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TCI Practical Example: Difluoromethylation of Phenols Using Diethyl (Bromodifluoromethyl)phosphonate

We are proud to present the difluoromethylation of 2-acetylphenol using diethyl (bromodifluoromethyl)phosphonate as a difluorocarbene precursor.

Used Chemicals

• 2-Acetylphenol [H0192]
• Diethyl (Bromodifluoromethyl)phosphonate [D3071]
• Potassium Hydroxide [P2849]
• Acetonitrile
• Water

Procedure

To a solution of potassium hydroxide (1.12 g, 20 mmol, 20 equiv) and 2-acetylphenol (136 mg, 1.0 mmol) in acetonitrile and water (10 mL, 1:1) was added diethyl (bromodifluoromethyl)phosphonate (534 mg, 2.1 mmol, 2.1 equiv) at -30 °C and the mixture was stirred at r. t. for 2 hours. The reaction mixture was extracted with IPE (20 mL, 2 times) and the organic layer was dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate:hexane = 0:1 - 1:9 on silica gel) to give 2'-difluoromethoxyacetophenone as a light yellow liquid (151 mg, 82%).

Experimenter's Comments

The reaction mixture was monitored by TLC (ethyl acetate:hexane = 1:4, Rf = 0.60).

Analytical Data

2'-Difluoromethoxyacetophenone

¹H NMR (270 MHz, CDCl₃); δ 7.77 (dd, 1H, J = 7.8, 1.9 Hz), 7.53 (dt, 1H, J = 7.8, 1.9 Hz), 7.30 (dt, 1H, J = 7.6, 1.0 Hz), 7.19 (brd, 1H, J = 8.1 Hz), 6.60 (t, 1H, J = 73 Hz), 2.64 (s, 3H).

Lead Reference

• Diethyl bromodifluoromethylphosphonate: a highly efficient and environmentally benign difluorocarbene precursor
• Y. Zafrani, G. Sod-Moriah, Y. Segall, Tetrahedron 2009, 65, 5278.

Other References

• Improvement of the synthesis of aryl difluoromethyl ethers and thioethers by using a solid-liquid phase-transfer technique
• B. R. Langlois, J. Fluor. Chem. 1988, 41, 247.