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).
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.
Ma Xingxing , Xuan Qingqing , Song Qiuling . N—H and O—H Difluoromethylation of N-Heterocycles[J]. Acta Chimica Sinica, 2018 , 76(12) : 972 -976 . DOI: 10.6023/A18070265
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