Sulfonamides, sulfamides, and sulfamates are sulfur(VI)-nitrogen compounds representing close to 27% of all FDA-approved sulfur-based medications. The tetrahedral sulfur center and hydrogen bond acceptors enable these motifs to act as potent enzyme inhibitors. These compounds were historically produced from sulfur-chloride precursors, but recent advances in sulfur fluoride exchange chemistry (SuFEx) have increased the viability of sulfur-fluoride precursors, which boast greater regioselectivity, lower reactivity, and milder reaction conditions that are favorable for late-stage functionalization. The Ball laboratory has recently developed a Ca(NTf2)2 and DABCO (1,4-diazabicyclo[2.2.2]octane) system that activates previously unreactive sulfamoyl fluorides (R2NSO2F) to form sulfamides (R2NSO2NR2) under very mild conditions (Scheme 1). However, the mechanism behind the calcium/DABCO activation remains unclear. Herein, we present mechanistic studies that provide insight on the role of Ca salts and DABCO in S–F cleavage using sulfamoyl fluorides. We further discuss 19F NMR kinetic studies to characterize the reaction’s transition state and Pulse Field Gradient NMR studies to identify the presence of a Ca(NTf2)2 mediated sulfamoyl-DABCO activated complex. Understanding the cooperative role of Ca and DABCO will serve as a foundation toward the expanded application of Lewis acid/base pairings in SuFEx and synthesis.

Mechanistic investigations of Ca(NTf2)2 and DABCO activation in SuFEx chemistry

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.