Aza- and thio-Michael addition reactions involving α,β- unsaturated keto acids

Abstract

Pyridazin-3(2H)-ones are an important class of heterocyclic compounds, especially in the fields of biology, pharmacology and bioorganic chemistry. Several comprehensive studies have illustrated in details their diverse pharmacological and biological actions. These observations prompted our interest to synthesize some novel 6-aryl-4,5-dihydropyridazin-3(2H)-ones bearing moieties with great importance like 1,3,4-thiadiazoles and thioglycolic acid at 4-carbon, accompanied by substituted 2-nitrogen. Thus, the present work is devoted to study the interaction of β-aroylacrylic acid (218) with three selected 1,3,4-thiadiazoles namely, 1,3,4-thiadiazole-2,5-diamine (219), 5-amino-1,3,4-thiadiazole-2-thiol (220), 1,3,4-thiadiazole-2,5-dithiol (221) and thioglycolic acid (222) in order to synthesize aza- and thio-Michale adducts, then using the formed compounds as starting material to synthesize fused and isolated pyridazin-3(2H)-one systems. In the first part of our study, the four adducts have been synthesized as follows; compound (218) has been reacted with 1,3,4-thiadiazole-2,5-diamine (219) in ethylene glycol to afford the aza-Michael adduct (223). Compound (218) were reacted with 5-amino-1,3,4-thiadiazole-2-thiol (220) in ethanol to produce thio-Michael adduct (224). Refluxing the same compound with 1,3,4-thiadiazole-2,5-dithiol (221) in toluene produced thio-Michael adduct (225). Finally, thio-Michael adduct (226) has been obtained by reacting compound (218) with thioglycolic acid (222) in methanol at room temperature. In the second part of the study, the synthesized adducts were then reacted with some hydrazines, namely hydrazine hydrate, acetohydrazide, formohydrazide, semicarbazide and thiosemicarbazide to achieve formation of some new dihydropyridazin-3(2H)-one derivatives. Thus, refluxing of aza-Michael adduct (223) with hydrazine hydrate, acetohydrazide, formohydrazide, semicarbazide or thiosemicarbazide in (DMF) at mild temperature afforded the dihydropyridazin-3(2H)-ones (227-231). Similarly, both of thio-Michael adducts (224) and (225) have been refluxed in (DMF) to produce the dihydropyridazin-3(2H)-ones (232-241). Following the same synthetic approach, thio-Michael adducts (226) was reacted with the selected hydrazines to afford the dihydropyridazin-3(2H)-ones (242-246). In the third part of the study, aza- adduct (223) or thio- adduct (224) were reacted with diethylmalonate or ethylacetoacetate in basic solution to produce thiadiazolobutanamides (247-250). The obtained thiadiazolobutanamides have been subjected into more investigation by interaction with different N-nucleophiles. Thus, interaction of compounds (247) or (249) with 2 moles of hydrazines, namely hydrazine hydrate, acetohydrazide, formohydrazide, semicarbazide or thiosemicarbazide in (DMF) at moderate temperature to afforded compounds (251-260). Under the same reaction conditions compounds (248) or (250) reacted with 2 moles of hydrazine hydrate to afford the thiadiazolopyridazin-3(2H)-ones (261) and (262) respectively. Then compound only (248) were reacted with the rest of hydrazine derivatives acetohydrazide, formohydrazide, semicarbazide or thiosemicarbazide to produce compounds (263-266). In the fourth part of the study, compounds (233) and (235) were treated with some active methylene derivatives in order to synthesize fused thiadiazolopyridazin-3(2H)-one derivatives. Thus, compounds (233) or (235) have been treated with malononitrile, ethyl cyanoacetate, acetylacetone or ethyl acetoacetate in acetic medium to afford the [1,3,4]thiadiazolo[2,3-b][1,3]thiazines (50-57). Structures of the synthesized compounds were con¬firmed via elemental analysis, IR, 1HNMR and Mass spectroscopy methods. Finally, some of the obtained compounds have been investigated for their in vitro antimicrobial activity, and most of them exhibited promising biocidal effect. Keywords: Aza-Michael addition, Thio-Michal addiction, hydrazines, 1,3,4-thiadiazole, Pyridazin-3(2H)-ones.