Efficien t Tr a n sester ifica tion /Acyla tion Rea ction s Med ia ted by
N-Heter ocyclic Ca r ben e Ca ta lysts
Gabriela A. Grasa, Tatyana Gu¨veli,‡ Rohit Singh, and Steven P. Nolan*
Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148
snolan@uno.edu
Received November 22, 2002
Imidazol-2-ylidenes, a family of N-heterocyclic carbenes (NHC), are efficient catalysts in the
transesterification involving numerous esters and alcohols. Low catalyst loadings of aryl- or alkyl-
substituted NHC catalysts mediate the acylation of alcohols with enol acetates in short reaction
times at room temperature. Commercially available and more difficult to cleave methyl esters react
with primary alcohols in the presence of alkyl-substituted NHC to efficiently form the corresponding
esters. While primary alcohols are selectively acylated over secondary alcohols with use of enol
esters as acylating agents, methyl and ethyl esters can be employed as protective agents for
secondary alcohols in the presence of the more active alkyl-substituted NHC catalysts. The NHC-
catalyzed transesterification protocol was simplified by generating the imidazol-2-ylidene catalysts
in situ.
In tr od u ction
or â-amino acids and â-lactams.4 Chiral DMAP deriva-
tives also have been efficiently employed as nucleophilic
catalysts for the dynamic kinetic resolution of secondary
alcohols5 and nonenzymatic acylation of amines.6
Specifically designed catalysts have been shown to play
a key role in optimizing the efficiency of a wide variety
of organic transformations. During the past few decades
small molecule synthesis has attracted attention owing
to its importance in the synthesis of key intermediates
or compounds in pharmaceutical, agrochemical, and fine
chemical industries. However, there is a growing interest
in finding metal-free catalyzed processes that would
provide efficient alternatives to classical organic trans-
formations and result in more economical and environ-
mentally friendly chemistry. To this end, nucleophilic
organocatalysts have successfully been employed in
diverse organic reactions.1 Notable examples are the
enantioselective pyrrole-catalyzed 1,3-dipolar additions,2
the Diels-Alder reactions,3 and the proline-catalyzed
Mannich reaction for the enantioselective synthesis of R-
The ester moiety represents one of the most ubiquitous
functional groups in chemistry, playing a paramount role
in biology and serving both as key intermediate and/or
protecting group in organic transformations.7 Usually,
esters are synthesized from carboxylic acids and alcohols.
However, this reaction requires harsh conditions. As a
consequence, efficient methods for the synthesis of esters
are in demand. In this context, the base or Lewis acid-
catalyzed acylation of alcohols by acetic anhydride or acid
halides suffers from poor selectivity between primary and
secondary alcohols or cleavage of acid-sensitive functional
groups. Lewis acidic catalysts such as Sc(OTf)3 and Sc-
(NTf2)3,8 TiCl(OTf)3,9 TMSCl and TMSOTf,10 La(OiPr)3,11
CoCl2,12 Sn(OTf)2,13 and TiCl4/AgClO4,14 and bases such
as phosphines15 or proazaphosphatrane16 have been used
‡ Visiting student from the Universite´ Pierre et Marie Curie, Paris,
France.
(1) For Bayliss-Hillman reaction: (a) Iwabuchi, Y.; Nakatani, M.;
Yokoyama, N.; Hatakeyama, S. J . Am. Chem. Soc. 1999, 121, 10219-
10220. Phase-transfer catalysis: (b) Corey, E. J .; Xu, F.; Noe, M. C. J .
Am. Chem. Soc. 1997, 119, 12414-12415. (c) Corey, E. J .; Bo, Y.;
Busch-Petersen, J . J . Am. Chem. Soc. 1998, 120, 13000-13001. (d)
O’Donnell, M. J .; Bennett, W. D.; Wu, S. J . Am. Chem. Soc. 1989, 111,
2353-2355. (e) Corey, E. J .; Zhang, F.-Y. Org. Lett. 1999, 1, 1287-
1290. Aldol reaction: (f) Eder, U.; Sauer, G.; Wiechert, R. Angew.
Chem., Int. Ed. Engl. 1971, 10, 496-497. (g) List, B.; Lerner, R. A.;
Barbas, C. F., III J . Am. Chem. Soc. 2000, 122, 2395-2396. (h) Hajos,
Z. G.; Parrish, D. R. J . Org. Chem. 1974, 39, 1615-1621. (i) Yang, D.;
Yip, Y.-C.; Tang, M.-W.; Wong, M.-K.; Zheng, J .-H.; Cheung, K.-K. J .
Am. Chem. Soc. 1996, 118, 491-492. (j) Yang, D.; Wong, M.-K.; Yip,
Y.-C.; Wnag, X.-C.; Tang, M.-W.; Zheng, J .-H.; Cheung, K.-K. J . Am.
Chem. Soc. 1998, 120, 5943-5952. (k) Tu, Y.; Wang, Z.-X.; Shi, Y. J .
Am. Chem. Soc. 1996, 118, 9806-9807. Ring-opening polymerization
of cyclic esters: (l) Nederberg, F.; Connor, E. F.; Glauser, T.; Hedrick,
J . L. Chem. Commun. 2001, 2066-2067. (m) Nederberg, F.; Connor,
E. F.; Moller, M.; Glauser, T.; Hedrick, J . L. Angew. Chem., Int. Ed.
2001, 40, 2712-2715.
(3) Ahrendt, K. A.; Borths, C. J .; MacMillan, D. W. C. J . Am. Chem.
Soc. 2000, 122, 4243-4244.
(4) List, B. J . Am. Chem. Soc. 2000, 122, 9336-9337.
(5) (a) Tao, B.; Ruble, C. J .; Hoic, D. A.; Fu, G. C. J . Am. Chem.
Soc. 1999, 121, 5091-5092. (b) Ruble, C. J .; Latham, H. A.; Fu, G. C.
J . Am. Chem. Soc. 1997, 119, 1492-1493. (c) Ruble, C. J .; Tweddell,
J .; Fu, G. C. J . Org. Chem. 1998, 63, 2794-2795.
(6) Ie, Y.; Fu, G. C. Chem. Commun. 2000, 119-120.
(7) Otera, J . Chem. Rev. 1993, 93, 1449-1470 and references
therein.
(8) Ishira, K.; Kubota, M.; Yamamato, H. Synlett 1996, 265-266.
(9) Izumi, J .; Shiina, I.; Mukaiyama, T. Chem. Lett. 1995, 141-142.
(10) Kumaresvaran, R.; Gupta, A.; Vankar, Y. D. Synth. Commun.
1997, 27, 277-278.
(11) Okano, T.; Miyamoto, K.; Kiji, J . Chem. Lett. 1995, 246.
(12) Iqbal, J .; Srivastava, R. R. J . Org. Chem. 1992, 57, 2001-2007.
(13) Mukaiyama, T.; Shiina, I.; Miyashira, M. Chem Lett. 1992, 625-
628.
(14) Miyashita, M.; Shiina, I.; Mukaiyama, T. Bull. Chem. Soc. J pn.
1993, 66, 1516-1527.
(15) Vedejs, E.; Diver, S. T. J . Am. Chem. Soc. 1993, 115, 3358-
3359.
(2) J en, W. S.; Wiener, J . J . M.; MacMillan, D. W. C. J . Am. Chem.
Soc. 2000, 122, 9874-9875.
10.1021/jo0267551 CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/08/2003
2812
J . Org. Chem. 2003, 68, 2812-2819