Electrochemical Oxidative C3 Acyloxylation of Imidazo[1,2- a]pyridines with Hydrogen Evolution

Article abstract of DOI:10.1021/acs.orglett.1c02032

The C3-functionalized imidazo[1,2-a]pyridines are versatile nitrogen-fused heterocycles; however, the methods for the C3 acyloxylation of imidazo[1,2-a]pyridines have never been reported. Herein we demonstrate the electrochemical oxidative C3 acyloxylation of imidazo[1,2-a]pyridines for the first time. Notably, by using electricity, the electrochemical oxidative C3 acyloxylation of imidazo[1,2-a]pyridines was carried out under mild conditions. Moreover, in addition to aromatic carboxylic acids, alkyl carboxylic acids were also competent substrates.

Full text of DOI:10.1021/acs.orglett.1c02032

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Letter
Electrochemical Oxidative C3 Acyloxylation of
Imidazo[1,2‑a]pyridines with Hydrogen Evolution
Yong Yuan,⊥ Zhilin Zhou,⊥ Lin Zhang,⊥ Liang-Sen Li, and Aiwen Lei*
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ABSTRACT: The C3-functionalized imidazo[1,2-a]pyridines are
versatile nitrogen-fused heterocycles; however, the methods for the
C3 acyloxylation of imidazo[1,2-a]pyridines have never been
reported. Herein we demonstrate the electrochemical oxidative C3
acyloxylation of imidazo[1,2-a]pyridines for the first time. Notably, by using electricity, the electrochemical oxidative C3
acyloxylation of imidazo[1,2-a]pyridines was carried out under mild conditions. Moreover, in addition to aromatic carboxylic acids,
alkyl carboxylic acids were also competent substrates.
he imidazo[1,2-a]pyridines, especially the C3-function-
alized imidazo[1,2-a]pyridines, are versatile nitrogen-
employing anodic oxidation or cathodic reduction, organic
electrosynthesis can realize redox transformations under
exogenous-oxidant-free or exogenous-reductant-free condi-
tions.12 Moreover, by modifying the operating current or
voltage, organic electrosynthesis can provide a new oppor-
tunity for the reactions that do not easily occur with traditional
chemical oxidants or reductants. As a part of our continuing
research interest in the area of electrochemical oxidative cross-
coupling with H2 evolution reactions,13 we herein report the
C3 acyloxylation of imidazo[1,2-a]pyridines for the first time
(Scheme 1b). Note that by using the strategy of electro-
chemical anodic oxidation, the C3 acyloxylation of imidazo-
[1,2-a]pyridines was conducted without the use of a metal
catalyst or exogenous oxidant. Furthermore, by using the
strategy of electrochemical oxidative C−H/O−H cross-
coupling with H2 evolution, this C−H acyloxylation reaction
exhibits excellent atom economy and produces valuable H2 as
the sole byproduct.
T
fused heterocycles that are not only significant structural
components in many natural products and biologically active
molecules1 but also frequently found in many commercially
available drugs,2 such as miroprofen, GSK812397, olprinone,
zolimidine, minodronic acid, and alpidem. Consequently, to
find many more biologically active molecules, the further C3
functionalization of imidazo[1,2-a]pyridines is greatly desir-
able. Much effort has been dedicated to modifying imidazo-
[1,2-a]pyridines, and a variety of effective transformations for
C3 arylation,3 alkylation,4 carbonylation,5 halogenation,6
amination,7 phosphonation,8 selenation,9 and sulfenylation10
have been established in the past decade (Scheme 1a).
Scheme 1. C3 Functionalization of Imidazo[1,2-a]pyridines
Our investigation was commenced with p-toluic acid (1a)
and 2-phenylimidazopyridine (2a) as model substrates, K2CO3
as an electrolyte and base, and a mixture of acetonitrile and
water as a cosolvent. Encouragingly, when the electrolysis of p-
toluic acid (1a) and 2-phenylimidazopyridine (2a) was
performed under a controlled current of 8 mA for 4.5 h, the
expected C3 acyloxylation reaction occurred smoothly and
resulted in 3a in 82% isolated yield (Table 1, entry 1). Control
experiments indicated that the electric current and K2CO3
were necessary for obtaining C3 acyloxylation product 3a
(Table 1, entries 2 and 3). Using Na2CO3 or K3PO4, a slight
However, even though there has been great achievement in the
C3 functionalization of imidazo[1,2-a]pyridines, the C3
acyloxylation of imidazo[1,2-a]pyridines still remains a stand-
ing challenge and has never been reported. Given that the C3-
functionalized imidazo[1,2-a]pyridines frequently exhibit
much better biological activity than imidazo[1,2-a]pyridines
themselves, we would like to explore an efficient and practical
method to realize the C3 acyloxylation of imidazo[1,2-
a]pyridines.
Received: June 17, 2021
Published: July 23, 2021
Organic electrosynthesis has been recognized as an environ-
mentally benign and powerful synthetic method.11 By
https://doi.org/10.1021/acs.orglett.1c02032
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5932−5936
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a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scope for Electrochemical Oxidative
C−H/O−H Cross-Coupling with Different Carboxylic
a
Acids
entry
variation(s) from the standard conditions
none
no electric current
no K2CO3 (0.1 mmol Bu4NBF4 was added)
Na2CO3 instead of K2CO3
K3PO4 instead of K2CO3
1.0 equiv of K2CO3
1.5 equiv of K2CO3
12 mA, 3 h
6 mA, 6 h
nickel plate as the cathode
stainless-steel plate as the cathode
carbon cloth as the anode
MeCN/H2O 10.5:0.5
MeCN/H2O 9:2
yield (%)
1
2
3
4
5
6
7
8
82
0
n
trace
78
67
68
78
78
74
37
56
66
80
44
9
10
11
12
13
14
a
Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), K2CO3 (1.2
equiv), MeCN (10 mL), H2O (1 mL), 40 °C (oil bath), N2, graphite
plate anode, platinum plate cathode, 8 mA, 4.5 h, isolated yields.
loss of yield was observed (Table 1, entries 4 and 5). The
amount of K2CO3 was next investigated. However, either
increasing or decreasing the amount of K2CO3 led to a
decreased C−H/O−H cross-coupling yield (Table 1, entries 6
and 7). Increasing the operating current to 12 mA furnished
the C3 acyloxylation product in a slightly reduced yield (Table
1, entry 8), whereas when the electrolysis was conducted at a
controlled current of 6 mA for 6 h, a 8% yield loss was
observed (Table 1, entry 9). The combination of a graphite
plate anode and a platinum plate cathode was important for
obtaining the C3 acyloxylation product in high yield. Either
replacing the platinum plate with a nickel plate or a stainless-
steel plate or replacing the graphite plate with a carbon cloth
led to the desired C−H/O−H cross-coupling product in low
yield (Table 1, entries 10−12). Finally, the amount of water
was also investigated. Performing the C−H/O−H cross-
coupling reaction with 0.5 mL of H2O as the cosolvent, the
expected C3 acyloxylation product was isolated in 80% yield
(Table 1, entry 13), whereas when the reaction was conducted
with 2.0 mL of H2O as the cosolvent, only a 44% yield of C−
H/O−H cross-coupling product was obtained (Table 1, entry
14).
Having the optimized reaction conditions in hand, we set
out to evaluate the substrate scope of this electrochemical
oxidative C3 acyloxylation reaction. First, we explored the
substrate scope with various carboxylic acids. As shown in
Scheme 2, aromatic carboxylic acids bearing electron-donating
groups led to the expected C3 acyloxylation products in good
to high yields (Scheme 2, 3a−3f), whereas when electron-poor
4-(trifluoromethyl)benzoic acid was used in the reaction, the
corresponding cross-coupling product was isolated in low yield
(Scheme 2, 3g). Employing benzoic acid as the reaction
partner, the electrolysis occurred smoothly with 2-phenyl-
imidazopyridine (2a) and resulted in the desired C−H/O−H
cross-coupling product in 71% yield (Scheme 2, 3h). In
addition to benzoic acid derivatives (Scheme 2, 3a−3h), 1-
a
Reaction conditions: graphite plate anode, platinum plate cathode,
constant current = 8 mA, 1 (0.3 mmol), 2a (0.6 mmol), K2CO3 (1.2
equiv), MeCN (10 mL), H2O (1 mL), 40 °C (oil bath), N2, 4.5 h,
isolated yields.
naphthoic acid and thiophene-2-carboxylic acid were also
competent substrates, generating the corresponding C3
acyloxylation products in 56 and 64% yield (Scheme 2, 3i−
3j), respectively. It is noteworthy that alkyl carboxylic acids
could also react with 2-phenylimidazopyridine (2a) under
standard electrochemistry conditions (Scheme 2, 3k−3n). For
example, when cyclohexanecarboxylic acid or cycloheptane-
carboxylic acid was used as the acyloxylation reagent, 51 and
53% yields of C−H/O−H cross-coupling products were
isolated (Scheme 2, 3k,3l), whereas when 1-phenyl-1-cyclo-
propanecarboxylic acid was treatment with 2-phenylimidazo-
pyridine (2a), the expected C3 acyloxylation reaction smoothly
occurred and afforded the corresponding C−H/O−H cross-
coupling product in high yield (Scheme 2, 3m). Interestingly,
the electrochemical oxidative C3 acyloxylation reaction was
also compatible with the 1-adamantane carboxylic acid, and the
expected C3 acyloxylation product was obtained in 65% yield
(Scheme 2, 3n).
Next, we explored the scope of imidazo[1,2-a]pyridines. As
shown in Scheme 3, 2-phenylimidazo[1,2-a]pyridines bearing
electron-donating substituents at the 2-phenyl moiety resulted
in the desired C3 acyloxylation products in 68−71% yields
(Scheme 3, 4a−4c). In contrast, 2-phenylimidazopyridines
with electron-withdrawing groups at the 2-phenyl moiety
delivered the corresponding C3 acyloxylation products in
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in moderate to high yields (Scheme 3, 4k−4m). Interestingly,
we note that 6-phenylimidazo[2,1-b]thiazole could also be
employed as the reaction partner (Scheme 3, 4n).
Scheme 3. Substrate Scope for Electrochemical Oxidative
C−H/O−H Cross-Coupling with Different Imidazo[1,2-
a
a]pyridines
To shed light on the mechanism of this electrochemical
oxidative C3 acyloxylation reaction, cyclic voltammetry (CV)
experiments were first performed. (For details see the SI,
Figure S1.) The oxidation peak of substrate 2a was observed at
1.58 V. The mixture of 1a and K2CO3 showed an oxidation
peak at 1.88 V, whereas no obvious oxidation peak of 1a was
observed at 0−2.5 V. These results indicated that imidazo[1,2-
a]pyridines are more readily oxidized than carboxylic acids and
its conjugate bases. Second, two control experiments were
conducted (Scheme 4). When the electrolysis of benzoic acid
Scheme 4. Control Experiments
with 2-phenylimidazopyridine (2a) was performed under
standard conditions, in addition to the 71% yield of C−H/
O−H cross-coupling product 3g, a 14% yield of homocoupling
product 5a was also isolated (Scheme 4a), indicating that
imidazo[1,2-a]pyridines could be converted into the corre-
sponding radical cation intermediate under the current
electrochemical conditions. Using sodium benzoate as the
acyloxylation reagent to react with 2-phenylimidazopyridine
(2a) in the absence of K2CO3 resulted in a 41% yield of C3
acyloxylation product 3g (Scheme 4b), suggesting that the role
of K2CO3 may be to remove the proton of carboxylic acid to
generate the corresponding carboxylate anion.
On the basis of our mechanistic studies and previous
reports,13c a plausible mechanism for this electrochemical
oxidative C3 acyloxylation reaction is presented in Scheme 5.
a
Scheme 5. Proposed Mechanism
Reaction conditions: graphite plate anode, platinum plate cathode,
constant current = 8 mA, 1 (0.3 mmol), 2a (0.6 mmol), K2CO3 (1.2
equiv), MeCN (10 mL), H2O (1 mL), 40 °C (oil bath), N2, 4.5 h,
isolated yields.
moderate yields (Scheme 3, 4d,4e). It is worth noting that in
addition to 2-phenylimidazo[1,2-a]pyridines, 2-biphenylimida-
zo-[1,2-a]pyridine, 2-naphthylimidazo-[1,2-a]pyridine, 2-thie-
nylimidazo-[1,2-a]pyridine, and even 2-tert-butylimidazo-[1,2-
a]pyridine were also compatible cross-coupling partners,
delivering the corresponding C3 acyloxylation products in
moderate to good yields (Scheme 3, 4f−4i). However, when
C-2 unsubstituted imidazo[1,2-a]pyridine was employed in the
reaction, the corresponding C−H/O−H cross-coupling
product was not obtained (Scheme 3, 4j). The reason for
this may be because the corresponding radical cation
intermediate is not stable. The effect of different substituents
on the pyridine ring of imidazo[1,2-a]pyridines was also
explored. To our delight, when 6-Me-, 6-OMe-, and 8-F-
substituted imidazo[1,2-a]pyridines were employed, the
corresponding C3 acyloxylation products could be obtained
The anodic oxidation of 2-phenylimidazopyridine (2a)
generates the corresponding radical cation intermediate A.
With the help of base, the deprotonation of carboxylic acid
leads to the generation of RCOO−. Next, RCOO− attacks the
intermediate A to access the radical intermediate B. Following
anodic oxidation and deprotonation, the desired C3 acylox-
ylation product 3 is finally produced. At the cathode, H2O is
reduced to generate OH− and H2.
In conclusion, the electrochemical oxidative C3 acyloxyla-
tion of imidazo[1,2-a]pyridines was developed for the first
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time. By using electricity, the oxidative C3 acyloxylation of
imidazo[1,2-a]pyridines was performed under mild conditions.
Moreover, in addition to aromatic carboxylic acids, alkyl
carboxylic acids were also competent substrates, generating the
corresponding C3 acyloxylation products in moderate to high
yields.
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02032.
Experimental procedure, characterization data, and
copies of 1H and 13C NMR spectra of all of the
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Aiwen Lei − National Research Center for Carbohydrate
Synthesis, Jiangxi Normal University, Nanchang, Jiangxi
330022, P. R. China; College of Chemistry and Molecular
Sciences, the Institute for Advanced Studies (IAS), Wuhan
University, Wuhan, Hubei 430072, P. R. China; Department
of Chemical and Materials Engineering, Faculty of
Engineering, King Abdulaziz University, Jeddah 21589,
Saudi Arabia; orcid.org/0000-0001-8417-3061;
Email: aiwenlei@whu.edu.cn
Authors
Yong Yuan − National Research Center for Carbohydrate
Synthesis, Jiangxi Normal University, Nanchang, Jiangxi
330022, P. R. China; Gansu International Scientific and
Technological Cooperation Base of Water-Retention
Chemical Functional Materials, College of Chemistry and
Chemical Engineering,, Northwest Normal University,
Lanzhou, Gansu 730070, China; orcid.org/0000-0003-
3196-1747
Zhilin Zhou − National Research Center for Carbohydrate
Synthesis, Jiangxi Normal University, Nanchang, Jiangxi
330022, P. R. China
Lin Zhang − National Research Center for Carbohydrate
Synthesis, Jiangxi Normal University, Nanchang, Jiangxi
330022, P. R. China
Liang-Sen Li − National Research Center for Carbohydrate
Synthesis, Jiangxi Normal University, Nanchang, Jiangxi
330022, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02032
Author Contributions
⊥Y.Y., Z.Z., and L.Z. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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