Novel MCRs

Of course, the above classification is just a guideline and not a strict definition. A key point that one can draw and that should be kept in mind from this analysis is that the presence of equilibrium steps is generally beneficial to MCR sequences. 

2) Michael addition could be reversible depending on the nature of the nucleophiles. However, when 

RM (R = alkyl, alkene, M = metal) were used as nucleophiles, the 1,4-addition became essentially 

Both computational methods and diversity-oriented reaction searches have been successfully applied to the discovery of novel MCRs [15]. However, MCRs can also be devised on rational grounds, and we give a few examples in the following sections to illustrate the basic principles that were used for the development of novel isocyanide-based MCRs (IMCRs) [16]. 

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In recent years, many novel MCRs - including Michael addition-initiated three-component domino sequences [10], Knoevenagel/hetero-Diels-Alder-based MCRs [11], radical chain MCRs [12], transition metal-catalyzed Pauson-Khand MCRs [13], as well as Petasis MCRs [14], have been added to the chemisf s armamentarium and successfully applied to all fields of organic synthesis. 

Besides numerous applications of a-acidic isocyanides in classical IMCRs, such as the Ugi and Passerini reaction, the presence of an a-acidic proton enables other reaction paths and, subsequently, the development of novel MCRs. Here we focus on novel MCRs involving a-acidic isonitriles that have been described in literature since 1998. 

In 2006, our research group reported a novel MCR based on the reactivity of a-acidic isocyano esters (1) toward 1-azadienes (84) generated by the 3CR between phosphonates, nitriles, and aldehydes [169]. Remarkably, the dihydropyridone products (85) for this 4CR contained the intact isonitrile function at C3. The exceptional formation of the 3-isocyano dihydropyridone scaffold can be explained by the Michael-attack of the a-deprotonated isonitrile (1) to the (protonated) 1-azadiene (84), followed by lactamization via attack of the ester function by the intermediate enamine. Although in principle the isocyano functionality is not required for the formation of the dihydropyridone (85) scaffold, all attempts using differently functionalized esters (e.g., malonates, ot-nitro, and a-cyano esters) gave lower yields of the dihydropyridone analogs [170] (Fig. 26). 

Finally, other a-activated carbonyl compounds such as a-nitroketones have been used successfully in very interesting and novel MCRs. Our group proposed an unprecedented reactivity of a-nitroalkanones towards two-substituted acroleins under aqueous conditions, with participation of water as third component [168]. 

Another useful scaffold, discovered recently by chance in our laboratories during an array synthesis, is now available for combinatorial chemistry [12]. All wells containing 2-picolinic amine reacted in an unexpected way. Detailed inspection of these reactions provided a novel MCR towards 1,2,4-trisubstituted lH-imidazol-4-yl-pyridines. Typical examples and their yields are given in Scheme 3.7. During... 

An extension of and systematic approach towards discovery by chance is the use of combinatorial chemistry. In a seminal paper [14], Weber and Lacke described a systematic approach involving array synthesis in order to discover novel MCRs. In this... 

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. 

Several variants of this useful and novel MCR thiazole synthesis have since been reported, including complexity-oriented syntheses of thiazolo-/> -lactams [18], in which two ring systems and five heavy atom bonds are newly formed (2 C-N, 2 C-S, 1 C-C), solid phase synthesis [19], and a Passerini variant of this reaction leading to 2-hydroxymethyl thiazoles [20], Scheme 3.13 illustrates some of the possibilities [21]. 

Another concept towards novel MCRs was established in 1993 by us the union of MCRs [23], Our objective was to find reactions with maximal numbers of participating starting materials. Thus we considered combining several MCRs, since a single MCR already contains a high number of educts. Two MCRs can be combined if the product or an advanced intermediate of the first MCR is a intermediate or starting material of the second MCR. The starting materials should ideally not have the possibility for irreversible side reactions under the reaction conditions used. Scheme 3.16 illustrates this approach. 

Finally the discovery of novel MCRs touches a very basic task of chemists and poses an intellectually challenging task. 

For example, amino-imidazoles and amino-thiazoles were also found to give a similar 3-CR product (Scheme 10.2). This experience inspired the idea of using combinatorial chemistry methods to find novel and unexpected reaction products and novel MCRs. 

However, in the reaction of cyclohexanone, benzylisonitrile, 4-methoxy-phenyl-hydrazine and acetic acid a dihydro-cinnoline was formed by a novel MCR (Scheme 10.4). 

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). 

Scheme 10.6. Systematic search for novel MCRs using the concept of replacing starting materials for oligomerization reactions.

This example clearly shows that introducing the concept of down-sizing polymerization reactions sequences can give useful novel MCRs. 

Scheme 10.7. Systematic search for novel MCRs by using the Daylight reaction toolkit on a reaction database.

The formation of this novel reaction product could be shown by the experiment a posteriori, thus representing an example of a computationally described novel MCR that has subsequently been validated in the laboratory. 

The development of novel MCRs is an intellectually challenging task since one has to consider not only the reactivity match of the starting materials but also the reactivities of the intermediate molecules generated in situ, their compatibility, and their compartmentalization. With advances in both theory and mechanistic insights into various classic bimolecular reactions that allow for predictive analysis of reaction sequences, the development and control of new reactive chemical... 

We hope that this monograph will be of value to both expert and novice practitioners in this area, further stimulating the development and application of novel MCRs and providing an appropriate perspective with which to evaluate the significance of new results. 

Scheme 5.21 Propargyl activation and coupling-isomerization reaction as an entry to novel MCRs.

From the previous examples it is clear that scaffold diversity can be achieved using MCRs and post condensation cyclizations. However, during the last decade much work has also been devoted to obtain scaffold diversity by using MCR strategies exclusively. Besides scaffold diversity, this has also lead to the development of a number of novel MCRs. These new multicomponent design strategies, to achieve scaffold diversity, can be divided into four main approaches ... 

The Union of MCRs (MCR, Fig. 9) is a fourth strategy for the rational design of novel MCRs that combines two (or more) different types of MCRs in a one-pot... 

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