Acta Chimica Sinica ›› 2018, Vol. 76 ›› Issue (12): 983-987.DOI: 10.6023/A18080337 Previous Articles     Next Articles

Special Issue: 有机氟化学



宋晓宁a, 杨杉a, 汪欣b, 王芒a   

  1. a. 东北师范大学化学学院 长春 130024;
    b. 吉林大学白求恩第一医院 长春 130021
  • 投稿日期:2018-08-15 发布日期:2018-11-07
  • 通讯作者: 汪欣,;王芒,;
  • 基金资助:


Difluorohomologization-Halogenation of Methyl Ketones: One-Pot Synthesis of β-Halo-α,α-Difluoroketones

Song Xiaoninga, Yang Shana, Wang Xinb, Wang Manga   

  1. a. Faculty of Chemistry, Northeast Normal University, Changchun 130024;
    b. First Hospital of Bethune, Jilin University, Changchun 130021
  • Received:2018-08-15 Published:2018-11-07
  • Contact: 10.6023/A18080337;
  • Supported by:

    Project supported by the National Natural Science Foundation of China (No. 21672032).

α,α-Difluoroketones represent an important subclass of organofluorine compounds, and have been widely applied in medicinal chemistry, particularly as enzyme inhibitors. Efficient use of organofluorine reagents plays a key role for the synthesis of fluorine-containing organic compounds. As an environmental and efficient difluorocarbene reagent, TMSCF2Br has been well utilized in synthetic applications. In 2013, Hu first utilized TMSCF2Br as a general difluorocarbene source for the difluoromethylenation of alkenes/alkynes as well as the difluoromethylation of O-, S-, N-, and P-nucleophiles. Moreover, Dilman realized the rapid assembly of various CF2-containing products by using TMSCF2Br as a difluorocarbene source, which depended on the concept of three independent components: difluorocarbene, nucleophile, and electrophile. Compared with the previous works, we recently reported a catalytic difluorocyclopropanation of enolizable ketones by using TMSCF2Br reagent, which acts as not only the difluorocarbene source but also the TMS transfer agent. The in situ generated siloxydifluorocyclopropanes were used for the synthesis of α-fluoroenones, o-fluoronaphthols, α,α-difluorocyclopentenones and α,α-difluorocyclopentanones compounds. Here, we report a simple and effective method for the conversion of enolizable ketones to α,α-difluoro-β-halo-substituted ketones. The whole process involves the in situ formation and regioselective ring opening halogenation of siloxydifluorocyclopropanes. The reaction features easily available raw materials, simple operation and practical method. A representative procedure for this reaction is as following: To a dried polytetrafluoroethene (PTFE) sealed pressure tube were added ketone 1 (0.5 mmol), n-Bu4NBr (0.05 mmol, 10 mol%), TMSCF2Br (0.75 mmol) and toluene (2.5 mL) in sequence. The reaction mixture was stirred at 110 ℃ for 2 h, followed by adding an additional amount of TMSCF2Br (0.5 mmol) for another 4 h. Removal of toluene under reduced pressure delivered a mixture mainly containing 2. The reaction system was allowed to cool to room temperature followed by adding NBS/NIS (0.75 mmol) and CH3CN (2 mL). The resulting mixture was stirred at room temperature for 2 h to consume 2 and then poured into saturated NaCl solution (30 mL), extracted with CH2Cl2 (10 mL×3). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to yield the crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate: 100/1, V/V) to afford the pure product 4/5.

Key words: ketone, α,α-difluoroketone, siloxydifluorocyclopropane, domino reaction