Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 140, Issue 6, Pages 2292-2300Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.7b12212
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Funding
- NIGMS [R01 GM100985]
- Bristol-Myers Squibb
- National Science Foundation [DGE-1148900]
- Swiss National Science Foundation
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM100985] Funding Source: NIH RePORTER
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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 alpha-amino radical formation. Accordingly, application of catalytic conditions to an intramolecular reductive coupling is demonstrated for the synthesis of endo- and exocyclic benzhydryl amines.
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