Ionic liquid-mediated, one-pot synthesis for 4-thiazolidinones

Article abstract of DOI:10.1080/00397910903245174

A convenient one-pot, three-component cyclocondensation mediated by ionic liquid for obtaining 2,3-disubstituted-4-thiazolidinones with excellent yields is reported. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903245174

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Ionic Liquid–Mediated, One-Pot Synthesis
for 4-Thiazolidinones
Dinesh Lingampalle a , Dhanaji Jawale a , Rahul Waghmare a &
Ramrao Mane a
a Department of Chemistry , Dr. Babasaheb Ambedkar Marathwada
University , Aurangabad, India
Published online: 26 Jul 2010.
To cite this article: Dinesh Lingampalle , Dhanaji Jawale , Rahul Waghmare & Ramrao Mane (2010)
Ionic Liquid–Mediated, One-Pot Synthesis for 4-Thiazolidinones, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:16, 2397-2401,
DOI: 10.1080/00397910903245174
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Synthetic Communications1, 40: 2397–2401, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903245174
IONIC LIQUID–MEDIATED, ONE-POT SYNTHESIS FOR
4-THIAZOLIDINONES
Dinesh Lingampalle, Dhanaji Jawale, Rahul Waghmare, and
Ramrao Mane
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada
University, Aurangabad, India
A convenient one-pot, three-component cyclocondensation mediated by ionic liquid for
obtaining 2,3-disubstituted-4-thiazolidinones with excellent yields is reported.
Keywords: Mercaptoacetic acid; N-methylpyridinium tosylate (ionic liquid); 4-thiazolidinones
INTRODUCTION
4-Thiazolidinones have been exploited over the past few decades because of
the wide range of biological activities displayed by this class of heterocycles. The
4-thiazolidinone scaffold has been reported to possess bactericidal,[1] antifungal,[2]
anticonvulsant,[3] anti-HIV,[4] and antituberculotic[5] activities. Even though an
enormous number of reports have been published, still development of convenient
synthetic protocols for 4-thiazolidinones remained a quest for chemists.
A literature survey revealed that commonly employed synthetic protocols for
4-thiazolidinones involve either one-pot, three-component cyclocondensation of
amines, carbonyls, and mercaptoacetic acid or two-step synthesis via Schiff base inter-
mediates and their successive cyclocondensation with mercaptoacetic acid. The two-step
synthesis requires 6–9 h for completion and gives poor to moderate yields. The use of
hazardous media such as benzene, toluene, 1,4-dioxane, and tetrahydrofuran (THF)
has been reported in this cyclocondensation. These paths need a provision to remove
the reaction water in an azotropic way using a Dean–Stark trap to expedite the rate
of the cyclocondensation. There are reports of a three-component, one-pot approach
for 4-thiazolidinones, carried using desiccants such as molecular sieves, anhydrous
ZnCl2,[6] sodium sulfate,[7] and N,N-dicyclohexylcarbodiimide (DCC).[8] It also has
been observed that the rate of cyclocondensation can be increased by microwave heat-
ing.[9] In a recent report, the cyclocondensation has been carried using a polyethylene
glycol (PEG)–ionic liquid[10] matrix under microwave heating.
These protocols are worthwhile if the carbonyl source is aldehydic. It is
reported that these methods need prolong heating if precursors are keto carbonyls.
Received May 20, 2009.
Address correspondence to Ramrao Mane, Department of Chemistry, Dr. Babasaheb Ambedkar
Marathwada University, Aurangabad 431 004, India. E-mail: manera@indiatimes.com
2397

2398
D. LINGAMPALLE ET AL.
The problems in the reported protocols such as prolonged reaction time, poor yields,
use of hazardous solvents, and industrially impracticable microwave heating
prompted us to develop a convenient, three-component, one-pot environmentally
acceptable synthetic method for 4-thiazolidinones.
Ionic liquids are emerging as substitutes for volatile organic solvents. They
have negligible vapor pressure, low volatility, and moderate moisture sensitivity
and offer homogenous media because of their ionic nature and organic structural
components. Ionic liquids are used as green media for various organic transforma-
tions. It also seems that there is scanty information on the use of ionic liquids in
the cyclocondensations for obtaining 4-thiazolidinones.
Considering the significance of the ionic liquids and the need to develop a rapid
synthetic protocol for 4-thiazolidinones, in the present endeavor a convenient one-
pot cyclocondensation of amines, aromatic ketones, and mercaptoacetic acid has
been carried out in freshly prepared N-methylpyridinium tosylate (ionic liquid),
which gave 4-thiazolidinones rapidly in excellent yields.
RESULTS AND DISCUSSION
Here, an attempt has been made to develop a one-pot synthetic protocol for
4-thiazolidinones. Imines generated in situ from aromatic amines and carbonyls have
been subjected to the cyclocondensation with mercaptoacetic acid in a nonvolatile
organic medium, freshly prepared N-methylpyridinium tosylate (ionic liquid),[11] to
obtain the desired 4-thiazolidinones. The imines formed in situ in the first step suc-
cessively undergo cyclocondensation rapidly to yield the desired 4-thiazolidinones at
120 ꢀC in the ionic liquid within 3 h (Scheme 1).
The ionic liquid was freshly prepared[11] by condensing pyridine and methyl-
4-toluene sulfonate at 5 ꢀC. An attempt has been also made to reuse and recycle
the ionic liquid for the same reaction (Scheme 2).
Scheme 1. Synthesis of 4-thiazolidinones from carbonyl compounds, aromatic=heteryl amines, and
mercapto acetic acid in ionic liquid.
Scheme 2. Synthesis of N-methylpyridinium tosylate (ionic liquid) from pyridine and methyl-4-toluene
sulfonate.

ONE-POT SYNTHESIS FOR 4-THIAZOLIDINONES
2399
Table 1. Physical parameters of the 4-thiazolidinones (4a–k)
Compound
R1
R2
R3
Yields (%)a
Melting point (ꢀC)
4a
4b
4c
4d
4e
4f
4-Hydroxyphenyl
4-Hydroxyphenyl
Phenyl
CH3
CH3
H
4-Methoxyphenyl
4-Methylphenyl
Phenyl
90
89
93
90
92
92
92
90
84
80
80
169–171
174–175
131–132b
119–120b
105–106b
115–116b
128–129b
110–111b
114–115
164–165
238–240b
4-Methylphenyl
4-Methylphenyl
Phenyl
H
4-Methylphenyl
Phenyl
H
H
4-Methylphenyl
Phenyl
4g
4h
4i
4-Chlorophenyl
Phenyl
H
H
4-Chlorophenyl
Isonicotinoyl amino
Isonicotinoyl amino
Isonicotinoyl amino
4-Methoxyphenyl
4-Chlorophenyl
4-Methoxyphenyl
H
4j
4k
H
H
aIsolated yields.
bThe melting points of these products prepared in this work are in good agreement with those reported
in the literature.[12,13]
When carried out under reflux conditions in a medium like toluene=dioxane,
the same cyclocondensation gave the products 4-thiazolidinones (4) in 55–60% yields
and the time required for the completion of the course was more than 7 h. Therefore,
the ionic liquid–mediated route is excellent for getting the 4-thiazolidinones. The
physical parameters are recorded in Table 1.
CONCLUSION
Here, we have developed a convenient, ionic liquid–mediated, one-pot syn-
thetic protocol for 4-thiazolidinones. The ionic liquid can be easily prepared and
is nonvolatile. The time required for the completion of the cyclocondensation is
markly reduced, and the yields of the products are near to stiochimetric. Hence,
we claim that this route is rapid, economical, and ecofriendly.
EXPERIMENTAL
All chemicals used were made by S.D. Fine or Spectrochem and of synthetic
grade. 1H NMR spectra were recorded on a Bruker DRX-300 instrument, and mass
spectra were recorded on a Jeol Sx-102 (FAB) Instrument. Melting points were taken
in open capillaries and are uncorrected.
Synthesis of Ionic Liquid
Pyridine (1.1 mol) was added to a methyl-4-toluene sulfonate (1 mol) at
0–10 ꢀC. After completion of the addition, the reaction mass was then stirred at
room temperature for 1 h. The solid, N-methylpyridinium tosylate (Scheme 2),
was filtered. The product was then washed with ethyl acetate to the remove
unreacted reactants and then dried. The physical parameters of the ionic liquid
are in good agreement with those reported in the literature[11] (Scheme 2).

2400
D. LINGAMPALLE ET AL.
General Procedure for the Synthesis of 2,3-Diaryl/Heteryl
4-Thiazolidinones
An equimolar mixture of aryl aldehydes=aryl ketones (25 mmol) and aromatic=
heteroaromatic amines (25 mmol) was dissolved in premolten N-methylpyridinium
tosylate, an ionic liquid (4 g), and the solution was stirred for 2 h at 120 ꢀC. Then
thioglycolic acid (37.5 mmol) was added, and the reaction content was allowded to
stir at 120 ꢀC for 1 h. The progress of the reaction was monitored by thin-layer
chromatography (TLC). After completion of the reaction, the reaction mixture
was cooled at room temperature and poured into ice water. The solid precipitated
was filtered, dried, and crystallized from the proper solvent. The purity of the
products was confirmed by TLC.
Recovery of the Ionic Liquid
An attempt was made to recover the ionic liquid. After completion of the reac-
tion, the reaction mixture was poured on ice water, and the product was filtered off.
The filtrate was extracted with ethyl acetate to recover unreacted reactants, and the
aqueous layer was subjected to evaporation of water to get viscous liquid, which on
cooling gave the ionic liquid. The recovered ionic liquid was reused for two more
cycles of the same cyclocondensation and found to act satisfactorily.
Spectral Data of a Few Representative Thiazolidin-4-ones
2-(4-Hydroxyphenyl)-3-(4-methoxyphenyl)-2-methylthiazolidin-þ4.-one
(Table 1, compound 4a). Mp 169–171 ꢀC, mass (m=z, % intensity): 315 (M , 58);
1H NMR (DMSO-d6) d: 3.34 (s, 3H, CH3), 3.78 (s, 3H þ 2H, overlapped OCH3 and
CH2), 6.82 (d, 4H, ArH, overlapped signals J ¼ 8 Hz), 7.44 (d, 4H, ArH, overlapped
signals) and 10.24 (s, 1H, OH).
N-(2-(4-Methoxyphenyl)-4-oxothiazolidin-3-yl) isonicotinamide (Table 1,
compound 4i). Mp 114–115 ꢀC, mass (m=z, % intensity): 329 (Mþ; 52);1H NMR
(DMSO-d6) d: 3.65 (s, 2H, CH2), 3.82 (s, 3H, OCH3), 5.21 (s, 1H, CH), 6.94 (d,
2H, ArH, J ¼ 8 Hz), 7.66 (d, 2H, ArH, J ¼ 8 Hz), 7.64 (d, 2H, ArH, J ¼ 8 Hz), 8.78
(d, 2H, ArH, J ¼ 8 Hz) and 11.72 (s, 1H, NH).
ACKNOWLEDGMENT
The authors are thankful to Professor D. B. Ingle for his invaluable discussions
and guidance.
REFERENCES
1. Dutta, M. M.; Goswami, B. N.; Kataky, J. C. Studies on biological reactive heterocycles,
part III: Syntheses and antibacterial of some 2-aryl=aralkyl-3-substitued-4-thiazolidi-
nones. J. Ind. Chem. Soc. 1990, 67, 332–334.
2. Jadhav, K. P.; Ingle, D. B. Synthesis of potential fungicidal compounds. J. Ind. Chem.
Soc. 1978, 4, 424–426.

ONE-POT SYNTHESIS FOR 4-THIAZOLIDINONES
2401
3. Gursoy, A.; Terzioglu, N. Synthesis and isolation of new regioisomeric 4-thiazolidinones
and their anticonvulsant activity. Turk. J. Chem. 2005, 29, 247–254.
4. Rawal, R. K.; Tripathi, R.; Katti, S. B.; Pannecouque, C.; Clercq, E. D. Design, synthesis,
and evaluation of 2-aryl-3-heteroaryl-1,3-thiazolidin-4-ones as anti-HIV agents. Bio. Org.
Med. Chem. 2007, 15, 1725–1731.
5. Shrivastava, T.; Gaikwad, A. K.; Haq, W.; Sinha, S.; Katti, S. B. Synthesis and biological
evaluation of 4-thiazolidinone derivatives as potential antimicrobacterial agents. Arkivoc
2005, 2, 120–130.
6. Desai, K. G.; Desai, K. R. A facile microwave enhanced synthesis of sulfur-containing
five-membered heterocycles derived from 2-mercaptobenzothiazole over ZnCl2=DMF
and antimicrobial evaluation. J. Sul. Chem. 2006, 27, 315–328.
7. Sharma, R. C.; Kumar, D. Synthesis of some new thiazolidin-4-ones as possible
antimicrobial agents. J. Ind. Chem. Soc. 2000, 77, 492–493.
8. Shrivastava, T.; Haq, W.; Katti, S. B. Carbodiimide-mediated synthesis of 4-thiazolidi-
nones by one-pot, three-component condensation. Tetrahedron 2002, 58, 7619–7624.
9. Veeresena, G.; Vie, N.; James, T. D.; Duane, D. M. Efficient microwave-enhanced
synthesis of 4-thiazolidinones. Synlett. 2004, 13, 2357–2358.
10. Fraga-Dubreuil, J.; Bazureau, J. P. Efficient combination of task-specific ionic liquid and
microwave heating applied to one-pot, three-component synthesis of a small library of
4-thiazolidinones. Tetrahedron 2003, 59, 6121–6130.
11. Kroutil, J.; Budesınsky, M. Preparation of diamino pseudodisaccharide derivatives from
1,6-anhydro-b-D-hexopyranoses via aziridine-ring cleavage. Carbohydrate Res. 2007, 342,
147–153.
12. Bolognese, A.; Correate, G.; Manfra, M.; Lavecchia, A.; Novellino, E.; Barone, V.
Thiazolidine-4-one formation: Mechanistic and synthetic aspect of the reaction of imines
and mercaptoacetic acid under microwave and conventional heating. Org. Bio. Mol.
Chem. 2004, 2, 2809–2813.
13. Desai, N. C.; Shulka, H. K.; Thaker, K. A. Some new 2-aryl-3-isonicotinamido-4-thiazo-
lidinones and their 5-carboxymethyl homologues as potential antitubercular and antibac-
terial agents. J. Ind. Chem. Soc. 1984, 61, 239–240.