Nickel-catalyzed electrochemical Minisci acylation of aromatic N-heterocycles with α-keto acids via ligand-to-metal electron transfer pathway

Article abstract of DOI:10.1016/j.jcat.2019.10.030

A nickel-catalyzed electrochemical methodology for the Minisci acylation of aromatic electron-deficient heterocycles with α-keto acids has been developed. The reaction is performed in an undivided cell under constant current conditions, featuring broad scope of substrates and avoiding the conventional utilization of silver-based catalysts in conjunction with excess amount of oxidants. Cyclic voltammetric analysis disclosed that a ligand-to-metal electron transfer process may be involved in the generation of the key acyl radicals.

Full text of DOI:10.1016/j.jcat.2019.10.030

Journal of Catalysis 381 (2020) 38–43
Contents lists available at ScienceDirect
Journal of Catalysis
journal homepage: www.elsevier.com/locate/jcat
Nickel-catalyzed electrochemical Minisci acylation of aromatic
N-heterocycles with
a
-keto acids via ligand-to-metal electron
transfer pathway
⇑
⇑
Hang Ding, Kun Xu , Cheng-Chu Zeng
Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science & Bioengineering, Beijing University of Technology, Beijing 100124, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A nickel-catalyzed electrochemical methodology for the Minisci acylation of aromatic electron-deficient
heterocycles with a-keto acids has been developed. The reaction is performed in an undivided cell under
constant current conditions, featuring broad scope of substrates and avoiding the conventional utilization
of silver-based catalysts in conjunction with excess amount of oxidants. Cyclic voltammetric analysis dis-
closed that a ligand-to-metal electron transfer process may be involved in the generation of the key acyl
radicals.
Received 19 July 2019
Revised 17 October 2019
Accepted 24 October 2019
Keywords:
Minisci acylation reactions
Nickel-catalysis
Ó 2019 Elsevier Inc. All rights reserved.
a-Keto acid
Electrosynthesis
1. Introduction
catalyst and oxidizing reagent [6]. Recently, Wu, Zhao and co-
workers have achieved the decarboxylative coupling of pyrazines
Minisci reaction refers to a radical substitution process in which
a nucleophilic carbon-centered radical reacts with an electron-
deficient aromatic heterocycle to assemble a new carbon-carbon
bond, thereby providing a complementary avenue to the function-
alization of electron-rich aromatics via classical electrophilic
Friedel-Crafts reactions [1]. Minisci-type radical reactions are espe-
cially useful for the late-stage functionalization of CAH bonds, thus
have attracted great attention in pharmaceutical, medicinal chem-
istry and material sciences [2,3]. To this end, undisputable
advances have been made in Minisci alkylation reactions, however,
the Minisci acylation reactions are less studied.
using Ag3PO4/K2S2O8 system [7]. In order to replace the expensive
sliver-based catalysts, we reported the Fe(II)-catalyzed decar-
boxylative acylation of N-heteroarenes (Scheme 1a) [8]. In addi-
tion, visible light-mediated decarboxylative coupling of
a-keto
acids with N-heterocycles has also emerged as a versatile approach
to the Minisci acylation reactions (Scheme 1b). For example, Zhang
and co-workers reported the acylation of N-heterocycles under
visible-light irradiation [9]. Later on, Wencel-Delord and co-
workers reported
heterocycles with
a
visible-light-induced acylation of N-
a
-keto acids in the presence of K2S2O8 as the oxi-
dizing reagent [10]. Recently, Prabhu et al. employed Ir(I) complex
Decarboxylative cross-coupling of a-keto acids with heteroaro-
as the photocatalyst to synthesize acylated pyridine derivatives
matics has proven to be one of the powerful and versatile
approaches to the Minisci acylation reactions. In 1991, Fontana
and co-workers reported for the first time the Ag(I)-catalyzed
[11]. In a word, for the decarboxylative cross-coupling of a-keto
acids with N-heteroarenes, expensive Ag(I)-based catalysts or Ir
(I)-based photocatalysts in conjunction with excess amount of oxi-
dant were generally employed, which is not practical. Therefore,
the development of new approaches using cheap metal catalyst,
specially under external oxidant-free conditions, are highly
desired.
oxidative decarboxylation of
a-keto acids with quinolone, pyra-
zine, quinoxaline and 4-substituted pyridines, using a combination
of AgNO3/(NH4)2S2O8 to prepare the corresponding mono- and dia-
cyl derivatives [4]. Oh and co-workers have also reported the direct
acylation of 2H-indazoles with
the selective C2-monoacylation of pyridine-N-oxides was accom-
plished by Muthusubramanian et al. using Ag2CO3 /K2S2O8 as the
a
-keto acid derivatives [5]. In 2014,
Organic electrosynthesis has emerged as a green and environ-
mentally friendly way to achieve CAH bonds functionalization,
and it is revolutionizing the way of organic synthesis [12]. In this
context, we have been working on the electrochemical construc-
tion of new CAC bonds and C-heteroatom bonds via indirect anodic
oxidation using redox mediators, such as halide ions, TEMPO, DDQ
⇑
Corresponding authors.
E-mail addresses: kunxu@bjut.edu.cn (K. Xu), zengcc@bjut.edu.cn (C.-C. Zeng).
https://doi.org/10.1016/j.jcat.2019.10.030
0021-9517/Ó 2019 Elsevier Inc. All rights reserved.

H. Ding et al. / Journal of Catalysis 381 (2020) 38–43
39
Scheme 1. Decarboxylative Minisci-type Acylation reactions of a-keto acids with N-heteroarenes.
Table 1
a.
Optimization of Reaction Condition
Entry
Catalyst (mol%)
Solvent
Electrolyte
T (°C)
Yield b(%)
1
2
3
4
5
6
7
8
Ni(acac)2(10)
Ni(acac)2(10)
Ni(acac)2(10)
Ni(acac)2(10)
Ni(acac)2(10)
Ni(acac)2(10)
Ni(acac)2(10)
Ni(acac)2(10)
Ni2SO4(10)
CH3CN
DCM
DMSO
MeOH
EtOH
DCE
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NPF6
Et4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
20
20
20
20
20
20
20
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
15
20
0
0
0
16
27
58
5
CH3CN:DCM (v:v 3:7)
CH3CN:DCM (v:v 3:7)
CH3CN:DCM (v:v 3:7)
CH3CN:DCM (v:v 3:7)
CH3CN:DCM (v:v 3:7)
CH3CN:DCM (v:v 3:7)
CH3CN:DCM (v:v 3:7)
CH3CN:DCM (v:v 3:7)
CH3CN:DCM (v:v 3:7)
CH3CN:DCM (v:v 3:7)
CH3CN:DCM (v:v 3:7)
CH3CN:DCM (v:v 3:7)
CH3CN:DCM (v:v 3:7)
CH3CN:DCM (v:v 3:7)
CH3CN:DCM (v:v 3:7)
CH3CN:DCM (v:v 3:7)
9
10
11
12
13
14
15
16c
17d
18
19
20e
21f
22 g
NiCl2(10)
7
Ni(cod)2(10)
NiCl2.glym(10)
Ni(acac)2(0)
Ni(acac)2(5)
Ni(acac)2(30)
Ni(acac)2(10)
Ni(acac)2(10)
Ni(acac)2(10)
Ni(acac)2(10)
Ni(acac)2(10)
Ni(acac)2(10)
Ni(acac)2(10)
17
20
8
12
45
13
46
44
37
36
5
0
a
Reaction conditions: 1a (1.0 mmol), 2a (3.0 mmol), 0.1 M supporting electrolyte in 10 mL solvent, undivided cell , current density of 5 mA cmÀ2, Pt net anode and graphite
plate cathode (working area: 3 cm2).
b
Isolated yields.
c
Current density of 3 mA cmÀ2
.
d
e
f
Current density of 10 mA cmÀ2
.
Graphite plate anode and graphite plate cathode (working area: 3 cm2).
Graphite plate anode and Pt net cathode (working area: 3 cm2).
No electrolysis.
g

40
H. Ding et al. / Journal of Catalysis 381 (2020) 38–43
Table 2
a,b.
Substrate Scope with a-Keto Acids
a
Reaction conditions: platinum net anode and graphite plate cathode (working area: 3 cm2, J = 5 mA/cm2), 1
(1.0 mmol), 2a (3.0 mmol)), Bu4NBF4 (0.1 M), solvent (7 mL DCM and 3 mL CH3CN), Ni(acac)2 (0.1 mmol) was added,
50 °C, undivided cell, 4.0 h.
b
Isolated yield.
and triarylimidazole [13]. For example, we have recently achieved
the NH4I-mediated Minisci acylation reaction of aromatic N-
Encouraged by this result, solvent screening was then performed
and it was observed that the yield of 3aa increased to 27% when
a mixture of CH3CN and DCM (v:v = 3:7) was used as the solvent
(entries 2–7). When the reaction was carried out at 50 °C, the yield
of 3aa improved to 58% (entry 8). Further catalyst screening dis-
closed that Ni2SO4, NiCl2, Ni(cod)2 and NiCl.2glym were not suitable
for the acylation reaction (entries 9–12). In addition, decreasing
the loading of catalyst Ni(acac)2 to 5 mol% or increasing to
30 mol% resulted in inferior results (entries 14 and 15). Besides,
it was observed that 3aa was afforded in 13% or 46% yields when
the CCE was carried out at 3 mA/cm2 or 10 mA/cm2 (entries 16
and 17). Further screening of the supporting electrolytes indicated
that Bu4NBF4 was superior since 3aa was obtained in lower yield
when n-Bu4NPF6 or Et4NBF4 were employed as the supporting elec-
trolytes (entries 18 and 19). Finally, we turned our attention to the
evaluation of electrode materials. When a graphite plate, instead of
a Pt net, was used as the anode, 3aa was obtained in 36% yield
(entry 20). Conversely, only 5% yield of 3aa was afforded when
Pt net was used as the cathode and graphite plate as the anode.
Notably, 3aa was afforded in only 8% yield or less when the reac-
tion was performed in the absence of the catalyst Ni(acac)2 (entry
13) and electricity (entry 22), which indicates that Ni(acac)2 and
electricity played an essential role for the Minisci acylation reac-
tion. At this stage of our investigation, we concluded that the opti-
mal conditions call for using 10 mol% of Ni(acac)2 as the redox
heterocycles with
a-keto acids (Scheme 1c) [14]. Herein, we
reported for the first time a Ni(II)-catalyzed electrochemical Min-
isci acylation reaction of electron-deficient N-heteroarenes with
a-keto acids (Scheme 1d). The chemistry is performed in an undi-
vided cell under galvanostatic conditions, avoiding the utilization
of Ag(I)-based catalyst and excess chemical oxidants. Distinct from
conventional Ni-catalyzed decarboxylative cross-coupling reac-
tions wherein Ni-catalysts work as a radical capturer [15], this
Ni-catalyzed electrochemical Minisci acylation may involve a
ligand-to-metal electron transfer process to generate the key acyl
radicals.
2. Results and discussion
We commenced our studies by choosing quinoxaline (1a) and
phenylglyoxylic acid (2a) as the model substrates to optimize the
reaction conditions. As shown in Table 1, when constant current
electrolysis (CCE) of 1a and 2a was performed in an undivided cell
with a platinum net as the anode and a graphite plate as the cath-
ode at a constant current of 5 mA cmÀ2 with Ni(acac)2 (10 mol%) as
the catalyst and CH3CN as the solvent at room temperature, the
desired product 3aa was isolated in 15% yield (entry 1).

H. Ding et al. / Journal of Catalysis 381 (2020) 38–43
41
Table 3
a,b.
Substrate Scope with N-Heteroarene
a
Reaction conditions: platinum net anode and graphite plate cathode (working area: 3 cm2, J = 5 mA/cm2), 1
(1.0 mmol), 2a (3.0 mmol), Bu4NBF4 (1 mmol), solvent (DCM 7 mL and CH3CN 3 mL), Ni(acac)2 (0.1 mmol), 50 °C,
undivided cell, 4.0 h.
b
c
d
Isolated yield. 16 h. 20 h.
Scheme 2. Control experiments.
catalyst and Bu4NBF4 in the mixed solution of CH3CN with DCM as
the supporting electrolyte. The reaction prefers performing in an
undivided cell equipped with Pt net anode and graphite plate cath-
ode at 5 mA/cm2 current density (see Table 1, entry 8).
With the optimal reaction conditions in hand, we then studied
the scope and the generality of the protocol by examining reactions
of quinoxaline 1a with a variety of
Table 2, it was observed that the aliphatic
a
-keto acids 2. As shown in
-keto acids proceeded
a
smoothly with 1a under the standard conditions to give the corre-
sponding Minisci acylation products. For example, when aliphatic
Fig. 1. Cyclic voltammograms of related compounds in 0.1 M LiClO4/CH3CN using
glass carbon working electrode, Pt wire, and Ag/AgNO3 (0.1 M in CH3CN) as counter
and reference electrode at 100 mV/s scan rate: (a) background, (b) Quinoxaline
(5.0 mmol/L), (c) PhCOCOOH (5.0 mmol/L), (d) Ni(acac)2 (2.0 mmol/L), (e) Ni(acac)2
(2.0 mmol/L) and Quinoxaline (5.0 mmol/L), (f) Ni(acac)2 (2.0 mmol/L) and
PhCOCOOH (5.0 mmol/L).
a-keto acids 2b, 2c and 2d were subjected to react with 1a, the cor-
responding 3ab, 3ac and 3ad were afforded in 45%, 36% and 30%
yields, respectively. Moderate to good yields of Minisci acylated
products were obtained in the cases of aromatic
a-keto acids. It
seems that the electron-withdrawing groups, such as F, Cl, Br and
CF3, gave higher yields than that of electron-donating groups
MeO and Me, when these groups were appended at the para-
position of the benzene ring. For example, CF3-substituted 3ah
was obtained in 71% yield, whereas methyl-substituted 3aj was
delivered in 37% yield. In addition, it was observed that lower
yields of products were obtained when the substituted group
was located at the ortho- or meta- positions. For example, 3ak
and 3al were afforded in 55% and 32% yields, respectively, whereas
the analogous 3ae was obtained in 75% yield.

42
H. Ding et al. / Journal of Catalysis 381 (2020) 38–43
Scheme 3. A proposed mechanism for the nickel-catalyzed electrochemical Minisci acylation.
To further explore the potential of the protocol, the reactions of
regeneration of Ni(acac)2. The radical 6 is very unstable, followed
by loss of CO2 to give acyl radical 7, which then undergoes radical
addition with protonated N-heteroarenes to afford adduct 8. After
further oxidation and deprotonation, the Minisci acylated products
3 are finally afforded. Simultaneously, the cathodic reduction of
proton offers hydrogen.
phenylglyoxylic acid 2a with a variety of quinoxalines 1 were also
investigated, and the results are summarized in Table 3. It was
observed that most of the quinoxalines tolerated the reaction con-
ditions. Notably, for non-symmetric quinoxalines (1b-1d), there
are two a-C-Hs to the nitrogen atom, therefore a mixture of regioi-
somers was afforded. In the cases of disubstituted substrates, 1f-
1h, the desired products 3fa-3ha were isolated in 20%-70% yields.
Other aromatic heterocycles were also tested. As shown in Table 3,
when acridine, 1i, was used as the substrate, the corresponding 3ia
was afforded in a 40% yield. Unexpectedly, when phenanthridine 1j
was used as a substrate to react with 2a under the standard condi-
tions, direct addition product 4ja was generated and isolated in
35% yield, without further conversion to 3ja. In addition, the
cross-coupling reactions of isoquinoline (1k) and benzothiazole
(1l) with 2a did not take place, instead, benzil from the homo-
coupling of benzoyl radical was isolated in 32% and 15% yields,
respectively.
3. Conclusion
In summary, we have developed an efficient Ni-catalyzed elec-
trochemical Minisci acylation reaction via decarboxylative cross-
coupling of N-heteroarenes with
ceeded in an undivided cell under constant current conditions,
thereby avoiding the utilization of a combination of silver-based
catalysts with oxidants. Control experiments and cyclic voltam-
metric analysis disclosed that a ligand-to-metal electron transfer
process may be involved in the generation of the key acyl radicals.
a-keto acids. The protocol pro-
To understand the mechanism for the nickel-catalyzed electro-
chemical Minisci acylation reaction of N-heteroarenes, control
experiments were performed. As shown in Scheme 2, when 2a
itself was subjected to electrolysis under the standard conditions,
benzil was isolated in 37% yield, whereas, only 9% yield of benzil
was afforded in the absence of Ni(acac)2. In addition, the formation
of benzil was observed in the reaction of 1k and 1l with 2a
(Table 3). These results indicate that acyl radical is the key inter-
mediate and Ni(acac)2 is able to promote its formation via decar-
boxylation of phenylglyoxylic acid.
Cyclic voltammetric analysis was also performed to understand
the mechanism. As shown in Fig. 1, the starting substrates, quinox-
aline 1a (curve b) and phenylglyoxylic acid 2a (curve c), are not
oxidized up to 2.0 V, whereas Ni(acac)2 exhibits an oxidation peak
at 1.46 V (vs. Ag/AgNO3 in 0.1 M CH3CN) (curve d). These results
disclose that Ni(acac)2 is easier to be oxidized than 1a and 2a. It
is worth noting that the oxidation peak potential of Ni(acac)2
shifted negatively by 0.19 V in the presence of 2a (curve f),
whereas a slight shift was observed in the presence of 1a (curve
e). These results indicate that complexation between Ni(acac)2
and 2a may occur to form a 2a-bound complex which rendered
easier the oxidation of Ni(II) to Ni(III) [16]. To further demonstrate
the interaction between Ni(acac)2 and 2a, the decarboxylative cou-
pling of 1a with 2a was electrolyzed at the controlled potential of
1.3 V, and the corresponding product 3aa was obtained in 42%
yield.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgements
This work was supported by grants from the National Natural
Science Foundation of China (No. 21871019) and National Key
Technology R&D Program (2017YFB0307502).
Appendix A. Supplementary material
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.jcat.2019.10.030.
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