Hydrochloric Acid → HCID 14817232, compound

Participants

Reaction Steps

To dry dimethylformamide (200 mL) were added 2-fluoro-4-hydroxybenzonitrile (13.71 g, 100 mmol), 1-iodooctane (28.82 g, 120 mmol) and potassium fluoride (11.6 g, 200 mmol). This mixture was stirred at room temperature for 16 h, and then at 50° C. for 2 h and then at 90° C. for 2 h. The mixture was then poured into wet-ice (400 g) and 37% HCl (10 mL). The resulting solution was extracted with diethyl ether (3×200 mL). The ether layer was washed with water (2×200 mL) and dried over Na2SO4. After filtration, rotary evaporation gave the crude desired intermediate 2-fluoro-4-n-octyloxybenzonitrile (27.83 g). This liquid intermediate was then added, over a 5-10 min period at 3-13° C. to a flask containing LiAlH(OEt)3 [which had been freshly prepared from LiAlH4 (5.03 g, 0.1326 mol) and ethyl acetate (15.24 g, 0.1730 mol) at 3-8° C. in diethyl ether (130 mL)]. The reaction mixture was stirred at 5° C. for 75 min and 5 N H2SO4 aqueous solution (120 mL) was added dropwise with cooling. After separation, the aqueous layer was extracted with diethyl ether (2×100 mL) and the combination extracts were washed with water (2×100 mL). Standard work-up procedures afforded crude 2-fluoro-4-n-octyloxybenzaldehyde (26.07 g). The crude material was then mixed with N-tert-butylhydroxylamine (8.6 g, 96.4 mmol), molecular sieves (50 g, 4 A) and silica gel (10 g) in chloroform (250 mL). The mixture was stirred at room temperature for 23 h and refluxed for 3 h under argon gas. The mixture was then filtered and rotary evaporated to give a residue which was purified by column chromatography over silica gel eluted with hexanes/ethyl acetate (4:1, v:v). The title compound (12.90 g) was obtained in 39.9% overall yield as a slightly yellowish solid. m.p. 35.6° C. (Rf=0.36 on a silica gel plate using hexanes/EtOAc, 4:1, v:v, as the eluant).

Provenance & Evidence