31)).
TIPSO
TIPSO
NaBH3CN, TFA
N ð31Þ
N –50 °C
CO2Bn OAc
CO2Bn OAc
78%
There are many examples of the reduction of aryl-substituted double bonds. In addition to hetero-
geneous catalysis <1991COS(8)417>, hydrides <1996SC763>, dissolving metals <1995BSB563>, and
ionic hydrogenations <1995H925, 2000BMCL2701> have been reported to proceed efficiently. The use
of hydrosilanes in the presence of a copper salt enables the selective reduction of aromatic-substituted
double bonds, without reducing alkyl-substituted alkenes <2000SL479>. Red phosphorus, in the
presence of hydrogen iodide, is able to reduce cinnamic acid derivatives (Equation (32))
<1998JOC432>. Diarylalkenes are easily reduced under acidic conditions, by hypophosphorus acid-
iodine in acetic acid (Equation (33)) <2002T4411> or by zeolites (Equation (34)) <1997CC127>.
F
F
Red P4, HI, H2O
O ð32Þ
O
89% OH
OH
H3PO2, I2
ð33Þ
AcOH, ∆, 24 h
99%
Ca Y (Si138,7Al53,3Na7,5Ca23,3O884)
ð34Þ
Hexane, 22 °C, 1 h
>90%
1,3-cis- or trans-Dialkyl indanes can be obtained from the same precursor by selective reduction
of the free or complexed alkene (Scheme 3) <1997JOC3365>. The reduction of solid-supported
alkenes has been performed using Stryker’s reagent (Equation (35)) <1999JOC1723> or ionic
hydrogenation <2001JA2428>. Ionic hydrogenation has also been proposed as a good method to
remove residual vinyl groups of a cross-linked polystyrene matrix arising from the co-polymerization
of divinylbenzene and styrene monomers <1997JOC8987>.
(OC)3Cr i. Mg, MeOH

H2, Pd/C ii. I2, THF
87% 57%
CO2Et CO2Et CO2Et CO2Et
Scheme 3
N N
N N
O O
ð35Þ
OMe O OMe O
N S [CuH(PPh3)]6 N S
O OMe O THF, H2O O OMe O
Homogeneous catalytic hydrogenation has been used for the reduction of aryl- or heteroaryl-
substituted alkenes. The use of a 1:1 mixture of THF:ButOH as a solvent enables the selective
reduction of double bonds in the presence of a highly reducible aromatic nitro group (Equation (36))
<2002JOC3163>.
F F
H2, RhCl(PPh3)3
NHt-BOC NHt-BOC ð36Þ
O2N O2N
5 THF/ButOH 1/1, 5 h 5
95%
The enantioselective hydrogenation of aromatic-substituted double bonds has made impressive

progress <2003MI33>. Enantioselectivities greater than 95% have been achieved with cationic
zirconocene catalysts <1999JA4916>, cationic iridium complexes with P,N- <1998AG(E)2897,
2001AG(E)4445, 2001CEJ5391>, or N-carbene <2001JA8878, 2003JA113> ligands. The use of
Pd-based <1997JOM(531)159>, Ti-based <1995OM4865>, lanthanide-based <1994JA10241,
1997OM4486>, or Ru-based catalysts <2000TL9471> has been reported for the reduction of
‘‘nonfunctionalized’’ double bonds, albeit with lower efficiency.
1.03.1.4 Reduction of Heteroalkyl-substituted Alkenes

Although the hydrogenolysis of the Cheteroatom bond is a known side reaction during catalytic
hydrogenations, heteroalkyl-substituted alkenes can be reduced by different methods. Introduc-
tion of fluorine-containing methyl groups at the C2 position of glucose has been attained by a
diastereoselective reduction of fluoroalkenes (Equation (37)) <1997SL669>. Although hydroge-

nation of vinylic fluorides or chlorides has been mainly described over palladium on carbon
<1998TL4009, 2000JMC4893, 2000JFC(102)43, 2000T4253>, homogeneous conditions are also
efficient in such reductions <1996TL2007>.
O OMe
O OMe O
O H2, 10% Pd/C
F ð37Þ
F Ph O
Ph O X = F, H: 100%
TBSO X
TBSO X
Enol ethers are reduced by hydrogen in the presence of various catalysts <1991COS(8)443>.
The presence of ammonia, pyridine, or ammonium acetate has been reported to inhibit hydro-
genolysis side reactions (Equation (38)) <1995TL3465>. Dihydrofuryl rings have been hydro-
genated over Pd/C in excellent yield <1995S1517>. The use of homogeneous catalysis enables
alkoxide-directed stereoselective reductions (Equation (39)) <2002OL937>.
H2, 5% Pd/C, Py (0.5 equiv.)

O O ð38Þ
MeOH
98%
MOMO OH NaH, THF OH

OMOM MOMO
[Rh(NBD)DIPHOS-4]BF4 OMOM
O O
O
H H2 (800 psi), rt HO H ð39Þ
OSEM O OSEM O
68%
NBD: norbornadiene
DIPHOS-4: 1,4-bis(diphenylphosphino)butane
Enamines can be reduced to the corresponding amines by different methods. Catalytic hydro-
genation of terminal enamines has been reported (Equation (40)) <1999EJO1459>. The use of
acidic conditions enables their reduction via the corresponding iminium ion, with Et3SiH
(Equation (41)) <2001TL8263>, (But)2MeSiH <1995TL7949>, or borohydrides (Equation (42))
<2000JOC7495>. These reductions can be performed in the presence of terminal double bonds
<1999SL1799>. Furthermore, the stereochemical issue of the ionic hydrogenation can comple-
ment the heterogeneous hydrogenation approach <1995TL4869>. The use of Birch conditions
has been reported for the reduction of conjugated enamino-oxazolines (Equation (43))
<2001T703>. N-Acyl-2,3-dihydropyridones have been reduced into the corresponding piperi-
dones with zinc and acetic acid (Equation (44)), whereas over-reduction to alcohols could not
be prevented using catalytic hydrogenation over palladium on carbon <2001JOC2181>.
NH2 NH2
H2, PtO2
OH OH ð40Þ
EtOH, 2 h
98%
MeO NHCO2Et Et SiH, TFA MeO NHCO2Et

3 ð41Þ
99%
MeO MeO
N N
MeO NaBH4, AcOH MeO ð42Þ
OMe OMe
75%
OMe OMe
N HN
N HN ð43Þ
Na, PriOH, THF
O
O 98%
O O
Zn, AcOH
ð44Þ
N 15 h, rt N
93% O
O
Although sulfur is known to be an excellent poison for heterogeneous catalysts, the reduction of
vinylic sulfides has been reported on Pd/C under hydrogen transfer conditions (Equation (45))
<2000S2004> or with Raney nickel (Equation (46)) <1996SL72>. Borohydrides can also be useful
in several cases <2000T4531>. Two general methods permitting the reduction of ketene dithioace-
tals to give the corresponding dithianes have been developed (Equation (47)). The use of magnesium
in methanol proved to be less reliable than the reduction with zinc and acetic acid <1997T17151>.
O O
BnN NBn BnN NBn

HCOOH, MsOH H H ð45Þ
H H
OH Pd/C OH
S S
85% O
O
H
H H
H
O S O
O S O Raney-Ni ð46Þ
MeO
MeO
THF H
H 89%
EtO2C CN EtO2C CN
Mg, MeOH: 77% ð47Þ

S S S S Zn, AcOH: >70%
The diimide reduction of vinylic tin compounds is a convenient entry to organostannanes

(Equation (48)). The preferred formation of the endo-compound has been explained by steric
interactions between an exo-2-bulky tin and the 7-syn-methyl group in the transition structure for
an endo-reduction <2002JCS(P1)1286>. A diastereoselective synthesis of -alkoxy stannanes and
silanes has been developed, based on the hydroxyl-directed hydrogenation of their vinylic pre-
cursors (Equation (49)). Interestingly, this method enables the diastereoselective synthesis of
heterobimetallic compounds <1994JOC6208>.
TsNHNH2, AcONa
SnMe3
ð48Þ
SnMe3 DME, H2O, ∆, 4 h SnMe3
80%
85 /15 endo /exo
OH SnBu3 +
H2, (dppb)Rh(NBD) BF4
– OH SnBu3
SiMe3 CH2Cl2 SiMe3

99% ð49Þ
dppb = PPh2
PPh2
Enantioselective reductions of various heteroatom-substituted alkenes have been developed

<2003MI103>. Enol acetates (especially cyclic ones) have been hydrogenated with ee up to
99% <1999AG(E)516>, but the catalytic activity has still to be improved (Equation (50)). The
reduction of acyclic (Equation (51)) <1999OL1679, 2001JA5268, 2002AG(E)847> or to a lesser
extent exocyclic enamides <2001MI331> also proceeds with excellent enantioselectivities, and
provides an interesting alternative to the difficult problem of the enantioselective reduction of
imines. Not only diphosphines, but also monodentate phosphoramidites <2002AG(E)2348> are
efficient ligands in these enantioselective reductions.
OAc OAc
H2, PennPhos-Rh
MeOH, rt, 24 h ð50Þ

Conversion = 100%
99% ee
PennPhos : P,P'-1,2-phenylenebis(endo-2,5-dialkyl-7-phosphabicyclo[2.2.1]heptane)
NHCOMe NHCOMe
H2 (3 atm), MeOH
Me But
P ð51Þ
Rh 99% ee
But P
Me
100%
Enantioselective reduction of dehydroamino acid derivatives is now a classical entry to enan-

tiopure amino acids and has been reviewed regularly <B-1999MI001, 2003MI103>. Interestingly,
these methods can be used to control the diastereoselectivity of the reduction in more complex
molecules (Equation (52)) <2000JPR736, 2001TL3159>. A new conceptual approach has been
reported in this field: the enantioselective reduction of dehydroamino acid can be performed by
an achiral biotinylated complex of rhodium using streptavidin as the host protein
<2003JA9030>. Tuning of the ‘‘chiral pocket’’ could be accomplished by site-directed mutagen-
esis, leading to ee improvement (Equation (53)).
AcO OAc
OAc
AcO OAc O
OAc AcO O
O O O
AcO O OAc
O O AcO OAc
OAc H2, toluene, 50 °C ð52Þ
AcO OAc
((S),(S))-Et-DUPHOS-Rh MeO2C
MeO2C
95% NHAc
NHAc >20:1 dr
PPh2
O N O
(+)-Biotin PPh2
AcHN AcHN
OH OH
H2, [Rh(COD)2]BF4 ð53Þ
Streptavidin S122G
96% ee
100%
COD: cyclooctadiene
Not only dehydroamino acids but also dehydroamino-phosphonic <1996SC777> or phosphi-

nic <1998AG(E)2851> acids can be hydrogenated in an enantioselective manner (Equation (54)).
A similar approach to the enantioselective synthesis of -hydroxy- or amino phosphonates has
been reported (Equation (55)) <1999OL387>. The reduction of alkenylboronic acids and esters
with enantioselectivities up to 80% has been described <2002JOM(642)145>.
Ph2
P
ButOOCN
Rh(COD)BF4
Ph
O ð54Þ
O P
Ph P
Ph2
P H OEt
OEt
NHCOPh
NHCOPh H2, H2O, 25 °C
96% eec
O
O
O Ph
O Ph H2 (4 atm.), MeOH, 25 °C MeO ð55Þ
MeO MeO P
MeO P ((S ),(S ))MeDUPHOS-Rh O
O
92% ee
1.03.1.5 Reduction of Remotely Substituted Alkenes

Remote groups can exert a dramatic influence on the reduction of alkenes. Allylic substituents are
readily prone to hydrogenolysis reactions when using Pd- and, to a lesser extent, Pt- or Rh-
catalyzed hydrogenations <1991COS(8)417>. The presence of a remote functional group is not
always a problem for selective hydrogenations, and in some cases can be very helpful to achieve
stereo- and regioselective reductions <1993CRV1307, 1995HOU(E21d)4317>. Hydroxyl-directed
reduction of cyclopentenes has been investigated with several catalysts. Whilst hydrogenation
with catalysts Rh(COD)(dppb)PF6 and Rh(C7H8)(dppb)PF6 was generally not selective, the use
of Crabtree’s catalyst or iridium–carbene complexes gave excellent stereoselectivity
<2002JOC5996>, but with low catalytic activity. Finally, the use of RedAl provided a cheaper
alternative for the reduction with the desired 1,2-anti stereochemistry (Scheme 4). A general
study of the hydrogenation of cyclopentenic esters bearing two different directing groups in a
trans-relationship has shown that a judicious choice of catalyst allows selective reduction to either
one or the other face of the double bond (Scheme 5) <2001TL1347>.
OH
F
Ir(COD)(Pyr)(PCy3)PF6 OH
OH F
F
4 RedAl (20 mol.%)
CO2Me
Toluene/ THF H2
OH –40 °C CO2Me
CO2Me
F
83%
1 4/1
CO2Me
Scheme 4
MeO2C NHt-BOC
OH
H2 (5 atm.), MeOH H2 (5 atm.), MeOH
Ir(COD)(py)(PCy3)PF6 ((R),(R))-MeDUPHOS-Rh
MeO2C NHt-BOC MeO2C NHt-BOC
OH OH
94% de 92% de
Scheme 5
Regioselective reductions are also observed with allylic alcohols, enabling the diastereoselective
hydrogenation of the most-substituted double bond (Equation (56)) <2000OL2737>. Chemo-
and regioselective reduction has also been reported using calcium in ammonia as a reducing agent
in the presence of magnesium perchlorate (Equation (57)). Homoconjugation of the diene and
hydroxyl-directed reprotonation of the transient radical-anion probably explains this result
<1995TL7607>.
H2
ð56Þ
OH O O [RuCl(S)-BINAP(p -cymene)]Cl OH O O
46–77%
OH OH
Ca, NH3/Et2O
ð57Þ
Mg(ClO4)2
72%
A particularly useful alkene reduction is the selective reduction of the CC double bond of
,-unsaturated carbonyl and related compounds. Since reduction of the carbonyl group is rare
during hydrogenation over palladium, the heterogeneous catalytic system is probably the most
suitable for this kind of reduction <B-2002MI002> and can be very chemoselective
<2001S2003>. The chemoselective conjugate reduction of ,-unsaturated carbonyl compounds
can be achieved with a Pd/C-pyridine combination as a catalyst in the presence of a benzylic
protective group <1997TL399>. The selective reduction of cinnamaldehyde can however be
problematic. The use of bimetallic palladium-based catalysts has been reported to selectively
hydrogenate this compound to dihydrocinnamaldehyde, without any carbonyl reduction and
less than 3% over-reduction (Equation (58)) <2000AC(192)247>. Different catalysts have been
tested in the stereoselective hydrogenation of tetrasubstituted enones <1997SL117>. Best results
were obtained using Rh/alumina, whereas Pd/C, PtO2, Pt/Al2O3, Pt/C, [RhCl(COD)]2,
RhCl(PPh3)3, and [Rh(COD) (dppp)]BF4 gave lower selectivity, Ru/C and OsCl3 were ineffective
and cationic [RhCl(COD)]2-AgBF4 promoted (E)/(Z) isomerization (Equation (59)). The chemo-
selective reduction of unsaturated ketones has been reported using hydrogenation over Cu/SiO2
(Equation (60)) <1996TL3529>.
O O OH OH
PdCl2–0.5Co(OAc)2–PPh3*
+ +
Ph H Ph H Ph Ph
H2, EtOH, 4 h 97% 0% 3% ð58Þ
92%
* First reduced by NaBH4
O O
H2, Rh/alumina
ð59Þ
Benzene, rt, 2 h
92%
14 /1 syn /anti
O O
H2
ð60Þ
Cu/SiO2
97%
Several examples of hydrogenation of ,-unsaturated phosphonates have been reported. Most

of the reductions were performed on Pd/C using hydrogen <1995S539> or hydrogen donors
<2001TA319> (Equation (61)). The enhanced diastereoselectivity of phosphorus-substituted olefins
in heterogeneous hydrogenations has been studied <1997TL8627>. Enantioselective reduction of
vinylphosphonic acids and esters has also been described <1998TL3473> (Equation (62)).
HCOONH4 (6 equiv.), 5% Pd/C

ð61Þ
MeOH, ∆, 3 h P(OEt)2
P(OEt)2
87% O
O
H2 (10 atm), 1% (R)-MeO-BIPHEP-Ru
MeOH, 80 °C ð62Þ
P(OH)2 P(OH)2
O 100% O
77% ee
The reduction of various ,-unsaturated carboxylic acid derivatives (ester, amide, nitrile, and
carboxylic acid) can be conducted with metallic samarium and iodine in alcohol <1995SL443>
(Equation (63)). It provides an alternative to the well-known SmI2-mediated reductions
<1980JA2693, 1997TL2121>. The low-valent titanium complex Cp2TiCl selectively reduces
selected ,-unsaturated ketones via a postulated single-electron transfer mechanism
<2002TL2013> (Equation (64)). A chemoselective reduction of ,-unsaturated esters has been
reported with Mg in methanol (Equation (65)). Interestingly, the reaction did not occur when
absolute ethanol was used under similar conditions <1996S455>. Selectivity can also be achieved
using lithium in ammonia (Equation (66)) <2001S1305>. The use of iodotrichlorosilane, gener-
ated in situ from SiCl4 and NaI, has also been reported for the reduction of ,-unsaturated
ketones and nitriles <1996TL2297>.
Sm, I2, MeOH CONH2

CONH2 Ph
Ph ð63Þ
3 min
99%
O O
Cp2TiCl (2 equiv.)
Ph Ph ð64Þ
THF, MeOH
56%
CO2Me CO2Me
H
Mg, MeOH
ð65Þ
H 98% H
HO HO
Li, NH3, –78 °C

ð66Þ
O 86% O
H
,-Conjugated double bonds are readily reduced by various hydrides, including LiAlH4
<1997TL3471, 2001TL4609> (Equation (67)), K-selectride (Equation (68)) <1997T7209>,
sodium borohydride in the presence of nickel <2000TL4363>, copper <1998TL4971> (Equation
(69)) or indium <2002TL7405> salts, and the combination of Co(acac)2-DIBAL-H <1999SL96>.
Aluminum tris(2,6-diphenylphenoxide) (ATPH) acts as a receptor binding carbonyls and inhibits
the troublesome 1,2-reduction <1996JOC2928> (Equation (26)). The reduction of ,-unsatu-
rated nitriles can be conducted with NaTeH (Equation (70)) <1996T8611>.
O O
H H
N LiAlH4 (2 equiv.) N ð67Þ
70%
O
O
K-Selectride ð68Þ
36%
O O
NaBH4, CuCl2·2H2O
O O ð69Þ
MeOH, 0 °C
H 90% H
CN CN
NaTeH
ð70Þ
NC AcOH, EtOH, 24 h NC
85%
Copper hydride is an efficient reducing agent. It can be generated from several hydrosilanes
<1997CC2159> by transmetallations, and can selectively reduce unsaturated ketones whereas
congested enones are recovered unchanged (Scheme 6). The use of CuCN/DIBAL-H/BuLi as a
source of copper hydride has also been reported in the chemoselective reduction of tetrasubsti-
tuted conjugated double bonds <2001JOC944>.
O O
99%
Ph Ph
HSiPhMe2 (2 equiv.) O
O
CuF(PPh3)3.2H2O 0%
Scheme 6
The use of less than 5 mol.% (based on copper for 1/6 [(PPh3)CuH]6) of Stryker’s reagent
allows the catalytic conjugate reduction of ,-unsaturated ketones and aldehydes with Bu3SnH
or PhSiH3 as hydride donors (Equation (71)), the lifetime of the catalytic [(PPh3)CuH]6/PhSiH3
combination being greater <1998TL4627>. Mn(dpm)3 has also been reported as an effective
catalyst with PriOH as a proton source (Equation (72)) <2000TL9731>.
CHO CHO
[(PPh3)CuH]6 (5 mol.% Cu)
ð71Þ
PhSiH3, toluene (H2O)
80%
O
O
H
Mn(dpm)3 (3 mol.%),
H
H PhSiH3 (1.3 equiv.) ð72Þ
i H H
H H Pr OH/DCE
O
O dpm: Dipivaloylmethanato
Enantioselective reduction of ,-conjugated double bonds can be achieved by several ways.

Besides homogeneous asymmetric reduction <2003MI103>, impressive progress has been made
in the field of catalyzed asymmetric conjugate reduction of esters <1998S1655, 1999JA9473> and
cyclic ketones <2000JA6797>. An elegant kinetic dynamic resolution of 3,5-dialkylcyclopente-
nones has been reported based on this reaction (Equation (73)) <2002JA2892>. The use of
polymethylhydrosilane (PMHS) as a polymeric hydride donor greatly enhances the utility of
this catalytic process.
O
O 10 mol.% CuCl(S)-p -Tol-BINAP i
Pr
Pr i NaOBut, ButOH, PMHS
Toluene, 26 h, then TBAF ð73Þ
94% Ph
Ph 93 / 7 syn /anti
93% ee
The enantioselective reduction of tetrasubstituted nitroalkenes <2001TA309> can be performed

with Baker’s yeast (Equation (74)). With unsaturated ketones, isolated enzyme enables the reduc-
tion with similar enantioselectivity as with the whole cell (Equation (75)) <1998TL5225>.
Baker's yeast
NO2 NO2 ð74Þ
72%
20% de
98% ee
O O
Baker's yeast
O2N O2N
ð75Þ
32% conv./h
99% ee
1.03.2 REDUCTION OF ARENES AND HETEROARENES
1.03.2.1 Types of Reactions

The reduction of arenes and heteroarenes can be accomplished by a variety of methods. It is
generally more difficult than that of alkenes, dienes, or alkynes, since the resonance energy has to
be overcome <B-1996MI001>. Heterogeneous hydrogenation using a number of different metals
as catalysts has been reviewed <1991COS(8)417, 1996AC(137)203>. Such reductions are of great
importance in several industrial processes. More recently, homogeneous hydrogenation of arenes
has been reported <1991COS(8)443, 2003MI103>. Dissolving metal reductions have found
considerable applications in synthesis, and recent progress has been made in their use for the
asymmetric synthesis of saturated heterocycles <1996TA317, 1996PAC553>. The reduction of
electron-deficient heteroarenes by hydrides is also one of the methods to prepare partially
saturated compounds, as are electrochemical methods. The following sections will consider each
of these methods separately.
1.03.2.2 Heterogeneous Hydrogenation

Even though benzene hydrogenation was reported at the beginning of the twentieth century using
finely divided nickel as the catalyst <1901CR210>, the hydrogenation of monocyclic arenes is
still an active area of research <2003JMOC(191)187>. Industrial applications, such as cyclohex-
ane synthesis, partial arene hydrogenation to cyclohexenes, aromatic saturation of distillates,
polystyrene, or lignin hydrogenations, are important transformations that stimulate discovery
of new processes. Monocyclic arene hydrogenation is usually performed using heterogeneous
catalysts with metal activities decreasing in the order Rh > Ru > Pt > Ni > Pd > Co
<B-1996MI002>, and metal sulfides, generally less active but also less sensitive to poisoning by sulfur
compounds, and therefore used in petroleum refining <1996AC(137)203>. An efficient Zr-based
catalyst has been reported for arene hydrogenation <1998JA13533>, and partial reduction of
benzene has been described by lanthanide precipitates <2001CL450>. The use of soluble transi-
tion-metal nanoclusters for the reduction of monocyclic aromatic compounds is a growing
research area, and has been reviewed <2003JMOC(191)187>. Polyphasic reduction conditions
have been described, as well as the use of ionic liquids <2003MI216> as a reaction medium. The
ease of hydrogenation parallels the loss of resonance energy. Thus, reduction of phenanthrene
and anthracene will be easier than that of naphthalene, and easier than that of benzene
<B-1996MI001>. The mechanism of benzene saturation can be presented as a series of hydrogen
transfers from the catalyst to the adsorbed reactive intermediates <1991COS(8)417> (Scheme 7).
While diene intermediates are usually not observed, the partial reduction to cyclohexene is
possible, even on an industrial scale <1990MI25>. When using a catalyst composed of a rhodium
complex grafted on silica-supported dispersed palladium nanoparticles, an improvement of the
arene hydrogenation speed has been observed <2003AG(E)2636>. A synergistic effect has been
proposed, with the cyclohexadiene intermediate being more rapidly reduced at rhodium while
cyclohexene predominantly hydrogenated at palladium.
(g) C6H8 (g) (g) (g)
C6H6 (a) C6H7 (a) C6H8 (a) C6H9 (a) C6H10 (a) C6H11 (a)
Scheme 7
Although cis-isomers are the principal products of hydrogenation of substituted benzenes

(Equation (76)) <1997T12497>, a competition between the addition of the six hydrogen atoms
and the desorption of intermediates can exist, leading to the formation of trans-isomers through
partially desorbed saturated species. Fine tuning of the catalyst, as well as experimental condi-
tions (temperature, pressure) <1979JCA370> can change the isomer ratio, which is also depen-
dent on the nature of the substituents (Equation (77) and (78)) <1995TL885>.
CO2H CO2H
H2 (4 bar)
5% Rh/C ð76Þ
MeO2C CO2Me MeOH MeO2C CO2Me
95%
H2 (50 bar)
CO2Me CO2Me
RuCl3, TOA, MeOH
ð77Þ
Me 89% Me
TOA: Trioctylamine 15 /1 cis /trans
H2 (50 bar)
CO2Me CO2Me
RuCl3, TOA, MeOH
ð78Þ
NH2 80% NH2
TOA: Trioctylamine 6 /1 cis /trans
Hydrogenation of various xylene isomers using stabilized rhodium suspension has been
described (Table 3). The cis/trans ratio varied with the isomer <2003MI222>. Haptophilicity
can play an important role in the diastereoselective reduction of arenes. The functional-group
directed hydrogenation of a series of monosubstituted indanes and tetralins has been studied
<1999JOC8862>. The methyl group (Equation (79)) led only to a small preference for the cis,cis-
isomer, whereas the amino group (Equation (80)) strongly interacted with the catalyst, leading to
almost exclusively the cis,trans-saturated compound. Hydrogenation of 1-indanol revealed a mild
haptophilic effect of the hydroxyl group, and a substantial amount of hydrogenolysis was
observed. This side reaction could be minimized by changing the catalyst support (Scheme 8).
Table 3 Reduction of xylenes with a stabilized aqueous rhodium suspension

<2003MI222>
Isomer Product Ratio (cis/trans)
o-Xylene 1,2-Dimethylcyclohexane 97:3
m-Xylene 1,3-Dimethylcyclohexane 90:10
p-Xylene 1,4-Dimethylcyclohexane 70:30
o-Methylanisole 1-Methoxy-2-methylcyclohexane 98:2
p-Methylanisole 1-Methoxy-4-methylcyclohexane 84:6
Me H Me
H2 (15 bar)
2 1
3 ð79Þ
Rh/C, EtOH
H
93% 2,3-cis
1,2-cis /trans 63 /37
NH2 H NH2
H2 (15 bar) 1
2
3 ð80Þ
Rh/C, EtOH
H
100% 2,3-cis
1,2-cis /trans 2 /98
OH OH H OH H
H H
H2 (15 bar) H2 (15 bar)
2 1 2 1
+ 3
+
3
Rh/Al2O3, Rh/C, EtOH
H H EtOH H H
88% 2,3-cis 10% 19% 2,3-cis 77%

1,2-cis/trans 67/33 1,2-cis/trans 59/41
Scheme 8
The stereoselective hydrogenation of disubstituted phenyl rings over heterogeneous catalysts

has attracted some attention in recent years. Until now, the use of a covalently bonded chiral
auxiliary gave the best selectivities (Equation (81)) <2000TA1809, 2000CEJ949>, while the use of
chiral adjuvant in colloidal systems has been described to give poor enantioselectivity (Equation
(82)) <1994JMOC107>, but might provide an interesting entry for enantioselective reductions of
arenes in the future.
O N CO2Me O N CO2Me
H2, 5 MPa, EtOH
O O ð81Þ
Rh/Al2O3
Me (at 100% conversion) Me
90% de
H2, RhCl3
OTMS OTMS
Me Me Me ð82Þ
6% ee
N(C8H17)2
Since benzene hydrogenation requires generally strong reducing conditions, hydrogenolysis is a

classical side reaction in such a process. The amount of benzylic hydrogenolysis is generally
important with palladium, whereas the use of Ru or Rh, enabling the reduction under milder
conditions, can lead to chemoselective hydrogenations. A two-stage procedure has been described
for the chemoselective hydrogenation of a benzylic alcohol in the presence of another phenyl ring
(Scheme 9) <2002OL1951>. Among the various catalysts tested, Rh supported on graphite with a
high surface area proved to be the most potent catalyst for the selective hydrogenation of
bisphenol diglycidyl ether (Equation (83)). Surface properties of the catalyst are one of the crucial
factors in controlling the selectivity <2002CL1116>. A similar selectivity has also been obtained
with colloidal ruthenium (Equation (84)) <1995TL885>.
OH
OH
OH H2 (50 psi) Ph Me H2 (300 psi) OH

OH Rh /Al2O3 + Pt /C OH
Ph Me OH Ph
MeOH, AcOH MeOH, AcOH Me
OH
Ph 74%
Me
Scheme 9
O O O O
H2 (15 MPa)
Rh/graphite
ð83Þ
O O O O
Conversion: 100%
Residual epoxy groups: 97%
O O
H2 (50 bar)
RuCl3 / TOA, 1 h O ð84Þ

O
71%
TOA: Trioctylamine
The reduction of phenolic systems can lead to hydrogenated compounds, cyclohexanone, or

cyclohexanol derivatives. The production of cyclohexanone is of great industrial interest, and can
be achieved with Pd catalysts. In a comparative study on the influence of different supports and Pd
precursors in the selective hydrogenation of phenol to cyclohexanone, monometallic catalysts pre-
pared from PdCl2 showed the following activity and selectivity order: Pd/La2O3 > Pd/CeO2 >
Pd/Al2O3 (Equation (85)) <2002AC(235)21>. Addition of calcium strongly improved the catalytic
performance of the Pd/Al2O3 catalyst, but no significant improvement could be observed with other
supports. Formation of the cyclohexanol product is favored using rhodium or ruthenium catalysts.
Raney NiAl alloy enables the efficient saturation of phenol in dilute aqueous alkaline solution
without any solvent (Equation (86)). Naphthol is reduced as well, leading to the corresponding
tetrahydro-naphthalene (Equation (87)) <2000TL5865>. The reduction of polysubstituted phenols
can occur stereoselectively with nanocluster catalysts (Equation (88)) <1997CJC1234>.
OH O
Pd/La2O3, H2
ð85Þ
160 °C
Selectivity >90%
at 50% conversion
OH Raney-Ni–Al OH
aq. KOH
90 °C, 2.5 h ð86Þ
93%
OH Raney-Ni–Al OH
aq. KOH
90 °C, 3.5 h ð87Þ
93%
Pr Pr
H2
Rh(0) nanocluster
ð88Þ
MeO OMe 100% MeO OMe
OH OH
Aniline reduction can be performed over Rh or Ru catalysts. A stereoselective hydrogenation

of 4-aminobenzoic acid has been reported with Rh/Al2O3 as catalyst <1996JFC35>. The reaction
temperature (65 C) was critical since no reduction was observed at lower or higher temperatures
(10 C) (Equation (89)).
H2 (50 bar), 30% aq. EtOH

H2N COOH H2N COOH
Rh/Al2O3 (5%), AcOH, 65 °C ð89Þ
66%
Reduction of heteroaromatic systems can be performed under heterogeneous conditions. In

some cases, the presence of a cyclic heteroatom (N, S) can lead to the formation of strongly
coordinating species on hydrogenation, and catalyst inhibition. The addition of acid is often
helpful to prevent poisoning by protonation. Unlike -deficient heterocycles, such as pyridine and
related compounds, -excessive heterocycles such as pyrroles, furans, and analogs are more
difficult to reduce <1991COS(8)603>. In several cases, heterocycles can be more difficult to
reduce than a phenyl ring, enabling chemoselective hydrogenations <1996BMCL1753>.
Furan can be hydrogenated over various catalysts <B-1996MI001>, including Ru or Rh
catalysts. Although Pd is generally not very convenient for arene hydrogenation, it is the catalyst
of choice for furan reductions. A chemo- and stereoselective reduction of aryl-substituted furans
has been described <2000S2069>. The 3,4-cis/trans ratio variation with the substitution of the
phenyl ring suggests that the reduction did not occur via a 1,4-addition mechanism (Scheme 10).
Reduction of 2,5-disubstituted tetrahydrofurans has been investigated <1996S349>. While
Pd/C and Rh/Al2O3 proceeded with low selectivity, a diastereoselectivity up to 70% could be
obtained using Raney nickel. The change of PriOH to MeOH as a solvent led to a reversal of
stereoselectivity (Scheme 11). Catalytic hydrogenation of thiophene is problematic since noble
metal catalysts are poisoned and Raney nickel causes desulfurization. The reduction of polysub-
stituted thiophene over Pd has been described in a biotin synthesis (Equation (90))
<1977JOC135>.
MeO2C CO2Me R1
H2, 100 MPa 3 2
MeO2C CO2Me R1 R2
Pd/C (4–5%) O
MeOH, 100 °C
R2 R3
O
R3
MeO2C CO2Me R1
3 2
R2
O
Yield R3
Compound (%) 2,3-cis/trans ratio
R1 = R2 = R3 = H 91 100/0
1 2 3
R = H, R = R = OCH2O 76 72/28
1 2 3
R = H, R = R = OMe 71 67/33
1 2 3
R = R = R = OMe 83 67/33
Scheme 10
H2 (80 bar) H2 (80 bar)

EtO Raney-Ni Raney-Ni EtO
OH EtO OH
MeOH OH PriOH
O O
EtO C12H25 O EtO
EtO C12H25
85–95% C12H25 85–95%
70% de 63% de
Scheme 11
EtO2CHN NHCO2Et EtO2CHN NHCO2Et

H2 (10.3 MPa), 50 °C
CO2H CO2H ð90Þ
S 4
Pd/C, AcOH S ( )4
95%
Pyrrole and its derivatives are known to be strong catalyst poisons, and their hydrogenation
generally requires protonation or the use of electron-withdrawing N-protective groups. Raney Ni,
Pt, Ru, and Rh catalysts have been used in the saturation of pyrrole ring, in the presence of acids.
The reduction of 1-methyl-2-pyrroleethanol has been investigated in detail <1996AC(143)309,
1996AC(147)407>. With this substrate, best results were obtained with Rh/C, in a nonacidic
medium (Equation (91)). Ruthenium on carbon had also high activity at 80 C. A similar trend
has been reported with the hydrogenation of N-methyl pyrrole <1997AC(152)143>, whereas
hydrogenation of pyrrole required acidic conditions. 2,5-Disubstituted pyrroles can be reduced
in a stereoselective manner (Equation (92)) <1996TL131>, as well as 2,3-derivatives (Equation
(93)). In the latter case, the pendant aromatic ring was not hydrogenated <1995TL6185>. The
use of a chiral auxiliary has been reported in the diastereoselective hydrogenation of 2-acetyl
pyrrole derivatives (Equation (94)) <2001AC(210)165>. Although indoles are readily hydroge-
nated, it is generally difficult to control the site and degree of reduction <1991COS(8)603>. A
partial hydrogenation of N-t-BOC-indole-propanoate has been reported to occur over Rh/Al2O3
(Equation (95)) <1995TL8693>.
H2 (6 bar), rt
OH ð91Þ
N OH Rh/C (5%), MeOH N
Me Conversion: 100% Me
H2, Rh/Al2O3
MeO2C N CO2Me ð92Þ
MeO2C N CO2Me 45% Me
Me
H H H
H2 (500 psi), PtO2 O
O ð93Þ
N 97% N
O O
t-BOC t-BOC
O O
H2 (20 bar), Rh/C
N N
N MeOH, rt N ð94Þ
H
Me MeO2C Me MeO2C
Conversion = 100%
95% de
H Me
Me H2 (200 psi), Rh/Al2O3 (5%) H
N CO2Et 88% N CO2Et ð95Þ
t-BOC t-BOC
5:1 dr
Catalytic hydrogenation of pyridine is a classical method for the synthesis of piperidines.

Complete reduction generally occurs, as partially hydrogenated intermediates are reactive under
the conditions employed. Rh, Pd, and Ru catalysts can be used, generally under acidic conditions,
and Ni requires higher pressure and temperature <1991COS(8)579>. When performed under
acidic conditions, hydrogenation of pyridines can suffer from a lack of chemoselectivity

<1996TL459>. A mild procedure for the reduction of pyridine N-oxides over Pd has been
reported (Equation (96)) <2001JOC5264>. Several reducible functions are unaffected with this
method. Partial hydrogenation can be achieved using this procedure (Equation (97))
<2003JMC2216>. Only 10% of debenzylation was observed, whereas the hydrogenation of the
corresponding pyridine over PtO2 under acidic conditions led to nearly 50% of C2 reduction
(hydrogenolysis). Selective reduction of pyridinium salts can also be achieved under mild condi-
tions (Equation (98)) <2000OL4201>. Hydrogenation of the unactivated alcohol prior to the
formation of the benzylpyridinium salt affords product only of hydrogenolysis. The chemoselec-
tive reduction of pyridine in the presence of an indolic nucleus has been described
<1996TL3071>. Pyridine rings included in polycyclic systems can be partially (Equation (99))
<1995T1941> or fully hydrogenated (Equation (100)) <2000OL875>. In the latter case, the
cis-perhydronaphthyridine was obtained as the major isomer. Diastereoselective reductions of
pyridines bearing a chiral auxiliary have been reported (Equation (101)) <2000AC(201)107>.
A two-step, enantioselective reduction of ethyl nicotinate has been described using modified
catalysts, albeit with limited success (ee 20% at 10% conversion) <1999JMOC253>.
HCOONH4, Pd/C (10%)

Ph Ph
N N N N ð96Þ
H MeOH, ∆, 14 h H H
90%
O
CO2Et CO2Et
HCOONH4, Pd/C (10%)
N MeOH, rt, 17 h N ð97Þ
H
OBn 76% OBn
O
OMe
OMe
N OH
N OH H2 (1 atm), PtO2
Et3N–MeOH ð98Þ
100% N
N Bn
Bn Br
85/15 cis /trans
H2, PtO2, AcOH HN

N
MeOH, rt N ð99Þ
N
MeN
MeN 100%
O
O
H H
N H2 (1000 psi), Rh/Al2O3 N
ð100Þ
N AcOH, rt N
H H
95%
90/10 cis /trans
H
H2 (50 bar), 50 °C N
N N ð101Þ
N Pd/C, MeOH MeOSO3 Me O CO2Me
MeOSO3 Me O CO2Me
100%
94% de
Although hydrogenation of 3-hydroxy- or aminopyridines can result in hydrogenolysis, some

examples of such reductions have been reported (Equations (102) and (103)) <2000TL8413,
2001BMCL2337>. Hydrogenation of pyrazine–carboxylic acid can be conducted over Pd/C
catalyst <1999BMCL1121>. The reduction of quinoline under mild conditions has been
investigated using Pd, Rh, or Ru/Al2O3 catalysts. 1,2,3,4-Tetrahydroquinoline was the main
product obtained with Pd and Rh catalysts, while Ru proved to be inactive. Perhydrogenation
could not be achieved with increasing temperature or pressure, or in the presence of Brønsted acid
or base, whereas the addition of Hünig’s base enabled the partial formation of decahydroquino-
line <2002JMOC(179)287>.
OH OH
CO2H CO2H
H2 (80 psi), Rh/C
ð102Þ
N NH
conc. NH4OH, H2O
93 %
H2 (60 psi), PtO2 ð103Þ

N NH
H2N EtOH H2N
3/2 cis /trans
1.03.2.3 Homogeneous Hydrogenation of Arenes

The hydrogenation of monocyclic arenes with homogeneous transition metal catalysts is not a
simple task <1991COS(8)443>. Furthermore, several claimed ‘‘homogeneous’’ arene hydrogena-
tion catalysts can in fact be ‘‘heterogeneous’’ nanoclusters described in Section 1.03.1.1
<1998JA5653>. The fact that the lack of catalytic activity in benzene hydrogenation has been
sometimes proposed, erroneously, as a test for the homogeneous character of a catalyst illustrates
this problem. However, several systems have been developed and have been proven to be
homogeneous. Among them, allylcobalt catalysts <1979ACR324> with phosphine or phosphite
ligands or Ziegler-type catalysts <1963JOC1947> have been known for sometime. A new gen-
eration of homogeneous arene hydrogenation catalysts has been described <1997CC1331>. These
Nb or Ta hydrido aryloxide complexes catalyze the reduction of a large variety of aromatic
hydrocarbons, including benzene. The hydrogenation of [2H8]-toluene affords the all-cis isotopo-
mer (Equation (104)). Polycyclic aromatic hydrocarbons are much more easily reduced using
homogeneous catalysts. Hydrogenation of naphthalene and anthracene is catalyzed by Ru cata-
lysts (Equation (105)) <2001JMOC(174)69>. Interestingly, a decrease of conversion has been
noted with increase of pressure, suggesting that a dissociation of dihydrogen is needed for
substrate coordination. Benzene was also reduced under these conditions, but inhibition by
addition of Hg(0) suggests the formation of colloids in this case.
CD3
CD3
D D
D D
H2 (1200 psi), 80 °C ð104Þ
D D
D D [Nb(OC6HPh4-2,3,5,6)2Cl3]/BuLi (3 equiv.)
D
D
H2 (3 bar), 80 °C
[RuH2(H2)2(PCy3)2] ð105Þ
Cyclohexane, 24 h
conversion: 25%
Removal of heteroatoms from fossil fuels under hydro-treating conditions is an important

industrial process. The partial or total saturation of benzo[b]thiophene (Equation (106)), quino-
line, acridine, or indole has been investigated using Rh <2001HCA2895, 2002OM1430> or Ru
catalysts <2002JMOC(189)211, 2003OM1630>. The regioselectivity of quinoline reduction can
vary with the catalyst (Equation (107) and (108)).
H2 (35 atm), 136 °C
S RuHCl(TPPMS)2(An)2 S
Water/decalin ð106Þ
Conversion: 98%
TPPMS = m-sulfonato- An = aniline
phenyldiphenylphosphine
H2 (3 bar), 80 °C
N [RuH2(H2)2(PCy3)2] N ð107Þ
Cyclohexane, 24 h
Conversion: 100%
H2
N N ð108Þ
[Rh(DMAD)(triphos)PF6
H
DMAD = Dimethyl acetylidenedicarboxylate
Several enantioselective hydrogenations of heteroaromatic compounds have been reported

<1998OM3308, 2000M1335, 2003MI103>. The partial asymmetric reduction of N-acyl indoles
occurs in good enantioselectivity (Equation (109)) <2000JA7614>.
H2 (5 MPa)
[Rh(nbd)2]SbF6
((S ),(S))-((R ),(R))-PhTRAP
Bui Bui
N CsCO3, PriOH N
ð109Þ
Ac Ac
91% 91% ee
TRAP: 2,2"-bis(diphenylphosphinoethyl)
–1,1"-biferrocene
nbd: norbornadiene
1.03.2.4 Dissolving Metal Reductions

The reduction of aromatic compounds by dissolving metals is an extremely useful transformation.
Because of the much higher electron affinity of arene substrates over the products, the formation
of partially reduced compounds is generally favored under such reducing conditions. Although
the first example of the partial reduction of an arene with sodium in ammonia was reported by
Wooster and Godfrey <1937JA596>, this reaction has been extensively developed by Birch and is
now known as the Birch reaction <1991COS(8)489>. Since the reduction involves two electron
transfers and two protonation steps, the exact pathway followed will depend on the substitution
pattern of the aromatic ring, the choice of the metal, and the proton source. Thus, the mechanism
involving radicals, radical-anions, and anions might be more subtle than the simple general
reaction pattern summarized in Scheme 12. Furthermore, iron impurities contained in ammonia
have been shown to be a major cause for the lack of reproducible results in several reductions.
G G G
M/NH3 M/NH3
G = electron withdrawing G = electron donating
Scheme 12
The Birch reduction is of great synthetic interest, either for the reduction of simple arenes
(Equation (110)) <2003TA71> or for the selective reduction of polyfunctional compounds
<2002TL2913>. Chemoselective aromatic reduction can be achieved by tuning their substitution
pattern (Equation (111)) <2002BMCL1981>.
OH
i. Na /NH3, MeOH, THF
ii. 9-BBN, THF

ð110Þ
HO
iii. H2O2, NaOH
39%
MeO MeO
NH NH
Li / NH3, THF/ButOH (1:1)
–78 °C
ð111Þ
95%
OBn OBn
Although only simple reductions will be described in this section, quenching the reaction with an
electrophile can lead to a reductive alkylation process, which has seen important developments in
recent years, mainly by the groups of Schultz <1999CC1263> and Donohoe <2003OBC3749>.
Several heterocycles can be reduced using Birch conditions. Thiophene-2-carboxylic acid (Equation
(112)) <1997T6019>, electron-deficient pyrroles (Equation (113)) <1998JCS(P1)667>, pyridines
<2001JCS(P1)1435>, silylfuroic acids (Equation (114)) <1996TL9119>, or aminopyridines
(Scheme 13) <2003BMCL689> have been reduced using dissolving metal conditions. In the latter
case, the proton source had a strong influence on the outcome of the reduction.
i. LiOH, H2O S
S CO2H CO2H
ii. Li, NH3 ð112Þ
iii. NH4Cl
75%
t-BOC O
t-BOC O
Na (3 equiv.) N
N
N
N
NH3, THF, –78 °C ð113Þ
then NH4Cl
71%
O O SiMe3
SiMe3 i. Na/NH3, PriOH, –35 °C
ii. NH4Cl, –33 °C ð114Þ
CO2H CO2Me
iii. CH2N2
iv. H2, 10% Pd/C 2/1 trans/cis
41%
Li/NH3, THF/EtOH Li/NH3, THF/EtOH
–78 °C –78 °C N NH
N NH N NH2 then NH4Cl H
H then H2O
64% 66%
Scheme 13
The asymmetric protonation of an enolate resulting from Birch reduction has been studied. The
better selectivity observed with protonation than with other electrophiles has been discussed on
the basis of quantum chemical calculations (Equation (115)) <1999T12309>.
H
N Li/NH3, –78 °C N
N N ð115Þ
t-BOC O NH4Cl
OMe t-BOC O OMe
81%
90% de
Reaction conditions other than the standard Birch protocol (group I and II metals in liquid
ammonia) have been reported for the reduction of arenes. The most popular alternative is the
Benkeser reduction, using low-molecular weight aliphatic amines as a solvent <1991COS(8)489,
1984TL2089>. The use of ultrasonic irradiation can improve the reduction of aromatics with
calcium (Equation (116)) <2000MI53>. Ammonia-free reduction is possible using lithium
di-t-butylbiphenyl (LiDBB) as a source of electrons and bis(methoxyethyl)amine (BMEA) as a
protonating agent <2002JOC5015>. Interestingly, the stereochemical outcome of the Birch
reduction of disubstituted electron-deficient pyrroles can be reversed using this new process and
a bulky acid (Scheme 14) <2003OL999>. The use of titanium trichloride in water has been
reported for the reduction of nonbenzenoid annulenes (Equation (117)) <2003TL1271>.
Ca, BuNH2–EDA
ð116Þ
))))), 20 °C, PriOH
74%
Li, DBB (cat.), THF

MeO2C N CO2Me
then 2,2-di-Butphenol H H
t-BOC
80%
>10/1 cis/trans
MeO2C N CO2Me
t-BOC
Li/NH3, THF MeO2C CO2Me

N
H H
then NH4Cl t-BOC
80% 6/1 trans/cis
Scheme 14
Aq. TiCl3, NaOH

ð117Þ
THF, MeOH
99%
1.03.2.5 Hydride Reductions

Aromatic CC double bonds are generally not reduced by metallic hydrides, but the reduction of
nitrogen heteroaromatic compounds is a classical entry for the synthesis of partially saturated
heterocycles <B-1997MI>. With pyridines, the presence of electron-withdrawing substituents will
enable the controlled reduction with borohydrides to dihydro- or tetrahydropyridines
<1991COS(8)579>. Tetrahydropyridines can generally be obtained via their corresponding pyr-
idinium salts. Activation can be performed by intermolecular alkylation (Equation (118))
<1996TA2775, 1998T5959> or in an intermolecular manner (Equation (119))
<2001JCS(P1)654>. A similar activation has been reported for the reduction of pyrrazolidinium
salts (Equation (120)) <1996T9193>. Although pyrrole is inert to hydride-reducing reagents,
indoles are reduced by several borohydride species <1991COS(8)603>. The stereoselective reduc-
tion of several substituted indoles with NaBH3CN has been reported to yield the corresponding
indolines in a completely stereoselective manner (Equation (121)) <1998BMCL745>.
SiMe2But SiMe2But
Bn H
N i. BnBr, MeCN N
(CH2)4OSiMe2But (CH2)4OSiMe2But
H ð118Þ
ii. NaBH4, MeOH, 0 °C
71%
CO2Me
i. MsCl, Et N3 CO2Me
N H
ii. NaBH3CN, MeOH N ð119Þ
iii. NaBH3CN, pH = 4
OH 66%
O 2N Me O2N Me O2N Me
+ NaBH4
N Et Me N Et Me N Et ð120Þ
Me N N N
–
EtOH
Ph BF4 79% Ph Ph
80:20
Me Me
NaBH3CN, AcOH
Me Me ð121Þ
80–99%
N N
H H
1.03.2.6 Electrochemical Reductions

Electrochemistry can be a valuable tool for the selective reduction of arenes, and has been widely
explored by industry. Since the classical Birch reduction proceeds by successive electron transfers
and protonations, it is not surprising that electrochemistry can be a useful alternative to this
method, although synthetic organic chemists might be reluctant to use it. The electrochemistry of
solvated electrons and its use in hydrogenation of aromatics has been reviewed <1995RTC259>.
The generation of solvated electrons and Birch reduction of 3-methylanisole in liquid ammonia
has been studied <2001JEC(507)144>. The use of power ultrasound, leading to faster mass
transport and electrode depassivation, allows the process to be conducted with high overall
rate. Several substituted cyclohexadienes have been prepared by the electrochemical reduction
of the corresponding arene precursors (Scheme 15) <2002EJO4037>.
R R
Al-Anode, LiCl
R = SiMe 2OPri, R1 = H: 99%
THF/HMPA
R1 R1
R1 R 1 R = R1 = Me: 98%
ButOH, 0.1 A
Scheme 15
In some cases, large-scale preparative reductions can be achieved with the use of a tubular flow
cell. Electrocatalytic hydrogenation of arenes can be an alternative route to partially hydroge-
nated derivatives <2000MI4279>. The stereochemical outcome of the reduction of m-xylene has
been reported to be dependent on the potential on which the hydrogenation has been carried out
<2000MI4291>.
1.03.3 REDUCTION OF ALKYNES AND ALLENES

The reduction of triple bonds to alkanes is a typical side reaction observed during partial
hydrogenation of alkynes. Although this reaction is generally less interesting than the semihy-
drogenation, it could be useful to introduce an alkyl group in combinatorial chemistry, using a
two-step sp–sp2 coupling/full reduction sequence. Saturation of triple bonds can be accomplished
by hydrogenation, using heterogeneous <1991COS(8)417, 2002EJO2288, 1996SL1041> or homo-
geneous <1991COS(8)443, 1995JOC7170> catalysts. Hydrogen transfer conditions can be used in
such transformations <1996JMC2971>. The reduction of functional alkynes has been reported
with the LiNiCl2–naphthalene combination (Equation (122)) <1997TL149>.
O O
Excess Li
OH NiCl2·2H2O (2.5 equiv.) OH ð122Þ

Naphthalene (cat.)
90%
Conjugated diynes can be reduced under various conditions (Equation (123)) <1995TL8087,
2000CL1416>. The selective reduction of conjugated enynes has been reported (Equation (124))
<1995TL5891, 2000SL1205>, as well as the chemoselective hydrogenation of a triple bond in the
presence of a hydrogenolysis-sensitive protective group (Equation (125)) <1998JOC7990>.
H2, Pd/C
O O C7H15
O O ð123Þ
OH C7H15 AcOEt OH
94%
H2 (2 equiv.), Pd/C (5%)

Pyr (5 mol.%)
O
ð124Þ
MeOH O
O 72% O
O O
O
O
H2 O N
O N H ð125Þ
H Pd/C EDA (1:1)
77%
EDA = ethylenediamine
Acyclic allenes can be hydrogenated with high selectivity to monoenes over palladium catalysts
<1991COS(8)417>. Terminal allenes are generally reduced at the terminal double bond. Sodium/
ammonia reduction of 1-methyl-1,2-cyclononadiene provides mainly cis-1-methylcyclononene in
excellent yield (Equation (126)) <1975S194>. A similar approach can be used for the preparation
of 1,6-cycloundecadiene <1972S612>. The reductive metallation of butatrienes has been investi-
gated (Equation (127)) <1996T6149>. Experimental procedures had to be carefully optimized to
get reproducible results. The reduction of 3,5-divinylidenepiperidine has been conducted under
several conditions (Scheme 16) <2001JOM94>, leading to partial or full reduction. The -facial
selectivities of nucleophilic addition to allenecarboxylate derivatives has been investigated
<1995SL711, 2000JCS(P1)3188>. Interestingly, the borohydride reduction can lead to (E)-alkene
in a diastereoselective manner via an internal delivery of hydride (Equation (128)).
H2, Pd/C Na (10 equiv.)

N N NH3 N
77% Bu
Bu Bu 47%
65:35 dr
Scheme 16
Na, NH3
ð126Þ
95%
i. Li +
ii. H2O
ð127Þ
82% 14:86
OH
CO2Me
Et NaBH4, EtOH HO ð128Þ
Me CO2Me Me Et
69%
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Biographical sketch
Laurent Micouin was born in Clermont Ferrand in 1968. He studied at

the Ecole Nationale Supérieure de Chimie de Paris, where he obtained
diploma in engineering in 1990. He obtained his Ph.D. in the laboratory
of Professor H.-P. Husson (University Paris V) under the guidance of
Professor J.-C. Quirion in 1995. After a postdoctoral stay in Marburg
(Germany) as a Humboldt Fellow under the direction of Professor
P. Knochel, he got a permanent position in CNRS in 1996 and turned
back to Paris (UMR 8638, Faculty of Pharmacy, Paris V) as Chargé de
Recherche. His scientific interests include the development of new syn-
thetic methods in the field of asymmetric synthesis of nitrogen com-
pounds, using diastereoselective dipolar cycloadditions, enantioselective
desymmetrizations, or organo-aluminum chemistry, as well as the diver-
sity-oriented synthesis of bioactive compounds or tools for biological
investigations.
1.04
One or More CC Bond(s) Formed
by Substitution: Substitution
of Halogen
M. SANTELLI and C. OLLIVIER
CNRS – Université Paul Cézanne, Faculté des Sciences
et Techniques de St-Jérôme, Marseille, France
1.04.1 INTRODUCTION AND SCOPE 122

1.04.2 CARBANIONS WITH NO STABILIZING GROUP 122
1.04.2.1 Group I Metals (Li, K) 122
1.04.2.1.1 Alkylation of alkyllithiums generated by intramolecular carbolithiation
of alkenes 123
1.04.2.1.2 Alkylation of allyllithium and allylpotassium species 123
1.04.2.1.3 Reactivity of propargyllithiums 126
1.04.2.1.4 Alkylation of benzyllithiums 127
1.04.2.2 Group II Metals (Mg, Ba) 134
1.04.2.2.1 Alkylation of organomagnesiums 134
1.04.2.2.2 Alkylation of organobariums 134
1.04.2.3 Organocopper Derivatives and Copper(I)-catalyzed Couplings 135
1.04.2.3.1 Transmetallation of organolithium derivatives—reactivity of organocuprates 135
1.04.2.3.2 Transmetallation of organozincs 136
1.04.2.3.3 Transmetallation of organozirconiums 140
1.04.2.3.4 Transmetallation of organomagnesiums 140
1.04.2.3.5 Transmetallation of organosamariums 141
1.04.2.4 Pd(0)- and Ni(0)-Catalyzed C(sp3)–C(sp3) Cross-couplings 142
1.04.2.4.1 Pd(0)-Catalyzed couplings 142
1.04.2.4.2 Ni(0)-Catalyzed couplings 144
1.04.2.5 Miscellaneous Species with No Stabilizing Group 145
1.04.3 CARBANIONS WITH ONE STABILIZING GROUP 146
1.04.3.1 Enolates and Related Carbanions 146
1.04.3.1.1 Alkylation of enolates 146
1.04.3.1.2 Asymmetric alkylation of amide enolates 157
1.04.3.2 Oxygen-stabilized Carbanions 160
1.04.3.2.1 Alkylation of nonstabilized -oxycarbanions 161
1.04.3.2.2 -Alkylation of 1-oxysubstituted allyllithiums 165
1.04.3.2.3 -Alkylation of 1-oxysubstituted benzyllithiums 166
1.04.3.3 Sulfur-stabilized Carbanions 168
1.04.3.3.1 Alkylation of nonstabilized -thiocarbanions 168
1.04.3.3.2 -Alkylation of 1-thiosubstituted allyllithiums and related compounds 172
1.04.3.3.3 -Alkylation of 1-thiosubstituted benzyllithiums 174
1.04.3.4 Nitrogen-stabilized Carbanions 174
1.04.3.4.1 Alkylation of nonstabilized -amino carbanions 175
1.04.3.4.2 Alkylation of stabilized -amino carbanions 176
1.04.3.4.3 -Alkylation of 1-aminosubstituted allyllithiums 177
1.04.3.4.4 -Alkylation of 1-aminosubstituted benzyllithiums 178
121
122 One or More CC Bond(s) Formed by Substitution: Substitution of Halogen
1.04.3.5 Phosphorus-stabilized Carbanions 181

1.04.3.5.1 Alkylation of phospholane oxides in the -position 181
1.04.3.5.2 Alkylation of phosphonates in the -position 182
1.04.3.5.3 Alkylation of allylphosphonates 182
1.04.3.6 Silicon-stabilized Carbanions 183
1.04.3.6.1 -Alkylation of alkyl silanes 183
1.04.3.7 Boron-stabilized Carbanions 184
1.04.3.7.1 Reactivity of 1,1-borio-zincioalkane reagents 184
1.04.3.7.2 Reactivity of 1,1-borio-zirconioalkane reagents 185
1.04.4 CARBANIONS WITH TWO AND THREE STABILIZING GROUPS 185
1.04.4.1 C- versus O-Alkylation of -Dicarbonyls and Related Compounds 185
1.04.4.2 Alkylation of Oxazoline, O-Stabilized Carbanions 186
1.04.4.3 Alkylation of Enolate, S-Stabilized Carbanions 187
1.04.4.4 Alkylation of Enolate, N-Stabilized Carbanions 188
1.04.4.5 Alkylation of O,S-Stabilized Carbanions 190
1.04.4.6 Alkylation of O,N-Stabilized Carbanions 190
1.04.4.7 Alkylation of S,S- or Se,Se-Stabilized Carbanions 190
1.04.4.8 Alkylation of N,S-Stabilized Carbanions 191
1.04.4.9 Alkylation of N,N-Stabilized Carbanions 192
1.04.4.9.1 By intermolecular substitution 192
1.04.4.9.2 By intramolecular substitution 192
1.04.1 INTRODUCTION AND SCOPE

Carboncarbon bond formation involving substitution of halogen by a carbon center represents
undeniably the most common and important transformation in organic synthesis. In most cases,
the selective introduction of an alkyl, allyl, benzyl, or propargyl chain in place of hydrogen atom
at the carbon center of elaborated substrates has been achieved by generation of related
organometallics and subsequent quenching with haloalkanes. In the context of this chapter,
mainly based on the functionalization of tetrahedral carbons, discussions will be limited to
C(sp3)–C(sp3) bond formation. Coverage of structural studies and practical procedures will be
kept to a minimum.
A great deal of effort has been devoted to the preparation of mono- and dicarbanions and their
reaction with alkylating agents. In this area, a large number of metallation methods have been
disclosed in the literature and, among these, proton abstraction is by far the main strategy
employed for the functionalization of activated position adjacent to benzyl, allyl, heteroatoms,
or electron-withdrawing groups, which can stabilize the intermediate carbanion. Alternative
methods such as halogen- or selenium-exchange, tin–metal transmetallation, reductive cleavage,
and carbometallation have also been developed.
Tremendous progress has also been achieved in asymmetric synthesis for stereoselective CC
bond formation including asymmetric alkylation of organometallic compounds generated by
metallation of prochiral methylene groups. Several methods based on asymmetric deprotonation
by chiral bases or on auxiliary controlled alkyl introduction have been reported and found to be
particularly efficient, offering a high degree of control in the CC bond formation. The
enormous interest to catalytic asymmetric CC bond formation and the recent progress in
asymmetric enolate chemistry have been the focus of many studies in synthetic organic chemistry.
Selected examples will be discussed herein. Furthermore, applications of these metallation–
substitution sequences in natural product and solid-phase synthesis are beyond the scope of this
chapter.
1.04.2 CARBANIONS WITH NO STABILIZING GROUP
1.04.2.1 Group I Metals (Li, K)

The use of organolithium reagents has steadily increased since the early 1990s and have become of
significant interest in organic synthesis. For a long time, their high reactivity and basicity were
considered as major drawbacks for chemoselective transformations. However, some of the observed
side-reactions, such as Wurtz coupling, metal–halogen exchange, electron-transfer process, -metal-
lation, and - or -elimination have been widely exploited for synthetic purposes. Synthesis of
diastereomerically and enantiomerically enriched alkyllithiums has also been intensively studied.
One or More CC Bond(s) Formed by Substitution: Substitution of Halogen 123
A lot of attention has been turned to sequential asymmetric deprotonation followed by substitution
of alkyl halides. Since 1995, several investigations and synthetic applications have been developed in
this area and various aspects will be covered throughout this work <1997AG(E)2282,
2002AG(E)716>.
1.04.2.1.1 Alkylation of alkyllithiums generated by intramolecular carbolithiation

of alkenes
Anionic cyclization of organolithiums onto alkenes has found widespread applications in synthesis
to the preparation of nonaromatic heterocycles. Intramolecular carbolithiation of a terminal alkene
by an -amino-stabilized carbanion leads to a novel nonstabilized alkyllithium, which can be
trapped by alkyl halides. During the process, two CC bonds have been created from an acyclic
precursor. Coldham and co-workers have been interested in the synthesis of elaborated amino-
containing heterocycles from -amino organolithiums. The metallic species, generated by
tinlithium exchange from the corresponding stannane, proved to cyclize easily onto the unacti-
vated terminal alkene. The 3-lithiomethylpyrrolidine intermediate gave the desired 2-substituted
product by addition of allyl bromide (Equation (1)) <1996JA5322>. Furthermore, the 2-functio-
nalized 7-azabicyclo[2.2.1]heptane system was elaborated from the 5-allyl-2-tri-n-butylstannyl-
N-benzylpyrrolidine following a similar reaction sequence. Both trans- and cis-organostannanes
undergo a stereoselective cyclization leading to the common and unique 2-exo isomer (Equation (2))
<1999TL1819>.
Li
BunLi Allyl bromide

ð1Þ
N SnBu3 Hexane/ether (10:1) N N
58%
–78 °C to rt Ph
Ph Ph
i. BunLi
hexane/ether/ THF (4:1:1)
Bu3Sn –78 °C to rt Ph N
N ð2Þ
ii. Allyl bromide
Ph
60%
syn or anti
1.04.2.1.2 Alkylation of allyllithium and allylpotassium species
(i) Metallation through hydrogen abstraction by lithiated or potassium bases

Deprotonation of a simple alkyl chain in the allylic position usually requires the use of strong
bases. Metallation of 3-methyl-3-buten-1-ol followed by alkylation of its dianion with allylic
halides was introduced in 1974 <1974TL2215> and more recently applied by Brückner to the
synthesis of a butyrolactone precursor. The protocol involved the deprotonation of 3-methyl-
3-buten-1-ol with BunLi in the presence of TMEDA or using KH. Subsequent alkylation gave
moderate-to-poor results (Equation (3)) <1998EJO1023>. Later, Chong reexamined the metalla-
tion conditions and tried to generalize this methodology to other alkylating agents, in order to
apply it to the synthesis of natural products such as -geraniol <2001JOC8248>. Different
experiments revealed that the solvent has a significant effect on the metallation/alkylation yield.
Indeed, the best results have been reached for sequences achieved in diethyl ether with TMEDA
(Equation (4)).
i. BunLi
hexane, 0 °C to rt OR
ð3Þ
OH ii. Allyl bromide OH O OH
28–33% O
i. BunLi.TMEDA
OH
OH ether, 0 °C
ð4Þ
ii. (CH3)2C=CHCH2Br, –78 °C
84% γ-Geraniol
Ganesan and co-workers studied the alkylation of 1,5-cyclooctadienyllithium by Br(CH2)6OTHP

under various conditions. Lithium–potassium alkoxide reagents (LICKOR) metallation of
1,5-cyclooctadiene followed by reaction with alkyl halides gave the 3-substituted 1,5-cyclooctadienes
in high yields compared to a simple BunLi deprotonation with or without TMEDA as co-solvent
(Equation (5)) <2002JOC6250>. The poor yield observed in this case confirms Winkler and Sridar’s
results <1986JA1708>. Schlosser showed that 3-methyl-2,4-pentadienylpotassium, obtained by
deprotonation with LICKOR superbase, was easily alkylated by 1-iodobutane at the - and -position
without any selectivity by opposition to other electrophiles such as TMSX, CO2, or B(OMe)3. The
configuration of the trisubstituted double bond formed was proved to be (Z) (Equation (6))
<2001S1830>. A synthetic equivalent of acetone enolate was easily generated by metallation of methyl
isopropenyl ether with LICKOR base. The organolithium intermediate can be trapped by various
alkylating agents at low temperature. Above 30 C, the metallated methyl isopropenyl ether decom-
poses rapidly to form allene. Acid hydrolysis of the enol ether adducts led to the expected methyl
ketones (Equation (7)) <1997CB45>.
Yield
(CH2)6-OTHP Base (%)
i. Base
THF, –78 °C ð5Þ
BunLi 45
ii. Br(CH2)6OTHP LICKOR 76
(BunLi or ButLi–KOBut)
BunLi–KOBut BunI C4H9

+
67%
ð6Þ
C4H9
K 54/46 γ/α
>97/3 (Z )/(E )
OCH3 HCl O
OCH3 BunLi–KOBut OCH3 Br(CH2)3Cl THF/H2O
ð7Þ
THF/hexane K
85%
–80 to –50 °C Cl (2 steps) Cl
Oshima and co-workers <1997TL5189> reported the regioselective -alkylation of a 1-silylallyl-

lithium directed by an anionic oxygen present on the silicon atom (Equation (8)).
OK OH
OK BunLi SiPh2 EtI OH
SiPh2 +
SiPh2 THF 89% Et SiPh2
HMPA Li Et ð8Þ
–45 °C α-Adduct γ -Adduct
2/98 α /γ
2/98 (Z )/(E ) of γ-adduct
(ii) Selenium–lithium exchange

During his studies on the reactivity of 1,1-bis(metallomethyl)ethenes, Livinghouse has been inter-
ested in the generation of [2-((trimethylsilyl)methyl)prop-2-enyl]lithium and its synthetic utilization
as a versatile 1,3-bis(nucleophile). The lithiated propenyl silane can be prepared through lithium–
selenium exchange according to Krief’s methodology. Treatment of the corresponding allyl selenide
with BunLi affords the lithio compound, which can be alkylated by 1-iodododecane providing the
2-substituted allyl silane in excellent yield (Equation (9)) <1997JOC4842>.
BunLi n-C12H25I
ð9Þ
THF, –78 °C 83%
Me3Si SeMe Me3Si Li Me3Si n-C12H25
(iii) Reduction of acetals

Barbier-type reductive alkylation of vinyl dioxanes and vinyl dioxolanes with alkyl halides in
lithium 4,4-di-t-butylbiphenyl (LiDBB) solution has been developed by Thompson and co-workers.
<2002JOC6503> and applied to the synthesis of phospholipids such as plasmenylcholines, used
for the delivery of low-molecular-weight drugs, proteins, and genes. LiDBB induces the reductive
acetal ring opening, and the reaction of the resulting allyllithium species with haloalkanes leads to
the (Z)-enol ethers in moderate yields (Equation (10)).
TBDMSO
Li O O
TBDMSO HO
TBDMSO Li O O
– P
Li, DBB n-C13H27I O
OLi O O O ð10Þ
O O THF, 0 °C TBDMSO 47% +
Me3N
C13H27 C13H27
OLi O
98/2 (Z )/(E ) Lysoplasmenylcholine
Li
(iv) Carbolithiation of aromatic rings

Recently, Clayden and co-workers reported the intermolecular addition of organolithium com-
pounds to hindered aromatic amides instead of their usual ortho-lithiation, without resorting to
the arene-chromiumtricarbonyl chemistry. Regioselective nucleophilic attack of various organo-
lithium compounds to N-benzoylamides of 2,2,6,6-tetramethylpiperidine gives the corresponding
dearomatized enolates, which can be alkylated by a range of alkyl and benzyl halides. Highly
substituted cyclohexadienes are obtained in moderate-to-good yields giving the trans-adducts as a
single diastereoisomer (Equation (11)) <2002CC2138, 2002EJO3558>.
N O N OLi N O
BusLi MeI
THF, –78 °C rt ð11Þ
H
71%
Me
OMe OMe OMe
(3:1 Mixture of diastereoisomers)
Kündig and co-workers <1992AG(E)1071, 2001S2040> developed two interesting approaches

for the synthesis of enantiomerically enriched trans-disubstituted cyclohexadiene compounds from
aromatic rings. Both routes are based on either regio- and diastereoselective addition of organo-
lithium reagents to chiral nonracemic phenyloxazolinechromium tricarbonyl complexes (Equation
(12)) or asymmetric addition of lithiated C-nucleophiles in the presence of a chiral ligand
(Equation (13)) <1996JOC2258> followed by quenching with allyl or propargyl bromide. High
diastereomeric (>98% de) and enantiomeric excesses (up to 93%) were reached for methyl-, vinyl-
and phenyllithium additions. An elegant application to the synthesis of bicyclo[3.3.0]octan-3-ones,
via an intramolecular Pauson–Khand cyclization of 1,6-enynes, is depicted in Equation (14)

<1997JA4773>. Finally, sequential addition of 2-lithio-1,3-dithiane and allyl bromide to -benzene–
molybdenum complex was recently reported in the literature (Equation (15)) <2002AG(E)4577>.
H H H
But But But
O N O NLi N
RLi R1X O
R
THF, –78 °C –78 °C R
H
(CO)3Cr (CO)3Cr R1 ð12Þ
RLi R 1X Yield (%) dr (anti /syn)
MeLi Allyl bromide 58 >98/2

– Propargyl bromide 79 >98/2
– Mel 58 >98/2
PhLi Allyl bromide 54 92/8
N i. PhLi, L*
O Ph Ph Me Me
toluene, –78 °C O N
L*: or
ii. Propargyl bromide MeO OMe MeO OMe ð13Þ
Ph
HMPA
93% ee 81% ee
–78 °C to rt
(CO)3Cr
66–72%
O
SiMe3
MeO i. LiCH2CCTMS i. Co(CO)8 H H
Me3Si
SiMe3 THF, –78 to 0 °C CH2Cl2
O ð14Þ
ii. Allyl bromide ii. NMO O
–78 °C to rt H SiMe3
88%
Cr(CO)3 iii. p-TsOH, H2O SiMe3 100% de, 90% ee
40%
S –
Li
S i. Methallyl bromide
S S S
S Me –78 °C to rt
ð15Þ
THF H ii. CO, 4 atm
(CO)3Mo +
–78 to –40 °C (CO)3Mo Li 68%
1.04.2.1.3 Reactivity of propargyllithiums

Alkylation of propargyl organolithiums can occur either in the propargylic or in the allenic
position, but usually after equilibration a mixture of both forms is observed. To solve this
problem of regioselectivity, other metals such Al, B, Zn, or Sn were tested with success
leading to the acetylenic adducts. Later, Oshima and co-workers <1998SL1096> reported the
effect on the regioselectivity of an anionic oxygen presents on the silicon atom. Treatment of the
dilithiated 1-alkynylsilanol with methyl iodide afforded the alkylated compound in the pro-
pargylic position (regio, 97:3). The reaction proceeds in a regioselective manner contrary to
1-alkynyldiphenylmethylsilane. In this case, a 89:11 ratio in favor of alkyne derivatives was
observed (Equation (16)).
Li OLi
Me OH
SiPh2
ButLi (2 equiv.) SiPh2
OH HMPA i. MeI +
Me SiPh2 THF, –78 °C Li ii. H2O ð16Þ
76% SiPh2
SiPh2 HO
LiO
Regio = 97/3
1.04.2.1.4 Alkylation of benzyllithiums
(i) Metallation by lateral hydrogen abstraction with lithiated bases or via

tin–lithium transmetallation
Benzylic organolithium compounds have a high tendency to undergo a rapid configurational
inversion compared to those bearing -heteroatoms. However, intramolecular lithium chelation
with the carbonyl group of amides or with heteroatoms can efficiently stabilize the intermediate
metallic species at low temperature, and no inversion is observed. For example, Clayden and
co-workers <2001JA12449> have reported the atroposelective lateral lithiation of aromatic
amides followed by an electrophilic quenching. The sequence involved deprotonation by BusLi
of naphthamides in the benzylic position (Equation (17)) <1997TL2561> or tin–lithium exchange
at 78 C (Equation (18)) <1997TL2565> followed by alkylation with ethyl iodide. The organo-
lithium intermediate proved to be configurationally stable and led preferentially to the anti-
product. The same diastereomeric ratios have been reported for the transmetallation at 78
and 40 C on the anti-stannane, but NMR studies on the syn-isomer showed no stereospecificity
in both organolithium formation and its subsequent alkylation explaining the inversion of
selectivity leading to the anti-product.
O N(Pri)2
O N(Pri)2 i. BusLi Et
THF, –78 °C
ð17Þ
ii. EtI
71% anti
97/3 dr
O N(Pri)2
SnBu3
O N(Pri)2 O N(Pri)2
i. BunLi
Et Et
THF, –78 °C
anti +
ii. EtI in excess
O N(Pri)2
–78 or –40 °C
SnBu3 ð18Þ
anti syn
Temperature Yield
syn Isomer (°C) (%) Ratio (anti /syn)
Anti –78 97 99/1

- –40 94 98/2
Syn –78 87 60/40
- –40 83 60/40
Asymmetric lateral lithiation of benzamides promoted by BusLi/(–)-sparteine proton abstrac-

tion (Equation (19)) or by BunLi/(–)-sparteine tin–lithium exchange (Equation (20)) was reported
by Beak and co-workers. Alkylation of the benzyllithium intermediate with alkyl halides takes
place in high yield and provides the related adducts with high enantiomeric ratios specially
if chlorides are used instead of bromides or iodides. A dynamic kinetic resolution, where a
rapid equilibration between both diastereomeric lithiated benzamide/(–)-sparteine complexes
occurs and where one diastereomeric organolithium/(–)-sparteine complex is more reactive with
the haloalkane than the other one, is operating. The asymmetric induction is controlled by the
complex/electrophile interaction in the transition state <1997JA8209>. (R,R)-1,5-Diaza-cis-
decalin used as ligand conferred modest-to-poor selectivity and the opposite configuration was
produced <2000OL875>. An application to the formal synthesis of both enantiomers of curcu-
phenol from a 2-ethyl-m-toluamide derivative was published by Kimachi. High and opposite
enantioselectivities were observed for the tertiary and secondary amide metallation–alkylation
sequences (Equation (21)) <2001JOC2700>.
i. BusLi.(–)-sparteine H
pentane/MTBE N
N O N O
–78 °C
N
ii. CH3(CH2)3Cl
H ð19Þ
(–)-sparteine
95%
MTBE = Methyl t-butyl ether
90/10 er
i. BunLi.(–)-sparteine
N O pentane/MTBE Stannyl compound (S/R) er
SnBu3 N O
–78 °C 50/50 94/6 ð20Þ
ii. Allyl chloride 91/9 91/9
(R)
62–69%
O i. BusLi.(–)-sparteine O
NR1R2 pentane, –78 °C NR1R2

ii. RX R
OH
ð21Þ
Yield ee
RX R1 R2 (%) (%)
(Me)2 C=CH(CH2 )2 Br Pri Pri 66 92(R)–(+)

Allyl chloride H n-C8H17 56 80(S)–(–)
(R)-(–) or (S)-(+)-Curcuphenol
Lateral lithiation of N-pivaloyl-o-ethylaniline in the presence of (–)-sparteine forms a config-

urationally stable diastereomeric complex at low temperature, which equilibrates at 25 C to the
thermodynamically favored diastereomer and reacts with alkyl halides at 78 C (Equation (22)).
Here, the substitution involves a dynamic thermodynamic resolution (for a review on this topic, see
Beak and co-workers <2000ACR715>). This implies that a warm–cool protocol is required for
inducing high enantioselectivities. The asymmetric induction is again controlled by the intermedi-
ate organolithium/chiral ligand complex in the transition state <1996JA1575, 1997JA8209>.
PivNH i. BusLi
PivNH
MTBE, –78 °C
ii. (–)-sparteine, (S) ð22Þ
–25 to –78 °C
iii. Allyl bromide 86% ee
67%
Reactivity of -lithiated--phenylcarbamides in the presence of (–)-sparteine was also investi-

gated. As shown previously, the enantioselectivity is induced in the post-deprotonation step
through a dynamic thermodynamic resolution and a possible contribution of dynamic kinetic
resolution <1996JA11391, 2002JOC6797>. When -methylbenzylamine is used as chiral auxili-
ary, the -lithiation–substitution sequence involves complete diastereocontrol <1998JOC2>.
Applications to dihydrocoumarin and 1,2,3,4-tetrahydroisoquinoline derivatives are shown
(Equations (23) and (24)) <1998JOC2, 2002JOC6797>.
O
O
BusLi.(–)-sparteine Spart..Li
MeO NH
MTBE/ THF (3:1) MeO N
Li.Spart.
–78 °C
Ph ð23Þ
PhCH2Br Ph O
–78 °C MeO
MeO NH
86% NH
Ph
89/11 er 95/5 dr
Me Me
BunI
HN Ph BusLi.TMEDA Li N Ph –78 to –10 °C
O Et2O, –78 °C OLi 63%
OMe OMe
ð24Þ
Bun O Me Bun
N Ph er > 99/1 from the major

H amide diastereoisomer
OMe O O
93/7 dr
Beak extended his studies to the asymmetric alkylation of lithiated cinnamylamines in the
benzylic position. The 3-allyllithium/(–)-sparteine complex intermediate, generated by metalla-
tion with BunLi/(–)-sparteine and characterized by X-ray <1998AG(E)2522>, can be trapped
by various alkyl halides leading to the desired enantiomerically enriched subtituted products
(Equation (25)). The substitution proceeds through an anti-SE0 reaction. Stannylation of the
intermediate followed by lithium–tin exchange in the presence of (–)-sparteine and methylation
led to the opposite enantiomer <1996JA12218, 1998AG(E)2522>.
BunLi. Ph
Ph Ph H
(–)-sparteine BnBr
spart..Li N
N Et2O, –78 °C Ar 88% N
t-BOC Ar t-BOC Ph Ar
t-BOC
Ar = p -MeOC6H4 98/2 er
Me3SnCl
BunLi.
H Ph
Ph (–)-sparteine
SnMe3
spart..Li N ð25Þ
N Et2O, –78 °C Ar
t-BOC Ar t-BOC
95/5 er Allyl bromide
Ph
H
N
Ar
t-BOC
90/10 er
(ii) Selenium–lithium exchange

Benzyl selenide bearing an -alkenyl chloride side-chain reacts with BunLi to provide exclusively
the trans-1-aryl-2-vinyl cyclopropane in high yield from any of the (E)- and (Z)-stereoisomers of
the -alkenyl chloride moiety. This one-pot process involves lithiation in the benzylic position by
selenium–lithium exchange followed by intramolecular SN20 reaction which liberates the vinyl
cyclopropane (Equation (26)) <1997TL8085>.
SeMe BunLi Li Ph
Ph Cl THF/hexane Ph Cl
–78 °C ð26Þ
E 75% 96/4 dr
Z 89% 93/7 dr
(iii) Lateral lithiation on arene chromium complexes

Axially chiral benzamides (Equation (27)) and anilides (Equation (28)) can be prepared by
desymmetrization of the corresponding prochiral arenetricarbonylchromium complexes through
enantioselective deprotonation with a chiral lithium amide base followed by electrophilic sub-
stitution. High enantiomeric enrichments were observed. The chromium complex was removed by
air oxidation and sunlight irradiation giving the axially chiral benzamides and anilides without
modification of the optical purity <2000SL1145, 2000OL1907, 2002JOC1929>.
O NEt2 O NEt2
i. BunLi.L* (Rax)
THF, –78 to –30 °C L*: N
H ð27Þ
ii. MeI, –78 °C
(CO)3Cr 85% (CO)3Cr
((R),(R))
86% ee
R i. BunLi.L1* or L2* O
O
Me THF Me O2
O N N R Me
–78 to –30 °C (Rax) hν N R
(Rax)
ii. BnBr Et2O
58%
Ph 0 °C Ph
(CO)3Cr (CO)3Cr
ð28Þ
R = p -MeOC6H4 L1* = N 94% ee

H
((R ),(R ))
Ph
N
R = But L2* = 94% ee
N NH-CH2But
Me
Brocard reported the selective proton abstraction of tricarbonyl(6-1-t-butoxycarbonyl-

2,3-dimethylbenzene)chromium in the benzylic position. Treatment of the arenechromium with
KOBut and methyl iodide gave preferentially the o-ethyl complex versus the m-ethyl complex
(Equation (29)) <1996JOM87>.
CO2But i. KOBut CO2But

ii. MeI
ð29Þ
iii. H2O
(CO)3Cr 82% (CO)3Cr
(iv) Competition between ortho- versus benzylic lithiation

Benzene derivatives substituted by a directing functional group can be easily metallated at the
ortho-position. With methylated substrates, deprotonation also takes place in the benzylic
position due to the intrinsic high acidity of the related protons. This chemistry has been reviewed
in 1995 by Clark and Jahangir <1995OR1>. More recently, Iwao showed that the lateral
lithiation of 4,4-dimethyl-2-(o-tolyl)oxazolines proceeds in THF or Et2O at 78 C by treatment
with BusLi, whereas in the presence of TMEDA in Et2O the ortho-alkylation is favored. The
resulting organolithium is quenched with methyl iodide (Equation (30)) <2002TL9069>.
O N i. BusLi, –78 °C O N O N
additive/solvent
+
ii. MeI, –78 °C
α -Alkylation o -Alkylation
ð30Þ
α -Alkylation o-Alkylation
Solvent Additive (%) (%)
THF 91 4
THF TMEDA (1 equiv.) 95 5
Et2O 81 1
Et2O TMEDA (1 equiv.) 14 68
Hlasta and co-workers <1996TL1335> have reported the selective directed ortho- versus
benzylic metallation of substituted N,N-diethylbenzamides followed by electrophilic substitution.
Ratios of - to ortho-lithiation products were shown to be dependent upon the anion formation
under kinetic conditions, the nature of the alkyl halide and the side-chain (Equation (31)).
CONEt2 i. LDA, THF, –78 °C CONEt2 CONEt2

+ ð31Þ
ii. EtI, –78 °C
79% 15:1
Studies on the metallation of secondary and tertiary p-tolylsulfonamides were carried out by
Snieckus and co-workers <2001JOC3662>. Kinetic and thermodynamic controlled deprotonation
lead to ortho- and benzylic metallation products, respectively. Consequently, the reaction of
secondary and tertiary p-tolylsulfonamide with BunLi gives either the ortho-anion at low tem-
perature (78 C) or the benzylic position is metallated under thermodynamic conditions using
BunLi or the Lochmann–Schlosser superbase (BunLi/ButOK) at room temperature. Methylation
of each anions gave the alkylated compounds in high yields (Equation (32)).
O O O
NEt2 NEt2 NEt2
O S i. BunLi O S i. BunLi O S
THF, –78 °C THF, –0 °C to rt
ð32Þ
ii. MeI ii. MeI
92% 83%
Deprotonation of thiobenzamides and thionaphthamides with BusLi readily forms a yellow

monoanion. Addition of a second equivalent of base results in lateral metallation. In the presence
of methyl iodide, the dianion was alkylated at sulfur atom and benzylic carbon center, then the
corresponding thioimido ester was isolated in high yield (Equation (33)). No ortho-metallation
product was detected <2002EJO2573>.
S NHMe LiS NMe S NHMe

BusLi MeI
ð33Þ
Li
THF, –78 °C 87%
(v) Lateral lithiation of heterocycles

Several groups have also been interested in benzylic metallation of heterocycles. Regioselective
lithiation of the CH activated benzylic position of 6-methyluracil (Equation (34)) <1996H1687>,
3-methyl-4-phenylsydnone (Equation (35)) <1998SL667>, 2-methyloxazole (Equation (36))
<1991JOC3058>, or 5-methyl-tetrazole (Equation (37)) <1996TL3655> with alkyllithium bases
results in the corresponding lithio heterocycle, which can be trapped by benzyl, allyl, or alkyl halides.
O i. LiHMDS O
N THF, –78 °C N
ð34Þ
O N ii. PhCOCH2Br, –50 °C O N
Ph
79% O
Li
+ +
N Ph BunLi + Allyl bromide N
N N Ph Ph ð35Þ
N N
O THF, –90 °C –90 °C
– O O
O – 67% O–
O
N Ph i. BunLi, THF, – 78 °C N Ph
O Br ð36Þ
ii. O
65%
Yield
N N RX (%)
N i. BunLi, THF, –78 °C N
R ð37Þ
N N N N BnBr 73
ii. RX, –78 °C to rt CyclohexylCH2Br 53
Tr Tr
n-BuBr 65
(vi) Carbolithiation of styrene systems

Carbometallation of alkenes, and particularly styrene systems, has progressed since the 1990s and
numerous reviews have been published dealing with this topic <B-1998MI271, 1999JCS(P1)535,
2001T5899>. Carbolithiation of unactivated olefins involves two CC bond formation in a one-
pot procedure by addition of an alkyllithium to the double bond. The new organometallic
generated can be trapped by an electrophic carbon. For example, Lai and Chen published the
stereoselective attack of cyclophanene derivatives by BunLi. Electrophilic quenching of the
aromatic indenide anion gave the ring-contracted adduct in good yield and with a high level of
diastereoselectivity (Equation (38)) <2003TL23>.
Bun
i. BunLi Me
THF, 0 °C ð38Þ
S SMe
ii. MeI
87%
Regio- and stereoselective carbolithiation of cinnamaldehyde can be used for the preparation of
enantiomerically enriched ,-substituted aldehydes. This approach, designed by Normant,
involves the addition of organolithiums to lithium aminoalkoxide derivatives of cinnamaldehyde,
and subsequent substitution of methyl iodide by the intermediate anion. Enantiomeric excesses up
to 93% have been measured (Equation (39)) <2001TL1883>. Finally, asymmetric carbolithiation
of (E)-cinnamyl alcohol by BunLi in the presence of (–)-sparteine leads to a red solution of benzyl
organolithium which can be trapped directly by methyl iodide. Formation of both contiguous
stereogenic centers has been controlled with a diastereoselectivity up to 96% and good level of
enantioselection (82% ee) (Equation (40)) <1995JA8853>.
OLi Ph i. BunLi Me O Me
THF, –20 to 0 °C NaBH4
N
Ph N Ph H Ph OH ð39Þ
ii. MeI, THF, –78 °C MeOH
Ph Bun Bun
iii. HCl
83% >95% de; 93% ee
Bun Bun
Ph BunLi.(–)-sparteine MeI
Ph Ph
OH Cumene 63% ð40Þ
0 °C Li OLi Me OH
>96% de, 82% ee
Stereoselective addition of ButLi or lithium anion of isobutyronitrile to ortho-substituted

tricarbonyl(styrene)chromium(0) derivatives was developed by Davies (Equation (41))
<1995SL69> and Gibson (Equation (42)) <1996JCS(P1)1007>, respectively. Arene-chromium-
tricarbonyl complexes proved to stabilize the benzylic carbanion and then favor the
carbometallation process. In addition, substituents present in the ortho-position showed their
influence on the stereoselectivity of the process. Application to the stereoselective synthesis of
cyclopropanes, prepared from -chloro organometallics, was also presented and is depicted in
Equation (42) <1996JCS(P1)1007>.
hν, O2,
Me Me
i. ButLi, THF, –78 °C Et2O
t
CH2Bu CH2But
ii. MeI, H 100% H ð41Þ
(CO)3Cr OMe (CO)3Cr
–78 to –30 °C OMe OMe
(1'(R))-(+) 72% >99% de, (1'(R),2(R))-(+) (2(R))-(+)
SiMe3 SO2Ph SiMe3 i. LiCMe2CN SiMe3

H ,LDA Me
Cl THF, –78 °C
H CN ð42Þ
(S) (S ) ii. MeI
40%
Cr(CO)3 H SO2Ph Cr(CO)3 –78 to –20 °C Cr(CO)3
61%
(>98% de) (–) (>98% de)
(vii) Reduction of dioxanes or ethers

An alternative to the previous carbometallation of cinnamyl alcohol strategy was proposed by
Azzena. Reductive lithiation of diastereoisomeric mixtures of 4-aryl-5-methyl-1,3-dioxanes gave
the corresponding -oxy-substituted benzyllithium intermediates with epimerization at the
benzylic center. A rapid interconversion led to diastereoisomeric organolithiums stabilized
by intramolecular chelation. Electrophilic substitution of alkyl and benzyl halides furnished
2-methyl-3-substituted-3-phenyl-propan-1-ol adducts in satisfactory to high diastereoselectivities
(Equation (43)) <2002TL5137>. Knochel and co-workers <1999AG(E)1457> reported the
reductive lithiation of a ferrocenyl ether by treatment with lithium naphthalenide. The inter-
mediate -ferrocenyllithium reagent reacts stereoselectively with benzyl bromide with complete
retention of configuration to give new chiral ferrocenyl derivatives (Equation (44)).
OLi OLi
O O Li O Li O i. i-Propyl bromide OH
Excess Li –80 °C
Ar Ar Ar Ar ð43Þ
THF, –78 °C ii. H2O
Me 70%
Ar = p -MeOC6H4 85/15 dr (anti/syn)
OMe Bn
Ph i. Li-Naphthalenide Ph
Fe SiMe3 Fe SiMe3 ð44Þ
ii. BnBr
–78 °C to rt
92% >99% ee
1.04.2.2 Group II Metals (Mg, Ba)
1.04.2.2.1 Alkylation of organomagnesiums

Since the historical discovery of Grignard in 1900, organomagnesium reagents have been widely
used for organic transformations. Numerous published reports dealing with the preparation and
the reactivity of these species prove that they are extensively utilized in synthesis. More recently,
Hoffmann has investigated the formation of Grignard reagents by carbenoid-homologation and
carbenoid-CH insertion reactions. A diiodoalkane treated with 3 equiv. of isopropylmagnesium
chloride first undergoes magnesium–iodine exchange giving the -iodoalkylmagnesium com-
pound. The second equivalent of isopropylmagnesium generates the expected Grignard reagent
and a variable amount of rearranged Grignard compound, which depends on the nature of
the solvent (THF or ButOMe). Therefore, the organomagnesium intermediate can be trapped
by -bromomethylacrylate (Equation (45)) as well as allyl iodide (Equation (46)) without any
magnesium–iodine exchange detected <2000AG(E)1462>.
MgCl
I (3 equiv.) I I –60 °C
Ph Ph + MgCl Ph
I THF, –78 °C MgCl Mg
ð45Þ
MgCl Br
CO2Et CO2Et
Ph + Ph
–90 to –78 °C Ph CO2Et
91% 77:13
i.
MgBr
MTBE/ THF (10:1)
Me3SiO I Me3SiO Me3SiO
–105 to –10 °C ð46Þ
+
I
ii. Allyl iodide, –10 °C
11% 58%
Titanocene-catalyzed double alkylation of styrene with alkyl halides in the presence of

BunMgCl was developed by Kambe and co-workers <1998JA11822>. The reaction involves
formation of a benzyl titanium intermediate through a radical pathway, and transmetallation
with BunMgCl. The resulting Grignard reagent can react with the second equivalent of haloalkane
(Equation (47)).
Cp2TiCl2 (cat.)
BunMgCl, THF, 0 °C Ph
Ph + ButBr + n -C5H11Br But ð47Þ
88%
1.04.2.2.2 Alkylation of organobariums

An efficient preparation of chiral-substituted (Z)-enol ethers involving isomerization of allylic
ethers and alkylation was developed by Langlois and co-workers <2000TL337>. Lithiation of allylic
ethers with BusLi followed by substitution of allyl halides gave poor yields of the corresponding
enol ethers. However, a prior transmetallation of the lithium homoenolate intermediates

with BaI2 and electrophilic quenching afforded the -alkylated products in good yields (Equations
(48) and (49)).
OMe OMe
OMe i. BusLi
i. BusLi.HMPA BaI2, THF
THF, –78 °C –78 °C
ð48Þ
O ii. Allyl bromide ii. Allyl bromide O
26% O 65%
i. BusLi
BaI2, THF, –78 °C
ii. I OTBS
60% EtO
EtO ð49Þ
i. BusLi.HMPA
THF, –78 °C OTBS
ii. I OTBS
48%
1.04.2.3 Organocopper Derivatives and Copper(I)-catalyzed Couplings

Organocopper chemistry represents a highly versatile tool for the transformation of organic mole-
cules. Highly efficient synthetic methods were developed and used for natural product synthesis as
well as preparation of fine chemicals. Conjugate addition, carbometallation of alkynes and alkenes,
SN20 allylic alkylations, and Sonogashira coupling reactions have been extensively investigated. A
majority of organocopper reagents employed in these transformations has been prepared from simple
organomagnesium and organolithium reagents. More recently, particular attention has been devoted
to the synthesis of highly functionalized organocopper reagents from less reactive organometallics
such as zinc, samarium, or zirconium reagents. Transmetallation with stoichiometric or catalytic
amounts of copper(I) salts proved to enhance their reactivity toward alkyl halides. In the presence of
chiral ligands, asymmetric transformations can be performed with high enantiomeric excesses.
1.04.2.3.1 Transmetallation of organolithium derivatives—reactivity of organocuprates
(i) Carbocupration of alkenes

In the 1990s, Nakamura and co-workers <1996H565> published several reports on the carbometallation
of cyclopropene derivatives. Studies based on stereoselective carbocupration followed by retentive
electrophilic quenching of the cyclopropyl copper intermediates leads to the cis-1,2-disubstituted cyclo-
propanone acetals. For example, addition of a vinyl cuprate to a cyclopropenone acetal and alkylation of
the resulting organocopper give the cis-disubstituted cyclopropane, which can be converted into a cross-
conjugated dienyl ketone. The transformation involves 1,5-hydrogen migration reaction under thermal
conditions and hydrolysis (Equations (50) and (51)).
)2CuLi O
i. , THF i. Benzene, 60 °C
–78 °C O O 94%
O O
ii. Me3SiCH2I ii. PPTS, Acetone SiMe3 ð50Þ
84% SiMe3 71%
98/2 (E)/(Z )
i. Cu(CN)MgBr O
i. Toluene, BSA, 20 °C
THF, –78 °C O O 97%
O O
ii. BnBr ii. Amberlyst ® 15/DTBP Ph ð51Þ
90% aq. Acetone, rt
Ph 81% (Z )/(E ) 68/32 >97/3 (E )/(Z )
DTBP = 2,6-di-t-butylpyridine
(ii) Alkylation of allyl organocoppers

Luth and co-workers <2001SL977> have shown that reaction of allylic dithioacetals with
dibutylcuprates results in nucleophilic attack at the sulfur atom with umpolung of the CS
bond. The -allylcopper intermediate can be alkylated regioselectively at the -position with
various alkyl halides leading to a mixture of (E)- and (Z)-vinyl sulfides. Nickel-catalyzed cross-
coupling of the previous vinyl sulfides with MeMgI affords the trisubtituted alkenyl adducts in
good yields (Equation (52)).
i. Bun2 CuLi
S
S THF, –78 °C R S Bun NiCl2(dppe) R Me
S
MeMgI Ph ð52Þ
Ph ii. RX = MeI Ph
RX = TMSCH2Cl 79% (83%) 1/1 (E )/(Z )
74% (84%) 100/0 (E )/(Z )
1.04.2.3.2 Transmetallation of organozincs

Organozinc derivatives have been used in many synthetic transformations due to their high
functional group tolerance. However, this moderate reactivity can be a serious drawback for
further functionalizations. To enhance this, transmetallation with copper(I) salts has become a
valuable tool to allow substitution reactions with alkyl halides. Many routes have been reported
for the elaboration of organozinc reagents and their subsequent alkylation but only selected
examples are presented below.
(i) Zinc insertion into carbon–halogen bonds

One protocol, first reported by Gaudemar and co-workers <1998SL379>, involves the insertion
of zinc into CI bond of alkyl iodides. This process was improved by Knochel using
1,2-dibromoethane and chlorotrimethylsilane to activate the metal. For example, treatment of
3-iodo-N-BOC-azetidines and 4-iodo-N-BOC-piperidines by activated zinc furnished the corre-
sponding organozinc intermediate which can be allylated by allyl bromide after transmetallation
with CuCN2LiCl (Equation (53)). More stable alkyl halides such as alkyl bromides need more
highly activated zinc. Various methods of activation such as reduction of zinc chloride by lithium
naphthalenide (Rieke zinc) or by potassium–graphite have been already reported. But more
recently, another protocol developed by Knochel, based on reduction of zinc chloride by sodium
dispersed on titanium(IV) oxide, allowed efficient synthesis of secondary alkyl and benzylic zinc
bromides without formation of Wurtz-coupling side products. After transmetallation with
CuCN2LiCl, the corresponding zinc–copper reagents react with different electrophiles giving
the expected functionalized compounds (Equation (54)) <1995S69>.
I ZnI Cu(CN)ZnI
Br
Activated Zn CuCN.2LiCl
ð53Þ
N THF, rt N 0 °C N –78 °C N
t-BOC t-BOC t-BOC 58% t-BOC
Br ZnBr CO2Et
Zn/ TiO2 i. CuCN.2LiCl
ð54Þ
THF, 25 °C
ii. Br
CO2Et
96%
(ii) Zinc halide exchange promoted by dialkylzincs

Functionalized diorganozincs can be easily prepared by the IZn exchange reaction. Several
methods have been published <1993CR2117> and for instance, simple dialkylzincs such as
diethylzinc in the presence of N-methylpyrrolidinone (NMP) <1996TL4495> or LiBr were
shown to be good reagents for ZnI exchange reaction. Indeed, Marek and co-workers
<2001SL818> reported the preparation of secondary organozinc iodides by treatment of gem-
diiodoalkanes with both dialkylzinc and NMP (or LiBr). Between 50 C to rt, the resulting
carbenoid readily undergoes an intermolecular nucleophilic rearrangement into a secondary organo-
zinc species. After transmetallation with CuCN2LiCl, the organocopper derivative can react with
various electrophiles (Equation (55)). A catalytic amount of mixed metals MnBr2 (5 mol.%)/CuCl
(3 mol.%) in the presence of diethylzinc and DMPU can induce the stereoselective radical
cyclization of unsaturated alkyl bromides to alkenes. The cyclized organozinc species are easily
allylated by reaction with ethyl (-bromomethyl)acrylate in 71–73% yields (Equation (56))
<1996TL5865>.
THF
Et i. CuCN.2LiCl
I Et Et
Ph NMP Zn Ph –78 °C to rt Ph
+ Et2Zn Ph + EtI ð55Þ
I –50 °C ZnI ii. Cl
I
65%
MnBr2 (5 mol.%) CO2Et

O O HH
Br CuCl (3 mol.%) Br CO2Et
Et2Zn (1.1 equiv.) H • H ð56Þ
O O • 71%
O O DMPU, 60 °C H H O O
H H H
(iii) Boron–zinc transmetallation

Investigations on BZn exchange were first reported in 1960 for the preparation of diethyl
zinc from dimethylzinc and triethylborane. This interesting property was widely developed by
Oppolzer for the enantioselective synthesis of allylic alcohols and, more recently, it was used by
Knochel in the preparation of functionalized dialkylzincs from the corresponding alkenes.
Organoboranes, obtained by hydroboration of olefins with diethylborane, undergo clean and
efficient BZn transmetallation with neat diethylzinc. Alkylation of the resulting diorganozinc
was achieved by transmetallation with CuCN2LiCl and substitution of various alkyl halides
(Equation (57)) <1996JOC8229>. It has to be mentioned that hydroboration of tetrasubstituted
olefins with BH3THF provides tertiary alkylboranes, which undergo stereoselective syn-
1,2-migration (Equation (58)) <1998AG(E)2460>. Hydroboration of trisubstituted cyclic and
acyclic olefins by monoisopinocamphenylborane affords enantiomerically enriched organoboranes.
They can be functionalized without any racemization after sequential diethylborane–diisopropyl-
zinc–CuCN2LiCl transmetallations and electrophilic trapping (Equation (59)) <1998SL1438>.
An example of allylation and allenylation of 1,3-dizinc derivatives was also reported (Equation (60))
<1996AG(E)218>.
AcO N i. Et2BH, Et2O, 0 °C AcO N

ð57Þ
ii. Et2Zn, 50 °C
iii. CuCN.2LiCl, THF
then Allyl bromide
N N
95%
i. Pr2i Zn, 25 °C
BH2 ii. CuCN.2LiCl,
Ph BH2
BH3.THF Ph THF, –90 °C Ph
Ph ð58Þ
50 °C iii. Allyl bromide
Ph Ph Ph –90 °C to rt Ph
61%
CuCN.2LiCl
i. (–)-IpcBH2 then Ph
Ph Ph
Ph Et2O, –35 °C i. Et2BH, 50 °C Allyl bromide
ii. Recrystallization ii. Pr2i Zn, 25 °C –78 °C to rt ð59Þ
BH-Ipc ZnPri
in Et2O, 0 °C 47%
97/3 trans/cis
trans-isomer 94% ee
CuCN.2LiCl
Br Br Br
then Br R
i. Et2BH –60 °C to rt
R Zn R = H, 84%
0–25 °C
BEt2 R R R = Bun, 87% ð60Þ
ii. Et2Zn Zn
R = H, Bu n 0–25 °C CuCN.2LiCl
then Bun
Br
–60 °C to rt
48%
(iv) Carbozincation of alkenes

Intermolecular carbozincation of alkenes can be illustrated by the important contribution of
Marek and Normant in this field. Some of their studies have been devoted to the stereoselective
formation and the reactivity of sp3-gem-bismetallic reagents, easily obtained by addition
of allylzinc to substituted vinyl metals. An application to the preparation of stereodefined
substituted cyclopropanes was reported. The sequence involved cyclization of the 1,1-dimetallic
species bearing a methoxymethyl ether in the -position and alkylation of the resulting organozinc
after transmetallation to the coresponding organocopper. High diastereoselectivities have been
observed (Equation (61)) <1995JOC2488>. Nakamura and co-workers <1997JAC5457>
reported the addition of zincated hydrazone to a vinyl Grignard. The gem-dimetallic intermediate,
generated in situ, can be selectively quenched with various electrophiles considering the important
difference of reactivity between Grignard and organozinc reagents (Equation (62)). In a recent
paper, they decribed the stereoselective addition of nonracemic chiral zinc enamides, derived
from (S)-valinol and (S)-t-leucinol, to ethylene. Copper(I)-catalyzed electrophilic trapping
of the -zincioimine intermediate led to the enantiomerically enriched -substituted ketone
(Equation (63)) <2003JA6362>.
i. ButLi (2 equiv.), –78 °C M M

Br OMOM ii. AllylMgBr OMOM –20 °C to rt
Bun iii. ZnBr2, –20 °C Bun
ð61Þ
ZnBr i. Me2CuCNLi2
Bun ii. Allyl iodide

Bun
65%
i. ButLi
NMe2 Et2O, 0 °C NMe2 i. CuCN.2LiCl NMe2
Ph N Ph N Ph N
ii. ZnBr2
MgBr –70 °C ð62Þ
iii. MgBr ii. Allyl bromide
ZnBr
Ph Ph 78% Ph
THF, 0 °C
i. MesLi O
OTMS
Et2O, 0 °C But CO2Et
But OTMS
ii. ZnCl2, 0 °C Br
N
NH iii. MeLi Zn Me 84% ð63Þ
–78 °C to 45 °C
iv. Ethylene, 60 °C CO2Et
MesLi = Mesityllithium 97% ee
Intramolecular carbometallation of alkenes has also been studied. For instance, Marek
and Normant have shown that allenyl zinc bromides (Equation (64)) and zinc-enolates
(Equation (65)) undergo diastereoselective and/or enantioselective carbocyclizations onto terminal
alkenes. In the presence of CuCN2LiCl, the resulting primary alkylzinc intermediate can be
functionalized with allyl bromide. A chair-like transition state was proposed to explain the
stereochemistry of the adduct. This approach provides a straightforward and valuable method
for the preparation of polysubstituted pyrrolidines <1997TL89, 1998JOC2442>.
TMS i. BusLi, Et2O

–80 °C CH2ZnBr
to –50 °C i. CuCN.2LiCl
ii. ZnBr2 R N ii. Allyl bromide R N TMS ð64Þ
TMS
R N
iii. –50 °C to rt Me 70% Me
Me
R = cyclohexyl 85/15 dr
i. LDA, Et2O CH2ZnBr

CO2Me –50 °C to rt i. CuCN.2LiCl
CO2Me CO2Me ð65Þ
ii. ZnBr2, Et2O, –40 °C N ii. Allyl bromide N
N
iii. –40 °C to rt Me 55% Me
Me
(v) Asymmetric allylation of organozinc reagents

Reactivity of organocopper reagents with allylic halides is now well documented. Several
investigations have been concentrated on the regio- and stereoselectivity of the process. An
SN20 mechanism leading to -alkylated products is highly favored. More recently, a copper(I)-
catalyzed allylation reaction of dialkylzincs has received a great deal of interest and some
applications to asymmetric synthesis have been published by Knochel <2000TL9233> and
Feringa <2001OL1169>, respectively. Regio- and enantioselective SN20 allylic alkylation of
cinnamyl halides with primary organozinc reagents takes place in the presence of catalytic amount
of CuBrMe2S and with either ferrocenyl amines (Equation (66)) or phosphoramidites
(Equation (67)) as chiral ligand. Enantiomeric excesses up to 98% and 77% have been reached,
respectively.
But
Cl
neo-Pentyl2Zn,
F 3C H CuBr.Me2S (1 mol.%), L* (10 mol.%)
NH2 F3C ð66Þ
But
THF, –30 °C
L*: SN2'/SN2 98/2
Fe 85%
SN2' 98% ee
But
CuBr.SMe2 (1 mol.%)
Et
Br diglyme, –40 °C
+ Et2Zn
L* (2 mol.%)
54%
SN2'/SN2 84/16 ð67Þ
Ph
SN2' 77% ee
O
L* = P N
O
Ph
1.04.2.3.3 Transmetallation of organozirconiums

Takahashi and co-workers <1997CC1599> showed that allylation of unsymmetrical bicyclic
zirconacyclopentanes can be promoted by copper(I) chloride in the presence of allyl chloride
(Equation (68)). The process occurs in the benzylic position with high regio- and diastereoselec-
tivities, and also with total retention of configuration.
Ph Ph
H H
i. Cat. CuCl
(C5H5)2Zr
ii. Allyl chloride ð68Þ
H 94% H
regioselectivity >98%
de >98%
1.04.2.3.4 Transmetallation of organomagnesiums

In his studies on the reactivity of gem-dihalocyclopropanes, Oshima has also examined the double
alkylation of gem-dibromocyclopropane compounds with tributylmagnesate and various electro-
philes. Upon treatment with Bun3MgLi, gem-dibromocyclopropanes first undergo bromide–
magnesium exchange to give magnesate intermediates which rearrange by 1,2-migration (or
intramolecular nucleophilic substitution) of an alkyl group. The resulting monoalkylated cyclo-
propylmagnesium species can be transmetallated by copper(I) salts and trapped by allyl bromide
<2002T1581>. In Equation (69), the product was isolated in 82% yield and with a 80:20 dr
<2002MI1730>. A similar protocol was carried out in the preparation and the alkylation of
-silylalkylmagnesium species generated from dibromomethylsilane (Equation (70))
<2001AG(E)2085>.
Ph
Ph Ph
Br Bun3MgLi Br Ph .
–
MgBun i. CuCN 2LiCl Bun
Ph
Br THF MgBun ii. Allyl bromide Bun ð69Þ
Bun
–78 to –30 °C Bun 82%
80/20 dr
i. CuCN.2LiCl
(30 mol.%)
Bun3MgLi, MgBun –78 to 0 °C ð70Þ
ButMe2SiCHBr2 ButMe2Si
–78 °C Bun ii. Propargyl bromide ButMe2Si
66% Bun
EtMgBr-mediated radical cyclization of allyl -iodoacetals and subsequent copper(I)-catalyzed

allylation of the tetrahydrofuranyl methylmagnesium intermediate have been performed in DME
in good yields (Equation (71)) <2000OL651>.
n -C5H11 n -C5H11 n -C5H11

EtMgBr O i. CuCN.2LiCl O
O
DME, rt BunO ii. Allyl bromide BunO ð71Þ
I
BunO MgBr 73%
53/47 dr
Alexakis and co-workers have also reported an example of copper(I)-catalyzed selective SN20
allylic substitution of cinnamyl chlorides by Grignard reagents. High regio- and moderate
enantioselectivities (up to 73% ee) were observed in the presence of a chiral phosphorus ligand
derived from TADDOL (Equation (72)) <2001SL927>.
EtMgBr (in Et2O), L* (1 mol.%)

CuCN (1 mol.%) Et
Ph Cl
CH2Cl2, –78 °C Ph
100% conv. 94/6 SN2'/SN2
ð72Þ
Ph Ph 73% ee
O O
L*: P O N
O O
Ph Ph Ph Me
Polylfunctional alkenyl-, aryl-, and heteroarylmagnesium reagents can be easily prepared from
related alkenyl and aryl halides through iodine or bromide–magnesium exchange with trialkyl-
magnesates at low temperature. Subsequent alkylation proceeds with retention of configuration of
the olefin. Several examples of reaction with heteroaryl halides <2000JOC4618, 2000T1349,
1998SL1359>, aryl and alkenyl halides <2002T4787, 2002AG(E)1610, 2001JOC4333,
2000AG(E)2481, 2000MI767, 2000JOC4618> are depicted in the literature. An application to
solid-phase synthesis was also proposed <1998AG(E)1701>.
1.04.2.3.5 Transmetallation of organosamariums

Considering the lack of reactivity of alkylsamariums toward alkyl halides, Berkowitz and Wu
have developed a new protocol of alkylation with copper salts as catalyst taking advantage of
Curran and Wipf research on conjugate addition. Reduction of alkyl iodides and bromides by
SmI2/HMPA led to alkylsamarium intermediates which can be transmetallated by a catalytic
amount of CuBr or Li2CuCl4, and therefore can undergo cross-coupling reactions with alkyl
iodides (Equation (73)) <1997TL3171>.
i. SmI2/HMPA, THF, rt
ButPh2SiO(CH2)10I ButPh2SiO(CH2)19CO2Me
ii. CuBr (20 mol.%)
ð73Þ
iii. I(CH2)9CO2Me
81%
1.04.2.4 Pd(0)- and Ni(0)-Catalyzed C(sp3)–C(sp3) Cross-couplings

Since the early 1980s, transition metal-catalyzed cross-coupling reactions have become an impor-
tant tool for modern organic transformations <B-1995MIT, B-1997MI, B-1999MI833>. They
proved to be extremely efficient in the formation of C(sp2)–C(sp2) and C(sp2)–C(sp) bonds
between poorly reactive organometallics (such as borane, Grignard, organozinc, or stannane
reagents) and aryl or alkenyl halides. However, only few reports on C(sp3)–C(sp3) bond formation
have been published. This was first explained by a slow oxidative addition of the alkyl halide to
the transition metal (such as Pd(0) or Ni(0)) and a possible -elimination of the organometallic
intermediate before the transmetallation and the reductive elimination steps. Some of the most
important studies on this topic are summarized here.
1.04.2.4.1 Pd(0)-Catalyzed couplings
(i) Suzuki-coupling process

The first report on Suzuki cross-coupling reactions between two C(sp3) centers appeared in 1992.
Suzuki and co-workers found that Pd(0)-catalyzed cross-coupling reactions of alkylboranes and
primary alkyl iodides proceed in good yields (up to 71%) (Equation (74)). But under these
conditions (Pd(PPh3)4, 60 C), no reaction with simple alkyl bromides was observed
<1992CL691>. An application of this protocol to solid-phase synthesis has been achieved
by Mioskowski (Equation (75)) <1999TL4335>. In the course of his studies on synthesis of
polycyclopropane natural products such as (–)-FR-900848 or (–)-U-106305, Charette has been
interested in cross-coupling reactions between iodocyclopropanes, on which no -hydrogen
is present, and cyclopropylboronate esters (Equation (76)) or boronic acids <1997TL2809>.
Deng and co-workers <2000JOC4444> demonstrated that the presence of silver oxide can
influence Pd(0)-couplings between cyclopropylboronic acids and allyl bromide (Equation (77)).
In 2001, Fu and co-workers reported major advances in C(sp3)–C(sp3) Suzuki reactions of alkyl
bromides and alkyl chlorides, possessing -hydrogen atoms, with 9-BBN-alkyl compounds. The
use of Pd(OAc)2/PCy3 catalyst system, in the presence of K3PO4H2O, proved to be extremely
efficient even at room temperature (Equation (78)) <2001JA10099, 2002AG(E)1945>.
O O
Pd(PPh 3)4 (3 mol.%), K 3PO4 O O
+ I(CH2)3CO2Me ð74Þ
Dioxane, 60 °C
B
57% (CH2)5CO2Me
PdCl2(dppp) (0.3 equiv.)

+ I(CH2)5OTHP ð75Þ
B K2CO3, DMF, 85 °C
(CH2)7OTHP
55%
Pd(OAc)2 (0.1 equiv.)

Ph O PPh3 (0.5 equiv.), KOBut
B + I OBn Ph OBn ð76Þ
O DME, 80 °C
60%
PdCl2(dppe)(3 mol.%)
OH Ag2O, KOH
Ph B Br Ph ð77Þ
+
OH Dioxane, 80 °C
64%
MeO2C(CH2)10 Pd(OAc)2/PCy3, K3PO4.H2O

B + Br(CH2)6CN MeO2C(CH2)16CN
THF, rt
ð78Þ
81%
(ii) Negishi-coupling type reactions

In order to circomvent the lack of reactivity of organozinc derivatives toward alkyl halides, Negishi
and co-workers developed a new methodology involving Pd(0)-mediated cross-coupling reactions.
Dialkylzincs can be alkylated with allyl, benzyl, and propargyl halides in the presence of a Pd(0)
catalyst (Equation (79)) <2000OM2417>. Utimoto and co-workers reported different examples of
[Pd2(dba)3]/tris(2-furanyl)phosphine-catalyzed coupling reactions of gem-bis(iodozincio) alkanes
with allyl chlorides or propargyl bromides. The organozinc intermediate can be functionalized
under the same palladium catalysis conditions or after transmetallation with copper cyanide by
reaction with allyl or propargyl bromide (Equation (80)) <1997AG(E)2804>. Similar studies
employing chiral phosphines as ligands did not show detrimental effect on the yield but an extremely
poor induction (up to 10% ee) was observed (Equation (81)) <2000SL987>.
Cp2ZrCl2 (10 mol.%) Allyl bromide
Zn
EtMgBr (20 mol.%) PdCl2(dppp)(5 mol.%) Oct
Oct Oct )2 ð79Þ
Et2Zn (0.5 equiv.) DMF, rt Et
Et
THF, 55 °C 60%
[Pd2(dba)3].CHCl3 (2.5 mol.%)

n-C5H11
P(2-Furyl)3 (10 mol.%)
n-C5H11
Br + CH2(ZnI)2
THF, rt
C 2H5 ZnI ð80Þ
Allyl bromide n-C5H11

70%
[Pd2(dba)3].CHCl3 (2.5 mol.%)

CH3CH(ZnI)2 + Ph Cl Ph
THF, rt ZnI
OMe
(10 mol.%)
PPh2
ð81Þ
i. CuCN.2LiCl, –25 °C
Ph
ii. Propargyl bromide
81% 10% ee (R)
(iii) Coupling of Grignard reagents

A recent extension of this reaction to organomagnesium compounds was proposed by
Demuth and co-workers. They developed a regioselective -alkylation process of allylic bromides
and chlorides with various benzylic Grignard reagents using a catalytic amount of palladium
catalyst. -Benzylated allylic derivatives are obtained rapidly in high yield at room temperature.
These compounds can be easily converted into abietane-type terpenoids and also into natural or
unnatural tetracyclic polyprenoids in two steps (Equation (82)) <2002JOC1167>.
Me
p-Me(C6H4)CH2MgCl SnCl4, THF
Pd(PPh3)4 (5 mol.%) –78 °C
Br ð82Þ
THF, rt 35%
79%
H
(iv) Stille coupling

In the early 1980s, Stille pioneered the use of palladium(0) in cross-coupling reactions between
tetraalkyltin reagents and allyl or benzyl halides <1986AG(E)508>. The Pd(0)-catalyzed reaction
of allylic chlorides and allyltributyltin has received a particular attention. The process involves
formation of a bis(3-allyl)palladium intermediate by oxidative addition and transmetallation

with allyltributyltin. The triphenylphosphine coordinates the palladium complex which undergoes
a reductive elimination and liberates the 1,5-hexadiene as coupling adduct (Equation (83)).
Without phosphine ligand, the allyl choride remains unchanged. In this case, the allyltributyltin
may react with other functions such as aldehydes present on the substrate, to furnish the
homoallylic alcohol <2001AG(E)3208>.
OH
[Pd2(dba)3].CHCl 3 (5 mol.%)
O
THF, rt Cl
H
Cl 88% O
+ H ð83Þ
SnBu3 [Pd2(dba)3].CHCl 3 (5 mol.%)
PPh3 (10 mol.%) 90
/
THF, rt O
10
74% H
(v) Coupling of aluminum reagents

An example of Pd(0)-catalyzed methylation of benzyl bromide by [3-(dimethylamino)propyl-
C,N]dimethylaluminum was examined by Blum and co-workers <1997JOC8681>. The reaction
operates quantitatively under mild conditions.
1.04.2.4.2 Ni(0)-Catalyzed couplings

Knochel and co-workers discovered that dialkylzincs undergo efficient cross-coupling reactions
with functionalized or unfunctionalized primary alkyl bromides and iodides <1995AG(E)2723,
1998AG(E)2387> in the presence of Ni(acac)2 as catalyst and additives such as LiI or NMP,
4-fluorostyrene as promotor, acetophenone as co-catalyst which enhances the rate of the reaction
and suppresses the IZn exchange side-reactions (Equation (84)). With benzylzinc bromide,
the use of 3 equiv. of tetrabutylammonium iodide proved to accelerate the coupling process
(Equation (85)) <1999OL1323>.
O O
Ni(acac)2 (10 mol.%)
+ [PivO(CH2)3]2Zn OPiv
(CH2)3I O
( )6
S (0.5 equiv.) S ð84Þ
Ph
THF/NMP, –35 °C
70%
O
O Ni(acac)2 (10 mol.%)
I
ZnBr THF/NMP, –35 to –10 °C
+
ð85Þ
(20 mol.%)
CN F
Bu4NI (3 equiv.)
74% CN
1.04.2.5 Miscellaneous Species with No Stabilizing Group
(i) Alkylation of organoboron derivatives

The ability of organoboranes to form ate-complexes has been greatly exploited in organic
synthesis particularly for CC formation. 1,2-Metallate Matesson rearrangement has received
great interest for homologation of trialkylboranes and alkylboronate esters. For instance,
Crudden and co-workers combined rhodium(I)-catalyzed asymmetric hydroboration and homo-
logation of pinacol boronate intermediates with chloro- or dichloromethyllithium. After oxidative
treatment, enantiomerically enriched alcohols or carboxylic acids were isolated. Ibuprofen could
be synthesized in 74% yield and with a 93% ee from the corresponding vinyl arene (Equation
(86)) <1999JOC9704>. Kabalka found that simple trialkylboranes also react with (-chloroar-
yl)methyl anions. The ate-complex intermediate can readily rearrange to afford the alkylarylcar-
binol after oxidative treatment (Equation (87)) <1997OM709>.
O
BH
O HO2C Me
O i. LiCHCl2
[Rh(COD)2] + BF4 – O B THF, –78 °C
(R)-BINAP ii. NaClO2 (pH, 7.5) ð86Þ
DME 74%
Bui Quench with pinacol Bui
Bui 98% ee
Ibuprofen
i. LiN(c-C6H11)2 OH
THF, –78 °C OH
PhCH2Cl + n-C6H13B + Ph ð87Þ
2 ii. H2O2/NaOH n-C6H13 Ph
8% 78%
(ii) Alkylation of organomercury reagents

The crucial role of mercury(II) salts in the benzylation of 1-aryl-1-propynes has been demon-
strated by the lack of reactivity of lithiopropargylic anions with benzyl bromides. By using HgCl2,
satisfactory yields of 1,4-diaryl-1-butynes are obtained with both benzyl bromides and benzyl
chlorides as electrophiles (Equation (88)) <1998JOC3497>.
i. BunLi
HgCl2 (1.5 mol.%)
Me
Br ð88Þ
ii. Br
Br
70%
(iii) Alkylation of organomanganese compounds

-Alkylcyclopropylmanganese reagents, obtained by treatment of gem-dibromocyclopropanes
with trialkylmanganates, react efficiently and stereoselectively with methyl iodide and allyl
bromide and give rise to the gem-dialkylated cyclopropanes. The reaction of the dibromide with
Bun3MnMgBr affords the cyclopropylmanganate intermediate, obtained via bromide–manganese
exchange, which undergoes 1,2-metallate rearrangement with inversion of configuration
(Equation (89)) <2000T2131>.
Br MnBun
Bun3MnMgBr (3 equiv.) Br
– n
Br
THF, 0 °C Mn Bu Bun
Bun
Br ð89Þ
Bun
+
88% Bun
97/3 dr
1.04.3 CARBANIONS WITH ONE STABILIZING GROUP
1.04.3.1 Enolates and Related Carbanions

One of the most straightforward methods used for the formation of CC bonds is the alkylation
of enolates and related carbanions with organic halides. Several methodologies taking advantage
of the versatility of such species have been developed to carry out chemo-, regio-, and stereo-
selective transformations. Recent advances in this area are disclosed in this part.
1.04.3.1.1 Alkylation of enolates
(i) Lithium ketone enolates

Lithium enolates have largely demonstrated their omnipresence in organic synthesis playing a
central role in CC bond formation. As carbon nucleophiles, they react with various carbon
electrophiles including haloalkanes to give -substituted carbonyl compounds. The main method
used for enolate formation is the direct deprotonation of ketones with strong and non-nucleo-
philic bases under either kinetic or thermodynamic conditions. Regio- and stereoselectivity in the
enolate formation and its subsequent alkylation depend on a variety of parameters already
discussed in COFGT (1995). Metallation of unsymmetrical ketones at low temperature with
hindered amide bases (such as LDA, LiHMDS, etc.) provides less substituted kinetic enolates
whereas at higher temperatures under ButOK/ButOH conditions, thermodynamic enolates are
alkylated at the more substituted carbon with moderate selectivities (for more recent investiga-
tions, see <1996JOC2232>). To enhance this regioselectivity in favor of ,-dialkylated com-
pounds, Yamamoto and co-workers proposed the use of hindered oxophilic Lewis acids to
generate exclusively the more substituted enolate by deprotonation under kinetic conditions.
With aluminum tris(2,6-diphenylphenoxide) (ATPH), the precomplexation of the unsymmetrical
ketone proceeds from the less hindered side. Selective lithiation by LDA at 78 C followed by
electrophilic trapping with allyl and propargyl halides afforded the ,-disubstituted ketones with
impressive regiocontrol (Equation (90)) <1997JA611>. Another method based on reductive
alkylation of -alkylated -cyanoketones with lithium naphthalenide was reported by Liu and
co-workers <1998TL4183> and gave also excellent results (Equation (91)).
i. ATPH Ph
O O O
toluene, –78 °C
+ ( O )3 Al
ii. LDA, THF ð90Þ
iii. Allyl iodide, –78 °C to rt Ph
69% >99/1 ATPH
O Lithium naphthalenide O
THF, –25 °C
CN ð91Þ
( )n then Allyl bromide ( )n
70–90%
n = 1, 2, 3
Chiral base-mediated asymmetric alkylation of cyclohexanone and 1-tetralone has been widely
investigated by Koga and co-workers. Treatment of the prochiral cyclic ketones with an equimolar
amount of phenylglycine-derived lithiated tetradentate chiral base and lithium bromide salt gives
the corresponding enolates, which react with a range of haloalkanes to furnish the enantioenriched
-alkylated carbonyl compounds in up to 98% ee (Equations (92) and (93)) <1998T2449>. The
incorporation of additives such as 1,1,4,7,10,10-hexamethyltriethylenetetramine provides a sub-
stantial rate acceleration <1999TL8129> and the presence of LiBr is essential for the selectivity. At
the same time, Knochel reported the preparation of a new chiral pseudo-C2-symmetric urea and its
use in enantioselective deprotonation. The monoanion, generated by deprotonation with BunLi,
acted as a chiral base and promoted the enolization of -tetralone. The transient lithium enolate was
benzylated in 83% yield and with 81% ee (Equation (94)) <1998AG(E)3014>.
O
O i. Chiral base, LiBr
toluene, –45 °C Ph
(R)
ii. Cinnamyl bromide
93%
88% ee
Ph
ð92Þ
O NMe2
N N
Li
Chiral base
O As above O
+ BnBr (R )
Bn
ð93Þ
63%
92% ee
Ph OLi Ph
Me Me
i. N N
Me H Me
O O
Ph Ph ð94Þ
Bn
ii. BnBr, THF, –20 °C
83%
81% ee
(ii) Reactivity of silyl enol ethers

Upon treatment with methyllithium, benzyltrimethylammonium fluoride or silver(I) catalysis,
direct alkylation of silyl enol ethers with organohalides occurs in modest yields. However, more
efficient procedures have been published since the early 1990s. For instance, Kad and co-workers
<1999SC3439> reported an interesting acceleration of the -alkylation of silyl enol ethers with
allylic, benzylic, and tertiary alkyl halides by using ZnCl2 impregnated on acidic alumina
as catalyst (Equations (95) and (96)). In general, silyl enol ethers react regioselectively from the
less substituted -side, whereas Duhamel’s group showed that potassium enolate of unsymme-
trical ketones, generated by reaction of KOBut with related silyl enol ethers, undergo alkylation at
the more substituted carbon whatever the regioisomer used (Equation (97)) <1998SL413>. A
recent report from Buchwald and co-workers described an elegant approach to enantiomerically
enriched trans-2,3-disubstituted cyclopentanones which involves asymmetric copper-catalyzed
Michael reduction of -substituted cyclopentenones with Ph2SiH2 and subsequent alkylation of
the resulting silyl enol ethers, promoted by the presence of fluoride anions (Equation (98))
<2001OL1129> (see also <2000T2779>).
OSiMe3 O
ZnCl2/Al2O3 Bn
ð95Þ
BnBr, –10 °C
65%
O
OSiMe3 ZnCl2/Al2O3
Br ð96Þ
–10 °C
72%
OSiMe3
OK O OK O
KOBut Allyl bromide
or ð97Þ
THF, –15 °C –78 °C
OSiMe3
82–86%
α/α' >41/1
Ph Ph
O 5% CuCl, 5% NaOBut Si O
O O TBAT
5% (S )-p -Tol-BINAP Bn
Ph2SiH2 BnBr ð98Þ
Toluene, 0 °C 62%
92/8 dr
TBAT: Triphenyldifluorosilicate
Enantioselective alkylation of silyl enol ethers mediated by MeLiLiBr and a chiral ligand present
in catalytic (Equations (99) and (100)) <1994JA8829, 1999TL2803> or equimolar amount
(Equation (101)) <1998T2449> was reported by Koga. The reaction proceeds through initial
LiSi exchange with methyllithium and subsequent alkylation of the lithium enolate/ligand
complex. It was mentioned that the incorporation of a second achiral bidentate ligand activates
the intermediate and provides an acceleration of the process. A variety of tetradentate amine ligands
were tested that led to enantioselectivities up to 96%, 97%, and 90% starting from silyl enol ethers
of tetralone, -substituted tetralone, and cyclohexanone, respectively (Equations (99)–(101)).
OSiMe3 i. MeLi–LiBr O
toluene, –45 °C Bn
ii. L* (5 mol.%) H
diamine (2 equiv.)
BnBr (10 equiv.)
96% ee ð99Þ
76%
Ph Me
N NMe2
L*: N N
Me2N NMe2
H
OSiMe3 As above O
L* (10 mol.%) Bn
BnBr H ð100Þ
52%
90% ee
OSiMe3 i. MeLi–LiBr O
Me toluene, –45 °C Bn
Me
ii. L* (1 equiv.)
diamine (2 equiv.)
BnBr (10 equiv.) 94% ee
93% ð101Þ
Ph Ph
L*: N N N N
H H
(iii) Alkylation of Sn(IV) enolates

Sn(IV) enolates are known to be stable intermediates which are less reactive than lithium or copper
enolates. However, they may undergo selective monoalkylations with organic halides in the presence
of a coordinating co-solvent such as HMPA. Usually prepared by transmetallation of more reactive
enolates (Li, Cu) or transesterification of enol acetates <1994OPP87>, tin(IV) enolates can also be
obtained by reduction of ,-unsaturated ketones (Equation (102)) <1996JOC5384> and tandem
ring-opening reduction of cyclopropyl ketones (Equation (103)) <1997JOC5248, 2001JOC5249> by
tin hydride, involving O-stannyl ketyl radical intermediates. After addition of 5 equiv. of HMPA prior
to haloalkanes, the enolate alkylation proceeds in good yields.
Bu3nSnH RX
AIBN (cat.) HMPA O
O Bun3SnO H ð102Þ
benzene, 80 °C R
RX = Benzyl bromide 65% (β/α = 4/1)
Allyl bromide 76% (β/α =1/2)
O
O OSnBun3
Bu3nSnH Allyl bromide
ð103Þ
AIBN (cat.) HMPA
benzene, 80 °C 80 °C
97%
(iv) Alkylation of samarium(III) enolates

Samarium(III) enolates, prepared from an -keto-tetrahydropyran (Equation (104))
<1995JOC1110> or cyclopropyl ketone (Equation (105)) <1999TL1019> via tandem SmI2-
generated ketyl/ring-opening, showed that they can also react efficiently with organic halides,
leading to related -alkylated ketones.
O i. SmI2 OSmI2 O
O HMPA–THF O HO ð104Þ
Ph Ph Ph
ii. BnBr 86% Bn
O i. SmI2 OSmI2 O
HMPA–THF Me
H ð105Þ
ii. MeI 37%
SO2Ph SO2Ph SO2Ph
(v) Alkylation of manganese(II) enolates

Manganese(II) enolates are readily available from carbonyl compounds by proton abstraction
with LiHMDS and Ph(R)NMnCl as described by Reetz <1993TL7395> and Cahiez
<1994TL3065>, by transmetallation of lithium enolates <1994TL3069> or by reduction of
acetoxy and siloxy groups or halogens adjacent to a carbonyl moiety with organomanga-
nese(II)-ate complexes. This approach was recently developed by Hosomi and co-workers. They
showed that reaction of -silyloxy ketones (Equation (106)) and -iodo ketones (Equation (107))
with Bun3MnLi affords the related manganese enolates, which can be selectively alkylated by
organic halides <1997JA5459>. The use of t-butyl dibromoacetate and N,N-diethyldibromoace-
tamide (Equation (108)) or dibromo -lactams (Equation (109)) instead of -silyloxy and -iodo
ketones gives the butylated manganese enolates, which result from bromide–manganese exchange
by Bun3MnLi and subsequent 1,2-butyl migration (see Section 1.04.2.5) <1998JOC910>.
O i. Bun3MnLi, THF O
OSiButMe2 –78 to 0 °C
Ph Ph CO2Me ð106Þ
ii. Br–CH2CO2Me/DMSO
Me Me
0 °C to rt
80%
O i. Bun3MnLi O
I THF, –78 °C
ð107Þ
Bu Bu Ph
ii. BnBr
Me Me
77%
O i. Bu3nMnLi
O
–78 to 0 °C
Br ð108Þ
NEt2 NEt2
ii. Allyl bromide
Br Bun
76%
Br O Bun O
i. Bun3MnLi, THF
Br
N ii. Allyl bromide N ð109Þ
Ph Ph Ph Ph
62%
26/74 trans/cis
(vi) -Alkylation of imines

In general, anions from ,-unsaturated imines are exclusively alkylated at the -position by a variety of
alkyl halides. This predominant formation of -products was illustrated by De Kimpe with studies on the
reactivity of 1-azapentadienyl anions. Deprotonation of N-(2-buten-1-ylidene)-alkylamines with LDA
generates conjugated 1-azaenolates which react with 1-bromo-3-chloropropane adjacent to the imine and
cyclize to 3-vinylpiperidines under NaBH4/MeOH reductive conditions or to 5-vinyl tetrahydropyridines
by treatment with LDA. These cyclic enamines are suitable dienes for Diels–Alder reactions. KOBut
isomerization of the -alkylated ,-unsaturated imines to conjugated analog followed by Michael
addition of cyanide anion and subsequent ring closure leads to 5-substituted tetrahydropyridines in
moderate yields (Equation (110)) <1998T2563>. Monoalkylation of unsymmetrical dihydropyrazines
was reported by Sayre and co-workers for the functionalization of symmetrical -diones. The selective
lithiation of the corresponding 1,2-diimides with LDA at 78 C occurs at the less hindered methyl
group, and then the monoanion intermediate is alkylated with a variety of alkyl halides in 34% to 84%
yields. The monoalkylated -diones are liberated under acidic hydrolysis (Equation (111))
<1998TL1877>.
i. KOBut, ButOH But

NBut THF, rt N
ii. KCN, MeOH
H ∆
56%
LDA, THF NBut CN
0 °C But
Li H NaBH4
then –78 °C NBu t Cl(CH2)3Br N
MeOH
H –78 to 0 °C rt, then ∆
Cl 69%
But
LDA, THF
0 °C to rt N
98%
ð110Þ
i. LDA O
THF, –78 °C N 1 M HCl
N O
N ð111Þ
N ii. BnBr, –50 °C 84%
Bn
Bn
(vii) -Alkylation of oxime derivatives

Stereoselective conjugate addition of organolithiums to standard 6H-1,2-oxazines generates the
4-lithiated 1,2-oxazines as Michael adducts, which can be trapped selectively by methyl iodide
and allyl bromide. The trans-diastereoisomer was isolated as the only product in good yields
(Equation (112)) <2002SL1412>.
i. PhLi Me
Ph
THF, –78 °C Ph Ph
N ii. MeI ð112Þ
EtO O N
–78 °C to rt EtO O
70% 95/5 dr
(viii) -Alkylation of hydrazones

Chiral hydrazones are important precursors for asymmetric synthesis. Most of the investigations
published in this area, particularly on chiral (S)-(–)-1-amino-2-methoxymethylpyrrolidine (SAMP)
and (R)-(+)-1-amino-2-methoxymethylpyrrolidine (RAMP) hydrazones, have been performed by
Enders and co-workers. In 1995, they reported the preparation of chiral nonracemic -substituted
nitriles by asymmetric alkylation of SAMP and (S)-(–)-1-amino-2-methoxydimethylpyrrolidine
(SADP) hydrazones and subsequent oxidative cleavage with magnesium monoperoxyphtalate
(MMPP). The optically active nitriles were isolated with high enantiomeric excesses (>95% ee)
(Equation (113)) <1995T10699>. Alkylation of -silylhydrazones has been successively examined
by Enders <1996LA189> and Richards <1998TL3617>. Sequential enolization of -silyl RAMP
and SAMP hydrazones followed by methyl iodide trapping occurred from the less substituted side
under kinetic conditions (LDA or ButLi, 78 C) and adjacent to the silyl group after equilibration at
0 C (or with BunLi at 78 C). -Silyl dimethylhydrazones tend to react much more from the less
substituted side leading to a better ratio at 78 C. Finally, the regioselectivity depends on a variety of
parameters such as the nature of the base, the hydrazone moiety and the temperature.
i. SAMP MMPP, 6H2O

O N
ii. LDA, Et2O, 0 °C N MeOH, buffer pH 7 CN
H OMe ð113Þ
iii. MeI 0 °C Ph
Ph H
67% >95% ee (R )
Ph
(ix) -Alkylation of nitriles

A large number of nitrile-containing natural products have been isolated in recent years. There-
fore, developments of new synthetic methods for their elaboration and precisely for the function-
alization of adjacent centers to nitriles, are still required. In reponse, Yokoyama reported the
introduction of allyl and prop-2-ynylic groups to cyanofluoromethylene units. Cleavage of the
SC bond of 2-fluoro-2-phenylthio-2-phenylacetonitrile with an organogermanium-ate complex
(Et3GeNa) gave the intermediate anion that can be captured by allyl and propargyl chlorides
(Equation (114)) <1998CC1093>. Fleming showed that 1,4-addition of Grignard reagents to
-hydroxy ,-unsaturated nitriles is highly favored by chelation control of the hydroxy moiety.
The alkyl group should be delivered intramolecularly and the nitrile-stabilized transient anion
alkylated with benzyl bromide (Equation (115)) <2000OL1477>. Finally, benzonitrile undergoes
regioselective para-addition of lithiated alkyl(diphenyl) phosphine boranes, thus resulting in
dearomatized lithium adducts which are readily trapped - to the cyano group with MeI, allylBr,
and BnBr to form functionalized 1,3-cyclohexadienes (Equation (116)) <2002TL9611>.
i. Et3GeNa
F CN THF–HMPA, –78 °C F CN
Ph ð114Þ
PhS Ph ii. Cinnamyl chloride, –78 °C Ph
98%
i. ButMgCl–PhMgCl Ph
THF, –78 °C
HO CN HO CN ð115Þ
ii. BnBr–HMPA
63% Bn
R CN Yield
i. BusLi–HMPA RX (%) dr
–
BH3 THF, –90 °C
+ Mel >97 1/1.2 ð116Þ
PPh2 Allyl bromide >97 1/1.5
–
ii. CN BH3
Benzyl bromide 77 >99/1
+ PPh2
iii. RX
(x) -Alkylation of carboxylic acids

Metallation of carboxylic acids can be performed successfully with lithium amide bases to provide
lithium dienolates, which can be regio- and stereoselectively alkylated at the -carbon center
<B-1991MI99, B-1994MI88>. In the 1990s, much attention has been turned to the reactivity of
,-unsaturated analogs, widely investigated by Parra and Mestres. On treatment with lithium
diethylamide, unsaturated carboxylic acids afford the corresponding -extended dienediolates.
Alkylation with alkyl, benzyl, or allyl halides were successively reported <1994T5109, 1998T4357,
1998T15305, 2000S1160, 2001SL156>. The attack occurs preferentially at the -site but usually
leads to a mixture of both regioisomers. This lack of selectivity depends on the reactivity of the
dienediolate with the electrophile, partially controlled by addition of lithium chelating compounds
which may influence the aggregation state (Equation (117)).
O O
LiNEt2 (2 equiv.) OLi RX
OH THF, –78 °C –78 °C to rt OH
OLi
R
Yield ð117Þ
RX (%) α /γ
EtCH(Br)Me 52 100/0
PhCH(Br)Me 83 83/17
3-Bromocyclohexene 72 78/17
(xi) -Alkylation of esters and lactones

Ester enolates are important intermediates for synthetic transformations. Their reactivity has been
widely investigated in recent years and applied in numerous total syntheses. This broad application
cannot be summarized in a few lines, but nevertheless selected examples will be provided herein.
(a) Diastereoselective alkylations. Particular attention has been devoted to the control of the
diastereoselectivity in alkylation processes and this still remains a challenge for organic chemists.
Investigations on 1,2-asymmetric induction in acyclic series have been reported on esters substituted
in the -position by stereodefined groups containing heteteroatoms. Ha and co-workers showed
that the enolate dianion of (S)-4-carboethoxymethyl-2-oxazolidinone, generated by proton abstrac-
tion with LiHMDS or NaHMDS at 78 C, undergoes diastereoselective alkylation with alkyl
iodides, and allyl and benzyl bromides (Equation (118)). The nature of the counter-cation of the
base and the presence of HMPA improve the selectivity in favor of the anti-product formation. This
result was rationalized by a stereoelectronic effect of the nitrogen atom <1996TL5723>. Chiral
heterocyclic -amino esters are versatile synthons for the synthesis of azabicyclic pyrrolizidine and
quinolizidine alkaloids. For their elaboration, direct allylation of lithium enolates derived from
chiral nonracemic pyrrolidyl and piperidyl acetates was developed by Knight and co-workers. But
low-to-moderate diastereomeric excesses were observed <1990TA147, 1991JCS(P1)1615>. More
recently, Lhommet showed that alkylation of chiral cyclic -amino esters, prepared from (S)-
methylbenzylamine, occurs with complete diastereocontrol (Equation (119)) <1997TL8507,
1999TL9019>. The bulky (tricarbonyliron) group also provides a remarkable stereocontrol. An
approach reported by Donaldson and co-workers deals with Fe(CO)3-stereodirected alkylation of
lithiated methyl (3,5-hexadienoate)Fe(CO3) complex adjacent to the ester functionality. An excellent
level of diastereoselectivity is reached (up to 96:4 dr) when methyl iodide is used as electrophile
(Equation (120)) <1997T4185>.
O
O O
HN i. NaN(TMS)2
HN
EtO2C O THF, –78 °C HN
EtO2C O + O
EtO2C ð118Þ
ii. BnBr
98% Bn Bn
96/4 dr
i. Base ( )n H
( )n H THF, –78 °C CO2Et
CO2Et N
N 1X (S) (R)
ii. R R1
R Ph H
Me
i. LiHMDS
ii. R1X Yield
n Base R1X (%) de
( )n H ð119Þ
CO2Et 1 LDA Allyl bromide 68 >95
N 2 LiHMDS Allyl bromide 92 98
t-BOC R1
Yield
n R1X (%) de
1 Allyl bromide 84 13
2 Allyl bromide 84 72
i. LDA
Fe(CO)3
Fe(CO)3 THF, –78 °C
ii. RX , –78 °C R
H CO2Me ð120Þ
CO2Me
RX = MeI 72–97% 96/4 dr

BnBr 59% 8.6/1 dr
(b) Intermolecular conjugate additions. Owing to their high reactivity toward nucleophilic attacks,
,-unsaturated esters are among the most studied substrates for Michael additions. To illustrate this
reactivity, two examples have been selected. In 1994, Davies and co-workers examined the sequential
conjugate addition of the chiral Hauser base to the t-butyl cinnamate and treatment of the lithium
enolate with methyl iodide. The syn-adduct was isolated as major product with a diastereomeric excess
of 95% (Equation (121)) <1994TA35>. In another example, Toru and co-workers showed that
enantioenriched -silyl--sulfinyl carbanions also add to ,-unsaturated esters with excellent 1,2-
asymmetric induction (dr > 98:2). Thus, the intermediate enolate reacts with various alkyl halides and
leads to the syn,anti,syn-trisusbstituted adducts as a single diastereoisomer (dr > 98:2) (Equation
(122)) <1997SL449>. When !-halo-,-unsaturated esters are used, the transient enolate undergoes
intramolecular alkylation with total diastereocontrol giving the corresponding cyclopropane, cyclo-
pentane or cyclohexane carboxylates (Equation (122)) <2000JOC1758>.
Bn
i. Ph N
MgBr
Bn
THF, –78 °C Ph N ð121Þ
CO2But
Ph CO2But
ii. MeI Ph
90%
95% de
i. LDA, THF, –78 °C – Ph

O– O
S CO2Me
p -Tol + ii. Ph S CO2Me
p -Tol +
iii. RX, –78 to 0 °C
SiMe3 R
Me3Si
i. LDA RX = MeI, 75% >98/2 dr

ii. Br ( ) CO2Et BnBr, 74% >98/2 dr
n ð122Þ
n = 1, 3, 4
80–93%
O – ( )n
S CO2Me
p -Tol +
Me3Si
(c) Intramolecular conjugate additions. Starting from !-iodo unsaturated esters or activated
!-iododienes, Cooke, Jr., and co-workers showed that intramolecular 1,4-addition of primary
organolithiums, initiated by a rapid lithium–iodide exchange with BunLi, followed by methylation
of the intermediate enolates proceeds in good yields (Equation (123)) <1997SL535>.
CO2But
Me CO2But
i. BunLi
THF, –78 °C
ð123Þ
ii. MeI
79%
I
(d) Alkylation of lactone enolates. An example of regio divergence in C- versus O-alkylation of

lactone enolates has been reported by Kim and co-workers. !-Iodo lactones, deprotonated either
by LiHMDS or KHMDS, readily underwent C- and O-intramolecular alkylation, respectively.
Thus, the C-alkylated compound or spiro lactone has been converted into ()-grandisol in a
stereospecific manner (Equation (124)) <1994TL9211>. Alternatively, lactone enolates can be
generated by 1,4-addition of organolithium reagents to related ,-unsaturated carbonyl com-
pounds. As shown by Hanessian, the lithiated chiral allylic phosphonamide reacts regiospecifi-
cally with various ,-unsaturated lactones (and lactams) to give -Michael adducts with high
diastereomeric excess. Electrophilic quenching of the intermediate lithium enolate occurs with an
excellent diastereoselectivity (Equation (125)) <2000JOC5623>.
O O O O
KHMDS O LiHMDS, THF
O
THF –78 to –50 °C
I
50% 90%
ð124Þ
OH
O
O
HO
(±)-Grandisol
O
Me i. BunLi Me R
N O THF, –78 °C N O
P H O
P
N ii. N ð125Þ
Me O O
Me
iii. RX
RX = MeI, 70% 96/4 dr
BnBr, 75% 98/2 dr
(xii) -Alkylation of selenolates, dithioesters and selenothioesters

In 1995, Kato and co-workers reported that alkylation of lithium 1-alkoxyeneselenolates, pre-
pared by direct deprotonation of selenoesters with LDA at 78 C, with propargyl bromide
involves sequential progargyl selenide formation and its subsequent [3,3]-rearrangement to liber-
ate allenic selenoesters in good-to-moderate yields (Equation (126)) <1995TL2807>. Under
similar conditions, lithiated -hydroxy selenothioic esters also undergo exclusive Se-alkylation,
a regioselectivity already observed in the sulfur series with dithioic esters <1995TL6225>.
Electrophilic quenching with allyl bromide leads to vinyl allyl selenides as excellent precursors
for seleno-Claisen rearrangement. The -allylated product was isolated in fair yield (Equation
(127)) <1999JOC2130>.
i. LDA Se
Se THF, –78 °C Se
R OEt
OEt ii. Propargyl bromide ð126Þ
R OEt R
R = Bun (62%); Ph (56%)
OH SeMe
MeI SBun
i. LDA 79%
Se LiO Se OH SeLi 97/3 (Z )/(E )
THF, –78 °C
SBun ii. MeCHO SBun SBun OH Se ð127Þ
Br SBun
89%
92/8 syn/anti
(xiii) -Alkylation of oxazolines

As Florio and co-workers recently found, 2-(1-chloroethyl)-4,4-dimethyl-2-oxazoline is easily
deprotonated with LDA at 80 C. The transient chlorocarbenoid, stabilized by an intramole-
cular chelation between chlorine and lithium atoms, can substitute methyl iodide in 95% yield
(Equation (128)) <2001S2299>. Otherwise, the lithiated 2-chloro-methyl-2-oxazoline tends to
‘‘trimerize’’ into trans-1,2,3-tris(oxazolinyl)cyclopropane which can be alkylated by sequential lithia-
tion with BusLi/TMEDA followed by electrophilic trapping (Equation (129)) <2002JOC759>.
Cl Li Cl Cl Me
N LDA N MeI N
Me Me Me ð128Þ
THF, –80 °C 95%
O O O
Li Cl N N
N N O O
N LDA –LiCl
Cl
O O
O THF, –98 °C N O
N O
ð129Þ
N N N N
O O O O
BusLi/ TMEDA Br
Li
THF, –98 °C –98 °C to rt
N O 95% N O
Naphthyl oxazoline compounds were shown to be excellent Michael acceptors for intermole-
cular addition of Grignard reagents and alkyllithiums such as -ethoxyvinyllithium, a useful acyl
anion equivalent (Equation (130)) <1998TL5301>. In the presence of alkyl halides, oxazoline
lithium enolates undergo electrophilic quenching adjacent to the oxazoline moiety <1994T2297,
2000JOC3018>. More recently, asymmetric addition to 3-methoxynaphthalen-2-yl oxazolines has
been reported (Equation (131)) <2000JOC3018>. Independently, Meyers and Clayden applied
this methodology to the preparation of natural products including aphanorphine
<1995JOC1265> and podophyllotoxin core <2002OL787>. In the last case, Clayden’s approach
involves the dearomatizing anionic cyclization of oxa-analogs of -lithiopropylnaphthalenes as
key step followed by alkylation of the resulting anion to the oxazoline (Equation (132)).
EtO
i.
O Li EtO O O O
THF–HMPA HCl ð130Þ
N –78 °C N N
Me THF Me
ii. MeI
98% 81%
OMe OMe
i. PhLi OMe
O THF, –78 °C O
ð131Þ
ii. MeI Me CHO
N Ph N Me
60% Ph
But But
Im Me Me Im
N O LiN O
MeLi MeI
SnBu3 O + O ð132Þ
THF
O 79%
O TMEDA
–78 °C OMe OMe
OMe OMe
>25/1 dr
(xiv) -Alkylation of amides and lactams

Amide enolates are synthetically very useful intermediates, particularly in the synthesis of natural
products. For their generation, several methods have been reported including metallation by
proton abstraction or Birch reduction of adjacent aromatic rings. For example, Ernst and
Helmchen studied the enolization of a bicyclic -lactam using LDA at 78 C and the stereo-
selective alkylation with methyl iodide leading to the related -branched lactam with a 10:1
diastereoselectivity, a synthetic intermediate which allowed the preparation of -skytanthine
(Equation (133)) <2002S1953>. Similarly, it is possible to alkylate a series of substituted pyr-
idinones (Equation (134)) <1995TL1035> and dihydropiperidones (Equation (135))
<2003TL757> with high diastereoselectivity.
H H H
O O
i. LHMDS, MeI LAH
NH ii. LDA, MeI N-Me THF N-Me ð133Þ
H 74% H 98% H
10/1 dr α-Skytanthine
Me i. BusLi Me
HMPA–THF
Ph N Ph N
R
ii. RX ð134Þ
O O
HO HO
RX = MeI, 91% >96 de
BnBr, 66% >96 de
OTBS OTBS OTBS

i. LDA
THF, –78 °C
+
N ii. R1X N N
R R R1 R R1 ð135Þ
–78 to 0 °C
O O O
R = Me R1X = i-PrI, 72% 100/0 anti/syn
R = t-BOC R1X = MeI, 89% 0/100 anti/syn
Clayden reported an interesting example of ButLi-mediated stereospecific and retentive cycliza-

tion of N-substituted tertiary 1-naphthamides bearing a chiral -butyl benzyl group, followed by
methylation of the intermediate enolate. The highly substituted pyrrolidinone was isolated in
enantiomerically pure form. The excellent stereospecificity may be explained by a selective
ortholithiation of one of the two atropisomers which are in equilibrium at 78 C, followed by
aryllithium translocation to a chiral -amino carbanion, which readily cyclizes to a unique
diastereoisomeric adduct with retention of configuration (Equation (136)) <1999TL8327>.
Another approach to pyrrolidinones was described by Guo and Schultz. N-Methylphthalimide
can be first alkylated in the benzylic position, as reported in Section 1.04.3.4, and then the related
adducts undergo sequential diastereoselective Birch reduction–alkylation to give 3-substituted-2-
methyl-2,3-dihydroisoindol-1-ones in good yields (Equation (137)) <2001JOC2154>.
But But
O N Ph O N Ph
Bun 76/24 at –78 °C Bun
Syn Anti
ButLi ð136Þ
X
THF, –78 °C
But But But But
LiO O
O N Ph O N Ph N N
Bun MeI Me Bun
Li Bun Bun Li Ph 66% Ph
H H
i. ButLi O i. Li, NH3–THF Et O

O
THF, –78 °C ButOH, –78 °C
NMe NMe ð137Þ
NMe ii. MeI ii. EtI
79%
Me Me
1.04.3.1.2 Asymmetric alkylation of amide enolates
(i) Introduction of chirality from chiral auxiliaries

The use of chiral auxiliaries proved to be very efficient for the preparation of enantiopure materials.
When the auxiliary is attached to an achiral carbonyl function, asymmetric enolate alkylation of the
acyl moiety can be realized with an excellent facial discrimination <B-1995MI, 2000T917>. Orginally
reported by the Evans group, studies with enantioenriched 4-branched-2-oxazolidinones, derived
from -amino acids, have attracted a great deal of attention and now represent the most popular
auxiliaries used for sequential enolization-asymmetric trapping with alkyl halides <1982AA23>.
Analogous chiral templates derived from amino indanol (Equation (138)) <1996TA2939>,
exo,exo-amino borneol (Equation (139)) <1994CC1861> or protected imidazolidinones (Equation
(140)) <1995HCA1185, 1996AG(E)2708, 1996TL4565, 1998EJO1337>, phenyliminooxazolidine
auxiliaries (Equation (141)) <2002TA9> and ‘‘Quat’’ (Equation (142)) <1994TL2373, 1995TA671,
1998SL963, 2002TA647> or ‘‘SuperQuat’’ (Equation (143)) <2000TA3475> have been synthesized
and tested in alkylation processes. In most cases, high levels of stereocontrol have been reached
and the corresponding acids liberated by selective cleavage of the NCO bond under mild conditions
without any racemization. Excellent diastereoselectivity has been also obtained with bicyclic
carbohydrate oxazolidinones derived from D-xylose (Equation (144)) <1996TA637>.
i. LDA
THF, –78 °C
ii. Allyl bromide ð138Þ
N O N O
THF, 0 °C
O O 100% O O
>99% de
i. NaHMDS
O O O O
O THF, –78 °C O
N N Na N O
O ii. Allyl bromide, THF O H ð139Þ
–78 °C to –30 °C Et
Et Et
>99.9/0.1 dr
O O i. LDA / ZnBr2 O O
THF, –20 °C
N N
N ii. PhCH2Br N ð140Þ
But 71% But Ph
BOC BOC
22/1 dr
PhN O i. LiHMDS PhN O

THF, –78 °C
O N O N
ii. BnBr ð141Þ
Bn
Pri 88% Pri
97/3 dr
O O i. LDA O O
THF, –78 °C
N N
ii. BnBr ð142Þ
Bn
80%
96% de
O O O O
i. LiHMDS
O N Ph THF, –78 °C O N Ph
ii. (Me)2C=CHCH2Br ð143Þ
Ph 83% Ph
97/3 dr
O O
O O i. LDA O
O
O But THF, –78 °C O
N But
ii. MeI N
O O ð144Þ
O 30% Me
O
99/1 dr
Chiral bicyclic lactams, developed by Meyers, are important examples of oxazoline type chiral
inductors often used for the stereoselective formation of quaternary carbon centers by dialkyla-
tion of related amide enolates or cyanoenamine anions with organic halides <1991T9503>. Endo-
versus exo-attack depends on the nature and the relative position of the substituents present on
the oxazoline ring. Good-to-excellent levels of stereoselectivity are observed in the formation of
,-dialkylated adducts. After reduction or alkyllithium addition and subsequent hydrolysis, 4,4-
disubstituted cyclopentenones (Equations (145) and (146)) as well as 4,4-dialkylcyclohexenones
(Equation (147)) are isolated in good yields <1996JOC5712, 1997CC1, 1997JA4565, 1998JA7429,
1998JOC1619, 1997T8795>.
Me i. BusLi Me
O O Bn
THF, –78 °C
N Bn N ð145Þ
ii. Allyl bromide
O 63% O
5/95 exo/endo
O
TBDPSO Me i. BusLi TBDPSO Me
O O Bn
THF, –78 °C
Ph N Ph N Bn ð146Þ
ii. BnBr
O 88% O
99/1 exo/endo
MeO i. LiTMP MeO Me O

Me O
O H
THF, –78 °C
N N H
ð147Þ
Ph ii. BnBr Ph
Bn
NC 83% O Bn
Larchevêque <1978TL3961, 1979JOM5>, and later Myers used the inexpensive and readily
available D-(+)-pseudoephedrine as chiral inductor for selective CC bond formation. In the
presence of lithium chloride, N-acyl derivatives undergo enolate alkylation with very high dia-
stereofacial selectivities (94% to >99% de) (Equation (148)) <1994JA9361, 1997JA6496>. A new
C2-symmetrical ferrocenyl amine, reported by Schwink and Knochel, has been effective in the
stereoselective alkylation of amide enolates with alkyl halides. Crystalline -substituted
ferrocenylamides are formed in 65–89% yields as a single diastereomer (dr 98/2). Then, the
auxiliary was easily removed by hydrolysis with 2 M HCl in dioxane:H2O at reflux (Equation
(149)) <1997TL3711>. The enantioenriched hydrazines introduced to synthesis by Enders for the
asymmetric alkylation of hydrazones can also be used as chiral auxiliaries for the -alkylation of
chiral N-(dialkylamino)lactams. Reductive NN bond cleavage by lithium in liquid ammonia led
to 2-substituted lactams in moderate with high enantiomeric excesses (71–99% ee) (Equation
(150)) <1996S941>. Finally, an example of asymmetric alkylation controlled by a chiral auxiliary
with an axis of chirality instead of stereogenic centers was reported by Simpkins. Atropisomeric
amides, available from o-t-butyl aniline, were deprotonated with LDA at 78 C to generate the
corresponding lithium enolates, which were treated by alkyl halides to produce the -alkylated
adducts with diastereomeric ratios up to 25:1 (Equation (151)) <1996TL7607>.
i. LDA, LiCl
Me O THF Me O
0 °C or –78 °C
N N ð148Þ
ii. I(CH2)2OTBS
OH Me OH Me OTBS
91%
97% de
i. LDA
Fc Fc
THF–HMPA
O 0 °C O
N N ð149Þ
ii. BnBr
Fc –78 to 0 °C Fc Bn
89%
Fc = ferrocenyl >98/2 dr
O O
i. LDA O
N N THF, –78 °C N N Li, NH3
NH
ii. PrI –33 °C ð150Þ
OMe OMe
82%
80% de
O O
i. LDA
MEM MEM
N THF, –78 °C N
But ii. EtI But ð151Þ
–78 °C to rt
89%
15/1 dr
(ii) Introduction of chirality from chiral lithium amides

The use of chiral lithium amide bases in deprotonation steps has largely contributed to the
development of new methods for asymmetric -alkylation of carbonyl compounds such as amides
and lactams <1998JCS(P1)1439>. On this subject, Kobayashi and Koga have reported an inter-
esting chiral base-mediated enantioselective alkylation of lactams and lactones, which proceeds
through sequential proton abstraction by a nonracemic tetradentate lithium amide in the presence
of LiBr and subsequent alkylation of the intermediate enolate (Equation (152)) <1998TL9723>.
Recently, a chiral pentamine ligand has been developed for -benzylation of acyclic amides
(Equation (153)) <1999OL345>. Finally, an example of asymmetric desymmetrization of meso-
imides by enantioselective deprotonation with a chiral bis-lithium amide has also been studied.
Simpkins showed that monalkylation of 4-aryl substituted glutarimides with methyl iodide, allyl
bromide, and benzyl bromide can be realized up to 97% ee (Equation (154)) <2002SL2074>.
i. Base-LiBr Li
O O
TMTHF, –20 °C N
Me Bn Me N N
N N Base:
ii. BnBr Ph ð152Þ
64%
N
98% ee
TMTHF: 2,2,5,5-Tetramethyltetrahydrofuran
Ph
i.
Me2N N N N
Li Li ð153Þ
O NMe2 O
Toluene, –78 °C
N N
ii. BnBr
40% Bn
84% ee
Ph Ph
F Me Me F F
i. N N
Ph Li Li Ph
THF, –98 °C
ii. RX, –78 to –40 °C R R R
+ ð154Þ
O N O O N O O N O
Bn Bn Bn
RX = MeI, 64% 97% ee (2/1)

BnBr, 61% 97% ee (2/1)
1.04.3.2 Oxygen-stabilized Carbanions

Despite the high electronegativity of the oxygen atom, generation of -oxygenated carbanions by
direct deprotonation of simple alkyl ethers at low temperature is far from being straightforward.
However, the presence of other activating groups such as trifluoromethyl, allyl, propargyl, and
benzyl substituents should favor the metallation and may also stabilize the organometallic reagent
generated. Alternative methods for metallation, based either on metal insertion, tin–metal
exchange, carbometallation of alkenes or reduction of sulfides, sulfoxides as well as selenides
have been developed. Selected examples are reported below.
1.04.3.2.1 Alkylation of nonstabilized a-oxycarbanions
(i) Metallation by proton abstraction

Shimizu and co-workers reported the stereoselective preparation and the alkylation of lithiated
epoxides derived from 2-alkynyl-3,3-dichloro-1,1,1-trifluoro-2-propanol. First, the gem-dichlo-
methyl group can be metallated at 98 C giving a -alkoxycarbenoid which undergoes successive
inter- and intramolecular substitutions of chlorine atoms by RLi and -OLi, respectively. A
lithium–fluoride chelation and a substitution of chlorine by RLi from the -OLi side may explain
the high level of diastereoselectivity observed. Then, the trifluoromethyllithiooxirane can be
quenched by allyl bromide or different alkyl iodides. Above 78 C, the carbenoid rearranges
into allylic alcohols through sequential -elimination and CH bond insertion of the carbene
(Equation (155)) <2001JA6947>. Uneyama and co-workers showed that the presence of a
trifluoromethyl group on a simple oxirane promotes -lithiation with BunLi at 102 C. The
enantiomerically enriched precursor was alkylated by methyl iodide in good yield and with a total
retention of configuration. No trace of by-product coming from -elimination reactions was
detected (Equation (156)) <2002OL173>. For more information, the chemistry of oxiranyl
anions has been successively reviewed by Satoh <1996CR3303> and Hodgson <2002S1625>.
F BunLi substitution
HO CF3
BunLi (3 equiv.) Li CF2 and cyclization
Cl
THF, –78 °C Cl
Cl Ph Cl OLi Ph
O
O MeI Me CF3
Li CF3 Bun ð155Þ
–98 to –78 °C
Bun
80% Ph
dr >95/5
Ph
–78 °C to rt HO CF3
n
Bu
Ph
O BunLi O MeI O
CF3 CF3 CF3 ð156Þ
H THF, –102 °C Li –102 to –78 °C Me
(S ), 75% ee 82%
(ii) Metallation by tin–lithium exchange

Stereoselective alkylation of lithiated oxazolines has been examined by Sardina and co-workers.
In the presence of BunLi at 78 C, the stannyl precursor may undergo a lithium–tin exchange
reaction that generates the -alkoxy -aminoalkylcarbanion, which can be trapped by methyl
iodide in 70% yield (Equation (157)). The sequence proceeds without loss of configuration and
-elimination side reaction <2001JA2095>.
Me SnBun3 Me Li Me Me Ph
BunLi MeI H
Pf = ð157Þ
N O THF, –78 °C N O 70% O
Pf Pf Pf N
(iii) Copper(I)-catalyzed cross-coupling reactions

Falck and co-workers have shown that -stannyl epoxides (Equation (158)) <1997SL481> and
-(acyloxy)alkylstannanes (Equation (159)) <1995JA5973, 1996JOC6492> can be coupled with
allyl bromide in the presence of a catalytic amount of copper(I) salt (Cu2S or CuCN). The
reaction is totally stereoselective. Only one diastereomer of the substituted oxirane is formed in
good yield.
O O H Allyl bromide O O H
Cu2S (8 mol.%)
Ph SnBun3 Ph ð158Þ
THF, 50 °C
H H
78%
OAc Allyl bromide OAc

ð159Þ
Ph SnBu3 CuCN (8 mol.%), THF, 65 °C Ph
80%
(iv) Metallation by reduction of sulfide or by lithium–sulfoxide exchange

-Alkoxysulfides and -alkoxysulfoxides were also shown to be excellent precursors of -alkoxy-
lithium reagents. Reductive lithiation of 4-(phenylthio)-1,3-dioxanes by lithium di-t-butylbiphe-
nylide (LiDBB) at 78 C represents a valuable method to generate anomeric carbanions with a
high stereoselectivity. The alkyllithium generated takes up preferentially an axial position and
may equilibrate above 20 C to the equatorial configuration (for unhindered substrates). After
transmetallation with CuCN2LiCl, electrophilic trapping with various electrophiles such as allyl
bromide affords the desired functionalized products with retention of configuration (Equation
(160)) <1999JOC6849>. Phenylsufinyl–lithium exchange may be an alternative to the previous
approach. Fernàndez-Mayoralas and co-workers have illustrated this reactivity by synthetic
studies on glycosides derived from -L-fucopyranose. Treatment of fucopyranosyl phenyl sulf-
oxide with ButLi then MeLiLiBr in THF at 78 C followed by methyl iodide quenching also
proceeds with retention of configuration but in low yield (Equation (161)) <2001JOC1768>.
n-Hex SPh n-Hex Li n-Hex

Li, DBB i. CuBr2.SMe2
O O O O O O
THF, –78 °C ii. Allyl bromide
67%
10/1 dr
–20 °C
ð160Þ
n-Hex Li n-Hex
i. CuBr2.SMe2
O O O O
ii. Allyl bromide
38%
dr >10/1
O i. MeLi.LiBr, –78 °C O
O ii. ButLi, –78 °C O
ð161Þ
O iii. MeI O
HO 19% HO
SOPh Me
(v) Alkylation of dipole-stabilized anions

-Lithiation of alcohols protected as esters or carbamates is highly favored first by the complexa-
tion of the organolithium base to the carbonyl group which directs the metallation and also by
a dipole-stabilization of the organometallic intermediate. Intensive studies on stereoselective
deprotonation induced by an alkyllithium base/(–)-sparteine complex and subsequent alkylations

have been reported by Hoppe and co-workers for the preparation of substituted nonracemic
secondary alcohols. To explain the asymmetric induction, they suggested the formation of an
aggregate between BusLi, (–)-sparteine and the carbamate prior to the deprotonation step. The
organolithium/(–)-sparteine complex generated is configurationally stable and can substitute
stereospecifically various electrophiles. Mechanistic studies based on kinetic isotopic effects,
NMR experiments and semi-empirical calculations have been reviewed by Hoppe and Hense
<1997AG(E)2282>. The first application of this methodology concerned the enantioselective
deprotonation of a carbon atom adjacent to a carbamate which derived from a primary alcohol.
The latter gives, upon treatment with BusLi/(–)-sparteine in THF at 78 C, the -oxygenated
organolithium complex (measurements of D/H kinetic isotopic effect revealed a preference for the
pro-S-proton abstraction) which can be trapped by different electrophiles such as methyl iodide
<1990AG(E)1422, 1992S1216, 1997AG(E)2282>. High enantiomeric excesses up to 98% have been
reached but a partial racemization involving single-electron transfer may explain the low ee
observed with allyl bromide. However, transmetallation successively with ZnCl2 and CuCN2LiCl
liberates the mixed CuZn, which can be allylated with an overall retention of configuration.
Several allyl bromides have been tested by Taylor and co-workers (Equation (162)) <2002OL119>.
Intramolecular SN20 substitution of allyl chloride by enantiomerically enriched -oxy-organo-
lithiums, generated in situ by SnLi exchange, furnishes disubstituted cyclopentanols as a single
diastereomer (dr > 98/2) and enantiomer (>95% ee) (Equation (163)) <2002OL2193>.
BusLi.(–)-sparteine H Li.spart. R1X H R1
R OCby
THF, –78 °C R OCby R OCby
R = CH3, n-C3H7 or n-C12H25 R1X = MeI, 60% (98% ee)
ii. ZnCl2 Allyl bromide, 60% (42% ee)
O
iii. CuCN.2 LiCl 83%
ð162Þ
Cby: N iv. Allyl bromide
O
OCby
(>99% ee)
i. BusLi.(–)-sparteine
Et2O, –78 °C TBSO OCby
TBSO OCby
ii. Bu3SnCl SnBun3
ð163Þ
(R )
Cl OCby BunLi, Et2O, –78 °C
OCby
(S)
SnBun3 96%
>98/2 dr >95% ee
A second carbamoyloxy group at the - or -position may interfere with the aggregate
organization, for instance by displacement of the (–)-sparteine ligand, and consequently should
influence the asymmetric induction. The enantioselective deprotonation of 1,3- as well as 1,4-
dicarbamates and subsequent alkylations with methyl iodide still gave the enantioenriched
adducts up to 97% ee. This result shows that the extra carbamoyloxy group does not modify
the selectivity (Equation (164)) <1992TL5327>. Moreover, the presence of a stereogenic center in
the -position promotes a diastereoselective lithiation by the BusLi/TMEDA complex whereas
deprotonation carried out in the presence of (–)-sparteine affords the opposite diastereoisomer.
With TMEDA, the selectivity is controlled by a double chelation of the carbamoyloxy groups
(Equation (165)) <1992TL5327>. A very similar explanation was suggested for the excellent
diastereomeric ratio observed with the acetonide of (S)-3,4-dihydroxybutyl dicarbamate without
additional diamine <1995SL978>. Stereoselective lithiation of 2- and 3-aminoalkyl carbamates
by BusLi with or without diamine has been also investigated. Only selected examples will be
presented here. A strong preference for the abstraction of the pro-(S) hydrogen was observed with
3-(piperidine-2-yl)ethyl carbamate. Starting from the racemic compound, a mixture of two dia-
stereoisomers was obtained and converted into (+)-sedridine and (+)-allosedridine (Equation
(166)) <1997AG(E)2282>. In addition, removal of pro-(R) hydrogen is much favored with
(R)-2-aminoalkyl carbamates. Without additive, a kinetic deprotonation was suggested to explain

this selectivity. In the presence of (–)-sparteine, the substrate remains unchanged because of a
mismatched-pair situation (Equation (167)) <1997AG(E)2282>. Hoppe’s methodology was then
applied to the desymmetrization of meso-dicarbamates by differentiation between the two enan-
tiotopic branches and a preferential abstraction of pro-(S) protons for each pair of diastereotopic
methylene protons (Equation (168)) <1999MI1905>.
Yield ee
i. BusLi.(–)-sparteine n (%) (%)
THF, –78 °C ð164Þ
CbyO ( )n OCby CbyO ( )n OCby 1 83 >97
ii. MeI
2 92 97
BusLi.(–)-sparteine
MeI CbyO OCby
Et2O, –78 °C CbyO O N
56%
Li O 94/6 de
N N
CbyO OCby *
ð165Þ
sLi.TMEDA
Bu
Et2O, –78 °C O N MeI CbyO OCby
44%
CbyO Li O
98/2 de
L
H H
i. BusLi.(–)-sparteine N OCby N OH
H(RH
)
(S )
H Et2O, –78 °C 29%
Bn H
>95% ee (+)-Sedridine
N OCby ii. MeI ð166Þ
Bn 49% H H
N OCby N OH
Bn H
89% ee (+)-Allosedridine
i. BusLi.TMEDA
NBn2 NBn2 NBn2
Et2O, –78 °C
O N OCby + OCby
ii. MeI ð167Þ
H(S ) H(R )O 72%
88/12 dr
H i. BusLi.(–)-sparteine E H
H
OCby Toluene, –78 °C OCby
OCby +
OCby ii. MeI OCby ð168Þ
OCby
H 70% H
H E
95/5 dr >95% ee
Allylation of magnesium carbenoids bearing an ester function was reported by Knochel

<1999SL1820>. Iodomethyl pivalate treated with PriMgCl in THF/N-butyl pyrrolidinone
(NBP) at 78 C undergoes an iodine–magnesium exchange and leads to the corresponding
magnesium carbenoid, which can be trapped by ethyl (2-bromomethyl)acrylate. The allylated
compound was isolated in 80% yield (Equation (169)).
CO2Et
O PriMgCl O Br O
But O I THF/NBP But O MgCl But O CO2Et ð169Þ

80%
–78 °C
NBP: N-butyl pyrrolidinone

1.04.3.2.2 a-Alkylation of 1-oxysubstituted allyllithiums

All the reports recently published on this topic were focused on the reactivity of enantioenriched
lithiated 2-alkenyl carbamates <1997AG(E)2282, 2002AG(E)716>. Asymmetric deprotonation
with alkyllithium bases can be induced by a chiral ligand such as (–)-sparteine or by a chiral
auxiliary already present on the substrate. The organolithium intermediate shows a limited
configurational stability even at low temperature. One epimer can be enriched by dynamic kinetic
resolution, caused by the preferential crystallization of one epimeric lithium complex or by a rapid
electrophilic trapping. -(3-Arenesulfonyl-1,3-oxazolidine)-substituted allyl carbamates were
deprotonated with BunLi/TMEDA complex at 78 C and treated with methyl iodide to give
exclusively -adducts as a single diastereoisomer. This result may be explained by a complete
epimerization of the allyllithium to the most thermodynamically favored intermediate where the
lithium chelates the chiral auxiliary. Therefore, a substitution with inversion of configuration may
justify the stereochemistry observed (Equation (170)) <2000SL950>.
BunLi O Li OCby O Li OCby O Me OCby

ArSO2 N O OCby TMEDA N N MeI N
ArSO2 ArSO2 ArSO2
Toluene 61%
–78 °C
α /γ 100/0
ð170Þ
dr >97/3
Ar =
This chemistry was then applied to intramolecular processes. The only examples reported in
this field concern the cyclization of lithiated 9-chloro-2,7-nonadienyl carbamates. A (2(E),7(E))
arrangement of double bonds gave the expected disubstituted cyclopentane as opposed to
a (2(Z),7(Z)) or (2(Z),7(E)) disposition which led to nine-membered carbocycles. Enantioselective
deprotonation of 9-chloro-2,7-nonadienyl carbamates with BusLi/(–)-sparteine proceeds with a
preference for the pro-(S) proton. The (2(Z),7(Z))-isomer cyclized to give a 1,2-dialkenyl-sub-
stituted cyclopentane with a regioselective , 0 -bond formation. An anti-SN0 –SE0 mechanism has
been proposed to explain the diastereoselectivity and the reaction was used for the synthesis of
(+)-(3(R),4(R))-1,2-dihydromultifidene (Equation (171)) <1999AG(E)546, 2001JOC2842>. In
addition, the (2(Z),7(Z))- and (2(Z),7(E))-isomers undergo intramolecular ,0 -coupling of both
allyl moieties with inversion of configuration. This method provides a straightforward route to
enantiomerically enriched functionalized 1,5-cyclononadienes (Equations (172) and (173))
<2000AG(E)2105, 2000OL2415>.
OCby i. BusLi.(–)-sparteine
toluene, –90 °C
Cl OCby ð171Þ
ii. MeOH
90%
99/1dr 80% ee (+)-(3(R ), 4(R ))-1,2-Dihydromultifidene
OCby i. BusLi.(–)-sparteine
(R)
toluene, –90 °C H
OCby OCby
ii. MeOH H (R) ð172Þ
Cl 82%
(+)-(M, R) (–)-(P, R)
(E )
97/3 dr 80% ee
OCby OCby
As above (R)
Cl
73% ð173Þ
(Z )
88% ee
1.04.3.2.3 a-Alkylation of 1-oxysubstituted benzyllithiums
(i) Lithiation by proton abstraction

Lithiation of arylmethyl alkyl ethers has received a particular attention. One protocol, first
reported by Yeh, involved a deprotonation of benzyl methyl ether with BunLi/TMEDA in hexane
followed by substitution of BunBr <1981JCS(P1)1652>. Several experiments carried out in THF
underline the relative instability of these metallic species. Indeed, due to their carbenoid
properties, -lithiated alkyl benzyl ethers may undergo -elimination or 1,2-Wittig rearrange-
ment. Azzena and co-workers found that benzyl methyl ether and isopropyl benzyl ether can
be deprotonated either with BunLi or BusLi in THF at 40 or 80 C, respectively. Then, the
resulting carbanion is sufficiently stable to react with alkyl iodides and alkyl bromides in
good yields (Equation (174)) <1998T12389>. An example of the enantioselective alkylation of
isochroman and phthalan was published by Nakai and co-workers. Asymmetric lithiation
with ButLi/(–)-sparteine complex at 78 C gave the chiral lithiated species which undergoes an
SE2 substitution of different alkyl halides. Poor-to-moderate enantiomeric excesses have been
measured. The origin of this enantioselectivity is the result of a dynamic thermodynamic
resolution mechanism where the epimerization is slower than the substitution. However, the
reactivity of the electrophile influences the enantiomeric excess and may explain the difference
between methyl bromoacetate (Equation (175)) and benzyl bromide as well as other halides
(Equation (176)) <2000TL6121>. Shimano and Meyers have shown that metallation of trans-
and cis-oxazolines, prepared from t-butyl cyanide and ((S),(S))-2-amino-3-phenylpropane-
1,3-diol, with -ethoxyvinyllithiumHMPA complex (EVLHMPA) results in the formation of
-alkoxybenzyllithium exclusively. The latter was quenched with methyl iodide with retention of
configuration (Equation (177)) <1997TL5415>.
Me
OMe i. BusLi, THF, –40 °C
OMe ð174Þ
ii. MeI then H2O
87%
i. ButLi.(–)-sparteine SO2NH2
hexane, –78 °C
O O
O ii. BrCH2CO2Me N ð175Þ
48% N
CO2Me
(+)-U-101387
60% ee
i. ButLi.(–)-sparteine
hexane, –78 °C
O O ð176Þ
ii. MeI (R)
92%
Me
36% ee
O Ph
EVL–HMPA
But
N THF, –78 °C
Ph O Ph
O MeI
OMe Li But Me
But ð177Þ
O Ph N 81–85% N
OMe
But OMe
N
OMe EVL = Ethoxyvinyllithium
(Alkyl benzyl ether)tricarbonylchromium(0) complexes have been reported to undergo facile

deprotonation at the benzylic position <1986JCS(P1)1581>. Sequential chiral lithium diamide-
mediated enantioselective lithiation-electrophilic quenching was examined by Gibson and
co-workers <2000CC989>. Methylation of methyl and benzyl benzyl ethers proceeds in 89%
and 96% yields with high enantiomeric excesses (97% and >99%), respectively (Equation (178))
<1996CC839>. A similar experiment carried out on the tricarbonyl(6-arene)chromium complex of
phthalan furnished the -methylated product in 75% yield and 79% ee (Equation (179))
<1996SL317>. An enantioselective benzylic deprotonation/silylation sequence generated the
nonracemic silylated intermediate, which was alkylated regioselectively to the TMS group
and diastereoselectively on the endo-face. Then, a second substituent was selectively introduced
at the benzylic position leading to the trans-1,3-dialkylated dihydroisobenzofuran (Equation
(180)) <2002AG(E)2525>. Synthesis of achiral cis-configured compounds has been already
reported by Davies <1989JOM81>.
Ph Ph
i.
N N
OMe Ph Li Li Ph
OMe ð178Þ
(CO3)Cr THF, –78 °C
ii. MeI (CO3)Cr
96%
97% ee
i. Ph N Ph, LiCl, THF, –100 °C Me

O Li
O ð179Þ
(CO3)Cr ii. MeI
75% (CO3)Cr
79% ee
Ph Ph
i. N N
Ph Li Li Ph
i. ButLi
THF, –100 °C O THF, –78 °C O
O
(CO3)Cr ii. TMSCl (CO3)Cr ii. MeI (CO3)Cr
TMS Me TMS
75%
>99% ee
i. ButLi
THF, –78 °C TBAF
O O
ii. Allyl bromide H2O
(CO3)Cr (CO3)Cr
91% Me TMS Me
ð180Þ
(ii) Lithiation by reductive cleavage

Siwek and Green have shown that (arene)tricarbonylchromium diethyl acetal in the presence of
LiDBB at 78 C undergoes reductive cleavage of the benzylic CO bond. Reaction of the
benzyllithium intermediate with methyl iodide afforded the functionalized chromium tricarbonyl-
benzyl ether in 63% yield (Equation (181)) <1996SL560>.
OEt i. LiDBB OEt
OEt THF, –78 °C Me ð181Þ

ii. MeI
(CO3)Cr 63% (CO3)Cr
(iii) Lithium–selenium exchange

Krief and Bousbaa reported the preparation of -methoxy-benzyllithiums from -methoxyalkyl
selenides through a LiSe exchange reaction. The CSe bond cleavage, promoted by addition of
ButLi in THF at 78 C, provides the -methoxy-organolithium which reacts efficiently with
various alkyl halides including benzyl chloride, allyl bromide, n-pentyl and s-butyl bromide
(Equation (182)) <1997TL6289>.
i. ButLi
OMe OMe
THF, –78 °C
Ph SeMe Ph Bn
ii. BnCl, –78 °C ð182Þ
Me Me
iii. –78 °C to rt
90%
(iv) Lithiation by intermolecular carbolithiation

Intermolecular syn-addition of alkyllithiums to 1-aryl-1-alkenyl N,N-diisopropylcarbamates forms
secondary -carbamoyloxy benzyllithiums stabilized by chelation. This intermediate can be
trapped by various electrophiles. To illustrate this reactivity, Hoppe and co-workers reported
the carbolithiation of (Z)-stilbene carbamate with BunLi/TMEDA complex followed by reaction
with methyl iodide, occurring with inversion of configuration. The expected adduct was isolated
in 61% yield. However, the organolithium/diamine complex acts as a base and deprotonates the
(E)-diastereomer instead of adding to the double bond <2002SL381>. The vinyl carbenoid
generated undergoes -elimination and liberates the diphenylethyne (Equation (183)).
(Pri)2N O BunLi (Pri)2N O (Pri)2N O (Pri)2N O

Ph TMEDA Ph MeI Ph Ph
Li Me Me
O O O + O ð183Þ
Toluene Bun 61% Bun Bun
Ph –78 °C Ph Ph Ph
13/87 dr
1.04.3.3 Sulfur-stabilized Carbanions

The chemistry of organosulfur compounds as synthetic intermediates is now well established in
organic synthesis. These compounds have been used in numerous important organic transforma-
tions and among these, great attention has been devoted to -metallation of sulfur-containing
functional groups, which can stabilize the adjacent carbanion by taking advantage of the polariz-
ability of the sulfur atom. The transient metallated species showed a good reactivity toward a
wide range of electrophiles, particularly alkyl halides.
1.04.3.3.1 Alkylation of nonstabilized a-thiocarbanions
(i) Alkylation of -lithio sulfides—carbolithiation of vinyl sulfides

Krief and co-workers reported the carbocyclization of benzyllithium intermediates across the acti-
vated double bond of a vinyl sulfide. The 6-methylseleno-6-phenyl-1-phenylthio-1-heptene is cleanly
metallated with ButLi at room temperature by CSe bond cleavage. Readily, the resulting benzyl-
lithium derivative undergoes a stereoselective cyclization and gives the cis-1,2-dialkyl-1-phenyl
cyclopentane intermediate. The -thioalkyllithium moiety can be alkylated with methyl iodide leading
preferently to the cis--adduct. A higher selectivity is obtained when the alkylation is carried out after
transmetallation with copper(I) salts (Equation (184)) <1995TL7917>.
Me Ph Me
ButLi SPh
Ph SeMe SPh Me Ph Li
pentane MeI 92/8
ð184Þ
Me 20 °C SPh THF, –78 °C Me Ph Me
93%
SPh
96/4 cis/trans
(ii) Alkylation of -lithio sulfoxides

-Sulfinyl carbanions exhibit an interesting configurational stability that can be rationalized by a
planar chelate structure. The stereochemistry of the alkylation is dependent on the choice of the
electrophile: electrophiles that chelate the lithium atom are delivered syn to the SO bond and
the others in an anti-fashion <2002AG(E)716>. Stammler and co-workers described the selective
lithiation of 4-(t-butylsulfinylmethyl)-2-phenyl-2-oxazoline at the carbon center adjacent to the
sulfinyl group, directed by the oxazoline and the sulfinyl moieties. Electrophilic trapping with
alkyl halides occurs in good yield and with high diastereoselectivity depending on the steric
hindrance of the alkylating reagent (Equation (185)) <1997LA1013>.
i. LDA H Et
But N THF, –78 °C
S Ph But N ð185Þ
O S Ph
H O ii. EtI O
H O
68%
(iii) Alkylation of -lithio sulfones—generation and reactivity of ,-dilithio sulfones

The synthesis of gem-dilithio sulfones by direct proton abstraction with a lithiated base has been
reported by Bonete and Nájera. The dianion is successfully generated by treatment with 2 equiv.
of BunLi in THF between 78 C and 0 C. The latter reacts with mono- and dialkyl halides to
give the dialkylated products in high yields (Equation (186)) <1996T4111>.
p -MeC6H4SO2 OMe BunLi (2 equiv.) p-MeC6H4SO2 OMe
OMe THF, –78 to 0 °C Li Li OMe
O
Br i.
i. i. BunI Cl Cl i.
Br Br
ii. H2O ii. H2O ii. H2O
ii. H2O
72% 97% 95% 70% ð186Þ
Ts OMe
OMe Ts OMe Ts OMe
OMe
Ts OMe Bun Bun OMe OMe
OH
92/8 dr
(iv) Conjugate addition to vinyl sulfones

Alkenyl sulfones are reknowned to be excellent acceptors for conjugate addition reactions. For instance,
Fuchs and co-workers achieved the addition of phenyldimethylsilyllithium or the related cyanocuprates
to vinyl sulfones. The Michael addition is followed by an intermolecular electrophilic trapping of the
-sulfonyl anion either with allyl or benzyl halides. In this case, the -alkylated -silyl sulfone when
treated with fluoride anion undergoes a 1,2-elimination of fluorosilane and phenylsulfinate providing
the trisubstituted olefin (Equation (187)). An example of intramolecular alkylation with an organic
chloride was also presented, giving a tricyclic sulfone derivative in 66% yield (Equation (188))
<1995TL4013>.
i. PhMe2SiLi Bn
SO2Ph PhMe2Si SO2Ph
THF, –78 °C Bu4nNF
Bn ð187Þ
MeO MeO MeO
ii. BnBr, HMPA THF, reflux
98% 96%
OMe
OMe OMe OMe
PhMe2SiLi
CuCN
Cl + HO 80%
Et2O, 20 °C OMe ð188Þ
SO2Ph SO2Ph
SO2Ph
TBDPSO RO SiMe2Ph RO SiMe2Ph
66% R = TBDPSi 19%
SO2
Ph
18%
In pioneering research, Eisch and Galle have reported a few examples of lithiation of -ami-
noalkyl sulfones followed by substitution of methyl iodide <1980JOC4534>. Sasaki and co-work-
ers have taken advantage of this transformation to devise a new methodology for the synthesis of
enantiomerically enriched nonproteinogenic -amino acids from L-serine. The THP derivative of
(2(R))-2-BOC-amino-3-phenylsulfonyl-1-propanol is available in five steps from N-BOC-L-serine
methyl ester. Alkylation of this -aminoalkyl sulfone involved monolithiation of the methylene group
adjacent to the sufonyl moiety with BunLi and reaction with various electrophiles
<1987TL6069>. The -lithio -aminoalkyl intermediate can also act as a 1,3-dinucleophile,
which is able to perform two successive substitutions with a dielectrophile such as 1,n-dihalides
(2 n 5). ,-Dialkylated compounds may also be prepared from gem-dilithio--aminoalkyl
derivatives. Further applications to different types of cyclic -amino acids, cycloalkylglycines, and
N-heterocyclic -amino acids synthesis have been published <1994TL237, 1997JOC765>. Simple
addition of nitrogen nucleophiles across the double bond of vinyl sulfones generates -amino
sulfones, readily alkylated at the -position (Equations (189)–(191)). Nàjera and co-workers have
reported the 1,4-addition of benzylamine to p-tolyl vinyl sulfone and -tosyl styrene (Equation
(192)). Functionalization to the sulfone was performed under usual conditions. This methodology
has been applied to the preparation of nitrogen-containing heterocycles and, for example, to the
synthesis of benzoazepine as precursor of capsazepine (Equation (193)) <1997T4791>. An exten-
tion of these studies to the enantioselective synthesis of acyclic -substituted -amino sulfones has
been investigated by Enders and co-workers Yb(OTf)3-Catalyzed conjugate addition of SAMP to
(E)-alkenyl sulfones generates the corresponding Michael adducts with introduction of a stereogenic
center at the -carbon. A moderate diastereoselectivity (de: 30–61%) was observed. After separation
of the diastereomers and removal of the chiral auxiliary by reductive cleavage, the major diaster-
eomer yields the (R)--aminoalkyl sulfone with a high enantiomeric excess (96% ee)
<1999AG(E)195>. Monolithiation with LDA/TMEDA generates the -sulfonyl carbanion which
can react with a range of electrophiles. The ((R),(R))-product was isolated in good-to-high diaster-
eomeric excesses (dr: 64–97%) and without any racemization (Equation (194)) <1999SL741>.
OH SO2Ph i. BunLi SO2Ph Et

THF, –78 °C
O OTHP OTHP O ð189Þ
t-BOCNH t-BOCNH ii. EtBr t-BOCNH t-BOCNH
H H H H
OMe 95% OH
(R)
i. BunLi, THF, –78 °C i. BunLi, THF, –78 °C

ii. Br(CH2)4Cl ii. Br(CH2)3Cl
iii. BunLi, THF SO2Ph iii. Bun Li, THF
–78 to 0 °C –78 °C to rt
N CO2H OTHP O ð190Þ
H iv. Na/ Hg (6%), MeOH, t-BOCNH iv. Na/ Hg (6%), MeOH t-BOCNH
t-BOC Na2HPO4 H Na2HPO4 H
OH
v. PPTS, EtOH v. PPTS, EtOH
vi. Jones oxidation vi. Jones oxidation
50% 51%
Route A
SO2Ph
i. BunLi, –78 °C
Br(CH2)2OTf OTHP
92% N ii. PhO2S PhO2S
SO2Ph
t-BOC OTHP OTHP
85% +
OTHP N N
t-BOCNH SO2Ph
H i. t-BOC t-BOC
ii. BunLi, –78 °C OTHP
79%
Allyl bromide t-BOCNH Route A, 6/94
H Route B, 89/11
95%
Route B
ð191Þ
Ts
Br
Br
i. BnNH2 R=H
R N
Ts THF, reflux 44%
R Ts Bn
ii. BunLi, NHBn
R ð192Þ
THF, –78 °C Li R1X Ts
NHBn
R1
R = H, R1X = BrCH2CO2But, 71%
R = Ph, R1X = BrCH2CO2Et, 45%
Ts HO
i. BunLi
MeO
Ts THF, –78 °C
NHBn HO N
MeO MeO N S
ii. Cl ð193Þ
Bn NH
Cl
MeO Cl
22%
Capsazepine
SAMP
Et
Yb(OTf)3 SO2Ph i. LDA / TMEDA Et
Et THF, rt HN Et THF, –78 °C Et
SO2Ph N SO2Ph SO2Ph
42% NBu2 ii. EtI NBu2 ð194Þ
–78 °C to rt
OMe 97% (68% de (>97)a, >96% ee)
64% de a Major diastereoisomer isolated after recrystallization
(v) -Alkylation of sulfoximines

The functionalization of sulfoximine derivatives at the adjacent position has been realized either
by metallation with BunLi and treatment with different alkyl halides or by substitution of related
-chlorosulfoximines with alkyl metals. Therefore, the reactive center can behave as a nucleophile
or an electrophile. Both aspects are illustrated by the following studies. Harmata and co-workers
reported the sequential -deprotonation of a -silylated benzothiazine and its subsequent alkyla-
tion. When methyl iodide and MEMCl are used as electrophiles, excellent stereocontrol is
observed in favor of the cis-isomer (25:1 and 37:1 mixture of diastereomers, respectively)
(Equation (195)) <1998T9995> but moderate selectivities are obtained with other organohalides.
Upon treatment with TBAF and after basic hydrolysis, these alkylated -silylbenzothiazines can
be converted into 2-alkenylanilines. Boßhammer and Gais have shown that alkenyl- and arylcup-
rates can substitute chiral nonracemic (+)-(R)-S-(chloromethyl)-N-methyl-S-phenylsulfoximine
and give rise to enantiomerically enriched allylic and benzylic sulfoximines (Equation (196))
<1998SL99>.
TMS i. BunLi TMS

THF, –78 °C i. TBAF
S O ii. Allyl bromide S O ii. KOH ð195Þ
N N NH2
p -Tol 89% p -Tol MeOH
(cis/trans = 4.6/1)
2 O NMe
O NMe O NMe S
S Ph2CuLi.LiCN S CuLi.LiCN Ph
Ph Ph ð196Þ
THF THF
Ph Cl
–78 to –5 °C –78 to –5 °C
60% 62%
>98% ee 98% ee (+)-(R) >98% de
1.04.3.3.2 a-Alkylation of 1-thiosubstituted allyllithiums and related compounds
(i) Alkylation of S-allylthiocarbamates

Despite all the studies on the configurational stability of chiral -heteroalkyllithium derivatives,
only a few of them concern the behavior of -thioallyllithiums. In a seminal work, Hoppe and
co-workers have shown that the configurational stability of enantioenriched -thioallyllithiums
deriving from S-allylthiocarbamates is highly dependent on the solvent and the temperature. The
organodilithiated species, obtained by deprotonation of (R),S-(2-cyclohexenyl)N-isopropyl-
thiocarbamate, readily racemizes in toluene and Et2O at 78 C, in contrast to THF, where
the organolithium is configurationally stable. Indeed, under these conditions, the ion-pair
separation is strongly disfavored. The main disadvantage of this reaction is the poor regioselec-
tivity observed in the alkylation step caused by the competing - versus -substitution of methyl
iodide which occurs with inversion of configuration (Equation (197)) <1999OL2081>. Similar
studies carried out on N,N-diisopropyl monothiocarbamates provide -alkylated products with
complete control of the regioselectivity and a total inversion of configuration. Upon treatment
with LAH/ZnCl2, highly enantioenriched tertiary cyclohexylthiols were isolated in good yield and
without modification of the optical purity (Equation (198)) <2002OL4217>.
H
N O
Me
S
H
N O Li
N O
S BusLi/ TMEDA MeI (21%), (S) 89% ee
Li ð197Þ
THF, –78 °C S
THF, –78 °C H
then H3O + N O
(R) 92% ee
S Me
(44%), (S) 68% ee
N O N O N O n-C6H13
BusLi / TMEDA n-C6H13I ( )4 HS
Li ð198Þ
S Toluene, –78 °C S 67% S
>94% ee
(–)-(S) 97% ee
(ii) Alkylation of allylseleniums

In 1999, Nishida and Sonada reported the deprotonation of 1-alkoxy-3-phenylseleno-1-alkenes
with LDA followed by a regioselective alkylation with organohalides. Stabilization of the lithium
anion intermediate by the phenylselenyl group may explain the exclusive -attack. Furthermore,
the presence of (Z)-enol ethers in the reaction mixture may result in a rapid isomerization of the
allyllithium and a stabilization by chelation of the alkoxy moiety by the metal (Equation (199))
<1999SL611>.
R i. LDA
R
THF, –78 °C
PhSe OEt ð199Þ
ii. n-C4H9Br, 0 °C PhSe OEt
82%
(E )/(Z ) 2.9/1
(iii) Alkylation of allyl sulfones

Allyl sulfonyl anions obtained by lithiation of allylic sulfones undergo alkylation exclusively
at the -position <1999CR665>. For example, Shechter and co-workers have reported that
(E)- and (Z)-silylsulfonylbutenes can easily be metallated by BunLi at 78 C in THF. The
lithiated intermediate reacts efficiently with different alkyl halides and leads preferentially to the
formation of -products in high yield with almost complete retention of configuration of the
double bond. A second alkylation can be carried out under similar condition. These compounds
are considered as valuable synthetic equivalents of the 1-(1,3-butadienyl) anion and the 1-(1,3-
butadienyl) dianion. Indeed, the alkylated silylsulfonylbutenes when treated with fluoride liberate
the corresponding substituted conjugated dienes (Equation (200)) <1998JOC4181,
1998JOC4193>. As reported by Caturla and Nájera, the dianion of (E)-N-isobutyl-4-tosyl-
2-butenamide undergoes exclusive -alkylation upon addition of benzyl bromide or t-butyl
bromoacetate. The regiospecific and stereoselective attack affords to -substituted (E)-N-isobutyl-
4-tosyl-2-butenamides in high yields. Under basic conditions, the elimination of the tosyl group
allowed the stereoselective synthesis of (2(E),4(E))-dienamides (Equation (201)) <1996TL4787>.
In other studies, Caturla and Nájera showed that the reaction of methyl (E)-4-tosyl-2-butenoate
with sodium hydride (2 equiv.) and various mono- or dihalides produces a mixture of ,- and
,- or ,- and ,-dialkylated products <1996T15243>.
i. BunLi Me3Si
Me3Si
THF, –78 °C TBAF
ii. RX, rt SO2Ph THF R
SO2Ph
R
(E)/(Z ) Yield (E )/(Z ) Yield (%) (E )/(Z ) ð200Þ

ratio substrate RX (%) ratio product of elimination ratio butadiene
98/2 Mel 97 98/2 76 >98/2

80/20 Benzyl bromide 99 79/21 52 >99/1
72/28 i-Butyl bromide 83 75/25 63 >93/7
98/2 i-Propyl bromide 97 98/2 85 >98/2
O OLi
BunLi/DMPU i. ButO2CCH2Br
Ts Ts
NHBu i
THF, –78 °C NBui
ii. NH4Cl
Li 72% ð201Þ
O O
ButO DBU ButO
NHBui NHBui
THF, rt
O Ts 96% O
1.04.3.3.3 a-Alkylation of 1-thiosubstituted benzyllithiums

As reported by Hoppe and co-workers, the enantioenriched tertiary -thio benzyllithium deriva-
tive, obtained by deprotonation of (S)-S-1-phenylethyl thiocarbamate with BusLi/TMEDA, exhi-
bits a remarkable configurational stability at 70 C, whereas at 0 C, decomposition competes
with racemization. The substitution of ethyl and hexyl iodide as well as allyl and benzyl bromide
is presumed to proceed with inversion of configuration (>98% ee) (Equation (202))
<1997AG(E)2784, 2001MI423>. In contrast, the secondary -lithio benzyl phenyl sulfide is
configurationally labile at low temperature. In a recent example, Toru and co-workers reported
the asymmetric alkylation of the lithiated benzyl phenyl sulfide, formed by SnLi exchange, with
alkyl halides in cumene at 78 C and in the presence of a bis(oxazoline) ligand (Equation (203)).
The influence of the nature of the electrophile on the enantioselectivity values suggests that a
dynamic kinetic resolution is operating here. The related -lithio benzyl 2-pyridyl sulfide inter-
mediate also undergoes electrophilic substitution with a higher enantiomeric excess. The reaction
proceeds through a dynamic resolution under thermodynamic conditions (Equation (204))
<2000JA11340>. In 1997, Gibson and co-workers reported the asymmetric alkylation of tricarbonyl-
chromium(0) complexes of benzene sulfide. Deprotonation with a chiral lithium diamide base
generates the enantioenriched -sulfenyl carbanion which can be quenched with various alkyl
halides. By increasing the steric bulk of the sulfide substituent, the enantiomeric excess drops
dramatically. However, reaction with methyl, ethyl, or benzyl sulfide complexes provides the
tertiary thioethers in high yields and in excellent enantiomeric purities (Equation (205))
<1997JCS(P1)2161>. The substitution proceeds with inversion of configuration, compared to
the analogous alkoxy systems (Equation (178)).
N N
Me H O Li Me O
BusLi / TMEDA Me O Allyl bromide
S N S N ð202Þ
O Et2O O
S N 90%
O
(S)
>98% ee
i. BunLi
cumene, –78 °C PhS Me O O
PhS SnBu3
Pri-BOX:
ii. Pri-BOX ligand N N ð203Þ
Ph Ph
iii. MeI
64% ee Pri Pri
100%
i. BunLi
N S Ph cumene, –78 °C N S Me O O
But-BOX:
t-BOX
ii. Bu ligand Ph N N ð204Þ
iii. MeI Bu t But
72% 89% ee
Ph Ph
i. N N Bn
SMe Ph Li Li Ph
SMe ð205Þ
THF, –78 °C
Cr(CO)3 ii. BnBr
Cr(CO)3
91% 88% ee
1.04.3.4 Nitrogen-stabilized Carbanions

Recent methodologies developed for the functionalization of nitrogen-containing derivatives,
particularly at the adjacent position to the amino group are of considerable interest for the
synthesis of natural compounds including alkaloids and amino acids. Among these, alkylation
of -amino carbanions is the most common and attractive route to the formation of CC bonds
at the -position of an amino group even if the use of allyl and benzyl halides can initiate
single-electron transfer (SET) processes. In contrast to organosulfur derivatives, generation and

stabilization of -amino carbanions are governed only by the inductive effect of the nitrogen
atom. In order to favor their formation, various strategies have been developed based on either
activation of the hydrogens present on the amino-substituted carbon atom or carbamate-directed
metallation. Functionalization of allylic- and benzylic-stabilized -amino carbanions as well as
reactivity of related chiral -carbanions have been also investigated and are disclosed here. Since
the early 1990s, several of these topics have been reviewed by Beak <1996ACR552>, Katritzky
<1998T2647, 1999CR665>, Hoppe <1997AG(E)2282>, and Basu <2002AG(E)716>.
1.04.3.4.1 Alkylation of nonstabilized a-amino carbanions
(i) Lithiation by deprotonation of borane-complexed amines

Borane complexation of tertiary amines revealed an extremely useful tool for activation of
methylenes adjacent to amino groups toward lithiation by proton abstraction. Seminal studies
reported by Kessar and co-workers showed that deprotonation of boron trifluoride-complexed
N-methylpiperidine can easily be carried out with BusLi at low temperature <1991CC568>. Alkyl
substituents have been successfully introduced at the -position in the presence of HMPA
(Equation (206)). However, the corresponding -stannylamine gave, after SnLi exchange, better
results in alkylation and also benzylation products. The critical effect of CsF on the latter reaction
has been strongly pointed out <2001SL517>. Another example of activation of tertiary amines by
borane complex formation was reported by Vedejs on simple aziridines (Equation (207))
<1997JA6941>. All these results have been reported in pertinent reviews published in 1997 by
Kessar and Singh <1997CR721> and in 1998 by Katritzky and Qi <1998T2647>. General
information on the chemistry of amine-boranes are available in another review by Carboni and
Monnier <1999T1197>.
i. BusLi / HMPA
BF3.OEt 2 + THF, –78 °C
N ð206Þ
N THF, –78 °C
– N ii. BunBr
Me F3B Me
68% Bu
Li
–
i. BusLi Me Me
H
N
BH3 THF, –78 °C – H H
+ N +
+ BH3 N N ð207Þ
ii. MeI
OTBDMS OTBDMS OTBDMS
OTBDMS
Major 65% Traces
(ii) Lithiation by LiSn(IV) exchange

In most cases, nonstabilized 2-lithio-N-methylpiperidines and -pyrrolidines were obtained
by transmetallation of the corresponding organostannanes with BunLi following Peterson’s
methodology <1971JA4027, 1974JOM209>. The related nonracemic secondary organolithiums
are configurationally stable at 78 C and their reaction with unactivated alkyl halides occurs
with inversion of configuration through a SE2inv mechanism. The partial racemization observed
with pyrrolidine derivatives may be explained by a competing retentive substitution
(SE2ret) <1995JOC5763>. In addition, activated alkyl halides such as benzyl bromide and
t-butyl bromoacetate yield racemic products arising from a radical mechanism involving SET
<2000JA3344>. For 2-tributylstannyl-N-methylpiperidines, the presence of a t-butyl group at the
C4 position locks the conformation and the axial alkyllithium, generated by transmetallation,
reacts in moderate-to-poor yields with organohalides. The reaction provides dimers and dispro-
portion by-products according to a SET process (Equation (208)). When the stannyl group is in
the equatorial position, transmetallation fails completely <2000OL1561>. Gawley reported the
allylation of 2-lithio-N-methylpyrrolidines through a [2,3]-ylide rearrangement. Allylation of the
stannyl precursor by allyl bromide affords the N-methyl-N-allylstannylpyrrolidinium bromide

which undergo a sigmatropic rearrangement after transmetallation with BunLi. The transforma-
tion occurs with inversion of configuration (Equation (209)) <1995JA11817>.
( )n ( )n ( )n
BunLi/ TMEDA RX
SnBu3 Li R
N N N
THF, –78 °C
Me Me Me
n = 1, 2 ð208Þ
n = 1, from (S)-Substrate, RX = BrCH2CO2But (77%) racemic
RX = Ph(CH2)3Br (75%) 51% ee (R)
n = 2, from (R)-Substrate, RX = LiO(CH2)4Br (78%) 90% ee (S)
RX = BnBr (91%) racemic
i. Allyl bromide Li
SnBu3 N
N Me N ð209Þ
ii. BunLi
Me Me
THF, –80 °C Br
94% ee 94% ee
1.04.3.4.2 Alkylation of stabilized a-amino carbanions
(i) Dipole-stabilized anions

Lithiation of -amino methylenes is usually facilitated by the formation of amide, formamidine,
and nitroso groups on the nitrogen atom of the substrate. The protecting group activates the
protons to the nitrogen atom, increasing their kinetic acidity, directs the metallation and
stabilizes the resulting organolithium to render it configurationally stable. Pioneering research
on lithiation of 2,2-diethylbutanamides and N-BOC-protected piperidines have been reported by
Beak and co-workers. They showed that -deprotonation can easily be promoted by BusLi/
TMEDA at low temperature so as to generate the racemic dipole-stabilized organolithium
intermediate which can be quenched with various alkyl halides (RI and allyl bromide) (Equation
(210)) <1984JA1010, 1989TL1197>. A few years later, Harrison and O’Brien published the
diastereoselective sequential lithiation/substitution of N-BOC bispiperidines under similar
conditions. A range of sparteine analogs has been synthesized (Equation (211)) <2000TL6161>.
Ph i. BusLi.TMEDA Ph
Et2O, –78 °C
ð210Þ
N ii. MeI Me N
83%
t-BOC t-BOC
Me i. BusLi.TMEDA Me
N cyclopentane, –78 °C Me N
ð211Þ
N ii. MeI, –78 °C to rt N
t-BOC t-BOC
71%
In 1991, Beak and co-workers reported the enantioselective deprotonation of N-BOC protected
pyrrolidine with BusLi and a chiral ligand. In the presence of (–)-sparteine, the pro-(S) proton
is removed more rapidly than the pro-(R) proton (Equation (212)) <1991JA9708>. The related
N-BOC indoline was functionalized at the C2-position using an identical protocol. The asym-
metric lithiation with BusLi/(–)-sparteine in cumene and subsequent reaction with allyl bromide
affords the regioselective 2-substituted N-BOC indolines in low yields with moderate enantiomeric
ratios. The addition of N,N0 -dimethylpropyleneurea (DMPU) to the reaction mixture increased
dramatically the selectivity to 99:1 er (Equation (213)) <1997JOC7679>. Dieter and co-workers
were interested in the reactivity of -aminoalkylcuprates toward competitive SN2/SN20 nucleo-
philic substitution of allylic halides. Cinnamyl and crotyl bromides undergo allylic substitutions
by organocuprates, prepared from N-BOC protected pyrrolidine, with poor regioselectivities
whatever the reaction conditions used. However, reaction of acyclic dimethylaminomethyl

cuprates gives the SN20 substitution adducts with excellent selectivities up to 4:96 SN2/SN20
(Equation (214)) <1997SL1114>.
Et2O, –78 °C Li
N N N Me ð212Þ
ii. MeI
t-BOC Bu tO O t-BOC
76%
95% ee
cumene, –78 °C
N ii. Allyl chloride/DMPU N ð213Þ
t-BOC –78 °C to rt t-BOC
15%
99/1 er
Et2O–THF, –78 °C Ph
N N + N
ii. CuCN or CuCN.2LiCl Ph
O O-But O O-But O ð214Þ
iii. Ph Br O-But
–55 °C to rt
CuCN, 70% 59/41
CuCN.2LiCl, 100% 32/68
1.04.3.4.3 a-Alkylation of 1-aminosubstituted allyllithiums

Functionalization of aminoallyl derivatives by sequential lithiation–substitution did not receive
much attention since the early 1990s. In 1999, Katritzky and co-workers reported the use of
N-allylbenzotriazole for the synthesis of 2-alkyl-substituted 1,3-butadienes. The 3-allyllithium
intermediate obtained by treatment of 1-allyl-1H-benzotriazole with BunLi at low temperatures
undergoes -attack upon alkylation with chloromethyltrimethylsilane. A second lithiation fol-
lowed by an electrophilic substitution of organohalides affords the ,-dialkylated N-allylbenzo-
triazole. At higher temperatures, the latter gives 2-alkyl-substituted 1,3-butadienes by elimination
of silicon and benzotriazole groups (Equation (215)) <1999JOC1888>. In contrast, sequential
asymmetric lithiation–substitution initiated by BunLi/(–)-sparteine with cinnamylamines
<1996JA12218> and cyclohexylallylamines <2001JA4919> leads predominantly to -products,
whereas lithiated N-BOC-2-N-(3-halopropyl)- and N-BOC-2-N-(3-halobutyl)-allylamines undergo
intramolecular substitution to the nitrogen atom (Equation (216)) <1999JOC1160>. More
details about these transformations reported by Beak and co-workers are presented in Section
1.04.2.1.
N i. BusLi i. BusLi
Bt Bt
N THF, –78 °C THF, –78 °C
N Me3Si Me3Si
ii. Me3SiCH2Cl ii. n-Propyl iodide,
–78 °C to rt –78 °C to rt
88% ∆ ð215Þ
87%
Allyl benzotriazole (AllylBt) Heat
BunLi.(–)-sparteine Ph
Cl N Ph
Et2O, –78 °C N
t-BOC ð216Þ
t-BOC
85%
90/10 er
1.04.3.4.4 a-Alkylation of 1-aminosubstituted benzyllithiums
(i) Metallation through hydrogen abstraction by lithiated bases

Schlosser and Limat first studied the asymmetric deprotonation of N-BOC-N-methylbenzylamine
with BusLi/(–)-sparteine followed by alkylation with methyl iodide. The resulting benzyl lithium/
sparteine complex immediately racemizes and one of both diastereomeric complexes reacts pre-
ferentially. They noted the precipitation of a single diastereoisomer in THF. The enantiomeric ratio
and the absolute configuration were proved highly dependent on the metallation time and the
nature of the solvent (THF/hexane), respectively (Equation (217)) <1995JA12342>. Extension
of this procedure to enantioselective synthesis of (S)-2-aryl-BOC-pyrrolidines from N-BOC-N-
(3-chloropropyl)-benzylamine has been investigated by Beak and co-workers. The benzyllithium
compound, generated by selective pro-(S) proton abstraction with BusLi or BunLi/(–)-sparteine
in toluene, undergoes rapid intramolecular alkylation without racemization (Equation (218))
<1996JA715>. At the same time, they showed that the enantioenriched dipole-stabilized lithium
carbanion/(–)sparteine complex of N-BOC-N-(p-methoxyphenyl)-benzylamine is configuration-
ally stable at 78 C and the substitution of isoprenyl bromide proceeds with retention of
configuration <1997JA11561>. The related epimer was obtained by invertive stannylation of the
organolithium and a retentive transmetallationalkylation sequence with a high enantiomeric ratio
(Equation (219)) <1997JOC1574>. An application of this methodology to lactam ring preparation
and its alkylation at the C-3 position has been provided (Equation (220)) <1999JOC1705>.
i. BusLi.(–)-sparteine Me ee
Me (%)
N Solvent, –78 °C Me Solvent (conf.)
* N ð217Þ
ii. MeI Hexane 75 (S)
O OBut Et2O 62 (S)
43–65% O OBut
THF 80 (R)
BusLi.(–)-sparteine (S)
Ar N Cl
Ar N
t-BOC Toluene, –78 °C ð218Þ
t-BOC
72%
96% ee
CO2H
i. O3
Br Ar Ar
N Ph ii. CrO3 N Ph
t-BOC 76% t-BOC
Ar BusLi.(–)-sparteine
N Ph 93/7 er
Toluene, –78 °C
ð219Þ
t-BOC CO2H
i. Me3SnCl
Ar = p -CH3OC6H4 Ar Ar
ii. BunLi.(–)-sparteine N Ph N Ph
t-BOC t-BOC
iii. 58%
Br 89/11 er
CO2H O i. LDA O Et
i. SOCl2, MeOH THF, –78 °C
Ar ð220Þ
N Ph ii. ButMgCl N ii. EtI N
Ar Ph 91% Ar Ph
t-BOC THF, –5 °C
In 1995, Clayden reported a straightforward and highly diastereoselective route to meso-bis-

(-methylbenzyl)amide through -lithiation of amide derivatives of N-benzyl--methylbenzylamine
with ButLi in THF at 78 C, then methylation with methyl iodide <1999TL8323>. Extensions of
this methodology to other alkyl halides gave the unsymmetrical benzylamide adducts in good yields
and with high stereoselectivities. Based on this approach, N-carbamate derivatives react selectively
with methyl iodide whereas allyl and benzyl bromides returned the alkylated product as a 50:50
mixture. This result suggests that a radical mechanism initiated by a SET may operate. However,
thermodynamic (rapid equilibration for amides) and kinetic (kinetic deprotonation—slow equilibra-
tion for carbamates) factors determine the formation of a single diastereoisomer of organolithium in
each case (Equation (221)) <2002TL1955>. Müller, Spingler, and Zehnder have been interested in
diastereoselective alkylation of chiral bicyclic phosphoric triamides derived from N-methyl benzyl-
amine. Thus, deprotonation in the benzylic position allows the formation of the stable chiral
-lithiophosphoric triamide, which can react with different alkyl halides (benzyl bromide, methyl
iodide, iso-propyl iodide, and allyl bromide). The best yields and diastereomeric ratios were obtained
with 2 equiv. of electrophile at 78 C in THF (Equation (222)) <1997SL1059>.
O i. ButMgCl O O
THF, –78 °C
p -MeOC6H4 N Ph p-MeOC6H4 N Ph + p-MeOC6H4 N Ph
ii. BnBr ð221Þ
Ph 84% Bn Ph Bn Ph
>98/2 dr
Me i. BunLi Me Bn
N O Ph THF, –78 °C N O Ph
P N P N
N Me
ii. BnBr
N Me
ð222Þ
Me 71%
Me
82/18 dr
Simpkins and co-workers showed that lithiation of borane-complexed benzylamine and tetrahy-
droisoquinoline followed by substitution of alkyl halides occurs regioselectively at the amino-sub-
stituted benzylic carbon atom <1995TL8697>. However, as reported in the literature <1997CR721>,
reaction of free and tricarbonylchromium-complexed amines with BunLi and electrophiles leads to
either ortho-substituted <1963JA2467, 1967JOC1479> or C4-alkylated products <1982JA7609,
1986JCS(P1)2257, 1991CC568> (Equations (223) and (224)). In 1998, they reported that the
N-methylisoindoline–borane complex undergoes diastereoselective alkylation in the benzylic position
syn to the borane group. Asymmetric lithiation with BusLi/(–)sparteine gives rise the enantioenriched
isoindoline–borane complex in up to 88% ee (Equation (225)) <1998SL189>. The borane-complexa-
tion methodology has been also used to functionalize Tröger’s base. In practice, the boron trifluoride–
amine complex renders the adjacent hydrogens more labile and favors lithiation with BunLi. Thus, the
resulting organometallic can react with a selection of alkyl, allyl, and benzyl halides diastereoselec-
tively in quite good yields (Equation (226)) <1996TL6267>.
i. BunLi
OH
Et2O–hexane i. BH3.THF
Ph
25–30 °C ii. BunLi, THF, rt
Ph NMe2 ð223Þ
ii. Ph2CO NMe2 iii. EtI
75% iv. EtOH, reflux Et
NMe2
64%
SiMe3 i. BunLi, THF i. BH3.THF

–78 to –40 °C ii. BunLi, THF, rt
N
N iii. MeI Me
N ii. Me3SiCl Me
Me Et3N iv. EtOH, reflux Me
79% 79%
i. Cr(CO)6
n-Bu2O/ THF
ii. BunLi ð224Þ
93%
THF, –78 °C
iii. EtI
Et
N
Me
(CO)3Cr
i. BusLi.(–)-sparteine, Et Et Et
BH3 Et2O, –78 °C BH3 BH3 EtOH
N N + N N Me ð225Þ
Me ii. EtI, –78 °C to 0 °C Me Me reflux
73%
3/1 dr, 88% ee
i. BF3.Et2O N
Me N Me
THF, 0 °C
Me ii. BunLi, –78 °C N Me

N
F3B Li
N ð226Þ
Me
5-Iodo-1-pentene
N Me
76%
The nitrogen atom of tetrahydroisoquinolines when converted into an amide group should
activate the methylenes adjacent to the nitrogen atom by increasing the acidity of the related
protons. Due to the coordinating ability of the oxygen atom, the amide functional group can
stabilize the benzylic organolithium, generated by deprotonation with BunLi, which reacts with
differents organohalides <1983T1963>. The use of chiral amides, derived from gulonic acid,
favors the formation of diastereomeric organolithium intermediates, which are in equilibrium.
Investigations revealed that the diastereoselectivity is determined during the post-deprotonation
step. Thus, methylation and benzylation lead to the corresponding substituted compounds in
good yields and with excellent diastereoselectivities in contrast to the allylation step. Functiona-
lization of tetrahydro--carbolines has been also discussed (Equation (227)) <2001JOC8744>.
Enantioselective protonation of the lithiated 1-methyltetrahydroisoquinoline by a chiral amine
gave the adduct in up to 86% ee. This methodology was applied to the synthesis of the natural
product salsolidine (Equation (228)) <2000SL1640>. As with chiral amides, formamides derived
from enantioenriched amino alcohols are able to provide asymmetric alkylations in the benzylic
position. A couple of diastereoselective lithiation–substitution sequences of 2-benzazepine for-
mamides occur with high diastereoselectivities (up to >99:1 dr) leading to the 1,1-disubstituted-
2-benzazepine products (Equation (229)) <1996H475>.
O
i. ButLi
O THF, –78 °C
N NH ð227Þ
ii. BnBr
O O
O iii. KOH–MeOH Bn
50%
84% de (98% de with LiBr)
MeO i. ButLi.TMEDA MeO

THF, –40 °C
N But N But
MeO ii. MeI, –78 to 0 °C MeO
O 99% Me O
i. ButLi.TMEDA MeO MeO ð228Þ

THF, –40 °C NaAlH4
N But NH
MeO THF MeO
ii.
Ph, –78 °C
Me O 76% Me
Ph N
H 86% ee Salsolidine
94%
i. ButLi i. BusLi
N THF, –78 °C N THF, –40 °C
OMe OMe NH ð229Þ
N ii. PrnBr, –90 °C N ii. MeI
80%
But But >99/1 ee
In 2002, Murai and co-workers reported studies on the functionalization of N-benzyl seleno-
benzamide. Its treatment with 2 equiv. of BunLi gave the dianion, which reacts with alkyl and allyl
halides selectively in the benzylic position. An excess of ethyl iodide gave the Se-ethyl thioimide in
high yield (Equation (230)) <2002OL1407>.
Se Se Et
BunLi SeLi Li EtI (1 equiv.)
Ph N Ph Ph N Ph
THF, 0 °C Ph N Ph 82%
H H
EtI (2 equiv.)
ð230Þ
95%
EtSe Et
Ph N Ph
(E )/(Z ) 86/14
(ii) Lithiation by reductive cleavage

-Amino-substituted benzyllithiums may also be obtained from oxazolidines by reductive clea-
vage of the benzylic CN bond <2001TL129>. The reaction involves formation of configu-
rationally labile benzylic radicals, which lead to racemic organolithium intermediates. Thus, the
latter undergo diastereoselective substitutions with various alkyl halides. syn-Amino alcohols are
isolated in moderate yields (Equation (231)).
LiO LiO HO
O Li Li Bn
Li i. BnCl
Ph
N N Ph N Ph N Ph ð231Þ
THF, –20 °C ii. H2O
74%
93/7 dr
1.04.3.5 Phosphorus-stabilized Carbanions

-Metallated alkylphosphorus compounds are useful intermediates, which have been extensively
studied because of their synthetic utility as Wittig or Horner–Wittig precursors of alkenes.
Investigations have revealed the ability of functional groups containing a phosphorus atom,
such as phosphonates and phospholane oxides, to stabilize adjacent carbanions. These
phosphorus anionic intermediates could be trapped by various carbon electrophiles including
haloalkanes.
1.04.3.5.1 Alkylation of phospholane oxides in the a-position

The increasing use of chiral lithium bases in asymmetric deprotonation involving discrimination
of two enantiotopic hydrogens has prompted Simpkins’ group to develop enantioselective
-lithiation of 1,2,5-triphenylphospholane oxide. The chiral lithiated intermediate can be effi-
ciently trapped by a range of alkyl halides and yields the triphenyl-substituted phospholane oxides
with good levels of enantioselectivity. Reduction to phospholanes was realized by treatment of the
oxides with a mixture of Cl3SiH and pyridine (Equation (232)) <1998JOC912>.
Ph N Ph Cl3SiH
i.
Li Ph pyr Ph
Ph Ph Et Ph Et Ph ð232Þ
P P P
LiCl, THF, –100 °C benzene
O Ph O Ph Ph
ii. EtI 96%
89% 90% ee
1.04.3.5.2 Alkylation of phosphonates in the a-position

The conjugate addition of organometallics to alkenylphosphonates, compared to ,-unsaturated
carbonyl compounds, has been briefly examined. As first reported by Russo and co-workers
<1984CC5>, nucleophiles such as simple cuprates can promote 1,4-addition to diethyl vinyl
phosphonate. Kabalka extended the reaction to acyl cuprates, generated by addition of dialkyl
cuprates to carbon monoxide <1999OM1811>. In each case, the resulting phosphonate-stabilized
anionic intermediate was trapped by allyl bromide liberating the -allylated alkyl- and oxoalkyl-
phosphonate, respectively (Equation (233)) <1996S34, 1999OM1811>.
i. CO, –110 °C O
O i. P OEt
O
ii. P OEt , –40 °C OEt OEt
O R P
O OEt Et2O, –78 °C R
R2CuX OEt
R P OEt
iii. –78 °C ii. Allyl bromide
OEt
iv. R1X
–78 to 0 °C ð233Þ
Yield Yield
Cuprate R2Cu(CN)Li2 R1X (%) Cuprate (%)
Bun Allyl bromide 65 Me2CuLi.SMe2 84

Bus Allyl bromide 80 (Allyl)2CuMgBr.SMe2 93
But Allyl bromide 51 Ph2CuMgBr.SMe2 64
Bun Methallyl bromide 75
Bun Dimethyl allyl bromide 66
In addition, conjugate addition of diethyl phosphite to ethyl acrylate gave, after further
transformations, -amidophosphonates. 1,5-Inductive alkylation adjacent to the phosphonate
group was readily obtained by lithiation with BusLi/TMEDA followed by electrophilic quenching
with methyl iodide and benzyl bromide. However, only poor diastereoselectivities have been
reached (up to 50%). This result may be explained by the presence of two intermediates in
equilibrium where the lithium chelates either the phosphonate oxygen atom or the nitrogen of
the amide group (Equation (234)) <2001EJO3031>.
OBn
O H BusLi–TMDEA
N Et
CO2Me +
(EtO)2 PNa O THF, –78 °C
P O
EtO OEt
ð234Þ
OBn
OBn OBn
Li OLi Bn O
Li N Et O BnBr O
O P N Et 70% P N Et
P OLi EtO OEt EtO OEt H
EtO OEt
50% de
1.04.3.5.3 Alkylation of allylphosphonates

The chemistry of P-stabilized allyl anions is well developed in synthesis for the preparation of
molecules containing olefin and polyene residues. The presence of the allyl moiety should render
hydrogens to the phosphonate functional group more acidic. Indeed, allylphosphonate anions
variously substituted can be generated by deprotonation with BunLi and reacted with halides to
give preferentially the -products (Equation (235)) <1998SC3601, 2000SC789>. In addition,
metallation of 3-trimethylsilylallylphosphonate with LiHMDS followed by substitution forms
exclusively -alkylated adducts in excellent yields (Equation (236)) <2001TL2345>.
O O
O BunLi (EtO)2P BunI (EtO)2P
(EtO)2P THF, –78 °C –78 °C to rt ð235Þ
Li 94%
(93/7 α /γ)
i. LiHMDS i. LiHMDS
O O O
THF, –78 °C THF, –78 °C
(EtO)2P (EtO)2P SiMe3 (EtO)2P SiMe3
ii. TMSCl ii. Mel ð236Þ
iii. H3O iii. H3O
90%
1.04.3.6 Silicon-stabilized Carbanions

The use of -silyl carbanions in organic synthesis is dominated by the seminal research of
Peterson reported in 1968 <1968JOC780>. Formation of carbanions adjacent to a silyl group
is highly favored due to their stabilization by overlap between the appropriate carbon–metal bond
orbital (or the 2p orbital on carbon) and the empty 3d orbital on silicon or the CSi * orbital.
Several methods of formation of -silyl organometallic compounds and their subsequent alkyla-
tions will be described in this section.
1.04.3.6.1 a-Alkylation of alkyl silanes

The ease of metallation and the stabilization of the resulting organometallic is usually increased
by the presence of neighboring heteroatoms and electron-withdrawing groups. However, Yoshida
showed that the presence of a simple pyridyl group can assist the generation of -silyl carbanions
by deprotonation with ButLi or LDA and stabilize the lithiated intermediate by intramolecular
coordination <1999TL5533>. Thus, the related (2-pyridyldimethylsilyl)methyllithium undergoes
alkylation with various alkyl bromides. Tamao oxidation of the silicon adducts leads to primary
alcohols quantitatively (Equation (237)) <1999TL5537, 2001JOC3970>.
ButLi RX
N SiMe2 N Si R
N SiMe3 Et2O, –78 °C –78 to 0 °C
Li Me Me
Yield Tamao ð237Þ

RX (%) Oxidation
Allyl bromide 95
R OH
Benzyl bromide 99
3-Phenylpropyl bromide 84
3-Chloropropyl bromide 86
In 1997, Shimizu and co-workers found that lithiation of dibromofluoromethyl(t-butyl)di-

methylsilane by metal–bromide exchange occurs at 78 C with BunLi to produce the silicon-
containing lithium carbenoid which can be alkylated with organic bromides in good yields
(Equation (238)) <1997TL4591>.
BunLi Br Br BunLi Br Li EtI Br F

ButMe2SiCl + CFBr3
THF/Et2O (2:1) t
Bu Me2Si F –98 °C t
Bu Me2Si F 85% Bu tMe
2Si Et
–130 °C
ð238Þ
The cross-coupling reaction of silyl-substituted dizinciomethanes, prepared from zinc insertion

into the corresponding dibromide, with (E)-cinnamyl bromide and under palladium catalysis,
affords the homoallylzinc species which is transmetallated by CuCN2LiCl at 30 C. The former
CuZn derivative can be alkylated with allyl or propargyl bromide in fair yields (Equation (239)).
Similarly, propargyl bromide as well as bromostyrene were coupled with the geminal dizinc
compound and the resulting monoalkylated species were functionalized after treatment with
(Equation (240)) or without copper salts (Equation (241)) <1998SL1315>.
i. Pd2dba3. CHCl3 (cat.)
P[3,5-(CF3)2C6H3]3 (cat.) i. CuCN.2LiCl
THF, 25 °C ZnBr THF, –30 °C
Ph Ph ð239Þ
Ph Br
ii. Me3SiCH(ZnBr)2 SiMe3 ii. Allyl bromide SiMe3
THF, 25 °C
88%
n-C8H11 n-C8H11
n-C8H11 i. CuCN.2LiCl
ZnBr ð240Þ
Br ii. Allyl bromide, 25 °C Me3Si
Me3Si
65%
SiMe3 Allyl bromide SiMe3

Br
Ph
25 °C ð241Þ
Ph ZnBr Ph
73%
1.04.3.7 Boron-stabilized Carbanions

Since H. C. Brown’s outstanding achievements in boron chemistry over the last century, organo-
boranes still remain omnipresent in organic synthesis. Many areas have witnessed a growth in the
preparation of new boron-containing compounds and their use in modern synthetic transforma-
tions, by taking advantage of the electron deficiency caused by the vacant p-orbital on the boron
atom. In particular, a negative charge in the -position can be stabilized by overlap of the filled
p-orbital on carbon with the vacant p-orbital on boron. A rich chemistry has been developed
around this property including alkylation of carbanions adjacent to boryl substituents.
1.04.3.7.1 Reactivity of 1,1-borio-zincioalkane reagents
(i) Synthesis via zinc insertion

As reported by Knochel in 1990, [-[(alkylenedioxy)-boryl]alkyl]zinc halides are readily accessible
by insertion of zinc dust into -haloboronic esters. Transmetallation with the copper salt
CuCN2LiCl gave a new mixed organo-gem-dimetallic species which can substitute different
allyl bromides in good yields (Equation (242)) <1990JA7431>.
CO2But
i. Zn, THF Br
O O
25 °C
B (CH2)3CO2Et B (CH2)3CO2Et
O ii. CuCN.2LiCl O 83%
Br 0 °C Cu(CN)ZnBr
ð242Þ
O
B (CH2)3CO2Et
O
CO2But
(ii) Synthesis via allylzincation reaction

A different method involves regioselective addition of allylzinc reagents to alkenylboronates and
liberates the boron and zinc 1,1-dimetallic species via a carbometallation process. The mono-
allylation of such intermediates was realized first by a selective transmetallation of the organozinc
moiety with copper(I) cyanide and its subsequent functionalization with allyl bromide (Equation
(243)) <2001OL3137>.
i. ZnBr2
ZnBu O ii. CuCN. 2LiCl
O OH
B ð243Þ
B THF, 0 °C to rt O iii. Allyl bromide
O
ZnBu iv. H2O2–NaOH
83%
1.04.3.7.2 Reactivity of 1,1-borio-zirconioalkane reagents

Zheng and Srebnik reported that hydrozirconation of alkenylboronic esters by Schwartz’s reagent
(Cp2Zr(Cl)H) gave the geminate borazirconocene alkanes. The new dimetallic species can react
selectively with propargyl bromide in the presence of a catalytic amount of copper(I) cyanide to
provide the corresponding -allenic boronic esters in good yields. These products can be either
oxidized into alcohols or added to a variety of aldehydes (Equation (244)) <1995JOC486>.
Br
ZrCp2Cl
R1 O
B Cp2Zr(H)Cl R1 O CuCN (10 mol.%)
B O O
O CH2Cl2 71–90% B
O
1
0 °C R
ð244Þ
H2O2
R2CHO
pH 10
OH R1 R2
R1
OH
1.04.4 CARBANIONS WITH TWO AND THREE STABILIZING GROUPS

In the light of previous studies, the presence of two or three functional units instead of one
branched on methylene groups should increase the acidity, labilize the hydrogens toward base
attacks, and strongly stabilize the organometallics generated. This area has been widely explored
since the early 1990s but only selected examples of alkylation will be reported in this section.
1.04.4.1 C- versus O-Alkylation of b-Dicarbonyls and Related Compounds

It is known from many years that the dianions of -keto esters and -dicarbonyls are first alkylated
at the 0 -position, which is considered to be the more nucleophilic site. A second alkylation of the
enolate, readily available by deprotonation with weak bases such as NaH or K2CO3, occurs this time
at the -position via nucleophilic substitution of organic halides. Numerous examples of dianion
functionalization have been reported in the literature. For instance, Pigge and Fang recently devel-
oped a new synthetic approach to substituted 2-tetralones. Selective alkylation of the dianion
of acetylacetone with 2-chlorobenzylchloride leads to the 0 -substituted -dicarbonyl adduct.
Complexation of the arene ring with the [(CH3CN)3RuCp][PF6] complex and its subsequent
nucleophilic aromatic substitution (SNAr) with the -dicarbonyl enolate affords the Ru-coordinated
1-acetyl-2-tetralone. The monoanion, generated by deprotonation with NaH, can then undergo
C-alkylation with allyl bromide and O-alkylation with methyl chloroformate (Equation (245))
<2001TL17>. Recent reports deal with successive intramolecular C- and O-dialkylations of
dilithiated 1,3-dicarbonyl compounds by 1-bromo-2-chloroethane or 1,4-dibromo-2-butene. These
reactions probably proceed through regio- and diastereoselective domino SN/SN and SN/SN0
processes, respectively. The methodology was then used in the synthesis of 2-alkylidenetetra-
hydrofuran derivatives from the respective 1,3-dicarbonyl dianions (Equation (246))
<2001JOC6057, 2002MI917> and also from the dimethyl acetone-1,3-dicarboxylate dianions
<1996SL339>.
ONa
O– O–
But But
i. Cl O O
Cl
90%
Cl
ii. [(MeCN)3RuCp][PF6] DMSO, 70 °C
85% RuCp PF6 76%
ð245Þ
O O
O O
Allyl bromide
NaH, THF, reflux
65%
RuCp PF6
RuCp PF6
O
O O i. LDA (2 equiv.) [Pd(dppe)2]
O O CO2Pri
THF, –78 °C (5 mol.%)
OPri OPri ð246Þ
Br DMSO
ii. Br H
60–90 °C
71% 92%
98/2 dr endo/exo 1.2/1
Pd(0)-Catalyzed allylation of -dicarbonyl monoanions with allylic halides has been extensively
investigated and applied in synthesis, leading to a variety of synthetically useful products
<B-1995MIT, B-1997MI, B-1999MI833>. Recently, Yamamoto and co-workers showed that
treatment of alkylidene malonitrile with allylic chlorides and trimethylsilyl cyanide in the presence
of Pd2dba3CHCl3/2dppf catalyst affords different cyanoallylation products in fair yields. The
combination of allyl chloride, trimethylsilyl cyanide, and palladium in a catalytic amount pre-
sumably generates a -allylpalladium cyanide complex which readily reacts with the activated
alkene. The cyanide ligand acts as a nucleophile and adds in a 1,4-fashion. Thus, the resulting
-allylpalladium intermediate undergoes reductive coupling and liberates the allylated adducts
(Equation (247)) <2000TL2911>.
TMSCN CN
But But
CN Pd2dba3.CHCl 3 (25 mol.%) CN
+ Cl ð247Þ
dppf (10 mol.%), THF, 75 °C NC
CN
>99%
1.04.4.2 Alkylation of Oxazoline, O-Stabilized Carbanions

In a series of papers, Florio and co-workers reported the direct lithiation of mono- and disub-
stituted oxazolinyloxiranes with BusLi/TMEDA at 100 C and their subsequent alkylation with
alkyl and allyl halides <1999EJO409>. The presence of the oxazolinyl moiety stabilizes the
lithiated intermediate at 100 C; however, upon warming to room temperature, the transient
lithiooxirane rearranges to -ketone-2-oxazoline (Equation (248)) <2000TL8835>. An interesting
stereochemical problem was observed with oxazolinyl p-tolyloxiranes. trans-Oxiranyllithium was
found to be configurationally stable and the reaction with electrophiles occurs with retention of
configuration whereas the cis-isomer exhibits a lack of stability leading to a mixture of diastereo-
isomers of alkylated adducts (Equation (249)) <2001JOC3049>.
N BusLi, TMEDA N EtI N

O H O H O H
Et2O, –100 °C 75%
H p -tolyl Li p-tolyl Et p-tolyl
O O O
>99/1 dr ð248Þ
–100 °C to rt
N p-tolyl
O O
i. BusLi, TMEDA
N Et2O, –100 °C N N
O H O H + O H
ii. EtI ð249Þ
H 70% Et Et
O p-tolyl O p-tolyl O p-tolyl
50/50
1.04.4.3 Alkylation of Enolate, S-Stabilized Carbanions

Very recently, Manthorpe and Gleason reported the stereoselective double alkylation of bicyclic
thioglycolate lactams relying on sequential deprotonation with LDA at 78 C and alkylation
with a range of organic halides. From these adducts, they developed a novel approach for the
stereoselective formation of (E)- and (Z)-disubstituted amide enolates <2001JA2091> and the
preparation of enantioenriched quaternary carbon centers <2002AG(E)2338>, that involves the
reduction of the CS bond of ,-dialkylated lactams with lithium di-(t-butyl)-biphenyl (LiDBB)
followed by O- or C-electrophilic trapping with TMS chloride or n-alkyl iodides, respectively
(Equation (250)).
O
Bn
N
i. LDA, LiCl ii. BunI Me Bun
O THF, –78 °C O Bn 76% H
then BnBr Me i. LiDBB
N N >99% de SBun
S S
ii. LDA then MeI THF, –78 °C ð250Þ
OTMS
H 88% H ii. TMSCl Bn
>99% de N
Me
H
STMS
92/8 (Z )/(E )
Metzner and co-workers also reported the C-alkylation of the enantioenriched (R)-2-cyclohex-
ylsulfinyl-N,N-dimethylethanethioamide enolate by allyl halides activated by electron-withdraw-
ing groups (CO2R, CN, SO2R) <2002JOC6852>, whereas simple allyl, methallyl, crotyl, and
cinnamyl bromides undergo S-allylation followed by a thio-Claisen rearrangement leading to the
corresponding -substituted -sulfinyl acetamides <2001JOC7841>. The C-allylation process
involves Michael addition–halide elimination or SN20 mechanism. The excellent 1,2-stereo-induc-
tion observed may be explained by an electronic control (Equation (251)) <2002JOC6852>.
i. ButLi i. ButLi O S
R1 S
O S THF, –40 °C O S THF, –40 °C Cy NMe2
S S
Cy NMe2 R1 Cy NMe2 R2 R2
ii. Br ii. Br
∆
ð251Þ
Temp. Yield dr
1 2
O S R R (°C) (%) (%)
S
Cy NMe2 Me 20 51 >98/2
- CO2Me 20 57 97/3
R1
1.04.4.4 Alkylation of Enolate, N-Stabilized Carbanions

A phenomenon of memory of chirality was observed by Kawabata and co-workers during the
-alkylation of phenylalanine derivatives <1998MI373>. The authors implied that the asymmetry
due to a stereogenic center present in the substrate may be preserved in the aggregate structure of
the enolate intermediate in the form of dynamic axial chirality. Enantiomeric excesses were shown
to be highly solvent- and electrophile-dependent (Equation (252)) <1994JA10809, 2000OL3883,
2003T965>. An original strategy based on Seebach’s concept of self-regeneration of stereogenic
centers (SRS principle) <1996AG(E)2708> using preformed chiral amine–borane complexes was
published by Mioskowski, Le Gall, and co-workers and was applied in the asymmetric alkylation
of alanine (Equation (253)) <1996AG(E)430> and proline derivatives (Equation (254))
<1996JOC7244>. Thus, deprotonation of a unique amine–borane diastereoisomer, obtained by
treatment of -amino acid derivatives with BH3SMe2 in hexane, with LDA or KHMDS gave the
resulting enolate which can be selectively quenched by a variety of primary haloalkanes. Another
example of asymmetric memory maintained by a stereogenic boron atom has been reported by
Vedejs for the enolate alkylation of oxazaborolidinones. Substrates are prepared from the
corresponding -amidino carboxylate derivatives as unique diastereomers by crystallization-
induced asymmetric transformation (AT). The alkylation proceeds under ButOK metallation
conditions without loss of configuration at the boron center and with good-to-high diastereo-
selectivities (Equation (255)) <1999JA2460>.
CO2Et CO2Et
Ph i. KHMDS Ph
N Me N
MOM t-BOC ii. MeI MOM t-BOC ð252Þ
Toluene/ THF (4:1), –78 °C
81% ee
96%
Me BH3 i. LDA Me
H3B. SMe2 THF, –78 °C
N CO2Me Me N CO2Me N CO2Me
Bn Bn
hexane, 20 °C Bn ii. MeO2CCH2Br ð253Þ
Me Me Me CO2Me
78% iii. aq. NH4Cl
95/5 dr 82% 80% ee
CO2Me i. LDA, THF

CO2Me Bn CO2Me
H3B. SMe2 ii. HMPA
BH3
N Bn hexane N iii. BnI N Bn ð254Þ
93% Bn iv. aq. NH4Cl
78% 82% ee
NaO O O O i. KOBut O O
F F
Bn PhBF3K B
Bn THF, –78 °C B
Ph Ph
N N N
H Me3SiCl H ii. Allyl bromide Bn ð255Þ
Me2N Me2N 81% Me2N
79% from phenylalanine
142/1 dr
after AT and recrystallization
The enantioselective alkylation of prochiral t-butyl glycinate-benzophenone Schiff bases under

mild phase-transfer conditions has been recently developed by Corey for the preparation of
variously substituted chiral nonracemic amino acids. The asymmetry was introduced by using
enantioenriched ammonium salts as phase-transfer catalysts. Experiments carried out with
O(9)-allyl-N-(9-anthracenylmethyl)-cinchonidinium bromide <1997JA12414> or Maruoka’s
C2-symmetric chiral spiro-ammonium salt <1999JA6519> gave excellent enantiomeric excesses
(Equation (256)). Copper(salen) complex is capable of catalyzing the asymmetric alkylation of
alanine enolates under mild conditions <2003TL2045>. Seebach and co-workers
<1987HCA1676> had initially investigated lithiation and functionalization of aziridine esters
and thioester analogs; for aziridine esters derived from D-serine it was recently reported by the
research group of Husson. The carboxylate anion of the (2(S))-t-butyl ester, generated by
deprotonation with LDA in THF, is chemically and configurationally stable at 78 C due to
the presence of a chelating methoxy group. Thus, the lithioenolate was alkylated with retention of
configuration. In contrast, the (2(R))-compound gives only self-condensation adducts. However, a
chelating solvent such as DME, can stabilize the lithioenolate intermediate and reduce the
amount of self-condensation (Equation (257)) <2000TL651, 2001EJO2589>. Recently, Palomo
used oxazolidinone auxiliaries for diastereoselective -alkylation of 3-oxazolidinyl azetidin-2-one
giving -substituted -amino -lactams as the key intermediates required in the preparation of
lactam peptide fragments (Equation (258)) <1999AG(E)3056, 2000T5563>. Within the context of
his studies on asymmetric enolization reactions, Simpkins recently achieved the desymmetrization
of a meso-piperidine diester via a diastereo- and enantioselective lithiation–substitution sequence
mediated by a chiral bis-lithium amide base. Substituted piperidines were isolated in good yields
(Equation (259)) <1999SL1292>.
O L*1 or L*2 O
Ph N Base/RX Ph N
OBut OBut
Solvent
Ph –60 or –78 °C Ph H R
Base: CsOH, H2O; solvent: CH2Cl2

O Yield ee
N RX (%) (%)
L*1: Br
N Mel 71 97
Cyclopropyl carbinylbromide 75 99
Allyl bromide 89 97 ð256Þ
ButMe2SiCCCH2Br 68 95
Benzyl bromide 97 94
β-Np
Base: 50% aq. KOH; solvent: toluene

L*2: Br N
Yield ee
RX (%) (%)
β-Np Mel 64 90
Allyl bromide 84 94
p-TolCH2Br 97 94
Ph
Ph i. LDA OMe
OMe
THF, –78 °C N
N CO2But
ii. Allyl bromide ð257Þ
t
CO2Bu DMPU (3 equiv.)
64%
>98/2 dr
Ph Ph Ph
O O O
N N BnBr N Bn
LDA
O O O
THF, –78 °C N –78 °C N ð258Þ
N SiMe3 SiMe3
O SiMe3 LiO to rt O
SiMe3 SiMe3 90% SiMe3
>98/2 dr
Ph Ph
i. N N
Ph Li Li Ph ð259Þ
THF, –78 °C CO2Me
MeO2C N CO2Me MeO2C N
ii. MeI Me
Bn Bn
75%
1.04.4.5 Alkylation of O,S-Stabilized Carbanions

Seminal studies on -lithiation of phenylsulfonyl epoxides were carried out by Jackson in 1991,
who confirmed the configurational stability of the related oxiranyl anions <1991JCS(P1)897,
1992JCS(P1)2863>. A general procedure for their alkylation was also described and then applied
by Mori and co-workers. Deprotonation with BunLi at 100 C in THF/DMPU followed by
reaction with elaborated alkyl iodides liberates the substituted epoxides in moderate yields
(Equation (260)) <1996TL2605>.
OBn i. BunLi. DMPU OBn

THF, –100 °C O
O
O ð260Þ
TolSO2 ii. O , –70 °C TolSO2
O
O
I 1/1 dr
50%
1.04.4.6 Alkylation of O,N-Stabilized Carbanions

As reported by Katritzky, a similar lithiation of benzotriazolyloxiranes with BunLi at low
temperature (78 C) gives benzotriazolyl-stabilized oxiranyllithiums, which react with primary
haloalkanes (Equation (261)) <2003JOC407>.
O i. BunLi O
H Ph THF, –78 °C Me Ph
N Ph N Ph ð261Þ
N ii. MeI N
N 82% N
1.04.4.7 Alkylation of S,S- or Se,Se-Stabilized Carbanions

Thiophilic addition of organolithiums and Grignard reagents to dithioesters has focused the
attention of several research groups over the past few years. These various studies are now part
of a review published by Metzner in 1992 <1992S1185>. Compared with carbonyl groups, the
small difference of electronegativity between sulfur and carbon atoms as well as the high polariz-
ability of sulfur were found to sometimes reverse the reactivity of thiocarbonyls toward nucleo-
philic addition of organometallics. Thus, the transient dithioacetal-stabilized anion, considered as
an equivalent of acyl anion, can be trapped by organic halides. To illustrate this reactivity,
Quéguiner and Metzner reported the sequential alkyl- and aryllithium addition to 2- and
3-pyridyl dithioesters followed by the electrophilic quenching of the resulting carbanions (Equations
(262) and (263)) <1998H(48)2019>, while Shi and Heimgartner achieved this transformation on
4,4-dimethyl-1,3-thiazole-5(4H)-thiones (Equation (264)) <1996HCA371>. According to research
by Zwanenburg <1978T1585, 1982RTC1>, and more recently Metzner <1993TL6741,
1996TL4507, 1998H(48)2019>, aliphatic and heteroaromatic sulfines behave like dithioesters
toward organolithiums leading to substituted dithioacetal oxides which are cleaved spontaneously
to related ketones at room temperature in moderate yields (Equation (265)). An example of
addition–alkylation of trithiocarbonate oxides is depicted in Equation (266) <1997T1323>.
i. BunLi
THF, –78 °C SMe
SMe ð262Þ
N N
ii. Allyl bromide
S BunS
59%
S i. BunLi BunS
THF, –78 °C
SMe
SMe
ð263Þ
ii. Allyl bromide
N 78% N
i. MeLi
N THF, –78 °C N
Bn ð264Þ
Ph S ii. BnBr Ph
S S SMe
78%
O i. MeLi O
THF, –78 °C 20 °C O
S
Me S SMe
ð265Þ
ii. MeI n-Octyl Me
n-Octyl SMe n-Octyl Me
61%
55/45 dr
O i. MeLi
O
S THF, –78 °C 20 °C
Me S Me
ð266Þ
EtS SEt ii. MeI, HMPA 100% EtS SEt
EtS SEt
–78 °C to rt
94%
By analogy with dithianes, metallation of 1,3-diselenanes has been investigated by Krief and
Defrère. Treatment of diselenanes with strong bases such as LDA leads to the formation of
2-lithio 1,3-diselenanes, whereas alkyllithiums act as nucleophiles and tend to cleave one of the
CSe bonds instead of the CH bond by proton abstraction <1996TL8011>. Methylation of the
generated metallic species with methyl iodide proceeds in good yield <1996TL2667>. On con-
formationally rigid systems including 4,6-dimethyl-1,3-diselenanes, deprotonation with metal
amides (LDA or KDA) or organolithiums affords the related organometallics exclusively in
the equatorial position, which undergo subsequent alkylation with retention of configuration
(Equation (267)).
H i. KDA H
THF, –78 °C
Me Se H Me Se Me
Se ii. MeI, –78 °C to rt Se ð267Þ
Me Me
70%
cis/trans 100/0
1.04.4.8 Alkylation of N,S-Stabilized Carbanions

Yus, Nájera and co-workers reported that N-(tosylmethyl)amides can be -lithiated with BunLi/
DMPU at 90 C. The monanion reacted with activated halides and gave the -substituted
amido sulfones (Equation (268)) whereas the unstable dianion underwent sequential alkylation
and intramolecular elimination of the sufinyl group affording N-acylenamines (Equation (269))
<1997SL491>.
O O Li O
BunLi Allyl bromide
N N N
ð268Þ
Ts DMPU, THF Ts 67% Ts
–90 °C
O Li Li H CO2But
BunLi (2 equiv.) O Li BrCH2CO2But O
But N Ts
DMPU, THF 62%
H But N Ts But N Ts
–90 °C
ð269Þ
O
CO2But
But N
H
1.04.4.9 Alkylation of N,N-Stabilized Carbanions
1.04.4.9.1 By intermolecular substitution

Synthetic equivalents of acyl anions are well represented by the chemistry developed on lithiated
dithianes and mixed ketals <1989T7643>. More recently, Coldham’s group showed that the
direct lithiation of imidazolidine with BusLi occurs at the C-2 position between the two nitrogen
atoms giving the corresponding anion, which may be also considered as a potential equivalent of
an acyl anion. This transient lithiated species reacts as a nucleophile with alkyl halides and yields
the C-2 alkylated imidazolidines. Thus, the carbonyl group can be liberated by hydrolysis of the
imidazolidine ring by action of TFA (Equation (270)) <1996SL1109, 1998T14255>.
H t-BOC i. BusLi t-BOC

H
N THF, –78 °C N
ð270Þ
N ii. Allyl bromide N
H t-BOC 48% H t-BOC
1.04.4.9.2 By intramolecular substitution

In this area, an example reported by Katritzky and co-workers concerns the preparation of
2-substituted N-BOC pyrrolidines by intramolecular substitution of primary chloride present on
the side chain of N-BOC-N-(benzotriazol-1-ylmethyl)-3-chloropropylamine, by the -lithiated
intermediate. The regioselective proton abstraction, achieved at the C-2 position with BunLi in
toluene at 78 C, leads to the related carbanion-stabilized by N-BOC and benzotriazole moieties.
Thus, alkylation at the C-2 position can be realized via nucleophilic displacement of the benzo-
triazolyl group by organozinc reagents (Equation (271)) <2000TL9691>.
Li
N N N
N N N Cl BunLi N N N Cl N N N
t-BOC Toluene t-BOC t-BOC
–78 °C ð271Þ
55%
RMgBr/ZnCl2
R N R = Ph, 86%
THF, reflux
t-BOC R = Ph-C=
=C, 77%
ACKNOWLEDGMENTS
The authors thank the Centre National de la Recherche Scientifique (CNRS) and the Ministère de
l’Education Nationale for the financial support.
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Biographical sketch
Maurice Santelli was born in Marseille in Cyril Ollivier was born in Neuilly, France, in
1939. He received his Ph.D. in chemistry 1971. He received his Diplôme d’Etudes
working with Professor M. Bertrand (homo- Approfondies in Organic Chemistry from
allenylic participation, nonclassical ion). He Pierre et Marie Curie University (Paris)
had a postdoctoral position at the University under the guidance of Professor Jean-François
of Cambridge (UK) in 1973 (Professor R. A. Normant and Dr. Fabrice Chemla in 1995,
Raphael). After an appointment at the Uni- working on the reactivity of carbenoids in
versity of Oran (Algeria) (1975–1977), he is 1,2-metallate rearrangement. After one year
presently Professor of Chemistry at the Uni- of national service at the ENSTA (Paris) as
versity of Aix-Marseille III. His main research scientist associate in the laboratory of
areas are physical organic chemistry, electro- Dr. Laurent El Kaim, he joined Professor
philic activation, palladium-chemistry with Philippe Renaud’s group at the University of
new ligands, and the synthesis of bioactive Fribourg in 1996 for a Ph.D. program in col-
products (polyunsaturated fatty acids, laboration with the laboratory of Prof. Max
Prelog-Djerassi lactone, non-natural steroids). Malacria, Pierre et Marie Curie University
(Paris). He worked on the utilization of orga-
noboranes as source of radicals, on the devel-
opments of novel radical hydroxylation and
azidation processes, and gained his doctorate
in cotutelle in 2000. He was awarded a Swiss
National Foundation Fellowship to pursue
research studies at the University of Texas at
Austin (Austin, TX) in Professor Philip Mag-
nus’ group where he was involved in the total
synthesis of guanacastepene. In 2002, he
joined the CNRS at Aix-Marseille III Univer-
sity where is working with Prof. Maurice
Santelli. His research focuses on the synthesis
of steroids, particularly vitamin D analogs.
1.05
by Substitution: Substitution of
Chalcogen
N. HOFFMANN
CNRS et Université de Reims Champagne-Ardenne,
Reims, France
1.05.1 SUBSTITUTION OF OXYGEN FUNCTIONS 201

1.05.1.1 Radical Reactions 201
1.05.1.1.1 Intermolecular reactions 202
1.05.1.1.2 Intramolecular reactions 202
1.05.1.2 Displacement of Alcohol Derivatives 203
1.05.1.2.1 Alkyl alcohol derivatives 204
1.05.1.2.2 Allylic alcohol derivatives 205
1.05.1.2.3 Propargylic alcohol derivatives 208
1.05.1.2.4 Benzylic alcohol derivatives 209
1.05.1.2.5 Vinyl alcohol derivatives 210
1.05.1.2.6 Aryl alcohol derivatives 213
1.05.1.3 Opening of Epoxides 215
1.05.1.3.1 Simple and vinylogous epoxides 215
1.05.1.3.2 Oxetanes and -lactones 217
1.05.1.4 Cyclopropanation of Carbonyl and Carboxyl Compounds 217
1.05.2 SUBSTITUTION OF SULFUR FUNCTIONS 218
1.05.2.1 Radical Reactions 218
1.05.2.2 Ring Constructions 222
1.05.2.3 Sulfur Leaving Groups 222
1.05.2.3.1 Sulfides as leaving groups 222
1.05.2.3.2 Sulfones and sulfonates as leaving groups 223
1.05.3 SUBSTITUTION OF SELENIUM AND TELLURIUM 224
1.05.3.1 Radical Reactions of Selenides 224
1.05.3.2 Reactions with Tellurium Compounds 224
1.05.1 SUBSTITUTION OF OXYGEN FUNCTIONS
1.05.1.1 Radical Reactions

Radical reactions have become an important tool in organic synthesis. Numerous reviews and
books have recently been published (e.g., <B2001MI001, B2001MI002>). Aspects of stereo-
selectivity have also been reviewed <B1996MI003>.
201
202 One or More CC Bond(s) Formed by Substitution: Substitution of Chalcogen
1.05.1.1.1 Intermolecular reactions

Various examples of radical formation from thiocarbonyl derivatives such as xanthates or
thiocarbonates and their subsequent addition to olefins have been mentioned in the corresponding
chapter 1.05 <1995COFGT(1)171>. For recent reviews on radical reactions with xanthates, see
<1997AG(E)672, B2001MI004>. Further examples involving cleavage of the CS bond, which is
frequently applied in organic synthesis, are discussed in Section 1.05.2.1. In the Barton–
McCombie reaction, which leads to deoxygenation, radical intermediates are generated with tin
reagents and a radical chain initiator (e.g., AIBN). These intermediates readily add to sterically
unhindered alkenes such as acrylate derivatives. There are several problems related to the use of
tin derivatives such as toxicity, difficulties in the work-up, and their complete removal from the
products. Other reagents such as tetraphenyldisilane 1 have been tested (Scheme 1)
<2000JOC2816>. Methylxanthate and imidazole thiocarbonyl groups were successfully used as
leaving groups. The procedure was applied to the addition of alkyl radicals to phenylvinyl sulfone 2
and nitrogen-containing heterocycles.
C8H17 C8H17
SO2Ph
S 1, AIBN
+
N O 2 51%
N PhO2S
1, AIBN
S
+
54% N
O SMe N
S N 1, AIBN
N
O SMe S 53%
S
Ph Ph
Ph Si Si Ph
H H
1
Scheme 1
1.05.1.1.2 Intramolecular reactions

As already shown in COFGT (1995), intramolecular radical reactions are more frequently studied
than intermolecular reactions and they have recently been reviewed <1996OR301>. The intra-
molecular cyclization of thiocarbonates was successfully applied to the synthesis of carbasugar
structures starting from pyranose derivatives (Scheme 2) <1999CC175, 2002TL5559>. These
examples indicate that the methodology is compatible with a large variety of functional groups
and can be applied to the synthesis of natural products and constrained oligocyclic systems
(Scheme 3). In the latter case, the methylxanthate function was used as a leaving group
<1997JA9929>.
In intermolecular reactions, the imidazole thiocarbonyl function was successfully used as a
leaving group. The reaction was applied to the synthesis of complex structures such as lycorine
derivatives (Scheme 4) <2002H2279>. It should be mentioned that the cyclization proceeded
according to an exo-cyclic process leading to a mixture of regioisomers and that the stereogenic
centers influence the stereoselectivity of the reaction. The epimer 3 stereospecifically yielded the
cyclization products 5 and 50 , whereas the stereoisomer 4 yielded 6 and 60 , in addition to the
diastereomeric lycorine derivative 7.
One or More CC Bond(s) Formed by Substitution: Substitution of Chalcogen 203
O OPh Ph Ph
O O O
Ph Bu3SnH
O AIBN O OTBDMS + O OTBDMS
OTBDMS 95%
O O O O O O
1:1.3
O OPh O O
O Bu3SnH
AIBN
O O O OEt + O O OEt
O 74%
OEt O O
O O O O O O
O 2:1
Scheme 2
S
OMe OMe
H O SMe H H
H Bu3SnH H
AIBN
H O H O
95%
Scheme 3
AcO OAc R
TMS
R'
H O N Cy3SnH H H
N O H
O AIBN
S
N O N
O
3 5 R=H, R'=TMS 42%
5' R=TMS, R'=H 42%
AcO OAc R OAc TMS

TMS
R'
H O N Cy3SnH H H H H
N O H O H
O AIBN
S +
N O N O N
O
4 6 R=H, R'=TMS 14% 7 12%
6' R=TMS, R'=H 27%
Scheme 4
1.05.1.2 Displacement of Alcohol Derivatives

Under various conditions, the hydroxy group or many of its derivatives are good leaving groups
and CC bonds can be formed via nucleophilic substitution by using C-nucleophiles. Recently, a
large variety of methods have been developed in the field of organometallic chemistry
<2000CRV2739, B1998MI009>. In this context, cross-coupling reactions have been particularly
studied <B1998MI005>. Halogen atoms are frequently used as leaving groups along with oxygen
derivatives such as esters and the triflates. In the following sections, cross-coupling reactions are
preferentially discussed. For further reviews and books, see <1995CRV2457, B1998MI009,
B2002MI010, 2002S2473, 2002SL1939, 2003AG(E)1604>. For reviews on asymmetric catalysis,
see <B1999MI016>.
1.05.1.2.1 Alkyl alcohol derivatives

The well-known dimethylcarbonate 9 was recently used for C-methylation under particular optimized
eco-friendly reaction conditions. This methylation reagent is nontoxic and biodegradable which make
it a ‘‘green reagent’’ <2002ACR706>. The monomethylation of the phenylacetonitrile derivative 8
leading to the ibuprofen precursor, compound 10 was achieved using special reaction conditions or
phase transfer catalysis (Equation (1)). For various other examples, see <2002JOC1071>.
O
CN + (a) CN
O O 95%
8 9 10 ð1Þ
(a) gas–liquid-phase transfer catalysis, plug-flow reactor,
catalyst: K2CO3 coated with 0.5–5 mol.% Polyethylene glycol PEG 6000
T = 160–180 °C
Cyclic sulfate derivatives have been used to synthesize complex natural products or products
possessing interesting biological activity <2000T7051>. For instance, the fluorinated chiral
butanol 12 was obtained by opening the optically active cyclic sulfonate 11 which was attacked
by the trifluoromethyl anion (Scheme 5) <2002OL4671>. This anion was generated by reduction
of trifluoromethyl iodide with tetrakis(dimethylamino)ethylene (TDAE). In the case of 13, the
oxathiazinane ring was opened by the attack of the cyanide anion and the obtained bicyclic
iminium derivative 14 was transformed to the indolizidine derivative 15 <2003JA2028>.
O O HO
S CF3I/ TDAE
O O TDAE: tetrakis(dimethylamino)ethylene
CF3
43%
12 >99.5% ee
11
O O NH2
S
N O i. KCN N NaBH4 N
ii. H3O+, ∆
HO HO 75% HO
H H OH H OH
HO OH HO overall HO
13 14 15
Scheme 5
For a long time, cross-coupling reactions of Grignard reagents with alkyl halides, triflates, or
tosylates had not been very efficient, since slow oxidative addition of the substrates and -elimination
from the alkyl metal intermediates easily occur <2003AG(E)384>. Recently, however, efficient
reaction conditions have been developed to carry out these cross-coupling reactions (Equation (2)).
In a nickel-catalyzed reaction, 1-phenylbutane 17 was obtained in high yields from the cross-coupling
of 2-phenylethyl tosylate 16 with ethylmagnesium bromide <2002JA4222>. The high efficiency of the
reaction is due to the use of 1,3-butadiene instead of phosphine ligands. Recently, a flexible method
for the coupling of various alkyl tosylates such as 18 with alkyl 9-borabicyclononane derivatives
(Suzuki cross-coupling) has been developed (Equation (3)) <2002AG(E)3910>. The reaction toler-
ates a variety of other functional groups such as esters, amides, nitriles, ketones, or free alcohols.
OTs NiCl2 (3 mol.%)
+ MgBr ð2Þ
1,3-Butadiene (30 mol.%)
16 17
87%
O Pd(OAc)2 (4 mol.%) O
P Bu2t Me (16 mol.%)
9-BBN- Octn
N ( )14 OTs + N ( )14 Octn
ð3Þ
O NaOH (1.2 equiv.) O
18 dioxane, 50 °C
76%
In the case of acetals or aminals, CC bonds can be formed by replacement of oxygen-contain-
ing groups. Recent examples are depicted in Scheme 6. Acetal 19 was transformed into 21 when
heated with allyltrimethyl silane 20 <2003OL55>. For a similar reaction with chiral induction, see
<2003OL2367>. In these reactions silicon-containing Lewis acids such as TMSOTf are used. For a
review on CC bond-forming reactions mediated by such Lewis acids, see <2003CRV733>. It is
worth noting that the reactions were carried out in ionic liquids such as butylmethylimidazolium
hexafluorophosphate ([bmim][PF6]). Reactions carried out in such media are eco-friendly and can
be easily performed <2000AG(E)3772>. The stereospecific reaction of oxazolidine 22 with methyl-
magnesium bromide yielded the piperidine derivative 23 <2003EJO2062>. Trifluoromethyl deriva-
tives are also obtained by the addition of nucleophiles such as allyltrimethyl silane 20 to the aminal
derivative 24 <2002JOC997>. A similar reaction was used for the addition of heterocyclic aromatic
compounds such as 26 to the trichloracetaldehyde-derived aminal 25. The reaction was also
performed with isocyclic aromatic compounds. The procedure was particularly efficient when
Cu(OTf)2 or more frequently Hf(OTf)4 were used as Lewis acid catalysts <2003JOC483>.
OMe SiMe3 TMSOTf (5 mol.%)

+
[bmim] [PF6]
OMe OMe
19 20 79% 21
O OTBDPS HO OTBDPS
+ MeMgBr N
N
Ph 89% Ph
22 23
BnO BnO
OSiMe3 i. BF3 /Et2O

Ph + SiMe3 ii. HCl (2 M)
F3C N >70% F3C NH3 Cl
Ph
24 20
Cu(OTf)2 H2N CCl3

NHSiMe3 or Hf(OTf)4
+
Me3SiO CCl3 N TMSCl
H N
25 26 90–92% H
Scheme 6
1.05.1.2.2 Allylic alcohol derivatives

The allylation of aromatic compounds was achieved using a cross-coupling of allyl esters with aryl
halides (Scheme 7) <2003JOC1142>. The reaction tolerates a variety of functional groups on the
aromatic ring and this reaction can also be carried out with heterocyclic aromatic compounds. The
reaction is catalyzed by CoBr2 which is regenerated by a sacrificial iron anode. This efficient
electrochemical process competes with more classical reaction conditions when zinc or manganese
in the presence of FeBr2 are used as reducing agents <2003OL1043, 2003JOC2195>. Recently, a
Cu(OTf)2 catalyzed addition of alkyl or aryl sustituents to cinamyl alcohol derivatives using
trialkyl- or triarylindium compounds has been published <2003JOC2518>.
Indium-mediated addition of allyl groups to carbonyl compounds, mainly to aromatic alde-
hydes, can be carried out in the presence of water. These reactions have recently been reviewed
<2003S633, 2003S765, 1999T11149, B1998MI007>. Allylic alcohols can also be used, and in this
case the reaction is catalyzed by palladium (Scheme 8) <2003S775>. When butenyl acetate 27 was
used, only the branched product 28 was isolated. In this case, an electrochemical method, using
only FeBr2, was also developed to perform the addition of allylic alcohol derivatives to aliphatic
and aromatic aldehydes and ketones with yields greater than 90% <2003JOC3121>.
Br
O
CoBr2
+
O
Iron anode
stainless steel cathode
I = 0.2 A
86%
CoBr2
+ EtO2C
EtO2C Br OAc Iron anode
stainless steel cathode
I = 0.2 A
70%
Scheme 7
OH
CHO In/InCl2/Pd(PPh3)4
+ OH
THF/H2O
94%
OH
CHO In/InCl2/Pd(PPh3)4
OAc
+
THF/H2O
27 90% 28
28/72 syn/anti
Scheme 8
The addition of pentadiene derivatives such as 29 to aromatic aldehydes mediated by zircono-

cene dichloride was achieved (Equation (4)) <2001TL1677>. The reaction was also carried out
with aliphatic aldehydes. The addition was regio- and stereoselective. For similar transformations,
see <1995T4507>.
OH
CHO OBn
Cp2ZrCl2, BunLi
+
ð4Þ
96%
29
14/86 syn/anti
In carbohydrate chemistry, the iodine-catalyzed addition of silylacetylene derivatives was applied

to the stereoselective synthesis of C-glycosides using an SN20 reaction (Equation (5)) <2003S247>.
The reaction was also carried out with methoxy or allyloxy functions as leaving groups.
O I2 Ph
+ Me3Si Ph O
92% ð5Þ
AcO
OAc AcO
The palladium-catalyzed addition of C-nucleophiles such as malonates or acetoacetate to allyl

acetates (Trost–Tsuji reaction) has been intensively studied by many research groups
<B2002MI006>. Recently, this reaction has been carried out in ionic liquids which enormously
facilitates the procedure (Equation (6)) <1999JMOC121>. The reaction was performed in the
ionic liquid 1-butyl-3-methylimidazolium chloride (BMICI) using palladium chloride as catalyst
precursor. Under these conditions, the reaction is faster, the catalyst is more stable, and no
cinnamyl alcohol is isolated as a by-product. The reaction was also performed on solid support
with various substrates <1998CC793>. For a review of palladium-catalyzed reactions on solid
phase, see <2003T885>.
Pd(TPPTS)3
O Methylcyclohexane CO2Et
OAc + CO2Et
BMICI ð6Þ
89% O
TPPTS: triphenylphosphinetrisulfonate, sodium salt
Intramolecular metalla-ene reactions can be catalyzed by Pd(0) to produce cyclic products.

When substrate 30 is treated with Pd(PPh3)4, one acetyl group of the acetal function acts as a
leaving group and compound 31 is isolated in good yield (Scheme 9) <1999T3467>. For another
interesting stereoselective cyclization of this type, see <2003TL653>. For a review on palladium-
catalyzed allylic substitutions, see <B1998MI014, B1998MI015>. A bifunctional heterogeneous
catalyst was developed for the sequential allylic alkylation Pauson–Khand reaction
<2002OL4361>. This reaction sequence is catalyzed by palladium and cobalt nanoparticles
deposited on silica (PCNS). The palladium nanoparticles catalyze the addition of allyl acetate
to 32 and the cobalt nanoparticles catalyze the Pauson–Khand reaction when carbon monoxide is
present. In the absence of CO, the Pauson–Khand reaction does not take place.
O O
O Pd(PPh3)4
O O
O
84%
OAc OAc
OAc 31
30
EtO2C PCNS EtO2C

O
EtO2C OAc EtO2C
32
CO
88% PCNS: palladium and cobalt nanoparticles
deposited on silica
Scheme 9
Recently, in the context of these reactions, much attention has been paid to chiral induction
and asymmetric catalysis <1996ACS189> in order to apply them to the total synthesis of natural
products and/or biologically active compounds <2003AG(E)2580> (see also Section
1.05.1.2.4). In Scheme 10, an iridium-catalyzed reaction effects the transformation of the
allylphosphonate derivative 33 to 34 and 35 <2003AG(E)2054>. The reaction is regiospecific
and highly diastereoselective and the enantioselectivity of both diastereomers 34 and 35 exceeds
90%. The high ee values result from the chiral induction of the binaphthol-derived ligand 36. An
F3C F3C
F3C
Ph [{IrCl(COD)}2]
OP(O)(OEt)2 + +
Ph N CO2 But Ph Ph
Ligand 36
33
Ph N CO2 But Ph N CO2But
34 (70%) 35 (8%)
O
P (CH2)2SEt
O
36
Scheme 10
iridium-catalyzed reaction with malonate and allyl acetate derivatives was also performed using
binaphthylphosphate ligands similar to 36 <2003EJO1097>. For a review on iridium-catalyzed
reactions, see <2002SL1954>.
Various sigmatropic rearrangements involving allylic alcohol derivatives have been carried out
and one of the main topics in these reactions concerns the stereoselectivity. For reviews on these
reactions, see <1996TA1847, 1999CSR43>. In Scheme 11, examples of stoichiometric chiral
induction are depicted. Compound 37 is stereospecifically transformed via a [2,3]-Wittig rearran-
gement and only the anti isomer 38 is obtained <1996S1438>. For examples in the acyclic series,
see <1996T1503>, and for a review of this reaction, see <2003SL1088>. Substrates such as 39
have been transformed with high diastereoselectivity, via a [3,3]-sigmatropic Carroll rearrange-
ment, into 40 and 400 <1995AG(E)2278>. For further examples, see <1996LA1095>.
Et Et Et Et
OMe OMe
N N
N N
O ButLi OH
81%
37 38 de > 96%
OMe OMe OMe

N N N
N O N N
i. LDA
O +
ii. LAH
69% OH OH
94:6
39 40 40′
Scheme 11
Chiral induction can also be performed via asymmetric catalysis. For instance, the glycine
derivative 41 was transformed into the chiral -amino acid derivative 42 with high dia- and
enantioselectivity (Scheme 12) <2002CEJ1850>. For this transformation, quinine was shown to
be the best asymmetric catalyst. For an application to the asymmetric synthesis of natural
products using a similar reaction, see <1995JA193>.
LHMDS
Al(OPri )3 i. H3O+
O
TFAHN Quinine ii. CH2N2 TFAHN CO2Me
O 98%
41 42 98% ds 87% ee
TFA: trifluoroacetyl
Scheme 12
1.05.1.2.3 Propargylic alcohol derivatives

In Scheme 13, some recent examples of metal-catalyzed nucleophilic substitution with pro-
pargylic alcohol derivatives are presented. The titanium-mediated coupling reaction between the
propargyl derivative 43 and the malonate derivative 44 yielded 45 in high yields <2003TL2113>.
Only one diastereomer was isolated. Using a binuclear ruthenium complex as catalyst, the
propargylic alcohol 46 can add to phenol to produce 47 which was isolated in high yield
<2003AG(E)1495>. The reaction was also extended to heterocyclic aromatic compounds such
as furans, pyrroles, or thiophenes, and to bicyclic aromatic compounds such as naphthalene and
azulene. For a review on ruthenium-catalyzed CC bond formation, see <2001CRV2067>. The
reaction is similar to the Nicholas reaction in which the triple bond is protected by a binuclear
TMS OTBDMS
TMS OTBDMS Ti(OPri)4
+ CO2Et CO2Et
PriMgCl
OP(O)(OEt)2 CO2Et 93% CO2Et
43 44 45 dr > 99:1
Ph
Ph
Ph OH Cat.
Ph +
ClCH2CH2Cl/60 °C
OH
80%
46 47
OH
Cat: [Cp*RuCl(µ -SMe)2Cp*Ru(OH2)]OTf
OMs Pd(OAc)2, PPh3

+ +
Et2Zn
OH OTBDMS OH OTBDMS
O OTBDMS
48 49 50 (73%) 51 (6%)
Scheme 13
cobalt complex. For a review on this reaction, see <2002T4133>. A palladium-catalyzed coupling
reaction between the propargylic mesylate 48 and the aldehyde 49 is also highly diastereoselective,
and the anti,anti,anti-polypropionate derivative 50 is obtained as the major product
<2001JOC7825>. Only minor amounts of the epimer 51 were isolated. The configuration of
the stereogenic center of the secondary alcohol formed in 50 is induced by the chiral center of the
propargylic mesylate 48. The configuration of the chiral center in the -position of the aldehyde
49 plays a minor role. For a review of palladium-catalyzed reactions of propargylic compounds,
see <1995AG(E)2589>.
1.05.1.2.4 Benzylic alcohol derivatives

Palladium-catalyzed addition of malonate to 52 (Trost–Tsuji reaction, cf. Section 1.05.1.2.2,
Equation (6)) has been very frequently reported (Scheme 14). Other electrophiles of this type
such as 54 <2003OL1713> or allyl alcohol derivatives and various C-nucleophiles, mainly
stabilized by adjacent carbonyl functions, can be used <B1995MI007, B2002MI006>. In some
cases, a rhodium catalyst was used. Stabilized carbanions such as the cyclopentadienyl anion 55
<2003TA511> have also been added. However, the transformation of 52 into 53 is frequently
used to test different reaction conditions. Recently, the reaction was studied in aqueous media
<2003ASC357> (for a review on this topic, see <1999JOM305>) and ionic liquids <2003OL31>.
RO2C CO2R
OAc
CO2R Pd/ligand
+
CO2R
52 53
OAc
M+
54 55
Scheme 14
Many investigations were performed on chiral induction by using different optically active ligands
<1995HCA265>. For reviews, see <1996CRV395, 1996ACS189, 1996SL705, B1999MI016,
1999JOM203>. Several studies have considered the design of suitable ligands. For a review on
this topic, see <2000ACR336>. Some recently investigated ligands are depicted in Scheme 15: 56
<2002CC1270>, 57 <2003OL1713> (in a rhodium-catalyzed reaction), 58 <2003TL1449>, 59
<2001AG(E)4289>, 60 <2002TL159>, 61 <2001SL1878>, 62 <2003TA537>, 63
<2003JOC3258>, 64 <2002JOC2206>, 65 <2003OL1349>.
R R1 Pd/L* R R1
C-Nucleophile (Nu) Nu
OR′′
Ligands = L*:
F17C8 C8F17
Ph Ph Ph Ph
Mn(CO)3 N P P
O
O O O NH HN
But N Ph2P
N N O O
P
2-Bp Ph Ph Ph
56 (95% ee) 57 (97% ee) 58 (94% ee) 59 (>86% ee)
p-Tol pTol
OMe
N O O P CH CN
OMe Ph S N N S
PPh2 Ph P(pTol)2
60 (85.6% ee) 61 (98% ee) 62 (95% ee)
EtO2C CO2Et
Fe
N PPh2
N N
Fe Ph2P PPh2
63 (94% ee) 64 (87% ee) 65 (98.9% ee)
Scheme 15
1.05.1.2.5 Vinyl alcohol derivatives

Vinyl triflates are now frequently used in cross-couplings. For a review, see <B1998MI013>. Since
several functional groups are tolerated, the method can be applied to the synthesis of complex
heterocyclic compounds such as 67 (Scheme 16) <2003JOC969>. Compound 67 was obtained from
the coupling reaction between the vinyl triflate 66 and an organocopper reagent prepared from N-
BOC-pyrrolidine. In this case, no further activation (e.g., by palladium) is necessary due to the
presence of the ,-unsaturated ester function in 66. Frequently, these reactions are mediated by
palladium, as in the synthesis of compound 70 <2003JOC2475>. In this case, an organozinc reagent
prepared from 68 was coupled with the vinyl triflate 69. For cross-couplings with palladium in
heterocyclic chemistry, see <B2000MI008>. After deprotonation, acetylides can also be coupled
with vinyl triflates as in the preparation of 71. Most frequently, such reactions need additional
copper catalysis and a secondary amine as base <2003JOC1154>. For similar examples, see
<1997JOC1582>. Recently, a process using silver co-catalysis was developed <1998JOM173>.
Under these reaction conditions, silylacetylene derivatives such as 72 could be coupled, and in this
case fluoride is used to activate the reaction instead of an amine base <2001TL8641>. Furthermore,
the use of silver instead of copper prevents a competitive ring opening of the epoxide. For further
Bn CO2Et
Bn CO2Et BuLi N
+ N N-t-BOC
N CuCN/LiCl
OTf
t-BOC 66 93% 67
O O F
O N O N
Br OTf N
BuLi/ZnCl2
+
N F Pd(PPh3)4
68 69 77% 70
i. CuI, Et2NH OH
Pd(PPh3)2(OAc)2
+ H
OSiMe3 ii. Bu 4NF
91% 71
H t-BOCHN OTBDMS
OTf
t-BOCHN OH
O
OTf O Pd(PPh3)4/AgI HO
+ HO
Bun4NF.3H2O
72 SiMe3 78%
OTf [Pd(dba)2],L*
+ L*: O
O N,N-Diisopropylamine
O
92% Ph2P N
73 (ee > 99%)
Scheme 16
discussion of the reaction conditions, see <2001EJO4391>. The reaction was also successfully
performed under asymmetric catalysis <1996AG(E)200>. By adding a chiral ligand, 73 was isolated
as an enantiopure compound.
When triflate 75 was added to the o-alkynylphenol derivative 74, a consecutive cyclization took
place, and the benzofuran derivative 76 was obtained (Equation (7)) <1996JOC9280>. For a
review on similar reactions, see <1999JOM42>.
OTf
O
Pd(OAc)2(PPh3)2 ð7Þ
+
CuI/Et3N
OH BzO DMF/80 °C 76
74 75 72%
BzO
Silyl enol ether 77 (Scheme 17) was transformed into a vinylzirconium intermediate which
undergoes a palladium- and zinc-catalyzed cross-coupling reaction with aryl halides
<2001SL123>. The steroid derivative 78 was coupled with the vinyltin compound 79 to yield
80 (Stille reaction) <1996JOC6693>. Under the same conditions, the vinyltin compound 79 was
OTMS I i. Cp2ZrCl(1 equiv.), BunLi (2 equiv.)

+
Ph ii. Pd(PPh 3)4, ZnCl2 Ph
77 60% O
O
OTf O
O Pd(PPh3)4, LiCl
+
THF, 65 °C
TBDMSO SnMe3 68% TBDMSO

78 79 80
OTs
PdCl2(PPh3)2 O
+ (HO)2B OMe OMe
O O THF/KF/H2O O
60 °C
82 81 93%
Scheme 17
replaced by the corresponding vinyl borate <2001TL9081>. Arylboronic acid 81 was coupled
with the vinyl tosylate 82. The reaction can also be performed with heterocyclic and bicyclic
arylboronic acids <2003JOC670>.
In a palladium-catalyzed reaction, in the presence of CO and the secondary amine 84, triflate 83
was transformed into the amide 85 (Pk11195) which is a ligand for the !3 receptor and by using
11
CO, the reaction was applied to the synthesis of isotopically labeled 85 (Scheme 18)
<2002JCS(P1)2699>. The reaction was also applied to the total synthesis of phomoidrides
<2003JOC1693>. For reviews on such carbonylation reactions, see <B1998MI012,
1996AG1050>. In a nickel-catalyzed electrochemical reaction, the vinyl triflate 86 was trans-
formed to the carboxylic acid 87 in the presence of CO2 <2002SL140>.
O
11C
OTf N
N Pd(PPh3)4 N
+ 11 + HN
CO
Cl THF, LiBr Cl
180 °C
83 84 85
NiBr2.bpy
+2e
O OTf Ni(0).bpy O CO2H

+ CO 2
79%
86 87
Scheme 18
The Claisen rearrangement was carried out with allyl vinyl ether. Particular catalysts have been
developed to induce chirality in this reaction. Sterically hindered trinaphthoxy-aluminum deriva-
tives such as 88 were particularly efficient (e.g., see Equation (8)) <1995JA1165>.
SiMe3 SiMe3
Cat.*/CH2Cl2 O)3Al ð8Þ
cat*:
78% CHO
O
92% ee
88
1.05.1.2.6 Aryl alcohol derivatives

Nucleophilic displacement of an oxygenated leaving group on aromatic compounds can be carried
out with C-nucleophiles. The nucleophilic substitution of the menthyloxy group in 89 by the
Grignard reagent 90 leads to the binaphthyl derivative 91 in relatively high enantiomeric excess
(Scheme 19) <2002T233>. In this field, many reactions were performed under palladium or
nickel catalysis. The anthracene triflate 92 was coupled with the furanose-derived enol ether 93
to yield the isonucleoside 94 <2003TL1215>. Aryl tosylates were also transformed under similar
reaction conditions. For another example, see <1999JA1473>. A palladium-mediated aryl–aryl
coupling was carried out between quinolinyl triflates 95 and phenylzinc bromide 96 <2003S233>.
Once again the reaction tolerates many functional groups. For an extensive review on aryl–aryl
coupling reactions, see <2002CRV1359>. Using nickel catalysts, cross-coupling and homocou-
pling reactions can be performed with aryl mesylates, tosylates, or triflates <1995JOC176,
O MgBr
NO2 OMe C6H6 OMe
+ NO2
51%
89 90
91 78% ee
HO i. Pd(OAc)2 , Ph3P
O
+
ii. HF. Pyr
OTf
OTBDMS
92 93 78% HO
O 94
EtO2C EtO2C
Pd(dba)2, tfp
+ MeO ZnBr
N OTf THF N
96%
OMe
95 96 tfp: tris-o-furylphosphine
O
O cat: (99)
OTf + N N
NaOBut
93%
97 98
Pd
cat: 99 Cl
Scheme 19
1995JOC6895, 1997JOC261>. A particularly efficient air-stable and well-defined palladium car-

bene catalyst 99, which belongs to a new generation of catalysts, was used for the coupling of 97
and 98 <2002OL4053>. Chirality was also induced via asymmetric catalysis.
Phenyl triflate was added to 2,3-dihydrofuran 100 using Pd(OAc)2 as a catalyst and biphenyl-
bisphosphine 103 as a chiral ligand (Scheme 20) <1997JA6315>. Both regioisomers 101 and
102 were obtained in high enantiomeric purity. The axial prochiral ditriflate 104 underwent
asymmetric monosubstitution with the Grignard reagent 105. Various reaction conditions have
been tested in order to minimize the formation of the achiral disubstituted product and to
enhance the enantiomeric excess of 106 <1996TL3161>.
O Ph O Ph O MeO PR2
Pd(OAc)2, Ligand 103
OTf + + MeO PR2
NEt(Pri) 2, C6H6
100 101 102 103 But
(65%) (3%)
ee > 98% ee > 98%
R:
But
MgBr
TfO OTf PdCl2[Lig] OTf N Cl
+ PdCl2[Lig]: Pd
Ph3Si
LiBr N Cl
SiPh3
91% Ph Ph
104 105 106 88% ee
Scheme 20
Intramolecular cross-coupling reactions have been performed using asymmetric catalysis. For a
recent review on such reactions, see <2003CRV2945>. Using the BINAP ligand for chiral
induction, the aryl tosylate 107 cyclized to yield the indole derivative 108 (Scheme 21)
<1997AG(E)518>. Further transformations lead to 109 with high enantiomeric excess. In a
similar way, 110 was transformed into the two regioisomeric benzocyclohexadienes 111 and 112
<1995TA2453>. The tricyclic compound 111 could be isomerized to 112 and the latter product
was transformed into 113 which was isolated with high optical purity. For an investigation which
focused on ligand optimization of a similar reaction, see <2003OL595>.
TBDMSO OTBDMS OH
O
N Pd-(R)-BINAP
O O
OTf
N N
107 N 108 92% ee 109
62%
OMe
OMe
OMe OMe
Pd(OAc)2
TfO (R)-BINAP TBDMSO
K2CO3 +
O
3:1
110 71% 111 112
113 95% ee
Scheme 21
1.05.1.3 Opening of Epoxides

Epoxides are versatile synthons in organic synthesis and ring-opening reactions are widely used.
The corresponding chapter in COFGT (1995) extensively reviews different electrophilic and
nucleophilic opening reactions. Recently, radical and transition metal-catalyzed transformations
have been developed. Some of these methods are presented here.
1.05.1.3.1 Simple and vinylogous epoxides

For a review on radical reactions with epoxides, see <2001T1>. In a titanium-mediated cycliza-
tion, epoxide 114 possessing an akynyl side chain was transformed stereospecifically into 115
(Scheme 22) <2001S2500>. Cp2TiCl2 was used in catalytic amounts in the presence of zinc
powder as reductant. The reaction was also successfully performed with substrates with an
olefinic substituent. Tetrahydrofuran or pyrrolidine derivatives were obtained when the unsatu-
rated side chain contained an ether function or sulfonamide, respectively. For a review on such
reactions, see <2000CRV2771>. Under similar conditions, !-epoxyketones and aldehydes can
cyclize to produce functionalized five- or six-membered rings. For example, the cyclopentanediol
derivatives 117 and 118 were isolated from the reaction of epoxyketone 116 <1999OL607>. For
another example, see <2002JOC8243>.
O HO
Cp2TiCl2
Zn
90%
H
114 115
O
Cp2TiCl OH
HO + HO
86% OH
O 1:1
116 117 118
Scheme 22
Titanium-mediated ring opening of epoxides can generate radicals which add intermolecularly
to activated alkenes. This reaction was performed in an enantioselective way using chiral titanium
catalyst 119 (Equation (9)) <2003CEJ531>.
CO2But OH
119 Cl Cl
O+ Ti ð9Þ
Zn, CO2 But
72% 81% ee 119
The palladium-mediated ring opening of vinylepoxides 120 in the presence of InI and benz-
aldehyde led to the exclusive formation of the 1,3-diol when the reaction was performed in water or
in a mixture of THF and water (Scheme 23) <2001JOC7919>. For similar examples, see
<2003S751>. The addition of the C-nucleophile 121 to the epoxide 122 was carried out under
asymmetric catalysis <2001JA12907>. The main product 123 resulted from a 1,2-addition of 121
to 122 followed by the formation of the lactol. This reaction occurred with high enantioselectivity.
The formation of the minor product 124 resulted from the 1,4-addition of 121 to 122. For an
application of this reaction to the asymmetric synthesis of natural products, see <2003OL1563>.
The alkyne tungsten complex 125, synthesized from 126, reacts in an intramolecular way with the
epoxide <2003JOC1872>. A large variety of -lactones such as 127 have been obtained by this
reaction. For a review on these reactions, see <2000CRV3127>.
OH
CHO
Pd(PPh3)4, InI
+
O THF/H2O: 1/1
120 88% HO
18/82 syn/anti
O
+ Pd2(dba)3 CO2Et
CO2Et O +
O Ligand EtO2C
HO OH
O
122 121 123 (67%, 99% ee) 124 (7%)
O O
Ligand:
NH HN
Ph2P
PPh2
O
(OC)3W
NTs CpW(CO)3Cl NTs i. BF3·Et2O O NTs
O O
CuI, Et2NH ii. H2O
HO
OH OH 92%
126 125 127
Scheme 23
A formal Lewis acid-catalyzed [3+2]-cycloaddition of epoxyalcohol derivative 128 was

performed with allyl silanes such as trimethylallyl silane (Scheme 24) <1999TL5877>. Under
optimized reaction conditions, the tetrahydrofuran 129 was isolated as the major product. How-
ever, the formation of the side products 130 and 131 indicated that formation of both the CO
O SnCl4
BnO + SiMe3 BnO SiMe3 + BnO + BnO Cl
O OH OH
128 129 (76%) 130 (4%) 131 (4%)
H H
Ath CAS1His477Asn H
+ +
HO HO
O H H
132 133 (88%) 134 (12%)
HO
H 135
Scheme 24
-bond and the CC -bond did not occur at the same time. A Johnson-type cyclization occurred
when oxidosqualene 132 was treated with an enzyme and four CC -bonds were created in a
cascade process <2002OL4459> (see also <2000AG(E)4090>). In this latter case, the reaction
was performed with the mutant of a cycloartenol synthase AthCAS1His477Asn which was
obtained by directed evolution. This enzyme only catalyzes the formation of lanosterol 133 and
to a minor degree the formation of parkeol 134 while the formation of cycloartenol 135 is not
observed. For a review on enzyme mechanisms for polycyclic triterpene formation, see
<2000AG(E)2812>.
1.05.1.3.2 Oxetanes and b-lactones

Oxetanes are less reactive than epoxides; however, some ring-opening reactions can be performed.
For reviews on chemical reactions with oxetanes, see <1997LA1627, 2000SL1699>. Several alkyl-
and aryllithium compounds were added to the oxetane 136 (Scheme 25), and diols 137 were
isolated in good yields <1998EJO2161>. For similar reactions, see <1999EJI2187>. For an
addition of alkyl- or aryllithium compounds under asymmetric catalysis, see <1997T10699>.
The dilithiated intermediate 138 was obtained when the oxetane 139 was treated with lithium
powder and trapped with electrophiles such as benzaldehyde to yield two diastereomeric diols 140
and 141 <1997TA2633>. The structurally related -lactones are more reactive. The copper-
catalyzed nucleophilic addition of Grignard reagent to lactone 142 occurred stereoselectively
with inversion of configuration <2002JOC4680>.
O PhLi OH
Pri
Ph BF3.Et2O Ph Ph
OH HO Pri
136 97% 137
Li powder PhCHO OH OH
+
Li
Ph Ph
O OLi OH OH
139 138 140 (46%) 141 (31%)
Ph
O
O CuBr HO2C
+ Ph MgBr Ph
TMSCl
Ph
142 94%
Scheme 25
1.05.1.4 Cyclopropanation of Carbonyl and Carboxyl Compounds

Recently, several methods have been developed for the synthesis of cyclopropanes starting from
carbonyl or carboxyl compounds. For a review on these reactions see <2000CRV2789>.
Titanium-mediated reaction of Grignard reagents such as ethylmagnesium bromide with ester
143 leads to cyclopropanol 144 (Kulinkovich reaction, Scheme 26) <1999SL1999>. The same
reactions could be carried out with amides. In this case, cyclopropyl amine 146 was readily
available from the corresponding formamide 145 <1996AG(E)413>. When less reactive Grignard
reagents such as cyclohexylmagnesium bromide are used, esters can react with more reactive
terminal olefins such as 147 to produce trisubstituted cyclopropanols <1996JA4198>. The same
reaction was also carried out with amides <2002CEJ3789>. Due to this reactivity, intramolecular
reactions can be carried out and the ester 148 was transformed to the tetracyclic indole derivative
149 <1997JA6984>. As in the case of the intermolecular version, the same reaction can also be
carried out with amides <1997JOC1584>.
O Ti(OPri) 4 O
CO2Me
P P OH
PriO EtMgBr PriO
OPri OPri
143 67% 144
O
Ti(OPri)4
N N
EtMgBr
76%
145 146
HO
CO2Me + Ti(OPri)
4
OTIPS
MgBr OTIPS
147
65%
Ti(OPri4) OH
CO2Me
N
PriMgBr N
148 94% 149
Scheme 26
Cyclopropanations have also been carried out in a zirconium-mediated way. A large variety of
ketones, aldehydes, especially ,-unsaturated ketones such as 150, can be transformed into
cyclopropane derivatives such as 151 (Equation (10)) <2000EJO3713>. The method was parti-
cularly efficient when the work-up was performed with Lewis acids such as TiCl4 or BF3OEt2.
For various reviews on such reactions as well as on other applications of titanium and zirconium
in organic synthesis, see <B2002MI011>.
H i. Cp 2ZrCl2 H
H H
EtMgBr ð10Þ
H H ii. TiCl 4 H H
O 90%
150 151
1.05.2 SUBSTITUTION OF SULFUR FUNCTIONS
1.05.2.1 Radical Reactions

As mentioned in Section 1.05.1.1, radical reactions became particularly interesting in organic
synthesis <B2001MI001, B2001MI002>. Recently xanthates were applied to the synthesis of
many different structures. In this context a principal mechanistic question emerged as the addition
of radicals to the thiocarbonyl function leads to the radical species 152 (Scheme 27). The radical
X
S
R + R'
X path a S O
S S
X + R R' R R'
S O S O
X
152 S
path b R +
R'
S O
Scheme 27
152 can fragment either by CO bond cleavage via path ‘‘a’’ or by CS bond cleavage via path
‘‘b.’’ The resulting carbon-centered radicals R0 or R can react with unsaturated molecules in order

to generate CC bonds. The conditions for path ‘‘a’’ or path ‘‘b’’ have been discussed in a review
<1997AG(E)673> and some examples of reactions via path ‘‘a’’ are discussed in Section 1.05.1.1
(Scheme 1). Many reactions involving path ‘‘b’’ have been recently published.
Xanthates have been added to a variety of olefins. The method tolerates many functional
groups, even those that might react under radical conditions. The benzotriazole derivative 154
was obtained in good yields when 153 was heated in the presence of N-phenylmaleimide and
when lauryl peroxide was used as a radical initiator (Equation (11)) <2001H301>. For similar
examples with tetrazole or triazole derivatives, see <1998TL19, 2001CC2618, 2002OL4345>.
Fluoroalkylation of olefins leading to products such as 156 was carried out in the same way
(Equation (12)) <2001OL1069>. In this case, the trifluoromethylxanthate 155 was used. High
yields were also obtained for the synthesis of boronates 157 (Scheme 28) <2001CC2618>.
The radical reaction could also be initiated by light instead of peroxides as shown for the
preparation of 158 <2000TL2979>. In these reactions the xanthate function is present in the
final products which can be interesting for further transformation. However, for many applica-
tions it is helpful when this substituent is removed in the same operation. This can be achieved
when the reaction is carried out with an excess of tin hydride reagent. Recently, a procedure to
avoid tin hydrides was developed using isopropanol as reductant (see also Scheme 29)
<1996TL5877>.
EtO
N S
Lauryl N S
N + peroxide N O
N O O ð11Þ
S OEt N N
ClCH2CH2Cl/∆
Ph N
153 S 65% 154 Ph
O
Lauryl SCSOR
F3C S OR
+ ( )8 OAc
peroxide F3C
( )8 OAc ð12Þ
S R = CH2CH2Ph
155 84% 156
O O
Lauryl SCSOEt
O O peroxide
+ B O
S S 94% B
157 O
OEt
EtOOC COOEt
hν (visible) O O
S OEt +
O O 44% EtOOC
SCSOEt
S
COOEt
158
Scheme 28
The intramolecular version of the reaction was successfully applied to the synthesis of nitrogen-
containing heterocycles. An example is shown in Scheme 29 <2001OL3125>. When the lauryl
peroxide was used in substoichiometric amounts, product 160 was obtained from 159, resulting
from an intramolecular radical addition with the olefinic double bond and a xanthate transfer.
Furthermore, product 161, resulting from a radical addition to the indole system, was isolated. In
the presence of isopropanol and an excess of peroxide, the desulfurized product 162 was obtained
together with 161. The reaction was more selective when the catechol derivative 163 was
0.2 equiv. Lauryl

N O N O
N peroxide N + N
H H H N
SCSOEt H O
H
R
159 160 R = SCSOEt (46%) 161 (22%)
1.2 equiv. Lauryl

peroxide
159 162 R=H (54%) 161 (24%)
2-Propanol
MeO MeO
MeO
N O 0.2 equiv. Lauryl N O
MeO peroxide MeO + N
H MeO
SCSOEt O
H
SCSOEt
163 (75%) (5%)
O O
Di-t-butyl
peroxide
NH NH
(1 equiv.)
I O I O
65%
SCSOEt
164 165
Scheme 29
transformed. Even if a radical attack at a benzene moiety is less favored, the absence of a competing
olefinic double bond as in 164 led to the cyclized product 165 (Scheme 29) <2002CC2306>.
Using photochemical or peroxide activation, an intermolecular tandem addition–cyclization
process could be carried out (Scheme 30) <1998SL1435>. Such transformations were also
performed in two steps <1997TL1759, 2000AG(E)731, 2002OL4345>.
S
OAc
Dilauryl OAc EtOSCS OAc
S OEt peroxide
+
COOEt or hν 72–76%
COOEt COOEt
Scheme 30
Various other sulfur-bearing groups have been used in radical reactions. The thioacetal 166
cyclized when heated with Bu3SnH/AIBN (Equation (13)) <1998JCS(P1)1763>. Only a small
amount of side product was isolated. The aryl sulfide group, as well as the corresponding sulfone,
has been used as leaving groups in intermolecular reactions of glucosyl derivatives such as 167
(Equation (14)) <1996JOC7463>. The radical generated from 167 attacks the olefin at the less
sterically hindered position, and after a -elimination of a PhS or a PhSO2 radical 168 was
isolated in high yields. For an intramolecular reaction of this type, see <2003SL1058>.
-Elimination of sulfone groups at vinyl positions can also occur after radical addition as
shown in the transformation of 169 to 170 and in the transformation of 171 to 172 (Scheme 31)
<1997JA4123>. For similar reactions, see <1999AG(E)1943>.
SPh SPh
O PhS O
O
PhS
H N
N Bu3SnH N ð13Þ
+
AIBN H
166 (52%) (13%)
Br OAc
O Bu3SnSnBu3 O
HO + AcO X HO
O OMe hν ð14Þ
O OMe
X = SPh 90%
167 168
X = SO2Ph 84%
F3CO2S OCOOEt AIBN O OCOOEt

+
Ph O ∆
97% Ph
169 170 16/1 (Z) /(E )
O O
AIBN
F3CO2S N + N
O ∆ O
Ph 82% Ph
171 172 100/1 (Z) / (E)
Scheme 31
As shown in Section 1.05.1.1, thiocarbonylimidazole derivatives are suitable precursors for

radical intermediates which can add to olefinic double bonds. In some intramolecular reactions
and when the hydrogen donor (tin derivatives) is used in large excess (5 equiv.), a CC bond is
generated and the thiocarbonyl sulfur group is eliminated (Scheme 32) <2003JA1492>.
N
N
N ButMe2SiO
Ph3SnH
(5 equiv.) O N
O S OEt
benzene H H
O COOEt
88%
OSiMe2But
N N N
S ButMe2SiO
O COOBut O N N
Ph3SnH
ButMe2SiO
C6H6, 80 °C COOBut
O
O O 87% O
Scheme 32
1.05.2.2 Ring Constructions

Sulfur compounds such as thienosultine 173 are frequently used for the synthesis of six-membered
rings such as 174 (Scheme 33) <2002JOC9267>. In these cases, biradical intermediates such as
175 are formed and trapped by alkenes or alkynes. For similar examples, see <1995T129>. In
the case of benzenoid analogs, the biradical intemediates possess a higher singlet character
and therefore the character of a quinodimethane <1997ACR238>. For a review on o-quinodi-
methanes, see <1999CRV3199>.
O O
O ∆
S + N Ph S N Ph + S SO2
S
O
O O
173 174 (91%) (6%)
175
Scheme 33
Sulfur reagents have been used for the synthesis of cyclopropane derivatives. Most frequently,
sulfur ylides such as 176 derived from sulfonium salts are used (Scheme 34) <1996TL6307>. Only
one diastereoisomer 177 was isolated from the reaction of 176 with ,-unsaturated nitro
compound 178. Similarly, sulfoxonium ylides such as 179 were used for asymmetric cyclopropa-
nation <1995CC141>. For a review on asymmetric ylide reactions, see <1997CRV2341>. In a
titanium-mediated reaction the thioacetal 180 was used to transform the terminal olefin 181 into
cyclopropane 182 (Equation (15)) <2002TL5641>. For further examples, see <1997JOC3678>.
O –78 °C O
O + Ph2S C(CH3)2 O
NO2 89% NO2
178 176 177
R R
Ph O O Ph O
SMe2 –78 °C CO2Me
N + N
H2 C
68–83%
CO2Me
O O
179
Scheme 34
SPh
Mg, Cp2TiCl2 Ph
SPh + Ph ð15Þ
P(OEt)3
180 181 77% 182 Ratio of isomers: 57:43
1.05.2.3 Sulfur Leaving Groups
1.05.2.3.1 Sulfides as leaving groups

The thio-Claisen rearrangement has been successfully performed with allyl vinyl sulfides
(Scheme 35) <1999JOC3585>. When 183 was treated under basic reaction conditions in the
presence of allyl halides such as 184, the allyl vinyl thioether 185 was formed as an intermediate
Ph
Ph O
O N
N + TBDPSO LDA
Br S
S 96%
183 184 185
OTBDPS
OTBDPS
Ph Ph
O O
N N
+
S S
11: 1
186 187 OTBDPS
Scheme 35
which immediately rearranged to give the major product 186. A further isomer was also isolated
in small quantities. It was characterized as the exo-isomer 187 and not as a diastereomer resulting
from a different stereochemical position of the (CH2OTBDPS) group. For investigations on metal
catalysis for this reaction, see <2000TL1363>. In a copper- and palladium-mediated cross-
coupling reaction, the heteroaryl thioether 188 reacted with stannyl aromatic compound 189 or
with the corresponding vinyl derivatives leading in high yield to the bis-aryl product 190
(Equation (16)) <2003OL803>. For further examples of this reaction, see <2003OL801>.
N CuBr.Me2S N
+
Pd(PPh3)4 N O ð16Þ
N SMe O SnBu3
189 95% 190

188
1.05.2.3.2 Sulfones and sulfonates as leaving groups

Alkynyl-zinc reagents have been added to functionalized compounds. When 191 was treated with
phenylacetylenyl zinc bromide 192, a displacement of a sulfone group occurred (Equation (17))
<2003JOC4392>. In an asymmetric rhodium-catalyzed reaction with the phenyltitanium reagents
194, the vinyl sulfone 193 was transformed into the corresponding allylaryl coupling product 195
(Equation (18)) <2003JA2872>. Aryl sulfonates have frequently been used as leaving groups in
nucleophilic substitution or in cross-couplings (see, for instance, Equation (3)). Recently, in a
nickel-catalyzed reaction, the neopentyl aryl sulfonates 196 were coupled with the arylmagnesium
bromide 197 (Equation (19)) <2003JOC3017>. Due to steric hindrance, the CS bond was
cleaved and not the CO bond of the neopentyl substituent.
THF
Ph ZnBr
MeO O SO2Ph 64% MeO O
ð17Þ
191 192 Ph
[Rh(OH)(S-binap)]2
+ PhTi(OPri)3
94% Ph ð18Þ
SO2Ph
193 194 195 ee > 99%
O O
S NiCl2(dppf)
O + BrMg
THF ð19Þ
87%
196 197
1.05.3 SUBSTITUTION OF SELENIUM AND TELLURIUM
1.05.3.1 Radical Reactions of Selenides

In the field of radical reactions, numerous applications of selenides have recently been described.
The glycosyl radical which was generated from the corresponding selenium derivative 198
has been added to activated alkenes such as the acrylate 199 (Scheme 36) <2002OL4623>.
Only the -isomer 200 was obtained. A radical intermolecular addition–cyclization has been
carried out with the selenoester 201 and a variety of electron-deficient alkenes such as 202
<2001JOC7547>.
OAc OAc
AcO O CO2But Bun3SnH AcO O
SePh +
AcO AIBN AcO
AcHN 76% AcHN CO2But
198 199 200
O CO2Me
SePh
CO2Me Bun6Sn2, hν
+ N
53% H
N
O
201 202
Scheme 36
Many intramolecular radical reactions with selenium derivatives have been performed. In the
case of the cyclization of the allylamine derivative 203, the ratio of the cis/trans isomers 204 and
205 depends significantly on the nitrogen atom substituents (Scheme 37) <2000OL1589>. Two
different kinds of products could be isolated from the reaction of the selenoesters 206 and 207
<2002JOC2323>. For compound 206, a decarbonylation takes place before the cyclization
leading to 208 and 209. This reaction was not observed in the transformation of 207 since 210
and 211 were isolated. For a review on reactions of radicals with carbon monoxide and on
decarbonylation of acyl radicals, see <1996AG(E)1050>. Product 213 was obtained in high
enantioselectivity from the cyclization of the seleno derivative 212 possessing a vinyl sulfoxide
which induced chirality and after cyclization, this auxiliary is eliminated as a sulfinyl radical
<1998AG(E)2116>. It is particularly interesting to note that in the absence of any Lewis acid the
S-enantiomer is formed while in the presence of the sterically hindered Lewis acid such as 214 the
R-enantiomer is obtained.
This reaction was also applied to combinatorial chemistry and, especially on solid phase,
to synthesize indoline derivatives (Scheme 38) <2003BMC465>. The indoline fragment 215
was linked via a selenoether function to the polymer. Various ,-unsaturated acids such as
216 were added to the amino function of 215. In a radical reaction, the -bond between selenium
and the methylene group of the indolamide moiety 217 was cleaved and the resulting carbon
radical attacked the double bond of the ,-unsaturated amide moiety. The radical cleavage
of the CSe bond induced the radical cyclization as the key step of the synthesis and the
separation of the product from the resin. Similar reactions were carried out with N-allylindole
derivatives.
1.05.3.2 Reactions with Tellurium Compounds

For a review on organic reactions with tellurium compounds, see <1997S373>. exo-Cyclization
was observed when the tellurium compound 219 was treated with Bu3SnSnBu3 (Equation (20))
<1995CC2515>. In this case, the TeAr group was transferred onto the terminal carbon of the
cyclopentylmethyl radical. In a copper-mediated 1,4-addition, the vinyl telluride 220 reacted with
the ,-unsaturated ketone 221 (Equation (21)) <1996JOC4975>. Only traces of 3-methylcyclo-
hexanone 222 were detected. Copper-mediated addition of vinyl tellurides to epoxides can also be
PhSe
nBu3SnH
N N + N
R AIBN, hν
R R
203 204 205
R=H 86% 1:4

R = P(O)Ph2 85% 20:1
Bn SeMe H Bn Bn
N H
N N
O TTMSS
+
AIBN
H H
CN CN
CN
208 (27%) 209 (42%)
206
O
Bn Bn
Bn H N
N SeMe H N
TTMSS
+
AIBN
H O H O
CN CN CN
207 210 (51%) 211 (20%)
PhSe E E
E E
But But
Et3B/O2
O Al O
O Bu3SnH
S
E: CO2Me OMe But But
212 213 214
In the absence of 214 : 93%, ee > 96 (S)

In the presence of 214 : 52%, ee 92 (R)
Scheme 37
Se CO2H Se H
DCC Bun3SnH
+ H
N DMAP N AIBN N
H
215 216 O O H
217 218 36% (overall)
Scheme 38
performed and a copper-mediated substitution at a vicinal position of the ,-unsaturated ketone

223 was carried out (Equation (22)) <1995SL180>. A copper- and palladium-catalyzed coupling
between the organotellurium dichloride 224 was carried out with the alkyne 225 (Equation (23))
<2003TL1779>. An interesting chemoselectivity was observed with the seleno–telluro derivative
226, and in this case only the tellurium function reacts (Equation (24)) <2003SL579>. Palladium-
catalyzed cross-coupling reactions were also performed with alkyl tellurofuran derivatives
<2001TL8927, 2003TL1387>.
HO
TePh Bu3SnSnBu3
TePh ð20Þ
OH hν
219 68% 1.3/1 cis/trans
O O O
+ Me2Cu(CN)Li2 Ph ð21Þ
Ph TeBun
90%
220 221 222 traces
O O
PhTe + (PhCH=CH)2Cu(CN)(ZnCl)2 THF ð22Þ
CF3 Ph CF3
88%
223
O PdCl2/CuI Ph O
+ ð23Þ
Ph TeCl2 Bun N MeOH N
224 225 87%
C5H11 C5H11
PdCl2/CuI
+ OH
MeOH MeSe ð24Þ
MeSe TeBun
226 77% OH
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Biographical sketch
Norbert Hoffmann studied chemistry at the RWTH Aachen (Germany)

and received his Ph.D. degree in 1992 under the supervision of Hans-
Dieter Scharf for research on asymmetric photochemical reactions and
their application to natural product synthesis. After one year of post-
doctoral research at the same university mainly in the field of asym-
metric radical reactions, he obtained a research position at the CNRS
(Chargé de Recherche) in Reims (France). In 2000, he obtained his
habilitation at the Université de Reims Champagne-Ardenne in organic
chemistry. In 2004 he was appointed as Research Director at the CNRS.
Actually, his main research interests concern photoinduced radical reac-
tions and their application to asymmetric synthesis. Furthermore, photo-
chemical cycloadditions of aromatic compounds are studied applying
special reaction conditions such as acidic reaction media or supramole-
cular structures.
1.06
by Substitution: Substitution of
Carbon–Nitrogen, –Phosphorus,
–Arsenic, –Antimony, –Boron,
–Silicon, –Germanium, and
–Metal Functions
C. KOUKLOVSKY
Université de Paris-Sud, Orsay, France
1.06.1 SUBSTITUTION OF NITROGEN FUNCTIONS 232

1.06.1.1 Nitro Compounds 232
1.06.1.2 Quaternary Ammonium Salts 232
1.06.1.3 Tertiary Amines 234
1.06.1.4 Secondary Amines 237
1.06.1.5 Diazotization of Primary Amines 237
1.06.1.6 Functionalized Benzotriazoles 237
1.06.1.7 Azides 241
1.06.1.8 Ring Opening of Aziridines 242
1.06.1.9 Radical-mediated Processes 246
1.06.1.10 Rearrangements 247
1.06.1.10.1 The Stevens rearrangement 247
1.06.1.10.2 Rearrangements of aziridines 251
1.06.1.11 Electrophilic Substitutions 252
1.06.2 SUBSTITUTION OF PHOSPHORUS, ARSENIC, AND ANTIMONY FUNCTIONS 252
1.06.2.1 Substitution of Phosphorus Functions 252
1.06.2.2 Substitution of Arsenic Functions 253
1.06.2.3 Substitution of Antimony Functions 255
1.06.3 SUBSTITUTION OF BORON, SILICON, AND GERMANIUM FUNCTIONS 256
1.06.3.1 Substitution of Boron Functions 256
1.06.3.1.1 Conjugate addition to ,-unsaturated ketones and aldehydes 256
1.06.3.1.2 Conjugate addition to , -unsaturated carboxylic acid derivatives 257
1.06.3.1.3 Conjugate addition to vinyl- and alkynylepoxides 257
1.06.3.1.4 Aromatic and alkenic substitution 258
1.06.3.1.5 Aliphatic substitution 262
1.06.3.2 Substitution of Silicon Functions 263
1.06.3.2.1 Alkylation 263
1.06.3.2.2 Hydroxylation/aldol reactions 266
1.06.3.2.3 Acylation 268
1.06.3.2.4 1,3-Dipole formation 268
231
232 One or More CC Bond(s) Formed by Substitution
1.06.3.2.5 Free-radical-mediated reactions 277

1.06.3.3 Substitution of Germanium Functions 277
1.06.4 SUBSTITUTION OF METAL FUNCTIONS 278
1.06.1 SUBSTITUTION OF NITROGEN FUNCTIONS
1.06.1.1 Nitro Compounds

Aliphatic nitro compounds are useful synthetic intermediates which may be transformed into
various other functions <B-1996MI106-2>. The substitution reaction of nitro group into tertiary
nitroalkanes by soft nucleophiles leads to the formation of a new carbon–carbon bond. Attempts
to achieve this substitution with hard nucleophiles such as lithium-dialkyl cuprates resulted in the
formation of alcohols as major products <1998MI537>.
The palladium-catalyzed substitution of primary, secondary, and tertiary allylic nitro com-
pounds was developed as an equivalent to the known Tsuji–Trost reaction (Equation (1)).
NO2 Nu, Pd(0) Nu

R R R R ð1Þ
R: H, alkyl, CO2Et Nu: CH(CO 2Me)2, CH(CN)CO2Me
In a recent study connected with carbapenem synthesis, allylic substitution reactions of ethyl
2-nitromethyl 1-cyclopentenecarboxylate with various soft nucleophiles (including carbon nucleo-
philes) were studied <1999OL1783>. Although the reaction with Meldrums’ acid gave cleanly the
substitution product, reaction with the malonitrile led to double substitution (Scheme 1).
Pd(OAc)2 (5 mol.%),
Me O
P(OEt)3 (15 mol.%),
NO2 O O O O
CH3NO2 / DMPU, rt, 2 h
+
CO2Et O O 74% Me O
CO2Et
Pd(OAc)2 (5 mol.%),
P(OEt)3 (15 mol.%), CN
NO2 CH3NO2 / DMPU, rt, 2 h NC
CO2Et
+ NC CN
CO2Et 73%
CO2Et
Scheme 1
Electrophilic substitution of arenes by tertiary allylic, benzylic, or tertiary nitroalkenes proceeds

under Lewis acid catalysis, generally with tin tetrachloride. This reaction proceeds through an SN1
mechanism with a carbocation intermediate. In an analogous reaction, allylation of tertiary-
benzylic nitroalkanes occurs by treatment with allyltrimethylsilane and tin tetrachloride.
1.06.1.2 Quaternary Ammonium Salts

Nucleophilic substitution of quaternary ammonium salts is rather a common reaction in synth-
esis, and has been especially applied to allylic and benzylic substrates. With allylic compounds,
nucleophilic substitution may be catalyzed by palladium complexes, as a variant of the Tsuji–
Trost reaction. Thus, treatment of various chiral allylic ammonium salts with soft and hard
nucleophiles was studied <1995TA389>. With soft nucleophiles, the reaction proved to be
One or More CC Bond(s) Formed by Substitution 233
solvent-dependent, the best results being obtained in acetonitrile. Although the reaction with
phenylzinc chloride was not regioselective, complete stereoselectivity was observed (Equation (2)).
Me MeMe PhZnCl, Pd(PPh3)4, THF Ph Ph

N Me + ð2Þ
I
30% 30%
Nucleophilic substitution of benzylic quaternary ammonium salts is a useful reaction, especially

when difficulties occur in the preparation of the corresponding benzylic halides. A typical reaction
is the Kametani gramine alkylation, which allows the introduction of 3-indolylmethyl moiety
(Scheme 2).
NMe2 NMe3 Nu
MeX Nu
N N N
H H H
Gramine
Scheme 2
This reaction was recently applied to the synthesis of helical peptidomimetics <1994BMCL2825>
and the preparation of a highly substituted thiazolidine derivative <2001JOC839> (Equation (3)).
In the latter case, the alkylation with gramine methyl sulfate was stereoselective. Asymmetric
alkylation of a chiral glycine equivalent with a quaternary guanine salt has been developed as a
stereoselective entry to tryptophan analogs <1999SL453>.
Me S
N
Me S N
NMe3 OSO3Me LDA, Li2CuCl4
N THF, –78 °C N
N O
+
N N 65% O
O
H
O
N
H
5 /1 cis / trans
ð3Þ
Another application of gramine alkylation is the ring opening of a cyclic quaternary ammo-
nium salt with a cyanide ion or cyanoacetic acid <1995TL3511> in the synthesis of macrocyclic
indole derivatives (Scheme 3).
CO2Me
NC
NC CO2Me Bn CN
NaH, THF N KCN, THF/H2O
R
Bn
Bn R = Bn, 70% N N N
N N R = Me, 90%
H H R
H R R = Bn, 92%
Scheme 3
Other benzylic substitutions with quaternary ammonium salts were used to prepare a naturally
occurring 2,2-dimethyl-2H-1-benzopyran derivative <2001T5335> (Equation (4)), for the intro-
duction of carborane to pyrroles <2001TL7759>, and for the synthesis of fused oligoporphyrins
<2000JA11295>.
OMe OMe
(MeO2C)2CH, K2CO3, DMF
MeO2C
I Me3N ð4Þ
75% MeO2C
O O
Electroreductive coupling of benzylic compounds, including benzylic quaternary ammonium

salts, with anhydrides or carbonyl compounds provides access to benzylic ketones or alcohols
(Equation (5)) <1996NJC375>. The influence of nitrogen substituents and of the anion was
studied, showing that iodides gave the best yields, with a phenyl substituent on nitrogen being
beneficial. The reaction was also applied to the coupling of heterocyclic compounds.
Acetone/DMF (50/50),
Me Mg anode, Ni cathode, 2 A.dm–2
N Br OH ð5Þ
Me
Me 40% MeO
MeO
Ammonium ylides, which are obtained by treatment of ammonium salts substituted in the
-position with electron-withdrawing groups, react with Michael acceptors to give cyclopropanes
or with carbonyl compounds to give epoxides. Thus, generation of ammonium ylides from
cyanomethyl trimethylammonium iodide and reaction with electron-deficient alkenes gave the
corresponding cyclopropanes in good yields as a mixture of stereoisomers <1999SL1085>
(Scheme 4). In a more recent study, ammonium ylides were generated in situ from -chlori-
nated carbonyl compounds and a tertiary amine such as 1,4-diazabicyclo[2.2.2]octane (DABCO).
Upon treatment with a base and reaction with various Michael acceptors, cyclopropanes were
obtained in good yields and with excellent stereoselectivity <2003AG(E)828>. The use of a chiral
ammonium salt derived from cinchonine gave cyclopropanes in ee’s up to 94% (Equation (6)).
NaOH, H2O/CH2Cl2
NMe3 NMe3 Z NMe3 R
or K2CO3, CH2Cl2 Z
R R R
Z 46–96% NC
CN CN CN
R = Ph, Z = CN, CO2Me, CO2But, CHO, COMe, SO2Ph
Scheme 4
O OMe
NaOH, MeCN, 80 °C O
+ N + CO2But ð6Þ
Ph CO2But
57% Ph
Br
OMe 94% ee
N
The preparation of cyclopropanes from ammonium ylides linked on a solid support was
attempted <1997TL7951>. Wang resin-bound pyridinium ylides were generated by treatment
with a tertiary amine and reacted with electron-deficient alkenes to give the corresponding
cyclopropyl derivatives, which were isolated after resin cleavage.
1.06.1.3 Tertiary Amines

Mannich reactions of enolates with iminium ions derived from N,N,N0 ,N0 -tetramethyldiamino-
methane are the most common examples of substitution of a tertiary amine. Activation with a
strong electrophile such as trifluoromethanesulfonic anhydride leads to an iminium ion, which
can react with nucleophiles. In a recent study, ,-unsaturated aminals after activation were
treated with various Grignard reagents to give polyfunctional allylic or propargylic amines
<2002S2143> and no conjugate addition was observed in these reactions (Scheme 5). In an
analogous reaction, 1,1-bis(dimethylamino)-2,2,2-trifluoroethane was treated with a variety of

carbon nucleophiles, e.g., alkynes, alkenes, or trimethylsilyl cyanide, to give trifluoromethylated
alkynyl or alkenylamines in good yields <2000JOC2134>.
MeO MgBr
NMe2 Me Me NMe2
TfOH, THF, –65 °C N THF/NMP, –65 °C
NMe2 OTf
67%
Ph Ph
Ph OMe
Scheme 5
Substitution of nitrogen functions at the anomeric position of pyranoses has been recently
described. Reaction of a cyclic urea with allyltrimethylsilane was achieved in the presence of
Lewis acid to give the C-glycosidic product <2003SL791>. The best yield and selectivity were
obtained using tin tetrabromide (Equation (7)).
Me
O
N
SnBr4, CH2Cl2, –78 °C to rt O
O N Me + Me Si
3
77%
ð7Þ
Ph Me
Me
80/20 dr
Substitution reactions of tertiary amines with hard or soft nucleophiles occurs easily with allylic
or benzylic amines. The gramine alkylation may be performed using gramine base instead of a
quaternary ammonium salt. In a recent example, treatment of 4-substituted gramine with for-
mamidomalonic acid ester in the presence of sodium hydroxide led to the formation of new
tryptophan derivatives <1995TL1425> (Equation (8)).
Me Me CO2Et
NMe2 EtO2C CO2Et Cat. NaOH, toluene CO2Et
+ NHCHO ð8Þ
N NHCHO 83% N
H H
3-Alkyl-2-exo-methylene ketones may be prepared by substitution of ,-unsaturated 2-alkyl-

aminomethyl ketones with carbon nucleophiles (Equation (9)). The advantages of using the
dialkylamino function as the leaving group are the easier preparation and greater stability of
the starting 3-dialkylaminoketone. In a project related to the synthesis of prostaglandin analogs,
reaction of a vinyl organolithium with a chiral 2-diethylaminomethyl cyclopentenone gave the
exo-methylene derivative with excellent stereoselectivity. Further conjugate addition to the exo-
methylene ketone provided new PGE2 analogs <2002BMC1093> (Scheme 6).
O O
–
Nu
R1 NR2 R1 ð9Þ
R2 R2 Nu
The same substitution reaction was employed for the coupling of pyrones with aryl ketones
<2000H2421> (Scheme 7). When the reaction was performed in the presence of a base, intra-
molecular conjugate addition of the hydroxyl group occurred.
Transition metal-catalyzed allylic substitution of allylic tertiary amines with hard and soft
nucleophiles has been recently studied. Since amines are not as good leaving groups as the
corresponding acetates or carbonates, highly reactive catalysts are necessary. Coupling of allyl
diethyl amine with soft nucleophiles such as malonates or acetoacetates proceeded in the presence
of the Ni(dppb)2 [dppb: 1,4-bis(diphenylphosphino)butane], which proved to be more efficient
than the corresponding palladium complex, although reaction with acetyl acetone showed severe
decrease of catalytic activity <1997CC1393> (Equation (10)) and double allylation was also
observed.
O
O I ButLi, 2-thienyl cyano-
NEt2 OTBS cuprate, ether, –78 °C
+ C3H7 OTBS
TBSO
C3H7
TBSO
CO2Me CO2Me
BrZn O
CuCN, LiCl, THF, –78 °C
61% OTBS
TBSO
C3H7
Scheme 6
OH OMe OH OMe O OMe

DMF Et3N
O + Me2N O O
48% 95%
O O O O O O
Scheme 7
Ni(COD)2/dppb
Bu4NClO4, DMF O O O O
O O 50 °C Me OMe +
NEt2 + Me OMe ð10Þ
Me OMe 95%
88 12
Nickel complexes were also used for the coupling of tertiary allylic amines with hard nucleo-
philes such as boronic acids <1995JCS(P1)2083> (Equation (11)). The regioselectivity was however
low, best results being obtained using the BINAPO ligand (BINAPO: 1,10 -bis-diphenylphosphinyloxy-
2,20 -binaphthalene). The mechanism of this allylation involves coordination of boronic acid to the
metal, followed by intramolecular alkyl or aryl group transfer. This study showed that amine
oxides were also good leaving groups for the substitution reaction.
Ni(acac)2 (10%)
BINAPO (20%)
PhMe, reflux Ph
+ PhB(OH)2 +
N 78% Ph
2.7/1 ð11Þ
OPPh2
BINAPO:
OPPh2
The first direct alkylation of enolates and related compounds with trialkylamines was recently
disclosed: in the presence of a ruthenium catalyst, enolizable ketones were alkylated with various
trialkylamines in moderate-to-good yields, without any polyalkylation <2001AG(E)958>
(Scheme 8). The reaction is highly regioselective as alkylation is occurring only at the less
hindered position. Imines were also efficient for alkyl group transfer.
O Bu3N (1 equiv.), RuCl3.nH2O (5 mol.%) O

PPh3 (15 mol.%), 1,4-dioxane, 180 °C Bu
Ph Me Ph
61%
Bu3N (1 equiv.), RuCl3·nH2O (5 mol.%)

O PPh3 (15 mol.%), 1,4-dioxane, 180 °C O
Bu
Ph Me 70% Ph
Scheme 8
1.06.1.4 Secondary Amines

The classical gramine alkylation of indole derivatives may also be accomplished using bulky
secondary amines instead of tertiary amines or quaternary ammonium salts (Equation (12)).
Substitution reaction with soft nucleophiles is achieved under basic conditions at a lower
temperature than for the tertiary amine. Despite its mild conditions, this reaction has encountered
little application in synthesis.
Nu
N –
Nu
H
ð12Þ
N
N H
H
1.06.1.5 Diazotization of Primary Amines

Diazotization of primary amines with nitrous acid gives diazonium salts, which react with various
nucleophiles with subsequent loss of nitrogen. Diazonium salts obtained from primary aliphatic
amines generally lose nitrogen to give carbocations which often rearrange. The diazotization
reaction of 9-aminomethyl-1-methyltriptycene has been shown to give predominantly a new cyclic
hydrocarbon derivative through insertion in the neighboring methyl group at C1; intermolecular
nucleophile trapping occurred only at the methyl at C1 position, proving the existence of an
internal hydride transfer. Further studies have been undertaken, showing the strong solvent
dependence on product distribution: protic solvents such as acetic acid favor formation of a
carbocation at C1 (Scheme 9). When an ethyl substituent is present at C1, products derived from
an elimination followed by a nucleophilic attack are predominant, because of the greater stability
of the secondary carbocation <2000CL454>.
1.06.1.6 Functionalized Benzotriazoles

The chemistry of functionalized 1-substituted benzotriazoles has been extensively studied in recent
years and comprehensively reviewed <1998CRV409, 2000PAC1597>. The benzotriazole group
may be considered as a stable, easy to handle, and recoverable pseudo-halogen group. Introduc-
tion of the benzotriazole function may be accomplished either by halide displacement, alkoxy
group displacement in acetals or ketals, by addition to carbon–heteroatom multiple bonds, or
through multiple-component synthesis (Equations (13)–(17)).
NaNO2, AcOH
+
9
1 Me
NH2
OAc
46% 34%
NaNO2, AcOH
+ +
Me Me
NH2 Me
Me Me OAc
Yield (%)
AcOH CHCl3
0 5
100 66
0 29
Scheme 9
R X + BtNa R Bt ð13Þ
RCOX + BtNa R-CO-Bt ð14Þ
R OR1 +
R Bt
Bt-H ð15Þ
R OR1 R OR1
Bt
X + Bt-H ð16Þ
XH
Bt
O + R-XH + Bt-H
XR
ð17Þ
N
R = H, alkyl, aryl; R1 = Me, Et, X = O, N, S Bt = N
N
Functionalized benzotriazoles may be used in a vast array of synthetic transformations, including

carbon–carbon bond formation. Recently, it was discovered that 1-acylbenzotriazoles were good
C-acylating reagents for ketone enolates, allowing the easy formation of -dicarbonyl compounds
<2000JOC3679> (Equation (18)). Acyl transfer was accomplished by treating the ketone
enolate (obtained by treatment of the ketone with lithium diisopropylamide (LDA) with the
acylbenzotriazole reagent; the reaction was selective as only C-acylation products were obtained.
O O O
O LDA, THF, –78 °C
R + R R2
R2 Bt 63–93% ð18Þ
R1 R1
R, R1 = alkyl, aryl; R2 = Me, Ph, t-amyl
Reaction of 1-benzotriazolyl alkyl ethers (obtained from acetals or ketals) with phenyl vinyl
ether provides another access to carbon–carbon bond formation <1998JOC1473>. The newly
formed 1-benzotriazolyl ether may react after deprotonation with a variety of electrophiles, to
give, after hydrolysis, polyfunctionalized ketones (Scheme 10).
OPh
OEt 70 °C Ph O
OEt Ph Bt
Ph Bt
Ph OEt
Bt
Ph E E Ph Bt
H3O Ph Bt LDA, E
OEt O OEt OPh OEt OPh
E = aldehyde, ketone, imine, silyl chloride
Scheme 10
Transition metal-catalyzed nucleophilic substitution of N-allylbenzotriazoles is a potentially

advantageous reaction since allylbenzotriazoles are easily prepared and transformed into -allyl
palladium complexes. In contrast with allylic amines, the use of more reactive nickel complexes is
not required and the nucleophilic substitution is highly regioselective (Scheme 11). This metho-
dology has been applied to a new synthesis of ,-unsaturated ketones by reaction of allylbenzo-
triazoles with enamines <1999JOC7625> (Scheme 12). Reaction was performed using a Pd(0)
complex with zinc bromide as additive. The ketones were obtained in a highly stereoselective
fashion, the (E)-isomer being predominant.
i. Base, R1X
ii. Base, R2X Bt Nu, Pd(0) R1
Bt
R 1 R2 Nu R2
Scheme 11
Pd(OAc)2, PPh3 O
Bt N H2O
N ZnBr2, benzene
+
Me Et i-C5H11 83% Et i-C5H11
i-C5H11 Et
Me Me
Scheme 12
One of the most important substitution reactions of benzotriazoles is the nucleophilic displace-
ment of BtCN type compounds with soft or hard nucleophiles (Equation (19)). The reaction
tolerates a wide variety of substituents on nitrogen, since amines, amides, or imines are suitable
substrates for the substitution reaction. Alkyl or aryl groups are introduced with Grignard
reagents, or better, organozinc compounds, whereas other nucleophiles such as cyanide, enolates,
or nitroalkanes are introduced via SN-type substitutions. Examples and applications may be
found in the review <1998CR409>. A recent representative example describes the synthesis of
hexahydropyrimidines and tetrahydroquinazolines <2002JOC3115> (Scheme 13). The hetero-
cyclic ring is prepared by a three-component synthesis with benzotriazole, formaldehyde, and a
1,3-diamine. Treatment with Grignard reagents allows the introduction of alkyl substituents on
nitrogen atoms.
Bt NR2 Nu Nu NR2
ð19Þ
R1 R1
HCHO, BtH i. PhCH2MgBr, THF

MeOH, H2O ii. CH2=CH-MgBr, THF
82% 61%
NH2 NH2 Bt N N Bt N N
Ph
Scheme 13
In an analogous strategy, condensation of a bis-aldehyde such as succinaldehyde with a diamine

and benzotriazole gives the hexahydro-1H-pyrrolo[1,2-a]imidazole ring system, which can be further
substituted by benzotriazole displacement <2000JOC3683> (Scheme 14). Reaction with Grignard
reagents allows the introduction of alkyl or aryl groups, whereas Lewis acid-mediated condensation
with silyl enol ethers gives ketones.
Me OSiMe3
Me OMe , BF3.Et2O MeMe

OHC CHO + BtH N N Ph N N Ph
NH2 Bt MeO
NH 82%
Ph 79%
O
Scheme 14
Asymmetric synthesis of 2,6-disubstituted piperidines using benzotriazole substitution was

recently accomplished as a modification of the classical method with chiral aminonitriles
<1998JOC6699>. Treatment of benzotriazole with glutaraldehyde and phenyl glycinol gave in
one step the chiral aminoalkyl benzotriazole (Scheme 15). Substitution with phenyl magnesium
bromide, followed by oxazolidine ring opening, gave, after hydrogenolysis of the chiral auxiliary,
the cis-disubstituted piperidine in an enantiomerically pure form.
Ph Ph H
Ph CHO CHO BtH PhMgBr Steps
OH + O O Ph N Me
Bt N Ph N
NH2 80% 85%
Scheme 15
Treatment of aminoalkyl benzotriazoles with a Lewis acid gives a planar iminium cation, which
may react with carbon nucleophiles such as alkenes, arenes, or silyl enol ethers <2000JOC3683>
(Scheme 16). These properties were applied to the synthesis of various heterocyclic systems such as
tetrahydroquinolines <2001TA2427> (Equation (20)), indolo-isoquinolines <2001JOC148>,
1,4-benzothiazepines (Equation (21)), or 1,4-benzoxazepines <2001JOC5590>. Addition of the
iminium cation to alkenes followed by intramolecular substitution onto an aromatic ring results in
an annulation reaction <2001JOC5595> (Equation (22)).
Ar NR2
ArH
R
TiCl4 or BF3.Et2O R1 R2
Bt NR2 NR2 R2
H NR2
R R
R1 R1 R
R2
OSiMe3 R2
R1 NR2
O R
Scheme 16
CO2Me AlCl3, CH2Cl2

CO2Me
reflux
N ð20Þ
H 72% N
H
Bt
O O
S N TiCl4 S N
Me Me ð21Þ
Bt 80%
OMe
OMe S
Ph, ZnBr2
S ð22Þ
72%
Bt
1.06.1.7 Azides
Substitution of alkyl azides with carbon nucleophiles is rather an uncommon reaction; however, it
was recently discovered that -azidoethers or -azidoamines react with Grignard reagents to give
ethers or amines in good yields. Thus, azidonation of an aryl dialkylamine gave an -azidoamine,
which reacted with phenylmagnesium bromide <1998S547> (Scheme 17).
N N N3 N Ph
TMSN3, PhI(OAc)2 PhMgBr, THF
95% 98%
Scheme 17
In contrast, the corresponding -azidoethers are less reactive toward substitution, and reaction
with Grignard compounds occurs only if toluene is used as solvent (Equation (23)). Under these
conditions, good yields of ethers are obtained <2002JCS(P1)509>.
N3 Ph
PhMgBr, toluene
OMe OMe ð23Þ
90%
1,2-Bis-azido-1-triisopropylsilyl ethers are prepared by bis-azidonation of triisopropylsilyl enol

ethers and undergo substitution of the azido function at the C1 position only (Equation (24)). The
overall sequence is highly stereoselective, giving cis-1,2 azidoethers <1995CC263>.
SnBu3,
TIPSO N3
N3 Me2AlCl, hexane, –70 °C TIPSO
ð24Þ
N3
71%
-Azidosilyl enol ethers, prepared by the azidonation of silyl enol ethers, undergo substitution
of the azido function by carbon nucleophiles, after treatment with tetrabutylammonium fluoride
<1998JA12486>. The reactive intermediate is believed to be an ,-unsaturated ketone, which
undergoes a conjugate addition (Scheme 18). Since intermediates need not to be isolated, the
overall process can be regarded as a -alkylation of ketones.
OSiMe3 O
OTIPS O
Bu4NF Ph O
68% Ph
N3
Scheme 18
1.06.1.8 Ring Opening of Aziridines

The synthesis and reactivity of aziridines have been the object of intense studies in recent years.
Carbon–carbon bond formation with aziridines as substrates has attracted much attention, with
the concomittant development of modern aziridination methods. As a consequence, many recent
reviews concerning the reactivity of aziridines toward carbon nucleophiles are available
<1994AG(E)599, 2000S1347, 2002CSR247>.
Reactivity of aziridines toward ring opening strongly depends on the nature of the nitrogen
substituent, simple N-alkyl aziridines being poorly reactive. Activation may be provided by
protonation, quaternarization with alkylating reagents or treatment with a Lewis acid. N-Benzyl-
trifluoromethyl aziridine was thus opened with various nucleophiles, including carbon nucleo-
philes, after treatment with trimethyloxonium tetrafluoroborate (Scheme 19). The intermediate
aziridinium ion was characterized by 19F NMR spectroscopy. The regioselectivity was in favor of
an attack at the less hindered position <1999JOC7323>.
Me3O , BF4,
Bn Bn Me Bn Me
CH2Cl2 N , BF4 NuM, 0 °C N
N
Nu
CF3 CF3 CF3
NuM = NaCH(CO2Et)2: 92%

NuM = LiCH2COPh: 56%
Scheme 19
In a multicomponent synthesis of unsymmetrical ketones, N-benzyl-2-methylene aziridines were

used as building blocks for alkyl group transfer. These highly reactive substrates were treated first
with a Grignard reagent in the presence of copper iodide to give a metallo-enamine in a highly
regioselective fashion. This metallo-enamine could be further alkylated with electrophiles to give
the corresponding ketone after aqueous treatment <2002JOC935>. This multicomponent ketone
synthesis tolerates a wide variety of nucleophiles and electrophiles; substitution on the exocyclic
double bond in the starting 2-methylene aziridine is also allowed (Scheme 20).
Me
i. CH2=CH-CH2-Br
Me Ph BrMg O
N Ph ii. H2O
C8H17MgBr, CuI
N
80% C8H17
C8H17
Scheme 20
Substitution of a nitrogen atom by an electron-withdrawing group strongly increases the reactivity

of the aziridine ring toward nucleophiles. N-Sulfonyl groups are widely used because of their stability,
ease of introduction, crystallinity, and absence of a competing reaction with nucleophiles, the only
drawback being the harsh conditions required for the deprotection. N-Tosylaziridines react with a
great variety of carbon nucleophiles, including organolithium derivatives <1995TA2033> or
heteroatom-substituted allyl anions <1999JCS(P1)1927>, the best reagents for this operation
being organo-copper reagents: an N-tosyl protected 2-aziridine methanol was reacted with Gilman
reagent to give the aminoalcohol in nearly quantitative yield <1999JOC3237>.
The regio- and stereoselectivity of ring opening of various N-tosyl-3-phenyl-2-aziridinemetha-

nols with methyl transfer reagents was studied <1995T8279>. Ring opening of the trans-isomer
showed complete regioselectivity in favor of an attack at the C3 position; cuprate reagents cleanly
gave inversion of configuration, whereas trimethylaluminum gave a mixture of inversion and
retention, depending on the protecting group at the hydroxyl function. Ring opening of the
cis-isomer is less selective (Equation (25)).
Me Me
Ts Me2CuLi
N Ph OH + Ph OH
Ph 70% ð25Þ
OH NHTs NHTs
99 1
Intramolecular reaction of N-tosylaziridine with allyl silanes was developed as an efficient approach
to cyclic systems with an amine function <1999JOC3237, 2002T7109>. Reaction was performed in
the presence of a Lewis acid to give selectively a -aminoalkene in high regio- and stereoselectivity
(Equation (26)). This strategy was applied to the synthesis of various alkaloid ring systems.
SiMe3
H
BF3.OEt2
ð26Þ
90% NHTs
N H
Ts
2.8 /1 trans /cis
Reaction of unfunctionalized N-tosylaziridines with a cyanide ion is achieved using lithium

perchlorate as catalyst <2002S2383> (Scheme 21). Regioselectivity is in the favor of an attack
at the less hindered position, unless a phenyl group substitutes the aziridine ring.
Ph
CN
N NaCN, LiClO4 NHTs
Ph
Ts 86%
C4H9
NaCN, LiClO4 NHTs
N CN
87% C4H9
Ts
Scheme 21
Besides the tosyl group, the t-butoxycarbonyl (t-BOC) protecting group was also used for
N-protection of aziridines. Ring-opening reactions of N-BOC aziridines are accomplished using
Grignard reagents in the presence of copper bromide–dimethyl sulfide complex; this method was
applied to the synthesis of chiral aminoalcohols as precursors of D-amino acids, starting from
protected aziridine-2-methanol <1998TL9389> (Equation (27)). Reactions occurred in high yield
and with complete regioselectivity. The same reaction conditions were used for the ring opening
of BOC-aziridines with the indole nucleus <1996TL683, 1997T8237>. This reaction was applied
to the synthesis of new serotonin analogs (Equation (28)).
OTBDMS PhMgBr, CuBr.SMe2 Ph

N ð27Þ
OTBDMS
t-BOC 100% t-BOCHN
Me
( )n ( )n
CuBr.SMe2 Me
+ NHt-BOC ð28Þ
N N
n = 1: 85% N
MgBr t-BOC n = 2: 80%
H
The diphenylphosphinyl (Dpp) group was recently introduced as an easily removable protecting
group for aziridines <1998T2181>. However, reactions of carbon nucleophiles with N-Dpp
aziridines suffered from a competitive attack at phosphorus. Once again, the combination of
Grignard reagents and copper bromide–dimethyl sulfide complex allowed selective ring opening
in good yields (Equation (29)).
PhCH2
PrMgBr, CuBr.SMe2 PhCH2
Pr
N
89% NHDpp ð29Þ
Dpp
Dpp = Ph2P(O)-
Aziridine 2-carboxylates are important building blocks since their ring-opening reactions lead
to -amino acids. Initial studies showed lack of regioselectivity in the ring-opening reactions and
competitive attack on the carboxylic ester function. The problem was circumvented by the use of
a free carboxylic acid as substrate and N-tosyl protection <1995TL151>. Under these conditions,
reactions with higher-order cuprates gave, regioselectively, the N-tosyl amino acids, with complete
attack at the C3 position (Equation (30)).
CO2H
Me2Cu(CN)Li2 CO2H
Me ð30Þ
N
68% NHTs
Ts
The same conditions were applied for the ring opening of 3-substituted aziridine 2-carboxylic
acids, albeit in modest yield and regioselectivity, only lithium trimethylsilyl acetylide giving
satisfactory yields and good regioselectivity. These conditions were also unsuitable for the
introduction of soft nucleophiles or a cyanide ion.
The introduction of a substituent on the C2 position of aziridine carboxylates increases reactivity
and selectivity in favor of an attack at the C3 position <1996T13035>. Reaction with Grignard
compounds in the presence of copper bromide–dimethyl sulfide may be achieved with the t-butyl
ester without a competing reaction (Equation (31)). The corresponding alcohols were also used as
substrates to give amino alcohols; yields were slightly better than with the aziridine esters.
Me
CO2But PriMgCl, CuBr.SMe2
Me
CO2But
Pri ð31Þ
N 60% NHTs
Ts
Ring-opening reaction of N-Cbz aziridine 2-carboxylates with indole nucleus in the presence of
a Lewis acid allows the formation of tryptophan analogs. Since initial conditions with zinc triflate
required high temperatures even for low conversions and yields, other Lewis acids have been
investigated. The use of scandium triflate strongly accelerated the reaction and allowed the use of
N-benzyloxycarbonyl-protected aziridines <1998SL754>. A more recent report recommended
scandium perchlorate as a superior Lewis acid for the ring opening of aziridine 2-carboxylates
with respect to regioselectivity and scaling up <2002S1658> (Equation (32)). The reaction could
be performed at low temperature, and allows the preparation of various tryptophan analogs.
CO2Me CO2Me
Sc(ClO4)3, 0 °C
+ N NHCbz
N N ð32Þ
75%
Me Cbz Me
Regioselectivity 95/5
2-Alkenylaziridines react with organocopper reagent to give allylic amines through an SN20
mechanism. 2,3-trans-N-Diphenylphosphoryl vinylaziridines are readily opened with low-order
cuprate reagents to give predominantly (E )-allylic amines <1996SL847> (Equation (33)). The use
of Grignard reagent resulted in lower regioselectivity. Soft nucleophiles like malonate anions could
also be used with the help of a palladium catalyst. A more recent study reported higher yields and
stereoselectivities with N-sulfonyl vinylaziridines using higher-order cuprate reagents (Equation
(34), Scheme 22). This study also revealed the importance of aziridine configuration as 2,3-cis-
aziridines gave better regio- and stereoselectivities than the 2,3-trans-aziridines <1998JOC7053>.
Ph
Bu2t CuLi Ph
But ð33Þ
N
70% NHDpp
Dpp
Me
MeCu(CN)Li.LiI Me
Me ð34Þ
N
91% NHSO2Ph
SO2Ph
Bui Me Me
Ph2Cu(CN)(MgCl)2 Bui
N Ph
58%
SO2-Ar NHSO2Ar
Bui Me
Ph2Cu(CN)(MgCl)2 Bui
N Me Ph
47%
SO2-Ar NHSO2Ar
Scheme 22
Investigation in the ring-opening reaction of hindered bicyclic aziridines revealed strong depen-
dence on the nature of the nucleophile <1996JA10752> (Scheme 23). Although Grignard
reagents or low-order cuprates gave predominantly syn-1,4-addition, high-order cuprates gave
divergent results: lithium dimethyl cuprate gave a syn-1,4-addition, whereas aromatic cuprates
gave an anti-1,2-addition.
Me
O O
O PhCu(CN)Li2/BF3.OEt2
Me2CuLi
O O
37% N 70% Ph
O
Ts NHTs
NHTs
Scheme 23
2-Vinylaziridines with an ester function on the double bond are precursors to (E )-alkene
dipeptide isosteres through a reaction with organometallic reagents <1994JOC4875>. A recent
study recommended the use of low-order cuprates or dialkylzinc reagents in the presence of
copper cyanide <1995JCS(P1)1359> (Scheme 24). Under these conditions, N-tosylaziridines are
opened in high yields and stereoselectivities through an anti-SN20 mechanism.
MeCu(CN)Li.LiBr MeCu(CN)Li.LiBr
or or
Me CO2Me Me Me
Me2Zn.CuCN.LiBr Me2Zn.CuCN.LiBr
Me
N CO2Me N CO2Me
92% with cuprate 82% with cuprate
Ts NHTs Ts
88% with zinc 95% with zinc
MeCu(CN)Li.LiBr MeCu(CN)Li.LiBr
or or
Me CO2Me Me Zn.CuCN.LiBr Me Me2Zn.CuCN.LiBr Me
2
Me
N CO2Me N CO2Me
92% with cuprate 94% with cuprate
Ts NHTs Ts
92% with zinc 93% with zinc
Scheme 24
When two ester functions are appended to the double bond of 2-vinylaziridines, reaction
with organometallic reagents results in the cyclopropane formation through an intramolecular
Michael addition <1996T12253>. The best results were obtained using Grignard reagents in
the presence of copper cyanide (Equation (35)); increasing steric bulk on nitrogen gave a better
cis/trans ratio.
Me
Me CO2Et
Me
N CO2Et
Me BuMgCl/CuCN
SO2 NHSO2 Me
48% CO2Et ð35Þ
Me CO2Et
Me H
Me
Bu
91/9 cis/trans
Aziridines may be used as precursors to azetidinones (-lactams) by carbon monoxide insertion

(Equation (36)). Treatment of N-tosylaziridines with a cobalt catalyst and carbon monoxide
under pressure resulted in azetidinone formation, with insertion at the less hindered carbon
<2002AG(E)2781>. The reaction occured with inversion of configuration.
Me [Cp2Ti(THF)2][Co(CO)4] (5 mol.%)
Me
TBDMSO 6200 kPa CO, DME TBDMSO
ð36Þ
N 95% N
Bn Bn O
1.06.1.9 Radical-mediated Processes

Carbon–carbon bond formation via radical-mediated cleavage of carbon–nitrogen bonds is rather
uncommon. This kind of proceess may occur with a radical initiator such as aza-bis-isobutyroni-
trile, which can recombine with carbon radicals. N-Aziridinylimines have been designed as good
precursors for tandem radical cyclizations: addition of a carbon-centered radical to this imine
results in the formation of a nitrogen-centered radical, which decomposes through aziridine-
opening, followed by loss of styrene and nitrogen (Scheme 25). A new carbon radical is therefore
generated, which can react with various acceptors. This tandem radical cyclization strategy has
been recently applied to the syntheses of zizaene <1997SL947>, cedrene <1998TL7713>, and
7-deoxypancratistatin <1998JOC9164> (Scheme 26).
R R
R1 R2 R1 R2 R1 R2
R –N2
N N N R
R1 R2 + Ph
N N N
Ph Ph Ph
Scheme 25
OTBDMS OTBDMS OH
O O O HO OH
O Ph3SnH, O
O I AIBN, PhH
N O O O OH
78%
N N NHOBn O NH
OBn O
Ph O O
7-Deoxypancratistatin
Scheme 26
1.06.1.10 Rearrangements
Many rearrangements of nitrogen-containing compounds involve the formation of a carbon–
carbon bond with a cleavage of the carbon–nitrogen bond.
1.06.1.10.1 The Stevens rearrangement

The Stevens rearrangement of ammonium ylides is a classical reaction, which has often been
used in natural product synthesis. Stereospecific [1,2]-shift from nitrogen to carbon allows the
formation of tertiary amines in good yields (Equation (37)). Ammonium ylides may be prepared
via two routes: deprotonation of quaternary ammonium salts or addition of carbenes to tertiary
amines.
R2 R3 Stevens rearrangement R2 R3
N N ð37Þ
R1
R4 R1 R4
The generation of ammonium ylides from quaternary ammonium salts is facilitated by the
presence of a substituent which increases proton acidity, such as unsaturation or an electron-
withdrawing group. Thus, quaternary diallylammonium salts easily undergo Stevens rearrange-
ment when treated with potassium t-butoxide <1997SL725> (Scheme 27) to give a tertiary amine,
which may lead to enamines via an Amino-Cope rearrangement.
R1 R1 R1 Heat R1
N KOBut, MeCN N Amino-Cope N
R1 R1
R1 = Et: 74%; R1 = Pr: 72%; R1 = Bu: 84%;

R1 = Bui: 64%; R1 = –(CH2)4–: 83%, R1 = –(CH2)5–: 72%
Scheme 27
Allyl transfer from nitrogen to carbon was also used in an approach to the synthesis of
allylated amino acids <2000SL236>. Glycine ester, when treated with an excess of allyl bromide
with 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU), gave the intermediate triallylammonium ylide,
which underwent rearrangement to give N,N-diallylallylglycine esters in good yields (Scheme 28).
Nitrogen deprotection gave allylglycine ester. Yields were lower when quaternary amino acids were
formed from alanine or phenylalanine. When enantiomerically pure N-benzylproline ester was
submitted to the same conditions, optically active -allylproline was obtained, thus suggesting an
enantioselective allylation of nitrogen atom followed by a stereospecific rearrangement. In a related
strategy, a C2 symmetrical N-allyl-N-methylpyrrolidine bis-ester was prepared in situ and treated
under basic conditions to give the corresponding 2-allylpyrrolidine with modest stereoselectivity in
favor of the cis-product <2002TL899> (Scheme 29).
Br
K2CO3, DBU, DMF
H2N CO2R
N CO2R N CO2R
R = Me: 80%; R = Et: 70%; R = But: 69%
Scheme 28
H
N
Me
Br
K2CO3, DMF CO2Et EtO2C CO2Et
EtO2C EtO2C N N
CO2Et Me
58% Me
Br
13:5 dr
Scheme 29
A new synthesis of chiral morpholines has been described, using N-allylation of ephedrine-derived
2-allyloxazolidines, followed by sodium hydride-mediated Stevens rearrangement <2000SL893>
(Scheme 30). Migration of the carbon–nitrogen bond in the oxazolidine ring gave a mixture of
diastereoisomeric morpholines with modest selectivity.
Ph O Ph
Ph Ph Ph O Ph
O Br Ph NaH, DMF, 70 °C
Me N
N Me 65% Me N Ph
Me
Me Me
Ph
67/33 cis/trans
Scheme 30
An unexpected intramolecular nitrogen alkylation followed by a Stevens rearrangement was

observed when a tertiary -hydroxyamine was treated under Mitsunobu conditions <1996TL8133>
(Scheme 31). Careful optimization of the reaction conditions leads to an appreciable yield of a
tertiary pyrrolidine. The hydrazodicarboxylate obtained through the Mitsunobu procedure is believed
to act as a base for the rearrangement.
O
N N
N N
CO2But O CO2But
PBu3 CO2But
N
N CO2But N CO2But
HO CO2But 77%
Scheme 31
Benzylic quaternary ammonium salts are also good substrates for the Stevens rearrangement.
The final step for the total synthesis of the morphine analog desoxycodeine-D involves
deprotonation at the benzylic position of octahydroisoquinoline ammonium salt <2000TL915>.
Stevens rearrangement occurred at low temperature to give the benzomorphane skeleton
(Scheme 32).
MeO MeO MeO
PhLi, Et2O, 0 °C
O N Me+ I O O
83% N Me
N
Me
Desoxycodeine-D
Scheme 32
The same strategy was applied to the preparation of isopavine alkaloids from azocine ions
<2001AG(E)3810>. Diastereoselective [1,2]-rearrangement occurred after deprotonation of azo-
cinium ions with potassium t-butoxide (Scheme 33). The stereoselectivity of the rearrangement
was explained by a favored reaction pathway involving deprotonation at the C5 position, whereas
the formation of the ylide at the concurrent C7 position yields an iminium ion which is destabi-
lized by allylic strain. This highly stereoselective rearrangement gave a family of isopavine analogs
which were tested as morphinomimetics <2003JMC34>.
OKBut
MeI 5 dioxane, 80 °C
85%
N Me N Me
N R N Me
Me Me Me
7
R1 R1 R1
OKBut
dioxane, 80 °C
R1 R1 R1
N N N
Cl ( )n ( )n ( )n
n R1 Yield (%)
1 H 77
1 F 72
2 H 80
2 F 50
Scheme 33
Stabilized ammonium ylides may also be prepared by addition of a carbene to a tertiary amine,
the carbene being generally generated in situ by rhodium or copper-mediated decomposition of a
diazoester. In recent years, the intramolecular version of this reaction, leading to cyclic ammo-
nium ylides, has been thoroughly investigated. Thus, morpholine-2-ones were prepared from
2-(N,N-dialkylamino)ethyl diazoacetates by heating in presence of copper <1994JOC6051>.
The intermediate cyclic ammonium ylide undergoes alkyl group transfer from nitrogen to a
neighboring carbon atom (Scheme 34). The overall process shows good generality, apart from
highly hindered substrates which fail to rearrange.
N2 O O O O
Cu(II), PhMe
Bn O
N N
N 79% Bn O
Me O O Bn Me O Me
Scheme 34
Intramolecular reactions of carbenoids with cyclic tertiary amines give spirocyclic ammonium
ylide intermediates which undergo Stevens rearrangement to yield bicyclic products. This rear-
rangement has been widely used in alkaloid synthesis, via diazo decomposition of proline
<1994JA8420> and serine <1995SL237> derivatives (Scheme 35). Diastereoselection was
controlled by the ester substituent that directs the carbenoid attack on the nitrogen atom. A
trialkylsilyl substituent on the nitrogen ring has also been used for directing the Stevens rearran-
gement of a 2-silylpyrrolidine <2002OL2813> (Scheme 35). The silyl substituent efficiently
controls diastereoselective ammonium ylide formation and may be used as a masked hydroxyl
group, thus allowing entry to hydroxylated pyrrolidines. Stereoselectivity in the Stevens rearran-
gement depends on the nature of alkyl groups on silicon, the bulkier phenyldimethylsilyl group
allowing isolation of a single diastereomer. It was also observed that partial racemization
occurred during the ammonium ylide formation, indicating a possible proton transfer to the
silicon atom.
CO2Bn CO2Bn O BnO2C O

N2 Cu(acac)2 H
N 80% N
O N
O O O
O Ac
N2
Rh2(OAc)4 O
N N O N
O O 52%
CO2Me MeO2C CO2Me
SiR3 Cu(acac)2 R3Si O OH OH

R3Si O H H
N N2 toluene, 85 °C
N
N N
O
R3Si = Me3Si: 65%, 2/1 cis/trans
R3Si = PhMe2Si: 58%, >95/5 cis/trans
Scheme 35
Phenylglycinol-derived morpholine-2-ones, after nitrogen alkylation with a diazoester, undergo

ammonium ylide formation followed by Stevens rearrangement in quantitative yield
<2000TA3449> (Scheme 36). Stereocontrol in the formation of the ammonium ylide was
less efficient with a six-membered ring than with a five-membered ring, giving a 2/1 mixture of
diastereoisomers. These compounds were easily separated since the minor trans-isomer was
insoluble in the reaction solvent.
O O
Ph O Ph
N
N CO2Et
O CO2Et
O O
O O
Cu(acac)2 1
Ph N O 2
CO2Et 100%
O O
EtO2C O
N2
Ph Ph
N N CO2Et
O O
O
Scheme 36
The isoindolobenzazepine ring system, a 5,7-fused nitrogen heterocycle, may be found in

rhoeadine and papaverrubine alkaloids. A rapid entry to this ring system employs the intramo-
lecular ammonium ylide formation–Stevens rearrangement sequence between a benzylic diazo-
ester and a tetrahydroisoquinoline <2001JOC2414> (Equation (38)). The carbenoid formation is
assured by the use of rhodium acetate.
O
O O
O N
O N Rh2(OAc)4
N2 OMe O OMe ð38Þ
75% MeO2C
MeO2C
Finally, [2,3]-sigmatropic rearrangements of unsaturated ammonium ylides have also been

studied. A recent example describes the preparation of 3-vinylproline derivatives through of
addition ethyl diazoacetate to N-methyltetrahydropyridine <2003JOC4083>. The rearrangement
gave stereoselectively the cis-product, and by using substituted diazoesters, quaternary proline
derivatives were obtained (Scheme 37). The best catalyst for carbenoid addition to the tetrahy-
dropyridine was copper(II) acetylacetonate.
N2 Cu(acac)2, PhMe
+ N CO2Me CO2Me
N Ph CO2Me Ph 71% N Ph
Me R
Me
Scheme 37
1.06.1.10.2 Rearrangements of aziridines

The aziridine ring system has been involved in many rearrangement processes, leading to nitrogen-
containing heterocycles. In recent years, ring expansion of aziridines to piperidines via an aza-Wittig
rearrangement has been thoroughly investigated <1994JA9781, 1996JOC8148>. Enantiomerically
pure trans-2-vinylaziridines with an acidic proton to the nitrogen atom undergo rapid and
stereoselective [2,3]-rearrangement to give tetrahydropyridines in high yields and stereoselectivity
(Equation (39)). cis-Substituted aziridines rearrange with low stereoselectivity. Substitution on the
C1 position of the double bond leads to 4-substituted 4-tetrahydropyridines with high selectivity
<1995TL3557>, and one stereoisomer has also been obtained (Scheme 38). The vinylaziridine is
prepared in situ by olefination of 2-acylaziridines, thus allowing a one-pot procedure.
ButO2C H
LDA, THF, –78 °C
N R N CO2But
ð39Þ
R
R = Me: 99%; BnOCH2: 93%; R = n -C6H13: 98%; R = But: 95%
Ph3PCH3Br (2 equiv.), Ph
ButO2C ButO2C
Ph BuLi, DME, 25 °C Ph
N O N
R N CO2But
R R
H
R = Me: 57%; R = Bu: 55%; R = Pri: 66%
Scheme 38
A [3,3]-rearrangement of a vinylaziridine leading to a seven-membered ring lactam has also

been described <1997JA8385> (Equation (40)). Once again, a single stereoisomer was obtained
from a trans-disubstituted aziridine.
O OBn
OBn
LiHMDS, –78 °C
N ð40Þ
N O
81%
Bn Bn H
Like 2,3-epoxyalcohols, secondary 2,3-aziridinoalcohols may undergo Lewis acid-mediated

rearrangement with aziridine ring opening and migration of an alkyl or aryl group. This
reaction has recently been applied to a cyclic aziridino alcohol, leading to a -aminoaldehyde
with a quaternary carbon center <2003OL2319> (Equation (41)). Zinc bromide-mediated
rearrangement occurred with high stereoselectivity, affording precursors to the crinane family of
alkaloids.
OH Ar
ZnBr2, CH2Cl2 CHO
Ar
N Ts 95%
NHTs ð41Þ
OMe
Ar =
OMe
1.06.1.11 Electrophilic Substitutions

Substitution of nitrogen functions with formation of a carbon–carbon bond generally involves
reactions with carbon nucleophiles, and electrophilic substitutions are extremely rare. Unsymme-
trical tertiary azocarboxylates may lose nitrogen upon treatment with an electrophile and a base
to give a mixture of alkylated and acylated products (Equation (42)). This reaction does not seem
to have been used in synthesis.
CN MeI, MeOLi CN CN
+ ð42Þ
N N CO Me Me CO2Me
2
1.06.2 SUBSTITUTION OF PHOSPHORUS, ARSENIC, AND ANTIMONY FUNCTIONS
1.06.2.1 Substitution of Phosphorus Functions

The formation of sp3 carbon–carbon bonds by substitution of alkylphosphorus compounds generally
involves cyclopropanation reactions between phosphorus ylides and activated alkenes. Although this
reaction was described well for nonstabilized ylides, their stabilized analogs show little reactivity.
Recent research work has introduced the use of 1,2-dioxines as cyclopropane precursors through
reactions with stabilized phosphorus ylides <1998CC333>. Reaction of 1,2-dioxines with a first
equivalent of phosphorane, which acts as a weak base, results first in oxygen–oxygen bond cleavage
and then rearrangement to give a -hydroxy ,-unsaturated ketone. Conjugate addition of a second
equivalent of the phosphorane and recyclization give cyclopropyl ketones in good yields and stereo-
selectivity, in the favor of a trans-1,2-disubstituted cyclopropane (Scheme 39). The scope and
mechanism of this synthetic transformation have been further investigated, showing good substrate
generality <2000JOC5531, 2001JOC7955>. Alkylphosphonates are also efficient for this reaction
<2002JOC3142>.
Recent studies on the cyclopropanation reaction with nonstabilized phosphorus ylides have
focused on the stereoselective synthesis using chiral substrates or auxiliaries. A general
review dealing with asymmetric cyclopropanation reactions has been published <2003CRV977>.
Isopropylidene mannitol-derived ,-unsaturated esters react with unstabilized phosphorus

ylides to give the corresponding chiral cyclopropanes. Although reaction with isopropylidene
triphenylphosphorane gave complete stereocontrol <1998TL1437> (Equation (43)), one with
methylene triphenylphosphorane gave low diastereoselectivity <1997TL7599>. In general, yields
and selectivities are lower with phosphonium ylides than with sulfonium ylides.
CO2Me
Ph O MeO2C Ph
Ph3P
Acid–base CH2Cl2, 25 °C
O CO2Me reaction Ph O
+ Ph3P
O Ph3P OH O Me
Me Me
O O
MeO MeO
+
Me Me
100%
Ph Ph
O O
82/18 trans/cis
Scheme 39
Ph3P=CMe2 O H
O H O
O CO2Me ð43Þ
CO2Me 72% Me
Me
98/2 dr
1.06.2.2 Substitution of Arsenic Functions

As for phosphorus, substitution of arsenic functions involves cyclopropanation reactions with
ylides. Arsonium ylides are generally more reactive than the phosphonium equivalents. For the
synthesis of trifluoromethylcyclopropyl phosphonates, reactions of an ,-unsaturated phospho-
nate with phosphonium and arsonium ylides were studied <1996JCR(S)328> (Equation (44)). As
expected, yields were better using arsonium ylides.
Ph3X=CMe2 CF3 P(O)(OPri)2

CF3
P(O)(OPri) 2 ð44Þ
X = P 40%
X = As 60%
In contrast with stabilized phosphonium ylides, stabilized arsonium ylides react with acceptors
such as methyl acrylate to give cyclopropanes. Higher homologs of alkoxycarbonylidene triphe-
nylarsonane have been synthesized in good yields via a new reaction sequence involving alkylation
of triphenylarsine with alkyl 2-trifloxyalkanoates and deprotonation with potassium fluoride on
alumina <1994T13765> (Scheme 40). Reaction with methyl acrylate gives the corresponding
cyclopropanes in good yields and in high stereoselectivity.
CO2Me CO2Et
CO2Et CO2Et KF/alumina EtO2C
+ AsPh3 + – AsPh3
Me OTf 91% Me AsPh3 OTf Me 61% Me
MeO2C
Scheme 40
Reactions of semistabilized arsonium ylides such as vinyltriphenyl arsonium ylides with

,-unsaturated aromatic ketones give selectively trans-2,3-disubstituted cyclopropyl ketones
<1997JOC954> (Equation (45)). This study investigated the role of base, solvent, and tempera-
ture and their effect on stereoselectivity. The best conditions for ylide formation were potassium
t-butoxide with lithium bromide, except for styryl-substituted arsonium salts, which were depro-
tonated with sodium hexamethyldisilazide.
Ph Ph
Ph Ph Ph Ph
Ph3As SiMe3 + +
O 94% O O ð45Þ
Me3Si Me3Si
cis trans
1/ 99 cis /trans
Reaction of stabilized arsonium ylides with 2-arylidene Meldrum’s acid derivatives gives unstable
cyclopropane products which are readily opened with water to give -butyrolactones. The stability of
the cyclopropane intermediate depends on the electronic effects of the aryl ring: electron-donating
groups strongly destabilize the cyclopropane ring, which is readily opened at room temperature,
whereas electron-withdrawing group-substituted arylcyclopropanes are opened in wet refluxing acet-
one (Scheme 41). This reaction sequence has been used to synthesize 4,5-disubstituted -butyr-
olactones with complete stereocontrol, starting from benzoylmethyl triphenylarsonium bromide
<2000SC3793>, or from methoxycarbonylmethyl triphenylarsonium bromide <2002SC1953>.
O K2CO3, H2O O
O H2O/DME O
Ph p-MeO-C6H4
Ph3As + O
O p-MeO-C6H4 O
O O
COPh
p-MeO-C6H4 O
H2O/acetone O
73% overall
PhCO
Scheme 41
Recently, new annulation techniques have been described, involving the reaction of stabilized
arsonium ylides with conjugated carbonyl compounds; when the ylide itself is conjugated, these
reactions do not give cyclopropane ring as expected, but cyclohexene rings through conjugate
addition and recyclization via a Wittig reaction (Scheme 42). Thus, crotonate arsonium ylides
react with conjugated carbonyl compounds to give a 1,3-cyclohexadiene carboxylate through an
initial 1,4-attack <1997SL126>. Hindered aldehydes or ketones give trienes via a normal Wittig
reaction (1,2-attack).
Conjugate addition H Me
Ph3As CO2Me + H Me
O
CO2Me
O H
Ph3As
Proton
transfer
H Me
H Me
Ph3As=O +
Wittig reaction O
CO2Me
CO2Me
Ph3As
33%
Scheme 42
2H-Pyran-5-carboxylates may undergo electrocyclic ring opening to give dienic ketoesters,

which are substrates for conjugate addition. Although the addition of nonconjugated 1,2-arso-
nium ylides gives rise to vinylcyclopropanes <1996TL9349>, reaction of 1,4-arsonium ylides such
as 3-(methoxycarbonyl-2-oxopropyl)triphenylarsonium bromide gives cyclohexenone dicarboxy-
lates through the annulation reaction <1997T2241> (Scheme 43). Arsonium salt deprotonation
was accomplished using potassium t-butoxide. The reaction products could be used as precursors
for highly functionalized aromatic compounds.
CO2Me CO2Me Ph3As CO2Me CO2Me

Me Me O Me Me
O O Me Me
52% CO2Me
Me Me Me O
Scheme 43
In an attempt to synthesize vinylaziridines by reaction of a conjugated hydroxyl group-contain-

ing arsonium ylide (obtained by deprotonation with potassium hydroxide) with an aromatic
aldimine, cyclization to a five-membered ring was observed instead of aziridine formation
<2000T2967> (Scheme 44). Formation of the dihydrofuran ring occurred with modest stereo-
selectivity.
Ph H
Ph
+ OH Ph O
N Ph3As AsPh3 O
Ts 54% TsHN
NHTs
61/39 syn/anti
Scheme 44
1.06.2.3 Substitution of Antimony Functions

The organic chemistry of antimony compounds (together with bismuth) has been reviewed
<B-1994MI761>. Despite the high reactivity of organoantimony derivatives, few applications
in carbon–carbon bond formations have been described. Allylation reactions of aldehydes with
allyldichlorostibines have been developed using Barbier-type conditions: treatment of allyl chlor-
ide with an aldehyde in the presence of antimony(III) chloride cleanly gave the allylated product;
the reactive intermediate is likely to be an allyldichlorostibine derivative <1998JOC59>. The
stability of antimony in the presence of aqueous solvents allowed the allylation of aliphatic and
aromatic aldehydes in water by mixing allyl chloride, antimony powder, and an aldehyde in dilute
hydrochloric acid solution <2001CJC1536> (Scheme 45). The presence of an acid was necessary
to activate the metal powder. Investigations into the nature of the reactive intermediate showed a
mixture of allyldichlorostibine and diallylchlorostibine to be the allylating species.
Sb, 0.5 M HCl PhCHO OH

Br SbCl2 +
( ) 2SbCl 100% Ph
Scheme 45
Pentaorganostiboranes are prepared by alkylation of trialkylstibines (R3Sb) to give tetraalkylsti-

bonium salts (R4Sb+). Treatment of this salt with an organometallic compound (e.g., butyllithium)
gives the corrresponding pentaalkylstiborane (Scheme 46). The reactivity of these compounds toward
carbonyl compounds has been studied. Recent work describes the preparation of acetylenic and
allenic stiboranes <1994JOM(471)77>. Reaction of propargyl bromide with tributylstibine gave
an allenylstiborane, whereas the reaction of 1-bromo-2-butyne gave an acetylenic stiborane (Scheme 47).
Both compounds reacted with aldehydes to give homopropargylic alcohols and allenic alcohols,
respectively. The regioselectivity was high for both reactions.
RBr BuLi
Bu3Sb Bu3SbR Bu4Sb-R
Stiborane
Scheme 46
RCHO OH
Bu3Sb + Br Bu3Sb • Bu4Sb •
R
OH
RCHO
Bu3Sb + Br Bu3Sb Bu4Sb •
R
Scheme 47
1.06.3 SUBSTITUTION OF BORON, SILICON, AND GERMANIUM FUNCTIONS
1.06.3.1 Substitution of Boron Functions
1.06.3.1.1 Conjugate addition to a,b-unsaturated ketones and aldehydes

The conjugate addition of triorganoboranes to ,-unsaturated carbonyl compounds to give
-alkyl ketones or aldehydes is a well-described reaction. Investigation into the reaction mechanism
has highlighted the radical character of the reaction, with the prior formation of a carbonyl–
organoborane complex <2000TL1195>. Oxygen is generally used as a radical initiator. Photo-
induced reaction of tetramethylammonium trialkylphenylborates has also been described
<1995TL5483>. This reaction has been recently applied to the regioselective alkylation of sub-
stituted quinones <1999TL4473> (Equation (46)). The regioselectivity depends on the nature of the
substituent, a hydroxyl group directing the attack on the vicinal position, whereas a methoxy group
favored 1,4-attack. It should be pointed out that reactive trialkylboranes such as trimethylborane
gave no selectivity.
O O O
OR R13B OR OR
+
R1 R1
O O O
ð46Þ
R R1
H Bus / 68%
Me Bun 81% /
The major drawback in the conjugate addition of trialkylboranes to ,-unsaturated carbonyl

derivatives is that only one of the three alkyl groups is transferred, thus restricting the methods to
readily available alkylborane reagents. Recently, the use of B-alkylcatecholborane as a convenient
source of alkyl radicals has been recommended <1999CEJ1468>. These compounds are conve-
niently prepared by hydroboration of alkenes with catecholborane and are converted to radicals
in the presence of oxygen (Equation (47)). Addition to ,-unsaturated aldehydes or ketones gives
good yields of the alkylated products.
O O2, H2O
O Me
DMPU, CH2Cl2
B + O ð47Þ
Me
O 74%
Me Me
1.06.3.1.2 Conjugate addition to a, b-unsaturated carboxylic acid derivatives

The radical-mediated cleavage of B-alkylcatecholboranes and subsequent addition to radical
acceptors such as ,-unsaturated esters, nitriles, sulfones, or phosphonates has recently been
reported independently by two groups <2000AG(E)925, 2000CC1017>. Irradiation of various
secondary B-alkyl catecholboranes in the presence of methylcarbonyloxy(pyridine-2-thione),
gave an alkyl radical that added to the activated double bond (Scheme 48). Radical chain
reaction is stopped by addition of the thiopyridyl radical. Excellent diastereoselectivity was
observed with -substituted cyclic secondary alkylboranes, the radical reaction occurring with
retention of configuration.
O hν, PhH/CH2Cl2, 0 °C
B +
N S
O
OCO2Me
CO2Me
MeO2C MeO2C
SPy 70%
Scheme 48
1.06.3.1.3 Conjugate addition to vinyl- and alkynylepoxides

Addition of organoboranes to vinylepoxides may result in a 1,2-addition to give homoallylic
alcohols or in a 1,4-addition to give allylic alcohols (Equation (48)). Reaction of cyclic and acyclic
vinylepoxides with allylic borane reagents has shown preference for a cis-1,2-addition for cyclic
substrates (Equation (49)) and 1,4-addition for acyclic substrates (Scheme 49) <2000OL3897>;
the stereochemistry of addition is oppposite to other allyl metal reagents. With epoxycyclopen-
tenes, a fragmentation reaction leading to trienols was observed.
R3B OH + R
OH ð48Þ
O R
1,2-Addition/1,4-addition
OH
O Et2O, rt
+ BEt2 OH +
82%
ð49Þ
1,2-Addition 1,4-addition
(cis/trans) (cis/trans)
81/19
(72/28) (63/37)
BCy2 BEt2
OH
OH OH OH
Me THF, 80 °C THF, 60 °C
+ Me +
65% Me O Me Me
65%
1,2-Addition/1,4-addition 1,2-Addition/1,4-addition
35/65 30/70
Scheme 49
Allylic carbonates possess a reactivity close to vinylepoxides, and their reactions with organo-
borates in the presence of nickel catalysts give alkylated products in good yields and high
regioselectivity <1995JCS(P1)2073> (Equation (50)). The presence of an alkene or ester function
directs attack of the organoborate to give the conjugated product.
O
Ni(PPh3)4 or Ni(dppf)2 O
+ O ð50Þ
Li
O B(OMe)3 O
CO2Et 56–62% HO
CO2Et
A nonconjugated addition of allyl- and crotylfluoroborates to vinylepoxides has been

described. In the presence of a Lewis acid, vinylic oxiranes rearrange to ,-unsaturated alde-
hydes which undergo classical allyl- or crotylboration <2000AG(E)4079> (Scheme 50). Cro-
tylation using crotylfluoroborates occurs with excellent diastereoselectivity depending on the
configuration of the boron nucleophile.
– +
Me BF3K
O BF3·OEt2 O OH
THF, 0 °C
H
Me 78%
Me Me Me
2.5/1 syn/anti
Scheme 50
1.06.3.1.4 Aromatic and alkenic substitution

Transition metal-catalyzed cross-coupling reactions of alkyl, alkenyl, alkynyl, and aryl groups
have gained enormous importance in modern synthesis. Amongst all the reactions, the Suzuki–
Miyaura reaction, which involves palladium-catalyzed cross-coupling of organoboron reagents
with alkenyl or aryl halides (or triflates), has found many applications, due to its mild reaction
conditions, functional group tolerance, and easier purification. Furthermore, the reaction may be
carried out in the presence of water. As a consequence, many recent reviews on this topic are
available <1995CRV2457, B-1998MI49, 1999JOM(576)147, 2002JOM(653)83, 2002T9633>. The
extension of this reaction to B-alkyl substrates has brought further interest to this cross-coupling
reaction, with alkyl transfer to alkenyl, aryl, or even alkyl groups (Equation (51)). A recent review
on the B-alkyl Suzuki–Miyaura reaction describes the conditions, scope, and applications of this
reaction in the synthesis of natural products <2001AG(E)4545>.
Pd(0)
R1–BR22 + R3–X R1–R 3
R1, R3 = alkyl, alkenyl, aryl ð51Þ

R2 = alkyl
X = I, Br, Cl, OTf
(i) With organoboron reagents

Organoboron reagents are the most often used substrates for the Suzuki–Miyaura reaction. These
compounds are generally prepared in situ from terminal alkenes; the alkylboron reagent is
not isolated but immediately engaged in the cross-coupling reaction with the aryl or alkenyl
halide (or triflate). 9-Borabicyclononane (9-BBN) is by far the most often used borane reagent.
Alternatively, treatment of a primary alkyl iodide with t-butyllithium and condensation to
9-methoxy-BBN affords boronate complexes which are immediately used in the coupling reaction.
Cross-coupling is accomplished in the presence of palladium(tetrakis)triphenylphosphine, or
better, palladium dichloride bis(diphenylphosphino)ferrocene (dppf), in the presence of a phos-
phine or arsine ligand (Scheme 51). An inorganic base is added to the reaction medium, usually
caesium carbonate; in the case of low reactivity, thallium salts (Caution: thallium salts are toxic)
may be added in order to increase the reactivity.
Ar–X
R
Ar
R1
9-BBN-H X
R R R1
9-BBN R
Not isolated X
R1 R
R1
PdCl2(dppf), base
R, R1= alkyl
X = I, Br, OTf
Scheme 51
Inter- or intramolecular cross-coupling reactions of alkylboron reagents with alkenyl halides,

triflates, or phosphates have widely been used in natural product synthesis. The recent examples
in the syntheses of gambierol <2002JA14983>, ciguatoxin <2002OL2771>, sphingofungins
<2001JA12191>, phomactin A <2003JA1712>, and epothilone analogs <2002JOC7730> illus-
trate the high efficiency and functional group tolerance in the synthesis of highly complex
molecules. An example of a B-alkyl Suzuki reaction as the key step in an approach to xestocy-
clamine <2002AG(E)1581> is shown in Equation (52).
HO
i. 9-BBN, THF HO
TBDPSO
ii. PdCl2(dppf).CH2Cl2, TBDPSO
Ts Tl2CO3, AsPh3, THF/DMF
N N Ts ð52Þ
O N N
60% O
Coupling of alkylboron reagents with aryl bromides or triflates is achieved under similar
conditions; the combination of PdCl2(dppf) and aqueous sodium hydroxide in DMF gives the
best results; base-sensitive substrates are generally reacted in the presence of sodium carbonate or
phosphate in DMF. Some recent examples include the allylation of an electron-deficient arene
<1998SL161>, alkylation of an azulene derivative <2001OL1081>, or the introduction of a
hydroxyl-containing alkyl chain onto 3-bromopyridine <2001T3125> (Equation (53)).
i. 9-BBN, THF
Br
ii. Pd(PPh3)4, K2CO3, DMF/H2O ( )6OH ð53Þ
OH +
N 93% N
Since aryl bromides or triflates are expensive, more reactive catalytic systems were designed for
the coupling of aryl chlorides. Recently, a general protocol for the coupling of organoboron
reagents, including alkylboron reagents, with aryl chlorides has been developed, using an imida-
zolium salt as ligand <2001SL290> (Equation (54)). A highly hindered biphenylic phosphine
ligand has also been reported to be effective for the same coupling reaction <1999JA9550>.
N N Cl
ð54Þ
Cl Ph C14H29 Ph
Pd(OAc)2 (2 mol.%)
C14H29 9-BBN +
N CO2Et KOMe, THF, reflux N CO2Et
Bn 83% Bn
The Suzuki–Miyaura reaction of allylboron reagents has been reported to be rather difficult,
giving low yields of coupled products, probably because of the instability of the organoboron
reagent. A recent study describes the preparation of B-allyl-9-BBN, which is activated by forma-
tion of the borate complex <1998SL161>. This ate complex undergoes cross-coupling reactions
with aryl halides or triflates in good yields (Scheme 52).
K
OMe Br MeO
B B B
Al MeOK
OMe O Me
MeO OTf
S
OMe O Me
S
O
PdCl2(dppf), THF
MeO
S
86%
S
Scheme 52
The synthesis of p-nitroaryl alkyl derivatives has been described, involving the mono-substitution
of p-dinitrobenzene with trialkylborane reagents <2003JOC4388>. The reaction is performed in the
presence of a base and gives the alkylated product via a radical anion intermediate (Equation (55)).
The use of alkyl-9-BBN reagents allows selective alkyl group transfer.
NO2
9BBN KOBut or PhOK
+ O2N NO2 ð55Þ
54%
(ii) With boronic acids and boronic esters

Boronic acids have the advantage over alkylboron reagents of being isolable, more water tolerant,
and that they give only inorganic by-products. Therefore, many attempts have been made to carry
out the Suzuki–Miyaura reaction with alkyl boronic acids or their boronate esters.
Cyclopropyl boronic acids, because of the sp2 character of the cyclopropane ring, enjoy good
reactivity in the cross-coupling reactions. They are easily prepared by cyclopropanation of
vinylboronates and may be stored. Cyclopropylboronic esters and acids may be easily coupled
with a variety of reagents including aryl bromides <1996JCS(P1)266, 1996SL893> and triflates
<2000S1095>, heteroaryl bromides <1999SC2477>, vinyl halides <1998SL198, 2000TL3951>
and triflates <2000TL9083>, allyl bromides (with added silver salts) <2000JOC4444>, or acyl
chlorides <2000OL1649, 2000JOC5034>. An example of such a coupling is shown in Equation
(56). When optically active cyclopropyl boronic acids (obtained by asymmetric cyclopropana-
tion) were used, complete retention of configuration occurred <1998AG(E)2845>; a bis-cyclo-
propane derivative could be synthesized by coupling with a iodocyclopropane <1997TL2809>
(Equation (57)).
Pd(PPh3)4 C6H13
C6H13
KOBut, DME
B O + Br OMe ð56Þ
O 80%
OMe
Pd(OAc)2, PPh3
C4H9 KOBut, DME, 80 °C C4H9
ð57Þ
+ I OBn
B(OH)2
54% OBn
Coupling of alkylboronic acids or esters with alkenyl or aryl halides suffers from a lack of
reactivity, and low yields of coupled products are obtained unless additives such as silver oxide
are used <2001TL7213, 2001JOC2459>. Therefore, various catalytic systems have been designed
in order to improve yields and turnovers. Thus, a palladium–imidazolium carbene catalytic
system allows low-temperature coupling of boronic acids and boronates with aryldiazonium
salts <2001OL3761> (Equation (58)).
N N Cl
ð58Þ
O Br Pd(OAc)2 (2 mol.%)
PhN2, BF4 + B Br
Ph
O 61%
Finally, a general method for the cross-coupling of primary alkylboronic acids with aryl
bromides and triflates and heteroaryl chlorides has been described, using PdCl2(dppf) in
the presence of potassium carbonate <2002T1465>. Good yields of coupled products are
obtained under mild conditions, the best results being obtained with electron-deficient arenes
(Equation (59)).
PdCl2(dppf), K2CO3
THF/H2O Cl
B(OH)2 + Cl ð59Þ
Ph OTf
94% Ph
One particular problem in the cross-coupling reaction of boronic acids is the transfer of a
methyl group, which generally shows poor reactivity. Various systems have been designed for
efficient methylation of alkenes or arenes via the Suzuki–Miyaura reaction: the use of
Pd(PPh3)4 as a catalyst has allowed polymethylation of porphyrins under harsh conditions
<1996JOC3590>, whereas imidazolopyridines were monomethylated under the same condi-
tions <2000JOC6572>. A general method for the methylation of aryl halides employs tri-
methylboroxine (the anhydride of methylboronic acid) and Pd(PPh3)4 as the catalyst, in the
presence of potassium carbonate <2000TL6237> (Equation (60)). Even aryl chlorides give
appreciable yields.
Me Pd(PPh3)4, K2CO3
H2N Br B dioxane H2N Me
+ O O
CF3 B B 95% CF3
ð60Þ
Me O Me
Trimethylboroxine
(iii) With alkylfluoroborates

Organotrifluroborates are easily prepared by treatment of various boron derivatives (boronic
acids and esters, dihaloboranes) with excess of potassium hydrogen fluoride. These reagents are
air stable, easy to handle, and may be stored for long periods. The coupling reactions of
alkyltrifluoroborates have been recently studied <2001OL393, 2003JOC5534>, and showed
excellent results in the palladium-catalyzed reaction with aryl bromides and triflates. The reaction
tolerates many functional groups on both coupling partners. A selected example in the alkyl–aryl
coupling is shown in Equation (61).
PdCl2(dppf), Cs2CO3
THF/H2O Ac
PhSO2 BF3 K + TfO Ac ð61Þ
70% PhSO2
1.06.3.1.5 Aliphatic substitution

Cross-coupling reaction of alkylboron reagents with alkyl halides is hampered by slow reaction
rates and competitive -elimination of the intermediate alkyl–palladium complex. Nevertheless,
alkyl–alkyl cross-coupling (including carbonylative cross-coupling) with alkyl iodides can be
undertaken using Pd(PPh3)4 as the catalyst in moderate-to-good yields. A spectacular improve-
ment was brought about by the use of bulky ligands which accelerate reductive elimination: thus,
palladium acetate in the presence of tricyclohexylphosphine and potassium phosphate allows
room-temperature coupling of various alkyl bromides <2001JA10099> with alkyl-9-BBN deri-
vatives in good yields and with high substrate generality. Further improvements allowed the
coupling of alkyl chlorides <2002AG(E)1945> (Equation (62)) and alkyl tosylates with
di-t-butylmethylphosphine <2002AG(E)3910>.
Pd(OAc)2 (4 mol.%), PCy3 (8 mol.%)

K3PO4, THF, 25 °C ð62Þ
C8H17–9BBN + C12H25Cl C20H42
83%
The latter catalyst is also efficient for the coupling of boronic acids with alkyl bromides at
room temperature <2002JA13662> (Equation (63)). Unhindered alkylboronic acids may be used
as substrates for this reaction.
Pd(OAc)2 (5 mol.%), P(But)2Me (10 mol.%)

KOBut, t-amyl alcohol, 25 °C ð63Þ
C6H13–B(OH)2 + C12H25Br n-C18H38
62%
Other aliphatic substitutions with organoboron reagents involve intramolecular alkyl group
transfer from a boron ate complex to a carbon-bearing leaving group. The deprotonation of an
-acetoxy -iminoester followed by treatment with a trialkylborane gives an ate complex that
undergoes alkyl transfer with subsequent departure of the acetoxy group. An enantioselective
version of this reaction has been developed, using a cinchona alkaloid as a chiral protonating
group <2002JA9348>, thus allowing the preparation of chiral amino acids (Equation (64)).
Ph N CO2But CdOH, BunLi, LiCl, THF, 0 °C Ph N CO2But

+ 9BBN
Ph OAc 84% Ph
ð64Þ
OH 92% ee
N
CdOH: N
Treatment of the anion of a sulfone with a trialkylborane gives an ate complex that transfers
one alkyl group from boron to carbon, the sulfone playing the role of the leaving group
<2003TL4451> (Scheme 53). This allows rapid assembly of tertiary alcohols from sulfones.
In a similar strategy, one carbon homologation of alkylcatecholboronates has been realized
with trimethylsilyl diazomethane <2000OL1455> (Scheme 54). Alkyl transfer with subsequent
loss of nitrogen gives -silylboronates which can be converted into alcohols.
i. BuLi, THF
–78 °C to rt
SO2Ph ii. BBu3, THF, rt BBu3 –PhSO2 BBu2 H2O2, OH OH
Ph Ph SO2Ph Ph Bu Ph Bu
Me Me Me 82% Me
Scheme 53
Me3Si N2 SiMe3 i. H2O2

Ph Me3SiCHN2
O ii. Bu4NF
B THF, reflux Ph –N2 O
O Ph B
O B Ph OH
O 60%
O
Scheme 54
Trialkylborane derivatives react with the arenesulfonylhydrazones of aryl aldehydes to give

alkylated products <1997JOC3688> (Scheme 55). The reaction is performed under basic condi-
tions and tolerates a wide variety of functional groups. Hydrazones derived from heteroaryl
aldehydes are also good substrates for the reaction.
H
N NaOH or Bu4NOH BBu2 Base
N Ts + BBu3 Ph Bu
Ph Bu 83%
Ph H
Scheme 55
1.06.3.2 Substitution of Silicon Functions
1.06.3.2.1 Alkylation
Substitution of carbon–silicon bonds with carbon–carbon bond formation generally involves
desilylation followed by reaction with an electrophile. Desilylation may be accomplished with a
fluoride source such as tetrabutylammonium fluoride (TBAF) or caesium fluoride. Fused salts
obtained from caesium fluoride and caesium hydroxide have been recommended as efficient
reagents for carbon–silicon bond cleavage <1999TL2065>.
Simple alkylation of carbanions obtained from alkyl silanes are not very common and often
involves perfluorinated silanes. Trifluoromethylation of primary tosylates was achieved with
trifluoromethyl trimethylsilane in the presence of fluoride anion <2001SL379>. The same con-
ditions were used for the nucleophilic substitution of an iodopurine with the heptafluoropropyl
anion derived from the corresponding silane <1999CCC229> (Equation (65)). Alkyl -trimethyl-
silyl-,-difluoroacetate also reacts with various electrophiles in the presence of fluoride ion to
give homologated difluoroesters <1999JOC6717> (Equation (66)).
I C3F7
N N N N
N N KF, CuI, DMF N N

C3F7 – SiMe3 + ð65Þ
O O
47%
O O
O O
Ph3CO Ph3CO
Me3Si KF/CuI, R–X CO2C6H13

Cl + CO2C6H13 ð66Þ
F F 85% F F
Condensation of the anion of 2-trialkylsilyl-1,3-dithiane with epoxides gives an alkoxide that

undergoes a silyl group transfer from carbon to oxygen (Brook rearrangement) to give a new
nucleophilic species. Under carefully controlled conditions, reaction with a different terminal
epoxide gives rise to unsymmetrical 1,5-diols <1997JA6925> (Scheme 56). This methodology
has been applied to the synthesis of spongistatin <1997TL8671, 1997TL8675, 2002OL783>,
bryostatin <2000OL2189>, and carbasugars <1999SL1322>.
ButLi, Et2O Silyl group

O –78 °C to –25 °C migration
+ S S S SO S S OTBS
OBn OBn
TBS OBn
TBS
O
OTBS
Et2O/HMPA
–78 °C to rt HO OTBS
S S
56% TBSO OBn
Scheme 56
Functionalized carbocycles may be prepared by a cascade reaction involving the condensation

of 2-lithio-2-trialkylsilyl thioacetals with epoxides bearing a leaving group within the side chain
<1998T11481>, with subsequent silyl group migration and internal nucleophilic attack
(Scheme 57). Symmetrical bis-epoxides were also used as substrates for this reaction
<1999TL2921>, and an aminohydroxylated cyclopentane was obtained by condensation with
1,2-epimino-3,4-epoxy butane <2001S577> (Equation (67)). Since chiral epoxides are readily
available compounds, this strategy provides access to chiral hydroxylated cycloalkanes.
OLi OSiMe3 OSiMe3

MeS SiMe3 O
+ ( )n OTs ( )n OTs
( )n
MeS Li
( )n OTs
MeS
MeS SiMe3 MeS Li
MeS MeS MeS
Scheme 57
i. THF, –80 °C MeS SMe

MeS Li Ts ii. BF3.OEt2
+ N O ð67Þ
MeS SiMe3 42%
TsHN OH
Other bis-electrophiles such as brominated alkyl isocyanates may be used in the same cascade
reaction to provide functionalized lactams <2000SL92> (Scheme 58). Silyl group transfer
occurs from carbon to a lactam enolate oxygen atom.
LiO N Me3SiO N
MeS Li n n
+ Br nN
MeS SiMe3 C MeS Br MeS Br
O Li
MeS SiMe3 MeS
Bn
N
N Me3SiO
O n
n
MeS SMe
O
n = 2: 57%
n = 3: 80%
Scheme 58
Besides electrophilic alkylation, nucleophilic substitution of -silyl ethers with allylic silanes or
silyl enol ethers has been developed <2000JA10244>. Electrooxidation of -silyl ethers gives
alkoxycarbenium ions (oxonium cations), which react with nucleophiles to give ethers in good
yields (Equation (68)). This electrochemical method allows preparation of high concentrations of
alkoxycarbenium ions.
SiMe3
–2e
OMe
OMe CH2Cl2, –72 °C OMe ð68Þ
C8H17
C8H17 SiMe3 C8H17 83%
Transition metal-catalyzed cross-coupling reactions of organosilane derivatives have recently

emerged as alternatives to the classical organotin or organoboron cross-coupling reactions
<2002ACR835>. The principal advantages in organosilane derivatives are their high reactivity,
low toxicity and molecular weight, and substrate diversity: strained organosilane reagents such
as alkenylsilacyclobutanes <1999JA5821> (Equation (69)), alkenylsilanols <2000OL565>
(Equation (70)), or alkenylsiloxanes <2001JOM(624)372> (Equation (71)) are coupled with aryl
iodides in the presence of fluoride ion and a palladium catalyst. Tandem hydrosilylation–cross-
coupling reactions of alkynes have also been developed as an entry into stereodefined trisubsti-
tuted alkenes <2003JOC5153>. All these cross-coupling reactions have been described using aryl
or alkenyl substrates and have not been applied so far to the coupling of alkyl silane derivatives.
TBAF, Pd(dba)2
C5H11 Me I 25 °C, 10 min C5H11
Si +
ð69Þ
MeO 94% MeO
TBAF, Pd(dba)2
I C5H11
C5H11
Si
OH 25 °C, 10 min ð70Þ
+
Me Me
MeO 93% MeO
Me
I TBAF, Pd(dba)2
Si O
O Si 25 °C, 10 min
Me Si Me + Me Me ð71Þ
O 88%
O Si O O
Me
1.06.3.2.2 Hydroxylation/aldol reactions

Aldol reaction of alkyl silanes involves cleavage of the carbon–silicon bond in the presence of
fluoride salts, and condensation of the resulting carbanion with carbonyl compounds. Generally,
stabilized carbanions such as benzyl, allyl, or acetyl are used for the reaction. Tetrabutylammo-
nium triphenyldifluorosilicate (TBAT) has been used as an efficient fluoride source in anhydrous
conditions for the condensation of alkyltrimethylsilanes onto aldehydes, ketones, and even
aldimines <1996JOC6901> (Equation (72)). Alkylation of the organosilicon derivatives with
primary bromides or iodides (but not sulfonates) is also efficient.
O Me3SiO
Bu4NPh3SiF2 (TBAT), THF
SiMe3 + ð72Þ
96%
Nucleophilic alkylation of carbonyl compounds with perfluoroalkylsilanes is the method of

choice for the preparation of fluorinated carbohydrate derivatives <1998TA213>, both in terms
of yields and stereoselectivity. Addition of various fluoroalkylsilanes on carbohydrate-derived
aldehydes (Equation (73)) or ketones (Equation (74)) occurs in the presence of tetrabutylammo-
nium triphenyldifluorostannate to give the corresponding secondary or tertiary fluorinated alco-
hols. Fluorinated organometallic reagents such as Grignard compounds gave lower yields and
lower stereoselectivities in the addition to ketones.
O H C4F9 C4F9
HO OH
O C4F9SiMe3, Bu4NPh3SnF2 O O
OBn OBn OBn
+
O O O ð73Þ
64%
O O O
95/5
O O O
O O O
O C4F9SiMe3, Bu4NPh3SnF2 O C4F9 O
OH
+ ð74Þ
O 70% O O
O O HO O F9C4 O
100/0
Desilylation of a chiral benzyl silane with TBAF and condensation with aldehydes gives
secondary alcohols with moderate stereoselectivity <1997TL5429>; yields and selectivities
strongly depend on reaction conditions (Equation (75)). A chiral siliconate complex is believed
to be the reactive species rather than an atropoisomeric benzylammonium derivative.
i-Pr2N O OMe i-Pr2N O OMe

Me Me
TBAF, THF
+ H
SiMe3 54%
O OH ð75Þ
96% ee 1/1 dr
64% ee one diastereomer
6% other diastereomer
Electrosynthesis of difluorobenzyltrimethylsilane and its condensation with carbonyl com-

pounds in the presence of potassium fluoride has been described <1999S829>. Alternatively,
perfluorinated alkyl silanes may be synthesized by samarium diodide-induced alkylation of
perfluoroalkyl iodides <1997JCS(P1)643>.
-Trimethylsilyl esters are easily condensed with carbonyl compounds through treatment with a
fluoride source (Equation (76)). Trimethylsilyl acetate, the simplest of these reagents, is a con-
venient source of acetate anion, which has been condensed onto aldehydes, ketones, and even
lactones <1995T5657>. The reaction generally occurs in the presence of TBAF. Recently, an
‘‘uncatalyzed’’ condensation of dimethylsilyl esters with aldehydes has been described
<1998TL2585>. Dimethylsilyl alkanes are more reactive than their trimethylsilyl counterparts
and react with carbonyl compounds upon heating in DMF, this solvent being crucial for the
reaction (Equation (77)). Branched -silyl esters cleanly give the aldol products without the self-
condensation that often occurs in the presence of fluoride salts. Another nonconventional
activation of silylacetic esters for the aldol reaction employs a hindered phosphine as the base
<2000TL103>. Tris(2,4,6-trimethoxyphenyl)phosphine efficiently cleaves carbon–silicon and even
oxygen–silicon bond to form enolates. In one example, treatment of ethyl trimethylsilylacetate
with this phosphine in the presence of benzaldehyde gave 60% of the aldol product when treated
at 120 C in dimethylformamide.
CO2R1 O F OSiMe3
+ R2
CO2R1
SiMe3 R2 R 3 R3
ð76Þ
R1 = Me, Et
R2 = H, alkyl, aryl
R3 = H, alkyl, aryl
O i. DMF, 50 °C O OH
ii. HCl, MeOH ð77Þ
SiMe2H + PhCHO
EtO 93% EtO Ph
Me Me Me Me
In the total synthesis of epolactaene, the key step coupling reaction between a bridged oxirane
and the side chain was accomplished by desilylation of a trimethylsilyl oxirane and condensation
of the corresponding anion with an ,-unsaturated aldehyde <1999TL7371> (Scheme 59).
The reaction occurred with retention of configuration at the oxirane ring.
O Me OH Me
O
TMS Bu4NF O
+ H
Me 53% Me Me CO2Me
O O Me Me CO2Me Me O O
O Me
O
Me Me Me CO2Me
N O
HO
H
Epolactaene
Scheme 59
2,2-Difluoro-2-trimethylsilyl acetate is a convenient reagent for the preparation of 2,2-difluoro-

esters by treatment with fluoride and condensation with electrophiles. Alkyl 2,2-difluoro-2-trimethyl-
silyl acetates are prepared by electroreductive silylation of trifluoroacetates <1999JOC6717> or
chlorodifluoroacetates <2000TL8763>, and react with carbonyl compounds such as aldehydes,
ketones, and ketimines upon treatment with potassium fluoride (Equation (78)). Yields were higher
with hexyl ester <1999JOC6717> than with ethyl ester <2000TL8763>.
O OH
Me3Si CO2C6H13 KF or Bu4NF
+ CO2C6H13 ð78Þ
F F 92% F F
1.06.3.2.3 Acylation
An -trimethylsilyl--lactone, obtained by a [2+2]-cycloaddition between trimethylsilyl ketene
and an aldehyde, was desilylated with TBAF and treated with carbon dioxide to give the
carboxylic acid in convenient yield <1998S1655> (Equation (79)), which after reduction led to
compound natural product 1233-A. It should be pointed out that all attempts to quench the anion
with formaldehyde were unsuccessful.
i. TBAF, CO2, –78 °C

O O
O ii. BH3·SMe2 O
iii. CF3CO2H, CH2Cl2
OH
SiMe3 ð79Þ
OBut 22% overall yield OH
O O
1233-A
Ethyl 2,2-difluoro-2-trimethylsilyl acetate may also be used as a difluoroacetate building

block for acylation reactions. Treatment of the silylacetate ester with acyl chlorides or fluorides
in the presence of potassium fluoride cleanly gives the fluorinated -ketoesters. A few examples
of this reaction have been recently reported <2000TL8763> and one of them is shown in
Equation (80).
O O
Me3Si CO2Et KF/DMF
+ F OEt ð80Þ
F F 79% F F
O
1.06.3.2.4 1,3-Dipole formation

Cleavage of a carbon–silicon bond is an efficient route for the generation of various dipolar
systems. The preparation of azomethine ylides, trimethylenemethane, and thiocarbonyl ylides are
the main applications of this reaction.
(i) Azomethine ylides

A comprehensive review on the chemistry of azomethine ylides (including those prepared from
organosilicon compounds) has been recently published <B-2002MI106-4>. Carbon–silicon
bond cleavage of an N-trialkylsilylmethylaminonitrile is a common way for the generation
of unstabilized azomethine ylides. Desilylation is generally accomplished with silver fluoride
(Equation (81)). Another mild method for the generation of azomethine ylides is the acid-
catalyzed elimination of trimethylsilylmethanol from an N-trimethylsilylmethyl aminoacetal
(Equation (82)). The azomethine ylides generated by these routes are generally substituted by a
benzyl group on nitrogen. Recent application of these methods involves the generation of the
simplest azomethine ylide and its diastereoselective cycloaddition with chiral unsaturated acyl
oxazolidinones <1997TA883> (Scheme 60). Trifluoroacetic acid-catalyzed decomposition of
N-benzyl-N-methoxymethyl-trimethylsilylmethylamine gave N-benzyl azomethine ylide, which
reacted with the ,-unsaturated amides in excellent yields and in modest-to-good stereose-
lectivity. The best results were obtained with a phenylglycinol-derived oxazolidinone by using
toluene as solvent. This reaction was applied to the synthesis of enantiomerically pure 3,4-
disubstituted pyrrolidines.
R1 R2 R1 R2
AgF
NC N SiMe3 N
ð81Þ
Bn Bn
R1, R2 = H, alkyl, aryl
R1 R2 R1 R2
Cat. CF3CO2H
MeO N SiMe3
ð82Þ
N
Bn Bn
O O
Et N O
O O
Ph O O
Cat. CF3CO2H Et N O Et N O
MeO N SiMe3 N Toluene, 0 °C
+
Bn Bn 99%
Ph Ph
N N
Bn Bn
77/23 dr
Scheme 60
The same azomethine ylide, obtained through the same method, was reacted with 2-phenylthio-
3,3,3-trifluoropropene and its sulfoxide and sulfone <1996T4383>. The three dipolarophiles
reacted with azomethine ylide in good yields to give 3-trifluoromethyl-pyrrolidine derivatives,
thus representing an efficient entry into fluorinated heterocycles. Although reaction with the
sulfide occurred in refluxing dichloromethane, cycloaddition with the sulfoxide and the sulfone
could be performed at room temperature (Equation (83)).
CF3
CF3 CH2Cl2 S(O)n Ph
N +
N
ð83Þ
Bn S(O)nPh
Bn
n = 0: 84%; n = 1: 65%; n = 2: 71%
Treatment of 2,5-bis(trimethylsilyl)pyrrolidine with silver fluoride gave the pyrrolidine azo-

methine ylide, which underwent diastereoselective dipolar cycloaddition with the acrylate of
camphorsultam <1999TL6065> (Scheme 61). Piperidine and azepane-derived azomethines also
gave good yields and stereoselectivity in the cycloaddition.
The preparation of N-unsubstituted azomethine ylides has been the subject of intense study in
the recent years. These nonstabilized dipoles are highly reactive and may be used for the
preparation of heterocycles which are otherwise difficult to prepare.
Caesium fluoride-mediated desilylation of N-trimethylsilylmethylthioureas has been reported to
give new azomethine ylides with a hydrogen on the nitrogen atom <1997CL945>. Initial
S-alkylation of the silylmethylthiourea, followed by treatment with the fluoride source, give the
azomethine ylide, which reacts with N-methylmaleimide to give bicyclic amidines after elimination
of methanethiol (Scheme 62). Cycloadditions with fumaronitrile have also been reported.
An important method for the generation of N-unsubstituted azomethine ylides is the silyl group
migration from carbon to nitrogen in -silylimines. This migration is promoted by heat or fluoride
reagents such as phenyltrifluorosilane. The incipient azomethine ylide undergoes cycloaddition to give
N-unsubstituted pyrrolidines after hydrolysis of the nitrogen–silicon bond (Scheme 63). This strategy
has been recently applied to solid-phase-supported synthesis of pyrrolidines <2003T197>: an
aromatic aldehyde, p-hydroxybenzaldehyde is linked to the Merrifield resin by the hydroxy group,
then condensed onto an -trimethylsilylamine to give the corresponding imine. Upon treatment with
phenyltrifluorosilane in the presence of N-phenylmaleimide, cycloaddition occurs to give the polymer-
supported bicyclic pyrrolidine, which can be released from the resin by acidic treatment (Scheme 64).
Although the endo/exo selectivity was poor, 2,5-cis-pyrrolidines were formed predominantly.
n ()
Me3Si N SiMe3
Bn
AgF, CH2Cl2 Bn
Bn
N
N
()
O
n O
( )n
H
( )n
+ +
N
N N
H O N
Bn O S
O O S
O O S
O
n Yield (%) Ratio
1 62 98/2
2 58 80/20
3 68 95/5
Scheme 61
H H OTf
H Me3Si N Me3Si N
Me3Si N + N
C S N MeS N
S
CsF
H O N O
N N N
N Me H
–MeSH N
SMe DME
51% MeS N
O N O
O N O
Me
Me
Scheme 62
SiMe3 SiF2Ph
∆ SiMe3 PhSiF3
N N + Me3SiF
R1 N R2
R1 R2 R1 R2
H2C CH2 R1, R2 = alkyl, aryl H2C CH2
SiR3 H H SiF2Ph
R1 N R1 N R1 N R1 N
R2 R2 R2 R2
Scheme 63
Ph
H2N SiMe3 O
Cl + HO CHO
O CHO
N SiMe3
Merrifield resin
PhSiF3 Ph
Toluene
40 °C
O N O
Ph
H H H
HO HO Ph
N Ph N Ph N
CF3CO2H, CH2Cl2
O
+
81% O
O N O O N O N
O
Ph 93/7 Ph Ph
Scheme 64
In a recent study, a traceless linker with the silicon atom linked to a resin was used for solid-
phase-supported azomethine ylide generation and cycloaddition <2002OL3505>. Resin-bound
-silylimines were heated in toluene to promote silyl group migration from carbon to nitrogen
and subsequent cycloaddition of the azomethine ylide (Scheme 65). Molecular diversity was
brought by the silylimine and the substituents on the dipolarophile. Resin cleavage was easily
accomplished by mild acidic treatment.
Ph
Me
LDA Me N ∆
Si Cl + Ph N Ph Si Me Si Me
Me Me Ph Ph N Ph
MeO2C
CO2Me
toluene, 180 °C
sealed tube
H
Ph N Ph
HCl or TFA Me Si Me
Ph N Ph
84%
MeO2C CO2Me
MeO2C CO2Me
Scheme 65
The properties of silicon migration from carbon to heteroatom have been applied to the generation
of various azomethine ylides. Thus, -silylimidates, obtained through O-alkylation of the correspond-
ing amides, are transformed into azomethine ylides when treated with phenyltrifluorosilane
<1999T12969>. Cycloaddition with activated alkenes gives, after alcohol elimination, pyrrolines in
low stereoselectivity, whereas cycloaddition with dimethyl acetylenedicarboxylate gives pyrroles after
rearomatization (Scheme 66). A one-pot protocol for the synthesis of pyrroles from -silylamides by
O-alkylation and desilylation with caesium fluoride has been developed.
In an analogous reaction, azomethine imines were prepared by silicon group migration of tertiary
-silylnitrosamines <1999TL8849> (Scheme 67). Cycloadditions of these dipoles with activated
alkynes gave pyrazole derivatives. Aromatic -silylnitrosamines and simple trimethylsilyl nitrosa-
mines were used as precursors to the azomethine imines. Reaction with terminal alkynes led
predominantly to 3-substituted pyrazoles. As for azomethine ylides, polymer-supported synthesis
and cycloaddition reactions of azomethine imines, with a resin-bound silicon group was developed
<2000TL691>.
Me3Si O OMe
MeOTf, Et3N Me3Si OMe F
Ph N Ph Ph N Ph
Ph N Ph
H SiMe3
MeO2C MeO2C CO2Me MeO2C CO2Me

CO2Me
+
88% Ph N Ph Ph N Ph
54/46
Scheme 66
H CO2Et EtO2C H
SiMe3 OSiMe3
∆ H CO2Et
NO N N + N
Ph N Ph N Ph Ph
72% N N
Me Me
Me 85/15 Me
Scheme 67
Silyl group migration from carbon to oxygen (Brook-type rearrangement) of -silylallylamides

has been used for the stereoselective synthesis of cis-enamides. Aliphatic and aromatic -triethyl-
silylallylamides were heated in toluene or xylene to give, after hydrolysis of the O-silylimidates,
the propenylamides in good yields <2002AG(E)512> (Scheme 68). The reaction is remarkable for
its stereoselectivity as only cis-propenylamides are obtained. Mechanistic investigations have
demonstrated the presence of an intermediate azomethine ylide, which is stabilized by allylic
resonance, with the favored cis-configuration of the allylic anion <2003JA5111>. This highly
stereoselective rearrangement has been used for the synthesis of the proteasome inhibitors
TMC-95A and TMC-95B <2002AG(E)512>.
O SiEt3 OSiEt3 O
∆ H2O
Ph N Ph N Ph N
81%
H H H
Single isomer
Scheme 68
(ii) Thiocarbonyl ylides

Thiocarbonyl ylides are reactive species which may undergo various reactions, including [3+2]-
cycloaddition. Applications of these reactions are directed toward the synthesis of sulfur-contain-
ing heterocycles. As for azomethine ylides, the chemistry of thiocarbonyl ylides has been recently
reviewed <B-2002MI106-5>.
There are many methods for the generation of thiocarbonyl ylides, including those involving
the cleavage of a carbon–silicon bond. In analogy with the formation of azomethine ylides,
treatment of trimethylsilyl(chloromethyl)sulfide with caesium fluoride leads to the formation of
a thiocarbonyl ylide through elimination of chlorotrimethylsilane (Equation (84)).
CsF, MeCN
S ð84Þ
Me3Si S Cl
This electron-rich dipole reacts with activated alkenes to give 3,4-disubstituted tetrahydrothio-
phenes. A diastereoselective version of this cycloaddition with chiral ,-unsaturated amides,
leading to enantiomerically pure tetrahydrothiophenes, has been described, using camphorsultam
as the chiral auxiliary <1999OL1667> (Scheme 69). The best diastereoselectivities were
obtained at 0 C despite long reaction times. Performing the reaction in refluxing acetonitrile
resulted in strong increase of reactivity, with slight decrease in selectivity. Enantiomerically pure
3,4-disubstituted tetrahydrothiophenes were obtained after hydrolysis of the chiral auxiliary.

These heterocycles are interesting compounds, since sulfur extrusion with Raney nickel gives
stereochemically defined 2,3-dimethyl carboxylic acids, which are difficult to prepare otherwise.
This strategy has been applied to the synthesis of a fragment of pheromone component of
Macrodiprion Nemoralis <2000S1863> (Scheme 70).
O O Bu O Bu
CsF, MeCN
N Bu + Me3Si S Cl N + N
0 °C, 3–4 days
S S S S S
92%
O O O O 90/10 O O
Scheme 69
O OBn OBn
LiAlH4 HO OBn
C4H9
N S S
76% Me Me S
S S S
O O
Ra-Ni
EtOH
72%
OH
C4H9
Me
Me Me Me
Pheromone of Macrodiprion Nemoralis
Scheme 70
A different route to the same thiocarbonyl ylides involves the thermal decomposition of bis-
trimethylsilylmethylsulfoxide <1995H249>. Thiocarbonyl ylides are obtained in situ under mild
conditions, generally heating at 100–110 C in an aprotic solvent, and without any fluoride source.
[3+2]-Cycloadditions with various activated alkenes gives the tetrahydrothiophenes in moderate-
to-good yields (Scheme 71). This method for thiocarbonyl ylide generation is quite general and
has become the method of choice for the synthesis of thiophene-type heterocycles: a recent report
described the thermal [3+2]-cycloaddition between unsubstituted thiocarbonyl ylide and
C[60]-fullerene <1999TL1543>. Cycloaddition of the same thiocarbonyl ylide with bis-trimethyl-
silylacetylene gives, after rearomatization, 3,4-bis(trimethylsilyl)thiophene <1997JOC1940>
(Scheme 72). This latter compound may be used as the starting material for the preparation
of various 3,4-disubstituted thiophenes.
S SiMe3 100 °C –(Me3Si)2O

Me3Si Me3Si S Me3SiO S
O
CO2Et
+ CO2Et
S
55% S
Scheme 71
Me3Si SiMe3 Me3Si SiMe3

Me3Si S SiMe3 + Me Si HMPA, 100 °C DDQ, 65 °C
3 SiMe3
O 15% 76%
S S
Scheme 72
The thermal elimination of sulfoxides for generation of thiocarbonyl ylides allows the prepara-
tion of new dipoles, in which an additional double bond is included. Thus, thermal elimination of
-benzylidine--trimethylsilylmethyl trimethylsilylmethyl sulfoxide gives an allenic dipole, which
undergoes cycloaddition with activated alkenes to give 2-alkylidene tetrahydrothiophenes
<1995H249> (Scheme 73).
CO2Et
SiMe3 EtO2C CO2Et
HMPA, 100 °C EtO2C
Ph Ph C
S SiMe3 S Ph
O 60% S
Scheme 73
Alkylidenethiocarbonyl ylides may also be prepared by fluoride-mediated desilylation: thus, a

1,3-indanedione-derived ketene dithioacetal was desilylated using caesium fluoride and underwent
cycloaddition with carbonyl compounds to give 2-alkylidene monothioacetals <1994TL3555>
(Scheme 74). Both electron-withdrawing and electron-donating groups were tolerated on the
carbonyl compound, although the former gave better yields in the cycloaddition reaction.
O O O O
SMe CsF O H
Ph H
SiMe3 Ph
S S 71% S
O O O
Scheme 74
(iii) Trimethylenemethane
As for azomethine ylides, carbon–silicon bond cleavage is a common and efficient way to generate
trimethylenemethane species. The acetate ester of 2-trimethylsilylallyl alcohol, when treated with a
palladium complex, gives rise to trimethylenemethane, which undergoes [3+2]-cycloadditions with
various unsaturated systems to give methylenecyclopentane derivatives, as well as the isomeric
product with a endocyclic double bond (Scheme 75). Product distribution depends on the nature
of palladium ligand, greater amount of methylene cyclopentane being obtained using phosphite
ligands. The scope and application of the trimethylenemethane cycloadditions have been extensively
reviewed <1996CRV49, B-2002MI106-6>. The concerted character of the [3+2]-cycloaddition of
palladium trimethylenemethane complex has been recently demonstrated <1999JA9313>.
Pd(0)L4
and/or
AcO SiMe3 PdL2
Scheme 75
Unsubstituted trimethylenemethane has been recently used for the preparation of new proline
derivatives, via diastereoselective cycloaddition with an enantiomerically pure ,-unsaturated
lactam <2003TL5033> (Scheme 76). Further cyclopropanation of the exocyclic double bond and
chiral auxiliary removal afforded a new fused proline surrogate.
AcO SiMe3
Pd(POPr3i )4, toluene, reflux
O N
O 80% O N
Ph N CO2H
O
t-BOC
Ph
Scheme 76
The regioselectivity of [3+2]-cycloaddition of substituted trimethylenemethane derivatives with

electron-deficient alkenes is the subject of continuous study. Three isomers may be formed during
the cycloaddition process, the major isomer being the exo-methylene cyclopentane derivative with
the substituent to the electron-withdrawing group. Similar results are obtained from both
isomeric precursors, due to probable isomerization of trimethylenemethane–palladium complex
before cycloaddition. This isomerization could be suppressed by the use of high pressure, which
favors the bimolecular process. Thus, cycloadditions between the methyl-substituted trimethyl-
enemethane complex and electron-deficient alkenes showed complete reversal of regioselectivity,
when the reaction was performed at high pressure <1995JA3284> (Scheme 77). Regioselectivity
was further increased when a bidentate phosphite ligand was used. Both isomeric precursors did
not lead to the same regioisomers, indicating that no complex isomerization occurred before
cycloaddition. This reversal of selectivity was observed for cyclic and acyclic systems.
EWG R
R R Pd(0)L4 R R
or + +
AcO SiMe3 AcO SiMe3
EWG EWG
EWG
Major
Me
Me
Pd(PPh3)4, THF,1 atm
Me Me +
+ +
O O AcO SiMe3 63%
O O O O
O O
9/0/91
Me
Pd(tpdp)2, 15 kbar
Me
Ph Me PhH, PhCH3
Me +
+
O 90% Ph Ph
AcO SiMe3
COMe
COMe
3.6/1
O O O O
tpdp: P P
O O
Scheme 77
The cyclopropyl-substituted trimethylenemethane–palladium complex is prepared from 2-(1-tri-

methylsilyl-1-cyclopropyl) allyl pivaloate and its reaction with dimethyl benzylidene malonate
shows reversal of regioselectivity depending on the nature of palladium ligand <1995TL2917>.
Although the use of the triisopropylphosphite ligand gave predominantly the methylenecyclopro-
pane derivative, the bidentate ligand tris (2,4-pentandedioxy)diphosphite (tpdp) gave the vinylcy-
clopropane derivative with excellent stereoselectivity. Reaction with methyl cinnamate or
coumarin showed preference for the formation of the vinylcyclopropane isomer, albeit with a
lower isomeric ratio.
Compounds in which the trimethylenemethane moiety is included in a cyclopentene ring have
recently been studied <2001EJO767>. These undergo [3+2]-cycloadditions in the presence of a
palladium complex, with the regioselectivity depending on the presence of substituents on the
cyclopentene ring. Although the presence of a gem-dimethyl substituent induced a regioselective
reaction, it was completely opposite to the one generally observed. This particular outcome has
been explained by the absence of equilibration of the trimethylenemethane species, due to
conformational freezing by the gem-dimethyl substituent.
Intramolecular trimethylenemethane cycloadditions represent an efficient strategy for the
synthesis of bicyclic ring systems. In the total synthesis of isoclavukerin, intramolecular cycload-
dition of an optically active precursor was studied <1996JA10094> (Scheme 78). The efficiency of
this cycloaddition depends on the nature of the electron-withdrawing group on the double bond.
Although a simple vinyl sulfone failed to react with the trimethylenemethane, an alkene doubly
activated with both sulfone and ester groups on the same carbon gave the perhydroazulene ring
system, as a mixture of isomers in good yields. Isomerization of the crude product gave the
compound with internal double bond as a single isomer. Surprisingly, the alkylidenemalonate
precursor (with two ester functions) gave a single cycloadduct, indicating that with the bis-ester,
cycloaddition is faster than trimethylenemethane isomerization.
DBU
O
O O O
SiMe3 Pd(OAc)2 H H
P(OPri)3, Me3SnOAc
OAc + +
EWG CO2Me CO2Me CO2Me
H H H
Me CO2Me Me EWG Me EWG Me EWG
EWG Yield (%) Ratio
SO2Ph 83 1.9/1/0.2
CO2Me 51 0/100/0
H
Me
Isoclavukerin
Scheme 78
A formal [3+2]-cycloaddition reaction of an allyl silane derivative leads to methylenecyclo-

pentane products via a nonconcerted mechanism, with an anionic or cationic intermediate. Sulfur-
substituted methylene cyclopentanes have been prepared by Lewis acid-catalyzed reaction of
2-trimethylsilylallylic acetates or benzoates <1996TL5943> (Scheme 79). In contrast to the
concerted [3+2]-cycloaddition of trimethylenemethane, electron-rich alkenes such as enol ethers
and vinyl sulfides are better partners for the reaction. This method may be therefore regarded as
complementary to the [3+2]-cycloaddition.
Bridgehead bicyclic systems have been prepared by a formal methylenecyclopentane annulation on
bicyclic -keto sulfones, followed by fragmentation <1999TL2053>. Desilylation of the allyl silane
with TBAF gave an allylic anion, which added onto the ketone. Upon basic treatment, fragmentation
gave a dienic ketone with a larger ring system. An example is shown in Scheme 80.
SMe
Me3Si Me3Si
EtAlCl2, CH2Cl2, –23 °C
PhCO2 SC5H11 SC5H11
Me Me
Me3Si
MeS SC5H11
Me SC5H11 –Me 3Si
SMe
81% 91/9
H Me
Scheme 79
OH
O TBAF, THF KOBut, THF O
SiMe3 82% 87%

PhO2S PhO2S
Scheme 80
1.06.3.2.5 Free-radical-mediated reactions

Homolytic cleavage of a carbon–silicon bond is often a difficult process and only precursors to
stabilized radicals such as benzyltrimethylsilane or allyltrimethylsilane have been employed.
The generation of alkyl radicals from alkyl silanes generally involves irradiation of the
substrate to give a cation radical, which fragments to a trimethylsilyl cation and an alkyl
radical. The photochemistry of organosilanes has been reviewed <1995CRV1527>. The rate of
the photodecomposition of benzyltrimethylsilane has been greatly increased by nucleophilic
assistance <1997JA1876>, a basic solvent such as acetonitrile or dichloromethane or an
alcohol coordinating to the silicon and therefore facilitating the generation of benzyl radical
(Scheme 81). These radicals are not trapped with carbon nucleophiles, but dimerized to give
1,2-diphenylethane, in the case of R¼Ph.
hν + +
R-CH2SiMe3 RCH2SiMe3 RCH2 + Me3Si
Scheme 81
1.06.3.3 Substitution of Germanium Functions

Although alkylgermanium derivatives possess little application in organic synthesis, the chemistry
of acyltrialkyl germanium derivatives has shown some interest in terms of acyl radical precursors
and radical acceptors. A general method for the synthesis of acyltrialkyl germanes has been
described, involving the addition of trialkylgermyllithium to aldehydes, followed by oxidation
<1994JCS(P1)1589>. Intramolecular reactions of alkyl halides (bromides or iodides) with acyl-
triphenylgermanes lead to the formation of cyclic ketones upon irradiation <1997JA4797>
(Equation (85)). In contrast to acyl silanes, no Brook-type rearrangement (migration of germa-
nium group from carbon to oxygen) was observed. Different ring-size cyclic ketones could there-
fore be synthesized from primary, secondary, or tertiary alkyl halides.
O
hν, benzene O
GePh3 ð85Þ
80% Me
Me
Br
1.06.4 SUBSTITUTION OF METAL FUNCTIONS

Carbon–carbon bond formation by reaction of an alkyl metal reagent with another organome-
tallic species is a very rare reaction. However, various carbon nucleophiles may react with cationic
3-allyl metal complexes in a regio- and stereoselective fashion to give allylated products. Since
chiral complexes are available, recent studies have focused on the preparation and reactions of
these systems.
Cationic tetracarbonyl (3-allyl) iron(I) complexes bearing an electron-withdrawing group (ester
or sulfone) are prepared from a -alkoxy-,-unsaturated ester or sulfone by reaction with iron
pentacarbonyl followed by acidic treatment (Equation (86)). Detailed preparation of a chiral
sulfone cationic iron complex from ethyl (S)-lactate has been described <2000OS177,
2000OS189>. This enantiomerically pure complex is obtained with inversion of configuration
with respect to the starting leaving group.
i. Fe2(CO)9
R SO2Ph ii. HBF4 R SO2Ph
ð86Þ
BF4
OAc Fe(CO)4
Reaction with nucleophiles occurs with high regioselectivity anti to the electron-withdrawing
group, and with high stereoselectivity, resulting in an overall retention of configuration, giving
allylated products after oxidative decomplexation of the resulting 2-iron complex. In contrast to
-allyl palladium complexes, hard nucleophiles may be used. Functionalized organozinc reagents
have been used on both sulfone <1996SL18> and ester <1997SL789> complexes, although yields
were slightly better with the sulfone complex (Equations (87) and (88)). All compounds were
obtained as single regio- and diastereomers after decomplexation. Allyl silanes are also excellent
reaction partners for the cationic iron complex. The stereoselective allylation of chiral cationic
tetracarbonyl (3-allyl) iron(I) complexes has been used as the key step for numerous syntheses of
natural products <1997SL421>.
i. EtO2C Cu(CN)ZnBr, THF

Me SO2Ph Me SO2Ph
ii. CAN/H2O ð87Þ
BF4
Fe(CO)4 48% EtO2C
Me SO2Ph MeO2C MeO2C S O2Ph

BF4 + Cu(CN)ZnI ð88Þ
Fe(CO)4 t-BOCHN 47% t-BOCHN Me
The reaction of silyl enol ethers or silyl ketene acetals provides an efficient and stereoselec-
tive entry to 1,6-diesters or 1,6-ketoesters <1996JOM(519)147> (Equation (89)). Reaction of
the chiral, enantiomerically pure ester complex gave the corresponding adducts essentially as
pure regio- and stereoisomers. This study also revealed the importance of a stereochemically
defined leaving group for the preparation of the chiral cationic tetracarbonyl (3-allyl) iron(I)
complex since diastereomeric -benzyloxy esters of 8-phenylmenthol gave a mixture of
diastereomeric iron complexes upon complexation and acidic treatment, showing that config-
uration of CFe bond is less controlled by chiral auxiliary than by the configuration of the
leaving group (Equation (90)).
OSiMe3 i. –78 °C to 0 °C Me CO2Me

Me CO2Me ii. CAN
+ Me MeO Me ð89Þ
OMe
Fe(CO)4 86% Me
Me O
Ph Ph
Ph i. Fe2(CO)9 O
O O
Me Me ii. HPF6 Me Me Me Me
Me + Me ð90Þ
Me O O
O
Me Me
OBn Me Fe(CO)4 Fe(CO)4
Condensation of the sulfone-containing chiral iron(I) complex with silyl enol ethers leads to
1,6-ketosulfones in a highly regio- and stereoselective fashion. This reaction was applied to a total
synthesis of the furanosesquiterpene myoporone <1997SL421>.
In another approach to chiral 1,6-ketoesters, a racemic cationic tetracarbonyl (3-allyl) iron(I)
complex was reacted with a variety of chiral nucleophiles, including chiral enamines, metallated
imines, or -silyl ketones <1996JOM(514)227>. Reactions occurred with moderate-to-good
stereocontrol, showing substrate control is more effective than reagent control. An example of
the alkylation of a chiral enamine is shown in Equation (91).
OMe i. –78 °C
CO2Me N ii. CAN O
+ Et Et ð91Þ
Fe(CO)4 41% CO2Me
72% ee
Planar chiral cationic molybdenum complexes are prepared from allylic acetates by treat-
ment with molybdenum carbonyl complexes followed by ligand displacement with cyclopenta-
dienyl anion. The cationic complex is obtained by treatment with nitrosonium
tetrafluoroborate. Recently, the use of the Mo(CO)4(Pyr)2 complex as a more reactive reagent
for preparation of 3-allyl molybdenum complexes has been recommended <2000SL1765>. In
the same way as for iron complexes, planar chiral molybdenum complexes are prepared from
enantiomerically pure allylic esters, benzoates giving the best yields. These highly electrophilic
complexes react with carbon nucleophiles with good stereoselectivity, after decomplexation
using cerium ammonium nitrate (CAN) or oxygen. In contrast to iron complexes, an electron-
withdrawing group on the allylic moiety is not necessary. Stereoselective allylation reactions
using chiral cationic molybdenum complexes have been used for the assembly of stereodefined
acyclic chains: in a synthesis of cryptophycin 4, reaction between an allylic molybdenum
complex and a functionalized organolithium reagent gave an allylated dioxane with high
stereocontrol, although regioselectivity was low (Scheme 82). One of the isomers was used
for completion of the cryptophycin 4 synthesis <2000SL463>.
A new approach to stereodefined C-glycosides involves alkylation of a chiral cationic molybde-
num complex with glucosyl copper reagents <1998SL425>. Reaction occurs with complete reten-
tion of configuration at the anomeric position, and with complete regioselectivity (Scheme 83). This
methodology has been applied to the synthesis of the C1C9 fragment of the naturally occurring
antibacterial compound salinomycin <1998JCS(P1)9>.
i. Mo(CO)4(Pyr)2
ii. LiCp R1 R2
R1 R2 iii. NOBF4
BF4
OCOPh ON Mo CO
Cp
OTIPS Ph OTIPS
Ph Me i. THF, –78 °C H
Cu
ii. O2 Me
+
ON Mo CO O O O O
Cp 71%
Ph Ph
+ 1/1.2
Me
O Me OTIPS
H
O O N Ph
O H O O
O N O OMe Ph
Me H
Cryptophycin 4
Scheme 82
OBn OBn
BnO O BnO O Li
i. BnO i. BnO
Li
CuBr.SMe2 CuBr.SMe2
OBn
THF/(Pri) 2S THF/(Pri)2S OBn
O Me
BnO ii. CAN ii. CAN Me
BnO BnO O
81% ON Mo CO 49% BnO
Me Cp
OSiPh2But
OSiPh2But i. –78 °C
Me
ii. O2 O Me
O Me +
ON Mo CO 44%
Cu(SPh)Li Cp Me
Scheme 83
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Biographical sketch
Cyrille Kouklovsky studied chemistry at Paris-Sud University, Orsay,

France, and did his postgraduate studies at the Institut de Chime des
Substances Naturelles, CNRS, Gif-sur-Yvette, under Prof. Yves Lan-
glois’ supervision, working on the development of asymmetric cationic
Diels–Alder reactions. He obtained his Ph.D in organic chemistry in
1989, and spent three years as a postdoctoral fellow in Professor Steven
V. Ley (Imperial College, London, UK, then Cambridge University),
working on the total synthesis of rapamycin. He returned to France in
1994, and was appointed by the CNRS at the Department of Chemistry
in Paris-Sud University. In 2003, he was promoted as Professor of
chemistry in the same University. His main research topics are the
development of new synthetic methodology, and the total synthesis of
biologically active natural products.
1.07
One or More CC Bonds Formed
by Addition: Addition of Carbon
Electrophiles and Nucleophiles to
CC Multiple Bonds
A. ARMSTRONG and N. J. CONVINE
Imperial College London, London, UK
1.07.1 INTRODUCTION 287

1.07.2 ADDITION OF CARBON ELECTROPHILES TO CC MULTIPLE BONDS TO GIVE
TETRACOORDINATE PRODUCTS 288
1.07.2.1 Addition of Alkanes and Alkyl Electrophiles to Alkenes 288
1.07.2.2 Addition of Alkenes to Alkenes 289
1.07.2.3 Hydroformylation, Hydroacylation, and Hydrocarboxylation 289
1.07.2.3.1 Hydroformylation 289
1.07.2.3.2 Hydroacylation 290
1.07.2.3.3 Hydrocarboxylation 290
1.07.2.3.4 Dicarboxylation 291
1.07.2.4 Cyclopropanation 291
1.07.3 ADDITION OF CARBON NUCLEOPHILES TO CC MULTIPLE BONDS TO GIVE
1.07.3.1 Introduction 291
1.07.3.2 Addition to Electron-deficient Alkenes 291
1.07.3.2.1 Introduction and general aspects 291
1.07.3.2.2 Addition of stabilized nucleophiles 292
1.07.3.2.3 Addition of unstabilized nucleophiles: alkyl, alkenyl, alkynyl, and aryl anion equivalents 301
1.07.3.3 Addition to Unactivated Alkenes 306
1.07.3.3.1 Addition of stabilized nucleophiles 306
1.07.3.3.2 Addition of unstabilized nucleophiles 307
1.07.1 INTRODUCTION
This chapter serves to update the earlier account <1995COFGT(1)293> of several key processes
in CC bond formation which formally involve addition of carbon electrophiles or nucleophiles
to CC multiple bonds. Because it is the formation of tetracoordinate products that is of interest,
virtually all the addition processes discussed involve addition to alkenes rather than to alkynes.
Since the original chapter was written, the most striking advances are the greatly improved levels
of reagent-controlled enantioselectivity that have been realized, particularly in catalytic asym-
metric conjugate addition processes.
287
288 One or More CC Bonds Formed by Addition
1.07.2 ADDITION OF CARBON ELECTROPHILES TO CC MULTIPLE BONDS TO

GIVE TETRACOORDINATE PRODUCTS
Addition of carbon electrophiles to alkenes plays a role in several synthetically useful reactions in
CC bond formation. Work by Mayr and co-workers in recent years <2003ACR66> has
allowed development of a set of quantitative parameters for -nucleophilicity, allowing prediction
of the reactivity of particular electrophile/nucleophile pairs. The initial product of formal electro-
philic addition to an alkene is a carbocation; a general discussion of the formation of these species
appears in Chapter 1.19. Subsequent reactions of carbocations (e.g., loss of a proton, trapping
with nucleophiles) often lead to the formation of functionality that are the subject of later
chapters, so only limited coverage is presented here. Hydroformylation is also briefly presented,
although it is also discussed later (Chapters 3.01, 3.04, 5.02, and 5.03).
1.07.2.1 Addition of Alkanes and Alkyl Electrophiles to Alkenes

Direct addition of alkanes to alkenes continues to be of industrial importance, but of lesser
significance in the laboratory due to issues of chemo- and regioselectivity. The overall alkylation
of alkenes is accomplished in a new system reported by Biermann and Metzger
<1999AG(E)3675>. These authors exploited the known decarboxylation of chloroformates in
the presence of Lewis acids, resulting in the formation of carbocations which can add to alkenes.
Thus, reaction of trans-4-octene with isopropyl chloroformate mediated by ethylaluminum
sesquichloride (Et3Al2Cl3) gave a good yield of 4-isopropyloctane (Equation (1)). Interestingly,
hydride is transferred from the aluminum more rapidly than ethyl. Addition of a more effective
hydride donor such as triethyl silane allowed the method to be extended to cyclohexene and to
1,1-disubstituted alkenes, reducing competing alkene oligomerization. Use of isopentyl or
neopentyl chloroformate gave products arising from rearrangement of these alkyl substituents.
i. Et3Al2Cl3, CH2Cl2
O Pr i
Prn –15 °C to rt
Pr
n + Prn ð1Þ
PriO Cl ii. H2O Prn
67%
A recently described Zr-catalyzed system allows reaction of styrenes with carbon electrophiles
(Equation (2)) <1998TL9201, 2000JA5977, 2001OL2097>; intramolecular reactions are possible
<2002OL395>. Knochel has demonstrated that hydroboration of enones which are protected as
acetals or dithianes, followed by boron–zinc exchange, leads to organozinc reagents, which may
be quenched with allylic, alkynyl, or propargyl halides. Overall, the transformation represents
addition of the carbon electrophile to the alkene. The boron–zinc exchange proceeds with
retention of configuration, allowing preparation of optically active products via asymmetric
hydroboration (Scheme 1) <2001AG(E)3022>.
Cp2ZrCl2 (5 mol.%)
BunMgCl (2 equiv.) n-C8H17
Ph + n-C8H17OTs ð2Þ
THF, 55 °C Ph
90%
O O O
i. (–)-IpcBH2 i. CuCN·2LiCl
O O O
ii. Et2BH (5 equiv.) ii. RBr
iii. Pr2i Zn (5 equiv.) ZnPri R
91% ee R = allyl: 54%
R = Me3SiC C: 46%
Scheme 1
One or More CC Bonds Formed by Addition 289
1.07.2.2 Addition of Alkenes to Alkenes

The most spectacular examples of addition of alkenes to alkenes are polyene cyclizations, which
mimic the biosynthetic pathway to steroids. Recent work has focused on control of enantio-
selectivity <2002JA3647>. A catalytic antibody has also been developed which effects polyene
cyclization <1999AG(E)1743>.
1.07.2.3 Hydroformylation, Hydroacylation, and Hydrocarboxylation

Hydroformylation and hydrocarboxylation (Equation (3)) are extremely important industrial
processes. Since these reactions and the related hydroacylations result in preparation of alde-
hydes, carboxylic acid derivatives, and ketones, respectively, they are also covered in Chapters
3.01, 3.04, 5.02, and 5.03.
H O
Catalyst
R + CO + H–X
R X
ð3Þ
Hydroformylation X=H
Hydroacylation X=R
Hydrocarboxylation X = OH, OR, NR2, Cl, etc.
1.07.2.3.1 Hydroformylation
Hydroformylation, the addition of carbon monoxide and hydrogen to an alkene, is generally
performed using cobalt or rhodium catalysts, the latter being more reactive. An industrial view of
the status and importance of the reaction has appeared <2002MI1>, as well as a comprehensive
account of recent work relevant to the use of the reaction in organic synthesis <2001S1>. The
hydrogen and aldehyde functionalities are added in a syn-fashion, and a wide range of functional
groups is tolerated. Generally, greater substitution on the alkene results in slower hydroformyla-
tion; reactive Rh-phosphabenzene complexes give promising results here <2001CEJ3106>. For
unsymmetrical alkenes, regiochemistry is an issue. 1,1-Disubstituted and trisubstituted alkenes
usually display high regioselectivity, with the formyl group becoming attached to the less sub-
stituted end of the alkene. Terminal aliphatic alkenes generally lead to linear aldehydes, although
specific ligand systems can promote the formation of branched products. Styrenes often afford
branched products. Regiocontrolled hydroformylation of 1,2-disubstituted alkenes remains
difficult.
Control of diastereoselectivity, i.e., stereocontrol relative to pre-existing stereocenters,
has received much attention recently. Breit has developed the concept of ‘‘substrate-bound
catalyst-directing groups’’ in which the substrate contains a phosphine binding site for the
rhodium catalyst <2003ACR264>. This allows syn-selective hydroformylation of methallylic
alcohols (Equation (4)). Leighton has explored the directing properties of dibenzophosphol-5-
ylmethyl ethers of allylic alcohols, resulting in highly diastereoselective formation of branched
aldehydes, the reverse of the usual regiochemical outcome (Equation (5)) <2001JA11514>.
Enantioselective hydroformylation has been reviewed <1995CRV2485, 1995TA1453, 2001S1>.
The most generally successful system appears to be a BINAPHOS 1 rhodium complex
<1993JA7033>.
0.7 mol.% Yield

Rh(acac)(CO)2/P(OPh)3 (4 equiv.) R (%) syn:anti
PPh2 PPh2
20 bar H2/CO (1:1) Et 81 73:27 ð4Þ
O O Toluene, 90 °C, 24 h O O Ph 99 92:8
55–99% CO2Me 80 90:10
R R CHO
Rh(acac)(CO)2 (2.5 mol.%) Yield

P P
R anti:syn (%)
50 psi H2/CO ð5Þ
O O Me 81:19 92
H MeCN, 65 °C CHO Ph 86:14 96
R R
H Pri 94:6 94
PPh2
O
P
O
O
= [(R ), (S )-BINAPHOS]
Tandem processes in which the aldehyde product is modified by, for example, olefination,
reductive amination, allylboration, or aldol addition have been comprehensively reviewed
<1999CRV3329, 2001S1>.
1.07.2.3.2 Hydroacylation
Hydroacylation, the addition of an aldehyde to an alkene, has progressed far less than hydro-
formylation. A key problem to overcome is the decarbonylation of the intermediate acylmetal
hydride formed from the oxidative addition of a transition metal into the aldehyde CH bond.
Strategies adopted have involved incorporating functionality capable of stabilizing this intermedi-
ate by chelation, e.g., by in situ preparation of picolylimine derivatives (generally limited to
nonenolizable aldehydes) <2001CC2558, 2002CEJ2423, 2003OL1365> or by the incorporation
of a -sulfide in the aldehyde <2004AG(E)340>. Intramolecular hydroacylation has been used
for obtaining cyclopentanones (Equation (6)) <2000JOC5806>.
Rh[(S)-BINAP]ClO4 (5 mol.%) O
CH2Cl2
rt, 1 h
OHC 84%
ð6Þ
dr 96:4
95% ee
1.07.2.3.3 Hydrocarboxylation
Hydrocarboxylation (Equation (3)) allows access to many different carboxylic acid derivatives via
reaction of an alkene with carbon monoxide and a catalyst in a protic solvent, HX. Palladium-
catalyzed hydrocarboxylation of vinyl aromatics is a convenient route to 2-arylpropionic acid
derivatives (Equation (7)) <1999OL459>; a review of the mechanism of this reaction has appeared
<2001EJI2719>. Relative to hydroformylation, control of regio- and stereochemistry in this
process has received little attention in recent years. An amine-directed hydrocarboxylation leading
to the formation of - and -lactones has been described <1998OM2076>. For direct introduction
of amido and ester groups to alkenes, as with hydroacylation, substrates capable of chelation to the
metal catalyst have been developed to minimize decarbonylation of the intermediate metal hydro-
acyl <2003OL2687, 2002JA750>. Asymmetric hydrocarboxylation of vinylarenes can be achieved
by asymmetric hydroboration followed by homologation <1999JOC9704>.
PdCl2(PPh3)2 (0.2 mol.%)

CO, H2O
Methyl ethyl ketone
COOH ð7Þ
TsOH/LiCl
0.22 h, 45 °C
91%
1.07.2.3.4 Dicarboxylation
Palladium-catalyzed dicarboxylation, the 1,2-addition of two carboxyl groups to an alkene, has
been known for some time (Equation (8)) <1976JA1810>, and proceeds in a syn-fashion
<1976JA1806>. More recently, the electrochemical dicarboxylation of aryl-substituted alkenes
has been described <2001SL418> (Equation (9)); this reaction is not stereospecific.
PdCl2 (5.6 mol.%), CuCl2 (2 equiv.)
NaOAc (2 equiv.), MeOH MeO2C CO2Me
ð8Þ
Prn 3 atm CO, rt, 72 h Prn
53%
Ph Pt cathode, Mg anode Ph CO2H

CO2H
3 F mol–1, 25 mA cm–2 ð9Þ
+ CO2
0.1 M Et 4NClO4 , DMF, –10 °C
65%
1.07.2.4 Cyclopropanation
Reaction of alkenes with carbenes or metal carbenoids is an extremely common approach for
the synthesis of cyclopropanes <2001T8589>. This topic is discussed in Chapter 1.08. Methods
for cyclopropane formation which involve initial nucleophilic attack on the alkene are covered
elsewhere in this chapter (Section 1.07.3.2.1).
1.07.3 ADDITION OF CARBON NUCLEOPHILES TO CC MULTIPLE BONDS TO

GIVE TETRACOORDINATE PRODUCTS
1.07.3.1 Introduction
This section considers addition of carbon nucleophiles to alkenes to form new CC single bonds
(Equation (10)). This process is clearly most facile for electron-poor alkenes, which have therefore
been most widely studied. These reactions are often known as conjugate addition, or, in the case
where a carbonyl group activates the alkene, as 1,4-addition. When stabilized nucleophiles are
used, the process is sometimes called the Michael reaction. Recent developments in nucleophilic
addition to unactivated alkenes are also discussed.
i. R– R E
ii. E+ ð10Þ
E = H or C
1.07.3.2 Addition to Electron-deficient Alkenes
1.07.3.2.1 Introduction and general aspects

In <1995COFGT(1)293> the principles governing reactivity of electron-poor alkenes and the
factors influencing the balance between 1,4- versus 1,2-addition to ,-unsaturated carbonyl
systems were summarized. It also gave an overview of attempts to render the additions
diastereoselective, for example, using chiral auxiliaries. In recent years, attention has focused
heavily on reagent-controlled asymmetric synthesis, particularly enantioselective catalysis, and so
the dramatic progress in this area will make up a large part of this section. Some excellent reviews
have appeared recently <2000T8033, 2001S171, 2003AG(E)1688>, so the emphasis here will be
on key reactions and the most recent developments. Reviews on asymmetric addition to specific
substrates—namely, nitroalkenes <2002EJO1877> and unsaturated nitriles <2003CRV2035>—
have also appeared.
A synthetically valuable aspect of many conjugate addition reactions is the possibility of
trapping the initially formed anion with an electrophile. A specific class of reaction is cyclopro-
panation using telluronium <1996JOC5762, 1997JOC954, 2000JOC6257> or sulfur ylides
<1997CRV2341>. Stoichiometric chiral sulfur ylides for asymmetric cyclopropanation have
been reported <1998AG(E)1689, 2002JA2432>. Aggarwal and co-workers <1997CC1785,
2000JCS(P1)3267> have developed a catalytic system in which a sulfur ylide is generated by
Rh-catalyzed reaction of a sulfide with a diazo compound. A recent advance is the ability to
generate the diazo compound in situ (Equation (11)) <2001AG(E)1433>. Another interesting
catalytic (albeit currently nonasymmetric) method for ylide-mediated CC bond formation which
formally involves conjugate addition and enolate trapping is shown in Equation (12)
<2003AG(E)1035>. Here, an allylic phosphorus ylide is generated by reaction of triphenylpho-
sphine with an allylic halide or acetate; conjugate addition and ring closure provides a
cyclopentene product and allows regeneration of the phosphine.
Rh2(OAc)4 (1 mol.%)
+
BnEt3NCl (20 mol.%) Ph O
O Na
– 2 (20 mol.%)
+ N ð11Þ
Ph Ph Ph N Ts 1,4-Dioxane, 40 °C Ph Ph
73% 4/1 trans/cis
91% ee
PPh3 (10 mol.%) EtO2C COPh

EtO2C COPh Br K2CO3 (1.5 equiv.)
+ ð12Þ
CO2Et Toluene, 110 °C
70% EtO2C
1.07.3.2.2 Addition of stabilized nucleophiles
(i) Addition of 1,3-dicarbonyl compounds and related nucleophiles

Addition of 1,3-dicarbonyl compounds to electron-poor alkenes is a well-established method for
CC bond formation, and has continued to attract considerable attention. Nitroalkenes are
excellent acceptors, and asymmetric Michael addition to these substrates has been reviewed
<2002EJO1877>. Ji and co-workers <1999JA10215> reported a catalytic asymmetric variant
of this reaction (Equation (13)) utilizing Mg(OTf)2 to promote enolization in the presence of
chiral bisoxazoline ligand 3.
O O
N N
O O 3 (5.5 mol.%) Yield ee

Mg(OTf)2 (5 mol.%) O Ph R (%) (%)
R OEt N-Methylmorpholine (6 mol.%) ð13Þ
+ NO2 Me 95 90
R OEt 92 92
CHCl3, sieves, rt
NO2 CO2Et
Ph
Addition of 1,3-dicarbonyls to ,-unsaturated carbonyl compounds is also of exceptional

synthetic value. Traditionally, strongly basic reaction conditions were employed, which often
led to several side reactions. Christoffers has summarized the advantages of using transition
metal catalysis <1998EJO1259>, which can avoid these problems. Ferric chloride trihydrate is
a particularly effective catalyst <2001SL723, 2003EJO1665>. Asymmetric catalysis of the
reaction has developed enormously in the last few years. Early results were summarized in
recent reviews <2000T8033, 2001S171, 2003AG(E)1688>. These include catalysis by rubidium
prolinates <1993AG(E)1176>; Ni(OAc)2 in the presence of a chiral diamine <1998EJO1259,
2000EJO701> or a supported quinine derivative <1999TL7091>; Co(OAc)2 in the presence of
a chiral ligand <1998CEJ818>; and the Rh-catalyzed addition of -cyano esters to enones
and acrolein <1994T4439, 2002CEJ2968>. More recently, asymmetric addition of cyclic
1,3-dicarbonyl compounds to unsaturated -keto esters catalyzed by chiral Cu(II)-bisoxazoline
complexes has been described <2003JOC5067>. Some of the most spectacular results in the
Michael addition of 1,3-dicarbonyls have come from Shibasaki and co-workers using metal
BINOL complexes. These include the heterobimetallic complex (Na3[La(BINOL)3] (LSB, 4)
<1995JA6194, 1996TL5561> and its aluminum counterpart (Li[Al(BINOL)2]) (ALB, 5)
<1996AG(E)104, 1996CEJ1368, 1998JOC3666, 1998JOC7547> which possess both Lewis
acid and Brønsted base properties, and can therefore activate both components of the Michael
addition <2002CRV2187>. The ALB complex 5, prepared by reaction of LiAlH4 with
2 equiv. of BINOL, may be used in low loadings (0.3–1 mol.%) at room temperature, but is
moisture sensitive. The initially formed Al-enolate can be trapped in an aldol reaction with
aldehydes (Scheme 2) <1996AG(E)104>, a feature that has been used in the synthesis of
prostaglandin derivatives <1998JOC3666>. -Nitro esters may be used as nucleophiles in place
of 1,3-dicarbonyls <1997TA3403>. The sodium-free version of the lanthanum BINOL complex 4
also gives excellent Michael addition enantioselectivities <1994JA1571>. Even better in terms of
practicality is the linked-BINOL system 6 <2000JA6506, 2002CRV2187, 2002MI3>. The ether
bridge can coordinate to the metal center, resulting in the catalyst being stable, storable, and
reusable. Relative to the ALB system 5, 6 is easier to handle but the reactions require higher
catalyst loadings (10 mol.%). Some examples of highly enantioselective Michael addition
catalyzed by 6 are shown in Equation (14). Excellent enantioselectivities are obtained for
addition to cycloalkenes, including seven- and eight-membered enones (Equation (14)), with
slightly lower ee for cyclononenone. Addition to acyclic enones was performed at lower reaction
temperature and affords good selectivity (Equations (15) and (16)). LSB 4 gives better ee (93%
ee) for the reaction in Equation (16), again at low temperature (50 C). Catalyst 6 has been
attached to an insoluble polymer to facilitate recovery <2000TL8473>. Low reactivity with this
polymer-supported system was countered by preparation of a more reactive LaZn-linked-
BINOL catalyst.
Na
O O O
O O Na Al
La O O
O O
O Li
Na
ALB O
LSB 5
4 O O
La
O O
H
OH OH
=
OH OH
(R,R)-La-linked-BINOL
6
O i. ALB 5 (10 mol.%) O O

EtO2C CO2Et rt, 72 h
+ + PhCHO Ph
ii. PCC
CO2Et
82%
CO2Et
89% ee
Scheme 2
Rxn Rxn Yield ee

n R1 R 2 temp. time (h) (%) (%)
O O
0 Bn H 4 °C 85 85 >99
( )n R1O2C CO2R1 6 (10 mol.%) ( )n 1 Bn H rt 72 94 >99
+ CO2 R1 1 Bn Me rt
ð14Þ
DME 84 84 98
R2 CO2R1 2 Bn H 4 °C 85 96 >99
R2
3 Me H rt 96 82 99
4 Bn H 4 °C 120 61 82
O O
6 (10 mol.%)
+ BnO2C CO2Bn CO2Bn
Ph DME Ph ð15Þ
–40 °C, 56 h CO2Bn
97%
78% ee
O O O
6 (10 mol.%) CO2Et
CO2Et
+
Toluene ð16Þ
–30 °C, 36 h O
97%
75% ee
As indicated in Scheme 2 and Equation (16), Shibasaki’s catalysts require low reaction tem-
peratures for the formation of quaternary centers. In this regard, very encouraging results have
been reported by Sodeoka and co-workers <2002JA11240, 2003AG(E)1688>, who have
described asymmetric Michael addition to enones by chiral palladium enolates, generated directly
from 1,3-dicarbonyl compounds in the presence of catalysts 7 and 8. Cyclic keto esters provide
quaternary stereocenters (Equation (17)). In an impressive example (Equation (18)), the method
allows the construction of highly crowded vicinal tertiary and quaternary stereocenters in good
diastereoselectivity and excellent enantioselectivity.
Ar2
P OH2
Pd2+
OH2
P
Ar2 2TfO–
7 Ar = Ph
8 Ar = tolyl
Rxn
time Yield ee
O O R1 R 2 R 3 (h) (%) (%)
O O O ð17Þ
(R)-8 (5 mol.%) –(CH2)3– But 24 92 92
R
1 + R1 OR3
OR3 THF, –20 °C –(CH2)4– But 72 92 90
R2
R2 O Me Me But 72 88 90
Me Me Ph 72 69 93
O
O O O O Rxn Yield ee
(R)-7 (5 mol.%) OBut R temp. (%) ds (%)
OBu t + ð18Þ
THF Ph 0 °C 83 3.6:1 97
R O Me –20 °C 89 8:1 99
R
Another highly promising and selective catalyst system involves Ru–amido complexes such as 9
<2003JA7508>, which affords excellent enantioselectivities for the addition of malonates and
methyl acetoacetate to cyclic enones (Equation (19)). Mechanistically, it is believed that 9 reacts
with the malonate to give a C-bound malonato complex, which then adds to the enone. Linear
,-unsaturated ketones give unsatisfactory results with this system.
Ms
Ph N
Ru
Ph N
H
O O Rxn time Yield ee

MeO2C CO2Me 9 (2 mol.%) n (h) (%) (%)
+ ð19Þ
( )n PriOH ( )n 1 24 99 98
CO2Me
30–60 °C 2 48 99 98
CO2Me 3 72 75 >99
The use of small organic molecules as catalysts in place of metals is attracting intense
interest due to operational simplicity and relative ease of product purification. Amine-cata-
lyzed reactions are proving particularly successful, and this concept has been applied to
Michael additions of malonates to acyclic enones (Equation (20)) <2003AG(E)661>. The

imidazolidine catalyst 10, prepared from phenylalanine, reversibly forms a reactive iminium
species with the enone substrate. The method works for a range of -aryl- and heteroaryl-
substituted enones; -alkyl-substituted enones reacted slower and with lower yields, although
enantioselectivities were still high. The size of the malonate ester substituent was found to be
important, with medium-sized malonates (e.g., ethyl, benzyl) giving best results. When non-
symmetrical malonates were used, little diastereoselectivity was observed.
NMe
Bn N CO2H
H
10
O O Ph ð20Þ
(10 mol.%)
BnO2C CO2Bn CO2Bn
Ph + 165 h, rt
86% CO2Bn
99% ee
(ii) Addition of other carbonyl compounds

Conjugate addition of the glycine derivative 11 to methyl acrylate, cyclohexenone, ethyl
vinyl ketone <1998TL5347>, and acrylonitrile <2000OL1097> catalyzed by the chiral quaternary
ammonium salt 12a proceeds with excellent enantioselectivity (Equation (21)), allowing efficient
synthesis of several important amino acid derivatives. Catalysts 12 are believed to form ion pairs
with the enolate derived from 11.
N R2
Br–
N+
OR–1
Br
12a R1 = CH2CH = CH2, R2 = H2C = CH

12b R1 = H, R2 = Et
12c R1 = Bn, R2 = Et
O
12a (10 mol.%)
O Ph CsOH·H2O CO2But
MeO
+ N CO2 But ð21Þ
MeO Ph CH2Cl2, –78 °C N Ph
85% Ph
11 95% ee
Following on from the results mentioned in Section 1.07.3.2.2.(i) using 1,3-dicarbonyl

nucleophiles, Shibasaki and co-workers <2001OL4251, 2003JA2582> have extended their
linked–BINOL ligand system to the use of -hydroxyketones 13 as nucleophiles (Equation
(22)). In general, best results are obtained with a 4:1 ratio of Et2Zn to ligand 14, with the
presence of activated molecular sieves also being important to ensure catalyst turnover. For
-unsubstituted enones, ligand loadings as low as 0.01 mol.% can be employed, but more
hindered enones require up to 10 mol.%. Kinetic resolution in the addition of racemic 13b to
methyl vinyl ketone was shown to be possible, leading to the formation of a quaternary
center.
OH HO
OH HO
(S),(S)-linked BINOL
14
O OMe Et2Zn (x mol.%) O R2 O OMe

O 3
R 14 (y mol.%)
+ R1
R1 R2
OH 3Å sieves, THF R3 OH
(2–5 equiv.) Rxn Rxn
temp. time Yield ee
13a R 3=H 1 2 3 ð22Þ
R R R x y (°C) (h) (%) (%)
13b R3 = Me 4 93
Ph H H 2 1 4 86
Me H Me 20 5 –20 16 88 96
Ph Ph H 20 5 –20 3 93 95(syn), 93(anti )
(syn:anti 78:22)
Alexakis and co-workers <2003OL2559> have demonstrated that hydroxyacetone may be

added to aromatic nitroalkenes in the presence of a chiral amine catalyst 15 (Equation (23)).
The reaction is unsuccessful for nonaromatic nitroalkenes. The opposite enantiomer of amine
catalyst has also been used for the addition of simple aldehydes and ketones to nitrostyrene
<2002OL3611>, with moderate enantioselectivities and general preference for the syn-product.
Asymmetric addition of aldehydes <2001OL3737> and ketones <2001JA5260, 2001OL2423,
2001TL4441, 2002SL26> to nitroalkenes <2002EJO1877> under amine catalysis has also been
reported by several other groups; enantioselectivities are observed to be generally moderate to
good. The use of readily available proline as a catalyst <2001JA5260, 2001OL2423, 2002SL26> is
particularly attractive; Enders reports best results using small amounts of MeOH as solvent to
solubilize the proline (Equation (24)).
N N
H
15
O Ph
O (15 mol.%) ð23Þ
Ph + NO2
NO2 HO CHCl3, rt, 7 days
79% OH
(10 equiv.)
17/83 syn/anti
97.6% ee
N CO2H
H
O O Ph
Ph (20–150 mol.%) NO2
NO2 + R1 R1
ð24Þ
MeOH, rt
2
R 30–93% R2
80–97% de
7–76% ee
Asymmetric addition of simple aldehydes and ketones to ,-unsaturated carbonyl compounds

has received less attention. Zhang and Corey <2000OL1097> have described an example of using
catalyst 12b for the addition of acetophenone to an aromatic enone. Barbas has reported
amine-catalyzed addition of acetone, cyclopentanone, and cyclohexanone to alkylidene malonates

(Equation (25)), albeit in moderate yields and enantioselectivities <2001TL4441>. Jorgensen
<2003JOC4151> has screened several chiral amines as catalysts for the addition of aldehydes
to vinyl ketones (Equation (26)). Again, yields and selectivities are currently moderate to good
and so further progress in this area is awaited.
N
N
H
CO2Et CO2Et ð25Þ
O (20 mol.%)
+ O CO2Et
CO2Et
THF, rt
Ph Ph
47%
59% ee
Ar
N
H Ar
(20 mol.%)
O O O O ð26Þ
(Ar = 3,5-(CH3)2C6H3)
+ H H
THF/(CF3)2CHOH
Et rt, 30 h Et
86% 79% ee
(iii) Addition of nitro compounds and other -aminocarbanion equivalents

Asymmetric addition of nitromethane to chalcones can be catalyzed by the Shibasaki and
co-workers heterobimetallic complexes <1998TL7557> or by the Corey and Zhang cinchoninium
salt 12c <2000OL4257>, amongst other methods <1997TL7259>. Itoh and Kanemasa
<2002JA13394> have proposed the term ‘‘catalytic double activation method’’ to describe the
simultaneous use of catalytic amounts of a chiral nickel complex 16 to activate the Michael
acceptor 17 and an amine base to activate nitromethane (Equation (27)). For addition of
nitromethane to cyclic enones, Hanessian and Pham <2000OL2975> have exploited L-proline
as a catalyst in the presence of 2,5-dimethylpiperazine as an additive (Equation (28)). Jorgensen
and co-workers <2002JOC8331> have investigated the addition of nitromethane to acyclic
enones, promoted by the chiral imidazolines such as 10 (Section 1.07.3.2.2.(i)).
O
O O
N Ni N
(OH2)3
Ph Ph
16
16 (10 mol.%) Yield ee

2,2,6,6-Tetramethylpiperidine R (%) (%)
(10 mol.%) N R 85 94
N R Me ð27Þ
N N
MeNO2/ THF Pr n 96 91
O 49–97% O
17 NO2 MeOOC 91 83
77–98% ee Ph 90 93
Yield ee
O O n R1 R2 (%) (%)
O2N R1 L-proline (3–7 mol.%)
+ 1 Me Me 66 75
2,5-Dimethylpiperazine ð28Þ
( )n R2 ( )n 2 Me H 61 71
CHCl3, rt R1
2 –(CH2)5– 73 93
R2
O2N 3 –(CH2)4– 71 87
An interesting reductive conjugate addition of nitrones to ,-unsaturated esters was reported

recently <2003AG(E)2265>, which formally effects umpolung of the C¼N bond (Equation
(29)). The reaction can be rendered diastereoselective by placing chiral substituents on nitrogen
<2003AG(E)2265>.
– HO
O + Bn R1 O SmI2, THF, –78 °C NBn R3
N ð29Þ
+ OR4
R2 OR4
R3 R1 R 2 O
Yield
R1 R 2 R3 R 4 (%) syn:anti
H H H Et 75
H H Me Me 74 >95:5
H Me H Me 66 >5:95
Me Me H Me 54
Beak and co-workers <1999JOC2996, 2001OL711, 2002JA11689> have reported that configur-
ationally stable amido-substituted benzylic and allylic organolithiums will undergo asymmetric con-
jugate addition to nitroalkenes and to unsaturated carbonyl compounds (Equations (30) and (31)).
Ph
i. BunLi, (–)-sparteine
Ph NBoc
Ph O2N NBoc
Ph
ii. O2N Ph Ph ð30Þ
93%
92:8 dr
>98% ee
i. BunLi, (–)-sparteine
NBoc
NBoc ii. O Ph
Ph ð31Þ
O
62% 83:17 dr
96% ee
(iv) Addition of silyl enol ethers and silylketene acetals: Mukaiyama–Michael reaction
As outlined in Section 1.07.3.2.2.(ii), direct enantioselective addition of simple aldehydes and
ketones requires further exploration if uniformly high enantioselectivities are to be achieved. An
alternative approach, known as the Mukaiyama–Michael reaction, involves the use of silyl enol
ethers or silylketene acetals as nucleophiles. Early results included high selectivity (90% ee) in the
addition of a thioester-derived silylketene acetal to cyclopentenone, catalyzed by a BINOL-
derived titanium oxide <1994CL97>, and further studies on the use of chiral titanium complexes
in the conjugate addition of silylketene acetals to 2-carboxycyclopentenones <1997T13009>.
Good results have been obtained by using substrates capable of bidentate coordination with
Cu(II) bisoxazoline catalysts <1996TL8921, 1997T17015, 1999JA1994, 1999OL865,
2001JA4480>. Evans showed that the addition of the thioester-derived silylketene acetal 18 to
alkylidene malonates could be rendered catalytic in Cu(II) bisoxazoline complex 19 by addition of
2 equiv. of hexafluoro-2-propanol <1999JA1994>. This additive promotes turnover but also
hydrolysis of 18, a side reaction that could be minimized by using a toluene/CH2Cl2 solvent
mixture. Excellent yields and enantioselectivities were obtained for alkylidene malonates bearing
substituents larger than methyl (Equation (32)). Evans and co-workers <1999OL865,
2001JA4480> have also studied the addition of silylketene acetals and enol silanes to oxazolidi-
none-bearing substrates such as 21 (Equation (33)), again mediated by Cu-complex 19, in some
detail. In general, (E)-enol silanes afford anti-products, whereas (Z)-enol silanes are syn-selective.
Pyrrole enol silanes such as 20 are particularly reactive. Mechanistic studies suggest that the
reaction proceeds via [4+2]-cycloaddition followed by hydrolysis of the resulting dihydropyran
intermediate.
2+
O O
N N
Cu –
2 SbF6
But But
19
OTMS MeO2C CO2Me O R

19 (10 mol.%)
+ tS CO2Me
t 2 equiv. (CF3)2CHOH Bu
Bu S R ð32Þ
PhMe/CH2Cl2 CO2Me
18 –78 °C
(2.2 equiv.) 86–99% ee
88–99% (R > Me)
OTMS O O O R O O
19 (10 mol.%) ð33Þ
N +
R N O (CF3)2CHOH N N O
CH2Cl2
20 21 –20 °C Yield ee
R Rxn time (%) anti:syn (%)
Me 5 min 88 99:1 98
CO2Et 1h 91 97:3 94
Ph 16 h 97 99:1 94
Asymmetric addition of silylketene acetals to simple acyclic enones is promoted by the

allo-threonine-derived B-aryloxazaborolidine 22 in good ee <2001OL2101> (Equation (34)).
The additive 2,6-diisopropylphenol is essential to retard competing racemic reaction pathways
promoted by electrophilic silicon species.
O O
BPh
2-NaphthylO2C N
22 Ts Yield ee ð34Þ
OTMS O (20–40 mol.%) O R O R (%) (%)
+ Ph 88 79
ButS R 2,6-diisopropylphenol (3 equiv.) ButS
–78 °C, CH2Cl2 Me 60 84
(3 equiv.)
(v) Addition of cyanide

Sammis and Jacobsen <2003JA4442> have described the first catalytic asymmetric conjugate
addition of cyanide to ,-unsaturated imides, catalyzed by the aluminum–salen complex 23
(Equation (35)). The reaction gives excellent enantioselectivities for a range of -alkyl-substituted
imides. The method used to generate the cyanide source proved to be important: no reaction was
observed with HCN alone, whereas in situ reaction of TMSCN and i-PrOH led to good reactivity.
H H
N N
Al
But O O But
Cl
But But
23
Yield ee
O O O O R (%) (%)
23 (10 or 15 mol.%)
Me 92 98
Ph N Ph N
TMSCN, PriOH Prn 90 97 ð35Þ
H H
R Toluene NC R But 90 97
R = alkyl CH2OBn 70 87
1.07.3.2.3 Addition of unstabilized nucleophiles: alkyl, alkenyl, alkynyl, and aryl anion equivalents
(i) Alkyl addition

Organocopper-based reagents are the classic choice for CC bond formation by conjugate addition to
electron-poor alkenes, particularly ,-unsaturated ketones and esters. Several comprehensive reviews
have appeared <1972OR(19)1, 1991COS(4)169, 1992OR(41)135, 1997AG(E)186, 2000AG(E)3751,
2000CSR393, B-2002MI002>, including a collection of practical procedures <B-1994MI001>. Under-
standing of the reagents’ structural features and the mechanisms of the conjugate addition reaction has
progressed considerably in recent years, and the reader is referred to two excellent recent reviews
<2000AG(E)3751, 2000CSR393>. Several different types of organocopper reagents have been
employed, differing in the stoichiometry and ratios of copper to lithium; the presence of alkali metal
salts and the nature of the solvent can also influence the reactive species. Mono-organocopper species,
RCu, prepared according to Equation (36), are less widely used than organocuprates because they are
generally less stable and less reactive. Lower-order organocuprates, R2CuLi, are usually prepared in
situ by the reaction between 2 equiv. of RLi and copper(I) iodide in ether (Equation (37)). There are
many examples of their use in conjugate addition, delivering alkyl, alkenyl, or aryl groups. It is not
generally possible to transfer alkynyl groups (see Section 1.07.3.2.3.(iii)).
CuX + RLi RCu + LiX ð36Þ
CuI + 2RLi R2CuLi + LiI ð37Þ
During conjugate addition of lower-order organocuprates, R2CuLi, only one of the two R groups
is transferred, with the other being lost as RH on work-up. While this is not a problem where
simple, commercially available RLi precursors are involved, the process is clearly unsatisfactory for
more valuable organolithiums. Much effort has therefore been expended in developing mixed
cuprates, RTRDCuLi, where RT is the transferable ligand and RD is a nontransferable, ‘‘dummy’’
ligand. Alkynes have been used for this purpose <1974JOC400>, as have neopentyl and neophyl
(CH2C(Me)2Ph) groups <1999S312> as well as cyanocuprates, prepared from 1 equiv. of RTLi
and CuCN. However, the latter species are relatively unreactive and so have not seen widespread
use. More effective are the ‘‘higher-order cyanocuprate’’ reagents formed by the addition of 2 equiv.
of organolithium to CuCN, in which the 2-thienyl group may be employed as a ‘‘dummy’’ ligand
<1987S325, 1990SL119, B-1994MI283>. Lipshutz formulated these as R2Cu(CN)Li2, but the
details of their structure have been the subject of considerable debate. Current evidence
<2000AG(E)3751, 2000CSR393> suggests that the tricoordinated species [R2Cu(CN)]2 is not a
stable structure in ethereal solution. Notwithstanding the structural and mechanistic intricacies, the
Lipshutz mix can prove more effective than conventional organocuprates.
Another approach that can greatly increase organocuprate reactivity as well as improving 1,4-
versus 1,2-selectivity is the addition of Lewis acids <1986AG(E)947, 1991COS(4)139> such as
boron trifluoride etherate <1982JOC119>. Trimethylsilyl chloride (in THF) is another additive that
has proved extremely effective at increasing the rate of conjugate addition processes. For example,
lower-order organocuprates by themselves undergo little addition to ,-unsaturated amides, but this
transformation is clearly achieved in high yield in the presence of trimethylsilyl chloride
<1986TL1047>. Use of trimethylsilyl chloride together with HMPA has also been recommended,
particularly for additions to ,-unsaturated aldehydes <1986TL4029>. The mechanistic role of the
silyl chloride has been the subject of some debate <2000AG(E)3751, 2000CSR393>.
The demand for a catalytic asymmetric method for conjugate addition of alkyl groups has driven
attention away from chiral analogs of standard organocuprate reagents to the use of organozinc
reagents, catalyzed by salts of Ni, Co, or, most commonly, Cu. An advantage here is the ability to
employ functionalized organozinc reagents. Numerous chiral phosphorus-containing ligands have been
investigated, progress in the area up to mid-2002 being summarized in some excellent reviews
<2000T8033, 2001S171, 2002EJO3221>. Some of the most impressive and general recent results have
come from Hoveyda’s group, who have developed novel peptide-based phosphine ligands that have
widened the scope of the addition process. High enantioselectivities are obtained for cyclic enones
(Equation (38)) <2001JA755>, with cyclopentenones being notably successful substrates, since these
are problematic for most ligand systems due partly to facile self-aldol reaction of the product enolate.
Equation (39) exemplifies the excellent enantioselectivities that may be obtained even for acyclic enones
using the modified ligand 24b <2002JA779>. Trisubstituted cyclic enones (five- or seven-membered
rings) also give good results: here, the simpler and readily prepared ligand 25 is optimum
<2002JA13362>. The example in Equation (40) demonstrates the powerful possibility of trapping the
intermediate zinc enolate with electrophiles. The chemistry has also been applied to unsaturated
N-acyloxazolidinones <2003AG(E)1276> and cyclic nitroalkenes <2002JA8192>; highly enantioselec-
tive addition to acyclic nitroalkenes using chiral phosphoramidite ligands has been reported
<2003JA3700>.
R1
H O
N NHBu
N NHBu N
O O
PPh2 PPh2
R2 25
24a R1 = R2 = H
24b R1 = Me, R2 = OBut
Et2Zn (3 equiv.) Yield ee

O (CuOTf)2.C6H6 (1 mol.%) O
n (%) (%)
24a (2.4 mol.%) ð38Þ
1 78 97
( )n Toluene, –30 °C ( )n 2 98 98
Et 3 98 98
Et2Zn (3 equiv.)
O (CuOTf)2.C6H6 (1 mol.%) Et O
24b (2.4 mol.%) ð39Þ
n-C5H11 Toluene, –22 °C n-C5H11
85%
95% ee
Et2Zn (3 equiv.)
(CuOTf)2.C6H6 (5 mol.%)
O 25 (12 mol.%) Ph O
Toluene, 0 °C
i
Pr ð40Þ
then PhCH2Br Pri
77%
Et
>20:1 ds
96% ee
(ii) Aryl and alkenyl addition

Complementary to the Cu-catalyzed asymmetric addition of dialkylzincs mentioned above, an
outstanding process for catalytic asymmetric conjugate addition of aryl and alkenyl groups is
the Rh-catalyzed addition of organoboronic acids to electron-deficient alkenes <1997OM4229,
1998JA5579>, which has been reviewed in detail <2001SL879, 2003CRV169, 2003CRV2829>.
The reaction affords excellent enantioselectivities for addition of a variety of alkenyl- and
arylboronic acids to both cyclic and acyclic ,-unsaturated ketones (Equations (41)–(43)); an
excess of boronic acid is used in some cases due to competing hydrolytic deboronation.
Replacing the boronic acids with lithium trimethyl arylborates (e.g., 26), generated in situ by
reaction of aryl bromides with butyllithium and trimethoxyborane (Equation (44)), can give
improved results for conjugate addition to enones if an equimolar amount of water is present,
which presumably displaces one of the methoxy groups on boron. These are the reagents of
choice for less reactive substrates such as acyclic enoates (Equation (45)), although cyclic
enoates work well with arylboronic acids (Equation (46)). ,-Unsaturated amides are also
less reactive than enones, and the addition of a base (e.g., K2CO3) can improve the yields of
addition of arylboronic acid <2001JOC8944>. Addition to ,-unsaturated phosphonates
<1999JA11591> and cyclic nitroalkenes <2000JA10716> has also been reported, the latter
being noteworthy since substitution to the electron-withdrawing group is present, usually not
possible with this reaction system.
Yield ee
O Rh(acac)(C2H4)2 (3 mol.%) O
n (%) (%)
(S)-BINAP ð41Þ
+ PhB(OH)2 1 93 97
( )n Dioxane/H2O: 10/1 ( )n 2 >99 97
(1.4–5 equiv.) 100 °C, 5 h 3 51 93
Ph
Rh(acac)(C2H4)2 (3 mol.%)
O O Ph
(S)-BINAP
+ PhB(OH)2 ð42Þ
n-C5H11 Dioxane/H2O: 10/1 n-C5H11
(2.5 equiv.) 100 °C, 5 h
92% ee
88%
n-C5H11 (S)-BINAP
+ B(OH)2
Dioxane/H2O: 10/1 ð43Þ
(2.5 equiv.) 100 °C, 5 h
64% n-C5H11
96% ee
i. BunLi, ether
PhBr Li[Ph(BOMe)3] ð44Þ
ii. B(OMe)3
26
26 (2.5 equiv.), H2O (2.5 equiv.)

Rh(acac)(C2H4)2 (3 mol.%)
Ph
(S)-BINAP
CO2Pri CO2Pri ð45Þ
Dioxane
100 °C, 3 h 95% ee
96%
O (S)-BINAP O
+ PhB(OH)2 ð46Þ
Dioxane/H2O: 10/1
100 °C, 3 h Ph
94% 98% ee
The essential details of the catalytic cycle for the Rh-catalyzed reaction of phenylboronic
acid with cyclohexenone <2002JA5052> are shown in Scheme 3. The use of water as co-
solvent in the reactions described so far precludes the trapping of the intermediate oxo-
-allylrhodium 27 with alternative electrophiles. Hayashi and co-workers <2002JA10984,
2003JOC1901> have developed aprotic conditions that allow this to be achieved (Equation
(47)). Trapping by intramolecular aldol reaction can occur even in the presence of water
<2003JA1110>.
Transmetallation [Rh]-Ph O Insertion

PhB(OH)2
Hydrolysis O
[Rh]-OH
h]-
O [R
H2O
Ph
Ph 27
Scheme 3
O [Rh(OMe)(COD)]2/(S )-BINAP (3 mol.%) B

Toluene O
+ Ph B
80 °C, 1 h ð47Þ
Ph
98% ee
Aryl and vinyl organosiloxanes have also been added asymmetrically to enones under
Rh(I)-catalysis <2003OL97>.
Friedel–Crafts-type reactions offer another important approach for the addition of aryl and
heteroaryl groups. Paras and MacMillan <2002JA7894> have extended their organocatalysis work
to the 1,4-addition of electron-rich benzenes to ,-unsaturated aldehydes, promoted by the chiral
amine 28, which forms a reactive iminium ion with the aldehyde. The reaction works well with a wide
range of anilines and for a wide range of substituents to the aldehyde (Equation (48)). Chiral Cu(II)-
bisoxazoline complexes catalyze the asymmetric addition of indoles to ,-unsaturated -keto esters
<2001AG(E)160, 2003S1117> and to alkylidene malonates <2001CC347>. Higher enantioselectiv-
ities have been observed using a trisoxazoline ligand 29 in the presence of hexafluoroisopropanol as an
additive (Equation (49)) <2002JA9030>. Asymmetric addition of indoles to ,-unsaturated
acylphosphonates is catalyzed by bis(oxazolinyl)pyridine–scandium(III) triflate complexes
<2003JA10780>.
O
NMe
Bn N But
H
OMe 28 NMe2 Yield ee
ð48Þ
R (%) (%)
CHO (10 mol.%)
R + Me 86 89
CH2Cl2 MeO CO2Me 90 92
Me2N –40 to –10 °C p -NO2Ph 87 92
CHO
R
N N
O O
N
O
29
Ph CO2Et
CO2Et 29 , Cu(ClO4)2·6H2O
+ Ph CO2Et
N (CF3)2CHOH (2 equiv.)
CO2Et ð49Þ
H Acetone–ether N
–20 °C H
84%
89% ee
(iii) Alkynyl addition

As mentioned in Section 1.07.3.2.3.(i), alkynyl groups are not readily delivered from copper for
conjugate addition, explaining the choice of this substituent as a nontransferable, ‘‘dummy’’
group in mixed cuprate reagents. However, conjugate addition of alkynylcoppers has been
observed in the presence of trimethylsilyl iodide <1993JOC7238, 1997JOC182> or TBSOTf
<1995MI783>. Other metal alkynylides that have been shown to react with unsaturated carbonyl
compounds include those of aluminum <1971JA7320>, which requires the enone to be able to
adopt the s-cis conformation, precluding the use of cycloalkenones. Addition of alkynylzincs in
the presence of TBSOTf <1990TL7627> appears more general. Alkynylboron reagents have also
been employed; again they are limited to enones which can adopt an s-cis conformation, but an
asymmetric variant has been developed (Equation (50)) <2000JA1822>. Good enantioselectivities
were obtained for -aryl-substituted enones, particularly with electron-rich aryl substituents, or
with a bulky -alkyl group.
Ph
O
B R1
O
Ph
1 = n-C
30a R 6H13
30b R1 = Ph
30c R1 = CH2OBn
Yield ee
R1 R1 R2 (%) (%)
n-C6H13 Ph 88 85
O rt, CH2Cl2 ð50Þ
+ 30a O n-C6H13 n-C6H13 80 16
R2 Ph n-C6H13 Bu t 87 82
R2 Ph
n-C6H13 2-Furyl 91 >98
An efficient Ru-catalyzed 1,4-addition of terminal alkynes to conjugated enones has been

reported (Equation (51)) <2001OL2089>; the reaction is limited to unsubstituted vinyl ketones,
but a wide range of functionality is tolerated in the alkyne, including a free hydroxyl. Another
interesting conjugate addition, which does not require prior formation of an acetylide anion, is
catalytic in copper, and is performed under aqueous conditions, has been described by Knopfel
and Carreira (Equation (52)) <2003JA6054>. The chemistry involves addition of aryl-
and heteroaryl-substituted terminal alkynes to acceptors 31, which are readily obtained by
condensation of Meldrum’s acid with aldehydes. The presence of ascorbate as reductant was
postulated to effect in situ conversion of Cu(II) to Cu(I), as well as preventing oxidative coupling
of the alkyne, although preliminary mechanistic studies suggested that it may play a wider role.
The addition products can be readily decarboxylated to afford -alkynyl acids.
[RuCl2(p-cymene)]2 (5 mol.%) O
O pyrrolidine (0.2 equiv.)
R1 + Me
Me Benzene, 60 °C, 12 h
58–98% R1
ð51Þ
R1 = n-octyl, 91%
R1 = Me3Si, 77%
1 = HOCH (CH ) CH , 58%
R 2 2 2 2
Yield
R Ar (%)
Cu(OAc)2 (20%) O O
O O Pri Ph 78
Na-ascorbate (40%)
+ Ar O O Ph Ph 85 ð52Þ
O O H2O:ButOH (10:1)
2-Furyl Ph 98
rt R
R Ph 2-Furyl 70
Ar
31
1.07.3.3 Addition to Unactivated Alkenes
1.07.3.3.1 Addition of stabilized nucleophiles

In 1980, Hegedus and co-workers <1980JA4973, 1980JA4980> showed that terminal or
disubstituted internal alkenes can be alkylated with stabilized nucleophiles (pKa 10–17)
mediated by stoichiometric palladium(II) chloride. Pei and Widenhoefer <2001JA11290>
have discovered that the intramolecular variant can be run using substoichiometric Pd(II)
(Equation (53)). The reaction proceeds with endo-regioselectivity, leading to a synthesis of
cyclohexanones from unsaturated 1,3-diones. Substitution to the carbonyls or at the alkene
terminus is tolerated.
Yield
O O O O R1 R2 (%)
R1
PdCl2(CH3CN)2 (10 mol.%) H H 81 ð53Þ
R1
Dioxane, rt Me H 61
R2 R2
H Me 81
A catalytic amount of potassium t-butoxide in NMP or DMSO mediates the addition of

ketones, imines, and nitriles to styrenes (Equation (54)) <2000OL3285>. Addition of zinc
hydrazones to simple alkenes has been reported <1997AG(E)2491>.
CN
KOBut (20 mol.%) CN
+ ð54Þ
NMP, rt
80%
1.07.3.3.2 Addition of unstabilized nucleophiles

Addition of organometallic reagents to unactivated alkenes to form a new CC bond and a new
organometal is known as carbametallation: the process <1991COS(4)865> and asymmetric
versions have been reviewed <1999JCS(P1)535, B-1999MI431>. The reaction also constitutes a
useful method for the synthesis of carbanions, so Chapter 1.19 should also be consulted.
Oligomerization by reaction of the organometal adduct with starting alkene must be avoided.
Performing intramolecular cyclizations, which are entropically favored, is a common tactic: in
particular, 5-exo cyclizations of organolithiums have been widely employed for the preparation of
carbocycles and pyrrolidines <2002CEJ195, B-2002MI003>. Using substrates with neighboring
heteroatoms capable of stabilizing the carbanion <2001T5899> is also a widely used strategy.
Direct intermolecular addition of organolithium reagents to styrenes <2000JCS(P1)1109> is
possible if ether is used as solvent; the resulting benzylic anion can be trapped with electrophiles
(Equation (55)), and the reaction can be rendered asymmetric by the addition of sparteine
<1997TA665>. Organolithium additions to cinnamyl derivatives <1999CEJ2055,
2000TL6575>, including asymmetric induction <1997TL7523, 1999CEJ2055>, have also been
accomplished.
i. BusLi, Et 2O, –78 °C CO2H

Ph Bus ð55Þ
ii. CO2 Ph
86%
Regioselective zirconium-catalyzed addition of Grignard reagents to terminal alkenes

<1985JOM(285)43, 1993JA6614> can be rendered diastereo- <1991JA5079, 1993JOC4237>
and enantioselective <1993JA6997, 1995JA7097> but is generally limited to the use of EtMgBr.
Zirconium salts also catalyze the addition of organoaluminums to unactivated alkenes
<2002PAC151>, and an iron-catalyzed addition of Grignard reagents or organozincs to strained
alkenes has appeared <2000JA978>.
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Biographical sketch
Alan Armstrong was born in Co. Durham. He Nicola Convine was born in Huntingdon,
studied at Imperial College London, where he Cambs in 1978. She studied at Imperial
obtained a B.Sc. in 1987 and his Ph.D. in 1990 College London where she obtained an M.Sci.
under the direction of Professor S. V. Ley. in 2001 and is currently researching for a
After two years as an SERC/NATO Postdoc- Ph.D. under the direction of Dr. Alan Armstrong
toral Fellow with Professor W. C. Still at in the area of catalytic conjugate addition
Columbia University, New York, he returned reactions.
to the UK as Lecturer at the University of
Bath. In 1996 he moved to the University of
Nottingham, and returned to Imperial College
as Reader in Organic Chemistry in 1999. His
research interests include new methods for
asymmetric synthesis, particularly asymmetric
heteroatom transfer, and the total synthesis of
complex natural products.
1.08
One or More CC Bond(s)
Formed by Addition: Addition
of Carbon Radicals and
Electrocyclic Additions to
CC Multiple Bonds
G. BALME, D. BOUYSSI, and N. MONTEIRO
Université Lyon I, Villeurbanne, France
1.08.1 ADDITION OF CARBON RADICALS TO CARBONCARBON MULTIPLE BONDS TO

GIVE TETRACOORDINATE PRODUCTS 313
1.08.1.2 Basic Principles 314
1.08.1.2.1 Synthetic advantages of carbon-centered radical reactions 314
1.08.1.2.2 Stability and structure of alkyl and vinyl radicals 314
1.08.1.3 Intermolecular Radical Additions 315
1.08.1.3.1 Introduction 315
1.08.1.3.2 Electronic nature of radicals 315
1.08.1.3.3 Stereoselectivity 315
1.08.1.3.4 Methods for conducting radical reactions 320
1.08.1.4 Intramolecular Radical Additions 329
1.08.1.4.1 Introduction 329
1.08.1.4.2 The 5-hexenyl radical: regioselectivity 330
1.08.1.4.3 Stereoselectivity in substituted 5-hexenyl radical cyclizations 330
1.08.1.4.4 Allyl, vinyl, and aryl cyclizations 330
1.08.1.4.5 Formation of six-membered rings 330
1.08.1.4.6 Formation of other ring sizes 330
1.08.1.4.7 Methods for facilitating radical cyclization reactions 332
1.08.1.5 Tandem Processes 340
1.08.1.5.1 Intramolecular/intramolecular sequences 340
1.08.1.5.2 Intramolecular/intermolecular processes 341
1.08.1.5.3 Intermolecular/intramolecular additions 341
1.08.1.5.4 Intermolecular/intermolecular additions 342
1.08.2 ELECTROCYCLIC ADDITIONS TO CARBONCARBON MULTIPLE BONDS TO GIVE
1.08.2.2 Formation of Three-membered Rings 343
1.08.2.2.1 Addition of free carbenes 343
1.08.2.2.2 Addition of metal carbenoids 343
1.08.2.3 Formation of Four-membered Rings 347
1.08.2.3.1 Thermal [2+2]-additions 347
1.08.2.3.2 Photochemical [2+2]-additions 348
313
314 One or More CC Bond(s) Formed by Addition
1.08.2.3.3 Metal-catalyzed [2+2]-additions 349

1.08.2.4 Formation of Five-membered Rings 350
1.08.2.4.1 [3+2]-Additions of three-carbon fragments 350
1.08.2.4.2 [3+2]-Additions of CXC fragments 357
1.08.1 ADDITION OF CARBON RADICALS TO CARBONCARBON MULTIPLE

BONDS TO GIVE TETRACOORDINATE PRODUCTS
Creation of carboncarbon bonds is crucial to construct organic molecules. In this area, the
chemistry of carbon-centered radicals has become an essential component for their capacity to
add to carboncarbon multiple bonds and create carboncarbon bonds. This review is a
complement to the original edition of this book <1995COFGT(1)319> covering the field of
addition reactions of carbon-centered radicals to carboncarbon multiple bonds from 1995 to
2003 and will focus on the reactivity, chemoselectivity, regioselectivity, and stereoselectivity of
carbon radical reactions. Reviews cited in COFGT (1995) are still relevant today. Nether-
theless readers are also directed to recent books, which cover the important concepts and
principles <B-2001MI011, B-2000MI010, B-1999MI009>. Numerous reviews have been pub-
lished covering all domains in radical chemistry. Among them, particular attention has been
devoted to intramolecular cyclizations <1996CRV339, 2001T7237, 1998ACA50, 2002H2413,
2002JCS(P1)2747>. Radical cascade and annulation processes which have known remarkable
developments in the construction of more and more complex frameworks have been reviewed
<2001AG(E)2224, 2001JCS(P1)3215, 2003S803>. New trends have emerged and gained in
popularity. The development of tin substitutes <2002JCS(P2)367, 2002S835,
1998AG(E)3072>, the emergence of new concepts such as the translocation reaction
<2001CSR94>, or even the use of polarity reversal catalysis <1999CSR25> show great
promise. First examples of radical reactions in aqueous media have also been developed
<2002SL674>. Reviews of transition metal-mediated radical reactions have been published
<1996CRV307, 2002JOM159>. The use of carbon-centered radical additions for the stereo-
selective formation of CC bonds is also under intense investigation <1998AG(E)2563,
2003CSR251>. First successes in enantioselective catalysis are particularly remarkable
<1999ACR163, 2003CRV3263>.
This chapter is organized according to the classification of the reaction (e.g., intermolecular,
intramolecular, or tandem radical additions) and the type of the method by which it is
conducted.
1.08.1.2 Basic Principles
1.08.1.2.1 Synthetic advantages of carbon-centered radical reactions

To avoid repetition of the basic principles readers are referred to COFGT (1995).
Carbon-centered radicals are generally prepared under neutral conditions which avoids side
reactions associated with ionic conditions. Moreover, they can be used with diverse function-
alities unreactive toward them, thus limiting the number of steps in syntheses. In addition,
another difference with ionic reactions is that -eliminations are not so favorable and are
limited to Br, SR, and SnR3, which can be a limitating factor or an advantage
<1995COFGT(1)319>.
1.08.1.2.2 Stability and structure of alkyl and vinyl radicals

As these data are well established, the readers should refer to COFGT (1995) <1995COFGT(1)>.
One or More CC Bond(s) Formed by Addition 315
1.08.1.3 Intermolecular Radical Additions
1.08.1.3.1 Introduction
The addition of carbon-centered radicals to alkenes leads to the formation of a new carboncarbon
bond at the expense of a carboncarbon -double bond. Theoretical and experimental studies
concerning quantification of factors controlling addition reactions to alkenes have been published
recently <2001AG(E)1340>. Factors determining the activation energy for reagents in radical
additions have also been studied empirically and by calculation <2000RCR153>. The angle of
attack of a radical onto an alkene is well defined as being a tetrahedral angle (109 ) with the double
bond <1995COFGT(1)319>.
1.08.1.3.2 Electronic nature of radicals

Carbon-centered radicals can be classified into three types: nucleophilic radicals such as simple
alkyl radicals that react preferentially with electron-poor alkenes, electrophilic radicals attached
to two electron-withdrawing groups (e.g., esters or nitriles) that react preferentially with electron-
rich alkenes, and ambiphilic radicals which have intermediate energies and can react with all types
of alkenes. These considerations are well documented in COFGT (1995) and will not be developed
in this chapter.
1.08.1.3.3 Stereoselectivity
(i) Introduction
Carbon-centered radicals have long been considered as highly reactive short-lived species
poorly suited for stereoselective transformations. In recent years, however, new methods
have emerged that allow radical reactions to be conducted under milder conditions (see
Section 1.08.1.3.4). This has led to a better understanding of the determining factors for
selectivity and, consequently, has spurred renewed activity in the development of stereoselec-
tive radical transformations. Today, the radical reactions can be highly diastereo- and
enantioselective in the formation of carboncarbon bonds. Remarkably, the first examples
of enantioselective conjugate additions of radical intermediates was only reported in the mid-
1990s. Since then, high levels of ee have been achieved. The strategies used to induce
stereoselectivity in radical reactions are essentially based on well-established precedents
learned from the ionic and pericyclic processes. Compared with the other methods the radical
reactions allow the formation of stereogenic quaternary centers with high levels of selectivity
and, being conducted under neutral conditions, they avoid acid- or base-induced epimeriza-
tion or decomposition of sensitive molecules. They are also compatible with many functional
groups. For an exhaustive and comprehensive illustration of stereoselective radical processes
the reader is referred to the following reviews <B-1996MI005, 1998AG(E)2563, 1999ACR163,
2000T8033, B-2001MI011, 2003CEJ28, 2003CRV3263, 2003CSR251>. Studies involving pro-
ton, deuterium, or halogen abstraction by chiral radicals will not come under the remit of this
chapter.
(ii) Cyclic radical additions

Substituent effects on the stereoselectivities of additions of alkenes to cyclic carbon radicals have
been investigated <B-2001MI011>. Steric effects can generally explain the steroselectivities
observed <1992JA4067>. It has been established that -substituents direct anti-addition. For
instance, Equation (1) shows the preferential addition of allylstannane to the less hindered face
(the face opposite to the sulfone group) of four-membered radical 1 to give the corresponding
allylated compounds 2 <1989T941>.
O O O O O O
Br SnBu3 S
S S
N N N ð1Þ
O AIBN O 93% O
CO2Me CO2Me CO2Me
1 2
Electronic interactions have been found to influence the stereochemical outcome of reactions
involving glycosyl radicals <1989AG(E)969>. The stereoselective addition of radicals at the
anomeric position of carbohydrates to alkenes proceeds generally with a marked preference for
axial pseudoanomeric bond formation <1999TL7063> (Equation (2)).
(OR)n
(OR)n O
OMe hν O
O P O
+ OMe ( )m OMe
( )m (Me3Si)3SiH P
Br R' OMe ð2Þ
27–80% R'
m = 1; α /β >99:1
m = 2; α /β 98:2
The use of additives to enhance diastereoselectivity has also been reported <1998AG(E)2563>.
For example, alcohol 3 was treated with methyl aluminum bis(di-2,6-t-butyl-4-methylphenoxide)
(MAD) 4 prior to radical reaction. The bulkiness of the resulting aluminum alkoxide derivative
allowed a remarkable steric differentiation of the two faces <1995HCA1001> (Equation (3)).
CO2Me MeO2C
I SnBu3
OAr
OH AIBN, hν, 10 °C O Al
69%
3 OH
OAr ð3Þ
O O 99% de
Al
Me
4
Induction of enantioselectivity through chiral Lewis acid complexation has been recently
achieved <2003CRV3263>. For instance, allylation of iodolactone 5 using the system Me3Al/
BINOL 6 afforded the corresponding product 7 in up to 91% ee <1997JA11713>. The reaction
also proceeds catalytically, albeit with a small decrease in asymmetric induction (Scheme 1).
SnBu3
I
OBn Et3B/O2 OBn
OBn
O O Me3Al/BINOL, 6 O O O
Et2O, toluene, –78 °C Me Al * O O
5 O 7
Et2O
SiPh3
Yield (%) ee (%)
OH 76 91
1.0 equiv. Me3Al
OH 78 71
0.1 equiv. Me3Al
SiPh3
6
Scheme 1
(iii) Acyclic radical additions

Stereoselectivity based upon conformational control and steric hindrance is more difficult to achieve
in acyclic radical additions to alkenes due to free rotation around the carboncarbon bond.
Particular attention has been given to 1,2-asymmetric induction in reactions of alkenes with carbonyl-
substituted radicals possessing a center of chirality in the -position. Radicals to a carbonyl group 8
are considered as planar, delocalized in a manner similar to an enolate anion and the observed
stereoselectivities can generally be rationalized using the concept of 1,3-allylic strain (Scheme 2)
<1999CRV1191>. In this planar radical model, the CH bond at the chiral center is pointing in
the direction of the carbonyl function and attack of the radical is preferred from the face opposite to
the large group (L). Addition reactions of alkenes to ester enolate radicals have been particularly well
studied and minimization of allylic strain (A1,3 and A1,2) as well as torsional strain have been found of
importance in these reactions. Further studies have shown that electronic effects may also dominate
for ester enolate radicals bearing -alkoxy substituents or other resident groups <1991SL425,
1992JOC4457, 1993T4841, 1998SL213, B-2001MI011>. Intramolecular hydrogen bonding has also
been used as a stereocontrolling element in allylation reactions of related systems in nonpolar solvents
<1996JA2507, 1996TL6335>. For instance, it was suggested that radical 9 adopts a pseudo-
six-membered ring conformation due to hydrogen bonding and the attack of allyltributyltin occurs
selectively from the face opposite to the methyl group. The same model was exploited to achieve high
stereoselectivity in 1,3-, 1,4-, and 1,5-asymmetric induction <1996JA2507>.
R
OMe
SnBu3
R Me Me
R O CO2Me
M O H N H 98% HN
S COCF3 COCF3
(H)
L dr >98/2
9
8
Scheme 2
Lewis acids have been recently investigated as important tools for inducing stereoselectivity
through chelation stereocontrol of the substrate conformation <1998AG(E)2563, B-2001MI011>.
-Hydroxy- <1996TL6335> and -alkoxy- <1995JCS(P1)389, 1996JA12528> ester enolate radi-
cals proved to be interesting models owing to their ready availability in enantiopure form and
their utility as starting materials for natural product synthesis. -Methoxy -halo (and seleno)
esters 10 react with allyltrimethylsilane in the presence of triethylborane as the initiator and
magnesium bromide as the Lewis acid to afford the corresponding anti-allylation products 12
with high diastereoselectivity <1996JA12528>. Formation of a six-membered ring chelate 11
accounts for the stereochemical outcome of the reaction (Equation (4)). In contrast, allylation
of 3-bromo-2-oxysuccinate 13 in the presence of lanthanium tris(6,6,7,7,8,8,8-heptafluoro-
2,2-dimethyloctane-3,5-dione) [La(fod)3] leads selectively to the corresponding syn-product.
It was suggested that the bulkiness of the t-butyldimethyl silyl protecting group disfavors
ring chelates involving the oxygen of the silyl ether, and the complexation of both ester carbonyl
groups to form a seven-membered ring chelate 14 was proposed to explain the observed
stereoselectivity (Equation (5)) <1996JCS(P1)389>.
OMe Ph Me OMe
SiMe3
CO2Me O Br CO2Me
Ph Ph
Mg
X Et3B 75–87% ð4Þ
O Br
MgBr2 (1 equiv.) MeO
10
–78 °C 11 12, 98% de
X = Br, I, SePh
SnBu3 EtO
OTBDMS OTBDMS
AIBN TBDMSO O
CO2Et CO2Et
EtO2C La(fod)3 EtO2C
La(fod)3 62% ð5Þ
O
Br (1.1 equiv.)
13 EtO
84% de
14
Chiral auxiliaries have been attached to the olefin moiety or at the radical center for asymmetric
1,4- or 1,5-diastereocontrol. Removal of the auxiliary allows the formation of enantioenriched
materials. Reactions of amides or imines containing chiral oxazolidines, C-2 symmetric 2,5-
disubstituted pyrrolidines, or Oppolzer’s sultam have been particularly studied and good levels
of diastereocontrol have been obtained <1991ACS296, B-1996MI005, B-2001MI011>. Recent
investigations in this area have focused on the use of the readily available and easily removable
oxazolidinone auxiliary in conjunction with Lewis acids <1998AG(E)2563, B-2001MI011>. For
instance, high levels of diastereoselectivity have been obtained using oxazolidinones derived from
diphenyl alaninol. Allylation of 15 in the presence of 2 equiv. of magnesium bromide was
achieved in high yield and in over 99% de. The Et3B/O2 initiation system offers the opportunity
to conduct the reaction at low temperature. The stereoselectivity was explained based on model A
(Scheme 3). Complexation of the Lewis acid with the bidentate radical ligand prevents free
rotation about the amide bond, the methyl group at the planar radical centre points away from
the nitrogen substituent thus avoiding steric interactions implying that the attack of allyltribu-
tyltin occurs from the face opposite to the diphenylmethyl group <1996AG(E)190>. It should be
noted that high levels of asymmetric 1,3-diastereocontrol have been recently achieved in acyclic
radical allylations based on Lewis acid chelation of chiral -hydroxyketones <2003TL531>.
-Stereoselectivity may also be controlled in radical additions to nonterminal acrylamides of
type 16. Generally, substrates complexed by Lewis acids are also much more reactive toward
radical addition than are free substrates which may allow the use of a catalytic amount of
the Lewis acid. For instance, the diastereoselective addition of the isopropyl radical to 16 was
promoted using substoichiometric amounts of ytterbium triflate. In the proposed model B
(Scheme 3), the enoyl system lies preferentially in an s-cis conformation as a result of the chelation
<1995JA10779, 1997AG(E)274, 2002JOC1738>. The stereochemical outcome of prochiral radical
addition to such -substituted enoyl oxazolidinones has also been studied <2002JA2924>.
O O O O SnBu3
SnBu3
Me Me
O N O N
O
Br O
Et3B/O2 H
N MgII
Ph –78 °C Ph O
Ph Ph Ph H
15 Ph Me
2 equiv. MgBr2 dr >99/1
none dr 36/64 A
Pr i
O O Pr iI O O Pr i
Bu3SnH O
O N Me O N Me H O
N M
Et3B/O2 O
Ph
Ph –78 °C Ph Ph
Ph Ph Me
16
2 equiv. ZnCl2 dr >87/17
0.3 equiv. Yb(OTf)3 dr 95/5 B
none dr 36/64 M = ZnII, YbIII
Scheme 3
Highly enantioselective radical additions can be achieved using chiral Lewis acids
<B-2001MI011, 2003CRV3263>. For instance, isopropyl radical addition to achiral enoyl oxazolidi-
none template 17 was investigated in the presence of magnesium diiodide and chiral bisoxazoline
ligands. 10 mol.% MgI2 proved sufficient to reach 95% ee and 88% chemical yield in the presence
of 18. Reactions could also be run at room temperature without much loss in selectivity. A model
C with cis-octahedral geometry around magnesium was proposed to explain the selective forma-
tion of the (R)-enantiomer (Scheme 4). The ligand confines the substrate into an s-cis confor-
mation and shields one of the diastereotopic faces thus forcing the radical to attack preferentially
from the opposite direction. Other ligands 19 were less selective. Interestingly, however, 19a
(R = Pri) led also to the (R)-enantiomer, whereas 19b (R = Ph) afforded the (S)-enantiomer. In
the latter case a model with a trans-octahedral geometry was suggested <1996JA9200,
1997JOC3800>.
O O O O Pr i
Pr iI, Bu3SnH, Et3B/O2
O N Ph O N Ph
10 mol.% MgI2/18 (R)
17 –78 °C
95% ee
88% O
N Pr i
O
I O
O O O Mg N
O
N N O N I O
N N
R R
Ph
18 19a, R = Pri
19b, R = Ph C
Scheme 4
The use of a pyrazole as an achiral template instead of an oxazolidinone also gave an inversion
of selectivity in the presence of zinc triflate and ligand 18. This reversal of enantioselectivity was
attributed to the change of the chelate ring size together with a trans-octahedral geometry
(Equation (6)) <1997TL5955>.
O PriI, Bu3SnH, TfO Me O Pri

N Et3B/O2 L* N N
Me N Ph Zn N Me Me N
L* (S) Ph
Zn(OTf)2/18 TfO O ð6Þ
Me 76% Me
Ph
L* ee 51%
= 18
L*
Enantioselective allylation reactions have also been studied with various template models. For
instance -acyl radicals 20 were reacted with allylstannanes or silanes in the presence of zinc and
magnesium Lewis acids in combination with bis-oxazoline ligands. Excellent levels of enantio-
selectivity were obtained. Interestingly, allyl silanes have been found to be superior to allylstan-
nanes in inducing enantioselectivity. This was explained by the fact that allylstannanes are
converted into stannyl halides. These may compete with the chiral Lewis acid in catalyzing the
reaction thereby producing racemic products <1997JOC6702>. Similar conditions allowed good
levels of enantioselectivity to be obtained in reactions of the cyclic N-pyridyl -lactam radical 21
with allyltrimethylsilane <1999TL6713>. The use of sulfonamide 22 as an acyclic template has
been investigated using aluminum, titanium, or magnesium Lewis acids with diamines, diols, and
sulfoxides as chiral ligands (Figure 1). The reactions, performed with allyltributyltin, proved
remarkably selective despite the presence of two oxygen atoms at the sulfur binding center
<2000TL7071>. In fact, the sulfur becomes a new asymmetric center by selective complexation
of one of the two enantiotopic oxygen atoms with the chiral Lewis acid. The sulfonyl group is
acting here as a chiral relay <2003CEJ28>.
R
O O O N O O O
S
O N R N N Tol
Bn
20 21 22
Figure 1
1.08.1.3.4 Methods for conducting radical reactions
(i) Introduction
To conduct successfully addition of carbon-centered radicals to alkenes, some factors must be
controlled. The initial radical must add faster to the double bond than any secondary processes
such as dimerization or disproportionation which can be avoided by working at a lower concen-
tration of radical (107108 M) than that of the alkene. In this case, the chain reaction is only
maintained if the rate of hydrogen atom-donation is not too low otherwise alkene polymerization
can occur. The evolution of the radical 23 can follow different pathways such as trapping by
hydrogen donors, heteroatom donors, electron donors, or intramolecular -elimination of a
suitable leaving group (Scheme 5). The rate of trapping must be faster than polymerization but
less than the trapping of the initial radical 23, otherwise no addition of this radical will occur.
Despite these limitations, radical additions know a growing interest in the area of organic
synthesis <B-1986MI001, B-2001MI011>.
Y Polymerization
Y H
R R H-donor
Y R
23 Y
–
e Donor
Trapping
R
Y
Z
Heteroatom-donor
R + X
X–Z Y
X R X –X R
R +
X = leaving group
23
Scheme 5
(ii) Initiation of chain reactions

Initiation of radical chain reactions is usually achieved by photolytic or homolytic fragmenta-
tion of a chemical initiator <2002JCS(P2)367>. Peroxides and azo compounds, particularly
2,2-azobis-isobutyronitrile (AIBN), have been widely used for this purpose <B-2001MI011>.
However, in recent years, the homolytic substitution reaction between triethylborane and oxygen
has become a very popular method to initiate radical reactions <B-2001MI011, 2001CRV3415>.
Indeed, the Et3B/O2 system offers the opportunity to conduct radical reactions under mild
conditions at low temperature (78 C), a great advantage when thermally unstable compounds
are involved or when the stereoselectivity has to be controlled. It also allows reactions to be
conducted in aqueous media <2002SL674> and, potentially, in ionic liquids <2002BCSJ853>.
Water-soluble azo-initiators have also been recently investigated <2001BCSJ1963>.
(iii) Chain reactions
(a) Tin hydrides. To date, most radical reactions are still conducted using tin hydrides
(Bu3SnH, Me3SnH, Ph3SnH) but these suffer from the toxicity of organotin compounds. The
difficulties encountered to remove the toxic by-products generated in these reactions limit the
applications of radical chemistry in the pharmaceutical industry <1987S665, B-1987MI002,
B-1995MI004, B-1997MI006, B-2001MI011>. The mechanism shown in Scheme 6 is well defined.
The chain carrier Bu3Sn_ (generated by an initiator, AIBN for example) reacts with an alkyl halide
to form an alkyl radical 23, which adds to the activated alkene 24 to generate a new electrophilic
radical 25. This latter radical abstracts an hydrogen atom from Bu3SnH to give the addition
product and regenerates Bu3Sn_ which can continue the chain reaction.
Y
24
R
R X
23
Y
Bu3Sn R
25
Y
R
Bu3SnH
Scheme 6
One of the major drawbacks of tin hydrides is the competitive trapping of the carbon radical 23
before addition to the double bond. This can be avoided by using excess alkene or low concentration
of the hydride donor. Generally, a slow addition via a syringe pump, or in situ generation of a
catalytic quantity of Bu3SnH (resulting from reduction of Bu3SnCl by NaBH3CN or NaBH4) are
the best methods to overcome this difficulty <1984AG51, 1986JA303>. Alternatively, if the rate of
hydrogen-atom donation is too slow then alkene polymerization can occur. The rate of reaction of a
tin radical with an organohalide depends on the nature of halogen groups and, to a lesser extent, on
the alkyl or aryl group <1998T2893>. Thus, the weaker carbon–iodide bond involves greater
reactivity compared to corresponding bromide or chloride. Other functional groups can undergo
similar reactions, the order of reactivity with tin radical <1984JA343, 1986AJC77> being in general
as follows: RI > RBr > RSePh ROC(¼S)SMe > RCl > RSPh. In recent years, major improve-
ments in organotin radical reactions have resulted from the development of new methodologies
using either catalytic quantities of organotin compounds <2002S835, 1998JOC2796>, new work-up
procedures facilitating elimination of tin by-products <1999TL6729, 1998TL2123>, or specially
designed tin hydrides easily removable from the reaction medium <2002JOC1192>. Furthermore,
Curran and co-workers have developed perfluorotin hydride catalysts such as 26, which are easily
removable and re-usable by a simple two phase extraction using a fluorinated and a conventional
organic solvent <1998AG(E)1174>. This method has been used for an efficient synthesis of a small
library of nine compounds (Equation (7)).
CO2Me
H2O Salts
(5 equiv.)
(10%) (C6F13CH2CH2)3SnH 26 CO2Me
+ C15H31 ð7Þ
C15H31 I NaBH3CN CH2Cl2
ButOH, BTF C6F14
(1 equiv.) 26
92%
(b) Germanium hydrides. Germanium hydrides, although they are not so reactive, can effi-
ciently replace tin hydrides. Hydrogen donor abilities of germanium hydrides have been measured
recently <1999OM2395>. Nevertheless, this weaker reactivity can be useful to minimize the
amount of reduction versus addition products <1991COS(4)715>. However, germanium deriva-
tives remain expensive and are rarely used in organic synthesis <2002S835>.
(c) Silicon hydrides. Despite their lower reactivities, silicon hydrides are extremely useful as
substitutes for toxic organotin hydrides <2002S835, 2002JCS(P2)367, 1998AG(E)3072>. How-
ever, due to the greater stability of SiH bond, H-abstraction from trialkylsilanes by C-radicals is
in general too slow to maintain chain reactions. Higher temperatures and excesses of silane
reagents are necessary. The method is therefore limited to substrates which are not too tempera-
ture sensitive. The most popular silicon-hydride is tris(trimethylsilyl)silane [(TMS)3SiH] for which
hydrogen-atom abstraction is accelerated by the presence of trimethylsilyl groups on the silicon
atom <1992ACR188, B-1998MI007, B-2001MI008>. The presence of bulky groups around
silicon weakens the SiH bond, enhancing its reactivity. For instance, the rate of hydrogen-atom
transfer to alkyl halides is only 10 times slower than with Bu3SnH <1991JOC6399>. All
classical radical precursors (halides, selenides, xanthates, etc.) can be used with this reagent. Other
silicon hydrides bearing bulky groups have been studied <1995CRV1229>. Among these, 1,1,2,2-
tetraaryldisilanes (Ar4Si2H2) have been recently developed and used as novel tin-hydride substitutes.
These reagents are crystalline, stable to air, and easy to handle. Bromocyclohexane adds to vinyl
sulfone with an excellent yield using Ph4Si2H2 (Equation (8)) <1998TL1921, 1999T3735>.
Ph4Si2H2 (2.5 equiv.) SO2Ph

Br + SO2Ph ð8Þ
EtOH, AIBN
78%
An interesting concept, named ‘‘polarity reversal catalysis,’’ has been developed by Roberts
<1999CSR25>. This ingenious method allows the use of less reactive silicon hydrides such as
triethyl or triphenylsilane with thiols as catalysts. A thiyl radical 27 generated by a suitable
initiator (which too slowly abstracts a halogen atom from alkyl halides to maintain the chain
reaction itself) reacts easily with triethylsilane forming silane radical 28 which can react with alkyl
halides (Scheme 7). The thiyl radical is regenerated by reaction of the carbon-centered addition
radical with thiol thus maintaining the chain reaction.
RS + HSiEt3 RS H + SiEt3
27 28
SiEt3 + X R R + XSiEt3
R + R RSH R + RS
Y Y Y
Scheme 7
Addition of bromoacetate 29 to alkene 30 using triphenylsilane and a catalytic amount of methylthio-

glycolate (MTG) provided the reductive addition compound 31 (Equation (9)) <1999JCS(P1)2061>.
OAc OAc
Ph3SiH, dioxane
Br CO2Me + MeO2C ð9Þ
MTG, initiator, ∆
29 30 75% 31
(d) Carbon hydrides. Generation of carbon-centered radicals directly from CH reagents is
generally difficult due to the strength of the CH bond compared, for example, to the SiH
bond. This method has been limited to activated CH bonds (adjacent to carbonyl groups) or to
generate reactive aryl or vinyl radicals <1995COFGT(I)319>. Recently, a new concept presented
in Scheme 8 has been developed by Walton <1997JCS(P2)757> based on the properties of
modified cyclohexa-1,4-dienes which present a weak methylene CH bond (305 kJ mol1)
where hydrogen-atom abstraction is facilitated. After generation of carbon radical 32a with
ButO_, the cyclohexadienyl radical undergoes fragmentation to toluene and alkoxycarbonyl radical
33. The latter fragments via -scission to carbon dioxide and the nucleophilic t-butyl radical 34
which adds to the double bond of acrylonitrile to form a new radical adduct that in turn reacts
with another molecule of cyclohexadiene 32 to maintain the chain reaction (Scheme 8).
Me CO2But Me CO2But Toluene O

ButOOBut
Heat OBut 33
32
32a
–CO2
32a 32
But CN
But NC But 34
NC
40%
Scheme 8
The limitations of this method were generally the formation of by-products (polymers, iso-
butane, etc.) resulting from competitive side reactions. Recently, in a similar strategy, Studer and
Amrein have synthesized other cyclohexadiene derivatives which possess a silyl function 35
(Figure 2). After fragmentation, a silyl radical is formed which can react with alkyl halides
(xanthate or phenyl selenide can also be used) to form carbon-centered radicals which can add
to alkenes <2000AG(E)3196>. Various silylated cyclohexadienes have been designed and their
reactivities evaluated <2003JA5726>.
SiMe2But
MeO OMe
35
Figure 2
(e) Mercury hydrides. Despite their important use in the 1980s <1985AG(E)555>, to date,
mercury hydrides seem to have been passed over in favor of less toxic reagents for generating
carbon radicals. Their use in synthesis has been reviewed by Barluenga <1988CRV487>.
(f) The Barton method and xanthates in radical reactions. Generation of carbon radicals from
carboxylic acids, the so-called Barton-ester method, is one of the most famous methodologies
developed in radical synthesis <B-1993MI003>. The commercially available N-hydroxypyridine-
2-thione 36 reacts with carboxylic acid 37 in the presence of dicyclohexylcarbodiimide (DCC) to
yield to the thiohydroxamate ester 38, which upon irradiation or heating undergoes elimination of
CO2 to generate the carbon-centered radical 23. This radical adds to an activated alkene, and the
newly formed radical 39 can then be trapped by the pyridyl sulfide to yield functionalized
products as useful precursors for functional groups (Scheme 9) <1992T7083, 2002HAC169>.
Recently, chaetomellic anhydrides were synthesized using this method <1997JCS(P1)2175>,
and the first addition of alkyl radicals onto double bonds on solid phase was realized
<1999JCO157>. When hindered carboxylic acids were used, lower yields were generally obtained
due to the incomplete formation of Barton esters. To overcome this difficulty, a new reagent S-
(1-oxido-2-pyridinyl)-1,1,3,3-tetramethylthiouronium hexafluorophosphate (HOTT) 40, which is
a stable white crystalline solid, was developed (Figure 3) <1998JOC5732>. It was successfully
used, for example, for the synthesis of hydroxyalkyl radicals which can add diastereoselectively to
carbon double bonds <2002JOC6195>.
36
N
HO
S Heat or Y
RCO2H N R
DCC RCO2 hν
37 S –CO2 23
38
Y
R
R Functionalized products
Y N S
39
Scheme 9
–
+ PF6
– N
O +
S NMe2
HOT T NMe2
40
Figure 3
Another development of Barton-ester chemistry is the two- or three-carbon homologation

methods using acrylate ester 41 or nitrile 42 (Figure 4) derivatives to give rise to diverse carbonyl
functions (acids, amides, esters, aldehydes, and ketones) <1993TL6505, 1992TL5017>.
EtO2C CF3 CN CF3
O O O O
41 42
Figure 4
Recently, this homologation has been widely used for the synthesis of sugar derivatives
<1996T2717, 1997T3723, 2001T8767, 1997TL367> and particularly polyols <1999OL1057>.
Barton has also developed a two-carbon homologation of carboxylic acids using acrylamide as
a radical trap <1997TL2431>.
(g) The borane method. Trialkylboranes are easily accessible by hydroboration of alkenes. They
were shown to react with molecular oxygen to generate alkyl radicals that may undergo conjugate
addition to activated olefins, most commonly ,-unsaturated ketones and aldehydes
<B-2001MI011, 2001CRV3415>. Traces of oxygen are generally sufficient to initiate the process
(Scheme 10). The presence of water in the reaction mixture allows hydrolysis of the intermediate
boron enolate 43 and thereby avoids its degradation through undesired radical side reactions.
O
O2
R3B R R
O OBR2 R3B
H2O
R R
43
Scheme 10
The major drawback of this process that initially impeded its synthetic potential was that only
one alkyl group was transferred from boron. To circumvent this problem, B-alkylboracyclanes
<1971JA3777> and more recently B-alkylcatecholboranes <1999CEJ1468, 2003S2740> have
been used as precursors of alkyl radicals. For instance, B-cyclohexenylcatecholborane 44 has
been generated in situ by hydroboration of cyclohexene with catecholborane and treated with
cyclohexen-2-one as a radical trap in the presence of a DMPU/H2O/O2 system to give the desired
adduct 45 in good yield (Equation (10)). An alternative approach has also been developed to
accommodate the method to use other radical traps such as unsaturated esters, nitriles, or
sulfones. Their lack of reactivity was attributed to the inefficiency of the propagation step. As
exemplified in Equation (11), the problem may be solved by using a chain-transfer reagent such as
Barton carbonate PTOC-OMe 46 (PTOC = pyridine-2-thione-N-oxycarbonyl) under irradiation.
The process is terminated by addition of a thiopyridyl group in the -position of the radical trap
which may eventually be removed <2000AG(E)925, 2003JOC5769, 2000CC1017>.
O
BH O O
O O
B ð10Þ
O
cat. Me2NCOMe H2O/DMPU
44 79%
45
O ii.
i. BH CO2Me S N
O 150 W lamp
CO2Me
ð11Þ
cat. Me2NCOMe (3 equiv.)
N S 46
OCO2Me
69%
(h) The fragmentation method. Fragmentation reactions involve addition of a radical to a

neutral alkene, followed by -scission of the resultant radical to produce an adduct radical
which propagates the chain reaction (Scheme 11). Relatively weak bonds such as CSn, CS,
or even CSi are prone to undergo such -elimination processes. Compared to the above
discussed methods for conducting radical chain reactions, the present method tolerates unacti-
vated alkenes and offers several other advantages. The nonreduction of the radical precursor,
contrary to the reaction achieved in the presence of metallic hydride donors as in the Giese
reaction (see Section 1.08.1.3.4.(iii).(a)), represents a major advantage. The nonreductive nature of
the method makes it particularly interesting for the preparation of functionalized compounds.
The fragmentation method is a very popular method to effect allylation transfer reactions which
have been mainly carried out by using allylstannanes as radical traps <B-2001MI011>, but allylic
sulfones <2003AG(E)2658> as well as allyl silanes <1996TL6387> have been recently suggested
as ‘‘tin-free’’ alternatives. However, SiR3 radicals (47, Z = SiR3) have been postulated to undergo
group transfer prior to fragmentation <1996JA12528, 1997JOC6702>.
Z
R Z R
47
Initiator
RX R Z
Z = Bu3Sn, S(O)nR, SiR3

ZX RX
Scheme 11
The fragmentation method has thus been recently applied to the allylation reaction of
B-alkylcatecholboranes using allyl sulfones as radical traps <2003AG(E)2658>. The process is
initiated with di-t-butylhyponitrite 48 and propagation of the chain is sustained by reaction of the
alkyl borane with the stable phenyl sulfonyl radical issued from fragmentation (Equation (12)).
O CO2Et
i. BH ii. CO2Et
O SO2Ph
ð12Þ
cat. Me2NCOMe ButON=NOBut, 48
CH2Cl2/MeOH 65%
(i) The atom transfer method. Homolysis of the CX bond in organic halides, followed by the
transfer of both radical components to an unsaturated system constitutes an attractive, non-
reductive way of conducting radical reactions <B-2001MI011>. The method is very interesting
from an atom economy point of view since all atoms remain in the reaction product
(Scheme 12). Initiation may be obtained by direct photolytic cleavage of the initial CX
bond or by conducting the reaction in the presence of an initiator, usually (Bu3Sn)2
<2002JCS(P2)367> but also Et3B/O2 <2001CRV3415> or dilauroyl peroxide (DLP)
<2000S1598> as tin-free substitutes. Halide atom transfer reactions generally involve addition
of electrophilic radicals to electron-rich terminal alkenes. By generating an adduct radical less
stable than the initial radical, this ensures that the rate of atom transfer is fast enough to avoid
unwanted side reactions such as polymerization. Halomalonates and -malononitriles, as well as

-haloesters, nitriles, or amides are commonly used as organic halides, with the iodo derivatives
generally giving better results. Lewis acids have recently been shown to significantly improve
intermolecular halide atom-transfer reactions by increasing the electron-withdrawing nature of
the functional group to the halide, which is expected to widen the scope of alkene partners
<1999JA5155>. Aside from the popular halide atom transfer reaction, recent developments have
also focused on phenyl selenide transfer processes as synthetically useful alternatives which allow,
for instance, photochemical additions of the sulfur-stabilized dithiane radical <1996TL2743>.
Although the selenium transfer is a relatively slow process compared to the corresponding iodine
transfer <1993JOC4691>, the stability and versatility of the incorporated phenylseleno group is
of value for subsequent transformations <2000TCC81>. The transfer of xanthates (dithiocarbo-
nates) <1997AG(E)693> is also a synthetically useful transformation, which can be applied to
strained cycloalkenes <2000TL2979, 2000TL9815> (Equation (13)).
R'
Initiation R'
RX R R
X = I, Br, Cl, SePh, SC(S)OEt, etc.

R' RX
R
X
Scheme 12
S
Lauroyl EtO S CO2Me
O CO2Me peroxide CO2Me
S OEt + CO2Me O ð13Þ
45%
S
5/1 trans/cis
(j) Phosphorus hydrides. Replacement of tin hydrides by nontoxic reagents in order to favor
green chemistry has been one of the major goals of free-radical chemistry. Phosphorus-based
compounds, firstly used by Barton <1993JOC6838, 1992TL5709>, have recently demonstrated
their abilities to generate carbon-centered radicals. The strength of the PH bond in dialkyl
phosphine is only around 310 kJ mol1 and these reagents can act as effective hydrogen-atom
donors <2002JCS(P2)367>. Phosphinyl radicals are not as reactive as the corresponding phenyl
silanes but, nevertheless, rate constants for the addition to double bonds are comparable
<1998JOC1327, 2002JCS(P2)367>. Rate constants for reactions of the diphenylphosphinoyl
radicals with some organohalides have been determined <1996JA7367, 1998JA11773,
1983JA3580>. One of the major difficulties encountered is the propensity of phosphorus
radicals to add themselves to double bonds. Nevertheless, it has been shown that CCl4 can
add to alkenes using benzoyl peroxide as initiator, dioxane as solvent, and diethyl phosphite 49
as hydrogen donor <2001SL1719> with large excesses of CCl4 (4 equiv.) and diethyl phosphite
(10 equiv.) (Equation (14)).
O
EtO P H 49
OEt CCl3
+ CCl4 C6H13 ð14Þ
C6H13
(PhCOO)2, ∆
dioxane
55%
Simultaneously, it was reported that hypophosphorous acid salts, first used by Murphy in
radical cyclizations <1999TL2415, 1999JCS(P1)3071>, can be used as reducing reagents in
intermolecular radical addition reactions. The reagent used, N-ethylpiperidine hypophosphite

(EPHP) 50 (3 equiv.), is commercially available, and allowed the generation of radicals
from primary, secondary, and tertiary halides and their additions to diverse alkenes (1 equiv.)
(Equation (15)) <2001SL1923>.
EPHP 50, Et3B

R
R I + Y Y
dioxane, rt
64–98% ð15Þ
R = cyclohexyl, adamantyl, C12H23
Y = SO2Ph, P(O)(OEt)2, CO2Me, COMe
The great advantage of the phosphorus compound is that polar by-products were easily removed
by simple flash-chromatography and that no slow addition was required. More recently, it has been
demonstrated that this addition can also be conducted with -substituted alkenes in water by using
acetyl trimethylammonium bromide (CTAB) and the water-soluble 4,40 -azobis(4-cyanovaleric acid)
(ABCVA) as radical initiator. However, this addition works only in the presence of indium metal
(2 equiv.), and large quantities of both the alkene (10 equiv.) and EPHP (7 equiv.) were also
required <2002SL631>. A Lewis acid (e.g., Yb(OTf)3) can also be used to replace indium metal
(Equation (16)) <2003MI15>.
O O
I
In, EPHP 50 ð16Þ

CTAB, ABCVA,
H2O, 80 °C
89%
Xanthates can also be used with diethyl phosphite and a suitable initiator in intermolecular
additions of radicals to alkenes <2003OL1645>.
(k) Indium hydrides. A promising methodology using a catalytic quantity of indium trichloride and
sodium borohydride which allows generation of indium hydride as catalytic active species has been
developed. No initiator is needed, and this new method has been applied with success to intermolecular
additions of organohalides (aryl or alkyl) to electron-rich or -poor alkenes (Equations (17) and (18))
<2002JA906>.
I InCl3 (0.1 equiv.)

NaBH4 (1.2 equiv.)
+ CO2Et ð17Þ
MeCN, rt CO2Et
(5 equiv.)
57%
I InCl3 (0.1 equiv.)

NaBH4 (1.2 equiv.)
+ CO2Me ð18Þ
MeCN, rt CO2Me
(10 equiv.)
62%
(iv) Nonchain reactions
(a) Organocobalt group transfer. In the 1980s, formation of alkyl radicals by photolysis or
thermolysis of organocobalt derivatives has been used in numerous addition reactions to alkenes
<1995COFGT(1)319, 1988CSR361>. Nevertheless, this methodology is currently not used
because it requires stoichiometric organocobalt reagents.
(b) Organotellurium compounds. Very recently, carbon-centered radicals have been generated
from organotellurium compounds under thermolysis or photolysis <1999TL2339>. This method
has been used to add carbon radicals to substituted quinones (Equation (19)) <2002T6805>.
O O
R3 hν (200 W Hg lamp) R R3
RTeTol +
C6H6, 100 °C
R1 R2 R1 R2
23–71% ð19Þ
O O
R = Bn, Pri, CH2CH=C(CH3)2 R1 = H, Cl, Me, Ph, But
R2 = H, Cl, OMe
R3 = H, OMe
(c) Indium. The usefulness of indium metal as a single electron transfer radical initiator in the
addition of an iodoalkane to phenyl vinyl sulfone has been demonstrated <2002OL131>. The
proposed mechanism involves formation of a first radical 23 which adds to the double bond. A
second single electron transfer (SET) leads to the anion 51 which is then trapped by water
(Scheme 13).
RI (5 equiv.), In (7 equiv.)
SO2Ph R
SO2Ph
H2O/MeOH 4/1, 20 °C
61–86%
R = Pr i, Bus, c-pentyl, But
SO2Ph
RI + In R + InI R
SO2Ph
+
23
In In
R H2O R
SO2Ph SO2Ph
51
Scheme 13
(d) Phthalimide N-oxyl (PINO). The generation of alkyl radicals directly from alkanes would
be the best method for conducting radical reactions but this is still a challenge in free radical
chemistry. From this perspective, a new methodology using N-hydroxyphthalimide (NHPI) and a
cobalt complex (Co(acac)3) as catalyst under an oxygen atmosphere has been developed. The
reaction involves the generation of an alkyl radical 23 by the NHPI/Co/O2 system followed by
radical addition to an alkene. Subsequent trapping of the addition radical by molecular oxygen
results in a formal oxyalkylation of the alkene (Scheme 14) <2001JOC6425, 2001MI397>.
OH O
cat. NHPI/Co
1 R1 + R
1
RH + R + O2 EWG EWG
EWG CH3CN, 60 °C, 6 h
R R
PINO
Co(II)/O2
NHPI
R1 O2
R EWG
23 R1 R
EWG
Scheme 14
The same concept has been applied to the addition of -hydroxy radicals to alkenes, which
leads to various lactones by subsequent cyclization <2000CC613>, as well as to the radical
addition of 1,3-dioxolanes <2000CC2457>.
(e) Electron-transfer processes. Carboncarbon bond formation can be mediated by transition
metals of higher valency via a single-electron transfer step. Metals, such as Mn, Co, Cu, Fe, Ag, Pb,
and Ce, have been widely used in organic synthesis <B-2001MI011>. Among them, manganese(III)
has received great attention for its ability to oxidize carbonyl compounds leading to electrophilic
radicals that can add to electron-rich double bonds (Scheme 15) <2002JOM159, 1996CRV339,
1998ACA50>.
O
O Mn(OAc)3 O R3 R1
R1 R1 R2
R2 R2 R3
52
Mn(OAc)3 R3
Cu(OAc)2 Addition
H-atom
abstraction Oligomers
O Oxidation
R1 R2 O
R1
R3 R2
R3
55
Ionic path
O O
R1 R2 R1 R2
or or cyclization with internal nucleophile
R3 R3
53 54
Nu
Scheme 15
However, the newly created radical 52 can react through different competitive pathways leading
to complex mixtures of products in some cases. An ionic path leads to the classical products of
carbocationic chemistry (products resulting from elimination 53, or from trapping by an external
nucleophile 54 or an internal nucleophile leading to cyclized products), whereas a radical path
leads to H-transfer products 55 or oligomers. When the radical intermediate is a tertiary radical,
Mn(OAc)3 is sufficient to oxidize it, whereas Cu(OAc)2 must be added in the cases of primary or
secondary radical <1996CRV339>. Recently, a methodology allowing selective formation of a
hydrogen-atom transfer product has been developed. This new approach is based on an in situ
generation of catalytic amounts of Mn(OAc)3 resulting from oxidation of Mn(OAc)2 by KMnO4
<2002JOMC159>. Due to milder reaction conditions, ceric ammonium nitrate (CAN) was found
to be superior in some cases to Mn(OAc)3 for applications in carbohydrate chemistry
<1997JA9377>. Nethertheless, despite their great interest, all these reported procedures suffer
from the large quantity of the metal reagent required. To avoid this problem a new procedure that
works with catalytic quantities of Mn(OAc)2 and Co(OAc)2 as co-oxidant under an oxygen
atmosphere in AcOH as solvent has been devised. To date, cyclic and acyclic ketones, malonates,
and anhydrides have given excellent results using these catalytic additions to alkenes
<2000CC2317, 2002JOC970, 2003JOC5974>. Such additions can also be conducted in ionic
liquids <2001CC1350>.
1.08.1.4 Intramolecular Radical Additions
1.08.1.4.1 Introduction
This section is organized similarly to the section dealing with intermolecular additions. The reader
is strongly recommended to read the previous section for a more detailed account of the
mechanisms and principles involved in carrying out radical reactions and to read the following
reviews which cover recent literature on cyclization reactions <1996CRV195, 1998AG(E)2563,
1999T9349, 2001JCS(P1)3215, 2001T7237, 2001AG(E)2224, 2002JCS(P1)2747, 2003S803,
2003CRV3263>. Radical cyclization reactions are favorable processes compared to intermole-

cular additions. All requirements have been discussed in COFGT (1995) which should be
consulted.
1.08.1.4.2 The 5-hexenyl radical: regioselectivity

To avoid repetition of basic principles concerning cyclization reactions, readers are directed to
COFGT (1995). In the 5-hexenyl cyclization type, between the two competing cyclization
modes, the 5-exo-trig mode is always the major pathway versus the 6-endo trig mode (50
times faster). Nevertheless, in most cases, final products are contaminated by products gener-
ated by the secondary process. However, when alkenes are substituted by an electron-with-
drawing group, products resulting from 6-endo cyclization become insignificant. The
presence of an alkyl substituent on the alkene, or a heteroatom in the chain strongly affects
the course of the cyclization <1995COFGT(1)319>. In certain cases, 5-endo-trig cyclizations
of 5-pentenyl radicals which are recognized as a disfavored process can be realized
<2002S695>.
1.08.1.4.3 Stereoselectivity in substituted 5-hexenyl radical cyclizations

The major stereomer in a 5-exo-radical cyclization can generally be predicted by using the
Beckwith transition state model as discussed in COFGT (1995) <1995COFGT(1)319>.
1.08.1.4.4 Allyl, vinyl, and aryl cyclizations

Vinyl radicals and aryl radicals are widely used in organic synthesis as they are more reactive than
their alkyl homologs (see COFGT (1995) for a more detailed account of their reactivities
<1995COFGT(1)319>) <2001T7237>. However, under tin-mediated cyclization conditions
vinyl radicals give a mixture of both 5-exo- and 6-endo-products which can be a limitation.
Generally, this ratio is a function of the tin hydride concentration, high concentrations favoring
the 5-exo-products. Unfortunately, this high concentration also increases the amounts of acyclic
products due to the trapping of the initial vinyl radical. Nevertheless, it has been reported that
5-exo-products can be obtained preferentially by adding a catalytic amount of PhSeSePh to the
reaction medium <1996TL3105>. Another study involving vinyl radicals has shown that six-
membered rings can be obtained selectively from 1-vinyl-5-methyl-5-hexenyl radicals
<2002TL4997>.
Allyl radicals, which are less reactive than vinyl radicals have been used in diverse syntheses of
complex natural products <1999TL9379>. Aryl radical cyclizations are widely used in synthesis
of complex frameworks and readers are directed to previous issue of this volume and to the
reviews cited in the introduction.
1.08.1.4.5 Formation of six-membered rings

Formation of six-membered rings by exo-cyclizations of 6-heptenyl radicals is slower than the
radical cyclization of 5-hexenyl radicals. Requirements for the formation of six-membered rings
have been developed in COFGT (1995) and are still relevant today <1995COFGT(I)319>.
1.08.1.4.6 Formation of other ring sizes

Formation of small rings via intramolecular radical addition to alkenes is a highly disfavored
process. For instance, 3-exo-cyclization of the parent 3-butenyl radical (56, n = 1) is 104 times
slower than the reverse ring opening of the resulting cyclopropylmethyl radical (57, n = 1)
(Equation (20)) <1980JA1734>. The equilibrium is thus strongly shifted toward the acyclic
intermediate unless the cyclized radical is strongly stabilized by adjacent unsaturation or keto
group, or if ring strain in the cyclization precursor induces favorable geometric alignments of the
carbon-centered radical and the alkene. The example depicted in Equation (21) takes advantage
of these two features <1997JCS(P1)177>. 3-Exo-radical cyclizations have also been shown to be
facilitated by intramolecular trapping of the cyclopropylmethyl radical via -elimination of a
phenylthio group <2001CR(C)599>.
( )n n = 1 or 2
( )n ð20Þ
56 57
O O O O
Ph Bu3SnH Ph Ph Ph
82%
Br AIBN
ð21Þ
gem-Disubstituent effects have been reported to significantly facilitate 4-exo-radical cyclizations

<1999TL2661>. For instance, while reaction of ethyl 6-bromo-2-hexenoate (58a, R = H) with
tributyltin hydride only furnished the reduced product 59, the analogous gem-diethoxy substrate
(58b, R = OEt) underwent clean cyclization to afford the corresponding cyclobutane derivative 60
(Scheme 16).
CO2Et CO2Et CO2Et

Bu3SnH
Br AIBN
R R R R
R R
58a, R = H
58b, R = OEt R=H 72% R = OEt
CO2Et
CO2Et
EtO OEt
59 60
Scheme 16
Methods for medium-sized ring elaboration have been recently reviewed <1999T9349,
B-2001MI011>. In general, formation of medium-sized rings using radical cyclization methods is
a relatively disfavored process and competitive reduction of the intermediate radicals by hydrogen
donors may represent a serious problem. These rings have therefore often been obtained via ring
expansion of smaller rings or by cyclization of the highly reactive -aryl radicals. Another method
for obtaining medium-sized rings is to cyclize electrophilic alkyl radicals onto weakly nucleophilic
alkenes or vice versa. In these reactions, endo-cyclizations are generally favored over exo-cyclizations.
The 8-endo-cyclization of unsaturated -haloesters has been investigated to access eight-membered
lactones <1998JA7469>. Macrocyclic lactones have been obtained via 12-, 15-, 18-, 21-, and
24-endo-cyclizations of !-iodopolyoxaalkyl acrylates <1998JOC6814> and water seems to be a
very promising solvent to promote the macrolactonizations <2000JA11041>. As demonstrated in
Scheme 17, one common method to control the regioselectivity in favor of the exo-mode of
cyclization is to substitute the terminal position of the alkene with electron-withdrawing groups to
direct radical addition onto the -position of the ,-unsaturated system <2002JOC3717>. Metal-
mediated radical approaches to medium-sized rings have also been reported and recently reviewed
<2000CRV2963>.
I
O
O OH Bu3SnH
O OH
O AIBN
O O O
O 50%
(8-endo mode)
CO2Me CO2Me
I Bu3SnH
slow addition OBn
O
O OBn
AIBN
O
O 50% O
O O
O (7-exo mode)
Scheme 17
1.08.1.4.7 Methods for facilitating radical cyclization reactions
(i) Introduction
The following sections indicate the different methods available to facilitate radical cyclization
reactions. The reader is strongly advised to first read Section 1.08.1.3.4 to become familiar with
the factors which affect the success of radical chain reactions.
(ii) Radical chain methods
(a) Tin hydrides and germanium hydrides. Tin hydrides remain the most commonly employed
reagents to facilitate radical cyclizations. An increasing number of syntheses have been developed
in recent years leading to various natural and non-natural products <B-2001MI011, 2001T7237,
2002JCS(P2)367, 2002JCS(P1)2747, 2002H2413>. The mechanism for the chain reaction has
already been described in Section 1.08.1.3.4.(iii).(a). In fact, carbon-centered radicals are gener-
ated in the same way as for intermolecular additions from various precursors, the order of
abstraction by Bu3Sn_ being I > Br > SePh OC(S)Me > Cl > SPh <1991CRV1237>. Alkyl,
vinyl, or aryl precursors typically react with AIBN and tin hydride and the formed radicals add
intramolecularly to a suitable double bond (Scheme 18).
Z Z Z Z
X
Bu3SnH
Bu3SnH
AIBN Y Y
Y Y
X = radical precursor Bu3SnH

Y = O, NR, CMe2 Z
Z = H or EWG H
Scheme 18
Factors governing radical cyclizations can be rationalized as follows:

(i) intramolecular addition of carbon-centered radicals is favored versus intermolecular addition;
(ii) 5-exo-cyclizations (2.3 105 s1) are faster than 6-endo-cyclizations (4.1 103 s1) as
mentioned previously (see Section 1.08.1.4.2);
(iii) competitive processes such as simple reduction of initial radical before cyclization can be
easily controlled by a low concentration of Bu3SnH (typically a 0.02 M concentration is required,
using usually syringe-pump technique). Another competitive process is addition of the tin radical
to alkene before cyclization. Nevertheless, this process is reversible and does not affect the course
of the reaction.
(iv) Structural beneficial effects can greatly enhance kinetics of addition of carbon radicals to
double bonds. For instance, the presence of a geminal dialkyl group or heteroatom within the
carbon chain results in faster cyclizations. This can be explained by a Thorpe–Ingold effect.
As described in Section 1.08.1.3.4.(iii).(a), highly toxic tin hydrides or tin-based by-products
may be avoided by applying new methodologies based on the use of catalytic quantities of
organotin compounds, or by following new work-up procedures facilitating the elimination of
tin by-products. Tin hydride methodologies have been widely applied to carbo- or heterocycle
syntheses <2002JCS(P1)2747, 2001T7237>. Highly diastereo- and enantioselective cyclizations
have been achieved using Lewis acids with chiral ligands <2003CRV3263> or chiral scaffolds
<2001OL145>. Numerous carbohydrates and nucleosides have been prepared by radical cycliza-
tion leading to complex monocyclic or polycyclic structures. For example, the key step of the total
synthesis of ambruticin, a natural antifungal agent, is the radical cyclization of 61 which
elaborates the monosaccharide unit 62 (Scheme 19) <2002AG(E)176>.
O O
MeO2C OTBS Bu3SnH, AIBN MeO2C OTBS
6 2
Br OBn benzene, reflux
OBn
OBn (2,6-cis/trans = 10/1)
OBn 62
61 83%
Ambruticin
Scheme 19
Nitrogen heterocycles such as pyrrolidines or -lactams have also been synthesized using tin
hydrides <2001CR(C)391>. Synthesis of tetrahydrofurans (THFs) by radical cyclization is a
common route allowing the synthesis of more complex molecules <2002AG(E)2103, 1999TL1337,
1998TL2783>. Aryl radicals are also widely used and can lead to benzoheterocycles (Equation (22))
<2002JOC3985, 2001EJO3461, 2001TL6499>.
H
Br NMe Bu3SnH, AIBN NMe
ð22Þ
N toluene, reflux N
O O
80%
O Bn O Bn
Vinyl radicals are less common but can also be generated from vinyl halides using the tin
method. Griseolic acid B has been recently synthesized using a radical cyclization as the key step
<2001OL3583> and, in a similar manner, the total synthesis of ()-7-epi--bulnesene involving
an unusual 7-endo-cyclization of a vinyl radical was achieved (Scheme 20) <1997JOC1922>.
I
Bu3SnH, AIBN
O 7-epi-Bulnesene
toluene, reflux
SiMe3
H 68% H OSiMe3
Scheme 20
Trialkylgermanium hydrides have been less widely used in radical reactions. Recently, tri-2-
furylgermanium hydride 63 was used as the radical mediator to synthesize various THFs and
dihydrobenzofurans. Interestingly, the reaction can be conducted in water using Et3B or 2,20 -
azobis(4-methoxy-2,4-dimethylvaleronitrile), a soluble form of AIBN, as initiator (Equation (23))
<2001BCJ747>. Tris(trimethylsilyl)germanium hydride, another source of radicals, has also
been used to realize the intramolecular addition of an aryl radical to pyridine <2003OBC4047>.
I 3
GeH 63
O ð23Þ
O Initiator, H2O, 80 °C O
75%
(b) Silicon hydrides. Development of alternative hydrogen atom donors to overcome difficulties in
removing highly toxic organotin reagents or by-products is a growing necessity with regard to potential
applications of radical chemistry in the pharmaceutical industry. Silicon hydrides, despite their lower
reactivities (see Section 1.08.1.3.4.(iii).(c)), are useful substitutes for organotin hydrides. In the recent
literature, two reagents predominate: tris(trimethylsilyl)silane (TTMSS) developed by Chatgilialoglu
<1995CRV1229> and 1,1,2,2-tetraphenyldisilane (TPDS) developed by Togo <2001CR(C)539>.
TTMSS-promoted radical cyclizations have been applied to the synthesis of complex structures such
as nitrogen heterocycles <2003T3009>, tri- and tetracyclic isoindolinones <1999TL7591>, as well as
spirolactones and lactams (Equation (24)) <1999TL7595, 2000TL2523>. The expeditious formation
of a complex aza-structure has also been reported which may be applied to the synthesis of recently
isolated polyguanidium alkaloids possessing important bioactivity against HIV <2001TL6637>.
O O
O (TMS)3SiH, AIBN
O ð24Þ
Benzene, ∆
Br
83%
O
O
TPDS is a promising, commercially available crystalline reagent, stable to air, which has been
successfully used in sugar chemistry to facilitate radical cyclizations. A comparative study has
been conducted with tributyltin hydride (Table 1). The use of silane reagents led exclusively to the
cyclization product, whereas tin hydride reagents gave mixture of cyclized and reduced products
<2000JOC5440>.
Table 1 Silicon hydride versus tin hydride for the cyclization of glycosyl radicals
AcO AcO AcO

O Radical reagent O O
initiator AcO O
AcO O AcO O +
AcOEt
AcO Br AcO AcO
H3C
Ph4Si2H2, Et3B 84 0
Ph4Si2H2, AIBN 78 0
Bu3SnH, Et3B 37 44
Bu3SnH, AIBN 65 32
(c) Mercury hydrides. Mercury hydrides can be used to carry out reductive radical cyclizations
<1995COFGT(1)319, 1988CRV487>. Limitations are mainly high toxicity and need for stoichio-
metric quantities of organomercurials. An 8-endo cyclization leading to an eight-membered lactone
has been realized by addition of ButHgI to an unsaturated acrylate ester and subsequent photolysis
of the resulting organomercurial in the presence of PhSSPh, the final radical being trapped by
PhSSPh <1996TL2557>.
(d) Hydrogen atom transfer reactions. In particular cases where radical precursors are difficult
to synthesize, or if a position is itself unreactive toward abstraction to give a carbon radical, a
methodology involving hydrogen atom transfer can be used. The strategy involves a radical
translocation, i.e., an intramolecular abstraction of an hydrogen atom by a radical center which,

in turn, can react with an unsaturation present in the molecule (Scheme 21) <2001CSR94>.
H H H
5 X1 1,5-H-abstraction X Cyclization X
4 2
3
Scheme 21
Generally, 1,5-hydrogen atom transfer is a favored process compared with 1,6- or 1,n-abstrac-
tions. The precursors can be vinyl, aryl, or more rarely alkyl radicals obtained from halides or
classical precursors. This methodology has been applied with success to the synthesis of diverse
structures such as pyrrolizidines (Scheme 22) <1996TL5825>, spironucleosides <1996JOC1908>,
as well as spiro- or fused-cyclic ketones <2000TL9865>.
TBSO OTBS
TBSO OTBS
Bu3SnH
H
N Br AIBN Me
N
64%
5-exo
TBSO OTBS TBSO OTBS
N H N H
Scheme 22
The mitomycins, a family of naturally occurring compounds which possess pronounced anti-
biotic and antitumor activities, can also be accessed using a similar strategy <2003SL1431>.
-Lactams have been synthesized using radical translocation to avoid the synthesis of unstable
-haloamino acids as radical precursors <1998TL5339>. In this case, the radical precursor is an
aryl halide which after 1,5-hydrogen atom transfer remains on the final cyclized compound as an
N-protective group. A similar strategy has been used as a new stereoselective entry to the
azaspirocyclic nucleus of halichlorine and pinnaic acids <2003OL3017>. Alkynes can also be
used as radical acceptors after a first 1,5-hydrogen atom transfer <2002JCS(P1)1438>.
(e) Carbon hydrides. Cyclohexadienes presented in Section 1.08.1.3.4.(iii).(d) can be useful
precursors of carbon radicals as demonstrated by the respective research of Walton
<2000CC2327> and Studer <2003JA5726>. Specially designed silylated cyclohexadienes have
been recently used to conduct radical cyclizations avoiding the use of toxic tin hydrides (Equation
(25)). These new reagents have been found superior to tin hydrides in some cases.
SiMe2But
MeO OMe
O (1.5 equiv.) O ð25Þ
I AIBN (0.5 equiv.)

hexane, 7 h
82%
The persistent radical effect has also been used by Studer to obtain cyclized structures using
2,2,6,6-tetra methylpiperidinooxy (TEMPO)-substituted precursors of carbon radicals. A cascade
reaction, where two carboncarbon bonds and a new carbonheteroatom bond are formed in
one operation illustrated the interest of this tin-free methodology <2000AG(E)1108>.
(f) The borane method. As already mentioned in Section 1.08.1.3.4.(iii).(g), B-alkyl catechol-
boranes, easily prepared in situ by hydroboration of alkenes, are valuable precursors of alkyl
radicals which undergo conjugate addition to activated alkenes. This sequential process has
recently been applied to the cyclization of dienyl systems where one of the double bonds is
substituted by an electron-withdrawing group <1999CEJ1468, 2003SL1485>. For instance, efficient
and selective hydroboration of the terminal electron-rich double bond in 64 was performed under
rhodium catalysis, and cyclization occurred under irradiation in the presence of Barton carbonate
PTOC-OMe as chain-transfer reagent. The overall process furnished -methyl--(S-pyridyl)lactone
65, which may subsequently be transformed into the -methylenelactone via thermal fragmentation
of the corresponding sulfoxide (Scheme 23) <2003SL1485>.
O O
BH N S
O
O O O OCO2Me
B O
[Rh(COD)Cl]2 (1 mol.%) 150 W lamp, hν
O
64
H H
O O O
O O O
63% PyS H H
65
Scheme 23
(g) The fragmentation method. Fragmentation reactions involve addition of a radical to a

neutral alkene, followed by -scission of the resultant radical to produce an adduct radical which
propagates the chain reaction (see Section 1.08.1.3.4.(iii).(h) for details). In contrast with the
method based on metallic hydride donors, reduction of the initial radical before cyclization is not
a matter of concern. The fragmentation method is therefore well suited for conducting particularly
slow radical cyclizations. Allyl- and vinylstannanes have often been used to generate the chain
carrier. Vinyl sulfoxides have recently been used as temporary chiral auxiliaries to effect enantio-
selective alkenylations (Equation (26)) <1998AG(E)2116, 1999JA11395>.
E E
p-Tol
MeO O
E E S Bu3SnH
ð26Þ
PhSe Et3B/O2
93% OMe
E = CO2Me
>98% ee
(h) Atom transfer reactions. The atom transfer of a CX group (X = halogens, SePh,
SC(¼S)OEt) across a double bond (see Section 1.08.1.3.4.(iii).(i)) is a suitable method for
performing slow radical cyclization provided there is no fast radical trap like tin hydride in the
reaction media, which may reduce the initial radical prior to cyclization. Radical cyclization of
allyl iodoacetate 66 in the presence of triethylborane as radical initiator was found to proceed
efficiently at room temperature in water to yield -lactone 67 (Equation (27)). Interestingly, this
reaction did not occur in organic solvents such as hexane or benzene. Calculations suggested that
this remarkable solvent effect was due to the large dielectric constant of water which lowers the
barrier to rotation from the (Z)- to the (E)-rotamer that undergoes cyclization. In addition, the
high cohesive energy density of water forces a decrease in the volume of the reactants and
therefore effects acceleration of the reaction <2000JA11041>. It is noted that the same transfor-
mation had been previously reported to occur in benzene in the presence of Bu3SnSnBu3 as
radical initiator but required higher temperatures (80 C) and resulted in lower yields (40%)
<1991JOC2746>. Highly enantioselective atom transfer radical cyclization reactions catalyzed by
chiral Lewis acids have been recently reported <2001JA8612>.
Et3B/trace O2 I
I H2O, 25 °C
O ð27Þ
O 67% O
O
66 67
(i) Phosphorus hydrides. Many efforts have been made to develop new radical mediators
avoiding the use of toxic tin hydrides. Among the newly developed reagents, hypophosphorous
acid and its salts have received considerable attention <2002S835>. N-Ethylpiperidinium hypo-
phosphite (EPHP) is the most widely used reagent to date. Its low cost and the easy removal of
the by-products by simple acid- and base-washes makes it very attractive. EPHP can be used in
organic solvents such as benzene and toluene and can lead to bi- or tricyclic structures in the
synthesis of various oxygen heterocycles (Equation (28)) <1999TL2415, 1999JCS(P1)3071,
2000TL1833>. Synthesis of THFs and more particularly dihydrosesamin have also been realized
using the same methodology <2002T2435>.
H H
Br
EBPH, AIBN
+ ð28Þ
benzene, ∆ O O
TBSO O O TBSO O TBSO O
77%
6.7 1
The cyclization can also be conducted in aqueous ethanol with a combination of hypophos-
phorous acid (H3PO2) and an inorganic base such as NaHCO3 (Equation (29)) <2000CL104,
2002SL674>. Selective deuteration can also be accomplished using D3PO2 and D2O as solvent
<2001BCJ225>. Cyclization reactions of hydrophobic substrates can be performed with EPHP in
water as the only solvent by using a surfactant (cetyltrimethylammonium bromide) and a water-
soluble initiator <2001OL1157, 2003T77>. Diethylphosphine oxide (DEPO), another phosphorus
derivative developed recently, gave also interesting results in this area. It allowed cyclizations to
be carried out in water with no extra additives but a water-soluble initiator <2003OL2971>.
BunO O n-C5H11 BunO O

H3PO2, NaHCO3 n-C5H11 ð29Þ
I AIBN, aq. EtOH, reflux
96%
(j) Indium hydrides and gallium hydrides. Indium hydride has been successfully used as a tin
hydride alternative to facilitate radical cyclizations (Equation (30)). This new procedure is based
on the use of a catalytic amount of indium chloride which is reduced in situ by sodium
borohydride (2 equiv.) in acetonitrile. The mechanism is similar to the mechanism reported for
the tin hydride-promoted reactions. The indium hydride acts as the hydrogen donor in the
reduction of the carbon radical <2002JA906>.
InCl3 (0.1 equiv.)

I
NaBH4 (2 equiv.)
ð30Þ
O MeCN, rt, 6 h O
62%
Gallium hydride (HGaCl2) is another tin substitute used in various radical 5-exo-cyclizations.
HGaCl2 is readily prepared in situ from commercially available GaCl3 and sodium bis(2-methoxy-
ethoxy)aluminum hydride (Red-Al, 1 equiv.) in THF. However, in contrast with indium hydride,
an initiator (Et3B) must be added to initiate the reactions (Equation (31)) <2001OL1853>.
Pr HGaCl2, Et3B
I Pr
THF, 0 °C ð31Þ
BuO 97% BuO
O O
(iii) Nonchain reactions
(a) Organocobalt group transfer. Organocobalt reagents have been widely used in radical
cyclizations but no major advances have occurred in this area since the publication of COFGT
(1995) <1995COFGT(1)319>.
(b) Manganese-mediated cyclizations. Oxidative radical cyclizations involving Mn(OAc)3 con-
tinue to grow in popularity since they allow generation of a carbon radical to carbonyl
compounds such as -ketoesters, -diketones, or -diesters <1996CRV339, 1998ACA50,
1997OR427>. As shown previously (see Section 1.08.1.3.4.(iv).(e)), the carbon radical produced
from addition or cyclization can react following different pathways. Generally, Mn(OAc)3 itself is
able to oxidize tertiary radicals giving rise to carbocations which can further lose a proton leading
to an olefin or react with a suitable internal or external nucleophile. In the case of primary or
secondary radicals, Mn(OAc)3 does not oxidize such intermediates and hydrogen abstraction
from the solvent or from an acidic hydrogen generally occurs. A co-oxidant must be added to
transform such radicals into carbocations which can react as previously described. In most cases
Cu(OAc)2 is added which is known to oxidize secondary radicals to alkenes 350 times faster than
Mn(OAc)3 <1971JA524, 1972JA2888>. When the elimination product is obtained, the less
substituted (E)-double bond is primarily formed, which is of interest for synthetic applications.
Snider has investigated the effects of alkene geometry on the stereochemistry of radical cycliza-
tions <1998T10641>. This methodology has been applied in numerous syntheses of complex
frameworks including macrocyclic lactones <2002TL9031>, spirolactams <2000JOC7257>,
-lactams (via a 4-exo-trig radical cyclization) <2000OL401>, polycyclic systems in a series of
naturally occurring phenolic sesquiterpenes (Equation (32)) <2001JCS(P1)206>, and pyrrolidi-
nones <2001JOC3726>. In some cases, Cu(OAc)2 has been substituted for Cu(OTf)2 to facilitate
the radical cyclization of methylthio-acetamides to access the erythrinane structure
<2003JOC312>. Enantioselective versions of the Mn(OAc)3-promoted cyclization have been
achieved and it has been demonstrated that lanthanide triflate can catalyze such reactions
<1999TA4427, 1999JA5579, 2000JA1658, 2000JOC2208>.
O
OO
CO2Me O
Mn(OAc)3
ð32Þ
O AcOH, 80 °C, 12 h
O
58%
(c) Samarium-mediated cyclization reactions. Samarium(II) iodide has become a very popular
reagent to generate alkyl, alkenyl, and aryl radicals via the reduction of organic halides. Interest-
ingly, in contrast with the tin hydride and the silicon hydride processes, SmI2-promoted cyclizations
are followed by reduction of the cyclized radical to the corresponding anion which can be trapped
with a number of electrophiles including aldehydes and ketones <1996CRV307, 1998T3321,
B-2001MI011>. In this process, fast cyclization rates are required to avoid competitive reduction
of the initial radical by SmI2. Aryl radicals (mainly generated from aryl iodides) have therefore
received a great deal of attention since they are particularly resistant to such reduction and have
been found to cyclize in a 5-exo-trig mode with rates up to 4 109 s1 (Scheme 24). HMPA is
generally used as co-solvent to enhance electron transfer from SmI2 to the halide but irradiation
with light at 560–700 nm has recently been found to be effective <1997JA2745>. Reactions have
X SmI2 SmI2
O O O
SmI2 E
O E+ O
Scheme 24
also been developed on polymeric support <1998TL2281>. SmI2-promoted cyclizations may alter-
natively terminate in an elimination process as illustrated in Equation (33) <1997TL1153>.
I
AcO
SmI2 (4 equiv.)
AcO
OAc ð33Þ
HMPA O O
O O –78 to 0 °C
82%
85% de
(d) Other metal-mediated radical cyclization reactions. Ni, Ru, Fe, and Cu complexes have
been used as an alternative to organotin hydrides to conduct intramolecular halogen atom
transfer reactions <B-2001MI011>. Initial studies have concerned cyclization reactions of unsa-
turated polyhaloalkane compounds and will not be described in this chapter. However, highly
activated copper complexes generated from copper salts and polydentate amine ligands have
recently been found to efficiently catalyze the cyclization of mono-halo substrates
<2002CSR1>. Ligands solubilize the copper salt and significantly alter the redox potential of
the catalyst system. The tetradentate Me6-tren ligand 68 is particularly effective and allows
cyclization of 2-chloroacetamide 69 at room temperature. In this oxidative cyclization, abstraction
of the bromine atom by CuBr generates CuBr2 and initiates the radical cyclization. The resulting
cyclic radical then abstracts a bromine atom from CuBr2 to produce the bromo -lactam 70 and
regenerate the catalyst (Equation (34)) <2000JCS(P1)671>.
Br CuBr (30 mol.%) Br

Me6-tren, 68 (30 mol.%)
O N CH2Cl2, rt O N
Ts 95% Ts
ð34Þ
69 70, 88% de
N
N
N N
68
The cyclization of haloalkenes may also be promoted by chromium(II) <1999S1> and man-
ganese(0) <1998SL1075>. For instance, the cyclization of 2-haloethanal acetal 71 was promoted
by an active manganese reagent prepared by reduction of Li2MnCl4 with magnesium turnings
activated by 1,2-dibromoethane (Scheme 25).
Li2MnCl4 + Mg Mn(0)* + MgCl2
Mn(0)*
O
I THF, rt BunO
BunO O
71 70%
Scheme 25
In the presence of organozinc reagents, Ni complexes also catalyze the cyclization of haloalk-
enes. For an overview of these reactions, see <2000T817, B-2001MI011>. The reaction is initiated
by one-electron transfer from the Ni(0) complex onto the alkyl halide. As shown in Scheme 26,
an advantage of this method is that the cyclic radical is converted via transmetallation into a
stable organozinc halide which can further react to give elaborated compounds <1995AG(E)2723,
1996JOC5743>.
BnO
Et2Zn (2 equiv.) BnO
cat. Ni(acac)2 BnO [Ni] ZnI
CO2Me O
THF, rt CO2Me
I
OMe
BnO
Et
Br Et
CuCN.LiCl CO2Me
86%
Scheme 26
1.08.1.5 Tandem Processes
1.08.1.5.1 Intramolecular/intramolecular sequences

Chemical processes that allow the creation of several bonds in a single operation, the so-called
cascade, tandem, domino, or sequential reactions, are among the most powerful methodologies in
terms of atom economy, cost, and time consumption. In this area, radical strategies have been
involved in numerous syntheses of polycyclic structures as reviewed recently <2001AG(E)2224,
1998S417>. Three general types of cascade reactions starting from linear acyclic precursors have
been defined by Curran <2000JOC2007>. The first one, the ‘‘zipper’’ strategy, involves an initial
radical which starts from the middle of the structure and moves to the end (Equation (35)). The
second one, the ‘‘macrocyclization-transannular cyclization,’’ is virtually the reverse of the zipper
cyclization, that is to say the initial radical is created at the end of the structure via a macro-
cyclization and goes to the middle of it (Equation (36)). Finally, the third one which is less
common has been called ‘‘round trip’’ strategy. In this case, the radical generated initially goes
from one end back to the same end (Equation (37)) <1996CRV195>.
Zipper mode
ð35Þ
Macrocyclization ð36Þ
transannular process
Round trip strategy

ð37Þ
During such reactions the same general rules which govern the regioselectivity and stereo-
selectivity of normal radical cyclizations can be applied. To avoid a premature termination step,
such as reduction with tributyltin hydride, all radical intermediates must add faster to the double
bonds than any trapping reactions. Consequently, a low concentration of the hydrogen donor or
catalytic methods are required for such processes. Zipper cyclizations are commonly used to
prepare easily polycyclic structures. The total synthesis of (+)-paniculin, a tetracyclic compound,
has been accomplished using this method <1999JA9875>. Pyrrolizidinones have been obtained
via a 5-endo/6-endo cyclization sequence <1999JCS(P1)427> and an approach to the five-fused
rings of pseudocopsinine has been based on a similar method <1996T647>. Methods using
Mn(OAc)3 to generate alkyl radicals are also widely used in cascade cyclizations as demonstrated
by the synthesis of the tetracyclic diterpene spongiatrol <1998JOC1162> and by the synthesis of
norlabdane oxide which is highly valuable in the fragrance industry (Equation (38))
<1998JOC4779>. Enantioselective synthesis of the two enantiomers of wilforonide, a bioactive
terpene has been realized via a Mn(OAc)3-mediated cascade cyclization, by using a chiral ester
derived from (R)-pulegone <2001OL1785>. Enantioselective zipper cyclizations using chiral

Lewis acids have also been investigated <2002AG(E)3014>.
OH OH
O
Mn(OAc)3 steps
ð38Þ
O Cu(OAc)2 O
H H
CO2Et 58% EtO2C
Norlabdane oxide
The macrocyclization-transannular strategy has been used in the synthetic approaches to

oestrogen steroids <2001CR(C)571> and taxanes <1998JCS(P1)3181>. A new access to the
BCD-ring system of progesterone has been developed <1999TL2363>. Round-trip radical reac-
tions are less common <2000JOC2007>. They have been applied to the synthesis of the triqui-
nane framework via three sequential 5-exo cyclizations (Scheme 27) <2001TL2157>. Other
tandem processes have been conducted based on atom transfer <2002AG(E)3014, 2002OL1239,
2000T6479> as well as translocation <2002SL1431>.
E I E E
E Bu3SnH E E
5-exo
E = CO2Me
CO2Me CO2Me CO2Me
E E
5-exo E 5-exo
E
83%
CO2Me CO2Me
Scheme 27
1.08.1.5.2 Intramolecular/intermolecular processes

The concept of a first radical cyclization followed by a second intermolecular addition of the
resulting cyclized radical has been used relatively rarely <1991CRV1237, 2002AG(E)3206>.
Difficulties encountered mainly arose from a premature intermolecular addition of the initial
radical before cyclization. This method has been used for the synthesis of a triquinane skeleton
<1994TL7845>.
1.08.1.5.3 Intermolecular/intramolecular additions

The process of one intermolecular radical addition followed by an intramolecular cyclization is
known as annulation. For reviews on radical-mediated annulations reactions, the following
reviews have to be read <2003S803, 2001JCS(P1)3215>. One major problem is that the initial
and final radicals are often electronically similar so that a further unwanted intermolecular
addition can take place <1995COFGT(1)319>. Among all the classical methods developed
previously, the fragmentation and atom transfer methods can be employed to terminate the
sequence thereby avoiding formation of by-products. Thus, annulation reactions have been
realized with diverse atom transfer groups such as xanthate, iodide, and selenide <1998SL1435,
1999EJO477, 1998AG(E)1128>. Based on this concept, an original transformation using a
cyclopropane ring-opening methodology for a novel generation of homoallyl radicals has been
realized. Such intermediates can add to electron-rich olefins to produce functionalized iodocyclo-
pentanes (Equation (39)) <2001TL2165, 2002JOC922>. Indium has also been used as initiator to
produce carbon radicals in such reactions conducted in aqueous media <2003OL3835>. The
fragmentation-terminated annulation is another process currently used with the great advantage
that the fragmentation of the final intermediate radical is often faster than other competing
processes. Trialkylstannanes, phenyl sulfides, and phenyl sulfones are commonly employed as
terminating functional groups <2001OL3679, 2002JA2924, 1997TL4165>. Oxidative radical

annulations with Mn(OAc)3 have also been applied in intermolecular/intramolecular addition
reactions <1995SC2337, 1996TL7615>. A tin-free procedure using xanthates as radical precur-
sors and dilauroyl peroxide as the radical initiator has been used in addition/cyclization strategies
and applied to the synthesis of natural products <2003OL3717> and nine-membered rings
<1999TL9239>.
R I
CO2Me Yb(OTf)3
R
MeO2C Et3B, O2 +
I ð39Þ
R1
CH2Cl2, rt MeO2C 67–80% MeO2C R1
CO2Me
CO2Me
1.08.1.5.4 Intermolecular/intermolecular additions

Sequential intermolecular/intermolecular additions are scarcely used because of their tendencies
to lead to oligomers or polymers. Reactions of this type generally involve conjugate addition of
nucleophilic radicals to ,-unsaturated compounds followed by intermolecular trapping of the
resulting radical with allylstannanes as illustrated in Scheme 28 <2003OL2885>. Stereocenters
can be created at the and carbon atoms in the ,-unsaturated acceptors, the relative and
absolute configuration of which may be controlled using chiral Lewis acid catalysis
<1995JA11029, 2003CRV3263>.
I (10 equiv.)
O O O O
SnBu3 (5 equiv.)
O N CO2But O N CO2But
Yb(OTf)3
Et3B/O2, –78 °C
72%
Scheme 28
1.08.2 ELECTROCYCLIC ADDITIONS TO CARBONCARBON MULTIPLE BONDS

TO GIVE TETRACOORDINATE PRODUCTS
The term ‘‘electrocyclic addition’’ is usually used for reactions which proceed in a concerted
manner. As it is often difficult to establish if a cycloaddition reaction is truly concerted, the
reactions proceeding via a two step mechanism have been included for short-lived intermediates.
This chapter will focus upon cycloaddition reactions involving C¼C bonds that have been
developed since COFGT (1995) <1995COFGT(1)319>. Most of these reactions are summarized
by Equation (40). It should be noted that addition of free carbenes to produce cyclopropanes is
not included in this review since the mechanism of ‘‘carbene transfer’’ from these ylides is clearly
stepwise. The conventional Diels–Alder reaction which could have been considered for the
electrocyclic addition to carbon–carbon multiple bonds is also not discussed here since it will be
included most properly in Chapter 1.17.
+ X X ð40Þ
The reader is strongly recommended to read COFGT (1995) <1995COFGT(1)319>, which

covers the general mechanistic aspects and principles of these electrocyclic reactions. Other
reviews on this topic have also appeared recently <B-2002MI012, B-2002MI013>.
1.08.2.2 Formation of Three-membered Rings
1.08.2.2.1 Addition of free carbenes

Free carbenes are in general too reactive to be useful for the preparation of cyclopropanes. Some
competing reactions are generally observed, in particular CH insertion. For the reasons devel-
oped in the introduction, the chemistry of these ylides is not reviewed here. The synthesis of
cyclopropanes is more usually achieved by using two classes of reagents, the zinc-based carbenoid
reagents and the transition metal-based carbenoid reagents. The cycloaddition chemistry of these
derivatives is described below.
1.08.2.2.2 Addition of metal carbenoids

Among the different methods of cyclopropanation, the Simmons–Smith reaction involving zinc-
based carbenoid reagents has been widely studied during the last decade. The most commonly
used cyclopropanating agents are generally prepared from diethylzinc and diiodomethane. Alter-
native methods to prepare these active reagents have been recently introduced <2001OR11,
B-1999MI014>.
In this cycloaddition reaction, bond formation proceeds, as if concerted, with retention of stereo-
chemistry and the mechanism of this reaction is therefore referred to as a [2+1]-cycloaddition
(Equation (41)) <1982JOC1615>.
I
+
ð41Þ
OH Zn–CuCl OH
OH
52%
76/24
Many publications on the Simmons–Smith reaction have focused on the cyclopropanation of

oxygen-containing olefins. In contrast, cyclopropanation of unfunctionalized olefins is much less
common, as the absence of a directing group reduces the substrate reactivity toward cyclopropa-
nation. Charette’s group reported that some reagents of general structure ArOZnCH2I are very
reactive species for the cyclopropanation of unfunctionalized olefins (Equation (42))
<2000AG(E)4539>.
CH2Cl2
Ph OBn
Ph OBn
OZnCH2I
Cl Cl ð42Þ
(2 equiv.)
Cl
95%
Furthermore, a Simmon–Smith reagent prepared from a 1:1:1 mixture of trifluoroacetic acid,

diiodomethane, and diethylzinc can react with alkenes without directing groups especially with
stilbene that is often unreactive under classical Simmons–Smith protocols <1998TL8621>.
Recently, many efforts have focused on the development of methods for the preparation of
enantio-enriched or enantiomerically pure cyclopropanes using a chiral catalyst or auxiliary
<B-2002MI015>. Efficient asymmetric Simmons–Smith reactions have been developed using a
variety of chiral auxiliaries such as chiral ketals <1998CC2479>, chiral enol ethers <1999CL831>,
chiral vinyl boronic esters <1996SL893>, and chiral allylic ethers <1999T8845>. Most of the
asymmetric Simmons–Smith reactions involving chiral catalysts were developed on allylic alcohols.
Relatively good enantioselectivities were obtained with a C2-symmetric chiral disulfonamide ligand
<1995T12013, 1997JOC584> or TADDOL (,,0 ,0 -tetraaryl-1,3-dioxolane-4,5-dimethanol) and a
titanium-Lewis acid <1995JA11367>. Charette reported <1998JA11943> a new chiral dioxaboro-

lane ligand derived from tetramethyltartaric acid diamide for the conversion of allylic alcohols,
unconjugated and conjugated polyenes, and homoallylic alcohols into the corresponding enantio-
merically enriched cyclopropanes (Equation (43)).
Me2NOC CONMe2
O O
B
i. (1.2 equiv.) ð43Þ
Bu
Ph OH Ph OH
ii. Zn(CH2I)2 (2.2 equiv.)
93% ee
98%
The first diastereoselective Simmons–Smith cyclopropanation of allylic amines was recently

achieved by using chelating groups in close proximity to the amine <2003OL4417>. Best results
were obtained with allylic amines derived from (1R,2R)-pseudoephedrine (Equation(44)). The
success of the cyclopropanation was attributed to the formation of a chelating complex between
the zinc reagent and the chiral amino alcohol group.
Ph Zn(CH2I)2 (1.1 equiv.) Ph

N Ph N Ph
CH2Cl2 /0 °C ð44Þ
OH OH
95%
98/2 dr
A diastereoselective Simmons–Smith cyclopropanation of chiral nonracemic alkenylsilanols was

recently reported <2002TA13>. In this reaction, the stereogenicity of the silicon center was
successfully transferred to the carbons via the Simmons–Smith cyclopropanation. However, the
introduction of a bulky substituent such as a cyclohexyl group on the silicon atom is necessary to
improve the diastereoselectivity (Equation (45)).
Ph CH2I2–Et2Zn Ph
Si * OH *
Si * OH
ð45Þ
Et2O
Me *
84% Me
>99:1
The common feature of the preceding strategies is the involvement of a directing heteroatom
in the alkenyl substrate. It was recently shown that the asymmetric Simmons–Smith cyclopro-
panation of unfunctionalized olefins can be realized by treating the dipeptide 72 with ZnEt2
and CH2I2 <2003JA13632>. For example, when a dihydronaphthalene was used as a sub-
strate, the corresponding cyclopropanation product was obtained in 83% yield and 90% ee
(Equation (46)).
CO2Me
Ph t-BOCHN Ph
N
72
ð46Þ
ZnEt2, CH2I2
90% ee
CH2Cl2
83%
The transition metal-catalyzed reactions of diazo compounds with various alkenes are another
route to make cyclopropanes. Metal-stabilized keto carbenoids have been widely used for this
purpose and are efficiently prepared by reaction of diazo esters or diazo ketones with rhodium(II),
palladium(II), and copper(I) or (II) salts (Equation (47)).
Z Z
O MLn
O
N2 –N2 Ln M
R R
ð47Þ
Z = alkyl, aryl, H, OR1,NR22
R = alkyl, aryl, H, SO2R3, CN, COR
M = Cu, Pd, Rh
The reaction between metal carbenes derived from -diazocarbonyl compounds and alkenes
assisted by metal complexes has been intensively studied over the last 10 years and is
summarized in several reviews <1994AG(E)497, 1998CRV911, 1998T7919, 1995COMCII387,
B-1998MI016>. New work in this area includes studies on the diastereocontrol and enantiocon-
trol during the intermolecular cyclopropanation of unsymmetrical olefins. Since the pioneering
work of Nozaki and co-workers’ <1968T3655> extensive studies have been conducted for the
synthesis of enantiomerically enriched cyclopropanes using chiral copper(I), ruthenium(II), or
rhodium(II) catalysts. The most important progress in this area was made with copper com-
plexes incorporating chiral ligands such as C2-symmetric semicorrin <1986AG(E)1005>, bisox-
azolines <1992AG(E)430> or ferrocene Schiff bases <1998SL617, 1998JA10270>. A typical
example is the asymmetric cyclopropanation of cyclic enol ethers such as dihydrofuran 73
<1998JOC6007>. An enantioselectivity higher than 95% and an excellent diastereoselectivity
have been reported by using ethyl diazoacetate and Evans’ bisoxazoline ligand 74 (Equation
48)). This reaction was used as the key step in the asymmetric synthesis of (+)-quebrachamine,
an indole alkaloid.
H
CO2Et
CuOTf (2 mol.%)
N2CHCO2Et (1.6 equiv.)
O O
73 74 (2.4 mol.%), CH2Cl2
52% 91/9 exo/endo ð48Þ
95% ee
O O
N N
Bu t But
74 = Evans’ ligand
Chiral ligands have also been used to modify rhodium and ruthenium catalysts. In particular,
Doyle and co-workers <1997CC211> have compared the enantiocontrol obtained in the
intramolecular cyclopropanation of diazoacetates using chiral copper, rhodium, and ruthenium
catalysts.
The cyclopropanation of styrene with alkyl diazoacetates is often studied as a model for the
diastereoselectivity of this reaction. However, this selectivity is often rather poor and most
catalysts lead to cis/trans ratio in the range 1/1 to 1/3 <1998T7919>. Recent studies have
showed that it is possible to increase significantly the proportion of the trans-isomer. Chiral
copper, cobalt, and ruthenium catalyst generally showed a marked preference for the trans-
isomer. Cyclopropanation of styrene with ruthenium-Pybox (2,6-bis (oxazolinyl)pyridine) as
catalyst results in high enantioselectivity (ee up to 91%). Asymmetric intermolecular cyclopro-
panations of alkenes with diazoacetates catalyzed by chiral ruthenium porphyrins <1997CC927,
2001JA4119> or cobalt porphyrins <2003JOC8179> were recently studied. In particular, it was
shown that cyclopropanation of styrene with ethyl diazoacetate, in the presence of a chiral
ruthenium porphyrin [Ru(P*)(CO)(EtOH)], gives the corresponding cyclopropyl esters in up to
98% ee with high trans/cis ratios and extremely high catalyst turnovers when the reaction was
performed at 40 C (Equation (49)).
H Complex Ph Ph CO2Et
+ N2 +
CO2Et –40 °C CO2Et
52% trans cis
ð49Þ
98% ee 36/1 trans/cis
complex:[Ru(P*)(CO)(EtOH)]
P* = 5,10,15, 20-tetrakis(1S,4R,5R,8S)-1,2,3,4,5,6,7,8-
octahydro-1,4:5,8-dimethanoanthracene-9-yl]porphyrinato dianion
The preparation of the cis-disubstituted cyclopropanes is often challenging and few catalysts
are known to favor the formation of the cis-isomer. Remarkable high cis-selectivity (up to
98/2) and high enantioselectivity (up to 98% ee) was reported for the reaction of styrene with
t-butyl diazoacetate in the presence of ruthenium-salen <1999SL1163> or cobalt-salen
<2000T3501, 2000TL3647>. Very high values of diastereoselectivity (cis/trans 97/3) toward
the cis-isomer have also been obtained for styrene when using a copper(I) homoscorpionate
catalyst <2002JA978>. Doyle and co-workers developed a new azetine-ligated dirhodium(II)
catalyst having a l-menthyl ester attachment that provided a significant diastereocontrol (up to
82:18) and high enantiocontrol for the preparation of the cis-cyclopropane adduct from
reaction of the trisubstituted styrene 75 with t-butyl diazoacetate (Scheme 29). The cis-
cyclopropane isomer was then converted to the urea-PETT derivative 76 (PETT = phenyl-
ethylthiazolylthiourea), a new class of potent non-nucleoside HIV-1 reverse transcriptase
inhibitors <2002OL901>.
Cl Cl
N2CHCO2But
CO2But
F F
Rh2(S,R-MenthAZ)4
O O
21%
82/18 cis/trans
97% ee cis isomer
75
Cl Cl
O
N NH N
H
F
O
76, urea-PETT derivative
Rh2(S,R-MenthAZ)4 = Dirhodium(II) Tetrakis[1R,2S,5R-menthyl

2-oxaazetidine-4(S)-carboxylate]
Scheme 29
Intramolecular cyclopropanation reactions of alkenyl diazocarbonyl compounds have been

widely used in organic synthesis to prepare polycyclic structures such as bicyclic ketones
with a cyclopropane ring fused to cyclopentanes or cyclohexanes. In these cases, the problems
of stereochemistry are avoided since the diastereocontrol is fixed <1991COS(4)1031>.
Recently, attention has been directed to the development of the enantioselective version by
means of chiral transition metal catalysts. Only modest enantioselectivities have been found
for -diazo--keto esters <2001HCA1093> while excellent enantioselectivities have been
obtained for the catalytic asymmetric intramolecular cyclopropanation of -diazoketones
<1995SL491, 2001OL3317>, and more recently of -diazo--keto sulfones <2003JA2860>
(Equation (50)).
Me
Me N2
CuOTf (10 mol.%)
SO2Mes
ligand 77 (15 mol.%) SO2Mes
O
90% O
Bn Bn 98% ee ð50Þ
O O
N N
Pri Pri
77
Mes = mesityl = 2,4,6-Me3C6H2
The first intramolecular cyclopropanation of -nitro -diazocarbonyls was reported recently

<2003JMOC83>. The nine-membered nitro cyclopropyl lactone 78 was obtained in high diastereo-
selectivity and with enantioselection up to 61% when using the commercial chiral Rh(II) carboxy-
late 79 (Equation (51)).
Ph Ph
O
Ph cat. 79 O O
O O NO2 + NO2
CH2Cl2, 50 °C O
O O
O
N2 NO2 66% 78 78'
major 95/5 minor
61% ee
H O Rh ð51Þ
N O Rh
O S O
C12H25 4
79
1.08.2.3 Formation of Four-membered Rings

One of the most efficient strategies for the construction of the four-carbon ring system is the
[2+2]-cycloaddition of alkenes. The thermal suprafacial [2+2]-cycloaddition of alkenes being
forbidden by the Woodward–Hoffmann rules, this cycloaddition has been achieved in three ways:
(i) by thermal reactions via biradical intermediates, (ii) photochemically, or (iii) by metal catalysis.
This topic has been recently reviewed <2003CRV1449>.
1.08.2.3.1 Thermal [2+2]-additions

The thermal suprafacial [2+2]-addition of alkenes is forbidden by the Woodward–Hoffmann
rules. However, such additions do occur. The review by Baldwin <1991COS(5)63> as well as the
introduction to this topic in March <B-1992MI017> are recommended for further reading.
A diastereofacial selectivity is generally observed in thermal [2+2]-additions <1991COS(5)63>.
This point is illustrated in Equation (52) by the cycloaddition of tetrafluoroethene to acrylate
esters derived from chiral auxiliaries leading to the formation of tetrafluorocyclobutane esters
<1997TL4277>. The largest stereoselectivity was found for the case of ()-(1R,2S,5R)-8-phe-
nylmenthyl ester, the addition of the tetrafluoroethene occurring preferentially on the si-face of
the chiral-substituted alkene.
F F
F
F
OR* Tetrafluoroethene
OR*
O 130–180 °C O
EtO EtO
70% ð52Þ
57% de
Ph
R* =
1.08.2.3.2 Photochemical [2+2]-additions

[2+2]-Photocycloaddition of activated alkenes is the most useful route to cyclobutane derivatives
and has been the subject of several recent reviews <1995CRV2003, 1996MI135, 1993OR297,
1998S683>.
The diastereoselective [2+2]-photocycloaddition of cyclohexenone carboxylates bearing a
chiral auxiliary to ethene was recently studied <2003CHIR504>. Best results (de = 81%) were
obtained using the ()-8-[(p-methoxy)phenyl]menthyl group (Equation (53)). In order to rationa-
lize the origin of the diastereoselectivity, it was suggested that the s-trans-stacked conformer (ST)
is the most stable of all the conformers.
O O O
OR* OR*
OR* hν, H2C CH2
+
Methylcyclohexane
O –78 °C O O
79% (S,S ) (R,R )
81% de ð53Þ
R* =
OMe
(–)-8-(p-Methoxyphenyl)menthyl
The [2+2]-photocycloaddition of alkenes to cyclic enones generally leads to the formation of

several regio- and stereoisomers depending on the nature of the substituents of the alkenes and
enones <1998S683>. The reaction in Equation (54) illustrates the substituent effects on the
stereochemistry in the [2+2]-photocycloaddition of homobenzoquinone 80 with various substi-
tuted alkenes. The preferred regioisomer for all the reactions was attributed to the more stable
1,4-biradical intermediate (major addition mode) and the minor isomer was attributed to the less
stable biradical (minor addition mode). With respect to the stereoselectivity, the alkenes with
relatively small substituents (R = EtO, CN) preferentially gave the endo-adducts while exo-selectivity
was observed with larger substituents (R = aromatic or t-butyl groups) <2002JA8912>.
O Ph
O Ph O Ph
Ph
Ph R R Ph
hν +
+
R O ð54Þ
O O
80 Major adduct > Minor adduct
R = EtO, CN, OAc exo < endo
R = 4-MeOC6H4, But exo > endo
An interesting application of the chiral tether methodology with alkenes having a chiral
auxiliary group is illustrated in Scheme 30 <1997TL1045, 2002JOC1061>. One of the major
advantages of this method compared to other diastereoselective [2+2]-photocycloadditions using
different temporary chiral linkers is the easy removal of the tether group. Compound 81 was
obtained with very good -facial selectivity with a diastereomeric excess up to 94%.
O
H
O
O H
hν MeONa
O
O
O CH2Cl2, –20 °C O H+ O
O
O 88% O
O 42%
O
81 Removal of the chiral tether
94% de
Scheme 30
A new concept based on the use of chiral complexing agents (hosts) binding one substrate and
thereby inducing facial discrimination was recently developed. In the presence of the chiral
benzoxazole 82 (chiral host), highly enantioselective inter- <2002JA7982> and intramolecular
<2000AG(E)2302> [2+2]-photocycloaddition reactions have been conducted. The chiral infor-
mation was almost completely transferred from the host to the corresponding substrates 83 and
84. The differentiation of the enantiotopic faces of the prochiral quinolone was explained by
assuming a coordination of this substrate to the lactam via two hydrogen bonds (Equation (55)).
AcOH2C AcOH2C
OMe MeO MeO
CH2OAc hν
+ H + H
–60 °C N O
N O 80% N O
H H ð55Þ
H
H 84
O O 83
N
N 83/84 95/5
82
1.08.2.3.3 Metal-catalyzed [2+2]-additions

While photochemically promoted [2+2]-cycloadditions of alkenes have been intensely studied
since the 1990s, related metal-catalyzed [2+2]-cycloadditions are less exemplified <1996CRV49>.
Some of them are catalyzed by Lewis acids. Methylenedithiolane was shown to be an excellent
cycloaddition partner for the reaction with chiral lactam 85 (R = H) in the presence of dimethyl-
aluminum. The cyclobutane adduct was obtained as a single diastereomer. Removal of the
phenylglycinol auxiliary by reductive cleavage gave the cyclobutane-pyrrolidinone 86 in 92%
yield and in very high ee values (>99%). This fused pyrrolidinone represents a rigid analog
of -aminobutyric acid (GABA), which has been shown to act as an inhibitory neurotransmitter
in the brain <1995JOC4359>. A novel route to the formation of an enantiomerically pure
cyclobutane-fused pyrrolidine 87 was recently developed <2001T2635> using a similar Lewis-
catalyzed (TiCl4) cycloaddition of a silyl allyl ether with the substituted chiral bicyclic lactam 85
(R = CO2But) (Scheme 31).
H
O S R=H O H
R + HN
N S
S Me2AlCl N
Ph O S O
85 92% Ph O
86
R = CO2But
SiMe2CPh3
TiCl4 H
75% O CO2But
N SiMe2CPh3
Ph O
87
Scheme 31
The thermal [2+2]-annulation of allenes generally leads to the formation of bis-methylenecy-

clobutanes as a mixture of regioisomers. It was recently shown <2000JA10776> that the nickel-
catalyzed [2+2]-annulation of electron-deficient allenes proceeds efficiently in a highly regioselective
manner under very mild conditions to afford the head-to-head bis-methylenecyclobutanes as
single isomers (Equation (56)). The high regioselectivity of the reaction was explained by the
regioselective formation of the metallacycle 88, which could be controlled by the electronic and
steric effects of the substituent of the electron-deficient allenic substrate 89.
EWG
• EWG EWG EWG EWG
10% Ni(PPh3)4
• Ni
EWG toluene • Ni
89 71% EWG 88
EWG = CO2Et
ð56Þ
1.08.2.4 Formation of Five-membered Rings
1.08.2.4.1 [3+2]-Additions of three-carbon fragments
(i) Additions of trimethylenemethane

Trimethylenemethane (TMM) has been the subject of numerous studies <1972ACR242,
1978ACR446>. The reader is also directed to the review of Nakamura <2002ACR867>. TMM
and its derivatives possess four -electrons which, on addition to alkenes, give cyclopentanes. Free
TMM (Equation (57)) is too reactive to be synthetically useful <1986AG(E)1> but the successful
use of precursors is described below.
or ð57Þ
+ –
(a) 2-Alkylidenecyclopentane-1,3-diyls. Diyl species are generated either photochemically or

thermally from bicyclic diazenes (Equation (58)). The diyl typically equilibrates before cycloaddi-
tion. This very reactive species can be trapped either inter- or intramolecularly by various
electron-deficient alkenes and alkynes to produce a great variety of ring systems. The various
methods for the preparation of these trimethylenemethane-like diradicals (TMM diyls) and their
chemical reactivity have been reviewed <1992SL107, 1996CRV93, 1998EJO1>.
∆ or hν
N ð58Þ
N
90
A low regio- and stereoselectivity is generally associated with the intermolecular cycloaddition
reaction with unsymmetrical electron-deficient alkenes <1996CRV93>. Little and co-workers
investigated <1996JOC1787> the intermolecular trapping of the dimethyl diyl 90 with symme-
trical diylophiles such as the bicyclic anhydride 91. A preferred isomer resulting from the endo-
transition state was obtained. It was suggested that, in this case, secondary orbital interactions
between the diyl and the diylophile could play a role in determining the stereochemical outcome
of the diyl trapping cycloaddition (Equation (59)).
O
O O
O O O
91
∆ O O + O ð59Þ
CH3CN, reflux H H
N
96% 5/1
N
90
The intramolecular diyl-cycloaddition reaction has been used to prepare complex tricyclic
structures. In this case, the intermediate 92 can undergo two different cycloaddition modes to
give the linearly fused adduct 93 or the bridged-tricyclic skeleton 94 (Equation (60)).
R Fused
R
N 93
N
ð60Þ
92
R
Bridged
94
It is possible to selectively form either regioisomers and the two typical examples in Equations
(61) and (62) illustrate this point <1997JOC1610>. Bridged-adducts are obtained via a 6-endo-trig
cyclization when a large substituent is present on the internal carbon of the diylophile (Equation
(62)), while a less bulky substituent such as the acetyl group led to the formation of the linear
fused tricyclic adduct via a 5-exo-trig process (Equation (61)).
MeO OMe
THF, reflux COCH3
COCH3
95% ð61Þ
N
N MeO OMe
18/1 Linear/bridged
CH3CN, reflux
O
N O 80% O ð62Þ
N O
10/1 Bridged/linear
The first example of the intermolecular diyl trapping reaction using allene diylophiles was
reported by Little and co-workers. The cycloaddition of the diazene 95 and symmetrical allene
diester 96 led to only one regio- and stereoisomer <1997TL15>. The stereochemical outcome of
the reaction was rationalized by suggesting that diradical 97 preferentially adopts a geometry
wherein the plane of the five-membered ring and the five-carbon side chain are nearly perpendi-
cular (Equation (63)).
CO2Me
H
H CO2Me
N + • CO2Me
MeO ð63Þ
N 2C H Hexanes, ∆ CO2Me
70% MeO2C
95 96 97
(b) Trimethylenemethane acetals. The use of 1,1-dialkoxy-2-methylenecyclopropane (DMCP) as

a precursor of trimethylenemethane (TMM) was pioneered by Nakamura <1989JA7285>. This
TMM species undergoes [3+2]-cycloadditions to a variety of electron-deficient alkenes and alkynes.
Generally, the reaction proceeds with retention of the olefin geometry (Scheme 32). The thermal
reaction of these dipolar trimethylenemethane species has been recently reviewed <2002ACR867>.
O O
Bu CO2Et
86% Bu CO2Et
O O O O
O O
Me3Si SOMe
88% H H
88% CN
Me3Si SOMe O
85%
Reactions performed in CH3CN at 80 °C O O
CN
Scheme 32
Further investigations by the same group <1993JA5344> established that the thermal [3+2]-
cycloadditions of the dipolar TMM with a variety of electron-deficient alkenes take place through
an endo-transition state (concerted endo-cycloaddition). However, a stepwise cycloaddition of
this dipolar TMM was observed with highly electron-deficient substrates such as benzyl methyl
-(methoxy)methylenemalonate. The simplicity of the cycloaddition of TMM acetals, which can
be prepared in three steps from the commercially available 1,3-dichloro-2-propanone, makes this
method of cyclopentane synthesis very attractive <2002OS1>. This was illustrated by a prepara-
tive scale synthesis of the bicyclo[3.3.0]octane 98 by this route (Scheme 33).
O O i. NaNH2 O O ButOK O O
NH3/Et2O DMSO
Cl Cl ii. MeI Me 80%
91% O
CH3CN
60 °C
87%
H O
O
O
H
98
Scheme 33
The cyclization of the dialkylthio analog is restricted to highly electron-deficient olefinic substrates.
This reaction is supposed to take place via radical ions pairs. For example, the dithiomethylenecy-
clopropane 99 was shown to react with tetracyanoethylene to give the ketene dithioacetal adduct 100
in 98% yield when the reaction was carried out at 120 C (Equation (64)) <1999OL7>.
S S
NC CN NC CN
+
S S 120 °C S S
+ + ð64Þ
NC CN 98% NC CN NC CN
NC CN
99 100
(c) Transition metal-trimethylenemethane complexes. Palladium complexes of trimethylene-

methane (Pd-TMM complexes), generated by reaction of 3-acetoxy-2-trimethylsilylmethyl-1-pro-
pene or substituted derivatives with a Pd(0) catalyst, are known to react with electron-deficient
olefins to produce methylenecyclopentanes (Equation (65)). The chemistry of these transition
metal trimethylenemethane complexes has been studied in detail by Trost and co-workers and has
been the subject of several reviews <1986AG(E)1, 1996CRV49, 1988PAC1615, 1991COS(5)271>.
Y
–
Pd(0) X ð65Þ
TMS OAc
+
Pd
L L X Y
A mixture of cis- and trans-adducts is generally obtained in the reaction with cis-alkenes. This
lack of stereospecificity suggests a stepwise process involving a conjugate addition at the first step.
However, a concerted mechanism has recently been proposed <1999JA9313> for the palladium
trimethylenemethane cycloaddition of the ‘‘nearly symmetrical fumarate ester amide’’ 101. Car-
bon kinetic isotope effects were determined at natural abundance for this reaction and the results
strongly suggested a concerted process for this cycloaddition (Equation (66)).
CO2CH3 Pd(OAc)2
TMS OAc +
ð66Þ
Et2NOC (Pr iO)3P H3CO2C CONEt2
Excess THF, reflux (Single isomer)
101 100% conversion
Intramolecular cycloadditions involving the palladium complex of trimethylenemethane have

been developed <1991JA7363, 1992JOC686>. The cyclization of the linear substrate 102 having a
vinyl sulfone was found to be highly regioselective. However, only a 2/1 diastereofacial selectivity
was observed during the formation of the perhydroindane ring (Equation (67)).
O Pd(OAc)2 O O
TMS H H
(PriO)3P
OAc +
SO2Ph ð67Þ
90% H H
OTBDMS TBDMSO SO2Ph TBDMSO SO2Ph
102 2/1
The factors that influence the stereocontrol of trimethylenemethane intramolecular cycloadditions

were then studied by the same group <1996JA10094>. The diastereoselectivity of palladium-
catalyzed TMM cycloaddition with respect to the stereogenic center adjacent to the acceptor
has been shown to be very high with doubly activated acceptors (Equation (68)). Thereby, the
Z-situated ester group was proposed as a diastereoselective control element. The effect of this
cis-substituent on the alkene was rationalized by an analysis of the possible cyclization
intermediates. A conformer seems to be preferred among the four possible reactive conformers
due to the interactions associated with this substituent.
O
O H
Pd(OAc)2
TMS
(PriO)3P
OAc CO Me CO2Me ð68Þ
2
(CH3)3SnOAc H CO Me
2
CH3
CH3 CO2Me toluene
50% (Single isomer)
Asymmetric versions of this reaction have been carried out using chiral olefins and good diaster-
eoisomeric excesses were obtained for the cycloaddition of these TMM species to chiral sulfoxides
<1989TL1803>, chiral cyclohexenyl sulfones, <1989JA7487> and chiral allylic ketals <1993S129>.
Another synthetic route to methylenecyclopentanes involves the palladium(0)- or nickel(0)-
catalyzed additions of methylenecyclopropanes to electron-poor alkenes. This approach was
pioneered by both Noyori <1970JA5780> and Binger <1987TCC77>. Extensive studies by
Binger and co-workers revealed that the regiochemical outcome of the [3+2]-cycloaddition of
methylenecyclopropane is dependent on the nature of the catalytic system (Equation (69)).
Palladium catalysts gave cycloadducts derived from distal ring cleavage, whereas, with ‘‘naked’’
nickel catalysts, the cycloadducts resulted from cleavage of the proximal bond of the cyclopro-
pane. This topic has been reviewed <1996CRV49, 1995COMCII923>.
Proximal attack
MeO2C CO2Me
+
Distal attack
η 3-allylCpPd Ni(COD)2
ð69Þ
+ CO2Me CO2Me
+
MeO2C CO2Me MeO2C CO2Me CO2Me CO2Me
25% 20% 70% 8%
The palladium-catalyzed [3+2]-cycloaddition of bicyclopropylidene 103 with electron-poor

alkenes was recently investigated and it was found that the cycloaddition proceeds with high
regioselectively with respect to the bicyclopropylidene and with high regio- and stereoselectivity
with respect to the alkene. For example, reaction of bicyclopropylidene 103 with methyl acrylate
produced the 4-methylenespiro[2.4]heptane derivative 104 as a mixture of diastereomers. This
compound results from a distal cleavage of one of the three-membered rings of 103 (Equation
(70)) <1998EJO113>.
Pd(dba)2
CO2CH3 P(Pri)2(But) +
+
110 °C H3CO2C Me Me CO2CH3 ð70Þ
103
58% 104 104'
104/104' 90/10
Intramolecular palladium-catalyzed cycloaddition reactions of methylenecyclopropanes con-

taining olefinic (Equation (71)) or acetylenic acceptors have been developed by Motherwell and
co-workers. Functionalized bicyclo[3.3.0]octanes were obtained in a regiocontrolled manner via
distal cleavage of the cyclopropane ring <1995T3289, 1995T3303>.
Ph Ph Ph
Ph
H
Pd(dba)2
ð71Þ
(PriO)3P
H O
O toluene, 110 °C
47%
(ii) Additions of allyl anions

Anionic [3+2]-cycloaddition of allyl anions or allyllithium compounds to double or triple bonds
is an efficient method for the formation of carbocyclic five-membered rings. This work was
pioneered by Kaufmann and co-workers <1970AG(E)380> and was further extended notably
by Beak and co-workers <1986JOC4627, 1989JOC1647>. Allyl anions are very electron-rich
systems, which react with olefins having aromatic or electron-withdrawing substituents.
Some allyl anions are known to react stereospecifically without forming any open-chain side
products <1986JOC4627>. As an example, the addition of 2-cyano-1,3-diphenylallyllithium to
trans-stilbene gave only two diastereomers among the 10 possible (Equation (72)).
Ph Ph Ph Ph
Ph THF
Li rt
Ph Ph + + ð72Þ
Ph Ph Ph Ph
CN Ph 46%
CN CN
1/1
Subsequent investigations <1998JA3357> have shown that cycloadditions of allyl anions with
dipolarophiles may occur in a stepwise or concerted manner. Indeed, it was found that the
reaction of 2-carbamoylallyllithium 105 with its parent alkene 106 was strongly dependent on
the temperature. The cyclopentane was produced at 65 C while open-chain products were
obtained at 60 C (Equation (73)).
CONR2 CONR2
CONR2 CONR2
CONR2 106
Li CONR2
–60 °C
ð73Þ
–60 to 25 °C 105
53%
CONR2 Mixture of 2 diastereomers
59%
R = CH(CH3)2
The allyl anion derived from deprotonation of benzoyl(cyanomethyl)ketene dithiacetal with

lithium diisopropylamide (LDA) was shown to undergo anionic [3+2]-annulation with various
activated olefins via tandem-Michael addition-aldol condensation to afford the corresponding
cyclopentenes in a highly diastereoselective manner <1994JCS(P1)2439> (Equation (74)).
MeS SMe
Ph
O i. LDA Ph
CN HO CN
MeS Ph ð74Þ
ii. Ph Ph
SMe Ph
O
O
88%
(iii) Additions of allyl cations

The used of alkoxy and trialkylsilyloxy groups for the preparation of allyl cations has been
studied by Hoffmann and co-workers <1988T3899>. There has been little further development
in this area. However, a new synthetic method for the preparation of functionalized cyclopenta-
nones was developed by the group of Kuwajima on the basis of a [3+2]-cycloaddition reaction
of 1-(methylthio)-2-siloxyallyl cationic species with various olefins such as enol ethers, vinyl
sulfides, styrenes, and trialkylolefins (Equation (75)). The methylthio group on the three-carbon
unit was chosen for its important role in stabilization of the 2-oxyallyl cation intermediate
as well as in control of the regiochemistry. These allyl cationic species were prepared by reaction
of 1-(methylthio)-2-siloxyallyl acetates with a Lewis acid, generally EtAlCl2 or AlCl3. The
reaction proceeds with almost complete regioselectivity and the sterically more hindered
regioisomer was predominantly formed in every case. In particular, a high stereoselectivity
was observed in the reaction of 107 with vinyl sulfide <1998JA1724>. Similar methylenecyclo-
propane annulation could also be effected by using a substrate having a –CH2TMS group in
place of the siloxy group <1996TL5943>. This strategy was used by the same group for the
key step of the synthesis of ()-coriolin, a triquinane having important biological activities
<1999JOC2648>.
SPh
OTIPS OTIPS PhS SMe
MeS OAc EtAlCl2
MeS O ð75Þ
CH2Cl2 82%
107 99/1 dr
The intramolecular version of the [3+2]-cycloaddition reaction of allyl cations has been
recently reviewed <1997T6235>.
(iv) Meta-photocyclization of arenes

The inter- as well as the intramolecular version of the m-photocycloaddition of arenes to alkenes
have been shown to be useful methods for the preparation of complex molecules <1996JOC3576,
1996TL7687> (Equation (76)).
hν
+
Cyclohexane ð76Þ
72% H H
2/1
This topic has been reviewed by Cornelisse <1993CRV615> and more recent work in this area
has been developed by the same group <1999EJO463>.
1.08.2.4.2 [3+2]-Additions of CXC fragments
(i) Additions of carbonyl ylides

The earliest approaches to carbonyl ylides involved thermolysis of certain epoxides <1981T3345,
1998JCS(P1)313>, oxadiazolines <2000JCS(P1)2161> or dioxolanones <1991COS(4)1069>, as
well as the reaction of a carbene or carbenoid with a carbonyl compound <1989TL4089>
(Equation (77)).
N N
–N2
O hν or ∆ –CO2 O
O ð77Þ
O
O
Transition metal
N2 + O
Nonstabilized carbonyl ylides bearing only alkyl substituents or no substituents through a

samarium-mediated reaction were recently prepared <1996TL9241, 1996JA3533>. These
carbonyl ylides react intermolecularly with alkenes to produce THFs as shown in Equation (78).
OMe
MeO OMe MeO OMe
Cl Sm metal–I2
+ + ð78Þ
Cl O Me THF
O Me O Me
OMe 86% 59/41
The intramolecular carbenoid-carbonyl group cyclization is one of the most effective methods
for generating carbonyl ylides from -diazoketones. Initially reported by Ibata and co-workers
with copper catalysts <1979BCJ3582>, the carbonyl ylide formation with dirhodium(II) carboxy-
late catalysts was further extensively studied by Padwa and co-workers. This chemistry has been
the subject of numerous articles and reviews <1998CRV911, 1996CRV223, B-1998MI018,
B-2002MI019, B-2002MI020, 1997TCC121>.
In this method, the rhodium(II) metal-catalyzed decomposition of an -diazo-ketone produced
a stabilized metallocarbenoid, which readily adds onto the oxygen of carbonyl groups such as
ketones, aldehydes, esters, amides, or ureas. These carbon ylides can be trapped by various
dipolarophiles in both an intra- or an intermolecular fashion. For example, cyclization of the
rhodium carbenoid generated from 108 with the carbonyl of the amide provided the carbonyl
ylide 109, which underwent an intramolecular cycloaddition leading to the oxo-bridged tricyclic
amide 110 <2000JA8155> (Equation (79)).
Rh2(OAc)4 71% O
O O N
N N2 N ð79Þ
CH2Cl2, 80 °C
O O
O O
O O
108 109 110
A Lewis acid-mediated stereocontrolled 1,3-dipolar cycloaddition of the cyclic ylide 112, derived
from the diazo-decomposition of 111, with N-substituted maleimides was recently reported
<1998TL3165>. While the rhodium-catalyzed (5% Rh2(OAc)4) reaction gave cycloadducts 113
with exo-selectivity (endo/exo = 11/89), the CuCl-Yb(OTf)3 catalyzed reaction gave cycloadducts in
an endo-selective manner (endo/exo = 94/6). The latter selectivity is probably due to an activation of
the cycloaddition reaction through a coordination of the Lewis acid to the oxygen dipolarophile
(Equation (80)).
O
O O O O
N
N2 O
cat. Me O
OMe O
OMe NMe
O OMe ð80Þ
O
111 112 113
Rh2(OAc)4 (5%), refluxing benzene, 70% (11/89 endo/exo)

CuCl (5%) + Yb(OTf)3 (5%) , refluxing benzene, 52% (94/6 endo/exo)
The first enantioselective intramolecular version of the tandem cyclization–cycloaddition of

-diazo ketones (up to 53% ee) was reported by Hodgson and co-workers in 1997. This has been
achieved through the use of dirhodium tetrakis(1,10 -binaphthyl-2,20 -diylphosphonate) catalysts
<1997TL6471>. Conceptually related (but intermolecular) asymmetric carbonyl ylide cycloaddi-
tions have been reported more recently <2000OL3145,1999JA1417>. High levels of enantioselec-
tivity (up to 92%) were obtained in the tandem formation of the carbonyl ylide from -diazo
ketone 114 followed by a 1,3-dipolar cycloaddition with dimethyl acetylenedicarboxylate
(DMAD) using a chiral rhodium catalyst having N-benzene-fused phthaloyl-(S)-valine as the
ligand (Equation (81)).
MeO2C CO2Me
Ph O N2 MeO2C CO2Me Ph O
O cat. 115 (1%)

PhCF3
114 92% ee
54%
ð81Þ
O Pr i
O Rh
N
O Rh
O 4
115
This methodology has recently been used <B-2002MI021, 2001OL1721> to prepare complex
polycyclic structures such as polyazacyclic and oxacyclic systems found in many bioactive natural
products.
(ii) Additions of thiocarbonyl ylides

While carbonyl ylides have been the subject of numerous studies, thiocarbonyl halides are less
common species. The cycloaddition chemistry of these 1,3-dipoles has been summarized in reviews
<B-2002MI022, 2000PJC1503>.
The methods of generation of thiocarbonyl ylides are very similar to those used for the
preparation of carbonyl ylides. Hence, thermal elimination of nitrogen from 2,5-dihydro-1,3,4-
thiadiazoles <2000EJO1685>, thermolysis of 1,3-oxathiolan-5-ones <1980JA744>, fluoride-catalyzed
elimination of silylated thioethers, addition of carbenes and carbenoids to thiocarbonyl groups
<1999OL1667, 1994TL3555>, deprotonation of sulfenium salts, <2000PJC1503> as well as photo-
chemical rearrangements of thioethers <1994JA1137> gave access to the dipolar structure 116
(Equation (82)).
R2 R4
R2 N N R4 R2 R4
R1 S R3 R1 R3
R 1 S R3 X Me3Si S
Cl
∆
–HX CsF
Base R1, R2, R3, R4 = H
–N2 ð82Þ
–Me3SiCl
R2 R4
O ∆ hν
R2 R4
R2 O R1 S R3 TCNE
R4 –CO2
R1 S R3
R1 S R3 116
These thiocarbonyl ylides undergo intra- and intermolecular 1,3-dipolar cycloaddition reactions
preferably with electron-deficient dipolarophiles to provide five-membered sulphur heterocycles.
2,5-Dihydrothiophenes may be efficiently prepared by reaction with acetylenic dipolarophiles
<2001HCA981>. Elimination of nitrogen from 2,5-dihydro-1,3,4-thiadiazole 117 generated in
situ the thiobenzophenone (S)-methylide which reacts with (DMAD) to afford the 2,5-dihydro-
thiophene 118 in 71% yield (Equation (83)).
Ph S –N2 Ph S H Ph S H
Ph N N
Ph H Ph H
117
71% MeO2C CO2Me
ð83Þ
Ph S
Ph
MeO2C CO2Me
118
The first auxiliary-induced diastereoselective cycloaddition between thiocarbonyl ylides and

dipolarophiles was investigated in 1999 <1999OL1667, 2000S1863>. As shown in Equation (84),
the CsF-catalyzed decomposition of chloromethyl dimethylsilylmethyl sulphide 119 produced a
thiocarbonyl ylide which reacted with the ,-unsaturated ((1S)-5-)-camphorsultam amide 120 as
chiral dipolarophile to give the two diastereomeric trans-3,4-disubstituted tetrahydrothiophenes
121 and 122 in high diastereoselectivities (dr 9/1).
O O
O Bu Bu
X* X*
CsF, CH3CN +
Me3Si S Cl + Bu X*
95% S S
119 120
121 122 ð84Þ
major minor
O O
S 121/122 9/1
X* = N
The first 1,3-dipolar cycloaddition reaction of [60]fullerene with a thiocarbonyl ylide, generated
in situ by sila-Pummerer rearrangement of bis(trimethylsilylmethyl)sulfoxide, was recently reported
<1999TL1543> (Equation (85)). The tetrahydrothiophene-fused C60 derivative was then obtained
and further oxidized to give the corresponding sulfone derivatives, which could be used for
further functionalization <1999TL1543>.
O 110 °C C60
Me3Si S SiMe3 S C60 S ð85Þ
41%
(iii) Additions of azomethine ylides

The nitrogen analogs of carbonyl and thiocarbonyl ylides are called azomethine ylides. They are
generally not isolable dipoles and thus they have to be prepared in situ from a stable precursor. These
species have been widely studied and used for a variety of organic syntheses and the reader is directed to
recent reviews of Harwood <B-2002MI023>, Kanemasa, <2002SL1371, B-2002MI024> and Pearson
<2003SL903, 1998CRV863>. For these reasons, in this review, this chemistry will be briefly summar-
ized and a more detailed discussion focused on recent developments involving nonstabilized ylides by
aryl or electron-withdrawing group as well as those concerning the asymmetric version.
The principal routes to stabilized azomethine ylides (those bearing an electron-withdrawing
group such as 123) (Figure 5) are the photolysis or thermolysis of aziridines 124 (Equation (86)),
reduction of the oxazolium salts 125 with Ph3SiH/CsF (Equation (87)), or proton abstraction of
imine derivatives of -amino acids 126 (Equation (88)). The intermolecular reaction of these
stabilized azomethine ylides with electron-deficient alkenes produces substituted pyrrolidines
(Equation (89)). The regioselectivity of these additions can be predicted since they are generally
highest occupied molecular orbital (HOMO) (dipole)-LUMO (lowest occupied molecular orbital)
(dipolarophile) controlled. However, the cycloadducts formed in these reactions are usually a
mixture of diastereomers.
R3
+
MeO2C – N R2
R1 H
123
Figure 5
CO2Me
N N CO2Me
ð86Þ
Ar
Ar
124
Me Me
Me
N PhSiH3, CsF N N OEt
Me
Me Me ð87Þ
OEt O OEt O
O
125
Ph N CO2Me Ph N CO2Me ð88Þ

H
126
CO2Bu
MeO2C N CO2Bu ð89Þ

+ MeO2C
Ar N
Ar
One of the most significant developments in the chemistry of stabilized azomethine ylides was
the discovery of N-metallated azomethine ylides. They are easily prepared from -(alkylidene-
amino) esters by treatment with lithium bromide and triethylamine <2002SL1371>. These
metallaazomethine ylides were shown to undergo endo-selective 1,3-dipolar cycloadditions with
,-unsaturated carbonyl acceptors. For example, only an endo-cycloadduct was obtained in 83%
yield during the reaction of an N-lithiated ylide with N-methylmaleimide (Scheme 34).
MB OMe
R N CO2Me N C
R
M O
MB = metal + base
H
Ph N CO2Me
LiBr/NEt3 OMe O N O
Ph N CO2Me Ph N C H H
Me
THF Li O
83% O N O
Me
Scheme 34
All of the reactions outlined so far involved stabilized azomethines ylides. As pointed out by
Pearson in his review <2003SL903>, nonstabilized azomethines ylides are less accessible and are
generally prepared by using various fluorine-mediated desilylation strategies.
Nonstabilized 1-alkyl and 1,3-dialkyl N-unsubstituted azomethine ylides were more recently
generated by protodesilylation of (2-azaallyl)stannanes or (2-azaallyl)silanes with protic acids.
Cycloadditions of these ylides with electron-deficient alkenes gave 2-alkyl- or 2,5-dialkylpyrrolidines.
High stereoselectivity was observed with azomethine ylides derived from (2-azaallyl)stannanes
<1999TL4467> (Equation (90)).
MeO2C CO2Me MeO2C CO2Me

MeO2C
SnBu3 HF–pyr
+ + ð90Þ
Pri N Pri THF, 50 °C Pri N Pri Pri N Pri
MeO2C H H
68% 18/1
Nonstabilized azomethine ylides have been prepared by an intra- or intermolecular N-alkylation

of (2-azaallyl)stannanes or (2-azaallyl)silanes <1997TL5441>. These ylides underwent cycloaddi-
tion with various dipolarophiles leading to indolizidines or monocyclic pyrrolidines. The formation
and the cycloaddition of these (2-azaallyl)stannanes or (2-azallyl)silanes may be accomplished in a
one pot operation by mixing the carbonyl compound, the -amino stannane or -amino silane and
the dipolarophile in refluxing toluene. (Equation (91)).
CO2Me
DMAD CO2Me
N
N M ∆, toluene
78%
Ph
Cl –MCl N
H
M = SnBu3, SiMe3 31%
Ph
O N
Cycloaddition from a stannyl or a silylimine (One isomer)

NPh ð91Þ
67% O
O
O
H NPh
O
+ + NPh Toluene, ∆
H 2N SiMe3
Cl N O
58%
O
In situ method (Mixture of isomers: 1/1)
Extensive studies on the asymmetric 1,3-dipolar cycloaddition reactions of azomethine ylides

have been developed over the past few years using either a chiral azomethine ylide, a chiral dipole,
or a chiral catalyst. Among these three approaches, the most popular has been the use of chiral
dipolarophiles.
Since the first asymmetric 1,3-dipolar cycloaddition reaction of a chiral azomethine ylide
reported in 1985 <1985TL3529>, several new asymmetric reactions using a chiral auxiliary
attached to the ylide have been successfully applied <1998CRV863>. In a series of papers,
Harwood and co-workers studied the asymmetric 1,3-dipolar cycloaddition, reaction of the chiral
azomethine ylide generated in situ by condensation of the (5S)-phenyl-morpholin-2-one with
paraformaldehyde <1995TA2465>. This 1,3-dipole was trapped with various electron-deficient
alkenes such as dimethyl fumarate to produce a single cycloadduct, which can be subsequently
hydrogenolyzed to furnish the substrate 127 (Scheme 35).
CO2Me
CO2Me
H
Ph N Ph Paraformaldehyde Ph N Ph MeO2C
Ph N CO2Me
Ph
xylene, ∆ 95%
O O O O O O
Hydrogenolysis
MeO2C CO2Me
H2, Pd(OH)2, MeOH, TFA
Ph
N CO2Me
H
127
Scheme 35
Simple oxazolidin-5-ones are known to undergo thermal decarboxylation (1,3-dipolar cyclo-

reversion) to give nonstabilized azomethine ylides <1988JCS(P1)2703>. This study was extended
to the -lactam-based oxazolidinone 128 <1997JA2309>. A thermolytic decarboxylation gener-
ated the oxazolidine-based ylide, which was trapped in situ by the dipolarophile. These
reactions proceeded regiospecifically and led to endo-selective cycloadducts in moderate yields
(Equation (92)).
O
H O H NPh
O
O 57%
N
MeCN N + NPh N O ð92Þ
O ∆ O
CO2Bn
O
CO2Bn
CO2Bn O
128
1,3-Dipolar cycloaddition reactions of azomethine ylides with chiral alkenes, in which a chiral
auxiliary directs the stereochemical outcome of the reaction, have been developed <1995T273,
1995TL2511, 1995TA2475, 1997TA883, 1999T8129>. As an example <1999TL6065>, the
asymmetric [3+2]-cycloaddition of the cyclic nonstabilized azomethine ylide 129 (generated in
situ by a sequential double desilylation using AgF as one electron oxidant) with a chiral
dipolarophile such as Oppolzer’s acryloyl camphor sultam led to the formation of the azabicy-
clo[m.2.1]alkane 130 in enantiomerically pure form after cleavage of the auxiliary from the
cycloadduct (Scheme 36).
A new development in the asymmetric version of the cycloaddition of azomethine ylides with
dipolarophiles concerned the use of a chiral metal complex catalyst (N-metallated azomethine
ylides). A typical example is shown in Equation (93). In this example, a cobalt salt in combination
with a chiral ligand was used for the cycloaddition of 131 with methyl acrylate. The pyrrolidine
product was isolated in 84% yield with an ee value of 96%.
O
CH2Ph CH2Ph
N N
AgF X*
+
O
–
TMS N TMS N 62%
+ H
CH2Cl2 X*
CH2Ph CH2Ph H O
*X
129 Major Minor
O O
S 98/2 de
X* = N
i. LiOH, MeOH
ii. SOCl 2, dry MeOH
CH2Ph
N
O
OMe
H
130
Scheme 36
MeO2C
OMe CoCl2/L*
N
+ CO2Me
O 84% N CO2Me
131 H
ð93Þ
96% ee
Ph Me
L* = HO N
(iv) Additions of azaallyl anions

2-Azaallyl anions 132 are the nitrogen analogs of allyl anions (see Section 1.08.2.4.1). The
traditional methods pioneered by Kauffmann <1977CB638> for the generation of these semi-
stabilized active reagents (those bearing aryl groups) were the lithiation of an imine bearing
two or more aryl rings <1974AG(E)627> and the electrocyclic ring opening of an N-lithiated
diarylaziridine. The chemistry of azaallylanions has been recently reviewed <2003SL903>
(Equation (94)).
R2
R1 R3
N
Li
R2 R2 SnBu3
Electrocyclic ring-
R1 N R3 opening R1 N R3
ð94Þ
R1, R3; at least 2 aryl groups R1, R3: aryl stabilization not needed
R2NLi BunLi
(Deprotonation) R2 Li
(Sn–Li exchange)
R1 N R3
132
Intramolecular versions of these two strategies involving stabilized anions have been developed
<1986JA2769, 1972AG(E)291>. Pearson and co-workers recently reinvestigated the intramole-
cular cycloaddition via electrocyclic ring-opening of a N-lithioaziridine. It was shown that
this method can be extended to semistabilized anions bearing one phenyl group as shown in
Equation (95). The thermal conrotatory ring-opening of the mono-aryl-substituted aziridine 133
occurs at 110 C in benzene to produce the pyrroline 134. At this high temperature, a lithium
hydride elimination from the initially formed N-lithiopyrrolidine was observed. However, this
method cannot be used to make nonstabilized anions since no cycloadduct was observed for the
reaction of aziridines bearing an alkyl group <2002MI91>.
R = Ph
R = alkyl n-BuLi
X R 110 °C N Ph
NH Benzene 81%
133 134
ð95Þ
H
Li
Ph
Ph
N N Ph H N
Li Li
The major new development in this area is the generation of nonstabilized 2-azaallylithiums
(e.g., those bearing only hydrogen or alkyl group) using a tin–lithium exchange method
<1992JOC6354, 1999JOC688, 2001JA6724>. These species were shown to undergo intermolecu-
lar addition with alkenes bearing aryl groups, vinyl sulfides, vinyl selenides, and vinyl silanes to
produce pyrrolidine products in generally good yields after quenching with an electrophile. A
typical example is given in Scheme 37.
SPh
R1 R2 SPh
R1 N R2 RLi
N
SnR3 THF Li R1 R2
N
Li
78% MeI
R1 = R2 = Pr i
SPh
R1 N R2
Me
(Mixture of isomers: 2.7/1)
Scheme 37
Recently, it has been reported that 2-azaallyllithiums bearing heteroatoms such as nitrogen,
oxygen, and sulfur may be engaged in cycloaddition reactions with alkenes. These nonstabilized
heteroatom-substituted 2-azaallylanions are generated by tin–lithium exchange on stannyl imi-
dates, thioimidates, and amidines. These reactions allowed access to 1-pyrrolines after loss of the
heteroatom group after the cycloaddition (Equation (96)) <1994TL2641>. Under the basic
reaction conditions, 135 is deprotonated to give the metalloenamine 136. This may be quenched
with water to regenerate 135 or may be alkylated to give a different 1-pyrroline such as 137. The
cyclic version of the heteroatom-substituted 2-azaallyllithiums was developed by the same group
<1998JOC9812>.
SiEt3
OMe SnBu3 SiEt3 OMe Li
MeO
N N N
2BunLi
Li
SiEt3
SiEt3
–LiOMe Bu nLi
N ð96Þ
N
Li 136
135
CH3I H2O
65% 97%
SiEt3
135
N
137
The first enantioselective addition of 2-azaallyl anions was recently achieved by using the hetero-
atom as an attachment point for a chiral auxiliary <2001TL7361>. As shown in Equation (97), the
chiral nonracemic amidine 138 in the presence of -methyl styrene and butyllithium gave the pyrroline
139 isolated in 46% yield with a 98% ee.
MeO Ph Ph
Me SnBu3 Me
BuLi Me
N N Me Me N N Me ð97Þ
Me N Me
Li
138 Ph 139
O
46% Me 98% ee
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Biographical sketch
Geneviève Balme was born in Saint Symphor- Didier Bouyssi was born in Valence, France, in
ien s/s Coise, a small town situated in the hills 1964 and studied chemistry at the University
about 30 km west of Lyon. After a first aca- of Lyon where he obtained his PhD degree in
demic position as a primary school teacher 1992 under the guidance of Professor Jacques
(2 years in France, 3 years in Island of Goré and Dr. Geneviève Balme for research
Reunion), she studied chemistry at the Uni- on new palladium-mediated cyclization pro-
versity of Lyon and received her PhD degrees cesses. After a 1 year period as ‘‘ATER’’
in the same University (Doctorat de 3ième (Attaché Temporaire d’Enseignement et de
cycle-1979: supervisors Professor Jacques Recherche) in the same university, he was
Goré and Dr. Max Malacria; Doctorat appointed by University of Lyon as a ‘‘Maı̂tre
d’état-1983: supervisor Professor Jacques de Conférences’’ in the group of Geneviève
Goré). In 1994, she was promoted to Direc- Balme. His current research interests cover
teur de Recherche at the Centre National de the development of organic synthetic methods
la Recherche Scientifique. Her main research using transition metal complexes as catalytic
interests focus on the development of new reagents, multicomponent reactions, and the
synthetic methods using transition metal com- synthesis of natural or unnatural bioactive
plexes such as palladium-catalyzed sequential compounds.
reactions, multicomponent reactions, and
their applications to the synthesis of natural
products and biologically active compounds.
Nuno Monteiro was born in Marinha Grande (Portugal) and studied

chemistry at the University of Lyon (France) where he obtained his PhD
degree in 1992 under the guidance of Professor Jacques Goré and
Dr. Geneviève Balme. After spending the following year in the same
university as ‘‘A.T.E.R.’’ (Attaché Temporaire d’Enseignement et de
Recherche), he joined the team of Professor Varinder K. Aggarwal at
the University of Sheffield (England) as a Marie Curie post-doctoral
fellow. In 1996 he returned to Lyon where he was appointed by the
CNRS as a ‘‘Chargé de Recherches.’’ His current research interests
concern the use of organometallics in organic synthesis, the development
of diversity-oriented synthetic methods directed toward heterocycles,
and the synthesis of bioactive natural products and structural analogs.
1.09
One or More CH and/or CC Bond(s)
Formed by Rearrangement
P. H. DUCROT
INRA, Versailles, France
1.09.1 TYPES OF REACTION 375

1.09.1.1 Substituent Migrates as a Cation 376
1.09.1.1.1 1,2-Electrophilic migration 376
1.09.1.1.2 Truce–Smiles rearrangement 376
1.09.1.1.3 Fritsch–Buttenberg–Wiechell rearrangement 376
1.09.1.2 Substituent Migrates as an Anion 377
1.09.1.2.1 Wagner–Meerwein rearrangement 377
1.09.1.2.2 Pinacol rearrangement 382
1.09.1.2.3 Rearrangement of epoxides 385
1.09.1.2.4 Semipinacol rearrangement 388
1.09.1.2.5 Favorskii rearrangement 391
1.09.1.2.6 Wolff rearrangement 393
1.09.1.2.7 Westphalen–Lettré rearrangement of steroids 395
1.09.1.3 Substituent Migrates as a Radical 396
1.09.1.3.1 [1,2]-Wittig rearrangement 396
1.09.1.3.2 [1,2]-Stevens rearrangement 399
1.09.1.4 Sigmatropic Rearrangements 401
1.09.1.4.1 [1,3]-Sigmatropic rearrangements 401
1.09.1.4.5 [3,3]-Sigmatropic rearrangement 414
1.09.1.5 Electrocyclic Reactions 415
1.09.1.5.1 Nazarov cyclization 415
1.09.1 TYPES OF REACTION

This chapter addresses the formation of saturated carbon atoms with no attached heteroatoms by
rearrangement reactions. It is divided into three sections according to mechanistic aspects: the
first one is devoted to the recent advances in nonsigmatropic rearrangements, involving the cases
where the migrating group is either an ionic species or not. The second and third sections are
devoted to sigmatropic rearrangements and electrocyclic reactions, respectively. In each subsec-
tion, a particular effort is made to emphasize the use of the discussed rearrangements in multistep
syntheses and its ability of being the key step of a retrosynthetic process.
This section discusses the main electrophilic and nucleophilic rearrangements. As outlined in
the corresponding chapter of the COFGT (1995) <1995COFGT(1)377>, electrophilic rearrange-
ments are essentially concerned with rearrangements of substituents able to support an additional
pair of electrons (namely aryl groups) and are therefore scarcely used, while mostly prohibiting
375
376 One or More CH and/or CC Bond(s) Formed by Rearrangement
the formation of asymmetric centers. The scarce examples of chirality transfer in related rearran-
gements are mainly found in recent advances in the carbenoid-mediated Fritsch–Buttenberg–
Wiechell rearrangement (Section 1.09.1.1.3) using alkyl migrating groups, and the chirality
transfer is, in this case, the result of the presence of an adjacent asymmetric center.
Alternatively, nucleophilic rearrangements have been widely used on polycyclic structures with
a good stereochemical control of the stereogenic centers formed in the course of the reaction.
Indeed, in nucleophilic rearrangements, interaction between the migrating group and the devel-
oping cation clearly occurs in most of the cases without complete ionization at the migration
terminus, thus allowing a quasi-concerted process to occur. In these cases, inversion of the
configuration at the migration terminus is observed, while the necessary colinearity of the forming
CC and the breaking CC (or CX) bonds allows the complete retention of configuration at
the migrating carbon atom (if this center is chiral).
1.09.1.1 Substituent Migrates as a Cation
1.09.1.1.1 1,2-Electrophilic migration

The 1,2-electrophilic migration of a substituent, mainly devoted to the migration of aryl groups, has
found no significant advances since the publication of chapter 1.09.1.1.1 in <1995COFGT(1)377>.
1.09.1.1.2 Truce–Smiles rearrangement

The originally reported Truce–Smiles rearrangement involving the formation of a CC bond
between a benzylic carbon and an aromatic ring migrating from a neighboring sulfonyl group
allows the formation of o-benzylarenesulfinic acids from the corresponding o-methyl aryl sulfone
(Equation (1)).
O
O
SO2Ph S SO2H
ButLi, Et2O ð1Þ
98% –
It has been clearly demonstrated that this rearrangement proceeded through an ipso mechanism
with attack of the benzylic carbanion on the aromatic ring at the carbon atom bonded to the
sulfur.
This rearrangement has been poorly used in synthetic research but an interesting report has
been made of a Truce–Smiles-type rearrangement in a study devoted to the synthesis of strobi-
lurine analogs. It shows the possible migration of an ester enolate on a pyridine ring, leading to a
substituted benzofuranone (Equation (2)) <2000TL4541>.
O
O O
KH, THF
N
ð2Þ
CF3 –20 °C N
COOCH3 Yield not given
CF3
1.09.1.1.3 Fritsch–Buttenberg–Wiechell rearrangement

The Fritsch–Buttenberg–Wiechell rearrangement, which was reported for the first time at the end
of the nineteenth century, has been for a long time a useful route for the synthesis of alkynes. This
rearrangement has been widely reviewed <1997AG(E)1164, 1998S271, 1996T8143> and used to
perform the synthesis of a variety of polyynes via alkyne migration in carbene/carbenoid
intermediates <2000JA10736, 2001TL8575>. This rearrangement is not discussed in this chapter,
since it produces sp2 or sp carbon atoms. However, an interesting modification of this rearrangement
One or More CH and/or CC Bond(s) Formed by Rearrangement 377
has been proposed in the aliphatic series <2000OL419>, which allows a novel chirality
transfer to occur in the 1,2-migration of a secondary aliphatic carbon <1999TL1899>
(Scheme 1).
Li
BrZn ZnBr PhSO2Zn Cl
MgBr PhSO2Cl
MEMO MEMO
ZnBr2 70%
Pri OMEM Pri
Pri
MEMO
Pri
Scheme 1
1.09.1.2 Substituent Migrates as an Anion
1.09.1.2.1 Wagner–Meerwein rearrangement

Since their discovery at the end of the nineteenth century, the Wagner–Meerwein rearrangement
(Equation (3)) and the related Nametkin rearrangement (Equation (4)) have attracted a lot of
research mainly in terpenoid systems.
Wagner–Meerwein ð3Þ
+
Nametkin +
+
ð4Þ
The nucleophilic Wagner–Meerwein rearrangement involves the 1,2-migration of a carbon

atom in polycyclic structures. It produces therefore interesting polycyclic structures, with rear-
ranged backbones, often difficult to access through conventional chemical methodologies. More-
over, since the stereochemical requirements for the 1,2-migration are well known (best
antiperiplanarity of the leaving and the migrating groups), the product of the rearrangement
can be in some cases predicted and the rearrangement used in a retrosynthetic analysis. Some
studies have been devoted to the density functional theory (DFT) study of this type of rearrange-
ment <1999JOC60>. The most widely accepted mechanism for these reactions involves a two-
electron, three-center bond termed a classical or nonclassical carbonium ion. The balance between
Wagner–Merwein and Nametkin rearrangement products depends on the geometry of the starting
material and the stability of the final product but can also be controlled in some cases by the
experimental procedure <1998T4607, 1998JOC2262>.
Even if the initially described Wagner–Meerwein rearrangement (Equation (5)) involves the
formation of the initial cation through addition of HCl on a double bond ending with the
trapping of the resulting cation by a chlorine atom, some new features in this reaction involve
either the design of other leaving groups, different reagents for the formation of the initial
carbocation, or the use of different nucleophilic species for the trapping of the final carbocation.
HCl ð5Þ
Quant..
Cl
Most of the research in the Wagner–Meerwein area has involved a noncatalytic methodology,
and may differ in the choice of the leaving group X and in the trapping of the resulting
carbocation, which can either undergo deprotonation (Equation (6)) or be trapped intra- or
intermolecularly by an appropriate nucleophile (Equation (7)). In the case where R0 is a hydroxy
group, a ketone is of course exclusively generated through deprotonation.
+ R R
R ð6Þ
R' X R'
R'
R – R
+ "Nu "
R Nu ð7Þ
R' X R'
R'
The leaving group X can be either a halogen <2001JCS(P1)1511>, or derived from an oxyge-
nated function. In this latter case, X can be either a hydroxy group <1997TL2235, 2001TA189>,
an ether <1997TL2159>, a sulfonic ester <2001EJO1279, 1996TL1035, 2003JOC6935>, or an
epoxide <1998T1615, 2001TA2091, 1996JAFC1840, 2000TA4437, 2001TA3325>. When the leav-
ing group is a halogen, a bromine atom is possibly introduced in the same step through nucleophilic
addition on a double bond (NBS) <2000TA4437, 2001TL6539, 2000TA3059>; in this case, the
bromonium intermediate can undergo a Wagner–Merwein rearrangement and the bromine atom is
incorporated in the resulting product; this type of methodology is compatible with the use of other
nucleophiles such as sulfides, selenides <2001TL5017>, or Eschenmoser’s salt <2002TA17,
2002TL1183> (Scheme 2).
OH
N+ , I–
PhSeCl
CH2Cl2, rt CHCl3, reflux
70% 98%
O
O
Se N
Ph
Scheme 2
Interestingly, the initial carbocation can also be generated directly from a carbonyl group
through treatment either by Tf2O in the presence of an organic base <2000TA3059>, in the
presence of TiCl4 <1999AG(E)2583>, or under the Leuckart reaction conditions <1996TL8177,
1999H611>; this methodology has the advantage that the carbocation is generated at a carbon
atom bearing either an oxygen or a nitrogen atom. As the hetero atom is conserved in the product
of the reaction, this Wagner–Meerwein rearrangement results in the formation of tertiary alcohols
and amines <2001EJO2805> of controlled configurations, which would have been difficult to
access using other methodologies (Scheme 3).
However, the experimental conditions have to be adapted to each particular case and no
generalization can be made. An interesting set of conditions has been proposed in the case
where the leaving group is an iodide using hypervalent iodine chemistry <2001JCS(P1)1511>.
Indeed, iodopregnane derivative 1 undergoes spontaneous Wagner–Meerwein-like rearrangement
upon treatment with MCPBA through an iodosyl intermediate as a masked carbocation, afford-
ing epoxide 2 through deprotonation and further nonstereoselective oxidation of the resulting
double bond (Scheme 4).
H2NCHO
+ +
HCO2H
O AcO OHCHN AcO NH
150 °C OHC
O
H2O
61%
HN NHCHO HN O N+ O
OHC H
Ac Ac Ac
OTf
Tf2O/base/CH2Cl2
95%
O
Scheme 3
I OAc
OAc
H MCPBA (6 equiv.) H O
H H t H
Bu OH / THF/H2O
O O
1 rt 2
77%
O
I OAc
+
OAc OAc
H H
Scheme 4
The formation of the initial cation can also be made from a free hydroxy group under
Mitsunobu conditions: in this case trapping of the resulting carbocation is effected by the benzoic
acid used, which avoids the deprotonation (Equation (8)) <1997TL2235>. Furthermore, the
crucial formation of the initial carbocation can be effected even if there are several carbocation
precursors in the molecule provided that their reactivity can be managed. An example of this
possibility is given in Scheme 5 <2001TA189>.
OH
NHTs i. p-NO2C6H4CO2H, PPh3 NHTs
DEAD, 0 °C to rt ð8Þ
ii. KOH, MeOH/H2O rt OH
80%
Br CN CO2H
Tf2O/base
OH
Br CH2Cl2
NC
95% NC
Scheme 5
The final step of the reaction, namely the trapping of the final carbocation, is also a source of
versatility for the Wagner–Meerwein-type of rearrangements. When the reaction is achieved in
alcoholic solution or in the presence of water, the trapping of the carbocation by an oxygen atom
is predominant and the deprotonation pathway mostly prohibited. However, the particular
structure of the starting material can also be such that an intramolecular trapping can be
observed. For example, in the case of the fenchone derivative 3, the reaction is conducted in an
aqueous hydrochloride ethanolic solution and the rearranged carbocation can either be trapped
intermolecularly by water or intramolecularly by the nitrogen atom of the chloroaniline moiety.
Since the acidic reaction conditions allow a chemical equilibrium between both products, after
1 day, the pyrrolidine is the only thermodynamically preferred product of the reaction, when the
kinetic product formed is the amino alcohol <1997TL2159> (Equation (9)). Surprisingly, in the
same study, the authors report the preference for the Nametkin rearrangement for derivative 4
(Equation (10)). This result shows the difficulty of predicting the result of such rearrangement
reactions when both rearrangements are competitive.
H2N OH
Cl Cl
HCl (10 M)/EtOH

reflux Cl ð9Þ
O
60% NH3+
NH
OMe OMe
3
NH
Cl
MeO
MeO
HCl, EtOH
OMe ð10Þ
OH 74%
O
Another spectacular intramolecular trapping is described in the case of a complex reaction

sequence involving double allyl silane-mediated [2+3]-cycloaddition, Wagner–Meerwein rearran-
gement, Friedel–Crafts alkylation, and final dehydration to give a pentacyclic structure starting
from a cyclopentanone derivative <1999AG(E)2583> (Scheme 6). In this case, the terminal cation
produced during the rearrangement plays the role of the electrophile in a Friedel–Crafts-like
alkylation.
This example emphasizes the ability of the Wagner–Meerwein rearrangement to be included in
complex reaction sequences where the driving force of the reaction is the thermodynamic stability
of the product formed <1996TL1535, 1998T1615>.
Another important feature of this rearrangement, predominantly used in camphor and fench-
one chemistry, is its ability of producing chiral inducers. In this field, the use of a chiral camphor
alumino thiol 5 has been proposed to effect a formal asymmetric Michael addition of hydrogen
–
TiCl4
O Pr3Si + SiPr3
SiPr3 O
Ph
TiCl4, CH2Cl2, 40 °C
Ph
SiPr3 SiPr3
–
TiCl4
O SiPr3
H
+ 46%
R3Si
Scheme 6
sulfide to ,-unsaturated carbonyl compounds in odorless conditions based on the easy Wagner–
Meerwein rearrangement of this type of compound allowing a mild release of the chiral inducer
<2001OL3121> (Scheme 7).
SC11H23
O SC11H23
BF3, Et2O
OBn then
Bn O C11H23SH
O OH
S Al S O
OBn CH2Cl2
H 89% HS
Cl Bn OBn
5 96% de Bn
Scheme 7
Alternatively, catalytic metal-mediated Wagner–Meerwein rearrangements have also been

proposed <2001JA7162, 1995JA6907, 1999JOC101>. When transition metals are used, due to
the potency of the metallic -allyl complexes, the addition of chiral ligands allows the induction of
chirality in the product of the reaction (Scheme 8). The synthesis of optically active cyclopen-
tanone 6 from an achiral hydroxy cyclobutane emphasizes the potential of this methodology
<2001JA7162> (Equation (11)).
+
[M]
R
R
HO O
R [M]
+
X – R
HO –X
R
HO [M] O
Scheme 8
Pd2(dba)3·CHCl3 (1 mol.%)
Tetramethylguanidine (20 mol.%) O
OH
L* (3 mol.%)
F3C
90%
ð11Þ
O 6
O
87% ee
O L* = O O
NH HN
Ph2P
PPh2
In conclusion, even if the main area of application of the Wagner–Meerwein (and/or Nametkin)
rearrangement remains the field of the camphor–fenchone chemistry, dedicated to design
new chiral auxiliaries, it has also been used as a useful transformation for the synthesis of
compounds of complex structure (for an example in the triquinane-type skeleton, see reference
<1999JOC101>).
One should also keep in mind that carbocations are often generated in synthetic reactions
involving Lewis acids and may rearrange through Wagner–Meerwein or Nametkin-type 1,2-alkyl
shift. As an example, the carbocation generated in the Friedel–Crafts-like intramolecular alkyla-
tion of compound 7 undergoes a 1,2-alkyl shift to finally afford the tricyclic derivative 8
<1996T15209> (Equation (12)).
O O O
OH OH
SnCl4, CH2Cl2
O
O O ð12Þ
83%
+
O
7 8
1.09.1.2.2 Pinacol rearrangement

The pinacol rearrangement of vicinal diols has been widely used to form quaternary centers to a
carbonyl group. Indeed, associated with a pinacol coupling, it offers a rapid and highly con-
vergent access to this type of carbon arrangement.
Pinacol rearrangement involves a 1,2-shift of substituent (H, alkyl, or aryl group) with
concomitant formation of a CH or CC bond to a carbonyl group. Because of the
difficulty of managing the different migrating abilities of the different substituents of the diol
subunit, it can lead to the possible formation of a complex mixture of rearranged products
(Equation (13)).
R3 R2 R1 R2 R2 R1 R1 R3 R1 R4
R4 R1 R4 R4 R2 R2 ð13Þ
HO OH R3 O R3 O R4 O R3 O
However, if the vicinal diol is included in a polycyclic structure, one may expect the regio-
and/or stereoselectivity of the rearrangement to be controlled by the stability of the different
expected products. Therefore, even if some reports of pinacol rearrangement may be found in
acyclic compounds <2000JA1908>, mainly involving aryl-group migration <2000JOC7438,
2000TL1433, 2002TL2161>, most of the publications in this area are now devoted to the use
of pinacol rearrangements in cyclic or polycyclic structures.
In acyclic pinacol rearrangements, the selectivity depends on the stability of the carbocation
formed in the initial step of the rearrangement (when one of the hydroxy groups is a primary one,
the corresponding aldehyde is obviously formed upon 1,2-hydrogen atom migration) and the
migrating ability of the different substituents (aryl>H>alkyl). In some cases, the products are
different depending on the kinetic or thermodynamic conditions. However, the result of a pinacol
rearrangement in almost symmetrical compounds remains difficult to predict <1998T2099>.
In the case of the ursenoate-type trans-diol 9, treatment with concentrated sulfuric acid led to the
formation of both compounds 10 and 11, respectively, obtained through hydrogen atom and
alkyl-group migration (Equation (14)).
COOCH3
COOCH3
HO H2SO4 10 (10%)
C6H6, reflux O ð14Þ
COOCH3
HO
HO
9 OHC
11 (7%)
The pinacol rearrangement appellation concerns only 1,2-diols, where the selectivity is only
dependent on the migrating ability of substituents R1–R4. Indeed, the alternative pathway for
controlling the selectivity in the pinacol rearrangement rises through switching to the ‘‘semipina-
col’’ strategy, where both hydroxy groups are clearly differentiated (e.g., through derivation as
sulfonic esters), one of them becoming definitely better as leaving group than the other. This
strategy has been widely used in the case of tetra-alkyl-substituted diols and will be further
described in Section 1.09.1.2.4.
The generally encountered sets of experimental conditions for pinacol rearrangement
involve either sulfuric (or hydrobromic <2000JOC7786>) acid treatment <1997JOC1463,
2001JOC3930> or the use of Lewis acids. The most widely used Lewis acid is boron trifluoride
etherate <1998JOC3855, 1996JOC4391>.
In order to emphasize the potency of the pinacol rearrangement in natural product total
synthesis, an example is found in the report of the synthesis of A-ring aromatic trichothecene
analogs (Equation (15)) <1998JOC3855>. In this case, treatment of tricyclic diol 12 with boron
trifluoride etherate at ambient temperature cleanly afforded the benzooxabicyclo[3.2.1]octanone
13. Explanation of the selectivity in this case is obviously due to the stabilization of the benzylic
cation as well as the stability of the bicyclo[3.2.1]octane compared to the bicyclo[4.2.0]octane
(see also reference <2000AG(E)937> for a pinacol-rearrangement-based synthetic approach of
diazonamide).
OH
OH O
BF3·Et2O, CH2Cl2
ð15Þ
O 87%
O
12 13
The pinacol rearrangement can be, in some cases, achieved in supercritical water
<2000JA1908> or under photochemical conditions <1998JOC7168>.
Examples can also be found, where the regioselectivity encountered in the pinacol rearrange-
ment is related to the presence of substituents remote in the carbon backbone from the reactive
centers of the rearrangement. Indeed in the case of porphyrin derivatives 14–16, the meso-
substituent plays a critical role in the regioselectivity of the alkyl-group migration
<2001JOC3930> (Scheme 9).
However, an interesting set of experimental conditions has been described that involves the use
of 1 equiv. of triethyl orthoformate or other related ortho esters to achieve the pinacol rearrange-
ment in the presence of a Lewis acid (BF3Et2O or SnCl4) <1997TL8315, 1998T14689>. This
method has the advantage of avoiding by-products eventually generated in the dehydration step
and to be compatible with acid-sensitive functional groups on the starting molecule, since the
amount of Lewis acid used for the reaction can be reduced to only 1 equiv. However, it presents
also the drawback of being dependent on the configurations at the carbon atoms bearing the two
hydroxy groups in the ability of forming a cyclic ortho ester intermediate in the case of polycyclic
or constrained structures (Equation (16)).
OMe OMe
H2SO4, rt
OH
40 %
OH
O
NH N NH N
14
n-Hept n-Hept n-Hept O
OH
OH H2SO4, rt
O
NH N NH N NH N
15
46% 36%
OHC O
OHC
OH
OH H2SO4, rt
100% NH N
NH N
16
Scheme 9
OPNB SnCl4, CH2Cl2

HC(OMe)3, [LA] OMe
OH
O+
0 °C to rt
O ð16Þ
85% O
OH PNBO OPNB
PNB = 4-nitrobenzoyle
It is important to note that, in the case described above, the regioselectivity of the pinacolic
rearrangement is not affected by the addition of the orthoformate but only the yield of the
transformation.
However, if some solutions have been proposed to alleviate the drawbacks of the pinacolic
rearrangement, most of the synthetic research using this reaction has preferred to turn to the
semipinacolic rearrangement (Section 1.09.1.2.4). Nevertheless, the pinacol rearrangement has
also been used in synthetic studies aimed at the synthesis of complex structures, mainly when
coupled with other reactions either before <1997T8927, 1995JA10391, 1995ACA107,
2003JOC7143> or after the pinacol rearrangement <1997CC2263, 2000JOC4864>.
Finally, in order to demonstrate once more the importance of the stability of the products in
such equilibrated rearrangements, an example of vinylogous retropinacol rearrangement
<1999EJO3413>, allowing the transformation of the ingenane to the tigliane skeleton through
mild acidic treatment, is shown in Equation (17) (in contrast, for an example of vinylogous
pinacol rearrangement suppress see also reference <2000JA10282>). For a similar spontaneous
pinacol rearrangement of a strained polycyclic structure driven by the stability of the product
formed, see also <1998TL7005>.
H O+ HClO4, MeOH
MeO – H H ð17Þ
OH
49%
O
HO HO OH HO HO OH
HO HO
1.09.1.2.3 Rearrangement of epoxides

The rearrangement of epoxides, like the pinacol rearrangement, proceeds via protonation or
Lewis acid complexation of the oxygen atom of the epoxide ring and produces a carbocation,
which thereafter rearranges through migration of one substituent of the epoxide ring to finally
lead to the formation of a new CC or CH bond to a carbonyl group (Equation (18)).
R3 R2 R1 R2 R2 R1 R1 R3 R1 R4
R 4 R1 R 4
R 4
R2 R 2 ð18Þ
O R3 O R3 O R4 O R3 O
The choice of the experimental conditions is crucial to determine the outcome of the reaction.
Indeed, the presence of nucleophilic species may inhibit the occurrence of a rearrangement and
preferentially lead to the nucleophilic ring opening of the epoxide. Particularly, in the case of
protic acid, the conjugate base may act as a nucleophile. Even in the absence of nucleophiles, the
presence of additives may also prevent the rearrangement <2002TL2851>. When the rearrange-
ment is observed, the regioselectivity and the stereoselectivity of the reaction follow the same rules
as in the related pinacolic rearrangement, depending on the migrating aptitudes of the substitu-
ents of the epoxide <1998JOC2699> but may also depend on the experimental procedures
<2001JOC8779>.
In rigid structures, the stereochemical requirements for substituent migration may also influ-
ence the outcome of the reaction as depicted on Scheme 10 for isomeric cyclohexene oxides 17
and 18. In the same experimental conditions, axial cleavage of the epoxide ring is preferred
leading through intermediates 19 and 20 either to the cyclopentyl methyl ketones 21 and 22 or
to the acyclic methyl ketone 23 derived from a Nametkin-like rearrangement (Section 1.09.1.2.1)
followed by the fragmentation of the six-membered ring in order to allow formation of the
carbonyl group. However, the selectivity of the reaction can be managed by changing the Lewis
acid catalyst as indicated <1998JCS(P1)2569, 2002JCS(P1)1581>.
AcO
Et O
21
O
AcO
+
AcO O
19 [LA] O OAc
17
[LA] 23
Et +O
O
AcO
AcO
18
20
AcO
O
22
Substrate [LA] 21 22 23
17 SnCl4 70%
17 BF3·Et2O 31% 54%
18 SnCl4 14% 59%
18 BF3·Et2O 44% 49%
Scheme 10
Nevertheless, as this reaction does not proceed by a strictly concerted mechanism, the stereo-
chemical course of the rearrangement may depend on the stability of the isomeric products
potentially formed. This assessment is particularly true when stabilized carbocations are formed
through the opening of the oxirane ring. As an example, treatment of isomeric epoxides 24a and
25a, derived from carvone, with boron trifluoride etherate results in the formation of a unique
cyclopentyl derivative (Equations (19) and (20)). The configuration of the rearranged product is
clearly a consequence of the minimization of the steric interactions between the different substitu-
ents during the formation of the five-membered ring, since the related oxiranes 24b and 25b both
rearrange to a mixture of isomeric cyclopentyl derivatives (Equations (21) and (22)) <1999TL7969,
1999JCS(P1)3393>. Alternatively, the concerted mechanism seems to be preferred in some cases
(particularly when the migrating group is a hydrogen) giving formal inversion of configuration at
the migration terminus as exemplified in the 1,2-hydrogen shift (Equation (23)) <1997S1381>.
O
O BF3·Et2O, CH2Cl2, –78 °C,
ð19Þ
85% OBn
OBn
24a
O
ð20Þ
Yield not given OBn
OBn
25a
O O
OBn ð21Þ
Yield not given OBn
OBn
24b 84:16
O O
ð22Þ
Yield not given OBn OBn
OBn
25b 63:37
O
O
O BF3·Et2O ð23Þ
O
56%
H OH H OH
As outlined at the beginning of this section, the use of a Lewis acid as catalyst in this type of
epoxide rearrangement has mainly replaced the use of other acidic conditions (Brönsted acids).
Different studies have been devoted to the study of the scope of epoxide rearrangement promoted
by bismuth- <2001TL8129, 2000TL1527> or antimony-derived Lewis acids <1998JCS(P1)2569,
2002JCS(P1)1581>.
As a consequence of the use of Lewis acids in the initial carbocation formation, one may
assume that the presence of nearby chelating groups may have a dramatic influence in the
outcome of the reaction. Particularly, the presence of a free hydroxy group on an eventually
migrating group may induce a different behavior compared to that obtained with a protected
hydroxy group. In the example shown, substrates can undergo either epoxide rearrangement or
carbocyclization due to the presence of the allyl silane moiety (Scheme 11). Authors report the
dramatic influence not only of the epoxide configuration but also of the protecting groups of both
the primary and the secondary hydroxy groups, which should be related to the formation of cyclic
transition states through possible chelation of the boron atom by the oxygens of the molecule
<2001JCS(P1)789>.
TMS CO2Et CO2Et

BF3·Et2O
CH2Cl2
TBDMSO TBDMSO
O 80%
HO OH
OH
TMS CO2Et TMS CO2Et
BF3·Et2O
CH2Cl2
TBDMSO TBDMSO
O 31%
OH
O
OH
TMS CO2Et CO2Et
BF3·Et2O TMS CO2Et
CH2Cl2
TBDMSO TBDMSO
TBDMSO
O
OTBDMS
O HO OTBDMS
OTBDMS
17% 62%
TMS CO2Et BF3·Et2O TMS CO2Et
CH2Cl2
BnO BnO
78%
O OH
O
OH
Scheme 11
An important feature of the rearrangement of epoxides is the use of epoxides of enol ethers.
This strategy leads to the formation of -hydroxy carbonyl compounds equivalent to the result of
the oxidative ring opening of epoxides <2000CCC490> but with a rearranged carbon skeleton.
This methodology allows, for example, an easy entry to the salvialane skeleton starting from an
eudesmanolide enol ether epoxide derived from santonin <2001TA1459> (Equation (24)).
Furthermore, the rearrangement of epoxides derived from 1,2-dihydroxy alkenes, obtained by
the 1,4-dioxene chemistry, allows an easy route to monoprotected 1,2-diketo-building blocks
(Equation (25)) <1995TL6475>.
ZnBr2, CH2Cl2 O
O H
87% O ð24Þ
O O
O O H
O
O
O
MOMO O
Dimethyldioxirane
MOMO
H3COOC O acetone
O ð25Þ
84% CHO
O
H3COOC
1.09.1.2.4 Semipinacol rearrangement

As anticipated in the previous sections, the semipinacol rearrangement has been, when possible,
preferred to the pinacol rearrangement, due to the complete control of regioselectivity. The
purpose of the semipinacol rearrangement is to induce a differentiation between the two putative
reactive centers of the substrate, where a carbocation can be formed (Equation (26)).
R3 R2 R4 R1 R3 R1
R4 R1 R2 R2 ð26Þ
RO X O R3 O R4
In this rearrangement, the regioselectivity of the initial carbocation formation is controlled

through the difference in leaving aptitude of the OR and the X groups, and the selectivity
in the migrating group is, as in the previous cases, controlled by the migrating abilities of
the substituents R3 and R4. The X group may be either an amine (Tiffeneau–Demjanov
rearrangement or aza-pinacol rearrangement <2002CC134, 2000JOC5693>) or an oxygen-
derived leaving group. In this latter case, two major pathways have been designed consisting
in either formation of a sulfonic ester of the hydroxy group (Ts, Ms, or Tf) or in the
incorporation of the oxygen atom in a cyclic structure. An alternative strategy is also, while
X remains a free hydroxy group, to use a suitable protecting group R for the hydroxyl group
so that it will be transformed into the keto group.
The more obvious strategy is the formation of a sulfonic ester of the hydroxy group. This
strategy indeed allows a good control of the regioselectivity of the initial carbocation forma-
tion since both hydroxy groups may have a different behavior upon esterification. This
is the case with a secondary hydroxy group vicinal to a tertiary one <2001T4705,
1997JCS(P1)1707>.
As an example of this possibility, this semipinacol strategy has been used in tandem with the
Kulinkovich reaction to afford a general and easy access to -substituted cyclobutanones from
hydroxyesters (Equation (27)) <2000OL1337>.
H
OH MsCl, Pyr ð27Þ
72%
O
OH
It is important to note that this strategy may invert the regioselectivity that would have
been the result of the pinacol rearrangement through formation of the more stable carbo-
cation. This discrepancy has been observed in the case described in Scheme 12
<2000JOC7786>. A pinacol-like rearrangement may be effected through acidic treatment
(HBr) of 26 leading, due to these drastic experimental conditions, to the formation of the
tertiary carbocation, which thereafter rearranges through either proton migration (compound
27) or alkyl migration 28 <1999TL6947>. Meanwhile, a semipinacol rearrangement may also
occur when 26 is treated under Mitsunobu conditions. In this case, the secondary carbocation
is formed, leading exclusively to the formation of ketone 29. Noteworthy, this set of condi-
tions is obviously only valuable when one of the hydroxy groups is protected. Indeed, when
the same reaction is carried out on diol 30, a mixture of 27 and 29 is formed through an
uncontrolled pinacol rearrangement.
The TsOH-initiated semipinacol-like rearrangement of bicyclic substrates incorporating a
tertiary methoxy group to a secondary alcohol has also been the key step for the synthesis of
some natural sesquiterpenes <2001TL699, 2002TL265>.
An interesting result has been found in this type of rearrangement, the diol subunit involved
in the semipinacol rearrangement being the result of the Mukaiyama addition of bis-trimethyl-
silyloxy-cyclobutene on dioxolanes and the semipinacol rearrangement leading to the formation
of cyclopentadiones (Equation (28)), which may undergo further annulation reactions
<1995JOC337>.
H H
Pinacol-like H H
H CHO
HBr
O
27 28
H
O 51% 22%
H
OH
26
Semipinacol O
H
DEAD, PPh3
H 29
69%
1,2-H shift Alkyl migration
H Pinacol
OH 27 29
DEAD, PPh3 40% 55%
OH
30
Scheme 12
TMSO OTMS TMSO

O O BF3·Et2O, CH2Cl2
O
58% O OH
ð28Þ
O
O
An alternative strategy widely used in the semipinacol rearrangement consists in incorporating

one of the oxygen atoms in a cyclic ether, which may be either an epoxide <2000OL1193,
2002TA395, 2000JCS(P1)3791, 1999TL2149>, an oxetane <1999JOC8041>, or a tetrahydrofuran
<1995JOC2526, 1996T14147> (Scheme 13).
O OH
BF3·Et2O
O
CH2Cl2
81%
OTMS
O
OEt
TfOH, CH2Cl2, –78 °C to rt
O
88%
HOH2C
But
O TiCl4, toluene, –78 °C
But 70% Ph OH
Ph OTMS O
Scheme 13
The use of a chiral Lewis acid, which may allow in some cases a kinetic resolution of the
starting material, is noteworthy <2002TA395> (Equation (29)).
Ph OH Ph OH O
Ph Ph Ph
Ti(OiPr)4/(R)-BINOL (2.5 equiv.)
Ph ð29Þ
O O
PhCH3
OH
63% conversion
94% ee 60% ee
A very promising solution to promote a semipinacol-like rearrangement involves the formation

in acidic conditions of either a cyclic oxonium or an iminium ion, which undergoes rearrangement
(Equation (30)).
n O
n
() () n
OH OH ()
X X ( )n
( )n + () X ð30Þ
n
n = 1, 2
X = NTs, O
This methodology has been used for the synthesis of some spirocyclic systems and the
stereochemical outcome of the rearrangement has been fully investigated. In the case of the
rearrangement involving an oxonium ion, cyclobutyl and cyclopentyl carbinols underwent ring
expansion by using camphorsulfonic acid <1996JOC1119, 1997JOC1702, 1997JOC1713,
1995JOC191> (Scheme 14) and grindelic acid 31 was synthesized in a stereocontrolled fashion
<1995TL6005>. When X is a nitrogen atom the corresponding rearrangements, involving an
iminium ion, are expected to be more difficult <2001OL2109>. Indeed, cyclobutyl carbinols
undergo an easy ring expansion due to the ring strain (HCl) while cyclopentylcarbinols only
afforded degradation products. However, when the double bond of the starting material is
transformed to an epoxide, the reaction proceeds smoothly to afford the expected spirobicyclic
compound (Scheme 15). For other related examples of semipinacolic rearrangements, see
Chapter 1.18.
HO
CO2H
O O O O
CSA
52%
Major isomer Grindelic acid 31
OTIPS OTIPS
TIPSO
CSA, CH2Cl2, rt
O O
O
HO 81%
OTIPS OTIPS
TIPSO TIPSO
O CSA, CH2Cl2, rt
O
HO O
58%
Major
Scheme 14
Ph Ph
O
OH HCl, CH2Cl2, rt
N 93% N
Ts Ts
Major
TBSO i. DMDO, acetone OH

TBSO O
OH ii. TiCl4, CH2Cl2
N
94% N
Ts
Ts
Scheme 15
1.09.1.2.5 Favorskii rearrangement

The nucleophilic Favorskii rearrangement involves a similar 1,2-migration of a substituent as an
anion, but, in this case, the initial carbocation is formed from an -haloketone in basic conditions
(Equation (31)). This rearrangement, which may also occur in a modified version <2002OL957>
in biosynthetic processes, has been used in syntheses of natural products <1996TL1463,
1998JCS(P1)3689> due to its ability of inducing ring contraction in cyclic ketones <1995JOC3414>.
O O
X NaOR4 R3
3
R1 4
R1 ð31Þ
R R O
R2 R2
Even if the scope of this rearrangement has been extensively studied, its mechanism remains
debated <1997JA1941, 2001JPC2453> in order to explain the regiochemical outcome of the
reaction, particularly in the case of -haloketones presenting a hydrogen atom in the 0 -position
of the carbonyl group. Two mechanisms are generally accepted and are called the semibenzilic
acid mechanism (Equation (32)), also referred to as the quasi-Favorskii rearrangement and the
Loftfield mechanism (Equation (33)).
–
O O O
X NaOR4 X R3
R1 R1 R1 ð32Þ
R3 R4O R4O
R3
R2 R2 R2
O R3
R1
– R4O
O O O
X NaOR4 X R2
R3 R1 R3 R1 R3 R1
ð33Þ
R2 O
H R2 R2
R3
R4O
R1
R2
The semibenzilic rearrangement involves at first a nucleophilic attack of the alkoxide on the
carbonyl carbon atom of the -haloketone followed by a concerted displacement of the halide ion
by the 1,2-migration of an alkyl group. Alternatively, the Loftfield mechanism involves the
formation of the enolate, which is thought to be followed by the cleavage of the carbon–halide
bond to form the corresponding cyclopropanone. Then, cleavage of the cyclopropane ring is
assumed to occur to form the more stable carbanion that is responsible for the final regiochemical
outcome of the rearrangement. The Loftfield mechanism is preferred in the case of 0 -enolizable
ketones, while the semibenzilic is operative in the absence of 0 -hydrogens or in the case where the
formation of the cyclopropanone is prohibited due to structural features.
Moreover, one also has to consider the stereochemical outcome of the reaction from this mechan-
istic point of view. Indeed, the Loftfield mechanism, involving an oxyallyl cation, may result in the
formation of a mixture of isomers, while the concerted quasi-Favorskii rearrangement will result in a
formal inversion of configuration at the carbon originally bearing the halogen atom. In fact, it has
been demonstrated, as reported in the corresponding chapter of the COFGT (1995), that the polarity
of the solvent used in the experimental procedure should influence the mechanistic pathway
<1995COFGT(1)377>. Both mechanisms have therefore to be taken into consideration.
However, the quasi-Favorskii rearrangement may be achieved through a sequential pathway
involving at first the 1,2-addition of an appropriate nucleophilic species on the carbonyl group,
followed by treatment with a base leading, through migration of an alkyl group, to the formation
of an aldehyde or keto group (Scheme 16) (the nucleophilic species can be either a hydride
(Equations (34) and (36)) or an organometallic reagent (Equation (35)).
O OH O
X X R3
R 1 Nu – R1 Base R1
R3 Nu 3
Nu
R
R2 R2 R2
Scheme 16
TBDMSO LiAlH4,THF, then TBDMSO

O KH, THF O
H Br H ð34Þ
46%
O O
MeLi, then
O KH, THF O
Br ð35Þ
47%
O O
LiAlH4, THF CH2OH

Br ð36Þ
O
98%
This version of the Favorskii rearrangement has been used on several haloketones and included as
a key step in the synthesis of natural products <2001TL5593, 2001OL2533>. It has also been used
either in the case of unsymmetrical ketones, the asymmetry of which was not expected to induce
a regiochemical control in a normal Favorskii rearrangement <1999TL1075> (Equation (35)),
or in the case of nonenolizable ketones <2002TL2347> (Equation (36)).
In the normal Favorskii rearrangement, the regiochemistry is mainly controlled through the
stability of the anion formed, which may be managed either by the difference of the substitution
patterns of the - and 0 -carbon atoms or by the presence of electron-withdrawing groups. The
presence of an acetal moiety can be responsible for the complete regioselectivity of the rearrange-
ment <2002JCS(P1)1297> (Equation (37)).
O O
NaOMe, O
OTs
OTs O CHCl3 O
O or ð37Þ
OTs O 44%
OTs COOCH3
OTs O
O
OTs
OTs
It is important to note, in this example, the use of the tri-tosylate moiety as a haloketone
equivalent in the Favorskii-like rearrangement.
In the same area, it has been demonstrated that sulfonyl azides may induce a Favorskii-type
rearrangement of benzocyclic -keto esters with loss of a molecule of nitrogen, through a triazole
intermediate (Equation (38)) <1998JOC4679, 1999JOC5132>. In this case, however, the nature of
the sulfonyl azide has a considerable influence on the nature of the product of the reaction, due to
their ability in forming the triazolic adduct and in inducing different fragmentation pathways for this
adduct or by performing preferentially a simple diazo-transfer with fragmentation of the cyclic structure.
RO2S HN SO2R
4-Nitrobenzenesulfonyl azide N
EtO2C –
N CO2Et
THF, Et3N O N O
CO2Et ð38Þ
O 75%
The experimental procedures encountered in the field of the Favorskii rearrangement are mainly
based on the classical use of alkoxides of group (I) metals but this rearrangement may also occur under
electrochemical <1997T4427, 1996TL5759> or photochemical <1997T16789> conditions. In some
cases, the use of non-nucleophilic bases is reported to induce Favorskii-like rearrangements (vide infra).
One may also consider the possibility of generating the enolate intermediate through
1,4-addition of an appropriate species on ,-unsaturated 0 -haloketone. This possibility should
offer the access to cyclopropanones, since the nucleophilic species used in the 1,4-addition step
would not be able to induce fragmentation of the cyclopropane ring. This possibility has been
exemplified in a sequential Favorskii, quasi-Favorskii-like sequence using cyanide as nucleophilic
species <1999JOC2667> (Equation (39)).
–
CN
Br O
Favorskii
O KCN, NCOC
Br MeCN–H2O
Br
quasi-Favorskii ð39Þ
80% NC NC
CN –
Alternatively, the cyclopropanone may be cleaved intramolecularly by an appropriate nucleo-

phile. It is the case when another enolizable ketone is present in the molecule and the rearrangement
achieved in non-nucleophilic basic conditions <1995JOC554>. In the example depicted in Equation
(40), the rearrangement is initiated by the DBU-induced formation of the enolate of one keto group
of the symmetric starting diketone and the cyclopropanone is thereafter opened in an intramole-
cular fashion by the enolate of the other carbonyl group, thus affording the more stable carbanion.
Br Br Br
O
O O O– Br
DBU, THF
ð40Þ
48%
Br O O O O
1.09.1.2.6 Wolff rearrangement

The Wolff rearrangement is the rearrangement of an -diazoketone-derived carbene, leading,
after quenching by an appropriate nucleophilic species, to the corresponding acid derivative as
depicted in Equation (41). The whole process involves the formation of a new CC bond to a
carboxylic acid group. This method has extensively been used for the homologation of carboxylic
acids (R1 = H, Nu = H2O) and referred to as the Arndt–Eistert synthesis <2001TL7099,
1995AG1217, 1996LA1121, 1998S837, 1997TL6145, 1997IJC(B)1103, 2000S395>. The mechanism
of this rearrangement has also been studied to know to what extent the nitrogen elimination and
substituent migration were concerted or not, allowing or not the trapping of the carbenoid
intermediate particularly under photochemical conditions (Scheme 17) <1999JCS(P2)1107,
1999JA2883, 1999JA5930, 1996JA12598, 2001JA6061, 2001JA6069>.
O
R2 Nu– R2
N2 C O C O
R2
R1 R1 Nu ð41Þ
R1
(Nu– = RO–, HO–, R3N–)
O
R2 R2
N2 C O CO2H
R2
R1 R1
R1
O O
R1 R1
R2 R2
N2
Scheme 17
The Wolff rearrangement is usually initiated through treatment of a diazoketone by either

rhodium <1998JOC9828, 1997T8501, 1996T10455, 1999CC1199, 1997TL1397, 2002OL873,
2001TL8455, 1999TL8219>, chromium <1997T7557>, or silver salts <1998JCS(P1)1919,
1998S837>, but may also be achieved either under microwave activation <2002JOC1574>,
photochemical conditions <2001JOC2611, 1998JOC8380, 2002OL2465, 1999JCS(P1)1207,
2000TL4053, 1998TL7541, 2001JCS(P1)2194, 2000OL2177, 2003OBC2556>, by heating
<2001JCS(P1)2266, 1999TL8219, 1995TL7859>, or ultrasound activation <1998S837>. The
rearrangement may also be induced, in the case of the particular aza-Wolff rearrangement by
HBF4 <2001EJO3705> through the rearrangement of the diazonium salt (Equation (42)).
CO2Et CO2Et CO2Et
MeOH
60 °C
ð42Þ
N+ N 57% N
+
N2 N2 BF4–
BF4– O COOCH3
O
Alternatively, the starting diazoketone may be obtained either by addition of diazomethane or

trimethylsilyl diazomethane to the corresponding acid chloride but may also be synthesized by
azide transfer using azide sulfonates <2001JCS(P1)2194, 1998JOC4679, 1999JOC5132,
2001TL8455, 1996T6665>.
As the product of the rearrangement, in the case of the ring contraction of cyclic ketone
exhibits an exocyclic carbonyl group, an additional decarboxylation may also occur after the
rearrangement. It is the case of cyclic 2-diazo-1,3-dicarbonylated compounds used for the pre-
paration of substituted oxindoles, as depicted in Scheme 18 <1999TL8219>.
MeO MeO MeO

O O Rh2(OAc)4
MsN3, DMF MeCN, reflux
N2
N Yield not given 87% N O
N
O O
Scheme 18
The stereochemical outcome of the rearrangement (R1 ¼ 6 H) has been studied and proved to be very
dependent on the experimental conditions. The best results were obtained when the Wolff rearrange-
ment was performed under photochemical conditions at low temperature <2000OL2177>.
Important features nevertheless arise from the recent developments of the Wolff rearrangement.
The first one is the possible intramolecular trapping of the ketene intermediate. Indeed, the presence
of an extra amino group in the molecule may be used for such purpose, leading to the correspond-
ing lactams. This modification of the Wolff rearrangement may be effected through a classical
Arndt–Eistert protocol <1998JCS(P1)1919> (Scheme 19), or as a possible ring-expansion of
-lactams <1998TL7541>. In this latter case, addition of trimethylsilyl diazomethane led to the
acyclic -amino-0 -azido ketone, which thereafter undergoes Wolff rearrangement and an intramo-
lecular amidation (Scheme 20). The outcome of the transformation nevertheless depends on the
nature of the starting material, and better results are obtained when -lactams are formed.
i. (COCl)2
O
HO O ii. CH2N2, Et2O
iii. PhCO2Ag, Et3N, THF C O
H
N HN Ts N Ts
Ts 42%
Scheme 19
TMSCHN2
NaN(TMS)2 Ph Ph
Ph hν (UV)
THF, –78 °C PhH
HN CBz N CBz
N 81%
O CBz O 81%
N2 O
Scheme 20
The second important feature of the Wolff rearrangement is to induce the formation of ketene
derivatives, which can be involved in other reactions <2003T3545, 2001JCS(P1)2266, 2001JOC2611,
1997TL1397>. It is especially the case when starting from -silyl -azido ketones <1999CC1199>.
Indeed, the silyl ketene intermediates are relatively stable <1998JCS(P1)2105> and may be, for
example, engaged in cycloaddition reactions <1998JOC8380, 2002OL2465> (Scheme 21).
O OH
hν (300 nm) O i
N2 PhH
i
(Pr )3Si C PhCH3, 150 °C (Pr )3Si COOCH3
Si(Pri)3 79%
H3COOC COOCH3
COOCH3
95%
Scheme 21
However, due to the particular structure of the starting material or the conditions used, a
competitive reaction may take place between the Wolff rearrangement and other reactions
involving carbene chemistry (insertion reactions, etc.) <1996T10455, 1999JPC7145, 1998T6457,
1998JOC9828, 1997T8501>.
1.09.1.2.7 Westphalen–Lettre´ rearrangement of steroids

It is worth noting that the well-known Westphalen–Lettré rearrangement of 5-hydroxy-steroids,
discovered in the early 1910s and involving dehydration (9,10-double bond formation) and
migration of the methyl group at C-10 to the carbon atom at C-5 with inversion of the config-
uration at C-5, is still being used in some studies devoted to biological activities of modified
steroid derivatives <1996CCC276, 1998CCC1549> (Equation (43)).
OBz OBz
H H
H2SO4, MeOH ð43Þ
H H 48% H
BzO BzO
OH
1.09.1.3 Substituent Migrates as a Radical
1.09.1.3.1 [1,2]-Wittig rearrangement

The [1,2]-Wittig <2001EG(E)1411> rearrangement corresponds to the 1,2-alkyl migration of an
-metallated ether (Equation (44)). This type of 1,2-alkyl migration is now well recognized to
proceed via the radical cleavage–recombination pathway with slight inversion of the configuration
at the carbon bearing the metal atom <1996JA3317, 1998JOC9756>. The scope of this rearran-
gement has been widely reviewed <1997LA1275>. In the gas phase, the same rearrangement has,
however, been demonstrated to be an anionic reaction <1998JCS(P2)1435, 1999JCS(P2)333>.
Important variants of this rearrangement have also been reported, including the rearrangement of
lithioalkyl vinyl ethers <2000CL418> (Equation (45)), 1,2-carbamoyl migration <1999CL759,
1996TL6061> (Equation (46)), and imino rearrangement of hydroximates <1999SL1915>
(Equation (47)).
M M R1 R1
ð44Þ
R1 R1 M
R2 O R2 O R2 O R2 OH
BunLi, THF, TMEDA

–78 to –25 °C ð45Þ
Ph O 59% Ph OH
CH(CH3)2
Bu3Sn O BunLi, Et2O M O N
O CH(CH3)2
CH(CH3)2 –78 °C ð46Þ
O N CH(CH3)2
O N OH
CH(CH3)2 46%
Ph CH(CH3)2
Ph Ph
OMe N OMe
N LDA, THF, –78 °C
O 82% HO ð47Þ
O
O
In contrast with the already-presented rearrangements, the scope and limitations of the
[1,2]-Wittig rearrangement are not only deduced from the migratory aptitude of the migrating
group but also from structural requirements at the carbon atom bearing the metal. Indeed, if
the migratory aptitude of the migrating group is roughly consistent with the stability order of
the corresponding radical, experimental observations reveal that a radical-stabilizing factor at the
carbon atom bearing the metal is required for the rearrangement. This means that the rearrange-
ment requires a good complementarity between the migratory aptitude of the R1 group and the
anion-stabilizing ability of the R2 group.
As an illustration of these findings (Scheme 22), upon transmetallation stannane 32 and 33 do
not undergo rearrangement, while stannanes 34 does.
SnBu3 Ph
BunLi Li
Ph O
Ph O HO
32
SnBu3 Li
BunLi
O C7H15 Ph O C7H15 HO C7H15
33
SnBu3 n Li Ph
Bu Li
Ph O Ph O HO
34
Scheme 22
Although the benzyl group remains the best migrating group in this rearrangement, its applica-
tion is relatively restricted. Furthermore, the use of an allyl moiety for the formation of the initial
carbanion (-oxyallylic carbanion) induces side reactions such as the formation of 1,4-products
prior to the desired 1,2-ones or competitive [2,3]-Wittig rearrangement <2002EJO478,
2003TL373>.
Alternatively, some stereochemical problems are related to the outcome of the rearrangement.
Many studies have been devoted to the rationalization of the stereochemical outcome of the
[1,2]-Wittig rearrangement <1997TL8939, 2001TL4865, 1998JA8551>. The most adopted asser-
tion, particularly in the case of rearrangement induced by transmetallation of chiral compounds,
advocates retention of configuration for the migrating group and inversion of configuration at the
metal-bearing carbon atom as depicted on Scheme 23. However, as this is not a concerted
mechanism, the stereochemical outcome of the reaction mostly depends on the reaction condi-
tions and on the presence, in the starting material, of an oxygenated function able to chelate the
metal atom in the transition state (Equation (48)) <1998JA8551>.
1 HO R3
M R3 R R2
O R2
Inversion
R1
Retention
Li
Li R3 R
1
R3 R1 O R1
R3
O R2 O R2 R2
Li
Scheme 23
H OH O HO H O
Bu3Sn H Ph O O
O O Ph Ph
Inversion Retention ð48Þ
O
BunLi, THF/hexanes (10:90), 47% 32:68

BunLi, LiCl-saturated THF, 79% 63:37
In a similar manner, the use of external chiral ligands may induce asymmetry in the rearrange-
ment of achiral ethers <1999AG(E)3741> (Equation (49)).
t
i. Bu Li / L*, Et2O, –78 °C
+ Ph
ii. H3O
Ph O Ph
90% Ph OH
ð49Þ
62% ee
O O
L* = N N
An interesting ring-contraction reaction has been reported in the case of cyclic bisallyl ethers
(Equation (50)) <1996JA10766>, the regioselectivity encountered in this rearrangement being
attributed to the relative acidity of the different allylic hydrogen atoms.
OH
O
BunLi, Et2O
ð50Þ
–78 to 0 °C
O TBS 92%
O TBS
Examples dedicated to the [1,2]-Wittig rearrangement with aryl migration <1996TL8903>,

which are related to the rearrangement of lithioalkyl vinyl ethers <2000CL418>, have also
been reported <2002OL1587>.
In order to alleviate the drawbacks of the classic [1,2]-Wittig rearrangement, most examples
now involve the rearrangement of acetals. Indeed, the relatively large stability of the -oxy radical
allows them to induce easy [1,2]-Wittig rearrangement. Moreover, the easy preparation of the
mixed acetals allows a facile access to the starting material of the reaction. The structural
requirements <1999TA4811> as well as the influence of the reaction conditions
<2000TA1003> have been studied.
In the same field, the rearrangement of acetals of O-glycosides has been used to allow the
preparation of the rearranged C-glycosides <1996JA3317, 2000AG(E)4500, 1995SL321>. In
this case, retention of configuration, generally observed in the migrating radical, allows the
configuration of the C-glycoside to be fixed in the starting material by the anomeric config-
uration. This version of the [1,2]-Wittig rearrangement has been used in total syntheses
including the synthesis of zaragozic acid <1999TL1917, 2000AG(E)4502> (the key step of
the synthesis (Scheme 24) allows the stereocontrol of two vicinal quaternary stereocenters in
a [1,2]-Wittig rearrangement). An example of [1,2]-thio-Wittig rearrangement has also been
reported <1996JA1398>.
TBDPS TMS TBDPS
OH
O TMS
O BunLi, THF, –78 °C O
BnO BnO
54%
TBSO OTBS TBSO OTBS
68% de
O
O OH
HO
HO2C O Ph
HO2C O
CO2H
OH
Scheme 24
1.09.1.3.2 [1,2]-Stevens rearrangement

As with the [1,2]-Wittig rearrangement, the Stevens rearrangement involves the 1,2-migration of a
group attached to an heteroatom. The initial step of the rearrangement involves the formation of
an ylide (generally ammonium, oxonium, or sulfonium). The 1,2-shift thereafter occurs via a
radical cleavage of the CX bond followed by a recombination (Equation (51)). As for the Wittig
rearrangement, the configuration of the migrating group is retained. The mechanism of this
rearrangement has been studied, particularly in the case of the rearrangement of ammonium
ylides <1996JOC7276>, and the absence of competition with a concerted pathway or the forma-
tion of ion pairs has been demonstrated. The asymmetric version of the rearrangement of ylides
has been reviewed <1997CR2341>.
R3 R3
R3
– R3 2 – + 2 2
+
R R R R2 ð51Þ
R4 X R4 X R4 X R4 X
R1 R1 R1 R1
Most of the recent advances in the field of the Stevens rearrangement, as well as in other related
ylide reactions, involve new methods for the formation of the starting ylides based on the use
of carbenes from diazo compounds, the features of which have been reviewed <2001CSR50,
1998CR911>.
(i) Rearrangement of ammonium ylides

In the original work of Stevens in the 1930s, the authors mainly reported the rearrangement of
ammonium ylides, and for many years, most of the research in this field has been devoted to this
type of rearrangement, especially due to the easy access to the starting materials. The main
experimental procedures involve treatment of the ammonium salt either with a group (I) metal
or with metal alkoxide or amide <2001AG(E)3810, 1997JCS(P1)1491>. However, most of the
reported Stevens rearrangements of ammonium ylides now use carbenes generated from diazo-
ketones, which allow a one-step procedure <1998TL4159, 2001JOC2414, 1996TL615> involving
metallo-carbenoid generation/ylide rearrangement cascade <1997TL3319, 1997JOC78,
1998JOC556, 2000JA8155, 2003TL2895>. In this type of cascade sequence, the reaction is
effected by rhodium or copper acetate catalysts. This strategy has been used in the synthesis of
some alkaloids <1997T16565, 1995TL2519, 2001JOC2414, 1996TL2165>. In the example shown
(Equation (52)) <1997T16565>, the formation of the spirocyclic ylide is demonstrated to be
stereoselective under steric control and the rearrangement occurs with a partial retention of
configuration at the migrating center.
BnO2C O
H
N CO2Bn
+ –
N
Cu(acac)2 O
N CO2Bn 5
PhCH3, reflux
.. ð52Þ
N2 84%
95
O BnO2C O
N CO2Bn H
– +
O N
75% ee
Other sets of experimental conditions have been proposed including Mitsunobu conditions
(in the case of !-hydroxy amines) <1996TL8133> and caesium fluoride <1999JOC581>.
These new features ensure that the Stevens rearrangement of ammonium ylides remains a useful
tool in alkaloid synthesis, but it still suffers from the same drawbacks as other related rearrangements,
mainly the selectivity for the migrating group <1997TL2113> and competition with other rearrange-
ments (see Section 1.09.4.4.4—the Sommelet–Hauser and the [2,3]-Stevens rearrangement).
(ii) Rearrangement of sulfonium ylides

The rearrangement of sulfonium ylides has not been widely used but has also benefited from
advances using carbenoid chemistry under photochemical conditions as proven by the following
example of fluorenylidene diinsertion in the SS bond of an aryl disulfide through two con-
secutive Stevens rearrangements <1997TL8989> (Equation (53)).
hν, O2
– SAr
benzene + S Ar
N2
15% Ar
S
S+
Ar Ar S+
–
)2 ð53Þ
–
ArSSAr
(iii) Rearrangement of oxonium ylides

As another consequence of the use of diazo compounds for the formation of ylides, the rearran-
gement of oxonium ylides becomes easily accessible. In most cases, the diazo precursor and
the ether containing the oxygen atom that will be involved in the oxonium are present in the
same molecule and the whole process leads to the formation of an -substituted cyclic ether.
The reaction may, however, be achieved in a bimolecular fashion <1996T3905>. In this case, the
reaction provides a new method for the ring expansion of cyclic ethers with a good control of
the absolute configuration of the inserted carbon when performed in the presence of chiral ligands
(Equation (54)), without, nevertheless, kinetic resolution at the racemic migrating center. Asym-
metric induction can also be effected in an intramolecular process using chiral ligands
<1997TL4367>.
Ph
Ph t Ph t
CO2Bu CO2Bu
CuOTf-L* (1 mol.%)
O O
O t
N2CHCO2Bu
88% 59:41 ð54Þ
75% ee 71% ee
N N
TBSO L* OTBS
As in the previously reported related Stevens rearrangements, the migrating group is usually a
benzyl or an alkyl group but can also be a silyl group <1995TL4845>.
In contrast to the rearrangement of ammonium ylides, the oxonium species may be in some
cases trapped either in an intramolecular or in a bimolecular fashion by a dienophile species and
therefore involved in a [2+3]-reaction <1997TL3319>.
The rearrangement of oxonium ylides has also been studied in the case where the oxygen
atom involved in the anion is also included in a cyclic dioxolane <1996TL5053, 1997JOC2123>.
The result of the rearrangement has been proven to be largely dependent on the reaction
conditions, since acidic conditions allow a rapid addition of H+ to the initially formed oxonium
ion (Scheme 25).
Rh2(OAc)4
O CH2Cl2 O O O Stevens shift O
O O O O +
O
without AcOH
68% O
N2 [Rh] O
+ + +
O O + H (fast) O O
with AcOH
O O
– +
+AcO –H 46%
41%
O O O
AcO O
O O
Scheme 25
If the most often reported conditions used for the formation of the oxonium ion remain the use
of the diazo-derived cabenoid chemistry <2003JOC4531>, an interesting report has shown in the
case of 1-hydroxy 3-ynyliodonium ethers that the addition of p-toluenesulfinate on the triple bond
induces an intramolecular cyclization/oxonium formation. The so-formed oxonium thereafter
rearranges in a Stevens rearrangement (Equation (55)) <2000JOC8659, 2000OL2603>.
PhIOTf +
–
IHPhOTf
O
TsNa – O
Ts O O ð55Þ
O + O
O
THF
O Ts Ts
∆
43% 90% ee
1.09.1.4 Sigmatropic Rearrangements

This section deals with the sigmatropic shift of a -bond across one or more double bonds. These
rearrangements occur according to the Woodward–Hoffmann rules. In this section, a particular
interest will be devoted to the [2,3]- and [3,3]-sigmatropic rearrangements as they have become
major tools in the synthetic chemistry of complex natural products. Other sigmatropic rearrange-
ments, namely [1,3]-, [1,5]-, and [1,7]-rearrangements, will be just mentioned but will not be
discussed in detail since they are scarcely used.
1.09.1.4.1 [1,3]-Sigmatropic rearrangements

The migration of a carbon atom by a thermal [1,3]-sigmatropic rearrangement proceeds suprafa-
cially with inversion of the configuration at the migrating carbon atom. No major improvement
related specifically to this type of rearrangement has occurred since the publication of chapter
1.09.1.4.1 in <1995COFGT(1)377>. The rearrangement of vinylcyclopropanes to cyclopentenes,
which is to be considered as a [1,3]-sigmatropic rearrangement, has however found some new
applications <1999JA11018, 1999JOC3567> and has been recently reviewed <2003CR1197>.

The thermal (or anion assisted) [1,5]-sigmatropic rearrangements have found no further advances
since the publication of chapter 1.09.4.2 in <1995COFGT(1)377> . One may, however, consider
some research about the mechanism of related rearrangements <2003JPC5479> and their use in
the synthesis of natural products <1999OL161>.

The thermal [1,7]-sigmatropic rearrangements have found no further advances since the publica-
tion of chapter 1.09.4.3 in <1995COFGT(1)377>.

The [2,3]-sigmatropic rearrangement <2000MI535> is widely used in the formation of new CC
bonds via a suprafacial process. At first, carbanion formed in the position to a heteroatom and
the rearrangement thereafter occurs, involving a five-membered envelope-shaped transition state.
The rearrangement generally involves an allyl moiety but may be performed with either pro-
pargylic or benzylic <2001OL2529> frameworks (Equation (56)).
G
G
X ð56Þ
X
(i) [2,3]-Wittig
The corresponding rearrangement of ethers (X¼O) is known as the [2,3]-Wittig rearrange-
ment <2001AG(E)1411, 1995HOU(E21d)3757, 1995COFGT(1)793, 1997LA2005>. A DFT
study of the [2,3]-Wittig rearrangement has been published <2003JOC2310, 1997CL81>. The
scope and interest in this type of rearrangement are wide due to the possibility of obtaining a
good selectivity for the geometry of the double bond formed in the course of the reaction and
on the stereochemistry of the rearrangement, which is mostly dependent on the geometry of
the double bond of the allyl moiety in the starting material. The stereochemical features
depend on the nature of the G group and will be discussed in each case. Some of the variants
modifying the nature of the G group (Scheme 26) provide a diastereoselectivity higher than
95% of either syn- and anti-diastereomers. Alternatively, as the rearrangement involves a well-
defined transition state in a suprafacial process, transfer of chirality across the allylic system is
generally observed allowing the formation of enantiopure rearranged products starting from
chiral allyl alcohols.
During the 1990s, the number of communications on the [2,3]-Wittig rearrangement and its
application in organic synthesis has continued to grow <1997MI1, 2002SL923> and particular
emphasis has been given to the design of asymmetric rearrangements <1997PAC595,
2000CL1394, 1995CC2135, 2001OL2529, 2002T2253, 1995SL631, 1996S1438>. Moreover,
chiral auxiliaries may be used either in an intramolecular or bimolecular process to induce
chirality in the rearranged product, when the starting material does not incorporate asym-
metric centers <1995SL321, 1997TL2633, 1999EJO2713, 1995T10699, 1996T1503, 1997CC737,
1998CPB335, 1998SL1429, 1999T6847, 1998TL5513, 2000CHIR505, 1996H(42)423>
(Equation (57)).
R1 R2
R2 R1 R2
O (E )-threo
R1
O G HO G
G
R1
R1 R2
R2
O R2 (E )-erythro
R1
O G HO G
G
3 4
G = H, aryl, heteroaryl, vinylic, alkynyl, oxazolines, and oxamines, R–C=O, R –C=N(R )
CO2– , CO2R, CONR2, CN, PO(OR)2, SnBu3, SPh, SO2R, and SiR3
Scheme 26
ButLi / L* (1.5 equiv.)

hexane, –78 °C
O
87% HO
ð57Þ
O O
L* = >90% de
N 89% ee
N
A number of natural or non-natural products have been synthesized featuring a [2,3]-Wittig

rearrangement as a key step. This is the case of kallolide A and B <1995JOC796, 1996JOC5729,
1998JOC5962>, cryptophycin <1999JOC1459>, epipatulolide <1999TL475>, conagenin
<1999S243>, cyclohexane epoxide arthrinone <2000TL10013>, phomactins <2003TL2713>,
tetronic acids <2001TL5215>, [2,2]-metacyclophanes <1999JOC7140, 2003TL23>, dihydropyr-
enes <1999JCS(P1)403>, oudemansin A <1995SL869>, brefeldin 1 <1995SL901>, epibrefeldin
C <1996H(42)423>, amphotericin B <1995TL2789>, -lactone L-659,699 <1998H(47)671>,
acetogenins <1995TL4073>, enediynes <1996BSF987>, kedarcidin <1996H(43)945>, and
difluorinated analogs of eldanolide <2001MI43>.
The conditions for the formation of the initial carbanion depend on the nature of the G group.
This latter group is most often an anion-stabilizing group (acyl, aryl, allyl, propargyl, etc.), but
may also be an unstabilized alkyl group. In this case, the anion has to be formed either through
transmetallation of the corresponding stannane (this rearrangement is known as the Wittig–Still
rearrangement, Section 1.09.1.4.4.iv), reductive lithiation of O,S-acetals <2001TL415> or
through 1,5-hydrogen transfer from the allylic moiety of the molecule <1997JOC7542>.
This section will therefore be divided according to the nature of the G group.
(a) G as an alkyl group. As mentioned above, the [2,3]-Wittig rearrangement of unactivated
alkyl groups is possible upon several conditions.
An interesting possibility has been found <1997JOC7542> taking advantage of the samarium
iodide-promoted vinyl radical formation, starting from alkyl -halogeno-allyl ethers. The vinyl
radical initially formed thereafter undergoes 1,5-hydrogen shift in order to generate the oxyalkyl
radical, which is further transformed by samarium iodide into the corresponding carbanion,
which is then able to undergo a rearrangement (Scheme 27). In this case, the geometry of
the initial double bond obviously did not influence the stereochemical course of the reaction,
and the diastereoselectivity (R2 = H, R1 6¼ H) is in good correlation with the rearrangement of the
(E )-isomer although being relatively low (de = 20%).
Samarium iodide has also been used in order to promote the rearrangement of monothioacetals
<2001TL415> (Equation (58)).
OH
X R1 R1 X
R2 R3
O R3 O R3
R2 R2 R1
SmI2 erythro (major)
R1 R1
O R3 O R3
R2 R2
R1 R3 SmI2 R1 – R3
O O
R2 R2
SmI2
I
PhH/HMPA (9:1) OH
rt
O n-C9H19
n-C9H19
63%
Scheme 27
Ph SmI2, THF/HMPA OH
S
ð58Þ
C9H19 O 12% C9H19
The Wittig–Still rearrangement, however, continues to be the most widely used solution for the
formation and rearrangement of unstabilized oxyallyl carbanions (see Section 1.09.1.4.4.(iii)).
(b) G as an aryl or heteroaryl group. As mentioned in Section 1.09.1.3.1 for the [1,2]-Wittig
rearrangement, aryl groups, because of their ability of stabilizing a carbanion in -position, have
been widely used for such rearrangements. The benzyl group, as one of the best migrating groups,
has been used to test enantioselective induction in Wittig rearrangements <1995TL2789,
1998CC123>. Other aromatic groups have also been used, including furyl <2000TA4725,
1995CC2135, 1999CC2263, 2000TA4725, 2003JOC10183> and benzotriazole <1996JOC4035>.
However, due to their high migratory aptitude, the most critical feature to manage is the
selectivity between [1,2]- and [2,3]-rearrangements <2001OL2529, 2002EJO478>.
(c) G as an allyl group. Allyl groups have also been used in [2,3]-Wittig rearrangements,
although in this case, the regioselectivity of the formation of the initial carbanion has to be
carefully controlled. An efficient way to control the regioselectivity is to use either -phenyl or
-trialkylsilyl allyl groups <1997TL6445>. Alternatively, since the rearrangement of bis-allylic
ethers produces vinyl allyl carbinols, conditions may be carefully adjusted in order to either avoid
(BunLi, low temperature) <1999TL475> or induce a further anionic oxy-Cope rearrangement
(KH, 18-C-6, room temperature) <1997TL6445, 1997TL6449, 1997TL6453> (Equation (59)).
KH (2.5 equiv.)
18-c-6 (1.5 equiv.)
THF, rt ð59Þ
O Ph –
67% O Ph O Ph
100% (E )
An alternative method for the control of the regioselectivity of anion formation is derived from
the radical formation induced by samarium iodide starting from bisallyl acetals derived from
,-unsaturated aldehydes (Equation (60)) <1998TL5229>, in a similar process to that proposed
for the samarium iodide-induced rearrangement of thioacetals (Equation (61)).
SmI2 OH
O CH3CN O
ð60Þ
–
O 56%
Ph
S SmI2, THF/HMPA OH
ð61Þ
O 80%
(d) G as a propargyl group. The use of propargyl (or -trialkylsilyl propargyl) groups for the
formation of the carbanion to be involved in the Wittig rearrangement has been extensively
studied since it alleviates the drawbacks of regiochemistry of the bisallyl ether rearrangements and
produces in most case very good stereochemical control of the stereocenters formed in the course
of the reaction, according to the geometry of the double bond of the starting material
<2002EJO3465>. These important aspects of this type of reaction have prompted several teams
to use this version of the [2,3]-Wittig rearrangement as the key step in the total synthesis of
natural products. The double bond of the starting material may be incorporated in a carbocycle
<1995TL4073, 2000TL10013> (Equation (62)) or in an acyclic system <1999JOC1459>
(Equation (63)).
BunLi
TMS THF, –78 °C TMS O
O
ð62Þ
95%
O H
OH
BunLi
O THF, –90 °C
ð63Þ
71% OH
80% de
An exemplary application of this methodology to the total synthesis of natural products has
been proposed for the synthesis of macrocyclic pseudopterolides. This synthesis involves the ring
contraction of a macrocyclic allyl propargyl ether through a completely stereoselective Wittig
rearrangement, leading to the stereocontrolled formation of two adjacent stereocenters
<1996JOC5729, 1998JOC5962> (Equation (64)).
OSEM BunLi
THF/pentane, –78 °C OSEM
O
O ð64Þ
73%
HO
O
(e) G as a phosphorus-containing anion-stabilizing group. Phosphorus anion-stabilizing groups

have been envisaged to induce [2,3]-Wittig enantioselective rearrangements. Two methodologies
have been developed either by using phosphonates of chiral alcohols <1995TL6635> (Equation
(65)) or oxazaphosphorinanes with a chiral phosphorus atom <1995TL6631> (Scheme 28). In
both cases the diastereomeric excesses are very good, leading, after removal of the chirality
source, to highly enantiopure compounds. Phosphorus groups have also been used in the
Stevens rearrangement of sulfonium ylides <1996PS(112)193, 1996PS(109–110)445,
1999HAC281, 1998S1635, 2001SL605>.
O
O
BunLi, THF, –78 °C P
OH
P O O
O O
O 95% ð65Þ
92% de
O O
BunLi, THF
O
O
P –70 °C P
O
N N
OH
But 73% But
>99% de
O HO
BunLi, THF
P –70 °C P
O O O O
N N
But 88% But
>93% de
Scheme 28
(f) G as an hydrazone. In a similar manner, -oxo-alkyl allyl ethers can be converted into the
corresponding chiral hydrazones, which may thereafter undergo a Wittig rearrangement, leading
to the corresponding rearranged product with high enantiomeric excess after removal of the chiral
auxiliary <1996S1438, 1996T1503, 1999S243>.
(g) G as an oxazoline. Oxazolines, as masked acid equivalents, may be used for promoting the
Wittig rearrangement. Moreover, the easy access to oxazolinyl methyl allyl ethers through
alkylation of allyl alcohols by chloromethyl oxazoline allows this rearrangement to be used as
the key step in total synthesis. For example, this methodology has been successfully employed for
the synthesis of the unsaturated moiety of the sex pheromones of some Matsuccocus species
<1995TL7197, 1995T10433>. In this example, the stereoselectivity of the rearrangement can be
fully controlled according to the experimental conditions used (Equation (66)).
O
i. Cl N
OH HO HO HO HO
ii. Conditions O O O O ð66Þ
N N N N
Conditions: Yields:
KH, C6H6, rt, 32 h 72.1 23.6 12.5 11.5
BunLi, THF/HMPA, –100 °C, 0.5 h 93.6 6.4 0 0
(h) G as an acid, ester, or amide. Classically, acids (in a dianionic process <1997CC1469>) or
acid derivatives have been widely used in order to induce the [2,3]-Wittig rearrangement, even if it
has been generally reported that this rearrangement requires the use of additives (mainly
Cp2ZrCl2, TMEDA, or DMPU) to be stereospecific <1997JOC137, 1997TL2633>.
However, this methodology presents the possibility of using chiral acid derivatives in order to
induce an enantioselective rearrangement. The best results in this field have been reported using a
chiral amide <1997TL2633> (Equation (67)).
O
O (R )
N N O
O LiHMDS
HMPA (5 equiv.), THF, –78 °C OH
O ð67Þ
67%
(2(R )) >98%
88% de
(ii) Rearrangement of dienolates

In the particular case of Wittig rearrangements of acid derivatives, one may pay attention to
the potency of the rearrangement of allyl ethers of -keto esters (Scheme 29) <2001EJO483>,
which, by using a chiral ester, allows an efficient access to -hydroxy esters (Scheme 30) with, in
general, a satisfying control of the stereogenic centers. The stereochemical outcome of the
rearrangement, however, depends on the substituents <1999T2625, 2000SL415, 2003SL663>.
This rearrangement, providing vinyl allyl carbinols, may also be associated to a subsequent
oxy-Cope rearrangement <1999EJO2713>. This particular [2,3]-Wittig rearrangement of ester
dienolates has been reviewed <2003SL1088>.
R2 R1
R4 – R4
O O
O Wittig R3 CO2R Oxy-Cope R3 CO2R
O–
R3
R1 R2 R1 R2
R4 OR
Scheme 29
O O
O O
LDA, THF OH
O O
O
TIPSO 92% TIPSO
O–
O
SOCl2 LDA, THF O

O
O
Pyr/CH2Cl2 O 90%
89%
TIPSO
TIPSO
O
OH
O TBAF, THF
OH
59% O
OTIPS O
Scheme 30
An interesting report has also shown the use of dilithiated hydroxy--keto ester enolates to
allow a rapid and efficient [2,3]-Wittig rearrangement to occur without addition of polar solvents
or transition metal salts <2001TL5215> (Scheme 31).
OPMB OPMB
i. LiHMDS (2.5 equiv.), THF, –78 °C
ii. TMSCl (2.5–3 equiv.)
O iii. SiO2 O
O
O
O 89%
EtO
EtO
88% de
Scheme 31
In addition to these different examples of [2,3]-Wittig rearrangement, one may also consider
the possibility to perform such rearrangement with fluorine-containing compounds. This type of
rearrangement may give access to polyfluoro-compounds of biological interest, which would have
been difficult to obtain by using other methods involving fluorine chemistry <2000TL4591,
2001TL1317, 1996JOC166, 1995JOC9201, 1995CC1857>.
In conclusion, the [2,3]-Wittig rearrangement, because of its stereochemical characteristics, has
widely been used in synthetic strategies. If the enantioselectivity of the rearrangement may be
achieved in an intramolecular manner, as depicted in several examples above, the use of bases
derived from chiral amines has also been reported <1999T6847, 1998CC83>, yielding good-to-
excellent enantiomeric excess in the rearranged products (Equation (68)).
OH
BunLi, (–)-sparteine (2.2 equiv.)
O
pentane, –78 °C
NEt2 NEt2 ð68Þ
O 83% O
60% ee
(iii) [2,3]-aza-Wittig rearrangement

The Wittig rearrangement of allylamines has been reported and is quite similar in scope and
limitation to the already reported rearrangement of ethers <1995AHC159, 2001JCS(P1)267,
1997JCS(P1)1517, 2000JOC9152, 1996JOC4820, 1998TL2649, 1995CC1835, 1998JCS(P1)2817,
1997JCS(P1)2951, 2003JOC6160, 2000TL10107>.
Successful [2,3]-aza-Wittig rearrangements have been described using tertiary amines where the
nitrogen atom is incorporated into a -lactam or aziridine ring system, or when protected with a
t-BOC group or with a phosphoramide group <1997TL2491>. It seems that the -amino
organolithium species, compared to the oxygenated analogs, are more reluctant to undergo the
[2,3]-sigmatropic rearrangement. A solution to this problem has been found in the use of Lewis
acids as activators that complex the nitrogen atom favoring the rearrangement <1997S497>. A
DFT study of the aza-Wittig reaction and other concerted rearrangements has been published
<2003JOC2310>.
In the context of the synthetic applications, this rearrangement has been extensively utilized for
the synthesis of nitrogen-containing natural products.
For example, a general rearrangement of allyl aziridines leading to the formation of substituted
piperidines in a stereocontrolled process has been reported (Equations (69) and (70))
<1995TL3557, 1998S109, 1995JCS(P1)2739, 1996JOC8148, 1995TL303, 1996TL2495,
1995T9747>.
LDA, THF, –78 °C

ð69Þ
N
t 97% N CO2But
CO2Bu H
t
Bu O2C Ph
LDA, THF, –78 °C ð70Þ

N
Ph 63% N CO2But
H
This rearrangement has also been used for the synthesis of some unnatural -amino acids
<2000JOC9152, 2000JCS(P1)3025, 2001JCS(P1)267, 2002JCS(P1)2871> and kainic acid
<2003JOC6160>.
(iv) [2,3]-Wittig–Still rearrangement

As mentioned in the introduction of the previous section of this chapter, the Still modification of
the [2,3]-Wittig rearrangement has been the most used solution to ensure complete regioselectivity
in the initial carbanion formation, especially when the G group (cf. Equation (56)) is an alkyl one,
through transmetallation of an organostannane (Equation (71)).
G
G SnR3 G Li ð71Þ
RLi X
X X
This methodology mostly offers the same stereochemical characteristics as the previously reported
Wittig rearrangements. The stereochemistry of the double bond formed in the course of the reaction may
depend on the substituent of the initial double bond <1999TL6257>, in the presence of other hetero-
atoms <1996TL389>, or on the solvent used to perform the reaction <2001OL1789>. The major use of
this rearrangement, however, remains the stereoselective introduction of a hydroxymethyl group either
on acyclic <1998JOC6735, 1999T13369, 1999TL5063> or cyclic structures <1997TL8841> (Scheme
32) <2001T9727, 2000OL3139, 1999AG(E)129> starting from an allylic alcohol, which is easily derived
to its trialkylstannylmethyl ether. In its acyclic version, the syn-/anti-diastereomeric ratio in the product
of the reaction mainly depends, as reported previously, on the geometry of the starting double bond but
may be largely dependent on the structure of the whole molecule <1996TL389, 1999TL6257> and
therefore difficult to predict (Equations (72) and (73) <1999TL5063>).
OH O
KH, THF O
SnBu3 BunLi, THF
Bu3SnCH2I –60 °C
O O O
82% 51%
O O OH
>98% de
Scheme 32
O BunLi, THF, –65 °C O O

O O O
62%
BnO BnO OH BnO OH
ð72Þ
O syn /anti 2 /3
SnBu3
O
O O
BunLi, THF, –65 °C O
BnO
ð73Þ
67% BnO OH
O SnBu3
The Wittig–Still rearrangement of enantiomerically defined -propargyloxystannanes proceeds

with complete inversion of configuration at the lithium-bearing carbon atom although important
amounts of the competitive [1,2]-rearrangement were also observed <1997SL1045>.
An important variant of this method has been reported, based on silicon–lithium exchange
reactions <1996TL2403>.
A number of synthetic applications for the synthesis of natural and non-natural products have
been reported <1998JOC7580, 1997JA5512, 2000H(52)99, 2002JA9812, 2001T9727, 2001TL4755,
1997SL441, 2001JA12432, 2003T6819, 2003JOC2913, 2003JOC2343, 2002JOC6152>.
(v) [2,3]-Stevens rearrangement

The [2,3]-rearrangement of allyl-substituted ylides, referred to as the [2,3]-Stevens rearrange-
ment, and the related Sommelet–Hauser rearrangement of benzylammonium ylides
<1997TL2113, 1997JOC2544, 1997JCS(P1)25>, have been widely studied as competing pathway
for the corresponding [1,2]-Stevens rearrangement <1996JOC7276>. Theoretical studies on the
Stevens rearrangement <1995AJC1413> have shown that the reaction proceeds via dissociation
to a pair of radicals, followed by recombination to the final product. However, in particular, the
rearrangement of ammonium ylides has been often used for the formation of rearranged
homoallylic tertiary amines. The specificities of these rearrangements are quite close to those
of the [2,3]-Wittig rearrangement (stereochemical features, choice of the G group, etc.)
(Equations (74) and (75)). Classical experimental procedures have been extensively discussed
in the corresponding section of the COFGT (1995) and include the use of several organic or
inorganic bases as well as, in the case of a trimethylsilyl G group, the use of caesium fluoride
and the use of carbenes, quite similar to the corresponding methodologies developed for the
[1,2]-Stevens rearrangement.
+ G
X G [2,3]-Stevens ð74Þ
–
X
R1 R1
R2
N+ Sommelet–Hauser N ð75Þ
R2
G G
(a) Rearrangement of ammonium ylides. The main diversity arising from this type of rearrange-
ment lies in the pathway chosen for the formation of the initial ylide. Indeed, the ylide, when formed
through alkylation of the corresponding amine by an appropriate alkyl halide <1997JCS(P1)2951>,
may be generated by addition of allyl bromide, resulting in a formal allylation of amines
<1996T2075> and has been proven to be compatible with the use of a phosphorus-containing G
anion stabilizing group. Moreover, the ylides may be generated directly through treatment of a
dihalogeno compound by N-methylallylamine <2002TL899> (Equation (76)) and results in the
formation of heterocycles with potentially two stereogenic centers (one being a quaternary) of
controlled configurations bearing the heteroatom.
Br
CO2Et +
N
EtO2C H
Br
K2CO3, DMF
58%
Br –
EtO2C CO2Et EtO2C + CO2Et ð76Þ
N N
EtO2C CO2Et
N
A very promising set of experimental conditions has also allowed the formation of secondary
rearranged amines starting from tertiary amines. This procedure involves the formation of ylides
through treatment of tertiary amines by an appropriate Lewis acid and a Schwesinger phospha-
zene base <2003TL3159>. This work has to be considered as the continuation of some pioneering
research in the formation of ylides through Lewis acid treatment <1995TL8481,
1998JCS(P1)2817, 1997JCS(P1)2951, 2000SL236> (Equation (77)).
Bn O O
BBr3, CH3Ph, –78 °C
N
N N
N NH
Bn ð77Þ
N P N P N
N
3
60%
An important aspect of the rearrangement of allylic ammonium ylides, lying in chirality

transfer from nitrogen to carbon, has been studied (Scheme 33). The asymmetric ammonium
ylide is formed through stereospecific alkylation of a chiral tertiary amine to a methyl ester
group. Rearrangement is thereafter promoted by treatment with potassium t-butoxide
<1999OL31>; in this case the methylammonium ylide derived from benzyl proline rearranges
through a [1,2]-Stevens shift and the Sommelet–Hauser product is not observed.
I– KOBut Ph
CO2Me THF CO2Me
+
N 73% N
Ph
53% ee
– t
Br KOBu CO2Me
+ CO2Me THF
N N
Ph 93%
90% ee
–
PF6 KOBut CO2Me
O THF O
+ CO2Me
N N
47%
61% ee
Scheme 33
However, most of the reported rearrangements of ammonium ylides involve the formation of
the ylide through a carbenoid species, in an intramolecular or bimolecular fashion. The carbene
may be derived from a diazo compound <2003JOC4083, 1997TL8283, 2000SL1208, 2002T10113,
2000SL1208> or from the Simmons–Smith reagent <2003OL1757>. In this latter case, the
diastereospecificity of the reaction is controlled through the conformation of the five-membered
oxazoline ring derived from the condensation of pseudo-ephedrine on cinnamaldehyde. The
favored transition state results as expected from the alkylation/ylide formation of the five-
membered heterocycle occurring cis to the adjacent substituent allowing a nice five-membered
envelope-shaped conformation, which is suitable for the [2,3]-rearrangement. However, the minor
ylide does not undergo [2,3]-rearrangement, due to its disfavored conformation but undergoes
1,2-alkyl shift (Equation (78)).
O
Ph Ph
O
N+ 72%
Ph Ph
Ph N
O
Zn(CH2I)2/Et2O
Ph ð78Þ
N Ph BuLi/ THF Ph O
– Ph O
N+
Ph 5%
N
The [2,3]-Stevens rearrangement of ammonium ylides, which may be effected in a Wittig–Still

version, is noteworthy <1995JA11817, 1997CUOC71, 2003TL1239>.
The rearrangement of ammonium ylides has been used for the design of efficient methodologies
aimed at the total synthesis of natural products such as -sinensal, cis-retinol, and plaunotol
<1996CL385, 1996CL671, 1998SL685, 2002JCS(P1)1387>.
Similarly the Sommelet–Hauser reaction has been applied to an ammonium ylide derived from
the HIV-1 reverse transcriptase inhibitor nevirapine <1995JHC1687>.
(b) Rearrangement of oxonium ylides. The [2,3]-rearrangement of enantiomerically pure oxo-
nium ylides has been reviewed <1997CRV2341, 1996CRV223, 2001CSR50> and a monograph
has recently been published on the chemistry of oxonium ylides <B-2002MI001>, which collects
the different methods for their preparation.
The rearrangement of allyl oxoniums has benefited from the progress of the diazo-derived
carbene chemistry <1998CRV911, 2001CSR50, 1995JOC53, 1999T6577>. Many chiral cata-
lysts have been studied (Scheme 34) <1996TL107, 2001TL6361, 1998JA7653, B-1998MI001,
1995JCS(P1)1373, 1997TL4705, 2001TA877> and allow a good enantiocontrol of the
rearranged products. The main problem to be managed in this catalytic process is to avoid
a competitive cyclopropanation reaction of the allyl moiety <1997TL5265, 2000TL6265>. The
main use of this methodology deals with the synthesis of substituted tetrahydrofurans
(Equation (79)) <1998TL8813, 1996TL5605>. Other examples of application in the field of
synthesis of natural products have been reported <1999CC749, 1998TL97, 2001CC459,
1996TL5053, 1997JOC3902, 1998TL1691, 2002IJ283, 2000TL6265, 2001JA5144>.
O
R
R R N N
O O
O O O O O
Rh Rh 4 Rh Rh 4 Rh Rh 4
Ph
R = menthyl, bornyl R= * R = Bn, Pr, Ph, . . .
Me
Scheme 34
O O Rh2[S-TBSP]4 (1 mol.%) H3COOC

O O O
O
O H Benzene
N2 47%
O Rh 34% ee
ð79Þ
Rh2[S-TBSP]4 =
N O Rh
S O
O
(c) Rearrangement of sulfonium and selenonium ylides. Allylsulfonium <2000JOC2532,

1995CC1245> and selenonium <2000TCC(208)201, 1995CC1243, 1996JOC2932, 1997JOC4562,
1995CC1245, 1997T12115, 2001TL2911> ylides may also undergo [2,3]-Stevens rearrangement.
When the selenonium ylides are formed through nucleophilic substitution of the chiral chloro-
selenurane 35 by (phenylsulfonyl)acetonitrile, the rearranged selenide 36 is obtained in high yield
as a single diastereomer (Equation (80)) <1997JOC4562>.
PhSO2CH2CN
O OH
Se Et3N, CH2Cl2 Se ð80Þ
Cl 87%
NC SO2Ph
35 36
The rearrangement of allylic sulfonium ylides has been, however, the most extensively studied
<1996CRV223, 1999RHA117, 1997CRV2341, 1998TA1, 1998PAC1123, 1998CRV911,
2001RCR655>. Catalyzed reactions of -diazoketones with allyl sulfides led to allylsulfonium ylides
that on rearrangement afforded the corresponding thiocarbonyl derivatives. This methodology may be
used either in a bimolecular fashion or in an intramolecular process <1996TL6523>. This methodology
has been applied to the synthesis of 3-piperidinol alkaloid precursors <2000TL2965> and for the
synthesis of the elemanoid type of sesquiterpenes <1995JCS(P1)2989, 1995T7697>. The decomposition
of the diazo compound is often effected with chiral metal catalysts. The main metals used are copper
<1997TL3435, 1999T649, 1999BCJ603, 2000JOC2532>, rhodium <2001H(54)623, 2002JOC5621,
2003TA891, 2003TA897, 2000JOC2984>, and rhenium <1995JA11730, 1996OM194, 1996OM4695,
1996PAC79> (Equation (81)).
Cl
S Cl
Rh2[S-TBSP]4 (11 mol.%) S
O C H
O
Toluene, –23 °C CO2Me
O 96% H
O
N2
73% ee ð81Þ
O Rh (major configuration not
determined)
Rh2[S-TBSP]4 =
N O Rh
S O
O
4
Although the most reported pathway for the generation of the ylides uses the decomposition
of an -diazoketone or ester, the use of trimethylsilyl diazomethane <1999TL8923, 1999TL1617,
2001T5219> or diiodomethane <2001TL2911, 2001JA4508, 1998SL1366> has also been
reported.
1.09.1.4.5 [3,3]-Sigmatropic rearrangement

[3,3]-Sigmatropic rearrangements have attracted considerable attention in the 1990s. Indeed, as
these rearrangements proceed through a six-membered ring transition state (usually in a chair
conformation unless prohibited by strong steric interactions), the stereochemical outcome of the
reaction may be predicted and the diastereomeric ratio is usually very good. These rearrange-
ments will only be mentioned in this chapter; their full description will be made in Chapter 1.18.
The general [3,3]-sigmatropic rearrangement is depicted in Equation (82). Cope rearrangement
deals with the rearrangement of systems with no heteroatoms (X=CR2) and Claisen, aza-Claisen,
and thio-Claisen rearrangements are the rearrangements of vinyl allyl ethers, amines, and sulfides,
respectively.
ð82Þ
X X
(i) Cope rearrangement

The Cope rearrangement deals with the rearrangement of 1,5-dienes and related compounds (see
below) in a reversible process. The experimental conditions and the structure of the starting
material therefore considerably influence the position of the equilibrium. In particular the oxy-
Cope rearrangement, which finally furnishes a carbonyl group through tautomerization, allows
the reaction to become irreversible.
The field of application and the experimental procedure generally used depends on the structure
of the starting diene involved in the Cope rearrangement. The different types of Cope rearrange-
ment are discussed in Equation (83).
Cope rearr. X, Z=C, Y=H, C
Y Y Oxy-Cope rearr. X, Z=C, Y=OR
Amino-Cope rearr. X, Z=C, Y=NR2 ð83Þ
Z Z Anionic oxy-Cope rearr. X, Z=C, Y=O–
X X aza-Cope rearr. X or Z=N, Y=H, C
oxonia-Cope rearr. X=O+, Z=C, Y=H, C
(ii) Claisen rearrangement

As previously stated, the Claisen rearrangement involves the rearrangement of allyl vinyl (or aryl)
ethers, amines, or sulfides (Scheme 35).
X X X X
Y Y
G G
Aromatic Claisen
X = O, N or S; G = H, CR3 Claisen, aza- or thio-Claisen
X = O, G = OSiR3 or O– Ireland–Claisen
X = O, G = NR2 Eschenmoser–Claisen
X = O, G = OR (R = alkyl) Johnson–Claisen
X = O, G = OH, Y = (C=O)R Carroll–Claisen
Scheme 35
1.09.1.5 Electrocyclic Reactions

This section is devoted to the study of the electrocyclic process allowing the formation of a new
CC bond starting from a polyenic compound, the -system of which is thereby reorganized.
The starting material has therefore one more -bond than the product of the rearrangement. As
outlined in the corresponding section of chapter 1.09.1.5 in <1995COFGT(1)377>, the most
important of these electrocyclizations are the 1,3-diene cyclobutene interconversion (Equation
(84)), the 1,3,5-triene cyclohexadiene interconversion <2000OL3407> (Equation (85)) and the
Nazarov cyclization (Equation (86)). As the two first transformations did not find significant
improvement in the time schedule covered by this review, the only detailed reaction will be the
Nazarov cyclization.
ð84Þ
ð85Þ
O O
ð86Þ
1.09.1.5.1 Nazarov cyclization

Divinyl ketones, although being often unstable, may undergo a rapid cyclization to cyclopente-
nones under acidic conditions. Both protic (H2SO4, H3PO4, HCl) and Lewis (BF3Et2O, FeCl3,
TiCl4, AlCl3) acids may be used. Other experimental procedures include superacids
<1997JA6774> and photochemical conditions <2001EJO2719>. The reaction proceeds through
protonation of the oxygen atom of the carbonyl group, which thereafter generates a pentadienyl
cation to be involved in a four-electron electrocyclization to the expected cyclopentenone
(Scheme 36). The intermediate allyl cation may, however, be trapped inter- or intramolecularly
by an appropriate nucleophile prior to the loss of a proton. This possibility has been the origin of
the main advances in the use of this reaction in the recent years.
+
O O O
+
R H or LA R R
+
Nucleophilic Deprotonation
trapping
O O
O
Nu
R Nu R
or R
Scheme 36
However, when the loss of an electron is allowed to form the cyclopentenone, the more
thermodynamically stable isomer is formed with the more substituted double bond. The presence
of trialkylsilyl groups to the carbonyl group may, however, influence the course of the reaction
<1997CC1177>. Indeed, desilylation is normally preferred to deprotonation and the stabilization
of the carbocation by the silyl group helps to prohibit unwanted side reactions.
Due to the difficulty of obtaining stable divinyl ketones, most of the reported examples of
Nazarov cyclization use aromatic vinyl ketones <2001JOC954, 2000JOM174, 2001JOC7632> or
other appropriate precursors of pentadienyl cations <2000CEJ4021>.
Albeit the deprotonation pathway has been used in some approaches to natural product
total syntheses <1998SL1372, 2001SL1399, 2001T1049>, the most promising feature of the
Nazarov cyclization remains, as previously stated, the possible trapping of the allyl cation
formed after formation of the five-membered ring. In this field, examples have previously
demonstrated the solvent or the acid counter-anion to be able to quench the carbocation.
However, the use of Lewis acids in aprotic solvents allows the use of other nucleophilic
species. Two representative examples are described in Equations (87) and (88) using either
intermolecular trapping by allyl silanes <2000AG(E)1970> or an intramolecular Friedel–
Crafts reaction <2001OL3033>.
–
BF3
O
–
BF3 +
O O SiMe3
SiMe3
+ Ph Ph
–
BF3·Et2O, CH2Cl2 BF3
Ph Ph Ph Ph O
+
SiMe3
ð87Þ
Ph Ph
O
O O
Ph SiMe3
Ph Ph Ph Ph
Ph
(30%) (13%) (40%)
O
O
TiCl4, CH2Cl2, –78 °C O
99% ð88Þ
H
O
An interesting report in the field of the Nazarov cyclization involves the reaction of a chiral
1-lithio 1-alkyloxy allene with a vinylic amide to afford the corresponding allenyl vinyl ketone,
which thereafter rearranges to the methylene pentenone with a good enantiomeric excess
<2001JA8509> (Equation (89)).
HCl O
1,1,1,3,3,3-Hexafluoro-2-propanol HO
2,2,2-Trifluoroethanol
O –78 °C
ð89Þ
N OO 78%
·
Li
O
86% ee
Alternatively, the use of a Lewis acid with chiral ligand may allow an enantioselective version
of the Nazarov cyclization <2003OL5075, 2002OL4931> (Scheme 37).
O O
N
N Sc N
O Ph (OTf)3 Ph O
(20 mol.%) O H
O
THF
53% H
61% ee
O O
N
O N N O
O O
i i
Ph Pr Pr Ph
(1 equiv.)
OEt OEt
Ph Ph CuBr2, AgSbF6 Ph Ph
CH2Cl2
98% 86% ee
Scheme 37
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Biographical sketch
Paul-Henri Ducrot was born in Paris. He studied at the ‘‘École

Polytechnique’’ (Palaiseau). He obtained his Ph.D. in 1990 from the
University of Paris X (Orsay) under the direction of Professor Jean-Yves
Lallemand. In 1990, he joined the National Institute for Agronomic
Research (Inra) in the laboratory of Charles Descoins. He is now
‘‘Directeur de Recherche’’ at the Inra research center in Versailles, where
he has his own research team (formed in 1994). He was awarded in 2002 the
‘‘ACROS-SFC’’ prize from the Organic Chemistry Division of the French
Chemical Society. His scientific interests include all aspects of the chemistry
of natural products, but he is mainly involved in the extraction, identifi-
cation, and total synthesis of insects pheromones and plants secondary
metabolites of agronomic interest (biopesticides) and also in the study of
the natural products involved in the elaboration of the quality of the food
products (organoleptic poperties and benefits for human’s health).
1.10
One or More ¼CH Bond(s)
Formed by Substitution
or Addition
G. ROUSSEAU
Université de Paris-Sud, Paris, France
1.10.1 ONE OR MORE ¼CH BOND(S) BY SUBSTITUTION 428

1.10.1.1 Reduction of ¼CHalogen Bonds 428
1.10.1.1.1 Reduction of aryl halides 428
1.10.1.1.2 Reduction of vinyl halides 432
1.10.1.2 Reduction of ¼CO Bonds 436
1.10.1.2.1 Reduction of phenols and derivatives 436
1.10.1.2.2 Reduction of enol ethers and derivatives 437
1.10.1.3 Reduction of ¼CS, Se, and Te Bonds 438
1.10.1.3.1 Reduction of aryl sulfides, selenides, and tellurides 438
1.10.1.3.2 Reduction of vinyl sulfides, selenides, and tellurides 439
1.10.1.4 Reduction of ¼CN Bonds 441
1.10.1.4.1 Reduction of arylcarbonnitrogen bonds 441
1.10.1.4.2 Reduction of vinylcarbonnitrogen bonds 443
1.10.1.5 Reduction of ¼CP, ¼CAs, ¼Sb, and ¼CBi Bonds 443
1.10.1.5.1 Reduction of arylcarbonphosphorus, arsenic, antimony, and bismuth bonds 443
1.10.1.5.2 Reduction of vinylcarbonphosphorus bonds 444
1.10.1.6 Reduction of ¼CB, ¼CSi, and ¼CGe Bonds 445
1.10.1.6.1 Reduction of aryl boranes, silanes, and germanes 445
1.10.1.6.2 Reduction of vinyl boranes, silanes, and germanes 447
1.10.1.7 Reduction of ¼CC Bonds 449
1.10.1.7.1 Reduction of arylcarboncarbon bonds 449
1.10.1.7.2 Reduction of vinylcarboncarbon bonds 450
1.10.1.8 Reduction of ¼CMetal Bonds 451
1.10.1.8.1 Reduction of arylcarbonmetal bonds 451
1.10.1.8.2 Reduction of vinylcarbonmetal bonds 451
1.10.2 ONE OR MORE ¼CH BONDS BY ADDITION 453
1.10.2.1 Addition to Alkynes 453
1.10.2.1.1 Addition of hydrogen to alkynes 453
1.10.2.1.2 Addition of CH to alkynes 455
1.10.2.2 Addition to Allenes 455
1.10.2.2.1 Addition of hydrogen to allenes 455
1.10.2.2.2 Addition of CH to allenes 456
427
428 One or More ¼CH Bond(s) Formed by Substitution or Addition
1.10.1 ONE OR MORE ¼CH BOND(S) BY SUBSTITUTION
1.10.1.1 Reduction of ¼CHalogen Bonds
1.10.1.1.1 Reduction of aryl halides

The reduction of aryl halides has been reviewed since COFGT (1995) <2002CRV4009>. The
main synthetic methods used to achieve these transformations are always the same and include
the use of hydrides, metals, or electrochemistry. However, significant efforts have been made to
improve the selectivity of the methods. Selective cleavage of CX bonds following the order of
reactivity I > Br > Cl > F now appear possible.
(i) Reduction of aryl fluorides

Activation of CF bonds by metal complexes has been reviewed <1994CRV373>. The use
of LAH in the presence of additives (ButOOH/h, CeCl3) or the use of CoCl2 in the presence of
Grignard reagents has already been reported. Much more efficient reagents have been reported in
recent years. For example, Cp2ZrCl2 in the presence of magnesium and mercuric chloride allows
a selective removal of one fluorine atom from polyfluoride compounds (Equation (1))
<1996CC1115>. Similar results were reported with the homogeneous catalysts (PMe3)3RhC6F5
<1995JA8674>, and Cp2ZrH2 used in stoichiometric amounts (Equation (2)) <2000JA8559>.
F F F F
Cp2ZrCl2 F H
F F
Mg, HgCl2 R F ð1Þ

F F
F F THF, rt F F
2 h: R = F 97%
13 h: R = H 93%
F
Cp2ZrH2 (1 equiv.)
ð2Þ
H2, 4 days, 85 °C
good yield
Reaction of hexafluorobenzene with the complex NiCl2-2,20 -bipyridine in the presence of zinc in
water and NH4Cl led to a mixture of penta-, tetra-, and trifluorobenzene <2000MC60> (see also
<2000JFC(101)65>). Nickel acetylacetonate in the presence of NaH and an imidazolium salt was found
to be able to transform fluorobenzene into benzene (Equation (3)) <2002OM1554, 2003MI(345)341>.
These conditions were found to be very efficient for the cleavage of other CX bonds.
+
N N
F Cl –
ð3Þ
Ni(acac)2 (3 mol.%), NaH
THF–PriOH
45%
Sodium hydride itself was found to be able to reduce fluorobenzene (29%) if nanometric
(23 nm) particles were used. Introduction of lanthanide chlorides increases this yield to 40%
<1997SC4327>. Laev <1998JFC(91)21, 2001JFC(110)43> showed that the monodefluorination
of polyfluoro compounds can be achieved by the reaction of zinc in 30% aqueous NH3 (Equation
(4)). Replacement of aqueous ammonia by aqueous dimethylformamide (DMF) in the presence of
cupric chloride is also possible <2001MI517>. The use of zinc in liquid ammonia gave, in some
cases, interesting results. For example, with pentafluorobenzoic acid, the reaction is very chemo-
selective, leading to the removal of the fluorine in the para position (Equation (5)) <1995TL4655>.
One or More ¼CH Bond(s) Formed by Substitution or Addition 429
F H H
F F Zn, NH4Cl F F F F
+
ð4Þ
F F 30% aq. NH3 F F F F
F 67% F H
95:5
CO2H CO2H
Zn, NH3(l) F F
F F
ð5Þ
F F
F F 90%
H
F
(ii) Reduction of aryl chlorides

It has been reported in COFGT (1995) that the best methods for the replacement of the chloride
of aryl compounds by hydrogen are catalytic hydrogenation and the reduction with Raney nickel,
which in turn have led to several new methods. Hydrogenolysis using a rhodium complex of the
type L2Rh(H)Cl2 promoted by Alper <B-1999MI193> was greatly improved using triethylsilane
<1999OM1110>, or 2-butanol <1999OM1299, 2002CC2964> as the hydrogen source (Equation
(6)). Monohydrogenolysis of polychloroarenes was reported to be effective by using RhCl(PPh3)3
(Equation (7)) <2001NJC775> or RuHCl(PPh3)3 (Equation (8)) <2000MI(195)187>.
Me Me
CpRh(OAc)2.H2O (2.5 mol.%)
ð6Þ
KOH, 2-butanol, ∆, 17 h
Cl 96%
Cl Cl RhCl(PPh3)3 Cl
ð7Þ
NaOCOH, PriOH, xylene
70%
Cl Cl Cl
Cl RuHCl(PPh3)3 Cl Cl
+ + ð8Þ
HSiEt3, octane
Cl Cl Cl
95%
Pd/C and Pd/Si were used for the reduction of chloroaryl compounds in earlier methods. These
reductions were improved under phase transfer catalyst conditions. So, in the example reported in
Equation (9), the ketone function remained untouched <1996S1109>. Anchored Pd on silica gel
also led to improved results <1999SC691>.
O O
Pd/C, H2
ð9Þ
KOH, aliquat 336
Cl
100%
Palladium chloride in the presence of HSiEt3 was examined. The hydrogenolysis of CX
bonds appears general <1996OM1508>. PdCl2 anchored on poly(N-vinyl-2-pyrrolidinone) in
the presence of a base such as KOH <1994TL4599> or sodium formate <2001MI287,
2001MI(175)153> can be used. Pd(OAc)2 in the presence of polymethylhydrosiloxane (PMHS)
led to a very efficient cleavage of the CCl bond, with the exception of chlorophenols (Equation (10))
<2002TL8823>.
O O
R Pd(OAc)2 (0.5 mol.%) R
ð10Þ
Cl KOH, PMHS
R = Me: 100%, R = H: 0%
A Pd(0) complex such as Pd(dba)2 in the presence of imidazolium salts was found to be a good
reagent for dechlorination of aryl halides <2001OM3607>. The use of nickel and its salts was also
reported. Raney–nickel–alumina alloy <1998TL5991> and nickel on charcoal in the presence of
Me2NHBH3 (Equation (11)) <2001SL970> were efficient, and polychloroaryl compounds were in
some cases completely transformed to aryl compounds. Nickel acetate <1995TL6051, 2000T4765>
and nickel chloride <1999T4441, 2000MI1017> also appear to be efficient catalysts. However, the
prevalent tendency is to use homogeneous catalysts. Excellent results for the cleavage of CCl
bonds were reported by using (Et3P)2NiCl2 <2000JOM(600)63>, (PPh3)2NiCl2 <2001TL7737>,
and Ni(0)IMe3 complex <2002OM1554>. NaBH4 in the presence of Cp2TiCl2 appears to be a very
powerful solution for dehydrochlorination of perchlorodioxine <1996NJC253> (Equation (12)).
NaBH4 in di- or tetraglyme in the presence of LiCl appeared to be able to reduce pentachlorophenol
(Equation (13)) <1997TL6561, 1998SC517>.
N N
Ni–C 5%, PPh3 20%
ð11Þ
Cl Me2NH. BH3, K2CO3
100%
Cl Cl
Cl O Cl Cp2TiCl2 O
ð12Þ
Cl O Cl NaBH4, pyridine O
Cl Cl good yield
OH OH
Cl Cl NaBH4, LiCl
ð13Þ
Cl Cl Tetraglyme, 130 °C, 2 h
Cl
85%
NaH (nanometric size particles) in the presence of LaCl3 led to a quantitative transformation of
chlorobenzene to benzene <1997SC3977>. Use of n-butylmagnesium chloride in the presence
of Cp2TiCl2 in THF (Equation (14)) <1999CC845> or calcium in ethanol (Equation (15))
<2001MI(35)4145> were also reported. Use of microorganisms was also examined
<1998MI633> and the results concerning the reduction of the very toxic chlorodioxins was
recently reviewed <2003AG(E)3718>.
Cl
BunMgCl (3 equiv.)
ð14Þ
Cp2TiCl2 (0.1 equiv.), THF, rt
99%
Cl Cl
Ca, EtOH
ð15Þ
24 h, 0 °C
Cl 100%
(iii) Reduction of aryl bromides

The use of palladium- and platinum-based catalysts has previously been reported extensively.
NaBH4 and LAH were also found to be powerful reagents. However, more recently a great
variety of new reagents have appeared. Very often the reagents used for the cleavage of CCl
bonds were also tested with success for the cleavage of CBr bonds (see the preceding section).
Some specific reagents have been reported such as Cp2Ti(BH4)2 (Equation (16)) <1995T4471>,
dichloro[1,10 -bis(phenylphosphine)ferrocene]Pd(II) <1997MI(126)L83>, PdCl2(MeCN)2
<1998MI(132)223> in the presence of NaBH4, PdCl2[PPh3]2 in the presence of PMHS
(Equation (17)) <2002TL7087>, and Pd(OAc)2 in DMSO/H2O in the presence of HCOOK
under microwave irradiation <2001TL331>.
Br
Cp2Ti(BH4)2
ð16Þ
DMA, diglyme
Cl Cl
90%
Br
PdCl2.PPh3, PMHS
ð17Þ
KF, THF
CHO CHO
79%
Aromatic bromides have also been reduced selectively using n-BuMgCl in the presence of
Cp2ZrCl2 (Equation (18)) <1997CL1251> or NaBH4 in the presence CuSO4 (Equation (19))
<1997BCJ1101>. The less common hydride LiGaH4 was reported to show reactivity close to that
of LAH <1997MI541>.
Cl BunMgCl, Cp2ZrCl2 Cl
ð18Þ
Br THF
98%
Cl NaBH4, CuSO4 Cl
MeOH ð19Þ
Br
100%
Radical processes were found to be able to induce the dehydrochlorination of aryl compounds.
The use of reagents such as Ph3SnH in the presence of 9-BBN or Et3B–oxygen <1998TL5437>,
PhSiH3–AIBN <1997SC1023>, or (Me3Si)3GeH–AIBN <1995OM5017> has been reported. The
radical process can be induced by visible light in the presence of methylene blue as sensitisor
<1999TL1441> or at 300 nm in the presence of YbI2 <1997TL9017>. The use of NaH in the
presence of Ni(OAc)2 <2000T4765> or Sm(OiPr)3 <1995MI457> also gave interesting results.
Chi showed that by using HBr in acetic acid, the bromine atoms of substituted bromo anilines can
replace by hydrogens. This unusual method widens the scope of the previously cited methods
(Equation (20)) <2001JA9202>. The use of lithium in the presence of polymer supported
naphthalene, and NiCl2 was also examined for the reduction of bromobenzene
<2003MI(345)275>.
Me Me
NH2 HBr NH2
ð20Þ
Br AcOH, Na2SO3
Br
NH2 95% NH2
(iv) Reduction of aryl iodides

Since aryl iodides are the most easily reduced halides, most of the methods reported for the
reduction of aryl chlorides and aryl bromides can be used. NaBH4 alone or in the presence of
metals is frequently employed. Recently, some specific methods have been reported. Modulation
of the reactivity of n-Bu3SnH was obtained by structural modifications. These new reagents allow
specific reduction of aryl iodides (Equation (21)) <1999CC1237, 2001TL5837> (Equation (22)).
Na2Te was found to be efficient for the selective removal of iodide atom (Equation (23))
<1998JOC3911>.
H
I
N Sn
2 Bun ð21Þ
AIBN, benzene, ∆
96%
Me
N Me
Sn Me
I CO2H CO2H ð22Þ
Me
NaHCO3, H2O, rt
87%
OH OH
I I Na2Te
ð23Þ
EtOH, ∆
Br 100% Br
Reduction of iodobenzyl alcohols was reported with NaBH4 in the presence of Ph3Ge–AIBN
<2001BCJ747> or di-t-butylperoxyoxalate <1997JA2628>. Phosphonic acid in the presence of
DBU or AIBN in ethanol was also quite useful <2001BCJ225> (Equation (24)). Clean and
selective reduction of functionalized aryl iodides was also observed with Pd on charcoal. This
selectivity was not observed with aryl bromides or aryl chlorides <2002JOC932> (Equation (25)).
OOctyln H3PO4, D2O, DBU OOctyln
ð24Þ
I EtOH
95%
I
Pd/C, H2, Et3N N3
N3
ð25Þ
MeOH
95%
1.10.1.1.2 Reduction of vinyl halides

The reduction of vinyl halides to alkenes has been achieved by a large variety of reagents,
including metals, complex hydrides, electrochemical reductions, and catalytic hydrogenation.
These different methods have been reviewed <2002CRV4009>.
(i) Reduction of vinyl fluorides

The CF bond appears to be the most difficult one to cleave due to its particular strength.
This cleavage can be achieved by catalytic hydrogenation with reagents such as LAH or NaBH4
(see COFGT (1995)); these reactions correspond in fact to the addition–elimination processes.
Tellier and Sauvêtre <1996JFC(76)181> found that mono-reduction of lithium alcoholate deriva-
tives from difluoroallylic alcohols could be carried out by using LAH. The stereochemistry of the
products was mainly E (Equation (26)). Similar monohydrogenolysis was reported for the reduction
of ,-difluoro-,-ethylenic esters <2000JOC627>. Monoreduction of polyfluoroalkenes of general
formula RCF¼CFCF3 was achieved ((E)–(Z) mixtures) <2001JOC4887>. Monoreduction of
trifluorovinyltrimethylsilane was also reported <2002OL1483>. Reductions were observed with
reagents such as Red-Al (Equation (27)) <1997SL669> or LiAlH(Ot-Bu)3 (Equation (28))

<1999JFC(97)109>. Only catalytic hydrogenolysis allows the complete removal of fluorine atoms
from polyfluoro compounds. No improvement of this reaction has been reported since the 1990s.
i. MeLi
R1 OH ii. LiAlH4, Et2O R1 OH
F
ð26Þ
R2 80–90% R2
F F
O OMe Red-Al O OMe

O O
F F
Ph O THF Ph O ð27Þ
TBSO F 95% TBSO
(Z )–(E ): 73–27
Y Y
F PPh2 LiAlH(OBut)3 H PPh2
F H THF, –78 °C F H ð28Þ

Y = O 92%
Y = BH3 87%
(ii) Reduction of vinyl chlorides

The main reagents used for the reduction of vinyl chlorides are complex hydrides. Good results
were reported by the combination of LAH with TiCl4 or NaH with Ni(OAc)2 (see COFGT
(1995)). Sodium in t-BuOH was also reported to be efficient. Yus found that lithium in the
presence of 4,40 -di-t-butylbiphenyl (DTBB) (or in the presence of naphthalene supported on
polymer <2003MI(345)275>) was able to transform vinyl chlorides into vinyllithium derivatives.
Subsequent hydrolysis led to the desired reduction products (Equation (29)) <1994TL7643>.
i. Li, DTBB, THF

ii. H2O (D2O) O O ð29Þ
O O
R 90% (88%) R H (D)
Cl
In fact recently, the use of zinc has increased. For example, transformation of hexachloro-
1,3-butadiene into 1,3-butadiene was reported by using zinc activated by a mixture NaI–CuCl
<1998JA2578>. Heathcock’s method <1976JOC636> was used successfully to remove a vinyl
chlorine to obtain a carbonyl function (Equation (30)) <1996TA1923>. Zinc activated by
ClSiMe3 was also used <1995T9823> (Equation (31)). Sodium in THF was found to be able to
remove two vinylic chlorines fixed on an exocyclic double bond of an oxazoline to lead to the
formation of an allylamine <1998CL1237> (Equation (32)).
Cl
Zn–Ag, MeOH, THF
ð30Þ
O O n-C6H11 90% O O n-C6H11
i. Zn, Me3SiCl O
O
Cl ii. AcOH ð31Þ
SiMe3 SiMe3
Cl 75% Cl
Cl
R Cl R
Na, THF
HN ð32Þ
N O ∆
Ac 90–95% Ac
R = Me, Bz, Pri, Bui, etc.
(iii) Reduction of vinyl bromides

The reduction of vinyl bromides is easier than the reduction of vinyl chlorides, so in the majority
of cases, the methods reported in the preceding chapter can be used. For instance, reduction of
vinyl bromides was reported with the zinc–silver couple <2002JOC4316> and Zn–ClSiMe3
<2000SL1749> (Equation (33)). Substitution of vinyl bromides by lithium has been extensively
studied. ButLi reacted with nonactivated vinyl bromides and the subsequent hydrolysis led to the
reduction products <1995TA1551> (Equation (34)), <1995JOC7791, 1998T9529, 2002SL607>.
O Zn /(ClSiMe3 (3 mol.%)) O
MeO O MeO O
THF, 90 h, 65 °C
ð33Þ
Br 74%
i. ButLi, ether, –78 °C

Me Me
ii. H3O +
ð34Þ
75%
HO Br HO
Other methods have been investigated to transform vinyl bromides into alkenes. Corey
<1999JA6771> reported the use of sodium amalgam (Equation (35)). Hudlicky studied the
electrochemical reduction (2.2 to 3.2 V versus Ag/Ag+ reference electrode) and demonstrated
that it can be used as a preparative method <1999JOC4909, 2003TL1575> (Equation (36)).
In these conditions, ring opening of epoxides and aziridines was observed. This method was
also found to be efficient with vinyl iodides. Reduction of bromostilbene was found to be
stereospecific with tin hydrides such as tris(2,6-diphenylbenzyl)tin hydride (TDTH) (Equation
(37)). With this reagent, (E)-bromostilbene was reduced to (Z)-stilbene exclusively
<2001AG(E)411>. In the same conditions, (Z)-bromostilbene gave 98% of (E)-stilbene. In the
presence of Pd(OAc)2, 3-bromoallylic alcohols were transformed into ,-ethylenic carbonyl
compounds (Equation (38)) <1996T12291>. Homoallylic alcohols led to less interesting results.
3-Bromoallylic alcohols protected as benzyl ethers reacted with SmI2 to generate the products
corresponding to 1,5-hydrogen atom transfer, followed by the [2,3]-Wittig rearrangement
(Equation (39)) <1997JOC7542>. This reaction was also observed with vinyl iodides.
OH OH
Br
Na /Hg, MeOH
ð35Þ
82 %
SiMe3 SiMe3
Br
O Electrolysis (–3.2 V) O
ð36Þ
HO O MeOH, Bun4NOH HO O
OH 62% OH
Br TDTH, cat. Et3B
Ph Ph CH2Cl2, –78 °C Ph Ph
62%
Ph ð37Þ
TDTH = CH2 SnH
Ph 3
Br Pd(OAc)2, PPh3, K2CO3
OH Benzene, reflux, 6 h O ð38Þ
85% H
Br
SmI2, benzene–HMPA (9:1) OH
O Ph ð39Þ
rt, 5 h Ph
62%
Numerous works have been reported on the monoreduction of 1,1-dibromoalkenes. The

(E)-isomer was mainly obtained by using indium <2001JOC4102>, diethylphosphite in the
presence of triethylamine <2000TL3215>, diethylphosphite in the presence of sodium ethoxide
<2002T1491>, PriMgCl in the presence of Fe(acac)3 <2001JOM(624)131> (Equation (40)), or
BunLi in pentane at 100 C <2000SL1070>. In contrast, the (Z)-isomer was mainly formed by
the reaction with tributyltin hydride in the presence of a catalytic amount of Pd(PPh3)4
<1998JOC8965> (Equation (41)).
N Br PriMgCl, cat. Fe(acac)3 N Br
Br ð40Þ
NMP–THF (1:1)
79%
Br Bu3nSnH, Cat. Pd(PPh3)3

R R
Br Benzene, rt Br
ð41Þ
R = Ph 79%
R = Ph 82%
(iv) Reduction of vinyl iodides

Although the cleavage of the CI bond is the easiest, this reaction appears not to be studied
extensively. This is due, in part, to the modest stability of iodides. Methods reported in the above
section employing complex hydrides, zinc, or ButLi can be used. Recently, specific methods have
been reported. Weavers and co-workers indicated that the reduction of vinyl iodides was observed
under irradiation at 254 nm in THF (Equation (42)) <1995T11257>. Curran and co-workers also
reported a photochemical transformation of 3-iodoallylic alcohols into allylic alcohols (Scheme 1)
<1997T5679>. Reduction of vinyl iodides was carried out by reaction with magnesium ate
complexes, such as PriBun2MgLi followed by hydrolysis (Equation (43)) <2001JOC4333>. Reduc-
tion of 1,1-diiodo-1-alkenes with zinc in a mixture of THF–MeOH was recently reported to lead
to the formation of (Z)-1-iodo-1-alkenes <2003TL8645>.
n-C5H11 O O n-C5H11 O O
H hν (254 nm) H
H
ð42Þ
THF H
MeO2C 85% MeO2C
I
H But I But
Si Si
O But (Bu3Sn)2, hν O But TBAF
OH
I H H
Ph Benzene, 80 °C Ph
43% (2 steps) Ph
Scheme 1
i. PriBun2 MgLi, THF, 0 °C, 1 h

n-C5H11 ii. D2O n-C5H11 ð43Þ
I D
93%
1.10.1.2 Reduction of ¼CO Bonds
1.10.1.2.1 Reduction of phenols and derivatives

The deoxygenation of phenols to aryl has been carried out by a large variety of reagents. The best
methods to achieve this process, rather than the direct deoxygenation of phenols that requires
harsh conditions, involves the cleavage of derivatives such as methyl ethers, phosphates esters,
2-chlorobenzooxazoles, 1-phenyl-5-chlorotetrazole, and perfluoroalkylsulfonates (e.g., triflates,
nonaflates). The hydrogenolysis can be accomplished with Na in THF (methyl ethers), alkali
metals in liquid NH3 or electrolysis (phosphate esters), or Pd/C (tetrazoles). The mildest condi-
tions were found for the cleavage of triflates and nonaflates due to the use of Pd(OAc)2 or Ni(0)
complex in the presence of phosphines (see COFGT (1995)).
Recently, new results have been reported. The monohydrogenolysis of polyphenols, considered to
be difficult, was found to be possible using hydrogen in the presence of Rh on alumina (Equation
(44)). Under these conditions, selective cleavage of methyl ethers was observed <2002JA5926>.
Pisano and co-workers studied the cleavage of phenolic ethers. A good regioselectivity was
observed using Li or K in THF (Equation (45)) <1995JCS(P1)261, 2000JOC322>.
OH
OH
H2, Rh/Al2O3
ð44Þ
1 M NaOH
HO
OH
OH 53%
OMe
Ph Ph i. Li–THF Ph Ph
ð45Þ
ii. H2O
100%
Cleavage of 4-phenoxyphenol to phenol was reported to be effective by electrohydrogen-

olysis using carbon electrodes entrapped by Raney nickel <1999CJC1225>. Aryl mesylates
have been reduced by Zn in the presence of NiBr2-based catalyst, using MeOH as hydrogen
donor. The use of MeOD as deuterium source led to labeled arenes (Equation (46))
<1997CL617>. Lipshutz and co-workers found that aryl nonaflates could be reduced by
Me2NHBH3 complex in the presence of a catalytic amount of a Pd(0) complex (Equation
(47)). This mixture tolerated amide and ester functions <1999TL6871>. Improvements
have also been reported in the hydrogenolysis of triflates by using Pd(OAc)2 as catalyst. The
classical mixture Et3N–HCOOH, as proton source, can be replaced by HSiEt3 <1995S1348>.
Woodgate found that addition of 5 mol.% of 1,10 -bis(diphenylphosphino)ferrocene (dppf)
improved the yields of these reactions in some difficult cases (Equation (48))
<2001JOM(629)114>. A mixture of Li-4,40 -di-t-butylbiphenyl and NiCl22H2O was also used
for the hydrogenolysis of aryl triflates. However, these conditions appeared more efficient for
the reduction of enol triflates <1999T14479>.
OMs
Zn, NiBr2(PPr3)2
dppb, MeOH, DMA ð46Þ
CN 16 h, 50 °C CN
68%
Br Me2NH–BH3, MeCN Br
ONf cat. Pd(PPh3)4, K2CO3 ð47Þ

40 °C
86%
OSO2CF3
Br Br
Et3SiH, cat. Pd(OAc)2
Me Me
ð48Þ
cat. dppf, DMF, 40 h
88%
MeO2C Me MeO2C Me
1.10.1.2.2 Reduction of enol ethers and derivatives

The reduction of enol derivatives to the corresponding alkenes has been reported by different
methods. This transformation can be carried out from silyl enol ethers (borane reduction) and
alkyl enol ethers (DIBAL-H or Na reductions). However, interesting results were found for the
reduction of enol phosphates (dissolving metal reductions in liquid ammonia or amines) and vinyl
triflates (Pd catalysis in the presence of hydrogen sources such as tin hydrides, silicon hydrides, or
formate) (see COFGT (1995)).
Recently, improved results have been reported in the reduction of these different enol deriva-
tives. Lithium in ethylamine was used for the reduction of enol phosphates to alkenes
<1995JOC1856>. Transformation of aryl or 1,3-ethylenic trimethylsilyl enol ethers into styrene
or 1,3-diethylenic derivatives was found to be an easy reaction by using the Cp2ZrCl2–2BuLi
mixture (Equation (49)) <2001SL123>. The same zirconium intermediate was reported by Marek
and co-workers to be able to reduce methyl enol ethers (Equation (50)) <2000JOC7218>. This
zirconium reagent also reacts with thioenol ethers, vinyl carbamates, vinyl sulfones, and vinyl
sulfoxides <2002S2473>. Nonconjugated dienes bearing an enol ether moiety undergo a tandem
isomerization–reduction reaction (Equation (51)) <2002JA10282>.
OSiMe3 D
i. Cp2ZrCl2, BuLi (2 equiv.), THF, –78 °C
Ph Ph ð49Þ
ii. D2O
76%
i. Cp2ZrCl2, BuLi (2 equiv.), THF, 3 h

OMe
ii. H3O+
90%
C5H11 C5H11
i. Cp2ZrCl2, BuLi (2 equiv.), THF
( )6 ( )5 ð51Þ
ii. H3O+
OMe
70%
A three-step transformation of silyl enol ethers was reported in moderate overall yields. This
transformation can be carried out in a one-pot procedure (Scheme 2) <1997S1134>. New
conditions have been reported for the reduction of vinyl triflates. The mixture Li-4,40 -di-t-
butylbiphenyl in the presence of NiCl22H2O was reported to be very efficient <1999T14479>.
Lipshutz by using the complex Me2NHBH3 in the presence of Pd(0), also published excellent
results <1999TL6871>. Reduction of an enol triflate was also reported by using Me3SnH in the
presence of Pd(PPh3)4 (Equation (52)) <1995H(40)939>.
(EtO)2P(O)SCl O NaBH4 (EtO)3P

Me3SiO Ph OEt S
S
Me P OEt Me Ph
Me CH2Cl2 Alcohol Me Ph 60% (3 steps)
Ph O
(E )–(Z ):14–86
Scheme 2
OTf
O Me3SnH, LiCl, CsF O
O O O O ð52Þ
O Pd(PPh3)4 (16 mol.%) O
49%
1.10.1.3 Reduction of ¼CS, Se, and Te Bonds
1.10.1.3.1 Reduction of aryl sulfides, selenides, and tellurides
(i) Reduction of aryl sulfides

Numerous methods have been developed to desulfurize aryl thiols and sulfides. One of the more
significant methods is probably the use of Raney nickel, even if its manipulation is not always
easy. Nickel boride, formed by the reaction of nickel(II) salts with NaBH4, appears to be a useful
reagent, allowing more chemoselective reactions than Raney nickel. Homogeneous nickel(0)
complexes in combination with hydrides have also been investigated. Metal carbonyls such
as Co2(CO)8, Mo2(CO)6, or Mn2(CO)10 were found to be effective desulfurization reagents. All
these utilizations are reported in COFGT (1995). A review has been published on this topic
<1999T10547>.
Dibenzothiophene is reported to be one of the more difficult substrates to be desulfurized, and
numerous conditions have been tried. In the 1990s, Fort and co-workers found that this com-
pound is transformed into biphenyl by using a mixture LiH–Ni(OAc)2-ButOH <1995TL6051>,
or better a mixture NaH–Ni(OAc)2-AmtOH <1998TL8987>. Bianchiri and co-workers found
that a mixture of rhodium and tungsten salts also gave interesting results <2001CC479>.
Verkade and co-workers utilized Na in a hydrocarbon solvent to obtain the same result (Equation
(53)) <1999EF23>. Reductive opening of dibenzothiins with lithium and a catalytic amount of
4,40 -di-t-butylbiphenyl (DTBB) in THF led to the formation of thiols <2002CL726> (Equation
(54)). A photochemical removal of thiophenyl group was reported to occur in satisfactory yields
<1995G315>. Desulfonization of difluorosulfonic acids was reported to occur in acidic as well as
in basic conditions. These reactions were conducted on industrial scales (Equation (55))
<2000JFC(101)85>.
S i. Na, tetradecane, 150 °C, 24 h

ii. MeOH, H2O ð53Þ
99%
i. Li/DTBB, THF SH
Y –90 or –78 °C Y
ii. H2O (D2O)
ð54Þ
S 50–98% H
(D)
Y = O, S, MeN
F F
R 80% H2SO4, ∆ R
or Na2CO3, DMI, 200 °C ð55Þ
F 78–80% F
SO3H
R = H, Me
(ii) Reduction of aryl selenides and aryl tellurides

Cleavage of aryl-CSe bonds has been reported to occur in the presence of Ph3SnH, Raney
nickel, Li in liquid NH3, or transmetallation with BuLi followed by hydrolysis (see COFGT
(1995)). No new procedures have been reported in this field.
Reduction of aryl-CTe bonds has been reported to occur in the presence of Ph3SnH, Li in
liquid NH3, or transmetallation by using BuLi (see COFGT (1995)). In the presence of YbI2, a
photochemical process was reported to induce this cleavage <1997TL9017>. The transmetalla-
tion method was applied to the formation of 1,3-dienes (Equation (56)) <1995CPB19>.
I I i. Na2S, hexane
But
Te
ii. BunLi, THF
But ð56Þ
iii. H2O Ph
70%
1.10.1.3.2 Reduction of vinyl sulfides, selenides, and tellurides
(i) Reduction of vinyl sulfides, sulfoxides, and sulfones

The reduction of vinyl sulfides to alkenes has been reported by using Raney nickel, nickel boride
(NaBH4 + Ni(II) salts), and nickel(0) complexes. All these methods gave interesting results
reported in COFGT (1995). A review has also been published on this topic <1999T10547>.
Concerning the reactivity of zirconium salts with ethylenic compounds, Marek shows that vinyl
sulfides can be easily transformed into alkenes (Equation (57)) <2002AG(E)1410>. Nickel boride
was reported to reduce selectively vinyl sulfides without the cleavage of sulfoxide or sulfone
groups (Equation (58)) <1998JOC7908>. A ketene thioacetal was stereospecifically transformed
into a vinyl sulfide by reaction with a copper reagent <1995TL1925>.
i. Cp2ZrCl2, BuLi (2 equiv.), THF, rt
SPh
ii. H2O (D2O) ð57Þ
n-C8H17 n-C8H17
80–85%
p-TolSO2 Ni2B, MeOH, THF p-TolSO2

ð58Þ
PrO SEt 79% PrO
The conversion of vinyl sulfoxides to alkenes is more rarely reported. Use of NaOEt or ButLi
has been reported in COFGT (1995). Subsequently, it has been shown that a mixture ButLi–MeLi
was more efficient than ButLi alone (Equation (59)) <2002JOC8166>. SmI2 in a mixture
THF–MeOH was also reported to be efficient as a reducing agent <2000OL365>. -Halovinyl
sulfoxides reacted with Grignard reagents to lead, after hydrolysis, to halovinyl compounds
(Equation (60)) <1998T5557>.
OH O OH
MeLi, ButLi, Et2O
S Bu t
But p-Tol ð59Þ
–78 °C
45% Bu n
Bun
i. EtMgX, Et2O, –70 °C

R1 X ii. H2O R1 X
Ar ð60Þ
R2 S 78–84% R2
O
X = F, Cl, Br
The reduction of vinyl sulfones has been extensively studied, and reagents such as nickel(0)
complexes, palladium(II) salts, Mg, Bu3SnH, NaTeH, Na2S2O4, amalgams (Al or Na), etc. were
used (see COFGT (1995)). Recently, new reagents have also been reported to give excellent
results. Desulfonation of vinyl sulfones by SmI2 was shown to lead mainly to (E)-alkenes
<1995JOC3194> (Equation (61)). Reaction with MeOD gave labeled products. Use of Sm was
reported in the case of ,-ethylenic nitriles and amides (Equation (62)) <2001OPP372,
2001JCR(S)26>. Vinyl sulfones were reduced, as vinyl sulfides, with zirconium salts (see Equation
(57)) <2002AG(E)1410>. Cleavage of the vinyl-CS bonds was reported to be possible with Na
in tetradecane at high temperature (Equation (63)) <1998TL2671>.
SO2Ph
SmI2, THF, DMPU, MeOH
Ph ð61Þ
Ph Ph
85%
Ph
SO2Ph Sm, AcOH, EtOH CN

ð62Þ
CN 90%
Br Br
SO2Ph Na, tetradecane
190 °C, 6 h ð63Þ

95%
-Sulfonyl-,-ethylenic esters were desulfonated by the reaction with DBU (Equation (64))
<1999TL5957>. Magnesium activated by ClSiMe3 in DMSO was used to selectively desulfonate
-methylthiovinyl sulfones (Equation (65)) and stereoselectively -alkyl vinyl sulfones (Equation
(66)) <2002CL478>. These cleavages were also observed with sulfoxides. Monodesulfonation of
(Z)-1,2-disulfonyl ethylene was reported to be possible with diphenylsilane in the presence of
PtCl2 <1996SC211>.
Ts DBU
R1 CO2Me R1 CO2Me
ð64Þ
R2 40–75% R2
OH OH
SMe Mg, ClSiMe3, DMSO

Ar Ar ð65Þ
SO2p-Tol SMe
57–72%
R Mg, ClSiMe3, DMSO

Ar Ar
SO2p-Tol R ð66Þ
77–97%
E > 99%
(ii) Reduction of vinyl selenides

Reduction of sp2 CSe bonds in vinyl selenides has been reported by the reaction with nickel
boride, addition of BunLi followed by protonolysis, and treatment with Bu3SnH–AIBN or P2I4
(see COFGT (1995)).
The reaction of vinyl selenides with BunLi was applied to the formation of enynes (Equation
(67)) <1998S39, 1998JCR(S)616>. This reduction was also effective with LAH and occurred with
retention of configuration (Equation (68)) <1996JOM(523)139>.
i. BunLi, THF, –78 °C

SePh
ii. H2O
Bun Bun ð67Þ
90%
Ph Ph
i. LiAlH4, THF
c-C6H11 n c-C6H11 n
C4H9 ii. MeOH C4H9
ð68Þ
100%
RSe
R = Me, Et
In the case of vinyl selenides, -functionalized by amino acids, the reaction with Bu3SnH–
AIBN led to substitution of the selenyl group by a tin group, and the reduction products were
obtained only after hydrolysis (Scheme 3) <2000JA11031>. It has been reported that an -sele-
nyl-,-enone was reduced by NaI in CH3CN. However, this reaction does not appear to be
general (Equation (69)) <2000JOC6293>.
R SePh Bu3SnH, AIBN R SnBu3 H3O +, ∆ R

MeO2C Toluene, ∆ MeO2C MeO2C
NHBz NHBz NHBz
83–87% (2 steps)
Scheme 3
N NaI, MeCN, BF3 . Et2O N

ð69Þ
HO 84% HO
SePh OMe
OMe O O
(iii) Reduction of vinyl tellurides

The most usual method used to cleave the sp2 CTe bond is transmetallation followed by
hydrolysis. This exchange reaction was carried out with BunLi and cuprates. Reduction of vinyl
tellurides was also reported with Raney nickel (see COFGT (1995)).
Convenient preparation of vinyl tellurides is reported by addition of diorganoditellurides to
acetylenic compounds. Since the subsequent transmetallation is an easy process, these reactions
were applied efficiently for the preparations of alkenes <1996JOC4975>. To the previous known
methods of transmetallations using BunLi and cuprates, new procedures based on the reactivity of
organozinc <1996TL4741> and Grignard reagents were published <2000TL5103> (Equation (70)).
A chemoselective reduction of a vinyl telluride using NaBH4 as reducing agent was reported
(Equation (71)) <2001JOC74>. This reduction is also possible with Bu3SnH–AIBN
<2002AG(E)1407>.
O i. EtMgBr, THF, –78 °C

O
TeBun ii. H3O +
(EtO)2P (EtO)2P
ð70Þ
Ph Ph
69%
p-TolSO2 NaBH4, THF, EtOH p-TolSO2

TePh
ð71Þ
Ph 76% Ph
1.10.1.4 Reduction of ¼CN Bonds
1.10.1.4.1 Reduction of arylcarbonnitrogen bonds

The direct displacement of aromatic nitro group to hydrogen is a rare reaction, and was reported
for particular substrates. This substitution is usually carried out after reduction of the nitro
compounds to the corresponding amines <1997MI(37)121>. These can then be transformed
into diazonium salts (reaction with sodium or potassium nitrite), and cleavage of these salts is
possible with a variety of reagents such as H3PO2, EtOH, formaldehyde, Zn, Sn, NaBH4,
Bun3 SnH, or Et3SiH <B-94MI1, 1990HOU(16a)1052>. Cleavage of aryl-CN bonds is also
reported from hydrazines, by oxidation into azo compounds, by using reagents such as HgO or
K3Fe(CN)6.
Since the publication of COFGT (1995) new results have been reported. Flash vacuum
pyrolysis at 1000 C of some aromatic nitro compounds led to the elimination of the nitro
functions (Equation (72)) <1997AJC1159>. Cleavage of aryl nitro functions has also been
reported by reaction of nitrophenylpyrazolidinones with pyridine hydrochloride. The mechanism
of this reaction seems still unclear (Equation (73)) <2000CC415>. Transformation of electron-
deficient arylamines into diazoniums was reported in the presence of NO2. The subsequent
decomposition occurred easily with Ca(H2PO2)2 in the presence of FeSO4 or Cu2O (Scheme 4)
<2000TL5567>. Decomposition of diazoniums with HSiCl3 was found to be a fast and clean
reaction. This chlorosilane reacted with the corresponding triazenes to lead to the same products
(Scheme 5) <2000TL3813>. Cleavage of triazenes was conducted on solid phase with the same
efficiency. Decomposition of diazoniums with Et3N in MeOH <1996SC1569> or FeSO4 in DMF
was also reported to give excellent results <1995JOC1713>. The direct reduction of arylamines
was carried out with Li in THF. This reaction is limited to aryl substituents (Equation (74))
<1999TL8291>.
FVP
NO2 ð72Þ
1000–1100 °C
O Me O Me
Me Me
HN Pyridinium chloride, Pyr HN
N N ð73Þ
NO2 115 °C
23%
+ –
NH2 N2 NO3 i. Ca(H2PO2)2, MeCN
NO2, MeCN ii. FeSO4 or Cu2O
84–98% (2 steps)
R R R
Scheme 4
+ N N (CH2Ph)2
N2 NO3– N
HSiCl3, CH2Cl2 HSiCl3, CH2Cl2
32 °C, 15 min 32 °C, 15 min

R R R
>95% >90%
Scheme 5
Li, THF, 24 h, rt
NMe2 ð74Þ
100%
Weinreb and co-workers found that arylamines substituted in the position by an amide
function reacted with NaNO2 and a catalytic amount of CuCl to lead to -methoxyamides
(Equation (75)) <1996JOC9483>. N,N-Dimethylarylamines, after transformation into ammo-
nium salts, were reduced by sodium in liquid NH3 <2002JA7894>. Primary arylamines, after
transformation into sulfonamides, were reduced under alkaline conditions to aryl compounds
(Scheme 6) <2001JOC8293>. This cleavage is compatible with the presence of functional groups
such as ketones, esters, amides, nitro groups, acids, etc. Aryltriazoles, in a mixture THF–MeOH,
were transformed under irradiation into arylamines (Equation (76)) <1996JA6522>.
NH2 O O
NaNO2, HCl, MeOH
N N ð75Þ
CuCl (5 mol.%), rt
71% MeO
MeSO2Cl, Pyr NaH, DMF, NH2Cl

ArNH2 ArNHSO2Me ArH
43–96% 53–96%
Scheme 6
N MeOH, THF, hν
N ð76Þ
N NH2
80%
H
Some interesting results have also been reported in the 1990s, concerning the reduction of aryl
hydrazines of type ArNH–NH2. Oxidation into azo compounds was reported using PbO2. The
subsequent decomposition led to the desired arylamines <1997MI6445>. Cleavage of the acyl-
CN bond was also carried out with NO in the presence of a very small amount of O2. Aryl
azides were formed as side products in small quantities (Equation (77)) <1997JOC3582>. Irra-
diation of aryl hydrazones at 300 nm in methanol also led to aryl compounds. In this case,
phenols were obtained as side products (Equation (78)) <1997JCS(P1)2451>.
NO, O2 (trace), THF

R NH NH2 R + R N3
ð77Þ
61–82% 8–23%
H2O, hν, O2
R NH NH2 R + R OH
(pH 7.4) ð78Þ
69–85% 6–13%
1.10.1.4.2 Reduction of vinylcarbonnitrogen bonds

The transformation of nitroalkenes into alkenes has been reported via the formation of -nitro-
trithiocarbonate intermediates, followed by a photochemical elimination (Barton procedure), or
directly by reaction with Bu3SnH. The transformation of enamines into alkenes was reported by
reaction with alane, diborane, and 9-BBN. For these two transformations, no new results have been
reported since those published in COFGT (1995). 3-Aminomethylene–dihydrofuranone derivatives
reacted with DIBAL-H to produce 3-methylene derivatives (Equation (79)) <2000TL8451>.
Similar results were reported using NaCNBH3 as reducing agent <1997T10633>. Reduction of
an aminofulvene to fulvene was carried out using DIBAL-H <1997ZN(B)911>.
Me Me
O O
O DIBAL-H, –78 °C, 3 h O
ð79Þ
H 65% H
Me2N
1.10.1.5 Reduction of ¼CP, ¼CAs, ¼Sb, and ¼CBi Bonds
1.10.1.5.1 Reduction of arylcarbonphosphorus, arsenic, antimony, and bismuth bonds
(i) Reduction of arylcarbonphosphorus bonds

The most common method to reduce aryl-CP(III) bonds consists in the use of alkali metals,
followed by hydrolysis. Complexes such as RuH2(PPh3)4 have also been used. The cleavage of
arylphosphonium salts can be carried out by hydrolysis (formation of phosphine oxides) or
reduction with LAH. The reduction of aryl-CP(V) bonds is much less widespread. A few
examples have been reported using solid KOH or NaH. More information can be found in
COFGT (1995).
Recently, it has been reported that lithium derivatives allowed cleavage of aryl-CP(III) bonds,
when an intramolecular attack on the phosphorus atom is possible (Equation (80)) <1996TL5347,
1996JOM(507)257, 2003BCJ1233>. A selective cleavage of the CP bond between a naphthyl
and a diphenylphosphonyl group is also possible in these conditions. This reaction appeared to be
reversible, and it was made irreversible by complexation of one of the phosphorus atoms by
BH3 (Equation (81)) <2001JOC8854>. Preparation of 1,2-bis(phenylphosphino)ethane from
1,2-bis(diphenylphosphino)ethane was reported by reaction of Li in THF (Equation (82))
<2000JOC951>. Ru(OAc)2 in the presence of HBF4Et2O allows the cleavage of aryl-CP(III)
bonds. The main drawback of this reaction is the very low rate of the reaction (2 weeks at rt)
<1998OM5213, 2001OM2990>. Degradation of phenylphosphonic acid into benzene and biphe-
nyl with a bacterium (Rhizobium sp.) is also reported <1995MI157>.
Me Me i. BunLi, –70 °C Me Me
ii. > –20 °C
+ PhLi ð80Þ
80%
P
I PPh2
Ph
O i. BunLi, THF, –78 °C

P Ph2 ii. MeOD D
ð81Þ
P Ph2 46% P Ph2
BH3 BH3
i. Li, NH3
H H
ii. H2O ð82Þ
Ph2PCH2CH2PPh2 PhPCH2CH2PPh
80%
(ii) Reduction of arylcarbonarsenic, antimony, and bismuth bonds

Triorganoarsenic compounds, diarsines, and diorganoarsenic halides are reduced by alkali metals
to afford diorganoarsenic species. The cleavage of aryl-CAs bonds has also been achieved using
NaHSO3 and aqueous bases. Pentaorganoantimony and -bismuth compounds were reduced with
electrophiles such as HF, HCl, and Br2 to conduct the formation of organoantimony(IV) and
-bismuth(IV) halides. The number of reports concerning these different reactions is limited (see
COFGT (1995)). Only one new report, concerning such reactions, has been published. To try to
prepare diorganobismuth compounds, reduction of diarylbismuth chloride was attempted. Only
cleavage of aryl-CBi bonds was observed (Equation (83)) <1995JOM(485)141>.
Ph Ph
Mg, THF, NaBr, NH3(l)
Ph BiCl Ph + Bi(0) ð83Þ
or cobaltocene
3 Ph
Ph
75%
1.10.1.5.2 Reduction of vinylcarbonphosphorus bonds

Substituted alkenes and allenes were obtained from vinyl phosphines by metallation with MeLi,
followed by hydrolysis of the resultant vinyllithium. Hydrolysis with bases or acids of vinyl-
phosphonium salts is also reported to give the corresponding alkenes (COFGT (1995)). Treatment
of a 2-phosphonyl 2,3-cyclopentenone with hot water <1996AG(E)1560>, or alkali bases
<1997TL2527>, led to the hydrolyzed product (Equation (84)).
O O
O NaOH or LiOH
P OMe ð84Þ
OMe H2O, MeOH, rt
57–62%
1.10.1.6 Reduction of ¼CB, ¼CSi, and ¼CGe Bonds
1.10.1.6.1 Reduction of aryl boranes, silanes, and germanes
(i) Reduction of aryl boranes

The aryl-CB bond cleavage is promoted with acids or bases in drastic conditions. It was found
that metal salts (e.g., CuCl2) catalyze this cleavage and allow milder reaction conditions. Aqueous
silver ammonium nitrate and aqueous ethanolic dimethylaminoethanol have also proved effective.
In the 1990s, some new results confirmed these previous results. For example, Carboni and
co-workers found that aryl compounds were obtained in good yields by cleavage of the aryl-CB
bond using aqueous silver ammonium nitrate in THF. This cleavage was applied to solid phase
(Equation (85)) <2000CC1275>.
O O Ag(NH3)2NO3 O OH
B Ar + H–Ar
THF, H2O ð85Þ
O OH
57–85%
The SuzukiMiyaura coupling reaction is well documented <1999JOM(576)147> using palla-

dium salts. In the absence of an acceptor (e.g., chloroarenes), this reaction proceeds to the
formation of biaryl compounds <1997SL131>. With electron-enriched boronic acids (Equation
(86)), no coupling was observed. It seems possible, even if this has not yet been reported, to find
conditions that lead to the exclusive substitution of the boron group by hydrogen. The aryl-CB
bond cleavage was also reported with [Rh(COD)Cl]2 in basic conditions <2002OL2105>.
OMe OMe
Pd(OAc)2, EtOH, Ba(OH)2
MeO B(OH)2 MeO ð86Þ
O2, rt
OMe OMe
91%
(ii) Reduction of aryl silanes

The ipso substitution of silicon by hydrogen in aryl silanes has been extensively studied, and applied
in synthesis. This chemistry is largely covered in books and review articles. For a recent example see
<B-2002MI685>. The aryl-CSi bond (as the vinyl-CSi bond) can be cleaved using electrophilic
or nucleophilic reagents (see COFGT (1995)). Cleavage of these bonds, in acidic conditions, is
commonly carried out with inorganic acids such as HCl, H2SO4, or carboxylic acids such as
CF3COOH and HCOOH. Nucleophilic reagents such as butoxides, sodium methoxide, NaH,
KH, K2CO3, and F (CsF, KF, TBAF) are usually used. Desilylation of aromatic compounds is
often planned in organic synthesis, and the choice of the reagent depends on the functionalization of
the substrates.
In the 1990s, this cleavage was applied to solid-phase organic synthesis for the preparation of
numerous compounds <1995JA11999, 1996TL2703, 1999TL8563, 1997JOC2885, 1997JOC6102,
1997JOC6726, 1998JOC4518, 2001TL1815>. Use of fluorides and TFA led to satisfactory results
in these particular conditions. Amphiphilic molecules with silicon are stable in organic solvents
and in aqueous solution. However, at pH 1 the cleavage occurred in less than 5 min (Equation (87))
<1999TL4935>.
+
–
H3O + +
RMe2Si O NMe3 I O NMe3 I
– + HOSiMe2R
(pH = 1) ð87Þ
100%
n
R = Me, Bun, C12H25
Some new or particular conditions have been reported for the cleavage of aryl-CSi bonds.
For example, this cleavage was observed in super-critical water (374 C under 22.1 MPa)
(Equation (88)) <2003JA6058>. It has been reported that the reduction was very fast in liquid
ammonia (1 min) using NaNH2 in the presence of FeCl3 (Equation (89)) <2000SL619>. In some
particular cases, the mixture Me3SiCl–KI in aqueous MeCN gave interesting results
<1995TL5093>. Treatment of a pyrazole with HBF4 led to the cleavage of the heterocycle
CSi bond instead of the aryl-CSi bond. No fluorine compound was formed (Equation (90))
<2001S1949>. Heterocyclic CSi bond cleavage was also observed during the oxidation of a
thiophene derivative (Equation (91)) <1997CL499>.
H2O, 390 °C
Me3Si Bun Bun
27 MPa, 30 min ð88Þ
91%
MeO MeO
NaNH2, FeCl3, liq. NH3
Me3Si ð89Þ
MeO 80% MeO
PhMe2Si Me Me
HBF4. Et2O, CH2Cl2
Ph N Ph N ð90Þ
N 90% N
Ph Ph
But But But But

MCPBA, BF3. Et2O, CH2Cl2
Me3Si
ð91Þ
S SiMe3 97% S
O
Aryl silanes in which the aryl group is electron poor can be cleaved by using anhydrous HF,
FSO3H, or CF3SO3H. These cleavages occurred rapidly under these conditions (Equation (92))
<1998JOM(570)255>. Liquid HI was reported to initiate the cleavage of ethylmesitylsilane to
trimethylbenzene and iodoethylsilane in 1 week at 35 C <2003MI(644)105>. PhSiH3 was
reported to be transformed into SiH4 in the presence of a stoichiometric amount of a lutetium
hydride complex (Equation (93)) <2001OM5598>.
F F F F
HF, rt, 12 h
F SiMe3 F H + FSiMe3 ð92Þ
or CF3SO3H, rt, 1 min
F F F F
100%
[Cp2LuH]2, H2
PhSiH3 + SiH4
Cyclohexane ð93Þ
80%
(iii) Reduction of aryl germanes

Germanecarbon bonds are susceptible to react with electrophiles similar to SiC bonds.
Cleavage of these bonds is reported with TFA or HClO4. In nucleophilic conditions, sodium
methoxide was reported to be effective. Aryl germanes are much less used in synthesis than aryl
silanes. However, they were examined as linkers in solid-phase synthesis for the preparation of
pyrazoles. Cleavage of the aryl-CGe bonds was carried out with TFA <2000JOC5253,
1997JOC2885>. Strong acids such as CF3SO3H or ClSO3H were also reported to cleave the
aryl-CGe bond of electron-poor aromatic compounds <1994HAC91>.
1.10.1.6.2 Reduction of vinyl boranes, silanes, and germanes
(i) Reduction of vinyl boranes

The hydroboration of alkynes is a method of choice to access vinyl boranes. This reaction has
been featured in reviews (e.g., <1997T4957>). Protonolysis of the CB bond can be carried out
under mild conditions, compatible with numerous functional groups owing to the utilization of
MeOH, carboxylic acids such as acetic or pivalic acids, or inorganic acids such as HCl. Reaction
of alkenyldialkylboranes with BunLi gave borates, which can be hydrolyzed with NaOH. Clea-
vage of vinyl-CB bonds with aqueous silver ammonium nitrate or Pd(OAc)2 has also been
reported (see COFGT (1995)).
Hevesi and co-workers found that the hydrolysis of vinyl borates was improved by addition of
CuI (Equation (94)) <2001T9109>. Addition of DIBAL-H to vinyl boranes was reported to
produce clean B ! Al exchanges, and the subsequent hydrolysis can be carried out by simple
addition of water (Scheme 7) <2002CC2146>. Selective cleavage of the vinyl-CB bond of a
silacyclopentadiene has been reported with 2-aminoethanol in THF (Equation (95)).
i. MeLi, THF, HMPA

R1 R2 ii. CuI R1 R2
ð94Þ
R3Y B(R4)2 iii. H2O R 3Y
Y = S, Se, Te 55–86%
c-Hex2B DIBAL-H, 1-hexene Bui2Al H2O (D)H
octyln 0 °C, 2 h octyln (D2O) octyln
84%
Scheme 7
Et2B Et Et
2-Aminoethanol, THF
Bu Bu ð95Þ
Si Bu 83% Si Bu
H Me H Me
(ii) Reduction of vinyl silanes

The chemistry of vinyl silanes has been extensively studied <1995CRV1375, B-1998MI1793,
B-2002MI713>. The cleavage of vinyl-CSi bonds can be carried out with electrophilic or nucleo-
philic reagents (see COFGT (1995)). A large variety of acids has been tested; among the most used
acids were HI, HF, HBr, AcOH, HCl (in MeOH, acetone, diethyl ether), TsOH, and CF3COOH. In
nucleophilic conditions, fluorides (TBAF, KF, CsF) or alkoxides are usually used. Cleavage of
CSi bonds with Ag(NH3)2NO3 or Pd(OAc)2 has also been reported (see COFGT (1995)).
As representative examples concerning reagents used in the 1990s, TBAF in DMSO
<2000JOC6508>, CsF in moist DMSO <1996JCS(P1)2803>, K2CO3 in EtOH <1999T6739>,
HCOOH in MeOH <2000CC569>, MeONa in MeOH <1996TL755>, KH in the presence of
18-crown-6 <1995T4665>, EtSHBF3Et2O <1998JA7411>, and TFA <2003JOC1929> can be
quoted. Some particular reactions can be emphasized. For example, chemoselective removal of a
trimethylsilyl group was reported to occur in the presence of a trimethylgermyl group (Equation
(96)) <1995JCS(P1)3>. Yamaguchi found conditions to selectively remove one, two, or three
triethylsilyl groups fixed on a 1,3,5-triene (Scheme 8) <1998JOC8086>. Treatment of a tetrahy-
drothiepine with CsF led to the clean removal of a dimethylphenylsilyl group, while with the more
nucleophilic TBAF shift of the CC double bond was observed (Scheme 9) <1996T4803>.
HO SiMe3 TsOH, CH2Cl2, rt HO

ð96Þ
Me3Ge Me3Ge
85%
HF, MeCN
Et3Si reflux, 2.5 h
octyln octyln
Et3Si Et3Si Et3Si Et3Si
78%
TBAF, THF, 0 °C TBAF, THF, ∆

94% 87%
octyln octyln
Et3Si
Scheme 8
O O O O O O
S TBAF, THF S SiMe2Ph CsF, MeCN S
60% 67%
Scheme 9
Cleavage of CSi bond followed by a transannular 1,6-cyclization was reported when a

,"-ethylenic decanone was treated with TFA (Equation (97)) <1997T14235>. Fürstner found that
AgF cleaved vinyl silanes of (E)-stereochemistry, included in large rings, without isomerization. In
addition, these conditions are compatible with the presence of a large number of functional
groups (Equation (98)) <2002CC2182>. Trost, on the same kind of substrates, reported that
the use of the mixture TBAF–CuI also led to excellent results <2002JA7922>. Cleavage of
vinyldimethylsilanes was reported with Ru3(CO)12 in toluene. This particular reaction seems to
take place by elimination of a silylene complex (Equation (99)) <1999CL717>. Chlorovinyltri-
methylsilanes were reported to be transformed into chloroethylenes by reaction with HCl in the
presence of FeCl3. This cleavage was also observed with dimethylchloro- and dichloromethyl-
silanes (Equation (100)) <1999MI375>.
Pr3i Si
CF3CO2H, CH2Cl2
ð97Þ
85%
OH
O
Si(OEt)3 AgF, THF, aq. MeOH H

ð98Þ
rt, 3 h
84%
Ru3(CO)12, toluene
SiMe2H(D) H(D)
Ph Ph
115 °C, 5 h
ð99Þ
70%
Cl HCl, FeCl3 Cl
ð100Þ
Cl SiMe3 rt, 3 h Cl
Interesting results have been reported for the removal of the vinyltrialkylsilyl group of allylic or
benzylic alcohols. Lautens and co-workers reported that a triethylsilyl group was selectively
removed by treatment of an allylic alcohol with NaH (Equation (101)). This result was explained
by a C ! O intramolecular migration of the triethylsilyl group, while the trimethylsilyl group
remained unchanged. This migration was not observed when MeLi was used as a base
<1995JOC4213>. The same migration of silyl groups was reported with furan and thiophene
derivatives <1997JOC8741>. In place of NaH, KF in DMSO at 150 C <2001SC3641> or
irradiation in benzene <2001JA3638> were also found to be efficient.
Pr3i Si OH OSiPr3i
NaH (0.1 equiv.), DMF
Me3Si ð101Þ
Me3Si
90%
(iii) Reduction of vinyl germanes

Preparation of vinyl germanes has been recently reported <2000SL495, 2000TL9981>. Very few
results exist which report their reaction with electrophiles. Cleavage of an sp2 CGe bond was
reported with conc. HCl (Equation (102)) <1985JGU1853>. Substitution of a vinyltrimethyl-
germane by a hydrogen was reported to be more effective by the intermediate formation of a vinyl
iodide (Scheme 10) <2002TL8575>.
Me3Ge OEt OEt

Conc. HCl, MeOH
ð102Þ
H N N 6 h, ∆ H
N
N
91%
ButMe2SiO GeMe3 ButMe2SiO I ButMe2SiO

Dichloroethane Bu3SnH, THF
ButMe2SiO O ButMe2SiO O ButMe2SiO O
NIS, 36 h, ∆ 55 °C
H H H
90% 83%
Scheme 10
1.10.1.7 Reduction of ¼CC Bonds
1.10.1.7.1 Reduction of arylcarboncarbon bonds

Heating (200–300 C) in quinoline in the presence of copper salts usually carries out the decar-
boxylation of benzoic acids <1986TL3045>. Improvements of these reaction conditions have
been reported. Microwave irradiation allows the CO2 elimination at lower temperature, in high
yields <2000JCR(S)42>. Heating in CH3COOH <1998T1943> or in hot water (250–300 C)
(Equation (103)) <1997JOC2505> was reported to lead to clean decarboxylation. Heating of
anhydrides at 80 C in the presence of Ba(OH)2 also led to interesting results <1996JOC1136>.
H2O, 255 °C, 20 min

CO2H
N N
ð103Þ
93%
H H
Deacetylation in strong acidic conditions (retro-Friedel–Crafts reaction) was reported by using

SnCl4 (Equation (104)) <2002JCR(S)463> or Nafion-H <1997JCS(P1)1193> (see also
<1983JOC3360, 1986S513>).
OMe OMe
O i. SnCl4, dichloroethane, ∆
O
ii. H2O
N OMe N OMe
ð104Þ
H 86% H
O
OMe OMe
Deformylation of aromatic aldehydes was reported using Nafion-H <1997JCS(P1)1193>,

Sc(OTf)3 <1996T11045>, or the Wilkinson catalyst (Equation (105)) <1995T11693>. A more
efficient Rh complex was used with success in a case for which Rh(PPh3)3Cl was inefficient
(Equation (106)) <2002JCS(P1)1622>.
BzlO BzlO
CHO
MeO MeO
Me Rh(PPh3)3Cl, toluene Me
MeO MeO
ð105Þ
MeO MeO
Me ∆, 2 days Me
MeO 87% MeO
CHO
BzlO BzlO
O O
O Rh(dppp)2+ BF4– , xylene O
ð106Þ
OAc 140 °C, 15 h OAc
CH2OH
48%
1.10.1.7.2 Reduction of vinylcarboncarbon bonds

Pyrolysis of cinnamic acids led to the formation of styrenes. However, as in the case of benzoic
acids, heating in quinoline in the presence of Cu or its salts led in general to better results.
Heating of ethyl cinnamate in H2O at 220 C led to the formation of styrene in good yield
<1997JOC2505>. Decarboxylation of cinnamic acid derivatives was reported by using plant
cell cultures. The more efficient plants tested were Catharanthus roseus and Nictoniana tabacum
(Equation (107)) <1999TL6595>. Specific decarboxylation can occur by pyrolysis of the acids
without the necessity of heating at high temperature. For example loss of CO2 for the lithium salts
of acid in Equation (108) was reported to occur at 180 C <1996JOC5013>.
MeO MeO
N. tabacum, H2O
ð107Þ
HO CO2H 5 days, rt HO
100%
Me i. LiOH, H2O Me
Me ii. 180 °C Me
CO2Me ð108Þ
O N 92% O N
H H
Deformylation of cinnamaldehyde was reported with RhCl(PPh3)3 in the presence of diphenyl-

phosphorylazide <1992JOC5075>. Sc(OTf)3-induced deformylation of an ,-unsaturated
aldehyde to produce chromenone. This reaction was also carried out with La(OTf)3 or Y(OTf)3
(Equation (109)) <1996T11045>.
O O
CHO Sc(OTf)3
ð109Þ
MeOH
O O
90%
1.10.1.8 Reduction of ¼CMetal Bonds
1.10.1.8.1 Reduction of arylcarbonmetal bonds

The substitution of metal by hydrogen atom in aryl metal compounds is mainly carried out with
water or inorganic acids diluted in water. Hydrolysis with D2O provides information on the
position of the metal atom. Metallation of dibenzofuran with BusLi (Equation (110))
<1995TL7657>, or reaction of bromoaryls (Equation (111)) <1997TL355, 2000JOC3626> with
ButLi, followed by reaction with D2O, was used to obtain labeled compounds. Hydrolysis of
Grignard reagents gave similar results <2001MI854>. An arylmercurial compound was treated
with DCl to also lead cleanly to the labeled product (Equation (112)) <1997CHE898>.
i. BusLi, Et2O
ii. D2O
ð110Þ
O 99% O
D
Br i. ButLi, Et2O D
ii. MeOD ð111Þ
N N
Ph S 93% Ph S
HgCl D
DCl, D2O, 3 h, rt
ð112Þ
Me O Me 90% Me O Me
1.10.1.8.2 Reduction of vinylcarbonmetal bonds

Numerous examples can be found in the literature concerning the reaction of vinyl metal intermedi-
ates (Li, Na, Ca, Ba, Cu, Mg, Al, Zr, Ni, etc.) with H2O or diluted inorganic acids. In the case of vinyl
boranes, reaction with acetic acid or transmetallation with alkyllithium (followed by addition of
water) is normally used. Vinyl mercurials are cleaved to the corresponding alkenes by protonolysis or
reduction (NaBH4) (see COFGT (1995)). Some new results have appeared concerning the hydrolysis
of alkenyllithiums. This reaction was used to prepare vinyl ethers possessing a chiral substituent
starting from ethyl vinyl ether (Scheme 11) <1996TL7255>. Addition of D2O to polyalkenyllithium
compounds allowed the elucidation of the mechanism of rearrangement of these compounds
<1998EJO793>. Hydrolysis by addition of water to vinyl titanates was used as a stereoselective
preparation of alkenes and 1,3-dienes (Scheme 12) <2001JOM(633)18>. Reaction of imines by a
titanate complex followed by hydrolysis led to amines (Scheme 13) <1997SL1353>.
i. ButLi, THF, –78 °C

OEt Br OR ii. H2O OR
R = menthyl, bornyl, fenchyl 100%
Scheme 11
R1
Cp2TiCl2 R2 H3O + (D + ) R1 R2
R1 R2 Cp2Ti
EtMgBr (2 equiv.) 93–95% (D)H
R1
Cp2TiCl2 R2 H3O + R1 R2
R1 R2 Cp2Ti H
BunLi (2 equiv.) Low yields H
R2 R1 R 1 R2
Scheme 12
Ti(OPri)2 i. D2O
R3 H
R1 N ii. H2O R1 N 3
N (PriO) 2Ti R
R2 R3 –40, –50 °C, 2 h 90–98% R2 D
R2
R1
Scheme 13
Numerous works have been reported on the destannylation of vinylstannanes. With com-
pounds stable under acidic conditions, the reaction can be achieved with CF3COOH
<1999JOC1447, 2001JOC7385, 2002T9117>, TsOH <1999JOC5377, 1995JOC4595>, aqueous
HCl <1998T12807, 1995SC1921> (Equation (113)), or EtOH, HCl(g) <1996JOC1354>. Nucleo-
philic conditions using reagents such as K2CO3 in MeOH, <1996TL8199>, NaOMe in MeOH, or
CsF in MeOHNH3 <1996T45> (Equation (114)) were also reported to produce the desired
cleavage. In the case of sensitive compounds such as alkyl enol ethers, thioenol ethers
<1999JCR(S)290, 1997SL1165>, and seleno-enol ethers (Equation (115)) <1999SL1055> trans-
metallation followed by hydrolysis appears to be a more appropriate method.
O O
(EtO)2P R 6 M HCl, CH2Cl2 (EtO)2P R
ð113Þ
Ph3Sn or 20% HF, CH2Cl2
90%
Me SnBu3 NaOMe, MeOH, THF, ∆ Me H

Ph Ph ð114Þ
F 64 % F
i. BunLi, THF
Me3Sn Bu ii. H2O Bu ð115Þ
PhSe 90% PhSe
Reduction of a vinylstannane has been reported to occur during the cleavage of a p-methoxy-
benzyl ether by DDQ (Equation (116)) <2000TL2821>. The use of AgOTf was also reported to
be efficient (Equation (117)) <1995T3997>.
SEMO OPMB SEMO OH

DDQ, CH2Cl2, H2O
Me ð116Þ
Me
(no yield reported)
Me Me SnMe3 Me Me
SnMe3
AgOTf, CH2Cl2, 20 min
ð117Þ
75%
Ph Ph
1.10.2 ONE OR MORE ¼CH BONDS BY ADDITION
1.10.2.1 Addition to Alkynes
1.10.2.1.1 Addition of hydrogen to alkynes

Numerous methods have been reported for the semihydrogenation of alkynes. The main methods
consist in addition of hydrogen to alkynes in the presence of heterogeneous or homogeneous
catalysts, or by using dissolving metal reductions. Currently, there is increased interest concerning
catalytic transfer of hydrides induced mainly by palladium catalysts or low-valent metals. Transi-
tion metal hydride reductions and addition of diimide are much less used.
(i) Formation of (Z)-alkenes

One of the most popular conditions for the reduction of alkynes to (Z)-alkenes is the use of
heterogeneous catalysis. Generally, Pd-, Pt-, and Ni-based catalysts are used. Homogeneous
catalysts such as the Wilkinson’s catalyst (RhCl(PPh3)3), or other Rh-, Ir-, Cr-, Fe, Ti-catalysts
are also reported to lead to (Z)-alkenes. Transition metal salts such as CoCl3–4PPh3, SmI2 in the
presence of alcohols as proton source, or copper(I) hydride gave satisfactory results. Reduction
with diimine or hydrometallation with B, Al, and Zr compounds followed by hydrolysis is also
interesting in the preparation of (Z)-alkenes. All these methods are discussed in COFGT (1995).
Currently the most frequently used catalysts for the semihydrogenation of alkynes to alkenes are
the Lindlar catalysts, usually poisoned with a base such as quinoline and P-2Ni (Ni(OAc)2–NaBH4
mixture) <1973CC553, 1973JOC2226>. Their success is probably due to their availability and the
facility to carry out the reactions. New conditions for the use of the Lindlar catalyst have been
reported. Ultrasound irradiations are claimed to lower the hydrogenation time <1996SC3809>. In
the presence of ethylenediamine, this catalyst was reported to improve the hydrogenation of
acetylenic compounds functionalized by free amines (Equation (118)) <2001JOC3634>.
H2, Lindlar cat., DMF

H2N H2N Ph
Ph ( )4 ( )3
( )3 ( )2 Ethylenediamine, 18 h ð118Þ
97.4%
Supported P-2 Ni on Amberlite resin was reported to have increased reactivity when compared to
the nonsupported reagent <1996TL1057>. New supported Pd heterogeneous catalysts have been
reported to give excellent stereo- and chemoselectivities. Pd(OAc)2 supported on a borohydride
exchange resin (BER) in the presence of CsI led to fast formation of (Z)-alkenes (Equation (119))
<1996TL8527>. Excellent stereoselectivity was also reported with a silica-supported PdCu cata-
lyst <2001JOC1647>, and Pd supported on pumice <2001TL2015>. Copper supported on
-Al2O3 led at 150 C under pressure (80 atm) to produce clean (Z)-alkenes <1996MI1057>. The
reduction of alkynes under homogeneous catalysis is often carried out, using the easily available
Wilkinson’s catalyst. In this field, new and more or less sophisticated complexes have been tested,
based on Pd (Equation (120)) <2002OM1546> or Rh(Rh(dppe)2(BF4)2) <2002AG(E)1607>.
H2, Pd(OAc)2, CsI

C5H11 C5H11
HO HO
EtOH, BER, 30 min ð119Þ
97%
BER = Borohydride exchange resin
H2, THF, 80 °C
Ph Me + Ph Pr
Ph Me
N Pri (cat.) (E )–(Z ): 3–97 ð120Þ
N
Pd 87% 10%
CO2Me
MeO2C
Reductions without hydrogen gas have been reported by using diphenylsilane as hydride source,
and Pd(OAc)2 as catalyst (Equation (121)) <1996TL8787> (see also <1989TL4657>). With diaryl
alkynes, utilization of the same catalyst (Pd(OAc)2) and NaOMe in THF as hydride source also led
to the formation of (Z)-alkenes. If the reaction was carried out in MeOH, over-reduction to alkanes
was observed <2003TL1879>. Yus found that in the presence of NiCl2, Li-naphthalene added to
alkynes to produce, after hydrolysis, (Z)-alkenes <1997TL149>. (COD)2Ni in the presence of 2,20 -
bipyridyl added similarly to alkynes (Equation (122)) <1998T1169>.
Ph2SiH2, 2AcOH, Pd(OAc)2, toluene
Me Me
N (bis-Benzylidene)ethylediamine, ∆ N ð121Þ
Cbz Cbz
78%
i. (COD)2Ni, THF, 2,2'-bipyridyl

ii. AcOH ð122Þ
Ph SO2Ph
90% Ph SO2Ph
Zn activated by sonoelectrolysis <1999EJO2845>, or by a mixture of Cu–Ag <1994JPR714,

1989TL4951> was found to add to alkynes. This second method appeared particularly interesting
for the reduction of polyacetylenic compounds. The use of the homogeneous catalyst Ru2(-CO)-
(CO)4(dppm)2 in the presence of HCOOH as hydrogen source reduced deactivated alkynes
<2001CJC915>. Isobe and co-workers reported that alkynes complexed by Co(CO)6 reacted
with Bu3SnH to give (Z)-alkenes (Equation (123)) <1998TL2609>. Cp2TiCl2 catalyzed the
addition of several reagents on alkynes. For example, in the presence of LAH, (Z)-alkenes were
mainly formed (Equation (124)) <2002TL1231>. Addition of ZnH2 (formed in situ from a
mixture ZnI2–2LiH), followed by hydrolysis with D2O led to the incorporation of deuterium
(Equation (125)) <1995JOC290>. Unsymmetrical alkynes led to regioselective addition. Cp2TiCl2
was also reported to catalyze the addition of organoaluminates. In this case, hydrolysis with D2O
led to the incorporation of two deuterium atoms (Scheme 14) <1997MI2150>. In the same way,
treatment of alkynes with triallylmanganate led to the formation of manganesealkyne com-
plexes, which after hydrolysis affords the corresponding (Z)-alkenes <2003T9661>.
SiMe3
O Bu3SnH, benzene, 65 °C O
AcO AcO ð123Þ
Co2(CO)6
SiMe3
55% AcO
AcO
LAH, Cp2TiCl2 (10 mol.%)

C6H13 (CH2)2CH2OH
THF, ∆ C6H13 (CH2)2CH2OH ð124Þ
75% (E )–(Z ): 1–10
i. ZnI2, LiH, Cp2TiCl2

D
ii. D2O
C5H11 C5H11 ð125Þ
99% C5H11 C5H11
(E )–(Z ): 2–98
Et
EtAlCl2, Cp2TiCl2 cat. D2O D D
Al
Ph Ph
Mg, THF Ph Ph Ph Ph
90%
Scheme 14
The unusual dysprosium(II) iodide (DyI2) was found to be a powerful reducing agent allowing
the formation of (Z)-stilbene at low temperature (Equation (126)) <2000JA11749>. Sato and
co-workers reported that when alkynes were treated with Ti(OPri)4 in the presence of PriMgCl
intermediate titanates were formed, which after hydrolysis led to (Z)-alkenes (Scheme 15)
<1995TL3203>. This method was applied to conjugated polyalkynes (formation of enynes)

<2002CC272> and skipped polyene systems <1998JCS(P1)1839> (for reviews on this work,
see <2000CRV2835> and <2000SL753>). The well-known hydroboration of alkynes using
mainly Cy2BH is also a useful method for obtaining (Z)-alkenes after hydrolysis (see Section
1.10.1.6.2).
i. DyI2, DME, –45 °C
ii. H2O ð126Þ
Ph Ph
100% Ph Ph
(OPri)2
Ti(OPri) 4 Ti D2O D D
C5H11 C5H11
PriMgCl, THF C5H11 C5H11 80% C5H11 C5H11
(Z )–(E ) > (99)–(1)
Scheme 15
(ii) Formation of (E)-alkenes

The reduction of alkynes to (E )-alkenes appears much more difficult and few examples are
reported. Reactions of acetylenic alcohols with LAH, Red-Al, or in some cases NaBH4 are
well-known methods to produce functionalized (E )-alkenes. This stereoselectivity is observed
whatever the relative position of the alcohol function compared to the triple bond in the chain.
Similar reductions are possible with acetylenic amines. Another general method is the dissolving
metal reduction. Metals such as Li, Na, Ca, and Yb have been used. This method has been
recently re-examined and the best conditions, to carry out this reduction, was Li in liquid NH3 in
the presence of ButOH. With skipped diynes, reductions were faster compared to mono-ynes,
however the addition of (NH4)2SO4 was necessary to observe clean reactions <1999EJO775>.
To avoid the use of liquid NH3, amines such as EtNH2 are often used with success
<1995TL7689>. CrSO4 in DMF was reported to reduce a triple bond to an (E )-alkene (see
COFGT (1995)). It was found that Cr(OAc)2 was in some cases a better reagent <1995JA8106>.
Trost and co-workers found that the trans-hydrosilylation of acetylenic compounds was catalyzed
by CpRu(MeCN)3PF6. Although this addition, in general, produces a mixture of the two
regioisomers, the subsequent desilylation using TBAF in the presence of CuI led to (E )-alkenes
in high yields (Equation (127)) <2002JA7922>, see also <2002CC2182>. The homogeneous
catalyst [IrCl(H)(BINAP)]2(-Cl)(OMe)2Cl was also reported to give the unique formation of
(E )-alkenes, accompanied by over-reduction products <1999CC1821>.
i. (EtO)3SiH, CH2Cl2, 0 °C
O
CpRu(MeCN)3PF6
C16H21 C16H21 ð127Þ
Me ii. TBAF, CuI, THF
O
96%
1.10.2.1.2 Addition of CH to alkynes

The addition of CH to alkynes is reviewed in Chapter 1.1.2.
1.10.2.2 Addition to Allenes
1.10.2.2.1 Addition of hydrogen to allenes

Semi-hydrogenation of allenes to alkenes has been achieved by the general methods reported in
the preceding chapter concerning the hydrogenation of acetylenic compounds. In general, hetero-
geneous (e.g., Lindlar catalyst) and homogeneous (e.g., RhCl(PPh3)3) catalysts can be used. In the
case of 1,2-dienes, only the terminal CC double bond is reduced to give (Z)-alkenes. Reduction
of these substrates with DIBAL-H led to the formation of the terminal alkenes (reduction of the
internal CC double bond). Dissolving metal reduction (Na in liquid NH3) of 1,2-dienes led to
(E )-alkenes by reduction of the terminal double bond. In the case of 1,3-disubstituted allenes,
mixtures of reduction products corresponding to addition of hydrogen on the two CC double
bonds are usually observed. Hydrogenation of allenes is much less studied than the reduction of
alkynes, and only few new results have been reported in the last period. Addition of LAH to
dimethyl 2,3-pentedienoate was found to be syn (Equation (128)) <1995SL711>. Similar results
were reported using NaBH4 on a 2,3-pentenoate (Equation (129)) <2000JCS(P1)3188>.
LAH, AlCl3 MeO2C H
MeO2C
ð128Þ
CO2Me 49% H CO2Me
HOH2C Et NaBH4, EtOH, rt, 2 h HOH2C H

CO2Me ð129Þ
Me 69% Me CO2Me
Et
1.10.2.2.2 Addition of CH to allenes

The addition of CH to allenes is reviewed in section 1.1.2.
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Biographical sketch
Gérard Rousseau was born in Versailles, France. He studied at the Orsay

University, where he obtained his Ph.D. in 1977 under the direction of
professor Conia on the reactivity of singlet oxygen with cyclopropanic
compounds. After spending a year at Harvard with Professor R. B.
Woodward (1978) he returned to Orsay and took a position at CNRS
and started his independent research activity. There, his main research
fields were the chemistry of ketene acetals, utilization of enzymes in
organic synthesis, and, more recently, the preparation of medium-ring
compounds. He is presently director of research. His main research
interest is currently in the preparation of small- and large-ring hetero-
cyclic compounds by electrophilic cyclization.
1.11
One or More ¼CC Bond(s)
Formed by Substitution or Addition
D. J. AITKEN and S. FAURE
Université Blaise Pascal, Clermont-Ferrand, France

1.11.2 BY SUBSTITUTION 464
1.11.2.1 Substitution of Halogen 464
1.11.2.1.1 Substitution of alkyl halides 464
1.11.2.1.2 Substitution of vinyl halides 467
1.11.2.1.3 Substitution of aryl halides 471
1.11.2.2 Substitution of Oxygen 476
1.11.2.2.1 Substitution of alkyl oxygen leaving groups 476
1.11.2.2.2 Substitution of alkenyl oxygen leaving groups 479
1.11.2.2.3 Substitution of aryl oxygen leaving groups 480
1.11.2.3 Substitution of Other Chalcogens 482
1.11.2.3.1 Substitution of alkyl chalcogen leaving groups 482
1.11.2.3.2 Substitution of alkenyl and aryl chalcogen leaving groups 483
1.11.2.4 Substitution of Nitrogen 484
1.11.2.5 Substitution of Boron 485
1.11.2.5.1 General remarks on boron substitution reactions 485
1.11.2.5.2 Substitution of arylboranes 486
1.11.2.5.3 Substitution of alkenylboranes 489
1.11.2.5.4 Substitution of alkylboranes 490
1.11.2.6 Substitution of Silicon, Germanium, and Tin 491
1.11.2.6.1 Substitution of silicon and germanium 491
1.11.2.6.2 Substitution of tin 494
1.11.2.7 Substitution of a Metal 497
1.11.2.8 Substitution of Hydrogen 498
1.11.2.8.1 Friedel–Crafts alkylations using alkenes and alkanes 498
1.11.2.8.2 Transition metal-mediated substitution of arenes using alkenes 499
1.11.2.8.3 Transition metal-mediated substitution of alkenes 500
1.11.3 BY ADDITION 506
1.11.3.1 Nucleophilic Addition to Allenes 506
1.11.3.2 Free Radical Addition to Allenes 510
1.11.3.3 Cycloaddition Reactions Involving Allenes 510
1.11.3.3.1 General observations 510
1.11.3.3.2 [2+2]-Cycloadditions 511
1.11.3.3.3 [4+2]-Cycloadditions 511
1.11.3.3.4 Other cycloadditions 514
1.11.3.4 Carbene Addition to Allenes 514
463
464 One or More ¼CC Bond(s) Formed by Substitution or Addition
1.11.1 INTRODUCTION
Since COFGT (1995), progress in the area of sp2 CC bond-forming reactions has been phenom-
enal, due in a large part to the major developments in transition metal catalysis, particularly
involving palladium. In some areas, activity has been so great that the space required to elaborate
all aspects of progress would go well beyond the limits of this tome. In such cases, leading reviews
are cited, and the reader is encouraged to consult them for more detailed presentations. Many of
the methods described here may be applied to other bond-forming reactions covered in other
chapters.
The structure of this chapter follows, as closely as possible, that of the corresponding con-
tribution to COFGT (1995). This means that reactions in Section 1.11.2 are classified strictly
according to the atom which is replaced, rather than the precise nature of the reactive inter-
mediates involved. Furthermore, many substitution reactions can be regarded in terms of both
reacting functions and to avoid repetition they have been treated once only. As far as possible, the
‘‘priority order’’ adopted here is the displacement of H(alkene), B/Si/Ge/Sn, N/O/chalcogen,
halogen, H(arene), and finally metal.
In Section 1.11.3, although some of the starting materials appear as propargylic compounds,
the intermediacy of an allene is authentic. There are a good number of electrocyclic processes that
involve simultaneous creation of an sp2 CC bond and other multiple bonds and/or functional
groups; these reactions are treated in other chapters.
1.11.2 BY SUBSTITUTION
1.11.2.1 Substitution of Halogen
1.11.2.1.1 Substitution of alkyl halides
(i) Friedel–Crafts alkylation

Since the 1990s, the Lewis acid-catalyzed alkylation of aromatic hydrocarbons with alkyl halides
(and other electrophiles; see appropriate later sections) has continued to enjoy widespread
application in organic synthesis. Recent developments in Friedel–Crafts alkylation methodology
have been shaped by several important issues: the quest (indeed, requirement) for atom economy,
environmental-friendly reagents and reusable materials capable of promoting high-yielding, selec-
tive monoalkylation reactions. Particularly in the heavy chemicals industry, traditional Friedel–
Crafts catalysts such as AlCl3 have the disadvantage of being destroyed by aqueous work-up, thus
liberating large amounts of hazardous waste. There is also a trend away from the use of alkyl
halides, toward ‘‘cleaner’’ alkylating agents such as alcohols or alkenes (see later sections).
Although recent advances are of major industrial significance (as testified by a voluminous patent
literature), the general synthetic applicability of the new catalyst/operating systems is often
uninvestigated—frequently, only one or two simple (albeit industrially important) arene/halide
combinations are studied. The potential uses (or limitations) of these new systems in reactions
involving multifunctional compounds currently remain largely unexplored. One of the busiest
areas of development is in the use of solid catalysts based on acidic clays <1995IJC(B)257,
1997AC(A)(149)257, 1999PJS56, 1999SC4409>, mesoporous zeolites <1998AC(A)(196)29,
2001AC(A)(218)25, 2001MI155, 2001MI509, 2002OPRD256>, and sol–gel-derived silicas,
aluminas, or aluminosilicates <1997JCS(F)2439, 1998JCS(F)789, 1998CJC382, 1999MI199,
2000MI164>, optionally modified by the exchange of cations and/or doped with acidic metal
halides. These cheap materials promote high selectivity and efficiency under mild conditions,
although the surface Lewis acidity and the pore size and shape are critical. Other useful
solid catalysts for simple Friedel–Crafts alkylations include iron-containing graphite
<2001JCA(201)105>, transition metal-doped phosphates <1996CL721, 2001AC(A)(218)25>,
and spinel-type materials <1998AC(A)(166)135, 2001MI331> some of which tolerate the
presence of water in the reaction medium. Selective monoallylation of aromatics with allyl halides,
a particularly tricky operation, has been achieved using a solid composite reagent Pb3BrF5
(Equation (1)) <1997CC1921> or the solid acid–solid base reagent combination ZnCl2–SiO2/
K2CO3–Al2O3 <1995CC1895>.
One or More ¼CC Bond(s) Formed by Substitution or Addition 465
Reagents GC yield (%)

Reagent
+ Cl Pb3BrF5 86
rt, 2 h Pb3ClF5 80
ð1Þ
NaBr–PbF2 48
PbF2 0
TiCl4 (10 mol.%) at 3–4 °C 65
ZnCl2–K-10clay (10 mol.%) 63
Although rare earth metal triflates have enjoyed greater application in Friedel–Crafts alkyla-
tions using oxygen-based electrophile precursors (see Section 1.11.2.2.1.(i)), Sc(OTf)3 and
Hf(OTf)4 are also effective in the reactions involving alkyl halides and can be recovered without
loss of activity <1995BCJ2053, 2000BCJ2325>. Yb(OTf)3 catalyzes the efficient alkylation
of benzene aromatics with ethyl -chloro--(ethylthio)acetate; the subsequent desulfuration of
the alkylation products represents the formal introduction of an ethyl acetate equivalent onto
the aromatic ring in electrophilic form <2000TL9109>. A variety of lanthanide chlorides—
themselves poor Friedel–Crafts catalysts—furnish highly active, long-life catalysts for arene
alkylation with alkyl chlorides when supported on K-10 clay; silica-based reagents are less
reactive <1998CR(C)41>. Gallium triflate is a water-tolerant, reusable, Lewis acid catalyst; it is
more active than rare earth metal triflates in the alkylation of toluene with adamantyl bromide
<2003MI1>. Other new catalysts include rhenium complexes <2000BCJ2779> and a chlorosil-
ane/InCl3 combination <2002T8227>, while p-toluenesulfonic acid monohydrate compares well
with conventional acid reagents in the alkylation of benzene and toluene <1998JOC2858>.
Other areas of activity include the preparation of a wide range of (chlorosilyl)alkyl benzene
derivatives from the corresponding chloroalkyl chlorosilanes <2000AOC145> and AlCl3-induced
simultaneous halide exchange/regiospecific alkylation of aromatics with (trifluoromethyl)arenes
giving diaryldichloromethanes <1996TL4063>. Microwave irradiation assists the alkylation of
naphthalene using halide derivatives; only a small quantity of nitromethane is necessary to initiate
the reaction <2001SC3309>. Lewis acid-catalyzed asymmetric Friedel–Crafts alkylation of aro-
matics with chiral esters of -chloro--(phenylthio)acetic acid allows access to useful chiral 2-aryl-
2-thioethanol synthons (Equation (2)) <2000TA2267>.
Ph O Ph O
TiCl4
Cl O H ð2Þ
+ O H
SPh CH2Cl2, 0 °C SPh
64% 98% de
(ii) Substitution by organometallic sp2 carbanions

Since the 1990s, studies on a wider selection of alkyl halides and vinyl or aryl organometallic
reagent combinations have focused on activation, higher functionalization, increased
efficiency, use of milder conditions, and improved stereoselectivity and chemoselectivity in
their cross-coupling reactions. These improvements have led to widespread application in total
synthesis.
Organolithium species, whose pioneering use by Murahashi is summarized in a historical note
<2002JOM(653)27>, have been readily superceded by Grignard reagents <B-1996MI001> and
other organometals: B, Si, Sn (see Sections 1.11.2.5 and 1.11.2.6) and Zn, Al, Zr, In
<B-2002MI001>. Because of their high intrinsic reactivity, organolithiums do not tolerate
many conventional polar functional groups and metal-catalyzed alkenylation or arylation with
lithium derivatives remains rather limited.
Grignard reagents, which are more compatible with many functional groups than previously
thought, are widely used (both with and without Ni or Pd catalysts) in Kumada–Corriu coupling
reactions with alkyl halides, and are well reviewed <2000AG(E)4414, B-2002MI27, 2003AG(E)4302>.
Some industrial applications of Grignard cross-coupling reactions are known <2002JOM(653)288,
B-2002MI165>. That being said, most alkyl halides involved in such Pd(0)-catalyzed coupling reac-
tions are activated compounds lacking -hydrogen (benzyl, allyl, propargyl halides) <B-2002MI551>;
exceptions are rare. In the catalytic process, Pd(0) undergoes ready oxidative addition to ,-unsaturated
alkyl electrophiles, allowing an efficient cross-coupling reaction. In the case of saturated alkyl or
even ,-unsaturated alkyl electrophiles, this oxidative addition is more difficult. Furthermore, the
metalloalkyl intermediates can readily undergo -dehydrometallation to give alkenes. These two
factors have made it traditionally difficult to achieve metal-catalyzed cross-coupling of sp3 halides
<2000CRV3187>. The ability to couple unactivated alkyl electrophiles has therefore dramatically
expanded the scope of the cross-coupling process. Substitution of a wide range of unactivated
primary alkyl chlorides, optionally containing various functional groups (ethers, esters, acetals,
fluorides, nitriles), by aryl Grignard compounds is achieved with good yield in NMP as solvent in
the presence of a Pd(OAc)2/PCy3 catalyst <2002AG(E)4056> and, even more efficiently, by using
a palladium/N-heterocyclic carbene catalyst (Equation (3)) <2003JOM(687)403>. Even unacti-
vated alkyl fluorides can now be arylated by Grignard reagents via Ni or Cu catalysis
<2003JA5646>. However, more sensitive functions (ketones or aldehydes) are, predictably,
incompatible with Grignard reagents.
MgBr
Pd/L (4 mol.%)
Cl +
NMP, rt
ð3Þ
Pd /L Yield (%)
IMes = Mes N N Mes Pd(OAc)2/PCy3 96
Pd(OAc)2/lMes-HCl 75
(Mes = mesityl) Pd(naphthoquinone)/lMes 98
Organocopper reagents attract continued interest <1995JOC2361, B-2002MI002>, including

use in industry <2002JOM(653)288>. The most commonly used reagents are obtained by the
treatment of aryl or vinyl halides with CuCN2LiCl, in either catalytic or stoichiometric amounts,
sometimes in the presence of additives (e.g., trimethylphosphite) <B-1999MI317, 2001OL2871>.
Use of the sterically hindered organocuprates, neopentyl2CuLi or neophyl2CuLi, facilitates
halide–copper exchange in the presence of sensitive groups, including ketones and aromatic
aldehydes (Scheme 1) <2002AG(E)3263>.
O Cu(R)Li O
Ph Ph
+ MeI
80%
CHO CHO
Cu(R)Li Br
+
80%
R = neopentyl
Scheme 1
Progress in metal-catalyzed CC bond formation has been dominated by the Negishi reaction,
namely palladium- or nickel-catalyzed cross-coupling through the use of organometals involving
metals of intermediate electronegativity (Zn, Al, Zr) <B-2002MI229>. Numerous factors are respon-
sible for this increasing interest: (i) easy access to the required organometals <2002S2473,
2000AG(E)4414>; (ii) the high chemo-, regio-, and stereoselectivities of cross-coupling reactions
using these reagents; and (iii) practical advantages deriving from their ease of handling and low
cost. Zinc has emerged as a particularly appealing metal since the 1990s <B-1996MI274,
B-1999MI213, 2002JOC79>. Organozinc derivatives have an almost covalent CM bond and are
therefore less reactive than organolithium or organomagnesium reagents and are compatible with the
presence of a large number of other functions in substrates; a wide range of applications are reported
<B-2002MI863>. NiCl2(PPh3)2 is a selective catalyst for the reaction between (monochloro)
phenyl zinc chloride and benzylic halides, whereas for more hindered nucleophiles a palladium
catalyst is recommended <1998T2953>. One-pot formation of functionalized aryl zinc iodides then
palladium-catalyzed cross-coupling with allylic bromides and chlorides (Scheme 2) <2003JOC2195>

or tandem vinyl zinc formation/Cu-mediated vinylation of allylic chlorides <2001SL123> can be
performed. Aryl zinc iodides react with methyl iodide under rhodium catalysis in the presence of
diverse phosphine ligands <1999CL1241>. Diorganozincs are useful for asymmetric reactions: one of
the most significant advances is the copper(I)-catalyzed substitution of unsymmetrical allyl chlorides
with diaryl zinc proceeding with SN20 regioselectivity and moderate-to-good enantioselectivity
(up to 87%) using a ferrocenyl amine as a chiral ligand (Equation (4)) <1999AG(E)379>.
Br Cl (1.1 equiv.) Br
Zn (1.5 equiv. )
I Me3SiCl (3 mol.%) Pd(dba)2 (5 mol.%)
THF, 70 °C 0 °C, 10 min

48 h 90%
Scheme 2
R2Zn NH2
CuBr.Me2S (1 mol.%) R
Ar
L* (10 mol.%)
Cl R Fe
+ L* = ð4Þ
THF, –50 to 90 °C
R = neopentyl 97:3
Ar = 2-naphthyl
72% 87% ee
Organoaluminum compounds have useful synthetic applications, their main interest arising
from the ease of control of the (Z)- or (E )-configuration of a substituted alkenyl moiety in such
reagents, and the retention of this configuration during cross-coupling with active alkyl halides
<B-2002MI863>. Indium also attracts some attention, with its low toxicity and a generally
selective reactivity profile <2000EJO2347>. Readily accessible trivinyl and triaryl indium com-
pounds can be used in the substitution of activated allylic halides (as well as acetates and
phosphates) with a copper catalyst (Equation (5)) <2003JOC2518> or benzyl bromide using
palladium catalyst <2001JA4155>. Cross-coupling reaction between pentaaryl antimony and
allylic halides can be performed under palladium or nickel catalysis <1996JOM(525)39>.
Bun
Bun3In
Ph Br Ph + Ph Bun
CuCN
65% Branched 80:20 Linear
Cu cat., L Yield (%) Ratio branched/linear ð5Þ
CuCN 65 80/20
Cu(OTf)2 40 72/28
CuBr.SMe2,P(OEt)3 33 68/32
CuCN, P(OEt)3 50 88/12
Cu(OTf)2, P(OEt)3 85 82/18
1.11.2.1.2 Substitution of vinyl halides
(i) Alkyl nucleophiles

Metal-catalyzed cross-coupling reactions between homoallyl, homopropargyl, or homobenzyl metals
and alkenyl electrophiles are reviewed <B-2002MI619>. Palladium-catalyzed vinyl halide cross-
coupling reactions involving saturated alkyl metals (Li, Mg) are well documented <2002JOM(653)27,
B-2002MI597>, although they are often surpassed by other organometals <B-2002MI285>. The high
reactivity of organolithium compounds often precludes the need for catalysis. Palladium-catalyzed
reactions with alkyl lithiums are in any case rather limited and nickel catalysts are incompatible with
organolithium reagents. Alkyl magnesium compounds remain popular alkylating agents.
Considerable progress has been made with zinc reagents. Dialkyl zincs show ever-increasing impor-
tance and are extensively studied by the Negishi and Knochel groups <1998T8275, B-1998MI387,
B-1999MI179, B-2002MI229>. Dialkyl zinc compounds are easily accessible by efficient, chemoselec-
tive, and clean carbozincation or hydrozincation of alkenes <1995TL1023, B-1996MI002,
B-1999MI77>. Isoalkyl zinc reagents readily undergo palladium-catalyzed cross-coupling reactions
with alkenyl halides, in contrast with isoalkyl magnesiums or isoalkyl alanes which react only sluggishly
or not at all <2000OM2417>. While -iodo ,-unsaturated ketones cross-couple smoothly with alkyl
zinc reagents <1999JOM(576)179>, studies by Rossi and co-workers <1998T135> reveal that the
reactions between ,-dibromo ,-unsaturated esters and organozincs take place preferentially at the
-position (Equation (6)). -Iodoacrylic acid undergoes efficient substitution by alkyl and allyl zinc
bromides without protection of the acid function <2002S543>. Indeed, organozinc reagents tolerate
most carbonyl functions, with the exception of acyl halides, anhydrides, and aldehydes. Over a short
period of time, they have become versatile tools for synthesis, as illustrated in the preparation of
alkenyl cyclopropanes <2002T3673>, pumiliotoxins <2002JOM(653)229>, discodermolide
<2001OL3281> as well as various isoprenoids <B-2002MI863>.
Pd(PPh3)4, THF, 20 °C
CO2Me or CO2Me R = Bun, 63% ð6Þ
Br + RZnCl R
PdCl2(dppf), THF, 20 °C R = Bui, 79%
Br Br
While palladium and nickel are the most often used metals for catalysis of cross-coupling reactions
involving Grignard and organozinc reagents <B-1998MI227>, other transition metals (Cu, Fe, Co)
can also be used. Cobalt-catalyzed cross-coupling of organozinc halides or diorganozincs with (E)- or
(Z)-alkenyl iodides lead to polyfunctional alkenes with complete retention of the stereochemistry of
the double bond <1998TL6163>. Grignard reagents undergo efficient and stereoselective cross-
coupling reaction with vinyl halides (I, Br as well as Cl) in the presence of a cobalt(II) catalyst and
a polar solvent (NMP or DMPU) <1998TL6159>. However, cobalt is less efficient for the introduc-
tion of a tertiary alkyl group because of competitive -elimination. Copper(I) and iron(III) catalysts
both give satisfactory results for cross-coupling reactions involving organomanganese or Grignard
reagents <1996TL1773, 1998S1199>. There is still much to do in this area.
Progress with group 13 metals is more limited. Heteroatom-stabilized complexes of methyl
aluminum and methyl gallium are particularly amenable to the palladium-catalyzed methylation
of vinyl halides (Br, I) <1997JOC8681>. Allyl indiums couple with alkenyl halides or gem-
dibromoalkenes in the presence of Pd(PPh3)4/LiCl. SN2 and SN20 processes compete, resulting
in low selectivity <2002JOC8265>.
The cross-coupling reaction can be neatly adapted for asymmetric induction at the organometallic
sp3-carbon center <2002JOM(653)41, B-2002MI791>. Stereoselective protocols are extensively devel-
oped for secondary alkyl Grignard reagents in the presence of palladium catalysts bearing chiral
phosphine ligands, including ferrocene-based structures <B-1995MI105, 1998CEJ950,
2000AG(E)4414> and -(dialkylamino)alkylphosphines <1997CB989, B-1999MI887>. P,N-
Ligands, derived either from axially chiral piperidine-naphthalenes <2003SL2047> or quincorine
and quincoridine, in which the nitrogen is a stereogenic center <2002JOM(643)98>, give good results
in palladium- or nickel-catalyzed asymmetric cross-coupling reactions (Equation (7)).
R
R
Me N
* N
MgX Br L1 = L2 = N
Me PPh2
ð7Þ
M, L1 or L2
Ph2P
R = Ph, M = PdCl2(MeCN)2, L1, PhCF3, 0 °C, 1 h; yield = 58%, 66% ee

R = H, M = NiCl2, L2, Et2O, 0 °C, 12 h; yield = 50%, 86% ee
(ii) Alkenyl nucleophiles

After a slow start, alkenyl–alkenyl coupling now represents a highly efficient, selective methodol-
ogy for the construction of stereodefined substituted conjugated dienes <B-1998MI1,
B-2002MI229, B-2002MI335, 2002JOM(653)34>. Almost all combinations of alkenyl metals
(Li, Mg, Zn, B, Al, Si, Sn, Cu, Zr) and alkenyl electrophiles can be achieved via a Pd- or Ni-
catalyzed cross-coupling process, which respects the stereochemistry of each reacting alkenyl
moiety. Furthermore, many of the alkenyl metal and alkenyl electrophile reagents can be pre-
pared conveniently with a high degree of stereoselectivity. The reaction proves particularly useful
in natural products synthesis <B-2002MI863> and in the preparation of polyconjugated materi-
als (Scheme 3) <B-2002MI807>.
Me3Al AlMe2
Pd(PPh3)2Cl2 cat.
Br
I
Pd(PPh3)2Cl2 (cat.)
DIBAL-H, ZnBr2
68% β-Carotene
Scheme 3
The methodology is readily extended to 1,1-bimetallic alkenes <2000CRV2887>. Some degree

of chemoselectivity is observed when two different metals are present in the same alkene: for
example, in the palladium-catalyzed reaction of methyl (E)--bromomethylacrylate with
(E)-Bu3SnCH¼CHZnCl, reaction occurs exclusively at the zinc center, providing a conjugated
dienyl stannane which can be further engaged in a Stille reaction (Scheme 4) <1999SL1966>.
Likewise, the smooth cross-coupling of an -bromo--alkenyl stannane with an alkenyl zirco-
nium gives a 1,3-dienyl stannane <2003JOM(687)462>. Di- and trihalogenoalkenes, too, can be
coupled, often chemoselectively and with retention of configuration, to provide di-, tri-, or
tetrasubstituted alkenes; both 1,1- and 1,2-dihalogenoalkenes are useful in this regard
<2000S1499, B-2002MI649>. For example, palladium-catalyzed cross-coupling of an alkenyl
zirconium with a 1,1-dibromoalkene provides a key (Z)-monobromo intermediate in a total
synthesis of the antibiotic lissoclinolide <1999TL431>. Palladium-catalyzed reactions involving
alkenyl halides usually proceed with retention of configuration; however, unprecedented inversion
of configuration is reported with 2-bromo-1,3-dienes <2003JA13636>. In certain cases, the
double bond configuration can be imposed during the cross-coupling reaction; for instance, a
(E,E)-1-chloro-1,3-diene is obtained when a (Z)/(E)-1,2-dichloroalkene mixture is cross-coupled
with an alkenyl alane under nickel catalysis (Equation (8)) <2002TL3007>.
CO2Me
Br
SnBu3 i. BuLi ZnCl CO2Me
Bu3Sn Bu3Sn Bu3Sn
ii. ZnCl2 Pd(PPh3)4 (4 mol.%)
DMF, THF, 0 °C
95%
Scheme 4
Cl AlBu2i Ni(PPh3)4 (5 mol.%) Cl

Cl + C5H11 C5H11
C6H6, Et2O ð8Þ
1/1 (Z ):(E ) (E,E ) >95%
72%
(iii) Aryl nucleophiles

Methodologies for palladium- or nickel-catalyzed aryl metal–alkenyl halide cross-coupling are
similar to those used for alkenyl–alkenyl coupling (see Section 1.11.2.1.2.(ii)) and are equally well
reviewed <2002JOM(653)23, B-2002MI335>. This is one of the two cross-coupling synthetic
strategies for the construction of an arylalkene bond, the other being aryl halide–alkenyl metal
(see Section 1.11.2.1.3.(ii)). The choice generally comes down to the relative ease of access of the
appropriate substrate partners. The majority of aryl nucleophiles containing electropositive metals
(Li, Mg, but also Zn) are prepared by oxidative metallation of aryl halides, while those containing
metals of intermediate electronegativity (B, Al, Si, Cu, Sn, Zn) are often generated by transmetalla-
tion <2000AG(E)4414, 2003AG(E)4302>. New catalysts, such as the commercially available, air-
stable complex Pd(PBu3t)2, improve the performance of Negishi cross-coupling with sterically
demanding vinyl chlorides and aryl zinc reagents <2001JA2719>. Aryl Grignard reagents couple
smoothly with alkenyl halides under Fe(III) catalysis (Scheme 5) <2001SL1901>.
I MgBr R R
PriMgBr X
THF, –20 °C Fe(acac)3 (5 mol.%)
FG 1–4 h FG FG
THF, –20 °C, 15–30 min
FG = COOEt, CN, OTIPS, ONf 50–73%
X = Br, I; R = Bun, Ph
Scheme 5
Dihaloalkenes, again, are versatile synthetic building blocks. For example, efficient stereoselec-
tive access to the more hindered cis-1,2-diarylalkenes from readily available trans-1,2-dibromoalk-
enes is achieved under palladium catalysis even when sterically demanding electrophiles or
nucleophiles are involved (Equation (9)) <2002JA14832>. Intramolecular o-alkenylation of phe-
nolates can be achieved with vinyl halides in the presence of a Pd catalyst, allowing access to the
substituted heterocycles (indoles, benzofurans, or benzopyrans) <1997TL6379>.
MgBr
Br PdCl2(PPh3)2 (0.1 mol.%)
+
Br
THF, rt, 8 h ð9Þ
92%
trans
cis
(iv) Addition–elimination displacements of vinyl halides

The substitution of haloalkenes by cuprate reagents is facilitated by the presence of a vicinal
electron-withdrawing group which permits an addition–elimination process, and generally does
not require a catalyst <B-1999MI179, B-2002MI27>. The (Z)/(E) stereochemistry of the mono-
substitution of 3,3-dichloro-1-(trimethylsilyl)-2-propenone using organo(cyano)cuprates such as
RCu(CN)M or R2Cu(CN)M2 (where R = alkyl or aryl, M = Li or MgCl) varies with the identity
of R; during the second substitution (if carried out), inversion of configuration dominates the
reaction profile <1995T9823>. The addition–elimination pathway allows access to rare -sub-
stituted Baylis–Hillman adducts: Grignard reagents in the presence of a catalytic amount of
LiCuBr2 couple efficiently and selectively with -iodo--(hydroxyalkyl)acrylic esters with reten-
tion of configuration (Equation (10)) <2000T805>. However, limitations are sometimes encoun-
tered: for example, substitution of -iodoacrylic acid with organocuprate reagents proceeds in low
yield and with low selectivity, providing a mixture of (Z)- and (E)-isomers <2002S543>. In some
cases, palladium-catalyzed cross-coupling with organomagnesium halide or organozinc may
provide a more rewarding alternative.
n-C5H11 n-C5H11
OH PriMgCl, LiCuBr2 (3 mol.%) OH
THF, –30 °C
I COOMe Pri COOMe
93–94% ð10Þ
(Z ) 100/0 (Z )/(E )
(E ) 0/100 (Z )/(E )
(Z ),(E ) 77/23 (Z )/(E )
1.11.2.1.3 Substitution of aryl halides
(i) Alkyl nucleophiles

This field is largely dominated by the use of palladium- or nickel-complex catalysts. Palladium-
catalyzed cross-coupling involving saturated alkyl metals is reviewed <B-2002MI597>. The usual
reactivity order is observed for the aryl electrophiles (I > Br > OTf >> Cl), so for successful cross-
coupling of aryl chlorides, ‘‘high-performance’’ ligands on palladium are usually required. However,
ligand-free iron-catalyzed cross-coupling proceeds very smoothly and rapidly, for a variety of alkyl
metals, with a modified order of reactivity for the aryl component (Cl > OTf > OTs > > I, Br)
(Equation (11)) <2002JA13856>. Lanthanide salts (CeCl3, Yb(OTf)3) are required as additives in
the PdCl2(PPh3)2-catalyzed alkylation of aryl bromides with triethylalane <2003TL8593>. A
heterogeneous Ni–C catalyst is described for Kumada–Corriu cross-coupling <2003JOC1177,
2003JOC1190>, although polymer-supported catalysts are not in as much profusion as for other
transition metal-catalyzed coupling reactions (Heck, Suzuki, etc.). Ni(0)-catalyzed alkylation (or
arylation) of polymer-bound substituted bromophenol by Grignard reagents is described as a means
for the development of polymer materials <2000MI57>. One example of a solid-supported alkyl
zinc and its palladium-catalyzed coupling with aryl iodides is described <2000CC1401>. An
interesting practical procedure for efficient removal of phosphine ligands at the end of a preparative
reaction by a polymeric scavenger is described <2001OL1869>.
CN Fe(acac)3 (5 mol.%) CN
+ n-C14H29MgBr
THF, NMP
X n-C14H29 ð11Þ
X = Cl 91%
X = OTf 80%
X = OTs 74%
Methyl triisopropoxytitanium cross-couples smoothly with 2-bromonaphthalene in the presence

of a Pd/ppfa catalyst (ppfa=N,N-dimethyl-1-[2-(diphenylphosphino)ferrocenyl]ethylamine), and
also with 2-chloronaphthalene in the presence of NiCl2(PPh3)2 <2002SL871>. Dialkyl and trialkyl
indium reagents can transfer all their organic groups efficiently <2001JA4155>. In situ-generated
allyl indium undergoes smooth palladium-catalyzed cross-coupling with aryl iodides
<2001OL3201>. Dialkyl indiums couple with functionalized aryl halides (I, Br) under palladium
catalysis in aqueous medium <2001OL1997>. To minimize homo-coupling, intramolecular het-
eroatom-stabilized aluminum, gallium, or indium alkylating reagents are available (Figure 1). In
odd cases, reagents like these may substitute an aryl chloride in preference to a bromide <2000S571,
2000TL7555, 2001S591, 2003S302, 2003SL1783>.
Me R R
Me N M Me Me
N N
O Me Me
O Al
M M
N Me Me Me Me Me
R R Me
M = Al, R = Me, Et, Bui, allyl M = Al, R = Me

M = Ga, R = Me M = Ga, R = Me
M = In, R = Me M = In, R = Me, Et
Figure 1 Intramolecular heteroatom-stabilized group 13 organometallic reagents.
Successful multiple-coupling reactions of polyfunctional aromatic compounds lead rapidly to ela-

borate molecular frameworks: diverse examples include polyhaloarenes <1995TL8565, 1997OPP137>,
2,3,5-tribromobenzofuran <2002TL9125>, and sym-pentachlorocorannulene <2003OL713>. Substi-
tuted aryl bromides and chlorides can be efficiently coupled with a variety of nitroalkanes in the
presence of Pd2(dba)3 to give monoarylated products in good yield and selectivity <2002JOC106>.
Progress in asymmetric arylation reactions is reviewed <2001AG(E)3284> and matches that
described for alkyl metal–vinyl halide asymmetric cross-coupling processes (see Section 1.11.2.1.2.(i)).
In a rare noncatalyzed process, aryl iodides combine with lithium trimethylzincate to give
mixed aryl dimethyl intermediates which furnish the corresponding tolyl compounds via oxidative
ligand coupling upon treatment with VO(OEt)Cl2 <2001JOC300>.
(ii) Alkenyl nucleophiles

Complementary to the alkenyl halide–aryl metal combination (see Section 1.11.2.1.2.(iii)), the success of
this approach to aryl alkenes depends largely on the availability of the alkenyl metal; for Mg, Li, and
Zn, most such species are now accessible. The various factors to be weighed up in a palladium- or nickel-
catalyzed cross-coupling reaction have been intelligently discussed <B-2002MI335>.
Alkenyl zirconium reagents, prepared in situ from terminal alkynes, react with aryl iodonium ions
to provide (E)--substituted styrenes <1998SC773>. Divinyl indium chloride cross-couples with
aryl iodides in the presence of Pd2(dba)3CHCl3/P(2-furyl)3 in aqueous THF <2001OL1997>. In
situ-generated tris(dihydropyranyl) indium reagents couple efficiently with aryl halides via
PdCl2(PPh3)2 catalysis to give substituted dihydropyrans (Scheme 6) <2003OL2405>. Intramo-
lecularly heteroatom-stabilized vinyl aluminum reagents undergo efficient palladium-catalyzed
cross-coupling with bromo- and iodoarenes as well as more reactive chloroarene–Cr(CO)3 com-
plexes <2003SL1783>. trans-Alkenyl gallium dichlorides undergo efficient reaction with aryl
halides (I, Br), while the cis-isomers do not provide coupling products <2002S1137>.
OMe
I
OTIPS OTIPS
O (Glucal)3In O
i. But
Li
(Glucal)2InBut
ii. InCl3 PdCl2(PPh3)2 OMe
TIPSO (Glucal)InBu2t TIPSO
THF, ∆, 24 h OTIPS
OTIPS
(+ dimer, <5%)
60%
Scheme 6
(iii) Aryl nucleophiles

The largest part of those studies devoted to cross-coupling reactions since the 1990s has focused on
aryl–aryl bond formation, since biaryls have widespread applications in diverse fields (pharmaceu-
ticals, agrochemicals, dyes, polymers, specialist ligands for asymmetric synthesis, etc.). A vast range
of aryl metals (Zn, Mg, Hg, Si, Ge, Pb, Bi, Sb, Cu, Zi, In, B, Sn) can be coupled with aryl halides
under Pd, Ni, or Cu catalysis; inventories of, and comparisons between, the various approaches for
(and applications of) aryl–aryl coupling techniques are extensively reviewed <1998T263,
2001MI575, B-2002MI311, 2002CRV1359, 2003CRV3213> along with progress reports in the
particular area of axial chirality control <2001AG(E)3284, B-2002MI791>.
Development of inexpensive and efficient air-stable ligands for palladium- or nickel-catalyzed
cross-coupling reactions involving aryl chlorides is a major challenge: success is achieved with
phosphinous acid ligands for palladium-catalyzed cross-coupling of either zinc <2002JOC3643>
or Grignard <2002JOM(653)63> reagents (Equation (12)). Nickelocene is a useful precatalyst,
obviating the problems associated with handling the air-sensitive reagents Ni(PPh3)4 and
Ni(COD)2 <2001JOC7539>. Unactivated aryl halides undergo straightforward cross-coupling
reactions with aryl Grignard reagents mediated by a palladium/N-heterocyclic carbene catalyst
<1999JA9889> or with aryl manganese chlorides in the presence of PdCl2(dppp)
<2001JOM(624)376>. Aryl bismuth reagents cross-couple selectively in the presence of
Pd(PPh3)4 with various (bromophenyl)boronic esters to give (biaryl)boronates, ready for conse-
cutive one-pot Suzuki coupling <2003AG(E)1845>. Although not often used, aryl lithiums
benefit from the reinvestigating of a noncatalyzed coupling protocol <2003CEJ3209>.
POPd (5 mol.%)
MeO Cl + ZnCl OMe
THF, NMP, reflux
83%
ð12Þ
Cl
POPd = HO P Pd P OH
Cl
With appropriate reagents and catalysts, biaryl cross-coupling reactions may be conducted in
aqueous medium <2001OL1997, B-2002MI2957>. Complexes derived from Pd(dba)2 and per-
fluorinated phosphines successfully catalyze the cross-coupling of aryl zinc bromides and aryl
iodides in a biphasic system, thus facilitating catalyst separation and recycling after completion of
the reaction <1997AG(E)2623>; similar advantages are observed in the use of an ionic liquid and
an ionic phosphine ligand (Equation (13)) <2000SL1613>. Polymer-supported catalysts are
viable <2001MI219>, although only a few solid-phase versions of biaryl cross-coupling are
described <1996TL5491, 1997SL1084, 1999JCO123>.
Pd(dba)2 (2 mol.%)
I + R2 ZnBr R2
R1 Phosphine (4 mol.%) R1
toluene, [bdmim][BF4]
R1 = p-COOEt, p-NO2, R2 = OMe, Cl, 70–92% ð13Þ
PF6
p-OAc, m-COOEt, CN, OTIPS
N N Bu
m-OMe Phosphine = Me
PPh2
bdmim = 1-butyl-2,3-dimethylimidazolium
Arylation of heteroaryl halides (and triflates) is also widely practiced <B-2002MI409,

2002JOC8991, 2002TL3547, 2003EJO3948> and is a powerful tool for the synthesis of conju-
gated polymers <B-2002MI807>. The cross-coupling of ferrocenyl zinc chloride with s-tribromo-
benzene <1997CL35> finds useful application in the construction of molecular octupoles
(Scheme 7) <2003S455>.
CpFe OMe
Br OMe O
O O O
O
O
i. ButLi O OMe Br Br FeCp
O OMe
Fe Fe ZnCl
ii. ZnCl2 PdCl2(PPh3)2
59% FeCp O
O
MeO
Scheme 7
(iv) Other methods

Recent applications of the reductive homo-coupling of an aryl halide through the action of copper
(the Ullman reaction) and its numerous variations are reviewed <2002CRV1359>. Catalyzed aryl
halide homo-coupling has several disadvantages: current methodologies are usually only effective
with aryl iodides and activated bromides, require a rather large quantity of a catalyst (Pd or Ni,
around 2–5%), and have a hard time competing with arene reduction reactions. Resolving these
problems remains a challenge; however, efforts to achieve homo-coupling are usually rewarded
through the use of a catalyst system derived from Pd(OAc)2 and phosphines (or arsines and
ammonium salts), or a palladacycle (Equation (14)) <1998T13793, 1998TL7939, 2002TL2327>.
A marked selectivity for cross-coupling leading to unsymmetrical biaryls is observed in the
Pd(OAc)2-catalyzed reaction of electron-rich aryl iodides with electron-poor aryl bromides,
although isolated yields are moderate (Equation (15)) <2001T7845>. New developments of
previously known nickel(0)-based reductive methods are described <1999JCR(S)664,
1999TL5993, 2000TL10319>, including the use of a catalytic amount of a zero-valent nickel
complex without an added reducing agent <1999TL4243>. Transient formation of tin or boron
metallo-intermediates may facilitate the coupling reaction. For example, binaphthyl formation
from 1-iodo-2-methoxynaphthalene can be performed via an in situ Suzuki reaction
<1996JOC9556> while intramolecular Stille–Kelly cross-coupling of bis(bromoaryls) in the pre-
sence of (Me3Sn)2 and Pd(PPh3)4 gives a 17-membered biaryl macrocycle, albeit in moderate yield
(17%) <2001H(54)259>.
Me
Ar Ar
Palladacycle (0.1 mol.%) P O O
I Pd Pd
NEtPr2i , DMF ð14Þ
O OP
110 °C, 12 h Ar Ar
Me
87%
Palladacycle (Ar = o -tolyl)
NO2 NO2
Pd(OAc)2, NBun4Br
I + Br
NEtPr2i , p-xylene ð15Þ
130 °C, 7 h
20%
Palladium-catalyzed coupling of an arene and an aryl halide, the formal ‘‘arene analog’’ of the
Heck reaction, is reviewed <B-2002MI1471>. Arylation of phenols by aryl halides, in both the
o-position and then the o0 -position of the newly introduced aryl substituent, is achieved in the
presence of a palladium catalyst and a base (preferably Cs2CO3); the same reaction applies for
preformed 2-aryl phenols. Coordination of the phenolate oxygen to the intermediate arylpalla-
dium species plays a key role in the process <1998BCJ2239, 1999CL961>. In the same
conditions, benzanilides react with aryl bromides to provide the double o-arylation products,
N-(2,6-diarylbenzoyl)anilines, in good-to-excellent yields <2000TL2655>. Rhodium complexes
with phosphite or phosphinite ligands catalyze the intermolecular ortho-coupling of the substi-
tuted phenolates with aryl halides, without further reaction <2003AG(E)112, 2003TL8665>.
Comparable palladium-catalyzed cross-coupling reactions involving heteroaromatic compounds
are known <1998BCJ467, 1998JOM(567)49>. The intramolecular process, catalyzed by Herr-
mann’s palladacycle, provides tricyclic compounds efficiently (Equation (16)) <1997JOC2>, and
various extensions of this ring-closing methodology are made for the synthesis of biaryl com-
pounds <1997JOC1286, 1998H(49)191, 1999AG(E)1229, 2000JOC2069>.
Me
Ar Ar
I Palladacycle (5 mol.%) P O O
Pd Pd
HO O Cs2CO3, DMA, 100 °C HO O O OP ð16Þ
Me Me Ar Ar
80% Me
Palladacycle (Ar = o -tolyl)
Ketones and ,-unsaturated carbonyl compounds are arylated by aryl halides at their - and
-positions, respectively, under palladium catalysis (Scheme 8) <1997TL7581, 1997JA12382,
1998JA1918, 1998TL6203>; this reaction is reviewed <2002T2041>. A wide range of aryl
chlorides couple smoothly with ketones when a Pd(OAc)2/PCy2(2-(2-tolyl)phenyl) catalyst is
employed in the presence of NaOBut, with a high selectivity for monoarylation and for reaction
at methylene rather than methine centers. The use of K3PO4 as the base allows widening of the
functional group compatibility <2000JA1360>. Similarly, efficient monoarylation of carboxylic
esters by aryl bromides is achieved at room temperature in basic conditions using a Pd(dba)2
catalyst in the presence of PBut3 or an N-heterocyclic carbene ligand <2002JA12557>. Triaryla-
tion at the - and two o-positions of benzyl phenyl ketones takes place upon treatment with
excess aryl bromides in the presence of Cs2CO3 and a catalytic amount of Pd(PPh3)4
<2001T5967>. Somewhat unusually, ,-disubstituted aryl methanols undergo C(sp2)C(sp3)
bond cleavage during their palladium-catalyzed arylation with phenyl bromides <2001JA10407>.
The photochemical formation of biaryl compounds is well reviewed <2002CRV1359,
2003CRV71>. Irradiation of aryl halides (I, Br, Cl) furnishes the corresponding aryl cations
that are trapped by arenes substituted by activating groups, via a photo-SRN1 process. Hetero-
aromatics, e.g., furans, pyrroles, or thiophenes undergo regioselective substitution with aryl
halides when irradiated in acetonitrile (Equation (17)) <2000T9383>. Aryl iodides couple regio-
selectively with azulene at C1 upon irradiation in n-hexane <2001TL715>.
Pd(OAc)2
CHO PPh3, Cs2CO3 CHO
+ PhBr
DMF, 100 °C Ph
93%
Br Pd(OAc)2 O
O Me
(S)-BINAP, NaOBut
Me + Me
Ph
Ph Toluene, 100 °C
Me
80% 94% ee
Cl O
O Pd(OAc)2 Me Me
Me Me L, NaOBut
+ Me
Me Toluene, 90 °C mono-/di-arylation 21/1
Bun 79% regioisomers 20/1
Bun
O Cl Pd(OAc)2 COOMe
O
L, K3PO4
+
Toluene, 90 °C mono-/di-arylation 5/1
COOMe 70%
Me
L=
PCy2
Scheme 8
NMe2 R2 R2
hν, MeCN
+ R1 R1
X X
NMe2
Cl X = NH, R1, R2 = H 64% ð17Þ
X = NH, R1, R2 = Me 75%
X = S, R1, R2 = H 54%
X = O, R1, R2 = H 32%
X = O, R1 = H, R2 = Me 52%
Recently, interest has arisen in aryl radical migration for the preparation of biaryls. This new
method usually involves intramolecular aryl radical migration from sulfur or silicon to another
aryl radical originating from an aryl halide. Motherwell and co-workers first described an
intramolecular free radical [1,5]-ipso-substitution of an aryl iodide under radical initiation condi-
tions (Bu3SnH/AIBN) using sulfonamide and sulfonate tethering chains (Equation (18))
<1997TL137>. The reaction takes place via a spirocyclic intermediate, which rearomatizes
through loss of sulfur dioxide to provide -arylated phenols or N-methyl anilines. Hindered
biaryls are easily prepared, since the presence of either electron-donating or electron-withdrawing
groups ortho- to the sulfonyl group facilitates the reaction. o-Halogenobenzyl arylsulfonates
<1997TL141>, arylphosphinates <2000TL1315>, and diarylsilyl ethers <2000OL985>
undergo similar reactions to give o-arylbenzyl alcohol derivatives. Studer and co-workers also
report the intramolecular 1,5-aryl radical migration from sulfur in sulfonates or sulfonamides to
variously substituted alkyl radicals (generated from the corresponding iodide or bromide) with
excellent stereocontrol <2002EJO2742>. In the analogous reaction with o-iodophenyl benzyl
ethers, there is no obvious leaving group, and mixtures of products tend to be formed
<2001TL961>. Intermolecular radical additions of aryl or heteroaryl radicals, generated from
the corresponding bromides with tris(trimethylsilyl)silane/AIBN, to aromatic solvents (benzene,
toluene, chlorobenzene) can be achieved, although the scope is limited by the fact that the
acceptor arene has to be the reaction solvent <2000OL3933>.
O2
S X SO2 XH
X Bu3SnH –SO2
I AIBN ð18Þ
X=O 64%
X = NMe 50%
Phenylacetic acid dianions react with aryl halides under photostimulation in liquid ammonia to
afford aryl substitution products. The regioselectivity of the arylation depends on the counter ion:
with potassium, only para-coupling is observed while with the smaller lithium counter ion
-substitution is observed exclusively <2000OL2643>. This methodology is useful for the
-arylation of ketones and is also neatly adapted for the synthesis of substituted indoles by
photostimulation of o-iodo- or o-bromoanilines which undergo substitution with enolates
followed by spontaneous ring closure <2003CRV71>.
1.11.2.2 Substitution of Oxygen
1.11.2.2.1 Substitution of alkyl oxygen leaving groups
(i) Friedel–Crafts alkylation and related processes

Considerable efforts are now in evidence for the use of more environmental friendly systems for
chemical transformations, particularly in the heavy chemicals industry. In this context, alcohols
and their derivatives (and also alkenes, see Section 1.11.2.8.1) are attractive alternatives to halides
as reagents for Friedel–Crafts alkylation of aromatic compounds, and many new ‘‘green’’ catalyst
systems are tested and developed specifically for such reagents <1999AC(A)(181)399>. New solid
catalysts for the alkylation of arenes with simple alkyl, allyl, or benzyl alcohols are generally
prone the following factors: high selectivity for monoalkylation, efficiency, tolerance to water
(which is liberated during alkylations involving alcohols), and recoverability for reuse.
They include acidic clays <2002MI363, 1999GC75>, acidic mesoporous zeolites <1999MI55,
1999AC(A)(188)99, 2000JCA(195)237>, iron-containing graphite <2001JCA(201)105>, rare
earth triflates <1997JOC6997, 1999CC1331> which can be supported <1998CR(C)41> or micro-
encapsulated <2000AC(A)(202)117>, gallium triflate <2003MI1>, and triflamide <1996SL1045,
2000AC(A)(202)117>. An AlCl3/MCM-41 solid catalyst gives selective 2,6-dialkylation of
naphthalene with isopropanol <2003JMOC(A)67>. Friedel–Crafts alkylations can be carried
out in supercritical or near-critical fluids. In CO2, anisole is alkylated with trityl alcohol using
only trifluoroacetic acid as the initiator <2002MI136>; a continuous flow process has been
described for the highly selective monoalkylation of anisole (or mesitylene) with isopropanol in
supercritical CO2 in the presence of a solid acid catalyst (Equation (19)) <1998CC359>. The
hydronium ion content of near-critical water (perhaps the ideal ‘‘green’’ solvent) is sufficiently
high that no other acid additive is required for the efficient alkylation of phenols with tertiary,
secondary, and even primary alcohols <1997IEC5175>.
OMe OMe OMe OMe

Acid-Deloxan®
+ OH Pri + Pr2i + Pr3i
scCO2
(3 equiv. ) (1 equiv. ) (30%) (6%) ð19Þ
(0%)
scCO2 = supercritical CO2 (Tc = 31.1 °C, pc = 73.8 bar)

Acid-Deloxan® = polysiloxane-based solid acid formed by sol–gel condensation
of alkylsulfonic acid functionalized organosilane monomers
Allylation of active arenes can be performed in high yield and without side reactions by using a
variety of transition metal-based catalysts and allylic alcohols, tosylates, or esters <1996SL557,
1996CL1021, 1997CC859, 1997CL137, 1999JOC5308, 2003SL1431>. Other oxygen leaving group
electrophile precursors for the alkylation of active arenes include methyl t-butyl ether, which is a better
t-butylating agent than either t-butyl alcohol or isobutylene in the presence of solid acid catalysts
<2001GC92>, and active silyl ethers <1997SL1145, 2002TL6391> in the presence of triflate-based
catalysts. Sc(OTf)3 <1999S603> and Cu(OTf)2 <2001T241> also catalyze efficient arene alkylation
with mesylates. Ultrasound irradiation improves considerably the efficiency of AlCl3-catalyzed reac-
tions of arenes with nonracemic 2-(mesyloxy)propanoates, without loss of stereochemical enrichment
<1996BSB755>. Methoxyacetate <1995NJC707> and N-sulfamoylcarbamate <2003OL193> ben-
zyl esters are new oxygen-based benzyl cation precursors, allowing highly efficient monobenzylation
of benzene and active derivatives; the former works well with lanthanide superacid salt catalysts, while
the latter succeeds even under noncatalyzed (thermal) conditions. Ketones and aldehydes have rarely
been used successfully in Friedel–Crafts alkylation reactions, due to the nonselective formation of
product mixtures. However, the corresponding dioxygenated alkyl systems (that is to say acetals and
related functions) have emerged as useful alkylating agents for active aromatic systems, formally by
the substitution of oxygen (Scheme 9) <1996TL375, 1997TL7021, 1997JOC151, 1999JCS(P1)1189,
2001HCA163>; in some cases, these reactions can be rendered stereoselective. In the presence of
Sc(OTf)3, acetals of arene carbaldehydes react with active benzenes to give diarylmethanes as the sole
products <1997JOC6997>. This remarkable reaction proceeds through a redox process involving a
Lewis acid-mediated hydride shift. Indeed, the arene carbaldehyde and the diol can be used as the
initial reagents, thus facilitating the operation. Similarly, benzene and other mildly activated aro-
matics are alkylated with ketones or aldehydes in the presence of hydrosilanes and catalytic amounts
of indium(III) salts (many other Lewis acids fail completely); the hydrosilane plays a dual role as both
co-catalyst and hydride donor for the redox process <1999T1017>.
Me
Me
HO OCOCF3 i. TiCl4, –15 °C HO
*RHN + *RHN
CF3 CF3
ii. H2O
O O
92%
R* = (R)-(–)-isobornyl 80% de
O O
TsOH (cat.)
O O O O
Benzene, ∆
HO Bu Bu
93%
Scheme 9
Some novel arene alkylation reactions involving heteroatom systems can be formally explained
in terms of substitution of an oxygen leaving group. Alkoxy halo diaziridines react with Lewis
acids to give alkoxy halo carbenes, which decompose to give halide, CO, and alkyl cations; these
latter alkylate benzene, used as the solvent, in moderate yield <2000JACS9878, 2001OL2305>.
Nonracemic -arylthioethanols in which the carbinol center is stereogenic alkylate arenes without
loss of enantiomeric excess, in intermolecular or intramolecular fashion <1996SL465,
2002TL351>; in each case, the configuration of the chiral center is controlled by the formation
of an episulfonium ion as the reactive electrophilic intermediate (Scheme 10).
HO H
Ph
H
Ph S S
BF3.OEt2
H
93% Ph S
Scheme 10
(ii) Substitution by organometallic sp2 carbanions

In most cases, alkyl tosylates are as efficient as alkyl halides in the role of electrophiles for the
transition metal-catalyzed alkylation of aryl and alkenyl nucleophiles <B-2002MI27,
2002JA4222>. In nickel-catalyzed processes, less expensive 1,3-butadiene can be used as a ligand
instead of a phosphine <2002JA4222>. Alkyl tosylates undergo efficient palladium-catalyzed
cross-coupling with alkenyl zinc reagents in presence of P(Cyp)3 in THF/NMP as solvents
<2003JA12527>. Phosphates are generally poorer leaving groups; isolated examples are described
for allylic phosphate arylation using triphenyl indium <2003JOC2518> or alkenylation using
zirconium or aluminum reagents <1995SL183> with variable regioselectivity (Equation (20)). The
cross-coupling reaction between phenyl magnesium bromide and alkoxy methyl diphenyl
phosphonium salts—with the latter prepared in situ from an alcohol, methyl iodide, and chloro-
diphenyl phosphine—occurs in good yield, with transfer of the alkyl group of the alkoxy function
via CO cleavage, when an excess of Grignard reagent is used without a metal catalyst
(Scheme 11) <2003CL676>. An internal phosphine function exerts a regio- and stereo-directing
influence during the nickel-catalyzed cross-coupling reaction of allylic methyl ethers with
PhMgBr <1995JA7273>. The stereoselective preparation of C-phenyl glycosides by the coupling
of 1-aryloxy 2-carbohydrates with aryl magnesium halides in the presence of NiCl2(dppe) occurs
with inversion of configuration, but with retention when PdCl2(dppf) is used as catalyst
<1998JOM(567)157>. Using chiral oxazolinylferrocenylphosphines as ligands in Ni(0)-catalyzed
asymmetric allylic substitution by phenyl Grignard reagents, best results (yield and ee) were
obtained with OAc, OMe, and OPh leaving groups; allylic alcohols give low yields while bromides
give decreased enantioselectivity (Equation (21)) <2000JCS(P1)2725>.
Bun
M CuCN (cat.)
OPO(OEt)2 + Bun
+
THF
Bun
ð20Þ
AlBu2i 62% 1:1

ZrMeCp2 40% 5:1
BuLi R
Me PhMgBr
Ph2PCl MeI
ROH Ph2POR Ph2POR
+ 99%
I–
R = p-MeO-C6H4CH2
Scheme 11
Ni(acac)2, L* Y X Yield (%) ee (%)

Y + PhMgX * Ph
THF, rt, 17 h OAc Cl 53 87
OCO2Me Br 79 69
OMe Cl 83 84 ð21Þ
O
L* = Fe OPh Br 98 87
N OH Br 36 82
Pri Br Br 95 15
PPh2
Epoxide opening by alkenyl or aryl metals has sustained interest and is further developed in its
asymmetric form <B-2002MI259, B-1996MI307, B-1996MI274>. As a route to chiral homoallylic
alcohols, it is much valued in total synthesis, as exemplified in the preparation of viridiofungin A
<1998TL877>, fostriecin <2001OL2233>, and 4,5-deoxyneodolabelline <2003JA1843>.
Several recent advances in this field merit particular mention. Aryl lithiocuprates react with
oxirane to give homobenzylic alcohols in good yield <2003EJO452>. Sequential nucleophilic
addition on C2-symmetric 1,2,3,4-diepoxybutane is achieved using high-order cyanocuprates bear-
ing a nontransferable ligand—R(2-thienyl)Cu(CN)Li2 where R is alkenyl group—for the first
epoxide opening, then aryl or vinyllithium or Grignard reagent in the presence of a copper salt for
the second <2002S2138>. Total control of the regiochemistry in epoxide opening of glycidol
derivatives with aryl or vinyl Grignard reagents is achieved using a copper halide catalyst (CuI,
CuBr) <2003TL2695>. The organozinc reagent PhZnOCOCF3—prepared in situ from diphenyl
zinc and trifluoroacetic acid—reacts with 1,3-cyclooctadiene monoepoxide via a regio- and stereo-
selective syn-1,2-addition, although with 1,3-cyclopentadiene or 1,3-cyclohexadiene monoepoxides,
regioisomeric mixtures arising from 1,2- and 1,4-addition are obtained <2002OL905>. Vinyl or
phenyl C-glycosides can also be obtained via tandem glycal epoxidation/epoxide opening in a syn-
fashion using excess of trivinyl- or triarylaluminum; stereochemistry can be controlled by varying
the nature of the metal <2000OL2707>. The opening of an epoxide or 2-substituted oxetane by
phenyllithium can be performed asymmetrically (Equation (22)). Using a chiral diether ligand in the
presence of a Lewis acid (BF3), trans-products are obtained exclusively, with ee up to 47%
<1996TA2483, 1997T10699>. Similar success is achieved using ()-sparteine as a ligand
<1998SL1165>. Arylation of cyclic and acyclic symmetrical epoxides (cyclohexene, cyclopentene,
or 1,2-dimethylethylene oxides) in the presence of a chiral Schiff’s base gives trans-adducts with
good ee (76–86%) <1998TL9023>. Ring opening of 3-isopropyl-2-phenyl-3-oxetanol by phenyl or
vinyl lithium in the presence of BF3 provides 1,2-diols regio- and stereoselectively <1998EJO2161>.
OH
O + PhLi
Ph
Ligand/conditions Yield (%) ee (%)
(R,R)-1,2-dimethoxy- 99 43
But 1,2-diphenylethane,BF3.OEt2, ð22Þ
Et2O, –78 °C
(–)-sparteine, BF3.OEt2, 95 48
Schiff's base = H Et2O, –78 °C
But
Schiff's base, hexane, rt 92 86
But N OH
OH
1.11.2.2.2 Substitution of alkenyl oxygen leaving groups

This area remains something of a monopoly for fluorosulfonate and phosphate ester leaving
groups. Substitution of enol triflates (or other oxygen leaving groups) by organo nucleophiles is
most usually accomplished using boron or tin derivatives; these transformations are discussed
later (see Sections 1.11.2.5 and 1.11.2.6.2). Costs and toxicity factors in the preparation of these
highly electrophilic substrates (triflic anhydride or exotic triflylating reagents are usually required)
are the main drawbacks in the otherwise highly valued enol triflate substitution methodology;
partly for these reasons, interest is increasing for the alternative use of enol phosphates, which
cross-couple in milder conditions than were previously thought necessary.
The scope, limitations, and ligand effects in the nickel-catalyzed cross-coupling reaction of
alkenyl triflates with alkyl Grignard reagents are established; di- and trisubstituted triflates
couple readily with a wide range of sp3-carbon Grignard reagents, but tetrasubstituted substrates
react sluggishly and give low yields of coupled products. Bidentate phosphines with small bite
angle (dppe and dppp) are found to be superior to other ligands <1999TL3101>. Cyclic 1,3-
dienyl 2-triflates undergo effective copper(I)-catalyzed coupling with Grignard reagents to give
2-substituted conjugated dienes <1998JOC2517> although the corresponding dienyl phosphates
fail to react. Success with these electrophiles is achieved using a nickel catalyst, NiCl2L2
(L = dppe or dppp). Thus, six- and seven-membered cyclic 1,3-dienyl 2-phosphates couple
smoothly with alkyl or phenyl Grignard reagents in ethereal solution; the (E)-isomer of an acyclic
derivative couples with alkyl Grignards with pronounced inversion of configuration, while the
(Z)-form provides near-equal mixtures of isomers (Scheme 12) <1999JOC1745>.
The alkylation of enol phosphates with dialkyl cuprates (especially Me2CuLi) is now a widely
used technique, particularly in natural product synthesis, when a ketone function is to be replaced
by an alkyl group. The enol phosphate of a -keto ester reacts particularly well, presumably
helped by an addition–elimination mechanism <1998T3279>. Allyl cyanocuprates undergo
efficient coupling with alkenyl triflates to give 1,4-dienes (Scheme 13) <2003OM2108>.
NiCl2(dppe)2 (1 mol.%)
OPO(OPh)2 Ph
PhMgBr (1.5 equiv.) n= 1 68%
n=2 92%
n Et2O, rt n
NiCl2(dppe)2 (1 mol.%)
OPO(OPh)2 Bu
BuMgBr (1.5 equiv.)
Et Et
Ph Ph
Et2O, rt
(E:Z )
(E ) 62% 5:95
(Z ) 43% 35:65
Scheme 12
R R R
[BuTeLi] Bu2CuCNLi2
X TeBu CuCNLi2
0 °C, 30 min rt, 1 h
2
X = Cl, Br
R = H, Me OTf
R
rt, 30 min
72–82%
OTf OTf OTf OTf OTf
Ph Ph
Triflates =
Scheme 13
Alkylation of lactam-derived enol triflates with lithiocuprates gives variable success, although
palladium-catalyzed arylation with phenyl zinc chloride proceeds in excellent yield
<1997JOC8131, 1998CC1757, 1999JA593>.
Enol triflates derived from -keto esters cross-couple successfully with Grignard-based zincate
complexes (R3ZnMgX) under copper catalysis, leading to tri- and tetrasubstituted ,-unsatu-
rated esters. Zincate complexes are milder than Grignard reagents and therefore avoid hydrogen
incorporation in the copper-catalyzed conditions <2001SL1511>. Activated enol nonaflates,
prepared from cyclic - and -diketones and cyclic or acyclic -keto esters and purportedly easier
to obtain and handle than triflates, undergo efficient and stereoselective palladium-catalyzed cross-
coupling with primary alkyl and aryl zinc chlorides with retention of configuration (Equation (23))
<1999T2103>. Triorganoindium reagents containing alkyl, vinyl, aryl (or alkynyl) groups undergo
PdCl2(PPh3)2-catalyzed cross-coupling with a representative vinyl triflate in good yield; all three
organic groups may be transferred during the reaction <2001JA4155>.
Me Cl Me
COOEt Pd(dba)2, dppf Cl COOEt
NfO
+ ð23Þ
Me THF, 65 °C Me
Cl ZnCl
77% Cl
1.11.2.2.3 Substitution of aryl oxygen leaving groups

Much of the methodology developed for cross-coupling reactions with aryl halides can be
effectively applied to aryl triflates (see Section 1.11.2.1.3). By careful selection of the phosphine
ligands, metal salt additives, and reaction conditions, as described by Hayashi and co-workers,
substitution of one of the two enantiotropic triflate groups of achiral biaryl ditriflates by aryl
Grignard reagents can be achieved in the presence of a Pd catalyst; an ee of 94% is obtained with
PhMgBr in presence of LiI and the complex PdCl2[(S)-alaphos] (alaphos=(2-dimethylamino)pro-
pyldiphenylphosphine) (Equation (24)) <1999T3455>.
TfO OTf PhMgBr, LiI Ph OTf Ph Ph

+
PdCl2[(S)-alaphos]
ð24Þ
Et2O/toluene, –20 °C
(71%) (3%)
94% ee
Organozinc reagents are now established as versatile nucleophiles for transition metal-catalyzed
cross-coupling reactions <B-1999MI179>. Studies by Knochel and co-workers show that dppf is
the required palladium ligand for coupling with aryl triflates; this means that controlled, chemo-
selective, sequential coupling of multifunctional arenes (e.g., iodophenyl triflate, or benzyl zinc
bromide bearing a triflate) may be performed through simple selection of the catalyst system
<1996SL573, 1997TL1749>. This methodology can be extended to sequential polymer-supported
aryl skeleton construction <1997SL1084>. Organoindiums are good nucleophiles although they
are less exploited. Triorganoindium reagents containing alkyl, vinyl, phenyl (or alkynyl) groups
undergo palladium(II)-catalyzed cross-coupling with a representative aryl triflate in good yield
and high chemoselectivity; all three organic groups may be transferred <2001JA4155>. This
reaction is employed in successive multifold cross-coupling reactions with oligoarene tris-triflates
to give dendritic molecules <2002CC2246>. Aryl and alkyl titanium reagents couple smoothly
with aryl triflates in the presence of a Pd/ppfa catalyst (ppfa=N,N-dimethyl-1-[2-(diphenylphos-
phino)ferrocenyl]ethylamine) (Equation (25)) <2002SL871> whereas aryl bismuth reagents cross-
couple with electron-poor (but not electron-rich) aryl triflates in the presence of Pd(PPh3)4
(Equation (26)) <1999OL1271>.
OTf PhTi(OPri)3 (1.2 equiv. ) Ph
[PdCl(π-C3H5)]2/ppfa (1.0 mol.%) ð25Þ

THF, reflux, 3 h
98%
Et
Et O ArOTf
Pd(PPh3)4 (10 mol.%)
N Bi Ph ArPh
NMP, 80 °C, 3 h
Et O 78–99%
Et ð26Þ
OTf OTf OTf OTf OTf
N
ArOTf =
Ac COPh CN
The search for oxygen leaving groups other than triflate for cross-coupling finds some success
in aryl nonaflates, which have all the reactivity benefits of triflates (and a few more advantages)
for selective palladium-catalyzed reaction with organozinc reagents <1998JOC203>. Aryl tosy-
lates are more attractive than triflates in terms of cost, stability, and availability of reagents, but
to compensate for their lower reactivity, higher reaction temperatures and higher catalyst loadings
may be required. Nonetheless, efficient cross-coupling has been reported for a variety of organo-
metallic nucleophile/catalyst combinations <2001JOC3642, 2002JA13856, 2003JA8704,
2003JA8704>. Aryl sulfonates also undergo nickel- or palladium-catalyzed homo-coupling in
mild conditions <1995JOC176, 1997JOC261>.
Cases of methoxy as a leaving group usually remain limited to nucleophilic aromatic substitu-
tion of anisoles with aryl Grignard reagents, which may nonetheless lead elegantly to complex
axially chiral biaryls. When regioselectivity is an issue, it is often determined by the other
substituents present on the anisole; some substitutions are highly diastereoselective, although
this is by no means always the case (Scheme 14) <1996TL6359, 2000OL2459>.
OMe MgBr Xylene

+
+
∆ COOMes COOMes
COOMes Cr(CO)3 Cr(CO)3
Cr(CO)3 81%
99:1
Mes = mesityl
But
But O
O
N
N
O N O N
+ THF
OMe 87%
1:1 mixture of
BrMg atropoisomers
OMe
MeO OMe OMe MeO OMe
Scheme 14
1.11.2.3 Substitution of Other Chalcogens
1.11.2.3.1 Substitution of alkyl chalcogen leaving groups

Substitution of unactivated alkyl sulfur by aryl or alkenyl nucleophiles remains extremely rare
in the literature; the formation of a C(sp2)C(sp3) bond by sulfur displacement is often better
achieved through an alkyl metal–alkenyl or aryl sulfur reagent combination (see Section
1.11.2.3.2). Partial redress of this situation may be underway, however, through use of
sulfonium salt leaving groups, described by Liebeskind and co-workers in palladium-catalyzed
cross-coupling reactions with alkenyl, aryl, and heteroaryl zincs. Reactive allylic, benzylic, and
heterobenzylic (from furan and thiophene, but not pyrrole) sulfonium salts are known
(Equation (27)), and are at least as stable and easy to handle as the corresponding halides
<1997JA12376, 1999JOC2796>.
RZnCl X R Yield (%)

S PdCl2(PhCN)2 (2 mol.%) R O p-Tolyl 67
X
ð27Þ
X P(OPh)3 (2 mol.%) N-t-BOC p-Tolyl 0
PF6 THF, rt S m-Methoxyphenyl 62
S p-Chlorophenyl 53
One-pot, high-yield, double functionalization of allyl phenylsulfones can be carried out by

sequential base-mediated -alkylation then palladium-catalyzed nucleophilic arylation with a zinc
reagent <1999T2889>, although the regiochemistry of the phenylsulfonyl substitution (SN versus
SN0 ) is not straightforward.
In the presence of excess triflic acid in benzene, a 4-(phenylthio)tetrahydroisoquinoline
derivative (generated in situ from a monocyclic precursor in an acid-mediated Pummerer
cyclization) undergoes substantial transformation to the 4-phenyl analog, presumably via
Lewis acid-induced departure of the phenylthio group to give a benzylic electrophile, which
then takes part in a Friedel–Crafts-type alkylation reaction with benzene used as the solvent
<2003CPB667>.
1.11.2.3.2 Substitution of alkenyl and aryl chalcogen leaving groups

Sulfur, selenium, and tellurium sp2 electrophiles undergo cross-coupling reaction with organo-
lithiums, organomagnesium halides, organocuprates, organozincs (also organoboranes and orga-
nostannanes) in the presence of Pd, Ni, or Cu catalysts <B-1998MI227, B-1999MI179>. Reaction
may occur without a catalyst in the case of lithium reagents (and, to a limited extent, Grignard
reagents).
Alkenyl sulfides, sulfoxides, and sulfones can be employed successfully as cross-coupling
reaction partners. Addition of alkyl or phenyl lithium to (Z)-trifluoromethyl thioenol ethers
provides trifluoromethyl alkenes stereoselectively in 80% yield if the thioenol moiety is con-
jugated at the -position <1996TL171>. Noncatalyzed vinylic nucleophilic substitution of the
sulfone group by Grignard reagents in ((E),(E))-5-tosylpentenamides gives ((E),(E))-dienamides
regio- and stereoselectively but in modest yield (25–60%) <1995TL3901>. The scope for stereo-
selective Grignard/Cu(I) reagent monosubstitution of -oxoketene dithioacetals <1995TL1925>
and nitroketene dithioacetals <1998T12973> has been widened, along with alkene preparation
through nickel-catalyzed alkenyl sulfide cross-coupling with Grignard reagents, although the
stereoselectivity is still not totally controlled for the latter <2001SL977, 1999JOC8582>. Attrac-
tive chiral 1,10 -binaphthyls can be prepared by ring opening of dinaphthiophene with organomag-
nesium halides under nickel catalysis in the presence of chiral oxazoline-phosphine (Equation
(28)) <2002JA13396, 2003CRV3213>. Alkenyl sulfones couple with aryl or alkyl lithiums to give
substituted alkenes in good yield <2000TL8917, 2003JFC195>. NiCl2(dppf) catalysis of the
cross-coupling reaction of alkyloxysulfonyl arenes with aryl magnesium bromides provides
unsymmetrical biaryls in good yield, although alkenyl Grignard reagents are less efficient
<2003JOC3017>. Competing electrophile reactivity can be regulated: treatment of 6-bromo-
2-pyridyl phenyl sulfone with PhMgCl without catalyst allows selective displacement of the
phenyl sulfonyl group, whereas the presence of a catalytic amount of Pd(dba)2/dppf promotes
exclusive substitution of bromide (Scheme 15) <2002T4429>.
i. Ni(COD)2/L* (3 mol.%)
L* =
4-MeC6H4MgBr, THF 4-MeC6H4 O
S HS ð28Þ
ii. H3O Ph2P N
97%
95% ee
i. PhMgCl, THF
i. PhMgCl, THF Pd(dba)2 (5 mol.%)
rt, 12 h dppf (5 mol.%)
Br N Ph Br N SO2Ph ii. H2O Ph N SO2Ph

ii. H2O
77% 71%
Scheme 15
It is possible to play off the reactivities of different alkenyl leaving groups during the regio- and
stereoselective preparation of di-, tri-, and tetrasubstituted alkenes (and conjugated dienes). The
1-tosyl moiety is selectively replaced in the NiCl2(PPh3)2-catalyzed cross-coupling reaction between
1,4-bis(arylsulfonyl)-2-phenylseleno-1,3-butadienes and a Grignard reagent <1996TL4161>.
Conversely, with alkenes of the type cis-TsCH¼CR(SePh), organocopper reagents of the type
RCu(SePh)Li selectively substitute the phenylseleno group with retention of configuration; no tosyl
displacement is observed <1998JOC7908>. Efficient and chemoselective nucleophilic substitution
of a phenylselenyl group can be achieved using dimethyl lithiocuprate <1999AG(E)2027>. None-
theless, ,-difunctional alkenes of the type (Z)-RCH¼C(SePh)OTs undergo palladium-catalyzed
tosylate group substitution first, with retention of configuration, when treated with an alkyl or aryl
cuprate reagent. Subsequent nickel-catalyzed cross-coupling of the resulting (Z)-alkenyl selenides
with MeMgBr provides stereoselectively trisubstituted alkenes (Scheme 16) <1995T4691>. In a
further demonstration of chemoselectivity control, (E)-1-(phenylselenyl)alkenylstannanes undergo
intermolecular Stille coupling with an aryl iodide electrophile under Pd(PPh3)4/CuI catalysis to give
the (Z)-alkenyl selenides, prior to nickel-catalyzed Grignard reagent coupling <1997S417>. Similar
sequential construction is possible using (E)-XCH¼CH(SeAr) (X = I, Br) and two different

Grignard reagents <1997SC39>. This powerful methodology also allows stereoselective synthesis
of conjugated dienes: (E)-(ArSe)CH¼CHZrCp2Cl cross-couples with (E)-alkenyl halides in the
presence of Pd(PPh3)4 to give (E,E)-1-arylselenyl-1,3-alkadienes, which are then coupled with aryl
Grignard reagents, as above <1996T9819>.
PhSe Bu Li2Cu(2-thienyl)(CN)Bu PhSe Bu MeMgBr, NiCl2(dppp) Me Bu
THF, – 40 °C Bu Benzene, rt
TsO Bu
65% 66%
Scheme 16
(Z)-Alkenyl tellurides undergo efficient and stereoselective cross-coupling with lower-order cya-
nocuprates leading to (Z)-disubstituted olefins; this reaction can be performed in the presence of a
vinyl chloride <1995SL671>. Like the phenylselenyl group, phenyltelluryl is substituted by primary
alkyl and aryl Grignard reagents under nickel catalysis <1996TL7417>. Dialkyl zincs are also
successfully employed for nucleophilic substitution of unsaturated organotellurium compounds in
the presence of a Pd(PPh3)4/CuI/DMF system (Equation (29)) <2000TL433>. A homo-coupling
reaction leading nonstereoselectively to 1,3-dienes is observed for the single case of distyryl tell-
urides, in the presence of a Pd(OAc)2 catalyst and silver(I) acetate <1996JOM(526)335>.
ZnEt2
PhS TeBu Pd(PPh3)4, CuI PhS Et ð29Þ
THF/DMF, rt
69%
Organotellurium(IV) compounds may behave either as nucleophiles or as electrophiles in metal-

catalyzed coupling reactions; diaryl tellurium(IV) dichloride gives biaryl products in good yields
in both palladium- or copper-catalyzed Stille cross-coupling with stannanes <1999CC2117> and
PdCl2/NaOMe-mediated reaction with hypervalent aryl iodonium salts <2001SC1721>.
1.11.2.4 Substitution of Nitrogen

Superior Lewis acid catalysis is reported for Sc(OTf)3 in the alkylation of indole in the 3-position
with nonracemic N-protected aziridine carboxylates, providing a facile entry to tryptophan
derivatives with high ee (up to 96%) <1997SL754>. Benzylation of electron-rich acid-sensitive
aromatics can be achieved via simple thermolysis of N-benzyl-N-nitrosoamides; no catalyst is
required (Equation (30)) <1997JOC8091, 1999JOC5966>. The reaction involves a nitrogen-
separated ion pair containing an effectively free carbocation intermediate as the reactive species.
Pyr Ph
O
(2 equiv. )
+ Ph +
N Ph N Ph N ð30Þ
H 40 °C H N
NO H
80%
62:38
Use of ammonium salts as sp3-carbon leaving groups in reactions with organometallic reagents
is reviewed <B-2002MI27>. Allylammonium salts are precursors for the formation of -allylpal-
ladiums, which may couple with nucleophiles such as Grignard reagents, cuprates or malonate
ester carbanions. Allylic substitution of a chiral amine leaving group by organocuprates in the
presence of a Lewis acid via addition–elimination occurs with up to 95% ee using a chiral
pyrrolidine auxiliary <B-2002MI259>. Reaction of the trimethylammonium salt of an optically
active allyl moiety with PhZnCl in the presence of Pd(PPh3)4 proceeds via the -allylpalladium
intermediate with predominant SN0 regioselectivity and 87% retention of configuration, in con-
trast to expectations based on previous work and on the behavior of a malonate ester carbanion
nucleophile under the same conditions (Scheme 17) <1995TA389>.
Pd(PPh3)4
+ +
NMe3 PhZnCl Ph
NH-t-BOC
OH 30%
Ph
I–
4:1
Pd(PPh3)4 67% ee
30%
NaCHE2
+ +
E = COOMe
E E E E E E
27:2:1
92% ee
Scheme 17
The copper-mediated aziridine ring-opening reaction by Grignard reagents is extensively used

in synthesis, notably in its asymmetric form using a chiral ligand <1999OL439>, but only a few
applications involve vinyl, aryl, or heteroaryl nucleophiles. Diversely substituted N-t-BOC aziri-
dines react regioselectively with sp2-carbon Grignard reagents and copper salts <1996TL3761,
1997T8237>. A catalytic amount of InCl3 is reported to effect N-tosylaziridine ring opening by
heteroaromatic nucleophiles with good yield but variable regioselectivity <2002TL1565>.
Arene diazonium tetrafluoroborates are effective electrophiles in cross-coupling reactions with
organometallics, and interest in their use has taken an upturn due to their superior reactivity and
the low cost of the aniline precursors, compared with aryl halides. Most work involves cross-
couplings with arylboronates and is treated later (see Section 1.11.2.5). With the exception of
aryltrimethylammonium salts, which are also useful as Suzuki cross-coupling electrophiles
<2003JA6046>, few advances are reported for other nitrogen leaving groups.
p-Dinitrobenzenes undergo rapid, moderate-to-high yielding, selective substitution of one nitro
group when treated with a range of alkyl boranes, although the scope of the reaction is rather
limited <2003JOC4388>.
1.11.2.5 Substitution of Boron
1.11.2.5.1 General remarks on boron substitution reactions

Aryl radicals generated by the action of Mn(OAc)3 on arylboronic acids react with aromatic
solvents giving unsymmetrical biaryl compounds in reasonable yields, but the scope of this
reaction is limited by the narrow range of solvent partners: benzene, thiophene, or furan; the
latter gives only moderate success <2003JOC578>. A limited number of alkenyl dialkyl boranes
furnish the corresponding alkenyl alkane via ‘‘ate’’ activation and then oxovanadium(V)-induced
oxidation <1998CC1209>. However, a recent historical perspective on CC bond formation via
boron-mediated (i.e., noncatalyzed) organic group transfer reveals the extent to which this
chemistry has really reached its term in synthesis <2003CUOC1725>.
Progress in the area is of course dominated by the Suzuki (or Suzuki–Miyaura) cross-coupling
reaction. This process, the palladium- (or other transition metal-)catalyzed reaction of an organic
(usually vinyl or aryl) halide or triflate with an organoboron compound (aryl, alkenyl, or alkyl) in
the presence of an inorganic base, is one of the most powerful methodologies currently available for
CC bond formation. Depending on the reagent combinations, biaryls, styrenes, or conjugated
dienes are the usual products, although recent developments allow for the smooth coupling of alkyl
reagents. General reviews underline the various features of recent progress <1995CRV2457,
B-1998MI49, 1999JOM(576)147, 2002JOM(653)83, 2002T9633, B-2002MI249, B-2002MI591>.
Many factors contribute to its contemporary popularity, including generally mild reaction condi-
tions, wide functional group compatibility, the nontoxic nature of the inorganic byproducts, and
the ease of access to the cheap, easy-to-handle organoborane reagents. Indeed, recent progress in
this latter field has allowed some success in ‘‘one-pot’’ tandem borylation/Suzuki cross-coupling
processes <2003JOC3729, 2003TL6007>. Some commercial processes now use Suzuki coupling as
a key step <2002MI101>. Considerable efforts now turn toward environmental and economic
issues. Methods for efficient removal of palladium following Suzuki coupling are described
<2003OPRD191, 2003JOC2633>. Solid-phase Suzuki cross-coupling reactions can be carried out,
using supported versions of either the boron compound or the halide partner <1999CRV1549,
2003T885>. Microwave acceleration may be observed for homogeneous, heterogeneous, and solid-
supported Suzuki reactions. Part of the success of the reaction is due to the continued development
of new ‘‘tricks’’ for avoiding problems in specific cases: in recent examples, a CuI additive prevents
catalyst deactivation by product chelation in the Suzuki synthesis of di(-pyridyl)benzene
<2001T2991>, while use of Ag2O as the base suppresses a competing ipso-substitution reaction
during Suzuki coupling of pentafluorophenylboronic acid <2003TL1503>.
1.11.2.5.2 Substitution of arylboranes

Most work focuses on the preparation of biaryl compounds from arylboronic acids, and the
impact of the Suzuki reaction in this area is thoroughly reviewed <1998T263, 2002CRV1359,
B-2002MI53>, including the particular field of polyarylene synthesis <2001JPS(A)1533>. A main
feature is the emergence of improved, refined (and sometimes air-stable) catalyst systems, allow-
ing greater efficiency, use of milder reaction conditions, and—very importantly—successful
coupling reactions with aryl chlorides. A selection of catalysts may achieve this latter objective
under mild conditions <2000JPR(342)334, 2002AG(E)4176>, including palladium complexes of
bulky electron-rich phosphines (both alkyl and aryl) <1999JA9550, 2000JA4020, 2000CC2475,
2001CC2408>, phosphinous acids <2002JOC3643>, and heterocyclic carbenes <2000TL595,
2000JOM(595)186, 2002JOM(653)69> (Figure 2) or palladacycles (see Equation (14))
<1995AG(E)1848, 2003OM987>. A wide variety of both electron-donating and electron-
withdrawing substituents may be tolerated on the chlorobenzene, depending on the catalyst
system. A catalyst incorporating Santelli’s ‘‘tedicyp’’ ligand (tedicyp=cis,cis,cis-1,2,3,4-tetrakis
[(diphenylphosphino)methyl]cyclopentane) performs well with electron-deficient chloroarenes
<2001SL1458>. Analogous coupling of arylboronates with heteroaryl chlorides <1999SL45,
2001T1323, 2001T2787, 2001TL2115> or with arylsulfonium salts <1997JA12376> is also
feasible. Arylboronic acids may even cross-couple with electron-deficient aryl fluorides
<2003JA1696, 2003CC578>. Other cross-coupling partners include hypervalent aryl iodides
<1996JOC4720>, aryldiazonium salts <1996BSF1095, 2000TL6271>, aryl lead acetates
<1998SL771>, and diaryl or di-(Z)-styryl tellurium dichlorides <2001JCR(S)283>.
Pd complexes with
R1 R2 R1
B(OH)2 Cl "high-performance"
ligands
+ R2
Mild conditions
Ligands:
Me2N PPh2 HP(O)Bu2t Ph2P PPh2

SiMe3 Ph2P
Mes N N Mes PPh2
Me Fe Me
PBu3t
Me Me
(Mes = mesityl) PCy2 "tedicyp"
Me
Figure 2 Successful Suzuki coupling with aryl chlorides.
To facilitate extraction after reaction, water-soluble phosphine ligands may be used for the
palladium-catalyzed coupling of a wide range of arylboronates and aromatic iodides and bro-
mides <1999JOM(576)305, 2001OL2757, 2003JOC6767>. Some Suzuki biaryl couplings may be
performed in ionic liquids <2000CC1249, 2003JMOC(A)(206)193>. For phosphine-free Suzuki
reactions, a variety of other types of ligand are available, including certain palladacycles and some
nitrogen heterocycle-based species <2002JOM(653)69, 2003T1837, 2003EJI1161>. Pd(OAc)2,

PdCl2, and PdCl2(SEt2)2 may also be used <2000TL8199, 2003S337>, the first-mentioned giving
satisfaction in an aqueous solvent medium if a tetraalkylammonium salt is present (Scheme 18)
<1997JOC7170, 1999OL965, 2003CC466, 2003JOC888>. An oxime-derived palladacycle catalyst
in conjunction with a tetraalkylammonium salt permits coupling of aryl chlorides with phenyl-
boronic acid in water <2002AG(E)179>.
B(OH)2 Pd(OAc)2 (0.2 mol.%)

O2N Br NBu4Br (1 equiv. )
+ O2N
CF3
K2CO3 (2.5 equiv. )
F3C
H2O, 70 °C, 30 min
93%
B(OH)2 Pd(OAc)2 (0.08 mol.%)

Cl
NBu4Br (5 equiv. )
Me
Me + K3PO4 (1.5 equiv. )
H2O, ∆, 17 h O
O
94.5%
Me B(OH)2 Pd(OAc)2 (0.4 mol.%) Me

Br NBu4Br (0.25 equiv. )
+
Na2CO3 (1 equiv. )
Me Me
H2O, ∆, 10 min
82%
Scheme 18
A plethora of heterogeneous catalyst systems for Suzuki biaryl cross-coupling has emerged.
Colloidal palladium, Pd nanoparticles, and Pd powder in the presence of KF show some success
as catalysts when more active halide partners are used <1996TL4499, 2000OL2385, 2001CC775>.
Ligandless heterogeneous Pd–C catalysts allow coupling of aryl chlorides <2001OL1555,
2002SL1118>, whilst more limited application of Pd(OH)2–C has been made <2003JOC1571>.
Clay, silica, glass bead, and synthetic polymer supports for catalysts are known <1999TL439,
2001GC23, 2003CC606, 2003TL5095, 2003TL7565, 2003JOC7733> along with a solventless
cross-coupling methodology based on a palladium-doped KF/alumina mixture, whose efficiency
is improved considerably by microwave irradiation <2003TL3817, 2003S217>. There is still some
debate as to the exact nature of the catalytic species derived from heterogeneous palladium
reagents, since they may possess a finite homogeneous component <2003MI931>.
One area of particular recent development is the asymmetric Suzuki cross-coupling to give
axially chiral biaryl systems. Once again, the key to success is the judicious choice of ligand, which
is chiral in this case. Following the first successful diastereoselective application, in the total
synthesis of vancomycin <1999CEJ2584>, atropo-enantioselective syntheses of binaphthyl, phe-
nylnaphthyl, and biphenyl compounds, whose structures often derive from the natural product
field, have appeared <2001CSR145, 2003JOC4897>. Using a single enantiomerically pure (bro-
moarene)chromium complex, either enantiomer of certain axially chiral biphenyls can be pre-
pared, through careful control of the reaction conditions (Scheme 19) <2000SL938>.
CHO Me Me
Pd(PPh3)4 OHC OHC
Br B(OH)2
+ Na2CO3 Xylene
Me
OMe MeOH/H2O ∆
(OC)3Cr OMe 98% OMe
75 °C, 30 min (OC)3Cr (OC)3Cr
80%
Scheme 19
Not quite so much development has been reported for arylboronic acid coupling with vinyl
halides or triflates, although where such reactions are investigated, good results are generally
obtained with catalysts which already perform well in cross-coupling with aryl halides. This
applies even for highly substituted alkenyl partners, and for chlorides, in some cases. Recent
illustrative examples include <2000JA4020, 2002JOC3643, 2003EJO1091, 2003OL3115>.
1,1-Dibromoalkenes may undergo single or double Suzuki cross-coupling, depending on the
conditions (Scheme 20) <2001SL254, 2000SL737>, while 1-fluorovinyl bromides or chlorides
cross-couple chemoselectively with one arylboronic acid equivalent to give the corresponding
-fluorostyrene derivatives <1999TL827>. Vinyl phosphates may be coupled successfully
<2001T6969>, as may the alkenyl or benzyl moieties of the corresponding tetramethylen-
esulfonium salts <1997JA12376>. New or improved procedures exist for arylboronic acid
cross-coupling with cyclopropyl iodides <1996JOC8718>, bromo-derivatives of active sp3-car-
bon compounds <2001CC669, 2002CC622, 2003TL3423, 2003OL1705>, and even with unac-
tivated alkyl bromides, which may react under remarkably mild conditions (Equation (31))
<2002JA13662>.
Ph Br Ph
excess PhB(OH)2 PhB(OH)2, Na2CO3
Me R H
Ph Na2CO3 Br Pd2(dba)3 (2.5 mol.%) Br
PdCl2(PPh3)2 (10 mol.%) P(2-furyl)3 (15 mol.%)
THF/H2O, 70 °C, 17 h Dioxane 65 °C, 4 h
95% 89%
COOMe (R = Me) COOMe (R = H) COOMe
Scheme 20
R1 R2 Yield (%)
Pd(OAc)2 (5 mol.%) n-Octyl Ph 87

R1–Br PBu2t Me (10 mol.%) ButOOC(CH2)6 p-MeS-C6H4 68
+ R1–R2 O ð31Þ
KOBut (3 equiv.) (CH2)10 1-Naphthyl 97
R2–B(OH)2 O
t-Amyl alcohol
NC(CH2)6 (E)-1-Hexenyl 85
rt, 24 h
n-Dodecyl n-Hexyl 66
A few alternatives to arylboronic acids have emerged as useful arylboron partners for cross-
coupling. Stable, easily prepared aryltrifluoroborate salts give excellent results <1999EJO1875,
2001TL9099> and may function with ligandless palladium catalysts <2003JOC4302>. Diaryl
difluoroborate salts react with aryl bromides and activated chlorides, transferring two aryl groups
<2003SL1435>. An example of phenyl-BBN coupling with a simple alkyl tosylate is known
<2002AG(E)3910>.
While palladium clearly dominates the center stage, some other useful catalysts for cross-
coupling are emerging. The most notable alternative is the use of nickel; advantages include
lower cost and the possibility of a better reactivity/selectivity profile. Progress tends to follow the
trends set in research on palladium-catalyzed reactions and has been included in a recent review
<2002T9633>. Highlights include biaryl formation by cross-coupling of arylboronic acids with
aryl chlorides and hindered aryl bromides <1997JOC8024, 1997TL3513, 1999TL2323,
2000T8657>, aryl sulfonate esters <1995JOC1060, 1996TL8531, 2001OL3049>, or aryl trimethy-
lammonium salts (Equation (32)) <2003JA6046> and successful use of phosphine-free
<1999T11889>, ligandless <2002TL4009>, or heterogeneous NiC <2000T2139> catalysts,
although this latter leaches considerable amounts of homogeneous species <2003JOC1177>.
Applications to other systems are rare; noteworthy are the observations that nickel-catalyzed
coupling reactions of arylboronic acids with vinyl phosphates <1999TL3321> or hindered allylic
carbonates <1996JOC5391> succeed where palladium catalysis fails. A chiral oxazolinylferroce-
nylphosphine ligand permits enantioselective coupling of allylic acetates with arylboronic acids,
albeit in moderate ee <2000JCS(P1)15>.
Bun
TfO –
NMe3 + Ni(COD)2 (10 mol.%)
B(OH)2
IMes·HCl (10 mol.%) N N
IMes = Mes Mes ð32Þ
+
CsF, dioxane
COMe Mes = mesityl
80 °C, 12 h
Bun COMe
87%
Recently, transition metal-free cross-coupling has been described. In superheated water, in the
presence of a base and a tetraalkylammonium salt, a number of arylboronic acids react with aryl
bromides (but not aryl iodides) giving biaryls; microwave irradiation improves the scope of the
reaction (Equation (33)) <2003JOC5660>.
NO2
Na2CO3, Bu4NBr
B(OH)2 NO2 sc H2O (150 °C)
+ ð33Þ
Br MW, 5 min
99%
Although other convenient methods exist for the preparation of biaryls, palladium-catalyzed
oxidative homo-coupling of arylboronates may be carried out. Sacrificial oxidants can be employed
<1997SL1199, 2002TL8149> but usually exposure to air is sufficient <1997SL131, 2002S2183>; a
base is not essential for the reaction to proceed <1996JOC2346, 2003TL1541>. The reaction can
even be carried out in water with ligandless PdCl2 as the catalyst (Equation (34)) <2002TL3067>.
Cl
B(OH)2 PdCl2 (3 mol.%)

Na2CO3 (2 equiv.)
TsCl (0.5 equiv.) ð34Þ
H2O, rt, 12 h
Cl
97%
Cl
1.11.2.5.3 Substitution of alkenylboranes

Although methodological development has been considerably less, the stereoselective catalytic
cross-coupling of an alkenylboron compound with an aryl or vinyl halide or pseudo-halide
continues to give great satisfaction, often in natural product synthesis. Usually, the catalyst is
a ‘‘standard’’ palladium complex such as Pd(PPh3)4. The limiting factor is perhaps the access
to alkenylboron starting materials, although new routes to these compounds are emerging,
facilitating one-pot vinylborane formation/coupling procedures <2002SL1880>. A general
lack of reactivity with aryl or vinyl chlorides is still evident. In those cases where the studies
are actually undertaken, successful new catalyst systems which are developed for arylboron
cross-coupling also perform well with alkenylboron reagents too <1997JOC7170,
2003JOC7733, 2003S217>. Alkenyltrifluoroborate salts are new, easy-access, stable reagents
for Suzuki cross-coupling with various aryldiazonium salts and aryl halides (Scheme 21)
<1999EJO1875, 2001TL9099, 2002JOC8424>. Alkenylboronates couple successfully with
cyclopropyl iodides <1996JOC8718> and with certain vinyl phosphates <2003JOC6360>.
One example of an Ag2O/CrCl2-mediated (E)-alkenylboronic acid homo-coupling to give the
(E,E)-diene is described (Equation (35)) <2002TL8149>.
Palladacycle
N2
+ (5 mol.%)
BF3
BF4 K
+
MeOH, rt MeO
MeO several min
81%
PdCl2(dppf).CH2Cl2 (2 mol.%)
Br ButNH2 (3 equiv. )
+
BF3
NC +
H2O/PriOH, ∆, 7 h
K NC
70%
Pd(OAc)2 (5 mol.%)
Br dppb (5 mol.%) (CH2)5CH3
BF3
+
Me + Cs2CO3 (1.25 equiv. )
Bu4N Me
CH3(CH2)5 H2O/DME, 50 °C, 24 h
O O
87%
Scheme 21
Ag2O (3 equiv. )
CrCl2 (5 mol.%)
B(OH)2 ð35Þ
THF, 65 °C, 12 h
95%
Single product
1.11.2.5.4 Substitution of alkylboranes

Mechanistic aspects, reactivity profiles, and applications of the B-alkyl Suzuki cross-coupling
reaction are thoroughly reviewed <2001AG(E)4544>. Unhindered, electron-rich organoboranes
are the most reactive partners and are most conveniently obtained from terminal alkenes as
9-BBN derivatives. Cross-coupling is achieved with a wide variety of vinyl or aryl iodides,
bromides, or triflates; other functional groups may be tolerated in either the boron or halogen
partner. Recently developed highly active catalysts may give success with aryl chlorides
<1998JA9722, 2001SL290>. The base plays a key role in the activation of the borane as a borate
species <1998JOC461>; in fact, formation of such an intermediate is a prerequisite for easy
handling of allylic or cyclopropyl reagents (Scheme 22) <1998SL161, 2000TL4251>. Intramole-
cular versions provide cyclic products with variable efficiency. In one case, an asymmetric
synthesis of cyclopentanes from prochiral bis(9-BBN-propyl)alkenyl triflates is reported, using a
palladium catalyst and chiral phosphine ligands, although the ee is moderate <1998TA3751>.
Apart from the cyclopropane derivatives <1996SL893, 1998SL198, 2000S1095>, whose reac-
tivity results from their significant sp2 character, alkylboronic acids or esters are generally poor
partners for Suzuki cross-coupling. Some recent success is reported for their reaction with aryl
halides <2001TL7213, 2002T1465, 2003CEJ3216> or aryldiazonium salts <2001OL3761>. Reac-
tivity is improved and scope enlarged through Ag(I) promotion <2001TL7213>, or after one-step
transformation into alkyltrifluoroboronate salts <2001OL393, 2003JOC5534> or ‘‘ate’’ com-
plexes <2001TL5817>. Cross-coupling of aryl halides with trimethylboroxine is a convenient
way of methylating the aromatic ring <2000TL6237>.
– OH RBr
i. 9-BBN-H B Pd(PPh3)4 R = Ph, m-tolyl, o -anisyl,
R
β-naphthyl, CH=CHBu,
Br ii. NaOH 65 °C, 8–16 h
CPh=CH2
60–92%
i. 9-BBN-OMe,
– OMe ArOTf
B Pd(PPh3)4 or
Al chips
Br PdCl2(dppf) Ar
ii. KOMe
65 °C, 0.5–1 h
81–86%
OTf OTf O OTf OTf O

ArOTf =
O O
MeO OMe S
O MeO OMe S
COPh
Scheme 22
1.11.2.6 Substitution of Silicon, Germanium, and Tin
1.11.2.6.1 Substitution of silicon and germanium

The palladium-catalyzed cross-coupling reaction of an aryl-, alkenyl-, or alkylsilicon reagent with
an sp2 (or active sp3) halide or triflate, for which the pioneering work by Hiyama engendered the
eponymous reaction, was outlined in COFGT (1995). Various general aspects of this reaction—
the requirement for the formation of a hypervalent pentacoordinate silicon intermediate, and in
this respect the promoting effect of an added fluoride source (usually TBAF), the preferred order
of organic group transfer from silicon, the high stereoselectivity, the possibility of cine-substitu-
tion—have been reviewed periodically since then <1995CRV1317, B-1998MI421, B-2002MI285>
while major recent advances, including notably those of Denmark and co-workers, are also
highlighted <2002ACR835, 2002CPB1531, 2003ACA75>. The appealing features of silicon—
the implication of low-molecular-weight, cheap, readily available, and easy-to-handle reagents,
combined with its compatibility with a wide range of functional groups and reaction conditions—
have encouraged these developments and improvements. One isolated application of solid-phase
Hiyama cross-coupling is described <2001JOM(624)208>.
Tetrabutylammonium triphenyldifluorosilicate (TBAT) is a possible alternative fluoride-promoter
source <1996JOC6901> and may even serve as a self-activated phenylating agent (Equation (36))
<1998JOC3156, 1999JOC3266>. However there has been a drift away from fluorosilane substrates,
and an initial interest in chlorosilanes has subsided in deference to oxygenated derivatives.
Br Bu4N + Ph
F Pd(dba)2 (10 mol.%)
–
+ Ph Si Ph ð36Þ
Ph THF, ∆, 5 h
F
COMe 90% COMe
(2 equiv.)
In the presence of TBAF and a palladium catalyst, aryl, ethenyl, and allyl trimethoxysilanes
cross-couple smoothly with active aryl halides <1997CC1309, 1999JOC1684>; occasionally, the
aryl halide homo-coupling product may present a minor problem. Aryl triethoxysilanes react with
allylic benzoates with complete inversion of configuration <2001JOC7159>. The presence of
N-heterocyclic carbene or electron-rich phosphine ligands extends the reaction scope to include
aryl chlorides <1999OL2137, 2000OL2053> and unactivated alkyl halides at room temperature
(Equation (37)) <2003JA5616>.
PdBr2 (4 mol.%)
PBu2t Me (10 mol.%)
R Br + Ar Si(OMe)3 R Ar
TBAF, THF, rt
R-Br
Ar Br ð37Þ
EtOOC 3 Br NC 3 Br
Phenyl 79% 81% 70%

p-Anisyl 66% 69% 82%
p-Fluorophenyl 55% 36% 50%
o-Tolyl 59% 76% 72%
2-Naphthyl 67% 70% 84%
Silicones, too, behave as aryl or alkenyl transfer agents for cross-coupling with aryl halides
<2001SL845, 2003SL1850>. Alkenyl silanols undergo highly stereoselective cross-coupling with active
aryl or alkenyl halides (Equation (38)) <2000OL565, 2002JOM(653)98>, although with aryl triflates
and nonaflates the presence of water seems desirable <2002OL3771>. This latter effect is also
prevalent for aryl triflate cross-coupling with aryl trimethoxysilanes; aryl trialkoxysilatranes are
suggested as superior reagents, although they are perhaps less easily accessed <2003JOC8106>.
Fluoride-free basic conditions (e.g., Ag2O, Cs2CO3) are now available for efficient palladium-catalyzed
cross-coupling of aryl and alkenyl silanols with active aryl halides <2000JOC5342, 2001JA6439,
2003OL1357>, rendering this procedure compatible with the presence of silyl ether functions.
Me R1 R1
Me Pd(dba)2
Si + R4 I R4
HO R2 TBAF, THF, rt R2
R3 R3
R1 R2 R3 R 4–I Yield (%)
H n-C5H11 H Ph-I 91
n-C5H11 H H Ph-I 90
H n-C5H11 H p-Anisyl-I 95 ð38Þ
n-C5H11 H H p-Anisyl-I 94
H n-C5H11 H I (CH2)4OH 91
n-C5H11 H H I (CH2)4OH 72
CH2OTHP H Me Ph-I 91
H CH2OTHP Me Ph-I 85
CH2OTHP H Me 2-Nitrophenyl-I 77
H CH2OTHP Me 2-Nitrophenyl-I 76
Elegant intramolecular developments of the above chemistry allow the stereospecific construc-
tion of highly substituted unsaturated alcohols. Five-, six-, and seven-membered cyclic alkenylsi-
loxanes undergo TBAF/Pd-mediated coupling with aryl or alkenyl halides giving the
corresponding !-hydroxy styrenes or dienes <2001OL1749>. The intramolecular version, invol-
ving coupling with a terminal (Z)-iodoalkenyl chain borne - to the ring oxygen, permits the
synthesis of medium-sized rings containing cis,cis-1,3-diene units <2002JA2102>, an achievement
which has been exploited in a total synthesis of (+)-brasilenyne <2002JA15196>. 5-Alkylidene
oxasilacyclopentanes are transformed into trisubstituted homoallylic alcohols <2001OL61,

2002OL4163> and since the substrates are readily available in either configuration by controlled
hydrosilylation of the homopropargylic alcohol, this makes for very attractive tandem reactions
(Scheme 23). Adaptation of this technique allows access to geometrically defined 5-hydroxy-
2-pentenals <2003JOC5153>. 6-Alkylidene dioxadisilacyclohexanes are prepared and cross-coupled
with aryl iodides in analogous fashion, giving trisubstituted allylic alcohols <2003OL1119>.
syn- ArX OH
OSiHPr2i Hydrosilylation Me
Pd(dba)2 Me
Me O
Pt (cat.) Si
TBAF, THF, rt
Pri Pri Ar
ArX
anti- OH
OSiHMe2 Pd(dba)2
Hydrosilylation O
Bu Si
Ru (cat.) Bu TBAF, THF, rt
Me Me Bu Ar
Scheme 23
Silacyclobutanes <1999JA5821, 1999OL1495, 2000S999> are interesting reagents for TBAF-

mediated palladium-catalyzed cross-coupling with sp2-iodides; there is some evidence that these
reactions proceed via ring opening through the same intermediate as that observed in silanol
cross-coupling <2000OL2491>. Other new coupling partners include aryl triallylsilanes for aryl
transfer <2003JOM(687)570> and alkenyl dimethyl(2-thienyl)silanes for alkenyl transfer
<2002CL138>; in the case of alkenyl dimethyl(2-pyridyl)silane, departure of the heteroaryl
moiety during the catalytic process protects the system from a competing Heck coupling
<2001JA11577>. (-Substituted)ethenyl dimethyl(phenyl)silane gives almost exclusive cine-
substitution in its palladium-catalyzed cross-coupling reaction with iodobenzene (Scheme 24)
<2002CC2018>. Highly substituted alkenyl benzyldimethylsilanes couple conveniently with aryl
iodides in the presence of TBAF and catalytic Pd2(dba)3CHCl3, and have the added advantage of
being stable to fluoride-induced silyl ether cleavage conditions <2003OL1895>. -Alkoxyalkenyl
silyl hydrides are transformed into aryl enol ethers upon palladium-catalyzed cross-coupling with
aryl iodides <2000OL3221>. Copper(I) salts in conjunction with a promoter (pentafluorophen-
oxide is recommended) may bring about aryl siloxane cross-coupling with aryl iodides in fluoride-
free conditions and without the requirement of a palladium catalyst <1997CL639>.
I Reagents
+
THF, rt, 45 min
SiMe2Ph
85%
9/1 (E )/(Z )
Me
I Me
t-BOC-NH Reagents
+ t-BOC-NH
Ph SiMe2Ph THF, rt, 16 h
42% Ph
Reagents: Pd 2 (dba)3 (10 mol.%), KOBut (2.5 equiv.), 18-c-6 (1.5 equiv.), TBAF (2 equiv.)
Scheme 24
Work with organogermanium compounds is extremely limited. In palladium-catalyzed cross-

coupling with aryl iodides, allyl, phenyl, and various alkenyl trioxygermatranes, although slightly
more reactive than the corresponding triethoxygermanes, are less so than stannanes, and require
TBAF activation <2002OM5911>; they are nonetheless considered more easily accessed than
carbagermatranes, which reportedly cross-couple with p-tolyl bromide <1996JOM(508)255>.
Success is rather limited for Pd(II)/Cu(I) co-catalyzed homo-coupling of ArnSiF4–n reagents in
the presence of a chemical reoxidant <1997SL1199>. However, conjugated polyenes containing
up to eight double bonds with all-(E)-configurations are obtained by the PdCl2-mediated homo-
coupling of dienyl, trienyl, or tetraenyl trimethylsilanes when an excess of the CuCl2/LiCl couple
is present for reoxidation of palladium(0) (Equation (39)) <1997JOC3291>. Stoichiometric
quantities of copper(I) salts seem to mediate such reactions in their own right; alkenyl and aryl
halogenosilanes homo-couple in good yield in polar aprotic solvents <2000BCJ985> and as little
as 5% CuI may suffice, with no other metal involved, providing that 1 equiv. of TBAF is present
<1997JCS(P1)797>.
O O
PdCl2 (25 mol.%)
Ph
Ph SiMe3 Ph
excess CuCl2, LiCl ð39Þ
O
MeOH, 3 h
61%
1.11.2.6.2 Substitution of tin

The Stille reaction (not covered as such in the first volume of COFGT (1995)) is the palladium(0)-
catalyzed cross-coupling of an organostannane and an organic electrophile; the latter is usually an
sp2 halide or triflate. One organic group is generally transferred from the tin reagent and the order
of group transfer is alkynyl > alkenyl > aryl > allyl, benzyl > alkyl. A wide variety of functional
groups can be tolerated on both reaction partners, and the reaction proceeds with an excellent
degree of retention of the configuration of unsymmetrical alkenyl moieties. The attractive balance
between reagent stability and reactivity has made this one of the most popular CC bond-
forming protocols. General reviews of historical progress and applications have appeared
<1997OR1, B-1998MI167, 2002TCC(219)87, B-2002MI263>. Although sometimes perceived as
less sterically tolerant than some other palladium-catalyzed reactions (e.g., Suzuki), it may in fact
proceed where other cross-coupling strategies fail. It is a favored tool for the preparation of
radiolabeled compounds <2003MI263>, has wide applications in biaryl synthesis <1998T263,
2002CRV1359>, and is a particularly good performer in intramolecular mode, leading to exten-
sive use in macrocyclizations <1999JCS(P1)1235, 2002JOM(653)261>. Stille coupling can be
incorporated as one of several mechanistic steps in palladium-catalyzed tandem or cascade
processes, notably involving Heck coupling (see Section 1.11.2.8.3.(i)).
The traditional catalyst Pd(PPh3)4 is now joined by several others, with AsPh3 and P(2-furyl)3
emerging as particularly successful ligands. A major advance is the discovery of the Pd/PBut3/CsF
catalyst system, which promotes the coupling of unactivated aryl chlorides (Equation (40))
<2002JA6343>. This catalyst can also be employed for the smooth coupling of very hindered
alkenyl or aryl substrates, even leading to some tetra-o-substituted biaryls. Another important
breakthrough is the development of the Pd/PCy(pyrrolidinyl)2/TMAF system (TMAF=tetra-n-
methylammonium fluoride), which catalyzes the room temperature Stille cross-coupling of alkyl
halides possessing -hydrogens with alkenyl and aryl tin reagents (Equation (41))
<2003AG(E)5079>. The Pd/PBut2Me/TBAF system is also highly active for sp3-electrophile–alke-
nyl tin cross-coupling <2003JA3718>. Relatively few applications of other ‘‘high-performance’’
ligands are made for Stille cross-coupling; those used for successful biaryl syntheses include
iminophosphines <1999JOM(576)169, 2002T6881>, nucleophilic N-heterocyclic carbenes
<1999JOM(585)348>, palladacycles <1998CC2095>, and phosphinous acid <2003JOC7551>,
the latter allowing coupling of aryl chlorides and arylstannanes in neat water. The complex
Pd(N-succinimide)(PPh3)2Br is a superior catalyst for cross-coupling of benzyl or allyl bromides
with alkenylstannnanes <2003CC2194>. There are limited but encouraging applications of poly-
mer-supported palladium catalysts <1999SL327, 2003TL639>.
R1 R2 Yield (%)
Pd(PBu3t)2
R1 R2 (0.1–3 mol.%)
H 2,6-di-Me 94
SnBu3 Cl R1 H p-MeO 94 ð40Þ
CsF
+ R2 H p-TfO 93
Dioxane, 100 °C 2-Me 2,6-di-Me 96
2,4,6-tri-Me 2,6-di-Me 89
[PdCl(π-allyl)]2 (2.5 mol.%)

R1 Br + R2 SnBu3 PCy(pyrrolidinyl)2 (10–15 mol.%)
R1 R2
TMAF, ButOMe or THF, rt
Alkyl bromide Aryl stannane Yield (%) Alkyl bromide Alkenyl stannane Yield (%)
SnBu3
72 O
n-C10H21 Br Bu3Sn OTHP 60
O Br 3
MeO SnBu3 ð41Þ

61 Ph
EtOOC
4 Br Bu3Sn 78
Br
SnBu3
EtOOC 63 Ph
4 Br EtOOC
Br Bu3Sn 89
Me 4
SnBu3
NC 68
EtOOC Bu3Sn OTHP
5 Br 4 Br 73
Me2N 3
SnBu3
64 NC Bu3Sn OAc
THPO Br 5 Br 68
3
F
In addition to the often-used halides and triflates, other new electrophile partners are known,
including hypervalent iodides <1996TL3723, 1996SC4311>, vinyl phosphates <1997JA5467,
1998CC1757, 1999TL701>, diaryl- or distyryltellurium(IV) compounds <1999CC2117> along
with a variety of sulfur-based reagents <1999JOC2796, 2003OL801, 2003JA15292>, although
aryl mesylates are unreactive <1995JOC6895>. While -trialkylstannyl-,-unsaturated carbo-
nyls remain poor reaction partners, the presence of a heteroatom in the vinylstannane
accelerates coupling reactions, possibly due to internal coordination of palladium in the
transmetallation step <2000JOC5917>. Somewhat unexpectedly, hexaalkyl ditin—normally a
stannylating agent—reacts under Pd catalysis with (chloroarene)Cr(CO)3 complexes to give
alkylarenes <2001OM1279>. The beneficial effects of certain additives in the Stille reaction,
such as LiCl or a Cu(I) co-catalyst, have been known for some time; more recently, the presence
of CuCl has been shown to accelerate coupling with sterically congested substrates, and thus
suppress cine-substitution, occasionally a complication in the Stille reaction <1999JA7600>.
Other promoters include diethylamine, which may suppress -elimination in Stille alkylations
<2001CC1662>, and TBAF, which probably activates the tin reagent as a hypervalent fluoro-
stannate; as a result, more than one organic function may be transferred (Scheme 25)
<1999SL63, 2001OL119>. Indeed, the designed use of hypervalent tin reagents generally gives
good results <2001OM1020>. Cross-coupling reactions may also be carried out in aqueous
<1999JOM(576)305> or supercritical <1998CC1397> media, and can be accelerated by micro-
wave irradiation <2002ACR717>.
One of the perceived drawbacks of using organotin reagents is their toxicity, and some efforts
have been made to address this issue. The use of fluorous <1996JOC6480, 1997JOC5583>,
monoorgano <1995TL125, 1997JOC5242>, and catalytically regenerated <2001JA3194> tin
reagents has been suggested, along with water-soluble, reusable stannatranes <2001TL5837>.
Br Pd(dba)2 (0.8 mol.%) Me

SnBu2
PPh3 (3.2 mol.%)
+ TBAF (2 equiv.)
Me
2 Dioxane, ∆, 24 h
MeO
OMe (0.5 equiv.) 94%
Pd(OAc)2 (3 mol.%)
Br SnMe3
IPr.HCl (3 mol.%) Pri Pri
+ N N
TBAF (2 equiv.) IPr =
dioxane, ∆, 1.5 h
Me Pri Pri
90%
Me
Scheme 25
Indeed, highly elaborate stannatranes may be used as cross-coupling partners <2000OL1081>.

Solid-phase Stille coupling can be performed, with either the electrophile or the tin reagent being
immobilized <2003T885>; polymer-supported, catalytically regenerated organotin reagents may
even be used <2003TL8601>. An elegant solid-phase cyclo-release strategy is used in a synthesis
of the macrocyclic natural product (S)-zearalenone (Equation (42)) <1998AG(E)2534>.
MEMO O
i. Pd(PPh3)4 (10 mol.%)
OH O
O toluene, ∆, 48 h
O ð42Þ
MEMO I ii. HCl, THF
Bu Bu HO O
rt, 5 days
Sn
O 43%
(S)-Zearalenone
Other transition metals, at one time heralded as potential rivals to palladium, have not
emphatically established themselves as catalysts. Despite the beneficial ‘‘copper effect’’ observed
for a good number of examples of palladium-catalyzed Stille reactions, copper has only limited
success on its own. CuCl catalyzes heteroarylstannane cross-coupling with allylic iodides
<1999SL1942>. Otherwise, a fairly large catalytic quantity (10%) of CuI or MnBr2 effects
reaction of aryl or alkenyl stannanes with sp2 iodides, provided NaCl is present
<1997JOC4208>; reactions proceed in milder conditions when more reactive hypervalent iodine
substrates are used <1996JOC9082, 1998TL2131>. The use of 1.5 equiv. of copper(I) thiophene-
2-carboxylate mediates the very smooth cross-coupling of aryl-, heteroaryl-, and vinylstannanes
with aryl and vinyl iodides under mild conditions <1996JA2748>. Nickel catalysts have a few
applications: in addition to the ‘‘simple’’ catalysis of biaryl formation from aryltin reagents and
iodonium ions by Ni(acac)2 <1999JCS(P1)2661>, a variety of aryl halides, including chlorides,
cross-couple with alkenylstannanes in the presence of nickel(0) complexes (Equation (43))
<1998S1544>.
Ni(acac)2/DIBAL-H (2 equiv.)
Cl (5 mol.%)
+ Bu3Sn
PPh3 (20 mol.%)
ð43Þ
PhOC PhOC
DME, 80 °C, 23 h
91%
Palladium and copper catalyze cross-coupling of diaryl- or distyryltellurium dichloride with

heteroaryl- or -styrylstannanes in the presence of a base <1999CC2117>. Similarly, aryllead(IV)
triacetates cross-couple with organotin reagents under mild conditions in the presence of
Pd2(dba)3CHCl3 catalyst, although an excess of base (NaOMe) is necessary, along with a CuI
co-catalyst to suppress homo-coupling <1998CC1317>. PdCl2-catalyzed arylation of a number of
alkenyl- or arylstannanes can be performed in mild conditions using triaryl antimony(V)
<2000JOM(610)38> or triaryl bismuth(V) <2001SC1027> derivatives.
Some aryltin reagents cross-couple with alkenes in Heck reactions <2000BCJ1409>. A cascade
process, reminiscent of some applications of the Heck reaction, explains the exclusive formation
of the exo–exo–cis–trans–cis-pentacycle when alkenyltin trichloride reacts with an excess of
norbornene (Equation (44)) <2003JOM(687)567>.
i. SnCl4 (1 equiv.) Me
toluene, rt, 2 h H H
Me
SnBu3
ii. Excess
ð44Þ
H H
PdCl2(PhCN)2 (5 mol.%)
toluene, 55 °C, 2 h
73%
The palladium-mediated homo-coupling of organostannanes is less familiar than cross-coupling

reactions, and requires reoxidation of the intervening Pd(0) complex to render the operation
catalytic. Chemical oxidants may be employed <1997SL1199, 1997SC641>, but air may also be a
simple alternative. A palladium complex with an iminophosphine ligand is a particularly good
catalyst for symmetrical arylstannane homo-coupling <1999JOM(576)169>. In the presence of a
PdCl2(MeCN)2/O2 system, alkenylstannanes undergo efficient homo-coupling and also chemose-
lective cross-coupling with allylstannanes giving well-defined 1,4-dienes <1997SL791>. CuCl
co-catalyzed intramolecular versions of di(alkenyl stannane) coupling are occasionally used for
complex cyclic skeletons <1996JA1215, 1996JOC700>. As an alternative to palladium, the use of
10% CuCl2 or MnBr2 in the presence of iodine may effect homo-coupling of aryl- and (E)-styryl-
stannanes on heating <1999TL2383>. Similarly, intramolecular coupling of two stannane functions
can be achieved through the action of an excess of CuCl <2000OL481>; a double inter-
molecular Cu(NO3)2-induced homo-coupling is described in a strained cyclophane synthesis
<2000OL2081>.
1.11.2.7 Substitution of a Metal

Organometallic reagents play a fundamental role in many of the CC bond-forming reactions
considered in this chapter, but they are treated throughout the various sections according to
the identity of the reaction partner. The exception, treated here, is the NiCl2(PMe3)2-catalyzed
cross-coupling reaction between aryl or heteroaryl nitriles and alkyl, alkenyl, or aryl Grignard
reagents, through CCN bond cleavage. The direct addition of the organometallic nucleophile
to the nitrile is suppressed by prior attenuation with LiOBut or LiSPh <2001TL6991,
2003TL1907>.
There is very little progress to report on homo-coupling reactions, as can be noted in a recent
historical perspective <B-2002MI973>. This is hardly surprising from a synthetic viewpoint since
the most common precursors of the organometallic reagents, the corresponding halides, undergo
coupling reactions at least as easily. Nonetheless, mild conditions are reported for palladium- and
copper-catalyzed dimerization of aryl lead triacetates <1997SC1893>. Air serves as the reoxidant
in the room temperature Pd(OAc)2-catalyzed homo-coupling of triaryl bismuth reagents; when
two different aryl derivatives are used simultaneously, mixtures of homo- and cross-coupled
biaryls are obtained <1999BCJ1851>. Oxidative homo-coupling of arylzinc reagents is achieved
by the use of NCS or O2 in the presence of a palladium catalyst <2001BCJ2415>. TiCl4
<2000T9601> or oxovanadium(V) compounds <1998OM5713> mediate a similar reaction for
a range of aryllithium and Grignard reagents.
Aryllithiums react with alkylaluminum halides to give mixed organoaluminum species, which
are transformed into the cross-coupled alkyl arenes by treatment with an excess of an oxovana-
dium(V) reagent <1998JA5124>. Similarly, cross-coupling reactions between an aryl and an alkyl
substituent in certain organozinc reagents are preferred to intermolecular homo-coupling reac-
tions in oxidative conditions (VO(OEt)Cl2 or AgBF4) <2000JOC1511>.
1.11.2.8 Substitution of Hydrogen
1.11.2.8.1 Friedel–Crafts alkylations using alkenes and alkanes

The Friedel–Crafts alkylation of arenes with unactivated alkenes is an important industrial
operation <2002MI3>. The search for cleaner, more environment-friendly processes reveals
new solid catalysts based on clays <1999JMOC(A)(145)237>, zeolites <1999AC(A)(184)231>,
or AlCl3 in immobilized or encapsulated form <1995CC2037, 2000JCA(195)412, 2002TL4555>.
In at least one example, triflic acid is a useful catalyst <2002MI37> although Sc(OTf)3 is active
only when immobilized in ionic liquids <2000CC1695>. Halogen-free ionic liquids improve the
product yield dramatically in the alkylation of benzene with 1-decene, although a sulfuric acid
catalyst is still required <2002GC134>. Supercritical conditions are used to effect efficient,
continuous-flow, solid acid-catalyzed alkylation of aromatics with propene <1998CC359>.
Significant ortho-regioselectivity is observed in the HBF4-mediated alkylation of anilines with
styrene when a catalytic amount of a rhodium complex is present (Equation (45))
<1999SL243>.
R1 R2 R1 R2
N HBF4.OEt2 (20 mol.%) N
R1 R2 R1
[Rh(COD)2]BF4 /4PPh3 N N Ph
(2.5 mol.%) Ph
+ Toluene, sealed tube
Ph
Ph 140 °C, 20 h ð45Þ
(5 equiv.) Yield (%)
o-Substitution p-Substitution N-Substitution
R1 = R2 = H 57 <0.1 24
1 = Me; R2 = H
R 82 <0.1 0
R1 = R2 = Me 17 7 0
Friedel–Crafts alkylation with alkenyl chlorosilanes is reviewed <2000AOC145>. Michael-

acceptor alkenes are convenient partners for Lewis acid-catalyzed alkylation of active aromatic
compounds. With furans, Cu(OTf)2 is the superior catalyst for C2 alkylation with ,-unsa-
turated ketones <2000JCR(S)220>. An alternative ‘‘green’’ procedure involves the use of a
solventless K-10 clay-catalyzed system under microwave irradiation <1998TL9301>; compet-
ing Diels–Alder reactions are disfavored under these conditions. Indoles are easily alkylated
at C3 with Michael-acceptor alkenes in the presence of rare earth metal triflates under
conventional conditions <1996SL1047> or in supercritical CO2 in the presence of a fluori-
nated organic additive as an accelerator <2002OL1115>. Indium tribromide, too, is a useful,
reusable catalyst for the addition of indoles to nitro alkenes in aqueous medium
<2002S1110>.
A major recent development in this area is the catalytic enantioselective version of the reaction.
MacMillan’s enantioselective ‘‘organo’’ catalytic system, which exploits the reversible formation
of iminium ions with chiral imidazolidinones, lends itself conveniently to Friedel–Crafts reactions
with ,-unsaturated aldehydes: impressive ee and yields are observed in the alkylation of
pyrroles <2001JA4370>, indoles <2002JA1172>, and electron-rich benzenes <2002JA7894>
under very mild conditions (Scheme 26). Cu(II)/chiral bisoxazoline complexes also catalyze the
alkylation of indoles, furans, and electron-rich benzenes with ,-unsaturated -keto esters in
good yields and with very high ee (above 99% in some cases) <2001AG(E)160>. Similarly,
alkylidene malonates alkylate indoles in good yield, although the ee is lower (40–60%)
<2001CC347>.
There is little development of the use of alkanes for Friedel–Crafts alkylations. Gallium
chloride promotes the alkylation of naphthalene or phenanthrene using cycloalkanes with a
notable preference for the formation of the equatorial isomer; yields and regioselectivities
(where appropriate) remain modest, however <2003JOC6752>. 1,1-Cyclopropanedicarboxylate
esters react by ring opening to alkylate indoles in the presence of Yb(OTf)3H2O, with CC bond
formation occurring specifically at the more hindered position of the cyclopropane ring. However,
high-pressure conditions are required to obtain reasonable yields <1997TL5949>.
COOMe
Ph Catalyst·HCl Ph CHO
(10 mol.%)
+ CHO
N MeOOC N
CHCl3
20 °C, 12 h 99% ee
94%
Me
OMe Catalyst·TFA OMe
CHO
(20 mol.%)
+ CHO
Me
CH2Cl2/PriOH N
N
Me –87 °C, 19 h Me
90% 96% ee
Catalyst·TFA
(20 mol.%)
+ CHO N CHO
N Ph
THF/H2O Me Ph
Me
–30 °C, 42 h
87% 93% ee
O Me
N
Catalyst =
Bn N But
H
Scheme 26
1.11.2.8.2 Transition metal-mediated substitution of arenes using alkenes

Aromatic compounds can be alkylated with alkenes in highly efficient, transition metal-catalyzed
processes. Although at a first glance these transformations formally resemble Friedel–Crafts alkyla-
tions, the reaction mechanisms are fundamentally different and in consequence so are the various
aspects of regioselectivity. The process is best seen as a hydroarylation of (i.e., the addition of an
aromatic CH bond across) an alkene. Various applications and discussions of the mechanistic
aspects of this exciting new field are reviewed <1999AG(E)1698, 1999EJI1047, 2002CRV1731>.
Murai’s pioneering work shows that acyl benzenes and related compounds undergo high-
yielding, selective alkylation at the ortho-position in the presence of ruthenium catalysts—
typically RuH2(CO)(PPh3)3—with the alkyl moiety being introduced with remarkable
regioselectivity, appearing as its anti-Markovnikov isomer <B-1999MI195>. It is likely that pre-
coordination of the metal catalyst induces ortho-metallation of the arene followed by the insertion
at the least hindered end of the olefin then formation of the CC bond by reductive elimination,
according to Equation (46). This reaction is quite widely applicable with respect to both the alkene
(often a vinyl silane derivative, but simple cases are described too) and the functionalized aromatic
component, the latter of which may be an aryl or heteroaryl ketone <1995BCJ62,
1995JOM(504)151, 1997JOM(530)211, 1998JA4228>, ester <1996CL109>, or aldimine
<1996CL111>. The only drawbacks are that dialkylated aromatics may be formed as byproducts
(if both ortho-positions are free), and the occasional observation of coupled arene–alkene (Heck-
type) byproducts. In the Ru(I)-catalyzed alkylation of ring-oxygenated acetophenones, the success
of the reaction may depend on the nature and position of the oxy-substituent(s), the identity of the
alkene partner, and even the nature of the catalyst <1997JOM(530)211>.
O O R Time (h) Yield (%)

RuH2(CO)(PPh3)3
(2 mol.%) Si(OEt)3 2 93 ð46Þ
+ R Bun 5 23
Toluene, ∆ R But 8 99
Rhodium-based catalysts effect similar ortho-alkylation reactions of aromatic ketones

<1999JA6616>, aldimines, and ketimines <2000AG(E)3440, 2001TL4853>, while 2-phenylpyri-
dines are ortho-alkylated in the phenyl ring in the presence of Wilkinson’s catalyst. In an exception
to the regioselectivity trend, Ru3(CO)12-catalyzed hydroarylation of styrene with N-methylaniline
gives exclusively the Markovnikov-coupled product <1999CC1133>; nevertheless, this result is
remarkable for its chemoselectivity, since NH bond insertion is actually a feasible alternative.
Intramolecular versions of the Rh-catalyzed reaction, involving hydroarylation of tethered alkenes
by aromatic imines (but not ketones) (Scheme 27) <2001JA9692> or nitrogen heterocycles
<2001JA2685>, lead to annulated products. Recent results show that an ortho-directing group
on the aromatic reagent is not a prerequisite: benzene and nonactivated derivatives are alkylated
with simple alkenes by an iridium complex catalyst, giving a significant preference for straight-chain
alkyl isomers <2002JMOC(A)(180)1>, and a catalytic amount of a ruthenium complex likewise
induces addition of benzene to ethene and propene under mild conditions <2003JA7506>.
BnN BnN
i. RhCl(PPh3)3 (5 mol.%)
toluene, 125 °C
ii. 1 M HCl (aq.)

85%
BnN BnN
i. RhCl(PPh3)3 (5 mol.%)
toluene, 125 °C
N ii. 1 M HCl (aq. ) N

O2S 53% O2S Ph
Ph
Scheme 27
1.11.2.8.3 Transition metal-mediated substitution of alkenes
(i) Initiation by CX bond insertion

The palladium-catalyzed coupling of an aryl or vinyl halide (or triflate) with an alkene is generally
referred to as the Heck reaction. This highly regio- and stereoselective transformation has enjoyed an
astonishing number of synthetic applications in recent years and is one of the most powerful methods
of CC bond formation available today, as testified by regular general reviews <B-1996MI153,
B-1996MI712, B-1998MI99, B-1998MI208, 2000CRV3009, B-2001RCC315, B-2002MI1133>. Indus-
trial applications are emerging <2001CJC1086, 2002MI101, B-2002MI1209>. Although they are not
themselves the subject of this review, mechanistic studies <1998CSR427, 2000ACR314, 2000SL925>
have helped to understand the various (often complex, sometimes competing) molecular processes
involved and have thus aided the conception and development of new, more efficient catalytic systems.
Apart from the mainstay use of iodides and bromides and the increased interest in aryl
chlorides as Heck-coupling reaction partners (vide infra), a number of other leaving groups may
be used successfully (Scheme 28); these include carboxylic acids <2002SL1721, 2002JA11250>,
esters <2002AG(E)1237>, anhydrides <1998AG(E)662>, certain tosylates <2002TL573>, and
aryl derivatives of the main-group elements: lead <1998JOC5748>, tin <2000BCJ1409>, silicon
<2000BCJ1409>, antimony <1999JOM(574)3>, and phosphorus <2003JA1484>. Some of these
main-group reagents may prove to be more effective than halides for Heck coupling when
rhodium-, ruthenium-, or iridium-based catalysts are used <2001JA5358, 2001JA10774,
2002AG(E)169, 2003AG(E)89>. Generally though, relatively little progress has been made with
catalysts based on metals other than palladium; the recognized economic argument for the
development of cheaper catalyst systems, based on nickel or cobalt, for example, has inspired
only isolated studies <1997TL8533, 2002TL5901, 2002OL2257>.
Phosphine ligands for the active palladium species remain popular and various refinements have
been investigated in order to improve catalytic performance, both in terms of catalyst stability and
observed turn-over number (TON), notably with a view to performing Heck-coupling reactions with
traditionally unreactive aryl chlorides <B-1999MI207, 2001T7449, 2001CEJ2908, 2002AG(E)4176>.
A wide range of additives (such as tetraalkylammonium salts, for example) often plays an important
NO2 Ph
O PdCl2 (3 mol.%), LiCl (10 mol.%)
Ph
O + Isoquinoline (10 mol.%) F
NMP, 160 °C, 16 h Ratio of 1,2-:1,1-
F
79% substituted alkenes = 13:1
O Pd(OOCCF3)2 (20 mol.%)

COOH Ag2CO3 (3 equiv.)
O
+ 5% DMSO–DMF
MeO OMe MeO OMe
80 °C, 30 min
90%
Ph
PO(OH)2 Pd(OAc)2 (5 mol.%)
Ph Me3NO.2H2O (3 equiv.)
+
TBAF (2 equiv.)
dioxane, 100 °C, 24 h
85%
[Ir(COD)Cl]2 (5 mol.%)
Si(OMe)3 COOBu
TBAF (1 equiv. ) COOBu
+
THF/H2O, 70 °C, 24 h
(3 equiv.)
70%
[Ru(p-Cymene)Cl2]2 (5 mol.%)
B(OH)2 COOBu COOBu
Cu(OAc)2 (2.5 equiv. )
+
Cl Quinuclidin-3-one (3 equiv.) Cl
(3 equiv.)
toluene, rt, 24 h
93%
Scheme 28
role, as can the identity of the precatalyst. The most active ligands resemble those which give best
results in Suzuki reactions, and include sterically hindered electron-rich monodentate phosphines (e.g.,
PBut3) <1999JA2123, 2000SL1589, 2001JA6989>, chelating diphosphines <1998CC1863>, rigid
tetraphosphanes <2003EJO1091, 2003TL1221>, and phosphinous acids <2001JOC8677>. Pallada-
cycles, ‘‘single phosphine’’ catalysts, have very high reactivity due to their nearly free coordination shell
<1995AG(E)1844, 1999JOM(576)23, 2003CC1787>. Another type of active system containing a
metalcarbon bond are the so-called ‘‘pincer’’ complexes <1997JA11687>, which display amongst
the highest TONs reported for Heck reactions (Equation (47)) <2003CC1787, 2003T1837>; the
catalytic mechanism for these complexes may be quite different to the traditional Heck cycle.
Catalyst COOMe
I (7 × 10–6 mol. equiv.)
COOMe
+
NMP
100%
TON = 1.4 × 105
ð47Þ
PPr2i PPr2i PBu2t
Catalyst Pd TFA Pd TFA Pd TFA

(and conditions)
PPr2i PPr2i PBu2t
(60 h, 40 °C) (20 h, 140 °C) (40 h, 140 °C)

There is a developing interest in phosphine-free ligands for palladium complex catalysts; these
include phosphites <1998SL792>, thioethers <2001TL7345>, chelating nitrogen heterocycles
<2003OL1451, 2003EJI1161>, diazabutadienes <2003JOM(687)269>, and macrocyclic trienes
<2003OL1559>. Stable N-heterocyclic carbenes are a recently developed class of catalyst ligands
<1995AG(E)2371, 2002JOM(653)69> and can be used in combination with phosphines. Some
phosphine-free palladacycles and pincer-type complexes catalyze the Heck coupling of aryl iodides
or active aryl bromides with alkenes, and although they are not always as immensely active as their
phosphine-based analogs, usually give satisfactory results <2003T1837, 2003OL983>.
Environmental issues have affected other developments of the Heck reaction. Although the general
utility of the reaction conditions is often left unexplored, alternative media in which successful
reactions may be carried out include: reusable solvent systems <1999OL997, 2000CEJ1017,
2002OL4399>, aqueous solution <1999JOM(576)305, 2002MI393>, and compressed or supercritical
fluids <1995OM4023, 1999TL2221, 2001TL8555, 2002JMOC(A)(180)35>, although use of these
media is not always beneficial <2000SL1661>; microwave acceleration of the Heck reaction is
observed in some cases <2002ACR717, 2002S1611, 2002JOC6243>. A variety of convenient solid
supports for the Heck reaction exist, providing for either halide or alkene immobilization
<1999CRV1549, 2003T885>. Heterogeneous catalysts based on palladium phosphine complexes
are usually limited to reactions involving aryl iodides <1997TL6581, 1998JOM(567)219>, although
they can work in aqueous medium <2002SL2045> or supercritical carbon dioxide <2002CC640>;
dendritic modification enhances catalytic activity considerably <2003OL1197>. Heterogeneous pal-
ladium metal catalysts <2001JMOC(A)(173)249> involving different kinds of supports—carbon,
inorganic oxides, molecular sieves, clays, etc.—give satisfactory results, with the obvious advantages
of easy catalyst separation and possible recycling; stabilized palladium metal colloids are also active
catalysts. Although the substrates are usually aryl iodides (or bromides, to a lesser extent), some
catalysts exhibit high activity with aryl chlorides <2002MI348, 2003TL3649>. One problem which
remains with immobilized catalysts is leaching; indeed, it may be that, at least in some cases, catalytic
activity is due to leached homogeneous species <2000CEJ843, 2002CEJ622>. In any event, palladium
nanoparticles may play an important role in catalysis <2000AG(E)165>.
The intramolecular version of the Heck reaction has developed into a particularly useful tool in
organic synthesis <1996MI447, B-1998MI231, 2002OR157, B-2002MI1223>. More highly substi-
tuted alkene moieties are tolerated than in the intermolecular case, and otherwise difficult-to-form
quaternary centers can be constructed effectively. Five-, six-, and seven-membered rings (both
carbocyclic and heterocyclic) are formed most efficiently, although smaller and larger rings are
also accessible; macrocyclizations well above 20-membered rings can be achieved. For up to six-
membered ring closures, the exo-mode predominates, while for larger rings the exo/endo-selectivity
depends on the particular system. The success of the operation depends also on the strain involved
in the cyclization process. Thus, with an !-alkenyl chain borne by an o,o0 -disubstituted biphenyl,
formation of a 13-membered cycle is less favorable than an intermolecular Heck coupling; however,
the resulting coupled product suffers no such constraint and undergoes smooth intramolecular
reaction to give a 26-membered macrocycle (Scheme 29) <2002TL9327>.
In its original form, the Heck reaction is not stereogenic. However, when the syn--H elimination
from the organopalladium intermediate occurs from a carbon atom not originally part of the alkene
system (as in the case of a cyclic alkene), a chiral product is liberated. The success of this operation
clearly depends on the selectivity of the -H elimination. Palladium complexes bearing chiral ligands
serve as effective enantioselective catalysts for this, the so-called asymmetric Heck reaction
<1996MI119, 1997T7371, 1998MI311, B-1999MI457, 1999JOM(576)1, 1999JOM(576)16,
B-2000MI136, B-2002MI1283>. BINAP is the most commonly used ligand, although others some-
times give better results. Intermolecular examples remain limited, for the most part, to simple cyclic
alkene substrates (particularly dihydrofurans) with the emphasis being on catalyst optimization
<2000JOM(603)40, 2003CEJ3073>. The intramolecular asymmetric Heck reaction has enjoyed
much more success for the enantioselective formation of diverse tertiary and quaternary centers
<B-2000MI675>, notably in the synthesis of complex natural product structures <2003CRV2945>;
illustrative examples are shown in Scheme 30 <1997JOC595, 2003JCS(D)2017, 2003JA6261>.
Perhaps one of the most endearing aspects of the Heck reaction is the facility with which it
can be incorporated into tandem, domino, or cascade processes, often leading to highly
complex molecular structures from simple components in a very efficient and selective manner.
These processes may involve further reactions of the organopalladium intermediate, or of the
coupled alkene product, or both. Double or multiple Heck coupling is possible, as are
combinations with many other reactions (and in various orders), be they palladium-catalyzed
or not <1999JOM(576)65, 1999JOM(576)88, 2000T5959, 2002JOM(653)129, B-2002MI1179,
OMe Pd(OAc)2, K2CO3

O
TBAB MeO OMe
I MeO OMe
DMF
MeO 110 °C, 16 h O
I
54%
MeO OMe
MeO OMe
Scheme 29
Pd(OAc)2 (10 mol.%) Ph OMe

OTf OMe
O (R)-BINAP (20 mol.%)
O
N PMP, THF, 80 °C, 4 h N
Bn Ph 86% Bn
PMP = 1,2,2,6,6-Pentamethylpiperidine 84% ee
O O
Pd(OAc)2 (10 mol.%) Ph Ph

L* (20 mol.%) O O
I MeO L* = P N
MeO O NMeCy2 (3 equiv.) O O O
CHCl3, ∆ Ph Ph
72% 96% ee
TfO Pd(OAc)2 (10 mol.%)

L* (20 mol.%) L* =
+ O
N N N
NEtPr2i , Toluene
N PPh2
O H 71% O H O H
But
6:1
87% ee ee > 99%
Scheme 30
B-2002MI1369>. Recent examples, illustrated in Scheme 31, include Heck/aromatic CH

activation <2003CEJ1511>, Heck/carbonylation <2003OL1523>, Heck/Suzuki <2003TL267>,
aminocyclization/Heck <2003BCJ1055>, and Heck/Diels–Alder <2002HCA3161>.
(ii) Initiation by CH bond insertion

Organometallic species generated by initial metal insertion into vinylic CH bonds may be alkylated
by other alkene functions (similar to the reactions seen for arenes in Section 1.11.2.8.2). ,-Unsatu-
rated ketones and esters are alkylated by vinyl silanes, styrene, or other alkenes (the latter give
variable yields) using ruthenium catalysts <1995JA5371, 1995CL679> while ruthenium or rhodium
PhI (10 equiv. ) Ph Ph

Palladacycle SO2Ph
SO2Ph (5 mol.%)
Ag2CO3, DMF, 120 °C

52%
Cl I TBDMSO
O Pd(OAc)2, P(o-tolyl)3 OAc
OTBDMS Et3N, TBAB, CO Br
N Cl
DMA /MeOH 2:1
Cl O
85 °C N
77%
Br Cl
EtOOC Pd(PPh3)4 (3 mol.%) EtOOC

Br + PhB(OH)2
EtOOC Cs2CO3, EtOH, 60 °C, 1 h EtOOC Ph
80%
OCOC6F5 Pd(PPh3)4 (10 mol.%)

N
Et3N (5 equiv.) N
Ph
DMF, 4 Å MS Ph
110 °C, 30 min
82%
Pd(OAc)2 (5 mol.%) MeOOCCH2NH2.HCl

Br N
PPh3 (10 mol.%), K2CO3 HCHO, H2O, rt CH2COOMe
HO MeCN, 80 °C, 18 h HO HO
38%
Scheme 31
complexes effect the cyclization of 1,5- and 1,6-dienes bearing a key (metal-complexing) 2-pyridyl
group at one terminal (Equation (48)) <1998BCJ285>. In the presence of a ruthenium complex and
various other additives, terminal allenes add smoothly from the central carbon to vinyl ketones,
undergoing concomitant double-bond migration, to give variously substituted 1,3-dienes
<1999JA4068>. Even unfunctionalized vinylarenes can be dimerized unsymmetrically at room
temperature with remarkable efficiency using a Pd(OAc)2/PPh3/In(OTf)3 catalyst <2003CC852>.
Cat. (10 mol.%)
N THF, ∆ N
Catalyst Time (h) Yield (%)

ð48Þ
RuH2(CO)(PPh3)3 15 62
Ru(CO)2(PPh3)3 15 86
RhCl(PPh3)3 3 89
1/2[RhCl(cyclooctene)2]2/3PCy3 1 64
[Rh(COD)(PPh3)2]PF6 19 78
As an alternative to the above reactions, the organometallic species obtained by insertion into CH
bonds of arenes or alkenes can participate in formal cross-coupling reactions with alkenes, via a
-hydride elimination from the carbometallated intermediate. Providing reoxidation of the metal can
occur, the catalytic cycle can be completed. Some historical aspects of the use of palladium in this
reaction are surveyed briefly <B-2002MI2863>. Products resulting from coupling of this type are
sometimes obtained as byproducts in the transition metal-catalyzed alkylations of arenes using
alkenes (see Section 1.11.2.8.2). A drawback with current systems is the relatively low turnover
number. Nevertheless, oxidative arylation of ethene with benzene to give styrene is effected efficiently
with rhodium or palladium catalysts under O2 <2000CL1064>. Substituted benzenes couple with
acrylate esters via ruthenium complex catalysis under O2 <2001JA337> or in the presence of a
catalytic quantity of Pd(OAc)2 and a reoxidant <1999OL2097, 2003JA1476>. Intramolecular trap-
ping in the Pd-catalyzed oxidative cross-coupling of 2-phenylphenols with acrylates gives variable
yields of the tricyclic dibenzo[b,d]pyran systems <1997CL1103>. One asymmetric variant of this type
of transformation is described, in which cyclic alkenes react with benzene in the presence of Pd(OAc)2,
a chelating, nonracemic oxazoline ligand, and t-butyl perbenzoate as the oxidant (Equation (49)). The
-elimination occurs from the opposite side of the entering aryl group, furnishing the coupled
products in modest yield and ee up to 49% <1999CL55>.
CN CN L* =
Pd(OAc)2 /L* O
Ph F3C
PhCO3But (1 equiv.) * NH N ð49Þ
S
benzene, ∆, 9 h O2
19% 49% ee F3C

Assuming reagent toxicity is not an issue, the asymmetric coupling of phenols with aryllead reagents
is quite successful in the presence of brucine; double coupling is observed if both ortho-positions are
free, with very good dl:meso selectivity for the terphenyls thus obtained <1999JA8943>. Heck-type
coupling of iodobenzene with styrene can be achieved without a catalyst in supercritical water in the
presence of a mild base <2003CC1548>. DABCO catalyzes the reaction of acrylate derivatives with
the acetate esters of Baylis–Hillman adducts, in what amounts to a formal hydrogen substitution at
the -carbon. This reaction constitutes an entry to substituted 1,4-pentadienes, although byproducts
may also be formed (Equation (50)) <2003SL1439>.
COOMe
AcO
R + DABCO
R
COOMe ð50Þ
THF/H2O
COOMe
rt, 30 h COOMe
65%
R = 3-(p-Tolyl)isoxazol-5-yl
Oxidative (usually symmetrical) aromatic coupling is a useful way of obtaining biaryls, particu-
larly binaphthols <B-2002MI479>. The technique is widely applicable to electron-rich aromatics,
but is more challenged in cases of highly substituted aryls and for unsymmetrical coupling. One
useful way to overcome these two hurdles simultaneously is to perform the reaction intramolecu-
larly by using a temporary tether between the two reacting arene moieties; this continues to be a
valuable tool for natural product synthesis. Various transition metal species can be used as oxidants
in either stoichiometric or catalytic amounts, but organic oxidants may be employed instead; the use
of hypervalent iodine reagents remains popular <2001OR327>. The nitrosyl cation gives
binaphthyls with simple alkyl naphthalenes with minimal ring nitration <1996JOC788>. A few
solid-supported metal-based catalysts which function under aerobic conditions have been developed
for this reaction <1996SC3075, 1997JOC3194, 1998MI113>. The well-known dehydrogenating
agents Pd–C and Pt–C are rarely used, but do induce oxidative dimerization of some aromatic
N-heterocycles <1997JOC3013, 1998S1596>. A polymer-supported hypervalent iodine reagent is
highly efficient and can be recovered and recycled (Scheme 32) <2001T345>.
Most progress appears in the area of catalytic asymmetric reactions, almost exclusively dedi-
cated to the enantioselective coupling of 2-naphthols. Following on from innovative work in the
early 1990s, chiral diamine–copper complexes are now available for the enantioselective homo-
coupling of 3-hydroxynaphthalene-2-carboxylates in aerobic conditions (Equation (51))
<1999JOC2264, 2001OL1137>. It is noteworthy that the ee falls off considerably if no carboxylate
is present, suggesting a metal-coordinating role for this function in the catalytic process.
Ruthenium(II)–salen complexes incorporating chiral diamines catalyze the photo-promoted asym-
metric aerobic oxidative coupling of several 6-substituted-2-naphthols in decent yield with ee
OMe
Me PSBTI (1.5 equiv.) OMe
Me
BF3.OEt2 (3 equiv.)
MeO CH2Cl2, –40 °C, 3 h Me

MeO
OMe 86%
OMe
MeO OMe
MeO OMe
PSBTI (1.5 equiv.)
MeO OMe BF3.OEt2 (3 equiv.) MeO OMe
CH2Cl2, rt, 24 h
N
N 80% COCF3
COCF3
PSBTI (1.5 equiv.)

OMe BF3.OEt2 (3 equiv.) OMe
OMe
CH2Cl2, rt, 24 h
89%
PSBTI = polymer-supported = I(OCOCF3)2

bis(trifluoroacetoxyiodo)benzene
Scheme 32
values up to 71% <2000SL1433>. Chiral tridentate oxovanadium(IV) complexes also perform

well for 2-naphthols bearing substituents in the 3-, 6-, or 7-positions, giving the corresponding
binaphthyls in generally good yield and with ee of nearly 90% in the best cases <2001OL869,
2001CC980, 2002OL2529>. More impressive is the treatment of a similar range of 2-naphthols
with a catalytic amount (5–10 mol.%) of related binaphthyl- or biphenyl-based chiral bis(oxova-
nadium(IV)) complexes under mild conditions to give the coupled products in very high yield and
ee (often both >90%) <2002CC914, 2002AG(E)4532>. On a philosophical note, it is interesting
to note the chemical filiation inherent in this approach, since both the catalyst and the engendered
reaction products belong to the same family.
H COOMe
N
COOMe NH (10 mol.%) OH

CuI (10 mol.%) OH ð51Þ
OH
O2, MeCN, 40 °C, 48 h COOMe
85%
90–93% ee
1.11.3 BY ADDITION
1.11.3.1 Nucleophilic Addition to Allenes

Direct addition of organometallic species to allenes has been little exploited in the 1990s.
A reexamination of the exclusive Michael-type attack of -allenyl ketones (i.e., at the central
sp-carbon) by Grignard reagents leads to stereodefined ,-unsaturated ketones <2002TL6009>.
Nickel-catalyzed addition of organozincs also takes place at C2, even with unactivated allenes; the
resulting metallo-intermediate is trapped intramolecularly with an aldehyde to give well-defined
cyclic homoallylic alcohols (Equation (52)) <2002OL4009>. Allylic indium reagents add in a
highly regio- and stereoselective fashion to the terminal carbon of allenyl alcohols, via a hydroxy-
chelated bicyclic transition state <1996JA4699>.
Ph MeLi/ZnCl2 Me Cyclopentane
Ni(COD)2 (10 mol.%) HO cis/trans > 97/3
O • Ph
ð52Þ
Et2O, 0 °C, 30 min Double bond
H
71% (Z )/(E ) > 97/3
Michael-type addition is also observed in an intramolecular endo-mode attack of malonate

carbanions on allenyl sulfone functions; decarboxylation ensues, and through appropriate selection
of the tether length, functionalized cyclopentene or cyclohexene structures are obtained
<2003TL1583>. In an interesting variation on this theme, a tungsten carbonyl complex mediates
the intramolecular attack of a silyl enol ether at the terminal carbon of an unactivated allene under
photoirradiation; this reaction provides another smooth entry to cyclopentene and cyclohexene
compounds <2003OL1725>. In certain conditions, the regioselectivity of nucleophilic attack on an
allene bearing an electron-withdrawing group can be completely inversed from the usual Michael-
type addition at C2. The key to the success of umpolung addition at C3 is the generation of a
1,3-dipole by initial interaction with a phosphine in a catalytic system (Equation (53))
<1995SL645>.
COMe PPh3 (5 mol.%) MeOC

• +
COOMe Benzene, rt, 5 h MeOC ð53Þ
COMe
65% COOMe
(E )/(Z ) > 97/3
Much more progress is reported for palladium-catalyzed reactions. Whereas previously many
transition metal-based species provoked unspecific oligomerization processes with allenes, much-
improved catalyst systems now allow highly selective, controlled reactions to take place under
mild conditions. Although only carbon nucleophilic and pronucleophilic additions (effectively,
additions of CH bonds across allenes, also called hydrocarbonations) are treated here, the scope
of palladium-mediated reactions involving allenes—including nitrogen, oxygen, and other het-
eroatom nucleophilic additions, carbonylations, inter- and intramolecular (annulation) processes,
cycloisomerizations, and a whole series of tandem and cascade reactions—continues well beyond
the confines of this chapter (see, e.g., <2000CRV3067>).
Most palladium-catalyzed allene hydrocarbonation reactions appear to proceed via a hydro-
palladation mechanism, although other possibilities (such as carbopalladation) are not system-
atically ruled out. The regioselectivity of intermolecular hydrocarbonation is controlled,
predictably, by steric effects in the pronucleophile (bulky reagents add to the least-hindered
center) and/or electronic effects in the allene (stabilization of charge distribution in the -allyl
intermediate) (Equation (54)) <1995JA5156, 1995TL2811, 1995SL969, 1996CC831>; with an
allenylstannane substrate, an addition–substitution product is obtained <1996CC381>. In gen-
eral, the olefinic products of -additions are often formed with a very high (E)-stereoselectivity.
Recently, Trost’s group has adapted this reaction successfully for asymmetric synthesis, through
careful optimization of the reaction conditions and the catalyst system in addition to benzylox-
yallene <2003JA4438>. Excellent C1 regioselectivity, chemical yields (up to 90%), and ee (up to
99%) are obtained with Meldrum’s acid derivatives, while azlactones behave almost as well and
display, in addition, high de (up to 20:1) (Scheme 33). Palladium-catalyzed hydrocarbonation of
unactivated allenes with malonate-type methylene or methine carbanions in basic conditions gives
mixtures of the C3 (major) and C2 (minor) addition products, although yields are moderate and
other processes may compete <1995TL3853>.
Pd2(dba)3.CHCl3 R R R R
R
dppb
• +
Nu Nu Nu Nu
NuH
C1 attack C2 attack (2 isomers) C3 attack
ð54Þ
Yield Yield Yield Yield
R NuH (%) (%) (%) (%)
p-CF3O-C6H4 CH(Me)(CN)2 50 17
p-CF3O-C6H4 CH(Ph)(CN)(COOEt) 46
PhCH2O CH(Me)(CN)2 80
PhCH2O CH(Ph)(CN)(COOEt) 62
O Pd(OCOCF3)2 BnO O
O
OBn O L*
• + Me Me
CH2Cl2, rt O
O
75% O
O
99% ee
O BnO O
Pd(OCOCF3)2
OBn Me
• + O L* O
N Me
N
Ph CH2Cl2, rt
Ph
85%
93% ee
dr 20:1
O O
L* = NH HN
PPh2 Ph2P
Scheme 33
The rewarding extension of this chemistry to the intramolecular case constitutes, formally, a
cycloisomerization reaction. Methylene pronucleophiles tethered to terminal allenes undergo
palladium-catalyzed exo-mode cyclization through addition to the proximal sp2-carbon, leading
to five- or six-membered carbocycles <1995JA5156, 1996TL7453>. With allenyl ethers, five-, six-,
and seven-membered cyclic ethers are formed <1999TL1747>. The system is sensitive to the
nature of the catalyst and the reaction conditions, and curiously dimethyl malonate derivatives
fail to react. The reactivity profile takes a dramatic change when medium-to-large tethers are
involved <1997AG(E)1750>. In dilute solution, ring closures take place essentially at the terminal
sp2-carbon, giving 12- to 17-membered carbocycles and/or macrocyclic lactones; the internal
double bond geometry is trans. With slightly smaller (nine- to ten-membered) lactone and lactam
rings, a cis-geometry is progressively imposed, although the regioselectivity remains unaltered.
While the origin of the selectivity in these reactions is not clear, the results represent an attractive
means of constructing difficult-to-form rings (Equation (55)).
SO2Ph
[(π-Allyl)PdCl]2 SO2Ph n Yield (%) (Z )/(E )
O
dppp O
O 1 65 100/0
• DMAP, HOAc O ( )n 2 82 50/50 ð55Þ
4 62 0/100
( )n THF, 100 °C
8 57 0/100
sealed tube 9 67 0/100
dilute solution
Tandem reactions are a powerful strategy for the rapid, controlled construction of complex
hydrocarbon skeletons, and the scope of palladium-catalyzed processes involving allenes is well
reviewed <B-2002MI1491>. The palladium-catalyzed formal [3+2]-cycloaddition between acti-

vated alkenes and allenes actually involves sequential hydropalladation/carbopalladation steps,
although the precise mechanism is not established <1999JOC694>. Recent emphasis on tandem
carbopalladation reactions involving three distinct partners—an aryl/vinyl halide/triflate, a carbon
(pro)nucleophile, and an allene—is on intramolecular combinations of the reaction components
(Scheme 34) <1998JOC2154, 2001CC964, 2002JOC2837, 2002CL1140>, although intermolecular
examples also work <1995TL5051, 1998CL397, 2003TL7445>. In most cases, the reaction is
explained in terms of initial Pd(0) insertion into the aryl/vinyl component then the formation of a
-allylic intermediate by coupling at the allene C2, although the regiochemistry may depend on a
variety of factors <1998T14835, 2002JOC2837>. When an additional alkene moiety is included in
the structure, a spectacular cascade—Pd(0) insertion, exo-trig cyclization, intermolecular allene
insertion, nucleophilic -allyl(palladium) complex capture—creates three new bonds and leads to
a spiro-fused ring system <2001CC964>. This kind of palladium-catalyzed tandem/cascade reac-
tion methodology may also incorporate nucleophilic heteroatom attack as one of the steps.
COOEt
COOEt
COOEt COOEt
Pd(OAc)2(5 mol.%) COOEt
•
+ +
COOEt
I Et Na2CO3, NBun4Cl Et
DMF, ∆ Et 1
9:1
(5 equiv.)
93% 98/2 (Z )/(E )
EtOOC EtOOC
I COOEt
COOEt Pd(PPh3)4 (3 mol.%)
+
• K2CO3, DMF, ∆
89%
I
Pd(OAc)2 (10 mol.%)
• COOMe
N P(2-furyl)3 (20 mol.%) COOMe
O
N
Cs2CO3
O
Toluene, 50 °C
COOMe 45%
MeOOC
MeOOC COOMe
Me Me Pd(OAc)2 (10 mol.%) Me
I + • P(2-furyl)3 (20 mol.%)
Me
TsN
COOMe
Cs2CO3 N
(4 equiv.)
COOMe Toluene, 100 °C Ts
72%
Scheme 34
Related palladium-catalyzed tandem reactions are described in which there is no real carbon
pronucleophile (i.e., a center capable of generating a stabilized carbanion). The efficient and
selective three-component assembly of a vinyl or aryl halide, an allene, and an arylboronic acid
makes use of Suzuki-type cross-coupling for the introduction of the carbon ‘‘nucleophile’’
<2002JOC99>. 2-Iodoaryl allenes undergo formal [4+2]-cycloadditions with alkenes to give
naphthalene-derived products; the termination step is -hydride elimination <1996TL4251>. Aryl
iodides react with appropriately spaced allene alkenes to give cyclic products resulting from either
-hydride elimination or a further carbocyclization on the aryl moiety <2003AG(E)2647>.
Other intramolecular metal-catalyzed reactions involving formal additions to allenes include the
mercury(II)-mediated spirocyclization of allenyl p-methoxybenzyl ketone <1998TL8969> and the
ruthenium- or rhodium-catalyzed cycloisomerization of -allene alkenes <2002TL6693,
2003TL6335>. Finally, it is worth noting the Pd(II)-catalyzed oxidative carbocyclization reactions
of allene alkenes <2001JOC8015, 2003JA6056> and the related Pd(0)-catalyzed carbocyclization
of allenic allylic carboxylates <2003JA14140>, in which the allene moiety plays the role of the
formal nucleophile. Similarly, an intermolecular amine-catalyzed 1,4-addition reaction of the C1
of allenic esters with ,-unsaturated carbonyl compounds is described <2003JA12394>; this
reactivity contrasts markedly with the [3+2]-cycloaddition products obtained from the same
substrates under phosphine catalysis (see Section 1.11.3.3.4).
1.11.3.2 Free Radical Addition to Allenes

Allenes are excellent radical acceptors, and recent work exploits radical cyclization reactions in
particular. As key steps in natural product syntheses, intramolecularly generated alkyl radical
centers undergo 6-exo-dig <1996T13181> or 5-exo-trig cyclizations <1997LA1155,
1999TL3375>, depending on the substrate. In a remarkable total synthesis of a membranoid
natural product, Myers and Condroski <1995JA3057> described the double transannular radical
cyclization of a macrocyclic alkene allene to give the tricyclic hydrocarbon skeleton with very good
selectivity. Related studies show that addition of an external radical species to the digonal carbon of
an allene can be followed by the reaction of this new radical with a suitable acceptor group within
the molecule, providing an alternative radical cyclization approach involving creation of unsatu-
rated five- and six-membered carbocycles (Scheme 35) <1995TL6685, 1997JOC1202>.
Ts
Ts Ts
TsBr
+ Br +
• AIBN, benzene, ∆ Br
35% 27% 31%
Bu3Sn
Bu3SnH
• NOMe
AIBN, benzene, ∆
77% NHOMe
Scheme 35
Electron-deficient (but not electron-rich) allenes may react with diyls (or diradicals) generated
by thermal decomposition of diazene precursors, showing roughly the same diylophilicity as
methyl acrylate <1997TL15>. The bicyclic products are obtained as single regioisomers, the
1,2-addition taking place at the electron-deficient end of the allene.
1.11.3.3 Cycloaddition Reactions Involving Allenes
1.11.3.3.1 General observations

Allenes participate in cycloaddition reactions, furnishing two, three, or (in the case of vinyl
allenes) four carbon atoms to the new cyclic skeleton. While these transformations are presented
formally as cycloadditions, this does not necessarily imply a concerted process; indeed, reactions
often proceed in a stepwise manner via identifiable intermediates. Apart from a few useful rules-
of-thumb, the reactivity profiles are not easy to generalize, being strongly influenced by complex
combinations of steric, electronic, and environmental factors (solvent, catalyst, thermal or photo-
chemical initiation, etc.). In numerous cases, mixtures of products arising from different types of
competing reactions are observed.
1.11.3.3.2 [2+2]-Cycloadditions
The thermal dimerization to give dimethylenecyclobutanes is described for variously substituted
allenes, although the reaction is not particularly regioselective <2000JOC1721, 1997JPR(339)233,
1996JOC8132>. Such reactions are taken as evidence for transiently formed highly strained cyclic
allenes <1995T6475, 1997AG(E)1187, 2003JOC1579> even though the cyclobutane products
sometimes undergo further rearrangement. A high degree of head-to-head regioselectivity is
observed in the [2+2]-dimerization of electron-deficient allenes when an Ni(0) catalyst is used
(Equation (56)) <2000JA10776>.
Ni(PPh3)4 (10 mol.%) C6F5 C6F5

•
C6F5 Toluene, rt, 30 min ð56Þ
81%
Allene–alkene [2+2]-cycloadditions lead to methylenecyclobutanes, usually via diradical or

dipolar intermediates. For successful thermal reactions, electron-rich alkene–electron-deficient
allene combinations <2002PS(177)893> and/or Lewis acid promotion <1996TL327,
1998CL331, 2000CPB405> or high pressure <2003EJO894> are typically required, although
strained cyclic allenes react rapidly with unactivated alkenes <1995T1973, 1997JOC4998,
1998EJO237>. 4-Ethenylidene oxazolidinones undergo smooth thermal intermolecular [2+2]-
cycloadditions with various alkenes (excluding some bearing electron-donating substituents but
including, remarkably, conjugated dienes) under unusually mild conditions with excellent regios-
electivity at the distal double bond; a concerted mechanism appears to operate <2003CEJ2419>.
In contrast, allenamides react with [60]fullerene at the C1C2 bond <2002S1655>.
Recent efforts reveal particular reagent types, which facilitate smooth intramolecular reactions
in mild conditions. A 1-arylsulfonyl substituent activates the allene’s C2C3 bond for highly
regio- and stereoselective intramolecular reaction with relatively unreactive alkene centers teth-
ered at either C1 or C3 <1995JA7071, 1995TL4521, 2003JOC6238>, although the regioselectivity
is occasionally inversed <2003T3461>. 2-Azetidinone-tethered alkene allenes also display very
high stereoselectivity and distal bond regioselectivity in moderate-yielding intramolecular thermal
[2+2]-cycloadditions <2003OL3795>.
Intramolecular [2+2]-photocycloadditions involving relatively unactivated allenes tethered to
enones (or other alkenes bearing electron-withdrawing substituents) proceed in good yield and
high stereoselectivity; a high degree of asymmetric induction can be obtained if chiral nonracemic
tethers <1995SL776> or 1,3-disubstituted allenes <1997JA2597, 1997T16253> are used. In
Tsuno and co-workers’ detailed study of the photochemical reactivity of allenyl(vinyl)methane
systems in which the vinyl moiety is conjugated with an electron-withdrawing group, the reaction
products vary considerably, depending notably on the use of sensitizers, but can lead to signifi-
cant proportions of the bicyclo[2.1.0]pentane adducts (Equation (57)) <1995BCJ3175,
1999BCJ519, 2001T4831, 2002T7681>.
COOMe
hν
COOMe Low pressure Hg lamp
COOMe ð57Þ
• MeCN, rt, 25 h
under argon COOMe
65%
1.11.3.3.3 [4+2]-Cycloadditions
Allene participation in Diels–Alder reactions continues to attract attention. In principle, vinyl
allenes as diene components have improved reactivity and selectivity compared to ordinary
conjugated dienes. The success of [4+2]-cycloaddition reactions of vinyl allenes appears to
depend on the precise nature of the diene unit, and requires a good dienophile, but when reactions
proceed they usually do so with a high degree of stereoselectivity and provide an interesting entry
to six-membered rings with tetrasubstituted exocyclic double bonds <1996LA1487,
1998JOC5283, 2001EJO1089>. Promising results are reported for metal-catalyzed reactions lead-
ing to 3-methylenecyclohexenes, via processes that involve metallacyclic intermediates. Although
most work focuses on analogous reactions of alkynes, ethene, a particularly unreactive alkene,
can be made to react in the presence of a Rh-based catalyst with an unactivated vinyl allene
<1998AG(E)2248>, while a palladium-based catalyst directs a [4+2]-cycloaddition between a
vinyl allene and an ordinary 1,3-diene, this latter being forced to behave exclusively as a 2
component <1997JA7163>; variable enantioselectivity is observed when this reaction is carried
out in the presence of chiral catalyst ligands (Equation (58)) <2000CC2293>.
COOEt COOEt
Pd2(dba)3.CHCl3 (2.5 mol.%)
+ L* (6 mol.%) Ph
• Ph
CH2Cl2, rt
ð58Þ
R1 R2 Yield (%) ee (%)

P(R1) 2
2 Ph H 62 6
L* = Fe R Ph SiPh3 90 47
Cy SiPh3 80 18
3,5-Bis(trifluoromethyl)phenyl SiPh3 85 83
Unactivated allenes (and 4-ethenylidene oxazolidinones <2003CEJ2419>) are not good dieno-
philes. With an electron-withdrawing group at C1, however, allenes participate more readily in
intermolecular Diels–Alder cycloaddition reactions with a variety of dienes (Scheme 36). When
this group is a carboxylic ester <1996LA1989, 1999JA3529>, a phosphoryl group
<2000EJO3945>, or a sulfonyl group <1997TL7993, 2000EJO3945>, addition invariably occurs
at the electron-deficient C1C2 bond; endo/exo-stereoselectivity can vary considerably. Curi-
ously, an -fluoroallenyl phosphonate reacts exclusively at the C2C3 bond (and with excellent
stereoselectivity) <2000JOC227>. Allenyl sulfoxides, normally sluggish dienophiles, display
hugely improved reactivity with cyclopentadiene under ultrasound irradiation <1998TL5413>.
With a symmetrical 1,3-bis(electron-withdrawing group) allene, [4+2]-cycloadditions with regular
dienes are particularly facile, and the question of regioselectivity disappears (Scheme 36). The
bis(phenylsulfonyl) derivative behaves appropriately <1998SL900>, while synthetic applications
of the dicarboxylate are described <1997TL7993, 1999AJC1013>. In a low-temperature Lewis
acid-catalyzed example, enantiomerically pure allene 1,3-dicarboxylates display excellent asym-
metric induction in their reaction with cyclopentadiene <1996JOC2031>. Electron-rich allenes
give cycloaddition products with pentamethylcyclopentadiene via a stepwise process involving
radical cation catalysis <1995JOC8223, 1996CEJ1031>. Predictably, strained cyclic allenes need
no particular encouragement to participate in Diels–Alder reactions with unreactive alkenes,
although the appearance of [2+2]-dimerization products may understandably compete
<1995T6475, 1997JOC4998, 1998EJO237, 1999JOC976, 2002T3079, 2003JOC1579>. To a cer-
tain extent, the regioselectivity (if any) can be explained in terms of the participation of the more
electron-deficient allene center.
Intramolecular Diels–Alder reactions are often fruitful, although the course of the reaction may
depend markedly on the nature and length of the tether (Scheme 37). With a C1-phenylsulfonyl
allene bearing an unactivated diene tethered to C3, thermal [4+2]-cycloaddition reactions proceed
easily <2000JCS(P1)3129>, although with the diene tethered at C1, other processes may compete
<1995JA7071>. The distal double bond of allene carboxylate and carboxamide derivatives
undergoes intramolecular [4+2]-cycloadditions with cyclic diene systems (including heterocyclic
and even carbocyclic aromatics) borne by the heteroatom, leading to elaborate tricyclic structures
<1997LA435, 1997JPR(339)233, 2002JA11292>. Likewise, an electron-rich allenyl ether under-
goes efficient cycloaddition with a diene tethered via the ether oxygen <1995H(41)245,
1998JOC5064>. Transition metal catalysis gives spectacular results in the intramolecular [4+2]-
cycloadditions of nonactivated allene–diene combinations under mild conditions, leading to 6,5-,
6,6-, or 6,7-fused ring systems <1995JA1843>. Excellent yields and regioselectivities are observed,
with the latter being determined by the choice of catalyst.
COOEt COOEt
120 °C, 4 d
+ •
72%
TBDMSO
4/1 exo/endo
SO2Ph
90 °C, 16 h N-t-BOC
N-t-BOC + •
45% H
SO2Ph
endo
SO2Ph
25 °C, 2 min
+ • SO2Ph
93%
SO2Ph SO2Ph
4/5 exo/endo
H COOR
AlCl3 (1.2 equiv.) ROOC
+ • COOR
H ROOC
+
CH2Cl2
H COOR COOR H
–78 °C, 2 h endo exo
R = (–)-Menthyl 96% 2%
Scheme 36
MeOOC COOMe MeOOC COOMe MeOOC COOMe

SO2Ph
• 80 °C, 5 h +
SO2Ph SO2Ph
96%
2:1
180 °C, 24 h
•
34% SO2Ph
SO2Ph
Single product
80 °C, 20 h
•
73%
SO2Ph SO2Ph
3/1 exo/endo
O • O
HO ∆, 2 h HO
80%
Single product
Scheme 37
1.11.3.3.4 Other cycloadditions

Rhodium-catalyzed intramolecular [5+2]-cycloadditions of vinyl cyclopropane allenes provide a
very efficient entry to bicyclic structures incorporating a seven-membered ring with an exocyclic
methylene adjacent to the bridgehead. The reaction works well with variously substituted, non-
activated allenes and is highly selective in favor of a cis-ring fusion <1999JA5348, 1999OL137,
2000OL2323>. Structurally related, but mechanistically different, the [5+2]-oxopyrylium
cycloaddition gives limited success with electron-rich allene partners, and fails with electron-
deficient ones <2001TL1695>. A useful phosphine-catalyzed cycloaddition of allenic esters with
electron-deficient alkenes has been described (Scheme 38) <1995JOC2906, 1999TL549,
2002JOC8901>. This reaction is in fact a [3+2]-annulation involving a 1,3-dipolar intermediate
derived from the allene, and leads to cyclopentenes. [60]Fullerene can participate as the two-
carbon component <1997CC79, 1997CC81>. The method has been adapted for asymmetric
synthesis using chiral nonracemic alkene partners <1997CC2267> or phosphine catalysts
<1997JA3836>. With tropone, allenic esters or ketones undergo unusual phosphine-catalyzed
[8+2]-annulation, presumably via the same dipolar intermediate, to give bicyclic trienes, with
high selectivity in some cases <2000OL787>. A palladium(0)-catalyzed head-to-head [4+4]-
cycloaddition reaction, formally a dimerization, is known for certain vinyl allenes; the process
represents an interesting entry to symmetrical cyclooctadienes, although it is of limited scope at
present. The contrast with vinyl allene–1,3-diene cycloadditions is noteworthy, since the latter
usually proceed in a [4+2]-mode <1999SL951>.
COOEt PPh3 (10 mol.%) COOEt

COOEt
+ • Benzene EtOOC
COOEt
EtOOC rt, 5 h
67% Single product
O O
O
COOEt PPh3 (10 mol.%) COOEt
+ • Toluene
rt, 11 h COOEt
93% 21:79
O O
COOBut PPh3 (10 mol.%) O
COOBut
BnN • Benzene BnN BnN
+ +
NBn NBn
∆, 12 h NBn COOBut
O O O
90% 26:74
Ph
P Pri
COOEt Pri (10 mol.%)
COOBui COOBui
+ • EtOOC
Toluene, 0 °C, 5 h
Single product
88% 93% ee
Scheme 38
1.11.3.4 Carbene Addition to Allenes

There is only limited synthetic exploitation of this and related types of reaction, partly due to the
existence of alternative, easier methods of obtaining the product methylenecyclopropanes, but
also due to a lack of selectivity and (importantly) the ease with which an allene reacts with two
carbene equivalents to give a spiropentane system. Thus, in the enantioselective synthesis of
spiropentanes from hydroxymethylallenes using bis(iodomethyl)zinc and a chiral dioxaborolane,

only the most sterically hindered substrate adds a single methylene unit; unsurprisingly, this
occurs at the least hindered center (with excellent enantioselectivity) <2001OL3293>. Diazo-
alkane precursors give the required methylenecyclopropane products with selected highly substi-
tuted allenes, although with moderate selectivity <2000JOC1721, 2001JOC7202, 2001CEJ4021>.
Despite its impressive enantioselectivity, the reaction of singlet (methoxycarbonyl)phenylcarbene
with enantiomerically enriched 1,3-dimethylallene gives a mixture of diastereoisomeric methylene-
cyclopropanes <1996JOC1030>. Dihalogenocarbenes give 1:1 products with substituted allenes,
with variable regioselectivity <1997JOC9039, 1999TL1261>. Intramolecular reactions, once again,
seem to give the most useful results: the diazoacetates of a range of (hydroxyalkyl)allenes undergo
smooth transformation in the presence of a Cu(II) catalyst to give methylenecyclopropyl lactones
with excellent yields and regioselectivity; diastereoisomeric excesses, however, remain only moderate
<1997TL3833>.
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Biographical sketch
David J. Aitken was born in 1963, studied Sophie Faure was born in 1973 in Saint-Dizier,
chemistry at the University of Strathclyde, studied chemistry at the University of Cham-
Glasgow, where he obtained a B.Sc. in 1983 pagne-Ardennes in Reims where she received
and his Ph.D. in 1987 under the joint direc- her Ph.D. in 1999 under the direction of Pro-
tion of Professors H. C. S. Wood and C. J. fessor O. Piva. She worked on the asymmetric
Suckling. After 2 years as a NATO-Royal synthesis of -fluoroketones in the group of
Society Postdoctoral Fellow at the Institut de Professor D. Enders in Aachen as a postdoc-
Chimie des Substances Naturelles in Gif-sur- toral fellow in 2000. After a postdoctoral posi-
Yvette, working with Professor H.-P. Husson, tion in medicinal chemistry in the laboratories
in 1989 he was appointed as a CNRS of Professor H.-P. Husson in Paris, she
Researcher in Professor Husson’s new medic- obtained, in 2002, a permanent position in
inal chemistry research laboratory at the the CNRS as a Chargée de Recherches in the
Faculty of Pharmacy, University of Paris-5. group of Professor D. J. Aitken in Clermont-
In 1998, he took up his present position as Ferrand. Her research interests include
Professor in organic chemistry in the faculty synthesis of macrocyclic peptides with anti-
of sciences at the University of Clermont- thrombotic activity and conformationally con-
Ferrand-2. His research interests include all strained aminoacids, especially cyclobutane
aspects of selective synthesis of molecules of derivatives.
biological interest, in particular the prepara-
tion and study of strained or conformationally
restricted compounds and the synthetic use of
aminonitriles.
1.12
One or More C¼C Bond(s) Formed
by Addition
A. C. REGAN
University of Manchester, Manchester, UK
1.12.1 REDUCTION OF ALKYNES TO ALKENES 534

1.12.1.1 Heterogeneous Catalytic Hydrogenation 534
1.12.1.1.1 Catalysts 534
1.12.1.2 Homogeneous Catalytic Hydrogenation 536
1.12.1.3 Dissolving Metal Reductions 537
1.12.1.4 Hydride Reducing Agents 539
1.12.1.4.1 Boron reagents 539
1.12.1.4.2 Aluminum reagents 539
1.12.1.4.3 Other hydride reducing agents 541
1.12.1.5 Miscellaneous Reducing Agents 541
1.12.2 CYCLOADDITION REACTIONS TO ALKYNES 542
1.12.2.1 [2+2]-Cycloaddition Reactions 542
1.12.2.2 Diels–Alder Reactions 545
1.12.2.3 1,3-Dipolar Cycloaddition Reactions 549
1.12.2.4 Ene Reactions 551
1.12.2.5 [3+2]-Cycloaddition Reactions 553
1.12.2.6 The Pauson–Khand Reaction 553
1.12.2.7 Cyclotrimerization of Alkynes 555
1.12.3 IONIC ADDITIONS 556
1.12.3.1 Hydrometallation of Alkynes Followed by CC Bond Formation 556
1.12.3.1.1 Hydroboration followed by CC bond formation 556
1.12.3.1.2 Hydroalumination followed by CC bond formation 557
1.12.3.1.3 Hydrosilylation followed by CC bond formation 558
1.12.3.1.4 Hydrostannylation followed by CC bond formation 558
1.12.3.1.5 Hydrozirconation followed by CC bond formation 559
1.12.3.1.6 Formation of alkyne–titanium complexes followed by CC bond formation 560
1.12.3.2 Ionic Additions of Stabilized Carbanions to Activated Alkynes 560
1.12.3.3 Carbometallation of Alkynes 561
1.12.3.3.1 Additions of organolithium and Grignard reagents to alkynes 561
1.12.3.3.2 Addition of organocopper reagents to alkynes 562
1.12.3.3.3 Addition of organoboron reagents to alkynes 564
1.12.3.3.4 Addition of organoaluminum reagents to alkynes 564
1.12.3.3.5 Addition of organozinc reagents to alkynes 566
1.12.3.3.6 Other carbometallation reactions of alkynes 566
1.12.3.4 Addition of Sulfur, Selenium, and Tellurium Reagents to Alkynes 567
1.12.3.5 Addition of Iron Reagents to Alkynes 567
1.12.3.6 Palladium-catalyzed Additions to Alkynes 567
1.12.4 FREE RADICAL ADDITIONS 569
1.12.4.1 Intermolecular Free Radical Additions 569
1.12.4.2 Intramolecular Free Radical Additions 569
1.12.5 CARBENE AND OTHER ADDITIONS 571
1.12.5.1 Addition of Simple Carbenes and Carbenoids to Alkynes 571
1.12.5.2 Reaction of Fischer Carbene Complexes with Alkynes: The Dötz Synthesis of Phenols 572
533
534 One or More C¼C Bond(s) Formed by Addition
1.12.1 REDUCTION OF ALKYNES TO ALKENES
1.12.1.1 Heterogeneous Catalytic Hydrogenation

The partial hydrogenation of alkynes over heterogeneous catalysts continues to be a widely used
method for the preparation of mono- and di-substituted alkenes. This topic has been reviewed
recently <B-2001MI001>, and also reviewed more briefly in general reviews of catalytic hydro-
genation <2001JMOC(173)185, B-2002MI001>. A useful monograph on the preparation of
alkenes <B-1996MI001> includes various protocols for the reduction of alkynes, including
heterogeneous catalytic hydrogenation. The hydrogenation of internal alkynes is a particularly
important method for the production of (Z )-alkenes (Equation (1)).
H2, cat. H H
R1 R2 ð1Þ
R1 R2
1.12.1.1.1 Catalysts
The most generally used heterogeneous catalysts are based on palladium or nickel, and are often
employed on an inert support. By far the best known is the Lindlar catalyst, which is palladium
on CaCO3, treated with Pb(OAc)2 to lower its activity <1973OSC(5)880>. Quinoline is often
added as a modifier to improve the selectivity <1973OSC(5)880>, although a variety of other
additives have also been used <1995COFGT(1)501>. A recommended protocol for partial
hydrogenation using Lindlar’s catalyst uses the example shown in Equation (2), giving a
(Z )-allylic alcohol <B-1996MI001>. Recent studies on how quinoline enhance the selectivity of
the hydrogenation indicate that electron-donating ligands render the metal–hydrogen species
more nucleophilic, and hence more reactive toward alkynes than alkenes <1998CC1103>. A
similar effect has been found for the Lindlar catalyst also <1997JOC8618>.
H2 (1 atm), Pd-CaCO3 H H
Ph CH2OH ð2Þ
quinoline, hexane Ph CH2OH
97%
Palladium on barium sulfate is a popular alternative to Lindlar’s catalyst

<1995COFGT(1)501>, and quinoline is again an often-used additive. A recent example is
shown in Equation (3) <1998SC1323>.
H2 (1 atm), Pd-BaSO4
ð3Þ
Quinoline, ligroin
The presence of extra functional groups in close proximity to, or in conjugation with, the alkyne,
can often be tolerated <1995COFGT(1)501>. For example, many propargylic alcohols have been
reduced to the corresponding (Z )-allylic alcohols (e.g., Equation (2) above). However, in the case of
amino-alkynes often difficulties are encountered, because the unprotected amino group accelerates
over-reduction of the product alkene and reduction loses its selectivity. This reaction has been
examined for a series of alkynes with the primary amine group separated from the alkyne by
different chain lengths (Equation (4)), and success has been achieved with Lindlar’s catalyst using
ethylenediamine (EDA) as a modifier, whereas quinoline was much less effective <2001JOC3634>.
H H
H2 (1 atm), Lindlar's cat.
Ph H2N Ph
H2N ð4Þ
DMF, EDA (1.2 equiv.), rt n
n
97% for n = 3
n = 1–4, 91.5–97.4% (Z )-selectivity
One or More C¼C Bond(s) Formed by Addition 535
An interesting series of closely related examples is shown in Equation (5), comparing the
effectiveness of Lindlar’s catalyst and Pd-BaSO4 + quinoline. In the most difficult reduction, an
increased pressure of hydrogen and a change of solvent to pyridine were required <1998T15541>.
Yield (%) Yield (%)

1
R R2 Lindlar Pd-BaSO4 + Quinoline
F R2
F R2 H2 (1atm), cat.
PO(OEt)2 Me H 89 ð5Þ
PO(OEt)2 Ph H <40 75
MeOH or R1
R1 Ph Me 0
EtOH
99 (40 psi H2, 48 h,
Pyr. solvent)
In demanding cases, it may be necessary to try several methods of reduction; for example, for
the 13-membered cyclic ketone 1 (Equation (6)), only hydrogenation using Pd-BaSO4 was suc-
cessful, whereas the use of other catalysts, as well as hydroboration and hydroalumination, all
resulted in failure <1998BCSJ221>.
O O O O
H2, Pd-BaSO4
+ +
PhH ð6Þ
1
36% 15% 2%
Although heterogeneous catalytic reduction of alkynes over palladium catalysts is usually a

reliable method for the synthesis of (Z )-1,2-disubstituted alkenes, occasionally this stereoselectiv-
ity is reversed. For example, both the quinoxaline substituted alkyne 2 and the related alkyne 3
are reduced to the corresponding (E )-alkenes (Scheme 1): the former using Lindlar’s catalyst, and
the latter using Pd-BaSO4 <2000H(52)911>.
MeO2C N H2, Lindlar cat. MeO2C N

H
N MeOH
N Ph
49%
Ph H
2
(E ) only
Ar H
N N Ar
H2, Pd-BaSO4
MeO N O Quinoline, THF H

MeO N O
Me 25%
Me
3 (Ar = C6H4-p-CO2Me) (E ) only
Scheme 1
Other supported palladium catalysts have appeared more recently, including one prepared by
adding Pd(OAc)2 to borohydride exchange resin <1996TL8527>. In the presence of CsI, 1 mol.%
of catalyst is effective for the rapid semi-hydrogenation of terminal alkynes at 1 atm pressure, and
it is not critical that the uptake of hydrogen is closely monitored since over-reduction of the
products is very slow. Hydrogenation of internal alkynes is much slower; however, the (Z )-alkene
products are readily obtained when 10 mol.% of catalyst is employed.
An interesting new supported catalyst is palladium on pumice <2001TL2015>. The activity of
this catalyst varies depending on the catalyst loading on the pumice. A variety of internal alkynes
have been reduced, in most cases with excellent stereoselectivity for the (Z )-products, and with
little over-reduction (Equation (7)).
H2 (1 atm), Pd-pumice (0.5 wt.%) H H

Ph CO2Me
EDA (2.5 mol.%), THF
ð7Þ
Ph CO2Me
99%
Apart from palladium, the metal which has been most generally used as a heterogeneous
catalyst is nickel <1995COFGT(1)501>. Early work used mainly Raney nickel, and while this
is sometimes not very selective, it is still employed. P-2 nickel is a more recent catalyst
<1995COFGT(1)501>, and often gives good stereoselectivities when ethylenediamine is used as
an additive. Two recent examples of (Z )-selective hydrogenations over P-2 nickel are shown in
Equations (8) and (9) <1995SC4035, 1997SL387>.
(CH2)6CH3
H2, P-2 Ni (CH2)6CH3 ð8Þ
CO2But EtOH
O O CO2But
97%
OH H2, P-2 Ni OH
EtOH ð9Þ
71%
A nickel boride catalyst, prepared from nickel acetate and borohydride exchange resin, is a very
effective catalyst for (Z )-selective semi-hydrogenation of internal alkynes bearing alkyl, aryl,
hydroxyl, or ester groups <1996TL1057>. Conversions are generally quantitative, with excellent
stereoselectivities and very slow over-reduction. The selectivity for reduction of alkynes over the
product alkenes appears to be steric in origin, since a terminal alkyne underwent considerable
over-reduction.
1.12.1.2 Homogeneous Catalytic Hydrogenation

Homogeneous catalysis has been comparatively little used for catalytic hydrogenation of alkynes,
compared to heterogeneous catalysis <1995COFGT(1)501, B-1996MI001>. Although Wilkinson’s
catalyst is the best-known homogeneous hydrogenation catalyst, it usually gives complete
reduction of alkyne triple bonds. Nevertheless, in benzene with acidic co-solvents, partial hydro-
genation is successful for terminal alkynes. Internal alkynes can be reduced stereoselectively to
(Z )-alkenes by complexes of the type [(arene)Cr(CO)3] <1985JOC1147>. It is also possible to
obtain (E )-selective hydrogenation using rhodium-based complexes, for example
[RhH2(OC(¼O)OH) (PPri3)2] <1983JA6273>.
A more recent application of Wilkinson’s catalyst is in the stereoselective hydrogenation of the
(E )-tosyl-enyne 4 to the conjugated (Z),(E)-diene 5 shown in Equation (10) <1997JOC6326>.
H2, RhCl(PPh3)3 Ts
Ts Benzene ð10Þ
4 5
84%
A homogeneous cationic ruthenium complex of the type [Cp*Ru(alkene)]+ has been reported
to effect the direct trans-hydrogenation of alkynes to (E )-alkenes <2001NJC423>. para-Hydrogen-
induced polarization NMR spectroscopy was used to establish the direct pairwise transfer of two
para-hydrogen atoms, which was rationalized on the basis of a mechanism proceeding via a
binuclear rhodium complex.
A new homogeneous palladium(0) catalyst bearing a bidentate nitrogen ligand gave
(Z )-selective hydrogenation of a wide variety of alkynes (Equation (11)), <1999AG(E)3715>.
Very high stereoselectivities (often >99:1) are found for simple alkynes, with superior results in
several cases to those obtained with either Lindlar’s catalyst or P-2 Ni. The stereoselectivities are
not quite as good for phenylalkynes, but still comparable to those of heterogeneous catalysts.
Conjugated enynes are reduced cleanly to the corresponding dienes, with uptake of hydrogen
stopping after reduction of the triple bond without over-reduction. Several other ligands were
tested for generation of the palladium(0) catalyst system, but the bidentate nitrogen ligand shown
below gave the best selectivities.
H2 (1 atm), cat . OH
OH
THF, 20 °C
>99.5% conversion >99% (Z )-Isomer
C6H4-p-OMe ð11Þ
N CO2Me
Precatalyst: Pd
N MeO2C
C6H4-p-OMe
In contrast to the palladium(0) catalyst above, a series of homogeneous palladium(II) catalysts

have been prepared with thiosemicarbazone ligands <1998JCS(D)2715>, and these show good
selectivities toward terminal alkynes.
The relative reactivities of enol ester and alkyne multiple bonds can be seen in Equation (12),
where the use of a catalyst prepared from a rhodium(I) salt and methyl DuPHOS results in
asymmetric hydrogenation of the enol CC double bond in the substrate to give an intermediate
(which can be isolated by interrupting the reaction), followed by (Z )-selective reduction of the
alkyne <1998TL5505>.
OAc OAc Ph
H2 (30 psi), Rh(COD)BF4 OAc
Me
DuPHOS H Me
Ph Ph H
THF or MeOH, rt
>97% 97.8% ee
ð12Þ
DuPHOS
P P
The use of several trinuclear ruthenium carbonyl complexes as catalyst precursors for the
homogeneous hydrogenation of diphenylethyne has been reviewed <1995SL579>. In some cases,
the clusters retain their trinuclear framework during the catalytic reactions. In general, cis-stilbene is
the kinetic product, and trans-stilbene the thermodynamic product of these hydrogenations.
Transfer hydrogenation of alkynes using homogeneous Pd(0) catalysts can be effected using
hydrosilanes and acetic acid as the hydrogen donor, or alternatively, formic acid. These processes
usually give the (Z )-alkene selectively, and have been reviewed <B-2002MI002>.
1.12.1.3 Dissolving Metal Reductions

Dissolving metal reductions of alkynes have been widely used as an effective approach for the
production of (E )-alkenes <1995COFGT(1)501>, for which relatively few general methods are
available, in contrast to the many methods for reduction to (Z )-alkenes. Dissolving metal
reductions have been reviewed by <B-1996MI001>, and a detailed experimental protocol is
given for the representative reduction of oct-2-yne to (E )-oct-2-ene using sodium and liquid
ammonia (Equation (13)). Other metals have been used, including lithium, calcium, ytterbium
and zinc <1995COFGT(1)501>, usually in combination with an amine, although in some cases
alcohols can be used as the proton donor.
H
Na /NH3
Me ð13Þ
Me
H
A detailed comparison of the reduction of alkynes of differing alkyl chain lengths using lithium
metal shows that the solvent is particularly important <1999EJOC779>. Mono-alkynes with a
chain length of 12 or less carbons were easily reduced using t-butanol and THF or ether as the
solvent. In contrast, for longer chain alkynes, HMPT was found to be necessary. Compounds
containing two (nonconjugated) alkyne bonds were reduced much more readily than mono-alkynes.
The combination of zinc and 1,2-dibromoethane is unusual in that it gives (Z )-selectivity with
internal alkynes, and this reagent has been more recently used for the (Z )-selective reduction of a
conjugated enyne in a macrocyclic lactone (Equation (14)) <2001OL3487>.
O O
O Zn, LiBr, CuBr O

BrCH2CH2Br ð14Þ
EtOH
71%
Two alkyne groups in the conjugated ene-diyne 6 are reduced simultaneously by activated zinc
in methanol–water, to give the triene 7 with 95% (Z )-selectivity (Equation (15)) <1995T1209>.
C5H11 Zn
MeOH–H2O C5H11 ð15Þ
6 50% 7
95% (Z )-selectivity
Conjugated trienes can also be prepared by zinc–copper couple reduction of all three alkyne
bonds in 8, in this case affording the all-(Z )-triene 9 (Equation (16)) <1997TL6917>.
i. Zn(Cu–Ag),
C5H11 Pr MeOH–H2O C5H11 Pr
ð16Þ
HO OH ii. BzCl, Pyr OBz 9 OBz
8 73%
Zinc in acetic acid–water also gives (Z )-selective reduction of the alkynoate ester shown in Equation
(17) with concomitant reduction of the hydroxylamine <1997TL5503>. The stereoselectivity is 93:7,
but this is highly sensitive to the solvent system used. By raising the proportion of acetic acid to water
from 1:9 to 4:1 the selectivity could be reversed, slightly favoring the (E )-product. In the presence of
di-t-butyldicarbonate, the (Z )-amine can be trapped out as the t-BOC-protected product, preventing
cyclization to the lactam <1999SL602>.
OH Ph
Ph N Zn (20 equiv.) Ph NH
+ N
AcOH–H2O (1:9) Pri O ð17Þ
Pri Pri CO2Et
CO2Et 60 °C, 30 min
70% 7:93
Rieke zinc has been used in THF–methanol–water to effect the (Z )-selective reduction of the
propargylic alcohol 10 in excellent yield (Equation (18)) <2000JCS(P1)2343>, whereas the use of
hydrogenation over Lindlar’s catalyst was found to be unsatisfactory, and the combination of
titanocene dichloride and iso-butylmagnesium chloride reduced the alkyne, but also removed the
t-BOC group. In contrast, the unsubstituted alcohol 11 was reduced satisfactorily using hydro-
genation over Lindlar’s catalyst.
N
N
N Rieke Zn
N
N
OH N
NHt-BOC THF–MeOH–H2O
heat, 16 h NHt-BOC ð18Þ
R
R OH 10 (R = Et): 94% yield using Rieke Zn

11 (R = H): 99% yield using H2/Lindlar
A wide variety of terminal alkynes bearing different propargyl functionalities have been
reduced using pulverized indium metal (prepared by sonication) in ethanol <2001JOC5624>.
No over-reduction was observed, and a range of reducible functional groups were unaffected.
The combination of nickel chloride dihydrate, lithium metal, and a catalytic amount of naphtha-
lene in THF can be used to reduce alkynes, either completely to the corresponding alkanes, or in
some cases partially to the alkenes, depending on the reaction conditions <1997TL149>.
1.12.1.4 Hydride Reducing Agents
1.12.1.4.1 Boron reagents

The sequence of hydroboration followed by protonolysis of the resulting alkenylborane has
become a well-established general method for the overall cis-addition of H2 to alkynes
<1995COFGT(1)501, 1995CRV2457>. In general, bulky dialkylboranes are used to avoid further
reaction of the initially formed alkenylboranes, and disiamyl and dicyclohexylborane have been
widely employed. A simple experimental protocol for the reduction of 3-hexyne (Equation (19))
using borane generated in situ is given in the review by Haworth <B-1996MI001>.
i. NaBH4, BF3.OEt2
diglyme
Et Et ð19Þ
ii. AcOH Et Et
70%
The protonolysis is generally carried out using acetic acid, although other procedures involving
hydrolysis under basic or almost neutral conditions have been developed
(<1995COFGT(1)501>). 9-BBN–H is a useful reagent for internal alkynes, and other boranes
such as catecholborane and haloboranes have also been used <1995COFGT(1)501,
1995CRV2457>.
Both terminal and internal nonconjugated alkynes can be hydroborated in the presence of
aldehyde or ketone carbonyl groups in the same molecule using dicyclohexylborane
<1997TL7681>. After protonolysis, the corresponding alkenes are obtained in good yields,
with internal alkynes resulting in (Z )-stereoselectivity, as expected (Equation (20)).
O i. (c -C6H13)2BH
THF O
Ph
Ph
ð20Þ
ii. AcOH
92%
Hydroboration reactions can be catalyzed by transition metal complexes, and these have been
reviewed <1997T4957>. A variety of metals can be utilized, including rhodium, titanium, and
zirconium. However, in most cases for the hydroboration of alkynes, the product alkenylboranes
have not been converted into the corresponding alkenes, although this should be straightforward
in principle.
Sodium borohydride (NaBH4) is not usually effective as a nucleophilic hydride reducing agent
for isolated nonconjugated alkynes, but has been successfully employed to reduce alkynes con-
jugated with amides, a second alkyne group, and allenes <1995COFGT(1)501>. Very recently,
NaBH4 has been used to reduce the alkyne triple bond in 4-oxo-ynoate esters to the correspond-
ing (E )-allylic alcohols (Equation (21)) <2003TL443>. When methyl and phenyl ketones are
used, none of the lactone resulting from reduction to give the (Z )-alkene was detected; however,
with more bulky alkyl groups (cyclohexyl and t-butyl) some loss of stereoselectivity is observed.
O OH
NaBH4, MeOH
CO2Me ð21Þ
CO2Me
70%
1.12.1.4.2 Aluminum reagents

Addition of an aluminum hydride reagent to an alkyne, followed by hydrolysis of the resulting
alkenyl aluminum compound, results in overall reduction to an alkene (<1995COFGT(1)501,
84OR375, 1991COS(8)733>). For isolated alkynes, diisobutylaluminum hydride (DIBAL-H) has
been often used, and for internal alkynes this generally gives the (E )-alkene. Terminal alkynes can
give problems with competitive metallation of the alkyne CH bond. A recent application of
DIBAL-H is in the preparation of (E )-allylic sulfides, shown in Equation (22) <1997SC3917>.
DIBAL-H
Bun Bun SPh
SPh Et2O-hexane ð22Þ
81%
A much more widely used class of alkynes for hydroalumination is that of propargyl alcohols,
where reduction to the corresponding (E )-allylic alcohols using LiAlH4 is a standard method
(Equation (23)) <1995COFGT(1)501>. This method allows selective reduction of the triple bond
of a propargyl alcohol in the presence of another alkyne group in the same molecule.
LiAlH4, Et2O
91% OH ð23Þ
Et OH Et
A recent application of LiAlH4 reduction to a chiral propargylic alcohol is shown in Equation

(24), where three functional groups are reduced in the same reaction <2000JOC7627>. In the di-
ynol 12, the two alkyne groups are rendered non-equivalent by the adjacent chiral center, and
selective reduction of one of the alkynes is possible using LiAlH4 (Equation (25)) <2001OL1057>.
OH OH
CO2Et LiAlH4, THF
C13H27 OH ð24Þ
reflux
C13H27 N3 50% NH2
MeO O MeO O MeO O

OH i. LiAlH4, THF OH + OH
ii. Pyr, TsOH, MeOH ð25Þ
Bun Bun
Bun Bun Bun Bun
12 85% 5%
Sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) also reduces propargyl alcohols to

(E )-allylic alcohols, and detailed procedures have been published <1986OS(64)182>. Red-Al has
been employed in the stereocontrolled synthesis of trienes (Equation (26)) <1996SC2831,
1996TL6547, 1999T4353>, and by the same group for the stereoselective reduction of homo-
propargyl alcohols (Equation (27)) <1997SL992>.
HO Red-Al, THF OH ð26Þ
HO
OH 56%
Ph Red-Al, THF
Ph ð27Þ
95% OH
OH
It is also possible to reduce an alkyne, which is remote to a hydroxyl group, using LiAlH4 in
diglyme resulting in (E )-alkenols, although the conditions required are often severe (e.g., 150 C). It
has been found recently that the use of titanocene dichloride as a catalyst allows this reaction to be
carried out in refluxing THF, and results in the opposite stereoselectivity, giving the (Z )-alkenols
(Equation (28)) <2002TL1231>. Interestingly, it was also found that a free hydroxyl group is not
necessary for the success of this reduction: a benzyl protected alcohol, an acetal, and even a simple
dialkylalkyne were reduced to the (Z )-alkenes.
LiAlH4, Cp2TiCl2 (0.1 equiv.)
OH n-C6H13
OH ð28Þ
n-C6H13 THF, reflux
10/1 (Z )/(E )
75%
No catalysis is required for the (E )-selective reduction by LiAlH4 of alkynes which are remote
to a hydroxyl group if they are conjugated with an aromatic ring (Equation (29)). In the seven
examples studied, all were reduced in good yield in refluxing THF, and no trace of the opposite
stereoisomer was observed <2002TL1735>.
OH LiAlH4, THF, reflux

Ph OH ð29Þ
Ph
86%
Similarly, a conjugated diyne 13 bearing a remote hydroxyl group has been reduced first with
LiAlH4 in ether to give (E )-selective reduction of only the alkyne proximal to the hydroxyl group, and
the distal alkyne was then reduced with (Z )-selectivity using Sia2BH (Scheme 2) <2001NJC223>.
OH LiAlH4, Et2O OH
n -C8H17 n -C8H17
13 70%
97% (E )-isomer
i. Sia2BH, THF
n-C8H17 OH
ii. AcOH
85% 99% (Z )-selectivity
Scheme 2
1.12.1.4.3 Other hydride reducing agents

Internal alkynes conjugated to both an ester and a ketone have been reduced using NaBH4 at low
temperature (Equation (21)) <2003TL443>. The reduction is (E )-selective, and the ketone is also
reduced; however, in some cases a minor amount of (Z )-alkenol is produced, which cyclizes to the
corresponding unsaturated lactone.
Hydrosilylation of an alkyne followed by protodesilylation, should, in principle, yield the
alkene, but the conditions required are usually harsh, and removal of the silicon using TBAF
requires elevated temperatures. However, it has been found that ruthenium catalyzed hydrosilyla-
tion of internal alkynes, followed by desilylation using TBAF in the presence of a Cu(I) salt is a
mild and effective method for the reduction to (E )-alkenes (Equation (30)) <2002JA7922>. The
same method has been applied to large-ring cycloalkynes, but using AgF for the desilylation step,
to give the corresponding (E )-cycloalkenes <2002CC2182>.
Et i. (EtO)3SiH, [Cp*Ru(MeCN)3]PF6
Et
(CH2)8OAc
(CH2)8OAc CH2Cl2, 0 °C to rt
ð30Þ
ii. CuI, TBAF, THF
89%
The combination of NaBH4 and dibutylditelluride effects an unusual chemoselective hydro-

metallation of only one alkyne group in conjugated terminal and internal diynes <1995T9839>.
Subsequent removal of the tellurium atom by transmetallation and protonation gives the corre-
sponding conjugated (E )-enynes (Equation (31)).
i. (BuTe)2, NaBH4, EtOH, reflux, 76%
Ph ð31Þ
HO HO
ii. BuLi, THF, –78 °C, then H2O, 69% Ph
Hydrozirconation followed by protonolysis is occasionally used for the reduction of alkynes, and
it has been found useful for the reduction of a macrocyclic diyne to the corresponding (E),(E )-
diene, where hydrogenation using Lindlar catalyst was ineffective <1997JOC5821>.
1.12.1.5 Miscellaneous Reducing Agents

Chromium(II) salts have been used to reduce a variety of terminal and internal alkynes, propargyl
alcohols, and conjugated ynones <1995COFGT(1)501>, and from internal alkynes (E )-alkenes
are usually formed. A particularly simple protocol for the reduction of phenylpropynoic acid to
(E )-cinnamic acid using CrSO4 has been published (Equation (32)) <B-1996MI001>.
CrSO4, DMF/H2O, rt
Ph CO2H Ph ð32Þ
CO2H
During the synthesis of zaragozic acid C, reduction of a conjugated ynone using either CrSO4 or
CrCl2 was problematic, possibly because of the air sensitivity of the Cr(II) reagents, and it was found
that commercially available chromium acetate monohydrate dimer gave higher yields and more
reproducible results <1995JA8106>.
A low-valent titanium alkoxide prepared from Ti(Oi-Pr)4 and i-PrMgCl reacts with alkynes to
form titanocyclopropene complexes, which can be hydrolyzed by water or acid to the (Z )-alkenes
with very high stereoselectivity <1995TL3203> (e.g., Equation (33)). This method has also been
used for the selective reduction of conjugated diynes to (Z )-enynes <2002CC272>, and for
reduction of skipped diynes to the corresponding (Z),(Z )-dienes <1998JCS(P1)1839>.
i. Ti(OPri)4-Pr iMgCl, Et2O, –78 to –50 °C D D

n-C6H13 Me
ii. D2O n-C6H13 Me ð33Þ
100%
>99/1 (Z )/(E )
The combination of sodium methoxide and catalytic amounts of Pd(OAc)2 and Ph3P gives
partial reduction of internal alkynes to (Z )-alkenes in THF, but complete reduction to the
corresponding alkanes occurs simply by changing the solvent to MeOH <2003TL1979>.
1.12.2 CYCLOADDITION REACTIONS TO ALKYNES

As in the previous review <1995COFGT(1)501>, this section includes formal cycloaddition
reactions to alkynes, which may be stepwise, as well as concerted electrocyclic additions. Transi-
tion metal-catalyzed cyclizations have been reviewed in general, including several cyclizations
onto alkynes <1996CRV49, 1996CRV635>.
1.12.2.1 [2+2]-Cycloaddition Reactions

Cycloaddition reactions of alkynes and alkenes give cyclobutenes, and this reaction may proceed via
a photochemical concerted process, or thermally. Photochemical [2+2]-cycloaddition is not always
a satisfactory method for the formation of cyclobutenes, since the product may undergo either
electrocyclic ring opening, or further cycloaddition reactions <1991COS(5)123, 1995COFGT(1)501,
B-1978MI813>. However, photochemical cycloaddition of alkynes to enones works well.
Photochemical cycloadditions of alkynes to quinones are well established <1995COFGT(1)501>,
and this has been extended to homoquinonones (Equation (34)) <2002JA8912>. Unsymmetrical
alkynes react regioselectively, with the selectivity being rationalized on the basis of the favored
products being formed from the more stable biradicals.
O O O
Ph Ph Me
hν (>300 nm)
+ +
C6D6, 42 h ð34Þ
Me Me Ph
O O O
83% 7%
The tetrahydrophthalic anhydride 14 undergoes photochemical [2+2]-cycloaddition with a

variety of alkynes and alkynols in good yields (Equation (35)) <1999T5875>. Other anhydrides
and imides react similarly, and the minor by-product is proposed to arise via a different
pathway, rather than from the major cyclobutene product. A structurally related tetrahy-
drophthalimide 15, which is linked to an alkyne via a silicon tether incorporating a chiral
group, allows an intramolecular cycloaddition, resulting in diastereoselective cyclobutene for-
mation with 4:1 selectivity (Equation (36)) <1997CC1385>. In a simpler achiral system, a
similar bis-alkoxysilane tether has been used to control the regioselectivity of an alkyne–alkene
cycloaddition <1995TL4189>.
OH
OH O O O
O
hν O
+
ð35Þ
O + O
MeCN, 2 h HO
O 14 80–89% O
7–8:1
Ph Ph
Si Pr i Pr i
HO HO
O O O H H
i. hν, MeCN, 5–6 h O O
N N
N O + O ð36Þ
ii. TBAF, THF
H
Pri 38%
O HO
HO
15 4:1
The diastereoselectivities of the photochemical cycloadditions of ethyne to a series of furanones

have been studied, and although the less hindered face of the furanone was favored, the selectiv-
ities were not as high as with ethene <2001TL6695>.
Uncatalyzed thermal [2+2]-cycloadditions usually require a particularly reactive combination
of alkyne and alkene. Electron-rich enamines will react successfully with electron-poor acetylene-
dicarboxylate esters <1986JOC2004>, and several examples have since been reported, some of
which proceed at low temperature (e.g., Equation (37)) <1997OPP541>.
CO2Et CO2Et
N Benzene N CO2Et
+ ð37Þ
5–7 °C, 7 h H
CO2Et 58%
Cyclic enol ethers have also been found to undergo uncatalyzed [2+2]-cycloaddition reactions
to Fischer alkynyl carbene complexes <1999JCS(P1)197>. If the alkyne group is also conjugated
with an alkene, the products can be used in thermal benzannulation reactions <2003JOC537>.
Silyl ketene acetals are sufficiently electron rich to add to electrophilic alkynes. In the example
shown in Equation (38), the best yields are obtained without the use of any catalyst
<1999TL839>. Other workers have found that with acyclic silyl ketene acetals, [2+2]-cycloaddi-
tion products can be obtained with ethyl propynoate and catalytic ZrCl4 <1992JOC6890>,
whereas DMAD results in ring opening of the cylcobutene products <1995BCSJ6890>.
OTMS CO2Et OTMS

O Heat, rt O CO2Et
+ ð38Þ
98%
CO2Et H CO2Et
Allenes undergo [2+2]-cycloadditions reactions with alkynes, and these can be photoche-
mical, catalyzed by transition metals or Lewis acids, or purely thermal <1997JA10869>.
Simple allenes often require high temperatures for thermal cycloaddition; however, oxazol-
idonones bearing an exocyclic allene group have been found to react at a much lower
temperature (Equation (39)) <1997JA10869>. Intramolecular allene–alkyne [2+2]-cycloadd-
itions are also possible, and in Equation (40) the propargyl alcohol group in 16 reacts to form
a chloro-allene in situ, and this then undergoes [2+2]-addition to the other alkyne group
<2001JOC6662>.
·
Ph
80 °C, 11 h O
Ph
O N Ts + ð39Þ
60% O N
O Ts
(Excess)
(Single diastereoisomer)
SOCl2, Pyr Ph Cl
OH ð40Þ
Ph 81%
16
Ketene itself does not generally undergo thermal cycloaddition to alkynes; however, the
reaction of dichloroketene is successful, and the chlorine atoms can be removed from the
product reductively with zinc, to give the same overall result <1990OS(68)32>. The generation
of dichloroketene for this reaction from trichloroacetyl chloride can also be carried out using
zinc and ultrasound, as a convenient alternative to zinc–copper couple <1995SC2781>. Thio-
substituted ketenes, generated by rhodium-catalyzed rearrangement of -diazothiol-esters,
undergo thermal cycloaddition to internal alkynes in moderate yields <2000JOC4375>. Het-
eroatom-substituted alkynes are required in order to obtain higher yields. Carbon suboxide 17
can be viewed as two cumulated ketene units, and in Equation (41) one of these undergoes
cycloaddition to the triple bond of propargyl alcohol, and the other reacts with the
alcohol group to give the bicyclic lactone 18 in modest yield <1998MI680>. Carbon
suboxide has also recently been found to react with internal alkynes to give cyclobutenes
fused to - or -pyrones, or bis-pyrones, depending on the molar ratios of reactants used
<2003JHC321>.
OH O
CHCl3 O
O C C C O + O ð41Þ
–70 °C to rt, 72 h
17
26% 18
[2+2]-Cycloaddition reactions of alkynes can be promoted by Lewis acids. For example,

methyl propynoate undergoes TiCl4-promoted addition to both (Z )- and (E )-disubstituted
allyl silanes, with stereospecific formation of the cyclobutene products (Equation (42))
<1998TL7705>. Cyclic allyl silanes have also been found to undergo cycloaddition to an
electron-deficient alkyne; however both the ring size and the nature of the Lewis acid
were critical, with only the combination of a five-membered ring allyl silane and Me2AlCl
being successful <1996T6685>. Gallium chloride has been used to catalyze one example of
an intramolecular [2+2]-cycloaddition; however, in other related examples isomerized
products are obtained, which are proposed to result from cyclobutene intermediates
<2002JA10294>.
Si(Pri)3
CO2Me MeO2C
TiCl4, CH2Cl2 Si(Pri)3
+ ð42Þ
–70 to –20 °C ,19 h
Me Me
65%
[2+2]-Cycloaddition reactions of alkynes can be catalyzed by transition metal complexes

<1994AG(E)580>, and Jordan and Tam have studied the ruthenium-catalyzed addition of
ethyl phenylpropynoate to a number of norbornenes and norbornadienes <2000OL3031,
2001OL2367, 2002TL6051>. In general, the exo-addition products are favored, and the less-
substituted alkene in substituted norbornadienes reacts preferentially. Some regioselectivity is
possible with substituted norbornenes and norbornadienes, even though the substitutent is remote
(e.g., Equation (43)). A similar indenyl Ru complex has also been used to catalyze [2+2]-
cycloaddition of norbornene with a range of alkynes <2001OM3762>. A cationic Ru-alkylidene
complex gives [2+2]-cycloaddition between dimethyl acetylenedicarboxylate and both ethene and
norbornene; however, between ethene and other alkynes, hydrovinylation reactions occur
<1999OM2043>. Cobalt complexes are also active catalysts for the cycloaddition of a wide
range of alkynes (not just electron-deficient ones) to benzo-fused oxa- and azanorbornenes
<2001JOC8804>.
CO2Et
Cp*Ru(COD) (cat.) Ph CO2Et
AcO + AcO + AcO
THF, 80 °C, 60 h ð43Þ
CO2Et Ph
Ph 89%
2.8:1
An interesting cyclobutene synthesis, which is equivalent to the overall addition of ethene to aryl
acetylenes, is shown in Equation (44), where the ethene equivalent is ultimately derived from an ethyl
Grignard reagent, and the reaction proceeds via organozirconium intermediates <1999JOC8706>.
Br
i. Cp2ZrEt2 (1.2 equiv.), rt, 1 h
Br + MgBr ii. I2 (1.2 equiv.), 0 °C, 2 h ð44Þ
iii. CuCl (1.2 equiv.), THF, rt, 6 h
63%
A number of other transition metal-catalyzed reactions result in the formation of cyclobutenes

from alkynes, even though the other two carbons in the ring do not arise from direct cycloaddi-
tion of an alkene. For example, a ruthenium complex catalyzes cyclodimerization of propargyl
alcohols (Equation (45)), with the intermediate complex reacting with a carboxylic acid to give
alkylidene cyclobutenes <2001AG(E)2912>.
Cp*RuCl(COD) (5 mol.%) OAc

+ Me CO2H ð45Þ
2 Isoprene, 40 °C, 20 h
OH 66% OH
Cyclobutenediones can be formed by transfer of two CO equivalents from iron carbonyls, and
both Fe(CO)5 <1997TL7229> and Fe3(CO)12 <2000TL2719> can be used as precursors.
1.12.2.2 Diels–Alder Reactions

Alkynes can react as dienophiles in the Diels–Alder reaction <B-1990MI001>, although isolated
alkynes are rather unreactive, and generally need to be combined with unusually reactive dienes
<1995COFGT(1)501>. Conjugation of the triple bond, e.g., with phenyl groups, improves the
reactivity, and as with alkenes, electron-withdrawing groups are particularly effective. In this
respect, diethyl and dimethyl acetylenedicarboxylate have been widely used as dienophiles (e.g.,
Equation (46)) <2002JCS(P1)1999>.
CPh3
CO2Me
Ph3C N O N
+ CH2Cl2, rt, 5 days
O CO2Me ð46Þ
21%
CO2Me
CO2Me
As in the example above, furans are reactive electron-rich dienes, and have been widely
employed in Diels–Alder reactions. This has been reviewed <1997T14179>, including the use
of both alkynes and benzynes as dienophiles, in both inter- and intramolecular fashion. Hexa-
fluorobutyne is an activated alkyne which has been previously used in Diels–Alder reactions
<1995COFGT(1)501>, and it reacts well with furans (Equation (47)) <1996JCS(P1)1095>, and
with cyclopentadienes <2001BCSJ1673>. A carbonyl homolog of diethyl acetylenedicarboxylate
19 has been prepared, with an extra carbonyl group between the alkyne and one of the ester
groups, and this reacts as a dienophile with an isobenzofuran (Equation (48)) <1995S236>.
O CF3 O
100–200 °C F3C CF3
+ ð47Þ
F3C 85% F3C
CF3 CF3
CF3
Ph O CO2Et Ph O
Benzene, rt, 30 min CO2Et
O + O ð48Þ
60% CO2Et
Ph CO2Et Ph
19
A more recent type of dienophile activating group is a Fischer carbene complex conjugated
with the alkyne group, and examples of this kind of dienophile have been reacted with a variety of
2-aminodienes (e.g., Equation (49)) <1998CEJ2280>.
MeO W(CO)5 W(CO)5
+ THF, rt OMe ð49Þ

71%
N N But
But
O O
Unactivated alkynes usually require very high temperatures before they will undergo Diels–
Alder reactions; however, 1-hexyne reacts with a fluorinated cyclohexadienone at 70 C (Equation
(50)) <2002RJOC196>. The activated dienophile methyl propiolate also reacts in similar yield
with a related, but unfluorinated dienone <1999SL225>. A different cyclic diene is the lactam in
Equation (51), where a reactive cyclic benzyne is employed as the dienophile <1997H15>. An
optimized example of an unactivated alkyne reacting with cyclopentadiene uses a combination of
high temperature (260 C) and elevated pressure (35 bar) <1995JOC852>; attempts to promote
the reaction using Lewis acids led to polymeric products.
O Cl F
F Cl O
Heat, 70 °C F
F + F ð50Þ
MeO F Bun 87%
F MeO F Bun
O
Pri
CH2Cl2 N
+ ð51Þ
N O 62%
Pri
Nonactivated alkynes are normally poor dienophiles; however, 1-arylalkynes have been found
to react with ortho-quinone dimethanes formed in situ under microwave irradiation, to give
quinoxalines (Equation (52)) <2002SL2037>.
Me
N CHBr2 N Me
NaI, DMF
+ ð52Þ
N CHBr2 Microwave, 15 min N Ph
Ph 43%
Unactivated internal (e.g., dialkyl) alkynes will react as dienophiles under mild conditions if a
transition metal catalyst is employed. Simple dienes react in good yields using a cobalt(I) catalyst
(Equation (53)), and the regioselectivity with unsymmetrical alkynes is controlled by steric effects
<2001TL2783>. This reaction has been extended to using 1,3-diynes as the dienophile component
<2002S686>. Alkoxy-substituted dienes have also been studied and the adducts from 1-alkox-
ydienes undergo elimination to give aromatic products; however, the adducts from 2-alkoxydienes
can be isolated as the 1,4-dihydrobenzenes <2002SL1081>. In related examples, where reductive
generation of the cobalt catalyst with borohydride also gives some reduction of the alkyne, zinc
powder can be used as the reducing agent <2003SL241>.
Et CoBr2(dppe) (3 mol.%)/ZnI2/Bu4NBH4
n
Et
+ ð53Þ
Me CH2Cl2, rt, 4 h
Me Et
Et 99%
Enantioselective catalysis of Diels–Alder reactions involving alkynals has been achieved

using boron coordinated with chiral alkoxy ligands <1997JOC3026>. Three catalysts have
been reported, and the best example, in terms of combining high yield with high enantios-
electivity, used a doubly activated alkyne, together with a binaphthol-derived ligand
(Equation (54)).
O
O
B (10 mol.%)
O OH
CHO ð54Þ
CHO
+
CH2Cl2, –78 °C
CO2Et CO2Et
97% 95% ee
Hetero-Diels–Alder reactions with alkynes are possible, although within the scope of this
chapter, the heteroatom is restricted to an internal position of the diene. Acyclic 2-aza-1,3-
dienes with electron-donating substituents have been reacted with DMAD <1996T10095>,
and conformationally restricted cyclic 2-azadienes react under very mild conditions in the
presence of a Lewis acid catalyst (Equation (55)) <2000SL713>. Two heteroatoms are
incorporated into the 1,3-diene in the inverse electron demand Diels–Alder reaction of
1,2,3,4-tetrazines with phenylacetylene, where the products also aromatize by loss of nitrogen
(Equation (56)) <1998JOC6329>. Intramolecular versions of this reaction have also been
achieved.
AlCl3, CH2Cl2
Me O O Me Ph
+ ð55Þ
0 °C, 20 min, –CO2
Cl N Cl Ph Cl N Cl
72%
NHAc NHAc NHAc

N N Mesitylene N Ph
+ N
N +
N N 140 °C, 60 h, –N2 N ð56Þ
Ph
Ph
SMe 87% SMe SMe
2:1
Wender has developed a ‘‘homo-Diels–Alder,’’ or [5+2]-cycloaddition of vinylcyclpropanes

with alkynes, first in an intramolecular fashion using Wilkinson’s catalyst <1995JA4720>. This
catalyst was not successful for intermolecular examples, but these have now been achieved using a
rhodium carbonyl catalyst, together with a silyloxycyclopropane as the 5-atom component
(Equation (57)) <1998JA10976>.
OTBDMS O
OTBDMS CO2Me
[Rh(CO)2Cl]2 (5 mol.%) 1% HCl
+ ð57Þ
CDCl3, 40 °C, 2 h EtOH
CO2Me MeO2C CO2Me >90% MeO2C CO2Me
Intramolecular Diels–Alder reactions are possible using alkynes as the dienophile

<1995COFGT(1)501>. Activation of the alkyne with an electron-withdrawing group is beneficial,
as for intermolecular reactions, and so ester and amide linkages of alkynoic acids often work well.
An amide linkage was used in the recent example shown in Equation (58), which employs a furan
as the diene and proceeds under thermal conditions, whereas Lewis acid catalysis using Me2AlCl
was not successful <2002TL943>. Surprisingly, the ester analogs showed the opposite behavior,
with thermal conditions giving only recovered starting materials, but Me2AlCl resulting in
formation of the Diels–Alder adducts in good yield.
Ph
Ph
O PhMe, 200 °C O
O ð58Þ
81%
O N CONHBn N
But CONHBn
But
The thermal intramolecular reaction shown in Equation (59) also used an ester linkage, and
was used as a key step in the synthesis of forskolin <1996TL1015>. Lewis acid conditions failed
here, and carefully developed thermal conditions were required. Other workers found that the
closely related reaction with R = H gives only a 10% yield, and this was ascribed to conforma-
tional flexibility of the diene, which could adopt the unproductive s-trans conformation
<1998JCS(P1)1269>. Replacement of the gem-dimethyl group on the cyclohexane with a spiro-
fused 1,3-dithian improved the yield to 65%, in refluxing THF.
O
O
O O
n-Decane, reflux, 14 h R
R
ð59Þ
(R = Me, 56%)
Restriction of available conformations has also been used in the example shown in Equation (60),
where the diester linkage reduces conformational flexibility as a result of the trans-disubstituted
cyclohexane ring, and a quantitative yield is obtained <1999T15045>.
O
H O
H H
O PhMe, 150 °C, 24 h
O ð60Þ
O O
Me O
H 100% Me
H
1:1 mixture of diastereoisomers O
Unactivated alkynes have been found to react thermally with 2-sulfinyldienes, in intramolecular
reactions where diastereocontrol is effected by the chiral sulfinyl group <2003CC2476>. Transi-
tion metal catalysis can also be used to facilitate the intramolecular reaction of unactivated
alkynes. A nickel(0) catalyst was employed by Wender in the reaction shown in Equation (61),
which is directed toward steroid synthesis <1995JOC2962>. The single chiral center in the linker
completely controlled the formation of the two new chiral centers, and the Ni catalyst was
essential, since only decomposition was observed under thermal conditions.
OMOM OTMS
Ni(COD)2, P(O-iC3HF6)3
ð61Þ
C6H12, 80 °C H
TMSO 90% MeO
MeO OMOM
Intramolecular Diels–Alder cyclization of unactivated alkynes can also be catalyzed by rho-

dium, and substrate 20 shown in Equation (62) has been cyclized using a number of catalysts,
with similar yields using either rhodium <1998TL2075> or palladium systems <1998TL3047>.
Intramolecular Wender-type [5+2]-cycloadditions (see above) are also possible using this sub-
strate. Use of a chiral phosphine ligand on a rhodium catalyst results in asymmetric cyclization of
20 in up to 95% ee <1998JOC10077>. A similar substrate has been cyclized thermally in a low
yield whereas an iridium catalyst improved this to 71%, and a chiral phosphine ligand on the
iridium complex resulted in enantioselective cyclization <2002SL1681>. The oxygen in 20 can
also be replaced by a C, or an N of a sulfonamide <2000TL8041>.
O [Rh(DIPHOS)(CH2Cl2)]SbF6
O
CH2Cl2, 25 °C, 6.5 h ð62Þ
H
20
75%
A final example of intramolecular reactions is a hetero-Diels–Alder reaction with inverse

electon demand, between a 2-azadiene system in a pyrazinone ring, and an unactivated alkyne
attached as a propargyl ether (Equation (63)) <1995T12463>. The pyridinone product is pre-
sumably formed by loss of cyanogen chloride from the initial Diels–Alder adduct. Lengthening
the linker by one atom, or replacing the alkyne terminal hydrogen by a methyl or phenyl group,
all retarded the rate of cyclization.
Bn Bn
Bn
O N
N O C6H5Br N O
Cl ð63Þ
reflux
Cl N O 2.5 h N O
O
98%
1.12.2.3 1,3-Dipolar Cycloaddition Reactions

1,3-Dipolar cycloadditions which generate alkenes with no attached heteroatoms are restricted to
1,3-dipoles where atoms 1 and 3 are both carbons. The most common examples involve azo-
methine and carbonyl ylides <1995COFGT(1)501, B-1984MI001>. A recent monograph in the
‘‘Practical Approach in Chemistry’’ series gives detailed protocols for the preparation of several
types of azomethine and carbonyl ylides, as well as their addition to alkynes <B-2002MI009>.
Recent developments have been mainly in methods for generations of ylides. Azomethine ylides
can be generated by thermal or photochemical ring opening of aziridines, which usually also
contain an anion-stabilizing group. Use of microwave irradiation has been found to accelerate the
thermal reactions; for example, the cycloaddition shown in Equation (64) requires only 10 min,
instead of 18 h using only thermal conditions <1996TL4203>.
CO2Me
Microwaves
N ð64Þ
+ Bz Ph
10 min
N
CO2Me 70%
Bz Ph MeO2C CO2Me
The photochemical ring opening of some 2,3-dibenzoylaziridines has been studied, together
with the trapping of the intermediate azomethine ylide with DMAD to give dihydropyrroles
<1996JOC4240>. 2-Aryl-3-benzoylaziridines also undergo the same reaction. Similarly, a
-aziridinylacrylonitrile has also been found to undergo photochemical ring opening, and the
trapping of the generated azomethine ylide with methyl propiolate is regioselective (Equation (65))
<2000JCS(P1)3022>.
Bn
Bn CO2Me hν, MeCN N
N CN ð65Þ
+ rt
CN
49%
CO2Me
An alternative to direct photochemical ring opening is photoinduced electron transfer (PET)

reaction of aziridines, to give a radical cation in the presence of 9,10-dicyanoanthracene as an
electron acceptor. Using this method, a 2,3-diphenylaziridine gives a moderate yield of the [3+2]-
cycloaddition product with DMAD; however, this is much better than with direct irradiation
<1997T14297>.
Thermal decarboxylation of -lactam-based oxazolidinones gives azomethine ylides at rela-
tively low temperatures; these can be trapped by alkenes or alkynes to give carbapenems
(Equation (66)) <1997JA2309>.
H
O H
Ph
O MeCN
N + Ph
80–100 °C N ð66Þ
O
CO2PNB 41% O
CO2PNB
PNB = p -nitrobenzyl
An interesting preparation of azomethine ylides from two neutral species involves the reaction
between a diazanorcaradiene and tetracyanoethylene oxide (Equation (67)) <1999T9515>. The
ylides undergo cycloaddition to strained alkynes such as cyclooctyne <2000T5443>, and also to
DMAD.
CN Ph MeO2C CO2Me
– + CO2Me
Acetone NC Ph
NC N H
+ N ð67Þ
N reflux, 5 h NC
88% N
CO2Me H
Ph
Ph
Fluoride-induced desilylation of -silyliminium ions has often been used to generate azo-
methine ylides, and a recent example also describes the cycloaddition of the ylide to DMAD
<1998JCR(S)82>. In the example shown in Equation (68), O-silylation of a vinylogous amide is
combined with -desilylation in order to generate the azomethine ylide <2002AG(E)1778>.
Generation of azomethine ylides from neutral imines and trapping by DMAD has been achieved
in a one-pot process involving silylation at the C, and then on N, followed by C-desilylation
<2003TL1603>. Most azomethine ylides used synthetically also incorporate an anion-stabilizing
group; however, an unstabilized example is shown in Equation (69), generated by SmI2-induced
loss of two tosyl groups <1999SL590>.
Et
CO2Me MeO2C Me
O Tf2O, Bun4SiF2Ph3 Et
+ MeO2C
ð68Þ
TMS N Me CHCl3, rt to 65 °C N OTf
Bn
Bn CO2Me 68%
Ph Ph Ph
Ts N Ts SmI2
+ ð69Þ
n -C6H13 THF, HMPA N
Ph 77% n -C6H13
Chiral azomethine ylides generated from morpholin-2-ones and paraformaldehyde react with both
DMAD (Equation (70)) and methyl propiolate, with good induction at the newly formed stereocenter
<1995TA2465>. In the example shown, phenylglycine is the origin of the template; however, chiral
morpholinones derived from alanine also undergo this cycloaddition <2001EJOC3133>.
H
CO2Me
Ph N Ph CO2Me
(CH2O)n
+ Ph N CO2Me ð70Þ
O O Xylene, mol. sieves, heat Ph
CO2Me 79% O O
Carbonyl ylides can be formed thermally at moderate temperatures (refluxing benzene) by extrusion
of a nitrogen molecule from silyloxy- or alkoxy-substituted oxadiazolines <1995TL7591,
2003TL5029>, and they readily undergo cycloaddition to acetylenedicarboxylates (e.g., Equation
(71)). A symmetrical non-stabilized carbonyl ylide has been generated from an (-iodoalkyl) silyl
ether using a combination of Sm(0) and HgCl2, and reacts stereoselectively with alkynes to give 2,5-
dihydrofurans <1996JA3533>. Exactly the same ylide formation and addition to alkynes has also been
achieved using Mn and a catalytic amount of PbCl2 <1997JOC8612>. The simplest possible comple-
tely unsubstituted carbonyl ylide can be prepared from bis(chloromethyl) ether (Equation (72)), by the
action of either Sm(0) + I2 <1996TL9241>, or alternatively Mn + catalytic PbCl2 <1997JOC8610>.
OMe OMe
CO2Et
OMe PhH, reflux OMe
+ CO2Et
N ð71Þ
O N 77% O
CO2Et CO2Et
OBn
OBn
Sm, I2, THF, rt ð72Þ
Cl O Cl +
92% O
Enantioselective cycloaddition of carbonyl ylides to alkynes has been accomplished by generation

of the ylides from diazocarbonyl precursors, using chiral rhodium catalysts. Equation (73) shows
intramolecular addition to an alkyne, and the same reaction can also be achieved with an extra C
atom in the alkyne tether <2003JOC6153>. The corresponding intermolecular cycloaddition to
phenylacetylene is also possible, in up to 61% ee <2003TA921>, and the same cycloaddition using
a carbonyl ylide generated from an -aryl--diazodiketone proceeds in up to 76% ee
<2002TL3927>. Related asymmetric cycloadditions onto DMAD have been achieved by Hashi-
moto and co-workers, where the carbonyl ylides are generated by rhodium-catalyzed intramolecular
cyclization of -diazodiketone onto ketone or ester groups <1999JA1417, 2000TL5931>.
C12H25
O Rh
O
P
O O Rh
ð73Þ
C12H25 4
O
N2 Hexane, –15 °C O
O ButO2C O
CO2But 42%
85% ee
The chemistry of carbonyl ylides generated from rhodium carbenes has been reviewed, includ-
ing cycloadditions to alkynes <1996CRV223>.
1.12.2.4 Ene Reactions

Ene reactions between an alkyne and an alkene usually involve the alkene component reacting as the
enophile, and generate 1,4-dienes <1991COS(5)1, 1995COFGT(1)501>. Alkynes are more reactive
than alkenes, although the thermal reaction can still require elevated temperatures of up to 200 C,
which limits the usefulness of this reaction in synthesis. Lewis acid catalysis allows ene reactions to
occur at room temperature using alkynes activated with a conjugated carbonyl group, although
[2+2]-cycloaddition is then often a competing reaction <1991COS(2)561, 1995COFGT(1)501>.
Using Me2AlCl as a Lewis acid, the reaction of butyn-2-one with allyl silanes has been found to
give exclusively the ene product for reaction with a six-membered cyclic allyl silane, but mostly the
[2+2] product using a 5-membered analog <1996T6685>.
A major development in the ene reaction of alkynes has been the introduction of ruthenium
catalysis <1998SL1, 2001CRV2067>, which allows reaction between unactivated alkynes and
alkenes. The catalyst initially employed was RuCl(Cp)(COD) <1995JA615>, which allowed
reactions to be performed at 65–100 C, and gave fairly good regioselectivities (typically 3 to
6:1) for branched versus linear products (e.g., Equation (74)).
n -C6H13
n - C6H13 n -C5H11 47%
CpRuCl(COD)
n -C5H11 ð74Þ
+ +
DMF/H2O
100 °C, 2 h n -C6H13 n -C5H11 9%
Reactions involving alkynoate esters result in the new CC bond being formed to the ester
carbonyl group, in contrast to the normal thermal behavior <1999JA1888>. The more reactive
cationic Ru complex [CpRu(MeCN)3]+PF 6 promotes the reactions at rt, with improved regio-
selectivities, and also permits reaction with 1,1- and 1,2-disubstituted alkenes, which were unreac-
tive with the original catalyst <1999TL7743, 2001JA12504>. A wide variety of other functional
groups can be tolerated within the substrates. The same catalyst can also be used for the reaction
between internal alkynes and terminal alkenes, which forms trisubstituted alkenes with good
control over the double-bond geometry, and moderate-to-high sterically controlled regioselectvity
with respect to the internal alkyne (Equation (75)) <2002CEJ2341>.
O
–
[CpRu(MeCN)3] + PF6
+ ð75Þ
DMF, rt, 4 h
OH
91%
O OH
Intramolecular ene reactions result in the formation of a new ring, and in most of the reactions
involving alkynes, five-membered ring formation has been involved, with relatively few examples
of six-membered ring formation <1978JOC2161>. Unactivated alkynes often require very high
temperatures for this reaction (e.g., up to 225 C); however, the allyl amine shown in Equation
(76) cyclizes to the pyrrolidine at only 110 C, and it is proposed that steric buttressing by the
bulky trityl group accelerates this reaction <2002JCS(P1)1999>. Even milder conditions are
successful for the ene reaction of the enamine-amide shown in Equation (77), which cyclizes to
a spirolactam at 80 C <1997JOC7106>.
Toluene, reflux ð76Þ

Ph3C N Ph3C N
88%
N O N O
80 °C, 1 h Me
Me N ð77Þ
N
95%
Just as for the intermolecular reaction, intramolecular ene reactions can also be catalyzed by
transition metals, and this has been a very active area recently <1998SL1, 2001CRV2067,
2002CRV813>. Ruthenium catalysts are effective for the formation of both carbocyclic
<1999TL7743, 2000JA714> and heterocyclic rings (e.g., Equation (78)) <2000JA6491>. Several
other transition metals are also effective catalysts for the ene reaction of 1,6-enynes. The reaction
shown in Equation (79) is catalyzed by a titanocene complex <1999JA1976>, and a very similar
susbtrate undergoes the same process using PtCl2 <2001JA10511>. Ene-type cyclizations of
allene-ynes are catalyzed by rhodium complexes, and have been used to form cross-conjugated
unsaturated six-membered carbocylic <2002JA15186> and heterocyclic rings <2003SL268>.
Ph
Ph
O Rh2Cl2(DPPB)2-AgSbF6 (cat.)
O ð78Þ
ClCH2CH2Cl
84%
Me
EtO2C Me
Ti(Cp)2(CO)2 (cat.) EtO2C
EtO2C ð79Þ
PhMe, 105 °C EtO2C
97%
Chiral phosphine ligands are very effective in promoting enantioselective ene-type processes,
and BINAP in combination with RhCl2(COD)2 and AgSbF6, has been used to form tetrahydro-
furans <2002AG(E)3457>, lactones <2002JA8198> and lactams <2002AG(E)4526>, all in
>99% ee (e.g., Equation (80)). This catalyst system is an improvement on earlier work, which
employed DuPHOS, and other phosphine ligands <2000AG(E)4104>. Similar enantioselective
cyclizations can also be achieved using a Pd(II) salt, in combination with either BINAP
<2001AG(E)249>, or an N,P-ligand containing a chiral oxazoline <2003EJOC2552>.
Ph
Ph
O [RhCl(COD)]2-(R )- BINAP (cat.), AgSbF6
O ð80Þ
ClCH2CH2Cl, rt
Prn 96% >99.5% ee
1.12.2.5 [3+2]-Cycloaddition Reactions

[3+2]-Cycloaddition reactions to alkynes result in cyclopentene formation, and there are several
examples of addition of trimethylenemethanes, which are formed by metal-catalyzed ring opening
of alkenylcyclopropanes <1995COFGT(1)501>. This approach has recently been developed to
realize intramolecular reactions of the type shown in Equation (81), where both the initial alkylation
and the subsequent [3+2]-cycloaddition are promoted by the same Pd catalyst, in a one-pot tandem
sequence <2003JA9282>. An alternative approach to a trimethylenemethane equivalent is to use a
phenylsulfonyl-stabilized carbanion, as shown in Equation (82), which undergoes conjugate addi-
tion to an activated alkyne, followed by ring closure to the cyclopentene product <2000TL5583>.
Pd2(dba)2 (8 mol.%)
Na+ – O
+ O
TsO P(OPr i)3 (27 mol.%) ð81Þ
O Dioxane, 20 °C, 10 min
TBDMS OTBDMS
51%
TBDMSO + BunLi Ts
CO2Et Cl Ts ð82Þ
THF–DMPU
48% TBDMSO CO2Et
The first example of the [3+2]-cycloaddition of an oxyallyl cation to an alkyne has been
reported <1995JOC1104>, and this results in the formation of a cyclopentenone (Equation
(83)). The reaction works well with activated alkynes such as phenylethyne and diphenylethyne,
but gives no cycloaddition product with 1-octyne.
O O
Fe(CO)5 (cat.)
+ PhO2S SO2Ph ð83Þ
Ph
TiCl4 (cat.), CH2Cl2
92% Ph
1.12.2.6 The Pauson–Khand Reaction

The Pauson–Khand reaction is the formal [2+2+1]-cycloaddition between an alkyne, an
alkene, and carbon monoxide, to yield a cyclopentenone <1991OR1>. Until recently, the
reaction was generally promoted by Co2(CO)8 at elevated temperatures (Equation (84)), and
gave good regioselectivity with respect to terminal alkynes, but little regioselectivity with
respect to alkenes in the intermolecular reaction. The intermolecular reaction is also limited
in scope with respect to the alkene, with only strained alkenes giving good conversion.
Intramolecular reactions work well, usually to give a five- or six-membered ring fused to the
cyclopentenone; however, variation of the nature of the tether has also allowed formation of
medium rings <2004CSR32>. The Pauson–Khand reaction has been an exceptionally active
area of research over the last few years, with several hundred papers appearing since 1995, and
only a few highlights are presented here; however, several recent reviews are available
<2000T3263, 2003AG(E)1800, 2004CSR32>.
R1 O
R3 R4 Co2(CO)8 1
R3
R R4
+ ð84Þ
Heat R5
R2 R5 R6 R2
Hydrocarbon or R6
ether solvent
The reaction can be accelerated by adsorption onto dry solid supports, and also by the use of
additives such as amine oxides, which have recently been used anchored to a solid support
<2000SL1573>. Cyclohexylamine has been found to work particularly well for intramolecular
cases (e.g., Equation (85)), whereas sulfides are more effective for intermolecular reactions
<1997AG(E)2801, 1999SL771>. The addition of molecular sieves improves conversions
<1999OL1187>, and this is also effective in the catalytic reaction <2002TL5763>.
Co2(CO)6
c-C6H11NH2 (3.5 equiv.)
O ð85Þ
83 °C
79%
A major goal in this field recently has been to achieve catalytic reactions <2003AG(E)1800>.
Livinghouse introduced a significant development with the use of catalytic amounts (0.05 equiv.)
of high-purity Co2(CO)8 together with only 1 atm of CO, under carefully controlled thermal
conditions (Equation (86)) <1998TL7637>. The need to use high-purity Co2(CO)8 can be avoided
by the use of cyclohexylamine as an additive <2001JOC3004>. A more stable catalyst than
Co2(CO)8 is obtained when one of the CO ligands is replaced by Ph3P <2002T4937>; the
resulting Ph3PCo2(CO)7 catalyst can be stored in air, and is effective under 1 atm of CO. A
polymer-supported version of this catalyst has also been reported <2000CC305>. A variety of
heterogeneous catalysts for the Pauson–Khand reaction has been reported by Chung and
co-workers, including the use of cobalt nanoparticles on a charcoal support <2002OL3983>,
and also an Rh/Co heterobimetallic nanoparticle, which allows the use of unsaturated aldehydes
as both the alkene component and also the source of CO <2004OL1183>. Other groups have also
reported the use of aldehydes as a source of CO, thus obviating the potentially hazardous use of
the toxic gas <2002JA3806, 2002JOC7446>.
EtO2C Sublimed Co 2(CO)8 (5 mol.%) EtO2C

O ð86Þ
EtO2C CO (1 atm) DME, 60–70 °C EtO2C
90%
Complexes based on metals other than cobalt can also serve as catalysts for the Pauson–Khand
reaction, and a commercially available titanium species, Cp2Ti(CO)2, has been found to be
effective for intramolecular cyclization of enynes at low pressures of CO <1999JA5881>. A
chiral titanocene complex promotes an enantioselective version of this cyclization in selectivities
of 87–96% ee <1999JA7026>. The same group has also achieved asymmetric reactions using the
original cobalt complex Co2(CO)8 together with a chiral chelating bis-phosphite, but the enantio-
selectivities are more modest (up to 75% ee) <2002JOC3398>.
The rhodium complex [RhCl(CO)2]2 is particularly effective for intramolecular cyclizations
involving electron-deficient alkenes and alkynes <2001JOMC(624)73>, and several other Rh(I)
complexes have also been utilized in the Pauson–Khand reaction by Jeong and co-workers
<2002PAC85>. The same group has also reported asymmetric intramolecular reactions using
the same Rh(I) complex and (S )-BINAP as the chiral ligand (Equation (87)) <2000JA6771>. An
iridium complex Ir(COD)Cl2 has been used in a very similar asymmetric cyclization to that in
Equation (87), with TolBINAP as the chiral ligand, with an enantioselectivity of 93% ee
<2000JA9852>.
(S )-BINAP (9 mol.%)
[RhCl(CO)2]2 (3 mol.%)
O O O
AgOTf (12 mol.%) ð87Þ
CO (2 atm) THF, 130 °C
86% ee
85%
The use of chiral auxiliaries in the Pauson–Khand reaction has been studied for a number of
years. Several recent examples lie outside the scope of this chapter, because the alkyne is attached
to the auxiliary by a heteroatom, but an intramolecular cyclization of alkenyl sulfoxides gives
good diastereoselectivities, although the sulfoxide auxiliary is destroyed by reductive removal
(Equation (88)) <2002EJOC2881>.
O But O
S* But
H S
Co2(CO)8 ð88Þ
O O
80 °C, 50%
96% de
1.12.2.7 Cyclotrimerization of Alkynes

The transition-metal catalyzed [2+2+2]-trimerization of alkynes is an effective method for the
formation of polysubstituted benzene rings (e.g., Equation 89) <1988CRV1081>. Recent develop-
ments have concentrated on the problem of regioselectivity in the formation of the benzene ring
<2000CRV2901>, which is particularly difficult when starting from three separate alkyne components.
R1 R1
Cat.
R2 ð89Þ
heat
R2 R3
R3
One approach is to make the reaction partially intramolecular, by tethering two of the alkyne
units together; for example, aminodiynes with 3- or 4-atom tethers can be cyclized using
Ni(PPh3)4 <1997H443> or Wilkinson’s catalyst <1999AG(E)2426>. Related oxygen-tethered
examples cyclizing onto substituted terminal alkynes have been found to be regioselective in
generating the meta-substituted product (e.g., Equation (90)) <1995JA6605>. The ruthenium
catalyst Cp*RuCl(COD) has been shown very recently to catalyze the cyclization of unsymme-
trical 1,6-diynes onto alkynes at ambient temperature, to give bicyclic benzenes with very good
regioselectivity, and the same catalyst also trimerizes ethyl propiolate in 89% yield, giving a 61:28
ratio of regioisomers (Equation (89), R1 = R2 = R3 = CO2Et) <2003JA12143>.
Me
Me
+ RhCl(PPh3)3 (cat.)
O O
54% OH ð90Þ
OH
Single isomer
Biaryls have been prepared in good yields using acetylene itself as two of the components, in a
nickel(0)-catalyzed reaction (Equation (91)) <1999TL5231>. In the palladium-catalyzed example in
Equation (92), all three alkyne units bear electron-withdrawing groups, and this has been extended
to a fully intramolecular case, with all three alkyne units tethered together <1999TL5035>.
CO2Me
+ Ni(acac)2 (cat.)
CO2Me ð91Þ
OMOM PPh3, DIBAL-H OMOM
(1atm) 94%
CO2Me
CO2Me
CO2Me Pd(0) (cat.) CO2Me
O + O ð92Þ
CO2Me 78% CO2Me
CO2Me
CO2Me
Benzynes can undergo the cyclotrimerization reaction, and 3-methoxybenzyne undergoes

the palladium-catalyzed formation of a triphenylene with high regioselectivity
<1998AG(E)2659>.
An alternative approach to the regioselectivity problem is to first form a conjugated enyne,
which can then undergo palladium-catalyzed [4+2]-cyclization, either with itself, or with another
alkyne component. This approach has been extended to a ‘‘one-pot’’ palladium-catalyzed process
where the enyne is formed by addition of a terminal alkyne to an ynoate ester, followed by [4+2]-
cyclization onto a diyne, giving tetrasubstituted benzenes as single products (e.g., Equation (93))
<2001JOC2835>.
Me CO2Et
Me CO2Et Bu Bu Me Ph
Pd(0) (cat.)
+ ð93Þ
EtO2C
Ph Ph
Bu Bu
54%
Benzenes can also be assembled from three alkyne units using stoichiometric quantities of
titanium or zirconium reagents, to generate first a metallopentadiene from two alkyne units,
followed by reaction with the third alkyne. A divalent titanium reagent prepared from
Ti(O-iPr)4 and i-PrMgCl has been reacted with three different alkyne units in this manner
<2001JA7925>, and has also been used to cyclize unsymmetrical diynes onto another alkyne
<2003JOC4980>.
1.12.3 IONIC ADDITIONS
1.12.3.1 Hydrometallation of Alkynes Followed by CC Bond Formation

Hydrometallation of alkynes generates alkenyl metal species (in the same processes discussed
above in Section 1.12.1.4), which can then undergo replacement of the metal atom with C. This
section will concentrate on examples where the emphasis is upon formation of a substituted
alkene by overall addition of H and C to the alkyne, rather than isolation of the intermediate
alkenyl metal compounds.
1.12.3.1.1 Hydroboration followed by CC bond formation

Alkenylboranes formed by hydroboration of alkynes can undergo a variety of reactions
replacing the CB bond with a CC bond <1995COFGT(1)501>. This process is most
often carried out on terminal alkynes, because of problems of regioselectivity in the hydro-
boration step with internal alkynes. A particularly important class of reactions is that of
palladium-catalyzed cross-coupling of alkenylboranes (or boronates) (Miyaura–Suzuki cou-
pling), and this has been reviewed <1995CRV2457>. The coupling is commonly performed
with alkenyl halides, resulting in a synthesis of conjugated dienes with retention of configura-
tion of the alkene geometry at both components, although activated (allylic and benzylic) alkyl
halides can also be used. A particularly efficient procedure involves hydroboration of a
terminal alkyne with catecholborane to give the alkenylborone, followed by palladium-
catalyzed coupling with an alkenyl halide <1995CRV2457>, and this has been used in the
synthesis of leukotriene B3 (Equation (94)) <1998T4327>. 1-Bromoalkynes can also be used as
the coupling partner to give (E)-enynes, and this has been used in the synthesis of sex
pheromone components <1999S107>. An alternative method for the preparation of (E )-
enynes involves the Cu(II)-catalyzed coupling of alkenylboranes with alkynylcopper com-
pounds, both of which are prepared in situ <1998CC807>. Recently, satisfactory conditions
have been found (using tricyclohexylphosphine as a ligand for Pd) for coupling reactions with
-bromoamides <2003TL7249>, which have proved problematic in the past.
OTBDMS
n - C8H17
i. Catecholborane OTBDMS OTBDMS
+ ð94Þ
CO2Me
ii. Pd(PPh 3)4(cat.) n -C8H17
OTBDMS
aq. NaOH
Br CO2Me 57%
Nickel complexes can also be used as catalysts for the coupling steps. Ni(acac)2 has been used
for the conjugate addition of alkenylboranes to ,-unsaturated ketones <1996SC2503>, and
NiCl2(PPh3)2 has been used for the coupling of alkenylborates to allylic acetates <1998TL601>.
The reaction of (E )-alkenyldialkylboranes with I2/NaOH, which is known to give (Z )-alkenes
with migration of an alkyl group from boron, has been extended to the reaction of alkenylborones
(prepared by hydroboraton of terminal alkynes using catecholborane) with Grignard reagents and
I2/NaOH (Equation (95)) <1995T2743>. This allows a greater variety of alkyl groups to be
incorporated into the product alkene.
i. Catecholborane
n -C8H17 + PhMgBr
n -C8H17 Ph ð95Þ
ii. I2, aq. NaOH
89%
Hydroboration of ,-alkynyl ketones with dicyclohexylborane gives alkenylboranes which

rearrange to boron enol ethers. These then undergo further aldol reaction, either with an excess
of the starting ketone <1999TL37>, or with an aldehyde, added as a second carbonyl component
(Equation (96)) <1999JOC5822>.
O
O (c -C6H11)2BH Bun But
n +
Bu EtCHO ð96Þ
But THF, 0 °C to rt, 1 h
OH
100% Et
Alkenylboranes can be transmetallated in situ by Et2Zn, and the resulting alkenylzinc com-
pounds undergo asymmetric addition to aldehydes in the presence of chiral ligands. A chiral
aminoalcohol derived from isoborneol was used for the intramolecular version in Equation (97)
<2001JOC4766>, and a similar method was used for intermolecular reactions to generate allylic
alcohols for the synthesis of -amino acids <2002JA12225>. Ligands based upon chiral
[22]paracyclophanes have also proved to be useful in the intermolecular reaction, particularly
with difficult substrates <2001OL4119>.
HO
i. (c -C6H11)2BH, hexane
O
ii. Et 2Zn
ð97Þ
OH
(cat.)
NMe2
60% 88% ee
1.12.3.1.2 Hydroalumination followed by CC bond formation

Alkenylalane intermediates derived from addition of aluminum hydride reagents to alkynes can
be reacted with a variety of C-centered electrophiles, with retention of stereochemistry at the
alkene <1984OR375, 1995COFGT(1)501>. The most often used combination is a terminal
alkyne and DIBAL-H, which gives an alkenylalane which reacts well only with reactive electro-
philes. Ni- and Pd-catalyzed cross-couplings are also possible. Addition of methyllithium to the
alane generates a more reactive alanate, which reacts with a wider range of electrophiles.
The alkenylalane derived from reaction of DIBAL-H with 1-pentyne undergoes Pd(0)-catalyzed
coupling with -bromoacrylates (Equation (98)), and this has been used in the synthesis of
pheromones <1996SC3297>.
i. DIBAL-H, pentane
CO2Me CO2Me
Prn + Br Prn ð98Þ
ii. Pd(PPh 3)4 (cat.)
65%
The intermediates formed by hydroxyl-directed LiAlH4 hydroalumination of propargyl alco-

hols undergo direct Pd-catalyzed cross-coupling with aryl halides, resulting in a stereoselective
synthesis of trisubstituted allylic alcohols (Equation (99)) <2002JOC2125>.
MeO2C
OH i. LiAlH4, NaOMe, THF
+ MeO2C I
ii. (MeO)2CO ð99Þ
OH
iii. Pd 2(dba)3 /AsPh3 (cat.)
78%
The hydroalumination of propiolate esters with DIBAL-H has recently become more attractive
with the finding that the usual requirement for HMPA can be substituted by NMO. The
intermediate alane undergoes reaction with a variety of carbonyl-based electrophiles, including
aldehydes, pyruvates, and -halocarbonyl compounds, to give Baylis–Hillman-type products
<2003JOC9310>.
1.12.3.1.3 Hydrosilylation followed by CC bond formation

Terminal alkynes undergo regioselective platinum-catalyzed hydrosilylation to give alkenylsilanes,
which are often isolated (see Chapter 2.18.2), rather than reacted directly with electrophiles (see
also Chapter 1.11.1.6). Hydrosilylation has been combined with Pd-catalyzed coupling with aryl
and alkenyl iodides in a one-pot procedure giving (E )-1,2-disubstituted alkenes with good regio-
and stereoselectivity (Equation (100)) <2001OL1073>. Interesting results have been obtained in
the hydrosilylation/cross-coupling of internal alkynes bearing hydroxyl groups. With a homo-
propargyl alcohol, overall cis-addition was observed, with the phenyl group attached to the
carbon nearer the hydroxyl group (Equation (101)) <2001OL61>. However, using a ruthenium
catalyst (rather than platinum) for the hydrosilylation step resulted in overall trans-addition, with
the silyl (and hence aryl) group attached to the carbon remote from the hydroxyl group
<2003JA30>.
(Me2SiH)2O
Bu 3t P-Pt[(CH2=CH-SiMe2)2O] n -C5H11
n -C5H11 + I OMe OMe ð100Þ
TBAF, Pd(dba)2 (cat.)
THF, rt, 10 min
94%
i. (Me2SiH)2NH
ii. Pt[(CH2=CH-SiMe2)2O]2 (cat.)
+ PhI OH ð101Þ
OH iii. TBAF, Pd(dba) 2 (cat.). THF Ph
85%
1.12.3.1.4 Hydrostannylation followed by CC bond formation

Alkenylstannanes can be generated by palladium-catalyzed hydrostannylation of (usually) term-
inal alkynes, and as with alkenylsilanes, they are often isolated before use (see Chapter 2.19.6).
Palladium-catalyzed hydrostannylation of propiolate esters results in the tin atom being intro-
duced to the carbonyl group, rather than on the terminal carbon, and the alkenyltin inter-
mediates undergo in situ Cu(I)-catalyzed coupling with ,-unsaturated acyl chlorides to give
dienones suitable for Nazarov cyclization (Equation (102)) <2003CC1380>. The tin can also be
directed to the internal carbon by a nearby nitrogen during hydrostannylation, and this has been
utilized in tandem cyclization-Stille couplings, in both intra- and intermolecular fashion
<2000T7451, 2001T607>. Recycling of the tin halide by-product back to tin hydride during one-
pot tandem Pd-catalyzed hydrostannylation/Stille couplings allows the overall process to be
carried out with only catalytic amounts of tin <2001JA3194>.
CO2Me i. Bu3SnH, Pd(dba)2/PPh3 (cat.) O
COCl
THF CO2Me
+ ð102Þ
ii. CuCl
Ph 87% Ph
1.12.3.1.5 Hydrozirconation followed by CC bond formation

The syn-addition of Cp2ZrHCl (Schwartz reagent) to alkynes gives (E )-alkenylzirconium reagents
21 with a high level of stereoselectivity, and many other functional groups are unaffected (Scheme
3) <1996T12853>. The reagent can be prepared from Cl2ZrCp2 and reducing agents
<B-1996MI002, B-2002MI003>. Terminal alkynes show good regioselectivity for attachment of
the zirconium to the terminal carbon. Internal alkynes give mixtures of regioisomers, which can
however be equilibrated with excess reagent, to place the zirconium atom on the less hindered
carbon, often with high selectivity.
Ar
ArCH2X R
Ni(0)
or
Pd(0)
R
Cp2ZrHCl ZrClCp2 VOCl(OPri)2
R
R 21 or CuCl
R
+ – + –
Ph2I BF4 Ph2I I
CO, Pd(0) Pd(0) Ph
O R
R Ph
Scheme 3
The alkenylzirconium intermediates 21 can be transformed into alkenes by a range of

C-centered electrophiles (Scheme 3) <1995COFGT(1)501, B-2002MI003>. Oxidative homocou-
pling to symmetrical (E,E )-dienes can be mediated by an oxovanadium(V) compound, as an
alternative to the previously used CuCl <1999JOMC76>. Cross-coupling with benzyl halides has
been found to be catalyzed by Ni(0) more effectively than by Pd(0) <1996T7265>. Palladium(0)-
catalyzed coupling with aryliodonium salts gives good yields of alkenylaromatics <1998SC773>,
and inclusion of carbon monoxide results an arylalkenyl ketones <2002JCS(P1)459>. The ther-
mal equilibration of the hydrozirconation product of an internal alkyne has been found to
improve the regioselectivity, and can be combined with Pd(0)-catalyzed coupling with vinyl
iodides in the preparation of unsymmetrical trisubstituted dienes <1997JOC4912>.
Palladium(0)-catalyzed cross-coupling with a four-carbon bromo-enyne has been used as a
strategy for the iterative stereoselective construction of (all-E)-polyenes (Equation (103))
<2002OL703>. Removal of the TMS group from the product allows the process to be repeated
on the new terminal alkyne.
TMS TMS
i. ZrCl(Bui)Cp2, THF
n - C6H13 +
ii. ZnCl 2, PdCl2(PPh3)2/DIBAL-H (cat.) ð103Þ
Br 91%
n - C6H13
The alkenylzirconium reagents 21 show a low level of nucleophilic reactivity toward carbonyl
compounds; however, this can be increased by the addition of either AgClO4, or AgAsF6 (which
has been suggested as a safer alternative) <1995T4483>. Another way of increasing the reactivity
is to transmetallate the alkenylzirconium intermediate 21 using a dialkylzinc reagent, and this
approach has been reviewed <2002CEJ1779>. Reaction with aldehydes gives allyl alcohols in
good yields, and catalytic amounts of dialkylzinc can be used (Equation (104)). ZnBr2 can also be
used in place of dialkylzinc. Asymmetric addition of the transmetallated alkenylzinc reagents can
be promoted by chiral amino alcohols or more effectively by aminothiols <1998JOC6454>.
Transmetallation by dialkylzinc has also been used to aid the addition of alkenylzirconocenes
to -ketoesters and -iminoesters <2003OL2449> and N-phosphinoylimines <2003JA761>. The
addition to imines bearing a range of other electron-withdrawing groups on the nitrogen is
catalyzed by RhCl(COD)2 <2003TL923>. Alkenylzirconocenes derived from a range of alkynes
have been coupled to -chloroethers using ZnCl2 as the additive <1995JOC6260>. Similar types
of products can also be obtained by insertion of carbenoids, formed from -chloroethers, which
have been deprotonated by lithium amide bases <2000TL6211>. Lithiated epoxynitriles also
undergo insertion reactions with alkenylzirconocenes to give 2-cyano-1,3-dienes <2000TL6201>.
i. Cp2ZrHCl, CH2Cl2, rt OH
Bun + PhCHO
ii. Me2Zn, –65 °C Bun Ph ð104Þ
iii. Add PhCHO, 0 °C
93%
1.12.3.1.6 Formation of alkyne–titanium complexes followed by CC bond formation

Reaction of alkynes with low valent titanium complexes, generated from Ti(Oi-Pr)4 and
i-PrMgCl, generates titanocyclopropene complexes as mentioned above in Section 1.12.1.5.
These complexes can be reacted with carbon-centered electrophiles, resulting in a process
which, overall, is equivalent to hydrotitanation of the alkyne followed by CC bond formation
<2000CRV2835, 2000SL753>. An intramolecular version, with an alkenylsulfoxide as the elec-
trophile, is followed by a Pummerer-type process to give cyclic aldehydes (Equation (105))
<2002AG(E)3671>. The titanium complex formed from a symmetrical internal alkyne has been
trapped with CO2 to give an ,-unsaturated carboxylic acid in good yield <2002JCS(P1)1159>.
Tol CHO
S Ti(OPri)4, PriMgCl, Et2O
O ð105Þ
74%
n-C6H13 n-C6H13
1.12.3.2 Ionic Additions of Stabilized Carbanions to Activated Alkynes

Conjugate addition of enolates and other stabilized carbanions to alkynes activated by a con-
jugated electron-withdrawing group can sometimes be stopped after mono-addition, but can also
be complicated by a second addition of the nucleophile, cyclization, or formation of ring-
expanded products <1991COS(4)1, 1995COFGT(1)501, B-1992MI001>.
The ruthenium species RuH2(PPh3)2 catalyzes the Michael addition of a cyanoacetate to both ethyl
propynoate and 3-butyn-2-one in up to 90% yield <1995JA12436>. The importance of the reaction
conditions is illustrated in Equation (106), where conjugate addition of cyclic -ketoesters to methyl
propynoate or 3-butyn-2-one was achieved using K2CO3 in acetone, to give the Michael addition
products as a mixture of geometrical isomers in good yield <1998TL6873>. However, changing the
solvent to benzene, ether, or THF resulted in significant amounts of ring-expanded products.
O
O
CO2Et CO2Et
+ K2CO3 (cat.)
CO2Me ð106Þ
acetone
90% CO2Me
1/1 (E )/(Z )
An imine-protected ethyl glycinate adds to ethyl propynoate at low temperature using KOBut
as a base, and this reaction is also successful with -alkylated glycinates <1995TL5823>.
In the reaction between various diethyl alkylmalonates and 2-alkynones, further cyclization
occurred to give -pyrones <2003TL2125>, and similar results were obtained with -ketoesters.
Changes in reaction conditions or substrate structure significantly affected the product distribution.
Conjugate addition of -ketoesters or 1,3-diketones to ethyl propynoate using N-methylmorpho-
line as a base results mainly in attack by the O of the enolate rather than the C <2003TL2125>. On
the other hand, the enamine formed between methyl acetoacetate and aniline undergoes clean
conjugate C-addition to methyl propynoate in 80–95% yield (Equation (107)) <2001SL1440>.
NHBn
O
MeOH CO2Me
CO2Me + CO2Me + BnNH2
ð107Þ
80–95%
CO2Me
Chiral imines of 2-methylcyclohexanone undergo asymmetric conjugate addition to methyl

propynoate on the more substituted side, to give ketones in 43% or 80% ee after hydrolysis,
depending upon the conditions for the addition <1996JOC4361, 1996JOC5362>. 2-Methylcyclo-
pentanone reacts similarly, but in a slightly lower selectivity of 71% ee <1997TA2731>.
Triphenylphosphine has also been found to be an effective promoter for selective Michael
additions, with an -cyanoester group reacting in preference to a -ketoester group within the
same molecule, in the addition to 3-butyn-2-one <1999JOC7178>. Several other standard bases
were ineffective. The same group has found that the phosphoramidite HMPT catalyzes (at
10 mol.%) the efficient addition of -cyano- and -ketoesters to 2-alkynones <2003JOC871>.
These reactions often proceed in seconds at room temperature, and without added solvent.
1.12.3.3 Carbometallation of Alkynes

Carbometallation of alkynes generates alkenylmetal compounds <1992COS(4)865, B-1996MI002>,
which can be protonated or reacted with C-centered electrophiles to give alkenes <1995COFGT(1)501>.
The carbometallation of alkynes containing adjacent heteroatoms has been reviewed recently
<2000BCSJ1071>, as has the carbometallation of conjugated alkynenitriles <2003CRV2035>.
1.12.3.3.1 Additions of organolithium and Grignard reagents to alkynes

The addition of the reactive and strongly basic organolithium and Grignard reagents to alkynes is
often unsatisfactory, and deprotonation of the substrate may occur, either at the terminal CH,
or at propargyl positions for internal alkynes <1992COS(4)865>.
Intramolecular additions often give good yields, and the cyclization of vinyllithiums onto alkynes in
a 5-exo manner has been used to prepare a range of five-membered cyclic bis-exo-dienes
<1996JOC8216>. The 5-exo cyclization of chiral carbamate-stabilized organolithiums, generated by
asymmetric deprotonation in the presence of ()-sparteine, gives good results if the internal propargyl
position is substituted to inhibit deprotonation <1998TL1745>. A tandem process is shown in
Equation (108), where an organolithium generated from the homopropargyl iodide adds to the
vinyl sulfide, and this is followed by 5-exo cyclization <2000AG(E)409>. Cyclopropyllithium species
have also been cyclized in a 5-exo manner to give spiro-fused bicyclic systems <1996S502>.
i. Bu t Li, Et2O, –78 °C
Et +
I PhS ii. MeOH ð108Þ
61% PhS Et
97/3 (E )/(Z )
Additions of Grignard and organolithium reagents to propargyl alcohols can also give good results,
with overall trans-addition of the alkyl group and the metal, and the intermediate alkenyl metal is
stabilized by coordination of the alkoxide <1995COFGT(1)501>. This has been extended to addition
of vinyl Grignard reagents to propargyl alcohols, and the intermediate dienylmagnesiums can be
trapped with electrophiles, e.g., aldeydes (Equation (109)) <2000TL11>. The addition of Grignard
reagents to homopropargyl methyl ethers is catalyzed by Mn(II), and results in the regio- and
stereoselective synthesis of trisubstituted alkenes (Equation (110)) <1996JACS6076>. Addition of
organolithiums to homopropargyl ethers gives similar results using catalytic Fe(acac)3, and trapping
with aldehydes is also possible <2001AG(E)621>.
OH
i. C6H12, reflux OH
Me + MgCl + PhCHO ð109Þ
OH Ph
ii. PhCHO, 0–22 °C
Me
80%
MnI2 (cat.), Et2O n -C6H13

n - C6H13 MgBr OMe ð110Þ
+
OMe 83%
Organolithium and Grignard reagents can be added to conjugated alkynenitriles, in a reaction

promoted either by a catalytic amount of a Cu(I) salt <1996JOC3542, 2003CRV2035>, or 1 equiv.
of ButMgCl <2003T5585>. The intermediate alkenyl Grignard species can also be activated by
ButLi, and then trapped by aldehydes to give tetrasubstituted alkenes (e.g., Equation (111)).
Pri
i. ButMgCl HO CN
CN + PriMgCl
HO ii. ButLi ð111Þ
iii. PhCH2CH2CHO HO Ph
65%
Conjugate addition of BunLi to conjugated alkynones has been mediated by a tris(alkoxyalu-

minum) compound in excellent yield, and if the additive is changed to a bis(alkoxyaluminum)
compound, then 1,2-addition to the carbonyl predominates instead <1995SL719>.
Several groups have studied the regioselective addition of Grignard reagents to conjugated
diynes bearing a terminal silyl protecting group. Addition of alkynyl Grignards gives conjugated
cis-enediynes <2000TL11, 2001JOC2146>, and the regio- and stereoselective addition of alkyl
and vinyl Grignards is catalyzed by Cu(I) in good yields (Equation (112)) <2002JOC6844>.
CuI (cat.) Me
SiEt3 + MeMgBr ð112Þ
HO Et2O HO SiEt3
(2.5 equiv.)
84%
1.12.3.3.2 Addition of organocopper reagents to alkynes
(i) Addition of organocopper reagents to activated alkynes

Organocopper reagents are commonly used in conjugate addition reactions, including additions to
alkynes conjugated with carbonyl groups <1991COS(4)169>. A variety of cuprates have been
added to the alkynylsilyl ketone 22, and the products can be desilylated to the corresponding
,-unsaturated aldehydes (Scheme 4) <2001T6267>.
O
CuBr·SMe2 O O
TBAF
SiPh3 + RLi
Me2S, Et2O, –78 °C R SiPh3 R H
22
R = Me, Bu, Ph, vinyl, alkenyl, 66–93%
Scheme 4
Unsymmetrical dialkenyl ketones can be prepared by conjugate addition of dialkylcuprates

to acetylenic alkenyl ketones, where the addition is completely selective for the conjugated
alkyne over the alkene <1999TL7109>. Preparation of an organocopper reagent from lithiated
N-BOC-pyrrolidine failed using the standard copper reagents, but the combination of LiCl-
solubilized CuCN and activation by TMSCl allows conjugate addition to an alkyne in excellent
yield (Equation (113)) <1997JOC3798>.
CO2Me CuCN·2LiCl
+ N Li CO2Me ð113Þ
Bun TMSCl, THF N
t-BOC Bun
93% t-BOC
The intermediates formed by conjugate addition of cuprates to alkynes may be trapped by

reactive electrophiles, resulting in a three-component coupling. Trapping with aldehydes results in
the formation of Baylis–Hillman-type products without any activation of the electrophile
(Equation (114)) <1999SC2959>; however, with bulkier menthyl esters activation by Et2AlCl is
necessary <1998TL8203>. Chiral N-tosylimines can also serve as the trapping agent if activated
by Yb(OTf)3, resulting in good diastereoselectivities <1999TL4611>. Alkyl halides can be used as
trapping agents, and the use of iodomethylboronate esters also introduces extra functionality;
however, HMPA is required for successful reaction <2002JA898>. Intramolecular trapping by an
ester group, which is incorporated into a zinc-copper nucleophile, results in cyclization to
cyclohexenones (Equation (115)) <1995TL7061>.
OH
CO2Me Et2O CO2Me
+ Me2CuLi + PhCHO Ph
69% ð114Þ
Me
99/1 (E )/(Z )
CO2Et O
CuCN-LiCl CO2Et
+ IZn CO2Et ð115Þ
TMSCl, HMPA n -C5H11
MOMO n -C5H11 68% OMOM
(ii) Additions of organocuprate reagents to unactivated alkynes

Organocopper reagents undergo addition to acetylene and terminal alkynes to give alkenylcopper
species with cis-addition to the alkyne. Detailed protocols for the mono-insertion of organocop-
per reagents prepared from Grignard reagents into terminal alkynes (Equation (116)) and the
addition of lithium dialkylcuprates to acetylene to give dialkenyl reagents (Equation (117)) are
given in the reviews by Normant <B-1994MI002> and Lipshutz <1992OR135, B-2002MI010>.
With excess acetylene, dienyl cuprates can be generated instead (Equation (117)), which can be
reacted with electrophiles in situ <1986JCS(P1)1809>.
R1 R Cu·MgX2
RMgX + CuX RCu·MgX2 ð116Þ
R1
2HC CH
R CuLi
2
2RLi + CuX R2CuLi ð117Þ
HC CH R
CuLi
(excess) 2
The alkenylcopper species can simply be protonated, or alternatively reacted with a wide variety
of C-centered electrophiles <1992COS(4)865>. These include: coupling with 1-bromoalkynes, ring
opening of epoxides, carboxylation to acids, ring opening of butyrolactone, conjugate addition,
and palladium-catalyzed coupling with alkenyl iodides and acyl chlorides (Scheme 5). Detailed
protocols for all of these conversions are given in the review by Normant <B-1994MI002>.
A range of terminal alkynes have been converted into 2-alkyl acrylonitriles by addition of HI
generated in situ, followed by reaction of the intermediate 2-iodo-1-alkenes with CuCN, in a
procedure which is equivalent to overall addition of HCN <1997TL8061>.
R1
R1
I R2
R2 Br R3
R3 R3 R3
Pd(0)
R1 O
R3COCl R1 R1
R 2 R3 R3
Pd(0) OH
O R2 CuLn R2
R3
CO2Et O
CO2
O R1
R1
R1 R2 CO2H
2
R CO2H
CO2Et R2
Scheme 5
1.12.3.3.3 Addition of organoboron reagents to alkynes

Although the addition of trialkylboranes to alkynes is not a widely used synthetic procedure
<1995COFGT(1)501>, the three-component coupling shown in Equation (118), involving Ni(0)-
catalyzed addition of triethylborane to alkynes and aldimines, gives good yields for several
examples <2003AG(E)1364>. Boronic acids can also be used in place of triethylborane. Boronic
acids also undergo addition to alkynes, catalyzed by rhodium(I) <2003JOC762> or palladium(0)
<2003AG(E)805>. This results in overall hydroarylation of the alkyne, and the mechanism may
involve formation of an alkenylmetal species, followed by coupling with the boronic acid.
Et NHMe
Ni(COD)2 (cat.)
Ph Me + Et3B + Ar NMe
(c -C5H11)3P (cat.) Ph Ar ð118Þ
MeOH–MeOAc Me
95% (Ar = p -ClC6H4)
1.12.3.3.4 Addition of organoaluminum reagents to alkynes

The carbometallation of acetylene itself works well with trialkylalanes, but is not satisfactory for
terminal or internal alkynes. The most widely used method for carboalumination of terminal
alkynes is the zirconocene-catalyzed syn-addition of trimethylalane, which is also highly regiose-
lective (Scheme 6) <B-1996MI002, B-2002MI003>. Internal alkynes are less reactive, and give
mixtures of regioisomers if unsymmetrical. Methyl-, allyl-, and benzylalanes all work well, and
other combinations of aluminum and zirconium reagents can be used for other alkyl groups. The
intermediate alkenylalane 23 undergoes the standard polar reactions with reactive C-centered
electrophiles, and also nickel and palladium-catalyzed cross- coupling reactions <1995COFGT(1)501,
B-1996MI002, B-2002MI003, B-2002MI004>. The reactivity of the alkenylalanes can be
increased by forming the alanate 24 with an alkyllithium, which allows reaction with a wider
range of electrophiles.
The alkenylalanes 23 can also be reacted with iodine, to give a stereoselective synthesis of
alkenyl iodides, which can then be coupled with organometallic reagents to give trisubstituted
alkenes. This approach is well suited to the synthesis of isoprenoid units, and has been used often
in the synthesis of terpenes (e.g., Scheme 7) <1997JOC8591>. It is interesting to note that the
opposite geometrical isomer 26 of the iodide 25, required in the same synthesis, was prepared by
Cu(I)-catalyzed carbomagnesiation of a common starting material. The direct reaction of
alkenylalanes 23 with chloroformates has also been used in natural product syntheses such as
polyene antiobiotics, e.g., Equation (119) <1998JOC6092>.
Me E
E+
R
Me3Al, Cp2ZrCl2 Me AlMe2
R ArX, or alkenyl-X Me Ar, alkenyl
R 23 Pd(0) or Ni(0)
R
BunLi
Me AlMe2BunLi +
Me E
E
R 24 R
Scheme 6
i. Me3Al
I OH
Cp2ZrCl2 (cat.)
ii. I2 25
OH 53%
I O
Steps O
i. MeMgBr, CuI (cat.) OH
ii. I2
26
30–75%
Scheme 7
+ Me3Al + BuiOCOCl
PhS
Cp2ZrCl2, Cl2CHCHCl2
ð119Þ
Me
CO2Bui 75%
PhS
A useful reversal of the stereoselectivity of methylalumination can be achieved using homo-

propargyl alcohols (Equation (120)). Initially, the syn-adduct 27 is formed as expected, but after
heating for 72 h, isomerizes cleanly under chelation control to the anti-adduct 28 <1997JOC784>.
The homopropargyl alcohol group is essential for the isomerization to occur, and this transfor-
mation was exemplified in the synthesis of (3Z)--farnesene.
Me AlMe2 Me H Me H
i. Me3Al +
Heat E
H AlMe E ð120Þ
OH Cp2ZrCl2 (cat.) OAlMe2 O OH
27 28
The zirconocene-catalyzed carboalumination of internal alkynes with triethylalane gives a cyclic

intermediate, e.g., 29, and this can be reacted with CO2 or chloroformates to give cyclopentenones
(Equation (121)) <1998TL2503>.
Bun Bun
Cp2ZrCl2 (cat.) Bun CO2 Bun
Bun Bun + Et3Al AlEt O ð121Þ
76%
29
Recently, the stereoselectivity of additions of alkenylalanes 23 to chiral electrophiles has been

studied, including additions to chiral aldehydes <2002TL4183> and N-tosylimines
<2002HCA3478>.
1.12.3.3.5 Addition of organozinc reagents to alkynes

The preparation and reactions of organozinc reagents, including additions to alkynes, has been
reviewed <1992COS(4)865, 1998T8275>. Recent developments in the addition of organozinc
compounds to alkynes have focused on the use of nickel catalysts <1998T8275, 2000T817>.
Dialkyl and diphenyl zinc reagents add to 1-phenylalkynes with high regio- and stereoselectivity
(e.g., Equation (122)) <1997AG(E)93, 1998T1299>. The intermediate alkenylzinc reagent can
also be quenched with electrophiles (e.g., acyl or allyl halides, and iodine) instead of being
protonated, to give tetrasubstituted alkenes. Intramolecular versions are possible, starting from
6-iodo-1-alkynes, resulting in stereoselective 5-exo-cyclization. Under an atmosphere of carbon
dioxide, terminal alkynes form a cyclic intermediate with the nickel catalyst and the CO2, which
reacts with organozinc reagents to give ,-unsaturated carboxylic acids <2001OL3345>.
Ni(acac)2 (cat.) Et H
n -C8H17 Ph + Et2Zn
THF-NMP n - C8H17 Ph ð122Þ
–35 °C, 20 h
69% >98/2 (Z )/(E )
Alkynes bearing a remote enone functionality undergo nickel-catalyzed reaction with dialkyl-
zinc compounds, giving products of cyclization onto the enone (Equation (123)) <1996JA2099>.
The mechanism may involve metallacycle formation, rather than carbozincation of the alkyne
<1998T1131>. The same reaction can be used to form O- and N-containing heterocycles
<1997T16449>, and cyclization onto a carbonyl group, rather than conjugate addition, has
also been achieved <1997JA9065>. Similar cyclizations can be carried out with a diene replacing
the enone group, with the intermediate then undergoing trapping by an aldehyde with high 1,5-
diastereoselectivity <2002AG(E)2784>.
O R
O
RZnCl
Ph + R2Zn H
Ni(COD)2 (cat.) Ph ð123Þ
THF, 0 °C
69%
R = Me, Bun, Ph, vinyl, 51– 82%
1.12.3.3.6 Other carbometallation reactions of alkynes

Alkynes undergo addition of organozirconium reagents, which can be prepared by in situ from
EtMgBr and Cp2ZrCl2, and conjugate addition of the intermediate zirconacyclopentene to cyclic
enones is catalyzed by CuCl2LiCl (Equation (124)) <1995T4407>. The same type of zircon-
acyclopentene intermediates reacts with CO/I2 to give cyclopentenones <1997T9123>. Alterna-
tively, interception of the intermediate by a combination of ethylene and an aldehyde, promoted
by AlCl3, results in an overall 4-component synthesis of ,-unsaturated ketones <2002CC142>.
O O
i. Cp2ZrCl2, THF
n -C6H13 + EtMgBr + Et
ii. CuCl.2LiCl (cat.) ð124Þ
n -C6H13
80%
7/1 (E )/(Z )
The organozirconium reagent can also be generated by hydrozirconation, and starting from
allenes this results in allylzirconium species, which have been used for regioselective carbometalla-
tion of terminal alkynes in the presence of methylaluminoxane, leading to 1,4-dienes (Equation
(125)) <1997TL3031>. Alkylzirconium reagents, prepared by hydrozirconation of alkenes, react
more slowly, and a trityl salt has been found to be a better catalyst <1999TL8407>. Unsymme-
trical internal alkynes can also be used, with the regioselectivity depending upon the steric
differences between the two alkyl groups <2001JOMC(624)143>.
OTBDPS
Ph
i. Cp2Zr(H)Cl
Ph + · OTBDPS +
ii. Methylaluminoxane Ph ð125Þ
i
[=hydrolyzate of Me3Al + Bu3Al (2:1)]
OTBDPS
–78 °C to 20 °C
93% 13:1
Unactivated terminal alkynes have been found to react with allylindium species in THF to give
1,4-dienes in good yields (Equation (126)) <1997JOC2318>.
i. In, THF, rt
I
Ph + ð126Þ
ii. THF, 70 °C Ph
94%
1.12.3.4 Addition of Sulfur, Selenium, and Tellurium Reagents to Alkynes

The hydrotelluration of alkynes has usually been performed by the reduction by NaBH4 of
dialkylditellurides, which however, are notorious for their malodorous nature. A recent procedure
generates the tellurols by the action of alkyllithiums on elemental tellurium, which avoids this
problem <2001JOMC(623)43>. Hydrotelluration of an alkyne forms the alkenyl telluride, which
can then be reacted with a variety of C-centered reagents to give the alkene.
A related strategy for the hydroselenation of alkynes involves the use of a selenoester to form
the intermediate alkenyl selenide, which can then be transformed into an alkene by the replace-
ment of the seleno group by a copper-mediated Grignard reagent <1996SC3607> (Scheme 8).
MeCOSePh Ph EtMgBr, CuI Ph Et

Ph CN +
PhSe CN THF, 10 °C, 2 h Et CN Ph CN
85% 20:1
Scheme 8
1.12.3.5 Addition of Iron Reagents to Alkynes

The reaction of Fe3(CO)12 with alkynes in the presence of n-butylamine gives the corresponding
cyclobutenediones after oxidation by Cu(II) (Equation (127)) <2000TL2719>.
i. Fe3(CO)12, BunNH2 O
n -C5H11 ð127Þ
ii. CuCl 2·2H2O
61% n -C5H11 O
1.12.3.6 Palladium-catalyzed Additions to Alkynes

Reaction of alkynes with aryl or alkenyl halides and a palladium(0) catalyst gives alkenylpalla-
dium intermediates, in a Heck-type coupling, and these can be reduced by formate to produce
alkenes <B-2002MI005>. With unsymmetrical alkynes the regioselectivity varies, depending upon
the nature of the substituents. The intermediate alkenylpalladium species can also be trapped by
other nucleophiles <B-2002MI005>, such as carbon monoxide or organometallic reagents. Intra-
molecular versions can be used to form exocyclic alkenes with five, six, or seven-membered rings,
and a recent example is shown in Equation (128), using triethylsilane as the reducing agent, which
gives better yields than formate <2003TL3785>.
EtO2C Br
Pd(PPh3)4 (3 mol.%) EtO2C ð128Þ
EtO2C
Cs2CO3, Et3SiH, DMF EtO2C
85%
Palladium-catalyzed cycloisomerizations of 1,6- and 1,7-enynes have been developed by Trost

as a method for the construction of bis-exocyclic 1,3-dienes <1995AG(E)259, 1998SL1>.
Reductive cyclizations are also possible by addition of a hydride source, giving exocyclic
alkenes instead of dienes, and has been used in a natural product synthesis (e.g., Equation
(129)) <1996TL8787>. The use of formic acid and triethylsilane has been investigated in
reductive cyclizations of 1,6-enynes, and they have been found to give different selectivities
<2000TL8365, 2001T1723>.
H
Pd(OAc)2-(PhCH=NCH2)2 (cat.)
N Polymethylhydrosiloxane ð129Þ
N
AcOH, PhH, reflux H
CO2Bn
78% CO2Bn
Reductive cyclization of 1,7-diynes is an alternative to cycloisomerization of the corresponding

enynes, since both methods can, in principle, give the same six-membered exocylic dienes, and this
may have advantages where the enyne cyclization fails for steric reasons <1996JA5146>. When
electon-rich phosphines are used as ligands for the palladium catalyst, the course of the reaction
changes with terminal enynes, and homo-coupling of the terminal alkyne is observed instead. This
has been extended to allow intermolecular cross-coupling of terminal alkynes onto internal
alkynes bearing electron-withdrawing groups <1997JA698>. The use of palladium catalysts
bearing water-soluble phosphine ligands allows cycloisomerization of 1,6-enynes to be carried
out in aqueous-organic media, and results in unsaturated alcohols by formal hydration of one of
the alkene bonds (Equation (130)) <2001T5137>.
OH
H
Pd(OAc)2, (10 mol.%) PhP(C6H4-p-SO3Na)2, (30 mol.%)
O O ð130Þ
Dioxane /H2O, 80 °C, 3 h
85%
A wide variety tandem and cascade additions and cyclizations onto alkynes are catalyzed by
palladium, and these have been extensively investigated by Grigg and co-workers
<1999JOMC(576)65>. After one or more palladium-catalyzed additions and/or cyclizations, the
process can be terminated by reaction of the organopalladium intermediate with CC -bonds
<B-2002MI006>, nucleophiles <B-2002MI007>, or by carbonylation <B-2002MI008>. This con-
cept is exemplified in Equation (131), where all three alkyne units in the substrate undergo
consecutive addition to form alkenes, before capture by allene and a nucleophile <1997TL1825>.
EtO2C Pd(PPh3)4, K2CO3

EtO2C
Allene, PhSO 2Na SO2Ph ð131Þ
EtO2C I EtO2C
DMF, 70 –75 °C, 3 h
65%
The hydroformylation of symmetrical internal alkynes to ,-unsaturated aldehydes is cata-

lyzed by (PCy3)2PdCl2, and the addition of Co2(CO)8 markedly improves the catalytic activity
<1997JA6448>. Propargyl alcohols undergo a cyclocarbonylation to unsaturated -lactones
using a palladium(0) catalyst and CO+H2 <1997JOC5684>. Other carbonylations of alkynes
include the regioselective hydroformylation of enynes <1999JOC3964>, and the carbonylation of
ynones <2000JOC4131>; however, both of these are catalyzed by rhodium.
Transition metal cyclizations have been reviewed as a general topic, and this includes several
palladium-catalyzed cyclizations of alkynes <1996CRV635>. Other relevant material may be
found in a recent review on transition metal-catalyzed reactions of 1,n-enynes <2002CRV813>.
1.12.4 FREE RADICAL ADDITIONS
1.12.4.1 Intermolecular Free Radical Additions

The intermolecular addition of C-centered free radicals to alkynes is seldom used as a synthetic
procedure, compared to additions to alkenes, and yields are often low <1995COFGT(1)501>. A
recent review comparing experimental and calculated rate constants for additions to both alkynes
and alkenes shows that additions of C-centered radicals to ethyne are slower than the correspond-
ing additions to ethene, and have higher activation barriers, even though the additions to ethyne
are more exothermic <2001AG(E)1340>. A radical generated by the oxidation of a malonate
ester by manganese(III) acetate adds to phenylacetylene, and, under high pressure of carbon
monoxide, gives the carboxylated product in moderate yields, which are improved by increasing
the pressure of CO <1996JOC5312>. This reaction is more successful when applied to intramo-
lecular additions (see below). Phenylacetylene also undergoes intermolecular addition of a
2-cyanophenyl radical, generated from a diazonium salt, and the alkenyl radical produced is
trapped by cyclization onto the nitrile, ultimately giving a cyclic ketone in low yield (Equation
(132)) <1998TL2441>.
+ –
N2 BF4
i. Cu or pyr
+
ii. Chromatography Ph ð132Þ
CN Ph 20%
O
1.12.4.2 Intramolecular Free Radical Additions

The intramolecular addition of a radical to an alkyne generates a new ring, and this process has
been surveyed in reviews on radical cyclizations, which include the more often used cyclizations
onto alkenes <1996OR301, B-1992MI002>. The most commonly used cyclizations are of
5-hexynyl radicals, which usually close in a 5-exo-dig manner, to give alkylidenecyclopentanes
(or heterocycles, if a heteroatom is included in the chain). There are several methods of generating
the radical for cyclization, and the most widely used is still reaction of a bromide or iodide with a
tin radical, formed from a tin hydride and a radical initiator, or by photolysis of a hexa-alkylditin.
If the alkyne is not terminal, then the cyclization generates a trisubstituted alkene, often as a
mixture of geometrical isomers. In the first example shown in Scheme 9, a high stereoselectivity
is obtained by steric shielding of one side of the alkenyl radical during hydrogen transfer
<1995JOC8332>. The second example shows that the opposite geometrical isomer can be
obtained by internal hydrogen transfer from the silicon.
Me Me
Si Ph MePh
But Me
H Ph H
O Bu3SnH Si TBAF
AIBN, PhH, reflux But O THF HO
I 50%
But H
Si Ph I
But H Ph H Ph
O (Bu3Sn)2, hν But TBAF
Si
PhH, reflux But O THF HO
I 80% 88%
Scheme 9
Another way to achieve excellent control of the double bond geometry is to use aluminum tris(2,6-
diphenylphenoxide) (ATPH) as a Lewis acid template <2001T135>. This results in complete selec-
tivity for the (Z)-isomer of the product shown in Equation (133), whereas standard tin hydride
conditions give a 1:1 mixture of geometrical isomers. The Lewis acid also prevents formation of
uncyclized reduction product, and these results can be explained by a templating and shielding effect.
Ph H
ATPH, (TMS)3SiH, Et3B Ph
I
PhMe, –78 °C, 1 h ð133Þ
O 99% O
>99% (Z )
Alkenyl radicals, generated from iodoalkenes by tin hydride, also cyclize onto alkynes, and
both 5- and 6-(-exo)-exo-dig modes are observed (depending on the chain length), resulting in
bis-exocylic five and six-membered ring dienes <2000OL2013>.
Aryl radicals have also been cyclized onto alkynes linked by an amide group, in 5-exo-dig
mode, and a removable silyl group on the alkyne helps to promote the cyclization
<2000JCS(P1)763>. Heterocyclic aryl radicals generated from 3-bromopyridines also undergo
5-exo cyclizations onto all-C alkynyl side chains at the 4-position, in good yields <2000T397>.
-(Alkynyloxy)acrylates undergo tributyltin-mediated radical cyclization, and acidic destanny-
lation yields the exo-methylene products (Equation (134)) <2000OL1275>. From five to eight-
membered ring sizes could be formed on the sugar derivatives, with the yields remaining high
except for the eight-membered ring.
H
O OMe H n Yield (%)
n i. Bu 3SnH, AIBN O OMe
n
EtO2C 0 85 ð134Þ
OBn PhMe, 80 °C EtO2C 1 85
H OBn
OBn ii. TsOH, CH 2Cl2 H 2 76
OBn 3 13
A suitable choice of heteroatom in the chain linking the alkyne to the radical precursor may
allow the tether to be cleaved after cyclization, resulting in an acyclic product. Silicon has been used
in the past, but a recent method uses tethered -boryl radicals, and after 5-exo cyclization onto an
alkyne, the CB bond can be oxidatively cleaved to give 2-alkylidene-1,3-diols <1999TL9183>.
The use of tin reagents to generate radicals can cause problems with removal of the tin by-products,
and with their toxicity and disposal. Radical cyclizations onto alkynes have been carried out on a solid
support, which allows the tin by-products to be simply washed away <1997SL61>. Nevertheless, the
quest for alternatives to tin reagents for radical generation is an active field of research. Formation of
radicals from -haloacetals by irradiation with UV light in the presence of triethylamine was
introduced by Cossy, and successfully applied to cyclization onto alkynes <1994TL8161>. The
same method has also been applied to -iodoenones (e.g., Equation (135)) <1998CC397>. However,
cyclization of related alkenyl iodides lacking the carbonyl group was unsuccessful.
O
O
I hν, Et3N, MeCN
ð135Þ
72% O
O
The generation of free radicals by manganese(III) oxidation of -dicarbonyl compounds and

-cyanoesters has been reviewed by Snider <1996CRV339>, including examples of cyclization onto
alkynes. Oxidation of malonates by Mn(OAc)3 has been mentioned in the previous section, and this
has also been applied to cyclization onto alkynes, with trapping of the resulting alkenyl radical by
CO (Equation (136)) <1996JOC5312>. A 6-exo cyclization was also achieved, but in lower yield.
CO2Me Mn(OAc)3·2H2O CO2H

CO2Me CO (1200 psi), 90 °C ð136Þ
AcOH–MeCN CO2Me
MeO2C
68%
An activated Mn(0) species, generated by the action of Li2MnCl4 on magnesium metal, has
been used to initiate 5-exo radical cyclizations of alkynyl -haloacetals in good yields (Equation
(137)) <1999T1893>. Exactly the same cyclization has also been carried out with radical forma-
tion by the combination of BunMgBr and catalytic FeCl2, but in lower yield <1998TL63>. Using
yet another method, the bromo analog has been cyclized with an indium hydride reagent together
with catalytic Et3B, in 71% yield <2003T6627>. Indium metal has been used together with iodine
to mediate radical cyclizations of some other alkynyl iodoacetals, and by changing the ratio of
indium to iodine the course of the reaction can be altered from an iodine atom transfer to a
reductive cyclization <2002TL4585>.
Mg, Li2MnCl4 Ph
O O
I Ph THF, rt
BunO BunO ð137Þ
85%
45/55 (E )/(Z )
An interesting tandem reaction initiated by a reduced titanocene is shown in Equation (138),

where the epoxide is opened to give a radical which cyclizes onto the alkyne, and the resulting
alkenyl radical is then trapped by intermolecular addition to an acrylate <2002AG(E)3206>. The
tetrasubstituted alkene is formed with very good stereoselectivity.
Me
HO
CO2But
O Cp2TiCl2 (cat.)
+ CO2But ð138Þ
Zn, EtOAc
69% H
Me
97/3 (E )/(Z )
1.12.5 CARBENE AND OTHER ADDITIONS
1.12.5.1 Addition of Simple Carbenes and Carbenoids to Alkynes

The addition of carbenes to alkynes can be used as a method for the synthesis of cyclopropenes
<1995COFGT(1)501>; however, there are limitations. Carbenes bearing electron-withdrawing
groups have been most generally used, such as dichlorocarbene, and carbenes with an -carbonyl
group. The addition of dichlorocarbene to internal alkynes gives geminal dichlorocyclopropenes,
which can be hydrolyzed to cyclopropenones. A recent procedure shown in Equation (139) gives
good overall yields <2000SC1767>, and this depends upon quenching the reaction with acid at
low temperature, since quenching with water at 0 C results in the formation of ynones.
O
i. BuLi, –78 °C, THF
Et Et + CHCl3 ð139Þ
+
ii. H , –78 °C
Et Et
90%
The most widely used carbenes for addition to alkynes are generated from -diazoesters by
rhodium(II) acetate, and the chemistry of these compounds has been reviewed <1994CRV1091,
B-1998MI001, B-1999MI001>. The addition is successful with both internal and terminal alkynes
(but not phenylacetylene), and gives cyclopropene-3-carboxylic esters, which are stable at room
temperature, or even above (Equation (140)). In recent examples of this procedure, the cyclopro-
penecarboxylates were isolated, and then subjected to further rhodium-catalyzed transformations
<1995HCA129>. Similar chemistry can be performed starting from diazomalonates
<1995HCA947>. The rhodium acetate procedure is much superior to the previous use of copper
catalysts for this reaction, which requires higher temperatures, and leads to further reaction of the
products. Conjugated enynes undergo addition to the alkyne, but the vinylcyclopropene products
are unstable, and react further, whereas isolated enynes react preferentially on the alkene double
bond <B-1998MI001>.
Rh2(OAc)4 CO2R3
2
R1 R + N2 CO2R3 ð140Þ
CH2Cl2
R1 R2
An enantioselective version of this reaction has been achieved by using chiral ligands on the
rhodium catalyst, with selectivities of 48 to 98% ee <1994JA8492>.
Intramolecular addition of acylcarbenes to alkynes is also possible, however the products

usually react further, via a vinylcarbene, which may be formed directly or from the cyclopropene
<1994CRV1091, 2001JOMC(617)3, B-1999MI001>. In general, the alkyne triple bond in the
starting material becomes a CC single bond, rather than an alkene, although there are a few
exceptions <1991JOC2523, 1994CRV1091>. However, cyclizations onto alkynes tethered by a long
chain can be successful in producing macrocyclic rings, as in the example shown in Equation (141)
<1999AG(E)700>.
O
H
O O
Rh2[4-(S)-ibaz] 4
+
CH2Cl2 O
O CHN2 * H
80% O O
84:16 O ð141Þ
O
H 97% ee 88% ee
O N CO2Bui 4
Rh2 (4-(S)-ibaz)4 =
Rh Rh
A very different type of carbene addition is shown in Equation (142), where dimethoxycarbene
(generated from an oxadiazoline) adds to DMAD, and the intermediate undergoes trapping by
benzaldehyde and cyclization <2003SL1446>. Other aromatic aldehydes can also be used.
MeO2C CO2Me
CO2Me
N N OMe PhMe OMe
+ + PhCHO H ð142Þ
O OMe 110 °C, 15 h Ph O OMe
CO2Me 81%
1.12.5.2 Reaction of Fischer Carbene Complexes with Alkynes: The Dötz Synthesis of Phenols
Fischer carbene complexes 30 are compounds which can be represented as a carbene, which is
formally doubly bonded to a transition metal carbonyl fragment, and generally bears an electron
donating substituent X, and a group R which can be alkyl, aryl, alkenyl or alkynyl (Scheme 10).
They can undergo an extraordinarily rich and diverse range of reactions, as shown in the extensive
review by de Meijere and co-workers <2000AG(E)3964>. Fischer carbenes are electron-withdraw-
ing groups, and so an alkene or alkyne conjugated to the carbene will be activated toward [4+2]-
and [2+2]-cycloadditions, as with a carbonyl group <2000AG(E)3964>.
OH O
RL
RL RL
R X Ox.
OR + Cr(CO)3
M(CO)5 RS e.g. CAN
RS
Cr(CO)5 RS
OR O
30
Scheme 10
However, the most widely used synthetic reaction of Fischer carbene complexes is the Dötz
reaction, which is the co-cyclization of an alkenyl- or aryl Fischer complex with an alkyne, and one
of the CO ligands from the metal (Scheme 10). The reaction results in the formation of a new
oxygenated arene complexed to the metal, which can be oxidatively removed to release the product
as a quinone. Reductive removal can also be used, to yield phenols. This reaction has received a
great deal of attention over the last few years, and several reviews are available <1991COS(5)1065,
1999CSR187, 2000AG(E)3964, B-1999MI001>. Chromium complexes are the most efficient, and
the reaction is of broad scope, with many functional groups being tolerated on the alkyne. The
yields are usually lower for electron-poor alkynes (e.g., 3-butyn-2-one) <1999CSR187>, although a
good yield has been obtained with DMAD, using a (4-methoxyphenyl) iron carbene complex
<1993JA9848>. Regioselective incorporation of unsymmetrical alkynes is observed, with the larger
group being incorporated next to the phenolic hydroxyl (Scheme 10) and the selectivity is usually
complete for terminal alkynes, but lower for internal alkynes.
Originally the reactions were performed thermally, but more recently photochemical conditions
have been employed <1995TL1871, 1998EJOC1739>. The use of ultrasound and dry-state absorp-
tion on silica allows the reactions to be performed at ambient temperature <1993T5565>, and
microwave irradiation has also been used <2002CC2262>.
Intramolecular Dötz reactions are feasible <1999CSR187>, for example a temporary silicon-
containing tether has been used to control and reverse the intrinsic regioselectivity of the reactions
<1994JA10921>, and the yields were found to be improved by the addition of external alkynes,
which were not incorporated into the final product.
A very wide variety of other cyclizations and additions of Fischer carbene complexes onto
alkynes have been reported, and these have been reviewed <1996CRV271, 2000AG(E)3964>.
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Biographical sketch
Andrew Regan was born in Rawtenstall, Lancashire, studied at the Uni-

versity of Cambridge, where he obtained his B.A. in 1981 (M.A. 1985), and
his Ph.D. in 1984, under the supervision of Professor Jim Staunton. From
1984–1985, he held an SERC-NATO Research Fellowship at Columbia
University in the laboratories of Professor Gilbert Stork. He returned to
UK in 1985 to a lectureship in organic chemistry at the University of Kent
at Canterbury, and since 1990 has been a lecturer in the Department of
Chemistry at the University of Manchester. His research interests include
the synthesis of phosphinic-acid hormone mimics, simplified macrolide
antibiotics and anti-tumor compounds, stereoselective methodology, and
the use of enzymes in synthesis.
1.13
One or More C¼C Bond(s) by
Elimination of Hydrogen, Carbon,
Halogen, or Oxygen Functions
O. PIVA
Université Claude Bernard Lyon I, Villeurbanne, France
1.13.1 BY ELIMINATION OF HYDROGEN 582

1.13.1.1 Dehydrogenation of Hydrocarbons 582
1.13.1.2 Dehydrogenation of Ketones and Aldehydes 582
1.13.1.3 Dehydrogenation of Silyl Enol Ethers 583
1.13.2 BY ELIMINATION OF CARBON FUNCTIONS 584
1.13.2.1 Elimination of Hydrogen Cyanide 584
1.13.2.2 Elimination of Carbon Oxides 584
1.13.2.2.1 Decarboxylation 584
1.13.2.2.2 Di-decarboxylation 585
1.13.2.2.3 Decarboxylation/dehydration 585
1.13.2.2.4 Decarboxylation/dehalogenation 586
1.13.3 BY ELIMINATION OF HALOGEN (OR H-HAL) 586
1.13.3.1 Elimination of Dihalides 586
1.13.3.2 Elimination of Hydrogen Halides 588
1.13.3.2.1 Dehydrofluorination 588
1.13.3.2.2 Dehydrochlorination 588
1.13.3.2.3 Dehydrobromination 588
1.13.3.2.4 Dehydroiodination 589
1.13.4 BY ELIMINATION OF OXYGEN FUNCTIONS 590
1.13.4.1 Dehydration 590
1.13.4.1.1 Using Burgess’ reagent 590
1.13.4.1.2 Using Martin’s sulfurane reagent 591
1.13.4.1.3 Dehydration by other methods 591
1.13.4.2 Elimination of Alcohols (H–OR) 592
1.13.4.3 Eliminative Ring Opening of Epoxides 593
1.13.4.4 Elimination of a Carboxylic Acid (H-OCOR) 594
1.13.4.5 Elimination of a Sulfonic Acid 594
1.13.4.6 Elimination of 1,2-Diols and Derivatives 595
1.13.4.7 Deoxygenation of Epoxides and Halohydrins 596
This chapter concern the formation of alkenes and provides an update to chapter 1.13 in COFGT
(1995) covering major advances in the last decade. Numerous procedures including dehydrogena-
tion, dehydration, elimination of hydrogen halide under acidic, basic conditions, or by using more
sophisticated reagents are discussed. The access to alkenes from carboxylic acids, ethers, epoxides,
1,2-diols, and derivatives is also described. A special emphasis has been made on methods, which
allow the formation of the double bond with high regio- and stereocontrol. Great attention has
been paid to processes which are consistent with the use of protective groups. Moreover, numerous
examples cited in this review are part of multistep syntheses of complex natural products.
581
582 One or More C¼C Bond(s) by Elimination of H, C, X, or O Functions
1.13.1 BY ELIMINATION OF HYDROGEN
1.13.1.1 Dehydrogenation of Hydrocarbons

Despite their cost and toxicity, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and chloranil are
the reagents of choice to abstract a hydrogen in the allylic, propargylic, and benzylic positions. The
intermediates can be easily trapped by various nucleophiles such as cyanide or water or can be
oxidized to the corresponding alkene when the reaction is performed in an inert solvent such as 1,4-
dioxane or acetonitrile. The major drawback in these reactions is the formation of a large amount of
dihydroquinol, which can be removed by filtration or chromatography on alumina. DDQ is also
commonly used to promote aromatization of carbocyclic and heterocyclic compounds but this aspect
will be not be covered in this chapter. Representative examples in the field of steroids (Equation (1))
<2000TL1729, 2001CR201> and pyrrolines (Equation (2)) <2003TL3701> are depicted.
O O
DDQ ð1Þ
Dioxane
BnO 60% BnO
Ph Ph
DDQ (2.2 equiv.)
Ph ð2Þ
N Dioxane, rt Ph N
H 81%
1.13.1.2 Dehydrogenation of Ketones and Aldehydes

The direct synthesis of enones or dienones from saturated ketones can be achieved by DDQ
<1996SC551>. In the field of natural product synthesis, dehydrogenation of eudesm-4-en-3-ones,
for example, gives the corresponding dienones in good yield (Equation (3)).
OAc OAc
DDQ
ð3Þ
Dioxane
O 75% O
Iodic acid (HIO3) and its anhydride I2O5, which are commercially available and stable at elevated
temperatures, can also be used for the direct conversion of ketones and aldehydes into the correspond-
ing unsaturated compounds <2002AG(E)1386>. Interestingly, these reactions can be carried out in
DMSO on substrates bearing sensitive functionalities such as tertiary alcohols (Table 1).
Table 1 Dehydrogenation with HIO3

Substrate Temperature ( C) HIO3 (equiv.) Product Yield (%)
O O
50 1.1 95
N CHO
65 2.5 N CHO
82
O O
50 1.2 77
O O
OH OH
One or More C¼C Bond(s) by Elimination of H, C, X, or O Functions 583
o-Iodoxybenzoic acid (IBX) is also of great interest to effect dehydrogenation of carbonyl

compounds <2002JA2245>. The reaction time can be dramatically decreased by addition of acids
such as TsOH (Equations (4) and (5)).
O O
IBX (2 equiv.)
Fluorobenzene/DMSO 2:1 ð4Þ
65 °C, 10 h
76%
1:2
O IBX (6 equiv.) O
Fluorobenzene/DMSO 2:1
85 °C
no additive ð5Þ
TsOH (0.3 equiv.) 55%
86%
Rearrangement observed on a well-designed cyclopropylaldehyde provides a strong support for

a single-electron-transfer (SET) process (Equation (6)). Furthermore, the reaction is highly
chemoselective as a ketoaldehyde is only oxidized in the -position of the aldehyde group
(Equation (7)).
Ph CHO
IBX (2.0 equiv. )
Ph Ph
ð6Þ
DMSO, 70 °C, 7 h
CHO Ph
98%
O O
CHO IBX (1.3 equiv.) CHO
( )4 ( )4 ð7Þ
DMSO, 70 °C, 15 h
79%
The dehydrogenation of cyclic ketones <1997MI1123> has also been investigated in the
presence of palladium(II) trifluoroacetate associated with an appropriate phosphine or sulfide.
1.13.1.3 Dehydrogenation of Silyl Enol Ethers

The scope and applications of palladium species toward the transformation of silyl enol ethers
into enones have been covered in a review <B-2002MI001>. Since the 1970s, palladium chemistry
has been a cornerstone in organic chemistry and widely applied in natural product synthesis. The
tolerance of numerous functionalities, the mildness of the conditions, and the selectivities
obtained renders this reaction very appealing. Two significant examples (<1998JOC5890> and
<1996JOC1119>) are shown in Equations (8) and (9).
O O O O
Pd(OAc)2 (1.1 equiv. ) ð8Þ

Me3SiO CH3CN, ∆ O
95%
H H
Pd(OAc)2 (1.1 equiv.)
O O ð9Þ
CH3CN, rt, 72 h
OSiMe3 O
90%
A major improvement for this process has been achieved by performing the reaction with only
10% Pd(OAc)2 in DMSO as the solvent and under 1 atm of oxygen as the cooxidant. Under these
conditions, aldehydes and ketones are converted at room temperature into ,-unsaturated
carbonyl compounds in impressive yields <1995TL2423, 1995TL9449> (Equation (10)).
O OSiMe3 O
Pd(OAc)2, O2 ð10Þ
O O DMSO, 25 °C, 72 h O
O O 86% O
1.13.2 BY ELIMINATION OF CARBON FUNCTIONS
1.13.2.1 Elimination of Hydrogen Cyanide

Elimination of hydrogen cyanide has been rarely observed. Dihydropyrazoles resulting from
1,3-dipolar cycloadditions of bis-nitrile imides can be aromatized under basic conditions
<1997T9293>. Other heterocyclic structures like indoloquinazolines were also obtained via the
elimination of HCN by treatment with DBU <2002RCB(E)1869>. A tetracyanoethylene deriva-
tive has been engaged in a tandem dimerization to give, after elimination of hydrogen cyanide and
ethanol, a bicyclic 2-aminopyridine <1999TL4707>. More interestingly, the functionalization of
chalcones can be effectively achieved by using a three-step sequence <1998BMC937> including a
Michael addition of HCN, a selective alkylation in the -position of the nitrile, and a regenera-
tion of the alkene moiety according to an E1cB mechanism (Scheme 1).
AllylO OCH3 AllylO OCH3

NaCN, NH4Cl
DMF, 100 °C
O OCH3 O CN OCH3
i. LDA, THF AllylO OCH3 AllylO OCH3

–78 °C NaH, PhCH3
ii. CH3I 130 °C
78% O CN OCH3 91% O OCH3
Scheme 1
1.13.2.2 Elimination of Carbon Oxides
1.13.2.2.1 Decarboxylation
The decarboxylation of acids under oxidative conditions can be achieved in the presence of lead
tetraacetate associated with copper(II) acetate. Applied to dipeptides, the resulting N,O-acetal
intermediates eliminate in the presence of a tertiary amine and lithium perchlorate
<2001JOC8215>. O-Acetyl sialic acid under similar conditions is converted into a conjugated
lactone <1996CAR181> in moderate yield (Equation (11)). Vinylphosphine oxides were also
obtained from (carboxyethyl)phosphine oxides by using these conditions <2000MI007>.
O
OAc OAc Pb(OAc)4
pyridine O
AcO
R O CO2H AcO
90 °C ð11Þ
AcO AcO
23% AcO R
OAc
R = NHAc
Of great interest, is the oxidative decarboxylation of allyl -keto esters promoted by palladium
catalysts like Pd2(dba)3 in refluxing acetonitrile and in the presence of triphenylphosphine
<B-2000MI001> (Equation (12)).
O O
O
Pd2(dba)3, PPh3
ð12Þ
O CH3CN
79%
,-Disubstituted O-acyl thiohydroxamates, under irradiation, are converted into alkenes,

unfortunately without noticeable regiocontrol <1999T3573> (Equation (13)). A two-step proce-
dure involving -silyl Barton esters allows rapid access to alkenes with (E)/(Z) stereocontrol up to
90/10 <2002OL4253> (Equation (14)).
hν
O ( )9 ( )9
Ph3CSNO, Ph-H
N + ð13Þ
( )9 O
1.1 h
S
39% 1:3
i. hν
PhMe2Si O
CH2Cl2, –10 °C
N ð14Þ
O n
ii. Bu4NF, THF, rt
S
40%
1.13.2.2.2 Di-decarboxylation
In the recent past, maleic acid and its anhydride have been conveniently implied into [2+2]- and
[4+2]-cycloadditions. A subsequent bis-decarboxylation promoted either by lead tetraacetate,
electrochemical conditions, or transition metal complex-mediated reactions allowed the genera-
tion of a double bond <1984T2585>. As already mentioned in COFGT (1995)
<1995COFGT(1)553>, the impact of this two-step strategy has considerably diminished since
the discovery of modern alkyne equivalents.
1.13.2.2.3 Decarboxylation/dehydration
3-Hydroxy carboxylic acids are readily available via aldolization. Their decarboxylation, com-
bined with the loss of the hydroxyl group, has been achieved directly or after formation of
the -lactone. For example, a catalytic amount of vanadium trichloride (10%) and other
vanadium(V) complexes, such as trichloro(arylimino)vanadium, can induce this reaction in chloro-
benzene, which is the solvent of choice <1997CRV2707> (Equation (15)).
O OH
V(p-tolylimino)Cl 3 (0.1 equiv. )
HO Ph ð15Þ
Ph-Cl, 49 h Ph
95%
The thermal decarboxylation of -lactones produces quantitatively and stereospecifically the

corresponding alkenes (Equation (16)). It is worth noting that these four-membered rings are
easily prepared from 3-hydroxyacids in the presence of benzene sulfonyl chloride <1995TL7643,
1998JCS(P1)2721>. In some cases, the decarboxylation has been also included in tandem pro-
cesses. For example, a one-pot synthesis of cycloalkenones has been reported <2001JOC7818>.
The highly strained bicyclic -lactones obtained by a [2+2]-cycloaddition between a keto ester
and an ynoate followed by a Dieckmann condensation underwent a fast decarboxylation to
deliver the target molecules in good yields (Equation (17)).
O 160 °C ð16Þ
93%
O
O-Li O O
CO2Et O
( )n O H3C O-Li Ph-H, ∆
EtO2C ð17Þ
O O
( )n ( )n n = 1 89% ( )n
Ph Ph Ph n = 2 84% Ph
1.13.2.2.4 Decarboxylation/dehalogenation
The decarboxylation/dehalogenation has not been widely developed in organic synthesis. A
remarkable example is, however, depicted in Equation (18). Microwave irradiation of 2,3-dibromo-
alkanoic acids in DMF gives exclusively the (Z)-bromoalkenes in a very short reaction time and
in high yields <2001TL3893>.
Br
Br2, CHCl3 Et3N, DMF R
CO2H CO2H
R R ð18Þ
MW, 1 min Br
Br 73–99%
1.13.3 BY ELIMINATION OF HALOGEN (OR H-HAL)
1.13.3.1 Elimination of Dihalides

The development of orthogonal protective groups is an important concept and very useful for
the total synthesis of complex natural products. Therefore, the protection of an alkene as a
1,2-dibromide is appealing. The regeneration of the alkene functionality can be achieved under
various procedures. Most of them require the use of low-valent metals in stoichiometric amount,
or as catalysts when combined with a suitable reducing agent. For example, nickel(0) can
be generated from the reaction of ethylmagnesium bromide with Ni(dppe)Cl2 in THF at 0 C
and the bis-dehalogenation is very rapid, tolerant to ketals and THP ethers, and gives mainly
quantitative yield in olefins <1995TL9189>. Alternatively, EtMgBr can be replaced by Bu3SnH
to generate nickel(0) <1998T1021>. Zinc has also been used to produce the corresponding
alkenes from the 1,2-dibromo compounds <1995TL7753, 1996JA2556> (Equations (19) and (20)).
O O
O
O O
N Zn/Ag ð19Þ
N
O THF O 96% O
Br Br
O N
F8 Zn/DMSO F8
Br ð20Þ
Br
Dichloroindium hydride (Cl2InH), easily obtained by mixing InCl3 and sodium borohydride,
can also reduce 1,2-dibromides to (E)-alkenes (Equation (21)) presumably by a radical process
<2003SL1012>.
InCl3 (0.2 equiv.)
Br
MeO NaBH4 (1.5 equiv.) MeO
OMe OMe ð21Þ
CH3CN, –10 °C, 5 h
Br
85%
The reductive power of samarium metal has been demonstrated for numerous reactions
<2002EJO2431> and advantageously used for the conversion of 1,2-dibromides into alkenes
when performed in the presence of a catalytic amount of HCl <1996TL9313> or NH4Cl
<1999T10695>. Miscellaneous conditions (Equations (22)–(24)) were reported including
the use of dibutyl telluride <1998JOC169, 1998JOC177> and 1,5-ditelluracyclooctane
<1998JCS(P1)3147>, heating in the presence of strong bases such as KOH <2001S2247>,
methyllithium <1996T3409> or with phosphorus reagents such as PPh3 at 70 C in a mixture
of acetonitrile/methanol (10/1) <2001HAC217> or HMPA at 155 C under inert atmosphere
<2001BCJ1089>.
Br Br Te
Te ð22Þ
CHCl3, 90 °C
O 100% O
i. MeLi
ii. Ethylene oxide
Br Br ð23Þ
iii. H3O+
MeO O
MeO O Br 20% OH
Br
PPh3, 70 °C
CO2Et ð24Þ
CO2Et
Br CH3CN, CH3OH
94%
Reductive elimination of trans-1,2-dibromocyclohexane has been also carried out by electro-

chemical catalysis in conductive microemulsions <1996JOC5972> to produce cyclohexene in
almost quantitative yield.
The cleavage of two vicinal chlorine atoms has been utilized for the synthesis of cyclobutene
derivatives from [2+2]-cycloadducts (Equations (25) and (26)). Treatment of vic-dichlorocyclo-
butanes with zinc in refluxing ethanol <2003TL69, 2003JOC3246> or with sodium naphthalenide
<1998JOC1379, 2001TL2855> affords unsaturated four-membered rings in good yield.
O O
PivO O O
PivO
H3C Zn, EtOH, ∆ ð25Þ
H3C
Cl Cl 60%
H 3C CH3
Cl
Sodium naphthalenide
ð26Þ
DME
Cl O O
HO HO
77%
Due to the great strength of the CF bond, perfluoro compounds are usually inert. However,
defluorination and subsequent aromatization has been achieved when perfluorodecalin was
stirred at room temperature in the presence of a titanium metallocene associated with aluminum
metal <1996JA1805>. As already pointed out in COFGT (1995), sodium/mercury amalgam or
tetrakis(dimethylamino)ethene can also be used for the synthesis of perfluoroalkenes
<2001JCS(P1)398> from the parent alkanes (Equation (27)).
N N
F
F F F F
N N F3C F
CF3
ð27Þ
F3C
F CF3
F F CH2Cl2, rt
F
66%
1.13.3.2 Elimination of Hydrogen Halides
1.13.3.2.1 Dehydrofluorination
The introduction of at least one fluorine atom usually has a strong impact on the properties
of drugs and biologically active compounds, and consequently, the elimination of HF
(the reverse process) has been less studied. The rare mechanistic studies are in favor to a
E1cB process <2001JA2712, 2003JOC718>. During the synthesis of modified urocanic
acids (Equation (28)), the elimination of HF was preferred to the elimination of HBr
<2002JOC3468>.
CO2CH3 F CO2CH3 CO2CH3

Et3N.3HF
NBS Br –HF Br ð28Þ
Tr N N
CH2Cl2, 0 °C Tr N N 63% Tr N N
Thermal cycloadditions of highly electrophilic alkenes with anthracene is accompanied by the

loss of HF <1998T4949> (Equation (29)).
CF3
F CF3
F F3C
F3C
F3C ð29Þ
CF3
H 300 °C, quartz tube 97%
1.13.3.2.2 Dehydrochlorination
Compared to fluorinated compounds, elimination of HCl can be achieved at room temperature
with DBU <2002T9839> (Equation (30)). From dichlorobutene, a two-step sequence MCPBA
oxidation/KOH elimination allows a short access to a 1,2-epoxy-3-chloro-3-butene (Equation
(31)), a promising synthon for the synthesis of different marine natural products
<2002JOC3847>. Potassium hydroxide can also be replaced by stronger base (ButOK in
DMSO) <1999T13205>.
CO2Me DBU, rt CO2Me

CH2Cl2 ð30Þ
Cl
ButO O 78% ButO O
3/1 (E )/(Z )
O O
MCPBA KOH ð31Þ
Cl Cl
Cl CH2Cl2, rt Cl 64% Cl
1.13.3.2.3 Dehydrobromination
As bromoalkanes are more stable than iodo compounds and more reactive compared to chloro-
alkanes, the bromo derivatives have been widely used in elimination processes and an astonishing
number of methods have been applied to this goal. Simple heating of -haloketones in DMF and
in the presence of lithium chloride (Equation (32)) efficiently induced dehydrobromination
<2002BMCL3317, 2003JNP588>.
O O
LiCl, DMF, ∆, 7 h ð32Þ
Br
84%
MeO2S MeO2S
With nonactivated substrates, the use of bases such as DBU, DBN in benzene, toluene, or
acetonitrile is required <2001TL4409, 2003JNP810, 1999T13205, 2002H(56)313> (Table 2).
Table 2 Dehydrobromination under basic conditions

Entry Substrate Conditions Product Yield (%)
Br DBU, CH2Cl2
1 94
N rt, 12 h N
O Bn O Bn
Br
O DBU, benzene O
2 66
O rt, 24 h O
Br
O TBAF, THF O
3 76
O rt, 6 h O
O O
OEt OEt
Al2O3, pentane
4 91
OEt rt, 12 h OEt
Br
Cbz Cbz
N N
DABCO,
5 Br >67
CH3CN, 80 C
Br
Of interest, proazaphosphatrane reacts faster than DBU or DBN in acetonitrile (Equation (33)).
A carbanion, generated by deprotonation of acetonitrile by the phosphorus base could be
implicated in this process. This hypothesis is supported by 31P-NMR studies <2002JOC420>.
P
N N
N
N ð33Þ
Br
OAc CH3CN, rt OAc
52%
1.13.3.2.4 Dehydroiodination
Elimination of HI has been noticed during the iodine-promoted thioetherification of an unsatu-
rated benzyl sulfide which led, after oxidation, to a cyclic sulfone <2003EJO209> (Equation
(34)). Similarly, iododihydropyrroles obtained from -enamino esters undergo dehydroiodination
and an in situ aromatization <1995JOC7357> (Equation (35)).
O O
S S
OTBDPS I2, NaHCO3 S
MCPBA ð34Þ
BnS
I OR OR 66%
OR
Ph NH O CO2Et CO2Et
I2, NaHCO3 DBU, PhMe, ∆

OEt I
N ð35Þ
N 85%
Ph Ph
Iodo derivatives are highly sensitive to UV irradiation. -Iodo ketones can be transformed at
300 nm into ,-unsaturated ketones (Equation (36)). Unfortunately, the enones are contami-
nated with the reduced ketones making the purification difficult <1999TL9263>.
O O O
hν
+ ð36Þ
n-Hexane, 1 h
I
58% 26%
An alternative to this photochemical reaction consists of submitting the same substrates to

MCPBA. The supposed iodoso-intermediate can eliminate ‘‘HOI’’ via a syn-elimination process.
However, this oxidative elimination is much more efficient with -iodo cycloalkanones than with
acyclic ketones <2004S202>.
1.13.4 BY ELIMINATION OF OXYGEN FUNCTIONS
1.13.4.1 Dehydration
1.13.4.1.1 Using Burgess’ reagent

The dehydration of alcohols occurs effectively with Burgess’ reagent (methoxycarbonylsulfonyl
triethylammonium hydroxide). This reagent is commercially available but as reported
<2000SL559>, it is better to prepare it just before use, by condensation between chlorosulfonyl
isocyanate and triethylamine in methanol (Equation (37)).
O O O
O O S OMe ð37Þ
MeOH, Et3N N N
S
Cl NCO
Burgess reagent is used with secondary and tertiary alcohols giving the expected alkenes according
to a mechanism similar to the Tschugaev syn-elimination of xanthates <2000JPR518>. A major
drawback for the use of this reagent is the absence of regioselectivity, as pointed out in a total synthesis
of naturally occurring taxadienes (Equation (38)). A tertiary alcohol is smoothly converted into a 1:1
mixture of two dienes <1995JOC7215>. Similarly, -alkylidene butenolides were prepared by an
efficient dehydration with the Burgess’ reagent <2000NJC659> (Equation (39)).
CH3 CH3 CH3
Burgess’ reagent
ð38Þ
H H CH Toluene, ∆ H H H H
HO 3 CH3
60%
1:1
HO Burgess’ reagent
(1.1 equiv.) O
S ð39Þ
HO O
S Hexane, 50 °C, 1 h
O 43% (Z )-isomer only
A supported-Burgess’ reagent has been designed and appears very useful for the cyclodehydra-
tion of -hydroxythioamides <1998T6987>.
1.13.4.1.2 Using Martin’s sulfurane reagent

Martin’s sulfurane reagent is highly sensitive to moisture and is also expensive. Despite these
disadvantages, it has been applied to very sensitive substrates. Table 3 shows representative
applications of Martin’s sulfurane reagent for the formation of alkene subunits in the presence
of functionalities such as an oxazolidinone <1996TL4317>, a ketal <1997MI487>, silyl ethers
<2002SL358>, a carbonate, or an epoxide <2002JA5380>.
Table 3 Use of Martin’s sulfurane reagent for dehydratation of sensitive alcohols

Entry Substrate Product Yield (%)
O O
H O H O
1 HO N N 64
O O
O O
2 80
TBDMSO TBDMSO
OH
O O O
O
O O
O
O
HO
3 MeO 79
MeO O O OTES
O O OTES
O
O
OTES
OTES
HO CO2Me CO2Me CO2Me
4 83
TBSO O RO O RO O
O OMe OMe O OMe
O
OMe 30:1 OMe
OMe
1.13.4.1.3 Dehydration by other methods

Dehydration of alcohols under acidic conditions is obviously a widely used method to prepare
alkenes. The efficiency of this process is correlated to the stability of the carbocationic inter-
mediate. In the last step of the synthesis of roseophilin, dehydration of a tertiary alcohol furnishes
the target molecule in good yield (Equation (40)) <1998JA2817>.
MeO N i. Bu4n NF, H2O

MeO N
OH SEM ii. aq. HCl HCl
ð40Þ
O O
76%
Cl N TIPS Cl N H
A new concept for the formation of CC double bond takes advantage of the reactivity of
S-propargylic xanthates under thermal conditions in the presence of a catalytic amount of
collidinium trifluorosulfonate <1999TL1305> (Equation (41)).
i. Base S S
ii. CS2 (10%)
OH O S O S
iii. X N
H TfO ð41Þ
∆ H
98%
Ph Ph Ph Ph
Tertiary and benzylic alcohols can also be converted in situ into pseudoureas which presumably
undergo an E1 process or an Ei reaction, which is typical of pyrolytic eliminations (Equation (42))
<1999NJC129>. The eliminations of the pseudourea obtained from primary or secondary
alcohols were less efficient and required higher temperatures.
OH
H OCH3 OCH3
H H
O O
C6H11
N ð42Þ
DCC, CuCl 90 °C, 4 h
25 °C NH-C6H11
O 76%
THF H OCH3
H
O
Dehydration of secondary alcohols can be carried out by thermolysis of alkyldiphenylphos-
phates in the presence of a base such as quinoline or calcium hydride. The phosphorus derivative
is prepared just before use with diphenylphosphorochloride or generated in situ by simple heating
with triphenylphosphate <1995S1300>.
1.13.4.2 Elimination of Alcohols (H–OR)

To overcome the poor nucleofugacity of alkoxy groups, the presence of a Lewis acid is usually
required to allow the elimination by treatment with bases like DBU. 4,6-Dialkoxy-7-arylthioheptenes
were converted into the corresponding dienes as a mixture of two regioisomers (Equation (43)) by first
activation with trimethylsilyltriflate followed by the addition of DBU <2002JOC7957>.
OMe
MeO
OMe OMe 7
S-Tol
TMSOTf DBU
+ + ð43Þ
S
S-Tol CH2Cl2, 20 °C, 5 h 50% OMe
p-Tol
TfO–
1
S-Tol
The use of strong bases like the superbasic butyllithium/potassium t-butoxide mixture
(LICKOR) known also as the Schlosser’s base is needed for the conversion of ,-unsaturated
acetals or ethers into 1,3-dienes <1998T14603, 2000S1615>. Polyenol ethers were similarly
synthesized from -phenoxy analogs <1998TL2335, 2002TL8759> (Equation (44)).
BunLi/ButOK HO
O THF, –95 °C ð44Þ
75%
Spiro-ketals are also opened by activation with trimethylsilyl triflate to deliver chiral enol
ethers, which are very useful for -functionalization (Equation (45)) <1999EJO2709>.
TMS-OTf O O
O O Bun4NF
Pr2i NEt OTMS OH ð45Þ
THF/H2O
CH2Cl2 79%
1.13.4.3 Eliminative Ring Opening of Epoxides

Rearrangement of epoxides into allylic alcohols under basic conditions has been extensively
reviewed <2002S1625>. Recent reports are devoted in part to mechanistic studies
<2003JA15893> and mainly to asymmetric developments. Desymmetrization of meso-epoxides
reported a long time ago with chiral bases in stoichiometric amounts <1998JCS(P1)1439>, can
now be achieved in a catalytic manner with similar level of induction. Since the first results
obtained with proline derivatives by Asami <2002T4655>, or with homochiral C2-symmetric
diamines prepared by Alexakis <1997TA1019>, the rearrangement of epoxides induced by a base
has been also applied to the kinetic resolution (Equation (46)) of nonsymmetric epoxides
<2002OL3777, 2000JA6610> (Table 4).
H
N
N
(0.1 equiv.)
R LDA (2 equiv.) R OH ð46Þ
DBU (5 equiv.), THF, 0 °C R
O O +
(+/–)
Table 4 Catalytic kinetic resolution of racemic epoxides to allylic alcohols
Epoxide Allylic alcohol
Entry R Conversion (%) Yield (%) ee (%) Yield (%) ee (%)

1 Me 52 38 87 40 94
2 Et 63 32 70 37 90
3 But 58 36 99 40 99
Promoted by a Lewis acid like aluminum tri(isopropoxide), the rearrangement of epoxides has
been included in the total synthesis of natural products such as brassinosteroids <2002TL3181>
(Equation (47)).
O Al(OiPr)3 (3 equiv.) HO ð47Þ

Toluene, ∆
CN Cl 98% CN Cl
1.13.4.4 Elimination of a Carboxylic Acid (H-OCOR)

-Aldols can be easily esterified to acetates or benzoates which under basic conditions are converted
into enones in convenient yields via an E1cB mechanism <1999TL2685>. Such a sequence has been
included in the total synthesis of 1,6-germacradienols <2002JOC1554> (Equation (48)).
DBU, THF, 0 °C ð48Þ

O O
56% O
O
Compared to other carboxylates, trifluoroacetate is a very good leaving group. Interestingly,

treatment of alcohols with trifluoroacetic acid or anhydride can give directly the products
resulting from the elimination <1997JOC1675> (Equation (49)).
OH
H
O H O N
N
O
TFA (50%), rt, 8 h ð49Þ
55%
OMe OMe
OMe OMe
Elimination of nonactivated acetates were reported to proceed by using molybdenum catalysts

as noticed in chapter 1.13.4.4 of COFGT (1995) <1995COFGT(1)553>. Further investigations in
this area have been devoted to the exact nature of the catalyst <1996JOM(506)139>. Allylic
cyclic carbonates undergo elimination in the presence of a catalytic amount of Pd(0) complex
<1995TL405>. A self-coupling process occurs with monosubstituted alkenes (Equation (50)).
MPMO
Pd2(dba)3.CHCl3 (0.05 equiv.)
OH
O ð50Þ
PPh3 (0.2 equiv.), THF, ∆, 15 min MPMO
O
O 93%
1.13.4.5 Elimination of a Sulfonic Acid

The elimination of mesylates or tosylates is a very popular process for the synthesis of alkenes.
Direct heating of primary tosylates in diglyme in the presence of sodium iodide and DBU allows
an access to methylene derivatives <2003S1324> (Equation (51)). The same sequence applied to
homoallylic alcohol derivatives gives 1,3-dienes with the same efficiency (Equation (52)). This
one-pot procedure avoids the isolation of alkyl iodide intermediates, which are usually unstable.
NaI (3 equiv.)
TsO OTBDMS DBU (2 equiv.) OTBDMS
ð51Þ
Diglyme, 85 °C OTBDMS
OTBDMS
95%
NaI (3 equiv. )
DBU (2 equiv. )
TsO OPMB OPMB ð52Þ
Diglyme, 85 °C
OTBDMS 98% OTBDMS
A similar sequence was reported during the last step of a synthesis of illudin C. The mesylate
prepared from the primary alcohol is converted into the alkene by addition of DBU
<2001OL2611> (Equation (53)).
O O
MsCl, Et3N,
HO CH2Cl2, –78 °C
DBU, rt ð53Þ
OH 73% OH
Illudin C
The elimination carried out on a 1,2-bis-tosylate has been combined with a regioselective
substitution on the primary tosylate by a chloride anion delivered by the tetrabutylammonium
salt <2001JMC1749> (Equation (54)).
H3CO OCH3 DBU, CH3CN, ∆ H3CO OCH3

H
O O NBun4Cl ð54Þ
O O
80%
TsO OTs
Cl
1.13.4.6 Elimination of 1,2-Diols and Derivatives

Vicinal dimesylates can be easily converted into alkenes by treatment with arene selenide
anions or telluride dianions. The generation of such species requires, however, strong reductive
conditions (the use of hydrides or alkali metals in ammonia) <1996JOC7426, 1997JOC3751>
(Equation (55)). Clive and co-workers <2000OL4029> were the first to develop a catalytic
version for this reaction. In order to remove the selenide by-products, Crich and co-workers
have taken advantage of a ‘‘light’’ fluorous reagent.
H
NaBH4, EtOH, ∆ H
O N O
(RfArSe)2 (0.4 equiv.) O N O
O N
TBDMSO 86% O N
TBDMSO ð55Þ
MsO OMs
RfAr = pCF3(CF2)5C6H4
When cyclic sulfates, prepared from 1,2-diols, are treated at room temperature with magnesium
iodide in acetonitrile, the corresponding alkenes are formed in high yields <1998SC871>.
Iodothiocarbonates submitted to lithium derivatives also afford terminal alkenes in impressive
yields <1999TL4019> (Equation (56)).
O
S
Ph-Li
O O SCH3
O CH3I 0 °C, THF ð56Þ
I
TBDPSO 96% 97%
OTBDPS
OTBDPS
Free-radical fragmentation of bis-thioxocarbamates performed with Bu3SnH, or better with

tris(trimethylsilyl)silane (TMSSH), provides access to alkenes and has been applied to the synth-
esis of 2,3-didehydronucleosides <2003TL4027> (Equation (57)).
H
O N O H
(Me3Si)3SiH, AIBN
O N O
O N Benzene, 80 °C, 4 h
TBDMSO ð57Þ
69% O N
S S TBDMSO
O O
PhHN NHPh
1.13.4.7 Deoxygenation of Epoxides and Halohydrins

Direct conversion of epoxides into alkenes has been described by using numerous procedures
<B-1999MI001>. For example, the use of trimethylsilyl iodide or a combination of LiI with
Amberlyst 15 <2000T1733> provides the corresponding alkenes, but with loss of stereocontrol as
it was noticed with (E)- and (Z)-stilbene oxides (Equation (58)).
Ph LiI, Amberlyst 15
Ph Ph
O Acetone, 3 h, rt
Ph ð58Þ
85–93%
Reactions catalyzed by low-valent titanium species <1995JA4468> can be easily performed on

a large number of substrates via a SET process <1998JOC356, 2002EJI3091>.
Methyl rhenium trioxide (MTO) can be used as catalyst for olefin epoxidation in the presence
of hydrogen peroxide. Associated with triphenylphosphine, MTO catalyzes the transfer of the
oxygen atom (Figure 1) of the epoxide to the phosphine <1995JMOC87>. Other rhenium
derivatives were used <2000OM944> including polystyrene-supported oxorhenium complexes
<2002HCA3225> which facilitated the work-up of the reaction.
R LReO2
O O=PPh3
R LReO3 PPh3
Figure 1 Deoxygenation of epoxides catalyzed by MTO in the presence of phosphine.
A tellurium-based method initially described by Dittmert and co-workers <1994JOC1004> has

been applied to the deoxygenation of trans-epoxy alcohols <2000JOC3047> (Equation (59)).
OH OH
i. Ac2O, pyr, DMAP
ð59Þ
O ii. Te, LiEt3 BH, THF
R R
75%
The conversion of ,-epoxy esters or ketones has been investigated in detail and the use of
NaI and Amberlyst in acetone <2000T1733, 2000TL9315> or thiourea dioxide (TDO) under
alkaline and PTC conditions <1997TL745> allows this transformation in high yields.
Metal complexes have also been reported for this purpose. Mo(CO)6 in refluxing toluene
<2003TL2355> or sodium amalgam in THF with a catalytic amount of cobalt(II) complex are
also efficient <1999TL8747>. A combination of tungsten hexachloride and butyllithium at very low
temperature was applied to a synthesis of oestrone derivatives <1995TL1237>. Other complexes
like Cp2TiCl were also widely considered for this deoxygenation <2002JOC6571, 2003TL435>.
Treated with samarium diiodide, ,-epoxy esters furnished unsaturated esters in very high
yields and in high (E)-selectivity <2002OL189>.
Deoxygenation of epoxytropane derivatives was achieved with a zinc/copper couple in alcoholic
media (Equation (60)). Side reactions such as ring-opening of the oxirane moiety could be
suppressed by using hindered t-butanol versus ethanol <2001JCS(P1)1044>.
R R R
N N N
Zn/Cu R'O
R'OH, ∆
+ ð60Þ
( )2 ( )2 ( )2
O OH
R' = Et 31% 40%
R' = t-Bu 52%
A combination of allyl silane with titanium tetrachloride was able to convert iodohydrins and
iodoethers into the corresponding alkenes by a stereospecific anti-elimination <1997TL5161>
(Equation (61)).
OH
O Bun4NI, TiCl4 SiMe3
R R R
R R R
CH2Cl2 TiCl4
I
(R = n-pentyl) ð61Þ
cis/trans (Z )/(E )
1/99 1/99
92/8 89/11
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Biographical sketch
Olivier Piva was born in 1960 in Ardennes (France), studied at the

University of Reims, where he obtained his Ph.D. in 1988 under the
direction of Professor J. P. Pete. After spending a year at RWTH,
Aachen in the group of Professor D. Enders, he entered in 1989 the
CNRS as Chargé de recherche, working in Reims on asymmetric photo-
chemical reactions. He spent one year at Cambridge University in 1996
working with Professor S. V. Ley on the synthesis of a complex marine
natural product. Back to France, he took a Full Professor position in
1998 at the University Claude Bernard – Lyon I. His scientific interests
are related to asymmetric synthesis, photochemistry, metathesis, and
their application to the synthesis of natural products.
1.14
One or More C¼C Bond(s) by
Elimination of S, Se, Te, N, P, As,
Sb, Bi, Si, Ge, B, or Metal Functions
J. EUSTACHE, P. BISSERET, and P. VAN DE WEGHE
Ecole Nationale Supérieure de Chimie de Mulhouse, Mulhouse,
France

1.14.2 BY ELIMINATION OF SULFUR, SELENIUM, OR TELLURIUM FUNCTIONS 602
1.14.2.1 Elimination of Sulfide, Selenide, or Telluride Groups 602
1.14.2.1.1 Elimination of sulfide, thiocyanate, and xanthate groups 602
1.14.2.1.2 Elimination of selenide groups 606
1.14.2.2 Elimination of Sulfoxide, Selenoxide, or Telluroxide Groups 607
1.14.2.2.1 Elimination of sulfoxide groups 607
1.14.2.2.2 Elimination of selenoxide groups 612
1.14.2.3 Elimination of Sulfone, Selenone, or Tellurone Groups 614
1.14.2.3.1 Elimination of sulfone groups 614
1.14.2.3.2 Elimination of selenone and tellurone groups 620
1.14.2.4 Elimination of Sulfimine, Selenimide, Tellurium Imide, Sulfinamide, Sulfoximine,
Sulfonamide, and Sulfonate Groups 620
1.14.2.5 Elimination of Sulfonium, Selenonium, and Telluronium Salts and Ylides 620
1.14.3 BY ELIMINATION OF NITROGEN FUNCTIONS 622
1.14.3.1 Elimination of Amine Oxides—The Cope Reaction 622
1.14.3.2 Elimination of Quaternary Ammonium Salts—The Hoffmann Elimination 623
1.14.3.3 Alkenes from Arenesulfonyl Hydrazones 625
1.14.3.4 Elimination of Amine Derivatives 630
1.14.3.5 Elimination of Nitro Groups 631
1.14.4 BY ELIMINATION OF PHOSPHORUS, ARSENIC, ANTIMONY, OR
BISMUTH FUNCTIONS 632
1.14.4.1 Elimination of Phosphorus Groups 632
1.14.4.1.1 Elimination of -hydroxyphosphane oxides and -hydroxyphosphonates:
the Horner–Wittig reaction 632
1.14.4.1.2 Via oxirane-opening reactions 637
1.14.4.2 Elimination of Arsenic, Antimony, and Bismuth Functions 638
1.14.5 BY ELIMINATION OF SILICON, GERMANIUM, OR BORON FUNCTIONS 638
1.14.5.1 Elimination of Silicon Groups 638
1.14.5.1.1 Elimination of -hydroxysilanes and -hydroxyallylsilanes 639
1.14.5.1.2 Elimination of -sulfonyloxy-, -acyloxy-, and -alkoxysilanes, and
-sulfonyloxy-, -acyloxy-, and -alkoxyallylsilanes 640
1.14.5.1.3 Long-range elimination of hydroxy-, sulfonyloxy-, acyloxy-, and alkoxyallylsilanes 645
1.14.5.1.4 Elimination of -halosilanes 646
1.14.5.1.5 Elimination of -aminosilanes 648
1.14.5.1.6 Elimination of sulfur-containing leaving groups 649
1.14.5.1.7 Other eliminations of silanes 650
1.14.5.2 Elimination of Germanium Groups 652
601
602 One or More C¼C Bond(s) by Elimination of Metal Functions
1.14.5.3 Elimination of Boron Functions 653

1.14.5.3.1 Elimination of alkylboranes 653
1.14.5.3.2 Elimination of -substituted alkylboranes 653
1.14.6 BY ELIMINATION OF METAL FUNCTIONS 654
1.14.6.1 Elimination of Tin 654
1.14.6.1.1 Elimination of -hydroxystannanes, derived ethers and esters 654
1.14.6.1.2 Other eliminations of stannanes 655
1.14.6.2 Elimination of Mercury 658
1.14.6.3 Elimination of Transition Metals 659
1.14.1 INTRODUCTION
-Elimination of heteroatoms is one of the most useful methods for the preparation of alkenes.
This elimination can be performed either from an isolable precursor (e.g., the -elimination of
sulfoxides) or as a step in a coupling reaction (e.g., the Wittig reaction). The distinction between
these two processes is not always clear-cut, however. Whereas in certain coupling reactions the
coupling and elimination steps are not readily distinguished (e.g., the Wittig reaction), in others
(e.g., the Peterson reaction) coupling intermediates can often be isolated. In the original Horner–
Wittig reaction, intermediate -hydroxyphosphine oxides are generally isolated and can be
chemically manipulated before elimination. In this chapter, the focus is on eliminations from
isolable precursors. Accordingly, important coupling reactions such as the Wittig, Horner–Wads-
worth—Emmons, or Peterson reactions in which spontaneous elimination generally occurs are only
briefly mentioned and dealt with in detail in Chapter 1.16. In addition, reactions such as the Julia
olefination (in its original version) or the Horner–Wittig reaction involving the formation of well-
defined intermediates and their chemical modification are more extensively discussed herein.
1.14.2 BY ELIMINATION OF SULFUR, SELENIUM, OR TELLURIUM FUNCTIONS
1.14.2.1 Elimination of Sulfide, Selenide, or Telluride Groups
1.14.2.1.1 Elimination of sulfide, thiocyanate, and xanthate groups

Apart from occasional reports where acidic conditions were used <1998H1599>, elimination of sulfide
groups is generally performed under basic conditions. For instance, elimination of thiophenol from a
nitrone-derived cycloadduct to form an ,-unsaturated ketone derivative was efficiently promoted
under mild basic conditions by simple heating in the presence of pyridine and acetic anhydride
(Equation (1)) <1995TL8665, 1997JOC7781>. In this particular case, the procedure proceeded in better
yield than the alternative pyrolytic elimination of the corresponding sulfoxide (see Section 1.14.2.2.1).
O O
HH SPh HH
Ac2O, Pyr
O O ð1Þ
N O 77% N O
HO Me HO Me
Me Me
Basic conditions also proved to be very efficient for xanthate removal in the last step of the
preparation of the terpenoid cinnamolide (Equation (2)). In contrast, a similar treatment per-
formed on the monocyclic lactone 1 invariably led to the undesired regioisomer possessing an
endocyclic double bond. The required exo-methylenic compound could however be obtained
using a pyrolytic elimination in the presence of copper powder under vacuum, as illustrated in
Scheme 1 <1996CC1631, 1999T3791>.
O O
O DBU, CHCl3 O
S ð2Þ
80%
S O
One or More C¼C Bond(s) by Elimination of Metal Functions 603
O O O
O
DBU S Cu, 180 °C
O S O
O 84% O 1 mm Hg O
O
C5H11 28% C5H11
MeO C5H11 MeO
MeO
1
Scheme 1
Stereoselective elimination of HSCN from a diastereoisomeric mixture of thiocyanates resulting

from thiocyanatoarylation of diethyl fumarate was also performed under mild basic conditions
<1998ZOR1576> as shown in Scheme 2. The diastereoisomeric ratio in the starting mixture of
thiocyanates and the cis/trans proportion of the resulting alkenes were similar.
OEt EtOOC H EtOOC H

– +
O KSCN H SCN H CO2Et
+ BF4 N2
O + + CO2Et + SCN
Cu
OEt
65 35
EtO O
OEt OEt
Piperidine O
O + O
OEt
65 35
Scheme 2
A new method for high-yield preparation of conjugated dienoic esters has been disclosed. It
involves the treatment of heterocyclic allyl sulfides with an excess of ethyl diazoacetate in the
presence of a copper(I) complex. A first [2,3]-sigmatropic sulfur ylide rearrangement leads to an
intermediate homoallylic sulfide, which can be isolated. This reacts further with ethyl diazoacetate
to undergo a formal -elimination implying the formation of a transient sulfur ylide as shown in
Scheme 3 <1997TL3289>.
+
N
N Cu
S Ph + N2CHCO2Et S S
S 20 °C
O
Ph OEt
O
OEt
–
N2CHCO2Et + N O
H S
20 °C S 76–94% Ph OEt
Ph OEt
O
Scheme 3
A synthesis of nonconjugated dienes from -hydroxy-homoallyl-2-benzothiazolyl sulfides has

also been reported. In this case, the elimination of sulfenic acid was accomplished in a two-step
procedure involving the formation of an episulfide which was stereospecifically converted to an
alkene in the presence of triphenylphosphine (Scheme 4) <1998TL3825>.
HO R1
N NaH S PPh3
R2 R1 R2 R1 R2
S
S
Scheme 4
As shown in Equation (3), the stereospecific anti-elimination of benzenesulfenic acid using

diphosphorus tetraiodide according to a method originally developed by Krief and co-workers
<1979TL4111>, allowed access to the sex pheromone of the stink bug Nezara viridula, one of the
most notorious agricultural pests <1998T11421>.
O O
P2I4, Et3N
H ð3Þ
49%
HO
SPh
A formally similar elimination was described recently. Sequential deprotonation of

bis(phenylthio)methane and reaction with a first carbonyl compound, then repeating the
sequence afforded a ,0 -dihydroxysulfide. Desulfurization (Li/di-t-butylbiphenyl (DTBB))
and spontaneous elimination of Li2O led to mixtures of alkenes as illustrated in Scheme 5
<1999TL8177>.
i. BunLi 1 3 1 3
ii. R1R2CO LiO R R OLi Li, DTBB LiO R R OLi
PhS SPh
iii. Li, DTBB R2 R4 R2 R4
iv. R3R 4CO SPh Li
R1 R3 R1 R3
OH + HO DTTB =
R2 R4 R2 R4
Scheme 5
Kuethe and Comins <1999OL1031> also used a benzenesulfenic acid elimination for the
elaboration of the tetrahydropyridine moiety, encountered in many pharmacologically active
agents. As depicted in Scheme 6, this transformation was best realized by first converting the
alcohol group of the -hydroxysulfide to a thiocarbamate. Access to the alkene was effected
under reductive radical conditions as previously reported <1977TL4223>. The elimination pro-
ceeded well regardless of the stereochemistry of the carbon atom bearing the thiocarbamoyl
moiety.
S
S
OH O N N
N N N
PhS N PhS Bu3SnH
O O O
DMAP AIBN
N OMe N OMe N OMe
75% 91%
CO2Bn CO2Bn CO2Bn
Scheme 6
Under basic conditions, -chloroalkyl sulfides may eliminate to afford terminal olefinic double
bonds. This was observed by Bachi and co-workers during a stereoselective synthesis of kainic
acid. The strategy relied on the use of a temporary, sulfur-containing linker allowing the directed
intramolecular displacement of a tosyloxy group. As shown in Scheme 7, basic treatment of
the kainoid chloroalkyl sulfide 2 did not induce the desired substitution but instead yielded the
alkene resulting from formal elimination of sulfenyl chloride (presumably via an episulfonium
species) <1996JOC7116>. The approach was successfully modified by prior oxidation of the
sulfide to the corresponding sulfone (see Scheme 38).
MeO
S O
Cl
MeO
O O
S N
O
Cl
OTs x BOC
KOMe
O THF
N
O –
OTs
BOC Cl +
S CO2Me O
2 50% N
O
BOC
Scheme 7
Elimination of two adjacent sulfide groups, although with a modest yield, was observed during
the treatment of an indolone derivative with TiCl4 in the presence of HCl gas (Scheme 8)
<1997H37>. Another related elimination was accomplished with lithium naphthalenide
<1995SL628>.
–
Cl –
SPh SMe TiCl4
PhS SMe
+ O
O
TiCl4 O N
N
N
HCl gas 29%
Br
Br
Br
Scheme 8
Treatment of episulfides with phosphines leads to desulfurization and formation of alkenes.

The method was recently used for the conversion of vinyl episulfides to conjugated dienes
<1999T3791>. Applied to highly sterically congested sulfides, however, desulfurization with
trivalent phosphorus compounds only proceeded in low yields or even failed completely in the
case of the sulfide 3 <1995BCJ1437>. Other attempts to desulfurize 3, including the action of
strong bases, thermolysis, or irradiation did not give the corresponding styrene. Instead, under
irradiation, sulfide 3 was converted into its less-crowded isomer 4, which then gave the corres-
ponding styrene as well as a rearranged vinyl-substituted Dewar benzene as illustrated in
Scheme 9.
S hν S + +
3 4
Scheme 9
The mechanism of tributyltin hydride-induced desulfurization of episulfides has been thor-

oughly investigated <1995JOC470> and new procedures for the elimination of sulfur have
appeared. They include the catalytic use of aminium salts <1995T8935> or of methyltrioxo-
rhenium in the presence of triphenylphosphine <1999CC1003>. The latter procedure is particularly
useful for speeding-up desulfurizations, which are otherwise too slow when triphenylphosphine
is used alone; as shown in Scheme 10, the mechanism is believed to involve a dioxo ReV as well
as a ReVII sulfide species.
Ph3P O
Me Me
S R
Re O + PPh3 Re
O O O
O
Ph3P S
Me R
PPh3
Re O
O
S
Scheme 10
1.14.2.1.2 Elimination of selenide groups

Elimination of -hydroxyselenides using the well-established Krief–Reich procedure
<1976TL3743, 1979JA6638> involves the use of mesyl chloride in the presence of triethylamine.
The reaction is an anti-elimination of the phenylseleno and the mesyloxy groups and proceeds via
an episelenonium ion. This method has continued to be widely used recently, for instance in the
preparation of sulfinyl butadienes <1996S1079>. The relatively basic conditions required for the
elimination may not be suitable for base-sensitive compounds, and in order to synthesize ,-
unsaturated carbonyl derivatives, Enders and Whitehouse investigated milder elimination condi-
tions <1996S621>. As shown in Equation (4), using trifluoroacetic anhydride in the presence of
barium carbonate allowed (E)-double bond formation while racemization of the -stereogenic
center was kept to a very low level (<5%). The use of other bases caused considerable racemiza-
tion (10–20% for K2CO3, 100% for Et3N).
O OH O
TFAA
ð4Þ
BaCO3
SePh
The stereochemical course of the Krief–Reich elimination in the case of the formation of
,-unsaturated carbonyl derivatives from syn-aldol products (Scheme 11) <2001T6703> has
been carefully investigated, recently. It was noted that pyridine (instead of triethylamine) was
required to ensure a good conversion to (Z)-isomers. With triethylamine, stereoselectivity dropped
considerably due to the formation of anti-aldol products via retroaldolization/recombination.
OH O MeO
Pyr, MsCl
R1 O
R1 OMe
SePh
MeO
R1 O
+
Se
Ph
Scheme 11
The stereochemical requirements of the Krief elimination were evident in the synthesis of
tetrahydropyridine derivatives from cyclic -hydroxyselenides: as shown in Scheme 12, only
the trans-isomer yielded the desired unsaturated compound while the mesylate derived from the
cis-isomer remained unchanged <1999OL1031>. Elimination from the cis-isomer could be
performed using a two-step radical elimination as mentioned earlier (see Scheme 6).
OH
PhSe O
O MsCl, Et3N
N OMe
100%
N OMe CO2Bn
CO2Bn
OH OMs
PhSe MsCl, Et3N PhSe
O O
N OMe 100% N OMe

CO2Bn CO2Bn
Scheme 12
A similar radical elimination from a polymer-supported -bromosulfide has been described by

Nicolaou and co-workers <1998CC1947>.
A -hydroxyselenophosphate and an episelenide were key intermediates in the one-pot conver-
sion of -oxo-selenophosphates to conjugated dienes as shown in Scheme 13 <1999TL3791>.
–
O O Se
P OEt NaBH4 P OEt
Se Se
OEt OEt
O O– O
P OEt
O OEt
96%
Se
Scheme 13
1.14.2.2 Elimination of Sulfoxide, Selenoxide, or Telluroxide Groups
1.14.2.2.1 Elimination of sulfoxide groups

Thermal syn-elimination of sulfoxides is a well-established procedure for alkene synthesis, which
proceeds particularly well and in mild conditions when conjugated alkenes are formed. For
example, a temperature of 40 C was sufficient for the preparation of butadienyl trifluoromethyl
ketones <1996CC861> from -phenylsulfinyl-,-unsaturated-trifluoromethyl ketones and elimi-
nation occurred at room temperature, along with ketal cleavage, in the one-pot formation of
,-unsaturated ketones shown in Equation (5) <1995TL3737>.
O HO
HO
S DOWEX
H2O, 14 h ð5Þ
82%
O O O
A similar facile elimination in acidic medium, leading to an ,-unsaturated lactone, has been
recently reported by Renard and Ghosez <1999TL6237, 2001T2597>.
Sulfenic acid elimination in the nucleoside derivatives shown in Scheme 14 also proceeded
at room temperature to afford (E)- and (Z)-cyanomethylene-deoxyuridine. Interestingly, the
stereochemical course of the reaction was dictated by the neighboring 30 -substituent: a free
hydroxyl group or the corresponding silyl ether orientated the elimination toward the formation
of the (E)- or (Z)-isomer, respectively <1996JOC6261>. Attempts to isolate the intermediate
sulfoxides, which appeared to be unstable on silica gel, failed in these cases.
O O
NH NH
O N O O N O
Si O Si O
i. MCPBA, –78 °C
O O
Si O
CN ii. 20 °C, 11 h Si O CN
SPh
79%
O O
NH NH
O N O As above O N O
Si O Si O
CN 82%
HO SPh HO
NC
Scheme 14
Except for the favorable cases mentioned above, higher temperatures are generally required for
the elimination. These conditions may be too harsh in the case of sensitive compounds. For
example, Node and co-workers reported a novel preparation of optically active allylic alcohols
from ,-unsaturated ketones involving as a key step a tandem Michael addition/Meerwein–
Pondorf–Verley reduction using 10-mercaptoisoborneol (Scheme 15) <2000JA1927>. After an
oxidation step, elimination of sulfenic acid was accomplished with calcium carbonate at 130 C
with a significant decrease of the enantiomeric excess (ee).
OH
O SH O i. NaIO4, MeOH OH
H S H OH
Ph Ph 94%, 98% ee ii. CaCO3, 130 °C, 4 h Ph Ph
Ph Ph 83%, 86% ee
Scheme 15
In such cases, the use of imidazolyl sulfoxides <2000SL1725> (which eliminate more readily
than the commonly used aryl sulfoxides), or promotion under microwave irradiation, have been
recommended <1996TL1855>.
When several possibilities exist for the formation of nonconjugated double bonds, the regio-
selectivity of the sulfenic acid elimination is often poorly controlled. For instance, the last step of
Edmondson and Danishefsky’s synthesis of the spiroindolone spirotryprostatin A relied on the
thermolysis of the tertiary sulfoxide 5. As shown in Equation (6), pyrolysis in refluxing toluene led
to a mixture of two alkenes. Remarkably, it was possible at this stage to cleanly convert
the undesired disubstituted alkene into the target compound by rhodium trichloride
treatment. Further migration of the double bond to form an enamide <1998AG(E)1138> was
not observed.
O O O
O H N O H N O H N
HN Toluene HN HN
N N + N
H H H
O Reflux O O ð6Þ
80%
MeO MeO MeO
S
Ph O 1:2.6
5 Spirotryprostatin A
A related elimination was used as a key reaction during the solid-phase preparation of
2--halomethyl penam derivatives <1999TA3893> (Scheme 16). After immobilization of the
dibromo precursor onto Merrifield resin and oxidation to obtain a resin-bound sulfoxide, pyr-
olytic elimination of the sulfenic acid moiety was assisted by mercaptobenzothiazole as reported
earlier in solution chemistry <1973TL3001>. As expected, the desired disubstituted alkene was
obtained exclusively. The isomeric tetrasubstituted isomer, which would result from a disfavored
elimination to the nitrogen atom, was not observed.
Br H Br H O N
–
S S SH
i. Cl, F
Br Br S
N N
O ii. MCPBA O Benzene, reflux
CO2H
O O
S
S Br H
Br H S
S N X
Br
Br N
N 50% O
O Overall yield
O OR
O O
R = H, Me; X = Cl, Br
Scheme 16
Still in the active field of solid-phase chemistry, safety-catch linkers based on the sulfoxide/
selenoxide syn-elimination have been developed recently <2000TL5287>. As expected, compared
to sulfoxides, selenoxides underwent elimination under much milder conditions; use of sulfoxides
was possible only when conjugated double bonds were formed. Other substrates such as pre-
cursors of the sensitive allylbenzene failed to react at low temperature or decomposed upon
raising the temperature (Scheme 17).
H H
O N O N
O O
Dioxane
+ +
100 °C
O 45% OH 13 1
S S
O
H
O N
DMF
x
Reflux
S
O
Scheme 17
In allylic sulfoxides, 1,2-elimination to give conjugated dienes competes with the well-known
[2,3]-sigmatropic rearrangement. Although the rearrangement pathway is generally favored, there
are exceptions. For example, Koprowski and co-workers observed significant amounts of diene
formation during a synthesis of tertiary allylic alcohols <2001T1105> (Equation (7)).
O O O
OEt OEt OEt
P P P
O OEt O OEt O OEt
OH
S
P(OMe)3 ð7Þ
O +
CN MeOH
CN CN
H 73% H H
1 2.5
In the reaction shown in Scheme 18, the electron-poor alkene resulting from sulfenic acid
elimination was not observed and immediately reacted with a neighboring diene in an intra-
molecular Diels–Alder cycloaddition to give a trans-fused octalin <1995SL909>.
O O O
O O
Toluene, reflux MeO2C H
S
23%
OMe
O
H
O O
OMe
Scheme 18
Apart from thermolysis, elimination of sulfoxides has been occasionally carried out by photo-
lysis, sometimes in excellent yield <1995LA1957>. A new very mild procedure based on the
radical fragmentation of o-bromophenyl sulfoxides has been described by Renaud and co-workers
<1999OL873>. As shown in Scheme 19, Bu3SnH treatment of the representative, optically pure
sulfoxide 6 in the presence of a Lewis acid, gave chiral 4-substituted cyclohexenes with very good
enantiomeric excesses. The key step of the process involves the abstraction of a hydrogen atom by
the initally formed aryl radical. By comparison, thermolysis of 6 gave phenylcyclohexene in only
54% ee and required a temperature of 200 C.
Br O
S Bu3SnH, AIBN, sun lamp
Lewis acid, C6H6, 10 °C Ph
Ph 65%
6 86% ee
O
S
Ph
Scheme 19
Formation of alkenes (mainly (E)) by the elimination of -chloro-, -mesyloxy-, or -acetoxy-

sulfoxides has been studied by Satoh and co-workers <1996T2349, 1998TL6935, 2000T6223>. As
-hydroxysulfoxides may be obtained by the condensation of sulfoxides with aldehydes, this
method may offer an interesting alternative to the well-known Julia–Lythgoe olefination
(see Section 1.14.2.3.1). For example, as shown in Scheme 20, the method could be applied
to the preparation of normally not accessible stilbenes and trisubstituted alkenes. Access to
stilbenes was spontaneous while, in other cases, a sulfoxide-metal exchange, after activation of
the -hydroxysulfoxide, was required.
H O
LDA / O Ph
S
O THF, –55 °C MsCl
S
Ph 92% OH 84%
MeO MeO MeO
i. LDA / O
O AcO
THF, –55 °C BunLi/–78 °C
S
Ph Ph ii. Ac2O/Pyr/DMAP Ph 83% Ph
S
84% O Ph
Scheme 20
The same group proposed an extension of the method to the synthesis of allenes from aldehydes
and alkenyl aryl sulfoxides <1995T9327, 1999TL8815, 2002T2533>. Starting from optically
active sulfoxides, allenes were prepared, usually in high ee values, as exemplified in the synthesis
of the chiral allenic pheromone shown in Scheme 21.
HO CO2CH3 i. Ac2O
LDA
O (CH2)7CH3
S O CO2CH3 O (CH2)7CH3 ii. Chromatography
Tol S
H Tol 51%
31%
AcO CO2CH3 PriMgCl H

C
O (CH2)7CH3 –78 °C, 10 min CH3(CH2)7
CO2Me
S
Tol 95% 81% ee
Scheme 21
Malacria’s group reported a novel preparation of functionalized allenes using an unprecedented

radical -elimination of vinyl sulfoxides. The radical precursor was obtained in two steps from
a carbonyl derivative and a vinyl sulfoxide as indicated in Scheme 22 <1999TL3565,
2002EJO1776>. The radical elimination was best effected by the exposure of the brominated
precursor to tris(trimethylsilyl)silane (TTMSS) in refluxing toluene, in the presence of AIBN.
O
O
R1 S Ar R1 R2 Ar NBS, Me2S TTMSS R1
R1 S Ar C
O S
R2 LDA, –100 °C HO O AIBN R2
R2 Br
Scheme 22
Allenes have also been prepared by the treatment of 1-chlorocyclopropyl phenyl sulfoxides with
Grignard reagents, thus providing an extension of the Doering–LaFlamme reaction based on
gem-dihalogenated equivalents <1958T75, 2001T5369> (Scheme 23).
Cl O
S PhMgCl (2.5 equiv.), 0 °C, 10 min C
Ph 89%
Cl
MgCl
Scheme 23
Dithiolane S-oxides were reported to eliminate ethylene under flash vacuum pyrolysis condi-
tions (Equation (8)) <1997ACS527>.
O
S FVP
S + CH2=CH2 ð8Þ
S 550 °C
54%
Sterically congested cycloalkenes can be prepared from sulfoxide/sulfone derivatives by

pyrolysis in 1,3-dimethyl-2-imidazolidinone (DMI) implying, as shown in Scheme 24, sequential
extrusion of SO2 and SO <2000JOC1799>.
O N
O O
S N , 224 °C, 1 h
S 69%
O
S
O
Scheme 24
1.14.2.2.2 Elimination of selenoxide groups

Elimination of the selenoxide group in a syn-pericyclic fashion resembles the analogous sulfoxide
elimination, but proceeds more easily and constitutes a well-established way to prepare alkenes
under very mild conditions <1995COFGT(1)589>. It has been widely used in recent years, in
particular during the synthesis of many classes of natural substances, both in solution and, since
1996, in polymer-supported chemistry.
(i) Oxidative elimination from polymer-supported selenide derivatives

Starting from a polymer-bound alkene, an iterative application of nitrile oxide 1,3-dipolar
cycloaddition and selenide oxidation/elimination steps was employed in a solid-phase synthesis
of polyisoxazolines as shown in Scheme 25 <1996JOC8755>.
Ruhland and co-workers <1998JOC9204> and Nicolaou’s group <1998CC1947> reported the
use of polymer-supported selenium reagents for organic synthesis. Ruhland’s group described
selenium-based linkers for traceless solid-phase synthesis. Nicolaou and co-workers used an air-
stable, polymer-supported lithium selenide, to investigate a loading onto polymer/release strategy,
the substrate being released from the polymer either by free-radical chemistry or under oxidative
conditions as shown in Scheme 26.
O O N
O SePh
+ O N SePh i. PhNCO O
2
O Et3N
ii. NaIO4, Repeat

O O N O O N O N
H2O/ i. and ii.
MeOH O n times O
n
15 h,
reflux
Scheme 25
Bu3SnH OTBDPS
SeLi AIBN
I OTBDPS 89% 2 steps
Se OTBDPS
23 °C, 12 h
H2O2
78%
OTBDPS
2 steps
Scheme 26
Since these preliminary experiments, the oxidation/elimination strategy has been used to cleave
selenium linkers from many polymer-supported compounds, including precursors to bicyclic
natural products <1999OL807>, polycyclic natural benzopyran derivatives <2000AG(E)734,
2000AG(E)739, 2000JA9939>, deoxysugars <2000AG(E)1089>, cyclic depsipeptide phytotoxins
<2001TL8337>, as well as vancomycin analogs <2000AG(E)1084, 2001CEJ3798>.
In the latter case, semisynthesis of vancomycin glycosides was developed using a pro-allyl,
selenium-based, safety-catch linker strategy. The method was first tested on a protected vanco-
mycin derivative as illustrated in Scheme 27. Loading of the carboxylic group onto the resin was
best accomplished in the presence of CsHCO3 and molecular sieves, whereas the cleavage back to
the starting vancomycin derivative was effected by selenoxide elimination and removal of the
resulting allyl ester by Pd(PPh3)4 and n-Bu3SnH.
Se I
CsHCO3, mol. sieves, 86%

RCOOH RCOO Se
H2O2, then Pd(PPh3)4
Bu3SnH
75% (two steps)
R'O
R'O R'O
CbzHN
OR'
O
O
O
O Cl
RCOOH =
O O
OR'
O Cl O O
H H
R'O HN N N
N N
O H O H O H NCbz
NH O
HOOC NH2
OR'
R' = TBDMS
R'O OR'
Scheme 27
Safety-catch linkers based on the sulfoxide or selenoxide elimination have also been developed
for the preparation of simple aromatic compounds <2000TL5287> (see Scheme 17). Selenoxides
were preferred as they underwent cleavage under much milder conditions than sulfoxides.
Polymer-supported selenocyanates have been prepared and used for solid-phase selenolactoniza-
tion <1999SL1760>. Oxidative deselenenylation yielded racemic ,-unsaturated lactones in fair
yields (Scheme 28). The same reaction was also performed in water, employing an amphiphilic
polymer-supported selenenyl derivative and H2O2 instead of MCPBA as an oxidant <2003TL3793>.
Ph O O
Ph CO2H MCPBA Ph O O
SeCN Se
CuCl2 56%
O O
Scheme 28
An asymmetric version of the latter selenolactonization using a chiral, polymer-bound, electrophilic

selenium reagent 7 was published by Uehlin and Wirth <2001OL2931>. The deselenenylation step
was generally performed under reductive radical conditions except in the experiment shown in
Equation (9) where oxidative elimination yielded an allylic ether with a fair enantiomeric excess.
O
OMOM
OMe
i. SeBr / MeOH
7 ð9Þ
ii. H2O2 (10 equiv.), 3 h, 20 °C

48% ee
56%
Recently, a new polymer-supported benzyl selenide was prepared and used in a stereocontrolled
synthesis of alkenes and allylic alcohols <2002TL5495>.
(ii) Oxidative elimination in solution

Oxidative elimination of selenoxides in solution continues to be frequently used as a convenient
way to introduce double bonds in many classes of chemical compounds. In recent reports, various
oxidizing agents have been used: H2O2 <1995JOC794>, H2O2/AcOH <1995NN1227, 1997JOC1501>,
NaIO4 <1997JOC4870>, NBu4IO4 <2001OL2737>, dimethyldioxirane <2000JOC6293>, ButOOH
<1995CC2519>, MCPBA <1997TL331>.
Although the reaction generally works well, the regioselectivity of the elimination (when several
possibilities exist) is sometimes difficult to predict <1997JOC4870> and may fail for labile
products and/or substrates <2000AG(E)237>.
1.14.2.3 Elimination of Sulfone, Selenone, or Tellurone Groups
1.14.2.3.1 Elimination of sulfone groups
(i) Elimination of sulfones

Although elimination of sulfinic acid from -ketosulfones is usually performed under basic
conditions <1995COFGT(1)589>, there are a few recent reports mentioning elimination under
acidic conditions. This was the case for the preparation of the diquinane derivative shown in
Equation (10) <1995JOC5135>, which was formed by exposing its bis-sulfonylated precursor to
silica gel.
O SO2Ph O
Silica gel column
O O ð10Þ
>75%
H SO2Ph H SO2Ph
Similarly, the sulfonylated bicyclic oxazolidinone 8 could be converted in one step to the
corresponding enone by HCl treatment (Equation (11)), <1997JOC2139>.
O O
HN HN
O O
TolO2S 35% HCl ð11Þ
OEt 62%
OEt O
8
A new method for the elimination of sulfinic acid from aryl sulfones bearing an o-(bromomethyl)-
dimethylsilyl moiety under mild radical conditions has been disclosed by VanDorst and Fuchs
<1997JOC7142>. As shown in Scheme 29, an o-silylmethylene radical forms first, followed by
intramolecular hydrogen abstraction and collapse of the radical to produce an alkene.
Ph O AIBN, Bu3SnH (slow addition)

O S 88% Ph
Br
Si
Ph O Ph O
O S O S
Si Si
Scheme 29
An impressive integrated chemical process has been reported for the preparation of alkynes and
allenes from alkyl sulfones <1997CL1023>. This one-pot preparation involves nearly four
quantitative steps, including Peterson elimination and a sulfone elimination. In the example
shown in Scheme 30, the allenic derivative was by far the major product.
i. BuLi TMS i. BunLi TMS

ii. TMSCl ii. PhCHO
SO2Ph SO2Ph PhO2S
OLi
PhSO2 KOBut
C +
46%
(34:1)
Scheme 30
(ii) Elimination of -substituted sulfones
(a) Julia olefination. Since its discovery in 1973 by Marc Julia and Jean-Marc Paris
<1973TL4833> and its development a few years later by Lythgoe and Kocienski (see for instance
<1980JCS(P1)1045>), the Julia olefination also commonly called the Julia–Lythgoe olefination
has demonstrated a pivotal role in organic synthesis. This reaction which has been reviewed several times
<1995COFGT(1)589> consists, in its original form, in four discrete steps involving: the metalla-
tion of a phenylsulfone, addition of the metallate to an aldehyde, acylation of the resulting
hydroxysulfone to a -acyloxysulfone, finally reductive elimination with sodium amalgam to
afford an (E)-alkene. Although this procedure, referred to as the classical Julia olefination has
proved to be very useful for the synthesis of complex systems (see, e.g., <2002EJO2613>) it
suffers from some drawbacks: it requires the use of a toxic and rather aggressive amalgam
reagent, it is not generally transposable to ketones and, furthermore, its use, which requires
several steps is rather cumbersome.
To obviate the first drawback, the use of magnesium in the presence of a few crystals of
mercuric chloride <1995TL5607, 1996SC1499> or SmI2, instead of sodium amalgam, has been
recommended. Based upon a few earlier pieces of work (<1990TL7105, 1992TL8065>), the SmI2-
induced reductive elimination of -acyloxysulfones has been much studied since 1995. Keck and
co-workers <1995JOC3194> compared Na(Hg) and SmI2-mediated reductions of vinyl as well as
-acetoxysulfones. Use of sodium/mercury amalgam proved unsuitable for preparing highly
conjugated alkenes, yielding products of over-reduction. In all cases, SmI2 in the presence of
HMPA (as described by Inanaga <1987CL1485>) or DMPU gave good results. Support to these
observations came from independent work from Fukumoto and co-workers <1995T9873>.
A revision of the mechanism of the classical Julia olefination using -acyloxysulfones emerged
from deuterium labeling experiments conducted by Keck’s group <1995JOC3194>. The
new mechanism presented in Scheme 31, which implies a vinyl anion intermediate is
proposed instead of the generally accepted mechanism which involves a -acetoxy anion
<1995COFGT(1)589>.
SO2Ph +
Na/Hg, MeOH SO2Ph Na
R2 – R2
R1 –NaOAc R2 R2 R1
R1 R1
OAc
Scheme 31
Marko’s group further investigated the SmI2 variant of the Julia olefination and used it for the
preparation of trisubstituted alkenes from ketones <1996TL2089, 2001T2609>. As depicted in
Equation (12), the classical Julia–Lythgoe olefination does not generally work with ketones
because the first, equilibrated step of the reaction does not favor the formation of the condensa-
tion product.
Li R3 LiO R1
+ R2 ð12Þ
R1 SO2Ph R2 O
R3 SO2Ph
By simply trapping the lithium alkoxides with PhCOCl, nevertheless, it was possible to prepare
in excellent yields the corresponding benzoyloxysulfones which were converted to trisubstituted
alkenes, often obtained as (E)/(Z) mixtures, by treatment at 78 C with SmI2 in the presence of
HMPA or DMPU (Scheme 32).
SO2Ph
i. BunLi SmI2
SO2Ph
O THF/HMPA
ii. OBz
–78 °C
then PhCOCl, –78 °C 73%
93%
Scheme 32
Using TMSCl as a trapping agent instead of PhCOCl also enabled the formation of -hydroxy-
sulfones and their conversion to trisubstituted alkenes with SmI2/HMPA or SmI2/DMPU. In this
case, however, the elimination only occurred when the temperature was raised to 0 C. Possible
mechanisms for these eliminations are shown in Scheme 33: formation of the -hydroxy radical
from -hydroxysulfones is particularly slow, which may explain the different kinetics observed.
OH OH
R1 SmI2 OH SmI2 R1 R1 R3
R3 R1 R3
R2 – R3 R2
–PhSO2 R2 R2
SO2Ph SmI2
OBz R1 SmI2
R1 SmI2 R3 SmI2 R1 R1 R3
R3 R2 R3
R2 – R2
SO2Ph –PhCO2 SO2Ph SO2Ph R2
Scheme 33
In addition to the work of Marko’s group, trisubstituted alkenes were also prepared from
ketones using a sulfoxide version of the Julia olefination as reported before (see Scheme 20 and
<1996T2349, 1998TL6935, 2000T6223>).
The SmI2 method allowed the first synthesis of allenes by Julia olefination starting from
-trifluoromethyl vinyl sulfones <2000CPB1395> (Equation (13)).
SO2Ph
R CF3 SmI2 R CF3
C ð13Þ
37–73% OEt
OAc OEt
Important improvements to the Julia olefination involve the use of various heteroaryl
sulfones among which are benzothiazolyl sulfones (BT-sulfones) (Scheme 34 <1991TL1175>;
Scheme 35 <1996JA10327>), pyridin-2-yl sulfones (PYR-sulfones) <2001TL5149, 2001TL6619>,
1-phenyl-H-tetrazol-5-yl sulfones (PT-sulfones) <1998SL26>, and 1-t-butyl-1H-tetrazol-5-yl sulfones
(TBT-sulfones) <2000SL365, 2002JCS(P1)2563, 2002JA11102> (Scheme 36).
Li O R2 Li
N 2CHO 2
SO2 R N 1 N O R –SO2 R2
R
S Li S
S O2 S S 1 R1
R1 O2 R
Scheme 34
O
TIPSO
H
NaHMDS TIPSO
N THF, DMF
–60 °C
S S 4 /1 (E )/(Z )
O2 >92%
Scheme 35
TBDMSO
O O
Br S N OTBDMS
i. KHMDS, –78 °C, 30 min
H H N
O N N ii. TBDMSO Br
Ph
CHO H H
O
OTBDMS
88%
Scheme 36
These modifications convert the four distinct step sequence of the original Julia reaction to one-
step coupling reaction, which will be more extensively treated in chapter 1.16. For a recent
exhaustive review on the modified Julia olefination see <2002JCS(P1)2563>.
A few reactions related to the final reduction step of Julia olefination have been reported like the
ring opening of (phenylsulfonylmethyl)isoxazolines with Mg in MeOH as shown in Scheme 37
<1999SC3165>.
N O Mg, MeOH, –23 °C NOH

Ph SO2Ph 98% Ph
N O
Ph –
Scheme 37
(b) Elimination of -silyl-, stannyl-, chloro-, and sulfonyl sulfones. New examples of reductive
eliminations of 1,2-disulfones, using sodium amalgam, to afford alkenes have been reported
recently <1995COFGT(1)589, 1995SL628, 1997JOC4162, 1998EJO2775>.
-Chlorosulfones are converted to alkenes upon treatment with tributyltin hydride/AIBN
<1996JOC7116>. Reductive elimination of the chlorosulfone can also be performed by using
SmI2. This was the basis of an elegant strategy, involving a temporary sulfone-containing spacer,
used for the synthesis of a kainic acid derivative (Scheme 38) <2001TA1101>.
O O CO2Me O O
S S CO2Me
Cl CO2Me
Cl OTs KOMe SmI2
72% 72% CO2But
CO2But N
N CO2But N
BOC
BOC BOC
Scheme 38
A few elimination reactions of -silyl and -stannyl sulfones have been reported (see Sections
1.14.5.1.3 and 1.14.6.3).
(iii) The Ramberg–Bäcklund reaction

The Ramberg–Bäcklund elimination of -halo sulfones in the presence of a base leading to alkenes
has been extensively investigated. It has been in particular very recently extensively reviewed by Taylor
and Casy <2003OR357>. In the Meyers modification, the starting sulfones are chlorinated in situ
in the presence of KOH, ButOH, and CCl4 <1995COFGT(1)589>. Despite its practical aspects, the
Meyers modification suffers from serious drawbacks partly arising from the presence of reactive
dichlorocarbene in the reaction medium and its use is essentially limited to the preparation of
stilbenes. Although side reactions can be suppressed by inclusion of a carbene scavenger in the
medium, the carbene adducts may be difficult to separate from the desired products. In 1994, Chan
and co-workers proposed an improved version of the Meyers method employing alumina-supported
KOH, CBr2F2, and ButOH. Using these conditions, a large variety of sulfones were converted into
alkenes <1994CC1771>. Key factors for the success of Chan’s method are (i) the use of a substitute
for CCl4, which does not readily form carbenic species and (ii) the serendipitous discovery that
alumina-supported KOH, in contrast to KOH alone, does not promote the formation of undesired
brominated side-products. Since its discovery, this protocol has been widely used, for example, for
the synthesis of paracyclophane derivatives <1997JOC2727>, azamacrocycles <2000JOC8367>, or
C2-symmetrical diaminodiols <1999TL3917>. The use of CH2Cl2 instead of ButOH as a solvent
was beneficial for the synthesis of very fragile enediynes (Equation (14)) <1996TL1049>.
KOH/Al2O3, –10 °C
CF2Br2, CH2Cl2 ð14Þ
S
O O 80%
1/1 (E )/(Z )
Taylor and co-workers have used both the Meyers and the Chan protocols for the elaboration
of C-glycosyl amino acids <1999CC1599>, C-disaccharides <1999AG(E)2939, 2003AG(E)1387>
as well as trehazolamine derivatives <2001TL1197>. In the example shown in Scheme 39, using
a newly described benzyl sulfonylphosphonate reagent enabled a straightforward preparation of a
C-glycoside from a suitably protected monosaccharide, either using a two-step or even a one-pot
procedure <2003AG(E)1387>.
O O
O O O O Ph
OH i. NaH, THF, 20 °C, 18 h
EtO
+ P S Ph
EtO ii. KOH/Al2O3, CF2Br2
O O O O O O O
0 °C, 30 min
78% overall KOH/Al2O3
NaH, –78 °C
O CF2Br2, 5 °C
86%
88%
O O
S Ph
O O
O O
Scheme 39
Two reactions derived from the Ramberg–Bäcklund rearrangement have been published: the
epoxy-Ramberg–Bäcklund reaction in which ,-epoxysulfones are converted into allylic alcohols
upon treatment with a base as shown in Scheme 40 <1997TL3055> and the decarboxylative
Ramberg–Bäcklund reaction exemplified in Scheme 41 <1995TL8367>.
Ph
O
ButOLi, THF Ph
S
O O 92%
OH
Ph –
O
Ph
S
O O
Scheme 40
Ph CCl4, KOH, ButOH

S CO2Et Ph
O O
O O
S Ph 61%
–
Cl O
O
Scheme 41
1.14.2.3.2 Elimination of selenone and tellurone groups

No new examples were reported during the period 1995–2003.
1.14.2.4 Elimination of Sulfimine, Selenimide, Tellurium Imide, Sulfinamide, Sulfoximine,

Sulfonamide, and Sulfonate Groups
In the course of their new asymmetric synthesis of -amino acid derivatives from allylic sulf-
oximines and aldehydes, Gais and co-workers <2003EJO1500> used aluminum/mercury amal-
gam, as recommended previously <1973JA6462>, to reduce -hydroxysulfoximines to an
equimolar mixture of the corresponding (E) and (Z) alkenes (Equation (15)). Related vinylic
sulfoximines were used by the same group to prepare terminal allenes under basic conditions
<2002JA10427>.
O O
O NH O NMe Al/Hg O NH
S ð15Þ
Me Ph 85% Me
OH
1 /1 (E )/(Z )
1.14.2.5 Elimination of Sulfonium, Selenonium, and Telluronium Salts and Ylides

Balenkova and co-workers developed a novel reagent quantitatively prepared by reacting BF3 gas
at 60 C with ethylsulfanylpropionyl fluoride. In the presence of alkenes this reagent yielded
cyclic sulfonium salts that could be converted under mild basic conditions into alkylthiopente-
nones as illustrated in Scheme 42 <1995TL6317>. The use of their novel reagent was extended
later to a new synthesis of aryl vinyl ketones <1998S89>.
S F
O
BF3
S + – O
O BF4 KHCO3 O
H +
–50 °C S 1 h, 0 °C S
62%
2 steps
Scheme 42
Under drastic basic conditions, novel aromatic thiaannulenes could be prepared from a
mixture of bis(dimethylsulfonium)tetrafluoroborates via a strained cyclophanediene as shown in
Scheme 43 <1996JA722>.
–
S BF4 S
KOBut, 80 °C, THF S
+ S+
S
30%
–
BF4
(mixture of isomers)
Scheme 43
Similar conditions were recently used for the elaboration of novel strained dihydropyrene
derivatives <1999JCS(P1)403>.
Under Pummerer conditions, the indole sulfoxide shown in Scheme 44 was converted to a
bicyclic sulfonium salt which underwent spontaneous -elimination/ring expansion to give inter-
esting N,S-heterocycles <1998JOC9190>.
O +
Tf2O, Pyr S
S S
N 65% N N
O H O
O H
Scheme 44
Warren and co-workers studied the decomposition of intermediate spirosulfonium salts, formed
by the treatment of 4-benzylsulfanyl-1,3-diols with tosyl chloride, to afford allylic alcohols
(Scheme 45), <2001JCS(P1)1504> and references cited therein.
OH OH HO
Ph S
TsCl, Pyr
OH S Ph +
S
48% 52%
HO
–
+ Cl
S
Ph
Scheme 45
Phenyl sulfides or phenyl selenides bearing an electron-withdrawing group at the -position can
be eliminated by treatment with a carbenoid <2002TL4959>. This elimination proceeds via a
sulfur ylide intermediate (Scheme 46).
Et2Zn /CH2I2 /CF3CO2H
SPh
O F3C O O
+ Zn I
O 97%
+ +
Ph – Ph
S S
O – O
Scheme 46
Other related sulfur ylide eliminations have recently been reported (see e.g., <1998JCS(P1)2181,
1999T10659>).
1.14.3 BY ELIMINATION OF NITROGEN FUNCTIONS
1.14.3.1 Elimination of Amine Oxides—The Cope Reaction

The widely used Cope reaction, which involves the cleavage of amine oxides, usually formed
in situ from the corresponding amines, leads to alkenes and hydroxylamine derivatives. The
reaction conditions are quite mild and there are few side reactions. The amine oxide elimination
occurs at temperatures ranging from 100 to 150 C (neat). In dry DMSO or THF, the reaction can
proceed at room temperature. The reaction is useful for the preparation of many alkenes
(Scheme 47). A limitation is that it does not open six-membered rings containing nitrogen, though
it does open 5- and 7–10 membered rings.
+ –
N Oxidation N O ∆ R1
R
R R
R1 R1
Scheme 47
The elimination of amine oxides involves concerted cyclic transition states in which an intra-
molecular proton transfer accompanies elimination to form the CC double bond. A five-
membered cyclic synchronous transition state with a 120 (C. . .H. . .O) angle is generally accepted
and the elimination proceeds in a syn-fashion (Scheme 48). In acyclic systems the (E)-alkene is
preferentially formed with low selectivity. In cyclic systems, conformational effects and the
necessity for a cyclic transition state determine the product composition.
–
+
O O
H N H N H N
Scheme 48
The effect of solvents on equilibrium was briefly studied (Equation (16)) <1995JOC5795>.
Solvents that are hydrogen-bond donors favor the formation of N-oxides 10a and 10b, whereas
hydrogen-bond acceptors favor the hydroxylamines 9a and 9b.
Yield (%)
Ph Ph 25 °C Ph Ph Solvent 9a 10a 9b 10b

Ph Ph N O
CD3OD 0 100 0 100
R CDCI3 0 100 23 77
ð16Þ
R N
OH CD3CN 15 85 68 32
9a R = Me 10a R = Me (CD3)2SO 55 45 >90 <10
THF-d8 60 40 >90 <10
9b R = Pri 10b R = Pri (CD3)2NCDO 67 33 90 <10
Chiacchio and co-workers developed an efficient access to unsaturated five-membered lactones

via 1,3-dipolar addition (Scheme 49). Conversion of isoxazolidines 11 to butenolides 13 has been
performed by a three-step sequence involving a Cope elimination as a final step through the
intermediate 12 <1998T5695, 1999JOC28>.
The Cope elimination was also used to remove amine-based chiral auxiliaries. The asymmetric
synthesis of (R)- and (S)-methyl (2-methoxycarbonylcyclopent-2-enyl) acetates, which are useful
synthons for monoterpene synthesis, was carried out by the addition of the dimethyl ester of
R1 R NMe2 R
R
i. TfOMe iii. MCPBA
Me N O R2 ii. H2/Pd O O R2 CH2Cl2 O O R2
11 12 0 °C, 4 h 13
Overall yield = 68–77%
R = alkyl
R1 = CO2Et
R2 = Me, CH2OH, CH2CH2Ph
Scheme 49
(E,E)-octa-2,6-dienedioic acid to lithiated (R)-(-methylbenzyl)benzylamide followed by a Cope

elimination (Scheme 50) <1997TA2683>. By a similar process, the conjugate addition of chiral
amides to t-butyl cinnamate followed by aldol reaction and Cope elimination affords Baylis–
Hillman products (Scheme 51) <2000TA2437>.
Ph NBn
Ph NBn
CO2Me Li CO2Me MCPBA CO2Me
86% 80%
CO2Me CO2Me CO2Me
Scheme 50
Ph NMe Ph N i. LDA Ph N
Li ii. B(OMe)3 H
CO2But CO2But CO2But
Ph Ph Ph
94% iii. PhCHO
62% Ph OH
H
92:8 ds
MCPBA
57%
CO2But
Ph
Ph OH
H
Scheme 51
1.14.3.2 Elimination of Quaternary Ammonium Salts—The Hoffmann Elimination

Elimination of quaternary ammonium salts to afford an alkene and an amine can be achieved
either by the thermal decomposition of quaternary ammonium hydroxides or by the treatment of
quaternary ammonium halides by bases.
In the former method, known as the Hoffmann degradation, the amine is converted first to a
quaternary ammonium iodide which gives the corresponding hydroxide upon treatment with
silver oxide. Elimination is induced by heating at temperatures ranging between 100 and 200 C
by distilling an aqueous or alcoholic solution of the hydroxide (Scheme 52).
– –
+ +
I OH
N MeI N Ag2O N ∆
R1
R
R R R
R1 R1 R1
Scheme 52
The mechanism is usually E2 leading to the product of trans-elimination. In certain cases, for
hindered molecules, the reaction proceeds via a five-membered cyclic transition state, similar to
that of the Cope reaction.
Treatment of quaternary ammonium halides with bases favors the elimination of the amine to
form a new CC double bond. The mechanism is different and involves a 2,3-rearrangement of
an ammonium ylide (Scheme 53).
–
X + + –
N N
Base H R1 + Me N
R 3
R R
R1 R1
Scheme 53
An important difference between this reaction and the Hoffmann degradation is that the
products of syn-elimination are usually formed. Thus, the two reactions complement each other.
A formal synthesis of 4-demethoxydaunomycin based on the asymmetric catalytic aminolysis of
a meso-epoxide followed by Hoffmann elimination was recently described. Methylation of the
trans--amino alcohol 14 affords a quaternary ammonium iodide which is converted to the allylic
alcohol 15 by treatment with excess butyllithium (Scheme 54) <2002T75> with only a slight loss
of enantiomeric excess.
OMe OMe
OH i. MeI (10 equiv.), K2CO3, MeOH, ∆, 24 h OH
NHC6H4OMe ii. BunLi (3 equiv.), THF, –78 °C, 1 h

OMe 52% OMe
14 15
95% ee 90% ee
Scheme 54
Isoxazolidines obtained by intramolecular [2+3]-dipolar cycloaddition of nitrones are useful

intermediates in synthesis. In the study reported in Scheme 55, two compounds are isolated
upon isoxazolidine treatment with methyl iodide (20 equiv.) in THF: the quaternary dimethyl-
ammonium salt 17 and the ,-unsaturated aldehyde 18. The former could be smoothly converted
to the aldehyde under Swern conditions/concomitant -elimination. A radical fragmentation was
suggested to explain the conversion of 16 to 17 <1995TL1899>.
–
I OH
O CHO
N OBn + N OBn OBn
MeI (20 equiv.)
+
BnO THF, ∆ BnO BnO
O O O
O 72% O O
16 17 18
25% Swern 30%
Scheme 55
Treatment of quaternized -amino alcohol 19a with NaH triggers a Grob-type fragmentation
leading to the formation of unsaturated aldehydes or ketones 20 in which the newly formed
olefinic double bond has the (Z)-configuration. The competitive displacement of the ammonium
group by the alkoxide, to give an oxetane 21, was observed only for isomer 19b (Scheme 56)
<1998EJO2185>.
– Ph
+ I O R
I
HO R NMe3 O NMe3
NaH ( )n
Ph R Ph
( )n ( )n
Grob-type fragmentation
19a 20
–
+ I
H
R OH NMe3 O R O Ph
NaH R I
Ph
Ph NMe3
( )n ( )n H ( )n
19b 21
Intramolecular substitution
Scheme 56
Caesium fluoride in DMF converts cyclic silylalkylammonium iodides to the corresponding

-arylcycloammonium N-methylides which rearrange either via an intramolecular Hoffmann
degradation in the case of the cis-isomer 22a or via Sommelet–Hauser or Stevens rearrangements
for the trans-isomers 22b to afford the isotoluene derivatives 24 and 25 (Scheme 57)
<1995JOC4272>.
R R
CsF
+
N DMF
– CH2SiMe3
I NMe2
22a 23
R
R
R
CsF
+ +
N DMF N N
– CH2SiMe3
I
22b 24 25
Scheme 57
The use of solid-phase organic synthesis has emerged as a very important tool for the produc-
tion of combinatorial libraries. The Hoffmann elimination can be used to prepare tertiary
amines and separate the products from the resin. Scheme 58 shows the Michael addition of
secondary amines to a resin bearing acrylate functionalities. Treatment by alkylating agents
introduced both chemical diversity and cleaved the tertiary amines/carrier bond, via Hoffmann
elimination, with recovery of the functionalized starting polymer <1997JA3288, 1998JOC1027>.
The reaction time was reduced when perfluorinated organic solvents were used instead of DMF
<2001TL7509>.
1.14.3.3 Alkenes from Arenesulfonyl Hydrazones

The reaction of arylsulfonylhydrazones, bearing a proton at the -position, with alkyllithiums
affords the corresponding vinyllithium derivatives that can be protonated or used as synthetic
O R1
HN
Cl R2 R1
OH O O N
DMF R2
O O
DMF R3–X
DMF
R2 R1
+
R1 N O N R2
R3 – R3
O X
Scheme 58
intermediates. The Shapiro reaction is one of the most powerful methods for regioselective
preparation of alkenes via alkenyllithium reagents (Scheme 59—path a). In some cases,
reductive alkylation occurs leading to alkanes. This side reaction is observed in particular when
R2 = H (i.e., for arylsulfonylhydrazones derived from aldehydes) (Scheme 59—path b).
R2 Li RLi R2 –N2 R2 H2O R2

R1 N R1 N R1 R1
N SO2Ar –ArSO 2Li N Li Li
–RH
RLi
Path a
–RH
R2 H
R1 N
N SO2Ar
RLi
Path b
–RH
R2 Li R R2 R R2 R2
RLi –N2 H2O
R1 N R1 N R 1
R 1
N SO2Ar N Li Li R
–ArSO 2Li
Scheme 59
The Shapiro reaction requires 2 or more equivalents of strong bases such as alkyllithiums or lithium
dialkylamides. The mechanism involves the initial formation of a lithiated vinyldiimide which
decomposes to vinyllithium. The Shapiro reaction works well with cyclic and alicyclic ketones. For
unsymmetrical ketones, the regioselectivity of the deprotonation depends on the stereochemistry of
the C¼N bond in the starting hydrazone, the proton in the syn-position to the arylsulfonyl group is
preferentially abstracted through chelation with the lithium ion (Scheme 60).
Li Li
ArSO2N ArSO2N
N Base N R
R Li R
Scheme 60
The stereoselectivity of vinyllithium generation from acyclic arylsulfonylhydrazones has been

studied in only a few cases. The Shapiro reaction gives the (Z)-alkene as the major product. This
result is consistent with the anti-position of the -alkyl group (R) to the hydrazone during dianion
formation (Scheme 61).
H BuLi N
N – Li (Z )
R NSHO2Ar
NSHO2Ar H R
R H –
H
–
Favored
H BuLi N
N – Li (E )
H NSHO2Ar
NSHO2Ar R H
R H – R
Disfavored
Scheme 61
The Shapiro reaction proceeds in low yield for ,0 -disubstituted substrates because the
formation of the dianion intermediate is very slow and substitution at the imino carbon atom
competes with elimination. However, when the substituents are phenyl groups, the enhanced
acidity of the benzylic hydrogen makes proton abstraction easier and the Shapiro reaction works
well, affording the expected elimination product in good yield (Scheme 62) <1997JOC3407>.
O NNHTs
Ph Ph TsNHNH2 Ph Ph i. LDA (2 equiv.), THF Ph Ph
EtOH ii. H2O
Py Py 76% Py Py 80% Py Py
Scheme 62
A catalytic version of the Shapiro reaction has been described using a phenylaziridinylhydra-
zone as arylsulfonylhydrazone equivalent in the presence of 0.1 equiv. of lithium amide; high
regioselectivities and stereoselectivities were obtained (Scheme 63) <1996JA2289>.
N Ph
N H
LDA (0.1 equiv.) H
Et2O, –20 °C, 1 h

89% >99.9/0.1 (Z )/(E )
R1
R2
N Ph
N
R2
R1
Li
N Ph
N
R3 R3
N H N Li
R4 R4
R2 Styrene + N2
R1
H
R2 Li
R1
H
H
Scheme 63
Initially, the Shapiro reaction was used for the formation of simple alkenes by protonation of
the intermediate alkenyllithium. Nowadays, major advances in this field exploit the versatility of
the vinyllithium intermediates with respect to trapping by electrophiles.
For instance, the Shapiro reaction was applied to the stereoselective synthesis of (E)-trisub-
stituted alkenes by a convergent process: double deprotonation of acetone 2,4,6-triisopropyl-
benzensulfonylhydrazone 26 followed by the coupling with R1X at low temperature produces
the hydrazone intermediate 27. A second deprotonation followed by rapid warm-up at 0 C
affords 28 which can be further modified (Scheme 64) <1997TL8915>.
H Li
N n N iii. BunLi, TMEDA,
N Trisyl i. Bu Li, DME, N trisyl Li v. Li(2-thienyl)CuCN R2
–78 °C to –60 °C –78 °C, 30 min –78 °C, 15 min
ii. R1X, –65 °C, iv. –65 °C to 0 °C, vi. R2X, –65 °C to 0 °C
R1 R1 R1
26 10–18 h 2 min
27 28 29
Trisyl: 2,4,6-triisopropylbenzenesulfonyl
Scheme 64
A one-pot procedure associating the Shapiro and Suzuki reactions was developed for the
synthesis of vinyl arenes and conjugated polyenes, including some analogs of retinoic acid. As
shown in Scheme 65, treatment of trisyl hydrazones with BuLi at 78 C and warming up to 0 C to
give the cyclohexenyllithium was followed by the addition of B(OPri)3 to afford the corresponding
boronic esters. Then, sequential addition of Pd(PPh3)4, a vinyl iodide and a base, yielded the
coupling product <1996TL429, 1997CJC1163, 2001JOC8483>. A limitation of this procedure is
the inefficient generation of cyclohexenyl boronate from ,0 -disubstituted hydrazones.
R 1 R2 R1 R2 R1 R2
N B(OPri)2 R R
NHtris i. BunLi I
ii. B(OPri)3 Pd(PPh3)4, TlOH
Scheme 65
A useful alternative to the Julia olefination was described involving the reaction between
arylsulfonylhydrazones derived from aldehydes and -metallated sulfones. For example, the reac-
tion of tosylhydrazone with unhindered alkylsulfones in the presence of LDA affords a mixture of
(Z)/(E) olefination products. With hindered alkylsulfones, however, by using butyllithium as a base,
the Shapiro products were isolated exclusively. The olefination products could be obtained in good
yield by using Bu2Mg as a base instead of BuLi (Scheme 66) <2000SL547, 2001JOC6994>.
N NHSO2Tol
PhO2S
Base
OMe OMe OMe
Olefination Shapiro
Base product product
BuLi 0 95%
Bu2Mg 85% 0
Scheme 66
A synthesis of the C-ring of Taxol based on the coupling between a vinyllithium intermediate—
obtained via a Shapiro reaction—and an aldehyde was described. Using 2 equiv. of BuLi, the
alkene 31 was the only isolated product. The problem could be overcome by using ButLi, instead
of BuLi (Scheme 67) <1999SL1555>.
OBn
BunLi
31
OBn
TrisHNN
30 TBSO CHO
OBn OBn
ButLi
OH OH
OH 2:1 OH
32 44% 33
Scheme 67
In the synthesis of the Taxol’s A-ring, described by Koskinen and co-workers, the key step is
also a Shapiro reaction. Tosylhydrazone gave the best results when compared to other
arylsulfonylhydrazones. Scheme 68 proposes a detailed description of the process. The electro-
phile (DMF) is added immediately when nitrogen evolution has ceased to avoid protonation of
the intermediate vinyllithium by THF <2002T2175>.
O i. BunLi (2.2 equiv.), O

TsHNN TsLiNN
THF, –55 °C
O O
ii. MeI (2.5 equiv.),
–50 °C
iii. BunLi (4 equiv.), O

OHC
–50 °C
O
iv. Warm-up to rt
v. DMF, rt
61%
Scheme 68
Nickon and co-workers compared the Shapiro reaction to the thermal and photolytic Bamford–
Stevens reactions. The tosylhydrazone derivative prepared in several steps from estrone methyl
ether was submitted to different conditions. The Shapiro reaction gave the two alkenes and an
unexpected product resulting from ring opening. The Bamford–Stevens reactions (thermal and
photolytic) afforded one major alkene in which the proton near the ring oxygen migrates
(Scheme 69) <1998T12161>.
O O O OH
H
NNHTs Bu
H H H H H
MeO
Shapiro 15 60 25
Bamford–Stevens (thermal) 84 4 12
Bamford–Stevens (photolytic) 83 6 11
H
O H O
H H
Thermal or photolytic Major
conditions
Scheme 69
1.14.3.4 Elimination of Amine Derivatives

Elimination of amines under conditions other than those employed for Cope and Hoffmann
reactions are also possible. In the presence of acids, -aminoketones (or other -aminocarbonyl
derivatives) are converted to the corresponding ,-unsaturated carbonyl products through a
retro-Michael reaction. This procedure is widely used in total synthesis, for example, for the
preparation of chiral ,-unsaturated carbonyl compounds by temporary inclusion of a chiral
amino auxiliary (Equation (17)) <1996TL1331, 1999TL4199, 1999JA4516>.
O
– O
Ph 1,4-addition (R )
ð17Þ
N then pTSA R
40–60%
Ph 2 steps
Addition of hemiaminals of polyfluoroaldehydes to enolizable carbonyl compounds affords

-amino--trifluoromethyl ketones. Acidic treatment induces retro-Michael elimination to yield
(E)--polyfluoromethyl enones (Equation (18)) <2001JOC4826>.
O CF3 O
TFA
R N R CF3
CH2Cl2 ð18Þ
R1 N Ph R1
80 °C
37–81%
An exhaustive review describes the numerous applications of Katritzky’s benzotriazole as

synthetic auxiliary, in particular for alkene synthesis <1998CRV409>. Elimination of the benzo-
triazole moiety to form an alkene can be performed by using low-valent titanium. This metho-
dology was applied to the synthesis of chiral allylamines obtained mainly as trans-isomers
(Scheme 70), <1998JOC3438> and to the preparation of cyclopropylidene derivatives
<1998JOC6710>. The yields obtained, using this procedure are moderate (50%) probably
reflecting the poor reproducibility of the preparation of TiCl3/M.
2,3-Disubstituted allylic alcohols were also prepared by the addition of lithiated 1-(arylmethyl)-
benzotriazoles to -monohaloketones—to form a 2,2-disubstituted epoxide – followed by the
removal of the benzotriazole moiety concomitant with radical opening of the epoxide. The
stereochemistry of the alkene depends on the bulkiness of the R group at C2 of the oxirane (Equation
(19)) <2001JOC2149>.
R * CO2Me
N OH
Si Si
Bt Bt Li R * R1 TiCl3 /Zn-Cu R * R1
BuLi
R1 R1 Bt then HCl/EtOH NH2
then NaBH4 N
Si Si
40–54%
N
Overall yield
Bt = N
N
Scheme 70
R O
Ar i. Naph , Li+ Ar OH OH
+ ð19Þ
Bt ii. H2O R Ar R
1.14.3.5 Elimination of Nitro Groups

The nitro group is one of the most versatile and useful functional groups in organic synthesis. In
particular, it allows the formation of CC bonds under mild conditions via the Michael and
Henry reactions. When -nitroketones or derivatives thereof are treated under basic conditions,
elimination of nitrous acid takes place to give ,-unsaturated carbonyl compounds. If the nitro
group is in the -position, alkene formation is impossible directly. However, the treatment of
-nitroketone tosylhydrazones with DBU eliminates nitrous acid, affording enone tosylhydrazones
exclusively as (E)-isomers (Scheme 71) <1995T4173>.
NTs NNHTs
NNHTs N
DBU
R R1 CH2Cl2 R R1 R R1
NO2
Scheme 71
Treatment of nitroaldehydes 34 and 35 (Scheme 72) with aqueous potassium carbonate gave
the aromatic derivatives 36 and 37, respectively. In contrast, under the same conditions, the
nitroaldehyde 38 cleanly gave a mixture of compounds resulting from aldol reactions, taking place
following nitrous acid elimination and oxidation <2001TL4625>.
CH2CH2R CH2CH2R
NO2 K2CO3
CHO H2O/MeOH CHO
34: R = CO2Me 36: R = CO2Me

35: R = CN 37: R = CN
CH2CH2R
O O
NO2 K2CO3
O
CHO H2O/MeOH
38 85:15:1
R = CH3CO
Scheme 72
The reductive elimination of tertiary -nitro-,-unsaturated esters to ,-unsaturated esters

was described employing Al, Mg, and Zn in methanol. The yields are modest and the best results
are obtained using Zn <2001SL857>.
The [2,3]-dipolar cycloaddition of azomethine to nitro-styrenes affords highly substituted

pyrrolidines 39. Oxidative cleavage of the nitro group with MnO2 at room temperature gives
rise to an unsaturated pyrrolidine 40 which could be further oxidized to pyrrole 41 using MnO2 in
refluxing THF (Scheme 73) <1999SL1268, 2000T8545>.
H H H
EtO2C N Ph MnO2 EtO2C N Ph MnO2 EtO2C N Ph
THF, rt THF, ∆
Ar NO2 Ar Ar
39 40 41
Scheme 73
1.14.4 BY ELIMINATION OF PHOSPHORUS, ARSENIC, ANTIMONY, OR

BISMUTH FUNCTIONS
1.14.4.1 Elimination of Phosphorus Groups

The most widely used method to form CC double bonds with phosphorus group elimination is
the Wittig reaction (and related reactions). The Wittig reaction involves the addition of phosphorus
ylides to aldehydes or ketones followed by the elimination of a phosphine oxide and the formation
of an alkene. The elimination occurs after the formation of a four-membered oxaphosphetane
intermediate or a betaine, depending on the ylide and the conditions used for its formation
(Scheme 74). In some cases, oxaphosphetane and betaine intermediates have been observed by
dynamic NMR at low temperature <1998JA10653, 1998EJO1085, 2000EJO2601>. Recently a
stable oxaphosphetane intermediate was isolated and a crystal structure analysis by X-ray was
obtained <2002EJO1143>. In most cases, the Wittig and the related Horner–Wadsworth–Emmons
reactions are one-step coupling reactions (the intermediate -hydroxyphosphonium salts or
-hydroxyphosphonates are not isolated), which are detailed in Chapter 1.16. In contrast, the
Wittig–Horner reaction leads to the formation of stable, isolable -hydroxyphosphane oxides,
which can be manipulated in several ways and will be discussed here.
R'
R3P R''
(Betaine
HO R1 intermediate)
O R2
R1 R'
R3P–CR'R'' +
R1 R2
R2 R''
R'
R'' (Oxaphosphetane R', R" = H, alkyl, aryl, COOR, CN, etc...
R3P
O intermediate)
R1
R2
Scheme 74
1.14.4.1.1 Elimination of b-hydroxyphosphane oxides and b-hydroxyphosphonates:

the Horner–Wittig reaction
With sodium or potassium bases the reaction of metallated phosphane oxides with aldehydes or
ketones affords alkenes directly. With lithium bases the reaction stops at the first step, the
formation of -hydroxyphosphane oxides which can be isolated and purified (Scheme 75).
The Horner–Wittig elimination from either syn- or anti--hydroxyphosphane oxides is usually
carried out with NaH/DMF or KOH/DMSO. The elimination is, in most cases, stereospecific
giving pure (Z)-alkenes from pure anti--hydroxyphosphane oxides and pure (E)-alkenes from
pure syn--hydroxyphosphane oxides. The Horner–Wittig reaction has been thoroughly studied
<1996AG(E)241>.
Base
R1
R2
M ≠ Li
R1
+ R2CHO OH
Ph2P O R1 R1
R2 R2
Ph2P O
Base Base
M = Li M ≠ Li
OH R2
R1 R1
R2
Ph2P O
Scheme 75
The Horner–Wittig reaction generally provides predominantly the anti--hydroxyphosphane oxi-

des, which can be isolated in pure form and in good yield (routinely 60–80%). Therefore, the method
is suitable only for the synthesis of (Z)-alkenes. In order to prepare (E)-alkenes by the Horner–Wittig
reaction with acceptable yields, the syn--hydroxyphosphane oxide must be obtained with a good
selectivity. This is usually achieved by reduction (NaBH4) of -oxophosphane oxides (Scheme 76),
which gives predominantly syn--hydroxyphosphane oxides. -Oxophosphane oxides can be
obtained either by the oxidation of the original mixture of -hydroxyphosphane oxides or by
the addition of metallated phosphane oxide to acyl chlorides (instead of ketones or aldehydes).
O OH
NaBH4 Base
R1 R1 R1
R2 R2 R2
M ≠ Li
Ph2P O Ph2P O
syn (major)
Scheme 76
Warren and co-workers reported a general route for the high-yield preparation of branched
(Z)-alkenes. The Luche reduction of -oxaphosphane oxides to give anti--hydroxyphosphane
oxides is highly stereoselective and superior to the anti-selectivity observed in the Horner–Wittig
reaction (Scheme 77) <1995TL7905>.
O O PPh2 O PPh2 O PPh2

i. BunLi PDC NaBH4
Ph2P Pri Pri Pri
ii. PriCHO DMF 85%
OH 71% O OH
anti:syn NaBH4 anti:syn
53:47 CeCl3 46:54
77%
O PPh2
NaH/DMF
Pri
OH Pri
anti:syn (Z )
89:11
Scheme 77
The anti-selectivity of the Luche reduction, observed by Warren and co-workers, does not seem
to be general, however. In work reported by Bartoli and co-workers, using LiBH4/CeCl3 in THF
as the reducing agent, the authors observed in most cases the formation of syn--hydroxyphos-
phane oxides. Using BH3 as a reducing agent and strongly chelating Lewis acids such as TiCl4 in
dichloromethane, the same authors developed a general and highly efficient methodology for the
preparation of anti--hydroxyphosphane oxides. The method was applied to the total synthesis of
stereochemical pure (Z)-muscalure (Scheme 78) <1997CEJ1941>.
Ph2P O Ph2P O
BH3/Py NaH/DMF
C13H27 C13H27
C8H17 TiCl4, CH2Cl2 C8H17 95% C8H17
O OH C13H27
–78 °C
>98%
92 /8 anti /syn
Scheme 78
Trisubstituted or tetrasubstituted alkenes are generally not accessible directly using the classical
Horner–Wittig reaction since the intermediate alkoxide undergoes a reverse aldol-type reaction
(Scheme 79). However, a useful procedure for preparing trisubstituted alkenes with excellent
diastereoselectivity has been described. The addition of RLiCeCl3 complexes to -oxophosphane
oxides afforded -hydroxyphosphane oxides. Treatment of the latter with KH in DMF gave the
corresponding alkenes in quantitative yields (Scheme 80) <1995AG(E)2046>.
R3
Very slow R1
R4
Ph2P O 2 R2
R3 R4 O RLi R
+ R1 Base (M = Li)
R4 3
Ph2P O R1 R2 R R3 R4 O
OH
+
Fast Ph2P O R1 R2
Scheme 79
O O MeLi/CeCl3 O OH
KH/DMF
Ph2P Ph2P Bu
Bu THF, –78 °C Bu 50 °C Bu
Bu 94% Bu 99%
96:4 94/6 (Z )/(E )
Scheme 80
The classical Horner–Wittig elimination proceeds via a four-membered ring intermediate to

yield the alkene. In contrast, the treatment of anti--hydroxyphosphines and the corresponding
syn-isomers with PCl3 and Et3N gives (E)- and (Z)-alkenes respectively by an anti-elimination
(Scheme 81). The reaction proceeds via the formation of an intermediate three-membered cyclic
phosphonium salt, followed by extrusion of the phosphorus group induced by triethylamine
(Scheme 82) <1998T15345, 1998T15361>.
OH OH
R1 LiAlH4/CeCl3 R1 PCl3, Et3N
R2 R2
R1 R2
Ph2P Ph2P
O 90/10 (Z )/(E )
OH OH R1
LiAlH4/CeCl3 PCl3, Et3N
R1 R1
R2 R2
R2
Ph2P Ph2P
O 5/95 (Z )/(E )
Scheme 81
Cl
P Cl PCl2 :NEt3
OH Cl O Ph Ph
R1 –HCl R1 –Cl 2PO P
R2 R2 R1 R2
Ph2P: Ph2P: R1 R2
Scheme 82
In most cases, the Horner–Wittig elimination of -hydroxyphosphane oxides works well by

using KOH in DMSO or NaH in DMF as bases. Sometimes, however, these conditions may
afford unwanted isomers and degradation products. This was the case during the total synthesis
of the cis-(Z)- and trans-(Z)-epoxy bisabolenes (Scheme 83), where the use of NaH in DMF
resulted in considerable amounts of retro-addition products. The optimal conditions for the
elimination were determined to be the addition of powdered KOH to a DMSO solution of the
-hydroxyphosphane oxides at room temperature <2000S269>.
O O O
O
O
LDA KOH, DMSO
+ Ph2P +
H rt, 30 min
HO
O PPh2
O 58%
12% 68%
Scheme 83
The Horner–Wittig reaction, in particular the role of the diphenylphosphinoyl group as diastereo-
selective auxiliary, has been extensively studied by Warren and co-workers. In order to determine
the factors which govern the sense and degree of asymmetric induction, the reaction of lithiated
chiral phosphine oxides with different electrophiles (Me3SiCl, MeI, ketones, aldehydes, esters) was
examined. The stereoselectivity appeared somewhat variable but syn-selectivity predominated in
most cases. The authors suggested a dynamic kinetic diastereoselection to explain the results
(Scheme 84). The method allowed the stereocontrolled synthesis of 1,4-disubstituted-2-alkenes
(Scheme 85) <1998JCS(P1)3405>.
Li TMSCl SiMe3
Ph Ph
O
Ph2P Ph2P
O
O syn syn, 93%
BuLi (57% recrystallized)
PPh2
Ph
Li TMSCl SiMe3
Ph Ph
O
Ph2P Ph2P
O
anti anti, 7%
Scheme 84
i. BunLi then
O HO
cyclohexanone KOH
PPh2
Ph ii. TFA Ph Ph DMSO
Ph2PO Ph2PO SPh 58% SPh
Ph
Scheme 85
The treatment of chiral -carbamoyloxy-,-epoxy-diphenylphosphine oxides with bases leads

to 4-alkenyl-oxazolidin-2-ones resulting from intramolecular nucleophilic attack of the carbamate
on the epoxide followed by Horner–Wittig elimination (Scheme 86) <1998JCS(P1)2923>. The
starting epoxyurethanes were obtained by kinetic resolution through Sharpless epoxidation of
diphenylphosphinoyl allylic alcohols.
O
O
KOH
O O O
Ph2PO DMSO Ph2PO N 80% N
BnHN O Bn Bn
O O
Scheme 86
Synthesis of optically active (E)- and (Z)-protected homoallylic alcohols was carried out by the
addition of phosphine oxides to aldehydes and esters followed by a Wittig–Horner elimination.
The reaction of lithiated phosphine oxides with aldehydes afforded -hydroxyphosphine oxides
with moderate-to-good stereoselectivities. The best stereoselectivities were obtained for phosphine
oxides featuring a benzyloxy group at the -position. These results suggest the formation of a
chelate in which the benzyl ether has displaced a solvent molecule from lithium (Scheme 87)
<1999JCS(P1)1963>.
O OH OH
Ph2P R1 i. BunLi R1 R1
R2 + R2
ii. R2CHO
Ph2PO Ph2PO
R1 = OBn 81 19
R1 = Et 59 41
NaH, DMF R2
R1
O H
Li O
P Major
H
R
OBn
Scheme 87
The Horner–Wittig reaction was also applied to the synthesis of oxidosqualene and analogs.
After separation of the two diastereoisomers by chromatography, the syn-isomer gives the
isomerically pure (E)-stereoisomer (Equation (20)) <1995TL5719, 1995T5255>. This reaction
was also used to prepare a chiral unsaturated phosphine oxide (Scheme 88) <2002JOC5864>.
O
PPh2 R1S
NaH, DMF
R1S R2
86% R2
OH
(E ) only
ð20Þ
1 O
R =
2
R =
Ph OH Ph
MeO MeO
PPh2 KH, THF
MeO O MeO
82%
PPh2 PPh2
O O
Scheme 88
Formation of alkenyl -hydroxyphosphonates via Baylis–Hillman-type reaction gives versatile

intermediates which can be readily converted to allenes by treatment with NaH in THF
(Scheme 89) <1998JOC6428>. Dithioallenes, isolated as dimers could also be prepared from
phosphonoketene dithioacetals via the Horner–Wittig–Emmons (HWE) reaction and treatment
with ButOK in DMF <1996JOC8132>.
R3
R2 OH R1 R2
NaH
C
R1 THF
PO(OEt)2 R3
52–72%
R1 = H, Me, Ph
R2 = Et, But, Ph, PhCH2CH2, 4-t-butylcyclohexanone
Scheme 89
1.14.4.1.2 Via oxirane-opening reactions

A wide variety of nucleophiles can react with epoxides to give -hydroxy intermediates and in
some cases a direct elimination occurs to afford the corresponding alkenes. Epoxides react with
triphenylphosphine at elevated temperatures to give alkenes via oxidophosphonium salt inter-
mediates. The sequence alkene epoxidation/opening by triphenylphosphine/elimination results in
an inversion of the alkene geometry. In the example shown in Scheme 90, however, where
inversion is not possible, oxirane deoxygenation was carried out with PPh3/I2 in acetonitrile at
low temperature. A mixture of positional isomers of alkenes was isolated along with other
compounds <1995T12403>.
H H
H H
O PPh3 / I2 O O
58%
CH3CN, –24 °C
H I
H O
O
HO
H H
H H
O O
31% 3%
Scheme 90
Stereoselective synthesis of trans-arachidonic acid was carried out by the treatment of an

epoxide with lithium diphenyl phosphide followed by quaternization with methyl iodide
(Scheme 91) <2001BMCL2415>. In the example shown in Scheme 92, addition of lithiated
diphenyl phosphite to a 2,2-disubstituted oxirane afforded the corresponding allylic sulfoxide
via a four-membered oxaphosphetane ring <1995T8289>.
CO2H i. Ph2PLi, THF CO2H
ii. MeI
O 74%
Scheme 91
(EtO)2P(O)Li
ArS F ArS F
O O THF, –60 °C O
51–57%
Scheme 92
In 1996, the reaction of triphenylphosphonium anhydride and triethylamine with oxiranes,

leading to dienes, was described. A bisphosphonium ether identified by 31P NMR was suspected
to be an intermediate in this reaction but the authors were not able to hydrolyze this compound
to the corresponding diol, which would have constituted a definite proof (Scheme 93)
<1999SL661>.
Ph3POPPh3/2 TfO Ph3P O O PPh3

Et3N
O R1 R1
ClCH2CH2Cl, reflux
50% Suspected
intermediate
Scheme 93
Recently, tetramethylphosphordiamidic chloride was used to convert epoxides to dienes. This

reaction requires the presence of water to proceed (under anhydrous conditions, only trace
amounts of dienes are obtained). In fact, water hydrolyzes the tetramethylphosphordiamidic
chloride to the corresponding acid which reacts with epoxides as shown in Scheme 94
<2001T227>.
(Me2N)2P(O)Cl + H2O (Me2N)2P(O)OH
O O
R (Me2N)2P(O)OH R O P(NMe2)2 (Me2N)2P(O)OH R O P(NMe2)2 ∆ R
O
R OH R O P(NMe2)2 52–92%
R R
O
Scheme 94
1.14.4.2 Elimination of Arsenic, Antimony, and Bismuth Functions

No new references were found between 1995 and 2003.
1.14.5 BY ELIMINATION OF SILICON, GERMANIUM, OR BORON FUNCTIONS
1.14.5.1 Elimination of Silicon Groups

-Elimination in -substituted organosilanes continues to be an important method for the pre-
paration of alkenes <1995COFGT(1)589>. Besides the well-known elimination of silanols from
-hydroxysilanes (Peterson elimination), other -substituents suitable for alkene formation
include alkoxy or acyloxy groups, halogen, sulfur, and nitrogen.
1.14.5.1.1 Elimination of b-hydroxysilanes and d-hydroxyallylsilanes

As initially shown <1968JOC780, 1974TL1133, 1975JA1464>, -hydroxysilanes readily eliminate
silanols to afford alkenes (Peterson elimination). The elimination can be carried out under basic
or acidic conditions and proceeds in a syn- or anti-fashion respectively, with almost complete
stereoselectivity (Scheme 95).
R3Si OH
anti-elimination R3 syn-elimination
R1 R2
R3 R2 H KH R3
R1 KH H R1 R2
R3Si OH
R3
syn-elimination anti-elimination
R1 R2
Scheme 95
Clean formation of (E)- and (Z)-alkenes, when possible (R2 6¼ H, R1 6¼ R3), will be dictated
by the stereochemical purity of the starting -hydroxysilanes. The latter can be obtained by
several methods: condensation of -silylcarbanions with alicyclic aldehydes or ketones (Peterson
olefination) is commonly used for accessing -hydroxysilanes. This coupling reaction is discussed
in Chapter 1.16.
-Hydroxysilanes can also be conveniently prepared by regioselective nucleophilic opening of
,-epoxysilanes <1975JA1464, 1975JA1993, 1992JCS(P1)3309>. Organocuprates <1997CCC1457,
1999TA3601, 2000SL1753>, phosphides <1997TL8117>, amides <1999JOC877>, thiols
<2000TL1111>, and halides <2001T549> afford -alkyl-/aryl-, -phosphino-, -amido-, -thio-,
and -halogeno--hydroxysilanes which can be converted to the corresponding substituted alkenes,
vinyl phosphonium salts, enamides, vinyl sulfides, and vinyl halides, respectively (Scheme 96).
Nu
R SiMe3 R Nu
R Nu
O HO SiMe3
Nu = R', R'S, N-(C=O)R, R'2P, X
Scheme 96
The method was recently used for the preparation of natural heptacosadienes (Scheme 97)
<1997CCC1457>, and synthetic precursors of isoquinoline alkaloids (Scheme 98) <1999JOC877>.
O
C13H27 Me3Si
Me3Si
C10H21 CuCNLi2 C10H21 C13H27
2
55%
OH
NaH
BF3.Et2O 95%
C10H21 59%
C13H27 C13H27
C10H21
Scheme 97
H H
N O N O +
O O H
O
100% 100% N O
SiMe3 SiMe3
OMe OMe
OMe OMe
OMe
OMe
Scheme 98
Besides the ‘‘classical’’ Peterson elimination, involving -hydroxysilanes, a vinylogous version

was reported earlier <1984CC534, 1995COFGT(1)589>. In this reaction, 4-trialkylsilyl-2-ene-1-
ols undergo base- or acid-induced elimination to afford conjugated dienes. The stereochemical
outcome of the reaction has been examined and like its ‘‘classical version’’ the reaction appears to
be highly stereoselective.
Under acidic or alkaline conditions, (Z)-4-trialkylsilyl-2-ene-1-ols are converted into (E)- or
(Z)-1,3-dienes (Equation (21)) <1992TL5969>, (Equation (22)) <1996TL7275>. The vinylogous
Peterson elimination was a key step in the synthesis of 2,4-disubstituted-1,3-dienes as shown in
Scheme 99 <1999JOC9310>.
+
OH H or Cp2ZrHCl, AgClO4, ∆
SiMe3 R ð21Þ
R
>96/4 (E )/(Z )
OH +
Me3Si H C5H11
C5H11 ð22Þ
80% OH
OTHP
>6/94 (E )/(Z )
Ni(COD)2 OH R2 R2
2
R1CHO + SiMe3 + ZnR2 SiMe3
R1 R1
Only isolated diene
37–75%
Scheme 99
In the base-induced vinylogous Peterson elimination of (Z)-4-trialkylsilyl-2-ene-1-ols

(Scheme 100), syn--hydroxysilanes afford trans,trans-dienes while anti--hydroxysilanes provide
cis,trans-dienes, the newly formed cis-double bond being placed at the carbon that previously
carried the hydroxy group <1998JCS(P1)2749>.
1.14.5.1.2 Elimination of b-sulfonyloxy-, b-acyloxy-, and b-alkoxysilanes, and

d-sulfonyloxy-, d-acyloxy-, and d-alkoxyallylsilanes
-Elimination in silanes featuring a leaving-group to the silicon atom is an alternative to, and in
several cases shows distinct advantages over, the Peterson reaction. In particular, the hydroxy
group in -hydroxysilanes can be activated by acylation or sulfonylation, and treatment of the
-sulfonyloxy and -acyloxysilanes thus obtained with fluoride anion leads to -elimination
(Equation (23)).
OH SiPhMe2
KH
37%
OH SiPhMe2
KH
80%
Me2PhSi OH
KH
79%
Me2PhSi OH
KH
47%
Scheme 100
–
F
Me3Si CH2=CH2
OR ð23Þ
OR = carboxylate, sulfonate
From the mechanistic standpoint the reactions usually proceed in an anti-fashion

<1995COFGT(1)589>, although deviations from this rule have been observed in several instances
<1999T10325>.
Lactones, bearing silyl substituents in the vicinity of the latent hydroxy group, can be opened
by treatment with fluoride <1995TL7545> or KH <1998JCS(P1)2733> (Scheme 101) to afford
,- or ,-unsaturated carboxylic acids.
TolMe2Si SiMe2Tol SiMe2Tol

H
KH HOOC
O O 100% O O
O HO TolMe2SiO
O
PhMe2Si NHt-BOC NHt-BOC
H + –
Me HOOC
Bu4N F
O 66% Me
O
Scheme 101
The -elimination of -sulfonyloxy- and -acyloxysilanes allows the preparation of strained systems.
This is illustrated in a recently reported preparation of methylenedifluorocyclopropanes (Equation (24))
<1999T10325>. Mesylation or acylation of 3-alkyl-2,2-difluoro-1-hydroxymethyl-1-trimethylsilanyl-
cyclopropane, followed by fluoride treatment, afforded the corresponding methylenedifluorocyclo-
propane, whereas silyl ether elimination was ineffective. This contrasts with the successful use of the
Peterson reaction for the preparation of nonfluorinated methylenecyclopropanes <1998CRV589>.
F F – F F
F
X
R SiMe3 R ð24Þ
X = OAc, OBz, OMs: 66–91% yield

X = OPMB: no reaction
The method was successfully extended to the preparation of alkylidenecyclopropanes

(Scheme 102). The stereospecificity of the -elimination was examined using diastereomerically
pure substrates and found to be low (Scheme 103).
F F F F F F OH
Swern R1MgBr
CHO
OH R1
R SiMe3 R SiMe3 R SiMe3
F F OAc F F
Ac2O, Pyr Bu4N+F–
R1 R1
R SiMe3 R
52–99%
Scheme 102
F F OAc + – F F + – F F OAc
Bu4N F Bu4N F
Et Et Et
H13C6 SiMe3 H13C6 H13C6 SiMe3
60% or 52%
4/1 or 4/3 (E )/(Z )
Scheme 103
Acidic treatment of 1-alkyl-2-trimethylsilanyl-cyclopropanols gives -trimethyl silyl ketones

while fluoride-induced -elimination of the corresponding mesylate affords substituted cyclopro-
penes (Scheme 104) <1999TL2557>.
O H2SO4 i. MsCl
HO
Me3Si R 80% ii. Bu4N+F– R
R SiMe3
66%
R=
Scheme 104
An elegant preparation of 2,4-disubstituted furans has been developed by Kabat

<1996TL7437>. The method relies on a -elimination of trimethyl silyl mesylate to afford
unstable allene oxides, which rearrange to furans. This approach was used for the synthesis of
steroidal furans (Scheme 105).
Li SiMe3 i. Sharpless
OH OMs
CHO ii. MsCl
SiMe3 SiMe3
R 96–97% 89–92% O O
R R
+ – OH (F)
Bu4N F O
O
or O – –
+ –
R OH (F) –
O + R
Bu4N F, H2O
Bu4N
OH (F)
O
R R = alkyl,
HO
Scheme 105
Double bonds are formed upon exposure of -alkoxysilanes to Lewis acids as shown in a series
of ring-opening reactions affording homoallylic or bishomoallylic alcohols (Scheme 106).
SiR3
O
O Si O
SiR3 R R OR1
HO
OH OH
Mode A Mode B Mode C
Scheme 106
For example, the reaction of substituted allylsilanes with nucleoside-derived aldehydes

under Lewis acid catalysis mainly afforded 3-silyl-substituted tetrahydrofurans which could be
converted to the originally expected homoallylic alcohols upon treatment with TiCl4 according to
a mode C fragmentation (Scheme 107) <1999T5831>. Similarly, the cycloadducts obtained by
photochemical [2+3]-cycloaddition of allylsilanes to 1,2-naphthoquinones suffer fluoride ion- or
Lewis acid-induced fragmentation leading, after oxidative treatment, to allylated o-naphtho-
quinones (Scheme 108) <2001S63>. Mode A fragmentation was used for the synthesis of eight-
membered lactones (Equation (25)) <1999SL1757>, or eight-membered cyclic ethers (Scheme 109)
<2000T2203>. Finally, an example of mode B elimination leading to homoallylic silyl ethers was
recently reported (Equation (26)) <2001JOC1966>.
O
Br NH
O O N O
O
NH Me3Si
N O TPSO
O
Br OHC BF3.OEt2
+ 100% TiCl4
82% O
SiMe3
TPSO
NH
Br
OH
N O
O
TPSO
Scheme 107
O OH
O O
R2 hν
+ SiMe3
SiMe3 R2
R1 R1
R R
O
–
O
i. F or BF3.Et2O R2
ii. CAN
R1
R
Scheme 108
R1
R1 CF3COOH
SiMe3 R2
R2 O O
ð25Þ
COOH O
R1, R2 = H, Me
SiMe3
O
OH O O
MsCl, Et3N CAN
91%
Co(CO)3 Co(CO)3
Ph Ph Co
Co
(CO)3 (CO)3 Ph
Scheme 109
But But But

But
Si Si
O CH2OBn BF3.OEt2 F O ð26Þ
H H 75% H H
O O O O
Vinylogous versions of -acyloxy-, -sulfonyloxy-, and -alkoxysilane eliminations have

been reported. Acetates derived from (E)- and (Z)-4-trialkylsilyl-2-ene-1-ols lead to dienes
upon treatment with fluoride anion (Scheme 110) <1998JCS(P1)2749>. The stereoselectivity of
OAc SiPhMe2
–
F, 42/43 = 60/40
86%
– +
OAc SiPhMe2 F, 42 /43 = 50/50
42 43
86%
Me2PhSi OAc
–
F
>98%
44
–
Me2PhSi OAc F
>95%
45
Me2PhSi
–
F
OAc 93%
Scheme 110
these eliminations differs from that observed for the vinylogous Peterson elimination of the
corresponding free alcohols (see Scheme 100). In some cases the reactions are highly stereo-
selective affording ((E),(E))- or ((Z),(E))-dienes depending on the stereochemistry (Z) or (E) of the
olefinic double bond in the starting material while in other, apparently very similar cases,
essentially no stereoselectivity is observed. The factors that govern the degree of selectivity of
these reactions are unclear.
A preparation of [3]cumulenes based upon the elimination of 4-(trimethylsilyl)-2-butyn-1-ol mesy-
lates has been reported. While yields are generally good, the reaction is not stereoselective and, when
applicable, (Z)- and (E)-isomers are formed in a 1:1 ratio (Scheme 111) <1995JOC1885>.
R i. BunLi R R2 i. BunLi R R2
R1 H R1 R3 C C C C
Me3Si ii. R2R3CO Me3Si OH ii. MsCl R1 R3
iii. TBAF
R ≠ R1, R2 ≠ R3; 1/1 (Z )/(E )
Scheme 111
Elimination of 4-(trimethylsilyl)-2-buten-1-yl ethers can be effected by Lewis acids or fluorides.

The method was used in a synthesis of (+)-Prelog–Djerassi lactonic acid (Equation (27))
<1998T11567>. Remarkably, the reaction proceeded in a highly stereoselective fashion to afford
exclusively an (E)-diene in excellent yield.
OTBDPS
OTBDPS
BF3.Et2O
O 95% ð27Þ
OH
Me3Si O
(E ) only
Besides the Lewis acid-induced elimination of silanol (a vinylogous Peterson elimination) mentioned
earlier <1996TL7275> (see Equation (22)), treatment of the THP-monoprotected allylic diol shown in
Equation (28) with fluoride leads to the elimination of the OTHP group to furnish a 2-hydroxyalkyl-
1,3-butadiene. Therefore, both 1,3-butadienes having an -hydroxyalkyl moiety at the 2-position and
1,3-alkadienes having a hydroxymethyl group at the 3-position can be obtained from the same
intermediate depending on the elimination conditions (compare Equations (22) and (28)).
OH – OH
Me3Si F
C5H11 ð28Þ
87% C5H11
OTHP
1.14.5.1.3 Long-range elimination of hydroxy-, sulfonyloxy-, acyloxy-, and alkoxyallylsilanes

Elimination of silanols from hydroxyallylsilanes or derivatives with concomitant formation of an
olefinic double bond and a carbocycle according to Equation (29) have been described previously
<1991T7689, 1989TL4845, 1984CC585>.
OR1
( )n
( )n SiR3 ð29Þ
R1 = H, acyl, sulfonyl, alkyl
n = 1, 3, 4
Accordingly, elimination of "-sulfonyloxyallylsilanes has been used for the preparation of

trans-vinylcyclopropanes (Equation (30)) <1997TL2057, 1999OL1257>.
OH
RO Tf2O, lutidine
RO ð30Þ
R = Ph, Bn SiMe3 (E ) exclusively
An iterative version of this method was examined as a stereocontrolled approach to oligo-

cyclopropane systems as found in certain natural, biologically active compounds <1997TL2057,
1999OL1257>. As shown in Scheme 112, in this study, the outcome of the reaction depends on
the nature of the OR group, phenyl ethers leading to the formation of single products whereas
benzyl ethers afforded 1:1 mixtures of diastereoisomers.
OH OH
RO RO RO
+
SiMe3 SiMe3
OH
RO Tf2O RO RO
+
Lutidine
SiMe3 R = Ph 1:0, >80%
R = Bn 1:1, 82%
OH
RO Tf2O RO RO
+
Lutidine
SiMe3 R = Ph 0:1, >80%
R = Bn 1:1, 80%
Scheme 112
Finally, recent applications of the general process shown in Equation (29) to the preparation of
vinyl cyclopentanes have been published (Equation (31)) <1997TL6537>. Here again, the stereo-
selectivity of the reaction depends on the nature of the R group, nonsubstituted -lactams
(R = H) leading to nonstereoselective reactions.
O R
O H
i. Lewis acid COOMe
ii. CH2N2 ð31Þ
R
SiMe3 81% H
R = H, Me, OBn 1/1 cis/trans
1.14.5.1.4 Elimination of b-halosilanes

-Halosilanes which can be prepared in various ways are useful synthetic intermediates for
the synthesis of strained alkenes <1995COFGT(1)589>. They have been used recently for
the preparation of unstable alkenyl- or alkynylcyclopropenes (Scheme 113) <1995TL3457>,
methylenecyclopropene (Equation (32)) <1997TL1115>, and allenes (Scheme 114)
<2001TL2605>. In the latter case, a more classical Peterson olefination was attempted with
limited success.
H, (Cl, Br) H, (Cl, Br)
Bu4NF, 4 × 10–2 mbar

25 °C
Me3Si Cl
Me3Si OH

25 °C
Me3Si Cl
Me3Si
25 °C
SiMe3 Cl
OH
Me3Si
25 °C
Cl
Scheme 113
CsF, 1.3 × 10–2 mbar

ð32Þ
Me3Si Br 25 °C
HO Ar Me3SiO Ar
R R
SiMe3 KH
SOCl2
CCl4
Pyr R C Ar
75–98%
TBAF, rt
Cl Ar
55–90%
R
SiMe3
Scheme 114
-Halosilane elimination was used in an elegant synthesis of a naturally occurring, halogenated

monoterpene (Scheme 115) <1997JOC8962>. The synthesis involved the use of a silicon tether for the
Diels–Alder cycloaddition, the chlorination of the resulting allylsilane, and the removal of the tether
with concomitant formation of the required methylene group via -halosilane elimination.
O CH3 CH3
H3C H3C Si H3C Si
O O O O
H3C Si O Br ∆
CH3 CH3
CH3 74% 61%
Cl
Br Cl Br
Cl
OH
DIBAL-H CH3 CH3
85%
Cl Br Cl Br
Scheme 115
1.14.5.1.5 Elimination of b-aminosilanes

Amides and sulfonamides featuring a -silyl group readily eliminate upon fluoride treatment to afford
olefinic double bonds. The reaction has been applied to the fragmentation of piperidines and
pyrrolidines (Equation (33)) <1996TL8493, 2001CC958, 1999TL3873> and aziridines (Equation
(34)) <2001T4423>. A new method for the preparation of medium-ring nitrogen heterocycles,
involving aziridine fragmentation/ring expansion was recently described. The fused aziridines were
prepared via intramolecular [2 + 3]-dipolar cycloaddition of azides (Scheme 116) <2001TL9175>.
Ph Ph
( )n TBAF ( )n
ð33Þ
SiMe3
N NHTs
Ts n = 0, 1
O
OEt O OEt
R P AcOH R P
OEt OEt ð34Þ
N CH2SiMe3 HN
COOEt COOEt
OH
OH ( )n OH
( )n
( )n TMS ∆ TMS hν
TMS
90% N H 77%
N H
N3 N
N
OH
( )n
TBAF
n = 0, 1
30–49%
N
H
Scheme 116
The 2-benzotriazolyl group behaves both as an activating group toward -proton abstr-
action and as a good leaving group for -elimination. This versatility was exploited in a new
preparation of styrenes (Scheme 117) <1997JA9321> and 2-alkyl-substituted 1,3-butadienes
(Scheme 118) <1999JOC1888>. A drawback of the latter procedure is the ambident character
of the intermediate anion. Whereas the method works well for linear alkyl halides and aldehydes,
cinnamyl bromide and hindered aldehydes react with poor regioselectivity resulting in mixtures of
- and -substituted products (Scheme 118).
The conversion of -azido-silanes to alkenes (Scheme 119) <2002OL4253, 2002OL4257> has
also been reported. The mechanism of the silylazide elimination was found to vary depending on
the substrate used. Whereas aliphatic substituents led to the expected E2 elimination, an E1cb
mechanism was suggested for aryl substituents <2002OL4253>.
Ar Bt R
i. BuLi Me3Si ∆
– ii. RX Ar Ar
F,∆ R
Bt i. BuLi Bt HO Ar'
Me3Si ii. Ar'CHO Me3Si ∆
Ar Ar
HO Ar' Ar
OH
i. BuLi Bt
ii. O Me3Si ∆ Ph
Ar
Ph
Ph Ar
OH
Scheme 117
Bt Bt
i. BuLi Me3Si + Me3Si
R
ii. RX R
Bt R = C6H13 0
1
PhCH2 1 0
Me3Si Ph-CH=CH-CH2 11.5
1
i. BuLi Bt Bt
ii. RCHO Me3Si + Me3Si R
X = Cl, Br, I HO R OH
R = PhCH(CH3) 1 0.15
(CH3)2CH 1 9.5
4-Cl-C6H4 1 0.66
Bt Bt
∆ ∆ R
Me3Si R Me3Si
R OH
HO R
Scheme 118
SiMe2Ph SiMe2Ph
F
N3 + N3 R + R
R R
R = Cyclohexyl 60:40 42:58

Octyl 76:24 24:76
Phenyl 92:8 81:19
Scheme 119
1.14.5.1.6 Elimination of sulfur-containing leaving groups

Numerous eliminations in silanes featuring -sulfur-containing leaving groups are known and
have been used for the preparation of alkenes (Equation (35)) <2002TL2381, 1999T2245,
1996TL3841, 2002TL2967, 1995TL4013, 1995TL4769, 1998T9995>.
"S"
R3Si CH2=CH2
ð35Þ
"S" = SO2R', SO3R', S(O)R', S(=NR")O2R'
The -sulfur-substituted silanes are prepared by a variety of methods including -alkylation

of sulfones, sulfonates/sultones, sulfonimides, or sulfoxides with R3SiCH2X (X = I, Cl)
<2002TL2967, 1996TL3841, 1999T2245, 1997SL449>, 1,4-addition of R3SiLi (or derived
cuprate) to vinylsulfones <1995TL4013>, or the reaction of N-phenylsulfonimidoyl chloride
with trimethylsilylethene <1995TL4769, 1998T9995>. The -sulfur-substituted silanes thus
obtained can be deprotonated again, then further functionalized.
Examples of alkene formation by the elimination of silanes featuring a -sulfur-containing
leaving group and the preparation of the latter are shown in Scheme 120.
–
SO2Ph i. BunLi SO2Ph F
Me3Si Me3Si
ii. PhCHO
Ph OH
Ph OH
SO2Ph PhO2S – E
i. PhMe2SiLi PhMe2Si E F
(CH2)n + (CH2)n (CH2)n
ii. E
RO RO RO
HO i. LDA
O i. LDA S ii. Br COOEt
S p -Tol ( )n ( )n
p-Tol ii. ICH2SiMe3 –
SiMe3 iii. F COOEt
n = 1, 2
–
O i. BunLi O F
S ii. ICH2SiMe3 S 53%
Pri O O Pri O O
78% Pri OH
SiMe3
TMS
O –
AlCl3 F
p -Tol S Cl HN p -Tol
TMS S O 95% S
N N p -Tol O
Ph 37%
+
S O
N p -Tol
Scheme 120
Chiral -silylsulfoxides have been proposed as new, easily cleaved linkers for solid-phase
synthesis (Scheme 121) <2002TL2381>.
Vinylogous equivalents of the above reactions have been described. Thus, fluoride treatment of
1-(phenylsulfonyl)-4-(trimethylsilyl)-2-butenes has been used for preparing a wide variety of
substituted butadienes (Scheme 122) <1998JOC4181, 1998JOC4193>.
1.14.5.1.7 Other eliminations of silanes

Besides the widely used reactions of -substituted silanes mentioned above, there is a number of
less common reactions of silanes leading to alkene formation.
From -trimethyl silyl ketones, alkenes can be obtained in three ways.
O O
S S
NaH
+
SiMe3 SiMe3
Cl
HO O
Spacer
O Ph Ph
i. LDA F
Spacer S COOMe COOMe
COOMe 51% *
ii. Ph (R ) 90% ee
SiMe3
Scheme 121
F
SO2Ph
Me3Si
i. LDA R
R
ii. RX
i. LDA
SO2Ph ii. RX SO2Ph F R'
Me3Si iii. LDA Me3Si
iv. R'X R R' R
i. LDA
X, Y = Br, Cl ii. X(CH2)nY
n = 2–5 SO2Ph F
iii. n-BuLi Me3Si
( )n
( )n
Scheme 122
(i) Treatment with CuCl2 affords ,-unsaturated ketones (Equation (36)) <1988T4757,
1996TA263>.
(ii) Treatment with CAN induces an oxidative fragmentation leading to !-alkenylcarboxylic acids
(Equation (37)) <2000JA5899>. The excellent regioselectivity of this fragmentation is attributed to the
stabilization by the -silyl group of the radical and cation successively formed during the oxidation.
Attempts to apply the CAN-induced fragmentation to the related -trialkyl stannyl ketones led to
formal -elimination of trialkyltin hydride and formation of conjugated ketones. Successful oxidative
fragmentations of -trialkyl stannyl ketones are discussed in Section 1.14.6.1.2.
(iii) Conversion of cyclic -trimethyl silyl ketones to the corresponding -trimethyl silyl ketox-
imes and acidic treatment (or, in some cases, fluoride treatment) of the latter leads to a silicon-
directed Beckmann fragmention and constitutes an excellent approach to a variety of alkenyl
nitriles (Scheme 123) <1983TL4021, 1984TL223, 1988T2413>.
O SiMe3 CuCl2 O
ð36Þ
R1 R2 n n' Yield (%)

O
CAN H SiMe3 1 1 82
( )n R1 COOH ð37Þ
( )n' H SiMe3 2 2 98
Me3SiCH2 H 1 2 72
R2 Me3SiCH2 H 2 3 82
-Silyl, strained cyclic systems fragment upon Lewis acid treatment (Equation (38))
<1983CPB3931, 1981CC460>, (Equation (39)) <1996TL1209>.
AcO
N SiMe3 N
TMSOTf
R' R'
81–94%
AcO
N N
R TMSOTf R
R' R'
SiMe3
90–94%
R, R' = alkyl, alkenyl, benzyl
Scheme 123
( )n BF3·Et2O ( )n
Me3Si R R ð38Þ
O n = 1, 2 O
HgBr
Hg(NO3)2
Me3Si ð39Þ
Ph 80–90% Ph Ph
Ph
Fragmentation of cyclobutyl ketones was recently used for the synthesis of vinylspirolactones
and lactams (Equation (40)) <1999TL6001>.
O O
H H
SiMe3 BF3.OEt2
36–84%
O O ð40Þ
X ( )n X ( )n
n = 1, 2
X = O, N-CH3
1.14.5.2 Elimination of Germanium Groups

Germanes bearing leaving groups at the -position eliminate in a way similar to -substituted
silanes <1995COFGT(1)589>. In particular, 1,2-elimination of -hydroxy or -siloxygermanes is
analogous to that of -hydroxysilanes <1994JOC491>. Coupled with the facile radical-mediated
hydrogermylation of silyl enol ethers, the reaction was used for the conversion of silyl enol ethers
to alkenes (Scheme 124) <2000OL1911>. The elimination is highly stereoselective, following the
same rules as the classical Peterson elimination.
R1
TMSOTf
R2
OSiMe3 OSiMe3
R3GeH
R2 R2
R1 Et3B, O2 R1
GeR3
Main isomer i. K2CO3
MeOH R2
R3GeH = GeH R1
O ii. KH
3
Scheme 124
1.14.5.3 Elimination of Boron Functions
1.14.5.3.1 Elimination of alkylboranes

Alkenes are always formed in conjunction with alcohols upon reduction of ketones/aldehydes by
trialkylboranes. For example, reductions with -(3-pinanyl)-9-borabicyclo[3.3.1]nonane release
3-pinene <1995COFGT(1)589>. The reaction is concerted for aldehydes and acetylenic ketones
while a two-step mechanism (the first step being a thermal elimination of 9-BBN) is operative in
the other cases <1982JOC1606>. Synthetically, however, the reaction has seldom been used for
the purpose of alkene formation. An exception is alkene isomerization via the sequence hydro-
boration/isomerization/borane elimination in which internal alkenes are converted to their term-
inal isomers (Scheme 125) <1995COFGT(1)589>.
BR2
NaBH4, BF3 ∆ B
C8H17 B
C8H17 +
3
Scheme 125
Upon attempted hydroboration of divinyltin, an unusual cyclization was observed, leading to a

3-borylstannacyclopentane. Treatment of the latter with benzaldehyde produced a mixture of allyl
and vinylstannacycles (Scheme 126) <1998TL2511>.
Me Me Me
Me (9-BBN-H)2 PhCHO
Sn Me Sn Me Sn + Me Sn
Me 100%
B 1:1
Scheme 126
1.14.5.3.2 Elimination of b-substituted alkylboranes

Elimination of alkylboranes bearing a -heteroatom to produce alkenes bears some similarities
with the elimination of -substituted silanes. Until now, however, its use in synthetic chemistry
has remained limited when compared with its silicon counterpart. The chemistry of boranes
substituted with a -heteroatom has been summarized in the previous edition of this book
<1995COFGT(1)589> and several recent reviews are available <1993T7077, 1994PAC223>.
In contrast to the poorly stereoselective addition of -lithiated silanes to aldehydes (Peterson
reaction), the addition of hindered -lithiated boranes to aromatic aldehydes affords mostly
erythro -hydroxyboranes <1993T2965, 1995JA6142>. Subsequent stereospecific anti-elimination
of the corresponding trimethylsilyl ether under acidic conditions leads to (E)-alkenes. The
corresponding trifluoroacetates, obtained by trapping of the intermediate lithium alkoxide with
trifluoroacetic anhydride eliminate spontaneously to afford mixtures of (Z)- and (E)-alkenes in
which the former isomer predominates (Scheme 127) <1993T7077, 1994PAC223>.
Finally, an example of thermolysis of -siloxyalkylboronates, giving exclusively a (Z)-alkene
has been reported <1995CL1107>.
OSiMe3 Ph
Mes2B HF
TMSCl Ph H
O R
H R
Mes2B
Mes2B-CH(Li)R + PhCHO Ph H O
R
H CF3
O Ph
Major TFAA Mes2B R
Mes =
Ph H
R
H
Scheme 127
Aliphatic aldehydes also react with hindered borane anions in the presence of acids leading to
mixtures of (Z)- and (E)-alkenes whose composition depends on the nature of the starting
aldehyde and acid used. The reaction, performed in the presence of strong acids, favors the
formation of (E)-isomers (Equation (41)) <1993T7119>.
Acid R1 R1 R2
Mes2B(Li)R1+ R2CHO +
R2
ð41Þ
Acid = AcOH: (E )/(Z ) from 1/1(straight-chain aldehydes) to >1/9 (branched aldehydes)
= CF3COOH: >9/1 (E )/(Z )
Addition of p-toluenesulfonyl iodide or bromine across the olefinic double bond of allyboro-
nates, followed by base-induced elimination, produced allylic sulfones or allylic bromides
respectively (Scheme 128) <1991SL267>.
O O R2 I O O O R2
S B NaOH S
Ar O Ar
ArSO2I
R3 R1 R3 R1
R2 O
B
O
R2 Br O R2
R3 R 1 Br2 NaOH
Br B Br
O
R3 R1 R3 R1
Scheme 128
1.14.6 BY ELIMINATION OF METAL FUNCTIONS
1.14.6.1 Elimination of Tin
1.14.6.1.1 Elimination of b-hydroxystannanes, derived ethers and esters

The reaction of trialkyl- or triarylstannyl alkyllithiums with aldehydes followed by the elimination
of hydroxystannane (tin-Peterson reaction) <1982AG(E)410> resembles the classical silicon-
based Peterson reaction. Only the second step is stereoselective and follows an anti (via acidic
treatment) or syn (via thermolysis) mechanism <2001TL8993, 1982CB1818>. -Hydroxy-
stannanes may also be obtained by the opening of epoxides with trialkylstannyllithiums
<1995COFGT(1)589>.
Elimination of -alkoxystannanes (or of the vinylogous 1-alkoxy-4-trialkylstannyl-alk-2-enes)
can be effected under a variety of conditions: by tin–lithium exchange (Equation (42))
<1996JA10930>, thermally (Scheme 129) <2001T791>, or by Lewis acid catalysis
<2000TA1997>.
Bu3Sn
O OH BunLi OH OH
R= ð42Þ
66%
HO
R R
Bu3SnH ∆
AIBN 82%
O O OH
69%
Bu3Sn Debromoisolaurinterol
Scheme 129
The vinylogous version of the -alkoxystannane elimination was used for the preparation of
carbohydrate-derived conjugated trans-1,4-dienes (Scheme 130) <2000TA1997>.
OBn
O ZnCl2 O
OBn OBn
O O
Bu3Sn O O
OBn ZnCl2
O O
OBn OBn
O
OBn OBn O
Bu3Sn
Bu3Sn
O ZnCl2
R1 R1 CHO
1 = H,
R R2 = OBn O
R2 O R2 OH
R1 = OBn, R2 = H
Scheme 130
Other useful leaving groups for stannane elimination include mesylates and esters. The method
was used for the synthesis of allenes <1992TL5093> and [3]cumulenes (Scheme 131)
<1998TL5549>. Elimination of -mesylates and -esters was shown to be anti by examining
the relationship between the chiral allenes and the starting chiral stannyl allylic alcohols
(Scheme 132) <1992TL5093>.
1.14.6.1.2 Other eliminations of stannanes

1,4-Addition of the trialkyltin group to activated olefinic double bonds can be achieved using
R3SnH/AIBN, or stannyl cuprates. Upon appropriate treatment, the resulting stannane will
eliminate to generate an alkene.
Following this protocol, sequential addition of tributyltin hydride to ,-unsaturated sulfones
and treatment of the resulting -stannyl sulfones by TBAF has been developed as a good method
for the desulfonylation of sulfonyl alkenes (Scheme 133) <1998TL5321>.
OH OH R2
Bu3SnH MsCl, Et3N
R1 R1 R2 C
R2 SnBu3 R1
OH
R1
R2
OH R2
SnBu3 MsCl, Et3N
R1 i. BunLi
R2 + C
ii. Bu3SnCl C
R1 OH
R1
Bu3Sn C R2
Scheme 131
OAc
H
Ac2O, DMAP H3C C6H13
SnBu3
O OH 81%
Catecholborane H
H 3C C6H13 C6H13 42% F
H Ph Ph H 3C
(R)
SnBu3 SnBu3
O H H
N B MsCl, Et3N
C
(cat.) Bu (S) C6H13
Me
78%
Scheme 132
H Cl
Nt-BOC Nt-BOC Nt-BOC N
Ts Bu3SnH Ts TBAF N
AIBN H
93–98%
78–91% SnBu3 Epibatidine
Scheme 133
When applied to cyclic precursors, the tin-directed Bayer–Villiger oxidation of -tributylstannyl

ketones and Beckmann fragmentation of -tributylstannyl oximes affords unsaturated carboxylic acids
and nitriles respectively, obtained in good-to-excellent yields <1990JA6729, 1993JOC7185, 1995TL43>.
The stannyl moiety was introduced either by 1,4-addition of stannyl cuprates to ,-unsaturated ketones
or by quenching ketone enolates by trimethylstannyl methyl iodide (Scheme 134).
The fragmentations do not involve intermediates typical of normal Bayer–Villiger reactions
(lactones). Lactams or amides, the products of classical Beckmann rearrangements were also not
observed. The mechanisms are likely to be concerted, the carbonyl (hydroxylamine) function
behaving as a leaving group (Scheme 135).
The closely related fragmentation of -hydroxystannanes under oxidative conditions generates
in good yield alkenes and ketones when the starting material is an alcohol <1984CC1007,
1985TL2209>, or lactones if the starting material is a cyclic hemiketal <1987CL133,
1994JOC6395, 1995SL543>, as summarized in Scheme 136.
Since their discovery in 1984 and 1987 respectively, the above methodologies have been well
exploited. For example, the method was used recently for a ring expansion of conjugated
cycloalkenones to homoallylic lactones (Scheme 137) <2000TL9655>.
HO
O O N
i. LDA NH2OH
( )n ( )n ( )n
SnBu3 SnBu3
ii. Bu3SnCH2I
46 48
Bu3Sn HO
O Cu(CN)Li2 O N
Bu
( )n NH2OH ( )n
( )n
98%
47 SnBu3 49 SnBu3
MCPBA
46 or 47 COOH n = 1–3
( )n
59–87%
SOCl2
48 or 49 ( )nCN
Pyr
85–99%
Scheme 134
O
RCOOH
O
HO O O +
MCPBA
R CH2=CH2
R
SnBu3 SnBu3 +
ArCOOSnBu3
Cl
RCN
HO S O
N SOCl2 O +
N CH2=CH2
R Pyr
SnBu3 R +
SnBu3 ClSnBu3 + SO2
Scheme 135
OH SnMe3 O
R" R"
Oxid.
R' R'
OH O
R" R"
R R OAc
Oxid.
R' Oxid. = Pb(OAc)4 or I
R' AcO
SnMe3
OH O
O O
Oxid.
( )n ( )n
R3Sn H
Scheme 136
HO H R2 H
R2
O O O
H HO H
( )n i. LiSnMe3 ( )n R1 ( )n R1
H H
ii. R1 R2 , BF3.OEt2 SnMe3 SnMe3
O
n = 1, 2
AcO
Pb(OAc)2 H
R2
O O H O O
Pb(OAc)4 ( )n H R1
R2
( )n H
CaCO3 30–52%
H R1
SnMe3
AcO–
Scheme 137
The scope of this approach was briefly examined. Generally, 1-substituted epoxides are good
substrates (an exception is styrene oxide). 1,2-Dimethyloxirane and cyclohexene oxide are also
suitable reagents whereas cyclopentene oxide and cycloheptene oxide do not react.
1.14.6.2 Elimination of Mercury

Beta-heterosubstituted organomercurials eliminate under a variety of conditions to afford the
corresponding olefinic double bond. Combined with intramolecular amidomercuration the reac-
tion allows the synthesis of sugar-derived vinyl pyrrolidines (Scheme 138) <1995TL8127,
1997S1415, 2001JOC4787>.
OH H OH OBn
H i. Hg (CF3COO)2
O O i. C12H23SH BnO
NHt-BOC ii. NaCl N ii. NaH/BnBr N

77% ClHg H t-BOC 64% t-BOC
OH
H O O H HO
O O
NHt-BOC NHt-BOC
N N
t-BOC t-BOC
Scheme 138
Fragmentation of -hydroxy organomercurials under oxidative conditions, analogous to that

reported earlier for -hydroxy stannanes, has also been described. The method was used for
accessing the diquinane skeleton (Equation (43)) <1998S537>.
ButO OBut
ClHg OH
Pb(OAc)4
CHO ð43Þ
Benzene, 80 °C
X X
X = H, COMe 86–91%
1.14.6.3 Elimination of Transition Metals

In this section only ‘‘true’’ -eliminations whose aim is solely to create an olefinic double
bond and not -eliminations leading to nonisolated intermediates are discussed. For example,
the -hydride eliminations, which are part of the catalytic cycle in coupling reactions, cyclizations,
cycloisomerizations catalyzed by weakly electropositive transition metals (e.g., Pd, Rh, Ru) are
not considered. There have been occasional reports, however, of -H elimination induced in
isolated organometallic complexes, which may be interesting for synthetic chemists. Representa-
tive examples are given below.
Treatment of cyclopentene with Ni(COD)2, in the presence of a ligand and under CO2 atmo-
sphere, affords stable NiII complexes from which cyclopentene carboxylic acids are obtained by
-hydride elimination (Scheme 139) <1991S395>.
i. 1,3-Butadiene
ii. HCl COOH
Ni(COD)2
95%
CO2
P(Cy)2
N Ni
O COOH
N P(Cy)2 i. BeCl2
O ii. HCl
95%
80%
Scheme 139
-H Elimination in organoiron complexes, to afford alkenes has been thoroughly examined
<1980JOC291, 1995COFGT(1)589>. In spite of its fairly broad scope, this reaction has not been
used to a significant extent in the recent years.
The elimination of transition metals in complexes featuring electronegative substituents at the
-position is characteristic of group 4 metals. Application of this useful reaction in organic
synthesis has been reviewed recently <1995SL299, 1995T4519, 1996T12853>.
The addition of Cp2ZrHCl to allyl or vinyl ethers is followed by elimination of zirconium
alkoxide and formation of an alkene. The method has been used for the fragmentation of
dihydropyrans <1991JOC6494> and five-membered heterocycles including dihydrofurans and
pyrrolidines (Scheme 140) <1994OM5166, 1996OM1208>.
ClCp2Zr
Cp2ZrHCl
OZrCp2Cl
O THF, 40 °C O
i. Cp2ZrHCl
THF, –20 °C
HO
O ii. TfOH, –78 °C to rt
60–90%
Scheme 140
The reaction of ‘‘Cp2Zr’’ (prepared from Cp2ZrCl2/2 BuLi) with allyl or propargyl ethers leads
to allylic zirconocenes via -alkoxy elimination. These intermediates can be further elaborated to
more complex molecules. The reaction was used as a new mild deprotection method for allyl
ethers (Scheme 141) <1995SL299>.
Treatment of Cp2ZrCl2 with ethylmagnesium bromide leads to a zirconocene–ethylene com-
plex, which can be coupled with allyl ethers. Protonolysis of the intermediate zirconium alkoxide
affords an alkene. Alternatively, the reaction can be conducted with ethylmagnesium bromide and
catalytic amounts of the zirconocene complex. The reaction works with acyclic and cyclic allyl
ethers (Scheme 142) <1993JA8485>.
OH
"Cp2Zr" PhCHO
OR OR Cp2Zr Ph
Cp2Zr
OR
O O
O O
O "Cp2Zr" O
O HO
O –78 °C to rt O
O 98% O
Scheme 141
R R
ZrCp2
R1 R1 R R1
R1 H+
R OR' Zr Cp2Zr 50–77%
Cp2 OR' R'O
EtMgBr
R
R1
Cp2Zr
C2H5
Scheme 142
Intramolecular versions of this reaction have been developed, illustrated for example by a
recent synthesis of (–)--kainic acid (Scheme 143) <2000JCS(P1)3194>.
Using chiral ketals as chiral auxiliaries, highly enantioselective, Ti(II)-induced reductive cou-
pling of 1,6-enynes has been reported (Equation (44)) <1999JA3559>.
PhO
I COOH
i. "Cp2Zr"
ii. I2 COOH
N N N
Bn OTBDMS 12% Bn OTBDMS H
Scheme 143
( )n
R ( )n R OH
O
O O
C5H11
Ti(O-Pri)2 C5H11
ð44Þ
*
30–100%
up to 96% ee
up to 20/1 (E )/(Z )
In the case of strained systems, similar -alkoxide eliminations also occur with late, non-
electropositive transition metals. By using chiral ligands, high enantiomeric excess may be obtained
(Equation (45)) <2003OL1621>.
OH
O Pd(Binap)Cl2
+ (CH3CH2CH2)2CHCOOH
Zn, toluene, 25 °C ð45Þ
89%, 90% ee
Finally, complexation of alkynes/reductive decomplexation allows a facile stereoselective

access to cis-olefinic double bonds. Acetylene biscobalthexacarbonyl complexes are widely used
for the protection of triple bonds. Under reducing conditions, the metal will eliminate with the
reduction of the alkyne to the corresponding alkene. Bu3SnH is a particularly effective agent for
this elimination (Scheme 144) <1998TL2609>. Using R3SiH instead of Bu3SnH leads to the
formation of vinyl silanes.
Bu3SnH
∆ THPO OH
THPO OH 65%
Et3SiH
Co2(CO)6
∆
THPO OH + THPO OH
65% SiEt3 Et3Si
1:1
Scheme 144
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Biographical sketch
Jacques Eustache was born in Cherbourg. He Philippe Bisseret was born in France in
studied at the Université Paris-Sud (Orsay) Angers. He studied at the Université Louis
where he obtained a Maı̂trise de chimie in Pasteur in Strasbourg where he obtained his
1968 and a Doctorat de 3e cycle in 1971. He Ph.D. in 1982 under the direction of
joined the Centre National de la Recherche Professor G. Ourisson and D. Y. Nakatani.
Scientifique (CNRS) in 1970. After a three- After spending a year as a postdoctoral fellow
year leave of absence spent in Ivory Coast as working on sulfolecithins in the laboratory of
instructor at the University of Abidjan within Prof. M. Kates at Ottawa University, he
the frame of a French program for help to joined the ‘Centre National de la Recherche
developing countries, he came back to Orsay Scientifique’ and worked for 12 years in the
and obtained his Doctorat d’Etat in 1979 laboratory of Prof. M. Rohmer in Mulhouse
under the supervision of Prof. S. David. (Université de Haute-Alsace) on bacterial
Following a postdoctoral stay in the labora- triterpenoids (hopanoids). Since 1996, he has
tory of Professor E. Vedejs at the University been working in the same city in the team of
of Wisconsin-Madison, he returned to Orsay Prof. J. Eustache, where he has been involved
for a short period, then left CNRS and moved in the synthesis of potential new antitubercular
to pharmaceutical research first in France drugs. His scientific interests include the
(Galderma R&D), then in Austria (Novartis chemistry of aza-sugar derivatives and
Research Institute, Vienna). In 1996, he organophosphorus chemistry.
decided to come back to academia and took
his present position as Prof. of Chemistry at
the Université de Haute-Alsace in Mulhouse.
He is currently the head of the Laboratoire de
Chimie Organique et Bioorganique (CNRS
UMR 7015). His research interests include
the application of transition metals in total
synthesis, carbohydrate chemistry, and medic-
inal chemistry.
Pierre van de Weghe obtained his Doctorat en chimie organique in 1995

from the Université de Paris-Sud (Orsay, France) under the guidance of
Prof. H. B. Kagan and Dr J. Collin. After postdoctoral work at the
University of Stuttgart (Germany) with V. Jäger as an Alexander von
Humboldt fellow, he joined the group of Prof. J. Eustache in 1997 as
‘‘chargé de recherches’’ (CNRS). His research is focused on new meth-
odologies for total synthesis via the Ring Closing Metathesis reaction.
1.15
by Condensation: Condensation of
Nonheteroatom-linked Functions,
Halides, Chalcogen, or Nitrogen
Functions
J. PRUNET
Ecole Polytechnique – DCSO, Palaiseau, France
and
L. GRIMAUD
Ecole Nationale Supérieure des Techniques Avancées, Paris,
France
1.15.1 BY CONDENSATION FROM NONHETEROATOM-LINKED FUNCTIONS 670

1.15.1.1 Oxidative Coupling of Hydrocarbons 670
1.15.1.2 Metathesis 670
1.15.1.2.1 General 670
1.15.1.2.2 Catalysts 670
1.15.1.2.3 Ring-closing metathesis 672
1.15.1.2.4 Cross-metathesis 677
1.15.1.2.5 ROM and tandem reactions 679
1.15.1.2.6 Ene-yne metathesis 681
1.15.1.2.7 Non-Chauvin metathesis 686
1.15.2 BY CONDENSATION OF HALIDES: METAL-MEDIATED CONDENSATION OF
gem-DIHALIDES AND RELATED COMPOUNDS WITH CARBONYL GROUPS 688
1.15.2.1 Chromium-mediated Condensation 688
1.15.2.2 Zinc-mediated Condensation 690
1.15.2.3 Condensations Mediated by Other Metals 691
1.15.3 BY CONDENSATION OF OXYGEN FUNCTIONS 694
1.15.3.1 Synthesis of -Lactones and Subsequent Decarboxylation 694
1.15.3.2 Conversion of Carbonyl Compounds to 1,3,4-Thia- and 1,3,4-Selenadiazolines
and Extrusion of N2 and S or Se and Related Reactions 695
1.15.3.3 McMurry Coupling of Carbonyl Compounds 695
1.15.3.4 Addition of Organometallic Reagents to Carbonyl Compounds and In Situ Dehydration 696
1.15.4 BY CONDENSATION OF SULFUR, SELENIUM, OR TELLURIUM FUNCTIONS 696
1.15.4.1 Alkylation of Sulfur(II)-stabilized Carbanions and Elimination 696
1.15.4.2 Alkylation of Sulfur(IV)-stabilized Carbanions Followed by Elimination 697
669
670 One or More C¼C Bond(s) Formed by Condensation
1.15.4.2.1 Alkylation of sulfoxides and elimination 697

1.15.4.2.2 Alkylation of sulfinamides and elimination 697
1.15.4.3 Alkylation of Sulfur(VI)-stabilized Carbanions Followed by Elimination 697
1.15.4.3.1 The Julia reaction and related transformations 697
1.15.4.3.2 The Ramberg–Bäcklund reaction 705
1.15.4.3.3 Alkylation of sulfoximine-stabilized carbanions followed by elimination—the Johnson
(N-methylphenylsulfonimidoyl)methyllithium method 709
1.15.4.4 Alkylation of Selenium(II)- and Selenium(IV)-stabilized Carbanions Followed by Elimination 709
1.15.4.5 Alkylation of Tellurium-stabilized Anions Followed by Elimination 710
1.15.5 BY CONDENSATION OF NITROGEN FUNCTIONS 710
1.15.5.1 Reactions of Diazo Compounds 710
1.15.5.2 The Mannich Reaction 712
1.15.5.3 The Aza Wittig Reaction 713
1.15.1 BY CONDENSATION FROM NONHETEROATOM-LINKED FUNCTIONS
1.15.1.1 Oxidative Coupling of Hydrocarbons

The oxidative coupling of hydrocarbons is mainly reported for the reaction of methane to give
ethylene. Since it is of little use in synthesis, only a recent reference <1998MI(171)283> will be
mentioned.
1.15.1.2 Metathesis
1.15.1.2.1 General
Alkene metathesis was discovered during early studies on olefin polymerization, and has found
several industrial applications (e.g., the shell higher olefin process and the neohexene process
<B-1997MI001>). The development of well-defined, highly active catalysts tolerant toward a
wide range of functional groups has contributed to the success of this reaction: in the 1990s it has
become one of the most powerful synthetic tools in organic chemistry <1997AG(E)2036,
B-1998MI002, 2000AG(E)3012>.
Olefin metathesis refers to the cleavage and reformation of double bonds catalyzed by alkyli-
dene complexes. The mechanism of this reaction was originally proposed by Chauvin
<1971MI161> and consists in a sequence of [2+2]-cycloadditions/cycloreversions proceeding
via metallacyclobutane intermediates. Each step of the mechanism is reversible, so an equilibrium
mixture of olefins is obtained. Five main variations have emerged: ring-closure metathesis (RCM)
and the reverse reaction ring-opening metathesis (ROM), ring-opening metathesis polymerization
(ROMP) and acyclic diene metathesis polymerization (ADMET) which are beyond the scope of
this chapter, and cross-metathesis (CM) (Scheme 1). The inherent competition between RCM and
ADMET depends on the size of the ring formed during the reaction and on the conformational
constraints present in the acyclic substrate; it can be somewhat shifted toward RCM by using
high-dilution conditions. In the case of RCM, the reaction is driven by entropy, because it
produces two molecules from one. If one of them is volatile (ethylene, propene, etc.), the
equilibrium is generally displaced toward the ring-closed product.
Since metathesis converts one alkene into a new one, tandem processes can be envisaged, which
will be discussed later in this chapter.
1.15.1.2.2 Catalysts
The number of catalyst systems that initiate alkene metathesis is very large <B-1997MI001>.
Tungsten and rhenium complexes were initially reported in COFGT (1995) <1998JCS(P1)371>.
More recently, this reaction has been catalyzed by molybdenum carbenes (for recent reviews, see
<1999T8141, 2003AG(E)4592>). Among these, Shrock’s catalyst 1 <1990JA3875> has been the
most successful and is now commercially available (Figure 1). Until the discovery of the
second-generation catalysts, it was the most active carbene which showed tolerance toward
some functional groups. Ruthenium carbenes also show high reactivity toward alkenes, and are
One or More C¼C Bond(s) Formed by Condensation 671
excellent candidates for metathesis catalysts (for recent reviews, see <1998T4413, 2001ACR18>).
The most widely used in the 1990s has been ruthenium carbene 2 (Figure 1) developed by Grubbs
(<1993JA9858, 1995AG(E)2039, 1996JA100>) because of its high activity and its exceptional
tolerance toward polar functional groups such as esters, amides, ketones, aldehydes, alcohols, and
even acids or water. It is also commercially available and can be handled in air, contrary to the
Schrock catalyst which requires the use of a glove box.
RCM
–C2H4
ROM
+C2H4 ROMP
MLn
ADMET
–nC2H4
n
R2
CM
R1 R2 –C2H4 R1
R2 R2
R1 R1
Scheme 1
F3C R R R
F3C R R
O N R
R N N
Mo O R O R
O Ph Mo Mo L
O Ph O Ph
F3C R
1
F3C
R = Pri 1a 1b
R R
R = Me, Pri
R =Pri, L = THF
PCy3 PCy3
Cl Ph Cl
Ru Ru PCy3
Cl Cl Cl
PCy3 O Ru
2 Cl
Cy = Cyclohexylphosphine PCy3 Ph
2a 2b
Mes N N Mes Mes N N Mes Mes N N Mes

Cl Ph Cl Ph Cl
Ru Ru Ru
Cl Cl Cl
PCy3 2c PCy3 2d O
Mes = Mesityl
2e
Figure 1
Complexes 1 and 2 have been the basis for many other catalysts. In the case of the molybdenum
complex, the most noteworthy application is the design of enantiopure catalysts 1a derived from
biphenol (BIPHEN) and 1b from binaphthol (BINOL), which open the way to asymmetric olefin
metathesis. Catalyst 2a <1999JA791>, reported by Hoveyda, is stable on silica gel and can be
recovered after flash chromatography of the reaction mixture. It possesses a similar activity to
that of 2. Fürstner showed that catalyst 2b <1999OM5416> is slightly more active than the
parent compound <1999CC601, 2001CEJ4811>.
The introduction of N-heterocyclic carbenes as Lewis basic ligands to ruthenium alkylidene com-
plexes of Grubbs type <2001CEJ3236> has encouraged the development of new highly active, easy-
to-handle catalysts 2c <1999JA2674, 1999TL2247> (for similar catalysts, see <1999TL4787>), 2d
<1999OL953>, and recyclable second-generation complex 2e <2000JA8168, 2000TL9973>. These
catalysts are compatible with a wide range of functionalities <2003OL2505> and are as active or
more active in some cases than Schrock’s carbene 1. In particular, they are able to promote the
formation of tetrasubstituted double bonds, which was impossible with catalyst 2. They possess the
same tolerance toward functional groups, and are even more stable: they can be stored on the bench
for months. In addition, complexes 2d and 2e are commercially available. Grubbs also reported a
vinylidene complex of ruthenium made in situ from [{(p-cymene)RuCl2}2], 1,3-dimesitylimidazol-
2-ylidene hydrochloride, sodium t-butoxide, and t-butyl acetylene <2001AG(E)247>, which is
almost as active as catalysts 2c and 2d. Blechert designed a BINOL equivalent of catalyst 2e,
which is more active but shows no asymmetric induction <2002AG(E)794>, and a biphenyl
derivative <2002AG(E)2403>, which is even more active than the latter. Very recently, a very
active ruthenium catalyst with two alkoxide ligands in place of the chlorides has been reported
<2003OM3634>.
Grubbs described water-soluble complexes derived from 2, which catalyze ROMP of strained
cyclic olefins in water <2000JA6601>. RCM has also been performed with ruthenium catalysts in
water <2002CC1070>, in ionic liquids <2002CC146, 2003JA9248, 2003AG(E)3395>, and in
supercritical CO2 with catalyst 1 as well <1997AG(E)2466, 2001JA9000>.
Some supported catalysts have been recently reported, based on an earlier result by Grubbs,
which describes the immobilization of 2 on a moderately cross-linked polymer functionalized with
PCy2 units <1995JOM(497)195>. More recently, Barrett invented the concept of a ‘‘boomerang
catalyst,’’ in which the carbene is the anchor group <1999TL8657> (for another example, see
<2000OL4075>). The carbene precatalyst becomes soluble during the course of the reaction and
is recaptured by the polymer at the end (Equation (1)).
PCy3 PCy3
Cl Initiation Cl
Ru Ru CH2
Cl Termination Cl ð1Þ
PCy3 PCy3
Precatalyst Catalyst
Complexes 2a and 2e were attached to various supports, such as a dendrimer <2000JA8168>,

monolithic sol–gel <2001AG(E)4251>, a soluble polyethylene glycol resin <2000AG(E)3896>,
cross-linked insoluble polystyrene polymers <2001CC37, 2001SL1547>, other polymers
<2002AG(E)3835>, as well as polyacrylamide polyethylene glycol (PEGA-NH2) and butyl-
diethylsilyl polystyrene (PS-DES) resins <2002BMCL1873, 2002TL9055>. Hoveyda and Schrock
also designed a polymer-supported version of complex 1a, which gives excellent ee values in
asymmetric ring-closing metathesis (ARCM) and AROM/CM reactions <2002AG(E)589>.
Immobilized catalysts are in general slightly less active than the parent complexes and can be
recycled several times, up to 7 or 8 for the best ones.
1.15.1.2.3 Ring-closing metathesis

The mechanism of RCM has been widely studied by Grubbs <1997JA3887, 2001JA6543>. The
individual steps are described in Scheme 2.
RCM is very sensitive to steric hindrance. With the original Grubbs catalyst 2, only di- and
trisubstituted double bonds can be formed, but with molybdenum catalyst 1 and the second-
generation catalysts, even tetrasubstituted alkenes are obtained (Table 1) <1997JOC7310,
1999TL2247, 2000JOC2204, 1999OL953>.
R
LnM
R1CH=CH2
R1CH=CHR
LnM CH2
L nM LnM
MLn
H2C CH2
Scheme 2
Table 1 Effects of Substitution on RCM

Conversion (%) Conversion (%) Conversion (%) Conversion (%)
Substrate Product with 2 with 1 with 2c with 2d
E E
E E
100 100 100 100
E E E E
(93) 100 100 100
But E E
E E
0 37 100 100
But
E E
E E
0 93 40 31
E E E
E
(93) 100
E
E
E E 0 52 95(89) 90
E = COOEt.
Yields in parenthesis are isolated yields.
Olefin metathesis is under thermodynamic control. With less active catalysts, the kinetic
product can be formed in some cases, then isomerized with molybdenum or second-generation
ruthenium catalysts, which are more active. One of the first examples was reported by Hoveyda in
the course of the synthesis of 14-membered lactam fluviricin B1 (Scheme 3) <1997JA10302>.
When treated with ruthenium catalyst 2, the macrocycle precursor dimerizes through the less
substituted double bond. The dimer can be equilibrated to the macrocycle, which is the thermo-
dynamic product, with molybdenum catalyst 1. Treatment of the linear product with 1 directly
furnishes the fluviricin precursor in excellent yield. More recently, Smith illustrated the same fact
during his synthesis of cylindrocyclophane precursors <2001JA990>.
OTBDMS O
2 TBDMSO OTBDMS
N
H O O
NH HN
1, benzene
1, ethylene
22 °C X 50–55%
90%
OTBDMS
Fluviricin B1
O
HN
Scheme 3
Prunet reported the synthesis of a trans-cyclooctene by RCM (Scheme 4) <2000AG(E)725>.

Catalysts 1 and 2 lead to the kinetic product in good yields (only one diastereomer of the starting
material cyclizes), under very harsh conditions. With complex 2c, both diasteromers react, and the
thermodynamic cis-cyclooctene is obtained (which is 7 kcal mol1 more stable than the trans-
isomer). Once again, the trans-isomer can be transformed into the cis-product by treatment with
the more active catalyst <2000S869>. Fürstner nicely illustrated the same effect in his synthesis of
herbarumin I <2002JA7061>.
2, benzene
80 °C, 8 days
or 1, benzene
O O 80 °C, 3 days O O O O
O 1:1 O One isomer O One isomer
2 34% 42%
1 41% 32%
2c, 1,2-dichloroethane (DCE)
86% 2c, DCE 2c, DCE
80 °C, 12 h 67% 96%
80 °C, 12 h 80 °C, 12 h
O O O O O O
O 1:1 O One isomer O One isomer
Scheme 4
Closure of small rings is very efficient, including the formation of heterocycles such as oxacycles
<1992JA5426, 1993JA9856, 2002TL7263, 1999TL4187>, cyclic enol ethers <1997TL123> and poly-
ethers <2000AG(E)372, 1999JOC3354, 1997TL6299>, azacycles <1992JA7324, 1993JA9856>, sila-
cycles <1997TL4757, 1997TL7861, 1999TL1429, 2002JA15196, 2003AG(E)1734>, boracycles
<2002AG(E)152>, phosphacycles <1999TL7333>, and sulfur-containing rings: sulfides and disulfides
<1997TL1283>, sulfones <2002OL427>, sultones <2003SL667>, and sulfonamides <2002TL917>.
The synthesis of medium-sized rings is more delicate, especially for all-carbon systems (for a
review, see <2000AG(E)2073>), and the RCM yields highly depend on the conformational
constraint in the starting material <2003OL2883>. Forbes showed the importance of the
Thorpe–Ingold effect in RCM (Equation (2)): the cyclization of the ketone bearing geminal
dimethyl substituents is possible even without solvent <1992JA10978>.
O O
R R
1 R R
Heat ð2Þ
R RR R
R = H, ADMET, and oligomers

R = Me, 95%
A similar trend was observed by Taylor and co-workers during their studies toward the
synthesis of laureatin (Equation (3)): in this case, it is the bulk of the alcohol protecting group
that increases the yield of the RCM reaction <1999TL4267>. Prunet also described the impor-
tance of protecting groups: if the secondary alcohol in the taxol precursor (Scheme 4) is protected
as a triethylsilyl ether (the tertiary alcohol remaining free), the yield of the cyclization is only 6%
with catalyst 2 <2000AG(E)725>, but excellent results are obtained with cyclic protecting groups
such as a silylene or an acetonide <2000S869>. Finally, Blechert emphasized the effect of
stereochemistry on the outcome of RCM (Equation (4)): only one diastereomer of the taxol AB
ring-system precursor cyclizes (the other one dimerizes through the less hindered double bond)
<1999S607>.
OR OR
2, CH2Cl2, reflux
ð3Þ
R=H 0%
R = TMS 26%
R = TBDMS 68%
R = TES 87%
OAc OAc
2, CH2Cl2, reflux ð4Þ
59%
An advanced precursor of cornexistin was prepared by RCM by Clark (Equation (5))

<2003OL89>. The cyclononene formation proceeds smoothly with both catalysts 2 and 2d.
O OH 2, CH2Cl2 70% O OH O OH
20 °C, 3 days
or 2d, benzene ð5Þ

61%
H reflux, 3 h H H
1:1 1:1
O O O
Medium-sized heterocycles such as bicyclic lactams <1995JA2108, 1999SL1127, 1999JCS(P1)1695,

2003JOC2728>, silacycles <1997TL4757, 1997TL7861>, azacycles <2002AG(E)2403, 2001SL37>,
oxacycles <2000SL1067>, or polyethers <2000AG(E)372, 1997TL127, 1997TL6299, 1999TL5405>
can also be synthesized by RCM with catalysts 1 and 2 in good yields.
RCM of large rings leads to the desired products in good yields, provided there is a polar
substituent properly placed in the linear precursor to function as an anchor group for the catalyst
<2003OL2785>. A thorough study by Fürstner and Langemann is illustrated in Figure 2
<1997S792>. Metathesis of hexadeca-2,15-diene with Cl2(PCy3)2Ru¼CHCH¼CPh2
<1992JA3974> only gives oligomers. When an ester function is present, the cyclized product is
formed in decent yield, but the reaction is very sensitive to steric hindrance. A larger distance
between the heteroatom and the alkene groups significantly improves the yield. When the
ruthenium is too tightly complexed by the polar functional group (five-membered chelate for
example), the reaction can be inhibited, as shown in Figure 3.
O O O O O O
0% 52% 10% 72%
Figure 2
O O
O O [Ru] O
N N R
t-BOC t-BOC
0% 84% Five-membered chelate
Figure 3
The (E)/(Z) selectivity of the double bond formation in macrocycles by RCM is rarely
predictable, and depends on many factors (for a recent review, see <2003AG(E)2826>): tempera-
ture, solvent, catalyst (Scheme 4), and substrate substituents (Equation (6)). The only example of
stereoselective formation of a trisubstituted double bond by RCM was described by Hoveyda
(Scheme 3) in the course of the total synthesis of fluviricin.
S S
RO 2, Benzene RO
N N Epothilone A
O 20 °C O ð6Þ
Y X O Y X O
X = α -OTBDMS, Y = O, R = TBDMS 86%, 1/1.7 (E )/(Z )

X = β-OH, Y = α -OTPS, R = TBDMS 81%, 9/1 (E )/(Z )
The usual catalysts for asymmetric ring closing metathesis (ARCM) are complexes 1a and 1b
developed by Schrock and Hoveyda (Figure 1) <2001CEJ945>. BIPHEN catalyst 1a (R = Pri) is
the reagent of choice for the formation of five-membered rings, whereas BINOL derivative 1b
gives better results for six-membered products (Scheme 5). This methodology was applied to the
total synthesis of (+)-endo-brevicomin by Burke <1999OL1827>.
Catalyst 1a (R = Pr i) and a closely related complex were also employed for the ARCM of
small- and medium-sized unsaturated amines <2002JA6991>.
Recently, Grubbs reported a chiral ruthenium catalyst derived from 2, which gives an excellent ee
for the RCM of a dihydrofuran when sodium iodide is added to the reaction mixture <2001OL3225>.
RCM has been employed on solid support, either to cyclize or to close/release simultaneously
immobilized substrates (Scheme 6) <2000AG(E)3012>. A typical application of the latter method
is the synthesis of a library of epothilone analogs by Nicolaou <1997NAT(387)268>.
Kinetic resolution
OTBDMS OTBDMS OTBDMS Catalyst krel

Cat.
1a 56
Benzene, 25 °C 1b 7
OTBDMS OTBDMS OTBDMS Catalyst krel

Cat.
1a 3.3
Benzene, 25 °C 1b >25
Desymmetrization
Si Si
O 1a, heat O O 1b, heat O
93% H 98% H
99% ee >99% ee
Scheme 5
[M] CH2
H2C CH2
[M] CH2
CH2
Scheme 6
RCM has found widespread applications in organic synthesis <B-1998MI002, 2003MI57,

1998JCS(P1)371>. Since the metathesis catalysts are very chemoselective and react almost exclusively
with alkenes (and alkynes), a new logic of retrosynthesis has emerged, avoiding protecting group
manipulations of polar functions. Numerous syntheses of bioactive natural products (laurencin
<1999JA5653, 1999OL2029>, dactylol <1996JOC8746>, laulimalide <2001AG(E)3842,
2001JOC8973>, macrosphelides A and B <2003OL2939>, ircinal A <1999JA866>, roseophilin
<1997TL2601, 1999JOC2361, 2000OL1157, 2001JA8515, 2001JA8509>, gloeosporone
<1997JA9130>, ciguatoxin <2001SCI(294)1904>, methynolide <2002SL715>, strictifolione
<2003OL1995>, fostriecin <2002OL969, 2002OL4615, 2003OL733>, etc.) include RCM as a key
step. Complex non-natural products such as catenanes <1997AG(E)1308, 1999JOC5463> or rotax-
anes <2003AG(E)3281> have also been prepared by RCM.
1.15.1.2.4 Cross-metathesis
CM reaction has proved to be a powerful tool to link unactivated olefins. Blechert very recently
reviewed this field <2003AG(E)1900> (for a previous review, see <1998MI155>). The first
reports were published by Crowe and co-workers <1993JA10998, 1995JA5162, 1996TL2117>.
They used molybdenum catalyst 1 in CH2Cl2 for the CM of functionalized terminal alkenes with
styrene, acrylonitrile, and allyl silanes (Table 2). An excess of one of the coupling partners is used
to drive the reaction to completion. With styrene, there is little self-metathesis, except when
electron-withdrawing substituents such as a bromine atom are present in the terminal alkene.
The excellent (E)/(Z)-selectivity in this case is due to the greater stability of the trans-disubstituted
metallacyclobutane intermediate. However, there is no clear explanation for the fact that CM
with acrylonitrile is kinetically controlled. With allyl silanes, the stereoselectivity increases with
the size of the silyl substituents. The lack of self-metathesis is due to the steric bulk of the silyl
group, while it was due to the electronic properties of styrene and acrylonitrile for the former
reactions. Vinylboranes, enones, dienes, enynes, and unsaturated esters do not undergo CM with
catalyst 1, but allylstannanes are good candidates <1997SL129> (Table 2).
Table 2 Examples of CM
Terminal alkene Alkene (2 equiv.) Product Yield (%)a Selectivity
BnO Ph BnO Ph 85 (E)/(Z) > 95:5
CN
BnO 60 (Z)/(E) = 7.6:1
CN
PhO SiMe3 PhO SiMe3 72 (E)/(Z) = 2.6:1
SiPr3i PhO SiPr3i 77 (E)/(Z) = 7.6:1
O O
SnPh3 78 (E)/(Z) = 2.7:1
MeO MeO SnPh3
a
Reactions performed with catalyst 1.
The more recent developments in this field are mainly due to the second-generation complexes:
2d and 2e seem to be the catalysts of choice for CM. With these catalysts, terminal alkenes can be
coupled with a wide range of olefins such as allyl silanes <2001OL2209>, protected homoallylic
alcohols or their dimers <2000JA58>, and ,-unsaturated carbonyl compounds <2000JA3783,
2001AG(E)1277>. Methylacrylate, acrolein, methyl vinyl ketone, acrylamides, and even acrylic
acid give good yields and selectivities with catalyst 2d (Table 3). The slow rate of dimerization of
these substrates, which are used in excess, prevents self-metathesis. Blechert reported the same
kind of reactions with catalyst 2e (the selectivities are consistently over 20:1) <2000TL9973>, and
Cossy demonstrated that chiral homoallylic alcohols <2001JOM(624)327> and allyltriphenylsi-
lane (Table 3) <2002MI(344)627> are good candidates for CM with acrylic derivatives.
Reactions with acrylonitrile catalyzed by 2e lead mainly to the (Z)-isomer, and the selectivities range
from 2:1 to 9:1 <2001SL430>. Vinyl and allyl phosphonates <2001SL1034>, vinyl- and allylphosphine
oxides <2003TL7133>, and phenyl vinyl sulfone also easily undergo CM with terminal alkenes or
styrene derivatives. For the latter substrate, Grubbs showed that the CM reactions were not productive
with catalyst 2d <2000JA3783>, but Grela was successful with the same catalyst <2001TL6425>.
Blechert found out that better results were obtained with complex 2e <2003AG(E)1900>.
Several functionalized alkenes have been tested successfully in CM reactions with terminal olefins
(Figure 4) <2000JA3783, 2002AG(E)3171>. Fischer showed that the reactivity of vinyl silanes
toward CM with styrene increases with the number of oxygen substituents (CH2¼CHSi(OR)3 >
CH2¼CHSiMe(OR)2 > CH2¼CHSiMe2OR > CH2¼CHSiMe3) <2000OM913> or other elec-
tron-withdrawing groups such as chlorides <2003TL7121>.
Cossy reported an interesting chemoselectivity for a CM reaction in the course of the
synthesis of the C1–C14 fragment of amphidinol 3 <2001OL1451> (Equation (7)). The allylic
acetate double bond does not undergo metathesis, probably because the corresponding metalla-
cyclobutane is deactivated through complexation of the ruthenium by the carbonyl group of the
acetate.
Table 3 CM with electron-deficient alkenes

Terminal alkene Alkene Product Yield (%)a Selectivity
BzO BnO 91 (E)/(Z) = 4.5:1

COOMe COOMe
7 7
AcO
AcO CHO 7 CHO 62 (E)/(Z) > 20:1
7
AcO
7 95 (E)/(Z) > 20:1
O O
N THPO N
THPO OMe 3 OMe 89 (E)/(Z) = 60:1
3 O O
H H
N THPO N
Ph 3 Ph 90 (E)/(Z) = 100:0
O O
OH THPO OH 100 (E)/(Z) = 100:0

3
O O
Ph3Si COOMe
86b (E)/(Z) = 30:1
Ph3Si COOMe
a b
Reactions performed with catalyst 2d. Reaction performed with catalyst 2e.
F F
O CF3 O
Si(OEt)3 B
F F F F O
Figure 4
2e, CH2Cl2
OAc OAc
25 °C, 12 h
CHO ð7Þ
CHO (3 equiv.)
73%
There are several examples of CM reactions of alkenes immobilized on solid supports

<1996AG(E)1979, 1997CC823>. One of the main advantages of this technique is the suppression
of self-metathesis of the bound alkene, and the other olefin need not be used in excess.
CM was applied to the synthesis of the bicyclo[3.3.1]nonane core of garsubellin A <2002OL1943>,
the ABC-ring fragment of thyrsiferol <2002OL593>, antifungal ()-FR900848 <2000TL8723>,
(+)-amphidinolide T1 <2003JA2374>, and to install the side chain of alkaloid ()-prosophylline
<2002JOC1982> and ciguatoxin <1999TL5405>.
1.15.1.2.5 ROM and tandem reactions

The opposite of RCM is ROM. The ring-opened product either polymerizes (ROMP) or under-
goes a CM reaction (for reviews, see <2003AG(E)1900, 1998MI155>). ROM/CM is efficient only
if the CM step is faster than the polymerization process, and if the CM partner dimerizes slowly
(e.g., styrene, allyltrimethylsilane, or ,-unsaturated carbonyl compounds). Since ring opening is
facilitated by release from ring strain, the ROM/CM process was first reported with highly
strained cyclic alkenes such as norbornenes and oxanorbornenes (for a review see
<2003EJO611>) <1996AG(E)411, 1997AG(E)257, 1999JOC9739, 1999T8169>, and cyclobu-
tenes <1995JA9610, 1997JA1478, 1997JA7157>, but a recent publication by Blechert describes
ROM/CM of unstrained rings <2001CC1796>.
Two different pathways are possible. Either the ROM step occurs first, and the ring-opened
species then undergoes CM (pathway 1), or the catalyst first reacts with the linear alkene and this
entity ring-opens the cyclic alkene (pathway 2). It seems that pathway 2 is preferred for cyclobu-
tenes and unstrained olefins, and pathway 1 for the other substrates.
When the substrate is unsymmetrical, the process is not regioselective in general (Scheme 7). The
(E)/(Z) selectivity is rather poor, except when CM is performed with ,-unsaturated carbonyl
compounds (Equation (8)). In this example, double CM is observed in all cases. The order of reactivity
of the cyclic alkenes is cycloheptene cyclopentene > cyclohexene, which corresponds to ring strain.
Catalyst 2e is superior to 2d, as it is the case for simple CM reactions <2003AG(E)1900>.
Cl2(PCy3)2Ru=CHCH=CPh2 Octyl
HO HO HO
Octyl
octyl (4 equiv.), CH2Cl2
1.3/1
56% 2.3/1 (Z)/(E) 1.7/1 (Z)/(E)
O
OAc AcO
OH 2, (4 equiv.) OH
O
OH CH2Cl2 OH
58%
2/1 (Z)/(E)
Me3Si
O SiMe3 (1 equiv.) O
2,
N CH2Cl2 N
t-BOC t-BOC
83%
2/1 (Z)/(E)
Scheme 7
n E (cat.) E
n
CH2Cl2 E ð8Þ
E = COOMe, CHO, COMe, COOH 2d 5–87%, only (E )
n = 0, 1, 2, 3 2e 45–97%, only (E )
The asymmetric version of this reaction (AROM/CM) was first reported by Schrock and
Hoveyda <1999JA11603, 2001JA7767>. Meso-norbornenes reacted with styrene derivatives in
the presence of catalyst 1a (R = Pri) to give the asymmetric ring-opened products in excellent ee
values (Equation (9)). Recently, Hoveyda designed a chiral ruthenium complex derived from 2e,
which performs the same reactions with similar results <2002JA4954>. This catalyst is air stable
and can be recovered after chromatography.
OR X
OR
1a, X (2 equiv.)
Benzene ð9Þ
R = TBDMS, TMS, MOM 48–96%
> 98/2 (E )/(Z ), 91–98% ee
X = H, OMe, CF3
Cuny applied solid-phase ROM/CM to synthesize a combinatorial library from resin-bound

norbornenes and substituted styrenes in the presence of 2 <1997TL5237>.
Numerous tandem reactions are possible. Grubbs described RCM/ROM/RCM of cyclic ethers
<1996JA6634>, and Blechert applied the same process to the syntheses of halosalin
<1999T8179> and astrophylline <2003JOC2913> (Scheme 8). Hoveyda reported an RCM/
ROM/CM (with ethylene) process leading to chromenes <1997JA1488, 1998JA2343>, and
Blechert showed that ROM/RCM/CM reactions were possible <1998SL169> (for a similar
case, see <2000TL9777>) (Scheme 8).
ROM RCM
H H
N 2d, CH2Cl2 N N
Ns H H H
82% t-BOC N N Ph
N Astrophylline
t-BOC Ns
RCM O
RCM Cl2(PCy3)2Ru=CHCH=CPh2
O
CM, H2C CH2, CH2Cl2 O
ROM 92%
R3
CM
1 or 2, CH2Cl2
ROM
33–88% R3
RCM R1 R2 R1
n R2
n = 0, 1, 2, 3
Scheme 8
1.15.1.2.6 Ene-yne metathesis

In a similar manner, a new method for 1,3-diene synthesis, resulting from the metathesis coupling
between an alkene and an alkyne, was first reported by Mori <1994SL1020>. An excellent review
was very recently published by Poulsen and Madsen <2003S1> (for another review, see
<1998MI133>). The best catalyst for this reaction seems to be second-generation complex 2d.
The different mechanistic pathways are shown in Scheme 9. In contrast to olefin metathesis, ene-
yne metathesis is an irreversible process because 1,3-butadienes are less active than alkenes or
alkynes toward the catalysts. No exact proof of a mechanism beginning with the yne or the ene
moiety has been established yet, but pathway 1 seems to be the main one for ring-closing
processes when the alkene is monosubstituted <1999OL277, 2001AG(E)4274>, and pathways 2
and 3 are preferred if the alkene is gem-disubstituted. Moreover, carrying out the reaction under
an ethylene atmosphere has an influence on the reaction rate and yield, especially when the alkyne
is monosubstituted (Scheme 10) <1998JOC6082>; it seems to help the release of the catalyst from
the conjugated carbene 3.
The substitution pattern of the enyne has a great influence on the yield of metathesis. Enynes
having a monosubstituted alkene are more reactive than enynes with a di- or trisubstituted alkene
(Scheme 11) <2003S1>.
Ene-yne RCM is not driven by entropy so it lacks an inherent driving force. As a consequence,
five-, six- (Scheme 11), and seven-membered rings (Scheme 12) <2001CEJ3236> are produced
in good yields if a heteroatom or a quaternary center is present in the precursor, but eight-
membered rings <2001S654> require two such conformational constraints for their formation
(Scheme 12).
R2
[Ru]
R1
Pathway 1
R2
[Ru]
R1 [Ru] R1
R2
3
R2
R1
R1 R2
[Ru] CH2
Pathway 2
R2
[Ru]
R1
[Ru] R2
R1
or [Ru]
R2 R2
R1
R1
R2
[Ru]
[Ru] CH2
R1
[Ru] [Ru] R2
Pathway 3
2
R R1
R1
Scheme 9
2, CH2Cl2, 20 °C 2, CH2Cl2, 20 °C
N N
Ts Ts EtOOC COOEt EtOOC COOEt
Argon atmosphere 19% Argon atmosphere 19%
Ethylene atmosphere 99% Ethylene atmosphere 99%
Scheme 10
R
R
R
R
cat. cat.
N N N N
Ts Ts Ts Ts
R = H, 2c 97% R = H, 2c 89%
R = Me, 2d 50% R = Me, 2d 56%
Scheme 11
2c 2
R NTs
81% N
N R NTs
Ts Ts 11%
R = CH2 95%
R = NTs
Scheme 12
Other small heterocyclic rings are also easily formed by ene-yne RCM, e.g., boracycles
<2002AG(E)3272>, silacycles <2001OL2069>, and polyethers <2000AG(E)372>.
Several tandem ene-yne reactions have been described, first by Grubbs (Scheme 13) <1994JA10801,
1996JOC1073>. In this case, the first metathesis site is the less hindered alkene, so the process can be
oriented by selectively hindering one of the double bonds in the starting material. Simple diene RCM is
not observed, presumably because it would lead to medium or large rings. Hanna described a carbocy-
clization of carbohydrate-derived dienynes <2001OL3095>, and Poulsen and Madsen
<2002JOC4441> performed an ene-yne RCM on the same kind of substrates followed by a Diels–
Alder reaction (Scheme 14).
OTES OTES OTES

Cl2(PCy3)2Ru=CHCH=CPh2
+
Benzene, 65 °C
86% 1:1
OTES OTES
Et
Benzene, 65 °C
83%
OTES OTES
Benzene, 65 °C
78%
Scheme 13
O 2d, CH2Cl2, reflux O
O 96% O
OTES OTES
TBDMSO TBDMSO
OHC
2d, CH2Cl2, H2C CH2 CHO H
O O O
66% 60 °C
O OTBDMS O OTBDMS 69% O OTBDMS
Scheme 14
Ene-yne RCM has been used for the total synthesis of natural products, such as stemoamide
<1996JOC8356> and longithorone A <2002JA773> (Scheme 15). In the latter synthesis, both
macrocycles bear a 1,3-disubstituted diene (which usually is the preferred CM product), proving
that RCM occurred through pathway 3 in Scheme 9.
MeOOC
H
O 2, CH2Cl2, 20 °C O O
MeOOC N N O N
H 96% H H
O
H
Stemoamide
MeO
2d, CH2Cl2 MeO OR
OR
H2C CH2
OR 31%
OR
OR R = TBDMS OR
Longithorone A
2d, CH2Cl2
RO OMe
MeO OR
H2C CH2
42%
OR
R = TBDMS
Scheme 15
Ene-yne CM with ethylene was first described by Mori with catalyst 2 <1997JA12388>.
Under these conditions, this reaction was limited to alkynes with esters or sulfonamides at the
propargylic position. More recently, use of catalyst 2d circumvented this problem and rendered
the reaction general <2000OL2271, 2002TL209, 2002TL2235>. With this transformation,
alkynes can be seen as masked 1,3-dienes. HIV-1 reverse transcriptase inhibitors (anolignan A
and B) were synthesized by Mori using this reaction as the key step (Scheme 16)
<2002JOC224>.
OMs
OAc OAc
OMs
O 2d, CH2Cl2 O
Anolignan A
OAc OMs
O H2C CH2 O
OAc OMs
86%
OSO2Ph
OAc OAc
OSO2Ph
2d, CH2Cl2 Anolignan B
OAc OMs
PhSO3 H2C CH2 PhSO3
OAc OMs
94%
Scheme 16
CM with substituted alkynes gives the 1,3-substituted dienes (Scheme 17) <1997AG(E)2518,
2001TL6699> and is not regioselective if the alkyne is unsymmetrically substituted
<2000TL5465>. Generally, 3 equiv. of the alkene are needed to drive the reaction to completion.
CM with more substituted olefins has not yet been reported. The (E)/(Z) ratios of the products
are poor, but very recently, an elegant method was designed to render the reaction stereoselec-
tively <2003OL1855>. The ene-yne CM is conducted under an atmosphere of ethylene, so a
tandem process is observed: ene-yne CM with ethylene, followed by diene-ene CM (Scheme 18).
The (E)/(Z) ratios are excellent, except in the presence of a polar substituent at the allylic position
(Scheme 17).
2
BnO But BnO But
82%
1/1 (E )/(Z )
2
BnO TMS BnO TMS
86%
1/1 (E )/(Z )
2
OTBDMS OTBDMS
AcO 80% AcO
1/1 (E )/(Z )
2d
BnO H2C CH2 BnO
88% 100/0 (E )/(Z )
2d
TBDPSO TMS TBDPSO TMS
H2C CH2
79% 1.3/1 (E )/(Z )
2d
TBDPSO OAc TBDPSO OAc
H2C CH2
49% 6.5/1 (E )/(Z )
Scheme 17
1
2d R
R
H2C CH2 R R R1
(E )-isomer
Scheme 18
Blechert reported ene-yne CM reactions of immobilized substrates. Terminal alkynes were

reacted with polystyrene-bound allyl silane <1998TL2295>, and a tandem ene-yne CM/Diels–
Alder process was effected on an alkyne immobilized on a Merrifield resin <1999SL1879>.
Although 1,3-dienes are not very reactive toward metathesis catalysts, tandem processes invol-
ving ene-yne metathesis followed by CM with monosubstituted olefins have been described by
Plumet <2000TL9777> and Blechert <2001TL5245, 2002MI(344)631>. Surprisingly, the order of
the different metathesis steps depends on the heteroatom present in the substrate, leading to
differently substituted dihydrofurans and pyrrolines (Scheme 19). There is no obvious explanation
for this intriguing mechanistic switch.
O O
OAc Ene-yne RCM/ROM/CM
2a
50%
AcO
4/1 (E )/(Z )
Ts Ts
N N
OR Ene-yne CM/RCM/ROM
2a
R = TBDMS 78%
1/1 (E )/(Z )
RO
Scheme 19
Recently, simple ene-yne RCM/CM sequences were reported by Grimaud (Equation (10))
<2003OL2007>. In this case, the CM reaction is very stereoselective in favor of the (E)-olefin.
E
OTBDMS TBDMSO
2e, COOMe
ð10Þ
CH2Cl2, reflux only (E )
X X
X=O 67%
X = CH2 88%
1.15.1.2.7 Non-Chauvin metathesis

Ene-yne metathesis can also be catalyzed by other transition metals, such as Pd(II), Ru(II), Pt(II),
and Ir(I). The mechanism is different from the mechanism reported by Chauvin for carbene
complexes (hence the name non-Chauvin), involving either an oxidative cyclization to give a
metallacyclopentene intermediate which undergoes a reductive elimination followed by a rearran-
gement, or a cationic intermediate coming from -complexation of the alkyne moiety (for a
review, see <2002CRV813>). Pd(II) complexes effect metathesis of 1,6-enynes, but only if
the alkyne is substituted by an ester (COFGT (1995)). The reaction proceeds via an oxidative
addition/reductive elimination sequence, giving an intermediate cyclobutene, which undergoes a
conrotatory thermal opening (Scheme 20). The overall process is stereospecific, the (E)-alkene
leading to the (Z)-product and vice versa <1993AG(E)1085>. This catalyst does not lead to the
desired product for 1,7-enynes.
E E
H E
E Pd E
E E
E
E E P(o -TolO)3, DMAD E
ClCH2CH2Cl, 60 °C E E
E = COOMe
68% only (E )
H E
E Same conditions E
E
E E E
E E
only (Z )
Scheme 20
Murai <1994JA6049> has shown that ruthenium complexes other than carbenes can promote
ene-yne RCM (Scheme 21). The reaction is stereoconvergent in this case, both isomers of the
starting alkene leading to the (E)-product. In contrast to Trost’s system, 1,7-enynes are good
candidates for this reaction, but not enynes substituted with an ester on the alkyne moiety.
Substitution of the olefinic portion enhances the reactivity, and even trisubstituted alkenes
undergo metathesis in good yields.
E = COOEt
E [RuCl2(CO)3]2 E
E Toluene, CO, 80 °C E
80/20 (E )/(Z ) 95%, only (E )

11/89 (E )/(Z ) 81%, only (E )
Ph
E [RuCl2(CO)3]2
E Toluene, CO, 100 °C E
Ph
E
86%
81/19 (E )/(Z ) only (E )
Scheme 21
The same group employed PtCl2 for ene-yne RCM <1996OM901>. No additional ligands
are necessary, and the reaction is compatible with a large array of substituents: Cl on the
alkene part and Cl, Br, Me, Ph, and even COOMe on the alkyne moiety (Scheme 22), which
was not the case with the ruthenium complexes. However, 1,7-enynes react more slowly and
give poorer yields.
E = COOEt
Cl
E PtCl2 E
Cl
E Toluene, 80 °C E
70%
Same conditions
Br 76%
TBDMSO TBDMSO Br
E Same conditions
E 4 days E
E
40%
Scheme 22
They also used iridium complexes for the same reaction <2001JOC4433>. With this metal, the
reaction pathway depends on the nature of the catalyst and on the structure of the substrates. The
best catalyst for ene-yne metathesis is [IrCl(CO)3]n, and monosubstituted alkynes are good
substrates (Scheme 23). When the alkene bears a cyclopropyl substituent, no [5+2]-cycloaddition
occurs and the cyclopropane remains intact in the product.
This methodology was applied to a formal synthesis of roseophilin <2000JA3801> and to the
total syntheses of streptorubin B and metacycloprodigiosin <1998JA8305>.
Ph
E [IrCl(CO)3]n E
E Toluene, 80 °C E
Ph
E = COOEt 91%
Ph
E Same conditions
E E
54% Ph
E
Scheme 23
1.15.2 BY CONDENSATION OF HALIDES: METAL-MEDIATED CONDENSATION OF

gem-DIHALIDES AND RELATED COMPOUNDS WITH CARBONYL GROUPS
1.15.2.1 Chromium-mediated Condensation

The chromium-mediated condensation of a gem-dihalide with a carbonyl compound giving
alkenes has been developed by Takai and Utimoto <1987JA951> (for recent reviews, see
<1999S1, 1999CRV991>). This convenient olefination protocol applicable to readily enolizable
substrates provides (E)-alkenes with a high selectivity <2001JMC3692> (Equation (11)). This
reaction proceeds under very mild conditions in THF, THF/DMF <1995T3713>, or THF/
1,4-dioxane <1993JA4497, 1992JA2260> and is compatible with a wide range of functionalities
<2001AG(E)2326> (Equation (12)). 1,1-Diiodoalkanes are the most reactive substrates, espe-
cially diiodomethane and diiodoethane, while gem-dibromides and dichlorides give poor yields.
O O
O (Me)3CCHI2 O
OMe OMe Bengamide B
O ð11Þ
CrCl2
O O O O
THF–DMF
63%
OAc I OAc
CrCl2 (4 equiv.)
PhCH2CH2CHO Ph
AcO I + AcO
THF–DMF ð12Þ
OAc OAc
rt, 30 min
70%
It is believed that the reaction proceeds via a gem-dichromium nucleophile, which attacks the
carbonyl compound (Equation (13)).
I CrCl2 CrX2 RCHO

ð13Þ
I CrX2 R
Recent modifications allow the use of catalytic amounts of Cr(III) in the presence of another
stoichiometric reducing agent such as Sm/SmI2 <1995CL259> or Zn/TMSCl <1999SL1268>
(Equation (14)). This method avoids the use of 6 or 8 equiv. of the air-sensitive and hygroscopic
CrCl2. The reduction power of Cr(II) can be enhanced by complexation with donor ligands such
as diamines (TMEDA) <1998SL253>.
CrCl3(THF)3 Time
R (h) Yield (%)(E):(Z) ratio
Zn, TMSCl
RCHO + CHI3 R
I Ph(CH2)2 4 84(95:5) ð14Þ
Dioxane, 25 °C c-C6H11 5 82(97:3)
Ph 3 78(93:7)
MeCO(CH2)8 4 71(95:5)
An interesting variant involves -acetoxy bromides, more readily available than dihalides, with
a Cr(II) species prepared in situ from CrCl3 and Zn in the presence of a donor ligand such as
DMF or TMEDA (COFGT (1995)) <1993SL837>. Ketones and esters remain unaffected under
these conditions.
This reaction tolerates other heteroatoms at the geminal position, so functionalized alkenes can
be synthesized: Bu3SnCHI2 <1998TL6419>, Bu3SnCHBr2 <1995T3713, 1999JCS(P1)2911>
(Equation (15)), Me3SnCHBr2 <1995TL763>, PhSCHCl2 <1987TL1443>, Me3SiCHBr2
<1987TL1443>, (Me3Si)2CBr2 <1997JCS(P1)2279> (Equation (16)), and (RO)2BCHCl2
<2001TL2517> (Equation (17)).
CrCl2 (10 equiv.) R Yield (%)

RCHO + Bu3SnCHBr2 R
SnBu3 ð15Þ
DMF, 25 °C, 24 h Me(CH2)7 85–89
c-C6H11 80
SiMe3
CrCl2 (8 equiv.) SiMe3
PhCHO + Br2C(SiMe3)2 Ph Ph
DMF, 25 °C, 24 h SiMe3 ð16Þ
O
84%
OTBDPS OTBDPS
(RO)2BCHCl2 O
B (–)-Equisetin ð17Þ
CHO
CrCl2, LiI, THF O
86%
The high (E)-selectivity and mild conditions make this reaction a powerful tool in organic
synthesis <2000JA9584, 1998TL8313, 1997TL4823, 2001OL3487, 2001TL2517, 2001JOC2118,
2001JMC3692, 2001JA12191, 2001AG(E)2326, 2002OL4403, 2002AG(E)4751, 2003JOC1771,
2003JOC1780, 2003CEJ389> (Equations (18)–(19)). The scope of this reaction has been extended
by coupling in situ the vinyl iodide formed with another carbonyl group to synthesize in one-pot
the corresponding allylic alcohol <1999S1, 1999CRV991>.
CH(OEt)2 RCHI2 CH(OEt)2

Z 3 Z 3
N CrCl2 (8 equiv.) N
Tetraponerine T7
DMF (8 equiv.) R
N O N ð18Þ
H H
Z THF Z
O R = Et 80%
O R = H 65%
Z=
CH3CHI2
OHC O O O O
CrCl2
(–)-Pironetin ð19Þ
THF, rt
OMe 80% OMe
Finally, Takai recently reported the synthesis of allenes from the condensation of a gem-
dichromium carbenoid with an alkene <2002SL1164> (Equation (20)).
R Yield (%)
CrCl2 (4 equiv.)
R + CCl4 R AcO(CH2)9 50 ð20Þ
THF, 0 °C, 24 h
Ph(CH2)2 60
1.15.2.2 Zinc-mediated Condensation

Organozinc reagents have also been successfully applied to such olefinations. Treatment of
carbonyl compounds or ,-unsaturated aldehydes with CH2X2-Zn provides methylenated pro-
ducts in good yields in the presence of a Lewis acid such as TiCl4 <2001JOM(617–618)39>.
Nysted’s reagent (cyclodibromodi--methylene(-tetrahydrofuran)trizinc), a commercially avail-
able gem-dimetallic compound, reacts with aldehydes in the presence of BF3OEt2 affording
methylenated products, whereas methylenation of ketones proceeds in the presence of BF3OEt2
and TiCl2 <1998SL313> (Scheme 24). This reaction is successful even with readily enolisable
carbonyl compounds.
Nysted’s reagent
O
(1.0 equiv.)
R H R H
BF3.OEt 2 (10 mol.%)
O THF, 0 °C to rt
Br
Zn Zn Br
R Yield (%)
Zn Ph 96
CH3CO(CH2)8 80
Nysted’s reagent
O Nysted’s reagent
(1.0 equiv.)
BF3.OEt 2 (10 mol.%)
TiCl2 (2.0 equiv.)
THF, 0 °C to rt
86%
Scheme 24
Condensation of 1,1-bis(halozincio)alkanes, prepared with Zn under Pb catalysis, with alde-

hydes proceeds smoothly without TiCl2, although the TiCl2-mediated reaction is much faster. One
equivalent of TiCl2 is essential to have good yields with ketones <1998SL1369, 2000SL495>
(Scheme 25) except for -oxygenated ketones <2001SL513> (Equation (21)). This method yields
poorer stereoselectivity than the chromium coupling. Methylenation of esters is carried out with
the gem-dihalide Zn in the presence of TiCl4 and TMEDA <1996OS73, 1998TL685, 2000SL737,
2001JCS(P1)1051> (Equation (22)), or by using 1,1-bis(iodozincio)methane with 4 equiv. of TiCl2
and 8 equiv. of TMEDA <1999CL825> (Equation (23)).
O O O
TiCl2, THF THF
H 74% H + CH2(ZnI)2 92% H
9 9 9
O O O
TiCl2, THF
CH2(ZnI)2
OMe + OMe
8 91% 8
Br Zn ZnBr TiCl2
R R R
Ph
Br cat. Pb ZnBr
O
Ph
R = SiMe3 54% ((E )/(Z ) 61:39)
R = Et3 Ge 63% ((E )/(Z ) 65:35)
Scheme 25
O
THF
Ph + CH2(ZnI)2 Ph
Ph Ph
25 °C
OR OR ð21Þ
R = H 79%
R = Me 88%
R = Ac 3%
TBDMSO O Zn, PbCl2

TBDMSO
TiCl4, TMEDA
Ph OEt + MeCHBr2 Ph OEt ð22Þ
THF, rt, 14 h
81%
TiCl2
O
TMEDA
n-C10H21 O + CH2(ZnI)2 n-C10H21 O
ð23Þ
THF, 25 °C, 4 h
86%
1.15.2.3 Condensations Mediated by Other Metals

Different titanium-based organometallic derivatives have been developed for olefination of car-
bonyl compounds, esters or amides: the Tebbe reagent derived from titanocene dichloride and
trimethylaluminum <2002T2011> and Grubbs’ titanacyclobutanes. Both tolerate no functional-
ity in the titanium reagent allowing thus only methylenation. Petasis reported a more easily
handled and a more general titanocene derivative prepared by thermolysis of dialkyltitanocenes,
for the mechanism (see <1996OM663, 2003OL1391>). This method is limited because the
organolithium or Grignard reagents used (Scheme 26) <2000TL1975> to synthesize the dialkyl-
titanocene cannot bear a hydrogen to the metal (Cp2TiCHR, R = H, Ar, SiMe3) (Equation
(24)) <1993OR1, 1996TL141, 1997TA1115, 2003OL399>.
Cp2TiCl2 + MeMgCl
THF
Cp2TiMe2 O
Flash chromatography H
N N N
O Toluene, 80 °C, 6 h SiO2, 53%
56% (crude)
Scheme 26
O Cp2TiCl2 O
ð24Þ
Me O But THF, 65 °C Me O But
88%
The synthesis of tri- and tetrasubstituted olefins has been performed by using Takeda’s
titanocene and gem-dihalides having two alkyl substituents (Scheme 27) <1998JOC7286> (easily
prepared by the treatment of the corresponding hydrazone with CuX2–Et3N in methanol
<1997T557>).
Cl Cl O O Cp2Ti(P(OEt)3)2 O
+ Ph
Ph
THF
52%
75/25 (E )/(Z )
Cl Cp2Ti(P(OEt)3)2
+ O
Cl THF
73%
Scheme 27
Desulfurizative titanation of thioketals developed by Takeda constitutes a very convenient

olefination reaction of carbonyl compounds (Scheme 28) <1997JA1127, 1998AG(E)453>.
Mg, P(OEt)3
Cp2TiCl2 Cp2Ti(P(OEt)3)2
4 Å Sieves, THF
PhS SPh
Ph H
Ph
Cp2Ti
O H
Ph
80%
54/46 (E )/(Z )
Scheme 28
Dithioketals, easily prepared from the corresponding carbonyl compounds, are treated with a
low-valent titanium complex [Cp2Ti(P(OEt)3)2] to form probably a titanium-alkylidene species,
which reacts smoothly with aldehydes, ketones, esters (Scheme 29) <1997JA1127, 2000T763,
2001CC625>, thioesters <1999SL1029>, and amides <2003TL5571> (Scheme 30). This reaction
gives poor selectivities except in the case of esters and amides.
O SPh Cp2Ti(P(OEt)3)2 O
OEt SPh THF, rt, 3 h

O 70% OEt
SPh O O
Cp2Ti(P(OEt)3)2 H3O+
OH
PhS O Ph Ph Ph
THF, rt, 3 h O 52%
Scheme 29
SPh O Cp2Ti(P(OEt)3)2
C6H13 C6H13 C6H13
+
PhS S S S
THF, rt, 3 h
48% 8%
O Ph Me
SPh Cp2Ti(P(OEt)3)2 N
Ph +
Ph N PhS Ph
THF, rt, 3 h
Me
76% only (Z )
Scheme 30
This convenient method is compatible with various functionalities (Equation (25))

<2001CC381> but is not efficient in the case of thioketals derived from dialkyl ketones (treat-
ment of such thioketals with Cp2Ti(P(OEt)3)2 gives the corresponding alkenyl sulfide
<1998JOC7286>).
Me OBn Me Me OBn
H Me H H O
H O O O
O O Cp2Ti(P(OEt)3)2
BnO O BnO
OH MOMO Me THF, reflux, 1 h OH MOMO Me
Me 52–67% Me ð25Þ
BnO PhS SPh BnO
Ciguatoxin CTX3C
The Takeda olefination of esters has been performed on solid phase toward the synthesis of
benzofurans and indoles <2003JOC387, 2000TL4987>.
The titanocene-promoted reaction of thioketals with alkynes offers an easy access to conjugated
dienes with a high stereoselectivity (Equation (26)) <1997CC1055>.
SPh H
Cp2Ti(P(OEt)3)2 Bn
Bn Et
SPh ð26Þ
Et Et Et
71% (E )/(Z ) 99:1
This method has also been applied successfully to the preparation of 1-alkenyl ethers and
sulfides by using di- and trithioorthoformates (Equation (27)) <1998TL2153>.
O SPh Y
Cp2Ti(P(OEt)3)2
Ph Y + X
X SPh THF Ph
ð27Þ
Y = SPh X = H 42% 55/45 (E )/(Z )
Y = OMe X = OEt 78% 53/47 (E )/(Z )
X = SPri 82% 17/83 (E )/(Z )
Synthesis of allyl silanes can be performed by using a -trialkylsilyl thioketal (Scheme 31)
<1998TL3753> or by treating a trialkylallylsilane with a thioketal (Equation (28)) <1998CC51>.
In the latter case, the -substituted allyl silane is obtained with a good (Z)-selectivity. A similar
reaction has been developed to prepare allyl silanes from 2,4-bis(phenylthio)but-3-enylsilane
(Equation (29)) <2000TL8377>.
O SPh X
Cp2Ti(P(OEt)3)2
+ Me3Si
Ph X SPh Ph SiMe3
THF, rt
X = Me 66% ((E )/(Z ) 53:47)

X = SEt 77% ((E )/(Z ) 39:61)
O SPh Cp2Ti(P(OEt)3)2 OMe
Ph OMe + PhMe2Si SPh Ph SiMe2Ph

THF, rt
81% 14/86 (E )/(Z )
Scheme 31
SPh Cp2Ti(P(OEt)3)2
Pri + Si(Pri)3 Si(Pri)3
SPh Pri ð28Þ
THF, reflux
11/89 (E )/(Z )
78%
SPh Cp2Ti(P(OEt)3)2 O
SiMe3 SiMe3 SiMe3
PhS Cp2Ti ð29Þ
53%
90/10 (E )/(Z )
1.15.3 BY CONDENSATION OF OXYGEN FUNCTIONS
1.15.3.1 Synthesis of b-Lactones and Subsequent Decarboxylation

Elimination of carbon dioxide from -lactones is an efficient route to alkenes. Reactions of
aldehydes with ketenes generated from Fischer chromium carbenes lead either to the -lactones
or directly to the enol ethers if the aldehyde is electron deficient (Equation (30)) <2003JOC6056>.
The formation of the -lactones is catalyzed by 4-dimethylaminopyridine (DMAP) and is stereo-
selective in favor of the syn-isomer.
Cr(CO)5 O O OMe
DMAP O Yield of 4 (%) Yield of 5 (%)
+ + R (syn/anti) (E )/(Z )
Ph OMe R H hν, CO OMe R Ph
R Ph Et 53 (15:1) 0
4 5 Me 55 (8:1) 0
Bun 43 (23:1) 0
Bui 35 (4:1) 0
Ph 33 (15:1) 0 ð30Þ
0 52 (3:1)
O
p-MeOC6H4 0 61 (3:1)
0 43 (1:1)
Addition of ynolate anions, generated from ,-dibromo esters and t-BuLi <1998T2411>, to
aldehydes and ketones provides the -lactone enolates in good yields <2001JOC7818>. These
anions can either be hydrolyzed to the corresponding -lactones which are in turn decarboxylated
to furnish alkenes, or involved in a tandem cycloaddition/Dieckmann condensation (Scheme 32).
O Bu OLi Bu O Bu
–78 °C H+
Bu OLi
Ph R Ph O Ph O
Ph R
R R
R = Me 50%
R = Ph 63%
R = Pentyl 73%
O
O Bu OLi
–78 °C EtOOC SiO2 Bu
EtOOC Ph Bu OLi
O Benzene
Ph reflux Ph
89%
Scheme 32
1.15.3.2 Conversion of Carbonyl Compounds to 1,3,4-Thia- and 1,3,4-Selenadiazolines

and Extrusion of N2 and S or Se and Related Reactions
Sequential extrusion of nitrogen and sulfur from 1,3,4-thia- or 1,3,4-selenadiazolines gives
alkenes. These compounds have been scarcely studied since 1995. A synthesis of spiro 1,3,4-
thiadiazolines was reported <1998JCR(S)824>.
Syntheses of sterically hindered alkenes by extrusion processes were recently described
<2000JOC1799>.
1.15.3.3 McMurry Coupling of Carbonyl Compounds

The reductive coupling between two carbonyl compounds in the presence of low-valent
titanium compounds to give an alkene is known as the McMurry reaction. It is applicable
to a large variety of aldehydes and ketones. It has been widely used in its intramolecular
version to synthesize a large array of compounds (for a review, see <1996AG(E)2442>):
strained olefins <1996AG(E)2442>, medium- <1995JA645> and large-size rings
<1996AG(E)2442, 1995S63, 1996LA655, 1997TL7353, 1998TL7079>, and heterocycles
<2003TL3035>. However, the intermolecular coupling was mainly used for homocoupling
reactions <1996TL645, 2000TL10277, 2002OM2993, 2002OM2635>. Few examples of effi-
cient cross-coupling reactions have been reported, and they generally require a similar redox
potential for both carbonyl compounds and the use of an excess of one of the coupling
partners <1997JOM(541)355>.
Previous studies supposed that the reaction proceeds via the formation of zero-valent Ti
particles. It is now admitted that the TiCl3 is reduced to a +(II) oxidation state and that a
carbenoid species is a possible intermediate <1995JOM(502)109, 1997AG(E)2234,
1997AG(E)2380, 2001CEJ3043, 2002OM2635>. The classical McMurry conditions are
[TiCl3(DME)1.5] in combination with a reducing agent such as Zn(Cu), Zn, Mg, Li, C8K,
Na/Al2O3 or Na/TiO2 <1995S63>, LiAlH4, and metal arene <1991JOC6447, 1996CRV877,
1998JOC5235, 2001JOC2990>. Reactivity of the low-valent titanium species depends on the
reducing metal, the solvent, and additives. For example, pyridine stops the reductive coupling
at the pinacol stage <1996JA5932>, substoichiometric iodine allows reaction at 0 C or
lower temperatures <1998JOC4925>, and activation with Me3SiCl renders the reaction cata-
lytic in TiCl3 <1995JA4468>. The (E)/(Z)-selectivity is rarely predictable <2002OM2635,
2000JOC7990>.
This reaction has been extended successfully to acyl silanes (Equation (31)) <1995T8875>.
Keto amides cyclize to give pyrroles and indoles <1995AG(E)678, 1995JOC6637, 1995JA4468,
1996T7329> (Equation (32)). The McMurry coupling was also used to couple ketones with esters
either in the intramolecular version to furnish heterocycles <1995JA4468> or more recently in an
intermolecular reaction <2000CA150547, 2000CA207841, 2002TL3645> (Scheme 33). In the
latter case, the reaction is limited to hindered ketones and benzoates.
O
SiMe3
Ti dust, Me3SiCl
SiMe3 ð31Þ
61%
SiMe3
Ph
Ph
O
TiCl3 (10 mol.%) ð32Þ
NH Ph
Zn dust, Me3SiCl N
Ph O H
80%
Ph
O
Ph
O Ti dust, Me3SiCl
O 91% O
O
OEt
EtO TiCl3, LiAlH4, Et3N
O
F 38% F 19%
Scheme 33
The McMurry reaction was employed in numerous total syntheses, such as zearalenone
<2000JOC7990>, dihydrocembrene and sarcophytol derivatives <2000JCS(P1)4250, 1999TL965>,
alkaloid ipalbidin <2003TL3035>, etc.
1.15.3.4 Addition of Organometallic Reagents to Carbonyl Compounds and In Situ Dehydration

No new significant examples of this process have been reported since COFGT (1995).
1.15.4 BY CONDENSATION OF SULFUR, SELENIUM, OR TELLURIUM FUNCTIONS
1.15.4.1 Alkylation of Sulfur(II)-stabilized Carbanions and Elimination

Addition of anions stabilized by adjacent sulfides to carbonyl compounds <1998T10801>,
followed by oxidation and reductive elimination of the resulting -hydroxysulfoxides, is
an efficient access to alkenes. Since 1995, only one example of such a tandem reaction has
been reported <1999OL1539>. The reaction is stereoconvergent (Scheme 34), leading to the
(Z)-isomer from both syn- and anti--hydroxysulfoxides.
F i. LDA, RCHO But(O)S F i. SO2Cl2 F

tS R R
Bu COOMe ii. MCPBA COOMe ii. CH2Cl2, 20 °C COOMe
OH
R = Ph 53%, 98/2 (Z )/(E )
R = n-C8H17 60%, 94/6 (Z )/(E )
Scheme 34
1.15.4.2 Alkylation of Sulfur(IV)-stabilized Carbanions Followed by Elimination
1.15.4.2.1 Alkylation of sulfoxides and elimination

Addition of sulfoxide-stabilized carbanions to carbonyl compounds has been extensively studied,
as well as the syn-elimination of the sulfenic acid for the synthesis of alkenes. However, the two
procedures have not been linked until recently, when Satoh published a sulfoxide version of the
Julia–Lythgoe olefination (Scheme 35) <2000T6223>.
i. LDA
PhCH2CH2CHO MsO
Ph RLi (4 equiv.)
Ph 98%
S Ph Ph Ph Ph
ii. MsCl, TEA S Ph THF, –78 °C, 5 min
O 87% O (E ):(Z ) 3:4
nLi
RLi = Bu 73%
ButLi 66%
Scheme 35
1.15.4.2.2 Alkylation of sulfinamides and elimination

Reaction of -lithiosulfinamides with carbonyl compounds, followed by thermal elimination of
the resulting -hydroxysulfinamides, furnishes alkenes (COFGT (1995)). No new report has been
published since 1995.
1.15.4.3 Alkylation of Sulfur(VI)-stabilized Carbanions Followed by Elimination
1.15.4.3.1 The Julia reaction and related transformations

The condensation of a sulfone anion with a carbonyl compound and the subsequent reductive
elimination is usually referred to as the Julia reaction <1973TL4833>. Further studies have
been reported by Lythgoe and Kocienski <1978JCS(P1)829, 1978JCS(P1)834>. This olefina-
tion method proceeds as follows: metallation of the sulfone, condensation of the sulfone anion
with a carbonyl compound, and reductive elimination of the resulting -hydroxysulfone
(Scheme 36).
R1
PhO2S H RLi or RMgX PhO2S M R3CHO PhO2S OH
R1 R2 R3
R1 R 2 R1 R2 R2 R3
M = Li or MgX
Scheme 36
The sulfone anion is generated by using alkyllithium bases such as BunLi in THF, ButLi
<1999S188>, MeLi <1986TL2095>, PhLi <1990JA7407>, lithium diisopropylamide (LDA)
<1988JOC4282>, LiHMDS <1995JA8258>, or magnesium bases in the case of easily enolizable
carbonyl compounds <1978JCS(P1)829>. Use of the co-solvent HMPA is sometimes required
<2003SL393>. For sulfones with additional acidic protons, it is possible to avoid protection with
the use of polyanions (Scheme 37) <2001JOC8973>.
H H OPMB
MOMO MOMO O
O
OPMB i. BunLi (2.1 equiv.)
O –78 °C, THF, 15 min OH
+
PhO2S OH ii. Ac2O, Et3N
O OTBS DMAP (cat.)
O OTBS
iii. Na/Hg, Na2HPO4
MeOH
44%
3.4/1 (E )/(Z )
(–)-Laulimalide
Scheme 37
The condensation of the metallated sulfone with the carbonyl is effected at low temperatures (in
case M = Li, the equilibrium is in favor of starting materials at high temperatures). It can be
promoted by Lewis acids such as BF3OEt2 <2002JOC4346>. The condensation of a sulfone
anion and a ketone requires the tertiary alkoxide adduct to be trapped with either TMSCl or
PhCOCl to obtain, after aqueous work-up, the corresponding -hydroxy- or -benzoyloxysulfone
(Equation (33)) <1996TL2089, 1995JA8258>.
SO2Ph R1 R2 Yield (%)

O
BunLi R1
n-C6H13 SO2Ph + n-C6H13 ð33Þ
R1 PhCH2CH2 H 69
TMSCl or BzCl OR2 PhCH2CH2 PhCO 81
The -hydroxysulfone can be reduced directly with sodium amalgam <2002JOC4346>. SmI2 in
THF does not effect the reductive elimination except in the case of imidazolyl sulfone
<1990TL7105>. The use of Inanaga’s conditions (SmI2 with 1–5 mol.% HMPA in THF at
0 C) provides the desired alkene from the -hydroxy phenyl sulfone in good yields
<1996TL2089, 2001T2609, 1995JOC3194, 1994SL859>. The -hydroxysulfone is generally con-
verted in situ into an ester (Ac <1993BSF256, 2002JA1664>, Bz <1996TL2089>, or trifluoro-
acetate <1990JA2786>) prior to reduction. Reduction generally proceeds at low temperatures
with sodium amalgam in methanol (Scheme 38) <2003SL393, 1999S188, 2002JA1664>, Mg in
ethanol (Scheme 39) <1995TL5607>, or SmI2 in the presence of 0–5 mol.% of HMPA (Scheme
40) <2001T2609, 1996TL2089> to produce mainly the (E)-alkenes. The mechanism of the
reduction of both -hydroxy- and -benzoyloxysulfone has been discussed by Marko and co-
workers <1996TL2089, 2001T2609>.
Generally, the more the chain-branching, the better is the trans-selectivity in this reaction
(Figure 5) <1980JCS(P1)1045>.
The -hydroxysulfone can be transformed into a xanthate which is eliminated in good yields
and high trans-selectivity even when the ester method fails. Elimination is carried out by treating
the xanthate with Bu3SnH <1988JOC4282>.
OMe
OMe
O OMe i. ButLi,
THF
PhO2S –78 °C OMe
OMe O
+
O O TBDMS ii. BzCl, Pyr OMe
0 °C Ph OTBDMS O
Ph OTBDMS
iii. 5% Na/Hg, EtOH
AcOEt, –30 °C, 5 h
35% TBDMS
Soraphen A1α
OTBDMS OTBDMS
OTIPS
i. BunLi, –78 °C OTIPS
O +
O
PhO2S ii. RCOCl
H
O iii. Na/Hg, –35 °C O
O
R = Ac, 88%, 64/36 (E )/(Z )

R = Bz, 63%, 92/8 (E )/(Z )
(–)-Macrolactin A
Scheme 38
SO2Ph SO2Ph
Mg Mg OBn
OBn OBn
BnO BnO BnO
cat. HgCl2 cat. HgCl2 OX
OX
EtOH EtOH
X = Ac or Bz
99%
Scheme 39
SmI2–HMPA Me SmI2–HMPA
HO SO2Ph BzO SO2Ph
Me
Me n-C4H9 Me
n-C4H9 Me THF, 0 °C THF, –78 °C n-C4H9 Me
69% 73%
Scheme 40
n-C6H13
n-C7H15 n-C7H15
80/20 (E )/(Z ) 90/10 (E )/(Z ) >99/1 (E )/(Z )
Figure 5
The formation of alkenes can also result from a two-step pathway: prior elimination of the
hydroxyl group (elimination of the acetate with LDA or 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU)
<1995JOC3194> or ButOK <2002JA1664>) followed by the reduction of a vinyl sulfone with
SmI2 <1995JOC3194>. This method provides (E)-alkenes with high selectivities (Equation (34)).
Ph Ph
SmI2, DMPU ð34Þ
SO2Ph MeOH, THF

89% (E) only
The Julia reaction is an efficient method for the preparation of (E)-1,2-disubstituted alkenes,
but few examples of trisubstituted alkenes have been described <1990JA2786>. Marko
<1996TL2089, 2001T2609> reported an efficient preparation of trisubstituted alkenes from
ketones with an (E):(Z) ratio in a typical range of 2:1 (the ratio is independent of the relative
stereochemistry of the starting hydroxy- or benzoyloxysulfone). Férézou obtained an (E)-trisub-
stituted alkene with an excellent diastereoisomeric excess when the reducing agent is Na/Hg,
whereas SmI2 is less selective (Scheme 41). This result suggests a different pathway for the two
reducing agents <1998SL1223>.
SO2Ph
MeO OMe MeO OMe
O i. LDA, –78 °C R
R O
PhO2S OMe
ii. RCHO O
OMe OMe OH
O
Na/Hg, SmI2–HMPA,
MeOH, –20 °C THF, rt
Yield ((E )/(Z )ratio) Yield ((E )/(Z )ratio)
R = Ph 78 (95:5) 87 (52:48)
CH2CH2Ph 81 (100:0) 87 (73:27)

95 (94:6) 86 (85:15)
OTBS
Scheme 41
A similar olefination called Julia type II involves the -alkylation of a sulfone with an
electrophilic -halo Grignard reagent <1992SL133>. This pathway can be an alternative method
in case the classical Julia fails (Equation (35)) <2001JA10942>.
OTBDPS OTBDPS
O i. BunLi O
(+)-Phorboxazole ð35Þ
O SO2Ph ii. PriMgCl, I
O
TIPS 95% Cl
TIPS 1/1 (E )/(Z )
A one-pot procedure, first reported by S. Julia, has been developed by replacing phenyl
sulfones with heteroaryl sulfones. The addition of the heteroaryl sulfone anion to a carbonyl
proceeds in a fashion analogous to the classical Julia olefination, but because of the heteroaro-
matic moiety the -hydroxysulfone is unstable and easily undergoes a Smiles rearrangement
<1991TL1175>. This powerful method is compatible with a large range of heteroaromatic
sulfones. The three types of sulfones commonly involved in the modified Julia olefination are
presented here <2002JCS(P1)2563>.
The first one is benzothiazo-2-yl sulfones (BT-sulfones). The great electrophilicity of the carbon
of the thiazolyl moiety renders the Smiles rearrangement very facile (Scheme 42) <1991TL1175,
1993BSF856, 1993BSF336>.
LiO Ar
Li Ar
N Me BunLi, –78 °C Smiles
N O
SO2 N
S p-MeOC6H4CHO SO2 rearrangement
S S
–78 °C, 90 min S
O2
then rt, 18 h
N
N O
OLi + SO2 + S
S Ar S O
Ar
64% O Li
Scheme 42
Deprotonation of these sulfones requires non-nucleophilic bases (to avoid ipso-substitution on

the heteroaromatic moiety) such as LDA <1991TL1175> or LiHMDS <2002TL1373>. This
metallation step is quite difficult because of the propensity of the sulfone to self-condense even
at low temperatures (Equation (36)).
N Me LDA, THF N
SO2 SO2 S
–78 °C, 3 h S ð36Þ
S
52% N
Barbier conditions can improve the olefination yields but are not always compatible with
highly functionalized carbonyl compounds. S. Julia reported a systematic study on the
stereochemical outcome of the addition/elimination sequence and proposed a mechanism
for the equilibration between syn- and anti--hydroxysulfones through retroaddition/addition
which dictates the corresponding selectivity of the alkene formation <1993BSF856,
1993BSF336>. This method generally provides 1,2-disubstituted alkenes, favoring the
(E)-isomer (Equation (37)).
N Ph
LDA R1
SO2 R1COR 2 Yield (%) (E )/(Z ) ratio
S R1COR2 Ph R2
CHO 67 50:50
O 61
ð37Þ
CHO 30 99:1
CHO 53 98:2
Ph CHO 82 46:54
More recently, Charette and co-workers <1996JA10327> (see also <2001TL5149>) described
the effect of solvent, counterion, and temperature on the selectivity of the alkene. They showed
that the (E)- or the (Z)-isomer can be obtained very efficiently simply by changing the solvent of
the reaction (Equation (38)).
O
N Conditions TIPSO
TIPSO
O2S + H
S see table
(E )
+
Conditions (E )/(Z ) ratio TIPSO
NaHMDS, THF 1.1:1

(Z ) ð38Þ
NaHMDS, DME 2.4:1
NaHMDS, DMF 3.5:1
KHMDS, THF 1.2:1
KHMDS, Toluene 1:3.7
NaHMDS, Et2O 1:7.7
NaHMDS, Toluene 1:10
NaHMDS, CH2Cl2 1:10
(+)-U-106305
This reaction has been successfully used in various total syntheses such as bengamide E and TMC-
95A/B <1996JA10327, 1998JCS(P1)3907, 2003OL197, 2001TA1251, 2002TL1373, 2001T681>
(Scheme 43).
O OBn OBn
LiHMDS
BTO2S + OTIPS OTIPS
H
THF, –78 °C to rt
OBn OBn
Bengamide E
Me O
Me
CbzN
BTO2S H O
LiHMDS
CbzN O + O O
N DMF/DMPU, 0 °C N
Me Me H H
I 79%, 5/1 (E )/(Z ) I
TMC-95A/B
Proteasome
inhibitors
Scheme 43
Pyridin-2-yl sulfones (Pyr-sulfones) constitute the second heteroaromatic sulfone moiety cur-
rently used in this one-pot procedure. The metallated sulfones are more stable; they are less
susceptible to self-condensation. Pyr-sulfones generally give lower yields of olefin, probably due
to a less efficient elimination step, but the cis-selectivity is enhanced compared to the analogous
BT-sulfones (Equation (39)) <2002JCS(P1)2563>.
BuLi, LiBr
THF, –78 °C Ph
SO2 n-C8H17
N Ph n-C8H17CHO ð39Þ
–78 °C to rt (E )/(Z ) 10:90
51%
Charette recently reported an efficient synthesis of (E),(Z)-dienes by coupling a Pyr-sulfone and

an ,-unsaturated aldehyde (Equation (40)) <2001TL5149, 2001TL6619>.
R2 R2 R2
OTIPS
CHO + PyrO2S R1 + R1 OTIPS
R1
OTIPS (E ),(E )
(E ),(Z )
ð40Þ
1 2
R R Conditions (base, solvent, temp.) Yield (%) (E ),(Z )/(E ),(E ) ratio
H Me NaHMDS, toluene, 25 °C 54 91:9

H Pr KHMDS, toluene, 25 °C 64 90:10
H Ph KHMDS, toluene, 25 °C 70 92:8
Kocienski has developed tetrazole analogs to achieve the modified Julia olefination. 1-Phenyl-
1H-tetrazol-5-yl sulfones (PT-sulfones) generally give high yields of trans-olefins, in the absence of
factors such as -chain branching or conjugation, with no significant amount of self-condensa-
tion. The best conditions for this coupling are DME as solvent and KHMDS as base (Equation
(41)) <1998SL26>.
n-C5H11
n-C5H11CHO + PTO2S
Solvent Base Yield (%) (E )/(Z ) ratio

ð41Þ
Toluene KHMDS 13 64:36
Et2O KHMDS 30 72:28
DME KHMDS 71 94:6
DME LiHMDS 95 77:23
Jacobsen reported the synthesis of (E)- or (Z)-isomer depending on the solvent/base system
used (Equation (42)) <2001JA10772>.
OTBDMS
OTBDMS
OTBDMS
H
TBDPSO O OTBDMS
O Me
+ TBDPSO O Me
O
Me Me Me
Me
PTO2S Me
O
Me
Me Me ð42Þ
Conditions (E)/(Z) ratio (+)-Ambruticin
NaHMDS, THF, –78 °C 1:8

NaHMDS, THF, –35 °C 1:6
KHMDS, DMF, –60 °C 1:1
KHMDS, DME, 18-crown-6, –60 °C 1:3
LiHMDS, THF/HMPA: 4:1, –60 °C 3:1
LiHMDS, DMF/HMPA: 4:1, –35 °C >30:1
LiHMDS, DMF/DMPU: 1:1, –35 °C >30:1
This coupling has been successfully applied to various total syntheses such as hennoxazole A
(Equation (43)) <1999JA4924, 2002JA384, 2001JA10772, 2002AG(E)176, 2000TL7373,
2001JA12426, 2002JCS(P1)2563, 2002TL213, 2001T5161, 1999TL4897, 2002T4425,
2001OL2289, 1999JOC9632>.
PivO OMe
PivO OMe H
H SO2PT OMe
OMe Me O
Me O KHMDS
+
Me DME N O
N O
H 85%
Hennoxazole A N ð43Þ
N
O O
H
O 91/9 (E )/(Z )
Me
H
The efficiency of PT-sulfones, probably due to the steric hindrance generated by the phenyl
group, encouraged Kocienski to develop other bulky tetrazole derivatives. 1-t-Butyl-1H-tetrazol-
5-yl sulfones (TBT-sulfones) have shown a low propensity toward self-condensation: this great
stability allows premetallation (Equation (44)) of the sulfone thereby broadening the scope of the
aldehyde that can be used in this reaction <2000SL365>.
KHMDS, DME
–60 °C, 2 h
SO2Het SO2Het
H2O
Recovered ð44Þ
Het = BT 0%
Het = PT 20%
Het = TBT 91%
The yields of 1,2-substituted alkenes are consistently higher with the TBT-sulfone compared with
the corresponding phenyl substituted analog, but the trans-selectivity decreases (Equation (45)).
KHMDS, DME
N N R2 –60 °C, 30 min R2
N
N S R3CHO R3
O2
R1 –60 °C to rt
ð45Þ
R1 R2 R3 Yield (%) (E)/(Z) ratio
Ph n-C4H9 Ph 48 >99:1
CH2=CH n-C9H19 39 67:33
But n-C4H9 Ph 80 79:21
CH2=CH n-C9H19 60 4:96
The synthesis of 1,2-disubstituted alkenes can be achieved with the classical or the modified
Julia olefination. The PT-variant of the modified reaction seems to be the most efficient to
provide (E)-alkenes in most cases. When chain branching <1996JA10327> or conjugation
<1996S285, 1996S652> is to be considered, both BT- and PT-sulfones are efficient and lead to
the desired olefin with high stereoselectivity. Very few trisubstituted olefins have been prepared
with the modified Julia olefination. According to these examples, olefins are prepared in good
yields but with modest selectivities <1999S1209, 2001OL1491>.
1.15.4.3.2 The Ramberg–Bäcklund reaction

Ramberg and Bäcklund reported in 1940 that the treatment of -bromoethyl sulfone with
aqueous potassium hydroxide provided (Z)-but-3-ene as the major product. Since then this
reaction has been widely studied <1991COS(3)861> (for a recent review, see <2003OR(62)357>).
The Ramberg–Bäcklund (RB) rearrangement involves the conversion of an -halo sulfone to
an olefin under basic conditions through the formation of the episulfone <1993SL660> and then
extrusion of SO2 (Scheme 44).
X X R1 R2
Base
R1
R1 S R2 R1 S R2 S R2 + SO2
O O O O O O
Scheme 44
The leaving group is a halogen <1996JOC7644, 1999JA8237, 1991JA9682>, a tosylate

<1980JOC1719>, or a sulfinate (p-toluenesulfinate <1986CL433>, trifluoromethanesulfinate
<1986JA2358>). An epoxide version of the RB reaction has been reported by Taylor to synthe-
size allylic alcohols (Scheme 45) <1997TL3055>.
Et
ButOOLi O ButOLi
Et Et
Ph S Ph S Ph OH
O O –78 to 0 °C O O THF
70% 75% 90/10 (E )/(Z )
Scheme 45
-Halo sulfones can be replaced by -halo sulfides <1973TL4395>, -halo sulfoxides

<1986CB1540>, or -halo-N-p-toluenesulfonyl sulfoximines <1978JOC4140>. The RB rearran-
gement can proceed under milder conditions by using phase transfer catalysts <1982S504>.
Different bases have been used in this rearrangement: strong hindered bases such as ButOK/
ButOH give the best yields of (E)-olefin, whereas aqueous KOH favors the (Z)-isomer (Scheme 46)
<2000JOC8367>. By using a nonprotic solvent, the reaction can be carried out at low temperature
under mild conditions (Scheme 47) <1995TL7767, 1989T455>. The RB rearrangement of trichloro-
methyl sulfones is carried out in dry chloroform in the presence of DBU to furnish 1,1-dichloroalkenes
in good yields (under classical conditions, 1,1-dichloroalkenes are only obtained in small amounts)
(Equation (46)) <2000TL1501, 1998T1901>.
t-BOC t-BOC
N i. NCS, CCl4 N
ii. MCPBA
S
iii. Base
KOBut 100%, 94/6 (E )/(Z )
anh. KOH 59%, 65/35 (E )/(Z )
t-BOCN i. NCS, CCl4 t-BOCN
S ii. MCPBA
iii. Base
KOBut 93%, 94/6 (E )/(Z )
aq. KOH 79%, 44/56 (E )/(Z )
Scheme 46
O
NHt -BOC N NH
AcO KOBut (2.2 equiv.) NHt -BOC
AcO
THF, –78 °C N N NH2
S Br AcO
O O 77%
trans-Carbovir
Scheme 47
R X R
DBU
H H
CHCl3
SO2CCl3 Cl ð46Þ
Cl
R=H 92%
R = Ph 85%
Vinylogous RB provides conjugated dienes. -Halovinyl sulfones can undergo one-pot tandem
conjugate addition-proton exchange-RB process (Scheme 48) <1997SL1043>.
Br Br
i. Br2 Nu
S Ph Nu
S Ph S Ph Nu Ph
O O ii. Et3N O O O O
Nu = MeO– 52% 75/25 (E )/(Z )

Nu = BnSH 77% 93/7 (E )/(Z )
Nu = BnNH2 60% 25/75 (E )/(Z )
Scheme 48
A one-pot chlorination/RB-rearrangement procedure has been described by Meyers

<1969JA7510>. Treatment of the sulfone with KOH, and CCl4 in a mixture ButOH/H2O gives the
desired olefin in good yields (under these conditions, acyclic dialkyl sulfones can give a significant
amount of the dichlorocyclopropane resulting from the addition of the dichlorocarbene to the alkene).
More recently, a new one-pot protocol has been developed using CBr2F2, KOH on Al2O3, and
CH2Cl2 <1995CC1297>. Replacement of CBr2F2 (bp 23 C) with CCl4 <1999AG(E)2939> or with
CBrF2CBrF2 (bp 47 C) <1999OL2149> at reflux can solve the reactivity problem (Scheme 49).
OBn KOH OBn

OMe Al2O3 H OMe
BnO O OC16H33 BnO O
SO2 OC16H33
BnO BnO
CBr2F2 No reaction
C2Br2F4, reflux 60% 1/1 (E )/(Z )
OH
OMe
HO O
OC16H33
HO
Anti-proliferative properties
Scheme 49
Extrusion of SO2 proceeds with retention of configuration but the cyclization, which is the rate-
determining step, is not normally stereocontrolled. One example of stereocontrol has been
reported by Schmittberger and Uguen <1996TL29>. The synthesis of (E)-alkenes resulted from
the treatment of -chloro sulfones with an excess of base, which led to both cis- and trans-
episulfones. The lack of reactivity of the cis-episulfone at room temperature allows its epimeriza-
tion into the trans-isomer which is quickly transformed into the corresponding (E)-alkene (the
(Z)-alkene is not formed at an appreciable rate below 80 C) (Equation (47)).
OTBDPS
TBDPSO
rt 73%
O O
S
OTBDPS
TBDPSO
trans
Cl KOBut
(3.5 equiv.) ð47Þ
TBDPSO S OTBDPS
O O THF, rt, 4 h
O O
S
TBDPSO OTBDPS
cis
rt
TBDPSO OTBDPS
Because of this lack of stereocontrol, the RB rearrangement has been mainly used for cyclization
of strained systems <1997JOC2727, 2000TL1501> such as cyclobutenes <1988JA8197>, cyclopen-
tenes (Scheme 50) <2001TL1197, 1996TL7457>, cyclohexenes <2002OL427>, seven-membered
rings (Scheme 51) <2000JOC8367>, and cyclic enediynes (Equation (48)) <2002JCS(P1)2485>.
The synthesis of larger rings suffers from low yields and poor selectivities.
i. ZnCl2 (cat.)
OBn BnO O
DCMME O ButOK
BnO
S OMe CHCl3, 50 °C S Cl THF
BnO OBn
ii. MCPBA –78 °C BnO OBn
BnO OBn
OBn 40% OBn 40% OBn
DCMME = dichloromethyl methyl ether
Scheme 50
O O KOH/Al2O3
Ph S Ph
CBr2F2
ButOH/THF (3:1)
78%
O O KOH/Al2O3
Ph S Ph
CBr2F2
ButOH/THF (3:1)
90%
Scheme 51
O KOH/Al2O3
CH2 n S CH2 n
O CBr2F2/CH2Cl2
n=2 50%
ð48Þ
n=5 73%
n=6 70%
n=9 74%
Very few examples of acyclic systems have been reported <1996T14437, 1999TL3917>. The
main application is the synthesis of highly conjugated acyclic systems such as enediynes (Equation
(49)) <2002JCS(P1)2485> and 1,3,5,7-octatetraenes (Equation (50)) <2002T1301>. In the latter
cases, the RB rearrangement is very selective.
KOH/Al2O3
n-C5H11 n-C5H11
S CBr2F2/CH2Cl2 ð49Þ
O O
80%
1.2/1 (E )/(Z )
KOH/Al2O3 R
Ph S R Ph
O O CBr2F2/CH2Cl2
only(E ) ð50Þ
R = Ph 90%
R = SiMe3 87%
-Isopropylsulfonyl propionic esters undergo RB rearrangement via the carbanion generated

by decarboxylation (Equation (51)) <1995TL8367>.
Me Ph Cl Me Ph Cl Me Ph Me
KOH
S COOEt S COO S ð51Þ
O O ButOH/CCl4 O O O O Ph
61%
The RB rearrangement has been widely used for the preparation of C-glycosides via exo-glycals
(Equations (52) and (53)) <1998TL8179, 1998TL8225, 1999OL2149, 1999CC1599,
1999AG(E)2939, 2001OL197, 2002BMCL997, 2002EJO1305, 2003TA79>.
BnO i. KOH, CCl4 BnO BnO

O aq. ButOH O O Br
BnO SO2Me BnO + BnO
ii. CBr2F2, KOH
BnO OBn Al2O3, ButOH BnO OBn BnO OBn
CH2Cl2 ð52Þ
α:β = 75:25
i. 60 °C 72%
ii. rt 57% 32%
ii. – 5 °C to rt 54% 15%
ii. –10 °C 10%
O
KOH
Bu2t Si
O O N
O O Al2O3 Bu2t Si O
O S O t-BOC
TBDMSO O O ð53Þ
NHAc C2Br2F4/ButOH TBDMSO H
t-BOCN NHAc
50 °C
38%
Recently, a phosphorus version of the RB rearrangement has been described by Lawrence:

dibenzylphosphonium bromide, treated with N-bromosuccinimide (NBS) in presence of 2,2,6,6-
tetramethylpiperidine, gives stilbene via the corresponding epiphosphonium (Equation (54))
<1998T15345, 1998T15361>.
Br Br Br
TMP, NBS Ph Ph Ph
Ph P Ph Ph P Ph P ð54Þ
Ph Ph rt, CHCl3 Ph Ph Ph Ph Br 70% Ph
20/80 (E )/(Z )
1.15.4.3.3 Alkylation of sulfoximine-stabilized carbanions followed by elimination—the Johnson

(N-methylphenylsulfonimidoyl)methyllithium method
Addition of anions of alkyl aryl sulfoximines to carbonyl compounds gives -hydroxysulfox-
imines, which can readily undergo reductive elimination using aluminum amalgam in aqueous
THF/acetic acid to give alkenes (COFGT (1995)). -Hydroxysulfoximines can undergo reductive
elimination via the corresponding trimethylsilyl ethers to give chiral alkenyl sulfoximines. This
reaction has been applied to the synthesis of isocarbacyclin (COFGT (1995)) <1998EJO1319>.
The -mesyloxysulfoximine derivatives can lead to allylic sulfoximines, which react with organo-
copper reagents in the presence of boron triflate and lithium iodide to give substituted alkenes
(Scheme 52) <1996JOC4379, 1998EJO1319>.
Bun
Ph i. BunLi, THF Ph BunCu.LiI
S Ph S
Ph
O NMe ii. PhCH2COMe O NMe BF3.Me2S
iii. MsCl, Et3N Et2O, 16 h
iv. DBU (E )/(Z ) 61/39 75% 60% ee
66%
Scheme 52
1.15.4.4 Alkylation of Selenium(II)- and Selenium(IV)-stabilized Carbanions

Followed by Elimination
Substituted selenides resulting from alkylation of selenium(II)-stabilized carbanions readily
undergo syn-elimination after oxidation with H2O2. This method has successfully been applied
to the synthesis of 2,4-dienoic esters in good yields from selenium-stabilized ester enolates
(Scheme 53) <2000T7483>, and alkenes or homoallylic alcohols from a user-friendly supported
selenide anion (Scheme 54) <2002TL5495>.
R R
COOEt KH or LDA COOEt H2O2, Pyr
R SePh COOEt
SePh Br CHCl3, 0 °C
HMPA, –35 °C R=H 96% 92%
R = Ph 81% 71%
R = Pr n 76% 84%
Scheme 53
LDA, THF, –60 °C H2O2

SeCH2Ph SeCHPh SeO2H + Ph
R
RCH2Br
CH2R
R = Ph 89% 96/4 (E )/(Z )
R = CH 2=CH-CH2 91% > 93/7 (E )/(Z )
LDA, THF, –60 °C H2O2

SeCH2Ph SeCHPh SeO2H + Ph Ph
O OH 86%
OH
Ph
Ph > 95/5 (E )/(Z )
Scheme 54
Addition of the titanium enolate derived from -seleno carbonyl compounds or esters to an
aldehydes provides -hydroxyselenides, which are easily transformed into (Z)-,-unsaturated
carbonyl compounds or esters (Scheme 55) <2001T6703>.
O TiCl4, Et3N O OH O
RCHO MsCl, Et3N
SePh R R
CH2Cl2, –78 °C SePh CH2Cl2, 0 °C
in the dark
R = n-C5H11 78% (98/2 syn/anti ) 93% > 98/2 (E )/(Z )
R = TMS C C 63% (98/2 syn/anti ) 88% > 98/2 (E )/(Z )
Scheme 55
Direct addition of selenoxide -anions to carbonyl compounds is less synthetically useful

(COFGT (1995)).
1.15.4.5 Alkylation of Tellurium-stabilized Anions Followed by Elimination

Elimination of telluroxides, which is analogous to that of selenoxides (COFGT (1995)), has not
been used for the synthesis of alkenes since 1995, so it is not going to be discussed here.
1.15.5 BY CONDENSATION OF NITROGEN FUNCTIONS
1.15.5.1 Reactions of Diazo Compounds

Alkene synthesis can be carried out by decomposition of diazo compounds catalyzed by rhodium or
ruthenium complexes. Recently, symmetrical <1997CC2163> or unsymmetrical <1999OM5091,
2000EJO2795> enediones have been obtained in good yields and excellent cis-selectivities by using
[RuCl(5-C5H5)(PPh3)2] (Equation (55)).
O O
[CpRu(PPh3)2 ]
N2 N2
EtO + EtO ð55Þ
CDCl3, 60 °C O O
59% cis -isomer only
The condensation of -diazo ketones with trimethylsilyl diazomethane provides cis-

RCOCH¼CHSiMe3 with high yields (>80%) because only the -diazo ketone is decomposed
by the ruthenium complex <2000EJO2795>.
An intramolecular version of this carbene–carbene coupling gives a macrocyclic cis-cycloalkene
<2000EJO2795, 2000OL1777>. The stereochemistry of the double bond depends on the catalyst
(Equation (56)).
O O O O O O
O CH2Cl2, reflux O
O CHN2 O
CHN2
O O
O O O O
O O ð56Þ
Catalyst Yield ( %) ((Z )/(E ) ratio)
Cu(MeCN)4PF6 73 (18:82)
MEPY = Methyl 2-pyrrolidinone- Rh2(OAc)4 43 (39:61)
5(R )-carboxylate Rh2(5(R)-MEPY)4 5 (74:26)
Decomposition of -diazo ketones bearing a tethered alkyne unit furnishes a rhodium carbe-
noid, which can lead to the synthesis of cyclic enones <2000OL2093, 2000JOM(610)88,
2001JOM(617-618)3, 1996CRV223, 1999OL1327> and bicyclic furans (Equation (57))
<2003JOC227>. The product depends on the metal complex and the solvent employed (Scheme
56). The mechanism has widely been discussed by Padwa <2001JOM(617-618)3,
2000JOM(610)88>.
O O O N O N
Rh2(OAc)4 Six electron
O N O O ð57Þ
O O
N2 Hexane RhLn cyclization
TMS 98% TMS
TMS
O O O
Rh2(OAc)4 Rh2(OAc)4
CH2Cl2 N2 Pentane
85% 80%
4
2/1 (Z )/(E ) CH2CH2CH2C CH
Scheme 56
More recently, Lebel and co-workers <2001AG(E)2887, 2002OL1671, 2002JOM(658)126>

reported a new methylenation of carbonyl compounds based on the in situ generation of methyl-
ene triphenylphosphorane from trimethylsilyl diazomethane catalyzed by Rh(I) (Scheme 57).
These conditions lead to terminal alkenes in excellent yields and are compatible with sensitive
and enolizable carbonyl compounds. This method constitutes a practical alternative to the Wittig
reaction under neutral conditions.
[RhCl(PPh3)3]
i Ph3P=CH2
TMSCHN2 + Pr OH
PPh3 Pri
THF, rt +
O 89% OTBDPS
i
Pr
H
OTBDPS
Scheme 57
Olefination of carbonyl compounds with ethyl diazoacetate, catalyzed by ReOCl3(PPh3)2 with

1 equiv. of P(OEt)3 <1997TL8125>, by RuCl2(PPh3)3 <1998TL625>, or by iron(II) porphyrin
complex <2002JA176, 2003OM1468> in the presence of a stoichiometric amount of triphenyl-
phosphine, is very trans-selective (Scheme 58). The Fe(II) complex can be replaced by the air-
stable and commercially available ClFe(TPP) or Ru(TPP)(CO) <2003JOC3714, 2003OM1468>.
O
OTBDMS ReOCl3(PPh3)2 OTBDMS O
CHO + OEt OEt
N2 P(OEt)3
90% 14/1 (E )/(Z )
O O O
FeII(TPP)
H + OEt OEt
N2 PPh3
94%
24/1 (E )/(Z )
TPP = meso-Tetra(p-tolyl)porphyrin
Scheme 58
A safe alternative to hazardous diazo compounds is tosylhydrazone <2003JA6034>. In the

presence of ButOK, the tosylhydrazone is tranformed into the corresponding diazo compound
which is decomposed into the alkoxy-substituted phosphorus ylide by treatment with P(OMe)3
and Fe(III). This new method gives (E)-alkenes in high yields and excellent selectivities
(Scheme 59).
ClFe(TPP)
H KOBut P(OMe)3
N Ph
Ph N Ts Ph N2 R
Toluene PTC (10 mol.%)
0 °C to rt RCHO
R = p-Cl-C6H4 92% 97/3 (E )/(Z )
40 °C, 48 h
TPP = meso-Tetra(p-tolyl)porphyrin R = c-C6H11 91% 93/7 (E )/(Z )
Scheme 59
1.15.5.2 The Mannich Reaction

-Methylene ketones can result from a Mannich reaction followed by deamination. Recently
these two steps have been described in a one-pot procedure with Et2NH/CH2Br2 <1994CC2041,
1998T5223>. More recently, it was shown that microwaves increase the rate of the reaction
(Scheme 60) <2003T1509>.
O O
CH2Br2, Et2NH
Ph Ph
CH2Cl2
Reflux, 3 days 77%

Microwave, 30 min 62%
O O O O
CH2Br2, Et2NH
OMe OMe
CH2Cl2, microwave, 5 min
85%
Scheme 60
In a similar way, -methylene ketones can be obtained by treating enolates of carbonyl

compounds with N,N-dimethylformaldimmonium trifluoroacetate (Equation (58)) <2002T61>.
O O
O O
O OMe O OMe
KH, THF Stemonamide
+ – and ð58Þ
N Me2N =CH2.CF3COO , rt N isostemonamide
O O
PMB PMB
OPMB OPMB
1.15.5.3 The Aza Wittig Reaction

Recently, Katritzky reported an efficient reductive elimination with low-valent titanium of
N-(-hydroxyallyl)- or N-(-hydroxybenzyl)benzotriazole, derived from condensation of the
N-allyl- or N-benzylbenzotriazole anion with a carbonyl compound, affording both di- and
trisubstituted alkenes in good yields and with excellent (E)-selectivities (Scheme 61)
<1997JOC238>. This method has been extended to a wide range of benzotriazole derivatives,
including those containing heteroaryl groups and tertiary-substituted benzotriazoles
<1998JOC6704>. This reaction has also been used successfully for the synthesis of dienes and
trienes (Scheme 62).
BunLi, THF Cl
Bt –78 °C Bt OH TiCl3 /Li
O Ar DME, reflux
Cl
72%
100/0 (E )/(Z )
BunLi, THF
–78 °C Bt OH TiCl3 /Li
Ph Bt Ph
DME, reflux Ph
PhCHO Ph
81%
N 12.7/1 (E )/(Z )
Bt = Ph
N
N
Scheme 61
Bt
BunLi
+
N TiCl3/Zn–Cu N
O
66%
9/1 (E )/(Z )
nLi
H Bu
Ph Bt + Ph
O TiCl3/Zn–Cu
Et3N, 38% 6/1 (E )/(Z )
Scheme 62
A similar olefination can be performed on tosylhydrazones <1999JOC3332>. In the presence

of a strong base, condensation of benzotriazole derivatives with tosylhydrazones of carbonyl
compounds provides (E)-stilbenes (Equation (59)).
Ts
Cl
Bt HN BuLi
N
+ ð59Þ
Cl THF, 61% Ph
Ph
98/2 (E )/(Z )
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Biographical sketch
Joëlle Prunet was born in Versailles (France). Laurence Grimaud was born in Limoges
She worked with Prof. Marc Julia in 1986 on (France). She studied at the Ecole Normale
the synthesis of avermectin during her under- Supérieure (Paris). She obtained her Ph.D. in
graduate studies at the Ecole Normale Supér- 1999 with Prof. Joëlle Prunet at the Ecole
ieure (Paris). She obtained her Ph.D. in 1993 Polytechnique, where she contributed to the
with Prof. David A. Evans at Harvard Uni- synthesis of dolabelide C. In 1999, she
versity, where she participated in the total obtained a position of Professeur Agrégé at
synthesis of bryostatin. In 1993, she joined the Ecole Nationale Supérieure des Techni-
the CNRS as Chargée de Recherche at the ques Avancées (Paris), where she joined the
Ecole Polytechnique (Palaiseau), where she laboratory of Prof. Laurent El Kaı̈m. Her
also has a teaching position since 1998. In research topics include chemistry of hydra-
2003, she was promoted to the position of zones and synthesis of natural products such
Directeur de Recherche. Her research interests as Paulitin.
include total synthesis of natural products
(taxol, dolabelide, FR182877, and bafilomy-
cin) and development of new methodologies
for organic synthesis.
1.16
by Condensation: Condensation of
P, As, Sb, Bi, Si, Ge, B, or Metal
Functions
P. SAVIGNAC
Ecole Polytechnique – DCPH, Palaiseau, France
B. IORGA
Institut de Chimie des Substances Naturelles, Gif-sur-Yvette,
France
and
M. SAVIGNAC
ENSCP, Paris, France
1.16.1 C¼C BONDS BY CONDENSATION OF P, As, Sb, OR Bi FUNCTIONS 724

1.16.1.1 Alkenation via the Wittig Reaction 724
1.16.1.2 Phosphonium Ylides 725
1.16.1.2.1 Mechanism 725
1.16.1.2.2 Stabilized ylides 726
1.16.1.2.3 Nonstabilized ylides 727
1.16.1.2.4 Formation of (E)-alkenes via Wittig–Schlosser modification 727
1.16.1.2.5 Semistabilized ylides 728
1.16.1.2.6 Asymmetric Wittig reaction 729
1.16.1.3 Arsonium Ylides 730
1.16.1.3.1 Comparison of stabilized, nonstabilized, and semistabilized ylides 730
1.16.1.4 Stibonium Ylides 732
1.16.1.5 Bismuthonium Ylides 732
1.16.1.6 P(O)-Activated Alkene Formation 733
1.16.1.6.1 Mechanism 733
1.16.1.6.2 Phosphonate-stabilized carbanions (Horner–Wadsworth–Emmons reaction) 733
1.16.1.6.3 Phosphoryl-stabilized carbanions (Horner reaction) 738
1.16.1.6.4 Asymmetric Horner–Wadsworth–Emmons and Horner reactions 742
1.16.2 C¼C BONDS BY CONDENSATION OF Si, B, Ge, OR Te FUNCTIONS 743
1.16.2.1 Silicon-mediated Alkenation: The Peterson Reaction 743
1.16.2.1.1 Mechanism 743
1.16.2.1.2 Preparation of silicon-stabilized carbanions 744
1.16.2.1.3 Methylenation reactions 744
1.16.2.1.4 Stereoselective formation of alkenes 745
1.16.2.2 Boron-mediated Alkenation 747
723
1.16.2.3 Germanium-mediated Alkenation 748

1.16.2.4 Tellurium-mediated Alkenation 748
1.16.3 METAL-INDUCED METHYLENATION AND ALKYLIDENATION 748
1.16.3.1 Tebbe Reagent 748
1.16.3.2 Petasis Reagents 749
1.16.3.3 Takeda Reagents 750
1.16.3.4 Takai–Lombardo Reagents 751
This chapter intends to give a selective coverage of the recent research (from 1995 to 2003) and
some representative examples of early work reported in COFGT (1995) <1995COFGT(1)719>.
1.16.1 C¼C BONDS BY CONDENSATION OF P, As, Sb, OR Bi FUNCTIONS
1.16.1.1 Alkenation via the Wittig Reaction

The Wittig reaction is the reaction of phosphonium ylides with carbonyl compounds leading to
the formation of alkenes and phosphine oxides by transfer of an alkylidene group to a carbonyl
compound with displacement of the carbonyl oxygen. It was discovered in 1953 when Wittig and
Geissler treated methyltriphenylphosphonium iodide 1 with phenyllithium and obtained triphe-
nylphosphonium methylide 2, which, in reaction with benzophenone, gave 1,1-diphenylethylene 3
and triphenylphosphine oxide (Scheme 1) <1953LA44>.
Ph
O
I
PhLi Ph
Ph3P CH3 Ph3P CH2 Ph3P CH2
1 2
O PPh3 O PPh3 Ph
CH2 + Ph3PO
Ph Ph
Ph Ph Ph
3
Scheme 1
The activity of phosphorus ylides in the Wittig reaction depends on their structure. They can be
classified as nonstabilized or reactive ylides, semistabilized or ylides of moderate activity and stabi-
lized or ylides of low activity. The greatest effect on the activity of ylides is that of ylidic carbon atom
substituents. Stabilized ylides bear on the ylidic carbon atom at least one electron-withdrawing group
such as COR, CHO, CO2R, CN, P(O)(OR)2, sulfonyl, etc., or groups capable of delocalizing the
negative charge. These ylides, owing to extensive delocalization of negative charge through participa-
tion of resonance structures, are less reactive. Semistabilized ylides are those that are functionalized
with moderate electron-withdrawing groups such as aryl, thioalkyl, vinyl, and halogen atoms. Non-
stabilized ylides are those that are unsubstituted or substituted by electron-donating groups such as
alkyl, OAlk, NAlk2. These ylides, in which the negative charge is localized on the -carbon, are the
more reactive. Introduction of electron-donating substituents on the phosphorus atom such as
tri-n-butyl or tris(dimethylamino) increases the activity of phosphorus ylides, whereas electron-
acceptor halide atoms decrease the activity of ylides. The reaction is very general and the aldehyde
or ketone can be aliphatic, aromatic, conjugated cyclic, or heteroaromatic.
The scope, mechanism, and stereochemistry of phosphonium ylides have been extensively
reviewed by Schlosser <1970TS1>, Gosney <B-1979MI002>, Maryanoff <1989CRV863>,
Johnson <B-1993MI004>, Vedejs <1994TS1, 1996MI1>, Lawrence <B-1996MI007>, Nicolaou
<1997LA1283> and Kolodiazhnyi <B-1999MI008>. Additionally, a chapter ‘‘Ylides and
Related Species’’ is included every year in the Organophosphorus Chemistry: A Specialist Period-
ical Reports published by The Royal Society of Chemistry.
1.16.1.2 Phosphonium Ylides
1.16.1.2.1 Mechanism
The mechanism of the Wittig reaction has been a subject of intensive investigations and the reader
is referred to the exhaustive study by Kolodiazhnyi <B-1999MI008>. It seems clear that the
Wittig reaction does not proceed by a uniform mechanism and that the structures of the reagents
(nonstabilized, semistabilized, stabilized), the reaction medium, the solvents, and the presence of
lithium salts have an influence on the reaction mechanism. The Wittig reaction is traditionally
explained by assuming that the initial step involves a reversible addition of the ylide at the
carbonyl carbon atom to generate two possible diastereomeric betaine intermediates (4a, 4b),
the zwitterionic adducts of phosphorus ylides and carbonyl compounds. Subsequent decomposi-
tion to the alkene is thought to involve cis- and trans-oxaphosphetanes (5a, 5b) leading from the
betaine to the (Z)- or (E)-alkenes, via intramolecular attack of the oxygen atom on the phospho-
nium cation (Scheme 2). Nonstabilized ylides react with aldehydes to give largely (Z)-alkenes, and
stabilized ylides give predominantly (E)-alkenes, but semistabilized ylides generally give a mixture
of (Z)- and (E)-alkenes with a ratio 50/50.
R1
PPh3 Ph3P O Ph3 P O
H H + H R2
R1 R2 R 1 H
4a 4b
erythro threo
R1
PPh3
+
R2 Ph3P O Ph3P O
O H H + H R2
R1 R2 R1 H
5a cis 5b trans
R2
R1 R2 R1
(Z ) (E )
Scheme 2
The mechanism of the Wittig reaction has been the subject of investigations mainly with
nonstabilized ylides. In 1973 Vedejs and Snoble confirmed that the Wittig reaction proceeds via
the formation of oxaphosphetane intermediates <1973JA5778>. In 1990, McEwen and Ward Jr.
studied the metal effects and observed that when lithium was used the product mixture was
enriched with the (Z)-alkene, while when sodium or potassium ions were present, the (E)-alkene
dominated <1990JOC493>. In 1996, Borisova and co-workers reported the first experimental
evidence of the formation of betaines <1996MC90>. Vedejs and co-workers showed experimen-
tally that the first step of the Wittig reaction proceeds under kinetic control to result in cis- and
trans-oxaphosphetanes. They suggested that oxaphosphetanes were obtained as primary inter-
mediates as a result of an asynchronous [2+2]-cycloaddition of ylides to carbonyl compounds.
The mechanism does not take into account the formation of betaines as oxaphosphetane pre-
cursors <1973JA5778>. Maryanoff and co-workers discovered the stereochemical drift of cis-
oxaphosphetanes into their trans-isomers. They observed by kinetic studies that the rate of
retrodecomposition of cis-oxaphosphetanes into ylide and benzaldehydes is 7–15 times faster
than the rate of retrodecomposition of trans-oxaphosphetanes <1985TL4587>. It was supposed
that the first step of the Wittig reaction is reversible for (Z)- and (E)-olefin and that the second
step is rate determining. Decomposition of the oxaphosphetanes proceeds in two directions: to
ylide and aldehyde, or to alkene and phosphine oxide.
Investigations of the mechanism of the Wittig reaction for semistabilized and stabilized ylides
are more difficult because the oxaphosphetanes are much harder to detect, having only transient
existence. Detailed analyses of the experimental results from the reaction of stabilized ylides with
carbonyl compounds have led to the assumption that a betaine is formed as a primary inter-
mediate and then transformed to oxaphosphetanes. The Wittig reaction of stabilized ylides with
aldehydes proceeds under the conditions of kinetic control. (E)-Selectivity results from selective
formation of trans-oxaphosphetanes. The presence of electron-withdrawing substituents destabi-
lizes the intermediary products and accelerates the decomposition of the oxaphosphetane
<B-1999MI008>.
1.16.1.2.2 Stabilized ylides

The Wittig reaction of stabilized ylides with aldehydes and unsymmetrical ketones leads stereo-
selectively to the preferential formation of the (E)-alkenes, and the (E)-isomer is often produced
with almost complete exclusion of the (Z)-isomer <1972JOC2579, 1975JA3512>. The degree of
stereoselectivity observed may be influenced by the substituents on the ylide. Replacing the phenyl
groups on phosphorus by alkyl groups such as butyl or cyclohexyl in the presence of catalytic
amounts of benzoic acid in toluene results in an increase in the (E)-selectivity and the yield of
alkenes (Equation (1)) <1960T130, 1965JOC1296, 2001OL3591>.
CO2Me
O OH HO
R3P CO2Me
O OH PhMe, 90 °C O OH
ð1Þ
O O
R = Ph, 55% (E ):(Z ) 50:50

R = Bun, 78% (E ):(Z ) 91:9
The stereoselectivity of the Wittig reaction depends on the reaction medium and temperature.
The highest amount of (E)-alkene is obtained below 0 C in nonpolar aprotic solvents
<1987T1895>. The presence of lithium salts in the reaction medium increases the (Z)/(E) ratio
and accelerates the formation of alkene <1964HCA159, 1967CB1144>. There is no limit to the
structure of aldehydes used and fullerenes bearing an unsaturated ester have been prepared as the
(E)-isomer in 89% yield from organofullerenes and methoxycarbonylmethylidenetriphenylphos-
phorane <1993JOC4796>. Recently, a one-pot Wittig reaction protocol for the production of
alkenes by in situ formation of the ylide using the efficient combination of solid-supported
triphenylphosphine and microwave dielectric heating has been developed (Equation (2))
<2001OL3745>.
O
K2CO3, MeOH R2
PPh3 + Br R1 + R2 H R1 ð2Þ
150 °C, 5 mi n
R1 = Ph, CO2Me, COPh 25–95%
The (E)-selectivity of the Wittig reaction of stabilized ylides may be affected by the introduction
of substituents at the position alpha with respect to the phosphorus atom. If the group is
sufficiently large, appreciable quantities of (Z)-alkenes are formed in addition to the (E)-isomers
<1963JA2790, 1974JCS(P1)2470>. For example, the reaction of methoxycarbonylethylidenetri-
phenylphosphorane with acetaldehyde gives a 96.5:3.5 mixture of the (E)- and (Z)-isomers of the
methyl ester of tiglic acid <1961JOC4278>.
Stabilized ylides are currently used at various stages of multistep syntheses where the need to
introduce double bonds in a controlled manner is of importance. For example, alkoxycarbonyl-
methylidenetriphenylphosphoranes have been used by Nicolaou and co-workers in the synthesis
of endiandric acids, ionophore antibiotic X-14547A, calicheamicin 1, zaragozic acid A, breve-
toxin B (Equation (3)) and taxol <1997LA1283> and by Lee and co-workers in the synthesis of
seselin analogs <1997BMCL2573>. A solid-phase synthesis of epothilone A has been carried out
using a Wittig reaction on solid phase, thus demonstrating the value of this kind of operation in
solid-phase and combinatorial chemistry <1997LA1283>.
O Me O
O Ph3P C CO2Et O
O
C6H6, 50 °C CO2Et ð3Þ
Ph O O Ph O
H H H O Me
TBDMS 90%
TBDMS
Interaction of stabilized ylides with unsymmetrical ketones almost always leads to a consider-
able amount of (Z)-isomer. For example, treatment of a nucleosidic ketone with ethoxycarbo-
nylmethylidenetriphenylphosphorane in CH2Cl2/THF at room temperature gives the (Z)-alkene
as a single stereoisomer <1997JOC11>. Ketones bearing electron-withdrawing substituents are
the most reactive. Thus, the Wittig reaction of ethoxycarbonylmethylidenetriphenylphosphorane
with fluorinated arylketones proceeds smoothly to give predominantly fluorinated (Z)-alkenes
<1994NJC263>.
1.16.1.2.3 Nonstabilized ylides

In the case of nonstabilized ylides, the thermodynamically less favorable (Z)-isomers tend to
dominate the mixture of alkenes obtained <1963JOC372, 1973HCA1176>. The degree of stereo-
selectivity varies considerably with the reaction conditions, especially with the nature of the
solvent and the base used. In very dipolar aprotic solvents (DMF, DMSO, HMPA) lithium
salts have little effect on the stereochemistry of the reaction with carbonyl compounds and a
mixture of alkenes containing predominantly the (Z)-isomer is obtained both in the presence or in
the absence of lithium salts. The use of HMPA <1974JOC3793, 1974OPP269, 1998JOC337,
1998TL771> or DMSO <1997S1195> as co-solvent to THF provides a suitable reaction medium
for promoting the formation of (Z)-alkenes (Equation (4)).
O O
I OHC
PPh3 OMe OMe ð4Þ
OTBDPS BunLi, THF/HMPA, –78 °C OTBDPS
63%
In nonpolar solvents (Et2O, C6H6) containing lithium salts, the Wittig reactions of nonstabi-
lized ylides produce a greater proportion of (E)-alkenes. It is argued that in the presence of Li+
the decomposition of both diastereomeric betaine intermediates to alkene is retarded by complex
formation with the cation, thus reducing the proportion of (Z)-alkene. When preparing
(Z)-alkenes in nonpolar media it is important to ensure that salt-free ylide solutions are used.
A variety of methods for the preparation of salt-free ylide solutions is accessible from the
literature <1958LA10, 1965AG(E)583, 1970LA211, 1975JA4327, 1976CB1694>. Thus, the salt-
free modification of the Wittig reaction provides the simplest access to (Z)-alkenes. The highest
(Z)-selectivity has been reported for the Wittig reaction of tris(2-methoxymethoxyphenyl)-
phosphonium ylides which react with unbranched, saturated aliphatic aldehydes to afford olefins
with very high (Z)-selectivity (99.5%) <1990S109, 1993TL1925>. A variation of this method is to
prepare the ylide with NaNH2 in boiling THF and to remove the insoluble inorganic salts by
filtration <1970LA211>. t-BuOK <1975JA4327> and NaHMDS <1976CB1694, 1995JOC6627,
1998TL249> in THF or LiHMDS <1996JOC838> in THF/toluene are frequently employed as
bases without the tedious necessity for filtration (Equation (5)).
PriO
CHO
PriO PriO
Ph3P CO2Me ð5Þ
i
NaHMDS, THF, –90 °C Pr O CO2Me
Br
51%
1.16.1.2.4 Formation of (E)-alkenes via Wittig–Schlosser modification

Schlosser described a method leading to alkenes in very high (E)-selectivity even with nonstabi-
lized ylides <1966AG(E)126, 1967LA1, 1970CB2814>. Thus, treatment of the initially formed
lithium bromide complexed ‘‘phosphorus betaines’’ 6, with predominantly the erythro-configuration,
with an equivalent of an organolithium reagent, provides an -lithiated betaine or ‘‘betaine

ylide’’ 7. Whereas the initially formed erythro-complex is relatively stable to inversion, its
lithium derivative rapidly interconverts. Stereocontrol is accomplished by the spontaneous
pyramidal inversion of the -lithiated betaine to result in the predominant formation of the
thermodynamically more stable threo-isomer 8. Addition of a proton donor occurs with remark-
able stereospecificity to form the new intermediate in the threo-configuration 9, which decomposes
selectively to give pure (E)-alkene (Scheme 3). The reaction has recently been reinvestigated
by Schlosser and co-workers, who demonstrated that only phenyllithium in ethereal solution
containing lithium bromide effects the -deprotonation rapidly and cleanly. If these conditions
are met, the (E)-selective modification of the Wittig olefination protocol works with absolute
reliability to provide good yields of (E)-alkenes from a variety of aliphatic and aromatic aldehydes
<2003CEJ570>.
LiX LiX LiX

Ph3P O PhLi Ph3P O 1:99 Ph3P O
H R2 Li R2 R1 R2
R1 H R1 H Li H
6 7 8
erythro erythro threo
LiX
H+ Ph3P O R1
R1 R2
H H R2
9 (E )
Scheme 3
1.16.1.2.5 Semistabilized ylides

This important class contains ylides of moderate activity stabilized by -substituents such as
vinyl, aryl, or alkynyl groups. They react with carbonyl compounds to give mixtures of (Z)- and
(E)-alkenes. There is little influence of solvent or lithium salts upon the stereoselectivity of the
reaction, which essentially depends on structural factors. Under no circumstances are the effects
appreciable, and the (E)-alkene usually dominates the product composition.
(i) Benzylic ylides

For Wittig reactions effected with triphenylphosphonium benzylides, the stereochemistry of the
products depends largely on the nature of the substituents in the aryl ring. For example, in the
preparation of 4-nitro-40 -methoxystilbene, the reaction of 4-nitrobenzyltriphenylphosphorane
with anisaldehyde leads predominantly to the (E)-alkene. By interchanging the ylide and
aldehyde substituents, a 1:1 mixture of (E)- and (Z)-alkenes is obtained <1962JOC4666,
1966JOC334>. Recently, performing the preparation of stilbenes from ortho-halo substituted
benzyltriphenylphosphonium salts and benzaldehydes, it has been found that there is a coop-
erative effect of one ortho-halo substituent on each of the two reacting partners which increases
(Z)-selectivity, and by contrast two ortho-halo substituents on the same reactant promotes high
(E)-selectivity <2002TL2449>. So in certain defined cases either (E)- or (Z)-isomer can be
predictably synthesized in good yield (Equation (6)). In the reaction of benzylidenetriphenyl-
phosphorane and benzaldehyde in two-phase organic solvent/water (NaOH) media, the use of
polar solvents increases (Z)-selectivity for the product stilbene; ortho-substituted benzaldehydes
bearing heteroatom substituents (CF3, Cl, Br, MeO, F) also confer a pronounced enhancement
of (Z)-selectivity <1999JMOC(A)(142)125>.
Ph3P
CHO X1 X2
X1 Y1 X2 Y2 NaOH
+
CHCl3
rt, 1 d Y1 Y2
ð6Þ
Ph3P Ph3P
CHO CHO
Hal Hal Hal Hal
High (Z ) Very high (E )
The isomer ratio may be shifted further in favor of the (E)-isomer by replacing the phenyl
groups on phosphorus by alkyl groups. In an EtOH solution of sodium ethoxide, substitution of
alkyl groups for phenyl groups leads to almost pure (E)-stilbene and also to better yields
<1962CB1894, 1970TS1>. By contrast with the conventional Wittig reaction, the mechanically
induced solid-state generation of semistabilized ylides using K2CO3 in the presence of stoichio-
metric amounts of solid organic carbonyl compounds discriminates between (Z)- and (E)-substituted
products in favor of the thermodynamically stable (E)-isomer <2002JA6244>. In general, struc-
tural changes in the carbonyl co-reactant exert only a minor effect on the stereochemistry of
Wittig reaction of benzylidenetriphenylphosphorane. (E)-Selectivity is preserved when using a
variety of aliphatic, unsaturated, and aromatic aldehydes under aprotic conditions.
(ii) Allylic ylides

Owing to the intrinsic nonstereoselectivity of allylic ylides, formation of conjugated dienes of
definite configuration is best conducted by reaction of saturated aliphatic reactive ylide with an
,-unsaturated aldehyde. This is exemplified by the synthesis of a major component of the sex
pheromone of the Egyptian cotton leafworm, which is a (9Z),(11E)-diene <1975CL103>. Trien-
omycins A and F have been synthesized using a double Wittig reaction of the diphosphonium salt
10 as a key step. The reaction produces a mixture of isomers including 21% of the required
(E),(E),(E)-triene unit 11 (Equation (7)) <1995JA10777>.
OH Cl Cl OH
PBu3
Bu3P
10
P P
N NaHMDS, DMF, 0 °C N
ð7Þ
O O 21% O O
CHO
O OHC OMe O OMe
P = CH2OCH2CCl3 11
A further stereochemical complication encountered during Wittig reactions with allylic ylides
having a terminal substituent is loss of configuration in the allylic double bond <1966JOC2907,
1972HCA1828>. Another difficulty that frequently arises is concurrent condensation at the -position
<1974JOC821>. As expected, increased steric hindrance at the -carbon inhibits -condensation
<1973JOC3625, 1973TL4425>.
1.16.1.2.6 Asymmetric Wittig reaction

Several articles are available that review asymmetric reactions of phosphorus ylides, written by
Rein <1996ACS369, 2002S579>, Li <1997CR2341>, and Kolodiazhnyi <1998TA1279>. Since
no new sp3 stereocenter is formed in the Wittig reaction, the asymmetric version of the Wittig
reaction has been focused mainly on alkylidenecycloalkanes with axial chirality. The first desym-
metrization of 4-substituted cyclohexanones using a chiral ylide containing a stereogenic phosphorus
center was described by Bestmann and Lienert <1969AG(E)763>. They obtained the axially
dissymmetrical 4-substituted alkylidenecycloalkane with reasonable asymmetric induction (43%
ee) from 4-methyl cyclohexanone. In 1980, Trost and Curran reported a synthesis of cyclopenta-
noid natural products based upon the desymmetrization of a meso-triketone by the asymmetric
intramolecular Wittig reaction depicted in Scheme 4 <1980JA5699>. Thus, a chiral phosphonium
salt prepared from (R)-CAMP (cyclohexyl-O-anisylmethylphosphine) and the bromide 12, under-
goes treatment with aqueous K2CO3 to generate the stabilized intermediate ylide 13 which evolves
through an intramolecular Wittig reaction to produce the bicyclic ketone 14 (bis-nor-Wieland–
Mieschler ketone) in up to 77% ee.
R1
2
P R
O R 3 O O
O i. C6H6, 80 °C O R1
2
Br P R O
ii. aq. K2CO3 R3 60–97%
O 40 °C O
12 13 14
1 77% ee
R = anisyl, R2 = Cy, R3 = Me
Scheme 4
Desymmetrization has also been realized by the reaction of an achiral stabilized ylide with a
symmetrical substituted cyclohexanone in the presence of a chiral host. This approach provides
the dissymmetric alkenes in up to 57% ee <1990JOC3446>. The use of a chiral catalyst in an
asymmetric Wittig reaction was first reported by Bestmann and Lienert in 1970 <1970CZ487>.
Among all the chiral acids investigated as catalysts, they found that mandelic acid was the most
effective. However, the levels of induction were low.
1.16.1.3 Arsonium Ylides

In general, arsonium ylides are markedly more reactive than their phosphorus counterparts. Like
phosphonium ylides, they may be classified according to their reactivities as stabilized, semista-
bilized and nonstabilized ylides. Stabilized ylides bear on the ylidic carbon atom at least one
electron-withdrawing group such as COR, CO2R, or CN, semistabilized ylides are functionalized
with aryl or vinyl groups, and nonstabilized ylides are unsubstituted or substituted by alkyl
groups. Stabilized ylides are inert to air and water at room temperature and isolable. Arsonium
ylides differ in behavior from their phosphorus counterparts in that they can react with carbonyl
compounds to give either alkenes or epoxides in Wittig-type or Corey-type reactions. The type of
product formed depends on the nature of the substituent on both the ylidic carbon atom and the
arsenic atom, and of solvent and base effects. The general pattern which has emerged is that
stable arsonium ylides provide alkenes whilst nonstabilized arsonium ylides give epoxides. The
chemistry of arsonium ylides has been extensively investigated <1987CSR45, 1996CR1641,
2001MI26>.
1.16.1.3.1 Comparison of stabilized, nonstabilized, and semistabilized ylides

Arsonium ylides stabilized by COR, CO2R, and CN groups or cyclopentadiene rings react well
with both aldehydes and ketones in Wittig-type processes to afford alkenyl products with
predominantly (E)-geometry <1982AOC115>. More complex stabilized arsonium ylides such
as -halo ylides react with aromatic aldehydes to give -halo ,-unsaturated esters, ketones,
and nitriles in excellent yields and (Z)-selectivities <1989SC2639, 1996SC677>. Similarly, the
reaction has been applied to the preparation of -phenylselanyl ,-unsaturated esters, ketones,
and nitriles from the corresponding -phenylselanyl arsonium ylides and aldehydes
<1995JCS(P1)95, 2002SC1775>.
Asymmetric Wittig-type olefination of chiral arsonium ylides containing 8-phenylmenthol as

the chiral auxiliary has been much less investigated compared to asymmetric reactions of phos-
phorus ylides. These arsonium ylides give diastereoselectivities of 47–80% in conversions of
4-substituted cyclohexanones to dissymmetric alkenes <1997TA1979>. Under the reaction con-
ditions investigated, the corresponding phosphonates containing the same chiral auxiliary gave
lower selectivity. More recently, the first atroposelective Wittig-type reaction of axially chiral
2-formyl-1-naphthamides with chiral arsonium ylides containing the same chiral auxiliary has
been reported. The olefination gives (E)-alkenes in excellent yields and in up to 88:12 diastereo-
meric ratio <2001TL2541>.
In contrast to their phosphorus counterparts, stabilized arsonium ylides such as 1-(methoxy-
carbonyl)methyl- or 1-(trimethylsilyl)methyltriphenylarsonium ylides react with ,-unsaturated
esters <1982AOC115> and ,-unsaturated ketones <1984TL4425> to give cyclopropanes
stereoselectively. Crotonylarsonium ylides react with 2H-pyran-5-carboxylates to give divinyl-
cyclopropanecarboxylates <1997JCR(S)130> and with ,-unsaturated aldehydes or ketones to
give 1,3-cyclohexadiene-1-carboxylates and/or acyclic trienes <1997SL126>.
The reactions of nonstabilized arsonium ylides are similar to those observed for the sulfur ylides.
Thus, simple nonstabilized ylides on treatment with aldehydes and ketones generally give good
yields of (E)-epoxides. For example, the ylide derived from an arsonium tetrafluoroborate 15 gives
epoxides with >99% (E)-selectivity in reactions with aldehydes (Equation (8)), and give good yields
of trisubstituted epoxides on reaction with 4-alkylcyclohexanones (Equation (9)) <1981JA1283>.
BF4 KHMDS, THF/HMPA

O
CHO –78 °C to rt ð8Þ
( )5 Ph3As ()
5
76%
15 (E ):(Z ) 98:2
O O
BF4 KHMDS, THF/HMPA
–78 °C to rt ð9Þ
Ph3As
t 66%
Bu 15 But
Semistabilized arsonium ylides are intermediate in behavior between stable and reactive ylides. It
means that substrate, base, counterion, and solvent are important factors in determining the outcome
of their reactions. Reactions with aldehydes and ketones may provide alkenes and/or epoxides, with
solvent effects playing an important role. For example, allylic arsonium ylides in reactions with
aldehydes and ketones give only vinylic epoxides in high yields when run in THF, whereas pure
diene is formed when HMPA is used as co-solvent <1983SC1193, 1991TL2913>. Highly stereoselec-
tive (E)-alkenation has been achieved through the reaction of a dibenzylic diphenylarsonium ylide
with aldehydes, and a significant increase of (E)-selectivity is observed in the presence of HMPA
<1989TL5263>. Similarly, reactions of the benzylic (2-oxyethyl)diphenylarsonium ylide with alde-
hydes are completely (E)-selective when HMPA is used as co-solvent <1990AG(E)1454>. -Halo-
substituted benzylic triphenylarsonium ylides have been prepared and used in situ to produce vinylic
halides in good yields but with moderate (E)/(Z)-selectivity <1998SC633>.
The formation of ,-unsaturated epoxides from allylic arsonium salt 16 and aldehydes has
been exploited in the synthesis of an (E)-vinylic epoxide, a key intermediate in a stereoselective
synthesis of castasterone <1996T5525>. These reactions are sensitive to the reaction conditions
and the selectivity for the formation of either epoxides or alkenes is dependent upon the choice of
base (LiHMDS or KHMDS) used for generation of the arsonium ylide. Thus, in reactions with
aldehydes, the lithium-generated allylic arsonium ylide gives epoxides, whereas the potassium-
generated allylic arsonium ylide gives dienes (Scheme 5) <1989JOC3229>.
It appears, at least in the case of semistabilized arsonium ylides and possibly for others also, that control
over the product can be achieved by suitable choice of substituents on arsenic, and of solvent and base.
(i) Mechanism
The behavior of arsonium ylides appears to be intermediate between that of sulphonium and phos-
phonium ylides. The energetic driving force to generate an arsenicoxygen bond is not as strong as
that to form a phosphorusoxygen bond, so that there is not the same compulsion to alkene formation
in the case of arsonium ylides, allowing the alternative epoxide pathway to compete (Scheme 6).
OMOM
KHMDS, THF, –65 °C
76%
OMOM
OMOM
BF4
CHO
Ph3As +
16 OMOM
OMOM
O
LiHMDS, THF, –65 °C
81%
OMOM
Scheme 5
R1 R1 R1
R3As R1 R1 R2
R3As R1 R3As R1 R3AsO
– O R2 O R2 R1 R2
O R2
R2 R2 R2
R1
R3As
1 R1 R1 R1 R1
+ R R3As R1 R1
R3As + R3As
O R2 O R2 O
–
R2 O R 2 R2
R2 R2 R2
Scheme 6
Several observations suggest that the first step, which is slow and reversible, is the rate-
determining step and that in alkene formation the reaction goes directly to a four-membered
ring transition state without the intermediate formation of a betaine. Formation of an epoxide
must involve an intermediate betaine which reacts further by intramolecular displacement of an
arsine. The electrons in the arseniccarbon bond are displaced in an opposite direction in the two
mechanisms. In alkene formation, displacement of electrons occurs away from the arsenic atom
and in epoxide formation displacement of electrons is towards the arsenic atom. The change in
pathway, depending upon the nature of the substituents at arsenic, could be associated with this;
electron-donating substituents on arsenic should assist the displacement of the electron away from
arsenic and favor alkene formation <1977AG(E)487>. For similar reasons, electron-withdrawing
substituents on the ylide carbon atom should favor alkene formation.
1.16.1.4 Stibonium Ylides

No significant progress has been made in this area since the appearance of chapter 1.16.1.4 in
<1995COFGT(1)719>. The chemistry of stibonium ylides has been reviewed recently
<2001MI53>.
1.16.1.5 Bismuthonium Ylides

No significant progress has been made in this area since the appearance of chapter 1.16.1.5 in
<1995COFGT(1)719>. The chemistry of bismuthonium ylides has been reviewed recently
<2001MI105>.
1.16.1.6 P(O)-Activated Alkene Formation

When compared to the Wittig reagents, the P(O)-activated reagents offer a number of advantages,
although the lesser stabilizing effect of the neutral phosphonyl group means that electron-withdrawing
-substituents are required at the carbanion center before preparative yields of alkenes can
be obtained. These advantages include: (i) greater nucleophilicity than the corresponding phos-
phonium ylides such that they react with both aldehydes and ketones under mild conditions;
(ii) the phosphinic and phosphoric acid derivatives obtained from P(O)-activated syntheses are
water-soluble, so separation from the alkene is easily achieved; (iii) considerable control of
stereochemistry is possible by change of reaction conditions to yield the alkene with either the
(E)- or the (Z)-geometry. The P(O)-activated reagents are divided into two groups, the phosphi-
noxy reagents introduced by Horner and co-workers in 1958 <1958CB61> and the phosphonate
reagents introduced by Wadsworth and Emmons in 1961 <1961JA1733> (Scheme 7). In the
literature the reaction using phosphinoxy reagents is called Horner–Wittig reaction, while the
reaction using phosphonate reagents is called Horner–Wadsworth–Emmons (HWE) reaction.
Both of them may be regarded as useful supplements to the Wittig reaction.
R1
O O C O O
Base R2 R1 H
R2P EWG R2P EWG + R2PO–
R2 EWG
R = Ph, EtO EWG = e.g., vinyl, alkoxycarbonyl, acyl, cyano, etc.
Scheme 7
The scope, mechanism, and stereochemistry of these types of reactions have been extensively
reviewed by Boutagy <1974CRV87>, Wadsworth <1977OR73>, Walker <B-1979MI001>,
Maryanoff <1989CRV863>, Kelly <1991COS(1)761>, Johnson <B-1993MI004>, Vedejs
<1994TS1>, Rein <1996ACS369>, Clayden <1996AG(E)241>, Nicolaou <1997LA1283>, Silveira
<2001PS(171/172)309>, Minami <2001S349>, Rein <2002S579>, Savignac <B-2003MI010>.
The accepted mechanism for P(O)-activated alkene synthesis is closely analogous to that of the
Wittig reaction. The selectivity is a result of both kinetic and thermodynamic control upon the
reversible formation of the erythro- and threo-adducts and their decomposition to the correspond-
ing (Z)- and (E)-alkenes, respectively. Some recent sophisticated quantum mechanical calcula-
tions, realized in systems with <1999JOC6815> or without <1998JOC1280, 1999JOC5845>
lithium countercation, indicate that the reaction occurs with the spontaneous complexation
between lithium enolate and aldehyde and the formation of hydrogen bonds between aldehyde
hydrogen and enolate or phosphonate oxygen, followed by addition, oxaphosphetane formation,
pseudorotation, PC bond cleavage, and then CO bond cleavage (Scheme 8). The observed
predominance of (E)-alkenes is attributed to a reversible addition step followed by a slow, rate-
determining, oxaphosphetane formation reaction. The development of an understanding of the
various factors affecting these equilibria, including the effect of changing the base, solvent,
temperature, and the nature of the associated cation has led to successful attempts to control
the stereochemical outcome in P(O)-activated alkene formation.
1.16.1.6.2 Phosphonate-stabilized carbanions (Horner–Wadsworth–Emmons reaction)

The greater reactivity of phosphonate-stabilized carbanions over the corresponding Wittig
reagents in alkene-forming reactions is ascribed to the fact that the phosphonyl group has a
lower net positive charge and accordingly provides less stabilization for the adjacent carbanion by
valence shell expansion. Globally, the phosphonate-stabilized carbanions are more nucleophilic
reagents than the corresponding Wittig reagents. Thus, ketones that react sluggishly, or not at all,
O
δ+
Li δ+
O O O Me H
MeO Complexation Li Addition
P O O
MeO δ– OMe Me H (H-bonds) MeO
P
H MeO δ– OMe
H
Li Me Me
OMe O
MeO H Oxaphosphetane
P LiO O H Pseudo-
MeO
O H
MeO OMe formation MeO P CO 2Me rotation P CO2Me
H MeO
OMe H OLi H
O
Me
MeO O H C–O bond MeO O Me H
P–C bond H
P P
cleavage MeO cleavage MeO OLi
O H CO2Me
Li O OMe
Scheme 8
with Wittig reagents stabilized by an alkoxycarbonyl or acyl group are smoothly converted into
the corresponding alkenes by their phosphonate counterparts under mild conditions. Due to a
steric effect, ketones are generally less reactive toward phosphonate carbanions than aldehydes,
and usually require much more vigorous conditions for alkene formation.
A prerequisite for the use of phosphonate carbanions in alkene synthesis is the presence of an
electron-withdrawing -substituent (Ar, vinyl, OR, SR, NR2, CO 2 , CO2Et, COR, CN,
P(O)(OR)2), at the carbanion center to promote the spontaneous decomposition of the stabilized
-hydroxyphosphonates. When the -hydroxyphosphonates do not contain an electron-withdrawing
or -stabilizing group, there is no low-energy pathway for collapse to the alkene.
Despite early discouraging results in converting nonstabilized -hydroxyphosphonates to
alkenes, the reaction has recently been re-investigated. Thus, it has been shown that nonstabilized
-hydroxyphosphonic acid monomethyl ester 18, prepared from benzyl methyl 2-phenylethylpho-
sphonate 17 and diethyl ketone, undergoes dehydration with diisopropylcarbodiimide (DIC) to
generate an oxaphosphetane, which is converted to alkene 19 and meta-phosphate by a retro-
[2+2]-fragmentation pathway (Scheme 9). The overall sequence can be extended to aliphatic and
aromatic aldehydes and executed on multigram scale in 45% overall yield <2003JOC1459>.
O O
BnBr, Cs2CO3 i. BunLi, THF, –78 °C
P OH P OBn
Ph OMe MeCN, reflux, 48 h Ph OMe ii. Et2CO, –78 °C
82% 17 iii. AcOH, –78 °C to rt
62%
O O
P OBn P OH
Ph OMe H2, Pd/C Ph OMe Ph
DIC
Et OH EtOH, rt, 16 h Et OH CHCl3, rt, 2 d Et Et
Et Et 68%
18 19
Scheme 9
(i) Formation of (E)-alkenes

The use of phosphonate carbanions favors the formation of (E)-alkenes when groups capable
of conjugating with the incipient double bond are present. Phosphonate carbanions are the
reagents of choice for the preparation of (E)-,-unsaturated carbonyl compounds, especially

in natural product multistep syntheses where they are used at various stages. For example,
dialkyl 1-(alkoxycarbonyl)methylphosphonates have been used in the synthesis of (E)-Royal
Jelly <1975JIC538>, of endiandric acid C and aurodox <1997LA1283>. Extensive use of the
(E)-stereochemistry has been made when the conjugation is extended by unsaturation. The
dehydro derivative of the C18 juvenile hormone of cecropia has been synthesized in 78% yield
from the condensation of diethyl 3-(methoxycarbonyl)-2-methyl-2-propenylphosphonate with
aldehydes <1971TL1821>. A prominent example can be seen in Nicolaou and co-workers’
landmark total synthesis of amphotericin B4, in which three olefination reactions were used to
construct the polyene section <1988JA4660, 1988JA4672, 1988JA4685, 1988JA4696>. The
first two employed diethyl 5-(ethoxycarbonyl)-2,4-pentadienylphosphonate leading to an acyc-
lic hexenal. Similarly, dimethyl 2-methyl-3-(2-methyl-5-oxazolyl)-2-propenylphosphonate 20 is
the key reagent for introduction of the (E),(E),(E)-triene 21 in the partial synthesis of rhizoxin
(Equation (10)) <1998JOC6952>, while dimethyl 3-(4-methoxy-5-methyl-2-oxo-2H-pyranyl)-
2-propenylphosphonate represents another valuable reagent used in the convergent synthesis
of (+)-asteltoxin <2003JA5415>.
O
O
OPMB
O O
O
H ð10Þ
OMe KOBut, DME, 0–60 °C OPMB
N
+ O
55%
N O
O
P(OMe)2 (E ) 21 MeO
20
However, significant loss of (E)-selectivity occurs when steric interactions in the product become
serious <1968BCJ1252, 1968CC1699, 1968CJC2225>. For example, in the reaction of diethyl
1-(ethoxycarbonyl)alkylphosphonates with aldehydes <1968CC1699>, only (E)-ester is formed when
the -substituent R1 = H. With the size of R1 increasing together with the branching of the alkyl
group of the aldehyde, the (Z)-ester becomes the major product. Loss of (E)-stereoselectivity does
occur in condensation with unsymmetrical ketones <1965IZV1504, 1967JA5292, 1968JCS(C)543,
1969AJC2145, 1971ABC1116, 1973ACS1401>. Thus, in the first step of the synthesis of racemic
,-carotene <1973ACS1401>, condensation of -ionone with diethyl 1-(methoxycarbonyl)methyl-
phosphonate is not highly stereoselective and a mixture of (E)- and (Z)-isomers is obtained in the
ratio 65:35. Similarly, during the synthesis of the juvenile hormone isolated from the giant silkworm
moth Hyalophora cecropia <1969AJC1737, 1969AJC2145>, treatment of the methyl ketone with
sodium dimethyl 1-(methoxycarbonyl)methylphosphonate in DME led to a mixture of the (E),(E)-
and (Z,E)-ester in the ratio 60:40. (E)-Selectivity can be maximized by increasing the size of the
substituents on the phosphonate group. Homologation of the 2-O-(methoxymethyl)-2-hydroxyhex-
adecanal using diethyl 1-(ethoxycarbonyl)methylphosphonate and LiBr–Et3N furnishes the unsatu-
rated ester with moderate stereoselectivity ((E):(Z) = 7:1), but when diisopropyl 1-
(ethoxycarbonyl)methylphosphonate is used, the (E):(Z)-selectivity is increased to 36:1 (Equation
(11)) <2000JOC7618>. The best (E):(Z)-selectivities (up to 120:1) are obtained from diisopropyl 1-
(ethoxycarbonyl)methylphosphonate using t-BuOK in THF at low temperature <1981T3873,
1982JA1109>.
O
R' LiBr, Et3N, THF, rt R' CO2Et
O (RO)2P CO2Et
R = Et, (E ):(Z ) 7:1 ð11Þ
OMOM OMOM
R = Pri, (E ):(Z ) 36:1
85–86%
The same effect is observed with cyanophosphonates, which are usually less stereodemanding
than their alkoxycarbonyl counterparts and produce mixtures of (Z)- and (E)-alkenes in the range
1:4 to 2:1 <1980SC509, 1980ZOB76, 2001JOC1200>. For example, in the reaction with -ionone,
sodium di-isopropyl cyanomethylphosphonate is found to be more (E)-selective ((Z):(E) = 18:82)
than the corresponding diethyl ester ((Z):(E) = 35:65) <1980SC509>. Choice of solvent can also
play a role in determining the final product ratios. In benzene, the reaction of diethyl cyano-
methylphosphonate with 3,3-dimethylcyclohexanone is (E)-selective, whereas in DMF or DMSO,
a moderate level of (Z)-selectivity is obtained.
The formation of ,-unsaturated esters and nitriles has been developed in less traditional
methods. The search for neutral and mild reaction conditions for generating phosphonate
carbanions has promoted the use of simple systems based on the association of an amine and a
lithium salt. Thus, LiCl–DBU, LiCl–DEPA, and LiCl–Et3N in dry MeCN or THF are effective
combinations to generate active species in the presence of base-sensitive substrates or reagents
<1984TL2183, 1995S920, 2000JOC7618, 2002OL3157>. Under these conditions a solid-phase
Horner–Wadsworth–Emmons reaction has been developed to generate ,-unsaturated amides.
Thus, polymer-bound diethyl 1-(acetamidocarbonyl)methylphosphonate was reacted with alde-
hydes, LiBr, and Et3N to give the resin-bound unsaturated amides <1994JOC658,
1999CRV1549>. The liquid–liquid two-phase system using aqueous NaOH and C6H6,
CH2Cl2, or CHCl3 has been employed to prepare (E)- and (Z)-2-methoxycinnamonitrile and
3-cyclohexyl-2-propenenitrile on large scale in excellent yields <1988JMC37, 1992CPB2391>.
Several other solid–liquid two-phase systems have been described, and the system using K2CO3
in water <1986TL1577, 1988TL477, 1996T9759> or in toluene <1994JA3367, 2000JOC6293>
appears as the most promising (Scheme 10).
O
N (EtO)2P CO2H N
SePh SePh
OH CH2Cl2, CDC, rt O
H O H O
88% O
P(OEt)2
O
K2CO3, 18-c-6 N
SePh
PhMe, rt, 4 h O
95% H
Scheme 10
Recently, the highly stereoselective (E)-olefination has been observed in the synthesis of
alkenylated chromium carbonyl complexes having nonlinear optical properties, by using
Cr(CO)3-complexed dimethyl benzylphosphonates and heteroaromatic aldehydes <1997TL1025,
1999OM5066>. Analogously, an extensive use has been made of the exclusive (E)-configured
double bond in the synthesis of poly(phenylenevinylene) dendrimers from new 1,3-bis- or 1,3,5-
tris[(diethoxyphosphonyl)methyl]benzene and aromatic aldehydes <2001JOC5664, 2003JOC832>.
(ii) Formation of (Z)-alkenes

Much of the research effort this decade has centered around the development of methods for
obtaining almost pure (Z)-alkenes from the reaction of phosphonate carbanions with aldehydes.
It was first discovered that incorporation of the phosphonyl group into a five-membered
<1978T997, 1991TL1317> or six-membered <1978T997, 1991SL517> ring, promotes the
(Z)-alkenes. The highest (Z):(E) ratio of alkenes 23 was obtained with the use of 1,3-dimethyl-
2-oxo-1,3,2-diazaphospholidines 22 (Scheme 11) <1991TL1317>. This high (Z)-selectivity is attrib-
uted to a rapid closure to the pentacoordinate intermediate owing to release of strain in the five-
membered ring coupled with an increase in the rate of elimination relative to the equilibration
of intermediates.
Me Me Me R1
N N N OEt
LDA (2 equiv.) ClCO2Et
P R1 P R1 P
N O THF, –70 °C N O Li THF, –70 °C NO O
Me Li
Me Me
22
Me
R2CHO H R1 N OLi
+ P
THF, –70 to 0 °C R2 N O
CO2Et
(Z ):(E ) 90:10 to 92:8
Me
65–80% 23
R1 = H, Me, Et, Pr n, n-C5H11
Scheme 11
A decisive modification was introduced in 1983 by Still and Gennari, who obtained high levels
of (Z)-selectivity with the use of bis(2,2,2-trifluoroethyl) 1-(methoxycarbonyl)methylphosphonate
24 in reaction with aldehydes (Equation (12)) <1983TL4405>. The improved (Z)-selectivity is
attributed to the electron-withdrawing effect of the trifluoromethyl group that accelerates the
elimination of the initially formed -hydroxyphosphonate adduct such that equilibration to the
thermodynamic (E)-alkene is severely restricted. Factors that accelerate the elimination step tend
to diminish the reversibility of the aldol step thereby favoring (Z)-products.
O
OBz (CF3CH2O)2P CO2Me OBz O OMe
H H H H
O O 24 O ð12Þ
H KHMDS, THF, 18-c-6, –78 °C
92% 10/1 (Z )/(E )
The magnitude of selectivity is dependent on the base and solvent used. KHMDS with 18-crown-6
(18-c-6) in THF appears to be the most effective combination by increasing the rate of elimination
relative to equilibration due to minimal complexation of the intermediate with its counterion.
Moreover, the conditions of Masamune–Roush <1984TL2183> or Rathke–Nowak
<1985JOC2624> (lithium or magnesium halides, 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU), Et3N,
i-Pr2EtN) can be used to achieve (Z)-selective olefination of base-sensitive aldehydes <1990JOC128,
1997T1707>. Still’s approach has been applied to a variety of carbanion stabilizing groups other
than esters, including cyano, which normally exhibits poor selectivity <1988TL419>. Still’s method
has been extensively used in total synthesis <1988JA2248, 1988JA3929, 1988JOC4274,
1995CRV2041, 2001OL213, 2002JCS(P1)999, 2003EJO2193, 2003AG(E)2711>.
However, the studies of Marshall and co-workers showed that an -alkyl substituent on the
phosphonate moiety can significantly alter the (Z)-selectivity of this type of reagent 25 (Equation (13))
<1986JOC1735>. Thus, it has been found that the (Z)-selectivity seems unaffected by
-substitution with a methyl group <1983TL4405, 1987JOC3883, 1987TL3075, 1988H(27)2077>,
but it is seriously compromised by long-chain -alkyl substituents <1986JOC1735, 1990JOC128,
2001OL1685, 2002OL1023>.
O
(CF3CH2O)2P CO2Et
25
CO2Et ð13Þ
TBDPSO CHO NaH, THF, rt TBDPSO
8/1 (Z )/(E )
More recently, the diphenyl 1-(ethoxycarbonyl)methylphosphonate 26, under Still’s conditions,

has appeared as effective as the bis(2,2,2-trifluoroethyl) 1-(methoxycarbonyl)methylphosphonate
for the synthesis of (Z)-,-unsaturated esters <1995TL4105>. Thus, condensation of diphenyl
1-(ethoxycarbonyl)methylphosphonate with aldehydes using NaI/DBU/THF gives good to excellent
yields of (Z)-,-unsaturated esters in high stereoselectivity <2000JOC4745>. On the other hand,
condensation of ring-substituted diaryl phosphonates 27 with aldehydes seems less affected by
-substitution. By a proper choice of base (Triton B, t-BuOK, NaH) and temperature, the
reactions of -substituted diaryl phosphonates 28 with several types of aldehydes are highly
(Z)-selective (Equation (14)) <1997JOC1934, 1998JOC8411, 2002OL1023>.
R3 R4
O O
(PhO)2P CO2Et R2 O P CO2Et
26 2
R5 R1
27
R1 = H, Me, Et, Bun
OMe
O
O P CO2Et
28
2 CO2Et ð14Þ
TBDPSO CHO NaH, THF, rt TBDPSO
(Z ):(E ) 34:1
91%
1.16.1.6.3 Phosphoryl-stabilized carbanions (Horner reaction)

The first olefinations using phosphinoxy reagents were described by Horner in 1958
<1958CB61>. They involved treating benzyldiphenylphosphine oxide with a potassium base
(t-BuOK) and then adding a carbonyl compound to give in situ an alkene in one step <1959CB2499,
1962CB581, 1964PAC225>. By contrast, when using lithium bases, the same reaction can be
stopped at the intermediate adduct and the -hydroxyphosphine oxide 30 isolated before elimina-
tion occurs <1964TL2467>. In this significant discovery, Horner showed that the -hydroxypho-
sphine oxide intermediates 30 were stable enough to be isolated, usually as crystalline compounds,
and consisted of a mixture of diastereomers that could be separated into a minor isomer with the
erythro-configuration 31 and a major isomer with the threo-configuration 32. Assignment of
configuration was based on subsequent decomposition of the adducts from the reaction of
benzyldiphenylphosphine oxide and benzaldehyde by treatment with phenyllithium or lithium
hydride to give (Z)- and (E)-1,2-diphenylethene, respectively, by syn-elimination of diphenylpho-
sphinic acid (Scheme 12).
O
H Ph
Ph2P Ph
O Ph
HO Ph
O Ph2P Ph H (Z )
i. PhLi
Ph2P Ph 31 erythro
ii. PhCHO
HO Ph O
H Ph
30 Ph2P Ph
HO Ph Ph
H
(E )
32 threo
Scheme 12
The fact that the Horner reaction can be stopped at the first stage and the intermediate
adducts isolated and separated into pure diastereomers provided the basis for the use of
phosphine oxide anions to form alkenes of specific geometry <1996AG(E)241>. Compounds
containing the Ph2P(O) group are very often crystalline. This property is important for the
synthetic application of stereoselective reactions because it allows the separation and purifica-
tion of stereoisomers by crystallization <1985JCS(P1)2307>. Because of the electronegativity
of the Ph2P(O) group, its stereochemical disposition relative to other polar groups in a
molecule dominates the overall polarity of the molecule. This aids the separation of diaster-
eomers by flash chromatography <1985JCS(P1)2307>. Recently, the role of the Ph2P(O)
group has been reviewed, showing the power of this group to control the stereochemistry of
alkenes, and to produce ‘‘on demand’’ either stereoisomer in high stereochemical purity
<1996AG(E)241>.
(i) Stereoselective formation of (E)- and (Z)-alkenes

Metallated alkyldiphenylphosphine oxides bearing functional groups in the -position (R1 = benzyl,
allyl, OR, SR) undergo a one-step Horner reaction with aldehydes and ketones without
isolation of intermediates. As for the Horner–Wadsworth–Emmons reaction, the one-step Horner
reaction gives selectively (E)-alkenes. The intermediate adduct decomposes easily because the
functional group in the -position provides conjugation or stabilization of the negative charge
and lowers the activation energy for the elimination. The (E)-selectivity is a result of the
reversibility of the addition to a carbonyl compound of an alkyldiphenylphosphine oxide bearing
an anion-stabilizing group in the -position. This reversibility allows interconversion of the two
diastereomers of the adduct, and faster elimination from the threo-adduct means that the
(E)-isomer of the product alkene is formed selectively.
The use of the one-step Horner reaction has been focused with success on the design and
synthesis of (E)-polyenes and especially of vitamin D and its analogs. This reaction is quite
appropriate, since Horner reversal, in conjunction with fast elimination, serves to increase the
proportion of (E)-product. The strategy of synthesis is based on the Lythgoe-type coupling
approach <1976JCS(P1)2386, 1978JCS(P1)590, 1980CSR449, 1991TL4643, 1992TL2937,
1995CR1877, 1997JOC3299, 2000EJO2755, 2001T681, 2002JMC1723, 2002JMC3366,
2003OBC257>. Thus, the reaction of the 25-hydroxy-Grundmann’s ketone 33 with the
lithiated carbanion derived from the (Z)-allylic diphenylphosphine oxide 34 gave compound
35 containing the newly formed double-bond assuming the natural (E)-geometry (Equation (15)).
An advantage of this high-yielding coupling approach is its convergency <1995CR1877>. Recently, a
solid-phase synthesis of the vitamin D system, obtained by coupling of the solid-supported ketone
with modified allylic phosphine oxide has been described. <2001JA3716>.
OH
O
OTMS PPh2 H
H
i. BunLi, THF, –78 °C ð15Þ
+ H
ii. Deprotection
H TBDMSO OTBDMS
O
33 34 35
HO OH
In the Horner reaction, the choice of base is often critical. For example, in the total synthesis of
()-milbemycin 3 38 it has been found that in the reaction of the (E)-allylic diphenylphosphine
oxide 36 carbanion with aldehyde 37, the alkene stereochemistry depended profoundly on the
choice of the base. In this case, NaHMDS effected the olefination almost quantitatively to give
the expected (E),(E)-diene 38 in a 7:1 ratio with its (Z),(E)-isomer (Equation (16))
<1986JA2662>. The effects of solvents on the type of product formed have been observed in
the reactions of allyldiphenylphosphine oxide with aldehydes. Thus, in the synthesis of natural
(+)-digitoxigenin, it has been demonstrated that when (E)-2-butenyldiphenylphosphine oxide was
treated with n-BuLi in THF, the presence of HMPA as co-solvent may be crucial. When the
HMPA is used, the desired (E),(E)-1,3-pentadienyl building block is cleanly isolated with high
stereoselectivity <1987T723, 1996JA10660>.
H O
O O H O
O
Ph2P
CHO
CO2Me
OTBDMS
OTBDMS
37 CO2Me ð16Þ
Base, THF
OMe
Base (E ):(Z ) Yield (%)
36 OMe
NaH 7:1 15
KHMDS 3:2 74 38
NaHMDS 7:1 >90
Change of base is often advantageous. For example, synthesis of the mutagenic (S)-3-(1,3,5,7,9-
pentaenyloxy)propane-1,2-diol with specific (E)-geometry has been carried out with LDA in the
initial addition followed by the use of t-BuOK to effect elimination <1984CC349>. Similarly,
(3Z,6E)--farnesene 41a has been prepared from MVK and 4,8-dimethyl-3,7-nonadienyldiphe-
nylphosphine oxide 39 with LDA. The intermediate -hydroxyphosphine oxides 40a and 40b have
been treated with NaH in DMF at 50 C to induce elimination of sodium diphenylphosphinate
(Scheme 13) <1995JOC6211>. The same approach, using two different bases (LDA then
NaH), has been employed in the synthesis of ()-16-oxa-2,3-oxidosqualenes <1995TL5719>.
O O O
H H
PPh2 PPh2 PPh2
i. LDA, Et2O, 0 °C
+
ii. MVK, Et2O
OH OH
–78 °C to 25 °C
65%
39 40a 40b
NaH
+
DMF, 50 °C
(Z ):(E ) 4:1
41%
41a 41b
Scheme 13
It is remarkable that most of these one-step reactions specifically make use of the particular
properties of the allylic phosphine oxides to prepare dienes and polyenes. These reagents are
chosen because the new double bond is usually formed with (E)-selectivity and the stereochem-
istry at the formerly allylic olefin group is retained.
In general, the one-step Horner reaction does not give pure (E)- or (Z)-alkenes. To obtain
stereochemically pure products, the Horner adducts prepared from stabilized lithium derivatives
of phosphine oxides (R1 = benzyl, allyl, OR, SR) are quenched below 50 C under carefully
adjusted conditions and isolated before being subjected to elimination <1994JCS(P1)1529>. The
use of a lithium base is crucial to this control because it slows down the attack of the Ph2P(O)
electrophile. The diastereomeric -hydroxyphosphine oxides 42a and 42b, preferentially formed
in a ratio of 85:15 erythro:threo, are separated by chromatography or crystallization
<1985JCS(P1)2307>. Treatment of each pure diastereomer with a sodium or potassium base in
a dipolar aprotic solvent (NaH/DMF or KOH/DMSO) <1984JCS(P1)243> generates a nucleo-
philic oxyanion leading to a single stereoisomer by syn-elimination of sodium or potassium
diphenylphosphinate <1981JOC459, 1985JCS(P1)2307, 1989JOC747, 1989JA1157>. The elimina-
tion is, in general, 100% stereospecific, giving pure (Z)-alkenes from pure erythro--hydroxyphosphine
oxides 42a, and (E)-alkenes from pure threo--hydroxyphosphine oxides 42b. This stepwise sequence
has been called by Clayden and Warren the ‘‘stereocontrolled Horner–Wittig reaction’’ (Scheme 14)
<1996AG(E)241>.
OH
R1 NaH, DMF R1
R2 R2
or KOH, DMSO
Ph2P
OH
R1 i. BunLi O 42b (E )
R1 Separation
R2 threo
2
Ph2P ii. R CHO
Ph2P OH
O
O R1 NaH, DMF
R2
NaBH4 or KOH, DMSO R1 R2
i. BunLi EtOH Ph2P
ii. R2CHO O O 42a (Z )
erythro
iii. Oxidation R1
R2
Ph2P
O
Scheme 14
Because of the erythro-selectivity of the Horner addition, this route is usually suitable only for
the synthesis of (Z)-alkenes. This methodology has been used with allyldiphenylphosphine oxides
to prepare dienes and polyenes in pure form <1979TL5043, 1986JA2662, 1988TL2401>. The
synthetic utility of this indirect method is demonstrated by the synthesis of the protected
(E),(E)-dienol 45a and (E),(Z)-dienol 45b, intermediates in the synthesis of some insect phero-
mones (Scheme 15). Thus, separation of the diastereomeric mixture of diol acetates (44a, 44b), formed
from hydroxyallylic phosphine oxide 43 and propionaldehyde, followed by hydrolysis, protection,
and elimination (NaH/DMF or KOH/DMSO) gave the protected dienols 45a and 45b
<1994JCS(P1)1529>. The optimal conditions for the elimination appear to be the use of pow-
dered KOH in DMSO at room temperature. Under these conditions, pure (Z)-isomer is obtained
free of the undesired (E)-isomer <2000S269>.
i. BunLi OAc
ii. EtCHO
HO HO
iii. Ac2O, Pyr
Ph2P Ph2P
43 O 44 O
OAc
i. HCl, MeOH
HO TrO
ii. TrCl
Ph2P iii. NaH, DMF
Separation 44a 45a
O
OAc
i. HCl, MeOH
HO TrO
ii. TrCl
Ph2P
44b iii. KOH, DMSO 45b
O
Scheme 15
Unfortunately, this stereospecificity is compromised when conjugating or anion-stabilizing

groups are present alpha to the phosphorus <1984JCS(P1)243>, in which case the increased
rate of Horner reverse reaction of erythro--hydroxyphosphine oxide may allow ‘‘stereochemical
leakage’’ to produce some of the more rapidly eliminating threo-diastereomer, and hence the
(E)-alkene <1983JCS(P1)2215, 1985JCS(P1)2307>. This leads to contamination of the (Z)-alkene,
often with predominating amounts of (E)-alkene.
The practical synthesis of (E)-alkenes by the Horner reaction requires a high-yielding route to
the threo-diastereomer. In a significant development, Warren <1986TL645, 1989TL601,
1996AG(E)241> introduced the selective reduction of -ketophosphine oxides to obtain both the
erythro- and threo-isomer adducts separately. Thus, reduction with NaBH4 in EtOH, which is
reported to favor threo-selectivity, followed by purification gives rise to the threo-diastereomer in
a yield of 80–95% (Scheme 14) <1983TL5293, 1985JCS(P1)2307, 1996AG(E)241, 2002SC947>.
1.16.1.6.4 Asymmetric Horner–Wadsworth–Emmons and Horner reactions

Several articles are available that review asymmetric reactions of phosphonates and phosphine
oxides, written by Rein <1996ACS369, 2002S579>, Li <1997CR2341> and Kolodiazhnyi
<1998TA1279>. Three types of asymmetric Horner–Wadsworth–Emmons reactions have been
achieved: desymmetrization of ketones, kinetic resolution of racemic carbonyl compounds, and
preparation of optically active allenes. As for the asymmetric Wittig reaction, the conversion of
4-substituted cyclohexanone to an axially dissymmetric alkene has been the key reaction by which
chiral phosphonate reagents have been evaluated. The first desymmetrization of 4-substituted
cyclohexanone using diethyl phosphonoacetate containing menthol as chiral auxiliary was reported
in 1962 <1962CI(L)2085>. In 1984, Hanessian and co-workers introduced a chiral phosphonamide
derived from N,N-dimethyl-1,2-diaminocyclohexane giving very high levels of asymmetric induction
(>90%) in the desymmetrization of 4-substituted cyclohexanones <1992TL7655, 1992TL7659,
1993JOC100>. Later, several easily available chiral phosphonoacetates derived from menthol 29
<1988TL1773, 1988TL1775, 1997LA2419> or benzopyrano-[4,3-c]-isoxazolidine <1996TL1077> as
chiral auxiliaries were introduced with success in reaction with symmetric ketones (Equation (17)).
O O
O O NaH O
+
(RO)2P THF Ph ð17Þ
O
But
29 Ph *
But
R = Me, Et, Pri, CF3CH2
Denmark and co-workers have described two types of chiral phosphonates, an oxazaphos-
pholane and an oxazaphosphorinane, both containing carbon stereocenters and a stereogenic
phosphorus center, and demonstrated their utility in asymmetric Horner–Wadsworth–Emmons
reactions <1992JA10674>. A chiral phosphinoxy reagent containing 8-phenylmenthol as chiral
auxiliary has been compared to the phosphonate analog <1994CC2167>.
As for the Wittig reaction, it has been demonstrated that promising levels of enantioselectivity could
be reached in reaction between a phosphonate, a 4-substituted cyclohexanone and a chiral host. For
example, chiral bases <1997CPB753>, chiral ligands <1998AG(E)515> and chiral catalysts
<1998TL2997> can be used with success. The desymmetrization concept has been extended to meso-
diketones <1997TL8943> and meso-dialdehydes (Equation (18)) <1998JOC8284, 2000OL2611>.
TBDMS
O O O O O KHMDS, 18-c-6
+ (CF3CH2O)2P
H H O THF, –90 °C
Ph 83%
ð18Þ
TBDMS TBDMS
O O O O
H H
O O O O
Ph 98:2 Ph
The idea of differentiating two enantiomers of a racemic monocarbonyl compound, which

contains one or more stereogenic centers adjacent to the carbonyl group, by kinetic or dynamic
kinetic resolution, with a chiral phosphonate reagent was introduced in the 1970s <1975TL437>
and developed preparatively in the following years <1984JA5754, 1994JOC6887>. In the stan-
dard type of resolution, the racemic carbonyl compound needs to be present in twofold excess in
order to allow complete conversion of the chiral phosphonate reagent to a single product isomer.
For example, racemic (Z)-2,4-dimethylcyclohexanone and 3-tert-butylcyclohexanone could be
resolved by reaction with chiral phosphonamides with high enantiomeric purity. Similarly, the
chiral phosphonoacetate derived from mannitol was used to resolve racemic 2-benzylcyclo-
hexanone to give the corresponding chiral alkene in high ee <1993CC102>.
Kinetic resolution of a racemic aldehyde was not reported until 1994 <1994AG(E)556>. Rein
and co-workers then showed that acrolein dimer could be efficiently resolved by reaction with
bis(2,2,2-trifluoroethyl) phosphonoacetate containing 8-phenylmenthol as chiral auxiliary. By
utilizing the easy equilibration of the two enantiomers of -amino aldehydes, Rein and
co-workers effected the first dynamic kinetic resolution of racemic -amino aldehydes by reaction
with the same chiral phosphonate <1995AG(E)1023>. They also demonstrated the first applica-
tion of kinetic resolution of an aldehyde to natural product synthesis by the preparation of a
subunit of iejimalide A <1997TL6375>. For more detailed information and examples, the reader
is referred to the recent review by Rein and Pedersen <2002S579>.
1.16.2 C¼C BONDS BY CONDENSATION OF Si, B, Ge, OR Te FUNCTIONS
1.16.2.1 Silicon-mediated Alkenation: The Peterson Reaction

The Peterson olefination involving -silyl carbanions <1968JOC780> is considered to be the silicon
variation of the Wittig and related reactions. The Peterson reagents offer an interesting profile: (i) their
reactivity is high enough to allow reaction with both aldehydes and ketones; (ii) the reagents are
frequently more (Z)-selective than the corresponding stabilized phosphorus reagents; (iii) the silicon
reagents are available via several synthetic routes. One practical advantage of the Peterson reaction
depicted in Scheme 16 is that the disiloxane by-product, usually a volatile compound, is easily
removed from the alkene product. The different aspects of the reaction have been discussed in several
papers, especially by Ager <1984S384, 1990OR(38)1, 2001MI789, 2002CSR195>, Colvin
<B-1988MI003>, Barrett <1991SL764>, Kelly <1991COS(1)731>, Luh <1993S349>, Kawashima
<1996SL600>, Armstrong <B-1996MI005>, Bienz <1997C133>, Iorga <2001SL447> and
Savignac <B-2003MI009>.
TMS i. BunLi, TMEDA LiO TMS Ph

Ph + TMS–OLi
ii. PhCOPh 77% Ph Ph
Ph Ph Ph H3O+
Et2O/pentane
0–35 °C
TMS–O–TMS
Scheme 16
Evidence that the reaction mechanism of the Peterson olefination involves the formation of a
four-membered intermediate corroborates the theory that this olefination is the silyl variant of the
Wittig reaction. Mainly two types of mechanism have been postulated, as depicted in Scheme 17.
A stepwise mechanism involves the addition of the carbanion to the carbonyl compound
followed by silicon migration from carbon to oxygen to give a carbanion, which then loses the
siloxy anion to form the alkene. The elimination of the silanoxide is so rapid that no rotation
about the CC bond is observed during steps 2A and 3A, giving the same outcome as a concerted
elimination from the betaine. In the concerted mechanism, steps 1 and 2B proceed simultaneously,
leading to the concerted formation of an oxasiletanide intermediate. The elimination of
the silanoxide moiety would proceed in a concerted manner (step 3B). There is experimental
evidence in support of both stepwise and concerted mechanisms <1996SL600, 2002CSR195,
2002JOC7378>.
SiR3
R1 R2 Base R3 R4 R3 R4
Step 2A Step 3A R1 R3
1
O Step 1 R R2 R1 R2 – R3SiO
R4 O OSiR3 R2 R4
R3 R3Si
Betaine
R4
Step 2B O Step 3B
R3
R2 – R3SiO
SiR3
R1 Oxasiletanide
Scheme 17
1.16.2.1.2 Preparation of silicon-stabilized carbanions

The different methods of preparation of -silyl carbanions have been covered in detail
<2001MI481, 2001MI789>. One of the major drawbacks of the Peterson reaction was considered
for a long time to be the difficulties experienced in producing -silyl carbanions. The bases most
commonly used for the direct deprotonation of alkylsilanes are either alkyllithiums/PMDETA or
TMEDA <2001MI789>. Indirect methods include the addition of an organometallic species to a
vinylsilane <1970JA7424>, formation of organometallic reagents from -halosilanes by metal–
halogen exchange <1993TL2111, 1999TL33>, transmetallation <1976AG(E)161, 1980TL3451>,
displacement of a phenylsulfanyl group by lithium naphthalenide <1981TL2923,
1986JCS(P1)183> or 1-(dimethylamino)naphthalenide <2002JOC6711> and cleavage of a SiC
bond with alkoxide or fluoride anions <1973TL4193>.
The approaches offering a direct access to -hydroxysilanes have received a growing attention and
represent the most versatile protocols. They involve the reduction of -silyl carbonyl compounds with
complex hydrides <1974TL1133, 1999T1717>, the addition to -silyl carbonyl compounds of
organometallic reagents, alkyllithiums and Grignard reagents, <2000S1223, 2001TL2605>, allyltita-
nate <1997JOC6326> chromium <1995SL498> or zirconocene <1999TL9325>, and the regio-
specific ring-opening of ,-epoxysilanes with nucleophiles <1975JOC2263, 2001OL3955, 2001T549>.
However, when the alkyl hydrogen of alkylsilanes is further activated by another group
(Ar, vinyl, halogen, OR, NR2, SR, COR, CN, SiR3, P(O)(OR)2, sulfonyl), then direct metallation
is the method of choice to generate the -silylalkyl carbanion.
1.16.2.1.3 Methylenation reactions

The Peterson reaction is widely employed in the synthesis of methylene derivatives. (Trimethyl-
silylmethyl)lithium (TMSCH2Li) <1973TL4193> has not found application as a consequence of
its poor chemoselectivity, which reflects its propensity to behave as a strong base. (Trimethylsilyl-
methyl)magnesium chloride (TMSCH2MgCl), a commercial reagent, has proved to be more
advantageous for methylenation of aldehydes and enolizable ketones. The reagent is compatible
with sterically hindered ketones <1973TL3497> and with a variety of sensitive functionalities,
including the anomeric alkoxy group <1982JOC3548>, the thioacetal group <1988TL4521>, and
an aziridine moiety <1988JOC3391>.
Hindered ketones can also be converted into an ethylidene unit by the use of -(trimethylsilyl)-
vinyllithium, which is accessible by metallation of the corresponding bromo compound <1980JA2463>.
The same reagent has been used for the preparation of terminal allenes <1978JOC1526>.
A decisive and efficient modification of the Peterson methylenation involves the use of Lewis
acids. In 1987 Johnson and Tait reported that for carbonyl compounds with an easily enolizable
-hydrogen, the -hydroxysilanes can be prepared in very good yields when TMSCH2Li in THF
was added to anhydrous CeCl3 at 78 C followed by the addition of carbonyl compounds
<1987JOC281>. As usual, the resulting -hydroxysilanes were treated with either HF or KH
to afford the olefins in good yields (Scheme 18).
TMS
TMSCH2Li HF
O OH CH2
CeCl3 or KH
Scheme 18
For example, the enolizable model compound cyclopentanone is methylenated successfully by

this protocol in yields superior to those obtained with the related Wittig reactions
<1993JA3855>. In another example involving a polyfunctional substrate, the addition of an
excess of organocerium reagent prepared from TMSCH2MgCl to the keto diol 46 affords the
stable triol 47, without competing -deprotonation of the cyclohexanone. Further treatment with
concentrated H2SO4 converts 47 into the methylene derivative 48 (Scheme 19) <1995JOC833>.
Analogously, the combination TMSCH2MgCl–CeCl3 is useful for the preparation of allylsilanes
<1997JOC1578>.
TMS
O OH
OH TMSCH2MgCl OH OH
CeCl3 H2SO4
O THF, –78 °C to rt O THF, 40 °C, 7 h O
74% 98%
H OH H OH H OH
46 47 48
Scheme 19
Other additives such as TiCl4 have been used in conjunction with TMSCH2MgCl, but yields of
methylenated product are inferior <1981TL5031>. In addition, a variety of acetals have been
transformed in good yields into the corresponding olefins upon treatment with TMSCH2CuLiI,
prepared from TMSCH2Li and CuI in Et2O <2000SL859>, or with TMSCH2MgCl and ZnI2 in
Et2O <2000JOC4694>. In these conditions, 2-(2-naphthyl)dioxolane gives the corresponding
styrene in 92% yield.
Recently, it has been reported that -lithiated alkoxysilanes undergo Peterson reaction with
carbonyl compounds to yield unstable -hydroxy alkoxysilanes. On heating in AcOH/AcONa,
they eliminate alkoxydimethylsilanol to give alkenes in good yield <2001JOM(625)13>.
1.16.2.1.4 Stereoselective formation of alkenes

There are two protocols for preparing alkenes from -silyl carbanions and carbonyl compounds.
One employs silyl carbanions where there is no stabilizing group alpha to the carbanion and gives
aliphatic alkenes. The other uses silyl carbanions containing a stabilizing group (Ar, CO2R, SR,
SOR, P(O)(OR)2) alpha to the carbanion and gives functionalized alkenes.
(i) Formation of aliphatic alkenes

In the Peterson reaction of -silylcarbanions with carbonyl compounds where (Z)- and
(E)-alkenes can be produced, both isomers are formed in almost equal amount. This lack of stereo-
specificity results from the formation, under kinetic control, of the intermediate -hydroxysilane
as 1:1 mixture of threo- and erythro--hydroxysilanes, which decomposes with a high degree of
selectivity. The ratio is not affected significantly by any change of the reaction conditions.
The -hydroxylsilyl intermediates can be treated with either acid or base to form the desired
alkenes stereoselectively, as illustrated in Scheme 20. The important feature of the Peterson
reaction is that both the (E)- and (Z)-isomers may be made from the same diastereoisomer. For
example, treatment of the erythro--hydroxysilane under acidic conditions favors the formation
of the (E)-isomer, whereas the (Z)-isomer is formed under basic conditions. Another attribute of
this reaction is that the (E)-isomer, like the (Z)-isomer, can be prepared stereoselectively from
both stereoisomers of the -hydroxysilane (Scheme 20) <2001MI789>.
R3Si R3 4 Base R1 R4
R
R1
R3Si O R2 OH R2 R3
Acid
R1 R2 R3 R4
R3Si R4 3 Base R1 R3
R
R1
R2 OH R2 R4
Scheme 20
For example, reduction with DIBAL-H of the -ketosilane occurs to give predominantly the
threo--hydroxysilane. On treatment with KH it leads to the stereospecific formation of (E)-oct-
4-ene (syn-elimination), whereas on treatment with BF3Et2O or H2SO4 it leads to the (Z)-oct-4-ene
(anti-elimination) <1975JA1464>. The same basic olefination conditions have been applied to the
preparation of (E)-configured allylic alcohol from the 2-silylated 1,3-diols generated by reduction of
-silylated -hydroxy ketones <1999T1717>.
The reaction of -tert-butyldiphenylsilyl aldehydes with organolithium or Grignard reagents
provides stereoselectively -hydroxysilanes following the Felkin–Anh model. The addition takes
place to form almost exclusively erythro--hydroxysilanes. The Peterson olefination can be used
in the stereoselective preparation of (Z)- or (E)-disubstituted alkenes by syn- or anti-elimination
using the standard acidic (BF3Et2O) or basic (KH) conditions <2000S1223> (Scheme 21).
The same method has been used to provide a stereoselective synthesis of trisubstituted alkenes
by the addition of MeLi to -ketosilanes <1976JOC2940, 1977TL1807>.
KH
R1
THF, 30 °C
(Z ):(E ) 95:5 R2
TBDPS TBDPS
R2M 80–93%
OH
R1 CHO THF, –78 °C R1
R2 = Me, Pri, Bun, Ph R2
49 50
60–90% BF3.Et2O Ph
M = Li, MgBr
CH2Cl2, 0 °C Bu
R1 = Ph, R2 = Bun
(E ):(Z ) 99:1
87%
Scheme 21
Synthetic access to diastereoisomeric -hydroxysilanes can also be obtained from ,-epoxy-

silanes. It is known that ,-epoxysilanes exhibit a regiochemical preference for -opening of the
epoxide ring with a variety of nucleophiles to produce diastereomerically enriched -hydroxy-
alkylsilanes <2001OL3955, 2001T549>.
(ii) Formation of functionalized alkenes

The Peterson reaction can be successfully employed for the synthesis of ,-unsaturated esters by the
addition of -silyl ester anions to aldehydes. Elimination occurs under the reaction conditions and the
alkene isomer ratio can be influenced by the solvent, the metal counterion, the temperature, the size of
the ester group and the nature of the aldehyde <2001MI789>. In search of a stereoselective synthesis
of 11(Z)-retinal, it was shown that treatment of the -ionylideneacetaldehyde–tricarbonyliron complex
51 with the lithium enolate of ethyl trimethylsilylacetate 52 affords the (Z)-isomer 53a predominantly
(77%) accompanied by the (E)-isomer 53b (15%) (Equation (19)) <2000JOC2438>. The generality of
this (Z)-stereoselectivity has been confirmed with various aldehyde–tricarbonyliron complexes.
EtO2C CO2Et
TMSCH2CO2Et
CHO
52
+
LDA, THF, –78 °C ð19Þ
Fe(CO)3 Fe(CO)3 Fe(CO)3
51 53a 77% 53b 15%
The countercation effect has been observed in the reaction of aldehydes with N,N-dibenzyl(tri-
phenylsilyl)acetamide using THF and KHMDS. Whereas the reactions with n-BuLi and
NaHMDS were unselective, KHMDS gave exclusively the (Z)-product <2002JOC4093>. More-
over, it has been shown that the stereoselectivity of the reaction of lithium 1,3-bis(trimethylsilyl)-
propyne with the monoketal of 1,1-diacetylcyclopropane was temperature dependent. Thus, the
(Z)-enyne is obtained at low temperature, whereas a mixture of (E):(Z) enynes is obtained if the
reaction is allowed to warm above 40 C <2000JA4915>.
A simplified version of the Peterson olefination reaction has been introduced using the CsF–DMSO
combination. Thus, addition of ethyl trimethylsilylacetate 52 to nonenolizable aldehydes in the
presence of catalytic CsF in DMSO at room temperature gives excellent yields of -siloxy carboxylic
esters 54, which on heating at 100 C eliminate TMSOH to produce the corresponding ,-unsatu-
rated esters 55 in high yield with excellent (E)-stereoselectivity (Equation (20)) <1995JOC6582>.
TMSCH2CO2Et OTMS
52
R–CHO CO2Et + CO2Et
CsF (cat), DMSO R R
54 55 ð20Þ
R = Ph: rt, 35 min 91% Traces
R = Ph: rt, 35 min, 0% 93%
then 100 °C, 1 h
The first asymmetric Peterson reaction of an alkyl trimethylsilylacetate with 4-substituted and
3,5-disubstituted cyclohexanones using a chiral host, a tridentate amino diether, has been reported
to give the axially dissymmetric alkenes with promising level of enantioselectivity (Equation (21))
<2002OL4329>.
Ph Ph
TMS Me2N O OMe

But
O CO2 LDA, toluene, –100 °C
95%
ð21Þ
H
CO2
But But
TMS – TMSOLi H
OLi
CO2
85% ee
1.16.2.2 Boron-mediated Alkenation

In comparison to the well-established Peterson olefination, the corresponding boron-Wittig
olefination using -boryl carbanions has received little attention. The boron-Wittig olefination
has been studied by Matteson and Pelter <1994PAC223, 1996SL600>.
Boron-stabilized carbanions, prepared from alkyldimesitylboranes and bases, react with

ketones to give the corresponding alkenes in good yield <1983TL635>. By contrast, in the case
of aldehydes, the initially formed and favored erythro-adduct has to be decomposed at low
temperature with various reagents to promote either syn- or anti-elimination of the boryl func-
tion. Thus, trapping of the adduct at low temperature with TMSCl followed by treatment with
aqueous HF gives predominantly the (E)-alkene. Alternatively, direct treatment of the adduct
with TFAA results in decomposition by a cyclic ester-type elimination to give predominantly the
(Z)-alkene on warming <1987CC297, 1994PAC223>.
By analogy with the silicon analogs, terminal alkenes are obtained in good yield by the addition
of boron-stabilized carbanions to carbonyl compounds <1994PAC223>. For example, the pina-
col (1-iodomethyl)boronic ester is converted into non-basic Zn/Cu -boryl carbanion, which is
subsequently reacted with aldehydes in the presence of BF3Et2O to give the corresponding
methylenated product in fair to good yield (Scheme 22). For aromatic or ,-unsaturated
aldehydes, the dehydroxyboronation smoothly occurs on heating. However, lower yields result
for the aliphatic aldehydes since the intermediates are quite stable toward elimination. The
reaction is available with various functional groups, such as esters and ketones <1996T915>.
O
RCH O BF3.Et2O ∆
B
O R O RCH CH2
57–84%
IZn(NC)CuCH2 B OBF2
O 57
56
Scheme 22
1.16.2.3 Germanium-mediated Alkenation

<1995COFGT(1)719>.
1.16.2.4 Tellurium-mediated Alkenation

<1995COFGT(1)719>.
1.16.3 METAL-INDUCED METHYLENATION AND ALKYLIDENATION

One-carbon homologation of carbonyl compounds can be achieved with titanium-based reagents. The
use of these reagents in synthesis is limited to the transfer of a methylene unit for the Tebbe reagent but
can be extended to alkenation for the other reagents. The methylenation of aldehydes and ketones by
these nonbasic, reactive reagents offers some advantages over other methylenation methods, particu-
larly with base-sensitive substrates or with sterically hindered carbonyl compounds. A further advan-
tage of the titanium reagents is their ability to methylenate carboxylic and carbonic acid derivatives.
The subject has been previously covered by Pine <1993OR(43)1>, Petasis <1996PAC667>, Hodgson
<B-1996MI006>, Takeda <1999RHA93> and Hartley <2002JCS(P1)2763>.
1.16.3.1 Tebbe Reagent

The Tebbe reagent 59 is a titanium–aluminum metallacycle prepared from titanocene dichloride
58 and trimethylaluminum in toluene <1978JA3611, 1990OS72>. The reagent is commercially
available as a solution in toluene. When the Tebbe reagent is treated with a Lewis base (Pyr or
DMAP), a highly reactive titanocene methylidene 60 is generated by removal of AlMe2Cl. This
species 60 methylenates cleanly and efficiently a range of carbonyl compounds including easily
enolizable aldehydes and ketones. The driving force is probably the formation of the strong
titanium–oxygen double bond (Scheme 23) <1984AG(E)587, 1997JA8574>.
Cl AlMe3 Me Pyr
Ti Ti Al Ti CH2
Cl Cl Me
PhMe
58 59 60
R1
O
Cp2Ti O R1
R2
R2 – Cp2TiO R2
R1
Scheme 23
There are a large number of examples of methylenation of esters, lactones, and amides by the
Tebbe reagent and an attractive feature of this reagent is its selective methylenation. For example,
the lactone 61 is methylenated to give the exo-methylene compound 62 without affecting the
pivaloate group (Equation (22)) <1994TL2537>, regioselective methylenation of the methyl ester
63 proceeds without affecting the bulky silyl ester group to give enol ether 64 (Equation (23))
<2000JCS(P1)2483>, and the methylenation of tertiary amides gives enamines in high yield
(Equation (24)) <1985JOC1212>.
O O
O O O
Tebbe reagent
THF/PhMe, –78 °C to rt ð22Þ
O O O O
O O 69% O O
61 62
OTBDMS OTBDMS
Tebbe reagent
THF, –78 °C to rt, 1 h ð23Þ
MeO2C CO2TBDMS CO2TBDMS
81–85% MeO
63 64
O
Tebbe reagent
N(Me)Ph THF/PhMe, 0 °C to rt N(Me)Ph
ð24Þ
97%
The advantage of the Tebbe reagent is that the reactive titanium methylidene is generated and
reacted at low temperature. Its disadvantages are the sensitivity to air and moisture, the Lewis
acid character and the fact that it is limited to methylenation.
1.16.3.2 Petasis Reagents

Dimethyltitanocene 65, the Petasis reagent, is prepared from methyllithium <1990JA6392> or
more preferably methylmagnesium chloride <2002OS19> and titanocene dichloride 58. This
reagent is relatively stable to both air and water. It has been shown by Petasis and co-workers
that carbonyl compounds are methylenated by dimethyltitanocene 65 on heating at 60–75 C
either in THF or toluene (Equation (25)) <1990JA6392, 1995TL2393>. The reaction proceeds by
rate-determining generation of titanocene methylidene 60 by -elimination and release of
methane, followed by reaction with the carbonyl compounds <1996OM663>.
Me ∆
Ti Ti CH2
Me THF or PhMe ð25Þ
65 60
Aldehydes and ketones can be selectively methylenated in the presence of less electrophilic
carbonyl compounds such as esters, amides, and carbamates. Examples include the final step in
the synthesis of 21-oxogelsemine <1997JA6226> and a key step in the synthesis of an -alkyl-
-amino acid <1993JOC5918>.
Dimethyltitanocene 65 is also able to methylenate esters with high selectivity, including the silyl
ester 66 (Equation (26)) <1995TL2393>, acid anhydrides, lactones, including spirolactone 67
(Equation (27)) <1995TL2393>, thioesters, selenoesters, and acylsilanes. The use of an excess of
dimethyltitanocene 65 results in the methylenation of a strained -lactam to produce 2-methyle-
neazetidine without affecting the ester or the t-BOC group <2000TL5607>.
O
Petasis reagent
Me OTBDMS PhMe, 70 °C Me OTBDMS ð26Þ
66 70%
Petasis reagent
O O O O THF, 65 °C O O ð27Þ
67 73%
A route to substituted titanium-alkylidene species and their use in carbonyl olefination has been
developed. Thus, a range of dialkyltitanocenes such as dibenzyltitanocene (Equation (28)),
bis(trimethylsilylmethyl)titanocene, and bis(cyclopropyl)titanocene has been introduced by Petasis
and co-workers to alkylidenate carbonyl compounds <1992JOC1327>. When dibenzyltitanocene
68 is heated with esters, (E)- and (Z)-enol ethers 69 and 70 are formed with good (Z)-selectivity.
CH2Ph
Ti
CH2Ph Ph Ph
O
68
+ ð28Þ
R1 OR2 PhMe, 45–55 °C R1 OR2 R1 OR2
(Z ):(E ) 26:74 to 86:14 69 70
35–84%
R1 = Me, Ph
R2 = OMe, OEt, O(CH2)11Me
1.16.3.3 Takeda Reagents

In 1997 Takeda reported that dithioacetals can be reduced by low-valent titanium complex 71 to
give a reactive titanium alkylidene species 72 presumably by desulfurization. The most important
subsequent reaction of 72 is carbonyl olefination, which proceeds smoothly with aldehydes,
ketones, esters, and thioesters <1997JA1127>. The low-valent titanium complex 71 is prepared
by reduction of titanocene dichloride 58 with Mg in the presence of P(OEt)3 in THF then added to
dithioacetals to generate the titanium alkylidenes 72 (Scheme 24). 4 Å Molecular sieves are essential
for rapid reduction. No limitations have been observed with respect to the structure of the
dithioacetals. Methylenation is ineffective under Takeda conditions, but allyl, benzyl, or alkyl
dithioacetals are suitable substrates for generating alkylidenating reagents. A disadvantage of the
reagent 72 is the unsatisfactory stereoselectivity observed for the olefination of aldehydes. Better
selectivities have been obtained in the olefination of carboxylic esters <1997JA1127>.
The Takeda reagent has been efficiently used in the synthesis of 5-heptyl-2,3-dihydrothiophene
74, contaminated by its isomer 2-heptylidenetetrahydrothiophene 75, by intramolecular carbonyl
olefination of the thioester 73 (Equation (29)) <1999SL1029>. Similarly, enol ethers of cyclic
ketones have been obtained by intramolecular carbonyl olefination of alkyl !,!-bis(phe-
nylthio)alkanoates <2001CC625>.
Mg, P(OEt)3 RS SR
Cl 4 Å Molecular sieves R 1 R2 R1
P(OEt)3
Ti Ti Ti
Cl THF, rt, 3 h P(OEt)3 – [Cp2Ti(SR)2] R2
58 71 (3 equiv.) 72
Scheme 24
Cp2Ti[P(OEt)3]2
PhS O
71
+
PhS S THF, rt, 3 h S S ð29Þ
n-C6H13 85:15 n-C6H13 n-C6H13
73 56% 74 75
The advantages of the Takeda reaction are the range of alkylidenating agents that can be
generated, the mildness of the conditions and the ease of synthesis of dithioacetal substrates.
Moreover, a range of functionality is tolerated within the carboxylic acid derivatives and the
alkylidene reagents.
1.16.3.4 Takai–Lombardo Reagents

The Takai–Lombardo methylenation reagent 76 is a titanium-methylidene species prepared from
dibromomethane, Zn, and TiCl4 in THF at 5 C for 3 days. The reagent must be kept cold at all
times because the active species slowly decomposes at room temperature. It reacts at room
temperature with ketones to give the methylenated product in high yield without enolization.
Moreover, the reagent is compatible with a wide variety of functional groups (THP ethers,
acetals, esters, carboxylic acids, alcohols, etc.). For example, 76 has been reacted with iso-
menthone 77 to give the methylenated derivative 78 in 89% yield (Scheme 25) <1987OS81>.
The CH2I2ZnTiCl4 system has also been tested and appears as more reactive than the
CH2Br2ZnTiCl4 system. The reagent is effective for the methylenation of aldehydes, and the
ester groups remain unchanged while ketone methylenation proceeds <1985TL5579>.
i. Zn, THF, –40 °C 77

CH2Br2 LnTi CH2
ii. TiCl4, THF, 5 °C, 3 days CH2Cl2, rt, 1.5 h
76 89% 78
Scheme 25
A further advantage of the Takai–Lombardo reagents is the possibility, in addition to methy-

lene units, of transferring substituted alkylidene units by using reagents prepared from
1,1-dibromoalkanes, Zn, TiCl4, and TMEDA in THF. The presence of trace amounts of lead(II)
is reported to be vital to the success of the reaction. Takai and co-workers have published a
definitive procedure for the preparation of their reagent <1996OS73>. The reaction proceeds via
a gem-dizinc compound, which is subsequently transmetallated with TiCl4 to the titanium-alky-
lidene species. The use of these reagents allows the general alkylidenation of carboxylic esters. In
this transformation, the (Z)-enol ethers are obtained with high stereoselectivity. Thus,
t-butyl ester 79 gives modest selectivity for (Z)-enol ether 80 (Equation (30)), but iso-butyrate
81 gives solely (Z)-enol ether 82 (Equation (31)).
MeCHBr2
O H Me
Zn, TiCl4, TMEDA
Ph OBut THF, 25 °C Ph OBut ð30Þ
79 81% 80
71/29 (Z )/(E )
n-C5H11CHBr2
O H n-C5H11
Zn, TiCl4, TMEDA
Pri OMe THF, 25 °C Pri OMe ð31Þ
81 89% 82
100/0 (Z )/(E )
The advantage of the Takai–Lombardo alkylidenation is that it is a mild one-pot procedure

that allows the alkylidenation of a range of carboxylic acid and carbonic acid derivatives with
good stereoselectivity. The major drawback of this method is the rather cumbersome access to the
respective substituted dihalomethane compounds, which prevents a broad application of this
reaction in organic synthesis.
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Biographical sketch
Philippe Savignac is Directeur de Recherche Bogdan Iorga was born in 1975 in Ploiesti,
(CNRS) at the Ecole Polytechnique (Palaiseau). Romania. He received his B.Sc. in chemistry in
Dr. Savignac graduated as an Ingénieur of the 1997 at the University of Bucharest working
ENSCT in 1963 and obtained his Ph.D. from with Professor C. T. Supuran. In 1997 he joined
the Université de Paris (Sorbonne) in 1968. He the European Program at the Ecole Polytechni-
became an Attaché de Recherche (CNRS) in que (Palaiseau), where he obtained his M.Sc.
1970 in the laboratory of Professor H. Normant (1998) and Ph.D. (2001) degrees on the electro-
and Directeur de Recherche in 1976. In 1977 he philic halogenation of phosphonates under the
joined the newly formed CNRS phosphorus supervision of Dr. P. Savignac. After a postdoc-
chemistry center in Thiais. Since 1987 he toral position in Dr. J. M. Campagne’s labora-
has been working at the Ecole Polytechnique. tory, he joined the Dr. C. Guillou’s group, also
Dr. Savignac has worked in several areas of at the Institut de Chimie des Substances Natur-
organic phosphorus chemistry. The majority of elles (Gif sur Yvette), as Chargé de Recherche
his work has concerned the organometallic (CNRS).
chemistry of phosphorus with particular empha-
sis on the synthesis of new phosphonylated
reagents, phosphoramidates, phosphonates,
and -halogenated phosphonates.
Monique Savignac, after a B.Sc. at the Université Claude Bernard (Lyon 1),
obtained her Ph.D. in 1980 at the Université Pierre et Marie Curie (Paris
VI) under the direction of Professor P. Cadiot. After spending a few years
with Professor G. Jaouen, she joined the laboratory of Professor J. P. Genêt
in 1989. She was appointed as Assistant Professor in 1995 and as Full
Professor in 2002 at the Ecole Nationale Supérieure de Chimie de Paris.
Her scientific interests concern palladium chemistry, in particular coupling
reactions in aqueous media, green chemistry, and synthesis of -lactam
antibiotics.
1.17
One or More C¼C Bond(s)
by Pericyclic Processes
J. LEBRETON and A. GUINGANT
University of Nantes, Nantes, France

1.17.2 FORMATION OF MONOENES BY RETRO-ENE AND RELATED REACTIONS 762
1.17.2.1 Cleavage of One CH (or One XH, X = Heteroatom) and One CC
(or One Heteroatomic) Bond 762
1.17.2.2 Cleavage of One CH and One CO Bond 763
1.17.2.2.1 Pyrolysis of acetates and related esters 763
1.17.2.2.2 Pyrolysis of xanthate esters 765
1.17.2.2.3 Other concerted pyrolytic eliminations 768
1.17.2.3 Cleavage of One CH and One CS Bond, Including Pyrolysis of Sulfoxides 769
1.17.2.4 Cleavage of One CH and One CSe Bond: Pyrolysis of Selenoxides 772
1.17.2.5 Cleavage of One CH and One CN Bond, Including the Cope Elimination 777
1.17.3 FORMATION OF MONOENES BY RETRO-CYCLOADDITION REACTIONS 777
1.17.3.1 Retro-[2+2]-cycloadditions 777
1.17.3.2 Retro-[4+2]-cycloadditions (Retro-Diels–Alder Reactions) 778
1.17.4 FORMATION OF DIENES AND POLYENES 781
1.17.4.1 Retro-cycloaddition Reactions 782
1.17.4.2 Retro-cheletropic Reactions 787
1.17.1 INTRODUCTION
This chapter deals with the creation of the CC bond by retro-pericyclic cleavage reactions and is
intended to provide a selective, rather than exhaustive, survey of these processes. Emphasis is given
to papers of recent origin (most of them after 1995) that were not covered in COFGT (1995).
Retro-sigmatropic-shift processes, which are considered first, are characterized by the cleavage of one
CH and one CX bond to create the alkene, whereas the retro-cycloaddition reactions, which form
the next section of the chapter, are characterized by cleavage of two CC (or CX) bonds. Formation
of dienes and polyenes is considered separately and includes a study of retro-cheletropic reactions.
Concerted rearrangements are reported in Chapters 1.09 and 1.18. Within each section, the mechanism
and stereochemistry of each process will be covered, together with an assessment of the scope,
limitations, and reaction conditions. Finally, attention will be primarily focused on those synthetically
useful reactions that have found application, often as key steps, in the field of natural product synthesis.
The majority of the relevant reactions are thermal eliminations that may be carried out either in
solution or in gas phase. This chapter describes ‘‘flow pyrolyses’’ as those reactions that are carried
out at atmospheric pressure or under low pressure under a stream of inert gas (nitrogen or argon)
by feeding a solution of the substrate down a heated tube packed with glass. In contrast, ‘‘flash
vacuum pyrolysis’’ (FVP) involves slow addition of the substrate at the top of a quartz column filled
with quartz chips and maintained at a high temperature (>500 C) under 0.2 mm pressure.
761
762 One or More C¼C Bond(s) by Pericyclic Processes
1.17.2 FORMATION OF MONOENES BY RETRO-ENE AND RELATED REACTIONS

The general reactions under consideration are shown in Equations (1) and (2). Equation (1)
involves hydrogen transfer via a six-membered ring transition state and is formally a [2s + 2s + 2s]
reaction. Equation (2) is isoelectronic with Equation (1) but involves a five-membered ring transition
state [2s + 2s + 2!s].
H H
Z V Z
+ V ð1Þ
Y W Y
X W
X
H H
Y
+ ð2Þ
Y X
X
1.17.2.1 Cleavage of One CH (or One XH, X = Heteroatom) and One CC
(or One Heteroatomic) Bond
Retro-ene reactions have been principally achieved under FVP conditions and often at very high
temperatures to give, in most examples, reactive intermediates that were characterized in situ by
special techniques such as matrix isolation IR spectroscopy <1997JOC4240, 1998JOC2619>.
Such technical constraints have certainly limited the application of this reaction in multistep
syntheses. However, several reactions that could be achieved at ‘‘reasonable’’ temperatures have
been reported recently in the field of natural product synthesis. Thermal decomposition of
urazole–indole adducts can be achieved in good to excellent yields at temperatures ranging
from 150 C to 250 C <2003OL1999>. Since the adducts are the result of an easily realized
ene reaction between indoles and 4-methyl-1,2,4-triazoline-3,5-dione (MTAD), this reaction,
which found application in the total synthesis of okaramine A <2003JA5628>, represents the
first method for protection–deprotection of the 2,3-indole bond (Equation (3)). The relatively
mild temperature required for this reaction to occur is certainly due to the fact that the migrating
hydrogen is borne by a heteroatom rather than by a carbon (Equation (1), Z = N). This favorable
situation was also exploited to convert (+)-zampanolide into (+)-dactylolide, two cytotoxic
macrolides of marine origin (Equation (4)) <2002OL635>.
O
MeO2C Me MeO2C Me
MeN NHH H
N O N O
N 150 °C
O
(quantitative)
ð3Þ
N Me Me N Me Me
O H
MeN N
(MTAD)
N
O
H O Me O
O O Benzene, 85 °C Me
O
O O 105 min O O
N H
H
Me (quantitative) Me
H H H H
O O
Me ð4Þ
O
NH2
(+)-Zampanolide (+)-Dactylolide
Me
One or More C¼C Bond(s) by Pericyclic Processes 763
The accelerating effect of alkoxides on concerted reactions is well recognized. Such an effect on the
rate of the retro-ene reaction has recently been demonstrated for the first time <2001OL3025>. Thus,
although the cis-diol 1 is reluctant to rearrange in toluene at reflux for days, it gives enone 2 when
treated with potassium hydride and 18-crown-6 (18-c-6) at room temperature. This transformation
was shown to arise via an exceptionally easy anionic oxy-retro-ene reaction to give a potassium
enolate that cyclizes to the bicyclic enone 2 (Scheme 1). Interestingly, the diastereoisomeric trans-diol,
when heated in deuterated chloroform at 60 C, was transformed to diketone 3. This dramatic change
in reactivity was accounted for by the fact that, in the latter example, the migrating hydrogen is no
longer borne by a carbon, as it is in the cis-diol, but by an oxygen (Scheme 1).
KH (2 equiv.)
Me 18-c-6 HO HO Me
OK OK
THF, rt
O
OH OH Me
H 2
1
KH (2 equiv.)
H O
O CDCl3, Me 18-c-6
Me
65 °C THF, rt
OH O
OH 80% 90%
OH
3
Scheme 1
Decarboxylation of carboxylic acids containing ,-unsaturation is another case, which follows

the general mechanism of Equation (1). A well-known and synthetically useful example is
represented by the decarboxylation of -keto acids and 1,3-diacids, which can be accomplished
under mild conditions. This operation is often the final stage of the acetoacetic and malonic
syntheses of methyl ketones and carboxylic acids.
In a different domain, a detailed kinetic investigation of the allylsulfinic acid desulfination has
concluded that a concerted, retro-ene mechanism is involved <1995JOC7166>.
1.17.2.2 Cleavage of One CH and One CO Bond
1.17.2.2.1 Pyrolysis of acetates and related esters

Many reviews of this topic (Equation (1); X = V = O; Z = Y = W = C) are available
<1960CRV431, B-1979MI117-001, B-1980MI117-002, 1991COS(6)1011>.
This reaction can be carried out in the gas phase under flow conditions at temperatures of
500–525 C or in FVP conditions at higher temperatures (600–700 C). The syn-nature of the elimina-
tion was proved by pyrolyses of specifically labeled acetates <1953JA6011, 1972JCS(P2)165>.
The regioselectivity of the elimination is dependent on a number of factors including statistical
effects, thermodynamic stability (arising from steric effects), and electronic effects, and the overall
stereochemical outcome can be rather modest <1963RTC1123>. Steric effects promote the
formation of the (E)- rather than the (Z)-alkenes and formation of a double bond endo- to a
ring is generally favored relative to the exo-double bond <B-1979MI117-001, 1959JA651>.
Electronic factors are now recognized as being dominant in governing the rate and direction of alkene
formation. The reaction is favored by electron donation at C-1 <1975JCS(P2)1025> and also by
electron-withdrawing groups at C-2 (Equation (5)) <1959JA2126>. Bulky electron-donating (alkyl)
substituents at C-2 can also cause a small enhancement due to ‘‘steric acceleration’’ <1976JCS(P2)280>.
Flow
CO2Me CO2Me CO2Me
435 °C
+ ð5Þ
OAc
97% 3%
The reaction is also slightly accelerated by electron-withdrawing groups at the carbonyl carbon
atom <B-1979MI117-001, 1969JCS(B)187, 1972RTC3>. Thus, cyclohexyl trifluoroacetate is
19 times more reactive than the corresponding acetate <1963JCS1246>. Although the use of
benzoates has the advantage that benzoic acid crystallizes at the exit point of the furnace, well
away from the more volatile alkene, acetates continue to be the most widely used ester groups
<1988ACA58>. FVP conditions are well suited to and particularly effective for the synthesis of
alkenes, which readily polymerize or decompose unless kept in the cold.
The major drawback of this method arises from the high temperature involved that pre-
cludes the presence of sensitive functional groups in the substrates. Consequently, the useful-
ness of the acetate elimination has been limited to simple substrates and is generally not
compatible with sensitive natural product intermediates. However, this method has been
successfully used in the total synthesis of natural curcuminoid antioxidants (Equation (6))
<1998JNP609>.
AcO Me Me
MeO 160 °C, reflux, DMSO MeO
ð6Þ
MeO R AcO R = H, 84% MeO R AcO
MeO R = OMe, quantitative MeO
In the course of the enantioselective synthesis of hydantocidin analogs, the chiral dihydrofuran
5 was prepared in excellent yield from the corresponding acetate 4 on a gram scale by heating at
190 C at 0.5 torr in a Kugelrohr apparatus (Equation (7)) <1999JOC2010>. The ABC tricyclic
portion of aflatoxins was obtained by pyrolytic elimination from the acetate intermediate 6,
carried out at 140–150 C in a high-boiling-point solvent under a stream of nitrogen removing
AcOH to prevent side reactions (Equation (8)) <1994JOC3775>.
Kugelrohr
190 °C, 0.5 torr
OTBDMS OTBDMS
AcO O O
ð7Þ
96%
4 5
TsO OAc PhOPh TsO

H H
140–150 °C
O O
75% ð8Þ
TsO O H TsO O H
Acetate pyrolysis was also used in a synthesis of the alkaloid peduncularine 7, when anionic
and cationic eliminations failed (Scheme 2) <1989JA2588>. The exocyclic methylene groups of
longifolene 8 <1990JA4609, 1993JOC2186> and sinularene 9 <1979AJC1819> were introduced
by classic ‘‘flow pyrolysis’’ methodology using benzene or toluene solutions of the substrates
(Scheme 3).
AcO FVP AcO Pri

Pri 600 °C, 0.05 torr
OAc Pri N
N N
54%
O NH
O
Peduncularine 7
Scheme 2
Flow
525 °C
OAc 56%
Longifolene 8
Flow
450 °C
66%
OAc
Sinularene 9
Scheme 3
1.17.2.2.2 Pyrolysis of xanthate esters

This method follows the general mechanism of Equation (1) (X = O, W = CSR, V = S, Z = Y = C);
invariably the S-methyl derivatives are used. However, earlier work on pyrolysis of steroid xanthates
showed that -cholestanyl-S-benzyl xanthate decomposed almost twice as fast as the corresponding
S-methyl xanthate <1952JA5454>. In addition to the reviews cited in the previous section, a specialized
account of this transformation—the Chugaev reaction—is available <1962OR57>.
Compared to acetates, the disadvantage of this method is that xanthates are obtained from
alcohols via the alkoxides, thus requiring strong basic conditions to be formed; the final products
are frequently contaminated with sulfur-containing impurities <1962OR57>. Treatment of the
alcohol with strong bases (NaH, KH, KOBut, BunLi, and MeLi) followed; by subsequent sequential
addition of carbon disulfide, and iodomethane (or sometimes dimethyl sulfate) continues to be
widely used on a broad range of substrates to prepare xanthate esters. Nevertheless, xanthates are
more reactive than acetates so that the reaction can be carried out under relatively mild conditions
(typically at a temperature of 150 C for a few hours either at atmospheric pressure or under
vacuum), thus minimizing the possible thermal isomerization of the alkene <1962OR57>.
The syn-stereochemistry of the process has been demonstrated <1949JA3883> (Equation (9)) and
the involvement of the C¼S sulfur atom in the elimination was proved by 34S and 14C isotope effects
<1961CJC348>.
Ph
H Ph
S 180 °C
ð9Þ
O SMe 49–52%
H
As with acetates, statistical, thermodynamic, and steric factors again govern the direction of the
elimination <1962OR57>. In addition, electron-withdrawing groups attached to the sulfur atom
further accelerate the reaction <1953JA2118>.
Xanthate pyrolysis is still used substantially in synthesis. A spectacular example in propellane
chemistry is represented below <1992JOC5121> (Equation (10)).
OCS2Me
HMPA
220 °C
ð10Þ
OCS2Me 91%
OCS2Me
In recent years, a number of applications in natural product synthesis have been found. In the first
synthesis of the insect–antifeedant (–)-dihydroclerodin, the alcohol 10 was converted into the xanthate,
which under heating at 216 C for 48 h gave the desired intermediate 11 with an exocyclic double bond
<1999JOC9178> (Scheme 4). It is worth noting that under these conditions the hexahydrofuro[2,3-b]-
furan motif is stable. All attempts to form the selenide intermediate from the alcohol 10 failed.
O O O
H H H H H H
H H H
O O O
H i. NaH, CS2, MeI H H
ii. Dodecane, reflux
36%
O O O OAc
HO O O
OAc
10 11 (–)-Dihydroclerodin
Scheme 4
In the formal synthesis of morphine via the racemic 3,4-dimethoxy-7-morphinanone, thermo-

lysis of the xanthate 12 afforded the desired cyclohexene intermediate 13 (Scheme 5)
<2000OL2785>. No elimination occurred when the epimeric xanthate 14 was heated under
various conditions but only a complex mixture was obtained. Presumably, this failure could be
explained by the fact that the required geometry in the transition state to permit the syn-
elimination could not be reached in this case due to steric repulsion between the xanthate moiety
and the axially disposed alkyl chain.
OPiv
MeO MeO
MeO MeO
o-Cl2C6H4
OPiv OMe OPiv MeO
MeO reflux
MeO
O SMe H 73% N
O
S H Me
S O
SMe
12 13
MeO OPiv MeO
OPiv S SMe OPiv

MeO H MeO
O SMe O
MeO
S
MeO
14 13
Scheme 5
In the course of synthetic studies on kincamycin antibiotics, the functionalized tetrahydrofluor-

enone intermediate 16 was synthesized by pyrolysis of the xanthate 15 at 300 C under reduced
pressure in a Kugelrohr apparatus (Equation (11)) <2001T2717>.
TBDMSO OTBDMS TBDMSO OTBDMS

BnO BnO
H
O 300 °C, 20 mmHg, 15 min O
O O 50% O ð11Þ
O S O
MeS
16
15
Xanthate thermolysis ensured an efficient route to (–)-epibatidine and analogs (Scheme 6)

<1994JOC1771>. Thus, tertiary xanthate 17 at refluxing toluene afforded the desired olefin 18
along with small amounts of the pyrrole derivative 19 arising from a retro-Diels–Alder reaction.
Similarly, thermolysis of the xanthate intermediate prepared from alcohol 20 afforded the racemic
epibatidine analog precursor 21. All attempts to prepare this compound by a dehydration step
proved unsuccessful <2001JCS(P1)2372>.
Cl Cl
t-BOC Cl H
N Toluene t-BOC Cl N
N reflux, 2 h N N
N N
+
O S
SMe t-BOC N (–)-Epibatidine
17 19 (6%) 18 (73%)
Cl
Cl
N i. NaH, CS2, MeI H
N
ii. Toluene, reflux Cbz N
Cbz N
N
OH 50% N
20 21 Cl
Scheme 6
Pyrolysis of xanthates has also been successfully used in the total synthesis of phytotoxins
solanapyrones D and E <2001OL251, 2002JOC5969>, sceletium alkaloids <1998TL7747>,
pseudoguaianolides <1998JOC920>, epothilones B and D from D-glucose <2002TL2895>, and
(+)-compactin <1995JCS(P1)777>.
In the course of an elegant and efficient synthesis of (–)-kainic acid, a tandem reaction featuring
a Chugaev syn-elimination and a subsequent intramolecular ene reaction led to intermediate 22,
isolated in 72% yield as the sole diastereoisomer (Scheme 7) <2000OL3181>.
NaHCO3
S PhOPh
H
reflux
O SMe
45 min O CO2H
O O
72 % CO2H
N O N
O N O N Cbz H
Cbz Cbz
22 (–)-Kainic acid
“exo” Transition state
Scheme 7
An enantioselective synthesis of both enantiomers of bicyclic ketone 23 was achieved from a common
intermediate 24 using, in each pathway, a xanthate thermal elimination (Scheme 8) <1996JOC142>.
i, ii i, ii
O 72% O 61% O
OTHP OH OTHP OH
(–)-23 24 (+)-23
i. NaH, CS2, MeI; ii. diglyme, reflux, 15 h
Scheme 8
1.17.2.2.3 Other concerted pyrolytic eliminations

Wide structural variation is possible, and some examples have been summarized <1991JOC846>.
Variations affecting the nucleophilicity of atom V and the electronegativity of atom W (Equation
(1)), although aiding the reaction, have not significantly displaced the acetate or xanthate
methods for preparative purposes <1991JCS(P2)1703, B-1979MI117-001>.
The heteroatom V is not required for a successful pyrolytic elimination and simple vinyl ethers
25 <1977JOC3899, 1982JCS(P2)1175, 1988JCS(P2)737>, 2-alkoxypyridines 26, and related het-
erocycles undergo a similar decomposition <1981JOC1969, 1982JCS(P2)1175, 1986JCS(P2)1255>.
O N O
25
26
Other examples of substrates with two heteroatoms that give alkenes in a similar manner to
ester pyrolyses are shown below. They include thionoacetate 27, the isomeric thioacetate
28 <1973JCS(P2)1293, 1975JCS(P2)317>, and benzimidate 29 <1966TL6279>. Within the series
of carbonates of type 30 <1983JCS(P2)291> and their possible sulfur analogs of type
31 <1988JCS(P2)177>, the major rate change occurs when OR is replaced by SR, with the change
from carbonyl to thiocarbonyl producing a relatively small effect. The pyrolysis of carbonates has
found some applications in total synthesis <1968CJC377, 1983SC559>. It should be noted that,
in some cases, p-tolylthiocarbamates appeared to be a good alternative to xanthates. An example
is shown in Equation (12) <1995JOC4602>.
S O NPh O
O S O Ph O OR
27 28 29 30
O Se
S
O NR2 O NHAr
O OR
32 33
31
25 to 200 °C
MOMO NHt-BOC MOMO NHt-BOC
12 torr
(t-BOC)2O ð12Þ
S
O 87%
O
Pyrolysis of N-aryl- and N,N-diarylcarbamates of type 32 can be carried out in the temperature
range of 375–420 C (lower temperatures than for the acetates) <1981JOC2804>. The thiocarbonyl-
diimidazolides offer clear advantages over the corresponding xanthates for those substrates that are
sensitive to strong basic conditions. A pertinent example is provided by the synthesis of jatropha-
trione, for which initial attempts to form the xanthate failed (Equation (13)) <2002JA6542>.
O O
O Imd2C=S O
O
O o-Cl2C6H4 O O
reflux
37% H ð13Þ
H H
HO H O
O O
Jatrophatrione
Pyrolysis of O-alkylselenocarbamates of type 33 occurred at 80 C; however, the syn-elimination

was complicated by a competing bimolecular (E2) mechanism <1994T639>.
Similar observations have been made from phosphates 34, thiophosphonates 35 <1995TL719>,
phosphinates 36, and sulfonates 37. Phosphates are much more reactive than the corresponding
acetates owing to the greater electronegativity of the phosphorus atom <1961JOC846>. Similarly,
tosylates have been found more reactive than either acetates or xanthates in 1,3-eliminations in the
adamantane series <1972JCS(P1)2533>. As an alternative to gas-phase methods <1989JOC5811>,
8-quinolylsulfonates or 2-pyridylsulfonates have been found to decompose cleanly at 150 C to
give good-to-excellent yields of simple alkenes <1989JOC389>.
O S O O
OR OR Ph R
P P P S
O OR O OR O Ph O O
34 35 36 37
1.17.2.3 Cleavage of One CH and One CS Bond, Including Pyrolysis of Sulfoxides
The pyrolysis of sulfoxides is synthetically an interesting method to form double bonds and has
widely been reviewed <1978ACR453, 1978CRV363, 1978S713, 1991COS(6)1011> (Equation (2);
X = S, Y = O). Given a ready facility to introduce selectively alkyl or aryl sulfur into many
substrates and to oxidize them cleanly to the corresponding sulfoxides, pyrolytic -elimination of
sulfenic acid constitutes a useful method to synthesize unsaturated compounds. The appropriate
sulfides are most commonly oxidized with MCPBA, sodium metaperiodate, or dimethyldioxirane
<2000EJO4079>. The thermolysis step usually takes place in solution in the temperature range of
80–130 C as S-aryl sulfoxides decompose at lower temperatures <1978ACR453, 2001JOC8722>.
In some cases, to be more efficient, the thermal elimination of phenylsulfenic acid in boiling
solvents required the presence of NaHCO3, CaCO3 <2003JOC7983>, or dihydropyran
<2003OL1563>. The Pummerer reaction may be predominant when the reaction mixture is
contaminated with protic sources (e.g., Scheme 9) <1993JOC3923, 1998JOC6939>.
O O O O O
S MCPBA S CCl4, Pyr S
Ph Ph reflux Ph +
49% 2%
Scheme 9
Electron-withdrawing groups on the S-aryl ring also accelerate the reaction <1978CL541>.
-Elimination of alkyl or aryl sulfoxides promoted by microwave irradiation gave excellent yields
and was over 1,300 times faster than under thermal conditions <1996TL1855>. The standard
syn-stereochemistry of the process for acyclic examples has been established and the solvent
independence of the reaction rate is consistent with a concerted mechanism <1960JA1810>.
Isotope effect studies suggest that the hydrogen transfer occurs via a linear transition state
<1978JA2802, 1978JA3927>. Acyclic alkenes are produced with (E)-stereochemistry
<1973JA6840, 1975JOC148> and fragmentation takes place toward the most acidic -hydrogen
atom <1978TL4903>. With -hydroxysulfoxides, easily prepared from epoxides by ring opening
with thiophenol, the elimination takes place away from the -hydroxy groups to give allylic
alcohols <1975TL2841, 2000TL2895>, as illustrated in Scheme 10 with the synthesis of the
prostaglandin analog 38 <1991JOC1329>.
Ring opening of oxiranes with thiophenol without catalysts in hexafluoroisopropanol can be
efficiently accomplished. Subsequent in situ oxidation under neutral conditions with MCPBA affords
a -hydroxysulfone, which was next converted by pyrolysis to an allylic alcohol <2000TL2895>.
This method has largely been employed for the synthesis of ,-unsaturated carbonyl and nitrile
compounds from the corresponding saturated starting materials by alkylation of the enolates with
diphenyl disulfide, phenylsulfenyl chloride, N-thiophenylphthalimide <2002SL1308>, or S-phenyl
benzenethiosulfonate <1977JA4405> followed by subsequent oxidation to the sulfoxide and pyr-

olysis. This sequence has been used extensively in the total synthesis of natural products, as
exemplified by the synthesis of artemisitene (Scheme 11) <2002JMC4321>.
O i. PhSNa O Toluene, reflux O

O ii. NaIO4 O CaCO3 O
O
SPh 80%
O
BzO OBn BzO OBn BzO OBn
OH OH
38
Scheme 10
O i. LDA i. MCPBA
O O
H ii. PhSS(O)2Ph H ii. 0 °C, NaHCO3 H
O O O O O O
67% 78%
O SPh
O O
O O O
Artemisitene
Scheme 11
Direct installation of the -sulfoxide substituent by trapping the enolate with methylphenyl-
sulfinate <1995TL7051> or methyl 2-pyridylsulfinate esters <1993JOC1579> avoids the oxida-
tion step. For instance, this method has been applied to the synthesis of piperidines
<2001OL3257, 2002OL2787> and silacyclohexenones <1998SL153> (Scheme 12).
Ph Ph
i. KH, PhSO2Me, THF, reflux H
O N O ii. Toluene, reflux, Na2CO3 O N
O N
86% HO
HO
Ph Ph i. NaH, PhSO2Me, ether Ph Ph

Si ii. CH2Cl2, rt Si
20%
O O
Scheme 12
Difluoroiodotoluene, a hypervalent iodine reagent, has been used as a fluorinating agent, as

well as an oxidant, on -phenylsulfanyllactone 39 to afford after thermolysis the 2-fluoro-
2-buten-4-olide (Scheme 13) <2000TL4463>.
p -Difluoroiodotoluene O
O O O
(DFIT)
PhS Ph S F
O CH2Cl2, 0 °C O Toluene, reflux O
F
Ph 41% Ph 72% Ph
39
Scheme 13
In this context, free-radical chemistry offers an original synthetic potential to introduce sulfur-
containing groups. For instance, intramolecular conjugate addition of a radical to activated
olefins, in the presence of Barton carbonate (N-methoxycarbonyloxy-pyridine-2-thione, PTOC-
OMe) as chain transfer reagent, has been used to synthesize bicyclic -methylenelactone 40
(Scheme 14) <2003SL1485>. Some similar examples have also been reported in this area using
the standard protocol for Barton decarboxylation <1995JOC6237, 1988CC285>.
i. Catecholborane,
[Rh(COD)Cl2] (1mol.%)
ii. PTOC-OMe H i. MCPBA, –10 °C H
O O O ii. EtOH, reflux O
150 W lamp
O O
63% 65%
S H H
N 40
Scheme 14
Sulfanyl radical addition–cyclization on the alkenyl-tethered-oxime ether 41, coupled with an

oxidation/elimination of the resulting sulfoxide, offered a unique opportunity to synthesize cyclic
-amino acids (Scheme 15) <2002T4459>.
i. PhSH, AIBN Ph
S i. MCPBA
NOMe ii. LAH
iii. (t-BOC)2O NHt-BOC ii. o-Cl2C6H4 NHt-BOC HO2C NH2
reflux
37%
41 76%
Scheme 15
The incorporation of sulfur-containing groups, eliminated as sulfoxide, has also been achieved
by conjugate addition of thiophenol <2000JOC1842, 2003JOC4422>, as illustrated by the synth-
esis of epoxybenzoxocin in the course of synthetic studies on nogarol anthracyclines (Scheme 16)
<2000JOC1842>.
i. MeOH, TsOH,
TFA
ii. MCPBA, rt
iii. Toluene,
OMe
EtO MEMO OBn PhSH EtO MEMO OBn CaCO3,
Et3N K2CO3, reflux O OBn
EtO EtO
O 98% PhS O 70%
O
OMe OMe
OMe
Scheme 16
A cerium-mediated conjugate addition of [(diethoxyphosphinyl)difluoromethyl]lithium to vinyl-

sulfoxides, followed by sulfoxide elimination, allowed the preparation of allylic difluoro-
phosphonate compounds (Scheme 17) <1998TL9085>.
An interesting route to chiral -butenolides using a one-pot condensation of enantiomerically
pure lithiated sulfoxide 42 to aldehydes, followed by thermal elimination of phenylsulfenic acid,
has been reported (Scheme 18) <1999TL6237>.
This sulfoxide-based elimination sequence has nicely been exploited in various syntheses.
Scheme 19 provides some more examples <2002OL2565, 2002JOC7303, 2002SL1308>.
LiCF2PO(OEt)2
CF2PO(OEt)2 Toluene, reflux CF2PO(OEt)2
CeCl3
Ph
S 75% Ph 75%
S
O
O
Scheme 17
i. –78 °C O
CHO ii. 2 M H2SO4
OO O
iii. Toluene, reflux
Li +
S O
82%
O
42
89% ee
Scheme 18
OMe OMe
i. MCPBA
PhS ii. Toluene, reflux
O 83% O
O O i. MCPBA O O
H
(EtO)2P P(OEt)2 ii. Toluene, reflux (EtO)2P P(OEt)2
O O 90%
S O O
Me
O O
O i. MCPBA, –20 °C O
ii. Benzene with BaCO3
O reflux O
O 57% TBDMSO O
TBDMSO SPh
HO HO
Scheme 19
1.17.2.4 Cleavage of One CH and One CSe Bond: Pyrolysis of Selenoxides
During the 1990s, increasing numbers of papers have reported the use of selenoxide elimination in
multistep syntheses, pointing out the superiority of this method over others (Equation (2);
X = Se, Y = O). A variety of efficient and mild methods using both nucleophilic and electrophilic
reagents are available to introduce arylseleno groups (usually phenylseleno), providing a broadly
applicable methodology to CC double bond formation. A number of reviews in this field are
available <1978T1049, 1979ACR22, B-1984MI117-003, B-1986MI117-004, 1991COS(6)1011>.
The phenyl selenide anion turns out to be a good and convenient nucleophile to prepare organo-
selenium compounds by nucleophilic displacement, and is less basic and more nucleophilic than the
corresponding sulfur compound. This air-sensitive anion can be generated in situ from diphenyl
diselenide by reduction with sodium metal, sodium borohydride, LAH <1996JOC851>, by treat-
ment with NaH (or KH) <1992S933>, or from PhSeH in the presence of bases (KOH, Et3N).
Selenyl halides (PhSeCl or PhSeBr) and PhSeOTf (generated in situ from PhSeBr and AgOTf) are
commonly used as efficient sources of electrophilic selenium. In some cases, N-phenylselenophthali-
mide is preferred due to the absence of a nucleophilic counterion <2001EJO507>. Free-radical and
organometallic chemistry <1998SL1432> have also been used to prepare aryl selenides.
Selenides are oxidized more easily to selenoxides than the corresponding sulfur to sulfoxides.
Many oxidative reagents (t-butylhydroperoxide, peracetic acid, ozone, and Oxone1) have been
employed to convert selenides into selenoxides, but hydrogen peroxide, MCPBA, and sodium
periodate are, by far, the most frequently used. In some cases, yields have been significantly
improved by using dimethyldioxirane <2000JOC6293> or Davis’ reagent <2001S1356>.
Selenoxides undergo a syn-elimination reaction about 1,000 times faster than the corresponding
sulfoxides. Aryl selenoxides bearing electron-withdrawing substituents (e.g., o-NO2C6H4) and
pyridylselenoxides have also demonstrated high efficiency in this process <1980TL5037,
1985T4347>. The elimination does not occur <1992JA10181> or is more difficult <2000TL7645>
if the required syn-conformation is not accessible or if the strain from the incipient double bond is too
great. Most of the time the selenoxides are not isolated. The elimination reaction occurs in the
temperature range from 78 C to boiling toluene, depending on the nature of the substrates.
Selenoxide elimination is not free of side reactions and it has proved advantageous, with electron-
rich olefin substrates such as enol ethers, to use DHP or 2-methoxypropene as cosolvent in order to
trap selenenic acid. Selenenic acid can also be converted into selenamide by the addition of amines.
It should be pointed out that aryl selenides are quite inert to many chemical transformations
and consequently could be introduced at the early stage of a synthesis. For example, hydrobora-
tion followed by oxidative work-up is compatible with the presence of a phenylselenide group
<2001JA30>. A phenylselenide can also be considered as a temporarily masked double bond.
This property has been exploited in the synthesis of peptides containing unstable dehydroamino
acids <2002OL1335>. The oxidation–elimination sequence is compatible with a range of func-
tional groups <2002JA10036>.
The reaction of lithium ester and ketone enolates with selenyl halides or with diphenyl
diselenide leads to -phenylselenocarbonyl intermediates, which are transformed in high yields
to the corresponding ,-unsaturated compounds following an oxidation–elimination sequence.
In the total synthesis of (+)-valienamine (Scheme 20) <1998JA1732>, selenation of the methyl
ester 43 using LDA and diphenyl diselenide followed by oxidation with MCPBA at 78 C gave the
desired diene 44. The oxidation step was performed in the presence of 2-methoxypropene, added
as a selenenic acid trap, to avoid the formation of fully aromatized compounds. The same
sequence was carried out using 2,2-dipyridyl disulfide in place of the phenylselenide. After
thermolysis in toluene of the corresponding 1:1 mixture of sulfoxide diastereoisomers, differing
in their configuration at sulfur, it appeared that only one of these diastereoisomers was prone to
elimination. Attempts to increase the reaction time and temperature led to aromatized products.
This point highlights the fact that selenoxides are more labile compared to sulfoxides and also
epimerize at selenium rather rapidly, whereas sulfoxides do not <1993OR1>.
i. MCPBA, –78 °C
OMe
ii. TBDPSO
OH i. LDA
TBDPSO CO2Me
ii. (PhSe)2 SePh iii. –78 °C to rt
CO2Me
iii. TBDPSCl CO2Me
62%
40%
44
43
OH
HO
OH
HO
NH2
(+)-Valienamine
Scheme 20
Introduction of the double bond into the A-ring of ()-arisugacin A was performed at the last stage
by the usual -phenylselenation/oxidation–elimination sequence (Scheme 21) <2003T311>.
OMe OMe
O O O O
OMe OMe
i. KOBut/LDA
O O
ii. PhSeBr
iii. H2O2
OH OH
67%
OH OH
(±)-Arisugarin A
Scheme 21
Regioselective ring opening of epoxides with sodium phenylselenide has been routinely used to
synthesize allylic alcohols. In the course of the total synthesis of ()-kelsoene (Scheme 22)
<2002OL3755>, the allylic alcohol 46 was obtained by a highly regioselective ring opening of
epoxide 45 with p-chlorophenylselenolate anion, followed by subsequent oxidative elimination. In
contrast, treatment of the same epoxide with LDA afforded exclusively the allylic alcohol 47
<2002OL3755>.
i. NaH
O O O O H2O2, EtOH O O
(p -ClC6H4Se)2 H
reflux
H
94% HO 92% HO H
O
45 Se 46
(±)-Kelsoene
Cl
LDA 80%
O O
HO
47
Scheme 22
In recent years, this transformation proved to be a powerful tool to deliver, in a stereocon-

trolled fashion, allylic alcohols from epoxides, and it has been exploited in many total syntheses,
e.g., (–)-galanthamine (Scheme 23) <2000JA11262>, (+)-pancratistatin <2000JA6624>,
(–)-morphine <2002JA12416>, and the core of agelastatin <2002TL723>.
The introduction of a double bond by highly efficient nucleophilic displacement of a halogen
with phenylselenide anion, and subsequent selenoxide elimination, has found extensive applica-
tion in organic syntheses <2002CC1940, 2002JA10036, 2002OL1335, 2003OL419>. An example
is provided by the synthesis of (+)-K252a, in which the iodide 48 is converted into an exocyclic
methylene intermediate 49, in high yield, upon treatment with PhSeNa, acetylation of the result-
ing alcohol, and a subsequent oxidation–elimination sequence <1999JA6501> (Scheme 24).
The Grieco procedure <1976JOC1485> provides an easy access to aryl selenides bearing
electron-withdrawing groups on the phenyl ring. The efficiency of this procedure is illustrated
by the one-pot conversion of the primary alcohol 50 into the corresponding vinyl compound 51
(Scheme 25), an advanced intermediate in the total synthesis of (+)-gelsemine <2000AG(E)4073>.
H H H
(PhSe)2 SePh
MeO O NaBH4 MeO NaIO4, 80 °C MeO
OH OH
98% 64%
N N N
Me Me Me
OH
H
MeO
N
Me
(–)-Galanthamine
Scheme 23
H H H
N O N O N
i. (PhSe)2, NaBH4 O
ii. Ac2O
iii. MCPBA, DHP, Et3N
N N 80% N N N N
H O H O
I Me
HO
OH OAc CO2Me
49
48
(+)-K252a
Scheme 24
OH
NC NC
O MOM O O
i. o -NO2C6H4SeCN, Bu3P MOM
Me N N ii. MCPBA then Et3N Me N N Me N NH
83%
O
PhOCO PhOCO
50 51
(+)-Gelsemine
Scheme 25
The electrophilic selenenylation of olefins followed by an oxidation–elimination sequence has

found numerous applications in total synthesis <1996TL275, 1996JOC2882, 2000EJO2145,
2000T309, 2001TA2649, 2002JOC6725, 2003JOC1172>. The efficiency of this methodology is
illustrated by the double-bond transposition of the Diels–Alder adduct 52 to the chiral allylic
alcohol 53, an intermediate in the total synthesis of (–)-polycephalin C (Scheme 26)
<2002AG(E)2786>.
A striking illustration of the power of selenium chemistry to create a double bond is demon-
strated by the total synthesis of ()-merrilactone A (Scheme 27) <2002JA2080>, which features
sequential carbonyl -selenylation and vinyl group bromoselenylation followed by a double
oxidation–elimination reaction.
i. MCPBA
CO2R* PhSeBr, MeCN/H O HO CO2R* HO CO2R*
2 ii. EtPr2i N, reflux
CO2R* 75% PhSe CO2R* 92% CO2R*

52 53
R*= (+)-Menthyl
O
HO Me
N
OH
O
O
OH
N
HO Me
O
(–)-Polycephalin C
Scheme 26
OTBS i. LiHMDS, TMSCl OTBS OTBS

H O PhSe H O i. O3, then 1-hexene O
PhSeCl
ii. PhSeBr, MeCN ii. PhH, Et3N, reflux
O O O O
O O O O O
77% overall yield
PhSe
Br Br
HO O
O O
O
(±)-Merrilactone A
Scheme 27
Strategies involving radical reactions to introduce arylselenium have been described in this context.
For example, in the course of a total synthesis of both enantiomers of cocaine (Scheme 28)
<1998JOC4069>, phenylselenides 55, first obtained by photochemical-induced radical decarboxyla-
tion of the O-thiohydroxamate derivative of the acid 54 in the presence of (PhSe)2, were next subjected
i. (COCl)2
ii.
+ N S Me Me
Me H
– N OH N N
Cl CO2H SePh NaIO4, 80 °C
iii. (PhSe)2, hν
72% 57%
54 55
(–)-2-Tropene
Scheme 28
to an oxidation–elimination sequence to give the chiral 2-tropene. A similar sequence has also been
described in the presence of a pyridylsulfide group. In this latter, it was observed that sulfoxide
elimination occurred only when DBU was added to the refluxing toluene solution <1990T2345>.
Efficient thermally cleavable linkers for solid-phase chemistry have been developed based on
selenoxide syn-elimination (Scheme 29) <2000TL5287>. This process requires an activated sub-
strate and higher reaction temperatures if the selenoxide is replaced by a sulfoxide.
O
Ph i. NaIO4, 0 °C Ph
N
H ii. Dioxane, 18 h, 20 °C
O Se O
Fmoc-NH Fmoc-NH
31%
O O
Scheme 29
1.17.2.5 Cleavage of One CH and One CN Bond, Including the Cope Elimination
Alkenes may be formed by pyrolysis of suitable amides or thioamides (Equation (1); X = N, V = O or S).
Although the temperatures required are higher than those for the corresponding acetate, a similar
isomer distribution is obtained <1959JA651, 1960CRV431>. The most important reaction in this
section is the Cope elimination <1960OR317, 1960CRV431, 1991COS(6)1011, 1993S263>.
Only a few applications of the Cope elimination to synthesis have been recently reported. In the
synthesis of the retinol analog 58, having a (Z)-terminal double bond, the N,N-dimethylamine 56
was oxidized with peracetic acid to the corresponding N-oxide intermediate 57. This underwent a
Cope elimination during the warm-up of the reaction mixture to 0 C. The desired triene 58 was
accompanied by side products originating from [2,3]- and [1,2]-sigmatropic rearrangements
(Scheme 30) <1996CL671>.
NaHCO3 –60 to 0 °C
O Me Me
Me NMe2 Me AcO3H, –60 °C Me NMe2 Me 30 min
EtO EtO
EtO
69%
O O
O OTBDMS
OTBDMS OTBDMS
56 57 58
Scheme 30
The Cope elimination was used in the synthesis of cyclopentadienyl-annelated cycloalkanes

(Scheme 31) <2002S1362> from a dimethylamino precursor. However, Hoffmann elimination of
the corresponding ammonium iodide gave a better yield.
–
O +
NMe2 NMe2
H2O2, rt, 48 h 1 torr, 150 °C
+
41%
24:76
Scheme 31
1.17.3 FORMATION OF MONOENES BY RETRO-CYCLOADDITION REACTIONS
1.17.3.1 Retro-[2+2]-cycloadditions
Retro-[2+2]-cycloadditions would formally be [2s + 2a]-processes and hence many of these
reactions (Equation (14); X = Y = Z = W = C) occur thermally by diradical mechanisms
<1986T2135> and will not be considered in detail here.
W Z W X
+ ð14Þ
X Y Z Y
In contrast to the pyrolysis of cyclobutanes, for which experimental evidence is in favor of a

diradical mechanism <1994TL2675>, the thermal decomposition of simple cyclobutanones and
-lactams (Equation (14); X = Y = Z = C, W = CO, and X = Y = C, Z = N, W = CO, respectively)
to alkenes are believed to follow a concerted mechanism <1982AG(E)225, 1970JA1763>. More
synthetically useful than the preceding processes is the decarboxylation reaction of -lactones
(Equation (12); X = Y = C, Z = O, W = CO), which is generally carried out neat or in solution
at moderate temperatures (below 200 C) and with high, if not complete, stereoselectivity. Theore-
tical and kinetic studies have concluded that, in the gas phase, the reaction can be described as an
asynchronous concerted process with little charge separation at the transition state level, whereas,
in solution, a polar mechanism with formation of a zwitterionic intermediate is probably involved
<1998CPL261, 1997JOC109>. Nevertheless, it has been shown, in several examples, that the
thermal decarboxylation of cyclobutanones is stereoselectively controlled when carried out neat or
in solution. The pyrolysis of the diastereoisomeric spiro--lactones 59, leading to the sole 1,4-
diene 60, provides a good example (Scheme 32) <1991TL7033>. The fact that, in the particularly
smooth conditions of the reaction, the retro-[2+2]-cycloaddition is favored over the retro-[4+2]-
cycloaddition is noteworthy. Compound 60 can thus be considered as an allene equivalent in which
one of the double bond is selectively protected. Overall, the transformation represents an alternative
to the classical Wittig reaction which, for the present substrates, works poorly. Thermal decarbox-
ylation of -aminomethyl and -thiomethyl -lactones as well as ester-functionalized -lactones,
all prepared by conjugate addition of suitable nucleophiles to -methylene -lactones, are
other examples of stereoselective retro-[2+2]-cycloadditions (Scheme 33) <1995JOC578,
1995JOC3879>. Thermal decomposition of -lactones has also been used for the preparation
of enol ethers under FVP conditions <1973CJC981>, allenes, <1991JOC5782, 1993JOC322> and
,-difluoroalkenes <1995JOC5378, 1998JFC41>. An application in the field of natural products
has been reported with the synthesis of cucumin E <2001OL2029, 2002TL5039>.
H O
O 40 °C, 0.1 torr
20 °C R
O 80% R
R 50–70%
H
60
R = Me, Pr i
R CO2
O
O
59
Scheme 32
1.17.3.2 Retro-[4+2]-cycloadditions (Retro-Diels–Alder Reactions)

This [2s + 2s + 2s] reaction (Equation (15)) has been used extensively to prepare either alkenes,
dienes, heterodienes (Section 1.17.4.1), or other multiple-bonded functional groups containing at least
one heteroatom. For the preparation of alkenes (Equation (15); Z = Y = C), which involves cleavage
of two CC single bonds, cyclopentadiene, anthracene, and furan adducts have been commonly used
as alkene precursors, the initial choice being dictated mainly by the ease of the final separation between
diene and alkene species. The initial Diels–Alder reaction is a commonly used and practical way of
temporarily masking a reactive double bond which, in most examples, is released at a later stage of a
multistep synthetic transformation. The retro-[4+2]-reaction can be accomplished in solution at
elevated temperatures (>200 C) or at much lower temperatures if the presence of a Lewis acid can
be tolerated <1989JOC6008>. The transformations depicted in Scheme 34 illustrate each of these
procedures <2000JOC6319, 1998JOC7037, 2001JOC6400>. Both feature the generation of a synthe-
tically versatile ,-unsaturated carbonyl function. Other examples of the use of the retro-[4+2]-
cycloaddition strategy to reach the same structural motif can be found later in this section and in
the literature <1995T173, 1996TL8637, 1996TL7841, 1998T12361, 1999TL5593, 2003TL5741>.
OBut
LiO Me
Me Me Me
ButO2C Me ButO2C Me
THF, –78 °C
O then NH4Cl O O
+
Me O 42% Me O Me O
Me Me Me
cis/trans 16/84
Me Me
ButO2C Me ButO2C Me
180 °C +
87% Me Me
Me Me
cis/trans 16/84
Scheme 33
U U
V Z Heat V Z
+ ð15Þ
W Y W Y
X X
O OTBDMS O OH
PhOPh, reflux
then HF (OTBDMS
O O O
deprotection) O
O O O O
O 73% O
(+,–)-Diepoxin σ
Maleic anhydride
O H MeAlCl2 O
CH2Cl2, 55 °C, 2 h
88%
Bun H Bun
Scheme 34
The concomitant liberation of an aromatic derivative, such as furan, may also help lower the
temperature of the retro-[4+2]-cycloaddition reaction as illustrated in the two following exam-
ples. Equation (16) shows the preparation of a chiral allylic amino alcohol, which is achieved
under relatively mild conditions <1996TL8729>. Scheme 35 depicts a cascade of three
reactions (namely, iminophosphorane formation, and Staudinger, then retro-Diels–Alder
reactions), which can be carried out in refluxing toluene. The final and rather unstable
3,4-dihydro-2H-pyrrolo[1,2-a]-pyrimidin-6-one 61 was used as a synthetic precursor of the anti-
tumor antibiotic phloeodictine A1 <2003OL765>. A review of the applications of furan
Diels–Alder chemistry has been published <1997T14179>.
n
O Bu 160 °C
NHBn
H 6h
Bun OH ð16Þ
OH 74% NH
Bn
O
O PPh3 (polymer-supported) O
PPh3 Toluene, reflux
Toluene, 25 °C, 30 min O N 4h
N N3
O N
O
+
H 2N NH2
O
N N HN
(CH2)5
N 43% N N
+
O O N
61 OH
Furan (CH2)10
Phloeodictine A1
Scheme 35
In addition to heating in an appropriate solvent, FVP, which is characterized by very short reaction
or contact times, is a very useful means to effect retro-[4+2]-cycloaddition reactions. The distinct
advantages of this technique allow the formation of highly unstable compounds and minimize the
occurrence of secondary reactions such as double bond migration and erosion of selectivity. Two
examples of the application of this technique are shown in Scheme 36 <1997T17335> and in Equation
(17) <2002OL1063>. Numerous other examples, which conclusively demonstrate the attractiveness
of the FVP technique, can be found in a review <1999CRV1163>.
FVP O O
O +
500 °C (0.05 mm) H3O
O O
O
92% MeO2C HO2C
MeO2C H n-C5H11 H n-C5H11
H n-C5H11
Methylenolactocin
Scheme 36
H O
O FVP, 500 °C
H ð17Þ
Me Me
85–90% Pri
Pri
From a synthetic point of view, a particularly attractive situation is found when the released
double bond is engaged in a subsequent ‘‘one-pot’’ transformation. Such a cascade reaction,
which allows the creation of molecular complexity in a single operation, is of great value for
the synthesis of natural compounds. This is well illustrated by the following two examples
(Schemes 37 and 38) in which the released double bond participates in a Claisen rearrangement
<1998TA2215> and in an ene reaction, respectively <1997TL857, 2001TL4523>.
In contrast to the preparation of alkenes (Equation (15); Z = Y = C), which involves the
cleavage of two single CC bonds, the preparation of a heteroatomic double bond (Equation (15);
Z = C, Y ¼6 C) involves the cleavage of one CC and one CX single bond (X = heteroatom) or two
CX single bonds. Examples leading to the formation of highly reactive intermediates such as
acylnitroso species <1996TL9287, 2000TL4265> and selenoaldehydes <2003TL1179> have been
reported.
Me
OH Me
OH
H
PhOPh, reflux
H O O H
H 51% Me
Me
Me Me Me
90% ee
Chiral nonracemic
>99% ee (+)-Curcuphenol
Scheme 37
H N CO2Me PhOPh, reflux N

MeO2C Cbz
H Cbz
80%
Chiral nonracemic
>99% ee
MeO2C CO2H
N N CO2H
Cbz H
99% ee (–)-Kainic acid
Scheme 38
Thermal equilibration of the primarily formed Diels–Alder adducts with the final production of
the more stable adduct(s) is also a process that implies a retro-[4+2]-cycloaddition step
<2002TA2003, 2002TL6067>.
A number of comprehensive reviews of retro-Diels–Alder processes are available <1987S207,
1991COS(5)551, B-1998MI117-005, 1998OR(52)1, 1998OR(53)223>. The reaction also continues
to be the subject of several theoretical studies <2000OL3505, 2002JA5091>.
1.17.4 FORMATION OF DIENES AND POLYENES

The methods described in the previous sections may be applied to generate dienes and polyenes.
In this section, only those retro-pericyclic reactions that allow the creation of two (or more)
double bonds in one single operation will be considered. Such processes are not common in
synthesis. An example can be found in the synthetic sequence leading to the formation of
(3(S),4(S))-2,5-dimethyl-3,4-hexanediol [(S)-DIPED] from ((R),(R))-tartaric acid as depicted in
Scheme 39. The pyrolysis of diacetate 62 was carried out on a 250 g scale and led to the
[(S)-DIPED] intermediate 63 in up to 85% yield <1987JOC5034>.
AcO OAc
FVP
HO2C CO2H 450–470 °C
O O O O
HO OH 85% HO OH
63 (S)-DIPED
62
Scheme 39
In a somewhat esoteric example leading to a fully conjugated cyclophane compound, a quadruple

sulfoxide elimination was employed to generate four alkene units <1991AG(E)1173>. Brief men-
tion will be made also of the case where an already installed double bond participates in the retro-
pericyclic reaction. This situation is illustrated by the example of the pyrolysis of furan
<1986JA4138> and benzofuran <1986JOC4208> derivatives (Scheme 40). Thus, the FVP of 64
led to the formation of the 2,3-dimethylene-2,3-dihydrobenzofuran 65, which was characterized by
low-temperature NMR spectroscopy. The formation of 65 may involve a direct -elimination or a
[3,3]-sigmatropic shift of the ester function prior to -elimination. Compound 65 is not thermally
stable and dimerizes at room temperature to give the [4+4]- and [4+2]-dimers.
FVP, 620 °C
OCOPh ( 10–4 torr)
Dimerization
O Me 35% O
64 65
Scheme 40
1.17.4.1 Retro-cycloaddition Reactions

As already mentioned, the retro-[4+2]-cycloaddition (retro-Diels–Alder reaction) can also serve
to generate a diene or a heterodiene. The general conditions of the reaction are described in
Section 1.17.3.
The process is especially simple when the released diene (Equation (15); U = V = W = X = C)
is integrated into an aromatic system. The accompanying alkene is most frequently a small stable
molecule (e.g., ethylene or isobutylene) although the release of a larger molecule may be encoun-
tered <1989CC1238, 1996TL3487>. [4+2]-Cycloaddition and retro-Diels–Alder reactions are
often sequential processes. Typical examples are shown in Schemes 41–43 <2003T481,
2001TL7367, 2003JA9602>.
Xylene
O
120 °C, 1 h
Ph O CO2Me
N O MeO2C CO2Me
O E E O
N N
70% Ph CO2Me
O Ph
E = CO2Me
Scheme 41
Toluene, reflux
OMe OMe OMe
TBDPSOCH2
CHO CHO CHO
Me
OTBDPS OTBDPS
TMSO Me 82% TMSO R
Me R = OTMS
Me SiO2
R = OH
Scheme 42
A diene may be generated by cleavage of two single CC bonds, as in the examples reported above,
or by cleavage of one single CC bond and one single CX bond (X = heteroatom) or even by the
cleavage of two single CX bonds. This is illustrated by the examples shown in Schemes 44
<1999TL3795> and 45 <1996JOC6028> where two single CS bonds, on the one hand, and two
single CN bonds, on the other hand, are broken to finally deliver a homodiene. Sulfur and nitrogen
are the accompanying small molecules released. The formation of the cage system 66 is somewhat
spectacular as it is the result of a one-pot sequential intermolecular inverse electron-demand
Diels–Alder, retro-Diels–Alder, and intramolecular Diels–Alder protocol.
H
H O O
Me O O
TMSO
Me 140 °C H
H TMSO Me
+ Me
Me
75%
OTMS Me OTBDMS
OTBDMS
TMSO
H H
O O O O
RO Me HH HO Me HH
OTBDMS O
Me Cl
OR OH
Me
R = TMS Cycloproparadicicol
SiO2
R=H
Scheme 43
H
O N O
H
O N O
S S
o -Dichlorobenzene
reflux SS
N N
H H N N
H H
S2
H H
N O N O
O O
–H2
36%
N N N N
H H H H
Arcyriaflavin-A
Scheme 44
The Diels–Alder–retro-Diels–Alder sequence featuring 2-pyrones has been extensively used in

the field of natural product synthesis, both in its inter- and intramolecular version <1992T9111,
B-1999MI117-006>. Scheme 46 gives an example with the synthesis of the naturally occurring
lycorine alkaloid anhydrolycorine-7-one <1996JOC1650>. Generally, owing to their partial aro-
matic nature, 2-pyrones need high temperatures to react with dienophiles, although, in the
example shown in Scheme 47, the reaction takes place quite easily under the influence of silica
<1998TL4261>.
When the dienophile possesses a triple bond, as in the reaction depicted in Scheme 46, and, more
generally, when the possibility of forming an aromatic structure exists <1996JOC7933,
2000OL2049>, the tendency is high for the Diels–Alder adduct to experience a retro-[4+2]-cyclo-
addition with extrusion of CO2. Similar behavior has been observed for some pyranylene–metal and
benzopyranylidene–metal complexes, <1990JA4550, 2000OM5525>, which represent the metal ana-

logs of 2-pyrones. For instance, the benzopyranylene–tungsten complex 67 reacted with electron-rich
olefins at room temperature to give naphthalene derivatives (e.g., 68) in good yields (Scheme 48)
<2000JA10226>. These reactions have been interpreted as a Diels–Alder condensation followed by a
pericyclic demetallation of a tungsten (or a chromium) hexacarbonyl.
CN
CHCl3, 110 °C
CN NC
N (sealed tube)
N
CN 98%
66
N
NC N NC
NC NC
N2
Scheme 45
CO2Me CO2Me CO2Me

O O
O O O O O
N N O N
O O
CO2
O O O
O N
O
Anhydrolycorin-7-one
Scheme 46
O O O
CH2Cl2, rt, 7 days
BnN SiO2 BnN O BnN
O OC
Si 50% Si Si
Me R O Me R Me R
CO2
R = -CH2-O2C-CH(CH3)2
Scheme 47
OEt
OEt
Ph THF, rt, 15 min Ph Ph

EtO OEt
TMSCl Ph
O O OEt
74%
W(CO)5 OEt
W(CO)5 OEt
67 W(CO)6 68
Scheme 48
Heteroaromatic structures can also be reached by a retro-[4+2]-cycloaddition. In these cases, the

process involves the breaking of one CC and one CX or two CX double bonds (X = hetero-
atom) with the concomitant release of a small stable heteroatomic molecule. In most examples,
a tandem Diels–Alder and retro-Diels–Alder sequence occurs. Thus, the condensation of
1,3,5-triazine 69 with acetamidine hydrochloride in DMF afforded the 1,3-diazine 70 in good
yield <1994JOC4950>. The reaction cascade proceeds with in situ amidine–enamine tautomerization,
[4+2]-cycloaddition, loss of ammonia from the Diels–Alder adduct with generation of an imine,
imine–enamine tautomerization, and, finally, a retro-Diels–Alder reaction with production of ethyl
cyanoformate (Scheme 49). 1,2,4,5-Tetrazines behave similarly to give 1,2-diazines, which are prone to
reductive ring contraction to yield synthetically useful pyrroles <2003JOC3593>.
NH.HCl
Me NH2
EtO2C N CO2Et H 2N N CO2Et
DMF, 100 °C, 22 h
N N N
85%
CO2Et CO2Et
69 70
NH.HCl NH2.HCl CO2Et
Me NH2 NH2
N
CO2Et CO2Et CO2Et
N N N
H2N N CO2Et HN N H2N N
CO2Et CO2Et
N N N
NH2 CO2Et CO2Et CO2Et
Scheme 49
A similar approach was used in the synthesis of purines and purine nucleosides <1996JOC5204,
1999JA5833> and a theoretical study has also been achieved <2001JOC6029>. The synthesis of
the 2-glycosylamino pyridine shown in Scheme 50 proceeds with an identical strategy
<1996T5845, 1996T13721>.
The Diels–Alder–retro-Diels–Alder sequence is particularly attractive when the cycloaddition
reaction occurs intramolecularly since an elaborate structure can be reached in one single opera-
tion. An illustration is provided by the synthesis of the alkaloid (–)-stemoamide (Scheme 51)
<2000JA4295>.
The retro-[4+2]-cycloaddition strategy is also applicable to the formation of heterodienes as
illustrated by the transformation of the 1-thia-3-aza-buta-1,3-diene 71 to the 1-thia-buta-1,3-diene
72 under particularly mild conditions (Scheme 52) <1985JOC1545>.
O MeO2C CO2Me E CO2Me

Me MeCN, reflux, 7 h E MeO2C
N O NH
MeO N NH MeO N NH
Me N N Gly
85%
O MeO O
OAc OAc
Me N C O
OAc OAc
OAc E = CO2Me OAc
Scheme 50
O O
O 7 steps Diethylbenzene Me H N
N (182 °C )
NH Me
MeO O 50–55% MeO
O
CO2H
N Me N MeCN
Me
O O O
H3C H N + Me H Me H
H N Reduction N
H
MeO O O
O O O
H H
(–)-Stemoamide
Scheme 51
CO2Me
Ph S Ph S CO2Me S
MeO2C
+ THF, rt THF, reflux
N N
81% CO2Me 83% MeO2C
CO2Me
N(Me)2 N(Me)2 N(Me)2
PhCN
71 72
Scheme 52
Heterodienes generated by the thermal decomposition of Diels–Alder adducts are sometimes

transient species that spontaneously convert to more stable structural forms. Thus, in the
transformation depicted in Scheme 53, the pyrolysis of triazine 73 proceeds via a retro-Diels–
Alder reaction to give a transient heterodiene that tautomerizes toward a stable 2-aminopyrrole,
as firmly demonstrated by 15N-labeling studies <1999OL537>.
NH2 CN NH CN CN
CN HN
250 °C C NC
N N
N N N
N N N N HN N H2N
Bn H Bn Bn Bn
73 N2
Scheme 53
Capture of an unstable heterodiene by a dienophile present in the reaction medium is also a situation
frequently observed. For example, the simple retro-[4+2]-cycloaddition of adduct 74 leads to a
nitroso alkene, which is captured by an enol ether in an inverse electron-demand [4+2]-cycloaddition
(Scheme 54) <2000OL1323>. Another example is provided by the transformation shown in

Scheme 55 <2000TA2661>. In these two examples, each of the primary Diels–Alder adducts behaves
as a source of an unstable diene in neutral medium.
OEt
CHCl3,
1:1 vol CO2Me
O
3 days, 33 °C N
O
N 52% N
EtO O
CO2Me
74
CO2Me
Scheme 54
NMe2
Me NMe2 Me NMe2
CHCl3, 60 °C, 5 days
Cl Cl
Pd Pd
50% H
P P
H
Me Me N(Me)2
SO2Ph O
Me Me
Scheme 55
A slightly different situation is shown in Scheme 56. In this case, the primary Diels–Alder
adduct is oxidized before being subjected to the conditions of the retro-[4+2]-cycloaddition with
diene trapping <1995TL5089, 1996T12233, 1996T12247>.
Me O Me O O
Me O OEt Me O OEt CHCl3, 60 °C
MCPBA
55% MeOC S MeOC S
MeOC S MeOC S
O O
Diels–Alder adduct O
Scheme 56
1.17.4.2 Retro-cheletropic Reactions

Retro-cheletropic processes are applicable to the stereospecific synthesis of conjugated dienes
(Equation (18)). The extruded group (X) is most often a stable small hetero-molecule such as CO,
N2, N2O, S, and SO2.
X X + ð18Þ
The reaction may be accomplished under FVP conditions or at reflux of appropriate solvents.
In most examples performed under FVP conditions, the highly reactive species generated are not
isolated but characterized in situ. One example is furnished by the pyrolysis of the 1,3-dioxine-4-
thione 75, which gives anisylthioketene and acetylene as the final products. The transformation
was interpreted as shown in Scheme 57 <2000JOC2706>. Loss of acetone from 75 leads to the
formation of a thioketene that rearranges to a thioacylketene (anisyl 1,3-shift). The latter then
undergoes electrocyclization to a thiet-2-one which decomposes, following a retro [2+2]-cyclo-

addition, to give anisylacetylene and, concurrently, by cheletropic extrusion of CO to give
anisylthioketene.
S O
FVP O
O H C S
Me 500 °C
O C
Me MeO H
S
MeO
75
OMe
O COS
S MeO H
S
C
OMe MeO
H
CO
Scheme 57
The stereochemistry of the thermal cheletropic decarbonylation of cis-2,5-dimethyl-3-cyclopen-

tenone has been determined by multiphoton infrared irradiation <2003JA8529>. In this parti-
cular case, the great advantage of the MP-IR photolysis/thermolysis technique over the classic
FVP is that the diene product is not prone to isomerization. The reaction leads to the exclusive
formation of trans–trans-2,4-hexadiene, thereby showing that the cheletropic fragmentation pro-
ceeds via the disrotatory pathway as predicted (Scheme 58) <1966JA1335>.
O Me
O
MP-IR
Me Me
S
Me
CO
Scheme 58
Photo-mediated cheletropic extrusion of CO has been reported as a route to C-15 mono-

substituted semibullvalenes <1998TL4899>.
A large-scale one-pot and convenient preparation (55% overall yield) of the useful synthon
3-chloro-2-(chloromethyl)propene by cheletropic extrusion of nitrous oxide from an N-nitrosoazir-
idine (Scheme 59), as well as a theoretical study of the reaction mechanism, has been reported
<2000JOC6784, 2000JOC3612>.
NaNO2
OH HCl
20 °C 50 °C
NH N NO
NH2 Cl Cl
HO 55%
Cl Cl Cl Cl
OH
N2O
Scheme 59
The cleavage of sulfur from 1,3-dipolar cycloaddition adducts to give pyridones has been
described but, in that case, it was difficult to make a choice between a cheletropic extrusion or
a stepwise mechanism to account for the departure of sulfur <2000T1247>.
The cleavage of SO2 from 3-sulfolene is, by far, the most synthetically useful retro-cheletropic
reaction and this topic has been reviewed <1993PHC1>. This reaction has been widely used to
synthesize diversely substituted electron-rich and electron-poor 1,3-butadienes. An example is the
cation-substituted diene 77, which was isolated after thermolysis of the 3-sulfolene 76, particularly
in mild conditions (Scheme 60) <1997JOC7812>. Despite its electron-deficient character, diene 77
reacts in normal demand with electron-poor dienophiles.
CH3CN
Br Br +N 140 °C +N
Pyr, rt, 48 h – (sealed tube) –
Br Br
S 40% S (quant.) –
O O O O PF6
76 77
Scheme 60
Thermolytic extrusion of SO2 from polymer-bound 3-(phenylsulphonyl)-3-sulfolene followed

by trapping of polymer-bound 2-(phenylsulphonyl)-1,3-butadiene with various dienophiles has
been recorded <2001JOC5528>. Due to the relatively simple thermal extrusion of SO2,
3-sulfolenes may also serve to temporarily protect a reactive diene. This strategy has been
exploited in a synthesis of 19-fluoro vitamin D derivatives <1996TL6753>. The effect of solvent
polarity on the cheletropic extrusion of SO2 from 3,4-dimethyl-3-sulfolene has been investigated
<1996T6241>.
The sulfone 78 resulting from the Diels–Alder cycloaddition between 3-sulfolene and cyclo-
pentadiene may be stereoselectively alkylated at its C-2 and C-5 positions. After pyrolysis,
effecting both retro-[4+2]-cycloaddition and cheletropic extrusion of sulfur dioxide, a diene
substituted at each of its terminii may be selectively isolated. An example of this protocol
<1986T4975> is presented in Scheme 61 with the synthesis of pellitorine, an insect sex
pheromone.
Selective exo face alkylation

and carboxylation
FVP O
650 °C
CONHBui n
C5H11 NHBui
90%
SO2 C5H11n SO2
Cyclopentadiene Pellitorine
78
SO2
Scheme 61
The pyrolysis of 1,3-sulfolenes with the formation of reactive o-quinodimethanes

<1999CRV3199, 2002T5367> has been employed in the preparation of natural products such
as alkaloids <1994TL1071> and steroids <1980HCA1703>. The pyrolysis of heteroaromatic
sulfolenes leads to heteroaromatic o-quinodimethanes, which are generally trapped by dienophiles
in both an intermolecular or intramolecular mode. Scheme 62 gives an example of each of these
modes <2002TL799, 2000JOC5760, 1998T12609>.
The extrusion of SO2 may be part of a cascade of reactions as in the example depicted in
Scheme 63. The sequence consists of three pericyclic reactions, namely, a Cope rearrangement
followed by cheletropic extrusion of SO2 leading to a heterodiene in which a [1,5]-sigmatropic
hydrogen shift leads finally to the 1,3-diene 79 <2001T5009>.
o -Dichlorobenzene
150 °C CO2Me
SO2 N
N N Bn CO2Me
Bn Bn 80%
O O O
N PhH N N
N N N
180 °C
(sealed tube)
O
S 94%
O2 O O
O
O
O
Scheme 62
Me Me Me Me
N 215 °C N N H NH
SO2 SO2
N N N 64% N
79
Scheme 63
The pyrolysis of sultines is sometimes more advantageous for the generation of heterocyclic-
fused o-quinodimethane species. For instance, the easily prepared sultine 80 undergoes cheletropic
extrusion of SO2 smoothly at reflux in benzene, whereas the corresponding sulfolene requires a
temperature of 230 C to generate the same o-quinodimethane intermediate <1998JOC977>. The
reaction has been applied to the synthesis of the nucleoside 81 (Scheme 64) with the aim of finding
new antiviral drugs. Other syntheses of heterocycles, using the pyrolysis of sultines as the key step,
have been reported <2000JOC3395, 2002JOC9267>.
CO2Et
OHCH2SO2Na.2H2O
Benzene
TBAB, DMF 80 °C Cl O2 N
Cl Cl O
Br 0 °C to rt S 10 h
Br O Cl 71% overall
Cl (quantitative) Cl
80 SO2
Cl NO2 Cl N
Cl
Cl CO2Et Cl N
HO
O
OH OH
81
Scheme 64
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Biographical sketch
Jacques Lebreton was born in Guérande André Y. Guingant is a director of research at

(France) in 1960. He received his Ph.D. degree the French National Center for Scientific
(1986) from the University of Paris XI-Orsay Research (CNRS) and works in the Organic
under the supervision of Professor Eric Brown Synthesis Laboratory at the University of
(Le Mans). His thesis work included the total Nantes. He attended the Pierre et Marie
synthesis of C-nor D-homosteroids. In 1986, Curie University (Paris) and received his
he started his first postdoctoral fellowship Ph.D. degree in 1979 under the supervision
with Professor James A. Marshall at the Uni- of the late Professor J. Ficini. After pursuing
versity of South Carolina working on the research as a postdoctoral fellow with Profes-
[2,3]-Wittig rearrangement and its application sor Samuel J. Danishefsky at the Universities
in total synthesis. Following a second post- of Pittsburgh and Yale, he joined the labora-
doctoral fellowship with Professor Robert E. tory of Dr. Jean d’Angelo at the ‘‘Ecole
Ireland at the University of Virginia working Supérieure de Physique et Chimie Indus-
on the total synthesis of monensine, he joined trielles’’ (ESPCI, Paris) in 1982. In 1992, he
in 1990 the laboratories of CIBA-GEIGY moved to the University of Nantes. His
(Novartis) in Basle, where he worked in research interests involve the development of
Dr. Alain De Mesmaeker’s group in antisens stereoselective methods, the total synthesis of
oligonucleotides. In 1994, he joined the CNRS natural products, and medicinal chemistry
and spent a few years in the group of Dr. Jean investigations in the field of nitrogen-contain-
Villéras (UMR-CNRS 6513, Nantes) exposed ing heterocycles.
to organometallic chemistry. In 1998, he was In 2000, A. Guingant and J. Lebreton set
promoted to Professor at the University of up a research group, named Symbiose,
Nantes. His major research interests are orga- devoted to develop research at the interface
nometallic chemistry, synthesis of bioactive between chemistry and biology. The Symbiose
molecules, and synthesis of labeled molecules group is a member of a network that aims to
to study biological processes. develop new pharmacological strategies and
design new antagonists to specifically target
small G protein signaling.
1.18
One or More ¼CH, ¼CC,
and/or C¼C Bond(s) Formed
by Rearrangement
M. T. MOLINA
Instituto de Quı´mica Médica, CSIC, Madrid, Spain
and
J. L. MARCO-CONTELLES
Instituto de Quı´mica Orgánica General, CSIC, Madrid, Spain
1.18.1 GENERAL INTRODUCTION AND METHOD OF CATEGORIZATION 798

1.18.2 REARRANGEMENTS INVOLVING [1,2]-SHIFTS AND [1, j ]-MIGRATION 798
1.18.2.1 Where Y = H 798
1.18.2.1.1 [1, j]-Migrations of hydrogen 798
1.18.2.2 Where Y = C 807
1.18.2.2.1 [1, j]-Rearrangements involving CC bond migration 807
1.18.2.3 Where Y = CC 813
1.18.2.4 Where Y = CCC 813
1.18.2.4.1 Cope rearrangement 813
1.18.2.4.2 Thermal/photochemical Cope rearrangement 813
1.18.2.4.3 Catalysis of the Cope rearrangement 815
1.18.2.4.4 Oxy-Cope rearrangement 816
1.18.2.4.5 Aza-Cope rearrangement 816
1.18.2.4.6 Anionic oxy-Cope rearrangements 817
1.18.2.4.7 Anionic amino-Cope rearrangements 820
1.18.2.4.8 2-Oxonia-Cope rearrangement 821
1.18.2.4.9 Cope rearrangement of divinyl cycloalkanes 821
1.18.2.4.10 Cope rearrangement of vinyl bicycloalkenes 825
1.18.2.5 Where Y = CZ (Z = Heteroatom) 825
1.18.2.6 Where Y = CCZ 825
1.18.2.6.1 Where Z = chalcogen 825
1.18.2.6.2 Thia-Claisen rearrangement 842
1.18.2.6.3 Selena-Claisen rearrangement 843
1.18.2.6.4 Where Z = N; the aza-Claisen rearrangement and related processes 843
1.18.2.7 Other Heteroatom Variants 847
1.18.2.8 Where Y = ZCZ0 848
1.18.2.8.1 Where Z and Z0 = chalcogen 848
1.18.2.8.2 Where Z and/or Z0 = nitrogen 850
1.18.2.9 Where Y = Z 851
1.18.2.10 Where Y = ZZ0 852
1.18.2.10.1 Where Z, Z0 = chalcogen 852
1.18.2.10.2 Where Z and/or Z0 = nitrogen, phosphorus 853
1.18.3 OTHER REARRANGEMENTS 856
1.18.3.1 Tandem and Higher Sigmatropic Rearrangements 856
797
798 One or More ¼CH, ¼CC, and/or C¼C Bond(s) Formed by Rearrangement
1.18.3.2 Rearrangements Involving Ring Opening 858

1.18.3.2.1 Ring opening of cyclopropanes 858
1.18.3.2.2 Photochemical ring opening of cyclic ketones 860
1.18.3.2.3 Rearrangement of epoxides 861
1.18.1 GENERAL INTRODUCTION AND METHOD OF CATEGORIZATION

Rearrangement reactions play a central role in functional group transformations and in the state
of the art in modern organic synthesis. The present chapter complements other parts in this work
devoted to rearrangements, Chapters 1.09 and 1.17. Allylic rearrangement during substitution,
aromatic rearrangements, and reductive transposition will not be examined within this chapter.
The reader is referred to the two books edited by de Mayo <B-1963MI001, B-1980MI001>, to
the corresponding chapter on rearrangements in the annual series Organic Reaction Mechanisms
edited by Knipe and Watts <B-1966MI001, B-2001MI001>, and to some other specific reviews
and relevant papers on sigmatropic rearrangements <1996TA1847, 1998S227, 2001CUOC1133,
2002ACR279>.
The order of discussion is based on the formation of compound type 2 from precursor 1
(Equation (1)).
X Y ð1Þ
1 2
In this section the same order that has been used in the excellent account by Murphy on the
present subject is followed <1995COFGT(1)793>. Accordingly, the rearrangements for [1,j]-
processes (j = odd number) for Y = hydrogen, carbon-, chalcogen-, or heteroatom-containing
substituents are described. These are not necessarily sigmatropic and the cases for Y = hydrogen
are discussed first, followed by Y = carbon and hetero- or chalcogen-containing substituents.
1.18.2 REARRANGEMENTS INVOLVING [1,2]-SHIFTS AND [1, j ]-MIGRATION

This section deals with rearrangements involving a [1,2]-shift of a double bond and migration of
the group X across the alkene moiety to give the new function Y (Equation (1)). These reactions
have been covered in a recent book <B-2000MI001> and in general texts <B-1970MI001,
B-1976MI001>; they are discussed in the following order: sigmatropic, acid- and base-catalyzed,
metal-catalyzed, and anion accelerated migrations of hydrogen atoms.
1.18.2.1 Where Y = H
1.18.2.1.1 [1, j]-Migrations of hydrogen
(i) Sigmatropic migrations of hydrogen

The photochemical or thermal migration of hydrogen across a -system has been reviewed several
times <1976CRV187, 1981MI1272, 1995HOU(E21d)4421, 1995COFGT(1)793> and has interest-
ing consequences from the synthetic point of view. The most common migrations are the
photochemical [1,3]-, thermal [1,5]-, and the photochemical or thermal [1,7]-hydrogen shifts.
According to the Woodward–Hoffmann rules, the simplest thermally allowed [1,3]-process should
take place antarafacially along the allylic carbon skeleton (Scheme 1). The photooxidation of
phenyl allyl sulfide gives ,-unsaturated sulfones in a typical [1,3]-H shift <2002JOC1036>. The
isomerization of imines proceeds via a [1,3]-hydrogen shift catalyzed by ruthenium-hydride
complexes in toluene, under a hydrogen atmosphere (Scheme 1) <1998CL1255>. The reaction
of Fe2(CO)9 with imine ligands derived from - or -naphthylcarbaldehydes gives new iron
complexes as the result of CH activation in the ortho-position with respect to the exocyclic
One or More ¼CH, ¼CC, and/or C¼C Bond(s) Formed by Rearrangement 799
imine function; the reaction then proceeds via subsequent [1,3]-hydrogen shift toward the former
imine carbon <1999OM4845>. A [1,3]-sigmatropic shift has been detected in the photo-Fries
rearranged intermediate of 2,4-dimethoxy-6-(p-tolyloxy)-s-triazine <1998JCS(F)3077>. The thermal
rearrangement of 5-methyleneisoxazolidines 3 afforded two isomers of 5,6-dihydropyrrolo
[2,1-a]isoquinolines 4 (Scheme 1) <1997JCS(P1)2973>. A new planar-chiral bidentate phos-
phaferrocene ligand coupled to a rhodium complex, [Rh(COD)2]BF4, has proved to be an
efficient catalytic system for the asymmetric isomerization of allylic alcohols to aldehydes; the
isomerization proceeds via an intramolecular [1,3]-hydrogen migration <2001JOC8177>. The
thermal and photochemical isomerization of tetraaryl tetrakis(trifluoromethyl)[4]radialenes has
been shown to take place by [1,3]-hydrogen migration <2000JOC1615>. (Cyclobutenyl)carbene
tungsten complexes are shown to rearrange to 1-tungsta-1,3,5-hexatrienes by ring opening of the
cyclobutene ring and subsequent [1,3]-hydrogen migration <1998OM1197>. A new highly
efficient enantioselective entry to versatile chiral building blocks such as tetrahydro-endo-1,4-
methano- and tetrahydro-endo-1,4-ethanonaphthalenones was achieved by desymmetrization of
meso-allylic 1,4-enediyls using a cationic chiral Binap–Rh(I) catalyst; the reaction mechanism
includes a suprafacial [1,3]-hydrogen migration pathway <1995AG(E)2287>.
H
R1 R2 R1 R2
[1,3] [Ru-H] catalyst
N N
H H [1,3]
R3 R3
H
MeO MeO
[1,3]
N ∆ N
MeO O MeO
Me
27%
EtO2C CH2 CH2CO2Et
3 4
Scheme 1
In contrast, the thermal antarafacial [1,5]-hydrogen shift is one of the best studied reactions
within the group of pericyclic rearrangements <1976CRV187> (Scheme 2). The general features
include a cisoid-geometry of a 1,3-pentadiene structural moiety, intramolecular process and first-
order kinetics, being independent of solvent polarity <1982T567> (Scheme 2). Density functional
calculations have been carried out for [1,5]-hydrogen shifts in 1,3-cycloalkadienes <2001JOC8902,
2002JOC6025>, pyrroles, furans, thiophenes <1997CEJ523>, pyrazoles, and related systems
<1998JCS(P2)2497>. A thermal [1,5]-hydrogen shift results in the synthesis of conjugated linoleic
acid isomers <2003MI3, 2002MI435, 2003T567>. A [1,5]-sigmatropic proton shift has been
observed in the oxidation behavior of oxatocopherol-type oxidants <2002JOC3607>, and in the
FVP of N-mesityl-C-acylketenimines leading to quinolines <1998JOC5779>. New annelation
methods for the synthesis of 8H-heptaleno[1,10-bc]furans, -pyrroles, and -thiophenes have been
described making use of [1,5]-hydrogen migrations <1997HCA2520>.
[1,5]-Hydrogen shifts have been involved in the conversions of [o-[1-halo-1-(p-tolylsulfonyl)alk-
yl]benzyl]trimethylsilanes to o-quinodimethanes and benzocyclobutenes <1998JOC2086>, and in
the synthesis of chiral indenyl ligands derived from verbenone <2002OM144>. The secondary
products obtained in the heptalene-forming reaction of azulene and acetylenedicarboxylates are
formed via [1,5]-hydrogen shifts <2002HCA27>. The thermal [1,5]-hydrogen shift of 7-alkoxy-
carbonyl tropylidene was found to be accelerated by conformational regulation at the carbonyl
group, which mainly affected the activation energy <1999CL1143>. Somfai reported that in
addition to the aza-[2,3]-Wittig rearrangement products, vinylaziridines were good substrates
for the homodienyl [1,5]-hydrogen migration, specially with substituents capable of conjugation
in the starting product 5 (R1 = COt2Bu, Ph) (Scheme 2) <1995TL1953, 1996JPO623,
1999T11595>. In a synthetic approach to mniopetals, it was found that compound 6 produces
stereospecifically itaconic acid derivative 7 via a thermal [1,5]-hydrogen shift <1999IJC(B)269>
R1 R1
[1,5]-H
N [1,5]-H N
H H
99% Me
MeOOC COOEt [1,5]-H MeOOC COOEt

toluene, ∆
MeOOC MeOOC
80%
6 7
[1,5]-H
H
∆
9%
H
8 9 10
Me Me Me Me
Me Me Me PhSCl/Et3N
OTBDMS
THF, –78 to 25 °C
SOPh
OH Me
Me 61%
Me
11 12
OTBDMS
O O OCH2CH2OH
120 °C O
EtO2C EtO2C O CO2Et
94%
15
13 14
Scheme 2
(Scheme 2). Thermolysis of cyclopenta[l]phenanthrene 8 afforded the Diels–Alder adduct 10 via

intermediate 9 as the result of a [1,5]-sigmatropic hydrogen migration in the precursor
<1998JOC3735> (Scheme 2). De Lera and co-workers have described a pericyclic cascade
reaction for the stereocontrolled synthesis of 9-cis-retinoids. The transformation of alkenynol
11 to polyene 12 is a process that comprises an ordered sequence of sigmatropic rearrangements:
a reversible [2,3]-allyl sulfenate to allyl sulfoxide shift, followed by a [2,3]-propargyl sulfenate
to allenyl sulfoxide rearrangement, and finally a stereodifferentiating [1,5]-sigmatropic hydrogen
shift (Scheme 2) <2000JOC2696>. In the first synthesis of mono- and dipyrrole-substituted
cyclopentadienes, it was observed that at higher temperatures substituted cyclopentadiene
systems interconvert via sigmatropic [1,5]-hydrogen migration <1997JOC7877>. UV irradiation
of 2-(1-adamantylidene-1-phenylmethyl)-3,3,3,4,4,5,5-hexafluoro-1-(3-thienyl)cyclopentene gave
40 ,50 -hexafluoropropano-60 -phenylspiro[adamantane-2,70 (6H)-benzothiophene] via a photochemical
6-electrocyclization followed by the thermal [1,5]-hydrogen migration <2003BCJ355>.
Electrochemical oxidation of 1-tosyl-3-aryl-1,3-dihydro-1,3-diazaazulanones at room temperature

afforded double-bond isomers, 1-tosyl-3-aryl-1,3-diazaazulanones via [1,5]-hydrogen migration,
together with 3-aryl-6-tosyl-1,3-dihydro-1,3-diazaazulanones <1999H(50)63, 2002H(58)63>. It
has been reported that heating at 120 C promoted the dioxolane ring opening followed by
[1,5]-hydrogen migration in enone ketal 13 yielding intermediate 14, ready for the intramolecular
Diels–Alder reaction to give cycloadduct 15 <2002JCS(P1)366> (Scheme 2). Compound
30 ,30 ,9,9-tetrachlorospiro(bicyclo[5.2.0]nona-2,4-diene-8,20 -oxetan)-40 -one underwent intramolecu-
lar [1,5]-hydrogen migration in the seven-membered ring at 115 C <2001JCS(P1)2257>. Stabi-
lized azomethine ylides with electron-withdrawing substituents react via a [1,7]-electrocyclization
with phenyl rings followed by [1,5]-hydrogen shift to yield dihydrobenzazepines <2003TL793>.
In the dimerization of product 16, compound 17 resulting from the [1,5]-hydrogen migration
was also detected in low, but significant yield (Equation (2)) <1997JOC4105>.
O O
Xylene, 120 °C
N O N O
Cl 25% Cl ð2Þ
16
17 + dimer
The reaction of 2-nitrovinamidinium hexafluorophosphate with methyl acetoacetate gives unex-

pectedly phenols or anilines in very good yield; the surprising formation of these anilines can be
rationalized by a keto-enol tautomerism of the initial adduct followed by an electrocyclic ring-
closure and a [1,5]-H shift; elimination of water restores the aromaticity (Scheme 3) <2002OL439>.
Chiral methyl groups in the form of chiral acetic acids substituted with hydrogen, deuterium, and
tritium atoms at the -carbon have been prepared by using a [1,5]-H shift <1999JA10848>. A [1,5]-
hydrogen shift has been invoked in a thermal sigmatropic rearrangement of 4-(4-aryloxybut-
2-ynyloxy)[1]benzopyran-2-ones to the corresponding thiones <2001S924>.
Me Me
N , PF6
O O MeO2C NO2
NO2
+
OMe Me
Me O N
N
Me
Me
MeO2C NO2 MeO2C NO2 MeO2C NO2

–HNMe2
Me Me
HO N HO N HO
Me Me
5–14%
[1,5]-H
MeO2C NO2 MeO2C NO2

– H2O
HO Me Me
N N
H
Me Me
65–78%
Scheme 3
The reaction of 1-triphenylphosphoranylidene-2-propanone with cis-2,3-bis(trimethylsilyl)-

cyclopropanone gave products arising from the unexpected [1,5]-sigmatropic rearrangement
featuring cyclopropane ring opening <2000TL3399>. Substituted vinyl cyclopropanes undergo
[1,5]-hydrogen shift in competition <2001JOC8751> with sigmatropic rearrangement to cyclopen-
tenes (see Section 1.18.2.2.1.(ii)). The [1,5]-hydrogen shift generally occurs at lower temperatures
than cyclopentene formation. The cis-configuration of the product from the cis-cyclopropane
coupled to the low activation energy suggests that this hydrogen rearrangement occurs by a
suprafacial, concerted homodienyl [1,5]-hydrogen shift <1997JOC1532>. The [1,5]-hydrogen shift
in cis- and trans-N-acyl-2-alkylcyclopropylamines has been described <1997JOC1532>. cis-1-Alkyl-

2-vinylcyclopropane acetal underwent a thermal [1,5]-hydrogen migration reaction to give the acetal
of a (Z),(E)-dienone (Scheme 4) <1996H(42)565>. The reaction of ,0 -cyclopropyl amino acid
18 with formaldehyde in hydrochloric acid gave the heterocyclic ring system 2,3-dihydro-1H-2-
benzazepine-3-carboxylic acid 19 in a process that involves a novel [3,3]-sigmatropic rearrangement
of the iminium ion of the N-methylene derivative followed by a [1,5]-hydrogen shift (Scheme 4)
<2001JOC2884>.
Me Me
Me Me
Toluene, 100 °C
O O BSA O O
97%
Ph Me Ph
BSA = N,O -bis(trimethylsilyl)acetamide
H CO2H
HCHO, 1 M HCl
NH2 99%
N
Cl H2 CO2H
18 19
Scheme 4
The adducts from the [4+2]-cycloaddition of 4-dialkylamino substituted 1,3-diazabuta-1,3-

dienes with butadienylketenes undergo [1,5]-hydrogen shifts <2002JCS(P1)774>. It has been
reported that the intermediate reactive o-quinodimethane 20 underwent [1,5]-hydrogen shift to
give organoborane 21 (yield not given) (Equation (3)) <1999JOM(581)108>. A [1,5]-hydrogen
shift has been invoked as the crucial step in the reaction of ammonia with 3-pyrrolidino-1,2,4-
triazine-4-oxide to give 5-amino-1,2,4-triazine-4-oxide <1999TL6099>.
i. Li Me3Sn [1,5]-H
C ii. Me 3SnCl THF, rt
B B
20
ð3Þ
Me3Sn
i. H2O2, NaOH
ii. CH 3COOH HO
B
51%
21
Regarding the [1,7]-sigmatropic hydrogen shift, several examples have been recorded in the
literature. In a project directed to the study of anerobic photocyclization of 3-styryl pyridines, it
was observed that the formation of 2-azaphenanthrenes in the absence of oxygen is attributed to
the conversion of the 4a,4b-dihydroazaphenanthrene primary photoproduct to a 1,4-dihydropy-
ridine intermediate by means of a formal [1,7]-hydrogen migration <2001JA3878>. Methylene-
propenylidene cyclohexadiene derivatives show competing [1,7]-hydrogen migrations with
1,6-electrocyclic reactions <1996JA10311>.
(ii) Acid- and base-catalyzed migrations of a hydrogen atom

Double-bond rearrangement is possible under mild basic conditions, as in the piperidine-mediated
conjugation of a ,-unsaturated ester to give the corresponding ,-unsaturated ester
<1998SL81>. The reaction of aldehydes or ketones with 2-arylsulfinyl acetonitrile gives the
highly functionalized four-carbon unit 5-hydroxyalk-2-enenitrile, in a very useful transformation
that is assumed to proceed by a double-bond isomerization (Scheme 5) <2001JOC1228>. A
new method for -pyrone synthesis has been proposed based on the base-catalyzed reaction of
1,2-allenyl ketones and conveniently substituted acetates with electron-withdrawing groups; the
reaction seems to proceed by a cascade Michael addition, carbon–carbon double-bond migration,
and lactonization <2002OL505>.
OH
O Piperidine
acetonitrile R2 CN
S CN + R2 CHO
Ar
Mislow–Evans
rearrangement
O
O
S CN
S CN Double bond migration Ar
Ar
R2
R2
Scheme 5
Unusual double-bond migration in the formation of saturated isoprenoid chains in the

biosynthesis of core membrane lipids has been reported <2000CC1545>. Acid-catalyzed double-
bond migration in steroid chemistry has been widely documented in recent years. The transforma-
tion of cholesta-5,7-dien-3-ol to 5-cholesta-8,14-dien-3-ol is a well-known reaction that has been
used to prepare the biosynthetic intermediates for the investigation of steroid biosynthesis
<1995MI290, 1999TL8863, 2000JCS(P1)1697, 2002JCS(P1)2395>.
,-Unsaturated carboxylic acids are synthetically useful building blocks, because upon
deprotonation by 2 equiv. of lithium dialkylamides they give dianion intermediates, dienedio-
lates, as ambident nucleophiles through their - or -carbon, and whose regioselectivity
depends on the electrophile as well as on the reaction conditions <1991COS(2)99,
1991COS(3)1, B-1994MI001>. Thus, it has been observed that -attack predominates in the
irreversible reaction with alkyl halides and protonation, while -attack has been attained by
counterion interchange with copper(I) salts or with allylic halides (Equation (4))
<2002CUOC283>. A number of theoretical <1996T11105> and experimental studies have
been conducted in order to determine the influence of the halides <1998T15305>, the type of
solvent <2001SL156>, effect of the leaving groups <1998T4357>, and the use of chiral bases
<2001TA915> in the regioselectivity of the reaction. Practical applications have been docu-
mented in the synthesis of pyridones <1999SL1088, 2000S273> and natural products
<1996SC1309>.
i. LDE, THF
O ii. MeI O O
iii. H3O + Me
Me OH OH OH
82% ð4Þ
Me
7:3
(LDE = lithium diethylamide)
Intramolecular Diels–Alder reaction of 1-(pentenoyl)-3-(tetrahydropyridinyl)indoles followed

by acid-catalyzed double-bond migration results in the aromatization of the intermediate and
formation of pentaheterocyclic ring systems related to those found in Strychnos alkaloids
<1998JOC1974>. The same type of acid-catalyzed rearrangement has been found between
1,2,3,9a-tetrahydro-9H-carbazoles and 1,2,3,4-tetrahydro-9H-carbazoles <2000JCS(P1)2395>
and in the synthesis of , 0 -fused metallocenoporphyrins <2001CC2646>. The base-promoted
methylation of ,-unsaturated nitrile 22 followed by acid hydrolysis gives a mixture of double-
migration products 23/24 <1995JOC2188> (Scheme 6).
KOBut, Mel +
NC NC HCl
Ts HO HO O HO O HO
Ts
22 23, 8% 24, 70%
Scheme 6
The photochemical irradiation of N-(2-phenylprop-2-enyl)thiobenzamides gives N-(2-phenyl-

prop-1-enyl)thiobenzamides after double-bond migration via two consecutive [1,4]- and
[1,6]-hydrogen transfers <1997JCS(P1)1851> (Equation (5)).
Ph
S Me
S Ph
Ph hν
Ph N + Ph
Ph N N ð5Þ
77% 5%
The reaction of allylic tosylamides with propynyl(phenyl)iodonium triflate in the presence of

lithium hexamethyldisilylamide affords azabicyclo[3.1.0]hexanes in a process that involves double-
bond migration driven by the high strain energy of endocyclic methylenecyclopropane-containing
fused bicyclic systems <1998TL4781, 1998JA4027>. The isomerization of but-1-ene with alumina
catalysts <2001CC701> and the photooxidation of 1-alkenes in the presence of zeolites
<1999JA5063> have been reported. The well-known base-catalyzed isomerization of allyl phos-
phonates to vinyl phosphonates has been applied in pyranosyl phosphonates <1996JMC1321>.
A nice example of transfer of central to axial chirality involving the base-mediated double
migration in enantiomerically pure (1R)-menthyl (R)- and (S)-1-(10 -indenyl)naphthalene-2-carboxy-
lates has been published <1996CC2571>. An unusual carbon–carbon double-bond migration has
been reported in the acid-catalyzed isomerization of 3-ylidine-2,5-piperazinediones (Equation (6))
<2000EJO1993>.
O O
48% HBr, dioxane
Me Me
N reflux N ð6Þ
N 82% N
Me
O H
O
The synthesis of C-11 methyl-substituted benzocycloheptapyridine inhibitors of farnesyl

protein transferase has been achieved by base-mediated double-bond deconjugation followed
by methylation <1999OL1371>. The regioselective enolization of 4-substituted cyclopentene

1,3-diones, under basic or acid conditions, gives enol ethers with simultaneous endocyclic
double-bond migration in the side-chain (Equation (7)) <1998T1589>.
O OMe
C3H7 0.25–0.3 M HCl/MeOH
reflux ð7Þ
C3H7
51%
O O
(E)-3-Penten-2-one has been prepared in large scale by 1,5-diazabicyclo[5.4.0]undec-5-ene

(DBU)-promoted isomerization of the corresponding ,-unsaturated ketone <1998SC4513>.
The triethylamine-promoted double migration of 1,5-anhydro-3-C-p-tolylsulfonyl-D-hex-2-enitol
derivatives and the corresponding 5a-carba-DL-sulfonyl sugar has been investigated from the
theoretical and experimental standpoint <2000MI783>. A new synthesis of ,-cyclopentenones
has been described using a base-mediated rearrangement of C-4-ulopyranosyl compounds;
depending on the basic conditions, variable mixtures of the double-bond migration derivatives
have been obtained (Equation (8)) <2001CAR(334)223>.
CH2OBn
CH2OBn CH2OBn
O Base OH OH
+
BnO 70–80%
ð8Þ
O BnO O BnO O
MeOH, Et 3N (1:9) 40:1

MeOH, Et3N (9:1) 1:25
(iii) Metal-catalyzed migrations of hydrogen

The well-known double-bond migration of allyl ethers and allyl acetals to vinyl ethers (prop-
1-enyl ethers) or vinyl acetals, respectively, has found many applications in organic chemistry
<1993HOU(E15a)1>. For instance, the allyl and the but-3-en-2-yl moieties have been used
traditionally as protective groups in carbohydrates, which are easily removed via isomerization
and hydrolysis of the respective vinyl ether <1996CC141>. This reactivity has been used with
advantage in tandem processes coupled to Claisen rearrangements for the synthesis of
,-unsaturated carbonyl compounds from allyl homoallyl ethers using iridium catalysts
<2000OL4193>, or from diallyl ethers with nickel catalysts <1998S305>.
A polymer-supported iridium catalyst has been found to efficiently catalyze the double migra-
tion in a number of allyl to vinyl ethers, and in the isomerization of C-substituted allyl aromatic
derivatives to the corresponding C-vinyl compounds <2002SL516>. Ruthenium-mediated
metathesis reactions leading to cyclic allyl ethers have been very often accompanied by double-
bond isomerization products to give cyclic enol ethers as undesired by-products <1997TL8635,
1999OL1123, 2000JOC2204, 2002TL1839>. Some authors have reported that the in situ gener-
ated ruthenium hydride species accelerates the isomerization process, after the metathesis reaction
(Equation (9)) <2002JA13390, 2003EJO816>.
O Grubbs’ catalyst (5% mol.), rt

NaH (30% mol.), toluene, 100 °C O ð9Þ
87%
The deconjugation of thermodynamically more stable ,-unsaturated esters is possible using

Ru complexes <2000JOC3966>. (E)-3-Dialkoxyphosphorylbut-2-enoates are conveniently trans-
formed into the deconjugated 3-dialkoxyphosphorylbut-3-enoates by palladium(II) assisted
photochemical double-bond migration <1999S1056>. The synthesis of 2-bicyclo[3.2.1]oct-2-en-
8-ones by carbonylation of cycloheptadiene-derived iron carbonyl complexes bearing alkyl-allyl
subunits proceeds by double-bond migration <1995S587>.
The oxidation of 5-unsaturated 3-hydroxy steroids to the corresponding 4-en-3-one deriva-

tives can be performed under Oppenauer oxidation conditions by using (PPh3)3RuCl2 and
potassium carbonate; the reaction proceeds by ruthenium-catalyzed dehydrogenation and subse-
quent hydrogen transfer to the acetone used as solvent, with simultaneous double-bond migration
<1996JOC6587>. Double-bond migrations have been detected in the hydrogenation of arylalk-
enes by using iridium metal complexes <2001CEJ5391>. Double-bond migration of allylamines
in the presence of transition metal complexes provides an efficient approach to the preparation of
aldimines of the aliphatic alkyl group <1999OL2161>. S-Allylic systems rearrange to the sulfur-
containing vinyl groups under [RuClH(CO)(PPh3)3] catalysis <2003JOM(665)167>.
In the course of Heck reaction, a number of double-bond isomerizations have been described
in the resulting products <1996JOC7147>. For example, in the Pd(BINAP)-catalyzed Heck
reaction of 2,3-dihydrofuran with 1-cyclohexenyl triflate substantial amounts of 2,3-dihydrofuran
derivatives have been found by CC double-bond migration, a process that can be minimized by
using chiral phosphinooxazoline/palladium complexes <1997S1338, 1999JOM(576)16>. The
Heck reaction of aryl iodides and trimethyl silane has been investigated, and conditions have
been found to prevent the desilylation and double-bond migration <2000TL8445>. The intra-
molecular Heck reaction of N-allyl (aryl or benzyl)-5-allyl-pyrrolidones or N-allyl (aryl or
benzyl)-6-allyl-piperidones catalyzed by Pd(II) salts gave the corresponding indolizidinones,
quinolizidinones, and benzoazepinones in moderate yields (56–90%), and exclusive 6-exo-trig
mode of cyclization accompanied by double bond migration (Equation (10)) <2002S87>.
O Pd(0), DMF, 115 °C

N O N O N
55% ð10Þ
Br
Ruthenium complexes allow the easy and synthetically useful rearrangement of N-allyl
ethanamides to (E)-N-aryl-N-(1-propenyl)ethanamides <2001TL7095>. An allyl, branched-
chain sugar has been isomerized in high yield to the corresponding vinyl analog by treatment
with rhodium trichloride in basic medium <2003JOC2123>. During the reductive decomplexa-
tion reaction of acetylene–cobalt complexes with triethyl silane to produce the corresponding
vinyl silanes, partial olefin isomerization in a terminal isolated double bond contained in the
substrate was observed <2002T6485, 1998TL2609>. In the total synthesis of the lignan schi-
zandrin <1995T11703> and the major metabolites of gomisin A <1996H(42)359>, the key step
is the rhodium complex triethyl silane catalyzed reaction of ,-unsaturated lactones 25 to
butenolides 26 (Equation (11)).
O O
O O
H
MeO MeO
O Rh(PPh3)3Cl, Et3SiH O
MeO MeO ð11Þ
71–99%
BnO O BnO O
MeO MeO 26
25
The pyridinium chlorochromate (PCC) oxidation of homoallylic alcohols gives ,-unsaturated

aldehydes by carbon–carbon double bond migration <2003TL1275>. The electrochemical, nickel-
catalyzed addition of carbon dioxide to (perfluoroalkyl)alkenes affords -fluoro--(perfluoroalkyl)-
-alkenyl carboxylic acids in a process that involves a double-bond migration with loss of a fluorine
atom <1998TL4831>. Alkylidene malonates have been described to lead to double-bond migration
products under electrochemical conditions <1998T14529>. Isomerization of homoallylic
amines promoted by catalytic iron carbene complexes <2001OM5419>, or of N-allylic substrates
in the presence of osmium clusters have been described <2002JOM(658)147>. Intramolecular
Nicholas reaction of compound 27 followed by reaction with titanium tetrachloride gives the
bicyclic derivative 28 through a mechanism that involves double-bond migration (Equation (12))
<2001SL1929>.
i. Co2(CO)8
HO ii. TiCl 4
Cl
iii. CAN H
ð12Þ
52%
H H
27 28
(iv) Anion-accelerated migrations of hydrogen atoms

Rigby has reported the first example describing the stereochemical course of alkoxide-accelerated
suprafacial [1,5]-hydrogen sigmatropic rearrangement <1996JOC7992>. In a project directed to
the synthesis of ingenane diterpenes, allylic epoxide 29 was opened with lithium diethylamide to
give a dienol 30 that on treatment with potassium hydride in the presence of 18-crown-6 ether
afforded the ,-unsaturated ketone 31, in a sigmatropic process where the proton to the
carbon bearing the hydroxy group was transferred with complete retention of stereochemistry to
the opposite bridgehead position <1998TL2265> (Scheme 7).
O
H
O
LiNEt2 HO H
H H KH
H H
58% 64%
O O O O O O
29 30 31
Scheme 7
1.18.2.2 Where Y = C
1.18.2.2.1 [1, j]-Rearrangements involving CC bond migration
(i) Sigmatropic migrations of CC bonds

Sigmatropic rearrangements involving CC bond migration are well known. These migrations
occur with retention or inversion of configuration at the migrating carbon atom depending on
whether it is a thermal suprafacial [1,5]- or a thermal suprafacial [1,3]-rearrangement, respectively
<1995COFGT(1)793>. The thermal [1,3]-sigmatropic shift of methyl across an allylic structure
has been studied by ab initio methods <2002JPC(A)5709>. A [1,3]-sigmatropic shift has
been invoked to explain the norbornene to norcarene rearrangement <2000PJC1645> in the
thermal rearrangement of compounds with the 7-methylbicyclo[3.2.0]hept-2-ene skeleton
<2000JOC5396> and in the amine-promoted transformation of 8-bromo-3,9-dimethylxanthine
<1998JHC949>. Photochemical [1,3]-sigmatropic shifts of carboncarbon bonds have been
described in the rearrangement of longipinene derivatives <1996TL8093> or in the migration
of allylic carbons in the cembrane–pseudopterane cycloisomerization and in some transformations
of the antifungal macrolactam ascomycin <1999IJC(B)1159, 1998JOC420>. The [1,3]-sigma-
tropic rearrangement of carboncarbon bonds in an azetidinone nucleus is an interesting example
that shows the synthetic potential of this type of rearrangement for the preparation of more
advanced molecules in a highly stereocontrolled manner (Equation (13)) <2002TL2627>.
O
Ph O
N Ph Ph
Ph Toluene, reflux Ph ð13Þ
Ph N
99% Ph Ph
Ph Ph H
Anion-accelerated examples of thermal [1,3]-rearrangements have been investigated <1996CC2369,

1996MI3, 1997T13971>. In a series of studies directed to the synthesis of fused-ring skeletons through
anionic [1,3]-rearrangements of bridged bicyclic compounds, the conversion of alcohol 32 into
diquinanes 33 and 34 has been described (Scheme 8) <1996CL389, 1996CL1035>.
Me Me Me Me H
H
Me Me
KH, toluene, 120 °C Me Me
OH +
Me [1,3] HO
HO H H
33, 26% 34, 65%

32
Scheme 8
The necessary structural requirements and parameters for the photochemical promoted
[1,3]-migration of a hydroxyimino or an acetoxyimino group in a ,-unsaturated oxime or
oxime acetate have been reported. The molecules undergoing the rearrangement should have a
quaternary carbon separating the two -systems and one of the radical centers in the cyclobutyl
1,4-biradical should be stabilized by conjugation with a phenyl ring <1996JCS(P1)107>.
The reaction of thallium 5-methyl-1,2,3,4-tetrakis(methoxycarbonyl)-cyclopentadienide with
p-nitrobenzyl bromide gave a mixture of isomeric p-nitrobenzylcyclopentadienes featuring a
[1,5]-sigmatropic shift of a p-nitrobenzyl group <2002MI1449>. Heating xylene solutions of
2-(N-allylanilino) or 2-[allyl(benzyl)amino]-substituted ((E)-oxochromenyl)propenoates at 220 C
leads to a [1,5]-shift of the allylic moiety, which is followed by intramolecular cyclization involving
the nitrogen atom and the ester function to give the 3-allyl substituted-1-phenyl or 1-benzyl-2H-
[1]benzopyrano[2,3-b]pyridine-2,5(1H)diones (more examples have also been described with crotyl
cinnamyl residues) (Scheme 9) <2003HCA169>. A consecutive [1,5]-sigmatropic rearrangement of
the phenyl ring is proposed for the transformation of 2-substituted benzo[b]thiophenium triflates to
give 3-phenyl-benzo[b]thiophenes <2002TL2239>. It is known that the [1,5]-alkyl migration in a
4a-alkyl-4a-hydrocarbazol-4-one yields a 3-alkylcarbazol-4-one with a rearomatized indole nucleus
<1999OL161>.
O
O
CO2Et ∆
R2
2
220 °C
O N R
O N O
R1
R1
R1=Ph, Bn; R2=H, Me, Ph
[1,5]-shift – EtOH
O R2 R2
O H
O
O
O N OEt O N OEt
R1 R1
Scheme 9
Further examples of thermal [1,5]-sigmatropic rearrangements on 3,3-spiroalkylated pyrazole

ring systems featuring the so-called Alphen–Huettel rearrangement have been reported
<2001H(55)1859>. A nitrogen ylide complex is the key intermediate in the reaction of amino-
carbenes with acetylenes to give pyrrolinones; a final [1,5]-migration of an alkyl group from
nitrogen to carbon accounts for the final result <1998JOM(567)101>. [1,5]-Sigmatropic rearran-
gements of carboncarbon bond have been detected in the thermolysis of a fluorinated indolyl-
fulgide featuring a novel [1,5]-indolyl shift, <2001JOC4739> as well as in some pyrazole
derivatives <1997CJC523>.
(ii) Rearrangement of vinylcyclopropanes

The rearrangement of vinylcyclopropanes to cyclopentenes is popular and has found diverse
applications in the synthesis of natural products. This rearrangement can be considered as a
formal [1,3]-shift of a carboncarbon bond (Equation (14)). The subject has been covered in
previous reviews <1985OR247, 1991COS(5)899, 1996RHA21, 1997HOU(E17c)2538,
B-2000MI001>. The reaction can be conducted under thermal, photochemical, and metal-cata-
lyzed conditions.
∆ ð14Þ
(a) Thermal rearrangements of vinylcyclopropanes. A recent review <2003CRV1197> gives a

clear picture of the currently accepted ideas on the mechanisms <1996JA299, 1997JA10543,
1997JA10545, 1998MI222, 1999JA11018, 2000JOC6791>, reaction stereochemistry
<1995JA10672, 1999JOC3567>, reaction kinetics <1997JPC(A)4097>, dynamics
<1999JA4720>, computational studies, and substituent effects <2001EJO3559,
2003CRV1151>. To summarize, two models account for the experimental results; in one
model, the vinylcyclopropane rearrangement involves a short-lived family of diradical intermedi-
ates; in the other, the vinylcyclopropane rearrangement may take place by either or both two-step
diradical and orbital-symmetry-controlled pericyclic mechanisms.
A number of synthetic applications of the thermal rearrangement of vinylcyclopropanes have
been published. 1-Methylene-2-vinylcyclopropane rearranges to 3-methylenecyclopentene via the
cross-conjugated 4-methylene-2-(Z)-pentene-1,5-diyl diradical <1997JA5857>. Bicyclopropyli-
dene undergoes a Pd(0) and Ni(0) [3+2]-co-cyclization reaction with alkenes to give 4-methyle-
nespiro[2.4]heptane derivatives 35 that on thermal rearrangement afforded compound 36 in
moderate yield (Equation (15)) <1998EJO113>.
600 °C
61% ð15Þ
EtO2C CO2Et EtO2C CO2Et
35 36
De Meijere has reported the rearrangement of cyclopropylketimines as the route for dihydro-
pyrrole- and dihydrofuran-fused bicyclic diazepine-2,5-diones <2000OL4249>, and the high-
yielding thermal isomerization of 1-cyclopropylidene-2-vinylcyclopropane to 4-methylenespiro[2.4]-
hept-5-ene <2001EJO3607>. The vinylcyclopropane–cyclopentene rearrangement has been
successfully applied in a series of highly functionalized heteroaromatic substrates
<1997CJC1256, 1997JCS(P1)835, 1998CPB151, 1999JOC6347, 2000MI209, 2001JOC3182>.
The thermal rearrangement of ,-unsaturated vinylcyclopropanes is possible and has been
documented <2001SL433>. The thermal rearrangement can also be accelerated by suitable
catalysts. In this context, diethylaluminum chloride or tin tetrachloride have been extensively
and successfully investigated <1996TL3565, 1998JOC6586>.
Related N-cyclopropylketimines and vinyl phosphiranes rearrange thermally to 1-pyrrolines
<1997JOC1532, 1999JA856, 1996JA1690, 2000JA3033, 2002JA13903>. Perfluorinated vinyl-
cyclopropanes rearrange easily under thermal conditions <2002JFC(117)199>; a kinetic study
is also available <1995JFC(70)249>. The rearrangement of donor–acceptor vinylcyclopropanes
to functionalized cyclopentene derivatives has been discussed <1996LA2007> and a theoretical
study concerning the substituent effects using density functional theory has been published
<1999EJO215>. The thermal rearrangement of 2-ethenyl-substituted cyclopropylamines leading
to 4-aminocyclopentenes has been investigated by de Meijere (Equation (16)) <1998TL7695,
1998JCS(P1)3699, 2002SL1362>.
NMe2 NMe2
FVP, 500 °C ð16Þ
90%
(b) Photochemical rearrangement of vinylcyclopropanes. The rearrangement of vinylcyclo-

propanes has been reported under photochemical conditions and has found useful synthetic
applications. The mechanism has been discussed by arguing that the rearrangement in these
conditions is a case where spin-inversion and orbital-symmetry requirements produce the same
product; the rearrangement is stereospecific and proceeds via a concerted process <1995T5871>.
The photochemically initiated Fe(CO)5 carbonylation of alkenyl cyclopropanes is known
<1996TL357, 1996JOM(525)155> and has been applied to the synthesis of enantiomerically
pure cyclohexanones <2000JA6807> (Equation (17)).
O
Fe(CO)5, hν ð17Þ
OBn OBn
61%
Related N-cyclopropylketimines rearrange under photochemical conditions to 1-pyrrolines

<2001OL4087>. Rearrangements of vinylcyclopropanes under photochemical conditions where
a transition metal—Cr, Mo, W—has been incorporated into the basic template are known
<1996SL806, 1996JA7873>. Armesto’s group has been very active on this subject, and they
have reported the photochemical rearrangement of 1-substituted-3-(2,2-diphenylvinyl)-
2,2-dimethylcyclopropanes to cyclopentenes or heterocycles <1999JOC1056>, and a novel vinyl-
cyclopropane rearrangement affording 6,7-dihydro-5H-benzocycloheptene was observed when
electron-withdrawing groups are located at C-1 <2000OL183> (Equation (18)). Irradiation of a
polyunsaturated cyclohexane derivative yielded a complex polycyclic structure implicating a
vinylcyclopropane–cyclopentene rearrangement <2002EJO1708>.
R2 R1
hν R2
R1
Acetophenone
Ph Ph ð18Þ
Ph 12–20%
R1=CO2R, C=N–OAc, R2 = H, Me, Ph
(c) Acid or metal-catalyzed rearrangement of vinylcyclopropanes. The reaction of a mixture of

C60 with dimethyl acetylenedicarboxylate (DMAD) in the presence of tricyclohexylphosphine does
not afford the expected product, but a new molecule whose structure was assigned and justified in
terms of acid-catalyzed (silica gel or AcOH) ring-expansion of the vinylfullerene intermediate—not
isolated—to give the corresponding fused-cyclopentafullerene derivative <2003JOC3811>. The
metal-catalyzed rearrangement of vinylcyclopropanes has been used with success and advantage
as the reaction takes place under mild conditions. Iwasawa has reported the Co2(CO)8-mediated
rearrangement of 1-(1-alkynyl)cyclopropanols to 2-cyclopentenones <1998JA3903, 1999SL13,
2000TCC(207)69>. Ma and co-workers reported that the Pd(0)-catalyzed coupling-cyclization of
2-(20 ,30 -allenyl)malonates with organic iodides gives mixtures of vinylcyclopropanes and the rear-
ranged cyclopentene derivatives <2002JOC2837>. The ring expansion of 1-alkenylcyclopropanols
to give 2-alkenylcyclobutanones can also proceed by transition metal catalysis. The enantioselective
transformation using a chiral palladium catalyst has been reported <2001JA7162> leading to
substituted cyclobutanones with high ee (Equation (19)).
Ph Ph
O O
NH HN PPh2
OH PPh2 ð19Þ
Me
Me O
OC(O)OMe Pd2(dba)3
100% 85% ee
The intermolecular palladium-catalyzed annulation of vinylic cyclopropanes and cyclobutanes

with aryl halides bearing functionality (hydroxyl, amino, tosylamino, etc.) in the ortho-position
provides a novel and efficient process for the synthesis of a wide variety of five- and six-membered
ring heterocycles and carbocycles <1996T2743>.
(d) Charge-accelerated rearrangement of vinylcyclopropanes. The thermal vinylcyclopropane

rearrangement suffers from serious limitations, as the reaction only proceeds at high tempera-
tures. However, it was found that charged substituents on the vinylcyclopropane accelerate the
rearrangement <1991COS(5)999>. It has been postulated that the base-induced ring-contraction
of 3,6-dihydro-2H-thiopyrans to give cyclopentenes proceeds via sulfur-charged vinylcyclo-
propanes <1996JOC4725> (Equation (20)).
i. LDA, HMPA, –78 to 0 °C

Me CO2Et Me CO2Et
ii. MeI
Me Me
Me S Me
87% S Li
ð20Þ
Me Me CO2Et
CO2Et
Me Me
Me Me
S SMe
Li
8:1 dr
Simple 2-(2-trimethylsilyl)ethenyl)cyclopropyl acetates on treatment with methyllithium at low

temperatures cleanly rearrange to polyfunctionalized cyclopentenes via the corresponding cyclo-
propanolates <1997TL3257, 2002JOC1786>. An anion-accelerated vinylcyclopropane–cyclopen-
tene rearrangement has been demonstrated by the treatment of 37 with tetrabutylammonium
fluoride at 78 C, as 38 was isolated in good yield <1998JOC2641> (Equation (21)).
O O
Ar
O Bu4n F, –78 °C O
O O
O 80% O ð21Þ
MeO OTBDMS
O
37 38
The rearrangement of vinylcyclopropanes to cyclopentenes has been shown to be greatly

accelerated by triarylaminium ((p-ClC6H4)3N+SbF 6 ) catalysis, and a stepwise, cation radical
mechanism seems to be the origin of the rate enhancement <1995TL7415>.
(iii) Rearrangement of vinylcyclobutanes

The rearrangement of vinylcyclobutanes <B-2000MI001, 2001JA6718, 2002ACR279> to
cycloalkanes is a similar and useful functional group transformation with interesting and practical
synthetic features <1986TCC(133)83>. A recent account on the application of cyclobutane
derivatives in organic synthesis <2003CRV1485> gives an updated summary for most of the
recent contributions in this area. Regarding the expansion to five-membered ring systems, acid
treatment of vinylcyclobutanol 39 afforded the expanded ring system 40 <1997JOC1713,
2001JOC2828> (Equation (22)). Different examples of vinylcyclobutanols and vinylcyclobuta-
nones giving expanded products and using different promoters (Lewis acids, palladium com-
plexes) have been reported <1996JA12541, 1997JOC7850, 1999JA10842, 2000JOC504,
2001JOC1455>. Hegedus reported the ring expansion of -alkoxy-1-vinylcyclobutanols shown
in Equation (23) <2000S953>. Uemura has described the oxidative transformation of vinyl
t-cyclobutanols by palladium catalysis under oxygen atmosphere <2001JOC1455>. The ring
expansion of 1-alkenylcyclobutanols to give 2-alkenylcyclopentanones using a chiral palladium
catalyst has been reported <2001JA7162>; facial selectivity for alkene complexation in some
examples is greater than 89% (Equation (24)).
OH O
Amberlyst-15
O ð22Þ
O 87%
39 40
O
HO
Pd(OAc)2
OEt Ph OEt ð23Þ
Ph 84% OBn
N OBn N
O O
Ph O Ph O
Ph Ph
O O
NH HN PPh2
OH PPh2 O ð24Þ
Me Me
OC(O)OMe Pd2(dba)3
52% 89% ee
Regarding the formation of six-membered carbocycles by ring expansion of vinyl cyclobutanes

several examples are known. Takeda and Fujiwara reported the cationic ring-expansion of
conveniently functionalized adducts from alkenyl metals and cyclobutenyl ketones catalyzed by
diethylaluminum chloride (Scheme 10) <1996SL481>. A general route to highly functionalized
benzonorbornadienes starting from 3,4-disubstituted cyclobutenediones has been reported
<1996SL155>. By using this ring-expansion methodology, quinone-like substrates linked to
porphyrin <2000JOC1650, 2000JOC1665> and -pyrones from cyclobutenediones
<1999JOC2145> have been prepared. Moore and co-workers have reported the thermal ring-
expansion of 4-allenyl-4-hydroxycyclobutenones to the corresponding o-quinone methides
<1996JOC329>. The utility and generality of anion-accelerated sigmatropic rearrangements has
been proved in nonracemic 2-vinylcyclobutanols <2001TL8769>.
O Me
O
EtAlCl2
Ph Me
89%
Ph
Me I
H Me
HgO, I2
OAc OAc
hν
OH
47% O
41 42
OH CHO
H Dess–Martin
OH 70% O
Me Me
43 44
Scheme 10
Medium-sized ring systems have been obtained using the vinylcyclobutane rearrangement.
Cyclobutanol 41 gave the bifunctional benzocyclooctadienone 42 in 47% yield upon treatment
with HgO/I2 under irradiation conditions (Scheme 10) <1995JCS(P1)49>. Oxidation of vinyl-
cyclobutanediols 43 afforded the dihydrooxacenes 44 in good yield (Scheme 10) <1997JOC6456,
2000OS141, 2002OL3891>.
Using the vinylcyclobutane rearrangement in the synthetic sequence, a number of natural
products, as gloiosiphone <1997T8913>, laurene <1997SL863>, and precapnelladiene
<1998JOC6905> have been prepared.
1.18.2.3 Where Y = CC

Baldwin has reported an anionic [2,3]-rearrangement of an all-carbon system <1970CC165>, but
in the period covered by this review no other major advances have been published.
1.18.2.4 Where Y = CCC
1.18.2.4.1 Cope rearrangement

Extensive and excellent full accounts have been published in the recent years covering the
different aspects and modifications of [3,3]-sigmatropic rearrangements, such as the Cope and
Claisen reactions <1995HOU(E21d)3301, 1996TA1847, 2001CUOC395, 2003S961>. A review is
available reporting the evolution of the accepted mechanisms of the Cope sigmatropic rearrange-
ment <1995ACR81>, and a number of papers have been published dealing with different aspects
of the mechanisms <1999JCS(P2)2357, 1999JA169, 2000JA186, 2002JOC1419>.
The Cope rearrangement is an important carboncarbon bond forming reaction in modern
organic synthesis <1975OR1, 1984CRV205, 1991COS(5)785>. Some new aspects of the Cope
rearrangement have been reviewed <2000MI1033>, including the effect of pressure
<2000JPR609>. The rearrangement of unsubstituted hexa-1,5-dienes is reversible to form pre-
ferentially highly substituted olefins in an equilibrium mixture (Equation (25)).
ð25Þ
Since the pioneering work of Doering and co-workers, the Cope rearrangement of acyclic 1,5-
dienes is generally considered to proceed via a highly ordered, six-membered, chair-like transition
state <1962T67>. In spite of its potential for chirality transfer processes, Cope rearrangements
have rarely been investigated in the context of acyclic stereoselection. In order to gain new
insights in this aspect, the Cope rearrangement of syn- and anti-aldols installed in differently
substituted acyclic 1,5-hexadienes has been investigated, showing that the reaction is more
stereoselective for the syn- than for the anti-precursors <1996SL212, 1996TL4471, 1996TL8899,
1997T133>. In this process a series of highly flexible and versatile intermediates have been
obtained for the synthesis of heterocyclic ring systems such as tetrahydrofurans <1997SL815>
and piperidines <1998SL652>.
1.18.2.4.2 Thermal/photochemical Cope rearrangement

Cyclohexadienones 45 and 47 give compounds 46 and 48, respectively, after thermal Cope
rearrangements (yields not given) (Scheme 11) <1995T6015>. It has been published that a
1,4-difluorobenzene-naphthalene underwent a facile Cope rearrangement followed by dehy-
drofluorination to give 1-(4-fluorophenyl)naphthalene 49 and 2-(3-fluorophenyl)naphthalene
50 in 76% and 16% yield, respectively (Equation (26)) <1995BCJ3557>. The Cope rearran-
gement of 3-ylidene-piperazine-2,5-diones has been reported <2002ZN377>. Functionalized
cis-decalins have been prepared by thermal Cope rearrangement of bicyclo[2.2.2]octenones
<2001CC2578>.
R1 R2 O R1
O
R2
R3 ∆, Cope
R4
R3
R4
45 46
R1 R2 O R1
O
R2
R3 ∆, Cope
R4
R3
R4
47 48
Scheme 11
F
F
F ∆ ð26Þ
+
49, 76% 50, 16%
The photochemical reaction of 2-pyridone and naphthalene gives an unstable intermediate that
slowly affords Cope rearrangement products on contact with silica gel (Equation (27))
<1999OL1775, 2000JOC1972, 2001S1185>. The photochemical reaction of furan with
1-naphthalenecarbonitrile at room temperature afforded a mixture of [4,4]-adduct 51 and
compound 52 that has proved to be the Cope rearrangement product of the other possible
[4,4]-adduct 53 (Scheme 12) <1996TL9329, 1998JOC1212, 1998JCS(P1)2501>.
H H H O
SiO2 H H
+ hν O N
+ NH
N O 13% O ð27Þ
H HN H H H H
7.2:1
CN
CN
O H
O hν, Pyrex, rt H
+ + H
NC H
51, 80% 52, 1.2%

hν, Pyrex, –78 °C
O O
rt
+ 51 (18%) + 52 (75%)
NC NC
51 53
Scheme 12
The tandem Wittig reaction and reverse aromatic Cope rearrangement of 2-allyl-1,2-dihydroin-
dol-3-ones gives good yields of 3-indole acetates after heating under reflux in toluene (Equation
(28)) <1995CC381, 2001JOC1200>. A facile tandem Wolff–Cope rearrangement has been used
for the synthesis of fused carbocyclic skeletons <2003JA13624>.
MeO2C MeO2C
O Toluene,
CO2Me reflux
+ Ph3P ð28Þ
N 78%
N N
Ac
Ac Ac
The allylation of a chiral dienolate combined with a Cope rearrangement has resulted in an
excellent method for the preparation of -chiral ,-unsaturated acid derivatives, that has found
application in the synthesis of the C6 side chain of zaragozic acid A <1996TL8895>. 3-Phos-
phorylated 1,5-hexadienes rearrange to the expected unsaturated 5-vinyl phosphonates under
strong thermal conditions <1997CJC1131>.
The homo-Cope rearrangement is a subtle variant of the usual Cope rearrangement where one
of the terminal double bonds of the 1,5-hexadiene is disubstituted with a trimethylsilylmethyl at
C-1 and with a hydroxymethyl group at the same carbon; on treatment with triflic anhydride not
only the Cope rearrangement takes place, but ring closing occurs to form 11-membered carbo-
cycles by a new five-carbon ring-expansion reaction (Equation (29)) <1995LA745, 2001TL1915,
2003T3157>.
SiMe3
Tf2O
OH ð29Þ
75%
Applications of the thermal Cope rearrangement to the synthesis of natural products have
been reported several times, as in the hemi-synthesis of sesquiterpenes vernolepin and 8-epi-
vernolepin from natural products salonitenolide and cnicin <1995TL311, 1998JCS(P1)4107,
2000TL7639>, and cnicin has also been the starting material in a recent synthesis of elemane
and heliangolane derivatives <2003EJO2690>. Other applications of the Cope rearrangement
can be found in the preparation of naphthofurans and phenanthrofurans related to morphine
<1998CC65>, in the first synthesis of floerkein B and barbilycopodin <1997H(46)123>, in the
synthesis of racemic diterpene obtunone <1999SC537>, in synthetic approaches to 3,8-taxane
tricarbocycles <1999TL4235>, in the synthesis of the racemic tetracyclic core of the complex
and in biological attractive molecule CP-225,917 <2002TL4559>. In addition to the standard
spectroscopic analysis, the absolute structures of natural products vibsanin B and C have been
established by chemical correlation between them through thermal Cope rearrangement
<1997TL1435>.
1.18.2.4.3 Catalysis of the Cope rearrangement

The Cope rearrangement is often accelerated by the presence of catalysts <1984CRV205>.
Palladium(0)-catalyzes the Cope rearrangement of acyclic 1,5-dienes <1999JA10850>. The rate
of Cope isomerization of germacranolides to elemanolides has been shown to be enhanced by
catalytic amounts of bis(benzonitrile)palladium(II). This observation made possible an efficient
approach from natural and commercially available costunolide to sesquiterpene lactones, stoebe-
nolide and dehydromelitensin <1998TL1401>. In the palladium-catalyzed Heck reaction on
N-methyl-N-(1,5-hexadiene-3-yl)-2-iodo-benzoic acid amide, some secondary products were
detected probably arising via chelation assisted Pd-catalyzed Cope rearrangement
<1997JMOC(116)99>. The Cope rearrangement can be accelerated by catalytic amounts of
acids. This was the case of the example shown in (Equation (30)); reaction of 2-exo-carbomethox-
ytricyclo[5.2.1.02,6]deca-3,8-dien-5-one with ethylene glycol in the presence of PTSA gave
1-carbomethoxy endo-dicyclopenta-1,4-diene-8-one 8-ethylene acetal <1996TL7827>.
COOMe
O O
HO OH, PTSA
ð30Þ
75%
O MeOOC
1.18.2.4.4 Oxy-Cope rearrangement

The oxy-Cope rearrangement <1991COS(5)785> has been reviewed <1995CRV9>. A full and
comprehensive analysis of the oxy-Cope rearrangement using density functional theory has been
published <2001HCA124>. The oxy-Cope rearrangement has become one of the methods of
choice for the synthesis of carbon–carbon bonds in a simple and efficient manner <1995T9767,
1997T13971, 1998TL9>. Diketone 54 was converted into the Cope rearrangement product 56 via
silyl enol ether 55 after heating at 250 C <1998TL659, 1998CC155> (Equation (31)).
O
CO2Me
OMe TMSO TMSO
OMe 250 °C
MeO2C MeO2C ð31Þ
OMe OMe 95% O
O O MeO OMe
54 55 56
The oxy-Cope rearrangement of fluorinated divinylcyclohexanols is a practical route for the

synthesis of cyclodecenones (Equation (32)) <1999CC2535>. The sigmatropic rearrangement in
fluorinated molecules has been reviewed <1992JFC(56)165, 1997TCC(193)131>.
O O
HO O
150 °C
F F ð32Þ
84%
F F
F F
The synthetic applications of the siloxy (or silyloxy)-Cope rearrangement have been reviewed
<2001SL1079>. In a number of examples, the protection of the alcohol moiety accelerates or
improves the chemical yield of the rearrangement process. Schneider’s group has made some
practical applications, such as the stereoselective synthesis of highly substituted piperidines
<1999EJO3353>, the asymmetric synthesis of protected 1,3,5-triols <1999CEJ2850>, the pre-
paration of highly substituted tetrahydropyrans <2000EJO73>, the efficient synthesis of func-
tionalized cyclohexanes <2002CEJ2585>, or bicyclic medium-ring-containing compounds
<2003JA14901>.
The siloxy-Cope rearrangement has been used as a key step in the synthesis of (+)-lasiol
<1998EJO1661> and in the synthesis of the core structure of Ras farnesyl transferase inhibitors
CP-225,917 and CP-263,114 <1999TL4605, 2000TL6259>. Leighton and Bio have also reported on
the application of the siloxy-Cope rearrangement in synthetic sequences leading to these potential
antitumor molecules <1999JA890, 2000OL2905, 2003JOC1693>. The siloxy-Cope rearrangement
of syn- and anti-aldols installed in differently substituted acyclic 1,5-hexadienes has been reported,
showing that the reaction is more stereoselective for the syn- than for the anti-precursors
<1996SL212, 1996TL4471, 1996TL8899, 1997T133>.
1.18.2.4.5 Aza-Cope rearrangement

The subject has been reviewed <1987RCR477> and updated recently <1996JOC978>. The aza-
Cope (also called the amino-Claisen rearrangement) reaction is the [3,3]-sigmatropic rearrange-
ment of an N-allyl enamine. Whereas neutral allylic enamines rearrange to -ene imines at rather
elevated temperatures, analogous protonated substrates, Lewis acid-coordinated or quaternarized
molecules rearrange in milder conditions <1997OM4248>. 3-Alkylideneindolin-2-ones have been

prepared from propargylbenzotriazoles in two steps via reaction of an allene dianion followed by
3-aza-Cope rearrangement and [1,3]-hydrogen shift <1997BSB419>. The aza-Cope rearrange-
ment has been applied to the synthesis of chain-extended amino sugar derivatives from N-glycosyl
homoallylamines <1998TL791> and has also been the key step in the synthesis of 2,3-dihydro-
1H-2-benzazepine-3-carboxylic acid derivatives, which are conformationally constrained peptide
analogs <2001JOC2884>. The aza-Cope reaction has been used for the synthesis of
5,6,7-trisubstituted 4-aminopyrido[2,3-d]pyrimidines as novel inhibitors of adenosine kinase
<2003JMC5249>. Reissig has applied a Cope-type rearrangement of vinylcyclopropylisocyanates
to the preparation of highly substituted azepinones, this reaction being accelerated by a 2-silyloxy
substituent <2000SL725>. An interesting example of a 3-aza-Cope rearrangement of a quatern-
ary N-allyl enammonium salt featuring a stereospecific 1,3-allyl migration from nitrogen to
carbon has been reported (Equation (33)) <2000JOC4938>.
Ph Ph
23 °C ð33Þ
N
99% N Br
H Br
H
An exotic extension of the aza-Cope rearrangement is the 1,3,4-triaza Cope rearrangement, a

process that starts with the reaction of 1-alkyl-1-cyanohydrazones with methyl triflates giving
2-(methylamino)-1-alkyl imidazoles as their triflate salts <1997BSB553>. The pericyclic process
involving 1,5-hexadienes usually proceeds under high temperatures and prolonged reaction times.
The analogous aza-Cope rearrangement also proceeds under drastic conditions <1996TA1847>,
but it has recently been found that the N-silyloxy iminoethers rearrange under milder conditions
in good yields, featuring the first 3-oxy-assisted 3-aza-Cope rearrangement (Equation (34))
<2002CC746>.
Ph Ph
188 °C
N 80% N ð34Þ
TBDMSO SO2Tol TBDMSO SO2Tol
99/1 syn/anti
An interesting variant of the aza-Cope is the aza-Cope–Mannich, a powerful method for

assembling nitrogen heterocycles based on the acid-promoted condensation of an acyclic homo-
allylic amine containing an allylic hydroxyl (or alkoxyl) group with an aldehyde or ketone. When
the amine and alcohol substituents are vicinally located on a ring, the aza-Cope–Mannich
reaction affords a product in which pyrrolidine annulation is combined with one-carbon ring-
expansion (Equation (35)) <1997IJ23>.
i. MeCHO, Na2 SO4 , 60–80 °C O

HO Ph Ph
ii. CSA (0.9 equiv.), MeCN, 23–60 °C
Me
86% N ð35Þ
NHMe H Me
CSA = camphorsulfonic acid
1.18.2.4.6 Anionic oxy-Cope rearrangements

The anionic oxy-Cope rearrangement has been reviewed <1995CRV9, 1997T13971,
1998EJO1709>. The mechanistic aspects concerning the variations and rate effects of alkoxy
and thioalkoxy substituents in the anionic oxy-Cope rearrangements have been investigated
<1999JA11880, 2000JCS(P1)1423, 2000JA10788>. Paquette’s group has made a number of
contributions in this subject showing the power of this methodology for the assembly of complex
polycyclic arrays from hydroxyl-substituted, 1,5-hexadienes; treatment of these substrates with
bases (sodium or potassium hydride, potassium hexamethyldisilazide, or potassium carbonate) at
room temperature allowed these authors to reach these objectives in a simple and efficient manner
(Scheme 13) <1997TL1271, 1998SC1509>. Paquette has extensively reported on the squarate
ester-polyquinane connection using the oxy-anion Cope rearrangement as the key step
<1995JOC889, 1995JOC897, 1995JOC7849, 1995JOC7857, 1997JA1230, 1997JA3038,
1997JOC627, 1997T8913>.
MeO OMe H H
OH OTBDMS
NaH, THF, MeOH
MeO Spinosyn A
84%
MeO H
OTBDMS
O
H
KH, 18-c-6, Et2O O
(+)-Dihydronepetalactone
–
OH
92%
H
BnO
OH O
KHMDS, toluene
CP225,917
95% H
OBn
Me
Scheme 13
The anionic oxy-Cope rearrangement of 1,2-divinylcyclohexanol derivatives give the corre-

sponding 2-methyl and 10-methyl-5-cyclodecenones <2001TL3815>. The anionic oxy-Cope rear-
rangement of divinyl cyclopropanes has been investigated and constitutes an excellent synthetic
method for the preparation of medium-sized carbocycles (Equation (36)) <1998JA4947,
2000S1327>. The effect of trialkylsilyl groups attached to the alkene moieties has been investi-
gated, and it has been observed that due to its bulkiness, this group modifies the stereochemical
course of the oxy-Cope rearrangement <1997T14235>.
Me
Me O
OAc
MeLi O–Li+
TBDMSO TBDMSO Me ð36Þ
TBDMSO
82%
SiMe3
SiMe3
SiMe3
The addition of -pentadienylindium(I) to unsaturated ketones afforded the conjugate addi-

tion product preferentially via tandem carbonyl addition In(I)oxy-Cope rearrangement
pathway (Equation (37)) <2003S790, 2000POL533, 1999TL7867>. The Grignard addition to
2-arylidene-1-tetraloneCr(CO)3 complex gave a tertiary homoallyl alcohol that on treatment
with potassium hydride underwent anionic oxy-Cope rearrangement to give the homoallylic
-alkylated 1-tetralone Cr(CO)3 complex <1996JOC8362, 2001IJC(B)1063, 2002JCS(P1)669>.
Trimethyl borate has been used to promote the thermal cycloaromatization of 1-aryl-1-
(prop-2-ynyl)-3,3-bis(alkylthio)-2-propen-1-ols <1996TL2817>.
Br
O O In
In O ð37Þ
Ph Ph Ph Ph
27% Ph Ph
The anionic oxy-Cope rearrangement has been investigated in furanoside templates for the
synthesis of nine-membered ethers with moderate success (Equation (38)) <1996CC1359>. The
charge-accelerated oxy-Cope rearrangement <1990AG(E)609, 1993OR93, 2000JA740,
2000TL747> has been used with advantage in a number of synthetic approaches for useful
group/structure transformations, as in model studies for the synthesis of antitumor compounds
CP-263,114 <1998JA10784, 2001OL2431> and CP-225,917 <1999T12059>, inhibitors of Ras
farnesyltransferase; in the synthesis of -hydroxycyclohexanones <1998TL685, 2000TL737,
2001JCS(P1)1051>; in enantioselective routes to highly functionalized steroidal nuclei
<1996TL6103, 1999SL1491>; the hydroazulenoid skeleton <1998TL4133>; enantiopure
cis-decalins <1996AJC639, 1996CC869, 1996TL5897>; for the synthesis of the dicyclopenta[a,d]-
cyclooctene core of ceroplastin sesterterpenes <1996JOC3268>; in studies directed to the synthesis
of taxane diterpenes <1995T3455, 2000S921, 1998SL897, 2000EJO2187, 1998H(48)235>; for the
synthesis of the sesterpenic acids bilosespenes A and B <2003OL4741> or the limonoid triterpene
dumsin <2003JOC6905>; for the synthesis of ()-dihydronepetalactone (Scheme 13)
<1998JCS(P1)2645>; the carbobicyclic substructure of CP-225,917 and CP-263,114 (phomoi-
drides A and B) (Scheme 13) <1997CC2157, 2001JCS(P1)2194>; the alkaloid norsuaveoline
<1998TL8009>; in the preparation of ()-palominol or ()-dolabellatrienone <1998TL741>,
()-salsolene oxide <1997JA2767, 1997JOC8155> and (+)-taxusin <1998JA5203,
1998JOC9968>; in the synthesis of paclitaxel <1998JOC6432>; ajmaline/sarpagine-related alka-
loids such as (+)-ajmaline, norsuaveoline, talpinine, talcarpine, and epiaffinisine <1998JOC9160,
1999JA6998, 2000JOC3173, 2001OL345, 2003JOC5852>; in the synthesis of an advanced inter-
mediate for the obtention of fungal metabolite penitrem D <1995JOC7837>, spinosyn A
(Scheme 13) <1998JA2543>, the antifungal antibiotic aleurodiscal <1998S495>; in studies
directed to vinigrol <1996SL625, 1997JOC5062, 2003OL1139, 2003OL3631, 2003JOC6096>; in
highly stereoselective approaches to cis-clerodanes <1998SL912>; in the total synthesis of
()-precapnelladiene <1998JOC6905>; in the synthesis of bioactive mesotricyclic diterpenoids
jatrophatrione <1999JOC3244> and citlalitrione <2003JA1567>; in the total synthesis of
()-o-methylshikoccin and (+)-o-(methylepoxy)shikoccin <1996JA11990, 1997JA9662>; in the
synthesis of a tetracyclic lactone structurally related to the kaurane diterpenoids <1996SL129>;
in the total synthesis of racemic tetracyclic diterpenoid scopadulin <2001JOC4831>, the sesquiterpene
()-patchoulenone <2003NJC50>, in the synthesis of Cyathin diterpene skeleton <1999T3553>, the
insect antifeedant ()-homogynolide A <1995S845>, natural sesquiterpene lactones as vulgarolide
<1995TL673, 1996JA5620> and deoxocrispolide <1996JA5620>.
O
O O 220–220 °C
O ð38Þ
O O
40%
OH O
The aromatic oxy-Cope rearrangement has been applied to the synthesis of aromatic com-
pounds such as helicenes (Equation (39)) <2002TL7827, 2003TL2167>.
O
Br
H
HO KH Br ð39Þ
H
89%
MeO OMe
An interesting case of a dianionic oxy-Cope rearrangement <1996CEJ182, 1999SL680,

2001EJO2519, 2001EJO93, 2002PAC57, 2002EJO1972> followed by intramolecular aldol reac-
tion has been observed after the nucleophilic attack of 1-ethoxy-1-lithioethene to the -diketone
57 to give compound 58 (Equation (40)) <1998EJO2719>.
OEt
i.
– O
Li –O
O OEt
O (2 equiv.) OEt
OEt
ii. 2 M HCl ð40Þ
OEt
O 54% –
O (OC)3Cr HO
(OC)3Cr (OC)3Cr
Cr(CO)3 O OEt EtO
57
58
Finally, the oxy-Cope rearrangement of substrates incorporating a C-alkynyl or C-allenyl onto

the tertiary alcohol moiety is also known <1996SC2119, 1996T7737>, and the effect of halogen
substitution on the alkynyl group has been investigated <1997T12637>.
1.18.2.4.7 Anionic amino-Cope rearrangements

The anionic amino-Cope reaction has been the subject of some interest in recent years. Some
ab initio theoretical calculations have been performed <1998JA205>, and recent results show that
a concerted mechanism is operating <1998TL3345, 1998SL1117>, although evidence has been
presented for an alternative stepwise mechanism <1999TL3801>. Thermally induced [3,3]-sigma-
tropic amino-Cope rearrangement of 3-amino-1,5-dienes occurs to furnish enamine products in
high yield and with excellent (E)/(Z)-enamine selectivity; these resulting final products are useful
building blocks for further synthetic development (Equation (41)) <1997SL725>.
R R
N X ∆ N X
R R ð41Þ
[3,3]
Y Y
In the anionic amino-Cope rearrangement of 3-amino-1,5-hexadienes, depending on the

solvent/additives used, in addition to the [3,3]-rearranged products, it has claimed the formation
of [1,3]-compounds, showing the complexity of this useful functional group transformation
(Equation (42)) <1999TL3119>.
RHN i. Bu nLi, solvent O

O
ii. H3O+
+
PhS PhS PhS
ð42Þ
[3,3] [1,3]
THF 1:2, 54%
Hexane 2:1, 31%
In 1998, the first example of asymmetric induction in an anionic amino-Cope rearrangement

using enantiomerically pure amines as chiral inductors was reported (Equation (43))
<1998TL3345>; this methodology was applied later for the enantioselective synthesis of tetra-
hydropyrans <2002TL4195>.
H
Ph N Ph NRLi O Ph
BunLi, THF [3,3]
Me 73% H Ph H3O+
ð43Þ
41% ee
Ph
R=
Me
Nitrogen-charged intermediates have been invoked in the mechanism for the reverse-Cope
elimination-Meisenheimer reaction <1995JOC5795, 1995JOC5803> of allyl amines or thiols
with nitrones for the synthesis of oxadiazinanes or thiazolidine-N-oxides (Equation (44))

<1997TL8545, 1997TL8549>.
R2
NH2 R2 CHCl3, 60 °C
+ O HN O
R1 N N ð44Þ
80–100% Me
Me R1
R1 = H, Me, Ph; R2 = H, Ph, c -C 3H5, n-hexyl
1.18.2.4.8 2-Oxonia-Cope rearrangement

The 2-oxonia-Cope rearrangement has been invoked as a competitive pathway in Prins cycliza-
tions and related transformations <2000TL9431, 2001CC835, 2001JOC4679, 2001OL3815,
2002OL577>. The rearrangement has been used in the synthesis of cis- and trans-2,6-disubstituted
tetrahydropyrans (Equation (45)) <1997JOC3426, 2000JA9836, 2001SL955>.
Ph O Ph
OH
TMSOTf, CH2Cl2, –78 °C O
Ph ð45Þ
49%
SiMe3
Ph
The 2-oxonia [3,3]-sigmatropic rearrangement is a new concept that has been introduced
recently as a mechanistic rationale for a simple functional group transformation such as the
allylation of aldehydes for the synthesis of homoallylic alcohols (Equation (46)) <1998JA6609,
2000JA1310, 2000CEJ2909, 2001JA9168, 2003AG(E)1273>, or for the synthesis of tetrahydro-
furans from homoallylic alcohols <2001AG(E)2921, 2001JA2450>.
OH
H Yn
R
R O M
R1 MYn R1 R1
anti
RCHO ð46Þ
OH
MYn H Yn
R1 R O M R
R1
R 1 syn
The 2-oxonia-Cope rearrangement has been applied in the total synthesis of the natural
cis-2,6-disubstituted tetrahydropyran ()-centrolobine <2002OL3919>, and in the stereocontrolled
synthesis of linear 22R-homoallylic sterols via triflic acid promoted rearrangement <2002OL2389>.
1.18.2.4.9 Cope rearrangement of divinyl cycloalkanes

Divinyl cyclopropane derivatives may undergo rearrangements <1991COS(5)971> following two
different routes. One way is the [3,3]-sigmatropic-Cope rearrangement leading to 1,4-cyclohepta-
dienes <1997HOU(E17c)2589>, and the other is a [1,3]-sigmatropic rearrangement giving
vinyl-substituted cyclopentenes (Scheme 14) <1997HOU(E17c)2538>. A DFT study on these
R1
R1 R2 R1 R2 R2
[3,3] [1,3]
Scheme 14
competitive reactions <1999EJO1107> and an ab initio study on the transition structures and
energetics <2003JST(625)251> have been published. The mechanism of the rearrangement of
7-vinylnorcaradienes has been investigated <1996TL7761>.
Piers has described an efficient synthesis of 1,2-bisalkenylcyclopropanes by Pd(0)-catalyzed
cross-coupling of the cyclopropylzinc chlorides and alkenyl iodides; the compounds prepared in
such a way thermally rearrange to the corresponding cycloheptadiene derivatives <2001S251>.
Chiral ethyl cyclohepta-2,5-diene carboxylates have been synthesized from suitable divinylcyclo-
propane derivatives via Cope rearrangement; these compounds are intermediates in the asym-
metric synthesis of natural products such as lamoxirene, isolated from a marine brown algae
<2000JOC2458>. Takeda and co-workers have reported a new [3+4]-annulation strategy in the
reaction of [-(trimethylsilyl)acryloyl]silanes with lithium enolates of ,-unsaturated methyl
ketones for the synthesis of diversely functionalized cycloheptanes <1995JA6400, 1998JA4947>
and they have proposed a mechanism via Cope rearrangement of the presumed divinylcyclopro-
pane intermediates. 1,2-cis-Divinylcyclopropyl derivatives, obtained by reaction on propenoyl-
chromium carbenes and conveniently functionalized 1,3-dienes, undergo Cope rearrangement to
give the expected cycloheptadiene <2002OL2719>. Very interesting differences have been
observed in the thermal rearrangement of C7-substituted divinylcyclopropyl[2.2.1]diazenes;
substrates with only one electron-withdrawing substituent (ketone or carboxylic ester) afford
Cope rearrangement products (Equation (47)) <1998TL1893, 2003TL2109>. 1-Silyloxy-2,3-divi-
nylcyclopropanes undergo thermal Cope rearrangement to give the corresponding cycloheptane
unsaturated silyl enol ethers in good yield; these compounds are good intermediates for further
elaboration <1995JA9919>.
Benzene,
COMe reflux +
N ð47Þ
N
MeOC
COMe
54% 36%
The intermolecular reaction of diazo compounds with conveniently substituted furan

<1996JA10774, 1996JOC2305, 2000JOC4261, 2001T7337>, 2-pyridone <2002JOC5683> or pyrrole
heterocyclic ring systems <1997JOC1095>, the intermolecular reaction of diazo compounds
with dienes <1998JOC657, 1998JA3326, 1999JOC8501> or rhodium octanoate [Rh2(OOct)4]-
mediated intramolecular reaction of diene, diazo compounds <1996TL3967, 1997TL1737> result
in the formation of divinylcyclopropane intermediates (Equation (48)) that undergo in situ Cope
rearrangement, affording highly functionalized 8-oxabicyclo[3.2.1]octane derivatives or polycyclic
arrays of complex molecules (Scheme 15). Following these strategies, the synthesis of sesqui-
terpenes tremulenolide A and tremulenediol A has been achieved <1998JOC657>.
R
Rh2[OOct]4 O
O 70 °C ð48Þ
N2 O
O
R
R = H, 45%; R = Ph, 24%
The reactions of 2-aza-1,3-butadienes with alkenyl Fischer complexes yield seven-membered

unsaturated lactams in moderate yield with no stereoselectivity, possibly via a novel vinyl-imino
cyclopropyl [3,3]-sigmatropic rearrangement (Equation (49)) <1997JOC9229>. The cyclization of
triene-conjugated nitrile ylides gives complex heterocyclic architectures such as 1,4-prop[2]-
enoisoquinolines via sigmatropic rearrangement of the presumed analogous vinyl-imino cyclopro-
pyl intermediates <1999JCS(P1)443>. In an approach to the synthesis of ,0 -cyclopropyl
aminonitriles, Salaün and co-workers have reported the formation of a series of azepines arising
via aza-Cope expansion of 1,2-cis-vinyl-imino cyclopropyl intermediates <1999JOC4712>.
O
Rh2[OOct]4 TBDMSOTf
O O 65 °C
O
N2 54%
40%
O O O
O TBDMSO
O
O O
O – O O
OTBDMS Si O TBDMSO
Scheme 15
Ph Ph Ph Ph Ph Ph
THF
+ OMe H N + H N
N
60 °C ð49Þ
TMSO W(CO)5 O OMe O OMe
42% 38%
The asymmetric synthesis of (+)-dictyopterene C0 has been accomplished via Cope rearrange-
ment of an appropriately substituted divinylcyclopropane intermediate (Equation (50))
<1998HCA1754>; the analogous aza-Cope rearrangement has also been described
<1999HCA315, 2000HCA1525, 2002TA551>.
∆, CCl4
ð50Þ
Bu 100%
In an interesting report, the benzophenone-sensitized photochemical reaction of vinylnorcara-

dienes gave isochroman-3-one derivatives in good yields (Equation (51)) <1997CC1973>. The
pyrolysis of tricyclic cyclobutane-fused sulfolanes gives cis-1,2-divinyl compounds that rearrange
to the Cope-derived products (Equation (52)) <1999JCS(P1)605>. Thermal reactions of
,-unsaturated Fischer carbene complexes with silyloxydienes give cyclohepta-1,4-dienes through
a mechanism that involves the Cope rearrangement of the presumed cis-1,2-divinyl intermediates
(Equation (53)) <1999CEJ876>. The reaction of -diazoesters with cycloalkanedienes affords
bicyclic derivatives in good yield as a result of cyclopropane formation and subsequent Cope
rearrangement of the intermediate divinyl cyclopropyl derivatives <2000TL2035>; this strategy
has been used to produce useful intermediates in a synthetic approach to the formal asymmetric
synthesis of sertraline <1999OL233>. The hydroxyl-directed zinc carbenoid addition to a sub-
stituted cycloheptatriene results in a sequential cyclopropanation/Cope rearrangement/cyclopropa-
nation process leading to a stereochemically pure tricyclic compound in good yield
<2001TA2727>.
O
hν, Ph2CO
X O X O
40–96% ð51Þ
O
X = H, Cl, Me, OMe, Ph
FVP
O2S O O O ð52Þ
–SO 2 55%
OMe
(OC)5Cr
MeO OTBDMS
MeO OTBDMS
Ph
+ 56 °C ð53Þ
OTBDMS 28% Ph Ph
Ph Ph
Ph
The synthesis and absolute configuration of desmarestene, the gamete-releasing and gamete-
attracting pheromone of the brown algae Desmarestia aculeate, has been reported using as the key
step the Cope rearrangement of 1,2-cis-vinylalkenylcyclopropanes (Equation (54))
<1995AG(E)1602, 1995T7927, 1997T13681>.
Cope
O CH2=PPh3 rt
ð54Þ
42%
Some examples of Cope rearrangement are known for divinylcyclobutanes, as for instance in
the synthesis of functionalized bicyclo[6.3.0] ring system (Equation (55)) <1997JA1478>, its
application to the synthesis of both enantiomers of asteriscanolide <2000JA8071>, and to the
synthesis of bicyclo[5.8.5] ring systems <2001OL2819>. The intramolecular photochemical
cycloaddition of 1,3-dienes with 2-pyridones affords 1,2-divinylcyclobutanes that undergo thermal
Cope rearrangement to give a polycyclic cyclooctadiene (Equation (56)) <1999TL3527>.
-Lactams have been used as templates for the divinylcyclobutane Cope rearrangement reaction
leading to azocinones (Equation (57)) <2001TL3081>. An AM1 study for the oxycyclobuta-Cope
aromatic rearrangement <2000JST(531)301> has been published.
Pr H OTBDMS Pr
200 °C H OTBDMS
H ð55Þ
70%
O O
Me
O 120 °C
O
66%
ð56Þ
O
N N
Me O
Me
Ph
Ph
120 °C,
toluene ð57Þ
N 79%
O N
Bn
O Bn
Moore has extensively reported on the oxy-Cope variant of the divinylcyclobutane rearrange-
ment <1995JA8486, 1996JOC7976, 1997JOC3792, 1998JOC6905, 2000JOC3379, 2000JOC8564>.
For example, the addition of vinyllithium to cyclobutanone 59 gives an intermediate that after
ring expansion via divinylcyclobutane rearrangement and transannular ring-closure affords the
polycyclic ring system 60 in good yield (Equation (58)) <1996JOC7976>.
i. Vinyllithium
Me ii. –78 °C to rt
O Me
iii. NaHCO3 ð58Þ
TMSO O
80%
H OH
H
59 60
1.18.2.4.10 Cope rearrangement of vinyl bicycloalkenes

The Cope rearrangement of vinyl bicycloalkenes leads to the formation of fused bicyclic dienes
<1997SC841>. The reaction of cyclopentadiene with pyridinium salt 61 affords two Diels–Alder
products 62 and 63; it has been found that compound 63 is transformed into product 62 under
thermal conditions featuring a Cope rearrangement process <1996JOC9293> (Equation (59)). A
similar reactivity has been discovered in the reaction of cyclopentadiene with 2-nitro-3-methyl-
1,3-butadiene <1996T9275> and with 10 ,20 ,30 ,40 ,50 -penta-O-acetyl-10 -C-[(1R)-2-nitrocyclohexa-
2,4-dienyl]-D-manno-pentitol 64 to give adducts 65–67 (Equation (60)) <1998TA449>.
N
N 60 °C Br + Br
+ 93%
N ð59Þ
Br
140 °C
61
62 63
110 °C
Cope
Sug
NO2 Cyclopentadiene
NO2
Sug
Sug 110 °C + +
ð60Þ
NO2 NO2
Sug
64 65, traces 66, traces 67, 67%
Sug = sugar moiety
The Cope rearrangement of vinyl bicycloalkenes such as bicyclo[2.2.2]octenones is a general and

stereoselective entry into functionalized cis-decalins <1997CC1085>. This strategy has been effi-
ciently applied into the synthesis of the norsesquiterpenoid eremopetasidione <2001OL263>. The
intramolecular Diels–Alder adducts from o-quinonoid monoketals give bicyclic ring systems that
after Cope rearrangement afford polyclic complex arrays, that have culminated in the synthesis of
xestoquinone <1997JOC2330>. 1,2-Dialkenylcyclohexene epoxides undergo thermal Cope rearran-
gement to furnish 1,6-oxygen-bridged cyclodeca-1,5-dienes <1999JOC3806>.
1.18.2.5 Where Y = CZ (Z = Heteroatom)

For Z = chalcogen, Y = CO (Wittig rearrangement, rearrangement of oxonium ylides),
Y = CS (thia-Wittig rearrangement); for Z = nitrogen, Y = CN (aza-Wittig rearrangement,
rearrangement of nitrogen ylides) or miscellaneous rearrangements (Y = Hal, CSe, CSi), see
Chapter 1.09.
1.18.2.6 Where Y = CCZ
1.18.2.6.1 Where Z = chalcogen

Extensive and excellent full accounts have been published in the last years covering the different
aspects and modifications of the [3,3]-sigmatropic Claisen and Cope reactions <1996TA1847,
2003S961, B-2000MI001>.
(i) Claisen rearrangement (Y = CCO)

The Claisen rearrangement of allyl vinyl ethers is one of the most important sigmatropic reac-
tions. The Claisen rearrangement has been extensively reviewed in recent years covering different
aspects, such as theoretical studies on the nature of the transition states <1999JA10865,
1997JA2877>, the effect of the substituents <2001JPC383>, the asymmetric Claisen rearrange-
ment <1999CSR43>, the effect of pressure <2000JPR609>, the use of water as solvent
<1997JCS(P2)71, 1997JOC2505, 2002CRV2751>, or Claisen rearrangements in carbohydrates
<B-2001MI001, 2001TCC(215)293>. It has found widespread synthetic application due to the
simplicity of the process and the high degree of stereoselectivity and functional group reorganiza-
tion <1991COS(5)827,1996AG(E)936, 1996T5461>. The effect of solvent and substituents has
been reviewed <1997ACR219>. This synthetic transformation has been the subject of a series of
different modifications that have contributed to enhance the value of the original proposal. As an
example, in a synthetic study directed to prepare functionalized vitamin D3 side-chain intermedi-
ates, Hatcher and Posner synthesized suitable precursors and compared the results of some of
these variants of the Claisen rearrangement (Scheme 16) <2002TL5009>. These rearrangements
proceed in high yield and excellent stereocontrol. A series of -fluoro and ,-difluoro allylic
alcohols have been submitted to typical [3,3]-sigmatropic rearrangements such as the classical allyl
vinyl ether, Johnson–Claisen and Eschenmoser–Claisen reactions to give the expected -fluoro
and ,-difluoro-carbonyl derivatives <1995T11327>. A review showing the applications of the
Claisen rearrangement in the synthesis of bioactive marine terpenoids has been published
<2002BCJ203>.
CHO
Claisen
O
97%
H H
TESO TESO
COOCH3
OCH3
O Johnson-orthoester
83%
H H
TESO TESO
O–
Carroll O
O O–
96%
H H
TESO TESO
Scheme 16
(a) Claisen rearrangement of allyl/propargyl vinyl ethers. A recent account reviewing the catalysis
on the Claisen rearrangement of allyl/propargyl vinyl ethers has been published <2002EJO1461>.
The use of n-butyl vinyl ether in reaction with allylic alcohols for the synthesis of substrates of the
Claisen rearrangement, the allyl vinyl ethers, has been documented <2002SC869>.
The thermal allene-Claisen rearrangement of allyl, allenyl ethers has been reported to be a
simple and facile entry to ,-unsaturated aldehydes <2000OL571> (Equation (61)). Analogous
propargyl, vinyl ethers also give the corresponding homoallenyl aldehydes <1995M1151,
1997BSB645>. In the case of simple allyl vinyl ethers the expected homoallyl aldehydes are
obtained in good yield <1996SL67, 1999JIC521>. This approach has been used for the prepara-
tion of the key aldehyde intermediate in a synthetic approach for faveline dimethyl ether
<1995T5819>, for the total synthesis of ()-myltayl-8(12)-ene and ()-6-epijunicedranol
<1999JCS(P1)2877>, or the preparation of chiral bicyclo[4.3.1]decanes, a structural motif present
in a number of natural products, such as ingenol or sanadaol <1999TL1031>.
O O
∆
R H ð61Þ
R 75–96% 1
R 1 R
The synthesis of a number of heterocyclic ring systems (tetronic acids, tetronates <1995SL425,
2001EJO1951>, coumarins, benzoxepinones) has been approached in two steps by Wittig olefina-
tion reaction with the readily available ketenylidene(triphenyl)phosphorane and carboxylic acids
bearing OH or NH groups followed by in situ Claisen rearrangement (Equation (62))
<1996JCS(P1)2799>. Sequential Wittig reaction of a conveniently functionalized benzaldehyde
or acetophenone derivatives followed by Claisen rearrangement of the resulting allyl vinyl ether
<1997S1420> has been efficiently applied to the synthesis of racemic sesquiterpene laurene
<1997JCS(P1)3127> and -cuparenone <1997T3167>.
O O
O O
+ Ph3P=C=C=O PPh3
NH2 N O
H
ð62Þ
O O
OH
[3,3]
40% N
N O O
N O H
H H
Allyl vinyl ethers can also be prepared by Lewis acid (TMSOTf, AlCl3, TMSI/HMDS, etc.)
cleavage of 3-vinyl-substituted 1,3-dioxolane acetals, and rearranged on heating to give the
expected ,-unsaturated carbonyl derivatives <1997SC663, 2002TL7757>. In a large series of
papers, Majumdar and co-workers have extensively exploited a diverse array of simple or tandem
[2,3]- <1998T11603, 1999T1449, 1998TL7147, 1998JOC9997, 1998JOC3550> or [3,3]-sigmatropic
rearrangements on conveniently functionalized heteropropargyl precursors <2001S1568,
2002S669> for the synthesis of heterocycles <1997JIC884, 1999H(50)1227>. The observed dia-
stereoselectivities in the Claisen rearrangement of cyclohexenyl allyl ethers an governed by the
Lewis acid catalysis employed rather than the thermal rearrangement conditions <1995TL803>.
Curran has reported on the accelerated Claisen rearrangement of 6-methoxy allyl vinyl ether in
the presence of a soluble diaryl urea <1995TL6647>.
The tin-mediated Claisen rearrangement of 2-allyloxycyclohexenone has been proved to be a
stannyloxy-accelerated Claisen rearrangement <1999JA8955, 1998JA3807>. Triisobutylalumi-
num <1996SL475> or aluminum tris(4-bromo-2,6-diphenylphenoxide) are effective catalysts for
the Claisen rearrangement of various allyl vinyl ethers, the reaction proceeding at low tempera-
ture, in good yield and with high diastereoselectivity <1995JA1165, 1996SL720>. Palladium(II)
catalysts efficiently promote the Claisen rearrangement of differently substituted allyl vinyl ethers
<1995BSF696, 1995SL447, 1995CL697, 1996TL7991>, as 2-alkoxycarbonyl-substituted allyl
vinyl ethers to give the ,-alkyl-substituted -keto esters in good yield and excellent syn/anti-
diastereoselectivity <1999SL1823>. Rhodium(II) complexes catalyze the reaction of allyl
-diazoacetates with di-t-butylthioketene affording 4-allyl-2-methylene-1,3-oxathiolan-5-ones
through the 1,5-cyclization of a thiocarbonyl ylide followed by Claisen rearrangement
<1995BCJ1393>. Eilbracht has extensively reported on an elegant and useful tandem ruthe-
nium-promoted Claisen rearrangement and hydroacylation reaction that allows the cyclization
reaction of differently substituted allyl vinyl ethers <1995S330, 1996SL1221, 1998TL1905,
1998TL9647> (Equation (63)). Iridium(I)-phosphine precatalysts promoted olefin isomerization
processes in conveniently functionalized bis(allyl) ethers leading to highly stereoselective Claisen
rearrangements of the resulting aliphatic allyl vinyl ethers <2003JA13000>.
Me
Me Me Me Me
Me RuCl2(PPh3)3
ð63Þ
O 73% O
O
Looking for a chiral catalyst, it was found that the combination of copper(II) triflate plus
molecular sieves promoted efficiently the Claisen rearrangement of 2-alkoxycarbonyl substituted
allyl vinyl ethers <2001OL49>; as an extension the use of chiral copper(II) bis(oxazoline)
complexes as catalysts for the enantioselective Claisen rearrangement has been documented
<2001AG(E)4700, 2003T4031>.
4-(O- or N)-Substituted (E)-allyl sulfides upon reaction with trichloracetyl chloride in the
presence of Zn/Cu couple are transformed in situ into the corresponding allyl thioethers that
after Claisen rearrangement afford the expected ,-unsaturated esters (Equation (64))
<1997HCA876, 2001T5607>. The thermally induced Claisen rearrangement of various isomeric
diethylphosphorylallyl vinyl ethers yields 1-alkenylphosphates and 2-alkenylphosphonates
<1995SC2533>.
OTBDMS TBDMSO
CCl3COCl Cl Cl Cl Cl
S Zn/Cu S
Me Me
TBDMSO ð64Þ
87% O S O
Me
94% de (syn/anti )
Tandem intramolecular [2+2]-cycloaddition and [3,3]-sigmatropic rearrangement of allenyl

ethers have been used in a novel synthetic strategy for the synthesis of oxa-taxane skeleton
<1995T3499> (Equation (65)), and for the -ketol isoprene unit elongation in a synthetic
approach to the natural product sarcophytol A <1995JCS(P1)751>.
C O
O O O O
KOBut,
O
O ButOH O
O ð65Þ
O 100% O O
O H O H
H O
Products arising from hetero-Diels–Alder reactions have been shown to rearrange to the
normal Diels–Alder adducts via Claisen rearrangements (Equation (66)) <1996CPB681>.
Hetero-Diels–Alder adducts from the reaction of cyclopentadiene with substituted ketenes also
react in the same way via Claisen rearrangements <1999JA4771>.
∆, Claisen
83%
Ph Ph PhOC
O O O ð66Þ
O O
H
+ +
EtOOC N O 100% O O
N N
Ph EtOOC Ph EtOOC Ph
The Claisen rearrangement of allyl or propargyl fluorovinyl ethers for the synthesis of -tri-
fluoromethyl unsaturated acids and derivatives has been extensively investigated in different
laboratories <1995JOC6289, 1996CC861, 1998TL305, 1998TL5041, 1998CC2441,
1999JFC(94)27, 2000EJO1933, 2000CC1691, 2001TL2665, 2001JOC4887, 2002JFC(113)167,
2003T4641>. -O-Substituted N-aziridinyl imines on treatment with rhodium(II) catalyst afford
carbenoid species that give enol ethers in a Bamford–Stevens-type reaction in good yields; for
similar O-allyl derivatives this intermediate isomerizes to give the Claisen rearrangement products
in a simple and efficient process (Equation (67)) <2002JA12426>.
N Ph OMe
OMe Rh2(OAc)4
N 130 °C [3,3]
O
O Ph
Ph 82%
ð67Þ
O C6H4OMe
H
Ph
dr > 20:1
The copper-catalyzed reaction of allylic alcohols with vinyl iodides gives allyl vinyl ethers that
rearrange in situ to the ,-unsaturated aldehydes in good yield and moderate diastereomeric
excess <2003JA4978>.
Paquette has shown that the Claisen rearrangement of 2-methylene-6-vinyltetrahydropyran is a
convenient method for the synthesis of medium-sized carbocycles <1995JOC1435, 1998TL5705,
1997JA8438>. The same methodology applied to 2-methylene-5-vinyl tetrahydrofuran has proved
to be successful for the total synthesis of sesquiterpenoid 7-epi-bulnesene <2002TL1939>. Follow-
ing these trends, the thermal or triisobutylaluminum (TIBAL)-promoted Claisen rearrangement has
been set up for the synthesis of bridged bicyclic [4.n.1] ring systems <1997S1258>, and in sugar
templates for the synthesis of cyclooctane carbaglucose derivatives as a new class of carbohydrate
mimetics <1997AG(E)2793, 2000AG(E)362, 2000AG(E)2466, 2000TA283, 2001EJO1053,
2002T10189> (Equation (68)). Zhang has applied the same protocol for the stereoselective pre-
paration of seven-membered carbasugars <2003TA2195> and also a similar process involving ring
expansion in fluorinated precursors <2000JCS(P1)2339> has been reported. Still in the sugar
domain a new method for the synthesis of C-glycosides has been developed using 3-O-allyl glucals
as suitable precursors <2000TL7589, 2003TL3631, 2003OBC3772>; a similar analysis has been
previously documented for the synthesis of cis-2,6-disubstituted pyrans using the Ireland–Claisen
rearrangement in suitable precursors on nonsugar-substrates <1997AJC43>. A new strategy has
been advanced for the synthesis of pseudo-sugars, based on the thermal Claisen rearrangement of
allyl vinyl ethers installed in a pyranose template (Equation (69)) <1998CC925>.
O TIBAL
HO OBn
ð68Þ
BnO OBn 98%
OBn BnO OBn
BnO BnO
∆, 240 °C
BnO Pseudosugars ð69Þ
BnO O
84%
OHC
The asymmetric Claisen rearrangement of allyl vinyl ethers in the presence of chiral bis(organo-
aluminum) Lewis acids gives the corresponding ,-unsaturated aldehydes in good chemical yield,
but moderate enantioselectivity <2002T8307>.
The synthesis of D/L-febrifugine and D/L isofebrifugine is an interesting case, where, depending
on the reaction conditions, the initial vinyl allyl ether rearranges normally to the expected product
(thermal conditions) or to a new vinyl allyl ether (Lewis acid catalysis -BF3OEt2—at room
temperature), that after Claisen rearrangement gives the key intermediate (Scheme 17)
<1999S1814, 1999CPB905>. Application of the Claisen rearrangement has been reported in
studies directed to the synthesis of natural products such as azadirachtin <1999SL1295,
2002OL3847>, in the asymmetric synthesis of cycloalkenones <2000JA3785>, in the synthetic
study on amphidinolide B <1998BCJ2433>, in the formal total synthesis of racemic acorones
<2001SL1986>, or in the promising compound for the treatment of Alzheimer’s disease garsu-
bellin A and related phloroglucins <2002OL1943>.
Among the natural products synthesized using the Claisen rearrangement of allyl vinyl ethers we
can cite flavor and fragrance compounds <2000MI1033>, acetoxycrenulide <1995JA1455,
1995JOC1435, 1996JA1309> (Scheme 17), anti-inflammatory sesquiterpene furoic acids
O O O
O 130 °C BF3.OEt2
69% Febrifugine
N 74% N N
N
CO2Bn CO2Bn CO2Bn
CO2Bn
Me
Me
O i. NaIO4
H
ii. Vinyl ethyl ether O H
O
O ∆ O
SePh O
H 55%
Me H
TBDMSO
TBDMSO Me
O H
Me
O (+)- Acetoxycrenulide
H
O
TBDMSO
Me
SOPh
OH O O
H i. BrCH2CH2S(O)Ph, NaH H H
ii. ∆, 150 °C
73%
H H H
H H
LiAlH4
O Ceratopicanol
H OH
H
Scheme 17
<1996T4245>, key intermediates such as 3a-(o-nitrophenyl)octahydroindol-4-ones for the synth-

esis of indole alkaloids <1996T4013>, the antitumor compound FR900482 <1996TL3475>,
sesquiterpene ceratopicanol <1995TL15, 1996JOC2095> (Scheme 17), the cardiotoxic agent
kalmanol <1996JA727>, (+)-cassiol <1999H(51)1321>, C(16),C(18)-bis-epi-cytochalasin D
<2000JOC6073>, in the stereoselective total synthesis of racemic tochuinyl and dihydrotochuinyl
acetates <1998T8133>, the asymmetric synthesis of the cytotoxic diterpenoid ()-sclerophytin
<2001JA9021>, the first enantioselective total synthesis of the sesquiterpene cyclomyltalane-5-
ol <2002JCS(P1)583>, pancratistatin <2002OL1343>, 12-oxo-phytodienoic acid <2002TL4361>,
the enantioselective synthesis of both enantiomers of labdane diterpene saudin <2002JA190>,
sesquiterpenes of the herbertane family <2002SL340>, nerylgeraniol-18-oic acid <2001SC2549>,
and the alkaloid mesembrine <2002TL2297>.
(b) Aromatic Claisen rearrangement. The transition state structures for the aromatic Claisen
rearrangement have been calculated by the molecular orbital method <1996JOC6218>. The
aromatic Claisen rearrangement is a [3,3]-sigmatropic transformation where an allyl ether gives
an o-dienone, which on enolization affords an o-allylphenol <1995IJC(B)1043, 1995AJC531,
2000CL116, 2000TL2039, 2000JCS(P1)1731, 2001T7965, 2002IJC(B)1460>. These rearrange-
ments have been extended to O-allylazulenes <2000EJO193> and to perfluoroallyloxy derivatives
<2001JFC(108)57>. Using enantiomerically pure O-allyl phenyl ethers it is possible to prepare

chiral C-alkylated phenols <1998JA815>. 1H NMR techniques are available in order to predict
the Claisen rearrangement regioselectivity in allylindanyl and allyltetrahydronaphthalenyl ether
derivatives <2000MRC970, 2003JOC5493>. The enantioselective aromatic Claisen rearrange-
ment on catechol mono allylic substituted ethers, using chiral boron reagents, has been described
<1997TL4815>.
Allyl aryl ethers undergo accelerated Claisen rearrangement in the presence of water
<2002MI434>. Sodium metabisulfite promotes the effective reductive Claisen rearrangement of
allyloxyanthraquinones <1996SC715, 1997AJC379, 1997OPP365>. The silver/potassium iodide
couple also efficiently promotes the Claisen rearrangement of allyloxyanthraquinones
<2000JOC2813>. It has been reported that the photo-aromatic Claisen <2002JA9768> rearran-
gement in zeolites as solid supports affords a mixture of the expected hydrogenolysis, ortho- and
para-rearrangement products <1996JA9428, 1998JMOC(134)129, 2001CL252>, and the effects of
-cyclodextrin on the photo-Claisen rearrangement of allyl phenyl ether have been published
<1997CJC1151>.
Different types of montmorillonites catalyze the regiospecific rearrangement of benzyl phenyl
ether to a mixture of the ortho- (major), para- (minor), and the debenzylated (traces) products
<1998IJC(B)301, 2001SL269>. The catalytic system nafion-H/silica nanocomposite has been
tested in the Claisen rearrangement of O-allyl phenol <2000JCA(193)132>. It has been reported
that florisil catalyzes the aromatic Claisen rearrangement and this can be applied to suitable
precursors for the synthesis of mycophenolic acid analogs <1997TL4725>. O-Allylsalicylic acids
rapidly rearrange in the presence of Merrifield resins under microwave irradiation
<2000SL1129>. Lewis acids such as Yb(OTf)3 or DIBAL-H are reported to efficiently catalyze
the Claisen rearrangement of allyl, crotyl, and prenyl aryl ethers <2000SL615>. The palladium-
catalyzed reaction of methylenecyclopropane 68 with phenol gives an intermediate that after
Claisen rearrangement leads to compound 69 (Equation (70)) <1999AG(E)3365>, and the
synthesis of N-allyl-2(1H)pyridones from 2-(allyloxy)pyridines has also been disclosed
<1996TL2829>.
OH
C7H15 [Pd(PPh3)4],
O OH
P(o -tolyl)3
+ ð70Þ
C7H15 C7H15
56%
68 69
Benzyl vinyl ethers do not undergo the Claisen rearrangement, but in the presence of lithium
perchlorate in diethyl ether, the 2-furyl and 2-thienylmethyl vinyl ethers give 1,3-rearrangement
products, being a convenient entry to -heteroaryl propanals <1995TL9527>. Even since the early
days of this reaction, rearrangements of certain allyl vinyl ethers have been observed which deviate
from the normal [3,3]-pattern which are called ‘‘abnormal’’ Claisen reactions <1996TL21,
2000JA8131, 2002IJC(B)868>. The transformation of allyloxybenzenes into p-allylphenols or
o-allylphenols and the 2,3-rearrangement of 4-allyloxyhydroazepin-2-ones are typical processes
<2001SL228, 2001TL4561, 2000JA8131, 2000TL6893, 2000TL6901>. Wittig reaction of 2-allyloxy-
benzaldehydes give the corresponding alkyl cinnamates, which on Claisen rearrangement go to the
o- or p-allylcoumarins <1995IJC(B)686, 1995H(40)817> (Scheme 18). The rearrangement of dif-
ferently substituted O-allyloxy-coumarins <1998IJC(B)662, 1999IJC(B)1242>, isocoumarins
<2000TL29>, flavones <2001TL7241, 2002T3589>, and flavanones <1998IJC(B)596> has been
reported.
OMe OMe
OMe
O Ph3P=CHCO2Et PhNEt2 O O
O
O 79%
CO2Et
Scheme 18
The synthesis of aromatic crown ethers (‘‘crownophanes’’), 2:2 macrocycles <2002SL1874> or

alkoxycalix[4]arenes <1995TL5567, 1996T13189, 1997JA12677, 1997TL8993, 1998CL307,
1998JA12226, 1999TL8007, 1999POL1153, 2000CC2197, 2000TL9261, 2000CC343, 2000TL8111,
2001CC595, 2001JCS(P1)588, 2002EJO1996>, rotaxanes <2002TL5747>, polymers
<2001MM6545>, tripodal hexadentate ligands <1998TL6211, 1998TL6215, 2002JA9988>, or
16-membered farnesylated p-benzoquinone derivatives <1999TL1941> have been reported from
conveniently functionalized aromatic-O-allyl derivatives. Thermal Claisen rearrangement of allyloxy
perfluorobenzene derivatives gives intermediates that finally afford intramolecular Diels–Alder
products <2002JFC(113)123>. The Claisen rearrangement of O-allyl or O-propargyl benzothio-
phenes has also been documented to give after sequential ring closure tricyclic fused thiophenes
<1999JCS(P1)3705>. The synthesis of furocoumarins by Claisen rearrangement of di-O-allyloxy
coumarins has been reported <1999IJC(B)545>. Sakamoto’s group has also reported the aromatic
Claisen rearrangement in the adduct formed in the reaction of 2,3-dihydro-1H-indol-3-ones
with allyl alcohols in the presence of camphorsulfonic acid and magnesium sulphate to give 2-allyl-
2,3-dihydro-1H-indol-3-ones in good yields and under thermal conditions <1996JCS(P1)729>.
Alternatively, 2-O-allyl-indol-3-ones upon Wittig reaction and Claisen rearrangement afford the
3,3-disubstituted-indol-2-ones in good yield <1996TL7525, 1998JCR(S)594, 2000TL4657>. An
interesting variant of the conventional aromatic rearrangement includes examples where a ketene
silyl acetal is the necessary ‘‘vinyl’’ functional moiety in the precursor <2002TL5837> (Scheme 19).
Similar processes have been described in trifluoromethyl substituted O-allyl furans and thiophenes
in a reaction that affords trifluoromethyl substituted butenolides and their thio analogs
<2001TL1657, 1995SUL173>. The Claisen rearrangement of 3-(prop-2-ynylsulfanyl)-1,2,4-triazi-
none is an efficient synthetic route to 2-methyl-thiazolo[3,2-b][1,2,4]triazinone <1998IJC(B)590>.
O OSiMe3 O
100 °C
OBn O Ph OSiMe3
99%
Scheme 19
A new method for the synthesis of tetrahydrofluorene has been reported via thermal domino
Claisen rearrangement on conveniently functionalized 3-(O-cyclohexyl) benzaldehydes
<1996SL283> (Equation (71)).
HO H
CHO CHO
Xylene
180 °C ð71Þ
H
O 73% OH OH
OMe OMe OMe
A new method for the synthesis of substituted naphthalenes based on the sequential Claisen
rearrangement of O-allyl acylbenzenes followed by photochemical irradiation in the presence of
potassium t-butoxide has been reported (Scheme 20) <2000JCS(P1)787>. Also a novel synthesis
of substituted naphthalenes has been developed in three steps from O-allylbenzaldehydes, via
Claisen rearrangement, Grignard addition to the aldehyde followed by a ring-closing metathesis
reaction <2001TL6155>. A sequential Claisen/ring-closing metathesis approach has been
described for the synthesis of spirocyclic cyclopentanes and cyclohexanes <2003TL8883>.
CHO CHO
i. 190 °C
ii. PriBr, K2CO3 KOBut, DMF
MeO MeO
93% MeO
O i 81% OPri
OPr
Scheme 20
O-Allyl and propargyl phenyl derivatives, naphthalenes, or indoles rearrange and cyclize, via
allenyl intermediates, to give a number of benzofuran <1998H(48)2173, 2000IJC(B)958,
2003H(59)237>, benzopyran <1995JHC219>, naphthopyran <1996H(43)751>, or pyrano[3,2-e]-
indole derivatives, respectively <2001BCJ675, 1995TL7019, 1996JCR(S)338, 2000TL3541,
2000JNP245> (Equation (72)). This strategy has been used for the synthesis of 1,7-dihydro-
pyrano[2,3-g]indole ring system of the natural indole alkaloid paraherquamide F
<2002TL2149>.
O C
O OH C O
MW
H ð72Þ
80%
Molybdenum hexacarbonyl [Mo(CO)6] catalyzes the rearrangement of allyl aryl ethers and the
subsequent dihydrobenzofuran formation <1997SL585, 1997S41, 1998S256, 2001JOC4965>. This
strategy has been used for the preparation of pyrano[6,5-h]quinolin-2-one heterocyclic ring
systems <1999TL4505>, and in a short synthesis of cordiachromene <1999TL8113> starting
from an O-propargyl aryl derivative (Equation (73)), for the synthesis of furo-fused 2H-chromenes
<1996CJC1649>, or the preparation of oxo-analogs of isopsoralen <2002T2831>. Caesium
fluoride (CsF) has been found to promote efficiently the Claisen rearrangement of O-propargyl
benzene derivatives <1997H(45)2261, 1997H(45)2273>.
AcO AcO
DMF, 150 °C
O Cordiachromene
85% O
ð73Þ
Synthetic studies directed to the preparation of 1-O-methylforbesione <2001AG(E)4264> and

to the bridged tricyclic core in Garcinia natural products <2002OL909> have been published
featuring a cascade biomimetic aromatic Claisen rearrangement and Diels–Alder reaction. The
Claisen rearrangement of O-allyl aryl ethers followed by ozonolysis is a convenient method for
the synthesis of O-hydroxyaldehydes <1997SC4235>.
Ogasawara and co-workers have reported the synthesis of 2-(cycloalk-2-enyl)phenols by Claisen
rearrangement of O-allylphenols obtained in situ by retro-Diels–Alder reaction of conveniently
functionalized unsaturated bicyclic derivatives. They have applied this elegant strategy to the
synthesis of (+)-curcuphenol <1998TA2215> and (+)-curcudiol <1998SL1004>. Practical use
and application of the aromatic Claisen rearrangement has been reported in the synthesis of new
cardanol and cardol derivatives <2002S2749>, in the synthesis of prenylated phthalides such as
salfredin B11 70 <1998JCR(S)292> (Equation (74)), in the synthesis of the di-O-methyl ether of
the aglycone of cesternoside A <1996JCR(S)342>, o-methoxylated phenyl-isopropylamines
<1996TL7889>, differently substituted flavones <1996IJC(B)1253>, 2,30 ,30 -trimethyl-20 ,30 -dihy-
droangelicins, seselin and other angelicin derivatives <1996JCR(S)148, 1995TL7109>, 4-allyl-2,6-
dimethoxyphenol, a naturally occurring compound with interesting biological activities
<1996SC2569>, 8-(1,1-dimethylallyl)-apigenin <1996H(43)277>, maxima flavanone A
<1999IJC(B)596>, the enantioselective synthesis of (S,R,R,R)-nebivolol <2000T6339>, subellip-
tenone F, an inhibitor of topoisomerase II <2000CL464>, neurotrophic illicinones
<1998JA12684, 2000JA6160>, the potent phytoestrogens 8-prenylnaringenin and 6-(1,1-dimethyl-
allyl)naringenin <2001T1015>, ()-aplysin and ()-debromoaplysin <2001TL4913>, the coumarin
trachypleuranin-A <2001TL6491>, in the synthesis of the prenylated flavonoid lupiwighteone
<2003T4177>, in the asymmetric synthesis of the antitumoral metabolite FR900482
<1997T10239>, 6-C-prenylflavanones <1997S1246>, the enantioselective synthesis of the alkaloid
()-pseudophrynaminol <2003TL1591>, the natural product carpanone <2001SL1482,
2002JCS(P1)1850>, tricyclic indane derivatives as melatonin receptor agonists <2002JMC4222>,
a series of oxepin- and oxocin-annulated coumarins, 6-prenylcoumarins and pyranocoumarins, such
as suberosin and toddaculin <2002JCS(P1)371, 2002TL7781>, enantioselective synthesis of chro-
man-2-ylmethanol <2002JCS(P1)496>, 3,6-dihydro-1H-benzo[c]oxocines <2002H(57)2021>,
2,5-dihydro[b]oxepines <2002H(57)1997>, the neolignans usiderin K and J <2001SC861>,
N-arylpiperazines as high-affinity 5-HT1A receptor ligands <1995JMC1942>, in synthetic studies

directed to the antitumoral diazonamide A <1997JCS(P1)2413>, analogs of antibiotic frenolicin B
<1995S780>, a high-yielding synthesis of racemic hongconin <1996SC867>, puraquinonic acid
ethyl ester, and deliquinone <2002JOC5857>.
O O
PhNMe2, 210 °C
O O ð74Þ
O 62% O
70
(c) The Eschenmoser amide acetal and Johnson orthoester Claisen rearrangements. The Eschen-
moser amide acetal <1964HCA2425, 1969HCA1030> and Johnson orthoester Claisen rearrange-
ments <1970JA741> are major developments of the original Claisen reaction of great importance
in synthetic organic chemistry in view of the number of examples documented in the literature
<2000TL8301, 1995JCS(P1)2033>. The use of microwave irradiation accelerates the classical and
conventional thermal orthoacetate rearrangement <1995T1809>.
The Johnson–Claisen rearrangement of trisubstituted allylic alcohols has been investigated and
it has been found that substrates with (E)- or (Z)-geometry at the double bond afford high levels
of syn/anti-diastereoselection <1997JOC1976>. Using the Johnson–Claisen rearrangement, the
stereoselective synthesis of trisubstituted alkenes <1995TL757, 1996SL747>, the synthesis of
threo-3,4-divinyladipic acid <1997JOC1906>, the preparation of substituted allenic esters
<1995SC4087, 2001JA12466>, and its application to 2-adamantanone substrates have been
reported <1998T11899>. Fluorinated succinic acid derivatives or trifluoromethylated compounds
have been prepared from fluoro and difluoro allylic alcohols via Johnson–Claisen or chelated
enolate Claisen rearrangements; these reactions occurred with moderate yield but with the
expected high diastereoselectivity <1996SL82, 1999JCS(P1)3345, 2000TL5269,
2000JCS(P1)3217, 2000JOC2104, 1997JFC(86)81, 2000JOC6231>. Allylic alcohols installed in
N,N-dialkylnaphthamides have been submitted to these [3,3]-sigmatropic rearrangements showing
that the Johnson orthoester Claisen rearrangement affords a better diastereoselectivity compared
to the Eschenmoser amide rearrangement, the chemical yields being similar <2000TL3279>.
Examples of the application of the Claisen–Johnson rearrangement in synthetic transformations
in the area of steroids <1997JCR(S)134, 2000CPB1480, 2000T9575, 2002MI597> and vitamin D
analogs <2002JMC1825> have been documented, and for the synthesis of versatile chiral inter-
mediates for fused cyclopentanoid natural products <2001ZN1227>.
The Johnson–Claisen rearrangement has been used in the efficient synthesis of , 0 -disubsti-
tuted ,-unsaturated esters containing quaternary centers <1999JOC8945>, in the synthesis of
both enantiomers of bicyclo[4.3.0]nonane-3,8-dione <2001JCS(P1)2040>, and in the synthesis of
-hydroxy ,-unsaturated ketones and nitriles <2001EJO713>. An enantioselective method for
the generation of benzylic stereocenters featuring the Johnson–Claisen rearrangement of a num-
ber of allylic alcohols was applied to the preparation of both enantiomers of 3-methyl-2-phenyl-
butylamine, an important resolving agent <2003TA2401>. The effect of an allylic located sulfur
atom in the stereoselectivity of the Claisen–Johnson rearrangement has been investigated
<1999JOC2928>. 1-Dimethyl phenylsilyl (or 1-phenylsulfonyl) substituted allylic alcohol deriva-
tives have been submitted to the standard Claisen–Johnson conditions to give the unsaturated
-silyl esters <1995TL8723, 2000T10263> or unsaturated -sulfonyl esters <1998TL5827>.
The Eschenmoser amide acetal rearrangement has been used as key steps for the synthesis of
natural products such as ()-ambrox <1996JOC2215>, morphine <1997SL441>, ()-carbovir
<2003TL4125>, paniculide A from D-glucose <1999T3855> (Scheme 21), the enantiomeric
forms of paraconic acids starting from D-mannitol <1999TL4829>, in a synthetic approach to
4,5-epoxyhasubanans, a type of morphinane compound <2000M997>, in the synthesis of
branched-chain cyclitols or pyranosides <1997CAR(300)183, 1997LA1983, 2002MI431>, in the
preparation of 4-(2-aminoethyl)indoles through an orthoamide rearrangement of 3-hydroxy-
2-methoxyindolines <1998H(47)367>, in the obtention of azachlorins, a novel type of hydro-
porphyrin <1995LA1509, 1995AG(E)784, 1995LA1033>, in the synthesis of 5-oxaprostanoid
derivatives <1995H(40)93>, and 13-alkylmilbemycins <1995H(41)2027>, racemic sesquicillin, a
C29 isoprenoid-related fermentation product <2002AG(E)1434>, unsaturated morpholine
amides <2002SL411>, and in the synthesis of gelsemine <2002TL545, 2002TL549>.
NMe2
OH
MeO OMe O
MOMO
Me NMe2 MOMO
D-Glucose
140 °C
OPMB
OPMB
PMB = p -methoxybenzyl
MOMO
Paniculide A CONMe2
OPMB
Me OEt OEt
OH i. EtO OEt, Hg(OAc)2
O
Propionic acid
OH ii. NaOH, MeOH, H2O

61% OH
CO2H
β-Necrodol
OH
Scheme 21
The orthoester Claisen rearrangement applied onto 1-hydroxymethyl-substituted cyclohexenes

has provided key intermediates for the synthesis of sesquiterpene AM6898D <2000TL4173>,
antifeedant terpenoid lactones <2000MI4973>, in the preparation of highly functionalized dienes
<2001T6261>, in the synthesis of intermediates toward indacene ring systems <1996TL8065>,
intermediates en route to thapsane type of sesquiterpenes <2002TL2765, 2002TL2769>, in
synthetic studies directed to analogs of the alkaloid deplancheine <1996H(43)1981>, and in the
enantioselective synthesis of the C1–C28 portion of the cytotoxic natural product amphidinolide
B1 <1997TL7909>. The orthoester Claisen rearrangement applied onto 1-hydroxy-3-cyclohex-
enes has afforded key intermediates for the synthesis of (+)-valerane <1996TL2863,
2000JCS(P1)4321> and (+)-pinguisenol <2000JCS(P1)2583>. Using allylic alcohols, obtained
by base-promoted epoxide rearrangement, derived from enantiomerically pure limonene, the
orthoacetate Claisen rearrangement afforded intermediates for the synthesis of spirolactones
<1998EJO2677>, tetracyclopropylmethane, a unique hydrocarbon with S4-symmetry
<2001AG(E)180, 2002JA6706>, and the ABC rings of the alkaloid manzamine A
<2002JOC6181>. The Claisen rearrangement on allylic and propargylic alcohols in substrates
containing the t-BOC-2-acyloxazolidine chiral moiety has been reported <2002EJO29>.
The orthoester Claisen rearrangement has been used as a key step in a number of synthetic
sequences leading to natural or non-natural products, as in the total synthesis of ()-albene
<1995P1699>, in the transformation of sugar templates <1998TA4203, 2000TA453,
2001MI57>, in the synthesis of carbocyclic nucleosides <2002TL6399>, in the synthesis of
novel indole analogs of mycophenolic acid as potential antineoplastic agents <2000T2583>, in
the total synthesis of R-()-baclofen <1997TA3801>, ,-unsaturated acid and aldehydes
<1995CL565>, modified prostaglandins <1995MI337>, non-natural nucleosides
<1998TL3443, 1999TL231, 2000CAR(328)37>, mono- and bis-tetrahydrofuran intermediates for

the synthesis of acetogenins <1999TL193>, ()--necrodol <1999TL4401, 2001T2011>
(Scheme 21), ()-trans-2-butyl-5-heptyl-1-methylpyrrolidine, an ant venom alkaloid,
<1999H(50)333>, immunosuppressant FR65814 <1999T2205>, (2S,4R)-4-propyl-glutamic
acid <1999TL6577>, homogynolide <1999JCS(P1)2069>, -pinguisene and pinguisenol
<1997JCS(P1)3295, 1999JCS(P1)1265>, in the preparation of pseudopterane analogs
<1999JOC5193>, L-glutamic acid analogs <2000MI91>, synthetic studies directed to spinosyn
A <2000CJC757>, racemic acorone <2000T8189>, 1,14-herbertenediol and 11-epi-herberteno-
lide <2002TL151>, 1,13-herbertenediol, - and -herbertenol <2003TL1027>, synthesis of
26-norbrassinolide, 26-norcastasterone and 26-nor-6-deoxocastasterone <2001P343>, sphingo-
sines <1995S868>, trail pheromone mimic of the subterranean termite Retculitermes virginicus
<1998JCR(S)706>, the antibiotic macrodiolide tartrolon <1998TL803>, the antitumor agent
halomon <1998AG(E)2085>, the glycoprotein processing enzyme swainsonine <1996JOC7217>
or 3-(hydroxymethyl)swainsonine <1997T11021>, the synthesis of RS-97613, a potent immuno-
suppressive and anti-inflammatory agent <1996JOC2236>, racemic pseudomonic acid A
<1995TL7631>, (3R)-()-A-factor, an autoregulator of cytodifferentiation <1995CC437>, enan-
tiomerically pure ()-tubifoline and related alkaloids <1996TA2775, 1997TA935>, the alkaloids
geissoschizine and isositsirikine <1995T8623>, (+)-arenarol <1997TL7769>, ()-mesembranol
from D-glucose <1997JCS(P1)275>, the synthesis of quadrilure, the pheromone of square-necked
grain beetle <1995TA463>, the preparation of capsaicin and analogs, a series of well-known
pungent principles of hot red pepper <1996T8451>, the synthesis of potential anticonvulsants
3-substituted alkenyl GABA derivatives <1998BMCL2599>, the naturally occurring pyrrole com-
pound porphobilinogen <2001JA9307>, the alkylidene cyclopentenone prostaglandin TEI 9826
<2003TL2579>, in a general approach to the synthesis of -substituted 3-bisaryloxy propionic acid
derivatives as specific matrix metalloproteinase inhibitors <2001BMCL295>, and the sesquiter-
penes AM6898A and AM6898D <2002T2513>.
(d) The Ireland ester enolate Claisen rearrangement. Some new aspects of the Ireland–Claisen
rearrangement and related processes have been reviewed recently <2002T2905>. The origins of
boat and chair preferences in the Ireland–Claisen rearrangement on cyclohexenyl esters have been
studied <2003JOC572>. The rearrangement of simple enolates from allylic esters is a practical
variant of the Claisen rearrangement <1999T3723> that usually proceeds with high stereo-
chemical control <1996TL3005, 2001JA3687>. The chelation-controlled Claisen rearrangement
yields (Z)-trisubstituted alkenes with high selectivity; this (Z)-selectivity has been rationalized by
postulation of a seven-membered ring chelate in the transition state prior to rearrangement
<1995JOC5093>.
The catalytic diastereoselective reductive Claisen rearrangement has been reported in the
reaction of allylic acrylates in the presence of chiral phosphine inductors <2002OL2743>
(Equation (75)) or different Lewis acids <2002TL4837>. The possibility to perform the Ireland
ester enolate Claisen rearrangement using a polymer-supported silyl triflate has been commu-
nicated, an important result that opens the way to carry out this reaction using the solid-phase
technique <1999TL3289>. An elegant implementation of the Ireland ester enolate Claisen rear-
rangement has been set up in the total synthesis of naturally occurring dolabellane, featuring an
unprecedented enantioselective Claisen rearrangement of an achiral 15-membered macrocyclic
lactone <1996JA1229>, and in synthetic studies directed to the synthesis of dihydroxyvitamin D
analogs <1999JMC3539>.
[Rh(COD)Cl]2
O MeDuPhos
Cl2MeSiH O Pr
O ð75Þ
79% HO
Me Me
8:1 dr
Using the Ireland ester enolate accelerated Claisen rearrangement, -silylated allyl alcohols
were transformed into the corresponding acetates or propionates, that after deprotonation and
silylation afforded ,-silylated-,-unsaturated carboxylic acids <1996HCA391>. The Ireland–
Claisen rearrangement has been used as a probe for the diastereoselectivity of nucleophilic attack
on a double bond adjacent to a stereogenic center carrying a silyl group <2003OBC4005>.
Polycyclic aromatic compounds have been prepared from benzannulated enyne-allene derivatives
obtained from Ireland–Claisen rearrangements <2003JOC8545>. In the sugar field, a full account
has been published on the stereochemistry and structural limitations of the Ireland–Claisen
rearrangement <1999S121>, and a new method for the synthesis of C-glycosides (Equation (76))
<1999TL5677>. Using conveniently functionalized N-(allyloxyacetates) -lactam templates, the
Ireland–Claisen rearrangement has given dienes that, under the ring-closing metathesis reaction
conditions using Grubbs’ catalyst, afforded medium-sized annulated -lactams <2000JOC3716>.
In the steroid area, the Ireland–Claisen rearrangement has been used with advantage in 23-22-
alcohols to perform 22,25-24-alkyl chain elongation <2000TL5765>. The Ireland–Claisen rear-
rangement has been tested in differently substituted tricarbonyliron complexes <1996CB427,
1997TL351>, in the synthesis of -methoxy--trifluoromethyl-,-unsaturated carboxylic acid
derivatives <1997TA223>, in a synthetic approach toward ciguatoxin <1997CL845>, toward
quartromicin spirotetronic acid subunits <1997TL8785>, in the stereoselective synthesis
of alkylidene cyclohexenes <1998TL7043>, in the construction of 1,3-dienes containing an
(E)-double bond and an exo-methylene group <1995CC1497>, in a new route to substituted
glutaric acid derivatives <1995SC183>, and in the preparation of 2,3-disubstituted succinates
<1998SL531>.
O
BnO O O CO2Me
BnO
KHMDS, TMSCl ð76Þ
BnO O Me
13% BnO
OBn
OBn
The Ireland–Claisen rearrangement has also been applied in synthetic studies directed to the
synthesis of sarcodictyins and eleutherobin <1999TL153>, in the stereoselective formation of
C2C3 bond in taxanes <1999TL4659>, in the preparation of key synthetic intermediates for
fumagillin and ovalicin <1999TL4797>, in the synthesis of C29–C44 fragment of spongistatin
<2000JOC4145>, fluoroalkylated <2001TA2743> or allyl silane-containing <2001TL191>
amino acids, in synthetic studies directed to forskolin <1997JOC6985>, in the stereoselective
synthesis of the rhizoxin C1–C9 and C12–C26 subunits <1998TL2239, 1998JOC6952>, in the
synthesis of novel matrix metalloproteinase inhibitors <1998BMCL1359, 2002JMC2289>, in a
synthetic approach to azadirachtin <2002OL2877>, or eupomatilones <2002OL19,
2002JOC2042>. The Still–Wittig and the Ireland–Claisen rearrangements have been used in the
synthetic sequences leading to serine cis- or trans-proline isosteres <2003JOC2343>. Recently,
chemists at Merck have disclosed the preparation of a series of highly potent benzodiazepine -
secretase inhibitors, with potential activity in Alzheimer’s disease, which were prepared using a
modified Corey asymmetric Ireland–Claisen rearrangement <2003JMC2275>, the enantiomeric
excess being higher than 99%.
In a new synthetic approach, the formation of the key enolate intermediates in the Ireland–
Claisen rearrangement has been promoted by Michael addition of organocuprates, or lithium
enolates, to ,-unsaturated esters; the enolates formed rearrange in situ or are trapped by silyl
chlorides before rearrangement <1995T12631, 1995JOC8140>. The 1,6-conjugate addition of
organocuprates to 2-propen-1-yl and 2-buten-1-yl 2-en-4-ynoates followed by in situ enolate
capture with silyl electrophiles is followed by a quick [3,3]-sigmatropic rearrangement that yields
2-substituted methyl 3,4-dienoates <1997LA725> (Scheme 22).
i. 20 °C
O i. Me2CuLi-LiI ii. H3O
OSiMe3 CO2Me
ii. TMSCl iii. CH2N2
O O
58%
83:17 dr
Scheme 22
This attractive strategy has also been proposed but using a radical-based Michael addition to a
suitably functionalized allylic ester acrylate promoted by a combination of reagents such as
manganese, lead dichloride, and trimethylsilyl chloride <1996JOC8728>.
In two consecutive articles in the same journal issue, Piscopio <1998JOC3158> and Burke
<1998JOC3160> reported enolate Claisen rearrangement and Ireland–Claisen rearrangement,
respectively, on allyl-heteroatom-(C, O, S, N)--substituted acetates for the synthesis of inter-
mediates that were transformed into carbocyles or heterocycles via ring-closing metathesis carbo-
cyclization strategies.
A tandem sequence based on the Diels–Alder reaction of dienes and acyclic dienophiles such as
methyl acrylate followed by in situ Ireland–Claisen rearrangement of the resulting adduct has
been reported <1999SL925, 2000HCA2712>; the whole process allows the synthesis of carbo-
cycles in good yield and stereoselectivity (Equation (77)). The same procedure has been applied to
N-butadienyl-N-alkyl-N,O-trimethylsilyl ketene acetals for the synthesis of fused heterocyclic ring
systems <1996S1239, 1996T11643, 2000HCA2266>.
OTBDMS
i. CH2Cl2, 40 °C, 12 kbar
Me O CO2Me
ii. H2SiF6
CO2Me iii. Me2SiCHN2 MeO2C ð77Þ
+
61%
Me
30:1:12:9 dr
Recently, a simple variant of the Carroll rearrangement has been proposed where instead of a
-keto ester a mixed allyloxy malonate has been used as template; this structural and functional
arrangement allows the incorporation of chirality on one of the ester moieties for asymmetric
synthesis; after trimethylsilyl ketene acetal formation the Ireland–Claisen rearrangement affords
the expected ,-unsaturated esters; this strategy has been applied to the synthesis of (+)-methyl
dihydroepijasmonate and (+)-methyl epijasmonate <2000AG(E)569>. Tandem Ireland–Claisen
rearrangement followed by Cope rearrangement of the resulting crude reaction mixture has been
described in the treatment of 2-hexenyl 3-methyl-2-butenoates with bases [LDA, LDE (lithium
diethylamide), LHMDS] followed by quenching with TMSCl; an Ireland–Claisen rearrangement
product was obtained that on heating afforded the Cope compound in good yield (Scheme 23)
<1998SL70>.
O HO2C
LDA, TMSCl C3H7
C3H7 O + C3H7
26% CO2H
92:8
∆ 80%
C3H7
CO2H
Scheme 23
Many applications to the synthesis of natural products have been described using the Ireland
ester-enolate Claisen rearrangement, as in the synthesis of (S)- and (R)-verapamil <2001EJO1349>,
long-chain unsaturated dienoic acids <1996TL2349>, for the synthesis of useful intermediates for
the preparation of substituted tetrahydrofurans <2002T1865>, (+)-breynolide (Scheme 24)
<1999TL9>, myxalamide A <1999JOC23>, aspidophytine <1999JA6771>, herboxidiene
<1999JCS(P1)955>, racemic patulolide <1999TL471>, the fragrant molecule Iso E Super1 used in
perfumery <1999HCA1016> (Scheme 24), epothilones B and D <2001TL8373>, the potent toxin
atractyligenin <1997JA11769>, the asymmetric synthesis of ()-methyl palustramine
<1998JOC7490>, sphydrofuran <1998JOC8595>, the hemiacetal pheromone of the spined citrus
bug Biprorulus bibax <1995LA1451>, (+)-Prelog-Djerassi lactone <1998T11567>, racemic samin
and other furanofuran lignans <1997JCS(P1)857, 1998JCS(P1)1779>, 14-membered macrolide
galbonolide B <1998JCS(P1)3541>, in synthetic approaches to 1--fluoro-25-hydroxy-vitamin D3
analogs <1998JOC6984>, total synthesis of -elemene and fuscol <1995JA193>, -lactone enzyme
inhibitor ()-ebelactone <1995JOC3288>, ()-indolizidine 167B <1997JOC8549>, total synthesis of

(+)-iridomyrmecin <1997SL657, 1999JCS(P1)3579>, an asymmetric synthesis of ()-fumagillol
<1997TL4437>, the alkaloids ()-trachelanthamidine, ()-iso-retronecanol, and racemic turnefor-
cine <1997JCS(P1)2089>, in the formal total synthesis of the alkaloid magellanine <2001CL546,
2003TL6029>, in the total synthesis of the antitumor antibiotics ()-methylenolactocin and
()-phaseolinic acid <2001SL120>, a practical synthesis of (+)-discodermolide <2001JA9535>,
the synthesis of ()-ciantrin B, a phospholipase A2 inhibitor <2002JOC4392> and in the synthesis
of brassinosteroids <2002TL3169>.
i. LHMDS, TMSCl
m-MPMO m-MPMO
ii. THF, 120 °C
OTBS OTBS
iii. LiAlH4
O H (+)-BREYNOLIDE
89% p-MPMO
O
OH
p-MPMO
H H i. ∆ H O
Me Me
BunLi, TMSCl ii. MeLi
O O 32%
O OSiMe3
Iso E Super ®
(p -MPM = p -CH3O-C6H4-CH2)
Scheme 24
(e) The Carroll rearrangement. The Carroll reaction is a useful method for preparing
,-unsaturated ketones from allylic acetoacetates <1940JCS704, 1940JCS1266, 1943JA1992>.
A facile entry to the synthesis of arylacetones and related derivatives has been communicated
using the Carroll rearrangement <1995TL3597>. A variant of the classical Carroll rearrangement
has been reported in the rhodium(II)-catalyzed reaction of -diazo-ketoesters with allylic alcohols;
under these conditions the intermediate OH insertion products rearrange to give -hydroxy-
-ketoesters and insertion products in good overall yield (Equation (78)) <1999OL371,
1999JA1748>. The first asymmetric Carroll rearrangement using chiral auxiliaries was reported
in 1995 by Enders <1995AG(E)2278, 1996LA1095> (Equation (79)).
OH
H
O O O
Rh2(OAc)4, PhH, ∆, 5–10 min O [3,3]
OMe
N2
COOMe
ð78Þ
O O
Me OH O
OMe
OMe + O
O
45% 34%
OMe
OMe
N
N i. LDA, THF, 100 °C N R4
N O
ii. LiAlH4 R3
R1 ð79Þ
R1 O R4 R 2
50–90%
R2 R3 HO
88–96% dr
(f) Charge-accelerated Claisen rearrangement. A zwitterionic intermediate species has been

invoked in the mechanism for the Claisen rearrangement leading to ,-unsaturated amides
from allylic amides and acetyl chloride (Equation (80)); the reaction proceeds in good yield and
moderate diastereoselectivity <1995JOC3773>. Esterification of N-t-BOC glycine with enantio-
merically pure unsaturated alcohols gives intermediates that on treatment with LDA and zinc
chloride gives Claisen rearranged products, presumably via nitrogen charged intermediates, in
good yield (70%) and with complete transfer of chirality <1996CC1683>.
AcCl, K2CO3 O
O Me3Al O Cl K2CO3
O N
82% O N
ð80Þ
O
O Cl K2CO3 O
N O N
O– O
3:2 dr
The Bui3Al-catalyzed formation of the enol ether 72 from alcohol 71 also promoted the
unexpected Claisen charged accelerated rearrangement to give product 73 in good yield; the
reaction has been extended to other alcohols showing the scope and limitations of the method
(Equation (81)) <1995JOC4318>.
O OMe Bu3i Al Bu3i Al

O
89% AlBu3
71 72 ð81Þ
OH
73
(g) The Ficini–Claisen rearrangement. In spite of the long-known seminal works by Ficini and
co-workers on the ynamine-Claisen reaction <1966TL6425, 1968TL4139>, it was only recently
that the first efficient and stereoselective acid-promoted Ficini–Claisen rearrangement has been
reported using chiral ynamides <2003SL1379>, under mild conditions, at low temperatures
<2002OL1383> (Equation (82)).
OH
O Toluene, 80–110 °C O
O O
PNBSA (0.1–0.2 equiv.)
N N
Bn Bn
56–75% ð82Þ
O
Ph
Ph
6:4 dr
PNBSA = p -nitrobenzenesulfonic acid
(h) The Holmes–Claisen rearrangement. This is a variant of Claisen rearrangement based on

the rearrangement of vinyl-substituted ketene acetals and enol ethers that has proved to be an
efficient method for the synthesis of unsaturated medium ring ketones and medium ring lactones
<1986CC325, 1991T7171, 2000CC629, 2000CC631, 2000TL117, 2002T1943>. In recent develop-
ments the Claisen rerrangement of 2-methylene-5-vinyl tetrahydrooxazoles has afforded unsatu-
rated seven-membered lactams (azepin-2-ones) <1994JCS(P1)3397>, studies that have been
extended to the synthesis of unsaturated eight-, nine- and ten-membered medium ring lactams
(n = 1, 2, 3) from vinyl-substituted precursors in the presence of DBU (Equation (83))
<1995CC2325, 1996JCS(P1)123>. Pearson has applied this methodology for the synthesis of
nine-membered ring lactones from suitable intermediate ketene acetals (Equation (84))
<1996JOC5546>. A related Claisen rearrangement was published by Petrzilka in 1978, and applied
to the synthesis of macrolides, such as racemic phoracantholide <1978HCA3075>.
Me
Me
Toluene, DBU, reflux
N O
Z N O Me N
Z
54% Z O ð83Þ
SePh
O
[Z = C(O)OCH2C6H5]
OBn OBn OBn OBn

DBU,
toluene [3,3]
BnO BnO
O O O O
SePh
O
BnO ð84Þ
BnO H H
BnO
BnO
+ H + BnO H
BnO
BnO O O O
BnO O BnO O
O
1:1 19%
54%
(ii) The Kazmaier–Claisen rearrangement

The allylic ester of protected amino acids undergo asymmetric chelate Claisen rearrangement in the
presence of cinchona alkaloids leading to ,-unsaturated amino acids, peptides, and aza-hetero-
cycles in a highly stereoselective manner <1995MI77, 1995MI283, 1997LA285, 1998CC2535,
1999JIC631, 1999JOC4574, 1999S1671, 1999TL479, 2000EJO1241, 2000S914, 2000SL1004,
2000SL1523, 2001S487, 2001CEJ456, 2001EJO4067, 2001CHIR357> (Equation (85)).
R R R
LDA (2.2 equiv.)
O O OH ð85Þ
YHN MXn (1.2 equiv.) YHN
YN
O M O O
The asymmetric chelate-enolate Claisen rearrangement <2002CEJ1850> has been applied to

the synthesis of allenic amino acids <1996S1489, 1998SL434>, quaternary amino acids contain-
ing ,- as well as ,-unsaturated side chains <1995AG(E)2012, 1995CC1991, 1995SL1138,
1996TL5351>, 5-epi-isofagomine <1998TL817, 1998EJO1155>, to the synthesis of unsaturated
polyhydroxylated amino acids <1996SL975, 1998S1321>, and highly demanding -alkylated
amino acids <1996TL7945, 1996T941, 1996JOC3694>. This strategy has also been used for the
synthesis of an -cyclohexyl glycine substituted intermediate en route to morphine
<1997JOC1194, 2001BMCL627>, and for the synthesis and determination of the stereochemistry
of 2-amino-3-cyclopropylbutanoic acid, a plant regulator <2002CC42>, in the synthesis of
furanomycin derivatives <2002BMC3905>, and in the preparation of the C-glycoside -D-C-
mannosyl-(R)-alanine <2002T9381>.
Recently, a modified Kazmaier–Claisen rearrangement has been investigated where the allylic
alcohol bears a trialkylsilyl substituent at C1, leading to final allyl silane modified amino acids in
good yield and excellent syn/anti-diastereoselectivity <2002HCA4165>.
1.18.2.6.2 Thia-Claisen rearrangement

The thia-Claisen rearrangement of allyl, vinyl sulphide and its applications in organic synthesis
have recently been investigated <1995HAC559>, reviewed <1997BCJ2571, 1999TCC(204)127,
2003T7251>, and attracted some synthetic interest in the last years <1995JOC2692, 1995CC2345,
1997TL2413, 1997T17253, 2000EJO3463>. Some theoretical studies have been advanced
<1996JCS(P2)2065, 1997JCS(P2)2737>.
The thia-Claisen rearrangement of S-allyl ketene dithioacetals gives the expected allylated
dithioesters with excellent diastereoselectivity <1996PAC863>. The thia-Claisen rearrange-
ment has been applied in S-allyl, propargyl, methylallyl thioiminium salts prepared from
N-benzyl thiopyroglutamates to give 4-substituted thioxoprolinates in a facile process and in good
yield <1995TL8467, 2003JOC993>. Meyers’ group has been particularly active in this sub-
ject <1997CC1> (Equation (86)), and has reported the total synthesis of ()-trichodiene
<1998JA5453>, the synthesis of chiral cyclohexenones with vicinal stereogenic quaternary centers
<1999JOC3585> and the palladium and nickel catalyzed thia-Claisen rearrangement of chiral
bicyclic thiolactams via N,S-ketene acetals <2000TL815, 2000TL1363>. Rawal and co-workers
have reported an efficient and highly diastereoselective version of the thia-Claisen rearrangement
using C2-symmetric pyrrolidine as chiral inductor and removable chiral auxiliary <2000JA190>.
The use of chiral bicyclic proline derivatives as chiral auxiliaries for the asymmetric thio-Claisen
rearrangement has been described <1996LA927>. Metzner and associates have reported on the
asymmetric Claisen rearrangement promoted by a sulfinyl group in a new method for the
synthesis of -sulfinyl dithioesters <1997AG(E)371, 2001JOC7841, 2002CEJ632>.
O Me O
O
LDA, then N
N [3,3]
N ð86Þ
Me Br Ph 72% S Ph
S Ph Me S
9:1 dr
The thia-Claisen rearrangement has also been documented in the rearrangement of camphor-
derived 1,3-oxathianes; this strategy allows the synthesis of macrocyclic thiolactones in high yield
and with complete control of the absolute configuration at tertiary and quaternary stereocenters
<2002CC2534>. Majumdar has described a thia-Claisen rearrangement example in the synthesis
of [6,6]pyranothiopyran ring system by refluxing conveniently functionalized 4-(40 -aryloxybut-20 -
ynylthio)[1]benzopyran-2-ones <1997JIC884, 2002OL2629, 2002TL2111, 2002TL2115>, and in
the synthesis of thieno[2,3-b]thiochromen-4-one derivatives <2002SC1271>.
Allylic S-methyl thiocarbonates (xanthates) rearrange in a thia-Claisen-like reaction to give
allylic thiols after basic hydrolysis <2000TL1703>. 3-Allylthioallyl triazoles rearrange to the
corresponding N-allyl derivatives (Equation (87)) <1999H(51)475>. Thioallenylidene complexes
have been prepared for the first time via thia-Claisen rearrangement of sulfonium salts formed
in situ from ruthenium-butatrienylidene intermediates <1999EJO2121>. Reports have highlighted
moderate chirality transfer in intramolecular [3,3]-sigmatropic thia-Claisen rearrangements with
sulfonium salts obtained upon treatment of 2-thioindoles with vinyl diazoacetates in the presence
of chiral rhodium(II) catalysts <1999EJO2459> (Equation (88)) <2003TA911>.
N N Toluene, reflux N N
S S ð87Þ
N 75% N
Me Me
NHt-BOC Rh2(S-DOSP)4 NHt-BOC
CH3CN, rt
SPh + CO2Et
N 65% S CO2Et
H N2
N Ph
H
CO2Et
t-BOCHN
H
O Rh
Rh2(S-DOSP)4 = N
SPh
N RC6H4O2S O Rh
R = C12H25 4
26% ee
ð88Þ
1.18.2.6.3 Selena-Claisen rearrangement

The reaction of lithium alkynyl selenolates generated from terminal acetylenes with thiols gave
rise to lithium selenenolates with high stereoselectivity, that on trapping with allylic bromides
afforded ,-unsaturated selenothioesters via selena-Claisen rearrangement (Scheme 25)
<1996TL2839, 1997T12237>. The [3,3]-sigmatropic selena-Claisen rearrangement of 2-pentynyl
phenylethynyl selenide 74 in the presence of amines gave compounds 76 and 77 via intermediate
75 (Equation (89)) <2001JOC4099>.
SeLi Br Se
i. BunLi, Se –78 to 66 °C Se
SBu SBu
Me3Si
ii. BuSH SiMe3 74% SBu
SiMe3
Scheme 25
C6H5 Se NBn Se
C6H5 Se
BnNH2, reflux C6H5 C 6H 5
Se NHBn
+
ð89Þ
C 2H 5 C2H5 C2H5 C 2H 5
74 75 76, 57% 77, 3%
1.18.2.6.4 Where Z = N; the aza-Claisen rearrangement and related processes

Ab initio calculations and computational studies on the aza-Claisen rearrangement have been
published <1996JOC978, 2002CEJ641>. The aza-Claisen rearrangement has been reviewed
<B-2000MI001, 2001MI89> covering essentially its application to the synthesis of unnatural
-amino acids for complex molecule preparation. The zwitterionic aza-Claisen rearrangement of
various N-allyl amines with carboxylic acid chlorides has been developed as a mild and efficient
method to form ,-unsaturated amides or lactams <1995AG(E)1026, 1996CEJ894,
1996JCS(P1)115, 1998AG(E)1140, 1996JOC3677, 2002T1317>. A significant improvement has
been observed by replacing the carboxylic acid chlorides by the corresponding fluorides (Equation (90))
<1999SL25, 2000JOC1710>.
EtCOF, H
Me3Al, K2CO3 CO2Et
N CO2Et N
73% Me ð90Þ
Bn Bn
O
6:1 dr
Davies has just reported a double diastereoselective [3,3]-sigmatropic aza-Claisen rearrange-

ment which takes place on N-allyl-N,O-silylketene aminals <2003CC2134>, the diastereoselec-
tivity obtained depends on the configuration of the starting aminal.
The Mukaiyama reaction of the trimethylsilyl enol ether of [1,4]oxazin-2-ones with -alkynyl
ketones gives intermediates that on heating afford bicyclic adducts via 2-aza-Cope rearrangement
<1999JOC6891>. A 2-aza-Cope rearrangement was invoked to rationalize the observed epimer-
ization in the enolate C-allylation of phenylglycine-derived oxazaborolidinones <1999JA2460>.
The sequence, Mannich reaction followed by in situ 3-aza-Cope rearrangement of the ammo-
nium salt, has been used in several instances for the preparation of chiral cyclopentenones from
sugar templates <1995TL3137> (Equation (91)) in the total asymmetric synthesis of both
enantiomers of strychnine <1995JA5776>, in a synthetic approach to the Stemona alkaloids
<2001JOC7751>, and in a novel synthetic approach to carbapenems <1995CC2527>. The
same synthetic sequence in related substrates leading to 2-aza-Cope rearrangement (also called
‘‘the Agami aza-Cope/iminium hydrolysis tandem reaction’’ <1993T7239>) has been applied in
the synthesis of N-benzyl allylglycine (Equation (92)) <2000TL7961>, N-benzyl-4-acetylproline
<2002TL903>, and in a synthetic approach to the core structure of the immunosuppressant
FR901483 <2001OL1347>.
i. Pyrrolidine
O I
O ii. O N
O O N O
OHC O
O O O
40% O
O O O
O
ð91Þ
O
O
O
O
2:1 dr
O
OH
H
. H 2O
O ð92Þ
N OH OH HN OH
NHBn N 60%
MeOH Bn O Bn O Bn O
The amino aromatic Claisen rearrangement (also called 3-aza-Cope rearrangement) is a variant
of the aromatic Claisen rearrangement where, instead of an O-allyl or an O-propargyl derivative,
an N-(allyl)aniline substrate was submitted to the rearrangement conditions to give the corre-
sponding o-allylanilines <1995TL4787, 2001S621, 1995MI508> (Equation (93)). The aromatic
aza-Cope reaction of N-allylic anilines is accelerated by zeolites, proceeding at low temperatures
and leading to mixtures of the o-C-allyl anilines and the corresponding indolines <1996TL5281>.
This transformation has been used for the synthesis of intermediates in a synthetic sequence
leading to conformationally fixed analogs of the antitumor indolactam-V <1995BMCL453>. The
usually harsh thermal conditions (200–350 C) have been changed to milder reaction parameters
using Lewis acids or protic acids as promoters <1995S1287>. For example, these o-allyl aniline
intermediates cyclize to the corresponding indolines in the presence of zinc montmorillonite under
microwave irradiation <2000SL487>.
p-TsOH (10 mol. %)

H
Me NH2
N CH3CN/H2O (1:0.1)
Me ð93Þ
Me
70%
Me
Examples document that the aza-Cope rearrangement is a highly competitive process in respect to
the Mannich cyclizations in systems containing allyl silane -nucleophiles <1996TL571,
1998JOC841>. Compounds with a non-nucleoside adenosine kinase inhibitor profile, having the
heterocyclic ring system pyrido[2,3-d]pyrimidine have been prepared via aza-Cope rearrangement of
intermediates obtained by imine formation between the corresponding benzaldehydes and 4,6-dia-
mino-5-vinylpyrimidines <2001JMC2133>. The sigmatropic rearrangement of N-allylenamines is a
useful method for the synthesis of ,-unsaturated carbonyl compounds and ,-unsaturated amines;
this rearrangement is accelerated by the use of Lewis acids such as zinc chloride <1995JOC2807>.
The rearrangement of 3-aza-1,2,5-hexatrienes, contrary to the normal forcing conditions that have
been employed in the Cope transformations, takes place at room temperature, under essentially
neutral conditions and with excellent chemical yields; these intermediate species allow the easy and
efficient transformation of N-allyl amides into ,-unsaturated nitriles using a number of reagents, the
best being triphenylphosphine in carbon tetrachloride (Equation (94)) <1996JOC55>.
O Ph
Ph PPh3, CCl4 Ph
N ð94Þ
N
H 94% CN
In a series of papers Majumdar and associates have reported the synthesis of unusual nitrogen-
containing heterocycles using aza- or amino-Claisen rearrangements <2002S121, 2001TL4231,
2001T4955, 2001M633, 1996CJC1592>. This author has recently reviewed his contributions on
this subject <2002JIC112>. The late transition-metal-catalyzed aza-Claisen [3,3]-sigmatropic
rearrangement is a convenient method for the synthesis of various allylic amides from the
corresponding alcohols <1999TL1449>. An aza-Claisen rearrangement was the invoked mechan-
ism for the Lewis-acid-catalyzed Claisen rearrangement for the synthesis of -amino-,,,-
unsaturated esters from simple allylic amines and allenoate esters <2002JA13646, 2001JA2448,
2001JA2911, 1999JA9726>. Using a chiral external ligand (ph-ambox) can form a cationic Pd(II)
catalyst for the chiral aza-Claisen of allylic imidates to allylic amides in high enantioselectivity
(up to 83% ee) <1999TL1449>.
The photochemical reaction between tertiary allylic amines and chromium complexes, in the
presence of Lewis acids in a carbon monoxide atmosphere, affords ,-unsaturated amides
(or lactams), via a zwitterionic aza-Cope rearrangement <1996JOC2871>.
The aza-[3,3]-Claisen enolate rearrangement of vinylaziridines is a convenient method for the
synthesis of mono-, di- and trisubstituted seven-membered lactams (Equation (95)) <1997JA8385,
1998S109, 2001CEJ94>.
[3,3]
Ac2O, Et3N, DMAP BnO
BnO LiHMDS
HN
N ð95Þ
N O
83%
O H
OBn
A new ring expansion reaction of 1-acyl-2-vinylpiperidine and the corresponding piperazine via
aza-Claisen rearrangement of amide enolates has been described (Equation (96)) <1996SC1675>.
X LHMDS X X
toluene, reflux H+
N N NH
40–92%
–O
ð96Þ
O O
R R R
(X = CH2, NCH2Ph; R = H, Me, OMe)

The imidate rearrangement is a variant of the aza-Claisen process. The asymmetric

base-catalyzed imidate rearrangement gives ,-unsaturated amides in moderate yield and high
enantiomeric excess <1997JOC4442, 1999T14941, 2003TA415>. The palladium-catalyzed rearra-
ngement allows the transformation of an allylic imidate into an allylic amide <1984AG(E)579,
1997JOC1449, 1997TL8837, 1998TA3213, 1998TA1065>; the use of chiral ligands has been
reported to produce the final product in a very enantioselective manner <1999JA2933,
1999CC2435, 2002TL9509> (Equation (97)). The photochemical rearrangement of a series of
O-allyl, N-benzoyl imidates has been reported (Equation (98)) <1996TL4019, 1998TL9711>.
O SiMe3
t-Bu
N Pd
Fe
X
2
Ph (X = OCOCF3) ð97Þ
Ph
R CH2Cl2, 2 days R
N O N O
57%
(R = p -CF3C6H4) 79% ee
Me R3
R 1 R2 R2
OH Me
N R1 O
+ hν, CH3CN Ph N O R1
ð98Þ
R2 R3 +
Ph
O
O R3 Ph N O
50–60% O
H Me
An aza-Claisen [3,3]-sigmatropic rearrangement has been the key step for the macrocycle
formation in the synthesis of fluvirucinine A1 (Equation (99)) <1999AG(E)3545>, in the total
synthesis of enantiomerically pure ()-antimycin A3b <2000TL7667>, in the preparation of the
tricyclic core of the cytotoxic marine alkaloid madangamine A <1997JOC1920>, and in the
synthesis of modified nucleosides such as 50 -branched 50 -aminothymidines <1997HCA1589>, in
synthetic studies directed to the preparation of inhibitors of protein kinase C isozymes
<1996JA10733, 1997BMC1725>, in the synthesis of the bicyclic core of the pumiliotoxin alka-
loids <2002EJO3304>, in the synthesis of C-allylglycines for the preparation of isoquinolones
<2002S242>, in the total synthesis of racemic gelsemine <1999AG(E)2934>, in the highly
enantioselective formal synthesis of indole alkaloid tryprostatin B <2000TL3611>, and in the
total synthesis of another indole alkaloid, okaramine J <2003OL2825>.
Me Me
LHMDS, toluene
reflux ð99Þ
N
Me 74% N
Me
O H
O
A new variant (the aza-Bergman) of the classical aza-Claisen rearrangement has been described
in the thermal rearrangement of C,N-dialkynyl imines for the synthesis of 2,5-didehydropyridines
<1997JA1464>. The [3,3]-sigmatropic rearrangement of a N-vinyl-O-acetylhydroxylamine,
obtained by acetylation of the corresponding nitrone, has been documented in the critical
quaternary center formation in the synthetic sequence for fumagillol, fumagillin, and TNP-470
<1999AG(E)971, 2003CHIR156>. The thermal rearrangement of N-alkyl-N-vinyl-
propargylamines leads to annulated[b]pyrroles with moderate to good yields via a tandem
aza-Claisen rearrangement–cyclization reaction (Equation (100)) <1996TL6709>.
O Me O Me O Me
N
N Toluene, 110 °C N
ð100Þ
Me
55%
1.18.2.7 Other Heteroatom Variants

Many heteroatom variants of the Claisen rearrangement (3-hetero-Cope rearrangement) have
been reported, playing an important role in the stereocontrolled introduction of allylic function-
ality involving secondary hydroxyl groups <1971CC328, 1984AG(E)579, 1996T13919>. The
mechanism of the addition of allyl metal (Zn, Sn, Li, Mg, etc.) to vinyl metal has been theore-
tically investigated by density-functional methods showing a dichotomy between the metallo-ene
reaction and metallo-Claisen rearrangement <1997AG(E)2469, 2000JA11791>. The stereoselec-
tive hetero-Claisen rearrangement of camphor-derived oxazoline N-oxides upon treatment with
acylating agents give -acyloxyoxazolines <1998TL2107, 1996SL297>. A new thiazole synthesis
has been discovered via the polyhetero-Claisen rearrangement in the intermediate resulting from
the cyclocondensation of thioamides with alkynyl(aryl)iodonium reagents <1996JOC8004>. A
similar iodonium-Claisen rearrangement has been investigated in allenyl(p-methoxyphenyl)iodine
substrates <1995JOC2274>. A very remarkable case is the [3,3]-sigmatropic rearrangement of
allylic azides (Equation (101)), a process that has proved to be of synthetic interest for the
preparation of advanced intermediates, useful in the preparation of natural products (pancratis-
tatin, conduramine-E) (Equation (102)) <1995TL8737>.
a b a b
N N ð101Þ
N N
N N
O O
[ η 3–C 3H5PdCl]2
O O MeO(O)CO N3
TMSN3
MeO(O)CO OC(O)OMe +
ð102Þ
O O O O
NH HN
MeO(O)CO
PPh2 Ph2P
N3
68%
Ab initio studies have been published on the phospha-Cope rearrangement <1995JOC7101>.

An oxa-Cope rearrangement has been reported for the synthesis of silenes from 1,2-bis[tris(trimethyl-
silyl)silylcarbonyl]alkanes <2001JA8400>.
The acid-catalyzed [3,3]-sigmatropic rearrangement of O-aryloximes <1998BMCL2099,
2003JOC770> (Equation (103)) and the thermal rearrangement of allyloxytetrazoles to N-allyl-
tetrazolones <1997JCS(P2)489, 2002JCS(P1)1213> are interesting cases of hetero-[3,3]-sigmatropic
rearrangements.
NMe2
NMe2
1 M HCl, AcOH, 100 °C ð103Þ
O2N
O2N
N 95%
O O
1.18.2.8 Where Y = ZCZ0

Polyhetero substituted precursors have been reported to rearrange in [3,3]-sigmatropic Cope
processes <1980T3, 1984AG(E)579, 1984CRV205, 1988CRV1423, 1989S71>. This is the case of
differently substituted ene hydroxylamines derived from carbocyclic or heterocyclic 1,3-dioxo
compounds; these substrates rearrange spontaneously or upon heating in good yields
<2003EJO190> (Equation (104)).
O
O
O
O
MsCl, Hünig's base S Me
OH
N O
Me 87% N
Me
ð104Þ
O O
H O O
O O S Me
S Me
O
O
N NH
Me Me
1.18.2.8.1 Where Z and Z0 = chalcogen

PdCl2(MeCN)2 <1999T4353> (Equation (105)) or Eu(fod)3 <2001TL4215> catalyze the
[3,3]-sigmatropic rearrangement of allylic acetates. CoCl2 also catalyzes the allylic rearrangement of
allylic acetates: tertiary acetates completely rearrange, whereas secondary acetates afford mixtures
of isomers. As a practical example, the synthesis of chiral 3E,5E-octadiene-1,2R,7R,8-tetraol
structural motifs by palladium-promoted hetero-Claisen rearrangement of allylic acetates has
been reported <1996T13919>. It has also been found that in the presence of catalytic amounts of
cobalt dichloride, acetic anhydride, and acetonitrile, allylic alcohols gave in a one-pot process
mixtures of allylic acetamides in moderate yield. Regarding the mechanism it seems that a -allyl
complex is the key reactive species rather than a [3,3]-sigmatropic rearrangement of an acetamidate
obtained in a Pinner reaction <1995JOC2670>.
C5H11 Me
OAc
48% PdCl2(MeCN)2
ð105Þ
C5H11 Me C5H11 Me
+
OAc OAc
75:25
Allylic bromides upon treatment with sodium acetate in boiling acetonitrile gave the rearranged
allylic acetates <2000JCS(P1)1753>. The sigmatropic rearrangement of allylic acetates in ortho-
quinone monoketals derived from 3-hydroxy-4-methoxybenzoate, such as 78, has been investi-
gated, showing that after treatment with silica gel in dichloromethane, compounds 79 and 80 were
isolated in a 6:4 ratio in 75% total yield (Scheme 26) <1999TL615>.
Allylic acrylates also rearrange to the corresponding isomer <2000EJO219>, and 6-fumaryl
1,3,8-nonatrienes substituted at the C-5 position by an unsaturated unit undergo [3,3]-sigmatropic
rearrangements which compete with the Diels–Alder cyclization <2002TL2753>. In a progress
report on the total synthesis of the enediyne antitumor antibiotic namenamicin, Nicolaou
described the [3,3]-sigmatropic rearrangement of allyl thiocarbonates (Equation (106))
<1999JCS(P1)545>.
MeO OAc
O
CO2Me
78
75%
[3,5] [3,3]
OMe OMe
O O
OAc AcO
CO2Me CO2Me
OMe OMe
OH OH
+
OAc AcO
CO2Me CO2Me
79 6:4 80
Scheme 26
O ONB O ONB
170 °C
O O O
75% S ð106Þ
OTES OTES
PhO S
PhO O
(NB = 2-nitrobenzyl)
The thiono–thiolo rearrangement <1997MI137> has been investigated in the case of the
reaction of allylic alcohols with thiophosgene in pyridine, which gives the corresponding thiono
chloroformates that spontaneously rearrange at room temperature to the thiolo chloroformates
in yields ranging from 54% to 77% <1999TL8059>. The [3,3]-sigmatropic rearrangement of
O-(2-alkenyl) S-alkyl dithiocarbonates (allylic xanthates) to S-(2-alkenyl) S-alkyl dithiocarbo-
nates (dithiolcarbonates) <1996TL2445, 2002CC2394> (Equation (107)) constitutes one of the
key steps in the total synthesis of (5S)-thiolactomycin <1997JCS(P1)417>.
R1 O S [3,3] R1
R2
S S S ð107Þ
R2
O
The thermal transformation of nitronic ester 81 at 80 C in benzene or ethanol into the

nitrosulfone 82 appears to be the first reported example of the [3,3]-sigmatropic rearrangement
of an O-allyl nitronic ester <2002CC1090> (Equation (108)).
O
N 80 °C SO2Ph
40% ð108Þ
SO2Ph NO2
81 82
1.18.2.8.2 Where Z and/or Z0 = nitrogen

The synthesis of N-tosyl allylic amines from allylic alcohols has been carried out via N-tosylcarba-
mates in a very stereoselective process catalyzed by palladium(II) <2000OL2357> (Scheme 27).
R1 TsNCO R1 Pd(OAc)2 R1 R3
R 2 R3 R 2 R3
OH OCONHTs R2 NHTs
Scheme 27
The rearrangement of trichloroacetimidates (Overman’s methodology) is one of the methods for

the synthesis of allylic amines from allylic alcohols. The Overman rearrangement in sugar templates
has been reviewed <B-2001MI001>. It has found many synthetic applications <1998TL1465>,
e.g., in the stereocontrolled synthesis of -amino aldehydes and -amino acids <1996TL2573,
2002JA12225, 2003JA12412>, in the synthesis of 1-aminocyclopropanecarboxylic acids
<1995TL2975>, in the preparation of novel 20 ,30 -dideoxynucleoside precursors <1995TL4311>,
in the synthesis of lincosamine and 7-epi-lincosamine precursors from D-galactose as starting
material (Equation (109)) <2000TL525>, and in the synthesis of cis-4-amino-2-cyclopentene-
1-methanol, a key intermediate for the synthesis of carbocyclic nucleosides <2002MI65>.
CCl3
O NHCOCl3
NH
200 °C H O
ð109Þ
H O O O
22%
O O O O
O O 1:1 dr
Allylic trifluoroacetimidates undergo [3,3]-sigmatropic rearrangement to the isomeric allylic

trifluoroacetamides, as in the example shown in Equation (110), a key step in the stereoselective
synthesis of polyoxamic acid <1999JCS(P1)3291>. This is an efficient process with total
1,3-transfer of chirality coherent with a chair-like transition structure. This rearrangement
seems faster than the trichloroacetimidate rearrangement and has been applied to the total
synthesis of thymine polyoxin C <1999JCS(P1)3305>.
O OSiPh2But O OSiPh2But
ButMe2SiO Me ∆ ButMe2SiO Me
ð110Þ
O HN O 80% O HN O
CF3 CF3
The [3,3]-sigmatropic rearrangement of allyl cyanates to isocyanates is an organic transforma-

tion that converts allylic alcohols into allylamines in a highly sterospecific manner. The synthetic
sequence starts from alcohols, followed by dehydration of the allyl carbamates to form the allyl
cyanates, rearrangement to the isocyanates and functionalization to the ureas or acetamides
<2001TL6133>. Its application in the carbohydrate 83 arena is a simple and efficient entry to
aminosugars 84 (Scheme 28) <1996JCS(P1)377, 1997JCS(P1)1449, 1997CEJ453>. It has also
been used in the total synthesis of blastidic acid and cytosinine, two components of the antibiotic
blasticidin S <2001SL1763>. A similar [3,3]-sigmatropic rearrangement has been reported using
thiocyanates as precursors <1997TL875, 2000TL525, 2001TL4401, 2002T1611>.
i. Ph 3P, CBr4
Me
Me ii. rt
Me
O iii. Me3Al
CCl3CONCO O AcHN
O
OPri 96% OPri 55% OPri
OH
OC(O)NH2
83 84
Scheme 28
A related [3,3]-sigmatropic rearrangement of isothiocyanates represents a new entry into vinyl

thiocyanates <2001EJO1089>.
1.18.2.9 Where Y = Z
The acid-catalyzed isomerization of allylic alcohols is a simple and ubiquitous reaction in organic
synthesis, whose efficient application has been usually hampered by the number of secondary
reactions leading to geometrical stereoisomers and skeletal rearrangements, typical of reactions
proceeding by cationic intermediates. This is the case of the camphorsulfonic-acid-catalyzed
allylic rearrangement of alcohol 85 to the cis-enediyne 86, isolated in 56% yield along with
other isomers (Equation (111)) <1996TL8413, 1999JOC5062>. Alternatively, the transformation
of compound 86 into isomer 85 has been carried out in two steps by a reaction with methane-
sulfonyl chloride followed by basic hydrolysis <1996AG(E)779>. However, the ability of allylic
alcohols to undergo allylic isomerization or 1,3-transposition reactions has been exploited in
organic synthesis <1991COS(6)829>.
SPh SPh
HO
CSA
HO ð111Þ
56% ( )3
( )3 OMe OMe
Ph Ph
85 86
In the presence of pyridinium p-toluenesulfonate an allylic alcohol moiety exocyclic to a lactam

ring undergoes stereo-controlled allylic isomerization <2001SC1753>. It has been reported that
the allylic alcohol 87 in a sugar template isomerizes to product 88 on treatment with DAST in
DMF as solvent; a hetero-Cope rearrangement has been invoked on an intermediate formate
species to account for this transformation <1998S201> (Equation (112)).
O O
HO
DAST, DMF, –50 °C
O O ð112Þ
OH
50%
87 88
B3LYP computations and NMR data showed that [1,3]-dialkylboryl shifts in cyclononatetrae-
nyl(dipropyl)borane is facile and slightly favored over [1,2]-shifts <1998CC2507>. The study of
the dynamic behavior of [1-4-4-exo-7-dipropylborylcyclohepta-1,3,5-triene]tricarbonyliron and
cycloheptatrienyl(dipropyl)borane allowed the authors to describe the first observation of a
[1,7]-boron shift <1996CEJ1483, 1998JA1034>. Using NMR techniques the kinetics of this
isomerization has been investigated. Both possible [1,3]-boron shifts are observed in phenale-
nyl(dipropyl)borane, but the benzylic rearrangement to position C9 is much faster than allylic
migration to position C3 <2000CC311> (Equation (113)). The transition state structures for the
chlorine [1,7]- and [1,5]-shifts in 1,7,7-trichlorocycloheptatrienes have been calculated
<2002JOC625>. A review has been published covering the chemistry of germoles, stannoles,
and siloles, based on progress in the period 1993–1998 <B-1998MI001>. The [1,5]-silicon shifts in
indenyl silanes have been extensively studied by X-ray and NMR techniques <2000JCS(P2)611,
2000OM590, 1999NJC317, 1998MI105>. Ab initio molecular orbital calculations of the
C¼CCSi torsion angle and the [1,3]-sigmatropic silyl shift in allyl silane have been per-
formed <1997JA807>. Theoretical studies on the 1,3-silyl migration in allyl silane have been
reported <1997JA1948, 1999JA8597>. Regarding migrations of tin-containing groups, a [1,9]-sigma-

tropic SnMe3 migration has been observed in cyclononatetraenyl(trimethyl)tin <1999CEJ2828>, and
the thermolysis of [-(silyloxy)propargyl]stannanes afford 1,3-rearranged [-(silyloxy)allenyl]-
stannanes <1997JOC8955> (Equation (114)).
Pr2i B BPr2i
3 1
[1,3](3)-B [1,3](9)-B BPr2i ð113Þ
9
OTMS
200 °C OTMS
R R ð114Þ
C
Sn(Pri)3 65–97% (Pri)3Sn
1.18.2.10 Where Y = ZZ0
1.18.2.10.1 Where Z, Z0 = chalcogen

The reversible [2,3]-sulfoxide/sulfenate rearrangement (the Mislow–Evans rearrangement) is an
interesting functional group transformation that converts allylic sulfides into allylic alcohols
<2000TL10107>. Theoretical studies and the elucidation of the transition structures and solvent
effects for the sulfenate–sulfoxide rearrangement have been published <1995JA9077,
1998JOC6061>, a homolytic scission giving a radical pair being the most likely mechanism for
the rearrangement. Hilvert has analyzed the antibody-catalyzed Mislow–Evans rearrangement
<1999JOC8334>. A number of examples have been recorded in the literature. Percy and co-
workers have reported the 2,3-rearrangement of a series of sulfenates and phosphinates prepared,
and transformed in situ, from the corresponding difluorinated primary, secondary, and tertiary
allylic alcohols in good yields (Scheme 29) <1996TL6403>.
OMEM OMEM O OMEM

O Ph2PCl PhSCl
OH
Ph2 P F Ph S
52% 72% F
F F F F
Scheme 29
The enantioselective synthesis of gabosines A, B, D, and E from ()-quinic acid <2002SL1341>

(Scheme 30), and the synthesis of model compounds from carbohydrate precursors <1998MI323>
used this rearrangement as a key step. A sulfoxide–sulfenate rearrangement was also described in a
synthetic approach to the hydroazulene portion of guanacastepene A; the vinylsulfoxide 89 is
isomerized to the corresponding allylic sulfoxide in basic medium and the [2,3]-sigmatropic rearrange-
ment takes place in situ to give the allylic alcohol 90 <2002TL9605> (Scheme 30).
In the one-pot synthesis of (E)--hydroxy and (E)--keto-,-unsaturated sulfoxides from bis-
sulfoxides, described by Llera, a [1,3]-H shift and a [2,3]-sulfoxide/sulfenate rearrangement were the
key steps <1995TL4889> (Scheme 31). Carreño and co-workers have extensively used the sulfoxide–
sulfenate rearrangement on Diels–Alder adducts from conveniently functionalized dienophiles and
p-tolylsulfinyl-1,3-pentadienes <1996TA2151, 1998TL1405, 1999TA3473, 2000TA1217>.
Propargylic dialkoxy disulfides undergo a double [2,3]-simatropic rearrangement to diallenic
vic-disulfoxides <2003TL777>. The reverse sulfenate–sulfoxide rearrangement has also been
described in a series of propargyl sulfenates leading to diallenic disulfoxides <2000TL6923>.
A similar process has been observed and documented for the [2,3]-sigmatropic-selenoxide/
selenate rearrangement <B-1999MI001, 1998SL987,1995MI220, 2002CC558>. Recently, the
first catalytic method for this rearrangement using vanadyl(IV)acetylacetonate (10%) has been
reported (Scheme 32); final reaction with phosphines results in allylic alcohols in good overall
yield <2000CC2031>. Uemura has reported the synthesis of chiral ferrocenyl diselenides and
has prepared enantiomerically pure allylic selenides that upon oxidation produced asymmetric
[2,3]-sigmatropic rearrangement giving allylic alcohols in high enantiomeric excess <1995JOC4114>.
Me Me OMe
Me Me OMe
MeO O i. MCPBA MeO O
O OTBDMS ii. (EtO)3P O OTBDMS
82%
OH
SPh
O OH
SPh
DBU/EtCN (1:1)
92%
OBn OBn
89 90
Scheme 30
Tol R1
R1
S O R2
R2
+ Tol
S O H S
Tol O
O
R1 O R1 O R1
R2 STol [1,3]-H R 2 STol [2,3]-shift R2 OSTol
STol STol S Tol

O O O
Scheme 31
VO(acac)2
CHP, CH2Cl2,
O Se Ar OSeAr OH
–10 °C PBu3 (1.2 equiv.)
Ph SeAr
Ph Ph Ph
Me 70%
Me Me Me
(Ar = 2-NO2C6H4)
(CHP = cumene hydroperoxide)
Scheme 32
1.18.2.10.2 Where Z and/or Z0 = nitrogen, phosphorus

The Meisenheimer rearrangement of allylic amine N-oxides to the corresponding N,N,O-trisub-
stituted hydroxylamines is a [2,3]-sigmatropic rearrangement that, after cleavage of the NO
bond, gives secondary or tertiary allylic alcohols <1919CB1667>. Enantiomerically pure sub-
strates for the asymmetric transfer in the Meisenheimer rearrangement have been described
<2000TL8279>. Davies reported the synthesis and in situ Meisenheimer rearrangement of the
N-oxides obtained by oxidation of the tertiary amine where the (R)-1-phenylethyl-N-methyl
amine has been incorporated as a chiral inductor <1996TA1001>. He has applied this strategy
for the enantioselective synthesis of (R)-sulcatol <1996TA1005, 1996JCS(P1)2467>; the
[2,3]-rearrangement was completely stereoselective, affording only one compound at the newly
formed stereocenter, having the E-stereochemistry at the double bond (Scheme 33).
Me Me
MCPBA O
Me Me
Ph N Me CHCl3 Ph N Me
Me OH 94%
Me Me OH
Me
Ph Me
OH Me
N
O Me Me
Me Me
Me OH (R )-sulcatol
Me
Scheme 33
Coldham has also reported moderate levels of stereoselectivity in the chirality transfer from
nitrogen to carbon in the [2,3]-amine oxide rearrangement, by using camphor-like amines or N-
allyl prolinol derivatives <1997SL322, 1998TA1995, 1999JCS(P1)2327>. Various BTAa’s
(bicycles derived from tartaric acid and -amino acids) employed as chiral auxiliaries did not
afford a high level of asymmetric induction <2000TA4227>. The interesting transformation of a
bicyclic 2-alkenyl aziridine into a -hydroxynitrone (Equation (115)) involves a [2,3]-Meisenhei-
mer rearrangement to give an endo-N-oxide which undergoes a rapid sigmatropic rearrangement
followed by in situ oxidation to the final nitrone <2001TL3029>. N-Oxides of 8-[(dialkyl-
amino)methyl] caffeines undergo the expected Meisenheimer rearrangement to the corresponding
O-(8-caffeinylmethyl)-N,N-dialkylhydroxylamines in moderate yields <1999EJO2419> (Equation
(116)). Finally, Cossy has reported the synthesis of unsaturated [1,2]oxazines by sequential
Meisenheimer rearrangement of unsaturated N-acryloyl-N-oxides followed by ring closing
metathesis reaction <2003TL8577>.
OH
OMe MCPBA
OMe
OMe MeCN, NaHCO3 OMe
ð115Þ
N 69% N O
O Me O Me
Me N Benzene, Me Et
N N N O N
reflux ð116Þ
N Et Et
O N 54% O N
O
Me Et
Me
Related rearrangements of N-aryl-N-allylhydroxylamines to O-allylhydroxylamines have been

communicated recently <2001CC1806> (Equation (117)). This rearrangement takes place spon-
taneously (initiated by air), by simply allowing the compound to stand at room temperature; it
was observed that the rate of the rearrangement depended on the type of the substituent on the
nitrogen atom, the most favorable being aryl.
H
Ph OH N
N Ph O
Air
Bun ð117Þ
Bun 62%
MeO MeO
In spite of previous reports <1998SL939> showing that allylic nitro compounds did not undergo
[2,3]-sigmatropic rearrangements at 110 C in toluene, in 1999 French authors reported the first
[2,3]-sigmatropic rearrangement of this type of compound (Equation (118)). Working under harsher
conditions (1,2,4-trichlorobenzene, reflux), the thermal reaction affords rearranged alcohols and
carbonyl compounds in almost equal amounts, in poor chemical yield <1999CC2009>.
OH O H
O2N R1 214 °C
R3 R1 3 R1
R3 R1 + R
X R1 R1
R2 X X
R2 R2 ð118Þ
X = O, NR
12–15% 13–18%
[R1 = H, Me; R2 = Ph; R3 = Me; R2–R3 = –(CH2)4–]
In 1998, Davies reported a new [2,3]-sigmatropic rearrangement when N-benzyl-O-allylhydroxy-

lamine afforded N-allylhydroxylamine on treatment with BunLi (Scheme 34) <1998CC2235,
2002JCS(P1)1757>; the reaction was shown to be very stereoselective when (E)-N-benzyl-O-(meth-
oxy-4-phenylbut-2-enyl)-hydroxylamine afforded syn-3-benzylamino-4-methoxy-4-phenylbut-1-ene
as a single diastereomer via a chelated transition state <1999CC2079, 2002JCS(P1)2141>
(Scheme 34). In an independent study published few years later, Saito et al. reported similar results
on closely related substrates <2001JA7734, 2001JA9724>.
Bn O Bn O Bn OH
N BunLi N N
H Li
OMe
OMe
Ph BunLi, THF
O –78 °C to 25 °C Ph
HN NHBn
Bn 94%
Scheme 34
The [3,3]-sigmatropic rearrangement of enolates derived from hydroxamic acid derivatives has
been used in a synthesis of the alkaloid eseroline (Equation (119)) <2001H(55)1029>.
PhS Me PhS Me
O i. KHMDS O
ii. H3O+
OH Eseroline ð119Þ
O
N 65% NH
CO2Me CO2Me
The analogous phospha-[2,3]-sigmatropic rearrangement has also been reported. This protocol
allows the formation of cyclic 1,2-diphosphane oxides 92 from diphenylphosphinites that are
readily prepared from the corresponding 1,2-diols 91 (Scheme 35) <1999TL4981,
2001AG(E)1235>. Allene phosphane oxides have been obtained by a similar [2,3]-sigmatropic
rearrangement of phenylphosphinites prepared and rearranged in situ from propargylic alcohols
<1995AG(E)2037, 1997JOC603>. The reaction of bisalkynol 93 with diethoxychlorophosphane
in the presence of triethylamine in dichloromethane gives phosphorylyne-allene 94 via a
[2,3]-sigmatropic rearrangement (Equation (120)) <1999EJO2367>.
OPPh2
OH OPPh2 P(O)Ph2
PPh2Cl Toluene
OH OPPh2 reflux P(O)Ph2

85%
91 P(O)Ph2
92
Scheme 35
O OEt
OH Me P
ClP(OEt)2
Me SiMe3 C OEt ð120Þ
Me Me
55%
93 94 SiMe3
1.18.3 OTHER REARRANGEMENTS
1.18.3.1 Tandem and Higher Sigmatropic Rearrangements

Tandem sigmatropic rearrangement processes are usually found in the current literature and have
been reviewed <B-1992MI001, 1998S227, 2000MI1033>. This strategy has been applied in
organic synthesis by taking advantage of putting together in the same protocol functional
group transformations that can be achieved separately <1991COS(5)875>.
The aromatic Claisen rearrangement of O-allyl-1-naphthols followed by the tandem o-phenol
oxygenation and oxy-Cope rearrangement has resulted in a convenient method for the synthesis
of 4-allyl-substituted 1,2-naphthoquinones <1996S699>. A tandem thio–Claisen–
Claisen rearrangement of thiochromene derivatives has been efficiently applied by Majumdar in
the preparation of pentacyclic heterocycles <2003T5289>. Tandem [2,3]-Wittig/anionic-oxy-Cope
rearrangements have been used for the synthesis of a series of bis-allylic ether substrates
<1997TL4679>, the stereoselective synthesis of trisubstituted -lactones and tetrahydropyrans
<1997TL6449, 1997TL6453>. The ester–enolate/dienolate [2,3]-Wittig rearrangements have been
described in tandem processes with other sigmatropic rearrangements, such as the anionic-
oxy-Cope <1997TL6445> or the Ireland–Claisen or ring-closing metathesis reactions
<2000JCS(P1)2916, 1997JOC137>. For the synthesis of the kinamycin core a tandem Cope-
cheletropic reaction has been applied <1996CC1181>.
Tandem oxy-Cope/ene/Claisen rearrangements have been shown to furnish a highly diastereo-
selective synthesis of decalin skeletons containing quaternary carbon centers (Equation (121))
<2002OL1371, 2000OL663>. An efficient sequence based on pericyclic reactions comprising the
ester dienolate [2,3]-Wittig/oxy-Cope rearrangement followed by a carbonyl ene reaction has been
described as a new entry to polyfunctionalized carbocycles <2001EJO483> (Scheme 36).
O MW, sealed tube HO

DBU, toluene, 220 °C O ð121Þ
OH
75%
OPri LDA, THF O

– 78 °C to 25 °C ∆
O
i
O 66% O OPr
OH OH O
+ +
CO2Pri CO2Pri
O OPri
62:2:36
Scheme 36
In a series of studies directed to the synthesis of fused-ring skeletons, the synthesis of a ring-
expanded ketone in good yield through tandem [1,3]- and oxy-Cope rearrangements has been
reported <1999TL511, 2002TL3633> (Scheme 37). The same strategy has been applied for the
preparation of useful intermediates in the total synthesis of ()-junicedranol <2000TL1939>.
H
KHMDS, 100 °C
Diglyme Ph +
OH
Ph HO H Ph O
53% [1,3] 13% (oxy-Cope)
Scheme 37
The tandem allyl vinyl ether isomerization of a di-O-allyl ether followed by in situ Claisen
rearrangement is catalyzed by the system Ru3(CO)12/imidazolinium salt/caesium carbonate
<2002CC1772>. A catalytic and enantioselective tandem Claisen rearrangement plus intramole-
cular carbonyl ene reaction has been elegantly applied in the synthesis of densely functionalized
carbocycles from open-chain molecules <2002SL1999> (Equation (122)). A tandem [3,3]-sigma-
tropic rearrangement/[1,2]-allyl shift has been applied by Wood to an efficient synthesis of
(+)-latifolic acid and (+)-latifoline <2001JOC7025>. A structural isomer of nerol has been
elegantly prepared by sequential tandem Ireland–Claisen and Cope rearrangement (Scheme 38)
<1999EJO2781>.
O
PriO
O OH
Cu[(S,S)-Ph-box](OTf)2 PriO
O ð122Þ
98%
89/11 dr (98% ee)

(box = bisoxazoline)
i. LICA
O ii. TMSCl
O
iii. AcOH, H2O
O OTMS
98%
CO2H Xylene CO2H CO2H OH

140 °C LiAlH4
+
73% 78%
Scheme 38
Propargylic dialkoxy disulfides undergo an unprecedented sequence of three [2,3]- and one
[3,3]-sigmatropic rearrangements followed by an intramolecular [2+2] cycloaddition affording
bicyclic derivatives <2003TL777>. Thermolysis of bis-thiocarbamates derived from but-3-yne-
1,2-diols gave buta-1,3-dienes with carbamoylthio groups in positions C1 and C2 with good yields
via tandem [3,3]–[3,3]-sigmatropic rearrangements <1995AG(E)1627, 1998AG(E)3289,
2000T5413> (Scheme 39).
S
O
OH Me2N O S NMe2
Toluene, 110 °C
OH O NMe2 100%
S NMe2
S O
1.4/1 E/Z
Scheme 39
An elegant sequential tandem process has been described starting from Claisen rearrangement
of the adducts from 2-methoxyphenols and functionalized dienes, followed by in situ Diels–Alder
reaction of these intermediates, and further Cope rearrangement; this is a convenient method for
the synthesis of highly functionalized cis-decalins <1997CC1085>. A beautiful example of ‘‘bio-
mimetic’’ cascade reactions, the tandem Claisen rearrangement/intramolecular Diels–Alder reac-
tion, has been achieved in the construction of bridged tricyclic scaffolds present in complex
natural products isolated from Garcinia. This strategy pioneered by Nicolaou
<2001AG(E)4264> has been extensively applied by Theodorakis <2002OL909> to the synthesis
of this family of natural products, including lateriflorone and derivatives <2003OL1491,
2003T6873>.
Numerous higher-order sigmatropic rearrangements are known and have been the subject of
some theoretical studies <1998JA10490>. In preliminary efforts directed to the synthesis of
natural products thiarubrine A and B, [3,4]- and [3,5]-sigmatropic rearrangements have been
reported <1997TL799>. The synthesis of phytochrome and related tetrapyrroles featured a
[3,5]-sigmatropic rearrangement of an N-pyrrolo enamide as the key step <1997JOC2894>. A very
unusual [9,9]-sigmatropic shift in a benzidine-type rearrangement has been described
<1997JOC3794>.
1.18.3.2 Rearrangements Involving Ring Opening
1.18.3.2.1 Ring opening of cyclopropanes

The cyclopropane ring is extremely sensitive to reactants and/or experimental conditions (thermal,
photochemical, metal-catalyzed, free radicals) leading to rearranged or opened products.
A convenient preparation of 2-fluoro-3-alkoxy-1,3-butadienes by thermolysis in quinoline
solution of 1-chloro-1-fluoro-2-alkoxy-2-methylcyclopropane has been reported
<2002OL3155>. The kinetics of thermal cyclopropane ring opening of a series of diaryl homo-
naphthoquinones have been examined <2000JCS(P2)135>. Free-radical conditions have been
investigated and reported in the literature concerning the ring opening of vinylcyclopropanes
<2000T8959, 2001CSR94, 1996JCS(P1)57, 1998TL1893, 1999TL3431>. The reaction of alkylthio
radicals with alkenyl cyclopropanes opens the cyclopropyl ring and generates a homoallylic
radical that is captured by a radical trap to give a new radical that adds back to the thioalkyl
allylic system to form, after elimination of the alkylthio radical, a polycyclic ring system
<1997JOC4601>.
There are many examples in the literature on the photochemical ring opening of cyclopropanes.
Thus, the photochemical ring opening of cyclopropyl p-benzoquinones has been reported
<1996JA1233>. The sensitized photochemical oxa-di--methane (ODPM) rearrangement of tet-
racyclo[3.3.0.02,8]octane derivatives produces cyclopropane ring opening leading to cyclopenta-
noid molecules, useful in organic synthesis <1997T13053>. The UV irradiation of
dibenzonorcaradienes bearing an acyl or alkoxycarbonyl substituent in the C7 position yields a
number of substituted phenanthrenes <2001OL1885>. Usually, these reactions proceed through a
1,3-diradical species <2001OL1885, 1998JOC3176>. 2-Aminocyclopropanols undergo an oxidative
ring-opening reaction leading to enaminones in moderate yields <1997T7855>. Density-func-
tional theory has been applied to study the effects of fluorine substitution on the kinetics of the
cyclopropylcarbinyl radical ring opening <1999JOC540>. Tandem free-radical processes have
been described giving complex carbocyclic arrays <1997TL3647> (Scheme 40). Reissig has
published a full account of the synthesis and reactivity of donor–acceptor-substituted cyclo-
propanes, highlighting the methods for their cleavage <2003CRV1151>. In particular, their
ring opening reactions for the preparation of substituted and functionalized 1,4-dicarbonyl
compounds and derivatives are of special interest. Pinacol rearrangement of -hydroxycyclopro-
pylcarbinols promoted by Lewis acids, in acid medium <1998T6903> or in the presence of
methanesulfonyl chloride/pyridine <2000OL1337>, gives 2-substituted cyclobutanones
(Scheme 40), that have been used in the asymmetric synthesis of 4-deoxyverrucarol
<2000JOC504>. The reaction of commercially available 1-triphenylphosphoranylidene-2-propa-
none with cis-2,3-bis(trimethylsilyl)cyclopropanone gave products arising from the unexpected
[1,5]-sigmatropic rearrangement featuring a clean cyclopropane ring opening (Scheme 40)
<2000TL3399>. Six-membered ring-fused trimethylsilyl-substituted cyclopropanols expand to
medium-sized carbocycles when treated with tetrabutylammonium fluoride (Equation (123))
<2002T9279>.
O O
H
HH
O H H
TTMSS/AIBN +
I
65% H H
H 2:1
OH H
MsCl, pyr
72%
OH O
Me
O
O
O
+ Ph3P
Me3Si SiMe3 Me 70%
Me3Si SiMe3
Me3Si Me3Si
+
Me3Si O Me Me
O
77/23
Scheme 40
TMSO Cl O
Bu4nF
ð123Þ
62%
The thermal [2,3]-sigmatropic rearrangement of allyl tetronates proceeds via 3-(spirocyclopro-

pyl)dihydrofuran-2,4-diones (Scheme 41). In some cases these intermediates have been isolated
and submitted to cyclopropane ring opening with alcohols or water <2001TL4561>. Jasmonoids
have been prepared by pyrolysis of a spiroannulated cyclopentanone <1998MI319>. The proce-
dure involves a retro-Diels–Alder reaction and a homo-1,5-hydrogen shift with concomitant
cyclopropane ring opening.
O O
[2,3]
O O
∆, toluene
( )n O 65% ( )n O
[3,3]-Claisen [1,3]-H shift
O O O
O O O
OH O OH
( )n
Scheme 41
The intramolecular hydroxyl-mediated opening of a cyclopropyl ring has been used in a model
study for the synthesis of the diterpenoid harringtonolide <1998JCS(P1)1555>. Vinylcyclopropanes
are opened in free radical-mediated three-component reactions with alkynes and diphenyl diselenide
<2000JOC7682>. Mesylate 95 on treatment with ButOK in DMF afforded the ring-opening product
96 in preference to the elimination of HBr or MeOH (Equation (124)) <2002EJO2160>.
H H
Ph KOBut Et
DMF, 50 °C Me
Ph
O Br ð124Þ
SO2 O
Me 85%
96
95
Rhodium compounds are the typical catalysts to accomplish the opening reactions of the
cyclopropane ring and it has been reported that treatment with rhodium(II) acetate of different
diazo propanones results first in a cyclopropanation reaction, followed by acid-catalyzed ring-
cleavage of the cyclopropyl moiety <1997TL5081>. A rhodium carbonyl complex catalyst
allowed the transformation of 4-pentynyl cyclopropanes into bicyclo[4.3.0]nonenones, which
proceeds by cleavage of the cyclopropane ring in moderate yields <1999CL705>.
Alexakis has reported the tandem enantioselective conjugate addition–cyclopropanation reac-
tion leading to trimethylsilyl-protected 3-cyclopropanols, a series of useful intermediates, that
have been submitted to a variety of experimental conditions for opening the cyclopropane ring
<2002JOC8753>. Tricyclo[3.3.0.02,8]octane-3-one ring systems upon treatment with tributyltin
hydride afforded open cyclopropane derivatives <1995TL6819, 2002AG(E)4090>. Similarly,
tricyclo[4.3.0.02,9]nonan-3-one systems reacted with different agents such as t-butyldimethylsilyl
iodide or trimethylsilyl trifluoroacetate to give cyclopropane cleavage products <1999T847>. The
hemi-synthesis of erythrolide K has been achieved by a cyclopropane ring opening involving a
[1,5]-sigmatropic hydrogen shift from erythrolide A <1998TL1469>.
1.18.3.2.2 Photochemical ring opening of cyclic ketones

The photochemical ring cleavage of cyclic ketones has found limited use in organic synthesis due to
the fact that usually several compounds are formed in the photolysis, in addition to the expected
!-unsaturated aldehyde. An interesting exception is the photolysis of 2,2-diphenylcycloheptanone,
which cleanly afforded 7,7-diphenyl-hept-7-en-1-al in 76% yield (Equation (125)) <1999BCJ103>.
O
Ph O Ph
hν ð125Þ
Ph
76% H Ph
1.18.3.2.3 Rearrangement of epoxides

The acid- or base-promoted rearrangement of epoxides into allylic alcohols is an extremely useful
functional group transformation that has found extensive application in organic synthesis
<1991COS(3)733, 1991TA1> and a number of reviews have been published in the last years
showing the interest in this reaction <1996T14361, 1996MI188, 1998JCS(P1)1439>. A recent
review on the asymmetric base-mediated epoxide isomerization is also available covering the
literature from 1997 up to 2001 <2002CSR223>, and the reader is directed to this excellent
account for all the relevant references on the subject for this period.
The opening of epoxides to give unsaturated alcohols is a functional group transformation
with a number of interesting synthetic applications, either using bases, as in the preparation of
sesquiterpenes <2002TL627>, or using acids, bases or hydroperoxides, as in the case of steroids
<2001T2185>. The acid-catalyzed rearrangement of caryophyllene oxide has been investigated
<1996JCS(P1)2507>. Palladium complexes have been reported to promote the ring opening of
trisubstituted epoxides giving mixtures of allylic alcohols and ,-unsaturated ketones
<2002JOC1580>. The first total synthesis of (+)-chrysanthemol included in the synthetic
sequence the cleavage of an epoxide to give an allylic alcohol using Lewis acids (boron
trifluoride etherate or aluminum isopropoxide) as promoters <1997CL1289>. Other Lewis
acids such as Et3Al have been shown to promote the ring opening of -hydroxy
epoxides leading to -hydroxy alkenes <2003TA2189>. An interesting example of photocycli-
zation of -hydroxybutyl ,-unsaturated ,-epoxynitriles has been described <1995LA19>
(Scheme 42).
NC CN CN
NC hν
OH Et 3N, THF
O + O
O O +
O O
O
(5%) (2%) (29%)
MeONa /
O O O
MeOH
O O O O O O
O 83% O O
H H
97 O O O
98 99
OH OH
Me Me
(1R,2S)–norephedrine, BunLi
O 63% HO
99% ee
Scheme 42
However, the base-promoted rearrangement of epoxides account for the largest amount of
the published work in this area. The influence of the solvent and the structure of the substrate in
the mechanism of the base-mediated isomerization of cycloalkene epoxides has been discussed
<1996JOC820, 2000JOC1461>. The lithium diethylamide/lithium tert-butoxide reaction with

1,5-cyclooctene diepoxide has been revisited, but not without problems of structure assignment
<1997T1855> and further correction <1998T13323>. Hodgson has studied the mechanism of
the base-mediated rearrangement in simple cyclopentene oxides and also in bicyclo[2.2.1] and
bicyclo[2.2.2]alkene-derived epoxides to give ketones and alcohols, giving new insights in the
mechanisms that operate following -lithiation in such systems <1997TL887, 1997TL8907>.
His group has also screened a number of external ligands, ()-sparteine, bisoxazolines, . . . , to
accomplish the synthesis of enantio-enriched unsaturated diols arising from the double ring
opening of epoxytetrahydrofurans <2003OBC1139>. The opening of epoxide intermediates
with magnesium amides provides valuable compounds for the synthesis of vitamin D3 deriva-
tives <1998JOC6984>. In a general synthetic route to the dihydroagarofuran sesquiterpenoid
from -()-santonin, the homoallylic alcohol 99 was obtained by sodium methoxide-promoted
rearrangement of epoxide 97 (Scheme 42); presumably the intermediate allylic alcohol 98, after
a [1,3]-hydrogen shift, gave the ,-unsaturated lactone <1998TL7935, 1998SC3751,
2002TL627>.
The use of chiral lithium bases in the rearrangement of epoxides has been intensively explored
in recent years as reviewed by Andersson <2002CSR223, 2000SL1092> and some theoretical
calculations have been performed <2003CL150>. Camps has disclosed a regio- and stereoselec-
tive synthesis of highly functionalized cyclopentanols using lithiated alkyldiphenyl phosphine
oxides as chiral bases <2002T3473>. Quaternary carbon-containing meso-epoxides were enantio-
selectively transformed into the corresponding allylic alcohols <1995TL1893> by treatment with
(1R,2S)-norephedrine and BunLi <1996TA407> (Scheme 42).
In a reported total synthesis of (+)-iridomyrmecin, a key step was a highly enantioselective ring
opening of a racemic epoxide promoted by a chiral base <1997SL657>. In his synthetic approach
to the ingenane type of diterpenes, Rigby has reported an improved method for the opening of the
key allylic epoxide leading to a dienol intermediate <2002OL799> (Equation (126)).
OMe
O OMe
H
H Pd(OAc)2, PPh3, Et3N HO
H ð126Þ
H
78%
O O
O O
The epoxidation of commercially available sesquiterpene (+)-ledene with MCPBA afforded a

rearranged allylic alcohol as the major compound in a mixture that included epoxy derivatives
along with other rearranged products <1996MI1840>. gem-Difluoroalkenes, obtained by epoxide
rearrangement, were submitted to LDA-promoted [2,3]-Wittig rearrangement to give the expected
gem-difluoro allylic alkenes in good yield (Scheme 43) <1995CC1857>.
OH
BunLi OH O
O LDA
R
R CF2Cl F F
R CF2 R CF2
Scheme 43
O’Brien has carried out exhaustive studies on the enantioselective base-mediated rearrangement
of numerous 4-amino-substituted cyclopentene oxides <1998TL8175, 2000T9633> and substi-
tuted hydroxycyclohexene oxides leading to a plethora of carbocyclic nucleoside analogs, con-
duritols (Equation (127)) <2002T4643>, aziridinocyclohexenols <2003OBC523> and densely
functionalized cyclohexenones <1998JCS(P1)2435>. A norephedrine-derived chiral base was
found to be very efficient in these transformations.
NHMe
N (2 equiv.)
Ph
BunLi (2 equiv.)
TBDMSO TBDMSO OH ð127Þ
0 °C rt
O
TBDMSO 93% TBDMSO
95% ee
Andersson has implemented the use of 3-substituted 2-azanorbornyl ligands as catalysts in the
preparation of several allylic alcohols (precursors of the prostaglandin core unit, epibatidine,
carbovir, faranal, lasiol) <1998JA10760, 2000JA6610, 2000SL1092, 2002CSR223> by reaction of
different epoxides with LDA in stoichiometric amount (Equation (128)), the enantioselectivity
being higher than 94% ee in most cases.
N
N ( )n' (5 mol.%)
(n' = 1, 2)
LDA (1.8 equiv.), DBU (5 equiv.), THF OH

ð128Þ
O
( )n ( )n
(n = 0 – 3)
ee > 94%
The boron trifluoride-etherate-promoted electrophilic cyclization of tetrasubstituted epoxides

containing a trimethylsilyl allyl moiety has been described 100 <1996JOC2075, 2001JCS(P1)789>
to give a major carbocyclic derivative 101 and a 1,3-hydroxyketone as a rearranged carbonyl
compound 102 <1998JOC8212> (Equation (129)).
TMS CO2Et CO2Et TMS CO2Et
BF3.OEt2
TBDMSO TBDMSO + TBDMSO
O OH OTBDMS
OTBDMS OTBDMS O
100 101, 62% 102, 17%

ð129Þ
The Lewis acid-promoted stereoselective rearrangement of the epoxy group of 5,6-epoxy

carotenoids gives open-chain molecules that can be considered as key intermediates for the
synthesis of the crassostreaxanthin type of natural product (Equation (130))
<1999JCS(P1)1625>.
OTBDMS
OAc SnCl4, –78 °C O
O ð130Þ
TBDMSO OAc
60%
Murphy has reported the enantioselective epoxide ring opening of cyclic epoxides using
dilithiated bases, obtaining the best results in terms of substrate conversion, but with low
enantioselectivity, with dilithiated ephedrine <2002T4675> (Equation (131)).
OBn Me Ph
OBn
LiHN OLi
S
R ð131Þ
91%
O OH
78% ee
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Biographical sketch
Marı́a Teresa Molina was born in Madrid and José Marco-Contelles studied chemistry at the
studied chemistry (honors) at the Universidad Universidad Complutense de Madrid (UCM)
Complutense de Madrid. She received her (graduating with honors), where he obtained his
Ph.D. degree in 1985 (Institute of Organic Ph.D. under Professor Benjamı́n Rodrı́guez
Chemistry, CSIC) under the supervision of (Instituto de Quı́mica Orgánica, Consejo Super-
Prof. Francisco Fariña. She was postdoctoral ior de Investigaciones Cientı́ficas (CSIC)) in 1984.
fellow from CSIC (1985–1986) and Fulbright- After two years as a postdoctoral fellow under Dr.
MEC fellow (1986–1988) in the United States, H.-P. Husson (Institut de Chimie de Substance
working at the Department of Chemistry Naturelles, CNRS, Gif-sur-Yvette, France)
(Iowa State University) with Professor George (CNRS methods in asymmetric synthesis) (1984–
Kraus (1985–1987), and at the University of 1985), he worked as an associate researcher under
Kansas (Department of Medicinal Chemistry) Professor Wolfgang Oppolzer (Département de
with Professors Lester Mitscher and Angelo Chimie Organique, Genève, Suisse) (aldol reac-
Vedani (1987–1988). In 1987 she was tion) (1986) and was a visiting professor at the
appointed as Tenured Scientist working at Department of Chemistry, Duke University,
the Institute of Medicinal Chemistry (CSIC). North Carolina working with Professor Fraser-
Her research interests are the synthesis of qui- Reid (free-radical chemistry; annulated furanoses;
nones and heterocyclic systems with biological formal total synthesis of phyllanthocin).
activity and the development of new synthetic In 1992, he was promoted to Research Scientist
methods. and in 2004, to Research Professor in the CSIC
(Spain).
He was Invited Professor at the Université
Pierre et Marie Curie, Paris VI (June 2000), at
the Université Jules Verne-Picardie (Amiens,
France) (May 2003, June 2004), and at the
Okayama University (Faculty of Engineering)
(September 2003).
In 2002, he secured the French-Spanish award
of the French Chemical Society.
His present interests include the development
of new synthetic methodologies in carbohydrates,
free-radical chemistry, organometallic chemistry
(Pauson–Khand reaction, PtCl2-mediated cyclo-
isomerization of polyunsaturated precursors),
and synthesis/biological evaluation of heterocyc-
lic systems (CSIC reaction, tacrine analogs).
He is the author of 154 scientific articles (146
papers and 8 reviews), 4 chapters in books, and 6
patents.
1.19
Tricoordinate Carbanions, Cations,
and Radicals
P. PALE
University de Louis Pasteur, Strasbourg, France
P. VOGEL
EPFL, Lausanne, Switzerland
1.19.1 TRICOORDINATE CARBANIONS (P. PALE, UNIVERSITY DE LOUIS PASTEUR) 890

1.19.1.1 General Aspects 890
1.19.1.2 Literature Survey 891
1.19.1.3 Carbanions and Organometallic Species 891
1.19.2 CARBANIONS BY PROTON LOSS 891
1.19.2.1 Deprotonation: General Aspects 891
1.19.2.2 Directed Deprotonation 891
1.19.2.3 Stereoselectivity Issues 892
1.19.2.3.1 Diastereo- and enantioselective deprotonation 892
1.19.2.3.2 Chiral enolates 893
1.19.3 CARBANIONS BY SCISSION OF CC OR CX BONDS 894
1.19.3.1 General Considerations 894
1.19.3.2 Oxidative Addition 894
1.19.3.3 Halogen–Metal Exchange and Related Processes 895
1.19.3.3.1 General aspects 895
1.19.3.3.2 Direct reduction of organohalides 895
1.19.3.3.3 Reduction of organohalides mediated by arenes 896
1.19.3.3.4 Organohalide–organometallic equilibria 897
1.19.3.3.5 Organometalloid–organolithium exchange 899
1.19.4 CARBANIONS BY ADDITION TO C¼C BONDS 899
1.19.4.1 General Aspects 899
1.19.4.2 Addition to Enones and Related Compounds 900
1.19.4.2.1 1,4-Additions (Michael-type reactions) 900
1.19.4.2.2 The Baylis–Hillman reaction 901
1.19.4.3 Carbometallation 901
1.19.4.4 Hydrometallation 903
1.19.5 CARBANIONS BY METAL–METAL EXCHANGE 904
1.19.5.1 General Aspects of Transmetallation: Tuning the Reactivity 904
1.19.5.2 Dicarbanions–Metallacycles 905
1.19.5.2.1 Titanium dicarbanions (the Kulinkovich reaction) 905
1.19.5.2.2 Zirconium dicarbanions and the Dzhemilev reaction 906
1.19.6 TRICOORDINATE CARBOCATIONS (P. VOGEL, EPFL, LAUSANNE, SWITZERLAND) 908
1.19.6.1 General Literature Survey 908
1.19.6.2 Historical Background 909
1.19.6.3 Carbenium and Carbonium Ion Nomenclature 911
1.19.7 CARBOCATIONS IN THE GAS PHASE 912
1.19.7.1 Methods for Generating and Investigating Ions in the Gas Phase 912
1.19.7.2 Gas-phase Thermochemical Data 913
1.19.7.3 Examples of Carbenium Ions in the Gas Phase 917
1.19.7.4 ‘‘Aromatic’’ Carbenium Ions 920
889
890 Tricoordinate Carbanions, Cations, and Radicals
1.19.7.5 ‘‘Antiaromatic’’ Carbenium Ions 921

1.19.7.6 The Cyclopropyl Substituent Effect 921
1.19.8 CARBOCATIONS IN THE CONDENSED PHASE 922
1.19.8.1 The Effect of the Nature of the Nucleofugal Group 922
1.19.8.2 The Use of ‘‘Super-Acids’’ 924
1.19.8.3 Carboranes as Super-Acids 925
1.19.8.4 Intermolecular Hydride Transfer Reactions 926
1.19.8.5 Carbocations Generated upon Irradiation 927
1.19.8.6 Carbocations by Fragmentation of Alkoxy(chloro)carbenes 929
1.19.8.7 Hydrocarbon Alkylation and Cracking with Zeolites 930
1.19.9 CARBOCATION REACTIONS 931
1.19.9.1 As Intermediates in Heterolysis 931
1.19.9.2 Heterolyses of Substrates -Substituted by Electron-withdrawing Groups 932
1.19.9.3 Remote Allyl Substituent Effects 934
1.19.9.4 Anchimeric Assistance versus (C,C) Hyperconjugation 935
1.19.9.5 Anchimeric Assistance by Heteroelements 938
1.19.9.6 Hyperconjugation and Participation by Metals 939
1.19.9.7 Characterization of Cationic Electrophiles and Their Reactivity with Nucleophiles 942
1.19.9.8 Carbocation Rearrangements 944
1.19.10 CARBODI- AND POLYCATIONS 949
1.19.11 CARBOCATIONS IN LIVING SYSTEMS 950
1.19.11.1 Mechanism of the Prenyl Transfer Reaction and Monoterpene Biosynthesis 951
1.19.11.2 Biosynthesis of Sesquiterpenes, Diterpenes 952
1.19.11.3 Squalene and Triterpenes 953
1.19.11.4 Nonmetal Hydrogenase-catalyzed Hydrogenation 956
1.19.11.5 Carbocations and Medicinal Chemistry 957
1.19.12 CARBOCATIONIC POLYMERIZATION OF ALKENES 960
1.19.13 TRICOORDINATE RADICALS (P. VOGEL, EPFL, LAUSANNE, SWITZERLAND) 960
1.19.13.1 General Features of Radical Formation 960
1.19.13.1.1 General literature survey 961
1.19.13.1.2 Historical background 962
1.19.13.2 Radical Initiators in Organic Chemistry 962
1.19.13.2.1 Thermal radical production 962
1.19.13.2.2 Photo-induced homolyses 964
1.19.13.2.3 Electrochemical generation of radicals 964
1.19.13.2.4 The reaction of dioxygen with organometallics 966
1.19.13.2.5 Single-electron chemical reductions 967
1.19.13.2.6 Single-electron chemical oxidations 969
1.19.13.2.7 Photoinduced electron transfer for the generation of radicals 971
1.19.13.2.8 The radical-polar crossover reaction 971
1.19.13.3 Reactions of Radicals 973
1.19.13.3.1 Rate constants for abstractions 973
1.19.13.3.2 Intermolecular addition reactions of radicals 974
1.19.13.3.3 Enhancement of alkene electron affinity by coordination with a Lewis acid 978
1.19.13.3.4 Abstraction of hydrogen from aldehydes: the hydroacylation of alkenes 980
1.19.13.3.5 Intermolecular radical additions to hetero double bonds 981
1.19.13.4 Radical Isomerizations 988
1.19.13.4.1 Five-membered versus six-membered ring formation 988
1.19.13.4.2 4-exo and 5-endo cyclizations 991
1.19.13.4.3 n-exo and endo cyclizations 992
1.19.13.4.4 3-exo-Cyclization: Homoallyl/cyclopropylmethyl Isomerization 993
1.19.13.4.5 Ring expansions 995
1.19.13.4.6 Ring contractions 995
1.19.13.4.7 Cascade radical cyclizations 996
1.19.13.4.8 Radical fragmentation 999
1.19.13.4.9 Radical polymerization 1002
1.19.1 TRICOORDINATE CARBANIONS (P. PALE, UNIVERSITY DE LOUIS PASTEUR)
1.19.1.1 General Aspects

In COFGT (1995), this section was mainly devoted to proton abstraction. Although deprotona-
tion is a useful method, it requires rather harsh conditions and has a relative lack of selectivity.
The increasing selectivity requirements in organic synthesis due to the increasing complexity of
targets have promoted the development of more selective and milder access to carbanions. Since
most organic syntheses deal with bioactive compounds, chirality and its control have also become
Tricoordinate Carbanions, Cations, and Radicals 891
very important issues. For these reasons, this section will emphasize selective carbanion formation
and when possible, stereoselectivity control.
1.19.1.2 Literature Survey

Since COFGT (1995), several reviews dealing with the formation and reactivity of carbanions
have been published. The selective preparation of organolithiums and some of their selective
reactions have been recently collected by Clayden <B-2002MI001>. Another book deals with the
structures and mechanisms associated with carbanions <B-2003MI002>. The formation of allylic
carbanions and the regioselectivity of their reactions have been reviewed <B-1996MI003>. The
formation and stability of carbanions in water have been addressed <2001ACR981>.
Asymmetric reactions using carbanions have been reviewed <1999MI1121>. Enantiocontrol in
carbanion formation and reaction have been detailed <1997AG(E)2282> as well as enantiomeri-
cally enriched carbanions <2002AG(E)716, 2002JOMC149>.
Some reactions of carbanions have also been reviewed, such as electrophilic aliphatic substitu-
tions <2003MI349>, reactions with carbon tetrahalides <1999OPP359> and with electrophilic
amino reagents <2000EJO1281>.
1.19.1.3 Carbanions and Organometallic Species

Although carbanions can be produced by a large variety of methods, their formation generally
implies a metal counter-ion, except for a few methods in which the counter-ion is different from a
metal, usually an ammonium ion.
Carbanions and organometallic species exhibit nucleophilic and basic properties, which render
them useful intermediates for organic synthesis. One property can be increased relative to the other
by changing the solvent, the counter-ion, and the temperature. However, organometallics offer a
further element of control, which is the nature of the metal and of its ligands. Depending on the
nature of the metal and its oxidation state, the carbon–metal bond can vary from ionic to polar or
apolar covalent, and cluster formation can occur. The reactivity obviously varies according to these
phenomena. Moreover, the metal ligands other than carbon ligands can strongly influence the
electronic properties of the metal, which in turn alter the property of the carbon–metal bond and
thus affect the reactivity. In the last decades, an impressive amount of work has been devoted to the
formation and use of carbanions having metals other than Li, Mg, and Zn as counter-ions.
1.19.2 CARBANIONS BY PROTON LOSS
1.19.2.1 Deprotonation: General Aspects

The formation of carbanions by proton abstraction has been extensively described in COFGT
(1995) and no significant improvement has been made in this area.
Nevertheless, it is worth noting that high regioselectivity can be achieved if deprotonation can be
directed by the coordinating and chelating groups. This process, initially developed for aromatic
compounds, is often referred as orthometallation <1990CRV879> or lateral lithiation <1995OR1>.
It is also worth mentioning the development of stereoselective deprotonations, which can be
either diastereo- or enantioselective <1997AG(E)2282, B-2002MI001>. New chiral enolates have
been produced, allowing the efficient formation of any aldol stereoisomer.
1.19.2.2 Directed Deprotonation

The presence of a Lewis base heteroatom in a molecular structure at an appropriate distance from
a proton can facilitate the abstraction by a two-step process if the deprotonating reagent is an
organometal. At first, the heteroatom will coordinate the organometallic base, usually an organo-
lithium, and this induces a change in the cluster structure of the base and therefore its reactivity
(steps 1–2, Scheme 1). Upon coordination, the deprotonation becomes entropically favored
and thus kinetically fast due to the proximity of the proton and the base. Secondly, once formed,
the new organometallic species is stabilized by chelation, which thermodynamically favors its
formation (step 3, Scheme 1).
R' R' R'

R' (BuLi)m n
R n R n R
R n
Z Z Z + Bu-H
Z
:
:
:
H
:
H H Li
(LiBu)m' Li
Bu
Scheme 1
It is worth noting that the same process is operative for enolate formation by amide bases and is
responsible for the highly organized transition state, which allows the stereoselective formation of
either Z- or E-enolates <1995COFGT869> and subsequent stereoselective reactions (Equation (1)).
R1 R1
R1
R2NM R 2 R3 R3
R2 R3 H R2NH + R2 ð1Þ
H
R2N O O
O
M M
Numerous synthetic applications benefit from this process. Applied to 2-methyl oxazoles, this
method allows a convenient access to marine natural products containing 2,4-disubstituted
oxazoles <1999OL87> such as phorboxazole B <2000JA10033> (Equation (2)).
i. Et2NLi
N OTES N OTES
THF, –78 °C Phorboxazole B
OTBDMS OTBDMS
O Ph OH O ð2Þ
ii. Ph(CH2)2CHO
73%
An efficient synthesis of substituted indoles has been achieved using directed metallation as the
key step <1990SL207> (Equation (3)).
F F Li F
H i. BusLi ii. Me2NCHO
N OBut N OBut N OBut ð3Þ
THF iii. Aq. HCl
O –40 °C OLi 86% O
1.19.2.3 Stereoselectivity Issues
1.19.2.3.1 Diastereo- and enantioselective deprotonation

Enantioselective syntheses with lithium–sparteine carbanion pairs have been achieved and have been
reviewed <1997AG(E)2282>. Racemic benzylic carbanions produced by directed deprotonation can,
in the presence of ()-sparteine, give products with high enantioselectivity upon alkylation. The
enantioselectivity as well as the sense of induction are strongly related to the nature of the electrophile
<1994JA9755>. Atropoisomerism of the lithiated intermediate can actually control such stereose-
lectivity <1997TL2561>. Atroposelectivity was then developed as a new tool for stereocontrol and
was used inter alia in diastereoselective deprotonation (Equation (4)) <1997TL2561>, desymmetriza-
tion (Equation (5)) <2001JCS(P1)371>, and dynamic resolution <2000ACR715>.
Pr2i N Pr2i N
O NPr2i O
Li H OE H
i. BusLi ii. E + ð4Þ

THF >90%
–78 °C dr > 97/3
E + = TMSCl, Etl, CD3OD, R2CO
O NPr2i NPr2i
O
i. Ph N Ph
TMS
Li ð5Þ
THF, –78 °C
ii. TMSCl
55% 89% ee
1.19.2.3.2 Chiral enolates

Enolate formations were well described in COFGT (1995) <1995COFGT869>, and no significant
advances can be noticed in this area. However, concerning their applications, some improvements
have since been made, especially in stereoselective aldolizations. Two major advances were
enantioselective aldolization by the Crimmins’ and Evans’ groups, while direct catalytic asym-
metric aldolizations were developed using Shibasaki-type catalysts or amino acids. The latter
aspects have been reviewed <2002EJO1595>.
With enolates bearing a chiral auxiliary group, Crimmins and co-workers demonstrated that
enantioselectivity can be reversed by using more coordinating auxiliaries together with an appro-
priate metal <1997JA7883>. Oxazolidinethiones give rise to a highly organized transition state, the
sulfur atom being coordinated to titanium (Scheme 2, top), as compared to the now classical Evans
oxazolidinones, which leads to a Zimmerman–Traxler transition state (Scheme 2, bottom).
O
Bn S Cl S O OH
N Cl
TiCl4 R' O Ti O N R'
DIPEA O Cl
R
X O
R'CHO R Bn
R X=S
O N
O
– O Bn O O OH
Bn B N
O N R'
R'CHO MLn
O R
X=O O
R' Bn
R
Scheme 2
Further research showed that, everything being equal, the nature of the base alone can reverse
the enantioface selection <2001JOC894>. Indeed, using 2 equiv. of a double-coordinating base,
such as tetramethylethylenediamine (TMEDA) or sparteine, completes the titanium coordination
sphere and thus avoids further coordination of the chiral auxiliary, preventing the formation of
the highly coordinated transition state (Scheme 3).
S
S O OH
Bn S Cl
TiCl4 N Cl S N R'
DIPEA R' O Ti
CH2Cl2 O Cl R
Bn
S O R'CHO R
R
S N
TiCl4 S S O OH
Bn Bn
CH2Cl2 S
N S N R'
N N
N N 2 equiv. Ti N R
O
O N Bn
R'CHO R'
N N = TMEDA, sparteine R
Scheme 3
Similarly, Evans showed that each enantiomer of anti-aldol adducts can be obtained
from optically pure N-acyloxazolidinones (Equation (6)) <2002JA392> or thiazolidinethiones
(Equation (7)) <2002OL1127> in the presence of magnesium salt. Only catalytic amounts of
Mg2+ are required for these general reactions.
O O PhCHO O O OTMS
NEt3 , TMSCl
O N Ph O N Ph
MgCl2 (10 mol.%) ð6Þ
AcOEt, 23 °C Ph
Bn Bn
91%
26:1 dr
S O 4-MeC6H4CHO S O OTMS
NEt3, TMSCl
S N S N
MgBr2 (10 mol.%) ð7Þ
Bn AcOEt, 23 °C Bn
92% 19:1 dr
All aldol stereoisomers are thus now available with high enantioselectivity through one of these
methods.
1.19.3 CARBANIONS BY SCISSION OF CC OR CX BONDS
1.19.3.1 General Considerations

Carbanion formations by scission of CC, CO, and CN bonds were well described in
COFGT (1995) <1995COFGT883> and no significant advance has been made in this area.
However, in the last decade carbanions have been produced through the rupture of carbon–
halogen and carbon–chalcogen bonds, mainly due to the development of organometallics derived
from transition metals. Three main processes were used to achieve carbanion formation by
scission of carbon–halogen bonds and are discussed below.
1.19.3.2 Oxidative Addition

Organohalides and related compounds act as oxidants toward metals, usually in a low oxidation
state. The resulting compounds correspond to a formal addition of the oxidant to the metal,
although such oxidative addition processes can be explained by three mechanisms
<B-2000MI003>.
Oxidative addition encompasses several well-known formations of metallic carbanions, such as
Grignard and organozinc reagents (Scheme 4), as well as the Reformatsky and Simmons–Smith
reactions (Scheme 5), but this process is more general and is the major entry to organometallics
derived from transition metals <B-2000MI004>.
R X + Mg(0) R Mg(II)X
R X + Zn(0) R Zn(II)X
Scheme 4
O O OZnBr O
Zn(0) E+
EtO Br EtO ZnBr EtO EtO E
Scheme 5
Oxidative addition sometimes fails, the bulk metal (powder, turning, etc.) being unable to react
with some organohalides. To overcome this problem, Rieke developed highly reactive forms of
magnesium and zinc, often written Mg* and Zn*, <1997T1925> and hundreds of Rieke orga-
nomagnesiums and organozincs are now commercially available.
Zinc insertion into halides has gained interest in carbohydrate chemistry and in organic
synthesis since fragmentation of the intermediate organozinc reagents derived from halocarbohy-
drates leads to enantiopure synthons, such as in Paquette’s approach toward Taxol (Scheme 6)
<1995JOC7849, 1995JOC7857>.
I IZn
OMe OMe O O
O O
D-Ribose Zn
MeOH H
O O 82% O O O
OMOM
O
R OPG'
Taxol
HO X
I O OPMB OTBDMS
OEt IZn OEt OPG
O O
Zn H
O O O
MeOH
PMBO O
O 95% PMBO O
Scheme 6
1.19.3.3 Halogen–Metal Exchange and Related Processes
1.19.3.3.1 General aspects

Two processes account for the formal substitution of halogen by metal: reduction of organo-
halides by metals or low-valent transition metals or lanthanide compounds, and organohalide–
organometallic equilibria (halogen–metal exchanges sensu stricto). The reduction of halides can
either be direct or mediated by arenes. A few atoms other than halogen can also be substituted by
a metal (see also Chapter 1.01).
1.19.3.3.2 Direct reduction of organohalides

Simple organolithium reagents are obtained by treatment of organohalides by lithium metal
through two successive single-electron transfer (SET) processes. Several other metals, such as, Na,
Sn, Sm, and In, behave in the same way. The formation of organochromium and organosamarium
species proceeds similarly by addition of the corresponding divalent salt to the halide (Scheme 7).
R X + 2 Li(0) R Li(I) + LiX
R X + 2 Cr(II)Cl2 R Cr(III)Cl2 + CrCl2X X = Cl, Br, I

R X + 2 Sm(II)L2 R Sm(III)L2 + SmL2X L = I, Cp, OTf
Scheme 7
Organochromium compounds, usually obtained from the commercially available chromous

chloride, behave as mild and selective carbanions. Their applications in organic synthesis are
thus growing and have been reviewed <1999S1, 1999CR991>.
Organosamarium species exhibit more complex reactivity with a dual pattern typical of carba-
nions and radicals. Their instability has precluded the development of synthetic applications other
than radical reactions until recently, where new methods for their preparation improved their
stability and reactivity as carbanions <1997TL6585>. Homoenolates can be obtained from
3-halo esters and added to ketones yielding lactones (Scheme 8) <1990JOC1628>. Interestingly,
dynamic kinetic resolution has been achieved by protonation of samarium propargylic carbanions
with chiral proton sources (Scheme 9) <2001T889,>.
O
O Sm O O Ph
cat. I2 Ph O
EtO Br EtO SmI2 71%
THF, rt
Scheme 8
O
Sm(III)Ln CO2Me H
SmI2 H
OPO(OEt)2 R CO2Me R Sm(III)Ln O
cat. Pd(PPh3)4 OH CO2Me
Sm(III)Ln
THF, rt 68%
CO2Me
10 min R 95% ee
CO2Me
Scheme 9
1.19.3.3.3 Reduction of organohalides mediated by arenes

The direct reaction of lithium metal with complex substrates is difficult and usually nonselective,
leading to complex mixtures and side-products. However, lithium–arene reagents or arene cata-
lysts have allowed a wider range of organolithiums to be prepared by reduction not only of
halides but also of sulfides and various ethers (Scheme 10).
M(0) R X M(0) E+
+ R R M(I) R E
R' R' – + R'
M
Scheme 10
Naphthalene <Np> was first used with sodium or lithium <1974CR243> but to solve some
reactivity and selectivity problems other arenes have been proposed and 4,40 -di-t-butylbiphenyl
(DTBB) and 1-dimethylaminonaphthalene (DMAN) emerged to be the most efficient reagents
(Figure 1) <1996CSR155>. DTBB reacts with lithium to give a blue-violet solution, acting as colored
indicator, and reacts rapidly even at very low temperatures (down to 100 C), especially with alkyl
halides. DMAN in turn gave a greenish solution but its radical-anion decomposed at 45 C. Its
major advantage lies in its amino group, which facilitates reaction work-up through acidic treatment.
NMe2
DTBB DMAN
Figure 1 Arenes used for the lithiation of organohalides.
It has been shown that a catalytic amount of arenes can be used in most cases <1991CC398>.
Either used in stoichiometric or catalytic amount, these reagents exhibit a similar reactivity
pattern. This reactivity follows the stability order of the intermediate radicals: alkyl halides
react faster (tertiary > secondary > primary alkyl) than alkenyl halides, which react faster than
aryl halides <1989ACR152>. The catalytic version proved to be a very useful method to prepare
functionalized organolithiums. Indeed, amido, amino, and acetal groups are compatible with this
reductive lithiation, but ethers and thioethers (sulfides) are not, since CO and CS bonds can
also be reductively cleaved in these conditions <1987AG(E)9727>. Nevertheless, such cleavages
can be another useful entry to organolithiums, as exemplified by the reaction of chiral epoxides
<1995TA1907> and even aziridines <1994JOC3210> (Scheme 11). The generation of carbanions
by reductive cleavage of alkoxy-substituted aromatic compounds has been reviewed
<1997MI55>.
OLi OH OH OH OH
O Li, THF PhCHO
OMOM Li OMOM OMOM + OMOM
69% Ph Ph
DTBB (5 mol.%)
1:1
–78 °C
Scheme 11
1.19.3.3.4 Organohalide–organometallic equilibria

The treatment of organohalides by organolithiums promotes a metathesis reaction. This reaction,
however, is in equilibrium since the nature of the compounds is the same before and after the
reaction (Equation (8)).
R X + R' Li R Li + R' X ð8Þ
The equilibrium is driven by the stability of the newly formed organolithium and, indeed, the
following reactivity order has been observed with regard to the starting halide: Csp2–X Csp2–
X > Csp3–X, and for alkyl halides: primary > secondary > tertiary (Equation (9)).
Br Br
MeLi
ð9Þ
THF
Br Li
–80 °C
The equilibrium can also be shifted if one of the newly formed species is trapped in situ. This is
usually achieved by using 2 equiv. of ButLi as reagent. Upon exchange, t-butyl halide is formed, which
is converted into i-butene and lithium halide by the second equivalent of ButLi (Scheme 12).
ButLi
R X + ButLi R Li + X + LiX
Scheme 12
A synthesis of (+)-herboxidiene A relies on such halogen–lithium exchange and on several

directed deprotonations (Scheme 13) <1996S652>.
I ButLi Li O
Et2O O
TESO TESO
Pentane MeO
–80 °C COOH
Herboxidiene A
OH
Scheme 13
Although it is still a matter of debate <1988JOM1>, the reaction mechanism probably involves
an ‘‘ate’’ complex. Such intermediates have indeed been detected in situ by NMR spectroscopy
<1989JA3444, 1998JA7201> and even isolated <1986JA2449>. Recent calculations support the
‘‘ate’’ mechanism <1998EJO1851>. However, a radical pathway is sometimes preferred, espe-
cially with alkyl bromides <1987JOC1291>. Nevertheless, the ‘‘ate’’ mechanism nicely explains
the reactivity order observed for halide exchange (I > Br >> Cl) since the larger and less electro-
negative atoms would better accommodate valence extension.
Usually performed at very low temperature (120 C, 80 C) and in ethereal solvents
(ether > THF), the lithium–halide exchange tolerates a wide range of functional groups. At
very low temperatures, lithium–halide exchanges are still fast, while other competitive reactions,
such as deprotonation, Wurtz coupling, are suppressed. Even nucleophilic addition does not
occur and thus lithium–halide exchanges can be performed in the presence of ketones, epoxides,
and related functional groups (Scheme 14) <1984TL4323>.
OH
BusLi 3h
X Li OH +
O Et2O O –78 °C
Hexanes 20%
X = Br 19:1
–78 °C 60%
X=I 21:1
Scheme 14
Moreover, this process is usually stereospecific and thus allows for stereoselective synthesis, as
shown in Equations (10) and (11) <1975TL3685>.
O
OH
Br OMe Li OMe H ð10Þ
ButLi OMe
Et2O 100%
–78 °C
O
( )5 OH
Br Li ( )5
ButLi H ð11Þ
Et2O OMe 85%
OMe OMe
–78 °C
Recently, iodine–magnesium exchanges have been reported and applied to a wide variety of
polyfunctionalized compounds. For example, the first functionalized cyclopropylmagnesium
reagent has been obtained through this exchange and trapped with various electrophiles
(Equation (12)) <2002AG(E)351, 2000CEJ767>. This exchange also proceeds through an ‘‘ate’’
complex as demonstrated by detection of such an intermediate <1998AG(E)824>; however, and
unexpectedly, the rearrangement of the ‘‘ate’’ complex could involve radicals depending on the
nature of the electrophile <2003OL313>.
O
ClMg OMe O
I COOMe PriMgCl PhCHO Ph O ð12Þ
THF 90%
–40 °C
Iodine–zinc exchanges have also been reported (Equation (13)) <1993TL7911, 1993JA7027>.
EtOOC
ZnEt2 COOEt
ZnLn
cat. Pd(PPh3)4 Br
NC I THF, rt, 2 h NC CuCN.2LiCl

83% NC
ð13Þ
1.19.3.3.5 Organometalloid–organolithium exchange

Organic compounds bearing a chalcogen or a main group metal atom from the third, fourth, or
fifth row react with organolithiums yielding new organolithiums. Due to its similarity to the
process discussed above, this reaction is often referred to as the lithium–metalloid exchange.
Mechanisms involve ‘‘ate’’ complexes <2002HCA3748, 1998EJO1851>. Organic selenides, tell-
urides, and tin have mostly been used.
This process is gaining importance in organic synthesis as a mild and efficient alternative to
halogen–lithium exchanges. Moreover, the conversion of CSn to CLi bonds by SnLi
exchange is now one of the most important general methods of making configurationally
defined organolithiums. It has, for example, been applied in carbohydrate chemistry
<1997TL1903> and in the synthesis of the polycyclopropane antibiotic FR-900848 (Scheme 15)
<1996JA6096>.
Li OTBDPS
Bu3Sn BusLi [Cu(l)(PBu3)]4
OTBDPS THF OTBDPS O2 TBDPSO
–40 °C
i. ButLi
OTBDPS Br
ii. [Cu(I)(PBu3)]4 TBDPSO
TBDPSO
O2
Scheme 15
A lack of stereospecificity has nevertheless been observed in the case of atropoisomeric

naphthamides, as seen from the comparison of Equations (14) and (15) <2001JA12449>.
Pr2i N Pr2i N
SnMe3 i. BusLi
H THF, –78 °C Et H
O O
ii. EtI ð14Þ
89%
97:3 dr
Pr2i N
Pr2i N i. BusLi Et H
O
H SnMe3 THF, –78 °C
O ð15Þ
ii. EtI
77%
91:9 dr
1.19.4 CARBANIONS BY ADDITION TO C¼C BONDS
1.19.4.1 General Aspects

These additions have been well described in COFGT (1995) <1995COFGT888>; nevertheless,
some aspects deserve to be discussed further, such as the catalytic and asymmetric versions of
Michael additions and the Baylis–Hillman reaction. Other processes such as carbo- and hydro-
metallations are gaining interest.
1.19.4.2 Addition to Enones and Related Compounds
1.19.4.2.1 1,4-Additions (Michael-type reactions)

1,4-Addition to an alkene or alkyne conjugate with a -accepting group leads to the formation of
a stabilized carbanion, which can be trapped by electrophiles. The conjugate addition of
carbanions to ,-unsaturated carbonyl compounds is a powerful strategy for CC bond
formation and their numerous applications to synthesis are well known <B-1992MI005>. One
of the most illustrative applications is probably the three-component prostaglandin synthesis
described by Noyori <1984AC(E)847>, which has been scaled up for industrial production
<1992TL6393> (Scheme 16).
O HO COOMe
3
OHC (CH2)3COOMe PGE2
BF3.OEt2 C5H11 PGF2α
O LnCu C5H11 O-M TBDMSO
83% OP'
P'O
THF, –78 °C C5H11
TBDMSO TBDMSO 70% O OH
OP'
COOMe
P' = TBDMS, THP OHC (CH2)5COOMe 5 PGE1
C5H11 PGF1α
TBDMSO
OP'
Scheme 16
A large number of stoichiometric reagents are known to induce high stereocontrol in 1,4-
additions <1992CR771, B-1992MI004> but chiral catalysts able to perform enantioselective
additions have now been discovered <2002JA13362, 2002JOC7244, 2000T2879, 2001JA4358,
2002JA5262, 2002JOC7244, 2003CR2829>.
A similar reaction has been developed starting from cyclopropanes bearing at least one
accepting group. Nucleophilic addition occurs and a stabilized carbanion is produced, which
can be quenched by various electrophiles (Scheme 17). The overall process offers a unique
three-carbon homologation <1985JOC2378>.
– E
Nu – E+
A
Nu A Nu A
R R R
Scheme 17
Even if useful, this process has not yet gained much interest in organic synthesis, but a three-
component reaction has nevertheless been developed (Equation (16)) <1983JA1052> as well as a
tandem opening-aldol reaction (Equation (17)) <2001T987>.
COOMe Br COOMe
SO2Ph
SO2Ph ButOK SO2Ph ð16Þ
O O SO2Ph
DMF, 90 °C
86%
O OH
O TiCl4 OTiLn MeCHO
Ph ð17Þ
Ph Bun4NI Ph I –78 °C
CH2Cl2, 0 °C 80% I
1.19.4.2.2 The Baylis–Hillman reaction

Although not recent, the Baylis–Hillman reaction is an interesting CC bond formation reaction
providing useful building blocks that have recently stimulated a lot of research <1997OR201,
2003CR811>. It is a base-catalyzed condensation of aldehydes with activated alkenes (Equation (18)).
R' OH
R'CHO A = COOR, COR, CHO, CN
A ð18Þ
NR3 NR3 = DABCO, Quinuclidine
A
Being quite slow with the tertiary amines normally used as catalysts, the reaction was recently
improved either by using tributylphosphine (Equation (19)) as catalyst at room temperature or by
cooling, which probably led to a better stabilization of the Z-enolate (Scheme 18) <1997JOC1521>.
COOMe OH Nu Time Yield

CHO
COOMe DABCO 10 days 84% ð19Þ
cat. Nu
PBu3 2 days 80%
– – O OH
O – O O O
O R'CHO –Nu
Nu + and/or R R'
R R Nu R R R'
+ +
Nu Nu
Scheme 18
Asymmetric versions have been developed and applied to total synthesis, as illustrated by the
synthesis of the immunosuppressive reagent ()-mycestericin E (Scheme 19) <2001CC2030>.
O
OH O
O O Cat* O O
OCH(CF3)2
CHO O CH(CF3)2
5 6 DMF, CH2Cl2 5 6
–85 °C
47% >97% ee
OH
O
Cat * = N
N O OH O
5
OH
6
H2N
OH
(–)-Mycestericin E
Scheme 19
1.19.4.3 Carbometallation
Organometallics can add across alkenes or alkynes in a highly stereo- and regioselective process
by Equation (20).
RMLn
MLn
ð20Þ
R
Since a new organometal is produced through this reaction, further addition is possible. What
could be a drawback turned out to be an advantage for making the so-called ‘‘living’’ polymers.
Organolithiums can add across alkenes in excess, yielding a new long-chain organolithium, which can
be trapped by another alkene to form a new elongated organolithium, which can react again. Such
successive trapping allows for formation of block-copolymers (Scheme 20) <B-1983MI006>.
R'
RLi n n p n Li
R Li R Li R
p
R'
Scheme 20
In organic synthesis <1991COS865, B-1998MI007>, carbometallations have been mostly

applied to alkynes due to the very high stereoselectivity. Nevertheless, interesting and useful
methods have been developed with alkenes, especially for ring formation and as an efficient
access to 1,1-bimetallic species, equivalent to dicarbanions <B-1998MI007>. Carbometallation
proceeds with syn-stereoselectivity, which can be nicely exemplified by Nakamura’s addition of
organocuprates to cyclopropenes (Scheme 21) <1990JA7428, 2000JA978>.
MeCuLn ECl
O O O O O O O O
THF +
–70 °C Me
Me CuLn Me E E
E = PhCO 76% >1:99

E = COOEt 80% >1:99
Scheme 21
In a series of papers, Normant demonstrated that compounds bearing an acidifying group

(A = alkyne, ester; Scheme 22) and an allyl group at the -position are easily cyclized after
deprotonation by organolithiums and treatment with zinc bromide. The cyclic organometallic
produced after carbometallation can then be trapped with various electrophiles, providing a very
efficient and highly diastereoselective synthesis of carbocycles <1996TL857> and heterocycles
<1995TL1263, 1997TL89>.
E
BusLi Li ZnBr2
Cy Cy
N TMS
Et2O Cy N TMS then E + N TMS
Me –80 °C Me
Me
E=H 90%
E= 70%
Scheme 22
Carbometallation of metallated alkenes provides 1,1-bismetallic species, which can react suc-
cessively with different electrophiles, depending on the nature of the metal (Scheme 23). The
formation and reactivity of 1,1-bismetallic species have been reviewed <1996CR3241>.
High diastereoselectivity can be achieved if chelation can organize the first intermediate. Using
chiral auxiliaries, Normant and co-workers were able to obtain chiral adducts with excellent
enantioselectivity (er >95:5) (Scheme 24) <1998TL4821>.
+
R R'M2Ln R M2Ln E1
+ R M2Ln E2 R E2
M1Ln R' M1Ln R' E1 R E1
Scheme 23
H Ph
H Ph
Ph ButLi N + O
I N H
N 2 equiv. MgBr N Ph H3O
H N Ph H
N Ph Et2O ZnBr2 70%
Li
Li >90% ee
LnZn
Scheme 24
The synthetic potential of alkene carbometallation has promoted the development of enantio-
selective versions, which has been reviewed <1999JCS(P1)535>.
1.19.4.4 Hydrometallation
In a process similar to carbometallation, compounds carrying a hydrogen–metal bond can stereo-
and regioselectively add to alkenes and alkynes (Equation (21)). As with carbometallation, this
process offers a direct entry to organometallics without prior deprotonation or lithiation; however
only a few stable reagents are able to stereoselectively add across unsaturated CC bonds.
Among them, organoboranes such as disiamylborane and catecholborane, DIBAL-H, and the
Schwartz’s reagent are the most useful (Figure 2).
R +
HMLn E R
R ð21Þ
H MLn H E
O
BH BH AlH Zr Cl
H
2 O 2
Disiamylborane Catecholborane DIBAl-H Schwartz’s reagent
Figure 2 Common reagents for hydrometallation.
Hydroboration of alkenes produces organoboranes with high regioselectivity, but the latter
cannot be considered as carbanions due to the low polarization of the CB bond. However,
upon activation by a Lewis base, some carbanionic character is observed in the presence of
electrophiles <B-2001MI008>. Organoborons have gained significant importance with the
emergence of the Suzuki reaction <1995CR2457>. This palladium-catalyzed cross-coupling
reaction allows for very mild CC bond formation without the requirement of basic and highly
reactive organometallics. In palladium-catalyzed cross-coupling, a nucleophilic organometallic
formally displaces an electrophilic vinyl or aryl halides. In Suzuki coupling, the nucleophile is
an organoborane; but, as for other organoborane reactions, it must be activated. This is usually
realized by running the reaction in the presence of mild bases, such as hydroxides, alkoxides, or
carbonates, which play a critical role in the reaction mechanism <1998JOC458, 1998JOC461>.
Under these mild conditions, sensitive systems such as carbapenems can be alkylated (Scheme
25) <1997T539>.
Hydrozirconation is of increasing importance in organic synthesis, providing a convenient entry
to organometallic species without using strongly basic organolithiums. The reaction is compatible
with various functional groups such as ethers, silyls, and some esters. Moreover, the huge volume
occupied by the zirconocene moiety ensures a very high regioselectivity upon addition of Schwartz’s
reagent. For example, a single organozirconium is obtained after treatment of a regio- and stereo-
isomeric mixture of alkenes by Schwartz’s reagent. Successive hydrozirconations and -eliminations
lead to isomerization of the less bulky organometallic (Scheme 26). The formation and the organic
chemistry of organozirconium reagents have been reviewed <1996T12854>.
TESO TESO
H H H H NHCO2PMB
9-BBN NHCO2PMB
OTf
N 2 M NaOH, PdCl2(dppf) N
O O
CO2PMB THF CO2PMB
64%
Scheme 25
Zr Cl
H +
E E
(Cl)Cp2Zr
Scheme 26
1.19.5 CARBANIONS BY METAL–METAL EXCHANGE
1.19.5.1 General Aspects of Transmetallation: Tuning the Reactivity

Once produced, the metallic part of a carbanion can be modified by a transmetallation reaction,
where a preformed organometallic is treated by a salt or a complex of another metal. This
treatment leads to an equilibrium (Equation (22)), which is shifted according to the stability of
the newly produced compounds.
RM1Ln + M2Xm RM2Ln' + M1Xm' ð22Þ
For example, going from a main group organometallic to a transition metal derivative can
increase carbon–metal bonding due to overlap with d-orbitals.
Transmetallation is often used to modulate carbanion reactivity. Indeed, organolithiums,
organomagnesiums, and some other organometallics are strongly basic entities; they can also
lead to electron transfer. These basic or redox properties obviously compete with the nucleophilic
character, useful for CC bond formation. Changing the metal nature can minimize properties
other than nucleophilicity, and some reactivity and selectivity problems have thus been solved.
Organocopper derivatives are probably the best-known example: they are commonly prepared
from organolithiums, organomagnesiums, or organozincs and exhibit high nucleophilicity without
the basicity of their progenitors <B-1999MI009>.
Organoceriums exhibit an even lower basicity, being, for example, able to add to the ketone of
-ketoesters without deprotonating them despite their high acidity <1989H703>. En route to
batrachotoxin, Kishi and co-workers were unable to displace Weinreb amides with organolithium
reagents. But transmetallation with CeCl3 overcame these difficulties and offered a mild and
direct method for the formation of saturated and ,-saturated ketones from tertiary amides
(Scheme 27) <1998TL4793>.
Alternatively, some carbanions are not reactive enough; transmetallation to a more reactive
organometallic can solve this problem. As mentioned above, hydrozirconation provides a direct
and efficient way to prepare metallic carbanions. However, the carbanionic reactivity of organo-
zirconiums is not always high, but transmetallation affords a way to more nucleophilic reagents.
Treatment with copper or zinc derivatives furnishes the corresponding organocoppers
<B-1999MI009> or organozincs and even allows for asymmetric addition to aldehydes
<1998JOC6454>.
O O HO
NR2
CeCl3, THF, –78 °C H
H H
then MeLi
H H H H H H
MeO MeO MeO
NR2 MeCeCl2 Time Yield (%) Ketone/alcohol
N 3 equiv. 1h 40 100/0
N 3 equiv. 1h 40 100/0
3 equiv. 5 min 95 100/0

N O 100/0
10 equiv. 15 min 95
Scheme 27
Transmetallation also offers the opportunity to switch from one organometallic to another
having a larger coordination sphere in which chiral ligands can be introduced. This method has
become very fruitful in asymmetric synthesis, specially in allylation reactions <2003CR2763>.
For example, the very efficient Duthaler’s reagent <1992JA2321> has been applied to the
syntheses of various natural products including the C14–C25 fragment of (+)-discodermolide
(Scheme 28) <1992CR807, 2001OL3995, 2003OL3029>.
Ph Ph
Cp O O
Ti
O O OH OTBDMS
NaBH4
Ph Ph MeOH
OTBDMS OH
Et2O, –78 °C 54%

98% ee
O O TBDMSO OH
Ph Ph 58%
HO
Cp O
Ti O
O
O
Ph Ph
Scheme 28
1.19.5.2 Dicarbanions–Metallacycles
Transmetallation also affords an entry toward dicarbanionic reagents. Indeed, the behavior of
some titanium and zirconium organometallics allows for the formation of metallocycles, which
act as dicarbanions <B-2002MI010>.
1.19.5.2.1 Titanium dicarbanions (the Kulinkovich reaction)

A formal diethylene dianion is produced by mixing alkylmagnesium bromide with titanium
isopropoxide <1991S234, 1993MI55> or chlorotitanium triisopropoxide <1994JA9345>. After
transmetallation and -elimination, an organotitanium is formed which is best described as a
titanacyclopropane. The two CTi bonds of this species can successively add to esters giving
cis-1,2-disubstituted cyclopropanols (Scheme 29). This reaction, referred to as the Kulinkovich
reaction, is gaining interest due to its complete diastereoselectivity and the usefulness of
cyclopropane derivatives <2000CR2789>.
Br 2 Mg MgBr XTi(OPri)3 Ti(OPri)2 R

2 R 2R R Ti(OPri)2
2
THF –78 to 0 °C
O
Ti(OPri)2
HO H3O+ O OR2 O Ti(OPri)2 OR2
1
R1 R1 R
R1 R
R R
R2O
Scheme 29
This reaction has been extended to amides (Equation (23)) <1998TL7695> and to cyanides
(Equation (24)) <2002JOC3965, 2003JOC7133>. Enantioselective versions <1994JA9345,
2000OL1337> as well as intramolecular versions <1996JA291, 2003OL2137> have been developed.
MeTi(OPri)3
O THF, 0–5 °C
Bn2N
H NBn2 MgCl ð23Þ
cis/trans
>98:2
59%
MgCl R R
R
BnO CN
MeTi(OPri)3 BnO NH2 BnO NH2
Et2O rt ð24Þ
R = H 75% -
R = Et 61% 70:30 dr
R = Bn 64% 64:36 dr
1.19.5.2.2 Zirconium dicarbanions and the Dzhemilev reaction

Zirconium species allow the addition of Grignard reagents to unactivated alkenes. In stoichio-
metric reactions, a zirconacyclopentane is formed, which reacts as a dicarbanion with a few
electrophiles (H+ or D+, Br2 or I2, CO, O2) (Scheme 30 right, Scheme 31) <1991JA6266>.
If a catalytic amount of zirconium species is used, the intermediate zirconacyclopentane reacts
further with the starting Grignard reagent giving a new organomagnesium, which can be trapped
with various electrophiles (Scheme 30, left) <1985JOM43>. Known as the Dzhemilev reaction,
this process may look like a carbometallation; however, the mechanism proceeds through trans-
metallations, -elimination, and insertion as depicted in Scheme 30.
Cl2ZrCp2
MgBr ZrCp2 ZrCp2 R
THF, –78 °C 2
+ +
E E E
Cp2Zr
R E
R R R
E MgBr Cp2Zr EtMgBr
R
MgBr
Scheme 30
The intramolecular version of the stoichiometric reaction produces either carbocycles with a
predominant cis-stereoselectivity (Equation (25)) <1994ACR124> or heterocycles but with
trans-stereoselectivity (Equation (26)) <1995SL1237>.
D
D2SO4 D
EtMgCl (2 equiv.) 7
82%
Cl2ZrCp2 (1 equiv.) I
Cp2Zr I2
7
THF, –78 °C I
7
CO 7
then
HO
H3O+
7
Scheme 31
i. BunLi (2 equiv.)
Cl2ZrCp2 ð25Þ
+
ii. H3O
R i. BunLi (2 equiv.) Y X Yield

Cl2ZrCp2
R N O 49% ð26Þ
Et2O, rt CH O 76%
Y X + Y X
ii. H3O
In the Dzhemilev reaction, high diastereoselectivity is observed when a hydroxy or alkoxy

group is present next to the double bond. Moreover, either syn- or anti-adducts can be formed,
depending on the nature of the adjacent oxygenated group (Equation (27)). With chiral zirconium
catalysts, Hoveyda and co-workers were even able to get enantio-enriched adducts (Scheme 33)
<1996AG(E)1262, 1995JA2943>.
PGO OH PGO OH
OPG i. EtMgCl, Cl2ZrCp2
Et2O, rt 8
+
8
8 ð27Þ
ii. B(OMe)3, H2O2
PG = H 70% 95:5 dr
PG = MEM 53% 10:90 dr
i. MgBr
CuI, bpyr i. PCC
MeO THF, MeO MeO MeO
Br Cp2ZrCl2 CH2Cl2
Benzene, rt
MeO Br ii. ButLi MeO BunLi MeO
ii. KOH MeO
–78 °C EtOH, rt
THF, –78 °C OH
95%
OH iii. NaBH4
OH
iii. O MeOH
47% 56% OH
OH
AlCl3 AlCl3
(CH2Cl)2 (CH2Cl)2
OH OH
bpyr = 2, 2'-bipyridine
–30 °C 76% –30 °C
47%
MeO MeO
MeO MeO
OH HO
OH HO
(±)-Isogalbulin (±)-Galbulin
Scheme 32
These diastereo- and enantioselective reactions have been applied to total syntheses
<1996JA1028, 1996JA10926, 1997JOC3263, 1997JA10302, 1998TL6525, 2000JOC3236> as
exemplified in Schemes 32 and 33.
NTs
OH OMgCl OH
i. EtMgBr CuBr.Me2S
MgCl THF, rt NH2
cat. Cp2ZrCl2
ii. Na, NH3 i. DCC
Et2O, rt –50 °C 99% ee HOBt, THF
50%
ii. TBDMSOTf
lutidine
EtMgBr i. PrMgBr Br CH2Cl2
O
L*ZrL'* cat. Cp2ZrCl2 ClMg cat. NiCl2(PPh3)2 54%
O
THF OH THF, rt OMgCl ii. NMO, TPAP OH
99% ee
MeCN
L*ZrL'* = (S)-(EBTHI)Zr(BINOL) 47%
HO NH2 OTBDMS
O
OH O
O
O
HN
HN
Fluvirucin B1
Scheme 33
1.19.6 TRICOORDINATE CARBOCATIONS (P. VOGEL, EPFL, LAUSANNE,

SWITZERLAND)
Carbocations as stable species are found everywhere, from interstellar space to your glass of wine.
The color of red wine, as well as that of many flowers, fruits, and leaves, is due in part to the
anthocyanins. They intervene as reactive intermediates in a large number of reactions including in
living systems. Over 30 000 natural isoprenoids have been characterized. They play important
roles in stabilizing membranes, and in the construction of signal transduction networks, visual
pigments, antibiotics, etc. <B-1994MI11>. Various polycyclic isoprenoids are generated from
simple linear polyene substrates such as geranyl pyrophosphate, farnesyl pyrophosphate, and
geranylgeranyl pyrophosphate in processes that involve cationic intermediates.
The study of carbocations is not only relevant to the understanding of organic reactivity and
biochemistry, but it has also helped us to develop better models for the chemical bonding in
organic and organometallic compounds.
1.19.6.1 General Literature Survey

Between 1968 and 1976, a five-volume treatise edited by Olah and von R. Schleyer was published
<B-1968MI001, B-1970MI002, B-1972MI003, B-1973MI004, B-1976MI005>. Monographs have
been written by Bethell and Gold <B-1967MI006> and Vogel <B-1985MI007> and reviews have
been published <1973AG(E)173, 1973TS253, B-1974MI008, B-1974MI92, 1979TCC1,
1979TCC19, 1981MI211, 1981CS97, 1991CRV375, B-1990MI287>. For a review of carbocations
in super-acid solutions, see Olah et al. <B-1985MI009>.
Olah <2001JOC5943> described 100 years of carbocations and of their significance in chem-
istry. Reviews on thermodynamic stabilities of carbocations <2002APO57> and on interactions
between carbocations and anions in crystals have appeared <1998CRV1277>. A general reactiv-
ity scale for n-, -, and - nucleophiles <2003JA286> has been proposed by Mayr and
co-workers. Carbocation stability in water can be evaluated by their intrinsic barriers to their
reactions <2001ACR981>. Monofunctionalized C60 ions have been reviewed by Takeuchi
<2001BCJ785>. An overview on isoprenoid biosynthesis, which also implies carbocation inter-
mediates, has been presented by Cane <1999CONAP1>. Managing and manipulating carboca-
tions in biology has been illustrated by reviewing the structures of terpenoid cyclases and the
mechanisms of the reaction they catalyze <1998MI695>. Dicarbocations have also been reviewed
<1983AG(E)390, B-1987MI425, B-1990MI439, 1995JA12005, 1997JA3407>.
1.19.6.2 Historical Background

In 1899, Stieglitz raised the possibility of ionic hydrocarbon compounds while studying salts of
imido ethers. In 1901, Norris, as well as Kehrmann and Wentzel <1901CB3815>, independently
discovered that colorless triphenylmethyl alcohol gave deep yellow solutions in concentrated
H2SO4 (Equation (28)). Triphenylmethyl chloride similarly formed orange complexes with AlCl3
and SnCl2.
Ph3COH + 2H2SO4 Ph3C + H3O + 2HSO4 ð28Þ
Baeyer and co-workers <1902CB3013> in 1902 recognized the salt-like character of these
compounds. The same year, Gomberg <1902CB3914> noted that triphenylmethyl chloride
gives colorless solutions in ether and benzene, whereas deep yellow solutions are obtained with
SO2, CH3COCl, or SO2Cl2. Walden <1902CB2018> also contributed to the understanding of
the ionic character of dyes such as fuchsine, malachite green, methyl violet, and fluorescein
(Scheme 34).
Me Me
H 2N C NH2 H2N C NH2

2 2
Fuchsine
H 2N C Ph Me2N C
2 3
Malachite green Methyl violet
HO O OH HO O OH
O
COO
O
Fluorescein
Scheme 34
Hantzsch in 1908 demonstrated that the yellow solutions of triphenylcarbinol in H2SO4 conduct
electricity and established the existence of the equilibrium shown in Equation (28). The trityl cations
were considered an isolated curiosity of chemistry and their fleeting existence was doubted until
1922 when Meerwein found that the rate of the Wagner rearrangement of camphene hydrochloride
to isobornyl chloride (Equation (29) <1899CB2302>) increased with the dielectric constant of the
solvent <1922CB2500, 1927LA16>. Furthermore, he found that certain Lewis acids such as SbCl5,
SnCl4, AlCl3, and SbCl3, as well as dry HCl, which promote the ionization of triphenylmethyl
chloride by formation of carbocations <1921CB2573> also considerably accelerated the rearrange-
ment. Meerwein concluded the existence of cationic intermediates capable of undergoing skeletal
rearrangement, a concept that has become a milestone of physical organic chemistry. For a recent
study of the historic camphenyl cation, see <2001JOC7294>.
Cl Cl
Cl ð29Þ
Me Cl
Camphene Isobornyl
hydrochloride chloride
Analogs of trityl (triphenylmethyl) cation continue to be of interest today. For instance, Ito
and co-workers <1999JOC5815> have prepared tris[6-(dimethylamino)-1-azulenyl]methyl hex-
afluorophosphate 1, which is an extremely stable methyl cation in DMSO/H2O as its pKR+
value has been determined to be 24.3 0.3. The extreme stability of 1 is attributed to the dipolar
property of the azulene rings, in addition to the contribution of the mesomeric effect of the
three dimethylamino groups. Homochiral triarylcarbenium ions such as 2 have been prepared.
They have been used to induce asymmetric Mukaiyama aldol additions <1997JA11341>
(Scheme 35).
Me2N
R R
NMe2
PF6 X
X = OTf, ClO4, PF6, SbCl6

Me2N R'
R = Me, Et
1 2 R' = H, But
Scheme 35
During the 1930s, Ingold and Hughes carried out detailed kinetic and stereochemical investiga-
tions on nucleophilic substitution at saturated carbon and polar elimination reactions
<1933JJCS526>. Their work relating to unimolecular nucleophilic substitution and elimination,
called SN1 (Scheme 36) and E1 reactions, in which formation of carbocations is the slow rate-
determining step, laid the foundation for the role of electron-deficient carbocationic intermediates
in chemistry and biochemistry.
R R'
R' SN2 R
X + Nu: H Nu + HX
rate
R'' R''
Substrate Nucleophile
d[Substrate][Nucleophile]
Rate (SN2) = – (Usually inversion)
dt
R R' R
R R'
Nu: H
Nu + Nu
R' R"
R'' R''
d[Substrate]
Rate (SN1) = –
dt
(Racemization for simple cases, but retention or inversion can
also be observed with this mechanism)
Scheme 36
With the advent of mass spectrometry, the existence of carbocations in the gas phase was
proven and their reactions in the absence of solvent could be studied <B-1979MI010> and results
compared with predictions based on quantum calculations <B-1986MI011>. A decisive break-
through was realized by Olah with the direct observation by IR and NMR spectroscopy of alkyl
cations in solution. An earlier case was the observation of the decarbonylation of the complex of
pivaloyl fluoride with SbF5 that generates the long-lived t-butyl hexafluoroantimonate (Equation
(30)) <1962JA2733, 1963JA1328>.
–CO ð30Þ
Me3CCOF + SbF5 Me3CCO SbF6 Me3C SbF6
1.19.6.3 Carbenium and Carbonium Ion Nomenclature

Trivalent ions of type R3C+ may be regarded as being derived from carbenes by addition of a
proton or a sextet ionic species R+, and it is logical, therefore, to call them carbenium ions
<1972JA808, 1972JA6371, 1972JA7859>.
Examples are given as follows:
(i) CH3+ carbenium ion or methylenium ion (methyl cation)
(ii) CH3CH2+ methylcarbenium ion or ethylenium ion (ethyl cation)
(iii) Ph3C+ triphenylcarbenium ion or triphenylmethylenium ion (trityl cation)
(iv) R2NCH2+ N,N-dialkylaminocarbenium ion
The real ‘‘carbonium ions’’ are derivatives of a five-coordinated carbocation: CH5+. With respect
to the pentavalent carbocations, especially for the bridged structure of the 2-norbornyl cation
(Scheme 37), the terminology used was ‘‘nonclassical’’ carbonium ion <1951JA5009,
B-1965MI012>. As we shall see, they can be derived by formal complexation of a CH or a
CC bond with a proton or an electrophile. They are denoted by the prefixes H or C; for
instance:
CH4 + H CH5 Methonium ion

H
CH3 CH3 + H CH3 CH4 ≡ CH3CH2 H H-ethonium ion
H3C CH2 ≡ CH3 CH3 C-ethonium ion
H H
H H
H H H H H-cycloproponium ion
+ H ≡ (corner-protonated
cyclopropane)
H H H-cycloproponium ion
≡ (edge-protonated
cyclopropane)
+ H H ≡ H ≡ H
H H H
H-nortricyclonium ion
(corner-protonated
nortricyclane)
Scheme 37
Radical cations that are considered to be formed by addition of a proton to a trivalent radical
may be named as follows:
(a) by adding the word ‘‘cation’’ to the name of the neutral compound having the same
empirical formula, or
(b) by adding the suffix ‘‘yl’’ to the name of the cation, for example:
C2H6+ (a) ethane cation (b) ethaniumyl cation
C6H6+ (a) benzene cation (b) benzeniumyl cation
Me2S+ (a) dimethylsulfane cation (b) dimethylsulfoniumyl cation
Ph3N+ (a) triphenylamine cation (b) triphenylammoniumyl cation
1.19.7 CARBOCATIONS IN THE GAS PHASE
1.19.7.1 Methods for Generating and Investigating Ions in the Gas Phase
The direct heterolysis of a neutral molecule A–B is not a feasible process in the gas-phase, because
the standard heteropolar bond dissociation enthalpies, DH (R+/X), are much too high.
Although heterolysis can, in principle, occur at extreme temperatures, it must compete with the
much more favorable homolytic fragmentation. Thermal ionization is, therefore, not a practical
technique for generating carbocations in the gas phase.
Classical methods used for the gas phase generation of ions involve the ionization of a neutral
molecule and subsequent detection of molecular and/or fragment ions by the techniques of mass
spectrometry (MS) <B-1978MI013> including the ion cyclotron resonance (ICR) method
<1971ACR114, B-1976MI014>. For gaseous precursors, ionization is generally induced by
interaction with protons (photoionization mass spectrometry: PIMS) or electrons (EI: electron
ionization; e.g., Equations (31) and (32)). Chemical ionization (CI: e.g., Equation (33)) and fast
atom (Xe or Cs) bombardment (FAB; e.g., Equation (34)) are also extremely useful, especially for
the generation of ions with relatively high molecular masses.
hν
RX RX• + e ð31Þ
or e
hν
RX R + X• + e ð32Þ
or e
CH5 + RX CH4 + RXH ð33Þ
Xe(Ecin) + RX RX• + e + Xe ð34Þ
More recently <2001SCI2527> a technique called ‘‘heavy electron’’ photoelectron spectroscopy

has been applied to measure vibrational frequencies and rotational constants of CH3+. Methyl
chloride is excited by vacuum ultraviolet photons that lead to Rydberg states of CH3Cl. They
couple with the long-range ion-pair state. Dissociation of this state gives rise to momentum-
matched Cl and CH3+ products, either of which may be detected with velocity map imaging. For
a structureless atomic anion such as Cl, the kinetic energy release directly reflects the internal
energy levels in the cation, a situation similar to what occurs during photoionization spectroscopy
(PES) of radicals into carbenium ions (R + h ! R+ + e (energy)). In the case of the
photoionization of MeCl into Me+ + Cl, it is the chloride anion that plays the role of a
‘‘heavy electron’’ (Equation (35)).
Me–Cl hν (Me–Cl)* hν Me + Cl
ð35Þ
Rydberg state Kinetic energy
release
Ionization can also be generated by -decay of tritiated compounds. Labeled methyl cations are
formed by spontaneous radioactive -decay of tritium atom contained in CT4 giving CT3+ in
82% yield (Equation (36)) <1970APO79, 1977JA5477, 1979JA4276>.
β-decay 3He ð36Þ
CT4 CT3 + + e
Tritium, T2, generates 3HeT+ by -decay which is a powerful Brønstedt acid and for which a
heat of formation of 1339 kJ mol1 has been evaluated <1969JCP5426>. It can thus tritiate
gaseous organic compounds such as methane (Equation (37)) <1984JA37>.
3HeT + CH4 CH4T + 3He ð37Þ
In all these techniques, an ion is usually recognized according to its mass/charge ratio (m/z) and
its kinetic energy. In most cases, gas-phase ion structures are based on indirect observables, and
on their reactivity, i.e., their degradations into smaller ions and their reactions with neutral
molecules. The measurement of the kinetic energy release in a fragment ion <1979AG(E)451>
can be done, for example, by analysis of the metastable peaks due to ions having rate constants
for fragmentation appropriate for decomposition within the field-free region of the mass spectro-
meter <B-1978MI1115>. Depending on the type of instrument, ions with lifetime of 1011 to
103 s can be analyzed. More recently, infrared fingerprints of small gaseous cations such as
CH3+ <1999SCI135>, CH3+ <2001SCI2527>, and protonated benzene (cyclohexa-2,4-dien-1-yl
cation) <2003AG(E)2057> have been reported.
ICR spectrometry adds another dimension to ion analysis as it can store circulating ions in
reservoirs and cool them or warm them by ion–molecule interactions. Thus, relatively high
pressure and long residence time can be realized in these machines. This has allowed the
measurement of accurate thermodynamic data for all kinds of ion/molecule reactions. Quantum
calculations have proved extremely useful for the interpretation of the results obtained by mass
spectroscopy techniques as they deal with free, nonsolvated ions.
1.19.7.2 Gas-phase Thermochemical Data

The assignment of absolute proton affinities (PA(A)) and standard heats of formation of carbo-
cations (Hf (R+)) relies on the use of suitable reference standards. The latter are usually derived
from spectroscopic measurements of ionization energies or appearance energies. For carbenium
ion, Hf (R+) = Hf (R) + IE(R). They have been reviewed by McMahon <2001JM187>.
Examples of themochemical data are given in Tables 1 and 2.
Table 1 Thermochemical parameters for selected carbenium ions and related radicals in the gas phase, in
kJ mol1. DH (Rþ/H): hydride affinity = Hr (RH > R+ + H); H f (R+): standard heat of formation
of carbenium ion R+, Hf (R): standard heat of formation of radical R, Hf (RH): standard heat of
formation of RH, DH (R/H): heat of the homolytic dissociation: Hr(RH > R + H))
R+ DH (R+/H) Hf (R+)b Hf (R) Hf (RH) gas DH (R/H)
H+ 1673.6 1530.0 218.0 436.0
CH+ 1368.2 1619.2 595.8 392.9 418.4
CH2+ 1397.5 1397.5 389.1 145.6 460.2
CH3+ 1311.3 1093.3 145.6 74.5 438.1
CH2¼CH+ 1217.5 1125.5 265.3 52.3 431.0
CH3CH2+ 1129.7 903.7 117.2 784.5 418.8
HCCCH2+ 1133.9 1175.7 343.1 187.0 374.0
CH2¼CHCH2+ 1079.5 945.6 163.2 20.5 361.1
CH2¼C+CH3 1112.9 991.6 238.5 20.5 435.1
CH3CH2CH2+ 1117.1 882.8 100.4 103.8 423.0
CH3C+HCH3 1050.2 798.7 93.3 103.8 415.9
CH3CH2CH2CH2+ 1108.8 836.8 75.3 127.2 423.0
CH3CH2C+HCH3 1037.6 765.7 71.1 127.2 414.6
(CH3)2CHCH2+ 1108.8 828.4 66.9 135.6 418.8
(CH3)3C+ 974.9 698.7 46.0 135.6 398.3
CH2¼C(CH3)CH2+ 1037.6 882.8 121.3 16.7 355.6
+
CH3 1041.8 928.8 213.4 23.8 405.8
CH3C+HCH2CH3
CH3+ 1008.3 723.8 146.9
H2NCH2+ 912.1 744.8 159.0 23.0 400.0
NCCH2+ 1330.5 1262.7 246.9 73.6 389.1
O¼CH+ 1066.9 815.9 41.8 108.8 368.2
HOCH2+ 1062.7 719.6 25.9 200.8 393.7
CH3CO+ 937.2 631.8 25.1 166.1 359.8
(CH3O)CH2+ 1016.7 682.0 12.6 184.1 389.5
Ph+ 1200.8 1138.0 330.5 82.8 466.1
+ 1016.7 815.9 62.8 405.8

Table 1 (continued)

R+ +
DH (R /H ) Hf (R+)b Hf (R) Hf (RH) gas DH (R/H)
+ 966.5 811.7 170.3
+
949.8 774.0 37.7
+
1045.2 829.3 101.7 77.0 396.6
+ 947.7 702.9 105.9
+ 945.6 669.4 136.8
+ 951.9 656.9 154.8
+ 970.7 782.4 51.9
+ 941.4 719.6 82.0
+
978.2 700.8 401.7
+ 938.5 661.1 412.1
+ 1008.3 895.4 25.1 407.5
+ 962.3 824.2 4.2
+ 912.1 748.9 25.1
924.7 761.5 25.1

+
+
866.1 820.1 92.0
2C-CH3
+ 941.4 832.6 36.0 343.1
+ 1069.4 1054.4 129.7 338.9

Table 1 (continued)

R + +
DH (R /H ) Hf (R+)b Hf (R) Hf (RH) gas DH (R/H)
866.1 623.4 104.6

+
+ 811.7 849.4 246.9 182.8 282.0
PhCH2+ 979.1 891.2 50.2 368.2

PhC+HCH3 945.6 836.8 30.1
PhC+(CH3)2 920.5 786.6 4.2
Ph2C+CH3 899.6 893.7 133.9
FCH2+ 1211.7 838.1 233.9 431.4
F2CH+ 1187.8 595.8 452.3 422.6
F3C+ 1251.0 415.5 695.8 444.3
a
National Institute of Standards and Technology chemistry WebBook, NIDST Standard Reference Data-base Number 69, Mallard,
W. G.; Linstrom, P. G., Eds.; Gaithersburg, MD, 2000 (http://webbook.nist.gov.). b H f (H) = 143.1 kJ mol1 used.
c
H f (But+) = 678.2 2.5 kJ mol1 is obtained by photoionization coupled with MS;H f (But+) = 711 kJ mol1 by proton affinity of
isobutene.
Table 2 Proton affinities of compounds B, 1 atm 25 C, gas phase. Substituent effects on the relative
stability of cations BH+ given by PA(substituted B) – PA(unsubstituted B). Reference is PA(NH3) = 846.4
8 kJ mol1, Hf (H+) = 1,530 kJ mol1. Proton affinities are the heat of reactions BH+ > H++B
Substituent effects
CH2¼CH2 ! CH3CH2+ 672.0
CH3CH¼CH2 ! CH3C+HCH3 754.8 82.8
(CH3)2C¼CH2 ! (CH3)3C+ 809.6 137.7
+ CH
3
! 816.7 144.8
H
! + 866.5 194.6
PhCH¼CH2 ! PhC+HCH3 833.5 161.9

PhC(CH3)¼CH2 ! PhC+(CH3)2 858.6 186.6
! + 822.6 150.6
! + 836.8
! + 819.6 144.8
! + 866.1
(∆H°f:12)
Table 2 (continued)
Substituent effects
! + 843.5
(∆H°f :21)
! + 799.1
+
! 910.0
(∆H°f :46)
H H
(∆H°f : 73.5) ! + 939.3
! + 904.2
(∆H°f : –2)
(∆H°f: 18.1) ! + 844.3
(∆H°f : 11) ! 860.6 16.3

+
! 838.5
(∆H°f:18.1) +
! 845.6
(∆H°f : 10.8) +
! 869.9
(∆H°f : 11) +
! + 891.6
(∆H°f : 4)
! 881.2
+
(∆H°f : –3)
! + 887.0
(∆H°f : +48.3)
Table 2 (continued)
Substituent effects
! + 836.8
O¼CH2 ! HOCH2+ $ HO+¼CH2 730.5

O¼CH(CH3) ! HOC+H(CH3) $ HO+CH(CH3) 774.0 43.5
O¼C(CH3)2 ! HOC+(CH3)2 811.3 80.8
+
O¼C¼CH2 ! OCCH3 818.4
HCOOH ! HC+(OH)2 753.5
CH3COOH ! CH3C+(OH)2 789.5 36.0
CF3COOH ! CF3C+(OH)2 725.1 28.5
HCON(CH3)2 ! HC+(OH)[N(CH3)2] 877.8
CH3CON(CH3)2 ! CH3C+(OH)[N(CH3)2] 894.5 16.7
CH2¼NH ! CH2¼N+H2 846.4
+
C6H7 + H
PhH ! 774.0
H
PhCH3 ! C6H6CH3+ 801.2 27.2

PhF ! C6H6F+ 770.3 3.8
PhCl ! C6H6Cl+ 769.9 4.2
a a
see footnote of Table 1.
1.19.7.3 Examples of Carbenium Ions in the Gas Phase

Applying the new technique called ‘‘heavy electron’’ photoelectron spectroscopy, CH3+ has been
characterized by vibrational and rotational energy levels <2001SCI2527>. Among C3H7+
cations, isopropyl cation, i-Pr+, is the most stable isomer. In between lay the corner-protonated
cyclopropane, or H-cycloproponium ion as shown in Scheme 38 <1976JA6834>.
CH3
≡
H ≡ ≡ H ≡ H
H CH3 H
H H H H
∆H °f : 799 830 kJ mol–1 Corner-protonated
cyclopropane
∆H °f : 883 kJ mol–1
Scheme 38
Lifetime for c-C3H7+ in the gas phase is estimated to exceed 107 s. It isomerizes to i-Pr+.
H-Cycloproponium ion has been suggested to be an intermediate in the gaseous reaction of methyl
cation with ethylene <1981JM7> and as a possible product of the H2 loss from C-proponium ion
<1998JPC(A)10798>. The metastable dissociation of propane molecules from cluster ions of
C3H7+ with neat propane or Ar/propane gas has been ascribed to the ionization of c-C3H7+ core
to give i-Pr+ proceeding by way of a transient n-Pr+ <1995MI415>. All attempts to trap n-Pr+ in a
gas phase reaction have failed, suggesting that it rearranges into c-C3H7+ and i-Pr+ in less than
1010 s <1984JA3917>.
The protonation of cyclopropane by gaseous Brønsted acids such as H3+, D3+, CH5+, and
C2H5+ generates c-C3H7+, which isomerizes into i-Pr+ competitively by its reaction with benzene,
giving n-propylbenzene (Friedel–Crafts alkylation Equation (38)), whereas i-Pr+ reacts with
benzene given i-propylbenzene (Equation (39)). The relative abundance of these two products
varies with the nature of the Brønsted acid (the more energetic the protonation reaction of
cyclopropane, the more c-C3H7+ is isomerized into i-Pr+), the pressure (up to 1 atm), temperature
and the presence of additives in the gaseous systems. Isomerization of c-C3H7+ ! i-Pr+ requires
more than 108 s. The reaction of c-C3H7+ with benzene occurs within the lifetime estimated to
be ca. 1010 s.
H
B:
c-C3H7 + Ph ð38Þ
–BH+
H
B:
i-Pr + Ph
–BH+ ð39Þ
Wheland intermediate
Using deuterated acids, it could be demonstrated that complete hydrogen scrambling in

c-C3H7+ occurs during that short time, thus showing that the energy barrier for migration of
hydrogen around the protonated cyclopropane (Equation (40)) must be very low, in agreement
with quantum calculations <2001MI2916>.
H
D H Very fast D H D H
H etc.
H
H ð40Þ
H
Edge-protonated Corner-protonated
cyclopropane cyclopropane
Using adequate precursors and ionization techniques, thermal (ion without excess energy than
RT) s-butyl, s-Bu+, and t-butyl, t-Bu+, ions can be prepared. Although the isomerization s-Bu+ !
t-Bu+ is exothermic by 67 kJ mol1, a high activation energy retards this reaction and allows the
study of various reactions of these ions in the gas phase. Irrespective of their origins, both i-Bu+ and
t-Bu+ dissociate into methane and propen-2-yl cation (CH3C+¼CH2). Another minor fragmentation
process is the loss of ethylene with generation of ethyl cation (Figure 3), a cation that adopts the
structure of a -complex of ethylene and a proton in its most stable form. Quantum calculations
+16 H H +17 +4
≡
H
–1
+43 +92 +76
+ CH4 • + CH3• H
≡
H
≡
H ≡
H
H
+21
H H
H H ≡ + H2C CH2
H H
Figure 3
estimate the bridged pH+-ethenium ion to be 25–33 kJ mol1 more stable than the classical
ethyl cation structure <1995JA8476>. Quantum calculations also predict a bridged structure
for s-Bu+ of the type pH+-(E)-but-2-enium <1993JA259>. The mechanism of the fragmenta-
tion C4H7+ ! C2H5+ + CH2 = CH2 is calculated to involve the protonated cyclobutane,
which is 150 kJ mol1 higher in energy than t-Bu+. The primary n-Bu+ and isobutyl cation
are not energy minima.
Distinction between t-Bu+ and s-Bu+ can be realized by collision-induced dissociation (CID)
using O2 as target gas. This activates the loss of methyl radical from these ions. The kinetic energy
release when s-Bu+ is activated by O2 to lose CH3 is ca. 500 meV, whereas it amounts to ca. 90
meV when t-Bu+ is used. The resulting C3H6+ fragment has the propene-radical/cation structure
<1998JPC(A)6441>.
The structure of the C4H+ 7 ions in still under debate after five decades of extensive investiga-
tion. Based on experimental and theoretical studies, the current consensus is that C4H+ 7 exists as
rapidly equilibrating species of nearly equal stabilities that are the bisected cyclopropylmethyl
cation 3 and the symmetrical 1H-bicyclobutonium ion 4 as shown in Scheme 39. The barrier of 3
> 4 interconversion does not exceed few tenths of a kcal mol1 <1978JA8018, 1979JA5537,
1998JA7652> (Scheme 39).
H H
H
H H
H
H H
3 4 3'
3 4' 3'' 4''
Scheme 39
When 3 and 4 produced from cyclobutanol or cyclopropylmethanol were dispersed in the bulk
gas containing benzene or hexadeuterobenzene and H2O, irrespective of the source of the ion and
of the intermolecular or intramolecular nature of the Friedel–Crafts alkylation (Equation (41) and
(42)), the C4H7+ ions undergo equilibration before they are trapped. The equilibrium constant 3/4
is close to unity at 300 K and equilibration occurs within a time interval of 1010 s
<2001MI2024>.
In another study, cyclopropylmethyl cation 3 was generated by the loss of chlorine atom from
cyclopropyl chloride radical-cation or from homoallyl chloride radical-cation. Cyclobutyl chlor-
ide radical-cation generates bicyclobutonium ion 4 preferentially. Under dilute gas phase con-
ditions, it was found that the reactions of cations 3 and 4 with ethylene do not give the same
products. Whereas 4 reacted with multiple competing reaction pathways, 3 underwent a
cycloaddition with ethylene generating cyclopentylmethyl cation 5, as shown in Scheme 40
<2001JPO17>.
Cl
–Cl
Cl –Cl H
H
4
3
Cl –Cl CH2=CH2
Scheme 40
X
X
B
3, 4 + C6X6 X Ar (41)
–BX+
X X
X = H, D
X
X CH2X
X
B (42)
–BX+ X
X
Scheme 41
Contrary to quantum calculations and the results described above, (Equations (41) and (42),
Scheme 41), these results suggest that the energy barrier separating 3 and 4 cannot be neglected.
1.19.7.4 ‘‘Aromatic’’ Carbenium Ions

The tropylium ion (cycloheptatrienyl cation) is a typical aromatic cation or 7C-6 Hückel system
(4n + 2, n = 1) that can be readily prepared in solution. In the gas phase, the tropylium ion 6 is more
stable than the isomeric benzyl cation (PhCH2+) as shown by Equations (43) and (44). It is note-
worthy that the latter ion has about the same stability as the t-butyl cation (Equations (45) and (46)).
CH2
ð43Þ
Benzyl cation 6 (Tropylium cation)
∆H °f : 891 849 ∆H °r (16) = –42 kJ mol–1
PhCH2 + Cycloheptatriene 6 + PhCH3

ð44Þ
∆H °f : 891 183 849 50 ∆H °r (17) = –175 kJ mol–1
t-Bu + Toluene Isobutane + PhCH2

ð45Þ
∆H °f : 699 50 –136 891 ∆H °r (18) = 2.5 kJ mol–1
t-Bu + PhCH2Cl t-BuCl + PhCH2

ð46Þ
∆H °f : 699 16.7 –182 891 ∆H °r (19) = 6.3 kJ mol–1
In the gas phase, the ‘‘thermal’’ tropylium ion is an unreactive species, whereas the benzyl
cation undergoes a number of reactions, e.g., hydrogen and chloride transfers, additions, and
condensations with aromatic hydrocarbons. The benzyl ! tropylium rearrangement could be
observed only at high internal energies <1981CJC1592, 1976JA6072, 1982JA5249> in contrast
with the facile toluene ! cycloheptatriene radical–cation rearrangement. The Hückel approxima-
tion gives the following -energies for tropylium ion and benzyl cation, to be compared with the
-energies of 3 ethylene + methyl cation and of benzene (Scheme 42). The difference in Hückel -
energies between tropylium ion and benzyl cation thus amounts to Hp = 0.27. Considering a
value of 134 kJ mol1 as estimated from the rotational barrier in ethylene, one calculates a
stability difference of 36 kJ mol1 between these carbocations, what is not significantly different to
the experimental value given by the equilibrium shown in Equation (43).
H
3 + C
H
Eπ (Hückel): 6α + 8.99β 6α + 8.72β 6α + 6β 6 α + 8β
Scheme 42
1.19.7.5 ‘‘Antiaromatic’’ Carbenium Ions

Thermochemical data give Hr(20) = 128 kJ mol1, which demonstrates that cyclopentadienyl
cation is a destabilized species compared with allyl cation (Equation (47)) <2001CRV1333>. In
open-chain analogs, conjugation of an allyl cation with a vinyl group stabilizes the carbocation
(cf. DH (c-cyclohex-2-en-1-yl+/H) = 937 kJ mol1 with DH (c-cyclohexa-2,4-dienyl+/
H) = 891 kJ mol1). Quantum calculations predict the cyclopentadienyl cation to be destabilized
by ‘‘antiaromaticity’’ as much as cyclobutadiene. Similarly, benzocyclopentadienyl cation (indenyl
cation) is predicted to be as antiaromatic as benzocyclobutadiene, but not as much as fluorenyl
cation <1997JA7075>. The following SN1 solvolysis relative rate constants (Scheme 43) are
consistent with the above hypothesis <1997JA2371>.
+ + + +
∆H °f : 833 130 36 1054 kJ mol–1 ð47Þ
∆H °r (20) = 128 kJ mol–1
OTf OTf
OTf
OTf
krel: 500 30,000 (1.0) ~1014
(CF3CH2OH, 25 °C)
Scheme 43
The cyclopentadienyl cation was generated in a matrix and observed to have a triplet ground
state as predicted by simple Hückel theory <1977ACR27> and by ab initio quantum calculations
<1997JA7075, 2001JCP9243>. It has a planar D5h geometry. The calculations indicate a C2V
singlet structure about 10 kJ mol1 higher in energy than the triplet D5h structure <1998CPH1,
1998MI1402> (Scheme 44).
1.514 Å
1.314 Å
1.393 Å
Planar D5h (triplet) C2v (singlet)
(all C–C bonds have
same length)
Scheme 44
The IR spectrum of the pentachlorocyclopentadienyl cation, C5Cl5+ has been measured in SbF5
matrix and is consistent with a D5h structure <1997JPC(A)1523>.
1.19.7.6 The Cyclopropyl Substituent Effect

Hydride affinities given below (Scheme 45) show that the cyclopropyl substitutent stabilizes
carbenium ions much better than the isopropyl group. It stabilizes almost as much as a phenyl
group <1991CB165>. For a long time it has been recognized that a cyclopropyl group resembles
more a vinyl group than a cyclobutyl group, although cyclopropane and cyclobutane have almost
the same strain energy.
DH°(R+/H–):
[kJ mol–1]
Me H Me H
H H H + H 1109
Me H Me H
H H
H + H 1008
H H
PhCH2–H PhCH2 + H 979
Me H Me H
H + H 1038
H H
Me Me
H H H + H 947
Me Me
Me
H + H 912
Me
PhCH2–H PhCMe2 + H 920
H
+ H 866
Scheme 45
1.19.8 CARBOCATIONS IN THE CONDENSED PHASE

Because charged species are more strongly solvated than neutral molecules, one expects the
heterolytic dissociation enthalpies to decrease significantly on going from the gas phase to the
condensed phase (solution, solid, surfaces). Ease of heterolytic R3CX bond cleavage into a
carbocation R3C+ and an anion X (counter-ion X) will depend on the intrinsic stability of
these ions in the gas phase (as expressed by DH (R3C+/X)) and on the general and specific
interactions they have with the surrounding molecules. Heterolysis (SN1 mechanism according
to Ingold) is not the unique reaction generating carbocation intermediates. Protonation of, or
electrophile addition to, a neutral compound is a general method to generate cationic species.
Other methods involve oxidation of neutral molecule, electrooxidation at the anode and by
photoinduced electron transfer (PET), fragmentation of carbenium ions or of alkoxychloro-
carbenes.
1.19.8.1 The Effect of the Nature of the Nucleofugal Group

Some of the more common leaving groups, X, in the order of their decreasing ease of displace-
ment by a nucleophile are as follows: N2+ > N = NOSO2R > PhI+ > OSO2R > OP(O)OR2 >
I > Br > OCOR > NO2 Cl > OH2+ > S+ Me2 > F > OSO3 > R3N+ > OR > NR2. It is
opposite to the order of basicity <1979ACR198>. For the sulfonates, the following order of
decreasing nucleofugacity can be retained (Scheme 46) <1978ACR107>.
FSO3 > F3C(CF2)3SO3 > CF3SO3 > F3CCH2SO3 > O2N SO3
Fluorosulfonate Nonaflate Triflate (TfO) Tresylate Nosylate (NSO)
> Br SO3 > Me SO3 ≈ CH3SO3
Brosylate (BsO) Tosylate (TsO) Mesylate (MsO)
Scheme 46
Fluorosulfonate salts of trimethylammonium sulfonyl esters (O-besylate 7, Scheme 47)

<1981CJC362> are ca. 105 times more reactive than the corresponding trifluoromethanesulfo-
nates (triflates).
N
R OSO2NMe2 + MeOSOF2 ROSO2NMe3FSO3 R OSO2 N
7 8
Scheme 47
Primary and secondary sulfonates are obtained readily by esterification of the corresponding
alcohols. However, problems arise with the esterification of tertiary alcohols. In some cases,
imidazolysulfonates (imidazylates 8) may be obtained. The latter are quite useful for SN2-type
substitutions <1981THL3579>.
In polar solvents (1,1,1,3,3,3-hexafluoroisopropanol, CH3CN) the lifetimes of dialkylcarboca-
tions arising from the decomposition of corresponding diazonium ion intermediates range from
100 ps to 40 ns at 22 C <1999JA6589>. Solvolytic formation of aryl cations as intermediates has
been demonstrated in the dediazoniation of arene diazonium ions, indicating the special properties
of the nitrogen leaving group <1992JCS266, B-1995MI015>. Somewhat related to the diazonium
ions are the tosylazoxyalkanes and -arenes <1983HCA1710> and the nonafluorobutylsulfonyl-
oxyazoxyarenes (‘‘azoxynonaflates’’ <1984CB3004, 1984CB3021>). Their solvolyses follow
mechanisms involving unimolecular fragmentation and the formation of carbenium ion inter-
mediates (Equation (48)).
O + –
R'OH R'OH
R N NOS Me [R N2O OTs]
Nu-H ð48Þ
O
O ROR' + R-Nu + TsOH + N2O + ROTs
Diazoalkanes are protonated into diazonium ions. They intervene in the carcinogenicity and
mutagenicity of N-alkyl-N-nitroso compounds <B-1992MI016>. N-Benzyl-N-nitrosopivalamide
decomposes to produce very short-lived nitrogen-separated ion pairs, which is essentially unsol-
vated (Equation (49)) <2000JOC1115>.
O O O
+ –
Bn N But Bn N N O But Bn N2 OC But
N
O ð49Þ
–
O
+
PhCH2 N2 O But Products
Salts derived from carbocations and carbanions are known. For instance, the reaction of
But C60 anion (1,2-dihydro-[60]fullerenes has a pKa of 4.7 <1994JPC13093>) with tricyclopropyl-
cyclopropenyl cation in tetrahydrofuran (THF) gives 1-t-butyl-4-(tricyclopropyl-2-cyclopropen-
1-yl)-1,4-dihydro[60]fullerene with CC covalent bond formation. This compound equilibrates
with the original cation and anion in a polar solvent such as dimethylsulfoxide (DMSO)
<2001T3537>.
1.19.8.2 The Use of ‘‘Super-Acids’’

Nonaqueous systems containing species of considerably higher acidity than H3O+ are called
super-acids <B-1985MI009>. In such media, it is possible to completely protonate many organic
compounds and to observe the corresponding ions directly by spectroscopic techniques.
ESCA studies <1997ACR245> of solid matrices of FSO3H/SbF5 or HF/SbF5 saturated with
CH4 at 180 C and in high vacuum (109 Torr) showed that the 1s ESCA shift differed by less
than 1 eV (the limit of resolution) from that of CH4. This is considered to be that due to CH5+.
Ethane has been shown to undergo CC bond protolysis in preference to CH bond proto-
lysis <1973JA4960>. The ratio of CH4 and H2 formed as the gaseous cleavage products of the
reaction of C2H6 with HF/SbF5 1:1 in SO2ClF is about 15:1. Protonation of the CC bond is
followed by cleavage of the ethonium ion intermediate, induced by attack of a molecule of ethane.
The base (in this case, probably the CH bond of ethane) attacks the developing methyl cation
in C2H7+ and generates a C–proponium intermediate, which then cleaves into Et+ intermediate
and CH4. Oligomerization reactions ensure the involvement of more molecules of ethane, giving
finally stable carbocations such as t-butyl and t-hexyl cations.
Propane bubbled into DF/SbF5 is slightly ionized but extensively deuterated at the primary and
secondary positions <1999JA10628>. Isobutane in DF/SbF5 at 0 C undergoes fast H/D exchange
at all CH bonds before being converted into t-butyl cation and dihydrogen (Scheme 48).
In the presence of carbon monoxide, t-butyl cation gives the acylium ion (Koch–Haaf reaction
<1964OS1>) that can be generated with ethanol to give ethyl pivalate (95%). A secondary
product is isolated, ethyl isobutyrate (5%), resulting from the concurrent fragmentation of the
C–isobutonium ion into methane and isopropyl cation <1997JA3274, 2000PAC2309>.
H HH H H H H D H D
C C C C
D
H H D
σ-Complex (III) σ-Complex
D H
DF/SbF5 H H H H
Fast
(CH3)3C-H C + C C CH2D
–10 °C D
H
Fast
+
Olah’s 3-center-2-electron
bond representations D
+D C
H
(95%) Slow
+ HD
H
D CH
3
H3C H
CH3 CO EtOH
HD + t-Bu CO COOEt
(III)
D CH3 CH3
D
H ≡ H
H3C CH3 CH3 CH3
Slower 5%
CO EtOH
CH3D + CO H COOEt
Scheme 48
The strongest known member of the super-acid family, 1:1 mixture of HF and SbF5, can
protonate carbon monoxide at 85 atm. and to the formyl cation, HCO+ can be characterized
by 1H-, 13C-NMR and IR spectroscopy <1997SCI776, 1998AG(E)603>.
In the presence of SO2ClF, the acidity of HF/SbF5 is weaker and the equilibrium shown in
Equation (51) competes with the addition (Equation (50)).
+ – ð50Þ
HF/SbF5 + CO HCO SbF6
+ + ð51Þ
HCO + SO2ClF CO + [HSO2ClF]
The Olah group has prepared cations ClCO+, BrCO+, and ICO+ in HSO3F/SbF5/SO2ClF solu-
tions <1991JA3205>. On treating t-butyl fluoroformate in a SO2ClF solution of HSO3F/SbF5 (1:1) at
78 C, they obtained FCO+, FC(OH)2+, and t-Bu+ <1997AG(E)1875>. Crystalline salts 9 have
been obtained and characterized by X-ray diffraction studies (Scheme 49) <1999AG(E)714>.
O C(-OSiMe3)2 + HF/MF5 C(OH)3MF6 + HF/MF5

9 (M = As, Sb)
Scheme 49
The X-ray crystal structure of the cumyl cation has been determined as the SbF6 salt. The
relatively short C+–Cipso bond and bond lengths within the benzene ring are consistent with
strong benzylic delocalization (Scheme 50) <1997JA3087>.
Cumyl cation
Scheme 50
1.19.8.3 Carboranes as Super-Acids

Most current super-acids are still nucleophilic (SbF6, HSO4, CF3SO2, fluorine, and oxygen have a
high affinity for silicon) and do not allow free silylium ion, R3Si+, to exist. Attempts to protonate
fullerene C60 with these super-acids lead to decomposition. The solid acid H(CB11H6Cl6) obtained by
condensing liquid HCl onto solid (C2H5)3Si(CB11H6Cl6) and removal of the volatiles under vacuum is
capable of protonating C60 quantitatively without decomposition (Equation (52)). In contrast to many
super acids such as HF/Sb5, HSO3F/SbF5, etc., carborane H(CB11H6Cl6) (and H(CB11H6Br6), which
is also available) is not a mixture of Brønsted and Lewis acids <2000SCI101>. Salts such as
[cyclohexadienyl+] [CB11H(Me)5Br6], [toluenium+] [CB11H6Br6], and [hexamethylbenzenium+]
[CB11H6Br6] have been obtained as stable crystalline materials by treatment of benzene, toluene,
and hexamethylbenzene, respectively, with acids of type H[CB11R6Br6]. Thus, the Wheland inter-
mediates (-complexes) postulated as intermediates in aromatic electrophilic substitutions are now
reagents. They have been used to bracket the solution phase basicity of C60 between that of mesitylene
(1,3,5-trimethylbenzene) and xylene <2003JA1796>. The azafullerenium cation C59N+ has been
isolated in good yield as the carborane salt [C59N]+[Ag(CB11H6Cl6)2] <2003JA4024>.
H –
C
Cl
H B H
B B H
B B Cl –
C60 + H H H+ + [CB11H6Cl6] ð52Þ
Cl B B Cl
B B
B
Cl Cl
Cl B
Cl
Likewise, treatment of fullerene C76 with [Ar3N+][CB11H6Br6] (Ar = 2,4-dibromophenyl) in 1,2-

dichlorobenzene or 1,10 ,2,20 -tetrachloroethane leads to [C76+][CB11H6Br6]+Ar3N <1996JA13093>.
Substituted fullerene derivatives form fullerene carbocations much more readily and under less
acidic conditions. For instance, C60Ar5Cl (Ar = Ph, or 4-F-C6H4) reacts with AlCl3 in CH2Cl2,
CHCl3, or CS2 at 25 C to give intense purple-red solutions of salts of C60 Ar5+ <1998CC2153>.
Treatment of C60 with AlCl3 in CHCl3 at 20 C results in the addition of 1 equiv. of CHCl3 giving
10, which is hydrolyzed into alcohol 11 in the presence of silica gel. Fullerol 11 dissolves in
CF3SO3H giving a reddish purple solution of alkylfullerenyl cation 12 (Scheme 51).
CHCl2 CHCl2
10 X = Cl 12
11 X = OH
Scheme 51
1.19.8.4 Intermolecular Hydride Transfer Reactions

A possible mechanism for the oxidation of an alkane is the transfer of a hydride to the electrophilic
agent, E+, with the formation of a carbenium ion intermediate (Equation (53)). The hydride
abstraction process might be the preferred mechanism if the resulting carbenium ion is a stable
species, for instance, a tertiary alkyl cation, thus making the carbonium ion intermediate energeti-
cally disfavored. Competition between electrophilic addition to the CH bond and hydride transfer
to the electrophile may also be affected by the nature of the hydrocarbon (-nucleophilicity, steric
factors, etc.), the nature of the electrophile, and the medium <1997JCS(F1)515, 1995CC121>.
δ δ δ
+ + +
C H + E+ C H E C + HE ð53Þ
The Bell–Evans–Polanyi theory gives the relationship (Equation (54)) between activation enthal-
pies and the heat of the reaction, where varies between 0 and 1 depending on the type of one-step,
concerted reaction. Looking at an ensemble of similar reactions in which structural parameters are
varied, Hammond and Leffler have derived the relationship shown in Equation (55) from Equation
(54), in which Gr expresses the change of the reaction-free enthalpy induced by structural
variation, and the proportionality constant reflects the fraction of this effect observable in the
activation free enthalpy G‡. The magnitude of has often been used for localizing transition
states <B-1963MI017>. A study on the kinetics of hydride abstractions from CH groups by
carbocations revealed that the variation of the hydride acceptor affects the rate constants of the
hydride transfer to a considerably greater extent than an equal change of the thermodynamic
driving force (exergonicity) caused by variation of the hydride donor (Equation (56)). Substitution
in the donor influences the heat of reaction (X, Y electron-releasing groups increase the exothermi-
city) and the intrinsic barrier of the hydride migration (opposite effect predicted by Equation (54)),
while substituent variation in the acceptor affects both terms in the same sense (in agreement with
Equation (54)). For the reactions shown in Equation (56), a value of 0.72 is found for Hammond–
Leffler’s = G‡/Gr when the hydride acceptor is varied, while = 0.28 is found (quantum
calculations) when the hydride donor is varied. These finding are interpreted in terms of a partial
positive charge of the migrating hydrogen in the transition state as shown in Equation (53)
<2002JA4084>.
∆H ‡ = α ∆Hr° + β ð54Þ
δ∆G‡ = αδ∆Gr° ð55Þ
H ‡
Y H H Me ∆G1 Y H H Me
+ + + +
H
X H H Me ‡ X H H Me
∆G–1
ð56Þ
Hydride donor Hydride acceptor X, Y: OH, Me, H
‡
δ∆G 1‡ δ∆G –1
α= = 0.28 α' = = 0.72
δ∆G °r δ∆G °r
1.19.8.5 Carbocations Generated upon Irradiation

The absorption of light by alkyl halides, RX, generally results in initial homolytic cleavage of the
carbon–halogen bond (Equation (57)) <B-1973MI018>. Depending upon the substrate and
solvent, the initially formed radical pairs can undergo subsequent electron transfer to afford an
ion pair and, ultimately, carbocationic products (Equation (58)).
hν
R-X (R-X)* [R•X•] solvent cage R• + X •
Free radicals ð57Þ
Radical products
+ – +
[R•X•] [R / X ] R + X
–
ð58Þ
Carbocationic products
Irradiation of 1-iodonorbornane 13 in CH2Cl2 (quartz vessel, 254 nm UV light) results in the

formation of 1-chloronorbornane (14, 80% yield) and chloroiodomethane (Scheme 52). The pro-
posed mechanism for this photoreaction involves the generation of 1-norbornyl bridgehead cation
14, which reacts with CH2Cl2 giving the chloronium ion intermediate 15. The latter undergoes
displacement by iodide anion to give the observed products <1996JA8135>. Irradiation of 13
thus affords an opportunity to explore the behavior of the unusually unstable and reactive
1-norbornyl cation. The contrasting reluctance of iodide 13 to undergo ionic Cl bond cleavage
under nonphotochemical conditions is emphasized by its quantitative recovery from extended
treatment with refluxing methanolic silver nitrate. Irradiation of 13 in methanol, ethanol, or
tetrahydrofuran gives the corresponding 1-norbornyl ethers together with small amounts
of norbornane, a reduction product of 1-iodonorbornane believed to arise principally via the
1-norbornyl radical, which can abstract a hydrogen atom from the solvent. Irradiation of 13 in
acetonitrile, followed by aqueous work-up, afforded 1-acetaminonorbornane (Ritter reaction).
hν CH2Cl2 I
I Cl Cl
I
CH2Cl + CH2ICl
13 14 15 16
Scheme 52
Under usual solvolytic conditions, the generation of simple vinyl cations requires the presence
of a super-leaving group such as triflate (CF3SO3) or nonaflate (C4F9SO3) <1972CB1465>
Irradiation of vinyl iodides affords mixtures of ionic and radical products.
Irradiation with a UV light at 254 nm of iodobenzene generates the phenyl radical. When Phl
was sublimed with a large excess of Ar and deposited on a cold spectroscopic window of Csl at
8 K, a matrix was formed. Its irradiation with the light of an argon discharge lamp (105–105 nm)
generated the phenyl cation (Equation (59)) and its IR spectrum could be recorded, showing
typical bands at 3110 and 713 cm1. If the argon matrix is doped with 5–10% N2, the phenyl-
diazonium ion is formed at the expense of Ph+ (the 3110 cm1 band decreases and the typical
stretching frequency of the diazonium ion appears at 2325 cm1). The IR data of phenyl cation
and of deuterated derivatives were in agreement with quantum calculations predicting a symme-
trical singlet ground state of phenyl cation <2000AG(E)2014>.
254 nm
PhI Ph
+ + N2 +
ð59Þ
105–107 nm
Ph PhN2
Ar, 8 K
Photolysis of 4-chloro (and -fluoro) anilines in a polar solvent generates the corresponding
4-aminophenyl cation, an intermediate otherwise difficult to access in solution <B-1997MI451>,
and that adds to alkenes, not to n-nucleophiles such as alcohols. Under nonacidic conditions,
irradiation of N,N-dimethyl-4-chloroaniline in CH3CN containing 1 M norbornene (bicy-
clo[2.2.1]hept-2-ene) gives a single major product, which is isolated in 33% yield and recognized
as 2-arylnortricyclene. In the presence of protic solvents such as alcohols, and arylalkoxynorbor-
nanes are produced concurrently with 2-arylnortricyclene <2003CC738>.
Laser flash photolysis (LFP) has been employed for the observation of reactive intermediates
and for the direct measurement of rate constants of their decay reactions. Photolyzing some
precursor with a laser pulse initiates a rapid photochemical transformation to the reactive species
of interest. This is detected, usually, by absorption (UV, visible, IR) spectroscopy, and the decay
is directly monitored. A number of applications involving carbocations have appeared, with the
intermediate being generated and directly studied under normal solvolytic conditions, i.e., H2O or
alcohols as solvent <1993CRV119, 1996T6823>. Detailed studies have been reported involving
species such as xanthylium, triarylmethyl, diarylmethyl, fluorenyl, benzyl, phenethyl, cumyl, and
substituted vinyl cations (Equations (60) and (61)) (Scheme 53) <1999CJC2069>. Laser flash
photolysis was used to generate 9-R-xanthenium cations (R = H, Ph) in subcritical water to
demonstrate the importance of ionic chemistry under these conditions. The carbocations were
generated at temperatures up to 330 C. At higher temperatures, the decrease of the dielectric
constant of H2O resulted in weak cation signals with short lifetimes. The temperature effect on
the intrinsic solvent decay (ko) followed the Arrhenius law and could be extrapolated all the way
from 25 to 300 C. The bimolecular rate constant kA for the reactions of xanthenium and
9-phenylxanthenium cations with n-pentylamine also followed the Arrhenius law between 100
and 300 C <2001JPC(A)8046>.
+
HO R R R OH2
hν + H2O
(60)
ko
O O O
+
kA (R = H) = (1.67 ± 0.62) 1011 × R NH2R'
exp [(–21.6 ± 1.2 kJ mol–1/RT ] M–1s–1 H2N(CH2)4Me
(61)
kA
kA (R = Ph) = (5.39 ± 3.25) 108 × O
exp [(–18.2 ± 3.9 kJ mol–1/RT ] M–1s–1
Scheme 53
Estimates of the lifetimes of the 2-propyl cation, cyclobutonium ion, cyclopropylethyl cation,
and 2-adamantyl cation in HFIP (1,1,1,3,3,3-hexafluoro-2-propanol), TFE (2,2,2-trifluoroetha-
nol), and acetonitrile (MeCN) have been obtained using electrophilic aromatic addition to 1,3,5-
trimethoxybenzene as a kinetic probe reaction in LFP experiments (Equations (62)). The lifetimes
range from 100 ps to 40 ns at 22 C. The precursors of the carbocations were oxadiazolines
<1999JA6589>.
MeO OMe – N
N hν ROH + –N2
O + N N2 H
N 308 nm + ð62Þ
R' R'' R' R'' R' R'' R' R''
H
1.19.8.6 Carbocations by Fragmentation of Alkoxy(chloro)carbenes

Because of the ring strain increase imposed on the intermediate bridgehead carbenium ion,
heterolysis of 1-bicyclo[2.2.1]heptyl (1-norbornyl) tosylate or triflate (k = 6.5 108 s1 at
70 C, H‡ = 118 kJ mol1 <1971JA3189>) is very difficult. For instance, the acetolysis of
bicyclo[2.2.1]hept-1-yl tosylate is 1010 times slower than that of adamant-1-yl tosylate
(AcOH, 70 C). On irradiating the alkoxychlorodiazine 17 (>320 nm, 25 C) in 1,2-dichloro-
ethane, carbene 18 is generated (Scheme 54). It fragmentates into ion pair 19 (as demonstrated
by interception by methanol) that collapses into carbon monoxide and 1-chloronorbornane 20.
Laser flash photolysis of 17 at 351 nm allows to measure the rate constant for the fragmentation
18 ! 19 to be measured. Doing that at various temperatures between 0 and 50 C allowed the
activation parameters Ea (18 ! 19) = 37.6 0.8 kJ mol1, log A = 11.2 0.1 s1, with k (18 !
19) = 3.3 0.4
104 s1 at 25 C to be estimated. This is 3 1015 times faster than acetolysis of
norbornyl tosylate at 70 C! Similar measurements with the carbenes derived from bicy-
clo[2.2.2]oct-1-yl and adamant-1-yloxychlorodiazirines (Scheme 55) led to rate constants for
the carbene fragmentation that are nearly the same, in contrast with the acetolysis of the
corresponding tosylates or triflates <2001TL6045>. For instance, (2,2-diphenylethoxy)chloro-
carbene fragments in MeCN at 25 C with a rate constant k = 2.1 106 s1 <2002JA5258>.
The alkoxychlorodiazine 17 was obtained by treatment of norbonan-1-ol (21: bicyclo[2.2.1]hep-
tan-1-ol) with an equivalent of cyanamide and one equivalent of trifluoromethanesulfonic acid.
This gave the isouronium salt 22, which is oxidized with 12% aq. NaOCl to give diazirine 17
(see also <2002OL2341>).
hν 25 °C
+ CO
k = 3.3.10–4 s–1
O N Cl Cl O Cl
CO
25 °C
Cl N Cl Cl
17 18 19 20
X
X X
X = OTf krel: 10–10 10–4 (1.0) AcOH, 70 °C (SN1)
X = O-C-Cl k: 3.3 × 104 1.5 × 105 5.9 × 105 s–1 (ClCH2CH2Cl, 25 °C)
Scheme 54
H2N C N NaOCl
17
TfOH
HO O NH2
TfO
NH2
21 22
Scheme 55
1.19.8.7 Hydrocarbon Alkylation and Cracking with Zeolites

Zeolites (molecular sieves) are important solid catalysts. They are crystalline aluminosilicates
of group IA and group IIA elements, such as Na, K, Mg, and Ca. They are represented by
the empirical formula Mx+ x
x/n [AlxSiyO2(x+y)]
nH2O. They are used in petroleum refining, synfuel
production, and petroleum production <1994CRV2095, 1995CRV637>; (see also <2003JA2136,
1998JA11804>). The Brønsted acid site has been established as the primary active site for zeolite
catalysts. Using in situ NMR spectroscopy, Haw and co-workers <1989JA2052, 1992JPC8106,
1994JA7753> observed the formation of cyclopentenyl cations on zeolites through propene
oligomerization. These cations are believed to be the true intermediates in aromatic formation
and coke deposition, which are undesirable in some reactions. The same authors <2000JA4763>
also found that cyclopentenyl cations not only play a catalytic role but also act as reactive
intermediates in methanol-to-olefin (MTO)/methanol-to-gasoline (MTG) chemistry. A study
with methylcyclopentene (Scheme 56) has shown that this compound is protonated already at
150 K to generate 1-methylcyclopentyl cation 23. It adds to methylcyclopentene to give 24.
Hydride abstraction by 23 then generates cation 26, which after a number of hydride shifts is
isomerized into the observable, stable allyl cation 27 <2001CC2008>. Inclusion of 4,40 -dimethyl-
aminodiphenylethylene and related alkenes within activated CaY zeolites results in the formation
of persistent monomeric carbocations. Their structure and consequently the color of the zeolite is
controlled by the water content within the zeolite <2003TL1615>. Stable carbocations formed by
absorption of alkenes on zeolite Y can be characterized by an IR band near 1510 cm1
<2001MI1870, 2000JOC3947>.
Zeolite HY
+ H
150–373 K
23 24
H
Hydride
24 + +
shifts
26 27
Scheme 56
In 1984, Haag and Dessau <1984MI305, 2000MI11> proposed that alkane cracking catalyzed
by zeolites follows mechanisms analogous to those proposed by Olah and co-workers for the
reactions of alkanes in super-acidic, liquid media. They postulated that the solid acid catalysts
protonate alkanes to give H– and C–alkonium ions that collapse to give the products of cracking,
thus establishing an important link between solution-phase and surface chemistry and between
homogeneous and heterogeneous catalysis. Quantum calculations have suggested the transition
structure 28 for the H/D exchange of methane with zeolites <2000JPC(B)6308> and 29 for the
process leading to cracking to ethane (Scheme 57) <1998MI1>.
H H H
H H H C
H
H H H C
H H
O O O O
Si Al Si Si Al Si
OO OO
28 29
Scheme 57
Most acid-catalyzed alkane cracking occurs following the -scission rule <B-1995MI019>
(Equation (63)).
Si + Al H3C
O
HC CH2
R
+
ð63Þ
Si R
+O
+ + Al
H or R Si Al
R O
zeolite
R
+
An alternative mechanism is the CC bond protonation via carbonium ion formation,
Equation (64) <1989MI611, 1998MI235>.
H H
H H R
+
R + O + H
Si Al
H O
Si Al
ð64Þ
H
H H H R
+ O
H3C CH2
Si + Al
H
1.19.9 CARBOCATION REACTIONS
1.19.9.1 As Intermediates in Heterolysis

For the reaction shown in Equation (65), the two main reaction coordinates are the distance
R . . . X and the distance O . . . R. One can draw the diagram shown in Figure 4 for possible
mechanisms of this reaction.
H
+ – ð65Þ
R X + S OH R O S X
+
The associative mechanism SN2 is preferred for primary alkyl derivatives that cannot generate
stable carbocations such as benzyl, allyl, cyclopropylcarbinyl, or organometallomethyl systems.
With secondary alkyl systems, depending on the nucleophile and the medium, the displacement
reaction can either obey the SN2 or the SN1 mechanism. With tertiary alkyl derivatives, electron
and steric reasons make the SN1 mechanism preferred.
The SN1 solvolysis rates for a series of similar compounds under similar reaction conditions
reflect directly the stability of their carbocationic intermediates <1979JA522>. This hypothesis
developed slowly over the last 50 years. It grew out of the observations of parallel reactivity
profiles for solvolysis reactions and reactions involving sp3–sp2 interconversions at the reacting
carbon atom, such as alcohol oxidation with chromic acid <1967JOC2003> or ketone reduction
with sodium borohydride <1957T221>. The lack of solvolytic reactivity of bridgehead deriva-
tives of the 1-norbornyl and trypticene type <1939JA3184, 1954CRV1066, 1960AG147> was
taken as indicative for the preferentially planar structure of carbenium ions, long before the
planar structure of the t-butyl cation was experimentally determined by X-ray crystallography
<1993JA7240>. The first attempt to rationalize rate constants of solvolysis of secondary
derivatives used strain estimates for carbenium ions, based on IR-stretching frequencies of
carbonyl groups and nonbonded interactions <1964JA1853, 1964JA1854, 1964JA1856>.
These qualitative estimates were subsequently replaced by empirical force-field calculations,
which were particularly successful in the context of bridgehead solvolysis <1971JA3189,
Products
S SN2 with formation
of an intermediate
O X RO(S)H X ROS + HY
H R
Associative two-step "Classical" Ingold
mechanism with one-step SN2 mecha-
2
formation of an adduct nism (associative
1
intermediate (sp 2-C mechanism; IUPAC:
electrophiles, Si DN + AN)
R⋅⋅⋅O
electrophiles) "Classical" Ingold two-
Winstein two-step step SN1 mechanism
mechanisms involving (dissociative mecha-
tight-ion pair or/and 2 nism; IUPAC: DN + AN)
solvent separated (Scheme 10.1)
ion-pair intermediates 1
Free ions: intermediates
Reactants:
R+X– R+// X – R⋅⋅⋅X R+ + X– + SOH
RX + SOH
Tight Solvent-separated
ion-pair ion-pair
Figure 4
1974JA7121, 1984C389, 1986HCA635, 1987HCA1017, 1989MI863, 1991HCA1808>, but were

also applied with various degrees of sophistication toward the solvolysis of secondary
aliphatic derivatives <1978JOC3588, 1980JA1424, 1983JA3356, 1982HCA1418, 1984TL1703,
1985HCA119, 1978JOC3878, 1981CB3336>. Arnet and co-workers <1939JA3184,
1954CRV1066, 1960AG147, 1978JA5408, 1983JA2889> reported heats of ionization (Hi) of
secondary and tertiary alkyl and aralkyl chlorides to stable carbocations in SbF5 – solvent
mixtures. Correlation of the heats of ionization with the respective free energies of activation for
ethanolysis afforded a straight line over a range of 92 kJ mol1 for Hi. These results
established the near energetic equivalency of carbocations in solution and the transition state
for solvolysis.
Abboud and co-workers <1999JOC6401, 1997JA2262> developed the dissociative proton
attachment method (DPA) based on Fourier transform ion cyclotron resonance spectroscopy
(FTICR) to determine the stability of carbocations in the gas phase. Comparison of the
experimental ion stabilities with ion stabilities calculated by ab initio methods at the MP2/6-
311G** level indicated the absence of rearrangements. In addition, correlation of the experi-
mental ion stabilities with the rate constants for solvolysis under standard conditions afforded
a straight line covering the full rate range of bridgehead derivatives. It was found that even
2-adamantyl derivatives that are typical representatives of secondary derivatives solvolyzing
without nucleophilic solvent participation fit the correlation between ion stability and solvo-
lytic reactivity, as established for bridgehead derivatives <2002JOC1057>. The same applies
to tertiary aliphatic derivatives in the absence of nucleophilic solvent participation
<2000JA7351>. The relative rate constants for solvolysis (log(k/k0)) of the bicyclic secondary
derivatives correlate with the stabilities of the respective carbocations in the same manner as
tertiary bridgehead derivatives, but simple monoderivatives and acyclic derivatives solvolyze
faster than predicted on the grounds of the ion stabilities. The corresponding stabilities of
cyclopropyl- and benzyl-substituted carbocations have been obtained by a combination of
experimental and computational data available in the literature with computational methods.
Correlation of the rate constants for solvolysis versus ion stabilities for these compounds
reveals a trend similar to that observed for bridgehead derivatives, but with much more
scatter, which is attributed to nucleophilic solvent participation and/or nucleophilic solvation
<2003JOC3786>.
1.19.9.2 Heterolyses of Substrates a-Substituted by Electron-withdrawing Groups

The chemistry of carbocations containing a strongly electron-withdrawing -substituent such as a
trifluoromethyl, a cyano, or a carbonyl group has been actively studied. The electronic effects of
the cyano and carbonyl groups are generally interpreted to include the mesomeric effect (M) as
well as the inductive/field effect (I), both being electron withdrawing, as formulated by the
resonance structures 30 $ 300 and 31 $ 310 (Scheme 58). The –M effect of the cyano group is
reflected in its more positive value of p (0.67) than m (0.62) <1994PAC2451>. This is also true
when the cyano group is conjugated with a carbocationic center through a benzene ring as shown
by +m (0.562) <1958JA4979>.
R R
R C N R C N C O C O
R R
30 30' 31 31'
Scheme 58
A number of solvolysis rate data relevant to -cyano and -carbonyl substrates have been
interpreted as supporting the notion that the -cyano and -carbonyl carbocations are stabilized
by electron-donating conjugation (+M) to an extent as to partly offset their destabilizing
inductive effect <1984AG16, 1985ACR3, 1991CRV1625>. In resonance formulations, the posi-
tive charge is designated to distribute on the electronegative nitrogen or oxygen atom as shown by
32 $ 320 and 33 $ 330 (Scheme 59).
R R R O R O
C C N C C N C C C C
R R R R R R
32 32' 33 33'
Scheme 59
The effect of geminal group interaction that destabilizes the ground state and enhances the
solvolysis rates has been pointed out by several groups <1990JA4556, 1990JA4557, 1993JA2522,
1993JA2523>. A typical example is the marked destabilization of 34a in comparison with 34b by
38–42 kJ mol1 (Scheme 60).
NC OTf
TfO NC
34a 34b
Scheme 60
Quantum calculations (MP2) 6-31G** <1988JA3788> on the 2-oxoethylcation suggest this ion
to be significantly less stable (by about 97.9 kJ mol1) than the oxiranyl cation. In other words,
the best way for 2-oxoethyl cation to profit from the -acyl substituent is a nonvertical effect
(a rearrangement) leading to the oxiranyl cation. The calculations predicted that the isodesmic
equilibrium of 2-oxoethyl cation and methane with methyl cation and ethanal favors the
2-oxoethyl cation by about 20 kJ mol1 only (Scheme 61).
?
H O H O O
Vertical ∆E = –97.9 kJ mol–1 H
conjugation Nonvertical H
H H H H H
effect stabilization
∆E( CH2CHO + CH4 CH3 + CH3CHO) = 20 kcal mol–1
Scheme 61
This suggests that the hypothetical -electron donating effect of the -formyl substituent is
relatively small for the intrinsically unstable methyl cation. One thus expects it to be very small or
nonexistent for more stable benzyl or secondary alkyl cations (the polarizability effect Vl of the
substituent diminishes faster with the charge delocalization than its inductive effect VC).
According to Creary <1982JA4151>, the carbenium destabilizing effect of a -carbonyl func-
tion due to its permanent dipole moment (P+(PhCO) = 0.406) can be offset by a stabilizing
conjugative (polarizability) effect. Similarly, the electron-withdrawing diethyl phosphonate sub-
stituent (P+ = 0.505) may be less destabilizing than expected due to its polarizability
<1983JA2851>. Alternatively, Takeuchi and co-workers, studying the solvolyses of 2-oxo bridge-
head substrates, conclude that the -conjugative stabilization of tertiary -carbonyl carbocation
intermediates is negligibly small, if present <1997JOC5696>. (For the trifluoromethyl substituent
effects, see <1984AG(E)20, 1985ACR3, 1991CRV1625, 1994JOC7185>; for the -thiocarbonyl
substituent effects see <1998JOC2209, 1998JA10372, 1998JPO701>.)
The solvolysis of bicyclic triflates 35 and 36 has been studied (Scheme 62). The ratio of SN1
reactivity between -thiocarbonyl-substituted compound and the unsubstituted compound (35H,
36H) increases from 106 to 102 when going from 35 to 36. This is consistent with stabilization
of the cationic transition state for solvolysis by conjugation 36 $ 360 . This effect is more efficient
for large rings than for less flexible systems <1998JOC2209>.
k35/k35H(SN1) ≅ 10– 6
TfO TfO
35 35H
k36/k36H(SN1) ≅ 10–2
TfO TfO
36 36H
S
OTf
36'
Scheme 62
The -thioamide cation 37 is 107-fold less reactive toward 1:1 MeOH/H2O than cation 37H,
indicating strong stabilizing interactions of the -thiocarbonyl group (Scheme 63) <1998JA10372,
1998CJC1910, 1998JPO701, 2001ACR981>.
NMe2
Me
MeO S MeO
H
37 37H
Scheme 63
1.19.9.3 Remote Allyl Substituent Effects

In the gas phase, the replacement of a methyl group of a methyl-substituted tertiary carbenium
ion by an ethyl, propyl, or isopropyl group leads to an extra stabilization of the carbocation by
ca. 12, 19, and 21 kJ mol1, respectively. Thus, the larger the alkyl substituent, the better it
stabilizes the cation. This effect corresponds to the ‘‘normal inductive order’’ of the alkyl
substituent effects on the stabilities of carbenium ions, i.e., H Me < Et < n-Prop < i-Prop < But
<1975JA5714, 1997JOC5374>.
Applying the FTICR technique to measure the differential bromide affinities G 39, Takeuchi
and co-workers <2001JOC2034> found that the relative stabilities of 1-adamantyl cation
increases by alkyl substitution at tertiary centers C(3), C(5), and C(7) (Equation (66)). Their
relative stability increases with the number of isopropyl substituents. The relative stabilities
calculated by the PM3 quantum calculation method were in good agreement with the experi-
mental results in the gas phase.
Br Br
+ –
+ + ð66Þ
R1 R3 R1 R3
R2 R2
1-Ad+ 1-Ad-Br
In contrast, the sequence of the rates for the solvolysis in nonaqueous solvents are 3,5,7-
(Me)3-1-AdBr < 1-bromoadamantane (1-AdBr) < 3,5,7-(Prn)3-1-AdBr < 3,5,7-(Pri)3-1-AdBr. The
rates of solvolysis of 3,5,7-(Pri)3-1-AdBr and 3,5,7-(Prn)3-1-AdBr relative to 1-AdBr at 25 C are
15 and 3.8 in EtOH, respectively, but markedly decrease with the increase in the amount of
added water, reaching 0.84 and 0.15, respectively, in 60% EtOH. Reflecting these effects of
water, the Grunwald–Winstein (GW) relationship for 3,5,7-(Pri)3-1-AdBr and 3,5,7-(Prn)3-1-AdBr
against YBr is linear for nonaqueous alcohols (EtOH, MeOH, TFE-EtOH, TFE, 97% HFIP),
but marked downward deviations are observed for aqueous organic solvents, in particular,
aqueous ethanol and aqueous acetone. The effect of the alkyl substituents to diminish relative
solvolytic reactivity in EtOH–H2O mixtures may be ascribed to a blend of steric hindrance to
Brønsted base-type hydration to the -hydrogens and hydrophobic interaction of the alkyl
groups with ethanol to make the primary solvation shell less ionizing. The introduction of
one nonyl group to the 3-position showed much smaller deviations in the GW relationship than
the case of 3,5,7-(Prn)3-1-AdBr. The markedly decelerated solvolysis of alkylated 1-bromo-
adamantanes in aqueous organic solvents is a kinetic version of anomalously diminished disso-
ciation of alkylbenzoic acids in aqueous ethanol and aqueous t-butyl alcohol that was
demonstrated by Wepster and co-workers earlier <1989JCS(P2)977, 1990RTC455,
1992RTC22> and ascribed to hydrophobic effects.
1.19.9.4 Anchimeric Assistance versus s(C,C) Hyperconjugation

The SN1 solvolysis of bicyclo[2.2.1]hept-2-exo-yl (2-exo-norbornyl) tosylate 38x is significantly
faster than that of its endo isomer 38n (Scheme 64). The rate constant ratio kexo/kendo varies from
350 in AcOH to 1120 in CF3COOH <1974JA181, 1978JA3143> and 1700 in HCOOH
<1978JA3143>.
OTs OTs
OTs
38x 38n 39
krel: 1730 1.5 1.0
(CF3COOH, 25 °C) Ts = p-MeC6H4SO2
CH3
OTs OTs
OTs
40H 40Me 41
krel: 8.9 24 0.7
Scheme 64
The products of solvolyses of both 2-exo and 2-endo-norbornyl derivatives are exclusively exo.
Furthermore, the solvolyses of labeled or optically active 2-exo-norbornyl esters yield completely
racemized products, thus suggesting a symmetrical structure (Cs) for the secondary bicyclo[2.2.1]-
hept-2-yl (2-norbornyl) cation intermediate. Winstein proposed the ‘‘nonclassical’’ bridged struc-
ture 42 <1952JA1147, 1952JA1154>, which can be seen as the -complex 420 (Scheme 65)
<1999MI225>.
≡ ≡
H H H
H H H
42 42'
43 43'
Scheme 65
Brown and co-workers have argued that the attack of the nucleophile on the endo face of a
‘‘classical’’ C1 2-norbornyl cation 43 is difficult for steric reasons <1978JA1865>. This hypothesis
has been challenged by several experiments. For instance, it is found that the N proton and the
methyl, ethyl, and isopropyl group have similar ability to usurp the exo position in protonated
N-alkyl-2-azanorbornanes (Equation (67)) <1978JA1503>.
K(40) R = Me K = 72/28
R H Et 69/31 ð67Þ
N+ N+ i-prop 55/45
H R
In the gas phase, the 2-norbornyl cation is about 24 kJ mol1 more stable than simpler acyclic
and cyclic secondary carbenium ions. This is illustrated by comparison of the hydride transfer
equilibria shown in Equations (68) and (69) <1984JA6917, 1979AG(E)951>.
+ + +
+
ð68Þ
∆H °f : –78 799 801 –100 kJ mol–1
∆H °r (41): –20 ± 8 kJ mol–1
+
+ + +
+ ð69Þ
∆H °f : –50 801 782 –78 kJ mol–1
∆H °r (42): –47 ± 8 kJ mol–1
The heats of ionization of 2-chloronorbornane, 4-methyl-, and 2-methyl-2-chloronorbornane in

SbF5/SO2CIF amounts to 96.2, 92.0, and 125 kJ mol1, respectively <1980JA398>. The rearran-
gement of secondary 4-methylbicyclo[2.2.1]hept-2-yl cation 44 into the tertiary 2-methylbicy-
clo[2.2.1]hept-2-yl cation 45 in Sb5/SO2CIF releases 27.2 kJ mol1. In contrast, the
rearrangement of but-2-yl cation into t-butyl cation releases 60.7 kJ mol1, confirming that the
secondary 2-norbornyl cations enjoy a special stabilization compared to simpler carbenium ions
(Scheme 66).
This fact could be interpreted in terms of a symmetrically bridged ion 42 or fast equilibrating
ions 43 > 430 whose extra stability would arise from the enhanced polarizability (hyperconjuga-
tion) of the norbornane skeleton. An ‘‘enhanced’’ vertical stabilization effect might also be
accompanied by partial -bridging. A relatively small stability difference between the secondary
Me
H
H Me
44 45
∆H °r = –27.2 kJ mol–1 ∆H °r = –60.7 kJ mol–1
Scheme 66
and tertiary 2-norbornyl ions cannot be considered as evidence for the symmetrical structure 42
since it is found that the stability difference between 2- and 1-adamantyl cations in the gas phase
differ by only at most 16 kJ mol1 <1979JA951>. At the present time, a variety of experimental
studies (e.g., NMR spectra at 4 K for ion in SbF5/SO2CIF <1996JA7849>; deuterium isotopic
substitution and its effect on the NMR data) as well as high-level quantum mechanics strongly
support the conclusion that the stable structure of bicyclo[2.2.1]hept-2-yl cation is the CS bridged
(‘‘nonclassical’’) structure 42 (potential energy hypersurface with a single energy minimum)
<1983ACR440, 1991CR375, 1995AG(E)1393>. Tertiary 2-norbornyl cations remain ‘‘classical’’
carbenium ions but may undergo deformation of their skeletons, compared with their precursors,
due to the C(1,6) bond participation to the positive charge delocalization. Laube
<1995HCA943> has obtained monocrystals for the Sb2F11 salt of 1,2,4,7-anti-tetramethylbicy-
clo[2.2.1]hept-2-yl cation 46 and has measured its structure by X-ray diffraction studies at 110 K
(Scheme 67). The data show an extra-long C(1,6) bond of 1.71 Å and relatively short C(2,1) bond of
1.41 Å and interatomic distance (2.11 Å) between C(2) and C(6). Thus, although this tertiary
carbenium ion has a much weaker electron demand than secondary 2-norbornyl cation, its
deformed structure reveals the importance of limiting structure 460 arising from the C(1,6)
bond participation to the charge delocalization (hyperconjugation 46 $ 460 ).
Me H Me H
1.543(8) Å Me 1.533(8) Å Me
1.409(9) Å
1.710(8) Å 1.491(8) Å H
Me Sb2F11
Me Sb2F11 HMe Me
2.113(9) Å
46 46'
Scheme 67
In super-acid solution 1-methylcyclohexyl cation exists as a rapidly equilibrating pair of

structures 47 and 48 (Scheme 68). In conformer 47, distortion about C(1) renders the 2p(C+)
hyperconjugation with the (C(2)–C(3)) and (C(5)–C(6)) bonds optimal, whereas in conformer
48, bending of the methyl substituent in a ‘‘more equatorial position’’ renders the 2p(C+)
hyperconjugation with the two axial (C(2)–H) and (C(6)–H) bonds optimal
<1987JA7811>. In agreement with the data given above for acyclic carbenium ions in the gas
phase, quantum calculations predict 47 to be slightly more stable (0.96–3.3 kJ mol1) than 48,
whereas the experimental results for the ion in solution show that 48 is more stable than 47.
Using the SCI-PCM solvation model in Gaussian 94, solvated 48 becomes the preferred
conformer. The two isomeric structures 47 and 48 have been called hyperconjomers
<2001JCS(P2)869>.
Me
5 6 Very fast H
“Hyperconjomers”
1
H Me
4 3 2 –140 °C H
H
47 48
Scheme 68
The secondary 2-norbornyl cation is a secondary carbenium ion substituted by a cyclopentyl

moiety, which makes it so special compared with other bicyclic and tricyclic secondary cations such
as 4-homoadamantyl cation <1993JOC7891> or 2-bicyclo[3.2.1]octyl cation <1961JA1397>.
Takeuchi and co-workers <2000JOC1680> have reported the solvolysis of 2-bicyclo[3.2.2]nonyl
p-toluenesulfonate 49 and [1-13C]-2-bicyclo[3.2.2]nonyl p-toluenesulfonate 49* (Scheme 69). The
solvolysis rate constant of 49 was nearly equal to that of cycloheptyl p-toluenesulfonate in TFE
(2,2,2-trifluoroethanol). This indicates that the ethano bridge in 49 does not significantly enhance
the rate and that 49 ionizes without anchimeric assistance. The solvolysis of 49* in MeOH or TFE
gave 2-substituted bicyclo[3.2.2]nonane, exo-2-substituted bicyclo[3.3.1]nonane, 2-bicyclo[3.2.2]no-
nene and 2-bicyclo[3.3.2]nonene whose 13C labels were exclusively found at only two positions with
proportions different from unity. These results were interpreted in terms of equilibrating classical
secondary 2-bicyclo[3.2.2]nonyl cations 50 > 500 .
Wagner–
SN1 Meerwein
13C
OTs OTs
49 49* 50 50'
SOH
Products
Scheme 69
1.19.9.5 Anchimeric Assistance by Heteroelements

The replacement of a CH2 group by a heteroatom can cause changes in rates and mechanism of a
solvolysis due to inductive effects (electronegativity difference), changes in ring strain, and
nonvertical participation by the n electrons. The stereoselective 1,4-rearrangement-ring expansion
of tetrahydrofurans via bicyclo[3.3.0]oxonium ion intermediates has been developed to prepare
oxocanes, as exemplified with the solvolysis shown in Equation (70) <2002OL675>.
H HO
OSO2CH3 H2O
Me ð70Þ
O H THF O
+
Me Me O Me
Me
lonization of trans-1,2-dibromocyclopentane 51 in SbF5/SO2ClF at 120 C gives the bicyclic

bromonium ion 52, which undergoes HBr elimination at 80 C to yield cyclopentenyl cation 53
(Scheme 70). Under the same conditions, trans-1,2-dichlorocyclopentane 54 gives 1-chlorocyclopentyl
cation 56 arising from intermediate 55 followed by hydride shift. The participation of the chlorine atom
to give the bicyclic chloronium ion 57 is less favored than participation by the larger bromine atom
giving 52. Due to this, hydride transfer 55 ! 56 becomes the dominant process <1974JA8112>.
Br SbF5 Br
+ HBr
–120 °C 80 °C
Br
51 52 53
Cl
Cl Cl –120 °C Cl
H ~H
Cl
57 54 55 56
Scheme 70
Chloronium ion transfer from 58 to alkene 59 generates the nonbridged, tertiary carbenium ion 60
(Scheme 71) <1998CC927>. Bridging by the chloro substituent is not observed.
Cl
CH2Cl2
+
SbCl6
58 59
Cl
+
SbCl6
60
Scheme 71
In aqueous trifluoroethanol trifluoroacetates 61a and 61b that are constrained to have
antiperiplanar relationship between the nucleofugal (CF3COO) and the 2-phenylthio and
2-phenylseleno substituents, respectively, are solvolyzed 105 and 106 times faster than the
analogous trifluoroacetate 62 (Scheme 72). Results are consistent with either vertical (hyper-
conjugative 63 $ 630 ) or nonvertical (heteroatom participation: 64) mechanisms
<2002MI2799>.
ZPh ZPh ZPh
But H But But
OCOCF3
61a Z = S 63 63'
61b Z = Se
Z Ph ZPh
But But
64 OH
65
+
But But
62 OCOCF3 66
Scheme 72
1.19.9.6 Hyperconjugation and Participation by Metals

In 1946, Sommer and co-workers <1946JA488, 1946JA485> found that -chlorosilanes are much
more reactive than the corresponding - and -chlorinated derivatives under ionizing conditions
and that the products of reaction are mostly alkenes (e.g., Equation (71)) resulting from an E1-
type of elimination. Compared with nonsilylated systems, the -chlorosilanes generate alkenes
1012 times as fast as the corresponding chloroalkanes. In the gas phase and for secondary
carbenium ions, -Me3Si substitution introduces a stabilization of nearly 126 kJ mol1
<1989JA5586, 1990T2677>.
+
R3Si R3Si + R3Si
+ R3SiCl ð71Þ
– –
Cl Cl Cl
In order to determine whether the -silicon effect is a vertical (hyperconjugative) or a non-

vertical (anchimeric effect) participation by the metallic center, Lambert and co-workers
<1993JA1317> have measured the kinetic isotope effect kH/kD of the SN1 trifluoroacetolyses of
3,5-dinitrobenzoates 67-H and 67-D. At 25 C, kH/kD = 1.17 0.01 typical for an SN1 or E1
process was found, which is consistent only with a vertical -Me3Si substituent effect (intermedi-
ates 68 $ 680 ) and not with the formation of a bridged cationic intermediate of the type 69. In the
latter hypothesis, kH/kD would have been close to unity, by analogy with what is found for the
SN1 solvolyses of trifluoromethanesulfonates 70 and 72 (Scheme 73). When participation of the -
acetoxy group is prohibited for geometrical reasons, as in the solvolysis of 70, kH/kD = 1.20. In
contrast, in the case of the solvolysis of 72 for which participation by the neighboring acetoxy
group intervenes, kH/kD = 1.03 is observed.
SiMe3 SiMe3 SiMe3

SN1, E1
H,D
ODNB H,D
ODNB ODNB
67-H,D kH/kD = 1.17 ± 0.01 68 (Hyperconjugation: kH/kD > 1) 68'
Me DNB = 3,5-(NO2)2C6H3
Me Me
Si
SN1, E1
H,D (Participation: kH/kD ≈ 1)

69
OAc SN1 OAc

OTf CF3CH2OH/H2O
Several products
H 53 °C kH/kD = 1.20
H,D H,D
70 (No anchimeric assistance) 71
H OTf
S N1
OTf
CF3CH2OH/H2O
AcO H,D H,D
H,D O O 53 °C O O
72 72' (Anchimeric assistance) 73
OH D
H2O
+
HO
D OAc
AcO
74 75
Tf = CF3SO2 kH/kD = 1.03
Scheme 73
The vertical, hyperconjugative -silicon stabilizing effect depends on the dihedral angle between
the -silyl substituent and the leaving group as exemplified by the relative rate constants of the
SN1 hydrolyses given in Scheme 74. The strongest hyperconjugative interaction intervenes when
these groups can adopt an antiperiplanar orientation as in 76. -Substituents R3Ge, R3Sn, and
R3Pb are even better than -R3Si in accelerating SN1 solvolysis and E1 eliminations, provided
they can be oriented antiperiplanar to the nucleofugal group (Scheme 75). The protolysis of
aryltrialkyl metals generate cyclohexadienyl cation intermediates in their rate-determining steps.
SiMe3
SiMe3
OMs OMs OMs
krel : 1.0 ~105 ~10 4 (CF3CH2OH/H2O

Dihedral angle Si-C-C-O ~0 ~120° 97:3, 25 °C)
SiMe3
X X X
SiMe3
SiMe3 X
krel : 1.0 z.3 × 104 5.7 × 109 76
Dihedral angle Si–C–C–X ~60° ~180°
Scheme 74
X X X X X
H GeMe3 SnMe3
GeMe3 SnMe3
k rel: 1.0 4.6 × 105 1011 >1.3 × 1011 >>1014
X = ODBN = 3,5-(NO2)2C6H3COO
(SN1 solvolyses in CF3CH2OH/H2O 97:3, 25 °C)
Scheme 75
The latter have relative stabilities following the sequence Si < Ge < Sn < Pb as suggested by the
kinetic data given in Equation (72) <1990JA8120, 1988JOC5422>. for -silyl, -germanyl, and
-stannyl substituent effects on the relative stability of tertiary carbenium ions, see <1999JPO564,
2000JOC3135>.
H , kM X H H2O
ArMR3 Ar–H + HOMR3
(SEAr) MR3
ð72Þ
Si Ge Sn Pb
krel : 1.0 40 4x105 2x108
The stabilizing effect of -tin groups on carbenium ions is significantly stronger that that of
-silicon groups. This is verified with the isolation and the characterization (X-ray structure) of
the secondary cation salts 78 obtained below by the reaction of Me3SnCl and ZrCl4 (or HfCl4)
onto a disubstituted alkene. The isolation of the salt does not require superacidic media (Scheme
76) <2002JA11266>.
Me3Sn CH2Cl2
CH CH(SiMe3) + Me3SnCl/ZrCl4 (HfCl4)
Me3Sn
77
Me3Sn H
CH C Zr2Cl9 (or Hf2Cl9)
Me3Sn CH SnMe3
Me3Sn
78
Scheme 76
1.19.9.7 Characterization of Cationic Electrophiles and Their Reactivity with Nucleophiles

For pure SN2 displacement reactions empirical measures of nucleophilicity may be obtained by
comparing relative rates of reaction of a standard electrophile with various nucleophiles (Scheme
77). One of the measures of nucleophilicity is the nucleophilic constant nCH3l defined by Swain
and Scott <1953JA141> by nCH3l = log[knucleophile/kMeOH] (in MeOH at 25 C), using methyl
iodide as electrophile. Interestingly the values nCH3l do not correlate with the basicity of the
nucleophile. An explanation is given by the hard-soft-acid-base (HSAB) concept <1967JA1827,
1975CRV1>.
MeOH NO3 F AcO Cl NH3 N3 Br MeO
nMeI: 0.0 1.5 2.7 4.3 4.4 5.5 5.8 5.8 6.3
pKa of conjugate acid: –1.7 –1.3 3.45 4.8 –5.7 9.2 4.7 –7.7 15.7
HO NH2OH NH2–NH2 Et3N CN I Ph3P PhS
nMeI: 6.5 6.6 6.6 6.7 6.7 7.4 8.7 9.9

pKa of conjugate acid: 15.7 5.8 7.9 10.7 9.3 –10.7 8.7 6.5
Scheme 77
The activation barrier of an SN2 reaction depends on the exothermicity of the reaction
(Dimroth principle) and on the ease by which the nucleophile can transfer an electron to the
electrophile (Bell–Evans–Polanyi theory, H‡ = Hr + ).
For SN1 displacement reactions, the reactivity of the carbocationic intermediates depends on
their relative stability, steric factors (bulk of the cation and of the nucleophile), solvation effects
(solvent stabilization of ion-pairs, desolvation of the nucleophile and ion-pair) and on the relative
stability of the products (Dimroth principle).
Relative stabilities of intermediates may be evaluated by competition experiments. Less stable
intermediates are expected to be more reactive and less selective. Hence, a very reactive (unstable)
carbocation will exhibit almost equal affinity for strong or weak nucleophiles, and in the limit the
rates are diffusion controlled. A more stable cation will lie in a deeper energy well and will
preferentially undergo reactions, which have low activation energies, assuming kinetic control.
This usually means that reactions with the strongest nucleophiles will be the fastest. The competi-
tion between the highly nucleophilic azide ion and water is often used. The competition constant
æ is given by the relation shown in Equation (73) if the concentration of N3 is in large excess
over that of the starting material RCl. It is defined as the ratio of second-order rate constants for
reaction with azide (kN) and water (kW). A value of æ ffi 1 signifies a very unselective and hence
reactive species. A large value of æ denotes a high degree of selectivity and thus a carbocationic
intermediate of high stability.
+
R–OH + H
H2O kN (Yield of RN3).[H2O]

+ – æ= =
R–Cl R Cl kW (Yield of ROH)·[N – ]
3 ð73Þ
–
N3
R–N=N=N
Linear relationships between æ and the relative solvolysis rates for a number of chlorides have
been reported. The substrates which solvolyze rapidly are the ones which yield stable cations, and
they show large selectivities of æ. The slowest substrates, for example those giving unstable
secondary cations show small æ values <1971JA4821, 1974JOC3085>.
Selectivity–reactivity relationships can be observed and interpreted provided the same type of
intermediates are responsible for the product formation in the investigated series of substrates. As
seen above, at least three kinds of discrete ionized species are formed in the SN1 solvolysis
process. These intermediates can have different selectivities toward various nucleophiles
<1980JA7039> and thus, make an apparent selectivity–reactivity relationship not representative

of the relative stabilities of the carbocation intermediates. Ritchie and co-workers
<1972ACR348> have found that the reactivities of a large number of nucleophiles toward
triarylcarbenium ions can be correlated by Equation (74).
log k = log ko + N+ ð74Þ
where k is the rate constant for the reaction of an electrophile with a given nucleophile in a
given solvent, ko is dependent solely on the electrophile, and N+ is a parameter characteristic of
the nucleophilic system. This correlation represents an apparent failure of the reactivity–
selectivity principle because the N+ values are independent of the nature of the electrophile!
In other words, different carbocation intermediates of different intrinsic stabilities can exhibit
constant selectivity. This is due to solvation effects which modify the relative stabilities of the
ion pairs, of the nucleophiles, and of the transition states of the nucleophile–electrophile combina-
tion reaction <1976JA776>. In the cases studied by Ritchie and co-workers <1972JA4966> the
selectivity, kN/kW, is essentially constant (106 M1) because the azide ion and the solvent respond
similarly to changes in carbocation stability; the nucleophile-trapping processes are activation
limited (desolvation of the nucleophile, the diffusional rate constant ffi5.109 M1s1 for N3)
<1982JA4689, 2001ACR381, 2003JA286>. A downward selectivity break is expected when the
azide-trapping rate constant reaches an invariant, diffusional value, because the rate constant of
solvent trapping remains activation limited and continues to increase as the carbocation becomes
less stable. With stable carbocations, direct observation of recombination barriers of ion pairs by
dynamic NMR spectroscopy has been possible in some cases <1982ACR2>. An energy barrier to
recombination of (CH3OC6H4)3C+ and NCS of 70 kJ mol1 has been measured in SO2/CD2Cl2
<1978CB1659>.
Mayr and Patz <1994AG(E)938, 2003ACR66> have found that the second-order rate con-
stants k of the electrophilic additions to alkenes (uncharged nucleophiles) are correlated by
Equation (75), where electrophiles are represented by a single electrophilicity parameter E,
while nucleophiles are characterized by the nucleophilicity parameter N and the slope parameter s,
which is usually close to unity.
log K (20 °C, CH2Cl2) = s(N + E) ð75Þ
The reactivity scales so-obtained cover more than 16 orders of magnitude; the individual rate
constants are reproduced with a standard deviation of a factor of 1.19. The reactivity parameter E
derived from the reaction of diarylcarbenium ions with -nucleophiles (Scheme 78) are also
suitable for characterizing the nucleophile reactivities of alkynes, metal--complexes, hydride
donors (Table 3) and for characterizing the electrophilic reactivities of heterosubstituted and
metal-coordinated carbenium ion (Table 4) <1995AG(E)2250, 2001JA9500>.
The kinetics of 82 reactions of benzhydrylium ions (Ar2CH+) with n-nucleophiles (their
reactive centers bear nonbonded electron pairs) has also been determined at 20 C. Evaluation
by the Equation log k = s(N + E) delivered the reactivity parameters N and s for 15 n-
nucleophiles (water, hydroxide, amines, etc.). All nucleophiles except water (s = 0.89) and

SCH2CO2 (s = 0.43) have closely similar slope parameters (0.52 < s < 0.71), indicating that
the reactions of most n-nucleophiles approximately follow Ritchie’s constant selectivity rela-
tionship (s = constant). The different slope parameter for water is recognized as the main
reason for the deviations from the Ritchie relationship. Correlation analysis of the rate
constants for the reactions of benzhydrylium ions with the n-nucleophiles (except H2) on the
basis of Ritchie’s Equation log k = N+ + log k0 yields a statistically validated set of N+
parameters for Ritchie-type nucleophiles and log ko parameters for benzhydrylium ions. The
N and s parameters of the n-nucleophiles derived from their reactions with benzhydrylium ions
were combined with the literature data for the reactions of these nucleophiles with other
carbocations to yield electrophilicity parameters E for tritylium, tropylium, and xanthylium
ions. While the E parameters for tropylium and xanthylium ions appear to be generally
applicable, it is demonstrated that the E parameters of tritylium ions can be used to predict
reactivities toward n-nucleophiles as well as hydride transfer rate constants but not rates for
the reactions of tritylium ions with -nucleophiles. It is now possible to merge the large data
sets determined by Ritchie and others with those of Mayr and co-workers and present a
nucleophilicity scale comprising n- (e.g., amines), - (e.g., alkenes and arenes), and -nucleo-
philes (e.g., hydrides) <2003JA286>.
R
Ar
Ar H R Ar R
Fast
Ar H
Slow Ar Ar
MYn + 1 MYn + 1
+ MYn + HY
TiCl2 R
or ZnCl2 Ar H Ar R
Z R Fast
Z = O, S, NR' Ar Z Ar Z
Ar H MYn + 1
+ MYn + HY
Ar Cl
Ar Ar Y
R Fast
Ar R Ar R
MYn + 1 + MYn
M'R3 Ar Ar
MR3 Fast
Ar Ar
MYn + 1 + MYn + R3M'Y
OSiR3
Ar OSiR3 Ar O
Fast
R' = alkyl, O-alkyl Ar R' Ar R'
MYn + 1 + MYn + R3SiY
R2N
Ar NR2
Ar
MYn + 1
Scheme 78
Values given in Tables 3 and 4 can help a rational design of organic transformations and of
carbocationic polymerizations (see Section 1.19.2.4.5). The electrophilicity parameters E and the
nucleophilicity parameters N can be employed for elucidating reaction mechanisms. For
instance, 1,1,3-triarylallyl cations 79 react with isoprene 80 to give Diels–Alder adducts 82
(Scheme 79). The second-order rate constants agree with those calculated for the stepwise
process by the correlation shown in Equation (75). Thus, cycloaddition 79 + 80 ! 83 implies
the formation of allyl cations 81A + 81B in its rate-determining step. If the reaction would be a
one-step, concerted [4 + 2]-cycloaddition, its rate constant would be greater than that calculated
with log k = s(N + E).
In the case of the reaction of iminium ion 84 with cyclopentadiene, giving adduct 85, the
second-order rate constant is 2
104 times larger than predicted for the stepwise cycloaddition
(applying Equation (75)). This suggests a concerted Diels–Alder addition with a degree of
concertedness corresponding to ca. 27 kJ mol1 (Scheme 80) <2000EJO2013>.
1.19.9.8 Carbocation Rearrangements

The intermediacy of carbocations in molecular rearrangements was first suggested by Meerwein
and van Emster <1922CB2500, 1922LA16> in 1922. These authors studied the conversion of
camphene hydrochloride into isobornyl chloride, discovered by Wagner <1899CB2302> in 1899.
Analogous rearrangements in acyclic systems were extensively studied by Whitmore and co-
workers <1932JA3274>.
In simple, acyclic carbenium ions, the energy barriers for hydride and alkyl group migration are
only 8–16 kJ mol1 higher than the energy difference between the rearranging ions. The energy
barrier for the 1,2-hydride shift in the but-2-yl cation (G‡ < 10 kJ mol1) is lower than that in
the 2,3-dimethylbut-2-yl cation (87) (G‡ = 13 kJ mol1) and is attributed to the intrinsic
stability difference between secondary and tertiary carbenium ion (Scheme 81). In the case of
Table 3 Nucleophilic parameters N for neutral nucleophiles.a The s parameter is shown in parenthesis when
it deviates from unity
-Nucleophiles
Cl SiMe3
Co2(CO3)
–2.4 (1.09) –2.2
–3.5 (1.62) –3.5 –1.11 (0.92)

N: –4.47 (1.32)
Ph SiMe2Cl SiPh3
Co2(CO)6
–0.4 –0.4 –0.13
–0.44 (1.06)
Low reactive nucleophiles:
Ph
OMe
SiMe3
0.78 (0.95)
PhCCH
–0.2 0.34 (0.65) 0.7
0.13 (1.27) 0.5
S O
Me
0.96 (1.0) 1.1 1.1 1.26 (0.96) 1.4
1.7
SiMe3 MeO OMe SnPh3 OSi(i-Pr)3
1.8 (0.94) 3.09 (0.90) 3.44 (0.94)

2.82 (0.90) Fe(CO)3
2.48 (1.09)
3.42 (0.94)
O OSiMe3
SiPh3 SiMe3 GePh3
OSiMe3
3.61 (1.11) 4.17 (0.83) 4.41 (0.96) 4.8

3.9
3.8 (0.79)
OSiMe3 OSi(i-Pr)3 OSiMe3 SnBu3 OSiMe3 OSiMe3
Ph
5.46 (0.89)
5.38 (0.85) 5.41 (0.91) 6.57 (0.93)
5.21 (1.0) 6.22 (0.96)
Table 3 (continued)
OSiMe3 OSiMe3 OSiMe3 OSiMe3

N O
SnBu3 OPh OMe OMe O
11.4 (0.83)
7.48 (0.89) 8.23 (0.81) 8.57 (0.84) 10.6 (0.86)
9.1
SiMe3
N
O most reactive nucleophiles
13.36 (0.81)
12.56 (0.70)
Hydride donors
PhSiH3 Ph3SiH PhMe2SiH Et3SiH Ph3GeH Bu3SiH
0.25 (0.67) 2.06 (0.68) 3.27 (0.73) 3.64 (0.65) 3.99 (0.62) 4.45 (0.64)
Ph3SnH Bu3GeH Et3N ! BH3 Bu3SnH
5.64 (0.59) 5.92 (0.73) 8.90 (0.75) 9.96 (0.55)
a
Taken from <2001JA9500>.
the -phenyl cations 88, 90, the phenyl group migrates faster than the hydride and leads to the
corresponding stable ethylenebenzenium ions 89, respectively. In these examples, the bridged
structures are more stable than the classical carbenium ions. In the case of diphenyl-substituted
derivatives, the bridged ions 91 are less stable than the classical benzyl cations 90. Thus, the
energy barrier of 1,2-shifts is a function of the stability of the ions involved and of the nature of
the migrating groups (phenyl vs. H or CH3).
The rates of Wagner–Meerwein rearrangements are higher for carbenium ions in which the
positive charge is highly localized, since the charge then interacts more efficiently with the
potential migration group. Conversely, for carbenium ions in which the charge delocalization
occurs either by vertical or nonvertical stabilization, the rearrangement is relatively slow.
Apart from the 6,2-hydride shift (G‡ ffi 25 kJ mol1), the secondary 2-norbornyl cation 42
undergoes an exo-3,2-hydride shift with a relatively high energy barrier (G‡ ffi 50 kJ mol1)
<1975JA1133, 1974JA189>. These two processes result in a scrambling of all the hydrogen and
carbon atoms in this cation (Scheme 82). In contrast, the energy barrier to the exo-3,2-hydride
shift in the 2,3-dimethylbicyclo[2.2.1]hept-2-yl 92 is only 27.5 kJ mol1 <1982JA7105>. This
result is expected as -delocalization of the positive charge in the classical tertiary carbenium
ion 92 is expected to be less important than in the nonclassical, bridged secondary ion 42. The
energy barrier for 92, remains significantly higher than that measured (G‡ = 13 kcal mol1) for
the 1,2-dimethylcyclopent-1-yl cation <1978JA7082, 2002AG(E)3628>. This difference can like-
wise be attributed to the higher degree of -delocalization in cation 92 compared to the cyclo-
pentyl cation 93. Conformational effects and ring strain effects may also affect the magnitude of
the energy barrier for degenerate 1,2-shifts. Indeed, the endo-3,2-hydride shift in 2,3-exo-dimethyl-
bicyclo[2.2.1]hept-2-yl 94 must have an energy barrier higher than 50 kJ mol1 <1975JA1133,
1974JA189>. The nonamethylcyclopentyl cation 95 in SbF5/SO2ClF shows two types of methyl
substituents in its 1H- and 13C-NMR spectra at low temperatures. Four Me groups undergo rapid
circumbulatory migration with a barrier <8 kJ mol1 while five Me groups are fixed to
ring carbon centers. The process that equalizes the two sets of Me groups has a barrier of
29.3 kJ mol1. Quantum calculations reveal a classical trivalent carbenium ion, but stabilized by
hyperconjugation and partial bridging of two quasi-axial -Me groups. This bridging is related to
the unique dynamic behavior of the nonamethylcyclopentyl cation. In agreement with the calcu-
lations, the 13C-NMR spectra of (methyl-d3)-octamethylcyclopentyl cation in SbF5/SO2ClF at
133 C showed four ring carbon atoms with the proportions 2:2:5:1 indicating that the minimum
energy structure of this ion is not symmetrically bridged <2000JA8067>.
The relatively high energy barrier (G‡ ffi 33.5 kJ mol1) measured for the degenerate hydrogen
scrambling in the benzenium in 96 <1978JA6299> compared with that for the 1,2-hydride shift in
1,2-dimethyl-1-cyclohexyl cation (G‡ ffi 15.5 kJ mol1) <1978JA7082> can be attributed to -
delocalization of the positive charge in 96 (Scheme 83). In the case of the stable heptamethylben-
zenium tetrachloroaluminate 98, an energy barrier Ea = 69 0.8 kJ mol1 (log A = 11.5 0.1)
was measured in CH2Cl2 solution <1983CC1533>. Permethylation of 96 (giving 98) is expected
Table 4 Electrophilic parameters E for carbocationic electrophilesa
H
X Y
X = Y = Cl X=Y=H H = F, H = H X=Y=F X = Me, X = Y = Me X = OPh, Y = H

Y=H
E = 6.02 E = 5.90 E = 5.60 E = 5.39 E = 4.59 E = 3.63 E = 2.90
X = OPh, Y = Me X = OMe, X = OMe, X=Y= X = Y = OMe X=Y= X=Y=
Y=H X = Me N(Me)CH2CF3
E = 2.16 E = 2.11 E = 1.48 Oph 0.0 N(Ph)CH2CF3 E = 3.85
E = 0.61 E = 3.14
X=Y= N O X=Y= X=Y=N

X = Y = Ph2N X = Y = PhNMe
Me2N
E = 4.72 E = 5.53 E = 5.89 E = 7.02 E = 7.69
X + + + Ph
Ph – +
OMe
OBCl3 Ph
+ X
H Cr(CO)3 Cr(CO)3
Ph
X = Cl X=H X = Me X = OMe
E = 3.25 E = 2.93 E = 1.95 E = 0.14 E = 1.06 E = 0.93 E = 0.28
H
+ + + S
R + H
Co2(CO)6 Ph O O S
Co2(CO)6
R=H R = Ph R = Me3Si
E = 0.83 E = 1.55 E = 1.59 E = 0.98 E = 1.36 E = 2.14
Table 4 (continued)
R + S + H
+ +
Ph
S Ph N+
+ Fe(CO)3 Co2(CO)5(PPh3)
Me
Fe H
R=H R = OMe
E = 2.67 E = 2.90 E = 3.50 E = 3.72 E = 5.88 E = 6.15 E = 7.14
+ H + H H
+ +
Fe H Fe + + +
Fe(CO)3 Fe(CO)3 Fe(CO)3
N N OMe
N N N N
E = 7.78 E = 8.54 E = 8.76 E = 8.94 E = 9.19 E = 9.45 E = 10.04
Ph
+
Pd(P(OPh)3)2
E = 10.33
(slow-reacting
electrophiles)
a
Taken from <2001JA9500>.
Ph Ph Ph
H
Ph Ph Ph
+
H Ph Me Ph Me Ph Me
79 80 81A 81B
ZnCl2.Et2O, –70 °C
Ph Ph
Ph Ph H
Ph –H Ph
OAc
Ph Me Ph Me
Ph 83 82
Scheme 79
N CH2Cl2, 20 °C
+ N
or CH3CN
SbCl6 “concerted” SbCl6
85%
84 85
Scheme 80
H
H ∆G‡ <10 kJ mol–1 H
H H H H
H 1,2-Hydride shift H
86 s-Bu
H
∆G‡ = 13 kJ mol–1
H H
1,2-Hydride shift
87 351
Ph H H Ph
H H H H
1,2-Phenyl shift R R
R R R R
88 R = H, Me 89 (stable)
90 R = Ph 91
Scheme 81
to enhance the charge delocalization, thus making the 1,2-shift more difficult. Kinetic measure-
ments on the degenerate rearrangements of acyclic carbenium ions suggest that 1,2-methyl shifts
are not much easier than the corresponding 1,2-hydride shifts <1978JA7082>.
1.19.10 CARBODI- AND POLYCATIONS

Small carbodications are abundant in the mass spectra of hydrocarbons. Well characterized (with
the help of ab initio quantum calculations) are CH4++, C2H6++, C3H6++, and C4H2++
<1989JA1155, 1989JA8995>. The parent six-coordinate diprotonated methane, CH6++, has a
C2V structure <1996JA8503>. Quantum calculations predict the seven-coordinate triprotonated
methane, CH7+++, to be an energy minimum with a C3V-structure <2001JOC5943>.
A large number of di- and polycarbenium ions have been obtained in super-ionizing media.
Examples as shown in Scheme 84 <1995JA12005, 1997JA3407>.
H ∆G‡ ≅ 50 kJ mol–1
H 42
Degenerate H
H
exo-hydride shift
H H
42
H ∆G‡ ≅ 27.5 kJ mol–1 Me
exo-Hydride H
Me
Me shift
Me
92 92'
42
H
Me ∆G‡ ≅ 13 kJ mol–1
H Me
1,2-Hydride shift
Me Me
93 93'
Me
Me 92
Degenerate Me
H
Me endo-hydride shift
H
94 94'
Me Me Me
Me Me
Me Me Me Me
Me Me
Me
Me
95 ( Me : fast migrating 95'

methyl groups)
Scheme 82
H H H H
H H
∆G‡ ≅ 33.5 kJ mol–1 H
H H 1,2-Hydride shift
H Cyclohexadienyl
cation
96 97 96
H Me Me Me
Me Me Me
Me
∆G‡ ≅ 69 kJ mol–1 Me
Me Me 1,2-Methide shift Me Me
Me Me
AlCl4 AlCl4
98 99
Scheme 83
1.19.11 CARBOCATIONS IN LIVING SYSTEMS

Wallach noted that many compounds, especially the fragrant principles of plants (essential oils)
could be formally dissected into branched C5 units called isopentenyl or isoprene units. For
instance, terpenes are multiples of C5 units linked together head to tail (isoprene rule
<1953E357>). Several modes of cyclization are conceivable and lead to various skeletons. The
terpenes are classified according to the number of C5 units: monoterpenes: C10, sesquiterpenes: C15,
diterpenes: C20, sesterterpenes: C25, triterpenes: C30, and tetraterpenes: C40. In 1956 Folkers and
co-workers <1956JA4499> isolated the easily incorporated mevalonic acid, and subsequently
Cornforth and co-workers <1966JBC3970, 1969NAT1212> showed how it functions as a building
block during the biosynthesis of the terpenes. They demonstrated that isopentenyl diphosphate
(IPP) and dimethylallyl diphosphate (DMAPP) derived from mevalonic acid are the universal
precursors of terpenes, one of the largest group of natural products comprising numerous medicin-
ally relevant compounds such as vitamins, hormones, and antitumor agents (Taxol)
<B-1992MI020>.
Ar Ar Ar Ar OH OH
HSO3F HSO3F
Ar Ar –78 °C Ar Ar
Ar Z Ar SbF5
Ar Ar
Ph Ph
Ar Ar
Ph
Ph
Ar Z Ar
Ph Ph
Z = CH2CH2; CH=CH; -C≡C-; ; Ph
Ph
Cl SbF5
SO2ClF
Cl
Cl
SbF5 "H "

C20H19
SO2ClF –H2
–78 °C
1-Chlorododecahedrane
(Oxidation)
SbF5, SO2ClF
–78 °C
Pagodane
SbF5
SO2ClF
F
Scheme 84
1.19.11.1 Mechanism of the Prenyl Transfer Reaction and Monoterpene Biosynthesis

Using fluorinated analogs of IPP and DMAPP, it could be shown that prenyl transfer takes place
by an ionization/condensation/elimination mechanism (Scheme 85). The exact timing of conden-
sation with regard to ionization is not known, but the presence of C(3)C(4) double bond of the
isopentenyl pyrophosphate is not required for the enzyme to trigger ionization of the allylic
pyrophosphate <1978ACR307>.
OPP
HS
HR
OPP OPP
DMAPP
Slow OPP
trans-Geranyl pyrophosphate (GPP)
OPP
IPP
OPP
OPP
all-trans-Farnesyl pyrophosphate
Scheme 85
trans-Geranyl pyrophosphate (GPP) is the precursor of most monoterpenes. It is isomerized

first into (3(R)) or (3(S))-linallyl pyrophosphate (LLP) and neryl pyrophosphate (NPP) before
cyclization <1985ACR220, 1987CRV929> as summarized in Schemes 86 and 87. These
bioreactions involve the intermediacy of tertiary carbenium ions.
Prenylation is not only a reaction limited to the biosynthesis of terpenes. Many important
proteins, nucleic acids, and cell wall components are prenylated within the cell. The reaction are
catalyzed by prenyltransferases using prenyl pyrophosphate as reagent <1990NAT425>.
Prenylation of aromatic substrates generates valuable compounds that can be catalyzed in vitro
by prenyltransferases isolated from rat liver, plant, yeast, bacteria, or from cloned E. coli strains
overproducing these enzymes <B-1999MI79>.
1.19.11.2 Biosynthesis of Sesquiterpenes, Diterpenes

Prenylation of all-trans-geranyl pyrophosphate generates all-trans-farnesyl pyrophosphate,
Schemes 86 and 87, the common precursor of sesquiterpenes. The latter is isomerized into cis,
trans-farnesyl pyrophosphate and finally into nerolidyl pyrophosphate. For instance, cyclization
of cis, trans-farnesyl pyrophosphate generates bisabolyl cation intermediate that can be rear-
ranged into various bicyclic cationic intermediates that react with H2O or eliminate a proton to
give sesquiterpenes such as -bergamotene, campherenol, sirenin, -acoradiene, and -cedrene
(Scheme 88).
Geranylgeranyl pyrophosphate is the precursor of the diterpenes. Phytol, 6,7,10,11,14,15-hexa-
hydrogeranylgeraniol, forming the lipophilic side chain of chlorophyll, is the most prominent
member of linear diterpenes. The biosynthesis of the majority of diterpenes is initiated by
electrophilic attack of the terminal double bond. This triggers a series of cyclizations leading to
mono, di-, tri-, and tetracyclic derivatives <1971MI395, 1976MI73>. The most important mono-
cyclic diterpene is Vitamin A (or retinol), essential in the process of vision. More often the
cyclization progresses to the bicyclic cation 100 (trans-decalin system), which eliminates a proton
to give labdadienyl pyrophosphate or reacts with water to furnish sclareol. Intramolecular
alkylation of the latter may generate 8-pimarenyl cation, the precursor of abietic acid and
rosenonolactone. The bicyclic cation 100 can also undergo 1,2-hydride and 1,2-methide shifts to
produce products such as hardwickiic acid (Scheme 89) <2002JA6998>.
Many proteins are modified in the cell by farnesylation and geranylgeranylation
<1996MI241>. The finding that the Ras protein is farnesylated and that inhibition of the enzyme
that catalyses this process (protein farnesyltransferase) in a variety of mutant Ras-induced cancer
models arrests the growth of tumor cells has resulted in the intense search of inhibitors that
prevent farnesylation <1997MI437, 1997MI2971>. In the case of Rat protein farnesyltransferase
an associative transition state has been proposed. This protein farnesyltransferase is a zinc
metalloenzyme that catalyzes the transfer of a 15-carbon farnesyl group to a conserved cysteine
OPP
OPP
OPP
GPP
OPP
Neryl pyrophosphate (–)-(3(R ))-LPP
(NPP)
Tight ion pair intermediates
OPP
γ-Terpinene (+)-α-Pinene
E1 Cyclization E1
1,2-H Cyclization
shift
α -Terpenyl cation
Homoallyl → Cyclization W–M
W–M
cyclopropylmethyl
E1 SN1 S N1
OH
OPP
(+)-Sabinene (+)-Bornyl (–)-endo
pyrophosphate Fenchol
W–M = Wagner–Meerwein rearrangement; E1 = elimination of H+
Scheme 86
residue of a protein substrate. By changing the metal and using modified substrates the mechan-
ism that best fits the data implies an ‘‘exploded’’ transition state where the metal-bound peptide/
protein sulfur has a partial negative charge and carbon center C(1) of farnesyl pyrophosphate
(FPP) has a partial positive charge, and the bridge oxygen between C(1) and the -phosphate of
(FPP) has a partial negative charge. This transition state suggests that stabilization of the
developing charge on the carbocation and pyrophosphate oxygen centers is an important catalytic
feature <2000B2593>.
1.19.11.3 Squalene and Triterpenes

Squalene was first isolated from shark liver, but was later found to be ubiquitously distributed.
By folding this compound in certain modes one can construct the basic triterpenoid skeletons
with angular methyl groups and side chain in correct positions. Squalene is the precursor of
PPO
PPO
PPO
(–)-(3S)-LPP
(linallylpyrophosphate)
Tight ion pair intermediates
PPO
E1
(–)-α-Pinene Myrcene
E1 Cyclization
Cyclization E1
(–)-Limonene
W–M
E1 Cyclization
W–M
(–)-β-Pinene
SN1 E1
W–M = Wagner–Meerwein
rearrangement
E1 = elimination of H+
PPO
(–)-Bornyl pyrophosphate (–)-Camphene
Scheme 87
cholesterol. It consists of two all-trans farnesyl groups joined tail to tail. The mechanism of this
coupling was indicated by the isolation of presqualene pyrophosphate that has a cyclopropane
unit (Scheme 90).
Squalene can be folded in a number of ways both with regards to ring size, start and terminus
of the cyclization <1993CR2189, 2000AG(E)2812, 2002JA10286>. There is also the possibility
that the naturally occurring all-trans form isomerizes at olefinic centers at one or the other stage
of the cyclization. With a few exceptions, the A, B, and C rings are six-membered rings and the
cyclization is always initiated at the terminal alkene unit. After the first cyclizations generating
carbocation intermediates, the latter can undergo Wagner–Meerwein rearrangements or/and
proton elimination.
In 1955, Stork and Burgstahler <1955JA5068> and Eschenmoser and co-workers
<1955HCA1890> suggested that the conversion of squalene into lanosterol implies the inter-
mediacy of cation 102 that initiates a stereospecific polycyclization in which all the alkene
moieties are oriented trans-antiparallel (Scheme 91). In 1966, van Tamelen <1966JA4752> and
Corey <1966JA4751> demonstrated that squalene-2,3-oxide 101 is an intermediate for the
biosynthesis of lanosterol and dammaradienol 103. These biotransformations are simpler than
OPP
OPP
OPP
Nerolidyl pyrophosphate cis-trans-Farnesyl trans-trans-Farnesyl

pyrophosphate pyrophosphate
1,2-H-shift c
Me addition H
b Ha
H
H
Bisabolyl cation
H2O
H 8 H
OH
α -Cedrene α -Acoradiene (4S,8S)-α -Bisabolol
Bisabolyl cation
a b c
H2O
–H [O]
CH2OH
OH
H
H
CH2OH
β -Bergamotene Campherenol Sirenin
Scheme 88
conversion of 101 into lanosterol as the carbon skeleton is not rearranged. Corey and co-workers
<1991JA8172> have isolated an enzyme called 2,3-oxidosqualene-lanosterol cyclase (sterol
cyclase) from Baker’s yeast (Saccharomyces cerevisiae) and have demonstrated that the C(10)
methylene group of 101 plays a key role in the required folding of this compound for its
transformation into lanosterol <1992JA1524>. It was shown that sterol cyclase isolated from
pig liver catalyzes the isomerization of (20E )-20,21-didehydro-18-tritio-2,3-oxidosqualene 104
into protostanediol 106.
In this case, cation 106 is postulated as an intermediate (Scheme 91). Its quenching with H2O is
stereospecific and is faster than rotation about the (C(17),C(20)) bond in 105, and faster than
migration of hydrides.
The synthetic analog of 106, benzoate 107 <1990JA6429> was treated with BF3 at 90 C in
CH2Cl2, 94% of alkene 108 was isolated (Scheme 92). Similarly, the 20-epimer of 106 was
OP OP
2 1 10 9
8
H 4 6
3 5 H 7
H
trans-trans-Geranylgeranyl 100
pyrophosphate OP
H
a
H
H
12
11 13
OH Ha
1 14
2 9 H
10 8
3 5 7 b
4 H 6
Vitamin A
8-Pimarenyl cation
a
b –H SN1
H2O
H OP
H H
–H
H 100
H
H [O] H H
[O]
Pimaradiene Labdadienyl 100
[O] pyrophosphate
a –H
–H [O] –H [O] H2O
OH
O H H H
O
O H H OH
H H H
HOOC COOH
Rosenonolactone Abietic acid Hardwickiic acid Sclareol
Scheme 89
converted chemically into the 20-epimer of 108, with high stereoselectivity. These reactions
imply highly stereoselective ionization of alcohol at C(20), giving a tertiary cation that subse-
quently undergoes a 1,2-hydride shift to give tertiary cation 109, which then undergoes four
successive (or concerted) migrations of hydride and methide groups (Wagner–Meerwein rear-
rangements). Wagner–Meerwein rearrangements are suprafacial. When two 1,2-shifts are coupled,
the migrating groups must adopt an antiperiplanar relationship for a facile, concerted reaction
(Scheme 92).
1.19.11.4 Nonmetal Hydrogenase-catalyzed Hydrogenation

The formation and consumption of H2 by microorganisms (anerobic protozoa, anerobic archea)
is catalyzed by enzymes named hydrogenases that are iron–sulfur proteins, most of them
additionally containing nickel. Hydrogenase without nickel and iron–sulfur has been found
in some methanogenic archea <1996CRV3031>. It catalyzes the reversible reduction of
R R R
R
Me
SN2 R R
+
PPO
H OPP PPO PPO
H
H H H H
Farnesyl pyrophosphate
1,3-elim –H
R R
Me H Me
H R H R
R
H H R
H H PPO H
OPP
(1R,2R,3S)-Presqualene pyrophosphate
R
R
H NADPH
R
(reduction)
H R
H
Squalene
Squalene
Scheme 90
N5,N10-methenyltetrahydromethanopterin (CHH4MPT+) with H2 to N5,N10-methylene-5,6,7,8-

tetrahydromethanopterin (CH2¼H4MPT) and a proton, an intermediate step in the formation of
CH4 from CO2 + H (Scheme 92).
It has been proposed that the reaction involves the formation of a complex between
dihydrogen and the diaminomethyl cation of CHH4HMPT+, in an analogous manner to the
hydrogenation of t-butyl cation in super-acidic media that equilibrates with isobutene and proton
<1995AG(E)2247>.
1.19.11.5 Carbocations and Medicinal Chemistry

The antiestrogen Tamoxifen 111 is widely used in the treatment of breast cancer
<1993BJP507>, and has received considerable recent publicity as a prophylactic agent for
women considered at risk of this disease. Like most carcinogens, Tamoxifen gives rise to
DNA adducts <1996MI4374, 1998MI201>. Metabolic activation is required before adduct
formation, and the key intermediate is -hydroxytamoxifene (112; Scheme 93). As a further
activation event, sulfation into 113, is also invoked as shown in Scheme 94. Sulfate 113
solvolyses in H2O/CH3CN to generate the Tamoxifen carbocation 114 > 115 that has a lifetime
of ca. 100 s <2000CJC1186>.
The carcinogenic activity of polycyclic aromatic hydrocarbons is due to their initial epoxidation
by cytochrome P-450 monooxygenases <1967MI1, 1980MI1107>, followed by epoxide hydrase
enzyme-mediated hydrolysis to the corresponding trans-diol, and a second epoxidation at the
adjacent double bond (Scheme 95). This metabolic process yields a diol epoxide 116 able to
alkylate DNA <B-1991MI021>. A critical step in the mechanism of carcinogenesis is the epoxide
ring opening to yield a carbocation 117 <1999JOC7738>.
The cytotoxicity of carbocations can be exploited to fight parasites (Scheme 96). For instance,
the antimalarial -sulfonylendoperoxide 118 undergoes a Fe(II)-induced degradation that gener-
ates cationic species 119 responsible for the alkylation of vital biomolecules of the parasite
<2001JOC5943>.
Oxidation H H
Squalene H
H H
O HO
(3(S))-2,3-Oxidosqualene 101 102

H
H H
H
HO
HO
H
Lanosterol Dammaradienol 103
20
Me
20
T 18 Sterol cyclase Me
Me H
from pig liver Me 17
HO 14
23 °C, pH 7
H Me
O Me T
H
104 105
OH
H Me
T
H2O
Me Me
H
HO
106
Scheme 91
OH
O O COO
H OH OH OH HO O
O N
H O P O
N COO
HN O
HMe
Me
H2N N N
H
H
CH H4HMPT
H2 H2
Hydrogenase H R
H H O H N
Me N Me
R H HN + H
H
N Me
N H2N N N
H
CH2=H2HMPT
Scheme 92
Me 20 OH 20 H
H H Me Me Me
Me H H
17 BF3, CH2Cl2
Me Me Me H
94%
H Me Me
BzO BzO H
Me Me Me Me
107 108
i. Ionization
ii. 1,2-H-shift –H (elimination)
H H
H BF3OH H Me
11 H
H
Me Me Quadruple antiperiplanar Me H
H Me 1,2-shift Me
3
BzO H BzO
Me Me Me Me
109 110
BF3, CH2Cl2
20-epi-107 20-epi-108
90%
Scheme 93
HO OSO3
Ph Sulfotransferase H2O/CH3CN
Ph Ph
Ar Ph
Ar Ph Ar Ph
111 (Tamoxifen) 112 113
Ar = Me2NCH2CH2 O
Ph Ph Ar Ar
+
Ar Ph Ar Ph Ph Ph Ph Ph
114 114' 115 115'
Scheme 94
P-450 EH
(O) +H2O
HO
O
OH
Benzo[a]pyrene
O
P-450 pH 7 HO
(O) Very fast
HO HO
OH OH
116 117
Scheme 95
OH OH
α -Scission
SO2Ph SO2Ph –PhSO2CH2COMe

O Fe(III) O
O O
118
OH OH
Fe(III) O Fe(II) O
119
Scheme 96
1.19.12 CARBOCATIONIC POLYMERIZATION OF ALKENES

Alkenes may be polymerized to their corresponding homopolymers via a variety of processes, of
which the most important are free-radical polymerization (see Section 1.19.3.4.9), anionic poly-
merization, coordination/migration (Ziegler–Natta) polymerization and carbocationic polymeri-
zation <B-1999MI022>. Several well-characterized Ziegler–Natta catalysts (e.g., TiCl4/Et3Al) can
also induce carbocationic polymerization of styrene, isobutene, vinyl ethers, and N-vinyl carba-
zole <2000CRV1471>.
The first polymer of isobutylene was reported in 1873 <1873MI146>. During the 1980s
Kennedy and co-workers described the living cationic polymerization of isobutylene producing
high molecular weight polyisobutylene (PIB, Mn = 120 000 g/mol) with relatively narrow distribu-
tion (Mw/Mn = 1.1) <1988MI473>. PIB-based materials are of interest due to a unique combina-
tion of properties such as low air permeability, high damping, and environmental and chemical
stability. These materials have been used in applications such as tubes, tyre inner liner, shoe sole,
adhesive components, motor oil additives, and polyethylene additives to improve resistance to
environmental stress cracking. The living polymerization of isobutylene made possible the synth-
esis of PIB-based thermoplastic elastomers <1996MI462> and other architectures such as star-
branched <1981MI67>, brush <1998MI85> or hyperbranched structures <1998MI1117,
2001MI565>.
The active sites of carbocationic initiation of alkene polymerization may be generated in a
number of ways including protonation of the alkene and electrophilic addition of R3Si+X or
R3C+X. The counter-ion X must be a very poor nucleophile, otherwise carbocations will
combine to give neutral compounds. Propagation involves repeated additions of alkene molecules
to the carbocationic intermediate, which migrates well away from the site of initial attack. Thus
the C¼C double bond must be the most nucleophilic species of the system. Chain-transfer may
involve deprotonation of the carbocationic end group by a monomer. Chain transfer is often the
limiting factor on molecular weights and thus the nature of the Lewis base X is very important.
Chain termination occurs if trace amounts of good nucleophiles are present (e.g., H2O, ROH) and
can quench the carbocationic site irreversibly. To obtain polymers of high molecular weights, it is
essential to carry out cationic polymerizations at low temperature (80 to 100 C). A compre-
hensive mechanism for living isobutylene polymerization is given in Scheme 97. A typical
initiator is 2-chloro-2,4,4-trimethylpentane (TMPCl) with the Lewis acid TiCl4 (co-initiator).
Solvent can be hexane, MeCl, or methylcyclohexane/MeCl mixtures. Kinetic measurements
show second-order dependence on the effective TiCl4 concentration <1999MI553, 2000MM53>.
1.19.13 TRICOORDINATE RADICALS (P. VOGEL, EPFL, LAUSANNE, SWITZERLAND)
1.19.13.1 General Features of Radical Formation

Radical reactions are now an important tool of organic synthesis, driven in part by the good
understanding of their dynamics and their structures. We restrict ourselves to gas phase and
solution phase studies, but realize the important contributions of studies in heterogeneous systems
and ordered environments, including living systems <2003JA13443, 2003CC2843>.
Initiation
TiCl4
Cl + TiCl4 TiCl5 Ti2Cl9
TMPCl
Cationation
TiCl5
Ti2Cl9
Chain Transfer Propagation
–HTiCl5 TinCl4n + 1
n
OR + HTiCl5
TiCl5 Chain termination
Cl + TinCl4
n
(dormant chain end)
Living polymerization
Polymer capped with t-butyl Heavier polymer capped with TMP
Scheme 97
1.19.13.1.1 General literature survey

Since 1970 there has been a dramatic increase in the generation, understanding, and use of
radicals in synthesis and this is reflected in the number of literature reviews. General texts in
the field include: Williams and Kelly <B-1995MI001> and Gilchrist <B-1995MI002>. Reviews
on atom transfer addition to alkenes and atom transfer in radical polymerization
<2002CUOC67>, on the prediction of reactivity in radical polymerization <2002CUOC83>,
on free-radical carbonylations <1996AG(E)1051> and acyl radical chemistry <1999CRV1991>,
on the chemistry of -(acyloxy)alkyl and -(phosphatoxy)alkyl radicals <1997CRV3273>, on
radical reactions as key steps in natural product synthesis <1996AG(E)405, 1997CRV53,
1996CRV177, 1996CRV195, 1996CRV207, 1996CRV289, 1996CRV339, B-2002MI003>, on the
factors controlling the addition of carbon-centered radicals to alkenes <2001AG(E)1340>, on the
persistent radical effect <2001CRV3581> and its role in alkene polymerization
<2001CRV3611>, on living radical polymerization <2001CRV3661, 2001CRV3689> have been
published. Thermochemical data obtained by mass spectrometry methods have been summarized
recently <2002CRV2855>. Reviews on more specific topics are: bridgehead radicals
<1989CRV975, 1992CSR105>, the captodative—or synergistic <1989JA7558>—effect
<1985ACR148, 1988PAC1635>, cyclopropyl methyl radicals <1992MI71, 1993CSR347>, dia-
stereofacial selection in intermolecular reactions <1991ACR296, 1994SL1>, organosilane
<1992ACR188> and organotin reagents <B-1986MI004, 1987S665>, retrosynthetic planning
<1991SL63>, and ring expansions <1993CRV2091>. Recent advances on radical nucleophilic
reactions <2003CUOC747>, the discovery and development of cyclobutanone-based free radical
ring expansion and annulation reactions <2002CUOC1015>, tin hydride-induced intramolecular
aryl radical cyclizations <1999CUOC469>, addition of free radicals to C60 <1998ACR63>,
homogeneous gas phase polymerization <1997ACR297>, the use of xanthates in radical reac-
tions <1997AG(E)673>, and the activation of alkanes with radicals <2002CRV1551> have been
reviewed. For annual reports, see <2002AR(B)317, 2001AR(B)3, 2000AR(B)3, 1999AR(B)3,
1998AR(B)321, 1997AR(B)55, 1996AR(B)51, 1996AR(B)103>.
1.19.13.1.2 Historical background

In the middle of the nineteenth century it was believed that the ethyl radical, CH3CH2, could be
liberated, for instance by reaction of ethyl bromide with certain metals. However, it was soon
realized that the gaseous products so-obtained are mixtures of ethane, ethane (Equation (76)) and
butane, forcing the conclusion that carbon is tetravalent in all its compounds. In 1900, Gomberg
<1900CB3150> at the University of Michigan demonstrated that triphenylmethyl (trityl) radical
equilibrates with 6-triphenylmethyl-3-diphenylmethylidenecyclohexa-1,4-diene, then believed to
be hexaphenylethane (Equation (76)). The combination of two trityl radicals into hexapheny-
lethane is impeded by Front- and Back-strain between the phenyl substituents. Conjugation
between the carbon-centered radical and the -electrons of the phenyl ring is not optimal in the
trityl radical due to gauche interactions between the o-hydrogen atoms of the phenyl groups that
force the radical to deviate from planarity and to adopt a propeller shape.
H H Ph
H 25 °C
2 H
H Ph
Benzene Ph
Ph Ph
ð76Þ
H H
Trityl radical 6-Triphenylmethyl-3-diphenyl-
methylidenecyclohexa-1,4-diene
Ph3C–CPh3
During the 1920s, Paneth <1929CB1335> demonstrated that alkyl radicals exist as reactive
intermediates. During the 1930s, Hey and Waters <1937CB169> observed that the decomposition
of aromatic peroxides and azocompounds led to the phenylation of benzene derivatives, reactions
with regioselectivities quite different from those expected for aromatic electrophilic substitutions,
thus forcing the conclusion that the reaction species is the electrically neutral phenyl free radical.
In Chicago, Kharasch <1937JOC393> discovered in 1937 that the addition of HBr to alkenes
does not always follow the Markovnikov regioselectivity rule. Especially when initiated by the
decomposition of peroxide, the reaction of HBr with an alkene implies a radical chain process.
The addition of HBr to the alkene might be accompanied by the formation of a homopolymer of
the alkene. In 1937, Flory <1937JA241> described the kinetics of the radical-induced polymer-
ization of alkenes. Of all the various type of polymerization processes that are available today, the
free-radical polymerization process is probably the most popular. It is easy to perform, requires
minimal purification of the monomers (alkenes, dienes, etc.), can be performed under a wide
variety of conditions (including in water) and is economical (see Section 1.19.3.6).
1.19.13.2 Radical Initiators in Organic Chemistry

The most common methods used today to engender radicals and a selection of their reactions
with applications in modern organic synthesis is described. The long-lived tricoordinate carbon
radicals have paramagnetic properties and thus can be detected by electron spin resonance (ESR)
spectroscopy <2000MI55>. When a reaction that generates radical intermediates (transient
radicals with a given concentration) is run in the probe of an NMR machine, unusual signals
might be seen with enhanced intensities or negative intensities (emission). The phenomena are
inferred as the chemically induced dynamic nuclear polarization (CIDNP) <1975MI319,
1972ACR18> and thus can be used to detect transient radicals.
The chemistry of radical reactions has made fantastic progress as a consequence of the discovery
of new initiators. Radical reactions at low temperature using highly active initiators faciliate the
generation of radicals at specific positions in the molecule and thus lead to high stereocontrol.
1.19.13.2.1 Thermal radical production

Compounds with homolytical bond dissociation enthalpies DH (R/X) < 140 kJ mol1 can be
used for the thermal generation of radicals; they are the peroxides, azo compounds (Table 5),
nitrite esters, and esters of N-hydroxy-2-thiopyridone (PTOC: pyridine thiocarbonyl esters;
Table 5 Approximate half-lives ( 1=2) for the unimolar decomposition of peroxides and azocompounds and
other radical initiators at 80 C unless indicated otherwise
Me Me Me
80 °C
X N N X N + 2X
Me Me Me
X= Me Bn Pho N C (AIBN) EtOOC Ph

τ½ : ~10 6h ~117000 h ~36200 h 1.5 h ~3 min ~2 min
O O
∆
ButO OC CO O-But 2ButO• + 2CO2 24 h at 20 °C (PhH)a
DPBO (di-t-butyl peroxyoxalate) 0.7 h at 45 °C (PhH)
∆
ButO N N O-But 2ButO• + N2 7 h at 45 °C (isooctane)
DTNB (di-t-butyl hyponitrite)
(ButO)2 > 2 ButO 3000 h

ButOO2CMe > ButO + AcO 600 h
PhCO2O-But > ButO + PhCO2 120 h
(PhCO2)2 > 2 PhCOO ! Ph + PhCO2 + CO2 3 h
(MeCOO)2 > 2 AcO ! Me + MeCO2 + CO2 3 h
BnCO2O-But ! Bn + CO2 + ButO 0.5 h
PhOCMe2CO2O-But ! But + CO2 + ButO 0.2 h
PhOCMe2CO2O-But ! PhOCMe2 + CO2 + ButO 1.2
105 h
a
Taken from the reference <B-1994MI010, B-1998MI1610>.
Scheme 98). For precursors with higher homolytical bond dissociation enthalpies, flash pyrolysis is
a means to general radicals in a rare gas <1992MI4003, 2003CSR59, B-1994MI005,
B-1998MI1610>.
∆
+ RCOCl
X–H
N S Na N S N SH
O O O
+ CO2
PTOC R + R–H
RCOOH, Me3N
DMAP (cat.)
NMe2
PF6
Me2N Cl NMe2
N S N S NMe2
OH O PF6
Scheme 98
The introduction of O-acyl thiohydroxamates (mixed anhydrides of carboxylic acids and

thiohydroxamic acids) by the Barton group in 1983 <1983CC939> has provided one of the
mildest and versatile sources of carbon-centered radicals. Their preparation consists in reacting
the sodium salt of 2-mercaptopyridine-N-oxide with the corresponding acyl chloride using
dimethyl formamide-catalyzed reaction with oxalyl chloride (Scheme 98) <1985T3901,
1986PAC675, 1989CRV1413, 1992T2529, 1994PAC1943> Other methods are also available
(Scheme 99) <B-2001MI109>.
Ag2N2O2
ArOH ArOCH2Cl [ArOCH2ON=]2
CD3CN, 23–37 °C
Ea ≅ 105 kJ mol–1; log A = 14.8
β -Scission
ArOOAr ArO• + CH2O 2ArOCH2O• + N2
Dismutation
ArOCHO ArOCHOH
H2O
ArOH + HCO2H ArOH + CH2O
Scheme 99
Tin-centered radicals are used routinely to initiate radical transformations (Equation (77)).
These radicals can be generated by heating hexaalkylditin or hexaarylditin above 200 C (or by
photolysis) (DH (Me3Sn/Me3Sn) ffi251 kJ mol1: standard dissociation enthalpy = heat of reac-
tion Me3Sn-SnMe3 > 2 Me3Sn).
∆
R3Sn SnR3 2R3Sn• ð77Þ
200 °C
The strength of metal–carbon bonds and of metal–metal bonds decreases as the size of the
element increases. Tetraethyllead (Et4Pb) has a particularly weak PbC bond (standard dissocia-
tion enthalpy: DH (Et/EtPb) ffi125 kJ mol1), which accounts for the ease of homolysis and
hence the effectiveness of this reagent as an anti-knock agent in gasoline <2002JCS(P2)367>.
Homolytic bond cleavage of the MnMn bond in decacarbonyldimanganese (Mn2(CO)10) can
be achieved by heating or by photolysis (standard dissociation enthalpy: DH (Mn(CO)5/
Mn(CO)5) ffi 159 20 kJ mol1 <1998JOM123, 1990CRV629>) (Equation (78)).
∆ ð78Þ
(OC)5Mn Mn(CO)5 2 •Mn(CO)5
Hyponitrites decompose at ambient temperature to give N2 and alkoxy radicals. In the case of
aryloxyalkoxy radicals, very fast -scission occurs yielding aryloxy radicals (Scheme 99)
<2002AG(E)804>.
1.19.13.2.2 Photo-induced homolyses

Photolysis (UV, visible light) or high-energy radiation (e.g., X-rays, -rays) of organic, organo-
metallic, and inorganic compounds generates radicals. For example, azo compounds and per-
oxides (Table 5) that absorb UV light are photolyzed into the same radicals as those engendered
on heating. Other examples of light-induced homolyses are given in Scheme 100.
1.19.13.2.3 Electrochemical generation of radicals

The first important electrochemical reaction of CC bond formation was discovered by Kolbe in
1849 when he electrolyzed carboxylates and obtained homocoupling of their alkyl groups
<1849LA257, 1860LA125>. This reaction generates alkyl radicals by anodic decarboxylation
(Scheme 101).
Heterocoupling (cross coupling) of two different carboxylates (mixed Kolbe electrolysis) is a
method to prepare unsymmetrical compounds. However, as the intermediate radicals combine
statistically, the mixed coupling product is always accompanied by two symmetrical products
resulting from the homocoupling. If the less costly carboxylate is used in excess, the yield of the
product of heterocoupling can be satisfactory and the method has been applied to prepare a large
number of important fatty acids, pheromones, and other natural products of biological interest
<1990TCC91>.
hν
Cl2 2Cl• (79)
hν
Br2 2Br• (80)
hν
R–I R• + I• (81)
hν
RCOR' RCO• + R'• (82)
Norrish I
R• + •COR' (83)
PhSSPh hν 2PhS• (84)
hν
MeSe–SeMe 2 MeSe• (85)
hν
BrCCl3 Br• + •CCl3 (86)
hν R• + •HgX
RHgX (87)
hν
R3Sn–SnR3 2R3 Sn• (88)
hν
(OC)5Mn–Mn(CO)5 2(CO)5Mn• (89)
O
hν •
R3B + R' R' C OBR2 + R• (90)
R'' R''
R
–O–N N–OH hν
Co R• + Co(II)(dmgH)2(py) (91)
HO N N–O–
Cobaloximes
RCo(III)(dmgH)2(py)
R
O O
Co
N N
hν
Co(II)(salen)(py) + R• (92)
N
RCo(II)(salen)(py)
S S S
O hν R
+ CO2 (93)
N N RCO N
O R 2
Scheme 100
R1 R'
Anode
R3 C COO R3 C COO
R2 –e R2
R1 R1 R1
Homocoupling
R3 C C R3 R3 C + CO2
R2 R2 R2
R1, R2, R3 = H, alkyl, arylalkyl

R1, R2 = H; R3 = COOMe, (CH2)n X (X = COR, CO2R, n > 1;
X = OAc, NHAc, Hal, n > 4)
Scheme 101
Radicals can be generated by cathodic reduction of carbocations, protonated C¼X bonds, and
by reduction of halides or onium salts (Schemes 102 and 103).
+
ButNMe3 Cathode But • + NMe3 (94)
–
+e
+ H
MeN MeN • MeN NMe
–
+e H
Air
+ +
MeN NMe (95)
O C-rod OH
MeOH, Et4NOTs •
– +
+e , H
98%
HO HO
MeOH
(96)
•
H
Scheme 102
Bu Bu
C-cathode, DMF
I • –
(CF3)2CHOH, R4NClO4 + I
+e
Bu Bu
•
MeOH
60%
Scheme 103
Stable cations such as tropylium salts <1978JEC275>, cyclopropenyl salts <1961JA1763>,

alkylpyridinium salts <1988TCC1>, and pyrylium salts <1994H1165> have been dimerized at
the cathode and radicals are proposed as intermediates. The cathodic dimerization of aromatic
aldehydes and ketones in slightly acidic medium via ketyl or hydroxymethyl radicals is a powerful
method for the preparation of pinacols. The corresponding azomethines, pyrimidines, quinazo-
lines, and iminium ions can be hydrodimerized in a similar way, presumably also via radicals
<B-1974MI220>.
1.19.13.2.4 The reaction of dioxygen with organometallics

Brown’s group established in 1970 that conjugate addition of trialkylborane is a radical reaction
<1970JA710>. A trace amount of dioxygen (O2) in the reaction medium reacts with trialkylbor-
ane to produce an alkyl radical (Equation (97)). Compared with other initiators such as
azobis(isobutyronitrile)(AIBN) and benzoyl peroxide (BPO) (Table 5), Et3B-induced radical
reactions have interesting features as the ethyl radical can be generated at 78 C
<2001CRV3415>.
SH2
Et3B + 3O2 Et• + R2BO2• ð97Þ
Highly reactive alkyl radical
When (+)-2-carene 120 was hydroborated with catecholborane in the presence of 10% of
Me2NCOMe, the so-obtained B-alkylcatecholborane 121 reacted with O2 (in the presence of
Et3N) giving a 2:1 mixture 124 and 125 (Scheme 104). The results can be interpreted in terms
of parallel radical and polar paths in the oxidation step, the first path giving the product of
cyclopropylalkyl ! homoallyl radical rearrangement 122 ! 123, the second path giving the
unrearranged alcohol 125 <2002JOC7193>.
H
R2B
i. Catecholborane (2 equiv.) H
Me2NCOMe (10 mol.%)
120 121
ii. O2/Et2O Et3N

iii. H2O
H H
HO
•
+
R2BO•2
125 122
Fast
R2BO•2
R2BH
•
OH
124 123
Scheme 104
The reaction of O2 with organomercurial compounds can also generate alkyl radicals (Equation (98)).
HgX • OH
i. 3O2
+ 3O
2
ð98Þ
ii. NaBH4
1.19.13.2.5 Single-electron chemical reductions

The seminal report on samarium(II) iodide by Kagan and co-workers <1980JA2693> outlined
numerous applications for this remarkable reducing agent. The recognition that SmI2 can com-
plement other reducing agents such as Bu3SnH, CrCl2, Na/NH3, and Zn(Hg) in the mediation of
radical reactions has led to the development of very powerful synthetic methods <1996CRV307,
B-2001MI153>. In a THF/HMPA mixture, the rate constant for the reduction of a primary alkyl
radical is ca. 6
106 M1 s1. This sets an inherent limit to the types of radical process that can be
carried out in the presence of SmI2 (Equation (99)). Bimolecular radical reactions are thus limited
and the method will give better results for intramolecular radical reactions.
Radical
R–X + SmI2 SmI2X + [R•] [P•]
reaction
ð99Þ
SmI2
R SmI2
reduction
The pinacol coupling reaction, traditionally carried out with active metals such as sodium,
magnesium, or aluminum, can also be accomplished with SmI2 <1999MI565>. Diastereoselective
pinacol homo- and heterocouplings have been realized as exemplified by Equations (100)
<1999CC2051> and (101) <1993CL959, 1993CL2129>.
Me
CHO OH
Me 2SmI2 OSmI2
2 OH ð100Þ
Fe THF, –78 °C R • H Me Fe
(92%) Fe
O
Ph CHO SmI2
+ Ph THF, HMPA
O 20 °C, (66%)
ð101Þ
OSmI2 OSmI2 OH O
• + • Ph
Ph H Ph Ph
O OH
Conjugated, electron-deficient alkenes can be reductively coupled in the presence of SmI2,

providing hydrodimerized products. Both intermolecular and intramolecular versions of the
reaction have been established as exemplified for the latter case by Equation (102)
<1991TL6557, 1999TL7499>.
•
E E SmI2 E E
THF, MeOH I2Sm
HMPA, 20 °C
SmI2 ð102Þ
•
E E E E E E
SmI2
+
MeOH
E = COOMe 7:1 (80%)
The use of nickel powder in combination with acetic acid has been introduced in 1992 by Zard
and co-workers <1992TL7849, 1994TL5629> to cleave an oxime ester (e.g., 126) into a carbo-
xylate anion and an iminyl radical (e.g., 127). The iminyl radical reacts as illustrated in Scheme
105 with the conversion of 126 into ketone 128.
OAc
Me N N• N
Me Ni/AcOH •
H +e
H H
AcO
126 127
N• N Me O
+e H2O Me
+ AcO
59%
H
H H
AcO
128
Scheme 105
Nickel powder in AcOH and isopropanol is an efficient means to generate alkyl radicals from
trichloroacetamides <1994TL9553, 1994TL1719, 1996TL1397>. A wide variety of functional
groups are compatible with these reducing conditions as shown in Equation (103).
X X Cl • Cl X
CCl3 Ni/AcOH
O
N O PriOH, 80 °C N O N ð103Þ
Bn +e +Cl Bn Bn
X = OH, I
Nickel boride (Ni2B) has been utilized as catalyst in many reactions. It is prepared by reducing
nickel salts with NaBH4 <1986CRV763, 1997OPP1>. When a catalytic amount of Ni(OAc)2 is
reduced with borohydride exchange resin (BER) in methanol, BER is covered immediately with a
black precipitate of nickel boride. The BERNi2B (cat.) has been used to catalyze the reduction of
nitro, halogeno, and azido compounds <B-2001MI183>. It can be used also for the semi-hydrogena-
tion of alkynes into alkenes <1996TL1057>. Secondary and tertiary alkyl bromides are reduced by
BERNi2B/MeOH with rates comparable to those of primary bromides, suggesting that the reduc-
tions proceed via radical intermediates <1997JOC2357>. For instance (Equation (104)) the radical
addition of alkyl iodides with ,-unsaturated esters, nitriles, and ketones can be carried out with
BER (3–5 equiv.)–Ni2B (0.05–0.2 equiv.) in methanol. This system is a good alternative to tributyltin
hydride for the coupling alkyl iodides with electro-deficient alkenes (Equation (104)).
•
BER–Ni2B
I I +
MeOH, +e
A ð104Þ
A
A = COOEt, CN
The Kharasch addition of alkyl halides to alkenes can be catalyzed by the nickel complex
Ni(NCN)Cl (0.01–10 mol.%) <1998MM6756, 1996MM8576> as illustrated in Scheme 106.
NMe2
E R •
Ni Cl + RBr Br[Ni(III)] + [R•]
E
NMe2 E = COOMe
Ni(NCN)Cl
Me Me
E R Br[Ni(III)] R Br + Ni(NCN)Cl
E E
(living polymer)
Scheme 106
1.19.13.2.6 Single-electron chemical oxidations

The oxidative addition of acetic acid to alkenes to give -butyrolactones (Scheme 107) was first
reported by Heiba and co-workers <1968JA5905> and Bush and Finkbeiner <1968JA5903> in
1968. This method which uses manganese triacetate as oxidant and generates free-radical inter-
mediates has been applied intensively in organic synthesis <B-2001MI198>.
A wide variety of CH-acidic compounds (1,3-dicarbonyl compounds, nitroalkanes) may serve as
precursors for the oxidative metal-mediated generation of radicals. Apart from Mn(OAc)3, ceriu-
m(IV) ammonium nitrate (CAN) serves as a convenient oxidant. Both oxidants have comparable
oxidation potentials (CAN: +1.61 V, Mn(OAc)3: +1.54 V vs. NHE (normal hydrogen electrode)).
CAN can be used at lower temperature than Mn(OAc)3 in MeOH/MeCN (Scheme 108)
<1997CSR127, 1999SL834>. Oxidation of a mixture of diketene and 1,1-diarylethene with
Mn(OAc)3
H2O gives the corresponding 5,5-diaryl-5-hydroxypentan-2-one <1996JOC8264>.
OMn(OAc)2 –Mn(OAc)2
AcOH
CH3COOH + Mn(OAc)3
∆ OMn(OAc)2
O O
O O O
Mn(OAc)2 Mn(OAc)2
OMn(OAc)2 R
R R
O
–Mn(OAc)2
O
Scheme 107
OH O OMXn –1
+MXn
R1 R1 R1 + HX
R2 R2 R2
+MXn
OH O
R1 R1
• R2 • R2
MXn MXn – 1 HX
Scheme 108
Like cerium(IV), iron(III) salts can oxidize electron-rich centers by single-electron transfer to
form radicals <1980JOC749, 1985TL5923, 1998CC209>. An example is shown in Scheme 107.
Single-electron oxidation and ring opening of cyclopropyl silyl enol ether 129 by FeCl3 affords
radical 130 as intermediate. The latter undergoes 5-exo-trig cyclization into radical 131 that is
trapped by FeCl3 to provide chloride 132 <1995JCS(P1)2315, 1997PAC601> (Scheme 109).
Me3SiO H
+FeCl3 O 5-exo -trig O
DMF, 0 °C
–FeCl2 H
129 –Me3SiCl 130 131
+FeCl3
–FeCl2
Cl
O H
H
132
Scheme 109
Copper(II), cobalt(III), silver(I), and vanadium(V) salts have also been applied to generate
radicals by one-electron oxidations <1994CRV519, 1995T7579, 1998T3321>.
1.19.13.2.7 Photoinduced electron transfer for the generation of radicals

The photoinduced electron transfer (PET) process involves a donor D and an acceptor A. Upon
light absorption of either A, D, or a complex A D, radical-ions D+ and A may form
<1970IL259, 1983CRV425>. Both radical ions may generate radicals as shown in Scheme 110.
Examples of reactions are given in Schemes 111–114 <B-2001MI229>.
hν + –
D: + A D• + A • Products
+ H
+ H Z
D• ≡ + Z
+
R1 R2 R1 R2
–
H X H
•
– + X –
A ≡
R3 R4 R3 R4
Scheme 110
CN Me CN Me
hν – +
+ +
MeCN
CN CN
CN CH2 NC
+ +
NC H CN
CH2Ph CN Ph
CN CN
Scheme 111
Ph – Ph
Ph +
hν + ~H
:N–H N–H :N
Me Me Me
Ph
N–Me
Scheme 112
1.19.13.2.8 The radical-polar crossover reaction

An easily oxidized sulfide can undergo single-electron transfer (SET) to an appropriate electro-
phile, generating a radical–cation/radical–anion pair. Fragmentation of the radical–anion may
afford an organic radical R that can directly recombine with the radical–cation or undergo
further reaction before recombining with the radical–cation to afford a sulfonium salt. The latter
–
O O
+
+ Et2NCH2SiMe3 hν + Et2NCH2SiMe3
MeCN
R R
OSiMe3 O
H2O
+ Et2NCH2
NEt2
R R
Scheme 113
O O H O
– + H
O + Et N: hν O
3 + Me NEt2
MeCN –
H O
+
H +
Me C NEt2
H2O
O O + O
MeCHO H2O
+ + MeCH2NEt2
Et2NH
– OH
OH O
+ MeCHO
+ Et2NH
Scheme 114
undergoes the usual polar reactions such as elimination and substitution, liberating the initial
sulfide and a new molecule (Scheme 115). The term ‘‘radical-polar crossover’’ arises since the
scheme involves a transition from radical to polar chemistry. An example is given for the
– + + –
Step 1: R–X + Ar2S [R–X]• + Ar2S• R• + Ar2S• + X
Step 2: R• R'•
+ – + –
Step 3: R'• + Ar2S• X R'–SAr2 X
+
–
Step 4: R'–SAr2 X R'–X + Ar2S
SN2
O O
TTF, acetone + –
+ TTF• BF4 + N2
N2 H2O, –N2
BF4
133
O H2O O O
+ –
+ TTF• BF4
OH
+S
134 S S S
S TTF:
– S S
S BF4
+ TTF + HBF4 Tetrathiafulvalene
Scheme 115
diazonium salt 133 that is converted into the rearranged alcohol 134 in acetone/water in the
presence of a catalytic amount of tetrathiafulvene (TTF) <1993CC295, B-1999MI123>.
1.19.13.3 Reactions of Radicals

Radicals react by atom or molecular group transfer, generating other radicals (bimolecular
homolytic substitutions SH2). They can add to unsaturated compounds generating other radicals.
They can also rearrange or fragment without undergoing the above reactions. Two radicals can
react giving a stable compound (termination of chain processes); they can also be reduced into
anionic species, or oxidized into cationic species by single-electron transfer, on dismutate (transfer
of an atom or a molecular group from one radical to another).
1.19.13.3.1 Rate constants for abstractions

A considerable range of alkyl and aryl iodides, bromides, and to a lesser extent chlorides react in
bimolecular homolytic substitution (SH2) reactions with tin-centered radicals to form carbon-
centered radicals (Equation (105)).
SH2
R'3 Sn• + R–X R'3SnX + R• ð105Þ
The rate of reactions (Equation (105)) depends, as predicted by the Bell–Evans–Polanyi

theory, on the exothermicity of the reactions and on the polarizability of the reactants. In
general, the weaker the CX bonds the faster are the reactions. In the case of alkyl halides,
iodides react faster than bromides and chlorides, as illustrated with the kinetic data summarized
in Table 6 <2002JCS(P2)367>.
Table 6 Absolute rate constants (k in dm3 mol1 s1) for reactions of organohalides with
Bu3Sn, Bu3Ge, Et3Si, and (Me3Si)3Si radicalsa
Bu3Sn Bu3Ge Et3Si (Me3Si)3Si
MeI 4.3 109
BnBr 1.5 109 8.0 108 2.4 109 9.6 108
ButBr 1.5 108 8.6 107 1.1 109 1.2 108
EtOOCCH2SePh 1.0 108
n-Pent-Br 2.6 107
EtOOCCH2Cl 1.0 106
BnCl 1.1 106 1.9 106 2.0 107 4.6 106
EtOOCCH2SPh 2.0 105
ButCl 2.7 104
a
Taken from <2002JCS(P2)367>.
The rate constants are usually greater than 109 dm3mol1s1 for alkyl iodides, around 107–
108 dm3mol1s1 for alkyl bromides, and around 105 dm3mol1s1 for alkyl chlorides, while alkyl
fluorides do not react. The more stable the carboncentered radical formed, the faster is the
reaction. Thus the following reactivity sequence can be obtained: benzyl allyl > alkyl > aryl
vinyl (Dimroth principle). Sulfides and selenides undergo similar SH2 reactions and the order of
reactivity toward tin radicals is typically as follows: Rl > RBr > RSePh ROC(S)SMe
(xanthates) > RCl > RSPh <1984JA343, 1986AJC1151>.
Similar reactions are observed for related germanium- and silicon-centered radicals (Table 6). The
tris(trimethylsilyl)silyl radical is 4–10 times less reactive than Et3Si (steric effect). For hydrogen
atom abstractions, the rate constants given in Figure 5 can be retained for the reactions of primary
alkyl radicals. As expected from the Bell–Evans–Polanyi theory (or the Dimroth principle
<1936TFS1340, 1938TFS11, 1936PRS414, 1933AG571, 1969JA7224, 1996JA12878>), the less
exothermic reaction (which implies the hydrogen donor with the strongest R0H bond (Et3SiH))
is the slowest.
kt
R• + R'–H R–H + R'• Diffusion
limited
(Me3Si)3SiH t-BuSH (~368) rate
constant
(~376) (~339) (~309) (348)
Et3SiH Bu3GeH Bu3SnH PhSH PhSeH
3 4 5 6 7 8 9 10
log(k·[mol–1 dm3s–1])
Figure 5 Rate constants for the bimolecular SH2 hydrogen atom abstractions from hydrogen donor R0H
by a primary alkyl radical R (standard homolytic dissociation enthalpy: DH (R/H) = H r(RH > R +
H)) values are given in kJ mol1 in parenthesis).
The pentacarbonylmanganese radical, Mn(CO)5, undergoes hydrogen- or halogen-atom

abstraction reactions, the driving force being the formation of the stronger HMn
(DH (H/Mn(CO)5) ffi 272 kJ mol1) and halideMn bond (DH (Cl/Mn(CO)5) ffi 293 kJ mol1;
DH (Br/Mn(CO)5) = 243 kJ mol1) compared with the MnMn bond in decacarbonyldiman-
ganese (DH ((CO)5Mn/Mn(CO)5) = 159 20 kJ mol1). Alkyl bromides react more rapidly
than alkyl chlorides. The former have lower bond dissociation enthalpies than the latter (e.g.,
DH (Et/Br) = 283 kJ mol1 vs. DH (Et/Cl) = 338 kJ mol1), which does not compensate for
the difference in bond energy of MnCl vs. MnBr.
The higher reactivity of alkyl bromides compared with alkyl chlorides results from the higher
electron affinity of the former compared with the latter <1983JA4359>, which makes the charge-
transfer configurations RBr + Mn(CO)5+ relatively more stable than configurations
RCl+Mn(CO)5+. It is the greater polarizability of the bromides that makes them react faster
than the corresponding chlorides toward the Mn(CO)5 radical.
For the SH2 reactions of various radicals with benzyl bromides, the absolute rate constants are
shown in Figure 6 <1997JOM545, 1996JA7367, 1991JPO485, 1997T8479, 1992PAC1473,
1988JA281>.
kt
Bn–Br + R' • R'–Br + Bn•
(Me3Si)3Si•
•
[( Pri)2NBH2] Bu3Sn•
•Mn(CO)
5 Ph2P•=O Et Bu3Ge• Et3Si•
5 6 7 8 9 10
log(k·[mol–1dm3s–1])
Figure 6 Rate constants for the bimolecular reactions BnBr + R0 ! R0Br + Bn.
1.19.13.3.2 Intermolecular addition reactions of radicals

Radicals (carbon-centered, metal-centered, oxygen-centered, and nitrogen-centered) can add to
multiple-bonded systems such as alkenes, alkynes, carbon monoxide, ketones, aldehydes, imines,
oximes, nitriles, isonitriles, azides, N¼O, O2, SO2, etc. . . . As predicted by the Bell–Evans–
Polanyi theory (Figure 7), the rates of the additions depend on steric factors, on the exother-
micity of the reactions (Hr) and on the polarizability of the reactants as demonstrated for the
additions (Equation (106)) of benzyl radical to alkenes (X = H, Me, Cl, Ph; Y = Cl, OAc,
SiMe3, C5H11, OR, OCOR, CHO, SO2Ph, CN, COOMe, Ph, But, Si(OEt)3, pyridin-2-yl) for
which Equations (107) and (108) hold.
E X X
•
R + • R• + •
ECT' Y Y
X 1,2-diradical intermediate
•
R +
ECT (h)
Y
charge
transfer (g)
configuration R• X R X R X
• •
? •
•
Y Y Y
ER
X
R• + ∆Er R X
reactants Y • product
ER
Y
Figure 7 Bell–Evans–Polanyi diagram for the addition of radical R to alkenes. The transition state of this
process implies an electron transfer from the radical to the alkene. An hypothetical, nonconcerted mechan-
ism (h) implies the rotation about the (C¼C) bond of the alkene to generate a 1,2-diradical. This process
requires a high-energy barrier. It does not occur because the reactants give a charge-transfer configuration
(g) that crosses the bond dissociation potential energy hypersurface before it reaches the 1,2-diradical
intermediate.
X Bn X
k •
+ Bn
Y Y
ð106Þ
hν, –CO
(by ESR in toluene, 296 K)
Bn2CO
log (k296/M–1 s–1) = (2.07 ± 0.40) – (0.037 ± 0.004).H°r (kJ mol–1) (r = 0.894) ð107Þ
log (k296/M–1 s–1) = (3.26 ± 0.15) – (1.03 ± 0.13)(–EA(alkene), eV) (r = 0.886) ð108Þ
For the additions of 2-hydroxyprop-2-yl, t-butyl, and hydroxymethyl radicals to the same
alkenes, the linear relationships of Equations (109), (110), and (111) have been found
<1995HCA910, 2001AG(E)1340>.
X OH
+ • : log(k296/M–1 s–1) = (6.46 ± 0.28) – (1.71 ± 0.19)(–EA, eV) ð109Þ
Y (r = 0.90, 20 reactions)
X
+ • : log (k296/M–1 s–1) = (6.13 ± 0.18) – (1.59 ± 0.19)(–EA, eV) ð110Þ
X
•
+ HOCH2 : log (k296/M–1 s–1) = (5.57 ± 0.23) – (1.53 ± 0.17)(–EA, eV) ð111Þ
A qualitative description of the polarizability effect (ability for the reactants to exchange
electrons) on the rates of radical additions to -systems (alkenes, alkynes, imines, carbonyl
derivatives, etc.) can be given by the FMO (frontier molecular orbital) theory. In this theory
(Figure 8), the better the stabilization arising from the overlap of the SOMO (single-occupied
molecular orbital) of the radical with the LUMO (lowest-unoccupied molecular orbital) and with
the HOMO (highest-occupied molecular orbital) of the -system, the lower the activation
enthalpy of the reaction. One can distinguish several situations, for instance that of an alkyl
radical (e.g., Me, Et), which has a relatively high-lying SOMO (C in the Hückel MO theory)
adding to electron-poor -systems such as acrylic esters, acrylonitrile, imines, or ketones that are
characterized by relatively low-lying LUMOs. Thus, the larger the overlap between these orbitals
A Electron-rich Electron-poor B Electron-poor Electron-rich

radical: π-system: radical: π-system:
high-lying low-lying low-lying high-lying
SOMO LUMO SOMO HOMO
(e.g.: alkyl•) (e.g.: acrylates) (e.g.: RO•) (e.g.: vinyl ether)
E
LUMO (π*) ↔ SOMO interaction
∆E2 has little effect
LUMO(π*) HOMO (π*) ↔ SOMO interaction
has a dominant effect
Stablization Stablization
~–|∆E1| ~–2|∆E1|+|∆E2|
∆E2
∆E1
LUMO (π*) ↔ SOMO interaction HOMO (π)

has a dominant effect ∆E1
HOMO (π) ↔ SOMO interaction
has little effect
HOMO (π)
Figure 8 FMO theory applied to the transition state of the radical additions to -systems: (A) electron-rich
radical adding to an electron-poor -system; (B) electron-poor radical adding to an electron-rich -system. The
relative importance of the orbital overlap diminishes as the energy difference between these orbitals increases.
and the smaller the energy gap between these orbitals (SOMO $ LUMO (*)) the better the
stabilization and thus the faster will be the reaction. Alternatively, an electron-poor radical such
as an oxygen-centered radical (o = c + in the Hückel theory) or an -ketoalkyl radical, which
has a relatively low-lying SOMO will prefer to add to electron-rich -systems such as vinyl ethers,
conjugated -systems, vinyl sulfides, etc. as they are characterized by relatively high-lying
HOMOs, making the SOMO $ HOMO interaction to dominate and to stabilize the transition
states of their additions. This qualitative theory treats the polarizability contribution of the
reaction, not the enthalpic term (Hr, Dimroth principle).
B-Alkylcatecholboranes prepared by Rh(I)-catalyzed hydroboration of alkenes are suitable
radical precursors for conjugate addition to activate alkenes. This procedure is particularly useful
to control the enantioselective hydroboration that can be coupled with the radical-chain reaction
in a one-pot operation (Scheme 116) <2003JOC5769>.
O [Rh(CO)Cl]2
+ BH
O (S,S)-BDPP B(OR)2
Benzene
COOMe, PhH Zn/AcOH

PTOC–OMe, hν COOMe (91%) COOMe
S 85% ee
N
PTOC–OMe: (S,S)-BDPP:
N S
O PPh2 PPh2
OMe
Scheme 116
Radical additions of enantiomerically pure B-alkylcatecholborane to ,-unsaturated ketones,

aldehydes <1999CEJ1468>, esters, and carbonitriles <2000CC1017> have also been reported.
(+)-Conocephalenol has been derived from (R)-pulegone (Scheme 117). The key steps 135 ! 136
Me Me
O Me
i. Br2, Et2O EtOOC O3 EtOOC
ii. NaOEt 85%
85% O
(R)-Pulegone
Br
Me Me
i. LiAlH4
HO OH, H EtOOC ii. H3O+ O
83% O iii. DCC Bu3SnH, AIBN
O 53% O PhH, 80 °C
135 70%
O H Me
Me
Me H2SO4, Et2O Me
H
25 °C, 75%
O
O
136 Me 137
Me H
Me
MeLi, Et2O
–10 °C, 80%
OH
(+)-Conocephalenol
Scheme 117
is an addition of a tertiary radical to enone 135 (Scheme 117) and an intramolecular aldol
cyclization 136 ! 137 under acidic conditions <1999T11289>.
The addition of reactive carbon-centered radicals to buckminsterfullerene (C60) produces
R-C60 as well as multiple-addition fullerenyl radicals <1998ACR63>. The high affinity of C60
toward radicals has been demonstrated by its ability to absorb up to 34 methyl radicals,
15 benzyl radicals <1991SCI1183>, 11 phenyl radicals <1991JA6274>, and 16 perfluoroethyl
radicals <1993SCI404>. Another possibility in the reaction of an alkyl radical with C60 is electron
transfer from the radical to C60. This has been observed with Crystal Violet radical (CRV), which
reduces C60 with the formation of CVR+C60 as a solid (Scheme 118) <1999CC1529>.
NMe2
Me2N NMe2
C60 CVR
NMe2
Me2N NMe2
CVR+ C60
Scheme 118
1.19.13.3.3 Enhancement of alkene electron affinity by coordination with a Lewis acid

Acrylate derivatives can be complexed by protic and Lewis acids on their carboxylic moieties.
This enhances the electron affinity (–EA) of the alkene, thus accelerating its reaction with a
radical R. This principle has been applied by Sato and co-workers <1995JOC3576> to improve
the yield and the syn/anti-diastereoselectivity (product ratio 139:140) of the addition of n-butyl
radical to -substituted acrylic esters 138 (Scheme 119).
site of coordination
OH for the Lewis acid OH OH
COO-But + Bun• COO-But + COO-But
R R R
H H
Bu Bu
138 BuI + Bu3SnH + Et3B 139 (syn) 140 (anti)
(1:1:0.1)
Without acid: 64:34, yield: 34%
With Et2AlCl: 87:13, yield: 76%
Scheme 119
The use of achiral auxiliaries as templates for chiral, nonracemic promoters is a valuable strategy for
asymmetric synthesis. Porter and co-workers have applied this approach to effect relative and absolute
stereocontrol in radical reactions as shown in Scheme 120 <1995TL8183, 1995JA11029>.
*
N N
Zn
O O O O
Zn(OTf)2
O N L* O N R
R–I
SnBu3
O O
R
L*: O N N O O N
Ph Ph
R = c-C6H11, 92% yield, 72% ee

R = But, 55% yield, 88% ee
Scheme 120
Hoshino and co-workers <1995CC481> have used enantioselective halide reduction using a
magnesium-based system with good yields and promising ee values. The use of a chiral, non-
racemic aluminum-based Lewis acid to effect a similar asymmetric hydrogen atom transfer to an
enolate radical (Scheme 121) has also been reported by Sato and co-workers <1995JOC3576>.
Using a naphthosultam template 141 and a homochiral Lewis acid derived from MgBr2 and
bisoxazoline 142, the addition of isopropyl radical generates a radical adduct 143 that abstracts
an atom of hydrogen from tributylstannane with high facial selectivity (stereoselectivity), produ-
cing 144 with 87% yield and 80% enantiomeric excess. It is an elegant example of an enantio-
selective hydrocarbonation reaction (Scheme 122), the enantioselectivity of it being induced by a
catalytic amount of ligand 142 <2002JA948>.
An enantioselective conjugate radical addition to -acyloxy acrylates has been reported by Sibi
and co-workers <2003AG(E)4521>. Nucleophilic radicals generated from alkyl halides add to
-acyloxy acrylates 143 (R1 = Me, Ph, 4-FC6H4, 4-MeOC6H4, 2,6-Me2C6H3, 1-naphthyl,
2-naphthyl) in the presence of a chiral Lewis acid (derived from MgI2 and ligand 144) to afford
acetate aldol products 145 in high yield and enantiomeric purity (Scheme 123) (see also
i.
O
AlCl
O
O O H
Bu
O O
ii. BuI, Bu3SnH, Et3B
toluene, –78 to 20 °C
47% 28% ee
Scheme 121
O A* O
O
O PriI
S N O S N Bu3SnH
O + A*
Et3B/O2
Catalyst
CH2Cl2, −78 °C
(30 mol.%)
141 141·A*
O O
A* O
O
Face selective O S N
O S N H
hydrogen delivery
87%
143 144, 80% ee

O
N O
N
A*
MgBr2/Et2O +
23
Scheme 122
<2003TA2879>, for reviews on enantioselective radical processes, see <2003CRV3263,

2003CEJ28, 2003CSR251>.
Enantioselective synthesis of ,-disubstituted--amino acid 148 (R1 = Me, Et, Prn, Pri, n-hept, Ph;
2
R = Me, Et, Br, Ph) have been realized by this approach as illustrated in Scheme 124
<2003JA11796>.
O
MgI2, ligand, Pri-I
O O O O I I O
Bu3SnH N Mg N
O N O R Et3B/O3/CH2Cl2 O
N
−78 °C
143 O OCOR
O O O O O
Ligand:
O N O R N N
145
144
e.g., with R = COPh: yield 90%, 93% ee
Scheme 123
O O O O
Me
BnNHOH, CH2Cl2 N Bn
N R1
Me H R2 O O R2 R1
146 N N 147
142
+ Mg(NTf2)2
O NH2 28–95%
H2/Pd–C
dioxane HO R1
90% R2
148 R1 = R2 = Me: 96% ee
96% de
Scheme 124
1.19.13.3.4 Abstraction of hydrogen from aldehydes: the hydroacylation of alkenes

The hydroacylation of alkenes with aldehydes via a radical-chain process involves the following
sequence: (1) hydrogen abstraction from the aldehyde (RCHO ! RCO + H), (2) addition of the
acyl radical (RCO) to the alkene leading to a -oxocarbon radical, and (3) abstraction of the aldehydic
hydrogen atom from another aldehyde by the -oxocarbon radical intermediate. As the bond dissocia-
tion enthalpies DH (MeCO/H) = 361 kJ mol1 is higher than that forming a secondary allyl radical
from the reacting alkene (DH (MeCHCH = CH2/H) = 351 kJ mol1), for the radical initiator to
select the aldehyde rather than the alkene to generate the initial RCO radical must be due to a
favorable polarity factor. As the acyl radical is electron-rich because of the nonbonding electrons of the
carbonyl oxygen center, an electron-poor radical initiator should be used preferentially. This is realized
by phthalimide N-oxyl radical (PINO) generated by oxidation of N-hydroxyphthalimide (NHPI) with
dibenzoyl peroxide (BPO) as shown in Scheme 125 <2001CC2352>.
a) Formation of acyl radicals and their additions to an alkene

O
O Faster O O
+ N O
Less
R1 H exothermic R1 R1
O
PINO + NHPI
E
O
E
N OH
½(PhCOO)2 E E
O
PhCOOH O E +NHPI O E
NHPI
–PINO
R1 R1 H
b) Concurrent reactions
O α-Scission E E
R1 + R1
R1 –CO
E E
E
+
E
Polymer
E E
Slower
+ PINO + NHPI E = COOEt
E More E
exothermic
Scheme 125
As fragmentation EtCO ! Et + CO is exothermic by 35.1 kJ mol1 (Hf (EtCO) =

+4.2, Hf (Et) = 117, Hf (CO) = 110.5 kJ mol1), acyl radical addition to the alkene must
be faster than this fragmentation. A high concentration is required to limit the formation of
secondary products resulting from the addition of radical R1 to the alkene.
Dang and Roberts have described a radical version of the aldol reaction <1996CC2201>.
Thiols can be used as catalysts to abstract the acyl hydrogen efficiently and thence to act as
hydrogen atom donors to the adduct radical as shown in Scheme 126.
R'SH OAc
O O H O OAc
R
R + R'S• R •
H • H
O OAc
R'S• + R
H R'SH
H
Scheme 126
1.19.13.3.5 Intermolecular radical additions to hetero double bonds

The additions of alkyl radicals to alkenes are much more exothermic than to aldehydes and ketones.
For instance (Equation (112)), Hr = 97.5 4 kJ mol1 has been calculated for the addition of
methyl radical to ethylene whereas Hr = 54 6 kJ mol1 is estimated for the addition of a methyl
radical to formaldehyde giving an ethyloxy radical (Equation (113)). The addition (Equation (114))
giving methoxymethyl radical is slightly less exothermic as Hr = 49.4 6 kJ mol1. Because of
the negative entropies of condensation, radical additions to carbonyl compounds will have to be
carried out at relatively low temperature if a suitable concentration of the corresponding adduct is to
be formed. Otherwise, a fast-reacting partner for the radical intermediate has to be present in the
solution, which gives a more stable adduct. Using more stable alkyl radicals than Me and ketones
their additions will be even less exothermic (see e.g., Equation (115)) (Scheme 127).
Me• + CH2=CH2 CH3CH2-CH2• (112)

°
∆Hf : 145.6 ± 1.3 52.3 ± 0.8 100.4 ± 2 ∆H°r (112): –97.5 ± 4 kJ mol–1
~44 kJ mol–1
Me• + CH2=O MeCH2O• (113)
∆Hf°: –108.8 ± 0.8 –17.2 ± 4 ∆H°r (113): –54 ± 6 kJ mol–1
∆Hf°: MeC•HOMe (114)

–12.5 ± 4 ∆Hr° (114): –49.4 ± 6 kJ mol–1
Me• + (CH3)2C=O ButO • (115)

∆H°f : 145.6 ± 1.2 –217.1 ± 0.4 –87.9 ± 4 ∆Hr° (115): –16.3 ± 6 kJ mol–1
Scheme 127
These thermodynamic data demonstrate that only highly unstable carbonyl functions will add
to alkyl radicals in intermolecular reactions. Kharasch and Brown reported the successful acyla-
tion of primary alkyl radicals using phosgene as a radical trap <1942JA329, 1942JA333>. The
addition of an alkyl radical to biacetyl gives the corresponding methylketone and acetyl radical
(Equation (116)) <1968JA3588>.
•
O •
(PhCO2)2 –MeCO O
R–H + CH3COCOCH3 ð116Þ
∆ R β-Scission R
O
32–70%
The intermolecular reaction of an aldoxime as a radical trap was first reported by Citterio in
1986 <1986S473>. The thermal decomposition of di-t-butyl peroxide generates ButO radical that
abstracts a hydrogen atom from cyclohexane giving a cyclohexyl radical that add to the C¼N
double bond of aldoxime 145, forming a nitrogen-centered radical 146 that is oxidized by ButO
furnishing the corresponding ketoxime 147 (Scheme 128).
•
HO NOH
N
∆ Me
+ (ButO)2 + Me
H H
O
O
145 146
+ButO• + ButOH
NOH
β-Scission Me
O
147
+2 ButOH
Scheme 128
Another example is the radical acylation reaction shown in Scheme 129, which involves the
addition of alkyl radicals to the C¼N bond of a sulfonyl oxime ether 148 giving a radical 149
that undergoes irreversible -scission with exclusion of the phenylsulfonyl radical. Hydrolysis of
the O-benzyloximes 150 so obtained furnishes the corresponding ketones 151 <1996JA5138,
1998TL1587, 1997JA5982>.
NOBn • NOBn
(Me3Sn)2 k = 7.3·104 M–1 s–1
R–I R• +
hν Me SO2Ph at 60 °C Me SO2Ph
β-Addition R
148 149
–PhSO2• NOBn O
H3O
β-Scission H2O
R Me R Me
150 151
Scheme 129
In 1939, Faltings observed the formation of acetone when a mixture of ethane and carbon
monoxide was irradiated with UV light <1939CB1207>. The results imply the formation of alkyl
radicals adding to CO. The heat of addition of methyl radical to CO giving the acetyl radical
(Equation (117)) amounts to Hr = 60.2 12 kJ mol1. The exothermicity of this addition is
lower with other alkyl radicals <1999CRV1991>.
α-Addition O
Me • + :C=O Me •
∆H°f : 145.6 ± 1.2 –110.5
α-Scission ð117Þ
–25.1 ± 2
∆H°r : (24) = –60.2 ± 3.5 kJ mol-1
In 1990 Ryu and co-workers (Equation (118)) reported the first efficient trapping of alkyl
radicals by CO leading to the synthesis of aldehydes, where alkyl bromides were used as
substrates and tributyltin hydride as mediator for trapping the acyl radicals <1990JA1295>.
O
AIBN (10 mol.%)
R–Br + CO + Bu3SnH R C H + Bu3SnBr ð118Þ
PhH, 70 atm
80 °C, 2 h
The intermediate acyl radicals can be trapped by agents other than Bu3SnH. As acyl radicals
are electron-rich radicals due to the conjugation of the unshared electron of the radical with the
n-(CO) electron pair of the carbonyl group, they react more rapidly with electron-poor alkenes
(Figure 7) than with electron-rich alkenes. For instance, in the presence of vinylacrylate and
allyl(tributyl)stannane the intermediate acyl radical 159 (resulting from the addition 158 + CO)
adds first to the electron-poorest double bond of the vinylacrylic ester, giving an electron-poor
-oxo radical 160, which then prefers to add to the electron-rich allylstannane (electron-richer
than a vinyl ester) giving radical 161 that fragments into product 162 and the radical-chain carrier
Bu3Sn (Scheme 130) <1993JA1187, 1996CRV177>.
•
O Bu3Sn O + CO (80 atm) O
•
O Br Br atom O α-Addition O
abstraction
157 O
158 159 (electron-rich)
COO
O SnBu3
H
O •
(electron-poor) (electron-rich)
O COO
160 (electron-poor)
O • SnBu3
O
O COO
161
O
• Fragmentation
Bu3Sn +
O
(β-Scission)
O COO
162 60% yield
Scheme 130
A new method for the synthesis of carboxylic acid esters from the combination of alkyl iodides,
alcohols, and CO has been proposed (Equation (119)). It is carried out under photoirradiation
(Xe-lamp, pyrex vessel) in the absence of a metal catalyst <1997JA5465>.
hν ð119Þ
R–X + CO + R'OH RCOOR' + HX
Five- to seven-membered lactones 167 have been obtained from !-hydroxyalkyl iodides 163 and
CO by atom transfer carbonylation without the need for transition metal catalysts (Scheme 131).
The process implies the intermediacy of !-hydroxyalkyl radicals 164 that add to CO, giving acyl
O
R OH
+ CO R O + HI
I n
n
163 167
AIBN, Bu3SnH, Et3N
hexane, 80 °C
R OH
OH COI OH
CO OH I
+ CO n
R n R n
R n
164 165 166
Scheme 131
radical intermediates 165 that carry to chain reaction by reaction with the !-hydroxyalkyl iodides
163. This gives rise to the corresponding acyl iodides 166 that immediately generate lactones 167
<2000OL389>.
Similar carbonylative cyclizations are reported in Scheme 132. They involve 4-alkenyl iodides
such as 168 (Scheme 132). Under 40 atm of carbon monoxide significant dicarbonylation (e.g.,
169 + CO ! 170) is observed <2002JA3812, 1996JA10670, 2003CC1190>.
O NEt2 O O
O O NEt2
CO (40 atm)
PhH/Et2NH
+
Pd(PPh3)4
I
hν (Xe-lamp, pyrex)
168 21% 45%
R–I, Et2NH R–I, Et2NH
O
O O
O O
+ CO
169 170
+ CO + CO
O
O
Scheme 132
A carbonylative access to -stannylmethylene lactams 172 from azaenynes 171 and CO has
been uncovered (Scheme 133). It involves an ,-unsaturated acyl radical 173 as the attacking
radical and an imino group as the acceptor giving intermediate 174. Cyclizations occur with high
regioselectivity favoring the N-philic mode for the synthesis of 4-, 5-, 6-, 7-, and 8-membered rings
<2003JA5632>.
H Bu3Sn O
AIBN, PhH
+ CO + Bu3SnH
n N 90 °C, 8 h N
(88 atm) n
171 53 n = 1, 2, 3, 4, 5
+ Bu3Sn• Bu3SnH
O H Bu3Sn O
n N N
n
H SnBu3
173
H –
O Bu3Sn O
• +
n N H
N
n
H SnBu3
174
Scheme 133
Shaw and Pritchard <1968CJC2721> observed isonitrile–nitrile isomerization of methyl and

ethyl isonitrile when they were heated in the presence of a catalytic amount of di-t-butyl peroxide
((ButO)2). A mechanism implying the addition of methyl and ethyl radical to the isonitrile was
invoked (Scheme 134) <1964BCJ635, 1983TL4671>.
(ButO)2 + R-N=C: [R•] + ButOCN + [ButO•]

R = Me, Et
α -Addition β-Elimination
[R•] + R-N=C: [R-N=C•-R] [R•]
– N≡C-R
Scheme 134
The intermolecular radical addition to isonitriles has been used to construct nitrogen-contain-
ing heterocyclic compounds as illustrated by Curran’s synthesis of Campthothecin derivatives
(Equation (120)) <1991JA2127-2132, 1995AG(E)2683, 1996CRV177>.
O
N O hν, Me6Sn2 O
+ N
H PhH, 70 °C
N I O N ð120Þ
C: OH 63%
Et O
Et
OH O
Campthothecin
Kim and co-workers <1996JA5138, 1997SL475, 1997JA5982, 1998TL1587> have reported that
sufonyloxime ethers such as 174–176 can serve as viable C1 radical acceptor synthons, which
serve as latent carbonyl groups, providing novel free-radical methods for acylation. When reacted
with alkyl iodides and CO, the latter synthons can generate vicinal singly and doubly acylated
oxime ethers <1999JA12190> as exemplified with a reaction that uses oxime derivative 176
(Scheme 135).
PhO2S H MeOOC SO2Me PhO2S COOMe
N N N
OBn OBn OBn
174 175 176
AIBN OBn
N
allylSnBu3
+ CO + 175 OMe
I Benzene, 90 °C
65–80 atm O O
84%
Scheme 135
Molecular oxygen and nitroxides react rapidly with alkyl radicals. The products so-obtained
can then be reduced to generate the corresponding alcohols (Scheme 136) <B-2001MI93>.
Bu3SnH Bu3SnH
R• + O2 R–OO• ROOH ROH
k > 109 M–1 s–1 –Bu3Sn• or NaBH4
•O Zn/AcOH
R• + N R O N
k ≈ 10 9 M–1 s–1 or Bu3SnH
Scheme 136
Resonance-stabilized alkyl radicals react with dioxygen (a triplet diradical) with second-order
rate constants 109 M1 s1 <1983JA5095>. Thus oxygen and nitroxides (e.g., TEMPO: 2,2,6,6-
tetramethylpiperidine N-oxide) are efficient radical scavenging agents and can be used as inhibi-
tors of reactions occurring via radical intermediates <1988JOC1629, 1992JA4992,
1995JPC8182>. With unsaturated carbon-centered radicals, O2 generates peroxide radicals that
can undergo intramolecular additions to the unsaturated moieties giving endoperoxides. One
example is given in Scheme 137 <1998JOC4697>.
O O
PhSH/O2 + O2
SPh
AcOH, 20 °C
O + PhS O
O O
OO
PhSH
SPh
75%
SPh
O O O O
O
+ PhS
SPh
HO O O
Scheme 137
Because of its free-radical character, nitric oxide (N¼O) can act as an efficient radical trap
<1984CC289, 1987TL1451>. As an example of application of this reaction, the conversion of
methyl 3,4,6-O-triacetyl-2-bromo-2-deoxy--D-glucopyranoside into an N-acetyl mannosamine
derivative is presented in Scheme 138 <1998CB1807, 1990SL166>.
AcO AcO
i. NaCo(dmgH)py
O (see Scheme 98) O
AcO OMe AcO OMe
AcO ii. NO, hν AcO
Br 60% NOH
H2/Pd–C AcO NHAc

AcOH, Ac2O O
AcO OMe
76% AcO
Scheme 138
The addition of alkyl radicals to sulfur dioxide is reversible <1983JOC3588, 1986JOC2871>

(Equation (121)). The rate of the reversal -scission depends on the relative stability of the alkyl
radical. In the case of PhCH2SO2, the rate of loss of SO2 exceeds 2
108 s1 at 295 K.
α-Addition O
R • + SO2 R S• ð121Þ
α-Scission O
The sulfonylation of alkyl radicals plays an important role in the copolymerization of alkenes
with SO2. Shevlin has shown that the cyclooligomerization of diallyl malonate can be controlled
by the addition of a chain transfer agent such as thiophenol (PhSH) (Equation (122))
<1998JOC3230>.
PhS SO2 X
+ SO2 PhSH
AIBN ð122Þ
E E E = COOEt E E n E E X = H, SO2H
Conversely -scissions of alkanesulfonyl radicals have been used to generate fluorinated alkyl
radicals. For instance the Cu(II)-mediated addition of trifluoromethanesulfinate to enol esters
affords -trifluoromethyl ketones (Equation (123)) <1993JOC2599>.
OAc O
CF3SO2Na /ButOOH
ð123Þ
Cu(OSO2CF3)2/MeCN CF3
20 °C, 66%
Carbon-centered radicals add to dioxygen (3O2) readily <1983JA5095>, leading to peroxyl

radicals (see Schemes 133 and 134). CIBAs antioxidant HP-136 reacts with (ButO)2 to give the
corresponding diphenylmethyl-like radical 177, which is estimated to react with O2 about 10,000
times more slowly than the diphenylmethyl radical. Thus HP-136 is an antioxidant because it is
not quenched rapidly with O2 but reacts with other radicals such as alkyl and peroxyl radicals
(Equation (124)) <2000OL899>.
3O
ButO • 2
H ð124Þ
–ButOH
•
O O
O O
HP-136 177
A novel approach for the formation of CN bonds by azidation of alkyl radicals with sulfonyl
azides has been proposed by Ollivier and Renaud <2001JA4717>. The alkyl radical generated by
reaction of allyl iodide either with dilauryl peroxide or with Bu3Sn was reacted with ethanesul-
fonyl azide (Scheme 139) or with benzenesulfonyl azide (Scheme 140).
∆
0.5 (n-C11H23CO2)2 n-C11H23 + CO2
n-C11H23 + RI n-C11H23I + R Initiation
or/and n-C11H23 + N3SO2Et n-C11H23–N3 + SO2 + Et
R
R + N=N=NSO2Et R–N–N=N–SO2Et or N=N–N
SO2Et
R–N3 + EtSO2 Et + SO2 + RN3 Propagation
Et + R–I Et – I + R
Scheme 139
hν •
R–I R• + I
∆
or ButO–N=N–O–But 2 ButO• + N2 Initiation
ButO• + (Bu3Sn)2 ButOSnBu3 + Bu3Sn•
R• + PhSO2N3 R–N3 + PhSO2

PhSO2• + (Bu3Sn)2 PhSO2–SnBu3 + Bu3Sn• Propagation
Bu3Sn• + R–I Bu3SnI + R•
Scheme 140
The method can be coupled with a radical isomerization (cyclization) process as shown in
Scheme 141.
PhSO2N3 (3 equiv.) N3 N3
H H
I
(Bu3Sn)2 (1.5 equiv.)
+
O O ButON=NO-But (cat.) O O O O
PhH, 42% H H
85:15
Scheme 141
Easily available chiral allyl silanes have been used as substrates for carboazidation as shown in
Scheme 142 <2002OL4257>.
SiPh3 EtOOCCH2SCSOEt SiPh3

R PhSO2N3, (Bu3Sn)2 EtOOC R
ButON=NO-But (3 mol.%)
OH N3 OH
PhH, 80 °C
Scheme 142
The first asymmetric syntheses of -amino acids based on the diastereoselective carbon radical
addition to glyoxylic imine derivatives has been reported <2000JOC176>. The addition of an
isopropyl radical to Oppolzer’s camphorsultam derivatives 178 of the glyoxylic oxime ether
afforded 179 with a diastereomeric ratio 96:4 in 80% yield (Scheme 143). The reductive removal
of the benzyloxy group of the major diastereomer (R)-179, by treatment with Mo(CO)6 and
subsequent removal of the sultam auxiliary by standard hydrolysis, gave the enantiomerically
pure D-valine R-180 without any loss of stereochemical purity.
O O
O PriI, Bu3SnH, Et3B
N NOBn N NHOBn
S
O R• BF3.Et2O SO2
H –78 °C, 80%
178 179 dr 96:4
i. Mo(CO)6/CH3CN/H2O HOOC NH2
ii. LiOH/H2O
79%
(R)-180
Scheme 143
1.19.13.4 Radical Isomerizations

Intramolecular additions of carbon-centered radicals to a double or triple bond leading to cyclic
compounds, i.e., radical cyclization reactions, have been used extensively in the synthesis of
complicated organic molecules. The reverse reaction, i.e., ring opening adjacent to radical centers
occurs readily with three- and four-membered rings, including oxiranylalkyl and oxetanylalkyl
radicals <2003AG(E)5556>.
1.19.13.4.1 Five-membered versus six-membered ring formation

The most frequently used reactions are the 5-exo-trig (Equations (125), (126)) and 5-exo-dig
isomerization (Equation (127)) of hex-5-en-1-yl and hex-5-yn-1-yl radicals, respectively. These
isomerizations are favored kinetically (Baldwin rules <1976CC734, 1993ACR476>) over the
more exothermic 6-exo-trig and 6-endo-dig ring closures, respectively.
5-exo -trig •
•
ð125Þ
favored
∆H°r (50) ≅ –67 kJ mol–1
293 K = 2.3·105 s–1
kexo
H
H 5-endo-trig •
H ∆H°r (51) ≅ –92 kJ mol–1 ð126Þ
H 293 K
kendo = 4.1·103 s–1
disfavored
(C-H/C-H eclipsing)
• 6-endo-dig 5-exo-dig •
slow • fast
∆H°r (endo) ≅ –88 kJ mol–1 ∆H°r (exo) ≅ –58.5 kJ mol–1

ð127Þ
(dig = digonal, trig = trigonal center is formed;

exo = exocyclic center, endo = endocyclic center).
The origin of these kinetic effects arises from the preferred trajectories followed by the
radical addition to the alkene and alkyne moieties <2002JOC2982>. The exo modes imply
conformations that are less strained than for the endo modes of cyclization. In the former
nearly unstrained zig-zag conformers of the starting radical reach the transition states, whereas
in the latter, the transition states imply conformations that resemble that of six-membered
boat conformers that are strained because of CH/CH eclipsing interactions. This theory
(Beckwith–Houk model <1987JOC959, 1980CC482, 1980CC484>) is supported by the obser-
vations reported in Scheme 144, which show that the major cyclopentylmethyl radicals
formed arise from transition structures resembling six-membered chair rings with the methyl
substituents residing in equatorial rather than axial positions (optimization of the gauche
interactions).
H H
Me Me(eq)
Me(ax) Me
trans (major) favored cis (minor)
(ax)Me Me
Me Me(eq)
cis (major) favored trans (minor)
H H
Me Me(eq)
Me(ax) Me
trans (major) favored cis (minor)
Scheme 144
In the case of acetal-derived radicals 181 (Equation (128)), the exo-trig cyclization generates
preferentially the cis-intermediates 183 as the transition states 182 of the cyclization can enjoy
conformational anomeric effects that stabilize the pseudoaxial OR0 group <1998JOC5144>.
R2 R2 R2
•
• OR1 R3
R3 R3 •
ð128Þ
R1O O O R1O O
181 182 183
The kinetic chemoselectivity kexo/kendo for the isomerization of the hex-5-en-2-yl radical
amounts to ca. 50 at 300 K (compare Equations (125) and (126)). If substitution increases, the
reaction enthalpy difference between these two competing ring closures decreases and products of
endo-trig isomerization are formed to a significant extent. For instance, in the case of the
isomerization of 5-methylhex-5-en-1-yl radical the endo-trig mode generates a tertiary alkyl
radical whereas the exo-trig mode gives a primary alkyl radical (Equation (129)). The greater
driving force for the formation of 1-methylcyclohexyl radical (ca. 42 kJ mol1) makes it a pre-
ferred product of cyclization.
•
Kinetic •
• + ð129Þ
control
33% 67%
The addition of a hydrogen radical engendered by pulsed radiolysis of H2 at 78 C ([H] ffi

1014 M) onto hepta-1,6-diene leads to a mixture of acyclic, cyclic, and dimeric products. Among
the cyclic products one finds all isomeric methylcyclohexenes and methylcyclohexane and these
are more abundant than cyclopentanes. Radical H adds regioselectively to hepta-1,6-diene giving
the hept-6-en-2-yl radical that is expected to undergo fast exo-trig cyclization (Baldwin’s rules)
generating (2-methylcyclopentyl)methyl radicals under conditions of kinetic control. In the
absence of radical scavenging agents such as Bu3SnH, these radicals have the time to rearrange
into the more stable 3-methylcyclohexyl radical, which then eliminates H to give methylcyclo-
hexenes, or reacts with H to furnish methylcyclohexane (dismutation) (Scheme 145)
<1994JA6683>.
H H
H• Fast
+
5-exo-trig
hν Favored kinetically
H2 Slow
6-endo-trig
+ Dismutation
Favored thermodynamically
Scheme 145
In 1960, Julia <1960CR(C)1030> found that heating cyanoester 184 with benzoyl peroxide
afforded the cyclohexane derivative 186 (Scheme 146). By contrast Lamb and co-workers
<1963JA3483> observed that heating peroxide 187 gave methylcyclopentane 189 as the major
product. The former reaction implies a reversible intramolecular radical addition to the alkene
moiety, whereas in the latter reaction an irreversible exo-trig cyclization occurs.
Ryu and co-workers <1998JA5838> have shown that acyl radicals add selectively on the
nitrogen (nucleophilic) rather than at the carbon (electrophilic) center of an imine group. Quan-
tum calculations on the exo-‘‘N-philic’’ cyclization (Equation (130)) and endo-‘‘C-philic’’ cycliza-
tion (Equation (131)) predicted energy barriers of 36.1 and 46.9 kJ mol1, respectively
<2002CC2338>. An aminoketone being about 80 kJ mol1 less stable than the corresponding
amide, and considering the fact that the exo-trig mode gives a carbon-centered radical stabilized
by the amido substituent, the exo-trig cyclization is much more exothermic than the endo-trig
H COOEt COOEt COOEt

(PhCOO)2 ∆
∆ CN CN
CN
Cyclohexane
184 185 186
COO)2
77 °C
Toluene
187 188 189
Scheme 146
cyclization. Although the acyl radical is an electron-rich radical it prefers to add onto the nitrogen
center rather than on the carbon center of the imine because the former cyclization (a carbox-
amide is about 85 kJ mol1 more stable than an amino ketone) is much more exothermic than the
latter (Dimroth principle).
O
O O
• • exo-trig ð130Þ
• •
•• + CO •• N N
N N “N-philic”
O O
• ð131Þ
endo -dig
•• •
N “C-philic” N
1.19.13.4.2 4-exo and 5-endo cyclizations

The 4-exo cyclizations of pent-4-en-1-yl radicals to give cyclobutylmethyl radicals are difficult
because of the strain build up in the cyclobutylmethyl radical. But, if the latter can be trapped
rapidly, four-membered ring systems can be isolated <1990TL2975, 1992CL1487, 1992TL6719,
1997TL6521, 1999TL2661, 1999SL843>. The first example of a 4-exo-trig radical cyclization was
reported by Araki and co-workers in 1989 (Equation (132)) <1989TL2829>. Belletire and
co-workers <1991TL2335> reported the efficient formation of -lactams via the 4-exo-trig
cyclization of bromo enamides (Equation (133)). In this case, the 4-exo-trig cyclization is facili-
tated by the formation of a stable benzhydryl radical intermediate.
I EtOOC
O Bu3SnH O
O O
EtOOC AIBN
O 71% O ð132Þ
THPO O THPO O
THP = AIBN: Me2C(CN)N=NC(CN)Me2

O
R Ph
Br Ph
Bu3SnH R Ph
O N Ph AIBN ð133Þ
R' PhH O R'
R = Me, Et; R' = C6Hn, But, Me yield: 40–70%
The groups of Parsons <1998TL2815>, Ikeda and Ishibashi <1998JCS(P1)1763> have found
an efficient 5-endo-trig radical cyclization of N-ethenyl--haloamides to form pyrrolidinones and
substituted pyroglutamates. The 5-endo closure of the 2-formylbenzoyl radical has also been
shown to be a particularly facile process <1994JA1718>. Morever, 5-endo-trig cyclizations
include heteroatomic-centered radicals such as Si <1998JCS(P1)467> or S-centered radicals

<1997JOC8630>. In comparison, the all-carbon pentenyl system has not led to high-yielding
5-endo-trig cyclizations <1965BSF1550, 1966JOC2255, 1966JOC3018, 1973JCS(P1)1655> except
for the special case of Equation (134) reported by Schmalz and co-workers in 1995
<1995AG(E)2385>.
• OSmI2
I2SmO
•
OMe Me OMe
H ð134Þ
66%
OMe OMe
Cr(CO)3 Cr(CO)3
Highly stabilized
benzyl radical
An efficient radical sequence involving a 5-exo-dig cyclization, a diastereoselective 1,5-H

transfer, and an all carbon 5-endo-trig cyclization has been discovered by Malacria and co-
workers (Scheme 147) <1999JOC4920>. It allows the construction of cyclopentenyl derivatives
191 bearing four controlled stereogenic centers from diisopropyl precursors 190. Alkenes 192 were
also isolated as minor side products. These reactions probably involve the radical intermediates
193–195.
Me Me Me
Me Me Me
Me i. Bu3SnH
Me Me
Me R PhH, AIBN
HO + HO Me
O ii. Tamao oxidation
Si Br HO HO
H R R
190 191 192

5-exo-dig
H H
Me Me H
Me Me Me Me H
R R Me
Me 1,5-Hydrogen Me R
H transfer H 5-endo-trig
O O Me O Si
Si H Si H
Me Me Me Me Me Me
193 194 195
Bu3SnH Bu3SnH
192 191
Scheme 147
Upon treatment of the -chloro amides 196 with Bu3SnH and AIBN the intermediate radicals
undergo 5-endo-trig cyclization giving radicals 197 that are reduced into -lactams 198 (Scheme
146). Alternatively, -haloamides 199 having a phenylthio substituent at the terminus of their
N-vinylic bond, cyclize in a 4-exo-trig manner giving -lactams 201 via radicals 200 (Scheme 148). In
this latter case, the highly radical stabilizing effect of the phenylthio substituent makes the
formation of the strained intermediates 200 possible <2001T7629>.
1.19.13.4.3 n-exo and endo cyclizations

Hept-6-en-1-yl radicals undergo preferential 6-exo-trig cyclizations giving cyclohexylmethyl radi-
cals, under kinetic (Baldwin’s rules) and thermodynamically controlled conditions. In some cases
(Scheme 149), the 6-exo-trig cyclization is a relatively slow process due to an entropy factor
(blockage of the free rotation of 5 (CC) bonds), and a concurrent reaction intervenes which
H R H R
Cl R Bu3SnH
O O
AIBN N N
N O
R' H R'
R'
196 197 198
PhS Cl R R R
Bu3SnH PhS PhS
AIBN N N
N O R' O R' O
R'
199 200 201
Scheme 148
transfers an hydrogen atom intermolecularly with formation of a stable allyl radical. If substitu-
tion of the hept-6-en-1-yl system blocks a number of freely rotating bonds, the rate of 6-exo-trig
cyclization increases significantly as shown below <1980CC484, 1974JA1613>.
k = 5.4·103 s–1 Bu3SnH

6-exo - trig
H
Easy H
H Bu3SnH
H
intramolecular
H atom transfer
k = 3·108 s–1
6-exo - trig
O O
Scheme 149
Medium rings (7–12) as well as large rings have been formed by intramolecular radical
additions to -systems (alkenes, alkynes, and O-alkyl oximes) <B-2001MI151, B-2001MI538>.
3-Oxahex-5-enyl radicals (CH2¼CHCH2OCH2CH2) undergo exo cyclization about 25 times
as fast as the hex-5-enyl radical at 80 C <1987AJC157, 1988JOC1632>. The effect of an oxygen
atom in the chain on the rates of cyclization of these alkenyl radicals has been attributed to the
decrease in the strain energy of the cyclization transition structures resulting from the replacement
of a carbon atom by oxygen <1985T3925>. The favorable oxygen atom effect has been exploited
to prepare substituted macrocyclic polyethers by radical cyclization <1997CC499, 1998JOC6814>
(Scheme 150). Iodides 202b–202j were all cyclized into cyclic polyethers 203b–203j (and some
cases 204g–204j), but no cyclized product could be obtained from 202a. Uncyclized products
formed by direct hydrogen transfer to the initially formed radicals were also detected.
1.19.13.4.4 3-exo-Cyclization: Homoallyl/cyclopropylmethyl Isomerization

The isomerization of the but-3-enyl (homoallyl) radical into the cyclopropylmethyl radical is
an endothermic reaction as shown in Equation (135). For the dimethyl-substituted derivative
(Equation (137)) first-order rate constants for the 3-exo-trig ring closure is less than 100 times
smaller than for the reverse reaction giving a mixture of primary and tertiary homo-
allyl radicals <1980JCS(P2)1473, 1993CSR347>. Unless substituents prohibit it, but-3-enyl
radicals will isomerize irreversibly into but-3-en-2-yl radicals (Equation (136)). In the case of
Bu3SnH (1.1 equiv.)

R O O
O I AIBN (cat.)
n
O PhH, 80 °C, 2 h
202 R
R
O O
O O + O O
O O
n n
203 204
a) n = 0, R = H c) n = 2, R = H e) n = 4, R = H g) n = 1, R = (E )-COOEt
b) n = 1, R = H d) n = 3, R = H f) n = 5, R = H h) n = 1, R = (Z )-COOEt
i) n = 2, R = (E )-COOEt
j) n = 2, R = (Z )-COOEt
Scheme 150
bicyclo[2.2.1]hept-5-en-2-yl chloride and bromide, Kuivila and co-workers <1966JOC3381> have

reported that their reduction under radical conditions (Scheme 151) gives a 1:1 mixture of product
of reduction of the bicyclo[2.2.1]hept-5-en-2-yl radical intermediate (norborn-5-en-2-yl) and of its
isomeric nortricyclyl radical arising from the intermolecular 3-exo-trig cyclization.
•
• ∆H°r (42): +20.9 ± 8.4 kJ mol–1
ð135Þ
∆H°f : 192 ± 1.7 213 ± 6.7
•
∆H°r (43): –58.6 ± 4.2 kJ mol–1
• ð136Þ
∆H°f : 192 ± 1.7 133 ± 2.5
• •
k = 5.6·106 s–1 k = 8.9·106 s–1 ð137Þ
+ •
• (298 K)
Bu3SnH, AIBN exo-3-trig

near 20 °C
X
X = Cl, Br Norborn-5-en-2-yl Nortricyclyl
radical radical
55:45
Scheme 151
If the cyclopropylmethyl radical intermediate can be stabilized by appropriate substitution, the

3-exo-trig cyclization will occur more readily as shown in Equations (138) <1990CC923> and (139)
<1994JOC718>.
I •
Bu3SnH Bu3SnH
+
(ButO)2 ð138Þ
•
Ph hν, –80 °C Ph Ph Ph Ph
1:8.8
E E
Bu3SnH
Br AIBN E E •
•
E E
ð139Þ
E = COOMe
75% E
E
1.19.13.4.5 Ring expansions

The one-carbon ring expansion according to Equation (140) was first observed by Barton
<1961JA4481> and then its synthetic potential was explored by Dowd <1993CRV2091,
1999T9349> and Beckwith and co-workers <1988JA2565>. Radical precursors are prepared by
alkylation of -ketoesters derived from Dieckmann condensations as shown with the examples
reported in Scheme 152. One of the best examples of three-carbon ring expansion is the total
synthesis of (R)-()-muscone starting from a cyclododecanone derivative <1992T4773>.
•
O O
O
•
ð140Þ
•
X X X
O O O
Br
E i. NaH Bu3SnH (1.1 equiv.)
E E
ii. CH2Br2 AIBN, benzene
(CH2)n (CH2)n 80 °C, 71–75% (CH2)n
n = 0, 1, 2 E = COOMe
Scheme 152
1.19.13.4.6 Ring contractions

The -(acyloxy)alkyl, or Surzur–Tanner <1967CR(C)1981, 1970BSF3060, 1969JA7535>, rear-
rangement is the archetypical radical ester migration <1993JCS(P2)1673>. These rearrangements
(1,2-acyloxy shifts) can be accelerated by Lewis acids such as Sc(OTf)3 <1998AG(E)2259>. Other
groups such -phosphate, -(nitroxy)alkyl, and -sulfate can also migrate according to Equation
(141) <1996JA7422>.
X O
O O X
•
O ð141Þ
R • R
X = CR, P(OR)2, N=O, SOR'
This type of rearrangement can occur with lactone-derived radicals. When bromolactones 205
were reacted with Bu3SnH and AIBN, all lactones 205 with n = 2–12 underwent ring contraction
giving 209, although with varying efficiency. In the case of 205 with n = 1, no products of ring
contraction was observed. In all the other reactions it is the high stability of the benzyl radicals
207 arising from the 1,2- or 3,2-shift of the COO group in 206 that drives the ring contraction
(Scheme 153) <1996JA7422>. Using 17O-monolabeled bromolactones and 17O-NMR spectro-
scopy, it has been demonstrated that the free-radical ring contraction of six-, seven-, and
eight-membered lactones occur by 1,2-shift of the carboxylic moiety, and not by 3,2-shifts
<1999JOC1762>.
O O O H
O Ph Bu3SnH O Ph O Ph
n
AIBN n n –1
Br
205 206 207
n = 1–7, 10, 12 O Ph O H
O O Ph
n
H H
208 (100%, n = 1) 209 (100%, n = 3)
Scheme 153
1.19.13.4.7 Cascade radical cyclizations

Cascade (tandem) radical reactions are among the most powerful methods to generate
polycyclic ring systems in one step from unsaturated acyclic precursors. Landmarks in this
concept include the total syntheses of ()-hirsutene by Curran and Rakiewicz <1985T3943>,
and a more elaborate version relying on the use of SmI2 and leading to an advanced precursor
of hyptnophilin and coriolin <1998JA5064>. Polycyclizations involving successive radical
6-endo-trig cyclizations have been used to generate poly-trans-decalin systems including a
precursor of ()-5, 4-methyl-D-homoandrostane-3,17a-dione (Scheme 154) <1996JOC1806,
1998JOC1162>.
COOEt
Me
Me CN
CN Mn(OAc)3
Cu(OAc)2
H Me
O
COOEt
H O
Me
CN Me H
H H H H
O O
Me H H
COOEt Me
(±)-5α-4α-Methyl-D-homoandrostane-3,17-dione
Scheme 154
Tandem radical cyclizations and carbonylative tandem cyclization of 5,5-disubstituted cyclo-

pentadiene 210 provide angular triquinanes 211 and 212 (Scheme 155) <1998JCS(P1)1591>.
Double carbonylation of 213 (Scheme 156) occurs with triple cyclization and no fragmentation
giving tetracyclic compound 214 (32%) as major product. The second product is 215 (20%).
Since the first examples reported by Beckwith and Schiesser in 1985 <1985T3925>, many
polycyclic skeletons including steroids <1994TL2593, 1999JA4894>, diterpenes
<1998JOC7945>, and also triquinanes <1994TL7845> have been obtained. Among them, a
linear triquinane framework 218 has been constructed from the acyclic enediyne 216 by a cascade
involving intra and intermolecular radical additions and also H-transfer and -elimination
(Scheme 157) <1998JOC6764>.
Pattenden illustrated the potential of the cyclopropylmethyl/homoallyl radical rearrangement
associated with 6-endo tandem, 9-endo macrocyclization, and transannular processes to form a
steroidal skeleton 222 starting from the acyl selenide 220 (Scheme 158) <1998CC311>.
Br COOMe
COOMe
Bu3SnH
+ CO (90 atm)
AIBN
210
COOMe COOMe
COOMe COOMe
O
COOMe COOMe
+ CO
COOMe COOMe
Bu3SnH (reduction) Fragmentation
COOMe
O
COOMe COOMe
H COOMe
O
211
Bu3SnH (reduction)
MeOOC
COOMe
H
O
212
Scheme 155
I
Bu3SnH
+
CO (95 atm) O O
AIBN, PhH
O
213 214 (32%) 215 (20%)
Scheme 156
Biomimetic synthesis of epi-illudol 223 <1997JA3427> and of the linear triquinane framework
224 <2002AG(E)3284> have been proposed by Malacria and co-workers (Scheme 159).
Zard and co-workers have built the tetracyclic skeleton of 13-deoxyserratine 227 via radical
polycyclization involving the intramolecular addition of amidyl radical 226 derived from 225
(Scheme 160) <2002AG(E)1783>. See also the synthesis of the precursor of ()-vindoline
<2002OL443>.
The ‘‘round trip’’ radical reaction of 11-iodo-2,7-dimethyldodeca-1,6,10-trien-5-one 228 is a
sequence of 5-exo, 6-endo, and 5-exo cyclizations in which the last radical cyclization occurs at the
same carbon atom as the initial generation, giving isogymnomitrene ketone 234 as major product
(31%). Gymnomitrene ketone 233 was obtained also together with 230–232 (Scheme 161)
<2000JOC2007>.
CN
Si
O Bu3SnH SiMe3
O
Si SiMe3
CN
Br
SiMe3 SiMe3
216 217
CN
Si Si
1,6-H transfer O Si O Si
+
6-endo-trig
β-elimination
218 (42%) 219 (24%)
Scheme 157
COOMe COOMe
6-endo -trig MeOOC
MeOOC 6-endo -trig
Cyclopropylmethyl → H
homoallyl rearrangement
O H
SePh O
220 221
COOMe
MeOOC H
9-endo -trig
Transannulation H H
5-exo -dig
45% H
O
222
Scheme 158
Br Si Si
O O
TBDMSO TBDMSO
OH OH
i. 5-exo -dig, transann. 4-exo -trig
transann. 6-exo -trig
ii. Tamao oxidation
47% HO Me
223
Br OMe OMe
Si
O
i. 5-exo -dig, transann. 4-exo -dig MeO

transann. 6-exo -trig
HO
ii. Tamao oxidation
45% HO Me
224
Scheme 159
Me OTBDMS Me OTBDMS Me OTBDMS

Cl
H H H
Bu3SnH 5-exo-trig
N
Cl O 6-endo-trig
Cl-reduction N
O O O
N 52%
O
BzO O
225 226 227
Scheme 160
O
Me
230
Bu3SnH, 23%
O
O Me
C10F12CH2CH2Sn(Me)2H
Me
g
AIBN, 80 °C g
I
228 229
O O O
Me H Me H Me H
20%
g g g
231 3% 31%
O
Me H Me H O Me H O
g g g
22%
232 233 234
Scheme 161
1.19.13.4.8 Radical fragmentation

Any radical can undergo a -elimination (Equation (142)) with the formation of another radical
and an unsaturated system. It is the reverse reaction of radical addition to an unsaturated moiety.
Fragmentation is favored by dilution (law of mass action), by temperature (entropy effect), and
by low endothermicities.
A Fragmentation
Z X• A• + Z X ð142Þ
Addition
Simpkins and co-workers <1995SL943> have proposed a radical alkene synthesis (235 ! 236)
involving a radical abstraction by -scission as illustrated in Scheme 162.
In an efficient example of a tandem process Harrowven and Browne <1995TL2861> have
proposed an approach to tributylstannyl-substituted benzothiophene 238 starting from aryl
bromide 237 (Scheme 163).
OBz
Br H Ph BzO Ph
R Bu3SnH
Ph AIBN, ∆ H
SO2 SO2 R SO2 R
PhH, 80 °C
OBz
235
R OBz
Ph
236
R = H (39%)
R = Me (42%)
Scheme 162
S S
Bu3SnH
S
S AIBN S
Br S
PhH, 80 °C
237
Bu3SnH Bu3Sn• SnBu3

S
S S S
H
H H
–PrS•
SnBu3
70% S
238
Scheme 163
Giese and co-workers <1998AG(E)460> have extended their studies on the dissociation of -
phosphatoxy radicals (e.g., 239) by examining the subsequent electron transfer reactions of the
resulting cation radicals (Scheme 164). In rigid double-standard DNA it was found that cation
radical 240 could abstract electrons from neighboring guanine bases provided they were <7 Å
distant.
G G G•
O Ar O Ar O Ar
O O O
• Heterolysis • SET
OPO3R OPO3R
239 240 241
Scheme 164
Chatgilialoglu and Gimisis <1998CC1249> have shown on the basis of 18O labeling experi-
ments that the peroxyl radical 243 partitions between heterolytic scission to give the 20 -cation 245
which in turn is hydrolyzed to give the 20 -ribolactone 246, and reaction with another peroxide
radical to give the 20 -alkoxy radical 244. The latter eliminates an uracil-1-yl radical also giving the
ribolactone 246 (Scheme 165).
Crich and co-workers <1999OL225> (Scheme 166) reported the synthesis of tetrahydrofurans
via a radical nucleophilic displacement from -(phosphatoxy)alkyl radicals 248 following a 1,5-
hydrogen atom abstraction by the initially formed alkoxy radical 247. The mechanism probably
involves a stepwise fragmentation of the -(phosphatoxy)alkyl radical 248 to give a styrene-type
radical cation/phosphate anion pair 249 which then ring closes to produce the more stable
benzylic radical 250.
HO Het HO Het HO Het

O O O
• O2 ROO•
• •
O O O
OH OH OH
242 243 244
•
–O2 –Het•
HO HO
O Het O O
+ H2O
–Het-H
OH OH
245 246
Scheme 165
O
O O
(PhO)2PO
(PhO)2PO (PhO)2PO
Ph O• Ph • OH Ph •
OH
R R R
247 248 249
•
O
Ph
+ (PhO)2PO2H
R
250
Scheme 166
-(Phosphatoxy)alkyl radical reactions are involved in the cleavage of DNA by anticancer

agents. Solvent effect studies and measured entropies of activation indicate that radicals of type
251 react via initial heterolysis to 252 (Scheme 167). This then either collapses to products 253
(net migration) or yields free radical cation 252 <1999OL153, 1999JA10685>.
O EtO OEt
O P(OEt)2 P O
Fragmentation O O Migration P(OEt)2
•
• O
Ar Ar • Ar
252 251 253
Scheme 167
An enantioselective preparation of 4-substituted cyclohexenes by radical fragmentation has

been proposed by Renaud and co-workers (Scheme 168) <1999OL873>. Treatment of cis-255a
and cis-255b with Bu3SnH/AIBN/benzene (sun lamp, 10 C) gave 256a and 256b with ee values of
70% and 80%, respectively.
Malacria and co-workers <1999JA11395> reported an asymmetric intramolecular radical
vinylation using enantiopure sulfoxides 257 as temporary auxiliaries (Scheme 169). The inter-
mediate radicals of type 258 undergo -elimination producing enantiomerically enriched methy-
lidenecyclopentanes 259.
Br O i. R Br O
MgX H
S S
O
X = Br or I
ii. Chromatography R
254 255a R = Ph
255b R = But
• H
• Bu3SnH
S R S R AIBN R
sunlamp
O O 256a R = Ph
256b R = But
Scheme 168
PhSe E E
E E E E
R
Bu3SnH
O
S init. 88%
R
MAD R
p-Tol O S
p-Tol
257 258 259
E = COOMe R = cyclohexyl
MAD: methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide) 93% ee
Scheme 169
1.19.13.4.9 Radical polymerization
(i) Living radical polymerization

In 1982, Otsu and Yoshida <1982MI127, 1982MI133> using phenylazotriphenylmethane as
initiator to polymerize methyl methacrylate at 60 C found that molecular weight increased
linearly with the conversion. The ‘‘living’’ character of the polymerization was demonstrated by
observing that the polymer so-obtained continued to grow on heating to 80 C in the presence of
the monomer, generating a high molecular weight polymer. Detailed studies on the initial step in
free radical polymerization of -(substituted methyl) acrylates have used ESR spectroscopy
(Scheme 170) <2003MI2883>.
H H R
∆
( ) CH2 X CH2 C • + X •
monomer
R R
H H
260 261
CH CH2 C• + X•
(dormant polymer) (active polymer) n
R R
262
H H
R + Y X (initiator + controller) CH CH2 C X
n
or Y Y (initiator) + X• (controller) R R
263 (longer polymer)
Scheme 170
Since this pioneering work, a large number of solutions have been proposed for the living
radical polymerization. The strategy for controlling radical polymerization lowers the (instanta-
neous) concentration of a growing radical species by introducing a covalent dormant species 260
that exists in fast equilibrium with a small amount of 261, the growth-active radical species. Such
a dynamic and rapid equilibrium not only minimizes the extent or probability of the radical
bimolecular termination but also gives an equal opportunity of propagation to all polymers (or
dormant) terminals via the frequent interconversion between the active and the dormant species.
These features thus lead to nearly uniform chain length (molecular weight) determined by the
molar ratio of monomers to the dormant species (or the initiator). Another factor for considera-
tion is the so-called ‘‘persistent radical,’’ a relatively stable radical that does not react with its own
kind but does combine with the growing end (e.g., Ph3C, TEMPO). Its importance has been
pointed out as it is necessary for the control <2001CRV3581>.
The covalent bonds of the dormant species include C–C (X = Ph3C), C–S (X = Et2NCS2,
PhCS2), C–Se (X = PhSe), C–O (X = TEMPO, BBN-O), C–Hal (X = l), and C–Metal
<2001CRV3689> (Scheme 171).
O•
B
TEMPO: N O• BBN-O:
R''
O N O N
XY: XY: H
R'
264 265
Scheme 171
The initial work of Hawker <1994JA11185, 1997MI373> on the use of alkoxyamines as unim-
olecular initiators demonstrated that the molecular weight of polystyrene could be accurately con-
trolled up to Mn values of ca. 75,000 using the assumption that one molecule of the TEMPO-based
alkoxyamine 264 initiates the growth of one polymer chain and the length, or degree of polymerization,
of the chain is governed by the molar ratio of styrene to 264. Subsequently, the second-generation
alkoxyamines, such as 265, have conclusively proved this ability and, especially in the case of 264, the
upper molecular weight limit (Mn) for controlled molecular weights has been increased to between
150,000 and 200,000. For typical monomers and polymerization conditions, values of ca. 200,000 may
represent an upper limit for nitroxide-mediated living free-radical systems <1999JA3904>.
(ii) Metal-catalyzed living radical polymerization

As already mentioned earlier (Scheme 106), the Kharasch addition of alkyl halides to alkenes can
be catalyzed by the nickel complex Ni(NCN)Cl. The transition metal complex (catalyst) induces
reversible activation of the carbon–halogen bond of the halide that generates an alkyl radical,
which on its turn initiates the polymerization of the alkene (Scheme 172).
Organic halides such as CCl4, CCl3Br, PhCH2Cl, Ph(Me)CHCl, PhCOC(Me)2Br,
CH3CH(CN)-Cl, or arenesulfonyl chlorides have been used for the radical polymerization
initiated by transition metal complexes such as RuCl2(PPh3), Cp2Fe2(CO)4, CpFe(CO)2Br, copper
complex 266, (Ph3P)2NiBr2, (Ph3P)2ReO2l, and many others <2001CRV3689> such as those
shown below (Scheme 173).
One of the most important applications of living polymerization is block copolymerization.
Block copolymers have interesting properties and are sought more and more in material sciences
(nanotechnology). Block copolymers are usually obtained via sequential living polymerization of
a monomer followed by that of another. The metal-catalyzed living radical polymerization
permits a wide variety of block copolymers to be prepared, starting with a large variety of alkenes
such as styrenes, acrylates, and methacrylates <1994SCI1710>. Organotellurium-mediated living
radical polymerization has been found suitable for the synthesis of di- and triblock copolymers
(Scheme 174) <2002JA13666>.
R Hal + MLnX [R•] + MLnXHal
MLnXHAL
[R•] + m R m–1 R m–1
R' R' R' R' R'
Dormant intermediate
R m –1 x R'
R' R' R' R'
MLn XHAL Hal, X

n
R' R' R' R'
Scheme 172
O C13H27 C13H27
O
O PPh3
Fe Fe Re I
Fe CO O PPh
Br CO Cu 3
O
O Br
Cp2Fe2(CO)4 CpFe(CO)2Br 266 (Ph3P)2ReO2I
Scheme 173
Ph
Ph(Me)CH-TeMe R• •TeMe polystyrene-TeMe
Me
COOMe
Polystyrene-TeMe PolySt• + •TeMe
PolySt-poly(meth)acrylate-TeMe
∆ COOBut
PolySt-polyMMA• + •TeMe
PolyStyrene-poly(meth)acrylate-poly(t-butyl)acrylate-TeMe
Scheme 174
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Biographical sketch
Patrick Pale was born in Charleville Professor Pierre Vogel was born in Cully, VD
(Ardennes), studied at the University of Switzerland. He received his education in
Champagne-Ardenne, where he obtained a Switzerland, was awarded a Chemical Engineer-
Ph. D. in 1982 under the direction of Prof. ing degree in 1966 from Polytechnic School and in
J. P. Pete and J. Muzart. After an industrial 1969 a Ph.D. degree from the Institute of Organic
stay in a pharmaccutical company, he joined Chemistry, University of Laussanne. He spent the
the laboratories of Prof. L. Ghosez at Lou- next two years (1969–1971) as a post-doctoral
vain-La-Neuve in Belgium for a postdoctoral research associate at Yale University (Prof. Saun-
work on synthetic applications of azadienes. ders), USA. He worked as a research chemist for
In 1984, he returned to the University of 1 year (1971–1972) in Syntax SA, Mexico. He
Champagne-Ardenne as a CNRS fellow. returned to University of Laussane in 1972 and
Working on rearrangements and reaction was an Assistant Professor from 1973 to 1976. In
mechanisms, he obtained a ‘‘Doctorat d’Etat’’ 1977, he was promoted as a full Professor. He
in 1987, then a research associate position at became a Vice Chairman of the Institute of
Harvard University in the group of Prof. Organic Chemistry, University of Laussane in
George Whitesides in 1988–1989. He returned 1991 and remained in Laussane until 2001. In
to the University of Champagne-Ardenne, 2001, he moved to Swiss Federal Institute of
and took up his present position as Professor Technology as a Professor of Organic Chemistry
in Organic Chemistry at the University and is presently continuing in that position.
L. Pasteur Strasbourg in September 1994. Professor Vogel is widely travelled and has
Subsequently, he was awarded Professor at taught in several universities of France and USA.
the Institut Universitaire de France from Professor Vogel is a member of several pro-
1996 to 2001. His scientific interests include fessional associations, Swiss, American, and
total synthesis of bioactive compounds, orga- French chemical societies, and was awarded
nometallic chemistry, asymmetric synthesis, the Swiss Chemical Society Werner medal in
and catalysis, in particular carbohydrate 1976.
chemistry and enzymatic chemistry. Professor Vogel is also a member of editorial
board of several journals, Helvetica Chimica Acta,
Chimia, Journal of Carbohydrate Chemistry, Car-
bohydrate letters, Current organic synthesis, etc.
Professor Vogel is author of 3 books and more
than 390 publications.
Professor Vogel has broad research interests in,
synthetic, physical organic and Carbohydrate
chemistry. His research interests also include new
reaction of SO2, new Organic Chemistry based on
SO2, new catalysts adaptive Chemistry and
dynamic libraries of ligands for biopolymers.
1.20
Allenes and Cumulenes
C. BRUNEAU and J.-L. RENAUD
CNRS – Université de Rennes 1, Rennes, France

1.20.2 BY CH BOND FORMATION 1020
1.20.2.1 Isomerization of Alkynic Compounds 1020
1.20.2.1.1 Isomerization of alkynes and diynes 1020
1.20.2.1.2 Isomerization of enynes 1021
1.20.2.1.3 Propargylic rearrangement 1022
1.20.2.1.4 Rearrangement into -allenic ketones 1023
1.20.2.2 Reduction of CC Triple Bonds 1023
1.20.2.2.1 Dehalogenation of alkynic halides 1023
1.20.2.2.2 Reduction of polyunsaturated hydrocarbons 1024
1.20.2.2.3 Reduction of propargylic derivatives 1025
1.20.2.2.4 Palladium-catalyzed reduction of propargylic derivatives 1026
1.20.2.2.5 Elimination involving H-migration 1027
1.20.2.2.6 Hydrolysis of alkynic silanes 1028
1.20.2.2.7 Allenes via hydroboration, hydrohalogenation, and hydrosilylation 1029
1.20.3 BY CC BOND FORMATION 1029
1.20.3.1 Nucleophilic Substitution with Organocopper Compounds from Propynyl Derivatives 1029
1.20.3.1.1 Alkylcuprates as nucleophiles 1029
1.20.3.1.2 Stoichiometric organocopper reagents as nucleophiles 1031
1.20.3.1.3 Copper(I)-catalyzed nucleophilic substitution 1033
1.20.3.1.4 Organocopper-mediated ring-opening reactions 1034
1.20.3.1.5 Copper-mediated 1,n-addition reactions 1035
1.20.3.2 Nucleophilic Substitution with Organomagnesium Reagents 1036
1.20.3.3 Miscellaneous Nucleophilic Substitutions 1037
1.20.3.4 Reaction of Electrophiles with Propargyl and Allenyl Organometallics 1038
1.20.3.4.1 Lithium derivatives 1038
1.20.3.4.2 Magnesium, aluminum, and manganese derivatives 1039
1.20.3.4.3 Tin-mediated allenylation reactions 1040
1.20.3.4.4 Reactivity of propargyl silanes 1041
1.20.3.4.5 Boron chemistry for allene synthesis 1043
1.20.3.4.6 Allene synthesis via titanium derivatives 1044
1.20.3.4.7 SmI2-mediated allene synthesis 1045
1.20.3.4.8 Indium-mediated allene synthesis 1045
1.20.3.4.9 Miscellaneous 1046
1.20.3.5 Palladium-mediated Coupling Reactions 1046
1.20.3.6 CC Bond Formation via Sigmatropic Rearrangements 1050
1.20.3.6.1 [2,3]-Wittig rearrangement 1050
1.20.3.6.2 [3,3]-Claisen–Cope rearrangement 1051
1.20.3.7 Miscellaneous 1053
1.20.4 BY C¼C BOND FORMATION 1054
1.20.4.1 Elimination Reactions 1054
1.20.4.1.1 1,4-Elimination 1054
1.20.4.1.2 Desulfurization, decarboxylation, and related reactions 1054
1.20.4.1.3 1,2-Elimination 1055
1.20.4.1.4 Elimination of HX 1055
1.20.4.1.5 Elimination of XY 1057
1.20.4.2 Reduction of Unsaturated Alcohols and Halides 1061
1019
1020 Allenes and Cumulenes
1.20.4.3 Wittig and Related Reactions 1061

1.20.4.3.1 Reaction of a ketene and an alkylidene phosphorane 1061
1.20.4.3.2 Reaction of a ketone and a vinylidene phosphorane 1063
1.20.4.3.3 Three-component reaction for allene synthesis 1064
1.20.4.3.4 Addition of carbene moieties to double bonds 1064
1.20.4.4 Dehalogenation 1065
1.20.4.4.1 Dehalogenation of halocyclopropanes 1065
1.20.4.4.2 Dehalogenation of gem-dihaloalkenes 1066
1.20.4.5 Reactions Involving Coordinated Organometallic Species 1066
1.20.4.6 Metal-catalyzed Homocoupling of Alkynes or Cumulenes 1067
1.20.4.7 Intramolecular Rearrangement with Formation of Heteroatom–Carbon Bond 1067
1.20.4.8 Cyclopropane Ring Opening 1069
1.20.4.8.1 Photolysis of cyclopropenes 1069
1.20.4.8.2 Photorearrangement of vinylidenecyclopropanes 1069
1.20.4.8.3 Ethynylcyclopropane rearrangement 1070
1.20.4.9 Miscellaneous Reactions 1070
1.20.1 INTRODUCTION
The preparation and reactivity of allenes and cumulenes have received special attention in several
reviews. After the first reviews on allenes <1964RCR1, B-1969MI120-01> and cumulenes
<1961BSF2176>, methods for preparation were described by Taylor <1967CR317>, Murray
<1977HOU(5)963>, Hopf <B-1980MI779>, Landor, <B-1982MI120-01>, and Brandsma
<B-1984MI120-01>. More specialized reviews have appeared dealing with propargylic rearrange-
ments <B-1969MI(7)365>, allenic ketones <1980T331>, strained cumulenes <1989CRV1111>,
and reactivity of allenes <1984T2805, B-1984MI120-02, 2003ACR773>. Recent synthetic meth-
ods and applications published during the 1990s has been reviewed here since the publication of
<1995COFGT(1)953>.
1.20.2 BY CH BOND FORMATION
1.20.2.1 Isomerization of Alkynic Compounds
1.20.2.1.1 Isomerization of alkynes and diynes

Allenes were initially prepared by isomerization of the RCH2CC moiety in the presence
of a strong base such as an alkali metal amide (NaNH2) at high temperature (Equation (1))
<B-1969MI120-01>, or when the -hydrogen is more acidic, with a tertiary amine
<1965CB2611> or basic alumina <1964T2177, 1990JA2402>. Activation of the triple bond
via coordination to a manganese moiety can facilitate the isomerization with Al2O3
<1979AG(E)688> and has been used to prepare chiral allene derivatives of high enantiomeric
purity from alkynic aldehydes <1998TA697> after the separation of the allene metal complex
enantiomers (Equation (2)). Internal acetylenes containing a hydroxy group can be regioselec-
tively isomerized to allenic alcohols with BuLi/TMEDA (Equation (3)) <1986TL4599>.
Recently, it has been shown that potassium hydroxide could be used as a base when the
reaction was performed under phase-transfer conditions in the presence of an ammonium salt
(Equation (4)) <2000SL493>. From diynes, the prototropic rearrangement leads to bisallenyl
derivatives in the presence of KOBut <1973TL3181> (Equation (5)), and from 1,4-diynes
milder conditions can be used (NaOH/EtOH) for the preparation of alkynyl allenes
<1958JA1376>.
KOBut NaNH2 •
R ð1Þ
R >100 °C 175 °C R
Allenes and Cumulenes 1021
Mn(CO)2 Mn(CO)2 Mn(CO)2

H Basic alumina
H H H R H ð2Þ
CHO • + •
R or DBU R H
CHO CHO
exo endo
i. BunLi, TMEDA
R ii. H2O • • OH ð3Þ
R ( )n OH R ( )n
( )n OH major
Ph
KOH (1 equiv.) H H
•
Toluene, rt Ph ð4Þ
X
tetrahexylammonium
X = H, 2-Br, 3-Br bromide (10 mol.%)
3-OMe X
77–82%
KOBut, ButOH
•
ð5Þ
•
From alkynic !-keto esters bearing a cyclic ketone in their skeleton, a cascade reaction
involving successive CC and CH bond formation was observed in the presence of tetrabutyl-
ammonium fluoride, which led to exocyclic allenes (Equation (6)) <2001OL2689, 2003TL4483>.
CO2Et
CO2Et
•
HO
O TBAF, THF, 20 °C ð6Þ
( )n
n = 1 (50%)
( )n n = 2 (87%) H
n = 3 (80%)
n = 1, 2, 3
1.20.2.1.2 Isomerization of enynes

1,4-Enynes have been isomerized using KOBut to produce conjugated ene-allenes (Equation (7))
<1965JOC2983>. 1,4-Enynes containing a hydroxy group have been transformed into conjugated
vinyl allenyl alcohol derivatives in the presence of 5% methanolic sodium hydroxide (Equation (8))
<1953JA1050>. Cross-conjugated ene-allenes and ene-diallenes have been produced by prototropic
shift from a 1,4-enediyne under selected conditions (Equation (9)) <1987TL2697>.
KOBut, 10 °C • ( )7 CO2Me ð7Þ

( )7 CO2Me 92%
CH2OMe CH2OMe
ð8Þ
NaOMe, MeOH
•
OH 75%
OH
KOBut, THF NaOMe, MeOH

• 64 °C
–78 °C ð9Þ
88% 60% •
•
1.20.2.1.3 Propargylic rearrangement

Propargyl derivatives with a heteroatom X attached to the sp3C(CCCHR1XR) easily
undergo a base-catalyzed rearrangement leading to stable allenes CH¼C¼CR1XR. Allenyl
ethers, efficient building blocks in organic synthesis <1993S165, 1993SL105, 1993JOC5709,
1992AG(E)1033>, are generally obtained in 80–100% yield by reaction of propargyl ethers
with KOBut (Equation (10)) <1968RTC916, 1993JOC5702>. Catalytic amounts of KOBut are
used for the selective transformation of 2-alkynyl ethers 1 containing a bromine into allenyl ethers
2 (Equation (11)) <1988JCS(CC)237>. This reaction can also be applied for the generation of
alkenyl allenes 4, precursors for Diels–Alder cycloadditions, from 3 (Equation (12))
<1993JCS(CC)270>.
KOBut, ∆ OR
OR
80–92%
• ð10Þ
R = alkyl
90%
R = CH(Me)(OEt)
Br KOBut (cat.), ∆ Br
O O
• ð11Þ
85–90%
1 2
•
O Br KOBut, Pentane, reflux O Br ð12Þ
65%
3 4
Cyclic enyne allene sulfones 6 have been prepared by oxidation of cyclic enediyne sulfides 5
with MCPBA (Equation (13)) <1993JCS(CC)1406>. Propynyl sulfones <1992JCS(CC)735> and
alkynyl amines can be converted into allenyl derivatives by treatment with potassium amide or
alumina <1968JCS(C)228, 1968JCS(C)606>. The allenyl benzotriazole 8 has been prepared in
satisfactory yield by treatment of propargyl benzotriazole 7 with NaOH (Equation (14))
<1993JOC3038>. Similarly, a variety of allenamides 10 have been obtained upon treatment of
the propargylic derivatives 9 with ButOK (20 mol.%) in THF at room temperature (Equation (15))
<2003ACR773, 2002OL2417, 2001T459, 1999TL6903>.
OR
MCPBA, CH2Cl2, 25 °C • OR
O2S
S 63–88% ð13Þ
5 6
N N
N NaOH, EtOH, 25 °C N
N 60% N ð14Þ
•
7 8
O
KOBut (20 mol.%)
O •
N N
X ( )n THF, rt X ( )n
9 10
X = CH2 n=1 (77%) ð15Þ
n=2 (80%)
n=3 (75%)
n=4 (74%)
X = NMe n = 1 (80%)
X = O, n=1 (62%)
The mild isomerization of the prop-2-ynyl into the allenyl group can also be achieved from
phosphine derivative ligands coordinated to metal complexes (Equation (16)) <1993CB1077>.
•
But P MoCp(CO)2 But P MoCp(CO)2
Et3N, THF, 25 °C
O O ð16Þ
95%
But But But But
1.20.2.1.4 Rearrangement into a-allenic ketones

The rearrangement of -alkynic ketones into -allenic ketones can be achieved by using NaHCO3 in
water, e.g., 11 to 14 <B-1984MI120-01>, basic alumina, e.g., 12–15 and 13–16, <1986JOC2623>
(Equation (17)), or silica gel <1998TL7491, 1986JOC2623, 1996JA8949>. A good method to produce
the allenynone 19 from the alkynyl homopropargylic alcohol 17 involves first, the Swern oxidation
into 18 followed by thermal <1993TL449> or basic <1994JOC7169> rearrangement (Equation (18)).
The oxidation of homopropargylic alcohols by the Dess–Martin periodinane reagent also affords
allenones in good yield after work-up over alumina or silica gel <1990JOC3450, 1994JOC7169> as
illustrated by the transformation of 20 into 22 via the ketone 21 (Equation (19)) <1998TL7491>.
R2 R2
Base, rt O
O
•
R1 R1
ð17Þ
11 R1 = H, R2 = Et, NaHCO3, 14 (85%)
12 R1 = Me, R2 = n-C3H7, Basic Alumina, 15 (68%)
13 R1 = Me, R2 = MeCH=CH Basic Alumina, 16 (62%)
Swern Toluene
OH O reflux O
oxidation
Bu Bu Bu ð18Þ
91% 100% •
17 18 19
OH O •
Dess–Martin O
oxidation Silica gel
ð19Þ
77%
CHO CHO CHO

20 21 22
1.20.2.2 Reduction of CC Triple Bonds
1.20.2.2.1 Dehalogenation of alkynic halides

Dehalogenation of -alkynic halides by reducing agents such as Zn-Cu/ROH or LAH constitute a
general access to allenic derivatives. Since the direct reduction of propargylic alcohols is not
possible under these conditions, -allenyl alcohols can be prepared from -halo-0 -hydroxy
alkynic compounds <1955JOC1337>. For example, in the synthesis of the first fluoroallenyl
amino acid 25, the fluoroallenyl group is formed by reduction of the chlorofluoropropargyl
synthon 23 into the fluoroallenic alcohol 24 (Equation (20)) <1987JA3491>.
F F F O
AlH3 –
OTHP • •
Cl OH 70% OTHP O ð20Þ
HO H3N +
23 24 25
The Hiyama reagent, CrCl2 generated from CrCl3 and LAH, or CrCl2 in the presence of AcOH
<1983T2185> are also useful reducing systems that led to allenes and vinyl allenes from pro-
pargylic halides <1978TL3801> and 1-bromo-4-ene-2-ynes <1979NJC321>. The use of a chiral
protonating agent such as ()-menthol or ()-borneol for the reduction of 1-bromo-2-alkynes leads
to the formation of enantiomerically enriched allenes <1981TL103>.
Alkynic halides of different structures, with the halogen separated from the triple bond by an
unsaturated conjugated chain, have been reduced by generation of vinylallenyl metal intermediates,
which release the allene on hydrolysis <1972TL4465, 1972JCS(CC)866, 1974BSF1119, 1976S755>.
1.20.2.2.2 Reduction of polyunsaturated hydrocarbons

The formal 1,4-addition of hydrogen to conjugated enynes affords allenes as illustrated by the
reduction of dicyclohexen-1-yl acetylene with hydrogen in the presence of an iron/aluminum catalyst
(Equation (21)) <1942AS363>. Conjugated 2-en-4-yn-1-ols are reduced to 3,4-dien-1-ols by LAH in
refluxing diethyl ether <1975BSF1407>. Enynes containing an allenyl group and either a hydroxy 26
or an acetate 27 group have been reduced into diallenes 28 with LAH (for 26) or with LiAlH3OMe
(for 26–27) (Equation (22)). With this latter reagent, less competing hydroxy substitution by the
hydride takes place. This reduction corresponds to a 1,4-addition of H/Hþ and the presence of a
hydroxy group in 26 probably facilitates the hydride transfer via an alkoxyhydrido aluminate-OAlH3
intermediate <1974TL1593>. The reduction of 1,1,6,6-tetraphenylhexapentaene with aluminum
amalgam in THF containing water gives 1,1,6,6-tetraphenyl-1,2,4,5-hexatetraene in 80% yield
(Equation (23)) <1961CB3060>, but this strategy has been scarcely used for allene preparation.
H2, FeAl •
ð21Þ
Quantitative
R4 H
• R4 H
R4 LAH or LiAlH3OMe • R3
R1
R2 R4 •
Ether or THF H
ð22Þ
OY
R2 OY 50–80% R2
R1
26, Y = H 28
27, Y = MeCO
H Ph
Ph Ph Al/Hg, H2O
Ph • ð23Þ
• • • • • Ph
Ph Ph 80%
Ph H
A specific reduction of the enyne 29, with the double bond linked to an ester group, has been
achieved by treatment with cyanocuprate in ether. After protonation with pivalic acid, the allene
30 is obtained, whereas the carbocupration product 31 is formed when the reaction is performed
in THF (Equation (24)) <1991TL7229>. It has also been shown that low temperature favors
CH rather than CC bond formation in the reaction of propargylic acetates with organocup-
rates and LAH <1976JCS(CC)183>.
Ether
R1 R2
•
R2 CO2Et
R1 + Cu(CN)Li2 30
CO2Et 2 ð24Þ
29 R1 R2
•
THF
CO2Et
31
A reduction sequence, formally with R and H+, is exemplified by the addition of an

organolithium <1977HOU(5)963> or a Grignard reagent <1974BSF1119> to enynes followed
by hydrolysis (Equation (25)). A similar strategy was applied to the formation of aminomethyl
allenes by addition of amines to 1,3-enynes or by reaction with lithium amides followed by
protonation (Equation (25)) <1977HOU(5)963>.
i. LiY (Y = alkyl, NR2)

ii. H2O R1 ð25Þ
R1
•
Y
1.20.2.2.3 Reduction of propargylic derivatives

-Allenyl alcohols 33 are obtained in good yields from the mono-O-tetrahydropyranyl ethers of
but-2-yn-1,4-diols 32 by reduction with LAH under mild conditions (Equation (26)). This reaction
is expected to produce first a CCH2OAlH3 intermediate 34 able to intramolecularly and
stereoselectively substitute the leaving group O-THP by transfer of the hydride
<1973JCS(P1)720>. -Allenyl ethers and tertiary amines have been respectively prepared by
reduction of 1,4-dialkoxybut-2-ynes and 4-dialkylamino-1-methoxybut-2-ynes with LAH and a
Lewis acid (MgBr2 or AlCl3) <1985S768>. An analogous transformation can be achieved from
35, which bears a quaternary ammonium group as the leaving group at the 0 -position of the
internal triple bond (Equation (27)) <1974S344>. The regioselective reduction of aryloxymethyl
ethynyl carbinols 36 into aryloxymethyl allenes 37 can be achieved using only LAH in THF and
in this case the regioselectivity observed is thought to result from the coordination of both oxygen
atoms to the aluminum center (Equation (28)) <1986TL3777>. This reaction has been used to
prepare liquid-crystalline allene derivatives with ferroelectric properties <1996LA1375>. A ver-
satile method to produce a variety of hydroxymethyl allenes of type 40 has been shown to result
from hydroxymethyl alkynes 38 by reduction with LAH in THF followed by treatment with solid
iodine at 78 C. The reaction proceeds via the alanate 39, whereas iodine in THF affords allylic
iodo alcohols 41 (Equation (29)) <1982TL3051>. A one-pot protocol has been used successfully
to reduce -methoxy--ynones into -allenols with high enantioselectivities in the presence of
Darvon alcohol and LAH <1994JA8526, 1993JOC5037>. It is however possible to transform
propargylic alcohols with no leaving groups such as steroids into the corresponding allenes in the
presence of LAH/AlCl3 (3/1) in THF <1975JCS(CC)362>. Propargylic alcohols 42 resulting from
treatment of (1R)-(+)-camphor with alkynyllithiums are reduced by AlH3 in THF at 90 C to
produce chiral allenes 43 in high diastereoselectivity (Equation (30)) <2002JOC1308>.
R1 LiAlH4 R1 R1
R2 R2 •
THP-O OH THP-O O R2 OH ð26Þ
H Al – +
Li
H H
32 34 33
R1 R3 R1
R2 R4 LiAlH4 •
R2 OH ð27Þ
R3N + OH R3 R4
35
O LiAlH4, THF, rt
90–95% O ð28Þ
R
HO •
36 37, R = H, Me, OMe, Cl
I2 solid HO
+ 60% •
– Li
HO OMe O
LiAlH4, NaOMe, THF AlH2 40
I ð29Þ
MeO I2/ THF
HO
38
39 OMe
41
AlH3, THF R
R 43–90% • ð30Þ
H
HO
42, R = alkyl, CH2OBn, CH2CH2OBn 43, (>95% de)
The reaction of propargylic ether or acetate 44 with ethylcuprate generated from excess
EtMgBr and CuBrMe2S in THF actually gives a reaction mixture containing the allenes 45
and 46 resulting from reduction and alkylation, together with the alkynic isomers (Equation (31))
<1984JOC4120>.
i. EtMgBr-CuBr.Me2S, THF, –30 °C

ii. H2O R R
R • + • ð31Þ
X Et
44, X = MeO, AcO 45 46
Cumulenes have been obtained from 4,5-dien-2-yn-1-ols 47 (or acetates), by reduction with
LAH. The addition of the hydride to the central allenyl carbon with elimination of the hydroxy
(or acetate) leads to the formation of cumulenes 48 (Equation (32)) <1975BSF2159>.
R3
i. LiAlH4 R1
•
ii. H2O R3
R4 • •
R2 ð32Þ
R4
YO R1
R2 48
47, Y = H, Ac
1.20.2.2.4 Palladium-catalyzed reduction of propargylic derivatives

Propargylic derivatives bearing a good leaving group (ester, carbonate, mesylate, phosphate,
or halide) are known to be transformed by palladium(0) complexes to afford allenyl palladium
intermediates. Their hydrogenolysis by an alcohol <1986TL5237>, or various sources of
hydride like metal hydride <1984TL845> or ammonium formate <1987S603,
1986JCS(CC)922, 1996TL3417> leads to the formation of allenes (Equation (33)). The reduc-
tion of propargylic phosphates and acetates in the presence of palladium(0) catalyst and SmI2,
which proceeds via an allenyl samarium intermediate, has been shown to be highly dependent
on the nature of the substrate and the proton source <1986TL5237, 1995TL907>. This
method was applied to the synthesis of an isocarbacyclin analog <1996TL8515>. By tuning
the proton source, regio-divergent synthesis of allenes/acetylenes from secondary propargylic
phosphates was made possible (Equation (34)) <1997SL1375>. Asymmetric synthesis of
allenes by reduction through a dynamic kinetic protonation of anionic allenyl samarium
species was performed successfully by using a chiral proton source such as pantolactone or
hydrobenzoin (Equation (34)) <1997AG(E)858, 2001T889>.
R2 R1 R2 R1 R2
R3 [Pd(0)] Proton source
R1 • •
R3 HCO2NH4
LG [Pd] + H R3
or LAH ð33Þ
LG = MeOCO2
or ROH
OAc, OMs
OPO(OEt)2, Br
SmI2, Pd(0), O OH
R2 H CO2Et
H H SmI2, Pd(0), ButOH, THF O ð34Þ
R1 •
• O P(OEt)
R1 R2 R1 ≠ H 2 68% R1
O 95% ee
R1 = c-C6H9CH2, R2 = CO2Et
-Hydroxy allenes have been obtained by a similar strategy, by reduction of alkynyl epoxides
with triethylammonium formate in the presence of Pd2(dba)3CHCl3 as catalyst precursor, but the
selectivity was not good and homopropargylic alcohols were also formed <1986JCS(CC)922>.
-Hydroxy allenes are more selectively formed starting from alkynyl cyclic carbonates in
the presence of Pd(dba)2/1,2-bis(diphenylphosphino)ethane (Equation (35)) <1994SL457>.
Palladium-catalyzed decarboxylation-hydrogenolysis of propargylic formates having a terminal
triple bond cleanly gives allenes at room temperature <1993TL2161>.
R HCO2H, Et3N in THF at 60 °C

Pd(dba)2 (cat.), Ph2PCH2CH2PPh2 R
•
O O H OH
ð35Þ
O
R = n-Bu 84%
R = Me 74%
R = CH2=C(Me) 62%
1.20.2.2.5 Elimination involving H-migration

The reduction of the tosylhydrazone derivatives 49 with catecholborane <1978JCS(CC)726>- or
NaBH3CN <1980JOC3925> produces allenes with loss of nitrogen and H-migration from a
diazene intermediate 50 (Scheme 1). The same type of elimination reaction, which generates
allenes with high stereospecifity from optically active propargylic alcohols <1989TL5747,
1994JA6622, 1996LA1375>, is involved in the direct oxidation of propargylic hydrazines 51 by
diethyl azodicarboxylate (DEAD) at 0 C. An improved straightforward stereoselective transfor-
mation is obtained by treatment of optically active propargylic alcohols with arenesulfonyl-
hydrazines under mild Mitsunobu conditions (Scheme 1) <1996JA4492, 1997JA2597,
2003JOC3739>.
R2 H2N-NHTs R2
R1 R1
O N-NHTs Catecholborane
49
or NaBH3CN
R2 R2 R1 H
R1 H R1 •
NH-NH2 N H R2
H2NNH2 51 H N
DEAD 50
rt
R2 ArSO2NHNH2 R2
R1 H R1 H
OH PPh3, DEAD N
H2N SO2Ar
Scheme 1
Another example of elimination-rearrangement involving a sigmatropic 1,5-migration is

illustrated by the formation of allenes with loss of SO2 via sulfinic acids generated from the
hydrolytic treatment of propargylic sulfinamides 52 (Equation (36)) <1990TL213>. The
reduction of alkynyl -ketosulfones with the aluminum amalgam in THF provides an efficient
method to synthesize trisubstituted allenes via H-migration (Equation (37)) <1995TL7925>.
The thermolysis of propargyl ketal at high temperature (390 C) also affords allene and
formate <1997T2049>.
R2 BF3.Et2O, H2O R1 R3
R1 R3 •
H R2
S
O N SO2, morpholine (46–77%)
O ð36Þ
52
R1 = alkyl
R2 = H, Me
R3 = Me, allyl, p-tolyl-CH2
R2
R1 R3 Al/Hg R1 R2
SO2 • ð37Þ
THF: H2O, rt H R3
O 74–95%
1.20.2.2.6 Hydrolysis of alkynic silanes

Electrophilic desilylation of propargylic silanes TMSCH2CCR 53, in the presence of car-
boxylic acids such as CF3CO2H <1980JOC5006> or BF32CH3CO2H <1987JOM(319)333>,
provides a regioselective synthesis of monosubstituted allenes 54 under mild conditions
(Equation (38)). Selective cleavage of the propargylic trimethylsilyl group from
TMSC(Me)2CCTMS 55 leads to the substituted allenyl silanes 56 on treatment with
CF3CO2H at 0 C <1981JCS(CC)1094, 1981TL3401> or MeSO3H at 25 C
<1972JOM(39)C44> (Equation (39)). 1-Trimethylsilylpropargyl alcohols are converted into
trimethylsilyloxy allenes in 63–96% yield by reaction of BunLi, via migration of the trimethylsi-
lyl group and protonation <1980TL623>.
R BF3.2MeCO2H, –5 to 20 °C R
TMS •
53 54 ð38Þ
R = Bun 97%
R = Ph 90%
R = But 82%
R TMS R
TMS R •
TMS CF3CO2H, 0 °C, R = Me, 95% R ð39Þ
55 or 56
MeSO3H, 25 °C, R = H, 80%
The cleavage of a CSi bond leads to a terminal allene via a propargylic proton transfer and
protonolysis. This method has been used to access 1,2,4,6-tetraenes 59 and 60 from a free 58 or
coordinated 57 trimethylsilyldienyne respectively, by cleavage with fluoride (Scheme 2)
<1992BSF151>.
R R
TMS Ce4+ TMS
R = H, 79%
MeO2C Fe(CO)3 MeO2C
58
57
R=H i. Bu4NF
100% ii. H2O
R
• •
Ce4+
MeO2C
R R = H, 65% MeO2C
R = Me, 86%
Fe(CO)3 59
60
Scheme 2
1.20.2.2.7 Allenes via hydroboration, hydrohalogenation, and hydrosilylation

Hydroboration of 1-chloro-2-alkynes with diisoamyl or dicyclohexylborane in THF at 0 C gives
-chloromethylvinyl boranes, which undergo an easy elimination on treatment with sodium
hydroxide to produce terminal allenes in good yield (Equation (40)) <1970JA1427>. 1,4-Addition
of HX to conjugated enyne derivatives leads to allenes in satisfactory yields in the presence of
Lewis acids, e.g., AlCl3 or ZnCl2 (X = Cl, Br) (Equation (41)), <1966JCS(C)1223> or palladium
catalysts (X = B(OR)2) <1989TL3789, 1992OM2732>.
HBR2 NaOH R1
R1 R1 Cl •
Cl BR2
R1 = Bun, 83% ð40Þ
R = cyclohexyl 1 = But,
R 92%
R1 = Ph, 91%
Lewis acid •
+ HX
X ð41Þ
X = Cl, 78%
X = Br, 54%
H2PtCl6 and RuHCl(CO)(PPh3)2 are excellent catalysts for the hydrosilylation of conjugated
cis-1,4-bis(trimethylsilyl)-1-buten-3-ynes to produce silylated allenes <2000JOM(609)130,
1998JA1421>, whereas the rhodium- and nickel-catalyzed hydrosilylation of butadiynes leads to
optically enriched silylated allenes in the presence of optically pure ligands <2000JOM(603)116>.
1.20.3 BY CC BOND FORMATION
1.20.3.1 Nucleophilic Substitution with Organocopper Compounds from Propynyl Derivatives
1.20.3.1.1 Alkylcuprates as nucleophiles

Since the first use of organocopper reagents to synthesize allenes from propargylic derivatives via
selective SN20 , displacement of a leaving group <1968JA4733>, many examples of this strategy
have been reported involving a variety of labile groups and copper derivatives <1995JA6345,
1998T9373>.
Diorganocuprates (Gilman’s cuprates) are the most reactive copper reagents and the easiest
to prepare. Thus, lithium cuprates allow the selective formation of allenes from propargylic
acetates, mesylates, carbonates and halides, etc. Spirocycloalkyl allenes were prepared by
addition of a dialkylcuprate to a propargylic acetate (Equation (42)) <1975TL4615>.
Pasto and co-workers <1978JOC1389> have observed the preferred formation of alkyl allenes
from mixed methyl alkyl cuprates and alkyl allenyl cuprates, and pointed out the competition
between reduction and substitution in the case of terminal chloroprogargylic derivatives
(Equation (43)). Chiral allenes, precursors of natural pheromones, have been obtained with
lithium dialkylcuprates starting from optically active propargylic carbamates 61 (Equation (44))
<1978JOC1950, 1978JOC2091>. Chiral allenes, precursors of enantiomerically enriched tricyc-
lic derivatives via a cobalt-mediated [2+2+2]-cycloaddition, were obtained with a similar
methodology <2000S985>.
AcO Pr
–10 °C to rt
Pr + Me2CuLi • ð42Þ
98% Me
Cl
0 °C
Me R1 H
R2 + Me(R1)CuLi • + • + • ð43Þ
R2 R2 2
R
R2 = H, Me R1 = Me, But, allenyl
O Et2O, –78 °C R H
R1 O N + R2CuLi •
60–88%
H H R1
ð44Þ
61 R = Bun, Et, n-octyl
R1 = Me, Et, Bun, MeOCOCH2CH2
>66% ee
As 2 equiv. of nucleophile are required for the formation of dialkylcuprate, a more

convenient procedure for functionalized nucleophiles was developed via heterocuprate chem-
istry. Thus, the use of alkyl cyanocuprates circumvents some of these problems; they are still
reactive species and allow the synthesis of allenes bearing nucleophilic functionalities such as
nitrogen moieties <1993SL499, 1995JOC2210, 2001JOC4904, 2001JCS(P1)1349> or hydroxy
functionality <2003EJOC2043>. Allenyl methylsilanes 62 have been produced by treatment of
propargyl tosylate with (trimethylsilylmethyl) cyanocuprate in ether (Equation (45))
<2002OL3497>. By this method, a chiral allene was synthesized in 70% ee starting from
commercially available enantiopure (S)-but-3-yn-2-ol. -Allenyl silanes have been produced by
a SN20 substitution reaction of propargyl bromide with a cuprate species formed from silyl-
substituted organozinc reagent and CuCN2LiCl (Equation (46)) <1998SL1315>. Chiral
allenes 63, precursors of the stereotriad subunits of polyketide natural products, have been
prepared by a silylcuprate SN20 displacement method (Equation (47)) <2000JOC630>.
-Aminoalkylcuprates, prepared from carbonates via sequential deprotonation and treatment
with CuCN2LiCl, react with propargyl bromides, mesylates 64, tosylates, and acetates to
afford aminoallenes <1999TL4293>. The reaction of a scalemic propargyl mesylate with the
-(N-carbamoyl)alkylcuprate afforded the N-t-BOC-aminoallene 65 in 82% yield and 83% ee
(Equation (48)) <2001OL3855>.
OMs Et2O
+ (TMSCH2)CuCNLi.LiCl •
61–77% TMS Me ð45Þ
Me
99% ee 62, 70% ee
i. CuCN.2LiCl
THF, –30 °C Ph
SiMe2R ii. CH2Br • ð46Þ
Ph
ZnBr 78–83%
SiMe2R
R = Me, p-MeOC6H4
OMs PhMe2Si H
R + PhMe2SiLi + CuCN • ð47Þ
R = H, 70% R Me
R = H, Et R = Et, 61% 63
MsO H Ph
Ph CH2Cl2
+ N CuCNLi.LiCl •
82% N ð48Þ
t-BOC
t-BOC
64 65 83% ee
Another route, based on the use of propargyl chloride and alkylcopper reagents arising from
optically active amino acids, has allowed the formation of enantiomerically pure protected amino
acids containing an allenyl group <1993SL219>. The same authors have described similar
syntheses of allenic amino acids based on the use of zinc-copper reagents (Equation (49))
<1993SL499, 1992JCS(CC)319>.
R NHt-BOC NHt-BOC
IZn(CN)Cu THF, 0 °C
+ R
TsO CO2Bn 51–81% • CO2Bn ð49Þ
R = H, Me, C5H11
An alternative to the alkyl cyanocuprate is the lithium alkyl(phenylthio)cuprate. Depending

on the reaction temperature and the stability of the intermediate copper species, the transfer of
an alkyl ligand from copper to the proximal allenic carbon is possible. Thus, from propargyl
acetates, substituted 66a <1997SL165> or terminal 66b <1993S577> allenes are readily
prepared (Equation (50)).
R1 = H
i. Bun(PhS)CuLi
R3 = H Et2O, –78 °C
R2 R1 Bun(PhS)CuLi R3 ii. NH4Cl aq. R2
• R2 R 1
• ð50Þ
H Bun R1 = H, 51%; Bun, 26% AcO 76–91% R3
66a 66b
2 = H,
R2 = C6H4 Ph R Me, ...
R3 = alkyl
For the synthesis of the bromoallene, ()-isolaurallene, the allenic moiety has been formed in a
related copper-mediated SN20 -substitution reaction by using triisopropylbenzenesulfonate as the
leaving group and LiCuBr2 as the bromide reagent <2001JA1533>.
1.20.3.1.2 Stoichiometric organocopper reagents as nucleophiles

As diorganocuprates are known to racemize optically active allenes, other organocopper deriva-
tives have been used for the synthesis of optically active allenes from chiral propargylic deriva-
tives. Chiral 1-phenyl-3-alkyl and 1,3-dialkyl allenes have been obtained from propargylic
sulfinates or sulfonates and (RCuBr)MgBrLiBr at 65 C (Equation (51)) <1989JOC3726>.
Dienylallene tricarbonyl iron complexes 68 have been obtained from dienylpropargylic carbonate
67 or mesylate complexes and (RCuBr)MgBrLiBr (R = Et, But) with very high diastereoselec-
tivity (Equation (52)) <1992AG(E)224, 1993T9775>. These organocopper derivatives are also
suitable reagents for the synthesis of silylated allenes 69 from trimethylsilyl propargylic sulfinates,
mesylates, or tosylates (Equation (53)) <1979S390>. Pure butatrienes 71 have been obtained
from 3-bromo-alk-3-en-1-ynes 70, as a result of anti-1,3-substitution, on treatment with a
copper(I) species in THF at 50 C (Equation (54)) <1982JOM(240)329>.
R2 R1
H (R1CuBr)MgBr.LiBr, THF, –65 °C H
•
Y
R2
Y = OS(O)Me, OS(O2)Me ð51Þ
R1 = alkyl
R2 = Ph (70–84%)
R1 = But (76–96%)
R1 = n-Oct (86–95%)
R
R
(EtCuBr)MgBr.LiBr, Et2O, –65 °C Et
MeO2C •
H MeO2C ð52Þ
(CO)3Fe O
O (CO)3Fe
OPh
67 68
R2 (R1CuBr)MgBr.LiBr, THF, –60 °C R2 R1

R3 TMS • ð53Þ
Me(O)SO R1 = alkyl, Ph; R2, R3 = H, alkyl R3 TMS
>85% 69
Br THF, –50 °C R2 R1
R3 + R1MgCl, LiCuBr2 • •
R2 85–95% R3 ð54Þ
70 71
R1 = R2 = Pri, But; R3 = H, D
Other organocopper(I) reagents have been prepared by using Grignard or zinc reagents in the
presence of stoichiometric amounts of Cu(I) halides in order to prepare liquid–crystalline allene
derivatives <1996CC977>. Fluorinated allenes and bisallenes have been prepared safely from
propargylic halides or tosylates and perfluoroalkyl copper(I) compounds <1990TL3703,
1990TL3699>. In a similar manner, stannylallenes were obtained by adding the stannylcopper
reagent to a suitable propargyl compound <1994SC789>. The synthesis of the protected -allenic
alcohols 72, of high optical purity, has been carried out starting from the appropriate chiral
propargylic bromide or tosylate and functional Cu(I) derivatives (Equation (55))
<1991JOC1083>. Stannyl alkynes react with alkylcopper(I) species at 60 C to give stannyl
allenes 73 in high yield, but quantitative transmetallation of the alkyne takes place with MeCu,
CH2¼CHCu, PhCu, and Me3SiCCCu (Equation (56)) <1984TL3019>. The copper(I)
enolate generated from the lithium enolate of acetylacetate and CuI at 78 C substitutes
propargylic esters to produce -allenyl esters <1978JOC555>.
CO2Me
rt TBDPSO
TBDPSO + Cu CO2Me • ð55Þ
88%
Br H
72
R2 R2 R1
R3 1Cu THF, –60 °C
SnPh3 + R •
>90% ð56Þ
Cl R3 SnPh3
R2, R3 = H, Me R1 = Et, Pr, Bu 73
The direct 1,3-substitution of the hydroxy group of propargylic alcohols has been performed
successfully by an organocopper derivative formed in situ from CuI, RLi, and (methyl-phenyl-
amino)tributylphosphonium iodide (Scheme 3) <1980JOC4536>.
Coupling either two propargylic acetate or two allenyl bromide 74 molecules in the presence of
CuCl in DMF at room temperature furnishes symmetrical diallenes 75 via allenyl radical inter-
mediates (Equation (57)) <1975JCS(CC)174>.
–
R3 R2 R3
R2 R4 •
OH R1 = Me, Bun, Ph R1 R4
34–82%
i. MeLi
ii. CuI
iii. R1Li
+
R3 Bu3nPN(Me)Ph I – R3
R 2 R2 R4
R4
OCuR1Li O–PBun3
(Ph(Me)NCuR1) – +
Scheme 3
R2 R1
R2 R2 R1
CuCl, DMF, rt • R2 CuCl, DMF, rt
2 R1 R2 2 • ð57Þ
R2 •
OAc R1 = R2 = Ph R2 Br
R1 R2 74
75 72%
1.20.3.1.3 Copper(I)-catalyzed nucleophilic substitution

The use of Grignard reagents in the presence of a catalytic amount of copper(I) salt avoids the
parallel formation of acetylenic derivatives resulting from simple nucleophilic substitution. Pro-
pargylic derivatives bearing an alkoxy leaving group have been used for access to polyalkylpropa-
1,2-dienes <1976JOM(108)159>, 1,2,4,6-tetraenes 76 (Equation (58)) <1979TL7> and -allenyl
amines <1987TL2207>. Chiral functional allenes are obtained with high stereoselectivity from
optically active propargylic ethers <1986TL5499, 1990JA8042> by using RMgBr, CuBr (5%),
and P(OEt)3 to inhibit racemization. Cyclic allenes 78 can be obtained from cyclic propargylic
esters 77 (Equation (59)) <1986TL4845>.
R1MgBr/CuBr (10 mol.%) R2

OMe •
R2 R 3 ð58Þ
R1 = Et, Bui, C5H11 R1 R3
R2, R3 = H, Me 20–77%
76
AcO c-C5H9 c-C5H9 c-C5H9

c-C5H9MgBr/CuI.Me2S •
THF, –78 to 20 °C
ð59Þ
(CH2)n n = 4, 92%
n = 7, 90% (CH2)n
77 78
Starting from nonpropargylic conjugated 1,3-alkadien-2-yl diethylphosphate 79, the substitu-

tion reaction with an organocopper reagent formed in situ from RMgX and CuX affords allene 80
in moderate yield, but suitable conditions have to be found to avoid the SN20 nucleophilic
substitution giving the 1,3-diene 81 (Equation (60)) <1983TL1297>.
PhCH2MgBr/CuI (10/20%) Ph
OP(O)(OEt)2
THF Ph • + ð60Þ
84%
79 80, 72% 81, 12%
1.20.3.1.4 Organocopper-mediated ring-opening reactions

The organocopper-mediated ring-opening reaction of propargylic epoxides affords the corre-
sponding hydroxyallenes in high regio- and anti-diastereoselectivity. Thus, addition of -
amidoalkylcuprates to epoxides has led to the synthesis of amino-allenol <1999TL4293>.
The use of CuX catalysts also allows the diastereoselective synthesis of -allenols from epoxides
(Equation (61)) <1991T1677> and cyclic carbonate or sulfate derivatives in the presence of a
Lewis acid <1992TA1509>. -Allenyl alcohols, precursors of dihydrofurans, have been prepared
by treatment of epoxy propargylic alcohols with methylcuprate <1993JOC7180>. The reaction of
the chiral epoxy alcohol 82 with organocuprates leads to a mixture of anti- and syn-diols 83 and
84 at 35 C, whereas the presence of dimethyl sulphide at 60 C selectively orientates the
nucleophilic substitution toward the formation of the anti-isomer 83 (Equation (62))
<1983TL5587>. 5-Trimethylsilyl-2-methylpenta-2,3-dien-1-ol has been produced by epoxide
opening with a trimethylsilylmethylcopper(I) species formed from trimethylsilylmethyl magnesium
chloride and LiCuBr2 <1985JOC5143>.
HO HO
O H Bu
BuMgBr/CuBr (5 mol.%)
• + •
Et2O, –50 to –20 °C Bu H
syn
ð61Þ
anti
Additive: PBu3, 74%; anti 100%

TMSCl, 100%; anti 12%; syn 88%
OH
R2CuMgBr HO HO
OH + R OH
O Et2O • •
82 R 83, anti 84, syn ð62Þ
35 °C, 50%: 83/84 40/60

DMS, –60 °C, 57%: 83/84 98/2
Chiral functional allenes are obtained with high stereoselectivity either from optically active
cyclic acetals <1985TL4197> by using RMgBr, CuBr (5 mol.%), and P(OEt)3 in order to inhibit
racemization (Equation (63)) or from racemic alkynyloxiranes (via kinetic resolution) by using
dialkylzinc reagents in the presence of copper(II) triflate and a chiral ligand (Equation (64))
<1999TL4893>. Tetrasubstituted chiral vinylallenes are formed from the enantioselective epox-
idation of an enyne followed by an SN20 addition of a cuprate <2000TL8033>.
O RMgX/CuBr (5 mol.%), 0 °C H O
•
O 100% HO
R
ð63Þ
R = Me, 56% de
R = Bun, 70% de
R = But, 100% de
O OH OH
R1 R2Zn, Cu(OTf)2, L* R1 R
• + •
–70 to 0 °C
R R1
R1 = H, Me anti syn
Ph
ð64Þ
O
L*: P N
O
Ph
Wan and Nelson have reported the use of optically active alkynyl-substituted -lactones as highly
reactive precursors of allenes through an SN20 reaction with Grignard reagents in the presence of
catalytic amounts of copper(I). Since the reaction occurs only via an anti-stereoselective addition
with complete chirality transfer from the stereogenic center of the lactone to the chirality axis of the
allene, the latter was isolated in high ee (Equation (65)) <2000JA10470>.
O
O R2 R3MgBr/CuI (10 mol.%) R2
•
R1 83–94% R1 R3
CO2H ð65Þ
93% ee R3 = Me, Pri, Ph, Bu, C11H23, But
R1 = H, Me, Bu 80–93% ee
R2 = CH2OBn, SiMe3, (CH2)2OPMB
The aza-analogs of hydroxyallenes can be readily prepared by ring opening of the correspond-
ing alkynylaziridines with diastereoselectivity from cyanocuprate reagents. Starting from chiral
2,3-trans- or 2,3-cis-ethynylaziridine, the addition of alkylcyanocuprate affords the (S,S)- and
(R,R)-aminoallenes (Equations (66–67)) <1999TL7393>. With substituted alkynes, considerable
differences were observed between the reaction of 2,3-cis- and 2,3-trans-aziridines with methyl-
cyanocuprate. Moderate selectivities were reported with the cis-derivative whereas complete
stereocontrol was obtained with the trans-isomer <2000T2811>.
R3
R4CuCNM R4
1
R • ð66Þ
N M = Li, MgCl R1 R3
90–99% NHR2
R2
R3
R4CuCNM R3
R1 •
N M = Li, MgCl R1 R4
NHR2
R2
ð67Þ
R1 = Pri, Bn, CH2OTBDMS
R2 = 2,4,6-trimethylbenzenesulfonyl
R3 = H, CO2Me, SiMe3
R4 = Me, Et, Bu, Pri, Bu3Sn
1.20.3.1.5 Copper-mediated 1,n-addition reactions

The copper-mediated conjugate addition of carbon, organosilyl, and organostannyl nucleophiles
to propyne iminium salts allows the synthesis of aminoallenes (Equation (68)) <1990SL399,
1991S1209, 1995S957>.
Ph R2CuCNLi2
Ph or R2CuLi Ph Ph
or R2CuMgCl •
N+ N R ð68Þ
14–73%
O
O
R = Bu, SBu, But, CH=CH2, Ph, SiButPh2, SiPh3, SnPh3, C≡CPh
3,3-Dimethylindoline-derived allenes are prepared by organocuprate addition to 2-(phenylethy-

nyl)-3,3-dimethyl-1-methylindolium triflate <1997JOC7744>.
The generation of allenyl enolates by 1,6-addition of lithium dialkylcuprate to conjugated
functional enynes makes possible the access to allenyl esters 85 by CC bond formation
<1995CB851, 1997AG(E)186, 1999ICA(296)1>, and to allenyl enol ethers 86 by CO bond
formation, on addition of electrophiles (Scheme 4) <1993CB251, 1993LA521>. When the starting
alkyne is substituted by a bulky group such as a t-butyl group, these allenyl enolates can be
trapped in the presence of iodine to selectivity afford allene derivatives 87 (Scheme 4)
<1993CB261>.
R1 Z
O
R2
Me2CuLi
R2 Z
R1 = Bun; R2 = H, Me
Me
Z = OEt • – O Li + R1 = But
E = Me, CH(Ph)OH, CH(But)OH R1 R2 = H
CH(CH=CH2)OH R1 = Bun TMSCl Z = OEt
C(Me2)OH R2 = H 76% 70%
I2
Z = Me
51–99% Me2CuLi Z
E Z R2
R2
R2 Z
• O • O
R1 85
• O-TMS R1 87
R1 86
Scheme 4
The Michael addition can be extended to 1,8-, 1,10-, and 1,12-addition with different dialkyl-
cuprates <1996LA1487>. A direct access to enantiomerically enriched and pure vinylallenes was
described by Krause through 1,5-substitution reaction of chiral enyne acetate with organocup-
rates or organolithium reagents in the presence of a catalytic amount of copper salt
<2000AG(E)4355>. The presence of tri-n-butylphosphine or triethylphosphite as an additional
ligand was necessary to avoid racemization of the product by reactive copper species.
Copper(I) arenethiolate with a tertiary amino substituent can also be used in catalytic amounts
in 1,6-addition reactions of lithium reagents to ynenoates to afford with excellent chemo- and
regioselectivities the corresponding allenes (Equation (69)) <1993JOC5849>.
R1 R1
RLi, [Cu]
CO2Et •
Et2O, 0 °C R CO2Et
ð69Þ
NMe2
[Cu]: R = Me, Bun
Cu (trimer)
S
1.20.3.2 Nucleophilic Substitution with Organomagnesium Reagents

The reaction of propargyl derivatives with Grignard reagents is well documented but the compe-
tition between alkyne and allene formation has brought some restriction to its use. However, the
selectivity of the 1,3-substitution has been improved by the use of specific leaving groups or
catalytic systems involving transition metals. Thus, propargylic alcohols, in situ protected by
1-chloro-2-methyl-N,N-tetramethylenepropenyl amine, lead to the selective formation of allenes
at 0 C with alkyl, phenyl, vinyl, and allyl Grignard reagents in very good yield (Equation (70))
<1984TL4007>. Pasto and co-workers <1976JOC3496, 1978JOC1382, 1978JOC1385> have
shown that iron (especially FeCl3) and cobalt derivatives were good catalysts for the production
of allenes from propargylic halides and Grignard reagents. From optically enriched propargylic
epoxides, the Fe(acac)3-catalyzed nucleophilic substitution with organomagnesium reagents leads
to 2,3-allenols derivatives with high stereoselectivity <2003AG(E)5355>. Palladium(0) is also an
efficient catalyst for the cross-coupling of propargylic and allenic halides with Grignard reagents
to selectively produce alkyl and aryl allenes <1980TL5019>. The nickel-catalyzed reaction
of propargylic alcohols 88 with organomagnesium bromides selectively gives silyl allenes 89
(Equation (71)) <1985JOC1122>.
Cl
N R3
R3 R2 R1MgBr R3 R2
ð70Þ
R2 O •
61–98%
HO N Cl – R1
+
1
R2 R (dppp)NiCl2 (cat.), 80 °C R2 TMS
TMS + MeMgBr (or PhMgBr) •
HO 97% Me(Ph)
R1
88 >95% ð71Þ
1 2
R = H, R = n-C3H7 89
R1 = R2 = -(CH2)5-
More recently, it has been shown that nickel-catalyzed cross-coupling reactions of propargylic
dithioacetals with Grignard reagents RMgX led to substituted allenes 90 via an allenyl thioether
intermediate (Scheme 5) <1996JOC8685>. Extension of this procedure, by first treating the dithioacetal
with lithium t-butylcuprate followed by the cross-coupling reaction, allows the introduction of two
different substituents on the allenes 91a and 91b formed (Scheme 5) <1997JOC4568, 1999JOC8582>.
i. Bu2tCuLi R3MgX
SBut SBut S R3 R3
ii. E + Cat. NiCl2(dppe)
E S S R1 S •
E –78 °C R2
THF/benzene (1/19) R2
• + R1 65 °C R1
R1 R2 R2 90
55–95%
R3 = Me, Et, Bu
R4MgX R3 = TMSCH2, Ph
NiCl2(dppf)
E = H, D, CH2CH=CH2, CH3
E R4 R4 E
• • R4 = Me, Ph, Pri, TMSCH2, Bun
R1 R2 R1 R2
91a 91b
Scheme 5
1.20.3.3 Miscellaneous Nucleophilic Substitutions

To avoid a mixture of metals such as lithium or magnesium in the presence of copper or nickel
complexes, nucleophilic reactions without metal or coupling reactions with only one metal are
useful alternatives.
For the synthesis of vinyl allenes, (2-propene)Ti(OPri)2, prepared in situ from Ti(OPri)4 and
i
Pr MgCl, appears to be a reagent of choice since it is able to mediate the coupling of an internal
alkyne with a propargyl carbonate at 50 C via a five-membered metallacycle (Equation (72))
<2000S975, 2001JA7937>. The same divalent titanium reagent reacts with arylaldimines and
propargyl halides to afford -allenylamines through a -elimination reaction of the azatitanacy-
clopentene intermediate (Equation (73)). Starting from optically active imines, the synthesis of
chiral allenes are possible <2003OL2145>.
OCO2Et
Electrophile
R1 R2
Ti(OPri)2 (H+, I+, EtCHO) R1 R2
+ Ti(OPri)2
47–65% E • ð72Þ
OCO2Et R1
R2
R1 = Pri, Bun, TMS
R2 = Pri, Bun, n-C6H13
OMe OMe
Ph OMe
Ph
i. Ti(OPr i)
2
N Ti(OPri) H2O NH
N Ph 2
Ar
Ether, –35 to 0 °C Ar 45–74%
R2 H •
Ar R2 ð73Þ
ii. R1 R 1 R1 R2
X
X
dr 93:7 to >98:2
R1, R2 = H, n-C6H13, Ph
X = Br, OP(O)(OEt)2, OAc
Nucleophilic reaction of a silyl enol ether with a propargylic cation, produced by treatment of a
substituted propargyl silyl ether with trimethylsilyl triflate (TMSOTf), leads to a substituted allene
<2001JOC4635, 2003OL51>. It is noteworthy that two phenyl substituents and the tetrasubsti-
tuted enol ether are necessary to exclusively afford the allene (Equation (74)).
Ph R
Ph OTBS TMSOTf (10 mol.%) •
Ph R + Ph Ph
TMSO CH2Cl2 ð74Þ
Ph
67–80% O
R = TMS, C3H7
Neutral phosphorus(III) nucleophiles, such as Me3SiPPh2, Me3SiP(Ph)(C5H11), or Me3SiOPPh2,

react with propyne morpholinium salt to afford (3-morpholinoallenyl)phosphines or (3-morpholi-
noallenyl)phosphine oxides <2003EJOC2071>. Interestingly, electron-rich phosphines (such as
Me3SiPEt2) or phosphites (Me3SiOP(OEt)2) delivered exclusively the propargyl derivatives.
Finally, addition of cyanide to substituted propargyl tosylate provides the opportunity to prepare
substituted cyanoallenes containing oxygen, nitrogen, or sulfur functionalities <1994SL717>.
1.20.3.4 Reaction of Electrophiles with Propargyl and Allenyl Organometallics
1.20.3.4.1 Lithium derivatives

Propargylic and allenic organometallics are usually prepared by reaction of a metal or an
alkyllithium with either the corresponding halide or the hydrocarbon. Metallation of allenic
hydrocarbons or halogen–lithium exchange from haloallenes with butyllithium at 78 C gener-
ates carbanions able to react with electrophiles to produce allenyl derivatives via CC bond
formation <1991COS(2)81>. Various electrophiles have been used leading to the synthesis of a
number of functional allenes <1999TL5491>.
The selective formation of mono-, di-, tri-, and tetraalkyl allenes (84–94%) is possible from
alkyl halides (Scheme 6) <1975JCS(CC)561, 1982SC739>. The cross-coupling between allenyl-
lithium compounds and aryl or vinyl halides, catalyzed by Pd(PPh3)4, makes possible the pre-
paration of vinyl and aryl allenes <1982S738>.
The reaction of allenyllithium with ketones and epoxides, respectively, leads to -allenic and
-allenic alcohols (Scheme 6) <1981S875, 1983JCS(CC)1133>, the selective formation of the latter
being improved in the presence of hexamethylphosphoramide. When CO2 is used as the electrophile,
allenic carboxylic acids are formed in good yields (Scheme 6) <1981S875, 1985JA6046, 1977JA7632>.
Whereas the reaction with amides gives allenic ketones <1977NJC373>, the cross-coupling reaction
with ureas <1981S875> or isocyanates <1997ZOR615, 2002TL1569> provides an efficient route to
allenic amides in satisfactory yields (Scheme 6).
In the presence of t-butyllithium, cyclic allenyl silanes were obtained from 1-(alkynylsilyl-
oxy)-2,3-epoxyalkanes (Equation (75) <2000TL9281>). The regioselectivity was dependent on
the configuration of the epoxy moiety. cis-Epoxides selectively provide the five-membered silyl
allenes, whereas trans-epoxides lead to a mixture of five- and six-membered silyl allenes.
Addition of lithiated methoxyallene to chiral cyclic nitrones provided N-hydroxy allenepyrro-
lidines diastereoselectively <2003EJOC1153>.
R4 R2
R5
•
R3
HO
R1
R4 R2
• R1 R4 R2
O R3 •
R O R3Si R3
R5
RC(O)NMe2 R3SiCl
R4 R2 (Me2N)2CO R4 R2 R4 R2
RX
• • •
O R3 Li R3 R R3
NMe2 O
CO2
RSSR R4 R2
R4 R2 •
• HO2C R3
HO
R3
R4 R2
•
RS R3
Scheme 6
HO
ButLi (2 equiv.) O O
But HO t
HMPA (2 equiv.) Si Si Bu
But But Pr i But + Bu t
O THF Pri
Si Bun • •
Prn O ð75Þ
–78 °C, 1 h
0 °C, 20 min H Prn H Prn
47% 3%
64% 16%
Functional allenic compounds have been prepared from -lithio--alkoxyallenes

<1968RTC1179>, silyl allenes <1980TL3987>, -methoxy--alkyl allenes <1978TL1137>, and
the synthesis of the first primary helicoidal molecule 92 was based on the reaction of lithio-
-methoxy--allene with tetrahydrofuranone moieties (Equation (76)) <1980JA2134>. The use of
enantiopure alkoxy allenes has allowed the preparation of enantiomerically enriched allenols by
reaction with aldehydes <1993SL105>. Silyloxypropargyl lithium reagents 93, generated either by
alkylation of silylated ketones or alkynylation of silyl ketones, react with electrophiles to produce
allenol silyl ethers 94 (Scheme 7) <1980JA1423, 1986JA7791>.
O
O
MeO OH OMe O
O Steps
+ • ð76Þ
O 95% O O O
Li •
5
92
1.20.3.4.2 Magnesium, aluminum, and manganese derivatives

Allenyl Grignard reagents have not been used extensively because of their lack of selectivity. However,
-allenyl ketones have been produced from allenyl magnesium bromide and esters <1969BSF898>.
–
O O
R2 + RLi R2 R
SiR13
SiR13 R2 R
+ R3X
R Li •
OSiR13
R2 Li + O R3
R13Si OSiR13
94
R2 R
–
93
Scheme 7
The organoaluminum derivative 95, generated by reaction of aluminum with trimethylsilylpro-

pargyl bromide selectively affords allenyl alcohols 96 and 97, on reaction with carbonyl compounds
(Scheme 8), whereas magnesium or zinc propargyl derivatives selectively give homopropargylic
alcohols <1981TL1579, 1991JOM(403)299>. Propargylic lithium alanates generated from methyl-
acetylenes, selectively afford allenes, -allenic alcohols, and acids by reaction with allyl halides,
carbonyl compounds and carbon dioxide, respectively. Reaction of 95 with triethyl orthoformate
affords the allenyl aldehyde 98, a useful intermediate for access to functionalized allenic alcohols on
reaction with organomagnesium, zinc, or aluminum reagents (Scheme 8) <1992JOM(440)277>.
With organoaluminum derivatives arising from substituted propargyl bromides, -allenic tertiary
amines have been produced with high selectivity (>90%) when the electrophile is an iminium salt
<1981JOM(218)1> or a gem-aminoether (Scheme 8) <1980JOM(198)1>.
R
•
N
Pri
R
59–70% •
+ R1
R1R2CO
N HO R2 96
Pri
R1 OEt
R
R Al
R Cl O R1 •
Br
95 Al2/3Br
Cl HO TMS
97
R12N R
HC(OEt)3
Bu 50–65% •
R2 O
OHC
98
R
•
R12N
R2
Scheme 8
The reduction of 3-substituted prop-2-ynylic bromides by tetrabutylmanganate, followed by the

addition of an aldehyde or even a ketone, produces the corresponding -allenyl alcohols. The allene/
alkyne selectivity mainly depends on the nature of the electrophile and on the substitution of the starting
bromide. From prop-2-ynyl bromide, only the prop-2-ynylic adduct was obtained <1997CC2077>.
1.20.3.4.3 Tin-mediated allenylation reactions

Stable organotin compounds react with activated aldehydes to produce -allenyl alcohols in good
yields. The in situ formation of organotin derivatives by stirring stannous chloride with pro-
pargylic halides leads to allenic alcohols on reaction with aldehydes at 0 C (Equation (77))
<1981CL621, 1993TL449>.
O SnCl2, DMI, DMF, 0 °C •

+ Ph Ph ð77Þ
80% OH
I H
The best selectivity in allenols is obtained when -substituted propargyl iodides are used. The same
result was obtained with tetrapropargylic stannanes in methanol. By contrast, starting from tetra-
allenic stannanes (prepared from the nonsubstituted propargyl halide by a Grignard reaction and an
exchange with SnCl4), the addition to an aldehyde selectively led to the homopropargylic alcohol
<1998SL909>. It is worth noting that the use of these stannane derivatives in trifluoroacetic acid in
the presence of a dimethylacetal, instead of an aldehyde, provides the allenic or homopropargylic
alcohol with higher selectivities. Depending on the reaction conditions (tin species, additive, solvent,
and temperature), allenols or homopropargylic alcohols were accessible from propargyl halide and an
aldehyde <1998CC2025>. Even mesylates can be used with tin derivatives to produce allenic alcohols
<2000CC2009, 2003TL2845>. However, the carbonyl allenylation dramatically depends on the
bulkiness of 1- or 3-substituents of 2-propynyl mesylates (Scheme 9) <2003SL1713>.
H R1
R2 = H
•
SnI2, TBAI R3
NaI 32–84% OH
DMI Allenyl:homopropargyl
OMs O
10 °C to rt 84:16 to 100:0
R2 +
R1 R3 H
R3
1 = H,
R Me,Pri R3 = aryl, alkyl R2 ≠ H OH
R2 = H, Me, Ph R2
41– 85%
R1
Allenyl:homopropargyl
14:86 to 0:100
Scheme 9
1.20.3.4.4 Reactivity of propargyl silanes

An alternative to toxic tin compounds is the use of silane derivatives. In the presence of copper(I)
chloride and a sterically hindered amine, trichlorosilane reacts with propargyl halides to selec-
tively afford propargyl silanes. Subsequent addition of an aldehyde delivers the allenic alcohol in
high selectivities (Scheme 10) <1995JA6392, 1997JOC8976>. The first catalytic enantioselective
allenylation of aldehyde was disclosed by Iseki using the chiral formamide 99 (Scheme 10)
<1998TA2889>. Enantiomeric excesses up to 95% were obtained with aliphatic aldehydes, but
no selectivity was observed from an aromatic aldehyde.
•
R
*
OH 56–95% ee
RCHO
HMPA Ph N Ph
CH2Cl2 CHO
–78 °C
99
CuCl RCHO •
+ HSiCl3
EtN(Pri)2 DMF, 0 °C R
Cl SiCl3
OH
Et2O/C2H5CN
rt
Scheme 10
In the presence of a Lewis acid catalyst, propargyl trialkylsilanes regioselectively react with
electrophiles to afford allenic derivatives via stabilized vinylic carbocations. This strategy has
allowed the preparation of a variety of allenes using electrophiles such as acyl chlorides
<1980JOC5006, 1981TL3401>, acetals <1981TL3609, 1985OM333>, aldehydes <1981TL455,
1984TL651, 1981TL1327, 1975JOM(93)43>, and ketones <1981TL455>. From propargyl tri-
methylsilanes containing a silyl ether or a hydroxy group, the reaction with aldehydes leads to
cyclic vinylidene compounds (Equation (78)) <1988JOM(349)43, 1986T2501, 1986T2017,
1984TL651>.
OTMS
X
X TiCl4
1 ð78Þ
+ R CHO •
TMS O
R1
Iminium salts, generated from formaldehyde and secondary amines in the presence of
CF3CO2H, react with propargyl silanes to afford tertiary allenyl amines <1990JOM(396)289>.
Similarly, cyclic vinylidene amines have been prepared from amino propargyl trimethylsilanes via
regiospecific intramolecular reaction <1987TL4689>.
Allenyl lactams have been produced by reaction of propargyl silanes with acyl iminium cations
used as electrophiles (Equation (79)) <1992T3445, 1983TL1407, 1984TL3115, 1984JOC1149,
1986TL1411, 1988TL4253>. Under similar conditions, allenyl ethers have been obtained from
oxonium derivatives, formed in situ with BF3Et2O <1987JOC1370, 1988JOC2450>. The acet-
olysis of 8-(trimethylsilyl)-6-octyn-2-ol tosylate led to an exocyclic allene via an electrophilic
intramolecular reaction <1980JA5120>.
TBDMSO TBDMSO R
H H H H
TMS OAc BF3.Et2O
R + • ð79Þ
N 65–71% N
R = H, Me O H O H
Propargyl silanes smoothly react with the activated double bond of alkylidene malonates in the
presence of TiCl4 at 20 C to produce allenes in moderate to good yield <1982JOM(236)177>.
Allenyl acyl cyanides are obtained in good yield from -unsaturated acylcyanides and 3-trimethyl-
silylprop-1-yne <1986JOC1199>. Intramolecular addition of propargyl silanes to conjugated
enones, in the presence of TiCl4 or EtAlCl2 at very low temperature (70 C) gives rise to
annelation compounds containing an exocyclic allenic structure via CC bond formation
(Equation (80)) <1988S263, 1986JCS(CC)829, 1985TL1831>. Recent examples of acid-catalyzed
or Lewis acid-promoted cyclizations from trimethylsilyl propargyl derivatives, leading to the
exocyclic terminal allenyl group, have been reported <1991CB247, 1992TL8017, 1993TL7849>.
This methodology was applied to the synthesis of disaccharides <2001SL82> and several glycals
(Equation (81)) <2001T10241>.
R •
EtAlCl2 R
O TMS ð80Þ
50–87% O
R = H, Me
O TiCl4 O H
AcO AcO H
+
CH2Cl2, –20 °C ð81Þ
AcO TMS AcO •
OAc 88%
The three-component reaction, involving an aldehyde, a carbamate, and propargyl trimethylsi-

lane, in the presence of BF3OEt2 allows the formation of an -allenyl amine in moderate-to-good
yield (Equation (82)) <2002TL1453>.
H2N O Ph
NHCO2Bn
O R H
N O Ph TMS R
+
BF3.Et2O, MeCN • ð82Þ
R H O
63–82%
O
R = alkyl, aryl
1.20.3.4.5 Boron chemistry for allene synthesis

Organoboranes react with lithium chloro- or acetato-propargylides to produce allenyl boranes at low
temperature. Their treatment with acetic acid gives allenes (>70% yield), corresponding to the
migration of an alkyl group from the boron atom to the terminal carbon of the initial alkyne
(Equation (83)) <1974JA5620, 1977JOC2650>. Propargylic organoborane intermediates react with
carbonyl compounds to produce allenic alcohols in good yield <1978JA5561, 1982JOC3364,
1983JOC5376>, with CO2 to give allenic acids and with allylic halides to form 1,2,5-trienes
<1982JOC3364>. 4-Alkenylpropargylic boranes react at 78 C with aldehydes to afford conjugated
1,2,4-trienols in more than 60% yield (Equation (84)) <1981JOC829>. Enantioselective syntheses of
chiral -allenols via reaction of aldehydes with enantiopure propargyl boranes have been described by
using a chiral auxiliary on the boron atom. The boron reagents can act as chiral catalyst
<1990JA878> or as chiral mediator <1995JOC8130>.
MeCO2H R
25 °C •
–90 °C R
Li + R3B •
X ð83Þ
R2B R
R1CHO
•
R1
OH
Li R2 R1 R2
Cl i. –78 °C i. R3CHO
+ ii. 25 °C R1 B ii. [O]
•
60–72% R3 ð84Þ
R2
1 OH
R
B Cl 100
Cl
The reaction of N-azidinylimines with alkynyl borane reagents offers a new route to allenes
from aldehydes and ketones <1996JOC6018>. After addition of the borane to the imine, the
corresponding N-azidinylamine decomposes to deliver a propargylic anion, which equilibrates to
an allenyl anion finally quenched by a proton (Equation (85)). Alkynyl Grignard reagents,
alkynyllithium, alkynylcuprate, or alkynylcerium reagents do not react at all with imines.
Ph
R1 N
i. N
R2
BunLi,
i. –78 °C –78 °C to rt
ii. BF3.Et2O, –78 °C R BF2 R3 ð85Þ
ii. H +
R or – + •
17–83% R R2
R BF3, Li
R = Ph, Bun, TMS,
R1 = Me, Pri, But, MeCH=CH,
CH2CH(SCH2CH2S)
PhCH2CH2, PhCH2, PhCH=CH
R2 = H, Me, Et
1.20.3.4.6 Allene synthesis via titanium derivatives

Transmetallation of 1-trimethylsilyl or 1-methylpropynyl lithium with titanium isopropoxide
at 78 C gives access to a titanium reagent which reacts with carbonyl compounds at 78 C
to afford allenic alcohols, whereas similar reactions from 1-trimethylsilyl-3-substituted pro-
pynyl lithium lead to alkynic alcohols (Equation (86)) <1982JOC2225>. Highly regio- and
diastereoselective syntheses of 4-hydroxy-1,2-alkadienyl carbamates have been obtained from
propargylic carbamates by using the corresponding titanium derivative, whereas no selectivity
was observed with the lithium reagent <1987T2457> (Equation (87)). Extension of this
work to the synthesis of enantiomerically enriched allenes was made possible by the use of
()-sparteine. A dynamic resolution of the lithium-()-sparteine complex by selective crystal-
lization, followed by transmetallation with ClTi(OPri)3 and subsequent addition of an alde-
hyde or an acid, results in the formation of allenyl carbinols or allenes with enantioselective
excesses up to 95% <2001OL1221, 2003SL1969>. Seebach demonstrated that titanated chiral
allenamides could be useful in stereoselective addition to aldehydes and ketones
<2002HCA963>. ,-Disubstituted allenamides were thus isolated in good yields and high
diastereoselectivities.
i. RLi
R3 = H R2
ii. Ti(OPri)4 •
80–93%
R3 iii. R1CHO HO
R2 R1
ð86Þ
R3 ≠ H R3
R2
42–92%
R1
HO
i. LDA
ii. [Ti]
OC(O)N(Pri)2 iii. R3R4CO R1 R2 R1 R2
R1 • + • ð87Þ
R2 >70% R3 OC(O)N(Pri)2 R3 OC(O)N(Pri)2
HO R4 R4 OH
syn 95:5 anti
However, the previous method (Li–Ti exchange) suffers from the limited number of allenyl-
and/or propargyl titanium reagents available. An extension of this protocol was made by using
divalent titanium reagent (3-propene)Ti(OPri)2 which can provide functional propargyl alcohol
derivatives from a wide range of propargyl- or allenyltitanium complexes, which react with
carbonyl compounds. Thus, vinylcyclopropylcarbonate, in the presence of (3-propene)Ti(OPri)2,
reacts with aldehydes at the less substituted carbon atom to afford the corresponding -allenyl
alcohol (Equation (88)) <1996AG(E)2848>. Propargyl halides react onto keto groups through an
inter- or intramolecular addition pathway to provide allenyl alcohols (Equation (89))
<1996SL437, 1995TL3207>.
OH
R1
R2 R1
OCO2Et Ti(OPri)2 OH
R1 R2 H • +
+
45–80% ð88Þ
O R2
R1 = Hexn, Ph, TMS R2 = H, Et, Ph Minor
Major
74:26 to >97:3
O
Br [Ti] •
R ð89Þ
R = Bun, 65% R
HO
R = Pri, 70%
1.20.3.4.7 SmI2-mediated allene synthesis

Nucleophilic organosamarium derivatives, formed by electron transfer from SmI2 to allenyl
palladium species, react with carbonyl compounds to afford homopropargylic and allenic alco-
hols, the proportions of which depend on the substitution pattern of the starting prop-2-yn-1-yl
acetate <1986TL5237, 1987CL2275>.
High regioselectivities were obtained by reacting propargylic phosphates with carbonyl deriva-
tives in the presence of SmI2 and palladium(0) (Scheme 11) <1995TL907>. It is noteworthy that,
with this procedure, secondary propargylic phosphates led to allenes, whereas primary pro-
pargylic phosphates gave acetylenic derivatives (Scheme 11). SmI2 was also able to promote the
reductive coupling reaction between alkynyl oxiranes and ketones, which provided 2,3-penta-
diene-1,5-diols (Equation (90)) <1995TL2501>. The observed anti-selectivity of the reaction
complements that observed with the cuprate methodology.
HO
R3
R2 = H R1
R2
R1 SmI2, Pd(0), R3CHO
O P(OEt)
2
O R3
R2 ≠ H HO R2
•
R1
Scheme 11
5
R4 R
R1 R1 OH
O R4 R5 SmI2, THF ð90Þ
R3 + •
O R2 R3
R2 OH
1.20.3.4.8 Indium-mediated allene synthesis

Metal-mediated reactions in aqueous media have found considerable applications in organic
synthesis and indium appears to be the metal of choice in this area. Thus, indium-mediated
coupling of aliphatic or aromatic aldehydes with -substituted prop-2-ynyl bromide gives
-allenols with high regioselectivities <1995CC1003, 1998JOC7472>. The intramolecular version
of this reaction has been applied to the synthesis of allenyl chromane derivatives <2004SL45>.
Highly regioselective synthesis of allenic or homopropargylic alcohols can be obtained from
various aldehydes and trialkylsilylpropargylic bromides in the presence of indium by changing
the silicon group and the reaction conditions <2003JA13042>. The use of a bulky silicon group
(TIPS or TBDPS) in THF/water mixture favored the formation of allenic alcohols, whereas the
use of the trimethylsilyl group in refluxing THF exclusively led to the homopropargylic alcohols
(Equation (91)).
R3Si In
In, InF3 (10 mol.%) Br THF:H2O = 1:5 SiR3
R3Si + •
R1 THF 45–56% ð91Þ
R1CHO R1
HO HO
R = Me (89–94%) R1 = PhCH2CH2, PhCH=CH, Ph, n-C8H17 R = Pri, Ph2But
3-t-Butyldimethylsilyloxyalk-2-enylsulfonium triflates, generated by addition of dimethyl sul-

fide to ,-enones in the presence of TBSOTf, undergo nucleophilic substitution with the
organoindium reagent derived from -substituted propargyl bromide (Equation (92))
<2003JA9682, 2003OL1725>.
OTBS
OTBS
+ R2
ð92Þ
SMe2, TfO – R2CHO HO
R1 + In
•
Br R1
• R1≠ H
R1
1.20.3.4.9 Miscellaneous
By reaction of aldehydes or ketones in the presence of HMPA, a very selective formation of
allenols has been observed when chromium(II) derivatives were used to generate the allenyl
organometallic intermediate from propargylic bromides <1981T1359>. This system allows the
use of propargylic halides containing various functionalities such as ester, halide, and nitrile
<1992JOC4070>.
Allenic ketones have been synthesized by reaction of propargyl mercury iodide with acyl
chlorides in the presence of AlCl3 at 40 C <1986JOC2623>.
Organozinc compounds prepared from propargylic halides usually give no selectivity on reac-
tion with carbonyl electrophiles, but after treatment with zinc, -substituted -acetylenic bro-
mides react with N-chloromethyl-N-methylformamide to afford allenic methyl formamides, which
are easy to convert into secondary allenyl amines with BunLi <1986BSF449>. Upon hydrolysis
with D2O, allenic zinc reagents, generated from propargylic mesylates or chlorides and triorga-
nozincates, give allenes in high yields via CC and CD bond formation (Equation (93))
<1993JOC6166, 1995TL723, 1996JA11377>. Synthesis of -allenols is achieved either by reaction
of allenyllithium with epoxides as described previously (see Section 1.20.3.4.1) or via reaction of a
2-iodozincio-1,3-alkadiene, generated from a propargyl halide and a gem-dizinc compound in the
presence of a catalytic amount of palladium(0), and a carbonyl derivative (Equation (94))
<2000SL995>.
(R3)3ZnLi H2O
R1 R1 R3 R1 R3
THF or D2O
R2 Y • •
R2 Zn 76–97% R2 H(D)
X
ð93Þ
X = OMs, Cl, OP(O)(OEt)2, OC(O)NPh2, OC(O)NEt2, OMe, OTBS
Y = H, Br
R1 = alkyl; R2 = H or R1–R2 = (CH2)5
R3 = alkyl, aryl, silyl
R5 R4
R4 ZnI R1
R1 R4CH(ZnI)2 R5CHO
R 3 R1 HO •
R2 33–65% ð94Þ
Br Cat.: Pd2(dba)3 R3 R2
R3 R2
P(3,5-(CF3)2C6H3)3
R1 = H, Me; R2 = Me; R3 = Bun; R4 = H, Me; R5 = Ph
1.20.3.5 Palladium-mediated Coupling Reactions

The reaction with palladium catalysts likely proceeds via oxidative addition of a propargylic ester,
halide, or carbonate to produce an allenyl organopalladium(II) moiety. Subsequent reaction with
nucleophiles gives rise to 1,2-diene derivatives <1997MI197>.
Starting from propargylic halides or esters and nucleophiles such as R-ZnCl, in the presence of
catalytic amounts of Pd(PPh3)4, functionalized allenes and bisallenes have been obtained with high
regio- <1981TL1451> and stereoselectivity <1983JOC1103> except in the case of 1-alkynylcyclo-
propyl derivatives which led to alkynic cyclopropanes as major compounds <1992JA4051>. Pre-
paration of highly substituted allenes of good-to-excellent optical purity was thus accomplished by a
cross-coupling reaction between chiral propargyl carbonates and organozinc reagents (Equation (95))
<1997CC2083>. Conjugated p-allenyl styrenes and vinyl allenes have been obtained from various
nucleophiles including zinc, aluminum, and tin organometallics (Equation (96)) <1986JOC4006>. The
cross-coupling is also possible from allenyl halides and organozinc <1984TL5571>, magnesium
<1980TL5019> or copper species <1983S32> as nucleophiles, catalyzed by palladium(0) complexes
(Equation (96)). Sterically hindered 1,1-diaryl-1,2-dienes were formed by treatment of 1-phenyl-
1-propyne with butyllithium and zinc bromide in the presence of 1.5 mol.% of HgCl2 in THF followed
by coupling with aryl iodides in the presence of a catalytic amount of palladium(0) <1998JOC9601>.
Ene-allenes are accessible either by coupling propargylic acetates and pentynoates, based on the
efficient activation of both substrates by palladium complexes <1993TL3129>, or by cross-coupling
reaction of vinyl iodides and allenyl zinc reagents as exemplified by the preparation of 101 (Equation
(97)) <1994TL1829>.
OCO2Et Pd(PPh3)4 Bu H
Bu + PhZnBr •
H THF-Et2O ð95Þ
Me Ph Me
84%
83% ee
R2 X
• R2 R4
R2 R3 Br R1-M R3 R2 R3
• + •
R3 R1 Pd(PPh3)4 (cat.) X = halide R4 ð96Þ
X = OAc R1
1 = aryl,
R1M = Ph2Zn; R2 = H; R3 = Ph, But X = OTs R alkenyl, alkynyl
R2 = H, Me, Ph
R1M = RMgX; R2 = H, Me; R3 = Me
R3, R4 = H, alkyl, vinyl, aryl
R1M = R1C≡CH/CuI/Et2NH; R2 = H, Me; R3 = Me, Prn
Bun
Bun R2 ZnCl Pd(PPh3)4 R1
R1 + • H
H R3 H 68–81% ð97Þ
R2
I • H
R1 = Me, Bu, Ph; R2 = H, Me; R3 = Me, n-C6H13 R3
101
In alcohol, under CO atmosphere, propargylic carbonates are easily converted into allenic esters 102
(Equation (98)) <1993JOM(451)15, 1993JA5865, 1986TL731>. 5-Hydroxyalka-2,3-dienoates were
prepared from cyclic alkynyl carbonates via a carbonylation reaction in the presence of palladium(0)
(Equation (99)) <1996SL218>. Cationic palladium(II) precursors were also able to catalyze the con-
version of ,-substituted propargyl alcohols into 2,3-dienoic acids under CO pressure <1994TL5889>.
Mono- and dicarbonylation of propargyl halides are also possible under phase transfer conditions, with
Ni(CN)24H2O as catalyst precursor, to produce allenyl mono- and dicarboxylic acids <1992OM493,
1993OM1871>. The carbonylation in the presence of carbanions generated from active methylene
compounds with NaH gives allenyl ketones 103 (Equation (100)) <1991SL697>.
R2 Pd(0) (cat.) R3 CO2R4
R1 R3 + CO • ð98Þ
OCO2Me R4OH R2 R1
102
R Pd(0) (cat.)
R
MeOH
O O + CO •
58–74% MeO2C ð99Þ
O HO
R = Me, Bun, Ph
R2 Z R3 R1
R3 Pd(0) (cat.)
R1 + CO + R4 – •
OCO2Me Z MeOH R2 O
Z ð100Þ
Z – – CO2Me Z R4
R4 –: O O O O 103
, ,
Z – CO2Me
From 4-amino-2-alkynyl carbonates, the carbonylation directly leads to allenic -lactams via
subsequent intramolecular CN bond formation <1991TL7683>.
Based on the easy formation of alkynyl copper derivatives from terminal alkynes, CuI and a
base, 1,2-dien-4-ynes, 1,2-dien-4-yn-6-ols, or their tetrahydropyranyl ethers have been obtained in
good yields in the presence of palladium catalyst precursors with KBr or LiCl
<1991JOM(417)305, 1990TL7179>. A large variety of substituted allenynes have also been
synthesized in one step from propargylic halides, tosylates or acetates, and terminal alkynes in
the presence of tetrakis(triphenylphosphine)palladium or palladium(II) and triphenylphosphine,
copper iodide, and a base (Equation (101)) <1993TL3853, 2000T1851>. Alkynyl cyclic carbo-
nates allow the formation of allenynols and unsaturated diols via a Sonogashira-type reaction
(Equation (102)) <1994CC1845>.
Pd(PPh3)4, CuI
R2 R1 R3
R3 + Et3N
R1 R4 •
5–93% R2
X ð101Þ
R1 = C4H9, C5H11; R2 = H, Me, Et; R3 = H, Me R4
R4 = Bun, Ph, TMS, CH2OH, CMe2OH, . . .
R Pd(PPh3)4, CuI
Et2NH, KBr R
O O + R1 •
76–98%
ð102Þ
O HO
R1
R = Me, Bun R1 = Bun, Ph, TMS, CH2OH, CMe2OH
Alkenyl allenes have been synthesized in one step from propargylic carbonates and activated
olefins via the Heck reaction, in the presence of Pd(OAc)2, PPh3, and KBr in DMF at 70 C
<1991TL3397>. Palladium-catalyzed reaction of aryl iodides with tertiary propargylic amides
affords highly substituted allenes (Equation (103)) <2003JOM(687)562>. This reaction proceeds
via a regioselective carbopalladation (which is controlled by the strong directing effect of the
amide)/-N-Pd-elimination reaction. Stille reaction of allenylstannanes and aryl or vinyl iodides
provides an efficient access to monosubstituted aryl allenes, disubstituted allenes, and alkenyl
allenes in good yields (Equation (104)) <2003T3635>.
Pd(0) (cat.)
Et3N, HCO2H
NHE Ar
Bun4NCl or LiCl
+ ArI • ð103Þ
Ph 47–85% Ph
E = Ts, Tf, 4-NO2-C6H4SO2
R1 R2 Pd(PPh3)4, LiCl R2
I + • •
Bu3Sn R3 DMF R1 R3 ð104Þ
44–96%
R1 = aryl; R2 = H, D; R3 = H, Me, Ph
The nucleophilic substitution of allylic esters catalyzed by palladium complexes is a well-

established reaction in organic synthesis. The corresponding reaction using propargylic esters as
substrates and mild nucleophiles such as trimethylsilyl cyanide affords cyanoallenes (Equation
(105)) <2000OL2635>. (Z)-1-Substituted-2-bromo-1,3-butadienes or chloroprenes, through a
-allylpalladium intermediate, are also efficient precursors to substituted allenes (Equation (106))
<2000AG(E)1042, 2001OL2615>.
Pd(PPh3)4 (5 mol.%)
R2 R1 R2
R3 + TMSCN THF
R1 •
35–91% R3
OCO2R4 NC ð105Þ
R1 = H, Bun, Hexn, Me2CHCH2CH2 R3 = H, Me
R2 = H, Me, Et, Me2CHCH2 R4 = Me, Et
R2 (Pd(η3-allyl)Cl)2, dpbp
R1 R2
R3 + MNu THF
R1 •
62–95% R3
Br
Nu
ð106Þ
R1 = Pri, Heptn, Ph, PhCH2, PhCH=CH
R2 = H, Me, Ph; R3 = H, Me
MNu = Na[CMe(CO2Me)2], Na[CH(CO2Me)2], K[CMe(CO2Me)2]
NaOPh, KNHt-BOC, LiPPh2
A large variety of soft nucleophiles, such as malonate derivatives, amine or phosphorus

nucleophiles, can be added to the -allyl intermediate. The enantiomerically enriched axially
chiral allenes have been prepared by using a palladium-BINAP chiral catalyst <2001JA2089>.
In the same manner, chiral (allenylmethyl)silanes were prepared from (3-bromopenta-2,4-dienyl)-
trimethylsilane with soft nucleophiles in the presence of an optically pure palladium catalyst
<2003OL217>. Allenamides can also be produced by an intramolecular cyclization of propargyl
bis-urethanes through an allenyl palladium intermediate (Equation (107)) <1997TL3963,
1990TL4887>. For nonsymmetrical propargyl carbamates, the oxidative addition to Pd(0) was
found to be in favor of the less hindered propargyl carbon, mainly leading to ,-disubstituted
allenes (Equation (108)). During the synthesis of carbacepham skeleton, Mori has shown that the
phosphine ligand orientated the aminocyclization of the propargyl carbamate. Whereas the
bidentate ligand dppf forced the attack of the nitrogen atom to the central carbon of the allenyl
palladium intermediate, leading to a conjugated diene, the monodentate ligand P(o-tolyl)3 orien-
tates the amination to the formation of the allenamide (Equation (109)) <2001TL4869,
2002TL1499, 2003JOC8068>.
O
•
O NH-Y
Pd2(dba)3, Et3N
O N-Y ð107Þ
Y-NH O rt to 70 °C
44–73% O
O Y = Ms, Bz, Ts
R1
O R2
R2 • •
R2 R1
O NH-Ts
R1 Pd(0)
O N-Ts + O N-Ts
ð108Þ
Ts-NH O
O O
O
R1 = H, Me; R2 = alkyl, aryl 1.7:1 to 30:1
TBSO TBSO TBSO

H H Pd2(dba)3, P(o -tolyl)3 H H Pd2(dba)3, dppf H H
Cs2CO3 Cs2CO3
N 57% NH 56% N
O O O
•
OCOPh
ð109Þ
A similar observation was made by Ma for the cross-coupling reaction of a propargyl mesylate
with (Z)-(2)-ethoxycarbonylethenyl zinc iodide or phenylzinc bromide <2003AG(E)4215>. The
use of bidentate ligands with one neutral coordination atom (such as a phosphine) and a
negatively charged coordination center is necessary to favor the allene synthesis.
In the presence of a catalytic amount of palladium complex, cyano-based pronucleophiles can be
added to conjugated enynes to give the corresponding allenes in good-to-excellent yield
<1996CC17>. It has to be pointed out that the scope of this addition is limited by the structure
of the enyne. Thus, the addition of pronucleophiles to enynes, bearing an internal triple bond or
substituted at the terminal olefinic position is either sluggish or may fail <1997T9097>. Axially
chiral allenyl silanes, which are useful intermediates in organic synthesis, as they react with a variety
of electrophiles in a regiospecific manner, can be prepared by asymmetric hydrosilylation of
4-substitued enynes <2001JA12915>. Enantiomeric excesses superior to 90% were obtained by using
a palladium(II) precatalyst and ((S)-(R)-bisppfOMe) 104 as chiral monophosphine (Equation (110)).
i. Pd(η3-allyl)Cl)2, L*
ii. MeMgBr R H
R + HSiCl3 •
37–94% Me3Si Me
61–90% ee
R= But, 2,4,6-Me3-C6H2, TBDMS ð110Þ
MeO
L* = (S )-(R )-bisppf(OMe): (Cp: cyclopentadienyl)

P
CpFe Ph FeCp
MeO
104
Allenylindium reagents, generated in situ by reaction of indium and propargyl bromides, are
efficient partners in palladium-catalyzed cross-coupling reactions with a variety of organic electro-
philes to produce 1,3-dienes in high yield, with complete regio- and chemoselectivity
<2002AG(E)3901>. It is emphasized here that even functionalized electrophiles can be used. Thus,
imidoyl bromide, cyclohexenyl triflate, and vinyl halides provide allenes in more than 86% yield.
An unusual reductive homocoupling reaction of 3-silylpropargyl carbonates opens a new entry
into allenyne derivatives via a propargylpalladium intermediate <1995JOC4650>.
1.20.3.6 CC Bond Formation via Sigmatropic Rearrangements

Sigmatropic rearrangements are powerful methods in organic chemistry to create new CC
bonds. In a general manner, starting from propargylic ethers, the preparation of allene derivatives
through such a rearrangement might be envisaged.
1.20.3.6.1 [2,3]-Wittig rearrangement

The [2,3]-Wittig rearrangement of propargylic ethers leads to allenic alcohols via a rigid five-
center transition state. Asymmetric [2,3]-sigmatropic rearrangement of acyclic bis-propargylic
ethers was demonstrated by Manabe <1997CC737>. Up to 62% ee was obtained by using a
modified ephedrine ligand. The use of chiral metal complexes in the asymmetric propargyl ylide
[2,3]--rearrangement was achieved by Gladysz <1995JA11730>.
The chiral allene 105 was obtained in 95% yield and 74% ee through a sigmatropic rearrange-
ment in the metal coordination sphere (Equation (111)). Enantiomerically enriched allenes have
been produced either by treatment of optically pure (propargyloxy)acetic ester 106 with LDA or
optically pure (stannylmethyl)propargyl ether 107 with n-butyllithium (Equation (112))
<1989JOC5854, 1991JOC4913>, or by treatment of an enantiopure stannyl ether 108 (prepared
by SN2 reaction of potassium propargyl alcoholate on pure stannyl mesylate) with BunLi
(Equation (113)) <1997SL1045, 1993JOC3233>. A total transfer of chirality, with complete
inversion of configuration, was observed during the previous example. Lewis acids such as
TMSOTf, TESOTf, in the presence of Et3N, promote the Wittig rearrangement
<1990JOC6246>. It is worth noting that, the major diastereomer produced in this reaction is
different from that obtained in the base-promoted rearrangements. Treatment of primary, sec-
ondary, and tertiary propargylic alcohols with 3-diazo-2-butanone and a catalytic amount of
dirhodium tetraacetate in benzene gives the allenic hydroxyketones in moderate-to-good diaster-
eoselectivity (Equation (114)) <1999OL367> (see also Chapter 1.09).
+ + –
–
TfO TfO
t
Re PPh3 KOBu Re PPh3
ON ON
S THF, –80 °C S ð111Þ
95%
•
105
74% de
R1 R1 i. NaIO4
H n HO H HO H
O LDA or Bu Li ii. NaBH4
Bun • •
85% 52%
Me Bun Me Bun Me ð112Þ
93% ee 93% ee
R1 = CO2H, 106
R1 = Bu3Sn, 107
BunLi
•
O THF, –78 °C + HO
ð113Þ
SnBu3 HO
95% ee 87:13
108, 95% ee
Rh2(OAc)4 HO
R2 O
C6H6 R3
R1 R3 +
• O ð114Þ
OH 44–75% R2 R1
N2
R1 = H, Me; R2 = H, Me, Ph; R3 = H, Et
1.20.3.6.2 [3,3]-Claisen–Cope rearrangement

The Claisen–Cope rearrangement is the second process to prepare allenes via sigmatropic rear-
rangement. This is a method of choice for access to -allenic aldehydes, ketones, esters, and
amides starting from propargyl vinyl ethers 109, according to the general (Equation (115)).
R1 H R1
R2 •
∆ R4
R4 O R2
R5 ð115Þ
O
R5 R3 R3
109 110
A classical route for access to intermediates of type 109 is the condensation under acidic
conditions of prop-2-yn-1-ols with enol ethers <1967HCA1158> or orthoesters <1977JOC353,
1982JOC4478, 1992TL1057>. The good diastereoselectivity of this reaction has been used for
the preparation of chiral methylmalonaldehyde derivatives <1988JOC4736>. The reaction of
amide acetals with prop-2-yn-1-ols in refluxing benzene has made possible the preparation of
allenic pyrrolidine and piperidine amides in more than 54% yield <1982JOC389,
1984JOC1204> or other tertiary allenic amides (Equation (116)) <2001JA12466>. The Claisen
rearrangement can also be extended to propargyl allyl ethers <1980JOC2080> and 2-propargy-
loxy imines <1992TL4447>. Allenic acids have been obtained in 47–88% yield starting from
propargyl glycolates via enolates generated by treatment with (Me3Si)2NLi <1985CL1457>.
Furans undergo ring opening in the presence of BunLi and the subsequent rearranged inter-
mediates can be trapped by electrophiles to give allenyl ketones <1979JA2208>. Preparation of
non-natural -allenic--amino acids <1996S1489> and -fluorinated allenes <2003T4641>
were also described via the propargyl-allene Claisen rearrangement. Other examples of sigma-
tropic rearrangements involving CC bond formation have been described, among them the
aza-Cope rearrangement from 2-(N-succinimidyl)-4-pentyne derivatives <1984JA1877>, or the
formation of the allenic thioether from the allylic sulfide and 3-chloro-3-methylbut-2-yn-1-yl
lithium <1974JCS(CC)10>. Allenyl sulfones have been obtained by nucleophilic substitution of
a phenyl sulfonyl group from 2,3-bis(phenylsulfonyl)-1,3-butadiene by soft carbanions
<1993JA3776>.
H R32NC(Me)(OMe)2 H R2
R1 R2 • NR32
HO 43–95% R1 ð116Þ
1 = H, O
R C5H11; R2 = H, But, Ph, C5H11
Butatrienes have been easily prepared from propynols via a two step procedure: a [3,3]-
sigmatropic rearrangement, to afford the corresponding bromoallene, followed by an elimination
reaction (Equation (117)) <1995AG(E)2709>. Starting from an enantiomerically enriched pro-
pargylic alcohol, using the same procedure, Tschierske synthesized the first axial chiral allenyl-
acetates as novel ferroelectric liquid crystal <1997JMAC1713>.
R1
R1 C(OR2) CO2R2
3 NaOEt, EtOH
Br • • •
HO EtCO2H, PhCH3, ∆ Br R1 = H CO2Et
95–98%
R1 ≠ H NaHMDS
or
95–98%
NaHMDS, AgOAc
R1
• •
CO2Et
ð117Þ
The hetero-Cope rearrangement involved in the reaction of the propargyl esters of N-acyl
amino acids 111 with phosgene leads to allenyl oxazolinones 112 after elimination of water and
prolonged heating at 50–70 C (Equation (118)) <1975AG(E)58>.
R2
R2
H O R2 • R1 O
COCl2 R1 O ∆
Ph N ð118Þ
O 50–70% N O
N O 43–78%
O R1 112
111 Ph
Ph
Highly substituted chiral homoallenyl alcohols can be obtained by a stereoselective Saucy–

Marbet rearrangement using chiral ynamides and propargyl alcohols (Equation (119))
<2003OL2663>.
H OH OH
O O R2
O • 2 O
R2
R R 1
R2 O •
N O N H
O R1 N ð119Þ
53–65% 54–79% O R1
Ph Ph Ph
dr from 91:9 to 96:4 dr > 96:4
All these reactions require relatively high temperatures. Improvement of these methods was
done by using organometallic complexes. Thus, -diazoketones react with propargylic alcohols in
the presence of the rhodium(III) catalyst Rh2(OAc)4 to give intermediate enols, which undergo
Claisen rearrangement to -hydroxyketones (Equation (120)) <1999OL371> (see also Chapter
1.18 for other examples).
O R1
R1 Rh2(OAc)4 (0.25 mol.%) •
R R2
+ R2 ð120Þ
OH ∆ HO
O
N2
26–60% R
1.20.3.7 Miscellaneous
The thermal ene-reaction between terminal alkynes and indane-1,2,3-trione involving CC bond
formation and H-migration gives rise to 2-allenyl-2-hydroxy indane-1,3-diones
<1992JCS(P1)2355>.
A titanocene system is able to provide an access to allene via a formal ene reaction of a
ynediene compound under mild conditions (Equation (121)) <1999JA1976>. The regioselective
ene-reaction of the vinyl hydrogen, rather than the allyl hydrogen of a twisted 1,3-diene, furnished
a novel synthesis of allenols via the photosensitized oxygenation of the 1,3-diene (Equation (122))
<1996TL7771, 1997CC2243, 1998JOC8704, 2001TL7307>.
R2
R1
R2
Cp2Ti(CO)2 (20 mol.%)
X X
R1
105 °C
• ð121Þ
X = (EtO2C)2C, R1 = H, R2 = Me 54%
X = (ButO2C)2C, R1 = H, R2 = Me 44%
X = PhN, R1 = H, R2 = Ph 36%
i. O2 H
ii. P(OEt)3 OH
iii. TBAF • ð122Þ
63%
OTES OH
Conjugate addition of allenoate esters to ,-unsaturated carbonyl compounds catalyzed by qui-

nuclidine opens a new route to functionalized allenes under very mild conditions (Equation (123))
<2003JA12394>.
H O O
Quinuclidine
• (10 mol.%) CO2Et
O + ð123Þ
OEt toluene, rt •
87%
1.20.4 BY C¼C BOND FORMATION
1.20.4.1 Elimination Reactions

1,2-Elimination from an unsaturated molecule or 1,4-elimination on both sides of a triple bond,
provide a simple route to allenes and cumulenes.
1.20.4.1.1 1,4-Elimination
1,2,3-Butatriene derivatives have been formed by treatment of propargylic methyl ether with
2 equiv. of ButLi by 1,4-elimination of methanol. The intermediate lithio butatriene 113 allowed
access to -silyl -silyloxy butatrienes 114 on reaction with Me3SiCl, to allenyl ketones and
aldehydes 115 upon hydrolysis <1981TL2827>, and to allenyl amines 116 starting from
1-dialkylamino-4-methoxy-4-methylpent-2-ynes (Scheme 12) <1982JOM(233)C25>.
R1 TMS
• •
R2 OTMS
TMSCl 114
Li + X = OTMS
R1 R1
2ButLi R1 – H2O •
R2 • •
X R2 O
R O R2 X H
113 115
ButOH
R1
X = NR2 • •
NR2
R2
116
Scheme 12
Butatrienyl ethers have been obtained from a reaction of 1-trimethylsilyloxy-4-alkoxy but-

2-ynes with ethyllithium by 1,4-elimination of Me3SiOH <1981RTC34>. [3]-Cumulenes 117 can
be easily prepared after condensation of aldehydes or ketones to propargylic trimethylsilanes and
subsequent TBAF-mediated 1,4-elimination reaction from the trimethylsilylmethane sulfonate
<1995TL3785, 1995JOC1885> or trimethylsilyl acetate derivatives (Equation (124))
<1994CC2121>.
i. BunLi
i. BunLi
ii. R3R4CO
ii. MsCl or AcCl
R1 iii. NH4Cl R1 R3 R1 R3
R4 iii. TBAF
R2 R2 • •
Me3Si Me3Si OH 45–84% R2 R4
ð124Þ
117
R1 = R3 = H, Me
R2 = H, Me, Bun, Ph
R4 = Me, Ph, Bun
1.20.4.1.2 Desulfurization, decarboxylation, and related reactions

The elimination of sulfur compounds provides an original route to cumulenes. Thus, desulfuriza-
tion of 4-vinylidene-1,3-dithiolane-2-thione 118 by 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholi-
dine 119 gives butatriene derivatives under very mild conditions (Equation (125)) <1991S1151,
1992AG(E)1611>. Treatment of episulfides with PBu3 at 130 C or with dimethyl diazomalonate
in the presence of a rhodium catalyst leads to desulfurization and affords cumulenes
<1986T1989>. 1,2,3,4-Pentatetraenes have been obtained in fair yields (>50%) by thermolytic
or photolytic desulfurization of episulfides <1989TL4271, 1987TL1803>. The thermal elimina-

tion of sulfur dioxide from alkylidene sulfones at 650 C affords vinyl allenes with good purity
and high yield <1983TL4691>.
R Ph
R R R
S P 0 °C
• + Me N N Me • •
S 70–95% H H ð125Þ
S
118 119
R = Me, Pri
Oxidation of cumulenes by MCPBA leads to alkylidene cyclopropanones, which photochemi-

cally release carbon monoxide to produce new cumulenes containing one double bond less
(Equation (126)) <1987JA4338, 1992JA5998>.
O
But But But
Oxidation
• • • • •
But But 38% But
But
But
hν ð126Þ
100%
But But
• • •
But But
Upon heating in dimethylformamide at 110–125 C, unsaturated -lactones undergo

decarboxylation to produce allenes in good-to-excellent yield (Equation (127)) <1993JOC322>.
O
H
H
O DMF, 125 °C ð127Þ
Me
•
73% Me Me
Me
1.20.4.1.3 1,2-Elimination
The highly sterically hindered tetra-t-butyl allene has been obtained by elimination of water under
acid catalysis from 1,1,3,3-tetra-t-butylprop-2-en-1-ol <1982AG(E)924>. However, there are only
a few examples of direct elimination of water from alcohols. In most cases, ester derivatives like
trifluorosulfonates <1975JOC657>, trifluoroacetates <1978JOC1526, 1988TL1355>, or sulfi-
nates <1985AG(E)851> facilitate the elimination of either a molecule of HX (X = leaving
group) or XY can be produced.
1.20.4.1.4 Elimination of HX
Dehydrohalogenation by strong bases has been widely used to prepare allenes in good yield from
unsaturated halopropenes with release of HX (Equation (128)) <1961JCS2687>. The reactive allenyl
diazomethyl ketone 120 has been obtained at 20 C in the presence of 1,5-diazabicyclo[4.3.0]non-
5-ene (DBN) from a bromo derivative (Equation (129)) <1976JOC3326>. Elimination of HCl by
triethylamine at 60 C from the -chlorovinyl aldehyde 121 gave allenyl aldehydes 122 (Equation
(130)) <1970TL4315>, whereas elimination of HCl from 123 by pyridine led to a ‘‘push–pull’’ type
cumulene 124 containing the fulvene and heptafulvene units linked by a cumulative double bond
(Equation (131)) <1987AG(E)335>. Similarly, 1,3-di-t-butyl-5-vinylidene cyclopentadiene was
obtained at low temperature by elimination of HCl from 6-chloro-6-methylpentafulvene with
2,2,6,6-tetramethylpiperidine lithium as a base <1986AG(E)466>. -Ketoallenes have been prepared
in 34–40% yield by reaction of dialkyl ketones with 1,4-dibromobut-2-ene in the presence of NaH in
dimethylsulfoxide (DMSO) at room temperature by elimination of HBr <1991JCS(CC)294>.
Tris(arylthio) butatrienes 126 have been obtained by elimination of HCl from 1,2-dichlorobuta-
1,3-dienes 125 (Equation (132)), but they rearranged at room temperature into enyne derivatives
<1984LA1873>. The elimination of HX (X = Cl, ClO4) from 1,1,3,3-tetrakis(dialkylamino) allylic
chloride or perchlorate 127 with BunLi yields 1,1,3,3-tetrakis(dialkylamino) allenes 128 in good yields
(Equation (133)) <1973AG(E)566>. Allenoyltrimethylsilane, a precursor of substituted furans, is
accessible in two steps from 3,3-dichloropropenoylsilane via a Michael addition followed by a smooth
dehydrochlorination in the presence of DBU (Equation (134)) <1995SC503>.
Ar Br KOH, ROH Ar Ph
• ð128Þ
Ar Ph 100% Ar
O N2
DBN, Et2O O
ð129Þ
N2 •
Br 59% 120
H
R1 R2
Et3N, 60 °C R1 O
Cl O • ð130Þ
R2
H
121 122
Ph
Cl Ph Ar
Et3N, Et2O
• •
61–90% ð131Þ
Ph Ar Ar
Ph
Ar
123 124
RS
Cl RS Cl
KOBut, rt
RS • • ð132Þ
86% RS SR
Cl SR
126
R = tolyl 125
R2N NR2 R2N NR2

+ BunLi
70%
•
R2N NR2
R2N NR2 ð133Þ
127 128
R1 O
R2 TMS O
DBU R1 TMS
Cl • ð134Þ
R1 O R2
R2 TMS
Cl
Allene-1,3-dicarboxylates are readily prepared from acetone-1,3-dicarboxylates either in a two step

procedure (treatment of the ketone with PCl5 followed by elimination in the presence of triethylamine)
<1996JOC2031> or in a one step synthesis by using 2-chloro-1,3-dimethylimidazolium chloride (DMC)
as a dehydrating reagent (Equation (135)) <1998TL6331>. This latter strategy was used to prepare an
optically active dimenthyl allene-1,3-dicarboxylate for the synthesis of ()-epibatidine <1998CC2363>.
O
RO2C CO2R DMC (1.2 equiv.), Et3N RO2C R1
•
R1 R1 CH2Cl2, rt CO2R ð135Þ
R1
70–92%
R = Me, Et, Bu
R1 = H, Me
Dehydrohalogenation is a very useful procedure to produce allenes, but vinyl chloride com-
pounds are not always easily available. An efficient protocol for the preparation of allenes from
ketones was developed by Brummond and co-workers <1996JOC6096> through enol phosphates
(Equation (136)).
R2 OP(O)(OEt)2
R2 i. LDA, THF, –78 °C LDA, THF
R2 R3
ii. ClP(O)(OEt )2, –78 °C to rt R1 R3 –78 °C
R1 R3 +
•
24–81% R1 H
O R2 ð136Þ
1 = alkyl,
R aryl
R1 R3
R2 = H, MeCO
OP(O)(OEt)2
R3 = alkyl
Addition of a ketone or a diketone to dibromotriphenylphosphine gives access to a bromide

salt; treatment with Et3N leads to elimination of triphenylphosphine oxide and formation of
terminal allenes and allenyl ketones <1972TL3257>. In the same way, silyl enol ethers can be
eliminated to produce functionalized allenes (Equation (137)) <2001CEJ573>. Even though this
methodology allows the direct formation of functionalized allenes (by trapping the polylithiated
intermediate allene with different hard electrophiles), it presents two main limitations. Only bulky
silicon groups (such as TBDMS or TIPS) allow the formation of allenes and the transformations
are actually limited to the use of aryl-substituted substrates.
Ph OTBS Ph Li Electrophile Ph E
• •
Ph Me Ph Li Ph E ð137Þ
E = H, TMS, CH(OH)R
The thermal elimination of ArSeOH from vinyl selenoxides leads to allenes when the syn-
elimination to form a CC triple bond is not possible <1980JA5967>. Based on the same
principle, the asymmetric oxidation of vinyl selenides by Davis oxidants, or ButOOH in the
presence of Sharpless catalysts, leads to chiral allenic sulfones <1992JCS(CC)46, 1993JOC3697>.
1.20.4.1.5 Elimination of XY
An alternative to the elimination of a molecule of HX is to remove two leaving groups, one in a
vinylic and the other in an allylic position, in the presence of a base or an acid.
Cyclic allenic esters have been produced by oxidation of 3,4-polymethylene-2-pyrazolin-5-ones
by thallium nitrate followed by ring opening with MeOH <1980JOC3522>.
Butatrienes have been stereoselectively obtained in two steps by C¼C formation via inter-
mediate divinyl boranes generated from 1-iodohex-1-yne and t-hexylborane on reaction with
MeONa <1991T343> .
Unsaturated -chlorosilanes can eliminate one molecule of chlorosilane in the presence of
fluoride (KF or Et4NF) to afford allenes <1974TL171, 1984S384>.
The rearrangement of acetylenic disilanes initiated by FeCl3 or TiCl4 leads to 1,1-bis(silyl)
allenes 129 with elimination of Me3SiOSiMe3 (Equation (138)) <1990TL5607>. The treatment of
2-halo-2-alkenoyl silanes 130 with organolithium reagent gives trimethylsilyloxy allenes 131 after
migration of the silyl group to the oxygen and elimination of LiX (Equation (139))
<1986JA7791>. A similar base-induced Brook rearrangement and elimination of an ether
group is observed in the formation of 4-[(benzyloxy)(t-butyl)(methyl)silyloxy)]penta-1,2,3-triene
by reaction of the corresponding acyl silane with lithium or bromomagnesium 3-tetrahydropyr-
anyloxy prop-1-ynide <1994TL1161>. Medium-sized cyclic allenes have been prepared from the
enol triflate of 6-(silylmethyl)-10-substituted bicyclo[4.4.0]decan-2-one via a CC bond cleavage
directed by the silyl group (Equation (140)) <1997SL461> and 10-membered allenes were thus
isolated in good yields.
Me OTMS TMSCl, FeCl3 TMS R1

Me Si •
R1 ð138Þ
TMS R2 52–82% ClMe2Si R2
129
R1 X R1 X Brooke
R3Li rearrangement R1 R3
O OLi •
R2 R2 TMS
ð139Þ
TMS TMS R3 R2
131
130
TMS
( )n Imidazole
DMF, 150 °C ( )n
• ð140Þ
82%
RO OTf 60%
RO
R = TIPS, n = 1
R = Me, n = 2
Addition of aryl Grignard reagents to -triethylsilyl enals gave rise to secondary allylic
alcohols, which can be converted into 1,3-disubstitued allenes either in the presence of KH, or
after transformation into allylic chlorides followed by elimination (Equation (141))
<2001TL2605>. The intramolecular version of this -elimination was described by Ito
<1996JOC4884>. Highly enantiomerically enriched allenyl silanes were then obtained by an
intramolecular bis-silylation reaction of optically active propargylic alcohols, catalyzed by palla-
dium catalysts, followed by treatment with BunLi (Equation (142)).
KH, THF, 0 °C
or
i. Et3SiH, RhCl(PPh3)3 (cat.) i. SOCl2, CCl4, rt
ii. R2MgX SiEt3 ii. TBAF, DMSO R2
R1
R1 CHO • ð141Þ
R2 OH 55–90% R1
R1 = c-Hex, n-C6H13
R2 = Ph, biphenyl, 2-tolyl, 3-Cl-C6H4
Ph SiMe R1
2 Ph
Ph Si Ph
Pd(acac)2 (2 mol.%) SiMe2R1 SiMe2R1
Si BunLi
O O •
Hex R ð142Þ
ButCH2CMe2-NC Hex 79–95%
R R
toluene, ∆ R = Me, c-Hex, Ph
R1 = Me, But, Ph
In the presence of BunLi, alkenyl triflates having a sulfoxy group on the C (allylic position)
lead to trisubstituted allenes, and even to macrocyclic allenes (Equation (143)) <1995T9327>.
Acetylenic alkyllithium derivatives bearing a methoxy group at the distal propargylic position
cyclize to give four-, five-, and six-membered alkenylidene cycloalkanes in good-to-excellent yields
<1995JOC754>.
1
O R R2 R1 H
S H Excess BunLi, –80 °C
•
Ar 42–74% R2 R3
TfO R3 ð143Þ
R1, R2 = alkyl, cycloalkyl
R3 = PhCH2, alkyl
1,2-Dienes have been obtained from stannyl allylic alcohols by -elimination either under basic
conditions <1992TL5093> or acidic conditions (Scheme 13) <1987TL2751, 1994TL3797>.
Chiral allenes of high enantiomeric purity can be prepared in a similar way starting from the
corresponding chiral alcohols <1994TL3797>.
R1 SnBu3 +
H R1
R2 •
40–100% R2
HO
R1 = TMSCH2, MEMOCH2
MsCl, Et3N R2 = H, Ph, Prn, Pri, n-C6H13
CH2Cl2
0 °C to rt R1
•
43–85% R2
R1 = n-C6H13, n-C4H9, Ph, 1-cyclohexenyl
R2 = Me, Et, Hexc, Ph, MeCH=CH
Scheme 13
Baylis–Hillman type reaction of vinyl phosphine oxide <2001JCS(P1)2240> or vinyl phospho-

nate <1998JOC6428, 2002T83> and an aldehyde in the presence of a base afforded the hydro-
xyphosphine oxide or the hydroxyphosphonate. Subsequent elimination provided the allene in
good yield (Scheme 14).
i. NaH i. LDA, –78 °C R2

ii. R1CHO R1 ii. R2CHO R1 OH
(RO)2(O)P P(O)(OR)2
0 °C P(OR)2 44–100% P(OR)2
81–85% O O
R = Et, Pri
R3 = H
KH, THF
R1 = H, c-Hex, But, Ph i. LDA, THF, –78 °C 17–92%
R2 = Me, Et, But, c-Hex, PhCH2CH2 ii. R2R3CO, –78 °C
R3 = Me iii. KOBut, 60 °C R2
•
47–73% R1 R3
Scheme 14
Ethylene and styrene derivatives have been reacted with propargylic ethers in the presence of
zirconocene to afford allenic products <1997TL8723>. The reaction proceeds via initial forma-
tion of a zirconacyclopentene, followed by -elimination of the ether and hydrolysis to liberate
the allene.
-Elimination of a sulfinyl group is also a versatile method to obtain allenes. Thus, the
sulfoxide metal-exchange reaction of a -acetoxy sulfoxide or a -mesyloxy sulfoxide (which
was derived from alkenyl aryl sulfoxides and aldehydes in two steps) with a Grignard or
alkyllithium reagent at low temperature gave allenes in good yield (Equation (144))
<1999TL8815, 2002T2533>. Optically active allenes were prepared from optically active 2-sub-
stituted ethenyl p-tolylsulfoxide. Thus, starting from the pure (+)-(E)-(Ss,1R)-1-acetoxy-1-
(2-naphthyl)-3-phenyl-2-(p-tolylsulfinyl)-2-propene, in the presence of 4 equiv. of EtMgBr,
()-(R)-1-(2-naphthyl)-3-phenyl-1,2-propadiene was obtained in 74% ee. Treatment of allylic
mesylates activated by a chiral sulfoxide group with Me2CuLiLiI in THF at 78 C gave allenes
corresponding to the formal elimination of MsOS(O)p-Tol <1992TL4985>. A radical approach
to this -elimination was described by Malacria (Equation (145)) <1999TL3565,
2002EJOC1776>. It is to be noted here that this reaction does not take place with sulfur groups
other than sulfoxide and sulfimide. Moreover, due to the high energy of activation, disappointing
results were observed for the synthesis of enantiomerically enriched 1,3-disubsituted allenes.
Finally, another methodology involving vinyl sulfoxides is based on consecutive carbocupration-
homologation--elimination reactions to afford polysubstituted propadienes in good yield
(Equation (146)) <2000OL2849, 2002EJOC4151>. Using a chiral ethynyl p-tolylsulfoxide, a
thermodynamic equilibration of secondary organometallic derivatives is brought about before
the syn--elimination and this opens a new access to chiral allenes.
Ph EtMgBr or PriMgCl
O S R2 R1 H
THF, –78 °C
•
Y-O R1 4–99% R2 R3
R 3 ð144Þ
R1 = H, Me, Ph, n-C4H9; R2 = H; R1–R2 = (CH2)5
R = aryl, PhCH=CH, PhCC
Y = Ms, Ac
Ar Ar
TTMS
O S NBS, Me2S H S O H
toluene, ∆
•
HO i. MsCl, THF R Br 30–80% R ð145Þ
H
R ii. LiBr
R = alkyl, aryl
i. R2Cu, MgBr2
ii. ICHR3ZnR R1 S(O)n-Tolyl R1
R1 S(O)n-Tolyl •
THF, rt R2 ZnR 50–95% R2 R3
ð146Þ
R3
R1 = Bun, n-Hex; n = 1, 2
R2 = Me, Pr i, Bun, But, Oct, EtO2CC6H4
R3 = H, PhCH2
Treatment of chlorinated vinylic phosphirenes 132 with BunLi at 78 C gives phosphino-
butatrienes 133 via CP bond formation, rearrangement and elimination of LiCl in good yield
(Equation (147)) <1992SL635>. Deprotonation of the benzothiophenium perchlorate 134 by
MeONa leads to ring opening and formation of the allene 135 (Equation (148)) <1992CL1357>.
Cl
t RLi, Et2O, –78 °C But
Bu
• •
P R2P ð147Þ
133
R
R = Me 79%
132
R = Bun 50%
Ph SPh
+ R
S
– MeONa, MeOH
ClO4 •
Ph R ð148Þ
Ph 135
134
R=H 89%
R = Et 100%
1-Halogeno-1-(1-haloalkenyl)cyclopropanes undergo elimination of halogen and form allenes

(alkenylidenecyclopropanes) when treated with methyllithium at a temperature between 30 and
20 C (Equation (149)) <1995TL3393>.
R3 R2 R3
R2 Br Br
MeLi R1
>60% • ð149Þ
R1 R1
R1
R1 = H, Me; R2 = H, Me; R3 = Me, Ph, CO2Me
The palladium/diethylzinc system was found to be efficient for the synthesis of terminal or
internal allenes, bearing aminoalkyl, alkyl, or aryl groups (Equation (150)) <2000TL5131,
2002JOC1359>.
Et2Zn (2 equiv.)
R2
Pd(PPh3)4 (10 mol.%) R1
R1 OMs •
THF, rt R2
Br ð150Þ
47–90%
R1 = alkyl, aryl
R2 = Me, Bun, Ph
Oxidative addition of 2-bromoalk-2-en-1-yl mesylates or 3-aryl-2-bromoalk-2-en-1-yl-trichloro-

acetates to palladium(0) affords 2-bromo--allylpalladium(II) intermediates, which produce
allenes by -elimination. Both (E)- and (Z)-bromomesylate or bromoacetate can be used. It is
noteworthy that there is no chirality transfer from the chirality center of the substrates to the axial
chirality of the resulting allenes.
1.20.4.2 Reduction of Unsaturated Alcohols and Halides

Reduction of 1,4-dihydroxy-2-butynes 136 by various reducing reagents, such as PBr3, SnCl2/HCl,
has been used for the preparation of tetrasubstituted butatrienes 137 (Equation (151))
<1966BSF2885>. The extension of this reaction to 1,6-dihydroxy-2,4-hexadiynes <1966BSF2885>
has been used to produce hexapentaenes and bis-hexapentaene compounds as potential molecular
materials for nonlinear optics <1993CM357> or as host molecules <1991BCJ659>.
Ar2 Ar3 Ar2 Ar3
Ar1 Ar4 SnCl2
• • ð151Þ
HO OH 58–80% Ar1 Ar4
136 137
Reductive dehalogenation of 1,4-dihalo-2-butynes by zinc dust provides a simple route to

cumulenes. From a 2,5-dihalo pent-1-en-3-yne like 138, the reductive cleavage of chlorine with
zinc dust leads to pentatetraenes 139 (Equation (152)) <1986AG(E)340>.
Cl Cl
Zn dust
• • • ð152Þ
138 139
It is also possible to generate butatrienes in good yield and high stereoselectivity by reduction
of 2,3-diiodobuta-1,3-dienes by BunLi at 70 C <1984CL131>.
Depending on the substituents, the annulene dione 140 was transformed into the corresponding
dehydroannulenes 141–143, by three different methods: reduction by SnCl2/HCl, dehydroxyla-
tion of the diol by treatment with PPh3/I2 or electron transfer reaction (Scheme 15)
<1995AG(E)1892>.
1.20.4.3 Wittig and Related Reactions

The formation of allenes from phosphorus ylides and carbonyl compounds can be considered
either starting from an alkylidene phosphorane and a ketene <1963CB1535> or from a vinylidene
phosphorane and a carbonyl compound. Both these strategies have been used for the access to a
variety of functionalized allenes.
1.20.4.3.1 Reaction of a ketene and an alkylidene phosphorane

Terminal allenes have been obtained in 59–80% yield by reaction of stable phosphorus ylides
with CH2¼C¼O at 0–5 C <1970S543>. Electron deficient allenes such as 1,1,3,3-(tetraalk-
oxycarbonyl) allenes have been prepared in more than 60% yield by treatment of alkylidene
phosphoranes with ketenes in refluxing benzene <1979LA1388>. A process based on the use
•
•
i. RMgBr, THF
•
ii. SnCl2, HCl, ether •
141
R = Ph, 4-But-C6H4 R
21–27%
O H
i. NaBH4/CeCl3
CH2Cl2, EtOH •
ii. PPh3, I2, imidazole •
•
142 •
O H
140
TBDMSCl OTBDMS
Zn, Et3N, THF
•
•
•
•
143
OTBDMS
Scheme 15
of carboxylic acids or acyl chlorides which can undergo ,-elimination reaction, can be used
to prepare allenes which is similar to the formation of ketenes. Thus, ethyl allenyl carboxylates
have been obtained from [(ethoxycarbonyl)methylidene] phosphoranes and acids, in the pre-
sence of Bu3N and 2-chloro-1-methylpyridinium iodide <1985HCA2244>. In dichloro-
methane, at room temperature, acyl halides react with [(alkoxycarbonyl)methylidene]
phosphoranes in the presence of Et3N to provide allenes <1992CPLI243> and alkenyl allenes
from ,-unsaturated acyl chlorides <1985HCA2249>. 4-Phenylchalcogeno allenic esters have
been synthesised from -(phenylchalcogeno)acyl chlorides and ethyl 2-(triphenylphosphoranyl-
idene) acetate or propionate in the presence of triethylamine (Equation (153)). The corres-
ponding allenic esters were isolated in 60 to 93% yield <2000TL1867>. When a phosphorane
bearing a chiral auxiliary is engaged in the Wittig–Horner–Emmons reaction, the diastereo-
merically pure allene is obtained in fair-to-good yield (Equation (154)) <2003TL6409>.
Pentafluorophenyl allenes 144 have been prepared from corresponding phosphoranes and
acyl bromide at 20 C in THF (Equation (155)) <1998JCR(S)602>. Unsymmetrical pentate-
traenes have been prepared in good yields (50–75%) on reaction of a phosphorus ylide with an
allenyl acyl chloride in the presence of Et3N at room temperature <1986CB1208>. The
coordination of vinyl ketenes to a Fe(CO)3 moiety makes possible the direct synthesis of
coordinated vinyl allenes 145 <1992JCS(P1)259, 1991JCS(CC)1290> on reaction with phos-
phonoacetate via a Wadsworth–Emmons-type reaction (Equation (156)). Photolysis of stabi-
lized phosphorane ylides with alkoxycarbene chromium complexes under a carbon monoxide
atmosphere leads to allenes via formation of a ketene, by classical coupling of the carbene
ligand with CO (Equation (157)) <1992JA4079>. On reaction with phosphonium ylides,
carbon dioxide allows the formal coupling of two carbenic moieties with the carbon atom of
CO2 <1974TL1275>.
O
Et3N, CH2Cl2, 0 °C R R1
R + R1 CO2Et
Cl •
60–93% Ph-X CO2Et
X-Ph PPh3 ð153Þ
R = H, Me, Bun
R1 = H, Me
X = Se, S
H R
O Et3N •
O + O H ð154Þ
PPh3 R
Cl 48–62% O
PhSO2 O PhSO2
C6F5 O C 6F 5 R1
THF, –60 °C to rt •
PPh3 + R 1 ð155Þ
R Br R
144
O CO2R1
Ph • O O NaH Ph •
+ (MeO)2P ð156Þ
OR1 25–71%
(CO)3Fe R2 (CO)3Fe R 2
145
OEt CO, hν OEt

PPh3
+ (CO)5Cr • ð157Þ
BnO2C 60%
But BnO2C But
Various allene carboxylates can be efficiently prepared from the corresponding 2,6-di-t-butyl-
4-methylphenyl (BHT) esters in a one-pot procedure via in situ ketene generation and subse-
quent Horner–Wadsworth–Emmons reaction with a phosphonoacetate anion (Equation (158))
<1995SL933, 1995TL9513>. On the basis of the one-pot procedure, Tanaka and Fuji developed
an asymmetric version of the Wittig-type reaction <1996TL3735, 2001TA669>. In situ gener-
ated ketenes react with the anion of the chiral phosphonate 146 to form optically active allenes
in good yields and up to 91% ee (Equation (158)). It has to be pointed out that aryl carbox-
ylates are required for the generation of the ketene. The high enantioselectivity can be under-
stood by a favorable chelation of zinc to the phosphate to produce a conformationally locked
anion.
i. BunLi/ZnCl2 or SnCl2
But –
R1 ii. (MeO)2P(O)CH CO2Me, Li + R1 CO2Me
O Me •
R2 15–93% R2
O But
R1 = Ph, Bn, β-naphthyl
R2 = Me, Et, Pri, Ph
ð158Þ
O O
Chiral version with P CO2Me R1-R2 = -(CH2)2-
O
146
A new allene synthesis involving a boron–Wittig reaction of aldehydes with boron stabilized
carbanions at 78 C has also been reported <1992JCS(P1)747>.
1.20.4.3.2 Reaction of a ketone and a vinylidene phosphorane

The other strategy based on the use of vinylidene triphenylphosphoranes can be exemplified by
the synthesis of push–pull allenes from cyclic 1,2-diketones and 2,2-diethoxyvinylidene phospho-
rane <1973TL3985, 1975TL4405>.
Regioselective halide displacement from halogenated phosphonium salts gives rise to phospha-
cumulenes, which react with ketones to afford butatriene derivatives <1969JA6112>. The bro-
moalkenylphosphonium bromide gave 53% yield of the cumulene diester 147 (Equation (159))
<1987AJC1675>, whereas on reaction with ketones in the presence of (Me3Si)2NLi at low
temperature dibromo- or dichlorophosphonium salts 148 led to halogenated butatrienes 149
(Equation (160)) <1990JOC2983, 1988TL411, 1987JOC443, 1984JCS(CC)152>.
Ph Br CO2Et Ph CO2Et
Et3N
+ O • •
53% ð159Þ
Ph PPh3, Br CO2Et Ph CO2Et
147
i. LiHMDS
H Cl
ii. R2R3CO H R2
+ • • ð160Þ
– THF, –70 °C
Cl PPh3, Br Cl R3
6–88%
148 149
A symmetrical butatriene has been obtained in 71% yield by reaction of fluorenone with a
propylidene phosphorane produced from methylidene triphenylphosphorane and gem-dihaloalkenes
<1975TL4025>. The Horner–Emmons-type reaction starting from allenyl diphenylphosphine oxide
<1990TL7469> or allenyl phosphonates <1985IJ136, 1986JA343> and aldehydes or ketones
makes possible the synthesis of butatriene derivatives, and bicyclic cumulenes via intramolecular
reaction. Another strategy based on the intermediate formation of a cumulenyl diylide is exempli-
fied by the synthesis of 1,4-diphenylbutatriene from benzaldehyde and a diphosphonium bistriflate
<1991T4539>. Higher symmetrical cumulenes have been obtained by Wittig reaction of carbon
suboxide with 2 equiv. of phosphorus ylide at room temperature <1986AG(E)93, 1987G625>.
1.20.4.3.3 Three-component reaction for allene synthesis

Branched allene carboxylates can also be conveniently prepared by a tandem Michael–Horner–
Wadsworth–Emmons reaction of ,-unsaturated BHT esters, a carbon nucleophile, and a
phosphonoacetate derivative (Equation (161)) <1995TL9513>.
i. RLi/ZnCl2 or SnCl2, THF, –78 °C
ii. (MeO)2P(O)CHCO2Me
R1 CO2BHT – + R1 CO2Me
Li
• ð161Þ
18–77% R2
R2
R
R1 = Me, Ph; R2 = Ph, Bun; R = Ph, Bu, CH2=C(O)OBut
A three-component reaction between an aldehyde, a 1-alkynylphosphine oxide, and a lithium

alkylthiolate (Equation (162)) or a lithium alkylselenolate (Equation (163)) allows the formation
of sulfur- or selenium-substituted allenes through a Michael/aldol/Horner–Wadsworth–Emmons
tandem reaction <2003TL5913, 2003CC1714>.
O rt R1 R3
R1 P + R2SLi + R3CHO •
Ph 61–83%
Ph R 2S
ð162Þ
R1 = Ph, MeOCH2, n-C5H11
R2 = Bu, Pri, Bus
R = aryl, Pr, PhCH=CH–
O rt R1 R3
R1 P + R2SeLi + R3CHO • ð163Þ
Ph 59–89%
Ph R2Se
1.20.4.3.4 Addition of carbene moieties to double bonds

Unsaturated carbenes generated in situ by treatment of propargylic halides or esters with KOBut
react with alkenes to produce alkenylidene cyclopropanes in moderate yield (10–52%)
<1971JA4527>. Extended unsaturated carbenes like alkadienylidene, alkatrienylidene, and alka-
tetraenylidene carbenes have been generated starting respectively from 1-ethynylvinyl triflates
<1979JA4772, 1982ACR348>, (1,3-diynyl)alkyl mesylates or halides <1981JA4638,
1988JOC3122>, and (1-butadiynyl)vinyl triflates <1981JA6437, 1982ACR348>. These unsatu-

rated carbenes provide access to a variety of cyclopropyl cumulenes and dimerized cumulenic
compounds <1987JA782>. Silicon-, germanium-, and tin-functionalized cumulenes have been
prepared (26–88%) on interaction of alkadienylidene <1981JA5429> and alkatetraenylidene
<1981JA6437> carbenes with group 4 hydrides.
cis-Cumulenes have also been prepared in 20–50% yields via homocoupling of two carbenes
generated from (-methylthiovinyl)copper reagents and CH3I at 0 C in THF <1975TL2923>.
Hydrostannylation of alkynyl-chromium carbene has led to the synthesis of -methoxyalle-
nylstannane, a useful reagent in organic chemistry which cannot be readily prepared by the SN20
substitution reactions of propargylic halides or sulfonates (Equation (164)) <1995TL1011>.
Interestingly, the regiochemistry of the hydrostannylation (allenyl versus propargyl derivative)
is very sensitive to the steric bulk of both the alkynyl carbene complex and the tin hydride
source.
Pyr (3 equiv.)
Cr(CO)5 Bu3Sn H
Hexane, –78 °C
R + Bu3SnH •
OMe 47–57% R OMe ð164Þ
R = Ph, CH2=C(Me), 1-cyclohexenyl
The olefin metathesis reaction catalyzed by well-defined transition metal alkylidene complexes
has been known for more than a decade and has been extensively explored. This is now an efficient
process for the creation of new double CC bonds. The Grubbs catalyst, Cl2(Cy3P)2Ru¼CHPh,
was found to catalyze the cross-metathesis of monosubstituted allenes to 1,3-disubstituted allenes in
low-to-good yield (Equation (165)) <2000OL551>.
Cl 2(PCy3)2Ru=CHPh (cat.) R
• • ð165Þ
R CH2Cl2, rt R
20–75%
Carbenoids can also be generated from 1-chlorovinyl p-tolyl sulfoxides with a Grignard reagent
by sulfoxide–magnesium exchange. Treatment of magnesium alkylidene carbenoids with lithium
-sulfonyl carbanions gives allenes in moderate-to-good yield (Equation (166)) <2002TL2043>.
i. ButMgCl (0.5 equiv.)
ii. EtMgCl (3 equiv.)
iii. PhSO2C(Li)R1R2 (3 equiv.)
O Cl THF, –78 °C to rt O R1
• ð166Þ
O S(O)-tolyl 14–63% O R2
R1 = H, Ph, Me(CH2)8, c-C6H11, naphthyl, vinyl, PhS, MeO2C

R2 = H, Me, Ph
1.20.4.4 Dehalogenation
1.20.4.4.1 Dehalogenation of halocyclopropanes

Treatment of gem-dihalocyclopropanes by alkyllithium reagents at low temperature (30 C to
room temperature), namely the Doering–Moore–Skatteböl reaction, gives allenes in good yield
<1962JOC4179, 1984TL2887, 1984CJC1558, 1985JCS(CC)1812, 1995SL880>. Butatrienes have
also been prepared in approximately 75% yield by reaction of BunLi with gem-dibromo methy-
lene cyclopropanes <1967JCS(C)194>. This strategy has been used for the synthesis of cyclic
allenes <1973JOC864, 1986TL4679> and bisallenes <1990TL1841>, bicyclic allenes
<1982JOC1435> and cyclopropyl allenes <1997T11069>, and small ring cyclic cumulenes such
as cyclonona-1,2,3-triene <1984JOC2880>.
Allenyl silanes have been prepared in good yield from allyl silanes by successive dibromocar-
bene addition and rearrangement of a cyclopropylidene (Equation (167)) <1996TL579,
1997TL3395>.
Br MeLi, ether
Br R1
R1 –78 °C ð167Þ
•
R2 70–95% RMe2Si R2
RMe2Si
An alternative to the Doering–Moore–Skatteböl reaction suggested by Satoh is based on sulf-

oxide–metal exchange, followed by rearrangement of a magnesium carbenoid (Equation (168))
<2001T5369>. Band and co-workers reexamined the ring-opening reaction mediated by Grignard
reagents <2002T1581> and found that, at room temperature, the magnesium carbenoid rearranged
to produce the allene and that EtMgBr was the preferred reagent (Equation (169)). This method
may offer benefits in allene synthesis as ethylmagnesium bromide is more stable and easier to
prepare than alkyllithium reagents.
O Ph
S MgCl
Cl PhMgCl Cl R1 R3
R3 R3
•
R1 R4 R1 R4 80–89% R4 ð168Þ
R2 R2 R2
R1 = H, Me, Ph; R2 = H, alkyl, (CH2)C6H4OMe, PhCH2CH2

R3 = H, alkyl; R4 = H, Ph
Br
Br EtMgBr, rt R1 R3
R3
•
R1 91–96% H
R2 ð169Þ
R2
R1 = H, Me, Ph; R2 = H, Hexn, Ph
R3 = H or R2, R3 = (CH2)6
1.20.4.4.2 Dehalogenation of gem-dihaloalkenes

Dimerization of gem-dihaloalkenes on treatment with alkyllithium reagents leads to butatrienes
via 1-halo-1-lithium alkene intermediates. Thus, cumulenic thioesters <1983CPB3306> and tetra-
(2-thienyl)butatrienes were prepared <1992JCS(CC)778>. From these intermediates, lithium can
be exchanged with copper <1986JA5371> to produce functionalized alkoxy <1988JA5567>,
alkynyl <1993AG(E)1187>, and fluorinated <1991JCS(CC)566> butatrienes. 1-Halo-1-lithio
alkene intermediates have also been generated by treatment of a terminal monohalogenated
alkenes by BunLi <1984JOM(264)135, 1984JOM(271)181>. Aryl-substituted butatrienes have
been conveniently prepared from 1,1-dibromoethenes using a nickel(0) catalyst at 50 C
<1984CL2005, 1989JCS(CC)1690>.
1.20.4.5 Reactions Involving Coordinated Organometallic Species

Coordinated cumulenes can be stoichiometrically generated by reaction of suitable substrates with
organometallic complexes. The cumulene moiety can be eliminated from the metal center by
ligand exchange <1989CB1237>, oxidation with Me3NO <1993OM3971>, or protonation
<1993AG(E)1315>. Cumulenic systems can also be formed from metal-vinylidene intermediates
by dimerization of the vinylidene ligand on thermal treatment <1985IJ131, 1990JOC1874,
1987JCS(CC)981> or ligand exchange (Equation (170)) <1992CB2667>.
Ph Ph Ph
(CO)5W • + NC NR2 • •
Ph Ph Ph ð170Þ
(CO)5W(NCNR2)
70–80%
Titanium complexes react with aldehydes or ketones to afford allenes (Equation (171))
<1983JA5490, 1993JOC1298, 1993AG(E)554, 1997JOC2574>. With the development of a step-
wise coupling procedure, the synthesis of unsymmetrical allenes was proposed <1997JOC2564>.
Using the same reagent, a highly efficient cyclization of alkyl- and polyether-tethered aromatic
dialdehydes was described, which afforded macrocyclic allenes in good yields <1997JA3429>. A
carbonyl allenation process mediated by other titanium reagents such as Cp2TiCl2 offers a direct
and versatile approach to highly functionalized allenes (Equation (172)) <1997JOC782>.
Cl NMe2
Ti Ar
(Me2N)3P P(NMe2)3 + ArCHO • ð171Þ
Ti Ar
Me2N Cl
R2
R1 R3R4CO R1 R3
Cp2TiCl2
•
40–89% R2 R4
Cp2Ti ð172Þ
R
R = Me, TMSCH2
R1, R2 = H, H; H, Me; Me, Me
Geminal organobimetallic derivatives became very attractive as they can create in situ several
carbon–carbon bonds. Thus, mixed titanium–aluminum complexes react with carbonyl com-
pounds to produce allenes <1981JA1276>. Under similar conditions, 1,1-zinc, zirconium alkene
reagents, generated by reaction of zinc acetylides with Zr(H)(Cl)(cyclopentadienyl)2, react with
aldehydes to smoothly produce allenes in dichloromethane at 25 C (Equation (173))
<1991JA9888, 1994OM94>. 1,1-Dizincioalkene reagents, prepared from lithium acetylide and
allyl Grignard reagent in the presence of zinc bromide, also react with aldehydes in ether to
produce allenes <1995TL7451, 1996S1499>.
R1 M1 CH2Cl2, 25 °C R1 R3
+ R3CHO •
M2 27–71% ð173Þ
R2 R2
M1= Ti, Zn; M2 = Zr, Zn, Al
1.20.4.6 Metal-catalyzed Homocoupling of Alkynes or Cumulenes

Activation of terminal alkynes by metal complexes, via a vinylidene intermediate, makes possible
the catalytic synthesis of cumulenes. Ruthenium complexes, such as H2Ru(CO)(PPh3)3
<1976JCS(CC)841> or Ru(cyclooctadiene)(cyclooctatetraene), <1991JA9604> catalyze the
dimerization of bulky terminal alkynes such as t-butylacetylene or trimethylsilylacetylene into
the corresponding 1,4-disubstituted butatrienes.
Iyoda and co-workers have shown that the nickel(0)-catalyzed cyclodimerization of tetra-
arylhexapentaenes led to new cumulenes, head-to-head dimers <1989JA3761>, whereas hexapen-
taenes bearing bulky alkyl substituents in refluxing benzene mainly gave head-to-tail dimers in
good yield <1990CL2149>.
1.20.4.7 Intramolecular Rearrangement with Formation of Heteroatom–Carbon Bond

Intramolecular rearrangement involving heteroatom–C and CC double bond formation can take
place from various functional propargyl derivatives. Thus, the condensation of Ph2PCl with prop-
2-yn-1-ol derivatives leads to intermediate alkynyl phosphinites, which undergo rearrangement into
allenes via intramolecular addition of the phosphorus atom to the triple bond <1962JOC1828,
1989JA1770, 1989TL4995>. Similarly, allenyl dihalophosphine oxides obtained at room tempera-
ture from propargylic alcohols and phosphorus trihalide via dihalo propargyl phosphites
<1976JOC3191> and are useful intermediates to access allenyl phosphonic derivatives and
oxaphospholenes. This method was extensively used for the preparation of functionalized dihydro-
furans <1999S463>, oxaphospholes <1998S710> or during the study of the Myers rearrangement
<1995TL4975, 1997TL7941>. Similarly, a selective monophosphorylation of the propargylic
hydroxy group of diols, containing both propargylic and -allenic alcohol functionalities, gives
access to diallenylphosphine oxides in high yield after sigmatropic rearrangement (Equation (174))
<1996S711>. Allenyl dialkyl phosphates have been prepared in 43–62% yields on rearrangement of
stable propargylic phosphates with AgClO4 as catalyst <1977JOC1804>.
R1
• R1
O
Ph2PCl, Et3N •
R HO Ph2P ð174Þ
THF, rt • HO
R OH
R = H, Me 49–94% R
R
R1 = Me, Bun
The reaction of propargylic alcohols with sulfenyl chloride at low temperature in the presence
of a base leads to allenyl sulfoxides via unstable propargyl sulfenates <1971JCS(C)1530,
1988JA4062, 1990JA4072, 1993SL931, 1997T12651>. The use of a sulfinyl chloride allows the
preparation of allenyl sulfones via a similar intramolecular rearrangement <1987JOC4031>.
Treatment of propargylic diol monothionocarbonates with (TMS)2NLi has been used to produce
heterocyclic allenes <1994TL1255>.
Other sulfur reagents can be used to promote the propargylic rearrangement into allenes.
Allenyl trifluoromethyl sulfones and allenic trichloromethyl sulfoxide are readily prepared
from propargyl alcohols and sulfinyl chloride or trichloromethanesulfenyl chloride
<1998TL5413, 2001TL1391>. A practical synthesis of allenyl sulfinates was also described
via a one-pot/two-step procedure: treatment of a symmetrical dialkoxy disulfide with propar-
gyl alcohol followed by spontaneous [2,3]-sigmatropic rearrangement (Equation (175))
<2003S2079>. The reaction of propargyl alcohol with SOBr2 affords an example of intramo-
lecular nucleophilic substitution with formation of a CC double bond. Bromoallenes are thus
preferentially formed when the reaction is carried out in the presence of propylene oxide
<1984TL3055>. Similarly, acyl allenes have been obtained by reaction of SOCl2 with acyl
propargylic alcohols <1985TL631>.
CHCl3, rt H H
PriOS SOPri + • ð175Þ
94%
OH OSOPri O S H
OPri
Allenyl trichloroacetamides are formed by thermal interconversion of propargylic trichloro-

acetimidates, which isomerize into trichloroacetamido dienes on prolonged heating
<1980ACR218>. Propadienyl isothiocyanates have been prepared by thermolysis of propynyl
thiocyanates via a sigmatropic rearrangement in 7–20% yield in dilute solution at 60–100 C, or
better in 95–100% yield in the gas phase at 400 C <1992AG(E)90>.
Allenamides have demonstrated a widespread synthetic potential. Two complementary
procedures dealing with this topic have appeared in 2003. The first one is the amination of
propargylic sulfides with a ketomalonate-derived oxaziridine under metal free conditions,
which led to the N-t-BOC-N-allenylsulfenimides in modest-to-good yield (Equation (176))
<2003OBC3142>. The second one is an iron(II)-catalyzed Bach reaction of t-butoxycarbonyl
azide and propargyl sulfides. Using FeCl2(dppe) as catalyst, the reaction proceeds at low
temperature in good yield <2003JOC4955>. In contrast to the previous method with oxazir-
idine, the reaction is limited by the product tolerance toward the catalyst and the closure of
the catalytic cycle by excess t-BOCN3.
O
EtO2C Nt-BOC
R2 R1 R1 R1
t-BOC-N3, CH2Cl2, 0 °C EtO2C
• R2 R2
t-BOC-N FeCl2(dppe) (10 mol.%) SAr S-Ar
S-Ar t-BOC-N
31–73%
R1 = H, Me; Ar = Ph, PhCH2CH2 31–88%

2
R = H, Me, PhC(OH)H, PhC(OAc)H
R2 R1
•
R1 = H, Me t-BOC-N
R2 = H, Me, Ph, CO2But S-Ar
ð176Þ
Iron(II) is also able to catalyze the reaction of propargyl sulfides with trimethylsilyldiazo-
methane or ethyl diazoacetate to give allenyl -silyl--sulfides in 48–90% yield (Equation (177))
<2001JOC5256>. It was noted that larger substituents on the alkyne gave higher yields, pre-
sumably because of an impossible second addition/rearrangement.
R1 TMSCHN2 R2 R1
R2 •
SAr FeCl2(dppe), ClCH2CH2Cl, ∆ TMS
48–90% S-Ar ð177Þ
R1 = H, Me
R2 = H, Me, PhC(OAc)H
-Hydroxyallenes have been prepared from 3-phenylselenobuta-1,3-dienes by oxidation with

H2O2 followed by sigmatropic rearrangement and elimination <1984TL1987>.
1.20.4.8 Cyclopropane Ring Opening
1.20.4.8.1 Photolysis of cyclopropenes

Under irradiation, substituted cyclopropenes rearrange to allenes in high yield (Equations (178)–
(179)) <1995TL7979, 2000CEJ1963, 2001EJOC663>. It was demonstrated that cyclopropenes
were converted into allenes via a noncarbenoid pathway.
R1
hν, λ = 254 nm R1
R2
•
Pentane or MeOH R2
78–90% ð178Þ
R1 = SiMe3, CH2=CH(CH2)nSiMe2
R2 = Ph, EtCO, CH2=CEt, ButCO, H, CH2=CH(CH2)nSiMe2
TMS hν, λ = 254 nm

Pentane TMS TMS
TMS
• ð179Þ
( )n heating at 380 °C TMS ( )n
TMS 87–93%
1.20.4.8.2 Photorearrangement of vinylidenecyclopropanes

Irradiation of some 1-(20 ,20 -diarylethenylidene)cyclopropanes allows the formation of 1,1-diaryl-
1,2,3-hexatrienes (Equations (180–181)) <2001OL581>. 2,2,3,3-Tetrasubstituted cyclopropanes
reacted faster than less substituted cyclopropanes and it was shown that the mechanism of this
reaction proceeded through an alkyl migration, due to the generation of a 1,3-biradical intermediate.
Ar hν, Benzene Ar
• • • ð180Þ
Ar 45–85% Ar But
Ar
• •
n=1 Ar
Ar
• ( )n hν, Benzene ð181Þ
Ar
Ar Ar
n=2
• • + • •
Ar Ar
1.20.4.8.3 Ethynylcyclopropane rearrangement

When ethynylcyclopropane and a carboxylic acid are treated in refluxing benzene with a ruthe-
nium catalyst, a regioselective ring opening of the cyclopropane takes place to furnish 1-acyloxy-
1-ethoxypenta-3,4-diene, a protected form of the corresponding aldehyde (Equation (182))
<2000SL1315>. It was shown that the yield of allene increased when the steric bulk of the acid
decreased.
EtO
Cat. [Ru(O2CH)(CO)2(PPh3)]2 RCO2 •
+ RCO2H
53–93% ð182Þ
EtO
R = Me, Pr c, Bun, But, Ar
In acidic medium, ethynyl norcoradiene, the ethynyl cycloheptatriene tautomer, undergoes a

ring cleavage into phenylallene in quantitative yield (Equation (183)) <2000OL3011>.
+
H ð183Þ
R •
R R R Quantitative Ar
t
R = H, Bu
-Cyclopropyl alkynes can lead, via ring opening under radical conditions, to allenes, but
synthesis of allenes takes place only in the absence of another unsaturated CC bond in the
starting molecule (Equation (184)) <2002SL923>.
i. Bu3SnH, AIBN R 1 R2
i. Bu3SnH, AIBN 2
HO R1 R ii. MeLi MeOCO2
ii. Tamao oxidation
• iii. ClCO2Me •
O ð184Þ
HO R1 = R2 = H 57–66%
TMS
Si
24%
Br
1.20.4.9 Miscellaneous Reactions

Push–pull butatrienes such as 1,1-bis(dimethylamino)-4,4-dicyanobutatriene <1993TL1779> and
1,1-bis(dimethylamino)-4,4-bis(methoxycarbonyl)butatriene <1978TL4263> have been synthe-
sized by coupling 1,1-dimethylaminoethylene with 1,1-dichloroethylene compounds. Homologa-
tion of acetylenic compounds to allenes has been performed with formaldehyde and
diisopropylamine in the presence of CuBr as catalyst in refluxing dioxane <1979JCS(CC)859>.
Enantiomerically enriched 2,3-allenols have been prepared by this CuBr-mediated homologation
of optically active terminal propargylic alcohols <2002S1643>. On bromination, divinylacetylene
derivatives containing naphthyl substituents lead to 1,6-dibromocumulatrienes via 1,6-addition of
bromine <1990PJC123>. Deprotonation of the bisallene by 2,2,6,6-tetramethylpiperidine lithium
(LTMP) followed by oxidation with CuCl2 at 80 C gives the hexapentaene <1990PAC531>.
5,5-Disubstituted-3-trimethylsilyl allenones are readily accessible from 1,4-trimethylsilyloxy-
but-2-ynes via an elimination-trimethylsilyl group migration within the propargylic framework
(Equation (185)) <1994TL2291, 1997TL25, 1999JOC9307>.
R1 OTMS TMSOTf R1 O
R2 TMS • ð185Þ
or Me2AlCl R2 TMS
X
67–93%
X = OMs, OTMS
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Biographical sketch
Dr. Christian Bruneau graduated from the Dr. Jean-Luc Renaud graduated from the
Institut National Supérieur de Chimie Indus- Ecole Nationale Supérieure de Chimie de
trielle de Rouen in 1974 and obtained his Paris (ENSCP) in 1995, and joined the team
Doctorate degree at the University of Rennes of Professor Max Malacria at the University
(1979). He got a CNRS position in 1980 on of Paris VI and obtained his Ph.D. degree in
environmental organic chemistry, and since 1998 working on cobalt catalyzed Conia-
1986 developing his activity at the Institut de ene type reaction under the supervision of
Chimie de Rennes, in the field of molecular Dr. Corinne Aubert. He was a Lavoisier Post-
catalysis in Pierre H. Dixneuf research labora- doctoral fellow in 1999 with Professor Mark
tory. He has been working on carbon dioxide Lautens at the University of Toronto working
chemistry, activation of cyclic carbonates and on enantioselective ring opening of oxa- and
allene synthesis. He is now mainly involved in azabicyclic derivatives catalyzed by palladium
selective catalytic transformations of alkynes complexes. He moved to the University of
and alkenes via metathesis and cycloisomeri- Louvain-La-Neuve (Belgium) in the team of
zation, and enantioselective reactions, mainly Professor Olivier Riant where he studied the
hydrogenation with transition metal catalysts. enantioselective pinacol coupling reaction cat-
Since 2000, he has been heading the CNRS – alyzed by titanium complexes. In 2000, he was
University of Rennes research unit ‘‘Organo- appointed as Maı̂tre de Conférences at the
metallics and Catalysis’’ (UMR 6509). University of Rennes to pursue his research on
enantioselective hydrogenation and enantio-
selective carbon–carbon or carbon–heteroatom
coupling reaction.
1.21
Alkynes
E. TYRRELL
Kingston University, Kingston-upon-Thames, UK

1.21.2 ALKYNES BY CH BOND FORMATION 1084
1.21.2.1 Reduction of Alkynylcarbon Functions 1084
1.21.2.2 Reduction of Alkynyl-metalloid Functions 1084
1.21.2.3 Reduction of Alkynyl-metal Functions 1085
1.21.3 ALKYNES BY CC BOND FORMATION 1085
1.21.3.1 Substitution Reactions of Alkynyl Carbanions 1086
1.21.3.1.1 Substitution of halogens 1086
1.21.3.1.2 Substitution of oxygen functions 1115
1.21.3.1.3 Substitution of sulfur, selenium, or tellurium functions 1122
1.21.3.1.4 Substitution of nitrogen, phosphorus, arsenic, antimony, or bismuth functions 1124
1.21.3.1.5 Substitution of boron, silicon, or germanium functions 1125
1.21.3.1.6 Oxidative homocoupling reactions of terminal alkynes and their derivatives 1125
1.21.3.2 Addition Reactions of Alkynyl Carbanions 1127
1.21.3.2.1 Addition to carbon–carbon multiple-bonded functions 1127
1.21.3.2.2 1,2-Addition to carbon–oxygen double-bonded functions 1128
1.21.3.2.3 1,2-Addition to carbonchalcogen double-bonded functions 1134
1.21.3.2.4 1,2-Addition to carbonnitrogen multiple-bonded functions 1135
1.21.3.2.5 1,2-Addition–elimination reactions 1138
1.21.3.2.6 1,4-Addition reactions 1141
1.21.3.3 Substitution Reactions of Propargyl/Allenyl Carbanions 1143
1.21.3.3.1 Substitution of halogen 1143
1.21.3.3.2 Substitution of oxygen functions 1145
1.21.3.4 1,2-Addition Reactions of Propargyl/Allenyl Carbanions 1146
1.21.3.4.1 1,2-Addition to carbonoxygen double-bonded functions 1146
1.21.3.4.2 1,2-Addition to other carbonchalcogen double-bonded functions 1151
1.21.3.4.3 1,2-Additions to carbonnitrogen multiple-bonded functions 1151
1.21.3.4.4 1,2-Addition–elimination reactions 1152
1.21.3.4.5 1,4-Addition reactions 1152
1.21.4 ALKYNES BY CC BOND FORMATION 1153
1.21.4.1 Elimination Reactions 1153
1.21.4.1.1 Elimination of carbon functions 1153
1.21.4.1.2 Elimination of halogen 1154
1.21.4.1.3 Elimination of oxygen functions 1158
1.21.4.1.4 Elimination of sulfur, selenium, or tellurium functions 1160
1.21.4.1.5 Elimination of nitrogen functions 1161
1.21.4.1.6 Elimination of phosphorus, arsenic, antimony, or bismuth functions 1164
1.21.4.1.7 Elimination of boron, silicon, or germanium functions 1164
1.21.4.1.8 Formation by isomerization reactions 1165
1.21.1 INTRODUCTION
Traditionally alkynes have been of considerable value to the organic chemist by virtue of the fact
that they may be readily transformed into a variety of other functional groups. In recent years,
1083
1084 Alkynes
however, their importance has intensified as novel applications of alkynes have been described
including those with antitumor activity <2000JNP1511>, cytotoxic activity <2003BMCL877>,
carbon-rich materials <1996T4925>, and solid-state materials possessing technologically useful
properties <1997CRV637, B-1995MI001>. Concomitant with this has been an increase in inno-
vative methods for the introduction of the alkynyl moiety into organic molecules and these are
discussed when appropriate.
The aim of this chapter is to provide the reader with an up-to-date review of current methods
for the formation of alkynes. This will be undertaken by adopting the format used in COFGT
(1995) <1995COFGT997> and focusing upon the preparation of alkynes via CH bond forma-
tion (Section 1.21.1), CC single bond formation (Section 1.21.2), and triple bond formation
(Section 1.21.3).
1.21.2 ALKYNES BY CH BOND FORMATION

As a rule, the synthetic organic chemist is more concerned with the application of terminal
alkynes for the formation of carboncarbon bonds to provide alkynyl derivatives. Historically,
a number of early papers have described methods for the reduction of alkynyl-heteroatoms to
terminal alkynes and these have been discussed previously <1995COFGT997>. Most recent
efforts have been directed toward the development and removal of terminal alkyne protecting
groups and deuterium quenching experiments.
1.21.2.1 Reduction of Alkynylcarbon Functions

As an improvement to existing methods for the synthesis of p-ethynylaniline, 2-propanol was
employed as a protecting group in 4-(N-(trifluoroacetyl)anilin-4-yl)-2-methyl-3-butyn-2-ol 1. The
trifluoroacetamido linkage was found to be a very effective blocking group for p-iodoaniline
during the coupling reaction. In addition, both the hydrolysis reaction and the deprotection of the
2-hydroxypropyl protecting group occurred simultaneously to afford the desired product in
excellent yield and with high levels of purity (Equation (1)) <1994JOC5818>.
CH3
KOH (2.5 equiv.)
HO C C C NHCOCF3 HC C NH2
Isopropyl alcohol ð1Þ
CH3 reflux, 2.5 h,
1 98%
1.21.2.2 Reduction of Alkynyl-metalloid Functions

Alkynyl silanes have proved to be versatile reagents in organic synthesis by virtue of their stability and
have been widely employed to protect terminal alkynes from organometallic reagents
<B-1983MI002>. As a consequence of this, a variety of reagents to effect the corresponding proto-
desilylation reaction have been discovered. Cleavage of the alkynylsilicon bond is an important
reaction in organic synthesis and provides access to a methodology for selectively functionalizing
terminal alkynes. Tetrabutylammonium fluoride, in diethyl ether, has been used to effect the
protodesilylation of alkynyl-TMS and alkynyl-TIPS moieties <2000T4951>, in tetrahydrofuran
(THF) to deprotect an alkynyl-TIPS group <2000TL2339>, and in ethane-1,2-diol for an alkynyl-
TMS moiety <2000JA939>. A regioselective protodegermylation of the diprotected alkyne 2 was
achieved using catalytic cuprous bromide in THF/MeOH to afford 3 <1996TL7959>. Alternatively,
the corresponding protodesilylation reaction was achieved to afford 4 using potassium fluoride in
THF and 18-crown-6 (Equation (2)).
Alkynes 1085
SiMe3
CuBr (cat.)
THF/MeOH
SiMe3 90%
3
H
ð2Þ
H
KF/ 18-c-6
2 aq. THF
GeMe3
88%
4
GeMe3
Other protodesilylating reagents that have been employed in recent years include potassium
hydroxide in methanol <2001JOM19>, sodium hydroxide in aqueous methanol <1995TL5167>,
ammonium fluoride <1995TL5167>, potassium carbonate <2002T10197, 1999TL3347,
2001TL3057, 2002T10387, 2003JOM17> caesium fluoride in dimethylformamide (DMF)/
MeOH <1997HCA2215>, and the silver nitrate/sodium iodide couple <2000T2183>. This parti-
cular set of reaction conditions has been observed to effect the regioselective protodesilylation of
a triple bond in the presence of a silyl enol ether <1987TL3923>. The cleavage of alkynylgerma-
nium bonds has been accomplished under acidic conditions <1997HCA2215>.
1.21.2.3 Reduction of Alkynyl-metal Functions

During recent studies in the generation and reactions of alkynylsamarium reagents, THF was
found to be the solvent of choice <2000T9927> and that these organometallic reagents coupled
with ketones in good yield using either Barbier or Grignard methodologies <1999CRV745>. The
samarium Grignard reaction (SGR) produced superior results and quenching of alkynylsamarium
reagents with D2O led to a 60% incorporation of deuterium at the terminal sp-carbon atom.
Analogous deuterium quenching experiments of alkynylsamarium species have been reported
<1995TL3707>. A Pd(0)–olefin complex that catalyses the alkoxycarbonylation of terminal
alkynes has been developed. Exposure of a terminal alkyne to CH3OD in the presence of this
catalyst led to a hydrogen/deuterium exchange (Equation (3)) <2001JMOC51, 1998OM630>.
H R
N
Pd ð3Þ
P
Ph
Ph
Ph H + CH3OD Ph D + CH3OH
1.21.3 ALKYNES BY CC BOND FORMATION

A variety of methods have been described for the preparation of alkynes that involve the
chemistry of substitution reactions, addition reactions, and addition/elimination reactions. A
number of noteworthy reviews have been published on acetylenic coupling reactions
<2000AG(E)2632>, alkylation reactions of alkynes <2002CCR171>, palladium–copper-cata-
lyzed cross-coupling reactions <2002JOM46, 1995OPP127>, palladium-catalyzed reactions on a
solid phase <2003T885>, the chemistry of the carbon–transition metal double and triple bond
<2002CCR1>, the 1,1-organoboration of alkynylsilicon, -germanium, -tin, and -lead compounds
<1995CCR125>, organozinc-mediated reactions <1998T8275>, luminescent polynuclear metal
acetylides <1999JOM3>, and the chemistry of platinum–alkyne complexes <2000JOM37>.
1086 Alkynes
1.21.3.1 Substitution Reactions of Alkynyl Carbanions

The synthesis of alkynes may be accomplished by the reaction of an alkynyl carbanion with an
alkyl halide (Section 1.21.2.1.1.(i)), by the reaction of a terminal alkyne or an alkynyl organometallic
reagent with an alkenyl, aryl, or allenyl halide (Section 1.21.2.1.1.(ii)) and from the formal substitution
reaction of an alkynyl halide (Section 1.21.2.1.1.(iii)).
1.21.3.1.1 Substitution of halogens
(i) The reaction of alkynyl carbanions with alkyl halides

The formation of Csp–Csp3-bonds tends to follow traditional ionic methodologies <1991COS3,
1997MI129> and may be readily accomplished by deprotonation of a terminal alkyne followed by
the reaction of the resulting alkynyl carbanion with a suitable alkyl halide. This method tends to be
limited to the alkylation of primary unhindered alkyl halides. Attempted alkylation reactions with
secondary, tertiary, or sterically hindered primary alkyl halides have a propensity to afford elimina-
tion products. The traditional methods for the formation of alkynyl metals derived from lithium,
sodium, potassium, and magnesium have been described <1995COFGT1000>. In general, these
methods are still in common practice and have been reviewed <B-1988MI003, B-1978MI004,
B-1983MI005, 2003JOM151>. Methods of avoiding undesired side-reactions associated with the high
reactivity and strong basicity of these reagents have been revealed <B-1981MI006>. Considerable
interest has been directed at finding alternative reagents and solvents for overcoming the problems
associated with the low solubility of the alkynyl carbanions, in liquid ammonia, as well as the variable
yields that result when this solvent is used <B-1955MI007>. The use of hexamethylphosphoramide
(HMPA) as a dipolar aprotic co-solvent, for facilitating the reaction between alkynyl anions and the
alkylating reagent, fell in popularity when the dangers associated with its use were highlighted.
Alternative reagents to HMPA, such as N,N-dimethylpropyleneurea (DMPU) in DMSO
<1988S250>, have been revealed but its use is limited to applications involving acid-stable alkynes
<1986TL5445>. Recent reports have highlighted the use of Grignard reagents <1995S299>, weak
bases such as morpholine <1997HCA2215>, as well as continued interest in alkyllithium reagents
<2001TL5825, 1999JOM223>, in THF for deprotonation of terminal alkynes. Despite the hazards
associated with the use of HMPA in the generation of alkynyl carbanions, this reagent has recently
regained its popularity in syntheses <2000SC1895, 1999EJO2167, 1999OL845, 2000TL4801,
1996T157, 1997JOC3332, 1999JOC5732>. When the alkylating reagent is particularly reactive, the
need for a co-solvent has been reported to be unnecessary and exposure of alkynyllithium reagents
with iodomethane <1999JOM223> or with an allylic halide <2000T7123> in THF affords the
alkylation product. Some recent representative examples are shown (Equations (4)–(9)).
OTHP
i. BunLi
ii. Br(CH2)5OTHP,
ð4Þ
HMPA/ THF, –78 °C 5
75%
CO2H
i. BunLi
Me
ii. Br(CH2)7CO2H,
OH HMPA/THF, –90 °C to rt ð5Þ
54% Me
OH
6
Me
i. BunLi
OTBDMS
ii. MeI OTBDMS
ð6Þ
90%
7
Alkynes 1087
() OTBDPS
7
( )3 BunLi, I(CH2)8OTBDPS ( )3
ð7Þ
THF/DMPU, –78 °C
N 48% N
8
Me
Br Me OTBDPS
i. BunLi, THF, –78 °C ð8Þ
OTBDPS
Br ii. MeI, –78 °C to rt
Me
84% 9
Me Me
Cl
TIPSC CMgBr
Me SiMe3 ð9Þ
Me CuCl/THF, reflux, 2 h
90% Me3Si TIPS
10
The synthesis of 5, a substrate in the synthesis of linear enediynes for cobalt-mediated [2+2+2]-
cycloadditions, was achieved by the monoalkylation of 1,7-octadiyne (Equation (4)) <1999TL707>
using a lithiation reaction in THF, as solvent, with HMPA as a co-solvent. The ether 5 was formed
in 75% yield and 12% of the product arising from dialkylation. Analogous reaction conditions have
been employed in other syntheses including a stereocontrolled synthesis of (+)-lycoperdic acid, a
novel neurotoxin <2000TL4801>, as well as a recent approach to the alcohol 6, a key intermediate
in a novel synthesis of (S)-coriolic acid (Equation (5)) <2000T327>. The methylation reaction of
the ether (Equation (6)) <2002TL2725> was carried out in the absence of HMPA to provide 7 in
90% yield. The synthesis of compound 8 (Equation (7)) <2003T1719> serves to emphasize the use
of DMPU as a co-solvent in conjunction with THF. The authors noted that the best yield (48%)
was only obtained by modification of the known procedure <1988S250>. This involved the
addition of DMPU to the reaction mixture prior to the addition of BunLi. The yield was only
optimized by varying the quantities of the iodide, DMPU, and BunLi used during the reaction.
Using a method developed by Corey <1972TL3769> for the in situ synthesis of terminal alkynes by
the exposure of the vinyl dibromide with BunLi, the ether 9 was prepared (Equation (8))
<2001TL3649>. Although this transformation was conducted at 78 C, the use of a co-solvent
was not necessary. The pentadiyne 10 (Equation (9)) <2000T9581> served as a precursor in the
synthesis of one of several macrocyclic enediynes that were used as probes in Bergman–Miles
cyclization reactions. Noteworthy was the deprotonation reaction of triisopropylsilylacetylene
with a Grignard reagent, the addition of CuCl prior to reaction of the alkynyl carbanion with
the chloride and that the substitution reaction was conducted at reflux. An investigation into the
synthesis of analogs for topostin B, an DNA topoisomerase 1 inhibitor, serves as a good example of
solvent dependency during the alkylation of lithiated alkynes (Equation (10))
<1998T551,1998T565>. Attempts at the alkylation of the lithiated derivative of 11 were thwarted
using THF–HMPA as the solvent. When the reaction was repeated having evaporated hexane from
the reaction mixture, originating from the butyllithium, a low yield of 12 resulted. The yield of this
reaction was optimized, however, by using a diethylether–HMPA solvent system. Addition of the
alkyl halide to the lithiated alkyne derivative of 11 was followed by removal of the volatiles by
evaporation. Normal work-up then provided 12 in an acceptable yield.
O i. BunLi O
O ii. Br(CH2)nMe O ð10Þ
HO (CH2)2C CH HMPA, –10 °C HO (CH2)2C C(CH2)nMe
11 >80% 12
-Fluoroalkylphosphonates have aroused considerable interest as selective fluorinating agents

<B-1996MI006, 1996T8619, 1996CC1447> and for their use in the study of biological phosphate
mimics <2000JBC4783, 1999BJP1419, 1997BP255>. In a recent study on the suitability of
1088 Alkynes
candidate molecules for the formation of ,-unsaturated -fluorinated phosphonates, the

difluoroalkyne 13 was revealed (Equation (11)) <2001JFC127>. The optimized method involved
a CuCl/Cd-promoted coupling reaction, pioneered by Burton <1996TL2745>, between a readily
available diethylbromofluoromethylphosphonate with 1-iodo-3-TIPS ethyne. This compound was
generated, in situ, by the lithiation of triisopropylsilylacetylene in THF at 78 C.
CuCl/Cd CF2P(O)(OEt)2
(EtO)2P(O)CF2Br + TIPS I TIPS
DMF, rt ð11Þ
67% 13
Burton’s own attempt at the synthesis of ,-difluorophosphonates focused upon the genera-
tion of stable organometallic reagents based upon (EtO)2P(O)CF2M (M = Zn 14, Cd, and Cu)
followed by reaction with electrophiles including alkynes (Equation (12)) <2002JFC15>. The
direct coupling of the zinc organometallic reagent 14 with alkynyl halides to afford 15 takes place
rather slowly; however, significant rate enhancements have been observed when stoichiometric
amounts of Cu(I)Br were added with the haloalkyne. This presumably facilitates the coupling
reaction by formation of the (EtO)2P(O)CF2Cu reagent in situ. The choice of solvent was
important for the success of the coupling reaction; thus, although DMF and dimethyl aluminum
chloride (DMAC) stabilize the (EtO)2P(O)CF2Cu reagent, the presence of accompanying side-
reactions complicated the reaction. Optimum, but variable, yields were obtained in THF as the
solvent. The authors noted that bromoalkynes provided higher yields of propargyl phosphonates
than the corresponding iodoalkynes as a result of a reduction in the amount of metal/halogen
exchange.
CuBr, THF
(EtO)2P(O)CF2ZnBr + R I (EtO)2P(O)CF2C CR
5 °C to rt ð12Þ
14 32–61% 15
The reactions of lithiated alkynes with primary alkyl halides tends to be viewed as low-
temperature reactions; however, studies on the alkylation of 1-alkynes in THF at elevated
temperatures have recently been reported (Equation (13)) <2001TL5825>.
i. BunLi , THF
R I R R′ ð13Þ
ii. R′X, ∆
50–95%
When conducted at ambient temperatures, coupling reactions were slow, although heating the
reaction mixture to a reflux temperature led to complete reaction in 8 h. Reactions involving
bromoalkanes were slower than with the corresponding iodides and in some examples the
reactions did not continue to completion, although the addition of catalytic amounts of tetra-n-
butylammonium iodide or NaI significantly increased the rate of reaction. The formation of
iodide from bromide, in situ, is expected to promote the SN2 reaction; however, this had no effect
when carried out with primary alkyl chlorides.
Skipped 1,4-diynes, such as 16, serve a useful role as precursors in the synthesis of materials,
fatty acids, and as hydrocarbon equivalents of 1,2,4,5-pentatetraols. Of the numerous methods
devised for their synthesis, the reaction between metal alkynyl reagents and propargylic electro-
philes receives the most attention <2003JOM151>. As a general observation lithiated and
magnesium alkynyl reagents couple with propargyl halides in low-to-moderate yielding reactions
<1995JOC218>. The corresponding bimetallic derivatives based upon a magnesium/copper
system have, however, been shown to couple with primary propargyl halides to afford 1,4-
pentadiynes using either stoichiometric or catalytic conditions <1995AG(E)805, 1995TL147>.
Using stoichiometric quantities of copper requires the use of HMPA as co-solvent in order to
dissolve the copper salts that otherwise precipitate from the solution. Under catalytic conditions
optimum yields are obtained using THF as solvent. Work-up procedures must avoid acidic and
basic media in order to circumvent potential isomerization of the skipped diyne to an allenyne.
The coupling reaction has been successfully accomplished with various CuX species. With regard
to the propargyl halides the leaving groups employed have been iodide <1995JOC218>,
bromide <1995T4359, 1997JOM211, 1998JOC337, 2001JOM94> and chloride <2000T9581>
(Equation (14)).
Alkynes 1089
R R
R
CuX (cat.), THF
R1 R + BrMg R2 ð14Þ
X = Cl, Br, I, CN
X 53–98% R1 R2
X = Cl, Br, I, OTs 16
In most syntheses of skipped diynes, the propargyl halide partners are primary halides (R = H);
however, couplings involving tertiary propargyl chlorides (R = Me) have been demonstrated as
shown for the one-pot synthesis of the diyne 17 involving the substitution of the bispropargylic
dichloride with alkynyl Grignard reagents (Equation (15)) <1994JA10275>.
R R
R R
+ 2 BrMg CuCl (cat.) OP
R R THF ð15Þ
Cl Cl OP PO
36–89%
R = H, Me R R
17
As long ago as 1992, the feasibility of coupling terminal alkynes directly, to afford diynes such
as 18 (Equation (16)), in the absence of a strong metal–alkyl base was first highlighted
<1992T5757>. Reversible deprotonation is facilitated by the presence, in situ, of sodium carbo-
nate. Improvements in the yield of the reaction have been demonstrated by using tetra-
butylammonium chloride <1996T6635>. The exact role that it serves has yet to be elucidated;
however, the use of TBAF appears as efficacious affording the diyne 19, an arachidonic acid
analog (Equation (17)) <1998TL771>, in 75% yield.
CuI, Na2CO3
R + H R1 ð16Þ
X Bun4NCl, DMF, rt R R1
76–91% 18
CuI/Na3CO3 OTBDMS OH
TBDMSO + H
Br OH [Bu4nN][I] ð17Þ
DMF, rt 19
75%
A comprehensive study, carried out in 1998 (Equation (18)) <1998S1015>, concluded that
regioselectivity, in terms of the propargylic–allenic coupling ratios, (20a:20b), depends upon a
range of criteria. These include the nature of the copper salt, the temperature of the reaction
mixture, the nature of the leaving group, and the necessity for DMF as solvent. Although the
reaction may be conducted in water, using stoichiometric copper, in acceptable yields the work-up
is arduous. The mild reaction conditions are compatible with a comprehensive range of substrate
substituents. Using NaI, as an alternative to TBAI <1993S65>, provided the triyne 21 (Equation
(19)) <1998TL621, 2000T8083> with no loss in yield for the coupling reaction.
HO
CuI (0.5 equiv.)
K2CO3, NaI HO OMe
+ Cl
DMF, rt 20a
H ð18Þ
OMe 86% MeO
OH
20b
20a /20b = 92 /8
CuI, K2CO3 OH
Br
+ NaI, rt
80%
ð19Þ
H
OH 60%
21
1090 Alkynes
Recent examples report the use of a high-yielding caesium–copper system for alkynyl–propar-
gyl couplings, in the presence of NaI (Scheme 1) <2002TL1681, 2002TA2071>. The enyne 22 was
obtained from the coupling of trimethylsilylacetylene and trans-1-bromo-2-pentene in 60% along
with the isomeric product 23. Sharpless enantioselective dihydroxylation of 22 <1992JOC2768>
provided the diol 24 in an impressive 95% yield and an enantiomeric excess of 85%. The diol 24
was then efficiently coupled to the bromo-derivative diyne 25, using the same experimental
reaction conditions for the coupling reactions, to afford triyne 26, a key precursor in the first
total synthesis of natural aplyolides C and E.
Cs2CO3, OH
TMS AD-mix α,
Br CuI, NaI ButOH–H2O 1:1
DMF, 20 h
+ 22 CH3SO2NH2,
60% OH
TMS + 0 °C, 20 h
TMS 95% 24
23 85% ee
30%
Cl OH Cs2CO3, CuI, NaI OH O

+ O
DMF, 20 h
90% OMe
OMe
25
O
Cs2CO3, CuI, NaI OH
24 + 25 OMe
DMF, 20 h
88%
OH 26
Scheme 1
Other workers have reported the first total synthesis of (–)-aplyolide A (Scheme 2)
<2001TA1407>. The partial reduction of the diyne, 27, and bromination provided diene 28
containing two of the skipped double bonds found in the natural product. The authors used
MeO2C K2CO3, CuI

+ OH
NaI, DMF MeO2C
Cl 27
OH 88%
Br
MeO2C
28
TMS
OAc
Br K2CO3, Cul
+
TMS
OAc NaI, DMF
82%
29
OAc
i. P-2 Ni, H2, EtOH
ii. Bun4NF, DMF
69% 30
OAc
K2CO3, CuI
28 + 30 NaI, DMF MeO2C
80%
31
Scheme 2
Alkynes 1091
analogous coupling conditions to provide the diyne 29 in good yield. This then underwent stereo-
and regiospecific reduction of the internal alkyne to afford the enyne, 30. Coupling between the
diene 28 and the enyne 30 was accomplished efficiently again exploiting the same experimental
methodology.
One of the few examples of a coupling reaction between crotyl chloride 32 and a terminal
alkyne was used in a reported total synthesis of ()-kumausyne (Equation (20)) <1997T2835>.
The Jeffery coupling reaction is a Cu(I)-catalyzed allylic substitution of (un)substituted allyl
halides by 1-alkynes <1989TL2225>. The propargyl alcohol and the allylic chloride 32 coupled to
afford the enyne 33 (Equation (20)). This was subsequently transformed either to an (E),(E)-
dienol using LAH or to an (E),(Z)-dienol using a Lindlar catalyst. The reported yields for both
coupling reaction and the reductions were 52%; however, the authors failed to comment whether
the isomeric product, analogous to 23, was formed. To conclude this section on coupling
reactions, the reader is directed to the following review on enediynes, enyne, and related com-
pounds <1996T6453>.
OH
Bu4NCl, CuI OH
+ K2CO3 ð20Þ
Cl 52% 33
32
(ii) Substitution reactions of alkenyl, allenyl, or aryl halides

The palladium-catalyzed coupling reaction between an aryl halide/tosylate and a 1-alkyne has
become an established method for the synthesis of alkynes and has been the subject of several
recent books and reviews <B-1998MI008, B-1995MI009, B-1998MI010, B-2002MI012,
2001YGK607, 2000CCR199, 1999JOM305>. Couplings are traditionally achieved by the reaction
of an alkenyl (Equation (21)), allenyl (Equation (22)), or aryl halide (Equation (23)) with a
terminal alkyne or with the corresponding alkynyl organometallic reagent.
R2
R Hal R4 ð21Þ
+ (H) Met R4 R1
R1 R2 R
R2
R4
R Hal ð22Þ
+ (H) Met R4
R1 R2 R1
R
R4
Hal ð23Þ
(H) Met R4 R
R +
The need for a bimetallic palladium–copper-catalyzed couple for these cross-coupling reactions
can impose limitations in their use especially with regard to industrial scale-up where the need for
1–5 mol.% of palladium has warranted the development of costly recycling processes. Further-
more, the development of solid support cross-coupling reactions has highlighted the incompat-
ibility of copper which, in examples using heteroatom linkers, has been shown to contaminate the
final products <1999TL6201, 2002BMC2415>. The development of copper-free cross-coupling
reaction conditions has been an ongoing process in an effort to reduce ‘‘Glaser’’ type homocou-
pling reactions between copper alkynides in the presence of oxygen <2000AG(E)2632>.
(a) Reaction of terminal alkynes with aryl, alkenyl, and allenyl halides/triflates in the presence of
catalytic palladium(II) or palladium(0) compounds in the absence of a copper co-catalyst. The first
to report the use of copper-free cross-coupling reaction conditions under palladium catalysis was
Linstrumelle (Equation (24)) <1993TL6403>, who was able to effect the synthesis of conjugated
1092 Alkynes
enynes and aryl alkynes in high yield by the reaction of terminal alkynes with vinyl and aryl
halides/triflates in piperidine or pyrrolidine, as solvent, in the presence of tetrakis(triphenylpho-
sphine)palladium.
Pd(PPh3)4
R1X + R2 Piperdine or R1 R2
pyrrolidine
R1= Vinyl, aryl ð24Þ
65–82%
R2 = C5H11, CH2OH,
(CH2)2OH, (CH2)2CO2Me
X = Br, I, OTf
Although the palladium-catalyzed cross-coupling reaction of aryl/vinyl triflates with terminal

alkynes provides an alternative to the use of the corresponding halides <2000OL2291,
1996TL605> vinyl tosylates are generally regarded as too inactive <2000TL2741>. The successful
copper-free coupling of vinyl tosylates with terminal alkynes has, however, recently been high-
lighted (Equation (25)) <2002TL6673>. Excellent conversions were recorded which took place
readily at ambient temperatures. The authors extended their investigations to successfully couple
the tosylate 34 with a range of terminal alkynes to afford derivatized coumarins 35 in good-to-
excellent yields (Equation (26)).
O O
Pd(OAc)2 (1.5 mol.%)/PPh3 ð25Þ

+ R DMA/DMF/Et3N, rt
TsO 77–100%
R
OTs
Pd(OAc)2 (1.5 mol.%)/PPh3
+ DMA /DMF/ Et3N, rt ð26Þ
R
O O 59–75%
O O
34
35
Cross-coupling reactions, under copper-free conditions, are often conducted at elevated tem-
peratures <1975JOM253, 1975JOM259> using either piperidine or pyrrolidine as base and
Pd(PPh3)4 as the catalyst <1993TL6403>. The presence of water-soluble ligands, however,
permits the reaction to take place in water or an aqueous solvent mixture. A copper-free Jeffery
reaction <1985TL2667, 1994TL3051, 1994TL4103> involving the catalytic Pd(OAc)2 coupling of
terminal alkynes with aryl halides under phase-transfer conditions was reported (Equation (27))
<1996TL5527>. When the coupling reaction was conducted using halides with electron-donating
substituents, a slight reduction in yield and extended reaction times were observed. Heterocyclic
bromides such as bromopyridine and bromothiophene coupled efficiently using lower amounts of
catalyst (2.5 mol.%) without poisoning or deactivating the catalyst although slightly longer
reaction times were reported.
Br Pd(OAc)2(cat.)/PPh3
S
R Bu4HSO4/ TEA
or + Ar R
Hal
R = Ph, HO(CH2)4 CH3CN/H2O (10:1), 25 °C
ð27Þ
62–92%
Y X CH2–
Hal = I or Br,
X = N or C
Y = H, NO2 or OCH3
Alkynes 1093
Palladium-catalyzed coupling of alkynes with iodoarenes or iodothiophenes, in the presence of

diaryliodonium salts in water, was reported (Equation (28)) <1996TL897>. Although the cou-
pling reactions described were conducted using 2 mol.% of cuprous iodide, the coupling of
p-iodonitrobenzene with phenyl acetylene occurred in a yield of 93% without CuI although the
reaction took longer to complete.
PdCl2 (PPh3)2 (1 mol.%)

CuI (2 mol.%), K2SO3, H2O
ArI + R H R Ar ð28Þ
Bu3N (10 mol.%), 60 °C
70–98%
It was suggested that the reaction proceeds in two steps (Scheme 3).
i. Ar2IX + PhC CH Phc CAr + ArI + [HX]

ii. ArI + PhC CH Phc CAr + [HI]
Scheme 3
For insoluble reagents aqueous DMF may be used which also facilitates the rate of reaction;
however, in most examples the reaction took place in water in the presence of K2CO3 and
10 mol.% Bu3N.
The use of an air- and moisture-stable phospha-palladacycle catalyst for the facile coupling of
aryl bromides with alkynes has been reported <1996JMOC51, 1999JOM23, 2000EJO3679>.
Although the catalyst was found to be very durable, without forming palladium black, the
coupling reaction itself was solvent dependent for triethylamine and optimum yields were only
obtained using phenyl acetylene as the sp-coupling partner. However, a copper- and amine-free
coupling procedure has been developed that uses an oxime-based palladacycle shown to be an
effective air- and water-stable precatalyst in a wide range of cross-coupling processes in organic
solvents <2000OL1729, 2000OL1823, 2002JOC5588> as well as in aqueous solvents
<2002AG(E)179, 2002JOM46>. The palladacycle 36 (Equation (29)), derived from 4,40 -dichloro-
benzophenone, effectively catalyzes the cross-coupling reaction between a range of aryl and
naphthyl halides and terminal alkynes in very high yields and with a high catalyst turnover
number <2002TL9365>. Optimized reaction conditions identified tetra-n-butylammonium acet-
ate (TBAOAc) as the best additive, with catalyst loadings as low as 0.1 mol.%, providing excellent
couplings using reagent-grade chemicals. N-Methyl-2-pyrrolidone (NMP) and NMP/water mix-
tures serve equally well as solvent with organic solvents such as THF requiring longer time for the
reaction to go to completion and affording lower yields of coupled products.
C6H4-p -Cl
X N OH
+ R1 H Cl Pd R1 ð29Þ
36 R
R Cl
)2
NMP, TBAOAc, 110–130 °C
79–100%
Reactions, conducted on a polymer support, have come into prominence in recent times for the
synthesis of molecules for high throughput screening using combinatorial techniques
<1996AG2436, 1996AG(E)2289, 1996T4527>. The benzylaminomethylpolystyrene-supported
triazene 37 (Scheme 4) underwent a palladium-catalyzed cross-coupling reaction with four differ-
ent alkynes to afford o-alkynyl aryl resins. Previously it was shown that the diazonium group,
formed upon cleavage from the resin, was lost as dinitrogen. In solution, however, in the presence
of a suitable nucleophilic o-substituent cyclization occurs to afford heterocyclic compounds
<B-1994MI011>. Thus, cleavage <1995LA775> using aqueous hydrogen chloride or hydrogen
bromide in acetone provided the cinnolines 38 in good-to-excellent yields <1999TL6201,
2002BMC2415>. The absence of copper, from the coupling reaction, was crucial in order to
prevent coordination to the triazene moiety. This coordination tended to afford contaminants in
the final product.
1094 Alkynes
N Ph N Ph
N N N R
R H N N
N R HY, acetone/H2O
Pd(OAc)2, NEt3
47–95% Y
X DMF, 80 °C, 12 h overall R1
R1 R1
X = Br, I Y = Br, Cl
37 38
Scheme 4
One of the first reports to describe the successful cross-coupling reaction between an ethynylox-
irane 39 and alkenyl triflates involved treatment of the substrates with tetrakis(triphenylphosphi-
ne)palladium in the presence of silver salts (Equation (30)) <1996TL2019>. Attempts to effect the
cross-coupling reaction using either copper as a co-catalyst or [Pd(OAc)2(PPh3)2] as the catalyst
<1986S320> proved to be a very inefficient method providing the epoxyenyne 40 in yields of 25%
and 45%, respectively, accompanied by considerable decomposition of compound 39.
OTf
OTBDMS Pd(PPh ) (10 mol.%)
3 4
+ O ð30Þ
O AgI (20 mol.%), DIPEA
DMF, 20 h, rt
39 78% 40 OTBDMS
Although silver iodide was shown to be the most effective co-catalyst for these coupling
reactions, silver nitrate, silver carbonate, and silver triflate were also effective but less efficient.
The use of vinylic tellurides in the copper-free cross-coupling reaction with terminal alkynes has
been highlighted as a method for the synthesis of alkynyl furans <2001TL8927, 1995SL1145>
and symmetrical/unsymmetrical alkynyl thiophene derivatives (Scheme 5) <2001TL7921,
2003TL685>. A range of catalysts, co-catalysts, and solvents were examined for their suitability
in the cross-coupling reactions involving these heterocycles with palladium(II) chloride
(20 mol.%) proving to be the best. Copper salts were shown to have little effect and triethylamine
as base and methanol as solvent provided optimal yields. Metallation of thiophene 41 and
treatment of the dilithio-derivative with elemental tellurium and n-bromobutane gave 42 in
excellent yield. Exposure of 2,5-bis-(butyltelluro)thiophene 42 with an excess of alkyne and
catalyst provided the symmetrical alkynyl derivative 43. Alternatively, by using 1 equiv. of both
42 and a terminal alkyne gave 44 in good yield. This compound could then furnish the unsymme-
trical alkynylthiophene derivative 45 upon exposure to the appropriate experimental conditions.
For an additional contribution in this area, see <2001OL4295>.
R
i. BunLi, hexane
H
TMEDA
BuTe S TeBu PdCl2, MeOH S
S ii. Te (2.5 equiv.)
41 iii. BunBr 42 Et3N, 25 °C R R
75–89% 43
95%
72–86% R1
H
S TeBu
PdCl2, MeOH S
R
Et3N, 25 °C R R1
44 65–78% 45
Scheme 5
(b) Reaction of terminal alkynes with aryl, alkenyl, and allenyl halides in the presence of a copper
co-catalyst. The Castro–Stephens reaction provides a method for coupling unactivated aryl
iodides with, in some examples, stoichiometric copper(I) alkynides without a palladium complex
Alkynes 1095
catalyst <1963JOC2163, 1963JOC3313>. The early developments in this area have been compre-
hensively discussed <1995COFGT1000>. Other examples of this chemistry reveal the use of
potassium carbonate as a base with catalytic copper and triphenylphosphine <1993JOC4716>,
catalytic copper with Aliquat-336 and 30% NaOH <1992JOC2188>, and the use of a
CuI:NaI:K2CO3 mixture (1:2:2) <1993S65>. It should be noted, however, that in the alkali
media required to effect these palladium-free coupling reactions, isomeric enynes and allenes
are observed. As a result, a variety of modifications, to the original experimental procedures,
have been developed with the aim of improving the compatibility of this reaction for molecules
that contain other diverse and sensitive functionality <1975TL4467, 1985TL3811>.
A catalytic tetrakis(triphenylphosphine)-palladium(0) and substoichiometric CuI to effect the
Castro–Stephens coupling between vinylic/allylic silanes and propargylic/homopropargylic alco-
hols has been used to provide access to polyunsaturated silanes <1995S299> (Equation (31)).
R
R2 R3 Pd(PPh3)4 (5 mol.%) R R2 R3
CuI (20 mol.%) or
TMS(CH2)n ð31Þ
TMS(CH2)n R1 BunNH2 (2 equiv.) TMS(CH2 )n
R1, R2, or R3 are DMF, 0.5–15 h, rt R
either H or halogen 42–90%
The copper alkynide was generated, in situ, by reaction of the terminal alkyne with a mixture
of copper(I) iodide in DMF in the presence of the palladium catalyst and base. Although
vinyl bromides gave good results, vinyl iodides exhibited higher reactivity. Interestingly, the coupling
reaction proved very efficient for the reaction between bromovinyl silane (R2 = R3 = H) and
the alkyne (R = H) (86%) compared to reaction with the ethoxyethyl-derivatized alkyne
(63%). Unprotected propargyl and homopropargyl alcohols appear to facilitate the coupling
reaction with vinyl halides.
The reagents used in this reaction were compatible with the cross-coupling of n4-tricarbonyliron
complexes. Thus, exposure of the n4-tricarbonyliron complex 46 (Equation (32)) with various
vinyl halides provided the coupled enediyne 47 in good yields. The coupling reaction was found to
be base sensitive; thus, for example where R = benzyl, the coupling took place efficiently using
n-butylamine, but for more base-sensitive protecting groups, such as the acetate moiety, 1,8-bis-
(dimethylaminonaphthalene), ‘‘proton sponge,’’ was needed to successfully produce the coupled
product in 89% yield.
OCH3
OCH3 (CO)3Fe
(CO)3Fe
TMS(CH2)n Br
Pd(PPh3)4 (5 mol.%) OR
OR CuI (20 mol.%), DMF
ð32Þ
0.5–15 h, rt
89% TMS(CH2)n
46
47
A novel one-pot tandem Castro–Stephens–Suzuki reaction was employed for the synthesis of
the 2-dienylindole 51, a key compound developed for the treatment of osteoporosis
<1998TL9347>. The initial alkynylaniline 48 was synthesized via a Castro–Stephens coupling
reaction followed by a subsequent alkyne deprotection <1994JOC5818> (Scheme 6). Proton
NMR studies conducted upon the product obtained from the Castro–Stephens coupling between
48 and the bromoboronate ester indicated chemoselective coupling to afford 49. Using a mod-
ification to a Suzuki coupling procedure, described by Wright <1994JOC6095>, the boronate
ester 49 underwent transformation to the dienyne 50 in a tandem sequence in a recorded yield of
63% overall yield. Compound 50 readily underwent a palladium-catalyzed cyclization reaction to
afford indole, 51, in an excellent 90% yield.
1096 Alkynes
OH Cl Br
i.
Cl I B(OPri)2
CuI, Cl2Pd(PPh3)2 CuI (5 mol.%)
Et3N Cl NH2
Cl NH2 Cl2Pd(PPh3)2 (2.5 mol.%)
ii. NaOBut, ButOH Et3N in THF
72% 48
B(OPri)2 CO2Me
Cl
Cl
PhI, 3 M K3PO4
OMe
DMF, Pd2dba3
Cl NH2 Cl
50 °C NH2
63%
49 50
CO2Me
Pd(CH3CN)2Cl2 (10 mol.%) Cl
DMF, 70 °C OMe
Cl NH
90%
51
Scheme 6
In general Castro–Stephens coupling reactions succeed only with aryl bromides, iodides, and
triflates as the sp2-partner, with aryl chlorides proving to be relatively unreactive toward oxidative
insertion of Pd(0) into the CCl bond. Exploiting the known mobility of 2-halogens in quino-
lines, however, allowed successful couplings to occur with a range of 2-chloroquinolines
(Equation (33)) <1996TL8281>.
R
R
R1
CuI (33 mol.%), N ð33Þ
N Cl Pd(PPh3)4(4 mol.%),
R1
Et3N
20–98% 52
The efficiency in the substitution of chloride, by Cu(I) acetylide, was found to dependent upon
C-3 alkyl substituents. Thus, when R = H, the couplings, to provide 52, were quoted as 50%
(R1 = Bun) but only 20% when R1 = Ph. In contrast to these results for cases when R = Me, the
yields were 98% and 88%, respectively. This enhancement in yield was attributed to a steric
acceleration process during the reductive elimination step from a Pd(II) complex to Pd(0).
(c) Reaction of terminal alkynes with aryl, alkenyl, and allenyl halides/triflates in the presence of
catalytic palladium(II) or palladium(0) compounds, a copper co-catalyst and a base. The palla-
dium-catalyzed cross-coupling reaction between sp2–C halides and terminal alkynes was first
reported concomitantly by Sonogashira <1975TL4467>, Heck <1975JOM259>, and Cassar
<1975JOM253>. Coupling utilizing copper(I) halides, as co-catalysts, in the presence of a base
is commonly known as the Sonogashira reaction. This reaction, which may be formally consid-
ered as an application of palladium catalysts to the Castro–Stephens reaction, has been put to
good use in a wide variety of natural product and heterocyclic syntheses. These have been the
subjects of review articles by the discoverer <2002JOM46> and others <1995OPP127,
1996T6453, 2000CCR199, 1999JOM305> in homogeneous media as well as on polymer supports
<2003T885>.
The development of a palladium–copper bimetallic catalyst facilitates the coupling reaction to
occur under very mild reaction conditions. For instance, in his original studies, Sonogashira identified
the optimal molar ratio between CuI and the palladium catalyst to be at least 2:1 respectively using
triethylamine as both the base and solvent. Under these conditions, the coupling of aryl and vinyl
halides with terminal alkynes was recorded to be very high at ambient temperatures.
From a mechanistic point of view the coupling reaction follows the accepted oxidative addi-
tion–reductive elimination process exemplified by most palladium catalysts. The precise details of
the mechanism, however, are still largely unknown particularly with regard to the structure of the
Alkynes 1097
catalytically active species and the precise role played by the copper co-catalyst. The most
frequently used palladium species is (PPh3)2PdCl2, although both Pd(OAc)2 and (CH3CN)2PdCl2
in the presence of phosphine ligands have also been employed where appropriate. For coupling
reactions involving less reactive aryl and alkenyl halides, attempts have been made to identify
conditions to minimize the side-reactions that often accompany attempted couplings at elevated
temperatures <2000OL1729>.
For the purpose of this review, the effects of the type of catalyst, substrate, base, and solvents
<2000CCR199> on the reaction outcome will be summarized. Representative examples will be
used to emphasize and couplings that generate carbocyclic and heterocyclic alkynyl derivatives in
both solution phase and syntheses conducted upon polymer supports. Developments in the use of
microwave synthesis will be highlighted.
Attempts have been made to improve and optimize the formation of the enyne 54 obtained
from the coupling reaction between an aryl bromide and the protected alkyne 2-methylbut-3-yn-
2-ol 53 (Equation (34)) <2000JMOC77>. The reagents shown were those that provided optimal
results from these investigations and included the choice of the palladium catalyst in combination
with triphenylphosphine. Copper salts were essential for high reaction rates, but interestingly
neither the oxidation state, the counter-ion, nor the presence or absence of water of crystallization
had any effect upon the rate. The choice of amine, which acts as both a solvent and a scavenger of
HBr, was critical as the reaction rate was very solvent dependent. A sum of both electronic and
steric factors appeared to be operating in this system with basic primary aliphatic amine providing
the highest yields in 1 h. With regard to the stoichiometry of reagents, these were optimized as
follows: both aryl halide and alkyne (5 mmol.), the ratio of catalyst (Pd:PPh3:Cu 90.025:0.075:
0.05 mmol, respectively) in 10 ml of amine at 55 C for 1 h.
Pd(OAc)2, PPh3
Br + C(Me2)OH C(Me2)OH ð34Þ
CuI, BunNH2
53 90% 54
The synthesis of the cationic guanidinophosphine ligand 55 facilitated the quantitative and
rapid biocompatible cross-coupling reaction of water-soluble iodoarenes, with terminal alkynes,
in aqueous solution at low temperatures (Equation (35)) <1998TL525>. Interestingly, when the
coupling reaction was repeated in the presence of the enzyme RNAase, the authors not only
observed an enhancement in the kinetics of the reaction, which were accelerated due to hydro-
phobic interactions, but the protein itself was recovered, intact, from the reaction mixture.
H NH2
P N +
N(CH3)2
– N N(CH3)2
OOC I H
+
NH2
55 – – ð35Þ
+ OOC (CH2)nCOO
– Et3N, 35 °C, Pd (5 mol.%),
H (CH2)nCOO
CuI (10 mol.%) , 55 (25 mol.%)
n = 0, 11 H2O/MeCN 7/3
95%+
Palladium-catalyzed coupling reactions have been used to attach fluorescent and enzymic
labels, containing terminal alkynyl moieties, with a range of biological electrophiles including
amino acids, nucleosides, and steroids (Scheme 7) <1997T1523>. Coupling of suitable fluorescent
labels, such as 57, with iodo-derivatized biomolecule such as the L-tyrosine derivative 56, gave an
excellent yield of 58 with the synthesis of the homocoupled product 59 being almost entirely
suppressed under the standard reaction conditions shown. Higher reaction temperatures, or
increasing the amounts of catalyst used, led to a predomination in the synthesis of the homo-
coupled product 59.
1098 Alkynes
O N (CH2)9 C CH
H H H
O N 57 H
I O N
(CH2)9 N O
Ph CO2Me CO2Me
Ph
57 (1.5 equiv.), 58
56
Pd(Ph3)4 (0.1 equiv.)
CuI (0.2 equiv.)

Et3N, DMF, 20 °C
96%
O N (CH2)9 C C C C (CH2)9 N O
59
Scheme 7
Problems such as these, related to issues, e.g., the compatibility of functional groups, homo-
coupling reactions, and reagent stability, serve to emphasize the care that must be taken in the
choice of substrates for coupling reactions as well as the careful selection of the reaction condi-
tions themselves.
Standard Sonogashira cross-coupling reactions have been put to good use in the synthesis of
biologically active compounds and natural products <1995OPP127>. Representative examples
include the taxane skeleton <1995TL5891>, enediynes <1996CC749, 1996T6453, 1999T2737>,
and other candidates for Bergman cyclization reactions <2000JA939>, antitumor compounds
<2003T1719, 2002TL2725, 2003T1627, 2000JOC7977, 2000JOC2479, 2000AG(E)3622>,
hormone analogs <2000JOC5647>, fatty acid metabolites <2000T327>, and toxins
<2000OL2479, 2000T10209>. The first total synthesis of the eight-membered ring ether (+)-
prelaureatin 60, a potent larvacidal agent against mosquitos, utilized the Sonogashira cross-
coupling reaction between a vinyl iodide and trimethylsilylacetylene in order to install the C-6
enyne motif (Equation (36)) <2000JA5473>.
OTBDMS OTBDMS OH
Me3Si
Pd(PPh3)4, CuI O
O O H H
H
H I Et2NH H H ð36Þ
Br H3C Br
H3C Br
H3C SiMe3
H
60
Using analogous chemistry provided access to (+)-laurallene, another member of the laurenan
class of metabolite derived from the red algae Laurencia nipponica. The macrocyclic polyene
lactam cyclamenol, 64, derived from Streptomyces spec. MHW 846, is an inhibitor of leukocyte
adhesion to endothelial cells an important event initiated by inflammation, tissue trauma, and
infections. The cyclization precursor 63 was accessed via the stereoselective cross-coupling reac-
tion between the C-12-C-19 alkynyl fragment 61 and vinyl iodide 62. This step provided the entire
carbon backbone of 64, which upon stereoselective reduction of the alkynyl moiety furnished 63
in good yield (Equation (37)) <2000TL625>.
Alkynes 1099
i. Pd(CN)2Cl2 NHTFA
NHTFA piperidine, CuI CO2Me
61 Benzene
I ii. Zn(Ag/Cu), MeOH HO
CO2Me 87% 63
OH 62 ð37Þ
NH
HO
64
Selective desilylation <1997JA2956> of diyne, 65, and exposure to standard cross-coupling

reaction conditions with 1,2-dichloroethene provided the monoene 66. Further desilylation and
intramolecular coupling with copper salts gave the macrocycle 67 in modest yield (Scheme 8)
<2000T9581>. A range of compounds based upon the bis(enediyne) 67 were synthesized with the
aim of evaluating their potential as Bergman cyclization ‘‘warheads’’. The use of cross-coupling
reactions in related syntheses of enyne macrocycles has been highlighted during the period of this
review <2000JA6917, 2000TL6775, 2000OL1757, 2000OL3849>.
Another recent application of the Sonagashira coupling reaction includes its use in the synthesis
of rigid spacers based upon aminopropynylbenzoic acid derivatives such as 68. These were used as
spacers to separate divalent phosphopeptide ligands, which possess high affinity for cellular signal
transduction protein (Syk tandem SH2) domains (Equation (38)) <2003BMC1241>.
TIPS
i. K2CO3, MeOH, Et2O
ii. cis-1,2-Dichloroethene
Pd(PPh3)4, CuI, BuNH2
42%
65 SiMe3 66
TIPS
TIPS
i. Bu4NF, EtOH, THF

ii. Cu(OAc)2, CuI, pyr
69%
67
Scheme 8
Pd(PPh3)4
MeO2C
MeO2C I + ð38Þ
BOCHN CuI, Et3N
NHBOC
CH3CN
68
Conjugated oligomers, based upon polyazulenes, are of commercial interest due to their
electrical, optical, and nonlinear properties <1996CRV537, 1999AC1440>. Cross-coupling reac-
tions have played an important role in the synthesis and development of these and other novel
materials <2000TL8343, 2000TL4079, 2000TL2855>.
The synthesis of oligo(phenylene ethynylene)s (OPEs), which may serve as potential molecular
electronic devices, emphasizes the importance of palladium-catalyzed coupling reactions in
obtaining suitable candidate structures for evaluation (Scheme 9) <2003T2497>.
1100 Alkynes
PdCl2(PPh3)2
i. NO BF4, CH3CN
H2N I CuI, Et3N H2N TMS
ii. NaI, I2, CH3CN
TMS
58% 78%
PdCl2(PPh3)2
I TMS TMS
CuI, Et3N
69 Ph 70
68%
I SAc
SAc
Pd(dba)2, PPh3
71
CuI, DIEA, THF
70%
Scheme 9
The cross-coupling reaction between the 1,4-disubstituted aryl halide 69 and phenyl acetylene
provided 70. This was deprotected and coupled with 4-(thioacetyl)iodobenzene in the presence of
N,N-diisopropylamine (DIEA) in good yield to afford the molecular wire 71.
Heteroatom containing OPEs were accessed using analogous chemistry (Equation (39)). Apply-
ing these cross-couplings with the diiododibromobenzene 72 followed by selective alkynylations
provided 73, a precursor to U-shaped OPEs. It was reported that these novel structures may
provide further insight into the relationship between conformation and electronic properties of
molecular electronic devices.
I I PdCl2(PPh3)2 ð39Þ
H2SO4, I2
41% CuI, Et3N, THF
Br Br Br Br Ph Br Br
72 58% 73
By conducting cross-coupling reactions in a high-density carbon dioxide atmosphere, 1,5-

naphthylethynyl nanostructure networks based upon 74 (Equation (40)) <2003TL2691> were
readily accessed. The associated Eglington–Glaser homocoupling reaction was suppressed under
these experimental conditions.
H C(Me2)OH
Me2N
PdCl2 (PPh3)2
ð40Þ
+ CuI, Et3N
CO2 atm at rt
C(Me2)OH
87%
NMe2 5 examples
74
The cross-coupling reaction involving cyclopentenyl vinyl bromides has been reported to take
place rather inefficiently <1997JOC1582> using Sonogashira conditions. Cyclopenten-2-enone
75, however, underwent smooth coupling to afford 76 in high yield and in the presence of
multifunctionality (Equation (41) <2001T6295>.
O R O
Br PdCl2(PPh3)2 (4 mol.%), CuI (9 mol.%)
OTBDMS OTBDMS
N,N-diisopropylamine (10 equiv.)
ð41Þ
THF, 50 °C, HC CR
OBut OBut
65–98%
75 76
Alkynes 1101
The reaction of 1-phenyl-2-trimethylsilylethyne with CuCl in DMF forms the alkynylcopper

species [Cu2Cl(CCPh)]n in situ via the transfer of the alkynyl group from silicon to copper. This
reagent then undergoes a palladium-catalyzed coupling reaction, in modest yields, with aryl
triflates. The corresponding homocoupled adduct forms the major by-product from this reaction
(Equation (42)) <2001JOM282>.
i. Pd(PPh3)4 (5 mol.%)
Ph SiMe3 CuCl (cat.), DMF, rt Ph Ar ð42Þ
ii. Ar-OTf
17%
The (Z)-eneyne 77 (Scheme 10) <2002JOM342> was obtained from the coupling of silyl
acetylene with (Z)-dichloroethylene. The coupled adduct was further coupled with a propargylic
ether, using analogous catalytic conditions, followed by desilylation, to afford 78.
SiMe3 H
SiMe3
Cl Pd(PPh3)4/CuI
Pd(PPh3)4/CuI LiOH/H2O2
BunNH2 BunNH2 THF
Cl SiMe3 Cl CH2OMe 35% overall
OMe OMe
77 78
Scheme 10
(Z)-3,7-Dimethylocta-2,6-dien-4-yn-1-ol 79, obtained in 78% yield from the coupling reaction

between commercially available (Z)-3-methylpent-2-en-4-yn-1-ol and 1-bromo-2-methylpropene
(Equation (43)) <1997CC1083>, readily cycloaromatized to afford the fragrant oil rosefuran.
Br PdCl2(PPh3)2
+
ð43Þ
HO
CuI, Et2NH
HO
78% 79
The Sonogashira cross-coupling reaction has been used extensively in the synthesis of enediyne
antitumor antibiotics <1996COS41, 1996COS93, 1996T6453>. In an attempt to obtain stereo-
selective cross-coupling conditions for the synthesis of the (Z)-ketoeneyne 80, both the base and
alkynyl-R group were investigated. Optimum stereoselectivity, in favor of 80, was established
using Et3N in CH3CN at 0 C with R other than hydrogen (e.g., when R = (CH2)4OMe 80/81
100%/0%, for R = Ph 80/81 91/9. (Equation (44)) <1997T9107>.
O Pd(PP

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Professor Richard J. K. Taylor

Richard Taylor is currently Professor of Organic Chemistry at the

Janine Cossy did her undergraduate and graduate studies at the

Chris Ramsden was born in Manchester, UK in 1946. He is

Keith Jones was born in Manchester. He studied at Cambridge

Professor Gary Molander was born in Cedar Rapids, Iowa. He

Ray Jones started his chemistry career as an undergraduate

Eric F. V. Scriven is a native of Wales, UK. After working at

The following additional notes apply:

REAGENTS, SOLVENTS, ETC.

1.01 One or More CH Bond(s) Formed by Substitution:

1.02 One or More C---H Bond(s) Formed by Substitution:

1.03 Two or More CH Bond(s) Formed by Addition to CC

1.04 One or More CC Bond(s) Formed by Substitution:

1.05 One or More CC Bond(s) Formed by Substitution:

1.06 One or More CC Bond(s) Formed by Substitution:

1.07 One or More CC Bonds Formed by Addition:

1.08 One or More CC Bond(s) Formed by Addition:

1.09 One or More CH and/or CC Bond(s) Formed by

1.10 One or More =CH Bond(s) Formed by Substitution

1.11 One or More =C---C Bond(s) Formed by Substitution

1.12 One or More C=C Bond(s) Formed by Addition,

1.13 One or More C=C Bond(s) by Elimination of

1.14 One or More C=C Bond(s) by Elimination of S, Se,

1.15 One or More C=C Bond(s) Formed by Condensation:

1.16 One or More C=C Bond(s) Formed by Condensation:

1.17 One or More C=C Bond(s) by Pericyclic Processes,

1.18 One or More =CH, =CC, and/or C=C Bond(s)

1.19 Tricoordinate Carbanions, Cations, and Radicals,

1.20 Allenes and Cumulenes, Pages 1019-1081, C. Bruneau

1.21 Alkynes, Pages 1083-1176, E. Tyrrell

1.22 Ions, Radicals, Carbenes, and Other

1.01.1 REDUCTION OF CHALOGEN BONDS TO CH 1

1.01.1 REDUCTION OF CHALOGEN BONDS TO CH

1.01.1.1 General Methods

1.01.1.2 Reduction of Fluoroalkanes

Pd/C, H2 (1 atm), EtOH

LiAlH4, hν, THF

CH2F Electrochemical reduction

CHF2 Electrochemical reduction

CF3 Electrochemical reduction

1.01.1.3 Reduction of Chloroalkanes

MeO OMe MeO OMe

O Pd/C, H2, NEt3, MeOH O

The dechlorination of -chloro--hydroxy esters presents a range of chemoselectivity issues including

1.01.1.4 Reduction of Bromoalkanes

Bu3SnH, C6H6, AIBN, ∆

OMe O MgBr2, Bu3SnH OMe O

Ph OEt 95% Ph OEt

CO2But LiAlH4, THF

1.01.1.5 Reduction of Iodoalkanes

borohydride as co-reductant) <1999OL1275>, poly(phenyl silane) <1997JOM475>, phenyl

OH Bu3SnH, PhCH3, AIBN, ∆

Bu3SnH, C6H6, AIBN, ∆

O O Bu3SnH, C6H6, BEt3 O O

TBDMSO OTBDPS 88% TBDMSO OTBDPS

O O Bu3SnH, C6H6, AIBN, ∆ O O