**1. Introduction**

Ludwig Knorr coined the term "Pyrazole" in 1883. A 5-membered ring structure made up of three carbon atoms and two nitrogen atoms in close proximity defines the family of simple aromatic ring organic compounds known as Pyrazoles. These compounds belong to the heterocyclic series. Although being rarely in nature, they are categorized as alkaloids due to their structure and pharmacological effects on humans. Watermelon seeds yielded the first natural Pyrazole, 1-Pyrazolyl-alanine, in 1959 [1, 2]. Pyrazole refers to both an unsaturated parent chemical and a family of simple aromatic ring organic compounds of the heterocyclic diazole series, which are distinguished by a 5-member ring structure made up of two nitrogen atoms in the

neighboring position and three carbon atoms in the central position (**Figure 1**). Pyrazoles have tautomerism because of the moving C-N double bond inside the heterocycle [3, 4]. Pyrazole's 1H-tautomer is known as 1H-pyrazole [5]. It is a base of a pyrazolium conjugate. It is an acid conjugate of pyrazol-1-ide. It is a tautomer of the 3H and 4H Pyrazoles (**Table 1**).

Two techniques have been used to synthesize substituted Pyrazoles (**Figure 2**):


**Figure 1.** *Structure of Pyrazole.*


**Table 1.**

*Chemistry and properties of Pyrazole [6].*

*Pyrazole Scaffold: Strategies toward the Synthesis and Their Applications DOI: http://dx.doi.org/10.5772/intechopen.108764*

**Figure 2.** *Traditional methods for synthesizing Pyrazoles are shown in scheme (a) cyclocondensation; cycloaddition (b) [7].*

Recently, new methods such multicomponent one-pot procedures, photoredox reactions, and transition-metal catalyzed reactions have been added to these two standard tactics to improve them. In this part, cyclocondensation will be covered first, then cycloaddition [7].

As [NN] synthons, substituted or unsubstituted hydrazines are easily accessible for the production of pyrazole derivatives. When hydrazines react with 1,3 dielectrophilic compounds like 1,3-dicarbonyl or with structures which are carbonyl, such as enones, ynones, and vinyl ketones possessing a leaving group, pyrazole molecules can be produced [8]. Hydrazines and comparable synthetic equivalents can efficiently condense to form substituted pyrazoles from 1,3-diketones, βketoesters, 2,4-diketoesters, and related compounds. The 1, 3-diketone and the appropriate hydrazine were cyclocondensed to create a series of powerful carbonic anhydrase, α-glycosidase, and cholinesterase enzyme inhibitors 1 [9]. Wang and coworkers reported a moderate and acid-free condensation of 1,3-diketones with substituted hydrazines to produce the 1,3,5-trisubstituted and completely substituted Pyrazoles [10]. Hydrazines and α-enones can be combined to produce pyrazolines, which can then be oxidized to produce the equivalent Pyrazoles. Iodine was used by Zhang *et al.* to mediate the creation of oxidative intramolecular C-N bonds, and the intermediate hydrazones were then cycled to produce Pyrazoles [11]. Ding *et al.* also described an air-promoted photoredox cyclization of substituted hydrazines with activated alkene (Michael addition reaction acceptors) to produce the corresponding Pyrazoles with good to outstanding yields [12]. Harigae *et al*. reported synthesizing 3,5-disubstituted pyrazoles in one pot with good yields using a regioselective method [13]. 3,5-disubstituted 1H-pyrazoles were also produced using propargylic alcohols, the reduced form of ynones [14]. According to Guo *et al.*, βamino vinyl ketone may cyclize with tosyl hydrazine in water to produce completely substituted pyrazoles when iodine and tert-butyl hydroperoxide (TBHP) were introduced [15].

1,3-dipolar cycloaddition plays a significant role in creating substituted Pyrazoles due to its inherent high regioselectivity and efficiency [16]. As a departing group, bromine works well. In order to create 3,5-diaryl-4-bromopyrazoles, Sha *et al*. used gemdibromoalkene as the substrate and devised a straightforward, highly effective, and regioselective approach [17]. Li and colleagues described a cycloaddition of dicarboxylic alkynes and hydrazines that was catalyzed by rhodium [18]. Kobayashi et al.

proposed a one-pot, multicomponent method for creating multisubstituted Pyrazoles starting with primary alcohols [19]. In order to assemble monosubstituted Pyrazoles, Yi et al. reported a brand-new silver-mediated [3 + 2] cycloaddition of alkynes and Nisocyanoiminotriphenylphosphorane (NIITP) [20]. Aldehyde hydrazones and maleimides were combined in a moderate reaction by Zhu et al. that used CuCl as a catalyst to produce dihydropyrazoles [21].

All of the [NN] pieces in each of the pyrazole synthesis methods discussed above were derived from azo compounds or hydrazine derivatives. Recent research by Pearce and colleagues describes an unique fragment combination mode [NC] + [CC] + [N] that produces multi-substituted Pyrazoles [22].

The numerous pharmaceutical uses of Pyrazoles have sped up the methodological advancement of pyrazole synthesis. Many general and practical methods, such as the use of transition-metal catalysts, photoredox reactions, one-pot multicomponent processes, new reactants, and novel reaction types, have resulted in fruitful advancements in the fields of the synthesis and functionalization of pyrazole derivatives over the past ten years [7]. A number of noteworthy biological properties of this molecule include those that are antibacterial, anti-inflammatory, anti-cancer, analgesic, anticonvulsant, anthelmintic, antioxidant, and herbicidal. Considering that Pyrazoles are heterocyclic planar five-membered rings, the research suggests that they have a variety of pharmacological effects [4].

#### **1.1 Strategies for pyrazole synthesis**

Pyrazoles are the five-membered heterocycles that constitutes several derivatives or compounds which are useful in various fields like drugs, dyes and in organic synthesis. In this section we represents description and discussion on most of the synthetic methods or strategies of pyrazole heterocyclic system.

There are various routes for pyrazole nucleus synthesis which is described as below:


3.Cyclocondensation of hydrazine with carbonyl system

4.Heterocyclic system

## **1.2 Multicomponent approach**

The multicomponent approach is used for synthesis of pyrazole nucleus by performing one pot synthesis reaction to get high yield of product.

#### *1.2.1* In situ *formation of carbonyl derivatives*

The 3,5-substituted pyrazole derivatives 4 can be synthesized in good yield by the treatment of terminal alkynes 1 with aromatic aldehyde, molecular iodine and hydrazines. It is a very simple and practical method for the preparation of 3,5-substituted pyrazole [13].

*Pyrazole Scaffold: Strategies toward the Synthesis and Their Applications DOI: http://dx.doi.org/10.5772/intechopen.108764*

The 1,3,5-substituted pyrazoles 6 was prepared by palladocatalyzed carbonylation of acetylenic acids on aryl iodides 5 in the presence of hexacarbonyl molybdenum with excellent yield [23].

### *1.2.2* In situ *formation of β-Aminoenones*

The β-Aminoenones synthesized by via coupling between alkyne 8 and an oxime 7 in dimethylformamide which was transformed into pyrazoles 10 with the addition of hydrazine in one pot procedure in good yield [24].

#### *1.2.3* In situ *formation of a Hydrazone*

It is a novel reaction in which the cyclization of diethyl oxalate 12 with the dianions of hydrazones 11 afforded the pyrazole-3-carboxylates 13 in good yields [25].

The condensation of hydrazine in the presence of phosphorus oxychloride gives the 4-formyl pyrazole 15 which is called as Vilsmeier-Haack reaction [26].

#### *1.2.4* In situ *formation of diazo compounds*

The Aggarwal team has developed a multicomponent process in which diazo 17 derivatives are generated in situ from various aldehydes 16 and tosylhydrazines, thus limiting the risks associated with the isolation of these compounds. These are then used in a 1,3-dipolar cycloaddition reaction to give corresponding pyrazoles 18 and 19 Diazo compounds derived from aldehydes were reacted with terminal alkynes to furnish regioselectively 3,5-disubstituted pyrazoles in 24–67% yields [27].

#### *1.2.5 Ring opening reaction*

A palladium-catalyzed ring opening reaction of 2H-azirines with hydrazones provides polysubstituted pyrazoles 23 with a wide substrate scope [28].

*Pyrazole Scaffold: Strategies toward the Synthesis and Their Applications DOI: http://dx.doi.org/10.5772/intechopen.108764*

#### *1.2.6 Multicomponent reaction*

Pyrazole or isoxazole derivatives 27 are prepared by a palladium-catalyzed fourcomponent coupling of a terminal alkyne 24, hydrazine 25 (hydroxylamine), carbon monoxide under ambient pressure, and an aryl iodide 26 [29].

### **1.3 Dipolar cycloadditions**

In this method the pyrazole nucleus was synthesized by the cycloaddition between an alkyne and 1,3-dipolar compounds such as diazo compounds.

#### *1.3.1 Cycloaddition of Diazocarbonyl compounds*

The action of ethyl diazoacetate 29 on phenylpropargyl 28 in triethylamine and in the presence of zinc triflate as a catalyst; the 1,3-dipolar cycloaddition reaction, leads to the corresponding pyrazole 30 in good yield (89%) [30].

#### *1.3.2 Cycloaddition of ethyl diazoacetate*

A facile one-pot procedure for the synthesis of pyrazole-5-carboxylates 31 by 1,3-dipolar cycloaddition of ethyl diazoacetate 32 with methylene carbonyl compounds utilizing 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as base and acetonitrile as solvent [31].

*1.3.3 Cycloaddition of acetylides with diazocarbonyl compounds*

A direct and efficient access towards 3-acylpyrazoles 36 that involves the copperpromoted cycloaddition of acetylides 35 with diazocarbonyl compounds under mild

conditions. A wide variety of substituents is tolerated at both the acetylide and the diazo compound [32].

#### *1.3.4 The syndones*

The pyrazoles can be obtained by a cycloaddition reaction of sydnones. The synthesis of a trisubstituted pyrazole 39, by 1,3-dipolar cycloaddition of arylsydnones and unsaturated ketone in dry xylene [33].

#### *1.3.5 Cycloaddition of* N*-isocyanoiminotriphenylphosphorane*

A silver-mediated [3 + 2] cycloaddition of *N*-isocyanoiminotriphenylphosphorane as "CNN" building block to terminal alkynes provides pyrazoles 42. *N* isocyanoiminotriphenylphosphorane is a stable, safe, easy-to-handle, and odorless solid isocyanide 41. The reaction offers mild conditions, broad substrate scope, and excellent functional group tolerance [20].

#### *1.3.6 Cycloaddition reaction of dialkyl azodicarboxylates*

A phosphine-free [3 + 2] cycloaddition reaction of dialkyl azodicarboxylates 44 with substituted propargylamines 43 provides functionalized pyrazoles 45 in good yields and high selectivity at room temperature [34].

*Pyrazole Scaffold: Strategies toward the Synthesis and Their Applications DOI: http://dx.doi.org/10.5772/intechopen.108764*

#### *1.3.7 Cycloaddition of diazo compounds and alkynyl bromides*

A simple, highly efficient, 1,3-dipolar cycloaddition of diazo compounds 46 and alkynyl bromides 47 gives 3,5-diaryl-4-bromo-3*H*-pyrazoles 48 or the isomerization products 3,5-diaryl-4-bromo-1*H*-pyrazoles 49 in good yields. The diazo compounds and alkynyl bromides were generated in situ from tosylhydrazones and *gem*dibromoalkenes, respectively. The reaction system exhibited high regioselectivity and good functional group tolerance [35].

### *1.3.8 Cycloaddition of diazoacetonitrile and nitroolefins*

A transition-metal-free [3 + 2] cycloaddition reaction between diazoacetonitrile 51 and nitroolefins 50 provides multisubstituted cyanopyrazoles 52. This protocol offers mild reaction conditions, broad substrate scope, good yields, and regioselectivities. A one-pot three-component reaction of nitroolefins with diazoacetonitrile and alkyl halides also provides multisubstituted cyanopyrazoles in good to high yields [36].

#### *1.3.9 Cyclocondensation of hydrazine with carbonyl system*

This is a leading method used for obtaining substituted pyrazoles is a cyclocondensation reaction between an appropriate hydrazine acting as a bidentate nucleophile and a carbon unit like a 1,3-dicarbonyl compound, a 1,3-dicarbonyl derivatives or an unsaturated ketone.

#### *1.3.10 From 1,3-diketones*

The cyclocondensation of the 1,3-dicarbonyl compounds 53 with the hydrazine derivatives is a simple and rapid approach to obtain polysubstituted pyrazoles 54 and 55. The first synthesis of the substituted pyrazoles was carried out in 1883 by Knorr et al. [11] who reacted diketone with hydrazine derivatives to give two regioisomers [37].

The condensation of phenylhydrazine 57 with the trifluoromethyl)-1,3-diketone 56 in ethanol, affording 1,3,4,5-substituted pyrazole in good yield (63%) [38].

### *1.3.11 From Acetylenic ketones*

The cyclocondensation reaction of hydrazine derivatives 60 on acetylenic ketones 59 to form pyrazoles. The reaction between hydrazine derivatives and acetylenic ketones forms pyrazoles and the reaction again results in a mixture of two regioisomers 61 and 62 [39].

The cyclocondensation of acetylenic ketones 63 on methylhydrazine or aryl hydrazines 64 in ethanol, which provides two difficultly separable regioisomeric pyrazoles 65 and 66 [40].

#### *1.3.12 From vinyl ketones*

The cyclocondensation reaction between an ethylenic ketone and a hydrazine derivative results in the synthesis of pyrazolines which, after oxidation, provide the pyrazole ring.

The condensation of an ethylenic ketone 67 with p-(4-(tert-butyl)phenyl) hydrazine 68 in the presence of copper triflate and 1-butyl-3-methylimidazolium

*Pyrazole Scaffold: Strategies toward the Synthesis and Their Applications DOI: http://dx.doi.org/10.5772/intechopen.108764*

hexafluorophosphate bmim] (PF6) as catalysts, to access pyrazoline 69. The corresponding 1,3,5-trisubstituted pyrazole was obtained after oxidation in situ of this pyrazoline [41].

Cyclocondensation of the ethylenic ketone 70 with phenylhydrazine (1.2 eq.) in acetic acid and in the presence of iodine (1.0 eq.) afforded the corresponding pyrazole 71 in good yield (70%) [42].

#### **1.4 From heterocyclic system**

#### *1.4.1 From imidazole*

Cycloaddition of (5Z)-1-acyl-5-(cyanomethylidene)-3-methylimidazolidine-2,4 diones 72 with arylhydrazonyl chloride under basic conditions to give pyrazole-5 carboxamides 73 in moderate 27–40% yields [43].

#### *1.4.2 From oxazole*

5-Trifluoromethyl-3-hydroxypyrazoles 75 were obtained in good yield (46–95%) by heating phenylhydrazine and 4-trifluoroacetyl-1,3-oxazolium-5-olates 74 under reflux of benzene [44].

#### *1.4.3 From pyrimidine*

The reaction of nitropyrimidine 76 with arylhydrazines in methanol at room temperature, to afford 4-nitro-3,5-diaminopyrazoles 77 in yields of 21–61% [45].

Tetrazolyl acroleins 78 reacts with fumaronitrile in xylene at 140°C to give the corresponding pyrazole formation 79 [46].
