Facile synthesis and biological evaluation of some ethoxyphthalimide derivatives of pyrazolylthiazoloisoxazoles and pyrazolylthiadiazoles

Abstract

Reaction of acetylacetone with hydrazine hydrate gave 3,5-dimethyl-1H-pyrazole (1) which when reacted with ethylchloroacetate in acetone and thiosemicarbazide yielded ethyl-3,5-dimethyl-1H-pyrazol-1-yl-acetate (2) and 2-[(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]hydrazine carbothioamide (3) respectively. Compound 3 acted as a key intermediate for both the series of final compounds. In one pathway, it was converted to corresponding thiadiazole (11) by treatment with conc. H 2 SO 4 and NH 3 which on condensation with (ω-bromoethoxyphthalimide (10) gave 5-[(3,5-dimethyl-1H-pyraz 1-yl)methyl]-N-ethoxyphthalimido-1,3,4-thiadiazol-2-amine (12). In another pathway, 3 reacted with chloroacetic acid to furnish 2-[(3,5-dimethyl-1H-pyrazolyl)-4-oxo-1,3-thiazolidin-2-ylidene acetohydrazide (4). Reaction of 4 with various araldehydes (5a-d) gave 5-[(4-substituted phenyl)methylidene]-4-oxo-1,3-thiazolidin-2-ylidene]-2-[(3,5-dimethyl-1H-pyrazolyl)acetohydrazide (6a-d) which were further treated in two alternate routes. Firstly, with 10 to yield 5-{[(4-substituted phenyl)methylidene]-3-N-ethoxyphthalimido-4-oxo-1,3-thiazolidin-2-ylidene}-2-(3,5-dimethyl-1H-pyrazolyl)acetohydrazide (8a-d). Cyclisation of these derivatives using hydroxylamine hydrochloride produced the target compounds 3-(4-substituted phenyl)-6-N-ethoxyphthalimido-3,3a-dihydro[1,3]thiazolo[4,5-c]isoxazol-5(6H)-ylidene-2-(3,5-dimethyl-1H-pyrazol-1-yl)acetohydrazide (9a-d). In parallel, 6a-d were first cyclised with hydroxylamine hydrochloride to give 3-[(4-substituted phenyl)-3,3a-dihydro[1,3]thiazolo[4,5-c]isoxazol-5(6H)-ylidene-2-(3,5-dimethyl-1H-pyrazol-1-yl)acetohydrazide (7a-d) and then condensed with 10 to yield the final compounds 9a-d. Structural elucidation of synthesized compounds was accomplished by IR, 1 H NMR, 13 C NMR and mass spectral data. Final compounds were screened for their antimicrobial activity.