Introduction

Heterocyclic compounds are extensively spread in nature and play a dynamic role in metabolism because their subunits are important constituents of natural products, including hormones, antibiotics, vitamins, and alkaloids (Saini et al. 2013; Al-Mulla et al. 2017). Among heterocycles, nitrogen-containing heterocyclic compounds are the core units of many biologically active compounds and display numerous applications in biology, chemistry and other sciences. Over the decades, research in pyrazole derivatives has significantly increased due to their interesting chemical, physical, and biological properties making them a privileged scaffold (Castillo and Portilla 2018). Pyrazole and its analogues are categorized as alkaloids despite their very low richness in nature as it is very difficult to generate the N–N bond. Moreover, another pyrazole-based alkaloid, l-β-(1-pyrazolyl)alanine, was isolated from the seeds of watermelon (Citrullus Vulgaris, Fig. 1) (Blair and Sperry 2013; Najim et al. 2016). In addition, a few other pyrazole-based natural products are presented in Fig. 1.

Fig. 1
figure 1

Pyrazole-based commercial drugs and bioactive molecules

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Pyrazole is a pattern found in an array of small molecules displaying a vast spectrum of medicinal and pharmaceutical properties (Kumar et al. 2013; Li and Zhao 2014). In past decade, several drugs decorated with the pyrazole framework have been marketed successfully (Fig. 1) (Khan et al. 2016). For example, Rimonabant acts as a cannabinoid ligand and is used to treat obesity (Chamberlain et al. 2010); Celecoxib displays anti-inflammatory effects and inhibits COX-2 (Abadi et al. 2003; Flower 2003); Sildenafil inhibits phosphodiesterase (Dale et al. 2000; Dunn et al. 2004); and Fomepizole inhibits alcohol dehydrogenase. Figure 1 represents a few examples of pyrazole-based drug candidates and bioactive molecules. Moreover, pyrazole and its analogues are well-known to display a vast spectrum of biological properties such as anti-HIV, anticancer, antitumor, anti-inflammatory, antidepressant, antipyretic, antiviral, antifungal, anticonvulsant and antibacterial (Manpadi et al. 2007; Abdel-Aziz et al. 2009; Singh et al. 2013; Schenone et al. 2014; Perez-Fernandez et al. 2014; Qin et al. 2014; Kalaria et al. 2014; Khloya et al. 2015; Kamal et al. 2015; Jha et al. 2016; Lusardi et al. 2023a, 2023b, 2023c).

In addition, pyrazole derivatives are also known to exhibit remarkable electroluminescence (Gao et al. 1999), solvatochromic effects (Karci et al. 2013) to get application in the field of material science as brightening agents (Wang et al. 2002). They can act as liquid crystals (Kauhanka and Kauhanka 2006), semiconductors (Burschka et al. 2013) and organic light-emitting diodes (Chou and Chi 2007). Pyrazole and its analogues have also received considerable attention because of their synthetic applications as chiral auxiliaries (Molteni and Buttero 2005), reagents in various multicomponent reactions (Tu et al. 2014) and guanylating agents (Castagnolo et al. 2011). Substituted pyrazoles are also utilized as chelating agents for the detoxification of undesired metal ions (Singh et al. 2006). Besides, pyrazole heterocycles also display fungicidal (Zhuang et al. 2016) (Bixafen, Furametpyr and Penthiopyrad), herbicidal (Fu et al. 2017) (Pyraclonil) and insecticidal (Verma and Nayal 2003; Wang et al. 2017) properties and have contributed to the plant and crop protection (Fig. 1).

Researchers are more interested in designing and making new pyrazole derivatives for drug discovery programmes because pyrazole-based building blocks are easy to make, have good chemical properties, and have many reactive sites. Among pyrazole derivatives, pyrazole C-3/C-5 carbaldehyde has aldehyde functional group at C-3 and C-5 positions of the pyrazole ring, can easily react with nucleophiles to make useful scaffolds based on pyrazoles. Furthermore, it is widely acknowledged that pyrazole C-3/C-5-based molecular hybrids are of great importance because they provide opportunities for multiple reactions such as transition-metal catalysed, coupling approaches, multicomponent that either result in novel tether/fused-pyrazoles derivatives or provide useful intermediates for further complex reactions. Particularly, substituted pyrazole-3/5-carbaldehydes, which can be readily synthesized, possess unique characteristics for the incorporation of desired patterns. Recently, our group comprehensively summarized the synthesis and applications of aldo-X precursors like 4-iodo-pyrazole-3/5-carbaldehydes (Sharma et al. 2020a, 2020b, 2020c).

The synthetic potential of pyrazole-3/5-carbaldehydes has not been previously studied, despite their considerable significance. Several research groups reviewed the synthetic and biological potential of pyrazole derivatives, but these synthetic methods were limited to particular substrates. Recently, our group summarized the exploration of pyrazole carbaldehydes, restricting it to the 4-iodo-pyrazole-3/5-carbaldehydes (Sharma et al. 2020a, 2020b, 2020c). This brief study aims to discuss the synthetic methods employed in the synthesis of biologically active fused and tethered scaffolds, especially based on pyrazole C-3/C-5. To the best of our understanding, this review represents the first synthetic and biological applications of pyrazole-3/5-carbaldehydes till 2023.

Gram-scale synthesis of pyrazole C-3/C-5 carbaldehydes as a starting substrates

The synthesis of pyrazole-3/5-carbaldehydes is described in Scheme 1 (Nag et al. 2007). The Claisen condensation of various substituted acetophenones 1a-c with diethyloxalate 2 to furnish the dioxo esters 3a-c (95–98%) was carried out. Further, the treatment of 3a-c with phenyl hydrazine afforded the pyrazole derivatives 4a-c and 5a-c (87–96%). Next, the pyrazole esters 4a-c and 5a-c were subjected to LiAlH4-mediated reduction and PCC-promoted oxidation to afford the pyrazole C-3/C-5 carbaldehydes (8a-c and 9a-c) in 82–87 and 75–86% yields (Scheme 1). Interestingly, the method was also applicable to the electron donating and electron withdrawing groups decorated acetophenones as a starting material.

Scheme 1
scheme 1

Gram synthesis of pyrazole C-3/C-5 carbaldehydes

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Synthetic and biological applications of pyrazole-3/5-carbaldehydes

This section describes the synthetic potential of pyrazole C-3/C-5 carbaldehydes towards the development of biologically active scaffolds. Moreover, the results of biological studies of the investigated compounds by the several research groups are also displayed in this section.

Exploration of pyrazole C-3 carbaldehydes towards the synthesis of biologically active derivatives

Particularly, this part illustrates the exploration of pyrazole C-3 carbaldehydes for the synthesis of biologically active molecular architectures. Additionally, the biological activity of pyrazole C-3-based derivatives is also discussed in this section.

In 2009, Lee et al. stated that a new series of N-chlorophenyl tethered piperazinylethylamino pyrazole-based 5-HT3A receptor antagonists 12 and 14 were developed and investigated their potency on the 5-HT3A receptor channel (Scheme 2) (Lee et al. 2009). The reaction of pyrazole C-3 carbaldehydes 10 with chloro-substituted aryl amine 11 delivered pyrazole-based molecular hybrids 12 and 14 in 28–81 and 69–89% yields, respectively. They observed that most of the synthesized derivatives 12 showed high potency towards the inhibition of I5-HT, while derivative 14 with m-chlorophenyl group exhibited low potency. These studies suggested that novel chlorophenyl linked piperazinyl-pyrazoles 12 and 14 could be a lead molecule for 5-HT3A inhibition. Moreover, p-chlorophenyl moiety might play a major role in enhancing the inhibition activity against 5-HT3A.

Scheme 2
scheme 2

Synthesis of 3-(N-arylpiperazinylethyl)aminomethylpyrazole derivatives

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In 2011, Rodionov et al. a new ferrocene-based pyrazole compound in the form of 5-ferrocenyl-1-phenyl-1H-pyrazole-3-carbaldehyde 15 Synthesized and as presented in Scheme 3 (Rodionov et al. 2011). The one-pot reaction of pyrazole C-3 carbaldehyde 15 and secondary amine 16 in the presence of DCE at room temperature delivered the pyrazole tethered amino derivatives 17 in 70–91% yields. The electrochemical data of 5-ferrocenyl-1-phenyl-1H-pyrazole-3-carbaldehyde 17 are shown in Scheme 3. The anodic electrochemical properties of compound 17 were measured by cyclic voltammetry in CH3CN solution with [n-Bu4N][PF6] as a secondary electrolyte. The involvement of electron-donating or electron-withdrawing groups in the phenyl ring of pyrazole derivatives does not impact the oxidation potential.

Scheme 3
scheme 3

Reductive amination reaction of 5-ferrocenyl-1-phenyl-1H-pyrazole-3-carbaldehyde

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In another study, the authors (Osipova et al. 2011) synthesized a modified pyrazole-ferrocene-based porphyrin 19 via a similar reductive amination approach to ferrocenyl-pyrazole carbaldehyde 15 and tetraphenyl porphyrinamine 18 (Scheme 4). The reductive amination of pyrazole carbaldehyde 15 was carried out in the presence of NaBH(OAc)3 in DCE at room temperature. It was revealed that the reaction only proceeded with ferrocenylformaldehydes that did not have any steric hindrances between substituents in the pyrazole unit. Therefore, the steric environment created by the ferrocene-pyrazole framework 15 was observed to play an important role in this reductive amination reaction.

Scheme 4
scheme 4

Synthesis of modified ferrocene-pyrazole-based porphyrins

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Next, they (Osipova et al. 2012) also synthesized a ferrocene-pyrazole-based framework 21 via the reductive amination reaction of 5-ferrocene-1H-pyrazole-3-carbaldehyde 15 with p-chloroaniline 20, as presented in Scheme 5. The targeted compound 21 was afforded in 63% yield under similar reaction conditions.

Scheme 5
scheme 5

Synthesis of ferrocene-pyrazole-based framework

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The authors extended the study to include the formation of metalloporphyrin 22 as outlined in Scheme 6. Initially, the reaction of ferrocenylpyrazole-3-carbaldehyde 15 with porphyrin 18 resulted in the formation of the anticipated product 19 with a 62% yield. Thereafter, porphyrin-modified ferrocene 20 was subjected to interaction with three transition metal salts (Zn2+, Cu2+ and Mn2+). The desired products 22 were achieved with excellent yields (95–98%). Osipova et al. also studied the electrochemical properties of newly synthesized metalloporphyrin 22. The incorporation of an electron-donating fragment into the ferrocene unit of the complex does not impact the oxidation and reduction potentials of the porphyrin fragment. However, the oxidation potential of ferrocene is slightly moved towards the cathode region. The results of electrochemical experiments in terms of oxidation and reduction potential are summarized in Scheme 6.

Scheme 6
scheme 6

The metalation method of 3-(5-(p-aminophenyl)-10,15,20-triphenylporphyrin)-5-ferrocenyl-1-phenylpyrazole (19)

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Here, an elegant metal-free approach for transforming aldehydes 23 into trifluoromethyl tethered pyrazole 24 has been presented (Qiao et al. 2014) (Scheme 7). The multi-step reaction of pyrazole C-3 carbaldehyde 23 afforded the trifluoro methyl pyrazoles 24 in 69% yield. This transformation provided additional advantages such as (1) less time for reaction completion; (2) low operational and labour cost; (3) metal-free; (4) less waste during workup; (5) easy-to-perform reactions; (6) nontoxic and stable reagents; and (7) one-pot procedure.

Scheme 7
scheme 7

Synthesis of 5-(furan-2-yl)-1-methyl-3-(2,2,2-trifluoroethyl)-1H-pyrazole

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A novel pyrazole-based molecular hybrids 30 have been synthesized as outlined in Scheme 8 (Yao et al. 2014). Briefly, the condensation of bromo compound 25 and pyrazole C-3 carbaldehyde 26 led to intermediate 27 that was converted by Witting reaction to derivatives 28 in 37–64% yields. The subsequent reduction of alkene functionality and the hydrolysis of the ester group led to the isolation of acid derivatives 29 in 57–84% yields. Compounds 29 treated with CoCl2, NH2OH.HCl, DIPEA in the presence of dry DCM resulted in the formation of final pyrazole-based molecular hybrids 30. In addition to this, the synthesized compounds 30 showed better selectivity for class I and IIb over class IIa HDAC isoforms compared to the FDA approved HDAC targeting drug SAHA. This work could serve as a fundamental platform for further exploration of selective HDAC inhibitors using designed molecular scaffold.

Scheme 8
scheme 8

Synthesis of pyrazole tethered molecular architectures

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In another study, the authors (Refat and Mohamed 2015) established an efficient and convenient strategy for the preparation of (Z)-2-(benzo[d]thiazol-2-yl)-3-(1,5-diphenyl-1H-pyrazol-3-yl)acrylonitrile (32) (Scheme 9). The reaction of 1H-pyrazole-C3-carbaldehyde 8a and 2-(benzo[d]thiazol-2-yl)acetonitrile (31) delivered the targeted framework 32 in the presence of catalytic TEA (triethylamine). The pyrazole C3 tethered benzothiazole 32 was obtained in 68% yield after refluxing.

Scheme 9
scheme 9

Reaction of pyrazole C-3 carbaldehyde and benzothiazole

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In 2018, a synthetic route for the synthesis of pyrazole silica based molecular hybrids 35 has been described (El-Massaoudi et al. 2018). The reaction of bis-pyrazole C-3 carbaldehyde 34 and SiNH2 33 delivered the pyrazole-Schiff base containing silico compounds 35 (Scheme 10). The synthesized hybrid material 35 was studied for its ability to uptake Zn (II), Cu (II), Pb (II) and Cd (II) ions in an aqueous solution via kinetics studies. The highest capacity for adsorbing Zn (II), Cu (II), Pb (II), and Cd (II) metals was determined to be 1.23, 0.32, 0.29, and 0.23 mmol g−1, respectively. In addition, hybrid material has demonstrated excellent recyclability and reusability, maintaining its performance up to five cycles.

Scheme 10
scheme 10

Synthesis of silica gel bonded bis-pyrazolyl-propane

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In 2020, our group (Sharma et al. 2020a, 2020b, 2020c) explored the pyrazole C-3 carbaldehydes 36 towards the synthesis of highly fluorescent pyrazole tethered imidazo[1,2-a]azines 39 and 41 as presented in Scheme 11. The reaction of pyrazole C-3 carbaldehydes 36, tert-butyl isocyanide 37 and 2-aminopyrazole 38 or thiazol-2-amine 40 in the presence of La(OTf)3 led to the fluorescent pyrazoles 39 and 41 that displayed excellent photophysical properties (fluorescence quantum yield up to 78%).

Scheme 11
scheme 11

Synthesis of pyrazole C-3 substituted imidazo[1,2-a]azine derivatives

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Next, the authors (Wassel et al. 2021) designed and synthesized a novel pyrazole-based carbonic anhydrase inhibitor 44 as demonstrated in Scheme 12. The reaction of adamantane-based hydrazide 42 and pyrazole C-3 aldehyde 43 afforded the final pyrazole-adamantane-based molecular hybrid 44. The simple condensation of the starting substrate in the presence of EtOH and acetic acid accomplished the present reaction. Furthermore, the novel derivative 44 was investigated for its antitumor activity against three cell lines (MCF-7, HepG-2 and A549). The synthesized scaffolds 44 displayed good IC50 values (3.75 to 7.46 μM) in comparison with Doxorubicin (3.58–8.19 μM) (Scheme 12). The molecular docking was performed to evaluate the binding modes and possible interactions of the adamantane derivatives within the active site of CAIX/XII and CAXII (PDB codes 3IAI and 1JD0 respectively). The results of molecular docking revealed that the binding affinity was enhanced by the presence of a pyrazole derivative due to its ability to form multiple interactions. Additionally, the presence of a carbonyl group, either at a side chain or directly attached to the pyrazole ring, further increased binding within the pocket.

Scheme 12
scheme 12

Reaction of adamantane-1-carbohydrazide with pyrazole C-3 carbaldehyde

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In the following year, the synthesis of novel anticancer agent as pyrazole containing hybrid molecules 51 reported as mentioned in Scheme 13 (Mohan et al. 2021). Firstly, the coupling reaction of bromo containing pyrazole C-3 carbaldehyde 45 with ethynyltrimethylsilane delivered intermediate 46 was further deprotected to afford compound 47. The treatment of aryl azide 48 with 47 in the presence of CuI, ethanol and water at 60 °C resulted in the formation of pyrazole tethered triazole compound 49 that was converted into the desired derivatives 51 by reacting with aryl cyanides 50 via a two-step reaction (Scheme 13). Additionally, the synthesized compounds were tested for their anticancer properties towards human cancer cell lines (PC3, DU-145 (prostate cancer), A549 (lung cancer) and MCF-7 (breast cancer)) by using MTT method with etoposide as a standard reference. The data from this study are summarized in Scheme 13.

Scheme 13
scheme 13

Synthesis of 1,2,4-oxadiazole incorporated 1,2,3-triazole-pyrazole derivatives

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Further, in 2022, a novel ligand synthesized 1,5-dimethyl-2-phenyl-4-{[(E)-(4-phenyl-1H-pyrazol-3-yl) methylidene] amino}-1, 2-dihydro-3H-pyrazol-3-one (DPD) 54 as illustrated in Scheme 14 (Ranjitha et al. 2022). Initially, a simple condensation reaction in EtOH of pyrazole amine 52 and pyrazole C-3 carbaldehyde 53 afforded the pyrazole-based imine intermediate 54 with a 63% yield. Imine intermediate 54 was further subjected to the chelation reaction for the synthesis of pyrazole complex 55. Interestingly, the redox nature of complex 55 was evaluated via a cyclic voltammogram method and it was noted that the physico-chemical characterization of the modified electrode displayed significant results with a long linear range 0.2–1.5 μM/L, sensitivity 1.65 μAμM−1 cm−2. Moreover, the antibacterial, antioxidant and cytotoxic activities of the ligand and its metal complexes were investigated through the agar well diffusion method against S. aureus, B. licheniformis, A. Sp and P. aeruginosa as well as antifungal P. expansum, A. flavus strains. The biological experiments demonstrated significant activity of the metal complexes 55 in comparison with the reference drug.

Scheme 14
scheme 14

Synthetic route for the formation of pyrazole based Co (II), Ni (II) and Cu (II) complexes

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In the same year, the authors (Jodeh et al. 2022) developed a route for the formation of pyrazole-based silico complex 59 as presented in Scheme 15. In the first step, the oxidation reaction of pyrazole alcohol in the presence of MnO2 yielded pyrazole C-3 carbaldehyde 58. After that, pyrazole C-3 carbaldehyde 58 reacted with organically modified silica to form the final pyrazole-silica-based copper complex 59. The synthesized materials 59 adsorbed a high percentage of TMP (trimethoprim), reaching more than 94% with increasing pH.

Scheme 15
scheme 15

Simple and efficient synthesis of pyrazole-silica-based copper complex

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A series of pyrazole tethered 1,2,4-oxadiazole derivatives 64 has been synthesized (Kulkarni et al. 2023). Firstly, the reaction of pyrazole C-3 carbaldehydes 60 with NH3 and iodine in dry THF at room temperature led to the corresponding pyrazole C-3 nitrile derivatives 61 (Scheme 16). The treatment of 61 with hydroxylamine hydrochloride and sodium carbonate in refluxing ethanol resulted in the formation of key intermediates 62 that were subjected to a base-mediated reaction with aryl ester 63 to form the final pyrazole tethered 1,2,4-oxadiazole 64 in 65–80% yields.

Scheme 16
scheme 16

Base-mediated reaction for the synthesis of pyrazole C-3 tethered 1,2,4-oxadiazoles

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Exploration of pyrazole C-5 carbaldehydes towards the synthesis of pharmaceutically active scaffolds

This section provides a summary of the exploration of pyrazole C-5 carbaldehydes for the preparation of pharmaceutically active molecular architecture and structures. Additionally, the results of the biological study for the synthesized compounds are also discussed in this section.

In 2007, Selvam’s group (Selvam et al. 2007) unfolded a simple and facile method for the construction of pyrazole C5 tethered xanthene derivative 66 as displayed in Scheme 17. This one-pot procedure was involved for the condensation of pyrazole-5-carbaldehyde 9a with 2-napthol 65 in the presence of 20 mol% anhydrous Ce(SO4)2 as the catalyst under solvent-free conditions. The resulting product 66 was obtained in high yield (81%) under conventional as well as microwave heating. The current protocol offers several advantages, such as mild reaction condition, shorter reaction time, high yield, general applicability, use of inexpensive and commercially available cerium(IV)sulphate.

Scheme 17
scheme 17

Synthesis of pyrazolyl xanthene

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Next, in 2008, Montalban and team (Montalban et al. 2008) described a protocol for the formation of pyrazole C-5 tethered ketoamide derivatives 72–74, which showed activity against p38 MAP kinase (Scheme 18). Initially, the reaction of pyrazole aldehydes 67 with trimethylsilyl cyanide (TMSCN) resulted in the formation of pyrazole-cyanohydrins 68; further simultaneous de-protection and hydrolysis of 68 furnished the pyrazole-α-ketoacids 70. The treatment of intermediates 70 with 4-(2-morpholinoethoxy)naphthalen-1-amine (71) afforded the targeted pyrazol-α-ketoamide 72 which was transformed into the corresponding oxime 74 and alcohol 73.

Scheme 18
scheme 18

Synthesis of pyrazole C5-based α-ketoamides

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The synthesized derivatives 72–74 were investigated for their biological profile towards the inhibition of mitogen-activated protein (MAP) kinase p38. Additionally, these compounds 72–74 were found to be novel allosteric inhibitors and displayed potential for the better treatment of inflammatory conditions. The quantitative data of the experiment are summarized in Scheme 18.

In 2008, the Murano’s group reported the synthesis of tert-butyl (2-(1-methyl-1H-pyrazol-5-yl)ethyl)carbamate (76) (Murano et al. 2008). In this work, Horner-Emmons reaction of 1-methylpyrazole-5-carbaldehyde (75) was performed to afford the tert-butyl (2-(1-methyl-1H-pyrazol-5-yl)ethyl)carbamate (76), followed by hydrogenation reaction, hydrolysis, and Curtius rearrangement. The final product as 76 was obtained with 86% yield. Moreover, the chemical transformations involved in this study are presented in Scheme 19.

Scheme 19
scheme 19

Synthesis of Boc-protected pyrazole derivative

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In the following year, the authors (Schlager et al. 2008) synthesized a pyrazole-based molecular hybrids 84 as demonstrated in Scheme 20. Initially, the formylation of substituted pyrazole 77 led to pyrazole C-5 carbaldehyde 78 that reacted with tosyl hydroxide, HC(OMe)3 and pyridinium bromide in the presence of MeOH to afford the pyrazole acetal 79. Next, the reaction of pyrazole acetal 79 with i-PrMgCl and n-BuLi delivered the intermediate 80, which was transformed into fused compound 81 and tether pyrazole framework 82. Furthermore, the treatment of pyrazole fused framework 81 with KOH in the presence of dioxane and H2O provided the N–H free pyrazole 83. Finally, the intermediate 83 was subjected under alkylation reaction to achieve the N–H protected pyrazole-based product 84. The affinity of the spirocyclic pyrazoles to the σ receptors was determined in receptor binding studies with radioligands. Moreover, the calculation of crucial distances of the spirocyclic pyrazole derivatives demonstrated a good correlation with the pharmacophore model of Glennon.

Scheme 20
scheme 20

Synthesis of pyrazole-based spirocyclic derivatives

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A method developed for the synthesis of tri-substituted pyrazole derivatives is depicted in Scheme 21 (Rikimaru et al. 2012). Initially, the pyrazole ester 87 was obtained through the reaction of DMAD 85 and hydrazine 86 at room temperature, followed by the formation of pyrazole acetal 88. As mentioned in Scheme 21, next, the pyrazole C-5 carbaldehyde 89 was achieved through a two-step synthetic process of 88. Horner–Wadsworth–Emmons and catalytic hydrogenation reaction resulted in the formation of pyrazole keto ester 90 via pyrazole carbaldehyde 89. Finally, compound 92 was formed from the reaction of 90 with NaH and DMF at room temperature followed by the two-step reaction of pyrazole N-benzylated compound 91.

Scheme 21
scheme 21

Multi-step synthesis of pyrazole and sulphonamide-based molecular hybrids

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The author also developed another pyrazole-based bioactive compound 100 through the various chemical transformations. The formation of key intermediate 96 as pyrazole C-3 carbaldehyde was achieved by using the various organic transformations of starting materials 93–95 as mentioned in Scheme 22. After that, the esterification and reduction of compound 96 were performed to afford another intermediate 97. Subsequently, the catalytic hydrogenation and hydrolysis of compound 97 delivered pyrazole-alcohol 98. Further, 97 underwent two-step synthesis process to achieve the pyrazole intermediate 99. Finally, the treatment of 99 with NaOH, THF, EtOH and 1-pentasulfonamide delivered the pyrazole tethered sulphonamide derivatives 100 in 66–94% yield. The optimization study of the synthesized derivatives 100 revealed SAR findings such as 3-substituent on the pyrazole ring being important for potent PPARγ agonism and substitution of a trifluoromethyl group for the para-chlorine atom of the benzyl moiety tending to enhance in vitro potency.

Scheme 22
scheme 22

Synthesis of pyrazole based derivatives

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In 2013, the authors (Fustero et al. 2013) reported a new approach towards the synthesis of 2,4-disubstituted pyrazole[1,5-a]pyridines, pyrazole[1,5-a]azepines, dienylpyrazoles and peptidomimetics by a ring-closing metathesis (RCM) method (Schemes 23, 24, 25). Initially, the dienylpyrazoles 103 were prepared in high yields by the addition of allyl- and vinyl-magnesium bromide 102 to form pyrazole-3-carbaldehyde 101 (Scheme 23). Intermediates 103 were then treated with 5 mol% Hoveyda Grubb’s catalyst to afford bicyclic alcohols 104 in high yields via the RCM reaction. Finally, the pyrazolo[1,5-a]pyridines 105 and pyrazolo[1,5-a]azepines 106 were obtained by using the dehydration reaction of intermediate 104 in the presence of 1 M HCl in dry THF.

Scheme 23
scheme 23

Synthesis of pyrazolo[1,5-a]pyridine and pyrazolo[1,5-a]azepine derivatives

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Scheme 24
scheme 24

Synthesis of dienylpyrazoles 109 and 110

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Scheme 25
scheme 25

Synthesis of peptidomimetics 115

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Next, the author also achieved the diastereoselective synthesis of dienylpyrazoles 109 and 110. The condensation of pyrazole-5-carbaldehyde 101 with substrate 107 resulted in the formation of the imine intermediate 108. Further, diastereomers of dienylpyrazoles 109 and 110 were obtained by employing different reaction conditions as outlined in Scheme 24.

To further demonstrate the scope of this protocol, the authors synthesized the peptidomimetics 115. Firstly, the treatment of dienylpyrazoles 109 and 110 with HCl-dioxane in methanol, followed by reactions with N-Boc-L-alanine, HBTU and DIEA in DMF led to the formation of intermediates 111. Thereafter, the RCM reaction of intermediates 111 was followed by reduction and treatment with ozone, resulted in the formation of bicyclic carboxylic acids 114. The final peptidomimetics product 115 was obtained by the reaction of ethyl glycinate salt with intermediates 114 in the presence of HBTU in DMF at room temperature, as illustrated in Scheme 25.

Next, Zhou and co-workers (Zhou et al. 2013) synthesized a series of biologically active compounds 118 containing dihydroquinazolinone skeletons, as illustrated in Scheme 26. The reaction was performed between pyrazole-5-carbaldehydes 117 and 2-aminobenzamide 116 substrate in the presence of p-toluenesulfonic acid as a catalyst in dry toluene to afford the final products 118 in 65–92% yields. The synthesized derivatives 118 were screened for insecticidal activity against oriental armyworm (Mythimna separata). The quantitative data indicated that most of the synthesized compounds 118 exhibited moderate to high activity at different concentrations (5, 10, 25 and 50 mg/L). The results from the current study revealed that the synthesized compound weakly affected the high voltage-gated calcium channel in the central neurons of S. exigua. During this study, it was observed that the maximal value of calcium currents (ICa) was not shifted after the neurons were treated with 118.

Scheme 26
scheme 26

Synthesis of pyrazole-based 2,3-dihydroquinazolinone derivatives

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In this study, a protocol presented a simple and convenient route towards the synthesis of pharmaceutically active pyrazole C5 substituted thiazolidinones 121 (Scheme 27) (Hamama et al. 2013). Briefly, the one-pot multicomponent reaction of 1,3-diphenyl-1H-pyrazole-5-carbaldehyde (9a), 2-mercaptoacetic acid (119) and 1,3,4-thiadiazol-2-amine (120) in the presence of pyridine allowed for the isolation of derivative 121 in 80% yield. 2-(1,3-diphenyl-1H-pyrazol-5-yl)-3-(1,3,4-thiadiazol-2-yl)thiazolidin-4-one (121) was investigated for its antioxidant and antitumor activity. The results of the study revealed that the compound 121 had weak antioxidant and antitumour activity in comparison with ascorbic acid and 5-fluorouracil, respectively.

Scheme 27
scheme 27

Multicomponent synthesis of 2-(1,3-diphenyl-1H-pyrazol-5-yl)-3-(1,3,4-thiadiazol-2-yl)thiazolidin-4-one (120)

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In 2015, the authors (Gouda et al. 2015) disclosed a method for the formation of pyrazole derivative (E)-2-cyano-N-(3-cyano-4-(furan-2-yl)-5,6-dimethylpyridin-2-yl)-3-(1,3-diphenyl-1H-pyrazol-5-yl)acrylamide (123) via the reaction of 1,3-diphenyl-1H-pyrazole-5-carbaldehyde (9a) with 2-cyano-N-(3-cyano-4-(furan-2-yl)-5,6-dimethylpyridin-2-yl)acetamide (122) in the presence of catalytic piperidine in ethanol as outlined in Scheme 28. They also evaluated the quantum mechanical parameters of compound 123 by using the PM3 (Parametric Method 3) semiempirical molecular model and the results are shown in Scheme 28. This study clearly indicated that compound 123 was found in E configuration.

Scheme 28
scheme 28

One-pot condensation for the preparation of pyrazole-based arylidene

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Next, the research group of Ibrahim et al. (2017) reported a simple and convenient method for the synthesis of Schiff base 125 (Scheme 29) through the one-pot condensation of 1H-pyrazole-5-carbaldehyde 9a and 5-phenyl-5H-thiazolo[4,3-b][1,3,4]thiadiazol-2-amine (124) in the presence of catalytic sulphuric acid. The newly synthesized compound 125 was screened for in vitro antifungal activity against the fungus, Candida albicans with clotrimazole as a reference drugs. The compound 125 has moderate antifungal activity against Candida albicans. The results of the antifungal study are summarized in Scheme 29.

Scheme 29
scheme 29

One-pot synthesis of N-((1,3-diphenyl-1H-pyrazol-5-yl)methylene)-5-phenyl-5H-thiazolo[4,3-b][1,3,4]thiadiazol-2-amine (125)

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A protocol for the synthesis of biologically active pyrazole derivatives 129 via a two-step operation has been developed as described in Scheme 30 (Cisar et al. 2018). Initially, the reaction of pyrazole-5-carbaldehyde 126 with N-Boc-piperazine 127 under reductive amination in the presence of NaBH(OAc)3 delivered the intermediate 128. Subsequently, deprotection and carbamoylation were achieved. 1,1,1,3,3,3-Hexafluoropropan-2-yl-4-((1-methyl-3-phenyl-1H-pyrazol-5-yl)methyl)piperazine-1 carboxylate (129) that was tested with respect to monoacylglycerol lipase (MGLL) potency and also for tolerance to PLA2G7 and ABHD6 off-target selectivity. The compound 129 was potentially inhibiting the MGLL, whereas it was weakly effective in inhibiting of PLA2G7 and ABHD6. MGLL is a serine hydrolase enzyme responsible for the proper functioning of the central nervous system (CNS) by controlling the signalling of the endogenous cannabinoid 2-arachidonoylglycerol (2-AG); further ABHD6 also plays a role in the signalling and function of CNS. Additionally, PLA2G7 is a gene that plays a crucial role in smooth muscle cell differentiation from stem cells. The results of these studies are depicted in Scheme 30.

Scheme 30
scheme 30

Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-((1-methyl-3-phenyl-1H-pyrazol-5-yl)methyl)piperazine-1-carboxylate (129)

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In the following year, the authors (Ammar et al. 2018) set up a synthetic method for the formation of pyrazole-based metal complex 132 as illustrated in Scheme 31. The simple condensation of 2‐hydrazineylquinoline 130 and pyrazole C-5 carbaldehyde 9a resulted in the formation of pyrazole-quinoline compound 131 that was complexed with Cr, Cu, Ni, Zn and Co in the presence of EtOH:THF. The pyrazole-based metal complexes 132 were obtained in 82–94% yield. The molar conductance data displayed that all the metal chelates 132 were non‐electrolytes, except the Cr(III) complex, which presents a ΛM value of 146.82 Ω−1 cm2 mol−1, showing that it is a 1:2 electrolyte. Moreover, all compounds showed significant antiproliferative activity against MCF-7 (breast cancer) and A549 (lung cancer) cell lines, still resulting in less effectiveness than cisplatin (Scheme 31).

Scheme 31
scheme 31

Synthesis of Schiff base metal(II/III) complexes

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In this work, a method has been reported for the synthesis of pyrazole derivatives as new anti-proliferative agent as displayed in Scheme 32 (Eldehna et al. 2018). The condensation of indolin-2-one 133 and pyrazole C-5 carbaldehyde 134 in refluxing MeOH afforded pyrazole and indolin-2-one-based molecular hybrids 135 (yield range: 74–85%). The synthesized derivatives 135 were evaluated in vitro for their anti-proliferative activity towards lung A-549, colon HT-29, and breast ZR-75 human cancer cell lines. The results of this study are summarized in Scheme 32.

Scheme 32
scheme 32

Synthesis of the pyrazole containing hydrazonoindolin-2-ones

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The authors (Khan et al. 2019) synthesized bioactive bis-pyrazole linked hydrazides 138 by condensing pyrazole benzohydrazides 136 and pyrazole C-5 carbaldehydes 137 in the presence of EtOH and acetic acid (Scheme 33). The bis-pyrazoles 138 were obtained in 60–80% yields and were evaluated for their antimicrobial activity against a panel of Gram-positive and Gram-negative bacteria along with Candida albicans MTCC 3017 strain (Scheme 33). The results showed excellent anti-Candida activity with MICs values of 3.9 μg/mL, which was equipotent to that of the standard Miconazole (3.9 μg/mL). Silico computational studies were carried out to predict the binding sites (Tyr116, Leu130, Ala291, Gly424, His420, Thr299, Ile423, etc.) and pharmacokinetic parameters of these conjugates 138. The molecular docking was performed with protein 3GW9.

Scheme 33
scheme 33

Simple condensation reaction for the synthesis of bis-pyrazole hydrazide derivatives

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In the same year, a strategy has been unfolded for the synthesis of pyrazole tethered fluoro derivatives as outlined in Scheme 34 (Nosik et al. 2019). In the first step, the treatment of pyrazole tethered alkene 139 with LDA and DMF resulted in the formation of pyrazole C-5 carbaldehyde 140. Next, the compound 140 was treated with HC(OMe)3 and TsOH to afford the pyrazole C-5 acetal 141 in 86% yield. The pyrazole C-5 acetal 141 was transformed into a pyrazole containing cyclopropyl 142 in the presence of sodium iodide. Finally, the 142 got converted into final pyrazole-based compound 143 with a 93% yield. Additionally, the approach demonstrated high efficiency when applied on a gram scale and could be utilized for the synthesis of several functionalized regioisomeric pyrazole derivatives containing a gemdifluorocyclopropane group, such as amines, carboxylic acids, aldehydes, bromides, and boronic esters.

Scheme 34
scheme 34

Synthesis of 1,5-disubstituted N-(gem-difluorocyclopropyl)pyrazole derivatives

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In the following year, a novel pyrazole fused oxazines have been developed as presented in Scheme 35 (Lindsay-Scott et al. 2020). Initially, the reaction of di-substituted pyrazoles 144 and bromo-containing compound 145 in the presence of cesium carbonate and acetonitrile afforded tri-substituted pyrazoles 146 that were converted into pyrazole C-5 carbaldehydes 147 in 74–94% yields. These intermediates underwent intramolecular cyclization, leading to the formation of pyrazolo[5,1-c][1,4]oxazines 148 that were reduced to the final compounds 149 in 68–84% yields.

Scheme 35
scheme 35

Multi-step synthesis of pyrazole fused framework

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Thereafter, in 2022, a route was developed for the synthesis of pyrazole-based molecular hybrids 154 as shown in Scheme 36 (Khidre et al. 2022). In the first step, amino thiophene carbonitrile 150 reacted with chloropyrazole carbaldehydes 151 to generate the Schiff bases 152 in good yield via the condensation approach. Next, compounds 152 were treated with secondary amines in the presence of DMF to form pyrazole derivatives 153. On the other hand, one-pot operation was involved in the synthesis of pyrazolo-α-aminophosphonates 154 by the reaction of pyrazole-5-carbaldehydes 151, N-heterocyclic amines 150 and trialkylphosphites in the presence of THF and FeCl3. In another route, α-Aminophosphonates 154 were also achieved in high yields by reacting Schiff bases 152 directly with dialkylphosphites. Next, the molecular modelling of the compounds 154 was studied to evaluate the binding interactions for the target protein quinone reductase-2 (4ZVM) and revealed that the synthesized compounds 154 were the most promising candidates compared with Doxorubicin. Anti-proliferative activity of newly synthesized derivatives 154 was investigated on three cell lines of liver such as HepG2, MCF7 and HCT-116 in comparison with human healthy cell line (BJ-1) by using the MTT assay method. The present studies showed that compound 154 exhibited strong activity towards the HepG2 and HCT-116 while having weak efficiency for the MCF7 in comparison with the reference drug.

Scheme 36
scheme 36

Synthesis of pyrazole tethered molecular hybrids

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In 2023, a novel anticancer agent 158 was synthesized by condensing coumarins 155, pyrazole-5-carbaldehydes 156 and malononitrile 157 (Scheme 37) (Srinivas et al. 2023). The multi-component reaction was carried out in the presence of ionic liquid (BMIM[OH]) at 70–75 °C with 87–90% yields of the final product 158. The cytotoxic activity of the synthesized derivatives against PC-3 and HepG-2 cells was screened by the authors. The investigated compounds demonstrated good to moderate activities against the PC-3 and HepG-2. The data of this study are summarized in Scheme 37.

Scheme 37
scheme 37

Multicomponent reaction for the synthesis of pyrazole containing molecular hybrids

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Exploration of pyrazole C-3/C-5 carbaldehydes towards the synthesis of valuable molecular architectures

This section presents an analysis of pyrazole C-3/C-5 carbaldehydes for the synthesis of pharmaceutically active molecular architectures and hybrids. Comprehensive findings from numerous international research teams have been presented in a simplified and accessible manner.

In 2020, our group (Sharma et al. 2020a, 2020b, 2020c) unfolded a method for the preparation of pyrazole linked imidazo[1,2-a]pyridine derivatives 162, 164, 166 (Scheme 38) and evaluated their photophysical properties. The pyrazole C-3/5 carbaldehydes 161, 163, 165 were reacted with isocyanides 159 and substituted 2-aminopyridines 160, in the presence of lanthanum triflate and pyrazolyl-imidazo[1,2-a]pyridines 162, 164 and 166 were obtained, as illustrated in Scheme 38. The photophysical properties of fluorescent pyrazole tethered imidazo-azines 162, 164 and 166 were investigated in CHCl3 as a solvent; it was found that all the synthesized compounds afforded good to excellent luminescent quantum yields (ФF = 3–83%). The developed methodology provides several advantages including high atom economy, high diversity, high yield of the products, and excellent fluorescence quantum yield.

Scheme 38
scheme 38

La(OTf)3-catalysed synthesis of pyrazole C-3/5 tethered imidazo[1,2-a]pyridine derivatives

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To further establish the scope of this protocol, dealkylation of Groebke–Blackburn–Bienayme (GBB) product 162 was studied by using aq. HBF4 in toluene. Surprisingly, the dealkylation of 162 furnished the 2-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-6-methylimidazo[1,2-a]pyridin-3-amine 167 in excellent yield (Scheme 39).

Scheme 39
scheme 39

HBF4-assisted dealkylation of 2-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-6-methylimidazo[1,2-a]pyridin-3-amine

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In the same year, our group (Sharma et al. 2020a, 2020b, 2020c) also developed a method for the synthesis of pyrazole C-3/C-5 tethered benzothiazole 169, 170 as presented in Scheme 40. The reaction of pyrazole C-3/C-5 carbaldehyde 161, 163, aryl amines 168 and elemental sulphur yielded pyrazole C-3/C-5 substituted benzothiazole 169, 170 in the presence of potassium iodide and dry DMF at 130 °C. The pyrazole C-3/C-5 tethered benzothiazole 169, 170 were obtained in 73–91% yields and investigated for their light-emitting character. Interestingly, the pyrazole C-3 tethered benzothiazoles 169 gave good fluorescence quantum yield in the range of 25–66%, whereas the pyrazole C-5 tethered benzothiazoles 170 gave low quantum yields (14–28%). The current method has several advantages including metal-free reaction, broad substrate scope, a good yield of the products, and excellent fluorescence quantum yield.

Scheme 40
scheme 40

Synthesis of pyrazole C-3/5 tethered benzothiazole derivatives

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The developed protocol was also applicable for the conventional synthesis of pyrazole tethered benzothiazole frameworks 172, 173. The reaction of pyrazole C-3/C-5 carbaldehydes 161, 163 and 2-aminothiophenol 171 in the presence of KI and DMF led to the corresponding compounds with good yields (73–77%) (Scheme 41).

Scheme 41
scheme 41

Scope of methodology for conventional synthesis of benzothiazoles using 2-aminothiophenols

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In 2023, an operationally simple and metal-free approach has been described by our group (Sharma et al. 2023) for the synthesis of pyrazole tethered thioamide and amide conjugates 175, 176 as depicted in Scheme 42. The thioamides 175, 176 were generated by employing a three-component reaction of diverse pyrazole C-3/5 carbaldehydes 161, 163, secondary amines 174 and elemental sulphur in a single synthetic operation.

Scheme 42
scheme 42

Metal- and catalyst-free preparation of pyrazole C-3/5-linked thioamide conjugates

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Moreover, the pyrazole C-3/5 linked amide conjugates 178, 179 were also synthesized via an oxidative amination of pyrazole carbaldehydes 161, 163 and 2-aminopyridines 177 using hydrogen peroxide as an oxidant (Scheme 43).

Scheme 43
scheme 43

H2O2-mediated synthesis of pyrazole-pyridine conjugates with amide tethers

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Summary and outlook

Over the past decades, the development of pyrazole derivatives has led to several facile, convenient, and useful synthetic methods that have provided access to a broad spectrum of biologically active heterocycles. A number of outstanding contributions from the researchers based on the new, reliable, and efficient methodologies available are highlighted in this review. In this perspective, pyrazole C-3/C-5 carbaldehyde precursors have witnessed a significant and valuable contribution in organic and medicinal chemistry. The exploration of pyrazole C-3/C-5 carbaldehydes afforded a series of biologically potent heterocyclic scaffolds, viz. pyrazole C-3/C-5-based silicon derivatives, pyrazole C-3/C-5-based Schiff base derivatives, pyrazole C-3/C-5-based metal complexes, pyrazole C-3/C-5-based imidazo[1,2-a]azines, pyrazole C-3/C-5-based sulphur containing derivatives and pyrazole C-3/C-5-based thioamide and amides other pyrazole fused/tethered polycyclic systems. These synthesized derivatives demonstrated potential applications such as 5-HT3A receptor antagonists, allosteric inhibitors, insecticidal activity, antioxidant, antifungal, antiproliferative and antimicrobial (Fig. 2). This review highlights the approaches towards the diversity-oriented synthesis of pyrazole C-3/C-5 based derivatives and their application in medical science.

Fig. 2
figure 2

A glimpse of medicinal attributes of pyrazole C-3/C-5-based molecular architectures

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Future scope

It is realized that the synthetic and practical utility of pyrazole C-3/C-5 carbaldehydes has not been explored to their potential. Furthermore, exploration of these formyl pyrazoles by employing multicomponent reactions (e.g. Ugi, Passerini, Biginelli, Bucherer–Bergs reaction, and Strecker synthesis) and other currently trending chemistry (C-H activation) remains unrevealed. Based on our in-depth literature analysis, the biological and medicinal potential of pyrazole C-3/C-5-based molecular frameworks has been carried out by a few research groups. It is depicted from the previous reports that the derivatives synthesized from the pyrazole C-3/C-5 carbaldehyde showed promising biological applications. On the basis of previous findings, if pyrazole C-3/C-5 carbaldehydes are explored to their full potential, more promising applications in the various domains of science may be anticipated. Our group has successfully investigated the light-emitting character of pyrazole-3(5)-carbaldehydes linked imidazo[1,2-a]azine and benzothiazole derivatives and observed excellent results with luminescence quantum yield up to 83%. Based on photophysical results, it is proposed that highly fluorescent pyrazole-based scaffolds are similar and have applications in the fields of bio-imaging, chemosensors, OLEDs, pH sensors, and material science.