Accelerated and Green Synthesis of N,S- and N,O-Heterocycles in Microdroplets

Nitrogen-based heterocycles are widespread in pharmaceutical and agricultural products, yet methods to synthesize them are often inefficient, requiring long reaction times, high temperatures, and catalysts. Here, we report an accelerated, simple, and generalized green synthetic method for the conversion of a series of amines into diverse N,S- and N,O-heterocycles (thiazolines, oxazolines, thiazines, oxazines, aminothiazoles, and thiazolidines) in microdroplets. These chemical transformations occur under ambient conditions during the millisecond flight time of the droplets to the mass spectrometer for online analysis or deposition onto a collector surface. The intrinsic superacidity at the air-liquid interface of microdroplets facilitates the reaction and enables the formation of highly pure products without the need for additional purification, as evidenced by mass spectrometry (MS), infrared (IR) spectroscopy, and nuclear magnetic resonance (NMR) analyses. High-throughput (HT) reaction screening based on desorption electrospray ionization (DESI) MS shows a wide scope (24 amines, four functionalization reagents, and four solvents), producing ca. 90% yields for the best solvent (acetonitrile) in a 25 min experiment covering 1536 samples (including 4 replicates of 384 reaction combinations). We also demonstrate the application of this methodology to site-selective modification of peptides.