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 α,β‐unsaturated carboxylic acids or α‐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. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) A general, straightforward method for the preparation of libraries of 1,5‐disubstituted hydantoins in good to excellent yields by a two‐step strategy relying on a highly regioselective domino reaction between carbodiimides and suitable carboxylic acids, followed by selective deprotection at the 3‐position of the ring is presented.