Synthesis of quinazolinone scaffolds from the cascade reaction of o-aminobenzamides/o-aminobenzonitriles and calcium carbide mediated by K2S

Abstract

An efficient multicomponent methodology has been developed for the synthesis of quinazolinones and dihydroquinazolinones through the reaction of o-aminobenzamides or o-aminobenzonitriles with CaC₂ mediated by K₂S. The process begins with the formation of thioacetaldehyde, which results from the direct nucleophilic attack of sulfur anions on the acetylene generated from CaC₂. Subsequently, the thioacetaldehyde reacts with o-aminobenzamide to produce an imine intermediate, which then undergoes cyclization to generate the target compound in moderate to excellent yields. Moreover, this methodology has been extended to a one-pot synthesis of dihydroquinazolinones using 2-aminobenzonitrile and CaC₂. In this approach, the nitrile group is hydrolyzed to form an amide, which then reacts with CaC₂ to yield the target product. Notably, this protocol exhibits excellent scalability and has been successfully applied to synthesize pharmaceutical compounds or drug intermediates. By using cost-effective and eco-friendly reagents such as CaC₂ and inorganic sulfides, this strategy provides a valuable and sustainable alternative to existing methods for the synthesis of quinazolinones.