Hydrochloric Acid → 3-[5-Chloromethyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzaldehyde

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Reaction Steps

A mixture of 3-(5-hydroxymethyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzaldehyde (1.76 g, 4.82 mmol) and 12N HCl (12 mL) in toluene (45 mL) was heated at reflux for 1 hour. The solution was cooled to room temperature and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic combined extract was washed with water, brine, dried (MgSO4), filtered and evaporated. To the residue obtained (3-[5-chloromethyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzaldehyde), diluted in toluene (20 mL), were added ethylene glycol (2.5 mL, 44.34 mmol) and p-toluenesulfonic acid monohydrate (0.44 mmol, 84 mg). The mixture was heated at reflux overnight using a Dean Stark apparatus. The solution was cooled to room temperature, poured into an aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The organic combined extract was washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was chromatographed on silica gel (50% ethyl acetate in hexane) to afford 830 mg of 2-[7-(5-[1,3]dioxolan-2-yl-2-trifluoromethoxy-phenyl)-3,3-dimethyl-2,3-dihydro-benzofuran-5-ylmethoxy]-ethanol. 38% yield. 1H-NMR (300 MHz, CDCl3): 1.37 (s, 6H), 1.99 (t, J=6.2 Hz, 1H), 3.62 (t, J=4.5 Hz, 2H), 3.78 (m, 2H), 4.02–4.15 (m, 4H), 4.24 (s, 2H), 4.53 (s, 2H), 5.86 (s, 1H), 7.11 (d, J=8.5 Hz, 2H), 7.34 (d, J=8.5 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.58 (s, 1H).

Provenance & Evidence