ECO-FRIENDLY SYNTHESIS OF THIAZOLIDINONE DERIVATIVES AND THEIR BIOLOGICAL STUDIES

Abstract

Microwave heating, ionic liquids and solid phase catalysts were employed and studied for the preparation of various 4-thiazolidinone derivatives and for “in vitro” antibacterial and antifungal activity. These techniques revealed several advantages over the conventional methods. In combination with microwave radiation, ionic liquids were used as phase transfer catalysts (PTC) and montmorillonite clays (K10 and KSF types) were used as solid phase catalysts. The catalytic efficiency of montmorillonite KSF was marginally inferior to that of montmorillonite K10. Compounds pertaining to main six different series were synthesized. In the first series; two methods Microwave procedure-I: Multi-Component Reaction in DMF and Microwave procedure-II: Solvent free, Multi- Component Reaction were used and it was found that first was better in yield ranging from 82.4% to 96.0% while yield in procedure-II ranging from 42.6% to 84.6%. The compound 4,6-dimethylpyrimidin-2-amine was treated with disubstituted aromatic aldehydes in dimethylformamide to form a Schiff base and Schiff base was further treated with sulfanyl acetic acid under microwave radiation to obtain the compounds (88-97). The compounds of first series were synthesized and elucidated as 2-(2,4-dimethylphenyl)-3-(4,6-dimethylpyrimidin-2-yl)-thiazolidin-4-one (88), 3- (4,6-dimethylpyrimidin-2-yl)-2-(2-hydroxy-4-methylphenyl)-thiazolidin-4-one (89), 2- (2,4-dihydroxyphenyl)-3-(4,6-dimethylpyrimidin-2-yl)-thiazolidin-4-one (90), 2-(2,4- dichlorophenyl)-3-(4,6-dimethylpyrimidin-2-yl)-thiazolidin-4-one 3-(4,6- (91), dimethylpyrimidin-2-yl)-2-(2-hydroxy-4-methoxyphenyl)-thiazolidin-4-one (92), 2-(4- chloro-2-methylphenyl)-3-(4,6-dimethylpyrimidin-2-yl)-thiazolidin-4-one (93), 3-(4,6- dimethylpyrimidin-2-yl)-2-(4-fluorophenyl)-thiazolidin-4-one (94), 3-(4,6- dimethylpyrimidin-2-yl)-2-(4-nitrophenyl)-thiazolidin-4-one (95), 2-(2,4- difluorophenyl)-3-(4,6-dimethylpyrimidin-2-yl)-thiazolidin-4-one (96) and 2-(3- (dimethylamino)phenyl)-3-(4,6-dimethylpyrimidin-2-yl)- thiazolidin-4-one (97). In the second series (98-107); two methods Microwave procedure-I: Multi- Component Reaction using Montmorillonite Clays (K-10 and KSF) and Microwave procedure-II: Solvent free, Multi-Component Reaction were employed. First procedure was found better in yield ranging from (yield 78.4% to 94.1% with K-10 and 68.3% to 88.1% with KSF) while yield in second procedure ranging from 14.3% xii to 76.4%. In this procedure Schiff base was treated with mercaptoacetic acid under microwave radiation followed by the condensation reaction of aniline and substituted benzaldehydes. The compounds 2-(3,5-dimethylphenyl)-3-phenyl-thiazolidin-4-one (98), 2-(3-hydroxy-5-methoxyphenyl)-3-phenyl-thiazolidin-4-one (99), 2-(3-chloro-5- methylphenyl)-3-phenyl-thiazolidin-4-one (100), 2-(3,5-dichlorophenyl)-3-phenyl- thiazolidin-4-one (101), 2-(3-nitrophenyl)-3-phenyl-thiazolidin-4-one (102), 2-(3- ethoxyphenyl)-3-phenyl-thiazolidin-4-one thiazolidin-4-one (105), (104), (103), 2-(3-methoxyphenyl)-3-phenyl- 2-[3-(dimethylamino)phenyl]-3-phenyl-thiazolidin-4-one 2-(3,5-difluorophenyl)-3-phenyl-thiazolidin-4-one (106) and 2-(3,5- dihydroxyphenyl)-3-phenyl-thiazolidin-4-one (107) were obtained. For the compounds (108-117), two methods Microwave procedure-I: Ionic Liquids (PEG, TBAB and TEBAC) and Microwave procedure-II: Solvent free, Multi- Component Reaction were used. The second procedure was found better in yield and environmentally than Ionic Liquids (PEG, TBAB and TEBAC). The yield ranged from 33.4%-48.8% with TBAB, 33.5%-52.2% with PEG and 20.4%-32.4% with TEBAC while in solvent free procedure-II 66.8% to 92.8%. The compounds 1,3- dipyridin-2-ylthiourea, chloroacetic acid and different aromatic aldehydes were used for the preparation of compounds (108-117) of third series named as 5-benzylidene- 3-(pyridin-2-yl)-2-(pyridin-2-ylimino)-thiazolidin-4-one (108), 5-(4- methoxybenzylidene)-3-(pyridin-2-yl)-2-(pyridin-2-ylimino)-thiazolidin-4-one (109), 5- (2-hydroxy-4-methoxybenzylidene)-3-(pyridin-2-yl)-2-(pyridin-2-ylimino)-thiazolidin-4- one (110), 5-[4-(dimethylamino)benzylidene]-3-(pyridin-2-yl)-2-(pyridin-2-ylimino)- thiazolidin-4-one (111), 5-(2,4-dichlorobenzylidene)-3-(pyridin-2-yl)-2-(pyridin-2- ylimino)-thiazolidin-4-one (112), 5-(4-nitrobenzylidene)-3-(pyridin-2-yl)-2-(pyridin-2- ylimino)-thiazolidin-4-one (113), 5-(4-ethoxybenzylidene)-3-(pyridin-2-yl)-2-(pyridin- 2-ylimino)-thiazolidin-4-one (114), 5-(2,4-difluorobenzylidene)-3-(pyridin-2-yl)-2- (pyridin-2-ylimino)-thiazolidin-4-one (115), 5-(4-ethylbenzylidene)-3-(pyridin-2-yl)-2- (pyridin-2-ylimino)-thiazolidin-4-one (116) and 5-(1,3-benzodioxol-5-ylmethylidene)- 3-(pyridin-2-yl)-2-(pyridin-2-ylimino)-thiazolidin-4-one (117). In the forth series; two methods Microwave procedure-I: Multi-Component Reaction using Montmorillonite Clays (KSF and K-10) and Microwave procedure-II: Solvent free, Multi-Component Reaction were used and it was found that first was better in yield ranging from 78.8% to 96.1% with K-10 and 70.8% to 84.2% with KSF xiii while yield in second ranging from 34.6% to 78.8%. In this series compounds (118- 127) were synthesized by adopting environmentally safe procedure. (4-substituted- phenyl)methylidene]aniline was treated with sulfanyl(thioxo)acetic acid in the presence of montmorillonite clays under microwave radiation for ten to twelve minutes. The compounds (118-127) (5-benzylidene-3-phenyl-2-thioxo-thiazolidin-4- one (118), 5-(4-methylbenzylidene)-3-phenyl-2-thioxo-thiazolidin-4-one (119), 5-(4- methoxybenzylidene)-3-phenyl-2-thioxo-thiazolidin-4-one 5-(3-hydroxy-4- (120), methoxybenzylidene)-3-phenyl-2-thioxo-thiazolidin-4-one (121), (dimethylamino)benzylidene]-3-phenyl-2-thioxo-thiazolidin-4-one nitrobenzylidene)-3-phenyl-2-thioxo-thiazolidin-4-one yl)benzylidene]-3-phenyl-2-thioxo-thiazolidin-4-one 5-(4- (124), 5-[2-(furan-2- (125), (126) 5-(4- 5-(2,4- (123), dichlorobenzylidene)-3-phenyl-2-thioxo-thiazolidin-4-one ethoxybenzylidene)-3-phenyl-2-thioxo-thiazolidin-4-one (122), 5-[4- and 5-(2,4- difluorobenzylidene)-3-phenyl-2-thioxo-thiazolidin-4-one) (127) were synthesized. The compounds (128-137) of fifth series were prepared by using environmentally benign procedure and reaction time was also dramatically reduced. In this series two methods Microwave procedure-I: Multi-Component Reaction using Montmorillonite Clays (KSF and K-10) and Microwave procedure-II: Solvent free, Multi-Component Reaction were employed and procedure-I was found better in yield ranging yields ranging from 78.8% to 94.4% with K-10 and 68.9-% to 88.6% with KSF while yield in procedure-II ranging from 34.4% to 65.3%. Sulfanylacetic acid was reacted with (2,5-disubstituted-phenyl)methylidene-4-methoxypyrimidin-2-amine followed by the condensation between 4-methoxypyrimidin-2-amine and various aldehydes. The compounds 2-(2,5-dimethylphenyl)-3-(4-methoxypyrimidin-2-yl)- thiazolidin-4-one (128), 2-(4-ethylphenyl)-3-(4-methoxypyrimidin-2-yl)-thiazolidin-4- one (129), 2-(4-methoxyphenyl)-3-(4-methoxypyrimidin-2-yl)-thiazolidin-4-one (130), 2-(2-hydroxy-5-methoxyphenyl)-3-(4-methoxypyrimidin-2-yl)-thiazolidin-4-one (131), 2-(4-ethoxyphenyl)-3-(4-methoxypyrimidin-2-yl)-thiazolidin-4-one (132), 2-[4- (dimethylamino)phenyl]-3-(4-methoxypyrimidin-2-yl)-thiazolidin-4-one (133), 2-(2,5- dichlorophenyl)-3-(4-methoxypyrimidin-2-yl)-thiazolidin-4-one difluorophenyl)-3-(4-methoxypyrimidin-2-yl)-thiazolidin-4-one (134), (135), 2-(2,5- 2-(2,5- dihydroxyphenyl)-3-(4-methoxypyrimidin-2-yl)-thiazolidin-4-one (136), 2-[3-(furan-2- yl)phenyl]-3-(4-methoxypyrimidin-2-yl)-thiazolidin-4-one (137) were thus achieved.