Fundamental Studies of Ni-Catalyzed Organic Reactions

项目摘要/摘要 贵金属催化剂通常用于合成活性药物成分(API)，甚至 尽管镍等第一排过渡金属更可持续，并可以促进独特的反应性。为了考试- Pe，Ni催化的反应很容易形成sp2-sp3C-C键，这为合成这些类型的化合物提供了方法 使用贵金属催化的反应制备具有挑战性的非平面原料药。然而，总的来说， 由于对镍催化反应的机理认识相对缺乏，阻碍了它们在合成反应中的应用。 原料药论文，因为它阻碍了改进系统的开发和新反应的合理设计。 阐明镍催化的转化途径的一个困难是经常引用NiI络合物 作为中间体，但关于它们的反应性的信息有限。在本项目中，新的NiII卤化物、烷基和芳基 由双齿氮配体支持的物种，这些配体被认为是反应中的中间体，包括 交叉偶联、交叉亲电偶联(XEC)和基于金属光氧化还原的工艺将被合成。 这些NiI络合物在催化中经历所建议的基本步骤的能力将被研究如下 使用实验和计算技术的辅助配体和反应条件的函数。 这些研究将得到实验的补充，以探索nii物种是如何通过同化作用形成的。 Ni0和NiII络合物之间的相互作用以及原位研究镍催化剂在催化过程中的形态。它 预计我们的基础研究将导致设计下一代镍催化 提供有关NiI络合物反应性的指南。开发过程中的另一个问题 镍催化反应的一个特点是，它们经常涉及多相还原剂，这使反应机理复杂化 研究，为扩大规模制造了困难，而且不能轻易地调整以改变还原潜力。派的群 已开发出一系列具有还原潜力的商用可调均相还原剂。 类似于锌。除了提高实用性，这些还原剂的可调性也是至关重要的。 开发控制Katritzky盐和1°烷基生成烷基的速率的新策略 Ni中的卤化物催化了C(Sp2)-C(Sp3)xec，导致了新的反应活性。在这里，可调的均质还原剂， 将制备出与常用的非均相还原剂Mn0类似的还原电位。动能 将进行研究，以了解还原剂控制烷基自由基形成速度的能力 来自N-羟基邻苯二甲酰亚胺(NHP)酯和1°、2°和3°烷基卤化物。这将伴随着实验- 识别NiII络合物上的辅助配体，使其能够容易地捕获烷基自由基，目前 未知。对烷基生成和捕获的研究将有助于解决C(Sp2)-中的重大问题。 C(SP3)xec，例如使用芳基和烷基氯化物以及3°烷基卤化物作为底物。最后，通过一个 与默克公司合作，新方法将根据药物化学目标进行评估，并应用于 纳米级化学，这是一种新兴的战略，以制备不同的生物活性化合物文库。

Project Summary/Abstract Precious metal catalysts are typically used for the synthesis of active pharmaceutical ingredients (APIs) even though first-row transition metals such as Ni are more sustainable and can facilitate unique reactivity. For exam- ple, Ni-catalyzed reactions can readily form sp2-sp3 C–C bonds, which provides methods to synthesize the types of non-planar APIs that are challenging to prepare using precious metal-catalyzed reactions. However, in general, the relative lack of mechanistic understanding about Ni-catalyzed reactions has hindered their use in the syn- thesis of APIs because it inhibits the development of improved systems and the rational design of new reactions. One difficulty in elucidating the pathway of Ni-catalyzed transformations is that NiI complexes are often invoked as intermediates but information about their reactivity is limited. In this project, novel NiI halide, alkyl, and aryl species supported by bidentate nitrogen ligands, which are proposed as intermediates in reactions including cross-coupling, cross-electrophile coupling (XEC), and metallaphotoredox based processes, will be synthesized. The ability of these NiI complexes to undergo the proposed elementary steps in catalysis will be investigated as a function of the ancillary ligand and reaction conditions using experimental and computational techniques. These studies will be complemented by experiments to probe how NiI species are formed via comproportionation between Ni0 and NiII complexes and in situ studies to elucidate the speciation of Ni catalysts during catalysis. It is expected that our fundamental investigations will lead to the design of the next generation of Ni-catalyzed reactions by providing guidelines about the reactivity of NiI complexes. Another problem with the development of Ni-catalyzed reactions is that they often involve heterogeneous reductants, which complicate mechanistic studies, create difficulties for scale up, and cannot readily be tuned to vary the reduction potential. The PI’s group has developed a series of commercially available tunable homogeneous reductants, with reduction potentials similar to Zn0. Apart from leading to improvements in practicality, the tunability of these reductants was crucial for developing novel strategies for controlling the rate of alkyl radical generation from Katritzky salts and 1° alkyl halides in Ni-catalyzed C(sp2)–C(sp3) XEC, which led to new reactivity. Here, tunable homogeneous reductants, with reduction potentials similar to Mn0, a commonly used heterogeneous reductant, will be prepared. Kinetic studies will be performed to understand the ability of the reductants to control the rates of alkyl radical formation from N-hydroxyphthalimide (NHP) esters and 1°, 2°, and 3° alkyl halides. This will be accompanied by experi- ments to identify ancillary ligands on NiII complexes that enable facile trapping of alkyl radicals, which is currently unknown. The studies on alkyl radical generation and trapping will aid in solving significant problems in C(sp2)– C(sp3) XEC, such as the use of aryl and alkyl chlorides and 3° alkyl halides as substrates. Finally, through a collaboration with Merck, the new methods will be evaluated against medicinal chemistry targets and applied to nanomole scale chemistry, which is an emerging strategy to prepare diverse libraries of bioactive compounds.