New Synthetic Methodology Enabled by Base-Promoted Halogen and Electron Transfer Processes

项目摘要 仍然迫切需要开发能够提高效率和多样性的综合方法 获得药物研究所需的化学品的权利。特别是，从根本上说，新的转型 利用大量可用的原料可以极大地促进新药的发现和制造。 这项研究计划的长期目标是使用强碱作为新反应的催化剂和促进剂。 这解决了有机合成中的主要限制。这个应用程序的总体目标是使用廉价的 Brnsted和Lewis碱实现芳基卤化物、杂芳烃和芳烃的新功能化方法 三氟甲基芳烃。这一提议建立在一个假设的基础上，即强大的基础可以解开以前未知的东西 或普通有机官能团的未充分利用的机械化过程。具体地说，研究计划将 开发碱催化的芳基卤化物异构化和分子间卤素转移以及单电子 从碱活化的有机硅酸盐转移过程。基于广泛的初步结果，一系列新颖的 描述了主要以改进杂芳烃为目标的芳烃官能化反应 衍生化。有机硅烷与三氟亚甲基芳烃的单选择性偶联也被描述为一种 实用的和广泛有用的二氟苯基化合物的方法。这些方法的影响是 通过一步访问以前无法访问或需要的化合物来演示 繁琐的多步骤手术，它们用于药物样结构的后期多样化和戏剧性 改进了通往特定候选药物的路线。在拟议的工作完成后，化学家将在他们的 处理一组强大的反应，提高了获得分子的效率、实用性和范围 在制药业中广受欢迎。

Project Summary There remains a critical need to develop synthetic methodology that increases the efficiency and diversity of access to chemicals desired in medicinal research. In particular, fundamentally new transformations that employ abundantly available starting materials can greatly facilitate the discovery and manufacture of new drugs. The long-term goal of this research program is to use strong bases as catalysts and promoters for new reactions that address major limitations in organic synthesis. The overall objective for this application is to use inexpensive Brønsted and Lewis bases to achieve new functionalization methods of aryl halides, heteroarenes and trifluoromethylarenes. This proposal is built on the hypothesis that strong bases can unlock previously unknown or underutilized mechanistic processes of common organic functional groups. Specifically, the research plan will exploit base-catalyzed aryl halide isomerizations and intermolecular halogen transfers, as well as single electron transfer processes from base-activated organosilicates. Based on extensive preliminary results, a series of novel arene functionalization reactions are described that are primarily targeted at improving heteroarene derivatization. The monoselective coupling of organosilanes to trifluoromethylarenes is also presented as a practical and broadly useful approach to difluorobenzylic compounds. The impact of these methods is demonstrated through single-step access to compounds that were either previously inaccessible or required tedious multistep operations, their use for late stage diversification of drug-like structures and dramatically improved routes to specific drug candidates. Upon completion of the proposed work, chemists will have at their disposal a set of powerful reactions that increase the efficiency, practicality and scope of access to molecules widely desired in the pharmaceutical industry.