An efficient and green procedure for synthesis of
rhodanine derivatives by aldol-thia-Michael
protocol using aqueous diethylamine medium†
Assem Barakat,
*
ab
Abdullah M. Al-Majid,
a
Hany J. AL-Najjar,
a
Yahia N. Mabkhot,
a
Hazem A. Ghabbour
c
and Hoong-Kun Fun
c
A simple, economical, and green approach to the synthesis of rhodanine derivatives using a tandem aldol
condensation-thia-Michael addition process in aqueous diethylamine medium was described. The
experiment protocol features simple operations, and the products were isolated in high to excellent
yields (82–96%). As spontaneous precipitation always occurs at the end of the process, this leads to easy
separation of the products via a simple filtration.
Introduction
The ve-membered rhodanine core is an interesting heterocy-
clic ring system featured in a large number of natural or
synthetic compounds with a wide range of pharmacological
activities.
1
Rhodanine derivatives have been reported as small
molecule inhibitors for targets such as hepatitis C virus NS5B
polymerase
2
and human cathepsin D.
3
Furthermore, they have
been reported as antimalarial, antiviral, antibacterial, and anti-
cancer, and antidiabetic agents (Fig. 1).
4
Epalrestat is a well-
known and highly marketed drug comprising the rhodanine
nuclei and used to delay the progression of diabetic neuropathy.
It is therefore not surprising that numerous synthetic routes
have been developed to obtain this heterocyclic core, many of
which were recently reported.
6
Due to stringent and growing
environmental regulations, organic chemists have endeavored
to develop clean, economical, and environmentally safer
methodologies.
7
Current emphasis on the development of
multiple chemical transformations sequentially performed in a
single reaction vessel, without intermediary purication steps,
has led to the generation of a variety of molecular complexity.
The benets of the green approach are based on reduced time,
costs, and waste generation, but compatibility and reliability
must be circumvented for such processes to become attractive
for industrial purposes. During the past decade, aldol-thia-
Michael protocol is an important process in organic chemistry
and has versatile applications in organic synthesis.
8
Different
catalysts and reaction media have been employed, such as Lewis
acids, cinchona alkaloids, ionic liquids, and solid support.
9
One
of the most promising approaches is using water as the reaction
medium as reported by Saeed Abaee, M. et al. on a multicom-
ponent synthesis of b-aryl-b-mercapto ketones.
10
With this in mind and in continuation of our research
program on the developments of new routes to heterocyclic
system,
11
we now report the aldol-thia-Michael addition process
for the synthesis of rhodanine derivatives where water is used as
a green solvent in the presence of diethylamine. These products
were subjected for biological and pharmacological evaluation.
Results and discussion
In a preliminary experiment, treatment of 2-thioxothiazolidin-4-
one (1) with benzaldehyde (2) using water–diethylamine at
room temperature for 3 h (TLC control) afforded the (Z)-5-ben-
zylidene-2-thioxothiazolidin-4-one adduct (3a$HNEt
2
).
12
The
Fig. 1 Bioactive compounds containing the rhodanine and thiazoli-
dinedione framework.
5
a
Department of Chemistry, College of Science, King Saud University, P. O. Box 2455,
Riyadh 11451, Saudi Arabia. E-mail: ambarakat@ksu.edu.sa; Fax: +966 1-4675992;
Tel: +966 1-4675884
b
Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426,
Ibrahimia, 21321 Alexandria, Egypt
c
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University,
P. O. Box 2457, Riyadh 11451, Saudi Arabia
† Electronic supplementary information (ESI) available. CCDC 930797, 931815,
930934 and 930932. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c3ra46551a
Cite this: RSC Adv. , 2014, 4, 4909
Received 10th November 2013
Accepted 2nd December 2013
DOI: 10.1039/c3ra46551a
www.rsc.org/advances
This journal is © The Royal Society of Chemistry 2014 RSC Adv. , 2014, 4, 4909–4916 | 4909
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