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

Abstract

AbstractThe 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.