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.

Figure 1. Examples of important chiral α-arylated cyclic amines and approaches for the construction of α-stereocenters

a, Numerous drug molecules, such as Cialis, CERC-501, and L-733,060, contain non-racemic α-arylated cyclic amines. These structures are ubiquitous throughout biological systems, where the orientation of the α –substituent can have a dramatic effect on the activity of the resulting product. b, Traditional approaches for asymmetric arylation and alkylation of pyrrolidines proceed via α-lithiation to install aryl and alkyl substituents. While effective for pyrrolidine substrates, the procedures are far less effective for larger ring systems or those with sensitive functional groups. c, In this work, enantioselective α-C(sp³)–H coupling of amines is carried out in the presence of a chiral phosphate anion, which permits the arylation of a diverse array of aliphatic amines through the use of a thioamide directing group.

Figure 2. Removal of the thioamide directing group

The directing group can be removed in two steps. The first step involves the reduction of 2a in presence of NiCl₂ and NaBH₄ to afford the dethiolated product 5. The second step involves the debenzylation of 5 in presence of BCl₃ to afford the free amine, followed by Boc protection to give 6 in 58% yield and 98:2 er.