Native amine-directed site-selective C(sp³)-H arylation of primary aliphatic amines with aryl iodides

Direct C(sp³)-H functionalization of N-unprotected aliphatic amines represents one of the most efficient and straightforward strategies for amine synthesis. Despite some recent progress in this field, the NH₂-directed γ-C(sp³)-H arylation of primary aliphatic amines except α-amino esters remained an unmet challenge. In this report, we established a simple and efficient method for site-selective C(sp³)-H arylation of primary aliphatic amines by aryl iodides. In the presence of only 5 mol% Pd(OAc)₂, a wide range of aliphatic amines including O-benzyl and O-silyl amino alcohols were arylated at γ- or δ-positions by aryl iodides containing a broad scope of functional groups. The synthetic application of this method had also been demonstrated by large-scale synthesis, the synthesis of a fingolimod analogue, and the conjugation with natural D-menthol and fluorescent 1,8-naphthalimide.