Highly Enantioselective Zirconium-Catalyzed Cyclization of Aminoalkenes

Aminoalkenes are catalytically cyclized in the presence of cyclopenta­dienyl­bis­(oxazolinyl)­borato group 4 complexes {PhB­(C5H4)­(OxR)2}­M­(NMe2)2 (M = Ti, Zr, Hf; OxR = 4,4-dimethyl-2-oxazoline, 4S-isopropyl-5,5-dimethyl-2-oxazoline, 4S-tert-butyl-2-oxazoline) at room temperature and below, affording five-, six-, and seven-membered N-heterocyclic amines with enantiomeric excesses of >90% in many cases and up to 99%. Mechanistic investigations of this highly selective system employed synthetic tests, kinetics, and stereochemistry. Secondary aminopentene cyclizations require a primary amine (1–2 equiv vs catalyst). Aminoalkenes are unchanged in the presence of a zirconium monoamido complex {PhB­(C5H4)­(Ox4S‑iPr,Me2)2}­Zr­(NMe2)Cl or a cyclopenta­dienyl­mono­(oxazolinyl)­borato zirconium diamide {Ph2B­(C5H4)­(Ox4S‑iPr,Me2)}­Zr­(NMe2)2. Plots of initial rate versus [substrate] show a rate dependence that evolves from first-order at low concentration to zero-order at high concentration, and this is consistent with a reversible substrate–catalyst interaction preceding an irreversible step. Primary kinetic isotope effects from substrate conversion measurements (k′obs(H)/k′obs(D) = 3.3 ± 0.3) and from initial rate analysis (k2(H)/k2(D) = 2.3 ± 0.4) indicate that a N–H bond is broken in the turnover-limiting and irreversible step of the catalytic cycle. Asymmetric hydroamination/cyclization of N-deutero-aminoalkenes provides products with higher optical purities than obtained with N-proteo-aminoalkenes. Transition state theory, applied to the rate constant k2 that characterizes the irreversible step, provides activation parameters consistent with a highly organized transition state (ΔS⧧ = −43(7) cal·mol–1 K–1) and a remarkably low enthalpic barrier (ΔH⧧ = 6.7(2) kcal·mol–1). A six-centered, concerted transition state for C–N and C–H bond formation and N–H bond cleavage involving two amidoalkene ligands is proposed as most consistent with the current data.氨基烯烃（aminoalkenes）在环戊二烯基双(噁唑啉基)硼酸盐第四族配合物（cyclopentadienylbis(oxazolinyl)borato group 4 complexes）{PhB(C₅H₄)(OxR)₂}M(NMe₂)₂（M=钛Ti、锆Zr、铪Hf；OxR=4,4-二甲基-2-噁唑啉、4S-异丙基-5,5-二甲基-2-噁唑啉、4S-叔丁基-2-噁唑啉）的存在下，于室温及更低温度下发生催化环化反应，生成五元、六元及七元氮杂环胺，多数情况下产物对映体过量值（enantiomeric excess, ee）大于90%，最高可达99%。 针对该高选择性体系的机理研究采用了合成测试、动力学分析及立体化学表征手段。二级氨基戊烯的环化反应需要一级胺参与，其用量为催化剂的1~2当量。当体系中存在单酰胺基锆配合物{PhB(C₅H₄)(Ox4S‑iPr,Me₂)₂}Zr(NMe₂)Cl或环戊二烯基单(噁唑啉基)硼酸盐二酰胺合锆{Ph₂B(C₅H₄)(Ox4S‑iPr,Me₂)}Zr(NMe₂)₂时，氨基烯烃不会发生环化反应。 初始速率对底物浓度的作图结果显示，反应速率的浓度依赖性从低浓度下的一级反应转变为高浓度下的零级反应，这与不可逆步骤前存在可逆底物-催化剂相互作用的机理模型相符。通过底物转化率测定得到的一级动力学同位素效应（k'_obs(H)/k'_obs(D)=3.3±0.3），以及初始速率分析得到的一级动力学同位素效应（k₂(H)/k₂(D)=2.3±0.4），均表明催化循环的决速且不可逆步骤中发生了N-H键的断裂。 N-氘代氨基烯烃的不对称氢胺化/环化反应所得产物的光学纯度，高于N-质子化氨基烯烃参与的对应反应。将过渡态理论（transition state theory, TST）应用于表征不可逆步骤的速率常数k₂，得到的活化参数与高度有序的过渡态（活化熵ΔS≠=-43(7) cal·mol⁻¹·K⁻¹）以及极低的活化焓垒（活化焓ΔH≠=6.7(2) kcal·mol⁻¹）一致。结合现有实验数据，最合理的机理模型为涉及两个氨基烯烃配体的六中心协同过渡态，该过渡态可同时完成C-N键、C-H键的形成以及N-H键的断裂。