Acetic Acid → 3-Chloro-6,7-difluorobenzo[d]isoxazole-5-carbaldehyde

Participants

Reaction Conditions

Reaction Steps

A solution of n-butyllithium (2.5 M in hexanes) (16.7 ml, 42 mmol) was added slowly to a solution of 2,2,6,6-tetramethylpiperidine (7.6 ml, 45 mmol) in THF (50 ml) cooled in a dry ice-acetone bath. The solution was warmed to 0° C. and re-cooled in a dry-ice acetone bath before transferring via syringe to a solution of 3-chloro-6,7-difluorobenzo[d]isoxazole (Intermediate 529, 5.64 g, 30 mmol) in THF (50 ml). After 1 hour stirring, DMF (1.0 ml, 13.2 mmol) was added all at once and the mixture was stirred with cooling in a dry-ice acetone bath for 45 min. The mixture transferred via cannula to a solution of acetic acid (6.8 ml, 119 mmol) in 100 ml Et2O and the mixture was warmed to room temperature. The mixture was diluted with EtOAc and washed with brine. The combined aqueous layers were extracted again with EtOAc, which was washed with brine. Drying (MgSO4) of the combined extracts and removal of solvent gave a brown oil that was chromatographed on silica gel (10% CH2Cl2 in hexanes followed by gradient elution to 100% CH2Cl2) to give 3.32 g of product as a white solid.

Provenance & Evidence