3-bromo-2-chloro-1-oxidopyridin-1-ium

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

Procedure: The reaction was also performed using the acylating agent dimethylcarbamoyl chloride. A solution of dimethylcarbamoyl chloride (12.9 mL, 0.14 mol) in dichloromethane (23 mL) was added drop-wise to a stirred solution of 3-bromo-2-chloropyridine 1-oxide (C27) (11.23 g, 53.9 mmol) and trimethylsilyl cyanide (17.5 mL, 0.14 mol) in dichloromethane (200 mL). The reaction mixture was heated under reflux for 3 days, then diluted with dichloromethane (450 mL) and washed with saturated aqueous sodium bicarbonate solution (2×200 mL), then with water (200 mL), dried over magnesium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 15% to 20% ethyl acetate in heptane) provided the title compound, contaminated with dimethylcarbamoyl cyanide (12.73 g, 100%) as an off-white solid. The impurity was reduced by repeatedly washing with aqueous sodium hydroxide solution (2 N) and a second chromatography on silica gel. Although the impurity could not be completely removed, the material was used in the next step without any detrimental effects. Yield: 7.83 g, 36.0 mmol, 67%. 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J=7.8 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H). The reaction mixture was heated under reflux for 3 days washed with saturated aqueous sodium bicarbonate solution (2×200 mL) with water (200 mL), dried over magnesium sulfate concentrated in vacuo Purification via silica gel chromatography (Gradient: 15% to 20% ethyl acetate in heptane)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Trimethylsilyl cyanide (19 mL, 0.15 mol) was added to a stirred solution of 3-bromo-2-chloropyridine 1-oxide (C27) (31.6 g, 0.152 mol) and triethylamine (63.4 mL, 0.46 mol) in acetonitrile (400 mL). The reaction mixture was heated to 50° C. for 2 hours. It was then cooled to room temperature and additional trimethylsilyl cyanide (19 mL, 0.15 mol) was added. After the reaction mixture was heated at 50° C. for 1.5 hours, a final portion of trimethylsilyl cyanide (28.5 mL, 0.23 mol) was added and the reaction was heated at reflux for 3 days. After dilution with dichloromethane (2 L), the reaction was washed with saturated aqueous sodium bicarbonate solution (800 mL), then with water (1 L), dried over magnesium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 20% to 25% ethyl acetate in heptane) afforded the title compound as a yellow solid. Yield: 14.92 g, 68.6 mmol, 45%. It was then cooled to room temperature After the reaction mixture was heated at 50° C. for 1.5 hours the reaction was heated at reflux for 3 days After dilution with dichloromethane (2 L), the reaction was washed with saturated aqueous sodium bicarbonate solution (800 mL) with water (1 L), dried over magnesium sulfate concentrated in vacuo Purification via silica gel chromatography (Gradient: 20% to 25% ethyl acetate in heptane)

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

Procedure: A solution of 3-bromo-2-chloropyridine (50 g, 0.26 mol) and 3-chloroperoxybenzoic acid (70-75% wet with water; 67.3 g, 0.39 mol) in 1,2-dichloroethane (600 mL) was heated under reflux for 7 hours. The reaction was then concentrated under reduced pressure to an approximate volume of 200 mL and purified by chromatography on silica gel (Gradient: 80% to 100% ethyl acetate in heptane, followed by 5% to 10% methanol in ethyl acetate) to yield the title compound as a brown solid. Yield: 32.9 g, 0.158 mol, 61%. LCMS m/z 210.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 7.09 (dd, J=7.8, 6.9 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 8.33 (d, J=6.4 Hz, 1H). under reflux for 7 hours The reaction was then concentrated under reduced pressure to an approximate volume of 200 mL purified by chromatography on silica gel (Gradient: 80% to 100% ethyl acetate in heptane, followed by 5% to 10% methanol in ethyl acetate)