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

用于高通量实验的镍预催化剂的连续流动合成

• 批准号: 9190842
• 负责人: Ashley Rose Longstreet
• 金额: $ 5.19万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2017-08-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9190842
• 关键词: Address; Air; Carbon; Catalysis; Chemical Engineering; Chemicals; Chemistry; Complex; Data; Development; Ensure; Institutes; Libraries; Ligands; Literature; Massachusetts; Methods; Nickel; Noble Gases; Phase; Phosphines; Process; Production; Reaction; Reducing Agents; Solvents; Source; System; Technology; Temperature; Testing; Time; Yang; base; carbene; catalyst; design; drug development; drug discovery; novel; oxidation; screening; small molecule; tool

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.

项目概要 均相镍催化的最新进展展示了镍促进 具有挑战性的转变。大多数反应是在温度、空气和湿度不稳定的条件下进行的 络合物，Ni(COD)2（COD = 1,5-环辛二烯）。针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是快速发展的重要工具 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。该提案描述了一种利用 Ni 催化进行 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 开发了一类新型 Ni(II)-预催化剂， 和哈特维格。与传统镍催化剂（如 Ni(COD)2）相比，预催化剂具有许多优点 其他可用的预催化剂，因为它们具有水分和空气稳定性、易于活化和减少的催化剂 负载。然而，由于配体是预先安装的，预催化剂不能直接参与HTE。 与传统间歇式化学相比，连续流化学具有几个显着的优势，包括 望远镜合成和纯化的能力。由于精简能力，开发了一个持续的 Ni(II)-预催化剂的流动合成将使其能够按需生产。此外，流合成 然后可以集成到 Jensen 小组先前开发的 HTE 系统中。 目前的 Ni(II)-预催化剂是基于膦的。基于 NHC 的预催化剂是存在的，但是，这些 预催化剂不易被激活。在设计基于 NHC 的预催化剂的流动合成之前，一个新类 类似于基于膦的预催化剂将被研究。 最后，HTE 系统的价值将通过优化一种新型高反应来证明。 重要性：Ni-光氧化还原催化的三氟甲基化。 Ni催化的三氟甲基化尚未被证实 由于镍难以在碳和高负电性基团之间形成键而实现。 然而，Ni-光氧化还原利用更高的氧化态 Ni(III)，这已被证明可以促进这些困难 债券的形成。通过利用 Ni-光氧化还原催化和开发的 HTE 系统，新的和 将开发有效的三氟甲基化方法。