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Organometallic Multicomponent Reactions

1.1. Introduction

The first multicomponent reactions were discovered in the second half of the 19th Century. Long considered as laboratory curiosities, these reactions, which allow the assembly of several reactants in a single process and hence the synthesis of complex molecules with high added value, prospered at the end of the 20th Century with the advent of combinatorial chemistry. This new tool, used mainly by pharmaceutical and agrochemical companies, aims to quickly and efficiently produce large libraries of small, often heterocyclic, molecules for high throughput screening tests in order to increase the chances of identifying new bioactive compounds. The enthusiasm generated by these reactions has been greatly amplified by the emergence of the concept of green chemistry, through which researchers have committed themselves to minimizing the impact that the chemical sector can have on the environment. These new approaches are well adapted to meet this type of challenge, particularly in terms of saving time, energy or atoms, reducing waste and safety risks, and converging and simplifying processes. Catalysis is essentially one of the pillars of green chemistry because of its ability to accelerate and facilitate chemical reactions. Transition metal complexes are among the most widely used in the design of catalytic multicomponent reactions because of the multitude of transformations they are capable of catalyzing with often high selectivities. This chapter, which is not intended to be exhaustive, aims to illustrate, through selected examples, how multicomponent reactions, merged with metal catalysis, can meet the requirements of green chemistry.

1.2. Multicomponent reactions: concept and applications

1.2.1. Concept and correlation with the principles of green chemistry

Synthetic organic chemists have a wide range of methods at their disposal to develop new functionalized target molecules on which future progress in medicine, biotechnology, crop protection and materials depend. Traditionally, over the last century, these molecules have been essentially developed through successive steps allowing the incorporation of the various fragments that make up the final structure. The desired structural and functional complexity is thus only accessible through a linear sequence of independent chemical reactions. Multicomponent reactions, on the other hand, are processes that condense at least three reactants (components) into a single synthetic operation to produce a final molecule that incorporates the majority of the initial atoms. In general, an initial transformation combining two initial components will generate a reactive intermediate that will then undergo further transformations in the reaction medium by combining with other components. All these transformations take place in a single reactor; we will refer to this as a one-pot reaction (Figure 1.1). Ideally, and from a puristic point of view, all components, reagents and possible catalytic systems should be present in the reaction medium from the beginning of the reaction. The various components must then be successively assembled in a predetermined order under the same reaction conditions to synthesize a single product. This therefore raises the problem of the compatibility of the various reactants involved, and therefore the formation of secondary products. However, in practice, the development of such reactions is very difficult, and it may be appropriate, when possible, to delay the addition of one or more components, reagents, catalysts or ligands. It may also be possible to modulate the reaction parameters during the reaction. Thus, in some extreme cases, the design of a multicomponent reaction will involve successively carrying out several independent steps in the same pot (Herrera and Marques-López 2015a; Zhu et al. 2015).

Figure 1.1. Linear approach compared to a multicomponent approach involving three reactants (components) A, B and C. For color versions of the figures in this book, see www.iste.co.uk/malacria/reactions.zip

Multicomponent reactions are very effective in terms of atom economy and selectivity; they allow complex and varied structures to be reached in a single synthetic operation, that is without isolating the intermediate products formed during the reaction. Synthesis therefore requires fewer steps than a linear approach, saving time, equipment and consumables (solvents and reagents) and thus significantly reduces its impact on the environment, in particular by producing less waste (Cioc et al. 2014). This also reduces safety risks. Multicomponent reactions thus satisfy many of the principles of green chemistry (Anastas and Warner 1998).

1.2.1.1. Step economy

In general, conventional chemical synthesis pathways can only create one bond per step. This approach is very costly in terms of solvents, reagents, auxiliaries, energy and time. Multicomponent reactions, on the other hand, create several bonds in a single operation in the same reaction medium, without purification of the intermediates. They are therefore clean reactions insofar as the use of solvents is limited to the reaction itself. As the intermediate products are not isolated, the purification steps, which consume large amounts of organic solvents, are therefore limited, which also reduces the cost of producing the desired molecules. One-pot reactions also aim to reduce the production of toxic waste that is difficult to dispose of or recycle. These are reactions that take place in a single reactor, resulting in energy savings and lower equipment costs. This strategy also saves a significant amount of time, which is also an economic advantage.

1.2.1.2. Atom economy

Multicomponent reactions are a perfect answer to the concept of atom economy since they capitalize on the functionalities of each reactant in the final product. Indeed, these reactions offer the possibility of reaching very complex molecular systems in a single step where most of the functionalities of the starting products are found in the finished product. Reduced energy consumption is therefore required to create these structures compared to the requirements claimed in multistage synthesis.

1.2.1.3. Convergence and selectivity

Multicomponent reactions are often compatible with many functional groups, which do not participate in the main reaction but can then be involved, in situ where possible, in derivatization reactions - also called post-condensation reactions. The latter make it possible to increase the structural complexity and/or functional diversity of the targeted products. These reactions, which take place in a single reactor, are very efficient, generating fewer by-products that are difficult to separate and eliminate. Tedious steps such as protection/deprotection of functional groups are avoided.

1.2.1.4. Process safety

Some solvents are dangerous. They can be toxic, flammable, polluting, explosive. Multicomponent reactions considerably reduce these risks by reducing the quantities of solvents used to prepare the required compounds. Multicomponent reactions also avoid isolating the reaction intermediates. These can be unstable or toxic. Such reactions therefore have the advantage of performing transformations that would not be feasible in several, independent steps, as well as minimizing some risks of chemical accidents.

1.2.1.5. Eco-compatible solvents

The use of water as a solvent has many advantages. Due to its physico-chemical properties, it makes it possible to increase the reactivity and selectivity of many reactions and to operate under milder conditions, as well as to avoid in some cases the protection/deprotection steps (Gawande et al. 2013). It also simplifies the isolation of products, which are generally not very soluble in this medium. It is therefore interesting from an economic point of view (reduced costs), but also ecological (total absence of toxicity). These beneficial effects of water have also been observed in some multicomponent reactions (Gu 2012). The use of other eco-compatible media, such as ionic liquids and deep eutectic solvents, polyethylene glycol, biosourced solvents, or simply solvent-free reactions, has also been documented (Isambert et al. 2011; Shankar Singh and Chowdhury 2012; Liu et al. 2015).

Multicomponent reactions have also benefitted from many non-conventional reaction techniques particularly adapted to the principles of green chemistry. These include sonication techniques, but above all microwave technology, the main advantage of which is to drastically reduce reaction times, thus reducing the energy cost of processes while often improving the efficiency and purity of reaction products (Hügel 2009). Likewise, continuous reactor technologies have developed considerably in recent years and are also gradually adapting to multicomponent synthesis. Among their many advantages, these continuous flow chemical production methods (flow chemistry) allow, through automation, reactions to proceed under optimal conditions of efficiency and safety, on a small or large scale, and in a reproducible manner (Newman and Jensen 2013). These technologies, particularly well adapted to the synthesis of chemical libraries, are used in pharmaceutical research and development departments.

1.2.2. Origins and areas of...