Mechanistic analysis and optimization of the copper-catalyzed enantioselective intramolecular alkene aminooxygenation.
Mechanistic analysis and optimization of the copper-catalyzed enantioselective intramolecular alkene aminooxygenation.
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DOI：
10.1021/jo3023632
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发表时间：
2013-01-18
期刊：
影响因子：
--
通讯作者：
Chemler SR
中科院分区：
文献类型：
--
作者：
Paderes MC;Keister JB;Chemler SR
烯烃的催化不对称氨氧化反应为制备手性邻氨基醇提供了一条有效而直接的途径。报道了以(2，2，6，6-四甲基哌啶-1-基)氧(TEMPO)为氧源，铜(II)催化的对映选择性分子内烯胺氧化反应，合成了手性吲哚和吡咯烷。动力学研究表明，该反应在底物和[Cu(R，R)-Ph-双(恶唑啉)]OTf2催化剂上均为一级反应，TEMPO为零级反应。此外，动力学同位素效应研究支持顺式氨化步骤，即在烯烃上添加N-铜，是速度限制步骤。氢标记实验表明，随后碳自由基中间体的形成和碳自由基与TEMPO的直接捕获是C-O键形成的可能机制。配体筛选表明，双恶唑啉上的C(4)-苯基取代是高不对称诱导的最佳方法。底物的N-磺酰基的大小也影响反应的对映选择性。证明了制备规模的催化氨氧化反应(GRAN规模)，并在较大规模的反应中发现了对反应温度的意外依赖。
The catalytic asymmetric aminooxygenation of alkenes provides an efficient and straightforward approach to prepare chiral vicinal amino alcohols. We have reported a copper(II)-catalyzed enantioselective intramolecular alkene aminooxygenation, using (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) as the oxygen source, which results in the synthesis of chiral indolines and pyrrolidines. Herein we disclose that kinetics studies indicate the reaction is first order both in substrate and the [Cu(R,R)-Ph-bis(oxazoline)]OTf2 catalyst, and zero order in TEMPO. Furthermore, kinetic isotope effect studies support that the cis aminocupration step, the addition of N-Cu across the alkene, is the rate-limiting step. Subsequent formation of a carbon radical intermediate, and direct carbon radical trapping with TEMPO is the indicated mechanism for the C-O bond formation as suggested by a deuterium labeling experiment. A ligand screen revealed that C(4)-phenyl substitution on the bis(oxazoline) is optimal for high asymmetric induction. The size of the substrate’s N-sulfonyl group also influences the enantioselectivity of the reaction. The preparative scale catalytic aminooxygenation reaction (gram scale) was demonstrated and an unexpected dependence on reaction temperature was uncovered on the larger scale reaction.
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