Methanol → Methyl 2-methylisonicotinate

Participants

Reaction Conditions

Reaction Steps

A suspension of 2-methyl-pyridine-4-carboxylic acid (1.0 g, 7.29 mmol) in methanol (50 mL) and H2SO4 (0.5 mL) is heated to 70° C. The solid material dissolves and stirring is continued at 70° C. for 18 h. The mixture is cooled to rt, filtered, and the filtrate is evaporated. The remaining solid is washed with diethyl ether and dried to give methyl 2-methyl-pyridine-4-carboxylate; LC-MS: tR=0.39 min, [M+1]+=152.05. This material is dissolved in 7 N NH3 in methanol (25 mL) and the mixture is stirred in a sealed vial for 20 h at 60° C. before it is filtered. The filtrate is evaporated to give crude 2-methyl-isonicotinamide (2.12 g) as a brownish solid. To a solution of this material in DCM (25 mL), pyridine (5.24 g, 54.0 mmol) is added. The mixture is cooled to 0° C. before trifluoroacetic anhydride (8.10 g, 38.6 mmol) is added portionwise. Stirring is continued at 0° C. for 2 h before the reaction is quenched with water. The mixture is diluted with DCM and the org. phase is separated and washed with 5% aq. citric acid solution followed by sat. aq. NaHCO3 solution. The washings are extracted back twice with DCM. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with heptane:EA 4:1 to give 2-methyl-isonicotinonitrile (330 mg); LC-MS: tR=0.55 min, [M+1]+=119.13.

Provenance & Evidence