Acetic Acid → 3-Ethyl-2-methoxy-6-methyl-5-(1,2,4-oxadiazol-5-yl)pyridine

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Reaction Conditions

Reaction Steps

In a round bottom flask under a nitrogen atmosphere a mixture of N-dimethylaminomethylene-5-ethyl-6-methoxy-2-methylnicotinamide (synthesized on 1.13 mmol scale) of Step 2, Example 16, hydroxylamine hydrochloride (103 mg, 1.48 mmol) and sodium hydroxide (59.4 mg, 1.48 mmol) and glacial acetic acid (1.7 mL) is treated with water (0.85 mL) and 1,4-dioxane (1.24 mL). The resulting dark mixture is stirred at 90° C. for 45 min. The reaction mixture is evaporated and the residue is partitioned between water and dichloromethane. The mixture is treated with excess solid sodium bicarbonate, the dichloromethane layer is separated and the aqueous layer is extracted with 2 further portions of dichloromethane. The combined organic layer is dried over magnesium sulfate and evaporated. The crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane. Fractions containing the product are combined, evaporated and re-purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane. Fractions containing the product are combined and the solvent evaporated to give 3-ethyl-2-methoxy-6-methyl-5-(1,2,4-oxadiazol-5-yl)pyridine as a white solid (138 mg, 56% yield, 2 steps). NMR (CDCl3, δ ppm): 8.45 (1H, s), 8.05 (1H, s), 4.02 (3H, s), 2.82 (3H, s), 2.62 (2H, q), 1.23 (3H, t).

Provenance & Evidence