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

形成碳-碳键的催化交叉偶联方法已成为医学研究的重要工具 化学和革命性的有机合成，但需要预先形成的有机金属试剂仍然存在 一个挑战.有限的商业可用性和有限的稳定性转化为合成中的额外步骤。因为 碳亲电体，如有机卤化物，比碳亲核体更丰富，是一种有吸引力的亲核试剂。 该问题的解决方案是两种不同亲电试剂的交叉偶联。虽然二聚化的 亲电体已经被发现了100年，实现交叉选择性和了解它的起源仍然存在 交叉亲电偶联的核心挑战。该计划的长期目标是发展 一般，选择性交叉亲电反应和控制选择性的因素的解释， 反应性在拟议的赠款中，一个由研究生、博士后和实验室技术人员组成的团队将 在前一个资助期的基础上，开发基于 围绕两个机制模型，并开发新的配体来支持这些努力。我们的指导机制 一种假设是，选择性交叉耦合产生于一个持久中间体与一个 短暂的活性中间体。在第一种情况下，持久性中间体是有机镍物种， 过渡中间体是有机自由基。在第二种情况下，持久中间体是 有机钯物种，并且过渡中间体是有机镍物种。具体目标是 建议是：（1）显着扩大亲电体的数量，可以参与自由基介导的 交叉亲电偶联反应并进一步研究反应中间体的提出机理;（2） 研究了交叉亲电偶联的新机理模型--多金属交叉亲电偶联， 开发不容易形成碳自由基的亲电试剂的新的交叉亲电试剂偶联;以及（3） 发现和研究新的配体交叉亲电偶联通过机制指导的设计和 新型配体库的筛选。该方法是创新的，因为它侧重于交叉亲电体 耦合，一个快速增长的领域，是互补的交叉耦合和C-H更好地研究领域 功能化通过关注一个尚未被广泛研究的领域， 发现新的键断裂类型和新的通用机制。所提出的研究是有意义的 因为它将使容易接近的构件能够以新的组合方式耦合， 有机合成此外，我们的机制研究将阐明选择性的基本问题 和协同催化作用，为今后在多个领域的进一步发展奠定了基础。

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.