Sustainable Routes and Mechanistic Study in Pyrazole Synthesis Using Deep Eutectic Solvents (DESs)

Abstract

Increasing demand for green and sustainable chemical processes has led to new investigations in organic synthesis. One of the significant groups of heterocyclic compounds, pyrazoles, finds widespread use in materials science, agrochemicals, and medicines. Pyrazoles have been synthesized using various volatile organic solvents by conventional methods. Due to their enormous importance, sustainable synthetic methods using various green solvents have been developed by researchers. This work focuses on the recent developments in green chemistry, particularly, for the production of pyrazole derivatives using deep eutectic solvents (DESs). DESs are biodegradable, low toxic, and have the ability to dissolve a wide range of organic and inorganic compounds. These properties can offer a more environmentally friendly option than the negative effects of traditional synthetic methods. The benefits of DES in pyrazole synthesis include accelerated reaction rates, high selectivity, and minimum solvent reaction conditions in DES. Moreover, we have summarized various mechanistic insights, optimization of the reaction, and practical applications of DES in pyrazole chemistry. This review article is designed to give a systematic overview of DES-mediated pyrazoles’ synthetic techniques with insightful information.

 

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Keywords

Deep eutectic solvents - Sustainable processes - Pyrazoles - Green synthesis - Bio-vital heterocycles - N-Heterocycles

Significance

This research work offers detailed systematic information on greener ways to create a library of biologically important pyrazole compounds, reducing harmful waste and energy use. This work directly supports SDG 12 (Responsible Consumption and Production) by encouraging sustainable chemistry and reducing pollution, which benefits both health and the environment. Furthermore, it also supports SDG 3 (Good Health and Wellbeing), SDG 9 (Industry, Innovation, and Infrastructure), SDG 13 (Climate Action), and SDG 15 (Life on Land).

1

Introduction

Rising environmental concerns over the last few decades have prompted the development of greener, more sustainable heterocycle synthetic strategies, most notably reducing the use of volatile and hazardous organic solvents. In organic synthesis, deep eutectic solvents (DESs) have recently surfaced as an environmentally friendly alternative to traditional volatile solvents and ionic liquids (ILs).[1] [2] Because their properties are aligned with the tenets of green chemistry, which were outlined by Anastas and Warner in 1998,[3] their popularity is increasing.

Due to their superior qualities and the lack of toxicity posed to bio-organisms and the environment, “green solvents” like subcritical water, supercritical fluids, ILs, and different deep eutectic solvents such as deep eutectic solvents (DESs), hydrophobic deep eutectic solvents (HDESs), and natural deep eutectic solvents (NaDESs) have been extensively utilized.[4] These solvents are considered more environmentally friendly and sustainable compared to traditional hazardous solvents. DESs are one among these solvents, which are a realistic alternative to traditional organic solvents based on the ease of their preparation with abundant and readily available materials.[5] Due to their high versatility and superior efficiency compared to even biomass-derived solvents, they have been the center of attention, especially in chemical synthesis.

The peculiar characteristics of the deep eutectic solvents or DESs have rendered them an efficient class of reaction medium since the groundbreaking research of Abbott.[6] These are environmentally friendly and nontoxic due to their very low vapor pressure, high thermal stability, and lack of flammability. Additionally, their easy recyclability contributes to their usefulness in green chemistry. Strong hydrogen bonding interactions between at least one hydrogen bond donor (HBD) and at least one hydrogen bond acceptor (HBA) are responsible for typically forming DESs from binary or ternary mixtures.[7] [8] DESs are characterized by their unique advantages, including low price, facile production methods, low volatility, biodegradability, and lack of toxicity. These aspects have made people increasingly interested in their use to replace common organic solvents in a series of applications, including electrochemistry and extraction. HBD and HBA associate through hydrogen bonding to form a eutectic mixture that has a melting point less than either of the two components. The most common HBAs include quaternary ammonium salts (QASs), while organic compounds containing hydrophilic functional groups (amino acid, diols, amines, and organic acids), which form hydrogen bonds, serve to function as HBDs in the process of forming the DES ([Fig. 1]). DESs can also be described as a eutectic mixture of Lewis or Bronsted acids and bases that consist of a mixture of a multitude of cationic or anionic species.[9]

Fig. 1 Typical HBA and HBD chemical structures used in the production of DESs.

Despite their numerous advantages, their possible toxicity is still a subject of debate. As a result, guidelines have been set to track the toxicity of DESs.[10] DES’s constituents also warrant particular scrutiny, specifically those that could amplify the risk of nitrosamine formation, including the amides derived from dialkanolamines.[11]

Heterocycles have a core significance in the realms of medicinal chemistry. Heterocycle chemistry is perhaps the most challenging area of chemistry, with special appreciation of the importance that industry and physiology hold for it. It also fascinates due to the variety of synthetic routes to the compounds as well as the deep theoretical undertones that are involved, making the chemistry of heterocycles the foundation of much scientific inquiry. A large number of heterocycles are added to the compendia of drugs every year. Apart from the substituent groups that are attached to the core framework, the ring structure size and composition of these compounds have important contributions to their physicochemical properties.[12] [13]

Heterocyclic structures are fundamental to biological systems, playing essential roles in metabolic pathways and forming the backbone of nucleic acids like DNA through pyrimidine and purine bases. From pharmaceuticals,[14] agrochemicals, to veterinary drugs, their utility also stretches to sensitizers, developers, antioxidants, corrosion inhibitors, copolymers, and dyes.[15] Additionally, they are the building blocks for many organic compounds, a function that attests to their universal applicability. Nitrogen-containing heterocycles are widely investigated in scientific literature and technical journals based on their unique structural features. These compounds are commonly encountered in natural compounds like vitamins, hormones, and alkaloids, highlighting their significance in both chemistry and biology.[16] [17]

The five-membered heterocycle pyrazole containing two nitrogen atoms is an interesting representative of nitrogen heterocycles for their impressive fluorescence, agrochemical, and biological activity. Due to the vast number of possible applications in organic chemistry, pharmacy, and medicine, the development of efficient and simple procedures for the generation of novel pyrazoles is of prime importance.

Pyrazole-containing pharmaceuticals have shown effectiveness across various medical applications, from inflammation control to cancer therapy. An example is the NSAID celecoxib, which is widely prescribed for the treatment of osteoarthritis, rheumatoid arthritis, acute pain, and menstrual pain.[18] [19] Entrectinib is a state-of-the-art solution for ROS1-positive metastatic nonsmall cell lung cancer,[20] while fomepizole is a life-saving antidote for methanol or ethylene glycol poisoning.[21] Aminophenazone is an example of other compounds that stand out for pain relief,[22] oxypurinol for the control of hyperuricemia and heart failure,[23] sulfaphenazole for the role of an antibacterial,[24] epirizol for the relief of pain and muscle pain as a strong NSAID,[25] phenazone as a pain reliever and antipyretic,[26] granisetron for combating nausea and vomiting through the inhibition of 5-HT3 receptors,[27] and rabeprazole for the treatment of ulcers and acid reflux through proton pump blockade.[28] The remarkable pharmacological potential of pyrazole derivatives has fueled interest in crafting novel therapeutics with unique mechanisms of action, aiming to tackle an array of diseases more effectively.

Many pyrazole-containing compounds have in recent times displayed a wide variety of different biological activities, ranging from antidepressant,[29] antihistaminic,[30] antitumor,[31] [32] antiviral,[33] to antimicrobial,[34] including fungicides and insecticide.[35] All this impressive array of activity points to the pyrazole ring itself as an important framework for pharmaceuticals, leading to the development of innovative therapeutic agents. These properties make pyrazole derivatives a focal point of research in drug development and medicinal chemistry. Some famous pyrazole-based drugs are represented in [Fig. 2].

Fig. 2 Illustrative examples of biologically active pyrazole compounds.

Recently, the synthesis of pyrazoles has been approached from green chemistry perspectives, but little attention has been given to DESs and their role in facilitating these reactions. DESs are starting to be recognized as green substitutes, but their role in the synthesis of pyrazole derivatives is still lacking consideration. This is the reason behind this review being prepared; it focuses on the most recent research efforts on this topic. In continuation to our efforts to provide a systematic review on greener methodologies for the synthesis of the imperious heterocycles,[36] the purpose of this report is to provide coherent, well-balanced analyses of sustainable and effective reaction pathways involving DESs and their impact on organic reaction mechanisms while also stressing their advantages from an eco-friendly point of view.

 

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2

Innovative Approach to Pyrazole Synthesis Utilizing Deep Eutectic Solvents (DESs)

The continuous search for synthetic routes to the pyrazole core, along with functionalization at different points, is an area of intense research activity aimed at increasing its bioactivity. Traditionally, pyrazole derivatives were formed using solvents like ethanol, methanol, acetonitrile, dichloromethane, etc.[37] [38] [39] [40] While these solvents may work well in many reactions, they also pose significantly detrimental disadvantages such as their high volatility, harm to human health, low reaction yields, severe environmental concerns, etc. Because of this, the scientific community was on the lookout for safer and greener alternatives.

Besides looking into other solvents such as water and DESs, some other modern approaches of chemistry are trying to find new ways of facile synthesis. One promising solution includes synthetic methods that do not require solvents. Synthesis without solvents has already shown impressive outcomes while maintaining eco-friendly principles as in pyrazole synthesis.[41] But most of the reported methodologies require some solvents. Recently, a few review articles and book chapters also reported on the synthesis of pyrazoles using ILs, microwaves, ultrasound, and other greener technologies,[42] [43] [44] [45] [46] [47] but most of them lack the inclusion of detailed systematic reports on DESs as efficient reaction media for the synthesis of pyrazoles, which is the fascinating highlight of the present work.

DESs appear to be both effective and sustainable alternatives to traditional solvents for pyrazole synthesis. They are new solvents, their synthesis is easy to process, and at the same time, they provide optimal results. The use of DES in synthesizing pyrazole derivatives represents a greener and more efficient alternative to conventional methods. DESs are a green alternative to traditional solvents due to their good catalytic properties, high solubility for a wide range of reactants, and requirement of mild reaction conditions. These synthetic approaches usually include multicomponent reactions, one-pot reactions, and functionalization methods, where DESs are employed to promote high selectivity and high yield. Consistent with the tools of green chemistry, the use of DESs also reduces the demand for harsh reagents and costly transition metal catalysts. The literature study exhibits the different pyrazole derivative production routes to explore the potential of DESs to further expand medicinal applications.

Vanegas et al. [48] performed the pyrazolopyridine derivative synthesis through a sustainable and effective process using choline chloride: urea DES. The work established a one-pot multicomponent reaction strategy involving aromatic aldehydes 1, ethyl acetoacetate 2, hydrazines 3, and ammonium acetate 4 leading to tetrahydridopyrazolopyridines 5a–w ([Scheme 1]). The DES was used as a catalyst and solvent in turn, enhancing the activity and product isolation through its low melting point, viscosity, and hydrogen bond abilities. The authors explored different compositions of the DES, concluding that choline chloride/urea gave better outcomes, and that yields exceeded 96%. The method was optimized for temperature, reaction times, and proportions of reactants, and the use of the DES was found to be recyclable for a few reactions without loss in activity. This method was tolerant for heteroaromatic aldehydes, aliphatic ketones, and aromatic aldehydes containing electron-withdrawing and electron-releasing groups. In addition, Vanegas et al. have compared the procedure to reported methods, highlighting benefits such as simpler reaction, less time, and environmentally friendly conditions. They highlighted the operating efficacy of the choline chloride/urea DES system, which, apart from making reaction progression easy, adhered to green guidelines through usage of less hazardous chemicals and solvents. Recyclability of the DES system together with high catalytic activity makes the method strong for synthesizing drug-relevant pyrazolopyridine derivatives, and it has shown promise for usage for sustainable organic synthesis.

Scheme 1 Synthesis of tetrahydridopyrazolopyridines in ChCl/urea DES.

[Scheme 2] shows a possible pathway for the synthesis of tetrahydridopyrazolopyridines. The Knorr condensation begins from ethyl acetoacetate 2 and hydrazine hydrate 3, producing intermediate 3-methyl-5-pyrazolone (I), which then tautomerizes to give compound (II). Next, Knoevenagel condensation between compound (I) and aldehyde 1 gives rise to intermediate A, followed by Michael addition of a second pyrazolone ring to yield intermediate B. An attack from a nucleophile, formed from an ammonia, takes place, followed by intramolecular cyclization and tautomerization, leading to the final product 5a–w. The exact role for DES as a catalyst has not been clearly established, but it is assumed that hydrogen-bonded activation of carbonyl groups, induced by urea, and the mild acidity and Brønsted basicity of choline chloride provide for improved reaction effectiveness through increased nucleophilic interactions and dehydration processes.

Scheme 2 Plausible mechanism for the synthesis of tetrahydridopyrazolopyridines.

Kalla[49] and others prepared a library of pyrazolyl phosphonate derivatives 9(a–av) through a three-component reaction between different aldehydes 6, pyrazolone 7, and trialkyl phosphites 8 in DES at 25 °C ([Scheme 3]). The DES was prepared from a 1:2 mixture of choline chloride and urea and it acted as a green, recyclable, and biocompatible catalyst. The reaction allows for the effective synthesis of C–C and C–P bonds toward a variety of biologically important molecules with satisfactory yields and atom economy. During exploration of several different aldehyde substrates, electron-withdrawing groups suppressed the reaction, whereas electron-releasing groups sped up the reaction. The environment-friendly DES proved highly reactive and could be recycled for use for up to four times without reducing its catalytic effectiveness.

Scheme 3 Synthesis of series of pyrazolyl phosphonates.

The 1,4-dihydropyrano[2,3-c] pyrazole-5-carbonitriles 13(a–d) procedure was established by Hameed and colleagues[50] employing piperidinium- and morpholinium-derived DESs through the reaction between aryl aldehyde 10, malononitrile 11, and hydrazine hydrate 12 under mild conditions ([Scheme 4]). They prepared DESs by mixing ILs like N-methyl morpholine– and N-methyl piperidine–derived salts with numerous HBDs like diethylene glycol and urea. The DESs acted as a catalyst and reaction medium and promoted multicomponent reactions efficiently. The morpholinium bromide and diethylene glycol-derived DES was particularly the best one, producing pyrazole-5-carbonitriles and derivatives, and indole derivatives, in excellent yields. Strong hydrogen-bond interactions between HBDs and ILs prevail in the DESs, which considerably enhance their activity, as revealed by molecular dynamics simulations.

Scheme 4 A procedure for producing 1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile using deep eutectic solvent based on morpholinium and piperidinium.

Kamble and Shankarling[51] created a catalyst-free aqueous-mediated multicomponent protocol involving ultrasound for the chemo- and regioselective synthesis of 4,4′-(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) derivatives 17a–n. The reaction is a one-pot reaction between aldehydes 14, ethyl acetoacetate 15, and phenyl hydrazine 16 using water and a choline chloride/tartaric acid DES ([Scheme 5]). The sonication under ultrasonic conditions is an efficient way to conduct the reaction for producing Knorr pyrazole and a Knoevenagel–Michael addition. The researchers highlighted improved yields and reaction rates achieved through the eco-friendly use of water as a solvent and the synergistic effect between the DES and ultrasonic conditions. The compounds produced were high in yield, and the process showed remarkable advantages such as lower reaction times, simplicity in operation, and the ability for reuse of the DES for five consecutive cycles without a drop in performance.

Scheme 5 An effective procedure for 4,4′-(arylmethylene)bis(1H-pyrazole-5-ol)s in the presence of ChCl/tartaric acid DES.

Aryan et al. [52] utilized a glucose and urea-derived recyclable DES as a medium as well as a promoter for the effective synthesis of diverse 3- and 4-substituted pyrazole-4-carbonitrile derivatives using various components 21a–p ([Scheme 6]). This catalyst-free method used aromatic aldehydes 18, different derivatives of hydrazine 19 as nitrogen sources, and malononitrile 20 under ambient temperature conditions to yield desired products in excellent yield (up to 96%) and short reaction times (as low as 10 minutes for certain reactions). The DES, constituted from glucose and urea in a mole ratio of 1:5, showed best results, attaining an ideal pH-neutral value of 6.80 and showing immense hydrogen-bonding ability, thereby activating reactants optimally.

Scheme 6 An efficient procedure for substituted pyrazole-4-carbonitrile derivatives using glucose/urea deep eutectic solvents.

The DES was reused over four reaction rounds with only a little loss of efficiency, highlighting its sustainability. The reaction was seen to have a broad scope, which supported aldehydes and hydrazines containing varied steric and electronic characters, excluding the use of chromatographic purification. A reasonable mechanism was suggested, suggesting DES-mediated reactant dipoles activation and tautomerization and aerobic oxidation under ambient conditions. This green protocol does away with the need for toxic organic solvents and catalysts, representing a significant step forward in green chemistry.

The hydrogen-bonding network of the DES facilitates the activation of reactant dipoles and enables them to interact under modest conditions in the proposed procedure for pyrazole-4-carbonitrile derivatives 21a–p synthesis mediated by the glucose/urea DES. The aldehyde 18 first reacts through nucleophilic addition to the malononitrile 20, and through Knoevenagel condensation, it forms a benzylidene malononitrile intermediate ([Scheme 7]). The intermediate then reacts with the hydrazine derivative 19 through a Michael addition, leading to adduct formation. Then, the adduct undergoes intramolecular cyclization through nucleophilic attack, forming a cyclized product. The product then undergoes tautomerization, thus stabilizing to the desired pyrazole-4-carbonitrile framework. Mild oxidation under atmospheric oxygen allows for product stability and yield. The role played throughout the reaction by the DES is crucial as it serves as a biocompatible and effective medium, and its hydrogen-bonding interactions enhance the reaction’s reactivity and selectivity. The catalyst-free, green protocol highlights the use of the DES as an environmentally benign reaction medium for the synthesis of bioactive heterocyclic compounds.

Scheme 7 Mechanism for the production of 5-aminopyrazole-4-carbonitrile using glucose/urea (1:2) DES.

Bhosle et al. [53] used a one-pot, four-component cyclocondensation procedure to create 6-amino-2H,4H-pyrano[2,3-c]pyrazole-5-carbonitriles 26a–o in a simple and environmentally friendly manner. This technique used a DES made of choline chloride/urea (2:1 molar ratio) in combination with aromatic aldehydes 22, malononitrile 23, hydrazine hydrate 24, and ethyl acetoacetate 25 ([Scheme 8]). The reaction was conducted at 80 °C, yielding products in excellent yields (up to 92%) within 20 minutes. In order to enhance the electrophilic character of carbonyl carbons and encourage the production of carbanion, the DES employed its strong hydrogen-bonding capabilities as a catalyst and medium. The protocol demonstrated broad applicability with various aldehydes and was environmentally friendly due to the reusability of DES for three cycles with consistent efficiency. This approach provided simplified product workup, demonstrated broad applicability with various aldehydes, and was environmentally friendly due to the reusability of DES for three cycles with consistent efficiency.

Scheme 8 Synthesis of 6-amino-4-(4-aryl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles.

A proposed mechanism for forming 6-amino-2H,4H-pyrano[2,3-c]pyrazole-5-carbonitriles (26a–o) starts with the DES promoting activation of aldehyde 22 and malononitrile 23 through hydrogen bonding, which enables their Knoevenagel condensation and leads to the formation of benzylidene malononitrile as an intermediate ([Scheme 9]). Concurrently, DES increases hydrazine hydrate 24 nucleophilic assault on ethyl acetoacetate 25, producing an intermediate pyrazolin-5-one. In the DES, these intermediates then go through a cyclocondensation process that produces the intended pyranopyrazole product. The DES not only stabilizes intermediates but also accelerates the reaction by maintaining a high concentration of reactants, ensuring rapid and efficient synthesis.

Scheme 9 Proposed mechanism for the synthesis of pyrano[2,3-c]pyrazoles.

Mohamed et al. [54] developed a green chemistry methodology for the synthesis of several heterocyclic compounds, such as isoxazoline, pyrazoline, pyrimidine, and pyridine derivatives, from chalcone precursors using a deep eutectic mixture (DEM) composed of choline chloride and urea (2:1) ([Scheme 10]). The synthesis involved stirring chalcones with appropriate reagents under reflux conditions in DES, facilitating efficient reactions with excellent yields while minimizing hazardous chemical usage. Pyrazoline derivatives 31a–f were prepared from chalcone 29a–c under reflux conditions with semicarbazide or thiosemicarbazide 30 using DES, which were found to exhibit high cytotoxicity in cancer cell lines such as HepG2, MCF-7, and Caco-2, among which pyrazoline was found to be the most potent. Antioxidant assessment by the DPPH assay revealed that some pyrazoline compounds reflected stronger radical-scavenging activity compared to ascorbic acid.

Scheme 10 Synthesis of pyrazoline derivatives.

The authors put forward a viable reaction mechanism for this strategy. Initially, a hydrazone intermediate forms when the nitrogen atom in semicarbazide or thiosemicarbazide (30) nucleophilically attacks the electrophilic carbon of the chalcone’s carbonyl group, leading to the generation of pyrazoline derivatives (31a–f) from chalcone substrates (29a–c) as illustrated in [Scheme 11]. The nitrogen then undergoes an intramolecular attack on the olefinic double bond, resulting in ring closure and pyrazoline ring formation. Hydrogen bonds that stabilize intermediates and increase reactivity require a DEM composed of urea and choline.

Scheme 11 Plausible mechanism for the production of pyrazoline derivatives.

Acting as a green solvent, the DEM promotes efficient synthesis of pyrazoline derivatives through both activation and facilitation of the cyclization step.

Hussein and coworkers[55] synthesized a series of benzothiazole-linked pyrazoles using a DES system under eco-friendly conditions at 70 °C. The reaction followed a one-pot protocol involving compound (32), a variety of aromatic aldehydes (33), and arylhydrazines (34) to yield pyrazole derivatives such as 4-(benzo[d]thiazol-2-yl)-1-phenyl-1H-pyrazoles (35a–n), along with their polyfunctionalized counterparts ([Scheme 12]). The DES, made from glycerol and potassium carbonate (Gly/K₂CO₃), functioned effectively as both catalyst and solvent. After heating the reaction mixture to 70 °C, the final products were isolated through recrystallization. This green approach utilized nontoxic reagents and featured reusability of solvents and low energy requirements, emphasizing the potential of DES in sustainable chemistry. Significant effectiveness against a range of pathogens, such as Staphylococcus aureus, Bacillus cereus, and Candida albicans, was found by antimicrobial screening; several compounds showed better activity than conventional medications. Molecular docking studies further supported these findings, indicating strong interactions with nitroreductase, a key enzyme in microbial metabolic pathways. One derivative, 4-(benzo[d]thiazol-2-yl)-3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-5-amine, emerged as the most potent candidate, showing notable inhibitory activity and potential as an antimicrobial agent.

Scheme 12 Synthesis of 4-(benzo[d]thiazol-2-yl)-3-(aryl)-1-phenyl-1H-pyrazol-5-amines and 4-(5-amino-4-(benzo[d]thiazol-2-yl)-3-(aryl)-1H-pyrazol-1-yl)benzoic acids.

The plausible mechanism for the synthesis of benzothiazole-tethered pyrazole derivatives revolves around a sequence of elegant transformations, facilitated by the alkaline nature of the DES glycerol and potassium carbonate (Gly/K₂CO₃). Initially, the reaction is initiated by a Knoevenagel condensation between 2-(benzo[d]thiazol-2-yl) acetonitrile 32 and aromatic aldehydes 33, forming arylidene intermediates via base-catalyzed activation of the methylene group. These intermediates then undergo nucleophilic attack by arylhydrazines 34, leading to the formation of hydrazinyl intermediates. Intramolecular cyclization ensues, driven by the electrophilicity of the aldehyde group and the nucleophilicity of the hydrazine nitrogen, giving rise to an iminopyrazolidine intermediate. The final transformation is a crucial oxidative aromatization step, where the intermediate undergoes dehydrogenation to yield the desired pyrazole derivatives ([Scheme 13]). The DES medium plays a multifaceted role by enhancing substrate solubility, stabilizing reactive intermediates, and facilitating electron transfer, while localized heating at the molecular level due to glycerol’s viscosity ensures efficient conversion. This orchestrated mechanism underscores the synergy between green chemistry principles and innovative synthetic design, leading to high yields of biologically potent pyrazole scaffolds.

Scheme 13 Proposed mechanism for the formation of benzothiazole-tethered pyrazole derivatives.

Gao et al. [56] introduced an efficient and environmentally friendly synthetic strategy involving a three-component reaction of aldehydes (36), 3-oxopropanenitrile (37), and 1H-pyrazol-5-amine (38) to generate 4,7-dihydro-1H-pyrazolo[3,4-b] pyridine-5-carbonitrile derivatives (39a–y), as shown in [Scheme 14]. This method utilizes a DEM composed of oxalic acid and l-proline, which serves both as a solvent and catalyst to deliver excellent yields under mild reflux conditions. The reaction takes place through a Knoevenagel condensation followed by a Michael addition and culminates in intramolecular cyclization. Electrophilic activation is facilitated by the DES through hydrogen bonds, thereby increasing overall efficacy. The methodology can handle various substrates such as aliphatic, aromatic, and heteroaromatic aldehydes and forms structurally diverse products. In addition, DEM catalyst can be recycled for numerous cycles without decreasing its catalytic activity. These compounds reinforce the importance and potential applications of sustainable, green chemistry procedures in modern synthetic processes, particularly in material science and pharmaceuticals.

Scheme 14 Proline/oxalic acid–catalyzed process of 4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile derivatives.

Gao et al. suggested a tenable process that involves a series of carefully planned stages for the DES-catalyzed process of 4,7-dihydro-1H-pyrazolo[3,4-b] pyridine-5-carbonitrile derivatives 39a–y. An activated acrylonitrile intermediate is first created when the aldehyde 36 and 3-oxopropanenitrile 37 go through a DES-assisted Knoevenagel condensation. The DES, composed of l-proline and oxalic acid, plays a crucial role by stabilizing the intermediates through hydrogen bonding and activating the carbonyl group. The resulting acrylonitrile intermediate then undergoes a Michael addition with 1H-pyrazol-5-amine 38, producing a Michael adduct. Intramolecular cyclization follows, where the amino group reacts with the electrophilic carbonyl group within the adduct, forming a cyclic intermediate. Finally, dehydration occurs, yielding the desired pyrazolo[3,4-b] pyridine-5-carbonitrile derivative. The hydrogen-bonding interactions and the acidic nature of DES are integral to enhancing electrophilicity and stabilizing intermediates, ensuring efficient transformation. This mechanism highlights the synergistic effect of DES in promoting green and sustainable chemical reactions ([Scheme 15]).

Scheme 15 Plausible reaction mechanism for the production of 4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile derivatives.

Beyzaei et al. [57] developed a green, two-step approach for synthesizing novel 5-amino-3-aryl-1-(2,4-dinitrophenyl)-1H-pyrazole-4-carbonitrile derivatives (43a–f) using a DEM composed of potassium carbonate and glycerol. The process involved the use of various benzaldehydes (40), malononitrile (41), and 2,4-dinitrophenylhydrazine (42), as illustrated in [Scheme 16]. Reaction conditions were fine-tuned to yield high product output in minimal time, with optimal results achieved using a 2:1 DES-to-water ratio at 80 °C. The proposed approach involves a preliminary Knoevenagel condensation for producing benzylidenemalononitrile intermediates, which subsequently react with 2,4-dinitrophenylhydrazine to yield the pyrazole ring. The compounds produced were found to have varying antibacterial activity against various Gram-positive and Gram-negative bacteria and fungi. Molecule 43b, which has a 4-methoxyphenyl group, proved to have the strongest antibacterial activity, indicating its potential as a lead compound for further investigations. This eco-friendly approach highlights the effectiveness of DES as a catalyst and a solvent for organic synthesis in an environmentally friendly manner.

Scheme 16 Synthesis of polysubstituted pyrazole derivatives.

Toreshettahally R. Swaroop and colleagues[58] introduced an innovative green synthesis strategy for pyranopyrazoles through a catalyst-free, room-temperature protocol using an IL as the reaction medium. Their synthesis involved a one-pot, four-component reaction of aldehydes (46), malononitrile (47), β-ketoesters (45), and either hydrazine hydrate (44) or phenylhydrazine, which was carried out in an IL based on urea and choline chloride. This protocol well yielded substituted 4H-pyrano[2,3-c] pyrazoles (48a–q) in high yields ranging from 80% to 96% under a brief reaction time between 10 and 25 minutes ([Scheme 17]). Analytical and spectral studies confirmed that the IL acted simultaneously as a catalyst and a solvent, facilitating crucial processes including Michael addition, cyclization, and Knoevenagel condensation.

Scheme 17 DES-mediated one-pot synthesis of pyranopyrazoles.

This environmentally benign protocol demonstrates key advantages, including mild reaction conditions, simplicity, and eco-friendliness, while avoiding the use of toxic or expensive catalysts, marking a significant advancement in green chemistry methodologies.

Hai Truong Nguyen and colleagues[59] devised an eco-friendly catalytic system utilizing sulfonated amorphous carbon (AC-SO₃H), derived from rice husks, supported on a DES composed of choline chloride and urea in a 1:2 ratio. This system enabled the efficient synthesis of pyrano[2,3-c] pyrazole derivatives (53a–q) via a four-component reaction involving aromatic aldehydes (49), ethyl acetoacetate (50), malononitrile (52), and hydrazines (51) at ambient temperature. The reaction proceeded with moderate to good yields, as detailed in [Scheme 18]. This approach showed benefits including reduced catalyst usage, environmental friendliness, and ease of use. Additionally, the catalyst system was recyclable with minimal loss of activity, emphasizing its potential for sustainable and large-scale applications.

Scheme 18 Synthesis of dihydropyran pyrazoles from aldehyde derivatives catalyzed by AC-SO₃H.

The proposed mechanism for the synthesis of pyrano[2,3-c] pyrazoles 53a–q using the AC-SO₃H/[Urea]₂[CholineCl] catalytic system begins with the activation of ethyl acetoacetate 50 by the sulfonated amorphous carbon catalyst (AC-SO₃H). This activation promotes an enol-keto equilibrium, enabling its interaction with hydrazine 51 to form a pyrazolone intermediate. Simultaneously, the C=O group of aldehydes 49 reacts with malononitrile 52 in the presence of the DEM, yielding a benzylidene malononitrile intermediate using Knoevenagel condensation. The pyrazolone and benzylidene malononitrile intermediates then undergo a Michael addition, leading to a highly reactive adduct. Subsequently, this adduct undergoes intramolecular cyclization, facilitated by the acidic catalytic sites of AC-SO₃H, to form the pyrano[2,3-c] pyrazole core. Finally, the product is stabilized through tautomerization. This innovative mechanism leverages the synergistic effects of AC-SO₃H and the DES, providing a seamless pathway for the multicomponent reaction under mild conditions. The strategy not only minimizes reaction time but also embodies the principles of green chemistry by reducing waste and employing recyclable materials, making it a breakthrough in eco-friendly organic synthesis ([Scheme 19]).

Scheme 19 Proposed mechanism for synthesis of pyrano[2,3-c]pyrazole.

Katariya and coresearchers[60] established an effective method for synthesizing fully substituted pyrazoles (61a–f) using DESs as the reaction medium. The scope and biocompatibility of the catalyst enabled the reaction to offer high yields within a short span. Choline chloride and urea-based DES delivered important benefits, for example, low cost, higher selectivity, and simplicity for product recovery. The authors highlighted the fact that the green approach not only made the reaction simpler but also avoided the use of toxic reagents and hazardous solvents. This strategy shows the increased role of green chemistry in contemporary synthetic design ([Scheme 20]).

Scheme 20 Pyrazole synthesis via DES-based one-pot method.

Sadiq et al. [61] developed a sustainable and efficient method for synthesizing spiropyrazoline–indolinone derivatives (61a–t) using neutral DES as both the catalyst and solvent ([Scheme 21]). The reaction utilized 5-chloro/bromo-isatin (58), aromatic ketones (59), and various substituted hydrazines (60) under mild conditions, producing high yields in a short time. The proposed mechanism includes an aldol condensation step followed by a Michael addition, facilitated by DES through hydrogen bonding with carbonyl groups, thereby enhancing electrophilicity and enabling spiro-junction formation. A comparative analysis highlighted that microwave-assisted synthesis offered faster reaction rates and similar yields compared to conventional heating methods. Additionally, the electronic characteristics and stability of the produced compounds were revealed by computational investigations employing density functional theory (DFT), indicating their potential for drug development.

Scheme 21 Formation of spiropyrazoline-indolinones from halo-substituted isatin.

The proposed mechanism for the synthesis of spiropyrazoline-indolinones (61a–t) involves a sequential two-step process initiated by an aldol condensation reaction followed by a Michael addition. An α, β-unsaturated ketone intermediate (I) is created in the first step when the carbonyl group of 5-Br/Cl-isatin (58a–b) combines with aromatic ketones (59a–b) while diethyl amine (DEA) is present as a base. DEA abstracts a proton from the ketone, generating a nucleophilic enolate that attacks the electrophilic carbonyl group of isatin, leading to condensation and the formation of the enone intermediate. In the second step, this intermediate undergoes a Michael addition with substituted hydrazines (60a–e), facilitated by DESs. The DES acts as both a catalyst and reaction medium, forming hydrogen bonds with the carbonyl oxygen to enhance electrophilicity, promoting nucleophilic attack by the hydrazine. This addition triggers cyclization, resulting in the formation of a pyrazoline ring fused with the indolinone core through a spiro junction. In accordance with the ideas of green chemistry, the DES medium stabilizes intermediates and speeds up the reaction in moderate circumstances, producing large yields with little by-products ([Scheme 22]).

Scheme 22 A proposed reaction mechanism of spiropyrazoline-indolinones in DES.

Tipale and coworkers[62] illustrated a four-component domino procedure using recyclable choline chloride/urea in a DES to prepare pyrazolopyranopyrimidines 66 in an environmentally sustainable and efficient way. The reaction used aldehydes 62, ethyl acetoacetate 63, barbituric acid 64, and hydrazine hydrate 65 under gentle conditions, and yields reached 92% within 1 h ([Scheme 23]). The DES served as a catalyst and solvent and induced hydrogen-bonding interactions that enhanced electrophilicity and accelerated the reaction rate. Importantly, the method was remarkably versatile, being applicable for a large range of substrates and exhibiting excellent yield and selectivity. The DES recyclability was also shown, and its catalytic activity was kept over multicycle reactions. This method is an indicator of the role played by green solvents for sustainable organic synthesis, and it is a cost-effective and environmentally sustainable substitute for traditional methods.

Scheme 23 Formation of 3-methyl-4-phenyl-1,4-dihydopyrazolo[4′,3′;5,6]pyrano[2,3-d]pyrimidine-5,7(6H,8H)-diones.

The reported mechanism for the pyrazolopyranopyrimidine synthesis involves a sequential multistep pathway under the influence of choline chloride: urea DES as catalyst and reaction solvent. Firstly, aldehyde 62 and barbituric acid 64 undergo Knoevenagel condensation to produce an enone intermediate (Ia) through the attack by a neighboring nucleophile and removal of water. Simultaneously, ethyl acetoacetate 63 reacts under normal conditions with hydrazine hydrate 65 to produce an enaminopyrazolone (Ib) through cyclization and condensation. The enone (Ia) thus produced performs an intramolecular Michael addition on the enaminopyrazolone (Ib), which is facilitated by DES through hydrogen-bond interactions that enhance electrophilicity and transition state stabilization. The product pyrazolopyranopyrimidine (66a–x) is obtained after intramolecular ring closure and removal of water ([Scheme 24]). The use of DES facilitates high yields and selectivity under benign situations through assistance in the in-situ generation and stabilization of intermediates and enhancement of reaction rate.

Scheme 24 Plausible mechanism for the synthesis of pyrazolopyranopyrimidines.

Zhang et al. [63] developed an innovative method for synthesizing 3,6-di(pyridin-3-yl)-1H-pyrazolo[3,4-b] pyridine-5-carbonitrile derivatives (70a–o) using a magnetically retrievable sulfonic acid catalyst (CoFe₂O₄-GO-SO₃H) supported on graphene oxide. This green, one-pot, three-component reaction utilized 1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine (67), aldehydes (68), and 3-oxo-3-(pyridin-3-yl) propenonitrile (69) in a DES system composed of choline chloride and glycerol ([Scheme 25]). The DES contributed to the environmentally benign nature of the protocol through its low toxicity, biodegradability, and reusability. Enhanced by microwave irradiation, the process achieved high product yields and allowed the catalyst to be reused up to eight times with minimal loss in efficiency. The integration of DES not only minimized environmental impact but also enhanced the reaction efficiency, showcasing its potential for sustainable synthetic methodologies.

Scheme 25 A novel process of 3,6-di(pyridine-3-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile derivatives.

Zhang et al. proposed a step–by–step cascade reaction pathway mediated by CoFe₂O₄-GO-SO₃H to generate 3,6-di(pyridin-3-yl)-1Hpyrazolo[3,4-b] pyridine-5-carbonitriles 70. In the first step, aldehyde 68 reacts with 3-oxo-3-(pyridin-3-yl) propenonitrile 69 with the assistance of the sulfonic acid group of the catalyst to undergo a Knoevenagel condensation to give the intermediate α, β-unsaturated nitrile. This intermediate is then activated by the acid sites of the catalyst by allowing a Michael addition with 1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine 67 that the nucleophilic center of the amine attacks the electrophilic β-carbon of the intermediate. Finally, the target compound is constructed by intramolecular cyclization followed by dehydration ([Scheme 26]). Example, the CoFe₂O₄-GO-SO₃H catalyst takes responsibility at each stage in the process by its capability to increase the reactivity of intermediates and offering acidic sites for reaction steps that guarantee a good yield.

Scheme 26 Proposed mechanism for synthesis of 3,6-di(pyridine-3-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile derivatives.

Zhang et al. [64] devised a sustainable protocol to synthesize spiro[indoline-3,4′-pyrazolo[3,4-b]pyridines] (74a–ah) using an NDDES composed of choline chloride/lactic acid. The three reactants in a one-pot synthesis under microwave irradiation at a temperature of 60 °C included isatin 72, enolizable C–H activated molecule 73, and 1H-pyrazol-5-amine 71. Besides improving the efficiency of the reaction, the use of NDDES, which is biodegradable and recyclable, was also in line with the ideas of green chemistry. The process was scalable, resulted in high yield, and did not require chromatography. The authors noted the two-fold role played by the NDDES as a catalyst and a solvent by way of a H-bonding and how it facilitates the generation of bioactive spiro oxindole-derived compounds in a sustainable way ([Scheme 27]).

Scheme 27 Pyrazolo[3,4-b]quinolinespirooxindole synthesis in choline chloride/lactic acid.

The plausible mechanism for producing spiro[indoline-3,4′-pyrazolo[3,4-b] pyridines] using an NDDES for 74a–ah requires a series of crucial reaction steps. Initially, a Knoevenagel condensation occurs between the enolizable C–H activated compound 73 and isatin 72 using a choline chloride–lactic acid DES, yielding an intermediate α, β-unsaturated carbonyl compound (Intermediate I). This intermediate is activated by the hydrogen-bonding interactions of the NDDES, which enhances its electrophilicity. After that, a Michael addition occurs, in which the β-carbon of Intermediate I is attacked by the nucleophilic amine group of 1H-pyrazol-5-amine 71, creating an adduct (Intermediate II). This is followed by intramolecular cyclization, wherein the amino group reacts with the adjacent carbonyl group, generating a cyclized intermediate (Intermediate III). The acidic character of the NDDES and microwave irradiation aid in dehydration, which produces the desired spiro[indoline-3,4′-pyrazolo[3,4-b] pyridine] product. In this simplified, environmentally friendly process, the DES acts as both a green solvent and a catalyst, guaranteeing effective bond activation and product creation ([Scheme 28]).

Scheme 28 A proposed mechanism for the synthesis of pyrazolo[3,4-b]quinoline spirooxindoles.

To create pyrazole-fused spiro compounds, 5-aminoindazole 75, barbituric acid 76, and aldehydes 77 were utilized as starting materials in a multicomponent reaction (MCR) technique.[65] This technique used deep eutectic mixtures (DESs) as a catalyst in moderate circumstances and ethanol as the reaction media. The process used a Michael addition using 5-aminoindazole after an aldehyde and barbituric acid Knoevenagel condensation. The final step involved intramolecular cyclization to produce the desired pyrazole-fused spiro compounds 78a–k and 79a–k. The protocol demonstrated high efficiency, good diastereoselectivity, and excellent yields, while maintaining eco-compatibility through the use of nontoxic and biodegradable DEMs ([Scheme 29]).

Scheme 29 A substrate-oriented multicomponent process to synthesize tetahydropyrazolo[4,3-f]pyrimido[4,5-b]quinolines and tetrahydrospiro[pyrazolo[4,3-f]quinoline]-8,5′-pyrimidines.

A multistep, sequential process is the likely mechanism for the production of pyrazole-fused spiro molecules. Initially, barbituric acid 76 reacts with the aldehyde 77 through a Knoevenagel condensation, catalyzed by the DEM, to form an α, β-unsaturated intermediate (Intermediate K). The acidic environment of the DEM activates this intermediate, enhancing its electrophilicity. Subsequently, a Michael addition occurs, where the nucleophilic amino group of 5-aminoindazole 75 attacks the β-carbon of Intermediate K, generating an adduct (Intermediate L). This intermediate undergoes intramolecular cyclization, facilitated by hydrogen bonding and acidity provided by the DEM. The spiro ring structure is formed by this cyclization phase. The pyrazole-fused spiro compounds 78a–k and 79a–k are formed when the reaction finally ends with dehydration step. The DES is essential to the process since it functions as a catalyst and a solvent, effectively promoting each chemical step in a mild, ecofriendly environment ([Scheme 30]).

Scheme 30 Plausible reaction mechanism for the synthesis of tetahydropyrazolo[4,3-f]pyrimido[4,5-b]quinolines and tetrahydrospiro[pyrazolo[4,3-f]quinoline]-8,5′-pyrimidines.

Sathish and associates,[66] show a successful one-pot synthesis of 4-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-N-methyl-3-nitro-4H-chromen-2-amine 86 and 3′-methyl-6′-(methylamino)-5′-nitro-1′-phenyl-1′H-spiro[indoline-3,4′-pyrano[2,3-c]pyrazol]-2-one 83 utilizing L-tartaric acid and dimethyl urea as a DEM. The reaction involved substituted isatins 80 or pyrazole aldehydes 84, nucleophiles 81 and 85, and (E)-N-methyl-1-(methylthio)-2-nitroethenamine 82 as starting materials. The optimal conditions utilized a 2:1 ratio of dimethylurea to L-tartaric acid at 80 °C, achieving excellent product yields within a short reaction time of 30 minutes. Additionally, the method was extended to water as a reaction medium, which produced comparable results in 1 hour, emphasizing its eco-friendly nature. This protocol highlights the versatility and efficiency of DES in promoting sustainable organic transformations ([Scheme 31]).

Scheme 31 One-pot three-component process of 4-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-N-methyl-3-nitro-4H-chromen-2-amine and 3′-methyl-6′-(methylamino)-5′-nitro-1′-phenyl-1′H-spiro[indoline-3,4′-pyrano[2,3-c]pyrazol]-2-one.

 

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Conclusions and Outlooks

The unique physicochemical properties of DESs, including low volatility, high heat stability, biodegradability, and hydrogen bonding ability, have rendered them extremely desirable for green synthetic processes. These environmentally friendly solvents provide a green alternative to classical organic solvents by reducing hazardous waste formation and enhancing reaction efficiencies. The positive influence of DESs on catalyzing diverse organic conversions is further reinforced, if integrated with benign reaction conditions. This integration method has been well explored for effective and sustainable important pyrazole derivatives’ synthesis. In this review article, we have compiled recent synthetic methodologies toward the greener synthesis of pyrazoles, including pyranopyrazoles, spiropyrazoles, bispyrazoles, and related pyrazole derivatives using DESs as an alternative reaction medium. Although with an increasingly emerging interest in this direction, some significant topics still need further study: (1) there is vast scope for achieving chiral pyrazole derivatives’ syntheses through enantioselective approaches using DESs under mild conditions; (2) application of new, nature-based DESs as reaction media for synthesis of various pyrazole architectures, including pyranopyrazoles and spiropyrazoles, is an area with high potential; and (3) comprehensive research must also be conducted in order to investigate and evaluate biological activity for novel pyrazole derivatives prepared with DES as green solvents.

We truly believe that this review article provides systematic information for further research studies about important pyrazole derivatives’ synthesis using DESs and can unlock avenues for further breakthroughs in this field in the future. Furthermore, mechanistic investigations on DESs behavior at a molecular level and design of biotransformation-based and recyclable eutectic systems could play an important role in achieving truly sustainable and innovative synthetic approaches.

 

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Ashish Kumar Aheer

Ashish Kumar Aheer was born in Ajmer, Rajasthan, India. He earned his MSc degree (2017) from Samrat Prithviraj Chauhan Govt. College, Ajmer, Rajasthan, India. Currently, he is pursuing his PhD degree under the supervision of Prof. Meenakshi Jain from the Department of Chemistry, University of Rajasthan, Jaipur, India. His research focuses on “Synthesis of biologically important pyrazoles through greener methodologies.”

Kanaram Choupra

Kanaram Choupra was born in Jaipur, Rajasthan, India. He earned his MSc degree (2018) from Indian institute of Technology Bombay, India. Currently, he is pursuing his PhD degree under the supervision of Prof. Meenakshi Jain from the Department of Chemistry, University of Rajasthan, Jaipur, India. His research focuses on “Facile synthesis of medicinally important indoles.”

Prof. Meenakshi Jain

Prof. Meenakshi Jain was born in Jaipur, Rajasthan, India. She earned her MSc (1987) and PhD (1992) degrees from University of Rajasthan, Jaipur, Rajasthan, India. Currently, she is working as Professor and Head at the Department of Chemistry, University of Rajasthan, Jaipur, India. Prof. Jain’s research focuses on the “Synthesis of medicinally important N-heterocyclic compounds” and “Green organic synthesis.”

Dr. Amit Sharma

Dr. Amit Sharma was born in Nohar (Hanumangarh), Rajasthan, India. He earned his MSc (2012) and PhD (2017) degrees from University of Rajasthan, Jaipur, Rajasthan, India. Currently, he is working as an Assistant Professor at the Department of Chemistry, University of Rajasthan, Jaipur, India. Earlier, he was an Assistant Professor in Govt. PG College, Sri Ganganagar, Rajasthan, India. Dr. Sharma’s research focuses on the “Greener synthesis of biologically vital heterocyclic motifs”; “Synthesis of nano-materials and their applications in catalysis”; and “Ayurvedic drugs and nanotechnology”.

Contributors’ Statement

Conception and design of the work: Ashish Kumar Aheer and Amit Sharma; Data collection: Ashish Kumar Aheer, Kanaram Choupra, Meenakshi Jain and Amit Sharma; Statistical analysis: Ashish Kumar Aheer and Amit Sharma; Analysis and interpretation of the data: Ashish Kumar Aheer, Meenakshi Jain and Amit Sharma; Drafting the manuscript: Ashish Kumar Aheer, Meenakshi Jain and Amit Sharma; Critical revision of the manuscript: Ashish Kumar Aheer and Amit Sharma

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgment

The authors are grateful to the Department of Chemistry, University of Rajasthan, Jaipur, India for providing the necessary facilities.

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Publikationsverlauf

Eingereicht: 18. Juni 2025

Angenommen nach Revision: 11. August 2025

Accepted Manuscript online:
11. August 2025

Artikel online veröffentlicht:
02. September 2025