Multicomponent reactions types

A library of 800 substituted prolines of type 112 was described using a similar synthetic approach. The [3 + 2] cycloaddition occurred via a multicomponent reaction of a-amino esters, aldehydes, and maleimides (Scheme 38). 

The multicomponent reactions have been widely used in solid and solution-phase chemistry during the last years. Multicomponent reaction strategies offer significant advantages compared with conventional liner type syntheses. Three or more reactants come together in a one pot reaction to form new products that contain portions of all the components [281]. There are several well-known multicomponent reactions that have been used in combinatorial chemistry. 

The most common methods suitable for the synthesis of different azolium compounds will be discussed here. Two routes are particularly useful for the preparation of the imidazolium salts (1) substitution reactions at the nitrogen atoms of imidazole [25] and (2) multicomponent reactions for the generation of an Af,Af -substituted heterocycle which are particularly useful for the synthesis of imidazolium salts bearing aromatic, very bulky, or particularly reactive N,N -sub-stituents (Fig. 3a,b) [26]. Both methods offer the opportunity to produce unsym-metrically substituted imidazolium salts of type 1 either by stepwise alkylation of imidazole or by the synthesis of an W-arylated imidazole derivative followed by 77 -alkylation [27]. Nevertheless, the method of choice for the preparation of the imidazolium salts 1 is the 77,77 -substitution of imidazole. Several other methods for the preparation of imidazolium salts with previously unattainable substitution patterns have also been described [28, 29]. 

The saturated imidazolidinium salts can be obtained by alkylation of dihydroimidazole or by selected cyclization reactions [22]. A multicomponent reaction leading to unsymmetric derivatives of type 2 has also been reported (Fig. 3c) [30]. 

The synthesis of a small library of very large (up to 60-membered) steroid/ peptide hybrid macrocycles has been achieved using double and fourfold Ugi reactions. This type of compound has not previously been described in literature. Neither have multicomponent reactions been used so far to form directly macrocycles of this size. In fact, synthetic macrocycles of this size with this structural complexity are very rare. 

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. 

Multicomponent reactions of this type, in the concepts of Tietze, who introduced the term domino reactions (96CRV115), can also be regarded as domino reactions of the type Knoevenagel-Michael-ljef-ero-Thorpe-Ziegler in accordance with the probable mechanistic scheme (Scheme 32). 

Finally, in the most complex multicomponent reaction involving isocyanides, the 7-CC proposed by Ugi in 1993 [93], a moderate diastereoselectivity, leading to a 2 1 mixture of epimeric thiazolidines 109 was observed. The reaction is a combination between an Asinger condensation, involving an a-mercaptoaldehyde (generated from the a-bromoaldehyde and SH ) and an Ugi-type 4-CC with a monoalkyl car-boxylate as acid component (Scheme 1.38). Although the relative configuration of the major stereoisomer was not demonstrated, it is probably trans, in line with the results of Ugi condensation with chiral thiazolines, reported above in Scheme 1.19. 

The combination of carbon monoxide with sulfonyl oxime ethers allow for a set of multicomponent coupling reactions involving consecutive Cl/Cl-type coupling, a rare class of radical multicomponent reactions. In Scheme 6.27, examples of three-, four-, and five-component coupling reactions are shown [46], In these reactions, allyltin is not incorporated into the product, but serves as an acceptor of the phenylsulfonyl radical and a source of the tributyltin radical, which delivers the radical chain. 

Despite this interest, new reaction types in organic chemistry have been more usually found by chance than by rational design or logical consideration. In this chapter we emphasize that, although they are rarely used, there are both rational and, in particular, algorithm-based methods to discover novel multicomponent reactions. 

This multigeneration strategy for the synthesis of pyrimidines combines efficiently a novel cyclocondensation reaction using the highly reactive acetylenic ketones 153215,218 to build the pyrimidine skeleton, with a multicomponent reaction, and a multidirectional cleavage procedure. The Ugi four component reaction is especially useful in the context of building peptidomimetic-derived combinatorial libraries as it affords directly dipeptide analogues of type 159. 

The utility of bicyclopropylidene (37) in multicomponent reactions is greatly enhanced by the fact that in the presence of tris(2-furyl)phosphine (TFP) instead of triphenylphosphine, the carbopalladation with an arylpal-ladium halide does not lead to an alkylidenecyclopropane of type 41, but to a CT-allyl-/7r-allylpalladium complex 53/54 which can quite efficiently be trapped with various nucleophiles (Scheme 8). The formal rearrangement... 

Recent Developments in Reissert-Type Multicomponent Reactions... 

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