Development of a Palladium-Catalyzed Direct N2-Arylation of Indazoles.

钯催化的吲唑直接 N2-芳基化反应的开发。

• 批准号: 8121108
• 负责人: Meredeth A McGowan
• 金额: $ 4.84万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121108
• 关键词: Address; Biological; Coupling; Development; Ensure; Generations; Goals; Health; Hepatitis C; Human; Indazoles; Metabolic syndrome; Methods; Nitrogen; Palladium; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Positioning Attribute; Protocols documentation; Reaction; Research Project Grants; Screening procedure; Site; Structure; catalyst; computer studies; drug candidate; method development; novel; research study

DESCRIPTION (provided by applicant): Indazoles bearing aryl groups attached at the N2 position have become increasingly prevalent amongst novel drug candidates.1-4. The primary aim of the research project proposed here is the development of a highly selective, palladium- catalyzed N2-arylation of unprotected indazoles. This goal is expected to be achieved through a comprehensive experimental and computational study of the catalytic cycle that effects the known N1-arylation of these heterocycles,5-9 and to aply that understanding towards manipulating the reaction components to achieve the desired N2- coupling. Finally, efforts will be made to ensure the generality of the method for a wide range of potential substrates. The successful development of this method would have a significant impact on the ease of synthesis of these important biologically active substructures particularly in a medicinal chemistry setting, allowing for the more rapid generation and screening of potential novel pharmaceuticals. PUBLIC HEALTH RELEVANCE: Indazoles bearing aryl substituents at the N2 position have recently become prevalent substructures amongst potential drug candidates indicated for the treatment of a wide variety of human health-related conditions including metabolic syndrome and hepatitis C. 1-4 The successful development of a protocol for the selective N2-arylation of unprotected indazoles, as proposed here, would allow for the rapid generation of a wide variety of these structures for biological screening and SAR studies, particularly in a medicinal chemistry setting.

描述（由申请人提供）：在N2位置上连接芳基的茚唑在新型候选药物中越来越普遍。该研究项目的主要目的是开发一种高选择性的，钯催化的无保护的茚唑的n2 -芳基化。这一目标有望通过对影响这些杂环的已知n1 -芳基化的催化循环进行全面的实验和计算研究来实现，5-9，并将这些理解应用于操纵反应组分以实现所需的N2-偶联。最后，我们将努力确保该方法的通用性，适用于广泛的潜在衬底。该方法的成功开发将对合成这些重要的生物活性亚结构的便利性产生重大影响，特别是在药物化学环境中，允许更快速地生成和筛选潜在的新药。