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

Abstract

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).

Synthesis of β‐Amino Alcohols Using Ethyl 2‐Cyano‐2‐(2‐nitrobenzenesulfonyloxyimino)acetate (o‐NosylOXY)

“…o ‐NosylOXY ( I) was synthesized efficiently by the reaction of Oxyma (ethyl 2‐hydroxyimino 2‐cyanoacetate) with ortho ‐nitrobenzenesulfonyl chloride in the presence of diisopropylethylamine (DIPEA) under the nitrogen atmosphere at 0 °C for 2 h as reported previously . Initially, we commenced the optimization studies with Fmoc‐Gly‐OH as a model substrate in various solvents such as DCM, THF, CH 3 CN, EtOAc, CH 3 OH, H 2 O and DMF (Table ).…”

OxymaPure Coupling Reagents: Beyond Solid-Phase Peptide Synthesis

“…In 2013, Mandal and co-workers also prepared various Oxyma sulfonate esters and used them as precursors in the synthesis of sulfonamides. 57 The main advantages of this protocol were that the synthesis was HCl-free and it worked well with even less nucleophilic anilines (Scheme 15).…”

Direct Synthesis of Sulphonates of Alcohol, Oxyma‐O‐sulphonates and Oxime‐O‐sulphonates under Microwave Irradiation

“…Some sulphonate esters are valuable intermediates in organic synthesis of APIs . The pentafluorophenol benzene sulphonate esters (3, Figure ) as well as the sulphonate esters of ethyl 2‐cyano‐2‐(hydroxyimino) acetate (Oxyma, 4, Figure ) are found to be stable intermediates for formation of sulphonamides, which are extremely important antibacterial agents and valuable structural motifs in medicinal chemistry . An important step in peptide bond formation is activation of the carboxylic acid group of the N ‐protected amino acid derivatives that are reactive enough to combine with amine group of a C ‐protected amino acid when both are mixed together.…”

“…Sulphonate esters of oximes are generally synthesized by corresponding sulphonyl chlorides at room temperature . Similarly, sulphonate esters of Oxyma were also synthesized by using sulphonyl chloride, which generates excess amount of HCl making difficulty in industrial use. However, the synthesis of sulphonate esters are reported from corresponding sulphonic acids also, but by reacting with diazoalkanes, which are highly toxic, explosive and often unavailable .…”