Diethyl Malonate → 1-(4-Chloro-2-nitrophenyl)ethan-1-one

Participants

Reaction Conditions

Reaction Steps

To a solution of 4-chloro-2-nitrobenzoic acid (30.0 g, 0.15 mol) in THF (400 mL) was added oxalyl chloride (26 mL, 0.3 mol) at 0° C., followed by DMF (2 drops). After stirring for 10 min at 0° C., the ice bath was removed and the reaction mixture was heated at reflux for 3 h. The resulting mixture was then cooled and evaporated under reduced pressure. A second 1 L round bottom flask was loaded with diethyl malonate (22.8 mL, 0.15 mol) and THF (150 mL): sodium hydride (60% dispersion in mineral oil, 7.2 g, 0.18 mol) was then added at 0° C., portionwise over a period of 30 minutes. The ice bath was then removed, and the mixture was heated at reflux for 3 h. The acyl chloride, dissolved in 2 portions of THF, was added and the resulting mixture was heated at reflux for 3 h and then stirred at room temperature overnight. The reaction mixture was partitioned between water and EtOAc; the organic layer was separated and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. A mixture of glacial AcOH (50 mL) and sulfuric acid (20% in water, 50 mL) was added to the residue, and the resulting mixture was heated at reflux for 6 h and then stirred at 80° C. overnight. The reaction mixture was basified to pH 10 by adding NaOH (aq) and then was extracted 3 times with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane) to give 7.1 g of 1-(4-chloro-2-nitro-phenyl)-ethanone.

Provenance & Evidence