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

摘要 N-杂环在化学探针、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的反应的发展，以简化获得 这些脚手架。我们的研究计划通过以下途径解决有机合成中尚未解决的重要问题 利用C-NHAR、C-C和C-O键选择性构筑新反应的研究进展 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 未被激活的苯胺。尽管C-NHAR键在生物活性的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，因为这些过程需要一个强电子- 退出N-取代基。与公认的N-磺酰基或N-氨基甲酰基金属化学不同 硝烯，其强吸电子基团对其与C-H键和π-体系的反应活性至关重要， N-芳基硝烯和硝基芳烃的反应性由于难以生成而知之甚少。 驯服它们的反应能力。这种理解的缺乏造成了综合方面的差距，这阻碍了 获得复杂的、官能化的N-杂环化合物，并强调需要开发 为这些问题提供解决方案的方法。我们之前的研究工作已经证实，N-芳基硝烷 可以由叠氮化合物形成，它们的反应性与含有强电子引出的硝烯截然不同 组。这些工作为我们今后发现N-芳基的新反应提供了基础 我们将利用硝烯和亚硝基芳烃来简化特权N-杂环支架的合成 嵌入到合成靶标中。在这项提议中，我们利用了我们对这些N-芳基氮的理解 活性中间体，以开发产生C-NHAR键的新转化。为此，在目标1中 我们将开发新的Fe(II)催化的还原级联反应，在OR内构建SP3-C-NHAR键 使用硅烷还原剂从硝基芳烃分子间转移；在目标2中，我们将开发新的单电子转移 生成氧转移能力可调的N-芳基反应中间体用于合成 N-羟基吲哚和氧吲哚；在目标3中，我们将开发获得亲电N-的氧化方法。 从苯胺中得到芳基硝基化合物，并应用于N-杂环的分子内和分子间合成。通过 建立C-NAR、C-C和C-O键立体选择性形成的新战略和新策略 利用N-芳基氮中间体的反应性，成功实现这些目标将产生新的 简化新型生物活性N-杂环结构的工具。

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.