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

Abstract

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)-^iPrDuPhos ((R,R)-^iPrDuPhos = (+)-1,2-bis[(2R,5R)-2,5-diisopropylphospholano]benzene) as a representative chiral bis(phosphine) ligand. A series of (R,R)-(^iPrDuPhos)Co(enamide) (enamide = methyl-2-acetamidoacrylate (MAA), methyl(Z)-α-acetamidocinnamate (MAC), and methyl(Z)-acetamido(4-fluorophenyl)acrylate (4^FMAC)) complexes (1-MAA, 1-MAC, and 1-4^FMAC), as well as a dinuclear cobalt tetrahydride, [(R,R)-(^iPrDuPhos)Co]₂(μ₂-H)₃(H) (2), were independently synthesized, characterized, and evaluated in both stoichiometric and catalytic hydrogenation reactions. Characterization of (R,R)-(^iPrDuPhos)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)-(^iPrDuPhos)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)-(^iPrDuPhos)Co(enamide) and H₂ but independent of the enamide concentration. Deuterium-labeling studies, including measurement of an H₂/D₂ 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)-(^iPrDuPhos)Co]-catalyzed hydrogenation of prochiral enamides.