Reaction of [2-(3-hetaryl-1,2,4-triazol-5-yl)phenyl]amines with ketones: a density functional theory study

• Published in: Theoretical chemistry accounts 2024-04, Vol.143 (4), Article 35
• Main Authors: Pylypenko, Olena O., Sviatenko, Liudmyla K., Shabelnyk, Kostyantin P., Kovalenko, Sergiy I., Okovytyy, Sergiy I.
• Format: Article
• Language: English
• Subjects: Amines; Atomic/Molecular Structure and Spectra; Biological activity; Biological properties; Chemistry; Chemistry and Materials Science; Cyclohexanone; Density functional theory; Inorganic Chemistry; Ketones; Organic Chemistry; Physical Chemistry; Reaction mechanisms; Spiro compounds; Theoretical and Computational Chemistry; Triazoles
• ISSN: 1432-881X; 1432-2234
• DOI: 10.1007/s00214-024-03110-3

The derivatives of 1,2,4- triazole have attracted great attention among medicinal chemists due to their wide range of biological activity, good pharmacodynamic and pharmacokinetic profiles, and low toxicity, that necessitates the development of various synthesis methods and a comprehensive study of their reaction mechanisms. A detailed investigation of possible pathways for formation of new spiro-condensed [1,2,4]triazolo[1,5-c]quinazolines, that combine two structural domains with different biological properties, was performed by computational study at the SMD/B3lyp/6-31+G(d) theory level. The mechanism of interaction between [2-(3-hetaryl-1,2,4-triazol-5-yl)phenyl]amine and cyclohexanone in methanol involves three main processes: formation of carbinolamine by addition of an amine to double bond C=O, elimination of a water molecule, and intramolecular cyclization leading to formation of spiro compounds. Results show increase in reactivity of reactants during acid-catalyzed reaction compared to uncatalyzed one. The nature of the heterocyclic substituent on the triazole ring has little effect on the reaction energy, while the mechanism is unchanged.