Efficient Construction\nof β‑Arylethylamines\nvia Selective C(sp<sup>3</sup>)‑H Arylation of Aliphatic Amines

The synthetic innovations in generating β-arylethylamines\nhave the potential to propel advancements in drug discovery, as β-arylethylamines\nare common structural motifs in various bioactive compounds and drugs.\nHere, we report an efficient Pd (II)-catalyzed method for the selective\nβ-C(sp<sup>3</sup>)-H arylation of aliphatic amines to construct\nβ-arylethylamine frameworks. With the easy installation and\nremoval of the nitroso directing group on the amine nitrogen, this\nPd-catalyzed method enables (hetero)arylation of the β-C(sp<sup>3</sup>)-H bonds on various aliphatic amine scaffolds to produce\nβ-arylethylamines and tolerates a variety of functional groups\non both coupling partners. It offers an approach to direct syntheses\nof β-arylethylamine drugs from common native amines, thereby\novercoming inherent limitations of previously known methods. This\nidentified Pd-catalyst-system features low catalyst loading for C–H\nfunctionalization and offers a high reaction rate, originating from\nthe pyridone-amide-ester ligand that increases the activity of the\nPd catalyst while protecting all active species from forming inactive\nPd complexes. Experimental and computational studies disclose that\nthe valuable ligand effect partially results from the pendant ester\ngroup that participates in several steps of the C(sp<sup>3</sup>)-H\nactivation process and favors the Pd-catalytic cycle.