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: 10225603
• 负责人: Tom G Driver
• 金额: $ 30.58万
• 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/10225603
• 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.

摘要 N-杂环化合物在化学探针、药物和材料中的普遍存在， 人类的生活质量和健康继续刺激新反应的发展，以简化获得 这些脚手架我们的研究计划通过有机合成解决重要的未解决的问题， 开发新的反应，用于通过利用C-NHAr，C-C和C-O键的选择性构建， 由硝基芳烃原位生成的N-芳基氮催化和活性中间体的独特反应性， 未活化的苯胺。尽管C-NHAr键在生物活性N-杂环中普遍存在，但它不能形成 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电子， 撤回N-取代基。与N-磺酰基或N-氨基甲酰基金属的成熟化学相反， 氮烯，其强吸电子基团对于它们与C-H键和π-体系的反应性至关重要， N-芳基氮烯和硝基芳烃的反应性知之甚少，因为难以生成 他们和驯服他们的反应。这种缺乏理解的情况造成了综合方面的差距， 获得复杂的，官能化的N-杂环化合物，并强调需要开发 提供解决这些问题的方法。我们先前的研究工作已经确定， 可以由叠氮化物形成，并且它们的反应性不同于具有强吸电子的氮烯 组这些工作为我们今后探索N-芳基的新反应提供了基础 氮烯和亚硝基芳烃，我们将利用它们来简化特权N-杂环支架的合成 嵌入合成目标中在这个提议中，我们利用了我们对这些N-芳基氮基的理解， 活性中间体，以开发新的转换，创造C-NHAr键。为此，目标1 我们将开发新的Fe（II）催化的还原级联反应，在内部或外部构建sp3-C-NHAr键， 在目标2中，我们将开发新的单电子转移， 产生具有可调氧转移能力的N-芳基反应性中间体的方法， N-羟基吲哚和羟吲哚;在目标3中，我们将开发用于获得亲电N- 芳基类氮杂环化合物，并应用于N-杂环的分子内和分子间合成。通过 建立了立体选择性形成C-NAr、C-C和C-O键的新策略和战术， 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 工具，以简化新的和生物活性的N-杂环的建设。