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

项目摘要 最近在均相镍催化方面的进展已经展示了镍促进催化剂的能力。 具有挑战性的转变。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-环辛烷）。这样做对镍催化剂的不稳定性，高通量 不能进行镍催化反应的实验（HTE）。HTE是一个快速的工具， 反应优化，因为许多变量被筛选并且收集大量数据用于 进一步了解反应性。该提案描述了用Ni催化剂进行HTE的策略， 加快药物开发所需的困难化学转化的优化。 最近，Jamison，Yang，Percec，Buchwald， 还有哈特维希预催化剂提供了许多优于传统镍催化剂如Ni（COD）2的优点， 其它可用的预催化剂，因为它们的水分和空气稳定性、易于活化和催化剂还原 装载量。然而，因为配体是预先安装的，所以预催化剂不能直接参与HTE。 连续流化学与传统的间歇化学相比具有几个显著的优点，包括 合成和提纯的能力。由于精简的能力，开发一个连续的- Ni（II）预催化剂的流动合成将使其能够按需生产。此外，流量合成 然后可以集成到以前由詹森小组开发的HTE系统中。 目前的Ni（II）-预催化剂是膦基的。存在基于NHC的预催化剂，然而，这些 预催化剂不容易活化。在设计NHC基预催化剂的流动合成之前， 将研究类似于膦基预催化剂。 最后，HTE系统的价值将通过优化一种高活性的新反应来证明。 重要性：Ni-光氧化还原催化的三氟甲基化。镍催化的三氟甲基化还没有被 这是由于镍难以在碳和高电负性基团之间形成键而实现的。 然而，Ni-光氧化还原利用更高的氧化态Ni（III），其已被证明有助于这些困难的氧化。 键的形成通过利用Ni光氧化还原催化和开发的HTE系统， 将开发三氟甲基化的有效方法。

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.