Hydrochloric Acid → Ethyl 3-(2,3-difluoro-5-iodophenyl)-3-oxopropanoate

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Reaction Steps

2,3-Difluoro-5-iodobenzoic acid (Preparation 19, 18.2 g) in tetrahydrofuran (100 mL) at room temperature is treated with 1,1′-carbonyldiimidazole (12.46 g) portion-wise over a one minute period under a nitrogen atmosphere and the mixture is stirred for 6 h. In a separate flask, ethyltrimethylsilyl malonate (14.38 g) in tetrahydrofuran (40 mL) is cooled to 0-5° C. and DBU (11.20 g) is added dropwise over a period of 15 minutes. After 5.5 h, this solution is cannulated into the ice cooled imidazolide solution over a 7 minute period with vigorous stirring. The mixture is allowed to slowly warm to room temperature overnight. The reaction mixture is poured into 600 mL of ice/water containing 41 mL of 6N HCl. The mixture is extracted 3 times with ethyl acetate. The combined organic extracts are dried (Na2SO4) and concentrated in vacuo. The crude product is purified by chromatography, using 600 g of silica gel, packed and eluted with methylene chloride/heptane/ethyl acetate/acetic acid (3/7/0.5%/0.5%), to afford the title compound in 65% yield as an orange oily solid. Physical characteristics: 1H NMR (CDCl3) δ12.65, 8.00, 7.94, 7.73, 7.58, 5.81, 4.35-4.19, 3.96, 1.35, 1.28; IR (diffuse reflectance) 2986, 1647, 1622, 1573, 1489, 1420, 1383, 1293, 1275, 1240, 1215, 1037, 958, 882, 801 cm−1; MS (EI) m/z 354 (M+); HRMS (FAB) m/z 354.9648 (C11H9F2IO3+H). Anal. Found: C, 37.34; H, 2.50; N, 0.15.

Provenance & Evidence