Transition-metal-free method for the synthesis of benzo[b]thiophenes from o -halovinylbenzenes and K2S via direct SNAr-type reaction, cyclization, and dehydrogenation process

Article abstract of DOI:10.1055/s-0033-1339289

A new, highly efficient procedure for the synthesis of benzothiophenes from easily available o-halovinylbenzenes and potassium sulfide has been developed. The reaction tolerated a wide range of functionalities, and various 2-substituted benzo[b]thiophenes

Full text of DOI:10.1055/s-0033-1339289

LETTER
▌1687
letter
Transition-Metal-Free Method for the Synthesis of Benzo[b]thiophenes from
o-Halovinylbenzenes and K2S via Direct SNAr-Type Reaction, Cyclization, and
Dehydrogenation Process
Synthesis of Benzo[b]thiophenes
Xiaoyun Zhang,a Weilan Zeng,a Yuan Yang,a Hui Huang,a Yun Liang*a,b
a
National & Local Joint Engineering Laboratory for New Petrochemical Materials and Fine Utilization of Resources, Key Laboratory of
Chemical Biology and Traditional Chinese Medicine Research, Ministry of Education, Hunan Normal University, Changsha, Hunan 410081,
P. R. of China
Fax +86(731)88872533; E-mail: liangyun1972@126.com
b
Beijing National Laboratory for Molecular Sciences, Beijing 100871, P. R. of China
Received: 15.04.2013; Accepted after revision: 27.05.2013
heavy metal. Accordingly, the development of a facile,
Abstract: A new, highly efficient procedure for the synthesis of
general, and transition-metal-free route to synthesize the
benzothiophenes from easily available o-halovinylbenzenes and po-
benzo[b]thiophene ring systems from readily available
starting materials would be quite attractive because of
tassium sulfide has been developed. The reaction tolerated a wide
range of functionalities, and various 2-substituted benzo[b]thio-
phenes are provided in the high yields in the absence of a transition- growing interest in these compounds.
metal catalyst.
Key words: transition-metal-free, benzo[b]thiophenes, o-halo-
vinylbenzenes, direct SNAr-type reaction, cyclization, dehydroge-
nation process
O
SH
+
X
X = F, Cl, I
R1
a
c
Benzo[b]thiophenes have attracted much attention from
organic chemists for many years due to their occurrence in
a wide variety of pharmaceuticals and natural products
possessing useful biological activities.1 Consequently,
much interest has been paid to the development of syn-
thetic methods for benzo[b]thiophenes.2–6 Most of these
approaches are focused on transition-metal-catalyzed syn-
thesis of benzo[b]thiophenes via constructing C–S
bonds.2 However, the need for high catalyst loading in
some of these processes results in a high economic cost.
And the presence of heavy transition-metal impurities in
the final products also presents a major problem regarding
purification. Therefore, the development of efficient and
transition-metal-free processes will significantly change
synthetic strategies for the assembly of benzothiophene
structures. Transition-metal-free approach to benzothio-
phenes focus on: (1) electrophilic cyclization of o-alkynyl
thioanisole3 (Scheme 1, path a); (2) electrophilic cycliza-
tion reaction of o-bromo alkynylbenzenes with sulfur
upon lithium–halogen exchange4 (Scheme 1, path b); (3)
SNAr-type reaction, cyclization of o-halobenzaldehyde
with benzylthiols5 (Scheme 1, path c); (4) SNAr-type reac-
tion, cyclization of o-bromo alkynylbenzenes with sodi-
um sulfide6 (Scheme 1, path d). However, the reacted
precursor o-alkynyl thioanisole and o-bromo alkynylben-
zenes all were synthesized using transition-metal-cata-
lyzed Sonogashira coupling reaction, and these methods
are limited in drug synthesis because of contamination of
b
R1
t-BuLi + S8
+
S
SMe
R2
Br
R2
R2
d
R1
R2
Na2S
+
Br
R1
DMF, 140 °C
24 h
K2S
R1
+
X
R2
S
X = F, Cl, Br, I
this work
Scheme 1 Approaches toward benzo[b]thiophene through transi-
tion-metal-free methods
During the course of our group’s research into synthetic
methodology involving heterocyclic compounds,7 we un-
expectedly found that in the absence of transition-metal
catalyst, K2S could couple with 2-halovinylbenzenes to
produce benzo[b]thiophenes. To the best of our knowl-
edge, only an analogous approach using the 2-dihalo-
vinylbenzenes has been reported. Takimiya and co-
workers reported the synthesis of [1]benzothieno[3,2-
b][1]benzothiophene from o-dihalostilbenes and sodium
sulfide nonahydrate in 180 °C via the direct SNAr-type re-
action, cyclization, and dehydrogenation process.8 Unfor-
tunately, the utility and applicability of this method suffer
from the harsh reaction conditions and low yields. As a
continuing interest in the synthesis of heterocyclic com-
pounds, we want to construct various 2-substituted ben-
zo[b]thiophenes using a more efficient and feasible
SYNLETT 2013, 24, 1687–1692
Advanced online publication: 28.06.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339289; Art ID: ST-2013-W0339-L
© Georg Thieme Verlag Stuttgart · New York

1688
X. Zhang et al.
LETTER
Table 1 Optimization of Reaction Conditionsa
method. Herein, we report the unexpected transition-met-
al-free reaction of 2-halostyrenes (synthesized via Wittig
reaction of phosphine ylides and aldehydes) and easily
available potassium sulfide leading to 2-substituted ben-
zo[b]thiophenes (Scheme 1).
Ph
K2S
solvent
Ph
Br
S
1a
2a
Initially, we tested the reaction of 1-bromo-2-styrylben-
zene with potassium sulfide as a model example (Table 1).
First, we tested different copper salts to see whether the
reaction is a metal-catalyzed process (Table 1, entries 1–
6). However, the control experiment results showed that
the 1-bromo-2-styrylbenzene can be effectively converted
into the 2-phenylbenzo[b]thiophene without addition of
any transition metals, which implies this reaction is not
catalyzed by a transition metal. Moreover, some transition
metals can even prohibit the reaction. To further optimize
the reaction parameters, the solvent and temperature were
varied (Table 1, entries 7–12). The reaction can be accel-
erated by use of polar aprotic solvents and/or by elevating
the reaction temperature. These experimental results indi-
cated that K2S acted as a nucleophile to synthesize 2-
phenylbenzo[b]thiophene via the direct SNAr-type reac-
tion, cyclization, and dehydrogenation process.8,9 Finally,
the reaction was performed under air and the yield of 2-
phenylbenzo[b]thiophene decreased slightly. Surprising-
ly, when the nitrogen atmosphere was replaced by oxy-
gen, the corresponding product was obtained in a trace
amount, and 78% of 1-bromo-2-styrylbenzene was recy-
cled. We attributed this reason to potassium sulfide which
could be oxidized to sulfur by oxygen. Therefore, the re-
action should be performed under an inert atmosphere.
Entry
Solvent
Additive
Yield of 2a10
(%)b
1
2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
NMP
MeCN
DMF
DMF
DMF
DMF
CuI
69
CuBr
68
3
CuCl
61
4
CuCN
71
5
CuCl2
75
6
Cu(OAc)2
trace
77
7
–
–
–
–
–
–
–
–
8
73
9
71
10
11c
12d
13e
14f
trace
73
58
68
trace
a Reaction conditions: 1a (0.30 mmol), K2S (0.90 mmol), additive (10
mol%), solvent (2 mL), N2, 140 °C.
Since such a SNAr-type reaction, cyclization, and dehy-
drogenation process is supposed, we then investigated the
effects of fluoro, chloro, bromo, and iodo substituents on
stilbenes (Scheme 2). As expected, perfect yields (96%
and 92%, respectively) were obtained when 1-fluoro-2-
styrylbenzene and 1-chloro-2-styrylbenzene were ap-
plied. In the reaction of 1-iodo-2-styrylbenzene, moderate
yield (66%) was observed. A comparison of the reaction
yields from halo-substituted styrylbenzene indicated a
significant halogen dependence in the following order: F
> Cl >Br > I. We believe that this observation supports the
hypothesis that the benzo[b]thiophenes formation pro-
ceeds via the SNAr mechanism.4,8
b Isolated yield.
c 120 °C.
d 100 °C.
e Air.
f O2, 78% 1-bromo-2-styrylbenzene was recycled.
tained under the optimal reaction conditions. Initially, R1
substituents at the terminal alkene moiety of 2-(1-alke-
nyl)fluorobenzenes were evaluated. The results demon-
strated that both electron-rich groups such as Me, OMe,
OH, or NMe2 and electron-deficient groups such as Cl,
CF3, or CN on the phenyl ring were compatible, and the
corresponding products were all obtained in high to per-
fect yields. For example, product 2e and 2h bearing the 3-
hydroxylphenyl or 4-trifluoromethylphenyl group was af-
forded in 95% and 96% yield, respectively, via the thiola-
tion annulation of the corresponding substrate with K2S.
Similarly, when the R1 substituent was 1- or 2-naphthyl,
the 2-(1-naphthyl)- or 2-(2-naphthyl)benzo[b]thiophene
was obtained in excellent yield. The benzo[b]thiophene
substituted with heterocyclic groups such as furyl, thienyl,
or pyridyl could all be obtained in good to excellent
yields. When we applied the method to the cyclization of
alkyl- and benzyl-substituted o-fluorostyrene, we ob-
tained unfavorable results. For example, n-butyl-, tert-bu-
tyl-, and benzyl-substituted o-fluorostyrene only afforded
42% of 2o, 30% of 2p, and 20% of 2q. We attributed this
K2S
S
DMF, 140 °C
X
1b X = F
1c X = Cl
1a X = Br
1d X = I
2a 96%
2a 92%
2a 77%
2a 66%
Scheme 2 Synthesis of 2-phenylbenzo[b]thiophenes
To extend the substrate scope of the cyclization reaction,
various benzo[b]thiophenes were synthesized and submit-
ted to the K2S/DMF system. Table 2 listed the results ob-
Synlett 2013, 24, 1687–1692
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Benzo[b]thiophenes
1689
reason to the lower reactivity of o-fluorostyrene due to the the group R2 to the thiolation annulations of 2-(1-alke-
well electron-donating ability of alkyl and benzyl. How- nyl)fluorobenzenes. The results indicated that electron-
ever, this observation supports the hypothesis that the for- deficient groups promoted the reaction, but electron-rich
mation of benzo[b]thiophenes proceeds via a cyclic groups hampered the reaction.
addition process. Finally, we investigated the effects of
Table 2 Formation of Benzo[b]thiophenes from Various 2-Fluorostyrenes and K2Sa
R1
R1
K2S
S
DMF, 140 °C
F
R2
R2
2
1
Entry
Substrate 1
Product 2
Yield (%)b
Me
1
2b
92
Me
S
S
F
OMe
OMe
2
3
4
2c
2d
2e
84
88
95
F
F
F
OMe
OMe
S
OH
OH
S
S
NMe2
NMe2
5
6
7
8
2f
93
77
96
94
F
F
F
F
Cl
Cl
2g
2h
2ic
S
S
S
CF3
CN
CF3
CN
9
2j
94
S
F
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1687–1692

1690
X. Zhang et al.
LETTER
Table 2 Formation of Benzo[b]thiophenes from Various 2-Fluorostyrenes and K2Sa (continued)
R1
R1
K2S
S
DMF, 140 °C
F
R2
R2
2
1
Entry
Substrate 1
Product 2
Yield (%)b
10
2k
91
S
F
F
S
N
S
11
12
13
2l
90
94
62
S
S
S
N
2m
2n
F
O
O
F
F
14
15
2o
2p
41
30
S
S
S
F
16
17
18
19
20
2q
2r
2s
2t
20
52
63
90
63
F
MeO
MeO
S
F
F
S
MeO
Cl
MeO
Cl
S
S
F
2u
Cl
Cl
F
a Reaction conditions: 1 (0.3 mmol), K2S (0.9 mmol), DMF (2 mL), 140 °C, under N2 atmosphere for 24 h.
b Isolated yields.
c DMF was replaced by MeCN.
Synlett 2013, 24, 1687–1692
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Benzo[b]thiophenes
1691
+
1) KOt-Bu, THF
PPh3Br–
O
+
2) K2S, DMF
140 °C
S
F
2a, 80%
Scheme 3 One-pot reaction to synthesize 2-phenylbenzo[b]thiophene
H(D)
Ph
D2O (3 equiv)
Ph
S
+
K2S
DMF, 140 °C, 24 h
F
1b
KF
92% (2a/2a-d = 4:1)
nucleophile
substitution
dehydrogenation
aromatization
D2O
H
Ph
D
cyclization
Ph
Ph
S
S
K
S
OD–
K
C
B
A
Scheme 4 Possible mechanism for the reaction
of Education of China (20094306120003), Training Program Foun-
dation for the Young Talents by Hunan Normal University of China
(ET21003), Hunan Provincial Natural Science Foundation of China
(12JJ2009), Scientific Research Fund of Hunan Provincial Educati-
on Department (12A095), and Aid Program for Science and Tech-
nology Innovative Research Team in Higher Educational
Institutions of Hunan Province for financial support.
To our delight, this synthetic method to synthesize ben-
zo[b]thiophenes could be further extended from the initial
starting material in one pot. For example, 2-fluorobenzal-
dehyde reacted with KOt-Bu and benzyltriphenylphos-
phonium bromide in THF for five hours, then K2S and
DMF were added, and the reaction was further stirred for
24 hours at 140 °C, and 2-phenylbenzo[b]thiophene was
isolated in 80% yield (Scheme 3). This method could be a
benign, one-pot method for synthesizing benzo[b]thio-
phenes.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
A possible mechanism for the cascade reaction that leads
to the formation of the benzo[b]thiophene ring is shown in
Scheme 4. The process is initiated by the SNAr-type reac-
tion of K2S to fluoro-substituted styrenes. This hypothesis
is substantiated by the observation that the highest yields
were obtained with fluoro-substituted styrenes, and the
leaving-group activity decreases in the following order: F
> Cl > Br> I. The intermediate A, subsequent addition to
the C=C bond gave intermediate B. Protonation of inter-
mediate B formed intermediate C. Subsequent dehydro-
genation and aromatization of intermediate C gave rise to
the 2-substituted benzo[b]thiophene product. This process
was proved by the deuteration experiment. When 1-fluo-
ro-2-styrylbenzene reacted with K2S and D2O in DMF, 2-
phenylbenzo[b]thiophene was obtained in 92% yield
(2a/2a-d = 4:1).
References and Notes
(1) (a) Berrade, L.; Aisa, B.; Ramirez, M. J.; Galiano, S.;
Guccione, S.; Moltzau, L. R.; Levy, F. O.; Nicoletti, F.;
Battaglia, G.; Molinaro, G.; Aldana, I.; Monge, A.; Perez-
Silandes, S. J. Med. Chem. 2011, 54, 3086. (b) Venturelli,
A.; Tondi, D.; Cancian, L.; Morandi, F.; Cannazza, G.;
Segatore, B.; Prati, F.; Amicosante, G.; Shoichet, B. K.;
Costi, M. P. J. Med. Chem. 2007, 50, 5644. (c) Romagnoli,
R.; Baraldi, P. G.; Carrion, M. D.; Cara, C. L.; Preti, D.;
Fruttarolo, F.; Pavani, M. G.; Tabrizi, M. A.; Tolomeo, M.;
Grimaudo, S.; Cristina, A. D.; Balzarini, J.; Hadfield, J. A.;
Brancale, A.; Hamel, E. J. Med. Chem. 2007, 50, 2273.
(d) Witter, D. J.; Belvedere, S.; Chen, L.; Secrist, J. P.;
Mosley, R. T.; Miller, T. A. Bioorg. Med. Chem. 2007, 17,
4562.
(2) For selected recent examples on transition-metal-catalyzed
synthesis of benzo[b]thiophenes, see: (a) Sun, L.-L.; Deng,
C.-L.; Tang, R.-Y.; Zhang, X.-G. J. Org. Chem. 2011, 76,
7546. (b) Kuhn, M.; Falk, F. C.; Paradies, J. Org. Lett. 2011,
13, 4100. (c) Guilarte, V.; Fernández-Rodríguez, M. A.;
García-García, P.; Hernando, E.; Sanz, R. Org. Lett. 2011,
13, 5100. (d) Zeng, F.; Alper, H. Org. Lett. 2011, 13, 2868.
(e) Huang, H.; Li, J.; Zhao, W.; Mei, Y.; Duan, Z. Org.
Biomol. Chem. 2011, 9, 5036. (f) You, W.; Yan, X.; Liao,
Q.; Xi, C. Org. Lett. 2010, 12, 3930. (g) Bryan, C. S.;
Braunger, J. A.; Lautens, M. Angew. Chem. Int. Ed. 2009,
48, 7064. (h) Newman, S. G.; Aureggi, V.; Bryan, C. S.;
Lautens, M. Chem. Commun. 2009, 5236. (i) Inamoto, K.;
Arai, Y.; Hiroya, K.; Doi, T. Chem. Commun. 2008, 5529.
(j) Nakamura, I.; Sato, T.; Yamamoto, Y. Angew. Chem. Int.
Ed. 2006, 45, 4473.
In summary, we have developed a simple, general, and
transition-metal-free method to synthesize the ben-
zo[b]thiophenes from easily utilized starting materials.
This reaction features SNAr-type reaction, cyclization,
and dehydrogenation process to construct sulfur-contain-
ing heterocycles. Further studies to elucidate the mecha-
nism and application to the synthesis of natural products
are in progress.
Acknowledgment
This work was supported by the Natural Science Foundation of Chi-
na (21072054), New Teachers’ Fund for Doctor Stations, Ministry
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1687–1692

1692
X. Zhang et al.
LETTER
(3) (a) Mehta, S.; Larock, R. C. J. Org. Chem. 2010, 75, 1652.
(b) Cho, C.-H.; Neuenswander, B.; Larock, R. C. J. Comb.
Chem. 2010, 12, 278. (c) Sanz, R.; Guilarte, V.; Hernando,
E.; Sanjuán, A. M. J. Org. Chem. 2010, 75, 7443. (d) Cho,
C.-H.; Neuenswander, B.; Lushington, G. H.; Larock, R. C.
J. Comb. Chem. 2009, 11, 900. (e) Mehta, S.; Waldo, J. P.;
Larock, R. C. J. Org. Chem. 2009, 74, 1141. (f) Ebata, H.;
Miyazaki, E.; Yamamoto, T.; Takimiya, K. Org. Lett. 2007,
9, 4499. (g) Zhou, Y.; Liu, W.-J.; Ma, Y.-G.; Wang, H.-L.;
Qi, L.-M.; Cao, Y.; Wang, J.; Pei, J. J. Am. Chem. Soc. 2007,
129, 12386.
(4) (a) Geng, W.-Z.; Wang, Z.-T.; Wang, H.-L.; Zhang, S.-G.;
Zhang, W.-X.; Xi, Z. Tetrahedron 2012, 68, 5283.
(b) Wang, Z.-T.; Geng, W.-Z.; Wang, H.-L.; Zhang, S.-G.;
Zhang, W.-X.; Xi, Z. Tetrahedron Lett. 2011, 52, 6997.
(c) Wang, Y.-F.; Parkin, S. R.; Watson, M. D. Org. Lett.
2008, 10, 4421. (d) Takimiya, K.; Konda, Y.; Ebata, H.;
Niihara, N.; Otsubo, T. J. Org. Chem. 2005, 70, 10569.
(e) Sashida, H.; Sadamori, K.; Tsuchiya, T. Synth. Commun.
1998, 28, 713.
(7) Zhang, X.-Y.; Yang, Y.; Liang, Y. Tetrahedron Lett. 2012,
53, 6406.
(8) Saito, M.; Yamamoto, T.; Osakaa, I.; Miyazaki, E.;
Takimiya, K.; Kuwabara, H.; Ikeda, M. Tetrahedron Lett.
2010, 51, 5277.
(9) (a) Shaw, J. E. J. Org. Chem. 1991, 56, 3728. (b) Cogolli, P.;
Maiolo, F.; Testaferri, L.; Tingoli, M.; Tiecco, M. J. Org.
Chem. 1979, 44, 2642.
(10) Benzo[b]thiophenes 2; General Procedure
Under the protection of nitrogen, an oven-dried Schlenk tube
was charged with K2S (0.9 mmol, 3 equiv) and the 1-fluoro-
2-styryl derivative (0.3 mmol). The tube was evacuated and
backfilled with nitrogen before DMF or MeCN (2 mL) was
added. The reaction mixture was stirred at 140 °C, and after
24 h was quenched with H2O. The mixture extracted with
EtOAc, and the combined organic layers were washed with
H2O and brine, dried over Na2SO4, concentrated in vacuo
and purified by column chromatography to afford the
product.
Analytical Data for Compound 2a
(5) Duan, Z.-Y.; Ranjit, S.; Liu, X.-G. Org. Lett. 2010, 12, 2430.
(6) (a) Kashiki, T.; Shinamura, S.; Kohara, M.; Miyazaki, E.;
Takimiya, K.; Ikeda, M.; Kuwabara, H. Org. Lett. 2009, 11,
2473. (b) Patel, M. V.; Rohde, J. J.; Gracias, V.; Kolasa, T.
Tetrahedron Lett. 2003, 44, 6665.
white solid; isolated yield 96% (60 mg; mp 172.2–173.0 °C.
1H NMR (500 MHz, CDCl3): δ = 7.82 (d, J = 8.0 Hz, 1 H),
7.77 (d, J = 7.5 Hz, 1 H), 7.72 (d, J = 8.5 Hz, 2 H), 7.54 (s,
1 H), 7.42 (t, J = 7.8 Hz, 2 H), 7.36–7.29 (m, 3 H). 13C NMR
(125 MHz, CDCl3): δ = 144.2, 140.7, 139.5, 134.3, 128.9,
128.2, 126.5, 124.5, 124.3, 123.5, 122.2, 119.4.
Synlett 2013, 24, 1687–1692
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.