Passerini reaction multicomponent reactions

Another approach that has been used in combinatorial chemistry is the use of a one-pot reaction such as the well-known Ugi multicomponent reaction " and the Passerini reaction. Multicomponent reactions are reactions in which three or more reactants come together in a single reaction vessel to form a new product that displays aspects of all the components. The reactions may be carried out in solution or on a solid support. ... 

F. De Moliner, L. Banfi, R. Riva, A. Basso, Comb. Chem. High Throughput Screen. 2011, 14, 782-810. Beyond Ugi and Passerini reactions. Multicomponent approaches based on isocyanides and alkynes as an efficient tool for diversity oriented synthesis. 

T. Sela, A. Vigalok, A<7v. Synth. Catal. 2012, 354, 2407-2411. Salt-controlled selectivity in on water and in water Passerini-type multicomponent reactions. 

Multicomponent reactions (MCRs) have been known to produce highly complex and diverse structures [76]. There is a considerable interest in the application of new multicomponent reactions to access biologically relevant molecules [77,78] and natural products [79]. A recent report has disclosed multicomponent Passerini and Ugi reactions to produce, rapid and efficiently, a library of redox-active selenium and tellurium compounds [80]. The compounds showed promising cytotoxicity against several cancer cell lines. 

Marcaccini S, Torroba T (2005) Post-condensation transformations of the Passerini and Ugi reactions. In Zhu J, Bienayme H (eds) Multicomponent reactions. Wiley-VCH, Weinheim, pp 33-75... 

Fig. 2 The Passerini and Ugi reaction, the most prominent examples of the isocyanide-based multicomponent reactions...

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 manufacturer of the commercially available Syrris Africa system [14] reports on the optimization of several multicomponent reactions Passerini, Biginelli and Ugi reaction. However, only the details of the three-component Passerini reaction were available [15]. 

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. 

Both Ugi and Passerini reactions have been explored, using 3-substituted propy-noic acids as dienophiles. The multicomponent adducts 93 have been submitted to IMDA under different conditions, depending upon the heteroatom X in the tether Ugi adducts could be converted smoothly, usually under thermal conditions, to give 94 as the major stereoisomer (less than 10% of any other stereoisomer detected). On the contrary, Passerini adducts proved to be unreactive under thermal conditions, but reacted cleanly under Me2AlCl catalysis to give bicyclic lactones in a highly stereoselective way (Scheme 1.33) [83],... 

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). 

The newly available biological high-throughput screening (HTS) systems have induced many initiatives in the field of combinatorial chemistry [42]. Besides oligopeptide syntheses [43], multicomponent reactions offer attractive methods for the production of high-diversity libraries. Passerini and Ugi reactions (Scheme 19) are frequently used for synthesis of libraries containing thousands of compounds [44],... 

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

Nerdinger, S., Beck, B. New heterocycle synthesis by using bifunctional reactants in multicomponent reaction chemistry the use of arylglyoxals and cinnamaldehyde in the Ugi-4CR and Passerini-3CR. Chemtracts 200Z, 16, 233-237. 

Banfi, L., Guanti, G., Riva, R. Passerini multicomponent reaction of protected a-amino aldehydes as a tool for combinatorial synthesis of enzyme inhibitors. Chem. Common. 2000, 985-986. 

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). 

Ideal reactions for solution-phase parallel synthesis are those that are kinetically and thermodynamically favored, are tolerant of diverse functionality, and have a broad range of reactant tolerance. In this approach, capture resins and extraction procedures are often used for preliminary purification. The solution-phase reaction conditions must be validated in terms of scope and optimal reaction conditions over the range of reactants. Two common strategies for solution libraries involve derivatization of preformed functionalized scaffolds and multicomponent condensation reactions, for example, the Ugi reaction, the Passerini reaction, and the formation of hydroxyamininimides from an ester, a hydrazine, and an epoxide. 

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