ORGANIC
LETTERS
2
011
Vol. 13, No. 10
584–2585
Trifluoroacetic Anhydride-Catalyzed
Oxidation of Isonitriles by DMSO: A Rapid,
Convenient Synthesis of Isocyanates
2
Hoang V. Le and Bruce Ganem*
Department of Chemistry & Chemical Biology, Baker Laboratory, Cornell University,
Ithaca, New York 14853-1301, United States
Received March 15, 2011
ABSTRACT
A smooth and efficient oxidation of isonitriles to isocyanates by sulfoxides is catalyzed by trifluoroacetic anhydride. With use of DMSO as the
oxidant and 5 mol % TFAA (dichloromethane, À60 to 0 °C), the process is complete in a few minutes, forming dimethyl sulfide as the only
3
byproduct. The newly formed isocyanates may be used directly or isolated in high purity by solvent evaporation.
As part of a program to redirect intermediates in the
Pummerer reaction of sulfoxides into useful new multi-
component processes, we serendipitously discovered a fast
and gentle catalytic oxidation of isonitriles to isocyanates
that promises to be of utility to synthetic chemists. Besides
using inexpensive, readily available reagents, the method
generates volatile and innocuous byproducts often making
possible direct isolation of the desired isocyanate without
extractive workup.
isonitriles are rapidly oxidized to isocyanates using DMSO
in the presence of catalytic quantities of trifluoroacetic
anhydride (TFAA, eq 1). Unlike the halogen-catalyzed
DMSO oxidations reported earlier, which require pro-
longed heating at reflux and have been proposed to involve
isonitrileÀhalogen adducts, the TFAA-catalyzed oxida-
tions occur rapidly at low temperature by a different
mechanism.
1
Given the broad synthetic utility of isocyanates, dozens
of procedures have been described for preparing them,
including several routes from isonitriles. Isonitrile-to-iso-
cyanate oxidations have been reported with use of mercuric
2
3
4
oxide, lead tetraacetate, and ozone, aswell ashalogen- or
5
acid-catalyzed oxidations by dimethyl sulfoxide (DMSO)
Initial attempts to generate and trap the putative sulfo-
nium intermediates in Pummerer reactions led us to in-
vestigate the reaction of TFAA with dibenzyl sulfoxide in
the presence of nucleophilic isonitriles such as t-BuNC
6
and pyridine N-oxide. However, recent interest in highly
functionalized isocyanates drives the continuing demand
7
for new synthetic methodology. Here we report that
(1:1:1 mixtures in CH Cl , 0 °C to rt, 10 min). In each case,
2 2
the only isolable product obtained was dibenzyl sulfide in
near-quantitative yield.
(
(
(
(
1) Ozaki, S. Chem. Rev. 1972, 72, 457.
2) Gautier, A. Ann. Chim. (Paris) 1869, 17, 229.
3) Hiebl, J.; Zhiral, E. Liebigs Ann. Chem. 1988, 765.
4) Feuer, H.; Rubinstein, H.; Nielsen, A. T. J. Org. Chem. 1958, 33,
Mechanistic considerations suggested that sulfoxide re-
duction might be accompanied by oxidation of the isoni-
trile either to the corresponding isocyanate R;NdCdO
or its hexafluoroacylal R;NdC(OCOCF ) . Real-time
1
107.
(
5) (a) Br -DMSO:Johnson, H. W., Jr.; Daughheter, P. H., Jr. J. Org.
2
3
2
Chem. 1964, 29, 246. Acid-DMSO:(b) Martin, D.; Weise, A. Angew.
Chem., Int. Ed. 1967, 6, 168.
(
(
200. (b) Ichikawa, Y.; Ohara, F.; Kotsuki, H.; Nakane, K. Org. Lett.
006, 8, 5009.
monitoring of the reaction mixture by IR unambiguously
À1
6) Johnson, H. W., Jr.; Krutzsch, H. J. Org. Chem. 1967, 32, 1939.
7) (a) Ichikawa, Y.; Nishiyama, T.; Isobe, M. J. Org. Chem. 2001, 66,
established the formation of isocyanate (2257 cm ). A
plausible mechanism for the overall redox process is shown
in Scheme 1.
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2
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0.1021/ol200695y r 2011 American Chemical Society
Published on Web 04/14/2011