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TCI Practical Example: 2,2,2-Trifluoroethyl Etherification Using 2,2,2-Trifluoroethyl p-Toluenesulfonate

We are proud to present the 2,2,2-trifluoroethyl etherification of 4'-hydroxyacetophenone using 2,2,2-trifluoroethyl p-toluenesulfonate.

Used Chemicals

• 4'-Hydroxyacetophenone [H0193]
• 2,2,2-Trifluoroethyl p-Toluenesulfonate [T1516]
• Sodium Hydride (60%, dispersion in Paraffin Liquid) [S0481]
• DMF

Procedure

To a solution of 4'-hydroxyacetophenone (1.0 g, 7.34 mmol) in DMF (10 mL) was slowly added sodium hydride (60%, 353 mg, 8.83 mmol) at room temperature and the mixture was stirred for 10 minutes. 2,2,2-Trifluoroethyl p-toluenesulfonate (2.24 g, 8.83 mmol) was added to the reaction mixture and stirred overnight at 130 °C. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL) and brine (50 mL), then 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 (on silica gel, ethyl acetate:hexane = 0:1 - 15:85) to give 4-(2,2,2-trifluoroethoxy)acetophenone as a pale yellow solid (1.40 g, 87% yield).

Experimenter’s Comments

The reaction mixture was monitored by UPLC.

Analytical Data

4-(2,2,2-Trifluoroethoxy)acetophenone

¹H NMR (270 MHz, CDCl₃); δ 7.98 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 4.43 (q, J = 8.1 Hz, 2H), 2.59 (s, 3H).

Lead Reference

• Synthesis and Evaluation of Antiplasmodial Activity of 2,2,2-Trifluoroethoxychalcones and 2-Fluoroethoxy Chalcones against Plasmodium falciparum in Culture
• K. Devi, V. Rajendran, Ayushee, T. M. Rangarajan, P. R. Singh, C. P. Ghosh, M. Singh, Molecules 2018, 23, 1174.