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.

中文翻译：

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中性双（膦）钴预催化剂烯酰胺不对称加氢机理研究

使用( R , R )- ^iPr DuPhos (( R , R )- ^iPr DuPhos = (+)-1,2-双[(2 R ,5 R )-2,5-二异丙基膦基]苯)作为代表性手性双(膦)配体。一系列 ( R , R )-( ^iPr DuPhos)Co(enamide) （烯酰胺 = 甲基-2-乙酰氨基丙烯酸酯 (MAA)、甲基 ( Z )-α-乙酰氨基肉桂酸酯 (MAC) 和甲基 ( Z )-乙酰氨基 (4 -氟苯基）丙烯酸酯（^4FMAC)) 配合物（1-MAA、1-MAC和1-4F MAC）以及双核四氢化钴 [( ^R , R ) -( ^iPr DuPhos)Co] ₂ (μ ₂ -H) ₃ ( H) ( 2 )，在化学计量和催化氢化反应中独立合成、表征和评估。通过 X 射线衍射对 ( R , R )-( ^iPr DuPhos )Co(enamide) 配合物的表征确定了与 ( S)-由催化反应得到的烷烃产物。通过紫外-可见光和冷冻淬火电子顺磁共振光谱对钴催化的氢化反应进行原位监测，发现 ( R , R )-( ^iPr DuPhos)Co(enamide) 配合物是所研究的所有三种烯酰胺的催化剂静止状态。甲醇中钴催化加氢反应的可变时间归一化分析动力学研究建立了 ( R , R )-( ^iPr DuPhos)Co(enamide) 和 H ₂中的一级速率定律，但与烯酰胺浓度无关。氘标记研究，包括 H ₂ /D _2的测量动力学同位素效应和 HD 催化氢化，建立了结合烯酰胺的不可逆 H ₂加成步骤。密度泛函理论计算支持该步骤是速率和选择性决定的。计算以及 HD 标记研究为催化循环期间涉及钴 (0) 和钴 (II) 中间体的双电子氧化还原循环提供了证据。总之，这些实验支持 [( R , R )-( ^iPr DuPhos)Co]-催化前手性烯酰胺氢化的不饱和途径。