Recent Advances in the Synthesis of Pyrazole Derivatives: A Review

Abstract

Pyrazole, characterized by a five-membered heterocyclic structure featuring two neighboring nitrogen atoms, serves as a core element. Pyrazoles hold a privileged status as versatile frameworks in various sectors of the chemical industry, including medicine and agriculture. Previous reviews have extensively highlighted the significance of pyrazoles and their diverse biological activities, encompassing roles such as antituberculosis, antimicrobial, antifungal, anti-inflammatory, anticancer, and antidiabetic agents. Consequently, they have garnered substantial interest from researchers. The aim of this review is to offer a comprehensive overview of the published research related to the synthesis of pyrazole derivatives, encompassing a discussion of diverse methods for accessing the pyrazole moiety. These methods span from utilizing transition-metal catalysts and photoredox reactions to employing one-pot multicomponent processes, novel reactants, and innovative reaction types. It encompasses studies conducted by numerous scientists worldwide, showcasing collective efforts in advancing the methodologies and applications of pyrazole derivatives.

1. Introduction

Over the past decade, there has been a significant increase in interest in pyrazole chemistry, primarily driven by the discovery of fascinating properties demonstrated by numerous pyrazole derivatives. The term “pyrazole” was initially discovered by Ludwig Knorr in 1883 [1], while Edward Buchner is recognized as the first to synthesize it in 1889 [2]. Pyrazoles, as five-membered heterocycles, belong to a class of compounds highly valued in organic synthesis. Within the azole family, they are among the most extensively studied groups of compounds. Over the years, a vast array of synthesis methods and synthetic analogues have been documented, highlighting their significant importance in research and applications [3]. Furthermore, the pyrazole fragment plays a crucial role in numerous organic ligands and serves as an essential coordinator. Recent research has uncovered intriguing applications of the pyrazole structure in organic synthesis, where it acts as both a directing and transforming group [4,5]. Pyrazole serves as a fundamental element present in various small molecules, exhibiting a diverse array of agricultural and pharmaceutical activities [3]. Specifically, they are classified as inhibitors of protein glycation, exhibiting properties such as anti-inflammatory, antibacterial, antifungal, anticancer, antidiabetic, antioxidant, antidepressant, anti-tuberculosis, and antiviral activities [3,6,7,8]. Additionally, certain pyrazoles find applications in supramolecular and polymer chemistry, in the food industry, and are utilized as cosmetic colorings [8]. In recent years, a number of FDA-approved and commercially available drugs, both patented and non-patented, have been formulated using pyrazole derivatives [9] (Figure 1). This trend highlights the extensive utilization of these groups in the creation of novel bioactive compounds. This review provides a succinct overview of pyrazole pharmacophore synthesis, making it a valuable reference guide for researchers exploring this field. The review is loosely organized into chemical synthesis categories.

2. The Primary Approaches for Obtaining the Pyrazole Nucleus

Pyrazole, as an aromatic heterocycle with π-electron excess, displays distinct reactivity patterns in organic chemistry. Nucleophilic attacks are favored at positions 3 and 5, while electrophilic substitution reactions preferentially take place at position 4 [10] (Figure 2).

Unsubstituted pyrazole can be represented in three distinct tautomeric forms, as illustrated in Figure 3. This propriety adds to the versatility and complexity of pyrazole’s chemical behavior and has significant implications in various chemical reactions and processes.

In the realm of organic chemistry, pyrazoles bearing diverse substitutions with aromatic and heteroaromatic groups exhibit a plethora of biological activities, making them exceptionally captivating. Since the first syntheses described by Knorr [1], the various approaches to accessing the pyrazole nucleus have undergone numerous modifications, advancing their synthetic versatility and potential applications in various fields. In this review, we will delve into this evolutionary process and explore the commonly employed methods to obtain substituted pyrazoles, namely:

• ▪ Cyclocondensation of hydrazine’s and similar nuclei with carbonyl systems;

• ▪ Multicomponent reactions;

• ▪ Dipolar cycloadditions.

2.1. Cyclocondensation of Hydrazine and Its Derivatives on 1,3-Difunctional Systems

The primary approach utilized to obtain substituted pyrazoles involves a cyclocondensation reaction between a suitable hydrazine, acting as a bidentate nucleophile, and a carbon unit including, 1,3-dicarbonyl (I), α,β-unsaturated carbonyl compounds (II, III), and β-enaminones or related compounds (IV) (Figure 4).

2.1.1. Pyrazoles from 1,3-Diketones

Cyclocondensation of hydrazine derivatives with 1,3-dicarbonyl compounds presents a straightforward and rapid method for obtaining polysubstituted pyrazoles. Knorr and his collaborators [1] accomplished the initial synthesis of substituted pyrazoles in 1883. They reacted hydrazine derivatives with β-diketones 1, providing the formation of a mixture of two regioisomers 2 and 3, where the substituted heteroatom is either next to the R₁ or the R₃ substituents (Scheme 1).

Konwar et al. [11] established an eco-friendly procedure for synthesizing pyrazole derivatives, employing lithium perchlorate as a Lewis acid catalyst. Initially, they react with acetylacetone and 2,4-dinitriphenylhydrazine as a model to determine the optimized reaction conditions. At first, they attempted the reaction solely with solvents, without adding any catalyst, but it did not proceed at all, highlighting the need for a catalyst. The synthetic pathway consisted of the reaction of hydrazines 5 with 1,3-diketones 4 in the presence of ethylene glycol. Pyrazoles 6 were afforded in good to excellent yields (70–95%) at room temperature (Scheme 2, Table 1).

Xu et al. [12] reported the synthesis of 5-aryl-3-trifluoromethyl pyrazoles, which involved a silver-catalyzed reaction using N′-benzylidene tolylsulfonohydrazides 7 and ethyl 4,4,4-trifluoro-3-oxobutanoate 8 as precursors. The process entailed sequential steps of nucleophilic addition, intramolecular cyclization, elimination, and ultimately, [1,5]-H shift, resulting in the formation of trifluoromethylated pyrazole derivatives 9 in yields ranging from moderate to excellent (Scheme 3). During the optimization process, the yield of the product improved when the reaction temperature was raised to 60 °C. However, increasing the temperature beyond 60 °C led to a decrease in the yield. The Cu(OTf)₂ transition catalyst resulted in a 60% yield, whereas Fe(OTf)₃ showed no productive outcome. In comparison to toluene, THF or dioxane provided a lower yield of the product. Additionally, K₂CO₃ exhibited higher effectiveness compared to NaH, t-BuOK, and t-BuONa. Furthermore, incorporating neocuproine as a ligand resulted in the most favorable performance with a yield exceeding 99%. In contrast, employing 2,2′-bipyridine or 1,10-phenanthroline as ligands led to lower yields of 57% and 92%, respectively.

Poletto and collaborators described a one-pot synthetic strategy to produce highly regioselective α-ketoamide N-arylpyrazoles 11, utilizing secondary β-enamine diketone 10 and arylhydrazines as precursors [13]. Significantly, the in situ-produced intermediate 4-acyl 3,5-dihydroxypyrrolone underwent nucleophilic substitution at C-5 by arylhydrazine. Subsequently, heterocyclization took place at the carbonyl carbon of the acyl group (refer to Scheme 4).

In their research, Kim et al. [14] devised a swift and effective “one-pot” method for synthesizing pyrazoles from (hetero)arenes and carboxylic acids. The procedure involves the sequential formation of ketones, β-diketones, and subsequent heterocyclization with hydrazine. Our initial assumption was that three straightforward steps could lead us to 3,5-disubstituted pyrazoles 16. First, the TfOH/TFAA-mediated “one-pot” synthesis of 1,3-diketones 15 from methylarylketones 13, utilizing arenes 12 and carboxylic acids 14. Then, the conversion of dicarbonyl compounds 15 to 3,5-disubstituted pyrazoles 16 was carried out under Knorr reaction conditions (see Scheme 5).

Girish et al. [15] conducted a remarkable study where they introduced a highly efficient and environmentally friendly approach using nano-ZnO catalyst for synthesizing 1,3,5-substituted pyrazole derivatives 19. The process involved the condensation of phenylhydrazine 18 with ethyl acetoacetate 17 under controlled conditions (see Scheme 6). The key advantages of this method include its exceptional yield, reaching an impressive 95%, short reaction time, and straightforward work-up procedure. The combination of excellent yield, short reaction time, and ease of handling makes this method a promising and valuable addition to the field of pyrazole derivative synthesis.

In their work, Gosselin et al. [16] described a remarkably regioselective synthesis of 1-aryl-3,4,5-substituted pyrazoles 22, which involves the condensation of 1,3-diketones 20 with arylhydrazines 21 (see Scheme 7). Notably, this reaction takes place efficiently at room temperature in N,N-dimethylacetamide, resulting in the formation of pyrazoles with high yields ranging from 59% to 98%.

In their study, Heller and Natarajan [17] introduced a highly innovative approach to the synthesis of pyrazoles in situ. The process involved the direct synthesis of 1,3-diketones 25 from ketones 23 and acid chlorides 24, which were subsequently transformed into pyrazoles 26 by the addition of hydrazine in good to excellent yields (see Scheme 8). This approach exhibits exceptional speed, generality, and chemoselectivity, enabling the synthesis of pyrazoles that were previously inaccessible, along with challenging pyrazole-containing fused rings. The fusion of rapidity, generality, and chemoselectivity in this approach makes it a valuable asset in the arsenal of synthetic chemists, opening new avenues for the creation of diverse pyrazole-based compounds with enhanced complexity and utility.

Komendantova and her team work devised an innovative method for the synthesis of 3,4-dicarbonyl-substituted pyrazoles 29 [18]. This approach involves the use of a broad array of 1,3-dicarbonyl compounds 27 and oxamic acid thiohydrazides 28 in an iodine-promoted cascade imination/halogenation/cyclization/ring contraction reaction in the presence of catalytic amounts of TsOH, accompanied by sulfur elimination (see Scheme 9). The result is a highly efficient and straightforward route to functionalized pyrazoles, utilizing readily available substrates and mild reaction conditions.

Yan et al. [19] made a remarkable discovery by uncovering a new metal-oxo-clusters-based inorganic framework called “3D platelike ternary-oxo-cluster” (NaCoMo), which serves as an efficient catalyst for generating novel pyrazole derivatives. Moreover, this catalyst exhibits exceptional catalytic activity in the condensation and cyclization reaction of sulfonyl hydrazides 30 and 1,3-diketones 31 to synthesize the pyrazoles 32, leading to an impressive yield of up to 99% for the desired product (see Scheme 10). The successful synthesis of NaCoMo signifies the introduction of a new type of non-classical polyoxometalates.

Chandak and his collaborators documented an environmentally friendly and efficient aqueous synthesis of pyrazoles 35 via the condensation of hydrazines or hydrazides 34 with 1,3-diketones 33 at room temperature, utilizing Amberlyst-70 as the catalyst (see Scheme 11) [20]. This innovative protocol benefits from the use of resinous, nontoxic, thermally stable, and cost-effective Amberlyst-70 as a heterogeneous catalyst, in addition to offering a simple reaction workup, thus presenting valuable eco-friendly attributes.

Liu et al. [21] made an exciting discovery of a novel Keggin-based U-POW (U(VI)-containing polytungstates) tetramer, referred to as U₄. This tetramer showcased remarkable bifunctional Lewis’s acid-base catalytic properties and exhibited excellent performance in the synthesis of pyrazoles 38 via the condensation of diverse hydrazines 37 with 1,3-diketones 36 under mild reaction conditions (see Scheme 12). This groundbreaking work not only presents a rare case of tetrameric U-POWs but also highlights the application of U-POWs in catalytic synthesis chemistry, potentially advancing the fields of POM (actinide-containing polyoxometalates) chemistry, actinide chemistry, and catalytic chemistry.

2.1.2. Pyrazoles from Vinyl Ketones and Vinyl Ketones Having a Leaving Group

As a general trend, the condensation of hydrazines with R-enones predominantly yields pyrazolines in a regioselective manner. Subsequently, to acquire the corresponding pyrazoles, these pyrazolines must undergo oxidation (see Scheme 13).

The α,β-Vinyl ketones that possess a leaving group can undergo a reaction with hydrazine derivatives, leading to the formation of pyrazolines. Subsequently, by eliminating the leaving group, the desired pyrazoles are generated (see Scheme 13).

The Corradi group conducted a study under microwave irradiation and solvent-free reaction conditions, wherein they successfully synthesized novel 3,5-disubstituted-1H-pyrazoles 40 [22] (see Scheme 14). This was achieved via the cycloaddition of tosylhydrazones and α,β-unsaturated carbonyl compounds containing a β-hydrogen 39. The cycloaddition reaction was investigated using three different ketones: trans-4-phenyl-3-buten-2-one, β-ionone, and trans-chalcone. Notably, the corresponding 3,5-disubstituted-1H-pyrazoles 40 were obtained in high yields and with short reaction times. To assess the environmental impact, the proposed synthetic route was compared to the classical synthetic route, aiming to provide a reliable methodology and tool for measuring their ecological implications.

Huang and Katzenellenbogen [23] successfully obtained a series of 4-alkyl-1,3,5-triarylpyrazoles 44 in a regioselective manner via the oxidation of pyrazolines 43. These pyrazolines were initially prepared via a cyclocondensation reaction between phenyl and 4-methoxyphenylhydrazine and chalcones 41, followed by alkylation at the C-4 position of the pyrazoline ring in 42 (see Scheme 15).

In their study, Rao and his collaborators demonstrated a condensation reaction of an α,β-ethylenic ketone 45 with p-(4-(tert-butyl)phenyl) hydrazine 46 using copper triflate and 1-butyl-3-methylimidazolium hexafluorophosphate [bmim] (PF₆) as catalysts, leading to the formation of pyrazoline 47. Subsequent in situ oxidation of this pyrazoline yielded the corresponding 1,3,5-trisubstituted pyrazole 48 [24] (see Scheme 16). The reaction protocol facilitated the production of 1,3,5-triarylpyrazoles with good yields (approximately 82%) via a one-pot addition-cyclocondensation between chalcones and arylhydrazines, followed by oxidative aromatization without the need for an additional oxidizing reagent. Notably, the catalyst displayed remarkable recyclability, retaining its catalytic activity for more than four cycles without significant loss.

Another study described by Bhat and his team work consists of the synthesis of 3,5-diaryl-1H-pyrazoles starting with β-arylchalcones 49. The process involved the reaction with hydrogen peroxide, leading to the formation of epoxides 50. Following this, the addition of hydrazine monohydrate resulted in pyrazoline intermediates 51, which upon dehydration yielded the desired 3,5-diaryl-1H-pyrazoles 52 [25] (see Scheme 17).

In 2020, Gerus et al. [26] conducted a study on the fluorination of enone 53 using XeF₂ in the presence of BF₃·Et₂O. The addition of pyridine to the reaction mixture resulted in the formation of fluoroenone 54, achieving a yield of 68%. Subsequently, the reaction of fluoroenone 54 with hydrazine sulfate yielded fluoropyrazole 55, demonstrating an impressive yield of 87% (see Scheme 18).

Stephan and his co-workers made a groundbreaking discovery by unveiling a novel method for synthesizing pyrazole derivatives [27]. Initially, they efficiently synthesized 3-(hetero)aryl propenals and propenones using a Heck reaction involving (hetero)aryl bromides 56 and acrolein or vinyl ketones 57. This reaction was carried out under a combination of Jeffery’s and Fu’s conditions, utilizing Beller’s CataCXium Ptb ligand. The resulting 3-substituted α,β-unsaturated carbonyl derivatives served as valuable three-carbon building blocks. Using this straightforward approach, they successfully synthesized 3-(hetero)aryl and 3,5-diarylpyrazoles 58 with a broad range of substitution patterns via consecutive three- and pseudo-four-component syntheses, achieving modest to excellent yields (see Scheme 19). This concise and modular methodology proves to be highly suitable for preparing substance libraries of diversified pyrazoles.

Paul Raj et al. [28] established a highly efficient protocol for synthesizing pyrazoles 61 via the oxidative [3 + 2] cycloaddition of electron-deficient terminal olefins 59 with α-diazoesters and amides 60, using Oxone and cetyltrimethyl ammonium bromide (CTAB) as catalysts (see Scheme 20). Notably, this protocol offers several key advantages, including shorter reaction times, moderate to excellent yields, and good regioselectivity.

Pizzuti and his research team synthesized a series of innovative 3,5-diaryl-4,5-dihydro-1H-pyrazole-1-carboximidamides 64 using a convenient and high-yielding method [29]. The process involved the utilization of chalcones 62 and aminoguanidine hydrochloride 63 under ultrasonic irradiation, as shown in Scheme 21.

Iminov and his colleagues devised a method to obtain the pyrazole moiety. It consists of the acylation of tert-butyl 3-(methylamino)but-2-enoate 65 using fluorinated acetic acid anhydrides at the enamine carbon atom [30]. Subsequently, the resulting product 66 was reacted with alkyl hydrazines, leading to mixtures of isomeric pyrazoles. These mixtures were separated via column chromatography to provide compounds 67 and 68, yielding moderate to poor results in terms of yields (see Scheme 22).

Tian et al. [31] devised a practical protocol to synthesize 4-sulfonyl pyrazoles. They achieved this by reacting readily available N,N-dimethyl enaminones 69 with sulfonyl hydrazines 70 under the catalysis of molecular iodine in the presence of TBHP and NaHCO₃ at room temperature. The resulting pyrazole products 71 were formed via a tandem C(sp²)-H sulfonylation and pyrazole annulation process, without requiring any transition metal catalyst or reagent (see Scheme 23). This innovative approach offers a convenient and efficient method for constructing novel pyrazoles containing a sulfonyl side chain in the heterocycle.

2.1.3. Pyrazoles from Acetylenic Ketones

The formation of pyrazoles via the cyclocondensation reaction of hydrazine derivatives 73 with acetylenic ketones 72 has been a well-known process for over a century [32]. However, despite its long-standing recognition, the reaction continues to yield a mixture of two regioisomers, namely 74 and 75 (as shown in Scheme 24).

Zora and his research group reported a comprehensive synthetic approach for the preparation of selenium-containing pyrazoles, specifically 4-(phenylselanyl)pyrazoles 78 [33]. The method involves reacting α,β-alkynic aldehydes 76 with hydrazines 77, followed by the addition of phenylselenyl chloride. This one-pot reaction enables the in situ formation of α,β-alkynic hydrazones, which undergo cyclization upon direct treatment with phenylselenyl chloride, leading to the formation of 4-(phenylselenyl)pyrazoles 78 (see Scheme 25).

Meng et al. [5] introduced a novel visible-light-promoted cascade of Glaser coupling/annulation, enabling the one-pot synthesis of polysubstituted pyrazoles 80 from alkyne 79 and hydrazine derivatives (see Scheme 26). This method stands out due to its mild reaction conditions, utilization of readily available starting materials, and the eco-friendly oxidant, O₂. Notably, it exhibits excellent functional group tolerance and efficiency while accommodating a wide range of substituted phenyl acetylenes and hydrazines. The proposed mechanistic pathways involve photochemical irradiation, intramolecular hydrogen-atom-abstraction (HAT), and enamine-to-imine tautomerization to elucidate the underlying transformation steps.

Golovanov and colleagues conducted a study focusing on the synthesis of substituted pyrazoles. They achieved this via the cyclocondensation of cross-conjugated enynones, dienynones, and trienynones 81 with arylhydrazines 82, resulting in the regioselective synthesis of pyrazole derivatives 84, including dihetaryl-substituted ethenes, buta-1,3-dienes, and hexa-1,3,5-trienes, or alternatively yielding 4,5-dihydro-1H-pyrazoles in good yield (Scheme 27).

Bhaskaran and his team devised a highly efficient, metal-free approach for synthesizing pyrazoles and chromenopyrazoles (87) using aldehyde hydrazones and acetylenic esters 86 [34]. This method allowed them to create a library of molecules with a wide range of functional groups, utilizing both symmetrical and unsymmetrical hydrazones and alkynes. The resulting derivatives were isolated in moderate to good yields (Scheme 28).

Savel’ev et al. [35] devised a highly effective method for synthesizing 1,3,5-trisubstituted pyrazoles using acetylenic ketones derived from ethyl 5-ethynylanthranilate in reactions with substituted hydrazines and hydrazides. During the study, they demonstrated that the cyclization of ethyl 5-(3-aryl-3-oxopropinyl)anthranilates 88 with arylhydrazines occurred with excellent regioselectivity, resulting in 1,3,5-trisubstituted pyrazoles 89 carrying an anthranilate moiety at position C-3. However, in the reactions of ethyl 5-(3-aryl-3-oxopropinyl)anthranilates with N-methyl- and N-tert-butylhydrazines, a significant deterioration of regioselectivity was observed 92 and 93. In some cases, the initial products formed were 5-hydroxypyrazolines 90. These 5-hydroxypyrazolines underwent dehydration in the presence of pyridine and thionyl chloride in benzene, eventually yielding the desired 1,3,5-trisubstituted pyrazoles 91, as exemplified by the reactions of ethyl 5-[3-(4-fluorophenyl)-3-oxopropinyl]anthranilate with benzoyl and isonicotinoyl hydrazides (see Scheme 29).

Thirukovela and his team achieved a significant milestone in 2019 by developing an advanced one-pot regioselective synthesis of 3,5-disubstituted and 3,4,5-trisubstituted pyrazoles [36]. They employed a Cu-free protocol, utilizing in situ generated Pd-nanoparticles (PdNPs) as the catalyst in an environmentally friendly PEG-400/H₂O medium (see Scheme 30). This innovative approach represents a notable advancement in the field of pyrazole synthesis.

Topchiy et al. [37] demonstrated an efficient method for synthesizing 3-CF₃-pyrazoles 99 by employing a silver-catalyzed reaction between trifluoromethylated ynones 97 and aryl (alkyl) hydrazines 98. The reaction exhibited remarkable speed, with rapid heterocyclization occurring within just 1 h at room temperature, utilizing AgOTf as the catalyst at a loading of 1 mol % (see Scheme 31). This process led to the highly regioselective formation of various 3-CF₃-pyrazoles, achieving exceptional yields of up to 99% for the isolated products. The researchers further investigated the reaction mechanism and discovered that it involves the formation of a hemiaminal as a crucial intermediate, shedding light on the underlying chemical pathways responsible for the synthesis of 3-CF₃-pyrazoles.

Yu et al. [38] established a straightforward approach for synthesizing 4-chalcogenylated pyrazoles 102 via electrophilic chalcogenation and cyclization of α,β-alkynic hydrazones 100. The cyclization of α,β-alkynic aldehyde hydrazones could be triggered by employing either sulfenyl chloride or the in situ-generated S-electrophiles from the reaction of NCS and arythiol 101 (see Scheme 32). This innovative method was effectively utilized in the synthesis of the sulfenyl analogue of celecoxib, demonstrating its versatility and potential for accessing valuable chalcogenylated pyrazole derivatives.

2.2. Dipolar Cycloadditions

2.2.1. Pyrazoles from Diazo Compounds

Li et al. [39] conducted an investigation on the 1,3-dipolar cycloaddition of N-tosylhydrazones 103 with acetylene gas using a balloon setup. Throughout the study, various bases and solvents were tested, and K₂CO₃ was identified as the most efficient base to facilitate this reaction. When dealing with N-tosylhydrazones derived from aldehydes, DMSO yielded superior results, whereas NMP proved to be a more appropriate solvent for the reaction of ketone N-tosylhydrazones. As a result of their work, Li and colleagues successfully provided a series of pyrazoles 104 in moderate to good yields (see Scheme 33). This practical approach is easy to handle and holds promise for potential industrial applications.

Devi and his colleagues devised a novel approach involving a formal 1,3-dipolar cycloaddition of α-diazo phosphonates, sulfones, and trifluoromethanes 106 with 2,4,6-trisubstituted pyrylium tetrafluoroborate salts 105 [40]. This innovative approach led to the synthesis of functionalized pyrazole-chalcones 107 (see Scheme 34). The reaction proceeds via an initial nucleophilic addition of diazo substrates to pyrylium salts, followed by a base-mediated pyrylium ring-opening and intramolecular 1,5-cyclization, resulting in formal 1,3-dipolar cycloaddition products. Afterward, the products underwent a Nazarov-type cyclization upon hydride reduction, followed by acidic workup, leading to the formation of the corresponding indenyl-pyrazoles in high yields. This methodology presents a promising strategy for the efficient synthesis of functionalized pyrazole-chalcones and indenyl-pyrazoles with potential applications in various fields.

Zhao et al. [41] presented a comprehensive study on cascade reactions involving alkyl α-diazoesters and ynones with Al(OTf)₃ as the catalyst. Through a sequence of [3 + 2] cycloaddition, 1,5-ester shift, 1,3-H shift, and N-H insertion processes, a series of 4-substituted pyrazoles 110 were successfully synthesized (see Scheme 35). To gain insights into the mechanism, the researchers conducted deuterium labelling experiments, kinetic studies, and control experiments, which provided valuable information for rationalizing the reaction pathways and understanding the underlying mechanisms involved.

In 2021, Kula and colleagues introduced an innovative investigation into pyrazole synthesis and properties. Their work encompassed both experimental and theoretical studies on the thermal decomposition of 3,3-diphenyl-4-(trichloromethyl)-5-nitropyrazoline 113 [42]. Additionally, they explored the [3 + 2] cycloaddition reaction between diphenyldiazomethane 111 and (E)-3,3,3-trichloro-1-nitroprop-1-ene 112, resulting in the synthesis of 3,3-diphenyl-4-(dichloromethylene)-5-nitropyrazoline at room temperature (see Scheme 36). This reaction serves as a notable instance of methylene-functionalized pyrazole derivatives.

2.2.2. Pyrazoles from Nitrilimines

In a notable contribution, Ledovskaya and her team discovered that the mild organic base trimethylamine (TEA) effectively facilitated the 1,3-dipolar cycloaddition of vinyl ethers 115 and hydrazonoyl chlorides 114, leading to the formation of 1,3-disubstituted pyrazoles 116 with absolute regioselectivity [43] (as shown Scheme 37).

In another study, Zhu et al. [44] presented a study involving a CuCl-catalyzed oxidative coupling reaction between aldehyde hydrazones 117 and maleimides 118, which enables the synthesis of dihydropyrazoles 119 under mild conditions. Employing this method, a diverse range of pyrrolo[3,4-c]pyrazoles was readily accessible from dihydropyrazoles using a one-step oxidation process (as depicted in Scheme 38).

Yi and colleagues introduced an innovative approach involving a silver-mediated [3 + 2] cycloaddition of alkynes and N-isocyanoiminotriphenylphosphorane (NIITP) to construct monosubstituted pyrazoles [45]. This reaction occurs under mild conditions, exhibiting a wide substrate scope and excellent tolerance towards various functional groups. Mechanistic investigations revealed that NIITP is activated by Mo(CO)₆, subsequently engaging in a [3 + 2] cycloaddition with a silver acetylide intermediate (as shown in Scheme 39).

For the first time, Han and his team successfully synthesized a novel and efficient difluoromethyl building block, namely difluoroacetohydrazonoyl bromides [46]. Demonstrating its synthetic versatility, this reagent enables the construction of difluoromethyl organic compounds via effective regioselective [3 + 2] cycloaddition reactions with ynones, alkynoates, and ynamides. These reactions offer a novel and efficient protocol to access difluoromethyl-substituted pyrazoles 126 and 127 with high yields, representing a significant advancement in difluoromethyl chemistry (as shown in Scheme 40).

Kula et al. [47] in 2022 explored the experimental and theoretical studies on the reaction between (E)-3,3,3-trichloro-1-nitroprop-1-ene 112 and N-(4-bromophenyl)-C-arylnitrylimine 128. The title process led to the formation of the corresponding pyrazoles 130 and 132 (see Scheme 41).

2.2.3. Pyrazoles from Sydnones

Bouton et al. [48] successfully synthesized the C-nucleoside natural products, formycin B, and pyrazofurin 134, in seven steps, utilizing a sydnone riboside 133 as a shared intermediate. The sydnone ribosides were created using a direct Lewis acid-catalyzed dehydrative glycosylation reaction. It was demonstrated that these intermediates could be employed for the diversity-oriented synthesis of pyrazole C-nucleoside analogues via thermal 1,3-dipolar cycloaddition reactions with various alkynes (as shown in Scheme 42). This approach not only provided access to the pyrazole C-nucleoside natural products but also opened up new possibilities for exploring the chemical space of nucleosides.

Lakeland and his research team reported a regioselective reaction achieved via a visible-light photoredox process, employing Ru(bpy)₃(PF₆)₂ as the catalyst [49] (as depicted in Scheme 43). This innovative approach enabled the synthesis of a wide range of 1,4-disubstituted pyrazoles 137 with excellent yields.

Delaunay et al. [50] presented a significant research study on the [3 + 2] dipolar cycloaddition of 4-halosydnones with 1-haloalkynes, offering a straightforward route to access 3,5-dihalopyrazoles. These dihalopyrazoles serve as valuable scaffolds for generating unsymmetrically 3,5-substituted pyrazole derivatives via site-selective Pd-catalyzed cross-coupling reactions. For instance, they demonstrated the flexible introduction of different (hetero)aryl substituents at the C-5 and C-3 positions of the PMP-protected pyrazole nucleus in a one-pot operation, utilizing sequential reactions with various boronic acids (as depicted in Scheme 44). This method offers a versatile strategy for the synthesis of diverse pyrazole derivatives.

2.3. Multicomponent Synthesis

Multicomponent Synthesis (MCS) is a powerful and innovative strategy in organic chemistry that has revolutionized the field of chemical synthesis. It is a method of constructing complex molecules by combining multiple starting materials in a single reaction step. This approach contrasts with traditional organic synthesis, which often involves sequential reactions and the use of protecting groups, leading to increased steps and waste generation.

Among the numerous significant studies mentioned in the literature, Chen et al. [51] introduced a transition metal-free method utilizing molecular iodine as a catalyst to synthesize sulfonated pyrazoles from sulfonyl hydrazides, 1,3-diketones, and sodium sulfinates under mild conditions. This innovative approach enabled the direct one-step formation of pyrazoles with two distinct sulfonyl groups. Through control experiments, the reaction described in [51] was elucidated, and a plausible mechanism was attributed to it. The process involves the facile generation of sulfonyl iodide by the interaction of sodium sulfinate 144 and molecular iodine. Subsequently, the condensation of sulfonyl hydrazides 142 and 1,3-diketones 143 forms an imine, which undergoes tautomerization to yield its enol form. An in situ generated sulfonyl iodide, derived from the enol form, undergoes nucleophilic attack leading to an intermediate, ultimately resulting in the desired products 145 via an intramolecular condensation (as depicted in Scheme 45).

In another study, Jacob and colleagues presented an exceptionally efficient one-pot procedure to synthesize 4-organylselanylpyrazoles 148 by means of direct cyclocondensation and C-H bond selenylation reactions. This method commences with hydrazines 146, 1,3-diketones 27, and diorganyl diselenides 147, employing Oxone as the promoting agent. The products were obtained using a metal catalyst-free approach, operating under mild conditions, leading to short reaction times, and yielding products in moderate to excellent yields [52] (see Scheme 46).

A recent groundbreaking contribution by Pearce and colleagues introduced a novel fragment combination mode [NC] + [CC] + [N] utilizing a multicomponent oxidative coupling to synthesize multi-substituted pyrazoles. These innovative reactions involved the formation of diazatitana-cyclohexadiene intermediates by combining alkynes, nitriles, and titanium imido complexes, leading to pyrazole derivatives 152 via a 2-electron oxidation process catalyzed by the oxidant TEMPO [53] (see Scheme 47).

In 2021, Mali and colleagues introduced an efficient and environmentally friendly multicomponent approach, catalyzed by taurine, for the synthesis of densely substituted therapeutic core dihydropyrano[2,3-c]pyrazoles 157 [54] (see Scheme 48). This pioneering method enabled the synthesis of a diverse array of 1,4-dihydropyrano[2,3-c]pyrazoles, incorporating isonicotinamide, spirooxindole, and indole moieties. The application of these synthetic strategies and technologies led to the creation of novel compounds.

In another study, Shahbazi and collaborators successfully prepared a range of pyranopyrazoles 162 using a convenient one-pot four-component reaction involving ethyl acetoacetate 160, hydrazine hydrate 158, aldehydes 161, and malononitrile 159. They employed Co₃O₄-SiO₂-NH₂ nanocomposites as the catalyst in this process [55] (see Scheme 49). The study highlights numerous benefits, such as remarkably short reaction times, outstanding yields, an environmentally friendly approach, straightforward purification methods, and the economical accessibility of the catalyst.

3. Conclusions

Pyrazoles constitute a class of five-membered heterocyclic compounds that contain two nitrogen atoms. They play a crucial role in drug development, acting as essential hit compounds for designing innovative pharmacological agents to target a variety of clinically significant infections. The extensive pharmaceutical applications of pyrazoles have driven swift progress in pyrazole synthesis methodologies. In the last decade, numerous effective and versatile approaches have arisen, encompassing the use of transition-metal catalysts and photoredox reactions, as well as one-pot multicomponent processes, novel reactants, and innovative reaction modalities. These developments have significantly contributed to the synthesis and functionalization of pyrazole derivatives. The comprehensive information presented in this review will prove valuable for aspiring researchers looking to delve into the world of pyrazole derivatives. By gaining insights from this review, researchers can explore the possibility of other derivatizations to expand the repertoire of pyrazole-based compounds. However, there is still room for further investigation, especially in cases where the pyrazole unit itself plays a pivotal role in the compound’s mode of action, as well as situations where the pyrazole serves more as a structural element. These aspects warrant further exploration to fully comprehend the diverse potential and applications of pyrazole derivatives. Nevertheless, these reactions have the potential to provide very interesting molecular structures. In view of the growing importance of pyrazoles, we believe that the development of new synthetic routes using condensations, cycloadditions, and other potential methods will enhance our understanding of this field in the future.

Author Contributions

Conceptualization, writing—original draft preparation, I.A.E.H.; investigation, K.R.; investigation, H.A.; writing—review and editing, K.K.; supervision, K.K. and M.A. All authors have read and agreed to the published version of the manuscript.

Acknowledgments

This work was supported by Mohammed V University.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

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Figures, Schemes and Table

Figure 1. Pharmaceutical drugs containing pyrazole moiety.

Figure 2. The pyrazole structure.

Figure 3. Tautomeric forms of unsubstituted pyrazole.

Figure 4. Examples of α,β-unsaturated carbonyl compounds.

Scheme 1. The synthesis of polysubstituted pyrazoles using hydrazine derivatives and 1,3-dicarbonyl compounds.

Scheme 2. Synthesis of 1,3,5-substituted pyrazoles from substituted acetylacetone.

Scheme 3. Synthesis of 5-aryl-3-trifluoromethyl pyrazoles in the presence of a silver catalyst.

Scheme 4. The synthetic route of arylpyrazoles using secondary β-enamino diketone and arylhydrazine.

Scheme 5. The synthetic route of pyrazoles from arenes and carboxylic acids via ‘one-pot’ synthesis.

Scheme 6. Synthesis of 3-methyl-1-phenyl-1H-pyrazol-5-ol using Nano-ZnO as catalyst.

Scheme 7. Synthesis of 3-trifluoromethyl-substituted pyrazoles.

Scheme 8. Synthesis of substituted pyrazoles from 1,3-diketones and hydrazine derivatives.

Scheme 9. Synthesis of substituted pyrazoles from 1,3-diketones and hydrazine derivatives.

Scheme 10. Synthesis of substituted pyrazoles using NaCoMo as catalyst.

Scheme 11. Amberlyst-70 catalyzed the synthesis of pyrazole derivatives.

Scheme 12. Synthesis of pyrazole derivatives catalyzed by U4.

Scheme 13. The synthetic pathway to pyrazole derivatives via cyclocondensation reaction of α,β-ethylenic ketone, α,β-ethylenic ketone with a leaving group.

Scheme 14. Microwave-assisted one-pot synthesis of pyrazole derivatives.

Scheme 15. Regioselective synthesis of 4-alkyl-1,3,5-triarylpyrazoles 44.

Scheme 16. Synthesis of the pyrazole 48 catalyzed by [bmim] (PF6).

Scheme 17. The synthetic pathway to 3,5-diaryl-1H-pyrazoles 52.

Scheme 18. The synthetic pathway to fluoropyrazole 55.

Scheme 19. Synthesis of 3(5)-substituted pyrazoles 58.

Scheme 20. Synthesis of 3,5-substituted pyrazoles using CTAB as catalyst.

Scheme 21. Synthesis of 3,5-diaryl-4,5-dihydro-1H-pyrazole-1-carboximidamides 64 under ultrasonic irradiation.

Scheme 22. Synthetic routes for pyrazoles 67 and 68.

Scheme 23. Synthetic routes for pyrazoles 71 using I2/TBHP, NaHCO3 as catalyst.

Scheme 24. Synthetic routes for the regioisomers 74 and 75 using cyclocondensation reaction of hydrazine derivatives 73 on the acetylenic ketones 72.

Scheme 25. Synthetic routes for pyrazoles 78 via one-pot reaction.

Scheme 26. Synthetic routes for pyrazoles 80 via one-pot reaction.

Scheme 27. The synthetic routes for pyrazoles 84.

Scheme 28. The synthesis of pyrazole derivatives 87.

Scheme 29. The synthesis of pyrazole derivatives using ethyl 5-(3-aryl-3-oxopropinyl)anthranilates 88.

Scheme 30. One-pot regioselective synthesis of pyrazole derivatives 96.

Scheme 31. The synthesis of pyrazole derivatives 99 utilizing AgOTf as the catalyst.

Scheme 32. The synthetic route for pyrazoles 102.

Scheme 33. The synthetic route for pyrazoles 104.

Scheme 34. The synthetic route for pyrazoles 107.

Scheme 35. The synthetic route for pyrazoles 110 using Al(OTf)3 as the catalyst.

Scheme 36. The synthetic route for pyrazole 113.

Scheme 37. Pyrazoles 116 synthesized via 1,3-dipolar cycloaddition with TEA promoter.

Scheme 38. Synthesis of pyrrolopyrazoles 119 using Cu(I)-catalyzed cycloaddition.

Scheme 39. Synthesis of pyrazoles 122 using Ag(II)-catalyzed cycloaddition.

Scheme 40. Synthetic routes for pyrazoles 126 and 127.

Scheme 41. Synthetic routes for pyrazoles 130 and 132.

Scheme 42. The [3 + 2] Cycloadditions of Sydnone Riboside 133 with Different Alkynes.

Scheme 43. Synthesis of pyrazoles 137 using Ru(II)-catalyzed photoredox cycloaddition.

Scheme 44. The synthetic route for pyrazoles 141.

Scheme 45. Synthesis of sulfonated pyrazoles 145 via transition metal-free method, using molecular iodine as a catalyst.

Scheme 46. Oxone promoted the synthesis of 4-organylselanylpyrazoles 148.

Scheme 47. Organotitanium promoted the synthesis of pyrazoles 152.

Scheme 48. Green Multicomponent Approach for the Synthesis of pyrazoles 157.

Scheme 49. Synthesis of pyranopyrazoles 162 by one-pot cyclization using Co3O4-SiO2-NH2 nanocomposites as a catalyst.

Table 1

Effect of substituents on pyrazole synthesis.

R	R1	Yield	R	R1	Yield (%)
2,4-diNO2	H	92	4-CN	H	95
H	H	80	H	Me	90
4-Br	H	90	4-Me	Me	95
H	Cl	90	4-CN	Et	85
4-Me	Cl	95	4-NO2	Me	87
4-Br	Cl	90	H	Et	92
4-NO2	Cl	90	4-Me	Et	95
4-CF3	Cl	80	4-Br	Et	80
4-CF3	H	70	4-Cl	H	95
4-CN	Cl	90	4-Cl	Cl	90

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