Direct benzothiophene formation via oxygen-triggered intermolecular cyclization of thiophenols and alkynes assisted by manganese/PhCOOH

Article abstract of DOI:10.1021/ol400719d

An intermolecular oxidative cyclization between thiophenols and alkynes for benzothiophene formation has been established. A variety of multifunctional benzothiophenes are synthesized. In addition, we demonstrated that the obtained benzothiophenes can be

Full text of DOI:10.1021/ol400719d

ORGANIC
LETTERS
2013
Vol. 15, No. 8
2026–2029
Direct Benzothiophene Formation via
Oxygen-Triggered Intermolecular
Cyclization of Thiophenols and Alkynes
Assisted by Manganese/PhCOOH
Kaisheng Liu,† Fan Jia,† Hui Xi,† Yuanming Li,† Xiaojian Zheng,† Qiaoxia Guo,‡
Baojian Shen,‡ and Zhiping Li*,†,‡
Department of Chemistry, Renmin University of China, Beijing 100872, China,
and State Key Laboratory of Heavy Oil Processing, China University of Petroleum,
Beijing 102249, China
zhipingli@ruc.edu.cn
Received March 18, 2013
ABSTRACT
An intermolecular oxidative cyclization between thiophenols and alkynes for benzothiophene formation has been established. A variety of
multifunctional benzothiophenes are synthesized. In addition, we demonstrated that the obtained benzothiophenes can be used for further
transformation to give diverse benzothiophene derivatives efficiently and selectively.
The benzothiophene skeleton is an important hetero-
cycle.1 Compared with other heteroaromatic rings, espe-
cially its analogues benzofuran and indole, the synthetic
methods for the formation of benzothiophene skeleton are
rather limited.2 The most common approach is intramole-
cular cyclizations of R-arylthioketones,3 o-alkynyl (or alke-
nyl or ynol) benzenthiols,4 and alkynyl(aryl)thioethers.5
These reactions are selective and efficient, but prefunctio-
nalized thiophenols had to be synthesized for the cycliza-
tions. The intermolecular cyclization of thiophenols with
alkynes is envisioned as the most direct, simple, and atom-
economical approach to benzothiophene skeleton. Sup-
prisingly, although oxidative annulations of alkynes with
phenols6 and anilines7 have been realized for the synthesis
† Renmin University of China.
‡ China University of Petroleum.
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r
10.1021/ol400719d
Published on Web 04/11/2013
2013 American Chemical Society

of benzofuran and indole rings, respectively, a similar
strategy is not successful for benzothiophene formation,8
possibly due to the following challenges: (1) the catalyst
used could be poisoned by mercapto group in the starting
materials; (2) the hydrothiolation of sulfur and hydrogen
atoms from thiols to carbonꢀcarbon triple bond is an
efficient and feasible reaction (Scheme 1, a).9 Herein, we
disclose an efficient method for synthesis of benzothio-
phenes by the reactions of thiophenols with alkynes
(Scheme 1, b).
the applicabilityofthecurrent reaction process. Symmetric
or unsymmetrical alkynes all reacted well with thiophenol,
giving various substituted benzothiophenes. It is note-
worthy that thiophenol 1a selectively reacted with unsym-
metric alkyne 2m, and a single isomer of benzothiophene
3m was obtained. Monosubstituted benzothiophene 3n
was also generated by the use of terminal alkyne, while a
low yield was obtained due to the formation of hydro-
thiolation products (>50% combined yield). Importantly,
thiophenol-fused polycyclic aromatic compounds (3o and 3p)
could be synthesized utilizing meta- or para-dithiophenols,
demonstrating
a
potential application in organic
materials.10 Interestingly, thiophenol 1a reacted with 1,4-
diphenylbut-2-yne-1,4-dione 2g under optimized reaction
conditions to give the benzothiophene 3q in a 41% yield,
along with a 42% yield of 2,3-substituted indanone 5
(eq 1). This result indicated that a radical cyclization most
likely involves the present transformation.11
Scheme 1. Reaction Pathways of Thiophenol and Alkynes
Table 1. Optimization of the Reaction Conditionsa
The reactions of thiophenol 1a with dimethyl acetylene-
dicarboxylate 2a were investigated (Table 1). Delightedly,
when 1a reacted with 2a under oxygen atmosphere, ben-
zothiophene 3a was obtained in 55% yield (entry 1).
Subsequently, we focused on the metal screening to en-
hance the efficiency the desired reaction. Metal sources
such as FeCl3, Fe(OAc)2, CuCl conducting in this trans-
formation gave a trace amount of 3a, while the hydro-
thiolation product of carbonꢀcarbon triple bond 4 was
obtained as the major product (entries 2ꢀ4). Although
Cu(OAc)2 and CoCl2 alsodid notpromote the efficiencyof
the benzothiophene formation (entries 5 and 6), manga-
nese salts could help this process (entries 7 and 8). Im-
portantly, further studies showed that the extra Brønsted
acids as additives influenced the efficiency of oxidative
annulations of 1a and 2a (entries 9ꢀ12, see more examples
in the Supporting Information). Benzoic acid gave the best
result, and 3a could be obtained in 84% yield (entry 10).
With the optimized reaction conditions in hand, we
examined the scope of this transformation by synthesizing
a variety of benzothiophenes (Figure 1). Electron-donating
and electron-withdrawing substituted thiophenols all
gave the desired benzothiophenes 3aꢀh in good to excel-
lent yields. Ortho- or para-substituted thiophenols all
proceeded well under optimized reaction conditions. How-
ever, m-MeO-thiophenol 1h utilized in this transformation
showed poorregioselectivity (3h:3h0 =45:35). Itwasfound
that β-naphthiophenol 1i selectively cyclized at the
R-position. A variety of alkynes were also tested to examine
entry
catalyst
additive
3ab (%)
4b (%)
1
55
4
2 (1:1)
49 (3:1)
12 (5:1)
78 (9:1)
9 (4:1)
4 (1:1)
4 (1:1)
4 (1:1)
13 (1:1)
4 (1:1)
3 (2:1)
2
FeCl3
3
Fe(OAc)2
CuCl
6
4
5
5
Cu(OAc)2
CoCl2
25
57
67
64
27
84
77
42
6
7
Mn(OAc)2
MnO2
8
9
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
AcOH
10
11
12
PhCOOH
HCOOH
CF3COOH
a Conditions: 1a (0.5 mmol), 2a (1.0 mmol), DCE (5.0 mL), 50 °C,
2 h, under O2 (balloon). b Reported yields were based on 1a and
determined by 1H NMR using an internal standard; the ratio of Z/E
isomers is given in parentheses.
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Montevecchi, P. C.; Navacchia, M. L. Phosphorus, Sulfur Silicon 2000,
166, 201. (c) Benati, L.; Montevecchi, P. C.; Spagnolo, P. J. Chem. Soc.,
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1973, 27, 595.
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Ananikov, V. P. Chem. Rev. 2011, 111, 1596. (c) Kondo, T.; Mitsudo, T.
Chem. Rev. 2000, 100, 3205.
To further demonstrate the utility of the present reaction
in synthesizing various benzothiophene derivatives, the
(10) (a) Shinamura, S.; Osaka, I.; Miyazaki, E.; Nakao, A.;
Yamagishi, M.; Takeya, J.; Takimiya, K. J. Am. Chem. Soc. 2011,
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2010, 75, 1228.
Org. Lett., Vol. 15, No. 8, 2013
2027

the developed decarboxylative reactions (Scheme 3).13 The
decarboxylation product 3n was obtained in an excellent
yield by a silver-catalyzed protodecarboxylation of 7.14
The Heck-type coupling product 8 could be also achieved
using Pd(OTFA)2 as a catalyst, although the yield of 8 is
not satisfied at this stage.15 By switching of Pd(OTFA)2
to PdCl2 and adding 0.6 equiv of AsPh3, the decarboxyla-
tionꢀarylation products 9aꢀc were smoothly synthesized
in good yields.16 To our satisfaction, a decarboxylationꢀ
homocoupling product 10 could be generated in moderate
yield using PdCl2 as a catalyst and PPh3 as a ligand,17
which is potentially applicable to synthesize extended
π-conjugation of benzothiophene-based skeletons.
Scheme 2. Selective Hydrolysis of 3a
Scheme 3. Synthetic Transformations of 7
Figure 1. Representative results for the oxidative annulation
of thiophenols with alkynes. (a) Conditions: 1 (0.5 mmol),
2 (1.0 mmol), Mn(OAc)2 (0.025 mmol), PhCOOH (1.0 mmol),
DCE (5.0 mL), 50 °C, 2 h, under O2 (balloon). (b) Reported yields
were based on 1 and determined by 1H NMR using an internal
standard;isolatedyieldsaregiveninparentheses. (c)For synthesis
of 3o and 3p, 2a (2.0 mmol) and PhCOOH (2.0 mmol) were used.
transformations of the dimethyl benzo[b]thiophene-2,3-
dicarboxylate 3a obtained above were then investigated.
To our satisfaction, 2,3-dicarboxyl benzothiophene 6 and
2-carboxyl benzothiophene 7 were selectively and effi-
ciently obtained by hydrolysis of 3a under mild basic
conditions (Scheme 2).12 Using these selective hydrolyzed
products, we examined the transformation of the 7 for
synthesis of various benzothiophene derivatives through
In an effort to realize our interests of generating synthet-
ically useful structures, we also explored the transforma-
tionof3l (Scheme 4). Conversionof the compound3lusing
Lawesson reagent could easily synthesize the fused cyclic
compound 11 in a good yield.18 Hydrazinolysis of the
acetyl-substituted 3l with hydrazine hydrate afforded the
heterocyclic compound 12 under mild reaction conditions.
Furthermore, reduction of 3l with sodium borohydride in
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2028
Org. Lett., Vol. 15, No. 8, 2013

ethanol furnished a 1:1 diastereomer of diol 13 in a good
combined yield.
intermediate III by hydrogen peroxyl radical. Benzoic acid
plays a proton donor to neutralize hydrogen peroxide
anion. Deprotonation of III assisted by benzoate leads to
the final benzothiophene 3a.
Scheme 4. Synthetic Transformations of 3l
Scheme 5. Tentative Reaction Mechanism
In order to clarify the possible pathways of the present
oxidative annulation, the reactions of 1a with 2a were
performed under nitrogen in the absence and presence of
Mn(OAc)2 (eqs 2 and 3). In both cases, vinyl thioether 4
was formed in excellent yields, while 3a was not observed.
Importantly, the transformation of 4 into 3a could be
excluded by the reaction of 4 under standard oxidative
cyclization conditions. Furthermore, a series of controlled
experiments, the starch iodide tests, were carried out (see
details in the Supporting Information). The preliminary
results indicated that H2O2 is generated simultaneously in
the course of benzothiophene formation. On the basis of
our results and literature reports,19 a tentative mechanism
for the oxidative annulation of thiophenol 1a with di-
methyl acetylenedicarboxylate 2a to form benzothiophene
3a is proposed in Scheme 5. Initially, a benzenesulfanyl
radical is generated by oxygen-triggered hydrogen abstrac-
tion of 1a, meanwhile releasing hydrogen peroxyl radical.
The catalyst, Mn(OAc)2, likely plays a role to activate
oxygen and/or stabilize hydrogen peroxyl radical.20 The
addition of thiyl radical to alkyne 2a leads to the vinyl
radical intermediate I. The 5-(π-endo)ortho cyclization
gives the intermediate II, which is oxidized to the cationic
In conclusion, we have developed an efficient and
practical protocol for benzothiophene formation through
direct intermolecular oxidative cyclization between simple
thiophenols and alkynes. A variety of functionalized ben-
zothiophenes was synthesized. In addition, the obtained
benzothiophenes also can be used for further transforma-
tion, such as selective hydrolysis, decarboxylation/cou-
pling, hydrazinolysis to give valuable compounds.
Acknowledgment. Financial support by the National
Science Foundation of China (20832002, 21072223,
21272267), State Key Laboratory of Heavy Oil Processing
(2012-1-06), the Fundamental Research Funds for the
Central Universities, and the Research Funds of Renmin
University of China (10XNL017).
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Supporting Information Available. Representative ex-
perimental procedure, characterization of all new com-
1
pounds, and H and 13C NMR data. This material is
available free of charge via the Internet at http://pubs.acs.org.
€
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The authors declare no competing financial interest.
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