Environmentally benign process for the synthesis of 2,3-disubstituted benzo[b]thiophenes using electrophilic cyclization

Article abstract of DOI:10.1016/j.tetlet.2013.05.139

We have developed a greener process for the synthesis of 2,3-disubstituted benzo[b]thiophenes using electrophilic cyclization as a key step. Our method not only employs an environmentally friendly solvent ethanol, but also utilizes safe and inexpensive in

Full text of DOI:10.1016/j.tetlet.2013.05.139

Tetrahedron Letters 54 (2013) 4373–4376
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Environmentally benign process for the synthesis
of 2,3-disubstituted benzo[b]thiophenes using electrophilic
cyclization
⇑
Seoyoung Kim , Nikesh Dahal , Tanay Kesharwani
Chemistry Program, Bard College, PO Box 5000, Annandale-on-Hudson, NY 12504, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed a greener process for the synthesis of 2,3-disubstituted benzo[b]thiophenes using
electrophilic cyclization as a key step. Our method not only employs an environmentally friendly solvent
ethanol, but also utilizes safe and inexpensive inorganic reagents to furnish the desired products in high
yields under mild reaction conditions. In addition to iodo- and bromocyclization, chlorocylization was
also successfully accomplished.
Received 20 April 2013
Revised 24 May 2013
Accepted 28 May 2013
Available online 7 June 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Green chemistry
Benzo[b]thiophenes
Electrophilic cyclization
Iodocyclization
Bromocyclization
Chlorocyclization
Benzo[b]thiophenes are naturally occurring1 heterocyclic com-
pounds with diverse applications in medicinal chemistry and
material science, resulting in high interest in industry as well as
academia. They display a wide range of biological and physiologi-
cal functions such as anti-inflammatory,2 anti-fungal,3 anti-
depressants,4 estrogen receptor modulator,5 FimH antagonists,6
anti-mitotic,7 kinases inhibitor,8 and anti-tumor activities.9 Several
commercially available drugs also contain the benzo[b]thiophene
core structure such as sertaconazole nitrate, zileuton, raloxifene,
and benocyclidine (Fig. 1). Along with various medicinal proper-
ties, these sulfur-containing molecules have found their interest
in organic materials.10 Benzothiophenes have superior durability
and solubility compared to their hydrocarbon analogues, which
make them better materials for organic semiconductors.
In recent years, halogen- and transition metal-mediated 5-
endo-dig cyclization of alkynes possessing a sulfur nucleophile in
close proximity has emerged as the most promising way to synthe-
size 2,3-disubstituted benzo[b]thiophenes derivatives.11 The het-
eroaromatic carbon–halogen bonds obtained in 5-endo-dig
cyclization reactions using halonium ions further allow the deriv-
atization of core structures by palladium-catalyzed cross coupling
reactions.12 These reactions proceed in high yields and tolerate a
variety of functional groups, but they do require toxic solvents
such as DCM and corrosive halogens. However, the chlorocycliza-
tion are rarely reported. Only one chlorocyclization of 2-alkynly-
thioanisoles has been reported by Wu and Lu, with
disadvantages of requiring high temperature and toxic acetonitrile
as a solvent.13
Herein, we report an environmentally benign process for the
synthesis of 2,3-disubstituted benzo[b]thiophenes using electro-
N
N
O
N
Cl
O
O
Cl
HO
OH
S
S
Cl
Sertaconazole
Raloxifene
H
S
CH3
N
N
NH2
O
S
HO
⇑
Corresponding author. Tel.: +1 845 752 2352.
E-mail address: tkesharw@bard.edu (T. Kesharwani).
Benocyclidine
Zileuton
These authors contributed equally to this work.
Figure 1. Examples of drugs containing benzo[b]thiophene core structure.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.139

4374
S. Kim et al. / Tetrahedron Letters 54 (2013) 4373–4376
SMe
philic cyclization as a key step (Scheme 1).14 In addition, we have
S
CuSO4/NaX
EtOH, r.t.
R
demonstrated high product yields under mild reaction conditions
requiring little or no purification. Our method not only employs
an environmentally friendly solvent ethanol, but also utilizes safe
and inexpensive inorganic salts to furnish the desired products at
room temperature. Along with iodo- and bromocyclization, this
method accomplishes the rare chlorocyclization using table salt
(NaCl) as a reagent and tolerates several functional groups leading
to a diverse library of benzo[b]thiophenes derivatives.
X
R
X=I, Br, Cl
Scheme 1. Synthesis of 2-phenyl-3-iodobenzo[b]thiophene framework via modi-
fied iodocyclization.
SMe
SMe
To further assess the applicability of our reaction the desired
starting reactants, 2-alkynlythioanisoles 1–9, were synthesized
using the Sonogashira coupling reaction (Scheme 2).
1 mol % Pd(PPh3)2Cl2
+
I
R
2 mol% CuI
Et3N, r. t.
R
We found that 2-phenylethynylthioanisole (1), when reacted
with equimolar CuSO4 and NaI mixture in ethanol at room temper-
ature for 24 h, resulted in the formation of 3-iodo substituted
benzo[b]thiophene 1a in a high yield of 83% (Table 1, entry 1). To
further study the scope of this green strategy, NaBr and NaCl were
employed along with CuSO4. Cyclization attempts using NaBr/
CuSO4 resulted in the formation of bromocyclized product 1b in
92% yield (entry 2). Chlorocyclization of 1 was also successful,
resulting in the formation of 1c in 92% yield, which is higher than
previously reported chlorocyclization (entry 3).13
(CH2)3CH3
C(CH3)3
1
4
91%
89%
2
97%
3
80%
(CH2)3CN
Si(CH3)3
5 98%
6
92%
Our reaction conditions work well with alkyl substituted thio-
anisoles. Both bulky tert-butyl (2) and linear n-butyl (3) substi-
tuted alkynes resulted in higher yields of iodocyclized
benzo[b]thiophenes 2a and 3a respectively (entries 4 and 7). Ear-
lier studies showed that bromocyclization of 2 was unsuccessful
in giving synthetically useful yield of 2b (10%) and resulted in high-
OMe
CH2OH
CH2OCH3
7
8
88%
9
71%
75%
Scheme 2. Synthesis of 2-alkynlythioanisoles via Sonogashira coupling.
Table 1
5-endo-dig Cyclization of 2-alkynlythioanisoles to corresponding 3-halosubstituted benzo[b]thiophenesa
Entry
Substrate
SMe
Reaction condition
Product
Yieldb (%)
83
S
S
Ph
1
1
A
1a
I
Ph
Ph
2
3
B
C
1b
1c
92
92
Br
S
Ph
Cl
SMe
S
t-Bu
4
2
A
2a
81
I
t-Bu
S
t-Bu
t-Bu
n-Bu
5
6
B
C
2b
2c
89
82
Br
S
Cl
S
SMe
SMe
7
8
3
4
A
A
3a
4a
89
81
I
I
n-Bu
S

S. Kim et al. / Tetrahedron Letters 54 (2013) 4373–4376
4375
Table 1 (continued)
Entry
Substrate
SMe
Reaction condition
A
Product
Yieldb (%)
S
SiMe3
OH
9
5
5a
91
I
SiMe3
OH
SMe
SMe
SMe
S
S
S
10
11
6
7
A
A
6a
7a
90
97
I
I
I
OMe
OMe
(CH2)3CN
12
8
9
A
A
8a
9a
82
86
(CH2)3CN
SMe
S
OMe
13
I
OMe
a
Reaction condition A: all reactions were performed using 0.30 mmol of thioether, 5.0 equiv of CuSO4, and 5.0 equiv NaI in 5 mL of EtOH at room temperature for 24 h.
Reaction condition B: reaction was performed using 5.0 equiv of NaBr instead of NaI for condition A. Reaction condition C: reaction was performed using 5.0 equiv of NaCl
instead of NaI for condition A.
b
Isolated yields.
Me
S
er amounts of addition product.13 On the other hand, our reaction
SMe
condition furnished only desired product 2b in high yield of 89%
when thioanisole 2 was subjected to cyclization using NaBr (entry
5), making our method superior. Chlorocyclization of 2 resulted in
the formation of 2c in a high yield of 82% (entry 6).
CuCl2
Ph
Ph
Ph
Cl
Cl
Cu
1
To explore the tolerance of several functional groups in our
reaction condition, thioanisole-containing functional groups were
employed. Our reaction conditions seem wide-ranging as vinyl,
TMS, alcohol, ether, and nitrile functionality were successfully em-
ployed (entries 8–13). Iodocyclization of cyclohexene holding al-
kyne 4 resulted in the formation of 4a in 81% yield (entry 8), and
alkyne 5 bearing TMS functionality furnished product 5a in 91%
yield (entry 9). Thioanisole bearing propargyl alcohol or propargyl
ether was also successfully employed for cyclization reactions and
the resulting products 6a and 7a were obtained in good yields of
90% and 97%, respectively (entries 10 and 11). Benzothiophene
8a tethered with nitrile functionality was prepared from alkyne 8
in 82% yield (entry 12). Using the strong electron-rich group, p-
methoxyphenyl, resulted in a slightly higher yield of cyclized prod-
uct 9a when compared with phenyl group (compare entries 1 and
13).
Cl
Me
Cu Cl
S
S
Ph
Cl
Cl
10
1c
Scheme 3. Proposed mechanism of cholorocyclization involving in situ generated
CuCl2 electrophile.
and Br2, respectively (Eq. 2).15 This could lead to plausible halo-
cyclization mechanism via initial co-ordination of electrophilic
halogen with the alkyne to form 12, followed by an attack from
nearby sulfur atom to give sulfonium salt 13 (Scheme 4). The io-
dine or bromine anion generated from the above process could
displace the methyl group attached to cationic sulfur via an
SN2 reaction resulting in the formation of benzo[b]thiophene
1a or 1b.
CuSO4 + 2 NaX
2 CuX2
Na2SO4
X = I, Br, Cl
+
CuX2
ð1Þ
ð2Þ
2 CuX
+ X2
X = I, Br
It is well established that CuSO4 when mixed with NaCl in situ
generated cupric chloride15 (Eq. 1) that could lead to the chlorocyc-
lization by the mechanism given in Scheme 3. The proposed mech-
anism involves the co-ordination of cupric chloride with the alkyne
followed by an anti-attack from sulfur to give cationic intermediate
10. The methyl group can subsequently be removed by SN2 dis-
placement with the help of CuCl2.
Copper sulfate when mixed with NaI and NaBr also produces
CuI2 and CuBr2, respectively (Eq. 1). However, CuI2 and CuBr2 are
known to quickly decompose into CuI and CuBr along with I2
Heteroaromatic carbon–iodine bond generated after halocycli-
zation is a very useful intermediate for the synthesis of a wide
variety of 2,3-disubstituted benzo[b]thiophenes. Larock and
co-workers have utilized palladium-catalyzed cross-coupling
reactions to generate a diverse library of benzo[b]thiophenes using
3-iodobenzo[b]thiophenes (Scheme 5).12
In summary, we have developed a green method for the synthe-
sis of benzo[b]thiophenes by employing an environmentally
friendly solvent ethanol, and inexpensive inorganic salts. Our
method is mild and tolerates a variety of functional groups. This

4376
S. Kim et al. / Tetrahedron Letters 54 (2013) 4373–4376
Me
S
Me
S
References and notes
SMe
X2
1. (a) Koike, K.; Jia, Z.; Nikaido, T.; Liu, Y.; Zhao, Y.; Guo, D. Org. Lett. 1999, 1, 197–
198; (b) Jeong, S.-J.; Higuchi, R.; Miyamoto, T.; Ono, M.; Kuwano, M.; Mawatari,
S. F. J. Nat. Prod. 2002, 65, 1344–1345.
2. (a) Bleavins, M. R.; de la Igelsia, F. A.; McCay, J. A.; White, L.; Kimber, L., Jr.;
Munson, A. E. Toxicology 1995, 98, 111–123; (b) Wright, C. D.; Stewart, S. F.;
Kuipers, P. J.; Hoffman, M. D.; Devall, L. J.; Kennedy, J. A.; Ferin, M. A.; Theuson,
D. O.; Conroy, M. C. J. Leukocyte Biol. 1994, 55, 443–451.
3. Raga, M.; Palacin, C.; Castello, J. M.; Ortiz, J. A.; Cuberes, M. R.; Moreno-Manas,
M. Eur. J. Med. Chem. Chim. Ther. 1986, 21, 329–332.
4. Berrade, L.; Aisa, B.; Ramirez, M. J.; Galiano, S.; Guccione, S.; Moltzau, L. R.;
Levy, F. O.; Nicoletti, F.; Battaglia, G.; Molinaro, G.; Aldana, I.; Monge, A.; Perez-
Silanes, S. J. Med. Chem. 2011, 54, 3086–3090.
5. (a) Magarian, R. A.; Overacre, L. B.; Singh, S.; Meyer, K. L. Curr. Med. Chem. 1994,
1, 61–104; (b) Jones, C. D.; Jevnikar, M. G.; Pike, A. J.; Peters, M. K.; Black, L. J.;
Thompson, A. R.; Falcone, J. F.; Clemens, J. A. J. Med. Chem. 1984, 27, 1057–1066;
(c) Bryant, H. U.; Dere, W. H. Proc. Soc. Exp. Biol. Med. 1998, 217, 45–52.
6. Han, Z.; Pinker, J. S.; Ford, B.; Obermann, R.; Nolan, W.; Wildman, S. A.; Hobbs,
D.; Ellenberger, T.; Cusumano, C. K.; Hultgren, S. J.; Janetka, J. W. J. Med. Chem.
2010, 53, 4779–4792.
Ph
+X
12
Ph
X-
Ph
X
11
1
X
Me
S
S
1a
1b
X = I
X = Br
Ph
Ph
X
X
13
Scheme 4. Proposed mechanism of cyclization involving in situ generated I2 and
Br2 electrophile.
7. Romagnoli, R.; Baraldi, P. G.; Carrion, M. D.; Lopez Cara, C.; Preti, D.; Fruttarolo,
F.; Pavani, M. G.; Tabrizi, M. A.; Tolomeo, M.; Grimaudo, S.; Di Antonella, C.;
Balzarini, J.; Hadfield, J. A.; Brancale, A.; Hamel, E. J. Med. Chem. 2007, 50, 2273–
2277.
8. Tao, Z.-F.; Hasvold, L. A.; Leverson, J. D.; Han, E. K.; Guan, R.; Johnson, E. F.; Stoll,
V. S.; Stewart, K. D.; Stamper, G.; Soni, N.; Bouska, J. J.; Luo, Y.; Sowin, T. J.; Lin,
N.-H.; Giranda, V. S.; Rosenberg, S. H.; Penning, T. D. J. Med. Chem. 2009, 52,
6621–6636.
9. (a) Valderrama, J. A.; Espinozaa, O.; Rodriguezb, J.; Theoduloz, C. Lett. Org. Chem.
2009, 6, 278–281; (b) Romagnoli, R.; Baraldi, P. G.; Salvador, M. K.; Preti, D.;
Tabrizi, M. A.; Bassetto, M.; Brancale, A.; Hamel, E.; Castagliuolo, I.; Bortolozzi,
R.; Basso, G.; Viola, G. J. Med. Chem. 2013, 56, 2606–2618.
10. (a) Laquindanum, J. G.; Katz, H. E.; Lovinger, A. J. J. Am. Chem. Soc. 1998, 120,
664–672; (b) Dimitrakopoulos, C. D.; Malenfant, P. R. L. Adv. Mater. 2002, 14,
99–177; (c) Tang, M. L.; Okamoto, T.; Bao, Z. J. Am. Chem. Soc. 2006, 128, 16002–
16003; (d) Yuan, Q.; Mannsfeld, S. C. B.; Tang, M. L.; Toney, M. F.; Luning, J.;
Bao, Z. J. Am. Chem. Soc. 2008, 130, 3502–3508; (e) Ni, Y.; Nakajima, K.; Kanno,
K.; Takahashi, T. Org. Lett. 2009, 11, 3702–3705; (f) Huang, J.; Luo, H.; Wang, L.;
Guo, Y.; Zhang, W.; Chen, H.; Zhu, M.; Liu, Y.; Yu, G. Org. Lett. 2012, 14, 3300–
3303.
S
S
R
R
ref. 12a
ref. 12a
ref. 12b
ref. 12b
O
R3
N
R2(H)
S
R2
R
I
S
S
R
R
O
R2
R2O
Scheme 5. Synthesis of 2-alkynlythioanisoles via Sonogashira coupling.
11. (a) Nakamura, I.; Sato, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2006, 45, 4473–
4475; (b) Nakamura, I.; Sato, T.; Terada, M.; Yamamoto, Y. Org. Lett. 2007, 9,
4081–4083; (c) Flynn, B. L.; Verdier-Pinard, P.; Hamel, E. Org. Lett. 2001, 3, 651–
654; (d) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905–1909; (e) Jacubert,
M.; Hamze, A.; Provot, O.; Peyrat, J.-F.; Brion, J.-D.; Alami, M. Tetrahedron Lett.
2009, 50, 3588–3592; (f) Hessian, K. O.; Flynn, B. L. Org. Lett. 2003, 5, 4377–
4380; (g) Nakamura, I.; Sato, T.; Terada, M.; Yamamoto, Y. Org. Lett. 2007, 9,
4081–4083; (h) Nakamuram, I.; Sato, T.; Terada, M.; Yamamoto, Y. Org. Lett.
2008, 10, 2649–2651; (i) Guilarte, V.; Fernández-Rodríguez, M. A.; García-
García, P.; Hernando, E.; Sanz, R. Org. Lett. 2011, 13, 5100–5103; (j) Kuhn, M.;
Falk, F. C.; Paradies, J. Org. Lett. 2011, 13, 4100–4103; (k) Sanz, R.; Guilarte, V.;
Hernando, E.; Sanjuán, A. M. J. Org. Chem. 2010, 75, 7443–7446; (l) Larock, R. C.;
Yue, D. Tetrahedron Lett. 2001, 42, 6011–6013.
method not only can be used to produce well established
iodo- and bromocyclized products, but also to produce relatively
scarce chlorocyclized products in high yields. Alkynes bearing aryl,
alkyl, vinyl, and TMS groups were also successfully cyclized. There-
fore, this facile and green method can be successfully utilized to
synthesize wide-ranging benzo[b]thiophene derivatives.
Acknowledgments
12. (a) Cho, C.-H.; Neuenswander, B.; Lushington, G. H.; Larock, R. C. J. Comb. Chem.
2009, 11, 900–906; (b) Cho, C.-H.; Neuenswander, B.; Larock, R. C. J. Comb.
Chem. 2010, 12, 278–285; (c) Cho, C.-H.; Jung, D.-I.; Neuenswander, B.; Larock,
R. C. ACS Comb. Sci. 2011, 13, 501–510.
The authors wish to thank Bard Summer Research Institute and
National Science Foundation Major Research Instrumentation
Award 1039659 for support of this research. The authors would
also like to thank Dr. Teresa A. Garrett, Dr. Christopher LaFratta,
and Dr. Emily McLaughlin for their help.
13. Lu, W.-D.; Wu, M.-J. Tetrahedron 2007, 63, 356–362.
14. Method A: to
a 6 dram vial containing 2-alkynylthioanisole (0.30 mmol),
CuSO4ꢀ5H2O (374 g, 1.5 mmol), NaI (224 mg, 1.5 mmol) and 3 mL of EtOH were
added. The solution was allowed to stir overnight. This mixture was
concentrated under vacuum, absorbed in silica gel and was purified by
column chromatography using hexanes as the eluent. 3-Iodo-2-
a
yellow oil; 1H NMR
Supplementary data
phenylbenzo[b]thiophene (1a) was isolated as
(400 MHz, chloroform-d) d 7.34–7.40 (td, J = 7.5, 1.5 Hz, 1H), 7.42–7.50 (m,
4H), 7.66–7.69 (m, 2H), 7.75–7.78 (m, 1H), 7.81–7.84 (m, 1H). Other
characterization data are in good agreement with the previous reported
data.11d
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
05.139.
15. (a) Brotherton, W. S.; Clark, R. J.; Zhu, L. J. Org. Chem. 2012, 77, 6443–6455; (b)
Kauffman, G. B.; Pinnell, R. P. Inorg. Synth. 1960, 6, 3–6.