Switchable multicomponent heterocyclizations for ...

Diversity Oriented Synth. 2014; 1: 43–63

Review Article

Open Access

Valentin A. Chebanov*, Sergey M. Desenko

Switchable multicomponent heterocyclizations for diversity oriented synthesis Abstract: The present comprehensive review1 contains the analysis of literature data concerning switchable multicomponent heterocyclizations and demonstrates the application of these types of reactions to solve the matters of Diversity Oriented Synthesis. Keywords: Diversity-oriented synthesis, microwave irradiation, multicomponent heterocyclization, selectivity, switchable reaction, ultrasonication DOI 10.2478/dos-2014-0003 Received July 23, 2014; accepted October 2, 2014

1 Introduction Diversity-oriented synthesis (DOS) [1, 2] is a promising and rapidly developing field of modern organic chemistry, which is focused on medicinal-orientated tasks and obtaining libraries of small organic molecules for highthroughput screening [3-6]. Among numerous synthetic tools, multicomponent reactions (MCRs) are perfectly suited for DOS since they allow the creation of diversity in decoration, skeleton or stereochemistry by simultaneously using each component of the reaction. Moreover, it is 1 This review includes some examples from earlier published work (Chebanov V.A., Desenko S. M., Chem. Heterocycl. Compd. 2012, 48, 566) *Corresponding author: A. Chebanov: Division of Chemistry of Functional Materials, State Scientific Institution “Institute for Single Crystals” of National Academy of Sciences of Ukraine, Lenin Ave. 60, 61001 Kharkiv, Ukraine, E-mail: [email protected] Sergey M. Desenko: Division of Chemistry of Functional Materials, State Scientific Institution “Institute for Single Crystals” of National Academy of Sciences of Ukraine, Lenin Ave. 60, 61001 Kharkiv, Ukraine Valentin A. Chebanov, Sergey M. Desenko: Chemistry Faculty, Karazin Kharkiv National University, Svobody sq., 4, 61022 Kharkiv, Ukraine

considered that the multicomponent reactions correspond well to the criteria of sustainability, ecology and safety [7], atomic [8] and process [9] efficiency and approach close to the “ideal synthesis” [10]. Thereby, one of the challenging problems of organic chemists is the development of novel MCRs allowing creation of structurally complex organic compounds from simple substrates. Today chemists have in their arsenal only a few MCRs that allow the synthesis of limited chemotypes of organic compounds, therefore, the design of novel multicomponent reactions is an important and attractive task. There are several main design strategies for MCRs [11, 12]: the single reactant replacement, the modular reaction sequence, the conditions-based divergence and the combination of several known MCRs. These approaches together with post-MCR cyclizations give an opportunity to somewhat increase molecular diversity and complexity. On the other hand, sometimes the potential of already known MCRs remains under-utilized for solving matters of DOS. Multicomponent reactions are not single-stage synchronous processes but tandem processes consisting of sequential stages. Treatment of the same starting materials can proceed via several tandem cascades and the final products for each cascade may differ sufficiently in their structure [13]. Thus, any three-component reaction involving reagents A, B, and C may proceed in at least three routes (Fig. 1), giving potentially different products D1, D2 and D3(Fig. 1). Therefore, the stoichiometric ratio of reagents [14, 15] or the sequence of their addition [16, 17] may significantly influence the selectivity of MCRs.

Figure 1: Possible tandem cascades for a three-component reaction involving reagents A, B and C.

© 2014 V.A. Chebanov, S. M. Desenko, licensee De Gruyter Open. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License.

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V.A. Chebanov, S. M. Desenko

In MCRs, the starting reagents may have several alternative reaction centres and this polyfunctionality increases the possibility of parallel reactions (Fig. 2a) or further intermolecular cyclizations (Fig. 2b). Thus, tuning the selectivity of MCRs, including multicomponent heterocyclizations, is an important task of modern organic chemistry due to the fact that non-optimized reactions of this type may frequently yield several products [13,18-29]. There are numerous reactions which simultaneously proceed in different

directions giving, for instance, a mixture of positionally isomeric (Scheme 1, Example 1) [22], regioisomeric (Example 2) [26], or non-isomeric (Example 3) [28] heterocycles. The development of a synthetic strategy which allows the control of the selectivity of multicomponent reactions gives an effective tool to switch reactions between several directions. This is very important for solving matters concerning diversity of organic compounds and, in particular, heterocyclic systems.

Figure 2: Polyfunctional starting reagents in MCRs: participation of alternative reaction centers (a) and post-MCR intermolecular cyclizations (b)

Scheme 1


Switchable multicomponent heterocyclizations for diversity oriented synthesis

2 Review The direction of heterocyclization is effectively influenced by the reaction parameters (nature of the catalytic system, temperature regime, type of the process activation, etc.), thereby, the solution of the problem of switching MCRs between several alternative pathways may be reduced to the searching for the optimal conditions which allow only one reaction pathway. The analysis of the known literature indicates that the main part of reviews and original articles is concerned with the partial problems of increasing enantio- and diastereoselectivity [30-34] or increasing the yields of one of the possible reaction products by application of effective catalysts [34-38], ionic liquids [39], or microwave or ultrasonic irradiation [19-45]. One of our recent reviews [13] was devoted to the heterocyclizations with controlled selectivity and in the present publication we evolve this topic with emphasis on Diversity Oriented Synthesis.

3 Kinetic control vs. thermodynamic control Numerous organic reactions may proceed either under kinetic or thermodynamic control [46] and one of the powerful and very effective tools to switch between these pathways is the variation of the reaction temperature. The classical example, included in the most organic textbooks, is the application of a temperature regime to control selectivity in the sulfonation of naphthalene proceeding at the α-position under 80oC and at the β‑position under 160oC [47] (Fig. 3a). Another well-known process of this type is the addition of HBr to 1,3-butadiene to form either 3-bromo1-butene (at -80°C) or 1-bromo-2-butene (at 40°C) [48] as the major products (Fig. 3b). There are other temperaturecontrolled organic reactions [46, 49-51], which in most cases are simple processes. However, in several recent works we showed that this approach, which generates

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molecular diversity starting from a limited number of starting reagents, may also be used for more complex three-component heterocyclizations. In order to control precisely the temperature regime and to use its broader range, many scientists apply non-classical methods of activation: ultrasonication to carry out heterocyclizations at room temperature and microwave irradiation for high temperatures processes, including higher than the solvents boiling point. Some publications contain data about the non-thermal influence of microwave irradiation on organic reactions [52-59], which is refuted in other articles [60-64], hence, it should be noted that the results discussed in the present review, in our opinion, can be justified by thermal microwave effects. Chen et al. showed [27] that the three-component reaction between 5-amino-3-methylthio-1,2,4-triazole aldehydes and derivatives of acetoacetic esters in water in the presence of p‑TsOH yielded a mixture of two heterocycles 1 and 2. This gave the potential to switch similar reactions between at least two routes. Indeed, a method of controlling the direction of the threecomponent heterocyclizations involving acetoacetamides, aminotriazoles and aromatic aldehydes has been suggested in publications [65, 66]. It was found that under ultrasonication at room temperature only the kinetically controlled reaction occurred to give the selective formation of the tetrahydrotriazolopyrimidines 3 (Scheme 2) [66]. The same reaction in refluxing DMF [66] or under microwave irradiation in ethanol [65] proceeded as thermodynamically controlled stepwise sequence and yielded dihydrotriazolopyrimidines 4. Such an approach was also effectively applied to tune a similar three-component reaction involving 4-substituted 5‑aminopyrazoles: at room temperature under ultrasonication compounds 5 were isolated as sole products of the reaction while refluxing in DMF selectively gave dihydropyrazolopyrimidines 6 [66]. It is interesting, however, that the application of the other type of 5-aminopyrazoles, containing no substituent at position 4 but having one in position 3, led to different

Figure 3: Examples of organic reactions proceeding both under kinetic andthermodynamic control


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Scheme 2

results. In this case, all attempts to carry out the MCR in boiling DMF or ethanol, which hypothetically should yield pyrazolopyrimidines 7 (Scheme 3), were unsuccessful [66] while heterocyclization under ultrasonication at room temperature, gave compounds 8 as expected. The variation of temperature becomes a much more effective tool for diversity oriented synthesis when it is combined with other methods of selectivity tuning. For instance, it was described that the three-component reaction of 5-aminopyrazoles, aldehydes and derivatives of 1,3-cyclohexanedione under conventional thermal conditions yielded a mixture of two heterocyclic systems

9 and 10 (Scheme 4) which formed via Hantzsch-type and Bigineli-type reactions, correspondingly [24, 25]. The application of non-classical methods of activation, the variation of temperature and the addition of certain catalysts allowed this reaction to proceed via three routes giving different heterocyclic systems. Thus, at room temperature under ultrasonication of the equimolar mixture of the starting materials in EtOH, without any catalyst, the MCR proceeded as a kinetically controlled reaction with the formation of the dihydropyrimidine ring (compound 12) [25]. In contrast, the microwave-assisted reaction of the same reagents in EtOH containing catalytic

Scheme 3



amounts of Et3N at 150°C enabled pyrazolopyridines 11 to be obtained selectively via the thermodynamically controlled pathway. This Hatzsch-type reaction may also be realized as an eco-friendly procedure by way of treatment of the starting materials in water under the action of microwave irradiation [67]. The third heterocyclic compound 13, which had not been obtained under the conventional conditions even in trace amounts, was selectively synthesized from the same starting materials by adding strong bases (EtONa or tBuOK) to the reaction mixture in a microwave field at 150°C [68] (Scheme 4). In this particular case, the application of microwave activation, together with strong bases and high temperature, is the key factor for the selectivity of the reaction, this is due to several factors acting simultaneously, including the very high rate of selfheating of the highly polar alcohol–alcoholate system, which may not be achieved under conventional heating [25]. In publications [25, 68] it was shown that this MCR, at room temperature, proceeded through the kinetically controlled intermediate 14, which after elimination of water was transformed into compounds 12 (Scheme 5,

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pathway A). In contrast, the thermodynamically controlled intermediate 15 was formed at high temperatures (pathway B) and its further transformation determined by the proceeding of the reaction according to route B1 or B2. In the presence of rather weak base (Et3N) the route B1 was selectively realized while the route B2 occurred only in the presence of strong base (EtONa or tBuOK) which are capable of initiating cleavage of the C–C bond (Scheme 5). However, the route B2 includes the formation of an unstabilized carbanion, making this mechanism debatable enough that necessitates further study of this multicomponent reaction. The approach based on the application of a special temperature mode under non-classical methods and special catalytic systems was also used to tune the analogous MCR involving 5-aminopyrazole, containing a carboxamide group in position 4 [69]. Thus, the three-component reaction of the starting reagents (Scheme 6) in boiling DMF, under microwave conditions (DMF, 150°C) or under ultrasonication at room temperature in pure acetic acid, always yielded pyrazolopyrimidines 16. However, the application of a DMF–HCl solvent mixture under ultrasonication switched the direction of the reaction towards the positional isomeric

Scheme 4


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heterocycles 17. It seems that in this case the role of the acidic catalyst was to promote the formation of the key azomethine intermediate (Scheme 6). Skeletal diversity of heterocyclic compounds may be introduced by the switchable three-component reaction of barbituric acids, 5-aminopyrazoles and aromatic aldehydes (Scheme 7). First of all, it was found [70] that depending on the nature of the substituent R1 under microwave irradiation or in refluxing DMF the reaction led to the formation of either pyrazolopyridopyrimidines 20 (R1 ≠ H), or their

dihydroderivatives 19 (R1 = H). On the other hand, the same MCR can be switched under ultrasonication at room temperature towards the four-component heterocyclization yielding spiroheterocycles 18. In both cases these MCRs proceed through the formation of arylidenebarbituric acid 21. Furthermore, it forms adduct 22 upon addition of 5-aminopyrazole, which is cyclized into pyrazolopyridopyrimidines 19 or 20. At room temperature the reaction also includes the formation of imine, which reacts with arylidenebarbituric

Scheme 5

Scheme 6



acid according to the mechanism of a formal aza-Diels– Alder reaction (Scheme 7). Often a slight variation in the structure of the starting reagents gives additional possibilities of increasing the diversity of the reaction products, especially, upon the application of changing temperature and other methods of selectivity control [26, 71- 76]. For example (Scheme 8), the MCR of aromatic aldehydes with 3-amino-1,2,4-triazole (R1 = H) and with pyruvic acid (R = H) in refluxing HOAc yielded azolopyrimidine carboxylic acids 24 [26] while

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introduction of an aryl substituent in aminotriazole (R1 = Ar1) switched the direction of heterocyclization towards triazolylfuranones 23 [74]. Application of arylpyruvic acids (R = Ar) instead of pyruvic acid directed the heated MCR with aldehydes and aminoazoles (R1 = H, Ar1) exclusively to azolylpyrrolones 25 [72]. On the other hand, the three-component reaction of these starting compounds (R = H, Ar, R1 = H) at room temperature under ultrasonication selectively yielded tetrahydroazolopyrimidines 26 [66, 72]. In addition,

Scheme 7

Scheme 8


50


the MCR involving some aminopyrazoles, aromatic aldehydes and arylpyruvic acids may be also controlled by the variation of temperature, enabling the heterocycles 27 or 28 to be synthesized [73].

4 Variation of parameters of the reaction medium Simple variation of the parameters of the reaction medium (e.g. the solvent and catalyst types) is an effective tool in organic synthesis and is widely used for controlling the direction of organic reactions. There are examples of multicomponent heterocyclizations which can be tuned selectively by this approach. However, most of them are not examples of switching reactions and only allow direct generation of one of the products. For instance, several publications [22,77-83] deal with MCRs between aminoazoles, active methylene compounds and aromatic aldehydes (Scheme 9). In particular, the reaction involving 3-amino-5-methylsulfanyl-1,2,4-triazole as a binucleophile reagent, Meldrum’s acid and aldehydes in a boiling ethyl acetate-pyridine system which proceeded nonselectively and yielded two regioisomeric triazolopyrimidinones 29 and 30 (Scheme 9) was described [77-82].

Use of DMF instead of this mixture of solvents allowedan increase in the selectivity of the heterocyclization with the sole formation of compound 29. Interestingly, when 3,5‑diamino-1,2,4-triazole was involved in the same MCR the situation was slightly different: the reaction in DMF yielded a mixture of compounds 31 and 32, while the reaction in methanol or 2‑propanol gave heterocycle 31. The nonselective character of the three-component heterocyclization involving two moles of acetophenone (components A and A’) and 3-amino-1,2,4-triazole (component B) is connected with the realization of two different cascades of reactions [22,83]. The reaction in the presence of ZnCl2 occurs with the formation of isomeric 4,5- and 4,7-dihydrotriazolopyrimidines 33 and 34 [22]. In contrast, when the reaction mixture contains catalytic amounts of acetic or mineral acids, only the second direction is observed (Scheme 9) [83]. There is data about multicomponent cyclizations in which the variation of solvent and/or catalyst switched the direction of the reaction to selectively obtain several final compounds. Thus, Tu et al. [84] showed the dependence of the MCR between aromatic aldehydes (component A), aminopyrazoles (component B) and cyclopentanone (component C) on the acid-base properties of the reaction medium that opened a way to obtain two

Scheme 9



different heterocyclic systems (Scheme 10). The reaction of the starting reagents under microwave irradiation at 120 °C in acetic acid underwent an initial interaction of the aldehyde with aminopyrazole with formation of azomethine. Its further reaction with the cyclopentanone molecule allowed the isolation of the angular tricyclic compound 35 (cascade (A+B)+C). In contrast, the application of basic conditions (DMF / NaOH mixture) redirected the reaction towards the initial formation of diarylidenecyclohexanone which then reacted with aminopyrazole and after elimination of water gave the

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isomeric linear tricyclic compound 36 (cascade (A+C)+B; involvement of the second mole of aldehyde, component A, at the first stage, leading to diarylidenecyclohexanone, does not play a significant role). In another publication Tu et al. [85] studied the three-component reaction of 2,6-diaminopyrimidin-4one, 4-hydroxychromen-2-one and aromatic aldehydes under microwave irradiation (Scheme 11). It was found that at 140 °C in DMF the MCR proceeded with formation of compound 39 while at 150 °C in the presence of HOAc (DMF / AcOH ratio of 4:1) the reaction was switched to

Scheme 10

Scheme 11


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selectively obtain another heterocyclic compound 38. It is clear that in this MCR a competition of the reaction centres occurs, enabling two independent directions to be taken. In both cases the multicomponent heterocyclization proceeds through the formation of adducts 37, which then can be cyclized using either the lactone fragment, leading to heterocycles 38, or the carbonyl group, yielding polycyclic compounds 39. Switching between two different pathways for the cyclization of α,β-unsaturated ketones, malononitrile and primary amines by varying the medium acidity was also demonstrated in publication [86]: the reaction in a DMFAcOH (1:4) mixture proceeds as a reaction of the ABC type with the formation of aminopyridines 40 (Scheme 12). In contrast, the same reaction in DMF proceeds without participation of the amine but as an ABB’ cyclization where malononitrile acts as both component B and B’ to give anilines 41.

Orru and co-workers [87] showed that by varying the catalyst and solvent it was possible to control the sequence of stages of the three-component reaction between α-acidic isocyanides, ketones and primary or secondary amines (Scheme 13).The most effective method of switching the reaction between the different directions to obtain either compounds 42 or compounds 43 is by carrying out the reaction with equimolar amounts of the reactants at room temperature in DMF–MgSO4 or in a methanol–MgSO4–AgOAc system, respectively. A very similar MCR involving α-isocyano-substituted amides, ketones and some primary amines may also be controlled by variation of the reaction conditions [88]: in the presence of catalytic amounts of AgOAc the MCR leads exclusively to dihydroimidazoles 45 (Scheme 13) while the addition of weak Brønsted acids allows the redirection of the reaction towards the formation of N-(cyanomethyl) amides 44.

Scheme 12

Scheme 13



5 MCRs with further intramolecular cyclization As it was mentioned in the introduction, one of the reasons for the multidirection character of MCRs is linked with possibility of intramolecular cyclization of the initial reaction products (Fig. 2b). For a real application of this that increases the diversity of multicomponent heterocyclizations, the starting materials should contain functional groups which are able to take part in intramolecular processes or the corresponding reaction centres have to be formed in the MCR. One of the classical starting reagents used in the MCRs which are followed by intramolecular heterocyclizations is o-substituted aldehydes, e.g. o-salicylic aldehyde. Thus, Gorobets et al. [28] described tuning the selectivity of three-component reactions involving acetone, 3‑amino1,2,4-triazole and o-salicylic aldehydes by varying the reaction temperature and method of activation (Scheme 14). The reaction in methanol in the presence of catalytic amounts of hydrochloric acid at 40oC led to the formation of tetrahydrotriazolopyrimidines 46, while using an ethanol–HCl system at 150oC under microwave heating allowed the selective synthesis of bridged compounds 47.

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In both cases the same cascades of tandem reactions occur in the initial stages; one of which included the intramolecular cyclization to give heterocycles 47. Apart from acetone, the authors of [28] studied other carbonyl-containing CH-acids (acetoacetate, acetoacetic esters, and 3-acetyldihydrofuran-2(3H)-one). Oxygen-bridged heterocycles were also obtained in the three-component reactions of ammonium acetate, 4-(2-hydroxyphenyl)but-3-en-2-one and different CH-acids (methyl acetoacetate, pentane-2,4-dione, dimedone [89] or Meldrum’s acid [90]); in the condensation of urea, salicylaldehyde and a carbonyl species (Meldrum’s acid [90], dimethyl acetone-1,3-dicarboxylate [91] or non-cyclic β-diketones [29, 92]); as well as by the sequential reaction of enaminonitriles with 4-(2-hydroxyphenyl)but-3-en-2one [89, 93]. Světlik and Kettmann [94] described a threecomponent reaction involving 3‑amino-1,2,4-triazole, salicylic aldehydes and acetoacetic methyl ester in boiling ethanol in the presence of hydrochloric acid, here, in place of the bridged compounds like 47, they obtained the spiroheterocycles 48 (Scheme 15). According to [94] the reaction proceeds through the intermediates 49 and 50 which then form imine 51 and undergo cyclization to spirocompounds 48.

Scheme 14

Scheme 15


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Světlik et al. [95] also described another type of MCR analogue. It was shown that the three-component reaction of 5-amino-3-methylpyrazole with salicylaldehyde and methyl acetoacetate in boiling ethanol was followed by lactonization leading to the formation of tetracyclic compound 52 (Scheme 16). However, the MCR of 5-aminopyrazole and salicylaldehydes with furan-2,4-dione in ethanol with catalytic amounts of Et3N gave dihydropyridopyrazoles 53. In this case the hydroxyl group of the salicylaldehyde was not involved in the intramolecular cyclization. The direction of the MCR involving salicylic aldehydes, pyruvic acids (R1 = H), and 5-aminopyrazoles (Scheme 17) depends on a temperature regime that allows the tuning of the selectivity towards two heterocyclic compounds, one of which is oxygen-bridged [76]. This three-component reaction can proceed either under

thermodynamic control (refluxing in acetic acid or MW heating) giving pyrazolo[3,4-b]pyridines 55 or under kinetic control (ultrasonication at room temperature) followed by intramolecular cyclization and yielding pyrazolobenzoxazocines 56. It is interesting that in case of arylpyruvic acids (R1 = Ar1) carrying out the MCR under ultrasonication yielded tetrahydropyrazolopyrimidines 54 instead of expected polycyclic pyridine derivatives like 56 (Scheme 17). The three-component reaction of salicylaldehyde, 5-amino-3-methylisoxazole and N-(2-methoxyphenyl)3-oxobutanamide was studied under different reaction conditions [96]. It was observed, that depending on the activation method and type of catalyst, three types of the final heterocyclic systems can be selectively obtained. For example, the reaction of the starting materials at room temperature by means of mechanical stirring or

Scheme 16

Scheme 17



under ultrasonication gives only chroman 57 (Scheme 18). The same reaction in the presence of ytterbium triflate leads exclusively to isoxazolopyridine 58, while application in this case of ultrasonic activation, leads to further intramolecular cyclization with formation of isoxazolobenzoxazocine 59. The MCR of the same aminoisoxazole and salicylic aldehyde with derivatives of 1,3-cyclohexanedione under

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similar conditions showed different behaviour without the formation of any oxygen-bridged heterocyclic compounds [97]. In particular, the authors observed that this reaction under microwave or thermal heating in DMF or water gave complicated mixtures containing isoxazoloquinolinones 60 and tetrahydroxanthenones 61 and 62 (Scheme 19). Variation of the reaction conditions allowed the selectivity of the heterocyclization to be tuned. In

Scheme 18

Scheme 19


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the presence of Brønsted or Lewis acids heating the starting materials in DMF or H2O led to the formation of isoxazoloquinolinones 60, while ultrasonication in EtOHEt3N gave mixtures of both tetrahydroxanthenones 61 and 62. Compound 62 may, in turn, be selectively obtained by the reaction of the reagents in boiling DMF when the second equivalent of salicylic aldehyde is added. It is most likely that this three-component reaction occurs via the formation of the Michael adduct 63 (Scheme 19), then further cyclised [97]. However, there are two alternative nucleophilic reaction centres which are able to take part in the heterocyclization, the NH2- and OH-groups. Acidic catalysis with Brønsted or Lewis acids promotes the Hantzsch type of MCR (where the NH2-group is the reaction centre), while basic conditions redirect the reaction towards the formation of xanthenones 61 and 62 (where the OH-group is the reaction centre). Apart from reactions which involve salicylic aldehydes other examples of intramolecular cyclizations have been published which increase the diversity of MCRs. Thus, post-Ugi heterocyclizations activated by gold(I)- and platinum(II)-catalysts lead to two types of compounds, as described by Van der Eycken et al. [98, 99]. They observed that Ugi-adduct 64, obtained by the four-component reaction between 2-formylpyrrole, a primary amine, an alkynoic acid and an isonitrile, in the reaction with Au(PPh3)OTf in chloroform at 50°C gave pyrrolopyridinones 65 via an exo-dig cyclization (Scheme 20). On the contrary, the reaction of the adduct 64 with PtCl2 under the same conditions via endo-dig cyclization yielded exclusively pyrroloazepinones 66. However, it was found [99] that this approach did not work in tuning the selectivity of MCRs involving 2-formyl derivatives of thiophene, indole and benzothiophene. In all these cases only the corresponding fused azepinones were obtained in the MCRs.

6 Influence of structure and other factors Protecting and activating (or deactivating) groups, steric effects, the electronic character of substituents, and the order of addition of starting reagents, etc. may frequently effect the direction of heterocyclization reactions. Some examples where the structure of starting reagents influences the behaviour of MCRs have already been described above. For some cases the structural factor was only one of several parameters which allowed the tuning of the selectivity of multicomponent heterocyclizations. Additionally, several other publications showing such an influence may be noted. For instance, the direction of the MCR involving 5-aminopyrazoles, aromatic aldehydes and acetoacetamides depends on several structural features (Scheme 21). The presence of the aryl substituent at position 3 of 5‑aminopyrazole enabled the selective formation of pyrazolopyrimidines 69. In case of 5-amino3‑methylpyrazoles, the electronic character of the substituent in the aldehyde component, affected the outcome allowing both pyrimidines 67 (electronwithdrawing substituents) and pyridines 68 (electrondonating substituents) to be obtained. Under ultrasonic irradiation at room temperature the acetoacetamides were not involved in the interaction, and the MCR finished with the formation of azomethines 70 irrespective of substituent type [54]. Cheng et al. showed [100] that varying the R substituent in 2-vinylindoles may influence the direction of the MCR with anilines and aldehydes (Scheme 22). It was described that R = methyl, benzyl, tosyl or allyl, forced the MCR to proceed towards the tetrahydroγ‑carbolines 72. In contrast, when R = H, the reaction

Scheme 20



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Scheme 21

Scheme 22

yielded tetrahydroquinolines 71 via an inverse aza-Diels– Alder reaction. The direction of the three-component reaction between aromatic aldehydes, anilines and mercaptoacetic acid depends on the character of the substituent in the aldehyde component [101]: when R = 4-F, 4-Cl and 4-Br

the heterocyclization gives thiazolidinones 74 while in all other cases the sole products of this reaction are 1,4-thiazepines 73 (Scheme 22). Světlik et al. described [91] the unusual influence of substituents in acetone-1,3-dicarboxylates on their behaviour in the MCR with salicylic aldehyde and (thio)


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urea. They showed that diethyl ester (R = Et) reacted in this MCR under solvent free conditions, in the presence of TsOH (2 mol%) at 80°C with the formation of dihydropyrimidine 75 (Scheme 23). The use of dimethyl acetone-1,3-dicaboxylate (R = Me) under the same conditions gave the oxygen-bridged heterocycle 76 as the sole reaction product. In this case, steric control seems to be the key factor in determining the structure of the final compounds. According to [91] the formation of an oxygen-bridged heterocycle depends on the effective distance between the phenol ortho-hydroxyl and pyrimidine C-6 atom. The optimal conformation for intramolecular cyclization to occur (where the distance between the reaction centers is 3.2 – 3.5 Å) is less likely for the diethyl ester than the dimethyl derivative due to the steric influence of ethoxycarbonyl moiety. In a very similar MCR between urea, salicylic aldehyde and acetoacetate or the methyl or ethyl esters of acetoacetic acid in boiling EtOH in the presence of PdO Jing et al. [92] exclusively observed the formation of tricyclic compounds 77 (Scheme 23). The steric influence of the substituents R1 and R2 in the amine component plays an important role in the direction of its MCR with 1,3-thiazolidinedione, malononitrile, and aromatic aldehydes (Scheme 24) [102]. In case of dimethylamine, piperidine or morpholine the heterocyclization yielded derivatives of dihydrothiophene 78. On the other hand, sterically bulky diisopropylamine

changed the direction of the cyclization towards the formation of spirocompounds 79. In both cases the reaction proceeds via the key intermediate 80. This can then be attacked by a small amine at the carboxamide group with opening of the thiazolidinedione ring which is followed by cyclization to give dihydrothiophenes 78. For the second pathway the secondary amine plays the role of catalyst, while intermediate 80 reacts with the second molecule of arylidenemalononitrile yielding compounds 79. Orru and co-authors [103] established that the choice of the carbonyl component influenced the direction of the three-component reaction of isocyanidopyridinone with carbonyls and primary or secondary amines (Scheme 25). Aliphatic aldehydes and ketones gave the expected oxazolopyridines 81. Whilst in case of benzaldehyde (R4 = Ph, R5 = H) and paraformaldehyde (R4 = R5 = H) the reaction yielded iminoimidazilidines 82 as side compounds. Gladkov et al. [104] found that the threecomponent reaction involving aromatic aldehydes, sulfonylacetone and urea or 3-amino-1,2,4-triazole may be switched between two different directions depending on the structure of the nitrogen-containing binucleophile (Scheme 26). When aminotriazole was used as binucleophile component the reaction under microwave conditions (DMF, 135°C) proceeded as a Biginelli-type heterocyclization with the formation of

Scheme 23



Scheme 24

Scheme 25

Scheme 26


59

60


dihydroazolopyrimidines 83. On the other hand, the introduction of urea (a classical reagent of the Biginelli reaction) to the same reaction gave, unexpectedly, the unusual product of a Hantzsch-type heterocyclization. This proceeded as an ABCC’ four-component reaction with chemodifferentiation of the ketosulfone, decomposition of urea and formation of the dihydropyridines 84. Qui et al. [15] showed that the direction of the three-component reaction of several symmetric iodinecontaining carbodiimides with primary amines and tertbutyl isocyanide (Scheme 27) was influenced by the stoichiometric ratio of the reagents. Thus, the tetracyclic compounds 85 containing two isocyanide fragments were formed when three equivalents of isocyanide were used. Product 86 which incorporates one molecule of isocyanide can be obtained using 1.1 equivalents of the isocyanide in the presence of tBu3P. As mentioned above, the addition sequence of substrates may also influence the pathway of multicomponent reactions giving another method of

switching them between several different directions. For example, Jing and co-authors [17] observed such an influence when they studied the reaction involving methyl 4-oxo-4-phenylbut-2-enoate, aniline and phenyl diazoacetate (Scheme 28) to obtain pyrrolidine 90 via an aza-Michael addition/ylide generation sequence with compounds 87 and 88 treated at the first stage of the one-pot reaction ((A+B)+C cascade, path I). In contrast, the realization of ylide generation/aza-Michael addition sequence ((B+C)+A cascade, path II) gave linear α-amino ester derivative 91. It should be noted that both reactions gave the final compounds with high degree of diastereoselectivity (ca. 9 : 1). Soleimani et al. [105] described the behavior of the reaction between 2-formylbenzoic acid, malononitrile, some isocyanides and primary amines in four-component and one-pot variants (Scheme 29). The simultaneous reaction of all starting reagents in ethanol at room temperature allowed non-heterocyclic compounds 92 to be isolated.

Scheme 27

Scheme 28



61

Scheme 29

On the other hand, when the starting materials reacted in a one-pot variant through the three-component reaction of malononitrile, formylbezoic acid and isocyanide (CH2Cl2, room temperature), the reaction proceeded to give formation of compounds 93. The subsequent addition of primary amine gavespiroheterocycles 94 as the sole reaction products.

7 Conclusion In summary, the comprehensive analysis of the literature demonstrates the high potential of switchable multicomponent heterocyclizations for Diversity Oriented Synthesis. This opens up the possibilities for efficient synthesis of diverse heterocyclic scaffolds from a limited set of starting materials. One of the main problems in the field of modern organic chemistry is the development of a strategy which allows tuning of the chemoselectivity of multicomponent reactions. In numerous cases this was solved by application of approaches such as the variation of the nature of the reaction medium, catalytic system, temperature regime, type of activation, etc.

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