Cyanogen bromide (BrCN) is a powerful reagent in organic synthesis, but due to its high toxicity it is rarely used in synthesis labs. In general, such hazardous reagents are best prepared in situ from benign precursors to avoid handling, storage, and transportation issues. With safety as a key feature, continuous flow processing is particularly suitable for the generation of hazardous materials.
C. Oliver Kappe, University of Graz and Research Center Pharmaceutical Engineering GmbH (RCPE), Graz, Austria, and colleagues have developed an entirely continuous process for synthesizing BrCN from an aqueous solution of Br2 and KCN. The risk of exposure to BrCN was eliminated because its separation by in-line extraction and the subsequent reaction with the substrate were fully incorporated into the process. By implementing in-line FTIR technology, the generated BrCN was monitored and quantified. To increase safety, Br2 was also produced directly within the setup: A continuous Br2 generator using the bromate–bromide reaction was connected upstream to the BrCN generator.
The modular Br2/BrCN generator produces a 0.8 M solution of BrCN (0.2 mmol BrCN per minute) and has been used for the continuous-flow synthesis of medicinally relevant cyclic guanidines. This concept could allow the safe use of BrCN as a reagent in a variety of synthetic transformations.
- Integration of Bromine and Cyanogen Bromide Generators for the Continuous-Flow Synthesis of Cyclic Guanidines,
Gabriel Glotz, René Lebl, Doris Dallinger, C. Oliver Kappe,
Angew. Chem. Int. Ed. 2017.