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INTRODUCTION: MULTICOMPONENT STRATEGIES

Juan V. Alegre-Requena, Eugenia Marqués-López and Raquel P. Herrera

Departamento de Química Orgánica, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC-Universidad de Zaragoza, Zaragoza, Spain

GENERAL INTRODUCTION

The goal of this book is to provide an overview of the most useful and noteworthy examples of multicomponent reactions (MCRs) published in this field between 2005 and 2014, in order to attract the attention of a wide range of readers. Previous examples are collected in an exceptional book edited by Zhu and Bienaymé, published in 2005 [1] . Since then, a great number of interesting and important reviews have also been written, and they will be cited throughout this book. For this reason, only the most pivotal examples will be reported and commented on in order to avoid repetitions.

MCRs are widely defined as reactions in which three or more components are added to a single vessel at the same time to lead to a final product that contains most of the atoms from the starting reagents. Therefore, these reactions encompass a sequence of more than one chemical transformation without the necessity of changing the reaction media after each transformation. It is not surprising then that MCRs lead to great molecular diversity and allow for the creation of libraries of small organic molecules while requiring less time and effort when compared with step-by-step procedures [2] . This is especially attractive for the pharmaceutical industry, for which the easy creation of large libraries of compounds with possible biological activity is a priority.

The significance of these processes can be observed in the large number of publications that have appeared in this field over the last decade. Also, the biological utility of compounds synthesized with MCRs has been confirmed by the discovery of many molecules with remarkable biological activity (Fig. 1.1) [7] .

FIGURE 1.1 Examples of drugs synthesized with MCRs: factor Xa inhibitors [3] , praziquantel [4] , farnesoid X receptor agonists [5] , and (-)-oseltamivir [6] .

Over the last decade, interest in performing sustainable chemistry has drastically increased [8] . The application of ingenious strategies to synthesize complex scaffolds and highly substituted molecules, combining molecular diversity [9] with ecocompatibility [10] , has been the main focus of many scientific groups. In effect, the rational design of reactions that transform simple and readily available substrates into complex structures in a single reaction is one of the current major challenges in organic synthesis. In this context, MCRs have become one of the best established approaches for reaching this goal, since these strategies imply atom economy [11] and bond-forming efficiency [12] .

There are some authors that consider the reaction between bitter almond oil and ammonia, carried out by Laurent in 1838, as the first MCR [13] . This mixture could promote a condensation of ammonia, hydrogen cyanide, and benzaldehyde, resulting in an a-aminonitrile intermediate that, once formed, reacts with another molecule of benzaldehyde to give its corresponding Schiff base. However, in the compositions reported by the authors, none of the examined products lined up with the MCR's possible products, neither the a-aminonitrile nor its subsequent Schiff base. Therefore, the Strecker reaction could be considered the first reported MCR, due to the fact that it was the first time that an author was able to determine the structure of a product formed in a MCR.

Since the development of the Strecker reaction in 1850 [14] , a great number of interesting MCRs have been reported, and amidst them, some of the most significant reactions are displayed in Table 1.1. In the following chapters, these pioneering reactions will be extensively discussed.

TABLE 1.1 Some historically significant MCRs

1.1 BASIC CONCEPTS

Some of the basic concepts related to MCRs are briefly described in the following text in order to familiarize the reader with this field and its characteristics.

1.1.1 Clarifying Terminology: One-Pot, Domino/Cascade, Tandem, and MCRs

The previous terms are probably familiar for most chemists, but they have crucial differences that are important to know in order to distinguish each term from the others. The term one-pot reaction includes reactions that involve multiple chemical transformations between reagents that are carried out in a single reactor. Thus, MCRs fall into the category of one-pot reactions due to the sole reactor required for carrying out the reaction and that there are multiple chemical transformations involved.

Furthermore, Fogg and dos Santos categorized the different types of multicatalyzed one-pot reactions in 2004 [25] , some years after Tietze set the definition of domino reactions [12] . In this categorization, domino/cascade catalysis, tandem catalysis, and multicatalytic one-pot reactions were distinguished depending on certain factors, such as the moment when the (pre)catalysts are added and the number of catalytic mechanisms involved (Fig. 1.2). Generally speaking, domino/cascade and tandem catalyses are one-pot reactions where all the components are introduced at the same time at the beginning of the reaction, while in multicatalytic one-pot reactions, all of the reaction's components are not added at the same time. Another requirement for domino/cascade and tandem catalyses is that all successive transformations must occur as a consequence of the intermediate generated in the previous reaction step. In Fogg's classification, domino/cascade and tandem catalyses are differentiated by the number of catalytic mechanisms present in the reaction.

FIGURE 1.2 Fogg's simple classification of one-pot processes involving multiple catalytic transformations.

With all the aforementioned concepts defined, it has been made clear that MCRs are one-pot reactions that might also fall under the category of domino/cascade or tandem reactions. A reaction is a domino/cascade or tandem MCR when it has the characteristics of one of these types of reactions in addition to including three or more reagents that react to form a final product.

1.1.2 Using Rational Design to Discover New MCRs

Designing new multicomponent approaches in a less haphazard and more rational manner is vital for increasing the limited scaffold diversity obtained by the MCRs reported until now. To do so, five different methods, most of them excellently explained by Orru and coworkers in their review [ 2 b], have been developed to discover new MCRs: single reactant replacement (SRR), reaction-operator strategy, modular reaction sequences (MRS), condition-based divergence (CBD), and combination of MCRs (MCR2).

1.1.2.1 SRR

This strategy was first proposed by Ganem [26] and involves the replacement of one reactant with a different reactant that shows the same essential reactivity with other reagents, carrying out the same role in the reaction mechanism (Fig. 1.3). This approach has been demonstrated to be a valuable tool, providing different final adducts by incorporating additional functionalities in the reactants.

FIGURE 1.3 Single reactant replacement method for MCRs.

1.1.2.2 Reaction-Operator Strategy

In this approach, defined by Mironov [27] , there is a simultaneous replacement of two or more reagents with different reagents that show the same essential reactivity (Fig. 1.4). The name of this strategy comes from the comparison of chemical reactions with mathematical functions: in reactions, a reaction operator would be the equivalent to a function operator in mathematics. This reaction operator is introduced as an algorithm in a computer-controlled system, whose function is to find new reactions by using preexisting reactions as a starting point with the help of reaction preparation and analytical automated systems.

FIGURE 1.4 Example of a reaction-operator strategy carried out by changing two substrates.

1.1.2.3 MRS

This third approach involves a versatile reactive intermediate that is initially generated though a MCR from different substrates [28] . This compound is further treated in situ with a range of different compounds to produce a diverse set of more complex structures (Fig. 1.5). This divergent synthesis approach is very useful for rapidly generating scaffold diversity, creating large compound libraries.

FIGURE 1.5 Modular reaction sequence approach in MCRs.

1.1.2.4 CBD

The use of specific catalysts, solvents, or additives could guide a reaction along different pathways, producing distinct final adducts (Fig. 1.6). There are some examples of MCRs that have different major products based on their reaction conditions [29] ; however, it is uncommon to achieve a wide variety of adducts through this method. Many of these examples were discovered serendipitously, which is reflected in the limited number of reported examples. Although this approach is not frequently used, it is an efficient strategy for obtaining products with an...