Synthesis of 3-(Arylsulfonyl)benzothiophenes and Benzoselenophenes via TBHP-Initiated Radical Cyclization of 2-Alkynylthioanisoles or -selenoanisoles with Sulfinic Acids

Article abstract of DOI:10.1021/acs.orglett.7b02971

tert-Butyl hydroperoxide-initiated radical cyclization of 2-alkynylthioanisoles or -selenoanisoles with sulfinic acids has been developed. This reaction is applicable to a wide substrate scope via one C(sp³)-S(Se) bond cleavage and two C(sp²)-S(Se) bond formation, leading to the synthesis of 3-(arylsulfonyl)benzothiophenes or -benzoselenophenes under mild conditions.

Full text of DOI:10.1021/acs.orglett.7b02971

Letter
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
pubs.acs.org/OrgLett
Synthesis of 3‑(Arylsulfonyl)benzothiophenes and
Benzoselenophenes via TBHP-Initiated Radical Cyclization of
2‑Alkynylthioanisoles or -selenoanisoles with Sulfinic Acids
Jian Xu, Xiaoxia Yu, Jianxiang Yan, and Qiuling Song*
Institute of Next Generation Matter Transformation, College of Chemical Engineering and College of Material Sciences Engineering,
Huaqiao University, 668 Jimei Boulevard, Xiamen, Fujian 361021, P. R. China
*
S Supporting Information
ABSTRACT: tert-Butyl hydroperoxide-initiated radical cycliza-
tion of 2-alkynylthioanisoles or -selenoanisoles with sulfinic
acids has been developed. This reaction is applicable to a wide
3
substrate scope via one C(sp )−S(Se) bond cleavage and two
2
C(sp )−S(Se) bond formation, leading to the synthesis of 3-
(
arylsulfonyl)benzothiophenes or -benzoselenophenes under
mild conditions.
5d,f
enzothiophene and its derivatives are an important class of
electrophilic reagents.
Recently, the Blum and Ingleson
B
heterocyclic compounds that have been extensively
exploited in medical chemistry, natural products, and materials
science. Among them, 3-substituted benzothiophenes are
groups independently reported ClBcat- or BCl -induced
3
borylative cyclization of 2-alkynylthioanisoles for the synthesis
1
5a,b
of C3-borylated benzothiophenes.
especially important since many pharmaceuticals as well as
drug candidates contain this scaffold. A variety of concise and
Synthesis of sulfone-containing compounds via radical
2
cascade reactions has attracted significant attention because of
6
robust synthetic protocols have been developed to access 3-
their simple operation and easily accessible substrates. These
3
substituted benzothiophenes; among them, 2-alkynylthioani-
transformations allow access to a wide range of sulfone-
containing heterocycles including 3-sulfonylindoles, 3-sulfo-
nated 4-quinolones and 3-arylsulfonylquinolines. Despite these
advances, continuous efforts are still required, especially for the
synthesis of 3-sulfonylbenzothiophene due to their importance
soles are usually chosen as the substrates. To date, two
pathways have been proven efficient and valuable to access 3-
substituted benzothiophenes from 2-alkynylthioanisoles: (i)
[
1,3] shift of the migrating groups including silyl, alkoxyalkyl,
7
4
in biology and the pharmaceutical chemistry (Figure 1).
and benzyl on the sulfur atom (Scheme 1a) and (ii)
electrophilic cyclization of the o-(1-alkynyl)thioanisoles
5
(
Scheme 1b). Larock and co-workers reported the synthesis
of 3-halo-substituted benzothiophenes with I2 and Br2 as
Scheme 1. Strategies for the Synthesis of 3-Substituted
Benzothiophene from 2-Alkynylthioanisoles
Figure 1. Representative examples of biologically active 3-
sulfonylbenzothiophene derivatives.
Meanwhile, radical cascade reactions have also emerged as
efficient approaches for the construction of benzothiophenes.
For example, the Li group reported the synthesis of
benzothiophene scaffolds through Mn-catalyzed intermolecular
8
cyclization of alkynes and thiophenols. Zanardi’s, McDonald’s,
̈
Schiesser’s and Konig’s groups disclosed the synthesis of
Received: September 27, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02971
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
benzothiophenes via annulation reaction between o-methylthio-
arenediazonium salts and alkynes. Very recently, Zhang and
Scheme 2. Scope of Sulfinic Acids
9
co-workers improved this method by using anilines instead of
1
0
diazonium salts.
As part of our ongoing interests in the synthesis of
11
heterocycles via radical cascade reactions, herein we described
a new approach to the construction of benzothiophenes via
radical cyclization of 2-alkynylthioanisoles with sulfinic acids
(
Scheme 1c).
Initially, we utilized p-tolylsulfinic acid (1a) and methyl-(2-
alkynylphenyl)sulfanes (2a) as the model substrates to optimize
the reaction conditions. When TBHP (100 mol %) was chosen
as the initiator with DMF as the solvent, 3a was obtained in
55% yield at 80 °C under argon (Table 1, entry 1). Encouraged
a
Table 1. Optimization of Reaction Conditions
b
entry
initiator (mol %)
temp (°C)
solvent
yield (%)
1
2
3
4
5
6
7
8
9
TBHP (100)
DTBP (100)
BPO (100)
80
80
DMF
DMF
DMF
DMF
DMF
DMF
DCE
55
34
40
48
33
39
49
58
60
78
65
81
75
82
80
TBHP (100)
TBPB (100)
DCP (100)
80
80
a
Reaction conditions: 1 (0.4 mmol), 2a (0.2 mmol), TBHP (80 mol
80
%
), in CH CN (2 mL) stirring under argon in 100 °C for 1 h.
3
TBHP (100)
TBHP (100)
TBHP (100)
TBHP (100)
TBHP (100)
TBHP (100)
TBHP (100)
TBHP (80)
80
80
dioxane
toluene
80
candidates as well, and the corresponding products 3l and 3m
were obtained in 55% and 42% yields, respectively, by the
reaction with 2a. Unfortunately, when aliphatic sulfinic acids
were used as substrates under the optimal reaction conditions,
no desired product was detected.
We next investigated the scope of 2-alkynylthioanisoles
(Scheme 3). Alkynes with electron-donating substituents on
the aromatic rings could be engaged in this reaction, providing
the desired benzothiophenes in good yields (3n−r). Halogens
at different positions of phenyl rings were also compatible (3s−
w). It is of note that electron-withdrawing substituents such as
10
11
12
13
14
80
CH CN
3
80
DMSO
100
70
CH CN
3
CH CN
3
100
CH CN
3
a
Reaction conditions: 1a (0.4 mmol), 2a (0.2 mmol), initiator (0.15
mmol) in solvent (2 mL) stirring under argon for 1 h. Yields of
isolated ones.
b
by this result, a variety of initiators, including DTBP, BPO,
TBPB, and DCP (Table 1, entries 2−6), were examined
carefully; however, no better results were observed. Sub-
NO or CN on the right benzene ring affect the transformation
2
significantly, and the corresponding products were only
obtained in acceptable yields (3x and 3y, 32% and 55%).
In terms of aliphatic alkynes, such as 1aa and 1ab, no
corresponding desired products were obtained probably due to
the unstable alkenyl radical intermediate. Additionally, our
approach is also applicable for constructing the thiophene ring
in view of 3ac.
sequently, different solvents were investigated, and CH CN was
3
found to be the most efficient one (78%) among THF, dioxane,
and DCE (Table 1, entries 7−11). Further temperature and
initiator loading optimization showed that 80 °C and 80 mol %
of TBHP were the best choice.
With the optimized reaction conditions in hand, a wide range
of sulfinic acids 1b−m were then examined with 2a, and the
results are summarized in Scheme 2. Sulfinic acids with
electron-donating substituents such as t-Bu and OMe on the
para position of the phenyl ring proceeded smoothly, and the
corresponding products 3c and 3d were obtained in 70% and
Most importantly, substituted 2-alkynylselenoanisoles were
also suitable substrates to deliver a series of 3-(arylsulfonyl)-
benzoselenophene derivatives in moderate yields (5a−f, 52−
65%) (Scheme 4).
The reaction could be easily scaled up to 4.0 mmol with the
model substrates, affording 3a in a slightly reducing yield (75%
yield). Furthermore, the Ts moiety could be easily removed
under reductive conditions to obtain 2-phenyl benzothiophene
(6) in 78% yield, and 3a also could be transformed to 7 with m-
CPBA as an oxidant (Scheme 5).
To gain some mechanistic insights, a series of control
experiments were performed. First, the reaction was conducted
in the absence of p-tolylsulfinic acid; not surprisingly, no
desired product 6 was observed (2a was recovered in 85%
75% yields. Halide substituents such as F, Cl, and Br on
different positions of the phenyl rings proceeded smoothly,
affording the desired products in moderate to good yields (3e−
i, 68−76%). Moreover, substrates bearing strong electron-
withdrawing groups such as NO and CN were also compatible
2
under the standard conditions, rendering the target molecules
3
j and 3k in 40% and 65% yields, respectively. Of note,
naphthyl- and thienyl-based sulfinic acids 1l and 1m were good
B
DOI: 10.1021/acs.orglett.7b02971
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Scope of Alkynes
Scheme 6. Control Experiments
reaction was completely inhibited (Scheme 6b). These results
implied that a single electron transfer pathway (SET) might be
involved in this transformation. When the methyl in the sulfur
atom was changed to ethyl and benzyl, 3a also could be
obtained in 81% and 85% yields, respectively. However, the
yield of 3a was reduced to 45% when phenyl was used as a
substituent, which might be due to the unstable of phenyl
radical. Additionally, benzene and toluene could be detected by
GC−MS in our reaction mixtures, which might be generated
from phenyl and benzyl radicals.
On the basis of control experiments as well as previous
reports, a plausible mechanism for this radical mediated
cyclization reaction is proposed in Scheme 7. Initially, the
a
Reaction conditions: 1a (0.4 mmol), 2 (0.2 mmol), TBHP (80 mol
%
), in CH CN (2 mL) stirring under argon in 100 °C for 1 h.
3
Scheme 4. Scope for the Formation of 3-
Scheme 7. Proposed Mechanism
a
(Arylsulfonyl)benzoselenophene Derivatives
combination of TBHP and sulfinic acid 1a leads to the
formation of sulfonyl radical A, which selectively attacks the C−
C triple bond of 2a to afford the vinyl radical B. This in situ
generated vinyl radical subsequently reacts with SMe moiety via
5
-exo-trig cyclization mode to lead to the final product 3a along
with the release of methyl radical. The methyl radical further
react via H-abstraction from the reaction mixture.
In conclusion, we have successfully developed a TBHP-
initiated tandem radical addition−cyclization reaction between
a
Reaction conditions: 1 (0.4 mmol), 4 (0.2 mmol), TBHP (80 mol
%
), in CH CN (2 mL) stirring under argon in 100 °C for 1 h.
3
2
-alkynylthioanisoles and sulfinic acids, rendering 3-
Scheme 5. Gram Scale-up and the Transformation of
Product 3a
(
(
arylsulfonyl)benzothiophenes in good yields with two C-
sp )−S bonds formation and one C(sp )−S bond cleavage in
2
3
one pot. This method features easily accessible substrates,
simple operation, and short reaction time.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02971.
1
yield) (Scheme 6a). When radical scavengers TEMPO or BHT
were added to the model reaction, the tandem cyclization
Experimental procedure, characterization data, and H,
C, and F NMR spectra (PDF)
13
19
C
DOI: 10.1021/acs.orglett.7b02971
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Accession Codes
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CCDC 1571247 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
(
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
Fax: 86-592-6162990. E-mail: qsong@hqu.edu.cn.
■
*
(
f) Zhang, L.; Chen, S.; Gao, Y.; Zhang, P.; Wu, Y.; Tang, G.; Zhao, Y.
Org. Lett. 2016, 18, 1286. (g) Fu, R.; Hao, W.-J.; Wu, Y.-N.; Wang, N.-
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W.-J.; Du, Y.; Wang, D.; Jiang, B.; Gao, Q.; Tu, S.-J.; Li, G. Org. Lett.
016, 18, 1884. (i) Zhu, Y.-L.; Jiang, B.; Hao, W.-J.; Wang, A.-F.; Qiu,
J.-K.; Wei, P.; Wang, D.-C.; Li, G.; Tu, S.-J. Chem. Commun. 2016, 52,
907. (j) Yang, Z.; Hao, W.-J.; Wang, S.-L.; Zhang, J.-P.; Jiang, B.; Li,
ORCID
2
Qiuling Song: 0000-0002-9836-8860
Notes
1
G.; Tu, S.-J. J. Org. Chem. 2015, 80, 9224. (k) Wei, W.; Wen, J.; Yang,
D.; Guo, M.; Wang, Y.; You, J.; Wang, H. Chem. Commun. 2015, 51,
The authors declare no competing financial interest.
7
68. (l) Yang, W.; Yang, S.; Li, P.; Wang, L. Chem. Commun. 2015, 51,
ACKNOWLEDGMENTS
7520. (m) Qiu, J.-K.; Hao, W.-J.; Wang, D.-C.; Wei, P.; Sun, J.; Jiang,
B.; Tu, S.-J. Chem. Commun. 2014, 50, 14782. (n) Lu, Q.; Zhang, J.;
Zhao, G.; Qi, Y.; Wang, H.; Lei, A. J. Am. Chem. Soc. 2013, 135, 11481.
■
Global Experts (1000 Talents Plan), National Natural Science
Foundation of China (21602065), Fujian Hundred Talents
Plan and Program of Innovative Research Team of Huaqiao
University (Z14X0047), and the China Postdoctoral Science
Foundation (163633) are gratefully acknowledged. We also
thank the Instrumental Analysis Center of Huaqiao University
for analysis support.
(
o) Lu, Q.; Zhang, J.; Wei, F.; Qi, Y.; Wang, H.; Liu, Z.; Lei, A. Angew.
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