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

摘要 苄胺通常存在于当前的候选药物和FDA批准的药物中。直接 将氮安装到苄基C-H键中，产生苄基胺，作为芳族化合物是重要的。 普遍存在于生物活性分子中。另外，普遍的C-H键的直接官能化消除了 需要预先安装功能，消除合成开销并加速药物多样化。一 高度位置选择性和化学选择性、廉价第一行过渡金属催化的苄基C-H胺化， 提出了拓扑结构复杂和功能多样的分子的快速多样化。述的方法 将被优化，催化剂的反应性将在各种常见的有机支架中进行评价， 药物设计选择性趋势将在更复杂的市售药物中详细说明。一旦 反应性和选择性的趋势，该方法将用于多样化复杂的药物支架， 天然产品。氮在药物和天然产物中含量丰富，使得氮耐受性低于 所需的反应条件，以显着拓宽所提出的方法的应用。生物活性 含有叔胺或吡啶的分子将经历与季盐的络合作用，以消除 有害的氮结合到苄基C-H中的反应中间体的不希望的副反应 胺化反应如果这项研究得以实现，将有许多新的小分子候选药物。 从现有的小分子、药物和天然产物中只需一步即可获得。这种方法 将广泛影响人类健康和医学领域，因为快速廉价地获得新药 使用地球上丰富的、无毒的第一行过渡金属催化剂的候选物将是可能的。

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.