Synthesis of benzothiophene derivatives from dilithio reagents, sulfur, and electrophiles via electrophilic cyclization

Article abstract of DOI:10.1016/j.tetlet.2011.10.098

Benzothiophene derivatives were synthesized in high yields from readily available o-(alkynyllithio)aryllithio compounds, sulfur, and 2 equiv of acid chlorides or other electrophiles. An acid chloride-induced electrophilic cyclization resulted in the forma

Full text of DOI:10.1016/j.tetlet.2011.10.098

Tetrahedron Letters 52 (2011) 6997–6999
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Tetrahedron Letters
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Synthesis of benzothiophene derivatives from dilithio reagents, sulfur,
and electrophiles via electrophilic cyclization
Zitao Wang a, Weizhi Geng a, Hanliu Wang a, Shaoguang Zhang a, Wen-Xiong Zhang a, Zhenfeng Xi a,b,
⇑
a Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry, Peking University, Beijing 100871, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry (SIOC), CAS, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Benzothiophene derivatives were synthesized in high yields from readily available o-(alkynyllithio)aryl-
lithio compounds, sulfur, and 2 equiv of acid chlorides or other electrophiles. An acid chloride-induced
electrophilic cyclization resulted in the formation of the thiophene ring.
Received 14 August 2011
Revised 29 September 2011
Accepted 18 October 2011
Available online 21 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Dedicated to Professor Christian Bruneau on
the occasion of his 60th birthday
Keywords:
Acid chloride-induced cyclization
Benzothiophene
Dilithio reagent
Electrophilic cyclization
o-(Alkynyllithio)aryllithio compound
Benzothiophene derivatives are a class of important compounds
in many aspects.1 Several synthetic methods have been reported in
the literature for the construction of benzothiophene skeletons.2–6
Our research group has been working on the synthesis and
applications of new types of organolithio reagents, including org-
ano-di-lithio reagents,7 organo-mono-lithio reagents,8 and alky-
nyllithio compounds.9 As a part of our further interest in the
generation and synthetic applications of dilithio compounds, we
attempted the in situ generation of o-lithiophenylethynyllithiums
2 from their corresponding o-bromoethynylbenzenes 1 and t-BuLi.
Upon successful generation of the dilithio compounds 2, we carried
out their synthetic applications. When this dilithio compound 2
was treated with 0.25 equiv of the element sulfur (S8), it could be
readily transformed to the intermediate 3. Further treatment of
the intermediate 3 with acid chlorides, anhydrides, or additional
sulfur triggered the cyclization reaction. In this Letter, we report
an alternative synthesis of benzothiophene derivatives 4 and 5
from readily available o-lithiophenylethynyllithiums 2, sulfur,
and 2 equiv of acid chlorides or other electrophiles. An acid chlo-
ride-induced and a sulfur-induced electrophilic cyclization took
place to afford the formation of the thiophene ring (Scheme 1).
o-Bromoethynylbenzene 1 was treated with 2 equiv of t-BuLi in
Et2O to afford o-lithiophenylethynyllithium 2, to which was then
added 0.25 equiv of S8. This reaction would afford the intermediate
3. As given in Table 1, when this intermediate 3a (R = H) was trea-
ted with 2 equiv of MeI or benzylbromide, double methylated
product 6a or the double benzylated product 6b was obtained in
87% and 89% isolated yields, respectively. This reaction clearly
demonstrated the formation of the intermediate 3. Meanwhile, this
H
Li
1) 2 t-BuLi
2) 1/4 S8
r.t.,1 h
r.t., 2 h
Br
Li
R
R
R
1
2
R'
SLi
O
S
3) 2 R'COCl
or 2 (R'CO)2O
S
SLi
R'
R
O
3
4
SE
3) 1/8 S8
4) 2 EX
SE
S
5
R
⇑
Corresponding author. Tel.: +86 10 6275 9728; fax: +86 10 6275 1708.
E-mail address: zfxi@pku.edu.cn (Z. Xi).
Scheme 1. Synthesis of benzothiophene derivatives via electrophilic cyclization.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.098

6998
Z. Wang et al. / Tetrahedron Letters 52 (2011) 6997–6999
Table 1
Synthesis of benzothiophene derivatives 4 via electrophilic cyclizationa
H
SLi
1) 2 t-BuLi, r.t., 1 h
2) 1/4 S8, r.t., 2 h
Br
R'
SLi
R
R
3
1
3) 2 R'COCl
or 2 (R'CO)2O
3) 2 R'X
r. t.,1 h
R = H
r. t., 1 h
SR'
O
S
SR'
S
R
R'
6
R
O
6a: R' = Me, 87%
6b: R' =CH2Ph, 89%
4
O
O
O
Ph
n-Pr
t-Bu
S
S
S
S
S
S
Ph
Ad
n-Pr
t-Bu
O
O
O
4a, 91% (91%)b
4b, 90% (90%)b
4c, 85%
O
O
Ad
S
S
S
S
S
S
O
O
4e, 57%
4d, 85%
O
O
n-Pr
Ph
MeO
S
S
S
S
n-Pr
Ph
Cl
O
O
4f, 40%
Isolated yields.
4g, 51%
a
b
The yields in parenthesis were obtained with anhydride.
reaction also demonstrated that no cyclization was induced. When
2 equiv of acyl chlorides was added, an electrophilic cyclization oc-
curred to afford the corresponding di-substituted benzo[b]thio-
phenes 4a–e under this condition.1f,i,10 Acyl chlorides with either
alkyl or aromatic substituents could all afford their corresponding
benzo[b]thiophenes 4a–d in high isolated yields.11 Heteroaromatic
acyl chloride, such as thiophene-2-carbonyl chloride was also
applicable, yielding 4e in a moderate yield. Benzoic anhydride
and butyric anhydride could also induce this electrophilic cycliza-
tion, leading to the cyclized products 4a and 4b in 91% and 90% iso-
lated yields, respectively (Table 1). To check functional group
tolerance in this reaction, we applied 1-bromo-2-ethynyl-4-
methoxybenzene and 2-bromo-4-chloro-1-ethynylbenzene and
found 4f and 4g were also obtained, but in relatively lower yields.
such
unprecedented.
a
functionalized ladder
p-conjugated compound is
Addition of another equivalent of element sulfur to o-lithi-
ophenylethynyllithium 3a could induce cyclization to give a ben-
zothiophene bearing two S–Li bonds.1f,i,10 Further reaction of this
Table 2
Synthesis of benzothiophene derivatives 5 via electrophilic cyclizationa
SLi
1) 1/8 eq. S8
Et
SE
2O, r.t., 1 h
SE
2) 2.0 eq. EX
THF, r.t., 1 h
S
SLi
3a
5
S
Ph
S
Since ladder p-conjugated compounds of fully ring-fused poly-
S
cyclic skeletons are an important class of materials possessing sig-
nificant potential for application in organic electronics,1f,i we
applied the above synthetic protocol starting with 1d (Scheme
2). As expected, the ladder-type ring-fused polycyclic product 4h
was synthesized. Although the yield is not good, the synthesis of
S
Ph
S
S
S
5a, 84%
S
S
5c, 71%
5b, 82%
O
O
S
S
S
S
Ph
n-Pr
O
S
S
S
n-Pr
O
S
O
S
Ph
n-Pr
S
Br
n-Pr
1) 4 t-BuLi, r.t., 1h
S
O
O
S
S
5d, 89% (82%)b
2) 1/2 S8, r.t., 2h
S
5e, 80%
S
n-Pr
Br
O
3) 4 n-PrCOCl
O
5f, 89%
n-Pr
1d
r. t., 1h
4h,
28%
O
a
Isolated yields.
Scheme 2. Synthesis of a ladder-type
synthetic protocol.
p-conjugated compound 4h via the above
b
The yields in parenthesis were obtained with anhydride.

Z. Wang et al. / Tetrahedron Letters 52 (2011) 6997–6999
6999
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R
O
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RCOCl
2 EX
RCOCl
S8
S
S
SLi
4
5
Li
SLi
S
8
10
SLi
S
SLi
SLi
7
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11. Typical procedure for the preparation of products 4: In a 25 mL of flask, t-BuLi
(2 mmol, 1.6 M in pentane) was added dropwise at À78 °C to a stirred solution
of o-bromoethynyl-benzene (1 mmol, 181 mg) or its derivative (1 mmol) in
Et2O (5 mL) and the reaction mixture was allowed to warm to room
temperature. After stirring at room temperature for 1 h, S8 (0.25 mmol,
64 mg) was added and the reaction was stirred at room temperature for 2 h.
The solvent of the reaction mixture was evaporated under vacuum and THF
(5 mL) was added. After that, acid chloride (2 mmol) or anhydride (2 mmol)
was added dropwise at room temperature. After stirring at room temperature
for 1 h, the solvent of the reaction mixture was evaporated under vacuum. The
residue was purified by chromatography to give products 4.
species with 2 equiv of electrophilic reagents (EX) such as acyl
chlorides or alkyl halides afforded a new type of di-S-substituted
benzo[b]thiophenes 5a–f as the sole products in good to excellent
isolated yields (Table 2).12 Until now, the synthesis of benzothi-
ophenes bearing carbonyl groups was seldom reported.
With the results in hands, we supposed the reaction mechanism
below (Scheme 3). The lithioalkynolate 3 should be isomerized to
the intermediate 7 which bears a thioketene part.13 In the presence
of acyl chloride or elemental sulfur, intermediates 8 and 9 bearing
the thioketene part might be formed. These intermediates 8 and 9
would then undergo intramolecular 5-exo-dig cyclization to con-
struct the thiophene rings 10 and 11. Further reaction of com-
pounds 10 and 11 with electrophiles generated the final products
4 and 5, respectively.
In summary, we reported a convenient synthesis of multi-
substituted benzothiophene derivatives from readily available
dilithio reagents, elemental sulfur, and 2 equiv of acid chlorides.
By carefully controlling the amount of sulfur, the thiophene ring
could be conveniently constructed bearing different substituted
groups by an acid chloride-induced or S-induced cyclization.
Acknowledgments
This work was supported by the Natural Science Foundation of
China and the 973 Program (2011CB808705).
Compound 4a, Yellow oil, isolated yield 91% (340 mg); 1H NMR (300 MHz,
CDCl3, Me4Si, 25 °C): d = 7.30–7.90 (m, 14H, CH); 13C NMR (75 MHz, CDCl3,
Me4Si, 25 °C): d = 121.90 (1 CH), 123.90 (1 CH), 124.96 (1 CH), 125.79 (1 CH),
127.64 (2 CH), 128.53 (2 CH), 128.77 (2 CH), 129.75 (1 quat. C), 129.87 (2 CH),
133.64 (1 CH), 134.15 (1 CH), 135.48 (1 quat. C), 137.59 (1 quat. C), 137.79 (1
quat. C), 141.10 (1 quat. C), 142.23 (1 quat. C), 187.73 (1 quat. C), 192.29 (1
quat. C). HRMS calcd for C22H14O2S2 [M+H]+: 375.0514, found 375.0514.
12. Typical procedure for the preparation of products 5: In a 25 mL of flask, 3 was
dissolved in 5 mL Et2O. Another S8 (0.125 mmol, 32 mg) was added and the
reaction was stirred at room temperature for 1 h. The solvent of the reaction
mixture was evaporated under vacuum and THF (5 mL) was added. After that,
electrophilic reagents (2 mmol) were added dropwise at room temperature.
After being stirred at room temperature for 1 h, the solvent of the reaction
mixture was evaporated under vacuum. The residue was purified by
chromatography to give products 5.
Supplementary data
Supplementary data (experimental procedures and character-
ization data for all new compounds and copies of NMR spectra)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.10.098.
References and notes
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Compound 5a, Yellow oil, isolated yield 84% (162 mg); 1H NMR (300 MHz,
CDCl3, Me4Si, 25 °C): d = 2.34 (s, 3H, CH3), 2.63 (s, 3H, CH3), 7.23–7.42 (m, 2H,
CH), 7.71–7.87 (m, 2H, CH); 13C NMR (75 MHz, CDCl3, Me4Si, 25 °C): d = 18.10
(1 CH3), 18.26 (1 CH3), 121.85 (1 CH), 121.96 (1 CH), 123.89 (1 CH), 124.34 (1
quat. C), 124.84 (1 CH), 138.44 (1 quat. C), 140.65 (1 quat. C), 145.11 (1 quat. C).
HRMS calcd for C10H10S3 [M+H]+: 227.0023, found 227.0018.
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