Nickel-Catalyzed Conversion of Amides to Carboxylic Acids

Article abstract of DOI:10.1021/acs.orglett.0c00885

We report the conversion of amides to carboxylic acids using nonprecious metal catalysis. The methodology strategically employs a nickel-catalyzed esterification using 2-(trimethylsilyl)ethanol, followed by a fluoride-mediated deprotection in a single-pot operation. This approach circumvents catalyst poisoning observed in attempts to directly hydrolyze amides using nickel catalysis. The selectivity and mildness of this transformation are shown through competition experiments and the net-hydrolysis of a complex valine-derived substrate. This strategy addresses a limitation in the field with regard to functional groups accessible from amides using transition metal-catalyzed C-N bond activation and should prove useful in synthetic applications.

Full text of DOI:10.1021/acs.orglett.0c00885

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Nickel-Catalyzed Conversion of Amides to Carboxylic Acids
Rachel R. Knapp, Ana S. Bulger, and Neil K. Garg*
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ABSTRACT: We report the conversion of amides to carboxylic acids
using nonprecious metal catalysis. The methodology strategically
employs a nickel-catalyzed esterification using 2-(trimethylsilyl)-
ethanol, followed by a fluoride-mediated deprotection in a single-pot
operation. This approach circumvents catalyst poisoning observed in
attempts to directly hydrolyze amides using nickel catalysis. The
selectivity and mildness of this transformation are shown through
competition experiments and the net-hydrolysis of a complex valine-
derived substrate. This strategy addresses a limitation in the field with
regard to functional groups accessible from amides using transition
metal-catalyzed C−N bond activation and should prove useful in
synthetic applications.
espite being well-known for their pronounced stability,
using Ni(cod)2 and the N-heterocyclic carbene ligand SIPr,
with water as a nucleophile (Figure 2). Unfortunately, we did
not observe the formation of the desired product, benzoic acid
(2). This was surprising given that many oxygen nucleophiles
D
amides have recently become valuable synthetic building
blocks in transition-metal-catalyzed reactions.1 An array of
carbon−carbon and carbon−heteroatom bond-forming reac-
tions using amides have now been disclosed using palladium,2
rhodium,3 or nickel4 catalysis. Figure 1 highlights several
Figure 1. Select examples of recent advances in the nickel-catalyzed
activation of amides.
Figure 2. Initial studies and control experiments for the nickel-
catalyzed hydrolysis of amides. Conditions: amide 1 (1.0 equiv),
Ni(cod)2 (10 mol%), SIPr (10 mol%), methanol or water (1.2 equiv),
and toluene (1.0 M) heated at 80 °C for 12 or 16 h in a sealed vial
under an atmosphere of N2. Yields were determined by H NMR
analysis using 1,3,5-trimethoxybenzene as an external standard.
functional group conversions beginning from amides that can
now be achieved using nonprecious metal catalysis.4a−c,g,l,n,s
Although several methodologies have been reported in recent
years, one of the most fundamental transformations, namely,
the conversion of amides to carboxylic acids,5 has not yet been
disclosed using transition metal-catalyzed C−N bond
activation. We report a means to achieve this transformation
using nickel catalysis.
a
1
Received: March 10, 2020
Our studies commenced with attempts to modify our
previously established protocol for the conversion of amides to
esters.4a,l Specifically, we evaluated the activation of amide 1
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A

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have been used in nickel-catalyzed amide esterification
reactions. To further assess if the direct conversion to the
carboxylic acid was possible, additional experiments were
performed involving the nickel-catalyzed esterification of
amide 1 using MeOH as the nucleophile. In the absence of
any additive, the reaction proceeded as expected to give ester 3
in 85% yield. However, when the reaction was carried out with
0.5 equiv of benzoic acid (2) as an additive, the esterification
failed, indicative of catalyst poisoning. Recognizing the
incompatibility of the carboxylic acid functional group with
the catalyst system, we sought to develop an alternative
strategy to effect the conversion of amides to carboxylic acids
using nickel catalysis.
An alternative one-pot approach to achieve the amide to
carboxylic acid conversion was conceived, as depicted using
amide substrate 4 (Table 1). Strategically, this process was
Figure 3. Scope of the amide substrate. Conditions: amide 8 (1.0
equiv), Ni(cod)2 (10 mol%), SIPr (10 mol%), 7 (1.25 equiv), and
toluene (1.0 M) heated at 110 °C for 24 h in a sealed vial under an
atmosphere of N2; TBAF (2.5 equiv) at 23 °C for 2 h. Yields reflect
the average of two isolation experiments. aYield was determined by 1H
NMR analysis using 1,3,5-trimethoxybenzene as an external standard.
a
Table 1. Optimization of Reaction Conditions
yield, thus demonstrating the tolerance of the methodology
toward an important nitrogen-containing heterocycle.
As shown in Table 2, variation of the amide N-substituents
was also possible. The use of benzamide 14a, bearing an n-
butyl group in place of a methyl group, afforded benzoic acid
(2) in 77% yield (entry 1). Additionally, the more sterically
encumbered N-isopropyl benzamide seen in 14b (entry 2) and
b
b
entry
alcohol
TMS-OH
TMS-ethanol (7)
TMS-ethanol (7)
temp (°C)
yield of 5
yield of 6
1
2
3
80
80
110
0%
0%
0%
-
83%
87%
a
a
Conditions: amide 4 (1.0 equiv), Ni(cod)2 (10 mol%), SIPr (10 mol
Table 2. Variation of the N-Substituents
%), alcohol (1.25 equiv), and toluene (1.0 M) heated at 80−110 °C
for 24 h in a sealed vial under an atmosphere of N2; TBAF (2.5 equiv)
b
at 23 °C for 2 h. Yields were determined by 1H NMR analysis using
1,3,5-trimethoxybenzene as an external standard.
designed to proceed by nickel-catalyzed esterification to give
protected carboxylic acid 5, which would then be deprotected
in the same reaction vessel through the addition of a mild
fluoride source. Table 1 shows select results using two types of
nucleophiles, each bearing a silyl group. Although the use of
trimethylsilanol (TMS−OH) as a nucleophile failed to
generate the desired ester intermediate 5 (entry 1), the use
of 2-(trimethylsilyl)ethanol (TMS−ethanol, 7) proved more
fruitful (entries 2 and 3). For example, using standard reaction
conditions at a temperature of 80 °C, the conversion of amide
4 to carboxylic acid 6 could be achieved in 83% yield using a
straightforward esterification/TBAF-mediated deprotection
protocol (entry 2).6 Increasing the temperature to 110 °C
gave naphthyl carboxylic acid 6 in a slightly improved yield of
87% (entry 3).
Having identified an operationally simple means to achieve
the nickel-catalyzed conversion of amides to carboxylic acids,
we evaluated several benzamide derivatives7 in the method-
ology (Figure 3). The use of the parent naphthyl substrate 4
(Table 1) furnished 2-naphthoic acid (6) in 90% isolated yield.
Benzoic acids 28 and 10−12 could also be accessed through
this transformation. The formation of carboxylic acids 11 and
12, in 84% and 79% yield, respectively, highlights the tolerance
of electron-withdrawing and electron-donating groups. Addi-
tionally, the use of a quinoline substrate gave rise to 13 in 60%
a
Conditions: amides 14a−d (1.0 equiv), Ni(cod)2 (10 mol%), SIPr
(10 mol%), 7 (1.25 equiv), and toluene (1.0 M) heated at 110 °C for
24 h in a sealed vial under an atmosphere of N2; TBAF (2.5 equiv) at
23 °C for 2 h. Yields reflect the average of two isolation experiments.
B
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the indoline present in 14c (entry 3) were tolerated. Moreover,
tosyl derivative 14d could be employed in the methodology to
provide 2 in 71% yield (entry 4).
Competition experiments were performed to gauge sub-
strate-based selectivity in the nickel-catalyzed conversion of
amides to carboxylic acids (Figure 4). The first involved
epimerizable stereocenter was subjected to our typical reaction
protocol. This gave benzoic acid (2) and amine 18 in 67% and
72% yield, respectively. Of note, amine 18 was recovered in
99% ee, and the ester functional group remained intact. As
classical hydrolysis conditions are often incompatible with
esters and epimerizable stereocenters,5 this result underscores
the mild nature of our strategy for the conversion of amides to
carboxylic acids.
We have developed an operationally simple procedure to
convert amides to carboxylic acids using nonprecious metal
catalysis. The methodology strategically circumvents catalyst
poisoning through the use of a nickel-catalyzed esterification,
followed by a fluoride-mediated deprotection in a single-pot
operation. We have demonstrated that a variety of amides with
aryl groups and N-substituents can be employed in this
transformation. Additionally, we have shown the process can
be utilized to cleave amides in a mild and selective manner.
This strategy offers a practical means to convert subclasses of
amides to carboxylic acids while addressing a limitation with
regard to functional groups accessible using transition-metal-
catalyzed amide C−N bond activation.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00885.
Experimental details and compound characterization
data (PDF)
Figure 4. Competition experiments demonstrate substrate selectivity.
Conditions: amide 1 (1.0 equiv), 15 or 16 (1.0 equiv), Ni(cod)2 (10
mol%), SIPr (10 mol%), 7 (1.25 equiv), and toluene (1.0 M) heated
at 110 °C for 24 h in a sealed vial under an atmosphere of N2; TBAF
(2.5 equiv) at 23 °C for 2 h. Yields reflect the average of two isolation
experiments.
AUTHOR INFORMATION
Corresponding Author
■
Neil K. Garg − Department of Chemistry and Biochemistry,
University of California, Los Angeles, Los Angeles, California
90095-1569, United States; orcid.org/0000-0002-7793-
2629; Email: neilgarg@chem.ucla.edu
benzamide 1 and cyclohexyl amide 15, which gave a selective
reaction of 1 to furnish net-hydrolyzed product 2 in 86% yield.
Aliphatic amide 15 was recovered in quantitative yield. We also
performed a competition experiment using tertiary amide 1
and secondary amide 16. This led to selective reaction of 1 to
give benzoic acid (2), with quantitative recovery of secondary
amide 16. The ability to preferentially manipulate subclasses of
amides through selective conversion to carboxylic acids should
prove useful in synthetic applications.
Authors
Rachel R. Knapp − Department of Chemistry and Biochemistry,
University of California, Los Angeles, Los Angeles, California
90095-1569, United States
Ana S. Bulger − Department of Chemistry and Biochemistry,
University of California, Los Angeles, Los Angeles, California
90095-1569, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00885
One further evaluation of the methodology to assess
mildness and selectivity is shown in Figure 5. Substrate 17
(derived from L-valine)4a bearing an amide, an ester, and an
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the NIH-NIGMS (R01-GM117016 to
N.K.G. and Supplement to R.R.K), the Trueblood Family
(N.K.G.), the Foote family (A.S.B), and the University of
California, Los Angeles, for financial support. These studies
were supported by shared instrumentation grants from the
NSF (CHE-1048804) and the NIH NCRR (S10RR025631).
Figure 5. Cleavage of a valine-derived amide in the presence of an
ester. Conditions: amide 17 (1.0 equiv), Ni(cod)2 (20 mol%), SIPr
(20 mol%), 7 (1.25 equiv), and toluene (1.0 M) heated at 110 °C for
24 h in a sealed vial under an atmosphere of N2; TBAF (2.5 equiv) at
23 °C for 2 h. Yields reflect the average of two isolation experiments.
C
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ACS Catal. 2018, 8, 9131−9139. (u) Meng, G.; Szostak, M.
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