3-chloro-2,4-difluorobenzonitrile

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

Procedure: t-Butyl, methyl malonate (7.5 g, 43 mmol) in DMF (50 mL) was cooled in an ice bath before NaH (60% in mineral oil, 1.0 g, 42 mmol) was added portionwise over 5 minutes with hydrogen evolution. The suspension was allowed to warm to RT for 30 minutes at which time everything was in solution. 3-Chloro-2,4-difluorobenzonitrile (5.0 g, 28.8 mmol) was added as a solid and the reaction was heated to 90° C. for 4 hours and then at RT for 12 hours. TLC (15% ethyl acetate/hexanes) indicated still some starting material but mostly product at a slightly lower Rf. The reaction was diluted with ether and quenched into water containing 2N HCl. The mixture was extracted twice with ether and the ether layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was taken up in 1:1 methanol:dichloromethane (50 mL) and 2M trimethylsilyldiazomethane in ether was added until the yellow color persisted to re-esterify any acid. The excess diazomethane was quenched with acetic acid and the mixture was reconcentrated. The product mixture was separated by flash chromatogrphy (5-10% ethyl acetate/hexanes, then 10-20%) to afford first some recovered starting material, then a mixture of product and isomeric t-butyl, methyl (R,S)-2-(2-chloro-6-cyano-3-fluorophenyl)malonate by NMR (900 mg), followed by clean title product isomer. the reaction was heated to 90° C. for 4 hours quenched into water containing 2N HCl The mixture was extracted twice with ether the ether layers were washed with brine dried over sodium sulfate concentrated in vacuo dichloromethane (50 mL) and 2M trimethylsilyldiazomethane in ether was added until the yellow color The excess diazomethane was quenched with acetic acid The product mixture was separated by flash chromatogrphy (5-10% ethyl acetate/hexanes 10-20%) to afford first some recovered

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

Procedure: t-Butyl, methyl malonate (7.5 g, 43 mmol) in DMF (50 mL) was cooled in an ice bath before NaH (60% in mineral oil, 1.0 g, 42 mmol) was added portionwise over 5 minutes with hydrogen evolution. The suspension was allowed to warm to RT for 30 minutes at which time everything was in solution. 3-Chloro-2,4-difluorobenzonitrile (5.0 g, 28.8 mmol) was added as a solid and the reaction was heated to 90° C. for 4 hours and then at RT for 12 hours. TLC (15% ethyl acetate/hexanes) indicated still some starting material but mostly product at a slightly lower Rf. The reaction was diluted with ether and quenched into water containing 2N HCl. The mixture was extracted twice with ether and the ether layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was taken up in 1:1 methanol:dichloromethane (50 mL) and 2M trimethylsilyldiazomethane in ether was added until the yellow color persisted to re-esterify any acid. The excess diazomethane was quenched with acetic acid and the mixture was reconcentrated. The product mixture was separated by flash chromatography (5-10% ethyl acetate/hexanes, then 10-20%) to afford first some recovered starting material, then a mixture of product and isomeric t-butyl, methyl(R,S)-2-(2-chloro-6-cyano-3-fluorophenyl)malonate by NMR (900 mg), followed by clean title product isomer. 1H-NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 9H), 3.79 (s, 3H), 5.15 (s, 1H), 7.448 (d, J=8.3 Hz, 1H), 7.56 (dd, J=6.0, 8.2, 1H). the reaction was heated to 90° C. for 4 hours quenched into water containing 2N HCl The mixture was extracted twice with ether the ether layers were washed with brine dried over sodium sulfate concentrated in vacuo dichloromethane (50 mL) and 2M trimethylsilyldiazomethane in ether was added until the yellow color The excess diazomethane was quenched with acetic acid The product mixture was separated by flash chromatography (5-10% ethyl acetate/hexanes 10-20%) to afford first some recovered