Copper-Catalyzed Aerobic C-H Oxidation Methods for Heterocycle Synthesis

 描述（由申请人提供）：杂环和C-N键是生物活性分子和药物中普遍存在的结构特征。例如，这些基序存在于近年来两种最突出的药物化合物中，立普妥（Lipitor）（r），其含有吡咯N-杂环核心，和Plastine（r），其含有苄基C-N键。获得杂环和C-N键的大多数方法涉及官能团相互转化。因此，通过C-H键的官能化直接形成这些结构是当前重要的兴趣。这种C-H氧化方法具有减少获得所需结构基序所需的步骤数量和减少浪费的潜力。氧化性C-N键形成反应是已知的;然而，它们的底物范围是有限的，并且使用O2作为唯一化学计量氧化剂的例子仍然很少。最近，已经公布了几个铜催化的氧化C-N键形成反应的实例。然而，这些方法不适合大规模应用，并且具有有限的底物范围，因为它们或者通过高反应性铜-氮烯中间体进行，或者它们使用苛刻的、冲击敏感的过氧化物氧化剂。本研究计划描述了铜催化的C-N键形成反应，使用O2作为终端氧化剂。由于O2是一种温和且廉价的氧化剂，该方法可以克服铜催化C-H氧化功能化的主要局限性。本文所述的化学将开始强调分子内C-N键的形成，提供有效的N-杂环，和分子间反应也将进行探索。所提出的方法有可能获得广泛的N-杂环，如恶唑烷酮，吡咯烷酮和吡咯。需氧化学将通过开发采用苯氧基和硝酰基助催化剂的铜催化剂系统来实现。铜催化剂的专用双功能配体将与苯氧基或硝酰基助催化剂一起开发。预期这些配体增加苯氧基和硝酰基介导的反应的选择性。

 DESCRIPTION (provided by applicant): Heterocycles and C-N bonds are ubiquitous structural features in biologically active molecules and pharmaceutical drugs. For example, these motifs are found in the two most prominent pharmaceutical compounds from recent years, Lipitor(r), which contains a pyrrole N-heterocyclic core, and Plavix(r), which contains a benzylic C-N bond. Most methods to access heterocycles and C-N bonds involve functional group interconversions. Consequently, the direct formation of these structures through the functionalization of C-H bonds is of significant current interest. Such C-H oxidation methods have the potential of reducing the number of steps required to access the desired structural motifs and of reducing waste. Oxidative C-N bond forming reactions are known; however, their substrate scope is limited, and examples that use O2 as the sole stoichiometric oxidant are still rare. Recently, several examples of copper-catalyzed oxidative C-N bond forming reactions have been published. However, these methodologies are not amenable to large-scale applications and have limited substrate scope because they either proceed through highly reactive copper-nitrene intermediates or they use harsh, shock sensitive peroxide oxidants. This research proposal describes copper-catalyzed C-N bond forming reactions that use O2 as the terminal oxidant. The proposed methodology could overcome the major limitations of copper-catalyzed C-H oxidative functionalization because O2 is a mild and inexpensive oxidant. The chemistry described herein will be initiated with an emphasis on intramolecular C-N bond formations, providing efficient access to N-heterocycles, and intermolecular reactions will also be explored. The proposed methods have the potential to access a wide array of N-heterocycles, such as oxazolidones, pyrrolidones, and pyrroles. The aerobic chemistry will be achieved by developing copper catalyst systems that employ phenoxyl and nitroxyl co-catalysts. Specialized bifunctional ligands for the copper catalysts will be developed with phenoxyl or nitroxyl co-catalysts tethered to the ligand. These ligands are expected to increase the selectivity of the phenoxyl and nitroxyl mediated reactions.