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

项目摘要 仍然迫切需要开发综合方法，以提高效率和多样性 药物研究所需的化学物质。特别是，从根本上说， 使用大量可获得的起始材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利用强碱作为新反应的催化剂和促进剂 解决了有机合成中的主要局限性。本申请的总体目标是使用廉价的 Brønsted和刘易斯碱，以实现芳基卤化物、杂芳烃和 三氟甲基芳烃。这一提议是建立在强碱基可以解开以前未知的假设之上的 或未充分利用的常见有机官能团的机械过程。具体来说，研究计划将 利用碱催化的芳基卤异构化和分子间卤素转移，以及单电子 碱活化有机硅酸盐的转移过程。基于广泛的初步结果，一系列新的 描述了芳烃官能化反应， 衍生化有机硅烷与三氟甲基芳烃的单选择性偶联也作为一种新的偶联方法提出。 这是一种实用和广泛有用的方法，用于二氟苄基化合物。这些方法的影响是 通过一步获得以前无法获得或需要 繁琐的多步操作，它们用于药物样结构的后期多样化， 改进了获得特定候选药物的途径。在完成拟议的工作后，化学家将在其 处置一套强大的反应，提高效率，实用性和范围的访问分子 在制药工业中被广泛期望。

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.