Tetrahedron Letters
PTSA catalyzed straightforward protocol for the synthesis
of 2-(N-acyl)aminobenzimidazoles and 2-(N-acyl)
aminobenzothiazoles in PEG
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Siddaiah Vidavalur , Mahaboob Basha Gajula, Ramu Tadikonda, Mangarao Nakka, Sudhakar Dega,
Santosh Kumar Yadav, Christopher Voosala
Department of Organic Chemistry & FDW, Andhra University, Visakhapatnam 530 003, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient PTSA catalyzed synthesis of 2-(N-acyl)aminobenzimidazoles and 2-(N-acyl)aminobenzo-
thiazoles has been described using S-ethylated-N-acylthioureas as substrates and polyethylene glycol
as solvent.
Received 23 November 2013
Revised 6 March 2014
Accepted 7 March 2014
Available online 17 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
2-(N-Acyl)aminobenzimidazole
2-(N-Acyl)aminobenzothiazole
p-Toluenesulfonic acid
Polyethylene glycol
O-Phenylenediamine
O-Aminothiophenol
2-Aminobenzimidazoles and 2-aminobenzothiazoles have
elicited considerable interest among medicinal chemists because
these are privileged in many pharmaceutical agents as well as in
natural products.1 In particular, compounds containing 2-(N-
acyl)aminobenzimidazole (2-NABI) and 2-(N-acyl)aminobenzo-
thiazole (2-NABT) sub structures exhibit a wide range of biological
activities such as antimicrobial,2 antiinflammatory,3 anticancer,4
and antiviral5 activities. 2-NABI are found to be potent inhibitors
in several receptor ligands like interleukin-2-inducible T-cell
kinase (ITK), vascular endothelial growth factor receptor-2 (VEG-
FR-2) and rapidly accelerated fibrosarcoma kinase (RAFK)6–8 etc.
Moreover, these scaffolds can also act as intermediates in the
synthesis of many commercially available drugs like Mebenda-
zole.9,10 Owing to their significant utility in both pharmaceutical
and medicinal chemistry, various synthetic methodologies for the
synthesis of 2-NABI10–12 and 2-NABT13 have been reported. Gener-
ally, these methods involved acylation of 2-aminobenzimidazoles
and 2-aminobenzothiazoles, respectively. Moreover, 2-NABI have
also been synthesized via cyclo-desulfurization of pre-formed
thioureas using various desulfonating agents such as HgO,14 PS-
carbodiimide,15 BOP/DBU,16 and EDC.17 However, these methods
have some drawbacks such as formation of a mixture of regio
isomers in conventional acylation, use of either expensive or toxic
reagents and solvents, and requirement of long reaction times in
oxidative cyclizations. Therefore, development of an efficient
method to synthesize 2-NABI and 2-NABT is still highly desirable.
Hazardous, toxic, and volatile organic solvents are being contin-
uously replaced either by the use of solvent-free techniques18 or by
using water,19 phase-transfer catalysts,20 ionic liquids,21 polyethyl-
ene glycol (PEG),22 etc. PEG is found to be an interesting
eco-friendly solvent system in synthetic organic chemistry with
unique properties such as nontoxicity, inexpensive nature, and
being a nonionic liquid solvent of low volatility. To the best of
our knowledge, no reports have been reported for the direct
synthesis of 2-NABI and 2-NABT from S-ethylated-N-acylthioureas
using BrØnsted acids. Thus, in continuation of our work on the
development of environmentally benign new synthetic methodol-
ogies for the synthesis of heterocyclic compounds,23 herein, we
report that PEG-400 mediated PTSA catalyzed a simple and
straightforward protocol for the synthesis of 2-NABI and 2-NABT
from S-ethylated-N-acylthioureas24 and O-phenylenediamines
and O-aminothiophenols (Scheme 1).
In order to investigate the reaction conditions for the synthesis
of 2-NABI (3), we have chosen the reaction of S-ethyl-N-ben-
zoylthiourea (1a) with readily available diamine (2a) as a model
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Corresponding author. Tel.: +91 8912544683; fax: +91 8912544682.
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.