2-(benzhydrylideneamino)acetonitrile

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

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

Procedure: A mixture of benzophenone imine (25 g, 0.138 mol, Aldrich) and aminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) in dichloromethane (1000 mL) was stirred in a 2 L Erlenmeyer flask under nitrogen at room temperature for five days. The reaction mixture was filtered to remove the precipitated ammonium chloride and the filtrate was evaporated to dryness in vacuo. The resulting residue was dissolved in ether (400 mL) and washed with water (200 mL) and brine. After drying over magnesium sulfate, the solution was evaporated to give (benzhydrylideneamino)-acetonitrile (47.89 g). The reaction mixture was filtered to remove the precipitated ammonium chloride the filtrate was evaporated to dryness in vacuo The resulting residue was dissolved in ether (400 mL) washed with water (200 mL) and brine After drying over magnesium sulfate the solution was evaporated

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

Procedure: To a solution of 2-(diphenylmethyleneamino)acetonitrile (1.21 g, 5.47 mmol, 1.0 equiv) in CH2Cl2 (9.12 mL) was added 4-fluorobenzyl bromide (0.75 mL, 6.02 mmol, 1.1 equiv), benzyltrimethylammonium chloride (0.10 g, 0.547 mmol, 0.1 equiv), and NaOH (0.99 mL of a 10 M aqueous solution, 9.85 mmol, 1.8 equiv). The reaction was stirred vigorously for 18 h, at which time TLC analysis indicated complete consumption of the starting nitrile. The reaction was added to water and extracted with CH2Cl2 (×3). The combined CH2Cl2 extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel chromatography (5-30% ethyl acetate/hexane) to provide the title compound (1.65 g, 92% yield) as a viscous yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.54-7.65 (m, 2H), 7.38-7.48 (m, 4H), 7.31-7.38 (m, 2H), 7.00-7.09 (m, 2H), 6.89-6.97 (m, 2H), 6.84 (d, J=6.30 Hz, 2H), 4.35 (dd, J=7.81, 6.04 Hz, 1H), 3.10-3.29 (m, 2H); LCMS (ES+, (M+H)+) m/z 329.25. consumption of the starting nitrile The reaction was added to water extracted with CH2Cl2 (×3) The combined CH2Cl2 extracts were dried (Na2SO4) concentrated in vacuo The crude product was purified by silica gel chromatography (5-30% ethyl acetate/hexane)

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

Procedure: A mixture of benzophenone imine (25 g, 0.138 mol, Aldrich) and aminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) in dichloromethane (1000 mL) was stirred in a 2 L Erlenmeyer flask under nitrogen at room temperature for five days. The reaction mixture was filtered to remove the precipitated ammonium chloride and the filtrate was evaporated to dryness in vacuo. The resulting residue was dissolved in ether (400 mL) and washed with water (200 mL) and brine. After drying over magnesium sulfate, the solution was evaporated to give (benzhydrylideneamino)-acetonitrile (47.89 g). The reaction mixture was filtered to remove the precipitated ammonium chloride the filtrate was evaporated to dryness in vacuo The resulting residue was dissolved in ether (400 mL) washed with water (200 mL) and brine After drying over magnesium sulfate the solution was evaporated

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

Procedure: To a suspension of sodium hydride (2.62 g) in dimethylformamide (100 ml) at 0° C. was slowly added a solution of [(diphenylmethylidene)amino]acetonitrile (13.20 g) in 40 ml of dimethylformamide. The reaction temperature varied between 2 and 8° C. during the addition. The color went from yellow to brown with gas evolution. The reaction mixture was stirred at 0° C. for 10 more minutes then 4-(bromomethyl)-3-fluorobenzonitrile from step 1 (12.72 g) was added very quickly in 60 ml of dimethylformamide. The temperature rose to 27° C. and the cold bath was removed. The reaction was stirred for 4 h. The flask content was poured into sodium dihydrogen phosphate solution (300 ml) and icy water (1.4 L). The mixture turned yellow and a big lump formed along with very small amounts of fine powder. The fine solid was filtered and the lump kept in the Erlenmeyer. The lump was dissolved in ether (500 ml) and put in a separating funnel along with water (200 ml). The phases were separated and the organic layer was washed with brine (100 ml) and dried over magnesium sulfate. The organic phase is concentrated under reduced pressure to give 4-{2-cyano-2-[(diphenylmethylene)amino]ethyl}-3-fluorobenzonitrile an orange solid that was used as such in the next step. The reaction temperature varied between 2 and 8° C. during the addition rose to 27° C. the cold bath was removed The reaction was stirred for 4 h The flask content was poured into sodium dihydrogen phosphate solution (300 ml) and icy water (1.4 L) a big lump formed along with very small amounts of fine powder The fine solid was filtered The lump was dissolved in ether (500 ml) put in a separating funnel along with water (200 ml) The phases were separated the organic layer was washed with brine (100 ml) dried over magnesium sulfate The organic phase is concentrated under reduced pressure

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

Procedure: To a suspension of 60% sodium hydride (4.0 g) in dry dimethylformamide at 0-2° C. under nitrogen was dropwise added a solution of N-(diphenylmethylene)aminoacetonitrile (11.1 g) in dry dimethylformamide (60 ml) and the mixture was stirred for 1 hour at 0° C., 2,3-Dichloro-5-trifluoromethyl pyridine (7 ml) in dry dimethylformamide (20 ml) was added dropwise over 10 minutes. The mixture was stirred at 0° C. for 30 minutes and then warmed to 22° C. over 3 hours. The mixture was re-cooled to less than 10° C., and ethanol (3 ml) was added dropwise and stirring continued for 15 minutes. The mixture was poured as a thin stream into a stirred mixture of diethyl ether (500 ml) and 20% saturated aqueous ammonium chloride solution. The phases were separated and the organic phase was washed with 20% saturated aqueous ammonium chloride solution (2×150 ml). The organic phase was dried over anhydrous magnesium sulphate, filtered and evaporated onto flash silica (50 g). Chromatography over silica eluting with 5-20% diethyl ether in 40/60° Bp petrol gave the title compound, m.p. 108-110° C. The mixture was stirred at 0° C. for 30 minutes warmed to 22° C. over 3 hours The mixture was re-cooled to less than 10° C. stirring continued for 15 minutes The phases were separated the organic phase was washed with 20% saturated aqueous ammonium chloride solution (2×150 ml) The organic phase was dried over anhydrous magnesium sulphate filtered evaporated onto flash silica (50 g)

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

Procedure: A mixture of benzophenone imine (25 g, 0.138 mol, Aldrich) and aminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) in dichloromethane (1000 ml) was stirred in a 2 L Erlenmeyer flask under nitrogen at room temperature for 5 days. The reaction mixture was filtered to remove the precipitated ammonium chloride and the filtrate was evaporated to dryness in vacuo. The resulting residue was dissolved in ether (400 ml) washed with water (200 ml) and brine. After drying over magnesium sulfate the solution was evaporated to give (benzhydrylideneamino)-acetonitrile (47.89 g). The reaction mixture was filtered to remove the precipitated ammonium chloride the filtrate was evaporated to dryness in vacuo The resulting residue was dissolved in ether (400 ml) washed with water (200 ml) and brine After drying over magnesium sulfate the solution was evaporated

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

Procedure: A mixture of benzophenone imine (25 g, 0.138 mol, Aldrich) and aminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) in dichloromethane (1000 ml) was stirred in a 2 L Erlenmeyer flask under nitrogen at room temperature for 5 days. The reaction mixture was filtered to remove the precipitated ammonium chloride and the filtrate was evaporated to dryness in vacuo. The resulting residue was dissolved in ether (400 ml) washed with water (200 ml) and brine. After drying over magnesium sulfate the solution was evaporated to give (benzhydrylideneamino)-acetonitrile (47.89 g). The reaction mixture was filtered to remove the precipitated ammonium chloride the filtrate was evaporated to dryness in vacuo The resulting residue was dissolved in ether (400 ml) washed with water (200 ml) and brine After drying over magnesium sulfate the solution was evaporated

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

Procedure: A solution of N-(diphenylmethylene)aminoacetonitrile (5.84 g, 26.0 mmol, commercially available from Aldrich) in THF (20 mL) and hexamethylphosphoramide (HMPA) (5.43 mL, 31 mmol) at −78° C. was reacted with lithium diisopropylamide (LDA) (15.4 mL of a 2M soln in heptane/THF/ethylbenzene) (commercially available from Aldrich). After 1 h, 5-(1-chloro-ethyl)-quinoline (Intermediate E1) (4.15 g, 21.7 mmol) in THF (15 mL) was introduced by dropwise addition. The mixture was kept at −78° C. for 5 m before removal of the cold bath. After 5 m, the mixture was quenched with cold water and extracted with ethyl acetate (3×). The organic solution was dried over MgSO4, filtered and concentrated to give 2-(benzhydrylidene-amino)-3-quinolin-5-yl-butyronitrile that was used in the next step without further purification. The mixture was kept at −78° C. for 5 m before removal of the cold bath After 5 m, the mixture was quenched with cold water extracted with ethyl acetate (3×) The organic solution was dried over MgSO4 filtered concentrated

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

Procedure: A solution of N-(diphenylmethylene)aminoacetonitrile (5.84 g, 26.0 mmol, commercially available from Aldrich) in THF (20 mL) and hexamethylphosphoramide (HMPA) (5.43 mL, 31 mmol) at −78° C. was reacted with lithium diisopropylamide (LDA) (15.4 mL of a 2M soln in heptane/THF/ethylbenzene) (commercially available from Aldrich). After 1 h, 5-(1-chloro-ethyl)-quinoline (Intermediate E1) (4.15 g, 21.7 mmol) in THF (15 mL) was introduced by dropwise addition. The mixture was kept at −78° C. for 5 m before removal of the cold bath. After 5 m, the mixture was quenched with cold water and extracted with ethyl acetate (3×). The organic solution was dried over MgSO4, filtered and concentrated to give 2-(benzhydrylidene-amino)-3-quinolin-5-yl-butyronitrile that was used in the next step without further purification. The mixture was kept at −78° C. for 5 m before removal of the cold bath After 5 m, the mixture was quenched with cold water extracted with ethyl acetate (3×) The organic solution was dried over MgSO4 filtered concentrated

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

Procedure: A mixture of benzophenone imine (25 g, 0.138 mol, Aldrich) and aminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) in dichloromethane (1000 mL) was stirred in a 2 L Erlenmeyer flask under nitrogen at room temperature for five days. The reaction mixture was filtered to remove the precipitated ammonium chloride and the filtrate was evaporated to dryness in vacuo. The resulting residue was dissolved in ether (400 mL) and washed with water (200 mL) and brine. After drying over magnesium sulfate, the solution was evaporated to give (benzhydrylideneamino)-acetonitrile (47.89 g). The reaction mixture was filtered to remove the precipitated ammonium chloride the filtrate was evaporated to dryness in vacuo The resulting residue was dissolved in ether (400 mL) washed with water (200 mL) and brine After drying over magnesium sulfate the solution was evaporated

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

Procedure: A mixture of benzophenone imine (25 g, 0.138 mol, Aldrich) and aminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) in dichloromethane (1000 mL) was stirred in a 2 L Erlenmeyer flask under nitrogen at room temperature for five days. The reaction mixture was filtered to remove the precipitated ammonium chloride and the filtrate was evaporated to dryness in vacuo. The resulting residue was dissolved in ether (400 mL) and washed with water (200 mL) and brine. After drying over magnesium sulfate, the solution was evaporated to give (benzhydrylideneamino)-acetonitrile (47.89 g). The reaction mixture was filtered to remove the precipitated ammonium chloride the filtrate was evaporated to dryness in vacuo The resulting residue was dissolved in ether (400 mL) washed with water (200 mL) and brine After drying over magnesium sulfate the solution was evaporated