A transition metal-free C–S bond cleavage and subsequent Mannich reaction of Ugi-adducts with alcohols as well as thiols is developed. Diverse novel peptidomimetics containing N,O- or N,S-aminals are synthesized in a rapid, highly efficient and step-economical fashion. This method features exclusive selectivity, broad substrate scope, excellent yield and functional group tolerance, and was applied on substrates derived from the pharmaceuticals febuxostat, probenecid and memantine.