Benzeneacetonitrile, 3-fluoro- → Methyl 4-cyano-3-(p-fluorophenyl)-4-(m-fluorophenyl)butyrate

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Reaction Steps

Sodium methoxide (3.0 g, 0.056 mol) is added in one portion to a stirred solution of m-fluorophenylacetonitrile (78.0 g, 0.577 mol) and methyl p-fluorocinnamate (100.0 g, 0.555 mol) in 700 mL of azeotropically dried toluene cooled in an ice bath under a nitrogen atmosphere. The reaction mixture is warmed to room temperature (18° C. to 24° C.) and stirred for five days. The mixture is concentrated under vacuum to yield a brown syrup which is partitioned between diethyl ether and water. The orange ether layer is washed three times with water, once with 1% aqueous hydrochloric acid, again with water and finally with a saturated aqueous sodium chloride solution. After stirring with magnesium sulfate, the filtrate is concentrated on a rotary evaporator using a water aspirator, followed by a vacuum pump at 0.5 mm Hg for eight hours. The title product is obtained in 95% yield (166.7 g) as a pinkish-orange semi-solid identified as an isomeric mixture of esters based on the proton and carbon magnetic resonance, infrared and chemical ionization mass spectra. The ratio of erythro/threo isomers is 62/38, respectively, based on the integrated areas of the CHCN doublets centered at δ4.38 (J=6 Hz) and 4.11 (J=7 Hz) ppm, respectively, in the proton nmr spectrum (CDCl3). Thin layer chromatography on Merck Silica Gel 60 F-254 plates (CH2Cl2) shows two major spots which are not completely resolved. Gas-liquid chromatography (10% SP 2100 programmed at 125°/five minutes to 250°/30 minutes at a rate of 10°/minute) indicates a 93 relative area percent purity for the isomeric esters.

Provenance & Evidence