3-bromo-2-methyl-1-oxidopyridin-1-ium

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

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 suspension of 60% NaH (577 mg, 14.4 mmol) in DMF (15 mL) at 0° C. was added thiophenol (1.47 mL, 14.4 mmol) and the resultant mixture was warmed to room temperature and stirred for 1.5 h. To this mixture was added the 3-Bromo-2-methyl-pyridine 1-oxide (900 mg, 4.79 mmol) and the resultant yellow solution was heated to 80° C. for 96 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with EtOAc (100 mL), washed with brine (4×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (EtOAc/MeOH, 100:0 then 95:5) gave a mixture of 2-methyl-3-phenylsulfanyl-pyridine 1-oxide and a di-substituted thiophenol by-product. The mixture was treated with Ac2O (3 mL) and heated at 80° C. overnight. The mixture was cooled to room temperature, diluted with CH2Cl2 (40 mL), H2O (10 mL) and saturated aqueous NaHCO3 (40 mL). The aqueous phase was separated and extracted with CH2Cl2 (2×20 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography on silica gel (Hexanes/EtOAc, 70:30) gave Acetic acid 3-phenylsulfanyl-pyridin-2-ylmethyl ester (259 mg, 25% over 2 steps) as a yellow oil. 1H NMR (CDCl3) δ 2.11 (s, 3H), 5.37 (s, 2H), 7.18 (dd, 1H, J=7.9, 4.9 Hz), 7.27-7.38 (m, 5H), 7.53 (dd, 1H, J=7.9, 1.7 Hz), 8.50 (dd, 1H, J=4.7, 1.8 Hz). The reaction mixture was cooled to room temperature concentrated under reduced pressure The residue was treated with EtOAc (100 mL) washed with brine (4×50 mL) dried (Na2SO4) filtered concentrated under reduced pressure Purification by flash chromatography on silica gel (EtOAc/MeOH, 100:0 95:5) gave heated at 80° C. overnight The mixture was cooled to room temperature The aqueous phase was separated extracted with CH2Cl2 (2×20 mL) The combined organic extracts were dried (Na2SO4) filtered concentrated Purification by flash chromatography on silica gel (Hexanes/EtOAc, 70:30)

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

Procedure: To a suspension of 60% NaH (577 mg, 14.4 mmol) in DMF (15 mL) at 0° C. was added thiophenol (1.47 mL, 14.4 mmol) and the resultant mixture was warmed to room temperature and stirred for 1.5 h. To this mixture was added the 3-Bromo-2-methyl-pyridine 1-oxide (900 mg, 4.79 mmol) and the resultant yellow solution was heated to 80° C. for 96 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with EtOAc (100 mL), washed with brine (4×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (EtOAc/MeOH, 100:0 then 95:5) gave a mixture of 2-methyl-3-phenylsulfanyl-pyridine 1-oxide and a di-substituted thiophenol by-product. The mixture was treated with Ac2O (3 mL) and heated at 80° C. overnight. The mixture was cooled to room temperature, diluted with CH2Cl2 (40 mL), H2O (10 mL) and saturated aqueous NaHCO3 (40 mL). The aqueous phase was separated and extracted with CH2Cl2 (2×20 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography on silica gel (Hexanes/EtOAc, 70:30) gave Acetic acid 3-phenylsulfanyl-pyridin-2-ylmethyl ester (259 mg, 25% over 2 steps) as a yellow oil. 1H NMR (CDCl3) δ 2.11 (s, 3H), 5.37 (s, 2H), 7.18 (dd, 1H, J=7.9, 4.9 Hz), 7.27-7.38 (m, 5H), 7.53 (dd, 1H, J=7.9, 1.7 Hz), 8.50 (dd, 1H, J=4.7, 1.8 Hz). The reaction mixture was cooled to room temperature concentrated under reduced pressure The residue was treated with EtOAc (100 mL) washed with brine (4×50 mL) dried (Na2SO4) filtered concentrated under reduced pressure Purification by flash chromatography on silica gel (EtOAc/MeOH, 100:0 95:5) gave heated at 80° C. overnight The mixture was cooled to room temperature The aqueous phase was separated extracted with CH2Cl2 (2×20 mL) The combined organic extracts were dried (Na2SO4) filtered concentrated Purification by flash chromatography on silica gel (Hexanes/EtOAc, 70:30)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 3-Bromo-2-methyl-pyridine (1.96 g, 11.4 mmol) in glacial HOAc (20 mL) at room temperature was added 50% H2O2 (0.77 mL) and the solution was heated to 70° C. After 2 h, the reaction mixture was cooled to room temperature, additional H2O2 (0.80 mL) was added, and the solution was heated at 70° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (80 mL) and treated with saturated aqueous NaHCO3 (20 mL). The aqueous phase was separated and extracted with CH2Cl2 (4×20 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to provide 3-Bromo-2-methyl-pyridine 1-oxide (1.79 g, 84%) as a white solid. 1H NMR (CDCl3) δ 2.70 (s, 3H), 7.00 (t, 1H, J=7.0 Hz), 7.44 (d, 1H, J=7.9 Hz), 8.23 (d, 1H, J=6.5 Hz). 3-Bromo-2-methyl-pyridine 1-oxide was used without further purification. the reaction mixture was cooled to room temperature the solution was heated at 70° C. overnight The reaction mixture was cooled to room temperature concentrated under reduced pressure The residue was dissolved in CH2Cl2 (80 mL) treated with saturated aqueous NaHCO3 (20 mL) The aqueous phase was separated extracted with CH2Cl2 (4×20 mL) The combined organic extracts were dried (Na2SO4) filtered concentrated

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 3-Bromo-2-methyl-pyridine (1.96 g, 11.4 mmol) in glacial HOAc (20 mL) at room temperature was added 50% H2O2 (0.77 mL) and the solution was heated to 70° C. After 2 h, the reaction mixture was cooled to room temperature, additional H2O2 (0.80 mL) was added, and the solution was heated at 70° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (80 mL) and treated with saturated aqueous NaHCO3 (20 mL). The aqueous phase was separated and extracted with CH2Cl2 (4×20 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to provide 3-Bromo-2-methyl-pyridine 1-oxide (1.79 g, 84%) as a white solid. 1H NMR (CDCl3) δ 2.70 (s, 3H), 7.00 (t, 1H, J=7.0 Hz), 7.44 (d, 1H, J=7.9 Hz), 8.23 (d, 1H, J=6.5 Hz). 3-Bromo-2-methyl-pyridine 1-oxide was used without further purification. the reaction mixture was cooled to room temperature the solution was heated at 70° C. overnight The reaction mixture was cooled to room temperature concentrated under reduced pressure The residue was dissolved in CH2Cl2 (80 mL) treated with saturated aqueous NaHCO3 (20 mL) The aqueous phase was separated extracted with CH2Cl2 (4×20 mL) The combined organic extracts were dried (Na2SO4) filtered concentrated

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

Procedure: Trifluoroacetic anhydride (0.52 mL, 3.6 mmol) was added to a solution of 3-bromo-2-methylpyridine 1-oxide (140 mg, 0.72 mmol) in methylene chloride (2 mL) and the mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-75% ethyl acetate in heptane) to afford the title compound as a yellow oil (110 mg, 75%). 1H NMR (400 MHz, DMSO) δ 8.56 (d, J=4.7 Hz, 1H), 8.10 (dd, J=8.0, 1.1 Hz, 1H), 7.32 (dd, J=8.0, 4.7 Hz, 1H), 4.64 (s, 2H); OH peak not observed. washed with saturated aqueous sodium bicarbonate solution (20 mL) The organic layer was separated dried over sodium sulfate filtered evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-75% ethyl acetate in heptane)

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

Procedure: A mixture of 3-bromo-2-methylpyridine (0.14 mL, 1.2 mmol) and m-chloroperbenzoic acid (420 mg, 1.8 mmol) in methylene chloride (4 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-10% methanol in dichloromethane) to afford the title compound as a white solid (140 mg, 61%), which was used in the next step without further purification. washed with saturated aqueous sodium bicarbonate solution (20 mL) The organic layer was separated dried over sodium sulfate filtered evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-10% methanol in dichloromethane)

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

Procedure: A mixture of 3-bromo-2-methylpyridine (0.14 mL, 1.2 mmol) and m-chloroperbenzoic acid (420 mg, 1.8 mmol) in methylene chloride (4 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-10% methanol in dichloromethane) to afford the title compound as a white solid (140 mg, 61%), which was used in the next step without further purification. washed with saturated aqueous sodium bicarbonate solution (20 mL) The organic layer was separated dried over sodium sulfate filtered evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-10% methanol in dichloromethane)

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

Procedure: To a suspension of 60% NaH (577 mg, 14.4 mmol) in DMF (15 mL) at 0° C. was added thiophenol (1.47 mL, 14.4 mmol) and the resultant mixture was warmed to room temperature and stirred for 1.5 h. To this mixture was added the 3-Bromo-2-methyl-pyridine 1-oxide (900 mg, 4.79 mmol) and the resultant yellow solution was heated to 80° C. for 96 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with EtOAc (100 mL), washed with brine (4×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (EtOAc/MeOH, 100:0 then 95:5) gave a mixture of 2-methyl-3-phenylsulfanyl-pyridine 1-oxide and a di-substituted thiophenol by-product. The mixture was treated with Ac2O (3 mL) and heated at 80° C. overnight. The mixture was cooled to room temperature, diluted with CH2Cl2 (40 mL), H2O (10 mL) and saturated aqueous NaHCO3 (40 mL). The aqueous phase was separated and extracted with CH2Cl2 (2×20 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography on silica gel (Hexanes/EtOAc, 70:30) gave Acetic acid 3-phenylsulfanyl-pyridin-2-ylmethyl ester (259 mg, 25% over 2 steps) as a yellow oil. 1H NMR (CDCl3) δ 2.11 (s, 3H), 5.37 (s, 2H), 7.18 (dd, 1H, J=7.9, 4.9 Hz), 7.27-7.38 (m, 5H), 7.53 (dd, 1H, J=7.9, 1.7 Hz), 8.50 (dd, 1H, J=4.7, 1.8 Hz). The reaction mixture was cooled to room temperature concentrated under reduced pressure The residue was treated with EtOAc (100 mL) washed with brine (4×50 mL) dried (Na2SO4) filtered concentrated under reduced pressure Purification by flash chromatography on silica gel (EtOAc/MeOH, 100:0 95:5) gave heated at 80° C. overnight The mixture was cooled to room temperature The aqueous phase was separated extracted with CH2Cl2 (2×20 mL) The combined organic extracts were dried (Na2SO4) filtered concentrated Purification by flash chromatography on silica gel (Hexanes/EtOAc, 70:30)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 3-Bromo-2-methyl-pyridine (1.96 g, 11.4 mmol) in glacial HOAc (20 mL) at room temperature was added 50% H2O2 (0.77 mL) and the solution was heated to 70° C. After 2 h, the reaction mixture was cooled to room temperature, additional H2O2 (0.80 mL) was added, and the solution was heated at 70° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (80 mL) and treated with saturated aqueous NaHCO3 (20 mL). The aqueous phase was separated and extracted with CH2Cl2 (4×20 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to provide 3-Bromo-2-methyl-pyridine 1-oxide (1.79 g, 84%) as a white solid. 1H NMR (CDCl3) δ 2.70 (s, 3H), 7.00 (t, 1H, J=7.0 Hz), 7.44 (d, 1H, J=7.9 Hz), 8.23 (d, 1H, J=6.5 Hz). 3-Bromo-2-methyl-pyridine 1-oxide was used without further purification. the reaction mixture was cooled to room temperature the solution was heated at 70° C. overnight The reaction mixture was cooled to room temperature concentrated under reduced pressure The residue was dissolved in CH2Cl2 (80 mL) treated with saturated aqueous NaHCO3 (20 mL) The aqueous phase was separated extracted with CH2Cl2 (4×20 mL) The combined organic extracts were dried (Na2SO4) filtered concentrated