Multicomponent reactions sequences

Nair and coworkers have used a type bde multicomponent reaction sequence to prepare N-amino-3-pyrrolin-2-ones (2001CL738, 2002T8113). 

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... 

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

Heterocycles with a l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine core are also available through this multicomponent reaction. Compounds with a related structure are of high interest either for synthetic applications or for biological purposes. For the first time we were able to propose a one-pot access to pyrrolopiperazine and azasteroide-type scaffolds, illustrating the potential of this ecocompatible sequence to create molecular complexity and diversity from simple and readily available substrates (Scheme 60) [164]. In this case, the primary amine partner bears a pyrrole nucleophile, which neutralizes the transient iminium intermediate to form a new C-C bond via an intramolecular Pictet-Spengler-type cyclization. 

A method of diversity-oriented synthesis consists in sequencing multicomponent reactions with subsequent transformations that further increase molecular complexity. Thus, amides 223a and b (Scheme 53, both obtained... 

With the exception of one-step multicomponent reactions, solid-phase organic syntheses are linear, because convergent sequences would require removal of intermediates from the polymer support.11... 

The conservation equations for the micropore, taking the reaction sequence of Eq. (31) into account, are given by the coupled multicomponent form of Eq. (32) for a cylindrical pore ... 

An iron-catalyzed multicomponent reaction of aldehyde 4a, acetophenone, acetyl chloride and acetonitrile, which was used as the solvent, gave P-amino ketones such as 32 (Scheme 8.11) [41]. It was assumed that the sequence starts with an aldol reaction of aldehyde and ketone and then proceeds further with a displacement of a P-acetoxy group by the nucleophilic nitrile-nitrogen. 

Radicals add to unsaturated bonds to form new radicals, which then undergo addition to other unsaturated bonds to generate further radicals. This reaction sequence, when it occurs iteratively, ultimately leads to the production of polymers. Yet the typical radical polymerization sequence also features the essence of radical-induced multicomponent assembling reactions, assuming, of course, that the individual steps occur in a controlled manner with respect to the sequence and the number of components. The key question then becomes how does one control radical addition reactions such that they can be useful multicomponent reactions Among the possibilities are kinetics, radical polar effects, quenching of the radicals by a one-electron transfer and an efficient radical chain system based on the judicious choice of a radical mediator. This chapter presents a variety of different answers to the question. Each example supports the view that a multicomponent coupling reaction is preferable to uncontrolled radical polymerization reactions, which can decrease the overall efficiency of the process. 

Since the late 1990s, new multicomponent reactions based on a palladium/ copper-catalyzed coupling-isomerization sequence of 1-aryl prop-2-yn-l-ols and electron-deficient sp2-hybridized halogen compounds leading to the correspond-... 

This simple sketch illustrates clearly that convergent multicomponent reactions performed with a limited set of reactive building blocks (reactophores) in a multigeneration format offer a tremendous potential to produce diverse small-molecule compound collections, depending on the reaction sequence used (the combinatorics of reactive building blocks ). The concept of combinatorics of reactive building blocks should ultimately lead to novel multicomponent reactions. In Section III we will focus on reactophores such as a-alkynyl ketones, which allow the construction of a wide variety of core structures. 

The usefulness of palladium-based chemistry is highlighted by the multicomponent cascade reaction sequence that uses o-ethylanilines, aryl iodides, primary amines, and carbon monoxide (Equation 99) <2005JOC6454>. 

Iminocoumarins are formed in high yield from the Cu-catalysed multicomponent reaction of salicylaldehyde, alkynes and sulfonyl azides. It is considered that an initially formed ketimine reacts with the salicylaldehyde hydroxy function and an intramolecular nucleophilic addition to the aldehyde moiety completes the sequence (Scheme 29) <06OL4517>. 

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. 

Due to their high atom economy, multicomponent reactions have emerged with a high potential in the fine chemicals and pharmaceutical industries [41]. These reactions are usually not concerted rather, they are tandem or domino processes in which multiple reactions are combined into one synthetic operation. This significantly reduces reaction time as well as the amount of waste in comparison to an alternative multistep synthetic process. The first step produces an intermediate that need not be isolated, but it must undergo a sequence of reactions until the stable... 

Considering efficiency, reaction sequences are most valuable in which structural variations can be introduced in such a way that the products can be used immediately in the next step. This condition is, of course, ideally fulfilled by multicomponent reactions (see above), but there are also other ways of approaching this aim. 

The radical carbonylation of an alkyl iodide in the presence of Kim s sulfonyl oxime ethers [58, 59, 60] provides a new type of multicomponent coupling reaction where plural radical Cl synthons are consecutively combined [61]. In the transformation, allyltin was used to serve as a trap of benzenesulfonyl radical which converts sulfonyl radical to a tin radical, thus creating a chain. Scheme 14 illustrates such an example, where the product was easily dehydroxylated to give the corresponding tricarbonyl compound on treatment with zinc/AcOH. The radical acylation reaction by Kim s sulfonyl oxime ethers can be conducted under irradiation with the addition of hexamethylditin. This is an alternative path for achieving a similar transformation without the use of photolysis equipment. Scheme 15 illustrates several examples where carbon monoxide and Kim s sulfonyl oxime ethers are successfully combined to create new tandem radical reaction sequences [61],... 

We were especially interested in reactive building blocks that would allow to carry out multicomponent-cascade reactions giving rise to different core structures depending on the sequence of mixing ( combinatorics of building blocks ). Ultimately, this excercise can lead into the discovery of novel multicomponent reactions. 

The use of multicomponent reactions (MCRs) constitutes an attractive synthetic strategy for rapid and efficient library generation because diverse products are formed in a single step. Usually, MCR transformations do not involve the simultaneous reaction of all components. Instead, they are undertaken in a sequence of steps that are determined by the synthetic design. A drawback of many MCR processes is that they can be slow and inefficient, but microwave heating can be used as a tool to overcome these problems, as illustrated here with selected examples. 

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