2-(4-fluoro-2-methylphenyl)acetonitrile

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: (4-Fluoro-2-methylphenyl)acetonitrile (6.0 g, 40 mmol), dissolved in THF (25 mL), was added to a suspension of NaH (2.1 g, 60% in mineral oil, 52 mmol) in THF (25 mL) under a stream of nitrogen. The mixture was then heated to reflux, which initiated the reaction. The reaction proceeded without external heating for 1 h whereupon the visual generation of gas ceased. The mixture was cooled and then 2-(2-bromoethoxy)tetrahydro-2H-pyran (10.9 g, 52 mmol), dissolved in THF (25 mL), was added. The mixture was stirred at 0° C. for 30 min and then at room temperature overnight. The mixture was poured over an aqueous solution of NH4Cl, which was extracted twice with ether. The combined organic solutions were dried over Na2SO4 and then the solvent was evaporated. The product was purified by chromatography on silica gel using CH2Cl2 and there was obtained 8.1 g (72%) of 2-(4-fluoro-2-methylphenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile as an oil. 1H NMR (300 MHz, CDCl3): 1.4-2.2 (m, 8H), 2.4 (s, 3H), 3.4-3.6 (m, 2H), 3.8-4.0 (m, 2H), 4.2 (m, 1H), 4.6 (m, 1H), 6.8-7.0 (m, 2H), 7.4 (m, 1H). The mixture was then heated to reflux the reaction without external heating for 1 h whereupon the visual generation of gas The mixture was cooled was added at room temperature overnight was extracted twice with ether The combined organic solutions were dried over Na2SO4 the solvent was evaporated The product was purified by chromatography on silica gel

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

Procedure: 1-(Chloromethyl)-4-fluoro-2-methylbenzene (12.8 g, 81 mmol) was dissolved in CH2Cl2 (50 mL) and to the resultant solution was added a mixture of tetrabutylammonium hydrogensulphate (1.4 g, 4.0 mmol), NaOH (0.32 g, 8.1 mmol) and water (50 mL) followed by an aqueous solution of potassium cyanide (5.0 g, 77 mmol). The mixture was stirred for 5 minutes and then the pH of the aqueous layer was monitored and adjusted to the alkaline side by the dropwise addition of aqueous sodium hydroxide (5M). The mixture was refluxed for one hour, stirred at room temperature overnight and then diluted with CH2Cl2 (50 mL). The organic layer was washed thrice with water and then dried over Na2SO4. The solvent was removed by evaporation and the product was purified by chromatography on silica gel using CH2Cl2. There was obtained 11.1 g (92%) of (4-fluoro-2-methylphenyl)acetonitrile as an oil. 1H NMR (300 MHz, CDCl3): 2.3 (s, 3H), 3.6 (s, 2H), 6.8-7.0 (m, 2H), 7.3 (m, 1H). was added The mixture was refluxed for one hour stirred at room temperature overnight The organic layer was washed thrice with water dried over Na2SO4 The solvent was removed by evaporation the product was purified by chromatography on silica gel

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

Procedure: 1-(Chloromethyl)-4-fluoro-2-methylbenzene (12.8 g, 81 mmol) was dissolved in CH2Cl2 (50 mL) and to the resultant solution was added a mixture of tetrabutylammonium hydrogensulphate (1.4 g, 4.0 mmol), NaOH (0.32 g, 8.1 mmol) and water (50 mL) followed by an aqueous solution of potassium cyanide (5.0 g, 77 mmol). The mixture was stirred for 5 minutes and then the pH of the aqueous layer was monitored and adjusted to the alkaline side by the dropwise addition of aqueous sodium hydroxide (5M). The mixture was refluxed for one hour, stirred at room temperature overnight and then diluted with CH2Cl2 (50 mL). The organic layer was washed thrice with water and then dried over Na2SO4. The solvent was removed by evaporation and the product was purified by chromatography on silica gel using CH2Cl2. There was obtained 11.1 g (92%) of (4-fluoro-2-methylphenyl)acetonitrile as an oil. 1H NMR (300 MHz, CDCl3): 2.3 (s, 3H), 3.6 (s, 2H), 6.8-7.0 (m, 2H), 7.3 (m, 1H). was added The mixture was refluxed for one hour stirred at room temperature overnight The organic layer was washed thrice with water dried over Na2SO4 The solvent was removed by evaporation the product was purified by chromatography on silica gel

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

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

Procedure: A solution of 29.6 parts of N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide and 14.9 parts of 4-fluoro-2-methylbenzeneacetonitrile in 90 parts of methylbenzene is added dropwise to a solution of 5.6 parts of lithium amide in 270 parts of methylbenzene at about 90° C. Upon completion, the whole is heated to reflux and stirred overnight at reflux temperature. The reaction mixture is cooled, poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from 2-propanol, yielding 27 parts (72.6%) of 4-(4-fluoro-2-methylphenyl)-1-(4-methylphenylsulfonyl)-4-piperidinecarbonitrile. Upon completion, the whole is heated to reflux at reflux temperature The reaction mixture is cooled poured onto water the layers are separated The organic phase is dried filtered evaporated The residue is crystallized from 2-propanol

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

Procedure: A mixture of 16 parts of 1-(chloromethyl)-4-fluoro-2-methylbenzene, 7.8 parts of a solution of potassium cyanide in a small amount of water, 0.1 parts of potassium iodide and 240 parts of 2-propanone is stirred and refluxed for 22 hours. The reaction mixture is cooled and filtered. The filtrate is evaported. The residue is taken up in water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated, yielding 13 parts (87.2%) of 4-fluoro-2-methylbenzeneacetonitrile as a residue. refluxed for 22 hours The reaction mixture is cooled filtered the product is extracted with methylbenzene The extract is dried filtered evaporated

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

Procedure: (4-Fluoro-2-methylphenyl)acetonitrile (6.0 g, 40 mmol), dissolved in THF (25 mL), was added to a suspension of NaH (2.1 g, 60% in mineral oil, 52 mmol) in THF (25 mL) under a stream of nitrogen. The mixture was then heated to reflux, which initiated the reaction. The reaction proceeded without external heating for 1 h whereupon the visual generation of gas ceased. The mixture was cooled and then 2-(2-bromoethoxy)tetrahydro-2H-pyran (10.9 g, 52 mmol), dissolved in THF (25 mL), was added. The mixture was stirred at 0° C. for 30 min and then at room temperature overnight. The mixture was poured over an aqueous solution of NH4Cl, which was extracted twice with ether. The combined organic solutions were dried over Na2SO4 and then the solvent was evaporated. The product was purified by chromatography on silica gel using CH2Cl2 and there was obtained 8.1 g (72%) of 2-(4-fluoro-2-methylphenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile as an oil. 1H NMR (300 MHz, CDCl3): 1.4-2.2 (m, 8H), 2.4 (s, 3H), 3.4-3.6 (m, 2H), 3.8-4.0 (m, 2H), 4.2 (m, 1H), 4.6 (m, 1H), 6.8-7.0 (m, 2H), 7.4 (m, 1H). The mixture was then heated to reflux the reaction without external heating for 1 h whereupon the visual generation of gas The mixture was cooled was added at room temperature overnight was extracted twice with ether The combined organic solutions were dried over Na2SO4 the solvent was evaporated The product was purified by chromatography on silica gel

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

Procedure: 1-(Chloromethyl)-4-fluoro-2-methylbenzene (12.8 g, 81 mmol) was dissolved in CH2Cl2 (50 mL) and to the resultant solution was added a mixture of tetrabutylammonium hydrogensulphate (1.4 g, 4.0 mmol), NaOH (0.32 g, 8.1 mmol) and water (50 mL) followed by an aqueous solution of potassium cyanide (5.0 g, 77 mmol). The mixture was stirred for 5 minutes and then the pH of the aqueous layer was monitored and adjusted to the alkaline side by the dropwise addition of aqueous sodium hydroxide (5M). The mixture was refluxed for one hour, stirred at room temperature overnight and then diluted with CH2Cl2 (50 mL). The organic layer was washed thrice with water and then dried over Na2SO4. The solvent was removed by evaporation and the product was purified by chromatography on silica gel using CH2Cl2. There was obtained 11.1 g (92%) of (4-fluoro-2-methylphenyl)acetonitrile as an oil. 1H NMR (300 MHz, CDCl3): 2.3 (s, 3H), 3.6 (s, 2H), 6.8-7.0 (m, 2H), 7.3 (m, 1H). was added The mixture was refluxed for one hour stirred at room temperature overnight The organic layer was washed thrice with water dried over Na2SO4 The solvent was removed by evaporation the product was purified by chromatography on silica gel