4-(difluoromethoxy)-3-methylaniline

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:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 4-amino-1-difluoromethoxy-2-methyl-benzene (5 g, 28.90 mmol) in HBr (20 mL) and water (20 mL) at 0° C. was added a solution of sodium nitrite (2.07 g, 30.00 mmol) in H2O (10 ml) dropwise over a period of 20 minutes. After the addition was complete, the reaction mixture was stirred for 30 minutes at 0° C. Copper (I) bromide (4 g, 27.87 mmol) was then added and the mixture was heated at 60° C. for 30 minutes. The resulting solution was extracted with EtOAc (3×50 mL) and the combined organic layers washed with H2O (1×20 mL), dried over Na2SO4 and concentrated to provide 2.5 g (37%) of 4-bromo-1-(difluoromethoxy)-2-methylbenzene. After the addition the mixture was heated at 60° C. for 30 minutes The resulting solution was extracted with EtOAc (3×50 mL) the combined organic layers washed with H2O (1×20 mL) dried over Na2SO4 concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 4-amino-1-difluoromethoxy-2-methyl-benzene (5 g, 28.90 mmol) in HBr (20 mL) and water (20 mL) at 0° C. was added a solution of sodium nitrite (2.07 g, 30.00 mmol) in H2O (10 ml) dropwise over a period of 20 minutes. After the addition was complete, the reaction mixture was stirred for 30 minutes at 0° C. Copper (I) bromide (4 g, 27.87 mmol) was then added and the mixture was heated at 60° C. for 30 minutes. The resulting solution was extracted with EtOAc (3×50 mL) and the combined organic layers washed with H2O (1×20 mL), dried over Na2SO4 and concentrated to provide 2.5 g (37%) of 4-bromo-1-(difluoromethoxy)-2-methylbenzene. After the addition the mixture was heated at 60° C. for 30 minutes The resulting solution was extracted with EtOAc (3×50 mL) the combined organic layers washed with H2O (1×20 mL) dried over Na2SO4 concentrated

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

Procedure: To a solution of 1-(difluoromethoxy)-2-methyl-4-nitrobenzene (10 g, 48.28 mmol) in ethanol (150 mL) and water (150 mL) was added iron powder (12 g, 214.29 mmol). Acetic acid (cat. amount) was added dropwise with stirring and the reaction mixture was heated at reflux for 20 minutes. The mixture was cooled to room temperature and solids were removed by filtration. Volatiles were removed in vacuo and the aqueous solution was extracted with EtOAc (3×150 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide 8 g (95%) of 4-amino-1-difluoromethoxy-2-methyl-benzene. the reaction mixture was heated at reflux for 20 minutes solids were removed by filtration Volatiles were removed in vacuo the aqueous solution was extracted with EtOAc (3×150 mL) The combined organic layers were dried over Na2SO4 concentrated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of toluene (50 ml) and pyridine (4.2 g) cooled at 0° C., thionyl chloride (1.3 g) was added, and a solution of 1-methylcyclopropanecarboxylic acid (1.0 g) in toluene was dropwise added thereto while stirring. A solution of 3-methyl-4-difluoromethoxyaniline (1.75 g) in toluene was dropwise added thereto. After the dropwise addition was completed, stirring was continued at room temperature for 3 hours. The reaction mixture was admixed with 5% hydrochloric acid (20 ml). The organic solvent layer was separated, washed with 1% sodium hydroxide solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give crude crystals (2.2 g). The crude crystals were recrystallized from ethanol to give N-(3-methyl-4-difluoromethoxyphenyl)-1-methylcyclopropanecarboxamide (1.8 g). M.P., 68°-69° C. After the dropwise addition stirring The organic solvent layer was separated washed with 1% sodium hydroxide solution and saturated sodium chloride solution dried over anhydrous sodium sulfate concentrated to give crude crystals (2.2 g) The crude crystals were recrystallized from ethanol

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 4-amino-1-difluoromethoxy-2-methyl-benzene (5 g, 28.90 mmol) in HBr (20 mL) and water (20 mL) at 0° C. was added a solution of sodium nitrite (2.07 g, 30.00 mmol) in H2O (10 ml) dropwise over a period of 20 minutes. After the addition was complete, the reaction mixture was stirred for 30 minutes at 0° C. Copper (I) bromide (4 g, 27.87 mmol) was then added and the mixture was heated at 60° C. for 30 minutes. The resulting solution was extracted with EtOAc (3×50 mL) and the combined organic layers washed with H2O (1×20 mL), dried over Na2SO4 and concentrated to provide 2.5 g (37%) of 4-bromo-1-(difluoromethoxy)-2-methylbenzene. After the addition the mixture was heated at 60° C. for 30 minutes The resulting solution was extracted with EtOAc (3×50 mL) the combined organic layers washed with H2O (1×20 mL) dried over Na2SO4 concentrated

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

Procedure: To a solution of 1-(difluoromethoxy)-2-methyl-4-nitrobenzene (10 g, 48.28 mmol) in ethanol (150 mL) and water (150 mL) was added iron powder (12 g, 214.29 mmol). Acetic acid (cat. amount) was added dropwise with stirring and the reaction mixture was heated at reflux for 20 minutes. The mixture was cooled to room temperature and solids were removed by filtration. Volatiles were removed in vacuo and the aqueous solution was extracted with EtOAc (3×150 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide 8 g (95%) of 4-amino-1-difluoromethoxy-2-methyl-benzene. the reaction mixture was heated at reflux for 20 minutes solids were removed by filtration Volatiles were removed in vacuo the aqueous solution was extracted with EtOAc (3×150 mL) The combined organic layers were dried over Na2SO4 concentrated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 4-amino-1-difluoromethoxy-2-methyl-benzene (5 g, 28.90 mmol) in HBr (20 mL) and water (20 mL) at 0° C. was added a solution of sodium nitrite (2.07 g, 30.00 mmol) in H2O (10 ml) dropwise over a period of 20 minutes. After the addition was complete, the reaction mixture was stirred for 30 minutes at 0° C. Copper (1) bromide (4 g, 27.87 mmol) was then added and the mixture was heated at 60° C. for 30 minutes. The resulting solution was extracted with EtOAc (3×50 mL) and the combined organic layers washed with H2O (1×20 mL), dried over Na2SO4 and concentrated to provide 2.5 g (37%) of 4-bromo-1-(difluoromethoxy)-2-methylbenzene. After the addition the mixture was heated at 60° C. for 30 minutes The resulting solution was extracted with EtOAc (3×50 mL) the combined organic layers washed with H2O (1×20 mL) dried over Na2SO4 concentrated

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

Procedure: To a solution of 1-(difluoromethoxy)-2-methyl-4-nitrobenzene (10 g, 48.28 mmol) in ethanol (150 mL) and water (150 mL) was added iron powder (12 g, 214.29 mmol). Acetic acid (cat. amount) was added dropwise with stirring and the reaction mixture was heated at reflux for 20 minutes. The mixture was cooled to room temperature and solids were removed by filtration. Volatiles were removed in vacuo and the aqueous solution was extracted with EtOAc (3×150 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide 8 g (95%) of 4-amino-1-difluoromethoxy-2-methyl-benzene. the reaction mixture was heated at reflux for 20 minutes solids were removed by filtration Volatiles were removed in vacuo the aqueous solution was extracted with EtOAc (3×150 mL) The combined organic layers were dried over Na2SO4 concentrated in vacuo