Electrochemical oxidative C-H/N-H cross-coupling for C-N bond formation with hydrogen evolution

Article abstract of DOI:10.1039/c8cc09899a

Under metal catalyst-free and exogenous-oxidant-free conditions, a series of C-3 aminated imidazo[1,2-a]pyridines were synthesized by electrochemical intermolecular oxidative C-H/N-H cross-coupling. Furthermore, by using a catalytic amount of ferrocene as

Full text of DOI:10.1039/c8cc09899a

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Electrochemical oxidative C–H/N–H
cross-coupling for C–N bond formation
Cite this:DOI: 10.1039/c8cc09899a
with hydrogen evolution†
Received 14th December 2018,
Accepted 7th January 2019
Yi Yu,‡a Yong Yuan, ‡b Huilin Liu,a Min He,a Mingzhu Yang,a Pan Liu,a
Banying Yu,a Xuanchi Donga and Aiwen Lei
*
ab
DOI: 10.1039/c8cc09899a
rsc.li/chemcomm
Under metal catalyst-free and exogenous-oxidant-free conditions, a C–H/N–H cross-coupling with hydrogen evolution for the synthesis
series of C-3 aminated imidazo[1,2-a]pyridines were synthesized by of C-3 aminated imidazo[1,2-a]pyridines has not been reported.
electrochemical intermolecular oxidative C–H/N–H cross-coupling. As a part of our recent research interest in the field of electro-
Furthermore, by using a catalytic amount of ferrocene as the mediator, chemical oxidative C–X bond formation,8 we herein report an
electrochemical intramolecular oxidative C–H/N–H cross-coupling for electrochemical oxidative C–H/N–H cross-coupling protocol for
the synthesis of 10H-benzo[4,5]imidazo[1,2-a]indole derivatives has the synthesis of C-3 aminated imidazo[1,2-a]pyridines. Under metal
also been accomplished.
catalyst-free and exogenous-oxidant-free conditions as well as using
cheap and commercially available NaNO3 as the electrolyte, a
series of significant C-3 aminated imidazo[1,2-a]pyridines were
synthesized with hydrogen evolution (Scheme 1a). Furthermore,
under electrochemical oxidative conditions, intramolecular oxidative
C–H/N–H cross-coupling for the synthesis of 10H-benzo[4,5]imidazo-
[1,2-a]indole derivatives has also been accomplished (Scheme 1b).
Our initial investigation started by using 2-phenylimidazo-
[1,2-a]pyridine (1a) and imidazole (2a) as the model substrates
(Table 1). Interestingly, when the reaction was conducted at
a constant current of 8 mA in MeCN/H2O/EtOH, the desired
C–H/N–H cross-coupling product could be obtained in 78%
1H NMR yield (Table 1, entry 1). Control experiments revealed
that the mixed solvent (MeCN/H2O/EtOH) and electricity were
important for the reaction efficiency (Table 1, entries 2–5).
Some organic electrolytes were then investigated, but all were
less effective than NaNO3 (Table 1, entries 6 and 7). Either
increasing the operating current to 16 mA or decreasing the
operating current to 4 mA also led to a decreased reaction yield
An imidazo[1,2-a]pyridine core is a very important structural
unit that widely occurs in many biologically active molecules,1
particularly in many commercially available drugs (such as
alpidem, zolpidem, necopidem and saripidem).2 In order to obtain
other new biologically active molecules, further modification or
functionalization of imidazo[1,2-a]pyridines is highly necessary.
Over the past few years, the modification of imidazo[1,2-a]pyridines
has received much attention and studies have revealed that C-3
substituted imidazo[1,2-a]pyridines exhibit a better biological
activity than imidazo[1,2-a]pyridines itself:3,4 for example, C-3
sulfenylated or aminated imidazo[1,2-a]pyridines. However, com-
pared with extensive research on C-3 sulfenylation, the C-3 amina-
tion of imidazo[1,2-a]pyridines still remains underexplored,5 and
the reported methods usually require stoichiometric oxidants,
long reaction times, and/or high reaction temperature. There-
fore, developing an alternative synthetic method to construct
C-3 aminated imidazo[1,2-a]pyridines is desirable.
Electrochemical synthesis is an efficient and environmentally
friendly synthetic method,6 which can realize C–X bond formation
via electrochemical oxidative C–H/X–H cross-coupling with hydrogen
evolution under metal catalyst-free and exogenous-oxidant-free
conditions. In recent years, electrochemical oxidative C–H/X–H
cross-coupling with hydrogen evolution has gained significant
attention.7 However, until now, electrochemical oxidative
a National Research Center for Carbohydrate Synthesis, Jiangxi Normal University,
Nanchang 330022, P. R. China. E-mail: aiwenlei@whu.edu.cn
b College of Chemistry and Molecular Sciences, Institute for Advanced Studies (IAS),
Wuhan University, Wuhan 430072, P. R. China
Scheme 1 Electrochemical oxidative C–H/N–H cross-coupling for C–N
bond formation with hydrogen evolution.
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8cc09899a
‡ Yi Yu and Yong Yuan contributed equally to this work.
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Table 1 Optimization of the reaction conditionsa
Table 2 Substrate scope of the electrochemical intermolecular oxidative
C–H/N–H cross-coupling reactiona
Entry
Variation from the standard conditions
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
Standard conditions
78, 75c
66
67
40
0
73
67
65
46
No H2O (MeCN/EtOH = 5.8/1.2)
No EtOH (MeCN/H2O = 6/1)
No MeCN (H2O/EtOH = 1/6)
No constant current
nBu4NBF4 instead of NaNO3
nBu4NPF6 instead of NaNO3
16 mA, 2.5 h
4 mA, 10 h
C(+)|Fe(À) instead of C(+)|Ni(À)
56
a
Standard conditions: graphite rod anode, nickel plate cathode, con-
stant current = 8 mA, 1a (0.3 mmol), 2a (2.0 equiv.), NaNO3 (0.3 mmol),
MeCN (4.8 mL), H2O (1.0 mL), EtOH (1.2 mL), 50 1C, 5 h (5.0 F molÀ1),
undivided cell. Yields were determined by 1H NMR using naphtha-
b
c
lene as the internal standard. Isolated yields.
(Table 1, entries 8 and 9). Further investigation showed that the
carbon rod anode and the nickel plate cathode were the best
choice for the electrode materials (Table 1, entry 10).
With the optimized reaction conditions in hand, we subsequently
explored the substrate scope of this electrochemical oxidative C–H/
N–H cross-coupling reaction with different imidazo[1,2-a]pyridines
and N-nucleophiles (Table 2). First, the effect of different sub-
stituents on the 2-phenyl moiety of imidazo[1,2-a]pyridines was
investigated. Imidazo[1,2-a]pyridine bearing an electron-neutral
methyl substituent at the 2-phenyl moiety produced the C–H/N–H
cross-coupling product in 75% yield (Table 2, 3a), while imidazo-
[1,2-a]pyridines with phenyl or electron-withdrawing ÀF and ÀCF3
substituents at the 2-phenyl moiety gave the corresponding pro-
ducts in moderate to good yields (Table 2, 3b to 3f). Moreover,
substrates with a methyl group at the C-5, C-6, or C-7 position of
a
Standard conditions: graphite rod anode, nickel plate cathode, con-
2-phenylimidazo[1,2-a]pyridines reacted smoothly with imidazole stant current = 8 mA, 1 (0.3 mmol), 2 (2.0 equiv.), NaNO3 (0.3 mmol),
MeCN (4.8 mL), H2O (1.0 mL), EtOH (1.2 mL), 50 1C, 5 h (5.0 F molÀ1),
(2a) and afforded the C-3 aminated products in moderate to good
yields (Table 2, 3g to 3i). It is worth noting that important benzo[d]-
imidazo[2,1-b]thiazole derivatives were also compatible with the
b
c
undivided cell. 4.5 h (4.5 F molÀ1). 2a (3.0 equiv.).
reaction conditions, generating the corresponding C–H/N–H the current electrochemical conditions, the intramolecular oxidative
cross-coupling products in moderate to high yields (Table 2, 3j to C–H/N–H cross-coupling products could not be obtained. Next, we
3l). Different azoles and other N-nucleophiles were also applied as tried to modify the reaction conditions to obtain the target products
substrates in this electrochemical oxidative C–H/N–H cross-coupling (for details about the optimization of reaction conditions, see the
reaction. Delightedly, 2-methyl-1H-imidazole, 1H-benzo[d]imidazole, ESI†). To our delight, when a catalytic amount of ferrocene (Cp2Fe)
2-methyl-1H-benzo[d]imidazole, and even 3,5-dimethyl-1H-pyrazole was added as the mediator, the intramolecular oxidative C–H/N–H
and morpholine all were suitable substrates for this transformation cross-coupling reaction proceeded well and the corresponding
(Table 2, 3m to 3q). However, when long-chain aliphatic amines, 10H-benzo[4,5]imidazo[1,2-a]indole derivative could be isolated
such as n-butylamine, were employed in the reaction, no desired in 83% yield (Table 3, 5a). The substrate scope of the electro-
product was detected (Table 2, 3r).
chemical intramolecular oxidative C–H/N–H cross-coupling
Having successfully established the feasibility of the electro- reaction was then investigated. Various N-(2-(1H-indol-1-yl)-
chemical intermolecular oxidative C–H/N–H cross-coupling of phenyl)benzenesulfonamide derivatives were all suitable sub-
imidazo[1,2-a]pyridines with N-nucleophiles, we became enthusiastic strates in this transformation (Table 3, 5b to 5f).
about the synthesis of significant 10H-benzo[4,5]imidazo[1,2-a]-
To investigate the details of the mechanism for this electro-
indole derivatives9 using the electrochemical intramolecular oxida- chemical oxidative C–H/N–H cross-coupling reaction, several
tive C–H/N–H cross-coupling strategy (Table 3). Unfortunately, under control experiments were carried out. First, cyclic voltammetry
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Table 3 Substrate scope of the electrochemical intramolecular oxidative
C–H/N–H cross-coupling reactiona
Scheme 3 Proposed mechanism of the intermolecular oxidative C–H/
N–H cross-coupling reaction.
The generated HOÀ or EtOÀ then deprotonates substrate 2a to
afford its conjugate base C. C is further oxidized at the anode,
forming the nitrogen radical D. Next, radical/radical cross-coupling
affords the C–H/N–H cross-coupling product 3a. Note that the
pathway of radical addition of nitrogen radical D to 1a could not
be fully ruled out. In addition, for some alkyl amines, the corres-
ponding nitrogen radicals are unstable, which may be the reason
why 3r was not obtained. As for the intramolecular oxidative C–H/
N–H cross-coupling reaction (Scheme 4), the reaction begins with
the anodic oxidation of Cp2Fe to afford Cp2Fe+,11 and Cp2Fe+ then
oxidizes the deprotonated 4 (A) to regenerate Cp2Fe and form
nitrogen radical intermediate B. Sequential radical addition, single
electron oxidation, and deprotonation finally afford the C–H/N–H
cross-coupling product 5.
In summary, we have developed an electrochemical oxidative
C–H/N–H cross-coupling reaction. Under metal catalyst-free and
exogenous-oxidant-free conditions as well as using cheap and com-
mercially available sodium nitrate as the electrolyte, a series of C-3
aminated imidazo[1,2-a]pyridines were synthesized with hydrogen
evolution. Furthermore, by using a catalytic amount of ferrocene as
the mediator, electrochemical intramolecular oxidative C–H/N–H
cross-coupling for the synthesis of significant 10H-benzo[4,5]-
imidazo[1,2-a]indole derivatives has also been reported.
a
Standard conditions: graphite rod anode, nickel plate cathode, con-
stant current = 8 mA, 4 (0.3 mmol), Cp2Fe (20 mol%), nBu4NBF4
(0.3 mmol), MeCN (3.5 mL), EtOH (3.5 mL), 70 1C, 4 h (4.0 F molÀ1),
undivided cell.
experiments on model substrates were carried out. 1a and 2a
have very similar redox potentials. 1a could be oxidized when
the oxidation potential exceeded 0.94 V, while 2a started to get
oxidized from 0.93 V (for more details about the cyclic voltam-
metry experiments, see the ESI†). This result showed that 1a
and 2a could be synchronously oxidized at the anode under our
electrochemical conditions. Second, the model reaction and
the electrolysis of 1a in the absence of 2a were investigated,
respectively (Scheme 2). Homo-coupling products of 1a were
detected in both reactions, while the capture product of A (see
Scheme 3 for the structure of A) by H2O or EtOH was not
detected. These results indicated that 1a could be converted to
the corresponding radical under our electrochemical condi-
tions and the pathway of radical cation intermediate A captured
by a nucleophile might be ruled out.
Based on the results of the above experiments and previous
reports,5c,10 a possible mechanism for the intermolecular oxidative
C–H/N–H cross-coupling reaction is shown in Scheme 3. The
anodic oxidation and deprotonation of 1a produce radical B. The
cathodic reduction of H2O or EtOH produces H2 and HOÀ or EtOÀ.
Scheme 4 Proposed mechanism of the intramolecular oxidative C–H/
Scheme 2 Control experiments.
N–H cross-coupling reaction.
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