3-bromo-4-(trifluoromethoxy)benzaldehyde

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

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

Procedure: To methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (300 mg, 0.918 mmol; Example 1, Step 2), MP-cyanoborohydride (1192 mg, 2.75 mmol), 3-bromo-4-trifluoromethoxybenzaldehyde (272 mg, 1.01 mmol) and AcOH (79 μl, 1.38 mmol) was added 5 mL of DMF. The reaction mixture was filtered, the resin was washed with DMF and the solvent was evaporated. The residue was dissolved in saturated aqueous NaHCO3 and extracted with DCM. The combined organic layers were evaporated to yield the title compound as a light yellow solid (330 mg) that was used without any further purification. The reaction mixture was filtered the resin was washed with DMF the solvent was evaporated The residue was dissolved in saturated aqueous NaHCO3 extracted with DCM The combined organic layers were evaporated

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

Procedure: 150 ml of 20% strength solution of n-butyl-lithium in n-hexane were added dropwise to a suspension of 129.6 g (0.3 mol) of dry isopropyl-triphenylphosphonium iodide in 500 ml of anhydrous tetrahydrofuran, under nitrogen at 0° C. and while stirring. The deep red solution thus obtained was stirred for a further 15 minutes at 0° C., and 80.7 g (0.3 mol) of 3-bromo-4-trifluoromethoxybenzaldehyde were then added dropwise at 0° to 10° C. The mixture was then stirred at room temperature until decolorization occurred (approximately 12 hours). 900 ml of water were then added to the reaction mixture, and the mixture was extracted with 5 times 200 ml of petroleum ether. The petroleum ether phases were dried over magnesium sulphate, and the solvent was then stripped off in a rotary evaporator, in the vacuum from a water jet. 150 ml of n-hexane were added to the residue, and the mixture was stirred thoroughly and then filtered. The solvent was then distilled off from the filtrate under normal pressure, and the oily residue was then distilled in vacuo. 50 g (56.5% of theory) of 1-(3-bromo-4-trifluoromethoxyphenyl)-2-methyl-prop-1-ene were obtained as a slightly yellowish liquid of boiling point 107° to 108° C./10 mm Hg. The deep red solution thus obtained was stirred for a further 15 minutes at 0° C. The mixture was then stirred at room temperature until decolorization (approximately 12 hours) the mixture was extracted with 5 times 200 ml of petroleum ether The petroleum ether phases were dried over magnesium sulphate the solvent was then stripped off in a rotary evaporator, in the vacuum from a water jet 150 ml of n-hexane were added to the residue the mixture was stirred thoroughly filtered The solvent was then distilled off from the filtrate under normal pressure the oily residue was then distilled in vacuo

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

Procedure: A mixture of 29.4 g (0.3 mol) of sulphuric acid, 50 ml of water and 2 ml of "Aliquat" 336 (tricaprylmethylammonium chloride) was added to a solution of 27 g (0.1 mol) of 3-bromo-4-trifluoromethoxybenzyl alcohol in 250 ml of methylene chloride at room temperature. Thereafter, 9.7 g (0.033 mol) of potassium dichromate were added to the reaction mixture, and the temperature was kept at approx. 25° C. for 2 hours by slight cooling. After 100 ml of water had been added to the mixture, the organic phase was separated off and the water was once again extracted by shaking with 100 ml of methylene chloride. The organic phases were washed twice with 100 ml of water, then once with 100 ml of saturated sodium bicarbonate solution, and once again with 100 ml of water, dried over sodium sulphate, and concentrated by evaporation in vacuo. The residue was distilled. In this manner, 20.4 g (75.8% of theory) of 3-bromo-4-trifluoromethoxybenzaldehyde were obtained as a colorless oil of boiling point 97° C./10 mm Hg. ##STR23## the organic phase was separated off the water was once again extracted The organic phases were washed twice with 100 ml of water once with 100 ml of saturated sodium bicarbonate solution, and once again with 100 ml of water, dried over sodium sulphate concentrated by evaporation in vacuo The residue was distilled

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

Procedure: To a solution of 3-bromo-4-trifluoromethoxybenzaldehyde (10.0 g, 37.2 mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid (11 g, 44.68 mmol, 1.2 eq) in a mixture of toluene (100 mL), ethanol (20 mL) and water (15 mL) was added potassium carbonate (10.28 g, 74.4 mmol, 2 eq). The solution was degassed with argon for 40 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.86 g, 0.74 mmol, 0.02 eq) was added and the mixture heated at reflux under argon for 22 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (silica: 70-230 mesh, 60A, 400 g, eluant: ethyl acetate/hexane, 5:95) to give 4-trifluoromethoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzaldehyde (11.1 g, 76%). 1H NMR (300 MHz; CDCl3) 1.25 (s, 6H); 1.32 (s, 6H); 1.70 (s, 4H); 2.08 (s, 3H); 7.06 (s, 1H); 7.18 (s, 1H), 7.48 (dd, J1=8.4 Hz, J2=1.5 Hz, 1H); 7.84 (d, J=2.0 Hz, 1H); 7.88 (dd, J1=2.0 Hz), J2=8.5 Hz 1H), 9.91 (s, 1H). The solution was degassed with argon for 40 minutes the mixture heated at reflux under argon for 22 hours washed successively with water and brine dried over MgSO4 filtered evaporated The residue was chromatographed on silica gel (silica: 70-230 mesh, 60A, 400 g, eluant: ethyl acetate/hexane, 5:95)

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

Procedure: To a solution of 4-trifluoromethoxybenzaldehyde (215 g, 1.13 mol) in a mixture of TFA (300 mL), CH2Cl2 (300 mL) and H2SO4 (150 mL) was added at room temperature N-bromosuccinimide (402 g, 2.26 mol) in equal portion over 7 hours. The reaction mixture was stirred for 4 days at room temperature, poured into ice-water and extracted with CH2Cl2. The organic layer was washed with water then treated with saturated NaHCO3 (1.5 L) for 2 hrs. The layers were separated and the organic layer further washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was triturated with hexane and filtered. After evaporation of the solvent, the residue was distilled to give 3-bromo-4-trifluoromethoxybenzaldehyde (190.2 g, 81° C., 1.0 mm/Hg, 62%). extracted with CH2Cl2 The organic layer was washed with water then treated with saturated NaHCO3 (1.5 L) for 2 hrs The layers were separated the organic layer further washed with water and brine dried over MgSO4 filtered evaporated The residue was triturated with hexane filtered After evaporation of the solvent the residue was distilled

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

Procedure: To a solution of 4-trifluoromethoxybenzaldehyde (215 g, 1.13 mol) in a mixture of TFA (300 mL), CH2Cl2 (300 mL) and H2SO4 (150 mL) was added at room temperature N-bromosuccinimide (402 g, 2.26 mol) in equal portion over 7 hours. The reaction mixture was stirred for 4 days at room temperature, poured into ice-water and extracted with CH2Cl2. The organic layer was washed with water then treated with saturated NaHCO3 (1.5 L) for 2 hrs. The layers were separated and the organic layer further washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was triturated with hexane and filtered. After evaporation of the solvent, the residue was distilled to give 3-bromo-4-trifluoromethoxybenzaldehyde (190.2 g, 81° C., 1.0 mm/Hg, 62%). extracted with CH2Cl2 The organic layer was washed with water then treated with saturated NaHCO3 (1.5 L) for 2 hrs The layers were separated the organic layer further washed with water and brine dried over MgSO4 filtered evaporated The residue was triturated with hexane filtered After evaporation of the solvent the residue was distilled

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

Procedure: To a solution of 4-trifluoromethoxybenzaldehyde (215 g, 1.13 mol) in a mixture of TFA (300 mL), CH2Cl2 (300 mL) and H2SO4 (150 mL) was added at room temperature N-bromosuccinimide (402 g, 2.26 mol) in equal portion over 7 hours. The reaction mixture was stirred for 4 days at room temperature, poured into ice-water and extracted with CH2Cl2 The organic layer was washed with water then treated with saturated NaHCO3 (1.5 L) for 2 hrs. The layers were separated and the organic layer further washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was triturated with hexane and filtered. After evaporation of the solvent, the residue was distilled to give 3-bromo-4-trifluoromethoxybenzaldehyde (190.2 g, 81° C., 1.0 mm/Hg, 62%). extracted with CH2Cl2 The organic layer was washed with water then treated with saturated NaHCO3 (1.5 L) for 2 hrs The layers were separated the organic layer further washed with water and brine dried over MgSO4 filtered evaporated The residue was triturated with hexane filtered After evaporation of the solvent the residue was distilled

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

Procedure: To a solution of 4-trifluoromethoxybenzaldehyde (215 g, 1.13 mol) in a mixture of TFA (300 mL), CH2Cl2 (300 mL) and H2SO4 (150 mL) was added at room temperature N-bromosuccinimide (402 g, 2.26 mol) in equal portion over 7 hours. The reaction mixture was stirred for 4 days at room temperature, poured into ice-water and extracted with CH2Cl2 The organic layer was washed with water then treated with saturated NaHCO3 (1.5 L) for 2 hrs. The layers were separated and the organic layer further washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was triturated with hexane and filtered. After evaporation of the solvent, the residue was distilled to give 3-bromo-4-trifluoromethoxybenzaldehyde (190.2 g, 81° C., 1.0 mm/Hg, 62%). extracted with CH2Cl2 The organic layer was washed with water then treated with saturated NaHCO3 (1.5 L) for 2 hrs The layers were separated the organic layer further washed with water and brine dried over MgSO4 filtered evaporated The residue was triturated with hexane filtered After evaporation of the solvent the residue was distilled

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

Procedure: To a solution of 3-bromo-4-trifluoromethoxybenzaldehyde (10.0 g, 37.2 mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) boronic acid (11 g, 44.68 mmol, 1.2 eq) in a mixture of toluene (100 mL), ethanol (20 mL) and water (15 mL) was added potassium carbonate (10.28 g, 74.4 mmol, 2 eq). The solution was degassed with argon for 40 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.86 g, 0.74 mmol, 0.02 eq) was added and the mixture heated at reflux under argon for 22 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (silica: 70-230 mesh, 60A, 400 g, eluant: ethyl acetate/hexane, 5:95) to give 4-trifluoromethoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzaldehyde (11.1 g, 76%). 1H NMR (300 MHz; CDCl3) 1.25 (s, 6H); 1.32 (s, 6H); 1.70 (s, 4H); 2.08 (s, 3H); 7.06 (s, 1H); 7.18 (s, 1H); 7.48 (dd, J1=8.4 Hz, J2=1.5 Hz, 1H); 7.84 (d, J=2.0 Hz, 1H); 7.88 (dd, J1=2.0 Hz, J2=8.5 Hz 1H), 9.91 (s, 1H) The solution was degassed with argon for 40 minutes the mixture heated at reflux under argon for 22 hours washed successively with water and brine dried over MgSO4 filtered evaporated The residue was chromatographed on silica gel (silica: 70-230 mesh, 60A, 400 g, eluant: ethyl acetate/hexane, 5:95)

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

Procedure: To a solution of 3-bromo-4-trifluoromethoxybenzaldehyde (10.0 g, 37.2 mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) boronic acid (11 g, 44.68 mmol, 1.2 eq) in a mixture of toluene (100 mL), ethanol (20 mL) and water (15 mL) was added potassium carbonate (10.28 g, 74.4 mmol, 2 eq). The solution was degassed with argon for 40 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.86 g, 0.74 mmol, 0.02 eq) was added and the mixture heated at reflux under argon for 22 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (silica: 70-230 mesh, 60A, 400 g, eluant: ethyl acetate/hexane, 5:95) to give 4-trifluoromethoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzaldehyde (11.1 g, 76%). 1H NMR (300 MHz; CDCl3) 1.25 (s, 6H); 1.32 (s, 6H); 1.70 (s, 4H); 2.08 (s, 3H); 7.06 (s, 1H); 7.18 (s, 1H); 7.48 (dd, J132 8.4 Hz, J2=1.5 Hz, 1H); 7.84 (d, J=2.0 Hz, 1H); 7.88 (dd, J1=2.0 Hz, J2=8.5 Hz 1H), 9.91 (s, 1H). The solution was degassed with argon for 40 minutes the mixture heated at reflux under argon for 22 hours washed successively with water and brine dried over MgSO4 filtered evaporated The residue was chromatographed on silica gel (silica: 70-230 mesh, 60A, 400 g, eluant: ethyl acetate/hexane, 5:95)

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

Procedure: To a solution of 3-bromo-4-trifluoromethoxybenzaldehyde (10.0 g, 37.2 mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) boronic acid (11 g, 44.68 mmol, 1.2 eq) in a mixture of toluene (100 mL), ethanol (20 mL) and water (15 mL) was added potassium carbonate (10.28 g, 74.4 mmol, 2 eq). The solution was degassed with argon for 40 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.86 g, 0.74 mmol, 0.02 eq) was added and the mixture heated at reflux under argon for 22 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (silica: 70-230 mesh, 60A, 400 g, eluant: ethyl acetate/hexane, 5:95) to give 4-trifluoromethoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzaldehyde (11.1 g, 76%). 1H NMR (300 MHz; CDCl3) 1.25 (s, 6H); 1.32 (s, 6H); 1.70 (s, 4H); 2.08 (s, 3H); 7.06 (s, 1H); 7.18 (s, 1H); 7.48 (dd, J132 8.4 Hz, J2=1.5 Hz, 1H); 7.84 (d, J=2.0 Hz, 1H); 7.88 (dd, J1=2.0 Hz, J2=8.5 Hz 1H), 9.91 (s, 1H). The solution was degassed with argon for 40 minutes the mixture heated at reflux under argon for 22 hours washed successively with water and brine dried over MgSO4 filtered evaporated The residue was chromatographed on silica gel (silica: 70-230 mesh, 60A, 400 g, eluant: ethyl acetate/hexane, 5:95)