Synthesis of 1,3,5-Trisubstituted Hydantoin via a Three-Component Reaction

Significance

Reported is the regioselective synthesis of trisubstituted 1,3,5-hydantoins bearing C5 hydrazone (4) and acyl (5) substituents. The reaction involves a three-component process using 1,2-diaza-1,3-dienes 1, primary amines 2 and isocyanates 3 proceeding via sequential aza-Michael addition-condensation reactions. Indeed, as demonstrated in a previous report (S. Santeusanio and co-workers Tetrahedron 2010, 66, 5121), compounds 1 undergo an analogous reaction as Michael acceptors with the primary amines 2 to afford α-aminohydrazones which, upon in situ treatment with isocyanates 3, give the corresponding asymmetric urea derivatives. The pre-sent reaction is accomplished under mild conditions in satisfactory yields (47-76%) and overcomes the drawback of regiocontrol, especially when weakly asymmetric carbodiimides are used (A. Volonterio, C. R. de Arellano, M. Zanda J. Org. Chem. 2005, 70, 2161). However, in the presence of aromatic amines, the reaction fails due to the poor amine nucleophilicity. Hydrolysis of hydrazone 4 under heterogeneous conditions leads to 5-acyl-1,3-disubstituted hydantoins 5.