电氧化诱导的自由基烷基化反应精准构建氟代杂环化合物

The introduction of fluorinated groups into heterocyclic molecules has been broadly used in small-molecule agents. However, a direct, convenient and environment-friendly fluorination method has not been well established, limiting the synthesis of fluorinated heterocyclic drugs. Compared with the traditional fluorination reactions, the strategy of using electrochemical fluoroalkylation to synthesize fluorinated heterocycles avoids the additive of oxidants and transition metals. The electrosynthesis, which employs mild conditions, has emerged as a powerful and green synthetic tool. Based on the advantages of electrochemistry, we will focus on promoting the fluoroalkyl radical, produced by electrolysis, efficiently and sequencely reacting with substrates through radical cascade cyclization. In this project, with the rational design of substrates and modification of fluoroalkylated reagent, we will investigate the electrochemical fluoroalkylation of alkynes, alkenes, allenes and alkanes (remote inert C(sp3)-H bond), using the strategy of radical cascade cyclization, radical shift, functional group migration, towards the precise construction of fluoroalkylated and fluorinated heterocycles. The preliminary study of antitumor activity will also be carried out. The fulfillment of this program will develop novel electrochemical fluoroalkylations, conferring a benign and efficient synthetic methodology for the building of fluorinated heterocyclic compounds with diverse structures, and stimulate the improvement of the synthesis of fluorinated heterocyclic drugs.

杂环分子中引入含氟官能团在药物分子中有广泛的应用。然而，由于缺少便捷、通用、以及绿色环保的氟化方法，使得含氟杂环药物的合成工艺受到极大限制。相较于传统的有机氟化反应，利用电化学氧化产生氟烷基自由基构建氟代杂环骨架的策略，可避免氧化剂和过渡金属的使用，反应条件温和、绿色节能。基于电化学的这些优势，本项目将针对如何使电解产生的氟烷基自由基高效有序地参与底物的可控串联环化反应进行研究。拟以具有重要生物活性功能的杂环骨架为导向，通过合理设计底物和氟烷基化试剂的修饰，利用自由基串联环化、自由基迁移、官能团迁移等策略实现烯（炔）烃、联烯和烷烃（远程惰性C(sp3)‒H键）的电化学氟烷基化反应，精准构建环外和环内氟代杂环化合物；并初步评价其抗肿瘤活性。本项目的实施可发展电化学氟烷基化反应的类型，并为构建结构多样的氟代杂环分子提供绿色、高效合成方法，为含氟杂环药物合成工艺的改进提供新思路。

功能杂环骨架在药物分子中具有广泛的应用。然而，由于缺少便捷、通用、以及绿色环保的构筑方法，使得修饰功能杂环骨架的合成工艺受到极大限制。相较于传统的有机合成反应，利用电化学氧化策略，可避免化学氧化剂和过渡金属的使用，反应条件温和、绿色节能。基于电化学的这些优势，通过自由基的生成与转化，本项目实现了丙烯酰胺类化合物、吲哚类、醛腙类、烯烃类、烷烃类等底物的电化学氧化转化，例如：氟烷基化反应、硫氰化反应、磷酰化反应、胺化反应以及硒化反应等，开发了构筑功能性杂环化合物的绿色高效合成方法。这些方法无需使用化学氧化试剂或金属催化剂。在项目的资助下，在Sci. China Chem.，Green Chemistry，Org. Lett.等杂志上发表标注SCI论文12篇，授权发明专利2项。