1-Bromo-2,3,5-trifluorobenzene → N,N-dimethyl-2-morpholin-4-yl-4-oxo-8-[1-(2,3,5-trifluoroanilino)ethyl]chromene-6-carboxamide

Participants

Reaction Conditions

Reaction Steps

To a mixture of 8-(1-aminoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (350 mg, 1.01 mmol), cesium carbonate (1288 mg, 3.95 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (147 mg, 0.25 mmol) and 1-bromo-2,3,5-trifluorobenzene (470 mg, 2.23 mmol) in degassed 1,4-dioxane (2.2ml), was added TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (69.6 mg, 0.08 mmol). The suspension was heated in a sealed container up to 85-95°C for 24 hours. The reaction mixture was filtered through a short pad of dicalite, concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford the N,N-dimethyl-2-morpholino-4-oxo-8-(1-(2,3,5-trifluorophenylamino)ethyl)-4H-chromene-6-carboxamide (400 mg, 83 %) as a yellow gum, which still containing some impurities. The product mixture was then re-purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml / minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford N,N-dimethyl-2-morpholino-4-oxo-8-(1-(2,3,5-trifluorophenylamino)ethyl)-4H-chromene-6-carboxamide (135 mg, 28 %) as a clear yellow solid.

Provenance & Evidence