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, and was 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. Implementing the Bucherer–Bergs reaction under continuous flow conditions results in substantial improvements over traditional batch processes. In batch, this reaction is often characterized by long reaction times, moderate to low yields, and significant safety concerns, particularly when scaling up due to the use of potassium cyanide and elevated temperatures. Flow chemistry addresses these challenges by enabling fine control over reaction parameters such as temperature, pressure, and residence time. The continuous system facilitates reproducible synthesis of high purity hydantoins, with shorter reaction durations and improved yields. Furthermore, flow reactors inherently offer a safer platform for handling hazardous reagents as only small volumes are present in the high temperature and pressure reaction conditions at any given time and are confined within secondary containment. These factors combine to minimize the risk associated with over pressurization or reagent exposure, especially during prolonged operation. The application of flow chemistry to this classical transformation not only enhances efficiency and safety but also facilitates practical scalability to pilot-scale production.