Computational Mechanistic Study of Stereoselective Suzuki Coupling of an α-Cyano-Activated Secondary Alkyl

Palladium-catalyzed cross-couplings of secondary alkyls are promising tools for the stereoselective formation of carbon–carbon bonds. We report a computational mechanistic study of the stereoselective Suzuki coupling between (S)-2-chloropropanenitrile and phenylboronic acid, following a recent experimental report on related α-cyanohydrin triflates (J. Am. Chem. Soc. 2010, 132, 2524). Added Lewis base helps accelerate SN2 oxidative addition, leading to the experimentally observed inversion of configuration. Undesired β-hydride elimination side reactions are reduced by the activating cyano group’s inductive effects, by cyano-PdII coordination, and by excess boronic acid. The catalyst ligand’s trans influence and steric bulk also affect the rate of β-hydride elimination, suggesting design rules for alkyl cross-coupling ligands.钯催化二级烷基交叉偶联反应是实现立体选择性构建碳-碳键的极具应用前景的手段。本文报道了一项针对(S)-2-氯丙腈与苯硼酸之间的立体选择性铃木-宫浦偶联（Suzuki coupling）反应的计算机理研究，该项研究基于近期一篇关于α-氰醇三氟甲磺酸酯的实验报道（*J. Am. Chem. Soc.* 2010, 132, 2524）展开。外加路易斯碱（Lewis base）可加速SN2型氧化加成过程，从而促成实验中观测到的构型翻转。不期望发生的β-氢消除（β-hydride elimination）副反应可通过活化氰基的诱导效应、氰基与Pd(II)的配位以及过量苯硼酸得到抑制。催化剂配体的反位效应（trans influence）与空间位阻同样会对β-氢消除的反应速率产生影响，这为烷基交叉偶联配体的设计提供了指导性规则。