2-(3-chloro-4-fluorophenyl)acetonitrile

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 3-chloro-4-fluoro-phenylacetonitrile (8.48 g), 1,2-dibromoethane (13 ml) and benzyltriethylammonium chloride (0.46 g) was added sodium hydroxide solution (50% in water, 20 ml) at room temperature. The mixture was vigorously stirred overnight. Water was added and the aqueous phase was extracted twice with diethyl ether. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (SiO2; heptane/EtOAc) to give 1-(3-chloro-4-fluorophenyl)-cyclopropanecarbonitrile as light yellow liquid (3.91 g). 1H-NMR (300 MHz, CDCl3, δ): 1.35-1.40 (m, 2H), 1.72-1.76 (m, 2H), 7.10-7.21 (m, 2H), 7.26-7.34 (m, 1H). the aqueous phase was extracted twice with diethyl ether The combined organic layers were washed with water and brine dried over MgSO4 concentrated The residue was purified by column chromatography (SiO2; heptane/EtOAc)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 3-chloro-4-fluoro-phenylacetonitrile (8.48 g), 1,2-dibromoethane (13 ml) and benzyltriethylammonium chloride (0.46 g) was added sodium hydroxide solution (50% in water, 20 ml) at room temperature. The mixture was vigorously stirred overnight. Water was added and the aqueous phase was extracted twice with diethyl ether. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (SiO2; heptane/EtOAc) to give 1-(3-chloro-4-fluorophenyl)-cyclopropanecarbonitrile as light yellow liquid (3.91 g). 1H-NMR (300 MHz, CDCl3, δ): 1.35-1.40 (m, 2H), 1.72-1.76 (m, 2H), 7.10-7.21 (m, 2H), 7.26-7.34 (m, 1H). the aqueous phase was extracted twice with diethyl ether The combined organic layers were washed with water and brine dried over MgSO4 concentrated The residue was purified by column chromatography (SiO2; heptane/EtOAc)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4.37 g of 3-chloro-4-fluoro-phenylacetonitrile (25 mmol) were dissolved in 40 ml THF and cooled down to 0° C. under nitrogen. 132 ml of a 1M borane-THF complex solution in THF were then added dropwise over 30 min keeping the temperature between 0-5° C. After addition the reaction mixture was stirred at rt for additional 20 min, and refluxed for 21 h. The reaction mixture was then cooled down to 0° C. and treated between 2 and 5° C. with 30 ml methanol over a period of 45 min. After 1 h refluxing the reaction mixture was concentrated, the residue dissolved in DCM and the amine extracted twice with 1N aqueous HCl. The combined aqueous phases were then treated with concentrated NaOH to adjust the pH to 12, and then extracted twice with DCM. The combined organic phases were then washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo leading to 4.3 g colorless oil. This was dissolved in 125 ml diethylether, treated with 15 ml 2.6N HCl in diethylether, stirred at rt for additional 1 h, filtered and dried under high vacuo, leading to 3.93 g white solid (75%). MS (ISP) 174.1 (M+H)+. between 0-5° C After addition the reaction mixture refluxed for 21 h The reaction mixture was then cooled down to 0° C. After 1 h refluxing the reaction mixture was concentrated the residue dissolved in DCM the amine extracted twice with 1N aqueous HCl The combined aqueous phases were then treated with concentrated NaOH extracted twice with DCM The combined organic phases were then washed with water dried over magnesium sulfate filtered concentrated in vacuo This was dissolved in 125 ml diethylether treated with 15 ml 2.6N HCl in diethylether stirred at rt for additional 1 h filtered dried under high vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Borane-tetrahydrofuran complex solution (1 M in THF, 132 mL, 132 mmol) was added dropwise over 30 min at 0-5° C. to a solution of 3-chloro-4-fluoro-phenylacetonitrile (4.37 g, 25.8 mmol) in THF (40 mL), then the reaction mixture was stirred at RT for 20 min and refluxed for 21 h. The reaction mixture was then cooled to 0° C., and methanol (30 mL) was added at 2-5° C. over 45 minutes. After refluxing for 1 h the reaction mixture was concentrated, the residue dissolved in dichloromethane and the amine extracted twice with 1 M aq. hydrochloric acid solution. The combined aqueous phases were then treated with concentrated aq. sodium hydroxide solution to adjust the pH to 12, then extracted twice with dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate, filtered and concentrated, leading to a colorless oil (4.3 g). This was dissolved in diethyl ether (125 mL), treated with hydrogen chloride solution (2.6 M in diethyl ether), and stirred at RT for 1 h. The precipitate was then collected by filtration to afford the title compound (3.93 g, 73%) White solid, MS (ISP) 174.1 (M−Cl)+. refluxed for 21 h The reaction mixture was then cooled to 0° C. After refluxing for 1 h the reaction mixture was concentrated the residue dissolved in dichloromethane the amine extracted twice with 1 M aq. hydrochloric acid solution The combined aqueous phases were then treated with concentrated aq. sodium hydroxide solution extracted twice with dichloromethane The combined organic phases were washed with water dried over magnesium sulfate filtered concentrated This was dissolved in diethyl ether (125 mL) treated with hydrogen chloride solution (2.6 M in diethyl ether) stirred at RT for 1 h The precipitate was then collected by filtration

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Borane-tetrahydrofuran complex solution (1 M in THF, 132 mL, 132 mmol) was added dropwise over 30 min at 0-5° C. to a solution of 3-chloro-4-fluoro-phenylacetonitrile (4.37 g, 25.8 mmol) in THF (40 mL), then the reaction mixture was stirred at RT for 20 min and refluxed for 21 h. The reaction mixture was then cooled to 0° C., and methanol (30 mL) was added at 2-5° C. over 45 minutes. After refluxing for 1 h the reaction mixture was concentrated, the residue dissolved in dichloromethane and the amine extracted twice with 1 M aq. hydrochloric acid solution. The combined aqueous phases were then treated with concentrated aq. sodium hydroxide solution to adjust the pH to 12, then extracted twice with dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate, filtered and concentrated, leading to a colorless oil (4.3 g). This was dissolved in diethyl ether (125 mL), treated with hydrogen chloride solution (2.6 M in diethyl ether), and stirred at RT for 1 h. The precipitate was then collected by filtration to afford the title compound (3.93 g, 73%) White solid, MS (ISP) 174.1 (M−Cl)+. refluxed for 21 h The reaction mixture was then cooled to 0° C. After refluxing for 1 h the reaction mixture was concentrated the residue dissolved in dichloromethane the amine extracted twice with 1 M aq. hydrochloric acid solution The combined aqueous phases were then treated with concentrated aq. sodium hydroxide solution extracted twice with dichloromethane The combined organic phases were washed with water dried over magnesium sulfate filtered concentrated This was dissolved in diethyl ether (125 mL) treated with hydrogen chloride solution (2.6 M in diethyl ether) stirred at RT for 1 h The precipitate was then collected by filtration

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A dispersion of sodium hydride, (60% in mineral oil, 0.7 g, 17.7 mmol) is added to ethanol (25 mL). When gas evolution ceases, 3-chloro-4-fluorophenylacetonitrile (Fluorochemicals, 2.0 g, 11.8 mmol) and 6-methyl-pyridine-2-carboxylic acid methyl ester (1.8 g, 11.8 mmol), are added. The mixture is refluxed for 2.5 h and adjusted to pH 7 with 1 N hydrochloric acid. The mixture is concentrated in vacuo. Concentrated hydrochloric acid (50 mL) is added to the mixture after which it is refluxed for 1.5 h. The mixture is poured over ice and adjusted to pH 8 with 5 N sodium hydroxide. The mixture is extracted with methylene chloride and the organic portions dried over anhydrous sodium sulfate. The mixture is filtered and concentrated in vacuo to yield the title compound, 2.1 g (68%), as a yellowish solid. The mixture is refluxed for 2.5 h The mixture is concentrated in vacuo Concentrated hydrochloric acid (50 mL) is added to the mixture after which it is refluxed for 1.5 h The mixture is poured over ice The mixture is extracted with methylene chloride the organic portions dried over anhydrous sodium sulfate The mixture is filtered concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A dispersion of sodium hydride, (60% in mineral oil, 0.7 g, 17.7 mmol) is added to ethanol (25 mL). When gas evolution ceases, 3-chloro-4-fluorophenylacetonitrile (Fluorochemicals, 2.0 g, 11.8 mmol) and 6-methyl-pyridine-2-carboxylic acid methyl ester (1.8 g, 11.8 mmol), are added. The mixture is refluxed for 2.5 h and adjusted to pH 7 with 1 N hydrochloric acid. The mixture is concentrated in vacuo. Concentrated hydrochloric acid (50 mL) is added to the mixture after which it is refluxed for 1.5 h. The mixture is poured over ice and adjusted to pH 8 with 5 N sodium hydroxide. The mixture is extracted with methylene chloride and the organic portions dried over anhydrous sodium sulfate. The mixture is filtered and concentrated in vacuo to yield the title compound, 2.1 g (68%), as a yellowish solid. The mixture is refluxed for 2.5 h The mixture is concentrated in vacuo Concentrated hydrochloric acid (50 mL) is added to the mixture after which it is refluxed for 1.5 h The mixture is poured over ice The mixture is extracted with methylene chloride the organic portions dried over anhydrous sodium sulfate The mixture is filtered concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A dispersion of sodium hydride, (60% in mineral oil, 0.7 g, 17.7 mmol) is added to ethanol (25 mL). When gas evolution ceases, 3-chloro-4-fluorophenylacetonitrile (Fluorochemicals, 2.0 g, 11.8 mmol) and 6-methyl-pyridine-2-carboxylic acid methyl ester (1.8 g, 11.8 mmol), are added. The mixture is refluxed for 2.5 h and adjusted to pH 7 with 1 N hydrochloric acid. The mixture is concentrated in vacuo. Concentrated hydrochloric acid (50 mL) is added to the mixture after which it is refluxed for 1.5 h. The mixture is poured over ice and adjusted to pH 8 with 5 N sodium hydroxide. The mixture is extracted with methylene chloride and the organic portions dried over anhydrous sodium sulfate. The mixture is filtered and concentrated in vacuo to yield the title compound, 2.1 g (68%), as a yellowish solid. The mixture is refluxed for 2.5 h The mixture is concentrated in vacuo Concentrated hydrochloric acid (50 mL) is added to the mixture after which it is refluxed for 1.5 h The mixture is poured over ice The mixture is extracted with methylene chloride the organic portions dried over anhydrous sodium sulfate The mixture is filtered concentrated in vacuo