Cesium carbonate → Methyl 3-methyl-2-oxo-1-(3-pyridinyl)-4-imidazolidinecarboxylate

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Reaction Steps

A solution of 3-bromopyridine (316 mg, 2. mmol) and methyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (316 mg, 2 mmol) (prepared as described in step (ii) of Example 8) in 1,4-dioxane (10 ml) was treated with cesium carbonate (977 mg, 3 mmol), Xantphos™ (87 mg, 0.15 mmol) (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, e.g. available from Aldrich, CAS no. 161265-03-8) and tris(dibenzylideneacetone)dipalladium(0) (45.8 mg, 0.05 mmol) and the mixture was heated under reflux under argon for 22 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give methyl 3-methyl-2-oxo-1-(3-pyridinyl)-4-imidazolidinecarboxylate (273 mg, 58%). LC/MS [M+H]+=236. (ii) A solution of methyl 3-methyl-2-oxo-1-(3-pyridinyl)-4-imidazolidinecarboxylate (0.27 g, 1.15 mmol) in tetrahydrofuran (3 ml) at 0° C. was treated with a solution of lithium hydroxide (0.030 g, 1.26 mmol) in water (2 ml) and the mixture was stirred at 0° C. for 90 minutes. Hydrochloric acid (2M) was added to adjust the pH of the reaction mixture to pH 2 and the solvent was evaporated. The residue was dried over phosphorus pentoxide to give crude 3-methyl-2-oxo-1-(3-pyridinyl)-4-imidazolidinecarboxylic acid which was used in the next step. LC/MS [M+H]+=222.

Provenance & Evidence