Chlorotrimethylsilane → Methyl 2,6-difluoro-3-hydroxybenzoate

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Reaction Steps

To a solution of 2,4-difluoro-1-(methoxymethoxy)benzene (2.00 g, 11.5 mmol) in THF (30 mL) under nitrogen at −70° C. was added a solution of n-butyllithium in hexanes (1.4 M, 8.20 mL, 11.48 mmol) dropwise over 10 min. The mixture was stirred at −70° C. for 1.5 hr and was then decanted onto freshly pulverized dry ice (˜20 g). Once the effervescence had subsided the mixture was allowed to warm to RT and water (20 mL) was added. The aq solution was extracted twice with ether and was then acidified to pH 1 by the addition of concentrated hydrochloric acid. The resulting suspension was sonicated for 5 min and was then extracted twice with DCM and the combined DCM extracts were dried (MgSO4) and evaporated in vacuo. The residue was triturated with a mixture of isohexane and ether (50:3 v/v) to furnish 2,6-difluoro-3-(methoxymethoxy)benzoic acid as a white solid (1.99 g, 77% yield); Rt 2.31 min (Method 1, basic); m/z 219 (M+H)+ (ES+), which was used directly in the next step (below). To a solution of 2,6-difluoro-3-(methoxymethoxy)benzoic acid (2.74 g, 12.6 mmol) in MeOH (50 mL) was added TMS-Cl (7.94 mL, 62.8 mmol) dropwise and the resulting colourless solution heated at reflux for 3 hr. The resulting mixture was cooled to RT and was then evaporated in vacuo and the residue was subjected to SCX capture and release to afford methyl 2,6-difluoro-3-hydroxybenzoate as a white solid (2.38 g, 100%); Rt 2.29 min (Method 1, basic); m/z 187 (M−H)− (ES−).

Provenance & Evidence