N-H and O-H Difluoromethylation of N-Heterooycles

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 Schield( 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 N-2 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.