权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结/摘要贵金属催化剂通常用于活性药物成分（API）的合成，尽管第一行过渡金属如Ni更可持续，并可促进独特的反应性。为了考试- 简单来说，Ni催化的反应可以很容易地形成sp2-sp3 C-C键，这为合成这类化合物提供了方法。使用贵金属催化反应制备具有挑战性的非平面API。然而，一般而言，相对缺乏对镍催化反应的机理理解阻碍了它们在合成中的应用，因为它抑制了改进系统的开发和新反应的合理设计。阐明镍催化转化途径的一个困难是，NiI络合物经常被调用作为中间体，但关于它们的反应性的信息是有限的。在这个项目中，新的NiI卤化物，烷基和芳基，由双齿氮配体支撑的物种，其被提议作为反应中的中间体，包括将合成交叉偶联、交叉亲电偶联（XEC）和基于金属光氧化还原的方法。这些NiI络合物在催化中经历所提出的基本步骤的能力将被研究为辅助配体和反应条件的函数，使用实验和计算技术。这些研究将通过实验来补充，以探索NiI物种是如何通过歧化作用形成的 Ni 0和NiII配合物和原位研究之间的关系，以阐明催化过程中Ni催化剂的形态。它预计我们的基础研究将导致下一代镍催化的设计，通过提供关于NiI络合物的反应性的指导来进行反应。发展的另一个问题是镍催化反应的一个重要特点是，它们通常涉及多相还原剂，这使得机理复杂化。然而，在研究中发现，这给扩大规模造成了困难，并且不能容易地调整以改变还原潜力。PI小组已经开发了一系列可商购的可调均相还原剂，具有还原电位类似于Zn 0。除了导致实用性的改进之外，这些还原剂的可调性是至关重要的用于开发控制Katritzky盐和1°烷基的烷基自由基生成速率的新策略在Ni催化的C（sp2）-C（sp3）XEC中的卤化物，这导致新的反应性。这里，可调均相还原剂，其还原电位类似于常用的非均相还原剂Mn 0。动力学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由N-羟基邻苯二甲酰亚胺（NHP）酯和1°、2°和3°烷基卤化物制得。这将伴随着经验- 目的是确定镍II络合物上的辅助配体，使烷基自由基的容易捕获，这是目前未知对烷基自由基生成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，并应用于纳米摩尔规模的化学，这是一种新兴的策略，以制备不同的生物活性化合物库。