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J Am Chem Soc. 2016 Mar 16;138(10):3562-9. doi: 10.1021/jacs.6b00519. Epub 2016 Mar 2.

Nickel-Catalyzed Asymmetric Alkene Hydrogenation of α,β-Unsaturated Esters: High-Throughput Experimentation-Enabled Reaction Discovery, Optimization, and Mechanistic Elucidation.

Author information

1
Department of Process & Analytical Chemistry, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
2
Department of Chemistry, Princeton University , Princeton, New Jersey 08544, United States.

Abstract

A highly active and enantioselective phosphine-nickel catalyst for the asymmetric hydrogenation of α,β-unsaturated esters has been discovered. The coordination chemistry and catalytic behavior of nickel halide, acetate, and mixed halide-acetate with chiral bidentate phosphines have been explored and deuterium labeling studies, the method of continuous variation, nonlinear studies, and kinetic measurements have provided mechanistic understanding. Activation of molecular hydrogen by a trimeric (Me-DuPhos)3Ni3(OAc)5I complex was established as turnover limiting followed by rapid conjugate addition of a nickel hydride and nonselective protonation to release the substrate. In addition to reaction discovery and optimization, the previously unreported utility high-throughput experimentation for mechanistic elucidation is also described.

PMID:
26890979
DOI:
10.1021/jacs.6b00519

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