Pd-Catalyzed C–H Activation vs β-H Elimination: An Experimental and Computational Insight into the Reactivity of Tertiary Alkylamines

Tertiary alkylamines can coordinate palladium salts and direct C–H activation reactions. However, these tertiary alkylamines can suffer from decomposition through oxidative pathways. This report describes the DFT analysis of acyclic and cyclic tertiary alkylamines with respect to C–H bond cleavage through either γ-C(sp3)–H activation on the exo N-substituent or β-H elimination at the endocyclic position. The study assesses the role of an N-acetyl amino acid ligand in suppressing the β-H elimination pathway. Experiments using tertiary alkylamines with isotopically labeled α-C–D bonds demonstrate the small differences in energy barriers that discern both reaction pathways. Guided by the insights of computational studies on methyl and strained methylene γ-C–H activation in tertiary alkylamines, we report a successful methine γ-C–H activation to construct ring-strained quaternary centers through intermolecular C–H arylation.