Amide-esters, from isocyanides

The postulated mechanism for the formation of esters from the Ugi products is depicted in Scheme 7.64. Internal nucleophihc attack of the amide nitrogen lone pair onto the protonated ester carbonyl of 183 (derived from isocyanide) forms the intermediate 184, which equilibrates with 185. Electron-donating groups on the phenyl ring accelerate the formation of intermediate 186 and help stabilize it by forming intermediate 187 after the loss of water. Nucleophilic attack by the solvent used at the amide carbonyl of 187 (derived from isocyanide) provides the desired esters 181. 

The addition of isocyanides and azide to aldehyde-derived enamines has led to tetrazoles (533,536). On the other hand the vinylogous amide of acetoacetic ester and related compounds reacted with aldehydes, isocyanides and acids to give a-acylaminoamides (534). Iminopyrrolidones and imino-thiopyrrolidones were obtained from the addition of cyclohexylisocyanide and isocyanates or isothiocyanates to enamines (535). An interesting method for the formation of organophosphorus compounds is found in the reactions of imonium salts with dialkylphosphites (536). 

In a three-component synthesis the amide (86-1) obtained from the ester (85-5) and benzyl isocyanide is reacted with the piperdone (86-2). The product from this transform consists of the addition product (86-3) where amide nitrogen in (86-1) as well as the carbon from the isocyanide have added to the carbonyl group on the piperidine. Treatment of the adduct (86-3) with a strong acid hydrolyzes the urethane function on the fert-butyloxycarbonic protecting group, leaving behind the primary... 

Finally, other reactions can be performed directly using water as a solvent. Ugi s four components reaction, for example, provides an expedient access to peptidic scaffolds starting from an isocyanide, an amine, an aldehyde and a carboxylic acid. However, in competition to Ugi s reaction, Passerini ester formation often pollutes the reaction mixture and it is of great interest to perform this type of highly complex transformation in supported versions. Indeed, when an ammonium chloride supported aldehyde, similar to those used in Grieco s multicomponent reactions, are dissolved in water in the presence of an amine, the imine formation occurs within 15 min and isocyanide and acid can subsequently be added to the mixture. After 24 h at room temperature, amides were isolated in high yield with no other purification than washing with diethyl ether [135] (Fig. 44). 

Ulrich Schollkopf (1927-1998) and Rolf Schroder of the University of Gottingen first reported the preparation of 4,5-disubstituted oxazoles (3) from the condensation of a-metalated alkyl isocyanides and a range of acid chlorides, esters, and amides in 1971. 

The preceding survey of the recent developments in the synthesis of CICs and their application in small molecules and bioactive natural products reflects an active current interest in this highly versatile class of useful reagents. From a practical point of view, CICs have revolutionized the application of IMCRs, in particular that of U-4CR, due to their mild removal conditions that are compatible with many commonly used functional handles and their odorless, fragrant-like smell. Post-Ugi modification using CICs provides a method of transforming Af-terminal secondary amides into carboxylic acids, esters, thioesters, ketones, aldehydes, and alcohols for further chemical diversification and thus helped remedy the lack of commercial isocyanide inputs. 

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