Synthesis of Five-Membered Heterocycle Fused Quinazolinone Via Buchwald-Hartwig Cross Coupling Reaction

Through the Buchwald-Hartwig cross-coupling reaction, we successfully coupled the 2 '-bromo five-membered heterocyclic ester derivative with the 2-aminopyridine derivative, and carried out an intramolecular cyclization reaction to synthesize quinazolinone derivatives with the substituted fived-membered heterocycle. Using Pd(OAc)2 as the catalyst and Xantphos ligand, we synthesized fived-membered heterocycle-fused quinazolinone derivatives with 23 different aminopyridines, as well as thiazole, imidazole, thiophene, pyrrole, and pyrazole, with yields from 7-99 %. To further expand the diversity of heterocyclic rings, we used mCPBA to oxidize the methylsulfide at the 2-position of thiazole to a sulfone group, and then optimized a desulfonative nucleophilic substitution reaction using a variety of nucleophiles. This allowed for the substitution of 11 nucleophiles, resulting in the construction of a library of 37 quinazolinone derivatives with substituted five-membered heterocycles.