Synthesis of 2-substituted benzo[b]thiophene via a Pd-catalyzed coupling of 2-iodothiophenol with phenylacetylene

Article abstract of DOI:10.1039/c6ra26611h

A Pd(ii)-catalyzed Sonogashira type cross-coupling reaction between 2-iodothiophenol and phenylacetylene has been developed. A series of 2-substituted benzo[b]thiophenes were obtained in moderate to good yield (up to 87%). The application of this method was demonstrated by the synthesis of 2-(4-(tert-butyl)phenyl)benzo[b]thiophene 1,1-dioxide and (4-methoxyphenyl)(2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)methanone, which exhibit a fluorescence quantum yield of up to 1 and can be used as a cannabinoid receptor ligand, respectively.

Full text of DOI:10.1039/c6ra26611h

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Synthesis of 2-substituted benzo[b]thiophene via
a Pd-catalyzed coupling of 2-iodothiophenol with
phenylacetylene†
Cite this: RSC Adv., 2017, 7, 7753
a
a
a
Jingwen Chen, Haifeng Xiang, Li Yangab and Xiangge Zhou
*
*
A
Pd(II)-catalyzed Sonogashira type cross-coupling reaction between 2-iodothiophenol and
phenylacetylene has been developed. A series of 2-substituted benzo[b]thiophenes were obtained in
moderate to good yield (up to 87%). The application of this method was demonstrated by the synthesis
of 2-(4-(tert-butyl)phenyl)benzo[b]thiophene 1,1-dioxide and (4-methoxyphenyl)(2-(4-methoxyphenyl)
benzo[b]thiophen-3-yl)methanone, which exhibit a fluorescence quantum yield of up to 1 and can be
used as a cannabinoid receptor ligand, respectively.
Received 10th November 2016
Accepted 9th January 2017
DOI: 10.1039/c6ra26611h
www.rsc.org/advances
reaction of o-bromoalkynylbenzenes with various thiol surro-
gates upon lithium halogen exchange at À78 ꢀC (Scheme 1a)4 or
the annulation of alkynylbenzenes (Scheme 1b).5 While in the
process of reporting this study, a similar study was reported by
Fu and co-workers using the electrophilic cyclization of o-
alkynyl thioanisole (Scheme 1c).6 However, the major obstacles
of these methods are a result of the harsh reaction conditions or
the limitation of the starting materials used.
On the other hand, the Sonogashira cross-coupling reaction7
between aryl or alkenyl halides with terminal alkynes in the
presence of a transition-metal catalyst has become one of the
most powerful methods to prepare alkyl-aryl and diary-
lsubstituted acetylenes.8 In a continuation of our study on
catalytic Sonogashira cross-coupling reaction and synthesis of
sulfur-containing heterocyclic compounds,9 herein we report
Introduction
As a crucial class of heterocyclic compounds, 2-substituted
benzo[b]thiophenes have broad biological properties1 and
diversied applications in the eld of materials science.2 They
are usually considered as important structural motifs in phar-
maceuticals and biologically active molecules. For example, as
shown in Fig. 1, Bi-BTBT, raloxifene, and iPr-BTBT are examples
of commercial drugs and organic semiconductors containing
benzothiophene cores.3
The normal approaches to synthesize 2-substituted benzo[b]
thiophenes are normally focused on a coupling cyclization
Fig. 1 Selected pharmaceutical and biologically active 2-substituted
benzo[b]thiophenes.
aCollege of Chemistry, Sichuan University, Chengdu 610064, P. R. China. E-mail:
zhouxiangge@scu.edu.cn; Fax: +86-28-85412904
bCollege of Chemistry & Chemical Engineering, Yibin University, Yibin 644000, P. R.
China
Scheme
1 Selected examples of the commonly used synthetic
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra26611h
methods to prepare 2-substituted benzo[b]thiophenes.
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the palladium-catalyzed synthesis of 2-substituted benzo[b] and ligand (Entry 9). Furthermore, silver salts were found to be
thiophenes using 2-halothiophenols and phenylacetylenes as benecial to the reaction. In addition, AgTFA was shown to be
starting materials.
the best one with a yield of 71% (Entries 10–12). Moreover, the
ligand was also proved to promote the catalysis by up to 81%
yield in the case of TMEDA (Entries 13–16). Lastly, screening the
reaction temperature and catalyst loading indicated that 110 ꢀC
and 15 mol% catalyst were optimal for the reaction with yields
up to 87% (Entries 17–23). Hence, it was concluded that the best
conditions were 15 mol% Pdꢀ(OAc)2, 20 mol% TMEDA, and 1.1
equiv. AgTFA in DMF at 110 C for 24 h.
With the optimal reaction conditions in hand, we then
explored the scope of 2-iodothiophenols and alkynes. As shown
in Scheme 2, different alkynes with either electron-withdrawing
groups (–F, –Br) or electron-donating groups (–tBu, –OCH3) can
generate the desired products in yields from 41 to 78% under
the standard conditions (3b–3e). Moreover, 2-iodothiophenols
with various functional groups (such as –F, –Cl, and –CF3) can
also be successfully applied in this method and novel
compounds such as 3g, 3h, and 3i were also obtained in around
50% yield, which have great potential, especially in pharma-
ceutical compounds and materials synthesis.
Results and discussion
Our investigation started with the model substrates 2-iodo-
thiophenol 1a and phenylacetylene 2a. As shown in Table 1,
a variety of transition metal salts were tested and palladium
acetate exhibited the best catalytic ability with a yield of 34%
(Entries 1–8). Moreover, other metals including nickel, cobalt,
and iron salts gave much less yields of 4%, 8%, and 5%,
respectively (Entries 3, 4, and 5). In the case of copper salt, the
coupling product between the alkyne was found to be the major
product (Entries 1 and 2).10 The blank experiment further
conrmed that no reaction occurred in the absence of a catalyst
Table 1 Optimization of the reaction conditionsa
To further explore the potential application of this method,
the reaction of 1a and 2a was scaled up to 10.0 mmol in a 50 mL
one-necked ask and the same efficiency was maintained
(Scheme 3). The desired product can be obtained in 75% yield,
which conrms its suitability for large-scale reaction.
Entry
Catalyst
Ligand
Additive
T/ꢀC
Yieldb (%)
1
2
3
4
5
6
7
8
CuI
CuCl
NiCl2
CoCl2$6H2O
FeSO4
Pd(PPh3)Cl2
Pd(PPh3)4
Pd(OAc)2
—
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
—
—
—
—
—
—
—
—
—
—
—
—
PPh3
TMEDA
L-Proline
Pyridine
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
—
—
—
—
—
—
—
—
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
105
110
115
120
110
110
110
14
Trace
4
8
5
28
21
34
Trace
68
66
71
75
81
69
72
82
85
84
84
87
87
86
9
—
10
11
12
13
14
15
16
17
18
19
20
21c
22d
23e
AgOAc
Ag2CO3
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
a
Reaction conditions: 2-iodothiophenol 1a (0.5 mmol), phenylacetylene
2a (4 equiv.), catalyst (10 mol%), ligand (20 mol%), and additive (1.1
Scheme 2 The synthesis of different benzo[b]thiophenes.a,b a Reac-
tion conditions: 2-iodothiophenol (0.5 mmol), alkyne (4 equiv.),
Pd(OAc)2 (15 mol%), TMEDA (20 mol%), and AgTFA (1.1 equiv.) in DMF (2
mL) under N2 at 110 ꢀC for 24 h. b Isolated yield.
b
c
equiv.) in DMF (2 mL) under N2 for 24 h. Isolated yields. Pd(OAc)2
(15 mol%). d Pd(OAc)2 (20 mol%). e Pd(OAc)2 (25 mol%).
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Scheme 3 The gram scale reaction performed under the standard
conditions.
Fig. 3 The absorption and emission spectra of compound 4 in MeCN
(1.0 Â 10À5 mol LÀ1).
Scheme 4 A comparison of the synthesized compounds 4 and 5.
unexpectedly high uorescence quantum yield of up to 1 that
was measured using quinine sulfate as a standard (quinine in
5.0 Â 10À5 mol LÀ1 sulfuric acid), which would shows broad
prospects for use in organic light-emitting diodes (OLEDS).
Besides this, we also tried to synthesize the benzothiophene
derivative
(4-methoxyphenyl)(2-(4-methoxyphenyl)benzo[b]
thiophen-3-yl)methanone 5 using product 3f as the starting
material in a higher yield than that reported in the literature.
Compound 5 has been reported as a new cannabinoid receptor
ligand and an intermediate of thrombin inhibitor.12
Fig. 2 Images of compound 4 in MeCN (1.0 Â 10À5 mol LÀ1) and the
solid state under sunlight (left) and under 360 nm UV light (right).
Furthermore, 2-(4-(tert-butyl)phenyl)benzo[b]thiophene 1,1-
dioxide 4 can be easily obtained aer adding H2O2 into 3e at
room temperature, which could shorten one step and uses
milder reaction conditions when compared with those reported
in the literature (Scheme 4).11 Furthermore, Fig. 2 shows images
of the compound 4 in MeCN and the solid state under sunlight
(le) and under 360 nm UV light (right). Fig. 3 displays the
absorption and emission spectra of compound 4 in MeCN (1.0
 10À5 mol LÀ1). Note that compound 4 in MeCN exhibited an
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Acknowledgements
We are grateful to the Natural Science Foundation of China
(grant no. 21372169, 21472128, J1310008). We also acknowledge
the comprehensive training platform of the specialized labora-
tory, College of Chemistry, Sichuan University for HRMS
analysis.
Scheme 5 The radical/electron trapping experiment.
Notes and references
1 For selected recent examples, see: (a) L. Berrade, B. Aisa,
M. Ramirez, S. Galiano, S. Guccione, L. Moltzau, F. Levy,
F. Nicoletti, G. Battaglia, G. Molinaro, I. Aldana, A. Monge
and S. Perez-Silanes, J. Med. Chem., 2007, 50, 5644; (b)
A. Venturelli, D. Tondi, L. Cancian, F. Morandi,
G. Cannazza, B. Segatore, F. Prati, G. Amicosante,
B. Shoichet and M. Costi, J. Med. Chem., 2011, 54, 3086; (c)
R. Romagnoli, P. Baraldi, M. Carrion, C. Cara, D. Preti,
F. Fruttarolo, M. Pavani, M. Tabrizi, M. Tolomeo,
S. Grimaudo, A. Cristina, J. Balzarini, J. Hadeld,
A. Brancale and E. Hamel, J. Med. Chem., 2007, 50, 2273;
(d) J. Chabert, B. Marquez, L. Neville, L. Joucla,
S. Broussous, P. Bouhours, E. David, S. Pellet-Rostaing,
B. Marquet, N. Moreau and M. Lemaire, Bioorg. Med.
Chem., 2007, 15, 4482.
2 (a) J. Gao, R. Li, L. Li, Q. Meng, H. Jiang, H. Li and W. Hu,
Adv. Mater., 2007, 19, 3008; (b) V. Bren, A. Dubonosov,
V. Minkin, A. Tsukanov, T. Gribanova, E. Shepelenko,
Y. Revinsky and V. Rybalkin, J. Phys. Org. Chem., 2007, 20,
917; (c) T. Zhang, J. O'toole and C. Proctor, J. Sulfur Chem.,
1999, 22, 1.
3 (a) M. Abe, T. Mori, I. Osaka, K. Sugimoto and K. Takimiya,
Chem. Mater., 2015, 27, 5049; (b) B. Fox and S. Olson, J.
Med. Chem., 2015, 58, 5256; (c) G. Schweicher, V. Lemaur,
Y. Geerts and Z. Bao, Adv. Mater., 2015, 27, 3066; (d)
E. Yamaguchi, C. Wang, A. Fukazawa, T. Higashiyama and
S. Yamaguchi, Angew. Chem., Int. Ed., 2015, 54, 4539; (e)
E. Amir, M. Murai and C. Hawker, Chem. Sci., 2014, 5,
4483; (f) X. Peng, J. Deng and H. Xu, RSC Adv., 2013, 3,
24146; (g) S. Kawai, T. Nakashima and T. Kawai, J. Mater.
Chem., 2009, 19, 3606; (h) S. Chen, W. Li, X. Li and W. Zhu,
RSC Adv., 2015, 5, 87626.
Scheme 6 The proposed reaction pathway.
To explore the reaction pathway, a radical trapping experi-
ment was carried out by the addition of a typical radical scav-
enger TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl). Almost the
same yield (80%) indicated that the reaction did not involve
a radical intermediate (Scheme 5). Furthermore, the interme-
diate 2-(phenylethynyl)benzenethiol 8 was observed by GC/MS
in the reaction between 2-iodothiophenol and phenylacetylene
aer 3 hours.
Based on the experimental and literature data, we proposed
a reaction pathway for the palladium-catalyzed synthesis of 2-
substituted benzo[b]thiophenes from 2-halophenols and
alkynes, which consists of two steps: the Sonogashira coupling
of 2-halothiophenol with the alkyne and the subsequent cycli-
zation of 2-alkynylthiophenol (Scheme 6). First, the Pd-catalyzed
Sonogashira coupling of 2-halothiophenol with the alkyne
affords intermediate 8. Then, coordination of Pd with inter-
mediate 8 may provide complex 6, whose subsequent addition
to the C–C triple bond gave intermediate 7. Protonation of
intermediate 7 results in the formation of benzo[b]thiophene
and the regenerated Pd-catalyst.
4 (a) H. Sashida, K. Sadamori and T. Tsuchiya, Synth.
Commun., 1998, 28, 713; (b) Y. Wang, S. Parkin and
M. Watson, Org. Lett., 2008, 10, 4421; (c) K. Takimiya,
Y. Konda, H. Ebata, N. Niihara and T. Otsubo, J. Org.
Chem., 2005, 70, 10569.
5 (a) T. Kashiki, S. Shinamura, M. Kohara, E. Miyazaki,
K. Takimiya, M. Ikeda and H. Kuwabara, Org. Lett., 2009,
11, 2473; (b) L. Sun, C. Den, R. Tang and X. Zhang, J. Org.
Chem., 2011, 76, 7546.
6 L. Gao, B. Chang, W. Qiu, L. Wang and X. Fu, Adv. Synth.
Catal., 2016, 358, 1202.
7 (a) K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron
Lett., 1975, 16, 4467; (b) H. Diek and F. Heck, Organomet.
Chem., 1975, 93, 295; (c) L. Cassar, Organomet. Chem., 1975,
93, 253; (d) M. Miller and C. Johnson, J. Org. Chem., 1997,
Conclusions
In summary, we developed an efficient catalytic system using 2-
iodothiophenols as the starting material for the synthesis of
a variety of 2-substituted benzo[b]thiophenes. This protocol
involves the following advantages: easily available starting
materials and simple operations with moderate to good yields,
and will contribute a new optional route for the construction
the benzo[b]thiophene ring. Moreover, the application of this
method was considered as an example by the synthesis of 2-(4-
(tert-butyl)phenyl)benzo[b]thiophene 1,1-dioxide and (4-
methoxyphenyl)(2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)
methanone, which exhibit a uorescence quantum yield up to 1
and use as a cannabinoid receptor ligand, respectively.
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62, 1582; (e) S. Thorand and N. Krause, J. Org. Chem., 1998, 10 (a) C. Meng and R. Yuan, ACS Catal., 2015, 5, 3760; (b)
¨
63, 8551; (f) A. Chandra and B. Singh, Tetrahedron, 2008,
64, 11680.
P. Rose, K. Harms and G. Hilt, J. Org. Chem., 2015, 80,
7311; (c) Y. Liu and J. Wan, Tetrahedron Lett., 2013, 54, 3953.
8 (a) T. Magdesieva, O. Nikitin, A. Yakimansky, M. Goikhman 11 (a) J. Liu, A. Narita, S. Osella, W. Zhang, D. Schollmeyer,
¨
and I. Podeshvo, Electrochim. Acta, 2011, 56, 3666; (b) L. Wu,
X. Shi, X. Xu, F. Liang and G. Huang, J. Chem. Sci., 2011, 123,
697; (c) Y. Liang, S. Tang, X. Zhang, L. Mao, Y. Xie and J. Li,
Org. Lett., 2006, 8, 3017.
D. Beljonne, X. Feng and K. Mullen, J. Am. Chem. Soc.,
2016, 138, 2602; (b) R. Mao, D. Zheng, H. Xia and J. Wu,
Org. Chem. Front., 2016, 3, 693.
12 (a) J. Romero-Parra, J. Mella-Raipa, M. Torres, R. Escobar,
´
9 (a) L. Yu and X. Zhou, Eur. J. Org. Chem., 2010, 29, 5560; (b)
F. Ke, Z. Li and X. Zhou, Org. Lett., 2011, 13, 454; (c)
H. Deng, Z. Li and X. Zhou, Chem.–Eur. J., 2012, 18, 4840;
(d) R. Che, Z. Li and X. Zhou, Chem.–Eur. J., 2014, 20, 7258.
M. Faundez and C. David Pessoa-Mahana, Eur. J. Med.
Chem., 2016, 124, 17; (b) D. J. Sall, D. L. Bailey,
J. A. Bastian and M. Zhang, J. Med. Chem., 2000, 43, 649.
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