Pd(II)-Catalyzed Regioselective 2-Alkylation of Indoles via a Norbornene-Mediated C-H Activation: Mechanism and Applications
Pd(II)-Catalyzed Regioselective 2-Alkylation of Indoles via a Norbornene-Mediated C-H Activation: Mechanism and Applications
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DOI：
10.1021/ja3058138
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发表时间：
2012-09-05
影响因子：
15
通讯作者：
Bach, Thorsten
中科院分区：
文献类型：
--
作者：
Jiao, Lei;Herdtweck, Eberhardt;Bach, Thorsten
基于降冰片烯介导的区域选择性级联C-H活化，建立了钯催化的游离N-H吲哚直接2-烷基化反应。通过核磁共振波谱分析、关键中间体表征、氘标记实验和动力学研究对反应机理进行了详细研究。结果表明，该反应是一个以n -降冰片烯型环为关键中间体的催化循环。烷基溴在中间体Pd（II）中心的氧化加成是反应的速率决定步骤。吲哚2-烷基化方法在天然产物全合成中的应用证明了该方法的实用性。以吲哚2-烷基化反应为关键步骤，建立了一种新的、通用的蜘蛛碱合成策略，并以简洁的路线合成了两种结构不同的蜘蛛碱，即蜘蛛精碱和棉子碱。
A palladium-catalyzed direct 2-alkylation reaction of free N-H indoles was developed based on a norbornene-mediated regioselective cascade C-H activation. The detailed reaction mechanism was investigated by NMR spectroscopic analyses, characterization of the key intermediate, deuterium labeling experiments, and kinetic studies. The results indicate that a catalytic cycle operates, in which an N-norbornene type palladacycle is formed as the key intermediate. Oxidative addition of alkyl bromide to the Pd(II) center in this intermediate is the rate-determining step of the reaction. The synthetic utility of this indole 2-alkylation method was demonstrated by its application in natural product total synthesis. A new and general strategy to synthesize Aspidosperma alkaloids was established employing the indole 2-alkylation reaction as the key step, and two structurally different Aspidosperma alkaloids, aspidospermidine and goniomitine, were synthesized in concise routes.