A-acyloxyamides

In the classical Passerini reaction [11], an isocyanide is condensed with a carbonyl compound and a carboxylic acid to afford a-acyloxyamides 7 (Scheme 1.2). When the carbonyl compound is prochiral, a new stereogenic center is generated. It is generally accepted that the reaction proceeds through intermediate 6, which rearranges to the product. The way this intermediate is formed is more debated. A possibility is a concerted non-ionic mechanism involving transition state 5. Since the simultaneous union of three molecules is not a very likely process, another possibility is a stepwise mechanism, with the intermediacy of a loosely bonded adduct 4 between the carbonyl compound and the carboxylic acid [2], Since all three... 

Passerini reaction The formation of an a-acyloxyamide when an isonitrile is treated with a carboxylic acid and an aldehyde or ketone. Related to the Ugi reaction. 

The Passerini reaction and the Ugi reaction provide a-acyloxyamides and a-acet-amidoamides, respectively. Naturally, these reactions have been applied in the synthesis of peptides and cyclopeptides/cyclodepsipeptides [91]. Recently, the application of these reactions in the synthesis of heterocycles was reported. One of the most notable examples is Fukuyama and co-workers total synthesis of ecteinascidin 743 (Et 743) (148), a complex natural product recently commercialized as an anticancer drug (Scheme 5.46) [92]. Thus, reaction of the amine 149, the amino acid 150, 4-methoxyphenyl isocyanide (151) and acetaldehyde afforded the corresponding Ugi adduct 152 in 90% yield. After a series chemical transformations, 152 was ultimately converted to Et 743. The connection between the structure of Et 743 and the peptidic nature of Ugi adduct is not obvious, but with the deep insight of an experienced synthetic chemist, the non-trivial link can be drawn and be put into practice [93, 94]. 

Maraccini and co-workers cycUzed a-acyloxyamides 382 with ammonium formate in refluxing acetic acid to prepare iV-cyclohexyl-2,4-diaryl-5-oxazolecar-... 

The Passerini reaction describes the coupling of three components, an aldehyde or ketone 1, an isonitrile 2, and a carboxylic acid 3, to form an a-acyloxyamide 4. The reaction is typically performed at high concentration, in organic solvents of low polarity (as permitted by the solubilities of the starting materials) at or below room temperature. In many cases, the a-acyloxyamides precipitate from solution as the reactions proceed and a simple filtration of the crude reaction provides the desired product. 

In the second communication, Passerini also determined that the addition of hydrogen peroxide was unnecessary and, to an extent, deleterious as it mediated the decomposition of /7-isonitrileazobenzene. The formation of a-acyloxyamides from isonitriles, carboxylic acids and ketones or aldehydes subsequently became known as the Passerini reaction or the Passerini multicomponent reaction. The process is sometimes denoted as P-3CR according to Ugi s classification of multicomponent reactions (MCR). ... 

Schreiber and co-workers have described the use of a copper(II) complex with an aminoindanol-derived pyBOX ligand for the catalytic enantioselective addition of isonitriles to bidentate aldehydes to give a-acyloxyamides such as 38. Excellent yield and good enantioselectivity is observed in many cases and the protocol was also applied toward tandem Passerini-intramolecular Diels-Alder reactions for use in complexitygenerating diversity oriented synthesis. 

Many protease/peptidase inhibitor peptidomimetics include a-ketoamide moieties as key bioactive functionalities and the Passerini reaction provides a facile entry for their preparation through the oxidation of a-hydroxy amides. Researchers at Schering-Plough have utilized this strategy to synthesize a variety of a macrocyclic a-ketoamides towards the development of Hepatitis C virus (HCV) NS3 protease inhibitors. Aldehyde 56 was treated with allylisocyanide and acetic acid to give a-acyloxyamide... 

The resulting a-acyloxyamide motif 4 is present in the backbone of many bioactive products, such as drugs and active peptidomimetics. Additionally, Passerini MCR offers a cheap and rapid way to generate interesting and useful compound libraries. 

An accepted mechanism for this important reaction is depicted in the following Scheme 8.2, where the reaction proceeds through intermediate 6 before the final Mumm rearrangement [4] to allow a-acyloxyamides 4. However, the way how 6 is formed is still the focus of active debate [5]. 

Performing the reactions under solvent-free conditions has been proved an alternative eco-friendly media [63] and in this sense recently has been reported a useful and efficient Passerini 3CR under solvent-free conditions at high temperature allowing the synthesis of a broad scope of a-acyloxyamides 70 with high yields (64-95%) in short reaction times (Scheme 8.26) [64], after the pioneering work appeared in 2(X)8 [65]. 

Activated A-alkyl-O-acylhydroxamic acid derivatives 75 undergo base catalysed rearrangement to give 2-acyloxyamides 76 in good to excellent yields (50-100%) (equation 26). These precursors of 2-hydroxy amides (77) are good intermediates to prepare ethanol-amines, oxindoles and oxazolidinediones. 

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