Dicationic ionic liquid mediated synthesis of 5-arylidine-2,4- thiazolidinediones

Article abstract of DOI:10.1002/cjoc.201190192

An efficient synthesis of 5-arylidine-2,4-thiazolidinediones has been developed using dicationic ionic liquid as green medium and catalyst. This method performed well for the condensation of both aryl as well as heteryl aldehydes with 2,4-thiazolidinedion

Full text of DOI:10.1002/cjoc.201190192

FULL PAPER
Dicationic Ionic Liquid Mediated Synthesis of 5-Arylidine-
2,4-thiazolidinediones
Jawale, Dhanaji V.
Pratap, Umesh R.
Lingampalle, Dinesh L.
Mane, Ramrao A.*
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431004,
Maharashtra, India
An efficient synthesis of 5-arylidine-2,4-thiazolidinediones has been developed using dicationic ionic liquid as
green medium and catalyst. This method performed well for the condensation of both aryl as well as heteryl alde-
hydes with 2,4-thiazolidinedione and gave 5-arylidine-2,4-thiazolidinediones with excellent yields.
Keywords 2,4-thiazolidinedione, dicationic ionic liquid, type 2 diabetes mellitus, Knoevenagel condensation,
sulfur heterocycles, aldehydes
Introduction
2,4-Thiazolidinedione and its derivatives elicit broad
spectrum of applications in the field of medicinal chem-
istry.1 Type 2 diabetes mellitus has been revolutionized
with the advent of 2,4-thiazolidinedione (TZD’s) class
of molecule that ameliorates insulin resistance and
thereby normalize elevated blood glucose, lipid and in-
sulin levels in rodent models of Type 2 diabetes and
obesity.2 TZD’s are also known to be a group of perox-
isome profililator activator gamma receptors (PPAR
gamma).3 TZD’s scaffold has been found the core nu-
cleus of various antidiabetic drugs viz., pioglitazone,4
rosiglitazone,5 KRP-297,6 lobiglitazone7 and DRF-
2189.8
Structure-activity relation ship (SAR) studies on
2,4-thiazolidinediones have shown that the substituent
at 5th position of the 2,4-thiazolidinedione ring system
influences the pharmacological activities.9 The various
antidiabetic drugs which are recorded in Figure 1 each
has Knoevenagel condensation as a key step in synthesis.
Various methods were reported for the synthesis of
5-arylidine-2,4-thiazolidinediones using piperidine in
ethanol,10 piperidine and benzoic acid in toluene,11
piperidine benzoate in toluene,12 potassium carbonate in
DMF13 and sodium acetate in acetic acid.14 Various al-
ternative methods are also reported for the synthesis of
5-arylidine-2,4-thiazolidinediones using microwave
irradiation of the substrates/reactants supported on
KF/Al2O3,15 alum16 and in PEG-300.17 The reported
methods have one or other kind of drawbacks like the
use of toxic, hazardous, flammable organic solvents,
expensive catalysts, prolonged reaction time and heating.
Therefore it was found that there is a scope and need to
develop a convenient synthetic protocol for the synthe-
sis of 5-arylidine-2,4-thiazolidinediones by applying
Figure 1 Antidiabetic drugs.
some of the green tools to minimize some of the lacu-
nas.
Ionic liquids are well explored as novel green sol-
vent18 and catalysts to accelerate rate of various organic
transformations19 leading to value added materials. Now
a days thermally stable20 ionic liquids, dicationic ionic
*
E-mail: manera2011@gmail.com; Tel.: 0091-2402403313; Fax: 0091-2402403335.
Received September 17, 2010; revised December 1, 2011; accepted January 10, 2011.
942
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 942— 946

Dicationic Ionic Liquid Mediated Synthesis of 5-Arylidine-2,4-thiazolidinediones
liquids are attracting much attention of many chemists.
Dicationic ionic liquids which have been synthesized
and characterized are found to be useful in organic
transformations21 like Diels Alder, Claisen etc. The ad-
vantageous associated with such dicationic liquids are
yet to be fully utilized. Literature survey reveals that,
there is scanty information on the use of dicationic ionic
liquids in organic transformations.
Considering the pharmacological importance of
5-arylidine-2,4-thiazolidinediones and the drawbacks
associated with their reported methods, therefore here it
was thought worth while developing a safer route for
the synthesis of 5-arylidine-2,4-thiazolidinediones. In
continuation of earlier work for the synthesis of bioac-
tive molecules using green tools,22 herein we report for
the first time a convenient route for the synthesis of
5-arylidine-2,4-thiazolidinediones using dicationic ionic
liquid as medium and catalyst.
of 5-arylidine-2,4-thiazolidinedines have been made
more economic by recovering and recycling of
C3[min]2•2[Br－] dicationic ionic liquid for the same
reaction sequences. We have attempted the reaction of
4-methoxy benzaldehyde 1b and 2,4-thiazolidinedione 2
in presence of dicationic ionic liquid 3 at 80 ℃ for 2 h.
After completion of 2 h, the reaction mass was poured
on ice water and obtained solid was filtered. The recov-
ery of dicationic ionic liquid was made by vacuum dis-
tillation of the filtrate. The recovered dicationic ionic
liquid has been reused for the same reaction sequence
and was found to give excellent yields of the
5-arylidine-2,4-thiazolidinedione 4b and the results
were recorded in Table 1.
Table 1 Recovering and reusability of dicationic ionic liquid
Batcha
Fresh
Ist
IInd
IIIrd
Yieldb/%
91
89
88
85
Results and discussion
We have developed an environmental benign syn-
thetic route for the synthesis of 5-arylidine-2,4-thia-
zolidinediones 4a—4k by allowing the condensation of
aryl/heteryl aldehydes, 1a—1k with 2,4-thiazolidine-
dione 2 in 3-methyl-1-[3-(methyl-1H-imidazolium-1-
a Reaction carried at 80 ℃. b Isolated yield of the product 4b.
To compare the convenience of dicationic ionic liq-
uid to those conventional ionic liquids we performed the
condensations in C4[min]•Br－ [3-(methyl-1H-imidazo-
lium-1-yl)benzyl bromide] under similar reaction condi-
tions and observed that the yields of products after 2 h
of reaction were between 63%—71%. The ways of re-
covery and reusability are identical in both cases. This
seems that the rate acceleration for the condensation is
relatively more in dicationic ionic liquid than in the
ionic liquid C4[min]•Br－.
yl)pr－opyl]-1H-imidazolium
(Scheme 1).
dibromide
(C3[min]2•
2[Br ]), dicationic ionic liquid23 3 at 80 ℃ for 2 h
Scheme 1 Synthesis of 5-arylidine-2,4-thiazolidinediones
With all the above optimized conditions in hand, we
continued to apply approach to condensation of various
aryl/heteryl aldehydes with 2,4-thiazolidinedione using
dicationic ionic liquid and obtained 5-arylidine-2,4-
thiazolidinediones with excellent yields (Table 2). It is
The developed synthetic strategies for the synthesis
Table 2 Synthesis of 5-arylidine-2,4-thiazolidionedines using dicationic ionic liquid
Melting point/℃
Entry
R
Producta
Yieldb/%
Observed
Reported
240—24216
217—21815
310—31215
223—22415
225—22615
220—22115
208—21015
194—19615
Not reported
Not reported
Not reported
1
2
Phenyl
4a
4b
4c
4d
4e
4f
89
91
87
88
90
87
83
85
84
89
86
241—242
218—219
311—312
222—223
225—226
219—220
207—208
195—196
200—201
205—206
220—221
4-Methoxyphenyl
3
4-Hydroxyphenyl
4
4-Chlorophenyl
5
4-Methylphenyl
6
4-Fluorophenyl
7
3,4-Dimethoxyphenyl
3-Hydroxy-4-methoxyphenyl
3-Hydroxy-4-ethoxyphenyl
1,3-Diphenylpyrazolinyl
2-Chloroquinolynyl
4g
4h
4i
8
9
10
11
4j
4k
a Products were characterized by 1H NMR, mass spectral analyses are in good agreement with those reported in literature15,16,17. b Isolated
yields of the products.
Chin. J. Chem. 2011, 29, 942— 946
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
943

Jawale et al.
FULL PAPER
noteworthy to mention that the methodology worked
well to both electron donating and withdrawing sub-
stituents on aromatic aldehydes. To the best our knowl-
edge, we have reported for the first time dicationic ionic
liquid mediated synthesis of 5-arylidine-2,4-thiazolidi-
nediones with excellent yields (Table 2).
being ionic liquid it has ability to maintain homogeneity
of the reaction mass when the reaction was in progress.
Conclusion
We have developed safer, economic, one pot syn-
thetic protocol for the synthesis of 5-arylidine-2, 4-thia-
zolidinediones. The fascinating scope of this synthetic
strategy is that products are rapidly obtained with non
tedious isolation work up. Dicationic ionic liquid has
been employed for first time for the synthesis of
5-arylidine-2,4-thiazolidinediones. Dicationic ionic liq-
uid circumvents problem associated with the toxic, haz-
ardous and flammable organic solvents. The synthetic
strategy has been made more economic by recovering
and recycling of dicationic ionic liquid. This method is
applicable to wide range of aryl/heteryl aldehydes. The
attractive features of this procedure are the mild reaction
conditions, cleaner reaction profiles and reuse of cata-
lyst and medium. Therefore this strategy is unique for
preparation of 5-arylidine-2,4-thiazolidinediones, pre-
cursors of antidiabetic drugs.
Dicationic ionic liquid encompassing with two
imidazole cations and bromide ions might be useful for
strong H-bonding with the substrates. It was also noted
that dicationic ionic liquid has dual nature as acid and
base. Plausible mechanism for the formation o－f
5-arylidine-2,4-thiazolidinediones using C3[min]2•2[Br ]
3 has been depicted in Scheme 2. The electrophilic
character of carbonyl carbon of aldehydes 1 might be
increased by forming intermolecular H-bonding be-
tween H atoms of imidazolyl cations and carbonyl oxy-
gen of the aldehydes and nucleophilicity of carbon atom
at the 5th position of 2,4-TZD 2 might be enhanced by
forming H bonding between H atom of carbon at the 5t－h
position of 2,4-TZD and bromide ions of C3[min]2•2Br .
Therefore the nucleophilic addition of carbon atom at
the 5th position of 2,4-TZD on the electrophilic car-
bonyl carbon might be enhanced and thus rate accelera-
tion would have been occurred leading to intermediate 4.
The obtained intermediate is being unstable and it might
have undergone dehydration to yield 5-arylidine-
2,4-thiazolidinediones 5. Thus dicationic ionic liquid
plays significant role for obtaining the 5-arylidine-2,4-
thiazolidinediones rapidly under mild condition as, (i) it
might be helping to enhance the nucleophilic character
of carbon atom at the 5th position of 2,4-TZD and elec-
trophilic character of carbonyl oxygen of aldehydes, (ii)
it would be useful for the dehydration of intermediate 4
for obtaining 5-arylidine-2,4-thiazolidinediones 5 and
Experimental
Chemicals and solvents required for the work were
1
obtained from Merck, Spectorchem and S.D fine. H
NMR spectra were recorded at 300 MHz on Bruker
DRX-300. The mass spectra were recorded on
JEOL-Accu TOF DART-MS-T 100Lc. The melting
points were taken in open capillary and are uncorrected.
Typical experimental procedure (4b)
A mixture of 4-methoxy benzaldehyde (10 mmol)
and 2,4-thiazolidinedione (11 mmol) in dicationic ionic
liquid (10 mmol) was heated at 80 ℃. The progress of
the reaction was monitored by thin layer chromatogra-
phy. After heating the reaction mass for 2 h, the reaction
mass was allowed to cool at r.t. and then to this ice cold
water (50 mL) was added. The solid separated
5-arylidine-2,4-thiazolidinedione was filtered and dried.
It was further purified by crystallization. Similarly the
other compounds of the series were prepared by using
the procedure.
Scheme
2
Plausible mechanism for the formation of
5-arylidine-2, 4-thiazolidinediones using dicationic ionic liquid
Spectral data of representative compounds
5-(4-Methoxybenzylidene) thiazolidine-2,4-dione
(4b) Yellow solid; m.p. 218—219 ℃; 1H NMR
(DMSO-d6, 300 MHz) δ: 12.60 (br s, 1H, NH, ex-
changeable with D2O, 2,4-TZD), 7.75 (s, 1H, olefenic
proton), 7.57 (d, J＝9.0 Hz, 2H, ArH), 7.10 (d, J＝9＋.0
Hz, 2H, ArH), 3.83 (s, 3H, OCH3); DART-MS (ESI )
m/z: 266 (M＋).
5-(4-Fluorobenzylidene) thiazolidine-2,4-dione (4f)
Yellow solid; m.p. 219—220 ℃; 1H NMR (DMSO-d6,
300 MHz) δ: 12.63 (br s, 1H, NH, exchangeable with
D2O, 2,4-TZD), 7.79 (s, 1H, olefenic proton), 7.34—
7.74 (m, 4H, ArH); DART-MS (ESI＋) m/z: 224 (M＋).
5-(3,4-Dimethoxybenzylidene)
thiazolidine-2,4-
944
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 942— 946

Dicationic Ionic Liquid Mediated Synthesis of 5-Arylidine-2,4-thiazolidinediones
dione (4g) Yellow solid, yield 83%; m.p. 207—208
Bioorg. Med. Chem. Lett. 1999, 9, 533.
1
℃; H NMR (DMSO-d6, 300 MHz) δ: 11.95 (br s, 1H,
(b) Murakami, K; Kobe, K.; Ide, T.; Mochizuki, T.; Ohashi,
M.; Akanuma, Y.; Yazaki, Y.; Kadowaki, T. Diabetes 1998,
47, 1841.
Hong, W. L.; Joong, B. A.; Sung, K. K.; Soon, K. A.; Deok,
C. H. Org. Proc. Res. Dev. 2007, 11, 190.
Brag, B. L.; Vidya, B.; Bheema, P. R.; Gurram, R. M.;
Nagahelli, M.; Kovvidi, N. R.; Pmaulapati, G. R.;
Chakraborthy, R.; Reeba, K. V.; Ramanujam, R.; Rao, N. V.;
Hemant, K. J.; Swaminathan, S. J. Med. Chem. 1998, 41,
1619.
NH, exchangeable with D2O, 2,4-TZD), 7.86 (s, 1H,
olefenic proton), 7.0—7.19 (m, 3H, ArH), 4＋.42 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3); DART-MS (ESI ) m/z: 268
(M＋).
7
8
5-(4-Ethoxy-3-hydroxybenzylidene) thiazolidine-
1
2,4-dione (4i) Yellow solid; m.p. 200—201 ℃; H
NMR (DMSO-d6, 300 MHz) δ: 12.21 (br s, 1H, NH,
exchangeable with D2O, 2,4-TZD), 7.93 (s, 1H, olefenic
proton), 6.84—6.96 (m, 3H, ArH), 4.03 (q, 2H, CH2),
1.39 (t, 3H, CH3); DART-MS (ESI＋) m/z: 268 (M＋).
9
(a) Mohareb, R. M.; Fleita, D. H. Heteroatom Chem. 2002,
13, 258.
5-[(1,3-Diphenyl-1H-pyrazol-4-yl)
methylene]
thiazolidine-2,4-dione (4j) Yellow solid, m.p. 205—
206 ℃; 1H NMR (DMSO-d6, 300 MHz) δ: 12.12 (br s,
1H, NH, exchangeable with D2O, 2,4-TZD), 8.55 (s, 1H,
olefenic proton), 7.64—8.15 (m, 11H, ArH); DART-MS
(ESI＋) m/z: 344 (M＋).
(b) Herrding, D. A.; Christmann, L. T.; Clark, T. J.; Holmes,
D. J.; Rittenhouse, S. F.; Takata, D. T.; Venslavsky, J. W.
Bioorg. Med. Chem. Lett. 2003, 13, 3771.
10 Bhattarai, B. R.; Kafle, B.; Hwang, J. S.; Khadka, D.; Lee, S.
M.; Kang, J. S.; Hamd, S. W.; Han, I. O.; Park, H.; Cho, H.
Bioorg. Med. Chem. Lett. 2009, 19, 6161.
5-[(2-Chloroquinolin-3-yl)
methylene]
thia-
zolidine-2,4-dione (4k) Yellow solid; m.p. 220—221
11 Madhavan, G. R.; Chakrabarti, R. K.; Reddy, A.; Rajesh, B.
M.; Balraju, V.; Rao, R. B.; Iqbal, J. Bioorg. Med. Chem.
2006, 14, 584.
12 Madhavan, G. R.; Chakrabarti, R.; Kumar, S. K. B.; Misra,
P.; Rao, N. V. S.; Balraju, M. V.; Kasiram, K.; Babu, R. K.;
Suresh, J.; Lohray, B. B.; Lohray, V. B.; Iqbal, J.;
Rajagopalan, R. Eur. J. Med. Chem. 2001, 36, 627.
13 Yoshitata, O.; Teruo, M.; Mishiko, N.; Motoyuki, J.; Norio,
K. Chem. Pharm. Bull. 1992, 40, 907.
14 Tuncbine, M.; Dundar, B.; Ayhan-Kilcigil, G.; Ceylan, M.;
Waheed, A.; Verspohl, E. J.; Ertan, R. I. Farmaco 2003, 58,
79.
15 (a) Yang, D. H.; Yang, B. Y.; Chen, B. C.; Chen, S. Y. Org.
Prep. Proced. Int. 2006, 38, 81.
1
℃; H NMR (DMSO-d6, 300 MHz) δ: 12.19 (br s, 1H,
NH, exchangeable with D2O, 2,4-TZD), 8.15 (s, 1H,
olefenic proton), 7.＋25—7.67 (＋m, 4H, ArH); DART-MS
(ESI＋) m/z: 291 (M ), 293 (M ＋2).
Acknowledgements
Authors are thankful to Professor D. B. Ingle for his
invaluable discussions and guidance. One of the authors,
D.V. Jawale is also grateful to U.G.C., New Delhi, India
for Research Fellowship in Sciences for meritorious
students.
References
(b) Villemin, D.; Alloum, A. B. Phoshphorus Sulfur Silicon
Relat. Elem. 1993, 79, 33.
16 Shelke, K. F.; Sapkal, S. B.; Kakade, G. K.; Sadaphal, S. A.;
Shingate, B. B.; Shingare, M. S. Green Chem. Lett. Rev.
2010, 3, 17.
17 Mahalle, S. R.; Netankar, P. D.; Bondge, S. P.; Mane, R. A.
Green Chem. Lett. Rev. 2008, 1, 103.
18 (a) Welton, T. Chem. Rev. 1999, 99, 2771.
(b) Pârvulescu, V. I.; Hardacre, C. Chem. Rev. 2007, 107,
2615.
1
2
3
(a) Oguchi, M.; Wada, K.; Honma, H.; Tanaka, A.; Taneko,
T.; Sakakibara, S.; Ohsumi, J.; Serizawa, N.; Fujiwara, T.;
Horikoshi, H.; Fujita, T. J. Med. Chem. 2000, 43, 3052.
(b) Malamas, M. S.; Sredy, J.; Gunawan, I.; Mihan, B.;
Sawicki, D. R.; Seestaller, L.; Sullivan, D.; Flam, B. R. J.
Med. Chem. 2000, 43, 995.
(a) Saltiel, A. R.; Olefsky, J. M. Diabetes 1996, 45, 1661.
(b) Fujita, T.; Sugiyama, Y.; Taketomi, S.; Sohda, T.;
Kawamatsu, Y.; Iwatsuka, H.; Suzuoka, Z. Diabetes 1983,
32, 804.
(c) Chang, A. Y.; Wyse, B. M.; Gilchrist, B. J.; Peterson, T.;
Diani, A. R. Diabetes 1983, 32, 830.
(a) Lehman, J. M.; Moore, L. B.; Smith Oliver, T. A.;
William, O. W.; Willson, T. M.; Kliewer, S. A. J. Biol. Chem.
1995, 270, 12953.
(c) Greaves, T. L.; Drummond, C. J. Chem. Soc. Rev. 2008,
37, 1709.
19 (a) Chakraborti, A. K.; Roy, S. R.; Kumar, D.; Chopra, P.
Green Chem. 2008, 10, 1111.
(b) Lombardo, M.; Chiarucci, M.; Trombini, C. Green Chem.
2009, 11, 574.
(c) Kumar, R.; Sharma, A.; Sharma, N.; Kumar, V.; Sinha, A.
Eur. J. Org. Chem. 2008, 5577.
(b) Klirwer, S. A.; Lenhard, J. M.; Wilson, T. M. Cell 1995,
83, 813.
(d) Martins, M. P.; Frizzo, C. P.; Moreira, D. N.; Zanatta, N.;
Bonacorso, H. G. Chem. Rev. 2008, 108, 2015.
20 (a) Fukumoto, K.; Yoshizawa, M.; Ohno, H. J. Am. Chem.
Soc. 2005, 127, 2398.
4
5
Momose, Y.; Meguro, K.; Ikeda, H.; Hatanka, C.; Oi, S.;
Sohda, T. Chem. Pharm. Bull. 1991, 39, 1440.
Cantello, B. C. C.; Cawthorne, M. A.; Haigh, D.; Hindley, R.
M.; Smith, S. A.; Thurlby, P. L. Bioorg. Med. Med. Lett.
1994, 4, 1181.
(b) Zhou, Z. B.; Matsumoto, H.; Tatsumi, K. Chem. Eur. J.
2005, 11, 752.
(c) Branco, L. C.; Rosa, J. N.; Ramos, J. J. M.; Afonso, A.
6
(a) Momura, M.; Kinoshita, S.; Satoh, H.; Maeda, T.;
Murakami, K.; Tsunodam, M.; Miyachi, H.; Awano, K.
Chin. J. Chem. 2011, 29, 942— 946
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
945

Jawale et al.
FULL PAPER
M. Chem. Eur. J. 2002, 8, 3671.
(d) Pernak, J.; Stefaniak, F.; Weglewski, J. Eur. J. Org.
Chem. 2005, 650.
(b) Mali, J. R.; Pratap, U. R.; Netankar, P. D.; Mane, R. A.
Tetrahedron Lett. 2009, 50, 5025.
(c) Jawale, D. V.; Lingampalle, D. L.; Pratap, U. R.; Mane,
R. A. Chin. Chem. Lett. 2010, 21, 412.
(d) Lingampalle, D.; Jawale, D.; Waghmare, R.; Mane, R.
Synth. Commun. 2010, 40, 2397.
(e) Mali, J. R.; Pratap, U. R.; Jawale, D. V.; Mane, R. A.;
Mali, J. R. Tetrahedron Lett. 2010, 51, 3980.
21 (a) Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000,
39, 3772.
(b) Dupont, J.; de Souza, R. F.; Suarez, P. A. Z. Chem. Rev.
2002, 102, 3667.
(c) Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis,
Wiley-VCH, Weinheim, 2003.
23 (a) Varma, R. S.; Namboodiri, V. V. Org. Lett. 2002, 4, 3161.
(b) Anderson, J. L.; Ding, R.; Ellern, A.; Armstrong, D. W. J.
Am. Chem. Soc. 2005, 127, 593.
(d) Han, X.; Armstrong, D. W. Org. Lett. 2005, 7, 4205.
22 (a) Pratap, U. R.; Mali, J. R.; Jawale, D. V.; Mane, R. A.
Tetrahedron Lett. 2009, 50, 1352.
(E1009174 Zhao, X.; Fan, Y.)
946
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 942— 946