Catalyst-free synthesis of 2,3-dihydro-1,5-benzothiazepines in a renewable and biodegradable reaction medium

Article abstract of DOI:10.1039/c8nj05611k

A clean and efficient strategy for the synthesis of benzothiazepines from chalcone and ortho-aminothiophenol has been reported. Here, glycerol, a biodegradable and reusable promoting medium, has been utilized under acid, base or metal-free conditions. The

Full text of DOI:10.1039/c8nj05611k

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Catalyst-free synthesis of 2,3-dihydro-1,5-
benzothiazepines in a renewable and
Cite this:DOI: 10.1039/c8nj05611k
biodegradable reaction medium†
Neetu Yadav,‡ Vijay B. Yadav,‡ Mohd Danish Ansari, Hozeyfa Sagir, Ankit Verma
and I. R. Siddiqui
*
A
clean and efficient strategy for the synthesis of benzothiazepines from chalcone and ortho-
Received 5th November 2018,
Accepted 8th April 2019
aminothiophenol has been reported. Here, glycerol, a biodegradable and reusable promoting medium,
has been utilized under acid, base or metal-free conditions. The significant features of the protocol
include a one-pot eco-friendly approach, short reaction time, high atom economy, broad substrate
scope, easy workup process and high yields.
DOI: 10.1039/c8nj05611k
rsc.li/njc
analgesic,17 anti convulsant,18 anti-HIV and squalene synthase
inhibitory activity.19–21 In recent times, 1,5-benzothiazepines
Introduction
In recent years, many efforts have been devoted to developing have been used in cardiovascular treatments (diltiazem, fluo-
new synthetic methodologies using renewable resources and rodiazepam, etc.), as muscle relaxants, and as antibiotics.22–25
trying to shift society’s dependence away from fossil resources For instance, the 1,5-benzothiazepine scaffold is extremely
to environmentally benign biomass resources.1–6 In all the versatile and possesses various features in a number of
experiments, solvents are needed in huge amounts for different clinically used drugs26–29 (Fig. 1). To date, some synthetic
applications including reaction media, dispersant media and approaches for the construction of 1,5-benzothiazepine deriva-
cleaning agents.7 Thus, organic chemists are continuously tives have been developed.30–33 However, all of these protocols
searching for the maximum use of eco-friendly and sustainable suffer drawbacks such as harsh reaction conditions including
reaction media. Recently, glycerol has emerged as an efficient high temperature, use of toxic agents, acid, base and metal
and convenient solvent in synthetic chemistry, as it meets with catalysts, corrosivity, tedious workup and unsatisfactory
various standards such as non-flammability, low toxicity, non- yields.34–36
volatility and ease of availability8,9 thereby fulfilling most of the
criteria of green chemistry. Since it is a biodegradable by-
product generated from biodiesel, it is inexpensive, easy to
handle and can be reused several times.10 In addition, it has the
potential to dissolve11 several organic molecules that are
immiscible in aqueous media and thus can accelerate reactions
that generally do not occurr in low boiling point media. Thus,
´ ˆ
as suggested by Jerome and co-workers, glycerol can be con-
sidered as ‘‘organic water’’ in chemical reactions.12
Fig. 1 Some clinically used drugs containing 1,5-benzothiazepine derivatives.
Fused heterocyclic compounds containing N and S atoms
have received a great deal of attention because of their privileged
role in nature and medicines.13 Among these compounds,
Therefore, new protocols for the preparation of 1,5-benzo-
1,5-benzothiazepines have attracted considerable interest.14,15 thiazepine scaffolds are still desirable for the development
For instance, 1,5-benzothiazepines have antibacterial,16 of an eco-friendly pathway for the synthesis of biologically
significant heterocycles. Consequently, in continuation of
our ongoing research program on the development of green
Laboratory of Green Synthesis, Department of Chemistry, University of Allahabad,
synthetic routes to important heterocyclic scaffolds,37,38 we
Allahabad, 211002, India. E-mail: dr.irsiddiqui@gmail.com; Tel: +91-9335153359
herein report a new, catalyst-free, clean and efficient one-pot
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
synthesis of 1,5-benzothiazepines using glycerol as a promoting
medium (Scheme 1).
c8nj05611k
‡ These authors contributed equally.
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Table
2
Optimisation of the temperature for the synthesis of
2,3-dihydro-1,5-benzothiazepinesa
Entry
Solvent
Temperature (1C)
Time (h)
Yieldb (%)
1
2
3
4
5
Glycerol
Glycerol
Glycerol
Glycerol
Glycerol
r.t.
60
70
80
90
12
8
6
6
6
60
70
85
85
85
Scheme 1 General synthetic strategy.
Results and discussion
a
Reaction condition: all reactions were carried out with 1 (1 mmol) and
To initiate our study, we chose chalcone (1) and ortho-amino-
thiophenol (2) as the model substrates for the synthesis of
2,3-dihydro-1,5-benzothiazepine (3k) and examined the impact of
various reaction conditions on the reaction outcome, including
solvents, temperature and so on (Scheme 2).
b
2 (1 mmol) in glycerol. Isolated yield of products.
temperatures, viz. 60 1C, 70 1C, 80 1C and 90 1C in glycerol
(Table 2). As expected, an improvement in the yield and
reduction in the reaction time were observed upon increasing
the temperature and the maximum yield of the product was
obtained within the minimum time when we performed the
reaction at 70 1C (Table 2, entry 3).
After optimizing the reaction conditions, the substrate scope of
this protocol was explored by employing ortho-aminothiophenol
Scheme 2 Model reaction for the synthesis of benzothiazepine 3k.
Table 3 Substrate scope for the synthesis of substituted benzothiazepinesa
Initially, we carried out the reaction in water at room
temperature (r.t.) and observed that the product was not
formed even after 12 h of stirring possibly due to limited
solubility of the organic reactants in water (Table 1). To over-
come this problem, we further performed the same experiment
in the presence of CTAB and SDS, respectively (Table 1, entries
2–5) but it did not give a better yield even after 12 h. Further,
the reaction was performed in different organic solvents like
THF, DCM and toluene but the reaction did not give satisfac-
tory yields. In our effort to increase the yield further, we carried
out the reaction in ethanol and methanol without any catalyst.
Pleasingly, the reaction occurred but with little success as there
was only a minimal increase in the yield in this case (Table 1,
entries 9 and 10). Surprisingly, instead of all these solvents
when we used glycerol, it led to a remarkable improvement in
the yield under the same conditions (Table 1, entry 11).
Table 1 Optimisation of the reaction conditions for the synthesis of
2,3-dihydro-1,5-benzothiazepinesa
Entry
Solvent
Catalyst
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
Water
Water
Water
Water
Water
THF
DCM
Toluene
Ethanol
Methanol
Glycerol
None
CTAB
CTAB
SDS
SDS
—
12
12
12
12
12
12
12
12
12
12
12
No reaction
No reaction
Tracec
No reaction
Tracec
Trace
Trace
Trace
30
37
—
9
10
11
—
—
—
60
a
Reaction conditions: all reactions were carried out at r.t. with 1
b
(1 mmol) and 2 (1 mmol) in glycerol. Isolated yield of products.
c
Reaction performed at 60 1C.
a
Next, to evaluate the effect of temperature on this reaction,
Reaction conditions: all reactions were carried out with 1 (1 mmol)
we performed a set of experiments under a diverse range of and 2 (1 mmol) in glycerol.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The authors gratefully acknowledge SAIF, Panjab University,
Chandigarh for providing all the spectroscopic and analytical
data. N. Yadav and V. B. Yadav are grateful to CSIR, New Delhi
for the award of a Junior Research Fellowship (JRF) and Senior
Research Fellowship (SRF), respectively. H. Sagir and Ankit
Verma acknowledge UGC, New Delhi for the award of a Senior
Research Fellowship (SRF) and Junior Research Fellowship
(JRF), respectively and Mohd Danish Ansari acknowledges
UPCST (Project No. CST/D-2276) for the financial support.
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