Mechanistic Investigations of the Asymmetric Hydrogenation of Enamides with Neutral Bis(phosphine) Cobalt Precatalysts

The mechanism of the asymmetric hydrogenation of prochiral enamides by well-defined, neutral bis(phosphine) cobalt(0) and cobalt(II) precatalysts has been explored using-(R,R)-(iPr)DuPhos ((R,R)-(iPr)DuPhos = (+)-1,2-bis[(2R,SR)-2,5-diisopropylphospholano]benzene) as a representative chiral bis(phosphine) ligand. A series of (R,R)-((iPr)DuPhOs)Co(enamide) (enamide = methyl-2-acetamidoacrylate (MAA), methyl(Z)-alpha-acetamidocinnamate (MAC), and methyl(Z)-acetamido(4-fluorophenyl)acrylate ((4F)MAC)) complexes (1-MAA, 1-MAC, and 1-(4F)MAC), as well as a dinuclear cobalt tetrahydride, [(R,R)-((iPr)DuPhos)Co](2)(mu(2)-H)(3)(H) (2), were independently synthesized, characterized, and evaluated in both stoichiometric and catalytic hydrogenation reactions. Characterization of (R,R)-((iPr)DuPhos)-Co(enamide) complexes by X-ray diffraction established the formation of the pro-(R) diastereomers in contrast to the (S)-alkane products obtained from the catalytic reaction. In situ monitoring of the cobalt-catalyzed hydrogenation reactions by UV-visible and freeze-quench electron paramagnetic resonance spectroscopies revealed (R,R)-((iPr)DuPhos)Co(enamide) complexes as the catalyst resting state for all the three enamides studied. Variable time normalization analysis kinetic studies of the cobalt-catalyzed hydrogenation reactions in methanol established a rate law that is first order in (R,R)-((iPr)DuPhos)Co(enamide) and H-2 but independent of the enamide concentration. Deuterium-labeling studies, including measurement of an H-2/D-2 kinetic isotope effect and catalytic hydrogenations with HD, established an irreversible H2 addition step to the bound enamide. Density functional theory calculations support that this step is both rate and selectivity determining. Calculations, as well as HD-labeling studies, provide evidence for two-electron redox cycling involving cobalt(0) and cobalt(II) intermediates during the catalytic cycle. Taken together, these experiments support an unsaturated pathway for the [(R,R)-((iPr)DuPhos)Co]-catalyzed hydrogenation of prochiral enamides.

Automated summary

The mechanism of asymmetric hydrogenation of prochiral enamides by well-defined cobalt(0) and cobalt(II) precatalysts using a chiral bis(phosphine) ligand has been investigated. Characterization of the resulting complexes and monitoring of the reactions revealed the resting state of the catalyst, the rate law, and the irreversible H2 addition step. Computational and labeling studies provided evidence for a two-electron redox cycling during the catalytic cycle. The experiments support an unsaturated pathway for the hydrogenation of prochiral enamides.