A convenient synthesis of novel 2,3,4-trisubstituted 1,5-benzothiazepines bearing a sulfonyl pharmacophore

Article abstract of DOI:10.1080/17415993.2011.594442

2-(Substituted phenyl)-3-[(methyl phenyl) sulfonyl] [(methyl sulfonyl) phenyl]-2,3-dihydro-1,5-benzothiazepines (5a-f) have been obtained in moderate yields by condensing 2-aminothiophenol with the chalcones 1-[(4′-methyl sulfonyl)phenyl]-2-[(4-methyl phenyl)sulfonyl]-prop-2-en-1-ones (4a-f) in toluene using trifluoroacetic acid as the catalyst. The benzothiazepines have also been synthesized by carrying out neat cyclocondensations of the chalcones supported on silica and 2-aminothiophenol at 80C. The precursors, chalcones (4a-f), were freshly prepared from -(4′-methyl sulfonyl phenyl)-4-methyl sulfonyl acetophenone (3).

Full text of DOI:10.1080/17415993.2011.594442

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A convenient synthesis of novel 2,3,4-
trisubstituted 1,5-benzothiazepines
bearing a sulfonyl pharmacophore
Sanjay N. Karale a , Umesh R. Pratap a , Shital R. Mahalle a &
Ramrao A. Mane a
a Department of Chemistry, Dr Babasaheb Ambedkar Marathwada
University, Aurangabad, 431 004, Maharashtra, India
Published online: 07 Jul 2011.
To cite this article: Sanjay N. Karale , Umesh R. Pratap , Shital R. Mahalle & Ramrao A. Mane
(2011) A convenient synthesis of novel 2,3,4-trisubstituted 1,5-benzothiazepines bearing a sulfonyl
pharmacophore, Journal of Sulfur Chemistry, 32:4, 303-309, DOI: 10.1080/17415993.2011.594442
To link to this article: http://dx.doi.org/10.1080/17415993.2011.594442
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Journal of Sulfur Chemistry
Vol. 32, No. 4, August 2011, 303–309
A convenient synthesis of novel 2,3,4-trisubstituted
1,5-benzothiazepines bearing a sulfonyl pharmacophore
Sanjay N. Karale, Umesh R. Pratap, Shital R. Mahalle and Ramrao A. Mane*
Department of Chemistry, Dr Babasaheb Ambedkar Marathwada University, Aurangabad 431 004,
Maharashtra, India
(Received 12 May 2010; final version received 2 June 2011)
2-(Substituted phenyl)-3-[(methyl phenyl) sulfonyl] [(methyl sulfonyl) phenyl]-2,3-dihydro-1,5-
benzothiazepines (5a–f) have been obtained in moderate yields by condensing 2-aminothiophenol with
the chalcones 1-[(4ꢀ-methyl sulfonyl)phenyl]-2-[(4-methyl phenyl)sulfonyl]-prop-2-en-1-ones (4a–f) in
toluene using trifluoroacetic acid as the catalyst. The benzothiazepines have also been synthesized by car-
rying out neat cyclocondensations of the chalcones supported on silica and 2-aminothiophenol at 80 ◦C.
The precursors, chalcones (4a–f), were freshly prepared from α-(4ꢀ-methyl sulfonyl phenyl)-4-methyl
sulfonyl acetophenone (3).
R
R'
R''
O
Br
S
N
O
S
O
S
O
O
1
O
S
O
5a-f
Keywords: 2-aminothiophenol; cyclocondensation; 1, 5-benzothiazepine; sulfonyl; convenient
1. Introduction
1,5-Benzothiazepines are a very important class of organic compounds because of their wide
pharmacological properties (1). These heterocycles are found to act as cardiovascular modu-
lators, vasodilators (2, 3), antiarrythmic (4), protease inhibitors (5), elastase (6), angiotensin
converting enzyme (ACE)-inhibitors (7) and antagonistic of G-protein coupled receptors such
as cholecystokinin receptors (8) and as interleukin-1b converting enzyme inhibitors and the
angiotensin II receptor (ACE) inhibitors (9). Some of the 1,5-benzothiazepine derivatives are
*Corresponding author. Email: manera@indiatimes.com
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2011 Taylor & Francis
DOI: 10.1080/17415993.2011.594442
http://www.informaworld.com

304 S.N. Karale et al.
also used clinically for central nervous system disorders which includes thiazesim (10) and que-
tiapine fumarate (11). Considering the significance of these seven-membered fused heterocycles,
various 2,4-disubstituted 2,3-dihydro-1,5-benzothiazepines have been reported in the literature.
Incorporation of sulfonyl pharmacophores in the molecular frameworks have resulted in COX-2
inhibition activity (12). Celecoxib and rofecoxib are the well-established anti-inflammatory drugs
having sulfonyl pharamacophore (13, 14).
A literature survey reveals that there are various routes to obtain 1,5 benzothiazepines using
2-aminothiophenols as one of the precursors. It has been found that most of the common synthetic
routes involve the cyclocondensation of 2-aminothiophenols with α, β-unsaturated ketones (9).
Several attempts have been made to optimize the reaction conditions of the cyclocondensation
to obtain high yields and to reduce condensation time. Cyclocondensations have been carried
out in inert solvents such as ethanol using bi-catalysts, organic bases and acids (15), and it was
noticed that the reaction time required for the completion of the condensation was longer and the
product isolation was also tedious.
Therefore, more attention has been directed to the development of convenient and rapid routes
for the synthesis of 2,4-disubstituted 1,5-benzothiazepines, for obtaining new leads.
Considering the dire need of providing rapid and excellent synthetic routes for benzothiazepines
and as well as generating new benzothiazepines, we here in report the continuation of our earlier
interest (16), the synthesis of new 2,3,4-trisubstituted 1,5-benzothiazepines.
2. Results and discussion
Withtheaimtoobtain2,3,4-trisubstituted1,5-benzothiazepinesbearingsulfonylpharmacophores,
the following attempts have been made and the developed reaction path is presented in Scheme 1.
O
O
O
S
O
CH
3
Br
DCM/water
TBAB
O
O
O
S
S
S
O
O
O
Na
1
2
3
O
S
CHO
R'
O
Ethylene dichloride
Piperidine
O
3
O
S
R
R''
O
R
R'
R''
4a-f
R
R'
R''
S
SH
NH
O
Method A or B
S
4a-f
O
N
2
O
S
O
5a-f
Method A=TFA/Toluene, Method B= SiO2, 80°C.
Scheme 1. Synthesis of 2,3,4-trisubstituted 1,5-benzothiazepines.

Journal of Sulfur Chemistry 305
α-(4ꢀ-Methyl sulfonyl phenyl)-4-methyl sulfonyl acetophenone (3) was subjected to Claisen–
Schmidt condensation with aryl aldehydes in the presence of piperidine in ethylene dichloride
(EDC) to give the intermediates 1-[(4ꢀ-methyl sulfonyl)phenyl]-2-[(4-methyl phenyl)sulfonyl]-
prop-2-en-1-ones (Table 1, 4a–f).This condensation was carried out using KOH/NaOH or organic
bases by following the normal Claisen–Schmidt condensation protocol. It was noticed that the
condensation was not complete at room temperature and even at elevated temperature. It was
then carried out in EDC in the presence of piperidine under reflux using a Dean and Stark sys-
tem for removal of water, these conditions gave excellent yields of 1,3-propen-1-ones (4a–f)
within 3 h.
The starting α-(4ꢀ-methyl sulfonyl phenyl)-4-methyl sulfonyl acetophenone (3) was obtained by
the condensation of α-bromo-4-methyl sulfonyl acetophenones (1) and 4-methyl sodium benzene
sulfinate (2).
Whenthechalcones(4a–f)wereallowedtointeractwith2-aminothiophenolinrefluxingalcohol
using piperidine and acetic acid as a bi-catalyst system, the expected products were not generated
even with longer heating. Several variations have also been made to optimize the cyclocondensa-
tion of 2-aminothiophenol and the chalcones by varying medium and bases. It was noticed that
cyclocondensation when run in refluxing toluene using catalytical amounts of trifluoroacetic acid
as catalyst gave better yields of the desired 2-(substituted phenyl)-3-[(methyl phenyl) sulfonyl]
[(methyl sulfonyl) phenyl]-2,3-dihydro-1,5-benzothiazepines (5a–f). It was also observed that
the neat cyclocondensations of the chalcones supported on silica gel with 2-aminothiophenol
occur rapidly at 80 ◦C and gave better yields of the desired trisubstituted 1,5-benzothiazepines
(Table 2, 5a–f).
Here, there is a possibility of getting more than two diastereomers. It was confirmed by high-
performance liquid chromatography (HPLC) and TLC that the cyclocondensed product has a
single isomeric form. The configurations of the chiral centers were not confirmed.
1
All the products and intermediates are well characterized by IR, mass and H NMR spectral
techniques. The purity of the products was also determined by HPLC.
Table 1. Characterization data of 1-[(4ꢀ-methyl sulfonyl)phenyl]-2-[(4-methyl phenyl)sulfonyl]-prop-2-en-1-ones
(4a–f).
Product
R
Rꢀ
Rꢀꢀ
Yields (%)
HPLC purity (%)
Melting point (◦C)
4a
4b
4c
4d
4e
4f
H
OCH3
H
H
H
F
H
OCH3
OCH3
H
H
H
55
52
53
50
60
54
98
92
93
88
96
91
208–210
195–196
185–187
177–179
204–205
Liquid
OCH3
OCH3
OH
OCH3
Cl
H
Table 2. Characterization data of 2-(substituted phenyl)-3-[(methyl phenyl) sulfonyl] [(methyl sulfonyl) phenyl]-2,
3-dihydro-1,5-benzothiazepines (5a–f).
Yields (%)
HPLC
Melting
point (◦C)
Product
R
Rꢀ
Rꢀꢀ
Method A
Method B
purity (%)
5a
5b
5c
5d
5e
5f
H
OCH3
H
H
H
F
H
OCH3
OCH3
H
H
H
60
54
56
59
61
51
76
64
69
72
78
59
88
86
87
83
88
84
263–265
213–214
235–237
205–207
242–243
218–219
OCH3
OCH3
OH
OCH3
Cl
H

306 S.N. Karale et al.
3. Experimental
3.1. General
Melting points were determined by the open capillary method and are uncorrected. IR spectra
were scanned on a Paragon 1000 FT-IR spectrophotometer, and 1H and 13C NMR spectra were
recorded on a Brucker 400 MHz. Mass spectra were obtained using API 3000 LCMSMS using
NH4 as an adduct. Elemental analyses were performed on Perkin Elmer elemental auto analyzer
and Thermo Finnigan CHNS auto analyzer. The purity of products and the progress of the reaction
were monitored by Water’s HPLC systems.
3.1.1. Synthesis of α-(4ꢀ-methyl sulfonyl phenyl)-4-methyl sulfonyl acetophenone (3)
To the stirred solution of α-bromo-4-methyl sulfonyl acetophenone (1) (0.18 mol) in
dichloromethane (DCM) (250 ml) was added sodium-p-tolyl sulphinate (2) (0.198 mol) and water
(150 ml). To this biphasic solution, tetrabutylammonium bromide (1 g) was added and the reac-
tion mixture was heated with stirring at 40–45 ◦C. The progress of the reaction was monitored
by HPLC. After 3 h of reaction, the reaction mass was cooled. An organic layer was separated
and washed with water (2 × 150 ml) and then dried over anhydrous sodium sulphate. The organic
layer was distilled off under vacuum. Then to the crude residue, ethanol (300 ml) was added and
the mass was heated to reflux. It was then cooled slowly to 10–15 ◦C and the obtained solid was
filtered, washed with ethanol and dried under vacuum to give the pure product (3):
1
IR (KBr, cm−1): 3104, 2932, 1679, 1396 and 1180; H NMR (DMSO-d6, 400 MHz) δ ppm:
2.40 (s, 3H), 3.30 (s, 3H) 5.36 (s, 2H, CH2) 7.41 (d, 2H, J = 8 Hz, Ar-H), 7.75 (d, 2H, J = 8 Hz,
Ar-H) 8.03 (d, 2H, J = 8 Hz, Ar-H) and 8.16 (d, 2H, J = 8 Hz, Ar-H). MS: m/z (% intensity):
370 (93, M+NH4), 371 (18, M+1+NH4).
3.1.2. Synthesis of 1-[(4ꢀ-methyl sulfonyl)phenyl]-2-[(4-methyl phenyl)sulfonyl]-prop-2-en-1-
ones (4a–f)
To the solution of α-(4ꢀ-methyl sulfonyl phenyl)-4-methyl sulfonyl acetophenone (3) (0.0142 mol)
in EDC (100 ml), substituted benzaldehyde (0.015 mol) and piperidine (0.5 ml) were added and the
reaction mass was then heated to reflux. Water formed in the reaction was removed simultaneously
by a Dean–Stark trap and the progress of the reaction was monitored by HPLC. After 3 h of
reaction, it was cooled to room temperature and poured into ice-cold water (150 ml). The organic
layer was separated and washed with water (2 × 50 ml). Then it was dried over anhydrous sodium
sulphate. The solvent was then distilled off under vacuum from the organic layer. The residue was
stirred with ethanol (100 ml) and the alcoholic mass was refluxed to get a clear solution. It was
then cooled to 20–25 ◦C and stirred for 1 h and the separated solid product was filtered and washed
with cold ethanol. The crude product was then dried under vacuum. Physical characterizations of
a series of compounds are incorporated in Table 1.
3.1.3. Spectral characterization of 2-[4ꢀ(methyl phenyl) sulfonyl]-1-[4-(methyl sulfonyl)
phenyl]-3-[4ꢀꢀ-fluorophenyl]-2-prop-en-1-one (4a)
1
IR (KBr, cm−1): 3004, 2922, 1673, 1601, 1509, 1398, 1220 and 1146. H NMR (DMSO-d6,
400 MHz) δ ppm: 2.91 (s, 3H,Ar-CH3), 3.27 (s, 3H, SO2CH3), 7.81 (d, 2H,Ar-H, J = 8 Hz), 8.00
(dd, 4H, Ar-H), 7.72 (d, 2H, Ar-H, J = 8 Hz), 8.23 (s, 1H, Vinylic-H). MS: m/z (% intensity): 476
(93, M+NH4), 477 (25, M + 1 + NH4); 13C NMR: 21.12, 49.94, 116.39, 127.64, 127.80, 128.21,
130.08, 130.2, 132.7, 132.77, 132.86, 136.28, 138.09, 141.36, 145.09, 162.34, 164.84, 191.35.

Journal of Sulfur Chemistry 307
3.1.4. Synthesis of 2-(substituted phenyl)-3-[(methyl phenyl) sulfonyl] [(methyl sulfonyl)
phenyl]-2, 3-dihydro-1,5-benzothiazepines (5a–f)
3.1.4.1. Method A. To the stirred solution of chalcones (4a–f) (6.5 mmol) in toluene (60 ml),
2-aminothiophenol (7 mmol) and few drops of triflouro acetic acid were added. The reaction
mixture was refluxed and the reaction water formed was simultaneously removed by a Dean–
Stark trap. The progress of the reaction was monitored by HPLC. After 4 h of reflux, toluene was
removed under vacuum. To the residue, cold water was added, and the content was then stirred
at room temperature for 20–30 min. The separated solid was filtered and washed with water. The
crude product was crystallized from ethanol. The characterization data of the 1,5-benzothiazepines
(5a–f) are presented in Table 2.
3.1.4.2. Method B. Silica gel (10 g) was added to the solution of 4a–f (6.5 mmol) in diethyl
ether (60 ml). The heterogeneous mass was stirred for 30 min at room temperature. Then the ether
was removed by using a rotary evaporator. 2-Aminothiophenol (10.5 mmol) was added to the
above residue and the mixture was warmed at 80 ◦C under nitrogen atmosphere. The progress of
the reaction was monitored by HPLC for the absence of chalcones (4a–f). After 2 h of heating,
ethyl acetate (100 ml) was added to the reaction mixture and stirred for 30 min. The silica gel was
separated by filtration. The solvent was removed from the filtrate under reduced pressure and the
products were purified by successive crystallization from ethanol.
3.1.5. Spectral characterization of 2-(4ꢀ-fluorophenyl) 3-[(methyl phenyl) sulfonyl] 4-[(methyl
sulfonyl) phenyl]-2,3-dihydro 1,5-benzothiazepine (5a)
IR (KBr, cm−1): 3353, 3019, 2919, 1646, 1396, 1255 and 1145. 1H NMR (DMSO-d6, 400 MHz)
δ ppm: 2.50 (s, 3H, Ar-CH), 3.27 (s, 3H, SO2CH), 3.44–3.71 (two undiagonistic doublets, 2H, 2
methine protons), 6.82–8.13 (m, overlap, 16H, Ar-H); 13C NMR: 23.1, 32.5, 45.2, 64.7, 123.8,
127.6, 128.2, 127.9, 161.5, 129.1, 126.4, 140.5, 145.3, 132.2, 129.5, 139.2, 142.7, 130.1, 132.0,
140.5, 135.1, 158.6, 165.7. MS: m/z (% intensity): 584 [97, (M + NH4)+], 585 [31, (MH +
NH4)+] Anal. for C29H24FNO4S3 Calcd. C, 61.57; H, 4.28; N, 2.48; S, 17.50. Found: C, 61.73;
H, 4.66; N, 2.54; S, 17.13.
3.1.6. 4-(4-(Methyl sulfonyl) phenyl)-3-tosyl-2-(3,4,5-trimethoxyphenyl)-2,3-dihydrobenzo[b]
[1,4]thiazepine (5b)
1H NMR (DMSO-d6, 400 MHz): 2.25 (s, 3H,Ar-CH), 3.16 (s, 3H, SO2CH), 3.78 (s, 6H, 2 OCH3),
3.86 (s, 3H, OCH3) 3.92–3.98 (dd, 2H, 2 methine protons), 6.18–8.10 (m, overlap, 14H, Ar-H);
13C NMR: 23.5, 33.3, 47.1, 64.4, 59.7 (2 OCH3), 60.5, 124.2, 128.5, 130.2, 128.3, 139.7, 159.2,
110.4, 140.4, 132.2, 129.5, 139.2, 142.7, 130.1, 134.1, 144.6, 137.8, 159.6, 167.3; Anal. for
C32H31NO7S3 Calcd. C, 60.26; H, 4.90; N, 2.20; S, 15.08. Found: C, 60.48; H, 4.97; N, 2.24; S,
15.17.
3.1.7. 2-(3,4-Dimethoxyphenyl)-4-(4-(methyl sulfonyl) phenyl)-3-tosyl-2,3-dihydrobenzo[b]
[1,4]thiazepine (5c)
1H NMR (DMSO-d6, 400 MHz): 2.28 (s, 3H, Ar-CH), 3.10 (s, 3H, SO2CH), 3.73 (s, 3H, OCH3),
3.79 (S, 3H, OCH3), 3.78–3.81 (dd, 2H, 2 methine protons), 6.08–7.91 (m, overlap, 15H, Ar-H);
13C NMR: 24.6, 35.3, 48.9, 68.4, 55.2 (2 OCH3), 55.8, 125.0, 129.9, 132.1, 128.3, 150.8, 153.6,
120.3, 130.4, 117.7, 138.2, 134.1, 128.3, 149.2, 152.7, 135.1, 132.9, 140.2, 133.0, 154.8, 168.6.

308 S.N. Karale et al.
Anal. for C31H29NO6S3 Calcd. C, 61.26; H, 4.81; N, 2.30; S, 15.83. Found: C, 61.15; H, 4.92; N,
2.21; S, 15.97.
3.1.8. 4-(4-(4-(Methyl sulfonyl) phenyl)-3-tosyl-2,3-dihydrobenzo[b][1,4]thiazepin-2-yl)
phenol (5d)
1H NMR (DMSO-d6, 400 MHz): 2.15 (s, 3H, Ar-CH), 2.79 (s, 3H, SO2CH), 3.51–3.86 (dd, 2H, 2
methine protons), 6.12–8.09 (m, overlap, 16H,Ar-H), 10.36 (s, 1H, OH, exchangeable with D2O);
13C NMR: 24.1, 35.5, 47.8, 61.9, 122.8, 137.6, 130.2, 128.1, 160.4, 118.91, 130.4, 135.7, 135.1,
128.2, 141.6, 143.8, 131.3, 132.5, 143.2, 131.1, 159.6, 169.3. Anal. for C29H25NO5S3 Calcd. C,
61.79; H, 4.47; N, 2.48; S, 17.06. Found: C, 61.89; H, 4.50; N, 2.54; S, 17.19.
3.1.9. 2-(4-Methoxyphenyl)-4-(4-(methyl sulfonyl) phenyl)-3-tosyl-2,3-dihydrobenzo[b][1,4]
thiazepine (5e)
1H NMR (DMSO-d6, 400 MHz): 2.32 (s, 3H, Ar-CH), 3.92 (s, 3H, SO2CH), 3.96 (s, 3H, CH3),
3.98–4.12 (dd, 2H, 2 methine protons), 6.21–8.15 (m, overlap, 16H, Ar-H); 13C NMR: 22.4, 30.2,
41.2, 63.8, 57.1, 121.3, 125.6, 126.7, 127.9, 160.3.5, 117.1, 132.5, 155.5, 131.2, 127.3, 136.7,
140.9, 131.1, 131.3, 139.5, 133.4, 157.1, 164.5. Anal. for C30H27NO5S3 Calcd. C, 62.37; H, 4.71;
N, 2.42; S, 16.65. Found: C, 62.53; H, 4.68; N, 2.35; S, 16.49.
3.1.10. 2-(4-Chlorophenyl)-4-(4-(methyl sulfonyl) phenyl)-3-tosyl-2,3-dihydrobenzo[b] [1,4]
thiazepine (5f)
1H NMR (DMSO-d6, 400 MHz): 2.48 (s, 3H, Ar-CH), 3.12 (s, 3H, SO2CH), 3.40–3.79 (dd, 2H,
methine protons), 6.78–8.28 (m, overlap, 16H, Ar-H); 13C NMR: 24.4, 30.2, 45.2, 63.2, 1202,
128.5, 124.3, 128.9, 132.5, 129.0, 130.9, 140.1, 132.6, 129.8, 139.6, 142.3, 130.5, 132.6, 140.1,
135.6, 158.2, 164.9. Anal. for C29H24ClNO4S3 Calcd. C, 59.83; H, 4.16; N, 2.41; S, 16.52. Found
C, 59.68; H, 4.13; N, 2.47; S, 16.61.
4. Conclusions
We have synthesized 2,3,4-trisubstituted 1,5-benzothiazepines bearing a sulfonyl groups in good
yields using the modified classical synthetic method.
Acknowledgement
The authors are thankful to Professor D.B. Ingle for his valuable discussion.
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