dynamic instability of the ketone derivatives.2 To circumvent
this, cyanohydrins from ketones are generally prepared in
O-protected form.3 The cyanosilylation of ketones is particularly
suitable since the silyl protecting groups can be removed under
very mild reaction conditions. A fast, efficient, general, and cost-
effective cyanosilylation of ketones is therefore required in order
to develop the kinetic resolution of racemic cyanohydrins into
a viable strategy.1b,4 Careful examination of the existing
literature procedures revealed that nearly all existing methods
for both racemic3a,5 and enantioselective3b,6 cyanosilylation of
ketones employ expensive and potentially hazardous Me3SiCN,
with Lewis acid or base catalysts being required.7 Syntheses of
ketone cyanohydrins containing silyl-protecting groups higher
than trimethylsilyl are only scarcely described. Therefore, we
aimed at developing a general and robust cyanosilylation method
Robust and Efficient, Yet Uncatalyzed, Synthesis
of Trialkylsilyl-Protected Cyanohydrins from
Ketones
Fabien L. Cabirol,†,‡ Angela E. C. Lim,† Ulf Hanefeld,‡
Roger A. Sheldon,‡ and Ilya M. Lyapkalo*,§
Institute of Chemical and Engineering Sciences, 1 Pesek Road,
Jurong Island, S(627833), Singapore, Institute of Organic
Chemistry and Biochemistry, FlemingoVo n. 2., 166 10 Prague
6, Czech Republic, and Biocatalysis and Organic Chemistry,
Delft UniVersity of Technology, Julianalaan 136, 2628 BL Delft,
The Netherlands
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ReceiVed December 4, 2007
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High-yielding cyanosilylation of ketones with NaCN and
various chlorotrialkylsilanes in DMSO proceeds smoothly
without catalysis to give silyl-protected ketone cyanohydrins.
The unique role of DMSO consists in rendering naked
cyanide anions that reversibly add to the CdO bond at the
rate-determining step followed by fast trapping of the
transient tertiary sodium cyanoalcoholates with chlorotri-
alkylsilanes or in situ generated cyanotrialkylsilanes. Pre-
paratively, the reaction matches the best known catalytic
cyanosilylation systems applying expensive Me3SiCN and
demonstrates unprecedented efficiency in the synthesis of
sterically congested trialkylsilyl-protected cyanohydrins.
Introduction
For our study of enzyme-catalyzed enantioselective cyano-
hydrin syntheses,1 we required a wide range of racemic ketone
cyanohydrins, both as reference material and as starting material
for enzymatic kinetic resolutions. The direct synthesis from
ketones and HCN proved difficult owing to inherent thermo-
* Corresponding Author. Phone: +420 220183420. Fax: +420 220183578.
† Institute of Chemical and Engineering Sciences.
‡ Delft University of Technology.
§ Institute of Organic Chemistry and Biochemistry.
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Synth. Catal. 2007, 349, 1341-1344. (c) Veum, L.; Hanefeld, U.; Pierre,
A. Tetrahedron 2004, 60, 10419-10425. (d) Chmura, A.; van der Kraan,
G. M.; Kielar, F.; van Langen, L. M.; van Rantwijk, F.; Sheldon, R. A.
AdV. Synth. Catal. 2006, 348, 1655-1661. (e) Cabirol, F. L.; Hanefeld,
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10.1021/jo702587e CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/29/2008
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J. Org. Chem. 2008, 73, 2446-2449