Catalytic Application of Ionic Liquids for the Green Synthesis of Aromatic Five-Membered Nitrogen Heterocycles

Abstract

Five-membered nitrogen heterocycles exhibit a diverse range of applications across various fields, including medicine, agrochemicals, and materials science. Worldwide industries have exploited hazardous organic solvents and catalysts to afford key bioactive heterocycles, which in turn have a devastating impact on the aqueous environment. The tremendous rise in environmental contamination has shifted the focus of the scientific community towards sustainable alternatives. In line with this, ionic liquids have received the attention of investigators and are widely preferred in organic transformations as catalysts, solvents, ligands, and co-catalysts. Ionic liquids exhibit superior physicochemical properties, such as non-volatility, excellent conductivity, low vapour pressure, non-flammability, and electrochemical and thermal stability, thereby emerging as a clean and efficient alternative to the hazardous volatile organic solvents. The ionic-liquid-assisted synthetic approach has become a popular, greener method owing to high efficiency and product yield with notable purity. Thus, the present article aimed at highlighting catalytic applications of ionic liquids in the synthesis of aromatic five-membered nitrogen heterocycles such as pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, and tetrazole. This article will provide an insight into ionic liquids for their further exploration in organic transformations and related applications.

1. Introduction

Nitrogen heterocycles provide the basic structural motifs of several drug candidates belonging to various categories, including antibiotics, anticancer agents, anti-inflammatory compounds, and antioxidants [1,2,3]. In addition to their medicinal properties, nitrogen heterocycles exhibit a wide array of applications in materials science, metal sciences, cosmetics, reprography, and genetic information storage (DNA and RNA) [4,5,6,7,8]. Among all nitrogen heterocycles, aromatic five-membered nitrogen heterocycles, viz., pyrrole, pyrazole, imidazole, triazole, and tetrazole are incredibly useful in synthetic and medicinal chemistry and are receiving significant attention from investigators [9,10,11]. Figure 1 illustrates examples of five-membered nitrogen heterocycles that serve as therapeutic candidates in various categories. An elegant view of this class of compounds brings long-lasting attention to the synthesis of these heterocyclic compounds. Several methodologies have been reported for their preparation, including the Paal–Knorr method for pyrrole synthesis [12], the dipolar cycloaddition reaction, and the click reaction for triazole and tetrazole synthesis [13,14].

The overall feasibility of the synthesis and functionalization of the lead compound depends on the reaction conditions, selectivity, yield, and reaction ease. Traditional organic reactions face challenges like selectivity and stability of intermediates, which can hinder yields and efficiency. Additionally, issues such as solubility, purification, and safety must be carefully managed. However, they often produce hazardous waste and require high energy, which raises environmental concerns and highlights the need for more sustainable methods. Worldwide researchers have shifted their attention to the green and sustainable protocols for the synthesis of these heterocycles under mild conditions. In recent times, ionic liquid-assisted synthesis has emerged as a reliable tool to address the global challenges by reducing the use of toxic solvents, energy, and cost [15].

The ionic liquids-mediated synthesis of nitrogen heterocycles represents a sustainable and environmentally benign approach that aligns well with the principles of green chemistry by reducing the use of hazardous reagents, minimizing waste, and being recyclable, which overall lowers the toxicity and ecological footprint of the process [16,17,18,19,20]. Ionic liquids, composed of ions, represent an ideal class of eco-friendly, safe solvents that act as reagents and reaction media in organic reactions, providing quantitative product yields, high purity, and short reaction times. Additionally, ionic liquids serve as catalysts due to their solvation properties, high thermal stability, and recyclability. Figure 2A illustrates different applications of ionic liquids in the field of biological, medicinal, and material chemistry. Figure 2B presents a showcase of reports published on the catalytic application of ionic liquids in the synthesis of five-membered heterocycles in recent decades.

The present review provides a detailed account of the catalytic applications of ionic liquids in the synthesis of aromatic five-membered nitrogen heterocycles such as pyrroles, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, and tetrazole. In the introduction section, the importance and applications of ionic liquids in organic reactions are discussed. Further, a brief outline of key properties of ionic liquids that help in their rational selection for a specific organic reaction. Later, a detailed overview of the catalytic application of ionic liquids in the synthesis of aromatic five-membered nitrogen heterocycles has been provided in separate sections. For each heterocycle, the role of ionic liquids and their potential benefits have been elaborated.

2. Structure and Properties of Ionic Liquids

Ionic liquids are salts having a melting point below 100 °C and exhibit several excellent properties, such as low flammability, high thermal stability, low volatility, non-hazardous, safe, eco-friendly, renewable, and easy to handle. Non-volatile properties of ionic liquids make them a reliable alternative to volatile organic solvents and have attracted chemists worldwide [21]. Ionic liquids comprise both organic and inorganic anions, as well as large, asymmetric organic cations. The structure of the most common cations and anions used in ionic liquids is presented in Figure 3. The ionic liquid contains anions like halides and coordinating ions such as ([Tf₂N]⁻) and ([PF₆]⁻), and cations viz. phosphonium, ammonium, pyridinium, imidazolium, and pyrrolidinium. The various combinations of cations and anions have been employed to tune the properties of ionic liquids according to the reaction conditions; thus, they are often referred to as designer solvents. In addition to their potential application as solvents and catalysts in organic synthesis, ionic liquids have been used in batteries, fuel cells, energy storage devices, high-energy propellants, carbon capture and conversion, electrochemical energy storage, and biofuel production [22].

3. Catalytic Application of Ionic Liquids in Organic Reactions

This section covers the synthetic route for the preparation of five-membered nitrogen heterocycles using ionic liquids Figure 4. Efforts have been made to highlight the progress and achievements of using ionic liquids as catalysts in the organic transformation in the last two decades, particularly in the synthesis of pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, and tetrazole.

3.1. Synthesis of Pyrrole Derivatives Using Ionic Liquids

The well-known name reaction for pyrrole synthesis is the Paal–Knorr condensation reaction. This reaction requires harsh conditions, such as an acidic medium and prolonged heating, to achieve pyrrole-containing compounds from 1,4-dicarbonyl compounds and primary amines [23,24]. Thus, classical Paal–Knorr condensation reactions are not suitable for the large-scale exploration of target chemical compounds. Recently, ionic liquid-assisted synthesis has emerged as an approach for the construction of diverse scaffolds in mild reaction conditions. Here, various synthetic routes for the synthesis of pyrrole derivatives using ionic liquids are discussed in homogeneous and heterogeneous phases.

3.1.1. Ionic Liquids Mediated Paal–Knorr Reaction in the Homogenous Phase

Wang and coworkers demonstrated a Paal–Knorr condensation reaction using ionic liquid 1-butyl-3-methylimidazolium iodide [BMIM]I, shown in Scheme 1. The 2,5-hexandione 1 was reacted with a variety of primary amines 2 in the presence of 1.5 g of ionic liquid [BMIM]I to obtain N-substituted-2,5-dimethylpyrrole 3 at room temperature with a yield of up to 95%. To understand the effectiveness of the ionic liquids, the same reaction was conducted in other solvents such as chloroform and toluene, and the results indicate that condensation was slow, with only a 45% and 39% yield. In addition, the advantages of this procedure include simple product isolation, high yield with a short reaction time compared to classical methods, mild conditions, and the avoidance of toxic solvents/catalysts [25].

Another ionic liquid-assisted strategy using Bronsted acidic ionic liquids 1-Methylimidazolium hydrogen sulphate [HMIM]HSO₄ was reported for the Paal–Knorr condensation reaction via efficient intermolecular cyclization of amine 4 and dicarbonyl compound 1 to achieve a set of twelve pyrrole derivatives 5 with exclusive yields. Mechanistically, carbonyl oxygen forms a coordinate bond with acidic ionic liquids, and then the amine attacks the carbonyl carbon, and undergoes cyclization to achieve substituted pyrrole. Mild conditions, room temperature, and the reuse of ionic liquids for up to three cycles indicate a cost-effective as well as greener methodology—Scheme 2 [26].

3.1.2. Ionic Liquids Mediated Paal–Knorr Reaction in Heterogeneous Phase

Yadav et al. reported the synthesis of pyrrole derivatives 8 using bismuth-immobilized ionic liquids Bi(OTf)₃/[BMIM]BF₄ (5 mol%). The immobilized ionic liquid assisted the intermolecular cyclocondensation between substituted dicarbonyl 6 and substituted amine 7 in a short reaction time. The variety of pyrrole hybrids was produced with high yield up to 90% and the products, as well as the catalyst bismuth triflate, were easily isolated from ionic liquids compared to toluene. It was observed that among various metal triflates, bismuth triflate was found to be an effective catalyst for enhancing the yield and reaction rates. However, the toxicity of bismuth after leaching from the ionic liquids affects the aqueous system—Scheme 3 [27].

3.1.3. Ionic Liquids Mediated Multicomponent Reaction for Pyrrole Synthesis in Homogenous Phase

The use of room temperature ionic liquids was reported for the formation of tetra-substituted pyrrole derivatives 12 from dimethyl acetylene dicarboxylates (DMAD) 11, acid chlorides 9, and substituted amino acids 10. This three-component and one-pot reaction for the synthesis of functionalized pyrrole derivatives was mediated in the aqueous medium and basic ionic liquids [BMIM]OH. The library of pyrrole derivatives was synthesized (30 examples) in a short reaction time with high yield. Several screenings on the selection of ionic liquids and solvents were examined to understand the efficacy of this reaction. Catalyst and solvent screening results revealed that [BMIM]OH is an effective catalyst for the synthesis of tetrasubstituted pyrrole, and it can be reused for five runs with minimum loss in efficiency. The side chain on the imidazolium cation influences the activity. Butyl methyl imidazolium hydroxide is a task-specific basic ionic liquids that show a higher yield up to 95% in short reaction times. The significant green credentials of this methodology are a facile and straightforward reaction in aqueous media, which offers high solubility of the substrate and may replace the conventional fundamental catalyst. An additional advantage of task-specific ionic liquids is that they are nonvolatile and non-corrosive, which makes the protocol economic for further exploration in the biological and materials fields—Scheme 4 [28].

Following this, a four-component coupling reaction was reported for the synthesis of tetrasubstituted pyrrole derivatives using [BMIM]HSO₄. This acidic ionic liquid [BMIM]HSO₄ mediated the four-component reaction between dicarbonyl 15, amine 13, aldehyde 14, and nitroalkane 16 to yield functionalized pyrrole 17 in a short reaction time with high yield up to 95%. This acid ionic liquid serves a dual role as both a solvent and a catalyst, facilitating the efficient transformation of desired heterocycles through a greener approach. Metal-free, mild conditions, and the reusability of ionic liquid make this protocol economic and eco-friendly (Scheme 5 [29]).

Meshram and coworkers further demonstrated the catalytic application of 1-n-butylimidazolium tetrafluoroborate [HBIM]BF₄ ionic liquids for the synthesis of functionalized pyrrole derivatives 22 via a four-component reaction between substituted amine 18, aldehyde 19, nitroalkane 20, and dicarbonyl 21 under catalyst-free conditions at room temperature. The set of 29 pyrrole derivatives was synthesized under mild conditions with quantitative yield. Several screenings with ionic liquid have been conducted for efficient transformation under moderate conditions—Scheme 6 [30].

In continuation of this, Shinde et al. further reported the use of 1-ethyl-3-methylimidazolium cyanoborohydride [EMIM][BH₃CN] ionic liquids for the one-pot four-component synthesis of pyrrole derivatives 27 from substituted amine 23, substituted dicarbonyl 24, para-chlorobenzaldehyde 25, and nitroalkane 26 under microwave conditions. The variety of pyrrole derivatives was accessed in good to excellent yields at 4 min under microwave conditions. Screening with several ionic liquids indicated that [EMIM][BH₃CN] is the best catalyst with efficient transformation—Scheme 7 [31,32].

A new set of pyrrole derivatives was prepared using acidic ionic liquids 3-methyl-2-(1-sulfobutyl)-imidazolium hydrogen sulphate [BSO₃HMIM]HSO₄, which catalyzed the one-pot three-component reaction between substituted amine 28, dicarbonyl 29, and nitromethane 30 to form functionalized pyrrole derivatives 31 in ethanol solvent at reflux conditions—Scheme 8 [33].

3.1.4. Ionic Liquids Mediated Clauson-Kass Reaction in Homogenous Phase

Yolacan and coworkers disclosed ionic liquid-assisted Clauson–Kass pyrrole synthesis under microwave conditions. The acidic ionic liquid [HMIM][HSO₄] was prepared from [HMIM][Br] under microwave irradiation. The developed ionic liquid catalyzed the reaction between 2,5-dimethoxytetrahydrofuran 32 and substituted amine 33 under microwave heating for 4 min to achieve the desired N-substituted pyrrole 34. Several screening experiments were performed with the developed acidic ionic liquids and compared with other ionic liquids. The results indicated that [HMIM][HSO4] provided 85% yield when compared to [HMIM][H2PO4] and [HMIM][BF4], 61% and 56% yield, respectively. The main problem with the Clauson–Kaas reaction is the decomposition of acid-sensitive derivatives, especially those derived from amino acids. Using this methodology, several amine compounds such as amino alcohols, aliphatic amines, heteroaromatic amine, and amino acid esters were converted to their pyrrole derivatives without any significant decomposition—Scheme 9 [34].

3.1.5. Ionic Liquids Mediated Functionalization of Pyrrole in Homogeneous Phase

Regioselective synthesis of N-substituted pyrrole 36 from pyrrole 35 and alkyl halides using 1-butyl-3-methylimidazolium hexafluorophosphate [BMIM]PF₆ ionic liquids and base potassium hydroxide at 40 °C was reported. The set of fourteen N-substituted pyrroles was prepared and analyzed by GC-MS analysis. The results of GC-MS analysis confirmed the formation of only one isomer. The reusability of the ionic liquids has been demonstrated up to three cycles without consecutive loss in the yield and catalytic activity—Scheme 10 [35].

This section showcases that imidazolium-based ionic liquids are widely used for the synthesis of many functionalized pyrrole derivatives. Imidazolium-based ionic liquids represent a versatile and environmentally friendly class of catalysts with broad applications in organic transformations. Notably, the imidazolium ring can be substituted with different alkyl or aryl groups, which in turn significantly influence the physical and chemical properties of the ionic liquid.

3.2. Synthesis of Pyrazole Derivatives Using Ionic Liquids

Pyrazole is an essential moiety in drug discovery and development. Many of the pyranopyrazoles are used as UV absorbers, bactericidal, fungicidal, and herbicidal agents [36,37]. Thus, there is a dire need for the development of an efficient synthetic protocol to afford pyrazole derivatives. Recently, ionic liquids mediated Knorr reaction, multicomponent reaction in homogeneous and heterogeneous phase, have been described in Scheme 11, Scheme 12, Scheme 13, Scheme 14, Scheme 15, Scheme 16, Scheme 17, Scheme 18, Scheme 19, Scheme 20, Scheme 21, Scheme 22, Scheme 23, Scheme 24, Scheme 25, Scheme 26, Scheme 27, Scheme 28, Scheme 29 and Scheme 30.

3.2.1. Ionic Liquids Mediated Paal–Knorr-Reaction in Homogenous Phase

The effect of 10 different ionic liquids, such as [BMIM][BF₄], [OMIM]BF₄, [DBMIM]BF₄, [BMIM][PF₆], [BMIM][Br], [DBMIM][Br], [HMIM][HSO₄], [HMIM][CF₃CO₂], [BMIM][OH], [BMIM][SCN] and EtOH was studied by Frizzo and coworkers for the synthesis of pyrazole derivatives 39 from the reaction of butanone 37 and amine 38. Among all ionic liquids, 1-butyl-3-methyl imidazolium tetrafluoroborate [BMIM][BF₄] facilitated cyclocondensation reactions and yielded the best result of 96% pyrazole derivatives, which can be attributed to its higher basicity—Scheme 11 [38].

Scheme 11. Synthesis of pyrazole derivatives using [BMIM]BF₄.

Scheme 11. Synthesis of pyrazole derivatives using [BMIM]BF₄.

Trifluoromethyl (CF₃)-containing heterocycles exhibit potent biological applications due to high metabolic stability, membrane permeability, and enhanced lipophilicity. Prompted by this fact, Buriol and coworkers developed an efficient protocol for the synthesis of CF₃-containing pyrazole derivatives using [BMIM][BF₄] ionic liquids under conventional and microwave irradiations. Notably, a better yield of product was obtained under microwave irradiation. Subsequently, the set of eleven CF₃-containing pyrazole 42 was achieved from the reaction of substituted alkenones 40 and phenylhydrazine 41 in 6 min at 200 W. This reaction required a very short reaction time, which revealed the synergistic effect of ionic liquid and microwave irradiation in the cyclization of alkenones and phenylhydrazine—Scheme 12 [39].

Scheme 12. Synthesis of CF₃-containing pyrazole using [BMIM][BF₄] ionic liquids.

Scheme 12. Synthesis of CF₃-containing pyrazole using [BMIM][BF₄] ionic liquids.

3.2.2. Ionic Liquids Mediated Multicomponent Reaction for Pyrazole Synthesis in Homogenous Phase

The catalytic use of 1-Ethyl-3-methylimidazolium acetate [EMIM]Ac ionic liquid was optimized for the regioselective synthesis of functionalized pyranopyrazole derivatives in a one-pot condensation reaction. Screening of various catalysts was examined for the reaction of benzaldehyde 43, NMSM 44, and 5-pyrazolone 45 to afford N-functionalized pyrazole 47 under solvent-free conditions. The screening result of this experiment revealed that 20 mol% of [EMIM]Ac ionic liquid provided the best yield of the target compounds. The same catalyst was explored for the synthesis of another set of pyranopyrazole derivatives 48 from the reaction of hydrazine hydrate, aromatic aldehyde 43, ethyl acetoacetate 46, and NMSM 44 under solvent-free conditions. The influence of catalyst proportion for this reaction was examined, which indicates that 25 mol% of ionic liquids furnished the highest product formation—Scheme 13 [40].

Scheme 13. Regioselective synthesis of pyranopyrazole derivatives using [EMIM].

Scheme 13. Regioselective synthesis of pyranopyrazole derivatives using [EMIM].

Zakeri and coworkers reported the green and eco-safe methodology for the synthesis of pyranopyrazole derivatives 53 via four-component reaction between substituted hydrazine 49, ethyl acetoacetate 50, malononitrile 52, and benzaldehyde 51. This reaction was optimized with various ionic liquids; the best yield of product was obtained with ionic liquids 1,3-dimethyl-2-oxo-1,3-bis(4-sulfobutyl) imidazolidine-1,3-diium hydrogen sulphate [DMDBSI].2HSO₄ and water. The ionic liquid catalyst promoted the Knoevenagel/Michael/cyclization in a short reaction time, and the catalyst was recovered for further catalytic reactions—Scheme 14 [41].

Scheme 14. Efficient synthesis of pyranopyrazole using [DMDBSI].2HSO₄ catalyst.

Scheme 14. Efficient synthesis of pyranopyrazole using [DMDBSI].2HSO₄ catalyst.

Another one-pot multicomponent was described to access the variety of imidazole derivatives 57 using triethylammonium hydrogen sulphate [Et₃NH][HSO₄] ionic liquid. This ionic liquid serves as a reaction catalyst as well as the reaction medium to accelerate the reaction at room temperature in a short time duration (15 min) with high yield. The solvent and metal-free reaction conditions are the eco-friendly merits of this methodology. Other advantages include excellent yields, a short reaction time, mild reaction conditions, and catalyst reusability—Scheme 15 [42].

Scheme 15. Multicomponent synthesis of pyranopyrazole using [Et₃NH][HSO₄] ionic liquids.

Scheme 15. Multicomponent synthesis of pyranopyrazole using [Et₃NH][HSO₄] ionic liquids.

The imidazole-based ionic liquids 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM]BF4 was used for the one-pot synthesis of pyrazole-bearing spirooxindolopyrrolizidines derivatives 61 from the three-component reaction of chalcones (dipolarophiles) 58, isatins 59, and L-proline 60. The reaction mixture was irradiated with ultrasonic waves for 6 min to afford the desired product with a good yield (83–92%). The reusability of [BMIM]BF₄ was observed up to five consecutive cycles without a significant loss in catalytic potential. The developed methodology offers several notable advantages, including a short reaction time, high yield, simple separation, and recyclability. The synthesized compounds showed comparable anti-tuberculosis activity to ethambutol—Scheme 16 [43].

Scheme 16. Ultrasound-assisted synthesis of pyrazole bearing spirooxindolopyrrolizidines derivatives using [BMIM]BF₄.

Scheme 16. Ultrasound-assisted synthesis of pyrazole bearing spirooxindolopyrrolizidines derivatives using [BMIM]BF₄.

Recently, in 2024, the same group of coworkers further explored [BMIM]BF₄ ionic liquids for the synthesis of 1,3-diphenyl pyrazole bearing functionalized spirooxindolopyrrolizidines derivatives under ultrasonic irradiation. The variety of 1,3-diphenyl pyrazole bearing compounds 63 was prepared via one-pot multicomponent reaction between chalcones 62, isatins 59, and L-proline 60. The optimization reaction in different solvents, such as water, methanol, ethanol, acetonitrile, THF, but it is observed that [BMIM]BF4 serves as an appropriate medium to stimulate the reactions. The ionic liquid [BMIM]BF₄ worked well as a medium and is expected to function as a catalyst. This methodology affords high product yield in short reaction times and catalyst can be reused up to five consecutive cycles. The prepared compounds were examined for in vitro anti-TB activity against the Mycobacterium tuberculosis H37Rv strain and compared with the standard ethambutol. Further molecular docking studies against M. tuberculosis enoyl–acyl carrier protein reductase inhibitor—Scheme 17 [44].

Scheme 17. Ultrasound-assisted synthesis of 1,3-diphenyl pyrazole bearing spirooxindolopyrrolizidines using [BMIM]BF₄.

Scheme 17. Ultrasound-assisted synthesis of 1,3-diphenyl pyrazole bearing spirooxindolopyrrolizidines using [BMIM]BF₄.

Bhatt and coworkers explored the application of microwave irradiation for the synthesis of novel pyrazole clubbed polyhydroquinolines using ionic liquids 1,1′-butylenebispyridiniumhydrogen sulphate (Bbpy)(HSO₄)₂. The three-component reaction between 1,3-diarylpyrazole-4-carbaldehyde 64, 1,3-diketone 65, and ammonium acetate was assisted in ionic liquids to yield pyrazole-quinoline hybrids 69, 70, 71 in high yield in a short microwave reaction time (2.5 min). The use of (Bbpy)(HSO₄)₂ in the reaction medium as both a catalyst and solvent may be attributed to the rapid synthesis of target compounds under mild conditions, as shown in Scheme 18 [45].

Scheme 18. Synthesis of pyrazole clubbed polyhydroquinolines using [Bbpy][HSO₄]₂.

Scheme 18. Synthesis of pyrazole clubbed polyhydroquinolines using [Bbpy][HSO₄]₂.

3.2.3. Ionic Liquids Mediated Functionalization of Pyrazole in Homogeneous Phase

Further efficacy of various ionic liquids was examined for the chemoselective synthesis of N-Alkylated trifluoromethyl-containing pyrazoles 73 and 74 from N-H pyrazole 72 and alkyl halides. Among various ionic liquids, [BMIM]BF₄ showed higher efficiency for the alkylation of the pyrazole in a mild and efficient reaction medium. This reaction proceeds by an SN2 mechanism, which could explain the good performance of IL in this reaction. In general, SN2 reactions have been carried out in organic solvents such as acetonitrile and acetone that have the drawback of a high boiling point, and high-boiling-point solvents such as DMF and DMSO are highly toxic and difficult to separate. In this reaction, the product was easily extracted from the ionic liquid with diethyl ether, and the ionic liquid was recovered by filtration to remove the inorganic salt. Thus, the use of ionic liquids in these reactions provided a mild and fast method for the N-alkylation of pyrazoles—Scheme 19 [46].

Scheme 19. Synthesis of N-alkyl trifluoromethyl pyrazole using [BMIM]BF₄.

Scheme 19. Synthesis of N-alkyl trifluoromethyl pyrazole using [BMIM]BF₄.

In continuation of this, the reaction of ionic liquid 1-Butyl-3-methylimidazolium chloride [BMIM]Cl and 3,4,5-trifluorobenzeneboronic acid was used for the synthesis of pyrazolo-pyridine hybrids 78 from carbonyl 76, pyrazole containing carbonyl 75, and alkene 77 at room temperature. It was observed that after the addition of boronic acid, the catalyst yield was increased considerably. The boronic acid catalyst provides an acidic medium to the reaction mixture, which helps in product formation with a yield of up to 85–92%. The catalyst and ionic liquid were recovered for further catalytic reaction—Scheme 20 [47].

Scheme 20. Synthesis of pyrazolo-pyridine hybrids using ionic liquids [BMIM]Cl.

Scheme 20. Synthesis of pyrazolo-pyridine hybrids using ionic liquids [BMIM]Cl.

Jadhav and coworkers reported the simple, rapid, and multicomponent reaction between aldehyde 79, acyl acetonitrile 80, and amino pyrazole 81 in the presence of [Et₃NH][HSO₄] ionic liquids, which was described to access pyrazole-pyridine hybrids 82 in quantitative yield (94.5%, 8.63 g) with high purity under solvent-free conditions. Ionic liquids [Et₃NH][HSO₄] played a dual role as solvent and as catalyst in this methodology, which was reused up to five times—Scheme 21 [48].

Scheme 21. Synthesis of pyrazolo-pyridine hybrids using [Et₃NH][HSO₄].

Scheme 21. Synthesis of pyrazolo-pyridine hybrids using [Et₃NH][HSO₄].

Another approach for the synthesis of pyranopyrazole derivatives 85 using task-specific ionic liquids [BMIM]OH was described. Task-specific ionic liquids play a dual role of solvent as well as catalysts in the three-component reaction between aromatic aldehyde, malononitrile, and pyrazolone to furnish the desired product in high yield. This methodology proves to be environmentally benign and efficient, with low reaction times, ease of recovery, high yield, and the reusability of ionic liquids after rinsing with ether and drying in a vacuum for 2 h at 90 °C. Tarped water in an ionic liquid was removed and reused for the next run. Of note, these ionic liquids can be reused for up to three runs with a significant loss in efficiency—Scheme 22 [49].

Scheme 22. Synthesis of pyranopyrazole using task specific ionic liquids [BMIM]OH.

Scheme 22. Synthesis of pyranopyrazole using task specific ionic liquids [BMIM]OH.

Similarly, Mahmoodi and coworkers reported the use of [BMIM]OH ionic liquids for the green and efficient synthesis of pyranopyrazole derivatives 88 under microwave conditions from aromatic aldehyde 86, malononitrile 52, pyrazolinone 87. This three-component reaction was assisted in water as a green solvent, and microwave conditions as energy-efficient technologies promoted the synthesis of a variety of pyranopyrazole derivatives in a short time with high yield up to 93%—Scheme 23 [50].

Scheme 23. Microwave-assisted synthesis of pyranopyrazole using [BMIM]OH ionic liquids.

Scheme 23. Microwave-assisted synthesis of pyranopyrazole using [BMIM]OH ionic liquids.

3.2.4. Ionic Liquids Mediated Paal–Knorr Reaction in Heterogeneous Phase

Noura and coworkers reported the catalytic use of nano gelatoric ionic liquids [NGIM]₃[Cit] for the synthesis of pyrazole derivatives in solvent-free conditions. The one-pot three-component reaction between the 3-nitrobenzaldehyde 90, malononitrile 52, and phenylhydrazine 89 was assisted in the presence of 1mol% of [NGIM]₃[Cit] to afford the desired pyrazole 91 in good yield. Mechanistically, these reactions proceed via the Knoevenagel condensation of activated 3-nitrobenzaldehyde and malononitrile, followed by the addition of phenylhydrazine, which consequently undergoes tautomerization and hydride transfer via anomeric effect, giving a product with a loss of water molecules. The recyclability of nano gelatoric ionic liquids was studied up to two times without loss in catalytic potential—Scheme 24 [51].

Scheme 24. Synthesis of substituted pyrazole using nano gelatoric ionic liquids [NGIM]₃[Cit].

Scheme 24. Synthesis of substituted pyrazole using nano gelatoric ionic liquids [NGIM]₃[Cit].

Another pectin-supported dual acidic pyridinium ionic liquid was reported for the facile synthesis of pyrazole derivatives. This three-component reaction of aldehyde 92, phenylhydrazine 93, and malononitrile 52 was assisted by ionic liquid (Pec-DAP-BS) to form pyrazole derivatives 94. Ionic liquid consists of biopolymer pectin (Pec), which is functionalized by 2,6-diamino pyridine (DAP), then subsequently reacted with 1,4-butane (BS) to form nano-Pec-DAP-BS. Various analytical techniques characterized the synthesized catalyst. The remarkable performance of the catalyst was observed in a short time, with high turnover frequencies (TOF) up to 184.7 h⁻¹ and excellent yield up to 96%. This catalyst can be easily recovered from aqueous solvent and can be reused up to several cycles—Scheme 25 [52].

Scheme 25. Synthesis of pyrazole derivatives using pectin-supported ionic liquids.

Scheme 25. Synthesis of pyrazole derivatives using pectin-supported ionic liquids.

Further report for the one-pot synthesis of N-phenyl substituted pyrazole 97 from phenyl hydrazine 95 and 1,3-diketone 96 using transition metal ionic liquids [C4mim][FeCl4], i.e., 1-ethyl-3-methylimidazolium, was described by Konwar and Coworkers. The prepared ionic liquids were reused up to four runs without significant loss in catalytic activity. This facile, convenient, and quick methodology furnished a set of 24 pyrazole derivatives. Other advantages include inexpensive, less toxic, efficient energy saving, and high yield—Scheme 26 [53].

Scheme 26. One-pot synthesis of pyrazole derivatives using [C₄mim][FeCl₄].

Scheme 26. One-pot synthesis of pyrazole derivatives using [C₄mim][FeCl₄].

Ionic-liquid-based nano-magnetic solid acid heterogeneous catalyst (Fe₃O₄@SiO₂@(CH₂)₃NH@CC@Imidazole@SO₃H) was used to access a set of 15 pyranopyrazole derivatives 100 from pyrazoline 98, aromatic aldehyde 99, and malononitrile 52. The metal-containing imidazole-based ionic liquids accelerated the three-component reaction in a short time with a yield up to 98%. This nanocatalyst can be recovered quickly using an external magnet and reused repeatedly for further catalytic runs—Scheme 27 [54].

Scheme 27. Synthesis of pyranopyrazole derivatives using magnetic ionic liquids.

Scheme 27. Synthesis of pyranopyrazole derivatives using magnetic ionic liquids.

The mechanistic pathway for the fast and efficient synthesis of pyranopyrazole derivatives was described using Lewis acidic ionic liquids, Choline chloride salt [ChCl][ZnCl₂]₂. This ionic liquid accelerated the reaction faster than Brönsted acidic ionic liquids N-methyl-2-pyrrolidonum hydrogen sulphate [H-NMP]HSO₄. The mechanism begins with the activation of the carbonyl group 101 by the Lewis acid catalyst, which subsequently undergoes condensation with malononitrile 103 and cyclization to afford pyrazole derivatives 104 with a yield of up to 91%—Scheme 28 [55].

Scheme 28. Synthesis and mechanism of pyrano [2,3-c]pyrazole using [ChCl][ZnCl₂]₂.

Scheme 28. Synthesis and mechanism of pyrano [2,3-c]pyrazole using [ChCl][ZnCl₂]₂.

Catalytic use of silica-grafted N-propyl-imidazolium hydrogen sulphate [Sipim]HSO₄ ionic liquids for the synthesis of pyranopyrazole derivatives 106 from aldehyde 105, malononitrile 52, pyrazoline 98. This reaction was accomplished in solvent-free conditions, and ionic liquids play a dual role as both catalysts and solvents in these methodologies. Ionic liquids were reused after washing with warm ethanol and drying for further catalytic runs, up to four times—Scheme 29 [56].

Scheme 29. Solvent-free synthesis of pyranopyrazole using silica-grafted ionic liquids.

Scheme 29. Solvent-free synthesis of pyranopyrazole using silica-grafted ionic liquids.

Water is inexpensive, non-hazardous, abundant, and eco-friendly, with a high boiling point. However, the solubility of organic compounds in water is poor, so surface-active agents such as micelles or vesicular structures were designed and preferred from both environmental and economic perspectives. In 2023, a novel water-SDS [BMIM]Br ionic liquids system was used for the selective synthesis of pyranopyrazole derivatives 110 via a three-component sequential addition of aromatic aldehyde 107, malononitrile 52, and pyrazoline-5-one 109. This reaction replaced the volatile organic solvents with water as a green reaction medium. The key advantages include broad substrate scope, eco-friendly approach, high yield, chromatography-free purification, and recyclability of the reaction medium—Scheme 30 [57].

Scheme 30. Synthesis of pyranopyrazole using water-SDS [BMIM]Br ionic liquids.

Scheme 30. Synthesis of pyranopyrazole using water-SDS [BMIM]Br ionic liquids.

3.3. Synthesis of Imidazole Derivatives Using Ionic Liquids

Imidazole is an important skeleton among nitrogen-containing five-membered heterocycles. Imidazole is a significant moiety of various pharmaceutically and biologically important compounds, including histamine, losartan, biotin, histidine, olmesartan, eprosartan, ketoconazole, miconazole, trifenagrel, and clotrimazole [58,59,60]. Imidazole-based ionic liquids serve as both electrolytes and green solvents due to their low chemical stability and low vapour pressure. The key synthon 1,2-diketones were used for the synthesis of imidazole derivatives using various ionic liquids, which were summarized in Scheme 31, Scheme 32, Scheme 33, Scheme 34, Scheme 35, Scheme 36, Scheme 37, Scheme 38, Scheme 39, Scheme 40 and Scheme 41.

3.3.1. Synthesis of Imidazole Derivatives in Homogeneous Phase

A rapid and high-yielding process was described for the synthesis of imidazole derivatives using 1-butyl imidazolium tetrafluoroborate [HBIM]BF₄ ionic liquids. The various substituted 1,2-dione 111 and benzaldehyde 112 were reacted in the presence of ammonium acetate base to afford imidazole derivatives 113 in high yield. The room temperature ionic liquids have attracted much attention as promising green solvents to replace hazardous traditional organic solvents due to their highly polar and non-coordinating properties. The inherent Brønsted acidity of ionic liquids promoted the cyclization with splitting of ammonium acetate to form ammonia for further condensation to form imidazole derivatives—Scheme 31 [61].

Scheme 31. Synthesis of imidazole derivatives using [HBIM]BF₄.

Scheme 31. Synthesis of imidazole derivatives using [HBIM]BF₄.

Lu and coworkers reported the catalytic use of neutral ionic liquid for the synthesis of imidazole derivatives under microwave conditions. The reaction of 1,2-dione 114 and substituted aldehyde 115 was reacted with ammonium acetate in catalyst 1-methyl-3-heptyl-imidazolium tetrafluoroborate [HeMIM]BF₄ to furnish imidazole derivatives 116 in a 91–93% yield. This ionic liquid plays dual roles as a solvent and a catalyst and avoids the use of toxic organic solvents and corrosive acids. Furthermore, the addition of a co-catalyst makes the protocol cheap and facilitates easy workup. The [HeMIM]BF₄ was a suitable catalyst, and the yield of product is significant after the fourth cycle—Scheme 32 [62].

Scheme 32. Synthesis of imidazole using (HeMIM)BF₄ ionic liquids.

Scheme 32. Synthesis of imidazole using (HeMIM)BF₄ ionic liquids.

A library of imidazole derivatives 119 was synthesized via a three-component reaction between 1,2-dione 114, aldehyde 117, and amine 118. This reaction was performed in the presence of 1-butyl-3-methylimidazolium bromide [BMIM]Br ionic liquids under conventional and microwave conditions. Notably, microwave heating facilitated the reaction, enabling a high yield in a short reaction time—Scheme 33 [63].

Scheme 33. Catalyst-free synthesis of functionalized imidazole using [BMIM]Br ionic liquids.

Scheme 33. Catalyst-free synthesis of functionalized imidazole using [BMIM]Br ionic liquids.

Another solvent-free multicomponent reaction was reported for the synthesis of imidazole derivatives 122 via a component reaction between 1,2-dione 114, aromatic amine 120, aldehyde 121, and ammonium acetate using 1-butyl-3-methyl-1-imidazolium tetrafluoroborate [BMIM][BF₄] ionic liquids. The catalytic scope of ionic liquid was examined in the synthesis of eleven imidazole derivatives under microwave conditions and conventional heating. The results of the study indicated that conventional heating in ethanol yielded 68–75%, whereas microwave irradiation expedited the reaction rate, resulting in a yield of 84–89% under solvent-free conditions—Scheme 34 [64].

Scheme 34. Synthesis of imidazole derivatives using [BMIM][BF₄] ionic liquids.

Scheme 34. Synthesis of imidazole derivatives using [BMIM][BF₄] ionic liquids.

The catalytic application of 2-ethyl imidazolium hydrogen sulphate [Et₂NH₂][HSO₄] ionic liquid was examined for the synthesis of imidazole derivatives 126 via a three-component reaction between 1,2-dione 114, ammonium acetate 123, hydroxy-bearing amine 124, and aromatic aldehyde 125. The effect of the ionic liquid was computationally optimized using Kohn–Sham DFT methods. The mechanism of a one-pot multicomponent reaction was estimated to achieve imidazole-based compounds—Scheme 35 [65].

Scheme 35. Synthesis of imidazole using [Et₂NH₂][HSO₄] ionic liquids.

Scheme 35. Synthesis of imidazole using [Et₂NH₂][HSO₄] ionic liquids.

Pyridinium hydrogen sulphate ionic liquids were explored for the synthesis of imidazole derivatives 129 via three-component reactions between 1,2-dione 114, aromatic aldehyde 128, and substituted amine chain 127. The variety of functionalized imidazole derivatives was prepared in mild conditions with an average to good yield. This catalyst is environmentally friendly and employed for the synthesis of five novel imidazole derivatives, that too without chromatography purification and use of other organic solvents—Scheme 36 [66].

Scheme 36. Synthesis of imidazole derivatives using pyridinium-based ionic liquids.

Scheme 36. Synthesis of imidazole derivatives using pyridinium-based ionic liquids.

Pyrrolidinium hydrogen sulphate ionic liquids were explored for the synthesis of imidazole derivatives. The four-component reaction between 1,2-dione 114, aromatic aldehyde 130, amine 131, and ammonium acetate was accelerated using ionic liquids to form imidazole, which undergoes subsequent reaction with indoline-2,3-dione 134 to achieve hydrazine-functionalized imidazole 135 with antioxidant properties—Scheme 37 [67].

Scheme 37. Synthesis of imidazole derivatives using ionic liquids.

Scheme 37. Synthesis of imidazole derivatives using ionic liquids.

A multistep reaction was proposed for the synthesis of imidazole derivatives 143 under microwave conditions. Initially, ionic liquids bearing functionalized diamine 136 undergo a reaction with a series of synthons to afford the desired product. This reaction furnished the product in good yield with smooth cleavage of the catalyst under microwave irradiation—Scheme 38 [68].

Scheme 38. Microwave-assisted synthesis of imidazole derivatives.

Scheme 38. Microwave-assisted synthesis of imidazole derivatives.

3.3.2. Synthesis of Imidazole Derivatives in Heterogeneous Phase

Catalytic application of magnetic nanoparticle-based ionic liquid was developed for the synthesis of imidazole derivatives 146 from aromatic aldehyde 144, 1,2-dione 114, and substituted amine 145. The 1-methyl-3-(3-trimethoxysilylpropyl)imidazolium chloride was immobilized on Fe3O4 nanoparticles, which accelerated the multicomponent reaction and provided the product with an excellent yield. A reusability test of the catalyst was performed, which indicated that the synthesized ionic liquids can be reused for up to six consecutive cycles. The reaction was performed at room temperature and without the use of organic solvents, which is a merit of the reaction—Scheme 39 [69].

Scheme 39. Synthesis of imidazole derivatives using magnetic nanoparticles.

Scheme 39. Synthesis of imidazole derivatives using magnetic nanoparticles.

Further, the catalytic activity of Fe₃O₄@SiO₂ modified by epichlorohydrin and 1-methyl-imidazole (Fe₃O₄@SiO₂EPIM) was explored for the synthesis of imidazole derivatives 149 from aldehyde 147, amine, and 1,2-dione 148. The mechanistic pathway for the synthesis of imidazole derivatives was presented in Scheme 40. The cation of the ionic liquid activates the carbonyl carbon, which undergoes nucleophilic addition with ammonia nitrogen and condenses with 1,2-diketone to form imidazole after rearrangement. The dehydration of the intermediate leads to the regeneration of the ionic liquid for a further catalytic cycle [70].

Scheme 40. Mechanism of imidazole synthesis using Fe₃O₄@SiO₂ EPIM.

Scheme 40. Mechanism of imidazole synthesis using Fe₃O₄@SiO₂ EPIM.

Another methodology for the synthesis of imidazole derivatives 151 from 1,2-dione 114 and aromatic aldehyde 150 was reported using a supported ionic liquid-like phase (SILLP). The Merrifield resin was employed for the synthesis of heterogeneous ionic liquids. The SILLP catalyst accelerates the reaction in good to excellent yield in a short time. This catalyst was separated simply by filtration, washed with ethanol, and reused up to four catalytic runs. Thus, SILLP acts as a green catalyst and allows easy recovery, making this method economical, environmentally benign, and user-friendly—Scheme 41 [71].

Scheme 41. One-pot synthesis of imidazole using SILLP ionic liquids.

Scheme 41. One-pot synthesis of imidazole using SILLP ionic liquids.

3.4. Synthesis of 1,2,3-Triazole Derivatives Using Ionic Liquids

The 1,2,3-triazoles have received incredible importance in medicinal chemistry due to their presence in a wide range of therapeutic agents such as anticancer, antibacterial, antifungal, antidiabetic, anticonvulsant, antiviral etc. [72,73]. In light of this fact, this section describes green synthetic methodologies explored for the synthesis of triazole derivatives using various ionic liquids. The click approach, cycloaddition reaction, and alkylation of triazole were assisted in ionic liquids to deliver the product in high yield without using hazardous and toxic solvents.

3.4.1. Ionic Liquids Mediated Cycloaddition Reaction in Homogeneous Phase

Ali and coworkers explored imidazole-based ionic liquid and copper iodide for the green synthesis of triazole derivatives 154 from azide 152 and terminal alkyne 153. The catalytic application of ionic liquids 1-methyl-3-butyl imidazolium hydroxide [BMIM]OH for a variety of triazole syntheses was achieved in excellent yield. This ionic liquid could efficiently be used as a solvent in copper-catalyzed azide-alkyne cycloaddition reaction without the need for bases, reducing agents, ligands, or inert atmosphere—Scheme 42 [74].

The ionic liquid 1-butyl-3-methyl imidazolium hexafluoro phosphate [BMIM]PF₆ was explored for the synthesis of triazole derivatives 158 from phosphoryl azide 156 and terminal alkyne 157. The phosphoryl azide was prepared using an ionic liquid, which undergoes a subsequent reaction with the terminal alkyne to afford the desired product in 4 to 6 h. The ionic liquids activate a medium for organophosphorus synthesis and demonstrate that it is a suitable recyclable medium for efficient synthesis of azidoalkylphosphonates, being useful intermediates for the synthesis of phosphorylated triazoles via coupling with a variety of alkynes. Scheme 43 [75].

The Cu-catalyzed azide alkyne cycloaddition reaction was reported for the synthesis of triazole derivatives 162 from sulfonyl bearing chloride 159 and iodoalkyne 160 using imidazole-based ionic liquids 1-Ethyl-3-methylimidazolium tetrafluoroborate [Emim]BF₄ ionic liquids. The CuI (10 mol%) with two equivalents of t-BuOK in [Emim]BF₄ under microwave irradiation at 200 W afforded benzothiazine-triazole hybrids as antibacterial agents. Mechanistically, intramolecular C–H arylation of in situ generated 5-iodotriazole under microwave irradiation in ionic liquid furnishes desired products. The advantages of this method include high yields, an easy workup procedure, and short reaction times—Scheme 44 [76].

Singh and coworkers explored 1,8-Diazabicyclo [5.4.0]undec-7-ene ionic liquids, DBU-based ionic liquids, for the triazole synthesis 166 via multicomponent reaction between indoline-2,3-dione 163, cyclic 1,3-diketone 164, malononitrile 52, and various nitro-substituted aryl azide 165. This task-specific ionic liquids accelerated the Knoevenagel condensation and then click reaction at room temperature to furnish the various triazole products in good yield within 20 min—Scheme 45 [77].

Convenient and straightforward synthesis of triazole glycoside 170 was reported from pyridinium-based ionic liquids [bpy]Br]. The one-pot sequential reaction between glycoside 167 and terminal alkyne 168 was accelerated in the presence of 0.5 mL of [bpy][Br] to achieve the desired product in a short reaction time. This ionic liquid acts as a dual promoter and solvent for the synthesis of a wide variety of long alkyl-chain acetylated triazolylglycosides—Scheme 46 [78].

Marra and coworkers reported the synthesis of novel triazole glycoside 173 from the reaction of sugar alkyne 171 and sugar azide 172 using N-octyl dabco-cation-based dicyanamide [C₈dabco][N(CN)₂] ionic liquids. The triazole glycoside was formed by the cycloaddition in ionic liquids. The described methodology revealed that Hunig’s base and ionic liquids are responsible for the formation of single isomers of desired products—Scheme 47 [79].

Further amino-acid-based ionic liquids (AAIL) were explored for the synthesis of triazole derivatives by Wang and coworkers. The substituted terminal alkyne 174, alkyl halides 175 and sodium azide were accelerated in 10 mol% CuI, 20mol% AAIL and [BMIM]BF₄ ionic liquids to afford substituted triazole derivatives 176. The feasibility of the reaction was examined in twenty reactions with varying yields from 67 to 99%. The developed ionic liquid can be recovered for six successive runs without significant loss in the yield percent Scheme 48 [80].

Catalytic application of 1-methyl pyridinium trifluoromethanesulfonate ([mpy]OTf) ionic liquids was reported for the synthesis of triazole derivatives via eliminative azide-alkene cycloaddition reactions. The efficacy of the ionic liquids was tested in the reaction of nitrostyrene 177 and benzylazide 178 to achieve substituted triazole 179 in 95% using additional Lewis acid catalyst. The developed catalyst can be reused up to five times and recovered efficiently for further catalytic runs. The proposed methodology is ecofriendly, efficient and cost effective for regiocontrol synthesis of the desired triazole derivatives Scheme 49 [81].

In 2021, Dutta and coworkers reported the design and synthesis of novel task-specific bifunctional basic ionic liquids for the synthesis of amino-triazole derivatives. The substituted benzyl cyanide 180 and substituted aryl azide 181 were reacted in 1,3-dihexadecyl-1H-imidazol-3-ium bromide [DHIM][OH] ionic liquid under microwave conditions (70W) to achieve the desired triazole heterocycles 182 with very high yield (94–99%). The fabricated [DHIM][OH] acts as task-specific ionic liquids to facilitate the formation of ketenimine intermediate to undergo regioselective 3+2 cycloaddition reaction to achieve desired products—Scheme 50 [82].

Recently, multifunctional ionic liquids 1-dodecylquinolin-1-ium bis(trifluoromethane)sulfonimide [DDQM][TFSI] were designed for their application in electrolytes as well as in the synthesis of triazole derivatives. Ionic liquid catalyzed a three-component reaction between substituted benzaldehyde 183, nitromethane 184, and sodium azide under microwave conditions. This was demonstrated for the synthesis of triazole derivatives 185. The synthesized ionic liquid accelerates the reaction in a few minutes with a high yield percentage—Scheme 51 [83].

A new set of triazolo annulated benzodiazepine derivatives 188 were synthesized from the reaction of 2-azidoaniline 186 and propargyl alcohols 187. Various ionic liquids such as [BMIM]BF₄, [BMIM]PF₆, [BMIM]Br, [BMIM]Cl, [BMIM]ClO₄, [BMIM]OAc, [BMIM]OH were explored for the desired transformation. Among all, [BMIM]BF₄ showed excellent catalytic activity at room temperature under ultrasonic irradiation for 1 h. The developed ionic liquid is simple, efficient, and reused for five consecutive cycles with a slight decrease in yield percentage, i.e., 90% to 82%—Scheme 52 [84].

Another report published on the catalytic application of [BMIM]PF₆ ionic liquids for dipolar cycloaddition reaction between terminal alkyne 189 and azide to obtain triazole derivatives 190 under microwave irradiation in 30 min with good yield—Scheme 53 [85].

The catalytic application of [BMIM]PF₆ was reported for the synthesis of triazole-pyridine hybrids 192 from iodoalkyne 191 and aryl azide under microwave conditions. The fused triazole heterocycles showed prominent anticancer activity against MCF-7, HeLa, A-549, and IMR-32 cell lines, Scheme 54 [86].

Multicomponent reaction between substituted azide, propargylated aldehydes 193, benzil 114, and ammonium acetate in the presence of 1-methylimidazolium trifluoroacetate [HMIM]TFA ionic liquids to achieve triazole derivatives 194 in solvent-free conditions. The catalytic activity of [HMIM]TFA was optimized with different solvents and temperatures; the best results were obtained in solvent-free conditions with elevated temperatures—Scheme 55 [87].

Dipolar cycloaddition reaction between aldehyde 195 and azide was catalyzed by task-specific [BMIM]OH ionic liquids to synthesize trisubstituted triazole derivatives 197. This basic ionic liquid serves as a reaction medium and the catalyst for organic reactions. The plausible mechanism for regioselective reaction involves initial formation of enolate ion 196, which undergoes cycloaddition with substituted azide to form triazole derivatives via elimination of water molecules—Scheme 56 [88].

The reaction of phenyl azide 198 and acetylene 199 in [BMIM][BF₄] ionic liquids to form triazole derivatives 200 was reported by Seregin and coworkers. This ionic liquid played a dual role as a catalyst and as a solvent to assist the reaction without using any external organic solvent and catalyst—Scheme 57 [89].

Nino and coworkers reported the regioselective synthesis of triazole derivatives 203 using [mpy]OTf ionic liquids. The catalytic activity of [mpy]OTf was examined in the synthesis of a set of sixteen triazole derivatives in aqueous medium from the reaction of carbonyl group-bearing moiety 201 and substituted azide 202. It was revealed that base triethylamine is important for water-assisted dipolar cycloaddition reactions—Scheme 58 [90].

The azide is explosive and toxic during the organic reaction. Thus, Rad and coworkers reported the catalytic use of ionic liquid bearing azide, i.e., hydroxyethyl methyl morpholiniumazide (HEMMorph)N₃ for efficient synthesis of triazole derivatives 206 from substituted halides 204 and terminal alkyne 205. The efficiency of the developed catalyst was examined under various temperatures and catalyst loading; the result revealed that 3.5mmol of catalyst and a higher temperature of 90 °C affords a high product yield—Scheme 59 [91].

Ionic liquid [BMIM]PF₆ bearing benzoyl chloride 207 was reacted with sodium azide and terminal alkyne to achieve triazole-bearing ionic liquids 208, which subsequently undergo alkylation to achieve disubstituted triazole 209. The cleavage of ionic liquids took place in the presence of ceric ammonium nitrate (CAN) reagent to obtain the desired products 210 in excellent yield—Scheme 60 [92].

3.4.2. Ionic Liquids Mediated Miscellaneous Reaction for Triazole Synthesis in Homogeneous Phase

The dimer of triazole derivatives 213 was obtained from the reaction of ethylene glycol 211 and terminal alkyne using various ionic liquids. The feasibility of ionic liquids was examined in the synthesis of triazole derivatives in good yield. Notably, the combination of TEA with MsO produced the highest yield of triazole derivatives—Scheme 61 [93].

Singh and coworkers reported metal-free synthesis of triazole derivatives 216 from substituted aldehyde 214 and azide 215 using butyl-substituted 1,8-diazabicyclo [5.4.0]undec-7-ene cation combined with a hydroxide anion [DBU-Bu]OH ionic liquids. The catalytic application of ionic liquids is optimized under conventional and ultrasonic conditions. The 30 mol% of ionic liquid promoted the reaction to achieve high yield within 10–20 min under ultrasonic conditions Scheme 62 [94].

The equivalent amount of 1-butyl-3-methylimidazolium nitrate [BMIM]NO₂ and 1-butyl-3-methylimidazolium azide [BMIM]N₃ ionic liquids was used for the synthesis of functionalized triazole derivatives. The substituted aniline 217 was reacted with dicarbonyl compound to achieve triazole derivatives 218 in good to excellent yield. The alternate use of sodium azide makes the protocol attractive for mild and efficient synthesis of desired nitrogen heterocycles in a short time—Scheme 63 [95].

3.4.3. Ionic Liquids Mediated Functionalization of Triazole in Homogenous Phase

The catalytic application of 1,8-diazabicyclo [5.4.0]undec-7-ene cation combined with a hydrogen sulphate anions [HDBU][HSO₄] ionic liquid was explored for the synthesis of quinolone-triazole hybrids 221 under conventional and ultrasonic conditions. The triazolyl aldehyde 219 undergo cyclocondensation with anthranilamide 220 in 20 mol% of [HDBU][HSO]₄ ionic liquids to form quinolone-triazole hybrids in 10–20 min under ultrasonic condition whereas 29–36 min in microwave conditions—Scheme 64 [96].

3.4.4. Ionic Liquids Mediated Cycloaddition Reaction in Heterogeneous Phase

The catalytic application of ionic liquid was explored for 1,2,3-triazole 225 synthesis from aryl azide 223, boronic acid 222, and terminal alkyne 224, yielding the product in an outstanding yield, as reported by Hosseini and coworkers. The four-component reaction was promoted by a functionalized ionic liquid catalyst (CuI@SBA-15/PrEn/ImPF6) based on a mesoporous silica SBA-15 skeleton, which bears a supported ethylenediamine/CuI complex and covalently anchored imidazolium/PF₆ ionic liquid. The developed catalyst exhibited high stability via forming a coordination bond with ethylenediamine functionality, which enabled the catalyst for reuse up to 14 times for consecutive catalytic reactions—Scheme 65 [97].

Another Cu-bearing ionic liquid was explored for the synthesis of a variety of triazole derivatives 227(a–c) via a one-pot condensation reaction between aryl halides 226(a–c), terminal alkyne, and sodium azide. The copper-immobilized polystyrene ionic liquid, Cu(II)-PsIL, is a stable green catalyst that affords the desired product in 99% yield using PEG-400 as the solvent. This catalytic system provided selectivity and a broad substrate scope of organic halides or bromoketone and alkyl/aryl terminal alkyne. The significant yield of the desired product was obtained using 0.2 mol% of the catalyst. The fabricated heterogeneous ionic liquid can be recycled and reused for seven cycles without loss in the catalytic activity—Scheme 66 [98].

Another example of copper-bearing Schiff base ionic liquid was reported for the triazole synthesis 230 via a three-component reaction between terminal alkyne 229, azide, and aryl halides 228. The ionic liquids assisted the cycloaddition reaction in an aqueous medium. Notably, the catalyst can be reused for further third runs, and the yield declines from 89 to 86% without significant loss in catalytic performance—Scheme 67 [99].

Sharma and coworkers reported the catalytic application of magnetically separable ionic liquids for the synthesis of substituted triazole derivatives 233 from substituted halides 231 and terminal alkyne 232. The fabricated heterogeneous catalyst consists of 1-butyl-4-methylpyridinium tetrafluoroborate coated CuFe2O4 over L-tyrosine functionalized titania nanospheres IL@CuFe2O4-L-Tyr-TiO2/TiTCI, prompting product formation in water within minutes. Employing the developed methodology, fifteen triazole derivatives were prepared with an 87–95% yield—Scheme 68 [100].

The heterogeneous ionic liquid system SMA-FA-CS-IL was prepared by using styrene (SMA), folic acid (FA), and chitosan (CS) for the synthesis of triazole derivatives 236(a,b) from substituted carbonyl 234(a,b) and alkyne 247. The developed catalyst was fully characterized and used for efficient synthesis of triazole derivatives in aqueous medium under ultrasonic irradiation—Scheme 69 [101].

Role of Er(OTf)₃ ionic liquid was demonstrated for the regioselective synthesis of triazole derivatives 237 from nitroalkene 177 and azide. The developed heterogeneous catalyst was formed from erbium(III) trifluoromethane-sulfonate, 1-methyl pyridinium trifluoro-methane sulfonate, and water, Er(OTf)3/[mpy]OTf/H2O, to accelerate the azide-olefin cycloaddition reaction for the synthesis of triazole derivatives in 94% yield—Scheme 70 [102].

Another example of imidazole-based ionic liquids supported copper(II) pre-catalyst carboxyl group linker 1-(1-carboxymethyl) 3-methylimidazolium tetrafluoroborate ([Carbmmim][BF₄]) for the regioselective synthesis of triazole derivatives 239 from benzyl azide 238 and terminal alkyne 224. The efficacy of the developed catalyst was examined under various solvents, temperatures, and microwave conditions. The result of optimization indicated that acceleration of dipolar cycloaddition reaction took place in methanol solvent to provide high product yield in 3 h—Scheme 71 [103].

Another magnetic polymeric ionic liquid comprises the polymerization of 3-carboxymethyl-1-vinylimidazolium in the presence of surface-modified magnetic nanoparticles, followed by the coordination of the carboxylate units in the polymer chains with copper sulphate. MNP@ImAc/Cu was explored for the facile and efficient click reaction. The efficacy of the catalyst was examined in the synthesis of 29 triazole derivatives 242 from substituted aryl bromide 240 and terminal alkyne 241, with an average to excellent yield—Scheme 72 [104].

The water-assisted protocol was discussed for the synthesis of a large set of triazole derivatives using Merrifield resin (polymer)-supported ascorbate functionalized task-specific ionic liquids (MR-IMZ-As) at room temperature. The ionic liquids were synthesized and fully characterized by different analytical techniques. The reaction of aryl diazonium tetrafluoroborate 243, sodium azide, and terminal alkyne 244 was catalyzed by 20 mol% MR-IMZ-As ionic liquids to afford the product 245 in high yield, 90–95%. This task-specific ionic liquids assisted the 1,3-dipolar cycloaddition reactions for the regioselective synthesis of 1,4-disubstituted-1,2,3-triazole derivatives—Scheme 73 [105].

Li and coworkers reported the synthesis of polytriazole 248 using copper-based ionic liquids from azide 246 and terminal alkyne 247. The ionic liquids cause acceleration of the click polymerization reaction under mild conditions. They employed copper-based ionic liquids to attain five different polytriazoles in very high yield (99%)—Scheme 74 [106].

Another example of a click reaction was demonstrated for the synthesis of triazole derivatives using copper immobilized silica supported [BMIM]PF₆ ionic liquids (Cu-SILC). This heterogeneous catalyst promoted the reaction between phenyl azide 249 and terminal alkyne alcohol 250 for the synthesis of triazole derivatives 251 at room temperature. The catalyst can be reused for six consecutive catalytic runs—Scheme 75 [107].

Simple and economical dipolar cycloaddition reaction between azide 238 and alkynes 224 was described for the synthesis of triazole derivatives 252 using [BMIM][CuCl₃] ionic liquids that were prepared by the reaction of CuCl₂ with 1-butyl-3-methylimidazolium chloride. This water-assisted methodology showed a broad substrate scope (20 examples) for the synthesis of disubstituted triazole derivatives—Scheme 76 [108].

The heterogeneous ionic liquids NHC-Cu@GO-IL, composed of N-heterocyclic carbene–copper complex grafted on graphene oxide with an ionic liquid framework, were designed and synthesized for the catalytic application in the synthesis of substituted triazole. This dipolar cycloaddition reaction between azide 253 and alkyne 254 was accelerated in an ethanol–water mixture and 1 mol% of ionic liquid to furnish a set of eight triazole derivatives 255. The feasibility of the catalyst was examined in different solvents and temperatures. Results indicated that an equimolar mixture of ethanol/water at 70 °C afforded the product in the highest yield, 93%, whereas a decrease in the temperature led to a reduction in the yield. This ionic-liquids framework has the potential to be reused up to ten successive catalytic cycles, and leaching of 21% copper was estimated by AAS Scheme 77 [109].

The diverse set of triazole derivatives 259, 260, 261 was prepared using silica-supported ionic liquids SNIL-Cu(II) described by Tavassoli and coworkers. The azide and alkyne dipolar cycloaddition reaction with a variety of substituted benzyl bromides 256, 257, and 258 was realized at room temperature using solvent PEG-400, sodium ascorbate, and Cu-immobilized ionic liquids in silica nanoparticles. The developed ionic liquid afforded the product above 90% yield and can be reused for six consecutive runs without loss in the catalytic activity—Scheme 78 [110].

3.4.5. Ionic Liquids Mediated Miscellaneous Reaction in Heterogeneous Phase

Immobilized copper (I) in imidazole-based ionic liquid was reported for the synthesize triazole derivative 263 from terminal alkyne 224 and epoxide 262. The developed catalyst led to the ring opening of the epoxide in mild conditions to afford the product in high yield—Scheme 79 [111].

3.5. Synthesis of 1,2,4-Triazole Using Ionic Liquids

The 1,2,4-Triazole is a five-membered nitrogen heterocyclic compound containing two carbon atoms and three nitrogen atoms. This compound exhibits a wide range of biological properties due to its unique chemical reactivity and hydrogen bonding ability. The 1,2,4-triazole is widely used in the pharmaceutical industry, particularly in the preparation of fluconazole as an antifungal agent [112,113,114]. In view of their popularity in medicinal and related fields, researchers have developed various greener methods for the synthesis of 1,2,4-triazole using different ionic liquids.

Ionic Liquids Mediated Synthesis of 1,2,4-Triazole Derivatives in Homogenous Phase

Patil and coworkers reported the catalytic application of acidic ionic liquid 1,10 sulfinyldipyridinium bis (hydrogen sulphate) [(Py)₂SO][HSO₄]₂ for the synthesis of 1,2,4-triazole-3-thiones 266 from the reaction of thiosemicarbazide 265 with ketone 264. This ionic liquid facilitated the cyclization of the substrate under mild conditions to afford triazole at room temperature in good yields (~90%). The green credentials of this procedure include the circumvention of the use of toxic organic compounds, high yield, high atom economy, ease of work, and reusability of the ionic liquids for further runs—Scheme 80 [115].

Another approach for the synthesis of triazolidinethiones using morpholine-based ionic liquids was reported by Dige and coworkers. The substituted benzaldehyde 267 was treated with thiosemicarbazide 268 in ethanol and 10 mol% of ionic liquids N-methyl morpholine [NBMMorph]Br to synthesize 1,2,4-triazole-3-thiones 269 at ambient temperature—Scheme 81 [116].

A variety of thiadiazole-triazole hybrids 272 were synthesized using imidazole-based ionic liquids [BMIM]Br. The substituted hydrazide 270 was reacted with aryl isothiocyanate 271 in the presence of ionic liquids (1.5 mmol) to afford the desired heterocycles in 80–95% yield at room temperature. The biological activity of synthesized compounds was investigated from molecular docking and experimental studies; results indicate that the p-chlorophenyl substituent showed a lower MIC value of 0.39 µg/mL against Candida albicans and showed the highest binding affinities with the CYP51 enzyme—Scheme 82 [117].

Another methodology for the synthesis of 1,2,4-triazolidine-5-thiones using Bronsted ionic liquids 1-(2-hydroxyethyl)-1-(4-sulfobutyl)piperidin-1-ium hydrogen sulphate [HEPiPYBSA]⁺HSO₄⁻ was reported. The quinoxalin-11-one 273 was treated with substituted thiosemicarbazide 274 in ethanol for the synthesis of spiro-1,2,4-triazolidine-5-thiones 275 in good to excellent yield. The developed catalyst is green, hydrophilic, and facilitates the reaction in a mild solvent ethanol—water mixture. The wide substrate scope, atom-economic procedure, and reusability of the catalyst are some of the advantages of the reported methodology—Scheme 83 [118].

Room temperature three-component reaction for the synthesis of triazole derivatives using Bronsted basic ionic liquids 2-hydroxyethylammonium acetate [H₃N⁺-CH₂-CH₂-OH][HCOO⁻] was described. The three-component reaction between arylaldehyde 277, malononitrile, and 4-phenylurazole 276 with a catalytic amount of ionic liquids (0.24 mol) realized the synthesis of functionalized triazole 278 in mild conditions within a few minutes. The developed catalyst can be reused for seven consecutive runs without loss of activity—Scheme 84 [119].

Another three-component reaction was demonstrated for the synthesis of triazole derivatives using DABCO-diacetate-based ionic liquids. The urazole 279, dimedone 164, and aryl aldehyde 280 were reacted with acidic dicationic ionic liquids under ultrasonic conditions to afford dimedone-triazole hybrids 281. Only 0.7 mmol of ionic liquids facilitated the formation of desired heterocycles at room temperature with a yield up to 96%. The reusability of the developed catalyst was studied up to 10 runs. Thus, developed methods are simple and offer a simple workup, mild conditions, and excellent yield in gram-scale synthesis in a short reaction time, showing the eco-friendly advantages of this procedure—Scheme 85 [120].

Catalytic application of tunable protic pyridinium trifluoroacetate ionic liquids [PyH]⁺CF₃CO₂⁻ was examined for the synthesis of functionalized triazole 284 from oxadiazoles 282 and substituted amines 283. The developed catalyst was recorded as an appropriate reagent for the formation of a variety of triazole derivatives in 20–30 min with a yield of up to 90–95% yield. Mechanism indicates that ring opening by the reaction with aryl amine to form N-acylamidrazone intermediate, followed by reaction with acid catalyst to initiate intramolecular cyclization to furnish 1,2,4-triazole derivatives. This green and efficient methodology is an alternative to traditional methods, which require hazardous reagents and volatile organic solvents—Scheme 86 [121].

Regioselective alkylation of 1,2,4-triazole was achieved using 1-hexylpyridiniumbromide ionic liquids and potassium carbonate base. The triazole 285 was reacted with alkyl bromide 286 and potassium carbonate under microwave conditions to afford alkylated triazole 287 in 15 min with a yield of up to 85%. The ionic liquids extracted from the reaction mixture using diethyl ether and reused for five catalytic runs. The green credentials of this methodology are short time for product formation, replacement of volatile organic solvents, and reusability of the catalyst—Scheme 87 [122].

3.6. Synthesis of Tetrazole Derivatives Using Ionic Liquids

Tetrazole is a five-membered cyclic ring containing four nitrogen atoms. Tetrazole-bearing compounds showed energy application and exhibit various biological properties. Currently, in 2019, the Cenobamate drug, containing a tetrazole skeleton, was approved by the FDA for the treatment of seizures [123,124,125]. To realize efficient synthesis of tetrazole derivatives, different homogeneous and heterogeneous ionic liquids were employed for the click reaction.

3.6.1. Ionic Liquids Mediated Click Reaction in Homogenous Phase

The ionic liquid tetrabutylammonium iodide (TBAI) was explored for the synthesis of tetrazole–pyrimidine hybrids. The variety of tetrazole-pyrimidine hybrids 289 were prepared from the reaction of pyrimidine-2-thione 288 and sodium azide with a catalytic amount of ionic liquids at room temperature under aqueous medium. This ionic liquid is non-toxic, reusable, and thermally stable in aqueous medium, making it superior to volatile organic solvents. The synthesized compounds showed potent antibacterial and antifungal properties—Scheme 88 [126].

Further pyridinium-based ionic liquids (1-disulfo-[2,2-bipyridine]-1,1-diium chloride) were explored for the synthesis of tetrazole derivatives 291 via click reaction between nitrile 290 and azide. The feasibility of the developed catalyst was examined in the synthesis of a variety of tetrazole derivatives in ethylene glycol solvents. The good to excellent yield of tetrazole derivatives was obtained in a short reaction time. The significant advantages of this procedure include ethylene glycol as a green solvent, inexpensive and easy preparation of the catalyst, mild conditions, easy workup, short reaction time, and simple experimental process—Scheme 89 [127].

Schmidt and coworkers reported safe and fast tetrazole synthesis using 1-octyl-3-methylimidazolium (OMIM-Cl) ionic liquids. The catalytic use of the developed catalyst was examined in twenty reactions for the preparation of a variety of tetrazole derivatives 293 from nitrile 292 with average to excellent yield. This methodology is significant to upscale the yield of valsartan. The industrial application of this procedure in drug synthesis is the main advantage of this procedure to facilitate the organic reaction in mild conditions—Scheme 90 [128].

The catalytic activity of triazine imidazolium (TAIm) ionic liquids was reported for the synthesis of tetrazole derivatives from three different precursors, such as substituted amine 294, substituted nitrile 295, and substituted carbonyl group 296. The nitrile undergoes cycloaddition reaction with azide to form tetrazole 298, the amine undergoes cyclization with triethyl orthoformate and azide to achieve tetrazole 297, and the last carbonyl precursor undergoes cyclization with azide and ammonium hydroxide to yield aryl tetrazole 299. The feasibility of the developed catalyst was examined under microwave and ultrasonic conditions. The broad utility of the ionic liquids in the feasible synthesis of tetrazole derivatives was assessed from different starting reactants—Scheme 91 [129].

Due to the inert nature of imidazole and toxicity of pyridine ionic liquids, several other ionic liquids were explored for organic transformation. The catalytic application of DBU-based ionic liquids was explored for the synthesis of tetrazole derivative via solvent-free click approach. DFT methods examined the stability of the developed catalyst. The developed catalyst facilitated click reaction between nitrile 300 and trimethylsilyl azide to afford tetrazole 301 in 95% yield [130]. Another catalytic application of quinoline-based ionic liquids was demonstrated for the synthesis of tetrazole derivatives in solvent-free conditions. The quinoline-based fluoride salts were prepared and their thermal stability was determined by TGA, DTG, and DSC analysis. The developed catalyst promoted the reaction between nitrile and trimethylsilyl azide (TMSN₃) to afford tetrazole derivatives in good yield—Scheme 92 [131].

The green source of azide 1-butyl-3-methylimidazolium azide [BMIM]N₃ ionic liquids was explored for the one-pot stereocontrolled synthesis of tetrazole derivatives from starting synthon isatin 302(a,b), aromatic aldehyde 303c. This reactant was treated with malononitrile, o-phthalimide-N-sulfonic acid, and ionic liquids under solvent-free conditions to furnish tetrazole derivatives 304, 305, and 306 in average to good yield. The regioselective nature of compounds was determined by quantum theory of atom in molecules analysis Scheme 93 [132].

3.6.2. Ionic Liquids Mediated Click Reaction in Heterogenous Phase

The copper immobilized chitosan supported ionic liquids [CS@Tet-IL-Cu(II)] was explored for the synthesis of tetrazole derivatives. The nitrile 307 was reacted with sodium azide in the presence of ionic liquid and DMF to produce tetrazole derivatives 308′ and 308″ in high yield in 30 min. The proposed mechanism indicates that electron withdrawing substituents affords 5-arylamino-1H-tetrazole and electron donating substituents furnish 1-aryl-5-amino-1H-tetrazole derivatives Scheme 94 [133].

The ionic liquids supported copper(II)-catalyst was explored for the synthesis of tetrazole derivatives 310 from nitrile 309 and azide under microwave conditions. This reaction was completed in 20–25 min with a yield of up to 96%. The developed catalyst was recyclable for three consecutive runs. This catalyst is thermally stable, green, and easily separated from the reaction mixture—Scheme 95 [134].

Another report for the catalytic applications of chitosan supported magnetic ionic liquid nanoparticles (CSMIL) in the synthesis of tetrazole derivatives was described. The fabrication of catalyst from chitosan (biopolymer), methyl imidazole, and ferric chloride FeCl₃ to furnish CS-EMImFeCl₄ catalyst. The two-synthon nitrile 311 and amine 312 was explored for the cycloaddition reaction with azide in presence of developed ionic liquid under solvent-free conditions to form tetrazole 313. The variety of tetrazole derivatives were prepared in average to good yield. This protocol illustrates simple methodology, wide applicability, environmental friendliness, and reusability up to five cycles. The main advantage of a biopolymer-supported catalyst is that it is noncorrosive, inexpensive, and safe for organic transformation—Scheme 96 [135].

The copper dopped layered double hydroxide composite Fe₃O₄@CuMgAl-LDH with imidazole ionic liquids IMIL were explored for the synthesis of tetrazole derivatives 315 from aryl iodide 314, K₄Fe[CN]₆ and sodium azide. The catalytic activity of the developed catalyst was examined in reactions with twelve different substrates. Outcomes of the study revealed good yield of desired product in 10–24 h. Notably, the catalyst can be reused for eight successive runs without significant decrease in the activity—Scheme 97 [136].

The aluminium-based ionic liquid grafted onto a biochar surface (BC/[TESPMI] AlCl₄) was explored for the synthesis of tetrazole derivatives via click reaction between nitrile 316 and azide to afford tetrazole derivatives 317 in 92–98% yield. The developed catalyst was completely characterized by analytical techniques and further catalytic application was examined for organic transformation. The eleven tetrazole containing product was formed by using developed catalyst and PEG 400 solvent at 25–55 min. The proposed mechanism revealed that heterogenous catalyst firstly coordinated with nitrile functional group followed by the attack of azide to furnish tetrazole derivatives—Scheme 98 [137].

Catalytic use of [BMIM]N₃ ionic liquids and expanded perlite was explored for the synthesis of substituted tetrazole derivatives 319 from substituted nitrile 318. The [BMIM]N₃ is a green alternative to the hazardous and explosive sodium azide. Solvent-free reaction between substituted nitrile and ionic-liquid-based azide afforded tetrazole derivatives in mild conditions with a yield up to 95%—Scheme 99 [138].

3.6.3. Miscellaneous Reactions

Dighe and coworkers reported the catalytic application of imidazole-based ionic liquids for the facile synthesis tetrazole derivatives 322 from substituted amine 320, sodium azide, and triethyl orthoformate 321 at room temperature. This reaction rate was promoted by the acidic ionic liquids and high polarity dimethyl sulfoxide solvent to achieve tetrazole derivatives in average to good yield—Scheme 100 [139].

Another approach for the tetrazole synthesis 325 by the three-component reaction between dimedone 164, tetrazole amine 323, and aldehyde 324. This reaction was catalyzed by 1-butyl-3-methylimidazolium tetrachloroaluminate [BMIM]Cl/AlCl₃ catalyst to achieve desired heterocycles in outstanding yield (90–95%) within 30–40 min. This task specific ionic liquids activate under mild conditions that would replace the corrosive and hazardous catalyst for the synthesis of condensed tetrazole derivatives. The short synthetic route, mild conditions, no chromatographic separation and operational simplicity are the merits of this procedure. Mechanistically, ionic liquids promote the intermolecular enamine formation than cyclization to furnished condensed tetrazole derivatives—Scheme 101 [140].

4. Research Gap and Novelty

The ionic liquids have been the subject of various reviews due to their immense significance in promoting the reaction in mild conditions (Figure 5). Recently, Mishra et al. (2015) [141] reviewed the ionic liquids-promoted synthesis of five and six-membered heterocycles, whereas Chudasama et al. (2021) described the aza and oxa heterocycles using ionic liquids [142]. Kaur et al. (2019) [143] reported the synthesis of five-membered nitrogen heterocycles using ionic liquids; however, the present work covers a broad interval of time and, of course, includes recent updates and classifies the reaction in homogeneous and heterogeneous phases. Other previous reviews encompass the synthesis of nitrogen, oxygen, and sulphur containing five and six-membered rings using ionic liquids. Still, they do not provide a comprehensive overview of the catalytic synthesis of five-membered heterocycles using ionic liquids. To achieve this, our review focuses on the recent advancement of ionic liquids in the synthesis of aromatic five-membered nitrogen heterocycles, depicting a myriad of examples. The glossary of ionic liquids used in the synthesis of five-membered nitrogen heterocycles is reported in

Table 1. Glossary of ionic liquids used in the synthesis of five-membered nitrogen heterocycles.

Abbreviated Name	Structure	Ref.
[BMIM]I	1-butyl-3-methylimidazolium iodide	[25]
[HMIM]HSO4	1-Methylimidazolium hydrogen sulphate	[26]
Bi(OTf)3/[BMIM]BF4	1-butyl-3-methylimidazolium tetrafluoroborate	[27]
[BMIM]OH	1-butyl-3-methylimidazolium hydroxide	[28]
[BMIM]HSO4	1-butyl-3-methylimidazolium hydrogen sulphate	[29]
[HBIM]BF4	1-n-butylimidazolium tetrafluoroborate	[30]
[EMIM][BH3CN]	1-ethyl-3 methylimidazolium cyanoborohydride	[31]
[BSO3HMIM]HSO4	3-methyl-2-(1-sulfobutyl) 1H-imidazolium hydrogensulphate	[33]
[BMIM]PF6	1-butyl-3-methylimidazolium hexafluorophosphate	[35]
[BMIM][BF4]	1-butyl-3-methyl imidazolium tetrafluoroborate	[38]
[EMIM]Ac	1-Ethyl-3-methylimidazolium acetate	[40]
[DMDBSI].2HSO4	1,3-dimethyl-2-oxo-1,3-bis(4-sulfobutyl) imidazolidine-1,3-diium hydrogen sulphate	[41]
[Et3NH][HSO4]	Triethylammonium hydrogen sulphate	[42]
(Bbpy)(HSO4)2	1,1′-butylenebispyridiniumhydrogen sulphate	[45]
[BMIM]Cl	1-Butyl-3-methylimidazolium chloride	[47]
[NGIM]3[Cit]	Biological-based(nano) gelatoric ionic liquids	[51]
Pec-DAP-BS	Pectin-supported Pyridinium-based ionic liquids	[52]
[C4mim][FeCl4]	Transition metal-based ionic liquids	[53]
Ionic-liquid-based nano-magnetic solid acid heterogeneous catalyst	Fe3O4@SiO2@(CH2)3NH@CC@Imidazole@SO3H	[54]
Choline chloride salt/N-methyl-2-pyrrolidonum hydrogen sulphate	[ChCl][ZnCl2]2 and H-NMP	[55]
water-SDS [BMIM]Br	Sodium dodecyl sulphate/1-butyl-3-methylimidazolium chloride	[57]
[HeMIM]BF4	1-methyl-3-heptyl-imidazolium tetrafluoroborate	[62]
[BMIM]Br	1-butyl-3-methylimidazolium bromide	[63]
[Et2NH2][HSO4]	2-ethyl imidazolium hydrogen sulphate	[65]
MNPs-IL	1-methyl-3-(3-trimethoxysi lylpropyl)imidazolium chloride was immobilized on Fe3O4 nanoparticles	[69]
Fe3O4@SiO2EPIM	Fe3O4@SiO2 modified by epichlorohydrin and 1-methyl-imidazole	[70]
SILLP was prepared by using Merrifield resin	Supported ionic liquids-like phase	[71]
DBU-based ionic liquids	1,8-Diazabicyclo [5.4.0]undec-7-ene ionic liquids	[77]
[bpy][Br]	Pyridinium bromide	[78]
[C8dabco][N(CN)2]	N-octyl dabco-cation-based dicyanamide	[79]
[DHIM][OH]	1,3-dihexadecyl-1H-imidazol-3-ium bromide	[82]
[DDQM][TFSI]	1-dodecylquinolin-1-ium bis(trifluoro methane)sulfonimide	[83]
[HMIM]TFA	1-methylimidazolium trifluoroacetate	[87]
[DBU-Bu]OH	Butyl-substituted 1,8-diazabicyclo [5.4.0]undec-7-ene cation combined with a hydroxide anion	[94]
[HDBU][HSO4]	1,8-diazabicyclo [5.4.0]undec-7-ene cation combined with a hydrogen sulphate anions	[96]
CuI@SBA-15/PrEn/ImPF6	Mesoporous silica SBA-15 skeleton which bears a supported ethylenediamine/CuI complex and covalently anchored imidazolium/PF6 ionic liquid	[97]
MR-IMZ-As	Merrifield resin (polymer)-supported ascorbate functionalized task specific ionic liquid	[105]
SNIL-Cu(II)	Silica nanoparticles-supported copper containing ionic liquid	[110]
[(Py)2SO][HSO4]2	1,10 sulfinyldipyridinium bis (hydrogen sulphate)	[115]
[NBMMorph]+Br−	N-methyl morpholine	[116]
DABCO-diacetate	1,4-Diazabicyclo [2.2.2] Octanium Diacetate	[120]
OMIM-Cl	1-octyl-3-methylimidazolium	[128]
[CS@Tel-IL-Cu(II)]	Chitosan-supported 1-phenyl-1H tetrazole-5-thiol ionic liquid copper(II) complex	[133]
BC/[TESPMI]AlCl4	Aluminium-based ionic liquid grafted onto a biochar surface	[137]

.

5. Conclusions

Ionic liquid-assisted synthesis has emerged as a versatile and promising green approach in organic synthesis, enabling reactions in mild conditions without the use of any toxic solvents. The present article summarizes the catalytic application of ionic liquids in the synthesis of five-membered aromatic nitrogen heterocycles such as pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, and tetrazole. In particular, focus has been given to the utilization of ionic liquids as a catalyst and solvent in the reaction medium to achieve the desired heterocycles in a short time, without column chromatographic separation, organic solvent-free, with high selectivity and quantitative yield. In addition, the review highlights the optimization of various ionic liquids to achieve particular heterocycles with high yield. Selectivity of ionic liquids is important for desired organic transformation; for instance, imidazole-based ionic liquids achieved the click reaction for tetrazole and triazole synthesis. Moreover, various imidazole-based ionic liquids could be functionalized and converted into nano-form to attain efficient desired transformations.

Ionic liquids offer several advantages over traditional organic solvents in chemical synthesis because ionic liquids have negligible vapour pressure, making them non-volatile and environmentally safer, reducing the risk of air pollution and flammability. The advantage of ionic liquids is that they allow reactions at higher temperatures without evaporation issues. The tunable properties of ionic liquids enhance solubility, reactivity, selectivity, improve yield, and minimize side reactions. Ionic liquids also stabilize reactive intermediates, reduce byproducts, and are recyclable, making the process more sustainable and efficient compared to traditional solvents for the synthesis of nitrogen heterocycles.

6. Challenges and Future Prospects

The catalytic application of ionic liquids in organic transformation is of immense benefit; however, high cost, high viscosity, and the selection rule for ionic liquids pose significant challenges to the investigators. The use of imidazolium systems with BF₄ anions exhibits serious drawbacks to the aquatic ecosystem due to the release of hazardous HF during recycling. The current limitations are overcome by the design of task-specific ionic liquids that facilitate easier catalyst recovery and expand substrate scope through the use of renewable feedstocks. Future research into the development of ionic-liquid-assisted isocyanide-based multicomponent reactions, particularly Ugi or Passerini reactions, for the construction of five-membered nitrogen heterocycles has opened new avenues in heterocyclic chemistry, offering environmentally friendly and efficient synthetic pathways. We believe that this review would attract the worldwide researchers to develop novel strategies to afford a broad range of heterocycles for varied applications using suitable, eco-friendly, and high-performing ionic liquids.