摘要/Abstract

有机氟化合物具有独特的化学、物理和生物性能，被广泛应用于医药、农药、新型功能材料、生命科学等领域.因此，发展便捷高效的合成方法，将单个的氟原子（—F）、二氟甲基（—CF₂H）或者三氟甲基（—CF₃）引入有机小分子，是有机合成领域的热点.相对于发展相对成熟的三氟甲基化反应，二氟甲基化反应发展相对滞后.利用廉价、易保存的溴二氟乙酸乙酯在Na₂CO₃的条件下产生二氟卡宾，并顺利发生N—H，O—H的二氟甲基化反应，成功的将二氟甲基引入到有机小分子中.该反应的底物适用性很广，官能团的兼容性也很好，卤素、醛基、硝基、腈基等取代的底物均能顺利的发生反应.
关键词: 含氟化合物, 有机氟化学, 碱催化, 二氟卡宾, 含氮杂环化合物
It is known that fluorine is the strongest in electronegativity and a peculiar element. Fluorinated compounds are extensively applied in the areas of pharmaceuticals, agrochemical, materials, life sciences, etc., due to the unique chemical, physical and biological properties of fluorine-containing compounds. Therefore, the development of expedient synthetic strategies for the introduction of —F, —CF₂H and —CF₃ into organic compounds has attracted much attentions of chemists. Although trifluoromethylation has been well developed, difluoromethylation has been less reported. We found that difluorocarbene (:CF₂) could be generated in situ from ethyl bromodifluoroacetate (BrCF₂COOEt) in the presence of Na₂CO₃, which could go through N—H, O—H difluoromethylation smoothly. The scope of substrates was broad, and various functional groups, such as halogen, formyl group, nitro-group, nitrile and so on could be tolerated well. This would be a potential and practical reaction in modification of various bioactive drugs beause benzimidazole, indazole and pyridine are the skeleton of medicine and nature molecule. In addition, a representative procedure for this reaction is as following: An oven-dried Schlenk tube (10 mL) was equipped with a magnetic stir bar, the substrates of nitrogen-containing or oxygen-containing (0.3 mmol), the base (Na₂CO₃,2 equiv., 0.6 mmol), ethyl bromodifluoroacetate (1.2 equiv., 0.36 mmol). The flask was evacuated and backfilled with N₂ for 3 times, acetone or acetonitrile as a solvent for 24 h under N₂ atmosphere. Where after the solvent concentrated in vacuo and the residue was purified by chromatography on silica gel with ethyl acetate:petroleum ether (EA:PE＝1:30) to afford the corresponding products.
Key words: fluorine-containing compounds, organofluorine chemistry, base-catalyzed, difluorocarbene, difluoromethylation, nitrogen-containing, oxygen-containing, heterocyclic compounds


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