Passerini 3-component reaction

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... 

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. ... 

One way to gain fast access to complex stmctures are multicomponent reactions (MCRs), of which especially the isocyanide-based MCRs are suitable to introduce peptidic elements, as the isonitrile usually ends up as an amide after the reaction is complete. Here the Ugi-4 component reaction (Ugi CR) is the most suitable one as it introduces two amide bonds to form an M-alkylated dipeptide usually (Fig. 2). The Passerini-3CR produces a typical element of depsipeptides with ester and amide in succession, and the Staudinger-3CR results in p-lactams. The biggest unsolved problem in all these MCRs is, however, that it is stUl close to impossible to obtain products with defined stereochemistry. On the other hand, this resistance, particularly of the Ugi-reaction, to render diastereo- and enantioselective processes allows the easy and unbiased synthesis of libraries with all stereoisomers present, usually in close to equal amounts. 

Tandem Passerini/Knoevenagel reactions were also performed by employing 2-nitrophenylacetic acid as the acid component to give the butenolides 65 that were reduced to the intermediate amines 66, which immediately cyclized to give indoles 67 in very high yields via a ring-switching process (Scheme 2.24) [52],... 

Another example, also reported by Ugi and co-workers, is the combination of an Ugi five center 4-component reaction (U-5C-4CR) with a Passerini-3CR (Scheme 16) [102]. This one-pot procedure uses an a-amino acid (L-aspartic acid, 168) as a 2-center-1-component input, which explains the origin of the U-5C-4CR. 

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. 

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). 

Just as in one at a time synthesis, linear syntheses are the most risky and produce the lowest yields. Converging methodologies address these limitations successfully, and in combinatorial work, Ugi (four-component) and Passerini (three-component) reactions are very flexible and popular. Generally one has less control over the specific products being produced by such reactions but this is largely compensated for by the molecular diversity available in this way. 

Last irreversible step in combination with other equilibrium steps. Notable examples are the Passerini and the Ugi reactions. As detailed in Scheme 5.3, the Ugi four-component reaction (U-4CR) produced a-acetamidoamide by simply stirring a methanolic solution of an aldehyde, an amine, a carboxylic add, and an isocyanide. The Mumm rearrangement (step 4), being irreversible, drove the reaction towards the formation of the Ugi adduct in good to excellent yield under extremely mild conditions. Evidently, having an irreversible step, espedally if it occurred at the end of the readion sequence, is advantageous, as the equilibrium steps will consequently be shifted to the final produd. 

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. ... 

Mannich and Passerini, to whom we owe the two best-known three-component reactions, are the grandparents of the four-component condensation, the Ugi reaction. Its parents are Ugi and Steinbrtick-ner, assisted by coworkers of that period. The godparents are Opitz and Merz, McFarland and Sjoberg. ... 

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

The divalent carbon of isocyanide has a pronounced nucleophilicity and undergoes readily a-addition to nucleophiles and electrophiles (Scheme 15.9). This chemical property is the basis of the Passerini three-component reaction (Eq. (1), Scheme 15.6) and the Ugi four-component reaction (Eq. (2), Scheme 15.6). However, the two aforementioned a-isocyanoacetate-based three-component reactions (cf. Scheme 15.7 and Scheme 15.8) were both initiated by the nucleophilicity of the a-carbon. The question one could ask is can we initiate the reaction sequence by taking advantage of the nucleophilicity of the isocyano function using similar substrates It is conceivable that, if the sequence can be initiated by the nucle-ophihcity of the isocyanide, a different reaction manifold wiU be induced leading to a different multicomponent adduct. 

The related Passerini-Smiles reaction, an analogous three-component coupling performed in the absence of the amine parmer, affords O-aryl carboxamides 76 via O to O aryl transfer fScheme 19.411. ... 

Kolb and Meier [43] prepared a malonate derivative of methyl 10-undecenoate, which was polymerised further with 1,6-hexanediol using titanium (IV) isopropoxide as a catalyst. This polymalonate, bearing a C9 aliphatic side chain with terminal double bonds, was then subjected to grafting by ruthenium-catalysed cross-metathesis reactions with acrylates or thiol-ene addition reactions. This functionalisation enabled a subsequent Passerini multi-component reaction [44] using the pendant carboxylic-acid moiety of the modified polymers that resulted from the thiol-ene addition of 3-mercaptopropionic acid into the initial double bonds of the polymer. 

Wang S-X, Wang M-X, Wang D-X et al (2008) Catalytic enantioselective Passerini three-component reaction. Angew Chem Int Ed 47 388-391... 

A three-component reaction comprising of Phenol-Passerini-Smiles rearrangement sequence of o-nitrophenol, cyclohexylisocyanide and propionaldehyde at 40 for 3 days provided the amide 158. In the course of the reaetion, a final Smiles rearrangement displaces all the equilibria to result in the product. Various aldehydes and isocyanides were employed to investigate the scope of this new reaction. It has been found that hindered isocyanides and aromatic aldehydes gave the desired product, whereas a,P-... 

Alternatively, cyclic enol ethers can serve as the electrophile in Passerini-type reactions as they undergo protonation by strong Bronsted acids to produce oxocarbeniums as the reactive partner. More recently, acyl cyanides have been demonstrated to participate as the carbonyl component in Passerini reactions, giving a-acyloxy-a-cyano amides in good yields. ... 

As an example supporting the above statements regarding parallel reaction steps, parallel reactions of isocyano-isocyanate 1752b at both the isocyano and iso-cyanato groups can be accomplished in a one-pot procedure, whereby methanol is added to the isocyanato group and a Passerini three-component reaction (P-3CR) with benzaldehyde and acetic acid occurs at the isocyano group, simultaneously affording both the urethane and Passerini product moieties in l-N-(0-methyl-carbamato)-10-N -[(2-acetoxy)-3-phenylacetamido]decane 1753 in 92% yield [1289]. 

Kalinski and coworkers explored the potential of different powerful MCRs (Ugi, Petasis, and Passerini) in the production of generic drugs such as the antiplatelet agent clopidogrel 42 synthesized in the racemic form (Scheme 4.20) [36]. Although the use of Ugi 3-component reaction afforded better yields in this synthesis, the PBM reaction allowed the preparation of the desired product 42 in 44% overall yield. 

Wessjohann and coworkers combined three different MCRs to efficiently create analogues of tubulysin, called tubugis [19]. Compound 36 was synthesized according to an Ugi-Nenajdenko MCR in 67% yield and a separable diastereomeric ratio of 1 1, while the thiazole 37 was conducted via a Passerini-Dbmling MCR (Scheme 6.3) [20]. Compounds 36 and 37 were further connected by an Ugi four-component reaction. The so obtained analogues 38 showed similar subnanomolar cytotoxicities as tubulysin A. 

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