基于单电子转移历程及过渡金属催化原理的氟卤代烃与碳氢卤代烃还原偶联反应研究

Development of new synthetic reactions between fluoroalkyl halides and counterpart nonfluorinated electrophiles with high chemo-selectivity and catalytic efficiency is greatly desirable due to the manufacturing need of fluorine chemical industry and environmental protection of ozone layer. As is known to all, electron-poor fluoroalkyl radicals usually show innate reluctancy in the radical addition with electron-deficient arene ring. With the aim of bypassing this limitation and introducing fluoroalkyl group to electron-deficient moiety efficiently, a reductive coupling strategy between RfX and RX (R= Ar, alkyl, alkenyl) is proposed based on the following reasons: (1) Fluoroalkyl halides are likely to be transformed to fluoroalkyl radical in the presence of reductive agents; (2) The carbon-halogen bond of RX can be activated by transition metal insertion with the assistance of proper ligand; (3) The generated organometallic intermediate can bind to the fluoroalkyl radical and undergoes subsequent reductive elimination to produce coupling product. The research includes the optimization of reaction conditions, elucidation of mechanism by electrochemical techniques, kinetic experiments, isolation and identification of reaction intermediates. It is expected that the establishment of this robust reductive coupling protocol could enrich the selective chemical transformations of fluoroalkyl halides and will find some applications in the synthesis of fluorinated molecules in relevant medicine and organofluorine material fields.

建立高选择性和高催化效率的氟卤代烃衍生化反应是实现氟卤代烃综合利用及臭氧层保护环保目标的重要途径。本项目基于氟卤代烃的单电子转移反应特征和过渡金属催化还原偶联反应理论基础，针对缺电子性的氟烷基自由基难以直接引入贫电子芳环的局限，以氟卤代烃RfX和碳氢亲电体RX（卤代芳烃、卤代烯烃、卤代烷烃）为原料，利用氟卤代烃在还原剂存在下易产生氟烷基自由基和过渡金属可插入活化亲电体RX碳卤键的特点，依靠中心金属、配体立体电子性质和还原剂还原能力筛选进行催化效率及反应活性调控，实现两类电子性质迥异的亲电体的高效交叉还原偶联。反应方法建立后，拟将此还原偶联应用于药物化学和材料科学中复杂分子的后期修饰，利用电化学技术、动力学测试和金属有机中间体表征等手段进行反应机理阐释，归纳少氟、全氟卤代烃在交叉还原偶联中的反应性差异及所体现出的“氟效应”，为氟卤代烃的反应学研究和衍生品工业开发提供科学基础和有益参考。

近年来，还原交叉偶联反应备受有机化学家关注，是一类构筑碳-碳键的便捷方法，可克服传统交叉偶联、氧化偶联等需要高活性亲核试剂参与的局限，目前已广泛应用于二芳基、芳基烷基、脂环类等化合物的合成中。我们在“基于单电子转移历程及过渡金属催化原理的氟卤代烃与碳氢卤代烃还原偶联反应研究”项目立项以来，遵循消化吸收、不断创新的思路开展具有自身特色的研究工作。主要进行了以下研究内容：（1）芳基惰性碳氯键、碳氧键的还原氟乙基化偶联反应，应用于许多天然生理活性分子的后期修饰；(2)以三氟乙基为配体，实现了一类新型氟烷基配位的镍基前催化剂设计合成，应用于Suzuki型烷基化反应；（3）从Langlois试剂出发，开发了三苯基膦介导的脱氧还原过程高效制备CuSCF3的新方法，应用于芳基卤化物的三氟甲硫基化；（4）以组合配体/镍催化剂为平台，开发了邻二卤代烷的Suzuki型偶联反应，应用于氟乙基及氯乙基取代芳香化合物的制备。项目过程中进行的一系列理论计算和控制性实验研究，加深了对镍催化的少氟烷基化还原偶联反应、Suzuki型交叉偶联反应的认识和理解，对后期催化剂设计开发、进一步提升反应效率和发展新型反应方法学可提供重要参考。