Second-Generation Palladium Catalyst System for Transannular C-H Functionalization of Azabicycloalkanes

This article describes the development of a second-generation catalyst system for the transannular C-H functionalization of alicyclic amines. Pyridine- and quinoline-carboxylate ligands are shown to be highly effective for increasing the reaction rate, yield, and scope of Pd-catalyzed transannular C-H arylation reactions of azabicyclo[3.1.0]hexane, azabicyclo[3.1.1]heptane, azabicyclo[3.2.1]octane, and piperidine derivatives. Mechanistic studies reveal that the pyridine/quinoline-carboxylates play a role in impeding both reversible and irreversible catalyst decomposition pathways. These ligands enable the first reported examples of the transannular C-H arylation of the ubiquitous tropane, 7-azanorbornane, and homotropane cores. Finally, the pyridine/quinoline-carboxylates are shown to promote both transannular C-H arylation and transannular C-H dehydrogenation on a homotropane substrate.