Angewandte
Communications
Chemie
Synthetic Methods
Nickel-Catalyzed Esterification of Aliphatic Amides
Liana Hie+, Emma L. Baker+, Sarah M. Anthony, Jean-Nicolas Desrosiers, Chris Senanayake,
and Neil K. Garg*
Abstract: Recent studies have demonstrated that amides can be
used in nickel-catalyzed reactions that lead to cleavage of the
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amide C N bond, with formation of a C C or C heteroatom
bond. However, the general scope of these methodologies has
been restricted to amides where the carbonyl is directly
attached to an arene or heteroarene. We now report the
nickel-catalyzed esterification of amides derived from aliphatic
carboxylic acids. The transformation requires only a slight
excess of the alcohol nucleophile and is tolerant of hetero-
cycles, substrates with epimerizable stereocenters, and sterically
congested coupling partners. Moreover, a series of amide
competition experiments establish selectivity principles that
will aid future synthetic design. These studies overcome
a critical limitation of current Ni-catalyzed amide couplings
and are expected to further stimulate the use of amides as
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synthetic building blocks in C N bond cleavage processes.
Figure 1. Nickel-catalyzed activation of benzamides and derivatives
(prior studies) and nickel-catalyzed esterification of aliphatic amides
(present study). Boc=tert-butyloxycarbonyl, Ts=tosyl, Bn=benzyl.
A
mides are prevalent functional groups found in synthetic
intermediates, natural products, proteins, and various other
molecules of importance.[1] Accordingly, the development of
conditions and in a predictable manner, using non-precious
metal catalysis.[11] Despite the promise of these method-
ologies, a notable drawback has been pervasive in nickel-
mediated amide cross-coupling chemistry. Specifically, such
methodologies have largely required that the amide substrate
bear an aromatic (or heteroaromatic) ring attached to the
carbonyl.[12] For amide activation methodologies to become
generally useful, we sought to overcome this limitation and
enable the activation and cross-coupling of amides derived
from aliphatic carboxylic acids.
Herein, we show that amides derived from aliphatic
carboxylic acids can indeed undergo nickel-catalyzed cross-
coupling, as demonstrated in the conversion of amides to
esters (Figure 1, 1!2). These studies not only provide a facile
means to convert amides to esters, which itself is a challenging
transformation,[13] but should also greatly enable the use of
amides as building blocks in chemical synthesis.[2]
Based on prior computational studies, oxidative addition
was believed to be the rate-determining step of our proposed
catalytic cycle.[14] We hypothesized that the choice of ligand in
the conversion of aliphatic amides to esters could have
a dramatic effect on the ease of oxidative addition.[7a] Thus, we
performed an extensive survey of reaction parameters in
collaboration with the Catalysis Group of Boehringer Ingel-
heim. The screening efforts, which involved the testing of over
100 ligands,[15] were ultimately fruitful and led us to focus on
the use of pyridine-type ligands in optimization studies
(Table 1). The challenging coupling of cyclohexyl amide 3
with (ꢀ)-menthol (4, 1.25 equiv), a sterically hindered
nucleophile, was selected for these efforts. Although the use
of bipyridine or phenanthroline led to no measureable yield
of 5 (entries 1 and 2), the coupling product was obtained in
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methods to construct amide C N bonds has been a popular
topic of study for many decades.[1] In contrast, the ability to
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harness amides as synthetic building blocks in C N bond
cleavage reactions has remained underdeveloped.[2,3] The
modest synthetic utility of amides can be attributed to the
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strength of the amide C N bond, which benefits from well-
known resonance stabilization.[4]
With this longstanding challenge in mind, recent efforts
have focused on the metal-catalyzed cleavage of amide C N
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bonds, with applications in C C and C heteroatom bond
formation.[5–10] Breakthroughs in this area include palladium-
catalyzed decarbonylative[6c] and non-decarbonylative[5,6a,d,e]
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C C bond formations using twisted amides or other activated
amide substrates. Additionally, we have shown that nickel
catalysis is effective to promote the non-decarbonylative
cross-coupling of anilides and Ts- or Boc-activated amide
derivatives (Figure 1).[7] In turn, esters,[7a] ketones,[7b,d] or
other amides[7c] can be readily prepared under mild reaction
[*] L. Hie,[+] E. L. Baker,[+] S. M. Anthony, Prof. Dr. N. K. Garg
Department of Chemistry and Biochemistry
University of California, Los Angeles
Los Angeles, CA 90095 (USA)
E-mail: neilgarg@chem.ucla.edu
Dr. J.-N. Desrosiers, Dr. C. Senanayake
Department of Chemical Development US
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 (USA)
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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