Thionyl chloride (18.5 mL) was slowly added dropwise to a stirred mixture of 1-BOC-piperidine-3-carboxylic acid (50.0 g, 218 mmol) and pyridine (44.0 mL) in anhydrous dichloromethane (300 mL) under nitrogen protection. After the reaction mixture was stirred at 25 °C for 20 min, cyclic (sub)isopropyl malonate (35.0 g, 243 mmol) and 4-dimethylaminopyridine (66.6 g, 546 mmol) were added and stirring was continued for 1 h under nitrogen protection. Subsequently, ether (2 L) was added and the mixture was washed sequentially with 1 M hydrochloric acid (3 x 500 mL), saturated saline (500 mL), the organic layer was dried with anhydrous sodium sulfate, filtered and the solvent was concentrated. The residue was dissolved in methanol (580 mL) and reacted at reflux for 4 hours. After concentration to remove the solvent, the residue was purified by silica gel column chromatography with dichloromethane/ethyl acetate (10:1, v/v) as eluent. The final light yellow oily product N-Boc-3-(3-methoxy-3-oxopropionyl)piperidine (26.5 g, 43% yield) was obtained.
