Green multicomponent synthesis of pyrano[2,3-c]pyrazole derivatives: current insights and future directions

The past decade has witnessed significant progress in synthesizing structurally diverse and biologically relevant pyrano[2,3-c]pyrazole derivatives through the integration of green methodologies. This review summarizes the recent advances in the green multicomponent synthesis of pyrano[2,3-c]pyrazole and spiro-pyrano[2,3-c]pyrazole derivatives. These include the application of energy-efficient techniques such as microwave and ultrasound-assisted synthesis, benign catalysts and biodegradable composites, solvent selection with a focus on water as a renewable and non-toxic medium, and solvent-free conditions. The review consolidates the current knowledge and future research directions, providing a valuable resource for researchers dedicated to advancing green chemistry practices.


Introduction
In recent years, the eld of organic synthesis has witnessed a remarkable paradigm shi towards sustainability and environmental consciousness.This transformation is illustrated by the emergence of green chemistry, which advocates for the development of eco-friendly and resource-efficient synthetic methodologies. 1,2Among the myriad reactions and strategies in organic synthesis, the multicomponent synthesis of heterocyclic compounds holds a prominent position due to its efficiency and versatility. 35][6] These compounds are composed of fused pyran and pyrazole rings, existing in four distinct isomer arrangements: pyrano[2,3-c]pyrazole, pyrano [3,2-c]pyrazole, pyrano [3,4-c]pyrazole, and pyrano [4,3-c]pyrazole (Fig. 1).However, pyrano [2,3-c]pyrazoles are the most extensively investigated due to the biological signicance of this isomer.These compounds have shown promising antimicrobial, 7,8 anticancer, 9 anti-inammatory, 10 and antiviral properties. 11Additionally, they exhibit the capability to potentially inhibit the activity of the human Chk1 kinase enzyme 12 (Fig. 2).Their structural diversity allows for the modulation of activity by modifying different regions of the molecule, opening up possibilities for structure-activity relationship studies. 13he synthesis of pyrano [2,3-c]pyrazole has, undeniably, been a subject of considerable research efforts, yielding numerous methods and synthetic routes.Yet, the existing body of literature predominantly focuses on achieving high yields and product diversity, oen overshadowing the critical importance of sustainability.Traditional methods for their synthesis oen require multiple reactions and purication steps in harsh reaction conditions, such as high temperatures or strong acids, leading to low yields and potential side reactions.Furthermore, the use of toxic solvents, hazardous reagents, and high energy consumption contribute to environmental pollution, waste generation, and carbon emissions. 2While the exploration of various reaction pathways and synthetic strategies is undoubtedly essential, it is equally imperative to acknowledge the environmental impact of these processes.The past decade has witnessed signicant progress in this area, with researchers developing innovative strategies and employing green principles to access pyranopyrazoles efficiently. 14,15Among the green techniques in organic chemistry are reactions involving solidsupported, bio-and asymmetric catalysis and synthesis, 16,17 water and other green solvents, 2 ionic liquids (ILs) or without solvents, microwave, ultrasound, ultraviolet (UV), and ow reactors. 18,19ne of the key strategies employed in the synthesis of pyranopyrazoles is multicomponent reactions.These are one-pot reactions that involve the sequential addition of multiple reagents and catalysts, enabling the rapid assembly of the target molecules in a single reaction vessel. 20,21The general reaction scheme of the one-pot multicomponent reaction of pyranopyrazoles typically involves an aldehyde, malononitrile, a bketoester/ethyl acetoacetate, hydrazine hydrate, and an appropriate catalyst or promoter. 22The reaction proceeds through a series of sequential transformations, including condensation, cyclization, and subsequent rearrangement, yielding the pyranopyrazole product (Fig. 3).MCRs oen proceed under mild reaction conditions, minimizing the need for harsh reagents. 23,24They offer several advantages, including atom economy, step economy, and the simultaneous assembly of multiple building blocks and thus comply with the principles of green chemistry.Furthermore, the one-pot nature of this reaction reduces the number of purication steps required, minimizing potential side reactions and simplifying the overall synthetic process. 25,26umerous preceding review articles have appropriately lauded the progress in pyranopyrazole synthesis through MCRs, 27,28 showcasing ingenious strategies, high yields, and novel applications.In this landscape, our review article aims to stand apart by offering a fresh perspective on the synthesis of pyranopyrazoles through MCRs, one that prioritizes the principles of green chemistry.
In this comprehensive review article, we have meticulously examined a decade's worth of research papers, spanning from 2012 to 2023, in order to provide a holistic overview of the advancements made in the green multicomponent synthesis of pyrano [2,3-c]pyrazoles and spiro-pyrano[2,3-c]pyrazole derivatives.Our primary objective was to focus on research that not only explored various synthetic routes but also adhered to the fundamental principles of green chemistry.Instead of limiting our scope to a single green chemistry principle, we sought out studies that harmoniously integrated multiple eco-friendly strategies, for instance, the application of energy-efficient techniques such as microwave and ultrasound-assisted synthesis, catalyst design using environmentally friendly metals and biodegradable composites, solvent selection with a focus on water as a renewable and non-toxic medium, and solvent-free conditions.This discerning approach allowed us to select and showcase papers that exemplied the multifaceted nature of sustainable synthesis.In our review, we have placed particular emphasis on elucidating the key ndings and novel methodologies outlined in these selected papers.Through this extensive exploration, we aim to offer readers a comprehensive and insightful understanding of the green multicomponent  synthesis of pyranopyrazoles, while highlighting the pivotal role of sustainable chemistry in shaping the future of organic synthesis.

Physical methods
Energy inputs play a crucial role in organic synthesis, inuencing reaction rates, yields, selectivity, and overall process efficiency.Conventional heating supplies the necessary energy to surmount activation barriers.However, to maintain a balanced energy system during prolonged reaction times, a cooling medium such as a water reux condenser is essential for the efficient transfer of thermal energy. 29Reaction temperatures can be high, which may cause undesired side reactions that can be less sustainable compared to green approaches like microwave heating, ultrasound irradiation, concentrated solar radiation, etc.These alternative energy inputs are characterized by their potential to reduce energy consumption, minimize waste, and promote sustainable practices.They can also lead to shorter reaction times, higher yields, and improved product selectivity. 30

Microwave-assisted technique
Microwave irradiation provides rapid and selective heating of reaction mixtures using electromagnetic waves.They accelerate reactions due to direct interaction with polar molecules and lead to shorter reaction times as well as increased yields making the process energy-efficient. 31,32athrotiya et al. 33 synthesized a series of indol-3-yl substituted pyrano[2,3-c]pyrazoles using two different methods: a conventional three-component reaction under reux conditions and a four-component reaction, with the assistance of microwave irradiation (Scheme 1).In the threecomponent reaction, 2-phenyl-1H-indole-3-carbaldehydes, malononitrile, and 3-methyl-1H-pyrazol-5(4H)-one were condensed in ethanol with piperidine.The reaction mixture was gradually heated and reuxed for 2-2.5 h.On the other hand, the four-component reaction involved the condensation of 2phenyl-1H-indole-3-carbaldehydes, ethyl acetoacetate, malononitrile, and hydrazine hydrate in ethanol with NaOH as the catalyst.Microwave irradiation at an output power of 280 W was applied to the mixture for a period of 5-6 min.A comparative analysis of the two methods revealed that microwave irradiation proved to be more effective in accelerating the reactions.
A regio-and stereoselective method for synthesizing heteroaryl pyranopyrazoles was developed by J. Parmar and colleagues. 34The procedure involved a multi-component domino reaction using indole-or quinolcarbaldehyde, pyrazolone, and enol ethers in triethylammonium acetate (TEAA) under the inuence of microwave irradiation (Schemes 2 and 3).microwave-assisted multicomponent approach, involving ethyl acetoacetate, hydrazine, malononitrile, and aldehydes using triethylamine base (Scheme 4).Assessing the two approaches according to yields obtained and reaction completion times, the researchers noted that although the conventional heating method yielded slightly superior results in terms of product yields, the microwave-assisted synthesis notably and substantially reduced reaction durations.using an MCR approach.Various substituted aldehyde derivatives were combined with 2,4-dinitrophenyl hydrazine, ethyl acetoacetate, and malononitrile using SnCl 2 as the catalyst (Scheme 6).Two methods were compared: conventional heating and microwave irradiation.In the conventional method at 80 °C, the reaction took 1.4 h and resulted in an 80% yield.
However, the microwave irradiation method produced the desired product in just 25 min, with an 88% yield.
In a very recent study by Yallappa et al., 38 potassium t-butoxide, a base catalyst, was employed in a one-pot fourcomponent approach to synthesize various 4H-pyrano[2,3-c] pyrazoles (Scheme 7).The condensation reaction involves a mixture of ethyl acetoacetate, hydrazine hydrate, malononitrile, and aromatic aldehydes in the methanol solvent with a catalytic amount of KOtBu.Microwave irradiation led to faster reaction completion (less than 5 min) and excellent yields for the synthesized compounds compared to conventional stirring at room temperature (Table 1).While microwave-assisted heating signicantly reduces reaction times, most reactions still yielded comparable results to those achieved with conventional reux heating.It is worth noting that there were instances where the yield was not as substantial.Hence, as a note to future research, it is essential to consider all factors, as they may not depend solely on the heating technique, but also on variables such as substituents, solvents, and catalysts.

Concentrated solar radiation technique
The concentrated solar radiation method involves focusing sunlight using a solar collector concentrated onto a reaction vessel with optical instruments and a temperature sensor to achieve the desired temperature for a chemical reaction.However, there is limited control over reaction temperature owing to the dependence on sunlight availability.These are also specic to certain reactions and geographical locations. 39,40atin U. Gadkari et al., 41 showcased the utilization of concentrated solar radiation for the synthesis of pyranopyrazole derivatives.This involved a solvent-free and catalyst-free approach employing a multi-component strategy.The aldehyde, ethyl acetoacetate, malononitrile, and hydrazine hydrate mixture was placed in a round-bottom ask and continuously stirred on a magnetic stirrer under concentrated solar radiation.The precipitate was observed within 3-4 min (Scheme 8).This method resulted in remarkable energy savings of approximately 98% compared to the conventional approach, while also exhibiting exceptional speed and high yields.
Despite having numerous advantages and signicant environmental importance, the CSR method has not received extensive research attention.Therefore, efforts should be directed toward comprehending its characteristics to harness its complete potential.

Ultrasound irradiation technique
Ultrasonic waves induce cavitation, leading to the formation and collapse of bubbles, which create localized high temperatures and pressures, enhancing reaction rates.It reduces the need for elevated temperatures and potentially hazardous reagents while improving selectivity and purity due to milder reaction conditions. 42,43n efficient four-component synthesis of dihydropyrano[2,3c]pyrazole derivatives using ultrasound irradiation was reported by Ablajan et al. 44 The desired compounds were successfully synthesized with favorable to exceptional yields using a ceric ammonium nitrate (CAN) catalyst in a water medium under the inuence of ultrasound irradiation (Scheme 9).
For the Ultrasound-assisted reactions, we witness shortened reaction durations, with aqueous media commonly employed as the solvent, rendering these reactions environmentally friendlier in multiple aspects.However, there remains ample room to investigate the impact of Ultrasonic irradiation further in the organic synthesis of pyrano-pyrazoles, particularly concerning their medicinal and biological properties.

Catalysis in green processes
In organic synthesis, catalysis offers several advantages, including increased reaction rates, enhanced selectivity, and milder reaction conditions.It plays a pivotal role in reducing energy consumption, minimizing waste, and improving overall process efficiency.The key difference between conventional and green catalysis lies in their environmental impact.Conventional catalysts may involve toxic or costly materials, while green catalysts emphasize sustainability, utilizing biodegradable, renewable, or benign substances, resulting in more eco-friendly and efficient organic synthesis processes. 30,48,49

Nano-catalysis
Nano-catalysis has evolved to provide rapid and sustainable routes, reducing waste and increasing reusability due to their high surface-to-volume ratio, allowing greener and more efficient synthesis of diverse heterocyclic structures. 50They oen exhibit high selectivity, allowing for precise control over the desired reaction pathways, thereby minimizing the formation of unwanted byproducts.Furthermore, they are highly stable and durable, withstanding harsh reaction conditions and prolonged use without signicant loss of activity. 16,51,52 U. Tekale and coworkers 53 documented a method for synthesizing 4H-pyrano[2,3-c]pyrazoles, utilizing a zinc oxide nanoparticle-catalyzed multicomponent water-based reaction.The crystalline structure of the ZnO nanoparticles was conrmed through XRD investigations.Moreover, TEM analysis unveiled particle sizes spanning from 50 to 100 nm, creating an extensive surface area that facilitated the accelerated formation of the desired products. Emloying an aqueous medium, a fourcomponent coupling reaction involving ethyl acetoacetate, aromatic aldehyde, malononitrile, and hydrazine hydrate, along with ZnO nanoparticles as a catalyst, resulted in the production of pyranopyrazoles with elevated yields in a brief timeframe (Scheme 13).
Azarifar et al. 54 developed highly efficient magnetic lanthanum strontium magnesium oxide (La 0.7 Sr 0.3 MnO 3 or LSMO) nanoparticles with remarkable swiness.Magnetic nanoparticles (MNPs) are easily accessible, enabling their widespread use due to their stable catalyst linkages.Additionally, their simple separation using an external magnetic eld streamlines the purication process.Moreover, they exhibit lower catalyst leaching compared to other material-supported catalysts, making them a highly promising choice for catalytic applications. 55,56The composite catalyst here, La 0.7 Sr 0.3 MnO 3 ,  15 min.The catalyst could be reused up to fourteen times with no signicant loss of catalytic activity.
Soleimani et al. 59 developed Fe 3 O 4 @SiO 2 core-shell nanoparticles as a magnetically separable nanocatalyst for a fourcomponent coupling reaction.This reaction involved the condensation of aromatic aldehydes, malononitrile, ethyl acetoacetate, and hydrazine hydrate in H 2 O/EtOH mixture to produce substituted pyranopyrazoles in high yields within 40 min (Scheme 17).The Fe 3 O 4 @SiO 2 NPs had a roughly spherical morphology with some agglomeration.XRD analysis conrmed that the silica-coated iron oxide NPs retained the magnetic properties of the bare Fe 3 O 4 NPs.The catalyst demonstrated durability and could be reused up to ve times without signicant loss in catalytic activity.
A highly efficient and recoverable nanomagnetic catalyst, Fe 3 O 4 @SiO 2 @OSi(CH 2 ) 3 -N(3-pyridoyl sulfonic acid) semicarbazide (FSiPSS), was designed, synthesized, and characterized using various techniques by Beiranvand et al. 60 for the synthesis of diverse pyranopyrazole derivatives through a one-pot four-component condensation reaction of ethyl acetoacetate, hydrazine hydrate, aromatic aldehydes, malononitrile under ultrasonication (Scheme 18).The catalyst's specic surface area was found to be 35.6 m 2 g −1 with an average size between 13.66 and 35.86 nm to facilitate the catalyst's effectiveness in carrying out the desired synthesis.The reaction achieved very short reaction times, good to high yields, and easy work-up.This novel nanomagnetic catalyst shows great potential for efficient and sustainable synthesis processes.
Maddila et al. 61 introduced a ceria-doped zirconia catalyst prepared via the wet impregnation method for the synthesis of pyranopyrazoles with remarkable yields within 15 min at room temperature (Scheme 19).The four-component reaction, involving hydrazine hydrate, ethyl acetoacetate, malononitrile, and substituted aldehydes in ethanol, was efficiently catalyzed using CeO 2 /ZrO 2 .The catalyst could be easily recovered through ltration and recycled for up to six cycles while maintaining its efficiency.
Patel et al. 62 utilized a recyclable nano-SiO 2 catalyst to prepare pyrano[2,3-c]-pyrazoles.The catalyst was synthesized from wheat straw agricultural waste through the sol-gel process.The catalyst exhibited a uniform distribution and a spherical shape, with a crystallite size ranging from 100 to 200 nm.BET analysis revealed important properties, including a surface area of 215.6 m 2 g −1 , a pore volume of 0.269 cm 3 g −1 , and a pore diameter of 7.1 nm.The reaction involved hydrazine hydrate, malononitrile, aromatic aldehydes, and ethyl acetoacetate in water as a multi-component system.Notably, using only 10 mol% of the nanocatalyst yielded the best performance, achieving excellent yields within 40 s (Scheme 20).The catalyst remained stable for up to ve runs without a signicant decrease in activity.
Shakiba Shahbazi et al. 63  spherical shape, as observed in the FE-SEM image.Excellent yields and quick reaction times were obtained from the reaction, which can be attributed to the Bronsted-Lowry base's strong catalytic activity and high surface-to-volume ratio.
Mishra et al. 64 presented a novel method for synthesizing pyranopyrazole scaffolds employing nanomagnetic iron material as a reusable catalyst in an aqueous solvent under the ultrasonication technique.The protocol involved the condensation of malononitrile, hydrazine hydrate, ethyl acetoacetate, and substituted aldehydes with the CoFe 2 O 4 catalyst (Scheme 22).Remarkably, both electron-withdrawing and electrondonating groups exhibited good reactivity and provided significant yields of the desired products.
Sedighinia et al. 65 introduced a highly efficient and recyclable nanocatalyst called yttrium iron garnet (Y 3 Fe 5 O 12 ; YIG).This catalyst was utilized for the synthesis of pyranopyrazoles through the combination of hydrazine hydrate, ethyl acetoacetate, malononitrile, and substituted aldehydes under solventfree conditions at 80 °C.The reaction exhibited excellent yields within a short duration of 20 min (Scheme 23).The nanocatalyst could be easily recycled and maintained its activity for up to eight runs.
Prakash Chhattise et al. 66 used a hydrothermal technique to synthesize nanostructured ZnO.The catalytic activity of this nanostructured ZnO was evaluated as a heterogeneous catalyst in the multicomponent synthesis of pyranopyrazole derivatives (Scheme 24).XRD analysis conrmed the formation of highly crystalline ZnO with a wurtzite structure.FESEM analysis revealed the formation of submicron-sized spherical structures resembling marigold owers.Remarkable yields were achieved within 15-30 min (Table 3).
The eco-friendliness of nano-catalyst production relies on factors like selecting non-toxic materials and preparation techniques, impacting energy consumption. 67Recent research emphasizes creating safe, sustainable nano-catalysts through energy-efficient methods like microwave and ultrasoundassisted synthesis, solvent-free synthesis, template-directed synthesis, and more. 68Nevertheless, our primary focus is optimizing reaction parameters to increase pyranopyrazole yields using nano-catalysts tailored to specic applications, all within shorter reaction durations.Future investigations should prioritize cost-effective and environmentally benign metal/ nanoparticle catalysts for pyranopyrazole synthesis, building upon the aforementioned references.

Organocatalysis
Organo-catalysis involves the use of small organic molecules as catalysts to facilitate chemical transformations.It's valuable in organic synthesis due to its compatibility with mild reaction conditions, oen avoiding the need for transition metals.This approach offers advantages like atom economy, reduced environmental impact, and improved selectivity.Madhusudana Reddy and colleagues 71 used an easily accessible, non-toxic, and environmentally friendly catalyst Glycine to synthesize pyranopyrazoles from ethyl acetoacetate, hydrazine hydrate, aldehyde, and malononitrile in aqueous medium at 25 °C in 5-20 min (Scheme 25).
Zolgol et al. employed biological organocatalyst isonicotinic acid under solvent-free conditions 72 to synthesize 1,4dihydropyrano[2,3-c]pyrazoles through a four-component condensation reaction involving ethyl acetoacetate, malononitrile, aryl aldehydes, and hydrazine hydrate, carried out at a temperature of 85 °C (Scheme 26).Remarkably, the catalyst retained its catalytic efficacy within the boundaries of experimental error for four consecutive runs.
Tayade et al. 73  characterized by its simplicity and environmentally friendly nature, leading to the production of pyranopyrazoles with moderate to excellent yields in a short span of reaction time (Table 4).
Organo-catalysis stands out as the safest and most efficient method to synthesize pyranopyrazoles offering mild reaction conditions with impressive yields.It can be done in aqueous media, thus, eliminating the need for toxic solvents and reducing conventional reaction time.This eco-friendly approach warrants further exploration in advancing pyranopyrazole synthesis.

Bio-catalysis/natural catalysis
Bio-catalysis involves the use of natural catalysts like enzymes to drive chemical reactions and has gained prominence due to its specicity and compatibility with mild conditions, minimizing byproducts and waste.In organic synthesis, it offers regio-and stereoselectivity, enabling complex transformations. 75uo et al. 76    Arefeh Dehghani et al. 79 effectively synthesized dihydropyrano[2,3-c]pyrazoles using nano-eggshell/Ti(IV) as a catalyst through a four-component reaction comprising ethyl acetoacetate, hydrazine hydrate, malononitrile, and aldehydes at room temperature under solvent-free conditions (Scheme 36).The technique offers notable advantages such as mild reaction conditions, quick reaction times, simple purication processes, excellent yields, the potential for catalyst reusability, and the removal of harmful organic solvents.
Bora and coworkers 80 showcased the dihydropyran-[2,3-c]pyrazole synthesis utilizing Aspergillus niger lipase as a catalyst.This lipase enzyme adeptly facilitated a four-component condensation reaction involving ethyl acetoacetate, hydrazine hydrate, malononitrile, and either aldehyde or ketone.Remarkable yields were achieved at a temperature of 30 °C (Scheme 37).Furthermore, the biocatalyst demonstrated reusability for up to three cycles.
Shinde and his research team 81 successfully developed a synthesis method using a natural catalyst made of bael fruit ash.Its efficacy was evaluated in synthesizing pyrano[2,3-c]pyrazoles and pyrazolyl-4H-chromene derivatives in an aqueous medium through four-component reactions involving ethyl acetoacetate, malononitrile, hydrazine hydrate, various aldehydes.These reactions were conducted at room temperature for a duration of 30 min (Scheme 38).The method was notably suitable for producing pyrazolyl-4H-chromenes, yielding excellent results ranging from 86% to 94% for different salicylaldehydes (Table 5).Impressively, the BFA catalyst demonstrated stability across ve cycles, exhibiting minimal loss of activity.
Bio-catalysis is an entirely eco-friendly method that eliminates reliance on metal catalysts and emphasizes natural products.Yet, further research is necessary to enhance reaction speed through a comprehensive understanding of catalytic efficiency and mechanisms.

Green solvents
Green solvents are crucial in organic synthesis due to their reduced environmental impact and health hazards compared to conventional solvents.Their use aligns with eco-friendly principles, driving cleaner and more sustainable organic synthetic practices. 82For instance, water, supercritical CO 2 , and ionic liquids have gained prominence.They offer advantages like improved atom economy, lower toxicity, and easier product separation. 83

Water
Water has emerged as a prominent green solvent in organic synthesis due to its abundance, low cost, and environmental benignity.Water's characteristics, including its high polarity and unique hydrogen bonding, facilitate various reactions.Advantages include improved safety, minimized waste, and facile product isolation.It promotes eco-friendly synthesis for heterocyclic compounds such as pyrano-pyrazoles by enabling milder conditions and reducing the need for toxic organic solvents, thereby aligning with green chemistry principles. 84,85 series of pyranopyrazole derivatives were synthesized in an aqueous medium by Vasuki and Kumaravel 86 through the multicomponent strategy.At room temperature, the reaction was carried out between ethyl acetoacetate, hydrazine hydrate, malononitrile, and various benzaldehyde in the presence of piperidine.Water proved to be the most effective solvent when compared to typical organic solvents (Scheme 39).
Siddekha et al. 87 investigated the inuence of different solvents dichloromethane (DCM), acetonitrile (CH 3 CN), ethanol, and water, for a model reaction of pyrano[2,3-c]pyrazole synthesis, employing a small amount of imidazole as an organocatalyst.Among the solvents tested, water demonstrated the highest yields within a relatively short reaction time of 20-30 min.Consequently, the aromatic aldehydes, malononitrile, hydrazine hydrate, ethyl acetoacetate, and imidazole were dissolved in water and the reaction mixture was heated on a preheated hot plate at 80 °C for 20-30 min (Scheme 40).

Review RSC Advances
Using ZnO nanoparticles at room temperature, Sachdeva and Saroj 88 investigated the solvent effect for the synthesis of pyrano[2,3-c]pyrazole-5-carboxylate derivatives.While yields in ethanol and methanol are poor, the best results are obtained with water (Scheme 41).
Majid Koohshari et al. 90 have outlined a method for synthesizing pyrano[2,3-c]pyrazoles where dialkyl 3-oxopentanedioate, Scheme 39 Synthesis of pyranopyrazole derivatives in aqueous medium using piperidine.aromatic aldehydes containing electron-withdrawing groups were taken, along with hydrazine hydrate and malononitrile.The reaction takes place in a water/ethanol mixture without the need for a catalyst (Scheme 43).This method was effectively used to produce the spiro-pyrano[2,3-c] pyrazoles from carbonyl compounds, isatin derivatives, and acenaphthenequinone (Scheme 44).
Under the ultrasound irradiation method, Priya M. Khandare et al. 93 synthesized pyranopyrazoles in an aqueous medium using lanthanum(III) nitrate as a catalyst.The reaction conditions were optimized by performing the model reaction of 4hydroxybenzaldehyde, ethyl acetoacetate, hydrazine hydrate, and lanthanum(III) nitrate under different conditions.Using the ultrasonication method and water as a solvent, high yields were achieved in a short time (Scheme 48).
A series of thiadiazole-pyranopyrazole derivatives was amalgamated by M. Reddy et al. 94 via the multicomponent reaction of 5-methyl-1,3,4-thiadiazole-2-thiol, hydrazine hydrate, ethyl 4chloro-3-oxobutanoate, malononitrile, and aryl aldehydes using K10 clay as a green catalyst and ethanol-water as solvent media (Scheme 49).Furthermore, the reaction was also conducted in solvent-free media, leading to low yields with impurities.Solvent-mediated reactions, however, resulted in quantitative yields with no byproducts or impurities.
Samahe Sadjadi et al. 95 examined the catalytic activity of a ternary hybrid catalyst including HPA (heteropolyacids), LDH (layered double hydroxides), and SBA-15 (mesoporous silica) for the development of pyranopyrazole and spiro-pyranopyrazoles derivatives in aqueous media.A mixture of hydrazine hydrate or phenylhydrazine, ethyl acetoacetate, malononitrile, and aldehyde in the presence of LDH/SBA/HPA was reuxed in water for 15 min (Schemes 50 and 51).
G. Kargar and coworkers 97 synthesized pyranopyrazole derivatives in an aqueous medium using a multi-core catalyst Fe 3 O 4 @NFC@Co(II) from ethylacetoacetate, hydrazine hydrate, aldehyde, malononitrile, and Fe 3 O 4 @NFC@Co(II) with vigorous stirring at 50 °C, resulting in excellent yields of the pyranopyrazoles in a short time (Scheme 53).
Fatemeh Mir et al. 98 reported the synthesis of dihydropyrano [2,3-c]pyrazole derivatives using a reusable Fe 3 O 4 @THAMpiperazine catalyst.The reaction is carried out in an ethanol/ water medium, where initially 3-methyl-2-pyrazoline-5-one was precipitated using the reaction between hydrazine hydrate, and ethyl acetoacetate at room temperature, to which then aromatic aldehydes, malononitrile, Fe 3 O 4 @THAM-piperazine were added to the reaction mixture and stirred for the suitable time at 60 °C (Scheme 54).
Given its safety, lack of toxicity, and natural abundance, water as a solvent offers a promising direction for pyranopyrazole synthesis.Nonetheless, careful selection of reaction parameters, including temperature, time, and catalyst, is crucial to optimize the yields (Table 6).Variability in mechanisms must be considered and managed accordingly.

Solvent-free synthesis
Solvent-free organic synthesis is an environmentally friendly approach that aims to reduce its ecological footprint by shunning conventional solvents and minimizing waste generation.This method boasts several notable characteristics, including shorter reaction times and simplied purication processes.These attributes confer several advantages, such as heightened safety, increased yield, and cost-effectiveness.][101] An effective solvent-free four-component synthesis of functionalized pyranopyrazoles was developed by Kanagaraj et al. 102 using per-6-amino-b-cyclodextrin as the catalyst.A small amount of per-6-ABCD (0.008 mmol) combined with hydrazine hydrate, ethyl acetoacetate, aldehyde/ketone, and malononitrile yields quantitative yields of pyranopyrazoles in about a minute under solvent-free conditions (Scheme 55).This solid base catalyst can be reused six times without losing any of its catalytic activity.Soleimani and coworkers 108 utilized Fe 3 O 4 @SiO 2 @-Si(OEt)(CH 2 ) 3 @melamine@TC@Cu(OAc) 2 nanomagnetic  it provides the shortest reaction time and the highest reaction yield.Additionally, the use of the magnetic catalyst signicantly reduced the synthesis time of these compounds under solventfree conditions (Scheme 62).S. L. Sangle et al. 109 utilized CuSnO 3 :SiO 2 catalyst, synthesized using a hydrothermal method for the synthesis of pyranopyrazoles through a one-pot, four-component reaction involving aldehydes, malononitrile hydrazine hydrate, and ethylacetoacetate under solvent-free conditions (Scheme 63).This method demonstrated high yield and short reaction time, with an economically available catalyst and easy purication.The catalyst also showed potential as an alternative catalyst for various acidic-mediated reactions.
S. Ganesan and P. Suresh 110 hydrothermally synthesized nitrogen-doped graphene oxide (NGO) and investigated its application as a solid-base heterogeneous catalyst for pyranopyrazoles synthesis.Malononitrile, ethyl acetoacetate, hydrazine hydrate, and different functional groups of substituted aldehydes were combined in a condensation reaction under solvent-free conditions using a grinding technique, yielding high yields of pyranopyrazoles within 2 min (Scheme 64).Notably, the catalyst material exhibited stability and could be recycled and reused for up to eight consecutive cycles with only a trivial decrease in efficiency.
P. Verma et al. 111 devised an eco-friendly approach devoid of metal catalysts, enabling the synthesis of a diverse array of dihydropyrano [2,3-c]pyrazole derivatives.This method involves 3-methyl pyrazolone, methyl arenes, malononitrile, and leverages urea hydrogen peroxide within a multicomponent reaction.Notably, this reaction is carried out under the solvent-free grinding method at ambient temperature (Scheme 65).
V. Sapkal et al. 112 reported an efficient, green, and facile multi-component one-pot synthesis of pyrano[2,3-c] pyrazoles with various aryl aldehyde, malononitrile, ethyl acetoacetate, hydrazine hydrate under solvent-free grinding condition using ionic liquid (NMPyTs) as a catalyst (Scheme 66).A notable advantage of this protocol is its simplicity, solvent-free approach, easy workup, high yield, neat and clean synthesis (Table 7).
The solvent-free approach offers numerous benets, including cost-effectiveness, ease of purication, and excellent yields.It should be explored to optimize reaction time and other factors.Moreover, combining diverse green methodologies might enhance outcomes.

Conclusion
This review integrates several green methodologies that demonstrate their potential in the creation of structurally diverse and biologically relevant pyrano [2,3-c]pyrazole and spiro-pyrano[2,3-c]pyrazole derivatives.The article has analyzed both the notable benets and constraints of these synthetic approaches to highlight forthcoming research directions, which prioritize safer reaction conditions, enhanced environmental factors, increased yields alongside improved selectivity, and the elimination of hazardous precursors, among other factors.
Techniques such as microwave heating, concentrated solar radiation, and ultrasound irradiation have emerged as rapid and energy-efficient alternatives to conventional heating.However, it is imperative that future investigations carefully consider scalability and reaction conditions to ensure practicality and effectiveness.
Catalytic strategies, including nano-catalysis, organocatalysis, and bio-catalysis, have demonstrated unique advantages such as accelerated reactions and improved selectivity, all while maintaining an eco-friendly prole.Nevertheless, sustainable catalyst synthesis and a deeper understanding of their mechanisms are essential to maximize their efficiency in pyranopyrazole synthesis.
The pivotal role of water as a green solvent cannot be overstated, as it enables milder reaction conditions and reduces reliance on toxic organic solvents.Additionally, solvent-free synthesis aligns seamlessly with green principles, offering better results and cost-effective reactions.Exploring emerging green solvents with a keen focus on reaction parameters holds great potential for the synthesis of novel pyranopyrazole derivatives.
While signicant strides have been made in the development of green multicomponent reactions for pyranopyrazole synthesis, there are still ample opportunities for further exploration and advancements.We hope that this comprehensive review article not only serves as a catalyst for further research but also inspires researchers to adopt these green approaches, leading to cleaner and more sustainable processes.
Scheme 25 Synthesis of pyranopyrazole derivatives using Glycine.
Scheme 27 Synthesis of pyranopyrazole derivatives using b-cyclodextrin.
epichlorohydrin as a catalyst and a xed micro-vessel under solvent-free thermal conditions.A mixture of aromatic aldehyde, phenylhydrazine, ethyl acetoacetate, malononitrile, and b-CD/EP was heated at 100 °C without any solvent for the pyranopyrazole synthesis, facilitated by the b-CD/EP catalyst (Scheme 59).For the synthesis of spiro[indoline-3,4 ′ -pyrano(2,3c)pyrazole] derivatives, a solvent-free reaction was conducted by stirring a mixture of phenylhydrazine, malononitrile, isatin, ethyl acetoacetate, and b-CD/EP at 100 °C.The b-CD/EP catalyst served as a stationary micro-vessel, enabling the reaction to proceed (Scheme 60).Dadaei and Naeimi 107 reported the synthesis of pyrano[2,3-c] pyrazole derivatives at room temperature from ethyl acetoacetate, hydrazine hydrate, different aldehydes, and malononitrile, under a solvent-free environment in the presence of CoCuFe 2 O 4 magnetic nanocrystals as a reusable catalyst (Scheme 61).