Urea/thiourea catalyzed, solvent-free synthesis of 5-arylidenethiazolidine- 2,4-diones and 5-arylidene-2-thioxothiazolidin-4-ones

Article abstract of DOI:10.1016/j.bmcl.2012.07.049

An efficient and organo-catalyzed method has been developed for the synthesis of 5-arylidenethiazolidine-2,4-diones and 5-arylidene-2- thioxothiazolidin-4-ones via Knoevenagel condensation of arylaldehydes 1 and 2,4-thiazolidinedione 2a/2-thioxothiazolidin-4-one 2b under mild conditions. Urea-adduct 4 and azomethine 5 also afford arylidene-products 3 by reacting with 2a-b via addition-elimination reaction. This protocol has the features of use of inexpensive, ecofriendly readily available, effective catalyst system viz. urea/thiourea, avoidance of volatile solvents, excellent yield and simple work-up procedure.

Full text of DOI:10.1016/j.bmcl.2012.07.049

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5388–5391
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Urea/thiourea catalyzed, solvent-free synthesis of 5-arylidenethiazolidine-
2,4-diones and 5-arylidene-2-thioxothiazolidin-4-ones
⇑
Sakshi Shah , Baldev Singh
Department of Chemistry, Punjabi University, Patiala 147002, Punjab, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and organo-catalyzed method has been developed for the synthesis of 5-arylidenethiazoli-
dine-2,4-diones and 5-arylidene-2-thioxothiazolidin-4-ones via Knoevenagel condensation of arylalde-
hydes 1 and 2,4-thiazolidinedione 2a/2-thioxothiazolidin-4-one 2b under mild conditions. Urea-adduct
4 and azomethine 5 also afford arylidene-products 3 by reacting with 2a–b via addition–elimination
reaction. This protocol has the features of use of inexpensive, ecofriendly readily available, effective cat-
alyst system viz. urea/thiourea, avoidance of volatile solvents, excellent yield and simple work-up
procedure.
Received 10 June 2012
Revised 10 July 2012
Accepted 12 July 2012
Available online 24 July 2012
Keywords:
5-Arylidenethiazolidine-2,4-diones
5-Arylidene-2-thioxothiazolidin-4-ones
Urea/thiourea
Ó 2012 Elsevier Ltd. All rights reserved.
Knoevenagel condensation
Solvent-free
Organocatalyst
Thiazolidines particularly thiazolidine-2,4-dione and 2-thioxo-
thiazolidin-4-one acquired much importance because of their
miscellaneous pharmacological activities such as antidiabetic,1
antimicrobial,2 antimalarials,3 antiviral,4 anticonvulsant,5 anti-
inflammatory6 and also act as thyroid hormone receptor antago-
nists.7 Additionally, these derivatives have been popular as small
molecule inhibitors of numerous targets such as 15-hydroxypro-
staglandin dehydrogenase (15-PGDH),8 HIV-1,9 aldose reductase,10
tyrosinase.11 Further, 5-arylidenethiazolidine-2,4-dione as well as
5-arylidene-2-thioxothiazolidin-4-one have been explored with
significant pharmacological activities such as antidiabetic,12 anti-
oxidant,13 cardiotonic,14 anti-inflammatory,15 anti-cancer16 and
also inhibits several targets such as HCV protease,17 b-lactamase,18
JNK-stimulating phosphatase-1 (JSP-1),19 aldose reductase inhibi-
tor,20 tyrosine phosphatases inhibitor,21 PMT1 mannosyl transfer-
ase inhibitor.22 In addition, 5-arylidenethiazolidine-2,4-diones
has substantial anti-proliferative effect on vascular smooth mus-
cle.23 Because of these prominent biological properties, synthetic
manipulations/developments on these molecules have been an
area of current interest for chemists as well as biologists.
5-benzylidenethiazolidine-2,4-diones and 5-benzylidene-2-thi-
oxothiazolidin-4-ones several protocols have been reported
employing different catalysts systems/reaction conditions such as
baker’s yeast,24 [bmim][OH],25 piperidine,26 tetrabutylammonium
bromide (TBAB),27 sodium acetate28,29 and piperidinium benzo-
ate.30 The use of microwave irradiation has also been employed
with solid inorganic support (Al2O3 or KSF) in a domestic micro-
wave oven.31 However, above reported methods suffer from one
or more drawbacks like prolonged reaction times, use of environ-
mentally unfavorable solvents and frequently with low yields.
Therefore, to overcome these difficulties the development of new
methodology in current organic synthesis mainly focused on Green
Chemistry principles is an important goal toward sustainable fu-
ture. Thus, we decided to explore the capability of our clean and
inexpensive catalysts system to perform these types of condensa-
tion reactions. During the last few years interest in the field of
organocatalysis32,33 has increased enormously. Urea/Thiourea and
its derivatives are one of the most promising catalyst attaining im-
mense significance in popular organic reactions.34–37 We herein re-
port the environmentally friendly, highly efficient and selective
method for the synthesis of Knoevenagel products of thiazoli-
dine-2,4-dione/2-thioxothiazolidin-4-one using urea/thiourea as
a catalyst in solid state.
5-Benzylidenethiazolidine-2,4-diones and 5-benzylidene-2-
thioxothiazolidin-4-ones have been synthesized preferentially via
Knoevenagel condensation of aromatic aldehydes with thiazoli-
dine-2,4-dione/2-thioxothiazolidin-4-one rather than employing
Perkin reaction conditions. For facile and efficient production of
Initially, we reacted benzaldehyde 1a (1.0 mmol) with thiazoli-
dine-2,4-dione 2a (1.0 mmol) in solid state at 110 °C in different
catalysts to optimize the reaction conditions to access 3a (Table 1)
with excellent yield and in possible shortest reaction time. When
the reaction was performed using urea or thiourea as catalyst,
⇑
Corresponding author.
E-mail address: sakshishah29@gmail.com (S. Shah).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.07.049

S. Shah, B. Singh / Bioorg. Med. Chem. Lett. 22 (2012) 5388–5391
5389
Table 1
Table 2
Condensation of 2,4-thiazolidinediones 2a and benzaldehyde 1a in presence of
Knoevenagel condensation of thiazolidines 2a–b and aldehydes in presence of
organocatalyst
different catalystsa
Entry
Catalyst
Mol%
Yieldb
Entry Aldehyde R
Thiazolidine
X
Producta Reaction
time (min)
Yieldb
1
2
3
4
5
6
7
No catalyst
Urea
Thiourea
Oxalic acid
FeCl3
—
—
10
10
10
10
10
10
94
94
80
92
88
90
1.
2.
1a
1c
O
O
3a
3b
5
8
98
(92)c
91
(90)c
93
LiBr
BiCl3
3.
4.
5.
6.
7.
1d
1e
1f
1g
1i
O
O
O
O
O
3c
3d
3e
3f
10
12
15
8
92
94
95
a
Reaction conditions: 1a (1 mmol), 2a (1 mmol), catalysts (10 mol %) heated at
110 °C on oil bath for 10 min.
3g
7
94
b
(91)c
95
Isolated yield.
8.
9.
1j
1l
O
O
3h
3i
10
12
92
(89)c
90
10.
11.
12.
13.
1n
1o
1p
O
O
O
O
3j
3k
3l
15
15
12
10
X
91
92
O
O
H2N
NH2
2-Furaldehyde
3m
90
CHO
(87)c
89
HN
solvent-free
NH
14.
15.
16.
Napthaldehyde
1a
1b
O
S
S
3n
3o
3p
9
5
6
S
S
O
110°C, 5 min
>99
95
O
2a
1a
3a
(93)c
93
17.
18.
1d
1e
S
S
3q
3r
7
8
Scheme 1. Synthesis of 5-benzylidenethiazolidine-2,4-diones in solid state.
94
(90)c
96
19.
1g
S
3s
5
(92)c
95
product 3a was formed in excellent yield that is 98% in 5 min only
(Scheme 1).38 To illustrate the need of urea for this condensation
we examined the reaction of benzaldehyde 1a and thiazolidine-
2,4-dione 2a in the absence of urea/thiourea. In this case the
reaction did not proceed even after 2 h (Table 1, entry 1). Different
catalysts such as oxalic acid, FeCl3, LiBr, BiCl3 (Table 1, entry 4–7)
were also tested under solvent-free conditions, but the best results
were found in case of urea and thiourea (Table 1, entry 2, 3). Both
catalysts urea and thiourea were found equally effective to catalyse
this Knoevenagel reaction.
20.
21.
22.
1h
1i
1j
S
S
S
3t
3u
3v
5
5
5
95
96
(93)c
92
23.
24.
25.
1k
1m
1p
S
S
S
3w
3x
3y
8
6
7
90
90
(86)c
93
26.
27.
28.
2-Furaldehyde
cinnamaldehyde
2-Thiophene
S
S
S
3z
3aa
3ab
5
6
8
91
94
carbaldehyde
These condensation reactions proceeded efficiently at 110 °C tem-
perature in 5–15 min and no undesired side product was observed.
This method is equally effective with aldehydes bearing electron
donating 1b–f, 1j, 1n–o as well as electron withdrawing substituents
1g–i, 1k–m, 1p in the aromatic ring (Table 2, Scheme 2). Moreover,
heterocyclic and conjugated aldehydes such as 2-furaldehyde,
napthaldehyde, cinnamaldehyde and 2-thiophenecarbaldehyde
(Entry 13, 14, 26–28) worked well without any decomposition/
by-products formation under these reaction conditions.
Further, to investigate the formation of Biginelli and Biginelli-
like (spiro-products) as obtained in case of other five or six mem-
bered active methylene heterocyclic compounds39–44 a set of
reactions was carried out, firstly a three component reaction of
1c (1 mmol), urea/thiourea (1 mmol) and 2,4-thiazolidinedione
(1 mmol) 2a was carried in solvent-free reaction conditions at
110 °C with catalyst (acetic acid 10 mol %)/without catalyst
(Scheme 3) but only Knoevenagel product that is 5-benzylidene-
thiazolidine-2,4-dione 3b was obtained with 90% yield (Table 2)
rather than the Biginelli product. Under identical reaction condi-
tions, when a mixture of urea/thiourea adduct 4 (1 mmol) or azo-
methine 5 (1 mmol) and 2,4-thiazolidinedione (1 mmol) 2a was
reacted, again addition–elimination product 3 was obtained with
comparable yield without formation of pyrimidine/pyridine ring
(Scheme 3, Table 3, Entry 1, 2, 5, 6).
a
Reaction conditions: 1a–p (1 mmol), 2a–b (1 mmol) and urea/thiourea
(10 mol%) heated at 110 °C on oil bath.
b
Isolated yield.
c
Reaction conditions: aldehyde (1 mmol), 2a–b (1 mmol) and urea/thiourea
(1 mmol) heated at 110 °C on oil bath.
X
X=O, S
NH2
O
O
H2N
R
R
CHO
HN
solvent-free
NH
S
S
X
110°C, 5-15 min
X
2a-b
2a: X=O, 2b: X=S
1a-e
3a-ab
1a:
1b: 1c:
1d:
R=3-CH3; R=4-OCH3;
R=H;
R=4-CH3;
1e: R=4-OH; 1f: R=2-OH; 1g: R=4-Cl; 1h: R=4-Br;
1i: 1j: 1k: 1l:
R=3-NO2;
R=4-CF3;
R=4-N(CH3)2;
R=4-NO2;
1m: R=2-Cl; 1n: R=3-OCH3,4-OH; 1o: R=2,4-(OH)2; 1p: R=2,4-(Cl)2.
Scheme 2. Urea/thiourea catalyzed synthesis of Knoevenagel products.
Conclusively, urea and thiourea both acts as catalyst not as
reactant and in this endeavor we optimised the amount of catalyst
by performing a set of reaction employing different amount of cat-
alyst (80, 50, 20, 10, and 5 mol %) and it was found that only 10
mole% amount was sufficient to afford corresponding Knoevenagel
products in excellent yields.
In another set of three component reaction of urea adduct 4
(1 mmol) or azomethine 5 (1 mmol), 1d/1g (1 mmol) and 2a–b
(1 mmol), similar products 3 (as mixture, Scheme 4) were obtained
in similar fashion, in spite of spiro-Biginelli/pyridine-1ike products
(Scheme 4, Table 3, Entry 3, 4, 7, 8).

5390
S. Shah, B. Singh / Bioorg. Med. Chem. Lett. 22 (2012) 5388–5391
R
X
CHO
O
H2N
X
NH2
HN
O
1
R
S
2a-b
X
R
R
NH
S
N
NH2
solvent-free
110°C
X
4
3
N
5
Scheme 3. Synthesis of 5-arylidene-2,4-thiazolidinedione via Knoevenagel/addition–elimination.
Table 3
Synthesis of 5-arylidene thiazolidines via addition–elimination
Entry
R
Adduct
Thiazolidines X
Producta
Reaction time (min)
Yieldb
1
2
3
4
5
6
7
8
1c
1i
4
5
4
5
4
5
4
5
O
O
O
O
S
S
S
S
3b
3g
3a + 3c
3a + 3f
3p
3t
3o + 3q
3o + 3s
9
8
10
12
7
8
10
10
89
90
48 + 39
43 + 45
92
91
49 + 40
44 + 49
1d
1g
1b
1h
1d
1g
a
Reaction conditions: 1 (1 mmol) + adduct 4, 5 (1 mmol)/adduct 4, 5 (1 mmol) and 2a–b (1 mmol) heated at 110 °C on oil bath.
Isolated yield.
b
X
O
Biginelli-Like or
Pyridine
1d or 1g
N
NH2
HN
4
S
X
2a-b
solvent-free
110°C
3a + 3c,
3a + 3f,
3o + 3q,
3o + 3s.
N
1d or 1g
5
Scheme 4. Obtained 5-arylidene-2,4-thiazolidinedione not Biginelli-type or pyridine like.
Table 4
the use of these solvents should be avoided as they are volatile
in nature and also require tedious work-up. Therefore, by employ-
ing the optimized conditions condensation of 1a–p (1 mmol), 2a–b
(1 mmol) using 10 mol % urea/thiourea as catalyst in solvent-free
media at 110 °C provide variously substituted 5-benzylidenethiaz-
olidine-2,4-dione 3a–ab in excellent yields.
As far as role of catalyst is concern, it forms a cyclic intermedi-
ate I via electronegative pull of active hydrogen of 2 by nitrogen
atom of catalyst and facilitate the nucleophilic attack of 2 on car-
bonyl carbon of 1 (Scheme 5). In results, intermediate II and III
are obtained and last step afford product 3 with dehydration and
regeneration of catalyst.
Condensation of 2,4-thiazolidinediones and benzaldehyde in presence of different
solventsa
Entry
Solvent
Time (min)
Yieldb
1
2
3
4
5
No solvent
EtOH
MeCN
EtCOCH3
CHCl3
10
20
20
90
75
96
85
80
80
55
a
Reaction conditions: 1a (1 mmol), 2a (1 mmol) and urea/thiourea (10 mol%) in
solvents/solvent-free at 110 °C on oil bath.
b
Isolated yield.
It is worth mentioning that for the first time the use of urea/
thiourea as organo-catalyst in Knoevenagel reaction of arylalde-
hyde and thiazolidine-2,4-dione/2-thioxothiazolidin-4-one has
proven as good and effective catalyst. This method is equally
effective with aldehydes bearing electron withdrawing as well as
electron donating substituents in the aromatic ring. Urea-adduct
and azomethines also provide arylidene-products via simple
addition–elimination with comparable yields. The advantage of
this method is that it involves mild reaction condition, simplicity
Furthermore screening of reaction solvents including acetoni-
trile, ethanol, ethyl acetate and chloroform has also been done
but it was found that difference was minimal when the reaction
was carried out in presence of solvent (EtOH, CH3CN) or without
solvent (Table 4, entry 1, 2,3). However, the same reaction in other
solvents did not give satisfactory results even after longer reaction
time. (Table 4, entry 5). The results showed that impact of these
solvents on reaction rate and yields was nearly superfluous so

S. Shah, B. Singh / Bioorg. Med. Chem. Lett. 22 (2012) 5388–5391
5391
X
X
X
X
H2N
O
NH3
O
O
H2N
NH2
H
II
H2N
NH3
H2N
NH2
H
H
O
O
S
OH
O
H
S
HN
NH
X
X
S
NH
NH
X
I
S
3
X
III
Scheme 5. Plausible mechanism of urea/thiourea catalyzed Knoevenagel reaction.
26. Safonov, I. G.; Heerding, D. A.; Keenan, R. M.; Price, A. T.; Erickson-Muller, C. L.;
Hopson, C. B.; Levin, J. L.; Lord, K. A.; Tapley, P. M. Bioorg. Med. Chem. Lett. 2006,
16, 1212.
of the experimental procedure, avoidance of toxic, moisture sensi-
tive catalysts and volatile solvents. Also no hazardous by-products
are formed during reaction work-up.
27. Zhou, J. F.; Zhu, F. X.; Song, Y. Z.; Zhu, Y. L. Arkivoc 2006, 14, 175.
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Acknowledgements
The authors are thankful to the University Grant Commission
(UGC) New Delhi, for financial assistance and Sophisticated Analyt-
ical Instrumentation Facility (SAIF) Panjab University, Chandigarh
for spectral analysis.
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arylidene-2-thioxothiazolidin-4-ones:
A mixture of aldehyde (1 mmol), 2,4-
thiazolidinediones/2-thioxothiazolidin-4-ones (1 mmol) using 10 mol % urea/
thiourea as catalyst was condensed at 110 °C on oil bath under solvent-free
reaction conditions. After completion of the reaction as indicated by TLC, the
crude product was cooled, washed with water (10 mL), filtered and
recrystallization from ethanol: DMF to afford 3a–ab.
General procedure for the Synthesis of 3 via addition–elimination reaction: A
mixture of urea-adduct
4 (1 mmol)/azomethine 5 (1 mmol) and 2,4-
thiazolidinediones/2-thioxothiazolidin-4-ones (1 mmol) was heated at 110 °C
on oil bath. Reaction progress was monitored by TLC, after reaction completion
crude product was cooled, washed with water (10 mL), filtered and
recrystallization from ethanol: DMF to afford 3a–ab.
The physical data of known compounds were found to be identical with those
28–31
reported in the literature.
provided below.
The Spectral data for selected products are
5-benzylidene-2,4 –thiazolidinedione (Table 2, entry 1): 1H NMR (DMSO-d6,
400 MHz, ppm): d = 12.66 (s, 1H), 7.80 (s, 1H), 7.69–7.64 (m, 5H); 13C NMR
(DMSO-d6, 125 MHz, ppm): d = 114.8, 128.4, 131.7, 132.3, 132.6, 133. 8, 135.5,
171.4, 173.5 (C@O).
5-(4-Methoxybenzylidene)-2,4–thiazolidinedione (Table 2, entry 3): 1H NMR
(DMSO-d6, 400 MHz, ppm): d = 12.51 (s, 1H), 7.76 (s, 1H), 7.69–7.54 (m, 4H),
3,75 (s, 3H); 13C NMR (DMSO-d6, 125 MHz, ppm): d = 55.5, 116.8, 129.3, 131.5,
132.8, 133.6, 134.8, 135.5, 171.2, 173.7 (C@O).
5-(4-Chlorobenzylidene)-4-thioxo-thiazolidine-2-one (Table 2, entry 19): 1H NMR
(DMSO-d6, 400 MHz, ppm): d = 13.86 (s, 1H, NH); 8.12 (s, 1H); 7.69–7.57 (m,
4H); 13C NMR (DMSO-d6, 125 MHz, ppm): d = 129.5, 131.28, 132.8, 1334.3,
134.3, 135.0, 171.3, (C@O), 195. 9 (C@S).
5-(4-Bromobenzylidene)-4-thioxo-thiazolidine-2-one (Table 2, entry 20) 1H NMR
(DMSO-d6, 400 MHz, ppm): d = 13.55 (s, 1H), 8.09 (s, 1H), 7.88–7.63 (m, 4H);
13C NMR (DMSO-d6, 125 MHz, ppm): d = 127.1, 131.8, 132.8, 133.7, 133.8134.8,
134.7, 135.9; 171.0 (C@O), 196.2 (C@S).
5-(2,4-Dichlorobenzylidene)-4-thioxo-thiazolidine-2-one (Table 2, entry 25): 1H
NMR (DMSO-d6, 400 MHz, ppm): d = 13.67 (s, 1H), d = 8.30 (s, 1H), 7.85–7.66
(m, 3H); 13C NMR (DMSO-d6, 125 MHz, ppm): d = 129. 3, 130.5, 131.8, 132.1,
133.7, 134.9, 137.1, 138.7; 171.4 (C@O); 196.5 (C@S).
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