One-Pot Aqueous Assembly of Sulfimides from Thiols, Alkyl Halides, and Oxaziridines

Abstract

A sequential one-pot method for the aqueous synthesis of sulfimides from thiols, alkyl halides, and an oxaziridine nitrogen-transfer reagent is reported. Thiols are first S-alkylated under aqueous conditions, and the resulting sulfides are converted directly into sulfimides without isolation. Independent variation of the thiol and alkylating agent enables rapid exploration of sulfide substrate space and reveals distinct requirements for the two reaction steps. Whereas S-alkylation generally shows broad substrate tolerance, oxaziridine-mediated sulfur imidation is strongly influenced by the electronic and steric environment around sulfur, substrate solubility, and the identity of the alkyl halide leaving group. Electron-rich, sterically accessible, and water-compatible sulfides give the most efficient nitrogen transfer, while electron-deficient, hindered, and hydrophobic substrates display reduced reactivity. Attempted extension to an N-acetyl cysteine methyl ester derivative further highlighted these requirements, as efficient S-alkylation was not followed by sulfimidation under the optimised conditions.