Ligand-Enabled Cross-Coupling of C(sp3)–H Bonds with Arylboron Reagents

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. Transition metal-catalyzed C–H activation directed by heteroatom directing groups has rapidly emerged as a fertile field for developing a diverse range of catalytic carbon–carbon and carbon–heteroatom bond forming reactions1–10. During our efforts towards the development of Pd(II)-catalyzed C–H activation reactions using a broad range of synthetically useful substrates, it has become evident that controlling the reactivity and selectivity of catalysts through the use of external ligands such as amino acids11–16, pyridines, and quinolines17,18 is crucial for realizing their full potential as useful tools for synthesis. We have previously demonstrated that weak coordinating functional groups such as-COOH,-OH,-CN, and-OMe can cooperate with a mono-N-protected amino acid Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use