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开发一种用于苯胺衍生物上的亲核芳香族取代的可靠协议。在常规条件下，这些富含电子的底物对亲核试剂不起反应。为了释放这种反应性，提出了在芳烃衬底上用可逆生成的氮基和自由基阳离子进行瞬时极性反转的关键策略。初步的密度泛函理论计算预测了苯胺基、卡伯基和磺酰苯胺基上的亲核芳香族取代反应的活化能显著降低(Δepsilon*=-17~-40kcal/mol)，以及苯胺基、N-苯基咪唑和咔唑基阳离子在对位上带有氯代亲核试剂，并以苯甲酸盐为模型亲核试剂。含氮自由基可通过MS-PCET或HAT对相应前驱体中的N-H键进行可逆(形式)均解而生成，含氮自由基阳离子可通过闭壳母体化合物的单电子氧化获得。为此，既考虑了光氧化还原催化，也考虑了化学氧化剂，并对各种反应参数进行了系统的筛选，以确定合适的条件。如果成功，将针对芳烃上可容忍的取代模式和官能团以及适用的核亲和剂和亲核剂调查反应的范围，重点是复杂的和具有生物活性的化合物。靶向转化代表了一种很有前途的新合成策略，可用于天然产品和药物的制备。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传统方式，有望获得有价值的见解。在此基础上，未来方法论的进一步发展是可以想象的。

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.