An efficient synthesis of 1,5-benzothiazepines in the presence of sub-stoichiometric amount of cyanuric chloride

Article abstract of DOI:10.1080/17415993.2011.572971

An efficient synthesis of 1,3-diaryl-2,3-dihydro-1,5-benzothiazepines has been developed by the reaction of various 1,3-diaryl-2-propenones with 2-aminothiophenol under thermal solvent-free conditions in the presence of a sub-stoichiometric amount of cyanuric chloride.

Full text of DOI:10.1080/17415993.2011.572971

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An efficient synthesis of 1,5-
benzothiazepines in the presence of
sub-stoichiometric amount of cyanuric
chloride
Pengli Sun a , Lizheng Fang a & Liqiang Wu a
a School of Pharmacy, Xinxiang Medical University, Xinxiang,
Henan, 453003, People's Republic of China
Version of record first published: 12 Apr 2011.
To cite this article: Pengli Sun , Lizheng Fang & Liqiang Wu (2011): An efficient synthesis of 1,5-
benzothiazepines in the presence of sub-stoichiometric amount of cyanuric chloride, Journal of
Sulfur Chemistry, 32:3, 257-261
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Journal of Sulfur Chemistry
Vol. 32, No. 3, June 2011, 257–261
An efficient synthesis of 1,5-benzothiazepines in the presence of
sub-stoichiometric amount of cyanuric chloride
Pengli Sun, Lizheng Fang and Liqiang Wu*
School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, People’s Republic of China
(Received 25 January 2011; final version received 14 March 2011)
An efficient synthesis of 1,3-diaryl-2,3-dihydro-1,5-benzothiazepines has been developed by the reaction
of various 1,3-diaryl-2-propenones with 2-aminothiophenol under thermal solvent-free conditions in the
presence of a sub-stoichiometric amount of cyanuric chloride.
Ar1
N
S
NH2
SH
O
+
Ar1
Ar2
Ar2
Keywords: 1,5-benzothiazepines; 2-aminothiophenol; cyanuric chloride; synthesis
1. Introduction
1,5-Benzothiazepines are important biologically active heterocyclic compounds which possess
antifungal (1), antimicrobial (2), anticonvulsant (3), antibacterial (4), anti-human immunodefi-
ciency virus (HIV) (5), Ca2+ channel antagonist (6), V2 arginine vasopressin receptor antagonist
(7), and HIV-1 reverse transcriptase inhibitor activities (8). The most common methods for the
preparation of 1,5-benzothiazepines are the reactions of 2-aminothiophenol with α,β-unsaturated
carbonyl compounds in the presence of Yb(OTf)3 (9), nanocrystalline aluminum oxide (10),
Ga(OTf)3 (11), HBF4-SiO2 (12), sodium dodecyl sulfate (SDS) (13), Mg(ClO4)2 (14), HClO4-
SiO2 (15), SmI2 (16), and HCl (17). In view of the importance of the benzothiazepines, there still
remains the necessity to develop a new methodology.
Cyanuric chloride 2,4,6-Trichlorotriazine (TCT) is a stable, non-volatile, inexpensive, and safe
reagent which has been used synthetically for the preparation of various types of compounds such
as 2-aryl-2,3-dihydroquinolin-4(1H)-ones (18), bis(indolyl)methanes (19), N-sulfonyl imines
(20), and 14-aryl or alkyl-14-H-dibenzo[a, j]xanthenes (21). In this paper, we wish to report a
*Corresponding author. Email: wliq870@163.com
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2011 Taylor & Francis
DOI: 10.1080/17415993.2011.572971
http://www.informaworld.com

258 P. Sun et al.
rapid and highly efficient method for the synthesis of 1,3-diaryl-2,3-dihydro-1,5-benzothiazepines
in the presence of sub-stoichiometric amount of cyanuric chloride at 80◦C (Scheme 1).
Ar1
N
S
NH2
SH
O
+
Ar1
Ar 2
Ar 2
3
2
1
Scheme 1. Synthesis of 1,5-benzothiazepines using cyanuric chloride.
2. Results and discussion
To choose optimum conditions, the effect of temperature and the amount of TCT on the rate
of the reaction was studied for the preparation of 2,4-diphenyl-2,3-dihydro-1,5-benzothiazepine.
Optimum conditions were observed at temperatures between 80◦C and 90◦C and a concentration
of 5 mol%. When this reaction was carried out in the absence of TCT, thin layer chromatography
(TLC) and 1H NMR spectra of the reaction mixture showed a combination of starting materials
and corresponding thia-Michael adduct, the yield of the expected product was very poor.
In order to extend the above reaction (Scheme 1) to a library system, various kinds of 1,3-
diaryl-2-propenones 2 (Table 1) were subjected to reaction with 2-aminothiophenol 1 to give
the corresponding 2,4-diaryl-2,3-dihydro-1,5- benzothiazepine, and representative examples are
shown in Table 1. All of the 1,3-diaryl-2-propenones, 2, gave the expected products in high yields
whether bearing electron-withdrawing groups (such as halide, nitro) or electron-donating groups
(such as the alkyl group). All of the structures were characterized by IR, 1H NMR, and elemental
analysis.
HCl generated in situ, from cyanuric chloride, efficiently catalyzes these reactions.Accordingly,
cyanuric chloride (5 mol %) reacts with ‘incipient’ moisture and releases three moles of HCl and
cyanuricacid(removablebywashingwithwater)asaby-product.Theinsitu-generatedHClactsas
protic acid and activates the carbonyl oxygen and forms a carbocation. Subsequent intramolecular
nucleophilic attack by the NH2 group on the carbocation followed by dehydration forms the 2,3-
dihydro-1,5-benzothiazepines. The reaction could be facilitated by wet glass wares or by the
presence of wet air. However, the reaction under dry reaction conditions in the presence of MS
4Å met with failure. Thus, it amply indicates that the ‘incipient’moisture plays an important role
for HCl generation in situ from TCT.
To illustrate the efficiency of the proposed method, Table 2 compares some of our results with
some of those reported for relevant reagents in the literature, which demonstrates its significant
superiority. Compared with some of the reported methods in Table 2, the present method has a
short reaction time, good yield, and solvent-free conditions.
3. Conclusion
In conclusion, we have established an efficient protocol for the synthesis of 2,4-diaryl-2,3-dihydro-
1,5-benzothiazepines using inexpensiveTCT. This method offers the advantage of shorter reaction
times and easy workup. We believe that this methodology could be an important addition to the
existing methodologies.

Journal of Sulfur Chemistry 259
Table 1. Preparation of 1,3-diaryl-2,3-dihydro-1,5-benzothiazepines.a
Entry
1
1,3-Diaryl-2-propenones
Time (h)
4
Product
Yield (%)b
m.p. (◦C) (reference)
3a
85
113–114 (114–115) (22)
2
5
3b
83
106–107 (104–107) (22)
3
4
5
5
3c
86
81
80–81 (78–80) (22)
3d
205–206 (200–204) (22)
5
6
5
3
3e
3f
80
88
154–156 (154–155) (11)
106–107 (106–108) (22)
7
3
3g
90
129–130 (127–129) (22)
8
9
3
5
3h
3i
91
89
178–179 (178–180) (22)
132–133 (130–132) (22)
10
5
3j
88
158–160
11
12
6
5
3k
3l
79
82
88–89 (88–89) (11)
171–172 (170–172) (11)
Notes: aReaction conditions: 2-aminothiophenol (10 mmol); 1,3-diaryl-2-propenones (10 mmol), TCT (0.5 mmol); 80◦C; neat.
bIsolated yield.

260 P. Sun et al.
Table 2. Synthesis of of 2,4-diphenyl-2,3-dihydro-1,5-benzothiazepine in comparison with other literatures.
Entry
Catalyst
Solvent
Temperature (◦C)
Time (h)
Yield (%)
Reference
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
25
110
60
100
80
0.5
12
4
12
4
84
71
30
65
85
(9)
(10)
(11)
(13)
This work
MeCN
H2O
–
TCT (5 mol%)
4. Experimental
4.1. General
IR spectra were determined on FTS-40 infrared spectrometer; NMR spectra were recorded on
Bruker AV-400 spectrometer at room temperature using TMS as an internal standard, and cou-
pling constants (J) were measured in Hz; Elemental analysis were 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.
4.2. General procedure for the preparation of 3
A mixture of the 2-aminothiophenol (10 mmol), 1,3-diaryl-2-propenones (10 mmol), and TCT
(0.5 mmol) was stirred at 80◦C using an electric mixer for the appropriate time (Table 1).
Completion of the reaction was monitored by TLC. The material was cooled to 25◦C, and after
addition of water (50 mL) the mixture was stirred for 5 min. The solid so obtained was filtered
off and purified by passing through a column of silica gel, eluting with 2% EtOAc in hexane to
afford 3. The structure of the products was confirmed by NMR, IR, and comparison with authentic
samples obtained commercially or prepared by reported methods. The spectral data of some new
1,3-diaryl-2,3-dihydro-1,5-benzothiazepine are given below.
4.2.1. 2,3-Dihydro-2-(2-chlorophenyl)-4-(4-chlorophenyl)-1,5-benzothiazepine (3j)
1
IR (KBr): v 2926, 1600 cm−1; H NMR (CDCl3, 400 MHz) δ: 7.02–7.70 (m, 10H), 5.29 (dd,
J = 4.8, 12.8 Hz, 1H), 3.22 (dd, J = 4.8, 13.2 Hz, 1H), 2.90 (t, J = 13.2 Hz, 1H), 4.92 (s, 1H),
1.01 (s, 9H); Anal. Calcd for C21H15Cl2NS: C 65.63, H 3.93, N 3.64, S 8.34; found: C 65.70, H
3.89, N 3.71, S 8.27.
Acknowledgements
We are pleased to acknowledge the financial support from Xinxiang Medical University.
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