Nucleophilic substitutions using O‐alkyl‐N,N′‐dialkylisoureas. Applications to ephedrines

Abstract

AbstractDialkylcarbodiimides in the presence of a Cu1 catalyst react cleanly with the hydroxyl group of N‐methylated (1R,2S)‐ephedrine and (1S,2S)‐pseudoephedrine. These adducts react with nucleophiles like alkyl and aryl thiols as well as thioic acids and phthalimide to form the substitution products with overall retention of configuration. It is postulated that intramolecular participation of the amino group via an SN2 reaction leads to aziridium salts, which are subsequently opened by the nucleophiles via a second SN2 reaction. This synthetic approach is also useful for the inversion of simple secondary alcohols; on treatment with dicyclohexylcarbodiimide followed by benzothioic acid and treatment with LiAlH4, menthol was converted in good yield to neomenthane thiol.