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

本研究项目的目标是为苯胺衍生物的亲核芳香族取代开发一个强大的协议。这些富电子底物在常规条件下对亲核试剂无反应。为了解开这种反应性，提出了在芳烃底物上可逆生成氮中心自由基和自由基阳离子的瞬态极性反转作为关键策略。初步的DFT计算预测了亲核芳香族取代苯胺、碳基和磺酰苯胺基自由基以及苯胺、n -苯基和咔唑自由基的活化能（δ δ ε * = -17至-40 kcal/mol）的显著降低（δ δ epsilon * = -17至-40 kcal/mol）。氮中心自由基可以通过MS-PCET或HAT对相应前驱体中的N-H键进行可逆（形式）均解产生，氮中心自由基阳离子可以通过封闭壳母化合物的单电子氧化得到。为此，光氧化还原催化和化学氧化剂都将被考虑，并将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，将调查反应的范围，包括取代模式和芳烃上耐受的官能团，以及适用的核试剂和亲核试剂，特别强调复杂和生物活性化合物。靶向转化是一种有前途的新合成策略，可用于制备天然产物和药物制剂。此外，对于氮中心自由基和自由基阳离子的反应性如何被驯服以用于非常规方式，预计将有价值的见解。在此基础上，进一步的方法的未来发展是可以想象的。

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.