Methane, dichloromethoxy- → 2,6-Difluoro-4-methoxybenzaldehyde

Participants

Reaction Steps

(Intermediates 26A and 26B were prepared in a similar manner to the preparation described in WO 2004046133). To a stirred solution of 3,5-difluoroanisole (1.0 g, 7.0 mmol) in dichloromethane (6 mL) at 0° C. was added dropwise titanium tetrachloride (1.23 mL, 11.2 mmol) and dichloromethyl methyl ether (0.63 mL, 7.0 mmol). Upon completion of addition, the reaction mixture was stirred for 1 h and then poured into ice-water (50 mL). The resulting mixture was extracted with dichloromethane (3×50 mL). The combined organics were washed with H2O (50 mL), brine (50 mL), dried over Na2SO4 and filtered. The volatiles were removed under reduced pressure to provide a residue. The residue was subjected to chromatography on silica gel eluting with 0 to 20% EtOAc/hexanes to give 2,6-difluoro-4-methoxybenzaldehyde, Intermediate 26A [less polar material, 230 mg, 19%, 1H NMR (400 MHz, CDCl3) δ ppm 3.85 (s, 3H), 6.47 (d, J=10.55 Hz, 2H), 10.17 (s, 1H)] and 2,4-difluoro-6-methoxybenzaldehyde, Intermediate 26B [more polar material, 740 mg, 62%, 1H NMR (400 MHz, CDCl3) δ ppm 3.91 (s, 3H) 6.43-6.51 (m, 2H) 10.30 (s, 1H)], both as white solids.

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