Tetrahydro-2H-pyran-4-carbonitrile

Thionyl chloride (10.0 mL, 137 mmol) was added to oxane-4-carboxamide (3.0 g, 23 mmol) and thereaction mixture was refluxed for 4 h, after which the reaction mixture was poured over ice andbasified to pH 14 with NaOH (50percent). The aqueous solution was extracted with EtOAc (3 × 50 mL), dried (Na2SO4) and concentrated in vacuo to give the product as a pale yellow oil (2.4 g, 94percent). Theproduct obtained did not require any further purification.IR νmax 2961, 2932, 2851, 2240, 1468, 1446, 1390, 1242, 1125, 1066, 1011 cm−1;1H-NMR (CDCl3, 500 MHz): 3.91 (2H, ddd, J 11.9, 6.3, 3.6, 2×2-HA), 3.61 (2H, ddd, J 11.9, 7.8, 3.3, 2×2-HB), 2.91–2.85 (1H, m, 4-H), 1.99–1.92 (2H, m, 2×3-HA), 1.91–1.84 (2H, m, 2×3-HB);13C-NMR (CDCl3, 75 MHz): 121.2, 65.6, 28.9, 25.3;HRMS (ESI+): Calculated for C6H10NO ([M+H]+): 112.0756. Found: 112.0754, Δ –1.8 ppm.A suspension of tetrahydro-2H-pyran-4-carboxamide (4.90 g, 37.9 mmol) in benzene (10 ml) was treated with thionyl chloride (5 ml) and the resulting mixture was stirred at reflux for 4 hours. The cooled mixture was poured onto ice and basified with 50percent potassium hydroxide. The aqueous fraction was saturated with salt and extracted with ethyl acetate. The organic fraction was then dried over anhydrous magnesium sulfate and concentrated. Distillation under reduced pressure gave 3.80 g (90percent yield) of the title nitrile as a clear oil: bp 80-90° C./15 torr (bulb to bulb distillation, air bath temperature). Intermediate 11 : 2-(Tetrahydro-2H-pyran-4-yl)-lH-imidazole-5-carbaldehydeStep a: tetrahydro-2H-pyran-4-carbonitrile[0473] A solution of dihydro-2H-pyran-4(3H)-one (10.0 g, 0.1 mol) and TosMIC (25.35 g, 0.13 mol) in DME (75.0 mL) was cooled to -10°C and t-BuOK (28.0 g, 0.25 mol) was added in portions to keep the temperature below 5°C. The reaction mixture was stirred at 0°C for 1 h and then at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was treated with water. The resulting mixture was extracted with ether and the combined organic layers were washed with brine, dried over anhydrous NaReference : Tetrahvdro-pyran-4-carbonitriIe. To a solution of tetrahydro-pyran-4-one (2.0 g, 20.0 mmol) and tosyl methyl isocyanide (5.06 g, 25.9 mmol) in dimethoxyethane (15 mL) was added ethanol (1.5 niL). The reaction mixture was cooled to 0°C and potassium tert-butoxide (5.57 g, 49.7 mmol) was added. The resulting reaction mixture was warmed to r.t. and stirred for Ih, then heated to 4Ot-BuOK (26.9g, 0.24mol) was added over 30min to a solution of tetrahydro-4H-pyran-4-one(1Og, O.lmol) and TOSMIC (25.38g, 0.13mol) in EtOH-DME (1:35 / 36OmL) under argon at0Tetrahydro-2H-pyran-4-carbonitrile. A solution of tetrahydro-4H-pyran-4-one (25 g, 250 mmol) and toluenesulfonylmethyl cyanide (53.7 g, 275 mmol) dissolved in ethylene glycol dimethylether (1 L) was cooled to 0° C. Added dropwise over 30 min was a solution of potassium t-butoxide (56 g, 500 mmol) dissolved in t-butanol (350 mL) and ethylene glycol dimethylether (150 mL). After stirring the resulting mixture for 3 h at room temp, diethyl ether (1 L) was added and the organic phase was washed with saturated aqueous NaHCOTetrahydro-2H-pyran-4-carbonitrile. A solution of tetrahydro-4H-pyran-4-one (25 g, 250 mmol) and toluenesulfonylmethyl cyanide (53.7 g, 275 mmol) dissolved in ethylene glycol dimethylether (1 L) was cooled to 0° C. Added dropwise over 30 min was a solution of potassium t-butoxide (56 g, 500 mmol) dissolved in t-butanol (350 mL) and ethylene glycol dimethylether (150 mL). After stirring the resulting mixture for 3 h at room temp, diethyl ether (1 L) was added and the organic phase was washed with saturated aqueous NaHCOIntermediate 4Tetrahydro~2H-pyran-4-carbonitrile. A solution of tetrahydro-4HA solution of tetrahydro-4H-pyran-4-one (25 g, 250 mmol) and toluenesulfonylmethyl cyanide (53.7 g, 275 mmol) dissolved in ethylene glycol dimethylether (1 L) was cooled to 0° C. In a glass flask having inner volume of 20 ml provided with stirrer, the thermometer, and the reflux condenser, 2.62 g (10.2mmol) of tetrahydropyranyl 4-p-toluenesulfonate, potassium cyanide 1.0g (15.4mmol), and 10 ml of dimethyl sulfoxide were added and the mixture was reacted at 80 degrees C for 7 hours. After completion of the reaction, the reaction mixture was analyszed by gas chromatography (internal standard method), 0.46 g of 4-cyanotetrahydropyran was obtained (reaction yield: 41percent).In a glass flask having inner volume of 20 ml provided with stirrer, the thermometer, and the reflux condenser, 1.85 g (10.2mmol) of tetrahydropyranyl 4-methanesulfonate, potassium cyanide 1.0g (15.4mmol), and 10 ml of dimethyl sulfoxide were added and the mixture was reacted at 80 degrees C for 7 hours. After completion of the reaction, the reaction mixture was analyszed by gas chromatography (internal standard method), 0.50 g of 4-cyanotetrahydropyran was obtained (reaction yield: 44percent).In a glass flask having inner volume of 20 ml provided with stirrer, the thermometer, and the reflux condenser, 1.69 g (10.2mmol) of 4-bromotetrahydrofuran, potassium cyanide 1.0g (15.4mmol), and 10 ml of dimethyl sulfoxide were added and the mixture was reacted at 80 degrees C for 7 hours. After completion of the reaction, the reaction mixture was analyszed by gas chromatography (internal standard method), 0.10 g of 4-cyanotetrahydropyran was obtained (reaction yield: 9percent).Thionyl chloride (10.0 mL, 137 mmol) was added to oxane-4-carboxamide (3.0 g, 23 mmol) and thereaction mixture was refluxed for 4 h, after which the reaction mixture was poured over ice andbasified to pH 14 with NaOH (50percent). The aqueous solution was extracted with EtOAc (3 × 50 mL), dried (Na2SO4) and concentrated in vacuo to give the product as a pale yellow oil (2.4 g, 94percent). Theproduct obtained did not require any further purification.IR numax 2961, 2932, 2851, 2240, 1468, 1446, 1390, 1242, 1125, 1066, 1011 cm'1;1H-NMR (CDCl3, 500 MHz): 3.91 (2H, ddd, J 11.9, 6.3, 3.6, 2×2-HA), 3.61 (2H, ddd, J 11.9, 7.8, 3.3, 2×2-HB), 2.91'2.85 (1H, m, 4-H), 1.99'1.92 (2H, m, 2×3-HA), 1.91'1.84 (2H, m, 2×3-HB);13C-NMR (CDCl3, 75 MHz): 121.2, 65.6, 28.9, 25.3;HRMS (ESI+): Calculated for C6H10NO ([M+H]+): 112.0756. Found: 112.0754, Delta '1.8 ppm.A suspension of tetrahydro-2H-pyran-4-carboxamide (4.90 g, 37.9 mmol) in benzene (10 ml) was treated with thionyl chloride (5 ml) and the resulting mixture was stirred at reflux for 4 hours. The cooled mixture was poured onto ice and basified with 50percent potassium hydroxide. The aqueous fraction was saturated with salt and extracted with ethyl acetate. The organic fraction was then dried over anhydrous magnesium sulfate and concentrated. Distillation under reduced pressure gave 3.80 g (90percent yield) of the title nitrile as a clear oil: bp 80-90° C./15 torr (bulb to bulb distillation, air bath temperature). 1HNMR 400 MHz (CDCl3) delta (ppm): 1.91 (4H, m, 2.x.CH2), 2.89 (1H, m, CH), 3.62 (2H, m, OCH2), 3.92 (2H, m, OCH2).d) Tetrahydropyran-4-carbonitrile can be prepared as follows: Slowly add 10 cm3 of thionyl chloride to 3 g of tetrahydropyran-4-carboxamide cooled on an ice bath. Heat the mixture at 80° C. for two hours, then concentrate under vacuum. Take up the residue in 20 cm3 of water and adjust the pH of the solution to pH 7 with potassium hydroxide. Extract the aqueous phase with ethyl acetate (4*50 cm3). The combined organic phases are washed with water (2*50 cm3), dried over magnesium sulphate, and then concentrated under vacuum to obtain 2.47 g of tetrahydropyran-4-carbonitrile.

Molecular Weight:111.14
XLogP3:0.3
Hydrogen Bond Acceptor Count:2
Exact Mass:111.068413911
Monoisotopic Mass:111.068413911
Topological Polar Surface Area:33
Heavy Atom Count:8
Complexity:107
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes