Multicomponent Reactions MCR

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. 

Multicomponent reactions (MCR), in which three or more reactions combine to give a single product, have lately received much attention. The Ugi four-component condensation in which an amine, an aldehyde or ketone, a carboxylic acid, and an isocyanide combine to yield an ot-acylamino amide, is particularly interesting, because... 

Application of the PdCy precatalysts to multicomponent reactions (MCRs)... 

Practically irreversible multicomponent reactions (MCRs), like the Ugi 4-component reaction (U-4CR), can usually fulfill aU essential aspects of green chemistry. Their products can be formed directly, requiring minimal work by just mixing three to nine educts. Often minimal amounts of solvents are needed, and almost quantitative yields of pure products are frequently formed. 

One-pot condensation of an aromatic aldehyde, urea, and ethyl acetoacetate in the acidic ethanolic solution and expansion of such a condensation thereof. It belongs to a class of transformations called multicomponent reactions (MCRs). 

Also reactions that rapidly create more diversity are sought after. In recent years, more and more multicomponent reactions (MCRs) have been developed and combined with modern synthetic methods such as RCM or Pd couplings to provide rapid access to complex, natural product-like structures in solution. 

A multicomponent reaction (MCR) represents a sequence of bimolecular events leading to products that incorporate essentially all atoms of three or more starting materials. MCRs allow for the rapid and facile access to complex target structures... 

An especially effective and fruitful way to synthesize heterocycles is by isocyanide-based multicomponent reaction (MCR).i... 

Abstract Piperazines and its congeners, (di)keto piperazines are valuable tools in drug discovery, providing a natural path for the process peptide > peptidomimetic > small molecule also called depeptisation. Moreover, they can provide molecular probes to understand molecular pathways for diseases of unmet medical need. However, in order to better understand the design of such value added compounds, the detailed understanding of scope and limitation of their synthesis as well as their 3D structures and associated physicochemical properties is indispensables. Isocyanide multicomponent reaction (MCR) chemistry provides a prime tool for entering the chemical space of (di)(keto)piperazines since not less then 20 different ways exist to access a diversity of related scaffolds. 

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. 

Fig. 2 Selected multicomponent reactions (MCRs) producing peptidic substructures, with the Ugi-4 component reaction (Ugi-4CR) as most commonly used one...

According to our definition a multicomponent reaction (MCR) comprises reactions with more than two starting materials participating in the reaction and, at the same time, the atoms of these educts contribute the majority of the novel skeleton of the product (Scheme 3.1) [1], For example, adenine may be formed by the addition of five molecules of isocyanic acid, a reaction of possible high prebiotic relevance [2]. 

This chapter contains a survey of free-radical-mediated multicomponent reactions (MCRs), which permit the coupling of three or more components. Even though they are not technically classified as MCRs, remarkable intramolecular radical cascade processes have been developed. Some examples, such as those shown in Scheme 6.3, use an isonitrile or acrylonitrile as the intermolecular component for each reaction [6]. These examples demonstrate the tremendous power of the combination of inter- and intramolecular radical cascade processes in organic synthesis. Readers are advised to be aware of remarkable intramolecular aspects of modem radical chemistry through excellent review articles published elsewhere [1, 7]. It should also be noted that there has also been remarkable progress in the area of living radical polymerizations, but this will not be covered here. 

Multicomponent reactions (MCRs) are processes that involve sequential reactions among three or more reactant components that co-exist in the same reaction mixture. In order to be efficient, MCRs rely on components that are compatible with each other and do not undergo alternative irreversible reactions to form other products or by-products. 

Multicomponent reactions (MCRs) are one-pot processes combining three or more substrates simultaneously [1], MCR processes are of great interest, not only because of their atom economy but also for their application in diversity-oriented synthesis and in preparing libraries for the screening of functional molecules. Catalytic asymmetric multicomponent processes are particularly valuable but demanding and only a few examples have been realized so far. Here we provide an overview of this exciting and rapidly growing area. 

The Petasis Reaction is a multicomponent reaction (MCR) that enables the preparation of amines and their derivatives such as 01-amino acids. 

Cyclization of imidoyl azides 150 into 1,5-disubstituted tetrazoles 5 (Equation 10) is widely used both in the laboratory and on an industrial scale. Imidoyl azides form in situ in the course of various multistage processes, and sometimes in the multicomponent reactions (MCRs). The problems related to generation of imidoyl azides and also to electrocyclization of these intermediates into 1-mono- and 1,5-disubstituted tetrazoles are of crucial importance for the tetrazole chemistry. These problems are traditionally treated at length in basic reviews <1984CHEC(4)791, 1996CHEC-II(5)621>. The traditional methods for the synthesis and cyclization of imidoyl azides into tetrazoles were broadly employed and further refined in more recent works <1997MI1375>. Several new methods based on this approach have also been developed. 

Multicomponent reactions (MCRs) have high efficiency in the construction of complex molecules [39,40]. In general practice, more than one reagent is used in excess to push the reaction to go to completion. The unreacted components left in the reaction mixture may complicate the product purification. The employment of a fluorous component as the limiting agent for the MCRs is a good way to simplify the purification. 

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 third, though far less studied possibility, is the one-step synthesis of macrocycles by a multicomponent reaction (MCR). MCR is a process in which three or more reactants are combined in a single reaction vessel to produce a product that incorporates substantial portions of all the components [29]. They have, by definition, sustainable chemistry and are inherently (a) chemo- and regioselective, a prerequisite for a successful MCR since at least three reactive functional groups are involved and they have to react in an ordered and selective fashion (b) atom-economic [30] since most of them involve addition rather than substitution reactions. 

Generally, domino reactions [23-26] are regarded as sequences of uni- or bimolecular elementary reactions that proceed without intermediate isolation or workup as a consequence of the reactive functionality that has been formed in the previous step (Fig. 2). Besides uni- and bimolecular domino reactions that are generally referred to as domino reactions, the third class is called multimolecular domino reactions or multicomponent reactions (MCRs). 

Abstract In the past decade, it has been extensively demonstrated that multicomponent chemistry is an ideal tool to create molecular complexity. Furthermore, combination of these complexity-generating reactions with follow-up cyclization reactions led to scaffold diversity, which is one of the most important features of diversity oriented synthesis. Scaffold diversity has also been created by the development of novel multicomponent strategies. Four different approaches will be discussed [single reactant replacement, modular reaction sequences, condition based divergence, and union of multicomponent reactions (MCRs)], which all led to the development of new MCRs and higher order MCRs, thereby addressing both molecular diversity and complexity. 

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