One-pot synthesis of benzo[b]thiophenes and naphtho[2,1-b]thiophenes in the presence of acidic and basic supported reagents

Article abstract of DOI:10.1055/s-2005-918928

A simple and efficient method has been developed for the synthesis of benzo[b]thiophenes and naphtho[2,1-b]thiophenes from aryl thiols and α-halo ketones by using an acid- and a base-supported reagent system, Na₂CO₃/SiO₂-PPA/SiO₂. Reaction of α-halo ketones with aryl thiols is promoted by Na₂CO ₃/SiO₂ to afford α-phenylthio ketones, which cyclizes in the presence of PPA/SiO₂ to give the corresponding arylthiophenes in one-pot. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918928

LETTER
2739
One-Pot Synthesis of Benzo[b]thiophenes and Naphtho[2,1-b]thiophenes in the
Presence of Acidic and Basic Supported Reagents
O
ne-PotSynthe
a
sisof Benz
d
o[
b
]thiophen
a
es
a
nd Na
p
s
htho[2,1-
b
h
]thiophenesi Aoyama,*a Toshio Takido,a Mitsuo Kodomarib
a
Department of Materials and Applied Chemistry, College of Science and Technology, Nihon University, Kanda Surugadai, Chiyoda-ku,
Tokyo 101-8308, Japan
Fax +81(3)32590818; E-mail: aoyama@chem.cst.nihon-u.ac.jp
b
Department of Applied Chemistry, Shibaura Institute of Technology, Shibaura, Minato-ku, Tokyo 108-8548, Japan
Received 28 July 2005
Abstract: A simple and efficient method has been developed for
the synthesis of benzo[b]thiophenes and naphtho[2,1-b]thiophenes
from aryl thiols and a-halo ketones by using an acid- and a base-
supported reagent system, Na2CO3/SiO2–PPA/SiO2. Reaction of a-
halo ketones with aryl thiols is promoted by Na2CO3/SiO2 to afford
a-phenylthio ketones, which cyclizes in the presence of PPA/SiO2
to give the corresponding arylthiophenes in one-pot.
traditional process
A
+
+
+
X
Y
Z
B
B
C
C
D
A
Y
Key words: one-pot synthesis, benzo[b]thiophenes, naphtho[2,1-
b]thiophenes, supported reagents
X
B
one-pot process
C
A
D
Z
supported reagent
=
S
Currently, one-pot synthesis, which can carry out multi-
step reactions or multiple reactions in one pot, is very
attractive in organic synthesis. In traditional process, the
reaction and the isolation of products have to be carried
out more than once to synthesize the target compounds.
One-pot processes, however, can provide the target com-
pounds in not only a single operation and with low cost,
but also in high total yield. Much effort has been devoted
to the development of one-pot reaction processes. One-pot
synthesis using inorganic solid-supported reagents is
unique because, if three kinds of inorganic solid-support-
ed reagents are used in one pot, three different reaction
stages are able to exist separately in the same vessel.1d
Thus, synthesis of a compound which is prepared step-
wise in homogeneous solution could be possible in one
pot if each step in the multi-step reaction can be achieved
using inorganic solid-supported reagents (Scheme 1).
D
S = X, Y, Z
Scheme 1 One-pot multi-step synthesis using supported reagents
system
also synthesized by using a base and an acid. First, precur-
sors of thiochromans and of thiocoumarins were formed
from the Michael reaction under the basic conditions, and
then the intramolecular cyclocondensation was carried
out in the presence of an acid.3 We tried to carry out the
two-step reactions in one pot using an inorganic solid-
supported acid and base in which the first step is promoted
by the base and second step is catalyzed by the acid.
The synthesis of benzo[b]thiophene and naphtho[2,1-
b]thiophene was chosen as a model for this process.
Benzo[b]thiophenes and naphtho[2,1-b]thiophenes were
very useful compounds. For instance, benzo[b]thiophene
derivatives present interesting synthetic targets and en-
compass numerous biological activities,4 and naph-
tho[2,1-b]thiophene derivatives were used as C1-
symmetric ligands for homogeneous stereoselective cata-
lysts.5 Many synthetic methods have been developed for
these compounds,6–16 but the most common method starts
from thiophenols, reacting with a-haloketones, followed
by cyclization using a strong acid. Herein, we report one-
pot synthesis of benzo[b]thiophenes and naphtho[2,1-
b]thiophenes using a couple of supported reagents,
Na2CO3/SiO2 and PPA/SiO2 as a base and an acid.
We have demonstrated the possibility of multi-step reac-
tions in one pot by using a couple of supported reagents,
e.g., ZnCl2/SiO2–K2CO3/Al2O3,1a CuBr2/Al2O3–KSCN/
1c,e
SiO2,1b KSCN/SiO2–RNH3OAc/Al2O3
and CuBr2/
Al2O3–Na2CO3/Al2O3.1d These analogous soluble re-
agents react with each other rapidly in solution. An acid
and a base cannot coexist in a homogeneous solution in
order to neutralize each other. A multi-step reaction pro-
cess using an acid and a base is applicable for many chem-
ical transformations. For instance, benzo[b]thiophenes are
synthesized from acid-catalyzed intramolecular cyclo-
condensation of a-phenylthio ketones, which was pre-
pared by the reaction of a-halo ketones and thiols under
basic conditions.2 Thiochromans and thiocoumarins were
First, we examined whether both the acidic and basic
supported reagents are able to function as an acid and a
base, respectively, in a model reaction of thiophenol and
3-bromo-4-phenyl butane-2-one (1a) in chlorobenzene
(Table 1). The desired product 3a was obtained in 80%
SYNLETT 2005, No. 18, pp 2739–2742
0
3
.1
1
.2
0
0
5
Advanced online publication: 10.10.2005
DOI: 10.1055/s-2005-918928; Art ID: U25005ST
© Georg Thieme Verlag Stuttgart · New York

2740
T. Aoyama et al.
LETTER
yield17 when the reaction was carried out in the presence Table 1 Synthesis of 2-Benzyl-3-methylbenzo[b]thiophene Using
of silica gel supported sodium carbonate (Na2CO3/SiO2)18
Various Reagents Systems
and silica gel supported polyphosphoric acid (PPA/
O
SiO2).19 When Na2CO3 and PPA were used for the reac-
Bn
+
SH
tion, 3a was not detected. Using the reagents system of
Na2CO3–PPA/SiO2 or only PPA/SiO2, 3a was formed in
moderate yields along with diphenyldisulfide as a by-
product. The reagents system, Na2CO3/SiO2–PPA, gave
3a in 46% yield along with 4-phenyl-3-phenylthiobutan-
2-one (2a) in 41% yield. These results suggest that
Na2CO3/SiO2 and PPA/SiO2 are able to coexist in the
same vessel and function as a base and an acid, respective-
ly. The reagents system Na2CO3/SiO2 promotes the reac-
tion of thiophenol with 1a, and PPA/SiO2 catalyzes the
intramolecular cyclocondensation of 2a to afford 3a. A
series of thiophenols was used for similar reactions. The
results obtained are shown in Table 2. The reaction of p-
toluene thiol with 1a gave a desired compound 3b in 71%
yield along with the 4-phenyl-3-(p-tolylthio)butan-2-one
(2b) in 20% yield. o-Toluene thiol was completely con-
sumed and 3d was obtained in 94% yield. Using m-tolu-
ene thiol, 3c and 3c¢ were formed in 34% and 61% yields,
respectively (entry 2). These yields were determined by
using 1H NMR spectroscopy. The reactions of 1a with 4-
bromothiophenol and 4-methoxythiophenol gave 3-(4-
bromophenylthio)-4-phenylbutan-2-one (2e) and 3-(4-
methoxyphenylthio)-4-phenylbutan-2-one (2f) as a main
product. For instance, the reaction with 4-bromothiophe-
nol gave 2e in 90% yield and a trace amount of 3e was ob-
served. When the reaction temperature was increased to
180 °C in dichlorobenzene, the intramolecular cyclocon-
densation of 2e and 2f occurred to give the corresponding
benzo[b]thiophenes. Compounds 3e and 3f were formed
in 8% and 30% yield, respectively. The intramolecular cy-
clocondensation on a naphthalene ring occurred at the first
position in preference to the third position. Thus, the reac-
tion of b-naphthalene thiol selectively produced 2-benzyl-
1-methylnaphtho[2,1-b]thiophene (3g) in 97% yield.
Br
1a
reagents system
S
Bn
3a
Reagents system
Yield (%)a
Na2CO3
PPA
0
PPA/SiO2
PPA/SiO2
PPA
44
Na2CO3
27
Na2CO3/SiO2
Na2CO3/SiO2
46 (41)b
80
PPA/SiO2
a Isolated yield.
b A figure in parentheses indicates the yield of the intermediate.
Table 2 One-Pot Synthesis of Benzo[b]thiophenes and
Naphtho[2,1-b]thiophenes from 1a and Various Arylthiols
Entry Aryl thiol
1
Product
Yield
(%)a
3b
3c
71 (20)b
SH
Bn
S
2
34c
SH
Bn
S
3c¢ 61c
Bn
S
3
3d
94
The results of the reaction of b-naphthalene thiol and a-
haloketones were summarized in Table 3. The reactions
with acyclic a-haloketones gave the corresponding naph-
tho[2,1-b]thiophenes in moderate to excellent yields. The
cyclic a-haloketone also reacted with b-naphthalene thiol
under similar conditions to give the corresponding naph-
thothiophene. For example, a-chlorocyclohexanone gave
3j in 87% yield (entry 3). When a-chloroacetoacetic acid
ethyl ester was used as a starting material, unexpected side
reactions occurred. Undesired compound 3h was formed
in 54% yield as a main product, and the desired compound
3k was obtained in 39% yield (entry 4). The reaction of a-
bromobenzyl phenyl ketone gave 3m in 57% yield, and
debrominated compound, benzyl phenyl ketone, was also
detected in 19% yield.
SH
Bn
S
4
5
6
3e
3f
8d
Br
Br
SH
Bn
S
30d
97
MeO
MeO
SH
Bn
S
3g
SH
Bn
S
a Isolated yield.
b A figure in parentheses indicates the yield of the intermediate.
c Yield was determined by 1H NMR.
In conclusion, we developed a simple and efficient
method for the synthesis of benzo[b]thiophenes and
naphtho[2,1-b]thiophenes in one pot using supported re-
agents system Na2CO3/SiO2–PPA/SiO2.20 Aryl thiols and
a-haloketones are commercially available, and some of
d At 180 °C for 6 h in o-dichlorobenzene.
Synlett 2005, No. 18, 2739–2742 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of Benzo[b]thiophenes
2741
1705. (b) Takeuchi, K.; Kohn, T. J.; Sall, D. J.; Denney, M.
L.; McCowan, J. R.; Smith, G. F.; Gifford-Moore, D. S.
Bioorg. Med. Chem. Lett. 1999, 9, 759. (c) Pinny, K. G.;
Bounds, A. D.; Dubgenab, K. M.; Mocharla, V. P.; Pettit, G.
R.; Bai, R.; Hamel, E. Bioorg. Med. Chem. Lett. 1999, 9,
1081. (d) Graham, S. L.; Shepard, K. L.; Anderson, P. S.;
Baldwin, J. J.; Best, D. B.; Christy, M. E.; Freedman, M. B.;
Gautheron, P.; Habecker, C. N.; Hoffman, J. M. J. Med.
Chem. 1989, 32, 2548.
Table 3 One-Pot Synthesis of Naphtho[2,1-b]thiophenes from
Various Haloketones and 2-Naphthalene Thiol
Entry Haloketone
Product
Yield
(%)a
O
1
3h
3i
89
92
87
Cl
S
(5) (a) Benincori, T.; Gladiali, S.; Rizzo, S.; Sannicolò, F. J.
Org. Chem. 2001, 66, 5940. (b) Sannicolò, F.; Benincori,
T.; Rizzo, S.; Gladiali, S.; Pulacchini, S.; Zotti, G. Synthesis
2001, 2327.
(6) (a) Ichikawa, J.; Wada, Y.; Okauchi, T.; Minami, T. Chem.
Commun. 1997, 1537. (b) Ichikawa, J.; Wada, Y.; Fujiwara,
M.; Sakoda, K. Synthesis 2002, 1917.
(7) (a) Mukherjee, C.; De, A. Synlett 2002, 325. (b)Mukherjee,
C.; Kamila, S.; De, A. Tetrahedron 2003, 59, 4767.
(8) Allen, D.; Callaghan, O.; Cordier, F. L.; Dobson, D. R.;
Harris, J. R.; Hotten, T. M.; Owton, W. M.; Rathmell, R. E.;
Wood, V. A. Tetrahedron Lett. 2004, 45, 9645.
O
Cl
S
S
3
4
3j
O
Cl
O
3k
39
O
O
(54)b
Cl
O
O
(9) Owton, W. M. Tetrahedron Lett. 2003, 44, 7147.
(10) Ho, J.-H.; Ho, T.-I. Tetrahedron Lett. 2003, 44, 4669.
(11) Cabiddu, M. G.; Cabiddu, S.; Cadoni, E.; Demontis, S.;
Fattuoni, C.; Melis, S. Tetrahedron 2002, 58, 4529.
(12) Kim, P.; Tsuruda, J. M.; Olmstead, M. M.; Eisenberg, S.;
Kurth, M. J. Tetrahedron Lett. 2002, 43, 3963.
(13) Katritzky, A. R.; Vvedensky, V. Y.; Tymoshenko, D. O. J.
Chem. Soc., Perkin Trans. 1 2001, 2483.
(14) Larock, R. C.; Yue, D. Tetrahedron Lett. 2001, 42, 6011.
(15) Gallagher, T.; Pardoe, D. A.; Porter, R. A. Tetrahedron Lett.
2000, 41, 5415.
S
5
6
3l
94
O
Ph
Br
Ph
S
3m 57
(19)c
O
Ph
Ph
Ph
Ph
Br
S
(16) Samanta, S. S.; Ghosh, S. C.; De, A. J. Chem. Soc., Perkin
Trans. 1 1997, 2683.
(17) Typical Procedure.
a Isolated yield.
b A figure in parentheses indicates the yield of compound 3h.
c A figure in parentheses indicates the yield of benzyl phenyl ketone.
A mixture of a-haloketone (1 mmol), arylthiol (1 mmol),
Na2CO3/SiO2 (1.0 g, 1.5 mmol) and PPA/SiO2 (3.5 g, 10
wt%) in chlorobenzene (15 mL) was stirred at 135 °C for 6
h, and then used supported reagents were removed by
filtration. The filtrate was evaporated to leave crude product,
which was purified by flash column chromatography to give
the desired product.
a-bromo ketones are easily synthesized by using our re-
ported methods.1d Several chemical transformations using
this reagents system are now under investigation.
(18) Preparation of Na2CO3/SiO2.
Silica gel [Wakogel C-200 (Wako Pure Chemical Ind.
LTD.), 16.82 g] was added to a solution of sodium carbonate
(30 mmol, 3.18 g) in distilled H2O, and the mixture was
stirred at r.t. for 0.5 h. Then, H2O was removed by rotary
evaporator under reduced pressure, and the resulting reagent
was dried in vacuo (10 mmHg) at 160 °C for 5 h.
(19) Preparation of PPA/SiO2.
References
(1) (a) Kodomari, M.; Nawa, S.; Miyoshi, T. J. Chem. Soc.,
Chem. Commun. 1995, 1895. (b) Suzuki, Y.; Kodomari, M.
Chem. Lett. 1998, 1091. (c) Kodomari, M.; Aoyama, T.;
Suzuki, Y. Tetrahedron Lett. 2002, 43, 1717. (d) Aoyama,
T.; Takido, T.; Kodomari, M. Tetrahedron Lett. 2004, 45,
1873. (e) Aoyama, T.; Murata, S.; Nagata, S.; Takido, T.;
Kodomari, M. Tetrahedron Lett. 2005, 46, 4875.
(2) (a) Francisco, M. A.; Kurs, A.; Katritzky, A. R.; Rasala, D.
J. Org. Chem. 1998, 53, 596. (b) Pinney, K. G.; Bounds, A.
D.; Dingeman, K. M.; Mocharla, V. P.; Pettit, G. R.; Bai, R.;
Hamel, E. Bioorg. Med. Chem. Lett. 1999, 9, 1081.
(c) Kim, S.; Yang, J.; DiNinno, F. Tetrahedron Lett. 1999,
40, 2909. (d) Queiroz, M.-J. R. P.; Dubest, R.; Aubard, J.;
Faure, R.; Guglielmetti, R. Dyes Pigm. 2000, 47, 219.
(e) Qiao, J. X.; Cheng, X.; Modi, D. P.; Rossi, K. A.;
Luettgen, J. M.; Knabb, R. M.; Jadhav, P. K.; Wexler, R. R.
Bioorg. Med. Chem. Lett. 2005, 15, 29.
The PPA (2.0 g) and CHCl3 (100 mL) were placed in a
round-bottom flask, and the mixture was stirred at 50 °C for
1 h. SiO2 [Wakogel C-200 (Wako Pure Chemical Ind. Ltd.),
18.0 g], which was dried in vacuo at 160 °C for 2 h, was
added to the mixture, and the mixture was stirred for another
1 h. Then, CHCl3 was removed with rotary evaporator and
the resulting solid was dried in vacuo at r.t. for 3 h.
(20) Compound 3b: mp 46–47 °C. 1H NMR (400 MHz, CDCl3):
d = 2.33 (3 H, s), 2.46 (3 H, s), 4.17 (2 H, s), 7.09 (1 H, d,
J = 8.3 Hz), 7.18–7.29 (5 H, m), 7.42 (1 H, s), 7.59 (1 H, d,
J = 8.3 Hz). 13C NMR (100 MHz, CDCl3): d = 11.7, 21.5,
34.4, 121.5, 121.8, 125.4, 126.4, 127.3, 128.4, 128.5, 133.5,
135.7, 137.7, 139.8, 141.1. HRMS (TOF-CI): m/z calcd for
C17H17S [MH+]: 253.1050; found: 253.1056.
(3) (a) Tércio, J.; Ferreira, B.; Catani, V.; Comasseto, J. V.
Synthesis 1987, 149. (b) Wei-Yuan, H.; Yan-Song, L.
Heteroat. Chem. 1995, 6, 287.
(4) (a) Nanteuil, G. D.; Lila-Ambroise, C.; Rupin, A.; Vallez,
M.-O.; Verbeuren, T. J. Bioorg. Med. Chem. Lett. 2003, 13,
Compound 3d: mp 60–61 °C. 1H NMR (400 MHz, CDCl3):
d = 2.36 (3 H, s), 2.47 (3 H, s), 4.20 (2 H, s), 7.07 (1 H, d,
J = 7.3 Hz), 7.18–7.30 (6 H, m), 7.48 (1 H, d, J = 7.6 Hz).
Synlett 2005, No. 18, 2739–2742 © Thieme Stuttgart · New York

2742
T. Aoyama et al.
LETTER
NMR (100 MHz, CDCl3): d = 16.9, 34.5, 120.7, 123.3,
13C NMR (100 MHz, CDCl3): d = 11.9, 20.2, 34.4, 119.1,
124.1, 124.3, 126.4, 128.3, 128.5, 128.5, 131.6, 137.2,
138.7, 139.8, 140.7. HRMS (TOF-CI): m/z calcd for C17H17S
[MH+]: 253.1050; found: 253.1044.
124.5, 124.7, 125.8, 126.5, 128.4, 128.6, 129.0, 130.4,
130.5, 132.1, 134.7, 136.5, 137.5, 139.8. HRMS (TOF-CI):
m/z calcd for C20H17S [MH+]: 289.1050; found: 289.1049.
Compound 3k: mp 103–104 °C. 1H NMR (400 MHz,
CDCl3): d = 1.24 (3 H, t, J = 7.1 Hz), 4.22 (2 H, q, J = 7.1
Hz), 4.29 (2 H, s), 7.41 (1 H, s), 7.50–7.62 (2 H, m), 7.72 (1
H, d, J = 8.7 Hz), 7.85 (1 H, d, J = 8.7 Hz), 7.95 (1 H, dd,
J = 8.0, 1.2 Hz), 8.43 (1 H, d, J = 8.3 Hz). 13C NMR (100
MHz, CDCl3): d = 14.1, 38.4, 61.1, 121.1, 122.9, 124.9,
125.3, 125.7, 126.2, 129.0, 129.9, 130.8, 131.9, 132.8,
139.4, 170.9. HRMS (TOF-CI): m/z calcd for C16H15O2S
[MH+]: 271.0792; found: 271.0798.
Compound 3e: 1H NMR (400 MHz, CDCl3): d = 2.33 (3 H,
s), 4.19 (2 H, s), 7.21–7.32 (5 H, m), 7.36 (1 H, dd, J = 8.5,
2.0 Hz), 7.56 (1 H, d, J = 8.5 Hz), 7.76 (1 H, d, J = 2.0 Hz).
13C NMR (100 MHz, CDCl3): d = 11.7, 34.4, 118.0, 123.5,
124.3, 126.6, 126.6, 127.0, 128.5, 128.6, 137.2, 139.3,
139.9, 142.6. HRMS (EI): m/z calcd for C16H13BrS [M+]:
315.9921; found: 315.9922.
Compound 3f: 1H NMR (400 MHz, CDCl3): d = 2.33 (3 H,
s), 3.88 (3 H, s), 4.18 (2 H, s), 6.92 (1 H, dd, J = 8.8, 2.4 Hz),
7.08 (1 H, d, J = 2.4 Hz), 7.21–7.31 (5 H, m), 7.59 (1 H, d,
J = 8.8 Hz). 13C NMR (100 MHz, CDCl3): d = 11.8, 34.5,
55.6, 104.3, 113.4, 122.8, 126.5, 127.4, 128.4, 128.5, 130.9,
139.1, 139.7, 141.9, 157.4. HRMS (TOF-CI): m/z calcd for
C17H17OS [MH+]: 269.1000; found: 269.1001.
Compound 3m: mp 166–168 °C. 1H NMR (400 MHz,
CDCl3): d = 7.15–7.29 (6 H, m), 7.36–7.45 (6 H, m), 7.51 (1
H, d, J = 8.5 Hz), 7.75 (1 H, d, J = 8.8 Hz), 7.89 (2 H, d,
J = 8.5 Hz). 13C NMR (100 MHz, CDCl3): d = 120.4, 123.7,
124.8, 125.6, 125.7, 127.4, 127.8, 128.2, 128.8, 128.9,
129.7, 130.1, 130.8, 132.2, 134.5, 134.5, 135.7, 137.1,
138.3, 139.9. HRMS (TOF-CI): m/z calcd for C24H17S
[MH+]: 337.1050; found: 337.1045.
Compound 3g: mp 98–100 °C. 1H NMR (400 MHz, CDCl3):
d = 2.80 (3 H, s), 4.30 (2 H, s), 7.20–7.32 (5 H, m), 7.48–7.59
(2 H, m), 7.65 (1 H, d, J = 8.8 Hz), 7.75 (1 H, d, J = 8.8 Hz),
7.93 (1 H, dd, J = 8.0, 1.2 Hz), 8.71 (1 H, d, J = 8.5 Hz). 13
C
Synlett 2005, No. 18, 2739–2742 © Thieme Stuttgart · New York