Electrochemical Oxidative C—H Sulfenylation of Imidazopyridines with Hydrogen Evolution

Article abstract of DOI:10.1002/cjoc.201800405

Selective oxidative C—H sulfenylation of imidazopyridine heterocycles is achieved using an undivided electrolytic cell. The reaction avoids the use of stoichiometric amount of external chemical oxidant and produces hydrogen gas as the only byproduct. Both

Full text of DOI:10.1002/cjoc.201800405

Electrochemical oxidative C-H sulfenylation of imidazopyridines with
hydrogen evolution†
Yong Yuan,+a,b Yangmin Cao,+a Jin Qiao,a Yueping Lin,a Xiaomei Jiang,a Yaqing Weng,a Shan Tang,*,b and Aiwen Lei*,a,b
ABSTRACT Selective oxidative C-H sulfenylation of imidazopyridine heterocycles is achieved using an undivided electrolytic cell. The reaction avoids the
use of stoichiometric amount of external chemical oxidant and produces hydrogen gas as the only byproduct. Both aryl and aliphatic thiols demonstrate
good reactivity for C-S bond formation.
KEYWORDS Electrochemical oxidative, C-H sulfenylation, imidazopyridines, thiols, hydrogen evolution
yield (Table 1 entry 1). At the same time, hydrogen gas could be
detected by GC analysis after electrolysis. The electrode materials
were important for achieving good reaction efficiency. Platinum
Introduction
Imidazopyridines serve as key structure motif in many natural
products and bioactive compounds.[1] A series of synthetic
plate cathode showed similar reactivity with nickel plate cathode
methods have been developed to access this class of
(Table 1, entry 2). However, iron plate and carbon rod cathodes
heterocycles.[2] In order to access functionalized molecules,
were less efficient for promoting this C-S bond formation reaction
further modification of imidazopyridines is necessary. Introducing
(Table 1, entries 3 and 4). As for anodic material, platinum plate
organosulfur group into imidazopyridines has been considered to
anode afforded the desired product in only a 25% yield (Table 1,
be important since it can lead to a new class of biologically active
entry 5). Decreasing the operating current to 6 mA led to slightly
compounds.[3] Actually, tremendous attention has been paid to
the C-3 sulfenylation of imidazo[1,2-a]pyridine over the past
decreased reaction yield (Table 1, entry 6). Delightfully, increasing
the operating current to 18 mA did not affect the reaction
decade.[4] However, either functionalized substrates or
efficiency (Table 1, entry 7). It will be beneficial for large scale
stoichiometric amount of chemical oxidants such as hypervalent
synthesis since increasing the operating current can shorten the
metal salts, organic halides, peroxides and oxygen are required in
reaction time. As for the choice of supporting electrolyte,
nBu4NBF4 demonstrated similar reactivity to nBu4NPF6 (Table 1,
these transformations. From the viewpoint of green chemistry, an
entry 8) while nBu4NClO4 was less effective than nBu4NPF6 (Table 1,
ideal way to achieve C-3 sulfenylation of imidazo [1,2-a]pyridine is
the oxidative C-H/S-H cross-coupling with hydrogen evolution.
entry 9). The effect of solvents was also explored. A yield of 67%
Electrochemistry has long been recognized as
a green
could still be obtained by using acetonitrile as the sole solvent
(Table 1, entry 10). Using water instead of methanol led to a
slightly decreased reaction yield (Table 1, entry 11). As was
expected, no desired product could be obtained without electric
current (Table 1, entry 12).
synthetic method and provides a new opportunity for organic
synthesis.[5] In the past few years, the application of
electrochemistry in cross-coupling reactions has become a hot
research area.[6] Our group has long been interested in developing
novel oxidative cross-coupling methods for the construction of
new chemical bonds.[7] Recently, we were able to achieve
oxidative cross-coupling with hydrogen evolution by combining
electrochemical anodic oxidation with cathodic proton
reduction.[8] In this work, we have successfully developed the
Table 1 Effect of reaction parameters a
.
selective
C-3
oxidative
C-H
sulfenylation
of
imidazo[1,2-a]pyridines using an undivided electrolytic cell
(Scheme 1). Notably, neither external chemical oxidants nor
catalysts were required for the C-S bond formation. Hydrogen gas
was produced as the only byproduct.
Scheme 1 Electrochemical oxidative C-H sulfenylation of imidazopyridines
with hydrogen evolution.
Results and Discussion
2-Phenylimidazo[1,2-a]pyridine (1a) and 4-chlorothiophenol
(2a) were chosen as the model substrates to test the reaction
conditions. By utilizing 12 mA constant current with carbon rod
anode and nickel plate cathode in an undivided cell, a mixture of
1a and 2a afforded the desired C-S bond formation product in 87%
a Reaction conditions: carbon rod anode, nickel plate cathode, constant
n
current = 12 mA, 1a (0.80 mmol), 2a (0.40 mmol), Bu4NPF6 (0.10 mmol),
MeCN (10.5 mL), co-solvent (0.5 mL), 40 oC, 3 h (3.3 F/mol). b Isolated
yields. n.d. = not detected.
a National Research Center for Carbohydrate Synthesis, Jiangxi Normal
University, Nanchang 330022, P. R. China.
*E-mail: aiwenlei@whu.edu.cn; tangshanrwx@whu.edu.cn
+ Yong Yuan and Yangmin Cao contributed equally to this work.
†This paper is dedicated to Professor Xiyan Lu on the occasion of his 90th
birthday.
b College of Chemistry and Molecular Sciences, Institute for Advanced Studies
(IAS), Wuhan University, Wuhan 430072, P. R. China.
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may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1002/cjoc.201800405
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Since the method had been established, efforts were then
paid to explore the scope of the substrates. First, different thiols
were explored as substrates (Table 2). Thiophenols with halide
substituents all demonstrated good selectivity toward C-H
yield of imidazo[1,2-a]pyridine is that it has a much higher
oxidation potential than 2-phenylimidazo[1,2-a]pyridine (See ESI
for details).
Table 3 Scope of imidazopyridines a
.
sulfenylation
(3aa-3ae).
Strong
electron-deficient
4-trifluoromethylthiophenol was also able to furnish the desired
C-S bond formation product in 85% yield (3af). Weak
electron-donating substituents including methyl, isopropyl and
tert butyl groups did not affect the reaction efficiency (3ag-3ai).
However, strong electron-rich 4-methoxylthiolphenol exhibited a
decreased reaction efficiency in this transformation (3aj).
Significantly, the scope of the thiols could be extended to aliphatic
thiols. For example, when benzyl mercaptan, 2-phenylethanethiol,
cyclopentanethiol, ethanethiol, and 1-dodecanethiol were used as
the reaction partners, corresponding products were isolated in
moderate to good yields (3ak-3ao).
Table 2 Scope of thiols a
.
a Reaction conditions: carbon rode anode, nickel plate cathode, constant
current = 12 mA, 1 (0.80 mmol), 2a (0.40 mmol), nBu4NPF6 (0.10 mmol),
MeCN (10.5 mL), MeOH (0.5 mL), 40 oC, 3 h (3.3 F/mol), isolated yields. b
h (4.5 F/mol).
4
The synthetic potential of this transformation was then
evaluated by performing a gram scale reaction. By utilizing 24 mA
constant current, 1.3g of 3aa could synthesized by performing a 5
mmol scale reaction after 20 h electrolysis (Scheme 2).
a Reaction conditions: carbon rode anode, nickel plate cathode, constant
Scheme 2 Gram-scale synthesis.
current = 12 mA, 1a (0.80 mmol), 2 (0.40 mmol), nBu4NPF6 (0.10 mmol),
MeCN (10.5 mL), MeOH (0.5 mL), 40 oC, 3 h (3.3 F/mol), isolated yields. b
h (4.5 F/mol). c 6 mA, 6 h (3.3 F/mol), 55 oC.
4
The scope of the imidazopyridines was also studied (Table 3).
Halide substituents including fluoride and chloride at the 2-phenyl
moiety of imidazopyridine were well tolerated (3ba and 3ca).
Strong electron-withdrawing groups such as trifluoromethyl and
cyano at the para position of the 2-phenyl moiety of
imidazopyridines decreased the reaction efficiency for C-S bond
formation (3da and 3ea). By contrast, electron-donating groups at
the para position of the 2-phenyl moiety of imidazopyridines
slightly increased the reaction efficiency (3fa and 3ga). Moreover,
methyl or fluorine groups at the C-5, C-6, or C-7 position of
2-arylimidazo[1,2-a]pyridine did not affect the reaction efficiency
in the electrochemical oxidative C-S bond formation (3ha-3la).
The C-2 substituent had a significant effect on the reaction
efficiency of the oxidative C-H sulfenylation. A moderate yield
could be obtained with 2-(naphthalen-2-yl)imidazo[1,2-a]pyridine
(3ma). However, imidazo[1,2-a]pyridine only demonstrated a low
reactivity for C-S bond formation (3na). The reason for the low
In the next step, efforts were taken to understand the reaction
mechanism using 1a and 2a as reaction partners. First, cyclic
voltammograms of the substrates were recorded. 1a could be
oxidized when the oxidation potential exceed 1.05 V while 2a
started to get oxidized from 1.10 V. During current controlled
electrolysis, the working voltage for whole electrolytic cell ranged
from 3.70 to 5.10 V while the oxidation potential of anode (vs
Ag/AgCl) ranged from 1.21 to 1.89 V. Thus, both 1a and 2a could
be oxidized at anode during electrolysis. Disulfides were observed
as side products in the reaction system. To confirm the role of
disulfides in the formation of C-S bonds, a control experiment by
utilizing disulfide 4a as the sulfenylation reagent was carried out.
The C-S bond formation product 3aa could be obtained in 90%
yield (Scheme 3).
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Scheme 3 Oxidative C-H sulfenylation with disulfide.
Acknowledgement
This work was supported by the National Natural Science
Foundation of China (21390402, 21520102003) and the Hubei
Province Natural Science Foundation of China (2017CFA010). The
Program of Introducing Talents of Discipline to Universities of
China (111 Program) was also appreciated.
Based on the experimental results, a plausible mechanism for
the reaction between 1a and 2a is shown in Scheme 4. Oxidation
of 1a at anode could generate an aryl [1,2-a] cation intermediate
A. Oxidation of 2a at anode could form a sulfur radical B. The
generated thiyl radical could undergo dimerization to give
disulphide 4a. C-S bond could be formed either from the
radical-radical cross-coupling between A and B or from the radical
homolytic substitution between A and 4a. Addition of B to 1a
could not be fully ruled out. Final deprotonation would lead to the
formation of the C-S bond formation product 3aa. At the cathode,
the co-solvent methanol could be reduced to give hydrogen gas
during the reaction.
References
[1] (a) Sato, Y.; Onozaki, Y.; Sugimoto, T.; Kurihara, H.; Kamijo, K.;
Kadowaki, C.; Tsujino, T.; Watanabe, A.; Otsuki, S.; Mitsuya, M.; Iida,
M.; Haze, K.; Machida, T.; Nakatsuru, Y.; Komatani, H.; Kotani, H.;
Iwasawa, Y. Bioorg. Med. Chem. Lett. 2009, 19, 4673-4678; (b)
Gudmundsson, K. S.; Boggs, S. D.; Catalano, J. G.; Svolto, A.;
Spaltenstein, A.; Thomson, M.; Wheelan, P.; Jenkinson, S. Bioorg.
Med. Chem. Lett. 2009, 19, 6399-6403; (c) Cecile, E.-G.; Alain, G.
Mini Rev. Med. Chem. 2007, 7, 888-899.
[2] (a) Wang, H.; Xu, W.; Xin, L.; Liu, W.; Wang, Z.; Xu, K. J. Org. Chem.
2016, 81, 3681–3687; (b) Huo, C.; Tang, J.; Xie, H.; Wang, Y.; Dong, J.
Org. Lett. 2016, 18, 1016-1019; (c) Wang, H.; Xu, W.; Wang, Z.; Yu, L.;
Xu, K. J. Org. Chem. 2015, 80, 2431–2435; (d) Pericherla, K.; Kaswan,
P.; Pandey, K.; Kumar, A. Synthesis 2015, 47, 887-912; (e) Bagdi, A.
K.; Santra, S.; Monir, K.; Hajra, A. Chem. Commun. 2015, 51,
1555-1575.
Scheme 4 Proposed mechanism.
[3] (a) Hamdouchi, C.; de Blas, J.; del Prado, M.; Gruber, J.; Heinz, B. A.;
Vance, L. J. Med. Chem. 1999, 42, 50-59; (b) Bochis, R. J.; Olen, L. E.;
Fisher, M. H.; Reamer, R. A.; Wilks, G.; Taylor, J. E.; Olson, G. J. Med.
Chem. 1981, 24, 1483-1487.
[4] (a) Rahaman, R.; Das, S.; Barman, P. Green Chem. 2018, 20, 141-147;
(b) Zhang, J. R.; Zhan, L. Z.; Wei, L.; Ning, Y. Y.; Zhong, X. L.; Lai, J. X.;
Xu, L.; Tang, R. Y. Adv. Synth. Catal. 2018, 360, 533-543; (c) Zhang, J.
R.; Liao, Y. Y.; Deng, J. C.; Feng, K. Y.; Zhang, M.; Ning, Y. Y.; Lin, Z. W.;
Tang, R. Y. Chem. Commun. 2017, 53, 7784-7787; (d) Sun, P.; Yang,
D.; Wei, W.; Jiang, M.; Wang, Z.; Zhang, L.; Zhang, H.; Zhang, Z.;
Wang, Y.; Wang, H. Green Chem. 2017, 19, 4785-4791; (e) Siddaraju,
Y.; Prabhu, K. R. J. Org. Chem. 2016, 81, 7838-7846; (f) Ravi, C.;
Reddy, N. N. K.; Pappula, V.; Samanta, S.; Adimurthy, S. J. Org. Chem.
2016, 81, 9964-9972; (g) Ravi, C.; Chandra Mohan, D.; Adimurthy, S.
Org. Biomol. Chem. 2016, 14, 2282-2290; (h) Jiao, J.; Wei, L.; Ji, X. M.;
Hu, M. L.; Tang, R. Y. Adv. Synth. Catal. 2016, 358, 268-275; (i)
Rafique, J.; Saba, S.; Rosário, A. R.; Braga, A. L. Chem. Eur. J. 2016,
22, 11854-11862; (j) Hiebel, M.-A.; Berteina-Raboin, S. Green Chem.
2015, 17, 937-944; (k) Bagdi, A. K.; Mitra, S.; Ghosh, M.; Hajra, A.
Org. Biomol. Chem. 2015, 13, 3314-3320; (l) Ravi, C.; Chandra
Mohan, D.; Adimurthy, S. Org. Lett. 2014, 16, 2978-2981.
Conclusions
In conclusion, we have demonstrated an environmentally
friendly method for the selective oxidative C-H sulfenylation of
imidazopyridines with hydrogen evolution using an undivided
electrolytic cell. Neither transition metal catalysts nor external
chemical oxidants were required to facilitate the C-S bond
formation process. Notably, the reaction could be conducted in
gram scale with high reaction efficiency.
Experimental
In an oven-dried undivided three-necked bottle (25 mL)
equipped with a stir bar, imidazopyridines (1, 0.80 mmol),
benzenethiols/thiols (2, 0.40 mmol), nBu4NPF6 (25 mol%, 0.10
mmol) were combined and added. The bottle was equipped with
graphite rod (ϕ 6 mm, about 18 mm immersion depth in solution)
as the anode and nickel plate (15 mm × 15 mm × 0.3 mm) as the
cathode and then charged with nitrogen. Under the protection of
N2, MeOH (0.5 mL) and MeCN (10.5 mL) were sequentially
injected into the reaction vessel via syringe. The reaction mixture
was stirred and electrolyzed with a constant current of 12 mA at
[5] (a) Tang, S.; Liu, Y.; Lei, A. Chem 2018, 4, 27-45; (b) Jiang, Y.; Xu, K.;
Zeng, C. Chem. Rev. 2018, 118, 4485-4540; (c) Wiebe, A.; Gieshoff,
T.; Möhle, S.; Rodrigo, E.; Zirbes, M.; Waldvogel, S. R. Angew. Chem.
Int. Ed. 2018, 57, 5594-5619; (d) Yan, M.; Kawamata, Y.; Baran, P. S.
Chem. Rev. 2017, 117, 13230-13319; (e) Horn, E. J.; Rosen, B. R.;
Baran, P. S. ACS Cent. Sci. 2016, 2, 302-308; (f) Francke, R.; Little, R.
D. Chem. Soc. Rev. 2014, 43, 2492-2521; (g) Yoshida, J.-i.; Kataoka,
K.; Horcajada, R.; Nagaki, A. Chem. Rev. 2008, 108, 2265-2299; (h)
Jutand, A. Chem. Rev. 2008, 108, 2300-2347; (i) Sperry, J. B.; Wright,
D. L. Chem. Soc. Rev. 2006, 35, 605-621.
o
40 C for 3 h. When the reaction was finished, the pure product
was obtained by flash column chromatography on silica gel.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
[6] (a) Qiu, Y.; Kong, W. J.; Struwe, J.; Sauermann, N.; Rogge, T.;
Scheremetjew, A.; Ackermann, L. Angew. Chem. Int. Ed. 2018, 57,
5828-5832; (b) Yoshida, J.-i.; Shimizu, A.; Hayashi, R. Chem. Rev.
2018, 118, 4702-4730; (c) Pletcher, D.; Green, R. A.; Brown, R. C. D.
This article is protected by copyright. All rights reserved.

Chem. Rev. 2018, 118, 4573-4591; (d) Yuan, Y.; Chen, Y.; Tang, S.;
Huang, Z.; Lei, A. Sci. Adv. 2018, 4: eaat5312; (e) Yang, Q.-L.; Li, Y.-Q.;
Ma, C.; Fang, P.; Zhang, X.-J.; Mei, T.-S. J. Am. Chem. Soc. 2017, 139,
3293-3298; (f) Xiong, P.; Xu, H.-H.; Xu, H.-C. J. Am. Chem. Soc. 2017,
139, 2956-2959; (g) Gieshoff, T.; Kehl, A.; Schollmeyer, D.; Moeller,
K. D.; Waldvogel, S. R. J. Am. Chem. Soc. 2017, 139, 12317-12324; (h)
Fu, N.; Sauer, G. S.; Saha, A.; Loo, A.; Lin, S. Science 2017, 357,
575-579; (i) Fu, N.; Li, L.; Yang, Q.; Luo, S. Org. Lett. 2017, 19,
2122-2125; (j) Horn, E. J.; Rosen, B. R.; Chen, Y.; Tang, J.; Chen, K.;
Eastgate, M. D.; Baran, P. S. Nature 2016, 533, 77-81; (k) Badalyan,
A.; Stahl, S. S. Nature 2016, 535, 406-410; (l) Gao, H.; Zha, Z.; Zhang,
Z.; Ma, H.; Wang, Z. Chem. Commun. 2014, 50, 5034-5036.
Gao, X.; Wang, P.; Huang, P.; Lei, A. J. Am. Chem. Soc. 2018, 140,
6006-6013; f) Huang, Z.; Tang, S.; Lei, A. Sci. Bull. 2015, 60,
1391-1394.
[8] (a) Tang, S.; Wang, S.; Liu, Y.; Cong, H.; Lei, A. Angew. Chem. Int. Ed.
2018, 57, 4737-4741; (b) Huang, P.; Wang, P.; Tang, S.; Fu, Z.; Lei, A.
Angew. Chem. Int. Ed. 2018, 57, 8115-8119; (c) Gao, X.; Wang, P.;
Zeng, L.; Tang, S.; Lei, A. J. Am. Chem. Soc. 2018, 140, 4195-4199; (d)
Wang, P.; Tang, S.; Huang, P.; Lei, A. Angew. Chem. Int. Ed. 2017, 56,
3009-3013; (e) Liu, K.; Tang, S.; Huang, P.; Lei, A. Nat. Commun.
2017, 8, 775.
(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2017
[7] (a) Liu, C.; Liu, D.; Lei, A. Acc. Chem. Res. 2014, 47, 3459-3470; (b)
Chen, M.; Zheng, X.; Li, W.; He, J.; Lei, A. J. Am. Chem. Soc. 2010, 132,
4101-4103; (c) Zhao, Y.; Wang, H.; Hou, X.; Hu, Y.; Lei, A.; Zhang, H.;
Zhu, L. J. Am. Chem. Soc. 2006, 128, 15048-15049; d) Tang, S.; Wang,
P.; Li, H.; Lei, A. Nat. Commun. 2016, 7, 11676; e) Tang, S.; Liu, Y.;
Revised manuscript received: XXXX, 2017
Accepted manuscript online: XXXX, 2017
Version of record online: XXXX, 2017
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Entry for the Table of Contents
Page No.
Electrochemical
oxidative
C-H
sulfenylation of imidazopyridines with
hydrogen evolution
This work describes an exogenous-oxidant-free C-H sulfenylation of imidazopyridines using an
electrochemical oxidative protocol.
Yong Yuan, Yangmin Cao, Jin Qiao, Yueping
Lin, Xiaomei Jiang, Yaqing Weng, Shan
Tang,* Aiwen Lei*
This article is protected by copyright. All rights reserved.