1-bromo-4-octoxybenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A Grignard reagent solution prepared from 0.8 g of magnesium, 10.3 g of (4-bromophenyl) octyl ether and 50 ml of tetrahydrofuran was added dropwise at 0°-5° C. within 30 minutes to a mixture of 7.5 g of crude 2-chloro-5-[(tetrahydro-2-pyranyloxy)methyl]pyridine, 75 ml of tetrahydrofuran and 0.36 g of 1,3-bis(diphenylphosphino)-propanenickel-(II) chloride. The reaction mixture was stirred for 3 hours, left to stand overnight, then adjusted to pH 8 with aqueous sodium hydrogen carbonate solution and diluted with diethyl ether. The organic phase was washed neutral with water, dried over sodium sulfate and concentrated. Chromatographic purification of the residue (14.6 g) on 210 g of silica gel with hexane/ethyl acetate (vol. 4:1) yielded 8.8 g of 2-[4-(octyloxy)-phenyl]-5-[(tetrahydro-2-pyranyloxy)methyl]pyridine. left to stand overnight The organic phase was washed neutral with water dried over sodium sulfate concentrated Chromatographic purification of the residue (14.6 g) on 210 g of silica gel with hexane/ethyl acetate (vol. 4:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A Grignard reagent solution prepared from 0.8 g of magnesium, 10.3 g of (4-bromophenyl) octyl ether and 50 ml of tetrahydrofuran was added dropwise at 0°-5° C. within 30 minutes to a mixture of 7.5 g of crude 2-chloro-5-[(tetrahydro-2-pyranyloxy)methyl]pyridine, 75 ml of tetrahydrofuran and 0.36 g of 1,3-bis(diphenylphosphino)-propanenickel-(II) chloride. The reaction mixture was stirred for 3 hours, left to stand overnight, then adjusted to pH 8 with aqueous sodium hydrogen carbonate solution and diluted with diethyl ether. The organic phase was washed neutral with water, dried over sodium sulfate and concentrated. Chromatographic purification of the residue (14.6 g) on 210 g of silica gel with hexane/ethyl acetate (vol. 4:1) yielded 8.8 g of 2-[4-(octyloxy)-phenyl]-5-[(tetrahydro-2-pyranyloxy)methyl]pyridine. left to stand overnight The organic phase was washed neutral with water dried over sodium sulfate concentrated Chromatographic purification of the residue (14.6 g) on 210 g of silica gel with hexane/ethyl acetate (vol. 4:1)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-bromo-4-(octyloxy)benzene (14.64 g, 51.3 mmol) was dissolved in dry tetrahydrofuran in nitrogen atmosphere and cooled to −78° C. Butyllithium (50 ml, 80.0 mmol) was then added drop wise and the reaction mixture was let to room temperature. After an hour the mixture was once again cooled to −78° C. and triethylborate (23.6 g, 0.162 mol) was added drop wise. The reaction mixture was stirred over night at room temperature, acidified with 2M HCl, and the organic phase was recovered. It was washed once with water and three times with 1M sodium hydroxide to form a white soapy solid. The combined alkaline phases were acidified with 2M HCl and extracted with ether three times. The combined ether phases were washed with water and dried over magnesium sulphate. The product precipitated in dichloromethane from the reduced ether phase to yield 4-(octyloxy)phenylboronic acid (7.15 g, 28.6 mmol) as a white solid. was let to room temperature After an hour the mixture was once again cooled to −78° C. the organic phase was recovered It was washed once with water and three times with 1M sodium hydroxide to form a white soapy solid extracted with ether three times The combined ether phases were washed with water dried over magnesium sulphate The product precipitated in dichloromethane from the reduced ether phase

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-bromophenol (10.46 g, 60.5 mmol), 1-bromooctane (15.43 g, 79.9 mmol) and potassiumcarbonate (90 g, 0.65 mol) in N,N-dimethylformamide and was heated to 90° C. for 4 h and then the potassiumcarbonate was filtered off. The reaction mixture was quenched with water and extracted three times with ether. The ether was then washed three times with 1M hydrochloric acid (HCl), one time with water, evaporated, and purified by distillation to obtain 1-bromo-4-(octyloxy)benzene (15.1 g, 52.9 mmol) as a colourless oil. the potassiumcarbonate was filtered off The reaction mixture was quenched with water extracted three times with ether The ether was then washed three times with 1M hydrochloric acid (HCl), one time with water evaporated purified by distillation

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4.2 g of the 4-bromo-1-n-octyloxybenzene, 0.5 g of tetrakis(triphenylphosphine) palladium(0), 53 ml of benzene, and 53 ml of an aqueous sodium carbonate solution (2 mol/liter), 26 ml of ethanol containing 3.0 g of 2,3-difluorophenyl boronic acid synthesized by the same method as in [1] in Example 1 was added dropwise, and then the solution thus formed was heated to reflux for 5 hours. After the solution was cooled, it was added with 200 ml of an ether to extract the product, washed with water and dried. The solvent was distilled off under a reduced pressure. The residue thus obtained was purified by a silica gel column chromatography using a mixed solvents of n-hexane and diethyl ether (10:2) to obtain 2.8 g of 4-n-octyloxy-2', 3'-difluorobiphenyl. was added dropwise the solution thus formed was heated to reflux for 5 hours After the solution was cooled to extract the product washed with water dried The solvent was distilled off under a reduced pressure The residue thus obtained was purified by a silica gel column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 100 ml of acetone, 8.0 g of 4-bromophenol, 8.9 g of n-octylbromide, and 13 g of potassium carbonate were heated to reflux for 12 hours. After the solvent was distilled off under a reduced pressure, the residue thus obtained was extracted with isopropyl ether, washed with a 5% aqueous sodium hydroxide solution and water in turn. The ether was distilled off, and the residue was purified by a silica gel column chromatography using a mixed solvents of n-hexane and diethyl ether (10:1) and subjected to distillation to obtain 8.4 g of 4-bromo-1-n-octyloxybenzene. to reflux for 12 hours After the solvent was distilled off under a reduced pressure the residue thus obtained was extracted with isopropyl ether washed with a 5% aqueous sodium hydroxide solution and water in turn The ether was distilled off the residue was purified by a silica gel column chromatography subjected to distillation

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4.2 g of the 4-bromo-1-n-octyloxybenzene, 0.5 g of tetrakis(triphenylphosphine) palladium(0), 53 ml of benzene, and 53 ml of an aqueous sodium carbonate solution (2 mol/liter), 26 ml of ethanol containing 3.0 g of 2,3-difluorophenyl boronic acid synthesized by the same method as in [1] in Example 1 was added dropwise, and then the solution thus formed was heated to reflux for 5 hours. After the solution was cooled, it was added with 200 ml of an ether to extract the product, washed with water and dried. The solvent was distilled off under a reduced pressure. The residue thus obtained was purified by a silica gel column chromatography using a mixed solvents of n-hexane and diethyl ether (10:2) to obtain 2.8 g of 4-n-octyloxy-2', 3'-difluorobiphenyl. was added dropwise the solution thus formed was heated to reflux for 5 hours After the solution was cooled to extract the product washed with water dried The solvent was distilled off under a reduced pressure The residue thus obtained was purified by a silica gel column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 100 ml of acetone, 8.0 g of 4-bromophenol, 8.9 g of n-octylbromide, and 13 g of potassium carbonate were heated to reflux for 12 hours. After the solvent was distilled off under a reduced pressure, the residue thus obtained was extracted with isopropyl ether, washed with a 5% aqueous sodium hydroxide solution and water in turn. The ether was distilled off, and the residue was purified by a silica gel column chromatography using a mixed solvents of n-hexane and diethyl ether (10:1) and subjected to distillation to obtain 8.4 g of 4-bromo-1-n-octyloxybenzene. to reflux for 12 hours After the solvent was distilled off under a reduced pressure the residue thus obtained was extracted with isopropyl ether washed with a 5% aqueous sodium hydroxide solution and water in turn The ether was distilled off the residue was purified by a silica gel column chromatography subjected to distillation

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-octyloxybenzene (Compound 6, 31.5 g, 0.111 mol) was dissolved in 300 mL tetrahydrofuran. The solution was cooled to −78° C. in a cooling bath and n-butyllithium (55.3 mL of 2.5M solution, 0.138 mol) was added to it. After stirring for 25 minutes at −78° C., triisopropylborate (36.4 g, 0.194 mol) was added quickly with a syringe. The cooling bath was removed, and 90 minutes later, the solution was re-cooled to 0° C. 150 mL of a dilute HCl solution was added. After 30 minutes, ethyl ether was added to the reaction mixture and the organic layer was washed with water (2 times), dried with MgSO4, and concentrated to provide an oil, which slowly crystallized over time. This crystallized product was re-crystallized once from acetonitrile to provide a colorless solid, 4-octyloxy-phenylboronic acid (Compound 7, 20.5 g, 74%). The cooling bath was removed 90 minutes later, the solution was re-cooled to 0° C 150 mL of a dilute HCl solution was added After 30 minutes ethyl ether was added to the reaction mixture the organic layer was washed with water (2 times) dried with MgSO4 concentrated to provide an oil, which slowly crystallized over time This crystallized product was re-crystallized once from acetonitrile

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-octyloxybenzene (Compound 6, 31.5 g, 0.111 mol) was dissolved in 300 mL tetrahydrofuran. The solution was cooled to −78° C. in a cooling bath and n-butyllithium (55.3 mL of 2.5M solution, 0.138 mol) was added to it. After stirring for 25 minutes at −78° C., triisopropylborate (36.4 g, 0.194 mol) was added quickly with a syringe. The cooling bath was removed, and 90 minutes later, the solution was re-cooled to 0° C. 150 mL of a dilute HCl solution was added. After 30 minutes, ethyl ether was added to the reaction mixture and the organic layer was washed with water (2 times), dried with MgSO4, and concentrated to provide an oil, which slowly crystallized over time. This crystallized product was re-crystallized once from acetonitrile to provide a colorless solid, 4-octyloxy-phenylboronic acid (Compound 7, 20.5 g, 74%). The cooling bath was removed 90 minutes later, the solution was re-cooled to 0° C 150 mL of a dilute HCl solution was added After 30 minutes ethyl ether was added to the reaction mixture the organic layer was washed with water (2 times) dried with MgSO4 concentrated to provide an oil, which slowly crystallized over time This crystallized product was re-crystallized once from acetonitrile