Diethyl Ether → 4-Cyano-3-(2,2,2-trifluoro-ethoxy)-benzoic acid methyl ester

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Reaction Conditions

Reaction Steps

CF3SO2Cl (2.7 ml, 25.5 mmol) was added under argon atmosphere to diethylether (60 ml) and cooled to 0° C. CF3CH2OH (1.8 ml, 25.5 mmol) and Et3N (3 ml, 21.25 mmol) were then added dropwise. The reaction mixture was stirred at 0° C. for 0.5 hour. The reaction was cooled to -20° C. to maximize ppt. of Et3N.HCl. The mixture was filtered and washed with cold diethylether (1×20 mL). The filtrate was concentrated to approx. 1/2 the volume in vacuo, keeping the flask at room temp. to minimize the loss of trifluoromethanesulfonic acid 2,2,2-trifluoro-ethyl ester. The resulting solution was treated with 4-cyano-3-hydroxybenzoic acid methyl ester. Example 34, Step 3 (1.5 g, 8.5 mmol) in DMF (28 ml) containing Cs2CO3 (5 g, 21.25 mmol). The reaction mixture stirred for several hours. The mixture was filtered and washed with DMF (3×5 mL). The solvent was removed in vacuo and the residue was purified by flash chromatography (5% EtOAc/Hexane) to yield the desired product.

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