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

The Pd-catalyzed gamma-position sp(3)-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 gamma-position sp(3)-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 degrees-amines into gamma-aryl-substituted ketones demonstrates synthetic utility. Density functional theory (DFT)-based calculations revealed the detailed reaction mechanism and the origins of the high selectivity (gamma-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.

Automated summary

The research reveals the use of 3-bromo-2-hydroxybenzaldehyde as a transient directing group in the Pd-catalyzed gamma-position sp(3)-C-H arylation of primary amines, and detailed the reaction mechanism and high selectivity origins through density functional theory calculations and X-ray crystal structure analysis.