Ligand-Promoted Pd(II)-Catalyzed Functionalization of Unactivated C(sp3)-H Bond: Regio- and Stereoselective Synthesis of Arylated Rimantadine Derivatives

Stereoselective functionalization of the adamantyl bridge methylene C(sp(3))-H bonds is a rather appealing, yet challenging strategy due to the bulky and unactivated nature. Here we present a palladium-catalyzed C(sp(3))-H arylation/hetereoarylation of the antivirus drug rimantadine with the picolinamide moiety as the bidentate directing group and a mono-N-protected amino acid (MPAA) as the ligand. Multisubstituted rimantadine substrates and diverse aryl/heteroaryl iodides are well tolerated, optically pure arylated rimantadine derivatives have been synthesized in high regio- and diastereoselectivity that compound space for further pharmaceutical research.