Integration of Bromine and Cyanogen Bromide Generators for the Continuous-Flow Synthesis of Cyclic Guanidines
Gabriel Glotz
Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
Institute of Chemistry, NAWI Graz, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
Search for more papers by this authorRené Lebl
Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
Institute of Chemistry, NAWI Graz, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
Search for more papers by this authorDr. Doris Dallinger
Institute of Chemistry, NAWI Graz, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
Search for more papers by this authorCorresponding Author
Prof. Dr. C. Oliver Kappe
Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
Institute of Chemistry, NAWI Graz, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
Search for more papers by this authorGabriel Glotz
Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
Institute of Chemistry, NAWI Graz, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
Search for more papers by this authorRené Lebl
Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
Institute of Chemistry, NAWI Graz, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
Search for more papers by this authorDr. Doris Dallinger
Institute of Chemistry, NAWI Graz, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
Search for more papers by this authorCorresponding Author
Prof. Dr. C. Oliver Kappe
Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
Institute of Chemistry, NAWI Graz, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
Search for more papers by this authorGraphical Abstract
Cyanogen bromide on tap: The highly toxic but synthetically powerful reagent cyanogen bromide (BrCN) was generated in a fully continuous fashion from benign precursors and directly used for the synthesis of medicinally relevant N-heterocycles.
Abstract
A continuous-flow process for the in situ on-demand generation of cyanogen bromide (BrCN) from bromine and potassium cyanide that makes use of membrane-separation technology is described. In order to circumvent the handling, storage, and transportation of elemental bromine, a continuous bromine generator using bromate–bromide synproportionation can optionally be attached upstream. Monitoring and quantification of BrCN generation was enabled through the implementation of in-line FTIR technology. With the Br2 and BrCN generators connected in series, 0.2 mmol BrCN per minute was produced, which corresponds to a 0.8 m solution of BrCN in dichloromethane. The modular Br2/BrCN generator was employed for the synthesis of a diverse set of biologically relevant five- and six-membered cyclic amidines and guanidines. The set-up can either be operated in a fully integrated continuous format or, where reactive crystallization is beneficial, in semi-batch mode.
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