Ni-Catalyzed Carbon-Carbon Bond-Forming Reductive Amination

Christoph Heinz, J. Patrick Lutz, Eric M. Simmons, Michael M. Miller, William R. Ewing, Abigail G. Doyle

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2292-2300
Number of pages9
JournalJournal of the American Chemical Society
Volume140
Issue number6
DOIs
StatePublished - Feb 14 2018

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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