Fused Imidazopyrazoles: Synthetic Strategies and Medicinal Applications
The current review summarizes the known synthetic routes of fused imidazopyrazoles. This review is classified into two main categories based on the type of annulations, for example, annulation of the imidazole ring onto a pyrazole scaffold or annulation of the pyrazole ring onto an imidazole scaffold. Some medicinal applications of imidazopyrazoles are mentioned.
Over the past two decades, imidazopyrazole and related drugs have been attracting the attention of the medicinal chemists due to their considerable biological and pharmacological activities. Medicinal properties of imidazopyrazole derivatives include anticancer [1–11]; for example, 2,3-dihydro-1H-imidazo[1,2-b]pyrazoles have in vivo effects on the proliferation of mouse leukemic , and the same compound has antiviral activity in herpes simplex virus type 1-infected mammalian cells , and substituted imidazo[1,2-b]pyrazole (cephem derivatives) is used as antimicrobials [13–15]. Also, imidazo[1,2-b]pyrazole nucleus used as photographic dye-forming couplers comprise, useful in photographic materials and processes, have improved absorption [16–19]. In view of the above fact and in connection to our previous review articles about biologically active heterocyclic systems [20–25], we decided to prepare this review to present for the reader a survey of the literature of the different azoles linked directly with imidazole nucleus; also some of the medicinal applications are mentioned.
Fused imidazopyrazole refers to three isomers according to the conjunction between imidazole and pyrazole nucleus. The three isomers of imidazopyrazole are shown in Figure 1.
Today, there are several approaches available for the synthesis of imidazopyrazoles and they may be classified into two main categories:(a)annulation of the imidazole ring onto a pyrazole scaffold;(b)annulation of the pyrazole ring onto an imidazole scaffold.
2. Synthesis by Annulation of the Imidazole Ring onto a Pyrazole Scaffold
2.1. Synthesis of Imidazo[1,2-b]Pyrazole
Ethyl 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carboxylate 3, obtained by reaction of 2-hydrazino-1-phenylethanol 1 with ethyl (ethoxymethylene)cyanoacetate 2, was treated with concentrated sulphuric acid at 0°C to give the 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxylate 4. Also, on condensation of 1 with ethoxymethylenemalononitrile in absolute ethanol the 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carbonitrile 6 was obtained and then hydrolysed in alkaline ethanol/water solution to form 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carboxamide 7. Finally, 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxamide 8 was prepared by cyclization in the presence of concentrated sulphuric acid . The synthesized 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole derivatives were tested in vitro in order to evaluate their ability to interfere with human neutrophil functions. All tested compounds showed strong inhibition of fMLP-OMe-induced chemotaxis (Scheme 1) [26, 27].
The synthesis of imidazo[1,2-b]pyrazoles was reported; thus the condensation of the hydrazinoacetaldehyde synthon with electrophiles such as ethyl (ethoxymethylene)cyanoacetate 2 and 3-oxo-2-phenylpropanenitrile 9 gave ethyl 5-amino-1-(2,2-diethoxyethyl)-1H-pyrazole-4-carboxylate 10 and 1-(2,2-diethoxyethyl)-4-phenyl-1H-pyrazol-5-amine 12, respectively. The latter compounds were cyclized in acid to produce imidazopyrazoles 11 and 13, respectively. Similarly, ethyl 5-amino-1-(2,2-diethoxyethyl)-1H-pyrazole-4-carboxylate 14 was reacted with hydrazine followed by reaction with nitrous acid to afford 1H-imidazo[1,2-b]pyrazole-7-carbonyl azide 15 rearranged to produce carbamates 16  (Scheme 2).
A series of 1H-imidazo[1,2-b]pyrazolecarboxylate derivatives were synthesized from reaction between ethyl cyanopyruvate sodium 17 and hydrazinoacetaldehyde diethylacetal in a biphasic water/chloroform in the presence of sulfuric acid to give ethyl 5-amino-1-(2,2-diethoxyethyl)-1H-pyrazole-3-carboxylate 18 followed by cyclization to give imidazopyrazole 19. The synthesized compounds were evaluated in vitro for 5-HT3 receptor affinity. The biochemical data show significant activity for these derivatives (Scheme 3) . On the other hand, imidazo[1,2-b]pyrazole-7-carbonitrile was prepared by the condensation of 2-hydrazinoacetaldehyde diethyl acetal with (ethoxymethylene)malononitrile 5, which gave pyrazole followed by ring closure under acid-catalyzed hydrolytic conditions to afford imidazopyrazole 21  (Scheme 3).
Amino-l-(2-hydroxyethyl)pyrazole 22 was formylated, treated with methanesulfonyl chloride and triethylamine, and then followed by cyclization with sodium hydride, to give 1-formyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole 23  (Scheme 4).
3-Amino-5-phenylpyrazoles 25 were reacted with 2-(4-methyl-2-phenyl-1,3-thiazol-5-yl)-2-oxo-N-phenylethanehydrazonoyl bromide 24 in boiling ethanol to give 3-phenylazo-2-(4-methyl-2-phenyl-thiazol-5-yl)-6-phenyl-5H-imidazo[1,2-b]pyrazoles 26 (Scheme 5) .
In the same fashion, it was reported that equimolar amounts of hydrazonoyl bromides 27 and 32 were reacted with 5-amino-3-phenyl-1H-pyrazole 25 in ethanol under reflux to afford the corresponding imidazo[1,2-b]pyrazoles 31 and 34, respectively (Scheme 6) [33, 34].
5-Aminopyrazole 25 was reacted with hydrazonyl halides such as 2-oxo--arylpropanehydrazonoyl chlorides 35 [35–37] and 2-bromobenzofurylglyoxal-2-arylhydrazones 37  in ethanol at reflux temperature to give 6-phenyl-3-(aryldiazenyl)-5H-imidazo[1,2-b]pyrazoles 36 and 38, respectively (Scheme 7).
Appel’s dehydration conditions of (2-oxo-1,2-diphenylethylidene)hydrazono)-N-phenylbutanamide 41, prepared from reaction of benzil hydrazone with acetoacetanilide, led to azinoketimine 42 which underwent electrocyclic ring closure under the reaction conditions to give imidazo[1,2-b]pyrazole-2-one 49 and 1H-imidazo[1,2-b]pyrazole 50  (Scheme 9).
In the same fashion, treatment of N-aziridinylimino carboxamides 52 prepared by the reaction of 1-amino-2-phenylaziridine 51 with acetoacetanilide in tetrahydrofuran at room temperature with a mixture of triphenylphosphine, carbon tetrachloride, and triethylamine (Appel’s condition) in dichloromethane at reflux temperature led to the formation of 2,3-dihydro-1H-imidazo[1,2-b]-pyrazoles 56 (54–82%) as a major product  (Scheme 10).
5-Amino-3-phenyl-1H-pyrazole 25 was reacted with hydroximoyl chloride 57 in ethanol at room temperature to give 3-nitroso-2-aryl-6-phenyl-1H-imidazo[1,2-b]pyrazoles 58 in 60–75% yields  (Scheme 11).
Intermolecular aza-Wittig reaction of 5-(triphenylphosphoranylideneamino)-3-phenylpyrazole 60 with -chloroketone, namely, 2-chloro-2-phenylacetophenone, chloroacetylchloride, and 1-chloro-1-(phenyldiazenyl)propan-2-one, afforded the imidazo[1,2-b]pyrazole derivatives 62a–c via elimination of hydrogen chloride from the initially formed intermediate 61  (Scheme 12).
A series of 2-aryl-7-cyano/ethoxycarbonyl-6-methylthio-1H-imidazo[1,2-b]pyrazoles 65 have been synthesized in moderate to good yields, via reaction of 5-amino-4-cyano/ethoxycarbonyl-3-methylthio-1H-pyrazole 63 with either -bromoacetophenones or -tosyloxyacetophenones followed by cyclocondensation of the formed intermediate 64 under acidic conditions. Using -tosyloxyacetophenones instead of -bromoacetophenones in the previous reaction has such advantages that the reactions gave the final products in higher yields, became more eco-friendly as well as less time consuming, and avoided highly lachrymatory and toxc -haloketones which are now not available commercially. Fungicidal activity of the synthesized compound was studied [43, 44] (Scheme 13).
3-Antipyrinyl-5-aminopyrazole 66 was reacted with either ethyl -chloroacetoacetate or chloroacetyl chloride to yield 1-(2-hydroxy-3H-imidazo[1,2-b]pyrazol-3-yl)ethanone 67 and 3H-imidazo[1,2-b]pyrazol-2-ol 68, respectively  (Scheme 14).
7-Chloro-6-methyl-2-phenyl-3-(phenylsulfinyl)-1H-imidazo[1,2-b]pyrazole 69, useful as starting materials for color photograph couplers and dyes, was prepared from treating 5-amino-4-chloro-3-methyl-1H-pyrazole 68 with phenacyl bromide in the presence of -collidine, reacting the product with PhSSPh in the presence of NaH and heating at 60° in the presence of HCl  (Scheme 15).
1H-Imidazo[1,2-b]pyrazole-7-carbonitrile derivatives, which are spleen tyrosine kinase (syk) inhibitors, are useful in the treatment of syk-mediated diseases. Thus, substituted imidazo[1,2-b]pyrazole-7-carbonitrile 76 was prepared by cyclocondensation of aminopyrazolecarbonitrile 73 with 3,4-dimethoxyphenyl isonitrile 74 and 2,4-dihydro-2-oxo-1H-benzo[d][1,3]oxazine-7-carbaldehyde 75  (Scheme 17).
In a recent report , 3-(benzylideneamino)-2-phenyl-5H-imidazo[1,2-b]pyrazole-7-carbonitriles 77 were synthesized, in moderate to high yields, from one-pot, four-component condensation reaction of aromatic aldehydes, toluene-4-sulfonylmethyl isocyanide, and 5-amino-1H-pyrazole-4-carbonitrile 73 in acetonitrile in the presence of p-toluenesulfonic acid as a catalyst at room temperature (Scheme 18).
Similarly, A series of N-alkyl-2-aryl-5H-imidazo[1,2-b]pyrazole-3-amines 78 in good to high yields were synthesized by the three-component condensation of an aromatic aldehyde, aminopyrazole, and isocyanide in acetonitrile in the presence of 4-toluenesulfonic acid as a catalyst at room temperature  (Scheme 19).
2.2. Syntheses of Imidazo[1,5-b]Pyrazole
2,3-Dihydroimidazo[1,5-b]pyrazoles 84 containing a structurally heterocyclic system corresponding to cyclized histamine were prepared by cyclodehydration of substituted N-(3-pyrazolylmethyl)acetamides 80 or N-(3-pyrazolylmethyl)acetamides 83, obtained by the catalytic hydrogenation of 1-benzoyl-4,5-dihydro-1H-pyrazole-3-carbonitriles 79 followed by acylation. These latter precursors 79 were conveniently obtained by the cycloaddition of substituted acrylonitriles with CH2N2 followed by in situ benzoylation using benzoyl chloride  (Scheme 20).
Recently, imidazo[4,5-c]pyrazoles 89 were synthesized in 65–96% yields by cyclization of -(4-halopyrazol-5-yl)amidine 88 under the conditions of copper-catalyzed cross-coupling reactions. Compound 88 was obtained via two pathways: (A) the reaction of 5-aminopyrazoles 25 with imidoyl chlorides 85 in dry 1,4-dioxane at room temperature and (B) the reaction of imino esters 87 with substituted aniline, followed by halogenations using either NBS in boiling acetonitrile or elementary iodine in the presence of KOH at room temperature  (Scheme 21).
Nitrosation of compound 25 with sodium nitrite yielded the 4-nitrosopyrazoles 90, which were reduced to the diamines 91 with hydrazine hydrate in the presence of palladized charcoal. Since 91 were often unstable during the usual work-up for isolation, they were directly reacted with thiophosgene to give the isothiocyanatopyrazoles 94. Heating of 94 in pyridine gave the imidazo[4,5-c]pyrazole-5-thiones 95. In order to obtain 5-substituted derivatives imidazo[4,5-c]pyrazole-5-thiones 95 were reacted with iodomethane in sodium hydroxide to give 5-methylthio derivatives 96, which were subjected to hydrogen peroxide to yield 3-methyl-5-methylsulfonyl-1-phenylimidazo[4,5-c]pyrazoles 97. Compound 96 was submitted to hydrogenolytic desulfurisation in the presence of Raney nickel, thus producing 98. When heated at 200°C for 2 h, 5-amino-4-ethoxycarbonylaminopyrazole 92, obtained by treatment of 91 with ethyl chloroformate, afforded imidazo[4,5-c]pyrazole-5-one 93. The key step in the synthesis of 5-methylimidazo[4,5-c]pyrazole 102 was the intramolecular cyclodehydration in boiling pyridine of 5-ethylamino-4-nitrosopyrazole 101, which was prepared from 5-acylaminopyrazole 100. Reduction of 99 with LiAlH4 afforded the 5-alkylaminopyrazole 100. Nitrosation of 100 with amyl nitrite in the presence of hydrochloric acid yielded 101. Imidazo[4,5-c]pyrazoles 93, 95, 96, 97, 98, and 102, which were considered of interest as potential herbicides, were examined for the preemergence, postemergence, and posttransplant control of weeds in rice against broadleaf and grass weed species. Some imidazo[4,5-c]pyrazoles have potential herbicidal activity against a wide range of weeds, with 5-thiomethyl 96 and 5-unsubstituted derivatives being the most efficient. No herbicidal activity was observed in the 5-methylsulfonylimidazo[4,5-c]pyrazole 97 and imidazo[4,5-c]pyrazolone 93 series  (Scheme 22).
Similarly, imidazo [4,5-c] pyrazoles 106 were synthesized by acylation 5-aminopyrazoles 25 either with benzoyl chloride or with acetic anhydride to give 5-acylaminopyrazoles 103. Reduction of compounds 103 with LiAlH4 afforded the corresponding 5-alkylaminopyrazoles 104. Nitrosation of compounds 104 with amyl nitrite in the presence of hydrochloric acid yielded 5-alkylamino-4-nitrosopyrazoles 105. Cyclisation of compounds 105 to imidazo [4,5-c] pyrazoles 106 was achieved by heating 105 in boiling pyridine for 15–90 min  (Scheme 23).
3. Syntheses by Annulation of the Pyrazole Ring onto an Imidazole Scaffold
3.1. Synthesis of Imidazo[1,2-b]Pyrazole
2,3-Dihydro-1H-imidazo[1,2-b]pyrazoles 112 and 113 were prepared by hydrazinolysis with 2,4-dinitrophenylhydrazine of ethyl 2-(1-(benzylideneamino)imidazolidin-2-ylidene)-2-nitroacetate 110 which was conveniently prepared from ethyl nitroacetate and N-benzylidene-2-(methylthio)-4,5-dihydro-1H-imidazol-1-amine 109 as described in Scheme 24 .
3.2. Synthesis of Imidazo[1,5-b]Pyrazole
Dihydro-1H-imidazo[1,5-b]pyrazole-4,6(2H,5H)-dione 119 was synthesized from treatment 1-(benzylideneamino)-5-(2-hydroxyethyl)hydantoin 117, prepared from treated sodium salt of acetone semicarbazone 115 withα-bromo-γ-butyrolactone 116 and the reaction mixture was then subjected to acid hydrolysis followed by condensation with benzaldehyde, with SOCl2 to give 1-benzylidene-2,3,3a,4,5,6-hexahydro-4,6-dioxo-1H-imidazo[1,5-b]pyrazolium chloride 118. Next the latter salt was treated with MeOH and ether  (Scheme 25).
3.3. Synthesis of Imidazo[4,5-c]Pyrazole
3-Amino-6-(β-D-ribofuranosyl)imidazo[4,5-c]pyrazole 125 was synthesized via an N–N bond formation strategy by a mononuclear heterocyclic rearrangement (MHR). Thus, 5-amino-1-(5-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-β-D-ribofuranosyl)-4-(1,2,4-oxadiazol-3-yl)imidazole 123, synthesized from treatment of 5-amino-1-(β-D-ribofuranosyl)imidazole-4-carboxamide 122 with sodium ethoxideat room temperature followed by reaction with ethyl acetate at reflux temperature, underwent the MHR with sodium hydride in DMF or DMSO to afford the corresponding 3-acetamidoimidazo[4,5-c]pyrazole nucleosides 124 in good yields. Subsequent protecting group manipulations afforded the desired 3-amino-6-(β-D-ribofuranosyl)imidazo[4,5-c]pyrazole 125 as a 5:5 fused analog of adenosine. Compound 125 was evaluated for activity against two herpes viruses, herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (HCMV), in a plaque reduction assay and an ELISA, respectively. Cytotoxicity was detected both in stationary human foreskin fibroblasts (HFF cells) and in growing KB cells. No activity was observed at the highest concentration tested (100 μM) against HCMV and HSV-1  (Scheme 26).
4. Miscellaneous Methods
1,5-Dihydrazino-2,4-dinitrobenzene 126 was treated with -ketoesters to give 65–95% corresponding dihydrazones 127, which were subjected to reductive cyclization using PtO2 catalyst to provide benzo [1,2-b:5,4-]bis (1H-imidazo[1,2-b]pyrazoles 128 in 47–54% yields  (Scheme 27).
Upon UV irradiation the substituted pyrrolo[2,3-d]-1,2,3-triazoles 129 (R = Me, Et; = Ph, substituted phenyl) were transformed toimidazo[4,5-c]pyrazoles 132 via intermediates 1,2,3,5-tetrazocine 130. X-ray crystal structure of 132 (R = Me, Ar = 4-BrC6H4) is reported  (Scheme 28).
This review has attempted to summarize the synthetic methods, reactions, and medicinal application of imidazopyrazoles. Synthesis of imidazopyrazole derivatives may be via two categories: annulations of imidazole ring onto a pyrazole scaffold or annulations of pyrazole ring onto an imidazole scaffold.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publishing of this paper.
The authors would like to thank the Research Center of College of Engineering at King Saud University for supporting this work.
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