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

Cobalt-Catalyzed Asymmetric Hydrogenation of Enamides: Insights into Mechanisms and Solvent Effects

“…While the formation of all four types of products for MAA thus appears to be more in line with mechanism B or C, it is important to note that if a background scrambling reaction between the catalyst and HD to form H 2 and D 2 takes place, it may complicate the results, as has been shown for the related iPr DuPhos catalyst. 52 Indeed, exposure of a mixture of H 2 and D 2 gases to (R,R)-( Ph BPE)Co(COD) shows the formation of HD by 1 H NMR within 20 min, supporting that scrambling does occur. Therefore, the labeled products do not provide conclusive evidence about the preferred mechanism.…”

“…This seems to be in contrast to ( iPr DuPhos)Co, which only can access the classical redox mechanism A. 52 The results indicate that the nature of the phosphine ligand could influence which hydrogenation pathway is operative. A decisive factor would be if the Co(II)-monohydride species essential for metallacycle mechanism C can be formed from the resting state under reaction conditions.…”

“…In order to obtain additional mechanistic information, catalytic reduction of a MeOH solution of DHL or MAA (0.10 M) with HD (60 psi) was performed at room temperature, using (R,R)-( Ph BPE)Co(COD) (2 mol %) and/ or (R,R)-( Ph BPE)CoCl 2 (with in situ Zn reduction, 2 mol % cobalt) as the precatalysts (Figure 2, Figures S3−S12 (MAA), and Figures S13−S18 (DHL) in the Supporting Information). 1 H, 2 H, and quantitative 13 C NMR spectroscopy demonstrated preferential deuterium incorporation into the Cα-position of MAA in a 1.35:1 ratio by (R,R)-( Ph BPE)Co(COD), which is comparable to the value found using identical conditions with (R,R)-( iPr DuPhos)Co(COD) as the precatalyst (1.45:1), 52 as well as that reported with [Rh(DIPHOS)(NBD)][BF 4 ] (1.36:1) in MeOH. 64 (R,R)-( Ph BPE)CoCl 2 formed in situ with Zn reduction also showed preferential deuterium incorporation into the Cα-position, with a 1.64:1 partitioning ratio for MAA and 1.20:1 for DHL.…”

“…We note that the related ( iPr DuPhos)Co complex shows a somewhat different mechanistic behavior, which will be reported elsewhere. 52 ■ METHODS Experimental Details. All air-and moisture-sensitive manipulations were carried out using vacuum-line, Schlenk, and cannula techniques or in an MBraun inert-atmosphere (nitrogen) drybox unless otherwise noted.…”

“…Here, the possible mechanistic pathways of ( Ph BPE)­Co-catalyzed enamide hydrogenation were addressed using experimental and computational approaches, with the aim of establishing the preferred mechanistic routes and obtaining a better understanding of the potential role of the protic solvent. We note that the related ( iPr DuPhos)­Co complex shows a somewhat different mechanistic behavior, which will be reported elsewhere …”