Palladium-catalyzed benzocyclization reactions of quinoline-2-carboxamides via sequential C–H/N–H functionalization

Abstract

Abstract

A novel benzocyclization protocol has been developed for the synthesis of quinoline-fused lactams by palladium-catalyzed sequential C–H/N–H functionalization of quinoline-2-carboxamides and 1,2-dihaloarenes. The reaction proceeds at the C–H bond on the quinoline adjacent to the amide group and at the amide N–H bond in the presence of 10 mol % Pd(OAc) 2 in o -xylene as a solvent to afford the cyclized product in 34% yield. The yield increases to 81% when the reaction is carried out with 80 mol % P(4-MeOC 6 H 4 ) 3 as a ligand and with an increased catalyst loading of 20 mol %. The reaction affords lactams in up to 83% yield using amides containing various functional groups and substituted 1-bromo-2-iodobenzenes. Furthermore, 1,2-dibromo heteroarenes, such as benzothiophene and pyridine, undergo annulation to give the corresponding heterocycle-fused compounds. The high chemoselectivity of the 1,2-dihaloarene functional groups is confirmed in this reaction, thus enabling divergent synthesis of various multifused heterocyclic systems.