Proline-mediated Knoevenagel-Doebner condensation in ethanol: a sustainable access to p-hydroxycinnamic acids

Naturally occurring p-hydroxycinnamic acids were obtained in good yields (50-85%) using a pyridine/piperidine-free Knoevenagel-Doebner condensation of the corresponding p-hydroxybenzaldehydes with malonic acid in ethanol. This method uses fully renewable and cheap non-toxic reagents and solvents. By combining a Design of Experiment (DoE) and a One Variable At a Time optimization (OVAT), the different reaction parameters were optimized in order to favor p-hydroxycinnamic acids production over that of the two other reaction by-products, the corresponding di-acid and vinyl phenol.