3-Hydroxybenzaldehyde → HCID 14349165, compound

Participants

Reaction Steps

To a gently refluxing dry tetrahydrofuran (75 ml) containing magnesium turnings (1.3 g; 53 mmol) and a small crystal of iodine, was added dropwise from a dropping funnel a solution of 5-(3-chlorophenoxy)pentyl bromide (13.87 g, 50 mmol) in dry THF (55 ml). After about 5-7 minutes, the Grignard reaction started as indicated by the disappearance of the brown iodine color. The heating was adjusted so that the solution refluxed gently. After the addition of the halide was complete (ca. 30 min.), the clear solution was refluxed for about 1 hour. This solution of the Grignard reagent was cooled to room temperature. A solution of 3-hydroxybenzaldehyde (5.5 g, 45 mmol) in dry THF (50 ml) was added dropwise to a well-stirred suspension of sodium hydride (2.8 g, 58 mmol) (50% oil dispersion) in dry THF (75 ml) at room temperature. The temperature was not allowed to go above ca. 40° C. After the addition of 3-hydroxybenzaldehyde was complete (ca. 30 min.) the slightly cloudy solution was warmed to 45°-50° C., and the stirred for 1 hour at this temperature. The resulting clear solution of sodium 3-formyl phenoxide was cooled to room temperature, and added dropwise, using a cannula, to the well-stirred solution of the Grignard reagent (whose preparation was described above). A thick precipitate immediately formed, and the solution was difficult to stir. This reaction mixture was maintained 40°-45° C. during the addition of the sodium salt. After the addition was complete (ca. 2 hours), the reaction mixture was stirred at this temperature for another hour, and then cooled in an ice bath. The excess reactive materials (sodium hydride, Grignard reagent, etc.) were destroyed slowly by carefully adding methanol (30 ml), and then a saturated ammonium chloride solution (350 ml) was added to dissolve all solids. The organic layer was separated, and the aqueous layer was extracted with ether (2×75 ml). The combined organics were washed with water, brine, and then dried over anhydrous magnesium sulfate. After drying the extract, all volatiles were removed to obtain a dark liquid. This oil was triturated with a 1:1 mixture of ether and petroleum ether (35°-55° C.) until an off-white solid was obtained (11.1 g; 78% yield). This can be crystallized from methanolethyl acetate to give a white solid, m.p. 125°-127° C.; mass spectrum: m/e (intensity observed at 320 (86.9%) and 322 (29.5%) which correspond to the molecular ion. The crude material was, however, pure enough to be used for the next reaction.

Provenance & Evidence