1-(2,2-diethoxyethoxy)-4-fluorobenzene

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

Procedure: A solution of p-fluorophenol (28.1 g., 0.25 mole) in dimethylformamide (30 ml.) is added dropwise to a suspension of hexane (2 × 30 ml.)-prewashed sodium hydride (50% oil dispersion, 12.5 g., 0.26 mole) in dimethylformamide (120 ml.). The resulting mixture is stirred at room temperature for 10 minutes, treated with bromoacetaldehyde diethylacetal (49.3 g., 0.25 mole), and finally heated on a steam bath for 4 hours. The reaction mixture is allowed to come to room temperature and the precipitated sodium bromide is filtered off. Dimethylformamide is then removed on a rotary evaporator, the oil residue is diluted with acetone (100 ml.) and another quantity of sodium bromide is precipitated which again is removed by filtration. The filtrate is then concentrated on a rotary evaporator leaving an oil residue which is vacuum distilled at 87° C./0.05 mm. to yield the desired product as colorless oil (46.7 g., 0.205 mole, 82%). ir (neat) 3.4~3.5, 6.21, 6.64, 8.00, 8.25, 8.83, 9.32, 12.08, 13.20μ; pmr (CCl4)δ1.17 (6H, t, J=7.5Hz), 3.57 (2H, q, J=7.5Hz), 3.61 (2H, q, J=7.5Hz), 3.85 (2H, d, J=5Hz), 4.68 (1H, t, J=5Hz), 6.6-7.1 (4H, m). finally heated on a steam bath for 4 hours to come to room temperature the precipitated sodium bromide is filtered off Dimethylformamide is then removed on a rotary evaporator the oil residue is diluted with acetone (100 ml.) another quantity of sodium bromide is precipitated which again is removed by filtration The filtrate is then concentrated on a rotary evaporator leaving an oil residue which distilled at 87° C./0.05 mm

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-fluorophenoxyacetaldehyde diethyl acetal (30 g., 0.13 mole), acetone (150 ml.), water (150 ml.) and concentrated sulfuric acid (0.8 ml.) is stirred and heated at reflux for 16 hours. After cooling to 25° C., the reaction mixture is extracted with methylene chloride four times. The combined organic extract is washed with aqueous sodium bicarbonate, dried over magnesium sulfate, and filtered. Evaporation of the filtrate in vacuo leaves a residual oil which is distilled to provide the title compound as a colorless oil (19 g., 94%) bp0.05 70° C.; pmr (CCl4) δ4.37 (2H, d), 6.6-7.1 (4H, m) and 9.68 (H, t). heated at reflux for 16 hours the reaction mixture is extracted with methylene chloride four times The combined organic extract is washed with aqueous sodium bicarbonate dried over magnesium sulfate filtered Evaporation of the filtrate in vacuo leaves a residual oil which is distilled

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-fluorophenoxyacetaldehyde diethyl acetal (30 g., 0.13 mole), acetone (150 ml.), water (150 ml.) and concentrated sulfuric acid (0.8 ml.) is stirred and heated at reflux for 16 hours. After cooling to 25° C., the reaction mixture is extracted with methylene chloride four times. The combined organic extract is washed with aqueous sodium bicarbonate, dried over magnesium sulfate, and filtered. Evaporation of the filtrate in vacuo leaves a residual oil which is distilled to provide the title compound as a colorless oil (19 g., 94%) bp0.05 70° C.; pmr (CCl4) δ4.37 (2H, d), 6.6-7.1 (4H, m) and 9.68 (H, t). heated at reflux for 16 hours the reaction mixture is extracted with methylene chloride four times The combined organic extract is washed with aqueous sodium bicarbonate dried over magnesium sulfate filtered Evaporation of the filtrate in vacuo leaves a residual oil which is distilled

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-fluorophenol (28.1 g., 0.25 mole) in dry dimethylformamide (30 ml.) is added dropwise to a suspension of hexane (2 × 30 ml.)--prewashed sodium hydride (50% dispersion in mineral oil, 12.5 g., 0.26 mole) in dry dimethylformamide (120 ml.). After stirring at 25° C. for 10 minutes, the reaction mixture is treated with bromoacetaldehyde diethyl acetal (49.3 g., 0.25 mole) and heated at 100° C. for 4 hours. Upon cooling to 25° C., the reaction mixture is filtered to remove insoluble sodium bromide. The filtrate is evaporated in vacuo, leaving an oily residue which is triturated with acetone (100 ml.) at 25° C. and filtered to remove additional sodium bromide. Evaporation of the filtrate in vacuo provides a residual oil which is distilled to afford the title compound as a colorless oil (46.7 g., 82%), bp0.05 87° C.; pmr (CCl4) δ1.17 (6 H, t) 3.57 (2H, q), 3.61 (2H, q), 3.85 (2H, d), 4.68 (H, t) and 6.6-7.1 (4H, m). heated at 100° C. for 4 hours Upon cooling to 25° C. the reaction mixture is filtered to remove insoluble sodium bromide The filtrate is evaporated in vacuo leaving an oily residue which is triturated with acetone (100 ml.) at 25° C. filtered to remove additional sodium bromide Evaporation of the filtrate in vacuo provides a residual oil which is distilled

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

Procedure: To a solution of 16.0 g of 1-(2,2-diethoxyethoxy)-4-fluorobenzene in 50 ml n-hexane was added 3.2 g of amberlyst 15 at room temperature. After the mixture was treated in a sealed tube at 200° C. for 11 hours, the amberlyst 15 was filtered off. The solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography (n-hexane), to give 4.8 g of the title compound as a colorless oil. After the mixture was treated in a sealed tube at 200° C. for 11 hours the amberlyst 15 was filtered off The solvent was evaporated the crude product was purified separated by silica gel column chromatography (n-hexane)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 10.0 g of 4-fluorophenol and 16.1 ml of bromoacetaldehyde diethylacetal in 100 ml dimethylformaldehyde was added 18.5 g of potassium carbonate at room temperature, and the mixture was stirred at 120° C. for two days. The reaction mixture was filtered through Celite, and the filtrate was diluted with ethyl acetate. The organic layer was sequentially washed with saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=0:10 to 1:20), to give 17.3 g of the title compound as a colorless oil. The reaction mixture was filtered through Celite the filtrate was diluted with ethyl acetate The organic layer was sequentially washed with saturated aqueous ammonium chloride solution and brine dried over anhydrous magnesium sulfate the solvent was evaporated The crude product was purified separated by silica gel column chromatography (ethyl acetate:n-hexane=0:10 to 1:20)

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

Procedure: A mixture of 4-fluorophenoxyacetaldehyde diethyl acetal (30.0 g., 0.131 mole) acetone (150 ml.), water (150 ml.), and concentrated sulfuric acid (0.8 ml.) is refluxed overnight (ca. 16 hours). The mixture is allowed to cool to room temperature, and is then extracted with methylenechloride four times. The combined extracts are washed with aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is stripped off on a rotary evaporator and the oil residue is subsequently distilled in vacuo at 70°/0.05 mm to give the title compound (19.0 g., 0.123 mole, 94%). ir (neat) 3.23, 3.50, 3.63, 5.71, 6.62, 7.00, 8.00, 8.24, 9.07, 9.38, 12.03, 12.51, 13.12μ; pmr (CCl4) δ 4.37 (2H, d, J=1Hz), 6.6-7.1 (4H, m), 9.68 (1H, t, J=1Hz). is refluxed overnight (ca. 16 hours) is then extracted with methylenechloride four times The combined extracts are washed with aqueous sodium bicarbonate dried over anhydrous magnesium sulfate The solvent is stripped off on a rotary evaporator the oil residue is subsequently distilled in vacuo at 70°/0.05 mm

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

Procedure: A mixture of 4-fluorophenoxyacetaldehyde diethyl acetal (30.0 g., 0.131 mole) acetone (150 ml.), water (150 ml.), and concentrated sulfuric acid (0.8 ml.) is refluxed overnight (ca. 16 hours). The mixture is allowed to cool to room temperature, and is then extracted with methylenechloride four times. The combined extracts are washed with aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is stripped off on a rotary evaporator and the oil residue is subsequently distilled in vacuo at 70°/0.05 mm to give the title compound (19.0 g., 0.123 mole, 94%). ir (neat) 3.23, 3.50, 3.63, 5.71, 6.62, 7.00, 8.00, 8.24, 9.07, 9.38, 12.03, 12.51, 13.12μ; pmr (CCl4) δ 4.37 (2H, d, J=1Hz), 6.6-7.1 (4H, m), 9.68 (1H, t, J=1Hz). is refluxed overnight (ca. 16 hours) is then extracted with methylenechloride four times The combined extracts are washed with aqueous sodium bicarbonate dried over anhydrous magnesium sulfate The solvent is stripped off on a rotary evaporator the oil residue is subsequently distilled in vacuo at 70°/0.05 mm

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

Procedure: A solution of p-fluorophenol (28.1 g., 0.25 mole) in DMF (30 ml.) is added dropwise to a suspension of hexane (2 × 30 ml.)-prewashed sodium hydride (50% oil dispersion, 12.5 g., 0.26 mole) in DMF (120 ml.). The resulting mixture is stirred at room temperature for 10 minutes, treated with bromoacetaldehyde diethyl acetal (49.3 g., 0.25 mole) and finally heated on a steam bath for 4 hours. The reaction mixture is allowed to come to room temperature and the precipitated sodium bromide is filtered off. DMF is then removed on a rotary evaporator, the oil residue is diluted with acetone (100 ml.) and another quantity of sodium bromide is precipitated which again is removed by filtration. The filtrate is then concentrated on a rotary evaporator leaving an oil residue which is vacuum distilled at 87°/0.05 mm to yield the desired product as colorless oil (46.7 g., 0.205 mole, 82%). Ir (neat) 3.4~3.5, 6.21, 6.64, 8.00, 8.25, 8.83, 9.32, 12.08, 13.20μ; pmr (CCl4) δ 1.17 (6H, t J=7.5Hz), 3.57 (2H, q, J=7.5 Hz), 3.61 (2H, q, J=7.5 Hz), 3.85 (2H, d, J=5Hz), 4.68 (1H, t, J=5Hz), 6.6-7.1 (4H, m). finally heated on a steam bath for 4 hours to come to room temperature the precipitated sodium bromide is filtered off DMF is then removed on a rotary evaporator the oil residue is diluted with acetone (100 ml.) another quantity of sodium bromide is precipitated which again is removed by filtration The filtrate is then concentrated on a rotary evaporator leaving an oil residue which distilled at 87°/0.05 mm

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

Procedure: A solution of p-fluorophenol (28.1 g., 0.25 mole) in dimethylformamide (30 ml.) is added dropwise to a suspension of hexane (2 × 30 ml.)-prewashed sodium hydride (50% oil dispersion, 12.5 g., 0.26 mole) in dimethylformamide (120 ml.). The resulting mixture is stirred at room temperature for 10 minutes, treated with bromoacetaldehyde diethylacetal (49.3 g., 0.25 mole), and finally heated on a steam bath for 4 hours. The reaction mixture is allowed to come to room temperature and the precipitated sodium bromide is filtered off. Dimethylformamide is then removed on a rotary evaporator, the oil residue is diluted with acetone (100 ml.) and another quantity of sodium bromide is precipitated which again is removed by filtration. The filtrate is then concentrated on a rotary evaporator leaving an oil residue which is vacuum distilled at 87° C./0.05 mm. to yield the desired product as colorless oil (46.7 g., 0.205 mole, 82%). ir (neat) 3.4~3.5, 6.21, 6.64, 8.00, 8.25, 8.83, 9.32, 12.08, 13.20μ; pmr (CCl4)δ1.17 (6H, t, J=7.5Hz), 3.57 (2H, q, J=7.5Hz), 3.61 (2H, q, J=7.5Hz), 3.85 (2H, d, J=5Hz), 4.68 (1H, t, J=5Hz), 6.6-7.1 (4H, m). finally heated on a steam bath for 4 hours to come to room temperature the precipitated sodium bromide is filtered off Dimethylformamide is then removed on a rotary evaporator the oil residue is diluted with acetone (100 ml.) another quantity of sodium bromide is precipitated which again is removed by filtration The filtrate is then concentrated on a rotary evaporator leaving an oil residue which distilled at 87° C./0.05 mm

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

Procedure: A solution of p-fluorophenol (28.1 g., 0.25 mole) in dimethylformamide (30 ml.) is added dropwise to a suspension of hexane (2 × 30 ml.)-prewashed sodium hydride (50% oil dispersion, 12.5 g., 0.26 mole) in dimethylformamide (120 ml.). The resulting mixture is stirred at room temperature for 10 minutes, treated with bromoacetaldehyde diethylacetal (49.3 g., 0.25 mole), and finally heated on a steam bath for 4 hours. The reaction mixture is allowed to come to room temperature and the precipitated sodium bromide is filtered off. Dimethylformamide is then removed on a rotary evaporator, the oil residue is diluted with acetone (100 ml.) and another quantity of sodium bromide is precipitated which again is removed by filtration. The filtrate is then concentrated on a rotary evaporator leaving an oil residue which is vacuum distilled at 87° C./0.05 mm. to yield the desired product as colorless oil (46.7 g., 0.205 mole, 82%). ir (neat) 3.4~3.5, 6.21, 6.64, 8.00, 8.25, 8.83, 9.32, 12.08, 13.20μ; pmr (CCl4)δ1.17 (6H, t, J=7.5Hz), 3.57 (2H, q, J=7.5Hz), 3.61 (2H, q, J=7.5Hz), 3.85 (2H, d, J=5Hz), 4.68 (1H, t, J=5Hz), 6.6-7.1 (4H, m). finally heated on a steam bath for 4 hours to come to room temperature the precipitated sodium bromide is filtered off Dimethylformamide is then removed on a rotary evaporator the oil residue is diluted with acetone (100 ml.) another quantity of sodium bromide is precipitated which again is removed by filtration The filtrate is then concentrated on a rotary evaporator leaving an oil residue which distilled at 87° C./0.05 mm

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-fluorophenoxyacetaldehyde diethyl acetal (30 g., 0.13 mole), acetone (150 ml.), water (150 ml.) and concentrated sulfuric acid (0.8 ml.) is stirred and heated at reflux for 16 hours. After cooling to 25° C., the reaction mixture is extracted with methylene chloride four times. The combined organic extract is washed with aqueous sodium bicarbonate, dried over magnesium sulfate, and filtered. Evaporation of the filtrate in vacuo leaves a residual oil which is distilled to provide the title compound as a colorless oil (19 g., 94%) bp0.05 70° C.; pmr (CCl 4) δ 4.37 (2H, d), 6.6-7.1 (4H, m) and 9.68 (H, t). heated at reflux for 16 hours the reaction mixture is extracted with methylene chloride four times The combined organic extract is washed with aqueous sodium bicarbonate dried over magnesium sulfate filtered Evaporation of the filtrate in vacuo leaves a residual oil which is distilled