Nucleophilic aromatic substitution on electron-rich aniline derivatives via transient polarity inversion with N-centered radical (cationic) substituents

通过 N 中心自由基（阳离子）取代基的瞬时极性反转对富电子苯胺衍生物进行亲核芳香取代

• 批准号: 527488163
• 负责人: Dr. Jan Seliger
• 金额: --
• 依托单位: Frick Chemistry Laboratory
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2023
• 资助国家: 德国
• 起止时间: 2022-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/527488163?language=en
• 关键词: Nucleophilic; aromatic; substitution; electron; rich

The goal of this research project is the development of a robust protocol for the nucleophilic aromatic substitution on aniline derivatives. These electron-rich substrates are unreactive towards nucleophiles under conventional conditions. To unlock this reactivity, transient polarity inversion on the arene substrate with reversibly generated nitrogen-centered radicals and radical cations is proposed as the key strategy. Preliminary DFT calculations predict substantially reduced activation energies (delta delta epsilon * = -17 to -40 kcal/mol) for nucleophilic aromatic substitutions on anilino, carbox-, and sulfonanilidyl radicals, as well as anilinium, N-phenyliminium, and carbazolium radical cations with a chloronucleofuge in the para-position and benzoate as the model nucleophile. The nitrogen-centered radicals may be generated by reversible (formal) homolysis of the N-H bonds present in corresponding precursors by MS-PCET or HAT, and the nitrogen-centered radical cations are accessible by single-electron oxidation of closed-shell parent compounds. To this end, both photoredox catalysis and chemical oxidants are considered, and a systematic screening of various reaction parameters will be carried out to identify suitable conditions. If successful, the scope of the reaction will be investigated with respect to substitution patterns and functional groups tolerated on the arene, as well as applicable nucleofuges and nucleophiles, with particular emphasis on complex and biologically active compounds. The targeted transformation represents a promising new synthetic strategy that could be used in the preparation of natural products and pharmaceutical agents. In addition, valuable insights are expected into how the reactivity of nitrogen-centered radicals and radical cations can be tamed for use in unconventional ways. Based on this, the future development of further methodologies is conceivable.

该研究项目的目标是开发一种用于苯胺衍生物亲核芳香取代的可靠方案。这些富电子底物在常规条件下不与亲核试剂发生反应。为了解锁这种反应性，提出了利用可逆生成的氮中心自由基和自由基阳离子在芳烃基底上进行瞬时极性反转作为关键策略。初步 DFT 计算预测，苯胺基、羧基和磺苯胺基自由基以及苯胺基、N-苯基亚胺基和咔唑基阳离子上的亲核芳香族取代的活化能大幅降低（δ δ epsilon * = -17 至 -40 kcal/mol）具有对位氯离核剂和苯甲酸盐作为模型亲核试剂。以氮为中心的自由基可以通过MS-PCET或HAT对相应前体中存在的N-H键进行可逆（形式）均裂来产生，并且以氮为中心的自由基阳离子可以通过闭壳母体化合物的单电子氧化来获得。为此，将考虑光氧化还原催化和化学氧化剂，并对各种反应参数进行系统筛选，以确定合适的条件。如果成功，将研究芳烃上取代模式和官能团的反应范围，以及适用的离核剂和亲核试剂，特别强调复杂和生物活性化合物。靶向转化代表了一种有前途的新合成策略，可用于制备天然产物和药剂。此外，对于如何驯服以氮为中心的自由基和自由基阳离子的反应性以用于非常规方式，预计可以获得有价值的见解。基于此，未来进一步发展方法论是可以想象的。