Copper-catalyzed asymmetric formal hydroaminomethylation of alkenes with n,o-acetals to access chiral β-stereogenic amines: Dual functions of the copper catalyst

Abstract

Chiral amines are synthetically versatile intermediates used for the preparation of a wide range of biologically active compounds and drugs. Compared with the well-developed synthesis of α-stereogenic amines, the establishment of enantioselective protocols to access β-stereogenic amines are very limited. Herein, we report an asymmetric synthesis of β-stereogenic amines through copper-catalyzed enantioselective formal aminomethylation of alkenes with N,O-acetals of formaldehyde. We carried out series of reactions using a variety of vinylarenes and 1,3-dienes with N,O-acetals of formaldehyde to generate the corresponding chiral β-branched alkylamines and (E)-homoallylamines in high yields, and with excellent enantioselectivity. The copper catalyst promoted not only the formation of alkylcopper nucleophiles from alkenes but also the generation of methylene imineelectrophiles fromN,O-acetals offormaldehyde. Our experimental design provides an attractive approach for the synthesis of chiral β-stereogenic amines fromreadily available alkenes and N,O-acetals with a base-metal catalyst under mild conditions.