1-Bromo-4-propylbenzene

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

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

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

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

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: n-Butyl lithium (34 ml of a 1.6M solution in hexanes) was added dropwise to a stirred solution of 1-bromo-4-propylbenzene (9.96 g) in dry THF (30 ml) at -70° C. under argon. The reaction was stirred for 1 hour at -70° C. before addition of triisopropyl borate (12.7 ml) and then stirred for a further 90 minutes at -70° C. before addition of saturated aqueous ammonium chloride solution (30 ml). The reaction was stirred at -70° C. for a further 10 minutes, water (100 ml) was added and the reaction was allowed to warm to ambient temperature. The reaction mixture was extracted with diethyl ether (3×50 ml), the combined organic layers were dried (MgSO4) and then the solvent was removed by evaporation. Trituration of the resultant clear oil with isohexane gave 4-propylphenylboronic acid as a white solid, 6.7 g, mass spectrum (negative electrospray (-ve ESP)): 163 (M-H)-. to warm to ambient temperature The reaction mixture was extracted with diethyl ether (3×50 ml) the combined organic layers were dried (MgSO4) the solvent was removed by evaporation

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4.5 g of 4-propylphenylboric acid obtained by reaction of a Grignard reagent prepared from 4-propylbromobenzene and magnesium with trimethoxy borane and subsequent hydrolysis with dilute hydrochloric acid, 5.0 g of 6-bromo-2-(3,4-difluorophenyl)-1,2,3,4-tetrahydronaphthalene synthesized in the example 15, 0.3 g of tetrakis(triphenylphosphine)palladium(0), and 3.0 g of potassium phosphate in 30 ml of dimethyl formamide was stirred for 10 hours at 80° C. The mixture was subsequently cooled to room temperature, water was added, and the mixture was extracted with toluene. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (hexane) and then recrystallized from ethanol, and yielded 4 g of 2-(3,4-difluorophenyl)-6-(4-propylphenyl)-1,2,3,4-tetrahydronaphthalene. This compound displayed a purity of 99.7% when analyzed by gas chromatography, and had a molecular weight of 362. The mixture was subsequently cooled to room temperature the mixture was extracted with toluene The organic layer was washed with a saturated aqueous solution of sodium chloride dried over anhydrous sodium sulfate concentrated The residue was purified by silica gel column chromatography (hexane) recrystallized from ethanol

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

Procedure: Metal magnesium in an amount of 12 g was suspended in 50 ml of THF under nitrogen gas stream, and a solution prepared by dissolving 100 g of 4-n-propylbromobenzene in 300 ml of THF was added dropwise and stirred at room temperature for 1 hour. A solution prepared by dissolving 78 g of 1,4-cyclohexanedione-monoethylene ketal in 300 ml of THF was added dropwise thereto and stirred at room temperature for 1 hour. After finishing of the reaction, 500 ml of a saturated aqueous solution of ammonium chloride was added and extracted with 500 ml of ethyl acetate. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain 98 g of 1,1-ethylenedioxy-4-hydroxy-4-(4-n-propylphenyl)cyclohexane. a solution prepared was added dropwise A solution prepared was added dropwise stirred at room temperature for 1 hour was added extracted with 500 ml of ethyl acetate Organic layer was washed with water dried over anhydrous magnesium sulfate the solvent was distilled off under a reduced pressure

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

Procedure: A solution of 1-bromopropane (1.32 g, 0.6 mmol) was added dropwise at room temperature at a rate such that a gentle reflux was maintained to a suspension of magnesium (258 mg, 12 mmol) in dry tetrahydrofuran. The cloudy suspension was stored at room temperature for an additional 30 minutes to produce a gray solution that was then added dropwise over 15 minutes to a mixture of 1-iodo-4-bromobenzene (3.0 g, 10.6 mmol) and tetrakis (triphenylphosphine) palladium (0) in 50 mL of dry benzene at room temperature. The mixture was stirred for 2 hours, diluted with 50 mL of water, the organic layer was separated and the aqueous layer was extracted with ether (2×50 mL). The combined organic extracts was dried and evaporated to yield 1.69 g (80%) of a light brown oil, which was used in the next step without further purification. a gentle reflux to produce a gray solution that the organic layer was separated the aqueous layer was extracted with ether (2×50 mL) The combined organic extracts was dried evaporated

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: n-Butyl lithium (34 ml of a 1.6 M solution in hexanes) was added dropwise to a stirred solution of 1-bromo-4-propylbenzene (9.96 g) in dry THF (30 ml) at -70° C. under argon. The reaction was stirred for 1 hour at -70° C. before addition of triisopropyl borate (12.7 ml) and then stirred for a further 90 minutes at -70° C. before addition of saturated aqueous ammonium chloride solution (30 ml). The reaction was stirred at -70° C. for a further 10 minutes, water (100 ml) was added and the reaction was allowed to warm to ambient temperature. The reaction mixture was extracted with diethyl ether (3×50 ml), the combined organic layers were dried (MgSO4) and then the solvent was removed by evaporation. Trituration of the resultant clear oil with isohexane gave 4-propylphenylboronic acid as a white solid, 6.7 g, mass spectrum (negative electrospray (-ve ESP)): 163 (M-H)-. to warm to ambient temperature The reaction mixture was extracted with diethyl ether (3×50 ml) the combined organic layers were dried (MgSO4) the solvent was removed by evaporation

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

Procedure: 50 g of 6-bromo-2-naphthol and 48 g of 4-propylphenylboric acid (synthesized by reacting a Grignard reagent prepared from 4-propylbromobenzene with trimethyl borate, and then subjecting the reaction product to hydrolysis with hydrochloric acid) were dissolved in a mixture of 200 ml of toluene and 100 ml of ethanol. To the solution was then added 200 ml of a 2 N aqueous solution of potassium carbonate. To the reaction mixture was then added 2.6 g of tetrakis(triphenylphophine)palladium (0). The reaction mixture was then heated under reflux for 6 hours. The reaction solution was then allowed to cool to room temperature. The resulting organic phase was then separated. The resulting aqueous phase was then extracted with toluene The material thus extracted and the organic phase ware together washed sequentially with diluted hydrochloric acid, water and saturated brine, and then dehydrated and dried over anhydrous sodium sulfate, The solvent was then distilled off to obtain 47 g of 6-(4-propylphenyl)-2-naphthol in crystal form. The reaction mixture was then heated under reflux for 6 hours The resulting organic phase was then separated The resulting aqueous phase was then extracted with toluene The material thus extracted the organic phase ware together washed sequentially with diluted hydrochloric acid, water and saturated brine dried over anhydrous sodium sulfate The solvent was then distilled off

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

Procedure: A mixture of (R)-2-methylpiperazine (3.00 g, 30.0 mmol, 1.0 eq), 1-bromo-4-propylbenzene (627 g, 31.5 mmol, 1.05 eq.), (+/−)-BINAP (747 mg, 1.2 mmol, 0.04 eq.) and sodium tert-butoxide (4.32 g, 45.0 mmol, 1.5 eq.) in toluene (70 mL) was degassed for 15 min with N2. Palladium(II) acetate (337 mg, 1.5 mmol, 0.05 eq.) was then added at once. The reaction mixture was then heated to reflux for 16 h then cooled to RT. The mixture was then filtered on a bed of cellite and washed with Et2O. The combined organic layers were then washed with H2O (3×), dried over MgSO4, filtered and evaporated to give a dark to brown oil. This residue was purified by chromatography on silicagel (DCM/MeOH 80/20) to give the title product as yellow oil (2.35 g, 36%). M+(ESI): 2192. was degassed for 15 min with N2 The reaction mixture was then heated to reflux for 16 h The mixture was then filtered on a bed of cellite washed with Et2O The combined organic layers were then washed with H2O (3×) dried over MgSO4 filtered evaporated to give a dark to brown oil This residue was purified by chromatography on silicagel (DCM/MeOH 80/20)

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3.4 g of 4-propylphenylboric acid (obtained by reacting a Grignard reagent prepared from 1-bromo-4-propylbenzene with trimethyl borate, and then subjecting the product to hydrolysis with hydrochloric acid) and 25.5 g of 6-bromo-2-naphthol were dissolved in a mixture of 92 ml of toluene, 46 ml of ethanol and 92 ml of water. To the solution were then added 25.5 g of potassium carbonate and 1.3 g of tetrakis(triphenylphosphine)palladium (0). The reaction mixture was then stirred at a temperature of 75° C. for 7 hours. To the reaction solution were then added water and toluene. To the reaction solution was then added diluted hydrochloric acid until the aqueous phase became weakly acidic. The reaction solution was then extracted with toluene. The material thus extracted and the organic phase were together washed with water and then with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to obtain 41.4 g of 6-(4-propylphenyl)naphthalene-2-ol. 12.7 g of 6-(4-propylphenyl)naphthalene-2-ol was then dissolved in 50 ml of dichloromethane. To the solution was then added 13.1 g of N-fluoro-5-trifluoromethoxypyridinium-2-sulfonate. The reaction mixture was then stirred at room temperature for 18hours. The reaction mixture was post-treated in the same manner as mentioned above to obtain an oily matter which was then purified through silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain 10 g of 1-fluoro-6-(4-propylphenyl)naphthalene-2-ol. The product was converted to S-ethyl dithiocarbonate which was then trifluoromethoxylated in the same manner as in Example 1 to obtain 2.3 g of the titled 1-fluoro-2-trifluoromethoxy-6-(4-propylphenyl)naphthalene. The reaction solution was then extracted with toluene The material thus extracted the organic phase were together washed with water with saturated brine, and then dried over anhydrous sodium sulfate The solvent was then distilled off under reduced pressure