Sulfonamide Synthesis via Oxyma-O-sulfonates – Compatibility to Acid Sensitive Groups and Solid-Phase Peptide Synthesis

A milder and more efficient procedure for the synthesis of sulfonamides by activating sulfonic acid groups as the corresponding sulfonate esters of ethyl 2-cyano-2-(hydroxyimino)acetate (Oxyma) is reported. This method is greener than all other existing protocols for the purpose. Other important advantages lie in (a) its applicability to less nucleophilic anilines under ambient and milder conditions and (b) its compatibility with solid phase peptide synthesis and acid-labile groups such as trityl (Trt) and tBu, which empowers the solid phase synthesis of sulfonamides of various peptides. To illustrate this, the syntheses of three sulfonamide derivatives of the peptide GAILG-NH₂, which is relevant in the context of drug design against type 2 diabetes, are demonstrated by using Fmoc-based solid-phase peptide synthesis (SPPS).