A 19F-Labeled Isothiocyanate Derivatizing Agent for the Chiral Discrimination of Cyclic Secondary Amines

Due to the widespread applications of cyclic secondary amines in drug development, rapid methods for detecting and distinguishing chiral cyclic secondary amines have become increasingly important. In this study, we successfully present a derivatizing strategy employing ¹⁹F-labeled isothiocyanate for the enantiomeric analysis of various cyclic secondary amines, including piperidines, pyrrolidines, piperazines, and morpholines (28 examples). The distinguishable chemical shift produced by the novel chiral ¹⁹F-labeled probe permits simultaneous differentiation of three pairs of cyclic secondary amines in a mixture. This approach eliminates the cumbersome purification steps of covalent modification of substrates, enabling rapid analysis of these chiral N-heterocyclic compounds with clear signals and high resolution. Besides, the mechanism of derivatizing interaction between a novel chiral ¹⁹F-labeled probe and the analytes was first verified by single-crystal X-ray analysis and DFT calculations, which generates a pair of diastereomeric thioureas with distinct ¹⁹F NMR signals. This technology provides an efficient, sensitive, and versatile solution for the analysis of chiral cyclic sec-amines, demonstrating significant value, particularly in the development of pharmaceutical synthesis processes.