Accelerated Click Reactions using Boronic Acids for Heterocyclic Synthesis in Microdroplets

Abstract

Click chemistry is important for its simplicity and versatility, however, condensation-based click reactions are limited by the general requirement of high temperatures and catalysts. Here, we report accelerated click reactions using boronic acids in microdroplets under ambient conditions without catalyst. The reaction between 2-formyl phenylboronic acid (2-FPBA) and substituted amines leads to the formation of multi-step click products, including iminoboronates, boroxines, thiazolidines, and diazaborines, depending on the selected amine. The reactions occur during microdroplet flight and are three orders of magnitude faster than the corresponding bulk reactions. MS and NMR spectral analysis confirmed the nature of the products. We suggest that the air-liquid interface of microdroplets serves both as a superacid and as a drying surface, facilitating dehydration by its superacidicity to access these products. We also demonstrate the application of these accelerated reactions as a late-stage functionalization (LSF) tool to access a range of antihistamine drug derivatives.