Bio-Inspired Primary Amine α-C–H Functionalization

The selective manipulation of complex amine architectures has received great attention in recent years with widespread applications including inter alia drug discovery. Inspired by an enzymatic copper amine oxidase process, a synthetic quinone co-factor mediated general platform for the construction of α-fully substituted primary amines from abundant α-branched primary amine starting materials is described. This procedure pivots on the efficient generation of reactive ketimine intermediates in situ which are primed to react with carbon-centered nucleophiles such as organomagnesium and organolithium reagents, and TMSCN. Extension to reverse polarity photoredox catalysis enables reactivity with electrophiles. Subsequent oxidative hydrolysis releases the unprotected α-fully substituted primary amine product. This efficient, broadly applicable and scaleable amine-to-amine synthetic platform was successfully applied to library and API synthesis and in the late stage functionalization of drug molecules.