Hydrochloric Acid → 2'-Hydroxy-3'-methoxyacetophenone

Participants

Reaction Steps

In a 250 mL dry flask was charged with 2-hydroxy-3-methoxybenzoic acid (6.0 g, 36.0 mmol) and anhydrous THF (20 mL) under N2. Methyl lithium in an ether solution (1.6 M, 73.5 mL, 117.6 mmol) was added dropwise over 20 min. The reaction mixture was heated to reflux for 20 h. After cooling the mixture was poured into 25 mL of brine with 6 N HCl and extracted with 100 mL of EtOAc. The organic layer was further washed with brine three times and dried over sodium sulfate. The solvent was evaporated and the residue was purified by column (hexane:EtOAc 2.5:1) to give 1-(2-hydroxy-3-methoxy-phenyl)-ethanone (4.3, 71.8%). 1-(2-Hydroxy-3-methoxy-phenyl)-ethanone (1.0 g, 6.0 mmol), 4-acetoxybenzoic acid (1.08 g, 6.0 mmol) and phosphorus oxychloride (0.923 g, 6.0 mmol) in 10 mL pyridine were stirred at rt overnight. The reaction mixture was poured into water (100 mL) and the isolated solid was washed with water. The solid was dissolved in dichloromethane and purified by column chromatography (hexane:EtOAc 2:1) to give the intermediate (1.05 g, 53.13%). Potassium tert-butoxide (0.4 g, 3.5 mmol) was added to this intermediate (1.05 g, 3.2 mmol) in 20 mL anhydrous THF. The reaction mixture was stirred for 4 h at rt. The mixture was poured into water (100 mL) with 1 mL AcOH (adjusted pH to 6-7.0). The solid was further rinsed with water and dissolved in dichloromethane. The organic layer was wash with brine and dried over sodium sulfate. The crude compound was treated with AcOH and two drops of concentrated HCl solution and heated to 110° C. for 1 h. The AcOH was evaporated and the solid residue was dissolved in MeOH and potassium carbonate (3.8 mmol) was added. The reaction mixture was stirred for 1 hour at rt. The reaction mixture was neutralized with AcOH and the solvent was evaporated. The residue was poured into water and the solid was collected by filtration and purified by column to give 150 mg of 2-(4-hydroxyphenyl)-8-methoxy-4H-chromen-4-one (17.4%). MS (ES) m/z: 269.93 (M+1), 268.91 (M); Mp. 281-283° C.

Provenance & Evidence