Pyrazole → 3-Ethyl-2-methoxy-6-methyl-5-(pyrazol-1-yl)pyridine

Participants

Reaction Conditions

Reaction Steps

Into each of 2 microwave vials is added 3-bromo-5-ethyl-6-methoxy-2-methylpyridine (200 mg, 0.869 mmol), potassium carbonate (180 mg, 1.30 mmol), copper iodide (16 mg, 0.084 mmol) and pyrazole (59 mg, 0.869 mmol). The vials are flushed with N2 before anhydrous dimethylformamide (5.5 mL) is added and then sealed. The first reaction is heated in the CEM Discover microwave at 160° C. for 20 minutes. LC/MS shows the reaction is incomplete. The reaction is re-microwaved to 180° C. for 20 min and LC/MS suggests that the reaction is approximately 50% complete. The reaction is re-microwaved at 185° C. for 20 min then 185° C. for 30 min and LC/MS shows the reaction is largely complete. Reaction 2 is heated in the microwave to 185° C. for 1.5 hr and LC/MS shows the reaction is almost complete. The 2 reactions are combined and diluted with water and extracted with 3 portions of dichloromethane. The combined organic layers are washed with 2 portions of aqueous sodium hydroxide (1M), then dried over magnesium sulfate and evaporated to give a dark oil. 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 and the solvent evaporated. The residue is further purified by flash chromatography on a 5-gram silica gel cartridge by elution with heptane:ethyl acetate (19:1) then dichloromethane:heptane (1:1, increasing to 1:0). Clean fractions containing the product are combined and evaporated to give 3-ethyl-2-methoxy-6-methyl-5-(pyrazol-1-yl)pyridine as a yellow oil (102 mg, 27% yield). MS: m/e=218 (M+H); NMR (CDCl3): 7.70 (1H, d), 7.53 (1H, d), 7.37 (1H, s), 6.44 (1H, t), 3.99 (3H, s), 2.59 (2H, q), 2.29 (3H, s), 1.10 (3H, t)

Provenance & Evidence