Nickel-Catalyzed Esterification of Aliphatic Amides

Article abstract of DOI:10.1002/anie.201607856

Recent studies have demonstrated that amides can be used in nickel-catalyzed reactions that lead to cleavage of the 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 heterocycles, 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 synthetic building blocks in C?N bond cleavage processes.

Full text of DOI:10.1002/anie.201607856

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201607856
German Edition: DOI: 10.1002/ange.201607856
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
ꢀ
ꢀ
ꢀ
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
ꢀ
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
ꢀ
methods to construct amide C N bonds has been a popular
topic of study for many decades.[1] In contrast, the ability to
ꢀ
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
ꢀ
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
ꢀ
ꢀ
ꢀ
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]
ꢀ
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
Homepage: http://garg.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:
http://dx.doi.org/10.1002/anie.201607856.
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Table 1: Optimization of reaction conditions.[a]
Entry
Ligand (Loading)
Equivs
of 4
Conc.
[m]
T
[8C]
Yield
[%]
1
2
3
4
5
6
7
8
bipyridine (15 mol%)
phenanthroline (15 mol%)
terpyridine (15 mol%)
terpyridine (30 mol%)
terpyridine (15 mol%)
terpyridine (15 mol%)
terpyridine (15 mol%)
terpyridine (15 mol%)
1.25
1.25
1.25
1.25
2.50
1.25
1.25
1.25
0.5
0.5
0.5
0.5
0.5
0.33
1.0
1.0
80
80
80
80
80
80
80
100
0
0
24
31
30
19
35
56
Figure 2. Evaluation of amide substrates. Yields reflect the average of
two isolation experiments. [a] Yield was determined by 1H NMR
analysis using 1,3,5-trimethoxybenzene as an internal standard.
[b] Reaction was performed using 2.5 equivalents of 7. [c] Reaction was
performed at 808C with 2.0 equivalents of 7. Ni(cod)2 =bis(1,5-
cyclooctadiene)nickel(0).
[a] Yields were determined by 1H NMR analysis using hexamethylben-
zene as an internal standard.
24% yield when terpyridine was employed (entry 3). Dou-
bling the ligand loading was also attempted (entry 4), but
15 mol% (1:1 Ni to terpyridine) was found to be ideal.
Additionally, increasing the equivalents of 4 did not lead to
improvement (entry 5). However, it was found that concen-
tration had an effect on the reaction (entries 6 and 7), with
higher concentrations giving slightly increased yield of
product 5. Finally, we found that increasing the temperature
to 1008C delivered ester 5 in 56% yield (entry 8).[16,17] As this
test transformation allowed for the coupling of two signifi-
cantly hindered fragments with the remaining mass being only
unreacted starting material, we opted to evaluate the scope of
our methodology under these reaction conditions.
Having identified suitable reaction conditions, we eval-
uated the scope of the amide substrate using 1.25 equivalents
of 1-hexanol (7) as the alcohol coupling partner (Figure 2).
We were delighted to find that lower catalyst loadings of 5 or
10 mol% nickel could be employed in all cases to give
synthetically useful yields of products. Non-a-branched sub-
strates were well tolerated, as illustrated by the formation of
9–11.[18] Of note, an aryl chloride was tolerated as shown by
the formation of ester 9b.[19] Moreover, the preparation of 11
in 92% yield (using 2.5 equivalents of 7), demonstrates the
feasibility of converting two amides to esters in the same pot.
Although our focus has been on amides derived from
aliphatic substrates, it should be noted that vinyl amides can
also be employed, as shown by the synthesis of 12. With
regard to a-branched aliphatic substrates, amides derived
from cyclopentane and cyclohexane carboxylic acids could be
used, as seen by the formation of 13 and 14, respectively. The
high-yielding preparation of 15 and 16 further exemplifies the
tolerance of our methodology toward a-branching, in addi-
tion to olefins and an oxygen-containing heterocycle. It was
also shown that a cyclopropane-containing amide and a steri-
cally hindered tertiary amide substrate were well tolerated, as
seen by the formation of 17 and 18, respectively.[20] Finally, it
should be noted that the esterification can be performed on
the benchtop using our laboratoryꢀs recent protocol involving
Ni(cod)2-paraffin capsules (see the Supporting Information
for details).[7e]
With regard to the alcohol component, the scope of the
methodology was found to be broad (Figure 3). Primary
alcohols were well tolerated, including alcohols that bear
olefins or ethers, as determined by the formation of 21 and 22,
respectively. In addition to oxygen-containing heterocyclic
esters (i.e., 23–25), we found that sulfur- and nitrogen-
containing heterocycles could be employed to give 26–28. The
tolerance of our methodology to furans, thiophenes, unpro-
tected indoles, and pyrrolidines bodes well for future appli-
cations in natural product synthesis and medicinal chemistry.
Secondary alcohols also underwent coupling as shown by the
formation of esters 29–32.[21] The fact that this methodology
can be used to couple hindered alcohols, such as (ꢀ)borneol
to give 32, is especially noteworthy.[22]
As a further test of this methodology, we assessed several
heterocyclic substrates that bear epimerizable a-stereocen-
ters (Figure 4). We were delighted to find that Ts- and Boc-
protected proline-derived substrates coupled well with 1-
hexanol (7) to yield esters 33 and 34. Moreover, an indoline
and a Cbz-protected piperidine substrate underwent esterifi-
cation to furnish products 35 and 36, respectively. In all cases,
the reactions proceeded without significant loss of stereo-
chemical integrity.[23] The mild nature of this methodology
bodes well for future synthetic applications.
Finally, we performed a series of competition experiments
to establish selectivity trends (Figure 5). First, we compared
substrates 3 and 37 in the coupling with 1-hexanol (7) and
found that aliphatic amide 3 reacts exclusively in the presence
of benzamide 37 to give ester 14. Ester 38 was not observed.
Next, we performed two competition experiments between
2
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Figure 3. Scope of the alcohol coupling partner. Yields reflect the
average of two isolation experiments.
Figure 5. Competition experiments. Yields were determined by 1H
NMR analysis using 1,3,5-trimethoxybenzene as an internal standard.
methodology is tolerant of heterocycles, substrates with
epimerizable stereocenters, and sterically congested coupling
partners. Finally, competition experiments reveal selectivity
trends of this methodology. This study is expected to prompt
Figure 4. Coupling of substrates bearing epimerizable a-stereocenters.
Yields reflect the average of two isolation experiments. [a] Reaction run
for 40 h. Cbz=carboxybenzyl.
ꢀ
ꢀ
the use of aliphatic amides in other C C and C X bond
forming reactions.
aliphatic substrates to probe steric and electronic effects.
Amide 3 underwent preferential esterification in the presence
of the more sterically hindered amide 39. Additionally,
a competition experiment between dioxane derivative 40
and cyclohexyl substrate 3 led to selective coupling to furnish
ester 16 in 86% yield. Finally, in an alcohol competition
experiment between 1-hexanol (7) and (ꢀ)-menthol (4) using
substrate 3, we exclusively observed the formation of the
corresponding n-hexyl ester, 14. These selectivity findings
should aid the design of future synthetic applications.
Acknowledgements
The authors are grateful to the NIH-NIGMS (R01 GM117016
for N.K.G), the Dreyfus Foundation, the UCLA Gold Shield
Alumnae, and the University of California, Los Angeles for
financial support. We thank Bristol-Myers Squibb (L.H.), the
Foote Family (L.H. and E.L.B.), the Majeti-Alapati family
(L.H.), and the University of California, Los Angeles
Graduate Division (L.H.) for fellowship support. E.L.B.
acknowledges a National Science Foundation predoctoral
We have discovered the first nickel-catalyzed activation of
amides derived from aliphatic carboxylic acids, as demon-
strated by the esterification of Boc-activated amides. The
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
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[10] A. Yada, S. Okajima, M. Murakami, J. Am. Chem. Soc. 2015, 137,
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fellowship (DGE-1144087). These studies were also sup-
ported by shared instrumentation grants from the NSF (CHE-
1048804) and the National Center for Research Resources
(S10RR025631).
[11] Nickel catalysis is considered to be attractive because nickel is
less expensive, more abundant, and displays a smaller CO2 print,
compared to its precious metal counterpart, palladium. For
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Keywords: aliphatic amides · cross-coupling · esterification ·
homogeneous catalysis · nickel
[12] No examples of non-decarbonylative aliphatic amide couplings
using nickel catalysis have been reported. In the context of
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benzylic substrates have been reported (see Ref. [9]).
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amide
+ . For
Ni/SIPr was calculated to be 26 kcalmolꢀ1
comparison, the corresponding oxidative addition barrier involv-
ing N-methyl-N-phenylacetamide was found to be 31.8 kcal
molꢀ1 (see Ref. [7a]).
[15] The use of mono(oxazolines), bis(oxazolines), pyridinebis(ox-
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mono- and bidentate phosphines, and Buchwald-type phos-
phines led either to no reaction or very low conversions.
[16] Heating beyond 1008C led to diminished yields, whereas
increased reaction times led to minimal improvement in
conversion.
[17] In the absence of Ni(cod)2, terpyridine, or both, the esterification
reaction fails. Thus, we conclude that Ni catalysis is indeed
operative. Analogous control experiments were performed for
all reactions presented in this manuscript to validate nickel
catalysis.
[18] A cyclic substrate, macrolactam i, was coupled with furfuryl
alcohol to give ester ii in 78% yield (by 1H NMR analysis using
1,3,5-trimethoxybenzene (TMB) as an internal standard).
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[19] In addition to the aryl chloride, couplings in the presence of aryl
bromides and aryl nitriles show promise. For robustness screen-
ing results see the Supporting Information.
[20] The coupling of 19a and 7 was performed in the presence of the
radical scavengers galvinoxyl, BHT, and TEMPO. In all cases,
the formation of the corresponding ester product 9a was
observed, suggesting that a radical mechanism is likely not
operative.
[21] Coupling of t-butanol with 19a under the standard reaction
conditions did not lead to product formation.
[22] Coupling of phenol with 19a under the standard reaction
conditions led to the recovery of starting material.
[8] For the nickel-catalyzed decarbonylative coupling of amides
with arylboronic esters, see: S. Shi, G. Meng, M. Szostak, Angew.
Chem. Int. Ed. 2016, 55, 6959 – 6963; Angew. Chem. 2016, 128,
7073 – 7077.
[23] See the Supporting Information for details.
[9] For the nickel-catalyzed decarbonylative borylation of amides,
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Received: August 12, 2016
Revised: September 23, 2016
Published online: && &&, &&&&
4
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Synthetic Methods
Going aliphatic: In prior studies the
nickel-catalyzed activation of aromatic
ꢀ
ꢀ
L. Hie, E. L. Baker, S. M. Anthony,
J.-N. Desrosiers, C. Senanayake,
amides to forge C C or C heteroatom
ꢀ
bonds through cleavage on the amide C
N bond has been developed. The first
nickel-catalyzed activation of amides
derived from aliphatic carboxylic acids is
now described, thus overcoming the key
limitation associated with this class of
reactions.
N. K. Garg*
&&&& — &&&&
Nickel-Catalyzed Esterification of
Aliphatic Amides
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