297

MACDONALD Porphyrin Synthesis

Acid promoted porphyrin synthesis of 3 (usually low yield) from dipyrrolomethanes 1 2, via
[2 2] and a modified [3 1] pyrrole condensation. Compare with RothemundLindsey.

OHC

NH

CHO
NH HN
Me

Me

NH HN

HOAc

N
HN
Me

Me

R
2
R = CH2CH2CO2Me
R

N O

Me

Et

3, 11%3 R
R

O
N
Et

Et
N O

N
H

R
5

Me

Me

NH HN

NH

H
R2

AcOH

NH
NH

Et

4
R1 = CH2Cl; R2 = CO2tBu

Me

2
6 R

HN
Et

Et
Me 7, 31%

Et

Porphyrin (3). To 2 (402 mg, 1 mmol) in HOAc was added 1 (150 mg, 1.02 mmol) in 150 mL glacial
HOAc, followed by 3.5 mL of 56% HCl in 200 mL glacial HOAc. After stirring for 1 h in the dark,
10 g NaOAc was added and the mixture was aerated for 30 h in the dark. Solvent was distilled in vacuum and the residue in 300 mL MeOH and 3 mL conc H2SO4 was refluxed for 2 d. After evaporation,
the residue in 200 mL DCM, was worked up, chromatographed and crystallized (MeOH/DCM) to give
55 mg, 11% of 3, mp 205  C.

1
2
3
4
5
6
7
8
9
10

MacDonald SF
MacDonald SF
Chang CK
Schore NE
Uno H
Nocera DG
Lash TD
Simonneaux G
Yi J
Lash TD

J Am Chem Soc
J Am Chem Soc
J Org Chem
Tet Lett
Chem Comm
J Org Chemc
Tetrahedroncc
Synlett
Korean J Chem Eng
Tetrahedron

1960
1960
1981
2000
2002
2002
2005
2006
2006
2007

82
82
46
41
67
61
23
63

4377
4384
4610
7423
116
1403
11615
2818
512
12343

298

MADELUNG Indole Synthesis

Indole 2, 4 synthesis by base catalyzed cyclization of N-acyl-o-toluidines 1, 3. Also on solid
support 3 (see 3 to 4).5
Cl

Me
O

BuLi, THF

N
H

Cl

-20 C

N
H
2, 94%4

CN

CN

KOBu
DMF

4, 88%5

5-Chloro-2-phenyl-1H-indole (2).4 To anilide 1 (491 mg, 2 mmol) in 4 mL dry THF at 20  C under
N2 was added dropwise n-BuLi (3.75 mL of 1.6 M in n-hexane, 6 mmol). The mixture was stirred at r.t.
for 15 h and after cooling it was slowly quenched with 2.4 mL of 2N HCl. The aq layer was washed
(PhH) and the organic layers were worked up to provide 2 (94%), mp 195196  C, after recrystallization (ether:PhH).
1
2
3
4
5
6R

Chem Ber
Bull Soc Chim Fr
J Org Chem
J Org Chem
Tet Lett
Chem Soc Rev

Madelung W
Pichat L
Hertz W
Houlihan WJ
Wacker DA
Song JJ

45

1912
1954
1960
1981
2002
2007

1128
85
2242
4511
5189
1120

25
46
43
36

MAKOSZA Vicarious Nucleophilic Substitution

Introduction of functionalized alkyls 2, 5, 8, of OH or of NH2 groups into electrophilic aromatic
rings (e.g. Pyrs 1, nitrobenzenes 4, 7), via replacement of hydrogen. Proceeds by conjugate
addition of carbanions to 1, 4, 7.
O 2N
+ CHCl3
N
1

NaOMe/
O2 N
NH3 liq
DMF

CHCl2
O 2N

3, 72% 3

EtO2 C
O2 N

CO2 Et

NO2

KO 2N
KOtBu, CuCl
Br-CH(CO2 Et) 2

NO 2

PhSCH 2CN
5
NaOH/
NC
O2N
NH
3

EtO2 C
O 2N

CN

6, 50%

CO2 Et
NO 2

10, 83%7

N
H

299
3-Dichloromethyl-5-nitropyridine (3).3 A solution of 3-nitropyridine 1 (372 mg, 3 mmol) and CHCl3
(395 mg, 3.3 mmol) in DMF (2 mL) was added dropwise to a vigorously stirred mixture of NaOMe
(650 mg, 12 mmol) in liq NH3 (10 mL) at 70  C. After 1 min stirring, NH4Cl (1.5 g) was added,
ammonia was evaporated, water (50 mL) was added to the residue and usual workup afforded
447 mg of 3 (72%).
Diethyl 2,6-dinitrophenyl malonate (10).7 To t-BuOK (393 mg, 3.5 mmol) in DME (15 mL) was
added CuCl (248 mg, 2.5 mmol) at 0  C and the mixture was stirred for 30 min. Pyr (1 mL) and
1,3-dinitrobenzene (168 mg, 1 mmol) were added and after cooling at 20  C diethyl bromomalonate
8 (211 mg, 1 mmol) in DME (5 mL) was added. After 2 h stirring at 20  C and 30 min at 0  C,
quenching and usual workup afforded after chromatography (20% EA in hexane) 250 mg of
10 (83%), mp 159160  C (MeOH).
1
2R
3
4R
5
6
7
8
9
10
11R
12

J Org Chem
Acc Chem Res
J Org Chem
Russ Chem Rev
Synthesis
Chem Ber
Synthesis
Liebigs Ann
J Org Chem
Eur J Org Chem
Chem Hetero Coump
Synlett

Makosza M
Makosza M
Makosza M
Makosza M
Makosza M
Makosza M
Nilsson M
Makosza M
McCluskey JG
Kozhevnikov DN
Donskaya OV
Makosza M

48
20
54
58

1983
1987
1989
1989
1991
1991
1994
1997
1998
2002
2002
2008

3860
282
5094
747
103
577
242
1805
41 99
1412
371
2938

124

63
38

MAMEDOV Heterocycle Rearrangement

Acid catalyzed rearrangement of quinoxalinone derivatives 1, 5 (obtainable from o-aminoanilines)
to 2-heteroaryl-substituted benzimidazoles 4, 8 by reaction with N-nucleophiles 2, 5. Proceeds
via spiro-quinoxalinones. Applicable to synthesis of 2-heterosubstituted Ims from pyrazinones
or to synthesis of aza-analogues of 4. Rearrangement of quinoxalines to benzimidazoles.1
Compare with Haddadin.
R1
H
N
H
N

R1
N

Cl
+

R2

N
H
1

R2

H
N
N
H

-HCl

Ar
O

NH 2NH 2 H2 O
6

-H2O
R

N
O
H
3, ~100%
H
H
H
N
N
H

N
H
O

7, 6481%

N
-H2O

N
H

R2

R1
4, 6578%3

Ar
Ar
N

AcOH,

-H2O

N
H

NH
R

8, 8599%4,5

300
3-Phenyl-10 H-spiro[2-pyrazoline-5,20 -quinoxalin]-30 (40 H)-one (7: R = H, Ar = Ph).4 6 (0.23 g,
5 mmol, 90%) in 10 mL n-BuOH and 5 (R H, Ar Ph, 0.13 g, 0.5 mmol) were refluxed for 16 h
and allowed to stand at r.t. overnight. 7 was filtered, washed with EtOH and crystallized from MeCN
to yield 70 mg (51%) of product. Evaporation of the filtrate produced 40 more mg (30%) of 7 (from
MeCN), mp 310312  C.
2-(5-Phenyl-1H-pyrazol-3-yl)-1H-bezimidazole (8).4 7 (200 mg, 0.7 mmol) in 10 mL HOAc was
refluxed for 8 h. Evaporation afforded 190 mg of 8, mp 316317  C.
1
2
3
4
5
6

Taylor EC, McKillop A

Mamedov VA
Mamedov VA
Mamedov VA
Mamedov VA
Mamedov VA

J Org Chem
Bull Russ Acad Sci (Chem)
Tet Lett
TetLett
Bull Russ Acad Sci (Chem)
Tet Lett

1965
2004
2008
2009
2010
2010

30
53
49
50
59
51

2858
164
4644, 6231
5186
1645
6503

MANDER Methoxycarbonylation Reagent

Methyl cyanoformate 2, a reagent for regioselective methoxycarbonylation of carbanions; can
also function as a dienophile, dipolarophile or radical cyanating agent in the presence of cobalt
catalysts. Compare with SzarvasySchoepf.

OMe
LiO

Et2O
NCCO2Me
2

OEt
R

OMe
O

H
CO2Me

3, 71%,4 98% de
CO 2Et
CO 2Et
NCCO2Et, Cp Co (cod)

PhMe, 50 C, 7 d

+
R

N
6

b-Ketoester (3).4 To a solution of 8-methoxy-4a-methyl-4,4a,9,10-tetrahydro phenanthren-2(3H)one (512 mg, 5 mmol) in liq NH3, Et2O and a small amount of t-BuOH (140 mg, 1.9 mmol) under
N2, was added Li (35 mg, 5 mmol) under stirring at 33  C to form 1. After 45 min, isoprene was
added, then NH3 was evaporated under a stream of N2, The residue was dried (high vacuum 5 min)
Et2O (20 mL) was added, the mixture was cooled to 78  C and 2 (187 mg, 2.2 mmol) was added
dropwise. After 20 min at 78  C, EA was added at 0  C, followed by water. Workup and chromatography (silica gel) afforded 449 mg of 3 (71%), mp 143145  C.
1
2
3
4
5
6
7
8

Krebs A
Padwa A
Akiyama Y
Mander LN
Potthoff B
Mander LN
Padwa A
Mander LN

Tet Lett
J Am Chem Soc
Chem Lett
Tet Lett
Synthesis
Synlett
J Org Chem
J Org Chem

1981
1982
1983
1983
1986
1990
1991
2005

22
104
24

56
70

1675
286
1231
5425
584
169
3271
1654

301

MANN Ether Dealkylation

Dealkylation of alkyl aryl ethers 1 or of alkyl aryl sulphides 6 by lithium diarylphosphide
(obtained from diarylphophane 2 and BuLi) or by arsenide ions (1 11). Compare with
ZeiselPrey.
Ph-OMe + Ph2PH + BuLi
1

2
Ph2PLi
7

Ph-S-CH2-Ph

Me

THF
Reflux, 4 h

Li

5, 87%
4, 83%4
Ph2As*
10
4 + Ph2As-Me

PhSH + Ph2P-CH2-Ph

PhOH + Ph2PMe

PHPh2

Ph O

9, 79%

11, 85%

Phenol (4).4 An ice-cooled 2 (9.1 g, 50 mmol) in THF (110 mL) was treated with n-BuLi (1.24M,
45 mL). 1 (5.8 g, 53 mmol) was added and the red solution was refluxed for 4 h. Evaporation, addition
of Et2O, water and distillation afforded 8.5 g of 5 (87%), bp 8790  C/0.2 mm from Et2O, and 3.81 g of
4 (83%) from the aq layer.
1
2
3
4
5
6
7
8

J Chem Soc
Chem Ind
Chem Ind
J Chem Soc
Acros Org Acta
Chem Comm
Tetrahedron
Eur J Org Chem

Mann FG
Mann FG
Mann FG
Mann FG
Veriott G
Furukawa N
Weissman SA
Nishida A

1963
1963
1964
1965
1995
2000
2005
2006

1155
1558
1386
4120
40
1667
7833
752

1
61

MANNICH Aminomethylation
Aminomethylation by addition of activated methyl or methylene groups (usually as an enol) to
an in situ formed iminium species (Me2NCH-R) (from an amine and an aldehyde). Can be
carried out as a three-component reaction between an amine, an aldehyde and a ketone (or phenol) (1 2 3), leading to b-aminoketones 4, 7. Asymmetric reaction (5 8) using chiral
catalysts,5,9,16 or an acidic BINOL catalyst.6 Compare with Eschenmoser methynylation or
with List.
NH2

CHO
O

Cl

HCl

Cl

Ph
N
H

4, 90% 2

O
O
O
F
NBoc

8
Toluene
-50 C

HN
O

Tol

NHBoc

7, 92%
97%ee9

N
H

N Ar
H

8, Ar = 3,5-CF3C6H3

302
1-Phenyl-1-(p-chloroanilino)-3-hexanone (4).2 To a mixture of p-chloroaniline 1 (127.5 mg,
1 mmol), 2-pentanone 2 (90 mg, 1 mmol) and PhCHO 3 (90 mg, 1 mmol) in EtOH (1 mL) was added
35% HCl (0.04 mL) under cooling (ice bath). After stirring 12 h at 14  C and 10 h at 0  C, the mixture
was neutralized (10% NaHCO3 to pH 7, filtration followed by recrystallization from EtOH afforded
4 (90%), mp 8486  C.
t-Butyl 2-(ethoxycarbonyl)-2-fluoro-3-oxo-1,3-di-p-tolylpropylcarbamate (7).9 To chiral catalyst
8 (15 mg, 0.03 mmol) was added imine 6 (118.7 mg, 0.45 mmol) in PhMe (6 mL). 5 (67.2 mg,
0.3 mmol) was added, the mixture was stirred at 50  C for 72 h. Evaporation and chromatography
(hexane:EA) afforded 7 (92%).

1
2
3R*
4R*
5R*
6*
7R*
8
9*
10*
11
12*
13*
14
15
16*

Mannich C
Jnhua Z
Cordova A
Schaus SE
Rutjes FPJT
Terada M
Arrayas RG, Carretero JC
Sieburth SMcN
Perica`s MA
Huang K-W, Lu Y
Wang M
Ricci A
Maruoka K
Kim SS
Namboothiri INN
Kim DY

Arch Pharm
Org Prep Proced Int
Acc Chem Res
Eur J Org Chem
Chem Soc Rev
Synlett
Chem Soc Rev
Org Lett
Chem Eur J
Angew Chem Int
Org Prep Proced Int
Angew Chem Int
Chem Eur J
Tetrahedron
Tet Lett
Tet Lett

1912
1996
2004
2007
2008
2008
2009
2009
2009
2009
2009
2009
2009
2010
2010
2011

250
28
37
37
38
11
15
48
41
48
15
66
51
52

647
618
102
5797
29
1661
1940
4540
10167
7604
315
5694
6678
5647
846
2356

MARKOVNIKOV Regioselectivity
Description of selectivity during addition of unsymmetrical reagents to unsymmetrical olefins, or acetylenes. HX adds selectively with H forming a bond to the less substituted olefin
carbon (Markovnikov). Now supplanted by the general term regioselectivity introduced by
A. Hassner,3 denoting selectivity in bond making between an unsymmetrical reagent XY
and an unsymmetrical substrate (1 + 2), sometimes depending on solvent polarity;4 now includes regioselective (o,m,p)-substitution and also applied to bond breaking reactions (regioselective elimination, 5 6). Regioselective addition of amines to terminal acetylenes
(Markovnikov 9 12 vs. anti-Markovnikov addition 9 11) depending on phenol-Ti
ligand.7

303

1+ 2

Pentane

+ BrN3
2

N3 Regioselective additions

Free rad

MeCN
Ionic

Br

Br
4

Br+

N3

OH

400 C
5

OAc

NH2 PhMe,

7, (Et2N)4Ti

100 C

OH

11, 70%7

10
8, (Et2N)4Ti

11

94:6

12

10:90

12

s-Butyloctylidene amine (11).7 To 7 (2.2 mmol) in 7.5 mL PhMe in a Teflon capped pressure tube
under Ar were added 10 (13.5 mmol), 9 (11.3 mmol), and Ti(NEt2)4 (1.1 mmol). All was heated
for 24 h at 100  C. Concentration and vacuum distillation gave 1.45 g (70%) of 11 + 12 (94:6),
bp 4143  C/0.1 mbar, GC yield 97%.
1
2R
3
4R
5
6
7
8

Markovnikov W
Stacey FW
Hassner A
Hassner A
Porter DJ
Alvarez P
Beller M
Bongardt T

Liebigs Ann
Org React
J Org Chem
Acc Chem Res
J Chem Edu
Tet Lett
Tet Lett
Tet Lett

153
13
34
4
72
42
45
47

1870
1963
1969
1971
1995
2001
2004
2006

256
150
2628
9
1039
8467
8875
4549

MARSCHALCK Aromatic Alkylation

An aldol type alkylation of hydroxyquinones 3 or of aminoquinones 1 with aIdehydes. Involves
quinone reduction, aldol condensation and reoxidation to quinone.
O

NH2

NH2

Na2S2O8

OH

HCHO, 40 C
1

2, 90%
O

O
O

OH

OH

Na2S2O8,
HCHO

OH

30% H2O2, 20 C, 3 h
Me

Me

4, 51%

304
1-Hydroxy-2-hydroxymethyl-5-methoxy-9,10-anthraquinone (4).6 After reduction of 3 (1 g,
3.92 mmol) with sodium dithionite (1.06 g) in 20 mL water and 60 mL MeOH containing 1N NaOH
(80 mL) under N2., 37% aq H2CO (5.66 g, 0.07 mol) was added at r.t. After 3 h (TLC monitoring) the
solution was poured into 100 mL water containing 0.4 mL 30% H2O2. Acidification with 1N HCl,
extraction with DCM chromatography (silica gel, DCM:5%MeOH) and crystallization from ether
afforded 4 in 51% yield.
1
2
3
4
5
6
7
8

Bull Soc Chim Fr

Bull Soc Chim Fr
Chem Ber
J Chem Soc
Angew Chem Int
Tetrahedron
Bioorg Med Chem Lett
Eur J Org Chem

Marschalck C
Marschalck C
Brockmann H
Havlincova L
Krohn K
Krohn K
Toshima K
Krohn K

3
6
91

1936
1939
1958
1970
1979
1988
2000
2004

18
44
10

1545
655
1920
657
621
49
2163
209

MARTIN Dehydrating Reagent

Sulfurane reagent 2 for conversion of trans diols 1 to epoxides 3, generally used for dehydration
of diols to cyclic olefins or to cyclic ethers, or as an oxidizing agent. anti-Elimination of water
(4 5).

20 C
Ph2S[OC(CF3)2Ph]2
Cl
2

OH
Cl

OH
1

O
3, 93%
H

HO

CH2Cl2

AcO

N
4

Ph2S[OC(CF3)2Ph]2
2

AcO

N
5, 73%7

(2S,7aS)-2-Acetoxy-1-methylidenehexahydro-1H-pyrrolizidin-5-one (5).7 To 4 (0.92 g, 4.32 mmol)

in DCM (9 mL) was added 2 (3.62 g, 2.92 mmol) in DCM (9 mL) over 5 min. Stirring the mixture at r.t.
for 2.5 h, followed by workup and chromatography (silica gel, EA, EA-MeOH, 95:5) gave 5 (73%), oil.
1
2
3
4
5
6
7
8
9
10

Martin JC
Martin JC
Martin JC
Martin JC
Bartlett PD
Eschenmoser W
Burnett DA
Shioiri T
Movassaghi M
Nicolaou KC

J Am Chem Soc
J Am Chem Soc
J Am Chem Soc
Org Synth
J Am Chem Soc
HeIv Chim Acta
J Am Chem Soc
Tet Lett
J Am Chem Soc
J Am Chem Soc

1971
1974
1977
1977
1980
1982
1984
2002
2009
2010

93
96
99
57
102
65
106
43
131
132

4327
4604
3511
22
3515
353
8201
8679
9648
7138

305

MASCARELLI Fluorene Synthesis

Synthesis of fluorenes 5 from 2-amino-20 -alkylbiphenyls 4 via diazonium ions. Also synthesis
of dibenzofuronium salts 3 from biphenyldiazonium salts 2.
+

N2

H2N
HNO2

DCM
DMSO

0 C
OMe

+
O BF4S
O-

3, 79%

OMe 2, 98%6

H2N
HNO2, 0 C
Urea, 70 C
4

5, 40%

2-Methoxybiphenyl-20 -yldiazonium fluoroborate (2).61 (7.8 g, 0.04 mol) in THF (30 mL) with 40%
aq HBF4 (75 mL) in water (20 mL) at 0  C and dropwise addition of NaNO2 (2.8 g in 30 mL H2O) gave
after 0.5 h 2, which was washed with cold fluoroboric acid and cold THF and dried to afford 11.6 g,
98% of 2.
O-methyldimethylsulfoxonium fluoroborate Dibenzofuronium salt (3). Decomposition of 2 (1 g,
3.3 mmol) in DCM (25 mL) and DMSO (1.3 g, 16.6 mmol) followed by removal of solvent and
extraction with ether gave 0.48 g, 79% of 3.
1
2
3
4
5
6
7
8

Gazz Chim Ital

Gazz Chim Ital
Gazz Chim Ital
J Am Chem Soc
J Org Chem
Tetrahedron
Synth Metals
Tetrahedron

Mascarelli L
Mascarelli L
Mascarelli L
Cohen T
Puskas I
Heaney H
Nogueira F
Liu Y

66
67
68
86
3
48
156
64

1936
1937
1938
1964
1968
1992
2006
2008

843
812
4565
2514
4237
4005
104
9033

MATTESON Asymmetric Boronic Esters

Chiral boronic esters 1, 6 in reaction with dihalomethyl carbanions leading to asymmetric
synthesis of a-halo boronic ester intermediates 2, 7, which on oxidation provide chiral aldehydes 8. Proceeds by alkyl migration of borates with chiral induction. Compare with Brown.
Cy
O
B

Cy ZnCl2

CHCl2

Cy
O
B

LiCHCl2

Cl

OBn

Cy
O
B
O

Cl
O

Cl

Cy
2

LiCHCl2/
ZnCl2

O
B
O
3

BnOMe
Cy

BnO

Cl

O
B
O
7

Cy

O
H2 O2

Cy

Cy

45

Cy

Cy
6

OBn
O

Cy

H 2 O2
pH 89

H
OBn O 8, 55%

306
[4R-[2(R*),4a,5b]]-4,5-Dicyclohexyl-2-[1-(phenylmethoxy)propyl]-1,3,2-dioxaborolane (4).5 To a
solution of 1 (54 g, 204 mmol) and DCM (52 g, 610 mmol) in THF (300 mL) at 40  C was added
LDA (120 mL, 2 M, 240 mmol) and after 10 min, ZnCl2 (55.5 g, 408 mmol). After 30 min, the mixture
was warmed to r.t. and kept for 2 h to give 2 (NMR analysis). After evaporation in vacuo, THF
(300 mL) was added and all was added dropwise to PhCH2OMe (from PhCH2OH 26 g and NaH
9 g in THF/DMSO). After 48 h stirring at r.t., hexane (1 L) and aq NH4Cl (500 mL) was added followed
by HCl (till acid). Workup and evaporation afforded 75 g of crude 4.
[S-(R*,R*)]-2-Methyl-3-(Phenylmethoxy)pentanal (8). To 7 (33 g) in THF (300 mL) and phosphate
buffer (150 mL) (pH 8) was added 30% H2O2 (30 mL) at 0  C followed by Na2CO3 (20 g, 188 mmol)
to keep the pH at 89. After 0.5 h, the mixture was kept at r.t. for 3 h. NaI (3 g, 20 mmol) was added at
0  C and I2 was reduced with sodium thiosulfate (24.8 g, 100 mmol). The aq layer was extracted with
ether and the combined organic layers were washed (10% Na2S2O3, 100 mL). Bulb-to-bulb distillation
afforded 8, 8.1 g, 55%.

1*
2*
3*
4R*
5*
6*
7R*
8*
9*
10*
11*

J Am Chem Soc
J Organomet Chem
J Am Chem Soc
Chem Rev
J Am Chem Soc
Tetrahedron
Chem Rev
Angew Chem Int
Angew Chem Int
Chem Comm
J Am Chem Soc

Matteson DS
Rathke MW
Matteson DS
Matteson DS
Matteson DS
Matteson DS
Matteson DS
Soderquist JA
Aggarwal VK
Crudden CM
Roush WR

85
122
102
89
118
54
89
46
46

1963
1976
1980
1989
1996
1998
1989
2007
2007
2009
2010

2599
145
7590, 7588
1535
4560
10555
1535
397
7491
6704
7881

132

MATTOXKENDALL Dehydrohalogenation
Dehydrohalogenation of a-haloketones by heating with 2,4-dinitrophenylhydrazine (1 2) or
with LiCl in DMF (3 4).
Br

Br

CO2Me

CO2Me

2,4-DNPH
O
Br H

O
O

N
N

Ar

CH2OAc
OH

LiCl(Br)
DMF, 100 C

O
Br H

O
3

4, 73%

CH2OAc
OH

307
Cortisone acetate (4). A solution of 4-bromo-3-keto steroid 3 (9.5 g, 2 mmol) and lithium chloride
(0.255 g, 6 mmol) in DMF (10 mL) was heated at 100  C under N2 for 2 h. The mixture was diluted
with water (5 mL) and cooled to precipitate crude 4, which on recrystallization from acetone afforded
pure 4 (73%).
1
2
3
4
5
6

J Am Chem Soc
J Am Chem Soc
J Am Chem Soc
J Org Chem
J Org Chem
Tetrahedron

Mattox VR, Kendall EC

Djerassi C
Holysz RP
Warnhof EW
Lewbart ML
Makosza M

1948
1953
1953
1963
1973
2003

70
75
75
28
38
59

882
3500
4432
887
2335
1995

Mc MURRY Carbonyl Coupling

Formation of olefins (or of a-ketol) by coupling or cross coupling of aldehydes or ketones,
mediated by low valent titanium. TiCl3 should be freshly prepared. Also coupling of enol ethers
of 1,3-dicarbonyl compounds.
H

OAc

TiCl3/
O Zn-Cu
AcO
1

AcO

H TiCl3 (DME)1.5
H Zn-Cu, 80 C

H
5

2, 94%, Mainly E

4, 80%7

Cyclotetradecene (4).7 TiCl3(DME)1.5 (5.2 g, 17.8 mmol) and zinccopper couple (3.8 g, 58.1 mmol)
were stirred under Ar while DME (150 mL) was added by syringe. After the mixture was heated at
80  C for 4 h to form the active titanium coupling reagent, tetradecanedial 3 (500 mg, 2.2 mmol) in
DME (50 mL) was added via syringe pump over 35 h. The mixture was heated for 6 h, cooled to
r.t., diluted with pentane (100 mL) and filtered (Florisil). The filtrate was evaporated in vacuo at
0  C to give 340 mg of 4 (80%), E:Z 9:1.
1
2
3R
4
5
6
7
8R
9
10
11
12
13
14

Mc Murry JE
Finocchiaro P
Mc Murry JE
Coe PL
Breitmaier E
Breitmaier E
Mc Murry JE
Mc Murry JE
Ephritikhine M
Hong BC
Gauthier S
Rajakumar P
Duan X-F
Navale TS

J Am Chem Soc
Chimia e Lindustria
Acc Chem Res
J Chem Soc Perkin I
Chem Ber
Synthesis
J Org Chem
Chem Rev
J Chem Soc Chem Comm
Syn Comm
Tetrahedron
Tet Lett
J Org Chem
Chem Comm

1974
1982
1983
1986
1986
1987
1989
1989
1998
1999
2000
2005
2007
2009

96
64
16
119
54
89
29
56
46
72

4708
644
405
475
1734
951
3748
1513
2549
3097
703
8543
10283
2857

308

McCORMACKKUCHTINRAMIREZ Phosphole Synthesis

Also known as McCormackKuchtinRamirez. Formation of phospholes1 4 from butadienes
1 or of dioxaphospholes 72,3 from 1,2-diketones 5.
Br
P

Br

Copper stearate
n-hexane
8d

P Ph
Br Br

CHCl3,
Reflux

P Ph
O

H2O

3, 52%

4, 62%5

O OEt
P
O O

(EtO)2POSiMe3 6

20 C

7, 65%6

Phosphole (4).5 To a suspension of copper stearate (1 g) in n-hexane (60 mL) was added 1 (16.8 g,
0.12 mol) and 2 (32 g, 0.12 mol). The turbid solution was kept in an amber bottle under N2 at r.t.
for 8 days, the solid was filtered under N2, washed with n-hexane and dried under N2 to give salt
3. The latter was refluxed in CHCl3 under N2 for 42 h (red to pale orange solution). The cooled mixture
was poured into aq NaHCO3 and after workup, drying and concentration in vacuo, crystallization (EA)
afforded 4 (62%).
1
2
3
4
5
6
7R
8

Mc Cormack WB
Kuchtin VA
Ramirej F
Mitsuo S
Quin LD
Gladiali S
Quin LD
Zutphen van S

US Pat
Doklad Akad Nauk USSR
J Am Chem Soc
J Org Chem
Tetrahedron
J Org Chem
Curr Org Chem
Tet Lett

1958
1960
1981
1983
1994
2006
2008

2,663,736; 2,663,737
466
2651
4030
401
6363
43
1734

121
82
46
39
59
10
49

McFADYENSTEVENS Ester Reduction

Reduction of esters to aldehydes 4, 6 by heating of their sulfonyl hydrazides 3, 5 in the presence
of base. Also microwave assisted reduction.6
OCH 3
NH 2NH 2
PhSO2Cl
N
1

CO2 Et

Na 2CO3
glycerol
160 C, 2 min
CO
NHNHSO2Ph
2, 100%

Na2 CO3
glycerol
250 W MW
5 min

CHO

CONHNHTs
3, 20%

OCH3

CHO
5, 68% 6

309
4-Methoxybenzaldehyde (5).6 4 (1 mmol), Na2CO3 (1.1 mmol), and powdered glass (250 mg) in ethylene glycol or glycerol (2.5 mL) was irradiated in a microwave oven at 150 W for a few minutes and
then at 350 W for 5 min. The mixture was cooled and neutralized. Extraction, drying and chromatography gave 5 (68%).
1
2
3R
4R
5
6

J Chem Soc
J Am Chem Soc
Chem Rev
Org React
J Org Chem
Synth Comm

McFadyen JS, Stevens TS

Nieman C
Ferguson LH
Mosetting E
Martin SB
Giri VS

1936
1942
1946
1954
1974
2002

584
1678
227
232
2285
2569

62
38
8
39
32

MEERWEIN Alkylating Reagent

R3 O BF4  reagent for O-alkylation of amides 1, 4, 6 to imino ethers 3, 5, 7. Also O-alkylation
of ketones or enols.
H
N

N
N

N
1

N
O
H 4

3 O

N
5

Me3O+BF4-

NHPh

MeO

H3O+

CH3CN

N
Ph

NHPh

MeO

N
7

OEt

NH
NHPh

H2N

EtO3+BF4N

20 C, 14 h

OH 2

EtO3+BF4-

N
8

Ph

Ph

Methyl 1-benzyl-4-N-anilino-4-piperidinecarboxylate (8).8 Na2HPO4 (325 mg, 2.22 mmol) and trimethyl-oxonium tetrafluoroborate (266 mg, I.786 mmol) followed by MeCN (3.4 ml) were added under
Ar to 1-benzyl-4-anilino-4-piperidinecarboxamide 6 (503 mg, 1.624 mmol) at 0  C. The mixture was
stirred at r.t. and 10% aq NaHCO3 (1 mL) was added. The organic layers were washed, dried and concentrated in vacuum to give 7 as a yellowish oil. To 7 was added 10% HCl and stirring was continued for
5 h at r.t. After extraction with ether, washing and drying, chromatography (silica gel, EA:hexane)
afforded 8 (60%).
1
2
3
4
5
6
7
8
9

Meerwein H
Eschenmoser A
Fujita A
Ayers WA
Potts KT
McMinn DG
Curphey TJ
McClure CK
Kataoka Y

J Prakt Chem
Pure Appl Chem
Chem Pharm Bull
Can J Chem
J Chem Soc Chem Comm
Synthesis
Org Syn
Syn Comm
Organometal

1937
1963
1965
1967
1970
1976
1988
1997
2004

147
7
13
45

6
27
23

17
297
1183
451
1025
824
1099
923
2095

310

MEERWEINPONNDORFVERLEY Reduction
Reduction of carbonyl groups to alcohols (1 2, 3 4) by means of Al(i-PrO)3 or Al(OR)3
and i-PrOH (which serves as H-donor).6 Also with lanthanide alkoxides (1 2). Reverse of
Oppenauer oxidation. Compare with Evans.
O

OH
La(iPrO)3

Ph

OH

O
1

Al(iPrO)3

Ph

PhH, 25 C

2, 87%

OH

Ph

Ph

OH OH

4, 91%
(100% selectivity)

OH

OH
6
Me3Al, iPrOH

Ph
5

cis:trans
23:77
Ph
7, 91%

4-Phenyl-1-cyclohexanol (7). Freshly distilled DCM (10 mL) was added to 2,7-dimethyl-1,8 molecular sieves (140 mg) under Ar. Me3Al (1 M,
biphenylenediol 6 (21.4 mg, 0.1 mmol) and 4 A
200 mL, 0.2 mmol) in hexane was added slowly at r.t. and after stirring for 30 min, i-PrOH
(184 mL, 2.4 mmol) was added. After 30 more min, this mixture was added to 4-phenylcyclohexanone
5 (348 mg, 2 mmol) in DCM. After 1 h stirring at r.t., the mixture was quenched with 1N HCl, and
extracted with ether. Workup and chromatography (silica gel, DCM) gave 7 (91%) as a cistrans
mixture.

1
2
3
4
5R
6R
7
8
9
10
11
12

Meerwein H
Verley A
Ponndorf W
Lund H
Wilds AL
Deno NC
Snyder CH
Merbach A
Kagan HB
Huskens J
Maruoka K
Polshettiwar V

Liebigs Ann
Bull Soc Chim Fr
Angew Chem
Chem Ber
Org React
Chem Rev
J Org Chem
Helv Chim Acta
Tet Lett
Synthesis
Angew Chem Int
Green Chem

1925
1925
1926
1937
1944
1960
1970
1972
1991
1994
1998
2009

444
37
39
70
2
60
35
55
32
37
2

221
537
138
1520
178
7
264
44
2355
1007
2347
1313

311

MEINWALD Epoxide Rearrangement

Rearrangement of vinyl or aromatic epoxides to aldehydes 2, 7 during peracid oxidation of
bicyclic dienes 1 or of vinylbenzenes, sometimes without isolation of epoxide intermediates 3;
involves carbocation intermediates. Also using Cu(II) salts.6

Na2CO3, 20 C

1
+
HO

OH

OH

MeCO3H-NaOAc

3a

CHO

1,2-Cleavage

3b

CH2Cl2, 60 min

O
7, 85% 6

(Cu(BF4)2.nH2O)

5, 70%

2-Phenylpropionaldehyde (7).6 a-Methylstyrene oxide 6 (254 mg, 1.90 mmol) in dry DCM (20 mL)
was stirred at r.t. with copper tetrafluoroborate (119 mg, 0.50 mmol) for 1 h. After addition of 60 mL
of DCM, the mixture was washed (H2O) and chromatographed (10% EA:PE) to afford 7 (85%).
1
2
3
4
5
6

J Am Chem Soc
J Am Chem Soc
J Am Chem Soc
Tet Lett
Tet Lett
Tet Lett

Meinwald J
Meinwald J
Meinwald J
Meinwald J
Kobayashi S
Graham AE

80
82
85
23
34
47

1958
1960
1963
1965
1993
2006

6303
5235
582
1789
665
5919

MEISENHEIMERJANOVSKY Aromatic Complex

An alcohol complex 3, 5 formed from a polynitroaromatic compound 1, 4 in alkaline solution
with RO, HO2 or an acetone complex formed by C-attack on 1, 4.1 Can be used as reactive
intermediates in nucleophilic aromatic substitution.

O2N

OCH3
NO2

OK
H+

NO2
OCH3
NO2

NO2 4

H3CO
O2N

H3CO
O2N

NO2

O
-

K+
2

KOMe
MeOH

NO2

OH3CO
-

NO2
K+
3

OCH3
NO2

NO2

K+
5, 81%3

2,4-Dinitroanisole methoxy complex (5).3 KOMe (1.2 mmol) in methanol (0.24 mL) was added to
2,4-dinitroanisole 4 (1.25 mmol) in dioxane (0.3 mL). The red crystals were collected under N2,
washed with benzene and ether and dried in a vacuum desiccator to afford 5 (81%).

312
1
2
3
4R
5R
6
7
8
9
10R
11

Chem Ber
Liebigs Ann
J Org Chem
Acc Chem Res
Chem Rev
Chem Comm
Angew Chem Int
J Org Chem
Chem Eur J
Molecules
J Am Chem Soc

Janovsky IV
Meisenheimer J
Byrne WE
Bernasconi CF
Terrier F
Rebek J Jr
Fornarini S
Um I-H, Dust JM
Forlani L
Al-Kaysi RO, Guirado G
Ray PC

19
323
32
11
82

1886
1902
1967
1978
1982
2007
2007
2007
2007
2008
2009

46
72
13
13
131

2155
205
2506
147
77
1605
1995
8797
9600
1282
13806

MEISENHEIMER N-Oxide Rearrangement

Rearrangement of tertiary amine oxides to hydroxylamine derivatives (6 7) via a [2,3] sigmatropic shift, with C to O migration. Also chlorination of Pyrs by reaction of their N-oxides
with POCl3, via chlorophosphates.
N
N

AcOH
AcO2H

O
N

POCl3
P2O5

CH3
N

H3C
m-CPBA

Cl

N
3, 57%2

N
4, 43%2 Cl
CH3
N
O

O
N

[2,3]-Shift
10 h

7, 89%3

2-(and-4-) Chloro-1,5-naphthyridine (3 and 4).21,5-Naphthyridine 1 (4.5 g, 34 mmol) was treated

with a mixture of AcOH (10 mL) and 40% peracetic acid (5 mL) for 3 h at 70  C. From the mixture of
mono and di-N-oxides, the mono N-oxide 2 was obtained by crystallization from methylcyclohexane.
N-Oxide 2 (770 mg, 5 mmol) was heated in POCl3 (30 mL) and P2O5 for 30 min. The product was
collected and analyzed by GC (15% SE-30 on Chromosorb W 240 C He, 40 psi) to be a mixture
of 3 (57%) and 4 (43%).
O-{2-(2-Methylbut-3-enyl)}-N-methyl-N-phenylhydroxylamine (7).3 m-CPBA (3.44 g, 50%,
10 mmol) in CHCl3 (50 mL) was added to a solution of amine 5 (1.75 g, 10 mmol) in CHCl3
(50 mL) at 05  C over a period of 20 min. After 10 h stirring, the mixture was washed with aq
K2CO3, dried (Na2SO4), the solvent evaporated and the residue chromatographed (silica gel, pet ether)
to afford 3.06 g of 7 (89%).
1
2
3
4
5*
6
7
8
9

Meisenheimer J
Brown EV
Majumdar KC
El-Bergmi R
Guarna A
Bailey PD
Micouin L
Williams EJ
Beauchemin AM

Chem Ber
J Org Chem
J Org Chem
J Org Chem
Tet Asymm
Chem Commun
Tet Lett
Tet Lett
J Am Chem Soc

1926
1967
1997
2000
2000
2000
2001
2004
2009

59
32
62
65
11
42
45
131

1848
241
1506
8574
4227
2451
537
3737
874

313

MELDRUMS Acid
A cyclic malonate derivative 3 with an acidic methylene group, used in place of malonates in
alkylations, acylations, or reaction with aldehydes or ketones (3 10),11 in conjugate additions.4
3 can be used in synthesis of ketenes,5 in ring expansions (1 4),10 or as precursors to aryl
propanoic acids.12 Also asymmetric reactions (5 7).9

S
PhOC

COPh

N
1

O
O

8, [RhOH(cod)]2 O
4 MS, DME, r.t. Ph

Ph

SiMe3 6

CH2Cl2
O

Ph

35 C

N
H

4, 97%10
Ph

O
MeO
MeO

P[C6H3(CH3)2]2
P[C6H3(CH3)2]2
8

SiMe3
5

OH

7, 91%, 98% ee 9

CHO
O
O

O
3

O
NO2

[bmim]BF4
Piperidine

O
NO2
O

O
10, 96%11

2-[2-Hydroxy-2-phenyl-2H-1,4-benzothiazin-3(4H)-yliden]-1-phenyl-1-ethanone (4).10 A mixture

of benzothiazole 1 (0.135 g, 1 mmol), dibenzoylacetylene 2 (0.234 g, 1 mmol) and Meldrums acid
3 (0.144 g, 1 mmol) in dry DCM (5 mL) was stirred at 35  C for 5 d. After evaporation of the solvent,
the residue was chromatograped (n-hexane:EA, 1:1) to afford yellow crystals of 4 (97%).

1
2R
3
4*
5
6
7R
8R
9*
10
11
12
13

Meldrum AN
McNab H
Popik VV
Carreira EM
Wentrup C
Spino C
Ivanov AS
Lipson VV, Gorobets NY
Fillion E
Adib M
Tahmassebi D, Wilson LJA
Dilman AD
McNab H

J Chem Soc
Chem Soc Rev
J Am Chem Soc
Org Lett
Org Biomol Chem
J Org Chem
Chem Soc Rev
Mol Divers
J Am Chem Soc
Tet Lett
Syn Comm
Tet Lett
Synthesis

1908
1978
2003
2003
2007
2008
2008
2009
2009
2009
2009
2009
2010

93
7
125
5
5
73
37
13
131
50
39
50

598
345
14153
4557
1437
7457
789
399
14608
4420
2605
2998
1361

314

MENCKELASZLO Nitration of Phenols

Preferential ortho nitration of phenols, or PhMe or nitration of other Ars by metal nitrates or by
alkyl nitrates catalyzed by Clayfen prepared from K-10-bentonite and Fe(NO3)3 in acetone.4
Also catalysis by zeolites.7
O

O
Claycop
Fe(NO3)3
PhMe, 20 C

HO

O2N

NO2
Clay, CCl4
3

HNO3, Ac2O

2, 55%4

HO
NO2

+
4

40:60

NO2

5, 92%8

Nitrobenzene (4) and 1,3-dinitrobenzene (5).8 3 (5 mmol) was added to a well stirred suspension
of clayfen (2.4 g, 0.5 mmol) in CCl4 (1.5 mL) and Ac2O (0.75 mL) at r.t. The mixture was cooled
to 0  C and fuming nitric acid (1 mL, 0.5 mmol) was added dropwise, then all was stirred well at r.t.
Filtration, washing the organic layer (H2O) and chromatography (silica, hexane:EA) afforded 92%
of 4 and 5 (4:6).

1
2
3
4
5R
6
7
8
9

Mencke JB
Laszlo P
Laszlo P
Laszlo P
Laszlo P
Braibante MEF
Kwok TJ
Gignate B
Cheng G

Rec Trav Chim Pays Bas

Tet Lett
Tet Lett
J Org Chem
Pure Appl Chem
J Org Chem
J Org Chem
J Org Chem
Cen Eur J Ener Mater

1925
1982
1983
1983
1990
1994
1994
1995
2007

44
23
24
48
59
59
60
4

141
5035
3101
4771
2027
898
4939
3445
59

MERRIFIELD Polymers and Peptide Synthesis

Polystyrene resin 1 or 5, copolymers of chloromethylstyrene (or the C55O derivative) with
styrene, used in solid-phase synthesis. Resins usually require swelling in polar solvents.
The Merrifield method of automated solid phase peptide 9, 10 synthesis1,2 consists of attaching
the C-terminal N-Boc-protected amino acid 6 to resin 5 followed by deprotection of the amine
with TFA and coupling to the next N-protected amino acid 8 (7 9) with final cleavage of the
resin by HF in an automated apparatus. Polymers 1, 3 or others can be used as supports in solid
phase organic synthesis, by attaching carboxylic acids, alcohols, phenols (2 3 4), thiols or
amines.

315
OAc

N3
OAc

HN

Cl
2

O
O

HO
Ph-Et, 135 C, 16 h

3, 67%

4, 25%3

HO

1
Cl

NBoc

1.

H2N

HO2C * R
6
2. TFA

NBoc

NHBoc

H
N

* R'
O TFA
O
HF

HO2C * R'
8
O
DCC

O
9

HN
HO2C * R
10

NH2
*
R'

Polymer attached ester (3).4 To a suspension of polystyrene resin 1 (485 mg, 0.60 mmol) in 1 mL
anhyd ethylbenzene was added phenol 2 (670 mg, 1.69 mmol) in 8 mL dry ethylbenzene and
73 mg (0.6 mmol) DMAP with stirring. After heating for 16 h at 136  C, filtration, consecutive washing with DCM, DMF and DCM. and 16 h of drying in vacuo, afforded 644 mg of resin 3 (67%) which
was converted to 4.
1
2
3
4
5
6
7
8

Merrifield RB
Barany G
Sanz V
Porier D
Wells A
Enders D
Rivero IA
Luis SV

Tetrahedron
Peptides
React Funct Poly
J Comb Chem
Org Proc Res Dev
J Comb Chem
J Comb Chem
J Comb Chem

1974
1980
1999
2000
2000
2001
2003
2004

17
2
42
2
4
3
5
6

3209
1
65
48
606
71
149
859

MEYERSCHUSTER Propargyl Rearrangement

Acid catalyzed rearrangement of acetylenic alcohols 1, 3 into a,b-unsatured carbonyl compounds 2, 4; can use InCl3 as Lewis acid catalysts.8,10 Compare to Rupe.
OH
115 C
2, 33%

Catalyst

CHO

28% H2SO4

OH 3

DME, 80 C,
36 h

4, 91%10 O

Catalyst = [ReOCl3(OPPh3)(SMe2)]

(S)-a-Ionone (4).10 A stirred mixture of [ReOCl3(OPPh3)(SMe2)] catalyst (18 mg, 0.026 mmol) and propargyl alcohol 3 (100 mg, 0.52 mmol) in DME (1.05 mL) was heated at 80  C for 36 h. After the
catalyst was filtered, evaporation and chromatography (silica, hexane:Et2O, 98:2) afforded 4 in
91% yield.
1
2
3
4R
5

Meyer KH, Schuster K

McGregor WS
Huggil HPW
Swaminathan S
Yoshimatsu M

Chem Ber
J Am Chem Soc
J Chem Soc
Chem Rev
J Org Chem

1922
1948
1950
1971
1995

55
72
71
60

819
183
335
429
4798

316
6
7
8
9
10

Org Lett
Synlett
Tet Lett
Org Biomol Chem
Chem Eur J

De Shong P
Prajapati D
Cadierno V
Dudley GB
Vidari G

2007
2008
2009
2009
2009

3209
3001
4773
4149
3940

50
7
15

MEYERS Chiral Oxazoline

Chiral oxazolines 1 in asymmetric alkylation (1 2) leading to carboxylic acids 3 on hydrolyisis, or to aldehydes on reduction-hydrolysis. Also synthesis of chiral dihydronaphthalene
derivatives 6 by conjugate addition to chiral naphthyloxazolines 4 or to unsaturated
oxazolines.11
O

Ph

N
1

OMe

Ph
O

LDA

BuI

-78 C

-98 C

Ph

OMe

N
C5H9Li

Bu *

CO2H

Ph H2SO4

N
OMe

9-BBN

Me-OTf

Bu

3, 66%2, 75%ee

OMe
N

MeI

CHO
HO

NaBH4
OMe

OMe

OMe

(S)-(+)-2-Methylhexanoic acid (3).2 4S, 5S-1 (15.4 g, 70 mmol) in THF (160 mL) under N2 at
78  C, was treated with LDA (from 9.8 mL of i-Pr2NH and 2.2 M n-BuLi (33 mL)) in THF
(75 mL) over 20 min. After 20 min, the mixture was cooled to 98  C and BuI (14.7 g, 80 mmol)
in THF (20 mL) was added over 20 min. After 2 h, the mixture was warmed to 20  C, poured into brine
and extracted with Et2O. Bulb-to-bulb distillation afforded pure 2 [a]589 32.2 . The crude oxazoline 2 (17.2 g) was refluxed for 1 h in 4N H2SO4. Extraction with Et2O (3.75 mL), washing with 5%
K2CO3 (3  100 mL), acidification (pH 1) of the aq extract with 12M HCl and extraction with Et2O,
gave on distillation 5.8 g of 3 (66%, 75% ee), [a]589 14.5 .
1*
2*
3*
4*
5*
6*
7*
8*
9*
10*
11*
12*
13*

Meyers AI
Meyers AI
Meyers AI
Meyers AI
Meyers AI
Meyers AI
Meyers AI
Meyers AI
Meyers AI
Meyers AI
Hassner A
Bayardon J
Meyers AI

J Am Chem Soc
J Am Chem Soc
Acc Chem Res
J Org Chem
J Org Chem
J Am Chem Soc
Tetrahedron
Tetrahedron
Tetrahedron
Tet Lett
Tetrahedron
J Org Chem
J Org Chem

1974
1976
1978
1980
1987
1988
1989
1991
1992
1998
2002
2004
2005

96
98
11
45
52
110
45
47
48
39
58
69
70

268
567
375
2785
4592
4611,7854
6949
9503
2589
5301
207
3121
6137

317

MICHAEL Conjugate Addition

Base promoted 1,4-additions of nucleophiles (usually C but also N, O, S) to electron deficient
alkenes (a,b-unsaturated esters, ketones, nitriles, sulfones, nitro compounds); often stereoselective addition. Also intramolecular.4 Effect of metal (Cu, Mg, Zn, Al) cations.19 Asymmetric
additions (Barbas).
O
COCH3

CO2Et
1

O
COCH3 VAp: calcium vanadate
apatite heterogeneous base
CO2Et

VAp catalyst
Water

3, 92%8

OMe
O

Ph
N

OMe

S
OMe

N
H

OEt

Ph

DBU
LiOTf

6, 88%16
Ph
O 2N
Ph

O
OEt
N

THF

Ph
7

N
OMe

NO2

Ph

CH2Cl2

O
Ph

MnO2
Silica gel

syn:anti 10.4:1

Ph
8

9, 90%13

1-(4,7-Dimethoxybenzo[b]thiophen-2-yl)-3-(4-phenylpiperazin-1-yl)propan-1-one (6).16 To 4
(100 mg, 0.40 mmol) and 5 (93 mg, 0.57 mmol), in 20 mL of DCM was added 5 g of 1:4 MnO2:
SiO2 with good stirring. After 15 min at r.t., evaporation, irradiation of the residue in a microwave
oven at 900 W for 4 min, then washing well (EA), evaporation and crystallization from EtOH:MeCN
5:1 afforded 6 (88%).
1
2
3R
4R
5R
6
7R
8
9
10R
11R*
12R*
13R
14R*
15
16
17
18
19
20
21

Komnenos A
Michael A
Bergmann ED
Little RD
Soloshonok VA
Namboothiri INN
Enders D
Kaneda K
Namboothiri INN
Ge Z-M, Li R-T
Vicario JL
Najera C
Tang Y
Gutnov A
Namboothiri INN
Pessoa-Mahana H
Du D-M
Chen W-Y
Knochel P
Namboothiri INN
Namboothiri INN

Liebigs Ann
J Prakt Chem
Org React
Org React
Curr Org Chem
J Org Chem
Eur J Org Chem
J Org Chem
Eur J Org Chem
Synlett
Synthesis
Tet Asymm
Acc Chem Res
Eur J Org Chem
Eur J Org Chem
ARKIVOC
Synlett
Syn Comm
Angew Chem Int
J Org Chem
Tet Lett

1883
1887
1959
1995
2002
2005
2005
2006
2006
2007
2007
2007
2008
2008
2008
2009
2009
2009
2009
2009
2010

218
35
10
47
6
70
71

18
41

xi
39
48
74
52

145
348 (2)
179
315
341
2235
29
7455
4693
1529
2065
299
937
4547
6106
316
925
2014
645
2601
258

318

MICHAELISNYLEN Phosphonylation
Nucleophilic attack of lithium dialkylphosphonates 3 on pyridinium salts 2 to produce
2-pyridine phosphonate 5.
O
LiP(OEt) 2

Me 2SO4
N
O

N
MeSO 4
OMe
2

P (OEt) 2

OMe O

5, 67%

P(OEt)2
O

Diethyl pyridine-2-phosphonate (5).4 BuLi (23% in hexane) (12.6 mL, 0.03 mol) was added dropwise to diethyl phosphonate (5.0 g, 0.036 mol) at 20 to 30  C over 2 h. To the resulting 3 was added
2 (from Pyr N-oxide 2.83 g, 0.03 mol and dimethyl sulfate 3.78 g, 0.03 mol) in diethyl phosphonate
(8 mL) over 1 h at 15  C. The mixture was stirred at r.t. overnight and water (20 mL) was added.
After extraction with CHCl3 (3  15 mL), the organic layer was extracted with 4N HCl, basified
and reextracted to afford 5.2 g (67%) of 5.
1
2
3
4
5
6
7R

Chem Ber
Chem Ber
Chem Ber
J Org Chem
J Org Chem
J Org Chem
Chem Rev

Michaelis A
Michaelis A
Nylen T
Gordon M
Redmore D
Kem KM
Stevens CV

30
31
57
31
35
46
109

1897
1898
1924
1966
1970
1981
2009

1003
1048
1023
333
4114
5188
2672

MIDLAND Asymmetric C55O Reduction

Asymmetric reduction of propargyl ketones 1, 3 with (R) or (S) Alpine borane (B-isopino-camphenyl-9-borabicyclo [3.3.1] noname 2). Compare with Brown and with Corey.
*
OH

O
1

3, 86%, 94%ee2

B
2

SiMe3

OH
2
2.5 d, 6 atm

*
5, 100%ee

R-(+)-1-Octyn-3-ol (3).2 To Alpine borane 2, (prepared from 800 mL of 0.5 M THF solution (0.4 mol)
of 9-BBN and ()-(a)-pinene (61.3 g, 0.45 mol) refluxed 4 h, and distilling excess a-pinene and THF at
0.05 mm, 40  C), 1-octyn-3-one 1 (35.3 g, 0.285 mol) was added under N2 at 5  C. The mixture was
warmed to r.t. After 8 h (GC monitoring) excess 2 was destroyed with propionaldehyde (0.3 mol)
by stirring for 1 h. a-Pinene was evaporated, THF (200 mL) was added followed by 3M NaOH
(150 mL) and 30% H2O2 (150 mL). After 3 h stirring at 40  C, the mixture was extracted with Et2O
(3  50 mL). The dried extract was evaporated and the residue distilled to afford 31 g of 3 (86%),
bp 6065  C/3 mm Hg, [a]D 7.5 , 94%ee.

319
1
2
3R
4
5

J Am Chem Soc
Tetrahedron
Chem Rev
J Org Chem
Syn Comm

Midland MM
Midland MM
Midland MM
Shigemasa Y
Haung S

70
40
89
56
30

1980
1984
1989
1991
2000

867
1371
1553
910
2423

MIESCHER Acid Chain Degradation

Stepwise, three carbon degradation of a carboxylic acid side chain (1 3). Compare with
BarbierWieland.
O
CO2 R
1. PhMgBr
HO

2. Ac2O

NBS
PhNMe2
Ac 2O

CrO3
NaOH
Ph

Ph

AcO

3, 27%

3a-Acetoxy-5b-[11,11,12,12-2H]pregnan-20-one (3).4 2 was prepared from ester 1 by reaction with

PhMgBr and heating with Ac2O, followed by allylic bromination and HBr elimination with PhNMe2.
CrO3 (5.4 g) in 80% AcOH (150 mL) was added dropwise to 5.4 g of 2 in 150 mL CHCl3 and 150 mL
80% AcOH at 5  C. After 3 h, sodium thiosulfate was added, the mixture was concentrated and
extracted with ether-CHCl3 (4:1). Workup and evaporation gave crude 3, which was treated with
4.8 g of Girard-T reagent in 60 mL MeOH and 6 mL HOAc and refluxed for 1 h. This was poured into
ice and 85 mL 1N NaOH and washed several times with ether. Acidification of the aq layer, workup
and crystallization afforded 1.5 g (27%) of 3, mp 9698  C.
1
2
3
4
5

Miescher K
Spring FS
Wettstein A
Shimizu K
Pines SH

Helv Chim Acta

J Chem Soc
Experientia
Steroids
Org Pro Res Dev

27

1944
1950
1954
1988
2004

1815
3355
407
283
708

51
8

MIGITASANO Quinodimethane Synthesis

In situ synthesis of quinodimethane 3 by proton induced 1,4-elimination of hydroxystannanes
2 and trapping of the unstable 3 with a dienophile 4 in a DielsAlder reaction to form 5.
O
O
OH

2 BuLi

OH
SnBu3

Bu3 SnCl
1

F3 CCO 2H
20 C

4 O
3

O
O
5, 96% 2 O

320
Anhydride (5).2 To 2 (100 mg, 0.24 mmol) and 4 (71.6 mg, 0.73 mmol) in DCM (0.2 mL) was added
TFA (0.038 mL, 0.48 mmol) at 20  C and the mixture was stirred for 1 h. DCM, TFA and unreacted
4 were removed in vacuo and the residue was treated with n-heptane (1 mL) to afford 47 mg of
5 (96%).

1
2
3

Angew Chem Int

J Am Chem Soc
Chem Lett

Kauffmann T
Migita T, Sano H
Kuwano R

21
110
34

1982
1988
2005

410
2014
728

MILAS Olefin Hydroxylation

Hydroxylation of a conjugated double bond 1, 4 to a 1,2-diol 2, 3, 5 with hydrogen peroxide and
OsO4 as catalyst. Compare with Criegee.

OsO4
30% H2O2
O

O
1

HO

O
OH

OH

2, (23%)
3, (4, 5, 28%)
OH O

OsO4
H2O2,
BuOH

OH
OH
5, 56%1

Phenylglyceric acid (5).1 To 4 (1.2 g, 0.0083 mol) and 6.3% H2O2 (4.33 mL, 0.0083 mol) in t-BuOH
(4.33 mL), in an ice-bath was added OsO4 solution (0.66 mL) as a catalyst. After completion of the
reaction overnight at 0  C, the solvent was evaporated in vacuo and water was added. The solid
was filtered and the filtrate was distilled in vacuo to afford 5 (56%), as a semi-solid.

1
2
3
4
5
6

Milas NA
Milas NA
Sharpless KB
Sharpless KB
Hartley WM
Beller M

J Am Chem Soc
J Am Chem Soc
J Am Chem Soc
J Org Chem
Org Synth
J Organomet Chem

1936
1959
1976
1978
1978
2001

58
81
98
43
58
621

1302
3114
1986
2063
43
70

321

MILLERSNYDER Aryl Cyanide Synthesis

Synthesis of benzonitriles 4, 8 from benzaldehydes via oxime ethers 3, 7 mediated by hydroxylamine 2 or p-nitrobenzonitrile 6. Formation of p-cyanophenol 8 from p-nitrobenzaldoxime
5 and p-nitrobenzonitrile 6 (used sometimes as a recyclable chain carrier (5 + 6 8 + 6).
O

O
H2NO
H

H+

+
NO2

O2N

O
1

O
N

NO2

O
4, 81%2

H
CN

DMSO, 114 C
Na2CO3

+
NO2

3
CN

N OH

+ 6
HO

CN

CN

Base

NO2

O
N
O2N

8, 83%

Nitrile (4).2 To stirred O-(2,4-dinitrophenyl)hydroxylamine 2 (0.995 g, 5 mmol) in EtOH (50 mL) was
added piperonal 1 (0.75 g, 5 mmol) and two drops of conc HCl. After cooling and filtration, the filtrate
was kept overnight at 23  C to give 3. To 0.5 g (1.51 mmol) of 3 in 50 mL of 95% ethanol, KOH
(20 mL, 0.2N in 95% ethanol) was added and the mixture was heated slowly to reflux for 3 h. Concentration in vacuo, extraction with CHCl3, drying, evaporation and crystallization from hexane
afforded 4 as a white solid (81%).
1
2
3
4

J Org Chem
J Org Chem
J Org Chem
J Org Chem

Snyder HR
Miller MJ, Loudon GM
Snyder HR
Ishii Y

39
40
40
65

1974
1975
1975
2000

3343
126
2879
6209

MILSTEIN Alcohol Amidation

Coupling of primary alcohols 1 with primary amines 2 under neutral conditions to form amides
3 with liberation of dihydrogen catalyzed by Ru complex 4. Sensitive to steric effects in 1 or 2.
Diamines produce bisamides. May involve intermediate aldehydes and hemiacetals.
Me

PBut2

OH
1 +
2

H2N

H
N

4 (0.1 mol%) Ar
NH2

PhMe, reflux, 9 h
3, 99%

H
N

NH2

5 +
6

Me
+ 2H 2

Ru

NEt 2

4 (0.1 mol%) Ar
NH

PhMe, reflux, 8 h
OH

N
H

HN

7, 88%1

CO
4

322
N-Pentyl-2-methoxyacetamide (3).1 Ru catalyst 4 (0.01 mmol), alcohol 1 (10 mmol), n-pentylamine
2 (10 mmol), and PhMe (3 mL) were refluxed under Ar. Solvent evaporation in vacuo and chromatography of the residue (silica gel, EA:n-hexane) afforded 3 (99%).

1
2
3
4

Science
Topics in Catalysis
J Am Chem Soc
Macromolecules

Milstein D
Milstein D
Guan Z
Milstein D

317
53
133
44

2007
2010
2011
2011

790
915
1159
in press

MINAMI Thiourea Dioxide Reducing Agent

Formamidine sulfinic acid (thiourea dioxide) H2N55C(NH2)22SO2  2 with NaOH or NaOR,
as a reducing agent of ketones, selective reduction of aromatic nitro ketones or aldehydes 1 to
alcohols 3.8 Also reduction of disulfides or sulfoxides to sulfides3 and of azo compounds to
hydrazo derivatives.7 Compare with MeerweinPonndorf.
OH

O
NH 2

SO 2

H2 N

NaOH, EtOH
90 C, 2 h
NO2

NO2
1

3, 80%9

m-Nitrobenzyl alcohol (3).9 Aq NaOH (40 mmol) and thiourea dioxide 2 (2.16 g, 20 mmol), were
added in one portion to 1 (3.02 g, 20 mmol) in 60 mL EtOH. After 2 h stirring at 90  C, EtOH was
evaporated, the aq layer was extracted with ether (3  30 mL). Workup and silica gel chromatography
(EA:hexane) gave pure 3 (2.44 g) in 80% yield.

1
2
3
4
5
6
7
8
9

Boeseken J
Shashova VE
Minami K
Drabowicz J
Lang ES
dos Santos RB
Makarov S
Dhillon RS
Dhillon RS

Proc Acad Sci

Biochemistry
Tet Lett
Synthesis
Syn Comm
Tet Lett
Russ J Gen Chem
Syn Comm
ARKIVOC

1936
1964
1972
1978
1989
1997
2006
2008
2009

39
3
5
19
38
76
38
x

717
1719
343
542
239
745
1599
2150
141

323

MINISCI Free Radical Substitution

Iron catalyzed substitution of protonated heteroaromatic bases 3, 5 by nucleophilic radicals;
free radical amination of aromatics, free radical carbamylation.
Me
NCl + PhH
Me

Me
Ph N
Me

FeSO4
AcOH

HCONH2/FeSO4
H2O2/H2SO4

2, 76%2

CONH2

4, 82%3

C6H11
(PhCOO)2

+
N

7, 88%

N,N-Dimethylaniline (2).2 To N-chlorodimethylamine 1 (0.43 g, 0.54 mmol), HOAc (5 mL), PhH

(3 mL) and H2SO4 (8.3 mL) was added FeSO4 with stirring. After 15 min the mixture was quenched
with ice, basified with (NaOH) and extracted with PhH. Distillation afforded 50.5 g of 2 (76%).
Quinoxaline-2-carboxamide (4).3 Quinoxaline 3 (1.3 g, 0.01 mol) and 98% H2SO4 (0.55 mL)
in HCONH2 (10 mL) was treated with 34% H2O2 (1.5 mL, 0.015 mol) and FeSO4.7H2O (4.17 g,
0.015 mol) under efficient stirring. After 15 min at 1015  C, HCONH2 was distilled, the residue
was extracted (CHCl3) and the solvent evaporated to give 1.4 g of 4 (82%), mp 200  C.
1
2
3
4
5
6
7
8

Chem Ind Milano

Tet Lett
Tet Lett
J Org Chem
J Org Chem
Heterocycles
J Heterocycl Chem
Res Chem Interm

Minisci F
Minisci F
Minisci F
Minisci F
Minisci F
Minisci F
Minisci F
Caronna T

47
9
11
51
52
28
27
33

1967
1968
1970
1986
1987
1989
1990
2007

705
5609
4153
4411
730
489
79
311

MISLOWBRAVERMANEVANS Sulfoxide Rearrangement

Reversible [2,3]-sigmatropic rearrangement of allylic sulfoxides 7 to allyl sulfenates 8 which
are cleaved by phosphites or thiols to allylic alcohols 9. Used in formal olefinic alkylation of
allyl alcohols (Evans, e.g. 1 2 3 5).3
I
O
OH

PhSO

2
SPh

CN mCPBA

HO
5, 58%6

CN

CN

SPh
O
6

PhSH

4
BuLi

S
Ph
3

SPh
O

CN
HO
9, 86%7

324
(+)-(E)-Nuciferole (5).6 To sulfoxide 3 (390 mg, 2 mmol) in THF (20 mL) at 50  C under N2 was
added dropwise BuLi (1.66 M) in hexane (1.3 mL, 2.16 mmol) and then 4 (1096 mg, 30 mmol) in THF
(2 mL) over 10 min. After 1 h stirring at 50  C and 2 h at 25  C the mixture was poured into brine,
extracted with Et2O:hexane (3:1) and evaporated. The residue was dissolved in MeOH (3 mL) and
treated with Ph-SH (1320 mg, 10.8 mmol) in MeOH (40 mL). BuLi (1.56 mL) was added under
N2 and the mixture was heated for 7 h at 65  C followed by purification (preparative TLC, Et2O:
hexane) to give 5 (58%).
Alcohol (9).7 Sulfide 6 (640 mg, 2.76 mmol) and m-CPBA (760 mg, 3.04 mmol) was stirred for 15 h at
78  C. Hydrolysis with aq NH4Cl, extraction with DCM and evaporation of the solvent gave 692 mg
of an oil, which was refluxed with MeOH (30 mL) and Et2NH (1460 mg, 20 mmol) followed by workup
and chromatography (silica gel, hexane:Et2O 1:1) to afford 9 (86%).
1
2
3
4
5R
6
7
8
9
10

Mislow K
Braverman S
Evans DA
Grieco PA
Evans DA
Grieco PA
Biellmann JF
Ruano Garcia JL
Satoh T
Poli G

J Am Chem Soc
J Chem Soc Chem Comm
J Am Chem Soc
J Chem Soc Chem Comm
Acc Chem Res
J Org Chem
J Org Chem
J Org Chem
Tet Lett
Org Lett

88

1966
1967
1971
1972
1974
1975
1992
1994
2006
2010

93
7
38
57
59
47
12

3138
270
4956
2245
147
2245
6301
3421
1981
320

MITSUNOBU Nucleophilic Displacement

Inter or intramolecular nucleophilic displacement of alcohols with inversion, at r.t. or below, by
means of diethyl (or diisopropyl) azodicarboxylate (DEAD), triphenylphosphane and a mildly
acidic nucleophile (RCO2H, ArOH, RSH, imides, b-ketoesters, tosyl- or Boc-hydrazones, heterocycles). Boron mediated reactions. Also Grieco alcohol dehydration via Se nucleophiles
(Ph3P and ArSeCN).15 Esterification of alcohols or alkylation of phenols and one step synthesis
of nitriles from alcohols using acetone cyanohydrin. Mechanism.8,10

CO 2Me

CO2Me

PPh 3, DEAD
0 to 20 C
OH

HO
OH

HO

Ph

NHTs

OH

Ph
5

O
OH
7

CO 2Me

O PPh3
OH 2

DBAD, PPh 3
THF, 0 C

PPh3 , DEAD
Toluene/THF
TosNHOTBS, 0 C

Ph

HO

O
3, 77% 2
Ph

NTs

6, 90%9

OTBS
N
Tos
8, 100% 12

325
()-Methyl cis-3-hydroxy-4,5-epoxycyclohex-1-enecarboxylate (3).2 To ()-methyl shikimate
1 (110 mg, 53 mmol) and Ph3P (278.5 mg, 1.6 mmol) in THF, was added with stirring DEAD
(185 mg, 1.21 mmol) at 0  C, under N2. After 30 min at 0  C and 1 h at 20  C, the product was vacuum
distilled (kugelrohr) at 165  C (0.1 mm) and taken up in Et2O. Cooling gave bis-(carbethoxy) hydrazine (5 mg, mp 133  C). Concentration, chromatography (prep TLC, silica gel, Et2O) and recrystallization (Et2O-pet ether) gave 3 (77%).
(E)-2-Benzyl-1-benzylidene-2-tosylhydrazine (6).9 To a stirred mixture of Ph3P (1 equiv) and THF (0.4
M with respect to hydrazone substrate) at 0  C was added DEAD (0.9 equiv). The reaction mixture was
stirred for 10  min. To this were added slowly a solution of 4 (0.5 equiv) and 5 (0.75 equiv) in THF (0.4 M)
over 10 min and stirred at 0  C. Usual workup and chromatography gave product 6 as a white solid (90%).
1
2
3
4
5R
6
7R
8
9
10R
11
12
13
14R
15*
16
17
19
20

Mitsunobu O
Berchtold GA
Hassner A
Szantay C
Hughes DL
Iranpoor N
Dembinski R
Schenk S
Keith, JM
Toy PH
Curran DP
Zakrzewski J
Fukuyama T
Kumara Swamy KC
Jamart-Gregoire B
Berree F
Sugimura T
Toy PH
Overman LE

Bull Chem Soc Jpn

J Org Chem
J Org Chem
Syn Comm
Org Prep Proced Int
Synthesis
Eur J Org Chem
J Am Chem Soc
J Org Chem
Chem Asian J
Org Lett
Tet Lett
Org Lett
Chem Rev
Tet Asymm
Eur J Org Chem
Tetrahedron
Synlett
J Am Chem Soc

1967
1981
1990
1995
1996
2004
2004
2005
2006
2007
2008
2008
2008
2009
2009
2009
2009
2010
2010

40
46
55
25
28

2380
2381
2243
1545
127
92
2763
12566
7113
1340
2453
6311
2259
2551
1809
329
6109
1115
7876

127
71
2
10
49
10
109
20
65
132

MOORE Cyclobutenone Rearrangement

Thermal (or photochemical) rearrangement of alkenyl or alkynyl cyclobutenones to highly
substituted phenols, benzofurans, quinones, or isoquinolines. Involves electrocyclic ring opening of cyclobutenones 3, 6 to vinylketenes 4, 7. Vinyl cyclobutenones are also intermediates in
thermolysis of cyclobutenones with alkynes.1
O

PrO

RO
PrO

+ -78 C

BuLi/ RO
THF

N
Naphth

RO

OH

O
6

OH
RO

N
Naphth

HO

R
Xylene, 2 h

PhCl
132 C
RO

OH

140 C
MeO

RO

5, 71% 6

MeO
MeO

O
R

OH
MeO

MeO
O

MeO
7

O
8, 71%

326
10,11-Diisopropoxy-N-methyl-7,8-dihydrobenzophenanthridine-9,12-diol (5).6 3 (0.10 g, 0.25
mmol) in 10 mL PhCl was added dropwise to 50 mL refluxing PhCl over 1.5 h. After 20 min of reflux,
the cooled mixtutre was concentrated in vacuo. Chromatography (hexanes:EA, 15:1) gave 5 (71%) as a
light purple solid.

1
2
3
4
5
6
7
8
9
10
11

J Org Chem
J Am Chem Soc
J Org Chem
J Am Chem Soc
J Org Chem
J Org Chem
J Am Chem Soc
J Org Chem
J Org Chem
Angew Chem Int
J Org Chem

Danheiser RL
Moore HW
Moore HW
Danheiser RL
Moore HW
Moore HW
Wulff WD
Hassner A
Moore HW
Harrowen DC
Danheiser RL

49
107
51
108
53
56
118
61
64
46
76

1984
1985
1986
1986
1988
1991
1996
1996
1999
2007
2011

1672
3392
3067
806
4166
6104
1808
4051
5979
425
1852

MORIN Penicillin Rearrangement

Ring expansion of five-membered ring penams 1 to six-memberd ring cephems 3 via sulfoxides
under acidic catalysis.
OS+

H
N

PhO
O

N
O
CO 2Me

H
N

PhO
TsOH
120 C

SOH

N
O

H
N

PhO

CO2 Me
2

S
N

O
3, 15%1

CO 2Me

Cephalosporin (3).1 Reflux of phenoxymethylpenicillin sulfoxide methyl ester 1, with a trace of

p-toluene-sulfonic acid in xylene gave 3 (15%), mp 141142  C.

1
2
3
4
5
6

Morin RB
Morin RB
Conway TT
Cooper LE
Farina V
Gates KS

J Am Chem Soc
J Am Chem Soc
Can J Chem
Chem Ind
Tet Lett
Chem Res Toxicol

1963
1969
1978
1978
1992
2008

85
91
56
33
21

1896
1401
1335
794
3559
1368

327

MORITABAYLISHILLMAN C55O C55C Coupling

Also known as BaylisHilman. C2
2C Coupling of activated alkenes 2 (activating group: CN,
5O, NO2) with C-electrophiles (aldehyde 1 or activated C55N 6) in the presence
C55O, SO2, P5
of a nucleophilic Lewis base (amines like DABCO 3 or phosphines), usually at r.t. Also with
microwaves. Ketones require activation, poor yields with b-substituted olefins except in the case
of nitroalkenes.69,17 Proceeds via conjugate addition of tert amine (2 to 5). Also with asymmetric induction. Reaction in water with Im catalysis.15 Compare with Krische. Compare with
RauhutCurrier.
N
O
CO2Me

R
1

O
R

(R)-9
THF,
-30 C

Ts

NH

R'3 N 4 CO2 Me

Ar C N Ts +
H
Ar
(substituted phenyl)
6

OH

CO2Me

O
OH
PPh2

Ar
8, 92%, 94%ee
(R)- 9

Aminoketone (8).12 To degassed tosylimine 6 (37 mg, 0.125 mmol) and catalyst (R)-9 (13 mg, 0.0086
mmol) under Ar was added MVK 7 (21 mL, 0.25 mmol) in DCM (1 mL). The reaction mixture was
stirred at r.t. for 2448 h, then concentrated in vacuo and the residue was chromatographed (SiO2, EA:
PE 1:4) to afford pure 8 (92%).
1
2

Morita K
Baylis AB, Hilman MED

3R
4
5R
6
7
8
9
10R
11R
12*
13R*
14R
15
16
17
18R
19*
20
21

Drewes SE
Basavaiah D
Ciganek E
Namboothiri INN
Namboothiri INN
Namboothiri INN
Namboothiri INN
Shi M
Batra S
Shi M
Krishna PR
Lamaty F
Matsubara S
Yadav LDS
Namboothiri INN
Basavaiah D
Wu Y
Miller SJ
Zhong W

Bull Chem Soc Jpn

Ger Offen 2,155,113, CA
US Pat
Tetrahedron
Tetrahedron
Org React
Tet Lett
Org Lett
Org Biomol Chem
Org Biomol Chem
Eur J Org Chem
Tetrahedron
Eur J Org Chem
Synlett
Chem Rev
Synthesis
Synlett
Tet Lett
Chem Rev
Tet Asymm
Tet Lett
Org Prep Proced Int

1968
1972
1973
1988
1996
1997
2004
2006
2006
2006
2007
2008
2008
2008
2009
2009
2010
2010
2010
2010
2011
2011

41
77
44
52
51
45
8
4
4
64

109

51
110
21
52
43

2815
34174q
3743,669
4653
8001
201
4745
1201
2525
3211
2905
4511
2150
2897
1
3219
1047
846
5447
903
2148
1

328

MOSHERS ACID for Chirality Determination

Synthesis and use of a-methoxy-a-(trifluoromethyl)phenylacetic acid (MTPA) 4, a chiral reagent for determination of enantiomeric purity of alcohols and amines by NMR. () or ()
MTPA is usually used in slight excess (1.4 equiv) with DMPA or as its acid chloride in reaction
with an amine or alcohol at r.t.3 The more nucleophilic thioacid analog of 4 is used as its amine
salt in SN2 displacements.12 Also for determination of absolute configuration.10
PhCOCF 3
1

Cl3CCO 2SiMe3
2

18-crown-6
K2CO3 , 150 C

CF3
Ph

KOH/MeOH

CCl3
OSiMe3
3, 83%

60 C

R
CF3
Ph

CO2 H
OMe
4, 79%

HO

R'

2 Diastereomeric esters

a-Methoxy-a-(trifluoromethyl)phenylacetic acid (4).4 A mixture of trifluoromethylphenyl ketone

1 (1.74 g, 10 mmol), 2 (2.83 g, 12 mmol), 18-crown-6 (0.132 g, 0.5 mmol), and K2CO3 was stirred at
150  C until the evolution of CO2 was complete (ca 30 min). Distillation of 3 afforded 2.98 g (83%), bp
6567  C/0.2 mm. To the above mixture was added under stirring KOH (5.6 g) in MeOH (50 mL).
Stirring was continued for 6 h at 60  C. The cooled mixture was treated with water (65 mL) acidified
with 10% HCl to pH 1, extracted with Et2O and distilled, to afford 1.85 g of racemic 4 (79%),
bp 9093  C/1 mm, which can be resolved.
Enantiomeric purity determination. ()-MTPA (0.77 mL, 0.38 M) in DCM was added to 0.26 mmol
of an alcohol, 0.28 mmol of DCC and 0.03 mmol of DMAP in 1 mL of dry DCM at r.t. After 4.5 h
(complete conversion by TLC), the urea was filtered, EA and water were added and the organic layer
afforded 130 mg of product, which was analyzed by NMR after chromatography.
1*
2*
3*
4*
5*
6*
7*
8*
9*
10*
11*
12*

Mosher HS
Mosher HS
Garner P
Alper H
Alexakis A
Gao L-X
Streinz L
Eames J
Agbossou-Niedercorn F
Plettner E
Hailes HC
Richman JE

J Am Chem Soc
J Org Chem
J Org Chem
J Org Chem
J Org Chem
Tet Asymm
Chirality
Tet Asymm
Tetrahedron
Tet Asymm
Tet Asymm
Tet Lett

1967
1969
1987
1992
1992
2005
2005
2008
2008
2009
2009
2010

89
34
52
57
57
16
17
19
64
20
20
51

4230
2543
2361
3731
1224
2141
378
1274
8700
449
1828
2793

MOUSSERONFRAISSEMcCOY Cyclopropanation
Stereoselective synthesis of cyclopropyl esters 2 or cyano cyclopropanes 5 or other di- (or poly)
substituted cyclopropane derivatives by Michael addition of enolates of a-halo-ketones, esters
or nitriles 4 to acceptor olefins 1, 3 followed by ring closure. Compare with HassnerGhera
Little.

329
H CO 2Me
CO2 Me
PhCOCH2 Br
O

Base, 25 C

COPh
O

Cl
+
CN
CN H
3
4

2, 57%7

CNCN
5

Trans Cyclopropane keto ester (2).7 4% NaOH (1 mL) was added dropwise at r.t. to benzopyranone
1 (1 mmol), phenacylbromide (0.2 g, 1 mmol) and 0.01 g of Aliquat 336 (tricaprylmethyl ammonium
chloride), in 4 mL CCl4 and the mixture was stirred for 1 h and then poured into ice-water and a few
drops of conc HCl. Usual workup afforded 2 in 57% yield; DBU leads to a trans:cis mixture.

1
2
3
4
5
6
7
8
9

Bull Soc Chim Fr

J Am Chem Soc
Compt Rendu
J Org Chem
J Am Chem Soc
J Org Chem
Tetrahedron
Tet Lett
Tetrahedron

Fraisse J
McCoy LL
Mousseron M
Warner DT
Wawzonek S
McCoy LL
Ivanov C
Toyota A
Escribano A

1957
1958
1959
1959
1960
1960
1993
1996
2001

986
6568
887, 465, 2840
1536
439
2078
2275
8507
9423

80
248
24
82
25
49
37
57

M
MUKAIYAMA Aldolization
Stereoselective aldol condensation of aldehydes with silyl (or Sn) enol ethers 2, 6, 9 catalyzed
by Lewis acids (Ti (IV), Sn (II),4 Yb (OTf)3,6 InCl3,9 molecular sieves,17 chiral Cu-oxazolines).
Z-enol ethers 2 to afford mainly syn aldols 3. Asymmetric reactions.5,10,13,14 Compare with
ChanBrassard.
O
O

EtS-SnOTf

OSnOTf

OH

Ph(CH 2) 2CHO

Ph

SEt
1

3 + 4, 75%4
syn:anti = 9:1

EtS

O
PhCHO +
5

OTMS

-78 C
7

HO
Ph

H O

8, 100% 5 , 90% ee

N
H

O
5 +

OTMS
9
OTMS

O
BnO

H
11

OH

InCl3, H2O
30 min

Ph
10, 69%9 anti + syn

Chiral
BnO
OEt Cu-oxazoline
12

OH O
OEt
13

O
H N B
Ts
Bu

330
Syn 3-(Ethylthiomethyl)-4-hydroxy-6-phenyl-2-hexanone (3 and anti 4).4 To ethane thiol (10 mg,
0.17 mmol) in THF (2 mL) was added 1.54M BuLi in hexane (0.1 1 mL) at 0  C under Ar. Stannous
triflate (69 mg, 0.17 mmol) was added and after 20 min the mixture was cooled to 45  C. MVK 1
(118 mg, 1.98 mmol) in THF (1.5 mL) was added followed by 3-phenylpropanal (350 mg, 2.61 mmol)
in THF (1.5 mL). After 12 h, aq citric acid was added and the organic material extracted with DCM.
The residue after evaporation was dissolved in MeOH and treated with citric acid. After 30 min
stirring, the mixture was quenched with pH 7 phosphate buffer. Usual workup and chromatography
afforded 336 mg of 3 and 4 (75%), syn:anti 9:1.
(R)-1-Hydroxy-1-phenyl-3-heptanone (8).5 To a solution of chiral catalyst 7 (28.6 mg, 0.056 mmol)
in EtCN (0.5 mL) cooled at 78  C was added 5 (0.028 mL, 0.25 mmol) followed by 2-trimethylsiloxy1-hexene 6 (0.08 mL, 0.41 mmol). After 14 h stirring at 78  C, the mixture was quenched with sat
NaHCO3 (10 mL). Usual workup and chromatography (silica gel, 520% EA in hexane) gave 58 mg
of 8 (100%, 90%ee).
Anti syn 2-Hydroxybenzylcyclohexanone (10).9 To InCl3 (22 mg, 0.1 mmol) was added 5 (51 mL,
0.5 mmol) and the mixture was prestirred for 30 min before addition of 9 (0.19 mL, 1 mmol) and water
(5 mL). After 15 h stirring at 20  C, usual workup and chromatography gave 70.1 mg of 10 (69%),
61:39 anti:syn.

1
2
3R
4
5*
6
7R
8
9
10R*
11
12
13*
14*
15
16
17

Mukaiyama T
Mukaiyama T
Mukaiyama T
Mukaiyama T
Corey EJ
Shibasaki M
Mukaiyama T
Evans DA
Loh TP
Nelson SG
Casiraghi G
Scettri A
Denmark JR
Rawal VH
Sommer J
Guindon Y
Hashimoto S

J Am Chem Soc
Chem Lett
Org React
Chem Lett
Tet Lett
Tet Asymm
Aldrichim Acta
J Am Chem Soc
Tet Lett
Tet Asymm
Pure Appl Chem
Tet Lett
Angew Chem Int
Angew Chem Int
Chem Eur J
J Org Chem
Heterocycl

1973
1982
1982
1986
1992
1995
1996
1996
1997
1998
2000
2005
2005
2006
2009
2009
2010

95
28
33
6
29
118
38
9
72
46
44
45
15
74
80

967
353
187
187
6907
71
59
5814
3465
389
1645
6141
4682
1
11229
64
1489

MUKAIYAMA Lactonization Reagent

N-Alkyl-2-chloropyridinium iodide 6 (also 2-Br or 2-F, e.g. 1) reagents for esterification of
RCO2H or for macrolactonization of hydroxy acids (2 4) in the presence of base (NaHCO3,
(iPr)2NEt), via 3, sometimes at r.t. Also for lactam formation3 and hindered peptide synthesis4
from amino acids. Improved reagents using OTf, SbCl5 or BF4 anions instead of iodide.35
Compare with Yamaguchi or with CoreyNicolaouGerlach.

331

HO 2C

+
Br

N
Et

NaHCO3

HO

N
Et

3
O
OH

POCl3, 100 C
NaI, Acetone
CH2 Cl2 , EtOH

O
N
5

15

Cl
I

10

O
HO

O
4

OH
O
13

13

O
I
N
+
15

N
Et3 N, 80 C
+
15
6, 80%

OH

17
O

N-Hexadecyl-2-chloropyridinium iodide (6).2 Pyridone 5 (8.5 g, 26.6 mmol) and POCl3 (34.8 g, 26.6
mmol) were heated at 100  C for 2 h and excess POCl3 was evaporated. The residue was dissolved in
acetone (28 mL) and the solution was added dropwise to NaI (7.20 g, 48 mmol) in acetone (32 mL).
The yellow precipitate was washed (ether), treated with sat NaHCO3 and crystallized (EtOH) to give
6, 80% mp 114  C.
Lactone (9). A solution of hydroxyacid 7 (554 mg, 2 mmol) and Et3N (1.616 g, 16 mmol) in 32 mL
DCE was added dropwise to pyridinium iodide 6 in 40 mL DCE at 80  C over 10 min. After 24 h, 9 was
isolated.
1
2
3
4
5
6

Chem Lett
J Org Chem
J Org Chem
Tetrahedron
J Am Chem Soc
J Am Chem Soc

Mukaiyama T
Halvorsen K
Rapoport H
Li P
Evans DA
Smith AB

1
59
63
56
125
131

1976
1994
1998
2000
2003
2009

49
415
8170
8119
13531
12109

MUKAIYAMAUENO Selective Diol Oxidation

Also known as DavidMukaiyamaUeno. Regiospecific oxidation of 1,2-diols 1, 3 to
ketoalcohols 2, 5 by Br2 via Sn derivatives 4.
OH
Ph

Ph

O
O

O
OH (Bu3Sn)O, Br2
CH2Cl2, 20 C

Ph
OCH2Ph Bu2SnO
Reflux
OH

HO
3

Ph

O
O
OCH2Ph
O
O
Sn
Bu2 4

OH
2, 76%4
Ph

O
O

Br2
Bu3SnOMe

OCH2Ph
O

OH
5, 72%

Hydroxyacetophenone (2).4 To diol 1 (285 mg, 2 mmol) and hexabutyldistannoxane (1.30 mL,
2.6 mmol) in DCM was added dropwise Br2 (0.13 mL, 2.6 mmol) in DCM (2.5 mL) under Ar with
stirring. After 3 h, solvent evaporation and crystallization gave ketol 2.

332
1
2
3
4
5
6
7

CR Acad Sci Paris (C)

Chem Lett
Bull Chem Soc Jpn
Tet Lett
Nouv J Chem
J Chem Soc Perkin 1
Tetrahedron

David S
Mukaiyama T
Mukaiyama T
Ueno Y
David S
David S
Arterburn JB

278

1974
1975
1976
1976
1979
1979
2001

49
3
57

1051
145
1656
4597
63
1568
9765

MUNDY N-Acyllactam Rearrangement

Formation of alkyl piperidine derivatives 3 by rearrangement of N-acyllactams 1 via hydrogenation of imine intermediate 2.

N
O
1

CaO, heat
1.5 h

H2
N

C3H7

C3H7

C3H7

N
H

10% Pt/C

2, 30%2

3, 74.5%

6-Methyl-2-n-propylpiperideine (2).2 Calcium oxide (1.5 g) was added to 1.5 g of imide 1 and the
mixture was gently refluxed for 1.5 h. Slow distillation at 1 atm afforded 0.65 g was purified by
Kugelrohr distillation to give 0.35 g (30%) of pure imine 2, bp 7075  C, 0.1 mm.
cis-Dihydropinidine (3). A solution of racemic 2 (278 mg) in 1 mL of 10% HCl was hydrogenated with
15 mg of 10% Pt/C at 1 atm for 35 h till 50 mL of H2 was taken up. Filtration, neutralization with cold 50%
KOH, ether extraction, drying and Kugelrohr distillation afforded 210 mg, 74.5% of 3, bp 175180  C.
1
2
3

Syn Comm
Tetraheron
Syn Comm

Mundy BP
Hill RK
Jun JG

2
33
30

1972
1977
2000

197
1569
73

MURAHASHI Allylic Alkylation

Allylic alkylation (SN20 ) of allyl alcohols (acetates) 1, 6 to give 5, 7, in the presence of copper
salts and phosphinimines 2 via (SN20 of cuprates). Compare with Lipshutz.
MeLi
CuI
Me
+
1 OH Bu3 P-N-Ph
2

_
Me
CuN-Me
3

Ph

+
OPhBu3
4

X
5, 70%5

R-Mg-Br
RCu-MgBr 2

6
7, 6080%
X = OH, OAc

Phosphinimine (2).5 Was obtained by Staudinger reaction of PhN3 with Bu3P in Et2O followed by
reaction with MeI.5
3,5-Dimethylcyclohexene (5). cis-5-Methyl-2-cyclohexenol (1, 1.12 g, 10 mmol) was treated with
MeLi (in Et2O, 6.7 mL, 1.4M) and all was added to a suspension of Cul (1.9 g, 10 mmol) in THF
(20 mL). After 30 min, the solution was cooled to 78  C and 1.49 M MeLi (6.7 mL) in Et2O was added
followed by 2 (0.1534 oz, 10 mmol) in THF (40 mL). After 3 h stirring at r.t., usual workup gave 763 mg
of 5 (70%), purified on a GC-capillary column.

333
1
2
3
4
5
6
7
8

J Am Chem Soc
J Organomet Chem
J Am Chem Soc
J Org Chem
J Org Chem
J Org chem
Tet Lett
Angew Chem Int

Murahashi SI
Lovisalles J
Murahashi SI
Trost BM
Goering HL
Goering HL
Fan C, Cazes B
Cordova A

1977
1977
1978
1980
1981
1985
1988
2006

99
136
100
45
46
50
29
118

2361
103
4610
4256
2144
1597
1701
1986

MYERSSAITO Cycloaromatization
Also known as MyersSaito Cycloaromatization of enyne-allenes 1 to 3. Proceeds via (s,p)1,4-biradicals (a,3-dehydrotolune). Also cycloaromatization of Z-enediynes 4 to 7, which
proceeds via an eneyne-allene 5 and H-transfer from cyclohexadiene to diradical 6. Compare
with Bergman.
TMS

TMS

TMS

70 C
3h
CO2Me

CO2Me
1
Ar

HS

O
DTSO

H O

S
Et 3N
DMSO
r.t.

CO2Me
3, 62%5

ODTS H S

7, 75%3

Tetrahydrothiophene (7).3 TEA (5 equiv) was added to a deoxygenated solution of the thiol
4 (0.01 M) and 1,4-cyclohexadiene (4.0 M) in DMSO at 23  C. To the reaction mixture was added
4-methoxythiophenol (3 equiv) and stirred at 23  C for 10 h. Usual workup and preparative TLC
(34% EA/hexanes) afforded 7 in 75% yield.
1
2
3
4
5
6
7
8

Myers AG
Saito I
Myers AG
Schimittel M
Schimittel M
Schimittel M
de Visser SP
Basak A

J Am Chem Soc
Tet Lett
J Am Chem Soc
Tet Lett
Tet Lett
Angew Chem Int
Phys Chem Chem Phys
J Am Chem Soc

1989
1989
1992
1995
1996
1996
2001
2009

111
30
114
36
37
35
3
131

8057
4995
9369
4975
7691
1843
1242
15695