The Continuous-Flow Synthesis of Ni-Precatalysts for High-Throughput Experimentation

项目摘要 均相镍催化的最新进展表明，镍具有促进 具有挑战性的转型。大多数反应都是在温度、空气和湿度不稳定的情况下进行的 配合物，Ni(COD)2(COD=1，5-环辛二烯)。对这种镍催化剂的不稳定性、高通量 无法进行镍催化反应的实验(HTE)。HTE是快速开发的一种重要工具 反应优化，因为筛选了许多变量并收集了大量数据 进一步了解反应性。这项建议描述了一种利用镍催化进行热电沉积的策略 加快优化药物开发所需的疑难化学转化。 最近，Jamison，Yang，Percec，Buchwald， 还有哈特威格。与传统的镍催化剂相比，预催化剂具有许多优点，如Ni(COD)2，以及 其他可用的前催化剂，因为它们的湿气和空气稳定性，易于活化，催化剂减少 装载量。然而，由于配体是预先安装的，预催化剂不能直接参与HTE。 与传统的间歇化学相比，连续流动化学有几个显著的优点，包括 观察合成和提纯的能力。由于精简能力，开发一个连续的- 流动合成的Ni(II)-预催化剂将使其按需生产。此外，流程合成 然后可以集成到先前由Jensen集团开发的HTE系统中。 目前的Ni(II)-预催化剂是以膦为基础的。然而，基于NHC的预催化剂存在，这些 前催化剂不容易被激活。在设计NHC基预催化剂的流程合成之前，一个新的类别 类似于膦基预催化剂的研究。 最后，通过优化一种新型的高选择性反应，验证了该体系的应用价值。 重要：镍-光氧化还原催化的三氟甲基化。镍催化的三氟甲基化反应尚未被 这是由于镍很难在碳和高电负性基团之间形成键而实现的。 然而，镍-光氧化还原利用了较高的氧化态Ni(III)，这已被证明有助于实现这些困难 形成粘结。通过利用镍-光氧化还原催化和开发的HTE体系，新的和 将开发有效的三氟甲基化方法。

Project Summary The recent advances in homogeneous nickel catalysis have showcased the ability of nickel to facilitate challenging transformations. Most reactions are performed using the temperature, air, and moisture unstable complex, Ni(COD)2 (COD = 1,5-cyclooctadiene). Do to the instability of this nickel catalyst, high-throughput experimentation (HTE) of nickel catalyzed reactions could not be performed. HTE is an important tool for rapid reaction optimization because many variables are screened and large quantities of data are collected for further understanding the reactivity. This proposal describes a strategy to perform HTE with Ni-catalysis to expedite the optimization of difficult chemical transformations necessary for drug development. Recently, a new class of Ni(II)-precatalysts have been developed by Jamison, Yang, Percec, Buchwald, and Hartwig. The precatalysts offer many advantages over traditional nickel catalysts, such as Ni(COD)2, and other available precatalysts because of their moisture- and air-stability, ease of activation, and reduced catalyst loadings. However, because the ligands are preinstalled, the precatalysts cannot directly participate in HTE. Continuous-flow chemistry has several notable advantages over traditional batch chemistry, including the ability to telescope syntheses and purifications. Due to the streamlining capabilities, developing a continuous- flow synthesis of the Ni(II)-precatalysts will enable their on-demand production. Furthermore, the flow synthesis could then be integrated into an HTE-system previously developed by the Jensen group. The current Ni(II)-precatalysts are phosphine-based. NHC-based precatalysts exist, however, these precatalysts are not easily activated. Before designing a flow synthesis for NHC-based precatalyst, a new class similar to the phosphine-based precatalysts will be investigated. Lastly, the value of the HTE system will be demonstrated through optimizing a novel reaction of high importance: Ni-photoredox catalyzed trifluoromethylation. Ni-catalyzed trifluoromethylations have not been realized due to the difficulty of nickel to form bonds between carbon and highly electronegative groups. However, Ni-photoredox utilizes a higher oxidation state, Ni(III), that has been shown to facilitate these difficult bond formations. Through leveraging Ni-photoredox catalysis and the developed HTE-system, new and efficient methods of trifluoromethylations will be developed.