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.

本研究计画的目标是发展一个稳定的苯胺衍生物的芳香族亲核取代反应。这些富电子底物在常规条件下对亲核试剂不反应。为了解锁这种反应性，瞬态极性反转的芳烃基板可逆产生的氮为中心的自由基和自由基阳离子提出的关键策略。初步的DFT计算预测显着降低的活化能（Δ Δ Σ * = -17至-40千卡/摩尔）的亲核芳族取代苯胺基，carbox-，和磺酰苯胺基自由基，以及苯胺，N-苯基，和咔唑自由基阳离子与chlorofluge在对位和苯甲酸酯作为模型亲核试剂。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，考虑光氧化还原催化和化学氧化剂，并将进行各种反应参数的系统筛选，以确定合适的条件。如果成功的话，反应的范围将进行调查方面的取代模式和芳烃上容忍的官能团，以及适用的离核和亲核试剂，特别强调复杂的和生物活性的化合物。靶向转化是一种很有前途的新的合成策略，可用于天然产物和药物制剂的制备。此外，有价值的见解，预计如何氮为中心的自由基和自由基阳离子的反应性可以驯服用于非常规的方式。在此基础上，可以设想未来进一步的方法学发展。