Pilot-Scale Flow Synthesis of Hydantoins via the Bucherer-Bergs Reaction

Hydantoins are valuable structural motifs with broad applications in medicinal chemistry and synthetic organic chemistry, particularly as core structures in anticonvulsants and as intermediates in the synthesis of unnatural amino acids. The Bucherer–Bergs reaction remains a foundational method for hydantoin synthesis; however, conventional batch protocols suffer from extended reaction times, modest yields, and significant safety concerns associated with handling cyanide. Here, we present the optimization and pilot-scale implementation of a continuous flow Bucherer–Bergs reaction that directly addresses these challenges. Systematic tuning of residence time, temperature, and solvent composition enabled a robust and scalable process that delivers hydantoin at up to 96.2% isolated yield under milder and more cost-efficient conditions than previously reported.[1] Improving reagent stability and preventing in-line precipitation enabled this conversion at a pilot scale, being demonstrated in a 600 g, 24-hour reaction. This work underscores the power of flow chemistry to modernize classical reactions for safer, more efficient, and industrially relevant applications.

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