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)-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 (4FMAC)) complexes
(1-MAA, 1-MAC, and 1-4FMAC), 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.