Synthesis of 1,3,5-trisubstituted hydantoins by regiospecific domino condensation/aza-Michael/O-->N acyl migration of carbodiimides with activated alpha,beta-unsaturated carboxylic acids.
[reaction: see text] Carbodiimides and suitably activated alpha,beta-unsaturated carboxylic acids react effectively to afford a vast array of 1,3,5-trisubstituted hydantoins by means of a regiospecific domino condensation/aza-Michael/N-->O acyl migration. The reaction works well in very mild conditions (20 degrees C, dichloromethane) with fumaric acid derivatives bearing an electron-withdrawing group in the beta position. Good results have been obtained also with less activated substrates bearing only one electron-withdrawing group in the beta position, using more polar solvents (acetonitrile, DMF), and in the presence of a base (2,4,6-trimethylpyridine). Reactions with asymmetric carbodiimides are generally highly chemo- and regioselective, giving rise to the formation of a single regioisomeric hydantoin. However, asymmetric carbodiimides bearing one alkyl group and one aryl group can produce variable amounts of N-acylurea byproducts. The latter could be easily recovered and transformed into the corresponding hydantoins. A detailed study of the influence of key reaction parameters such as solvent, base, and structure of the reactants on the reaction outcome and mechanism is presented. This methodology is particularly convenient for the synthesis of trifluoromethyl-substituted hydantoins, which could be interesting as bioactive compounds in medicinal chemistry, as well as precursors of the corresponding alpha-amino acids.
Volonterio
Alessandro
A
Dipartimento di Chimica, Materiali ed Ingegneria Chimica "G. Natta" del Politecnico di Milano, C.N.R.-Istituto di Chimica del Riconoscimento Molecolare, Sezione "A. Quilico", via Mancinelli 7, I-20131 Milano, Italy. alssandro.volonterio@polimi.it
Ramirez de Arellano
Carmen
C
Zanda
Matteo
M
D002234:Carbodiimides / Q000737:chemistry*; D002264:Carboxylic Acids / Q000737:chemistry*; D006827:Hydantoins / Q000138:chemical synthesis*; D015394:Molecular Structure; D013237:Stereoisomerism
D002234:Carbodiimides; D002264:Carboxylic Acids; D006827:Hydantoins