In the past two decades, sulfamides have gained notable attention in medicinal chemistry as stable and modifiable bioisosteres of amides, ureas, carbamates, sulfonamides and other important functional groups. Traditional methods of sulfamide synthesis frequently go through sulfamoyl chloride intermediates, which are highly reactive, synthesized with dangerous compounds, and prone to decomposition. Recently, our group reported a new Ca(NTf2)2-mediated sulfur-fluorine exchange (SuFEx) reaction toward synthesizing sulfonamides. In this study, we expand on this method for synthesizing sulfamides using sulfamoyl fluorides. Additionally, we detail mechanistic investigations into role of Ca(NTf2)2. Both Ca2+ and NTf– are found to be imperative for the reaction to proceed. Additives intended to scavenge fluoride or increase Lewis acidity inhibit reaction. Optimized reaction conditions have been applied to synthesize novel asymmetric and symmetric sulfamides. Future work will study and apply this method to fluorosulfonates and other S(VI)-F compounds.

Lewis acid-mediated SuFEx reactions toward nitrogen-based sulfonylated compounds.

2019 Spring National Meeting

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