4-Bromo-2-fluoro-benzoic acid methyl ester → Methyl 4-cyano-2-fluorobenzoate

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Reaction Steps

Slurry methyl 4-bromo-2-fluoro-benzoate (5 g, 21.5 mmol) and copper(I) cyanide (3.8 g, 42.9 mmol) in anhydrous DME (90 mL). Heat the mixture to reflux for 20 h under a nitrogen atmosphere. Cool the mixture to room temperature, dilute with hexane/EtOAc (1:1, 300 mL) and water (150 mL). Filter the mixture through Celite® washing with hexane/EtOAc (1:1) to reduce the emulsion layer. Separate the organic layer and extract the aqueous layer with hexane/EtOAc (1:1, 2×200 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1 gradient) to obtain the desired intermediate (2.9 g, 76%). GC-MS m/z: 179 (M+).

Provenance & Evidence