ORGANIC
LETTERS
2009
Vol. 11, No. 5
1155-1158
A New Entry of Copper-Catalyzed
Four-Component Reaction: Facile
Access to r-Aryl ꢀ-Hydroxy Imidates
Eun Jeong Yoo,† Sae Hume Park,† Sang Hyup Lee,‡ and Sukbok Chang*,†
Department of Chemistry and School of Molecular Science (BK21), Korea AdVanced
Institute of Science and Technology (KAIST), Daejeon 305-701, Korea, and College of
Pharmacy, Duksung Women’s UniVersity, Seoul 132-714, Korea
Received January 7, 2009
ABSTRACT
r-Aryl ꢀ-hydroxy imidates are efficiently obtained by the four-component reaction of ethyl glyoxylates, aryl acetylenes, sulfonyl azides, and
alcohols using a copper catalyst. The developed procedure is characterized by high selectivity, mild reaction conditions, a wide substrate
scope, and an excellent functional group tolerance. Facile transformations of the obtained sulfonylimidate moiety to other carbonyl groups
such as sulfonamides or esters were also demonstrated.
Multicomponent reactions (MCRs)1 constitute an ideal
approach to transformations for generating complex molec-
ular skeletons in one pot. The Ugi four-component reaction
(4-CR),2 in which primary amines, oxo species, carboxylic
acids, and isocyanides react, is one of the most representative
MCRs leading to R-acylamino amides (peptoids) under
ambient conditions. It can be regarded that the isocyanide-
based Ugi 4-CR is an expansion of the Passerini three-
component reaction (3-CR),3 which affords depsipeptides and
ꢀ-peptide analogs from the coupling of ketones, carboxylic
acids, and isocyanides. This example offers an insightful
demonstration that a modification of reacting components
in previously established MCRs may lead to a new version
of transformations with great additional significance.
philes such as amine, alcohol, water, and pyrrole to afford
amidines, imidates, amides, and 2-iminopyrrole derivatives,
respectively.4 The reactions are featured to show a wide
substrate scope, a high tolerance to various functional groups,
and very mild reaction conditions.
Although a wide range of biologically interesting com-
pounds are readily obtained with good efficiency, selectivity,
and synthetic applicability, a limitation in our catalytic 3-CR
procedure has been pointed out: a substituent R to the imino
or carbonyl position cannot be directly introduced.5,6
The mechanistic pathway of the Cu-catalyzed 3-CR was
proposed to proceed via a reactive ketenimine intermediate
(A), generated in situ by the catalytic cycloaddition of
(4) (a) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038–
2039. (b) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc.
2005, 127, 16046–16047. (c) Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang,
S. Org. Lett. 2006, 8, 1347–1350. (d) Chang, S.; Lee, M.; Jung, D. Y.;
Yoo, E. J.; Cho, S. H.; Han, S. K. J. Am. Chem. Soc. 2006, 128, 12366–
12367. (e) Cho, S. H.; Chang, S. Angew. Chem., Int. Ed. 2007, 46, 1897–
1900. (f) Cho, S. H.; Hwang, S. J.; Chang, S. Org. Synth. 2008, 85, 131–
137. (g) Kim, J. Y.; Kim, S. H.; Chang, S. Tetrahedron Lett. 2008, 49,
1745–1749. (h) Cho, S. H.; Chang, S. Angew. Chem., Int. Ed. 2008, 47,
2836–2839. (i) Yoo, E. J.; Chang, S. Org. Lett. 2008, 10, 1163–1166.
(5) For an example of R-substitution of N-phosphryl amidines, see: Kim,
We have recently developed the Cu-catalyzed 3-CR of
1-alkyne, sulfonyl- or phosphoryl azide, and various nucleo-
† Korea Advanced Institute of Science and Technology.
‡ Duksung Women’s University.
(1) For recent reviews, see: (a) Do¨mling, A.; Ugi, I. Angew. Chem.,
Int. Ed. 2000, 39, 3168–3210. (b) Do¨mling, A. Chem. ReV. 2006, 106, 17–
89.
(2) (a) Ugi, I.; Steinbru¨ckner, C. Angew. Chem. 1960, 72, 267–268. (b)
Ugi, I. Angew. Chem. 1962, 74, 9–22.
S. H.; Jung, D. Y.; Chang, S. J. Org. Chem. 2007, 72, 9769–9771
.
(3) (a) Passerini, M.; Simone, L. Gazz. Chim. Ital. 1921, 51, 126–129.
(b) Wang, S.-X.; Wang, M.-X.; Wang, D.-X.; Zhu, J. Angew. Chem., Int.
Ed. 2008, 47, 388–391.
(6) For a recent example of R-substitution of preisolated N-sulfonyl
imidates, see: Matsubara, R.; Berthiol, F.; Kobayashi, S. J. Am. Chem. Soc.
2008, 130, 1804–1805
.
10.1021/ol900023t CCC: $40.75
Published on Web 02/11/2009
2009 American Chemical Society