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C. Mukherjee, A. De
LETTER
cyclisation of the deprotonated species afforded the thio- This synthetic method has the potential to provide a gen-
indoxyls 3 (Table1) which were purified by column chro- eral route to substituted benzo[b]thiophenes. Work is in
matography over silica gel (eluent ethyl acetate–light progress for the synthesis of benzo[b]thiophenes carrying
petrol, 1:9)
a wider variety of substituents.
Table 1 Side Chain Deprotonation of 2 to Thioindoxyls 3
References
Entry
R1
R2
R3
R4
mp (°C) Yield
(1) Kamila, S.; Mukherjee, C.; De, A. Tetrahedron Lett 2001,
42, 5955.
(EtOH)
(%)
67
78
70
65
65
69
66
(2) (a) Iddon, B.; Scrowston, R. M. In Advances in Heterocyclic
Chemistry, Vol. 11; Katritzky, A. R.; Boulton, A. J., Eds.;
Academic Press: New York, 1970, 178. (b) Scrowston, R.
M. In Advances in Heterocyclic Chemistry, Vol. 29;
Katritzky, A. R.; Boulton, A. J., Eds.; Academic Press: New
York, 1980, 172.
(3) (a) Campaigne, E.; Knapp, D. R.; Neiss, E. S.; Bosin, T. R.
Adv. in Drug Res. 1970, 5, 1. (b) Bosin, T. R.; Campaigne,
E. Adv in Drug Res. 1977, 12, 191.
(4) Chapmann, N. B.; Clarke, K.; Iddon, B. J Med Chem. 1966,
9, 1899.
(5) (a) Jones, C. D.; Suarez, T. Ger. Offen 1977, 647, 864; Chem
Abs. 1977, 87, 102155. (b) Akaita, T.; Araki, F.; Kurono,
H.; Harada, T. Japan Kokai 1976, 118, 835; Chem. Abs.
1977, 86, 66846.
a
b
c
d
e
f
H
H
H
H
60
H
H
OMe
H
H
112
63
OMe
OMe
OMe
H
OMe
H
H
OMe
H
H
97
H
H
101
99
H
H
OMe
H
g
SMe
H
H
121
Though the thioindoxyls were susceptible to slow decom-
position upon prolonged exposure to air, they could be
kept in the refrigerator for long periods with no visible
sign of deterioration. Borohydride reduction2 of thioin-
doxyls in 10% aqueous alkali afforded the substituted
benzo[b]thiophenes 4 (Table 2) in good yield. Unfortu-
nately we were unable to isolate pure 4-methylsulfanyl-
benzo[b]thiophene 4, from the reduction of 3g although it
constituted a substantial part of the reaction product as ev-
ident from the 1H NMR.
(6) (a) Connor, D. T.; Cetenko, W. A.; Mullicans, M. D.;
Sorenson, R. J.; Unangst, P. C.; Weibert, R. J.; Adolphson,
R. L.; Kennedy, J. A.; Thueson, D. O.; Wright, C. W.;
Conroy, M. C. J. Med. Chem. 1992, 35, 958. (b) Hrib, N. J.;
Jurcak, J. G.; Bregna, D. E.; Dunn, R. W.; Geyer, H. M. J.
Med. Chem 1992, 35, 2712. (c) Boschelli, D. H.; Kramer, J.
B.; Khatana, S. S.; Sorenson, R. J.; Connor, D. T.; Ferin, M.
A.; Wright, C. D.; Lesch, M. E.; Imre, K. J. Med. Chem.
1995, 38, 4597. (d) Francesco, G.; Loredana, S.; Lamartina,
L.; Spinelli, D. J. Chem. Soc, Perkin Trans. 1 1995, 1243.
(7) Malamas, M. S.; Sredy, J.; Moxham, C.; Katz, A.; Xu, W.;
McDevitt, R.; Adebayo, F.; Sawtcki, D. R.; Seestaller, L.;
Sullivan, D.; Taylor, J. R. J. Med. Chem. 2000, 43, 1293.
(8) (a) Levacher, V.; Bonsad, N.; Dupas, G.; Bourguignon, J.;
Queginer, G. Tetrahedron. Lett. 1992, 48, 831. (b) Dutta,
S.; De, A. J. Chem. Soc., Perkin Trans 1 1989, 603.
(c) Mukherjee, S.; Jash, S. S.; De, A. J. Chem. Res. (S) 1993,
192. (d) Bhattacharya, S.; De, A.; Ewing, D. F. J. Chem.
Soc., Perkin Trans 1 1994, 689. (e) Samanta, S. S.; Ghosh,
S. C.; De, A. J. Chem. Soc., Perkin 1 1997, 3673.
Table 2 Reduction of Thioindoxyls 3 to Benzo[b]thiophenes 4
Entry R1
R2
R3
R4
mp/bp
(°C)
Yield
(%)
a
H
H
H
H
H
H
H
32 (lit2 31–31.5)
67
73
b
OMe
(82/0.1 mm)
(lit2 80/0.1 mm)
(9) Kamila, S.; Mondal, S. S.; De, A. unpublished work.
(10) All the compounds reported in this paper showed correct
elemental analysis and the structures were corroborated by
characteristic spectroscopic data.
c
d
e
OMe OMe
H
H
H
H
Oil
72
85
82
OMe
OMe
H
H
OMe
H
75 (cyclohexane)
(80/0.05 mm)
(11) Representative Procedure for Synthesis of Compound 2:
Compound 1 (R1 = OMe, R2 = H, R3 = OMe, R4 = H) was
added to a stirred mixture of sec- BuLi (1.1 equiv) and
TMEDA (1.1 equiv) in THF at -78 °C. After 40 minutes the
ortho lithiated species was quenched with dimethyldisulfide
(2 equiv) at -78 °C. The reaction mixture was allowed to
attain room temperature and was kept at that temperature for
10 hours. Usual aqueous work up afforded compound 2d.
Yield: 84%; mp 80 °C (Ether–Petroleum ether); IR (KBr) =
1637.5 cm–1; 1H NMR (300 MHz, CDCl3) H: 6.4 (d, 1 H, J
= 2 Hz), 6.27 (d, 1 H, J = 2 Hz), 3.78 (s, 3 H), 3.76 (s, 3 H),
3.24 (q, 4 H), 2.42 (s, 3 H), 1.13 (t, 6 H); 13C NMR (300MHz,
CDCl3) c: (167.15, 161.18, 157.13, 137.76, 119.75, 104.39,
96.09, 56.04, 55.83, 43.03, 39.14, 16.75, 14.22, 13.01.
(12) Representative Procedure for Synthesis of Compound 3:
Compound 2d was treated with LDA (2 equiv) in THF at –
78 °C for 50 min and the reaction mixture was stirred for 12
h at room temperature. Usual work up of the reaction
(lit20 141/17 mm)
f
H
H
H
OMe (87/0.1 mm)
(lit20 85–90/0.1 mm)
71
The simple procedure described above constitutes a sig-
nificant improvement over earlier methods of synthesis of
methoxybenzo[b]thiophenes2 because of the fewer steps
involved and the avoidance of expensive thiols.2,18 Syn-
thesis of thioindoxyls, the key intermediates, is yet anoth-
er demonstration of the power of directed metallation in
the regiocontrolled introduction of substituents onto an ar-
omatic ring and the subsequent utilisation of substituents
for annelation purposes. Earlier syntheses21 of thioindox-
yls through intramolecular cyclisation used much more
difficult to access intermediates.
Synlett 2002, No. 2, 325–327 ISSN 0936-5214 © Thieme Stuttgart · New York