Cross-Coupling Without Organometallic Reagents:New Electrophiles, Reactions and Mechanisms for Cross-Electrophile Coupling

无有机金属试剂的交叉偶联:交叉电偶联的新型亲电试剂、反应和机制

• 批准号: 9528133
• 负责人: Daniel John Weix
• 金额: $ 19.71万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9528133
• 关键词: Address; Alcohols; Area; Carbon; Carboxylic Acids; Catalysis; Collection; Coupling; Development; Dimerization; Disease; Drug Industry; Foundations; Future; Goals; Grant; Libraries; Ligands; Light; Mediating; Metals; Methods; Mission; Modeling; Nickel; Organic Synthesis; Outcome; Pharmaceutical Chemistry; Pharmaceutical Preparations; Postdoctoral Fellow; Public Health; Reaction; Reagent; Research; Source; System; Testing; Time; Translating; United States National Institutes of Health; Work; base; design; dimer; feeding; functional group; graduate student; improved; innovation; novel; programs; screening; small molecule; tool

Catalytic cross-coupling methods that form carbon-carbon bonds have become an essential tool of medicinal chemistry and revolutionized organic synthesis, but the need for pre-formed organometallic reagents remains a challenge. Limited commercial availability and limited stability translate to extra steps in synthesis. Because carbon electrophiles, such as organic halides, are more abundant than carbon nucleophiles, an attractive solution to this problem is the cross-coupling of two different electrophiles. Although the dimerization of electrophiles has been known for 100 years, achieving cross-selectivity and understanding its origins remain the central challenges of cross-electrophile coupling. This program’s long-term goals are the development of general, selective cross-electrophile reactions and the explanation of the factors that control selectivity and reactivity. In the proposed grant, a team composed of graduate students, a postdoc, and a lab technician will build upon the advances of the previous grant period to develop cross-electrophile coupling reactions based around two mechanistic models, and develop new ligands to support these efforts. Our guiding mechanistic hypothesis is that selective cross-coupling arises from systems where one persistent intermediate reacts with a transient, reactive intermediate. In the first case, the persistent intermediate is an organonickel species and the transient intermediate is an organic radical. In the second case, the persistent intermediate is an organopalladium species and the transient intermediate is an organonickel species. The specific aims of this proposal are to: (1) dramatically expand the number of electrophiles that can participate in radical-mediated cross-electrophile coupling and to further study the reactive intermediates in the proposed mechanism; (2) study a new mechanistic model for cross-electrophile coupling, multimetallic cross-electrophile coupling, and develop new cross-electrophile couplings of electrophiles that do not as easily form carbon radicals; and, (3) discover and study new ligands for cross-electrophile coupling through both mechanism-guided design and the screening of novel ligand libraries. The approach is innovative because it focuses on cross-electrophile coupling, a rapidly growing area that is complementary to the better-studied areas of cross-coupling and C-H functionalization. By focusing on an area that has not been extensively studied, there is the potential to discover new types of bond disconnections and new, general mechanisms. The proposed research is significant because it will enable the coupling of easily accessible building blocks in new combinations, simplifying organic synthesis. In addition, our mechanistic studies will shed light on fundamental questions of selectivity and cooperative catalysis, laying a foundation for further development in several fields.

形成碳-碳键的催化交叉偶联方法已成为药物研究的重要工具 化学和革命性的有机合成，但对预先形成的有机金属试剂的需求仍然存在 这是一个挑战。有限的商业供应和有限的稳定性意味着合成过程中需要额外的步骤。因为 碳的亲电性，如有机卤化物，比碳的亲核性更丰富，这是一个有吸引力的 解决这个问题的办法是两种不同的亲电体的交叉偶联。尽管分子的二聚化 亲电性已有100年的历史，实现了交叉选择性，但人们对其起源的理解仍然存在。 交叉亲电偶联的主要挑战。这项计划的长期目标是发展 一般的、选择性的交叉电泳反应以及控制选择性和选择性的因素的解释 反应性。在拟议的拨款中，由研究生、博士后和实验室技术员组成的团队将 在上一批资助期的基础上发展交叉亲电偶联反应 围绕两个机械模型，并开发新的配体来支持这些努力。我们的导向机制 假设选择性交叉耦合产生于其中一个持久性中间体与一个 瞬变的反应性中间体。在第一种情况下，持久性中间体是一种有机镍物种，而 过渡中间体是一种有机自由基。在第二种情况下，持久中间层是一个 有机钯物种，过渡中间体为有机镍物种。这样做的具体目的是 建议是：(1)大幅增加可参与自由基介导的亲电体的数量 交叉亲电偶联及进一步研究活性中间体的作用机理；(2) 研究了一种新的交叉亲电偶联机理模型--多金属交叉亲电偶联 开发不那么容易形成碳自由基的亲电体的新的交叉亲电偶联；以及，(3) 通过机制导向设计和研究发现和研究用于交叉亲电偶联的新配体 新型配基文库的筛选。这种方法是创新的，因为它专注于交叉亲电泳法 耦合，这是一个快速增长的领域，是对交叉耦合和C-H研究较好的领域的补充 功能化。把重点放在一个没有得到广泛研究的领域，有可能 发现新类型的键断开和新的、一般的机制。这项拟议的研究具有重要意义 因为它将以新的组合实现易于访问的构建块的耦合，从而简化 有机合成。此外，我们的机械研究将阐明选择性的基本问题。 和合作催化，为几个领域的进一步发展奠定了基础。