1-tert-butyl-4-fluorobenzene

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:-45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 1-tert-butyl-4-fluoro-benzene (4.54 g, 30 mmol) in THF (100 mL) cooled at −78° C. was treated dropwise with a 2.5M solution of nBuLi in hexane (24 mL, 59 mmol). The reaction mixture was stirred for 5 h at −45° C. then DMF (3.5 mL, 44 mmol) was added at −75° C. and the reaction mixture was stirred for 0.5 h at −75° C. The reaction mixture was poured onto 1N aq. HCl and extracted with Et2O. Combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The title compound was obtained after chromatographic purification (Combi Flash, 40 g silica gel, hexane to hexane-EtOAc 10:1) as a light yellow oil: TLC (hexane-EtOAc 10:1) Rf=0.48, HPLC RtA=2.10 min; 1H NMR (400 MHz, CDCl3): δ10.36 (s, 1H), 7.85 (dd, 1H), 7.62 (m, 1H), 7.08 (dd, 1H), 1.32 (s, 9H). the reaction mixture was stirred for 0.5 h at −75° C extracted with Et2O Combined organic layers were washed with brine dried over Na2SO4 filtered evaporated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In this example 5-t-butyl-2-fluorophenol, the starting material for the dealkylation process of this invention, was prepared by first alkylating 480 grams of fluorobenzene with 370 grams of t-butylchloride in the presence of 16.6 grams of aluminum chloride and 33 grams of nitromethane as solvent for the reaction at a temperature ranging from about 0° to 2° C., the t-butylchloride being added incrementally to the mixture of fluorobenzene, aluminum chloride and nitromethane in about 2.5 hours and maintained for about an additional hour at this temperature. The resulting 4-t-butyl-fluorobenzene was recovered by treating the reaction mixture with 150 ml water at 0°-10° C. followed by washing with 5% aqueous NaOH, and the organic layer was then separated, followed by fractionation at about 5 mm reduced pressure and 547 grams of product collected from about 48°-52° C. to yield about a 70% conversion and 86% selectivity to p-t-butylfluorobenzene via gas liquid chromatographic analysis. Following this 304 grams of 4-t-butylfluorobenzene so prepared and a catalyst comprising 12.3 grams of iodine were placed in another reaction apparatus and brominated by incrementally adding about 372 grams of bromine during a period of about 3 hours while maintaining the temperature of the reaction at about 60°-65° C., and then maintaining the reaction mixture for about an additional 9 hours. Upon completion of the bromination the organic layer was washed with saturated sodium thiosulfate solution and then with water, dried and the recovered 312 grams of product was fractionated under a reduced pressure of about 3 mm to isolate about 224 grams of the desired 4-t-butyl-2-bromofluorobenzene distilling at about 40°-77° C. The heart cut of this distillate of about 171 grams analyzed about 90% pure via gas liquid chromatography. To obtain the next product comprising 5-t-butyl-2-fluorophenol the thus formed 4-t-butyl-2-bromo-fluorobenzene (20.0 grams) was hydrolyzed by treatment with 160 ml of water in the presence of 18.6 grams of potassium fluoride and 1.0 grams of cuprous oxide plus 40 grams of sulfolane as a co-solvent, said reaction being effected at an elevated temperature of 250° C. and under a nitrogen atmosphere at a total pressure of about 525 pounds per square inch. At the end of about eight hours of reaction period, the autoclave and contents thereof were allowed to return to room temperature, the excess pressure was discharged, and the product recovered from the mixture by extraction with toluene. Distillation under reduced pressure provided about 11.4 grams of the desired product comprising 5-t-butyl-2-fluorophenol corresponding to a conversion of about 85% and a selectivity of about 70%. N-methylpyrrolidone may also be effectively used as the co-solvent in this hydrolysis. so prepared while maintaining the temperature of the reaction at about 60°-65° C. maintaining the reaction mixture for about an additional 9 hours Upon completion of the bromination the organic layer was washed with saturated sodium thiosulfate solution with water, dried

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In this example 5-t-butyl-2-fluorophenol, the starting material for the dealkylation process of this invention, was prepared by first alkylating 480 grams of fluorobenzene with 370 grams of t-butylchloride in the presence of 16.6 grams of aluminum chloride and 33 grams of nitromethane as solvent for the reaction at a temperature ranging from about 0° to 2° C., the t-butylchloride being added incrementally to the mixture of fluorobenzene, aluminum chloride and nitromethane in about 2.5 hours and maintained for about an additional hour at this temperature. The resulting 4-t-butyl-fluorobenzene was recovered by treating the reaction mixture with 150 ml water at 0°-10° C. followed by washing with 5% aqueous NaOH, and the organic layer was then separated, followed by fractionation at about 5 mm reduced pressure and 547 grams of product collected from about 48°-52° C. to yield about a 70% conversion and 86% selectivity to p-t-butylfluorobenzene via gas liquid chromatographic analysis. Following this 304 grams of 4-t-butylfluorobenzene so prepared and a catalyst comprising 12.3 grams of iodine were placed in another reaction apparatus and brominated by incrementally adding about 372 grams of bromine during a period of about 3 hours while maintaining the temperature of the reaction at about 60°-65° C., and then maintaining the reaction mixture for about an additional 9 hours. Upon completion of the bromination the organic layer was washed with saturated sodium thiosulfate solution and then with water, dried and the recovered 312 grams of product was fractionated under a reduced pressure of about 3 mm to isolate about 224 grams of the desired 4-t-butyl-2-bromofluorobenzene distilling at about 40°-77° C. The heart cut of this distillate of about 171 grams analyzed about 90% pure via gas liquid chromatography. To obtain the next product comprising 5-t-butyl-2-fluorophenol the thus formed 4-t-butyl-2-bromo-fluorobenzene (20.0 grams) was hydrolyzed by treatment with 160 ml of water in the presence of 18.6 grams of potassium fluoride and 1.0 grams of cuprous oxide plus 40 grams of sulfolane as a co-solvent, said reaction being effected at an elevated temperature of 250° C. and under a nitrogen atmosphere at a total pressure of about 525 pounds per square inch. At the end of about eight hours of reaction period, the autoclave and contents thereof were allowed to return to room temperature, the excess pressure was discharged, and the product recovered from the mixture by extraction with toluene. Distillation under reduced pressure provided about 11.4 grams of the desired product comprising 5-t-butyl-2-fluorophenol corresponding to a conversion of about 85% and a selectivity of about 70%. N-methylpyrrolidone may also be effectively used as the co-solvent in this hydrolysis. so prepared while maintaining the temperature of the reaction at about 60°-65° C. maintaining the reaction mixture for about an additional 9 hours Upon completion of the bromination the organic layer was washed with saturated sodium thiosulfate solution with water, dried

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In this example 5-t-butyl-2-fluorophenol, the starting material for the dealkylation process of this invention, was prepared by first alkylating 480 grams of fluorobenzene with 370 grams of t-butylchloride in the presence of 16.6 grams of aluminum chloride and 33 grams of nitromethane as solvent for the reaction at a temperature ranging from about 0° to 2° C., the t-butylchloride being added incrementally to the mixture of fluorobenzene, aluminum chloride and nitromethane in about 2.5 hours and maintained for about an additional hour at this temperature. The resulting 4-t-butyl-fluorobenzene was recovered by treating the reaction mixture with 150 ml water at 0°-10° C. followed by washing with 5% aqueous NaOH, and the organic layer was then separated, followed by fractionation at about 5 mm reduced pressure and 547 grams of product collected from about 48°-52° C. to yield about a 70% conversion and 86% selectivity to p-t-butylfluorobenzene via gas liquid chromatographic analysis. Following this 304 grams of 4-t-butylfluorobenzene so prepared and a catalyst comprising 12.3 grams of iodine were placed in another reaction apparatus and brominated by incrementally adding about 372 grams of bromine during a period of about 3 hours while maintaining the temperature of the reaction at about 60°-65° C., and then maintaining the reaction mixture for about an additional 9 hours. Upon completion of the bromination the organic layer was washed with saturated sodium thiosulfate solution and then with water, dried and the recovered 312 grams of product was fractionated under a reduced pressure of about 3 mm to isolate about 224 grams of the desired 4-t-butyl-2-bromofluorobenzene distilling at about 40°-77° C. The heart cut of this distillate of about 171 grams analyzed about 90% pure via gas liquid chromatography. To obtain the next product comprising 5-t-butyl-2-fluorophenol the thus formed 4-t-butyl-2-bromo-fluorobenzene (20.0 grams) was hydrolyzed by treatment with 160 ml of water in the presence of 18.6 grams of potassium fluoride and 1.0 grams of cuprous oxide plus 40 grams of sulfolane as a co-solvent, said reaction being effected at an elevated temperature of 250° C. and under a nitrogen atmosphere at a total pressure of about 525 pounds per square inch. At the end of about eight hours of reaction period, the autoclave and contents thereof were allowed to return to room temperature, the excess pressure was discharged, and the product recovered from the mixture by extraction with toluene. Distillation under reduced pressure provided about 11.4 grams of the desired product comprising 5-t-butyl-2-fluorophenol corresponding to a conversion of about 85% and a selectivity of about 70%. N-methylpyrrolidone may also be effectively used as the co-solvent in this hydrolysis. ranging from about 0° to 2° C. maintained for about an additional hour at this temperature The resulting 4-t-butyl-fluorobenzene was recovered by treating the reaction mixture with 150 ml water at 0°-10° C. by washing with 5% aqueous NaOH the organic layer was then separated collected from about 48°-52° C.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In this example 5-t-butyl-2-fluorophenol, the starting material for the dealkylation process of this invention, was prepared by first alkylating 480 grams of fluorobenzene with 370 grams of t-butylchloride in the presence of 16.6 grams of aluminum chloride and 33 grams of nitromethane as solvent for the reaction at a temperature ranging from about 0° to 2° C., the t-butylchloride being added incrementally to the mixture of fluorobenzene, aluminum chloride and nitromethane in about 2.5 hours and maintained for about an additional hour at this temperature. The resulting 4-t-butyl-fluorobenzene was recovered by treating the reaction mixture with 150 ml water at 0°-10° C. followed by washing with 5% aqueous NaOH, and the organic layer was then separated, followed by fractionation at about 5 mm reduced pressure and 547 grams of product collected from about 48°-52° C. to yield about a 70% conversion and 86% selectivity to p-t-butylfluorobenzene via gas liquid chromatographic analysis. Following this 304 grams of 4-t-butylfluorobenzene so prepared and a catalyst comprising 12.3 grams of iodine were placed in another reaction apparatus and brominated by incrementally adding about 372 grams of bromine during a period of about 3 hours while maintaining the temperature of the reaction at about 60°-65° C., and then maintaining the reaction mixture for about an additional 9 hours. Upon completion of the bromination the organic layer was washed with saturated sodium thiosulfate solution and then with water, dried and the recovered 312 grams of product was fractionated under a reduced pressure of about 3 mm to isolate about 224 grams of the desired 4-t-butyl-2-bromofluorobenzene distilling at about 40°-77° C. The heart cut of this distillate of about 171 grams analyzed about 90% pure via gas liquid chromatography. To obtain the next product comprising 5-t-butyl-2-fluorophenol the thus formed 4-t-butyl-2-bromo-fluorobenzene (20.0 grams) was hydrolyzed by treatment with 160 ml of water in the presence of 18.6 grams of potassium fluoride and 1.0 grams of cuprous oxide plus 40 grams of sulfolane as a co-solvent, said reaction being effected at an elevated temperature of 250° C. and under a nitrogen atmosphere at a total pressure of about 525 pounds per square inch. At the end of about eight hours of reaction period, the autoclave and contents thereof were allowed to return to room temperature, the excess pressure was discharged, and the product recovered from the mixture by extraction with toluene. Distillation under reduced pressure provided about 11.4 grams of the desired product comprising 5-t-butyl-2-fluorophenol corresponding to a conversion of about 85% and a selectivity of about 70%. N-methylpyrrolidone may also be effectively used as the co-solvent in this hydrolysis. ranging from about 0° to 2° C. maintained for about an additional hour at this temperature The resulting 4-t-butyl-fluorobenzene was recovered by treating the reaction mixture with 150 ml water at 0°-10° C. by washing with 5% aqueous NaOH the organic layer was then separated collected from about 48°-52° C.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-Fluoro-4-t-butylbenzene (10 g, 65.79 mmol) was dissolved in concentrated sulfuric acid (40 ml) at 0° C. Solid potassium nitrate (6.64 g, 65.79 mmol) was added in small portions during 1 hour. The temperature was kept below 5° C. Following the addition stirring was continued for 2 hours. The reaction mixture was poured into ice-water (400 ml) and extracted with dichloromethane (3×50 ml). The organic phase was washed with water, aqueous sodium bicarbonate (1 M) and water successively, dried over MgSO4 and filtered through silica gel (5 g). Evaporation of solvent left the crude product (10.32 g). Column chromatography on silica gel using petroleum ether containing 1% dichloromethane as the eluent afforded the pure product (7.6 g colorless oil). was kept below 5° C the addition extracted with dichloromethane (3×50 ml) The organic phase was washed with water, aqueous sodium bicarbonate (1 M) and water successively dried over MgSO4 filtered through silica gel (5 g) Evaporation of solvent left the crude product (10.32 g)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-Fluoro-4-t-butylbenzene (10 g, 65.79 mmol) was dissolved in concentrated sulfuric acid (40 ml) at 0° C. Solid potassium nitrate (6.64 g, 65.79 mmol) was added in small portions during 1 hour. The temperature was kept below 5° C. Following the addition stirring was continued for 2 hours. The reaction mixture was poured into ice-water (400 ml) and extracted with dichloromethane (3×50 ml). The organic phase was washed with water, aqueous sodium bicarbonate (1 M) and water successively, dried over MgSO4 and filtered through silica gel (5 g). Evaporation of solvent left the crude product (10.32 g). Column chromatography on silica gel using petroleum ether containing 1% dichloromethane as the eluent afforded the pure product (7.6 g colorless oil). was kept below 5° C the addition extracted with dichloromethane (3×50 ml) The organic phase was washed with water, aqueous sodium bicarbonate (1 M) and water successively dried over MgSO4 filtered through silica gel (5 g) Evaporation of solvent left the crude product (10.32 g)

反应条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-t-Butylaniline (14.9 g, 100 mmol) was suspended in aqueous hydrochloric acid (50 ml, 6M) at 5° C. Sodium nitrite (7.6 g, 110 mmol in 10 ml water) was added at such a rate that the temperature was kept between 5°-7° C. Following the addition the resulting solution was stirred for 15 min. and sodium tetrafluoroborate (15.4 g, 140 mmol in 30 ml water) was added at 5-8° C. The mixture was stirred for 15 min. 4-t-Butylbenzenediazonium tetrafluoroborate was filtered off, dried with suction and washed with diethyl ether to yield 20.96 g. This diazonium salt was decomposed by heating to 140° C. on an oil-bath. The product was distilled off at reduced pressure. Yield 11.15 g colorless oil. was kept between 5°-7° C the addition the resulting solution The mixture was stirred for 15 min 4-t-Butylbenzenediazonium tetrafluoroborate was filtered off dried with suction washed with diethyl ether to yield 20.96 g The product was distilled off at reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-Fluoro-4-t-butylbenzene (10 g, 65.79 mmol) was dissolved in concentrated sulfuric acid (40 ml) at 0° C. Solid potassium nitrate (6.64 g, 65.79 mmol) was added in small portions during 1 hour. The temperature was kept below 5° C. Following the addition stirring was continued for 2 hours. The reaction mixture was poured into ice-water (400 ml) and extracted with dichloromethane (3×50 ml). The organic phase was washed with water, aqueous sodium bicarbonate (1M) and water successively, dried over MgSO4 and filtered through silica gel (5 g). Evaporation of solvent left the crude product (10.32 g). Column chromatography on silica gel using petroleum ether containing 1% dichloromethane as the eluent afforded the pure product (7.6 g colorless oil). was kept below 5° C the addition extracted with dichloromethane (3×50 ml) The organic phase was washed with water, aqueous sodium bicarbonate (1M) and water successively dried over MgSO4 filtered through silica gel (5 g) Evaporation of solvent left the crude product (10.32 g)

反应条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-t-Butylaniline (14.9 g, 100 mmol) was suspended in aqueous hydrochloric acid (50 ml, 6M) at 5° C. Sodium nitrite (7.6 g, 110 mmol in 10 ml water) was added at such a rate that the temperature was kept between 5°-7° C. Following the addition the resulting solution was stirred for 15 min. and sodium tetrafluoroborate (15.4 g, 140 mmol in 30 ml water) was added at 5-8° C. The mixture was stirred for 15 min. 4-t-Butylbenzenediazonium tetrafluoroborate was filtered off, dried with suction and washed with diethyl ether to yield 20.96 g. This diazonium salt was decomposed by heating to 140° C. on an oil-bath. The product was distilled off at reduced pressure. Yield 11.15 g colorless oil. was kept between 5°-7° C the addition the resulting solution The mixture was stirred for 15 min 4-t-Butylbenzenediazonium tetrafluoroborate was filtered off dried with suction washed with diethyl ether to yield 20.96 g The product was distilled off at reduced pressure

反应条件: temp:-45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 1-tert-butyl-4-fluoro-benzene (4.54 g, 30 mmol) in THF (100 mL) cooled at −78° C. was treated dropwise with a 2.5M solution of nBuLi in hexane (24 mL, 59 mmol). The reaction mixture was stirred for 5 h at −45° C. then DMF (3.5 mL, 44 mmol) was added at −75° C. and the reaction mixture was stirred for 0.5 h at −75° C. The reaction mixture was poured onto 1N aq. HCl and extracted with Et2O. Combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The title compound was obtained after chromatographic purification (Combi Flash, 40 g silica gel, hexane to hexane-EtOAc 10:1) as a light yellow oil: TLC (hexane-EtOAc 10:1) Rf=0.48, HPLC RtA=2.10 min; 1H NMR (400 MHz, CDCl3): δ10.36 (s, 1H), 7.85 (dd, 1H), 7.62 (m, 1H), 7.08 (dd, 1H), 1.32 (s, 9H). the reaction mixture was stirred for 0.5 h at −75° C extracted with Et2O Combined organic layers were washed with brine dried over Na2SO4 filtered evaporated