Ugi-Smiles coupling reaction

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. Massoudi, I. Amini, A. Ramazani, F. Z. Nasrabadi, Y. Ahmadi, Bull. Korean Chem. Soc. 2012, 33, 39-42. Four-component synthesis of 2-(V,V-diaIkylamino)-2,4-6-cycloheptatrien-l-one derivatives from tropolones, an isocyanide, a primary amine and an aldehyde via Ugi-Smiles coupling reaction. 

A one-pot conversion of phenols to anilines using 2-chloroacetamide/K2C03/DMF system catalysed by KI via Smiles rearrangement has been described (Scheme 174). The effects of each of the four reactants on the energy profile for an Ugi-Smiles coupling reaction have been reported. ... 

The adduct resulting from this Ugi-Smiles coupling contains an N-aryl unit that offers great synthetic potential for further functionalization. Scheme 5.26 shows just one such an example. The reaction of 2-iodo-4-nitrophenol (90) with allylamine, 3-methylbutanal, and benzyl isocyanide in the presence of ammonium chloride afford the Ugi-Smiles adduct 91, which, without purification, underwent palladium-catalyzed Heck cydization to afford indole 92 in 72% yield. Trifluoroacetic add (O.lequiv.) was introduced before addition of the palladium catalyst in order to destroy any remaining isocyanide, which was harmful to the subsequent cydization due to catalyst poisoning [51]. 

Scheme 19.40 Mercaptobenzothiazoles and benzoxazoles in Ugi-Smiles couplings. Scheme 19.41 Passerini-Smiles reaction of 2-nitrophenol.

Scheme 19.SI Consecutive Ugi-Smiles/Heck reaction towards indole derivatives. Scheme 19.S2 Ugi-Smiles couplings followed by palladium-triggered ring cleavage of...

During the last decades, excellent revisions concerning the reactivity and use of the Ugi reaction [2], isocyanides [3-8], MCRs [9-12], and the Ugi-Smiles coupling [13] have been reported. All of them contain information related to the topic of this chapter, and they should be consulted for obtaining detailed information about the literature that appeared in the last years. 

The reaction was also carried out with five-membered heterocycles, but only mercaptotriazoles 111 showed moderate reactivity for different substituents (Scheme 7.45a) [101]. In the same publication, the authors showed that mer-captobenzoxazoles and benzothiazoles (112) could also be used as starting materials for the Ugi-Smiles coupling, giving the final thioamides 113 in good yields with aliphatic aldehydes and ketones, and with lower yields in the case of aromatic aldehydes (Scheme 7.45b). 

Once the Ugi-Smiles coupling was established, different woiks related to the derivatization of the products were carried out Some of the examples were performed in a one-pot manner, but most of them required previous isolation of the Ugi-Smiles adducts. One of the first examples was developed by El Kaun and Grimaud by combination of the Ugi-Smiles reaction and a ring-closure metathesis, affording interesting pyrintido azepine scaffolds 120 (Scheme 7.49) [ 106]. However, the one-pot procedure could not be carried out probably... 

The combination of the Ugi-Smiles coupling with the reduction of the nitro group of the aryl group has been used for the synthesis of benzimidazolopiperazines 128 [110]. Thus, the use of aminoacetaldehyde dimethyl acetal 125 with 2-nitrophenol 107 in the Ugi-Smiles reaction yielded the piperazine 127 (Scheme 7.53) throngh the opened intermediate 126. Then, the hydrogenolysis of the piperazine 127 provided the fused system 128 at 60 C in the presence of acetic acid to ensure a faster cycUzation. 

Imidazolinium salts 136 were synthesized via a one-pot, two-step procedure involving an Ugi-Smiles coupling and copper-catalyzed reaction, starting from mercaptotriazine... 

Westermann and coworkers have recendy reported on tandem Ugi-Mumm/Ugi-Smiles reactions using various phenol-substituted carboxylic acids tScheme 19.46i. As the Ugi-Mumm is very rapid, it is possible to perform sequential couplings to reach products with seven points of diversity. ... 

Recendy, different enol sources have been investigated to replace the starting phenol. For instance, Charton and coworkers reported a similar reaction using squaric acid 83 instead of an electron-deficient phenol fScheme 19.47T Similarly, Ramazani and coworkers described the application of tropolone 84 in Ugi-Smiles or Passerini-Smiles couplings to synthesize substituted cycloheptatrien-l-one derivatives 85 fScheme 19.48T... 

---