Multicomponent reactions defined

One very important aspect in modern drug discovery is the preparation of so-called substance libraries from which pharmaceutical lead structures might be selected for the treatment of different diseases. An efficient approach for the preparation of highly diversified libraries is the development of multicomponent reactions, which can be defined as a subclass of domino reactions. One of the most... 

The combination of the two approaches that have obvious advantages therefore presents an attractive reaction design with added value in the inventions and optimizations of existing processes. We hereby give an overview of current achievements in this field. However, there is a rather limited number of published data on strictly defined multicomponent reactions in which aU the reactants are added at once to the reaction mixture, due to the technical characteristics of the systems (e.g. number of inlets) or the possible complications due to side reactions such reactions are conducted in a multistep mode or employ preformed intermediates. These reactions are also taken into account on the condition that the process is conducted continuously without purification of the intermediates and that the final product contains scaffolds originating from three or more starting molecules. 

One way to gain fast access to complex stmctures are multicomponent reactions (MCRs), of which especially the isocyanide-based MCRs are suitable to introduce peptidic elements, as the isonitrile usually ends up as an amide after the reaction is complete. Here the Ugi-4 component reaction (Ugi CR) is the most suitable one as it introduces two amide bonds to form an M-alkylated dipeptide usually (Fig. 2). The Passerini-3CR produces a typical element of depsipeptides with ester and amide in succession, and the Staudinger-3CR results in p-lactams. The biggest unsolved problem in all these MCRs is, however, that it is stUl close to impossible to obtain products with defined stereochemistry. On the other hand, this resistance, particularly of the Ugi-reaction, to render diastereo- and enantioselective processes allows the easy and unbiased synthesis of libraries with all stereoisomers present, usually in close to equal amounts. 

Combining structural diversity and complexity with synthetic efficiency has led to an increased interest in multicomponent domino reactions. A multicomponent reaction is defined as a reaction in which more than two substrates, all present together, react with each other to form a product that is derived from all components in that system. Domino reactions as classified by Tietze [2b] are processes involving two or more bond-forming transformations, which take place under the same... 

This brief review places emphasis on (1) the use of stereoselective multicomponent reactions to access diverse and complex pure analogues in a powerful combinatorial way and (2) to review recent synthetic pathways and concepts devoted to exploring chemical space (both defined or expanded). 

Multicomponent reactions (MCRs) can be defined as three or more reactants that join together in a single synthetic step to form new products containing portions of all the components. These time and cost-effective reactions are powerful tools that are applicable to combinatorial and parallel syntheses in particular (16-20). However, MCRs for library synthesis are often selected to produce only high quantities of new compounds rather than high quality products (i.e., more diverse and chiral products in pure form). Thus, recent efforts have been made to offset this trend by building chirality into collections of new componnds with the help of efficient stereoselective MCRs (21). 

Multicomponent reactions represent a flexible tool for the synthesis of a large number of target molecules from three or more starting molecules. They are one-step, one-pot reactions, economic regarding resotrrces and today considered to be close to what is defined as ideal synthesis [1]. Their general synthetic value was recognized when I. Ugi and collaborators reported on some important variants of four-component reactions [2] and their application in the production of known drugs an illustrative example is presented in the next section. 

Finally, multicomponent reactions (MCRs) are a subclass of domino reactions and can be defined as processes in which three or more starting materials react to form a product, where basically all or most of the atoms contribute to the newly formed product [10]. A recent example reported by our group (Scheme 1.4c) involves the reaction between p-ketoamides, acrolein, and aminophenols, allowing the preparation of an enantioenriched diazabicyclo[2.2.2]octanone (2,6-DABCO) scaffold [11]. The chemoselective reaction sequence installs five new bonds and three stereocenters, with excellent yields and high levels of stereocontrol. 

Multiple bond-forming transformations (MBFTs) involving multicomponent reactions (MCRs) can be defined as processes in which three or more reactants introduced simultaneously are combined through covalent bonds to form a single product, regardless of the mechanisms and protocols involved [1],... 

As a requisite for all domino reactions, the substrates used must have more than two functionalities of comparable reactivity. They can be situated in one or two molecules or, as in the case of multicomponent domino reactions, in at least three different molecules. For the design and performance of domino reactions it is of paramount importance that the functionalities react in a fixed chronological order to allow the formation of defined molecules. 

This review focuses on the cross-metathesis reactions of functionalised alkenes catalysed by well-defined metal carbene complexes. The cross- and self-metath-esis reactions of unfunctionalised alkenes are of limited use to the synthetic organic chemist and therefore outside the scope of this review. Similarly, ill-defined multicomponent catalyst systems, which generally have very limited functional group tolerance, will only be included as a brief introduction to the subject area. 

Although the bulk of this review is concerned with well-defined metal carbene catalysts, it is important to note the contributions made to cross-metathesis chemistry by ill-defined or multicomponent catalysts. A brief discussion of the cross-metathesis reactions of functionalised alkenes using catalysts of this type will therefore be included here [1]. 

Previously acrylonitrile had proved to be inert towards transition metal catalysed cross- and self-metathesis using ill-defined multicomponent catalysts [lib]. Using the molybdenum catalyst, however, acrylonitrile was successfully cross-metathesised with a range of alkyl-substituted alkenes in yields of40-90% (with the exception of 4-bromobut-l-ene, which gave a yield of 17.5%). A dinitrile product formed from self-metathesis of the acrylonitrile was not observed in any of the reactions and significant formation (>10%) of self-metathesis products of the second alkene was only observed in a couple of reactions. 

In general, DOS demands well-defined, selective reactions that are still able to introduce a significant degree of complexity and diversity. Multicomponent and tandem processes fit this profile very well [65, 66], and several groups have used this approach [41, 67-71]. 

In particular, it is useful to define the critical point through F(nc) = 0 (the stationary state). Since multicomponent chemical systems often reveal quite complicated types of motion, we restrict ourselves in this preliminary treatment to the stable stationary states, which are approached by the system without oscillations in time. To illustrate this point, we mention the simplest reversible and irreversible bimolecular reactions like A+A —> B, A+B -y B, A + B —> C. The difference of densities rj t) = n(t) — nc can be used as the redefined order parameter 77 (Fig. 1.6). For the bimolecular processes the... 

A general way to improve synthetic efficiency, which in addition also gives access to a multitude of diversified molecules in solution, is the development of multi-component domino reactions which allow the formation of complex compounds starting from simple substrates. Domino reactions are defined as processes of two or more bond-forming reactions under identical conditions, in which the subsequent transformation takes place at the functionalities obtained in the former transformation thus, it is a time-resolved process [la,c,f,3]. The quality and importance of a domino reaction can be correlated to the number of bonds formed in such a process and the increase of complexity. Such reactions can be carried out as a single-, two- or multicomponent transformation. Thus, most of the known multicomponent transformations [4], but not all, can be defined as a subgroup of domino transformations. 

A component is a particular chemical substance. A chemical reaction at equilibrium is therefore a multicomponent system. In discussing the equilibria of multicomponent systems, it is important to be aware of what constitutes a complete and sufficient specification of the system. If too few variables are specified, the system is not completely defined if too many are specified, the values of these variables may be inconsistent with equilibrium. It is possible to waste much time considering improperly specified systems. 

---