2,4-Bis-trifluoromethyl-phenol synthesis

Yield: 23%

Reaction Conditions:

Stage #1:2,4-bis(trifluoromethyl)aniline with sulfuric acid;sodium nitrite in water at 0; for 3 h;
Stage #2: with urea in water at 0; for 0.166667 h;
Stage #3: with sulfuric acid;water for 1 h;Heating / reflux;

Steps:

1
Example 12,4-(Bis-trifluoromethyl)-phenol (Method F)To an ice-cold solution of 2,4-bis(trifluoromethyl)-aniline (1.26 g, 5.50 mmol) in sulphuric acid (33%, 40 ml) was added a solution of sodium nitrite (0.46 g, 6.67 mmol) in water (2 ml). After 3 h at 0⁰C urea (0.10 g, 1.67 mmol) was added and the reaction mixture was stirred at 0⁰C for an additional ten minutes. The reaction mixture was then added to boiling sulphuric acid (33%, 100 ml) and refluxed for Ih. The reaction mixture was allowed to reach room temperature and was then extracted with ethyl acetate. The organic phase was washed first with water and then with brine, dried over sodium sulphate, filtered and evaporated to dryness. The crude product was chromatographed on silica gel using heptane/ethyl acetate (4/1) as eluent to give 0.29 g (23 %) of the title compound. IH NMR (CDCl₃) δ 7.08 (d, IH), 7.17 (bs, IH), 7.67 (dd, IH), 7.80 (d, IH).

References:

ACTIVE BIOTECH AB WO2008/97180, 2008, A1 Location in patent:Page/Page column 15