4-methyl-1-oxidopyridin-1-ium

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

Procedure: 4-methylpyridine-N-oxide (3.7 g) was dissolved in methylene chloride (68 ml), trimethyloxonium tetrafluoroborate (5.0 g) was added to the mixture, and the mixture was stirred for 90 minutes at room temperature. The solvent was removed under reduced pressure, the obtained residue was dissolved in methanol, and an aqueous solution (6.8 ml) of ammonium peroxodisulfate (1.54 g) was added under heat reflux. An aqueous solution (3.4 ml) of ammonium peroxodisulfate (0.77 g) was further added to the mixture after 30 minutes, and the mixture was stirred for 1 hour. After allowing the mixture to be cooled to room temperature, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give (4-methyl-2-pyridinyl)methanol (2.9 g). (4-methyl-2-pyridinyl)methanol (2.5 g) was dissolved in methylene chloride (25 ml), DMF (3 droplets) was added to the mixture, thionyl chloride (3.8 ml) was added to the mixture at 0° C. and the mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure, and a solution (9.1 ml) of the obtained residue in water was added dropwise to an aqueous solution (64 ml) of 4-aminothiophenol (1.82 g) and sodium hydroxide (1.74 g) in methanol. The mixture was stirred for 1 hour at room temperature, the solvent was removed under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[[(4-methyl-2-pyridinyl)methyl]sulfanyl]aniline (2.0 g). The solvent was removed under reduced pressure the obtained residue was dissolved in methanol an aqueous solution (6.8 ml) of ammonium peroxodisulfate (1.54 g) was added under heat reflux An aqueous solution (3.4 ml) of ammonium peroxodisulfate (0.77 g) was further added to the mixture after 30 minutes the mixture was stirred for 1 hour to be cooled to room temperature the solvent was removed under reduced pressure the obtained residue was purified by silica gel column chromatography

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

Procedure: 4-Methylpyridine N-oxide (2.0 g, 18.3 mmol) was dissolved in nitroethane (25 ml), and trimethylsilyl cyanide (2.0 g, 20.2 mmol) and N,N-dimethylcarbamoyl chloride (1.7 ml, 18.5 mmol) were added thereto. The reaction mixture was stirred at room temperature for 5 days, concentrated under reduced pressure, combined with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure. The obtained crystals were collected by filtration, washed with diisopropyl ether and dried to give the titled compound (0.91 g, 42%). concentrated under reduced pressure extracted with ethyl acetate The extract was washed with saturated brine dried The solvent was evaporated under reduced pressure The obtained crystals were collected by filtration washed with diisopropyl ether dried

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

Procedure: 4-Methylpyridine N-oxide (2.0 g, 18.3 mmol) was dissolved in nitroethane (25 ml), and trimethylsilyl cyanide (2.0 g, 20.2 mmol) and N,N-dimethylcarbamoyl chloride (1.7 ml, 18.5 mmol) were added thereto. The reaction mixture was stirred at room temperature for 5 days, concentrated under reduced pressure, combined with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure. The obtained crystals were collected by filtration, washed with diisopropyl ether and dried to give the titled compound (0.91 g, 42%). concentrated under reduced pressure extracted with ethyl acetate The extract was washed with saturated brine dried The solvent was evaporated under reduced pressure The obtained crystals were collected by filtration washed with diisopropyl ether dried

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

Procedure: To a solution of 4-picoline-N-oxide (20 g) in CH2Cl2 (360 mL) was added TMSCN (26.5 mL), stirred 5 minutes, added dimethyl carbamyl chloride (16.6 mL) was added slowly dropwise. The mixture was stirred at RT overnight, poured onto 400 mL H2O, and 40 g NaCO3. Separation of layers and evaporation of CH2Cl2 gave 17.25 g of 2-Cyano-4-methylpyridine-N-oxide, recrystallized from hexane, m.p. 95°-98° C. was added slowly dropwise The mixture was stirred at RT overnight Separation of layers and evaporation of CH2Cl2

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

Procedure: 4-Methylpyridine N-oxide (2.0 g, 18.3 mmol) was dissolved in nitroethane (25 ml), and trimethylsilyl cyanide (2.0 g, 20.2 mmol) and N,N-dimethylcarbamoyl chloride (1.7 ml, 18.5 mmol) were added thereto. The reaction mixture was stirred at room temperature for 5 days, concentrated under reduced pressure, combined with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure. The obtained crystals were collected by filtration, washed with diisopropyl ether and dried to give the titled compound (0.91 g, 42%). concentrated under reduced pressure extracted with ethyl acetate The extract was washed with saturated brine dried The solvent was evaporated under reduced pressure The obtained crystals were collected by filtration washed with diisopropyl ether dried

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

Procedure: 4-Methylpyridine N-oxide (2.0 g, 18.3 mmol) was dissolved in nitroethane (25 ml), and trimethylsilyl cyanide (2.0 g, 20.2 mmol) and N,N-dimethylcarbamoyl chloride (1.7 ml, 18.5 mmol) were added thereto. The reaction mixture was stirred at room temperature for 5 days, concentrated under reduced pressure, combined with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure. The obtained crystals were collected by filtration, washed with diisopropyl ether and dried to give the titled compound (0.91 g, 42%). concentrated under reduced pressure extracted with ethyl acetate The extract was washed with saturated brine dried The solvent was evaporated under reduced pressure The obtained crystals were collected by filtration washed with diisopropyl ether dried

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 4-picoline N-oxide (13.64 g, 0.124 mole) in 82 ml of THF, under an inert atmosphere, was added trimethylsilyl cyanide (20.1 ml, 0.15 mole) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (4.4 ml, 0.028 mole). After stirring at 25 ° C. for 12 hours, the reaction mixture was heated to reflux. After 4.5 hours, the solvent was removed under reduced pressure and the crude sample was eluted with methylene chloride through a pad of Florisil®. The solvent was removed under reduced pressure to provide (8.7 g, 60%) of 2-cyano-4-methyl pyridine, a white crystalline solid: mp 88°-89 ° C. Anal. Calc'd. for C7H6N2 : C, 71.17; H, 5.12; N, 23.71. Found: C, 70.71; H, 5.16; N, 23.44. the reaction mixture was heated to reflux After 4.5 hours the solvent was removed under reduced pressure the crude sample was eluted with methylene chloride through a pad of Florisil® The solvent was removed under reduced pressure

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 4-picoline N-oxide (13.64 g, 0.124 mole) in 82 ml of THF, under an inert atmosphere, was added trimethylsilyl cyanide (20.1 ml, 0.15 mole) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (4.4 ml, 0.028 mole). After stirring at 25 ° C. for 12 hours, the reaction mixture was heated to reflux. After 4.5 hours, the solvent was removed under reduced pressure and the crude sample was eluted with methylene chloride through a pad of Florisil®. The solvent was removed under reduced pressure to provide (8.7 g, 60%) of 2-cyano-4-methyl pyridine, a white crystalline solid: mp 88°-89 ° C. Anal. Calc'd. for C7H6N2 : C, 71.17; H, 5.12; N, 23.71. Found: C, 70.71; H, 5.16; N, 23.44. the reaction mixture was heated to reflux After 4.5 hours the solvent was removed under reduced pressure the crude sample was eluted with methylene chloride through a pad of Florisil® The solvent was removed under reduced pressure

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

Procedure: Triethylamine (13.4 mL, 91.9 mmol) and trimethylsilyl cyanide (25 mL, 187.5 mmol) were added sequentially to a solution comprising 4-methylpyridine N-oxide (5 g, 45.8 mmol) and acetonitrile (20 mL). The mixture was heated at reflux for 24 hours, cooled and diluted with methylene chloride (150 mL). Saturated sodium bicarbonate solution (100 mL) was added slowly to the mixture and then the aqueous layer was separated and extracted with methylene chloride (100 mL). The combined organic layers were washed with water (2×150 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexanes to provide 4-methylpyridine-2-carbonitrile (3.5 g, 29.6 mmol) as a dark solid, 1H-NMR (300 Mhz, DMSO-d6): 2.4 (s, 3H), 7.6 (d, 1H, J=5 Hz), 7.8 (s, 1H), 8.6 (d, 1H, J=5 Hz), MS (ESI), Calculated for C7H6N2 : 228.24, Found (MH+): 119. The mixture was heated at reflux for 24 hours cooled the aqueous layer was separated extracted with methylene chloride (100 mL) The combined organic layers were washed with water (2×150 mL) dried (MgSO4) concentrated under reduced pressure The residue was crystallized from ethyl acetate/hexanes

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

Procedure: To a solution of 4-picoline-N-oxide (20 g) in CH2Cl2 (360 mL) was added TMSCN (26.5 mL), stirred 5 minutes, added dimethyl carbamyl chloride (16.6 mL) was added slowly dropwise. The mixture was stirred at RT overnight, poured onto 400 mL H2O, and 40 g NaCO3. Separation of layers and evaporation of CH2Cl2 gave 17.25 g of 2-Cyano-4-methylpyridine-N-oxide, recrystallized from hexane, m.p. 95°-98° C. was added slowly dropwise The mixture was stirred at RT overnight Separation of layers and evaporation of CH2Cl2

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

Procedure: A solution of 4-picoline-N-oxide (3.0 g, 27.52 mmol) in 90 ml of methylene chloride at room temperature is reacted with trimethyloxonium tetrafluoroborate (4.07 g, 27.52 mmol, 1.0 equiv.) for 1.5 h. The reaction mixture is concentrated directly at reduced pressure, the white solid dissolved in 60 ml of refluxing methanol and treated with ammonium persulfate (1.25 g, 5.50 mmol, 0.20 equiv.) in 5.5 ml of water with another addition of ammonium persulfate (0.625 g, 0.10 equiv.) in 2.5 ml of water 30 min later. After refluxing for an additional 40 min, the contents are concentrated at reduced pressure, treated with 75 ml of saturated brine plus 75 ml of water and finally 50 ml of 3N HCl. After stirring at room temperature for 1 h, the mixture is basified with 20 ml of 29% ammonium hydroxide, extracted 4 times with chloroform, dried the combined organic extracts with anhydrous Na2SO4 and concentrated in vacuo. Chromatography with 250 g of silica gel, packed and eluted with acetone-chloroform-methanol (1:2:2%), yielded 2.65 g (78%) of 2-hydroxymethyl-4-methylpyridine. The reaction mixture is concentrated directly at reduced pressure the white solid dissolved in 60 ml of refluxing methanol After refluxing for an additional 40 min the contents are concentrated at reduced pressure treated with 75 ml of saturated brine plus 75 ml of water and finally 50 ml of 3N HCl extracted 4 times with chloroform dried the combined organic extracts with anhydrous Na2SO4 concentrated in vacuo eluted with acetone-chloroform-methanol (1:2:2%)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 4-picoline N-oxide (13.64 g, 0.124 mole) in 82 ml of THF, under an inert atmosphere, was added trimethylsilyl cyanide (20.1 ml, 0.15 mole) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (4.4 ml, 0.028 mole). After stirring at 25° C. for 12 hours, the reaction mixture was heated to reflux. After 4.5 hours, the solvent was removed under reduced pressure and the crude sample was eluted with methylene chloride through a pad of Florisil®. The solvent was removed under reduced pressure to provide (8.7 g, 60%) of 2-cyano-4-methyl pyridine, a white crystalline solid: mp 88–89° C. Anal. Calc'd. for C7H6N2: C, 71.17; H, 5.12; N, 23.71. Found: C, 70.17; H, 5.12; N, 23.44. the reaction mixture was heated to reflux After 4.5 hours the solvent was removed under reduced pressure the crude sample was eluted with methylene chloride through a pad of Florisil® The solvent was removed under reduced pressure