A convenient synthesis of 5-arylidenethiazolidine-2,4-diones catalyzed by alkaline ionic liquid

Article abstract of DOI:10.3987/COM-08-11533

A series of 5-arylidenethiazolidine-2,4-diones was synthesized by the Knoevenagel condensation of thiazolidine-2,4-dione with aromatic aldehydes with alkaline ionic liquid l-butyl-3-mefhylimidazolium hydroxide ([bmim]OH) as dual solvent and catalyst. This

Full text of DOI:10.3987/COM-08-11533

HETEROCYCLES, Vol. 78, No. 3, 2009
757
HETEROCYCLES, Vol. 78, No. 3, 2009, pp. 757 - 761. © The Japan Institute of Heterocyclic Chemistry
Received, 26th August, 2008, Accepted, 15th October, 2008, Published online, 20th October, 2008
DOI: 10.3987/COM-08-11533
A CONVENIENT SYNTHESIS OF 5-ARYLIDENETHIAZOLIDINE-
2,4-DIONES CATALYZED BY ALKALINE IONIC LIQUID
Yi Hu, Tao Xie, Kai-Mei Fu, Hui Kang, Ping Wei, and He Huang*
State Key Laboratory of Materials-Oriented Chemical Engineering, College of
Life Science and Pharmaceutical Engineering, Nanjing University of Technology,
Nanjing, 210009, P. R. China
E-mail: biotech@njut.edu.cn
Abstract – A series of 5-arylidenethiazolidine-2,4-diones was synthesized by
the Knoevenagel condensation of thiazolidine-2,4-dione with aromatic aldehydes
with alkaline ionic liquid 1-butyl-3-methylimidazolium hydroxide ([bmim]OH)
as dual solvent and catalyst. This method provides many advantages such as
being environmentally benign, simple work-up, short reaction times, obtaining in
good to excellent yields, and the reusability of ionic liquid.
5-Arylidenethiazolidine-2,4-diones constitute an important class of chemically, biologically and
pharmaceutically significant compounds.1,2 For example, they are key intermediates for the synthesis of
anti-diabetic drugs such as troglitazone, pioglitazone, rosiglitazone, englitazone.3 The conventional
synthesis of 5-arylidenethiazolidine-2,4-diones involves the Knoevenagel condensation of aromatic
aldehydes with thiazolidine-2,4-dione catalyzed by organic base or salt in refluxing volatile organic
solvent such as benzene,1 toluene,4 acetic acid,4,5 ethanol,2,6,7 etc. However, these reactions require long
reaction times (16-24 h), tedious work-up procedures, and sometimes only moderate yields obtained.
Recently, some methods have been developed such as facilitated by solid base,8 ionic liquids,9 solid
condensation,10 or MW irradiation.11,12 Although the condensation reactions could be completed in short
times, these methods have their own disadvantages yet, such as using unamiable organic solvent, added
catalyst required, difficult to prepare in large scale, etc. Considering the importance of
5-arylidenethiazolidine-2,4-diones, we think it is still significant to develop more facile and practical

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HETEROCYCLES, Vol. 78, No. 3, 2009
Recently, the interest in room temperature ionic liquids is increasing as green reaction media for synthetic
organic chemistry,13,14 and some reports have shown the Knoevenagel condensation could be performed
efficiently in task specific ionic liquids.15-17 In continuation of our interest in using ionic liquids as
eco-friendly medium and catalyst for the condensation reactions,18,19 we report herein
5-arylidenethiazolidine-2,4-diones could be synthesized conveniently by the condensation of
thiazolidine-2,4-dione
with
aromatic
aldehydes
catalyzed
by
alkaline
ionic
liquid
1-butyl-3-methylimidazolium hydroxide ([bmim]OH). (Scheme 1).
O
O
H
[bmim]OH
NH
O
ArCHO
+
NH
Ar
S
S
O
1
2
3
Scheme 1
For this study, the functional ionic liquid [bmim]OH was synthesized as lit.20 The results were
summarized in Table 1, all the products were characterized by NMR, IR spectrum and melting points that
were consistent with the literature data. As can be seen from the Table 1 that this procedure was found to
be general and applicable to the aromatic aldehydes bearing various substituents such as methoxyl,
N,N/-dimethylamino, hydroxyl, chloro, bromo, nitro, etc. It is noteworthy that aromatic aldehydes bearing
electron-withdrawing groups reacted more easily compared with those containing electron-donating
groups the same as described in the literature,8 and only Z-isomers were obtained as literatures
described.4,9,11 Besides, the reaction of the hindered aldehyde 2,6-dichlorobenzaldehyde (Entry 8), the
heteroaromatic aldehyde 2-furancarboxaldehyde (Entry 13) and α,β-unsaturated Cinnamic aldehyde
(Entry 14) with thiazolidine-2,4-dione also could be completed efficiently with high yields obtained.
Moreover, the functional alkaline ionic liquid [bmim]OH could be typically recovered and reused with no
appreciable decrease in yields and reaction rates (Entries 15-16).
In conclusion, we have demonstrated that 5-arylidenethiazolidine-2,4-diones could be conveniently
synthesized by the condensation of thiazolidine-2,4-dione with aromatic aldehydes in task specific ionic
liquid [bmim]OH for the first time, which play a dual role as solvent and base catalyst in this reaction.
The present method has many obvious advantages compared to the previous methods, including no need
for the use of any added catalyst, being environmentally more benign, simple work-up, high yield,
potential for recycling of ionic liquid, and the generality.

HETEROCYCLES, Vol. 78, No. 3, 2009
759
Table 1. Synthesis of 5-arylidenethiazolidine-2,4-diones catalyzed by [bmim]OH
Entry
Product
Ar
Time (h) Yielda (%)
Mpb (℃)
Lit.mp(℃)
1
2
3a
3b
3c
3d
3e
3f
p-MeOC6H4
p-Me2NC6H4
p-HOC6H4
o-HOC6H4
C6H5
6
6
6
6
2
3
4
4
4
4
2
91
85
81
71
74
82
86
87
90
91
89
218-219
296-297
>300
21812
29621
3
>3004,11
225-22612
247-2494
231-23222
17223
4
226-227
247-248
230-231
183-184
153-154
212-213
241-242
208-209
5
6
p-ClC6H4
7
3g
3h
3i
o- ClC6H4
2,6- Cl2C6H3
3,4-Cl2C6H3
p-Br C6H4
m-NO2C6H4
8
152-15424
---------
9
10
11
3j
242-2444
2456
3k
185-19012
267-27012
230-23312
218-22012
21812
12
13
14
15
16
3l
3m
3n
3a
3a
p-NO2C6H4
2-furyl
2
2
3
6
6
87
81
265-267
228-230
219-221
218-219
218-219
C6H5CH=CH
p-MeOC6H4
p-MeOC6H4
92
88c
89d
21812
a Isolated yield. b Melting points were uncorrected. c-d Second and third recycling of [bmim]OH.
EXPERIMENTAL
Melting points were determined on a digital melting point apparatus and were not corrected. Infrared
13
spectra were recorded on an AVATAR-360 Infrared Spectrophotometer. 1H NMR and C NMR spectra
were recorded on a BRUKER-300 MHz spectrometer using DMSO-d6 as the solvent with
tetramethylsilane (TMS) as an internal standard. Elemental analysis was performed on an Elementar
Vario MICRO analyzer. TLC was accomplished on Merck silica gel 60 F254 on aluminium sheets.

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HETEROCYCLES, Vol. 78, No. 3, 2009
General Procedure for the Preparation of 3a~3n
Aromatic aldehyde 1 (2 mmol), thiazolidine-2,4-dione 2 (2 mmol), were added in ionic liquid
[bmim]OH (1 mL). The reaction mixture was stirred at 80 °C for an appropriate time, reaction was
monitored by thin layer chromatography (TLC). Upon completion of the reaction, after adding 1 mL
water and filtering the solid directly from the reaction mixture, gave the desired product 3 in high yield,
which was purified by recrystallization from EtOH. After isolation of the product, the remainder of the
ionic liquid was dried for 4 h under vacuum at 70 °C. The next run was performed under identical
reaction conditions.
Spectroscopic data for 3g, 3i and 3k:
3g: IR (KBr): 3421, 3145, 3052, 1743, 1735, 1604, 1462, 1431, 1318, 1162 cm-1. 1H NMR (DMSO-d6): δ
= 7.50-7.54 (m, 2H), 7.55-7.60 (m, 1H), 7.64-7.67 (m, 1H), 7.93(s, 1H), 12.76(brs, 1H). 13C NMR
(DMSO-d6): δ = 168.08, 167.43, 134.95, 132.28, 131.47, 130.80, 129.33, 128.54, 127.69, 127.17. Anal.
Calcd for C10H6ClNO2S: C, 50.11; H, 2.52; N, 5.84. Found: C, 50.01; H, 2.43; N, 5.61.
3i: IR (KBr): 3417, 3172, 1754, 1705, 1578, 1466, 1321, 1108cm-1. 1H NMR (DMSO-d6): δ = 7.59(s, 1H),
7.61(d, 1H,
J
=
2.1 Hz), 7.85-7.86(m, 2H), 12.81(brs, 1H). 13C NMR (DMSO-d6):
167.88, 167.69, 137.02, 134.32, 133.15, 132.52, 132.49, 129.43, 129.38, 126.77.
Anal. Calcd for C10H5Cl2NO2S: C, 43.81; H, 1.84; N, 5.11. Found: C, 43.64; H, 1.95; N, 4.98.
1
3k: IR (KBr): 3420, 3163, 1745, 1690, 1605, 1532, 1352, 1326, 1152 cm-1. H NMR (DMSO-d6): δ =
7.83(t, 1H, J = 8.1 Hz), 7.96(s, 1H), 8.03(d, 1H, J= 7.8 Hz), 8.28-8.32(m, 1H), 8.46(t, 1H, J = 1.8 Hz),
12.80(brs, 1H). 13C NMR (DMSO-d6): 167.79, 167.49, 148.74, 135.88, 135.26, 131.37, 129.87, 127.14,
124.94, 124.84. Anal. Calcd for C10H6N2O4S: C, 48.00; H, 2.42; N, 11.20. Found: C, 47.97; H, 2.61; N,
10.89.
ACKNOWLEDGEMENTS
This work was supported by the national key technology R&D program (No. 2006BAE02B04), hi-tech
research and development program of China (No. 2006AA020101), and Post-doctoral Science Fund of
China (No. 20070420980).
REFERENCES
1. S. Hossain and S. Bhattacharya, Bioorg. Med. Chem. Lett., 2007, 17, 1149.
2. R. Maccari, R. Ottana, R. Ciurleo, M. G. Vigorita, D. Rakowitz, T. Steindl, and T. Langer, Bioorg.
Med. Chem. Lett., 2007, 17, 3886.
3. A. Les, W. Pucko, and W. Szelejewski, Org. Process Res. Dev., 2004, 8, 157.
4. R. G. Giles, N. J. Lewis, J. K. Quick, M. J. Sasse, M. W. J. Urquhart, and L. Youssef, Tetrahedron,
2000, 56, 4531.

HETEROCYCLES, Vol. 78, No. 3, 2009
761
5. P. C. Unangst, D. T. Connor, W. A. Cetenko, R. J. Sorenson, C. R. Kostlan, J. C. Sircar, C. D.Wright,
D. J. Schrier, and R. D. Dyer, J. Med. Chem., 1994, 7, 322.
6. R. Maccari, R. Ottana, R. Ciurleo, M. G. Vigorita, D. Rakowitz, T. Steindl, and T. Langer, Bioorg.
Med. Chem., 2005, 13, 2809.
7. B. Y. Kim, J. B. Ahn, H. W. Lee, S. K. Kang, J. H. Lee, J. S. Shin, S. K. Ahn, C. I. Hong, and S. S.
Yoon, Eur. J. Med. Chem., 2004, 39, 433.
8. J. Sun, X. Jin, and C. G. Yan, Chem. Res., 2001, 12, 23.
9. D. H. Yang, Z. C. Chen, S. Y. Chen, and Q. G. Zheng, Synthesis, 2003, 1891.
10. G. S. Li, C. Wang, J. C. Li, Y. X. Zhou, H. R. Zhao, P. Li, and H. J. Geng, Chin. J. Appl. Chem.,
2004, 21, 1069.
11. B. R. P. Kumar, M. D. Karvekar, L. Adhikary, M. J. Nanjan, and B. Suresh, J. Heterocycl. Chem.,
2006, 43, 897.
12. D. H. Yang, B. Y. Yang, Z. C. Chen, and S. Y. Chen, Org. Prep. Proced. Int., 2006, 38, 81.
13. P. Wasserscheid and T. Welton, Ionic Liquids in Synthesis, Eds: VCH Wiley, Weinheim, Germany,
2003.
14. V. I. Parvulescu and C. Hardacre, Chem. Rev., 2007, 107, 2615.
15. B. C. Ranu and R. Jana, Eur. J. Org. Chem., 2006, 3767.
16. Y. Q. Cai, Y. Q. Peng, and G. H. Song, Catal. Lett., 2006, 109, 61.
17. C. Paun, J. Barklie, P. Goodrich, H. Q. N. Gunaratne, A. McKeown, V. I. Pârvulescu, and C.
Hardacre, J. Mol. Cat. A: Chemical, 2007, 269, 64.
18. Y. Hu, P. Wei, H. Huang, Z. G. Le, and Z. C. Chen, Synth. Commun., 2005, 35, 2955.
19. Y. Hu, P. Wei, H. Huang, S. Q. Hang, and P. K. Ouyang, Heterocycles, 2006, 68, 375.
20. J. M. Xu, Q. Wu, Q. Y. Zhang, F. Zhang, and X. F. Lin, Eur. J. Org. Chem., 2007, 1798.
21. C. P. Lo, E. Y. Shropshire, and W. J. Groxall, J. Am. Chem. Soc., 1953, 75, 4845.
22. M. J. Korohoda, Pol. J. Chem., 1981, 55, 359.
23. I. F. B. Dains and F. Eberly, J. Am. Chem. Soc., 1933, 55, 3859.
24. H. B. Olsen, N. C. Kaarsholm, P. Madsen, S. Ostergaard, S. Ludvigsen, P. Jakobsen, A. K. Petersen,
and D. B. Steensgaard, WO 2003027081.