In situ activation of an acetate ester - a novel alternative to malonate chemistry

11 June 2004

At a recent conference in Berlin, Kai Rossen from Degussa described some synthetic approaches to 4-(hydroxyphenyl)-2-alkoxypropionic acids during his lecture. In these systems the benzyl alcohol can be alkylated directly, rather than having to use the benzyl halide, via a postulated quinomethide intermediate. A one-pot synthesis was developed using a diethyl 2-alkoxymalonate as the nucleophile (see Scheme). Unfortunately 2-alkoxymalonates are not commercially available and are difficult to prepare, and are not particularly atom economic. In an ideal world one would use ethyl alkoxyacetate, and this could be achieved by in situ activation with diethyl oxalate. Under the reaction conditions potassium hydroxide is formed as a by-product and this cleaves the oxalate activating group, which ends up as potassium oxalate, and can, in principle, be recycled.

K. Rossen, presentation at Modern Synthetic Methods — Reaction to Reality, Berlin, May 6-7, 2004