含氮杂环的N—H和O—H二氟甲基化反应
收稿日期: 2018-07-11
网络出版日期: 2018-11-08
基金资助
项目受国家自然科学基金（No.21772046）、中组部青年千人计划和福建省自然科学基金（No.2016J01064）资助.
N—H and O—H Difluoromethylation of N-Heterocycles
Received date: 2018-07-11
Online published: 2018-11-08
Supported by
Project supported by the National Natural Science Foundation of China (No. 21772046), the Recruitment Program of Global Experts and the Natural Science Foundation of Fujian Province (No. 2016J01064).
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.
马星星 , 轩晴晴 , 宋秋玲 . 含氮杂环的N—H和O—H二氟甲基化反应[J]. 化学学报, 2018 , 76(12) : 972 -976 . DOI: 10.6023/A18070265
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.
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