sensitive or easily oxidizable groups.3i Chlorination of the kinetic
enolates or the corresponding silyl enol ethers provided a
solution to the regiochemical problem to some extent.4 Not-
withstanding these limitations, a few of these reagents have been
found to be useful in enantioselective R-chlorination of carbonyl
compounds.5
Copper(I)-Promoted Synthesis of Chloromethyl
Ketones from Trichloromethyl Carbinols
Ram N. Ram* and T. P. Manoj
Department of Chemistry, Indian Institute of Technology,
Delhi, Hauz Khas, New Delhi-110016, India
There are only a few methods available for regiospecific
synthesis of chloromethyl ketones. Some of these methods
employintroductionofachloroacetylgroupthroughFriedel-Crafts
reaction1d,h with activated aromatics or organometallic reactions.1f,6
In another approach, a chloromethyl group has been linked to
a carbonyl group by reaction of a suitable carbonyl compound
with a carbenoid reagent. This approach includes the classical
reaction of acid chlorides with CH2N2/HCl, which has been
found to be very useful for the synthesis of bioactive chlorom-
ethyl ketones derived from sugars,1i amino acids, and peptides;2a,b
a practical alternative involves the reaction of esters with
LiCH2Cl7 or CH2dS(O)Me2/HCl8 without the use of hazardous
diazomethane, the reaction of aldehydes with LiCCl2S(O)Ph9
or LiCHCl2,10 and the reaction of aldehydes11 or esters9 with
LiCHClS(O)Ph. Several aryl and heteroaryl chloromethyl
ketones have recently been obtained by the reaction of dichlo-
roacetaldehyde diethyl acetal with aryl- or heteroaryllithiums
followed by acid hydrolysis of the products 1-aryl/heteroaryl-
1-ethoxy-2-chloroethenes.12 However, most of these reactions
ReceiVed April 06, 2008
Reaction of several trichloromethyl carbinols with 2 equiv
of CuCl/bpy in refluxing DCE for 3 h afforded chloromethyl
ketones in excellent yield by 1,2-H shift in the copper-
chlorocarbenoid intermediate.
Chloromethyl ketones are versatile synthetic intermediates
for the preparation of compounds of considerable importance
in medicine and agriculture.1 Some chloromethyl ketones are
known to be enzyme inhibitors and affinity labeling agents.2
Therefore, numerous methods have been reported for the
synthesis of chloromethyl ketones. A majority of these methods
employ direct chlorination of ketones with elemental chlorine
or various inorganic or organic chlorinating agents.1a,3 However,
these methods are not regiospecific and are not suitable for the
preparation of chloromethyl ketones from methyl alkyl ketones
having a hydrogen atom at the R′-carbon atom because
chlorination occurs predominantly at the more substituted R′-
carbon atom. Some of these methods also suffer from the
problem of overchlorination,3g–i,k,l,n nuclear chlorination of
activated aromatic ring,3g–i failure with deactivated aromatic
ring,3g,j,m or incompatibility with olefinic bonds3b and acid-
(3) For reviews, see: (a) Larock, R. C. ComprehensiVe Organic Transforma-
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pp 459-478. For some other references, see: (c) Xu, Z.; Zhang, D.; Zou, X.
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Y. H.; Lee, S. J. Tetrahedron Lett. 2004, 45, 191–193. (PhI(OTs)(OH)/MgCl2/
microwave). (f) Lee, J. C.; Bae, Y. H.; Chang, S.-K. Bull. Korean Chem. Soc.
2003, 24, 407–408. (NCS/PTS). (g) Yakabe, S.; Hirano, M.; Morimoto, T. Synth.
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10.1021/jo8007644 CCC: $40.75
Published on Web 06/24/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5633–5635 5633