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 nontoxic reagents and solvents. By combination of a design of experiments (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 byproducts, the corresponding diacid and vinylphenol.