Ni-Catalyzed Carbon–Carbon Bond-Forming Reductive Amination

This report describes a three-component,
Ni-catalyzed reductive
coupling that enables the convergent synthesis of tertiary benzhydryl
amines, which are challenging to access by traditional reductive amination
methodologies. The reaction makes use of iminium ions generated in situ from the condensation of secondary N-trimethylsilyl amines with benzaldehydes, and these species undergo
reaction with several distinct classes of organic electrophiles. The
synthetic value of this process is demonstrated by a single-step synthesis
of antimigraine drug flunarizine (Sibelium) and high yielding derivatization
of paroxetine (Paxil) and metoprolol (Lopressor). Mechanistic investigations
support a sequential oxidative addition mechanism rather than a pathway
proceeding via α-amino radical formation. Accordingly, application
of catalytic conditions to an intramolecular reductive coupling is
demonstrated for the synthesis of endo- and exocyclic benzhydryl amines.