Recent Advances in Synthesis and Properties of Pyrazoles

Abstract

Pyrazole-containing compounds represent one of the most influential families of N-heterocycles due to their proven applicability and versatility as synthetic intermediates in preparing relevant chemicals in biological, physical-chemical, material science, and industrial fields. Therefore, synthesizing structurally diverse pyrazole derivatives is highly desirable, and various researchers continue to focus on preparing this functional scaffold and finding new and improved applications; this review highlights some of the most recent and strategic examples regarding the synthesis and properties of different pyrazole derivatives, mainly reported from 2017–present. The discussion involves strategically functionalized rings (i.e., amines, carbaldehydes, halides, etc.) and their use in forming various fused systems, predominantly bicyclic cores with 5:6 fusion taking advantage of our experience in this field and the more recent investigations of our research group.

1. Introduction

Pyrazole derivatives are a special class of N-heterocyclic compounds (NHCps) bearing a heteroaromatic five-membered ring with two adjacent nitrogen atoms in the annular structure, one pyrrole-type (proton donor) and one pyridine-type (proton acceptor). Pyrazoles can act as weak bases or acids, with possible strength highly dependent on the nature of their substituent groups. The other three positions in the ring permit structural variants starting from the appropriate precursors or using post-functionalization reactions once the pyrazole ring is formed [1,2,3,4,5]; these variations give the pyrazoles diverse and valuable synthetical, biological, and photophysical properties; indeed, more complex structures with various relevant examples can be formed from them (Figure 1) [1,2,3,4,5,6,7,8,9].

Some fused pyrazoles also have demonstrated different biological activities, exceptional photophysical properties, and high synthetical versatility that allow the obtention of industrially and pharmaceutically crucial chemicals [1,2,3,4,5,6,7,8,9]; thus, synthesizing pyrazole derivatives efficiently and selectively is an important area of organic chemistry. For instance, pyrazoles have biological activities in many specific areas, such as anticancer, antibacterial, antifungal, antioxidant, and anti-inflammatory, among others [1,8]. Many drugs containing pyrazole core have been reported, such as the analgesic antipyrine, the arthritis treatment phenylbutazone, the non-steroidal anti-inflammatory drugs (NSAIDs): Lonazolac, Rimonabant, and ramifenazone, etc. (Figure 2a) [10,11]; moreover, drugs involving axitinib, zaleplon, reversan, sildenafil, and tracazolate, are exciting fused systems (Figure 2b) [6,12,13,14,15]. On the other hand, some pyrazoles, pyrazolo[1,5-a]pyrimidines, and pyrazolo[3,4-b]pyridines have exhibited excellent physicochemical properties [7,16].

Inside the last-mentioned features, the photophysical properties have been extensively studied because they allow research in environmental, biological, and industrial fields; these features in N-heteroaromatic pyrazole derivatives are unique given that saturated NHCps behave analogously to open-chain compounds. Thus, pyrazole derivatives with conjugation properties tend to be molecules with unique and intrinsic photophysical properties, which can be employed to develop sensors and organic materials [17,18,19,20,21]. One of the most studied topics is the detection of ions [7,20,21] (Figure 3).

Many ions play an essential role in biological and environmental processes; however, in excess, they may result in toxicity, making it an important topic to discover more accessible and manageable ways to detect and quantify them. Anions are more challenging due to their increasing diffuse charge compared with the corresponding isoelectronic cations, a large variety of geometries, and greater pH dependence [7]; they are heavily solvated by polar solvents, making them more challenging to detect on aqueous samples [20]. Molecular sensors have been used for this purpose since they help overcome several problems of conventional methods such as expensive equipment and complex and time-consuming process [21]; they also provide high sensitivity, specificity, and selectivity.

The chemistry of pyrazole derivatives has been extensively documented for several years due to their synthetic versatility and applicability in diverse fields [1,2,3,4,5,6,7,22,23]. Despite rings with oxygen or sulfur atoms being part of some fused pyrazole derivatives, nitrogenous rings predominate in heteroaromatic structures (Figure 1b). Thus, this contribution focuses on the recent advances in synthesizing pyrazoles and some of their aza-fused derivatives, mainly in the last five years; moreover, an approach to the biological or photophysical properties of some compounds is described. In general, this review was conceptualized considering our expertise in pyrazole derivatives chemistry, and we hope that it will be a helpful contribution to further applications in the area. A schematic summary depicting the most pertinent syntheses discussed in this work is shown in Table 1.

2. Synthesis and Functionalization of Pyrazoles

Due to the relevance of pyrazole derivatives applications, it is crucial to understand their different synthetical approaches to continue innovating around the pyrazole ring; this scaffold construction is carried out via classical cyclocondensation reactions of 1,3-biselectrophilic compounds with hydrazine derivatives or by [3 + 2] cycloaddition reactions of diazo compounds with different alkynes [4,10]. Pyrazoles classical synthesis requires harsh reaction conditions, high temperatures, organic solvents that often are toxic and volatile, and extensive reaction times; this long time has significant energy waste, increasing the final synthesis cost. Thus, protocols continue to be improved to maximize synthetical efficiency, cost, time, eco-compatibility, and the economic aspect. For example, multicomponent reactions (MCR) are reported to generate the intermediate reagents in situ; in addition, both ultrasound (US) and microwave (MW) assisted organic synthesis are tools to reduce the solvent quantity and reaction purification [19,24].

As previously mentioned, pyrazoles can be functionalized by introducing diverse groups in the starting reagents or by aromatic substitution reactions on the pyrazole ring [4,24]. For example, α,β-unsaturated nitriles bearing an easily displaceable group at Cβ react with hydrazine derivatives to generate 5-aminopyrazoles; as observed, the amino group is obtained directly from the starting material (Scheme 1a). On the other hand, Scheme 1b shows the synthesis of 4-aminopyrazoles using a post-functionalization strategy involving the reduction reaction of a nitro group previously introduced via an electrophilic aromatic substitution (AES) reaction on an unsubstituted ring; this contribution shows examples of similar approaches in Scheme 1: functionalizations through the ring construction or aromatic substitution reactions.

In the following sections of this chapter, we will discuss various synthetical protocols, mainly reported from 2017–present, to access important functionalized pyrazoles such as aminopyrazoles, acylpyrazoles, halopyrazoles, and other interesting systems.

2.1. Aminopyrazoles

We start this chapter by discussing synthetical procedures used to obtain 5-aminopyrazoles, whose chemistry has been well documented for a long time [4,22]. We wanted to expose examples from the last five years; however, other earlier key examples are worth mentioning. For instance, we have decided to mention the work reported in 2016 by Kallman et al. [25], which is not a standard procedure for accessing 5-aminopyrazoles. Specifically, the authors reported a regioselective synthesis of aminopyrazoles from isoxazoles 1a–g as they are synthetic equivalents of ketonitriles 1′. The reaction proceeds via ring-opening, generating a ketonitrile 1′ intermediate that then reacts with hydrazine derivatives 2a–d to form the respective cyclocondensation product 3a–m (Scheme 2a).

In 2021, Hassan and co-workers [26] reported the synthesis of pyrazole-oxindole hybrid systems 6a–g by the condensation reaction of 5-aminopyrazoles 5a–e with N-substituted isatin 6′ (Scheme 2b). Heteroamines 5a–e were obtained by the cyclocondensation reaction of N-aryl-3-(arylamino)-2-cyano-3-(methylthio)acrylamides 4a–e with hydrazine hydrate (2a). Intermediates 5 are substituted with arylamines and amides at positions 3 and 4, making it possible for the core to have a wide range of post-functionalizations. In this case, final products 6a–j were used for in vitro cytotoxicity assays against four human cancer-type cells; it is important to note that in the examples about 5-aminopyrazoles synthesis mentioned above, and in most others involving ketonitriles or enaminonitriles as 1,3-bis-electrophilic substrates, it is necessary to have an easy displacement group on the Cβ of the substrate to generate the required unsaturation in the product.

On the other hand, Pilakowski et al. [27] synthesized 5-alkyl-3-amino-1H-pyrazoles 8a–b starting from carboxylic acids 7a–b (Scheme 3a). First, an esterification reaction was developed, and the respective ester was treated with sodium hydride and acetonitrile to form the corresponding ketonitrile 7′. Next, this intermediate was treated with hydrazine hydrate to obtain the desired products 8a–b, which were then coupled to dichloropyrimidine to yield N-substituted pyrazoles tested as Nek1-inhibitors. The low yield of 8b (17%) versus 8a (82%) is due to the last step, where the authors subjected the reaction with substrate 7′b to different conditions; they possibly wanted to obtain the product as the expected light yellow solid; however, they only managed to isolate it as a viscous orange oil.

In another recent approach, Annes et al. [28] reported a free-metal and free-solvent multicomponent synthesis mediated by iodine to obtain aminopyrazole-thioether derivatives 12a–ad in the range of 39–91% yield. The multicomponent reaction comprises substituted hydrazines 9a–m, nitriles 10a–h benzenethiols 11a–j. Reagents 9a–m and 10a–h undergo a Michael reaction in the presence of Lewis acid, followed by intramolecular cyclization with the elimination of ammonia to afford 5-aminopyrazoles 12′. At the same time, iodine reacts with 11 to form the electrophilic derivative 12″. Finally, the C-S bond was formed via an electrophilic aromatic substitution (EAS) reaction on 12′. The reaction scope was studied, including diverse aromatic and aryl groups at positions 1, 3, and 4 (Scheme 3b); this reaction proceeded with a wide range of substrates; however, the best yields are obtained when the aminopyrazole 12′ has an electron releasing group (ERG) or the electrophilic reagent 12″ has an electron-withdrawing group (EWG).

In 2018, Ren et al. [29] synthesized 5-amino-1-arylpyrazole-4-carbonitriles 14a–d starting from a mixture of arylhydrazine hydrochloride 9a, 2-(ethoxymethyl)malononitrile 13, ethanol, and sodium hydroxide via a classical cyclocondensation reaction (Scheme 4a). With 5-aminopyrazoles 14a–d in hand, the authors transformed them into the carboxamide derivatives 15a–d, which then were evaluated against three fungal strains and as inhibitory compounds against succinate dehydrogenase. A year later, Elnagdy and Sarma [30] reported a homogenous catalytic system using FeCl₃/PVP and green solvent water/PEG-400 to synthesize 4-amino-1-aryl-1H-pyrazole-4-carbonitriles 17a–q using a cyclocondensation reaction of arylhydrazines 9a–f with malononitrile derivatives 16a–c. A mixture of FeCl₃ and polyvinyl pyrrolidine (PVP) was used to accelerate the addition of 9a–f to the double bond of 16a–c; then, an intramolecular cyclization allows the formation of products 17a–q in up to 97% yield with reaction times of 2–4 h (Scheme 4b).

In 2020, Sapkal and Kamble [31] obtained 5-aminopyrazole-4-carbonitriles 20a–m using a green protocol based on a three-component cyclocondensation of phenylhydrazine 9a, aldehyde derivatives 18a–m, and malononitrile (19) adding sodium p-toluenesulfonate (NaPTS) as a catalyst in aqueous media (Scheme 5a). The authors mentioned that NaPTS was used as a hydrotrope that helps increase the solubility of poorly soluble organic compounds in water. First, water hydrates the hydrotrope head groups, decreasing their electrostatic attraction. Both head groups move apart, displacing water molecules interacting with hydrophobic parts; this action helps the reactant molecules interact, enhancing the reaction on aqueous media. The reaction mechanism starts with the nucleophilic attack of 19 on the electrophilic carbon of arylaldehydes 18a–m to form arlylidenemalononitrile derivatives 19′. Then, 9a proceeds by a nucleophilic attack over the double bond of 19′, and finally, the addition intermediate undergoes intramolecular cyclization to afford products 20a–m. Although the authors mention that the presence of NaPTS favors the reaction by increasing the solubility of reactants, we believe it mainly helps in the product aromatization step (20′ in Scheme 5a) as 19′ do not possess a leaving group. For this synthesis, the substituent electronic effects do not influence the yields and scope of the reaction.

This section started with a “non-classic” method to obtain 5-aminopyrazoles, and in 2015, another not classic strategy was described via a nucleophilic aromatic substitution (NAS) reaction on 5-chloropyrazole derivatives. Specifically, 5-(N-alkyl)aminopyrazoles 23a–e were synthesized in high yields via the microwave-assisted reaction between 5-chloro-4-formylpyrazoles 21a–c and primary alkylamines 22a–e [32]. The reaction was possible because the amine nucleophilicity is favored under MW by the cesium effect and the substrate 21a has a 2-pyridyl group at position 1, which is a strong EWG; however, using the N-aryl substituted substrate 21b–c, the reaction needs harsh conditions and even CuI as a catalyst to form 23f–l; this reaction type has been scarcely studied since the pyrazole ring exhibits a moderate π-excedent character, which disfavors the initial nucleophilic attack. Therefore, these results corroborate the difficulty of the NAS reaction on pyrazole derivatives justifying its limited study (Scheme 5b).

2.2. Acylpyrazoles

In this section, synthetical methods commonly used to obtain acylpyrazoles are described. Specifically, 4-formylpyrazoles synthesis under Vilsmeier-Haack conditions and the preparation of other acyl derivatives (i.e., ketones, esters, amides, etc.) are discussed.

2.2.1. Formylpyrazoles

Formylpyrazoles are strategic intermediates in obtaining a wide range of biologically active compounds, with the 4-formyl derivatives being more usual; they possess a high synthetical versatility allowing them a plethora of reactions for the insertion of more functional groups. Our research group has reported the synthesis of 3-aryl-1-(pyridin-2-yl)-1H-pyrazole-4-carbaldehydes 27a–f via Vilsmeier-Haack cyclization-formilation of different hydrazones 26a–f, which were generated from acetophenones 24a–f and 2-hydrazinylpyridine (25). Precursor 26 was transformed in the 1,3-biselectrophilic intermediate 26′ under Vilsmeier-Haack conditions. Subsequently, 26′ is cyclocondensed to pyrazole 26″, which is finally formylated to deliver 4-formylpyrazole 27 in 66–85% yields (Scheme 6a).

Notably, heteroaldehydes 27 were successfully used as reagents in chemosensors synthesis to detect cyanide ions (CN⁻) [33,34]; for example, indolium salts (hemicyanine derivatives) 28 were synthesized and used as colorimetric probes for CN⁻ recognition with limits of detection (LODs) of up to 0.99 μM [34]. On the other hand, the 1-(2-pyridyl)-4-styrylpyrazole 29, obtained from 27 via a Witting olefination followed by a Mizoroki-Heck coupling, was used to detect Hg²⁺ with a LOD of 0.31 μM [35] (Scheme 6b); these LODs values are below the respective limits of the World Health Organization (WHO) [21].

Similarly, Kaur et al. [36] synthesized 4-formyl-1-phenylpyrazoles 31a–f using the Vilsmeier-Haack reaction with phenylhydrazones 30a–f, POCl₃, and DMF. The corresponding substrates 30a–f were obtained by a condensation reaction between phenylhydrazine (9a) and acetophenones 24a–f in ethanol using acetic acid as a catalyst (Scheme 7a). In this case, the yields are not particularly dependent on the different substituents.

From 4-formylpyrazoles 31, new hybrid isatin derivatives 32a were obtained and tested for their α-Glucosidase inhibition for controlling postprandial hyperglycemia in diabetic patients. A similar methodology was used by Kumar and co-workers, who synthesized the 4-formylpyrazoles 31c–g starting from acetophenones 24c–g and 9a in yields between 63–86% (Scheme 7b) [37]. The heteroaldehydes 31c–g were used as intermediates for synthesizing pyrazole-coumarin derivatives 32b, and their antitubercular activity against the Mycobacterium tuberculosis H37Rv strain was tested.

Most formilations over pyrazole rings are carried out via a classical Vislmeier-Haack (VH) reaction (i.e., POCl₃/DMF), and modifications changing the chlorination agent can be performed so as not to use the toxic reagent POCl₃. For instance, Kumari et al. [38] synthesized 4-formylpyrazoles 31′a–g in a similar route that shown in Scheme 7a, that is, through the hydrazone derivative 30′a–g; nevertheless, the VH reagent was derived from phthaloyl dichloride (PDC, 33) and DMF (Scheme 7c). Once the electrophile E′ is formed, the reaction of it with 30′a–g is performed under MW irradiation to afford products in high yields (78–81%), without particular dependence on the effect of the substituent.

In the previous section, 5-alkylaminopyrazoles 23 were mentioned (see Scheme 5b), where the substrates used for that synthesis were 5-chloro-4-formylpyrazoles 21, which were obtained from the respective pyrazolones 35; these starting materials undergo a chloroformylation reaction under Vilsmeier-Haack conditions to afford heteroaldehydes 21 (Scheme 8a). In the next synthetic step, chlorine was substituted, generating only the 5-amino-4-formylpyrazoles 23 chemoselectively [32].

In practically all the literature about formylpyrazoles synthesis, the Vilsmeier-Haack conditions are used; however, in 2007, Nag et al. obtained 3/5-formyl derivatives 39 in an interesting and unconventional example [39,40] that we decided to consider since we found no more examples of this methodology. For synthesizing products, pyrazole esters 37 were obtained by the cyclocondensation reaction between diketoesters 36a–c and phenylhydrazine (9a). Subsequently, compounds 37 were reduced with LiAlH₄ in dry diethyl ether to give the respective pyrazole alcohols 38, which by PCC-promoted oxidation reaction yielded the desire 3/5-formylpyrazoles 39 in high yields (Scheme 8b).

2.2.2. Other Acylated Derivatives

Regarding other acylpyrazoles, Poletto et al. [41] recently developed a regioselective synthesis of 4,5/3,4-disubstituted N-methylpyrazoles 42/43 from 4-acyl-1H-pyrrole-2,3-diones 41 and methylhydrazine 2b in the presence or not of acid (Scheme 9a).

The pyrrole derivative 41 is generated in situ when the β-enaminodiketone 40a–x is cycled in the presence of DBU. Treatment of the pyrrole-2,3-dione 41 with p-toluenesulfonic acid (PTSA) leads to the formation of specie N-acyliminium 42′, which is then converted to the fused system pyrrolo[2,3-c]pyrazole 42″; finally, the cleavage of 42″ affords the 4,5-disubstituted pyrazoles 42a–ad. The absence of PTSA in the reaction allows 2b to directly attack C5 of the intermediate 41 followed by cleavage of the pyrrole ring generating a non-cyclic intermediate 43′. Afterward, an amino group performs a nucleophilic attack on the carbonyl carbon of the α-ketoamide group; ultimately, water elimination in 43″ gives the 3,4-disubstituted pyrazoles 43a–r. In both cases, high yields were obtained regardless of the substituents used, and various ERGs and EWGs were tested to evaluate the scope of the reaction.

Similarly, Qui et al. [42] reported a divergent domino annulation reaction between sulfur ylides 44a–e with aryldiazonium tetrafluoroborates 45a–g to afford tri- and tetra-substituted acylpyrazoles 46a–o and 47a–l, respectively; this synthesis proceeded via the interaction of the in situ generated 1,3-dipole 45′ with more molecules of 44 (Scheme 9b).

In a different work, He et al. [43] synthesized acylpyrazoles 50a–ac from N-substituted isoindoline-1,3-dione derivatives 48a–ac (Scheme 10a). Precursors 48a–ac were obtained by reaction between 1,3-dioxo-1,3-dihydroisobenzofuran-5-carboxylic acid with the appropriate primary amine in anhydrous acetic acid. The substrate 48a–ac and 2-chloro-1-methylpyridinium iodide (CMPI) reacted to then formed the respective pyrazole esters 49a–ac with 1,3-dimethyl-1H-pyrazol-5-ol (48′). The esters molecules were then transformed, through a Fries rearrangement, into the final products 50a–ac; these 4-aroylpyrazoles 50a–ac were tested for Arabidopsis thaliana 4-hydroxyphenylpyruvate dioxygenase (AtHPPD) inhibition activities. For these derivatives, once EWGs were inserted the yields were slowly lower than for those with ERGs.

Recently, Loro et al. [44] obtained pyrazole-4-carboxylic acids 52a–n starting from isoxazole-5(4H)-ones (51a–n) using [RuCl₂(p-cymene)]₂ as a catalyst. The transformation begins with a ring-opening non-decarboxylative path that generates a vinyl Ru-nitrenoid intermediate that undergoes cyclization to afford the desired pyrazoles (Scheme 10b). Specifically, the catalytic cycle starts with the oxidative addition of catalyst to 51, generating intermediate 51′, which is stabilized due to the formation of a hydrogen bonding; this complex undergoes ring-opening resulting in a Ru-nitrenoid intermediate affording the final product via reductive elimination of the metal; it is worth mentioning that the catalytic cycle mechanism is not well elucidated, and the authors explain just a proposal.

2.3. Further Functional Pyrazoles

Considering the broad applicability of pyrazole, in addition to the already discussed examples of the most frequent functionalized pyrazoles (i.e., aminopyrazoles and acylpyrazoles), other functional derivatives bearing substituent groups such as halogens, trifluoromethyl, hydroxyl, pyrenyl, thiophenyl, and nitro, among others are also essentials. Consequently, the below mention will be made of some of these other pyrazoles.

2.3.1. Halopyrazoles

In 2019, Onodera et al. [45] reported a regioselective halogenation of 3-trimethylsilylpyrazole 53 (Scheme 11a). The introduction of halogen atoms at positions 3, 4, and 5 was possible thanks to the different character and orthogonal reactivity of each one; position 3 has the trimethylsilyl group (TMS), which can be easily removed under mild conditions generating a carbanion that can react towards electrophilic substrates such as N-chlorosuccinimide (NCS) and 1,2-dibromotetrachloroethane (DBTCE), affording chlorinated 54 and brominated 55 pyrazoles, respectively. On the other hand, position 4 is the most nucleophilic on the ring; therefore, the direct reaction with N-bromosuccinimide (NBS) followed by deprotection of the TMS group affords the 1-aryl-4-Bromopyrazole 56. Finally, position 5 possesses the most acidic proton of the ring; thus, using a base such as n-butyllithium and tetrabromomethane, followed by deprotection of TMS, allows a halogenation at position 5 of the pyrazole ring to afford the respective 5-bromopyrazole 57. A similar approach was recently reported by Zarate and co-workers [46], in which the authors synthesized the 4-iodopyrazole derivative 59 through a condensation/iodination sequence starting from bicyclo[1.1.1]pentan-1-ylhydrazine 58 and using tetramethoxypropane as an additive in the reaction carried out in ethanol (Scheme 11b).

In 2017, Bonacorso et al. [47] Synthesis of 4-bromo-5-(trifluoromethyl)-1-phenyl-1H-pyrazoles 63a–d by two interesting methodologies; the first proceeded through the brominated 1,3-bis-electrophilic substrate 61 whereas, in the second, the pyrazole ring in 62 was brominated using NBS as the brominated agent. The synthesis of 63a–d was developed by utilizing 1,1,1-trifluoro-4-methoxy-alken-2-ones 60a–d as starting reagents. On the one hand, substrate 60a was brominated and then cyclocondensed with phenylhydrazine (9a) to form product 63a. On the other hand, 60b–d cyclocondensed with 9a to obtain pyrazoles 62a–c, which finally brominated to obtain products 63b–d (Scheme 12a). Compounds 63a–d were successfully used in the one-pot three-step synthesis of polysubstituted 4-(5-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazoles 64a–o; they carried out a sequential Sonogashira cross-coupling, desilylation, and a copper(I)-catalyzed azide-alkyne cycloaddition reaction (CuAAC) with high overall yields. The authors cited that the CF₃ group in 63 made the Sonogashira cross-coupling reaction challenging (Scheme 12b).

As we can see, in the above approaches, halogenation of the pyrazole is carried out once the ring; however, other methods use the commercial halogenated pyrazole as a start reagent in the synthesis of more complex structures; these protocols exist due to the versatility of halosubstituted products, allowing different reactions such as aromatic substitutions on the rings or coupling reactions to form new C–C bonds. For example, Tsui and collaborators [48] used 4-bromopyrazoles 66a–e in palladium-catalyzed benzannulation to obtain substituted indazoles 67a–h. The presence of bromine facilitates the oxidative addition step on C4; it is important to note that despite some halopyrazoles being commercial, various halogenated substrates are obtained by other transformations that do not involve direct halogenation; in this respect, the Tsui group synthesized the N-alkyl-4-bromopyrazole derivative 66e by the respective N-alkylation reaction of 4-bromo-1H-pyrazole (65) and alky bromides potassium carbonate-mediated in DMF (Scheme 13a).

In the above sections, we cited the previous work of Orrego-Hernandez et al. [32], in which 5-alkylaminopyrazoles 23 were obtained through NAS reactions on 5-chloro-4-formylpyrazoles 21 and using primary alkyl amines as nucleophiles. The substrates 21 were obtained by the chloroformylation reaction under Vilsmeier-Haack conditions of the respective pyrazolones 35 (see Scheme 5b and Scheme 8a). Consequently, this methodology is another fundamental example of access to halopyrazoles, particularly 5-chloropyrazoles, from ethyl acetoacetate (68) as the starting material (Scheme 13b).

2.3.2. Additional Systems

Throughout the entire contribution, several functionalized pyrazole derivatives have been mentioned (i.e., rings substituted with NH₂, CHO, OH, CF₃, SR, CN, CO₂R, Cl, Br, etc.), and some of them managed to be classified within a particular section due to their recurrence (pyrazoles bearing amino or acyl groups); however, there are examples on other functional pyrazoles that are not part of such sections; therefore, in the last section of this chapter, seven works on different or highly functionalized pyrazoles are discussed.

In the first example, Fricero et al. [49] reported the regioselective condensation between ynone-trifluoroborates 69a–e and hydrazine derivatives to obtain pyrazole 5-trifluoroborates 70 (Scheme 14a). The reaction generates a nitrile intermediate just such as the ones studied in Section 2.1. In this case, products are stable, allowing a chemoselective halogenation of 70 to obtain the fully functionalized pyrazoles 71a–t. The halogenation methodology is such as the ones mentioned in the above section, using N-halosuccinimides and shows that the halogenation is compatible with the trifluoroborate systems as it does not undergo halodeborylations.

On the other hand, Wei and co-workers [50] reported the synthesis of trifluoromethylated pyrazoles 75a–c; these pyrazoles were obtained via a double hydroamination reaction of β-CF₃-1,3-enyne 72 with hydrazine derivative 73a–c (Scheme 14b). First, reagents 72 and 73 undergo an intermolecular hydroamination generating intermediate 74, in which amine performs a nucleophilic attack over the central sp-carbon to obtain the cyclization products; it is to notice that product 75a was obtained alongside pyrazolidine which is the non-aromatized product. When 73c was used, pyrazolidine was obtained, but as it was air sensitive, it was readily oxidized into pyrazole 75c.

Another example is the preparation of nitro-substituted pyrazoles. Zhang et al. [51] synthesized 1-nitro-3-trinitromethylpyrazole (78) from 3-formylpyrazole (76) (Scheme 15a). Compound 78 was used to obtain hydrazinium 5-nitro-3-dinitromethyl-2H-pyrazole 79. The synthetical route, 76 was treated with hydroxylamine hydrochloride to yield compound 77. Subsequently, 77 was treated with N₂O₄ to obtain 78, which reacted with hydrazine to obtain the dinitromethylide salt 79. In this case, in the process of dinitration, C5 was nitrated, too, making it clear that isomerization of N-nitropyrazole was carried out during the last step. The isomerization mechanism was elucidated using DFT computational calculations, and the final product was used as an energetic salt.

Continuing, Sar et al. [52] reported the synthesis of seven pyrene-pyrazole pharmacophores for targeting microtubules (Scheme 15b,c). The pyrenyl-substituted pyrazoles 81a–f were prepared with the corresponding hydrazones 80a–f and had side-chain modifications at N-1 and C-3 positions, inserted from the alkenyl hydrazones via C-N dehydrogenative cross-coupling using a copper triflate catalyst under aerobic conditions. Furthermore, the reaction of pyrenylacetophenone (82) with dimethyloxalate produced molecule 83 that then undergoes cyclization reaction with phenylhydrazine to produce 84 via C-N bond formation in one pot. Finally, 84 was treated with KOH/MeOH to yield 85.

The following two examples imply the amino or the keto group, and their preparation involves analog functional groups to the ones mentioned in the previous sections; though, we mention them since they are highly functionalized compounds. In this context, Galenko et al. [53] synthesized 1-aminopyrazole-4-carboxylic acids using an iron II catalyst (Scheme 16a). The synthesis starts with the isoxazoles 86a–h, which react with 2,4-dinitrophenylhydrazine (DNPH) to generate both E/Z isomers of 4-hydrazonomethylisoxazoles 87a–h. Afterward, the catalyst FeCl₂·H₂O is added with dry acetonitrile developing a domino rearrangement of the isoxazole via the formation of aziridine intermediate 87′. The mechanism starts with forming a Fe-isoxazole complex, followed by the ring’s opening via N–O bond cleavage to form a Fe-nitrene complex; this complex then undergoes recyclization to form the Fe-azirine complex 87′. The three-membered ring is open, generating another Fe-nitrene complex that allows the 1,5-cyclization producing the complex Fe-N-aminopyrazole 87″. Lastly, cleavage of the catalyst affords pyrazoles 88a–h in high yields. Notably, the yields shown are obtained starting from the E isomer of the isoxazoles, although the reaction proceeds smoothly for both isomers.

Later, Wei et al. [54] reported a three-component reaction of aroylacetonitriles 7a–x with arylsulfonyl hydrazides 89a–r to form 5-amino-4-arylthio-3-aryl-1H-pyrazoles (Scheme 16b). The reaction could afford 1-H or 1-SO₂Ph products, but in the presence of NIS, the reaction became selective to the 1H-pyrazole. Various substituents in arylsulfonyl hydrazides and the β-ketonitrile were tested to investigate the scope of the reaction; it was found that the electronic effects of the aryl group did not influence the reaction. The mechanism reaction proceeds via sequential cyclization and sulfenylation reactions under NIS catalysis. The reaction starts with the reduction of 89′ that after losing HI and N_2, affording two disulfide spices; that is, 1,2-diphenyldisulfane 89″ and S-phenylbenzenesulfonothioate 89‴. Meanwhile, 7 reacts with 89 via a cyclization reaction to generate the desired 5-amino-1-arylthio-3-arylpyrazole 7′. Two routes are possible to afford the final products. In the first one, 7′ undergoes electrophilic substitution with 89 to afford the arylthio group at position 4; this product treated with NIS provides the desired aminopyrazoles 90a–ab. In the other proposed route, 7′ then loses the arylthio group in the presence of NIS and reacts with 89 to afford 90a–ab which possesses the thioether group at position 4.

To finish, Tsutsumi et al. [55] reported phosphorescent trinuclear Au(I) complexes using NH-pyrazoles as ligands (Scheme 16c). Pyrazole is prepared from 2,4-pentanedione (90), which is alkylated using K₂CO₃ as a base and an alkyl bromide to afford the α-substituted β-diketones 91a–c. Afterward, 91a–c undergoes a cyclization reaction with hydrazine to afford the pyrazoles 92a–c that then were used to prepare the trinuclear complexes 94a–c with tetrahydrothiophene-AuCl (93). Complexes 94 were recrystallized, and all the crystals exhibited broad unstructured luminescence around 730 nm with quantum yields of 75%, 61%, and 63%, respectively. The complexes did not reveal a good luminescence in diluted solutions; however, the isolated molecules exhibited the opposite behavior, indicating that the formation of aggregates induces the luminescence of the complexes.

3. Applications in Fused Systems

Similar to the pyrazoles, the fused pyrazoles have a wide range of applicability in diverse fields, which has led to several of their derivatives being applied in pharmaceutical, agricultural, biological, physical-chemical, and industrial fields. Thus, the synthetical transformations involving this class of heterocyclic systems have been and will continue to be a research area of extensive interest in various researcher groups. Within the large number of structures that these heterocyclic systems possess, those with a pyrazole nucleus fused to six-membered aromatic rings predominate; indeed, there is a diversity of combinations involving bicyclic, tricyclic, tetracyclic systems, etc; however, the bicyclic systems serve as a reference to know the properties of the other heteroaromatic fused systems, in which only those containing nitrogen atoms as heteroatom are predominant [5,21,24,56,57].

Except for indazoles, the synthetical approaches to access 5:6 fused N-heterocyclic systems are mainly based on constructing the six-membered nitrogenous ring, starting from the appropriate pyrazole derivative [5,56,57]. In this section, the syntheses of some representative aza-heteroaromatic products are described; that is, pyrazolo[1,5-a]pyrimidines, pyrazolo[3,4-b]pyridines, indazoles, and the least recurrent pyrazolo[3,4-d]pyrimidines, pyrazolo[4,3-d]pyrimidines, and pyrazolo[1,5-a][1,3,5]triazine rings. Likewise, syntheses of other scarce rings such as imidazo[1,2-b]pyrazole and pyrazolo[3,4-b]azepine are also discussed. The pyrazolo[1,5-a]pyrimidine ring is perhaps the most frequently studied fused-pyrazole due to its applicability and synthetical versatility. Therefore, several specialized reviews on this type of ring have been described in recent years [6]; indeed, more of our recent investigations are pyrazolo[1,5-a]pyrimidines-based [6,19].

3.1. Pyrazolo[1,5-a]pyrimidines

The pyrazolo[1,5-a]pyrimidine (PP) ring is a heteroaromatic system that admits structural variations in the periphery during ring construction and via later functionalization steps. 5-Aminopyrazoles have been widely studied as 1,3-bis-nucleophilic reactants in cyclocondensation reactions with 1,3-bis-electrophiles such as β-dicarbonyl compounds, β-ketonitriles, β-enaminones, etc. [5,6]. For example, in 2019, Metwally and co-workers [58] synthesized the functionalized pyrazolo[1,5-a]pyrimidine 97 through the cyclocondensation reaction between the 5-aminopyrazole derivative 95 with acetoacetanilide (96). Then, the Knoevenagel reaction of 97 with various aldehydes 18 led to forming a family of the acrylonitriles 98a–i in good yields (Scheme 17a). Compounds 97, 98a, and 98b exhibited higher cytotoxicity (doxorubicin is the control) and inhibitory activity against histone lysine demethylases (KDMs); while the 4-chlorophenylidene derivative gave the lowest cytotoxic activity. Notably, 98a is the most active KDM inhibitor showing a total apoptotic effect of 10 folds more than the control. The authors presume these results are due to the π–π interactions between the heteroaromatic moieties and the enzyme active site.

Recently, Stefanello et al. [59] carried out the regioselective synthesis of 7-(trifluoromethyl)-3-(aryldiazenyl)pyrazolo[1,5-a]pyrimidin-2-amines 101a–q in 50–90% yields by the cyclocondensation reaction in acetonitrile of 4-(aryldiazenyl)pyrazol-3,5-diamines 99a–g with substituted 4-methoxy-1,1,1-trifluoro-3-buten-2-ones 100a–j (Scheme 17b). Due to the verified photophysical properties of pyrazole derivatives [16,19], the authors evaluated these properties in the products. In this context, absorption and emission spectra of 101a–q were performed in different polarity solvents. All products presented good absorption in the ultraviolet region, although they had low quantum emission fluorescence yields. The spectral changes vary with the solvent polarity according to the electronic nature of the molecules evaluated in the presence or absence of the diazo group –the authors prepared a similar product without the aryldiazenyl moiety. Likewise, the effects of pH variation on 101a did not seem to affect its ground state or excited state properties.

In the same line, our group has intensively investigated β-enaminones use as 1,3-electrophilic systems in pyrazolo[1,5-a]pyrimidine synthesis in recent years [24,60,61]. Some products have shown photophysical applications, explicitly developing chemosensors for detecting cyanide [19,62] or water in some organic solvents [63] (Scheme 18).

In particular, we have synthesized various pyrazolo[1,5-a]pyrimidines derivatives starting from different β-enaminones, some of which are shown in Scheme 17. In those works, the 7-aryl substituted products 104a–x were synthesized in high yields via the MW-assisted cyclocondensation reaction of 5-aminopyrazoles 102a–d with β-enaminones 103a–i under solvent-free conditions (Scheme 18a) [24,60,61]. Regarding the photophysical usages, some 7-arylpyrazolo[1,5-a]pyrimidines 104 have been used as precursors to obtain chemosensors 105–107 to detect CN⁻ with excellent LODs [19,62]; likewise, the two integrated pyrazolo[1,5-a]pyrimidine–triphenylamine systems 108 and 109 were used as a fluorescent indicator for the sensing of water content in organic solvents [63] and the ethanol quantification of distilled spirits [16], respectively (Scheme 18b).

3.2. Pyrazolo[3,4-b]pyridines

Pyrazolo[3,4-b]pyridines (PPys) can be accessed from appropriately functionalized pyridines where the pyrazole ring is formed, or starting from substituted pyrazoles in which the pyridine ring is constructed. In pyrazolo[3,4-b]pyridine synthesis is also possible to introduce functional groups during the ring construction or by subsequent functionalization reactions; these processes generally involve the reaction of N-substituted 5-aminopyrazoles with 1,3-bis-electrophilic substrates, which can be generated in situ by multicomponent reactions (MCRs) when they are α,β-unsaturated carbonyl compounds generated from arylaldehydes and active methylene compounds such as β-dicarbonyl compounds. When 5-aminopyrazoles unsubstituted at the ring nitrogen atom are used to synthesize PPys, the pyrazolo[1,5-a]pyridines formation is mainly observed; however, PPys are favored by using enones 1,3-bis-electrophilic substrates [6,24,64].

In 2017, we reported the MW-assisted regioselective synthesis of fully substituted pyrazolo[3,4-b]pyridines 112 through an isobenzofuranone ring-opening reaction from the 1,3-bis-electrophile 111. N-Substituted 5-aminopyrazoles 110 were used in this approach; however, the reaction proceeded by a domino aza-Michael-cyclization-dehydration sequence via the isolated pyrazolyl-enamine intermediate, allowing us to clarify the reaction mechanism involved with the unusual 1,3-biselectrophile 111 (Scheme 19a) [65].

Subsequently, the MW-assisted pseudo-tricomponent synthesis of fluorescent 1,7-dipyridyl-bis-pyrazolo[3,4-b:4′,3′-e]pyridines 114a–e was reported for the same group [66]; these fused-pyrazoles were obtained by the reaction of arylaldehydes 18 with two molecules of 5-amino-3-methyl-1-(2-pyridyl)pyrazole (113). Tricyclic products 114a–e were obtained in high yields, and they were used as turn-off reversible chemosensors for nanomolar detection of metal ions such as Cu²⁺, Co²⁺, Ni²⁺, and Hg²⁺, through the complexes formation 114-M (Scheme 19c). In our last example on PPys synthesis, indeno[1,2-b]pyrazolo[4,3-e]pyridines 116a–x were obtained in high yields by MCRs between arylaldehydes 18, indan-1,3-dione (115), and 5-amino-N-arylpyrazoles 110. Products 116a–x are 4-azafluorenone systems that, combined with malononitrile (19), produced the dicyanovinylidene derivatives 117 bearing different acceptor or donor aryl groups at position 4 (Scheme 19c). The final products were preliminarily studied to detect CN⁻, and photophysical and computational studies confirmed an intramolecular charge transfer (ICT) phenomenon [64].

The last two examples correspond to MW-assisted MCRs, in which the 1,3-bis-electrophilic reagent is in situ generated from an active methylene compound and an aldehyde molecule via a condensation reaction [64,66]. In this context, Gutiérrez et al. [67] developed the MCR of 5-amino-1-phenyl-3-methylpyrazole (110a), formaldehyde, and β-diketones 109 in water using InCl₃ as a catalyst; this MW-assisted reaction produces pyrazolo[3,4-b]pyridine derivatives 111a–i in high yields (Scheme 20a).

Similarly, Bhuyan et al. [68] carried out the MW-assisted multicomponent reaction between 5-amino-1-phenyl-3-(3-pyridyl)pyrazole (112), hetaroylacetonitrile 113, and arylaldehydes 18 in choline chloride (ChCl)/glycerol; this synthetical approach allows to obtain 1,3,4,6-tetraaryl-5-cyanopyrazolo[3,4-b]pyridines 114a–o in high yields and short reactions times by using sulfonic acid nanoparticles anchored by graphene oxide (G) a catalyst system (Scheme 20b). On the other hand, as a different and unusual example, Cajal and co-workers [69] recently synthesized 6-amino-4,6-diarylpyrazolo[3,4-b]pyridines 117a–m by constructing the pyrazole using hydrazine derivatives 2a–b, on the preformed and functionalized pyridines 116 (Scheme 20c). The final products were obtained in moderate to good yields under microwave conditions, such as the preparation of intermediates 115 were obtained starting from strategically substituted acetophenones 24 and arylaldehydes 18; it is important to note that the authors carried out a rational design to identify and validate the 4,6-diaryl-pyrazolo[3,4-b]pyridin-3-amine scaffold as the core for mitogen-activated protein kinases (MAPKs) inhibitors; they concluded that aryl groups at positions 4 and 6 of the fused ring are essential for the activity of the compounds.

3.3. Indazoles and Other Bicyclic Pyrazole-Based

Similar to pyrazolo[1,5-a]pyrimidine, indazole is another recurrent bicyclic ring type containing pyrazole; this one is a benzo-fused system with two possible tautomeric forms (1H- and 2H-), in which the 1H-indazole tautomer is the most stable and predominant form. Different indazoles possess significant pharmacological activities and serve as structural motifs in drug molecules. Thus, various approaches have been developed to obtain indazole derivatives, and some specialized reviews have been published on this scaffold’s synthetical and biological properties. The indazole ring construction is usually accessed from appropriately functionalized benzene derivatives, on which the pyrazole ring is formed. In this context, two representative examples are shown below [56,70,71].

First, Sawant et al. [70] synthesized a series of amides indazole-substituted 121a–x, which were evaluated for anticancer, antiangiogenic, and antioxidant activities; moreover, the potential to inhibit the pro-angiogenic cytokines associated with tumor growth of indazole derivatives 121a–x was evaluated finding quite promising results (Scheme 21a). Indazole derivatives 121a–x were obtained in eight steps starting from 2-methylbenzoic acid (118), which was brominated, nitrated, esterified with methanol, and then reduced in the presence of zinc to obtain the aminoester 119. With the aniline derivative 119, a cyclization was carried out to form the benzo-fused pyrazole, which was subjected to coupling and hydrolysis reactions to obtain the N-substituted indazole 120. Finally, the carboxylic acid 120 reacted with different primary amines to yield 121a–x.

On the other hand, Zhang et al. [71] obtained potential p21-activated kinase type 1 (PAK1) inhibitors with kinase selectivity 1H-indazole-3-carboxamides-based. First, the THP-protected (THP = 2-tetrahydropyranyl) methyl indazole-3-carboxylate 125 was obtained from the commercial 6-bromoindoline-2,3-dione (122), which was subjected to cleavage in basic media, diazotization and finally the reduction and cyclization of the diazonium salts previously created to yield 123. Compound 123 was esterified and then converted to the THP-protected 124 and subjected to a Suzuki reaction with 125 to afford the coupling product 126. Then, a conversion to the respective amide 127a–o via hydrolysis of 126 and amide coupling reactions was developed (Scheme 21b). Finally, THP deprotection afforded the final products 128a–o. Indazole 124 and other intermediates were used to obtain products similar to 128, and their biological activities were tested.

Below are three examples of other 5:6 fused rings that are less recurrent but equally relevant in the biological properties of their derivatives; these are pyrazolo[3,4-d]pyrimidine [72], pyrazolo[4,3-d]pyrimidine [73], and pyrazolo[1,5-a][1,3,5]triazine rings [74]; remember that the second core is part of the famous Viagra (sildenafil) [12]. The pyrimidine or 1,2,5-triazine rings are constructed on the appropriate pyrazole derivatives in the three presented examples [72,73,74]. In this context, Nassar and co-workers [72] obtained the pyrazolo[3,4-d]pyrimidine derivative 132, as a strategic intermediate, starting from 2-(p-tolylamino)acetohydrazide (129). The reaction of 132 with D-glucose and D-xylose, in the presence of a catalytic amount of acetic acid, afforded the amino-sugar products 133 and 134, respectively. Products 132–134 were obtained in high yields (Scheme 22a). Compounds 133, 134, and other twelve products, obtained starting from 132 (i.e., ten pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines and the two thioglycosides), were designed as novel cyclin-dependent kinases type 2 (CDK2) targeting drugs. Results revealed these compounds showed superior cytotoxic activities against MCF-7 (IC₅₀ of 45–97 nM) and HCT-116 (IC₅₀ of 6–99 nM). The growth of the three examined cell lines was significantly inhibited by most of the prepared compounds.

Regarding pyrazolo[4,3-d]pyrimidine derivatives, Islam et al. [73] carried out the design, synthesis, and biological evaluation of 7-(N-aryl)amino-5-chloro-1-methylaminopyrazolo[4,3-d]pyrimidines 140a–I as inhibitors of tubulin polymerization and colchicine binding. Products 140 were obtained in four steps from the nitrated pyrazole ester 135, which was reduced to the aminopyrazole 136 and then cyclized with urea to afford the fused pyrazole 137. Subsequently, 137 was chlorinated under Vilsmeier-Haak conditions forming the dichloro-derivative 138, which finally suffered a NAS reaction with different aniline derivatives 138 to deliver the final products 139a–I (Scheme 22b); it should be noted that the authors also prepared the arylamines 138 since these have a specific substitution that is part of the structural design study.

In the last analyzed work of 5:6 fused N-heterocyclic systems, Lim et al. [74] reported the multicomponent synthesis of a series of 5-aza-9-deaza analogs of purine using a selective annulation of 1,3,5-triazine ring starting from 4-aminopyrazole-4-carboxylates 141a–r (Scheme 22c). The mechanism undergoes the creation of an amidine intermediate 141′, which then reacts with cyanamide 142 through cyclization reaction to afford the desired pyrazolo[1,5-a][1,3,5]triazines 143a–x. The method was proven practical due to its economy and operational simplicity, short reaction times, good yields, and purity of products.

In the final part of this review, we describe four additional examples that are part of two rings with a fusion of type 5:5 and 5:7. Two of the works correspond to the imidazo[1,2-b]pyrazole ring [75,76] and the other ones to the pyrazolo[3,4-b]azepine ring [77,78]. In these examples, the 5- or 7-membered ring is built on the respective pyrazole derivative, and, similar to the two previous examples, they are scarce fused rings to find. Regarding imidazo[1,2-b]pyrazoles, Schwärzer et al. [75] reported a selective functionalization of the fused ring to obtain products 146–148 (Scheme 23a), beginning with the exchanging Br for Mg (to form 146) from the SEM-protected fused pyrazole 148 (SEM = trimethylsilylethoxymethyl), and continuing with a regioselective magnesiations (to form 147) or zinc cation (to form 148) using TMP-bases (TMP = 2,2,6,6-tetramethylpiperidyl).

Precursor 144 was selectively brominated with NBS producing the 7-bromo substituted derivative 145, which was used as a substrate in the reaction with i-PrMgCl$·$LiCl, forming the magnesiated intermediate 145′ that then reacts with varios electrophiles (i.e., S-methyl sulfonothioate, tosyl cyanide, and TESCl) and by transmetallations to give 146a–i. Notably, the authors found that using CuCN·2LiCl or Pd(PPh₃)₄ as a catalyst allows the allylation or acylation/arylation on 146j′, respectively, obtaining crosscoupling products with electron-rich and electron-deficient groups. Products 146a–I were submitted to a selective magnesiation on C3 using TMPMg·LiCl (via 147b′), and various reaction conditions allowed products 148a–j. The third functionalization on C5 was developed using TMP₂Zn MgCl₂·LiCl (via 148′), and products 148a–k, after different reactions, were obtained. The pyrazole ring of these compounds was fragmented, accessing to push-pull dyes of which absorption and photoluminescence properties were studied.

In 2020, Peytam et al. [76] reported synthesizing a new series of imidazo[1,2-b]pyrazole derivatives 151a–o, which were tested in vitro to evaluate their α-glucosidase inhibitory activity; these products were prepared via a three-component reaction between arylaldehydes 18, 3-amino-5-phenyl-1H-pyrazole-4-carboxylate 149, and isonitrile derivatives 150 in the presence of ammonium chloride. Initially, 18 and ammonium chloride form intermediate 18′ during an acid-base equilibrium. Subsequently, this intermediate produces the conjugated iminium salt 149′ through its condensation with the aminopyrazole derivative 149. To finish, treatment of the iminium salt 149′ with isonitriles 150 affords the heteroaromatic products 151a–o through a chelotropic reaction (via the carbene-type species 150) and future oxidation reaction on the adduct 151′ (Scheme 24b).

On the other side, Quiroga and co-workers [77] reported a new series of pyrazolo[3,4-b]azepines 151a–i via a condensation reaction between 5-aminopyrazoles 101 and pyruvic acid 148 using L-proline (149) as a catalyst (Scheme 24a).

The proposed mechanism for the authors starts with substrate 152 reacting with 153 to form the enamine 153′. At the same time, 110 performs a nucleophilic addition over the carbonyl group of another molecule of 152 with subsequent dehydration and to generate 110′. Later, 153′ performs β nucleophilic addition over 110′, rendering intermediate the dipolar 154. The amino group of 154 performs an intramolecular nucleophilic addition over the iminium carbon followed by a reorganization of the negative charge and elimination of L-proline to obtain the final products 155a–i in moderate to good yields either under MW irradiation or conventional heating. Notably, three synthesized pyrazolo[3,4-b]azepines 155 inhibited Neisseria gonorrhoeae growth.

Ultimately, Bortnak et al. [78] reported a series of 5,7-bicyclic framework 158a–c from 1-perfluoroaryl substituted 5-aminopyrazoles 110 ad 2,5-dimethoxytetrahydrofuran 156 (Scheme 23b). First, the aminopyrazoles 110 the cyclocondensation reaction of the appropriate perfluorinated hydrazine with 3-oxo-3-phenylpropanenitrile (benzoylacetonitrile) 7. Subsequently, 110 was subjected to Clauson-Kaas reaction in which a mixture of 5-(1-pyrrolyl)pyrazoles 157a–c and pyrazolo[3,4-b]azepines 158a–c was obtained in moderated yields after separation by flash chromatography using silica gel and ethyl acetate/isohexane (1:19) as eluent; the major product corresponded to the azepine derivative 158. Notably, molecular structures of the perfluorinated aminopyrazoles and the two types of bicyclic products were confirmed by single crystal X-ray diffraction.

4. Conclusions

In summary, the literature search on the synthesis and properties of pyrazoles allows us to evidence many works published since 2017 and even from more years ago; however, the investigation regarding pyrazole derivatives in synthetic, biological, and physical-chemical fields remains attractive. Thus, various works should have been left out of our discussion, although we try to cover in the best way the most relevant aspects of the analyzed papers. An acceptable contribution to the synthesis and properties of some pyrazole derivatives was achieved, allowing us to find some generalities summarized below.

Both pyrazoles and their 5:6 fused derivatives are obtained mainly by cyclocondensation reactions using 1,3-biselectrophilic substrates; for example, the reaction with hydrazine derivatives afford pyrazoles, while with 5-aminopyrazoles, pyrazolopyridines or pyrazolopyrimidines are obtained. Usually, reactions are carried out in highly polar solvents under heating, and functionalized products using specific reagents to avoid later reaction steps are obtained; indeed, aminopyrazoles are obtained when the substrate has a nitrile group. Regarding acylpyrazoles, most works are limited to Vilsmeier-Haack reactions on pyrazoles; however, many acyl groups are introduced via the ring construction.

Due to the exceptional synthetical flexibility and electronic properties of pyrazole-containing compounds, different reactions that allow modular structural modifications can be carried out. From these transformations, the biological and photophysical properties of the products can be enhanced, and thus, novel and better applications would be developed by a rational design. Notably, various biologically and photophysically active pyrazole derivatives possess the 4-methoxyphenyl group; the donor nature of this group favors specific interactions in the environment where it acts, as well as internal charge transfer phenomena. Compounds substituted with halogen atoms, such as fluorine or chlorine, have also shown important biological properties.

Author Contributions

Both individuals listed as authors have contributed substantially to the development of this manuscript, and no other person was involved with its progress. The contribution of the authors is as follows: Literature review, analysis of articles and original draft composition, M.-C.R.; Conceptualization, analysis of articles, writing, manuscript review & editing, supervision, and resources, J.P. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We thank the Chemistry Department and Vicerrectoría de Investigaciones at the Universidad de los Andes for financial support. J.P. wishes to credit current and former Bioorganic Compounds Research Group members whose names appear in the reference section for their valuable collaboration in the different investigations.

Conflicts of Interest

The authors declare no conflict of interest since this literature research was conducted in the absence of any commercial or financial relationships.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures, Schemes and Table

Figure 1. Structure of (a) NH-pyrazoles and (b) some fused pyrazoles with peripheral numbering.

Figure 2. Structure of different drugs based on (a) pyrazoles and (b) some of their 5:6 fused systems.

Figure 3. Physically relevant molecules based on (a) pyrazoles and (b) their fused systems.

Scheme 1. Synthetical methodologies for (a) 5-aminopyrazoles and (b) 4-aminopyrazoles.

Scheme 2. Synthesis of 5-aminopyrazoles by (a) isoxazole ring-opening and (b) from enaminonitriles.

Scheme 3. 5-Aminopyrazole synthesis forms (a) carboxylic acids and (b) enaminonitriles.

Scheme 4. Pyrazole synthesis from malononitrile derivatives (a) 13 and (b) 16a–c.

Scheme 5. Synthesis of 5-aminopyrazoles from (a) malononitriles and (b) 5-chloropyrazoles.

Scheme 6. Synthesis of (a) 4-formyl-1-(2-pyridyl)pyrazoles and (b)chemosensors based on pyrazoles.

Scheme 7. Synthesis of (a) 4-formylpyrazoles and (b) biologically activity pyrazoles. (c) Reaction de VH using PDC 33.

Scheme 8. Synthesis of formylpyrazoles from (a) pyrazolones and (b) diketoesters.

Scheme 9. Synthesis of acylpyrazoles from (a) β-enaminodiketones and (b) sulfur ylides.

Scheme 10. Synthesis of acylpyrazoles from (a) 1,3-dimethyl-1H-pyrazol-5-ol and (b) isoxazolones.

Scheme 11. (a) Halogenation of the pyrazole 53 and (b) synthesis of the 4-iodopyrazole 59.

Scheme 12. Synthesis of (a) 4-bromo-5-(trifluoromethyl)pyrazoles and their (b) synthetical utility.

Scheme 13. Synthesis of (a) indazoles from 4-bromopyrazoles and of (b) 5-chloropyrazoles.

Scheme 14. Synthesis of pyrazoles from (a) ynone trifluoroborates and (b) from 1,3-enynes.

Scheme 15. (a) Synthesis of nitro pyrazoles and of pyrene-pyrazoles (b) 81 and (c) 85.

Scheme 16. Synthesis of (a) pyrazoles 88, (b) aminopyrazoles 90 and (c) trinuclear complexes 94.

Scheme 17. Synthesis of PPs from (a)acetoacetanilide (96) and (b) 1,1,1-trifluoro-3-buten-2-ones.

Scheme 18. (a) Synthesis of PPs 104 from β-enaminones and their (b) photophysical applications.

Scheme 19. MW-assisted synthesis of pyrazolo[3,4-b]pyridine derivatives (a) 112, (b) 114, and (c) 116.

Scheme 20. MW-assisted synthesis of PPys (a) 111 and (b) 114. (c) Synthesis of PPys 117.

Scheme 21. Synthesis and functionalization of indazole derivatives (a) 120 and (b) 123.

Scheme 22. Synthesis of pyrazolo (a) [3,4-d]pyrimidines, (b) [4,3-d]pyrimidines, and (c) [1,5-a]triazines.

Scheme 23. Synthesis of 1H-imidazo[1,2-b]pyrazole derivatives (a) 145–148 and (b) 151.

Scheme 24. Use of 5-aminopyrazoles in synthesizing pyrazolo[3,4-b]azepines (a) 155 and (b) 158.

Table 1

Overview of synthesis of pyrazole derivatives ^[a].

Synthesis and Functionalization		Pyrazole Derivatives	Synthesis of Fused Pyrazoles
Section 2.1	Aminopyrazoles: β-ketonitriles, β-enaminonitriles, acrylonitriles, etc.[Image omitted. Please see PDF.]	[Image omitted. Please see PDF.]	Pyrazolo[1,5-a]pyrimidines: NH-aminopyrazoles and 1,3-biselectrophiles.[Image omitted. Please see PDF.]	Section 3.1
Section 2.2	Acylpyrazoles: Vilsmeier-Haack conditions and using already acylated precursors.[Image omitted. Please see PDF.]		Pyrazolo[3,4-b]pyridines: NR-aminopyrazoles and 1,3-biselectrophiles.[Image omitted. Please see PDF.]	Section 3.2
Section 2.3	Further functional Pyrazoles: halogenations, nitrations, etc. [Image omitted. Please see PDF.]		Other fused rings: imidazopyrazoles, pyrazoloazepines, indazoles, etc.[Image omitted. Please see PDF.]	Section 3.3

^[a] General examples of some relevant synthetical ways involving pyrazole derivatives are shown.

References

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