A concise review on synthesis, reactions and biological Importance of thienopyrazoles

Pyrazoles are five membered heterocycles constitute a higly significant class of compounds in organic synthesis. Nowadays, pyrazoles and condensed pyrazoles have attracted substantial attention of the scientists owing to their excellent pharmacological and agrochemical properties. Pyrazole derivatives exhibit a wide range of pharmacological effects such as:


Introduction
Thienopyrazoles occupy a unique position in medicinal chemistry as a result of their broad spectrum of biological activities.4][5] They are used as antioxidants against the toxicity of 4-nonylphenol in Clarias gariepinus (African catfish). 66][17][18] Moreover, thieno [3,4-c]pyrazoles show remarkable analgesic, antiinflammatory and antipyretic activities in mice or rats, as well as a anti platelet-aggregation activity in vitro. 19lso, thieno [3,2-c]pyrazoles were identified as a new class of bacterial cell wall biosynthesis inhibitors 20 and antimicrobial agents against different strains of fungi and bacteria 21,22 as well as anti-tubercular agents against Mycobacterium tuberculosis H 37 RV . 23 Thienopyrazoles are organic compounds in which a pyrazole and a thiophene ring are fused to form a single unit.Depending on the position of the sulfur atom in the thiophene ring with respect to diazo group in pyrazole ring, there are three different regioisomers Figure (1).

Scheme 4
The proposed mechanism for the formation of products 13, 14 is described below in Scheme 5.

Scheme 12
Zaitsev et al. 48,49 found a new method for preparing of thieno [2,3-c]pyrazole derivatives starting from dinitropyrazole derivative 35.The carbonitrile 37 was synthesized from dinitropyrazole 35 by two methods.According to the first method, reaction of 35 with dimethyl formamide dimethyl acetal (DMF-DMA) followed by nitrosation with sodium nitrite solution in HCl afforded the isonitroso-aldehyde 36.Treatment of 36 with trifluroacetic anhydride and 4-dimethylaminopyridine (DMAP) resulted in the corresponding pyrazole carbonitrile 37 according to the reported procedure.In the second method, oxidation of the methyl group of 4methyl-3,5-dinitropyrazole 35 afforded the corresponding carboxylic acid 38, which was esterified to give ester 39.By treatment with aqueous ammonia, ester 37 was converted into carboxamide 40, which was treated with phosphorus pentoxide to give the carbonitrile 37. Carbonitrile 37 was reacted with thioglycolic acid anilide in the presence of two equivalents of potassium carbonate in boiling acetonitrile to give the substituted thieno[2,3-c]pyrazole 42.Evidently, carbonitrile 41 resulting from displacement of the 5-NO 2 group underwent Thorpe-Ziegler-cyclization in situ at the CN group to give bicyclic thienopyrazole compound 42 (Scheme 13).
Gernot A. Eller et al. 54 have synthesized thieno[2,3-c]pyrazole from pyrazole derivatives using Sonogashira coupling method, starting from easily accessible and commercially available 1,3-disubstituted-5-chloro-1Hpyrazoles 57a,b, a second halogen substituent was introduced at position 4 of the pyrazole nucleus by a standard halogenation protocol (I 2 − IO 3 -) to obtain the corresponding 5-chloro-4-iodopyrazoles 58a,b.The latter compounds were selectively linked to phenylacetylene in a Sonogashira cross-coupling reaction, yielding only the 4-(phenylethynyl)pyrazoles 59a,b in good yields (87-92%).In the final reaction step, compounds 59a,b were reacted with sodium sulfide in dimethyl formamide to produce the target fused heterocyclic ring system of compounds 60a,b Scheme 17.
Magdy W. Sabaa et al. 55 and Samira T. Rabie et al. 56 have synthesized thieno[2,3-c]pyrazole using the Gewald reaction.The N-phenyl pyrazolone 43 undergoes the Gewald reaction and reacts with sulfur and malononitrile in equimolar ratios under reflux for 3 h in presence of triethyl amine (TEA) and absolute ethanol as a solvent to give the aminocyano derivative of thienopyrazole 61 (Scheme 18).65) in 30% yield 57 (Scheme 19).

Scheme 20
In similar manner, aldehyde 66 reacted with phenylhydrazine in the presence of TsOH in THF followed by treatment with 30% H 2 SO 4 gave a mixture of two derivatives of thienopyrazole 69 and 70 in 50 and 5% yield respectively [58][59][60] (Scheme 21).

Scheme 21
The reaction might proceed by hydrolysis of the 1,4-dioxolane ring to ketone group followed by condensation of phenyl hydrazine with an aldehyde group and loss of H 2 O of the enol form of keto group, or by condensation with ketone group followed by loss of H 2 O from the enolised form of aldehyde as outlined below (Scheme 22).
Airey et al. 71 have reported a practical synthesis of multi gram quantities of 1H-thieno[3,2-c]pyrazole in which the Jacobson reaction serves as the key step.Two methods of synthesis of 122 have been reported by Gronowitz and co-workers. 72The first synthesis started from 3-bromothiophene-2-carbaldehyde 118, which was subjected to aromatic nucleophilic substitution with sodium azide to give the azide 119 in 48% yield.Treatment of azide 119 with hydrazine hydrate in boiling ethanol containing a small amount of acetic acid gave the desired thieno[3,2-c]pyrazole 122.In the second method, also starting from azide 119, the azide group was reduced to amine 120, which was then diazotized.Reduction of the resulting diazonium salt 121 gave the unsubstituted thieno[3,2-c]pyrazole 122.Thus, 122 was available in a 7.7% overall yield by a two-step sequence or in a 5.7-12% yield through a four-step sequence (Scheme 35).

Scheme 36
When a solution of ester 125 was added slowly to a suspension of lithium aluminum hydride in refluxing 1,4-dioxane, 74 subsequent work up gave crude (2-methyl-3-thienyl)amine 126 which was then used directly in the cyclization step as shown below.Cyclization of 126 was affected simply by acetylation of the amine group in toluene in the presence of potassium acetate, followed by treatment of the resulting mixture with isoamyl nitrite and heating for several hours.The overall yield of this three-steps sequence to un-substituted thieno [3,2-c]pyrazole 122 was 47%.Condensation of the methyl group of compound 126 with the nitroso group followed by ring closure upon elimination of ROH gave 127 Scheme 37.

Scheme 37
Another route for synthesizing the thieno [3,2-c]pyrazoles 130-133 according to a patent 75 20) was reacted with elemental sulfur in the presence of triethylamine in ethanol to give 4-mercapto-3-methyl-1H-pyrazol-5(4H)-one (139).Compound 139 was reacted with ethyl acetoacetate in the presence of triethylamine in ethanol to give mercapto pyrazolopyrazoledione 140, which in turn was reacted with compounds containing activated methylene in the presence of triethylamine to give thienopyrazolopyrazoles 141-144 77 (Scheme 41).

Scheme 46
Ernest et al. 81 reported that the arylhydrazone in the previous reaction with substitution in ortho position failed to cyclized into pyrazole and they also reported the synthesis of pyrazole 152 from the 4-tolyl-and 4methoxyphenyl hydrazones.Contrary, the ring formation is so rapid in case of the using 4-tolylhydrazone that the hydrazone is not isolated andthe pyrazole is formed directly.Singh et al 82 have reported a novel radical cyclization approach to thienopyrazole heterocycles.The scope and generality of this efficient radical-mediated thiophene annulation protocol was further evident by extending the methodology to the synthesis of tetra substituted thieno[3,2-c]pyrazoles.Thus when acrylonitrile precursors 153a,b were subjected to radical cyclization under identical conditions, this led to the formation of 5-substituted thieno[3,2-c]pyrazole-6-carbonitrile 154a,b (Scheme 47).

Scheme 47
Anand Acharya et al 83,84 have developed a method for synthesis of thieno [3,2-c]pyrazole and other fused systems through palladium-catalyzed oxidative C-H functionalization-intramolecular aryl thiolation.The reaction might proceed through nucleophilic addition of active methylene group of 155, 159 to the C=S-bond of compound 156 followed by elimination of MeSH to give the non-isolated compounds 157, 160 which underwent cyclization to afford 158, 161 respectively (Scheme 48).

Scheme 51
A literature survey on thienopyrazoles revealed that most of papers focus on synthesis of the thienopyrazole substituted at position 5 similar to structure B. Few reports deal with o-bifunctionalized thienopyrazole similar to structure A [89][90][91] .Kamal El-Dean et al. have continued their previous work in the synthesis of heterocyclic compounds containing the pyrazole moiety.They have reported a novel facile method of synthesis of thieno [2,3-c]pyrazoles substituted at positions 4 and 5 similar to structure A 4 .When the amino thienopyrazole carboxamide compound 47b was subjected to reaction with triethyl orthoformate in the presence of catalytic amount of acetic acid, 3-methyl-1-phenyl pyrazolo [3',4':5,4]  thieno [3,2-d]pyrimidin-7(6H)-one 169 was obtained.The pyrazolothieno-pyrimidinone 169 was converted to the corresponding chloropyrimidine compound 170 by the reaction with phosphorus oxychloride.The chloride atom in the chloropyrimidine compound 170 underwent nucleophilic substitution reactions with various aromatic and/or heterocyclic amines upon reflux in ethanol to afford the corresponding 4-aryl (heterocyclyl) aminomethyl compounds 171a-c.Also, compound 169 was converted to the pyrazolothienopyrimidinethione 172 using phosphorus pentasulfide in refluxing pyridine.The latter compound was obtained via an alternative route by the reaction of the chloropyrimidine derivative 170 with thiourea.The products obtained from the two routes were identical in all aspects.Alkylation of thione 172 by using different α-halocarbonyl compounds, namely: ethyl chloroacetate, chloroacetone and phenacyl bromide in ethanol in the presence of sodium acetate afforded the S-alkylated mercaptopyrazolothienopyrimidine derivatives 173a-c 4, 50 (Scheme 52).

Scheme 54
The amino function of 32 could be easily converted into a pyrrol-1-yl group in a Paal-Knorr-reaction on treatment with 2,5-dimethoxytetrahydrofuran (DMTHF) in refluxing acetic acid following the reported procedure to give 181 46 (Scheme 55).

Scheme 55
The pyrrolyl ester 181 reacted with hydrazine hydrate to afford the corresponding hydrazide 182.Condensation of 182 with some aromatic aldehydes yielded the expected hydrazones 183a-c.The carbohydrazide 182 proved to be a versatile precursor for the synthesis of several thieno[2,3-c]pyrazole derivatives.Thus, the oxadiazole thione 184 was obtained directly by the reaction of 182 with carbon disulfide in the presence of pyridine.However, the 1,2,4-triazole thione 186, was obtained in two steps via the reaction of 182 with phenyl isothiocyanate, followed by heating the resulting aroyl thiosemicarbazide 185 in aqueous NaOH.The thioamide groups of both 184 and 186 were readily methylated by methyl iodide in the presence of sodium acetate to give the corresponding methylthio derivatives 187a and 187b respectively 46 (Scheme 56).

Scheme 57
The synthetic utility of the acid azide 191 as a key intermediate in the synthesis of new thienopyrazole derivatives is shown below 46 .Thus, when 191 was heated with various alcohols, Curtius rearrangement occurred to give the isocyanate intermediate 192 which reacted with the alcohols to afford the corresponding carbamates 193 a-d.The symmetrical disubstituted urea 194 was obtained when the acid azide 191 was heated in boiling water.The urea derivatives 195 a,b were obtained when the acid azide 191 was heated with aniline and morpholine, again via Curtius rearrangement.Attempts to hydrolyse the carbamates 193 to the amino-thienopyrazoles 196 by boiling with aqueous ethanolic sodium hydroxide were unsuccessful; the starting carbamates were recovered unchanged.When the acid azide 191 was heated in an inert solvent such as dry benzene and in the absence of any other reactants, the Curtius rearrangement was followed by intramolecular ring closure to give 5,7-dihydro-9-methyl-7-phenyl-4H-pyrazolo [4',3':4,5]thieno [2,3-e]pyrrolo [1,2-a]pyrazin-4-one (197) (Scheme 58).

Conclusions
This review described the several efficient synthetic approaches and reactions of thienopyrazoles and their related compounds.The synthetic strategies of these heterocyclic compounds designated in this review comprise the construction of the pyrazolopyrazine moiety starting with from thiophene, pyrazole, and bifunctionalized systems of them where indicated.We hope this review is useful and appealing to researchers in the field of heterocyclic synthesis.Also, it can help them to prepare novel thienopyrazole heterocycles with promising biological activities.