Applications of pyrazolone in multicomponent reactions for the synthesis of dihydropyrano[2,3-c]pyrazoles and spiro-pyrano[2,3-c]pyrazoles in aqueous medium

Pyrazolone is an important class of heterocyclic compounds with numerous applications in the fields of organic/material/pharmaceutical chemistry, food/textile industry and cosmetics. Dihydropyrano[2,3c]pyrazoles and spiro-pyrano[2,3-c]pyrazoles are synthesized from pyrazolone and hold huge potential in the field of medicinal chemistry because of their wide-ranging biological activities. This review article will summarize the up to date advances on the application of pyrazolone in multicomponent reactions for the synthesis of pyrano[2,3-c]pyrazoles in an aqueous medium.


Introduction
Due to increasing apprehension about an environmental issue, the design and development of a chemical transformation that directs the efficient and practical synthesis of molecular complexity has emerged as one of the most significant ambitions for chemists in industry and academia. 1 In recent years, compared to other step-wise synthetic methods which involved separation, complex purification techniques which utilizes large amount of solvent, reagent, and byproduct, multicomponent reactions (MCRs) have increasingly gained favor as they avoid the waste of solvent, reagent, and product. Multicomponent reactions (MCRs) have provided a useful and important influential implement for the construction of organic compounds and biologically active molecules, in which three or more reactants are mixed in a single operation and result in the formation of a product with the creation of several new bonds. 2,3 From the viewpoint of green chemistry, organic synthesis /organic transformation via multicomponent reaction (MCRs) should need to be designed in such a way that utilizes alternative pathway and materials which are not only environmentally friendly but also be easily available anywhere in bulk quantities at very cheap price. 4 Also, one of the major risks to the environment is due to the chemical waste produced during a chemical process, which is mainly generated from hazardous organic solvents, and therefore, avoiding or minimizing the use of hazardous organic solvents by using green ones is a critically important goal of modern synthetic chemistry. 5,6 In this context, Breslow 7 rediscovered the use of water as a green solvent in organic reactions in the 1980s, and currently, the utilization of water as a reaction medium in catalytic process for the synthesis of either natural products or pharmaceutically active compounds has received considerable attention due to the abundantly available, non-hazardous, nonflammable, unique redox stability and its cheap nature. 8,9,10 Heterocyclic compounds are important bioactive molecules found in nature. Due to their characteristic properties, heterocyclic compounds have a significant application in the pharmaceutical industry. Among heterocyclic compounds, pyrazolones are important compounds with numerous applications in the fields of synthetic organic chemistry, material science, medicinal and pharmaceutical chemistry, food industry, textile industry, cosmetics products, chemical industry, and also as powerful synthon for generating biologically active heterocycles. 11 The medicinal application of pyrazolone includes antipyretic activity (A, B, H) and using water as a reaction medium (Scheme 1). 52 The reaction was carried out at different reaction condition by changing the temperature of the model reaction from 20°C to 90°C and it was found that by increasing the reaction temperature, the yield of the product was increased and it was excellent at 60°C which indicates the best condition for the reaction. The methodology has several benefits such as mild reaction conditions, shorter reaction time, simple work-up procedure, eco-friendly and environmental friendliness.

Scheme 1: Catalyst-free synthesis of spiro[indoline-3,4-pyrano[2,3-c]pyrazoles] 4 in aqueous medium.
In 2012, Mandha and his co-worker described another catalyst-free protocol for the four-component synthesis of pyrano [2,3-c]pyrazole derivatives in good yield via the one-pot reaction of several aromatic aldehydes, malononitrile, hydrazine hydrate, and ethyl acetoacetate in presence of aqueous ethanol as a reaction media at a temperature ranging from 25°C to 100°C (Scheme 2). 53 But upon replacing the hydrazine hydrate with phenylhydrazine, the same four-component reaction strategy to accomplish the pyrano[2,3c]pyrazole derivatives 8 was not observed. However, the preparation of 3-methyl-1-phenyl-1H-pyrazole-5(4H)one 3 from an initial condensation of ethyl acetoacetate and phenylhydrazine and its treatment with aldehyde 5 and malononitrile 2, was found to lead to the desired product in very good yield. Similarly, the preparation of 3-methyl-1H-pyrazol-5(4H)-one 6 alone also results in a better yield of product 7 as compared to the corresponding one-pot four-component reaction. Furthermore, the reaction of substituted isatin, or 9fluorenone, or dialdehyde terephthalaldehyde with malononitrile, and pyrazolone under the same reaction afforded the corresponding product-spiro[indoline-3,4-pyrano [2,3-c]pyrazoles], spiro[fluorine-9,4-pyrano [2,3c]pyrazole], and 4,4 / -(1,4-phenylene)bis(6-amino-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile) in high yield respectively. hydrazine 39 and ethyl acetoacetate 13 in aqueous ethanolic solution under refluxing condition for 7-12 hours. For optimizing reaction condition, the reaction was performed in presence of different ammonium triflates and different solvent system such as MeOH, EtOH, DMF, THF, H2O, and EtOH/H2O. However, the reaction in presence of aqueous ethanol afforded the product in the highest yield. The mechanism suggested by authors for this transformation involves the in situ formation of pyrazolone 41 from ethyl acetoacetate 13 and hydrazine 39 activated by MorT. Then Knoevenagel condensation reaction between aldehyde 5 with malononitrile 2 took place in presence of the catalyst to form α-cyanocinnamonitrile that can undergo Michael addition with pyrazolone 41 resulting in the formation of the final product 40, after cyclization and tautomerization (Scheme 15).
Treatment of several substituted aryl aldehydes 10, malononitrile 2, hydrazine hydrate 9, and ethyl acetoacetate 13 in presence of an aqueous solution of boric acid as a green catalytic system was found to lead to the formation of pyrano [2,3-c]pyrazole derivatives 14 in 70-85% after 10-20 minutes at 70°C (Scheme 16). 66 The interaction of B(OH)3 with water released the H + in an aqueous solution that could effectively catalyze the reaction. Initially, the ethyl acetoacetate 13 was activated by H + and then hydrazine 9 attacked the carbonyl group of the activated ethyl acetoacetate and removed one molecule of H2O. Then, another NH2 group of hydrazine attacked the next carbonyl group of ethyl acetoacetate to give 5-methyl-2,4-dihydro-pyrazol-3-one 16 after removing one molecule of EtOH. In the subsequent step, the reaction of an activated aromatic aldehyde with malononitrile afforded the arylidene malononitrile 15, which can then undergo tandem Michael addition-cyclization reaction with 5-methyl-2,4-dihydro-pyrazol-3-one 16 and yielded the final product 14. By applying this tandem one-pot four-component protocol total of 17 compounds were synthesized in the highest yield.
Recently, Govindaraju and their team introduced citric acid as a biodegradable and reusable catalyst that facilitates the one-pot multi-component strategy for the construction of several dihydropyrano [2,3-c]pyrazole derivatives 47 in good to excellent yield (90-97%) from simple starting material including several aldehydes 5, 4-nitrophenylacetonitrile 46, ethyl acetoacetate 13 and hydrazine 34 in presence of water as green solvent at 25°C (Scheme 18). 68 The methodology offers several benefits like simple workup procedure, mild reaction condition, green catalyst, high yield, and also eco-friendly protocol.

Base catalyzed synthesis
In 2008 Vasuki et al. 69 reported a single step construction of dihydropyrano[2,3-c]pyrazole derivatives 7 in good to excellent yield ranging from 66-94% through the four-component reaction of substituted aldehyde 5, malononitrile 2, hydrazine 34, and ethyl acetoacetate 13 by employing piperidine as a base catalyst in aqueous medium at room temperature within 5-10 minutes (Scheme 19). Not only the aromatic aldehydes but also heteroaromatic as well as aliphatic aldehydes were well tolerated by this method and the yields of the products depended on the substitution in different positions of the aldehydes group. All halogenated substrates afforded the final product in quantitative yield.
A very simple procedure for the one-pot synthesis of several spiro[indoline-3,4-pyrano[2,3-c]pyrazole] derivatives 49 in 80-97% yield via the four-component condensation reaction of substituted isatin 48, malononitrile 2, β-ketoesters 21, and hydrazine hydrate 34 in the water at room temperature for 5 hours by using secondary amine piperidine as a base catalyst has been discovered by Ahadi's group in 2010 (Scheme 20). 70 The investigations carried out for the reaction mechanism involving the initial formation of pyrazolone from 21 and 34 that can then react with the Knoevenagel adduct produced from the reaction of isatin 48 and malononitrile 2, followed by an intramolecular cyclization and tautomerization after which the desired product 49 was obtained. Later, the research group of Kiyani introduced sodium benzoate as an efficient base catalyst that could effectively catalyze the one-pot condensation reaction of aromatic aldehyde 10, malononitrile 2, hydrazine hydrate 39, and ethyl acetoacetate 13 in presence water as a solvent at room temperature for 30-75 minutes, leads to the formation of dihydropyrano [2,3-c]pyrazole derivatives 50 in 78-94% yield (Scheme 21). 71 Use of water as reaction medium, mild reaction condition, short reaction time, easy isolation, wide substrate scope makes this protocol very significant in terms of synthetic efficiency as well as green chemistry point of view. In 2013, Ilovaisky's group reported the "on water" one-pot three-component reaction of aromatic aldehyde 10, malononitrile 2, and pyrazolone 16 in presence of sodium hydroxide (NaOH) as a basic catalyst at 100°C for the synthesis of several pyrano [2,3-c]pyrazole derivatives 37 in 85-98% yield (Scheme 22). 72 The methodology displays several advantages such as mild reaction conditions, short reaction time, wide substrate scope, high yield of the product, eco-friendly as well as environmentally friendly protocol. By applying this green synthetic protocol, seven compounds possessing electron-rich as well as electron-poor substituents were synthesized in good to excellent yield mainly ranging from 85-98% within a very short reaction time.  73 Not only the aryl aldehydes but also heteroaryl aldehydes were well tolerated by this green strategy and a total of 20 compounds were synthesized in good to excellent yield.
Another achievement has been gained by Chougala and co-workers in 2016, by applying 4dimethylaminopyridine (DMAP) as a base catalyst for the construction of several coumarins based dihydropyrano[2,3-c]pyrazoles 53 in 82-92% yield from the one-pot reaction of substituted chromenecarbaldehyde 51, malononitrile 52, hydrazine hydrate 9 and ethyl acetoacetate 13 in presence aqueous ethanolic solution at room temperature under the stirring condition for 2-3 hours (Scheme 24). 74 A plausible mechanism that explains this transformation starts with the initial formation of coumarin based Knoevenagel product 54 from the DMAP catalyzed reaction of substituted coumarin carbaldehyde 51 and active methylene compound 52 that can then experiences nucleophilic attack from the -OH form of pyrazolone 55 produced in situ in the reaction from ethyl acetoacetate and hydrazine. In the next step, intramolecular cyclization and tautomerization yield the corresponding coumarin-based dihydropyrano[2,3-c]pyrazoles 53 (Scheme 25).   75 Aldehydes 10 possessing several electron-withdrawing and electron-donating groups affect the yield of the product and aromatic as well as heteroaromatic aldehydes afforded the product in excellent yield. The same author also reported the utilization of sodium lactate as an efficient base catalyst for the construction of dihydropyrano[2.3-c]pyrazoles 37 in aqueous ethanolic solution and the reaction starts with the four component treatment of several substituted aldehydes 10, malononitrile 2, ethyl acetoacetate 13 and hydrazine hydrate 9 at room temperature (Scheme 27). 76 The methodology offers several advantages and by using this method 12 compounds were synthesized in 74-94% yield within 10-20 minutes.

Organocatalyzed synthesis
In 2010, the research group of Reddy demonstrated that the utilization of glycine as a non-toxic organocatalyst in the four-component reaction of aldehyde 10, malononitrile 2, hydrazine hydrate 9, and ethyl acetoacetate 13 in presence of water as a solvent at 25°C, afforded the corresponding dihydropyrano[2,3c]pyrazole derivatives 37 in 85-95% yield after 5-20 minutes (Scheme 28). 77 When the reaction was carried out in presence of different solvents like DMF, DCM, EtOH, MeOH; the yield of the product did not increase. However, when the polarity of the solvent system was increased by using water as a solvent the yield of the product increased even though the low amount of the catalyst was used. From the optimization, it was clear that the yield of the product increased as the polarity of the solvent increases. Hence, water was chosen as the best solvent system and the reaction has proceeded very smoothly with all aromatic as well as heteroaromatic aldehydes, and a total of 16 compounds were synthesized.

Scheme 28: Glycine as an organocatalyst for the synthesis of dihydropyrano[2,3-c]pyrazole 37.
A very convenient organocatalytic approach for the construction of alkyl and aryl-substituted dihydropyrano[2,3-c]pyrazoles 7 in 65-93% yield was developed by Mecadon's group. The methodology involves the four component treatment of aldehyde 5, malononitrile 2, hydrazine hydrate 34, and ethyl acetoacetate 13 in a water medium under the influence of 10 mol% of L-proline for 10-20 minutes of reflux. The catalytic activity of L-proline for this transformation was compared by using other catalysts like-γalumina, basic alumina, and KF-alumina. When the reaction was carried out in γ-alumina, basic alumina, and KF-alumina under the same reaction condition, the products were obtained in 42-68%, 45-62%, and 30-59% respectively which was comparatively very low in comparison to L-proline due to which L-proline was found to be the best catalyst for this reaction (Scheme 29). 78 Scheme 29: L-proline catalyzed synthesis of aryl/alkyl-substituted dihydropyrano[2,3-c]pyrazoles 7.
Another successful organocatalytic method for the one-pot construction of dihydropyrano[2,3-c]pyrazole derivatives 37 has been accomplished by Siddekha et al. in 2011. In this regard, imidazole was introduced as an efficient organocatalyst that effectively catalyzed the four-component reactions of aromatic aldehyde 10, malononitrile 2, hydrazine hydrate 9, and ethyl acetoacetate 13 in presence of an aqueous medium at 80°C for 20-30 minutes (Scheme 30). 79 Several electron-withdrawing and electron-donating groups in aldehydes affect the yield of the product. The electron-withdrawing group increases the yield of the product whereas the electron-donating group decreases the yield. A series of a total of 10 compounds in 85-90% yields were obtained by using this eco-friendly protocol. The mechanism for these transformations starts with the protonation of ethyl acetoacetate 13 by imidazole, followed by an intermolecular attack by hydrazine hydrate 9 and subsequent loss of water, and intramolecular nucleophilic attack by -NH2 group on the carbonyl carbon afforded the 5-methyl-2,4-dihydro-pyrazol-3-one 16. Similarly, protonation of aldehyde by imidazole and reaction with 3-imino-acrylonitrile may afford arylidene malononitrile 15. The next addition of 16 to 15 in the presence of imidazole followed by rearrangement yielded the final product 37. The research group of Prasanna L-proline catalyzed one-pot reaction of dialkyl acetylene dicarboxylates 24, malononitrile 52, β-ketoesters 21, and hydrazines 57 by using water as a solvent for the construction of a series of dihydropyrano[2,3-c]pyrazole derivatives 58 under refluxing condition (Scheme 32). 81 This "on water" chemodivergent reaction proceeded through the initial formation of pyrazolone 59 from hydrazine and βketoesters that can undergo Michael addition with acetylene dicarboxylates 24 under the influence of Lproline followed by a subsequent [1,3]  non-volatile, reusable catalysts, a total of 24 compounds were synthesized and the products were formed by a simple workup procedure in 86-96% yield. All substituted aryl and heteroaryl aldehydes were smoothly providing the reaction and the rate of the reactions were depends on the substitutions.  [2,3-c]pyrazole derivatives 50 was prepared within 25 to 50 minutes and the prepared catalyst was found to be very effective for this transformation. A total of 32 compounds were synthesized by this methodology in 70-92% yields (Scheme 38d). 88 for the preparation of dihydropyrano[2,3-c]pyrazole derivatives 7 in presence of water as a solvent under refluxing condition within 35-90 minutes (Scheme 39). All aliphatic and aromatic aldehydes were smoothly undergoing the reaction and the yield of the product ranges from 61-90%. The reaction was also performed in presence of other catalysts like KF-alumina, basic alumina and it was found that the rate of the reaction was faster and the yield of the product was increases when γ-alumina was used as a catalyst. The orders of catalytic activity of the tested catalyst for this transformation are as follows-γ-alumina > KF-alumina > basic alumina.  90 The reaction was also carried out in heating condition. However, the yield of the product was not much increased as compared to the yield of the product obtained at room temperature. By applying this method, 10 compounds were synthesized in 85-90% yield and the catalyst was reused up to 3 cycles with negligible loss in catalytic property.

Scheme 40: Zinc catalyzed synthesis of dihydropyrano[2,3-c]pyrazoles 69.
In 2013, the research group of Niknam reported the three-component synthesis of dihydropyrano [2,3c]pyrazole derivatives 38 from the one-pot reaction of aromatic aldehyde 10, malononitrile 2, and pyrazolone 3 by introducing silica bonded N-propylpiperazine sodium n-propionate (SBPPSP) as an efficient heterogeneous catalyst and aqueous ethanol as a solvent under refluxing condition within very short reaction time (Scheme 41). 91 The simple work-up procedure, mild reaction condition, reusability of the catalyst, wide substrate scope, environmentally as well as eco-friendly nature is the advantage of this method and by using this economically viable method, 10 compounds were synthesized and all the halogenated substrate afforded the product in high yield.  92 The effect of a catalyst on the reaction was also examined by using three types of the catalyst including Fe3O4, and Fe3O4 nanoparticle. However, the best yield of the product was obtained in presence of Fe3O4 NPs due to the greater diffusion of Fe3O4 nanoparticles in the reaction mixture and the catalyst could be easily recovered by using an external magnetic field and the possibility of recyclability was examined for the reaction. From the experiment, it was found that the catalyst could be very efficient for further reaction, leads to a similar yield to the fresh one and the methodology also displays flexibility in tuning the molecular complexity and diversity in a single step. The synthesis of dihydropyrano[2,3-c]pyrazole derivatives 38 can also be obtained via the threecomponent reaction of aromatic aldehyde 10, malononitrile 2, and pyrazolone 3 using silica sodium carbonate (SSC) as a novel catalyst in aqueous ethanolic solution at 80°C for 25-35 minutes (Scheme 43). 93 The catalyst was prepared from the reaction of silica chloride with sodium hydrogen carbonate and it was fully characterized by FT-IR, XRD, XRF, TG-DTA analysis. The efficacy of the catalyst was found to be very high in this reaction and the catalyst could be recovered simply from the reaction mixture. By applying this simple, mild protocol 10 compounds were synthesized with several electron-poor and electron-rich groups in 86-94% yield.

Scheme 43: Preparation of SSC and its application in the synthesis of pyrano[2,3-c]pyrazole 38.
In 2014, Pradhan et al. 94 reported a one-pot four-component condensation reaction of dialkyl acetylene dicarboxylates 24, malononitrile/ethyl cyanoacetate 52, ethyl acetoacetate 13, and substituted hydrazine 39 for the preparation of a series of dihydropyrano[2,3-c]pyrazole derivatives 70 in 85-97% yield by introducing nanocrystalline CuFe2O4 as an efficient catalyst in presence of water that served as a reaction medium at 60°C for 2-3 hours (Scheme 44). The reaction was carried out in presence of different solvents as well as a catalytic system. However, CuFe2O4 was found to be the best catalyst, and water was chosen as the best solvent for this methodology. By using water as the solvent, the protocol worked well for a vast array of substrate scope and a total of 11 compounds were synthesized in good to excellent yield. The several advantages displayed by this methodology include mild reaction condition, short reaction time, eco-friendly, easily recoverable and reusable catalyst, environmentally friendly protocol, broad substrate scope, simple workup procedure etc. Moeinpour and Khojastehnezhad have demonstrated a polyphosphoric acid-functionalized silica-coated nanocatalyst, namely [Ni0.5Zn0.5Fe2O4@SiO2-PPA] for the preparation of dihydropyrano[2,3-c]pyrazole derivatives 37 proceeding through the four component one-pot reaction of aryl aldehyde 10, malononitrile 2, hydrazine 34, and ethyl acetoacetate 13 using water as a solvent at room temperature (Scheme 45a). 95 They also synthesized cesium carbonate supported on hydroxyapatite-coated Ni0.5Zn0.5Fe2O4 magnetic nanoparticles Ni0.5Zn0.5Fe2O4@Hap-Cs2CO3 and the catalytic activity of the catalyst was tested in the one-pot reaction of aromatic aldehyde 10, malononitrile 2, hydrazine 28, and ethyl acetoacetate 21 in aqueous ethanolic solution at room temperature. It was found that the synthesized catalyst could effectively catalyze the reaction in a very short time and results in the formation of several dihydropyrano [2,3-c] In 2015, Saha et al. 97 reported the use of ZrO2 nanoparticle as a heterogeneous and reusable catalyst in the one-pot reaction of various derivatives of aryl aldehyde 10, malononitrile 2, hydrazines 39, and ethyl acetoacetate 13 by introducing aqueous ethanolic solution as a solvent for the preparation of dihydropyrano [2,3-c]pyrazole derivatives 50 at room temperature within 2-10 minutes (Scheme 46). To compare the catalytic activity of ZrO2 in this transformation, the reaction was performed in presence of other catalysts like Et3N, L-proline, piperidine, meglumine, γ-alumina; but most of the reaction required a higher temperature and not environmentally friendly, also the yield of the product was not satisfactory due to which the utilization of ZrO2 provides best alternatives to the reported catalytic system in terms of product yield, reaction time as well as green chemistry point of view.

Scheme 46: Zirconium oxide catalyzed preparation of dihydropyrano[2,3-c]pyrazoles 50.
In 2015, the research group of Soleimani's prepared magnetic Fe3O4@SiO2 core-shell nanoparticle as a heterogeneous catalyst and fully characterized by FT-IR, powder X-ray diffraction, dynamic light scattering, and transmission electron microscopy. The catalytic activity of the prepared catalyst was tested for the fourcomponent reaction of aromatic aldehyde 10, malononitrile 2, hydrazine 34, and ethyl acetoacetate 13 using the aqueous ethanolic solution as a solvent at 70°C and was found to be very efficient that leads to the construction of several dihydropyrano [2,3-c] A simple and highly efficient methodology that described the construction of several dihydropyrano [2,3c]pyrazole derivatives 37 from in situ generated pyrazolone was introduced by Javad et al. in 2016. Preysslerheteropoly acid (H14NaP5W30O120) supported silica-coated NiFe2O4 magnetic nanoparticles (NiFe2O4@SiO2-Preyssler, shortened as NFS-PRS) was prepared in this regard and the catalytic activity was tested by employing it in the reaction of aldehydes 10, malononitrile 2, ethyl acetoacetate 13, and hydrazine hydrate 34 under the influence of water as solvent at room temperature (Scheme 49). 100 The prepared catalyst was found to be very suitable for the construction of 25 derivatives of pyrano [2,3-c]pyrazole in high yield.
A very efficient procedure for the synthesis of dihydropyrano[2,3-c]pyrazole derivatives 12 in 83-93% yield from the one-pot condensation reaction of aromatic aldehyde 10, malononitrile 2, hydrazine hydrate 9, and dimethyl acetylenedicarboxylate 11 by using nanocrystalline ZnZr4(PO4)6 ceramics as an efficient heterogeneous catalyst in aqueous medium at room temperature for 30-42 minutes has been discovered by Javad's group (Scheme 50). 101 In 2020, Mohtasham and Gholizadeh demonstrated the extraction of natural mesoporous silica from horsetail plant as support for the preparation of H3PW12O40 immobilized on aminated epibromohydrin functionalized Fe3O4@SiO2 nanoparticles (Fe3O4@ SiO2-EP-NH-HPA) that could be applied as a heterogeneous nanocatalyst in the one-pot four-component construction of several dihydropyrano[2,3-c]pyrazole derivatives 37 from the reaction of aryl/heteroaryl aldehyde 10, malononitrile 2, hydrazine hydrate 9 and ethyl acetoacetate 13 by using water as a solvent at room temperature (Scheme 57). 108 By applying this operational simplicity, eco-friendly, non-toxic, environmentally friendly protocol, twenty compounds possessing both electron-withdrawing groups as well as electron-donating groups were synthesized in 89-98% yield. The research group of Konakanchi developed a one-pot four-component strategy for the construction of pyrano [2,3-c]pyrazole derivatives 38 in 88-98% yield via ultrasound-assisted condensation reaction of several substituted aromatic aldehyde 10, malononitrile 2, and pyrazolone 3 by using sodium fluoride (NaF) as a catalyst in aqueous methanol at room temperature for 5-10 minutes (Scheme 60). 111 The reaction can proceed through the Knoevenagel condensation of aldehydes and malononitrile, Michael's addition of pyrazolone with Knoevenagel product followed by cyclization and tautomerization reaction. Recently, Kiyani and his groups discovered the utilization of sodium ascorbate as an efficient, environmentally benign heterogeneous catalyst for the one-pot four-component cyclo condensation reactions of several aldehydes 10, malononitrile 2, hydrazine hydrate 9, and ethyl acetoacetate 13 in presence of water as a reaction medium under reflux of 2-25 minutes and the catalytic activity of the reported catalyst was found to be very successful in the transformation of the reactant into the corresponding dihydropyrano [2,3c]pyrazole derivatives 37. The methodology displays several advantages like-use of readily available reactants, operational simplicity, easy isolation of product, green reaction media, use of inexpensive and non-toxic catalyst, eco-friendly protocol, etc (Scheme 61). 112 The reaction mechanism for this transformation begins with the initial formation of pyrazolone from the reaction of hydrazine hydrate and ethyl acetoacetate that can then undergoes Michael addition with the in situ generated arylidene malononitrile from the Knoevenagel condensation reaction of aldehydes with malononitrile under the influence of sodium benzoate. In the final step, an intramolecular cyclization followed by tautomerization afforded the desired product.
In 2017, Patel et al. 119 derived nano-silica from agricultural waste wheat straw and it can be applied as a heterogeneous catalyst for the one-pot preparation of several dihydropyrano [2,3-c]pyrazole derivatives 37 from the four-component reaction of aromatic aldehyde 10, malononitrile 2, hydrazine hydrate 9 and ethyl acetoacetate 13 by using water as a solvent at 80°C (Scheme 67). The catalytic activity of the prepared catalyst was compared with other catalysts and it was found to be very superior to the reported catalyst for this transformation. By applying this catalytic system, 11 compounds were synthesized within a very short reaction time in good to excellent yield ranging from 87-94%. In the same year, the research group of Sachin has developed another nature-derived catalyst for the construction of dihydropyrano[2,3-c]pyrazole derivatives 7 from the in situ generated pyrazolone by employing water as a reaction medium. The synthesis was carried out via the one-pot reaction of several derivatives of aryl/heteroaryl aldehyde 5, malononitrile 2, hydrazine hydrate 34, and ethyl acetoacetate 13 in an aqueous medium at room temperature under the influence of bael fruit ash (BFA) as a natural catalyst (Scheme 68). 120 The presence of metal oxides having active M 2+ , oxide, and hydroxides provides several Lewis basic sites (O 2and OH) along with Lewis acid sites (M 2+ ) that activate the reactants towards the completion of the reaction. Although this is not included in the multicomponent reaction. However, several advantages such as mild reaction conditions, environmentally friendly nature, operational simplicity, low cost, an excellent yield of the product make this methodology very attractive for future application in organic synthesis (Scheme 69). 121 In this reaction WEB plays an important role both as the catalyst as well as a solvent without using any other ligand, base, metal additives, acid, etc.  122 All aromatic, heteroaromatic as well as aliphatic aldehydes, ketones were smoothly undergoing the reaction in the successful transformation to the corresponding product.  124 The catalytic activity of BSA was found to be very efficient for the successful conversion of aldehydes, ketones, and isatins possessing various electron-withdrawing as well as the electron-donating group to the desired product. The utilization of BSA as an efficient catalyst provides an alternate route to metal catalysts as well as finding further applications in the field of synthetic organic chemistry and biocatalysis.  125 The catalytic activity of α-casein was found to be very efficient that lead to the construction of a total of 12 compounds in very high yield and the product could be achieved by a simple work-up procedure without using any other purification techniques.

Conclusions
Because of the marvelous application in synthetic organic chemistry, material science, medicinal and pharmaceutical chemistry, food industry, textile industry, cosmetics products, chemical industry; the exploitation of pyrazolone in organic synthesis has rapidly increased continuously. Tremendous efforts have been devoted over the last decades for the construction of dihydropyrano [2,3-c]pyrazole and spiro[indoline-3,4-pyrano[2,3-c]pyrazole] derivatives based on pyrazolone via several sequential strategies including basecatalyzed, acid-catalyzed, nano catalyzed, and organocatalyzed multicomponent reactions. Development of catalytic synthetic processes by environmentally benign reaction media instead of hazardous materials, volatile organic solvents, and reagents in order to control the production of dangerous byproducts that can affect human health and the environment has been the foremost goal for synthetic chemist in industry and academia. In this regard, the use of water as a replacement of organic solvents in the development of the organic synthetic procedure has received substantial attention due to their abundantly available, nonhazardous, non-flammable, unique redox stability, and cheap nature. Furthermore, the utilization of water in synthetic processes sometimes leads to different modes of reactivity or selectivity which are often difficult to achieve with organic solvents. Given the importance of both topics in organic synthesis, we have summarizes the up to date advances for the synthesis of dihydropyrano [2,3-c]pyrazoles and spiro-pyrano[2,3-c]pyrazoles based on pyrazolone via multicomponent reactions in the aqueous medium. Although remarkable results are obtained, various simple, effective, and concise methodologies are still highly desired and it is significant to expand the scope of the reactions and mildness of the conditions for the synthesis of pyrano[2,3-c]pyrazole derivatives. We hope the reviewed methodology has been beneficial for researchers working in this field and is projected to encompass vital applications to the amalgamation of complex natural products and the design of new pharmaceutical compounds that will be of industrial interest in application to many branches of chemistry.