Fundamental Studies of Ni-Catalyzed Organic Reactions

镍催化有机反应的基础研究

基本信息

批准号：
10552202
负责人：
Nilay Hazari
金额：
$ 41.88万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-06-30
项目状态：
未结题

项目摘要

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.

项目概要/摘要贵金属催化剂通常用于活性药物成分 (API) 的合成，甚至尽管第一行过渡金属（例如镍）更具可持续性，并且可以促进独特的反应性。例如，Ni催化的反应可以很容易地形成sp2-sp3 C-C键，这提供了合成这些类型的方法使用贵金属催化反应制备非平面 API 具有挑战性。对镍催化反应的机理理解相对缺乏阻碍了它们在合成中的应用 API 的论文，因为它抑制了改进系统的开发和新反应的合理设计。阐明 Ni 催化转化途径的一个困难是 NiI 配合物经常被调用作为中间体，但有关其反应性的信息有限。在该项目中，新型 NiI 卤化物、烷基和芳基。由二齿氮配体支持的物质，建议作为反应的中间体，包括将合成基于交叉偶联、交叉亲电子偶联（XEC）和金属光氧化还原的工艺。这些 NiI 配合物在催化中经历所提出的基本步骤的能力将被研究为使用实验和计算技术的辅助配体和反应条件的函数。这些研究将通过实验来补充，以探究 NiI 物质是如何通过复合形成的 Ni0 和 NiII 配合物之间的关系以及原位研究，以阐明催化过程中 Ni 催化剂的形态。预计我们的基础研究将导致下一代镍催化的设计通过提供有关 NiI 配合物反应性的指导来解决反应问题是开发的另一个问题。镍催化反应的一个主要问题是它们经常涉及异质还原剂，这使机理变得复杂研究，给扩大规模带来了困难，并且无法轻易调整以改变减少潜力。开发了一系列市售可调均质还原剂，具有还原潜力与 Zn0 类似，除了提高实用性外，这些还原剂的可调性也至关重要。开发新策略来控制 Katritzky 盐和 1° 烷基的烷基自由基生成速率 Ni催化的C(sp2)–C(sp3) XEC中的卤化物，这导致了新的反应性，在这里，可调节的均相还原剂，将制备具有与常用的非均相还原剂 Mn0 类似的还原电势的材料。将进行研究以了解还原剂控制烷基自由基形成速率的能力 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经验。鉴定 NiII 配合物上的辅助配体，这些配体能够轻松捕获烷基自由基，目前正在研究未知对烷基自由基产生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以及3°烷基卤作为底物。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摩尔级化学，这是一种制备多种生物活性化合物库的新兴策略。