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).

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).

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.

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).

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.