Methyl triflate → 4-Cyclopropyl-6-methyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester

Participants

Reaction Conditions

Reaction Steps

2-Cyclopropanecarbonyl-3-oxo-butyric acid ethyl ester [Jung, J.-C.; Watkins, E. B.; Avery, M. A. Tetrahedron (2002), 58(18), 3639-3646] (4.7 g, 24 mmol) was dissolved in acetonitrile (40 ml) and cooled to 0° C. Cesium carbonate (7.8 g, 24 mmol) was added and the reaction stirred for 0.5 h before the addition of trifluoro-methanesulfonic acid methyl ester (2.6 ml, 24 mmol) and the reaction stirred for a further 2 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried (Na2SO4) and concentrated to afford a crude mixture of (E,Z)-2-cyclopropanecarbonyl-3-methoxy-but-2-enoic acid ethyl ester and/or 2-[1-cyclopropyl-1-methoxy-meth-(E,Z)-ylidene]-3-oxo-butyric acid ethyl ester (6.3 g, quant). A third of this material (2.1 g, 8 mmol) was dissolved in ethanol (10 ml) and added dropwise to a solution of 3-trifluoromethyl-benzamidine hydrochloride (1.8 g, 8 mmol) and sodium tert-butoxide (0.8 g, 8 mmol) and the mixture stirred overnight. The reaction was concentrated, re-dissolved in EtOAc, washed with 1N hydrochloric acid solution, dried (Na2SO4) and concentrated. Purification by flash column chromatography (EtOAc/Heptane 1:9) afforded the title product (1.2 g, 42%) as clear oil. MS: 351.2 (MH+).

Provenance & Evidence