Synthesis of Quinazolinones by Combined Ullmann Coupling-Oxidative C-H Amidation

Significance

Reported is an efficient synthesis of quinazolinone derivatives from substituted 2-halobenzamides 1 and (aryl)methanamines 2 through a sequential copper-catalyzed Ullmann coupling and aerobic oxidative C-H amidation. Screening of bases, catalysts, solvents, and reaction temperature led to the optimized CuBr/K₂CO₃ catalyst-base combination. As expected, 2-iodobenzamides show higher reactivity than the corresponding bromides; further, only aryl chlorides containing EWGs were effective coupling partners. In general, the nature of the substituent (EWGs or EDGs) on the halobenzamides or (aryl)-methanamines was inconsequential to reactivity and ether, Cl, NO₂ functional groups as well as ­nitrogen, oxygen or sulfur heterocyles were well tolerated in the amine component.