Carboxylic acids Passerini reaction

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 ... 

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... 

In this period, the most important reactions of the isocyanides were the formations of tetrazole derivatives from isocyanides and hydrazoic acid, a process introduced in 1910 by Oliveri-Mandala and Alagna, and then in 1921 Passerini introduced the reaction (P-3CR), which was the first 3-component reaction of the isocyanides. In the 1940s Baker,and later Dewar, proposed mechanisms of the P-3CR. The important role of the intermediate hydrogen bond between the carboxylic acid and the carbonyl compound in suitable solvents was mentioned. ... 

Four-component condensation (4CC) of carboxylic acids, C-isocyanides, amines, and carbonyl compounds to afford diamides. Cf. Passerini reaction. 

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... 

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],... 

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... 

A recent screening of various chiral carboxylic acids has allowed the selection of galacturonic derivative 12 as a very efficient control in the stereochemical course of some Passerini reactions (Scheme 1.5). Although the de seems to be strongly dependent on the isocyanide employed, this result suggests the possibility of employing carboxylic acids as easily removable chiral auxiliaries in the asymmetric synthesis of biologically important mandelamides [16]. 

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 the classic Passerini reaction (P-3CR), an a-acyloxy carboxamide is formed from the reaction of an isocyanide, an aldehyde (or ketone), and a carboxylic acid. The... 

In term of diversity-oriented strategies, multicomponent reactions (MCR) represent an attractive and rapid access to libraries of macrocycles inspired by biologically active natural products. Combined with Passerini and Ugi reactions, M-RCM has already shown promising synthetic potential, as illustrated by the pioneering work of Domling and coworkers [46]. Condensation of isocyanide 69 with carboxylic acid 70 in the presence of paraformaldehyde leads to bis-olefin 71, which is subsequently submitted to RCM in the presence of G1 and titanium isopropoxide to give the 22-membered macrocycle 72 (Scheme 2.27). 

A few years later Passerini, developed a new 3CR towards a-acyloxy amides 9 which are formed by reacting an aldehyde or ketone 6, a carboxylic acid 8 and an isocyanide 7 (Scheme 2) ([25] and see for review [26]). Since the first synthesis of isocyanides (formerly known as isonitriles [27]) in 1858, the Passerini 3-component reaction (P-3CR) was the first MCR involving these reactive species. It has become one of the renowned examples of an important subclass of MCRs, the isocyanide-based MCRs (IMCRs). Especially important for the Passerini reaction, but also for a lot of other IMCRs, is the ability of isocyanides to form a-adducts, by reacting with nucleophiles and electrophiles (at the carbon atom). The nucleophilic... 

Protection of carboxyl groups. The deblocking reaction discussed above with 2 is also applicable to a halogenated protected derivative of the terminal carboxyl group of peptides. The N-protected amino acid is converted by the Passerini reaction with an o-halo aldehyde into a protected derivative such as 4. The derivative is cleaved by reiietion with 2 at 20° in acetonitrile or methanol (equation III). 

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. 

L. Banfi and co-workers utilized the Passerini three component reaction to prepare a 9600 member hit generation library of nor-statines. " ° These compounds are potential transition state mimetics for the inhibitors of aspartyl proteases. The authors produced the library by starting out from eight A/-Boc-a-aminoaldehydes, twenty isocyanides and sixty carboxylic acids. The key Passerini reaction occurred under mild conditions. This transformation was followed by removal of the Boc protecting group and acyl transfer. Three representative examples of the library are shown. 

Passerini multicomponent reaction Condensation of isocyanides with carboxylic acids and carbonyl compounds to afford a-acyloxycarboxamides. 330... 

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). 

The same authors have broadened the scope of the solid-phase application of this reaction by employing different cyclic amidines instead of only the 2-aminopyridine nucleus and using a Wang resin-bound isonitrile ester [357]. In this paper the authors justified the use of catalytic PTS A instead of a carboxylic acid such as AcOH, because the latter would trigger a Passerini [342, 358] side reaction (Scheme 93). 

The Passerini reaction, also called the 3-CC reaction, which consists of the reaction of a carboxylic acid, a carbonyl compound, and an isocyanide providing an a-(acyloxy)carboxamide in a single step, was carried out for the first time in [bmim] [BFJ (Fig. 12.1) [1]. 

Application of the Davidson oxazole synthesis to products of the Passerini reaction has expanded the usefulness of this well-known route <91LAll07>. The a-acyloxy ketones or a-acyloxy -keto esters employed in the Davidson synthesis are not readily available. However, the use of arylglyoxals as the carbonyl component of the Passerini reaction, along with cyclohexyl isocyanide and carboxylic acids, gives a wide variety of iV-cyclohexyl-2-acyloxy-3-aryl-3-oxopropionamides (151). Reaction of these intermediates with ammonium formate in acetic acid affords A -cyclohexyl-2,4-diaryl-5-oxazolecarboxamides (152) in fair yields (Scheme 69). 

Between 1921 and 1931,Passerini introduced and investigated the reaction which bears his name [8-10], forming the products 16 from carbonyl compounds 1, carboxylic acids 3A and isocyanides 13. The discovery of the P-3CR was a milestone in the development of isocyanide-based MCRs, as it was the introduction of the first practicably irreversible MCR of these compounds. 

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