Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States.
J Am Chem Soc. 2020 Jun 24;142(25):10996-11005. doi: 10.1021/jacs.0c02126. Epub 2020 Jun 11.
A dipyrrin-supported nickel catalyst (L)Ni(py) (L: 1,9-di(1-adamantyl)-5-perfluorophenyldipyrrin; py: pyridine) displays productive intramolecular C-H bond amination to afford N-heterocyclic products using aliphatic azide substrates. The catalytic amination conditions are mild, requiring 0.1-2 mol% catalyst loading and operational at room temperature. The scope of C-H bond substrates was explored and benzylic, tertiary, secondary, and primary C-H bonds are successfully aminated. The amination chemoselectivity was examined using substrates featuring multiple activatable C-H bonds. Uniformly, the catalyst showcases high chemoselectivity favoring C-H bonds with lower bond dissociation energy as well as a wide range of functional group tolerance (e.g., ethers, halides, thioetheres, esters, etc.). Sequential cyclization of substrates with ester groups could be achieved, providing facile preparation of an indolizidine framework commonly found in a variety of alkaloids. The amination cyclization reaction mechanism was examined employing nuclear magnetic resonance (NMR) spectroscopy to determine the reaction kinetic profile. A large, primary intermolecular kinetic isotope effect (KIE = 31.9 ± 1.0) suggests H-atom abstraction (HAA) is the rate-determining step, indicative of H-atom tunneling being operative. The reaction rate has first order dependence in the catalyst and zeroth order in substrate, consistent with the resting state of the catalyst as the corresponding nickel iminyl radical. The presence of the nickel iminyl was determined by multinuclear NMR spectroscopy observed during catalysis. The activation parameters (Δ = 13.4 ± 0.5 kcal/mol; Δ= -24.3 ± 1.7 cal/mol·K) were measured using Eyring analysis, implying a highly ordered transition state during the HAA step. The proposed mechanism of rapid iminyl formation, rate-determining HAA, and subsequent radical recombination was corroborated by intramolecular isotope labeling experiments and theoretical calculations.
一种二吡咯啉配体支持的镍催化剂（L）Ni(py)（L：1,9-二（1-金刚烷基）-5-全氟苯基二吡咯啉；py：吡啶）在使用脂肪族叠氮化物底物时，显示出高产的分子内 C-H 键胺化反应，得到 N-杂环产物。催化胺化条件温和，需要 0.1-2mol%的催化剂负载量，在室温下操作。探索了 C-H 键底物的范围，成功地对苄基、叔、仲和伯 C-H 键进行了胺化。通过具有多个可活化 C-H 键的底物检查了胺化的化学选择性。一致地，该催化剂表现出高化学选择性，有利于键离解能较低的 C-H 键以及广泛的官能团耐受性（例如，醚、卤化物、硫醚、酯等）。具有酯基的底物的顺序环化可以实现，为各种生物碱中常见的吲哚嗪骨架的简便制备提供了可能。通过核磁共振（NMR）光谱研究胺化环化反应机制来确定反应动力学特征。大的、初级的分子间动力学同位素效应（KIE = 31.9 ± 1.0）表明 H 原子提取（HAA）是速率决定步骤，表明 H 原子隧道效应在起作用。反应速率对催化剂呈一级依赖，对底物呈零级依赖，与催化剂的休眠状态一致，对应于相应的镍亚氨基自由基。在催化过程中观察到多核 NMR 光谱确定了镍亚氨基的存在。通过 Eyring 分析测量了活化参数（Δ = 13.4 ± 0.5 kcal/mol；Δ= -24.3 ± 1.7 cal/mol·K），表明在 HAA 步骤中存在高度有序的过渡态。快速亚氨基形成、速率决定的 HAA 和随后的自由基重组的提议机制得到了分子内同位素标记实验和理论计算的证实。
