Work

Ni-Catalyzed Carbon–Carbon Bond-Forming Reductive Amination

Year: 2018

Type: article

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.

Source: Journal of the American Chemical Society

DOI: 10.1021/jacs.7b12212

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

Institutions: Princeton University, Bristol-Myers Squibb (United States)

Language: English

Topic: Catalytic Cross-Coupling Reactions

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

Open Access status: green

Funders: Bristol-Myers Squibb, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, National Institute of General Medical Sciences, Division of Graduate Education

Awards: Metal-Catalyzed Cross Coupling with N,O-Acetals and Acetals, G3163124650