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.