3-Hydroxybenzaldehyde → 1-(Methoxymethoxy)-3-(1-propenyl)benzene

Participants

Reaction Conditions

Reaction Steps

To a solution of 3-hydroxybenzaldehyde (11.0 g, 90.1 mmol) in DMF (110 mL) at 0° C. was added methoxymethyl chloride (7.5 mL, 99.1 mmol) followed by NaH (99.1 mmol, 3.96 g, 60% dispersion in oil) in three portions (violent deprotonationl). The mixture was stirred at 0° C. for 15 min and then at room temperature for 15 h. The reaction was quenched with water and more water was added until all the precipitate dissolved. The solution was extracted in ether (2×150 mL) with water (50 mL), then with saturated Na2CO3 (100 mL), and finally with water (100 mL). The crude product was used in the next reaction. To a suspension of (ethyl)triphenylphosphonium bromide (36.8 g, 99.1 mmol, dried at 90° C. under high vacuum overnight) in THF (250 mL) at 0° C. was added n-BuLi (39.6 mL, 99.1 mmol, 2.5 M in hexanes) over five min. The resulting pretty dark burgundy mixture was stirred at 0° C. for 10 min and then at room temperature for 30 min. It was re-cooled to 0° C. and a solution of the above crude 3-methoxymethoxybenzaldehyde in THF (15 mL) was added slowly. The resulting medium brown mixture was stirred at 0° C. for 2 h and then at room temperature for 2 h. The mixture was quenched by exposing it to air for several min. Because filtering the mixture for this particular Wittig reaction would result in a sticky precipitate clogging the sintered-glass filter, the THF was removed in vacuo and the crude material was dissolved in DMF (100 mL). Extraction in hexanes (4×100 mL) with 50% saturated brine (100 mL) eliminated triphenylphosphonium oxide into the aqueous layer. Flash chromatography with silica gel (gradient to 6% ether/hexanes) produced 1-(methoxymethoxy)-3-(1-propenyl)benzene [(E)/(Z)˜1:1] as a colorless liquid (13.2 g, 82% yield for two steps). A suspension of 3 produced 1-(methoxymethoxy)-3-(1-propenyl)benzene (13.2 g, 74.1 mmol), NaHCO3 (1.24 g, 14.8 mmol), and 10% palladium on carbon (3.3 g) in EtOAc (75 mL) and EtOH (19 mL) was stirred at room temperature for 20 h with a hydrogen balloon attached. The round-bottom flask was purged with nitrogen, the mixture was filtered through Celite, and the Celite was washed well with EtOAc to furnish 1-(methoxymethoxy)-3-propylbenzene as a colorless liquid (13.4 g, 100% yield): 1H NMR (300 MHz, CDCl3) δ 0.94 (t, 3H, J=7.4 Hz), 1.64 (m, 2H), 2.56 (t, 2H, J=7.7 Hz), 3.48 (s, 3H), 5.17 (s, 2H), 6.80-6.90 (three overlapping peaks, 3H), 7.19 (m, 1H).

Provenance & Evidence