Employing acetoacetamide as a key synthon for synthesizing novel thiophene derivatives and assessing their potential as antioxidants and antimicrobial agents

The objective of this study is to synthesize novel heterocyclic scaffolds containing a thiophene moiety using easily accessible acetoacetamide as a key synthon. The reaction of acetoacetamide with diazonium salts resulted in the formation of the corresponding thiophene derivatives 4a – c . Additionally, the reaction of acetoacetamide derivative 3 with malononitrile, ethyl cyanoacetate, or 2‐cyanoacetamide, along with elemental sulfur, under refluxing in dioxane containing triethylamine afforded thiophene‐containing derivatives 5a – c . Furthermore, compound 3 reacted with phenyl isothiocyanate in dry dimethylformamide and K 2 CO 3 to yield compound 7 . In situ alkylation of the non‐isolable salt 6 was achieved by the addition of methyl iodide, resulting in the formation of methylthio‐thiophene‐2‐carboxamide 8 . Compound 7 was employed with numerous alpha‐halogenated reagents in ethanol, affording thiazole derivative 9 and thiophene derivatives 10a and 10b , respectively. Moreover, compound 8 was reacted with hydrazine to produce the 1 H ‐pyrazole‐4‐carboxamide derivative 11 . Additionally, refluxing acetoacetamide derivative 3 with malononitrile and/or ethyl cyanoacetate in dioxane, in the presence of catalytic amount of triethylamine afforded 4‐imino‐3,7‐dimethyl‐4 H ‐pyrido[1,2‐ a ]thieno[3,2‐ e ]pyrimidin‐9(5 H )‐one derivatives 12a and 12b . Furthermore, the reactivity of acetoacetamide derivative 3 with 2‐cyanoacetohydrazide was investigated through refluxing the reactants in dioxane, which subsequently yielded the corresponding cyanoacetamide derivative 13 . The chemical identity of the newly synthesized compounds was determined by employing infrared spectroscopy (IR), 1 H NMR, and 13 C NMR techniques. Newly synthesized heterocycles incorporating thiophenes were evaluated for their antioxidant and antimicrobial potentials. Notably, thiophene scaffolds 5a , 10b , 11 , and 13 displayed notable antioxidant and antimicrobial activities.