The Passerini Reaction

Almost certainly, the most famous of Passerini s discoveries was the generalization of the simple reaction for characterization of a newly synthesized product, para-isocyanide-azobenzene. This experiment came about almost by accident in 1921, when he was not yet in his 30s [3]. The generalization of this reaction was not correctly interpreted immediately it took several years before Passerini correctiy recognized its specificity [4]. 

In 1921, he published his first paper on what would later be called the Passerini reaction. This three-component reaction, a carboxylic acid, a carbonyl compound (such as a ketone or an aldehyde) and isocyanides, opened the way for direct synthesis of hydroxylated carboxamide. 

The Passerini reaction followed the reaction of Pietro Biginelli (1860-1937) who, in 1891, proposed the revolutionary idea of a multi-component reaction [5-8]. 

A few months after announcement of the discovery, Passerini sent a second note to the Italian Chemical Society, concerning this multi-component reaction. To ensure that the above-mentioned reaction could be regarded as a general reaction, he repeated it with different isocyanides and ketones. Surprisingly, the product he 

Subsequently Passerini tried to determine the reaction mechanism for this new type of reaction. At first, he proposed a trimolecular process but, shortly afterward, he was inclined to propose a different mechanism, more consistent with traditional rules of organic chemistry. This mechanism would have proceeded through a non-isolable intermediate, generated by addition of the ketone to the acid, which would have, finally, reacted with isocyanides. 

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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. 

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. 

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... 

Because of the retained isocyano functionality, the dihydropyridone MCR product 85 can be used in various follow-up (multicomponent) reactions. For example, the Passerini reaction between 85, a carboxylic acid, and an aldehyde or ketone produces a series of dihydropyridone-based conformationally constrained depsipeptides 86 [171]. The subsequent Passerini reaction could also be performed in the same pot, resulting in a novel 6CR toward these complex products containing up to seven points of variation. Reaction of 85 with an aldehyde or ketone and amine component resulted in the isolation of dihydrooxazolopyridines (DHOPs, 87) [172] via a similar approach as the 2,4,5-trisubstituted oxazole variant toward 42 reported by Tron and Zhu (Fig. 15) [155]. The corresponding DHOPs (87), which... 

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

Imidates, rearrangement of, 14, 1 Imines, additions of allyl, allenyl, propargyl stannanes, 64, 1 additions of cyanide, 70, 1 as dienophiles, 65, 2 synthesis, 70, 1 Iminium ions, 39, 2 65, 2 Imino Diels-Alder reactions, 65, 2 Indoles, by Nenitzescu reaction, 20, 3 by reaction with TosMIC, 57, 3 Ionic hydrogenation, 71, 1 Isocyanides, in the Passerini reaction, 65, 1... 

D. Marquarding, G. Gokel, P. Hoffmann u. I. XJgi, The Passerini Reaction and Related Reactions, in I. 

This reaction is similar to the Passerini reaction. It is characterized by the four components going into the reaction mix ... 

Utilizing a postcondensation modification of the Passerini reaction,48 both Banff and workers at Amgen49 recognized the potential for a one-pot, two-step transformation to produce nor-statines with the general structure 104 containing three points of potential diversity. Recognizing their... 

Scheme 13. Application of the Passerini reaction for the preparation of nor-statines. Reagents and conditions (i) 0.1 M solutions in MeOH, 18 h, RT, then PS-TsNHNH2 in CH2C12. (ii) Ten percent trifluoroacetic acid (TFA) in CH2C12. (iii) PS-iV-me thy I morphol i lie in CH2C12.

Finally a fourth way to achieve asymmetric induction in the Passerini reaction is by way of a chiral catalyst, such as a Lewis acid. This approach is not trivial since in most cases the Lewis acid replaces the carboxylic acid as third component, leading to a-hydroxyamides or to other kinds of products instead of the classical adducts 7 (vide infra). After a thorough screening of combinations of Lewis acids/ chiral ligands, it was possible to select the couple 13 (Scheme 1.6), which affords clean reaction and a moderate ee with a model set of substrates [17]. Although improvements are needed in order to gain higher ees and to use efficiently sub-stoichiometric quantities of the chiral inducer, this represents the first example of an asymmetric classical Passerini reaction between three achiral components. 

When a mineral or Lewis acid replaces the carboxylic component in the Passerini reaction, the final products are usually a-hydroxyamides. Also in this case, when chiral carbonyl compounds or isocyanides are employed, the asymmetric induction is, with very few exceptions, scarce [18, 19]. For example, the pyridinium trifluoroacetate-mediated reaction of racemic cyclic ketone 14 with t-butyl isocyanide is reported to afford a single isomer [19] (Scheme 1.7). This example, together with those reported in Schemes 1.3 and 1.4, suggests that high induction may be obtained only by using rigid cyclic or polycyclic substrates. 

The Passerini reaction between a-chloroketones, isocyanides, and carboxylic acids afforded a-acyloxy-jS-chlorocarboxamides 52, which, on treatment with an excess of powdered KOH in tetrahydrofuran, underwent O-deacylation followed by a Darzens-type O-alkylation to give the functionalized oxiranes 53. When carboxamides 52 were treated with an excess of CsF, with or without a phase-transfer catalyst, a different ring closure took place to afford 3-acyloxy-2-azetidinones 54 in high yields (Scheme 2.21) [46]. 

Davidson s synthesis consists of the cydization of a-acyloxyketones with ammonia or ammonium acetate to give 2,4,5-trisubstituted oxazoles. The Passerini reaction between arylglyoxals, carboxylic acids, and isocyanides afforded N-substituted 2-acyloxy-3-aryl-3-oxopropionamides 83 in high yields. Upon heating with an excess of ammonium acetate in acetic acid, compounds 83 were cydized to N,2,4-trisubstituted oxazole-5-carboxamides 84 in fair yields [59]. A large number of a-acyloxy-jS-ketoamides can be prepared by changing the reaction components, so the method provides straightforward access to a variety of oxazole-5-carboxamides (Scheme 2.30). 

In summary, the Passerini reaction (and related modifications) are beginning to find utility in the drug discovery process, albeit confined to lead generation and... 

The Passerini Reaction proceeds rapidly if the reaction is performed in aprotic solvents at room temperature. High yields are obtained with high concentrations of the starting materials in the reaction mixture. 

From these findings, it is assumed that the Passerini Reaction does not follow an ionic pathway. Hydrogen bonding is believed to play a crucial role in the formation of the presumed cyclic transition state for this reaction. 

A related reaction is the addition of isonitriles 75 to aldehydes 1 (the Passerini reaction). Denmark has demonstrated that SiCU, upon activation by a chiral Lewis base, which increased the Lewis acidity of the silicon (vide supra Scheme 7.14), can mediate this reaction to produce a-hydroxy amides 77 after aqueous work-up (Scheme 7.16). Phosphoramide 60 was employed as the chiral Lewis-basic catalyst [74]. Modification of the procedure for hydrolysis of 76 gives rise to the corresponding methyl ester (rather than the amide 77) [74]. (For experimental details see Chapter 14.5.5). 

The Passerini reaction is a useful method for the synthesis of substituted a-acyloxy carbocyclic acids. This is another reaction that one might assume an epoxide would not survive. Reaction of an epoxy aldehyde with benzoic and TosMIC provided the Passerini product in good yield as a mixture of diastereomers <07SL83>. 

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