Formation of 4,4-dialkoxycyclohexa-2,5-dienone N-(thiol-S-yl)imine during reaction of 4-alkoxynitrosobenzenes with thiols in alcoholic solvents

During the interaction of nitrosoarenes with glutathione in aqueous media, intermediate generation of a highly resonance-stabilized sulfenamide cation has been repeatedly suggested. Most intermediates and end products could b e explained by reactions of this sulfenamide cation with different nucleoph iles such as excess thiol, solvent water, and metabolically produced arylam ine, The present paper presents evidence for adduct formation of the sulfen amide cation with solvent alcohol at neutral pH, Sulfenamide cations genera ted from 4-nitrosophenetole and 4-nitrosoanisole, respectively, are strongl y suggested to form the metastable ketals 4-ethoxy-4-methoxycyclohexa-2,5 - dienone N-(glutathion-S-yl)imine and 4,4-dimethoxycyclohexa-2,5-dienone N-( glutathion-S-yl)imine, respectively, during reaction with solvent methanol, Reaction of the two sulfenamide cations in ethanol yielded 4,4-diethoxycyc lohexa-2,5-dienone N-(glutathion-S-yl)imine and 4-ethoxy-4-methoxycyclohexa -2,5-dienone N-(glutathion-S-yl)-imine, respectively. Although the metastab ility of the ketals did not allow isolation of pure solid material, chromat ographic and chemical behavior as well as tandem MS fragmentation substanti ate a ketal structure of these inter mediates, To confirm the proposed stru cture, new compounds, 2,6-dimethyl-4-nitrosophenetole, 2,6-dimethyl-4-nitro phenetole, 2,6-dimethyl-4-phenetidine, and N-glutathion-S-yl)-N-hydroxy-4-a minoacetophenone, were synthesized and included in supportive experiments. In summary, the detection of ketals corroborates once more the occurrence o f a sulfenamide cation which obviously not only reacts with soft nucleophil es such as GSH but, to a limited extent, also reacts with hard nucleophiles . The toxicological significance of this result is discussed.