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(,)-DuPhos ((,)-DuPhos = (+)-1,2-bis[(2,5)-2,5-diisopropylphospholano]benzene) as a representative chiral bis(phosphine) ligand. A series of (,)-(DuPhos)Co(enamide) (enamide = methyl-2-acetamidoacrylate (MAA), methyl()-α-acetamidocinnamate (MAC), and methyl()-acetamido(4-fluorophenyl)acrylate (MAC)) complexes (, , and ), as well as a dinuclear cobalt tetrahydride, (,)-(DuPhos)Co(H) (), were independently synthesized, characterized, and evaluated in both stoichiometric and catalytic hydrogenation reactions. Characterization of (,)-(DuPhos)Co(enamide) complexes by X-ray diffraction established the formation of the pro-() diastereomers in contrast to the ()-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 (,)-(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 (,)-(DuPhos)Co(enamide) and H but independent of the enamide concentration. Deuterium-labeling studies, including measurement of an H/D kinetic isotope effect and catalytic hydrogenations with HD, established an irreversible H 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 [(,)-(DuPhos)Co]-catalyzed hydrogenation of prochiral enamides.