178 RESEARCH PAPER
MARCH, 178-179
JOURNAL OF CHEMICAL RESEARCH 2009
Synthesis of 1,5-benzothiazepines with microwave irradiation under
solvent and catalyst-free conditions
M. Rahman, A. Roy, A. Majee* and A. Hajra
Department of Chemistry, Visva -Bharati University, Santiniketan, West Bengal, 731235, India
Microwave irradiation of a,13-unsaturated ketones (chalcones) and o-aminothiophenol
in the absence of solvent and
catalyst provides a highly efficient methodology for the synthesis of 1,5-benzothiazepines in moderate to good yields.
Keywords: microwave, a,13-unsaturated ketone, o-aminothiophenol
1,5-Benzothiazepines
feedant,2 analgesic,3 anti-convulsant,4
have anti-fungal,
anti-bacterial, 1 anti-
conditions. The yields of some products were verified by
repeating some experiments for two to three times.
anti-HIV,5 and squalene
synthetase inhibitory activity. 6Recently 1,5-benzothiazepin-2-
ones have been used as calcium antagonists (e.g. Clentiazem),
In conclusion
microwave
provides a highly efficient methodology
with moderate to
irradiation
of chalcones
and
o-aminothiophenol
for the synthesis of 1,5-benzothiazepine
coronary vasodilators
(e.g. Thiazesim). In addition to their biological activity 1,5-
benzothiazepine are used as starting materials for the synthesis
(e.g. Diltiazem)
and antidepressants
good yields. The procedure has the advantage of operational
simplicity, solvent free and, mild reaction conditions. It is
of fused ring heterocyclic compounds.4
environmentally
friendly, and it is compatible with various
The usual strategy to construct the ring skeletons of 1,5-
functional groups. We believe that this will present a better
benzothiazepine
is via the reaction of 2-aminothiophenol
with
alternative to the existing methodologies
1,5-benzothiazepines.
for the synthesis of
a,13-unsaturated carbonyl compounds.7,8 Many of the methods
cited in the literature employ catalysts such as Mg(CI04)2 in
DCE under reflux} SiOb10 AcOH (3 mL mmot-1) in DMF
under MW,l1 AcOH or TFA(1 mL mmot-1) in EtOH or toluene
under reflux for 3-6 h,12 AcOH in DMF or EtOH at 60°C for
5 h followed by treatment at room temperature overnight, 13
and EtOH/HCl under reflux for 3 h.14 Piperidine(l mLmmot-1)
in toluene under reflux for 8 h and pyridine (15 mL mmot-1)
under reflux for 3 h have also been used. 15
Experimental
Melting points were determined on a glass disk with an electric
hot plate and are uncorrected. 'H NMR (300 MHz) and l3C NMR
(75 MHz) spectra were run in CDCI) solutions. IR spectra were taken
as KBr plates in a Shimazdu 8400S FTIR. Elemental analyses were
done by Perkin- Elmer autoanalyser.
Synthesis of 1,5- benzothiazepine; general procedure
2,4-Diphenyl-2,3-dihydro-I,5-Benzothiazepines
These methods have some disadvantages
reaction time, difficulties in the isolation of the products,
strongly acidic medium and hazardous reagents. Recently two
methods for the preparation of 1,5- benzothiazepines
developed using Ga(OTf)3 in MeCN at 60°C16 and SDS in
water.17 Though these methods are general for the preparation
such as a long
(entry 1): A mixture
of a,13-unsaturated ketone (l,3-diphenylprop-2-enone,chalcone)
(208 mg, I mmol), and o-aminothiophenol (137 mg 1.1 mmol), was
irradiated under MW for 5-6 min to complete the reaction (TLC).
The reaction mixture was then dissolved in ethyl acetate (20 mL).
The ethyl acetate was washed with (5%) NaOH sol. (3 x 5 mL) and
brine solution (2 x 5 mL) and dried over anhydrous sodium sulfate.
Evaporation of the solvent followed by column chromatography of
the crude product over silica gel (hexane/ethyl acetate 98:2) furnished
the pure product (220 mg, 70%) as a yellowish solid; m.p.lI4-115 °e,
(Lit.l7 114-116°C) whose spectroscopic data (IR and NMR) were
given below.
have been
of 1,5-benzothiazepine
but in the case of Ga(OTf)3 in MeCN
the reaction time is long and only chalcones with OH, OMe
substituents were studied. The overall experimental procedure
using SDS is little bit tedious.
As a part of our research to provide a greener methodology,18-32
we have shown that the reaction of a,13-unsaturated ketones
(chalcone) and o-aminothiophenol
with MW irradiation without any solvent or catalyst (Scheme 1).
A wide range of chalcones (see Table 1) were converted
'H NMR 83.01 (t, 1H, J= 12 Hz), 3.38 (dd, 1H, J= 4.5, 12.5 Hz),
5.05 (dd, 1H, J= 4.5,12 Hz), 7.10-7.15 (m, 1H), 7.22-7.33 (m, 5H)
7.35-7.55 (m, 4H) 7.62 (d, 2H, J = 6 Hz) 8.02 (d, 1H, J = 7 Hz).
This 'H NMR spectrum was in full agreement with an authentic
give 1,5-benzothiazepines
sample. This procedure is followed for the synthesis of all the
9
to the corresponding
evidence for the formation of any side products. The reaction
conditions were the same for all the substrates.
1,5-benzothiazepines.
There was no
substrates listed in Table 1. The known compounds have been
identified by comparison of spectroscopic data (IR and 'H NMR)
and m.p. with those reported. The m.p. and spectral data of the new
compounds are presented below in order of their entries.
2-Furan-2-yl-4-phenyl-2,3-dihydro-benzo[b}[I,4]thiazepine (entry 2):
Oily liquid; IR(cm") 2923, 1650, 1596. 'HNMR83.01 (t,J= 12.9Hz,
1H), 3.37 (dd, J = 4.8, 12.9 Hz, 1H), 5.06 (dd, J = 4.8, 12.9 Hz, 1H),
6.19-7.62 (m, 12H). l3e NMR 8: 34.2, 53.0, 105.4, 110.4, 112.6,
116.1, 119.4, 125.0, 127.4, 128.7 (2C), 130.8, 132.7, 135.4, 141.9,
144.9, 151.7, 153.6, 168.7 with Anal. Calcd.
In
a,13-unsaturated
thiophenol (1.1 mmol), was irradiated
radiation for 5-6 minutes to give the 1,5-benzothiazepine.
Several sensitive functionalities such as -OH, OMe, NOb
O-allyl, and ester were unaffected under the present reaction
a
typical experimental
ketone (chalcone) (1 mmol), and o-amino-
under microwave
procedure,
a mixture of the
Neat, MW
6 min
Scheme
1
Rahman
