Integrated Synthesis Using Isothiocyanate-Substituted Aryllithiums by Flow Chemistry

Abstract

The isothiocyanate (NCS) group is an attractive functional group in the field of organic and pharmaceutical chemistry. It can be transformed into other heteroatomic functional groups. It usually acts as the inductive group of biological activity and has also been traditionally used as the fluorescent-labeling reagent. However, it is not compatible with strong bases. When the NCS group is atparaposition in halobenzenes, it generally undergoes nucleophilic additions upon reaction with strong bases. To the best of our knowledge, there is currently no general methodology for the formation and reactions of NCS-functionalized aryllithiums formetaandparasubstituents. Herein, we report the continuous-flow generation of NCS-substituted aryllithiums from the corresponding haloarenes via a selective halogen-lithium exchange reaction and its reaction with various electrophiles to yield NCS-containing products. We also achieved an integrated synthesis through sequential reactions of the NCS-containing compounds with additional nucleophiles using the continuous-flow reactors.