Reaction Passerini

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. 

As a further development, the substitution of Lewis acids or mineral acids for carboxylic acids in the Passerini reaction has allowed for the direct generation of a-hydroxyamides 5. 

In studies summarized over two reports in 1920 and 1921, Mario Passerini described that the treatment of p-isonitrileazobenzene (6) with an acetone 

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).  

Through further followup studies, Passerini expanded the scope of substrates to include a number of aldehydes and ketones as the carbonyl component and a variety of isonitriles including saturated alkyl isocyanides. Passerini also examined reactions where two components were combined into a single bifunctional substrate such as levulinic acid (8), where the carboxylic acid is proximally connected to a ketone. The reaction of levulinic acid with phenyl isocyanide gave amide 9 with the acyloxy moiety of the generic product now a y-lactone.  

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

L Lohberger, S. Karl, R. In Comprehensive Organic Synthesis, Trost, B. M. Fleming, L, Eds, Pergamon Oxford, 1991, Vol. 2, p.l083. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 191, Springer-Verlag Berlin Heidelberg 2009 

Passerini, M. Gazz. Chim. Ital. 1921, 51, 126-129. (b) Passerini, M. Gazz. Chim. Ital. 1921,51,181-188. Mario Passerini (b, 1891) was bom in Scandicci, Italy. He obtained his Ph.D. In ehemistry and pharmaey at the University of Florenee, where he was a professor for most of his eareer. 

Williams, D. R. Passerini reaction. In Name Reactions for Homologa-tions-Part IP, Li, J. J., Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2009, pp 765-785. (Review). 

Photoinduced electrocyclization of a carbonyl with an alkene to form polysubsti-tuted oxetane ring systems 

Patemo, E. Chieffi, G. Gazz- Chim. Ital. 1909, 39, 341. Emaubuele Paterno (1847—1935) was born in Palermo, Sicily, Italy. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 204, Springer International Publishing Switzerland 2014 

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Like the Strecker synthesis, the Ugi reaction also involves a nucleophilic addition to an imine as the crucial step in which the stereogenic center of an a-amino acid derivative is formed4. The Ugi reaction, also denoted as a four-component condensation (A), is related to the older Passerini reaction5 (B) in an analogous fashion as the Strecker synthesis is to cyanohydrin formation. In both the Ugi and the Passerini reaction, an isocyanide takes the role of cyanide. 

When an isocyanide is treated with a carboxylic acid and an aldehyde or ketone, an a-acyloxy amide is prepared. This is called the Passerini reaction. The following mechanism has been postulated ... 

The first MCR involving isocyanides (IMCR) was reported in 1921 with the Passerini reaction (P-3CR) [8], and over the years these reactions have become increasingly important and have been highlighted in several publications (for discussions, see below). Another older MCR which leads to (non-natural) a-amino acids is the Bucherer-Bergs reaction (BB-4CR), which was first reported in 1929 [9]. This type of transformation is closely related to the Strecker reaction, with C02 employed as a fourth component. 

In a more recent approach, the same group synthesized macrocycles using a Passerini reaction followed by a ring-closing metathesis [23], but the final cycliza-tion gave only low yields. 

It should be mentioned that the Passerini reaction has also been used by Marcac-cini s group to prepare p-lactams [24], oxazoles [25], and furanes [26]. Natural products have also been accessed using this procedure as one of the key steps. The syntheses of azinomycin by Armstrong [27] and eurystatin A by Schmidt [28] represent two good examples of this procedure. 

Synthesis of Heterocycles Through Classical Ugi and Passerini Reactions... 

In this chapter we focus only on post-condensation transformations that follow classical Ugi or Passerini reactions (including the intramolecular ones) and that lead to heterocycles. Therefore, we will not report the many examples of postcondensation reactions applied to non-conventional Ugi or Passerini scaffolds generated by variants of these venerable reactions. Also post-IMCR transformations that involve the inclusion, in the final cyclic system, of sub-structures not initially present in the starting component will be overlooked. 

In the discussion of the various examples, we will concentrate more on the secondary transformations than on the Ugi or Passerini reaction themselves, which are in most cases carried out under standard conditions (alcoholic solvents for the Ugi and apolar solvents for the Passerini). Classical IMCRs are well known to be, in most cases, poorly diastereoselective and thus the stereochemical aspect, aheady described in a previous review [13], will be mostly ignored in this chapter. 

The amide (typically a tertiary one) or the ester derived from the carboxylic acid component in classical Ugi and Passerini reactions can undergo nucleophilic S Ac by various nucleophiles [54], These post-condensation reactions, however, do not... 

Also acetylenic dienophiles have been used, this time both in the Ugi [127,128] and in the Passerini MCRs [128]. The bicyclic compounds 148 (Z = NR ), stemming from an Ugi reaction on furaldehyde, are somewhat unstable and can be converted, under Lewis acid catalysis, into isoindolinones 149 [127,128]. On the contrary, compounds 148 (Z = O), coming from a Passerini reaction, are stable under the same conditions and therefore are not converted into isobenzofuranones. 

Banfi L, Riva R (2005) The passerini reaction. In Overman LE (ed) Organic reactions. Wiley, Hoboken, pp 1-140... 

Bossio R, Marcaccini S, Pepino R (1991) Synthesis of isocyanides and related compounds. Synthesis of oxazole derivatives via the Passerini reaction. Liebigs Ann Chem 1107-1108... 

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