Synthesis
The carboxylic acid (13.8 g, 69 mmol, 1.0 equivalents) was dissolved in dry THF under an inert atmosphere and cooled to 0 ºC. CDI (13.4 g, 83 mmol, 1.2 equivalents) was then added in small portions over several minutes. After 10 min, the reaction was allowed to warm slowly to room temperature and was then stirred for 1 h. In a separate flflask, monomethyl malonate (9.8g, 83 mmol, 1.2 equivalents) was dissolved in THF under an inert atmosphere and cooled to −78 ºC. To this solution was added dibutylmagnesium (1.0 M in heptane, 0.6 equivalents). A white solid formed instantly on addition of the base. After 10 min, the reaction was warmed to room temperature and stirred for 1 h. The acylimidazole was then added by cannula to the flflask containing the magnesium salt. The resulting slurry was stirred for 3 days. The reaction mixture was then concentrated on a rotary evaporator and the residue redissolved in EtOAc. The resulting solution was washed with 1.2 M HCl, saturated aqueous NaHCO3, and brine. The organic phase was dried over sodium sulfate, fifiltered, concentrated, and the residue purifified by flflash chromatography (7:1 hexanes:EtOAc) to give the β-keto ester (14.7g, 83%).
Reference: Durham, T. B.; Miller, M. J. J. Org. Chem. 2003, 68, 27–34.
