Development of a Deactivation-Resistant Dialkylbiarylphosphine Ligand for Pd-Catalyzed Arylation of Secondary Amines

Abstract

Despite the prevalence of N-heteroarenes in small-molecule pharmaceuticals, Pd-catalyzed C–N cross-coupling reactions of aryl halides and amines containing these rings remain challenging due to their ability to displace the supporting ligand via coordination to the metal center. To address this limitation, we report the development of a highly robust Pd catalyst supported by a new dialkylbiarylphosphine ligand, FPhos. The FPhos-supported catalyst effectively resists N-heteroarene-mediated catalyst deactivation to readily promote C–N coupling between a wide variety of Lewis-basic aryl halides and secondary amines, including densely functionalized pharmaceuticals. Mechanistic and structural investigations, as well as principal component analysis and density functional theory, elucidated two key design features that enable FPhos to overcome the limitations of previous ligands. First, the ligated Pd complex is stabilized through its conformational preference for the O-bound isomer, which likely resists coordination by N-heteroarenes. Second, 3′,5′-disubstitution on the non-phosphorus-containing ring of FPhos creates the ideal steric environment around the Pd center, which facilitates binding by larger secondary amines while mitigating the formation of off-cycle palladacycle species.