title: Enantioselective amine α-functionalization via palladium-catalysed C-H arylation of thioamides.
abstract: Saturated aza-heterocycles are highly privileged building blocks that are commonly encountered in bioactive compounds and approved therapeutic agents. These N-heterocycles are also incorporated as chiral auxiliaries and ligands in asymmetric synthesis. As such, the development of methods to functionalize the α-methylene C-H bonds of these systems enantioselectively is of great importance, especially in drug discovery. Currently, enantioselective lithiation with (-)-sparteine followed by Pd(0) catalysed cross-coupling to prepare α-arylated amines is largely limited to pyrrolidines. Here we report a Pd(II)-catalysed enantioselective α-C-H coupling of a wide range of amines, which include ethyl amines, azetidines, pyrrolidines, piperidines, azepanes, indolines and tetrahydroisoquinolines. Chiral phosphoric acids are demonstrated as effective anionic ligands for the enantioselective coupling of methylene C-H bonds with aryl boronic acids. This catalytic reaction not only affords high enantioselectivities, but also provides exclusive regioselectivity in the presence of two methylene groups in different steric environments.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Pankaj
authors.identifier: 0000-0002-2834-1427
authors.initials: P
authors.lastname: Jain
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Pritha
authors.initials: P
authors.lastname: Verma
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Guoqin
authors.initials: G
authors.lastname: Xia
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Jin-Quan
authors.initials: JQ
authors.lastname: Yu
mesh_terms: D000588:Amines / Q000737:chemistry*; D001897:Boronic Acids / Q000737:chemistry; D002244:Carbon / Q000737:chemistry; D002384:Catalysis; D056831:Coordination Complexes / Q000737:chemistry; D006859:Hydrogen / Q000737:chemistry; D008024:Ligands; D010165:Palladium / Q000737:chemistry*; D010756:Phosphoric Acids / Q000737:chemistry; D013237:Stereoisomerism; D013854:Thioamides / Q000737:chemistry*
chemical_list: D000588:Amines; D001897:Boronic Acids; D056831:Coordination Complexes; D008024:Ligands; D010756:Phosphoric Acids; D013854:Thioamides; D010165:Palladium; D002244:Carbon; D006859:Hydrogen