Facile synthesis of 1,5-benzothiazepines in water using tetrabutylammonium tribromide

Article abstract of DOI:10.1080/10426507.2011.627900

A simple, environmentally benign, and efficient method was developed for the preparation of 1,5-benzothiazepines via a one-pot condensation reaction of 2-aminothiophenol with 1,3-diaryl-2-propenones using tetrabutylammonium tribromide as an efficient and versatile catalyst in water.

Full text of DOI:10.1080/10426507.2011.627900

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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Facile Synthesis of 1,5-Benzothiazepines
in Water Using Tetrabutylammonium
Tribromide
Yunhui Yan a , Xiaojuan Yang b & Liqiang Wu c
a School of Basic Medicine , Xinxiang Medical University , Xinxiang ,
Henan , China
b College of Chemistry and Chemical Engineering , Xinxiang
University , Xinxiang , Henan , China
c School of Pharmacy , Xinxiang Medical University , Xinxiang ,
Henan , China
Published online: 27 Mar 2012.
To cite this article: Yunhui Yan , Xiaojuan Yang & Liqiang Wu (2012) Facile Synthesis of 1,5-
Benzothiazepines in Water Using Tetrabutylammonium Tribromide, Phosphorus, Sulfur, and Silicon and
the Related Elements, 187:5, 573-579, DOI: 10.1080/10426507.2011.627900
To link to this article: http://dx.doi.org/10.1080/10426507.2011.627900
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Phosphorus, Sulfur, and Silicon, 187:573–579, 2012
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.627900
FACILE SYNTHESIS OF 1,5-BENZOTHIAZEPINES IN
WATER USING TETRABUTYLAMMONIUM TRIBROMIDE
Yunhui Yan,1 Xiaojuan Yang,2 and Liqiang Wu3
1School of Basic Medicine, Xinxiang Medical University, Xinxiang, Henan, China
2College of Chemistry and Chemical Engineering, Xinxiang University, Xinxiang,
Henan, China
3School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, China
GRAPHICAL ABSTRACT
R1
O
NH2
N
TBATB
H2O, 80 oC
+
R1
R2
SH
S
R2
75%–94%
Abstract A simple, environmentally benign, and efficient method was developed for the prepa-
ration of 1,5-benzothiazepines via a one-pot condensation reaction of 2-aminothiophenol with
1,3-diaryl- 2-propenones using tetrabutylammonium tribromide as an efficient and versatile
catalyst in water.
Keywords 1,5-Benzothiazepines; 2-aminothiophenol; 1,3-diaryl-2-propenones; tetrabutylam-
monium tribromide
INTRODUCTION
Organic reactions in water have become an important research area. Many reactions
have been accomplished in aqueous medium.1 Water has therefore become an attractive
medium for many organic reactions, not only for the advantages concerning the avoidance
of expensive drying reactants, catalysts, and solvents but also for some unique reactivity
and selectivity.
1,5-benzothiazepines are an important class of heterocyclic compounds and exhibit
a wide range of biological properties, such as antifungal,2 antimicrobial,3 anticonvul-
sant,4 antibacterial,5 anti-HIV,6 Ca+2 channel antagonist,7 V2 arginine vasopressin receptor
Received 20 July 2011; accepted 25 September 2011.
We are pleased to acknowledge the financial support from Xinxiang Medical University.
Address correspondence to Liqiang Wu, School of Pharmacy, Xinxiang Medical University, Xinxiang,
Henan 453003, China. E-mail: wliq1974@sohu.com
573

574
Y. YAN ET AL.
antagonist,8 and HIV-1 reverse transcriptase inhibitor activities.9 Various methods for the
synthesis of 1,5-benzothiazepines have been reported. Among these methods, the most
widely used are the reactions of 2-aminothiophenol with α, β-unsaturated carbonyl com-
pounds in the presence of Yb(OTf)3,10 nanocrystalline aluminum oxide,11 Ga(OTf)3,12
HBF4-SiO2,13 sodium dodecyl sulfate,14 Mg(ClO4)2,15 HClO4-SiO2,16 SmI2,17 and HCl.18
However, still there remains a need to develop a more efficient method, particularly from
the viewpoint of today’s environmental concerns.
The use of organic molecules as catalysts has become an attractive alternative to tra-
ditional metal-catalysts. Interest in the field of organocatalysis has increased spectacularly
in the last few years as the result of both the novelty of the concept and, more importantly,
the fact that the efficiency and selectivity of many organocatalytic reactions meet the stan-
dards of established organic reactions.19 Tetrabutylammonium tribromide (TBATB) is one
such catalyst, which has recently received considerable attention as a catalyst in various
organic transformations.20 We now report a highly efficient procedure for the prepara-
tion of 1,5-benzothiazepines via a one-pot condensation reaction of 2-aminothiophenol
with 1,3-diaryl-2-propenones using TBATB as an efficient and versatile catalyst in water
(Scheme 1).
R1
O
NH2
N
TBATB
H2O, 80 oC
+
R1
R2
SH
S
R2
3
1
2
Scheme 1
RESULTS AND DISCUSSION
Initially, to optimize the reaction temperature, the reaction of 2-aminothiophenol
with 1,3-diphenyl-2-propenones to the corresponding 2,3-dihydro-2,4-diphenyl-1,5-
benzothiazepine was studied in water in the presence of 5 mol% TBATB at different
temperatures. The results were summarized in Table 1. As shown in Table 1, the reaction
at 80 ◦C proceeded in the highest yield.
The effect of amount of catalyst on the conve◦rsion and rate of the reaction was studied
by varying the amount of TBATB in water at 80 C (Table 2). It was found that 5 mol%
of TBATB was sufficient to carry out this reaction smoothly. An increase in the amount of
TBATB to more than 5 mol% showed no substantial improvement in the yield, whereas the
yield was reduced by decreasing the amount of TBATB to 4 mol%.
These results encouraged us to investigate the scope and generality of this new
protocol for various 1,3-diaryl-2-propenones under optimized conditions. As shown in Table
3, a series of 1,3-diaryl-2-propenones containing either electron-withdrawing or electron-
donating substituents successfully react with 2-aminothiophenol and afforded good to high
yields of products with high purity, at 80 ◦C in water.
A comparison of the efficiency of this method with selected previous methods is
collected in Table 4. The results show that this method is superior to some previously

FACILE SYNTHESIS OF 1,5-BENZOTHIAZEPINES IN WATER
575
Table 1 Temperature optimization for the synthesis of 2,3-dihydro-2,4-diphenyl-1,5-benzothiazepinea
Entry
Temperature (◦C)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
25
50
60
70
80
12
10
8
6
6
38
56
67
79
87
85
83
90
100
6
6
aReaction conditions: 2-aminothiophenol (1 mmol); 1,3-dienyl-2-propenone (1 mmol); TBATB (0.05 mmol);
H2O (5 mL).
bIsolated yield based on three experiments.
Table 2 Amount of catalyst optimization for the synthesis of 2,3-dihydro-2,4-diphenyl-1,5-benzothiazepinea
Entry
TBATB (mol%)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
0
1
2
3
4
5
6
7
12
10
8
8
6
6
6
6
15
46
55
68
76
87
86
87
aReaction conditions: 2-aminothiophenol (1 mmol); 1,3-dienyl-2-propenone (1 mmol); H2O (5 mL); 80 ◦C.
bIsolated yield based on three experiments.
Table 3 Preparation of 1,3-diaryl-2,3-dihydro-1,5-benzothiazepinesa
1,3-diphenylprop-
2-enone
Time
(h)
Yield
(%)b
mp (◦C)
(lit.)
Entry
1
Product
6
87
113–114
(114–115)21
2
8
84
106–107
(104–107)21
(Continued on next page)

576
Y. YAN ET AL.
Table 3 Preparation of 1,3-diaryl-2,3-dihydro-1,5-benzothiazepinesa (Continued)
1,3-diphenylprop-
2-enone
Time
(h)
Yield
(%)b
mp (◦C)
(lit.)
Entry
3
Product
7
85
80–81 (78–80)21
4
7
80
205–206
(200–204)21
5
8
84
154–156
(154–155)12
6
5
90
106–107
(106–108)21
7
5
88
129–130
(127–129)21
8
5
94
178–179
(178–180)21

FACILE SYNTHESIS OF 1,5-BENZOTHIAZEPINES IN WATER
577
Table 3 Preparation of 1,3-diaryl-2,3-dihydro-1,5-benzothiazepinesa (Continued)
1,3-diphenylprop-
2-enone
Time
(h)
Yield
(%)b
mp (◦C)
(lit.)
Entry
9
Product
7
87
132–133
(130–132)21
10
7
80
88–89 (88–89)12
11
7
80
171–172
(170–172)12
12
13
7
8
78
75
Oil
Oil
aReaction conditions: 2-aminothiophenol (1 mmol); 1,3-diaryl-2-propenones (1 mmol); TBATB (0.05 mmol);
80 ◦C; H2O (5 mL).
bIsolated yield.
reported methods in terms of yields and reaction times. There are four new things in
the present work when compared to previous publications: (a) Water is an environmen-
tally friendly solvent; (b) The reaction temperature is lower than those reported in refer-
ences 10 and 11; (c) The time is somewhat shorter than in the previous publication with

578
Y. YAN ET AL.
Table 4 TBATB-catalyzed synthesis of 2,3-dihydro-2,4-diphenyl-1,5-benzothiazepine in comparison with other
literatures
Entry
Catalyst
Solvent
Temp. (◦C)
Time (h)
Yield (%)
Ref.
1
2
3
4
5
Yb(OTf)3 (5 mol%)
nano-Al2O3 (3 mol%)
Ga(OTf)3 (10 mol%)
SDS (10 mol%)
[bmim][BF4]
H2O
MeCN
H2O
25
110
60
100
80
0.5
12
4
12
6
84
71
30
65
87
10
11
12
14
TBATB (5 mol%)
H2O
This work
◦
comparative yields; and (d) The reaction using 5 mol% TBATB at 80 C proceeded in
highest yield.
CONCLUSION
We developed a simple, environmentally benign, and efficient method for the prepa-
ration 1,5-benzothiazepines using TBATB in water. The notable features of this procedure
are the use of a cheap, easy to handle, and commercially available catalyst, and water as
the reaction medium in place of harmful volatile organic solvents, which make it a useful
and attractive process for the synthesis of 1,5-benzothiazepines.
EXPERIMENTAL
NMR spectra were determined on Bruker AV-400 spectrometer at room temperature
using TMS as an internal standard, and coupling constants (J) were measured in Hz;
Elemental analysis was performed by a Vario-III elemental analyzer; melting points were
determined on a XT-4 binocular microscope and were uncorrected; commercially available
reagents were used throughout without further purification unless otherwise stated.
General Procedure for the Synthesis of 1,5-benzothiazepines
A mixture of 1,3-diaryl-2-propenones (1 mmol) in water (5 mL) was heated at
80 C until it formed a melt admixed with water as tiny liquid droplets, after which 2-
◦
aminothiophenol ◦(1 mmol) was added followed by TBATB (0.05 mmol) and the mixture
was stirred at 80 C for the appropriate time (Table 3). The reaction was cooled to room
temperature and extracted with EtOAc (3 × 5 mL). The combined EtOAc extracts were
washed with brine, dried (Na2SO4), concentrated under rotary vacuum evaporation, and the
crude product purified by column chromatography over silica gel using n-hexane/EtOAc
(v:v = 2:1) as eluent to afford the pure product. The spectral data of some new 1,5-
benzothiazepines are given below.
2-(2-thienyl)-4-phenyl-2,3-Dihydro-1,5-benzothiazepine (3l): IR (KBr) ν: 2926,
1658, 1594; 1H NMR (400 MHz, CDCl3): δ 7.66–7.26 (m, 8H), 7.01–6.59 (m, 4H), 5.04
(dd, 1H, J = 4.8, 12.4, Hz), 3.42 (dd, 1H, J = 4.8, 13.2, Hz), 3.04 (t, 1H, J = 12.4 Hz);
Anal. calcd for C19H15NS2: C 70.99, H 4.70, N 4.36, S 19.95; found: C 71.10, H 4.72, N
4.20, S 20.01.
2-(1H-pyrrol-2-yl)-4-phenyl-2,3-Dihydro-1,5-benzothiazepine (3m): IR (KBr) ν:
2930, 1660, 1596; 1H NMR (400 MHz, DMSO-d6): δ 10.15 (brs, 1H), 7.64–7.49 (m, 5H),
7.23–6.99 (m, 4H), 6.42–5.81 (m, 3H), 5.01 (dd, 1H, J = 4.8, 12.8, Hz), 3.42 (dd, 1H,

FACILE SYNTHESIS OF 1,5-BENZOTHIAZEPINES IN WATER
579
J = 4.8, 12.8, Hz), 2.95 (t, 1H, J = 13.2 Hz); Anal. calcd for C19H16N2S: C 74.97, H 5.30,
N 9.20, S 10.53; found: C 75.06, H 5.23, N 9.30, S 10.48.
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