5-bromo-2-methoxy-1,3-dimethylbenzene

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 2,6-dimethyl-4-bromoanisole (4.14 g) and tetrakis (triphenylphosphine) palladium (0.69 g) in toluene (40 ml) and 2.0 molar aqueous sodium carbonate (20 ml) was added phenylboric acid (2. 7 g) in ethanol (10 ml). The reaction was heated at reflux for 16 hours, at which time a solution of phenylboric acid (1.0 g) in ethanol (3 ml) was added. The reaction was heated at reflux for a further 6 hours and then cooled to 25° C., and 30% hydrogen peroxide (1.0 ml) was added. The mixture was stirred for one hour, then poured into water and extracted with ether. The organic phase was dried and evaporated and the residue was chromatographed on silica gel, eluting with 9:1 hexane either, so as to afford 2,6-dimethyl-4-methoxybiphenyl. The reaction was heated was added The reaction was heated at reflux for a further 6 hours extracted with ether The organic phase was dried evaporated the residue was chromatographed on silica gel eluting with 9:1 hexane either

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 94 g of 4-chloro-3,5-dimethyl-phenol, 129 g of 4-bromo-2,6-dimethyl-anisole, 40 g of potassium hydroxide and 5 g of copper powder was slowly heated to 180°-190° C. During this operation, first the corresponding potassium phenolate formed, and the water formed separated by distillation with a small amount of 4-bromo-2,6-dimethylanisole. At about 200°-220° C., further reaction yielding phenoxy-anisole took place. After about 4 to 5 hours, the reaction was complete. The cooled substance was extracted to exhaustion with a solvent which is not miscible with water, such as methylene chloride. The filtrate of inorganic salts formed was then shaken several times with 2 N sodium hydroxide solution and water. After vaporization of methylene chloride a crude product was obtained which was still contaminated by 4-bromo-2,6-dimethyl-anisole. After distillation, 86 g of 4(4-chloro-3,5-dimethyl-phenoxy)-2,6-dimethyl-anisole were obtained, boiling point: 186° C. under a pressure of 3 mm mercury. The cooled substance was extracted to exhaustion with a solvent which The filtrate of inorganic salts formed After distillation

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 94 g of 4-chloro-3,5-dimethyl-phenol, 129 g of 4-bromo-2,6-dimethyl-anisole, 40 g of potassium hydroxide and 5 g of copper powder was slowly heated to 180°-190° C. During this operation, first the corresponding potassium phenolate formed, and the water formed separated by distillation with a small amount of 4-bromo-2,6-dimethylanisole. At about 200°-220° C., further reaction yielding phenoxy-anisole took place. After about 4 to 5 hours, the reaction was complete. The cooled substance was extracted to exhaustion with a solvent which is not miscible with water, such as methylene chloride. The filtrate of inorganic salts formed was then shaken several times with 2 N sodium hydroxide solution and water. After vaporization of methylene chloride a crude product was obtained which was still contaminated by 4-bromo-2,6-dimethyl-anisole. After distillation, 86 g of 4(4-chloro-3,5-dimethyl-phenoxy)-2,6-dimethyl-anisole were obtained, boiling point: 186° C. under a pressure of 3 mm mercury. The cooled substance was extracted to exhaustion with a solvent which The filtrate of inorganic salts formed After distillation

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Bromine is added dropwise to a solution of 2,6-dimethylanisole (12.0 g) in chloroform (100 ml) at about 5°. The solution is stirred at 5° for 2 hr and then allowed to warm to 20°-25°. The reaction mixture is poured into ice-water, and the phases are separated. The chloroform phase is washed with water, aqueous sodium bisulfite solution, then with water, dried over sodium sulfate and concentrated under reduced pressure to give 3,5-dimethyl-4-methoxybromobenzene. to warm to 20°-25° the phases are separated The chloroform phase is washed with water, aqueous sodium bisulfite solution with water, dried over sodium sulfate concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Bromine is added dropwise to a solution of 2,6-dimethylanisole (12.0 g) in chloroform (100 ml) at about 5°. The solution is stirred at 5° for 2 hr and then allowed to warm to 20°-25°. The reaction mixture is poured into ice-water, and the phases are separated. The chloroform phase is washed with water, aqueous sodium bisulfite solution, then with water, dried over sodium sulfate and concentrated under reduced pressure to give 3,5-dimethyl-4-methoxybromobenzene. to warm to 20°-25° the phases are separated The chloroform phase is washed with water, aqueous sodium bisulfite solution with water, dried over sodium sulfate concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 4-bromo-2,6-dimethylanisole (PREPARATION 1, 12.98 g) in tetrahydrofuran (40 ml) is added drop by drop to a mixture of magnesium turnings (1.87 g) in tetrahydrofuran (5 ml). The Grignard reaction is initiated with iodine crystals. After the addition is complete, the mixture is refluxed for 2 hours. The Grignard reagent is cooled to about 10° and then a solution of ethyl chloroformate (7.5 ml) in tetrahydrofuran (40 ml) is added in a 2 minute period. The mixture is stirred for 45 minutes at ice-water temperature and then at 20°-25° for 2 hours. The reaction is quenched with a saturated solution of ammonium chloride and diluted with ether. The phases are separated, the organic phase is washed with water and then with saline, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound. The Grignard reaction After the addition the mixture is refluxed for 2 hours The reaction is quenched with a saturated solution of ammonium chloride diluted with ether The phases are separated the organic phase is washed with water with saline, dried over sodium sulfate concentrated under reduced pressure

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 2,6-dimethyl-4-bromoanisole (4.14 g) and tetrakis (triphenylphosphine) palladium (0.69 g) in toluene (40 ml) and 2.0 molar aqueous sodium carbonate (20 ml) was added phenylboric acid (2. 7 g) in ethanol (10 ml). The reaction was heated at reflux for 16 hours, at which time a solution of phenylboric acid (1.0 g) in ethanol (3 ml) was added. The reaction was heated at reflux for a further 6 hours and then cooled to 25° C., and 30% hydrogen peroxide (1.0 ml) was added. The mixture was stirred for one hour, then poured into water and extracted with ether. The organic phase was dried and evaporated and the residue was chromatographed on silica gel, eluting with 9:1 hexane either, so as to afford 2,6-dimethyl-4-methoxybiphenyl. The reaction was heated was added The reaction was heated at reflux for a further 6 hours extracted with ether The organic phase was dried evaporated the residue was chromatographed on silica gel eluting with 9:1 hexane either

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 2,6-dimethyl-4-bromoanisole (4.14 g) and tetrakis (triphenylphosphine) palladium (0.69 g) in toluene (40 ml) and 2.0 molar aqueous sodium carbonate (20 ml) was added phenylboric acid (2. 7 g) in ethanol (10 ml). The reaction was heated at reflux for 16 hours, at which time a solution of phenylboric acid (1.0 g) in ethanol (3 ml) was added. The reaction was heated at reflux for a further 6 hours and then cooled to 25° C., and 30% hydrogen peroxide (1.0 ml) was added. The mixture was stirred for one hour, then poured into water and extracted with ether. The organic phase was dried and evaporated and the residue was chromatographed on silica gel, eluting with 9:1 hexane either, so as to afford 2,6-dimethyl-4-methoxybiphenyl. The reaction was heated was added The reaction was heated at reflux for a further 6 hours extracted with ether The organic phase was dried evaporated the residue was chromatographed on silica gel eluting with 9:1 hexane either

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 94 g of 4-chloro-3,5-dimethyl-phenol, 129 g of 4-bromo-2,6-dimethyl-anisole, 40 g of potassium hydroxide and 5 g of copper powder was slowly heated to 180°-190° C. During this operation, first the corresponding potassium phenolate formed, and the water formed separated by distillation with a small amount of 4-bromo-2,6-dimethylanisole. At about 200°-220° C., further reaction yielding phenoxy-anisole took place. After about 4 to 5 hours, the reaction was complete. The cooled substance was extracted to exhaustion with a solvent which is not miscible with water, such as methylene chloride. The filtrate of inorganic salts formed was then shaken several times with 2 N sodium hydroxide solution and water. After vaporization of methylene chloride a crude product was obtained which was still contaminated by 4-bromo-2,6-dimethyl-anisole. After distillation, 86 g of 4(4-chloro-3,5-dimethyl-phenoxy)-2,6-dimethyl-anisole were obtained, boiling point: 186° C. under a pressure of 3 mm mercury. The cooled substance was extracted to exhaustion with a solvent which The filtrate of inorganic salts formed After distillation

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under cooling at −78° C., a solution of 1.50 g of 4-bromo-2,6-dimethylanisole in 20 ml of tetrahydrofuran was added to a solution of 1.6M hexane solution of 4.8 ml of n-butyl lithium in 20 ml of tetrahydrofuran. The mixture was stirred for 1 hour. A solution of 1.50 g of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate in 20 ml of tetrahydrofuran was added to the mixture. After stirring for 30 minutes, the mixture was stirred at ambient temperature for further 3 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 628 mg of tert-butyl 4-[2-hydroxy-2-(4-methoxy-2,6-dimethylphenyl)ethyl]piperidine-1-carboxylate as an oil. To the oil was added 15 ml of 10% hydrochloric acid and the mixture was heated under reflux for 2 hours. After cooling, the reaction mixture was alkalized with 20% aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 291 mg of tert-butyl 4-[(E)-2-(4-methoxy-2,6-dimethylphenyl)vinyl]piperidine-1-carboxylate. After stirring for 30 minutes the mixture was stirred at ambient temperature for further 3 hours followed by extraction with ethyl acetate The organic layer was washed with saturated aqueous sodium chloride dried over anhydrous sodium sulfate After filtration the filtrate was concentrated the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate)