Ugi-Smiles coupling

Figure 5.5 Phenols and thiophenols used in Ugi-Smiles coupling.

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 19.33 Energies and structures of spiro intermediates in Ugi-Smiles coupling of 2-nitrophenol.

Scheme 19.34 Ugi-Smiles coupling of 2-allyl-4-nitrophenol derivatives.

Scheme 19.38 Thioimidate formation in attempted Ugi-Smiles coupling of 2-mercaptobenzoic acid derivative.

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...

Scheme 19.32 Substituent effects in Ugi-Smiles couplings of 4-nitrophenols.

Scheme 19.36 Hydrox3 5n imidines and hydrox3 5a azines in Ugi-Smiles couplings.

Scheme 19.52 Ugi-Smiles couplings followed by palladium-tri ered ring cleavage of fiirans and cyclopropanes.

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. 

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). 

El Kaim and Grimaud also used cyclic imines as starting materials for the Ugi-Smiles coupling [103]. Cyclic imines were obtained by oxidation with A-chlorosuccinimide (NCS) followed by elimination of HCl with a base (DBU). Then, the imine reacted with isocyanides and electrodeficient phenols to afford A-aryl piperidines 114 and pyrrolidines in good yields (Scheme 7.46). 

SCHEME 7.43 Heterocyclic products obtained using the Ugi-Smiles coupling. 

Scheme 7.48). The acid reacted following the Ugi-Mumm sequence, whereas the nitroaryl group reacted following an Ugi-Smiles coupling pathway. Thus, the sequential functionalization of different aryl acid derivatives was performed allowing the formation of eight bonds and the synthesis of highly functionalized amides 117 and 119 (Scheme 7.48).

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. 

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