Reaktion #1274170

Reaktionsgleichung

3-Chloro-2,4-difluorobenzonitrile

methyl malonate

NaH

DMF

hydrogen

→

title product

(2-Chloro-4-cyano-3-methoxyphenyl)ethylene oxide

Lösungsmittel

ether

Reaktionsbedingungen

Aufarbeitung

1. 1
   Temperaturthe reaction was heated to 90° C. for 4 hours
2. 2
   Sonstigequenched into water containing 2N HCl
3. 3
   ExtraktionThe mixture was extracted twice with ether
4. 4
   Waschenthe ether layers were washed with brine
5. 5
   Trocknendried over sodium sulfate
6. 6
   Einengenconcentrated in vacuo
7. 7
   workup.ADDITIONdichloromethane (50 mL) and 2M trimethylsilyldiazomethane in ether was added until the yellow color
8. 8
   SonstigeThe excess diazomethane was quenched with acetic acid
9. 9
   SonstigeThe product mixture was separated by flash chromatography (5-10% ethyl acetate/hexanes
10. 10
    Sonstige10-20%) to afford first some recovered

Vorschrift

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).

Quelle