Communications
DOI: 10.1002/anie.200705468
Organocatalysis
Direct and Waste-Free Amidations and Cycloadditions by
Organocatalytic Activation of Carboxylic Acids at Room
Temperature**
Raed M. Al-Zoubi, Olivier Marion, and Dennis G. Hall*
The amide bond is ubiquitous in nature. It links amino acids to
form peptides and proteins and is an important component of
many natural products. Furthermore, it has been estimated
that as many as 25% of all synthetic pharmaceutical drugs
contain an amide unit.[1] Consequently, the development of
efficient amidation methods continues to be an important
scientific pursuit.[2,3] Despite the favorable thermodynamic
stability of the resulting amide bond, the simple thermal
dehydration reaction between a carboxylic acid and an amine
is plagued by a large activation energy. The initial formation
of a stable ammonium carboxylate salt deters the dehydration
step, and the intermediate salt collapses to provide the amide
product only at very high temperatures (over 1608C) that are
and often toxic coupling reagents such as carbodiimides or
phosphonium or uronium salts to activate and dehydrate the
carboxylic acid.[2] These reagents and their associated co-
reagents, including bases, supernucleophiles, and other addi-
tives, generate large amounts of wasteful by-products that
complicate the isolation of the desired amide product.
Our interest in the applications of ortho-functionalized
arylboronic acids[6] led us to examine the catalytic potential of
these compounds, with the objective of identifying a catalyst
for direct amidation that would function under practical and
mild conditions at room temperature. Precedent for this
approach was reported in 1996, when Yamamoto and co-
workers described the clever use of electron-poor arylboronic
acids as catalysts for direct amidations.[7,8] However, even the
most efficient boronic acid, 3,4,5-trifluorophenylboronic acid,
required heating at reflux in solvent at temperatures over
1108C for several hours (for other boronic acids, also at high
temperatures, see references [9,10]). Using a model amida-
tion reaction between phenylacetic acid and benzylamine, we
undertook a systematic evaluation of over 45 ortho-function-
alized arylboronic acids in different organic solvents (see the
Supporting Information for a complete list). A handful were
active at room temperature, and in all cases it was found
essential to scavenge the water by-product of the reaction,
which was conveniently accomplished by the use of molecular
sieves.[11] A second round of evaluation of the most promising
candidates revealed ortho-bromophenylboronic acid (1) and
the hitherto unknown ortho-iodophenylboronic acid (2)[12] to
be the most efficient catalysts (Scheme 2). The iodo deriva-
tive (2) in particular was found to give higher yields within
shorter reaction times than the commercially available 1.
Both of these catalysts are clearly superior to 3,4,5-trifluoro-
phenylboronic acid[7] and boric acid.[13,14] Further optimiza-
tion of reaction conditions identified methylene chloride and
tetrahydrofuran as the optimal solvents. As excess amine was
found to slow down the reactions, it was deemed preferable to
use a slight excess of the carboxylic acid.
incompatible
with
most
functionalized
molecules
(Scheme 1).[4] Consequently, there are still no general meth-
ods to access amides directly from free carboxylic acids and
amines in a simple, green, and atom-economical fashion at
ambient temperature.[5] Common means for forming amide
bonds involve the use of stoichiometric excesses of expensive
Scheme 1. Direct amide formation by reaction of free carboxylic acids
and amines.
[*] R. M. Al-Zoubi, Dr. O. Marion, Prof. Dr. D. G. Hall
Department of Chemistry
Gunning-Lemieux Chemistry Centre
University of Alberta
Edmonton, Alberta, T6G 2G2 (Canada)
Fax: (+1)780-492-8231
E-mail: dennis.hall@ualberta.ca
The examples compiled in Table 1 demonstrate the
versatility and scope of the new catalysts 1 and 2 in promoting
direct amidations at room temperature. Standard conditions
employed the commercially available catalyst 1 in methylene
chloride containing 4 molecular sieves. To ensure reaction
completion in the case of slower substrates, a reaction time of
48 h was chosen. Carboxylic acids and primary amines
containing aromatic substituents, straight aliphatic chains, or
branched aliphatic chains, are suitable substrates (Table 1,
entries 1–7). Although an acyclic secondary amine failed to
react at room temperature (Table 1, entry 2), cyclic ones
[**] Acknowledgement for financial support of this research is made to
the Natural Sciences and Engineering Research Council (NSERC) of
Canada (Discovery Grant to D.G.H.) and the University of Alberta.
We thank Dr. R. McDonald for the X-ray crystallographic analysis
and Prof. F. Dean Toste for helpful suggestions.
Supporting information for this article is available on the WWW
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 2876 –2879