Development of Strategies for the Functionalization of Amines

说明(申请人提供)：大多数对人类健康至关重要的药物由含氮化合物组成。一种特别吸引人的方法是通过C-H键官能化的方法来修饰廉价和容易获得的胺。然而，有效地完成这项任务的方法很少，而且范围严重不足。此外，目前已知的方法通常需要使用昂贵的过渡金属催化剂和/或氧化剂。这项建议的重点是设计和开发有效和实用的胺功能化方法。主要目标是通过概念上新的和不发达的底物活化方法对胺进行？和？-功能化。一个主要的焦点是氧化还原中性的C-H键功能化方法，这种方法不需要昂贵的氧化剂或贵金属催化剂。我们拟议工作的中心主题是将氧化C-H键官能化与生产性还原事件结合起来，通过允许生成额外的C-C键或C-X键来促进产品的形成。我们建议的反应通过亚胺离子、甲亚胺叶立德和烯胺中间体进行，这些中间体可以在相对温和的条件下进行。除了目标是快速制备具有生物活性的化合物，如表喹酰胺、哈米明和喹唑烷酮生物碱外，我们的努力还将集中在开发特别强大的反应，快速生成新的多环胺。一个优先事项是产生新的结构框架，这些框架是当前药物发现筛选文库所没有的。 与公共卫生相关：由于大多数药物含有氮，以最快的方式制备这些材料的能力至关重要。药物的广泛可获得性直接取决于是否存在能够可靠地构建复杂分子结构的具有成本效益的方法。这项提议的目标是开发强有力的胺C-H键功能化的新方法和战略，以促进快速获得用于合成生物活性化合物和药物的有价值的构件。

DESCRIPTION (provided by applicant): The majority of pharmaceutical drugs that are essential for human health consist of nitrogen containing compounds. A particularly attractive approach to these targets is the modification of cheap and readily available amines by means of C-H bond functionalization. However, methods that accomplish this task efficiently are scarce and severely lacking in scope. Moreover, the currently known approaches typically require the use of expensive transition metal catalysts and/or oxidants. This proposal is focused on the design and development of efficient and practical methods for amine functionalization. The main goal is the ?- and ?-functionalization of amines through conceptually new and underdeveloped methods of substrate activation. A major focus is on redox-neutral approaches to C-H bond functionalization that do not require expensive oxidants or precious metal catalysts. The central theme of our proposed work is to couple an oxidative C-H bond functionalization with a productive reduction event that contributes to the formation of products by allowing for the generation of additional C-C, or C-X bonds. Our proposed reactions proceed via iminium ion, azomethine ylide and enamine intermediates that can be accessed under relatively mild conditions. In addition to targeting the rapid preparation of biologically active compounds such as epiquinamide, harmicine and quinazolinone alkaloids, our efforts will center on the development of particularly powerful reactions that rapidly generate new polycylic amines. A priority is the generation of novel structural frameworks that are absent from current drug discovery screening libraries. PUBLIC HEALTH RELEVANCE: As most pharmaceutical drugs contain nitrogen, the ability to prepare these materials in the most rapid way possible is of the utmost importance. The broad availability of drugs is directly dependent on the existence of cost-efficient methods that can reliably build complex molecular structures. The objective of this proposal is the development of powerful new methods and strategies for amine C-H bond functionalization that will facilitate rapid access to valuable building blocks for the synthesis of biologically active compounds and pharmaceuticals.