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医学的重要工具 化学和有机合成发生了革命性的变化，但对预制有机金属试剂的需求仍然存在 有限的商业可用性和有限的稳定性转化为额外的合成步骤。 碳亲电子试剂，例如有机卤化物，比碳亲核试剂更丰富，这是一种有吸引力的 解决这个问题的方法是两种不同亲电子试剂的交叉偶联。 亲电子试剂已为人所知 100 年，实现交叉选择性并了解其起源仍然存在 该计划的长期目标是开发跨亲电子偶联。 一般选择性交叉亲电子反应以及控制选择性和影响因素的解释 在拟议的资助中，一个由研究生、博士后和实验室技术人员组成的团队将 以先前资助期的进展为基础，开发基于 围绕两种机制模型，并开发新的配体来支持我们的指导机制。 假设是，选择性交叉偶联是由一种持久性中间体与一种持久性中间体发生反应的系统产生的。 在第一种情况下，持久性中间体是有机镍物质，而持久性中间体是有机镍物质。 在第二种情况下，瞬时中间体是有机基团，持久中间体是有机基团。 有机钯物种和瞬时中间体是有机镍物种。 建议是：（1）大幅增加可以参与自由基介导的亲电子试剂的数量 (2)交叉亲电子偶联并进一步研究所提出的反应中间体的机理； 研究交叉亲电体耦合、多金属交叉亲电体耦合的新机制模型，以及 开发新的不易形成碳自由基的亲电试剂交叉亲电子偶联；以及，(3) 通过机制引导设计和研究发现和研究用于交叉亲电子偶联的新配体 该方法具有创新性，因为它专注于交叉亲电子试剂。 耦合，一个快速发展的领域，与交叉耦合和 C-H 的更好研究领域互补 通过关注尚未主要研究的领域，有可能实现功能化。 发现新的键断裂类型和新的通用机制，所提出的研究具有重要意义。 因为它将能够以新的组合方式耦合易于访问的构建块，从而简化 此外，我们的机理研究将揭示选择性的基本问题。 和协同催化，为多个领域的进一步发展奠定基础。