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

• Published in: Journal of heterocyclic chemistry 2024-07, Vol.61 (7), p.1075-1090
• Main Authors: Almatari, Altaf S., Saeed, Ali, Abdel‐Ghani, Ghada E., Abdullah, Mahmood M. S., El‐Demerdash, Amr, Abdel‐Latif, Ehab
• Format: Article
• Language: English
• Subjects: Alkylation; Antimicrobial agents; Antioxidants; Chemical synthesis; Dimethylformamide; Ethanol; Hydrazines; Infrared spectroscopy; Malononitrile; NMR; Nuclear magnetic resonance; Pyrazole; Reagents; Refluxing; Scaffolds; Thiophenes; Triethylamine
• ISSN: 0022-152X; 1943-5193
• DOI: 10.1002/jhet.4832

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 K2CO3 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 1H‐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‐4H‐pyrido[1,2‐a]thieno[3,2‐e]pyrimidin‐9(5H)‐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), 1H NMR, and 13C 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. Synthesis of novel substituted thiophenes hybridized with thiazole, pyrazole or pyrimidinone ring systems and assessing their potential as antioxidants and antimicrobial agents.