反应详情

To a solution of 3-chlorophenol (8 ml, 77 mmol, ABCR) in DCM (120 ml) was added dimethoxymethane (32 ml, 362 mmol, Aldrich) and then p-toluenesulphonic acid (0.164 g, 0.952 mmol, Alfa Aesar). The solution was heated to reflux under nitrogen using a Soxhlet apparatus containing 3A activated molecular sieves (approximately 20 g)* for 24 h. *The 3A molecular sieves were replaced after 6 h. Approximately a quarter of the reaction mixture was applied to a 70 g aminopropyl cartridge (prewashed with methanol). The cartridge was eluted with methanol (1-2 column volumes) and several fractions collected. Appropriate fractions were combined (TLC 50:50 DCM in cyclohexane) and the solvent removed in vacuo to give 1-chloro-3-{[(methyloxy)methyl]oxy}benzene as a colourless mobile oil (1.66 g). The remaining reaction mixture was applied evenly to 3×70 g aminopropyl cartridges (pre-washed with methanol). The cartridges were eluted with methanol (1-2 column volumes) and several fractions collected. Appropriate fractions were combined (TLC 50:50 DCM in cyclohexane) and the solvent removed in vacuo to leave a colourless mobile oil (first batch). The mixed fractions were combined and the solvent removed in vacuo to leave a colourless mobile oil. The residue from the mixed fractions was applied to a 70 g aminopropyl cartridge (pre-washed with methanol) and eluted with methanol. Appropriate fractions were combined (TLC 50:50 DCM in cyclohexane) and added to the first batch. The solvent was removed in vacuo to give another batch of 1-chloro-3-{[(methyloxy)methyl]oxy}benzene as a colourless mobile oil (5.27 g). To THF (20 ml) under nitrogen at 0° C. was added 1.6 M n-butyllithium in hexanes (18.1 ml, 29.0 mmol, Aldrich). To the solution at −60° C. was added a solution of 2,2,6,6-tetramethylpiperidine (4.90 ml, 29.0 mmol, Alfa Aesar) in THF (5 ml) and then a solution of 1-chloro-3-{[(methyloxy)methyl]oxy}benzene (5.01 g, 29.0 mmol) in THF (10 ml). The temperature was maintained below −50° C. during the addition. The solution was stirred at −60° C. to −70° C. for 1 h. To the solution was added a large excess of freshly ground solid carbon dioxide and the mixture allowed to warm to ambient temperature. The reaction mixture was diluted with water (100 ml) and diethyl ether (130 ml). The phases were separated and aqueous phase carefully acidified to pH1 using concentrated HCl. The suspension was extracted with dichloromethane (3×40 ml). The solvent was removed in vacuo to give the title compound as a white solid (4.36 g);

1. temperatureThe temperature was maintained below −50° C. during the addition
2. customThe phases were separated
3. extractionThe suspension was extracted with dichloromethane (3×40 ml)
4. customThe solvent was removed in vacuo