Tetrahedron Letters
A new and facile tetrachlorosilane-promoted one-pot condensation
for the synthesis of a novel series of tetracyclic 1,5-thiazepines
⇑
Tamer K. Khatab , Khairy A. M. El-Bayouki, Wahid M. Basyouni
Organometallic and Organometalloid Chemistry Department, National Research Centre, Dokki, Cairo 12622, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and facile approach for the one-pot synthesis of a novel series of tetracyclic 1,5-thiazepines is
described. The reaction occurs through cyclocondensation of fused cyclic ketones, aromatic aldehydes,
Received 15 June 2014
Revised 24 August 2014
Accepted 3 September 2014
Available online xxxx
and 2-aminothiophenol using tetrachlorosilane as
temperature.
a
promoter in methylene chloride at ambient
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
1,5-Benzothiazepine
Tetracyclic
Tetrachlorosilane
One-pot synthesis
Multicomponent coupling reactions1 (MCRs) are powerful tools
in modern drug discovery and allow fast, automated, and high
throughput synthesis of diverse structural scaffolds required in
the search for novel therapeutic and pharmacologically active mol-
ecules.2–4 Industrial and academic research have developed MCR
strategies as efficient and cost-effective tools for combinatorial
synthesis.5 The development of novel MCRs is a challenging task
not only for the reactivity match of the starting materials, but also
regarding the reactivity of the intermediate molecules generated
in situ, their compatibility, and their compartmentalization.6
Tetrachlorosilane (TCS) has gained increasing importance due
to its many positive features. TCS is used widely in industry and
is a readily available cheap material that exhibits favorable safety
and toxicological profiles. It has been used as a dehydrating agent
for the formation of amides, hydrazides, dipeptides, carboxamides,
heterocycles, and also as a transsilylating and defluorinating agent.
More importantly, TCS is a weak Lewis acid that has been success-
fully employed to develop several transformations.19 TCS has
played a significant role in our research,20 and in continuation of
our investigations on the development of new methods for the
synthesis of heterocyclic compounds and the design of novel mul-
ticomponent reactions using TCS as an in situ transformation
reagent, we have devised an efficient protocol for the synthesis
of tetracyclic 1,5-benzothiazepines in excellent yields. The synthe-
sis occurs via a three-component, one-pot reaction between fused
cyclic ketones, aromatic aldehydes, and 2-aminothiophenols using
TCS in methylene chloride as the solvent and with stirring at ambi-
ent temperature. As a model reaction indeno-thiazepine was syn-
thesized from 1-indanone (1a) and 4-anisaldehyde (2a) using TCS
in CH2Cl2. The mixture was stirred for 2 h at ambient temperature,
followed by the addition of 2-aminothiphenol (3) and stirring at
room temperature until the reaction was complete (Scheme 1).
The model reaction was optimized by comparing TCS, ZnCl2,
SnCl2, FeCl3, Al2O3 (neutral), and silica gel catalysts. All the reac-
tions were stirred at ambient temperature in methylene chloride
as the solvent with the exclusion of moisture. TLC monitoring of
the reaction indicated that all the tested catalysts gave by-products
and low yields (20–50%) except for TCS which gave an excellent
1,5-Benzothiazepines play
a pivotal role in drug discovery
programs as they display a wide spectrum of biological activities
including antifeedant,7 analgesic,8 anticonvulsant,9 calcium
antagonism,10 antibacterial,11 anti-anginal,12 anti-HIV,13 squalene
synthetase inhibition,14 V2 arginine vasopressin receptor
antagonism15 and HIV-1 reverse transcriptase inhibition.16 This
has stimulated interest to develop new methodologies for the
synthesis of 1,5-benzothiazepines and has encouraged us to
develop a facile and effective method to prepare a new series of
1,5-benzothiazepines. The common strategy for the construction
of the 1,5-benzothiazepine moiety17 involves the preparation of
a,b-unsaturated ketones (chalcones) as the first step, followed
by their reaction with 2-aminothiophenol to give the
a
1,5-benzothiazepines. A few examples describe one-pot reactions
to prepare 1,5-benzothiazepines.18
⇑
Corresponding author. Tel.: +20 233371010; fax: +20 237601877.
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.