Ethyl 4,4,4-trifluoroacetoacetate → 8-trifluoromethyl-3,4-dihydro-2H,5H-1-oxa-4,5-diaza-anthracen-6-one

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Reaction Steps

To a solution of 3,4-dihydro-2H-benzo[1,4]oxazin-6-yl amine (0.56 g, 3.73 mmol) in toluene (20 mL) was added ethyl 4,4,4-trifluoroacetoacetate (0.55 mL, 3.73 mmol) and 4 drops of pyridine. The solution was heated to reflux for 6 hours, then allowed to stir overnight at room temperature. The solvent was removed under vacuum and the residue triturated with diethyl ether. The solid was filtered off and washed with diethyl ether to yield a gray solid which was determined by 1HNMR to contain crude N-(3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-4,4,4-trifluoro-3-oxo-butyramide. The rest of the material in the filtrate was also determined by 1HNMR to be crude N-(3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-4,4,4-trifluoro-3-oxo-butyramide, but much less pure than the gray solid filtered off. The mixture was recovered by evaporating the ether. This mixture (0.8 g) was stirred in of concentrated sulfuric acid (8 mL) overnight at room temperature. The reaction mixture was then poured onto ice and neutralized by adding 1N sodium carbonate. The resulting solution was extracted three times with ethyl acetate, the extracts dried over magnesium sulfate, filtered and evaporated under vacuum to yield a brown oil. The brown oil (crude material) was purified by column chromatography on a Biotage system eluting with 4% methanol/ethyl acetate to yield 8-trifluoromethyl-3,4-dihydro-2H,5H-1-oxa-4,5diaza-anthracen-6-one as the main product.

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