A Mild, Efficient Approach for the Synthesis of 1,5-Disubstituted Hydantoins

An efficient and straightforward two-step procedure for the synthesis of N-1 alkyl/aryl-substituted hydantoins was developed, starting from easily available starting materials. The procedure envisages a highly regiospecific domino condensation/aza-Michael (nucleophilic substitution)/O -> N acyl migration between activated alpha,beta-unsaturated carboxylic acids or alpha-haloaryl acetic acids, respectively, and N-tert-butyl- or N-tritylcarbodiimides, leading to the regioselective formation of hydantoins bearing the tertiary alkylic substituent in the 3-position, followed by selective removal the substituent. This process avoids the use of harsh reaction conditions and toxic reagents and is high yielding. A detailed study of the influence of the structure of the reactants on the reaction outcome is presented. A wide variety of final products having a primary, secondary, cyclic and aryl substituent at the N-1 position were successfully synthesized by this method, ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)