ethyl 2-cyanopropanoate

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: Using the procedure of Example 9 with 3,616 parts of ethyl cyanoacetate, 10 parts of hydroquinone, 4.3 parts of piperidine, 45 parts of a 3% palladium on charcoal catalyst and 6,500 parts of toluene, treated over 4 hours with 4,000 parts of a solution of 3,000 parts of formalin (36%), 225 parts of glacial acetic acid, 258 parts of piperidine and water to give a total of 4,500 parts, gave 1,488 parts of crude ethyl 2 cyanopropionate which on redistillation yielded 1198.5 parts of a purified product of boiling point 83°-85°C/12-13 mm. of mercury. to give a total of 4,500 parts

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

Procedure: 904 Parts of ethyl cyano acetate, 10 parts of hydroquinone, 4.3 parts of piperidine, 45 parts of 3% palladium on charcoal catalyst and 6,500 parts of toluene are mixed at 60°C under an atmosphere of hydrogen maintained at 30 p.s.i.g., 1,000 Parts of a solution made from 1,000 parts of formalin (36%), 75 parts of acetic acid, 86 parts of piperidine and water to give a total of 1,500 parts are added at a uniform rate over 3 hours the temperature being maintained at 60°-65°C. The reaction mixture is cooled, filtered and the toluene layer separated. Distillation under reduced pressure of the toluene layer yields 374.7 parts of ethyl 2-cyanopropionate boiling point 91°-118°C/20 mm. of mercury. maintained at 30 p.s.i.g to give a total of 1,500 parts are added at a uniform rate over 3 hours the temperature being maintained at 60°-65°C The reaction mixture is cooled filtered the toluene layer separated Distillation under reduced pressure of the toluene layer

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

Procedure: 904 Parts of ethyl cyano acetate, 10 parts of hydroquinone, 4.3 parts of piperidine, 45 parts of 3% palladium on charcoal catalyst and 6,500 parts of toluene are mixed at 60°C under an atmosphere of hydrogen maintained at 30 p.s.i.g., 1,000 Parts of a solution made from 1,000 parts of formalin (36%), 75 parts of acetic acid, 86 parts of piperidine and water to give a total of 1,500 parts are added at a uniform rate over 3 hours the temperature being maintained at 60°-65°C. The reaction mixture is cooled, filtered and the toluene layer separated. Distillation under reduced pressure of the toluene layer yields 374.7 parts of ethyl 2-cyanopropionate boiling point 91°-118°C/20 mm. of mercury. maintained at 30 p.s.i.g to give a total of 1,500 parts are added at a uniform rate over 3 hours the temperature being maintained at 60°-65°C The reaction mixture is cooled filtered the toluene layer separated Distillation under reduced pressure of the toluene layer

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

Procedure: Following the procedure of Example 5 omitting the 0.25 parts of piperidine and 0.025 parts of hydroquinone and adding 9.6 parts of the formalin, piperidine and acetic acid solution in place of the 8.6 parts of Example 5 over 151/4 hours gave 6.8 parts of ethyl 2-cyanopropionate of boiling point 82-90°C/8 mm. of mercury.

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred suspension of anhydrous K2CO3 (79.5 g, 575 mmol) in anhydrous DMF (365 mL) is heated to 150° C. and treated with ethyl 2-cyanopropionate (71.8 g, 564 mmol) via addition funnel over 20 min. The reaction is allowed to cool gradually to ambient temperature over 90 min, and then cooled further (to ca. 12° C.) with a mild ice bath. The yellow reaction mixture is at this point treated with 3,4,5-trifluoronitrobenzene (94.8 g, 535 mmol) via addition funnel over 20 min. The deep purple reaction mixture is stirred overnight at ambient temperature. The deep green reaction mixture is then poured into ice/water (950 mL) and made acidic (from pH 11 to pH 5) with 20% v/v H2SO4/H2O while stirring vigorously and ensuring ample cooling with ice bath. The mixture is then chilled in a refrigerator for 2 h. The amber-brown liquid is extracted with Et2O (1.2 L), taking care to dissolve the large clumps of green-black solid (which accounts for a significant amount of the product). The ethereal layer is washed with H2O (250 mL), saturated aqueous NaHCO3 (2×150 mL), and H2O (2×150 mL), dried over MgSO4, and concentrated under reduced pressure. Trituration (cold hexanes) affords the title compound as a pale tan solid in 77% yield; 1H NMR (400 MHz, CDCl3) δ 7.86 (m, 2H), 4.35 (q, 2H), 2.06 (t, 3H), 1.31 (t, 3H). to cool gradually to ambient temperature over 90 min cooled further (to ca. 12° C.) with a mild ice bath while stirring vigorously ensuring ample cooling with ice bath The mixture is then chilled in a refrigerator for 2 h The amber-brown liquid is extracted with Et2O (1.2 L) to dissolve the large clumps of green-black solid (which The ethereal layer is washed with H2O (250 mL), saturated aqueous NaHCO3 (2×150 mL), and H2O (2×150 mL) dried over MgSO4 concentrated under reduced pressure

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

Procedure: To a 100 mL flask with a Dean-Stark condenser and an argon inlet was added N-Boc-L-serine tert-butyl ester 2 (5.00 g, 19.1 mmol), ethyl-2-cyanopropionate (3.65 g, 28.7 mmol), p-toluenesulfonic acid monohydrate (0.200 g, 1.05 mmol) and anhydrous toluene (60 mL). The reaction mixture was heated to reflux while stirring. Solvent was removed through the Dean-Stark trap and replaced with an equal amount of fresh toluene. After refluxing for 6 h, the reaction mixture was cooled to room temperature. The solution was washed once with saturated aqueous NaHCO3, twice with H2O, and twice with saturated aqueous NaCl. The organic layer was separated, dried over anhydrous MgSO4, and concentrated to a viscous yellow oil. 1H NMR (CDCl3): δ 1.43 (m, 21H, CH3—CH—NH—, 2 (CH3)3), 3.25 (s, 1H, CH3-CH—CN), 3.85 (t, 2H, CO2, —CH2—CH—), 3.85 (t, 2H, CO2—CH2—CO2Bu), 4.25 (s, 1H, NH—CH—CH2—), 5.55 (d, 1H, NH). This material can be converted to the cyanoacrylic monomer by following the general procedure set forth above for the alanine-derived monomer. The reaction mixture was heated to reflux Solvent was removed through the Dean-Stark trap After refluxing for 6 h The solution was washed once with saturated aqueous NaHCO3, twice with H2O The organic layer was separated dried over anhydrous MgSO4 concentrated to a viscous yellow oil

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred suspension of anhydrous K2CO3 (79.5 g, 575 mmol) in anhydrous DMF (365 mL) is heated to 150° C. and treated with ethyl 2-cyanopropionate (71.8 g, 564 mmol) via addition funnel over 20 min. The reaction is allowed to cool gradually to ambient temperature over 90 min, and then cooled further (to ca. 12° C.) with a mild ice bath. The yellow reaction mixture is at this point treated with 3,4,5-trifluoronitrobenzene (94.8 g, 535 mmol) via addition funnel over 20 min. The deep purple reaction mixture is stirred overnight at ambient temperature. The deep green reaction mixture is then poured into ice/water (950 mL) and made acidic (from pH 11 to pH 5) with 20% v/v H2SO4/H2O while stirring vigorously and ensuring ample cooling with ice bath. The mixture is then chilled in a refrigerator for 2 h. The amber-brown liquid is extracted with Et2O (1.2 L), taking care to dissolve the large clumps of green-black solid (which accounts for a significant amount of the product). The ethereal layer is washed with H2O (250 mL), saturated aqueous NaHCO3 (2×150 mL), and H2O (2×150 mL), dried over MgSO4, and concentrated under reduced pressure. Trituration (cold hexanes) affords the title compound as a pale tan solid in 77% yield; 1H NMR (400 MHz, CDCl3) δ 7.86 (m, 2H), 4.35 (q, 2H), 2.06 (t, 3H), 1.31 (t, 3H). to cool gradually to ambient temperature over 90 min cooled further (to ca. 12° C.) with a mild ice bath while stirring vigorously ensuring ample cooling with ice bath The mixture is then chilled in a refrigerator for 2 h The amber-brown liquid is extracted with Et2O (1.2 L) to dissolve the large clumps of green-black solid (which The ethereal layer is washed with H2O (250 mL), saturated aqueous NaHCO3 (2×150 mL), and H2O (2×150 mL) dried over MgSO4 concentrated under reduced pressure

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred suspension of anhydrous K2CO3 (79.5 g, 575 mmol) in anhydrous DMF (365 mL) is heated to 150° C. and treated with ethyl 2-cyanopropionate (71.8 g, 564 mmol) via addition funnel over 20 min. The reaction is allowed to cool gradually to ambient temperature over 90 min, and then cooled further (to ca. 12° C.) with a mild ice bath. The yellow reaction mixture is at this point treated with 3,4,5-trifluoronitrobenzene (94.8 g, 535 mmol) via addition funnel over 20 min. The deep purple reaction mixture is stirred overnight at ambient temperature. The deep green reaction mixture is then poured into ice/water (950 mL) and made acidic (from pH 11 to pH 5) with 20% v/v H2SO4/H2O while stirring vigorously and ensuring ample cooling with ice bath. The mixture is then chilled in a refrigerator for 2 h. The amber-brown liquid is extracted with Et2O (1.2 L), taking care to dissolve the large clumps of green-black solid (which accounts for a significant amount of the product). The ethereal layer is washed with H2O (250 mL), saturated aqueous NaHCO3 (2×150 mL), and H2O (2×150 mL), dried over MgSO4, and concentrated under reduced pressure. Trituration (cold hexanes) affords the title compound as a pale tan solid in 77% yield; 1H NMR (400 MHz, CDCl3) δ 7.86 (m, 2H), 4.35 (q, 2H), 2.06 (t, 3H), 1.31 (t, 3H). to cool gradually to ambient temperature over 90 min cooled further (to ca. 12° C.) with a mild ice bath while stirring vigorously ensuring ample cooling with ice bath The mixture is then chilled in a refrigerator for 2 h The amber-brown liquid is extracted with Et2O (1.2 L) to dissolve the large clumps of green-black solid (which The ethereal layer is washed with H2O (250 mL), saturated aqueous NaHCO3 (2×150 mL), and H2O (2×150 mL) dried over MgSO4 concentrated under reduced pressure

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

Procedure: A mixture of diphenylphosphinodithioic acid (ALFAAESAR, 37.4 g, 149 mmol) and 2-cyanopropionic acid ethyl ester (ABCR, 9.90 mL, 74.7 mmol) in isopropanol (350 mL) was heated under reflux for 5 h. TLC (Hex:EtOAc 7:3) showed reaction had gone to completion. Reaction mixture was allowed to cool and was placed in the fridge overnight. Reaction mixture was filtered off and washed with isopropanol. Residue was partitioned between ethyl acetate (250 mL) and 1N NaOH (250 mL). Phases were separated and organic phase was washed with water (300 mL), brine (300 mL), dried over sodium sulfate and concentrated to dryness. Crude was purified by chromatography on silica gel using a hexane/EtOAc gradient. Appropriate fractions were combined and evaporated to yield title compound as a white solid (6.6 g, 40.9 mmol, 54.8% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.60 (s, 1H), 9.40 (s, 1H), 4.05 (q, 2H), 3.74 (q, 1H), 1.29 (d, 3H), 1.15 (t, 3H). [ES+MS] m/z 162 (MH+). was heated under reflux for 5 h reaction Reaction mixture to cool was placed in the fridge overnight Reaction mixture was filtered off washed with isopropanol Residue was partitioned between ethyl acetate (250 mL) and 1N NaOH (250 mL) Phases were separated organic phase was washed with water (300 mL), brine (300 mL) dried over sodium sulfate concentrated to dryness Crude was purified by chromatography on silica gel using a hexane/EtOAc gradient evaporated

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

Procedure: A mixture of 127 mg (1.0 mmol) of ethyl 2-cyanopropanoate, 0.12 ml (1.5 mmol) of methyl vinyl ketone, and 9.4 mg (0.01 mmol) of Rh(acac)(CO)(L) obtained in Example 8 was stirred in 5 ml of toluene at 0° C. for 13 hours. The reaction mixture was concentrated to yield 170 mg (86%) of ethyl 5-oxo-2-cyano-2-methylhexanoate. The product was found to have an optical purity of 73% e.e. as analyzed by high performance liquid chromatography using a Chiralcel OJ column manufactured by Daicel Chemical Industries, Ltd. The reaction mixture was concentrated