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.

项目摘要/摘要贵金属催化剂通常用于合成活性药物成分（API）尽管诸如NI之类的第一行过渡金属更可持续，并且可以促进独特的反应性。进行考试 ple，ni催化的反应可以很容易地形成SP2-SP3 C – C键，这提供了合成类型的方法挑战使用贵金属催化反应的非平面API。但是，总的来说对Ni催化反应的相对缺乏机械理解，阻碍了它们在合成中的使用 API的论文是因为它抑制了改进的系统的发展和新反应的合理设计。阐明Ni催化转化的途径的困难是NII复合物通常被调用作为中间体，但有关其反应性的信息是有限的。在这个项目中，新型NII卤化物，烷基和芳基由鸟类氮配体支撑的物种，这些物种是在包括的反应中的中间体将合成交叉耦合，跨电动耦合（XEC）和基于掌托氧的过程。这些NII复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功能。这些研究将通过实验来完成，以探测如何通过构成形成NII物种在NI0和NIII复合物之间以及原位研究之间，以阐明催化过程中Ni催化剂的规范。它预计我们的基本投资将导致下一代NI催化的设计通过提供有关NII复合物反应性的指南来做出反应。发展的另一个问题 Ni催化的反应是，它们通常涉及异质性还原，这使机械化复杂化研究，使扩大规模难度，并且无法轻易调整以改变减少潜力。 Pi的小组已经开发了一系列可欣赏的可调均匀均匀减少，具有降低电位类似于ZN0。除了导致实践改善之外，这些还原剂的可线性性至关重要为了制定用于控制烷基盐和1°烷基烷基自由基发电速率的新型策略 Ni催化的C（SP2）–C（SP3）XEC中的卤化物，导致了新的反应性。在这里，可调节的均匀减少，将制备与MN0相似的降低电势，即一种常用的异质性还原。动力学将进行研究，以了解还原的能力控制酒精自由基形成速率从N-羟基苯胺（NHP）酯以及1°，2°和3°烷基卤化物中。这将通过实验来完成 - 鉴定在niii络合物上识别辅助配体的物种未知。烷基自由基产生和捕获的研究将有助于解决C（SP2） - 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，通过一个与默克的合作，新方法将针对医学化学目标进行评估，并应用于纳米尔量表化学，这是制备生物活性化合物的潜水文库的新兴策略。