# Fused Imidazopyrazoles: Synthetic Strategies and Medicinal Applications

Authors: Rizk E. Khidre; Bakr F. Abdel-Wahab; Othman Y. Alothman
Journal: Journal of Chemistry
 (2014)

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## Abstract

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.


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## Body

## 1. Introduction

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 havein vivo effects on the proliferation of mouse leukemic [1], and the same compound has antiviral activity in herpes simplex virus type 1-infected mammalian cells [12], 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 Figure1.(a)
(b)
(c)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-carboxylate3, obtained by reaction of 2-hydrazino-1-phenylethanol1 with ethyl (ethoxymethylene)cyanoacetate2, was treated with concentrated sulphuric acid at 0°C to give the 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxylate4. Also, on condensation of1 with ethoxymethylenemalononitrile in absolute ethanol the 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carbonitrile6 was obtained and then hydrolysed in alkaline ethanol/water solution to form 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carboxamide7. Finally, 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxamide8 was prepared by cyclization in the presence of concentrated sulphuric acid [26]. The synthesized 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole derivatives were testedin 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].Scheme 1The synthesis of imidazo[1,2-b]pyrazoles was reported; thus the condensation of the hydrazinoacetaldehyde synthon with electrophiles such as ethyl (ethoxymethylene)cyanoacetate2 and 3-oxo-2-phenylpropanenitrile9 gave ethyl 5-amino-1-(2,2-diethoxyethyl)-1H-pyrazole-4-carboxylate10 and 1-(2,2-diethoxyethyl)-4-phenyl-1H-pyrazol-5-amine12, respectively. The latter compounds were cyclized in acid to produce imidazopyrazoles11 and13, respectively. Similarly, ethyl 5-amino-1-(2,2-diethoxyethyl)-1H-pyrazole-4-carboxylate14 was reacted with hydrazine followed by reaction with nitrous acid to afford 1H-imidazo[1,2-b]pyrazole-7-carbonyl azide15 rearranged to produce carbamates16[28] (Scheme 2).Scheme 2A series of 1H-imidazo[1,2-b]pyrazolecarboxylate derivatives were synthesized from reaction between ethyl cyanopyruvate sodium17 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-carboxylate18 followed by cyclization to give imidazopyrazole19. The synthesized compounds were evaluatedin vitro for 5-HT3 receptor affinity. The biochemical data show significant activity for these derivatives (Scheme 3) [29]. On the other hand, imidazo[1,2-b]pyrazole-7-carbonitrile was prepared by the condensation of 2-hydrazinoacetaldehyde diethyl acetal with (ethoxymethylene)malononitrile5, which gave pyrazole followed by ring closure under acid-catalyzed hydrolytic conditions to afford imidazopyrazole21[30] (Scheme 3).Scheme 3Amino-l-(2-hydroxyethyl)pyrazole22 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]pyrazole23[31] (Scheme 4).Scheme 43-Amino-5-phenylpyrazoles25 were reacted with 2-(4-methyl-2-phenyl-1,3-thiazol-5-yl)-2-oxo-N-phenylethanehydrazonoyl bromide24 in boiling ethanol to give 3-phenylazo-2-(4-methyl-2-phenyl-thiazol-5-yl)-6-phenyl-5H-imidazo[1,2-b]pyrazoles26 (Scheme 5) [32].Scheme 5In the same fashion, it was reported that equimolar amounts of hydrazonoyl bromides27 and32 were reacted with 5-amino-3-phenyl-1H-pyrazole25 in ethanol under reflux to afford the corresponding imidazo[1,2-b]pyrazoles31 and34, respectively (Scheme 6) [33, 34].Scheme 65-Aminopyrazole25 was reacted with hydrazonyl halides such as 2-oxo-N′-arylpropanehydrazonoyl chlorides35 [35–37] and 2-bromobenzofurylglyoxal-2-arylhydrazones37 [38] in ethanol at reflux temperature to give 6-phenyl-3-(aryldiazenyl)-5H-imidazo[1,2-b]pyrazoles36 and38, respectively (Scheme 7).Scheme 7Regioselective cyclization reaction between compound25 and oxaldiimidoyl dichlorides39 in THF in the presence of triethylamine afforded 3H-imidazo[1,2-b]pyrazoles40 in good yields [39] (Scheme 8).Scheme 8Appel’s dehydration conditions of (2-oxo-1,2-diphenylethylidene)hydrazono)-N-phenylbutanamide41, prepared from reaction of benzil hydrazone with acetoacetanilide, led to azinoketimine42 which underwent electrocyclic ring closure under the reaction conditions to give imidazo[1,2-b]pyrazole-2-one49 and 1H-imidazo[1,2-b]pyrazole50[40] (Scheme 9).Scheme 9In the same fashion, treatment ofN-aziridinylimino carboxamides52 prepared by the reaction of 1-amino-2-phenylaziridine51 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]-pyrazoles56 (54–82%) as a major product [41] (Scheme 10).Scheme 105-Amino-3-phenyl-1H-pyrazole25 was reacted with hydroximoyl chloride57 in ethanol at room temperature to give 3-nitroso-2-aryl-6-phenyl-1H-imidazo[1,2-b]pyrazoles58 in 60–75% yields [30] (Scheme 11).Scheme 11Intermolecular aza-Wittig reaction of 5-(triphenylphosphoranylideneamino)-3-phenylpyrazole60 with α-chloroketone, namely, 2-chloro-2-phenylacetophenone, chloroacetylchloride, and 1-chloro-1-(phenyldiazenyl)propan-2-one, afforded the imidazo[1,2-b]pyrazole derivatives62a–cviaelimination of hydrogen chloride from the initially formed intermediate61 [42] (Scheme 12).Scheme 12A series of 2-aryl-7-cyano/ethoxycarbonyl-6-methylthio-1H-imidazo[1,2-b]pyrazoles65 have been synthesized in moderate to good yields,viareaction of 5-amino-4-cyano/ethoxycarbonyl-3-methylthio-1H-pyrazole63 with either α-bromoacetophenones or α-tosyloxyacetophenones followed by cyclocondensation of the formed intermediate64 under acidic conditions. Using α-tosyloxyacetophenones instead of α-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 α-haloketones which are now not available commercially. Fungicidal activity of the synthesized compound was studied [43, 44] (Scheme 13).Scheme 133-Antipyrinyl-5-aminopyrazole66 was reacted with either ethyl α-chloroacetoacetate or chloroacetyl chloride to yield 1-(2-hydroxy-3H-imidazo[1,2-b]pyrazol-3-yl)ethanone67 and 3H-imidazo[1,2-b]pyrazol-2-ol68, respectively [45] (Scheme 14).Scheme 147-Chloro-6-methyl-2-phenyl-3-(phenylsulfinyl)-1H-imidazo[1,2-b]pyrazole69, useful as starting materials for color photograph couplers and dyes, was prepared from treating 5-amino-4-chloro-3-methyl-1H-pyrazole68 with phenacyl bromide in the presence of γ-collidine, reacting the product with PhSSPh in the presence of NaH and heating at 60° in the presence of HCl [46] (Scheme 15).Scheme 15Ethyl 2-hydrazinylacetate hydrochloride70 was reacted with 2-oxo-N′,2-diphenylacetohydrazonoyl cyanide71 to afford 6-phenyl-7-(phenyldiazenyl)-1H-imidazo[1,2-b]pyrazole-2(3H)-one72 [47] (Scheme 16).Scheme 161H-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-carbonitrile76 was prepared by cyclocondensation of aminopyrazolecarbonitrile73 with 3,4-dimethoxyphenyl isonitrile74 and 2,4-dihydro-2-oxo-1H-benzo[d][1,3]oxazine-7-carbaldehyde75[35] (Scheme 17).Scheme 17In a recent report [36], 3-(benzylideneamino)-2-phenyl-5H-imidazo[1,2-b]pyrazole-7-carbonitriles77 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-carbonitrile73 in acetonitrile in the presence of p-toluenesulfonic acid as a catalyst at room temperature (Scheme 18).Scheme 18Similarly, A series ofN-alkyl-2-aryl-5H-imidazo[1,2-b]pyrazole-3-amines78 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 [37] (Scheme 19).Scheme 19


### 2.2. Syntheses of Imidazo[1,5-b]Pyrazole

2,3-Dihydroimidazo[1,5-b]pyrazoles84 containing a structurally heterocyclic system corresponding to cyclized histamine were prepared by cyclodehydration of substitutedN-(3-pyrazolylmethyl)acetamides80 orN-(3-pyrazolylmethyl)acetamides83, obtained by the catalytic hydrogenation of 1-benzoyl-4,5-dihydro-1H-pyrazole-3-carbonitriles79 followed by acylation. These latter precursors79 were conveniently obtained by the cycloaddition of substituted acrylonitriles with CH2N2 followed byin situ benzoylation using benzoyl chloride [48] (Scheme 20).Scheme 20


### 2.3. Imidazo[4,5-c]Pyrazole

Recently, imidazo[4,5-c]pyrazoles89 were synthesized in 65–96% yields by cyclization of N′-(4-halopyrazol-5-yl)amidine88 under the conditions of copper-catalyzed cross-coupling reactions. Compound88 was obtainedvia two pathways: (A) the reaction of 5-aminopyrazoles25 with imidoyl chlorides85 in dry 1,4-dioxane at room temperature and (B) the reaction of imino esters87 with substituted aniline, followed by halogenations using either NBS in boiling acetonitrile or elementary iodine in the presence of KOH at room temperature [49] (Scheme 21).Scheme 21Nitrosation of compound25 with sodium nitrite yielded the 4-nitrosopyrazoles90, which were reduced to the diamines91 with hydrazine hydrate in the presence of palladized charcoal. Since91 were often unstable during the usual work-up for isolation, they were directly reacted with thiophosgene to give the isothiocyanatopyrazoles94. Heating of94 in pyridine gave the imidazo[4,5-c]pyrazole-5-thiones95. In order to obtain 5-substituted derivatives imidazo[4,5-c]pyrazole-5-thiones95 were reacted with iodomethane in sodium hydroxide to give 5-methylthio derivatives96, which were subjected to hydrogen peroxide to yield 3-methyl-5-methylsulfonyl-1-phenylimidazo[4,5-c]pyrazoles97. Compound96 was submitted to hydrogenolytic desulfurisation in the presence of Raney nickel, thus producing98. When heated at 200°C for 2 h, 5-amino-4-ethoxycarbonylaminopyrazole92, obtained by treatment of91 with ethyl chloroformate, afforded imidazo[4,5-c]pyrazole-5-one93. The key step in the synthesis of 5-methylimidazo[4,5-c]pyrazole102 was the intramolecular cyclodehydration in boiling pyridine of 5-ethylamino-4-nitrosopyrazole101, which was prepared from 5-acylaminopyrazole100. Reduction of99 with LiAlH4 afforded the 5-alkylaminopyrazole100. Nitrosation of100 with amyl nitrite in the presence of hydrochloric acid yielded101. Imidazo[4,5-c]pyrazoles93,95,96,97,98, and102, 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-thiomethyl96 and 5-unsubstituted derivatives being the most efficient. No herbicidal activity was observed in the 5-methylsulfonylimidazo[4,5-c]pyrazole97 and imidazo[4,5-c]pyrazolone93 series [50] (Scheme 22).Scheme 22
Reagents: a, NO+; b, N2H4, Pd/C; c, CSCl2; d, reflux, pyridine; e, MeI; f, Raney Ni; g, H2O2; h, ClCO2Et; i, heat at 200°C, 2 h; j, Ac2O; k, LiAlH4.Similarly, imidazo [4,5-c] pyrazoles106 were synthesized by acylation 5-aminopyrazoles25 either with benzoyl chloride or with acetic anhydride to give 5-acylaminopyrazoles103. Reduction of compounds103 with LiAlH4 afforded the corresponding 5-alkylaminopyrazoles104. Nitrosation of compounds104 with amyl nitrite in the presence of hydrochloric acid yielded 5-alkylamino-4-nitrosopyrazoles105. Cyclisation of compounds105 to imidazo [4,5-c] pyrazoles106 was achieved by heating105 in boiling pyridine for 15–90 min [51] (Scheme 23).Scheme 23


## 2.1. Synthesis of Imidazo[1,2-b]Pyrazole

Ethyl 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carboxylate3, obtained by reaction of 2-hydrazino-1-phenylethanol1 with ethyl (ethoxymethylene)cyanoacetate2, was treated with concentrated sulphuric acid at 0°C to give the 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxylate4. Also, on condensation of1 with ethoxymethylenemalononitrile in absolute ethanol the 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carbonitrile6 was obtained and then hydrolysed in alkaline ethanol/water solution to form 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carboxamide7. Finally, 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxamide8 was prepared by cyclization in the presence of concentrated sulphuric acid [26]. The synthesized 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole derivatives were testedin 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].Scheme 1The synthesis of imidazo[1,2-b]pyrazoles was reported; thus the condensation of the hydrazinoacetaldehyde synthon with electrophiles such as ethyl (ethoxymethylene)cyanoacetate2 and 3-oxo-2-phenylpropanenitrile9 gave ethyl 5-amino-1-(2,2-diethoxyethyl)-1H-pyrazole-4-carboxylate10 and 1-(2,2-diethoxyethyl)-4-phenyl-1H-pyrazol-5-amine12, respectively. The latter compounds were cyclized in acid to produce imidazopyrazoles11 and13, respectively. Similarly, ethyl 5-amino-1-(2,2-diethoxyethyl)-1H-pyrazole-4-carboxylate14 was reacted with hydrazine followed by reaction with nitrous acid to afford 1H-imidazo[1,2-b]pyrazole-7-carbonyl azide15 rearranged to produce carbamates16[28] (Scheme 2).Scheme 2A series of 1H-imidazo[1,2-b]pyrazolecarboxylate derivatives were synthesized from reaction between ethyl cyanopyruvate sodium17 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-carboxylate18 followed by cyclization to give imidazopyrazole19. The synthesized compounds were evaluatedin vitro for 5-HT3 receptor affinity. The biochemical data show significant activity for these derivatives (Scheme 3) [29]. On the other hand, imidazo[1,2-b]pyrazole-7-carbonitrile was prepared by the condensation of 2-hydrazinoacetaldehyde diethyl acetal with (ethoxymethylene)malononitrile5, which gave pyrazole followed by ring closure under acid-catalyzed hydrolytic conditions to afford imidazopyrazole21[30] (Scheme 3).Scheme 3Amino-l-(2-hydroxyethyl)pyrazole22 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]pyrazole23[31] (Scheme 4).Scheme 43-Amino-5-phenylpyrazoles25 were reacted with 2-(4-methyl-2-phenyl-1,3-thiazol-5-yl)-2-oxo-N-phenylethanehydrazonoyl bromide24 in boiling ethanol to give 3-phenylazo-2-(4-methyl-2-phenyl-thiazol-5-yl)-6-phenyl-5H-imidazo[1,2-b]pyrazoles26 (Scheme 5) [32].Scheme 5In the same fashion, it was reported that equimolar amounts of hydrazonoyl bromides27 and32 were reacted with 5-amino-3-phenyl-1H-pyrazole25 in ethanol under reflux to afford the corresponding imidazo[1,2-b]pyrazoles31 and34, respectively (Scheme 6) [33, 34].Scheme 65-Aminopyrazole25 was reacted with hydrazonyl halides such as 2-oxo-N′-arylpropanehydrazonoyl chlorides35 [35–37] and 2-bromobenzofurylglyoxal-2-arylhydrazones37 [38] in ethanol at reflux temperature to give 6-phenyl-3-(aryldiazenyl)-5H-imidazo[1,2-b]pyrazoles36 and38, respectively (Scheme 7).Scheme 7Regioselective cyclization reaction between compound25 and oxaldiimidoyl dichlorides39 in THF in the presence of triethylamine afforded 3H-imidazo[1,2-b]pyrazoles40 in good yields [39] (Scheme 8).Scheme 8Appel’s dehydration conditions of (2-oxo-1,2-diphenylethylidene)hydrazono)-N-phenylbutanamide41, prepared from reaction of benzil hydrazone with acetoacetanilide, led to azinoketimine42 which underwent electrocyclic ring closure under the reaction conditions to give imidazo[1,2-b]pyrazole-2-one49 and 1H-imidazo[1,2-b]pyrazole50[40] (Scheme 9).Scheme 9In the same fashion, treatment ofN-aziridinylimino carboxamides52 prepared by the reaction of 1-amino-2-phenylaziridine51 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]-pyrazoles56 (54–82%) as a major product [41] (Scheme 10).Scheme 105-Amino-3-phenyl-1H-pyrazole25 was reacted with hydroximoyl chloride57 in ethanol at room temperature to give 3-nitroso-2-aryl-6-phenyl-1H-imidazo[1,2-b]pyrazoles58 in 60–75% yields [30] (Scheme 11).Scheme 11Intermolecular aza-Wittig reaction of 5-(triphenylphosphoranylideneamino)-3-phenylpyrazole60 with α-chloroketone, namely, 2-chloro-2-phenylacetophenone, chloroacetylchloride, and 1-chloro-1-(phenyldiazenyl)propan-2-one, afforded the imidazo[1,2-b]pyrazole derivatives62a–cviaelimination of hydrogen chloride from the initially formed intermediate61 [42] (Scheme 12).Scheme 12A series of 2-aryl-7-cyano/ethoxycarbonyl-6-methylthio-1H-imidazo[1,2-b]pyrazoles65 have been synthesized in moderate to good yields,viareaction of 5-amino-4-cyano/ethoxycarbonyl-3-methylthio-1H-pyrazole63 with either α-bromoacetophenones or α-tosyloxyacetophenones followed by cyclocondensation of the formed intermediate64 under acidic conditions. Using α-tosyloxyacetophenones instead of α-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 α-haloketones which are now not available commercially. Fungicidal activity of the synthesized compound was studied [43, 44] (Scheme 13).Scheme 133-Antipyrinyl-5-aminopyrazole66 was reacted with either ethyl α-chloroacetoacetate or chloroacetyl chloride to yield 1-(2-hydroxy-3H-imidazo[1,2-b]pyrazol-3-yl)ethanone67 and 3H-imidazo[1,2-b]pyrazol-2-ol68, respectively [45] (Scheme 14).Scheme 147-Chloro-6-methyl-2-phenyl-3-(phenylsulfinyl)-1H-imidazo[1,2-b]pyrazole69, useful as starting materials for color photograph couplers and dyes, was prepared from treating 5-amino-4-chloro-3-methyl-1H-pyrazole68 with phenacyl bromide in the presence of γ-collidine, reacting the product with PhSSPh in the presence of NaH and heating at 60° in the presence of HCl [46] (Scheme 15).Scheme 15Ethyl 2-hydrazinylacetate hydrochloride70 was reacted with 2-oxo-N′,2-diphenylacetohydrazonoyl cyanide71 to afford 6-phenyl-7-(phenyldiazenyl)-1H-imidazo[1,2-b]pyrazole-2(3H)-one72 [47] (Scheme 16).Scheme 161H-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-carbonitrile76 was prepared by cyclocondensation of aminopyrazolecarbonitrile73 with 3,4-dimethoxyphenyl isonitrile74 and 2,4-dihydro-2-oxo-1H-benzo[d][1,3]oxazine-7-carbaldehyde75[35] (Scheme 17).Scheme 17In a recent report [36], 3-(benzylideneamino)-2-phenyl-5H-imidazo[1,2-b]pyrazole-7-carbonitriles77 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-carbonitrile73 in acetonitrile in the presence of p-toluenesulfonic acid as a catalyst at room temperature (Scheme 18).Scheme 18Similarly, A series ofN-alkyl-2-aryl-5H-imidazo[1,2-b]pyrazole-3-amines78 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 [37] (Scheme 19).Scheme 19


## 2.2. Syntheses of Imidazo[1,5-b]Pyrazole

2,3-Dihydroimidazo[1,5-b]pyrazoles84 containing a structurally heterocyclic system corresponding to cyclized histamine were prepared by cyclodehydration of substitutedN-(3-pyrazolylmethyl)acetamides80 orN-(3-pyrazolylmethyl)acetamides83, obtained by the catalytic hydrogenation of 1-benzoyl-4,5-dihydro-1H-pyrazole-3-carbonitriles79 followed by acylation. These latter precursors79 were conveniently obtained by the cycloaddition of substituted acrylonitriles with CH2N2 followed byin situ benzoylation using benzoyl chloride [48] (Scheme 20).Scheme 20


## 2.3. Imidazo[4,5-c]Pyrazole

Recently, imidazo[4,5-c]pyrazoles89 were synthesized in 65–96% yields by cyclization of N′-(4-halopyrazol-5-yl)amidine88 under the conditions of copper-catalyzed cross-coupling reactions. Compound88 was obtainedvia two pathways: (A) the reaction of 5-aminopyrazoles25 with imidoyl chlorides85 in dry 1,4-dioxane at room temperature and (B) the reaction of imino esters87 with substituted aniline, followed by halogenations using either NBS in boiling acetonitrile or elementary iodine in the presence of KOH at room temperature [49] (Scheme 21).Scheme 21Nitrosation of compound25 with sodium nitrite yielded the 4-nitrosopyrazoles90, which were reduced to the diamines91 with hydrazine hydrate in the presence of palladized charcoal. Since91 were often unstable during the usual work-up for isolation, they were directly reacted with thiophosgene to give the isothiocyanatopyrazoles94. Heating of94 in pyridine gave the imidazo[4,5-c]pyrazole-5-thiones95. In order to obtain 5-substituted derivatives imidazo[4,5-c]pyrazole-5-thiones95 were reacted with iodomethane in sodium hydroxide to give 5-methylthio derivatives96, which were subjected to hydrogen peroxide to yield 3-methyl-5-methylsulfonyl-1-phenylimidazo[4,5-c]pyrazoles97. Compound96 was submitted to hydrogenolytic desulfurisation in the presence of Raney nickel, thus producing98. When heated at 200°C for 2 h, 5-amino-4-ethoxycarbonylaminopyrazole92, obtained by treatment of91 with ethyl chloroformate, afforded imidazo[4,5-c]pyrazole-5-one93. The key step in the synthesis of 5-methylimidazo[4,5-c]pyrazole102 was the intramolecular cyclodehydration in boiling pyridine of 5-ethylamino-4-nitrosopyrazole101, which was prepared from 5-acylaminopyrazole100. Reduction of99 with LiAlH4 afforded the 5-alkylaminopyrazole100. Nitrosation of100 with amyl nitrite in the presence of hydrochloric acid yielded101. Imidazo[4,5-c]pyrazoles93,95,96,97,98, and102, 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-thiomethyl96 and 5-unsubstituted derivatives being the most efficient. No herbicidal activity was observed in the 5-methylsulfonylimidazo[4,5-c]pyrazole97 and imidazo[4,5-c]pyrazolone93 series [50] (Scheme 22).Scheme 22
Reagents: a, NO+; b, N2H4, Pd/C; c, CSCl2; d, reflux, pyridine; e, MeI; f, Raney Ni; g, H2O2; h, ClCO2Et; i, heat at 200°C, 2 h; j, Ac2O; k, LiAlH4.Similarly, imidazo [4,5-c] pyrazoles106 were synthesized by acylation 5-aminopyrazoles25 either with benzoyl chloride or with acetic anhydride to give 5-acylaminopyrazoles103. Reduction of compounds103 with LiAlH4 afforded the corresponding 5-alkylaminopyrazoles104. Nitrosation of compounds104 with amyl nitrite in the presence of hydrochloric acid yielded 5-alkylamino-4-nitrosopyrazoles105. Cyclisation of compounds105 to imidazo [4,5-c] pyrazoles106 was achieved by heating105 in boiling pyridine for 15–90 min [51] (Scheme 23).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]pyrazoles112 and113 were prepared by hydrazinolysis with 2,4-dinitrophenylhydrazine of ethyl 2-(1-(benzylideneamino)imidazolidin-2-ylidene)-2-nitroacetate110 which was conveniently prepared from ethyl nitroacetate andN-benzylidene-2-(methylthio)-4,5-dihydro-1H-imidazol-1-amine109as described in Scheme 24 [52].Scheme 24


### 3.2. Synthesis of Imidazo[1,5-b]Pyrazole

Dihydro-1H-imidazo[1,5-b]pyrazole-4,6(2H,5H)-dione119 was synthesized from treatment 1-(benzylideneamino)-5-(2-hydroxyethyl)hydantoin117, prepared from treated sodium salt of acetone semicarbazone115 withα-bromo-γ-butyrolactone116 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 chloride118. Next the latter salt was treated with MeOH and ether [53] (Scheme 25).Scheme 25


### 3.3. Synthesis of Imidazo[4,5-c]Pyrazole

3-Amino-6-(β-D-ribofuranosyl)imidazo[4,5-c]pyrazole125 was synthesizedvia 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)imidazole123, synthesized from treatment of 5-amino-1-(β-D-ribofuranosyl)imidazole-4-carboxamide122with 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 nucleosides124 in good yields. Subsequent protecting group manipulations afforded the desired 3-amino-6-(β-D-ribofuranosyl)imidazo[4,5-c]pyrazole125 as a 5:5 fused analog of adenosine. Compound125 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 [54] (Scheme 26).Scheme 26
Reagents and conditions: (a) NH2OH, EtOH, reflux, 90 min, 70%; (b) (i) Na/EtOH, rt; (ii) MeCO2Et, EtOH, reflux; (c) NaH, DMSO, 75–100°C, 15 min,124b: 74% from123; (d) (i) NaH, DMF, 75–100°C, 15 min; (ii) TBAF, THF, 0°C, rt, overnight,124a: 43% from123; (e) (i) NaH, DMF, 75–100°C, 15 min; (ii) TBSCl, imidazole, cat. DMAP, DMF, rt, 8 h,124b: 55% from123.


## 3.1. Synthesis of Imidazo[1,2-b]Pyrazole

2,3-Dihydro-1H-imidazo[1,2-b]pyrazoles112 and113 were prepared by hydrazinolysis with 2,4-dinitrophenylhydrazine of ethyl 2-(1-(benzylideneamino)imidazolidin-2-ylidene)-2-nitroacetate110 which was conveniently prepared from ethyl nitroacetate andN-benzylidene-2-(methylthio)-4,5-dihydro-1H-imidazol-1-amine109as described in Scheme 24 [52].Scheme 24


## 3.2. Synthesis of Imidazo[1,5-b]Pyrazole

Dihydro-1H-imidazo[1,5-b]pyrazole-4,6(2H,5H)-dione119 was synthesized from treatment 1-(benzylideneamino)-5-(2-hydroxyethyl)hydantoin117, prepared from treated sodium salt of acetone semicarbazone115 withα-bromo-γ-butyrolactone116 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 chloride118. Next the latter salt was treated with MeOH and ether [53] (Scheme 25).Scheme 25


## 3.3. Synthesis of Imidazo[4,5-c]Pyrazole

3-Amino-6-(β-D-ribofuranosyl)imidazo[4,5-c]pyrazole125 was synthesizedvia 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)imidazole123, synthesized from treatment of 5-amino-1-(β-D-ribofuranosyl)imidazole-4-carboxamide122with 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 nucleosides124 in good yields. Subsequent protecting group manipulations afforded the desired 3-amino-6-(β-D-ribofuranosyl)imidazo[4,5-c]pyrazole125 as a 5:5 fused analog of adenosine. Compound125 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 [54] (Scheme 26).Scheme 26
Reagents and conditions: (a) NH2OH, EtOH, reflux, 90 min, 70%; (b) (i) Na/EtOH, rt; (ii) MeCO2Et, EtOH, reflux; (c) NaH, DMSO, 75–100°C, 15 min,124b: 74% from123; (d) (i) NaH, DMF, 75–100°C, 15 min; (ii) TBAF, THF, 0°C, rt, overnight,124a: 43% from123; (e) (i) NaH, DMF, 75–100°C, 15 min; (ii) TBSCl, imidazole, cat. DMAP, DMF, rt, 8 h,124b: 55% from123.


## 4. Miscellaneous Methods

1,5-Dihydrazino-2,4-dinitrobenzene126 was treated with β-ketoesters to give 65–95% corresponding dihydrazones127, which were subjected to reductive cyclization using PtO2 catalyst to provide benzo [1,2-b:5,4-b′]bis (1H-imidazo[1,2-b]pyrazoles128 in 47–54% yields [55] (Scheme 27).Scheme 27Upon UV irradiation the substituted pyrrolo[2,3-d]-1,2,3-triazoles129 (R = Me, Et; R1 = Ph, substituted phenyl) were transformed toimidazo[4,5-c]pyrazoles132via intermediates 1,2,3,5-tetrazocine130. X-ray crystal structure of132 (R = Me, Ar = 4-BrC6H4) is reported [56] (Scheme 28).Scheme 28


## 5. Conclusions

This review has attempted to summarize the synthetic methods, reactions, and medicinal application of imidazopyrazoles. Synthesis of imidazopyrazole derivatives may bevia two categories: annulations of imidazole ring onto a pyrazole scaffold or annulations of pyrazole ring onto an imidazole scaffold.



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*Source: 217596-2014-08-14.xml*