Ligand-enabled cross-coupling of C(sp3)–H bonds with arylboron reagents via Pd(II)/Pd(0) catalysis

Abstract

There have been numerous developments in C–H activation reactions in the past decade. Attracted by the ability to directly functionalize molecules at ostensibly unreactive C–H bonds, chemists have discovered reaction conditions that enable reaction of C(sp2)–H and C(sp3)–H bonds with a variety of coupling partners. Despite these advances, the development of suitable ligands that enable catalytic C(sp3)–H bond functionalization remains a significant challenge. Here, we report the discovery of a mono-N-protected amino acid (MPAA) ligand that enables Pd(II)-catalyzed coupling of γ-C(sp3)–H bonds in triflyl-protected amines (R–NHTf) with arylboron reagents. Remarkably, no background reaction was observed in the absence of ligand. A variety of amine substrates and arylboron reagents were cross-coupled using this method. Arylation of optically active amino acid-derived substrates also provides a potential route for preparing non-protenogenic amino acids.