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[(2 R ,5 R )-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 )-α-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 (μ 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 H 2 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.