Amino Acid‒Catalyzed Marschalk Reaction and Its Application to an Integrated Continuous-Flow Synthetic Process

Anthraquinone derivatives serve diverse functional roles in materials science. Substituted 1,4-dihydroxy,9,10-anthraquinone (quinizarins) can be synthesized by acid- or base-catalyzed condensation reactions of leuco-quinizarin and aldehydes, known as the Marschalk reaction. We identified piperidine-3-carboxylic acid as a particularly effective catalyst for this transformation. Kinetic studies revealed that piperidine-3-carboxylic acid was responsible for the enol formation step of leuco-quinizarin, which is the rate-limiting step. The reaction rate depended heavily on the concentration of leuco-quinizarin but not on that of aldehydes. We integrated the Marschalk reaction into a continuous-flow system for leuco-quinizarin synthesis, using a flow-batch-separator (FBS) unified reactor system. This system enabled high reactant concentrations even when a highly diluted leuco-quinizarin solution from the upstream continuous-flow reactor was employed. Finally, a full continuous-flow hydrogenation‒Marschalk reaction was constructed using a combined reactor system, with piperidine-3-carboxylic acid as the catalyst.