Accelerated and Concerted Aza‐Michael Addition and SuFEx Reaction in Microdroplets in Unitary and High‐Throughput Formats. Issue 50 (10th November 2022)

• Record Type: Journal Article
• Authors: Ghosh, Jyotirmoy; Mendoza, Joshua; Cooks, R. Graham
• Is Part Of: Angewandte Chemie international edition. Volume 61:Issue 50(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-11-10
• Subjects: Aza-Michael Addition -- Click Chemistry -- High-Throughput Experimentation -- Microdroplet Acceleration -- SuFEx Reaction; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.202214090
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: 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 ∼10 4 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. Abstract : Accelerated, catalyst‐free, coupled Aza‐Michael addition and SuFEx reactions between amines and ethenesulfonyl fluoride under ambient conditions in microdroplets are analyzed by electrosonic spray mass spectrometry (ESSI‐MS) while high‐throughput desorption electrospray ionization mass spectrometry (DESI‐MS) is used to follow reaction scope.