Hydrochloric Acid → 2-Fluoro-3-(methoxymethoxy)-6-(neopentyloxy)pyridine

Participants

Reaction Conditions

Reaction Steps

A solution of 3-bromo-2-fluoro-6-(neopentyloxy)pyridine (5.6 g, 21.36 mmol) in THF (50 mL) was cooled to −100° C. and a solution of n-butyllithium (1.6M in hexane; 14.69 mL, 23.50 mmol) was added drop wise. The reaction mixture was allowed to stir for 10 min at −100° C. Triisopropyl borate (7.35 mL, 32.0 mmol) was added and the reaction mixture was allowed to warm to rt. Aqueous NaOH solution (5M; 29.9 mL, 150 mmol) was added, followed by hydrogen peroxide (30%; 15.28 mL, 150 mmol). The reaction mixture was allowed to stir for 30 min at rt. The reaction mixture was acidified with 2N HCl and extracted with EtOAc. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure, the residue was dissolved in acetone (50 mL) and the solution was cooled to 0° C. K2CO3 (3.25 g, 23.50 mmol) was added, followed by chloromethyl methyl ether (1.785 mL, 23.50 mmol). After 30 min, additional K2CO3 (3.25 g, 23.50 mmol) and chloromethyl methyl ether (1.785 mL, 23.50 mmol) were added and the reaction mixture was warmed to rt. After 2 h brine and diethyl ether were added. The organic was separated and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (0-20% EtOAc/hexanes) to yield 2-fluoro-3-(methoxymethoxy)-6-(neopentyloxy)pyridine (2.88 g, 11.84 mmol).

Provenance & Evidence