ethyl 2-(1-benzylpiperidin-4-ylidene)-2-cyanoacetate

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: 1,3-Dimethyl-5-bromobenzene (15.6 g) was dissolved in anhydrous diethyl ether (60 ml) and added to a vigorously stirred mixture of magnesium turnings (2.2 g) and 2-3 iodine crystals under a nitrogen atmosphere. Gentle heating was applied to initiate formation of the Grignard reagent and once the spontaneous refluxing had subsided the mixture was heated under reflux for a further 30 minutes. The mixture was cooled in an ice-bath and a solution of ethyl 2-(1-benzylpiperidin-4-ylidene)-2-cyanoacetate (8.0 g) (see Preparation 2) in anhydrous tetrahydrofuran (80 ml) added over 20 minutes. The mixture was stirred at 0° C. for 15 minutes before being left to stand at room temperature for 3 days. The mixture was then poured into saturated aqueous ammonium chloride solution (300 ml) and extracted twice with diethyl ether. The organic extracts were combined and the solvent removed under reduced pressure to give a residue which was chromatographed on silca gel eluting with a solvent gradient of 3:0 changing to 3:1, by volume, dichloromethane:diethyl ether to give the title compound (4.7 g) as an oil. Gentle heating once the spontaneous refluxing was heated under reflux for a further 30 minutes The mixture was cooled in an ice-bath before being left to stand at room temperature for 3 days extracted twice with diethyl ether the solvent removed under reduced pressure to give a residue which was chromatographed on silca gel eluting with a solvent gradient of 3:0 changing to 3:1, by volume, dichloromethane

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

Procedure: 2-Bromonaphthalene (26 g) was dissolved in anhydrous diethyl ether (100 ml) and 1/5 of this solution added to a vigourously stirred mixture of magnesium turnings (3.3 g) and 2-3 iodine crystals under a nitrogen atmosphere. Gentle heating was applied to initiate formation of the Grignard reagent since it proved difficult to maintain spontaneous refluxing. The remainder of the 2-bromonaphthalene solution was added in 4 portions, allowing the refluxing to subside after each addition, and the mixture finally heated under reflux for 1 hour after which time two dark organic phases had formed. The mixture was cooled in an ice-bath and anhydrous tetrahydrofuran (50 ml) added followed by dropwise addition of a solution of ethyl 2-(1-benzylpiperidin-4-ylidene)-2-cyanoacetate (12 g) (see Preparation 2) in tetrahydrofuran (100 ml). The single phase mixture was stirred at 0° C. for 30 minutes before being left to stand at room temperature overnight. The mixture was then poured into saturated aqueous ammonium chloride solution (450 ml) and extracted twice with diethyl ether. The organic extracts were combined and the solvent removed under reduced pressure to give a residue which was chromatographed on silica gel eluting with a solvent gradient of 4:0 changing to 4:1, by volume, dichloromethane:diethyl ether to give the title compound (5.9 g) as an oil. Gentle heating to maintain spontaneous refluxing after each addition the mixture finally heated under reflux for 1 hour after which time two dark organic phases had formed The mixture was cooled in an ice-bath before being left to stand at room temperature overnight extracted twice with diethyl ether the solvent removed under reduced pressure to give a residue which was chromatographed on silica gel eluting with a solvent gradient of 4:0 changing to 4:1, by volume, dichloromethane

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

Procedure: N-Benzylpiperidin-4-one (25 g), ethyl cyanoacetate (16.4 g), glacial acetic acid (6 ml) and ammonium acetate (2.54 g) were heated together in toluene (200 ml), with removal of water using a Dean and Stark apparatus, for 90 minutes. The mixture was cooled, a further amount of toluene (100 ml) added and the solution washed sequentially with water (100 ml) and brine (100 ml) at which point a red oily product precipitated. The phases were separated and the oily product dissolved in dichloromethane. The toluene and dichloromethane solutions were combined and the solvents removed under reduced pressure to give a residue. The residue was dissolved in dichloromethane and washed sequentially with water and saturated aqueous sodium hydrogen carbonate solution before removal of the solvent under reduced pressure. The crude product was chromatographed on silica gel eluting with 98:2, by volume, dichloromethane:methanol to give the title compound (30.8 g) as an oil. The mixture was cooled the solution washed sequentially with water (100 ml) and brine (100 ml) at which point a red oily product precipitated The phases were separated the oily product dissolved in dichloromethane the solvents removed under reduced pressure to give a residue washed sequentially with water and saturated aqueous sodium hydrogen carbonate solution before removal of the solvent under reduced pressure The crude product was chromatographed on silica gel eluting with 98:2, by volume, dichloromethane

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

Procedure: To a solution of (1-benzyl-piperidin-4-ylidene)-cyano-acetic acid ethyl ester (112.9 g, 0.40 mol) in EtOH (500 ml) and H2O (100 ml), potassium cyanide (64.6 g, 0.99 mol) is added at ambient temperature. The reaction mixture is stirred at 65 C.° for 24 h. After removal of EtOH, H2O is added to the residue. The waster phase is extracted with diethyl ether. The combined extracts are washed with H2O and brine, dried over sodium sulfate and evaporated down to give 77.7 g of 1-benzyl-4-cyanomethyl-piperidine-4-carbonitrile. After removal of EtOH, H2O is added to the residue The waster phase is extracted with diethyl ether The combined extracts are washed with H2O and brine dried over sodium sulfate evaporated down

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

Procedure: To a solution of 1-benzyl-piperidin-4-one (75.1 g, 0.40 mol) in toluene (400 ml), cyano-acetic acid ethyl ester (50.6 ml, 0.48 mol) and acetic acid (18.2 ml, 0.32 mol) are added at ambient temperature. The reaction mixture is refluxed for 4 h, quenched with ice-water and extracted with diethyl ether. The combined extracts are washed with H2O, brine and dried over sodium sulphate to give (1-benzyl-piperidin-4-ylidene)-cyano-acetic acid ethyl ester in quantitative yield. The reaction mixture is refluxed for 4 h quenched with ice-water extracted with diethyl ether The combined extracts are washed with H2O, brine dried over sodium sulphate

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

Procedure: To a solution of 1-benzyl-piperidin-4-one (75.1 g, 0.40 mol) in toluene (400 ml), cyano-acetic acid ethyl ester (50.6 ml, 0.48 mol) and acetic acid (18.2 ml, 0.32 mol) are added at ambient temperature. The reaction mixture is refluxed for 4 h, quenched with ice-water and extracted with diethyl ether. The combined extracts are washed with H2O, brine and dried over sodium sulphate to give (1-benzyl-piperidin-4-ylidene)-cyano-acetic acid ethyl ester in quantitative yield. The reaction mixture is refluxed for 4 h quenched with ice-water extracted with diethyl ether The combined extracts are washed with H2O, brine dried over sodium sulphate

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

Procedure: To a solution of (1-benzyl-piperidin-4-ylidene)-cyano-acetic acid ethyl ester (112.9 g, 0.40 mol) in EtOH (500 ml) and H2O (100 ml), potassium cyanide (64.6 g, 0.99 mol) is added at ambient temperature. The reaction mixture is stirred at 65 C.° for 24 h. After removal of EtOH, H2O is added to the residue. The waster phase is extracted with diethyl ether. The combined extracts are washed with H2O and brine, dried over sodium sulfate and evaporated down to give 77.7 g of 1-benzyl-4-cyanomethyl-piperidine-4-carbonitrile. After removal of EtOH, H2O is added to the residue The waster phase is extracted with diethyl ether The combined extracts are washed with H2O and brine dried over sodium sulfate evaporated down

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

Procedure: To a solution of 1-benzyl-piperidin-4-one (75.1 g, 0.40 mol) in toluene (400 ml), cyano-acetic acid ethyl ester (50.6 ml, 0.48 mol) and acetic acid (18.2 ml, 0.32 mol) are added at ambient temperature. The reaction mixture is refluxed for 4 h, quenched with ice-water and extracted with diethyl ether. The combined extracts are washed with H2O, brine and dried over sodium sulphate to give (1-benzyl-piperidin-4-ylidene)-cyano-acetic acid ethyl ester in quantitative yield. The reaction mixture is refluxed for 4 h quenched with ice-water extracted with diethyl ether The combined extracts are washed with H2O, brine dried over sodium sulphate

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

Procedure: To a solution of 1-benzyl-piperidin-4-one (75.1 g, 0.40 mol) in toluene (400 ml), cyano-acetic acid ethyl ester (50.6 ml, 0.48 mol) and acetic acid (18.2 ml, 0.32 mol) are added at ambient temperature. The reaction mixture is refluxed for 4 h, quenched with ice-water and extracted with diethyl ether. The combined extracts are washed with H2O, brine and dried over sodium sulphate to give (1-benzyl-piperidin-4-ylidene)-cyano-acetic acid ethyl ester in quantitative yield. The reaction mixture is refluxed for 4 h quenched with ice-water extracted with diethyl ether The combined extracts are washed with H2O, brine dried over sodium sulphate