Hexane → 5-Ethyl-6-methoxy-2-methyl-nicotinic acid methyl ester

Participants

Reaction Conditions

Reaction Steps

An oven dried round-bottom flask is charged with toluene (35 mL) and cooled to −15° C. in a dry ice/acetone bath. A solution of butyl lithium in hexane (1.6M, 11.22 mL, 18.0 mmol) is added in one portion. To this mixture is added a solution of butylmagnesium bromide in tetrahydrofuran (2 M, 4.5 mL, 9.0 mmol) drop-wise over 1.25 hr to give a suspension. The reaction is stirred at −10° C. for 1 hr after which a solution of 3-bromo-5-ethyl-6-methoxy-2-methylpyridine (5 g, 21.7 mmol) in anhydrous toluene (10 mL) is added drop-wise over 1.25 hr. The resulting suspension is stirred at −10° C. for 30 min. The bath is cooled to −30° C. and allowed to warm slowly to 0° C. over 12 hr. The reaction is allowed to stir at −10° C. for 5 hr before diluting with anhydrous tetrahydrofuran (15 mL) to give a cloudy cream solution. This solution is added drop-wise over 1.5 hr to a cold solution of dimethyl carbonate (9.14 mL, 108 mmol) in anhydrous toluene (10 mL) stirring under a nitrogen atmosphere at −20° C. The resulting mixture is allowed to warm slowly to 0° C. After 5.5 hr, the reaction is quenched with saturated aqueous ammonium chloride (20 mL) and then partitioned between water and ethyl acetate. The ethyl acetate layer is washed with a further portion of water, and the combined aqueous washes are extracted with seven portions of ethyl acetate and two portions of dichloromethane. The combined organic extract is dried over magnesium sulfate, filtered and evaporated to give crude 5-ethyl-6-methoxy-2-methyl-nicotinic acid methyl ester (5.58 g) as an orange oil. This material is used without further purification. MS: m/e=210 (M+H); 1H NMR (CDCl3, δ, ppm): 7.94 (1H, s), 4.02 (3H, s), 3.90 (3H, s), 2.77 (3H, s), 2.59 (2H, q), 1.23 (3H, t).

Provenance & Evidence