2814██

2814 SPOTLIGHT

SYNLETT Chloromethyllithium
spotlight

Spotlight Compiled by Ashenafi Damtew Mamuyea,b

This feature focuses on a re-
agent chosen by a postgradu-
ate, highlighting the uses and
preparation of the reagent in
current research
Ashenafi Damtew Mamuye was born in Alem-Ketema, Ethiopia in
1984. He completed his B.Sc. in Applied Chemistry at the Univer-
sity of Gondar (2006) and received his M.Sc. in Medicinal Chemis-
try from Addis Ababa University (2009). He worked as teaching
assistant from 2009 to 2011 in Ethiopia. In 2012 he joined the Uni-
versity of Sassari to undertake doctoral studies in Chemical Science
and Technology under the supervision of Prof. Ugo Azzena. Start-
ing from October 2013, he is a visiting PhD student at the Universi-
ty of Vienna under the supervision of Dr. Vittorio Pace and Prof.
Wolfgang Holzer. His research focuses on α-substituted organolith-
iums (e.g. carbenoids), arene-catalyzed lithiation, and pyrazole
chemistry.
a
Department of Pharmaceutical Chemistry - Division of Drug Syn-
thesis, University of Vienna, Althanstrasse 14, 1090 Vienna,
Austria

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
b
Dipartimento di Chimica, Università di Sassari, I-07100-Sassari,
Italy
E-mail: ashenafi.mamuye@univie.ac.at

Introduction or below); however, performing the reaction in the pres-

ence of the electrophile (i.e. Barbier-type conditions) al-
Chloromethyllithium (LiCH2Cl) is a synthetically useful lows to realize efficient processes. The presence of
reagent belonging to the category of carbenoids, which lithium halides and the use of ethereal-type solvents (THF
are known to exhibit an ambiphilic behavior ranging from or diethyl ether) had beneficial effects on its stability.3
nucleophilic (at low temperatures) to electrophilic (at Li+
higher temperatures). This fact can be deduced by the res- H– H
Li
H
Li
onance structures represented in Scheme 1, in which the H
C
Cl
H
C
Cl
H
C+ Cl
–

extreme ionization of the polar bonds could lead, in prin- 1a 1 1b

ciple, to the carbanionic (1a) or carbocationic (1b) spe-
cies.1 Chloromethyllithium can be prepared via a Scheme 1 Ambiphilicity of chloromethyllithium
halogen–lithium exchange reaction on a given dihalo-
methane. Iodo- and bromo-chloromethane (ICH2Cl and Interestingly, Le Floch and co-workers showed that by re-
BrCH2Cl) are the ideal precursors jointly with methyllith- placing the two hydrogens with electron-withdrawing
ium–lithium bromide complex or n-butyllithium.2 It is groups, it is possible to dramatically improve the stability
highly unstable except at very low temperatures (–78 °C of the corresponding carbenoid.4
Abstracts
(A) Carbonyl-type compounds have been homologated with lithium O OH
ICH2Cl (1.10 equiv) Δ O
carbenoids. The addition of LiCH2Cl to an aldehyde or a ketone (2) 1 2 1
Cl
R R R
after mild acidic treatment provides the corresponding halohydrin (3) MeLi–LiBr (1.05 equiv) R2 R1
R2
in high yields. Interestingly, when the reaction is allowed to reach 2
THF, –78 °C, 30 min
3 4
room temperature, an intramolecular nucleophilic displacement takes (65–97%) (82–99%)
R1 = Alk, Ar
place, thus affording directly the epoxide 4.5 The strategy has very re- R2 = H, Alk, Ar
cently been applied to cyclic α,β-unsaturated enones to access chloro-
methyl allylic alcohols in high yield.6

(B) Concellón and co-workers conveniently used a strategy for the R2

preparation of β-chloro amines (7,7a) starting from activated N-aryl- N

sulfonamido imines 5.7 R1 H

NHR2
ICH2Cl, MeLi (R2 = Ts) R2 Li
R1 Cl ICH2Cl, MeLi N NHR2
–78 °C
5 Cl
THF, –78 °C Cl
NBn2 THF, –78 °C R1 R1
R1 = Bn, dr = 9/1 7a
7 6
R1 = Alk, Ar (60% to >98%)

SYNLETT 2014, 25, 2814–2815

Advanced online publication: 05.11.20140936-52141437-2096
DOI: 10.1055/s-0034-1379442; Art ID: st-2014-v0496-v
© Georg Thieme Verlag Stuttgart · New York
SPOTLIGHT A. D. Mamuye 2815

(C) Very recently Pace and co-workers reported the treatment of iso- ClCH2I (1.5 equiv) O
cyanates 8 with LiCH2Cl to access versatile N-chloro acetamides 9 in C
O MeLi–LiBr (1.25 equiv)
R X
high yields even in the presence of optically active starting materials R
N N
H
Et2O, –78 °C, 0.5–1 h
which did not racemize during the process.8 8
then NH4Cl aq
9 X = Cl, Br, I

(82–97%)
R = Alk, Ar
no optical purity loss in the case of R groups containing asymmetric centers

(D) A general method for the synthesis of α-arylamino-α′-chloro ke- Z O

tones in the presence of various substituents on the nitrogen atom has N OMe
Li O
Me
Z O
ICH2Cl, MeLi–LiBr
been developed by Pace et al. who employed Weinreb amides9 10 as Ar N Z
O N Me
NH4Cl, H2O
N Cl
Me
electrophilic starting materials for the chloromethylation.3 Remark- THF, –90 °C Ar
N
Cl
Ar
11
ably, the use of such amides could be successfully extended to the 10 10a (76–92%)
synthesis of α′-halo-α,β-unsaturated ketones 13 for which the use of
esters provided exclusively the double addition products (i.e. carbi- Me
nols).10 In this regard, the high stability under the reaction conditions R1 O LiCH2Cl (3.0 equiv) Li O
of tetrahedral intermediate 12a, formed upon the addition of chloro- OMe
THF, –78 °C, 1 h O N
Me
NH4Cl, H2O R1 O
R N R1
methyllithium to Weinreb amide 12, prevents the deleterious double X R
Cl
R2 Me
addition of the reagent. R R 2
R 2

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
12 12a 13
exceptional stability at –78 °C (75–95%)

R = cycloalkyl, alkenyl, Ar, Hetar

R1 = H, Me
R2 = H, F, Me

(E) Simpkins and co-workers realized an efficient synthesis of the key O

Cl
intermediate 15 needed for the total synthesis of fumagillol 16. Inter- H HO
H O H O
estingly, the chloromethylation of the complex ketone 14 proceeded
in good yield and dr.11 ClCH2I (5.0 equiv)
O O
O n-BuLi (5.0 equiv) OMe
O
–80 °C, 64%, dr = 16:1 OH
14 15 16

(F) Matteson pioneered the chemistry of monohalolithium carbenoids 1) LiCH2X (2.2 equiv) OH
with boronic esters.2c Recently, Aggarwal reported the homologation Et Bpin THF, –78 °C to r.t.
Et
HO Et

of tertiary boronic esters 17 with chloromethyllithium followed by ox- Ph Me 2) H2O2, NaOH Ph Me

Ph Me
idation to produce the corresponding enantiopure alcohols 18. In ad- 17 18 19
dition, they rationalized that the formation of 18 or 19 depends on the
intermediate complex formed from 17 and chloromethyllithium, X = Cl (71% yield) 20%
X = Br (83% yield) 5%
which can undergo O-migration (giving 19) or C-migration.12 By
switching to LiCH2Br the undesired O-migration can be minimized.

References
(1) For seminal studies, see: (a) Köbrich, G.; Akhtar, A.; Ansari,
F.; Breckoff, W. E.; Büttner, H.; Drischel, W.; Fischer, R.
H.; Flory, K.; Fröhlich, H.; Goyert, W.; Heinemann, H.;
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2b.
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N.; Le Floch, P. Angew. Chem. Int. Ed. 2007, 46, 5947.
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(9) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22,
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activation strategies of amides towards organometallics, see:
(d) Pace, V.; Holzer, W.; Olofsson, B. Adv. Synth. Catal.
2014, in press (DOI: 10.1002/adsc.201400630). (e) Pace,
V.; Holzer, W. Aust. J. Chem. 2013, 66, 507.
(10) Pace, V.; Castoldi, L.; Holzer, W. J. Org. Chem. 2013, 78,
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(11) Hutchings, M.; Moffat, D.; Simpkins, N. S. Synlett 2001,
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© Georg Thieme Verlag Stuttgart · New York Synlett 2014, 25, 2814–2815