Metal-free direct regioselective thiolation of imidazoheterocycles in water at room temperature

Article abstract of DOI:10.1016/j.tet.2019.01.059

A metal-free direct thiolation of imidazoheterocycles with various thiophenol in water at room temperature has been developed. In addition, the chemistry provides several advantages including mild condition, high yields, good functional group tolerance, g

Full text of DOI:10.1016/j.tet.2019.01.059

Accepted Manuscript
Metal-free direct regioselective thiolation of imidazoheterocycles in water at room
temperature
Dulin Kong, Qinghe Wang, Tiao Huang, Min Liang, Qiang Lin, Mingshu Wu
PII:
S0040-4020(19)30113-9
https://doi.org/10.1016/j.tet.2019.01.059
TET 30111
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 December 2018
Revised Date: 22 January 2019
Accepted Date: 25 January 2019
Please cite this article as: Kong D, Wang Q, Huang T, Liang M, Lin Q, Wu M, Metal-free direct
regioselective thiolation of imidazoheterocycles in water at room temperature, Tetrahedron (2019), doi:
https://doi.org/10.1016/j.tet.2019.01.059.
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Metal-free direct regioselective thiolation of
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imidazoheterocycles in water at room temperature
Dulin Konga,b, Qinghe Wanga,c, Tiao Huanga,c, Min Lianga,c, Qiang Lina,c , Mingshu Wua,c
aKey Laboratory of Water Pollution Treatment & Resource Reuse of Hainan province, College of chemistry and chemical engineering, Hainan Normal
University, Haikou 571158, Hainan Province, P.R. China.
bSchool of Pharmaceutical Sciences, Hainan Medical University, Haikou 571199, Hainan Province, P.R. China
cKey Laboratory of Tropical Medicinal Plant Chemistry of the Ministry of Education, College of Chemistry & Chemical Engineering, Hainan Normal
University, Haikou 571158, Hainan Province, P. R. China.

2
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Tetrahedron
journal homepage: www.elsevier.com
Metal-free direct regioselective thiolation of imidazoheterocycles in water at room
temperature
Dulin Konga,b, Qinghe Wanga,c, Tiao Huanga,c, Min Lianga,c, Qiang Lina,c , Mingshu Wua,c
aKey Laboratory of Water Pollution Treatment & Resource Reuse of Hainan province, College of chemistry and chemical engineering, Hainan Normal
University, Haikou 571158, Hainan Province, P.R. China.
bSchool of Pharmaceutical Sciences, Hainan Medical University, Haikou 571199, Hainan Province, P.R. China
cKey Laboratory of Tropical Medicinal Plant Chemistry of the Ministry of Education, College of Chemistry & Chemical Engineering, Hainan Normal University,
Haikou 571158, Hainan Province, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A metal-free direct thiolation of imidazoheterocycles with various thiophenol in water at room
temperature has been developed. In addition, the chemistry provides several advantages
including mild condition, high yields, good functional group tolerance, green solvents and
suitable for large-scale operations.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Metal-free
Thiolation
Imidazoheterocycles
water
Corresponding author. Tel.: +86 13807654689; e-mail: linqianggroup@163.com (Q. Lin).
Corresponding author. Tel.: +86 13518886382; e-mail: wmsh@hainuu.edu.cn (M. Wu).

1. Introduction
imidazoheterocycles with thiols in water at room temperature
(Fig.2(c)).
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Imidazo[1,2-a]pyridines are recognized to exhibit a broad
range of applications in pharmaceuticals.1 Several commercially
available drugs have the imidazo[1,2-a]pyridines motif in their
core structure, for example, the sedative Zolpidem, the anxiolytic
Alpidem or Saripidem, or the heart failure drug Olprinone
(Fig.1). In particular, sulfenyaltion of imidazo[1,2-a]pyridines
derivatives gained attention in recent years. sulfenylation of C3-
position of imidazo[1,2-a]pyridines has been well-developed in
the presence of disulfides, elemental sulphur, thioether,
sulfonothioates, sodium sulfinates and sulfonyl hydrazides
(Fig.2(a)).2 Though these strategies were successfully employed
for the sulfenylation of imidazo[1,2-a]pyridines, most of them
have various disadvantages. In those protocols, such highly pre-
functionalized sulfenylating reagents require several steps to
prepare. In addition, the use of metals and bases limited the
further application of these protocols in industry and pharmacy.
Recently, direct functionalization of inert C–H bonds is a
straightforward transformation in synthetic chemistry.3 There is
no doubt that direct thiolation of imidazoheterocycles using thiols
is more economical and practical because of its advantages of
low cost, easy availability, and high atom economy. A literature
survey indicated that using this synthetic strategy for the
preparation of thiolation of imidazoheterocycles is rare, and in
this respect, several groups using thiols as the thiolation reagents
have been reported (Fig.2(b)).4 Nevertheless, the majority of
these procedures carried out in harsh reaction conditions, limited
substrate scope, expensive catalyst and toxic organic solvents,
which make them environmentally unfavourable. To solve these
problems, water is an ideal choice as the reaction medium
because it is a costeffective and non-toxic solvent in synthetic
chemistry from a “green and sustainable chemistry” perspective.5
In addition, water with its chemical and physical properties
imposes unique selectivity and reactivity in reactions conducted
in aqueous media which cannot be gained using organic solvents.
Fig. 2. Thiolation of imidazo[1,2-a]pyridines.
Fig. 1 The drugs containing imidazo[1,2-a]pyridine unit.
2. Results and Discussion
More recently, Huang’s and Saima’s group have developed
Cobalt-catalyzed and BSA-I2 thiolation of imidazoheterocycles
with thiols in water (Fig.2(b)).6 Nonetheless, still the reported
methods have some drawbacks such as high temperature, the use
of expensive and toxic transition-metal catalyst. In recent years,
iodine salts emerged as extremely powerful tools for the
construction of C-S bond formation.7 As part of our continued
interest in the synthesis of heterocyclic compounds and green
chemistry,8 along this line, we herein disclose the first example of
Intially, we carried out the reaction of 2-phenylimidazo[1,2-
a]pyridine 1a (0.5 mmol) with 4-methylbenzenethiol 2a (0.75
mmol) in the presence of KI (0.2 equiv) and tert-Butyl
hydroperoxide(TBHP) (2 equiv) in H2O at room temperature. To
our delight, the reaction proceeded smoothly, and the desired
product 3a was achieved in 69% yield within 6 h (Table 1, entry
1). After screening different solvents like EtOH, CH3CN, THF,
DMF etc (entries 18-25), H2O proved to be the best choice for the
reaction. Next, various reactions with other halides were also
carried out, such as KBr, KCl, CuI, and NH4I, and KI was the
a
metal-free
direct
regioselective
thiolation
of

4
TBHP with respect to 2-phenylimidazo[1,2-a]pyridine (entry 5).
Table 1. Optimization of the reaction conditiAonCsa CEPTED MANUSCRIPT
Other oxidants such as potassium persulfate, hydrogen peroxide,
oxygen were investigated, and TBHP was found to be the most
effective since 3a was isolated after 6 hours at room temperature
in 92% yield.
With the optimized conditions in hand (Table 1, entry 5), we
investigated the substrate scope of 2-arylimidazo[1,2-a]pyridines
and aromatic thiols (Scheme 1). We first applied this thiolation
protocol to Imidazo[1,2-a]pyridines. As shown in Scheme 1, a
range of electron-donating groups (Me and OMe) and electron-
withdrawing groups (Cl, Br, CF3) substituted imidazo[1,2-
a]pyridines underwent the sulfenylation reaction with 4-
methylbenzenethiol 2a to afford the corresponding 3-
sulfenylimidazopyridines 3a-3j in good to excellent yields. The
influence of the substituents on the phenyl ring of 2-
phenylimidazo[1,2-a]pyridines was also examined. Presence of
electron donating (Me and OMe) as well as electron withdrawing
(Cl, NO2, CN) groups did not prevent the smooth formation to
the desired products (3l-3p) in good yields (76–84%). Alkyl
substituted imidazo[1,2-a]pyridines gave a lower yield of the
sulfenylation product 3k than their corresponding aryl
substituents. Finally, we examined the scope of other aromatic
thiols under the optimal reaction conditions. The reaction
tolerates different aromatic thiols bearing electrondonating
(OMe) and withdrawing groups (F, Cl, NO2) in good yields (3q-
3w).
Entry
1
Solvent
H2O
[X] (equiv)
KI (0.2)
KI (0.5)
KI (1)
Oxidant (equiv)
TBHP(2)
TBHP(2)
TBHP (2)
TBHP (2)
TBHP (3)
TBHP (3.5)
TBHP (1.5)
TBHP (2.5)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
-
bYield(%)
69
2
H2O
80
3
H2O
84
4
H2O
KI (1.5)
KI (1)
82
5
H2O
92
6
H2O
KI (1)
88
7
H2O
KI (1)
70
8
H2O
KI (1)
86
9
H2O
KBr (0.2)
KCl (0.2)
CuI (0.2)
NH4I (0.2)
-
trace
trace
65
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
H2O
H2O
H2O
61
H2O
0
H2O
KI (0.2)
KI (0.2)
KI (0.2)
KI (0.2)
KI (0.2)
KI (0.2)
KI (0.2)
KI (0.2)
KI (0.2)
KI (0.2)
KI (0.2)
KI (0.2)
0
H2O
O2
trace
30
H2O
H2O2 (2)
H2O
K2S2O8 (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
15
EtOH
CH3CN
Toluene
Acetone
1,4-dioxane
DCM
THF
58
62
10
35
45
60
55
DMF
46
aReaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), halide, and oxidant in
solvent (2 mL) at room temperature for 6 h. bIsolated yields.
optimal catalyst (entries 1, 9–12). When the reaction was carried
out in the absence of any catalysts and oxidant, no desired
coupling product 3a was obtained (entries 13,14). Different ratios
of KI and TBHP to effect this reaction (entries 1–8) revealed the
optimum requirement as the usage of 1 and 3 equiv of KI and

tolyldisulfane with 1a gave the desired 3a in 91% yield
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suggesting that the thiolation reaction may proceed through a
disulfide intermediate (Scheme 3(b)). The reaction of 1a with 2a
gave the desired 3a in 88% yields in the presence of iodine as a
catalyst (Scheme 3(c)). This result indicated that KI might be
transformed to I2 during the reaction.
Scheme 1. Substrate scope of sulfonation reactions. Reaction conditions: 1
(0.5 mmol), 2 (0.75 mmol), KI (0.5 mmol), and TBHP (1.5 mmol) in water
(2 mL) at room temperature for
chromatography.
6 h. Isolated yields after column
Next, to demonstrate the generality of this methodology the
reaction conditions were applied to other imidazoheterocyclic
compounds (Scheme 2). The reaction of various substituted
thiophenols with 2-phenylbenzo[d]imidazo[2,1-b]thiazole, and 6-
phenylimidazo[2,1-b]thiazole gave the sulfenylated products
4a−4d in excellent yield (81-88%). However, 7-chloro-2-
phenylimidazo[1,2-b]pyridazine
and
6-chloro-2-
phenylimidazo[1,2-b]pyridazine failed to yield the desired
products.
Fig. 3. Results for the reaction for large-scale operation. Reaction conditions:
5 mmol 1a, 7.5 mmol 2a, 5 mmol KI, 15 mmol TBHP, 20 mL H2O, at room
temperature, 6 h. Isolated yields.
Scheme 2. Substrate scope of sulfonation reactions. Reaction conditions: 1
(0.5 mmol), 2 (0.75 mmol), KI (0.5 mmol), and TBHP (1.5 mmol) in water
(2 mL) at room temperature for
chromatography.
6 h. Isolated yields after column
Finally, investigations were also conducted to assess the
potential for recycling of aqueous solution in the model reaction
(Fig. 3). Meanwhile, we scaled up the reaction to 5 mmol to
show the possibility for large-scale operation. After completion
of the reaction, the reaction medium was extracted with EtOAc (3
× 50 mL) and reused in the next run directly. The process could
be repeated five times and 3a were obtained in 90%, 91%, 88%,
89% and 89% yields respectively. Therefore, this protocol
represents a practical method for the synthesis of biologically
relevant lead compounds.
To get some insight into the reaction mechanism, some control
experiments were performed (Scheme 3). First, the reaction of 2-
arylimidazo[1,2-a]pyridines (1a) and 4-methylbenzenethiol (2a)
under the standard conditions in the presence of radical inhibitors
(TEMPO or BHT) proceed well to form 3a in 90% and 88%
yields indicating that the reaction is not proceeding through a
radical mechanism (Scheme 3(a)). Next, the reaction of 1,2-di-p-
Scheme 3. Mechanistic investigations of the thiolation of
imidazoheterocycles.
On the basis of the above results and several previous
references,4e,9 a plausible mechanism has been proposed (Scheme
4). In the first step, I2 was easily formed under the oxidation
conditions of TBHP. Next, the reaction of thiol with I2 gave the
disulfide intermediate (A). Intermediate (A) further reacts with I2
to give the intermediate (B). Finally, An electrophilic attack of
intermediate (B) on the C-3 position of 2-phenylimidazo[1,2-
a]pyridine (1a) gave the product 3 (Scheme 4).

6
7.37 (m, 1 H), 7.02 (d, J = 12 Hz, 2 H), 6.90 (d, J = 8 Hz, 2 H),
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6.67-6.69 (m, 1 H), 2.43 (s, 3 H), 2.26 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3) δ = 151.2, 147.5, 137.9, 136.0, 133.7, 131.9,
130.3, 128.6, 128.5, 128.4, 125.8, 123.8, 116.3, 115.7, 106.1,
21.5, 21.0 ppm. Anal. calcd for C21H18N2S: C, 76.33%; H, 5.49%;
N, 8.48%. Found: C, 76.35%; H, 5.60%; N, 8.78%.
4.2.3. 6-methyl-2-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine
3c
eluent: 20% EtOAc/PE, white solid, mp: 130-131 °C, yield 88%
1
(145 mg). H NMR (400 MHz, CDCl3) δ = 8.18-8.20 (m, 2 H),
Scheme 4. The proposed mechanism for the reaction.
8.08 (s, 1 H), 7.63 (d, J = 8 Hz, 1 H), 7.40-7.44 (m, 2 H), 7.33-
7.37 (m, 1 H), 7.16-7.18 (m, 1 H), 7.03 (d, J = 8 Hz, 2 H), 6.91
(d, J = 8 Hz, 2 H), 2.30 (s, 3 H), 2.26 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3) δ = 151.2, 146.2, 136.0, 133.6, 132.0, 130.3,
129.8, 128.5, 128.4, 128.3, 125.7, 123.0, 122.3, 117.0, 106.3,
21.0, 18.5 ppm. Anal. calcd for C21H18N2S: C, 76.33%; H, 5.49%;
N, 8.48%. Found: C, 76.06%; H, 5.25%; N, 8.74%.
3. Conclusions
In summary, we have developed a simple, environmentally
friendly method to introduce various thiophenol on imidazo[1,2-
a]pyridines, imidazo[2,1-b]thiazoles and without any transition-
metal catalyst in a non-toxic medium. Moreover, the procedure is
mild condition, good functional group tolerance, green solvents
and simple workup procedures, making it more environmentally
friendly and suitable for large-scale operations.
4.2.4. 7-methoxy-2-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine
3d
eluent: 20% EtOAc/PE, white solid, mp: 66-67 °C, yield 86%
1
(148 mg). H NMR (400 MHz, CDCl3) δ = 8.16-8.28 (m, 2H),
4. Experimental section
8.05 (d, J = 7.4 Hz, 1H), 7.38-7.49 (m, 2H), 7.30-7.38 (m, 1H),
6.97-7.07 (m, 3H), 6.86-6.96 (m, 2H), 6.47-6.58 (m, 1H), 3.85 (s,
3H), 2.24 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ = 159.4,
151.1, 148.5, 135.9, 133.6, 132.0, 130.2, 128.4, 128.1, 125.7,
124.9, 107.7, 105.3, 95.1, 55.6, 20.9 ppm. Anal. calcd for
C21H18N2OS: C, 72.80%; H, 5.24%; N, 8.09%. Found: C, 72.52%;
H, 5.11%; N, 8.31%.
4.1. General information
All compounds were fully characterized by spectroscopic
data. The NMR spectra were recorded on a Bruker Avance III
(1H: 400 MHz, 13C: 100 MHz,), chemical shifts (δ) are
expressed in ppm, and J values are given in Hz, and CDCl3 was
used as solvent. The reactions were monitored by thin layer
chromatography (TLC) using silica gel GF254. All chemicals
and solvents were used as received without further purification
unless otherwise stated. Elemental analysis was carried out with a
Yanaco Chncorder MT-3 analyzer (Japan).
4.2.5.
2-phenyl-3-(p-tolylthio)-6-(trifluoromethyl)imidazo[1,2-
a]pyridine 3e
eluent: 30% EtOAc/PE, Beige solid, mp: 161-162 °C, yield 78%
1
(149 mg). H NMR (400 MHz, CDCl3) δ = 8.59-8.75 (m, 1H),
8.19-8.37 (m, 2H), 7.82 (d, J = 9.3 Hz, 1H), 7.33-7.54 (m, 4H),
7.04 (d, J = 8.0 Hz, 2H), 6.92-6.99 (m, 2H), 2.26 (s, 3H) ppm. 13C
NMR (100 MHz, CDCl3) δ = 152.6, 146.7, 136.8, 132.7, 130.5,
129.2, 128.6, 128.5, 126.4, 124.8, 123.5 (q, J = 5.6 Hz), 122.5 (q,
J = 2.9 Hz), 122.2, 118.4, 117.5 (q, J = 34.1 Hz), 109.4, 20.9
ppm. Anal. calcd for C21H15F3N2S: C, 65.61%; H, 3.93%; N,
7.29%. Found: C, 65.42%; H, 3.61%; N, 7.52%.
4.2. General procedure for preparation of targeted molecules
A mixture of imidazoheterocycles 1 (0.5 mmol), thiophenol 2
(0.75 mmol), TBHP (1.5 mmol) and KI (0.5 mmol) in water (2
mL) was stirred at room temperature for 6 h. After the reaction
was finished, the mixture was extracted with EtOAc (3 × 15 mL)
and then the combined organic extracts were washed with brine
(15 mL), dried over sodium sulfate, and filtered. The solvent was
removed under reduced pressure and the residue was purified by
flash column chromatography to give compound 3-4
4.2.6. 6-bromo-2-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine 3f
eluent: 10% EtOAc/PE, white solid, mp: 172-173 °C, yield 70%
1
(138 mg). H NMR (400 MHz, CDCl3) δ = 8.17-8.24 (m, 2H),
4.2.1. 2-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine 3a
8.07-8.14 (m, 1H), 7.87-7.92 (m, 1H), 7.41-7.48 (m, 2H), 7.34-
7.41 (m, 1H), 6.98-7.07 (m, 2H), 6.84-6.97 (m, 3H), 2.26 (s, 3H)
ppm. 13C NMR (100 MHz, CDCl3) δ = 151.8, 147.0, 136.4, 133.1,
131.0, 130.4, 128.9, 128. 6, 128.4, 126.1, 124.9, 120.7, 119.9,
117.0, 107.7, 21.0 ppm. Anal. calcd for C20H15BrN2S: C, 60.77%;
H, 3.82%; N, 7.09%. Found: C, 60.62%; H, 3.58%; N, 6.92%.
eluent: 20% EtOAc/PE, white solid, mp: 140-142 °C, yield 92%
(145 mg). H NMR (400 MHz, CDCl3) δ = 8.24-8.27 (m, 3 H),
1
7.71-7.73 (m, 1 H), 7.43-7.46 (m, 2 H), 7.35-7.39 (m, 1 H), 7.26-
7.31 (m, 1 H), 7.81 (d, J = 8 Hz, 2 H), 6.91-6.93 (m, 2 H), 5.80-
5.83 (m, 1 H), 2.24 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3) δ
= 151.2, 147.1, 136.1, 133.5, 131.6, 130.2, 128.6, 128.4, 128.3,
126.6, 125.9, 124.5, 117.7, 113.0, 106.9, 20.9 ppm. Anal. calcd
for C20H16N2S: C, 75.92%; H, 5.10%; N, 8.85%. Found: C,
75.56%; H, 4.96%; N, 8.96%.
4.2.7. 6-chloro-2-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine
3g
eluent: 16% EtOAc/PE, white solid, mp: 158-159 °C, yield 82%
(143 mg). 1H NMR (400 MHz, CDCl3) δ = 8.19-8.26 (m, 1H),
8.06-8.14 (m, 2H), 7.50-7.60 (m, 1H), 7.30-7.38 (m, 2H), 7.26-
7.30 (m, 1H), 7.13-7.21 (m, 1H), 6.91-6.97 (m, 2H), 6.78-6.85
(m, 2H), 2.17 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3) δ =
152.0, 145.4, 136.5 133.1, 131.0, 130.5, 128.9, 128.6, 128.4,
128.1, 126.1, 122.6, 121.6, 118.1, 108.0, 21.0 ppm. Anal. calcd
4.2.2. 7-methyl-2-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine
3b
eluent: 20% EtOAc/PE, white solid, mp: 132-133 °C, yield 91%
1
(150 mg). H NMR (400 MHz, CDCl3) δ = 8.18-8.20 (m, 2 H),
8.13 (d, J = 8 Hz, 1 H), 7.48 (s, 1 H), 7.41-7.45 (m, 2 H), 7.34-

for C20H15ClN2S: C, 68.47%; H, 4.31%; N, 7.98%. Found: C,
68.40%; H, 4.01%; N,7.64%.
4.2.13. 2-(4-methoxyphenyl)-3-(p-tolylthio)imidazo[1,2-a]pyridi
ne 3m
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4.2.8. 6-bromo-7-methyl-2-phenyl-3-(p-tolylthio)imidazo[1,2-a]
pyridine 3h
eluent: 20% EtOAc/PE, white solid, mp: 161-162 °C, yield 84%
(145 mg). H NMR (400 MHz, CDCl3) δ = 8.26 (d, J = 8 Hz, 1
1
H), 8.18 (d, J = 8 Hz, 2 H), 7.72 (d, J = 12 Hz, 1 H), 7.31 (t, J =
8 Hz, 1 H), 7.01 (d, J = 8 Hz, 2 H), 6.97 (d, J = 8 Hz, 2 H), 6.90
(d, J = 8 Hz, 2 H), 6.84 (t, J = 8 Hz, 1 H), 3.83 (s, 3 H), 2.25 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3) δ = 160.1, 151.1, 147.0,
136.1, 131.7, 130.3, 129.8, 126.7, 126.0, 125.8, 124.5, 117.4,
114.0, 113.0, 106.0, 55.4, 21.0 ppm. Anal. calcd for C21H18N2OS:
C, 72.80%; H, 5.24%; N, 8.09%. Found: C, 72.56%; H, 5.05%; N,
7.84%.
eluent: 15% EtOAc/PE, white solid, mp: 169-170 °C, yield 67%
(137 mg). H NMR (400 MHz, CDCl3) δ = 8.43 (s, 1H), 8.14-
1
8.25 (m, 2H), 7.56 (s, 1H), 7.43 (m, 2H), 7.33-7.39 (m, 1H), 7.03
(d, J = 8.1 Hz, 2H), 6.87-6.95 (m, 2H), 2.48 (s, 3H), 2.27 (s, 3H)
ppm. 13C NMR (100 MHz, CDCl3) δ = 151.7, 146.4, 137.7, 136.3,
133.2, 131.4, 130.4, 128.8, 128.6, 128.4, 126.0, 124.7, 116.9,
112.1, 106.5, 22.9, 21.0 ppm. Anal. calcd for C21H17BrN2S: C,
61.62%; H, 4.19%; N, 6.84%. Found: C, 61.42%; H, 4.41%; N,
6.61%.
4.2.14. 2-(3-nitrophenyl)-3-(p-tolylthio)imidazo[1,2-a]pyridine
3n
4.2.9. 4-(7-methyl-3-(p-tolylthio)imidazo[1,2-a]pyridin-2-yl) ben
zonitrile 3i
eluent: 25% EtOAc/PE, yellow solid, mp: 135-136 °C, yield
76% (137 mg). H NMR (400 MHz, CDCl3) δ = 9.15 (t, J = 2.0
1
eluent: 20% EtOAc/PE, white solid, mp: 201-202 °C, yield 80%
Hz, 1H), 8.51-8.68 (m, 1H), 8.28-8.36 (m, 1H), 8.11-8.25 (m,
1H), 7.69-7.81 (m, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.29-7.43 (m,
1H), 7.01 (d, J = 8.0 Hz, 2H), 6.79-6.96 (m, 3H), 2.24 (s, 3H)
ppm. 13C NMR (100 MHz, CDCl3) δ = 148.5, 148.2, 147.1, 136.7,
135.3, 134.1, 130.7, 130.4, 129.4, 127.3, 126.3, 124.7, 123.3,
123.1, 117.9, 113.7, 108.5, 21.0 ppm. Anal. calcd for
C20H15N3O2S: C, 66.47%; H, 4.18%; N, 11.63%. Found: C,
66.32%; H, 4.39%; N, 11.82%.
1
(142 mg). H NMR (400 MHz, CDCl3) δ = 8.35 (d, J = 8 Hz, 2
H), 8.13 (d, J = 8 Hz, 1 H), 7.68 (d, J = 8 Hz, 2 H), 7.46 (s, 1 H),
7.02 (d, J = 8 Hz, 2 H), 6.87 (d, J = 8 Hz, 2 H), 6.71-6.73 (m, 1
H), 2.43 (s, 3 H), 2.25 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3)
δ = 148.6, 147.6, 138.6, 138.2, 136.5, 132.2, 131.0, 130.4, 128.7,
125.9, 123.8, 119.1, 116.4, 116.3, 111.6, 107.7, 21.5, 21.0 ppm.
Anal. calcd for C22H17N3S: C, 74.34%; H, 4.82%; N, 11.82%.
Found: C, 74.12%; H, 4.91%; N, 11.61%.
4.2.15. 4-(3-(p-tolylthio)imidazo[1,2-a]pyridin-2-yl)benzonitrile
3o
4.2.10. 2-(4-methoxyphenyl)-7-methyl-3-(p-tolylthio)imidazo[1,2-
a]pyridine 3j
eluent: 20% EtOAc/PE, white solid, mp: 172-173 °C, yield 78%
(133 mg). H NMR (400 MHz, CDCl3) δ = 8.35-8.42 (m, 2H),
1
eluent: 20% EtOAc/PE, white solid, mp: 91-92 °C, yield 82%
(147 mg). 1H NMR (400 MHz, CDCl3) δ = 8.14-8.16 (m, 2 H),
8.11 (d, J = 8 Hz, 1 H), 7.47 (s, 1 H), 7.00 (d, J = 8 Hz, 2 H),
6.95 (d, J = 8 Hz, 2 H), 6.89 (d, J = 8 Hz, 2 H), 6.66 (d, J = 8 Hz,
1 H), 3.82 (s, 3 H), 2.41 (s, 3 H), 2.25 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3) δ = 160.0, 150.8, 147.3, 138.0, 135.9, 132.0,
130.2, 129.7, 126.1, 125.7, 123.7, 115.9, 115.6, 113.9, 105.1,
55.3, 21.5, 21.0 ppm. Anal. calcd for C22H20N2OS: C, 73.30%; H,
5.59%; N, 7.77%. Found: C, 73.63%; H, 5.85%; N, 7.59%.
8.27-8.34 (m, 1H), 7.67-7.77 (m, 3H), 7.30-7.44 (m, 1H), 7.03 (d,
J = 8.1 Hz, 2H), 6.81-6.97 (m, 3H), 2.26 (s, 3H) ppm. 13C NMR
(100 MHz, CDCl3) δ = 148.8, 147.2, 138.0, 136.6, 132.3, 130.7,
130.5, 128.8, 127.4, 126.0, 124.7, 119.1, 118.0, 113.7, 111.8,
108.6, 21.0 ppm. Anal. calcd for C21H15N3S: C, 73.87%; H,
4.43%; N, 12.31%. Found: C, 73.62%; H, 4.72%; N, 12.52%.
4.2.16. 2-(4-chlorophenyl)-3-(p-tolylthio)imidazo[1,2-a]pyridine
3p
4.2.11. 2-methyl-3-(p-tolylthio)imidazo[1,2-a]pyridine 3k
eluent: 15% EtOAc/PE, white solid, mp: 131-132 °C, yield 82%
(143 mg). H NMR (400 MHz, CDCl3) δ = 8.22-8.29 (m, 1H),
1
eluent: 30% EtOAc/PE, white solid, mp: 102-103 °C, yield 58%
(73 mg). H NMR (400 MHz, CDCl3) δ = 8.14 (d, J = 6.8 Hz,
1
8.15-8.22 (m, 2H), 7.65-7.74 (m, 1H), 7.35-7.43 (m, 2H), 7.25-
7.34 (m, 1H), 7.00 (d, J = 8.0 Hz, 2H), 6.86-6.92 (m, 2H), 6.79-
6.87 (m, 1H), 2.24 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3) δ =
149.9, 147.0, 136.3, 134.5, 132.0, 131.2, 130.3, 129.6, 128.7,
126.8, 125.9, 124.6, 117.6, 113.2, 107.1, 20.9 ppm. Anal. calcd
for C20H15ClN2S: C, 68.47%; H, 4.31%; N, 7.98%. Found: C,
68.22%; H, 4.53%; N, 7.73%.
1H), 7.58 (d, J = 8.9 Hz, 1H), 7.20-7.29 (m, 1H), 6.98 (d, J = 8.0
Hz, 2H), 6.71-6.88 (m, 3H), 2.56 (s, 3H), 2.22 (s, 3H) ppm. 13C
NMR (100 MHz, CDCl3) δ = 151.1, 146.7, 136.1, 131.8, 130.1,
126.3, 126.2, 124.5, 116.9, 112.8, 108.3, 20.9, 14.0 ppm. Anal.
calcd for C15H14N2S: C, 70.83%; H, 5.55%; N, 11.01%. Found: C,
73.62%; H, 5.84%; N, 11.32%.
4.2.12. 2-methyl-3-(p-tolylthio)imidazo[1,2-a]pyridine 3l
4.2.17. 2-phenyl-3-(phenylthio)imidazo[1,2-a]pyridine 3q
eluent: 20% EtOAc/PE, white solid, mp: 140-141 °C, yield 84%
(138 mg). H NMR (400 MHz, CDCl3) δ = 8.16-8.28 (m, 1H),
eluent: 20% EtOAc/PE, white solid, mp: 107-108 °C, yield 85%
(128 mg). 1H NMR (400 MHz, CDCl3) δ = 8.22-8.25 (m, 3 H),
7.73 (d, J = 8 Hz, 1 H), 7.42-7.45 (m, 2 H), 7.35-7.39 (m, 1 H),
7.27-7.32 (m, 1 H), 7.17-7.21 (m, 2 H), 7.09-7.13 (m, 1 H), 6.99-
7.01 (m, 2 H), 6.80-6.83 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3) δ = 151.4, 147.1, 135.2, 133.4, 129.5, 128.6, 128.4, 128.3,
126.7, 126.1, 125.5, 124.5, 117.6, 113.1, 106.3 ppm. Anal. calcd
for C19H14N2S: C, 75.47%; H, 4.67%; N, 9.26%. Found: C,
75.77%; H, 4.80%; N, 9.58%.
1
8.08 (d, J = 7.9 Hz, 2H), 7.53-7.76 (m, 1H), 7.21-7.25 (m, 1H),
7.20 (d, J = 7.8 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.2
Hz, 2H), 6.77 (t, J = 6.7 Hz, 1H), 2.33 (s, 3H), 2.19 (s, 3H) ppm.
13C NMR (100 MHz, CDCl3) δ = 151.4, 147.1, 138.5, 136.0,
131.7, 130.7, 130.2, 129.2, 128.3, 126.5, 125.9, 124.5, 117.6,
113.0, 106.5, 21.4, 21.0 ppm. Anal. calcd for C21H18N2S: C,
76.33%; H, 5.49%; N, 8.48%. Found: C, 76.62%; H, 5.64%; N,
8.32%.
4.2.18. 3-((4-methoxyphenyl)thio)-2-phenylimidazo[1,2-a]pyrid
ine 3r

8
eluent: 20% EtOAc/PE, white solid, mp: 125-126 °C, yield 81% (s, 3 H), 2.38 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3) δ =
ACCEPTED MANUSCRIPT
1
(134 mg). H NMR (400 MHz, CDCl3) δ = 8.30-8.32 (m, 1 H),
8.24-8.26 (m, 2 H), 7.69-7.72 (m, 1 H), 7.43-7.47 (m, 2 H), 7.36-
7.40 (m, 1 H), 7.28-7.32 (m, 1 H), 6.97-7.01 (m, 2 H), 6.84-6.87
(m, 1 H), 6.73-6.77 (m, 2 H), 3.71 (m, 3 H) ppm. 13C NMR (100
MHz, CDCl3) δ = 158.7, 151.0, 147.0, 133.6, 128.6, 128.5, 128.1,
126.6, 125.6, 124.6, 117.7, 115.3, 113.1, 107.9, 55.4 ppm. Anal.
calcd for C20H16N2OS: C, 72.26%; H, 4.85%; N, 8.43%. Found:
C, 72.35%; H, 4.77%; N, 8.25%.
159.9, 151.1, 147.4, 137.8, 135.6, 129.6, 129.4, 126.0, 125.9,
125.4, 123.5, 115.9, 115.5, 113.8, 104.4, 55.2, 21.4 ppm. Anal.
calcd for C21H18N2OS: C, 72.80%; H, 5.24%; N, 8.09%. Found:
C, 72.63%; H, 4.99%; N, 8.25%.
4.2.24. 6-phenyl-5-(p-tolylthio)imidazo[2,1-b]thiazole 4a
eluent: 11% EtOAc/PE, white solid, mp: 101-102 °C, yield 84%
(139 mg). H NMR (400 MHz, CDCl3) δ = 8.14-8.16 (m, 2 H),
1
7.39-7.43 (m, 2 H), 7.31-7.37 (m, 2 H), 6.98-7.05 (m, 4 H), 6.75-
6.77 (m, 1 H), 2.27 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3) δ
= 152.2, 151.2, 136.1, 133.6, 132.1, 130.2, 128.4, 128.1, 127.5,
4.2.19. 3-((4-chlorophenyl)thio)-2-phenylimidazo[1,2-a]pyridine
3s
eluent: 20% EtOAc/PE, white solid, mp: 165-166 °C, yield 74% 126.2, 118.0, 112.9, 108.4, 20.9 ppm. Anal. calcd for C18H14N2S2:
1
(124 mg). H NMR (400 MHz, CDCl3) δ = 8.23-8.24 (m, 1 H),
8.16-8.19 (m, 2 H), 7.72-7.75 (m, 1 H), 7.42-7.46 (m, 2 H), 7.32-
7.40 (m, 2 H), 7.15-7.18 (m, 2 H), 6.86-6.93 (m, 3 H) ppm. 13C
NMR (100 MHz, CDCl3) δ = 151.7, 147.3, 133.9, 133.3, 132.2,
129.7, 128.8, 128.6, 128.4, 126.9, 124.4, 117.9, 113.4, 105.8 ppm.
Anal. calcd for C19H13ClN2S: C, 67.75%; H, 3.89%; N, 8.32%.
Found: C, 67.55%; H, 4.10%; N, 8.21%.
C, 67.05%; H, 4.38%; N, 8.69%. Found: C, 67.28%; H, 4.25%; N,
8.76%.
4.2.25. 6-phenyl-5-(phenylthio)imidazo[2,1-b]thiazole 4b
eluent: 11% EtOAc/PE, white solid, mp: 130-131 °C, yield 82%
1
(126 mg). H NMR (400 MHz, CDCl3) δ = 8.13-8.15 (m, 2 H),
7.35-7.43 (m, 2 H), 7.31-7.36 (m, 2 H), 7.21-7.26 (m, 2 H), 7.12-
7.16 (m, 1 H), 7.06-7.08 (m, 2 H), 6.78 (d, J = 4 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3) δ = 152.5, 151.4, 135.8, 133.5,
129.4, 128.4, 128.2, 127.5, 126.1, 125.8, 118.0, 113.0, 107.7 ppm.
4.2.20. 3-((4-fluorophenyl)thio)-2-phenylimidazo[1,2-a]pyridine
3t
eluent: 20% EtOAc/PE, white solid, mp: 123-124 °C, yield 76% Anal. calcd for C17H12N2S2: C, 66.20%; H, 3.92%; N, 9.08%.
1
(121 mg). H NMR (400 MHz, CDCl3) δ = 8.21-8.27 (m, 3 H),
7.71-7.73 (m, 1 H), 7.43-7.47 (m, 2 H), 7.36-7.40 (m, 1 H), 7.29-
7.34 (m, 1 H), 6.95-7.00 (m, 2 H), 6.84-6.93 (m, 3 H) ppm. 13C
NMR (100 MHz, CDCl3) δ = 162.8, 160.4, 151.4, 147.2, 133.3,
130.2 (d, JC-F = 3.1), 128.8, 128.5, 128.4, 127.7 (d, JC-F = 7.9),
126.8, 124.4, 117.8, 116.8 (d, JC-F = 22.3), 113.2, 106.7 ppm.
Anal. calcd for C19H13FN2S: C, 71.23%; H, 4.09%; N, 8.74%.
Found: C, 71.45%; H, 4.29%; N, 8.98%.
Found: C, 66.28%; H, 3.74%; N, 8.86%.
4.2.26. 2-phenyl-3-(phenylthio)benzo[d]imidazo[2,1-b]thiazole
4c
eluent: 12% EtOAc/PE, white solid, mp: 149-151 °C, yield 88%
1
(157 mg). H NMR (400 MHz, CDCl3) δ = 8.24-8.35 (m, 1H),
8.02-8.13 (m, 2H), 7.62-7.70 (m, 1H), 7.36-7.42 (m, 2H), 7.27-
7.35 (m, 3H), 7.20-7.26 (m, 2H), 7.08-7.17 (m, 3H) ppm. 13C
NMR (100 MHz, CDCl3) δ = 153.8, 150.9, 136.6, 133.6, 133.3,
130.3, 129.7, 128.5, 128.5, 127.9, 126.5, 126.3, 125.8, 125.1,
124.1, 114.5, 110.1 ppm. Anal. calcd for C12H14N2S2: C, 70.36%;
H, 3.94%; N, 7.81%. Found: C, 70.27%; H, 3.79%; N, 7.66%.
4.2.21. 2-(4-methoxyphenyl)-3-((4-nitrophenyl)thio)imidazo[1,2-
a]pyridine 3u
eluent: 20% EtOAc/PE, yellow solid, mp: 162-163 °C, yield
68% (114 mg). H NMR (400 MHz, CDCl3) δ = 8.15-8.17 (m, 1
1
4.2.27. 3-((4-chlorophenyl)thio)-2-phenylbenzo[d]imidazo[2,1-b]
thiazole 4d
H), 8.01-8.07 (m, 4 H), 7.71-7.73 (m, 1 H), 7.33-7.37 (m, 1 H),
7.04 (d, J = 8 Hz, 2 H), 6.87-6.94 (m, 3 H), 3.79 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3) δ = 160.3, 152.2, 147.6, 146.0,
145.2, 129.6, 127.3, 125.4, 125.2, 124.6, 124.1, 117.7, 114.0,
113.5, 102.6, 55.3 ppm. Anal. calcd for C20H15N3O3S: C, 63.65%;
H, 4.01%; N, 11.13%. Found: C, 63.48%; H, 4.24%; N, 11.26%.
eluent: 12% EtOAc/PE, white solid, mp: 167-168 °C, yield 81%
1
(159 mg). H NMR (400 MHz, CDCl3) δ = 8.27-8.29 (m, 1 H),
8.06-8.08 (m, 2 H), 7.68-7.70 (m, 1 H), 7.40-7.44 (m, 2 H), 7.29-
7.38 (m, 3 H), 7.19-7.23 (m, 2 H), 7.07-7.10 (m, 2 H) ppm. 13C
NMR (100 MHz, CDCl3) δ = 154.0, 151.1, 135.2, 133.4, 133.1,
132.2, 130.3, 129.9, 130.3, 129.9, 128.6, 128.5, 127.9, 126.9,
126.5, 125.2, 124.2, 114.3, 109.4 ppm. Anal. calcd for
4.2.22. 2-(4-methoxyphenyl)-3-(phenylthio)imidazo[1,2-a]pyrid
ine 3v
eluent: 20% EtOAc/PE, white solid, mp: 109-110 °C, yield 79% C21H13ClN2S2: C, 64.19%; H, 3.34%; N, 7.13%. Found: C,
(131 mg). 1H NMR (400 MHz, CDCl3) δ = 8.16-8.19 (m, 3 H),
7.68 (d, J = 8 Hz, 1 H), 7.21-7.25 (m, 1 H), 7.13-7.17 (m, 2 H),
7.05-7.09 (m, 1 H), 6.92-6.98 (m, 4 H), 6.73-6.76 (m, 1 H), 3.76
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3) δ = 159.9, 151.1,
146.9, 135.2, 129.5, 129.3, 126.5, 125.9, 125.8, 125.4, 124.3,
117.2, 113.8, 112.8, 105.2, 55.1 ppm. Anal. calcd for
C20H16N2OS: C, 72.26%; H, 4.85%; N, 8.43%. Found: C, 72.53%;
H, 4.98%; N, 8.29%.
64.26%; H, 3.70%; N, 7.26%.
4.3. The procedure of recycling aqueous solution and large-scale
operation
After completion of the reaction, the reaction medium was
extracted with EtOAc (3 × 50 mL) and reused in the next run
directly. To the recylced aqueous solution, 2-phenylimidazo[1,2-
a]pyridine 1a (5 mmol), 4-methylbenzenethiol 2a (7.5 mmol),
TBHP (15 mmol) and KI (5 mmol) was added, and the reaction
was stirred at room temperature for 6 h.
4.2.23. 2-(4-methoxyphenyl)-7-methyl-3-(phenylthio)imidazo[1,
2-a]pyridine 3w
eluent: 20% EtOAc/PE, white solid, mp: 109-110 °C, yield 82%
(142 mg). 1H NMR (400 MHz, CDCl3) δ = 8.11-8.15 (m, 2 H),
8.07 (d, J = 8 Hz, 1 H), 7.45-7.49 (m, 1 H), 7.15-7.19 (m, 2 H),
7.07-7.11 (m, 1 H), 6.91-6.98 (m, 4 H), 6.61-6.63 (m, 1 H), 3.79
Acknowledgments

Wang, X.; Lin, Q. Chinese J. Struct. Chem. 2016, 35, 1849; (d) Li,
We are thankful for the financial supportAfrComCtEhePNTaEtuDral MANUSCRIPT
G.; Wu, M.; Kong, D.; Liu, R.; Zhou, X.; Liu, F. New J. Chem. 2014,
38, 3350; (e) Kong, D.; Wang, X.; Shi, Z.; Wu, M.; Lin, Q.; Wang,
X. J Chem Res. 2016, 40, 529.
9 (a) Li, B.; Chen, Z.; Cao, H.; Zhao, H. Org Lett 2018, 20, 3291; (b)
Siddaraju, Y.; Prabhu, K. R. J. Org. Chem. 2016, 81, 7838.
Science Foundation of Hainan Province of China (No: 20162033)
and the Cultivation Research Foundation of Hainan Medical
University (HY2015-02).
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