A General Intermolecular Benzylic C-H Amination Employing an Earth Abundant Metal

摘要 目前的候选药物和FDA批准的药物中常见的是苄基胺。直接式 将氮安装到苄基C-H键上，生成苄基胺，作为芳烃将具有重要意义 普遍存在于生物活性分子中。此外，普遍存在的C-H键的直接官能化消除了 需要预先安装功能，消除合成管理费用，加快药物多样化。一个 高位和化学选择性，廉价的第一排过渡金属催化的苄基C-H胺化是 为拓扑复杂和功能多样的分子的快速多样化而提出的。方法 将对催化剂进行优化，并将在各种常用的有机支架中评估催化剂的反应性 药物设计。选择性趋势将在更复杂的商业可用药物中详细阐述。一次 建立了反应性和选择性趋势，该方法将用于使复杂的药物支架多样化和 天然产品。氮在药品和天然产品中含量丰富，使氮的耐受性低于 反应条件大大拓宽了所提方法的应用范围。生物活性 含有叔胺或吡啶的分子将与季铵盐发生络合作用，以平息 从有害的氮结合到苄基C-H反应中间体的不良副反应 胺化反应。如果拟议的研究得以实现，许多新的小分子药物候选药物将被 与现有的小分子、药物和天然产品只有一步之遥。这样的一种方法 将广泛影响人类健康和医学领域，因为快速和廉价地获得新药 候选人将有可能拥有一种富含地球的、无毒的第一排过渡金属催化剂。

Abstract Benzylic amines are commonly found in current drug candidates and FDA approved drugs. The direct installation of a nitrogen into a benzylic C–H bond, generating a benzylic amine, would be significant as aromatics are ubiquitous in bioactive molecules. Additionally, direct functionalization of a prevalent C–H bond eliminates the need for pre-installed functionalities, eliminating synthetic overhead and accelerating drug-diversification. A highly site- and chemoselective, inexpensive first row transition metal-catalyzed benzylic C–H amination is proposed for the rapid diversification of topologically complex and functionally diverse molecules. The method will be optimized and the catalyst reactivity will be evaluated in a variety of common organic scaffolds used in drug design. Selectivity trends will be elaborated in more complex commercially available pharmaceuticals. Once reactivity and selectivity trends are established, the method will be used to diversify complex drug scaffolds and natural products. Nitrogen is abundant in pharmaceuticals and natural products, making nitrogen tolerance under the reaction conditions necessary to significantly broaden the applications of the proposed method. Bioactive molecules containing a tertiary amine or pyridine will undergo complexation to the quaternary salt, to quell unwanted side reactions from detrimental nitrogen binding to reaction intermediates in the benzylic C–H amination reaction. If the proposed research is achieved, many new small molecule drug candidates will be accessible in only one step from existing small molecules, pharmaceuticals, and natural products. Such a method would broadly impact human health and the field of medicine as rapid and inexpensive access to new drug candidates will be possible with an earth-abundant, non-toxic, first-row transition metal catalyst.