Ugi-Smiles couplings: new entries to N-aryl carboxamide derivatives

The scope of the Ugi reaction has been extended by the use of phenols as carboxylic acid surrogates to afford N-aryl carboxamides. A Smiles rearrangement occurs as the last step of the mechanism instead of the classical final Mumm process. Various parameters concerning the nature of these inputs have been studied: the use of heteroaromatic derivatives, the substitution of the hydroxyl moiety by a thio entity (to afford functionalized thioamides), as well as the influence of the nature and position of substituents on the phenol. A three-component version (Passerini-Smiles) of this coupling has been developed as well. Following these couplings, various post-condensation transformations have been performed to reach more complex heteroaromatic fused systems. The easy functionalizations of phenols offer many opportunities for cyclization strategies: the reduction of the nitro group allows the formation of o-phenylenediamine derivatives, which, in turn, can be transformed into quinoxalines, benzotriazoles, and benzimidazoles. Various organometallic reactions of the Ugi-Smiles adducts have been successfully carried out, either from iodophenols (Heck couplings to give indoles, Ullmann reaction to form quinoxalines), or from allyl pyrimidines (azepine formation by RCM strategy) as starting phenol inputs. Finally, a new palladium-mediated oxidative cyclization led to the formation of tricyclic systems.