Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides

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. Chiral, saturated N-heterocycles are prized as pharmaceutical agents and chiral auxiliaries, but are challenging to access without using prefunctionalized starting materials. Now, chiral phosphoric acids are found to enable the enantioselective Pd(II)-catalysed arylation of α-methylene C–H bonds in a wide variety of amines using thioamide as the directing group.