Since its inception in 2014, sulfur-fluoride exchange (SuFEx) chemistry has drawn increased attention from the synthetic, chemical biology and medicinal chemistry communities. Recent developments to install sulfur(VI) fluorides (–SO2F) have offered unique opportunity to explore new directions in this rapidly growing field. Nitrogen-based sulfur(VI) compounds like sulfonamides (C–SO2–N), sulfamides (N–SO2–N) and sulfamates (O–SO2–N) constitute more than 25% of all sulfur-based FDA approved drugs, with therapeutic applications from bacterial infections, cardiovascular diseases to cancer. Sulfur(VI) chlorides are commonly used intermediates to access these sulfonylated compounds. However, the hydrolytic, redox and thermal instability of sulfur(VI) chlorides, in addition to competing addition of nucleophiles to the chlorine or sulfur atom, can pose significant difficulties in their use. Sulfur(VI) fluorides eliminate many of the challenges associated with sulfur(VI) chlorides. Because of the reduced electrophilicity at the sulfur center, an activation of the sulfur(VI) fluoride toward nucleophilic addition is required. To this end, we have developed a unified approach to activate sulfur(VI) fluorides (i.e. sulfonyl fluorides, fluorosulfates and sulfamoyl fluorides) with a unique combination of calcium triflimide and DABCO. The methodology enables access to diverse array of sulfonamides, sulfamates, and sulfamides at room temperature under a single-set of conditions. Additionally, we utilized parallel medicinal chemistry (PMC) to demonstrate the effectiveness of this operationally simple protocol toward medicinal chemistry relevant heterocyclic templates.

General method to access sulfamides, sulfamates and sulfonamides from sulfur(VI) fluorides via calcium triflimide and DABCO activation

ACS Fall 2020 Virtual Meeting

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