Copper-Catalyzed Stereospecific C–S Coupling Reaction of Enantioenriched Tertiary Benzylic Amines via in Situ Activation with Methyl Triflate

Abstract

A one-pot protocol for the synthesis of highly enantiopure benzylic thioethers, thioacetates, and sulfones (94–99% ee) via a ligand-free, copper-catalyzed stereospecific C–S coupling reaction of thiols and enantioenriched tertiary benzylic amines via in situ activation by methyl triflate is developed. Various enantioenriched tertiary benzylic amines, including 1-arylalkylamines, 1-tetrahydronaphthylethylamine, heterocyclic amines (e.g., 1-(thiophen-2-yl)ethanamine), and amino acid esters containing a benzylamine moiety, are highly efficient substrates, and their chirality is efficiently transferred to the products (94–99% ee). The absolute configurations of the products are predictable and follow the pattern of SN2-type substitutions; an inversion of the absolute configuration of the tertiary amines occurs during the C–S coupling reaction. Not only are various alkene-, arene-, and heteroarenethiols suitable for this C–S coupling reaction but also potassium thioacetate and sodium phenylsulfinate are as well. A plausible mechanism was proposed on the basis of the experimental results.