Phenol → 4-[2-(2,6-Difluorophenyl)-4,5-dihydro-1,3-oxazol-4-yl]phenol

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Reaction Steps

The compound of Step A, Example 1 (51 g, 0.2 mol) and phenol (32 g 0.3 mol) were dissolved in trifluoroacetic acid (85 mL), stirred for 2 days and then evaporated under reduced pressure. The residue was taken up in dichloromethane (200 mL), washed with sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The residue was subjected to chromatogaphy on silica gel using hexanes/ethyl acetate (2:1). The residue from the column (30 g) was dissolved in tetrahydrofuran (100 mL) and treated with lithium borohydride (60 mL, 2N in tetrahydrofuran) and heated at reflux for 3 h. The reaction mixture was treated with aqueous hydrochloric acid (1N, 300 mL) and extracted with dichloromethane (200 mL), dried and evaporated. The residue was treated with toluene (150 mL) and thionyl chloride (30 mL, 0.4 mol). After being heated at reflux for 1 h, the mixture was evaporated under reduced pressure. The residue was dissolved in methanol (200 mL) and treated with sodium hydroxide (20 mL, 50%) and heated at reflux for 1 h. The mixture was neutralized with aqueous hydrochloric acid and extracted with dichloromethane (200 mL). The dichloromethane was dried, evaporated, and subjected to chromatography on silica gel with hexanes/ethyl acetate (3:1 to 2:1). The second major fraction to elute was the title compound (7.7 g) as a white solid: m.p. 145°-147° C. 1H NMR (CDCl3, 200 MHz) δ 9.3 (br s,OH), 7.7-6.8 (m,7H), 5.4 (m, 1H), 4.8 (m, 1H), 4.3 (m, 1H).

Provenance & Evidence