Synthesis and antimicrobial activity of 2,4-diaryl-2,3-dihydrobenzo[b][1,4] thiazepines

Article abstract of DOI:10.1007/s11164-012-0782-8

A new series of structurally diverse 2,3-dihydrobenzo[b][1,4]thiazepines (2,3-dihydro-1,5-benzothiazepines) with substituted phenyl groups at C(2) and C(4) have been synthesized by reaction of 3-(5-bromo-2-methoxyphenyl)-1- arylpropen-1-ones with 2-aminobenzenethiols. The structures of all the synthesized compounds were confirmed by their analytical and spectral data (IR, ¹H NMR, ¹³C NMR). All the synthesized compounds were evaluated for antibacterial and antifungal activity against a variety of bacterial and fungal strains and interesting results were obtained. Some of the compounds had antibacterial and antifungal activity comparable to that of ciprofloxacin and fluconazole.

Full text of DOI:10.1007/s11164-012-0782-8

Res Chem Intermed (2013) 39:2555–2564
DOI 10.1007/s11164-012-0782-8
Synthesis and antimicrobial activity of 2,4-diaryl-2,
3-dihydrobenzo[b][1,4]thiazepines
•
Mahendra Kumar Kailash Sharma
•
•
•
Ankur Kumar Fogla Kanika Sharma
Madhu Rathore
Received: 26 May 2012 / Accepted: 18 August 2012 / Published online: 11 September 2012
Ó Springer Science+Business Media B.V. 2012
Abstract A new series of structurally diverse 2,3-dihydrobenzo[b][1,4]thiazepines
(2,3-dihydro-1,5-benzothiazepines) with substituted phenyl groups at C(2) and C(4)
have been synthesized by reaction of 3-(5-bromo-2-methoxyphenyl)-1-arylpropen-
1-ones with 2-aminobenzenethiols. The structures of all the synthesized compounds
1
were confirmed by their analytical and spectral data (IR, H NMR, 13C NMR). All
the synthesized compounds were evaluated for antibacterial and antifungal activity
against a variety of bacterial and fungal strains and interesting results were obtained.
Some of the compounds had antibacterial and antifungal activity comparable to that
of ciprofloxacin and fluconazole.
Keywords 2-Aminobenzenethiols Á 1,3-Diaryl-2-propen-1-ones Á 2,4-Diaryl-2
3-Dihydrobenzo[b][1,4]thiazepines Á Chalcones Á Antimicrobial activity
Introduction
Chalcones, 1,3-diaryl-2-propen-1-ones, are promising bioactive molecules with wide
ranging biological activity, for example antibacterial [1], anticancer [2], antimicrobial [3],
anti-tuberculostatic [4], anti-inflammatory [5], anti-infective [6], antiproliferative [7], anti-
angiogenic [8], and anti-allergic [9]. Some natural products have been reported to have
anticancer activity because of the presence of the a,b-unsaturated carbonyl group in their
chemical structures [10–13]. Structure–activity relationship studies of chalcones [14] have
revealed that, in addition to the nature of the substituents on both the aromatic rings, the a,
b-unsaturated carbonyl structure is essential for the wide ranging activity of the chalcones.
M. Kumar (&) Á K. Sharma Á A. K. Fogla
Department of Chemistry, University of Rajasthan, Jaipur 302055, India
e-mail: mahendrakpathak@gmail.com
K. Sharma Á M. Rathore
Department of Botany, Mohanlal Sukhadia University, Udaipur 313001, India
123

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M. Kumar et al.
Chalcones are well known intermediates in the synthesis of a variety of heterocyclic
compounds. The heterocyclic compounds derived from chalcones can have high
structural diversity and can be useful as therapeutic agents with a wide range of activity.
The wide ranging activity of chalcones, as a result of the presence of the a,b-enone
system and the structural diversity of heterocyclic systems, led to the concept of
converting the a,b-unsaturated carbonyl functionality of chalcones into heterocyclic
systems. This drug-design concept has been used to synthesize five-membered
heterocycles of biological interest by converting the a,b-enone functionality to
pyrazoles, isoxazoles, andoxazoles, withtheobjectiveofobtainingpotentialanti-cancer
agents, and these derivatives have, indeed, been reported to have significant activity
against cancer [15]. The concept has also been successfully applied to combretastatin
CA-4, on the basis of which tetrazole analogues were designed and discovered to have
anticanceractivity[16, 17]. AsanaloguesofcombretastatinCA-4,themodeofcytotoxic
action of chalcones has been reported to be similar to that of combretastatins. They bind
to the colchicine site of tubulin and inhibit tubulin polymerization [18, 19].
Structure–activity relationship studies have shown that the chalcones with
methoxy, ethoxy, hydroxy, and halogen substituents have significant activity against
cancer [20]. In an effort to develop potential drugs, chalcones substituted with
methoxy, ethoxy, and halogen substituents have been synthesized by Claisen–
Schmidt condensation [21] of acetophenones and benzaldehydes. The a,b-enone
functionality of synthesized chalcones has been converted into a biodynamic
heterosystem, benzothiazepine, by heterocyclization with 2-aminobenzenethiols via
(4 ? 3) annulation involving Michael addition and subsequent cyclization. Insertion
of heteroatoms would result in a new structural system with different pharmaco-
dynamic and pharmacokinetic features. The availability of lone pair electrons on
heteroatoms might enhance water solubility and new additional interactions with
biological targets.
Benzothiazepines are an important class of biodynamic heterocycles which have
attracted substantial synthetic and therapeutic interest because of their diverse range
of biological activity, for example anticancer [22], antihypertensive [23], analgesic
[24], anti-arrhythmic [25], antidepressant [26], antifungal [27], and antibacterial
[28]. Some members of this class are also potent bradykinin agonists, growth
hormone secretagogues, ligands for Src Hz protein spasmolytics, and squalene
synthetase inhibitors [29]. Encouraged by the promising biological activity of the
structurally diverse heterocycles with fused heterocyclic systems and our continuing
research programme on the synthesis of therapeutically interesting heterocycles
[30–34], we have designed and synthesized structurally diverse 2,3-dihydro-
benzo[b][1,4]thiazepines (2,3-dihydro-1,5-benzothiazepines).
Results and discussion
Chemistry
2-Aminobenzenethiol intermediates were prepared by hydrolytic cleavage of
2-aminobenzothiazoles, which were prepared by cyclization, with Br2, of the
123

Synthesis and antimicrobial activity
2557
corresponding thioureas, obtained by thiocyanogenation of substituted anilines
(Scheme 1) [35, 36].
The chalcone intermediates were prepared by the Claisen–Schmidt condensation
of 5-bromo-2-methoxybenzaldehyde and substituted acetophenones under basic
conditions (Scheme 2) [37].
2-(5-Bromo-2-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]thiazepines (2,3-dihydro-1,
5-bezothiazepines) with different aryl substituents at C(4) were synthesized in
quantitative yields in a single step by reaction of 2-aminobenzothiols with chalcone
intermediates in ethanol in the presence of catalytic amounts of acetic acid (Scheme 3).
The structures of the final products were confirmed by elemental analysis and
from their spectral characteristics. The IR spectra contained characteristic absorp-
tion bands arising from C=N, C–O–C, and C=C stretching vibrations along with
other absorption bands. The absorption band in the region of 1,635–1,605 cm-1 is
ascribed to C=N stretching vibrations and the absorption bands in the region
1,270–1,210 cm-1 and 1,080–1,030 cm-1 are assigned to C–O–C asymmetric and
symmetric vibrations. The absence of characteristic absorption bands of NH2, SH,
and C=O groups in IR spectra of the products indicate that heterocyclization of
2-aminobenzenethiols with chalcone intermediates took place involving a Michael-
type addition of the thiol group to the b-carbon of chalcone intermediates followed
1
by dehydrative cyclization. In the H NMR spectra, three double doublets at d
3.90–3.65 (HB, dd, JAB = 15.3–16.2 Hz and JBX = 5.4 Hz, H2C(3)), d 3.35–3.20
(HA, dd, JAB = 15.3–16.2 Hz and JAX = 11.4 Hz, H2C(3))and d 5.25–5.10 (HX,
dd, JAX = 11.4 Hz and JBX = 5.8 Hz. H–C(2)) in the ABX pattern were
characterized as arising from the two H-atoms at C(3) and the methine H-atom at
C(2) in all the synthesized compounds.
Biological activity
Antibacterial activity
The synthesized compounds (2,4-diaryl-2,3-dihydrobenzo[b][1,4]thiazepines)
were evaluated for their in-vitro antibacterial activity against two representative
Gram-positive bacteria, viz. Bacillus subtilis and Klebsiella pneumonia, and two
R
R
R
S
Br2
NH4SCN
NH3Cl
C
NH2.HBr
CHCl3
N
NH
C
S
NH2
liq. NH3
R
SH
R
S
1. KOH
2. 5N AcOH
C
NH2
N
NH2
R= H, Cl, Br
Scheme 1 Synthesis of 2-aminobenzenethiols
123

2558
M. Kumar et al.
O
O
O
R
R
2
Br
Br
R2
R1
H C
3
H
NaOH
EtOH
OCH3
1
OCH
3
(a) R = R = H (b) R = OCH , R = H (c) R = F, R = H(d) R = OC H , R = H (e) R = R =OCH
1
2
1
3
2
1
2
1
2
5
2
1
2
3
Scheme 2 Synthesis of chalcones
H CO
3
H
O
X
Br
S
N
R
R
SH Br
R
R
2
H
H
A
EtOH
B
AcOH, reflux
NH
OCH
R
R
2
3
1
2
1
(I) R = R = R = H
(II) R = H, R = OCH , R = H (III) R = H, R = F, R = H
1 3 2 1 2
1
2
(IV) R = Cl, R = R = H
(V) R = Cl, R = OCH , R = H (VI) R = Cl, R = F, R = H
1 3 2 1 2
1
2
(VII) R = Cl, R = OC H , R = H (VIII) R = Cl, R = R =OCH
3
1
2
5
2
1
2
(IX) R = Br, R = OCH , R = H
(X) R = Br, R = R =OCH
1 2 3
1
3
2
Scheme 3 Synthesis of 2,4-diaryl-2,3-dihydrobenzo[b][1,4]thiazepines
Gram-negative bacteria, viz. Pseudomonas aeruginosa and Escherichia coli, by the
Agar well diffusion method [38] in nutrient agar medium at concentrations of
100 lg/mL, using DMF as solvent. These solutions were added to each filter disc
and the plates were incubated at 37 °C. After incubation at 37 °C for 24 h the zones
of inhibition were measured in millimeters. The standard drug ciproflaxacin
(100 lg/mL) was also screened for antibacterial activity under similar conditions,
for comparison. The results from determination of ciprofloxacin activity are
presented in Table 1.
Antifungal activity
The antifungal activity of thiazepine derivatives was evaluated against Candida
albicans and Aspergillus fumigatus by the agar well diffusion method using
Sabouraud dextrose agar medium. The compounds were dissolved in DMF at a
concentration of 100 lg/mL, diluted with distilled water, and then mixed with the
medium. After incubation for 72 h at 37 °C, the zones of inhibition were measured
in millimeters. The standard antifungal drug fluconazole (100 lg/mL) was also
screened for antifungal activity under similar conditions, for comparison. Controls
123

Synthesis and antimicrobial activity
2559
Table 1 Antimicrobial activity of compounds I to X
No.
Antibacterial activity (zones of inhibition in Antifungal activity (zones of inhibition in
millimeters)
millimeters)
Gram ?ve
Gram -ve
A
B
C
D
E
F
(I)
22
25
18
24
24
21
26
29
27
30
17
22
15
17
18
17
21
25
20
25
28
–
11
16
10
11
12
14
17
21
16
22
24
–
30
26
17
24
27
10
28
30
28
29
32
–
06
07
–
09
10
04
07
08
03
10
12
07
13
–
(II)
(III)
(IV)
(V)
03
06
–
(VI)
(VII)
(VIII)
(IX)
(X)
07
08
06
09
–
Ciprofloxacin 31
Fluconazole
–
12
16
A, Bacillus subtilis; B, Klebsiella pneumoniae; C, Pseudomonas aeruginosa; D, Escherichia coli;
E, Candida albicans; F, Aspergillus fumigates
included use of the solvent DMF without test compounds; no antimicrobial activity
was noticed for the solvent. The results from determination of antimicrobial activity
are presented in Table 1.
Conclusion
In this study we synthesized 2,4-diaryl substituted 2,3-dihydrobenzo[b][1,4]thiaze-
pines (2,3-dihydro-1,5-benzothiazepines) in quantitative yields by a simple and
convenient synthetic method involving reaction of substituted 2-aminobenzenethiol
with substituted chalcone intermediates (a,b-enones). The synthesized compounds
were evaluated for antimicrobial (antibacterial and antifungal) activity. The
antibacterial activity of most of the compounds against standard and pathological
strains was found to be similar (statistically with insignificant difference). All
compounds I to X were found to be effective against B. subtilis, K. pneumoniae,
P. aeruginosa, and E. coli. Compounds I, II, IV, V, and VII–X had the highest
activity against E. coli and B. subtilis. Compounds VIII and X had excellent activity
against all four species, comparable with that of the standard drug ciprofloxacin.
The results are summarized in Table 1. Compounds I to VII and IX had mild to
moderate antifungal activity but compounds VIII and X had significant activity
against fungi.
The antimicrobial activity of these compounds have been attributed to the presence
of the N and S-containing seven-membered thiazepine ring. In addition, structural
features, for example substituents on the phenyl rings, which result in structural
diversity in the molecules, are also responsible for the activity of the compounds.
123

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M. Kumar et al.
Experimental
Melting points were determined on an electric melting-point apparatus and are
uncorrected. Reactions were monitored by thin-layer chromatography using silica
gel G as adsorbent and EtOH–benzene–acetone (1:8:1) as mobile phase. IR spectra
1
(KBr pellets) were recorded on a Shimadzu 8400S FT-IR spectrophotometer. H
NMR spectra were recorded in CDCl3 at 300 MHz (Jeol AL 300 FT NMR) with
TMS as internal standard. The chemical shifts are expressed in d (ppm).
Preparation of substituted 2-aminobenzenethiols
Substituted 2-aminobenzenthiols were prepared from substituted anilines in three
steps:
1. Preparation of substituted phenylthioureas
A mixture of substituted aniline (0.1 mol), conc. HCl (9 mL), and water (25 mL)
in a round-bottomed flask was heated under reflux for 0.5 h. The solution of aniline
hydrochloride thus obtained was left to cool to room temperature and then
ammonium thiocyanate (0.1 mol) was added. The mixture was then heated under
reflux for 4 h until two layers were formed. The solution was poured into crushed
ice, filtered, and the residue was dried and crystallized from EtOH.
2. Preparation of substituted 2-aminobenzothiazoles
Substituted phenylthiourea (0.1 mol) and chloroform (100 mL) were place in a
two-necked round-bottomed flask (500 mL) equipped with a mechanical stirrer. A
solution of Br2 (0.1 mol) in chloroform (100 mL) was added dropwise with stirring
to the mixture while maintaining the temperature below 5 °C. After complete
addition of the Br2, stirring was continued for 4 h. The contents of the flask were
then heated under reflux on a water bath until evolution of HBr ceased. Chloroform
was removed by filtration. The resulting solid material was treated with an aqueous
sulphur dioxide solution and filtered. The filtrate was neutralized with aqueous
ammonia solution and the precipitate obtained was filtered, washed with water, and
crystallized from EtOH.
3. Preparation of substituted 2-aminobenzenethiols
Substituted 2-aminobenzothiazole, KOH (5 times by weight of thiazole), and
water (10 times by weight of thiazole) were placed in a round-bottomed flask and
heated under reflux until evolution of ammonia ceased. The contents were filtered
and diluted with ice-cold water. Addition of 5 M acetic acid with vigorous stirring
neutralized the filtrate. The temperature of the solution was not allowed to rise
above room temperature (controlled by adding ice), otherwise a decomposed
greenish mass is obtained. The semisolid yellowish precipitate was extracted 2–3
times with ether. The ether was evaporated and the product was crystallized from
ethanol.
123

Synthesis and antimicrobial activity
2561
2-amino-5-chlorobenzenethiol Yield: 28 %; mp (°C); 110–112. IR (KBr, t max in
1
cm-1); 3,385–3,295 (N–H), 2,520 (S–H), 1,080 (C–Cl), H NMR (CDCl3, d ppm);
6.75–7.15 (3H, m), 4.35 (2H, d), 1.75 (1H, s), Anal. calcd. for C6H6NSCl: C, 45.14;
H, 3.78; found: C, 45.17; H, 3.81.
2-amino-5-bromobenzenethiol Yield: 32 %; mp (°C); 113–115. IR (KBr, t max in
cm-1); 3,400–3,290 (N–H), 2,480 (S–H), 1H NMR (CDCl3, d ppm); 6.80–7.29 (3H,
m), 4.42 (2H, d), 2.15 (1H, s), Anal. calcd. for C6H6NSBr: C, 35.46; H, 2.97; found:
C, 35.51; H, 3.01.
Synthesis of substituted 3-(5-bromo-2-methoxyphenyl)-1-arylpropen-1-ones
Substituted acetophenone (0.05 mol), EtOH (15 mL), and 2 M NaOH solution
(12 mL) were stirred at room temperature for 5 min. 5-Bromo-2-methoxybenzal-
dehyde (0.05 mol) was then added and the resulting solution was stirred at r.t. for
15 min. The product obtained was filtered, washed with water, and recrystallised
from aqueous EtOH to obtain the desired compound.
3-(5-bromo-2-methoxyphenyl)-1-phenylpropen-1-one Yield: 64 %; mp (°C); 142–144.
1
IR (KBr, cm-1); 1,650 (C=O), 1,585 (C=C), H NMR (CDCl3, d ppm); 7.82 (1H,
d, b-H), 7.06 (1H, d, a-H), Anal. calcd. for C16H13O2Br: C, 60.58; H, 4.13; found:
C, 60.61; H, 4.17.
3-(5-bromo-2-methoxyphenyl)-1-(4-methoxyphenyl)propen-1-one Yield: 68 %; mp (°C);
1
192–194. IR (KBr, cm-1); 1,655 (C=O), 1,575 (C=C), 1,090, 1,200 (C–O–C); H
NMR (CDCl3, d ppm); 7.86 (1H, d, b-H), 6.99 (1H, d, a-H), Anal. calcd. for
C17H15O3Br: C, 58.80; H, 4.35; found: C, 58.85; H, 4.39.
3-(5-bromo-2-methoxyphenyl)-1-(4-fluorophenyl)propen-1-one Yield: 58 %; mp
1
(°C); 175–177. IR (KBr, cm-1); 1,665 (C=O), 1,580 (C=C); H NMR (CDCl3, d
ppm); 7.77 (1H, d, b-H), 7.01 (1H, d, a-H), Anal. calcd. for C16H12O2BrF: C, 57.33;
H, 3.60; found: C, 57.36; H, 3.66.
3-(5-bromo-2-methoxyphenyl)-1-(4-ethoxyphenyl)propen-1-one Yield: 60 %; mp
(°C); 225–227. IR (KBr, cm-1); 1,660 (C=O), 1,565 (C=C), 1,100, 1,220 (C–O-C);
1H NMR (CDCl3, d ppm); 7.91 (1H, d, b-H), 6.97 (1H, d, a-H), Anal. calcd. for
C18H17O3Br: C, 59.85; H, 4.74; found: C, 59.90; H, 4.77.
3-(5-bromo-2-methoxyphenyl)-1-(3,4-dimethoxyphenyl)propen-1-one Yield: 65 %; mp
(°C); 219–221. IR (KBr, cm-1); 1,662 (C=O), 1,573 (C=C), 1,110, 1,235 (C–O–C);
1H NMR (CDCl3, d ppm); 7.76 (1H, d, b-H), 6.99 (1H, d, a-H), Anal. calcd. for
C18H17O4Br: C, 57.31; H, 4.54; found: C, 57.35; H, 4.60.
Synthesis of 2,4-diaryl-2,3-dihydrobenzo[b][1,4]thiazepines (2,4-diaryl-2,
3-dihydro-1,5-benzothiazepines)
Substituted 2-aminobenzenethiol (0.001 mol) and chalcone (0.001 mol) were
dissolved in 10 mL dry EtOH. The mixture was heated under reflux for
20–30 min then glacial acetic acid (1–2 mL) was added. Heating under reflux
123

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M. Kumar et al.
was continued for nearly 3 h. The mixture was cooled and the solvent was removed
under reduced pressure. The solid product thus separated was treated with petroleum
ether and crystallized from dry EtOH.
2-(5-bromo-2-methoxyphenyl)-4-phenyl-2,3-dihydrobenzo[b][1,4]thiazepine (I) Yel-
low. Yield: 68 %; mp (°C); 190. IR (KBr, cm-1); 1,620 (C=N), 1,450 (C=C),
1
1,050,1,210 (C–O–C); H NMR (CDCl3, d ppm); 3.79 (s, 3H, C2-OCH3), 3.20–3.30
(dd, 1H, C3-HA), 3.65–3.70 (dd, 1H, C3-HB), 5.10–5.22 (dd, 1H, C2-HX), 7.35–8.15 (m,
8H, aromatic protons); Anal. calcd. for C22H18BrNOS: C, 62.29; H, 4.27; found: C,
62.34; H, 4.30.
2-(5-bromo-2-methoxyphenyl)-4-(4-methoxyphenyl)-2,3-dihydrobenzo[b] [1,4]thia-
zepine (II) Dark brown. Yield: 65 %; mp (°C); 184. IR (KBr, cm-1); 1,608 (C=N),
1
1,465 (C=C), 1,050,1,230 (C–O–C); H NMR (CDCl3, d ppm); 3.82–3.90 (s, 6H, C2
and C4–OCH3), 3.22–3.35 (dd, 1H, C3–HA), 3.68–3.75 (dd, 1H, C3–HB), 5.10–5.25 (dd,
1H, C2–HX), 6.75–8.20 (m, 11H, aromatic protons); Anal. calcd. for C23H20BrNO2S: C,
60.80; H, 4.44; found: C, 60.83; H, 4.46.
2-(5-bromo-2-methoxyphenyl)-4-(4-fluorophenyl)-2,3-dihydrobenzo[b] [1,4]thia-
zepine (III) Dark yellow. Yield: 70 %; mp (°C); 180. IR (KBr, cm-1); 1,615 (C=N),
1,440 (C=C), 1,080,1,210 (C–O–C); 1H NMR (CDCl3, d ppm); 3.54 (s, 3H,
C2–OCH3), 3.21–3.33 (dd, 1H, C3–HA), 3.74–3.90 (dd, 1H, C3–HB), 5.12–5.15 (dd,
1H, C2–HX), 6.67–8.06 (m, 11H, aromatic protons); Anal. calcd. for C22H17BrF-
NOS: C, 59.76; H, 3.87; found: C, 59.81; H, 3.90.
2-(5-bromo-2-methoxyphenyl)-8-chloro-4-phenyl-2,3-dihydrobenzo[b] [1,4]thia-
zepine (IV) Pale yellow. Yield: 69 %; mp (°C);148.IR (KBr, cm-1); 1,635 (C=N),
1,420 (C=C), 1,050,1,250 (C–O–C); 1H NMR (CDCl3, d ppm); 3.85 (s, 3H,
C2–OCH3), 3.20–3.32 (dd, 1H, C3–HA), 3.66–3.75 (dd, 1H, C3–HB), 5.10–5.25 (dd,
1H, C2–HX), 7.55–8.12 (m, 7H, aromatic protons); 13C NMR (CDCl3, d ppm); 38.3,
56.2, 59.7, 115.4–151.6 (aromatic carbons), 156.2, 165.6 Anal. calcd. for
C22H17BrClNOS: C, 57.57; H, 3.73; found: C, 57.60; H, 3.77.
2-(5-bromo-2-methoxyphenyl)-8-chloro-4-(4-methoxyphenyl)-2,3-dihydrobenzo[b]
[1,4]thiazepine (V) Dark yellow. Yield: 58 %; mp (°C); 170. IR (KBr, cm-1); 1,625
(C=N), 1,450 (C=C), 1,035,1,246 (C–O–C); 1H NMR (CDCl3, d ppm); 3.81–3.93 (s,
6H, C2 and C4–OCH3), 3.25–3.35 (dd, 1H, C3–HA), 3.68–3.75 (dd, 1H, C3–HB),
5.14–5.21 (dd, 1H, C2–HX), 7.42–8.10 (m, 7H, aromatic protons); Anal. Calcd. for
C23H19BrClNO2S: C, 56.51; H, 3.91; found: C, 56.54; H, 3.96.
2-(5-bromo-2-methoxyphenyl)-8-chloro-4-(4-fluorophenyl)-2,3-dihydrobenzo[b]
[1,4]thiazepine (VI) Dark yellow. Yield: 72 %; mp (°C); 218. IR (KBr, cm-1);
1
1,618 (C=N), 1,400 (C=C), 1,080,1,215 (C–O–C); H NMR (CDCl3, d ppm); 3.79
(s, 3H, C2–OCH3), 3.22–3.35 (dd, 1H, C3–HA), 3.67–3.74 (dd, 1H, C3–HB),
5.12–5.25 (dd, 1H, C2–HX), 7.63–8.16 (m, 7H, aromatic protons); Anal. calcd. for
C22H16BrClFNOS: C, 55.40; H, 3.38; found: C, 55.43; H, 3.42.
2-(5-bromo-2-methoxyphenyl)-8-chloro-4-(4-ethoxyphenyl)-2,3-dihydrobenzo[b]
[1,4]thiazepine (VII) Pale yellow. Yield: 59 %; mp (°C); 210. IR (KBr, cm-1);
1
1,620 (C=N), 1,430 (C=C), 1,075,1,210 (C–O–C); H NMR (CDCl3, d ppm); 3.82
(s, 3H, C2–OCH3), 3.22–3.34 (dd, 1H, C3–HA), 3.65–3.71 (dd, 1H, C3–HB),
5.15–5.22 (dd, 1H, C2–HX), 7.50–8.19 (m, 7H, aromatic protons); Anal. calcd. for
C24H21BrClNO2S: C, 57.32; H, 4.20; found: C, 57.36; H, 4.23.
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Synthesis and antimicrobial activity
2563
2-(5-bromo-2-methoxyphenyl)-8-chloro-4-(3,4-dimethoxyphenyl)-2,3-dihydro-
benzo[b][1,4]thiazepine (VIII) Dark yellow. Yield: 60 %; mp (°C); 212. IR (KBr,
cm-1); 1,630 (C=N), 1,390 (C=C), 1,080,1,270 (C–O–C); 1H NMR (CDCl3, d ppm);
3.80–3.90 (s, 9H, C2 and C4–OCH3), 3.20–3.33 (dd, 1H, C3–HA), 3.66–3.75 (dd, 1H,
C3–HB), 5.11–5.23 (dd, 1H, C2–HX), 7.51–8.15 (m, 6H, aromatic protons); Anal.
calcd. for C24H21BrClNO3S: C, 55.55; H, 4.07; found: C, 55.59; H, 4.10.
2-(5-bromo-2-methoxyphenyl)-8-bromo-4-(4-methoxyphenyl)-2,3-dihydrobenzo[b]
[1,4]thiazepine (IX) Dark brown. Yield: 64 %; mp (°C); 262. IR (KBr, cm-1); 1,610
1
(C=N), 1,360 (C=C), 1,030,1,230 (C–O–C); H NMR (CDCl3, d ppm); 3.75–3.95 (s,
6H, C2 and C4–OCH3), 3.25–3.35 (dd, 1H, C3–HA), 3.69–3.75 (dd, 1H, C3–HB),
5.12–5.20 (dd, 1H, C2–HX), 7.51–8.15 (m, 6H, aromatic protons); Anal. calcd. for
C23H19Br2NO2S: C, 51.80; H, 3.59; found: C, 51.85; H, 3.62.
2-(5-bromo-2-methoxyphenyl)-8-bromo-4-(3,4-dimethoxyphenyl)-2,3-dihydro-
benzo[b][1,4]thiazepine (X) Brown. Yield: 75 %; mp (°C); 206. IR (KBr, cm-1);
1,620 (C=N), 1,420 (C=C), 1,070,1,215 (C–O–C); 1H NMR (CDCl3, d ppm);
3.78–3.90 (s, 9H, C2 and C4–OCH3), 3.24–3.35 (dd, 1H, C3–HA), 3.66–3.72 (dd,
1H, C3–HB), 5.12–5.25 (dd, 1H, C2–HX), 7.51–8.15 (m, 6H, aromatic protons);
Anal. calcd. for C24H21Br2NO3S: C, 51.18; H, 3.75; found: C, 51.22; H, 3.79.
Acknowledgments The authors are thankful to the Head, Department of Chemistry, University of
Rajasthan, Jaipur, for providing laboratory and instrumentation facilities. RSIC, CDRI, Lucknow, is also
acknowledged for providing analytical and spectral data of the compounds. One of the authors (Kailash
Sharma) thanks University of Rajasthan Jaipur (India) for the meritorious research fellowship.
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