ORGANIC
LETTERS
2011
Vol. 13, No. 9
2256–2259
Facile Amide Bond Formation from
Carboxylic Acids and Isocyanates
Kaname Sasaki and David Crich*
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS,
1 Avenue de la Terrasse, 91190 Gif-sur-Yvette, France
Received February 27, 2011
ABSTRACT
A wide variety of carboxylic acids in the form of their salts condense with aryl isocyanates at room temperature with loss of carbon dioxide to give
the corresponding amides in high yield. Application of the reaction to acyl isocyanates gives unsymmetric imides. The reaction is compatible with
hydroxyl groups and both Fmoc and Boc protecting groups for amines and is applicable to aliphatic, aromatic, and heteroaromatic acids.
Amide bond formation is, in principle, one of the
simplest chemical transformations requiring only the con-
densation of an amine with a carboxylic acid with the
extrusion of a molecule of water. Yet, it is also one of the
most important of reactions, as amides are important
constituents of many fine chemicals, drugs, chemical inter-
mediates, biopolymers, and polymers. Indeed, amide bond
formation is one of the most common chemical transfor-
mations in the pharmaceutical industry and in scaled up
reactions.1 As such, it is difficult to underestimate the
importance of amides in both the bulk, specialty and
polymer fields. Such condensations are achieved through
activation of the acid, either by conversion to an acyl
chloride or anhydride or, for fine chemicals, by means of
a coupling reagent. Such protocols are inherently ineffi-
cient generating stoichiometric quantities of byproduct
that can be both difficult and expensive to remove,
resulting in the frequent identification of amide-forming
reactions as an area in need of improvement from a
chemical perspective.1 Accordingly, much attention has
been devoted to the design of improved coupling
reagents2 and the development of alternative methods
such as, for example, the reaction of carboxylic3 or
thiocarboxylic acids4 with isonitriles and other reagents,
of thiocarboxylic acids with azides,5 and the recent
oxidative coupling of bromonitroalkanes with amines.6
For our part, we have described the facile condensation of
thiocarboxylic acids with readily available isocyanates
and isothiocyanates leading directly to amide bonds with
the formation of only carbon oxysulfide or carbon dis-
ulfide as stoichiometric byproduct.7 Here, we outline a
method for amide bond formation that responds to many
of the principles of atom economy;8 the room-tempera-
ture condensation of widely available carboxylic acids
with aryl and other electron-deficient isocyanates that
leads to the high-yield formation of anilides with only
carbon dioxide as byproduct.
(3) Li, X.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, 5446–
5448.
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2009, 50, 5152–5155. (b) Wang, P.; Danishefsky, S. J. J. Am. Chem. Soc.
2010, 132, 17045.
(5) (a) Shangguan, N.; Katukojvala, S.; Greenberg, R.; Williams,
L. J. J. Am. Chem. Soc. 2003, 125, 7754–7755. (b) Kolakowski, R. V.;
Shangguan, N.; Sauers, R. R.; Williams, L. J. J. Am. Chem. Soc. 2006,
128, 5695–5702. (c) Merkx, R.; Brouwer, A. R.; Rijkers, D. T. S.;
Liskamp, R. M. J. Org. Lett. 2005, 7, 1125–1128.
(6) Shen, B.; Makley, D. M.; Johnston, J. N. Nature 2010, 465, 1027–
1033.
(7) Crich, D.; Sasaki, K. Org. Lett. 2009, 11, 3514–3517.
(8) (a) Anastas, P. T.; Kirchhoff, M. M. Acc. Chem. Res. 2002, 35,
686–694. (b) Trost, B. M. Science 1991, 254, 1471–1477. (c) Sheldon,
R. A. Chem. Commun. 2008, 3352–3365.
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Biomol. Chem. 2006, 4, 2337–2347. (b) Constable, D. J. C.; Dunn, P. J.;
Hayler, J. D.; Humphrey, G. R.; Leazer, J., J. L.; Linderman, R. J.;
Lorenz, K.; Manley, J.; Pearlman, B. A.; Wells, A.; Zaksh, A.; Zhang,
T. Y. Green Chem. 2007, 9, 411–420. (c) Dugger, R. W.; Ragan, J. A.;
Brown Ripin, D. H. Org. Process Res. Dev. 2005, 9, 253–258.
(2) Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606–631.
r
10.1021/ol200531k
Published on Web 03/23/2011
2011 American Chemical Society