Methyl Esters as Cross-Coupling Electrophiles: Direct Synthesis of Amide Bonds

Article abstract of DOI:10.1021/acscatal.9b00884

Amide bond formation and transition metal-catalyzed cross-coupling are two of the most frequently used chemical reactions in organic synthesis. Recently, an overlap between these two reaction families was identified when Pd and Ni catalysts were demonstrated to cleave the strong C-O bond present in esters via oxidative addition. When simple methyl and ethyl esters are used, this transformation provides a powerful alternative to classical amide bond formations, which commonly feature stoichiometric activating agents. Thus far, few redox-active catalysts have been demonstrated to activate the C(acyl)-O bond of alkyl esters, which makes it difficult to perform informed screening when a challenging reaction needs optimization. We demonstrate that Ni catalysts bearing diverse NHC, phosphine, and nitrogen-containing ligands can all be used to activate methyl esters and enable their use in direct amide bond formation.

Full text of DOI:10.1021/acscatal.9b00884

Research Article
pubs.acs.org/acscatalysis
Cite This: ACS Catal. 2019, 9, 4426−4433
Methyl Esters as Cross-Coupling Electrophiles: Direct Synthesis of
Amide Bonds
Yan-Long Zheng and Stephen G. Newman*
Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10
Marie-Curie, Ottawa, Ontario K1N 6N5, Canada
S
* Supporting Information
ABSTRACT: Amide bond formation and transition metal-
catalyzed cross-coupling are two of the most frequently used
chemical reactions in organic synthesis. Recently, an overlap
between these two reaction families was identified when Pd
and Ni catalysts were demonstrated to cleave the strong C−O
bond present in esters via oxidative addition. When simple
methyl and ethyl esters are used, this transformation provides
a powerful alternative to classical amide bond formations,
which commonly feature stoichiometric activating agents.
Thus far, few redox-active catalysts have been demonstrated to activate the C(acyl)−O bond of alkyl esters, which makes it
difficult to perform informed screening when a challenging reaction needs optimization. We demonstrate that Ni catalysts
bearing diverse NHC, phosphine, and nitrogen-containing ligands can all be used to activate methyl esters and enable their use
in direct amide bond formation.
KEYWORDS: nickel, amide bond formation, cross-coupling, esters
hydrolyzing to the corresponding carboxylic acid and
activation with, e.g., thionyl chloride or peptide coupling
reagents prior to amide bond formation.8
INTRODUCTION
■
As one of the important functional groups of peptides,
pharmaceuticals, agrochemicals, and synthetic materials,
amides play a central role in the function of organic
molecules.1 As a consequence, the synthesis of amide bonds
is one of the most frequently run chemical reactions, usually
accomplished by uniting a carboxylic acid and free amine.2
While progress has been made in enabling this reaction to be
performed directly,3 the majority of procedures first activate
the carboxylic acid moiety as an acid chloride or by using
coupling reagents such as EDC, HATU, and PyBOP (Scheme
1A),4 rendering the carbonyl group sufficiently electrophilic for
attack by the amine nucleophile. The high need for amide-
containing molecules along with the high cost and waste
generated using these common amide bond-forming proce-
dures has led to numerous calls for more efficient methods.5
Esters can provide a promising alternative to carboxylic acids
as reaction partners for amide bond formation. Simple methyl
and ethyl esters are broadly available, stable, and capable of
being carried through multistep synthesis. Alkyl groups are
considered a protecting group for carboxylic acids. Further,
esters are a useful functional group for α-functionalization and
heterocycle syntheses. Due to their nonionizable nature, a
different set of challenges is encountered when trying to use
esters as electrophiles in amide bond formation. Existing
methods primarily rely on activation of the ester by a Lewis
acid6 or activation of the amine with aggressive organometallic
base,7 with each strategy having significant scope limitations.
As a consequence of these limitations, it is common for
synthetic chemists to convert esters to amides by first
In recent years, the development of transition-metal-
catalyzed C−O bond activation methods has expanded the
diversity and robustness of (pseudo)halide coupling partners
that can participate in cross-coupling reactions.9 For instance,
esters can be used as a viable alternative to acid chlorides for
the synthesis of diverse carbonyl-containing and decarbony-
lated coupling products.10 This strategy, commonly accom-
plished with Pd and Ni catalysis, is facilitated by oxidative
addition into the C(acyl)−O bond. Early reports in this area
used easily activated species such as anhydrides, nitrophenyl
esters, enol ether esters, and pyridyl esters.11 More robust
phenyl esters were first reported by Itami, Yamaguchi, and co-
workers using Ni(0) to catalyze C−H functionalization
reactions.12 A number of powerful C−C and C−heteroatom-
forming reactions were reported afterward using phenyl esters
as aryl electrophiles via decarbonylative coupling13 and as acyl
electrophiles via a carbonyl-retention mechanistic pathway.14
While phenyl esters are significantly more robust than
traditional activated acyl electrophiles such as acid chlorides
and anhydrides, they are still nonabundant functional groups
that must first by synthesized prior to application. More useful
catalytic methods would be able to directly use abundant
methyl and ethyl ester starting materials, though the strength
Received: February 28, 2019
Revised: April 2, 2019
© XXXX American Chemical Society
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Research Article
the transformation does not rely on traditional nucleophile−
electrophile pairing, both electron-donating and electron-
withdrawing functional groups were tolerated on either
reaction partner. Similarly, the absence of any basic or acidic
additives in the reaction conditions enabled epimerizable
stereocenters, acetals, ketals, Michael acceptors, and sites
susceptible to attack via SNAr reactions to be untouched.
Given the high demand for more efficient amide bond-
forming reactions and the traditional reliance on acid/base
chemistry to functionalize esters, we wished to expand the
boundaries of our Ni-catalyzed process. Although our initially
reported substrate scope showed over 50 examples of diverse
ester and amine reaction partners, many substrates could not
be prepared in synthetically useful yields. For example,
sterically hindered substrates (e.g., ortho-substituted anilines,
benzoates), certain heterocycles (e.g., furans, coumarins), and
dialkylamines were found to be problematic. Given that any of
the elementary steps of the catalytic cycle could feasibly be
turnover limiting, we proposed that different ester−amine pairs
may have different optimal conditions. Herein, we describe our
efforts in identifying a more diverse subset of ligands that can
be used to catalytically activate esters and apply these
privileged ligand scaffolds to improve the yields of many
challenging amide bond-forming reactions.
Scheme 1. Example Methods for Amide Bond formation
RESULTS AND DISCUSSION
■
Our originally developed conditions for direct formation of
amide bonds from esters and amines used a catalyst formed
from mixing Ni(cod)2 with the free N-heterocyclic carbene
1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr). With
this mixture, methyl benzoate 1 and aniline 2 react to form
benzanilide 3 in 83% yield in toluene at 140 °C (Table 1, entry
1). No product is observed in the absence of the Ni (entry 2)
or ligand (entry 3), even with stoichiometric base present
(entry 4). While this catalyst is promising, both the metal and
the ligand are air sensitive and must be weighed inside a
glovebox, hindering adoption of the methodology. The air-
stable, commercially available salt IPr·HCl was found to give a
comparable yield to IPr if potassium tert-butoxide (entry 5) or
potassium phosphate (entry 6) is used to release the NHC
ligand in situ. Moving away from oxygen-sensitive Ni(cod)2
was less successful. In situ reduction of Ni(OAc)2 by
stoichiometric Zn10a was inefficient (entry 7), as was the air-
stable Ni(0) precatalyst Ni[P(OPh)3]4 (entry 8).21 The Ni(II)
precatalyst Ni(TMEDA)(o-Tol)Cl 422 provided only 43%
yield of product (entry 9). Preformed Ni-NHC complexes23
were similarly inefficient, including the commercial Ni(II)
catalysts 5 (entry 10) and 6 (entries 11 and 12), and styrenyl
complex 7 (entries 13 and 14).24 These results point to a clear
need for more active and more stable alternatives to Ni(cod)2
if methodologies based on this catalyst are to be of broad use.25
Continuing with Ni(cod)2 as the metal source and with the
knowledge that NHC salts can be effectively deprotonated in
situ, we sought to uncover more viable ligands. While our
originally identified ligand IPr (L1) was found to be quite
general, there were numerous transformations that gave
unsatisfactory yields that we hoped to solve by ligand
screening. Using the synthesis of benzanilide 3 as a test
reaction, over 60 different ligands were screened (Table S1−
S3, Supporting Information)a subset of these are provided
in Scheme 2 using 10 mol % ligand if bidentate and 20 mol %
ligand if monodentate.26 Most phosphine ligands were entirely
ineffective, including XantPhos (L2), CyPAd-Dalphos (L3),
of the corresponding C−O bond makes them more
challenging to activate.15 In 2016, Garg and co-workers
reported the first amide bond-forming reaction of methyl
esters using a Ni(0) catalyst and Al(Ot-Bu)3 as an activating
agent (Scheme 1B).16 This seminal report was unfortunately
limited to use of methyl 1-naphtholate esters and N-alkyl
anilines. Computational studies and control experiments
supported a cross-coupling-type mechanism with the Ni
catalyst oxidatively adding to the ester C−O bond. Further
progress was made toward nontraditional amide bond
formation pathways from esters by our group on the use of
Pd catalysis17 and by Hu and co-workers in 2017, who
reported a nickel-catalyzed coupling of nitroarenes mediated
by stoichiometric zinc.18 Their reaction was proposed to
proceed by insertion to the C−O bond with an Ni(II) nitrene
intermediate. Notably, a large portion of anilines is derived
from nitroarenes, making this method highly step economical.
Very recently, our group reported that a Ni−NHC catalyst
system could enable direct, additive-free synthesis of amides
from simple alkyl esters.19 The reaction worked with esters
bearing both sp2-(arene)- and sp3-(alkyl)-hybridized carbons at
the α position. Furthermore, both aliphatic amines and anilines
derivatives could be used. Mechanistically, a cross-coupling-
type pathway was proposed and later supported by mechanistic
studies by Hong and co-workers, who showed that all three key
stepsoxidative addition, proton transfer, and reductive
eliminationhave similar transition state energies.20 Since
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a
low-yielding reactions. Challenging ester reactants were first
targeted. For each ester + amine pair, all of the new ligands
(L11−L13 and L20−L25) were tested and compared to L1.
The most efficient ligand was identified for each product, and
the isolated yield is provided in Scheme 3. For instance,
sterically hindered methyl 3-methyl-2-furoate provided amide
Table 1. Conditions for Direct Amide Bond Formation
1
8 in 43% yield by H NMR under the standard reaction
entry
Ni source
ligands/additives
IPr (20 mol %)
none
% yield
conditions when using IPr as the ligand. Using L22 instead
provides 8 in 79% yield (75% after isolation). The Ni/L22
catalyst could be used to make derivatives 9−11 with similar
efficiency. A similar observation was found for the synthesis of
the isomeric furan derivative fenfuram (12). This fungicide can
be manufactured from the corresponding methyl ester using
aniline as solvent in the presence of stoichiometric Al as an
activating agent.30 With Ni catalysis under our previous
standard conditions, only 8% yield was observed. Use of L22
provided 50% isolated yield, and analog 13 could be
synthesized in a similarly improved 64% isolated yield. Various
ortho-methoxy benzamides have been demonstrated to be
inhibitors of cyclooxygenases.31 These electron-rich and
sterically hindered amides (14−16) were most efficiently
prepared using SIPr L20 as the ligand. The saturated backbone
of SIPr gives a slightly increased buried volume relative to
IPr,32 which could potentially facilitate a more challenging
reductive elimination step. Other ortho-substituted products
bearing a fluorine (17) or phenyl (18) group were similarly
enabled by the presence of L20.
1
2
3
Ni(cod)2
Ni(cod)2
none
83
0
IPr (20 mol %)
0
4
5
6
7
none
KOtBu (20 mol %)
IPr·HCl + KOtBu (20 mol %)
trace
83
Ni(cod)2
Ni(cod)2
Ni(OAc)2
IPr·HCl (20 mol %) + K3PO4 (1 equiv) 73
IPr (20 mol %) and Zn (1 equiv) trace
8
Ni[P(OPh)3]4 IPr (20 mol %)
0
9
4
5
6
6
7
7
IPr·HCl + KOtBu (20 mol %)
none
none
IPr·HCl + KOtBu (10 mol %)
none
IPr (10 mol %)
43
8
0
12
53
53
10
11
12
13
14
a
Reactions run at 0.2 M concentration on 0.2 mmol scale. Yield
determined by GC-FID of the crude mixture with 1,3,5-trimethox-
ybenzene as an internal standard.
3-Carboxamido coumarin derivatives such as 19 have been
shown as efficient inhibitors against human monoamine
oxidases.33 During medicinal chemistry synthesis, they were
prepared from the corresponding ester and aniline derivatives
by first hydrolyzing the ester in aqueous base and then
activating the corresponding acid as an acid chloride or with a
diimide coupling reagent. Using L25 as the ligand,
carboxamides 19−25 could be directly prepared in 70−90%
isolated yields. Notably, even anilines with electron-with-
drawing groups could be used, including selective intermo-
lecular coupling with the coumarin ester over potential
polymerization to prepare 25. IPr as a ligand was also
observed to be poor for performing coupling reactions with α-
secondary esters, such as for the formation of proline derivative
26. Here, L20 was observed to give synthetically useful 65%
yield, and more nucleophilic anilines with dimethyl (27) and
OMe (28) group as well as less nucleophilic anilines with
acetyl (29) and COOMe (30) are tolerated. Lastly, pyrrazole-
bearing amides such as 32 are privileged structures in a number
of commercial fungicides. Given the large scale generally
required for agrochemical manufacturing, routes to these
molecules generally avoid the use of coupling reagents and
instead proceed by multistep procedures involving acid
chloride intermediates.34 While no ligand could be identified
that provided exceptional yields, L24 was found to be superior
to IPr, providing 31 and 32 in 40% and 39% yield, respectively.
Next, we turned our attention to amine-coupling partners
that proved to be challenging using the Ni/IPr catalyst
(Scheme 4). Cyclic amines such as morpholine and pyrrolidine
are excellent reactants; however, bulky primary amines and
noncyclic secondary amines are challenging to couple. For
example, adamantan-1-amine provided amide 33 in just 18%
yield using L1. Screening of the newly identified ligands
enabled the yield to be improved to 91% by the application of
L24. This ligand also provided improved yields when using N-
methyl benzylamine and dibenzylamine, giving 34 and 35 in
dppp analog L4, P(o-Tol)3 (L5), SPhos (L6), and PCy3 (L7).
Bidentate ligands (L8−L10) showed significant product
formation, and dcype (L11) and dcypp (L12) were
comparable to L1. One bidentate nitrogen species, L13, also
proved to be a viable alternative, demonstrating that three
different ligand classes can be used. Next, we focused on
varying the steric and electronic environment around the
heterocyclic ring and aryl substitutions of L1. Well-known
ligands L14−L19 gave low yields of product. In contrast,
ligands L20−L25 proved to be viable alternatives to IPr.
Notably, several of these ligands are not known to be
particularly effective for Ni-catalyzed C−N bond formation.
For instance, 2,4,6-tricyclopentylaniline-derived L24 was first
synthesized by Plenio in 2014 but has never been reported in
any catalytic reactions.27 Pyridine-containing L25, recently
reported by Michaelis and co-workers to enable Ni-catalyzed
allylation reactions,28 was particularly promising. This ligand
has been observed to be bidentate when ligated to many
metals,29 making it unique among the other promising NHC
ligands identified.
With a variety of promising ligands identified as viable in the
catalytic synthesis of benzanilide, we explored whether this
knowledge could be used to improve previously attempted
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Scheme 2. Selected Ligand Evaluation
53% and 22% yield, respectively. Hindered nicotinamide
derivatives were next studied, representing the core scaffold
of the fungicide Boscalid. While SIPr (L20) and SIMes (L17)
were poor ligands for preparing amide 36, the unsymmetrical
mixed analog L23 gave a useful 50% yield. Similar moderate
yields were obtained for the preparation of 37−39, suggesting
there is a subtle balance of steric factors required when using
hindered aniline coupling partners. The most challenging
family of amines thus far identified are N-alkyl aniline
derivatives. Their reaction with esters is highly thermodynami-
cally uphill, though success was achieved by Garg and co-
workers when coupling with naphthalene esters in the presence
of stoichiometric Lewis acids.16 Unfortunately, attempts to
synthesize N-methyl-N-phenylbenzamide were ineffective with
all privileged ligands under additive-free conditions (Table
S17, Supporting Information). In contrast, indoline was found
to be a good coupling partner, providing amide 40 in near
quantitative yield when using L13. Amide 41, which has been
demonstrated to inhibit growth human leukemia cells,35 was
prepared with similar efficiency. Lastly, amine nucleophiles
with remote basic sites were studied, which can potentially
compete with the ligand for coordination to the metal center
during the catalytic cycle. With pyridylmethyl amine as a
nucleophile, L24 was most effective, enabling the synthesis of
amides 42 and 43 in moderate yield. Synthesis of 44 was more
challenging, but L15 showed a drastic improvement over IPr to
give a 32% yield.
Given the efficient synthesis of amides 25 and 30, which
involve selective coupling among two different esters, we next
ran competition studies to understand selectivity between
different esters (Figure S1). In general, methyl esters bearing
α-aryl groups react favorably relative to those bearing α-alkyl
groups with the exception of α-benzylic esters which are most
reactive. To demonstrate this selectivity, amine 45 was
selectively coupled with esters 46 and 47 using L24, affording
ester-containing amides 48 and 49 in 79% and 43% yield,
respectively (Scheme 5). Substrate 50 underwent a similarly
efficient selective reaction at the α-benzyl ester site instead of
the α-aryl ester.
CONCLUSION
■
In summary, we have greatly expanded the scope of the Ni-
catalyzed amide bond formation from simple methyl esters and
amines. This was accomplished by identifying new ligand
families that can enable this transformation. Of the 60 ligands
initially tested, 9 were identified as being comparable to our
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a
a
Scheme 3. Substrate Scope of Challenging Ester
Scheme 4. Substrate Scope of Challenging Amine
a
General reaction conditions: ester (0.20 mmol), amine (0.24−0.4
mmol), Ni(cod)2 (10 mol %), ligand (20 mol %), t-BuOK (20 mol
%), toluene (0.2 M), 140 °C for 16 h. Assay yields of the crude
reaction mixture are given in parentheses; isolated yields are reported
b
in bold. 10 mol % ligand.
Scheme 5. Selective Amidation of Esters and Amines
a
General reaction conditions: ester (0.20 mmol), amine (0.24−0.4
mmol), Ni(cod)2 (10 mol %), ligand (20 mol %), t-BuOK (20 mol
%), toluene (0.2 M), 140 °C for 16 h. Assay yields of the crude
reaction mixture are given in parentheses; isolated yields are reported
b
in bold. Ligand (10 mol %) and t-BuOK (10 mol %) were used.
originally identified ligand, IPr, in the synthesis of benzanilide.
Notably, these new ligands are highly diverse, including NHCs,
phosphines, and a phenanthroline derivative. With these
effective ligands, several challenging coupling reactions can
be drastically improved, particularly when using more sterically
hindered reactants. In particular, bioactive scaffolds were
targeted and yields were improved to provide a synthetically
viable alternative to more traditional multistep synthesis.
Finally, selective coupling was demonstrated when multiple
esters are present, again enabled by the expanded ligand scope.
Further efforts are still required to identify a robust, air-stable
catalyst. Moreover, the ligands identified still require the use of
high reaction temperatures, hindering scale up. With these
future developments in mind, the research outlined herein
demonstrates that Ni catalysis has the potential to streamline
the synthesis of important amides. Application of these new
4430
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Green Chem. 2007, 9, 411−420.
catalysts to more cross-coupling reactions featuring catalytic
activation of methyl esters is underway.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.9b00884.
■
(6) (a) Ishihara, K.; Kuroki, Y.; Hanaki, N.; Ohara, S.; Yamamoto,
H. Antimony-Templated Macrolactamization of Tetraamino Esters.
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( )-Verbacine, ( )-Verbaskine, and ( )-Verbascenine. J. Am. Chem.
Soc. 1996, 118, 1569−1570. (b) Han, C.; Lee, J. P.; Lobkovsky, E.;
Porco, J. A. Catalytic Ester−Amide Exchange Using Group (IV)
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10039−10044. (c) Tsuji, H.; Yamamoto, H. Hydroxy-Directed
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S
Experimental procedures, characterization of organic
molecules, and optimization tables (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: stephen.newman@uottawa.ca.
■
ORCID
Stephen G. Newman: 0000-0003-1949-5069
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Financial support for this work was provided by BASF, the
National Science and Engineering Research Council of Canada
(NSERC), and the Canada Research Chair program. Martin
McLaughlin, Mathias Schelwies, Stephan Zuend, and Roland
́
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Green Chem. 2012, 14, 1335−1341. (e) Ohshima, T.; Hayashi, Y.;
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Gotz (BASF) are thanked for helpful discussions. The
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Ministry of Research, Innovation, & Science are thanked for
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