2-(Azolyl)anilines are a versatile tool in organic synthesis, that makes it possible to form both substituted and condensed derivatives of various heterocyclic systems on their basis. Approaches to the synthesis and modification of these compounds are quite diverse, and the products of their modification often exhibit various biological activity: antifungal, antibacterial, antitumor, cardioprotective, hypoglycemic, antihypoxant, plant growth stimulation, selectivity toward α1В-, α1D-, and α1-adrenergic receptors, ability to act as antagonists of kainate receptors, etc., which has given rise to a significant number of publications on this topic. Despite this, no attempts have previously been made to systematize and critically analyze information on the synthesis, modification, and biological activity of the above objects. This work is the first attempt to present data of the chemistry and biological effect of 2-(azolyl)anilines. Particular attention is paid to the reactions of cyclization based on these substances, taking into account their role in the formation of polycondensed heterocyclic systems, published from 1942 to 2016.

1. Methods of synthesis of 2-(azolyl)anilines

1.1. Synthesis of 2-(azolyl)anilines from о-nitro-substituted benzene derivatives

The first report on 2-(azolyl)aniline synthesis dates from 1942. Cass1 showed that 2-nitrobenzaldehyde (1) reacted with (2,2-dimethoxyethyl)amine in ethanol to form (2,2-dimethoxyethyl)[ 1-(2-nitrophenyl)methylidene]amine (2), which after acid hydrolysis yielded aldehyde 3 (Scheme 1). The latter gave nitro derivative 4 upon treatment with concentrated sulfuric acid in the presence of phosphorus(V) oxide, which after the reduction by Raney Ni formed [2-(1,3-oxoazol-2-yl)phenyl]amine (5) with 97% yield.

scheme 1

Scheme 1.

Domány et al.2 have developed a method for the synthesis of 2,3-disubstituted imidazo[1,2-c]quinazolines 8 and their hydrogenated analogs 9 on the basis of 2-(2-aminophenyl)-1H-imidazoles 7, which were reduced by catalytic hydrogenation of the nitro group in compound 6 by Pd/C as catalyst (Scheme 2). Compounds 6 were synthesized from 2-nitrobenzaldehyde (1) and appropriate dicarbonyl compounds. Despite the diversity of the reported chemical transformations, not all compounds had enough reported data for their decisive evaluation.

scheme 2

Scheme 2.

The same researchers2 elaborated the synthesis of benzimidazo[1,2-c]quinazoline (12) and its hydrogenated analog 13 by reduction of an appropriate nitro-substituted compound 10 to 2-(1H-benzimidazol-2-yl)aniline (11) (Scheme 3). A step by step approach was used to synthesize compound 10. Formation of the imidazole system was accomplished via interaction of compound 1 with thionyl chloride and o-phenylenediamine in dichloromethane. The reaction proceeded through formation of geminal 1-(dichloromethyl)-2-nitrobenzene and intermediate 2-(2-nitrophenyl)-2,3-dihydro-1H-benzimidazole system. The complex of physical and chemical methods definitely proved the structure of compounds.

scheme 3

Scheme 3.

Speake et al.3 synthesized 1,3-disubstituted 5-(2-nitrophenyl)-1H-pyrazoles 16 and 1,5-disubstituted 3-(2-nitrophenyl)-1H-1,2,4-triazoles 17 by the reaction of 2'-nitroacetophenone (14) or 2-nitrobenzylamide (15) with acetals and ketals, followed by cyclocondensation of the obtained α,β-unsaturated ketones 16 or hydrazones 17 with hydrazines (Scheme 4). The resulting (2-nitrophenyl)-azoles 18 and 19 were converted into the corresponding heterylanilines 20 and 21 via palladium-catalyzed reduction with quantitative yields.

scheme 4

Scheme 4.

Janjic et al.4 obtained (2E)-3-(dimethylamino)-1-(2-nitrophenyl) prop-2-en-1-one (16) by interaction of 2'-nitroacetophenone (14) with N,N'-dimethylformamide dimethyl acetal (DMFDMA). Compound 16 interacting with alkylor arylhydrazines formed 1-substituted 5-(2-nitrophenyl)-1H-pyrazoles 22 in 53–97% yield. Consequently compounds 22 were reduced to the corresponding 2-(1H-pyrazol-5-yl)-anilines 23 by catalytic hydrogenation in the presence of Pd/C with higher yields – 62–100% (Scheme 5). IR, LC-MS, EI-MS, 1H, 13C NMR spectra, and X-ray analysis were properly reported to establish the compound structure.

scheme 5

Scheme 5.

Abramov et al.5 obtained 4-(2-nitrophenyl)-1,2,3-thiadiazole (24) by the Hurd–Mori reaction between ethyl hydrazinecarboxylate, 2'-nitroacetophenone (14), and thionyl chloride. Compound 24 was easily reduced by hydrazine hydrate in the presence of the Pd/C catalyst to 4-(2-aminophenyl)-1,2,3-thiadiazole (25) (Scheme 6). However, the Hurd–Mori method had peculiarities, such as a need for very low temperature (–78°С), which was reached by cooling the reaction with an solid CO2 in acetone.

scheme 6

Scheme 6.

Biagi et al.6 showed that for the synthesis of 1-(2-nitrophenyl)-1H-1,2,3-triazoles 27, 1-azido-2-nitrobenzene (26) and carbonyl compounds with an activated methylene group could be used (Scheme 7). Compounds 27 were hydrogenated at room temperature and ambient pressure in the presence of 5% palladium on activated charcoal or reduced with tin(II) chloride at reflux to [2-(1H-1,2,3-triazol-1-yl)phenyl]amines 28. The cyclization of the latter in cumene in the presence of triethyl phosphite yielded substituted 3-methyl-9aλ5-[1–3]triazolo-[1,2-a][1–3] benzotriazoles 29. However, the formation of the latter seems questionable, and, beside the provided not very informative 1H and 13C NMR spectra, as well as elemental analysis, the proof of structure would require X-ray diffraction data.

scheme 7

Scheme 7.

Saha et al.7 have developed an approach that has been successfully used to form 2-(1H-tetrazol-1-yl)aniline (33). The interaction of 1-isothiocyanato-2-nitrobenzene (30) with sodium azide in chloroform and allowed to obtain 1-(2-nitrophenyl)-1H-tetrazole-5-thiol (31) (Scheme 8). Desulfuration of the latter and further reduction of compound 32 resulted in the desired product 33.

scheme 8

Scheme 8.

1.2. Synthesis of 2-(azolyl)anilines from substituted benzonitriles

Koguro et al.8 examined the reactivity of benzonitrile 34 toward sodium azide in toluene in the presence of triethylamine hydrochloride (method A, Scheme 9). It was established, that yield of the desired product is determined by various factors: the temperature range (30–115°С), the ratio of the initial reagents (1:1 to 1:3), the catalyst basicity (mono-, di-, and trialkylamine hydrohalides, tetraalkylammonium halides), the nature of the solvent, the presence of acids, and reaction time. It was shown that tetrazole 35 was formed with nearly quantitative yield by the interaction of the starting compounds in the ratio 1:3 in the presence of di- or triethylamine hydrochloride in toluene, nitrobenzene, or xylene at temperature 95–100°С and reaction time 30 h. The similar reaction was discussed in the work of Lang et al.9 The usage of zinc sulfate nanospheres as a catalyst distinguished this reaction from the one above. In addition, a comparative assessment was carried out of the effect of other catalysts (zinc chloride, bromide, acetate, oxide, sulfide, and tungstate), solvent, and reaction time on the yield. It was shown, that tetrazole 35 was formed in almost quantitative yield (95%) by treatment of benzonitrile 34 with sodium azide in DMF in the presence of zinc sulfate nanospheres at 120°С with the reaction time up to 36 h (method B). Qi et al.10 used a variety of crystalline forms of iron(III) oxide (α-Fe2O3, γ-Fe2O3), Fe3O4, and iron(III) hydroxide as catalysts in the synthesis of tetrazole 35. It was presented, that procedures with γ-Fe2O3 resulted in high yields of the target product 35 in the interaction of substituted benzonitrile 34 with sodium azide in DMF (method C). The use of hollow Fe3O4–ZnS nanospheres as catalyst for the same reaction was discussed in their later publication.11 The authors compared its efficiency with that of other catalysts (ZnS, Fe3O4, FeS, α-Fe2O3, ZnCl2, FeCl3·6H2O) and claimed that Fe3O4–ZnS catalyst was effective in the synthesis of tetrazole 35 ensuring yield of 93% (method D). Interestingly, in the reaction of benzonitrile 34 with sodium azide in DMF, it was possible to use aluminum, its oxides, hydroxides, and salts as catalysts.12 The yield of 91% of tetrazole 35 were reached using mesoporous aluminum phosphate (method E).

scheme 9

Scheme 9.

Valgeirsson et al.13 developed a synthesis of 5-chloro-2-(1H-tetrazol-5-yl)aniline (37) by reaction of 2-amino-4-chlorobenzonitrile (36) with sodium azide in the presence of triethylamine hydrochloride in toluene in moderate yield (Scheme 10).

scheme 10

Scheme 10.

The same author13 established a two-step synthesis of 3-(2-amino-4-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one (39) consisting of the interaction of benzonitrile 36 with hydroxylamine hydrochloride in the presence of sodium bicarbonate (Scheme 11). The intermediate 2-amino-4-chloro-N'-hydroxybenzenecarboximidate (38) was heterocyclized under action of diethyl carbonate in the presence of sodium ethoxide in ethanol.

scheme 11

Scheme 11.

In the works of Fujisawa and coworkers14 , 15 the interaction of 2-aminoalkanols with 2-aminobenzonitrile (34) in the presence of zinc chloride was described (Scheme 12). The reaction proceeded with the formation of [2-(4,5-dihydro-1,3-oxoazol-2-yl)phenyl]amines 40a 15 and 40b 14 with 85 and 61% yields, respectively. The attempt to optimize this method by using a threefold excess of zinc chloride as a catalyst was described in the work of Wolińska16 and revealed formation of compounds 40a–d in higher yields, namely 71–99%.

scheme 12

Scheme 12.

The method for synthesis of 2-(4,5-dihydrooxazol-2-yl)-aniline (41) was described in the work of Ge et al.17 It was found that the optimal conditions are sulfur and Co(NO3)2 as the catalyst system90°C temperature with conventional or microwave (800 W) heating without solvent. It is noteworthy, that the solvent-free conditions were not only beneficial in reagent costs, but also more efficient than reaction in a solvent (Scheme 13). It was shown, that microwave-assisted synthesis increased yield by 7%. In the cited paper the role of catalyst and mechanism of the reaction was discussed in detail.17

scheme 13

Scheme 13.

Li18 discussed tandem synthesis of 2-(4,5-dihydrothiazol-2-yl)aniline (42) and 2-(4,5-dihydrooxazol-2-yl)aniline (41). It was shown that 2-aminobenzonitrile (34) with 2-mercaptoethylammonia chloride or 2-aminoethanol with various copper catalysts and bases formed compounds 42 and 41, respectively (Scheme 14). Copper methacrylate was used as catalyst and sodium acetate as base.

scheme 14

Scheme 14.

An example of heterocycle formation involving benzonitrile 34 and ethane-1,2-diamine in the presence of phosphorus(V) sulfide has been shown in the work of Korshin19 (Scheme 15). Thus, 2-(4,5-dihydro-1H-imidazol-2-yl)aniline (43) was synthesized in xylene with the yield of 93%.

scheme 15

Scheme 15.

1.3. Synthesis of 2-(azolyl)anilines by catalytic N-arylation of halo-substituted anilines or benzenes by azoles

Copper–diamine catalyzed N-arylation of pyrrole and pyrazole was presented in the paper by Antilla.20 It was shown, that the treatment of 2-bromoaniline (44a) with pyrrole or pyrazole in toluene in the presence of copper(I) iodide, potassium phosphate or potassium carbonate, and a suitable ligand lead to the formation of a new C–N bond resulting in 2-(1H-pyrrol-1-yl)aniline (45) and (1H-pyrazol-1-yl)aniline (46), respectively (Scheme 16).

scheme 16

Scheme 16.

The N-arylation of 1H-indazole (47) was investigated under similar conditions.20 The reaction proceeded with the formation of two products, namely, [2-(1H-indazol-1-yl)-phenyl]amine (48) and its regioisomer 2-(2H-indazol-2-yl)-aniline (49). It is important to note that structure of the starting aniline significantly affected the ratio of isomers. Thus, in the case of 2-bromoaniline (44a) the ratio was 1.4:1, while for 2-iodoaniline (44b) it was 20:1 (Scheme 17). The products were chromatographically separated, and the structure of products was established by LC-MS, 1H and 13C NMR analysis.

scheme 17

Scheme 17.

The paper published by Du21 was dedicated to the synthesis of 3-difluoromethyl-N-[2-(1H-heteryl)phenyl]-1-methyl-1H-pyrazole-4-carboxamides 53. Copper-catalyzed N-arylation of nitrogen heterocycles with 2-chloronitrobenzene (50) was used for the synthesis of coupling products 51 (Scheme 18). In this case, hexamethylenetetramine (HMTA) was used as a ligand and cesium(I) carbonate as a base. The resulting nitro derivatives 51 were reduced by hydrazine hydrate over a Pd/C to 2-(heter-1-yl)-anilines 52.

scheme 18

Scheme 18.

Wanniarachchi22 described a convergent synthesis of bis [2-(pyrazol-1-yl)phenyl]amines 58 which were employed as ligands in carbonylrhodium(I) complexes. 2-(1H-Pyrazol-1-yl)anilines 56 and 1-(2-bromophenyl)-1H-pyrazoles 57 were formed by the interaction of the corresponding 2-bromoanilines 54 and 1-bromo-2-fluorobenzenes 55 with pyrazole in DMF (Scheme 19). Compounds 56 and 57 consequently formed diphenylamines 58 by a catalytic coupling reaction in the presence of copper(I) iodide in dioxane.

scheme 19

Scheme 19.

A number of studies23 , 24 has been devoted to the synthesis of 2-(1H-pyrazol-1-yl)anilines 56, which were used as precursors for the formation of fluorescent boron complexes 60 (Scheme 20). The copper(I) iodide-catalyzed N-arylation of 2-bromoanilines 54 was used for their preparation. The latter were obtained by bromination of anilines 59 with tetrabutylammonium tribromide in a mixture of methanol and dichloromethane. The paper describes the structure of pyrazolylanilines 56 and the boron complexes 60 which they form with triphenylborane. 1H, 13C NMR spectra, as well as UV/Vis adsorption and emission spectra of complexes 60 were presented, and their fluorescent properties were investigated.

scheme 20

Scheme 20.

A good example of the copper-catalyzed N-arylation of 1H-pyrazole by 2-iodoaniline (44b) was described in the work of Liu.25 2-(1H-Pyrazol-1-yl)aniline (46) was synthesized in 74% yield (Scheme 21). 3-(Diphenylphosphino)-propanoic acid was used as a ligand for copper ion for the formation of the active catalytic species.

scheme 21

Scheme 21.

1.4. The hydrolytic cleavage of pyrimidine ring

The first report, which described the hydrolytic cleavage of the pyrimidine ring of 2-alkyl[1, 2, 4]triazolo[1,5-c]-quinazolines 61 was published in 1977.26 It was shown, that refluxing compounds 61 in an aqueous potassium hydroxide solution led to 2-(5-alkyl-1H-1,2,4-triazol-3-yl)-anilines 62. In addition, there are several papers concerning hydrolytic cleavage of the pyrimidine cycle of the mezoionic [1, 2, 4]triazolo[1,5-c]quinazolines and 2-thioxo[1, 2, 4]-triazolo[1,5-c]quinazolines.27 , 28 It was established that the hydrolytic cleavage of the pyrimidine cycle of the 2-substituted [1, 2, 4]triazolo[1,5-c]quinazolines 61 occurred under the influence of various nucleophiles.29 , 30 However, nearly quantitative yield of 2-(5-alkyl-1H-1,2,4-triazol-3-yl)-anilines29 , 30 62 were obtained by the interaction of the starting compounds with mineral acids in aqueous alcohol solutions (Scheme 22).

scheme 22

Scheme 22.

Antypenko et al.31 explored methods of the formation of substituted tetrazolo[1,5-c]quinazolines 64, and have established that 4-hydrazinoquinazolines 63 interacting with aqueous sodium nitrite solution and acetic acid in some cases formed compounds 65 (Scheme 23). Thus, the presence of electron-withdrawing substituents (fluorine, chlorine, and bromine) at positions 8 and 10 of compounds 64 led to a spontaneous hydrolytic cleavage of the pyrimidine cycle and formation of N-[2-(1H-tetrazol-5-yl)phenyl]-formamides 65. Further investigations of the behavior of compounds 64 and 65 with mineral acids showed that the corresponding 2-(1H-tetrazol-5-yl)anilines 66 were formed in all cases.

scheme 23

Scheme 23.

New potential inhibitors of vascular endothelial receptors of type 1 and 2 have been found among 2-(1-aryl-1H-1,2,4-triazol-3-yl)-N-(hetarylmethyl)aniline derivatives 70 synthesized using a four-step method by Kiselyov32 (Scheme 24). It was shown, that interaction of 4-chloroquinazoline (67) with arylhydrazides 68 in anisole could be regarded as a nucleophilic substitution followed by nucleophilic opening of pyrimidine ring and formation of 2-(1-phenyl-1H-1,2,4-triazol-3-yl)anilines 69. The latter were acylated with of hetarylcarboxylic acid chlorides. The obtained acyl derivatives were processed with phosphorus pentasulfide and reduced over Raney Ni catalyst. In this method, the target products 70 were formed with satisfactory yields.

scheme 24

Scheme 24.

Molina27 also studied the hydrolytic cleavage of the [1, 2, 4]triazolo[1,5-c]quinazoline pyrimidine cycle (Scheme 25). It was shown that 1-amino-5-aryl-1H-[1, 2, 4]triazolo[1,5-c]-quinazolin-4-ium-2-thiolates 71 with hydrochloric acid were transformed into N-[2-(4-amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)phenyl]aroylamides 72 which subsequently formed the respective 2-(6-aryl[1, 2, 4]triazolo[3,4-b]-[1, 3, 4]thiadiazol-3-yl)anilines 73 with phosphorus pentasulfide. The key structure 73 was confirmed by X-ray diffraction analysis.

scheme 25

Scheme 25.

1.5. Other methods of synthesis of 2-(azolyl)anilines

Hunt33 in his work studied the reaction of 2H-3,1-benzoxazine-2,4(1H)-diones 74 with 2-aminoethanol and showed that products of nucleophilic degradation – 2-amino-N-(2-hydroxyethyl)benzamides 75 were cyclized in organic solvent in the presence of catalysts into the corresponding N-substituted (4,5-dihydrooxazol-2-yl)anilines 76 (Scheme 26). It was also shown that nucleophilic degradation of compounds 74 in a tandem process by using 2-chloroethylamine in triethylamine and DMF leads to the oxazoline derivatives 76. The yields of products 76 in the latter reaction were higher than the combined yield of the twostep process through compound 75. The method of the synthesis of 2-(4,5-dihydrooxazol-2-yl)aniline (41) was also described by Hu.34 2H-3,1-Benzoxazine-2,4(1H)-dione (74) with (2-chloroethyl)ammonium chloride in DMF in the presence of trimethylamine after stirring for 2.5 h at 80° C formed product 41 with 86% yield (Scheme 26). It was further investigated in polymerization reactions in the presence of scandium triflate.

scheme 26

Scheme 26.

Shang et al.35 synthesized compound 41 by hydrolysis of N-[2-(4,5-dihydro-1,3-oxazol-2-yl)]phenyl)-2-(aryl(hetaryl)-amino)benzamides 77 (Scheme 27). Product 41 was formed with high yield (93%) and was afterward used to create a combinatorial library of amidated heterocycles.

scheme 27

Scheme 27.

An original approach for the synthesis of 2-(1,3,4-oxadiazol-2-yl)aniline (81), consisting of the reaction of anthranilic acid (79) with a Wittig reagent N-isocyanoiminotriphenylphosphorane (79), was shown by Rouhani36 (Scheme 28). It was established that the reaction proceeded in dichloromethane at room temperature for 12 h, while the microwave synthesis (200 W) at the same temperature acted instantly and with nearly quantitative yields. The reaction mechanism and the structure of heterocyclic compounds were evaluated in the study by 1H, 13C NMR and IR spectra. Anthranilic ester 80 was proposed as a likely intermediate.

scheme 28

Scheme 28.

The method of synthesis of 1,2-disubstituted 5-(2-nitrophenyl)-1H-pyrroles 84 was developed in the work by Speake.3 The essence of the method was interaction of 1-bromo-2-nitrobenzene (82) with 1,5-disubstituted 2-tributylstannyl-1H-pyrroles 83 under palladium catalysis in water in the presence of dimethoxyethane (Scheme 29). Compounds 84 were reduced via palladium catalysis to the corresponding 1,2-disubstituted 2-(1H-pyrrol-2-yl)anilines 85.

scheme 29

Scheme 29.

Three-component condensation 2-fluoronitrobenzole (86) and benzonitrile with sodium azide was developed by Saha.7 It was shown, that the starting compounds in the presence of a catalytic amount of copper, iron(III) chloride, and sodium bicarbonate in water for 7 h formed nitro derivatives 87 which after the reduction yielded 2-(5-phenyl-1H-1,2,3-triazol-1-yl)aniline (88) (Scheme 30).

scheme 30

Scheme 30.

2. The reactivity 2-(azolyl)anilines in cyclocondensations

In this section, some reactions indicating the reactivity of 2-(azolyl)anilines are reviewed. The title compounds are represented as classical binucleophiles which form various fused heterocyclic systems or assemblies thereof.

A systematic study, devoted to the imidazoquinazoline formation from 2-(4,5-dihydro-1H-imidazol-2-yl)aniline (43) was described by Korshin.19 It was shown, that compound 43 interacting with orthoformate or orthoacetate under N2 formed 2,3-dihydroimidazo[1,2-c]quinazolines 89. Besides, the reaction of compound 43 with methyl acetimidates or benzimidates in toluene with potassium tertbutoxide also led to the formation of compounds 89 (Scheme 31). The interaction of compound 43 with aldehydes in tetrahydrofuran or acetonitrile in the presence of anhydrous magnesium sulfate under N2 led to the formation of 2,3,5,6-tetrahydroimidazo[1,2-c]quinazoline (90). Both compounds 89 and 90 were oxidized to imidazo-[1,2-c]quinazolines 91.19

scheme 31

Scheme 31.

2-(4,5-Dihydro-1H-imidazol-2-yl)anilines 43 react with acid anhydrides or carbon disulfide in alcoholic potassium hydroxide to produce 5-alkyl-2,3-dihydroimidazo[1,2-c]-quinazolines 89 and 2,6-dihydroimidazo[1,2-c]quinazoline-5(3H)-thiones 92, respectively (Scheme 32).37 Compounds 89 were also obtained by dehydrocyclization of 4-(1-hydroxyethyl)aminoquinazolines 95 in phosphorus oxychloride. Compounds 95 were obtained by interaction of substituted 4-chloroquinazoline 94 and ethanolamine in benzene. The oxidation of thiones 92 with potassium permanganate in potassium ethanolate solution produced the corresponding 2,6-dihydroimidazo[1,2-c]quinazolin-5(3H)-ones 93.

scheme 32

Scheme 32.

Janjić4 presented a study of the behavior of 2-(1H-pyrazol-5-yl)anilines 23 in the cyclocondensation with acetone and cyclopentanone in methanol in the presence of Pd/C catalyst (Scheme 33). It was established, that in the case of N-unsubstituted pyrazole derivatives 23, 5,5-disubstituted 5,6-dihydropyrazolo[1,5-c]quinazolines 96 were formed, while N-phenyl pyrazoles 23 reacted with acetone producing N-isopropyl-2-(1-phenyl-1H-pyrazol-5-yl)aniline (97).

scheme 33

Scheme 33.

In the patent38 a synthesis of imidazo[1,5-a][1, 2, 4]-triazolo[1,5-d][1, 4]benzodiazepine and its substituted derivatives 102 synthesis was described. The synthetic sequence started from 2-aminobenzonitriles 36 which upon treatment with ethyl chloroformate afforded carbamates 98 (Scheme 34). Treatment of intermediate 98 with hydrazides in N-methyl-2-pyrrolidone (NMP) led to the formation of [1, 2, 4]triazolo[1,5-c]quinazolin-5(6H)-ones 99 which were converted to 2-(1H-1,2,4-triazol-3-yl)anilines 64 by hydrolytic cleavage. The latter, interacting with chloroacetyl chloride in a mixture of pyridine and dioxane formed 5H-[1, 2, 4]triazolo[1,5-d][1, 4]benzodiazepin-6(7H)-ones 100. Compounds 100 were activated via phosphorus oxychloride, diphenyl phosphoryl chloride, or mixture of phosphorus oxychloride and 1,2,3-triazole to obtain derivatives 101. The latter were treated without isolation, with lithium diisopropylamide (LDA) or lithium hexamethyldisilazide (LiHMDS) in THF and with (E)-(dimethylaminomethylenamino) acetic acid ethyl ester or with a mixture of a cooled solution of ethyl isocyanoacetate in THF and potassium tert-butoxide or sodium hydride to give tricyclic compounds 102.

scheme 34

Scheme 34.

Pařik39 reported that refluxing 2-(1H-imidazol-2-yl)-aniline (7) with isocyanates in acetonitrile for 5 h resulted in the formation of 1-alkyl(aryl)-3-[2-(1H-imidazolyl-2-yl)-phenyl]ureas 103 (Scheme 35). The target compounds 103 were obtained in low yields, which can be due the higher solubility of side products (imidazo[1,2-c]quinazolin-5(6H)-ones) in acetonitrile. Their formation was not discussed in the cited paper.

scheme 35

Scheme 35.

Black et al.40 studied the reactivity of 2-(1H-pyrazol-1-yl)anilines 56 in diazotization in view of the possible in situ heterocyclization of the respective diazonium salts 104. It was shown that the diazonium salts 104 with ethyl 2-methyl-3-oxobutanoate formed a mixture of (E)- and (Z)-isomers of ethyl 2-{[2-(1H-pyrazol-1-yl)phenyl]-hydrazono}propionates 105. The mixture was separated chromatographically on silica gel using ethyl acetate – petroleum ether as eluent. Further, hydrazones 105 were converted to ethyl 7-(1H-pyrazol-1-yl)-1H-indole-2-carboxylates 106 by refluxing for 2 h in polyphosphoric acid to be easily hydrolyzed to the corresponding carboxylic acid 107 (Scheme 36). It was also demonstrated that 2-(3,5-diphenyl-1H-pyrazol-1-yl)benzenediazonium chloride (104) kept at room temperature for 2 days formed 2-phenylpyrazolo[1,5-f]phenanthridine (108) (Scheme 36).40 However, this reaction is still uncertain, as the structure of compound 108 was not studied by physicochemical methods.

scheme 36

Scheme 36.

The synthesis of azolo[c]quinazolines by palladium(II)-catalyzed aerobic oxidation of 2-(1H-1,2,4-triazol-3-yl)-aniline 62 or 2-(1H-tetrazol-5-yl)aniline 66 was developed by a group of scientists from the Netherlands (Scheme 37).41 It was shown that compounds 62 in reaction with isocyanides in different solvents formed a mixture of two isomeric heterocycles, namely, 2-substituted 5-amino[1, 2, 4]triazolo-[1,5-c]quinazolines 109 and 3-substituted 5-amino[1, 2, 4]-triazolo[4,3-c]quinazolines 110. A solvent screen revealed that the selectivity and yield were highly dependent on the solvent. 2-Methyltetrahydrofuran (MeTHF) and acetonitrile compounds 109 in high yields and good selectivity, while only dioxane had a slightly higher selectivity for compounds 110. The 'renewable' MeTHF was chosen as solvent for further studies. Compounds 66 in reaction with isocyanides formed 5-aminotetrazolo[1,5-c]-quinazolines 111. The structure of key compounds was proven by X-ray diffraction analysis.41

scheme 37

Scheme 37.

An effective copper-catalyzed synthesis of N-substituted heterocycles using ligands for the formation of the C–N bond was discussed in the work of Subramanian and Kaliappan42 (Scheme 38). It was shown, that 2-(1H-imidazol-1-yl)-aniline (112a), 2-(1H-benzimidazol-1-yl)aniline (112b), or 2-(1H-1,2,4-triazol-1-yl)aniline (112c) reacted with 2-bromopyridines 113 in DMF in the presence of copper(II) acetate, potassium phosphate, and ligands (phenanthroline monohydrate or tetrabutylammonium iodide) affording 9-phenyl-9H-imidazo[1,2-a]benzimidazole (114a), 5-phenyl-5Hbenzimidazo[1,2-a]benzimidazole (114b), or 4-phenyl-4H-[1, 2, 4]triazolo[1,5-a]benzimidazole (114c), respectively. The role of the ligand, catalyst, and base in the mechanism of the reaction was considered in detail in the paper. The structure of representative products has been determined by X-ray analysis.

scheme 38

Scheme 38.

Interaction of substituted (1H-1,2,4-triazol-3-yl)anilines 115 with ethyl carbamate or trichloromethyl chloroformate led to the formation of 2-phenyl[1, 2, 4]-triazolo[1,5-c]-quinazolin-5(6H)-ones 116 43 , 44 (Scheme 39). The corresponding 5-aryl-2-(2-pyridyl)-5,6-dihydro[1, 2, 4]triazolo[1,5-c]-quinazolines 117 were synthesized by cyclization of compounds 115 with aldehydes in ethanol.45 , 46 The heating of the starting compounds 115 with bromocyane in methanol for 18 h under N2 resulted the formation of 2-R-[1, 2, 4]-triazolo[1,5-c]quinazolin-5(6H)-imines 118.44 Gatta47 obtained 9-chloro-5-(chlorometyl)[1, 2, 4]triazolo[1,5-c]-quinazolines 119 via cyclization of compounds 115 with 2-chloroacetyl chloride in acetic acid in the presence of sodium acetate (Scheme 39).

scheme 39

Scheme 39.

Interaction of 2-(1H-1,2,4-triazol-3-yl)aniline (62) with cis- or trans-1-(4-R-cyclohexyl)piperidin-4-ones led to the formation of spiro compounds 120 which can undergo N-methylation by formic acid in the presence of sodium borohydride producing 1-(4-cyclohexyl)-6'-methyl-6'Hspiro[piperidine-4,5'-[1,2,4]triazolo[1,5-c]quinazolines] 121 48 (Scheme 40). It was claimed that the reaction led to the formation of [1,5-c]-fused isomers. In favor of their formation attests specific chemical shift of proton at position 2' in the triazole ring (8.04 ppm).48

scheme 40

Scheme 40.

Balo49 developed the synthesis of [1, 2, 4]triazolo[1,5-c]-quinazolines 122a–h and 123 by reaction of 2-(1H-1,2,4-triazol-3-yl)anilines 62a–h with triethyl orthoformate or cyanamide, respectively (Scheme 41). It was also shown, that compound 123c reacts with acetic anhydride forming N-acetyl derivative 124.

scheme 41

Scheme 41.

9-Chloro-2-(furan-2-yl)[1, 2, 4]triazolo[1,5-c]quinazolin-5-amine (125) was obtained via condensation of 4-chloro-2-[5-(furan-2-yl)-1H-1,2,4-triazol-3-yl]aniline (62a) with cyanamide in the presence of sulfuric acid in isopropanol (Scheme 42).50 The cited paper also describes the alternative synthesis of compound 125, using 5,9-dichloro-2-(furan-2-yl)[1, 2, 4]triazolo[1,5-c]quinazoline.

scheme 42

Scheme 42.

Saha discussed the possibility to use 2-(azolyl)anilines 33 and 126 in the Pictet–Spengler reaction with aldehydes and ketones.7 It was shown that the starting compounds in the presence of toluenesulfonic acid formed C–N bond to give tetrazolo[1,5-a]quinoxalines 127 and [1–3]triazolo-[1,5-a]quinoxalines 128 (Scheme 43). The authors note that in the case of compound 33 condensation with 4-(dimethylamino) benzaldehyde, propionaldehyde, and acetophenone did not take place. Similarly, the reaction did not proceed in the case of interaction of compound 126 with 4-(dimethylamino) benzaldehyde.

scheme 43

Scheme 43.

Voloshina et al.51 studied the reaction of 2-(1H-1,2,4-triazol-3-yl)anilines 62 with dicarboxylic acid anhydrides and demonstrated formation of ([1, 2, 4]triazolo[1,5-c]-quinazolin-5-yl)alkylcarboxylic acids 130. The paper discussed the role of solvent and found that compounds 130 were obtained in the medium of glacial acetic acid. The authors obtained the acyl intermediate derivatives 129 and determined, that under thermolysis in these conditions they undergo cyclization to compounds 130 (Scheme 44). The IR, 1H NMR, LC-MS, and MS-EI spectra of the synthesized compounds are deeply discussed in the paper.

scheme 44

Scheme 44.

A group of Ukrainian scientists52 , 53 investigated heterocyclization of 2-(1H-1,2,4-triazol-3-yl)anilines 62 with synthetic equivalents of phosgene (Scheme 45). It was noted, that the reaction had certain peculiarities, namely, the interaction of compound 62 with 1,1'-carbonyldiimidazole (CDI) in dioxane and DMF led to the formation of an isomeric mixture of [1, 2, 4]triazolo[1,5-c]-quinazolin-5-ones 131 and [1, 2, 4]triazolo[4,3-c]quinazolin-5-ones 132. While compound 62 interacting with ethyl chloroformate in acetic acid in the presence of sodium acetate formed only compound 131. Compounds 131 were also prepared from the corresponding 1-[2-(1H-1,2,4-triazol-5-yl)phenyl]-3-phenylureas 133 in acetic acid. Structural modification of compounds 131, namely the alkylation by ethyl chloroacetate in DMF in the presence of sodium hydride, resulted the formation of structure 134. The structure of the cyclization products 134 was confirmed by X-ray studies.

scheme 45

Scheme 45.

Interaction of 2-(1H-1,2,4-triazol-3-yl)anilines 62 with carbon disulfide in potassium ethoxide or potassium (sodium) xanthogenate in alcohol led to potassium [1, 2, 4]triazolo-[1,5-c]quinazoline-5-thiolates 135 (Scheme 46).54 , 55 The interaction of the starting compound 62 with isothiocyanatobenzene in 2-propanol and acetic acid yielded the mixture of products: starting amine, the respective thiourea, and thione in the ratio 2:7:1, whereas the raising of reaction temperature resulted in formation of the corresponding thiones 136 and anilines 137 in a ratio 2:1.55 In addition, the modification of thiolates 135 to the corresponding [([1,2,4]triazolo[1,5-c]quinazolin-5-yl)sulfanyl]acetic acids 138 and their amides 139 was also carried out. Amides 139 were obtained by interaction of acids 138, activated by CDI, with the corresponding amines in anhydrous dioxane

scheme 46

Scheme 46.

Upon the diazotation of substituted 2-(1H-tetrazol-5-yl)-anilines 68 the corresponding diazonium salts spontaneously formed a new heterocyclic system – tetrazolo[1,5-c]-[1–3]benzotriazines 140 which were extracted with chloroform (Scheme 47).56 The synthesized compounds were found to be explosives and can be used as detonators.

scheme 47

Scheme 47.

A number of works by Antypenko et al.57,58, – 59 has been devoted to heterocyclization of 2-(1H-tetrazol-5-yl)aniline (66). It was shown that the starting compound interacting with carbon disulfide in potassium ethoxide or potassium (sodium) xanthate in alcohol formed potassium tetrazolo-[1,5-c]quinazoline-5-thiolate (141). The latter was modified in reactions with halogen compounds, such as alkyl halides, halogen carboxylic acids and their esters to obtain the corresponding sulfanyl derivatives (Scheme 48). In addition, amides 144 were prepared via interaction of CDI activated acids 143 and benzyl(aryl)amines in anhydrous dioxane.

scheme 48

Scheme 48.

The same authors60 investigated the reactivity of 2-(1Htetrazol-5-yl)anilines 66 toward alkyl and aryl isocyanates (Scheme 49). The treatment of the starting compounds in acetic acid at 20°С resulted in the formation of N-alkyl-(aryl)-N'-[2-(1H-tetrazolo-5-yl)phenyl]ureas 145, whereas refluxing provided cyclization of tetrazolo[1,5-c]quinazolin-5(6H)-ones 146.

scheme 49

Scheme 49.

An original strategy for the synthesis of 2-arylquinazolin-4-amines 149 via 5-aryltetrazolo[1,5-c]quinazolines 147 was shown in the work by Jia61 (Scheme 50). It was found, that the interaction of 2-halobenzonitriles 147 with sodium azide and aromatic aldehydes in DMF with Fe–Cu catalysis led to an unexpected result: an "elegant domino process" involving an iron-catalytic [3+2] cycloaddition, coppercatalytic S NAr reaction, cyclocondensation, oxidation, copper-catalytic nitrogen elimination, and reduction led to the target compounds 149. It is noteworthy that control experiments to detect compounds 148 and some other intermediates were used to prove the mechanism and control the experiment.

scheme 50

Scheme 50.

In the work of Kholodnyak et al.,62 2-(5-aryl-1H-1,2,4-triazol-3-yl)anilines 62 were used as 1,5-binucleophiles in the synthesis of triazolo[1,5-c]quinazolines. The interaction of anilines 62 with aromatic and aliphatic aldehydes in acetic acid for 3–6 h led to formation of the product mixture of 2-aryl-5,6-dihydro[1, 2, 4]triazolo[1,5-с]quinazolines 150 and their aromatic analogs 151 in the ratio 2:1 (Scheme 51). The most significant factors that facilitated oxidation of compounds 150 were prolongation of time and increasing the temperature of reaction. Increasing the time of refluxing to 8 h in most cases led to the quantitative oxidation of compounds 150 into 2-aryl[1, 2, 4]triazolo[1,5-c]-quinazolines 151. The formation of compounds 150 can be rationalized as a double nucleophilic addition, wherein the corresponding Schiff base A plays the role of an intermediate. To convincingly locate the oxidation process in the overall mechanism, compounds 151 were prepared by two alternative protocol based either on a one-pot process, included acylation followed by cyclization of formed N-acyl derivatives B, or the oxidation of compounds 150 with bromine or potassium permanganate.

scheme 51

Scheme 51.

The same authors in their later work63 estimated that interaction of equimolar quantities of anilines 62 with ketones in isopropanol in the presence of acid catalyst resulting in formation of the corresponding 5-substituted 2-aryl-5-methyl-5,6-dihydro[1, 2, 4]triazolo[1,5-c]quinazolines 152 in good yields (Scheme 52). A modification of the synthetic protocol by changing the solvent (alcohols, dioxane) and duration of the process (up to 6 h) have not resulted in increased yield of compounds 152. Like in the case of condensation between anilines 62 and aldehydes, this reaction could represent a double nucleophilic addition, wherein Schiff base A played a role of intermediate.

scheme 52

Scheme 52.

Formation of compounds 153 occurred as competitive acylation of anilines 62 followed by cyclization of intermediate B (Scheme 53). Probably, acylation was possible as the result of low reactivity of ketones as electrophiles and spatial structure of their molecules. This hypothesis was supported by an experiment where refluxing anilines 62 in glacial acetic acid during 6 h yielded compounds 153 in 31–57% yield.

scheme 53

Scheme 53.

Further investigation by the same group64 allowed to obtain spiro derivatives 154 as products of binucleophilic addition of compounds 62 to cycloalkanones (cyclopentanone, cyclohexanone) (Scheme 53). Furthermore, amines 62 readily reacted with a conformationally rigid bicyclo[2.2.1]heptan-2-one, whereas the reaction of aniline 62 with camphor and mention failed due to the steric hindrance.

To study the reactivity of cycloalkanones with a heteroatom, anilines 62 were treated with heterocyclanones (N-substituted piperidones, dihydrothiophen-3(2H)-one, dihydro-2H-pyran-4(3H)-one, dihydro-2H-thiopyran-3(4H)-one). It was observed that condensation of compound 62 with appropriate electrophiles proceeded without peculiarities with formation of the corresponding 2'-aryl-6'H-spiro-[cycloalkane-1,5'-[1,2,4]triazolo[1,5-c]quinazolines] 154 (Scheme 53). Also condensation with indoline-2,3-dione (isatin) and its N-substituted derivatives gave proper 2'-aryl-6'H-spiro[indoline-3,5'-[1,2,4]triazolo[1,5-c]quinazolin]-2-ones 155 (Scheme 54) with high yields. It was established that the above-mentioned reactions could be carried out in different organic solvents.

3. Biological properties of 2-(azolyl)anilines

Analysis of the presented data showed that 2-(azolyl)-anilines and products of their heterocyclizations contained various known pharmacophore fragments, including heterocyclic systems and other functional groups (amino, thio, carboxylic, etc.). This fact allowed researchers to purposefully search for biological active agents among them. Hence, the summary of their biological properties are given below.

There are several studies about usage of 2-(azolyl)-anilines as ligands in complexation reactions to form fluorescent compounds.22,23, – 24 , 40 , 61

A detailed study dedicated to the search of α1-adrenergic receptor agonists among derivatives of 2-(1H-pyrazol-5-yl)-aniline (21) and 2-(1H-1,2,4-triazol-3-yl)aniline (21) was done by Speake.3 As a result, it was found that these compounds showed high selectivity toward α1В- and α1D-receptors. Moreover, N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-(4H-1,2,4-triazol-3-yl)aniline was an agonist of all types of α1-adrenergic receptors, so this compound is a promising cardioprotective agent.

The work of Valgeirsson13 was devoted to the study of nonselective antagonists of kainate receptors by in vitro methods. It was detected that 5-chloro-2-(1H-tetrazol-5-yl)-aniline (37) had a significant IC50 (2.0 μM) and attracted attention as a neuroprotective agent.

Exhaustive research of antifungal activity using molecular docking was conducted by Du,21 and it was found that 1-methyl-N-[2-(1H-heteryl)phenyl]-3-(difluoromethyl)-1Hpyrazole-4-carboxamides 53 inhibited the growth of Сolletotrichum orbiculare, Rhizoctonia solani, Phytophthora infestans, Pythium aphanidermatum, Fusarium moniliforme, Botryosphaeria berengeriana, and Botrytis cinerea up to 17–94%. Molecules bearing the 1-indazole and 5-bromo-1-indazole fragments were the most effective (IC50 5.5–96 μg/ml) exceeding the reference fungicide boscalid (2-chloro-N-(4'-сhlorobіphenyl-2-yl)-nicotinamide). Besides, structure–activity relationship was discussed in this paper.21

Testing the inhibitory properties of [2-(1-aryl-1H-1,2,4-triazol-3-yl)phenyl](heterylmethyl)amines 70 toward VEGF-1 and VEGF-2 receptors showed that compound with 3-fluoro(bromo, tert-butyl)phenyl substituents and 4-pyridyl fragment had IC50 of 0.046–0.13 μM.32 The molecular docking studies with VEGF receptor inhibitor vatalanib as reference have shown that lead compounds were the promising anticancer drugs.

Two publications discussed the results of antibacterial activity of 2-(1H-1,2,4-triazol-3-yl)anilines 62 against the S. aureus ATCC 25923, E. coli ATCC 25922, P. aeruginosa ATCC 27853, and C. albicans ATCC 885-653.55 , 65 It was shown, that compounds 62 possess a modest activity, having MIC and MBC values toward the strains of E. coli and S. aureus in the range of 50–100 and 100–200 mg/ml, respectively. However, the derivatives with 2(3)-thienyl substituents at position 5 of the azole ring were active against S. aureus with MIC of 25 mg/ml. Interestingly, these compounds promoted the growth of plant crops.66

The more interesting biological aspect appeared in structurally modified 2-(1H-tetrazol-5-yl)anilines 66.60 Thus, 1-(2-(1H-tetrazol-5-yl)phenyl)-3-aryl(ethyl)ureas 145 and tetrazolo[1,5-c]quinazolin-5(6H)-ones 146 have significantly reduced the glucose level in the blood of experimental rats. The studies on rats at the dexamethasone diabetes models (glucose tolerance, insulin, and short adrenaline tests) revealed a number of compounds which exceeded the activity of metformin and gliclazide.

The cytotoxicty investigation against luminescent bacteria Photobacterium leiognathi Sh1 has allowed researchers to plan further studies of potential anticancer drugs.55 , 57 , 58 The high levels of growth inhibition served as a cytotoxicity marker of potential possession of the antitumor activity. It was shown, that tetrazolyl- and ([1, 2, 4]-triazol-3-yl)anilines their condensed derivatives (compounds 62, 137–139, 142–144) possess antitumor activity against 60 human cancer cell lines. Besides, the inhibition of protein kinase CK2 was established as one of the possible mechanisms of the detected antitumor activity.59

In papers of Antypenko et al.57 , 58 it was shown, that S-substituted tetrazolo[1,5-c]quinazoline-5(6H)-thiones 142–144 exhibit anticancer, antimicrobial, and antifungal activity. Thus, 1-(4-methoxyphenyl)-2-(tetrazolo[1,5-c]quinazolin-5-ylsulfanyl)ethanones, 5-(3-chloropropylsulfanyl) tetrazolo[1,5-c]quinazolines inhibited growth of C. albicans, 5-[2-(N,N-dialkylaminoethyl)sulfanyl]tetrazolo[1,5-c]-quinazolines did it in respect to S. aureus and E. faecalis. These compounds were also characterized by a low antitumor activity against 60 cancer cell lines (MID 83–105%).

The same authors investigated hypoglycemic activity in the series of 1-[2-(1H-tetrazol-5-yl)phenyl]-3-phenyl(ethyl) ureas 145 and tetrazolo[1,5-c]quinazolin-5(6H)-ones 146 at concentration of 50 mg/kg.62 The most active substances were 1-[4-chloro-2-(1H-tetrazol-5-yl)phenyl]-3-ethylurea, 1-[2-methyl-6-(1H-tetrazol-5-yl)phenyl]-3-[3-(trifluoromethyl) phenyl]ureа and tetrazolo[1,5-c]quinazolin-5(6H)-one, in some cases exceeding in activity reference drugs metformin (both at concentrations 50 and 200 mg/kg) and gliclazide (at 50 mg/kg).

Derivatives of (1,2,4-triazole)anilines and 1,2,4-triazolo-[1,5-c]quinazolines were studied as antihypoxants in in vivo models of acute cerebrovascular stroke with antiorthostatic hypokinesia of rats.67

A large combinatorial library of substituted 1,4-diamino-2-(thiazol-2-yl)benzenes was developed as dyes for coloring the keratin fibers.68 A series of substituted (isoxalin-3-yl)-(acyl)benzenes were proposed as effective herbicides.69

Thus, the analysis of the literature data showed that synthesis, physical and chemical properties has not been reviewed before. Furthermore, the derivatives of these substances exhibit the a variety of biological activities and are promising for creation on their basis novel highly effective drugs in near future.