Sonochemistry: A good, fast and clean method to promote the synthesis of 5-arylidene-2,4-thiazolidinediones

Article abstract of DOI:10.1016/j.ultsonch.2014.04.013

The efficient synthesis of sixteen 5-arylidene-2,4-thiazolidinediones by aldol condensation reaction of 2,4-thiazolidinedione, mono- and di-substituted arenealdehydes and KOH using ultrasound irradiation is reported. The desired compounds were obtained in

Full text of DOI:10.1016/j.ultsonch.2014.04.013

Accepted Manuscript
Short Communication
Sonochemistry: A good, fast and clean method to promote the synthesis of 5-
arylidene-2,4-thiazolidinediones
Bruna B. Drawanz, Camila S. Ribeiro, Hellen G. Masteloto, Patrícia D.
Neuenfeldt, Claudio M.P. Pereira, Geonir M. Siqueira, Wilson Cunico
PII:
S1350-4177(14)00138-2
DOI:
http://dx.doi.org/10.1016/j.ultsonch.2014.04.013
ULTSON 2588
Reference:
Ultrasonics Sonochemistry
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Revised Date:
Accepted Date:
3 May 2013
4 April 2014
22 April 2014
Please cite this article as: B.B. Drawanz, C.S. Ribeiro, H.G. Masteloto, P.D. Neuenfeldt, C.M.P. Pereira, G.M.
Siqueira, W. Cunico, Sonochemistry: A good, fast and clean method to promote the synthesis of 5-arylidene-2,4-
thiazolidinediones, Ultrasonics Sonochemistry (2014), doi: http://dx.doi.org/10.1016/j.ultsonch.2014.04.013
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Sonochemistry: A good, fast and clean method to promote the
synthesis of 5-arylidene-2,4-thiazolidinediones.
Bruna B. Drawanza, Camila S. Ribeiroa, Hellen G. Mastelotoa, Patrícia D. Neuenfeldta,b,
Claudio M.P. Pereirac, Geonir M. Siqueira,a Wilson Cunicoa*
a- Laboratório de Química Aplicada à Bioativos (LaQuiABio), Universidade Federal de Pelotas - UFPel, Campus
Universitário, s/n°, 96010-900 Pelotas, RS, Brazil
b- Laboratório de Estrutura e Atividade (LEAT), Universidade Federal de Santa Catarina- UFSC, Campus Trindade,
s/n, 88040-970 Florianópolis, SC, Brazil
c- Laboratório Heterociclos Bioativos e Bioprospecção- Universidade Federal de Pelotas - UFPel, Campus
Universitário, s/n°, 96010-900 Pelotas, RS, Brazil.
ABSTRACT
The efficient synthesis of sixteen 5-arylidene-2,4-thiazolidinediones by aldol
condensation reaction of 2,4-thiazolidinedione, mono- and di-substituted
arenealdehydes and KOH using ultrasound irradiation is reported. The desired
compounds were obtained in a few min (10-30 min) with moderate to good yields (25-
81%).
Keywords: thiazolidinediones; sonochemistry; aldol condensation
1 INTRODUCTION
Many studies have described the biological properties of 5-arylidene-2,4-
thiazolidinediones [1] such as: anti-inflammatory activity due to the capacity of PPARγ
ligands [2], reduction of retinal neovascularization activity [3], aldose reductase
inhibitor [4,5], anti-inflammatory and antioxidant properties [6] and antifungal action
[7].
With all these promising biological activities, it would be useful if the synthesis
of these compounds were easy, fast and showed goods yields. The literature reports
several methods for the synthesis of 5-arylidene-2,4-thiazolidinediones such as sodium
acetate in acetic acid under reflux conditions [8], KOH and ethanol under reflux [9],
piperidine in ethanol under reflux [10-12], polyethene glycol (PEG-300) under reflux
[13] and ethylenediamine diacetate as catalyst at room temperature [14].

Under all previously mentioned reaction conditions, products were formed after
several hours of reaction. Currently, studies are performed looking for new methods that
facilitate and speed up some reactions. The literature shows the emerging use of
microwave irradiation to promote synthesis, including the synthesis of 5-arylidene-2,4-
thiazolidinediones which takes 10-30 min [15-17].
Likewise, another good possibility is the use of sonochemistry. Ultrasound
irradiation produces the cavitation effect that accelerates some synthetic reactions.
Cavitation is the formation, growth and violent collapse of bubbles in liquid medium
that cause high temperatures and pressures inside the bubbles promoting chemical and
physical transformations by enhancing mass transfer and turbulence in the liquid
[18,19]. Due to this capacity, ultrasound irradiation is used in a great number of
chemical reactions such as: acetylation of alcohols [20], synthesis of stilbenes by Suzuki
cross-coupling [21], synthesis of ketones from aryl tannanes [22] and Michael addition
[23]. The aldol condensation reaction was also reported [24, 25] and provides good
support for performing this work. Our research group also showed the efficiency of
ultrasound energy for the synthesis of thiazolidinones in good yields for 5-35 min [26,
27]. Recently, a few 5-arylidene-2,4-thiazolidinediones were synthesized in good yields
using an ultrasound bath at 80°C for 20 min in the presence of ionic liquids [28],
however, this is the first time that such compounds have been synthesized using the
more efficient ultrasound irradiation by probe.
Therefore, continuing our research program, the aim of this paper is to reduce
the reaction time for the synthesis of 5-arylidene-2,4-thiazolidinediones using the non-
conventional ultrasonic methodology.
2 RESULTS AND DISCUSSION
All compounds were previously published in the literature according to: 3a
[29];3b, 3f, 3j [14]; 3c, 3h, 3i [11]; 3d, 3e, 3k [9];3g [30]; 3l [31]; 3m [32]; 3n [33]; 3o
[34]; 3p [35].
First of all, we synthesized the compound 3c (yield 59%) by reaction of 2,4-
thiazolidinedione 1, 4-methoxybenzaldehyde 2c and KOH (excess) in reflux of ethanol
for 6 hours according to Venkatesan et al. [8]. The study of the conditions for the
synthesis of compound 3c using ultrasound irradiation is summarized in Table 1 and the
progress of reactions was monitored by GC analysis. The reaction carried out only with

ultrasound irradiation did not result in the desired product (Entry 1) and a base was
needed, applying the Knoevenagel condensation. Thus, the reaction with triethylamine
and sodium acetate showed a small amount of 3c (Entry 2-5). The best condition found
was the reaction using excess potassium hydroxide as a base for 20 min (Entry 8). It is
interesting to note that only trace of compound 3c was observed when the reaction was
carried out with refluxing ethanol for 20 min. The formation of product 3c was
confirmed by CG/MS and NMR [36].
Table 1.Study of reaction conditions to synthesis of compound 3c
Equimolar proportion
Time
(min)
30
GC-analysis
(%) 3c
None
Trace
19
Entry
Base
(1:2c:base)
1:1
1
2
3
4
5
6
7
8
9
-
Triethylamine
1:1:1
1:1:2
1:1:1
1:1:2
1:1:1
1:1:2
1:1:2
1:1:3
20
Triethylamine
30
Sodium acetate
20
Trace
Trace
Trace
84
Sodium acetate
20
Potassium hydroxide
Potassium hydroxide
Potassium hydroxide
Potassium hydroxide
15
15
20
100
20
100
Thus, all the compounds 3a-p were synthesized from reaction of 1 mmol of 2,4-
thiazolidinedione 1, 1 mmol of arenealdehyde 2a-p and 2 mmol of potassium hydroxide
(Scheme 1). The reaction times of all arenealdehydes were continuously monitored and
the final times for each of them were shown in Table 2. The crude products were
purified by a simple washing with a hot solution mixture of hexane:ethyl acetate (9:1)
All compounds were obtained from moderate to good yields and were submitted
to GC–MS analysis which proves the aldol condensation, with exception of compound
1
13
3n [37] that was analyzed by H and C NMR due to the fact that it is only soluble in
DMSO. The configuration of 5-arylidene-2,4-thiazolidinediones might be Z according
to previously studies found in the literature [11,17].

Scheme 1.
O
H
O
O
R
S
+
HN
S
i
HN
R
25-81%
O
O
3a-p
1
2a-p
i: KOH, ethanol, ultrasonic irradiation, 10-30 min.

Table 2: Yields and selected physical properties of 5-arylidene-2,4-thiazolidinediones 3a-p synthesized by ultrasonic methodology.
Comp.
3a
3b
3c
R
Time (min) m.p. (C)a Yield (%)b
GC–MS analysis m/z (%)
2-OCH3
3-OCH3
4-OCH3
2-Cl
15
15
20
30
15
15
15
15
10
15
15
20
10
15
15
10
235-237
195-196
205-207
217-220
211-213
228-230
194-196
167-169
214-215
225-226
239-240
163-165
241-243
147-149
147-149
148-150
51
65
34
43
81
72
50
62
54
40
25
51
69
58
79
80
235 (M+, 65), 164 (100), 149 (45), 121 (40), 77 (35).
235 (M+, 40), 164 (100), 134 (15), 121 (20), 77 (20).
235 (M+, 35), 164 (100), 149 (60), 121 (25), 77 (27).
239 (M+, 15), 204 (90), 168 (100), 133 (30), 89 (45).
239 (M+, 30), 168 (100), 133 (20), 89 (35), 84 (15).
239 (M+, 25), 168 (100), 133 (20), 84 (15), 66 (10).
223 (M+, 20), 180 (10), 152 (100), 107 (20), 76 (15).
223 (M+, 28), 152 (100), 107 (20), 76 (15), 69 (10).
223 (M+, 20), 152 (100), 107 (20), 76 (15), 69 (5).
219 (M+, 35), 148 (100), 115 (15), 91 (15), 74 (15).
221 (M+, 30), 150 (100), 121 (25), 77 (15), 39 (10).
235 (M+ - OCH3, 45), 164 (100), 149 (60), 121 (25), 77 (20).
3d
3e
3-Cl
3f
4-Cl
2-F
3g
3h
3i
3-F
4-F
4-CH3
3-OH
3j
3k
3l
2,3-OCH3
2,4-OCH3
2,5-OCH3
2,6-Cl
2-Cl, 6-F
265 (M+, 4), 235 (50), 164 (100), 149 (40), 121 (20), 77 (37).
3m
3n
3o
3p
c
273 (M+, 10), 238 (100), 202 (80), 167 (30), 123 (30), 101 (20).
257 (M+, 15), 222 (90), 186 (100), 151 (25), 93 (30).
a - melting points are uncorrected; b - yields of isolated compounds; c - not determined because it is only soluble in DMSO.

We tried to obtain the 5-arylidene-2,4-thiazolidinediones from there action of
electron-withdrawn nitrobenzaldehydes (orto, meta and para), however to our surprise
we only identified the starting materials by CG analysis. Furthermore, these reactions
produce an emulsion that can be harmful to ultrasound equipment.
3 EXPERIMENTAL
All common reagents and solvents were used as obtained from commercial
suppliers without further purification. The reactions were carried out with a microtip
probe (3 mm) connected to a 500W Sonics Vibra-cell ultrasonic processor operating at
20 kHz at 25% of the maximum power output. The progress of reactions was monitored
by TLC and by a Shimadzu Gas Chromatograph GC-2010, Column I.D., 0.25 mm;
Columnlength, 30 m; Column Head Pressure, 14 psi, program: T0 = 50 °C; t0 = 2.0 min;
rate 16.0 °C/min; Tf = 250 °C; tf = 10.0 min; Inj. = 250 °C; Det. = 270 °C. Melting
points were determined using open capillaries on a Fisatom model 430 apparatus and
are uncorrected. GC–MS analyses were performed on a GC 2010-plus GC–MS-
1 13
QP2010SE System AOC-20i – auto injector. H and C NMR spectra were recorded
using a Bruker Ac-200F spectrometer (1H at 200MHz and 13C at 50 MHz) in DMSO.
3.1 General procedure for the preparation of 5-arylidene-2,4-thiazolidinediones 3a-p.
A mixture of 2,4-thiazolidinedione 1 (1 mmol), corresponding arenealdehyde
2a-p (1 mmol) and 2 or 3 mmol KOH in ethanol (10 mL) were placed in a 25 mL
beaker. The reaction mixture was then sonicated by an ultrasonic probe with a
frequency of 24 kHz at room temperature from 10 to 30 min according to
arenealdehyde. After reaction time, the solvent was evaporated, the resultant solid was
neutralized with solution of HCl 1 mol/L and filtrated under reduced pressure. When
necessary, the compounds were washed with a hot solution of hexane:ethyl acetate (9:1)
to supply the pure products (3a, 3l, 3n and 3o).
4 CONCLUSIONS
In summary, ultrasound irradiation is an excellent method to promote the clean
and fast synthesis of sixteen 5-arylidene-2,4-thiazolidinediones in moderate to good
yields, in some cases without any further purification. This methodology reduces the
amount of solvent and diminishes the reaction time.

5 ACKNOWLEDGMENTS
The authors thank CNPq, CAPES and FAPERGS for the financial support. We
also thank Ms. Hedy Hofmann for the English correction.
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3
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and vinylic); 55.9 (OCH3); 55.4 (OCH3).

Universidade Federal de Pelotas
Centro de Ciências Químicas, Farmacêuticas e de Alimentos
Sonochemistry: A good, fast and clean method to promote the
synthesis of 5-arylidene-2,4-thiazolidinediones.
Bruna B. Drawanza, Camila S. Ribeiroa, Hellen G. Mastelotoa, Patrícia D. Neuenfeldta,b,
Claudio M.P. Pereirac, Geonir M. Siqueira,a Wilson Cunicoa*
> Sixteen 5-arylidene-2,4-thiazolidinediones were synthesized by ultrasound
irradiation> The desire products were obtained in short reaction times (10-30 min)>
Ultrasound irradiation is efficient to aldol condensation reaction.