N—H and O—H Difluoromethylation of N-Heterocycles

doi:10.6023/A18070265

Abstract

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

Cite this article

Ma Xingxing, Xuan Qingqing, Song Qiuling. N—H and O—H Difluoromethylation of N-Heterocycles[J]. Acta Chim. Sinica, 2018, 76(12): 972-976.

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含氮杂环的N—H和O—H二氟甲基化反应