Preparative Radical Chemistry for Biomedical Research

描述（由申请人提供）：芳烃和杂芳烃是生物体的基础，因此，在药物和其他生物活性化合物中普遍存在。尽管人们对（杂）芳烃功能化一直很感兴趣，但发现化学的时间和成本限制不断增加，仍然需要开发快速、高效和操作简单的程序。由于这是一项艰巨的任务，本提案将重点关注氟烷基和烷基基团在（杂）芳烃上的附着物（即碳氢到碳碳的转化）。目前有许多方法可用于（杂）芳烃功能化，每种方法都有其优点和缺点。虽然“程序化”的C-C键形成，如卤素-金属交换/亲电陷阱、亲核芳香取代和交叉偶联方法在化学的各个方面都是至关重要的，但这些方法需要使用预功能化（通常是卤化）（杂）芳烃，从而增加了合成的额外步骤。在这方面，一步法更有吸引力，然而，氢-金属交换/亲电陷阱，亲电芳香取代和C-H活化方法也存在缺点，例如使用高酸性/碱性试剂，低温条件或昂贵的过渡金属催化剂。使用基于自由基的功能化策略可以潜在地克服这些缺点：最近的结果表明，锌二（二氟甲烷磺酸盐）可以产生二氟甲基自由基，这可以在室温下在露天条件下添加到各种杂环中。在这些结果的基础上，本提案旨在生成一系列用户友好的，货架稳定的锌（烷磺酸盐）试剂。这些试剂将广泛使用，它们的反应将从操作简单的优势出发进行优化。本提案分为三个部分：1)第一部分详细介绍了直接（杂）芳烃氟烷基化锌双（氟烷磺酸盐）试剂的合成；2)第二部分概述了用于杂芳烃烷基化的双烷磺酸锌试剂的发展，以及采用顺序加成策略对杂芳烃的双官能化；最后一节通过动力学分析来指导优化过程，阐明溶剂对区域选择性的影响。虽然这三个目标将同时进行调查，

DESCRIPTION (provided by applicant): Arenes and heteroarenes form the basis of living organisms and, as a consequence, are ubiquitous in pharmaceuticals and other biologically active compounds. Although there has been sustained interest in (hetero)arene functionalization, ever-growing time and cost constraints of discovery chemistry still demand the development of rapid, efficient and operationally trivial procedures. As this presents an immense task, this proposal will focus on the appendage of fluoroalkyl and alkyl groups onto (hetero)arenes (i.e., C-H to C-C transformations). Many methods are currently available for (hetero)arene functionalization, each of them presenting advantages and disadvantages. Although "programmed" C-C bond formations such as halogen-metal exchange/electrophilic trap, nucleophilic aromatic substitution and cross-coupling methodology are vital in all aspects of chemistry, these methods require the use of pre-functionalized (typically halogenated) (hetero)arenes, thus adding extra steps to the synthesis. In this regard, one-step methods are more attractive, however, hydrogen-metal exchange/electrophilic trap, electrophilic aromatic substitution and C-H activation methodology all present drawbacks as well, such as the use of highly acidic/basic reagents, cryogenic conditions, or expensive transition metal catalysts. These drawbacks can be potentially overcome by using a radical-based functionalization strategy: recent results have shown that zinc bis(difluoromethanesulfinate) can generate difluoromethyl radicals, which can add to a variety of heterocycles at room temperature under open air. Building upon these results, this proposal aims to generate a series of user-friendly, shelf-stable zinc bis(alkanesulfinate) reagents. These reagents will be made widely accessible and their reactions will be optimized from the vantage point of operational simplicity. This proposal is organized into three parts: 1) the first section details the synthesis of zinc bis(fluoroalkanesulfinate) reagents for direct (hetero)arene fluoroalkylation; 2) the second part outlines the development of zinc bis(alkanesulfinate) reagents for (hetero)arene alkylation, as well as the bis- functionalization of hetero(arene)s using a sequential addition strategy; and 3) the final section describes kinetic analysis to guide the optimization process and to elucidate solvent effects on regioselectivity. While these three objectives will be investigated in parallel, they will all contribute in establishing reactivity trends of zinc bis(alkanesulfinate) reagents. Generating an armamentarium of these stable reagents and user- friendly procedures would accelerate discovery in medicinal chemistry, food chemistry, agrochemistry, and other chemical and scientific disciplines.