Synthesis and pharmacological evaluation of 1,5-benzothiazepine derivatives

Article abstract of DOI:10.1080/10426500701724555

A simple method for the synthesis of 1,5-benzothiazepines integrated with 5-methyl-2-oxo-3-phenyl-Δ4-1,3,4-oxadiazoles in 75-95% yield is devised. A comparison of microwave-accelerated reaction with conventional heating is also illustrated. Structures of

Full text of DOI:10.1080/10426500701724555

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Synthesis and Pharmacological
Evaluation of 1,5-
Benzothiazepine Derivatives
Ravindra R. Kamble a & Belgur S. Sudha b
a Post-Graduate Department of Studies and Research
in Chemistry , Karnatak University , Dharwad, India
b Department of Chemistry and Food Science,
Yuvaraja's College , University of Mysore , Mysore,
India
Published online: 24 Jun 2008.
To cite this article: Ravindra R. Kamble & Belgur S. Sudha (2008) Synthesis and
Pharmacological Evaluation of 1,5-Benzothiazepine Derivatives, Phosphorus,
Sulfur, and Silicon and the Related Elements, 183:7, 1691-1709, DOI:
10.1080/10426500701724555
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Phosphorus, Sulfur, and Silicon, 183:1691–1709, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701724555
Synthesis and Pharmacological Evaluation of
1,5-Benzothiazepine Derivatives
Ravindra R. Kamble1 and Belgur S. Sudha2
1Post-Graduate Department of Studies and Research in Chemistry,
Karnatak University, Dharwad, India
2Department of Chemistry and Food Science, Yuvaraja’s College,
University of Mysore, Mysore, India
A simple method for the synthesis of 1,5-benzothiazepines integrated with 5-methyl-
4
2-oxo-3-phenyl-ꢀ -1,3,4-oxadiazoles in 75–95% yield is devised. A comparison of
microwave-accelerated reaction with conventional heating is also illustrated. Struc-
tures of all the newly synthesised compounds were characterised by physical, analyt-
1
ical and spectral (UV, IR, H NMR, and MS) data. Title compounds were screened
for their antimicrobial, anticonvulsant, anti-inflammatory, and diuretic activities.
Keywords 1,3-Dipolar cycloaddition; 1,5-benzothiazepine; 4-acetylphenylsydnone; mi-
crowave irradiation; thermal method
INTRODUCTION
The use of microwaves in organic synthesis has increased dramatically
in last few years, receiving wide spread acceptance and becoming an in-
dispensable tool. The combination of solvents, acids and long reaction
time period make conventional synthetic methods environmentally haz-
ardous. The rapid one-pot preparation of heterocyclic compounds from
in situ generated reactive intermediates and the general application
to multi-component reactions, that are adaptable for building a library
of compounds has been accomplished using MW technique.1 The mi-
crowaves enhance the rate of chemical reactions and hence they have
gained popularity over the usual homogenous and heterogeneous reac-
tions as they can be carried out rapidly, and can provide pure products
Received 7 June 2007; accepted 20 July 2007.
The authors are grateful to the University of Mysore, for financial assistance and
University Scientific Instrumentation Centre, Mysore for spectral analyses. The authors
also thank Dr. K. Yeshodha Nanjappa, Head, Department of English for grammatical
corrections.
Address correspondence to Ravindra R. Kamble, Department of Chemistry and
Food Science, Yuvaraja’s College, University of Mysore, Mysore 570 005, India. E-mail:
ravichem1234@rediffmail.com
1691

1692
R. R. Kamble and B. S. Sudha
in quantitative yields with minimized by-products.2 Because of short
reaction time requirement, ease of workability and eco-friendliness, mi-
crowaves provide an alternative to environmentally unacceptable pro-
cedures and expensive reagents.
The chemistry of heterocycles has been an interesting branch of the
subject in organic chemistry as it offers a challenging task in the de-
velopment of new synthetic strategies. The 3-arylsydnones, belonging
to a class of mesoionic compounds and their derivatives possess diverse
chemotherapeutic properties. Hence, sydnone is serendipitous hetero-
cycle as it readily undergoes ring transformation to various heterocycles
by 1,3-dipolar cycloaddition reaction.3 This concept has been adopted
to synthesise a number of heterocyclic compounds by one-pot process
from 3-arylsydnones.4−7
The present work involves incorporation of 1,3,4-oxadiazole, which is
1,3-dipolar cycloaddition product of sydnone with 1,5-benzothiazepine
to explore their structure activity relationship (SAR). The attractive
bioactivity leading to the immense chemotherapeutic applications of
1,5-benzothiazepines are the treatment of ailments of cardiovascular
system such as, hypertension,8 maintenance of Ca+2 ion concentration.9
A patented report has claimed that integration of additional hetero-
cyclic ring as a pharmacophore in the 1,5-benzothiazepine nucleus has
resulted into the compound of useful bioactivity.10,11 While carrying out
drug designing, it was found that the introduction of halogeno groups
like chloro, fluoro in analogous benzodiazepines nucleus lead to the
discovery of CNS drugs, chlordiazepoxide.12 flurazepam,13 which are
currently in use. Thus, it seemed that the halogens might act as poten-
tial pharmacophores. The coveted drug ‘diltiazem’ being used as a cal-
cium channel blocker,14 calcium channel modulator,15 calcium channel
antagonist,16 vasodilator,17 antihypertensive,18,19 blood platelet aggre-
gation inhibitor,20 antiarrhythmic,21 antithrombotic,22 antianginal,23
antiischemic,24 and so on, also possesses a 1,5-benzothiazepine nucleus
having an aryl substituent at position 2. In recent years, “clentiazem,”25
also having this moiety, has been found to be a better drug than
diltiazem.
In the light of above observations, we wish to report the use of
MORE (Microwave induced Organic Reaction Enhancement) and
conventional method of synthesis of 5-methyl-3-[p-(2ꢀ-aryl-2ꢀ,3ꢀ-
dihydro-benzo[b][1ꢀ,5ꢀ ]-thiazepin-4ꢀ -yl)-phenyl]-3H-2-oxo-ꢀ4-1,3,4-
oxadiazole 8a–d herein.
RESULTS
Synthesis of biheterocycles, which is effected sequentially, requires bi-
functional precursors, which are not always readily accessible. The

1,5-Benzothiazepine Derivatives
1693
SCHEME 1
4-acetylphenylsydnone 1, which can be conveniently prepared from p-
amino acetophenone, serves as an important synthetic precursor for the
synthesis of title compounds. As shown in Scheme 1, our initial syn-
thetic strategy involved the preparation of 4-acetyl phenylsydnone26
1. The compound 1 is reacted with an aromatic aldehyde 2a–d in
ethanol afforded trans 3-[p-(3ꢀ-aryl acryl-1ꢀ-oyl) phenylsydnone 3a–d
as a predominant product (Claisen-Schmidt reaction). The trans iso-
mer is favored, since in the transition state, two large substituents are
not eclipsed and there is no interference with coplanarity of the eno-
late system. Of the two, the later factor is more important.27 The trans
3a–d on bromination in acetic anhydride sydnone ring underwent 1,3-
dipolar cycloaddition to give meso 3-[p-(2ꢀ,3ꢀ-dibromo-3ꢀ-aryl-propion-
1ꢀ-yl)-phenyl]-5-methyl-3H-2-oxo-ꢀ4-1,3,4-oxadiazole 4a–d. During cy-
cloaddition reaction, chalcone moiety was also brominated. Dibromo

1694
R. R. Kamble and B. S. Sudha
derivative 4a–d on treatment with o-amino thiophenol did not form
the target compound 8a–d. Therefore, this method of ring transforma-
tion of sydnone into oxadiazoline and approach for synthesis of the tar-
get molecule was not advantageous due to the bromination of chalcone
moiety.
Now the strategy of synthesis is changed. The starting material
1 was brominated in presence of acetic acid to 4-bromo-3-(4ꢀ-acetyl)-
phenylsydnone 5, which upon treatment with aromatic aldehydes 2a–
d in ethanol afforded trans 4-bromo-3-[p-(3ꢀ-aryl- acryl-1ꢀ-oyl)] phenyl-
sydnone 6a–d. Compound 6a–d upon heating in the presence of acetic
anhydride at 135◦C or on microwave irradiation, sydnone ring under-
went 1,3-dipolar cycloaddition along with the elimination of bromine
as acetyl bromide to afford exclusively trans 5-methyl-3- [p-(3ꢀ-aryl -
acryl-1ꢀ-oyl)-phenyl]-3H-2-oxo- ꢀ4-1,3,4-oxadiazole 7a–d. Nucleophilic
ꢀ
addition of sulfhydryl electrons of o-amino thiophenol on C2 of 7a–d
is followed by intermolecular dehydrative cyclization afforded the final
product 8a–d.
On comparison, the synthesis by microwave assisted method, with
that by conventional method, it is observed that the reaction progressed
very fast with excellent yield in the former. Microwave irradiation facil-
itates polarization of the molecule under irradiation causing rapid re-
action to occur. This is consistent with the reaction mechanism, which
involves a polar transition state.
Antimicrobial Activity
Antibacterial activity of newly synthesised compounds was determined
against Staphylococcus aureus and Pseudomonas aeruginosa by cup
plate method.28 The test compounds were dissolved in DMF and differ-
ent aliquots were placed in each cup. Incubation was carried out at 37oC
for 24 h. Chloromycetine was used as standard drug. The diameter of
zone of inhibition was measured for 100 µg/ml concentration.
The antifungal activity of the compounds was evaluated against As-
pergillus niger and Fusarium poa by adopting the usual cup plate tech-
nique and using Griseofulvin as the standard. The diameter of zone of
inhibition was measured for 100 µg/ml concentration. The results of
antibacterial and antifungal activities were recorded in Table I.
Anti-Inflammatory Activity
Anti-inflammatory activity was measured using the carrageenan-
induced paw edema test in rats.28 Commercially available ibuprofen
was used as standard drug. Male swiss rats (150–200 g) were divided

1,5-Benzothiazepine Derivatives
1695
TABLE I Results of in vitro Antimicrobial Activity
Diameter of zone of inhibition (mm)*
Entry no.
S. aureus
P. aeruginosa
A. flavus
F. oxysporium
8a
8b
8c
8d
10.0
19.4
11.5
18.3
25.0
—
09.6
23.0
08.5
15.0
24.0
—
11.5
09.8
11.0
13.0
—
09.0
10.5
14.0
17.0
—
Chloromycetine
Griseofulvin
28.0
25.0
Size of the inhibition zone by disk diffusion method, Control (DMF) = No activity.
Both test compounds and standards were tested at 100 µg/ml conc.
into control, standard, and test groups—each consisting of six rats. A
group of rats was treated with Tween-80 (1%) suspension i.p. (control).
Another group was treated with 100 mg/kg of the suspension of the test
compounds. After 30 min, the animals were injected with 0.1 ml of car-
rageenan (1% w/v) in the sub plantar region of left hind paw of the rats.
The volume of the paw was measured using the mercury displacement
technique with the help of a plethysmograph both in control, as well as
in standard animals including the test animals 2 h and 4 h after injec-
tion. The initial volume of the paw was measured within 30 sec of the
injection. The percent inhibition of the inflammation after 2 hour and
4 hour was calculated using the % inhibition = (1 − vt/vc)×100, where
vt and vc are the mean relative changes in the volume of paw edema
in the test and control respectively. The results are summarized in
Table II.
TABLE II Results of Anti-Inflammatory Activity
Edema volume (ml)x
Different interval (mean S. E. M.)
% Inhibition
Dose
Entry No.
mg/kg
2h
4h
2h
4h
8a
8b
8c
8d
100
100
100
100
100
—
0.33 0.02
0.31 0.02
0.29 0.02
0.30 0.02
0.27 0.03
0.38 0.03
0.28 0.03
0.28 0.02
0.24 0.03
0.21 0.03
0.20 0.02
0.34 0.02
13.0
18.0
24.0
21.0
29.0
—
18.0
18.0
30.0
38.0
41.0
—
Standard (Ibuprofen)
Control (Tween)
x Values = mean S.E.M; no.of animals in each group = 06.

1696
R. R. Kamble and B. S. Sudha
Anticonvulsant Activity
The anticonvulsant activity of title compounds was based on maximal
electroshock induced convulsions in rats.28 Male swiss rats were pro-
cured from Virus Diagnostic Laboratory, Dharwad and maintained at
Department of studies in Botany, Karnatak University Dharwad, were
fed with standard diet, water, and libitum. All protocols of animal ex-
periments have been approved by the Institutional Animal Ethics Com-
mittee (IAEC). Six groups of three rats were selected, and to the first
group, saline (control) injected i.p. corneal electrodes were placed on
the cornea, and then the prescribed current was applied. The different
stages of convulsions were noted and used as control. To the second
group, 25 mg/kg of phenytoin sodium (standard) was injected i.p., and
after 30 min, they were subjected to electro-convulsions. The same pro-
cedure was repeated for remaining four groups using test compounds
8a–d. Various stages of convulsions were recorded at different inter-
vals. The mean value for each group was calculated and compared with
control. The results are summarised in Table III.
Diuretic Activity
Diuretic activity evaluation is based on the effects of drugs on water
and electrolytes excretion in rats.28 The animals were marked, weighed
and divided into six groups. To the first group, a water load of 25 ml/kg
(control) p.o. was administered orally. To the second group frusemide
(standard) was given i.p. along with a water load of 25 ml/kg. To the
remaining four groups, suspension of test compounds (100 mg/kg) was
administered i.p. along water. The animals were observed for diuresis,
and the volume of urine collected was measured periodically. Results
TABLE III Results of Anticonvulsant Activity
Time (sec) in various phases of convulsion
Dosea
Recovery/
Death
Entry no.
mg/kg Flexion Extensor Clonus
Stupor
8a
8b
8c
8d
25
25
25
25
—
25
3.3
3.1
1.6
2.5
4.0
1.5
5.0
4.5
4.0
3.9
11.0
2.0
2.5
2.4
2.25
2.20
3.0
88
85
90
95
120
100
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Control (Saline)
Standard (Phenytoin)
1.5
aNo. of animals in each group = 06.

1,5-Benzothiazepine Derivatives
1697
TABLE IV Results of Diuretic Activity
Total amount of urine collected (ml)
Compd.
Doseamg/kg
15ꢀ
30ꢀ
60ꢀ
120ꢀ
240ꢀ
8a
8b
8c
8d
10
10
10
10
10
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
4.0
4.5
4.9
4.8
5.4
3.4
4.5
3.9
4.4
4.3
4.6
3.2
Standard (Frusemide)
Control (Water)
25 ml/kg
aNo. of animals in each group = 06.
were expressed as the mean of six samples and were compared to that
of standard frusemide (Table IV).
DISCUSSION
All the newly synthesised compounds were confirmed by spectral char-
acterisation. Ultraviolet spectra of the chalcones 3a–d, 6a–d, and 7a–d
have shown a strong band in the range 290–345 nm (Ethanol) due to
π → π* transition indicating the formation of only trans chalcone. Ab-
sence of this band in 4a–d indicated the formation. UV spectra of com-
pounds 8a–d showed a considerable bathochromic shift due to π → π*
(λmax 440–460 nm) as compared to that of π → π* in 3a–d, 6a–d, and
7a–d (λmax 290–345 nm). A weak band in the range 320–360 nm present
in the compounds 3a–d, 6a–d, 7a–d ,and 8a–d is due to the n→ π* tran-
sition of lone pair of electrons.
In case of IR spectral analyses a band around 1652–1660 cm−1 in
3a–d indicated the presence of the α, β-unsaturated carbonyl function.
Another band around 1722–1739 cm−1 was observed due to sydnone
carbonyl group. A sharp stretching C H band was observed around
3100–3125 cm−1, which is characteristic of C4, unsubstituted sydnones.
Compounds 4a–d have shown two sharp absorption bands in the func-
tional group region around 1672–1695 cm−1 and 1760–1776 cm−1 due
to saturated keto group and lactone carbonyl function. In case of com-
pound 5, two carbonyl groups (keto and sydnone) absorptions appeared
at 1684 and 1725 cm−1. A band around 3100 cm−1, which is character-
istic of sydnone was absent due to C4-bromo substituent. Compounds
6a–d have shown IR absorption band in the region 1650–1668 cm−1 and
1715–1734 cm−1 as in case of 3a–d due to enone and sydnone carbonyl
stretchings. Absorption peaks around 1647–1658 and 1771–1793 cm−1
due to enone and lactone carbonyl were observed in 7a–d. The title

1698
R. R. Kamble and B. S. Sudha
compounds 8a–d have a stretching band around 1595–1610 cm−1 due
to C N group. A band around 1767–1774 cm−1 due to lactone carbonyl
function was observed.
PMR spectra of 3a–d have shown a characteristic singlet around δ
6.56–6.94, which was due to C4 proton. Two doublets in the range δ
ꢀ
ꢀ
8.00–8.45 and 8.15–8.61 appeared due to C2 and C3 vinylic protons
with coupling constant around 11–13 Hz. Similar type of observations
were made in case of 6a–d and 7a–d, each showing two doublets due
ꢀ
ꢀ
to C2 and C3 vinylic protons in the range δ 7.63–8.24 ppm. (J = 10-
14 Hz) and δ 8.24–8.75 (J = 11–15 Hz), respectively. Compounds 4a–d
ꢀ
ꢀ
have shown two doublets due to C3 and C2 protons in the range δ
5.40–5.66 and 5.54–5.89 ppm, which was up field shift than in case
of their precursors 3a–d. A common singlet due to C5-methyl protons,
which were resonated in the range δ 2.15–2.44 ppm. is exhibited by
4a–d. Compound 5 showed a singlet at δ 2.19 and two doublets in AA’
BB’ pattern at δ 7.95–8.05 were observed due to methyl and aromatic
protons respectively. The compounds 3a–d, 6a–d and 7a–d showed the
J values in the range 11–15 Hz, indicating the trans isomers.
1
The characteristic feature of H NMR 8a–d is the splitting pattern
for the HA, HB, and HX protons. HA and HB are diastereotopic and also
anisochronous as they differ in chemical shifts and since this difference
ꢀ
is not large they may be identified as AB protons. The C2 - methine
proton with larger shift downfield is the HX proton and all together
form the ABX pattern. The HA and HB protons appear as doublet of
doublet due to geminal and vicinal coupling. The HA and HB differ in
coupling with HX; hence, they are also anisogamous.
HA and HB experience shielding and deshielding by the adjacent π-
electrons differentially. HB is more shielded as it would be probably in
ꢀ
the diamagnetic region of π-cloud of aryl ring present on C2 . HB proton
appeared as doublet of doublet in the up field range δ 3.1–3.4 with
two coupling constants J in the range 16.4–17.6 Hz and J in the
BA
BX
range 7.85–11.8Hz. The dihedral angle θ is approximately 160◦ since
the HB and HX cannot adopt coplanarity in the molecule. HA proton
also appeared as doublet of doublet in the range δ 3.6–4.1 with two
coupling constants viz. J in the range 17.0–17.65 Hz and J in the
AB
AX
range 4.0–5.02 Hz. J is the Jee (i.e., distorted diequatorial) value as
AX
◦
◦
ꢀ
the dihedral angle θ is not 90 but 120 due to large aryl ring on C2 .
HX appeared as a four line spectrum with JXA in the range δ 4.50–
5.0 Hz and J in the range 7.87–11.84 Hz. All the compounds 8a–d
XB
has shown a characteristic singlet in the range δ 1.97–2.19 ppm, due
to C5-methyl protons. The above characterised compounds have shown
aromatic protons in the expected region either as multiplet in some or as

1,5-Benzothiazepine Derivatives
1699
doublet of doublet in AA’BB’ pattern. 13C NMR of all these compounds
showed number of signals, which are consistent with the number of
carbons in the molecule.
In the electron impact studies, all compounds showed molecular ion
peaks at their respective m/z. Compounds 3a, 3b, 3c, and 3d have
shown peaks at 131, 209 (M + 2), 145 and 165 due to aryl substituted
cinnamoyl cation. The formed cinnamoyl cations from these 3a–d in-
turn lose CO, resulting in the aryl substituted styryl radical cation at
103, 182, 117, and 137 respectively. The formation of this type of ions
is typical of the chalcones.29 All the compounds 3a–d have shown a
ꢀ
base peak commonly at m/z 190 due to prototropic shift from C3 to car-
bonyl carbon atom attached directly to the phenyl ring and bond fission
ꢀ
between same carbonyl carbon and C2 .
The dibromo derivatives 4a, 4c, and 4d have shown low abundant
molecular ion peaks M+, M + 2 and M + 4 due to the presence of two
bromine atoms in the abundance ratio 1:2:1. This is the typical pattern
for two bromine atoms and is in accordance with the literature.18 Inter-
estingly, the compound 4b has shown four low abundant peaks at 548
(M + 6), 546 (M + 4), 544 (M + 2), and 542 (M+) in the ratio 1:3:3:1
which is due to presence of three bromine atoms. All these compounds
4a–d have shown a base peak at 204 in common. The electron impact
mass spectrum of compound 5 shows a molecular ion peak at 284 and
282 (M + 2 and M+), which agrees with the molecular weight of the
compound. Loss of bromine results in the formation of a base peak 203.
The compounds 6a, 6c and 6d exhibited two molecular ion peaks
(M + 2 and M+) due to the presence of bromine in all except for the
compound 6b which has two bromine atoms. Compound 6b has shown
three low abundant molecular ion peaks in 1:2:1 ratio. All these com-
pounds 6a–d have shown a base peak at 268. The mass spectra of 7a–d
have shown molecular ion peaks at their respective m/z with molecular
ion peak at 204. The title compounds 8a–d have also shown molecular
ion peaks at their respective m/z and the base peak is obtained in all
compounds due to loss of methyl free radical.
From the antibacterial activity analyses (Table I), it was observed
ꢀ
that compounds 8b and 8d with chloro and bromo substituents on C2 -
phenyl nucleus were more active than methyl substituted 8c and un-
substituted 8a. Similar trend was observed in case of antifungal ac-
tivity data also. Compound 8a has comparatively good inhibitory ac-
tivity against A. flavus. The anti-inflammatory activity (Table II) also
revealed that compounds 8c (30.0%) and 8d (38.0%) showed signifi-
cant activity compared to standard Ibuprofen (41.0%). Amongst the
compounds subjected to anticonvulsant activity (Table III), compounds

1700
R. R. Kamble and B. S. Sudha
8c and 8d were found to possess promising activity compared to that
of standard Phenytoin. The diuretic activity (Table IV) results showed
that the test compounds produced slight diuresis compared to standard
frusemide.
EXPERIMENTAL
Melting points were determined using Thomas Hoover capillary melt-
ing point apparatus and are uncorrected. UV and IR spectra were
recorded on Specord-50 and Nicolet Impact – 410 FT –IR spectropho-
tometer, respectively. 1H and 13C NMR spectra were recorded on a
Bruker 300 MHz FT-NMR spectrometer at 300 and 75 MHz, respec-
tively. The chemical shifts are in δ units and reported as ppm rela-
tive to internal standard TMS. The coupling constants (J) in Hz. Mass
spectra were recorded on a EI-70 eV spectrometer. Elemental analyses
results are within 0.4% of the calculated value. TLC was performed on
preactivated (110◦C) silica gel plates using acetone methanol (6:4) as
an irrigant, and the plates were visualised with UV light. Microwave
irradiations were carried out in a BPL 2300 ET domestic microwave
oven. Starting compound 1 was prepared according to literature
method.26
3-[4ꢀ-(3ꢀꢀ-Aryl-acryl-1ꢀꢀ-oyl)-phenylsydnone (3a–d)
Thermal Method
A mixture of 1 (2.04 g, 10.0 mmol), aromatic aldehyde 2a–d (10.0
mmol) in ethanol (10 ml) and sodium hydroxide solution (0.5 g in 5 ml
of water) was taken in a conical flask (100 ml). The reaction mixture
was stirred for 45 min at room temperature. The precipitate formed was
immediately collected and washed thoroughly with water. The chalcone
derivative 3a–d obtained was dried and crystallized using methanol:
dioxane::1:1 (v/v) to get bright yellow crystals in 80–85% yield (Tables
V and VI).
Microwave Method
To a solution of 1, (2.04 g, 10.0 mmol) and aromatic aldehyde 2a–d
(10.0 mmol) in dry ethanol (20 ml) taken in a borosil beaker (100 ml),
sodium hydroxide (0.5 g in 5 ml of water) was added, and the reaction
mixture was zapped inside a microwave oven at 55◦C (210 W, i.e., 30%
microwave power) for 8 min and then cooled in an ice bath; the product
formed was filtered and crystallized using methanol: dioxane::1:1 (v/v)
to give bright yellow crystals of 3a–d (Yield 85–92%) (Table V and VI).

1,5-Benzothiazepine Derivatives
1701
TABLE V Comparison of Time Required and Yield
Thermal
Microwave
Time (Minutes)
Entry no.
Time (Minutes)
Yield %
Yield %
3a
3b
3c
3d
4a
4b
4c
4d
5
6a
6b
6c
6d
7a
7b
7c
7d
8a
8b
8c
8d
45
40
40
45
90
85
95
86
30
45
50
44
50
120
125
115
115
180
190
175
180
81
80
85
83
74
70
71
70
70
65
68
65
64
72
66
70
68
60
49
62
58
8
7
8
7
5
4
5
4
—
10
11
13
10
8
11
9
10
9
90
86
92
85
80
84
90
83
—
73
90
72
88
95
86
90
89
86
90
84
89
11
8
10
Compound (3a). uv λmax: (Ethanol), 290, 325 (strong) and 355 (weak)
nm; IR: enone CO 1660 sydnone CO 1739 and C4-H 3110 cm−1; 1H NMR:
δ 6.94 (s, 1H, C4-H), 7.81–7.14 (m, 9H, ArH), 8.45 (d, 1H, trans-olefinic
C3 -H, J = 13 Hz), 8.61 (d, 1H, trans-olefinic C2 -H, J = 13 Hz); 13C
ꢀ
ꢀ
ꢀ
ꢀ
NMR: δ 94.23 (C4), 119.8 (C2 ),+126.2–137.0 (ArC), 141.6 (C3 ), 164.1
ꢀ
(C1 ), 169.7 (C5); MS: m/z 292 (M , 5%), 262 (33), 234 (20), 207 (45), 190
(100), 160 (72), 132 (61), 131 (80), 105 (11), 103 (17), 90 (40).
Compound (3b). uv λmax: (Ethanol) 253, 310 (strong) and 340 (weak)
1
nm; IR: enone CO 1654 sydnone CO 1727 and C4-H 3100 cm−1; H
ꢀ
NMR: δ 6.56 (s, 1H, C4-H), 7.19 (d, 2H, C3 -ArH, J = 5.0 Hz), 7.38 (d,
ꢀ
2H, C3 -ArH, J = 5.0 Hz), 7.63 (d, 2H, N3-ArH, J = 6.9 Hz), 7.85 (d, 2H,
ꢀ
N3-ArH, J = 6.9 Hz), 8.04 (d, 1H, trans-olefinic C3 -H, J = 11 Hz), 8.15
(d, 1H, trans-olefinic C2 -H, J = 11 Hz); 13C NMR: δ 93.85 (C4), 125.6
ꢀ
ꢀ
ꢀ
ꢀ
(C2 ), 128.4–138.0 (ArC), 140.7 (C3 ),162.4 (C1 ), 170.2 (C5); MS: m/z 372
(M+2, 4%), 370 (M+, 5), 342 (21), 340 (23), 314 (15), 312 (15), 287 (40),
285 (41), 211 (75), 209 (71),190 (100), 181 (12), 170 (25),168 (34), 132
(56).

1702
R. R. Kamble and B. S. Sudha
TABLE VI Characterization Data of the Synthesized Compounds
Found (Calculated) %
Entry
no.
Empirical formula
C
H
N
m.p. ◦
C
R f
3a
3b
3c
3d
4a
4b
4c
4d
5
6a
6b
6c
6d
7a
7b
7c
7d
8a
8b
8c
8d
C17H12N2O3
C17H11BrN2O3
69.84 (69.86) 4.12 (4.14)
54.96 (55.01) 2.95 (2.99)
70.55 (70.58) 4.58 (4.61)
62.47 (62.48) 3.33 (3.37)
46.34 (46.38) 3.00 (3.03)
39.70 (39.67) 2.42 (2.40)
47.55 (47.53) 3.39 (3.36)
9.55 (9.58)
7.50 (7.55)
9.18 (9.15)
8.55 (8.57)
5.97 (6.01)
5.13 (5.14)
5.58 (5.83)
5.60 (5.62)
9.90 (9.94)
7.52 (7.55)
6.19 (6.22)
7.25 (7.27)
6.94 (6.92)
9.17 (9.15)
7.24 (7.27)
8.72 (8.74)
8.24 (8.22)
177–179 0.46
182–184 0.22
163–165 0.64
220–222 0.34
211–213 0.52
157–159 0.19
204–206 0.34
157–159 0.50
160–162 0.52
212–214 0.41
153–155 0.37
124–126 0.26
232–234 0.68
137–139 0.46
182–184 0.31
125–127 0.49
196–198 0.40
C18H14N2O3
C17H11ClN2O3
C18H14Br2N2O3
C18H13Br3N2O3
C19H16Br2N2O3
C18H13ClBr2N2O3 43.30 (43.33) 2.60 (2.61)
C
10H7BrN2O3
C17H11BrN2O3
17H10Br2N2O3
C18H13BrN2O3
17H10ClBrN2O3
42.40 (42.43) 2.53 (2.49)
55.05 (55.01) 2.95 (2.99)
45.36 (45.37) 2.20 (2.24)
56.10 (56.12) 3.45 (3.40)
50.41 (50.43) 2.45 (2.47)
70.56 (70.58) 4.63 (4.61)
56.10 (56.12) 3.38 (3.40)
71.29 (71.24) 5.04 (5.03)
63.42 (63.44) 3.84 (3.85)
C
C
C18H14N2O3
C18H13BrN2O3
C
19H16N2O3
C18H13ClN2O3
24H19N3O2S
C
69.68 (69.71) 4.60 (4.63) 10.12 (10.16) 167–169 0.77
C24H18BrN3O2S
C25H21N3O2S
C24H18ClN3O2S
58.50 (58.54) 3.67 (3.68)
70.20 (70.23) 4.97 (4.95)
64.37 (64.35) 4.01 (4.05)
8.56 (8.53)
9.85 (9.83)
9.40 (9.38)
221–223 0.43
187–189 0.35
143–145 0.66
Compound (3c). uv λmax: (Ethanol) 300, 345 (strong), and 360 (weak)
nm; IR: enone CO 1663 sydnone CO 1730 and C4-H 3125 cm−1; 1H NMR:
ꢀ
δ 2.35 (s, 3H, CH3), 6.71 (s, 1H, C4-H), 7.01 (d, 2H, C3 -ArH, J = 6.2 Hz),
ꢀ
7.18 (d, 2H, C3 -ArH, J = 6.2 Hz), 7.42 (d, 2H, N3-ArH, J = 7.0 Hz), 7.80
ꢀ
(d, 2H, N3-ArH, J= 7.0 Hz), 8.31 (d, 1H, trans olefinic C3 -H, J= 12 Hz),
8.54 (d, 1H, trans olefinic C2 -H, J = 11.7 Hz); 13C NMR: δ 20.9 (CH3),
ꢀ
ꢀ
ꢀ
ꢀ
88.40 (C4), 112.0 (C2 ), 122.3–136.6 (ArC), 144.1 (C3 ), 163.8 (C1 ), 169.0
(C5); MS: m/z 326 (M+, 9%), 300 (16), 272 (23), 245 (32), 190 (100), 160
(61), 145 (90), 132 (50), 117 (12),105 (9),104 (51).
Compound (3d). uv λmax: (Ethanol) 243, 305 (strong), and 340 (weak)
nm; IR: enone CO 1652 sydnone CO 1722 and C4-H 3104 cm−1; 1H NMR:
ꢀ
ꢀ
δ 6.65 (s, 1H, C4-H), 7.10 (d, 2H, C3 -ArH, J = 6.2 Hz), 7.18 (d, 2H, C3 -
ArH, J = 6.2 Hz), 7.30 (d, 2H, N3-ArH, J = 7.0 Hz), 7.39 (d, 2H, N3-ArH,
ꢀ
J = 7.0 Hz), 8.00 (d, 1H, trans-olefinic C3 -H, J = 11.5 Hz), 8.34 (d, 1H,
13
ꢀ
ꢀ
trans-olefinic C2 -H, J = 11.5 Hz); C NMR: δ 94.35 (C4), 118.7 (C2 ),
+
ꢀ
ꢀ
122.6–137.0 (ArC), 143.5 (C3 ), 164.1 (C1 ), 169.5 (C5); MS: m/z 326 (M ,
7%), 300 (16), 272 (23), 245 (31), 190 (100), 160 (54), 165 (91), 137 (10),
132 (50), 124 (47).

1,5-Benzothiazepine Derivatives
1703
3-[p-(2ꢀ,3ꢀ-Dibromo-3ꢀ-aryl-propion-1’-yl)-phenyl]-5-methyl-3H-
2-oxo-∆4-1,3,4-oxadiazole (4a-d)
Thermal Method
To a solution of 3a-d (5.0 mmol) in acetic anhydride (10 ml) at 0◦C
was added bromine (10 mmol) in acetic anhydride (10 ml) with constant
stirring. After complete addition of bromine solution, the stirring was
continued for 30 min. The reaction mixture was then heated to 60◦C
for 1h until the evolution of carbon dioxide ceased; then the mixture
was cooled and poured into water. The solid separated was filtered and
dried. Crystallisation of the product from methanol gave 4a–d in 70–
74% yield.
Microwave Method
In a typical method, addition of bromine (10 mmol) in acetic anhy-
dride (10 ml) to 3a–d (5.0 mmol) was similar to the thermal method at
0◦C. The brominated reaction mixture was then introduced into the mi-
crowave oven in a conical flask (100 ml) capped with a funnel. The flask
was irradiated at 25◦C (80 W 12% microwave power) for 5 min. The
reaction mixture was cooled, and the solid, thus separated, was filtered
and recrystallized from methanol to afford 4a–d (Yield 80–90%).
Compound (4a). uv λmax: (Ethanol) 243 and 340 nm (weak); IR: C O
1695 and C5-C O 1772 cm−1; 1H NMR: δ 2.44 (s, 3H, C5-CH3), 5.64 (d,
ꢀ
ꢀ
1H, C3 -H, J = 13 Hz), 5.89 (d, 1H, C2 -H, J = 13 Hz), 8.21-7.24 (m, 9H,
13
ꢀ
ꢀ
ArH); C NMR: δ 14.9 (CH3), 47.2 (C3 ), 57.0 (C2 ), 118.7-138.4 (ArC),
ꢀ
155.0 (C5), 157.3 (C2),175.0 (C1 ); MS: m/z 470 (M + 4, 5%), 468 (M +
2, 11), 466 (M+, 5), 385 (61), 306 (70), 204 (100), 160 (70), 131 (13), 103
(9), 90 (4).
Compound (4b). uv λmax: (Ethanol) 210 and 326 nm (weak); IR: C O
1690 and C5-C O 1776 cm−1; 1H NMR: δ 2.33 (s, 3H, C5-CH3), 5.40 (d,
ꢀ
1H, C3 -H, J = 12 Hz), 7.26 (d, 2H, N3-ArH, J = 6.7 Hz), 5.54 (d, 1H,
ꢀ
ꢀ
ꢀ
C2 -H, J = 12 Hz), 6.85 (d, 2H, C3 -ArH, J = 6.2 Hz), 7.01 (d, 2H, C3 -
ArH, J = 6.2 Hz), 7.91 (d, 2H, N3-ArH, J = 6.7 Hz); 13C NMR: δ 15.04
ꢀ
ꢀ
(CH3), 45.6 (C3 ), 57.4 (C2 ), 113.2-138.0 (ArC), 155.3 (C5), 157.9 (C2),
ꢀ
179.0 (C1 ); MS: m/z 548 (M + 6, 4%), 546 (M + 4,10), 544 (M + 2, 12),
542 (M+, 4), 467 (9), 465 (17), 463 (9), 386 (13), 384 (15), 204 (100), 160
(61), 131 (17).
Compound (4c). uv λmax: (Ethanol) 225 and 330 (weak); IR: C O
1687 and C5-C O 1769 cm−1; 1H NMR: δ 2.15 (s, 3H, C5-CH3), 2.27 (s,
ꢀ
ꢀ
3H, ArCH3), 5.66 (d, 1H, C3 -H, J = 14 Hz), 5.73 (d, 1H, C2 -H, J = 14
ꢀ
ꢀ
Hz), 7.06 (d, 2H, C3 -ArH, J = 6.2 Hz), 7.30 (d, 2H, C3 -ArH, J = 6.2

1704
R. R. Kamble and B. S. Sudha
Hz), 7.34 (d, 2H, N3-ArH, J = 6.7 Hz), 7.95 (d, 2H, N3-ArH, J = 6.7 Hz);
13
ꢀ
ꢀ
C NMR: δ 14.87 (CH3), 21.2 (ArCH3), 47.5 (C3 ), 57.9 (C2 ), 119.1-137.5
ꢀ
(ArC), 154.2 (C5), 156.1 (C2), 174.0 (C1 ); MS: m/z 482 (M + 4, 5%), 480
(M + 2, 11), 478 (M+, 5), 401 (8), 399 (9), 320 (21), 204 (100), 160 (80),
145 (43), 131 (78), 117 (31), 104 (45), 43 (21).
Compound (4d). uv λmax: (Ethanol) 210 and 366 (weak) nm; IR:
1
C O1672 and C5-C O 1760 cm−1; H NMR: δ 2.24 (s, 3H, C5-CH3),
ꢀ
ꢀ
5.51 (d, 1H, C3 -H, J = 12 Hz,), 5.60 (d, 1H, C2 -H, J = 12 Hz), 7.10 (d,
ꢀ
ꢀ
2H, C3 -ArH, J = 6.2 Hz), 7.35 (d, 2H, C3 -ArH, J = 6.2 Hz), 7.57 (d,
2H, N3-ArH, J = 6.7 Hz), 7.80 (d, 2H, N3-ArH, J = 6.7 Hz); 13C NMR:
ꢀ
ꢀ
δ 15.0 (CH3), 46.8 (C3 ), 57.4 (C2 ), 109.2 (C5), 136.1–151.0 (ArC), 157.9
+
ꢀ
(C2), 179.0 (C1 ); MS: m/z 502 (M + 4, 6), 500 (M + 2, 11), 498 (M , 4),
421 (12), 419 (13), 340 (47), 204 (100), 160 (17), 137 (33), 131 (80), 124
(50), 43 (27).
4-Bromo-p-(acetyl)-phenylsydnone (5)
Bromine (0.3 ml) taken in 5 ml of glacial acetic acid was added at room
temperature with stirring to a suspension of (2.04 g 10.0 mmol) of 1 in
glacial acetic acid (5 ml). After complete addition, stirring was contin-
ued for 30 min. The reaction mixture was poured into ice-cold water.
The colourless solid separated was filtered and dried. Crystallization
of the solid from ethanol yielded white crystalline compound 5 in 70%
yield (1.98 g).
uv λmax: (Ethanol) 225 and 374 (weak) nm; IR: sydnone C O 1725
1
and C O 1684 cm−1; H NMR: δ 2.19 (s, 3H, CH3), 7.95 (d, 2H, ArH,
J = 8.04 Hz), 8.05 (d, 2H, ArH, J = 8.04 Hz); 13C NMR: δ 22.8 (CH3),
100.8 (C4), 129.6-111.9 (ArC), 170.6 (C5), 196.5 (CO); MS: m/z 284 (M +
2, 6%), 282 (7), 254 (9), 252 (9), 252 (10), 226 (13), 224 (15), 203 (100%),
177 (80), 43 (21).
4-Bromo 3-[p-(3ꢀ-aryl-acryl-1ꢀ-oyl)] phenylsydnone (6a-d)
Thermal Method
A mixture of 5 (2.82 g, 10.0 mmol), aromatic aldehyde 2a-d (10.0
mmol) in ethanol (10 ml), and sodium hydroxide solution (0.5 g in 5 ml
of water). The reaction mixture was stirred for 45 min at room tem-
perature. Final work up was as in case of 3a–d to get 6a–d in 64–68%
yield.

1,5-Benzothiazepine Derivatives
1705
Microwave Method
The experimental for preparation of 6a–d was similar to that of
preparation of 3a–d and time required for completion of the reaction
was 10 min. (Yield 73–90%).
Compound (6a). uv λmax: (Ethanol) 280, 305 (strong), and 340 (weak)
1
nm; IR: enone C O 1653 and sydnone C O 1729 cm−1 ; H NMR: δ
ꢀ
7.74–7.95 (m, 9H, ArH), 8.16 (d, 1H, trans olefinic C3 -H, J = 12 Hz),
8.24 (d, 1H, trans olefinic C2 -H, J = 12 Hz); 13C NMR: δ 96.40 (C4),
ꢀ
ꢀ
ꢀ
ꢀ
119.0 (C2 ), 121.5–135.0 (ArC), 141.2 (C3 ), 164.0 (C1 ), 169.5 (C5); MS:
m/z 372 (M + 2, 8%), 370 (M+, 9), 342 (15), 340 (17), 314 (19), 312 (21),
270 (97.38), 268 (100), 233 (60), 208 (44), 131 (77), 105 (34), 103 (270),
90 (54).
Compound (6b). uv λmax: (Ethanol) 245, 290 (strong), and 325 (weak)
nm; IR: enone C O1650 and sydnone C O 1734 cm−1; 1H NMR: δ 7.10
ꢀ
ꢀ
(d, 2H, C3 -ArH, J = 5.0 Hz), 7.22 (d, 2H, C3 -ArH, J = 5.0 Hz), 7.59
(d, 2H, N3-ArH, J = 6.9 Hz), 7.80 (d, 2H, N3-ArH, J = 6.9 Hz), 7.92 (d,
ꢀ
ꢀ
1H, trans olefinic C3 -H, J = 13 Hz), 8.00 (d, 1H, trans olefinic C2 -H, J
= 13 Hz); 13C NMR: δ 101.5 (C4), 116.8 (C2 ), 120.1–133.9 (ArC), 140.6
ꢀ
ꢀ
ꢀ
(C3 ), 160.3 (C1 ), 169.0 (C5); MS: m/z 453 (M + 4, 7), 451 (M + 2, 13),
449 (M+, 7), 423 (11), 421 (20), 419 (10), 395 (7), 393 (13), 391 (8), 314
(34), 312 (36), 288 (60), 286 (64), 270 (96), 268 (100), 105 (81).
Compound (6c). uv λmax: (Ethanol) 250, 305 (strong), and 330 (weak)
nm; IR: enone C O 1663 and sydnone C O 1730 cm−1; 1H NMR: δ 2.38
(s, 3H, ArCH3), 7.06 (d, 2H, N3-ArH, J = 5.8 Hz), 7.20 (d, 2H, N3-ArH,
ꢀ
ꢀ
J = 5.8 Hz), 7.43 (d, 2H, C3 -ArH, J = 8.4 Hz), 7.62 (d, 2H, C3 -ArH, J =
ꢀ
8.4 Hz), 7.91 (d, 1H, trans olefinic C3 -H, J = 10 Hz), 8.14 (d, 1H, trans
olefinic C2 -H, J = 10 Hz); 13C NMR: δ 25.0 (ArCH3), 106.0 (C4), 122.3
ꢀ
ꢀ
ꢀ
ꢀ
(C2 ), 126.1-136.9 (ArC), 140.0 (C3 ), 165.8 (C1 ), 168.4 (C5); MS: m/z 386
(M + 2, 9), 384 (M+, 11), 356 (17), 354 (19), 328 (28), 326 (30), 270 (97),
268 (100), 247 (65), 221 (46), 145 (38), 117 (20), 105 (80), 104 (66).
Compound (6d). uv λmax: (Ethanol) 250, 347 (strong), and 370
(weak)nm; IR: enone C O 1668 and sydnone C O 1715 cm−1; 1H NMR:
δ 7.11 (d, 2H, N3-ArH, J = 5.8 Hz), 7.35 (d, 2H, N3-ArH, J = 5.8 Hz),
ꢀ
ꢀ
7.42 (d, 2H, C3 -ArH, J = 8.4 Hz), 7.50 (d, 2H, C3 -ArH, J = 8.4 Hz),
ꢀ
7.63 (d, 1H, trans olefinic C3 -H, J = 10 Hz), 7.95 (d, 1H, trans olefinic
13
ꢀ
ꢀ
C2 -H, J = 10 Hz); C NMR: δ 100.5 (C4), 118 (C2 ), 119.0-133.0 (ArC),
+
ꢀ
ꢀ
141.6 (C3 ), 160.9 (C1 ), 172.0 (C5); MS: m/z 406 (M + 2, 8), 404 (M , 9),
376 (18), 374 (21), 348 (30), 346 (33), 270 (98), 268 (100), 267 (60), 241
(40), 165 (31), 137 (19), 124 (18), 105 (88).

1706
R. R. Kamble and B. S. Sudha
5-Methyl-3-[p-(3ꢀ-aryl- acryl-1’-oyl)-phenyl]-3H -2-oxo–∆4 -
1,3,4-oxadiazole (7a–d)
Thermal Method
Compound 6a-d (10.0 mmol) was suspended in pure acetic anhydride
(5.0 ml) and the mixture was heated on oil bath until the brown fumes
of acetyl bromide were removed (2 h). The mixture was poured into
water and allowed to stand for 30 min. Colorless solid was filtered and
washed with water and recrystallized using methanol-dioxane to get
bright yellow crystals of 7a–d in 66–72% yield.
Microwave Method
A mixture of 6a–d (0.0 mmol) and pure acetic anhydride (3.0 ml) was
taken in a borosil beaker (100 ml) was zapped inside a microwave oven
at 80◦C for a duration of 8 min (280 W, i.e., 40% microwave power). The
reaction mixture was cooled and treated with water, dried. Bright yel-
low crystals of 7a–d were obtained on recrystallization from methanol-
dioxane mixture. (Yield 86–95%).
Compound (7a). uv λmax: (Ethanol) 285, 346 (strong) and 356
1
(weak)nm; IR: C O 1652 and C5-C O 1772 cm−1; H NMR: δ 2.33 (s,
ꢀ
3H, C5-CH3), 7.93–8.22 (m, 9H, ArH), 8.67 (d, 1H, trans olefinic C3 -H,
J = 13 Hz), 8.71 (d, 1H, trans olefinic C2 -H, J = 13 Hz); 13C NMR: δ
ꢀ
ꢀ
ꢀ
15.4 (CH3), 120.9 (C2 ), 123.3-142.8 (ArC), 144.2 (C3 ),150.1 (C5), 155.0
+
ꢀ
(C2), 187.0 (C1 ); MS: m/z 306 (M , 8%), 204 (100), 160 (75), 131 (61),
103 (33), 90 (45), 43 (21).
Compound (7b). uv λmax: (Ethanol) 256, 341 (strong) and 364
1
(weak)nm; IR: C O 1647 and C5-C O 1784 cm−1 ; H NMR: δ 2.14
(s, 3H, C5-CH3), 7.07 (d, 2H, N3-ArH, J = 7.2 Hz), 7.27 (d, 2H, N3-ArH,
ꢀ
ꢀ
J = 6.4 Hz), 8.01 (d, 2H, C3 -ArH, J = 7.2 Hz), 8.33 (d, 2H, C3 -ArH,
ꢀ
J = 6.4 Hz), 8.51 (d, 1H, trans olefinic C3 -H, J = 15 Hz), 8.60 (d, 1H,
13
ꢀ
ꢀ
trans olefinic C2 -H, J = 15 Hz); C NMR: δ 14.9 (CH3), 119.4 (C2 ),
ꢀ
ꢀ
120.8–140.0 (ArC), 144.0 (C3 ), 155.01 (C5), 161.7 (C2), 181.6 (C1 ); MS:
m/z 386 (M + 2, 8%), 384 (M+, 9), 211 (10), 209 (11), 204 (100), 183 (15),
181 (17), 170 (19), 168 (21), 160 (64), 131 (50), 43 (20).
Compound (7c). uv λmax: (Ethanol), 285, 320 (strong), and 350
1
(weak) nm; IR: C O 1658 and C5-C O 1793 cm−1; H NMR: δ 2.09
(s, 3H, C5-CH3), 2.32 (s, 3H, ArCH3), 7.71 (d, 2H, N3-ArH, J = 7.0 Hz),
ꢀ
7.82 (d, 2H, N3-ArH, J = 7.0 Hz), 8.25 (d, 2H, C3 -ArH, J = 5.9 Hz),
ꢀ
ꢀ
8.44 (d, 2H, C3 -ArH, J = 5.9 Hz), 8.63 (d, 1H, trans olefinic C3 -H, J =
11 Hz), 8.75 (d, 1H, trans olefinic C2 -H, J = 11 Hz); 13C NMR: δ 16.7
ꢀ
ꢀ
(CH3), 16.7 (CH3), 21.1 (ArCH3), 122.2 (C2 ), 123.6-145.1 (ArC), 146.8

1,5-Benzothiazepine Derivatives
1707
+
ꢀ
ꢀ
(C3 ), 151.6 (C5), 158.1 (C2), 179.4 (C1 ); MS: m/z 320 (M , 10), 204 (100),
160 (70), 131 (40), 145 (33), 117 (24), 104 (60), 43 (18).
Compound (7d). uv λmax: (Ethanol) 265, 357 (strong), and 370 (weak)
nm; IR: C O1650 and 1771 (C5-C O) cm−1; 1H NMR: δ 2.08 (s, 3H, C5-
CH3), 7.05 (d, 2H, N3-ArH, J = 7.2 Hz), 7.21 (d, 2H, N3-ArH, J = 6.4
ꢀ
ꢀ
Hz), 7.54 (d, 2H, C3 -ArH, J = 7.2 Hz), 7.67 (d, 1H, C3 -ArH, J = 6.4 Hz),
ꢀ
8.24 (d, 1H, trans olefinic C3 -H, J = 15 Hz), 8.35 (d, 1H, trans olefinic
13
ꢀ
ꢀ
C2 -H, J = 15 Hz); C NMR 188.7 (C1 ), 159.3 (C2), 155.0 (C5), 145.2
+
ꢀ
ꢀ
(C3 ), 144.0-125.7 (ArC), 120.1 (C2 ), 15.0 (CH3); MS: m/z 340 (M , 11),
204 (100), 160 (63), 131 (34), 165 (28), 137 (20), 124 (54), 43 (22).
5-Methyl-3-[p-(2ꢀ-aryl-2ꢀ,3ꢀ-dihydro-benzo[b][1’,5ꢀ]thiazepin-4ꢀ-
yl)-phenyl]-3H-2-oxo-∆4-1,3,4-oxadiazole
(8a-d)
Thermal Method
Compound 7a-d (10.0 mmol) and o-amino thiophenol (10.0 mmol)
were taken in absolute ethanol (20.0 ml) and saturated with dry HCl.
The reaction mixture was refluxed on a water bath for 3 h, and the
solvent was evaporated to obtain 8a–d. The brown colored crude product
on further crystallization from ethanol gave red crystals in 49–62%
yield.
Microwave Method
A mixture of chalcone 7a–d of (10.0 mmol), o-amino thiophenol (10.0
mmol) and glacial acetic acid (5.0 ml) in DMF (15 ml) was taken in a
conical flask (100 ml) capped with a glass funnel and placed in a mi-
crowave oven and irradiated for 9 min at 65◦C (250 W, 35% microwave
power). The reaction mixture was cooled and treated with cold water.
The solid 8a–d separated was filtered, washed with water, and recrys-
tallized from ethanol. (Yield 84–92%).
Compound (8a). uv λmax: (Ethanol), 245, 350 (weak), 446, and 450
1
(strong) nm; IR: and C=N 1600 and C5-C O 1768 cm−1 ; H NMR: δ
ꢀ
2.19 (s, 3H, C5-CH3), 3.1 (dd, 1H, C3 -HB, J = 17.6 Hz, J = 11.8
BA
BX
ꢀ
Hz), 3.6 (dd, 1H, C3 -HA, J = 17.6 Hz, J = 4.49 Hz), 4.91-5.0 (m,
AB
AX
ꢀ
1H, C2 -HX, JXA = 4.50 Hz, J = 11.84 Hz), 7.50-6.31 (m, 13H, ArH);
XB
13
ꢀ
ꢀ
C NMR: δ 19.0 (CH3), 40.1 (C3 ), 40.8 (C2 )+, 115.3-137.4 (ArC), 154.9
ꢀ
(C5), 160.0 (C2), 164.6 (C4 ); MS m/z 413 (M , 5%), 398 (45), 354 (11),
313 (21), 238 (100), 211 (34), 179 (65), 77 (50).
Compound (8b). uv λmax: (Ethanol) 232, 346 (weak), 440, and 448
(strong) nm; IR: C=N 1610 and C5-C O 1781 cm−1; 1H NMR: δ 2.11 (s,

1708
R. R. Kamble and B. S. Sudha
ꢀ
3H, C5-CH3), 3.2 (dd, 1H, C3 -HB, J = 17.65 Hz, J = 11.84 Hz), 3.9
BA
BX
ꢀ
ꢀ
(dd, 1H, C3 -HA, J = 17.65 Hz, JAX = 4.49 Hz), 5.5–5.6 (m, 1H, C2 -HX,
JXA = 4.50 Hz, JAB = 11.80 Hz), 6.36–6.90 (m, 4H, ArH), 6.92 (d, 2H,
XB
ꢀ
ꢀ
C2 -ArH, J = 8.0 Hz), 7.31 (d, 2H, C2 -ArH, J = 8.0 Hz), 7.58 (d, 2H,
N3-ArH, J = 6.4 Hz), 7.67 (d, 2H, N3-ArH, J = 6.4 Hz); 13C NMR: δ 16.3
ꢀ
ꢀ
ꢀ
(CH3), 43.7 (C3 ), 44.0 (C2 ), 110.0–131.4 (ArC), 151.5 (C4 ), 155.0 (C5),
156.5 (C2); MS m/z 493 (M + 2, 6%), 491 (M+, 7), 478 (21), 476 (23), 434
(41), 432 (42), 393 (11), 391 (14), 318 (97), 316 (100), 291 (24), 289 (26),
259 (44), 257 (47), 157 (37), 155 (39).
Compound (8c). uv λmax: (Ethanol), 246, 334 (weak) 452 and 460
(strong) nm; IR: C=N 1605 and C5-C O 1767 cm−1; 1H NMR: δ 1.97 (s,
ꢀ
3H, C5-CH3), 2.25 (s, 3H, ArCH3), 3.4 (dd, 1H, C3 -HB, J = 17.0 Hz,
ꢀ
J
BX
= 8.08 Hz), 4.1 (dd, 1H, C3 -HA, J = 17.65 Hz, J BA= 7.02 Hz),
AB
AX
ꢀ
5.4-5.8 (m, 1H, C2 - HX, JXA = 6.96 Hz, J = 7.99 Hz), 6.57-7.01 (m,
XB
ꢀ
ꢀ
4H, ArH), 7.12 (d, 2H, C2 -ArH, J = 8.0 Hz), 7.18 (d, 2H, C2 -ArH, J
= 8.0 Hz), 7.60 (d, 2H, N3-ArH, J = 5.5 Hz), 7.69 (d, 2H, N3-ArH, J
13
ꢀ
ꢀ
= 5.5 Hz); C NMR: δ 17.0 (CH3), 24.7 (ArCH3), 40.4 (C3 ), 41.2 (C2 ),
+
ꢀ
112.0–141.2 (ArC), 150.0 (C5), 156.0 (C2), 165.7 (C4 ); MS m/z 427 (M ,
7%), 412 (40), 368 (10), 327 (19), 252 (100), 225 (30), 193 (61).
Compound (8d). uv λmax: (Ethanol) 236, 337 (weak), 441, and 448
1
(strong) nm; IR: C=N 1595 and C5-C O 1774 cm−1; H NMR: δ 2.00
ꢀ
(s, 3H, CH3), 3.1 (dd, 1H, C3 -HB, J = 16.40 Hz, J = 7.85 Hz), 3.6
BA
BX
ꢀ
ꢀ
(dd, 1H, C3 -HA, J = 16.40 Hz, J = 8.50 Hz), 4.9 (m, 1H, C2 - HX,
AB
AX
JXA = 8.48 Hz, J = 7.87 Hz), 6.59–6.74 (m, 4H, ArH), 4.8–7.04 (d, 2H,
XB
ꢀ
ꢀ
C2 -ArH, J = 8.0 Hz), 7.12 (d, 2H, C2 -ArH, J = 8.0 Hz), 7.31 (d, 2H,
N3-ArH, J = 6.4 Hz), 7.40 (d, 2H, N3-ArH, J = 6.4 Hz); 13C NMR: δ 15.4
ꢀ
ꢀ
ꢀ
(CH3), 41 (C3 ), 42 (C2 ), 116.2-146.0 (ArC), 155 (C5), 162.9 (C4 ), 164.0
(C2); MS m/z: 447 (M+, 7%), 432 (31), 388 (11), 347 (19), 272 (100), 245
(30), 213 (61), 111 (44).
CONCLUSIONS
In summary, this work demonstrates a rapid, efficient, and environmen-
tally friendly method for the synthesis of 1,5-benzothiazepine deriva-
tives (8a–d) under thermal and microwave heating, and the results
obtained confirm the superiority of the microwave irradiation method
over the classical heating one.
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1709
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