Nucleophile-nucleophile coupling is ac hallenging transformation in organic chemistry.Herein we present anovel umpolung strategy for a-functionalization of aldehydes with nucleophiles.T he strategy uses organocatalytic enamine activation and quinone-promoted oxidation to access O-bound quinol-intermediates that undergo nucleophilic substitution reactions.T hese quinol-intermediates react with different classes of nucleophiles.T he focus is on an unprecedented organocatalytic oxidative a-thiolation of aldehydes.T he reaction scope is demonstrated for ab road range of thiols and extended to chemoselective bioconjugation, and applicable to alarge variety of aldehydes.This strategy can also encompass organocatalytic enantioselective coupling of a-branched aldehydes with thiols forming quaternary thioethers.S tudies indicate as tereoselective formation of the intermediate followed by as tereospecific nucleophilic substitution reaction at aquaternary stereocenter,w ith inversion of configuration.

This article discloses the direct α-amination of αbranched 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, MeNO 2 , 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 S N 2-DKR manifold provided distinct regimes leading to refinement in yield and enantioselectivity.

Nucleophile–nucleophile coupling is a challenging transformation in organic chemistry. Herein we present a novel umpolung strategy for α‐functionalization of aldehydes with nucleophiles. The strategy uses organocatalytic enamine activation and quinone‐promoted oxidation to access O‐bound quinol‐intermediates that undergo nucleophilic substitution reactions. These quinol‐intermediates react with different classes of nucleophiles. The focus is on an unprecedented organocatalytic oxidative α‐thiolation of aldehydes. The reaction scope is demonstrated for a broad range of thiols and extended to chemoselective bioconjugation, and applicable to a large variety of aldehydes. This strategy can also encompass organocatalytic enantioselective coupling of α‐branched aldehydes with thiols forming quaternary thioethers. Studies indicate a stereoselective formation of the intermediate followed by a stereospecific nucleophilic substitution reaction at a quaternary stereocenter, with inversion of configuration.