基于协同活化策略的过渡金属催化选择性惰性碳氟键烷基化反应研究

In recent years, with the rapid development of fluorine chemistry, more and more fluorine-containing organic molecules were synthesized and applied in drugs, materials, etc. which made the fluorine-containing organic molecules gradually enriched in nature. However, the chemical inertness of the fluorine-containing organic molecules makes it extremely difficult to be degraded. Owing to the high bond dissociation energy (BDE) of the C-F bond, selective activation and transformation of the inert C-F bond has become a formidable challenge in organic chemistry. Therefore, the study of the selective C-F bond activation and transformation will not only help to understand the nature of this type of inert chemical bond, but also facilitate the development of degradation method toward the waste fluorine-containing organic compounds. Although the direct activation and transformation of inert C-F bonds have recently been developed, the research work so far have focused on the aryl-aryl couplings with aryl Grignard reagent (Kumada-type), aryl borate (Suzuki-type) and aryl zinc reagents (Negishi-type) and the synthesis of aryl boronic acid derivatives, while the aryl-alkyl coupling from selective defluoroalkylation reaction has been scarcely reported, where the alkyl zinc reagents that don’t contain any β-H were used. The reason could be ascribed to the competitive β-H elimination event which is adverse to the expected defluoroalkylation when the β-H is present in the alkylating agents. Since the ubiquity of fluorine-containing molecules in drugs and organic materials, together with the importance of an alkyl pendent for the activity of the parental drug molecules, this project aims at the development of methodology toward the selective activation and defluoroalkylation of inert C-F bond by a B/Al…F synergistic interaction strategy, which benefits from the strong Lewis acidity and high fluorophilicity of trialkylaluminium and trialkylboron reagents, thus, entails the facile conversion of fluorine-containing molecule to the corresponding alkyl-substituted derivatives. This study will provide new methodology for the late stage functionalization and programmed transformation based on inert C-F bonds.

近年来，随着氟化学的迅猛发展，越来越多的含氟有机分子被合成并使用到药物、材料等领域，使得自然界中含氟有机分子逐渐被富集。然而，由于含氟有机分子的化学惰性，致使其在自然界中极难被降解。鉴于C-F键断裂能极高，有关惰性C-F键选择性活化与转化也成为有机化学中极具挑战的研究课题。因此，研究C-F键选择性活化与转化不仅有助于认识这类惰性键的化学本质，且对含氟有机废弃物降解方法的发展具有重要意义。有关C-F键烷基化的报道局限于使用不含β-H的烷基锌试剂，其原因可能在于，当烷基化试剂中存在β-H时，竞争性β-H消除反应对偶联反应不利。本项目拟借助烷基铝（硼）试剂强路易斯酸性和高亲氟性，通过B/Al…F协同活化模式实现含有β-H的烷基铝（硼）试剂参与的惰性C-F键选择性活化烷基化，实现含氟分子与其对应烷基衍生物的快速转化。该研究将为基于惰性C-F键的后期官能团化及程序性官能团化提供新的方法学依据。