Radical Cyclization of Arenesulfonyl Chlorides and Alkynes: A Rapid Access to π-Conjugated Benzothiophenes

Article abstract of DOI:10.1002/ejoc.201501439

A metal-free radical cyclization of arenesulfonyl chlorides with alkynes has been developed, which provides a rapid and practical access to a variety of π-conjugated benzothiophenes with a broad reactive functional group tolerance. Furthermore, dialkynyl compounds could also undergo this transformation to give extended π-systems in good yields.

Full text of DOI:10.1002/ejoc.201501439

DOI: 10.1002/ejoc.201501439
Communication
Radical Cyclizations
Radical Cyclization of Arenesulfonyl Chlorides and Alkynes: A
Rapid Access to π-Conjugated Benzothiophenes
Danyang Wan,[a] Yudong Yang,*[a] Xingyan Liu,[a] Mingliang Li,[a] Siling Zhao,[a] and
Jingsong You*[a]
Abstract: A metal-free radical cyclization of arenesulfonyl thiophenes with a broad reactive functional group tolerance.
chlorides with alkynes has been developed, which provides a Furthermore, dialkynyl compounds could also undergo this
rapid and practical access to a variety of π-conjugated benzo- transformation to give extended π-systems in good yields.
Introduction
π-Conjugated benzo[b]thiophenes widely exist in pharmaceuti-
cals, agrochemicals, organic functional materials and intermedi-
ates for organic synthesis.[1] In particular, 2,3-diarylbenzo[b]thio-
phenes are known as excellent structural features for various
bioactive molecules and optoelectronic materials, such as non-
steroidal antiestrogens,[2] photochromic materials,[3] light-emit-
ting diodes (LEDs)[4] and field-effect transistors (FETs)[5]
(Scheme 1). Thus, the development of concise and efficient
methods to construct these skeletons by starting from easily
available precursors would provide novel opportunities to rap-
idly assemble divergent libraries for screening of specific func-
tional molecules.
The existing approaches for the synthesis of π-conjugated
2,3-diarylbenzo[b]thiophenes mainly involve cyclization of thio-
phenol with desyl halides,[6] transition-metal-catalyzed C–X/C–
M coupling of benzothiophenes and arenes,[7] palladium-cata-
lyzed intramolecular cyclization of thioenols[8] and nickel-cata-
lyzed cycloaddition of thiophthalic anhydrides with alkynes[9]
[Scheme 2, Paths (a)–(d)]. Despite their efficiency, these meth-
ods generally require the participation of transition metal cata-
lysts and suffer from disadvantages such as tedious synthetic
procedures, not readily available precursors and narrow sub-
strate scope, which to a certain extent limit the rapid diversifica-
tion of 2,3-diarylbenzo[b]thiophenes. Recently, intermolecular
radical cyclizations of thiophenols and disulfides with alkynes
to synthesize benzothiophenes have been reported by Li and
Wang,[10,11] respectively. Although these two reactions are effi-
cient, only electron-deficient alkynes worked smoothly under
the standard conditions. Most notably, both of these reactions
Scheme 1. Selected functional molecules containing 2,3-diarylbenzo[b]thio-
phene structures.
failed to afford 2,3-diarylbenzo[b]thiophenes. Thus, the devel-
opment of complementary alternatives, particularly transition-
metal-free methods, to rapidly assemble 2,3-diarylbenzo[b]thio-
phenes from simple precursors is still an appealing task.[10–12]
Herein, we disclose an expedient and practical method to con-
struct a diverse set of π-conjugated benzo[b]thiophenes by rad-
ical cyclization of arenesulfonyl chlorides and alkynes under
metal-free conditions [Scheme 2, Path (e)]. Furthermore, the
metal-free conditions obviate trace metal impurities in the end
products, which would be highly advantageous in pharmaceuti-
cal and material industry.
[a] Key Laboratory of Green Chemistry and Technology of Ministry of
Education, College of Chemistry, and State Key Laboratory of Biotherapy,
West China Medical School, Sichuan University
29 Wangjiang Road, Chengdu 610064, P. R. China
E-mail: yangyudong@scu.edu.cn
jsyou@scu.edu.cn
http://www.scu.edu.cn/en/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501439.
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Table 1. Optimization of the one-pot cyclization reaction of tosyl chloride
with 1,2-diphenylacetylene.[a]
Entry
Solvent
Oxidant
Time [h]
Yield [%]
1
2
3
4
5
6
7
8
9
10
11[b]
12[b]
13[b]
toluene
toluene
toluene
toluene
toluene
toluene
xylene
dioxane
DMF
DTBP
Cu(OAc)2
DDQ
24
24
24
24
24
24
24
24
24
24
24
24
24
37
n.d.
n.d.
n.d.
10
n.d.
29
trace
27
21
41
49
67
O2
TBHP
K2S2O8
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
THF
toluene
THF
Scheme 2. Strategies for the synthesis of 2,3-diarylbenzo[b]thiophenes.
toluene/THF =
0.5 mL:0.5 mL
xylene/THF =
0.5 mL:0.5 mL
xylene/THF =
1.0 mL:1.0 mL
xylene/THF =
0.1 mL:1.0 mL
xylene/THF =
1.0 mL:0.1 mL
xylene/THF =
0.5 mL:0.5 mL
xylene/THF =
0.5 mL:0.5 mL
xylene/THF =
0.5 mL:0.5 mL
14[b]
15[b]
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
24
24
24
24
24
18
18
71
57
52
71
76
59
56
Results and Discussion
The current reaction was found serendipitously in our effort to
explore the palladium-catalyzed annulation of tosyl chloride
(1a) with diphenylacetylene (2a) to synthesize benzo[b]thio-
phene S,S-dioxides. Unexpectedly, benzothiophenes were ob-
tained instead of the desired product. Subsequently, this inter-
molecular annulation reaction was observed even in the ab-
sence of a metal catalyst. Considering the wide utility of benzo-
thiophenes and easy availability of arenesulfonyl chlorides, we
were interested in this metal-free benzothiophene synthesis. It
was observed that only organic peroxides could promote this
transformation, and other oxidants such as Cu(OAc)2, DDQ, O2,
and K2S2O8 were inefficient in our investigation (Table 1, En-
tries 1–6). The solvent parameter was next explored, and a mix-
ture of xylene/THF (1:1) was found to be the optimal choice,
giving the desired product in 71 % yield (Table 1, Entries 7–16).
Increasing the amount of PPh3 to 6.0 equiv. led to a modestly
increased yield (Table 1, Entries 10 and 12). Heating the reaction
mixture of 1a, 2a and Ph3P at 120 °C for 3 h before the addition
of DTBP slightly improved the yield of the desired product 3aa
from 71 % to 76 % (Table 1, Entries 14 and 18).
16[b]
17[b,c]
18[b,c]
19[b,c]
20[b–d]
[a] The reaction was performed with 1a (0.75 mmol, 3.0 equiv.), 2a
(0.25 mmol, 1.0 equiv.), oxidant (4.0 equiv.) and PPh3 (3.0 equiv.) in solvent
(1.0 mL) under N2; isolated yields; n.d. = not detected, DDQ = 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone, DTBP = di-tert-butyl peroxide, TBHP = tert-
butyl hydroperoxide. [b] 6.0 equiv. of PPh3 was used. [c] DTBP was added
after heating of the reaction mixture at 120 °C for 3 h. [d] Air was used
instead of N2.
ated under the optimized conditions, which facilitates further
synthetic manipulations (Table 3; 3ac–3ad and 3af). We were
pleased to find that dithienylacetylene could also undergo the
With the optimized conditions in hand, we next examined cyclization to give the desired product 3ah in 80 % yield. The
the substrate scope of this transformation. Arenesulfonyl chlor- reactions of unsymmetrical alkynes regioselectively delivered
ides with both electron-donating and electron-withdrawing the corresponding products with the aryl moieties on the 3-
groups worked smoothly to afford benzothiophenes in moder- position of the resulting benzothiophenes (Table 3; 3ai and
ate to high yields under the standard conditions, whereas elec- 3aj). The structure of 3aj was confirmed by X-ray diffraction
tron-donating groups led to a negative effect on the yield analysis (Figure S1).[13]
(Table 2; 3aa–3ia). It was observed that the annulation occurred
regioselectively at the α-position of β-naphthalenesulfonyl
chloride to give 3da in 82 % yield. In contrast, 3-methyl-substi-
tuted arenesulfonyl chloride gave a mixture of two regioisomers
(Table 2; 3ja + 3ja′).
π-Extended polyheterocycles are important skeletons for
optoelectronic materials. To further elucidate the utility of our
protocol, we conducted this transformation with dialkynyl com-
pounds. Dialkynes with electron-withdrawing benzothiadiazole
(BT) and tetrafluorobenzene substituents, two important struc-
This reaction also exhibited good compatibility with a rela- tural units for organic optoelectronic materials,[14] smoothly un-
tively broad range of symmetrical and unsymmetrical alkynes derwent the cyclization with tosyl chloride to afford the donor–
(Table 3; 3ab–3aj). It is noteworthy that a variety of functional acceptor–donor (D–A–D) structures 4aa and 4ab in satisfactory
groups such as alkyloxy, ketone, ester, and bromo were toler- yields (Scheme 3).
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Communication
Table 2. Scope of arenesulfonyl chlorides.[a]
Table 3. Scope of alkynes.[a]
[a] Reaction conditions: 1 (3.0 equiv.), 2a (0.25 mmol, 1.0 equiv.), and PPh3
(6.0 equiv.) were stirred in xylene/THF (0.5 mL:0.5 mL) at 120 °C for 3 h; DTBP
(4.0 equiv.) was then added and the mixture further stirred at 120 °C for 21 h;
isolated yields.
[a] Reactions conditions: 1a (3.0 equiv.), 2 (0.25 mmol, 1.0 equiv.), and PPh3
(6.0 equiv.) were stirred in xylene/THF (0.5 mL:0.5 mL) at 120 °C for 3 h; DTBP
(4.0 equiv.) was then added and the mixture further stirred at 120 °C for 21 h;
isolated yield.
Next, we were interested in the mechanism of this reaction.
It is known that arysulfonyl chlorides are reduced by triphenyl- servations indicated that disulfide might act as the intermediate
phosphine to yield arylthiols,[15] arenesulfenyl chloride[16] and/ in this cyclization reaction. It should be noted that this result
or disulfides.[17] To confirm, which sulfur species is responsible is different from our previous finding in the sulfenylation of
for this annulation reaction, controlled experiments were con- (hetero)arenes with arenesulfonyl chlorides, in which arenesulf-
ducted. The reaction of PPh3 with tosyl chloride gave rise to enyl chloride is proposed to be the active intermediate.[16b] At
the corresponding disulfide in 69 % yield in a mixture of xylene/ last, butylated hydroxytoluene (BHT), a well-known radical-cap-
THF (1:1) at 120 °C for 3 h [Equation (1)]. When disulfide, aryl- turing reagent, was introduced into the reaction system under
thiol or arenesulfenyl chloride were heated with diphenylacet- the standard conditions [Equation (4)]. The reaction was almost
ylene in the presence of 4.0 equiv. of DTBP, only p-tolyl disulfide completely inhibited, and the BHT-trapped complex p-MePhS–
gave the corresponding benzenthiophene in 71 % yield [Equa- BHT was detected by GC–MS analysis (see the Supporting Infor-
tion (2)], whereas p-toluenesulfenyl chloride and p-tolylthiol mation), which indicated that this transformation might un-
failed to undergo this transformation [Equation (3)]. These ob- dergo a radical pathway.[18]
Scheme 3. Cyclization with dialkyne substrates.
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Communication
Scheme 4. Proposed mechanism for cyclization.
agents, and leaving groups. In this work, we disclosed that ar-
enesulfonyl chlorides can be used as handles for the construc-
tion of a variety of π-conjugated benzothiophenes by a metal-
free radical cyclization with alkynes, which extends the utility
of this versatile regent. The application in the construction of
π-extended polyheterocycles demonstrates the potential in the
exploitation of novel optoelectronic materials. Preliminary
mechanism studies suggest that disulfide might be the active
intermediate for this annulation reaction. Further studies on the
application of this method are ongoing in our laboratory.
(1)
(2)
Experimental Section
Detailed experimental procedures are given in the Supporting Infor-
mation.
Supporting Information (see footnote on the first page of this
(3)
article): Experimental details, characterization data, and copies of
1
the H and 13C NMR spectra of all key intermediates and final pro-
ducts.
Acknowledgments
This work was supported by grants from the National Natural
Science Foundation of China (NSF of China) (nos. 21432005,
21272160, and 21321061), and the Comprehensive Training
Platform of Specialized Laboratory, College of Chemistry, Sich-
uan University.
(4)
On the basis of the above observations and previous re-
ports,[11] a plausible mechanism for this metal-free cyclization
is depicted in Scheme 4. Initially, arenesulfonyl chloride 1a is
reduced by triphenylphosphine to generate diaryl disulfide 5a,
which then undergoes homolytic cleavage to generate thiyl
radical A in the presence of DTBP. Subsequently, the addition
of thiyl radical A to acetylene 2a produces alkenyl radical inter-
mediate B, followed by intramolecular radical annulation to
give intermediate C. Finally, hydrogen abstraction of intermedi-
ate C by tert-butyl peroxy radical leads to the desired product
3aa.
Keywords: Metal-free reactions · Radical reactions ·
Cyclization · Arenesulfonyl chlorides · Alkynes ·
Benzo[b]thiophene
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Received: November 11, 2015
Published Online: December 9, 2015
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