Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States.
J Am Chem Soc. 2020 May 13;142(19):8928-8937. doi: 10.1021/jacs.0c02237. Epub 2020 Apr 29.
We previously reported the development of an electron-deficient olefin (EDO) ligand, Fro-DO, that promotes the generation of quaternary carbon centers via Ni-catalyzed Csp-Csp cross-coupling with aziridines. By contrast, electronically and structurally similar EDO ligands such as dimethyl fumarate and electron-deficient styrenes afford primarily β-hydride elimination side reactivity. Only a few catalyst systems have been identified that promote the formation of quaternary carbons via Ni-catalyzed Csp-Csp cross-coupling. Although Fro-DO represents a promising ligand in this regard, the basis for its superior performance is not well understood. Here we describe a detailed mechanistic study of the aziridine cross-coupling reaction and the role of EDO ligands in facilitating Csp-Csp bond formation. This analysis reveals that cross-coupling proceeds by a Ni cycle with a Ni azametallacyclobutane catalyst resting state. Turnover-limiting C-C reductive elimination occurs from a spectroscopically observable Ni-dialkyl intermediate bound to the EDO. Computational analysis shows that Fro-DO accelerates turnover limiting reductive elimination via LUMO lowering. However, it is no more effective than dimethyl fumarate at reducing the barrier to Csp-Csp reductive elimination. Instead, Fro-DO's unique reactivity arises from its ability to associate favorably to Ni intermediates. Natural bond order second-order perturbation theory analysis of the catalytically relevant Ni intermediate indicates that Fro-DO binds to Ni through an additional stabilizing donor-acceptor interaction between its sulfonyl group and Ni. Design of new ligands to evaluate this proposal supports this model and has led to the development of a new and tunable ligand framework.
我们之前报道了一种缺电子烯烃（EDO）配体 Fro-DO 的开发，该配体通过 Ni 催化的与氮丙啶的 Csp-Csp 交叉偶联反应促进季碳原子的生成。相比之下，电子和结构相似的 EDO 配体（如富马酸二甲酯和缺电子苯乙烯）主要提供β-氢消除副反应。只有少数催化剂体系被确定能够通过 Ni 催化的 Csp-Csp 交叉偶联反应促进季碳的形成。尽管 Fro-DO 在这方面是一种很有前途的配体，但它优越性能的基础尚不清楚。在这里，我们描述了对氮丙啶交叉偶联反应和 EDO 配体在促进 Csp-Csp 键形成中的作用的详细机理研究。该分析表明，交叉偶联通过 Ni 循环进行，Ni 氮杂金属环丁烷催化剂处于休眠状态。限速 C-C 还原消除从与 EDO 结合的光谱可观察到的 Ni-二烷基中间体中发生。计算分析表明，Fro-DO 通过降低最低未占轨道（LUMO）来加速限速还原消除。然而，它在降低 Csp-Csp 还原消除的能垒方面并不比富马酸二甲酯更有效。相反，Fro-DO 的独特反应性源于其与 Ni 中间体有利结合的能力。对催化相关的 Ni 中间体进行自然键轨道（NBO）二阶微扰理论（second-order perturbation theory，SOPT）分析表明，Fro-DO 通过其磺酰基与 Ni 之间的额外稳定的供体-受体相互作用与 Ni 结合。设计新的配体来评估这一假设支持了这一模型，并导致了一种新的可调谐配体框架的开发。
