Facile and regioselective synthesis of thiazolidin-4-one derivatives catalyzed by basic ionic liquid [bmim]OH under ultrasonic irradiation

Article abstract of DOI:10.1080/17415993.2013.800061

2-Iminothiazolidin-4-one derivatives were synthesized regioselectively in good to high yields by condensation of N,N-disubstituted thioureas and ethyl chloroacetate in the presence of basic ionic liquid [bmim]OH as a catalyst under conventional and ultrasonic irradiation conditions. Under ultrasonic irradiation, the reaction furnished the desired 2-iminothiazolidinones in higher yields (76-87%) and lower reaction times (30-55 min).

Full text of DOI:10.1080/17415993.2013.800061

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Facile and regioselective synthesis of
thiazolidin-4-one derivatives catalyzed
by basic ionic liquid [bmim]OH under
ultrasonic irradiation
Manouchehr Mamaghani a , Mozhgan Pourranjbar a & Roghayeh
Hossein Nia a
a Department of Chemistry, Faculty of Sciences , University of
Guilan , PO Box 41335-1914, Rasht , Iran
Published online: 08 Jun 2013.
To cite this article: Manouchehr Mamaghani , Mozhgan Pourranjbar & Roghayeh Hossein
Nia (2013): Facile and regioselective synthesis of thiazolidin-4-one derivatives catalyzed
by basic ionic liquid [bmim]OH under ultrasonic irradiation, Journal of Sulfur Chemistry,
DOI:10.1080/17415993.2013.800061
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Journal of Sulfur Chemistry, 2013
http://dx.doi.org/10.1080/17415993.2013.800061
SHORT COMMUNICATION
Facile and regioselective synthesis of thiazolidin-4-one
derivatives catalyzed by basic ionic liquid [bmim]OH under
ultrasonic irradiation
Manouchehr Mamaghani*, Mozhgan Pourranjbar and Roghayeh Hossein Nia
Department of Chemistry, Faculty of Sciences, University of Guilan, PO Box 41335-1914, Rasht, Iran
(Received 7 December 2012; final version received 24 April 2013)
2-Iminothiazolidin-4-one derivatives were synthesized regioselectively in good to high yields by condensa-
tion of N,N-disubstituted thioureas and ethyl chloroacetate in the presence of basic ionic liquid [bmim]OH
as a catalyst under conventional and ultrasonic irradiation conditions. Under ultrasonic irradiation, the
reaction furnished the desired 2-iminothiazolidinones in higher yields (76–87%) and lower reaction times
(30–55 min).
Keywords: regioselective; ionic liquid [bmim]OH; thiazolidin-4-one; ultrasound, thiourea
1. Introduction
Thiazolidinones (TZDs) and their derivatives are an important group of heterocyclic compounds,
having valuable biological activities in the areas of medicine and agriculture (1). They have
found uses, for example, as insecticides, tuberculostatic (2), anti-inflammatory (3) and antiviral
agents (4). In recent years, 4-thiazolidinones are among the most extensively investigated hete-
rocycles. TZDs have been the subject of extensive researches because of their deep involvement
in the regulation of different physiological processes. Thiazolidinedione derivatives have been
shown to possess potent immunostimulatory property, anti-arthritic activity as well as oncostatic
activity (5). TZDs such as troglitazone, pioglitazone and rosiglitazone are potent reducers of
*Corresponding author. Email: mchem41@gmail.com; m-chem41@guilan.ac.ir
© 2013 Taylor & Francis

2
M. Mamaghani et al.
plasma glucose level in vivo. Besides their anti-diabetic potency, these compounds have been
shown to exert anti-inflammatory effects on vascular cells (6). TZDs were also found to inhibit
the production of inflammatory cytokines and the expression of inducible nitric oxide syntheses
in monocytes/macrophages (7, 8). In addition, the potent activity of 2-imino-4-thiazolidinones
has established them as important structure elements in medicinal chemistry (9–13). These prod-
ucts have demonstrated significant antiviral, pesticidal, bactericidal, insecticidal, antiproliferative,
antihistaminic, fungicidal, tuberculostatic, anticonvulsant, anticancer, anti-inflammatory, Ca2+
antagonist, SHP-2 inhibitor and PTC readthrough activities (14–20).
Several synthetic methods have been reported for the synthesis of 2-imino-4-thiazolidinones
(21–25). However, some of these methods use expensive starting materials, harsh reaction condi-
tions, long reaction times and low yields. Therefore, the development of an efficient and versatile
method is still required.
On the other hand, ionic liquids have attracted extensive interest as environmentally friendly
catalysts as well as excellent alternatives to organic solvents, due to their favorable properties. The
use of ionic liquids as the reaction medium may offer a convenient solution to both the solvent
emission and the catalytic recycling problem and results in minimal pollution and waste material
production (26–30).
These observationsled usto attemptthesynthesisof somenew2-iminothiazolidin-4-onederiva-
tives using of N,N-disubstituted thioureas and ethyl chloroacetate in the presence of basic ionic
liquid [bmim]OH as a catalyst under conventional and ultrasonic irradiation conditions.
2. Results and discussion
As part of our program aimed at developing highly expedient, selective and environmentally
friendly methodologies for the preparation of heterocyclic compounds (31), we describe here an
efficient method for the regioselective synthesis of new derivatives of thiazolidin-4-one under con-
ventional conditions and ultrasounic irradiations in the presence of basic ionic liquid [bmim]OH
as a catalyst.
The requisite disubstituted thioureas (1) were prepared by the addition of amines to N-
substituted isothiocyanates in CHCl3 at room temperature. Stirring a mixture of equimolar
amounts of 1 and ethyl chloroacetate in CHCl3 in the presence of ionic liquid [bmim]OH
(0.15 g/1 mmol substrate) at room temperature afforded derivatives of thiazolidin-4-one 3a–j
in a regioslective cyclization reaction (Scheme 1).
Scheme 1. Schematic diagram showing the synthesis of thiazolidin-4-one 3a–j.
To optimize the reaction conditions, preparation of 3a as a model reaction was attempted in
several solvents (1,4-dioxane, H2O, EtOH, THF) and catalysts (Et3N, DBU, pipyridine, l-prolin,
NaHCO3, AcOH) (Tables 1 and 2). The best results (73% yield) were obtained when ionic liquid

Journal of Sulfur Chemistry
3
Table 1. Effect of various catalysts in the synthesis of 3a.
Entry
Catalyst
Yield (%)a
1
2
3
4
5
6
DBU
60
73
45
40
40
15
Ionic liquid [bmim]OH
l-Proline
NaHCO3
Et3N
Piperidine
Note: aIsolated yield.
Table 2. Effect of various solvents in the synthesis of 3a.
Entry
Solvent
H2O
CHCl3
1,4-dioxane
THF
Yield (%)a
1
2
3
4
5
0
73
45
55
20
EtOH
Note: aIsolated yield.
[bmim]OH was used as a catalyst in CHCl3 after 24 h stirring at room temperature (Tables 2
and 3). We also verified the amount of catalyst in the preparation of 3a in CHCl3 and the best
result was obtained using 0.15 g ionic liquid [bmim]OH for 1 mmol substrate.
Table 3. Synthesis of products (3a–j).
Conventionala
Yield(%)a,b Yield (%)b Time (min)
Ultrasound
Entry
Product
Thiourea
S
3a
73
79
80
78
81
87
50
55
O
N
S
HN
NH
N
O
S
N
3b
3c
HN
NH
S
N
O
30
S
N
HN
NH
N
S
(Continued)

4
M. Mamaghani et al.
Table 3. Continued
Conventionala
Yield(%)a,b Yield (%)b Time (min)
Ultrasound
Entry
Product
Thiourea
O
3d
76
75
78
74
80
80
82
78
40
45
45
40
S
N
HN
NH
N
S
S
O
3e
3f
HN
NH
N
N
S
S
O
HN
NH
N
N
S
S
O
3g
O
O
HN
NH
N
N
S
O
O
S
3h
3i
72
80
83
76
86
85
45
40
35
N
N
O
HN
NH
S
O
S
N
HN
NH
N
S
F
O
S
3j
N
N
F
HN
NH
S
Notes: aReaction time 24 h at room temperature.
bIsolated yield.
Recently, there has been an increasing interest in using ultrasonic irradiations as a clean, green
and environmentally benign source of energy for the preparation of organic compounds of syn-
thetic and biological value (32). Encouraged further by our recent findings in facilitating the

Journal of Sulfur Chemistry
5
synthesis of important heterocyclic compounds by exploiting ultrasound methodology (31a, b),
we investigated the effect of ultrasonic irradiation on the synthesis of novel thiazolidin-4-one
3a–j. Therefore, an equimolar mixture of reactants 1 and 2 in the presence of basic ionic liq-
uid [bmim]OH (33, 34) (0.15 g/mmol substrate) in CHCl3 (5 ml) was placed in a Pyrex-glass
open vessel and irradiated at room temperature by ultrasonic irradiations (40 kHz) to furnish the
desired products (3a–j) in lower reaction times (30–55 min) and in good to high yields (76–87%)
(Table 3).
For unsymmetrical thioureas, regiocontrol in cyclization step is typically influenced by
electronic factors that predispose electron-withdrawing substituents to maintain conjugative sta-
bilization with imine nitrogen (R1 in structure 3). For example, in the case of 3c–j, the NH proton
flanked by a phenyl moiety is more acidic compared to the other NH proton flanked by benzyl or
allyl moiety; therefore, enolization of thiourea from the phenyl side of the substrate is facilitated.
This allows regioselective cyclization of thiourea bearing one alkyl and one aryl substituent (21).
A plausible mechanism for the formation of 3a–j is outlined in Scheme 2. The formation of
these products can be visualized by addition of ionic liquid [bmim]OH as a base catalyst and
producing intermediate 4 which then cyclizes and loses EtOH to furnish the desired thiazolidin-
4-one 3a–j.
Scheme 2. Mechanism of synthesis of products 3a–j.
3. Conclusion
In conclusion, we have developed a simple and efficient protocol for the synthesis of novel deriva-
tives of thiazolidin-4-one catalyzed by ionic liquid [bmim]OH 3a–j in a regiochemical manner at
room temperature under ultrasonic irradiations and conventional conditions. The reaction induced
by ultrasound offered better yields and much lower reaction times than the reaction carried out by
conventional heating. This method involves mild reaction conditions, easy work-up and cleaner
reaction profiles.
Acknowledgement
The authors are grateful to the Research Council of University of Guilan for the financial support of this research work.
Supporting information available
Supporting information is available on the publisher’s website at http://dx.doi.org/10.1080/17415993.2013.800061

6
M. Mamaghani et al.
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