Proline-Mediated Knoevenagel–Doebner Condensation in Ethanol: A Sustainable Access to p-Hydroxycinnamic Acids

Abstract

Naturally occurring p-hydroxycinnamic acids were obtained using an amine-and toxic solvent-free Knoevenageltype pathway. This method uses not only non-toxic reagents (i.e., L-proline and magnesium oxide as catalyst) and ethanol as green solvent, all reagents and solvent being renewable and accessible at low price. By combinaing a Design of Experiment and a One Variobale At a Time optimization (OVAT), the different reaction parameters optimized in order to favor sinapic acid synthesis over that of the two other possible by-products, the corresponding di-acids and vinyl phenols. This alternative to classical Knoevenagel reaction allowed to substitute traditional pyridine-and piperidine-catalyzed pathway while obtaining each natural phydroxycinnamic acids in good conversions and yields (50-85%).

Sustainable Synthesis of p-Hydroxycinnamic Diacids through Proline-Mediated Knoevenagel Condensation in Ethanol: An Access to Potent Phenolic UV Filters and Radical Scavengers

“…It is important to note that, for this study, ferulic diacid production from vanillin and malonic acid was selected as the model reaction. As reported in a previous work by Peyrot et al, phydroxycinnamic acids can be obtained through Knoevenagel-Doebner condensation between phydroxybenzaldehydes and malonic acid in ethanol using proline as catalyst [27]. It was observed that the mechanism of the p-hydroxycinnamic diacid formation strongly depends on the reaction conditions as depicted in Figure 2.…”

“…It was observed that the mechanism of the p-hydroxycinnamic diacid formation strongly depends on the reaction conditions as depicted in Figure 2. In their study, the formation of ferulic diacid in 68% yield was observed using the following conditions: 1 equivalent (eq) of vanillin in ethanol (0.5 M), 3 eq of malonic acid, and 1.1 eq of proline, 16 h at 40 °C ( Figure 3) [27]. This result served as foundation for the optimization of the phydroxycinnamic diacid synthesis.…”

“…This result served as foundation for the optimization of the phydroxycinnamic diacid synthesis. The Knoevenagel-Doebner condensation of malonic acid with p-hydroxybenzaldehydes is known to be highly dependent on four parameters: temperature (Temp), reaction time (t), mMalonic acid equivalents (MEq), and proline equivalents (PEq) [27]. In order to determine the impact of these four variables on the conversion to ferulic diacid, a design of experiment (DoE) based on a D-optimal The Knoevenagel-Doebner condensation of malonic acid with p-hydroxybenzaldehydes is known to be highly dependent on four parameters: temperature (Temp), reaction time (t), Malonic acid equivalents (MEq), and proline equivalents (PEq) [27].…”

“…The Knoevenagel-Doebner condensation of malonic acid with p-hydroxybenzaldehydes is known to be highly dependent on four parameters: temperature (Temp), reaction time (t), mMalonic acid equivalents (MEq), and proline equivalents (PEq) [27]. In order to determine the impact of these four variables on the conversion to ferulic diacid, a design of experiment (DoE) based on a D-optimal The Knoevenagel-Doebner condensation of malonic acid with p-hydroxybenzaldehydes is known to be highly dependent on four parameters: temperature (Temp), reaction time (t), Malonic acid equivalents (MEq), and proline equivalents (PEq) [27]. In order to determine the impact of these four variables on the conversion to ferulic diacid, a design of experiment (DoE) based on a D-optimal design consisting of 28 experiments, including a triplicate at the central point to evaluate the reproducibility, was performed.…”

“…Proline (eq) 1. This method allowed to access ferulic diacid with enhanced atom economy compared to Peyrot et al conditions as not only the equivalents of malonic acid were reduced three-fold, but also the proline amount was divided 11 times, turning proline from a reagent to a catalyst [27]. Moreover, the heating time was reduced four-fold, thus reducing the energetic demand of our synthetic procedure.…”