Chemoselective Diazine Dearomatization: The Catalytic Enantioselective Dearomatization of Pyrazine.

Abstract

Despite much progress in the area of dearomatization, the enantioselective dearomatization of heterocycles is limited to those with a single heteroatom. Here we report a highly enantioselective copper-catalyzed dearomatization of pyrazine, a diazine, leading to chiral C-substituted piperazines. When exposed to a chloroformate and an alkyne in the presence of a catalyst derived from a copper salt and the chiral ligand StackPhos, pyrazine is readily dearomatized to provide a 2,3-disubstituted dihydropyrazine as single diastereomer in high enantiomeric excess. Mechanistic studies support a noninnocent involvement of chloride ion preventing a second iminium alkynylation, thus enabling subsequent functionalization at the second reactive site. The synthetically useful dihydropyrazine products, obtained in up to 95% yield and 99% ee, can be further manipulated to form optically active C-substituted piperazines and C1-symmetric 1,2-diamines.