tert-butyl 3,5-difluoro-4-formylbenzoate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of tert-butyl 3,5-difluoro-4-formylbenzoate (21 g, 86.7 mmol) in MeOH was portionwise added NaBH4 (3.28 g, 86.7 mmol) at 0° C. After 20 min, the reaction mixture was evaporated in vacuo and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography (Hex/EtOAc=4:1) to give tert-butyl 3,5-difluoro-4-(hydroxymethyl)benzoate (20.7 g, 97%) as a white solid. at 0° C the reaction mixture was evaporated in vacuo the product was extracted with ethyl acetate The organic layer was washed with brine dried over MgSO4 evaporated in vacuo The residue was purified by flash column chromatography (Hex/EtOAc=4:1)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of diisopropylamine (5 mL, 35.5 mmol, 1.2 eq) in THF (100 mL, anhyd) was slowly added BuLi (1.6M in hexanes, 20 mL, 32.3 mmol, 1.1 eq) at below 0° C. After addition was completed, the solution was cooled to −78° C. and then charged dropwise with a solution of tert-butyl 3,5-difluorobenzoate (6.3 g, 29 mmol) in THF (50 mL, anhyd) over 1 h. The resulting solution was stirred for another 2 h at −78° C. Next anhyd DMF (2.5 mL, 32.3 mmol, 1.1 eq) was added dropwise and, after 30 min, AcOH (4 mL) and water were added successively to quench the reaction. The reaction mixture was warmed to room temperature and diluted with EtOAc (100 mL). The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (Hex/EtOAc=4:1) to give tert-butyl 3,5-difluoro-4-formylbenzoate (5.8 g, 83%) as a white solid. at below 0° C After addition to quench the reaction The reaction mixture was warmed to room temperature The organic layer was washed with brine dried over MgSO4 concentrated in vacuo The residue was purified by flash column chromatography (Hex/EtOAc=4:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of tert-butyl 3,5-difluoro-4-formylbenzoate (21 g, 86.7 mmol) in MeOH was portionwise added NaBH4 (3.28 g, 86.7 mmol) at 0° C. After 20 min, the reaction mixture was evaporated in vacuo and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography (Hex/EtOAc=4:1) to give tert-butyl 3,5-difluoro-4-(hydroxymethyl)benzoate (20.7 g, 97%) as a white solid. at 0° C the reaction mixture was evaporated in vacuo the product was extracted with ethyl acetate The organic layer was washed with brine dried over MgSO4 evaporated in vacuo The residue was purified by flash column chromatography (Hex/EtOAc=4:1)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of diisopropylamine (5 mL, 35.5 mmol, 1.2 eq) in THF (100 mL, anhyd) was slowly added BuLi (1.6M in hexanes, 20 mL, 32.3 mmol, 1.1 eq) at below 0° C. After addition was completed, the solution was cooled to −78° C. and then charged dropwise with a solution of tert-butyl 3,5-difluorobenzoate (6.3 g, 29 mmol) in THF (50 mL, anhyd) over 1 h. The resulting solution was stirred for another 2 h at −78° C. Next anhyd DMF (2.5 mL, 32.3 mmol, 1.1 eq) was added dropwise and, after 30 min, AcOH (4 mL) and water were added successively to quench the reaction. The reaction mixture was warmed to room temperature and diluted with EtOAc (100 mL). The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (Hex/EtOAc=4:1) to give tert-butyl 3,5-difluoro-4-formylbenzoate (5.8 g, 83%) as a white solid. at below 0° C After addition to quench the reaction The reaction mixture was warmed to room temperature The organic layer was washed with brine dried over MgSO4 concentrated in vacuo The residue was purified by flash column chromatography (Hex/EtOAc=4:1)