Electrophilic Amination Reagents for Pd & Cu Catalyzed Non-directed C-H Amination

描述（由申请人提供）：芳香族和苄基氨基在生物活性分子中的重要性通过以下事实说明：10种最畅销的药物中有7种含有此类官能团。尽管它们的重要性，很少有直接合成的氨基取代的化合物从未官能化的基板是已知的，相反，间接路线通常用于安装关键的芳香族和苄基C-N键。的 我们的研究目标是建立广泛适用的一步C-H键胺化方法，该方法消除了对预官能化底物的需要。具体而言，这里的目标是建立非定向芳香族和苄基C-H胺化。该研究由中心假设指导，即当与合适的金属催化剂和配体组合时，新型胺化试剂将使这些非定向C-H官能化成为可能。拟议研究的基本原理是，为非定向C-H胺化建立的原理将适用于各种各样的分子，包括复杂的有机分子，如大多数药物。在初步数据的指导下，中心假设将通过追求两个具体目标进行测试：（1）建立Pd催化的芳烃C-H胺化;（2）建立Cu催化的苄基C-H胺化。实现这些特定目标的方法结合了试剂和催化剂设计以及底物范围研究。实验和计算机理研究将使合理的预测和优化的选择性和反应性。这项研究具有重要意义，因为它有望通过提供更有效，直接的胺合成和快速获得生物活性化合物类似物的方法来加速药物的发现和合成。该方法是创新的，因为它使用了新的亲电胺化试剂，旨在促进非定向C-H胺化的机理理解。此外，胺上的可变亚结构可以很容易地用新试剂引入，为广泛使用的亲电胺化试剂如叠氮化物或氯胺-T提供更安全、更通用和更实用的替代品。最终，新方法有可能为现有和未来的药物生产提供更有效的途径。

DESCRIPTION (provided by applicant): The importance of aromatic and benzylic amino groups in biologically active molecules is illustrated by the fact that 7 of the 10 top-selling pharmaceuticals contain such functionalities. Despite their significance, very few direct syntheses of amino-substituted compounds from unfunctionalized substrates are known; instead, indirect routes are typically used to install crucial aromatic and benzylic C-N bonds. The goal of our research is to establish broadly applicable one-step C-H bond amination methods that eliminate the need to pre-functionalize substrates. Specifically, the objective here is to establish non-directed aromatic and benzylic C-H aminations. The research is guided by the central hypothesis that novel amination rea- gents will enable these non-directed C-H functionalizations, when combined with suitable metal catalysts and ligands. The rationale of the proposed research is that the principles established for the non-directed C-H amination will be applicable to a broad variety of molecules, including complex organic molecules like most pharmaceuticals. Guided by preliminary data, the central hypothesis will be tested by pursuing two specific aims: (1) Establish Pd-catalyzed C-H aminations of arenes; and (2) establish Cu catalyzed benzylic C-H aminations. The approach to achieve these specific aims combines reagent and catalyst design as well as substrate scope studies. Experimental and computational mechanistic investigations will enable rational predictions and optimization of selectivity and reactivity. The proposed research is significant as it is expected to accelerate the discovery and synthesis of pharmaceuticals by providing more efficient, direct syntheses of amines and methods to quickly access analogues of bioactive compounds. The approach is innovative because it uses novel electrophilic amination reagents that are designed to facilitate the mechanistic understanding of non-directed C-H aminations. Furthermore, variable substructures on the amine can be introduced easily with the new reagents, providing safer, more versatile, and more practical alternatives to widely used electrophilic amination reagents like azides or Chloramine-T. Ultimately, the new methodologies have the potential to provide more efficient routes for the manufacturing of existing and future pharmaceuticals.