Metal-free, Oxidative α-Coupling of Aldehydes with Amine Nucleophiles for the Preparation of Congested C(sp3)-N Bonds.

Abstract

This article discloses the direct α-amination of α-branched aldehydes applying nitrogen-based nucleophiles. Under organocatalyzed, oxidative conditions α-branched aldehydes are umpoled to their electrophilic synthons and, subsequently, displaced by a variety of nucleophilic amines to form tetrasubstituted tertiary centers. A similar strategy has been previously employed to form congested C-C, C-O, and C-S bonds; however, unsatisfactory results were received when extending the methodology to include C-N bonds. Initially, intramolecular α-amination reactions were undertaken to foster dihydroquinoxaline-type products. A solvent exchange to the polar, aprotic solvent, MeNO2, proved critical to facilitate intermolecular α-C-N bond formation with a wide range of amine coupling partners (N-heterocycles, N,N-diaryl amines, and anilines). Application of the solvent exchange to the enantioselective SN2-DKR manifold provided distinct regimes leading to refinement in yield and enantioselectivity.