Understanding Coupling Reactions of Heteroaryls

项目摘要 杂二芳基是一类重要的亚结构，广泛存在于生物体内。 活性分子和FDA批准的药物。这些脚手架通常是通过 传统的交叉耦合策略。不幸的是，这些协议对于 杂芳基片段的掺入。这里提出的工作的目标是开发一种 对杂芳烃的交叉偶联反应有基本的了解。我们的目标还包括 将我们的发现应用于开发新的高效和可预测的交叉偶联反应 杂环芳香族偶联伙伴。这项工作最终将使合成和医用 化学家设计可预测和可靠的合成策略来从生物上获得这些 相关中间体和目标化合物。我们最近发现了正电子的场效应- 取代基是脱羧基和氧化速率的主要预测因子 苯甲酸的脱羧基偶联反应。第一阶段的研究将 将这种预测能力扩展到杂芳烃羧酸盐的ODC反应和 不含典型的邻位取代基的苯甲酸酯。我们假设新的配体 支架可以被设计来减少在这些反应中对邻位取代基的需求，因为 场效应参数描述了穿越空间的影响。在我们研究的最后阶段， 我们将把这些新的配体结构应用于其他类型的交叉偶联反应，这些反应具有 历史上受到相关邻位取代基的限制。发展一种大型的 收集可预测和可靠的交叉偶联反应，在广泛的 (杂环)芳香族偶联伙伴的范围很大，因为它提供了一种 生物相关核心结构库。因此，发展一个根本性的 对这些和其他偶联反应的趋势和限制的理解 杂芳烃将使现有的和正在开发的合成方法能够适用于 建造复杂的和药用相关的结构。

Project Summary Heterobiaryls are an important class of substructures found in a large number of biologically active molecules and FDA approved drugs. These scaffolds are typically constructed through traditional cross-coupling strategies. Unfortunately, these protocols are inefficient for the incorporation of heteroaryl fragments. The objective of the work proposed here is to develop a fundamental understanding of the cross-coupling reactions of heteroarenes. We also aim to apply our findings to the development of new efficient and predictable cross-coupling reactions of heteroaromatic coupling partners. This work will ultimately allow synthetic and medicinal chemists to design predictable and reliable synthetic strategies to access these biologically relevant intermediates and target compounds. We recently identified the field effect of ortho- substituents as being a dominant predictor in the rate of decarboxylation and oxidative decarboxylative coupling (ODC) reactions of benzoic acids. The first phase of research will extend this predictive power to the ODC reactions of heteroaromatic carboxylates and benzoates without the typically required ortho-substituents. We hypothesize that new ligand scaffolds can be designed to mitigate the need for ortho-substituents in these reactions because the field effect parameter describes a through-space influence. In the final phase of our study, we will apply these new ligand structures to other classes of cross-coupling reactions that have historically suffered from related ortho-substituent limitations. The development of a large collection of predictable and reliable cross-coupling reactions that operate efficiently for a broad scope of (hetero)aromatic coupling partners is significant because it provides access to a large library of biologically relevant core structures. Thus, the development of a fundamental understanding of the trends and limitations in these and other coupling reactions of heteroarenes would allow existing and developing synthetic methods to be adapted for the construction of complex and pharmaceutically relevant structures.