Pd-Catalyzed Regio- and Stereoselective sp³ C−H Arylation of Primary Aliphatic Amines: Mechanistic Studies and Synthetic Applications

The Pd-catalyzed γ-position sp³−C−H arylation of primary amines bearing an aliphatic chain or cycloalkyl substituent and related mechanistic studies are disclosed. 3-Bromo-2-hydroxybenzaldehyde plays a key role in γ-position sp³−C−H arylation as a transient directing group (TDG) to assist the regio- and stereoselective C−H activation of a Pd catalyst, and the development of a tandem reaction to transform 1°-amines into γ-aryl-substituted ketones demonstrates synthetic utility. Density functional theory (DFT)-based calculations revealed the detailed reaction mechanism and the origins of the high selectivity (γ-position and cis-only). The X-ray crystal structure of the isolated endo-palladacycle intermediate supported the DFT results, and a kinetic isotope experiment confirmed the results of DFT calculations indicating that the C−H activation step via simultaneous palladation and deprotonation is rate-determining.