multicomponent reactions and combinatorial chemistry

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 12, pp. 2628–2646. © Pleiades Publishing, Ltd., 2010. Original Russian Text © M.A. Mironov, 2009, published in Rossiiskii Khimicheskii Zhurnal, 2009, Vol. 53, No. 5, pp. 116–132.

2628

Multicomponent Reactions and Combinatorial Chemistry M. A. Mironov

El’tsin Ural State Technical University, ul. Mira 19, Yekaterinburg, 620002 Russia e-mail [email protected]

Received July 10, 2009

Abstract―Multi-component reactions (MCRs) constitute a methodology to shorter syntheses of natural products or complex molecules for drug discovery. Due to the large number of accessible compounds, this type of chemistry has become very popular between scientists who are working in the area of combinatorial chemistry. Over the last decade combinatorial chemistry has evolved from the synthesis of great quantity of simple compounds to the parallel synthesis of complex molecules with a widely varied structure. MCRs are ideally suited for this trend, being free of limitations of a traditional multistep synthesis. The close connection and interference of multicomponent reactions and combinatorial chemistry are discussed in this review.

INTRODUCTION

Combinatorial chemistry has fairly recently (in late 1980s) formed as an individual field. Combinatorial chemistry widely uses approaches which have been developed over many decades, for example, multicom-ponent reactions in the synthesis of compound libraries [1]. It should be noted that the synthetic approach based on mixing of several starting compounds to obtain a single complex product is as old as organic chemistry. As far back as 1838, the reaction of benzaldehyde with ammonia and hydrocyanic acid, leading to Schiff base I was described [2]:

peptides [4]. Below we present some examples of classical reactions of this type.

Mannich reaction [5]:

DOI: 10.1134/S1070363210120297

H

O

NH3, HCN N

CN

I

Me

O

CH2O, HN(Me)2

O

NMe

Me

N

PhCOCl, HCN

N CN

O Ph

Slightly later, in 1850, an analogous reaction was used as a convenient two-stage synthesis of amino acids, known as Strecker synthesis [3]. Just these two dates are the starting point of the development of a group of reactions, which presently includes hundreds of examples.

Many of multicomponent reactions (MCRs) dis-covered more than 150 years ago have found practical application in organic synthesis for preparing a great diversity of heterocyclic compounds, amino acids, and

Hansch synthesis of dihydropyridines [6]:

Reissert reaction [7]:

H

O

MeCOOEt, NH

O

NH

EtOOC COOEt

Me Me

BrCMe2CHO + CO2 + t-BuNC

NaSH Me2CHCHO

NH3 MeOH

N

SMe

Me

Me

Me

NHt-Bu

COOMeO

43%

Passerini reaction [8]: (1) MCRs involve much less chemical stages and isolation and purification operations;

(2) Such reactions open up the way to a huge number of derivatives.

Actually, the main barrier to automation of organic synthesis is that it is a multistage, and, therewith, even a simple four- or five-stage synthesis may prove too complicated to adapt to robotic systems because of the necessity to optimize all operations involving isolation and purification of intermediate products. Multicom-ponent reactions involve no isolation of intermediate products and, therefore, are free of this problem. At the same time, target products can always be isolated by a standard procedure, for instance, by parallel pre-parative chromatography. Therefore, along with solid-phase synthesis, MCRs are best suited for fully auto-mated organic synthesis [4].

Further advantage of MCRs is that they considerably extend the range of available structures. Their number can be estimated by the formula Xn, where X is the number of starting reagents and n, reaction dimension. For example, with ten amines, aldehydes, carboxylic acids, and isocyanides, ten thousands of derivatives can be obtained by the Ugi reaction [11]. This quantity seems too large, but it is not quite necessary to synthesize all accessible com-pounds to find one that meets requirements.

On the other hand, the large number of accessible compounds provides great scope for structural optimization. Such optimization may involve not only side-chain substituents, but also a central molecular fragment (scaffold). The number of possible cycliza-

It should be admitted that the overwhelming majority of published syntheses present a sequence of two-component reactions. Therewith, MCRs are traditionally considered as a spectacular but slightly exotic approach in organic synthesis. This is primarily associated with the fact that in planning organic synthesis one most commonly consecutively breaks the target structure into separate blocks (synthons), which implies a standard set of two-component reactions [9]. A multicomponent reaction is much more difficult to correlate with a randomly chosen target structure that a sequence of two-component reactions. In com-binatorial chemistry which exemplifies a functionally oriented approach to organic synthesis, there is no strictly specified structure, and, therefore, it is free to use multicomponent reactions [1]. This explains a strong impact combinatorial chemistry has made on the development of MCRs which, in their turn, have become one the most efficient ways to intensify organic synthesis.

What is the secret of the popularity of MCRs among organic chemists? The first and, probably, main advantage consists in that they allow one to construct fully convergent synthetic protocols with a minimum number of stages. Ideally, this is as little as one stage forming a multitude of new chemical bonds. Therewith, the number of starting compounds may reach 7–8, like in the following example [10]:

NC Me

MeCHO,

HN

O MeO

OMe Me

MeCOOH

From this, we can draw two practically important conclusions:

NH2

COOMe

C6H13CHO NOPh

CNO+

LiBr

NH

C6H13

N

MeOOCPh

N

O

O

II, 95%

MULTICOMPONENT REACTIONS AND COMBINATORIAL CHEMISTRY

RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 12 2010

2629

NH2+ H

O

NH

Ph

III

tions for a liner MCRs product is equals to (n2–n)/2, say, six for a four-component reaction. Therefore, all other conditions being the same, this reaction can provide six time more scaffolds than a two-component system, and this gap will become even larger if polycyclic structures are taken into account [11]. As an example, we can present the synthesis of a complex polycyclic compound II by one of the versions of the Ugi reaction [12].

Thus, MCRs proved to be quite a useful tool in the arsenal of combinatorial chemistry, which allows an extremely efficient synthesis due to a sharply reduced number of stages. Other advantages of these reactions, not unimportant in terms of combinatorial chemistry, are associated with the reduced number of stages and isolation and purification operations, which considerably reduces the consumption of organic solvents and total cost of the synthesis.

However, the interpenetration of MCRs and com-binatorial chemistry is not exhausted by the use of MCRs as one of the methods of combinatorial chem-istry. No less fruitful is the use of combinatorial methods for the design and optimization of new multi-component reactions [13]. Actually, here, too, the same mathematical laws are valid, and, therefore, to find a new reaction one should test Xn variants. This number of experiments is hardly feasible without combinatorial methods. Thus, we can observe not one but several intersection points of MCRs and com-binatorial chemistry.

It should be noted that over the past years a great number of reviews [3, 14–22] and one monograph [4] devoted to various facets of MCRs, which give a fairly comprehensive view of the progress in this field. This work is an attempt to systematize the information on planning organic involving MCRs aтв search for new reactions of this type. These issues are quite important for the present stage of development of combinatorial chemistry, where the diversity and quality of scaffolds is more important than the possibility of wide variation of side-chain substituents. The most part of examples in this paper are taken from the isocyanide chemistry; this is associated with the fact that reactions involving isocyanides form the most abundant group of MCRs, as well as the scientific focus of the author.

Theory of Multicomponent Reactions

Since early 1990s multicomponent reactions have got to be referred to as a specific group, and presently

this classification is already commonly accepted [4]. A characteristic feature of this group of reactions is not mechanistic in nature, which most commonly forms a basis of classification, but a procedure of synthesis. Thus, according to the classical definition of MCRs, given by Ivar Ugi, these are reactions involving three and more reagents, and the final structure retains fragments of all the starting reagents [23].

As known, the overwhelming majority of chemical reactions in solutions occur on collision of two molecules, and, therefore, the mechanism of any multicomponent transformation will involve con-secutive reaction of molecules of different kind, which simultaneously present in the reaction mixture. Consequently, any MCRs can be divided into several stages implemented consecutively with isolation and fixation of all intermediates. This thesis can be confirmed by the reaction of aniline, benzaldehyde, and cyclopentene (the Povarov reaction), where the final tetrahydroquinoline III can be obtained either with isolation of the intermediate Schiff base or by mixing all the starting reagents [24]. Thus, in the first case we classify this synthesis as a sequence of two reactions, while in the second we speak about a multicomponent reaction. Here a question arises whether the classification based on methodical synthetic approaches varied depending on concrete researcher’s targets is justified.

In this connection we should note that any classification not only systematizes the available information, but also allows one to more definitely accentuate the main trends in this field. An unconditional impetus for further research was given by the classification based on classes of compounds and groups of reactions, formed in terms of their mechanisms. Such classification made it possible to reveal unexplored gaps which were then immediately filled with new compounds and reactions.

At present particular attention is being paid to the selectivity of organic synthesis, in a wide sense of this word. Organic chemists now set themselves the task not only to synthesize some target compounds, but also to perform synthesis with a minimum consumption of


MIRONOV 2630

A + B C D P,

A + B C D P,

A + B C D P.Cat Cat Cat

(I)

(II)

(III)

material resources, labor, and time, as well as with a minimum environmental hazard [25, 26]. Conse-quently, the goal of modern classifications and concep-tual constructions is to find and develop such ap-proaches that could ensure realization of these tasks [27].

The main advantages of MCRs include the highest possible convergence of the synthetic scheme, facility of implementation, minimum consumption of reagents and solvents, and they are widely exploited in the search for new drugs and development of new catalysts, synthetic receptors, and polymers. The recognition of MCRs as a separate group enabled to reveal a number of their intrinsic regularities, which is important for searching for new reactions of this type.

Regardless of the fact that theoretical research on MCRs has just been initiated, and the mechanisms of many of such reactions have still not been established, certain characteristic features of this group of reactions can already been recognized. In principle, any organic synthesis can be transformed into a multicomponent reaction, by mixing all reagents simultaneously in a single vessel. However, in doing so, a high yield of the final product is almost impossible to obtain because of competitive reactions. The number of such reactions will grow in geometric series with the number of starting reagents (reactions of all starting reagents with each other alone give (n2–n)/2 combinations, and if we include all possible reactions in the system, a value above n2, where n is the number of starting reagents, will result). Thus, instead of a clear sequence of chemical reactions following a definite plan, we have a molecular chaos with tens and hundreds of concurrent reactions.

At the same time, the multicomponent synthesis suggests high yields of target products, which are generally higher than in the consecutive synthesis; otherwise, the multicomponent synthesis would be impracticable [15]. Actually, regardless of the great number of competitive reactions, the MCRs used in practice are highly selective and provide a single major product in a high yield, sometimes reaching 98–99%.

Ivar Ugi performed a mathematical analysis of multicomponent systems with chemical reactions and identified those of them which may lead to a single product in a high yield [3, 23]. His classification includes three idealized systems of chemical reactions: first- (I), second- (II), and third-type (III):

Here A and B are the starting compounds; C and D, intermediate compounds (may be several); and P, reaction product.

The first type represents a system of reversible reactions, where one of the products can accumulate due to their physicochemical features, for example, poor solubility or volatility. The chemical equilibrium in the system will shift to this product, and, therefore, its yield will reach high values. At the same time, the concentrations of by-products in equilibrium with the starting reagents will fall, since they are not removed from the system. Thus, in spite of the complicated composition of the reaction system and the multitude of concurrent reactions, the yield of the target product may reach 90% and more due to the reversibility of all chemical reactions in the system.

The second type represents a modified version of the first one. The final product here is removed by means of one selective and irreversible chemical reac-tion which is referred to as the “exit” from the system. Therewith, the position of the chemical equilibrium in the system plays here a much slighter role than in the first case, since an appropriately chosen “exit” reaction allows one to remove low-concentration components from the equilibrium mixture.

The third type relates to cases where reaction selectivity is catalyst-controlled. Therewith, the rates of all reactions in the system are assumed to be negligibly low in the absence of catalysts. Such reac-tion systems are uncharacteristic of modern organic synthesis but are common in the live nature. As known, reactions in prokaryote cells are spatially poorly separated and not infrequently occur con-currently; therewith, the high selectivity of all processes is underlain by unique properties of enzymes. The catalyst-assisted approach provides a synthesis highly efficient in all respects (material, time, and space saving).

Analysis of known mechanisms of MCRs shows that their absolute majority can be related to the second type. Such widely used reactions as Hantzsch dihydropyridine synthesis, Bidginelly, Passerini, and Ugi reactions, as well as most versions of the Mannich reaction are classed with this type [23]. Formation of



2631

R1−NH2 + R2

H

ON

R2

R1−H2O

R3COOH

NR2

R1

H+

R3COO−

R4−NC

IV

R3

NR2

N

O

OR1

R4

H

H

NR2

NOR1

R4

R3

OV

Scheme 1. Ugi reaction.

imines [28], C=C compounds [21, 29], zwitter-ionic adducts [30], and salts [31] are generally reversible reactions.

As an example, we can consider one of the most known multicomponent reactions, specifically the four-component Ugi condensation [32] (Scheme 1). It occurs on simultaneous mixing of four components: isocyanide, amine, carbonyl compound, and acid. This system involves a great number of two-component side reactions. Thus, isocyanide and amine can react independently with all other reagents; carbonyl compound and acid can react with amine and iso-cyanide, and, therewith, the reactions between aldehydes and isocyanides can form several different products. Moreover, these reaction products (for ex-ample, imine IV) can enter further reactions with the starting reagents to give by-products. By even rough estimates, no less than 10 concurrent reactions can occur in this system, but actually a lot more can be expected. Thus, a complex mixture of products would be expected to form, contrary to what is actually observed: The yields in the Ugi reaction sometimes reach 98%. The high selectivity of this reaction is explained by the fact that most side reactions are reversible, and the rate of irreversible reactions is quite low at room temperature.

The situation changes when the reaction mixture is heated to 100ºC or more or Lewis acids are added [33].

In this case, a great diversity of products are observed, thus providing evidence for the model of molecular chaos in MCRs under conditions allowing several irreversible reactions to occur concurrently. The idealized Ugi’s model suggests only one irreversible reaction (forming the final product) which is just the “exit” from the system of equilibrium transformations. The exit reaction in the four-component Ugi condensation is acyl transfer to amine, a reaction which occurs almost immediately and irreversibly at room temperature [11]. This reaction shifts the chemical equilibrium to the target product V and is responsible for the high selectivity of the entire synthesis. Quite a different picture is observed, when the amino group is blocked. In this case, the quantity of by-products sharply increases, and the efficiency of the synthesis falls.

Since imines IV are formed by an irreversible reaction, their preliminary synthesis normally does not affect the yield of the final products. The equilibrium between the starting aldehyde, amine, and imine, which is usually shifted to imine formation, is fast established in the system. In its turn, the forming imine is rapidly protonated and reacts with isocyanide. This is an approach to suppress the competitive Passerini reaction, since, first, the concentration of aldehyde is lows and, second, it protonation in the presence of amine is hindered. However, by varying conditions, for example, by changing the solvent, one can switch from one reaction to another [34].

Generally, the model suggested by Ivar Ugi adequately reflects all observed characteristic features of MCRs. There are three factors primarily responsible for the high selectivity of multicomponent syntheses: (1) system of reversible reactions, (2) irreversible and selective “exit” reaction, and (3) mild reaction conditions. It, however, should be borne in mind that an exact reconstruction of an MCR is quite difficult to perform on the basis of data on its separate stages and overall reaction kinetics.

Here we have to deal with purely mathematical complications associated with an analysis of a complex system of differential equations, where even a minor uncertainty in input data entails considerable errors in the final model. Moreover, a limited information on the composition of the equilibrium compound mixture formed in an MCR is available, since only final reaction products are normally isolated and identified [13]. This results in much simplified breakages of a complex reactions into elementary stages and ignoring the equilibrium processes not leading to the final product.


MIRONOV 2632

N CCl3Cl3C

OO NH

SN

N

SNC

Me−NH2

CHOCCl3

Cl3CCOOH

Me

VI

MeO

Me

OHN

NH

O

OO

O

O

NHO

HOVII

MeO

Me

OH

O

O H

O

CNNH

OO

NHO

HO

Scheme 2.

It should also be noted that the choice of starting reagent radically affects the configuration of the network of equilibrium reactions in a multicomponent system. A model adequate for one version of an MCR may prove inadequate for another; for example, for the Ugi reaction alone more than a hundred of variants have already been described. Thus, with most MCRs we have to resort to a “rough” mechanistic description, which does not account for many details and does not allow one to construct an adequate mathematical model. Such situation gives full scope to introduction of combinatorial methods for studying MCRs.

In closing it may be stated that MCRs were initially combined in a group in terms of synthetic value, as methods of one-pot synthesis of complex compounds from several simple starting materials. However, the subsequent comparative study of these reactions showed that their high efficiency is realized by means of a special mechanism intrinsic in virtually all representatives of this class. Characteristic features of MCRs were recognized, which dictate a special approach to their description, study, and search for new representatives of this group.

Multicomponent Reactions and Retrosynthetic Analysis

The classical organic synthesis suggests the presence of a target structure whose role can be played by a natural molecule, an analog of a known medicine, or a structure developed on the basis of some hypothesis. Furthermore, some hardly accessible or an exotic structure can serve as a target. The efficiency of the synthesis of such target structure is assessed by the total yield and number of stages, which should be high and small, respectively.

The MCR concept suggests a radical decrease of the number of stages and an increase of the yield of the target product by decreasing losses associated with the isolation and purification of intermediate compounds. However, it should be noted that MCRs are fairly rarely used to synthesize target structures, for example, compounds isolated from natural sources [4]. Such situation can be explained by the fact that usually a target structure is fairly difficult to consider as a single whole, correlating it with the product of an MCR. On the other hand, the potential of multicomponent chemistry is far from exhausted, and structures available by MCRs are still not infrequently obtained by multistage syntheses.

An original approach to get rid of this drawback has been suggested fairly recently [11, 15]. This method named by the author “smallest-atom connectivity” allows chemists, using a special software, to compare different reactions by searching in the target structure for fragments synthesizable by MCRs. Consequently, it makes it possible to decrease the total number of stages in the synthesis of the target compound. Thus, for example, the Ugi reaction opens up the way to the NCCNC fragment, whereas the passerini reaction allows one to generate the NCCOC fragment. Below we give examples of the practical implementation of this concept. A natural structure can sometimes be synthesized by a one-stage MCR, as with toxin VI [35], isolated from the sea sponge Desidea or the antitumor antibiotic azinomicine VI [36] (Scheme 2).

On the other side, planning combinatorial syntheses cannot be based exclusively on known reactions; much more possibilities are provided on an approach



2633

CHO

CHO

+ H2N−Me +

COOH

COOH

ON

Me

O−2CO2

involving the design of new MCRs on the basis of structural features of target compounds [15]. In this case, a researcher should be free of limitations posed by known MCRs and to choose by himself reagents and conditions for a new reaction. Unfortunately, such approach is quite rarely faced in practice, since most known MCRs are not a result of retrosynthetic breakage of the target molecule into separate blocks. Here we face basic difficulties which arise when one attempts to combine the retrosynthetic analysis and design of new MCRs [22]. The case in point is that the retrosynthetic analysis makes use, as a rule, already known reactions and is directed from the target molecule to starting reagents. At the same time, MCRs are usually designed in the opposite direction, by testing various sets of chemical reagents. Actually, it is difficult to find a common solution for differently directed logic schemes; however, examples of such solutions are available in the literature.

The earliest and most impressive example is pro-vided by the Robinson tropinone synthesis described as far back as 1917 [37]:

absolute majority of such reactions showed a low selectivity in a chemical experiment. In the analysis of a multicomponent system with chemical reactions, one hardly predicts all possible side reactions leading to undesirable products, which forms the major barrier to the use of computer programs for designing MCRs. As a rule, the reaction found by means of a computer program characteristically provides low yields of the target product and requires further optimization, and nobody can guarantee that the yield will be actually improved. The new methods of synthesis of natural products, developed by means of specially designed MCRs, appear due to a favorable concatenation of circumstances, which is a fairly rare case.

New possibilities for the practical use of MCRs are associated with combinatorial chemistry, in particular the concept of diversity-oriented synthesis (DOS) developed several years ago [39]. The aim of this approach in organic synthesis is to obtain series or libraries of compounds widely scattered in the chemical space, including low-populated areas which best fit the desired characteristics. In its turn, the chemical space is defined as an n-dimensional space defined by descriptors which relate both to chemical and biological properties of a molecule in focus.

Such formalism allows a maximally exact com-parison of chemical structures on the basis of clear mathematical criteria. Therewith, the fact that two molecules fall in the same segment of the chemical space implies their actual similarity in the chosen coordinate system, i.e. in terms of a combination of certain parameters (for example, log P, dipole moment, or affinity to a certain enzyme). Consequently, a possibility arises to depart from empirical assessments of similarity of one or other structures, based on the visual perception of chemical formulas, which not infrequently entails wrong conclusions or even a wrong research plan.

The DOS concept can be used to success in the design of MCRs, since it contains no concept of target structure [40]. The concept of structure here is replaced by the concept of chemical space which may also be the same for molecules with different structural elements. Consequently, chemical synthesis is targeted to a certain segment of the chemical space, which implies a preset combination of properties. Actually, researchers are most commonly interested in a com-bination of properties of his synthesized compounds, rather than a formal structure drawn on paper.

This reaction was specially developed on the basis of the versions of the Mannich reactions, known by that time, and features of the target structure. Regardless of the fact that the yield of this reaction was initially not above 17%, but subsequent optimiza-tion allowed the tropinone yield to be increased to 90% [38]. This is quite characteristic of MCRs, when the initial yields of target products use to be fairly low, and further effort is required to optimize the reactions for their practical application. On the other hand, this effort is justified, since the efficiency of MCR-based syntheses is extremely high, as evidenced by the tropinone synthesis.

Specially developed computer programs might fa-cilitate the search for new MCRs on the basis of structural features of the target structure, but, as already mentioned, this is quite a challenging problem. In mid-1990s at the Ivar Ugi’s lab, an attempt was made to create a computer program for designing MCRs with preset parameters (IGOR) [34]. However, it was found out in practice that computer fairly easily finds reagents necessary for new reactions, but an


MIRONOV 2634

Scheme 3.

Obviously, this approach is impossible to realize by means of the retrosynthetic analysis; quite a different synthesis planning approach is required.

This method of analysis preceding synthesis is being only established, and its working name is forward-synthetic analysis (FSA). The main principle of the FSA can be formulated as follows: the synthetic scheme should be designed from starting products toward a multitude of structures combining maximally possible complexity and diversity. Therewith, the number of stages not be no more than five. Complexity here means the number of new C–C bonds, number of fused rings, spatial structure of molecules, or number of chiral centers. All these parameters can be assessed by means of special computer programs. Therewith, the references are polycyclic natural molecules, such as morphine or taxol. In its turn, diversity relates to the arrangement of side-chain substituents in the structures.

The DOS concept puts much emphasis to the molecular carbon frame, since it is varying the frames themselves and their stereochemistry that provides structures falling in different segments of the chemical space. Analysis shows that varying side-chain sub-stituents cannot actually “move” structures in the chemical space. The concept and its practical applica-tions are described in detail in the review [41].

As already mentioned, the DOS opens up great prospects for using known and designing new MCRs. Actually, here one does not need to construct a compound with a strictly defined structure, but, vice versa, of importance is a combination of parameters by the researcher’s choice, which can be obtained by combining various structural elements.

An example is provided by the live nature, where an almost inexhaustible diversity of forms is formed by a limited number of structural elements. We can refer here to the chemistry of terpenes, steroids, and carotenoids: The diversity of carbon frames is built on the basis of a single structure, specifically isopentenyl pyrophosphate [42]. The multicomponent chemistry is an ideal candidate for the role of such a chemical construction mechanism which allows a great number of complex and diverse structures to be synthesized with a minimum number of stages. This is exemplified by the synthesis of a complex polycyclic compound VIII, described by Lee et al. [43] (Scheme 3).

This synthesis includes as little as three stages but forms all at once four new rings and five new carbon–carbon bonds. The first stage is a version of the Ugi reaction, where the classical condensation of four starting compounds is followed by the Diels–Alder reaction, and, therewith, all transformations are

O CHOPh NC

+HN ArHOOC

O

H2N

OR

ORNOO

HN

PhO

H

NHAr

O

VIII

Br

NPh O

NO

H

O

N

OH

H

ArH

ORCatalyst OR

ONN

OH

Ph

O

ONAr



2635

performed without isolation of intermediate products [44]. Thus obtained compound serves as a precursor for further reactions leading to complication of the structure. In the present case, double allylation and metathesis reactions were performed, whose direction was defined by the structure of the product of the four-component Ugi condensation. It should be noted that the starting materials in this synthesis were fairly simple and accessible reagents. To synthesize such structure not resorting to an MCR would require more stages or more complex reagents. Thus, the practical implementation of the DOS concept or methodo-logically similar approaches (tandem synthesis or domino reactions) is hardly imaginable without MCRs.

The main problem in the modern combinatorial chemistry is to generate a real diversity of complex structures. It should be admitted that even such a flexible and multiversion reaction as the four-com-ponent Ugi condensation is unable to provide the diversity of structures, required for biological screen-ing. Like any other reaction, this reaction, too, has certain limitations which can be overcome in no other way than by passing to new MCRs. The diversity-oriented synthesis concept intrinsically involves no indications on what methods are best suited to design a new MCR; its function is to give impetus to research in this field. In the present review we made an attempt to describe and classify the principal methods of the MCR design of isocyanides, known by the time when it was written.

Methods of Design of Multicomponent Reactions

Substrate Method

The methods of MCR design are developed not nearly to the same extent: some of them are widely used, whereas others are tested on a few examples. Combining MCRs and subsequent intramolecular transformations should be related to the most explored ways to new reactions of this type [4]. The practice showed that this approach makes it possible to obtain tens or even hundreds of new structures. Different methods of combining inter- and intramolecular reac-tions are based on several common principles.

First, the starting reagents should contain additional functional groups. As a rule, in terms of reagent ac-cessibility, compounds with one additional func-tional group or, much rarer, with two such groups are used.

Second, the additional functional group should not enter the MCR or induce any competitive reactions in

the multicomponent system. This result is easy to reach, taking into account a large rate difference between intra- and intermolecular reactions.

It should be mentioned here that most isocyanide MCRs are performed in very mild conditions and with a great number of functional groups. Most frequently, groups fairly inert under normal conditions are used; therefore, no protective groups are usually needed. An excellent example is provided by the above-mentioned combination of the Ugi and Diels–Alder reactions, with furfural and a maleic acid derivatives as starting reagents [43, 44]. These compounds do not enter a two-component reaction under normal pressure and room temperature but readily react when are present in the same molecule.

The third condition to follow in planning such combinations is to take into account the mutual spatial arrangement of functional groups. Obviously, intramolecular reactions can be realized only at a definite mutual arrangement of the reacting centers.

In total, these rules are not something new in the heterocyclic chemistry, since such syntheses generally make use of bifunctional reagents. However, in the case of MCRs we have to deal with a much more intricate system which requires special approach. Actually, as we mentioned in the introduction, four-component reaction products having two reactive groups can undergo six {(42–4)/2} different cycliza-tions. At the same time, two additional reaction center increase the number of possible-level competitive reactions in the multicomponent system to 14{(62–6)/2 minus one target reaction} [11].

Thus, planning such reactions involves analysis of numerous reactions and a lot of experiments on the optimization of the entire synthetic scheme. This effort is quite justified, since as a result we obtain an efficient one-stage synthesis of a complex compound from simple reagents, which simultaneously forms several new bonds. Therewith, the number of available variants is quite high, which is very important in combinatorial synthesis planning.

It should be noted that the overwhelming majority of research in this field relates to the four-component Ugi condensation. An illustrative example is the new synthesis of pyridazinones IX, where the Ugi reaction is combined with the intramolecular Knoevenagel reaction [45] (Scheme 4). The starting hydrazone contains a keto group which is inert enough for two-


MIRONOV 2636

COOH

O

H2N COOMe

N

N

O

RO

O

R−NCXI

Scheme 5.

component reactions and intramolecular cyclizations. However, as part of an intermediate structure it readily reacts with an active methylene group to form a new С–С bond. It is interesting to note that the authors of the cited work obtained performed a two-stage synthesis with isolation of product X to obtain the target product in a lower yield. As discussed above, an irreversible reaction (here intramolecular acylation followed by heterocyclization) allows the chemical equilibrium to be effectively shifted to the target structure. Therewith, this approach not infrequently surpasses physical methods, such as more azeotropic distillation with a Dean–Stark trap. Therefore, there is no practical sense to break this synthesis into separate stages, since this decreases the total yield of the target compound.

Analysis of this synthesis reveals other features of MCRs. Thus, it is easy to imagine a two-component reaction of hydrazone IX with acid and subsequent cyclizations into the corresponding pyridazinone. In an MCR, along with forming a target heterocycle, one can introduce simultaneously two side-chain groups. This feature is particularly valuable for structure–activity correlations in large compound series or libraries. Moreover, the introduction of additional functional groups not only allows one to diversify the structure of heterocycles, but also to accomplish a number of consecutive cyclizations, thus opening up the way to

polycyclic structures. Such strategy is well exemplified by the synthesis of bicyclic lactam XI from accessible starting materials [46].

It should be noted that the Ugi reaction is quite fre-quently combined with some subsequent intramole-cular reaction, and this approach is well documented [11, 14, 16]. Detailed discussion of this methodology is beyond the scope of the present paper, and we refer the reader to a comprehensive review on this issue [47].

Protective groups are most commonly not used in Ugi reaction–heterocyclization combinations, since this adversely affects the overall efficiency of the syn-thesis because of additional operations on protection introduction and removal. An exception is the UDC (Ugi reaction/protection removal/cyclization) metho-dology [48]. It involves the Ugi reaction with reagents containing an amino group protected with the tert-butoxycarbonyl group. Removal of this protective group makes possible diverse cyclizations forming pharmaceutically valuable chemicals. As a example, we present here the synthesis of benzimidazole XII [49] (Scheme 5).

It is readily seen that the presented approach is a peculiar combination of the peptide chemistry and MCRs. Removal of protective groups and subsequent condensations are accomplished by the methods of the peptide chemistry, whereas the use of the Ugi reaction considerably extends the range of available structures and reduces the number of required stages.

Ar

Ar

N

O

NH2 + R2O

H

Ar

Ar

N

O

N R2

NC COOH

R1−NC

NN

OCN

Ar

Ar

HN

R1

O

R2

IX

X NC COOH

R1−NC

Scheme 4.

NH2

BHBoc

+ NC

CHO

PhCOOH

2stages

N

N

Ph

ONH

XII



2637

Scheme 6.

N

SO

R3 R1

O

COOR

N

N

N NNROOC

R1R2

NMe2

NCROOC

N

SN

R3 R1

O

COORR2

NH

N

OROOC

R1R2

XIII

Scheme 7.

SH

COOHK2CO3

Cl

O

S

COOH

O

R1−NCR2−NH2

XVI

N

S

O R2

NHO

R1

XV

Obviously, each reaction of this type can be designed independently of others, since it will be based on a unique combination of functional groups in the starting reagents. Quite important is the possibility to prepare diverse structures from a limited set of com-mercially available standard reagents. The most fruitful approach in the implementation of this strategy in the multicomponent reactions of isocyanides turned to be the use of so-called key reagents. The role of such reagents is frequently played by isocyanides whose additional functional groups are capable of entering various reactions. Thus a possibility arises to synthesize different structures starting from a single standard reagent. The first reagent of this type was 1-isocyanocyclohexene which was given the name “universal isocyanide” owing to the fact that the 1-aminocyclohexehe residue can be readily removed after the Ugi reaction [36] (Scheme 6).

A reverse synthetic sequence is possible, when additional functional groups react first and then an MCR is accomplished. A good example of such strategy is provided by the synthesis of benzo-diazepines XV, developed by our group [53]. We used accessible reagents, thiosalicylic acid and chloro-acetone, were used to prepare a compound containing carboxyl and carbonyl. This keto acid XVI was brought, without isolation and purification, into a new version of the Ugi reaction. The other participants of the Ugi reaction (isocyanide and amine) were then added to obtain the target heterocycle in one stage:

At present more than ten such isocyanides are known, and this list is constantly augmented. For example, compound XIII enters reactions charac-teristic of isocyanides and enamines, thus opening the way to a variety of heterocyclic compounds [50, 51] (Scheme 7).

Reagent XIV allows one to design complex reaction sequences with cycloaddition as the key stage [52]:

NOPh

CNO

R1R2NHR3CHO

N

OR3

N

Ph

NO

R1 R2

XIV

NC

R1CHO,R2NH2,

R3COOH

R3 NHN

O

O

R1

R2

R3 NOH

O

O

R1

R2

R3 NOAlk

O

O

R1

R2

R3 NSAlk

O

O

R1

R2

H2O

AlkOH

AlkSH

Thus, the combination of an MCR and intra-mole-cular cyclizations gave a qualitative impetus to the extension of the range of really diverse structures in combinatorial libraries. This is one of a few ap-proaches to preparing series or libraries of scaffolds.


MIRONOV 2638

This is undeniably a new step in the development of combinatorial approaches to generating compound series for biological screening.

Mechanism-Based Methods for Designing Multicomponent Reactions

The above-considered so-called substrate methods open up wide possibilities for designing new MCRs. However, these new reactions are all based on already known transformations and designed by adding new functional groups into the starting reagents. Therefore, this method gives way to design numerous versions of known MCRs but not to discover new ones. Surely, a real diversity of structures, for example, a library of heterocycles, should not only include different-size cycles, but also different successions of atoms in them. As mentioned above, MCRs are quite convenient to divide into groups in terms of the concrete atomic sequence they form [15].

Such classification has an undeniable practical interest, since it allows one to recognize atomic sequences, and, consequently, structural types, ac-cessible via MCRs. This information can further used in the retrosynthetic analysis for developing more efficient synthetic schemes [41]. Furthermore, it will be useful for designing combinatorial compound libraries on the basis of several scaffolds. The consideration of the theory of MCRs allows a conclusion that various atomic sequences in a structure are defined by various sequences of individual stages. However, by simply combining stages with one another one, as a rule, will not reach a positive result because of the difficulties associated with accounting for all competitive reactions and optimizing the entire reaction sequence.

Therefore, quite important proved to be the feature of MCRs, consisting in their ability to combine with each other. Thus, the four-component Ugi reaction can be represented as a combination of two three-component reactions: Mannich and Passerini. Amine and carbonyl compounds traditional for the Mannich reaction were here combined with carboxylic acid and isocyanide, the participants of the Passerini reaction, and, therewith, the latter reagent functions of the С-nucleo-phile [13]. It is easy to imagine that this approach can open the way to a great number of new MCRs.

Actually, over the past decade the method called the combination of MCRs, has made it possible to design reactions with an extremely high number of

participants. Thus, the seven-component reaction mentioned in the introduction is a combination of the Ugi and Asinger reactions. Further example is provided by the six-component combination of the Ugi and Petasis reactions [54] (Scheme 8).

The yields of the target products in such six–eight-component reactions are 40–50%, which is quite ac-ceptable, taking into account the quantity of newly formed bonds and facility of syntheses. Thr success of such combinations is based on the mechanistic features of the starting reactions which form networks of reversible chemical transformations. Therefore, a combination of two such networks does not increase the number of by-products and, as shown in practice, such reaction can be successfully optimized, even though it involves a great number of participants. No doubt that this approach has a lot of limitations which are primarily associated with choice of appropriate starting reactions.

We developed an original approach to searching for new MCRs, given the arbitrary name “reaction operator” [22]. Like the functional operator in mathe-matics, which allows transformation of one function into another, the suggested approach opens up possibilities for passing from known to new reactions. By contrast with what is done in combining MCRs, for the starting reaction here one can choose any chemical trans-formation involving several reversible stages. It may be already both known MCRs and oligomerization reactions.

The search for a new reaction begins with analysis of published data and search for an appropriate starting reaction. Then the key stage is determined, changes in

Scheme 8.

−B(OH)3−H2O

R2 NN

HN

R6

R1

R4R3

R5O

O

H COOH

O

NHR1

R2

R3−B(OH)2

+

R4−NH2

R5−CHO

R6−NC



2639

Scheme 9. which do not disturb the sequence of other stages of the MCR but allows varying the sequence of atoms in the target structure. As a rule, the key stage is reorganized by using a new reagent set or by changing its conditions. The last stage involves optimization of the new reaction, which should result in a convenient synthesis of the modified structure.

As an example of the practical implementation of this approach we can present a new method of functionalization of benzothiazines, based on a number of new MCRs [55, 56]. In 1930s, a series of azine reactions with diethyl acetylenedicarboxylate was described, involving addition of two alkyne molecules to form a quinolizine system and two C–C bonds [57]. All reactions occurred in mild conditions and gave high yields. From the viewpoint of combinatorial chemistry, these reactions hold little promise in terms of the synthesis of both libraries of derivatives and libraries of scaffolds because of the impossibility of structural variation of alkyne.

We decide to generate new MCRs by replacing two molecules of diethyl acetylenedicarboxylate by two different reagents [55]. In this case, a possibility arises to form various polycyclic systems with different atomic sequences in the structure. Moreover, the use of three components extends considerably the range of structures with allows different side-chain substituents. Actually, among different reagents with double or triple bonds we could find those meeting all our requirements. In the scheme below, Ai and Aj stand for reagents containing double and triple bonds.

The reaction of isoquinoline with isocyanides and benzylidenemalonodinitriles gave pyrrolidine deriva-tives XVII (Scheme 9).

This reaction presents interest because it forms exclusively trans isomers with respect to pyrrolidine hydrogens. Further optimization of this reaction allowed development of convenient methods for func-tionalization of isoquinoline, quinoline, and phthala-zine. The purposeful structural modification of a com-pound with a highly electrophilic double bond allowed us to find a series of reactions of benzazines with isocyanides and isothiocyanates [56] (Scheme 10).

As shows analysis of published data, the promise this approach holds for combinatorial chemistry can hardly be overestimated, since the isoquinoline molecule can be successively attacked by an electrophilic reagent by the nitrogen atom and by a nucleophilic reagent by the first position of the ring. The number of com-

binations of such reagents is huge, and, therefore, the purposeful search in this direction can open up the way to libraries of structures with different atomic sequences. Certain reactions of this family, found in different years and differing from each other with only one reagent, are shown below [58–60] (Scheme 11).

N

N

N

R

R

+ 2

+ Ai + Aj

+ R1−NC +NC CN

R2

N R

RR

R

?

N NR1

H

R2NCCN

XVII

Scheme 10.

N+ R1−NC + X Y

R2

N

X

N

YR2

R1

X = N, Ph−C; Y = O, S, Ph−N

N+ R1−NC + N S

Ar

N+

NAr

NH

S−

R1


MIRONOV 2640

MeCOOH

O+

R1−NC

R2−NH2

N

O

Me

R2

NHR1

O

XVIII

Scheme 11.

R = COOMe; COOEt.

This example provides evidence to show what a great variety of compounds can be made available by varying concurrently two reagents.

Conditions of Multicomponent Reactions

Quite an important issue in searching for new MCRs is to choose their optimal conditions. As mentioned above, MCRs are very sensitive to solvent; many of them provide good product yields only under definite conditions. Therefore, in the search for a new reaction one can easily miss such optimal conditions. This can be avoided only when solvent becomes one more system parameter, along with reagents. This thesis is well illustrated by the new synthesis of β-lactams XVIII [61]:

This reaction forms the target product in water, and in no other solvents.

One more important factor to ensure the required selectivity of MCRs is proper choice of catalysts. Not infrequently, catalysts allow changing the direction of an MCR, thereby opening up new ways in organic synthesis. Just in this way we could discover a new reaction leading to propanamide XIX. This product formed exclusively when pyridine was added to the reaction mixture; other bases did not affect the reaction direction [62]:

N+COOMe

C−COOMe

N

NN

R

RR

R

N

O

R

RR R

N

N

R

RPhO

N

O

R

R

O

N

N

R

RTosylAr

N

N

R

RRR

N=NR R

OR

RPh−NCO

O

O

NAr

Tosyl

R2−NCCNNC

R1

+

OH

N+O

O−

Pyridine

N+O

O−

HN

R2

CN CN

R1

XIX



2641

rivatives have long attracted attention of medical chemists. These compounds reportedly exhibit a broad-spectrum biological activity, and, in particular, they are cardiac stimulants, inhibit gastric acid secretion, and possess antibacterial and fungicide properties [63].

The simplest and widely known method of synthesis of these compounds is based on the alkyla-tion of 2-aminopyridine with halogenated ketones followed by heterocyclization [64]. The advantages of the multicomponent synthesis of imidazo[1,2-а]pyri-dines consists in the possibility to widely vary several side-chain groups and to decrease the synthesis cost, which potentially makes it possible to drive the search for new biologically active compounds in this series.

In 1998, three research groups simultaneously reported a new version of the Ugi reaction, involving the reaction of 2-aminopyridine, aldehydes, and iso-cyanides in the presence of an acid catalyst to form imidazo[1,2-а]pyridines XX in one stage [65] (Scheme 12).

Consequently, in searching for new MCRs one should vary a lot of parameters, including starting reagents, solvent, and catalyst. Thus the number of experiments increases avalanche-like, which calls for combinatorial methods to search for and optimize new MCRs. Here the circle is closed, and MCRs, which are justifiably considered as one of the most efficient methods of combinatorial chemistry, become in them-selves its object. Over the past years a practice has already formed, when, initially, combinatorics is used to find a new reaction, and this reaction is then used to find a desired structure, again, be means of combinatorial tools.

Combinatorial Methods in the Search for New Multicomponent Reactions

The mechanism of a typical MCR includes a multitude of equilibrium reaction and is quite a complex object for mathematical analysis. The practice showed that a rational approach to the design of complex multicomponent systems with chemical reactions betrays itself, even if up-to-date computers and software are used. As a rule, on attempted prac-tical implementation of thus designed reactions, a low reaction selectivity and a variety of products instead a single target product were observed.

Since mid-1990s there have been attempts to apply combinatorial tools for search and optimization of new MCRs [13]. The choice of combinatorics is optimal if a researcher has a limited information about the system, say, about the mechanism of potential MCR. In this case, the number of experiments is directly related to the level of knowledge about this system. The situation best suited for combinatorial approach is a situation when the reaction mechanism is roughly understood, and the series of experiments should reveal an optimal set of reagents or conditions for a highly selective synthesis of a single product. On the other hand, there is no sense to resort to combinatorics if the level of knowledge about the system is too low, and the number of required experiments increases to astronomic values. Also, to avoid high consumption of reagents and other resources, these methods are senseless to resort to, when a rational approach is possible.

The above theoretical postulates can be illustrated by examples from the isocyanide chemistry. The first example of combinatorial approach to searching for new isocyanide MCRs is the development of synthesis of imidazo[1,2-а]pyridines. Imidazo[1,2-а]pyridine de-

Scheme 12.

N

NH2

+CN−R1

R2O

H

MeOH, H+ NHN OMe

R2 N−R1

N

NR2

N−R1H XXI

XX

It is interesting to note that the three research groups all came to this synthesis in the same way, i.e. having analyzed a great body of information on the libraries of compounds formed by the four-component Ugi condensation. In mid-1990s, many research groups of major pharmaceutical companies synthesized and tested large compound libraries on the basis of the Ugi reaction. The qualitative analysis of these compounds was performed by LC–MS. It was therewith found that the classical structure described by Ivar Ugi was not always the major reaction product. Not infrequently, depending on starting reactions and reaction conditions, products with lower or higher molecular weights compared with the expected structure formed.

To explain this phenomenon, we have again to return to the theory of MCRs. The formation of one or


MIRONOV 2642

another final product in an MCR is associated with an irreversible reaction which is usually called the “exit” from the system. The classical variant of such “exit” in the case of the Ugi reaction is intramolecular acylation of the amino group; however, this is far not the only possibility. It was found immediately after the discovery of the Ugi reaction that it has a great number of variants leading to a broad spectrum of structures. Careful analysis of these variants shows that there is a correlation between features of the final structure and “exit” reaction which can be heterocyclization, rearrangement different from classical, or exchange between the intermediate structure and solvent.

One of such nontrivial reactions is the formation of amidines from two molecules of secondary amine and one molecule of aldehyde and isocyanide [66]. However, the reaction leading to amidines has not found practical application because of its low selectivity. Amidines were usually registered as by-products in the classical Ugi reaction in cases where the formation of the target compound was hindered. The situation radically changes if both amino groups are present in the same molecule, like in 2-aminopyridine. The formation of imidazo[1,2-а]pyridines from 2-aminopyridine as the amino component of the Ugi reaction can be explained by the intramolecular cyclizations of unstable imidate XXI under the action of an acid catalyst.

Analysis of a series of the mass spectra for compounds from the library on the basis of the Ugi reaction showed that the molecular ion in the spectra of compounds obtained with 2-aminopyridine did not correspond to the target structure (an acid residue). The NMR spectra and independent synthesis left no room for doubts as to the structure of the resulting com-pounds. Thus a new synthesis of imidazo[1,2-а]pyri-dines was discovered [13].

Further this approach was extended to other compounds containing the amidine fragment. It should be stressed once again that the three research groups all did not set themselves the goal to develop a new version of the Ugi reaction, and 2-aminopyridine was taken as an accessible reagent frequently used for preparing compound libraries; therefore, figuratively speaking, this reaction was found spontaneously.

Why the rational approach failed in this specific case? Indeed, in view of the known data on the me-chanism of the Ugi reaction one might expect hetero-cyclization of the intermediate compound containing

the 2-aminopyridine fragment. There are several ex-planation for this situation.

First, in one of his early works Ivar Ugi used 2-aminopyridine as the amino component and observed no deviations from the classical route [67]. Second, the rational design of this reaction is almost impossible, provided one takes account of all reversible and irreversible reactions possible in the system; however, this is quite a difficult task.

Actually, in terms of the MCR theory, several other products can form in this system along with imidazo[1,2-а]pyridines. Therefore, it seemed impossible to expect a high selectivity of the discovered reaction. Rather one might expect that imidazo[1,2-а]pyridines would be minor products of the Ugi reaction. We face here a situation ideal for combinatorics: On the one hand, some information of reaction mechanism and products is available but on the other, one is unable to model the effect of reaction conditions and starting reagents on the composition of final products.

The development of the new synthesis of imidazo-[1,2-а]pyridine has triggered development of com-binatorial tools for search for new MCRs. With 2-amino-pyridine, the discovery of a new reaction was not planned. However, combinatorial reagent screening can also be used for purposeful search for new MCRs. The most illustrative example of such approach is the development of a new synthesis of dihydrocinnolines XXII on the basis of the Ugi reaction. The experiment involved 10 starting compounds (Scheme 13) [68].

It is readily seen that the choice of these compounds (isocyanide, ketone, aldehyde, two amines, two structurally different amino acids, and acetic acid) was based on published versions of the Ugi reaction. All reactions possible with these components, from two- to ten-component, were performed, which made 2n– n – 1 = 1013 combinations. All these reactions were performed at room temperature in methanol using an automated equipment for mixing reagents and analyzing reaction mixtures.

It might seem that such a great number of experiments would results in an unjustifiably large consumption of material resources and time. However, in reality, this experiment took as little as 11 standard 96-well plates, about 300 ml of methanol, about 10–15 g of each reagent, and about one working week of an LC-MS system. Automated search was focused on the selectivity of processes in reagent mixtures, and,



2643

Scheme 13.

therefore, then and only then when a new product with a yield of above 30% yield (by LC data) was detected, the mixture was considered perspective for further research.

During the experiment several fairly selective isocyanide MCRs were detected (yield >50% under optimized reaction conditions). One of these reactions, namely, the synthesis of dihydrocinnolines by the Ugi reaction, was previously unknown. This reaction mechanism is generally similar to the mechanism of imidazo[1,2-а]pyridine formation, but the intermediate compound here is hydrazone instead of imine, and C–C bond forms instead of C–N. It is interesting to mention that, like 2-aminopyridine, hydrazones, too, were previously used as one of the starting compound of the Ugi reaction, but no deviations from the standard reaction route were revealed [69].

Thus, we can note a general regularity: Com-binatorial methods allow one to discover new reactions which are difficult to model by rational methods. Therewith, parallel synthesis, as well as low reagent and solvent consumptions is a single experiment make it possible to accomplish a lot of such experiments (104 and more) for searching for new MCRs.

Along with search for new reactions, parallel synthesis in standard 96-well plates is quite frequently used for optimization of MCRs designed on the basis of some rational hypothesis. An illustrative example from the isocyanide chemistry is provided by the new synthesis of imidazoles XXIII by the reaction of aldehydes, ortho-picolylamines, and isocyanides [70]:

O

H2N OH

O

H2NOH

O

OH

OCl

O

MeOMeO

O

O

OH

O

Nr NH2NC

HN

OMe

NH2

O

+

NC

+

HN

OMe

NH2

OH

O

NH

NNH

MeO

XXII

N

NH2

R

+R1−NC

R2O

HN

R

NN

R2 R1

Lewisacid

XXIII

This reaction was suggested on the basis of known reactions of isocyanides with compounds containing an active methylene group. The C=N bond in the inter-mediate compound would induce cyclization into imidazolines which are redily oxidized to imidazoles. Such reaction route looks sufficiently reasonable, provided competitive reactions, including the reactions of isocyanides with aldehydes and imines in 2:1 and


MIRONOV 2644

scaffolds. On the other hand, another synthetic approach to complex organic compounds, which is so easily accomplishable and adaptable to automated systems is hardly existent. This combination of the simplicity of experimentation and an enormous structural potential is especially attractive for chemists working in the field of functionally oriented organic synthesis. At the same time, MCR design is a nontrivial task necessitating creative approach and diversified tools, including combinatorial, which is a challenge for chemists.

REFERENCES

1. Terrett, N.K., Combinatorial Chemistry, New York: Oxford Univ. Press, 1998. 2. Laurent, A. and Gerhardt, C.F., Ann. Chim. Phys., 1838, vol. 66, p. 181. 3. Strecker, A., Justus Liebigs Ann. Chem., 1850, vol. 75, p. 27. 4. Multicomponent Reactions, Zhu, J. and Bienayme, H., Eds., Weinheim: Wiley–VCH, 2005. 5. Mannich, C. and Krosche, W., Arch. Pharm., 1912, vol. 150, p. 647. 6. Hantzsch, A., Justus Liebigs Ann. Chem., 1882, vol. 215, p. 1. 7. Popp, F.D., Adv. Heterocycl. Chem., 1968, vol. 9, p. 1. 8. Passerini, M., Gazz. Chim. Ital., 1921, vol. 51, p. 126. 9. Corey, E.J. and Cheng, X.-M., The Logic of Chemical Synthesis, Weinheim: Wiley–VCH, 1995, p. 23. 10. Dömling, A. and Ugi, I., Angew. Chem. Int. Ed., 1993, vol. 32, p. 563; Dömling, A., Ugi, I., and Herdtweck, E., Acta Chem. Scand., 1998, vol. 52, p. 107. 11. Ugi, I. and Dömling, A., Angew. Chem. Int. Ed., 2000, vol. 39, p. 3168. 12. Gonzalez-Zamora, E., Fayol, A., Bois-Choussi, M., Chia- roni, A., and Zhu, J., Chem. Commun., 2001, no. 17, p. 1684. 13. Weber, L., Illgen, K., and Almstetter, M., Synlett, 1999, no. 3, p. 366. 14. Dömling, A., Chem. Rev., 2006, vol. 106, p. 17. 15. Dömling, A., Curr. Opin. Chem. Biol., 2000, vol. 4, p. 318; Ibid., 2002, vol. 6, p. 306. 16. Zhu, J., Eur. J. Org. Chem., 2003, no. 7, p. 1133. 17. Bienayme, H., Hulme, C., Oddon, G., and Schmitt, P., Chem. Eur. J., 2000, vol. 6, p. 3321. 18. Orru, R.V.A. and de Greef, M., Synthesis, 2003, no. 10, p. 1471. 19. Tetrahedron, 2005, vol. 61, no. 48. 20. Ramon, D.J. and Yus, M., Angew. Chem. Int. Ed., 2005, vol. 44, p. 1602. 21. Lieby-Muller, F., Simon, C., Constantieux, T., and Rodriguez, J., QSAR Comb. Sci., 2006, vol. 25, p. 432. 22. Mironov, M.A., QSAR Comb. Sci., 2006, vol. 25, p. 423.

1:2 ratios, as well as Ugi and Passerini reactions are not taken into account.

To find optimal reaction conditions and reagents, the authors had to perform several series of experiments in 96-well plates. Each well was used to test some combination of reagents and catalysts; therewith, the quantities of starting compounds was no more than 5 µmol. These experiments showed that ortho-picolylamines suitable reagents for imidazole formations, whereas benzylamines and meta- and para-picolylamines form other products. Moreover, a negative impact of sterically congested substituents in isocyanides on the normal reaction route.

In the research we have tested a great number of catalysts and solvents to reach acceptable yields which were no higher than 15% in the first experiments. This heavy experimental work including hundreds of runs and spectral measurements, was fulfilled over as little as two months by a group og four people. This result would be impossible to reach without combinatorial methods.

At present most research groups focused on MCRs in pharmaceutical companies widely use combinatorial methods. This practice presently little-by-little extends to academic research, too.

It should also me noted that the most part of thus discovered MCRs are applied in practice in the synthesis of compound libraries, and, therefore, the suggested schemes should be well suited for the available equipment for parallel synthesis. As a rule, any new reaction is tested in a multiwell (96 or more) plate to determine the range of its application. Combinatorial chemistry and MCRs are related fields of organic chemistry and have numerous intersection points.

CONCLUSIONS

Over its fairly short history, combinatorial chemistry has made considerable progress from the synthesis of mixtures of relatively simple organic compounds to libraries of individual compounds with really diverse structures, which do not rank below natural creations in complexity. Over the course of this process, the sphere of combinatorial chemistry has incorporated tools favoring solution of such a complicated task. The use of MCRs in the synthesis of combinatorial compound libraries is one of such tools. On the one hand, they provide access to an almost indefinite diversity of side-chain substituents and



2645

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multicomponent reactions and combinatorial chemistry

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