2-chlorobicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile

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

実験手順: A solution of 3-chloro-1,2-dihydrocyclobutabenzene-1-carbonitrile (196 mmol, 32 g) and potassium hydroxide (978 mmol, 54.9 g) in EtOH (500 ml)/water (100 ml) was stirred at reflux for 2 h. After evaporation of the organic solvent, the aqueous residue was washed with Et2O. The organic layer was extracted with 2N NaOH aq. and combined aqueous layers were acidified with 5 N HCl and extracted with Et2O. The extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was washed with heptane/Et2O (5/1) to afford 3-chloro-1,2-dihydrocyclobutabenzene-1-carboxylic acid (85% yield, 30.3 g). at reflux for 2 h After evaporation of the organic solvent the aqueous residue was washed with Et2O The organic layer was extracted with 2N NaOH aq. and combined aqueous layers extracted with Et2O The extracts were washed with brine dried over Na2SO4 concentrated in vacuo The residue was washed with heptane/Et2O (5/1)

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

実験手順: A solution of 3-chloro-1,2-dihydrocyclobutabenzene-1-carbonitrile (196 mmol, 32 g) and potassium hydroxide (978 mmol, 54.9 g) in EtOH (500 ml)/water (100 ml) was stirred at reflux for 2 h. After evaporation of the organic solvent, the aqueous residue was washed with Et2O. The organic layer was extracted with 2N NaOH aq. and combined aqueous layers were acidified with 5 N HCl and extracted with Et2O. The extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was washed with heptane/Et2O (5/1) to afford 3-chloro-1,2-dihydrocyclobutabenzene-1-carboxylic acid (85% yield, 30.3 g). at reflux for 2 h After evaporation of the organic solvent the aqueous residue was washed with Et2O The organic layer was extracted with 2N NaOH aq. and combined aqueous layers extracted with Et2O The extracts were washed with brine dried over Na2SO4 concentrated in vacuo The residue was washed with heptane/Et2O (5/1)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A dried 2 L 3-neck flask was fitted with a card-ice condenser, sealed under nitrogen and cooled to −78° C. Ammonia gas was condensed into the flask from a cylinder until approximately required volume was present (˜300 mL). Commercial sodium amide (800 mmol, 31.2 g) was added to the ammonia at −78° C. and after stirring for 10 minutes 3-(2,6-dichlorophenyl)propanenitrile (200 mmol, 40 g) was added over a 5 minute period. The mixture was allowed to warm such that the resultant mixture was stirred at reflux for 4 h before being neutralised with solid ammonium nitrate (800 mmol, 64.0 g) and allowed to stand overnight under a flow of nitrogen. The ammonia was evaporated and water was added to the solid residue and the products were extracted with dichloromethane (×3). The combined organics were washed with dilute hydrochloric acid (5%), followed by water. The organics were dried with sodium sulfate and concentrated to afford crude 3-chloro-1,2-dihydrocyclobutabenzene-1-carbonitrile as a brown residue (98% yield, 32 g). A dried 2 L 3-neck flask was fitted with a card-ice condenser sealed under nitrogen condensed into the flask from a cylinder until approximately required volume was added over a 5 minute period at reflux for 4 h The ammonia was evaporated water was added to the solid residue the products were extracted with dichloromethane (×3) The combined organics were washed with dilute hydrochloric acid (5%) The organics were dried with sodium sulfate concentrated

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

実験手順: 5.0 g of 3-chloro-1-cyanobenzocyclobutane (prepared according to the process described in Patent EP 119,107) are added to a solution of 6.0 g of potassium hydroxide in 58 ml of ethanol The mixture is stirred at room temperature overnight. 7.5 ml of water are then added and the mixture is heated to reflux for 6 hours. The ethanol is evaporated off to dryness. The residue is taken up with water and the aqueous phase is washed with ethyl ether, then acidified (pH 1) with 1N hydrochloric acid and extracted with dichloromethane. The organic phase is dried, filtered and evaporated to dryness. the mixture is heated to reflux for 6 hours The ethanol is evaporated off to dryness the aqueous phase is washed with ethyl ether extracted with dichloromethane The organic phase is dried filtered evaporated to dryness

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

実験手順: 5.0 g of 3-chloro-1-cyanobenzocyclobutane (prepared according to the process described in Patent EP 119,107) are added to a solution of 6.0 g of potassium hydroxide in 58 ml of ethanol. The mixture is stirred at room temperature overnight. 7.5 ml of water are then added and the mixture is heated to reflux for 6 hours. The ethanol is evaporated off to dryness. The residue is taken up with water and the aqueous phase is washed with ethyl ether, then acidified (pH 1) with 1N hydrochloric acid and extracted with dichloromethane. The organic phase is dried, filtered and evaporated to dryness. the mixture is heated to reflux for 6 hours The ethanol is evaporated off to dryness the aqueous phase is washed with ethyl ether extracted with dichloromethane The organic phase is dried filtered evaporated to dryness

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

実験手順: A solution of 3-chloro-1,2-dihydrocyclobutabenzene-1-carbonitrile (196 mmol, 32 g) and potassium hydroxide (978 mmol, 54.9 g) in EtOH (500 ml)/water (100 ml) was stirred at reflux for 2 h. After evaporation of the organic solvent, the aqueous residue was washed with Et2O. The organic layer was extracted with 2N NaOH aq. and combined aqueous layers were acidified with 5 N HCl and extracted with Et2O. The extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was washed with heptane/Et2O (5/1) to afford 3-chloro-1,2-dihydrocyclobutabenzene-1-carboxylic acid (85% yield, 30.3 g). at reflux for 2 h After evaporation of the organic solvent the aqueous residue was washed with Et2O The organic layer was extracted with 2N NaOH aq. and combined aqueous layers extracted with Et2O The extracts were washed with brine dried over Na2SO4 concentrated in vacuo The residue was washed with heptane/Et2O (5/1)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A dried 2 L 3-neck flask was fitted with a card-ice condenser, sealed under nitrogen and cooled to −78° C. Ammonia gas was condensed into the flask from a cylinder until approximately required volume was present (˜300 mL). Commercial sodium amide (800 mmol, 31.2 g) was added to the ammonia at −78° C. and after stirring for 10 minutes 3-(2,6-dichlorophenyl)propanenitrile (200 mmol, 40 g) was added over a 5 minute period. The mixture was allowed to warm such that the resultant mixture was stirred at reflux for 4 h before being neutralised with solid ammonium nitrate (800 mmol, 64.0 g) and allowed to stand overnight under a flow of nitrogen. The ammonia was evaporated and water was added to the solid residue and the products were extracted with dichloromethane (×3). The combined organics were washed with dilute hydrochloric acid (5%), followed by water. The organics were dried with sodium sulfate and concentrated to afford crude 3-chloro-1,2-dihydrocyclobutabenzene-1-carbonitrile as a brown residue (98% yield, 32 g). A dried 2 L 3-neck flask was fitted with a card-ice condenser sealed under nitrogen condensed into the flask from a cylinder until approximately required volume was added over a 5 minute period at reflux for 4 h The ammonia was evaporated water was added to the solid residue the products were extracted with dichloromethane (×3) The combined organics were washed with dilute hydrochloric acid (5%) The organics were dried with sodium sulfate concentrated

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

実験手順: 5.0 g of 3-chloro-1-cyanobenzocyclobutane (prepared according to the process described in Patent EP 119,107) are added to a solution of 6.0 g of potassium hydroxide in 58 ml of ethanol The mixture is stirred at room temperature overnight. 7.5 ml of water are then added and the mixture is heated to reflux for 6 hours. The ethanol is evaporated off to dryness. The residue is taken up with water and the aqueous phase is washed with ethyl ether, then acidified (pH 1) with 1N hydrochloric acid and extracted with dichloromethane. The organic phase is dried, filtered and evaporated to dryness. the mixture is heated to reflux for 6 hours The ethanol is evaporated off to dryness the aqueous phase is washed with ethyl ether extracted with dichloromethane The organic phase is dried filtered evaporated to dryness