Facile Access to Benzothiophenes through Metal-Free Iodine-Catalyzed Intermolecular Cyclization of Thiophenols and Alkynes

Article abstract of DOI:10.1055/s-0034-1378841

A novel iodine-catalyzed method for the synthesis of benzothiophene derivatives through cascade reactions of substituted thiophenols with alkynes has been demonstrated under metal- and solvent-free conditions. The present protocol uses inexpensive and env

Full text of DOI:10.1055/s-0034-1378841

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1890–1894
letter
1890
K. Yan et al.
Letter
Synlett
Facile Access to Benzothiophenes through Metal-Free Iodine-
Catalyzed Intermolecular Cyclization of Thiophenols and Alkynes
Kelu Yana
Daoshan Yang*a,b
Mengqi Zhanga
Wei Weia
Yao Liua
Laijin Tiana
Hua Wang*a,b
a Shandong Province Key Laboratory of Life-Organic Analysis, School of
Chemistry and Chemical Engineering, Qufu Normal Univesity, Jingxuan
Road, Qufu 273165, Shandong, P. R. of China
b Jining Functional Materials and Surface Treatment Technology R & D
Center, Southern Shandong Academy of Engineering Technology,
Jining 272000, Shandong, P. R. of China
yangdaoshan@tsinghua.org.cn
huawang_qfnu@126.com
Received: 04.04.2015
Accepted after revision: 10.05.2015
Published online: 14.07.2015
cyclization of thiophenols and alkynes for the synthesis of
benzothiophenes.7
DOI: 10.1055/s-0034-1378841; Art ID: st-2015-w0241-l
O
Abstract A novel iodine-catalyzed method for the synthesis of ben-
zothiophene derivatives through cascade reactions of substituted thio-
phenols with alkynes has been demonstrated under metal- and solvent-
free conditions. The present protocol uses inexpensive and environ-
mentally friendly molecular iodine as the catalyst, and the correspond-
ing products are obtained in moderate to excellent yields. Such an effi-
cient, economical, and green transformation should provide an
attractive approach to various benzothiophenes within organic and me-
dicinal chemistry.
H
N
OH
OH
H
N
B
N
NH
S
H
O
S
H2N
O
antibiotic agents
antitumor agents
O
O
O
MeO
NH2
O
Key words iodine-catalyzed, metal-free, benzothiophenes, thiophe-
nols, alkynes
S
OH
anti-inflammatory agents
S
HO
Benzothiophene derivatives are important heterocycles
that are known to have remarkable biological and medici-
nal properties (Figure 1),1 and they are also widely applied
in material chemistry.2 For these reasons, considerable ef-
forts have been devoted to the development of new and ef-
ficient methods for the construction of benzothiophene
and its derivatives. However, a literature survey indicates
that synthetic methods that are available for the construc-
tion of benzothiophene skeletons are rather limited.1a,3
Generally, these methods proceed either by electrophilic
cyclization of o-alkynyl thioanisoles or alkynyl thiophe-
nols,1a,4 or by transition-metal-catalyzed or strong-base-
enhanced cyclization of o-haloalkynylbenzenes with various
thiol surrogates.5 In 1973, Undheim and co-workers report-
ed a metal-free method for the formation of benzothio-
phene derivatives through cyclization of thiophenols and
alkynes; unfortunately, long reaction times (5–22 days)
were required, and the resulting yields were very low.6 In
2013, Li’s group described Mn(OAc)2-catalyzed oxidative
raloxifene
Figure 1 Significant biological and medical compounds containing the
benzothiophene motif
Recently, there has been increasing demand for metal-
free transformations because of the problems associated
with trace-metal impurities in the target molecules.8 Very
recently, our group developed a metal-free approach to
benzothiophenes through n-Et4NBr-catalyzed radical cy-
clization of disulfides and alkynes.9 However, the method
has some drawbacks, including: (a) that use of disulfides as
substrates, which need to be preprepared; (b) two equiva-
lents of thiophenol are generated from disulfide and only
one equivalent of thiophenol is used for the formation of
benzothiophene; (c) the use of chlorinated solvent. In re-
cent years, molecular iodine as an inexpensive, green and
efficient reagent, has been extensively used in organic
transformations.10 Herein, we report a metal-free molecu-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1890–1894

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K. Yan et al.
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lar iodine catalyzed approach to benzothiophenes from
more readily available benzenethiols and alkynes under
solvent-free conditions.
Table 1 I2-Catalyzed Coupling Reaction of 4-Methylbenzenethiol (1a)
with Methyl 3-Phenylpropiolate (2a) Leading to Methyl 3-Phenylben-
zo[b]thiophene-2-carboxylate (3a): Optimization of Conditions[a]
Thiophenol (1a) and methyl 3-phenylpropiolate (2a)
were chosen as model substrates to optimize the catalysis
conditions, which include an assessment of the influence of
catalysts, oxidants, reaction temperatures, and the amounts
of oxidant under a nitrogen atmosphere. As shown in Table
1, four catalysts: I2, n-Bu4NI, NIS, and KI (10 mol% relative to
thiophenol) were investigated by using di-tert-butyl perox-
ide (DTBP; 5.0 equiv) as the oxidant at 90 °C, and I2 was
found to be the most effective oxidant (entries 1–4). We as-
sessed the use of different oxidants (entries 1, 5, and 6), and
DTBP was found to be superior to the other oxidants (entry
1). A range of reaction temperatures were examined (en-
tries 1 and 7–9), and 110 °C was established to be more
suitable for this reaction (entry 8). The results obtained
with different amounts of DTBP (entries 8 and 10–11) were
also compared, and the use of five equivalents of DTBP was
found to provide the highest yield (entry 8). Notably, less
conversion was observed when the reaction was conducted
in the absence of iodine (entry 12). In addition, different
amounts of I2 were employed in the reactions (compare en-
tries 8, 13, and 14), and 10 mol% I2 provided the highest
yield (entry 8). Having optimizing the process, a range of
benzothiophene derivatives were synthesized under the
standard conditions: I2 (10 mol%) as the catalyst and 5
equiv of DTBP as the oxidant under solvent-free conditions
at 110 °C.
The scope of the I2-catalyzed cascade reactions of sub-
stituted thiophenols with alkynes was investigated under
the optimized conditions; the results are summarized in
Scheme 1. It was found that moderate to excellent yields
were obtained under the standard conditions. For substi-
tuted thiophenols, substrates containing electron-rich,
electron-neutral, and electron-deficient groups did not
cause an evident difference in reactivity. For unsymmetri-
cal alkynes, substrates with electron-withdrawing groups
exhibited higher reactivity (products 3f–h, 3af, and 3ag). It
is noteworthy that the present method shows high regiose-
lectivity. When thiophenol reacted with unsymmetric
alkyne, a single isomer of benzothiophene was obtained.
The reason might be that the carbocation of intermediate II
was more favored than that of II′ (see reaction mechanism
in Scheme 4 below). Unfortunately, 1,2-diarylethyne and 3-
phenylpropiolic acid were poor substrates in this transfor-
mation (products 3al–am). As expected, meta-substituted
substrates gave a mixture of two regioisomeric products
(products 3o/3o′). The metal-free I2-catalyzed cyclization
reactions could tolerate some functional groups, including
esters (products 3a–ak), ethers (products 3l–o, 3o′, 3u, and
3v), C–Cl moieties (products 3w–ab) and C–Br moieties
(products 3ac–ai).
Ph
SH
cat., oxidant
COOMe
Ph
COOMe
+
S
2a
3a
1a
Entry
Cat. (mol%)
Oxidant (equiv)[b]
Temp (°C) Yield (%)[c]
1
2
I2 (10)
n-Bu4NI (10)
NIS (10)
KI (10)
I2 (10)
I2 (10)
I2 (10)
I2 (10)
I2 (10)
I2 (10)
I2 (10)
–
DTBP (5.0)
DTBP (5.0)
DTBP (5.0)
DTBP (5.0)
H2O2 (5.0)
TBHP (5.0)
DTBP (5.0)
DTBP (5.0)
DTBP (5.0)
DTBP (4.0)
DTBP (3.0)
DTBP (5.0)
DTBP (5.0)
DTBP (5.0)
90
90
59
trace
47
53
0
3
90
4
90
5
90
6
90
0
7
100
110
120
110
110
110
110
110
65
77
74
68
56
39
69
45
8
9
10
11
12
13
14
I2 (20)
I2 (30)
a Reaction conditions: benzenethiol (1a; 0.5 mmol), methyl 3-phenylpropio-
late (2a; 0.75 mmol), catalyst (0.05 mmol), oxidant (2.5 mmol), 18 h, nitro-
gen atmosphere.
b DTBP = 2-(tert-butylperoxy)-2-methylpropane; TBHP = tert-butyl hydroper-
oxide solution (5.5 M in decane).
c Isolated yield.
Furthermore, we explored the synthetic applicability of
the method. As shown in Scheme 2, the gram-scale reaction
was performed in common laboratory apparatus with a
single-necked round-bottomed flask fitted with a nitrogen
balloon, and the reaction afforded 3a in 74% yield. This ex-
ample clearly demonstrates the practical applicability of
this newly developed method.
To explore the possible mechanism, several control ex-
periments were performed as shown in Scheme 3. When
thiophenol (1a) was added independently under the stan-
dard conditions, 1,2-diphenyldisulfane (4a) was obtained in
95% yield (Scheme 3, eq. 1). Furthermore, treatment of 1,2-
diphenyldisulfane (4a) with methyl 3-phenylpropiolate
(2a) under the standard conditions led to the formation of
3a in 81% yield, indicating that 1,2-diphenyldisulfane might
be an intermediate in this transformation (Scheme 3, eq. 2).
Additionally, the reaction of methyl 3-phenylpropiolate
(4a) with 3-phenylpropiolate (2a) was conducted without
iodine. As expected, the yield was significantly decreased
(Scheme 3, eq. 3). To understand the mechanism further,
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO; 4.0 equiv.; a
well-known radical inhibitor) was added to the reaction
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1890–1894

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K. Yan et al.
Letter
Synlett
mixtures under the standard reaction conditions. Under
these conditions, the formation of 3a was completely inhib-
ited, which implies that the transformation should involve a
free-radical mechanism (Scheme 3, eq. 4).
R3
SH
I2 , DTBP, N2
18 h
R3
COOR2
R1
+
COOR2
R1
S
1
2
3
COOMe
COOEt
COOBn
COOi-Pr
COOn-Bu
S
S
S
S
S
3a (77%)
3b (81%)
3c (83%)
3d (75%)
3e (75%)
Cl
Br
COOMe
COOEt
COOMe
COOEt
COOEt
COOMe
COOEt
S
S
S
S
S
3f (77%)
3g (71%)
3h (78%)
3i (86%)
3j (86%)
OMe
COOMe
COOMe
COOMe
COOMe
COOMe
H3CO
S
S
COOMe
COOn-Bu
COOi-Pr
COOMe
3o
3o'
S
S
S
S
OMe
OMe
OMe
76% (1:1.2)
MeO
3k (92%)
3l (74%)
3m (73%)
3n (75%)
Br
COOEt
COOMe
COOEt
COOMe
COOMe
COOBn
S
COOEt
S
S
S
S
3p (79%)
3q (78%)
3r (89%)
3s (92%)
3t (74%)
COOMe
MeO
Cl
Cl
Cl
MeO
COOMe
COOi-Pr
COOBn
COOMe
COOi-Pr
S
S
S
S
S
3u (77%)
3v (74%)
3w (73%)
3x (76%)
3y (74%)
Br
COOEt
Cl
Br
Br
Cl
Cl
COOEt
COOMe
COOi-Pr
COOn-Bu
COOEt
S
S
S
S
S
3z (73%)
3aa (79%)
3ab (77%)
3ac (77%)
3ad (73%)
Cl
COOMe
COOEt
Br
Br
COOMe
COOEt
Br
Br
Br
S
S
COOEt
COOn-Bu
COOMe
S
S
S
3ae (72%)
3af (74%)
3ag (78%)
3ah (79%)
3ai (76%)
COOEt
COOMe
COOH
COOEt
COOMe
S
S
S
S
3aj (75%)
3ak (76%)
3al (0%)
3am (0%)
Scheme 1 Iodine-catalyzed synthesis of benzothiophene derivatives through cyclization of thiophenols with alkynes. Reagents and conditions: substi-
tuted benzenethiol (0.5 mmol), alkyne (0.75 mmol), I2 (0.05 mmol), DTBP (2.5 mmol), N2 atmosphere, 110 °C, 18 h. Isolated yields, based on the
amount of 1, are given.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1890–1894

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Ph
SH
+
I2 (10 mol%), DTBP
110 °C, N2, 18 h
COOMe
Ph
COOMe
S
3a
1.98 g, 74% isolated yield
1a
2a
15 mmol, 2.40 g
10 mmol, 1.10 g
Scheme 2 Synthesis of 3a on a gram scale
On the basis of the preliminary results discussed above,
a possible mechanism for the I2-catalyzed cyclization reac-
tions for the synthesis of benzothiophene derivatives is
proposed in Scheme 4. In this pathway, thiophenol (1a) is
initially oxidized to 1,2-diphenyldisulfane (4a) under the
standard conditions. The reaction of 4a with I2 forms an
electrophilic species PhSI (I),11 which is then attacked by 3-
phenylpropiolate (2a) to yield intermediate II, intramolecu-
lar arylation of which provides III. This is followed by the
loss of HI to form 3a. Finally, reaction of the t-BuO· radical
with HI leads to the catalyst I2.
SH
S
I2, DTBP
S
(1)
95%
1a
4a
S
I2, DTBP
S
+
+
Ph
COOMe
COOMe
3a (2)
81%
2a
4a
In summary, a novel and useful protocol12 has been de-
veloped for the synthesis of benzothiophene derivatives
through I2-catalyzed tandem cyclization of thiophenols and
alkynes. A series of biological benzothiophene frameworks
could be conveniently and efficiently obtained in moderate
to good yields with excellent functional group tolerance.
S
S
S
DTBP
Ph
3a
(3)
(4)
39%
4a
2a
2a
TEMPO
S
Ph
COOMe
3a
+
I2, DTBP
6%
4a
Acknowledgment
Scheme 3 Control experiments
The authors gratefully acknowledge financial support from the Na-
tional Natural Science Foundation of China (Nos. 21302110,
21375075 and 21302109), the Taishan Scholar Foundation of Shan-
SH
S
S
I2, DTBP
oxidant
4a
1a
t-BuO
.
DTBP
Ph
I2
HI
COOMe
SI
S
3a
COOMe
Ph
I
+
I–
Ph
S
Ph
II' (unfavored)
COOMe
S
Ph
COOMe
2a
III
+
S
COOMe
II (favored)
Scheme 4 Proposed mechanism for the direct transformation
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1890–1894

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K. Yan et al.
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dong Province, the Natural Science Foundation of Shandong Province
(ZR2013BQ017 and ZR2013BM007), the Project of Shandong Province
Higher Educational Science and Technology Program (J13LD14), and
the Scientific Research Foundation of Qufu Normal University (BSQD
2012021). We thank Ning Zhang in this group for reproducing the re-
sults for 3a and 3ad.
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(12) Synthesis of Substituted Benzothiophenes; General Proce-
dure: A 25 mL Schlenk tube equipped with a magnetic stirring
bar was charged with I2 (12.7 mg, 0.05 mmol), substituted thiol
1 (0.5 mmol) and alkyne 2 (0.75 mmol). The tube was evacu-
ated twice and backfilled with nitrogen, and DTBP (2.5 mmol)
was added into the tube under nitrogen atmosphere. The tube
was sealed with a balloon and the mixture was stirred under
nitrogen atmosphere at 110 °C for 18 h. Upon completion of the
reaction, the resulting solution was cooled to r.t., and the
solvent was removed with the aid of a rotary evaporator. The
residue was purified by column chromatography on silica gel
(PE–EtOAc) to give 3.
Methyl
3-Phenylbenzo[b]thiophene-2-carboxylate
(3a):
Compound 3a was obtained according to the general procedure
and purified by column chromatography (PE–EtOAc, 30:1). 1H
NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 8.0 Hz, 1 H), 7.60 (d, J =
8.0 Hz, 1 H), 7.50–7.57 (m, 4 H), 7.46 (d, J = 8.0 Hz, 2 H), 7.39
(t, J = 8.0 Hz, 1 H), 3.83 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ =
163.0, 144.3, 140.5, 134.6, 129.7, 128.2, 128.1, 127.8, 127.3,
125.4, 124.9, 122.5, 52.3. MS (ESI): m/z = 268.1 [M + Na]+.
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1905. (c) Sanz, R.; Guilarte, V.; Hernando, E.; Sanjuán, A. M. J.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1890–1894