Three-component 2-aryl substituted benzothiophene formation under transition-metal free conditions

Article abstract of DOI:10.1039/c6ra07730g

A base-mediated 2-aryl substituted benzothiophene formation from 2-bromobenzene aldehydes, benzylic esters and elemental sulfur under transition-metal-free conditions is described. Various 2-aryl substituted benzothiophene were efficiently obtained under mild conditions.

Full text of DOI:10.1039/c6ra07730g

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COMMUNICATION
Three-component 2-aryl substituted benzothiophene formation under
transition-metal free conditions
Pengcheng Jiang,a Xingzong Che,a Yunfeng Liao,a Huawen Huanga* and Guo-Jun Denga*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
NH2
I
[Cu] cat.
cat.-free
N
S
A base-mediated 2-aryl substituted benzothiophene formation
from 2-bromobenzene aldehydes, benzylic esters and elemen-
tal sulfur under transition-metal-free conditions is described.
Various 2-aryl substituted benzothiophene were efficiently
(a)
(b)
(c)
+ S +
R
R
O
NO2
N
S
10 obtained under mild conditions.
+ S +
+ S +
Ar
LG
LG
Ar
R
X
Benzothiophene derivatives are basic skeletons frequently found
in electronic materials as well as various biologically active mo-
lecules.1 The benzothiophene motifs also can be found in a num-
15 ber of medicinally important molecules such as raloxifene (selec-
tive estrogen receptor modulators), arzoxifene (antitubulin agents)
and zileuton (selective inhibitor of 5-lipoxygenase).2 Consequent-
ly, the development of convenient synthetic methods to these
sulfur-containing heterocycles has received much attention during
20 the past decades. However, compared with other heteroaromatic
rings, especially its analogues benzofuran, indole and benzothia-
zole, efficient methods for the preparation of benzothiophene
skeleton are rather limited. The most common approach is based
on the intramolecular cyclization procedures.3 α-Arylthioketones,
25 o-alkynyl (or ynol or alkenyl) benzenthiols, and alky-
nyl(aryl)thioethers are frequently used as the substrates for this
transformation. Other methods recently developed include metal-
promoted annulation approaches with highly functionalized thio-
phenols and photocatalytic synthesis of benzothiophenes with
30 visible light from o-methylthio-arenediazonium salts and al-
kynes.4 These reactions are proved efficient and selective, but
prefunctionalized thiophenols had to be synthesized before the
cyclization reactions. To overcome this limitation, Li et al. devel-
oped an oxygen-triggered intermolecular cyclization of thiophe-
35 nols with electron-deficient alkynes to provide a more direct ap-
proach to benzothiophene skeleton.5 Alternatively, the transition-
metal catalyzed cross-coupling reactions of metalated benzothio-
phenes and halogenated arenes could provide an efficient ap-
proach for aryl-substituted benzothiophene.6 More recently, the
40 direct arylation of benzothiophene has emerged as an attractive
approach for the preparation of substituted benzothiophenes by
skipping prefunctionalization of the substrates.7 Transition metals
such as palladium and copper were proved to be effective cata-
lysts for these reactions.
CHO
base
R
S
this work
X
1
3
2
base
CHO
S
-LGOH
OH
base
LG
R
LG
S
II
R
I
Scheme 1 Sulfur-containing heterocycle formation using elemen-
tal sulfur. X = F, Cl, Br; LG = leaving group.
50
In recent years, sulfur-containing heterocycle formation using
cheap, non-volatile and readily available elemental sulfur as the
sulfur source has attracted great attention.8 Zhou and co-workers
developed a copper-catalyzed multicomponent reaction for the
55 synthesis of 2-substituted benzothiazoles from 2-iodo-anilines,
aldehydes, and elemental sulfur (Scheme 1a).8a Using elemental
sulfur as the sulfur source for the synthesis of benzothiazoles,
Nguyen8b,8c and Han8d independently disclosed a concise reaction
by redox condensation between o-halonitrobenzenes and methy-
60 larenes under catalyst-free conditions (Scheme 1b). Based on our
previous efforts of sulfur-containing heterocycle synthesis from
elemental sulfur,9 we suspect the coupling of 2-
halobenzaldehydes, methylarenes, and elemental sulfur could
form aryl sulfide intermediate I, which then proceed through
65 condensation and subsequent elimination to afford benzothio-
phenes (Scheme 1c). Herein, we report such a three-component
approach for the 2-aryl benzothiophene formation from 2-
halobenzaldehydes, benzylic esters and sulfur under air.
To obtain the optimized reaction conditions, we began our
70 study by examining a series of methylarenes with a range of leav-
ing groups. Based on previous report, toluene even 4-methyl
pyridine were firstly tested, and unfortunately the desired product
was not observed (Table 1, entry 1). Moreover, benzylamine was
also found unproductive (entry 2). To our delight, when we tested
75 benzyl chloride as the substrate, the desired benzothiophene 3a
was formed, albeit in a low yield. Since the reaction is proposed
to be base-initiated transformation, the reactants with electron-
withdrawing leaving group such as carboxyl and ester were then
screened. While phenylacetic acid gave a low yield of 3a, methyl
80 phenylacetate enhanced the yield to 60% (entry 5). The promising
O
O
N
N
O
O
HO
N
NH2
O
OH
OMe
S
S
S
HO
HO
Raloxifene
Arzoxifene
Zieuton
45
Figure 1 Some medicines based on benzothiophene motifs.
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[journal], [year], [vol], 00–00 | 1

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Page 2 of 5
result encouraged us to screen the effect of base. Gratefully,
lower yield was obtained when the chloro substituent was located
at the ortho position of the aldehyde group (entry 11).
among the inorganic bases investigated, K2CO3 showed the best
efficiency to give the corresponding product in 92% yield (entry
6). Cs2CO3 is also a proper base to promote this kind of transfor-
mation to afford 3a in 88% yield (entry 7). However, the use of
strong base such KOH significantly decreased the yield (entry 8).
In addition, organic bases such as pyridine and triethyl amine
were not effective for this reaction (entries 9-10). Solvent plays
an important role in this reaction, and the use of DMA as the
View Article Online
45
Table 2 Reaction of 2-bromobenzene aldehyDdOesI:(120).1w03it9h/C16aR.aA07730G
5
10 solvent decreased the yield to 78% (entry 11). Other organic sol-
vents such as toluene and NMP were not suitable media (entries
12-13). No product was observed when the reaction was carried
out in aqueous media (entry 14). The reaction yield was slightly
o
improved to 97% when the temperature was decreased to 130 C
15 (entry 15). High yield could be remained when the reaction tem-
perature was further decreased to 110 oC (entry 16).
Table 1 Optimization of reaction conditions.a
Entry
1
2
3
4
5
6
7
8
LG
Base
Solvent
Yieldb
ND
ND
12
18
60
92
88
14
ND
ND
78
30
16
ND
97
96
H
NH2
Cl
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
Cs2CO3
KOH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
NMP
toluene
H2O
COOH
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
a Reaction conditions: 1a (0.3 mmol), 2 (0.2 mmol), S (0.8 mmol),
o
b
K2CO3 (0.6 mmol), DMF (0.5 mL), 110 C, 16 h under air.
9
Et3N
50 Isolated yield based on 2. c At 120 oC.
10
11
12
13
14
15c
16d
pyridine
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
To further examine the scope and limitations of the reaction,
various 2-arylacetate esters (1) were treated with 2-
bromobenzaldehyde (2a) and sulfur under the optimized
55 conditions (Table 3). Lower yields were obtained when electron-
donating groups such as methoxy and amine were presented at
the para position (Table 3, entries 1 and 5). Moderate yields were
obtained when electron-withdrawing halogen and nitro groups
were presented (entries 2-6). The position of substituents on
60 phenyl ring of methyl phenylacetates significantly affected the
reaction yield (entries 7-9). When methyl 2-(2,3-
DMF
DMF
20 a Reaction conditions: 1 (0.3 mmol), 2a (0.2 mmol), S (0.8 mmol),
base (0.6 mmol), solvent (0.5 mL), 150 oC, 16 h, under air unless
b
otherwise noted. GC yield based on 2a using dodecane as an
internal standard. c At 130 oC. d At 110 oC.
dichlorophenyl)acetate
(1k)
and
methyl
2-(2,4-
dichlorophenyl)acetate (1l) were used, the corresponding
products 3s and 3t were obtained in 82% and 79% yields,
65 respectively (entries 10 and 11). The reaction of steric substrate
such as methyl 2-(naphthalen-2-yl)acetate (1m) with 2a and
sulfur still afforded the product 3u in 63% yield (entry 12).
Notably, pyridyl ester reacted well in this reaction to afford the
product 3v in 85% yield (entry 13). In addition, ethyl and tert-
70 butyl phenylacetates could also react with 2a and sulfur to pro-
vide the products 3a in good yields (entries 14 and 15).
We reason that the formation of 2-substituted benzothiophene
compounds could be attributed to a tandem nucleophilic
substitution and intramolecular cyclization process (Scheme 1c).
75 To probe such a procedure, a serious control experiments were
conducted. While benzylic ester 1a was completely recovered
when the reaction was performed in the absence of 2a (Scheme
2a), the combination of 1a and 2a in the absence of sulfur was
also unfruitful, with the two reactants recovered (Scheme 2b).
80 Moreover, 2-bromobenzene aldehyde (2a) could react with sulfur
to form disulfide A in the absence of 1a (Scheme 2c). Then, the
25
With the optimized reaction conditions in hand, the substrate
scope with respect to 2-halobenzaldehydes was explored (Table
2). Good yields were obtained when methoxy and chloro
substituents were located at the para position of the bromine
atom (Table 2, entries 2-3). To our delight, 2-
30 fluorobenzaldehydes also reacted with 1a and sulfur to give the
corresponding products (entries 4-8). When a trifluoromethyl
group was located at the para position of the fluoro atom, the
corresponding product 3e was obtained in 87% yield (entry 6).
However,
a much lower yield was obtained when 2,6-
35 difluorobenzaldehyde (2g) was employed (entry 7). Moderate
yield could be achieved when 2,3-difluorobenzaldehyde (2h) was
used as the substrate (entry 8). We also investigated the reaction
of 2-chlorobenzaldehyde (2i) with 1a and sulfur under the same
reaction conditions. High yield could be achieved when slightly
o
40 increasing the reaction temperature to 120 C (entry 9). The de-
sired product 3i was obtained in 82% yield when 2,6-
dichlorobenzaldehyde (2k) was used (entry 10). Similarly, much
2
| Journal Name, [year], [vol], 00–00
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K2CO3 (3 equiv)
intermediate A could transfer into the target benzothiophene 3a
with almost full conversation (Scheme 2d). Finally, to demon-
Ph
Ph
CO2Me
+ S (4 equiv)
(a)
no reaction
DMF, 110 oC, 16 h
View Article Online
DOI: 10.1039/C6RA07730G
strate the coupling of disulfide and 1a, two disulfides without
carbonals were subjected to the system (Scheme 2e). Both the 2-
F- and 4-Me-reactants could afford the coupling products, albeit
in low yields (GC-MS analysis). Those observations along with
several reported works10 give the basis for the mechanistic insight
of the present reaction. As shown in Scheme 3, the base-
promoted coupling of 2-bromobenzene aldehyde with elemental
1a
CHO
K2CO3 (3 equiv)
5
+
CO2Me
1a
(b)
(c)
no reaction
DMF, 110 oC, 16 h
Br
2a
CHO
CHO
Br
K2CO3 (3 equiv)
S
S
10 sulfur, which would be activated by the base/heat conditions,8
would be the first step, which forms disulfide intermediate A.
Subsuquently, the nucleophilic attack of 1a to A occurs to give
intermediate B. Intramolecular aldol-type reaction of B affords
intermediate C. Then, the demethoxycarbonylation promoted by
15 base generates the intermediate E, which undergoes dehydration
to afford the final 3a.10a-b This procedure releases 2-
formylbenzenethiolate D, which could be readily oxidized into
disulfide A under air.
+ S (4 equiv)
DMF, 110 oC, 2 h
54%
OHC
A
2a
CHO
K2CO3 (3 equiv)
DMF, 110 oC, 16 h
S
S
+
Ph
CO2Me
(d)
(e)
Ph
S
OHC
99%
A
1a (3 equiv)
3a
Table 3 Reaction of benzylic esters (1) with 2-bromobenzene
R
as above
20 aldehyde (2a).a
S
S
S
+ 1a
R
R
CO2Me
O
R2
R3
S, K2CO3
O
R2
R=2-F, 15%
R=4-Me, 33%
+
DMF, 110 o
C
O
S
Br
1
2a
3
Scheme 2 Control experiments.
entry
2-arylacetate ester
O
product
yieldb (%)
30
R2
O
1
2
3
R2 = 4-OCH3
R2 = 4-F
R2 = 4-Cl
1b
1c
1d
1e
1f
3j
28
51
43
48
30
50
77
61
3k
3l
R2 = 4-Br
3m
3n
3o
3p
3q
4
5
6
R2 = 4-NH2
R2 = 4-NO2
R2 = 3-OCH3
R2 = 3-F
1g
1h
1i
7
8
9
R2 = 2-Cl
1j
3r
3s
3t
73
82
79
10
11
R2 = 2, 3-Cl2
1k
1l
R2 = 2, 4-Cl2
O
12
13
1m
1n
3u
3v
63
85
Scheme 3 Possible mechanism.
O
O
O
N
Conclusions
O
Ph
14
15
3a
3a
78
55
35
In summary, we have developed a novel approach for 2-aryl
substituted benzothiophene formation from 2-bromobenzene
aldehydes, benzylic esters and elemental sulfur under transition-
metal-free conditions. The use of potassium carbonate signifi-
cantly improved the reaction yield. Functional groups such as
40 halogen, trifluoromethyl and nitro were well tolerated under the
optimized reaction conditions. Since elemental sulfur is cheap
and stable, this three-component approach affords an efficient
route for the rapid synthesis of 2-aryl substituted benzothiophenes
in the absence of transition-metal-catalyst. The scope, mechanism,
45 and synthetic application of this reaction are under investigation.
1o
1p
O
O
Ph
O
a Conditions: 1 (0.3 mmol), 2a (0.2 mmol), S (0.8 mmol), K2CO3
o
b
(0.6 mmol), DMF (0.5 mL), 110 C, 16 h under air. Isolated
yield based on 2a..
25
Acknowledgments
This work was supported by the National Natural Science Foun-
dation of China (21372187, 21572194), the Program for Innova-
tive Research Cultivation Team in University of Ministry of Edu-
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Page 4 of 5
cation of China (1337304) and the Hunan Provincial Innovative
Foundation for Postgraduate (CX2014B264).
View Article Online
DOI: 10.1039/C6RA07730G
Notes and references
a Key Laboratory of Environmentally Friendly Chemistry and Application
5 of Ministry of Education, College of Chemistry, Xiangtan University,
Xiangtan 411105, China. Fax: (+86)0731-5829-2251; Tel: (+86)0731-
5829-8280; E-mail: hwhuang@xtu.edu.cn; gjdeng@xtu.edu.cn
1
(a) C. Wang, H. Dong, W. Hu, Y. Liu and D. Zhu, Chem. Rev., 2012,
112, 2208. (b) L. Li, M.-C. Mathieu, D. Denis, A. G. Therien and Z.
Wang, Bioorg. Med. Chem. Lett., 2011, 21, 734. (c) S. Vangvera-
vong, M. Taylor, J. Xu, J. Cui, W. Calvin, S. Babic, R. R. Luedtke,
R. H. Mach, Bioorg. Med. Chem., 2010, 18, 5291. (d) S. Wang, R.
Beck, T. Blench, A. Burd, S. Buxton, M. Malic, T. Ayele, S. Shaikh,
S. Chahwala, C. Chander, R. Holland, S. Merette, L. Zhao, M.
Blackney and A. Watts, J. Med. Chem., 2010, 53, 1465. (e) I. Fouad,
Z. Mechbal, K. I. Chane-Ching, A. Adenier, F. Maurel, J.-J. Aaron,
P. Vodicka, K. Cernovska, V. Kozmik and J. Svoboda, J. Mater.
Chem., 2004, 14, 711. (f) K. H. Jung, K. H. Kim, D. H. Lee, D. S.
Jung, C. E. Park and D. H. Choi, Org. Electron., 2010, 11, 1584. (g)
D. A. Horton, G. T. Bourne and M. L. Smythe, Chem. Rev., 2003,
103, 893.
10
15
20
2
3
(a) Z. Qin, I. Kasrati, E. P. Chandrasena, H. Liu, P. Yao, P. A.
Petukhov, J. L. Bolton and G. R. J. Thatcher, J. Med. Chem., 2007,
50, 2682. (b) C.-N. Hsiao and T. Kolasa, Tetrahedron Lett., 1992,
33, 2629.
(a) B. Gabriele, R. Mancuso, E. Lupinacci, L. Veltri, G. Salerno and
C. Carfagna, J. Org. Chem., 2011, 76, 8277. (b) Y.-S. Kim, S. H.
Kwak and Y.-D. Gong, ACS Comb. Sci., 2015, 17, 365. (c) K.
Inamoto, Y. Arai, K. Hiroya, T. Doi, Chem. Commun., 2008, 5529.
(d) I. Nakamura, T. Sato, Y. Yamamoto, Angew. Chem. Int. Ed.,
2006, 45, 4473. (e) M. C. Willis, D. Taylor, A. T. Gillmore,
Tetrahedron, 2006, 62, 11513.
25
30
4
5
6
(a) D. P. Hari, T. Hering and B. König, Org. Lett., 2012, 14, 5334.
(b) Z. Duan, S. Ranjit and X. Liu, Org. Lett., 2010, 12, 2430.
K. Liu, F. Jia, H. Xi, Y. Li, X. Zheng, Q. Guo, B. Shen and Z. Li,
Org. Lett., 2013, 15, 2066.
(a) B. Join, T. Yamamoto and K. Itami, Angew. Chem. Int. Ed.,
2009, 48, 3644. (b) H.-Q. Do, R. M. K. Khan and O. Daugulis, J.
Am. Chem. Soc., 2008, 130, 15185. (c) C. S. Bryan, J. A. Braunger
and M. Lautens, Angew. Chem. Int. Ed., 2009, 48, 7064. (d) K.
Takimiya, H. Ebata, K. Sakamoto, T. Izawa, T. Otsubo and Y.
Kunugi, J. Am. Chem. Soc., 2006, 128, 12604. (e) F. Zeng and H.
Alper, Org. Lett., 2013, 15, 2686.
35
40
45 7
(a) X. Qin, D. Sun, Q. You, Y. Cheng, J. Lan and J. You, Org. Lett.,
2015, 17, 1762. (b) C.-Y. He, S. Fan and X. Zhang, J. Am. Chem.
Soc., 2010, 132, 12850. (c) V. P. Reddy, R. Qiu, T. Iwasaki and N.
Kambe, Org. Lett., 2013, 15, 1290. (d) J. Dong, Z. Long, F. Song, N.
Wu, Q. Guo, J. Lan and J. You, Angew. Chem. Int. Ed., 2013, 52,
580. (e) N. Kuhl, M. N. Hopkinson and F. Glorius, Angew. Chem.
Int. Ed., 2012, 51, 8230. (f) J. Wencel-Delord, C. Nimphius, H.
Wang and F. Glorius, Angew. Chem. Int. Ed., 2012, 51, 13001. (g)
H.-Q. Do and O. Daugulis, J. Am. Chem. Soc., 2011, 133, 13577. (h)
Y. Huang, D. Wu, J. Huang, Q. Guo, J. Li and J. You, Angew. Chem.
Int. Ed., 2014, 53, 12158. (i) X. Qin, X. Li, Q. Huang, H. Liu, D.
Wu, Q. Guo, J. Lan, R. Wang and J. You, Angew. Chem. Int. Ed.,
2015, 54, 7167. (j) P. Xi, F. Yang, S. Qin, D. Zhao, J. Lan, G. Gao,
C. Hu and J. You, J. Am. Chem. Soc., 2010, 132, 1822.
50
55
8
(a) H. Deng, Z. Li, F. Ke and X. Zhou, Chem. Eur. J., 2012, 18,
4840. (b) T. B. Nguyen, L. Ermolenko and A. Al-Mourabit, Org.
Lett., 2013, 15, 4218. (c) T. B. Nguyen, L. Ermolenko, P. Retailleau
and A. Al-Mourabit, Angew. Chem. Int. Ed., 2014, 53, 13808. (d) Y.
Tong, Q. Pan, Z. Jiang, D. Miao, X. Shi , S. Han, Tetrahedron Lett.,
2014, 55, 5499.
60
65 9
Y. Liao, Y. Peng, H. Qi, G.-J. Deng, H. Gong and C.-J. Li, Chem.
Commun., 2015, 51, 1031.
10 (a) S. R. Chemburkar, D. G. Anderson and R. E. Reddy. Synthetic
Commun., 2010, 40, 1887. S. W. Landvatter, Heterocycles, 1996, 43,
1189. (c) C. F. Roberts and R. C. Hartley, J. Org. Chem., 2004, 69,
6145.
70
4
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A
base-mediated efficient entry for 2-aryl substituted
benzothiophene from 2-bromobenzene aldehydes, benzylic esters
and elemental sulfur