Copper-catalyzed synthesis of benzo[b]thiophene-fused imidazopyridines via the cleavage of C-H bond and C-X bond

Article abstract of DOI:10.1016/j.tetlet.2015.12.091

A new and straightforward approach to synthesize benzo[b]thiophene-fused imidazopyridines has been developed by tandem cross-coupling reaction of K₂S with 2-(2-bromophenyl)imidazo[1,2-a]pyridines, and K₂S as sulfur source constructed

Full text of DOI:10.1016/j.tetlet.2015.12.091

Accepted Manuscript
Copper-catalyzed synthesis of benzo[b]thiophene-fused imidazopyridines via
the cleavage of C-H bond and C-X bond
Hui Huang, Pan Dang, Lijun Wu, Yun Liang, Jianbing Liu
PII:
S0040-4039(15)30507-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.091
TETL 47138
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 October 2015
7 December 2015
23 December 2015
Please cite this article as: Huang, H., Dang, P., Wu, L., Liang, Y., Liu, J., Copper-catalyzed synthesis of
benzo[b]thiophene-fused imidazopyridines via the cleavage of C-H bond and C-X bond, Tetrahedron Letters (2015),
doi: http://dx.doi.org/10.1016/j.tetlet.2015.12.091
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Copper-catalyzed synthesis of
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benzo[b]thiophene-fused imidazopyridines
via the cleavage of C-H bond and C-X bond
Hui Huang, Pan Dang, Lijun Wu, Yun Liang*
and Jianbing, Liu*

1
Tetrahedron Letters
Copper-catalyzed synthesis of benzo[b]thiophene-fused imidazopyridines via the cleavage of C-H bond
and C-X bond
Hui Huang, Pan Dang, Lijun Wu, Yun Liang* and Jianbing, Liu*
Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research, Ministry of Education, Key Laboratory of the Assembly and Application of
Organic Functional Molecules, Hunan Normal University, Changsha, Hunan 410081, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new and straightforward approach to synthesize benzo[b]thiophene-fused imidazopyridines has been
developed by tandem cross-coupling reaction of K2S with 2-(2-bromophenyl)imidazo[1,2-a]pyridines,
which K2S as sulfur source constructed double C-S bonds via the cleavage of C-H bond and C-X bond.
In addition, the optical properties of a library of benzo[b]thiophene-fused imidazopyridines were for the
first time fully characterized. Moreover, this synthetic strategy could be applied in preparation of
benzo[b]thiophene-fused indoles.
Available online
Keywords:
K2S
2015 Elsevier Ltd. All rights reserved.
Copper
Benzo[b]thiophene-fused
Imidazopyridines
Benzo[b]thiophene-fused indoles
As an important class of heteroaromatic ring systems,
benzo[b]thiophenes have found widespread application in many
biologically active compounds and organic materials.11 In
addition, the derivatives of aza-heterocyclics have shown
interesting biological activities and have been found in many
drugs,12 and they are also potentially used in material science as
charge transporters.13 With this background, we believe that
fusion of such two classes of heterocycles into a single frame will
have new and interesting properties. As a part of our continuous
efforts for the synthesis of novel heterocycles containing
benzo[b]thiophenes,14 herein we wish to report an unexpected
ligand-free inexpensive copper-catalyzed cascade reaction of 2-
(2-bromophenyl)imidazo[1,2-a]pyridine with easily available
potassium sulfide leading to novel benzothiophene-fused
imidazopyridines.
Transition metal-catalyzed C-S bond cross-coupling
reaction presents one of the most useful methods in the synthesis
of natural products, pharmaceuticals, and materials.1 In
particular, the traditional coupling of C-X (X = Cl, Br, I, OTf)
bonds with sulfides under metal-catalyzed conditions is of utmost
importance in construction of C-S bond (Scheme 1, a).2
Compared with the traditional coupling, the atom-economic
sulfuration via C-H functionalization became known only until
recently (Scheme 1, b).3-8 In these methods, various sulfides such
as disulfides,4 thiols,5 sodium sulfinates,6 sulfonyl hydrazides7
and arylsulfonyl chlorides8 are needed as coupling partners for
the reaction. However, despite their usefulness in forming C–S
bonds, these methods have significant limitations, requiring
either the implementation of metal–ligand combination or highly
pre-functionalized precursors, suffering from difficulties in
preparation of starting sulfur-containing materials.9 Recently, we
developed an efficient protocol for the synthesis of
benzothiazoles via copper-catalyzed the traditional coupling and
the oxidative coupling reaction from easily available potassium
sulfide and N-benzyl-2-iodoanilines.10 The nontoxic, odorless,
and readily available metal sulfides should be a desired sulfur
sources for the coupling partners. Encouraged by these results,
we envisioned that the metal sulfides could be used to construct
double C-S bonds, which the metal sulfides as sulfur source
constructed double C-S bonds via the cleavage of C-H bond and
C-X (X = Br or I) bond. (Scheme 1). To the best of our
knowledge, the direct double sulfuration of C(sp2)-X bond and
C(sp2)–H bond from metal sulfides as sulfur source has not been
reported previously.
Scheme 1 Method for Construction of C-S Bond
In this work, 2-(2-bromophenyl)imidazo[1,2-a]pyridine (1a)
as the model substrate, was treated with K2S to obtain the optimal
reaction conditions, and the screening results are compiled in
Table 1. Our investigation started by an attempted sulfuration of
substrate 1a with K2S in DMF at 140 oC in the presence of CuI as
the catalyst and air as the oxidant, and the desired product 2a was
isolated in 40% yield (entry 1). The product yield decreased to
----------------
* Corresponding author.
E-mail address: yliang@hunnu.edu.cn (Y. Liang);
1485192973@qq.com (J. Liu)

2
Tetrahedron Letters
21% when the reaction was performed under nitrogen
bromophenyl)-6-phenylimidazo[1,2-a]pyridine could react with
K2S and afford the expected product in 83% yield (2j).
Importantly, 2-(2-bromophenyl)-6-(phenylethynyl)imidazo[1,2-
a]pyridine and 2-(2-bromophenyl)imidazo[1,2-a]quinoline were
also tolerated in this transformation generating corresponding 2k
and 2l in 63% and 95% yield. Then, we also evaluated effects of
the substituent on the benzene ring. Compared with the yields of
unsubstituted 2a, the desired products bearing the electron-
withdrawing groups such as fluoro and chloro on the benzene
rings, were obtained in a lower yields. However, 2o well-
tolerated under the same conditions and proceeded with superior
efficiency. Finally, we investigated the effects of chloro
substituents on 2-phenylimidazo[1,2-a]pyridine. As expected,
moderate yield (46%) was observed when 2-(2-
chlorophenyl)imidazo[1,2-a]pyridine was applied.
atmosphere (entry 2), and increased to 59% when oxygen was
used as the oxidant (entry 3). However, these results were not
satisfactory. Subsequently, further investigation of other oxidants
such as PhI(OAc)2, DDQ, 1,4-benzoquinone, I2 indicated that I2
was superior to the others (entries 4−7). When the reaction was
performed under nitrogen atmosphere, the yields of the target
product 2a decreased slightly (entry 8). Then, we explored other
copper catalysts, such as CuBr and CuCl, but the product yields
decreased slightly (entries 9−10). Other solvents such as DMSO
and NMP were examined and showed lower efficiency (entries
11−12). Finally, relatively low yields were found when we
reduced the amount of catalyst and oxidant or decreased
temperature in the reaction (entries 13-16). Thus, the optimized
reaction conditions were as follows: 1a (0.3 mmol), K2S (0.9
mmol), CuI (20 mol %), I2 (0.3 mmol), in DMF (2 mL) under air
atmosphere at 140 oC.
Table 2 Synthesis of Benzothiophene-fused Imidazopyridines a,b
.
Table 1 Optimization of Reaction Conditionsa
Entry
Catalyst
Oxidant
Solvent Yield 2a (%)b
1
2c
3d
4
5
6
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
CuBr
CuI
CuI
CuI
-
-
-
-
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
NMP
DMF
DMF
DMF
DMF
40
21
59
73
82
49
96
88
94
90
11
42
87
8
PhI(OAc)2
DDQ
1,4-Benzoquinone
7
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
8c
9
10
11
12
13e
14
15f
16g
CuI
CuI
77
56
a Reaction conditions: 1a (0.3 mmol), K2S (0.9 mmol), Cu salt (20
mol %), oxidant (0.3 mmol), solvent (2 mL), under air atmosphere in
sealed Schlenk tube, at 140 oC, for 24 h. b Isolated yields. c Under
nitrogen atmosphere. d Under oxygen atmosphere. e CuI (10 mol %). f
Oxidant (0.15 mmol). g At 120 oC.
a
Reaction conditions: 1 (0.3 mmol), K2S (0.9 mmol), CuI (20 mol
%), I2 (0.3 mmol), DMF (2 mL), under air atmosphere in sealed
After the optimal reaction conditions were established, we
then extended the substrate scope of the cyclization reaction. The
results obtained under the optimized conditions are listed in
Table 2. Initially, a various of imidazo[1,2-a]pyridines bearing
substituents on pyridine rings were screened. The results
demonstrated that both electron-withdrawing and donating
groups were tolerated, and could smoothly transform into the
desired products. Furthermore, a methyl group at different
positions of the imidazo[1,2-a]pyridine did not obviously affect
the efficiency and gave the desired products in 90-96% yield (2b-
2e). It is noteworthy that the reactions of halo-substituted
imidazo[1,2-a]pyridines proceed well and offered the halo-
substituted products, which could be used for further
modification (2f-2h). For example, bromo-substituted target
product 2h was obtained in 61% yield. Unluckily, the ester group
substituted 2i was obtained only in 27% yield. In addition, 2-(2-
b
c
Schlenk tube, at 140 oC for 24 h. Isolated yields. DDQ instead of
I2. d 2-(2-Chlorophenyl)imidazo[1,2-a]pyridine was applied.
The successful synthesis of
a
small library of
benzo[4',5']thieno[3',2':4,5]imidazo[1,2-a]pyridine and their π-
expanded analogs gave us an excellent opportunity for measuring
their photophysical properties for the first time. Among the
benzo[b]thiophene-fused imidazopyridines presented here, 2l was
found to exhibit the highest fluorescence quantum yield.
Substitution with a heavy atom (bromo-derivative 2h), according
to expectations, led to a further decrease in fluorescence
intensity. The spectroscopic data collected for compounds 2a, 2l,
2h and 2k are shown in table 3, figure 1. Comparison of the
properties of compounds 2a, 2l and 2h with unsubstituted
imidazo[1,2- a]pyridine (IP) led to a conclusion that fusion with
a benzo[b]thiophene scaffold results in 30–40 nm and 39–46 nm

3
bathochromic shift of absorption and emission maxima,
respectively. While, 70 nm bathochromic shift of emission
maxima was found at 2k.
To elucidate the reaction mechanism, two control
experiments were conducted (Scheme 2). First, iodinated product
5 was obtained in 68% in the reaction of 1a with I2 (1 equiv) and
CuI (20 mol%) (Eq. 1). Then, the reaction of the iodinated
product 5 with K2S (3 equiv) was performed in the absence of I2,
and the target product 2a (57%) together with deiodinated
product 1a (38%) were found (Eq. 2). These results suggested
that iodinated product 5 should not be a dominating intermidate
in this reaction because of the depressed yields. Furthermore,
under the standard reaction conditions, the iodinated product 5
was not probed from crude reaction mixtures of the reaction of 2-
(2-bromophenyl)imidazo[1,2-a]pyridine (1a) with K2S by using
GC-MS analysis.
Table
3
Spectroscopic Properties of Benzothiophene-fused
Imidazopyridines a
b
Compd Absmax
(nm)
ε (×10−3
Emissionmax Stokes
Φfl
M−1 cm−1)
(nm)
shift
(cm−1)
4800
4640
IPc
318
376
415
255
32.9
9.06
37.2
14.4
30.6
30.4
8.43
42.7
0.311d
0.344d
0.026e
2a
348
249
421
422
4740
4240
2l
351
242
2h
259
358
299
446
1100
0.192f
2k
a Measured in DCM. Measured with quinine sulphate as a standard.
c IP = unsubstituted imidazo[1,2-a]pyridine (data taken from ref. 15).
d Excited at 344 nm. e Excited at 351 nm. f Excited at 305 nm.
b
Scheme 2 Control Experiments.
According to the present results and previous reports2-8, a
reaction mechanism with two possible pathways for the cascade
reaction that leads to the formation of the benzo[b]thiophene ring
is shown in Scheme 3. For Path I, the copper catalyzed coupling
reaction of 2-(2-bromophenyl)imidazo[1,2-a]pyridine with K2S
provides the intermediate A firstly. Then A reacts with I2 to form
an electrophilic species B, which can attack to imidazo[1,2-
a]pyridine to give an intermediate C. Finally, the intermediate C
gives the desired product via deprotonation. For Path II, the
substrate 2-(2-bromophenyl)imidazo[1,2-a]pyridine undergoes a
iodination process firstly. Then, a copper-catalyzed double C-S
bonds formation via Ullmann-type S-arylation takes place. Due
to the lower yields of benzo[b]thiophene-fused imidazopyridines
bearing electron-withdrawing groups on the ring of pyridine, the
reaction Path I is more likely. However, the reaction Path II
cannot be ruled out completely.
Figure 1 Normalized fluorescence (bottom) spectra of 2a (black), 2l
(red), 2h (blue) and 2k (green) measured in DCM.
Considering indoles with widespread application in biological
chemistry and material science,16 we decided to further expand
the synthetic strategy to preparation of benzo[b]thiophene-fused
indoles. Fortunately, under similar reaction conditions,
benzo[b]thiophene fused indoles 4 were obtained in 42−83%
yield (Table 4).
Table 4 Synthesis of Benzo[b]thiophene-fused Indoles a,b
Scheme 3 Plausible Mechanism
In summary, we have demonstrated a novel copper-
catalyzed coupling reaction to synthesize benzo[b]thiophene-
fused imidazopyridines and benzo[b]thiophene-fused indoles,
which are potentially used in biologically active compounds and
organic materials. Efforts to extend the applications of the
transformation in organic synthesis as well as screen for
a Reaction conditions: 3 (0.3 mmol), K2S (0.9 mmol), CuI (20 mol
%), I2 (0.3 mmol), DMF (2 mL), under air atmosphere in sealed
Schlenk tube, at 140 oC for 24 h. b Isolated yields. c 2-(2-
bromophenyl)-1H-indole was applied.

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Tetrahedron Letters
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Acknowledgments
This work was supported by the Natural Science Foundation
of China (21072054, 21572051), the Ministry of Education of
China (213027A), the Hunan Provincial Natural Science
Foundation (12JJ2009), and the Scientific Research Fund of
Hunan Provincial Education Department (15A109).
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