Smiles rearrangement components

A new multi-component Ugi-Smiles coupling reaction of heteroaromatic phenols (pyridines and pyrimidines) 151 with carbonyl compounds 152, amines 153 and isocyanides 154 involves a Smiles rearrangement to form a library of heterocyclic scaffolds 155. The first Ugi-Smiles conversion of thiols 156 was also performed. The reaction of 156 with a carbonyl compound, an amine and an isocyanide afforded the desired product 157 at 80 °C. 

A three-component reaction comprising of Phenol-Passerini-Smiles rearrangement sequence of o-nitrophenol, cyclohexylisocyanide and propionaldehyde at 40 for 3 days provided the amide 158. In the course of the reaetion, a final Smiles rearrangement displaces all the equilibria to result in the product. Various aldehydes and isocyanides were employed to investigate the scope of this new reaction. It has been found that hindered isocyanides and aromatic aldehydes gave the desired product, whereas a,P-... 

Recently, Kaim and coworkers have developed a variation of the Ugi reaction, called the Ugi-Smile four-component reaction (US-4CR), by replacing the carboxylic acid component of the U-4CR with a phenol component [113]. Mechanistically, the US-4CR (Scheme 7.99) is quite similar to that of the U-4CR (Scheme 4). Condensation of the amine 6a and aldehyde 9a forms the imine 15. Protonation of the imine 15 by the phenolic compound 326 activates the carbon atom of the C=N bond. The isocyanide Ic then attacks the electrophilic carbon of the activated imine 15a. The phenolate ion 327 attacks the electrophilic carbon of the isocyanide of the intermediate 16. Smiles rearrangement [114] of the a-adduct 328 provides the Ugi-Smile product 329. 

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