Acyloxycarboxamide

Modern MCRs that involve isocyanides as starting materials are by far the most versatile reactions in terms of available scaffolds and numbers of accessible compounds. The oldest among these, the three-component Passerini MCR (P-3CR), involves the reaction between an aldehyde 9-1, an acid 9-2, and an isocyanide 9-3 to yield a-acyloxycarboxamides 9-6 in one step [8], The reaction mechanism has long been a point of debate, but a present-day generally accepted rational assumption for the observed products and byproducts is presented in Scheme 9.1. The reaction starts with the formation of adduct 9-4 by interaction of the carbonyl compound 9-1 and the acid 9-2. This is immediately followed by an addition of the oxygen of the carboxylic acid moiety to the carbon of the isocyanide 9-3 and addition of this carbon to the aldehyde group, as depicted in TS 9-5 to give 9-5. The final product 9-6 is... 

Three-component condensation (3CC) of carboxylic acids, C-isocyanides, and carbonyl compounds to afford a-acyloxycarboxamides. Cf. Ugi reaction. 

The Passerini reaction is a condensation between a carbonyl, a carboxylic acid and an isocyanide to form an ot-acyloxycarboxamide (Scheme 1) [5],... 

Isocyanides, formal divalent carbon functionalities, are ideal candidates for the development of MCRs. Their reaction with carbonyls and imines, through an a-addition process, generates a zwitterionic intermediate, which is then trapped by a nucleophile. The resulting double a-addition adduct is unstable and rapidly undergoes the Mumm rearrangement to afford the final product (Scheme 12.32). The venerable three-component Passerini reaction is the first MCR based on this type of reaction process [116]. It addresses the formation of a-acyloxycarboxamides, which constitute a class of very versatile synthons in organic chemistry. In the present context, this reaction was utilized by Schmidt and collaborators for the elaboration of intermediate 234 [117], a key fragment for the synthesis of the prolyl endopeptidase inhibitor Eurystatin A 231 (Scheme 12.33) [118]. 

The mechanism of the Passerini reaction was widely examined. A plausible mechanism that is consistent with experimental data is as follows First, the carbonyl compound and the carboxylic acid forms a hydrogen bonded adduct. Subsequently, the carbon atom of the isocyanide group attacks the electrophilic carbonyl carbon, and also reacts with the nucleophilic oxygen atom of the carboxylic acid. The resulting intermediate cannot be isolated as it rearranges to the more stable a-acyloxycarboxamide in an intramolecular transacylation. 

In 1921 Passerini reported the synthesis of the a-acyloxycarboxamides (6a-e) according to the scheme below. The formation of a-acyloxycarboxamides by a three-component reaction of carboxylic acids (3), carbonyl compounds (4) and isocyanides (5) is the proper Passerini reaction. The reactions described in Sections 4.6.2.2-4.6.2.4 are closely related to the Passerini reaction we call them reactions of the Passerini type. ... 

Concentrated solutions of the components (3)-(S) in inert organic solvents react at 0-20 C to form (6) the reaction time varies with the nature of the components and the reaction conditions (1-100 h), as does the yield (18-95%). A wide variety of a-acyloxycarboxamides (6) have been prepared by the Passerini reaction, including some depsipeptide derivatives and their phospho analogs. ""... 

Aldehydes and isonitriles undergo hydrative condensation. Depending on the hydro-philicity of the isonitriles, either a-hydroxycarboxamides or a-acyloxycarboxamides are formed. 

If in Chapter 7 different aspects about Ugi reaction have been discussed, in this chapter, we are going to disclose to the reader a vision about the new contributions regarding other crucial isonitrile-based multicomponent reaction (MCR) the Passerini reaction (P-3CR) discovered in 1921 [1], The traditional multicomponent Passerini reaction [2] is another isonitrile-based MCR that provides easy access to a-acyloxycarboxamides 4 in a one-pot synthesis involving an aldehyde 1, a carboxylic acid 2, and an isonitrile 3 (Scheme 8.1), which has been subject of intensive studies in the last decade [3], The importance of using isocyanides lays in its dual role as nucleophile and electrophile, and moreover, if R R, a new stereocenter could be created under asymmetric conditions. 

In this context, Zhu and coworkers envisioned the great utility of alcohols in Passerini reaction instead of aldehydes, which are unstable and sometimes difficult to handle, since the carbonyl compounds can be obtained by direct oxidation of the corresponding alcohols. Thus, the authors generated in situ the aldehydes by oxidation of the alcohols 29 using IBX to obtain a-acyloxycarboxamide derivatives 30 in good yields (Scheme 8.10) [22]. 

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