Palladium Direct Arylation and Annulation for the Catalyzed Regiocontrolled Synthesis of Quinolone Derivatives

Abstract

A palladium-catalyzed strategy for the one pot synthesis of quinolone derivatives from (hetero)arylamides and functionalized 1,2-dihalobenzenes is described. The transformation likely proceeds through a Pd 1,4-migration from the amide nitrogen atom to the (hetero)aryl ring or via a direct ortho-metalation process, enabling first the ortho-arylation of the (hetero)arylamide. The key C–C bond is formed via the direct functionalization of two distinct C–H bonds, avoiding the need for prefunctionalized amide coupling partner. Subsequent intramolecular C–N bond formation via Pd-catalyzed coupling efficiently furnishes the quinolone scaffold. The protocol exhibits broad functional group tolerance, accommodating diverse substituents on the 1,2-dihalobenzene as well as a range of (hetero)aryl amides. This methodology allows the installation of functional groups at defined positions on the (hetero)aromatic rings. Additionally, the use of an air-stable, readily accessible palladium catalyst in combination with an inexpensive base enhances the synthetic utility of the process.