Modular Synthesis of α-Tertiary Amines Enabled by Nickel-Catalyzed Reductive Alkylation of N -unprotected Ketimines

The straightforward construction of sterically hindered α-tertiary primary amines remains a stubborn challenge in organic synthesis. Although a wide array of approaches for the synthesis of this motif has been developed, the leveraging of ketimines as an amine source is underexplored. General reductive alkylative additions of unactivated alkyl halides to N-unprotected ketimines remain unknown. Herein, we disclose a nickel-catalyzed cross-electrophile coupling between N-unprotected heteroaryl ketimines and readily available alkyl halides, including primary, secondary, and tertiary ones, to directly furnish diverse primary amines with steric congestion without attendant deprotection sequences. This synthetic protocol circumvents the use of preformed organometallic reagents, leading to broad functional group tolerance and high step-economy. Preliminary mechanistic investigations support a radical-type cross-coupling pathway of N-H ketimines with unactivated alkyl radicals involving a Ni(I)/Ni(II)/Ni(III) redox cycle. The practicality of this method has been demonstrated in successful application in the synthesis of various cholesteryl ester transfer protein (CETP) inhibitors.