Nickel-Catalyzed Claisen Condensation Reaction between Two Different Amides

Article abstract of DOI:10.1021/acs.orglett.0c00485

A nickel-catalyzed Claisen condensation reaction between two amides, where one possesses an α-proton, for the synthesis of β-ketoamides was developed. Ni(glyme)Cl₂ and terpyridine serve as the active catalysts in the presence of Mn and LiCl. N,N-Methylphenyl and N,N-diphenyl benzamide derivatives react with cyclic and noncyclic amides to give their corresponding β-ketoamides in moderate to good yields. In addition, a DFT calculation suggests that reductive elimination is the rate-determining step.

Full text of DOI:10.1021/acs.orglett.0c00485

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Letter
Nickel-Catalyzed Claisen Condensation Reaction between Two
Different Amides
Jiajia Chen, Man Xu, Subeen Yu, Yuanzhi Xia,* and Sunwoo Lee*
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ABSTRACT: A nickel-catalyzed Claisen condensation reaction
between two amides, where one possesses an α-proton, for the
synthesis of β-ketoamides was developed. Ni(glyme)Cl2 and
terpyridine serve as the active catalysts in the presence of Mn
and LiCl. N,N-Methylphenyl and N,N-diphenyl benzamide
derivatives react with cyclic and noncyclic amides to give their
corresponding β-ketoamides in moderate to good yields. In
addition, a DFT calculation suggests that reductive elimination is
the rate-determining step.
Scheme 1. Condensation and Coupling Reactions of Amide
ost of the materials we use on a regular basis are
polymers and consist of long carbon chains. The
M
Claisen condensation reaction, first reported in 1881, is one of
the most classical reactions used for formation of carbon−
carbon bonds.1 This reaction occurs between an ester and
another carbonyl compound containing an α-proton in the
presence of a base to afford a β-keto carbonyl compound. β-
Keto carbonyl functionality has been widely employed in
further transformations and is found in many valuable organic
molecules.2
In particular, β-ketoamides are useful building blocks found
in bioactive molecules.3 The Claisen condensation reaction
between an ester and an amide has frequently been employed
as a useful tool for the construction of a β-ketoamide backbone
(Scheme 1a).4 However, this approach requires harsh reaction
conditions, such as a strong base and low temperatures,
because the α-proton of an amide is much less acidic than that
of other carbonyl compounds such as esters and ketones,
which leads to poor functional group compatibility.
Transition-metal-catalyzed carbon−carbon bond forming
reactions are attractive because they can be carried out
under mild conditions. Hartwig and Buchwald independently
developed the palladium-catalyzed coupling reaction between
aryl halides and the α-carbon atom in carbonyl compounds
such as ketones,5 and esters.6 Hartwig demonstrated that the
α-carbon of an amide can be activated under mild reaction
conditions and shows good functional group tolerance in the
carbon−carbon bond forming process (Scheme 1b).7
an amide is allowed to react with carbon nucleophiles such as
aryl boronic acid derivatives in the presence of a nickel catalyst
Recently, activation of the C−N bond in an amide using
transition metal catalysis has received attention because the
reaction may be useful for synthesizing other carbonyl
compounds.8 The reaction between an amide and an amine
affords a new amide via transamidation.9 Nickel-catalyzed
transamidation of an amide with an alcohol provides the
corresponding ester.10 Furthermore, a ketone is formed when
Received: February 6, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00485
© XXXX American Chemical Society
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A

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(Scheme 1c).11 However, there are no examples of the reaction
utilizing the α-carbon of carbonyl compounds.
performed in the absence of Ni(glyme)Cl2, terpyridine, Mn,
and LiCl either did not afford the desired product or resulted
in exceedingly low yields of the product (entries 2−5).
Reactions carried out using NiCl2 and Ni(OAc)2 afforded 3a in
41% and 30% yields, respectively (entries 6 and 7). Bipyridine
gave a higher product yield than other nitrogen-based ligands
including PMDETA and 4,7-Me2Phen (entries 8−10).
Reactions using phosphine ligands such as Xantphos, dppb,
PPh3, and PCy3 provided 3a in 54%, 47%, 69%, and 27%
yields, respectively (entries 11−14). The reactions performed
using LiI instead of LiCl gave the desired product in 44% yield.
However, other salts such as LiBF4 and KCl did not lead to the
desired product (entries 15−17). In addition, the yield of the
desired product decreased to 23% when the amount of LiCl
was reduced to 0.5 equiv (entry 18). The use of diglyme as a
solvent led to a poor product yield (entry 19). When the
amount of catalyst or Mn was reduced, the product yields
decreased (entries 20−22). The reaction at 150 °C gave an
inferior product yield (entry 23). Unfortunately, the reaction at
low temperature (50 °C) did not give the desired product
(entry 24).
To the best of our knowledge, Claisen condensation
reactions between two different amides have not been reported
to date, although the transition-metal-catalyzed α-arylations of
amides and transamidation reactions have. The development
of Claisen condensation between two amides is challenging
because of the high stability of the C−N bond and low activity
of the α-proton of the amide. To overcome this challenge, we
employed a nickel-based catalytic system. Here, we report for
the first time the nickel-catalyzed coupling reaction of the acyl
group of an amide and α-carbon of another amide for the
synthesis of β-ketoamides (Scheme 1d).
N-Methyl-N-phenylbenzamide and N-methylpyrrolidin-2-
one (NMP) were chosen as model substrates to identify the
optimal conditions for the coupling reaction (Table 1).
After extensive screening of the reaction parameters, we
established that Ni(glyme)Cl2 and terpyridine in mesitylene
afforded the desired product 3a in 81% yield in the presence of
Mn and LiCl at 170 °C (entry 1). The impact of several
reaction parameters is summarized in Table 1. Reactions
After establishing optimal conditions, we proceeded to
evaluate the substrate scope of the reaction. To this end, we
used a variety of tertiary amides in reaction with NMP (Table
2).
Table 1. Optimal Conditions for the Nickel-Catalyzed
Coupling Reaction between 1 and 2a
a
a
Table 2. Reaction of 2a with a Variety of Benzamide
b
entry
change from the standard conditions
none
no Ni(glyme)Cl2
yield (%)
1
2
3
81
trace
8
no terpyridine
4
no Mn
0
5
no LiCl
0
6
7
8
9
NiCl2 instead of Ni(glyme)Cl2
Ni(OAc)2 instead of Ni(glyme)Cl2
bipyridine instead of terpyridine
PMDETA instead of terpyridine
4,7-Me2Phen instead of terpyridine
Xantphos instead of terpyridine
dppb instead of terpyridine
PPh3 (20 mol %) instead of terpyridine
PCy3 (20 mol %) instead of terpyridine
LiI instead of LiCl
41
30
70
56
21
54
47
69
27
44
0
a
Reaction conditions: 1 (0.3 mmol), 2a (1.5 mmol), Ni(glyme)Cl2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
(0.03 mmol), terpyridine (0.03 mmol), Mn (0.75 mmol), and LiCl
(0.3 mmol) were reacted in mesitylene (0.4 mL) at 170 °C for 24 h.
b
Isolated yield.
The reaction with N,N-diphenylbenzamide provided 3a in a
similar yield to that observed with N,N-diphenylbenzamides
(entry 1). However, N-ethyl-N-phenylbenzamide, N-benzyl-N-
phenylbenzamide, and N,N-dimethylbenzamide afforded 3a in
poor yields (entries 2−4). Interestingly, N-phenylbenzamide, a
secondary amide, reacted with NMP to give 3a in 25% yield
(entry 5), while activated amides such as N-phenyl-N-
tosylbenzamide did not give the desired product (entry 6).
Based on these results, we confirmed that N-methyl-N-
phenylbenzamide and N,N-diphenylbenzamide are suitable
activated amides for the nickel-catalyzed Claisen condensation
with NMP.
Next, we evaluated a variety of N-methyl-N-phenyl-
benzamides and N,N-diphenylbenzamides bearing a substitu-
ent at the benzoyl group for reaction with NMP under the
optimal conditions (Scheme 2). Benzamides with an alkyl
substituent at the meta- or para-position afforded the
corresponding β-ketoamides in good yields. However, 4-
LiBF4 instead of LiCl
KCl instead of LiCl
0
0.5 equiv of LiCl instead of 1.0 equiv
diglyme instead of mesitylene
5 mol % Ni and L instead of 10 mol %
1.0 equiv of Mn instead of 2.5 equiv
0.5 equiv of Mn instead of 2.5 equiv
150 °C instead of 170 °C
50 °C instead of 170 °C
23
29
62
30
3
66
0
a
Reaction conditions are as follows: 1 (0.3 mmol), 2a (1.5 mmol),
Ni(glyme)Cl2 (0.03 mmol), terpyridine (0.03 mmol), Mn (0.75
mmol), and LiCl (0.3 mmol) were reacted in mesitylene (0.4 mL) at
170 °C for 24 h. Yields are isolated.
b
B
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Scheme 2. Claisen Condensation Reaction between
Benzamides and NMP
Scheme 3. Claisen Condensation Reaction between N-
Methyl-N-phenyl Benzamide and a Variety of Amides
a
a
a
Reaction conditions: 1 (1.0 mmol), 2 (5.0 mmol), Ni(glyme)Cl2
(0.1 mmol), terpyridine (0.1 mmol), Mn (2.5 mmol), and LiCl (1.0
mmol) were reacted in mesitylene (2.0 mL) at 170 °C for 24 h. The
numbers in parentheses are isolated yields.
a
Reaction conditions: 1 (1.0 mmol), 2a (5.0 mmol), Ni(glyme)Cl2
(0.1 mmol), terpyridine (0.1 mmol), Mn (2.5 mmol), and LiCl (1.0
mmol) were reacted in mesitylene (2.0 mL) at 170 °C for 24 h. The
numbers in the parentheses are isolated yields. A is yield obtained
from N-methyl-N-phenylbenzamide, and B is yield obtained from
N,N-diphenylbenzamide.
yields. However, pyrrolidinylpropan-1-one afforded 4n in only
18% yield. Interestingly, N-methyl-N,2-diphenylacetamide
reacted with N,N-dimethylacetamide to afford 4o in 48% yield.
We ran control experiments to gain insight into the reaction
mechanism (Scheme 4).
methyl-N-methyl-N-phenylbenzamide provided 3c in only 33%
yield. 1,1-Biphenyl and 1-naphthyl amides gave 3e and 3f in
good yield. Methoxy- and N,N-dimethylamino-substituted
benzamides gave their corresponding products 3g, 3h, 3i,
and 3j, in moderate to good yields. However, dimethoxy-
substituted benzamides gave 3k in low yield for both A and B.
Benzamides bearing a fluorine group at the meta- or para-
position gave 3l and 3m in moderate to good yields. 2- and 3-
Furamide derivatives afforded the desired products 3n and 3o,
albeit in low yields. Unfortunately, benzamides bearing an
ortho-substituent afforded only trace amounts of the desired
product.
Scheme 4. Control Experiments
We then attempted to expand the scope of the amides
bearing an α-hydrogen in the reaction using a variety of N-
methyl-N-phenyl benzamides derivatives (Scheme 3). We
employed 1-methylpiperidin-2-one instead of NMP and
reacted it with a variety of benzamide derivatives to afford
the desired β-ketoamides in 48% to 85% yields. When 1-
methylazepan-2-one was reacted with benzamide derivatives,
we obtained the desired product 4e in 64% yield in the case of
N-methyl-N-phenyl benzamide. In contrast, substituted N-
methyl-N-phenyl benzamides gave the products 4f, 4g, and 4h
in low yield. A noncyclic amide, N,N-dimethylacetamide, was
also employed in the reaction with the N-methyl-N-phenyl
benzamide derivatives and gave the desired product in good
When NMP was treated with TMSCl under standard
conditions in the absence of benzamide, silyl enolate 5 was
detected by GCMS analysis. In addition, when NMP reacted
with D2O under standard conditions, 32% deuteration
occurred at the α-carbon of NMP. The reaction with NMP
in the presence of 1,1-diphenylethylene, a radical trapping
C
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reagent, did not provide any trapping product but gave the
hydrogenation product 1,1-diphenylethane.12 These results
indicate the reaction occurs via an ionic mechanism, with the
formation of hydrogen.
To better understand the transformation, we did DFT
calculations using 1a and 2a as model reactants to investigate
the detailed mechanism (Scheme 5).13,14 According to the
substrates that gave good product yields. Cyclic amides having
five-, six-, and seven-membered rings, N-methylpyrrolidin-2-
one, 1-methylpiperidin-2-one, and 1-methylazepan-2-one,
served as good nucleophiles that reacted with benzamide to
produce the corresponding β-ketoamides in good yields. In
addition, a noncyclic amide, N,N-dimethylacetamide, showed
good activity for this reaction. Details of the transformation
were provided by DFT calculations, which uncovered that the
main steps include oxidative addition of Ni(0) to the C−N
bond of the amide, formation of the manganese enolate,
transmetalation, and reductive elimination. Among them, the
reductive elimination step might be the rate-determining step.
This is the first report of a metal-catalyzed Claisen
condensation of two different amides. Future work in our lab
will focus on further studies of the mild reaction conditions
and expansion of the substrate scope.
Scheme 5. Computed Potential Energy Surface for the Ni-
Catalyzed Condensation between 1a and 2a (L = TPY;
Relative Gibbs Free Energies in Solution Are in kcal/mol)
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00485.
Experimental procedures and spectral data for the
products (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
reaction conditions, LNi(0) should be formed as an active
catalyst for the C−N bond cleavage of 1a by first formation of
complexes IN1 and IN2. Calculations found that the oxidative
addition of 1a with LNi(0) is very facile via TS1 with a very
small barrier of 2.0 kcal/mol from IN2. Once IN3 is formed, it
complexes with MnCl2L, generated in the reduction process of
Ni(II). The reaction is exergonic by 5.6 kcal/mol to form IN4,
which readily forms IN5 and IN6 by dissociation. The Mn(II)
complex IN6 is responsible for the enolization of 2a. This step
is difficult with Ni or other forms of Mn (see SI for details).
From complex IN7, the alpha deprotonation of 2a occurs via
TS2 with the assistance of the amino group. This step has a
barrier of 18.4 kcal/mol and forms intermediate IN8.15,16
Dissociation of N-methylaniline from IN8 forms IN9 ender-
gonically. To undergo the transmetalation, IN9 would complex
with IN5 to form IN10, which then generates IN11 slightly
exergonically and regenerates MnCl2L concurrently. The last
step of C−C formation occurs via reductive elimination via
TS3. This transition state has the highest relative free energy
and is 31.3 kcal/mol above the local minimum IN4, suggesting
that the reductive elimination should be the rate-determining
step of the whole reaction. We also explored the alternative
five-membered ring transition state involving enolate oxygen−
nickel interaction; however, much higher energy was calculated
due to the instability of the enolate intermediate with oxygen−
nickel interaction. The effective combination of Ni and Mn
was well supported by DFT results as much higher activation
barriers if only one metal is used. The energy profiles for all
unfavorable pathways are given in the Supporting Information.
In summary, we developed a nickel-catalyzed Claisen
condensation of two different amides to furnish the desired
β-ketoamides in the presence of manganese and LiCl. Among
the electrophilic amides tested, we found N-methyl-N-phenyl
benzamides and N,N-diphenyl benzamides to be effective
Sunwoo Lee − Department of Chemistry, Chonnam National
University, Gwangju 61186, Republic of Korea; orcid.org/
0000-0001-5079-3860; Email: sunwoo@chonnam.ac.kr
Yuanzhi Xia − College of Chemistry and Materials Engineering,
Wenzhou University, Wenzhou, Zhejiang Province 325035, P.
R. China; orcid.org/0000-0003-2459-3296; Email: xyz@
wzu.edu.cn
Authors
Jiajia Chen − Department of Chemistry, Chonnam National
University, Gwangju 61186, Republic of Korea; College of
Chemistry and Materials Engineering, Wenzhou University,
Wenzhou, Zhejiang Province 325035, P. R. China
Man Xu − College of Chemistry and Materials Engineering,
Wenzhou University, Wenzhou, Zhejiang Province 325035, P.
R. China
Subeen Yu − Department of Chemistry, Chonnam National
University, Gwangju 61186, Republic of Korea
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00485
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Research
Foundation of Korea (NRF) grant funded by the Korea
government (MSIP) (NRF-2017R1A2B2002929). Y.X. ac-
knowledges financial support from NSFC (21873074 and
21572163). The spectral and HRMS data were obtained from
the Korea Basic Science Institute, Gwangju center and Daegu
center.
D
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F. α-Arylation of Esters Catalyzed by the Pd(I) Dimer [P(t-
Bu)3]Pd(m-Br)]2. Org. Synth. 2011, 88, 4−13.
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(12) Calculations found that formation of Ni-hydride is possible by
reaction of Ni(0) with 2a. See Supporting Information for details.
(13) DFT calculations were done by gas phase optimization and
frequency calculation at the B3LYP/6-31G(d) (LANL2DZ for Ni and
Mn) level of theory, and the solvation effects of mesitylene were
E
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evaluated with the M06/6-311+G(d,p) (SDD for Ni and Mn)
method. The energies provided are relative free energies (in kcal/
mol) corrected by solvation effects. More details are given in the
Supporting Information for details.
(14) For a recent mechanistic study on Ni-catalyzed C−N bond
activations, see: (a) Wang, H.; Zhang, S.-Q.; Hong, X. Computational
Studies on Ni-Catalyzed Amide C-N Bond Activation. Chem.
Commun. 2019, 55, 11330−11341. (b) Gao, Y.; Ji, C.-L.; Hong, X.
Ni-mediated C-N Activation of Amides and Derived Catalytic
Transformations. Sci. China: Chem. 2017, 60, 1413−1424.
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(15) The formation of Mn enolate has been reported: Concellon, J.
M.; Rodríguez-Solle, H.; Díaz, P. Sequential Reactions Promoted by
Manganese: Completely Stereoselective Synthesis of (E)-α,β-
Unsaturated Amides, Ketones, Aldehydes, and Carboxylic Acids. J.
Org. Chem. 2007, 72, 7974−7979.
(16) We failed to dectect the Mn enolate in the reaction mixture.
However, we detected the aldol condensation prouduct 9 in GCMS
when 2a was treated under the standard conditions.
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