Chemistry and Therapeutic Review of Pyrazole

 

Biplab De¹, Sandip Sen²*, T.S. Easwari²

 

ABSTRACT:

Pyrazole is a five membered heterocyclic compound.1, 4-Diketones are found to be good synthons for the synthesis of pyrazole. On the based of the literature it was found that good yield can be achieved by chemoselective and regioselective synthesis. Pyrazole under goes ellectrophillic substitution but nucleophillic substitution is rare one. This interesting group of compound has diverse biological activities- antimicrobial, anticancer, cytitoxicity, analgesic, anti-inflammatory, CNS activity like antiepileptic, antidepressant, antihypertensive activity etc.  In the present review our main interest is to emphasize the various synthetic approaches and chemistry reported by researchers on pyrazole for their various. pharmacological activities.

 

 

 

INTRODUCTION:

Pyrazole is five-membered aromatic heterocyclic compound. The molecule is planar; bond lengths and bond angles have been calculated from microwave spectra. It was found from the structural formula that the bond between atoms 3 and 4 is the longest¹. 2-Pyrazolines seem to be the most frequently studied pyrazoline type compounds². C5 atom is deviated from the almost planar system of the other four atoms of the heterocyclic ring³ which plays a crucial role in biologically active compounds and therefore represents an interesting template for combinatorial as well as medicinal chemistry.

 

The pyrazole nucleuses have medicinal values⁴ such as antibacterial, antifungal, antiviral, antitubercular, antiamoebic, antiandrogenic etc. Some of these compounds have also exhibited anti-inflammatory, antidiabetic, anesthetics, analgesic and antiparasitic properties. Many pyrazoles have been found to be luminescent and fluorescent agents. In addition pyrazoles have played a crucial role in the development of theory in heterocyclic chemistry and also used extensively as useful synthon in organic synthesis. This current review emphasis different synthetic approaches on chemistry and medicinal values of pyrazole derivatives.

 

Synthesis of Pyrazoles

Heller et al. prepared pyrazole from reaction between hydrazine and 1, 3-diketones⁵. This method allows a fast and general synthesis of previously inaccessible pyrazoles and synthetically demanding pyrazole containing fused ring.

 

 

A highly regioselective synthesis of 1-aryl-3,4,5-substituted pyrazoles⁶ based on the condensation of 1,3-diketones with aryl hydrazines  was proceeded at room temperature by Gosselin et al. in N,N- dimethylacetamide and furnishes pyrazoles in good yields.

 

Mori et al.⁷ prepared pyrazole or isoxazole derivatives by a palladium  catalyzed four-component coupling of a terminal alkyne, hydrazine (hydroxylamine), carbon monoxide, aryl iodide under ambient pressure, and room temperature.

 

Grestenbeger⁸ developed simple one-pot method for the synthesis of diversely functionalized N-aryl pyrazoles from aryl nucleophiles, di-tert-butyl azo dicarboxlate, and 1, 3-dicarbonyl or equivalent compounds.

 

A regioselective  synthesis of tri- or tetra substituted pyrazoles by the reaction of hydrazones with nitro olefins mediated with strong bases such as t-BuOK exhibits a reversed, exclusive 1,3,4-regioselectivity. Subsequent quenching with strong acids such as TFA is essential to achieve good yields. A stepwise cycloaddition reaction mechanism is proposed by X.deng et al⁹.

 

X.deng et al. also proposed two general¹⁰ protocols for the reaction of electron-deficient N-arylhydrazones with nitroolefins allow a regioselective synthesis of 1,3,5-tri and 1,3,4,5-tetra substituted pyrazoles.Studies on the stereochemistry of the key pyrazolidine intermediate suggest a stepwise cycloaddition mechanism.

 

A regioselective¹¹ one-pot synthesis of substituted  pyrazoles from N-mono substituted hydrazones and nitro olefins gives products in good yields. A key nitro pyrazolidine intermediate is characterized and a plausible mechanism is proposed.

 

R. Martin et al.¹² have been developed highly flexible Cu-catalyzed domino C-N coupling hydroamination reaction constitutes a straight forward alternative to existing methodology for the preparation of pyrroles and pyrazoles.

 

According to O.Jackowski¹³Alumino-heteroles  are obtained from simple precursors in a fully chemo and regioselective manner by a metalative cyclization. The carbon-aluminum bond is still able to react further with several electrophiles, without the need of transmetalation providing a straightforward access to 3, 4, 5-trisubstituted isoxazoles and 1, 3, 4, 5-tetrasubstituted pyrazoles.

 

1-Acyl-5-hydroxy-4, 5-dihydro-1H-pyrazoles have been prepared in good yields from the corresponding 2-alkyn-1-ones by C.Larock et al ¹⁴. The resulting dihydropyrazoles undergo dehydration and iodination in the presence of ICl and Li₂CO₃ at room temperature to provide 1-acyl-4-iodo-1H-pyrazoles.

 

Doug E. Frantz and coworkers¹⁵ by tandem catalytic cross-coupling or electrocyclization performed the conversion of differentially substituted acyclic and cyclic enol triflates and an elaborated set of diazoacetates to provide the corresponding 3, 4, 5-trisubstituted pyrazoles with a high degree of structural complexity.

 

M.A.P.Martins¹⁶ prepared a series of 4-substituted 1H-pyrazole-5-carboxylates from the cyclocondensation reaction of unsymmetrical enamino diketones with tert-butylhydrazine hydrochloride or carboxy methylhydrazine. The compounds were obtained regiospecifically and in very good yields.

 

G.Huang¹⁷ developed easy  and efficient copper-catalyzed reaction for the synthesis of polysubstituted pyrazoles from phenylhydrazones and dialkyl ethylene dicarboxylates tolerates a range of functionalities, and the corresponding adducts can be obtained in moderate to good yields.

 

The reaction  of diazo (trimethylsilyl) methyl magnesium bromide with aldehydes or ketones gave 2-diazo-2-(trimethylsilyl)ethanols, which were developed by Y.Hari¹⁸ and applied for  the synthesis of di- and trisubstituted pyrazoles via [3+2] cycloaddition reaction with ethyl propiolate or dimethyl acetylene dicarboxylate.

 

 

N. Nakamichi and coworkers¹⁹ found that in the presence of activated carbon, 1, 4-dihydropyridines and 1,3,5-trisubstituted pyrazolines were aromatized with molecular oxygen to the corresponding pyridines and pyrazoles in excellent yields.

 

Chemistry of Pyrazole

Acid base reactions

Pyrazoles  are much weaker bases than imidazoles, but can be precipitated as picrates²⁰. The conjugate acid of pyrazole has a pKa value of 2.52. The difference is due to the fact that the positive charge in the pyrazolium ion is less delocalized than in the imidazolium ion. The gas-phase basicity (intrinsic basicity) for pyrazoles and imidazoles has been determined, as have their thermodynamic and kinetic basicities and proton affinities. Pyrazoles unsubstituted in the 1 position show NH-acidity. The pKa value of pyrazole is 14.21 and equals that of imidazole. Pyrazole reacts with sodium to give the sodium salt. The sparingly soluble silver salt is formed with aqueous silver nitrate solution.

 

Annular tautomerism

Pyrazoles unsubstituted²¹ in the 1, 2-position undergo tautomerism. In solution, equilibrium is attained so rapidly that the existence of tautomers can only be demonstrated by means of ¹³C and ¹⁵N NMR spectroscopy. Other than for R = CH₃, the equilibrium lies to the left i.e. the 3-substituted isomer predominates.

 

Reactions with electrophilic reagents

The best procedure ^{20, 21} for methylation of pyrazole is via the sodium salt which reacts with iodomethane or dimethyl sulfate, Benzylation, acetylation, benzoylation methyl sulfonation, methoxy carbonylation and trimethylsilylation of pyrazole are affected by analogous methods. Mixtures of 1,3- and 1,5disubstituted pyrazoles are formed from 3- and 5- substituted pyrazoles because of the ambient nature of the pyrazolyl anion, e.g.:  Electrophilic substitution on the C-atoms of pyrazole proceeds more slowly than for pyrrole and at about the same rate as for benzene. The pyrazole anion reacts faster and the pyrazolium ion much more slowly. The corresponding 4-halopyrazoles are produced by the action of chlorine or bromine in acetic acid. Nitrating acid yields 4-nitropyrazoles and, dependent on the substituents in the pyrazole ring, reaction takes place either with pyrazole itself or the pyrazolium ion. Sulfonation involves the pyrazolium ion. For this reason, heating in oleum is necessary, which leads to pyrazole-4-sulfonic acid. Pyrazoles with substituents in the 1 -position yield pyrazole-4-carbaldehyde in the Vllsmelerhaack  formylation and are amenable to Friedel-Crafts acylation. 4- and 5- aminopyrazoles can be diazotized.

 

Reactions with nucleophilic reagents

Pyrazoles either do not react with nucleophiles, or react with them only very slowly^20,21. For instance, pyrazoles unsubstituted in the 3 -position undergo ring opening on heating with alkali hydroxides.Nucleophilic subsution of a halogen in halopyrazoles is also difficult.

 

Biological activity of pyrazole

Pyrazole and their derivatives could be considered as possible antimicrobial, antitubercular, antiepileptic, antiinflammatory, antipsychotic, antidepressant, inhibitors of protein kinases, anti-aggregating, antiarthritic, cerebro protectors, reverse transcriptase inhibitor, COX-2 inhibitor, nematicidal and soluble guanylate cyclase activity etc. The paper includes different biologically activity of pyrazoles.

 

 

TABLE -1: Pyrazole as Antimicrobial agent

Name of author	Structure	Active against strains
Vijay V. Dabholkar et al.22		S. aureus C. diphtheriae
		C. diphtheriae
Rafat M. Mohareb et al. 23		S.aureus, C.albicans A. niger.
R.N. Sharma et al. 24		P.piosineus, S.albus  S.aureus, C.albicans A. niger.

Vetrivel Nadaraj et al.25		E. coli, P.aeruginosa, K. aerogenes, B.subtilis , St albus.
Nirav K. Shah et al.26		E.coli, C. albicans , C.glabrata
Abdel-Rahman et al. 27		P.aeruginosa, A.parasitcus, P. oxalicum, S.marcescns.
Samir  Bondock et al.28		A. fumigatus F.Oxysporum
Smaail Radi et al.29		E. coli, S cerevisae F.oxysporum C..ablicans.
Ozdemir et al.30		E.coli, St.aureus, S.typhimurium, B.cereus, St. faecalis, A.hydrophila, C. albicans C.glabrata.
Abdelwahab et al.31		E.coli, St.aureus, C. albicans   C.glabrata
Stirrett et al.32		M. tuberculosis, Y. pestis.
Abunada et al.33		E. coli, S. aureus, As. flavus , C. albicans.
Bhatt e t al.34		B. mega, B.subtilis, E. coli, M. tuberculosis, H37 Rv.
Bharmal et al.35		S. typhosa  A. niger.
Basawaraj et al.36		S. aureus,  E. coli.
Desai et al.37		E.coli, St.aureus, S.typhimurium, B.cereus, St. faecalis, A.hydrophila, C. albicans C.glabrata
Jamode et al. 38		S. aureus, E. coli, P.s mirabilis, P.aeruginosa
Shenoy et al.39		E.coli, St.aureus, S.typhimurium, B.cereus,
Chimenti et al.40		H. pylori
Mogilaiah et al. 41		E.coli, St.aureus, B.cereus, St. faecalis, A.hydrophila, C. albican , C.glabrata
Vijayvergiya et al. 42		S. aureus, S.albus, S. pyogenes, S. viridansand, E. coli, S. typhosa.
Waheed et al. 43		E.coli, St.aureus, S.typhimurium, B.cereus, , A.hydrophila,,  C.glabrata

 

TABLE-2: Pyrazole as anticancer agent

Name of author	Structure	Active against specific celllines
Mohammed S. M. et al. 44		Leukemia, melanoma and renal celllines.
R. Kalirajan, et al.45		MCF7 human breast cell line
Xiao Hong Wang et al. 46		Colon cancer cell lines especially on HT 29
Havrylyuk et al.47		Leukemia, Melanoma, Lung, Colon, CNS, Ovarian, Renal, Prostate And Breast Cancer Cell Lines
Bhat et al. 48		A panel of human cancer cell lines
Manna et al. 49
Pyrazole Against Lung Cell Carcinoma (A549)
Hirotani et al. 50		Antiproliferative activity against human lung cancer cell lines and inhibited tubulin polymerization
Wei et al. 51		A549 lung cancer cell growth
Fan et al. 52		Inhibit the growth of A549 cells
Xie et al.53		Inhibitory effects on the growth of A549 cells
Zhang et al.54		Inhibit the growth of A549 cells
Pyrazole Moiety Against Various Other Cell Lines
Chou et al.55		NCI-H226 non-small cell lung cancer and A-498 renal cancer cell lines
Ghorab et al.56		Ehrlich ascites carci-noma (Eac) cell line
Joksovic et al.57		Cervix-adeno carcinoma,Hela, Melanoma,Fem-X ,Myelogenous Leukemia K562 cell Lines 85
Abu-Surrah et al.58		The fast growing head and neck squamous carcinoma cells SQ20B and SCC-25
Lv et al.59		Potential EGFR kinase inhibitors as well as antiproliferative activity against MCF-7 W
Hassan et al.60		Human breast adenocarcinoma mcf-7 cell line
Lv et al.61		H322 lung cancer cells
Peng-cheng LV et al,62		Antiproliferative activity against MCF-7
Michael S. Christodoulo et al.63		inhibit the growth of human breast (MCF-7)and cervical (Hela) carcinoma cells
Pyrazole as Cytotoxic Agent
Bu et al.64
LeBlanc et al.65
Tan et al.66
Nagarapu et al.67
Zhang et al.68

 

TABLE-3: Pyrazole As analgesic and anti-inflammatory agent

Barsoum et al.69	Amir et al70
Rathish et al.71	Rani et al.72
Panneer Selvam T et al73

 

 

TABLE-4: Pryazole as Antiepileptic agents

Ozdemir et al.74
Kucukguzel et al. 75	Singh et al.76

 

TABLE-5: Pryazole as Antidepressant Agents

Palaska et al.77	Prasad et al.78
	Jayaprakash et al. 79

 

TABLE-6: Pryazole as Antitubercular

Kini et al.80
Babu et al.81

 

TABLE-7: Pyrazole as other therapeutic agent

Name of author	Structure	Activity
Budakoti et al. 82		Antiamoebic activity
Abid et al.83		Antiamoebic activity
Chimenti et al.84		MAO-inhibitory activity
Silver et al. 85		Insecticidal activity
Godoy et al.86		Antinociceptive activity
Turan-Zitouni et al. 87		Hypotensive activity
Jeong et al.88		Cholesterol inhibitory activity
Manna et al.89		Amine Oxidase inhibitory  activity
Babu et al.90		Antioxidant activity
Macro Bonesi et al.91		ACE inhibitor

 

CONCLUSION:

Pyrazole is a five membered heterocyclic compound. There are different conventional methods used by different scientist for the synthesis of pyrazole.1,4-diketones and are found to be good synthons for the synthesis of pyrazole by cyclo condensation reaction but it gives the mixture of isomer. Another good conventional approach by catalysis induced coupling reaction.  On the based of the literature it was found that good yield can be achieved by chemoselective and regioselective synthesis . Pyrazole is basic in nature due to the nitrogen atom. It also shows annular tautomerism.It under goes electrophilic substitution in same rate as benzene but nucleophillic substitution is rare one. From the extensive literature survey  it was found that  it have antimicrobial, anticancer, cytotoxicity, analgesic, anti-inflammatory, CNS activity like antiepileptic and  antidepressant, antihypertensive activity etc. So from the above discussion it can be conclude that pyrazole is a therapeutically active versatile moiety.

 

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Received on 05.12.2012        Modified on 18.12.2012

Accepted on 20.12.2012        © AJRC All right reserved