Citation: Song Xiaoning, Yang Shan, Wang Xin, Wang Mang. Difluorohomologization-Halogenation of Methyl Ketones: One-Pot Synthesis of β-Halo-α, α-Difluoroketones[J]. Acta Chimica Sinica, ;2018, 76(12): 983-987. doi: 10.6023/A18080337 shu

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

Song Xiaoning ^a ,
Yang Shan ^a ,
Wang Xin ^b,, ,
Wang Mang ^a,,

a.
Faculty of Chemistry, Northeast Normal University, Changchun 130024
b.
First Hospital of Bethune, Jilin University, Changchun 130021

Corresponding author: Wang Xin, wangm452@nenu.edu.cn Wang Mang, docxinwang@126.com
Received Date: 15 August 2018
Available Online: 5 December 2018
Fund Project: Project supported by the National Natural Science Foundation of China (No. 21672032)the National Natural Science Foundation of China 21672032

Figures(2)

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.
- ketone,
- α, α-difluoroketone,
- siloxydifluorocyclopropane,
- domino reaction
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