Efficient Construction of β-Arylethylamines via Selective C(sp3)-H Arylation of Aliphatic Amines

The synthetic innovations in generating β-arylethylamines have the potential to propel advancements in drug discovery, as β-arylethylamines are common structural motifs in various bioactive compounds and drugs. Here, we report an efficient Pd (II)-catalyzed method for the selective β-C(sp3)-H arylation of aliphatic amines to construct β-arylethylamine frameworks. With the easy installation and removal of the nitroso directing group on the amine nitrogen, this Pd-catalyzed method enables (hetero)arylation of the β-C(sp3)-H bonds on various aliphatic amine scaffolds to produce β-arylethylamines and tolerates a variety of functional groups on both coupling partners. It offers an approach to direct syntheses of β-arylethylamine drugs from common native amines, thereby overcoming inherent limitations of previously known methods. This identified Pd-catalyst-system features low catalyst loading for C–H functionalization and offers a high reaction rate, originating from the pyridone-amide-ester ligand that increases the activity of the Pd catalyst while protecting all active species from forming inactive Pd complexes. Experimental and computational studies disclose that the valuable ligand effect partially results from the pendant ester group that participates in several steps of the C(sp3)-H activation process and favors the Pd-catalytic cycle.