Accelerated and Concerted Aza-Michael Addition and SuFEx Reaction in Microdroplets in Unitary and High-Throughput...

The sulfur fluoride exchange (SuFEx) reaction is significant in drug discovery, materials science, and chemical biology. Conventionally, it involves installation of SO₂ F followed by fluoride exchange by a catalyst. We report catalyst-free Aza-Michael addition to install SO₂ F and then SuFEx reaction with amines, both occurring in concert, in microdroplets under ambient conditions. The microdroplet reaction is accelerated by a factor of ∼10⁴ relative to the corresponding bulk reaction. We suggest that the superacidic microdroplet surface assists SuFEx reaction by protonating fluorine to create a good leaving group. The reaction scope was established by performing individual reactions in microdroplets of 18 amines in four solvents and confirmed using high-throughput desorption electrospray ionization experiments. The study demonstrates the value of microdroplet-assisted accelerated reactions in combination with high-throughput experimentation for characterization of reaction scope.