The Combined Role of Catalysis and Solvent Effects on the Biginelli Reaction: Improving Efficiency and Sustainability

The traditional Biginelli reaction is a three-component condensation between urea, benzaldehyde and an acetoacetate ester to give a dihydropyrimidinone. An investigation into catalytic and solvent effects has returned the conclusion that the diketoenol tautomerisation equilibrium of the dicarbonyl reactant dictates the yield of the reaction. Whereas the solvent is responsible for the tautomerisation equilibrium position, the catalyst only serves to eliminate kinetic control from the reaction. Generally, to preserve reaction efficiency and improve sustainability, bio-derivable p-cymene was found to be a useful solvent. The metalenolate intermediate that results from the application of a Lewis acidic catalyst often cited as promoting the reaction appears to hinder the reaction. In this instance, a BrOnsted acidic solvent can be used to return greater reactivity to the dicarbonyl reagent.