Methyl iodide → 3-Chloro-4-fluoro-2-methylbenzoic acid

Participants

Reaction Conditions

Reaction Steps

BuLi (68.8 mL, 110 mmol) was diluted with tetrahydrofuran (THF) (80 mL) and cooled to −20° C. 2,2,6,6-tetramethylpiperidine (18.56 mL, 110 mmol) was added dropwise and the mixture stirred at −20° C. for 15 minutes. The solution was cooled to −50° C. whereupon 3-chloro-4-fluorobenzoic acid (8.73 g, 50 mmol, commercially available from e.g. Sigma-Aldrich, Fluorochem or Apollo) dissolved in tetrahydrofuran (THF) (20 mL) was added dropwise. The mixture was stirred at −50° C. for 4 hours before iodomethane (12.51 mL, 200 mmol) was added dropwise. The mixture was allowed to reach room temperature overnight and quenched with water (100 mL). The mixture was acidified with 5N HCl (200 mL) and extracted with tert-butyl methyl ether (3×300 mL). The combined extracts were washed with water (100 mL), brine (100 mL) dried over anhydrous magnesium sulfate and concentrated to a crude product. The solid was recrystalised from cyclohexane (note: some insolubles not satisfactorarily removed) to afford product in 5.73 g.

Provenance & Evidence