Methyl chloroformate → (3-Bromo-5-chloropyridin-4-yl)methanol

Participants

Reaction Conditions

Reaction Steps

To a solution of diisopropylamine (0.963 ml, 6.76 mmol) in THF (45 ml) at −78° C. was added n-butyllithium (2.5M in hexanes, 2.5 mL, 6.24 mmol). The reaction mixture was stirred for 15 minutes, at which time 3-bromo-5-chloropyridine (CAS#73583-39-8, 1.0 g, 5.20 mmol) in THF (10.0 mL) was added followed by a 1.5 mL THF wash. After 10 minutes methyl chloroformate (0.443 ml, 5.72 mmol) was added. The reaction was stirred for 20 minutes and then quenched at −78° C. with 5% AcOH in MeOH. The reaction was then diluted with saturated aqueous ammonium chloride and placed at room temperature. The reaction was then diluted with DCM and saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting ester was used without further purification. To a solution of lithium aluminum hydride (109 mg, 2.87 mmol) in THF (30 ml) at −78° C. was added a solution of the ester prepared above (450 mg, 1.797 mmol) in THF (7.0 mL). The reaction was permitted to warm to −30° C. and stirred for 45 minutes. The reaction was then quenched with 0.9 mL of a 9:1 THF/H2O solution followed by 2 N NaOH (0.3 mL). The reaction was placed at rt and water (1.0 mL) was added followed by THF (9 mL). The reaction was stirred for 5 minutes and then charged with magnesium sulfate (ca. 1.0 g). The resulting mixture was filtered through a pad of Celite® and the filtrate was concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 7%) to afford (3-bromo-5-chloro-pyridin-4-yl)-methanol; 1H NMR (400 MHz, CDCl3) δ ppm 4.94 (s, 2H), 8.52 (s, 1H), 8.62 (s, 1H).

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