Desarrollo de nuevas variantes de la reacción de Ugi

Abstract

A novel multi-component reaction of isocyanides, imines and electron-deficient enols has been developed. This condensation takes place smoothly at room temperature with no need of catalysis, providing a convergent approach to synthesis of amino acid-derived enamines containing up to six elements of diversity. Enol-Ugi condensations can combine a broad diversity of all the three starting materials, affording structurally diverse adducts. Thus, we have used enols derived from coumarin, pyrimidone, furanone, pyrrolidinone and Meldrum's acid. Likewise, imines obtained by the condensation of aromatic aldehydes, both with aromatic and aliphatic amines, and different isocyanides have been employed in the reaction. Moderate to excellent yields are obtained in all the cases. Moreover, the reaction is tolerant to different functional groups, which could exponentially broaden the attainable structural diversity by the use of post-condensation transformations. In parallel with the first steps of the Ugi four-component condensation, the mechanism of the enol-Ugi reaction involves the addition of the enolate to a nitrilium ion intermediate, leading to a primary adduct. From this point the mechanism significantly diverges, and the primary adduct suffers an intramolecular conjugate addition of the amine nitrogen to the heterocyclic ring, followed by ß-elimination of the imidate oxygen. This last step requires the presence of an electron-withdrawing group in a to the enol. We argue that this final rearrangement must be thermodynamically favoured, being the driving force of the whole process.