Synthetic access to diverse thiazetidines a one-pot microwave assisted telescopic approach and their interaction with biomolecules

• Published in: Organic & biomolecular chemistry Vol. 22; no. 16; pp. 3249 - 3261
• Main Authors: Rao, Ramdas Nishanth, Das, Soumyadip, Jacob, Kezia, Alam, Mohammed Mujahid, Balamurali, M. M, Chanda, Kaushik
• Format: Journal Article
• Published: 24.04.2024
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/d4ob00075g

A one-pot microwave assisted telescopic approach is reported for the chemo-selective synthesis of substituted 1,3-thiazetidines using readily available 2-aminopyridines/pyrazines/pyrimidine, substituted isothiocyanates and 1,2-dihalomethanes. The procedure involves thiourea formation from 2-aminopyridines/pyrazines/pyrimidine with the substituted isothiocyanates followed by a base catalysed nucleophilic attack of the C&z.dbd;S bond on the 1,2-dihalomethane. Subsequently, a cyclization reaction occurs to yield substituted 1,3-thiazetidines. These four membered strained ring systems are reported to possess broad substrate scope with high functional group tolerance. The above synthetic sequence for the formation of four membered heterocycles is proven to be a modular and straightforward approach. Further the mechanistic pathway for the formation of 1,3-thiazetidines was supported by computational evaluations and X-ray crystallography analyses. The relevance of these thiazetidines in biological applications is evaluated by studying their ability to bind bio-macromolecules like proteins and nucleic acids. Computationally revealed mechanistic pathway of one-pot telescopically approached thiazetidine synthesis revealed the formation of a single product. The position of alkyl substitution plays significant role to enhance biomolecular interactions.