New MCRs

A number of new MCRs, that are either facilitated or accelerated by microwave irradiation, have been reported recently for the synthesis of simple N-, 0- and S-containing heterocycles. These one-pot domino processes offer... 

In the last decade, Bossio et al. have formed cychc products of many different types by using a variety of new MCRs. Thus, 80 was made from 76-79 (Scheme 1.19). Recently, Domling and Chi prepared 83 from 81, 82, and 27, and synthesized similar polycyclic products from other a-aminoacids with 82 and 27. 

In practice there are different approaches to the development of new MCRs. These are random discovery or chance, combinatorial chemistry, rational and computer-assisted design and the concept of unions of MCRs, and these will be described in the following sections. 

Thus the completely random approach to the discovery of new MCRs was transformed in a systematic, semi-rational and powerful way. Future research using this elegant approach will certainly reveal many more novel MCRs. 

The challenge in developing new MCRs involving amines and carbonyls is to identify additional components that do not undergo irreversible nucleophilic addition to the carbonyl component, leading to carbonyl addition products. 

In a recent example, Mironov used the rational replacement of starting materials for oligomerization reactions to discover new MCRs in a systematic way [31]. A reaction library of six alkenes/alkynes, two isonitriles, two nitriles and isoquinoline was set up, giving (n1 — n)/2 different reactions products. A minimum peak height of 30% of the total reaction product was used as a criterion for identifying an efficient MCR. In this way, a novel MCR that yields pyrrolo[2,l-a]isoquinolin-1-ones from electron-deficient olefins, isonitriles and isoquinoline was found (Scheme 10.6). 

It is dear from the variety of natural products described in this chapter that multi-component reaction strategies encompass a very broad scope of synthetic transformations. The development of new MCRs constantly generates new opportunities, and it is likely that the application of these powerful processes in natural product synthesis is still in its infancy. Appealing characteristics of MCR strategies such as convergence and step-economy are expected to draw more and more synthetic chemists to design and implement MCRs in the total synthesis of complex natural products. 

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. 

The SRR strategy (Fig. 6), a phrase first introduced by Ganem, involves the development of new MCRs by systematic assessment of the mechanistic or functional role of each component in a known MCR [55]. In this method one reactant (C) is substituted for reactant (D) that displays a similar chemical reactivity mode required for condensation with A and B. By incorporation of an additional reactivity or functionality into D, the resulting MCR might be directed to a different outcome, leading to scaffold diversity [55]. 

From the reported examples in this paragraph it is clear that SRR is a fast way of developing new MCRs and extremely useful for application in DOS, since it can quickly afford many different scaffolds. 

In addition to the examples reported here there are several other publications that apply SRR to achieve new scaffolds, thereby discovering new MCRs [55, 75, 76]. 

In the combinatorial chemistry of the MCRs, recent progress has been achieved in two ways. At Hoffmann-La Roche, Weber et al. were able to prepare and analyze all products formed by automated combinatorial chemistry of seven different reactive educts. All possible mixtures of seven, six, five, etc. components were reacted and subsequently evaluated automatically by a HPLC-MS protocol. By adstraction of the starting materials signals [137], several new MCRs could be found in the complex reaction mixtures. Previously in 1961, and again in 1971, it was shown that M4 new constitutionally different products can be formed by the U-4CR, if M different educts of each class of their educts are formed [8]. 

Discovering New MCRs with Automated Combinatorial Reaction Finding... 

Although most of the established metal-catalyzed MCRs are based on palladium or copper catalysts, the search for new MCR products has resulted in the development of new catalytic systems in the last decade. This chapter has been... 

With this new methodology in hands, Hu et al. [166] explored the trapping of the 1,4-addition intermediate with a different electrophile for the development of a new MCR. RhjCOAc) was again the most active catalyst in the 1,4-addition/aldol-type intramolecular cascade reaction. Under the optimized reaction conditions, this three-component reaction worked well with a broad family of bifunctional substrates 135 bearing different substituents on the aryl group next to the enone moiety and a variety of alcohols 136 (Scheme 3.63). In all cases, 1-indanols 137 were obtained in 60-83% yield and with complete diastereoselectivity. Enantiopure 1-indanol was obtained employing a L-menthol-derived diazo compound. The intermolecular four-component version was also attempted, but the formation of the desired product was not observed. 

L. El Kaim, M. Gizzi, L. Grimaud, Org. Lett. 2008, 10, 3417-3419. New MCR-Heck-isomerization cascade toward indoles. 

A new MCR was reported using an ammonium salt as new Lewis base catalyst 58 as effective catalysts in the... 

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