3-oxobutanenitrile

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

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of α-acetylacetonitrile (2 g, 12.6 mmol) in ethanol was added triethylamine (1.05 mL, 7.6 mmol) and hydrazine dihydrochloride (1.6 g, 15.1 mmol). The mixture was heated to 80° C. and stirred for 2 h before cooling to rt. The volatile materials were removed in vacuo. The crude residue was purified by flash chromatography (gradient: 5% methanol in CH2Cl2 to 10% methanol in CH2Cl2) to provide 1.92 g of 3-methyl-4-phenyl-1H-pyrazol-5-amine (11.1 mmol, 88% yield). 1H NMR (400 MHz, CDCl3): δ7.40 (m, 2H), 7.34-7.32 (m, 2H), 7.27-7.23 (m, 1H), 3.71 (br s, 2H), 2.30 (s, 3H); MS (EI) for C10H11N3: 174 (MH+). before cooling to rt The volatile materials were removed in vacuo The crude residue was purified by flash chromatography (gradient: 5% methanol in CH2Cl2 to 10% methanol in CH2Cl2)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of α-acetylacetonitrile (2 g, 12.6 mmol) in ethanol was added triethylamine (1.05 mL, 7.6 mmol) and hydrazine dihydrochloride (1.6 g, 15.1 mmol). The mixture was heated to 80° C. and stirred for 2 h before cooling to rt. The volatile materials were removed in vacuo. The crude residue was purified by flash chromatography (gradient: 5% methanol in CH2Cl2 to 10% methanol in CH2Cl2) to provide 1.92 g of 3-methyl-4-phenyl-1H-pyrazol-5-amine (11.1 mmol, 88% yield). 1H NMR (400 MHz, CDCl3): δ7.40 (m, 2H), 7.34-7.32 (m, 2H), 7.27-7.23 (m, 1H), 3.71 (br s, 2H), 2.30 (s, 3H); MS (EI) for C10H11N3: 174 (MH+). before cooling to rt The volatile materials were removed in vacuo The crude residue was purified by flash chromatography (gradient: 5% methanol in CH2Cl2 to 10% methanol in CH2Cl2)

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

Procedure: To a suspension of 10.5 g of sodium salt of cyanoacetone in 200 ml of dimethylformamide 9.0 ml of carbon disulphide are gradually added while stirring cooling in ice and keeping under nitrogen, succeeded by 4.5 g of sodium hydride dispersion. After stirring for an hour with cooling, 8.4 ml of chloroacetone are added dropwise under the same reaction conditions. After stirring for another hour, 0.4 g of powdered NaOH are added and finally, after again stirring for another 0.5 hour, 8.0 ml of ethyl iodide under the same conditions. After stirring, the reaction mixture for again another hour and leaving to stand overnight it is poured 1 l of ice water and extracted with diethyl ether. The organic phase is washed with water three times, dried, treated with charcoal, filtered and evaporated. After recrystallisation from isopropanol, the residue yields the desired product in a yield of 9.54 g; melting-point 51°-52° C. are gradually added cooling in ice After stirring for an hour with cooling After stirring for another hour finally, after again stirring for another 0.5 hour After stirring the reaction mixture for again another hour leaving extracted with diethyl ether The organic phase is washed with water three times dried treated with charcoal filtered evaporated After recrystallisation from isopropanol

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

Procedure: A mixture of acetoacetonitrile (41 g, 493 mmol), t-butoxybis(dimethyl amino)methane (86 g, 493 mmol) and DMF-DMA (263 mL, 1.97 mol) was heated at 100° C. overnight and evaporated to remove the volatiles. The residue was triturated with hexanes/ether (1:1) and the solids were collected by filtration and washed with hexanes/ether (1:1) and a minimum amount of EtOAc to give 64.3 g (67%) of 5-(dimethylamino)-2-[(dimethylamino)methylene]-3-oxopent-4-enenitrile as a light yellow solid, which was used for the next step without further purification. evaporated to remove the volatiles The residue was triturated with hexanes/ether (1:1) the solids were collected by filtration washed with hexanes/ether (1:1)

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

Procedure: Scheme 2 below shows an alternative procedure for the preparation of 3-oxo-butyronitrile ii. This alternative procedure involves conversion of acetic acid vi to the corresponding acid chloride by reaction with a chlorinating agent such as thionyl chloride (SOCl2) followed by reaction of the anion of tert-butylcyanoacetate prepared by reaction of tert-butylcyanoacetate with a base such as sodium hydride (NaH) in a solvent such as THF to give 2-cyano-3-oxo-butanoic acid tert-butyl ester vii, which undergoes deprotection of the ester and decarboxylation to give 3-oxo-butyronitrile ii by reaction with an acid such as trifluoroacetic acid (TFA).

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of α-acetylacetonitrile (2 g, 12.6 mmol) in ethanol was added triethylamine (1.05 mL, 7.6 mmol) and hydrazine dihydrochloride (1.6 g, 15.1 mmol). The mixture was heated to 80° C. and stirred for 2 h before cooling to rt. The volatile materials were removed in vacuo. The crude residue was purified by flash chromatography (gradient: 5% methanol in CH2Cl2 to 10% methanol in CH2Cl2) to provide 1.92 g of 3-methyl-4-phenyl-1H-pyrazol-5-amine (11.1 mmol, 88% yield). 1H NMR (400 MHz, CDCl3): δ7.40 (m, 2H), 7.34-7.32 (m, 2H), 7.27-7.23 (m, 1H), 3.71 (br s, 2H), 2.30 (s, 3H); MS (EI) for C10H11N3: 174 (MH+). before cooling to rt The volatile materials were removed in vacuo The crude residue was purified by flash chromatography (gradient: 5% methanol in CH2Cl2 to 10% methanol in CH2Cl2)

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

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

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

Procedure: 3-Oxo-butyronitrile (4.94 g, 60.9 mmol), triethylorthoformate (15.0 mL, 90.2 mmol), and acetic anhydride (0.3 mL, 2.7 mmol) were warmed to about 95-115° C. for about 1 hours, over which time a distillate was collected and discarded. After cooling the resultant mixture to room temperature, hexanes were added and a precipitate formed. The resultant mixture was filtered and the solids washed with hexanes, to yield the title compound as a solid. was collected hexanes were added a precipitate formed The resultant mixture was filtered the solids washed with hexanes

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

Procedure: 3-Oxo-butyronitrile (113 g, 1.36 mol) and DMF.DMA (215 g, 1.81 mol) were heated to 80° C. for two hours. The solvents were then removed under vacuum to yield a solid. The solid was partitioned between ethyl acetate (1.5 L) and saturated sodium bicarbonate solution (1 L). The layers were separated and the aqueous layer was extracted with ethyl acetate (1.5 L). The organic layers were combined and the solvent removed under vacuum to yield the title compound as a solid. The solvents were then removed under vacuum to yield a solid The solid was partitioned between ethyl acetate (1.5 L) and saturated sodium bicarbonate solution (1 L) The layers were separated the aqueous layer was extracted with ethyl acetate (1.5 L) the solvent removed under vacuum