Aminoazole-Based Diversity-Oriented Synthesis of Heterocycles

The comprehensive review contains the analysis of literature data concerning reactions of heterocyclization of aminoazoles and demonstrates the application of these types of transformations in diversity-oriented synthesis. The review is oriented to wide range of chemists working in the field of organic synthesis and both experimental and theoretical studies of nitrogen-containing heterocycles.


INTRODUCTION
Heterocyclic compounds are backbone of drug design-about 80% of the known small molecule drugs belong to this type of substances and among them 60% relates to nitrogen containing heterocycles (Kombarov et al., 2010;Vitaku et al., 2014;Taylor et al., 2016). On the other hand, heterocyclic compounds play important role in other branches of science and are the base of all living organisms. Therefore, study of the appropriate field of organic chemistry is a very important challenge that has been attracting attention of numerous scientific groups for last decades and stimulating for detailed study of the topic including the search for novel and development of known synthetic methods.
One of the important pathways to nitrogen containing heterocycles is reactions of aminoazoles (two-component, one-pot, multicomponent, etc.) being efficient mono-, bi-and polynucleophiles with different electrophiles. The presence of several alternative reaction centers in aminoazoles often makes them useful reagents in controlled multidirectional interactions providing the possibility to synthesize diverse chemotypes of final products (see some examples in Figure 1). Such approach is widely used in the modern heterocyclic chemistry and some books and reviews have been already published in this field (Desenko, 1995;Chebanov and Desenko, 2006Chebanov et al., 2008aChebanov et al., , 2010Moderhack, 2011;Sedash et al., 2012;Tkachenko and Chebanov, 2016;Aggarwal and Kumar, 2018), however, many of them deal with particular problems of aminoazole chemistry and actually during long period no comprehensive analysis of the problem has been made.
Thus, the present review is devoted to diversity-oriented reactions of heterocyclization involving aminoazoles as a key reagent. It presents analysis of literature mainly from 2010 till present and three main types of such reactions are discussed: multicomponent reactions including application of condition-based divergence strategy for the control of their directions; twocomponent heterocyclizations and one-pot cascade processes; "click"-chemistry concerning azoles and aminoazoles.

Multicomponent Reactions of Aminoazoles Involving Cyclic CH-Acids
Multicomponent reactions (MCRs) involving aminoazoles and aldehydes with cyclic CH-acids (different ketones, 1,3diketones, Meldrum's acid etc.) are similar to the classic Hantzsch or Biginelly condensations. In early publications they had often resulted in the formation of mixtures of positional and regioisomers, therefore, some efficient methods for tuning chemo-and regioselectivity of such multicomponent heterocyclizations, including Condition-based divergence strategy to switch their directions by simple variation of the reaction conditions (solvent, temperature, method of activationmicrowave irradiation (MW) and ultrasonication (US), catalyst, etc), were found and developed (Desenko, 1995;Desenko, 2006, 2012;Chebanov et al., 2008aChebanov et al., , 2010Ruijter et al., 2011).
In the process of optimization, the new multicomponent reaction was found: t-BuOK being a stronger nucleophile then Et 3 N attacked the carbonyl group of cyclic 1,3-diketone moiety in the intermediate which resulted in the ring opening and recyclization with the formation of quinolizinones 8. Later on the greener methodology of obtaining pyrazoloquinolinenones 6 was elaborated using microwave synthesis in water (170 • C, 10 min; Andriushchenko et al., 2011). Similar to compounds 6 pyrazoloquinolinenones 9 were synthesized even without solvent using L-proline as a catalyst (MW, 110 • C, 15 min; Bhattacharjee et al., 2016).
The analogous to heterocycles 7 linear quinazolinones 10 were obtained on the basis of 3-amino-1,2,4-triazole (5a) applying the great variety of conditions (only the endocyclic aminogroup in the position 2 took part in the condensation; Puligoundla et al., 2013;Petrov and Kasatochkin, 2014;Vibhute et al., 2017a,b). It should be noted, that in all cases tetrahydroderivatives 6-10 were formed. However, Petrov and Kasatochkin (2014) oxidized partially hydrogenated pyrimidine ring of 10 to obtain compounds 11 using ceric ammonium nitrate (CAN) in acetone. Later on the compounds 11 were synthesized in the three-component reaction of 1, 2a and 5a in water under microwave irradiation also with application of CAN (Figure 2; .
Using 5-aminopyrazoles 41 bearing carboxamide fragment in the fourth position in condensations with 1,3-cyclohexanediones 2a,b and aromatic aldehydes 1 led to widening the scope of target compounds whereas varying reaction parameters and applying non-classical methods of activation (ultrasonication and microwave irradiation) allowed to switch cyclizations between several directions (Figure 4; Chebanov et al., 2012b).
Thus, condensation of starting reagents 1, 2a,b, and 41 upon heating or MW irradiating in DMF or ultrasonication in HOAc at room temperature always afforded tricyclic dihydropyrimidines 42. Addition of catalytic amounts of hydrochloric acid resulted in switching the reaction to another direction and yielding positionally isomeric angular compounds 43. Implementation of the third route with the formation of acrydindiones 44 occurred upon increasing the temperature and introducing the double excess of diketone 2 (Chebanov et al., 2012b).
Meldrum's acid is also widely used as a building block for the synthesis of azoloazine systems. A significant contribution to the study of the condensations involving aminoazoles and aldehydes with Meldrum's acid was made by Lipson's group (Figure 4; Lipson and Gorobets, 2009). It was established, that in some cases these multicomponent reactions afforded positional isomers. For example, condensations involving 3-amino-5-methylthio-1,2,4triazole (46) gave 5-pyrimidinones 50a or 7-pyrimidinones 50b with impurities of 50a depending on solvent and catalyst (Lipson and Gorobets, 2009).
The presence of four non-equivalent reaction centers in 1,2-diamino-4-phenylimidazole (57) makes possible new alternative reaction routes with electrophilic reagents. Due to the lower nucleophilicity of exocyclic amino groups in comparison with endocyclic CH-group, 1,2-diaminoimidazoles in the reactions with α,β-unsaturated ketones, their mono-and dibromo derivatives, with aroylacrylic acids, and in the three-component reactions with aldehydes and Meldrum's acid formed not triazepine fragments but pyridazine and pyrimidine systems fused with azole cycle (Lipson et al., 2012). This fact was also confirmed in the multicomponent reaction involving 1,3-cyclohexanediones 2a,b upon boiling in DMF (1 h) or methanol (2 h) which resulted in the formation of dihydroimidazo[1, 5-b]cinnolinones 58. Only in case of 4-nitrobenzaldehyde 1 the short-term boiling the compounds 1, 2 and 57 in DMF led to the formation of heteroaromatic derivatives 59 ( Figure 5; Lipson et al., 2012). N-Unsubstituted 2-aminoimidazole exhibited similar properties (lower nucleophilicity of exocyclic aminogroup than endocyclic reaction centers) in the reactions with aromatic aldehydes and different CH-acids (dimedone, barbituric acid), but instead of cyclic products the treatments yielded Michael adducts (with participation of CH-center in the position 3; Andriushchenko et al., 2013). On the other hand, the formation of Mannich bases in the similar reactions involving 2-aminothiazole indicates on the higher reactivity of its exocyclic NH 2 -group in comparison with the endocyclic nucleophilic centers (Ghatole et al., 2015).
When Meldrum's acid was used, different compounds−4,7dihydroisoxazolo [5,4-b]pyridine-6(5H)-ones 68 (6-9 min) or spiroheterocycles 69 (9-13 min) were got under almost the same conditions by Tu et al. in two consecutive publications (Tu et al., 2009;Ma et al., 2010). Later on Morozova et al. (2017) reproduced the synthesis of compounds 68 and 69 under the same conditions, however, all the attempts gave only the mixtures of compounds 68 and 69 or heterocycles 69 were isolated in the lower yields than in the previous work (Tu et al., 2009). Therefore, Morozova et al. (2017) studied in details the reactions of 5-amino-3-methylisoxazole (60a) and aromatic aldehydes 1 with Meldrum's acid (45) and developed the preparative methodologies for selective synthesis of the products 68 (boiling in DMF or n-BuOH) and 69 (ultrasonication in EtOH).
In A multicomponent reaction involving 2-aminobenzimidazole (48), cyclohexanedione (2a) and arylglyoxales 83 was thoroughly studied by Petrova et al. (2015b); all the compounds including intermediates were isolated in individual form, characterized and their structures were proven with the help of X-Ray analysis (Figure 7).
It was established that the reaction of the reagents 2a, 48, and 83 in ethanol at room temperature for 5-10 min yielded Michael adduct 87 that remained stable upon latter refluxing in primary alcohols. However, after adding the second equivalent of cyclohexanedione (2a) and further prolonged refluxing the reaction mixture in ethanol salts 90 were isolated. All the attempts to convert them into the products of condensation with FIGURE 10 | MCRs involving α-aminoazoles, aldehydes and non-cyclic carbonyl compounds.
2-aminobenzimidazole (48) upon refluxing in DMF or acetic acid or fusion under neat conditions were unsuccessful. In all cases the mixtures of xanthenediones 91 and salts 92 were obtained.
The authors (Petrova et al., 2015b) established that Michael adduct 87 had been also formed after heating the starting reagents in acetic acid at 100 • C; after longer heating, they turned into condensed quinazolinones 88. Microwave irradiation of the starting reagents 2a, 48, and 83 in DMF (150 • C) afforded to get heterocycles 89 as the main products (Figure 7).
Linear pyrazolopyridinones 93 (Petrova et al., 2015a) were synthesized by the condensation involving 5-amino-3methyl-pyrazole (4) and arylglyoxales 83 with indane-1,3dione (22a) upon short-term heating in ethanol. Further prolonged treatment of compounds 93 at room temperature in isopropanol with the addition of KOH led to their transformation into heteroaromatic derivatives 94. When the authors (Petrova et al., 2015a) applied 5-aminopyrazole 21 containing an aryl substituent in the first position, in the
compounds (pyruvic acid and its derivatives), malonic acid and its derivatives, cyanoacetamide etc.
Recently published review by Sedash et al. (2012) clearly illustrates the diversity and complexity of MCRs of aminoazoles, carbonyl compounds and non-cyclic CH-acids on the example of the Biginelly-type transformations involving 3-amino-1,2,4triazoles as 1,3-binucleophiles. It was shown that the stepwise character of the MCRs themselves and polyfunctional character of that 1,3-binucleophile could lead to at least eight possible products A-H from one set of the starting reagents usually depending on the reaction conditions (and sometimes specific structure of the starting reagents themselves). The pairs A-B,

C-D, E-F, and G-F could be considered as positional isomers whereas the pairs A-C, B-D, E-G, and F-H-as regioisomers.
As a consequence of such diversity of the possible reaction products their structural elucidation often becomes problematic (Figure 8).
The authors (Sedash et al., 2012) explored the literature dealing with this type of reactions and concluded that the existing data about the structure of the reaction products A-H was not always comprehensive and found that most of the literature sources concerning Biginelli-like MCRs involving 3-amino-1,2,4-triazoles had described structure A as the most usual product under quite harsh conditions and different reagents (acetophenone, ethyl and methyl esters of acetoacetic acid and its fluorinated derivatives, substituted amides of acetoacetic acids, pyruvic acid, 1-(methylsulfonyl)propan-2-one and 2-(methylsulfonyl)-1-phenylethanone, aliphatic ketones). The structure C was sometimes reported as a side product accompanying the formation of the main product A (in the reactions with pyruvic acid or methyl acetoacetate). Only the condensation involving acetylpyrazole derivative afforded compound of structure C as the only product (Ali et al., 2016). Tetrahydroderivatives of type F were described in the reactions under mild conditions (with phenylpyruvic acid or ethyl acetoacetate). Products of E-type could be obtained on the basis of fluorinated esters of acetoacetic acid and further converted into A-type heterocycles thus being the products of kinetically and thermodynamically controlled reactions. The products of structure B could be formed when two molecules of acetophenone (or cyclohexanone, see compound 14, Figure 2) reacted with 3-amino-1,2,4-triazole derivatives. The products D were not obtained by Biginelli-like MCRs, they could be synthesized using other approaches whereas products of structure G and H were not described at all (Figure 8; Sedash et al., 2012).
It is worth noting that the analogous behavior of 5aminopyrazoles substituted in the fourth position with electronwithdrawing groups [CN, CO 2 CH 3 , CONH 2 (Muravyova et al., 2011)] in the condensations being similar to the described above and leading to tetrahydro-and dihydropyrimidines of types 99 and 100 as well.
It should be noted, that Thorat et al. (2013) obtained imidazopyrimidines (EtOH-ionic liquid catalyzed, r.t.) with another positional orientation of substituents than in compounds 102b. However, there was not enough data (2D NMR experiments or X-Ray analysis) proving that structure while the structure of azolopyrimidines 102 was proven with the help of X-Ray analysis in cases of heterocycles 102d (Zhao et al., 2013) and 102e (Zhao et al., 2014).
The introduction of 1-and 4-unsubstituted 5-aminopyrazoles (3, 4, 29 or 113) to the reactions with aldehydes and CHacids enables the formation of the regioisomers. Thus, 4,7-dihydropyrazolopyridines 117a were the products of condensation of 5-aminopyrazoles 3, 4 or 29 and aldehydes 1 with substituted 3-oxopropanenitriles 114 (A: DMF-Et 3 N, ). The volatile substances were removed from the reaction mixture and the residue was oxidized with sodium nitrite in acetic acid (B), which resulted in isolation of pyrazolopyridines 118a (Hill, 2016). Regioisomeric pyrazolopyrimidines 117b were formed under the same conditions when 5-aminopyrazoles contained a sufficiently large substituent R 3 at position 3 (for example, tert-butyl in compound 113) which complicated the electrophilic aromatic substitution with the participation of the C4 nucleophilic center in the aminopyrazole 113 and led to cyclization into compounds 117b. The authors (Hill, 2016) also discovered the steric influence of an aldehyde component 1 on the ratio of products 118a and 118b in the mixture (Figure 9). Analogous to heterocycles 117a dihydropyrazolopyridines were isolated as a result of heating the compounds 1, 4 and 114 in ethanol with adding Fe(III)-montmorillonite (Mamaghani et al., 2013).
When methyl cyanoacetate 116 was introduced into the reaction with compounds 1 and 4 under refluxing in ethanol (Mahdavinia and Rahmati, 2015) or ethanol with p-TSA (Rahmati, 2010) 6-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridines 120 were obtained. Isomeric pyrazolopyrimidinones 119 (Hossein Nia et al., 2014) were isolated in the condensation involving dimethyl malonate 115 under ultrasonication in THF with adding of Fe 3+montmorillonite (Figure 9). Cyclizations involving acetoacetic acid derivative 98e proceeded involving endocyclic amino group of 5-aminopyrazole 4 with the formation of dihydropyrimidines 121 (Finlay et al., 2012(Finlay et al., , 2013. Steric and electronic effects of a substituent R in aldehyde 1 significantly influenced the ability to oxidation of dihydropyrimidine cycle in the condensations involving 5-amino-3-methylisoxazole (60a) and aromatic aldehydes 1 with N-arylacetoacetamides 98c. Thus, under identical conditions (n-BuOH, , oxygen of air) dihydropyridines 122 were isolated only in case of para-halogeno-and orthosubstituted aldehydes 1. The authors (Tkachenko et al., 2014b) associate this with the electronic influence of the halogenaryl moiety or the steric effect of ortho-substituents, which complicates the oxidation of heterocycles 122 to 123. In case of other aldehydes such conditions led to the formation of heteroaromatized systems 123. Only carrying out the reaction in the argon atmosphere afforded isolation of dihydropyridines 122 (except hydroxy-substituted ones). However, blowing oxygen through their ethanol solutions led to the transformation of compounds 122 to 123 (Figure 10).
A special attention should be also paid to the multicomponent reactions of aminoazoles and aromatic aldehydes with pyruvic acid and its derivatives, especially because of the ambiguity in the realization of directions of such processes. Chebanov's group (Chebanov et al., 2005(Chebanov et al., , 2007a(Chebanov et al., , 2012aSakhno et al., 2008Sakhno et al., , 2010Sakhno et al., , 2011Sakhno et al., , 2015 contributed a lot to studying both stepwise and MCR reactions involving pyruvic acid and aminoazoles and showed that their chemo-and regioselectivity, positional orientation of the substituents in the final products significantly depend on the reaction parameters and structure of the starting reagents. Thus, in the heterocyclizations involving 3-amino-1,2,4triazole (5a) and aromatic aldehydes 1 with pyruvic acid (140a) (R 1 = H) dihydrotriazolopyrimidines 144 (Chebanov et al., 2005) with the same positional orientation as for acetoacetic acid reaction (heterocycle 100, Figure 8) were formed (HOAc, , 4 h). When compounds 1, 5a, and 140a were refluxed in DMF dihydrotriazolopyrimidine 144 was obtained in a mixture with regioisomer 145 (which was impossible to isolate in a pure state). Later on it was found that prolonged heating of compounds 1, 5a, and 140a (HOAc, , 65 • C, 48 h) also afforded tetrahydroderivatives 143  that could be converted into dihydropyrimidines 144 after refluxing in HOAc for 4 h (Figure 11).
Heterocyclizations involving 5-aminopyrazolecarboxamides (Chebanov et al., 2007a) under the same conditions afforded products of types 141, 142 and 144 that again indicated on the similar behavior of substituted in the position 4 pyrazoles and 3-amino-1,2,4-triazole that had been already mentioned for the condensations with acetoacetic acid derivatives (see Figure 8).
The analogous tetrahydropyrazolopyrimidines 160 (Sakhno et al., 2018) were synthesized in the reaction of 3-aryl-4-alkylsubstituted 5-aminopyrazoles 158 and aromatic aldehydes 1 with alkyl pyruvates 149 in acetic acid at room temperature. At the same time refluxing compounds 1, 149 and 158 in acetic acid for 7 h led to the formation of a pyrimidine ring followed by an oxidative heteroaromatization process which gave 6-hydroxysubstituted alkyl pyrazolopyrimidine-5-carboxylates 159 (Sakhno et al., 2018). That was explained by disproportionation process; it was confirmed by carrying out this reaction in the inert atmosphere (where neither dihydropyrazolopyrimidine nor the compound without a hydroxyl group was observed). As it was expected, heterocycles 160 were transformed into heteroaromatic derivatives 159 upon boiling in acetic acid for 9 h (Figure 11).
Varying the conditions of the reaction and structures of the starting reagents afforded to synthesize three different classes of compounds 166-168 from the same reagents (Tkachenko et al., 2014a). Ultrasonication of 5-amino-3-methylisoxazole (60), N-aryl-3-oxobutanamide (161) and salicylaldehyde (162)  It's worth to note, that in case of other substituted N-aryl-3-oxobutanamides 161 (R 1 = 2-OH, 2-CH 3 , 2-Cl, 3-Cl) only heterocycles 167 were isolated both with the help of mechanical stirring and under ultrasonication. The authors (Tkachenko et al., 2014a) suppose that the direction leading to benzoxazocines 166 is favored by the formation of 3-coordinated complex of Yt(OTf) 3 with NH-and CH 3 O(C 2 H 5 O)-groups of carboxamide fragment and OH-group of intermediate tetrahydroisoxazolopyridine. In turn, ultrasound supplies to the reaction system a sufficient amount of energy that is needed for nucleophilic substitution and bridged moiety formation (Figure 12).

Other Multicomponent Reactions of Aminoazoles
Isocyanide-based reactions may be separated into an individual large group and certainly should be described in special reviews, a lot of brilliant examples of which have already been published (Dömling and Ugi, 2000;Banfi et al., 2010;Ruijter et al., 2011;Dömling et al., 2012;Cioc et al., 2014;Koopmanschap et al., 2014;Devi et al., 2015;Zarganes-Tzitzikas et al., 2015;Shaaban and Abdel-Wahab, 2016). As it's recognized the classical components of the Ugi four-component reaction (Ugi-4CR) are aliphatic or aromatic amines and aldehydes, carboxylic acids and substituted isocyanides, that are generally well responsive to the formation of Ugi products at room or slightly elevated temperatures (Dömling and Ugi, 2000;Dömling, 2006). Groebke-Blackburn-Bienaymé three-component reaction (GBB-3CR) usually undergoes with participation of 2-aminoazines or 2-aminoazoles, aromatic or aliphatic aldehydes and substituted isocyanides. Brønsted or Lewis acids are often used in GBB-3CR (sometimes in Ugi-4CR) for activation of intermediate imine. Almost all the types of solvents (including water and ionic liquids) and catalysts, different temperature regimes (conventional or microwave heating) were studied in GBB-3CR (Figure 14; Devi et al., 2015).
Although there are a lot of variations and modifications known for the Ugi-4CR there is only one example of using aminoazole as an amine component in this reaction, which includes the treatment of 3-amino-5-methylisoxazole, aromatic aldehydes, phenylpropiolic acid and tert-butylisocyanide with formation of Ugi-product 182 (Figure 14; Murlykina et al., 2017).
Application of heterogeneous solid base, silica sodium carbonate (SSC) as a catalyst allowed isolation of dimethyl 4, 5dihydrotriazolopyrimidine-6,7-dicarboxylates 196 in the MCR of dimethyl acetylenedicarboxylate (195) with 1 and 5a. The authors (Karami et al., 2015b) suggested that the base favors the formation of an intermediate product of condensation between nucleophilic NH in the position 2 of 3-amino-1,2,4-triazole (5a) and electrophilic CH-center of dimethyl acetylenedicarboxylate (195) followed by the attack of aldehyde 1, cyclization and dehydration (Figure 15).
In some cases, synthesis of starting materials for MCRs is also a difficult task. For example, the formation of acetoacetamide building-block by synthetic methods is an expensive and difficult procedure. Therefore, to avoid laborious stage of acetoacetamide synthesis, as a continuation of the work of Shaabani et al. (2009) four-component procedure for obtaining N,7-disubstituted-5-methyl-4,7-dihydrotetrazolo[1,5a]pyrimidine-6-carboxamides 199 (Zeng et al., 2012) was elaborated. It consisted of the reaction of primary amines 198, diketene 197, 5-aminotetrazole (5b) and aldehydes 1 (EtOAc-I 2 , , 78 • C, 4 h). In this MCR acetoacetamide was formed in situ by the addition of amine to diketene molecule (Figure 15).

Two-Component Condensations of Aminoazoles
To the best of our knowledge the condensations of aminoazoles with α,β-unsaturated carbonyl compounds 200 could be performed as one of the simplest and effective ways to the diverse azoloazine systems, such as 203, 204, since this type of starting materials usually contains alternative nucleophilic and electrophilic reaction centers. The most utilized α,βunsaturated carbonyl compounds in such reactions are chalcones or cinnamic acid derivatives. The condensations of the enones with aminoazoles could be performed in various solvents within wide range of the temperatures and with application of different types of catalysis (Kolos et al., 2011;Yoshida et al., 2011;Orlov and Sidorenko, 2012; Figure 16).
Two-component heterocyclizations of the aminoazoles could be considered as convergent procedures concerning the corresponding multicomponent synthesis, or as independent transformations. Thus, in the previous section of the review it was shown that multicomponent heterocyclizations of the pyruvic acid derivatives with α-aminoazoles and carbonyl compounds could be applied for the synthesis of diverse heterocyclic systems. However, preliminary condensation of the pyruvic acid with aromatic aldehyde gives arylidenepyruvic acids 205 and their further reaction with 5-aminopyrazoles 150 in comparison to the multicomponent procedure allows to obtain different regioisomers 208, 209 (Chebanov et al., 2007a(Chebanov et al., , 2012a. At the same time, in the article (Sakhno et al., 2011) it was shown that the two-component condensation of arylidenepyruvic acid 205 and 1-(4-chlorophenyl)-3,5-diamino-1,2,4-triazole (5c) in DMF resulted in the formation of the same furanones 148 as in the corresponding MCR, however, in smaller yields (Figure 16).
The opposite pattern was observed in case of the 5-amino-3methylisoxazole (60a) (Morozova et al., 2016). Multicomponent condensation of this aminoazole, pyruvic acid and aromatic aldehyde resulted in the decomposition of the initial amine due to the low stability of the isoxazole moiety in the acidic media. Application of the two-component procedure, via preliminary synthesis of unsaturated acids 205, under Sc(OTf) 3 catalysis in CH 2 Cl 2 :H 2 O (20:1) allowed to isolate compound 211 in low yields. An unexpected result was obtained when the unsaturated acid was replaced by the corresponding ethyl ester 212: the condensation of the starting reagents in MeCN containing Sc(OTf) 3 at −18 • C resulted in the formation of tetrahydroisoxazolopyridine system 213. Typically, such compounds cannot be isolated due to the fast water elimination with the formation of dihydropyridine rings. Indeed, the condensation at higher temperatures led to the formation of dihydropyridine 214, which was further spontaneously oxidized (Figure 16).
The condensation of ethyl arylidenepyruvate 212 with 5aminopyrazoles 158 in acetic acid without additional catalyst (Sakhno et al., 2018) had a different character and allowed to isolate both pyrazolopyrimidines 159 (under heating) and dihydropyrazolopyrimidines 216 (at room temperature) having OH-group in position 6 (Figure 17). The yields of the product 159 for this two-component condensation were better in comparison to the multicomponent procedure (Figure 11).
The application of 1,3-dielectrophiles in the azoloazine synthesis is not limited to the enones. β-Dicarbonyl compounds, for example, derivatives of acetylacetone 98 and acetoacetate 225 (Marjani et al., 2015) are used for the formation of the pyrimidine ring with substituents in positions 4 and 6. The asymmetric βdicarbonyl compounds can produce positional isomers, but often the reactions give only one compound. The aminoazoles with pyrrole N-atom in the α-position to the NH 2 -group are most often used as 1,3-binucleophiles (Gujjar et al., 2011;Ivachtchenko et al., 2011;Gege et al., 2012;Patnaik et al., 2012; Figure 17).
Among reactions involving β-diketones there is rather interesting condensation of 5-aminopyrazole 158 and dehydroacetic acid 227 (Aggarwal et al., 2014). It was found that the reaction did not stop on the formation of 228: the presence of the reactive toward 5-aminopyrazole acetylacetone fragment induced further condensation with the second molecule of the amine 158 that gave bis(pyrazolo[1,5-a]pyrimidinyl)-7-ones 229 (Figure 18).
Despite the fact that compounds containing 4H-chromen-4-one moiety don't have real 1,3-dicarbonyl fragment in the presence of alkali in the reaction mixture the ringopening process with the generation of the corresponding 1,3dicarbonyl compound takes place (Zhang et al., 2011). In such way 7-diphenylpyrazolo[1,5-a]pyrimidine derivatives 232 were synthesized by the condensation of isoflavone 230 and 3-aminopyrazole (31) in MeOH-MeONa in moderate to good yields (Figure 18).
Quite interesting heterocyclizations of 5-aminotetrazole were reported by Goryaeva et al. (2015): heterocyclization of 5aminotetrazole (5b) and 2-ethoxymethylidene-3-oxo esters 240, depending on the ester type and/or the condition, could give 2-azidopyrimidines 241 or tetrazolo[1,5-a]pyrimidines 242. The starting materials under refluxing in EtOH or 1,4-dioxane didn't react completely even after long duration of the treatment and resulted in the formation of inseparable mixtures. Carrying out the reaction in the 2,2,2-trifluoroethanol (TFE) gave 2azidopyrimidines 241 due to the opening of the tetrazole ring. At the same time, 4-methyl-2-azidopyrimidine was not stable and converted into the 242 even while standing as solid on air. The synthesis of the substance 242 could be carried out in EtOH at r.t. from 5-aminotetrazole (5b) and ester 240, the presence of the 241 was indicated by TLC in the reaction mixture, which allows to assume that the reaction could pass through the formation of azide (Figure 19).
Despite the fact that the condensation of 5-aminotetrazole (5b) with the fluorinated reagents in 1,4-dioxane resulted in the mixtures of compounds, the presence of the catalytic amounts of sodium acetate led to the formation of azide 241 with further elimination of the nitrogen and nitrenes that gave ethyl 2-amino-4-(polyfluoroalkyl)pyrimidine-5-carboxylates 243. In case of the CF 3 -substituted ester the formation of the side product 244 was observed as well. On the other hand, 2-benzoyl-3-ethoxyprop-2-enoate in the condensation with 5-aminotetrazole in TFE under reflux yielded the mixture of compounds 245 and 246 due to the decomposition of the initial ester and the formation of the reacting ethyl benzoylacetate. Application of 2-ethoxymethylidene malonate 240 under refluxing in EtOH allowed to isolate ethyl-7-hydroxytetrazolo[1,5-a]pyrimidine-6-carboxylate 247.
Acetoacetic esters may be easily replaced by malonic ester or sodium nitromalonaldehyde monohydrate (Ren et al., 2012). The malonic esters 248 were used as efficient starting materials for the synthesis of the azoloazines 249 substituted in the position 5 (Saito et al., 2011; Figure 20).
The condensations of aminoazoles with carbonyl compounds are not limited to the vicinal amines. The azoles with an amide group next to the amine one also can be used as the reagents for the synthesis of pyrimidinones, but the condensation should be promoted by catalysts. Mulakayala et al. (2012) showed that condensation between 4-amino-1H-pyrazole-5-carboxamide (268) and aromatic aldehydes 1 occured without Lewis acid neither at room temperature nor under refluxing, however, the presence of the catalytic amounts of InCl 3 promoted the cyclocondensation. Among the studied solvents, the best result was observed in case of MeCN (10% mol of the catalyst) at room temperature. Variation of the solvents (MeOH, i-PrOH, EtOAc, CH 2 Cl 2 , CHCl 3 ) or Lewis acids (AlCl 3 , TiCl 4 , BF 3 -OEt 2 , FeCl 3 , CuCl 2 ) led to the yields decreasing. Later on another method for synthesis of the similar 1,6-dihydro-7H-pyrazolo[4,3d]pyrimidin-7-one (270) was performed (Mohammed et al., 2015). Metal-free condensation of aromatic ketones 269 with azole 268 was induced by the molecular iodine (10% mol) with oxygen in DMSO at 110 • C and resulted in the formation of the Schiff bases but not the oxidation of the acetophenone to the 2-oxo-2-arylacetaldehyde that was observed in case of 110% I 2 excess. Continuous heating promoted further intermolecular condensation with the formation of 1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one 270. Attempts to expand the range of the substrates have shown that aliphatic ketones couldn't be used as the reagents; N-substituted amides also did not undergo the condensation under such conditions. Application of the K 2 S 2 O 8 in acetonitrile-water mixture (1:1) at the room temperature (Hudwekar et al., 2017) allowed to apply the procedure not only for carbonyl compounds, but also for benzylamines or benzyl alcohol via their in situ oxidation. The formation of 1, 5-dihydro-4H-pyrazolo[3,4d]pyrimidin-4-ones 273 was also observed in the reaction of 5-amino-1H-pyrazole-5-carboxamide 271 and methyl phenylacetate (272) in EtOH-EtONa (Tintori et al., 2015; Figure 21).
Reactions of aminoazoles and β-halogen containing carbonyl compounds were reported as a way for the synthesis of angular fused heterocyclic systems. The copper catalyzed synthesis of the pyrazolo[1,5-a]quinazolines 293 was published by Gao et al. The most promising results were obtained in the system DMF-CuI-K 2 CO 3 while other types of alkali media gave the worth results. It was found, that the application of the CuI, additionally stabilized by ethylenediamine was the most effective ; Figure 23).
On the other hand, Nue et al. showed that 2-F and 2-NO 2derivatives 294 may be also applied in such reactions. Simple heating of the starting reagents in dry DMF-Cs 2 CO 3 yielded angular heterocycles 295. Unlike previous authors, application of the K 2 CO 3 instead of Cs 2 CO 3 gave worth results. The absence of the molecular sieves decreased the yield of the target [1,2,4]triazolo[1, 5-a]quinazoline 295 from 84 to 74%. Monitoring the reaction mixture by HRMS showed the presence of the Schiff base, that could be one of the intermediates of the heterocyclization Niu et al., 2014; Figure 23). Hedidi et al. reported the copper catalyzed synthesis of pyrido[2,3-e]pyrimidines 297 (Hedidi et al., 2017). The attempts to obtain the target compounds via simple heating of the reagents 5a, 31, 101a, and 296 with Cs 2 CO 3 in DMF, as it had been reported in Niu et al. (2014), were unsuccessful while application of the procedure reported by Gao et al. (2014) allowed to fix their traces. The best results were observed in the system DMSO-CuI-K 3 PO 4 without any ligand (Figure 23).
3-Amino-5-methylisoxazole was sometimes considered as a 1,3-binucleophile reacting with the preservation of the isoxazole moiety. However, in some cases establishing structures of the compounds synthesized without X-Ray data was not sufficient (Rajanarendar et al., 2016;Diyanatizadeh and Yavari, 2017). Sometimes the structures of final compounds were assigned similarly with the pyrazole-containing compounds, which in our opinion may be incorrect due to the possibility of isoxazole ring opening. For instance, the condensations of 3-amino-5-methylisoxazole (298) with arylisothiocyanate 193 with further Boulton-Katritzky rearrangement result in the formation of the 1,2,4-thiadiazoles 300 (Pokhodylo and Shyyka, 2014;Proshin et al., 2014; Figure 24).
Thus, two component reactions involving aminoazoles and substrates of various origins allow forming diverse azoloazine, azinoazine and other heterocyclic systems. The substrates for condensations are not limited to 1,3-dielectrophiles or carbonyl compounds although they constitute the overwhelming majority of typical reagents.

Click Chemistry Concerning Azoles and Aminoazoles
Click chemistry, by B. Sharpless definition (Kolb et al., 2001), describes reactions that are wide in scope, suitable for most substrates, stereospecific, have high yields and low amount of side products, the latter can be removed without application of chromatography methods. The process itself needs to be conducted in mild conditions, the reactants-to be readily available, the solvent-to be easily removed or absent, and the product-to be effortlessly separated from the reaction mixture.
The concept of click chemistry perfectly goes along with the principles of green chemistry and with diversity oriented synthesis due to the possibility to build different types of molecular skeleton and may be used for synthesis and further modification of aminoazoles as well.
Talking about click chemistry, azide-alkyne cycloaddition is always the first thought, but the authors of the term (Kolb et al., 2001) also include to the massive of click reactions the following:   and medicinal chemistry (Choi et al., 2006;He et al., 2016). Wastelessness and bioorthogonality of this reaction type promoted its implementation into medicinal chemistry and caused, for example, development of new molecules for contrast identification of cancer cells (Lee et al., 2014), RNA and DNA molecules, proteins (Shieh et al., 2015), etc. Although, as it was mentioned, the most popular first thought about click-chemistry is the Cu(I)-assisted synthesis of 1,2,3-triazoles, in this part of the review we will focus on the procedures with different starting reactants rather than publications discussing new catalysts for the reaction of azide and alkyne.
The pre-click triazole-forming cycloaddition reactions were well-known in the nineteenth century, but were very inconvenient as they required long-term heating in closed vessels, thus, could be in no way characterized as "click" reactions. As an example, one of those methods (Michael, 1893) included addition of 2-phenyl-2H-triazirine (301) to dimethyl  acetylenedicarboxylate (195) in molten form and the product 302 was formed in low yields (Figure 25).
The first azide-alkyne reaction involved transformation of hydrogen azide (303) and acetylene (304) in ethanol-acetone mixture in a closed vessel for 70 h (Dimroth and Fester, 1910). Such unfriendly reaction conditions closed the door to 1,2,3triazole (305) synthesis and research of the properties of these heterocycles for decades (Figure 25). It should be noted, that the original paper (Dimroth and Fester, 1910) can be hardly found in the journal, though there exists a plenty of references in many papers and theses.
Regardless of the novelty of CuAAC method it has quickly become the most popular procedure for the synthesis of 1,2,3triazole derivatives. Variations were also invented for preparation of these heterocycles from alkenes. For instance, Janreddy et al. (2013) report successful cycloaddition of organic azides 308 to α,β-unsaturated ketones 200, such as vinyl ketones and chalcones, in an oxidative atmosphere of pure oxygen. As an oxidant CuO can also be employed, as a more convenient reagent than gaseous oxygen (Figure 26). In another paper, the triazole ring was also arylated by aryl halides without separation to obtain triazoles 307 (Zhang et al., 2012).
1,2,3-Triazole fragments were also obtained by multicomponent ways. For example, Wu et al. (2005) reported reaction of organic azide 308 and terminal alkyne 183 in the presence of Cu(I) salts and following cleavage of C-Cu bond in an Ullmann-like reaction by an alkylating agent 309, which resulted in 1,4,5-substituted triazole 310 (Figure 26).
Another multicomponent approach (Figure 26) included consecutive reaction of terminal alkyne 183 with acyl halide 311, and then with sodium azide with application of zinc bromide, which served as a catalyst for both steps of the process (Keivanloo et al., 2013).
Another type of click reactions-syntheses of tetrazoles-were carried out even more than a century ago (Pinner, 1894;Dimroth and Merzbacher, 1910), but those tries took a lot of time and energy, requiring 40 h-long refluxing in ethanol, heating in a sealed vial under high pressure etc. Such methods were reviewed by Benson (1947).
Only the second half of XX century contributed easier and faster procedure of tetrazole fragment formation. An end-ofthe-century review was published in 1994 (Wittenberger, 1994) and included latest advances in synthesis, functionalization and applications of these heterocycles.
Three-component reactions of primary amines 55 of various origin, including aminoazoles, orthoformic ester 313 and sodium azide leading to 1-substituted tetrazoles 315 (Figure 27) was thoroughly studied by Gaponik group and their followers (Gaponik et al., 1985(Gaponik et al., , 1990Voitekhovich et al., 2005Voitekhovich et al., , 2013. One of the latest and most complete reviews was presented in Grigoriev et al. (2017).
Synthesis of C-substituted tetrazoles 317 is more widely studied, and the number of methods for their preparation is larger. A Lewis acid-assisted reaction of organic nitriles 316 and sodium azide is probably the most popular (Figure 28).  Yields were reported to be as high as 90% for benzonitriles in the presence of ZrOCl 2 , but using zinc salts became a classic procedure (Galante and Somerville, 1996).
Nitriles 316, reactive toward [3 + 2]-cycloaddition reactions with azide, can be formed in situ from primary alcohols 318 or aldehydes 1 by oxidation with iodine in aqueous ammonia under microwave irradiation (Shie and Fang, 2007; Figure 28). Tetrazoles 317 were reported to be separated in high yields in such procedure.
Diphenylphosphorazidate (DPPA) served as a reactant in conversion of aldoximes 319 to 5-substituted tetrazoles 317 (Figure 28), making the publication (Ishihara et al., 2018) different from other methods employing aldoximes as initial compounds by the relative safety of the procedure, which excludes explosive azide sources and heavy metals.
5-Aryl-1-substituted tetrazoles 321 can also be obtained via click reactions. The method (Kaim et al., 2011) suggests mixing of isonitriles 180 with bromine and sodium azide in acetonitrile; arylboric acid with Suzuki catalysts are introduced to the reaction mixture without separation of an intermediate product 320.
Other method of preparation of 1,5-disubstituted tetrazoles 323 can include one-pot transformation of an alkene 322, Nbromosuccinimide, nitriles and trimethylsilane azide, catalyzed by triflates and is reported by Hajra et al. (2007). Yields appeared to be higher when zinc triflate was used (Figure 29).  Methods of preparation of tetrazole 325 starting from carboxamides 324 are also known. In this case, amide group needs to be activated, for example, by trifluorosulfonic acid anhydride (Thomas, 1993) and then [3 + 2]-cycloaddition of azide proceeds (Figure 29).
Tetrazolopyridine 327 synthesis was described by Keith (2006). Pyridine N-oxides 326 were allowed to react with phosphorylazides in hot pyridine as a solvent. Various phosphorylazides were tested, but diphenylphosphorazidate (DPPA) proved to be the most convenient source of azide group (Figure 29).

CONCLUSIONS
In summary, comprehensive analysis of the literature concerning the topic of the present review demonstrates that reactions involving aminoazoles as key reagents possess a high potential for diversity-oriented synthesis and open up effective and convenient pathways to numerous types of final heterocyclic compounds. Classical two-component and stage-by-stage procedures as well as multicomponent reactions of aminoazoles allow to synthesize diverse five-, six-and seven-membered heterocycles using a limited set of reagents the most common of which are α,β-unsaturated carbonyl and carboxyl compounds, cyclic and non-cyclic CH-acids, aldehydes, ketones and diketones of different origin. Additional benefits may be obtained by application of such innovative approaches as microwave-and ultrasonic-assisted organic synthesis, methods of click-chemistry, using special catalysts etc. The compounds synthesized from aminoazoles are useful as building-blocks for further construction of complex heterocyclic systems, as promising objects of medicinal-oriented chemistry to search for the novel drug-like substances and as components of functional materials.

AUTHOR CONTRIBUTIONS
YS and SD collected most publications related to this review article and sorted them. MM analyzed the literature and wrote the chapter about multicomponent reactions. AM analyzed the literature and wrote the chapter about two-component reactions. IZ analyzed the literature and wrote the chapter about clickchemistry. VC developed the concept of the review, co-wrote and corrected the manuscript.

FUNDING
Authors thank National Academy of Sciences of Ukraine for financial support in the frame of the projects Development of methods of synthesis of novel chemotypes of drug-like nitrogen containing heterocyclic compounds (0116U001209) and Development of methodology of click-chemistry for the creation of components for novel chelating materials (0117U001280) and President of Ukraine for financial support in the frame of the project Multicomponent isocyanidebased reactions of functionalized starting reagents and posttransformations of the compounds synthesized (F-78/205-2018).