Harnessing Electrophilic N-Aryl Catalytic Intermediates for Versatile C-N Bond Formation

利用亲电 N-芳基催化中间体形成多功能 C-N 键

• 批准号: 10026372
• 负责人: Tom G Driver
• 金额: $ 30.62万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10026372
• 关键词: Address; Aniline; Anions; Azides; Chemicals; Chemistry; Complex; Cyclization; Development; Electron Transport; Electrons; Future; Generations; Goals; Health; Heterocyclic Compounds; Human; Hydrogen Bonding; In Situ; Indoles; Iodides; Iodine; Metals; Methods; Nitrogen; Organic Synthesis; Oxidants; Oxygen; Pattern; Pharmacologic Substance; Process; Quality of life; Reaction; Reagent; Reducing Agents; Research; Scheme; Silanes; System; Temperature; Transition Elements; catalyst; cold temperature; design; hydroxyindole; improved; method development; migration; nitrene; novel; oxidation; oxindole; programs; scaffold; selectfluor; tool

Abstract The pervasive presence of N-heterocycles in chemical probes, pharmaceuticals and materials that improve the quality of life and health of humans continues to spur the development of new reactions to simplify access to these scaffolds. Our research program addresses important unsolved problems in organic synthesis through the development of new reactions for the selective construction of C–NHAr, C–C and C–O bonds by harnessing the unique reactivity of N-aryl nitrogen catalytic and reactive intermediates generated in situ from nitroarenes and unactivated anilines. Despite the ubiquity of the C–NHAr bond in bioactive N-heterocycles, it cannot be formed using existing metal-catalyzed N-atom transfer reactions because these processes require a strong electron- withdrawing N-substituent. In contrast to the well-established chemistry of N-sulfonyl- or N-carbamoyl metal nitrenes, whose strong electron-withdrawing group is critical for their reactivity with C–H bonds and π-systems, the reactivity of N-aryl nitrenes and nitroarenes is poorly understood because of the difficulties in generating them and taming their reactivity. This lack of understanding has produced a gap in synthesis that obstructs access to complex, functionalized N-heterocyclic compounds and emphasizes the need for the development of methods to provide solutions to these problems. Our prior research efforts have established that N-aryl nitrenes can be formed from azides and that their reactivity is distinct to nitrenes bearing strong electron withdrawing groups. These efforts have provided the basis to support our future efforts in discovering new reactions of N-aryl nitrenes and nitrosoarenes that we will harness to simplify the synthesis of privileged N-heterocyclic scaffolds embedded in synthetic targets. Within this proposal, we have leveraged our understanding these N-aryl nitogen reactive intermediates to develop new transformations that create C–NHAr bonds. Towards this end, in Aim 1 we will develop new Fe(II)-catalyzed reductive cascade reactions that construct sp3-C–NHAr bonds intra- or intermolecularly from nitroarenes using silane reductants; in Aim 2 we will develop new single-electron transfer processes that generate N-aryl reactive intermediates with tunable oxygen transfer abilities for the synthesis of N-hydroxyindoles and oxindoles; and in Aim 3, we will develop oxidative methods for accessing electrophilic N- aryl nitrenoids from anilines and apply to the intra- and intermolecular synthesis of N-heterocycles. By establishing new strategies and tactics for the stereoselective formation of C–NAr, C–C and C–O bonds through harnessing the reactivity of N-aryl nitrogen intermediates, successful realization of these Aims will produce new tools to simplify the construction of novel and bioactive N-heterocycles.

抽象的 在化学问题，药物和材料中，N-杂环的普遍存在可以改善 人类的生活质量和健康继续刺激新反应的发展，以简化进入 这些脚手架。我们的研究计划解决了通过 通过利用c – nhar，c – c和c – o债券的选择性构建的新反应开发 N-芳基氮催化和反应性中间体的独特反应性，从硝化和原位产生 未激活的苯烷。尽管C-NHAR键在生物活性N-杂环中的普遍存在，但无法形成 使用现有的金属催化的N原子转移反应，因为这些过程需要强的电子 撤回n-拟合。与公认的N-磺酰基或N-卡巴马酰金属的化学相反 Nitrenes，其强的电子与绘图组对于它们与C – H键和π系统的反应性至关重要， N-芳基硝酸和硝化烯的反应性很难理解，因为难以产生 他们并驯服了反应性。缺乏理解已经产生了综合差距，阻碍了 访问复杂的，功能化的N-杂环化合物，并强调开发的需求 为这些问题提供解决方案的方法。我们先前的研究工作已经确定N- Aryl Nitrenes 可以由叠氮化物形成，它们的反应性与具有强电子的氮不同 组。这些努力为支持我们未来的努力提供了基础，以发现N-Aryl的新反应 我们将利用的硝酸和亚硝酸烯烯可以简化特权n-杂环脚手架的综合 嵌入合成目标中。在此提案中，我们利用了我们的理解 反应性中间体开发出创建C – NHAR键的新变换。为此，目标1 我们将开发新的Fe（II）降低的级联反应，构建SP3-C – NHAR键内或 使用硅烷还原的氮气间分子。在AIM 2中，我们将开发新的单电子转移 生成具有可调氧转移能力的N-芳基反应性中间体的过程 n-羟基吲哚和氧滴；在AIM 3中，我们将开发用于获取亲电N-的氧化方法 从苯胺中芳基硝酸盐，并应用于N-杂环的分子内和分子间合成。经过 通过建立新的策略和策略，以通过C -NAR，CC和CO键的立体选择性形成 利用N-芳基氮中间体的反应性，这些目标的成功实现将产生新的 简化新颖和生物活性N-核苷的构建的工具。