Cobalt Homeostatic Catalysis for Coupling of Enaminones and Oxadiazolones to Quinazolinones

Transition metal catalysis has revolutionized modern synthetic chemistry for its diverse modes of coordination reactivity. However, this versatility in reactivity is also the predominant cause of catalyst deactivation, a persisting issue that can significantly compromise its synthetic value. Homeostatic catalysis, a catalytic process that can sustain its productive catalytic cycle even when chemically disturbed, is proposed herein as an effective tactic to address the challenge. In particular, a cobalt homeostatic catalysis process has been developed for water-tolerant coupling of enaminones and oxadiazolones to quinazolinones. Dynamic covalent bonding serves as a mechanistic handle for preferred buffering of water onto enaminone and reverse exchange back by released secondary amine, thus securing reversible entry into cobalt dormant and active states for productive catalysis. Through this homeostatic catalysis mode, a broad structural scope has been achieved for quinazolinones, enabling further elaboration into distinct pharmaceutically active agents.