2,4-Dichloropyridine → Ethyl 2-[(4-chloro-2-pyridinyl)amino]-1,3-oxazole-5-carboxylate

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Objective: Peparation of the above coupled product on a larger scale for hydrolysis-protodecarboxylation study. To an oven-dried microwave vial was added ethyl 2-aminooxazole-5-carboxylate (546 mg, 3.50 mmol), 2,4-dichloropyridine (0.378 mL, 3.50 mmol), cesium carbonate (2279 mg, 6.99 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (80 mg, 0.09 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (152 mg, 0.26 mmol) and the vial was capped and purged with nitrogen. dioxane (18 mL) (degassed) was added and the reaction mixture was heated to 160 °C for 1 h under microwave irradiation. LCMS of the crude reaction mixture shows the required product to be the major product together with an isomer of the same mass (Rt= 1.91), the ratio of the desired product to this isomeric product being circa 5:1. LCMS also shows that a small amount of the 2-aminooxazole ester starting material remains (Rt= 0.99 min) and so the reaction with this particular substrate may benefit from slightly longer reaction times, maybe 90 mins. A small amount of the coupled and decarboxylated product was also present (Rt= 1.68 min). Saturated ammonium chloride (15 mL) was added to the crude reaction mixture and the mixture was transfrred to a separating funnel. Ethyl acetate (80 mL) was then added and the organic layer was separated (keeping the interfacial material with the organic layer). The aqueous layer was washed with ethyl acetate (2 x 80 mL portions). (Note: During this extraction, a solid, presumably the required product was seen to crash out in the organic layer. If this reaction is to be repeated a work-up free approach is recommended where the crude reaction mixture is dry-loaded directly onto silica for chromatographic purification). The solvent was removed from the combined organics under reduced pressure. The crude product was loaded onto a pre- wetted silica column using the minimum DCM and methanol. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% DCM (5% methanolic ammonia) in DCM. Pure fractions were evaporated to dryness to afford 744 mg of impure product. The crude residue was triturated with Et2O to give a solid which was collected by filtration and dried under vacuum to give ethyl 2-(4-chloropyridin-2-ylamino)oxazole-5-carboxylate (415 mg, 44.3 %) as a beige solid. Conclusion: The desired product was isolated in moderate yield and high purity (95% based on strength NMR). The moderate yield may be improved under a longer reaction time, it is also probable that purification difficulties were also detrimental to the yield of this reaction.

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