3-(dimethylamino)prop-2-enenitrile

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

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

Procedure: First 9.7 g of 3-dimethylaminoacrylonitrile are added dropwise, then 10.5 g of triethylamine are added to a solution of 21.25 g of 2,3,4,5-tetrafluorobenzoyl chloride in 75 ml of anhydrous dioxane, while cooling in ice and stirring at about 10°-15° C. The mixture is heated to boiling under reflux for 4 hours, the solvent is removed by distillation in vacuo, and the residue is taken up in methylene chloride/water. The phases are separated, and the aqueous solution is again extracted with methylene chloride. The combined organic phases are washed with water, dried with sodium sulphate, and the methylene chloride is removed in vacuo. After recrystallization of the crystalline residue from ethanol, 23.5 g of 3-dimethylamino-2-(2,3,4,5-tetrafluorobenzoyl)acrylonitrile of melting point 149°-151° C. are obtained. while cooling in ice The mixture is heated under reflux for 4 hours the solvent is removed by distillation in vacuo The phases are separated the aqueous solution is again extracted with methylene chloride The combined organic phases are washed with water dried with sodium sulphate the methylene chloride is removed in vacuo After recrystallization of the crystalline residue from ethanol, 23.5 g of 3-dimethylamino-2-(2,3,4,5-tetrafluorobenzoyl)acrylonitrile of melting point 149°-151° C. are obtained

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

Procedure: First 9.7 g of 3-dimethylaminoacrylonitrile are added dropwise, then 10.5 g of triethylamine are added to a solution of 21.25 g of 2,3,4,5-tetrafluorobenzoyl chloride in 75 ml of anhydrous dioxane, while cooling in ice and stirring at about 10°-15° C. The mixture is heated to boiling under reflux for 4 hours, the solvent is removed by distillation in vacuo, and the residue is taken up in methylene chloride/water. The phases are separated, and the aqueous solution is again extracted with methylene chloride. The combined organic phases are washed with water, dried with sodium sulphate, and the methylene chloride is removed in vacuo. After recrystallization of the crystalline residue from ethanol, 23.5 g of 3-dimethylamino-2-(2,3,4,5-tetrafluorobenzoyl)acrylonitrile of melting point 149°-151° C. are obtained. while cooling in ice The mixture is heated under reflux for 4 hours the solvent is removed by distillation in vacuo The phases are separated the aqueous solution is again extracted with methylene chloride The combined organic phases are washed with water dried with sodium sulphate the methylene chloride is removed in vacuo After recrystallization of the crystalline residue from ethanol, 23.5 g of 3-dimethylamino-2-(2,3,4,5-tetrafluorobenzoyl)acrylonitrile of melting point 149°-151° C. are obtained

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

Procedure: 9.6 g of 3-dimethylaminoacrylonitrile and 10.5 g of triethylamine are added dropwise to a solution of 22.75 g of 2,4-dichloro-5-fluorobenzoyl chloride in 100 ml of anhydrous dioxane, while cooling in ice and stirring. The mixture is stirred at room temperature for 1 hour and then heated to boiling under reflux for 4 hours. The solvent is removed by distillation in vacuo, and the residue is taken up in methylene chloride/water. The methylene chloride phase is washed with water, dried with sodium sulphate, and evaporated in vacuo. The crystalline residue is recrystallized from ethanol. 22.2 g of 3-dimethylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylonitrile of melting point 138°-139° C. are obtained. while cooling in ice The mixture is stirred at room temperature for 1 hour heated under reflux for 4 hours The solvent is removed by distillation in vacuo The methylene chloride phase is washed with water dried with sodium sulphate evaporated in vacuo The crystalline residue is recrystallized from ethanol

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

Procedure: 9.6 g of 3-dimethylaminoacrylonitrile and 10.5 g of triethylamine are added dropwise to a solution of 22.75 g of 2,4-dichloro-5-fluorobenzoyl chloride in 100 ml of anhydrous dioxane, while cooling in ice and stirring. The mixture is stirred at room temperature for 1 hour and then heated to boiling under reflux for 4 hours. The solvent is removed by distillation in vacuo, and the residue is taken up in methylene chloride/water. The methylene chloride phase is washed with water, dried with sodium sulphate, and evaporated in vacuo. The crystalline residue is recrystallized from ethanol. 22.2 g of 3-dimethylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylonitrile of melting point 138°-139° C. are obtained. while cooling in ice The mixture is stirred at room temperature for 1 hour heated under reflux for 4 hours The solvent is removed by distillation in vacuo The methylene chloride phase is washed with water dried with sodium sulphate evaporated in vacuo The crystalline residue is recrystallized from ethanol

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

Procedure: 20.0 g of 2,3-dichlorophenacylamine hydrochloride and 10.0 g of 3-dimethylaminoacrylonitrile are heated for 1 hour under reflux in 300 ml of ethanol. Then an ethanolic solution of sodium ethylate, prepared from 2.1 g of sodium and 30 ml of ethanol, is rapidly added dropwise and the reaction mixture is stirred for another 10 minutes under reflux. The reaction mixture is cooled to room temperature and then poured into ice/hydrochloric acid and the resultant mixture is stirred for 11/2 hours. The precipitate is isolated by filtration, washed with water and dried, affording 15.4 g (78% of theory) of title compound with a melting point of 152°-154° C. is rapidly added dropwise under reflux The precipitate is isolated by filtration washed with water dried

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

Procedure: 20.0 g of 2,3-dichlorophenacylamine hydrochloride and 10.0 g of 3-dimethylaminoacrylonitrile are heated for 1 hour under reflux in 300 ml of ethanol. Then an ethanolic solution of sodium ethylate, prepared from 2.1 g of sodium and 30 ml of ethanol, is rapidly added dropwise and the reaction mixture is stirred for another 10 minutes under reflux. The reaction mixture is cooled to room temperature and then poured into ice/hydrochloric acid and the resultant mixture is stirred for 11/2 hours. The precipitate is isolated by filtration, washed with water and dried, affording 15.4 g (78% of theory) of title compound with a melting point of 152°-154° C. is rapidly added dropwise under reflux The precipitate is isolated by filtration washed with water dried

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

Procedure: 3-Dimethylamino-acrylonitrile (0.05 mL, 0.50 mmol) was dissolved in EtOH (1 mL) and NaOEt solution (21 wt % in EtOH, 0.19 mL, 0.50 mmol) was added. This was stirred for 1 h and then (1-Carbamimidoyl-cyclopropyl)-carbamic acid tert-butyl ester hydrochloride (50 mg, 0.25 mmol) was added. The reaction was stirred for 1.5 h at 60° C. and then solid NH4Cl (27 mg, 0.50 mmol) and NH3 (7 M in MeOH, 0.50 mL, 3.5 mmol) were added and stirring was continued at 60° C. for 1 h and then at 100° C. for 17 h. Additional 3-dimethylamino-acrylonitrile (0.1 mL, 0.87 mmol) was added to the reaction and stirring was continued at 100° C. for 22 h. The solvent was removed under a stream of N2 and the residue was directly purified by reversed phase HPLC (20% MeCN/H2O+0.1% TFA) to give a red semisolid that was neutralized by dissolving in EtOAc (5 mL) and washing with saturated aqueous NaHCO3 (2×5 mL). The organic phase was dried with Na2SO4 and concentrated to give 29 mg of the title compound as a red semisolid, m/z 251.44 [M+1]+. The reaction was stirred for 1.5 h at 60° C. stirring was continued at 60° C. for 1 h at 100° C. for 17 h stirring was continued at 100° C. for 22 h The solvent was removed under a stream of N2 the residue was directly purified by reversed phase HPLC (20% MeCN/H2O+0.1% TFA) to give a red semisolid that washing with saturated aqueous NaHCO3 (2×5 mL) The organic phase was dried with Na2SO4 concentrated

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

Procedure: 3-Dimethylamino-acrylonitrile (0.05 mL, 0.50 mmol) was dissolved in EtOH (1 mL) and NaOEt solution (21 wt % in EtOH, 0.19 mL, 0.50 mmol) was added. This was stirred for 1 h and then (1-Carbamimidoyl-cyclopropyl)-carbamic acid tert-butyl ester hydrochloride (50 mg, 0.25 mmol) was added. The reaction was stirred for 1.5 h at 60° C. and then solid NH4Cl (27 mg, 0.50 mmol) and NH3 (7 M in MeOH, 0.50 mL, 3.5 mmol) were added and stirring was continued at 60° C. for 1 h and then at 100° C. for 17 h. Additional 3-dimethylamino-acrylonitrile (0.1 mL, 0.87 mmol) was added to the reaction and stirring was continued at 100° C. for 22 h. The solvent was removed under a stream of N2 and the residue was directly purified by reversed phase HPLC (20% MeCN/H2O+0.1% TFA) to give a red semisolid that was neutralized by dissolving in EtOAc (5 mL) and washing with saturated aqueous NaHCO3 (2×5 mL). The organic phase was dried with Na2SO4 and concentrated to give 29 mg of the title compound as a red semisolid, m/z 251.44 [M+1]+. The reaction was stirred for 1.5 h at 60° C. stirring was continued at 60° C. for 1 h at 100° C. for 17 h stirring was continued at 100° C. for 22 h The solvent was removed under a stream of N2 the residue was directly purified by reversed phase HPLC (20% MeCN/H2O+0.1% TFA) to give a red semisolid that washing with saturated aqueous NaHCO3 (2×5 mL) The organic phase was dried with Na2SO4 concentrated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (3E)-1-Chloro-4-ethoxy-1,1-difluorobut-3-en-2-one (7.36 g, 40 mmol) was dissolved in dry toluene (40 mL) and treated with 3-dimethylaminoacrylonitrile (4.61 g, 48 mmol) at room temperature. The solution was heated at about 100° C. for 3.5 hr. The solvent was then removed under reduced pressure and the remaining mixture was re-dissolved in DMF (20 mL), treated with ammonium acetate (4.62 g, 60 mmol) and stirred at room temperature overnight. Water was added to the reaction mixture and the resulting mixture was extracted with ether-CH2CH2 (1:2, v/v) twice. The combined organic layer was washed with brine, dried, filtered and concentrated. The residue was purified on silica gel to give 3.1 g of 6-[chloro(difluoro)methyl]nicotinonitrile (A) as light colored oil in 41% yield. GC-MS: mass calcd for C7H3ClF2N2 [M]+ 188. Found 188. The solvent was then removed under reduced pressure the remaining mixture was re-dissolved in DMF (20 mL) the resulting mixture was extracted with ether-CH2CH2 (1:2 The combined organic layer was washed with brine dried filtered concentrated The residue was purified on silica gel

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

Procedure: A mixture of 3-phenoxybenzoyl chloride (6.9 g), 3-dimethylaminoacrylonitrile (2 g) and triethylamine (4 g) in dry dioxan (50 ml) was refluxed for 6 hours under a nitrogen atmosphere. After standing at room temperature overnight, the dioxan was evaporated in vacuo and dichloromethane added to the residue. The extracts were washed with water, 2N NaOH, brine and finally dried over MgSO4. After filtration and evaporation of the dichloromethane, the residue was purified on a silica gel column using 5% methanol-dichloromethane as eluant to give the title compound (2.2 g, 36%) as a white solid of m.p. 80°-82 C. (identical to that described in Example 46). was refluxed for 6 hours under a nitrogen atmosphere the dioxan was evaporated in vacuo and dichloromethane added to the residue The extracts were washed with water, 2N NaOH, brine finally dried over MgSO4 After filtration and evaporation of the dichloromethane the residue was purified on a silica gel column

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

Procedure: A mixture of 3-phenoxybenzoyl chloride (6.9 g), 3-dimethylaminoacrylonitrile (2 g) and triethylamine (4 g) in dry dioxan (50 ml) was refluxed for 6 hours under a nitrogen atmosphere. After standing at room temperature overnight, the dioxan was evaporated in vacuo and dichloromethane added to the residue. The extracts were washed with water, 2N NaOH, brine and finally dried over MgSO4. After filtration and evaporation of the dichloromethane, the residue was purified on a silica gel column using 5% methanol-dichloromethane as eluant to give the title compound (2.2 g, 36%) as a white solid of m.p. 80°-82 C. (identical to that described in Example 46). was refluxed for 6 hours under a nitrogen atmosphere the dioxan was evaporated in vacuo and dichloromethane added to the residue The extracts were washed with water, 2N NaOH, brine finally dried over MgSO4 After filtration and evaporation of the dichloromethane the residue was purified on a silica gel column