2-Chloro-4-cyanopyridine → Ethyl 2-[(4-cyano-2-pyridinyl)amino]-1,3-oxazole-5-carboxylate

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Objective: To test substrate scope in 5-ester substituted 2-aminooxazole coupling. TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.87 mg, 0.02 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (43.4 mg, 0.075 mmol), cesium carbonate (651 mg, 2.00 mmol), ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol) and 2-chloroisonicotinonitrile (138 mg, 1.00 mmol) were placed in an oven dried microwave vial. The vial was then capped and placed under an inert atmosphere. Dioxane (4 mL) was added and the mixture was heated to 160 °C for 1 h under microwave irradiation. LCMS of the crude reaction mixture indicated the presence of the desired product as well as a significant amount of amine starting material. DCM (10 mL) was added to the crude reaction mixture together with C-18 silica (2 g), and the solvent was removed under reduced pressure. The solid residue was then placed in a dry-load tube prior to chromatography. The crude product was purified by reverse-phase flash chromatography on C-18 silica, elution gradient 20 to 60% MeCN in water (1% ammonium hydroxide). Pure fractions were evaporated to dryness to afford ethyl 2-(4-cyanopyridin-2-ylamino)oxazole-5-carboxylate (155 mg, 60.1 %) as a beige solid. Conclusion: The desired product was isolated in moderate yield.

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