Microwave-Assisted and DoE-Optimized Protocol for the High-Yield Synthesis of L-DOPA-Derived Enamines

An optimized protocol was established for the synthesis of L-DOPA-derived enamines via a pseudomulticomponent Schiff reaction involving 1,3-dicarbonyl compounds and low-molecular-weight alcohols, under microwave irradiation (MW). The reaction parameters were optimized using a Box–Behnken response surface design (BBD), enabling systematic assessment of nonlinear factor interactions with fewer experiments. Because the two 1,3-dicarbonyl precursors used in this work (cyclohexane-1,3-dione and acetylacetone) showed markedly different reactivity, the design was analyzed as two independent yield responses. For the cyclohexane-1,3-dione route, stoichiometry, time, temperature, and their interactions—including a pronounced temperature curvature—were significant, and numerical optimization predicted a maximum yield of 99.8% at a 1.90 dicarbonyl ratio, 34.2 min, and 119.2 °C. For the acetylacetone route, only time, temperature, and their interaction were significant, with a predicted optimum of 93.7% at a 1.45 ratio, 21.0 min, and 119.8 °C. Both optima closely matched experimentally validated yields (96% and 94%, respectively), confirming the models’ reliability. Products were purified by column chromatography using petroleum ether/ethyl acetate mixtures. The optimized protocol improves reaction efficiency and reproducibility compared with conventional multistep approaches.