Nucleophilic substitutions using O-alkyl-N,N'-dialkylisoureas. Applications to ephedrines

Article abstract of DOI:10.1002/recl.19941130705

Dialkylcarbodiimides in the presence of a Cu(I) 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 paricipation of the amino group via an S_N2 reaction leads to aziridium salts, which are subsequently opened by the nucleophiles via a second S_N2 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.