Solvent-free synthesis of some 1,5-benzothiazepines and benzodiazepines and their antibacterial activity

Article abstract of DOI:10.1080/10426500701852661

An efficient and convenient synthesis of 1, 5-benzothiazepines (3a-3f) and 1, 5-benzodiazepines (4a-4f) from chalcones (2a-2f) by the action of o-amino thiophenol and o-phenylenediamine in the presence of inorganic support is reported. These compounds are

Full text of DOI:10.1080/10426500701852661

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Solvent-Free Synthesis of Some
1,5-Benzothiazepines and
Benzodiazepines and Their
Antibacterial Activity
R. K. Saini a , Y. C. Joshi a & P. Joshi b
a Department of Chemistry , University of
Rajasthan , Jaipur, India
b S. S. Jain Subodh P. G. College , Jaipur, India
Published online: 12 Aug 2008.
To cite this article: R. K. Saini , Y. C. Joshi & P. Joshi (2008) Solvent-Free Synthesis
of Some 1,5-Benzothiazepines and Benzodiazepines and Their Antibacterial Activity,
Phosphorus, Sulfur, and Silicon and the Related Elements, 183:9, 2181-2190, DOI:
10.1080/10426500701852661
To link to this article: http://dx.doi.org/10.1080/10426500701852661
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Phosphorus, Sulfur, and Silicon, 183:2181–2190, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701852661
Solvent-Free Synthesis of Some 1,5-Benzothiazepines
and Benzodiazepines and Their Antibacterial Activity
R. K. Saini,1 Y. C. Joshi,1 and P. Joshi2
1Department of Chemistry, University of Rajasthan, Jaipur, India
2S. S. Jain Subodh P. G. College, Jaipur, India
An efficient and convenient synthesis of 1, 5-benzothiazepines (3a-3f) and 1, 5-
benzodiazepines (4a-4f) from chalcones (2a-2f) by the action of o-amino thiophenol
and o-phenylenediamine in the presence of inorganic support is reported. These
compounds are characterized by elemental analysis and spectral studies viz: IR,
1
13
H NMR, and C NMR. Newly synthesized compounds were screened for their
antibacterial activity against β-subtilis, E-coli, and S. typhis.
Keywords Antibacterial activity; benzothiazepines and benzodiazepines; o-amino thio-
phenol; o-phenylenediamine
INTRODUCTION
Benzodiazepines and benzothiazepines are an important class of com-
pounds in the medicinal chemistry. They constitute the basic framework
of drugs such as diltiazem1,2 and thiazesim3 and are well recog-
nized for their multifaceted pharmacological and medicinal applica-
tions. Benzothiazepines have displayed a wide range of biological ac-
tivities viz. antifungal, antibacterial,4 antifeedant,5 analgesic,6 and
anticonvulsant.7
Benzodiazepines are used as tranquilizers, anti-inflammatories and
anticonvulsants, anticancer,8 antiasthamatic,9 antiepileptic drugs, and
in the treatment of Alzheimer’s disease.10
In addition, 1,5-benzothiazepines and benzodiazepines are used as
starting materials for the preparation of fused ring compounds such
as triazolo11 and oxadiazolo-benzodiazepines.12 Despite their impor-
tance from a biological and synthetic point-of-view, few methods of
Received 6 September 2007; accepted 22 November 2007.
The authors are thankful to Head, Department of Chemistry, University of Rajasthan,
Jaipur, for providing laboratory facilities. Rajendra Kumar Saini is thankful to the CSIR,
New Delhi, for the award of Senior Research Fellowship.
Address correspondence to R. K. Saini, Department of Chemistry, University of
Rajasthan, Jaipur, India. E-mail: sainirk97@yahoo.co.in
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R. K. Saini et al.
SCHEME 1
synthesis of 1, 5-benzodiazepines are reported in the literature. These
includes condensation reactions of o-phenylenediamine with α, β-
unsaturated carbonyl compounds,13 β-haloketones,14 Yb(Otf),15 MgO
and POCl3,16 silicagel,17 amberlyst-15,18 and acetic acid under mi-
crowave conditions.19 1,5-Benzodiazepines are also prepared by the re-
action of α, β-unsaturated ketones with o-nitroaniline induced by TiCl4-
Sm20 and o-nitro phenyl azide induced by SmI2.21 1,5-Benzothiazepines
have generally been synthesized by the reaction of o-amino thiophenol
with α, β-unsaturated ketones;22 1,5-benzothiazepines have also been
synthesized from o-amino thiophenol, ω-bromo acetophenone and aro-
matic aldehyde.23 They were also prepared by reacting α, β-unsaturated
ketones with bis (2-nitrophenyl) disulfide in the presence of TiCl4/Sm.24
1,5-benzothiazepines have also been synthesized by the use of inorganic
solid support under solvent free condition.25 We report herein the syn-
thesis of 1,5-benzodiazepines and benzothiazepines by the reaction of
chalcones with o-phenylenediamine or o-amino thiophenol in the pres-
ence of an inorganic solid support.
RESULT AND DISCUSSION
Chalcones (2a-f) react with o-amino thiophenol in the presence of sil-
ica gel at 80◦C for 3 h under solvent free conditions resulting in the
formation of 2,3-dihydro-2(1,3-benzodioxol-5-yl) 4-phenyl derivative-1,
5-benzothiazepines(3a-f) in good yield (Scheme 1, Tables I and II). These
compounds were screened for their antibacterial activity against β-
subtilis, E-coli, and S. typhis (Table III).
The thiazepine derivatives (3a-f) probably involves the intermediate
[5] (Scheme 3) which was formed by 1,2- and 1,4- type addition26 of o-
amino thiophenol with chalcones (2a-2f). The sulfur atom, being more
nucleophilic in nature than the nitrogen atom, attacks the β-carbon of
chalcones and give intermediate that undergoes dehydration in a non-
aqueous medium, easily. The newly synthesized thiazepines derivative

Benzothiazepines and Benzodiazepines
2183
were characterized on the basis of their elemental analysis (Table I)
and IR, 1H NMR, 13C NMR (Table II).
The reaction of chalcones with o-phenylenediamine was performed
in the presence of an inorganic support alumina at 80◦C for 4 h to af-
ford the corresponding 2,4- dihydro-1H,-1,5-benzodiazepines (Scheme
2). The heterocyclic products were characterized based on their elemen-
tal analysis (Table I) and IR, 1H NMR, 13C NMR (Table II).
The IR spectrum of 2a showed an absorption band at 1645 cm−1
corresponding to the carbonyl group which were absent in the titled
compounds 3a and 4a. 2-amino-thiophenol displayed peaks at 3430–
2550 cm1 corresponding to NH and SH, which were also found to be
absent in the IR spectrum of 3a and 4a thus further confirming the
ring closure.
The appearance of a sharp absorption band near 1620 cm−1 in 3a
and 4a confirmed the presence of C N group. The 1H NMR spectrum of
3a and 4a showed signals at δ 3.06 (t, 1H, J = 12.7 Hz) for HX, 3.30 (dd,
1H, J = 13.0 Hz, J = 4.6 Hz) for Ha, 4.98 (dd, 1H, J = 12.6 Hz, J = 4.6
Hz) for Hb, 6.0 (2H, s) for dioxymethylene group, and peaks for aromatic
protons appears in the range of δ 7.23–7.8 ppm. The 13C NMR spectrum
of 3a and 4a were recorded in DMSO-d6 as a solvent and showed signals
at δ 158.47 (C N), 59.33 (CH), 55.81 (CH2) 116–138 ppm (12 Aromatic
carbon) and δ 100.2 (OCH2O). To conclude, the present investigation
describes a two-step synthesis of the heterocycles 3 and 4.
Antibacterial Activity
The compound 3a-3f were screened for their antibacterial activity
against pathogenic organisms B. subtilis, E. coli, and S. typhi at concen-
tration of 1000 µg using norfloxacin as standard. Solution was made in
acetone and the method employed was cup plate method.27 The zones
of inhibition formed were measured in mm and are shown in Table III.
CONCLUSION
In summary, this work demonstrates an efficient and convenient
method for synthesis of 1,5-benzothiazepines and benzodiazepines and
results so obtained confirms the superiority of the solvent free condi-
tions over previously reported classical methods.
EXPERIMENTAL
General
Melting points of all the synthesized compounds are uncorrected.
The purity of compounds was checked by thin layer chromatography

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R. K. Saini et al.
TABLE III Antibacterial Activities of the
Compounds 3a-3f
Antibacterial activity (zone of inhibition in mm)
Compounds
B. subtilis
E. coli
S. typhis
3a
3b
3c
3d
3e
3f
12
12
14
15
17
13
26
15
14
13
14
11
12
28
17
13
10
17
13
14
26
Norfloxacin
< 11 mm = Inactive; 12–16 mm = weakly active; and 17–
21 = moderately active.
using silica gel ‘G’ as adsorbent. The infrared spectra were recorded on
Nicolet-Megna FT-IR 550 Spectrometer by using KBr pellets. 1H NMR
and 13C NMR spectra were recorded on a Model DRX-300 at 300.13 and
75.48 MHz spectrometer using TMS as internal standard.
(1) Preparation of 2, 3-Dihydro-2(1, 3-benzodipxol-5-yl)
4-Phenyl derivative-1, 5-Benzothiazepines (3a-f)—General
Procedure
A concentrated solution of chalcones (2a-f) (0.05 mol) in diethyl ether
(30 ml) were mixed with Silica gel (4 g), followed by addition of o-
aminothiophenol. The reaction mixture was stirred at 80◦C for 3 h un-
der a nitrogen atmosphere. Silica gel was separated by filtration after
eluting the product with ethyl acetate. Solvent was removed by evap-
oration under reduced pressure. The crude product was crystallized
from methanol. Analytical and spectroscopic data of the synthesized
compounds are given in Tables I and II.
SCHEME 2

Benzothiazepines and Benzodiazepines
2189
SCHEME 3
(2) Preparation of 2, 3-Dihydro-2(1, 3-benzodipxol-5-yl)
4-Phenyl Derivative-1,5-Benzodiazepines (4a-f) —General
Procedure
A concentrated solution of chalcones (2a-f) (0.05 mol) in diethyl ether
(40 ml) were mixed with Alumina (2 g), followed by addition of
o-phenylenediamine. The reaction mixture was stirred at 80◦C for 4 h
under nitrogen atmosphere. Alumina was separated by filtration after
eluting the product with ethyl acetate. Solvent was removed by evapo-
ration under reduced pressure. The crude product was crystallized from
methanol. Analytical data & Spectroscopic data of the synthesized com-
pounds are given in Tables I and II.
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