Copper-catalyzed three-component reaction of imidazo[1,2-a]pyridine with elemental sulfur and arylboronic acid to produce sulfenylimidazo[1,2-a]pyridines

Article abstract of DOI:10.1016/j.cclet.2017.12.013

In this work, an efficient copper-catalyzed three-component reaction for the synthesis of sulfenylimidazo[1,2-a]pyridines using elemental sulfur as the sulfenylating agents has been developed. The reaction could proceed smoothly with a high degree of functional group tolerance and provide the desired products in moderate to good yield.

Full text of DOI:10.1016/j.cclet.2017.12.013

Accepted Manuscript
Title: Copper-catalyzed three-component reaction of
imidazo[1,2-a]pyridine with elemental sulfur and arylboronic
acid to produce sulfenylimidazo[1,2-a]pyridines
Authors: Genhua Xiao, Hao Min, Zhilei Zheng, Guobo Deng,
Yun Liang
PII:
DOI:
Reference:
S1001-8417(17)30547-8
https://doi.org/10.1016/j.cclet.2017.12.013
CCLET 4375
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Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
7-10-2017
8-12-2017
18-12-2017
Please cite this article as: Genhua Xiao, Hao Min, Zhilei Zheng, Guobo Deng, Yun
Liang, Copper-catalyzed three-component reaction of imidazo[1,2-a]pyridine with
elemental sulfur and arylboronic acid to produce sulfenylimidazo[1,2-a]pyridines,
Chinese Chemical Letters https://doi.org/10.1016/j.cclet.2017.12.013
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Communication
Copper-catalyzed three-component reaction of imidazo[1,2-a]pyridine with elemental
sulfur and arylboronic acid to produce sulfenylimidazo[1,2-a]pyridines
Genhua Xiao, Hao Min, Zhilei Zheng, Guobo Deng*, Yun Liang*
National & Local Joint Engineering Laboratory for New Petro-chemical Materials and Fine Utilization of Resources, Key Laboratory of Chemical Biology and
Traditional Chinese Medicine Research, Ministry of Education, Key Laboratory of the Assembly and Application of Organic Functional Molecules, College of
Chemistry and Chemical Engineering, Hunan Normal University, Changsha 410081, China
 Corresponding authors.
E-mail addresses: gbdeng@hunnu.edu.cn; yliang@hunnu.edu.cn.
Graphical Abstract
A copper-catalyzed three-component reaction for the synthesis of sulfenylimidazo[1,2-a]pyridines using elemental sulfur as the
sulfenylating agents has been developed.
ARTICLE INFO
ABSTRACT
Article history:
In this work, an efficient copper-catalyzed three-component reaction for the synthesis of
sulfenylimidazo[1,2-a]pyridines using elemental sulfur as the sulfenylating agents has been
developed. The reaction could proceed smoothly with a high degree of functional group
tolerance and provide the desired products in moderate to good yield.
Received 7 October 2017
Received in revised form 8 December 2017
Accepted 12 December 2017
Available online
Keywords:
Copper
Three-component
Pyridine
Sulfur
Arylboronic acids
The imidazo[1,2-a]pyridine core is of great interest on account of their broad applications in many bioactive natural products and
pharmaceuticals [1], such as alpidem [2], zolpidem [3], necopidem [4], saripidem [5], zolimidine [6], minodronic acid [7] and
olprinone [8]. Furthermore, sulfur-containing substances play a particularly significant role in a variety of synthetic drugs and natural
products, and represent a ubiquitous “privileged scaffold” [9]. Therefore, there has been increased interest in the exploration of
synthetic methods for the formation of sulfenylimidazo[1,2-a]pyridines in recent years. To the best of our knowledge, lots of methods
have been reported to prepare aryl sulfides by various organic sulfenylating agents such as disuldes [10], thiols [11], sodium sulfinates
[12], sulfonyl chlorides [13], sulfonyl hydrazide [14] and sulfinic acids [15], etc. (Scheme 1, b). However, most of these organic
sulfenylating agents are foul-smelling, toxic, unstable, or expensive, which limited their widespread application. In order to comply
with environmental friendly chemistry principles, more and more scientists focus much attention on inorganic sulfur as a source of
C−S bond formation. For example, Adimurthy group [16] and Deng group [17] all reported the three-component one-pot synthesis of
sulfenylimidazo[1,2-a]pyridines using haloarenes and elemental sulfur with a copper catalyst (Scheme 1, b). Compared with organic

sulfenylating agents, use of haloarenes and elemental sulfur [18] as a thioarylation source is of significant interest in organic synthesis.
However, some unfavourable halides as by-products will be produced during the reaction, which is harmful to our environment.
Therefore, choosing an environmentally friendly sulfenylating agent is still highly desirable. Arylboronic acids as arylation reagents
are used in organic synthesis due to low toxicity, high stability (against air, moisture and temperature) and good chemical reactivity.
Very recently, Jiang and co-workers [19] described a palladium-catalyzed C−H bond oxidative sulfenylation of imidazo[1,2-
a]pyridines with arylboronic acids and elemental sulfur in ionic liquids (Scheme 1, c). However, the complex and expenxive catalytic
system (Pd(OAc)2/CuI/1,10-Phen/Ag2CO3/Cs2CO3) should be limited in the practical production process. Consequently, simple and
cheaper strategy to construct sulfeny- limidazo[1,2-a]pyridines is still highly appealing. In continuation of our endeavors devoted to the
development of the synthetic strategies of sulfur-containing substances [20], we report herein the sulfenylation of imidazo[1,2-
a]pyridines through a one-pot three-component system using catalytic amount of copper catalyst and ligand, and oxygen as a green
oxidant. (Scheme 1, d).
Scheme 1. Synthesis of sulfenylimidazo[1,2-a]pyridines.
We began our investigation on the model reaction of 2-phenylimidazo[1,2-a]pyridine (1a), phenylboronic acid (2a), and elemental
sulfur (S8) to optimize the reaction conditions (Table 1). The expected product 2-phenyl-3-(phenylthio)imidazo[1,2-a]pyridine (3aa)
o
was obtained in 52% yield by employing CuI (10 mmol %) as catalyst, and 1,10-Phen (20 mmol%) as ligand in DMF at 140 C for 24
h (entry 1). To our delight, the expected product yield increased to 86% when the reaction was performed with O2 balloon (entry 3),
and resulted in rather poor yield with N2 balloon (entry 2). Then, we focused our efforts on searching for an efficient copper catalysts
(including CuI, CuCl, CuBr, CuCl2, CuBr2, Cu(OAc)2, and CuF), and the results revealed that CuI as the best catalyst (entries 3-9).
Further, no improvements were observed when the reactions were carried out in other ligands (including substituted 1, 10-Phen,
DMEDA, TEMED, L-proline and bipy) (entries 10-16). We then investigated various solvent effects on this transformation, and DMF
was found to be the optimal solvent (entries 17 and 18). It is noteworthy that the yield decreased when changed the reaction
temperature and the amount of CuI and 1,10-Phen (entries 19-22). Thus, the optimized reaction conditions were as follows: 1a (0.30
mmol), 2a (0.60 mmol), S8 (0.11 mmol), CuI (10 mmol %), 1,10-Phen (20 mmol%), in DMF (2 mL) under O2 balloon at 140 oC for 24
h.
Table 1
Optimization of reaction conditions. a
Entry
1c
2d
3
4
5
6
7
8
9
Catalyst
CuI
CuI
Ligand
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Yield (%)b
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
-
52
5
86
82
56
42
62
81
65
CuI
CuCl
CuBr
CuCl2
CuBr2
Cu(OAc)2
CuF
CuI
CuI
CuI
10
11
trace
17
trace
Bathocuproin
1,10-Phen-4,7-
diol
12
13
14
15
16
CuI
CuI
CuI
CuI
DMEDA
TEMED
L-proline
bipy
DMF
DMF
DMF
DMF
20
21
20
65

17
CuI
CuI
CuI
CuI
CuI
CuI
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
NMP
DMSO
DMF
DMF
DMF
DMF
42
45
60
42
55
55
18
19e
20f
21g
22h
a Reaction conditions: 1a (0.30 mmol), 2a (0.60 mmol), S8 (0.11 mmol), Cu catalyst (10 mmol%), Ligand (20 mmol%), solvent (2 mL), O2
balloon, at 140 oC for 24 h.
b Isolated yields.
c Under air atmosphere.
d Under nitrogen atmosphere.
e At 120 oC.
f At 100 oC.
g Cu catalyst (5 mmol%), ligand (10 mmol%).
h Cu catalyst (20 mmol%), ligand (40 mmol%).
With the optimal reaction conditions in hand, the scope of the benzene rings of 2-arylimidazo[1,2-a]pyridines was investigated. As
can be seen from Table 2, the optimal reaction conditions were applicable to various groups on the benzene rings of 2-arylimidazo[1,2-
a]pyridines, providing the corresponding sulfenylated products (3aa-3ag) in moderate to good yield. When the 2-arylimidazo[1,2-
a]pyridines bearing a variety of electron-donating groups, such as methyl and methoxy, the highly reactive coupling partner provided
corresponding products (3ab) and (3ac) in 83% and 81%, respectively. Gratifyingly, various electron-withdrawing groups, such as
chloro, bromo, iodine, and trifluoromethyl groups, were compatible with the reaction conditions and afforded desired products (3ad-
3ag) in moderate yield. The result represented a significant electronic effect of 2-arylimidazo[1,2-a]pyridines. It was worth noting that
the thiophene-substituted imidazo[1,2-a]pyridines could also be easily converted into desired product (3ah) in 78% yield and
imidazo[1,2-a]pyridines was also transformed to desired product (3ai) in 26% yield.
Table 2
Substrate scope on the benzene rings of 2-arylimidazo[1,2-a]pyridines. a
Entry
1
R
C6H5
Product
3aa
3ab
3ac
3ad
3ae
Yield (%)b
1
2
3
4
5
6
7
8
9
1aa
1ab
1ac
1ad
1ae
1af
1ag
1ah
1ai
86
83
81
61
46
57
57
78
26
4-MeC6H5
4-OMeC6H5
4-ClC6H5
4-BrC6H5
4-IC6H5
4-CF3C6H5
thiophene
H
3af
3ag
3ah
3ai
a Reaction conditions: 1 (0.30 mmol), 2a (0.60 mmol), S8 (0.11 mmol), Cu catalyst (10 mmol %), Ligand (20 mmol %), solvent (2 mL), O2
balloon, at 140 oC for 24 h.
b Isolated yield.
Subsequently, we investigated the substrate scope on the pyridine moiety of 2-arylimidazo[1,2-a]pyridines (Table 3). It was found
that the position of substituents did not obviously effect on the reaction. The substrates with methyl group at C-5 (1ba), C-6 (1bb), C-7
(1bc) and C-8 (1bd) gave the desired products (3ba–3bd) in good yield. Similarly, other substrates (8-OMe, 6-Ph) can be easily
converted to the desired product (3be) and (3bf) in 73% and 82%, respectively. Moderate yields (3bg-3bk) were achieved when the
electron-withdrawing groups at C-6 of 2-arylimidazo[1,2-a]pyridines. The results indicated that an electronic effect on the substituted
group played a significant role in the reaction.
Table 3
Substrate scope on the pyridine moiety of 2-arylimidazo[1,2-a]pyridines. a
Entry
1
1ba
1bb
1bc
1bd
1be
1bf
R
Product
3ba
3bb
3bc
3bd
3be
3bf
Yield (%)b
1
2
3
4
5
6
7
8
5-Me
6-Me
7-Me
8-Me
8-OMe
6-C6H5
6-F
65
80
69
71
73
82
36
49
1bg
1bh
3bg
3bh
6-Cl

9
10
11
1bi
1bj
1bk
6-Br
6-CN
6-CF3
3bi
3bj
3bk
44
23
41
a Reaction conditions: 1 (0.30 mmol), 2a (0.60 mmol), S8 (0.11 mmol), Cu catalyst (10 mmol %), Ligand (20 mmol %), solvent (2 mL), O2
balloon, at 140 oC for 24 h.
b Isolated yield.
To further examine the scope and limitations of the reaction, we next set out to test various arylboronic acid derivatives for this kind
of reaction. As can be seen from Table 4, the o-, m- or p-methyl-phenylboronic acids and halogen-phenylboronic acids all could
efficiently react with 2- arylimidazo[1,2-a]pyridine and elemental sulfur to afforded corresponding products (3ca-3ci) in moderate to
good yield. Importantly, p-cyano-phenylboronic acid and 1-naphthylboronic acid could performed with 2-phenylimidazo[1,2-
a]pyridine, elemental sulfur and produced the desired product in 78% and 76% yield, respectively. We were pleased to find that the
method could be extended to aliphatic boric acid, such as cyclopropaneboronic acid, to afford the corresponding sulfenylated product
(3cn) in 28% yields. Interestingly, p-hydroxy phenylboronic acid could also convert to the desired product (3co) in 23% yields.
Table 4
Substrate scope on the arylboronic acids. a
Entry
1
2
3
4
5
6
7
8
2
R
Product
3ca
3cb
3cc
3cd
3ce
3cf
3cg
3ch
3ci
3cj
3ck
3cl
3cm
3cn
3co
Yield (%)b
2ac
2bc
2cc
2dc
2ec
2fc
2gc
2hc
2ic
2jc
2kc
2lc
2mc
2nc
2oc
2-MeC6H5
3-MeC6H5
4-MeC6H5
2-FC6H5
3-FC6H5
4-FC6H5
4-ClC6H5
2-BrC6H5
4-BrC6H5
4-OMeC6H5
4-CF3C6H5
4-CNC6H5
1-naphthyl
cyclopropane
4-OHC6H5
56
83
73
74
74
66
67
51
72
53
58
78
76
28
23
9
10
11
12
13
14
15
a Reaction conditions: 1a (0.30 mmol), 2 (0.60 mmol), S8 (0.11 mmol), Cu catalyst (10 mmol %), Ligand (20 mmol %), solvent (2 mL), O2
balloon, at 140 oC for 24 h.
b Isolated yield.
To investigate the mechanism of this type of reaction, several control experiments were performed, as shown in Scheme 2. Under the
standard conditions, when phenylboronic acid was employed to react with elemental sulfur for 24 h, the complicated mixtures A was
obtained (see the Supporting information for details), and the desired product 3aa was obtained in 56% yield after addition of 1a for 12
h. The result suggested that either diphenyl disulfide or diphenyl sulfide was a possible intermediate in this process. Subsequently, 1a
was allowed respectively to react with diphenyl disulfide and diphenyl sulfide
for 12 h under the standard conditions. To our delight, diphenyl disulfide could give 98% yield of 3aa. However, diphenyl sulfide
could not give the corresponding product. These results indicated that the three-component reaction underwent the process of diphenyl
disulfide as intermediate.
Scheme 2. Control experiments.
Based on the present experimental results and the previous reported mechanism [21], a proposed catalytic cycle for the formation of
sulfenylimidazo[1,2-a]pyridines is given in Scheme 3. Initially, arylboronic acid and elemental sulfur could converted to diphenyl
disulfide in the presence of CuI, 1-10-Phen, and O2 catalytic system. Then CuI reacts with diphenyl disulfide to form electrophilic

species PhS+ C. Subsequently, the regioselectively electrophilic attack of PhS+ C on imidazole ring to form imidazolium intermediate
D, which can undergo proton elimination to afford the desired product 3aa, with the concomitant formation of copper catalyst. At the
same time, the PhSH could reproduce diphenyl disulfide by O2 to complete the catalytic cycle.
Scheme 3. Proposed reaction mechanism.
In summary, we have developed a simple and efficient method for synthesis of sulfenylimidazo[1,2-a]pyridines by copper-catalyzed
one-pot three-component system with arylboronic acids and elemental sulfur. Further more, The method has a broad substrate scope,
with a variety of substituent groups on aryl boronicacids as well as 2-arylimidazo[1,2-a]pyridines. In addition, efforts to extend the
applications of the transformation in organic synthesis as well as screen for biological activity of these types of compounds are now in
progress in our laboratory (General experimental procedures and spectral data of product are provided in supporting information).
Acknowledgments
This work was supported by the National Natural Science Foundation of China (Nos. 21072054, 21572051, 21602057), the
Ministry of Education of China (No. 213027A), and the Scientific Research Fund of Hunan Provincial Education Department
(No. 15A109).
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