4,5-difluoro-2-methoxybenzonitrile

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of NaH (60% in mineral oil, 0.33 g, 8.3 mmol) in dry DMF (20 mL) was stirred and cooled to 0° C., and di-tert-butyl malonate (1.5 g, 7.1 mmol) was added. The mixture was allowed to warm to room temperature before addition of 4,5-difluoro-2-methoxybenzonitrile (1.0 g, 5.9 mmol). The mixture was heated at 80° C. for 4 h with stirring, then the reaction mixture was cooled to room temperature and poured into a mixture of ice-water (100 mL) and AcOEt (100 mL). The layers were separated, and the organic layer was washed successively with water, and brine, then dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica gel, EtOAc/hexanes, 0->10%) to give the di-tert-butyl (4-cyano-5-fluoro-2-methoxyphenyl)propanedioate. LCMS: [(M+1)−t-Bu, CO2−t-Bu]+=210.1; tR=2.2 min. The mixture was heated at 80° C. for 4 h with stirring the reaction mixture was cooled to room temperature The layers were separated the organic layer was washed successively with water, and brine dried over Na2SO4 concentrated The residue was purified by flash chromatography (silica gel, EtOAc/hexanes, 0->10%)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of NaH (60% in mineral oil, 0.33 g, 8.3 mmol) in dry DMF (20 mL) was stirred and cooled to 0° C., and di-tert-butyl malonate (1.5 g, 7.1 mmol) was added. The mixture was allowed to warm to room temperature before addition of 4,5-difluoro-2-methoxybenzonitrile (1.0 g, 5.9 mmol). The mixture was heated at 80° C. for 4 h with stirring, then the reaction mixture was cooled to room temperature and poured into a mixture of ice-water (100 mL) and AcOEt (100 mL). The layers were separated, and the organic layer was washed successively with water, and brine, then dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica gel, EtOAc/hexanes, 0→10%) to give the di-tert-butyl(4-cyano-5-fluoro-2-methoxyphenyl)propanedioate. LCMS: [(M+1)-t-Bu,CO2-t-Bu]+=210.1; tR=2.2 min. The mixture was heated at 80° C. for 4 h with stirring the reaction mixture was cooled to room temperature The layers were separated the organic layer was washed successively with water, and brine dried over Na2SO4 concentrated The residue was purified by flash chromatography (silica gel, EtOAc/hexanes, 0→10%)