Sodium Hydroxide → (2-Chloro-5-fluoropyridin-3-yl)methanol

Participants

Reaction Steps

2-Chloro-5-fluoronicotinic acid (4.50 g, 25.6 mmol) was dissolved in dichloromethane (100 mL) and dry dimethylformamide (1 mL) and cooled in an ice bath. Thionyl chloride (20 ml, 274 mmol) was added slowly and the reaction stirred for 20 minutes then it was removed from the ice bath. After another 15 minutes the solution was evaporated to dryness under reduced pressure. The crude acid chloride was further dried under high vacuum then dissolved in dry tetrahydrofuran (20 mL) and slowly added to an ice cooled solution of sodium borohydride (2.5 g, 66.1 mmol) in water (100 mL with about 80 mL of ice) over 40 minutes. The reaction was stirred for an additional 15 minutes. Ethyl acetate (400 mL) and additional water (100 mL) were added and the phases stirred. Sodium hydroxide (5 N, 40 mL) was added to make the aqueous layer basic. The mixed phases were stirred for 2 hours then the layers were separated. The organic layer was dried with magnesium sulfate before evaporating to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the desired (2-chloro-5-fluoropyridin-3-yl)methanol (1.42 g, 8.79 mmol, 34.3% yield) as a brown oil that solidified on standing.

Provenance & Evidence