Advances in Pyranopyrazole Scaffolds’ Syntheses Using Sustainable Catalysts—A Review

Heterogeneous catalysis plays a crucial role in many chemical processes, including advanced organic preparations and the design and synthesis of new organic moieties. Efficient and sustainable catalysts are vital to ecological and fiscal viability. This is why green multicomponent reaction (MCR) approaches have gained prominence. Owing to a broad range of pharmacological applications, pyranopyrazole syntheses (through the one-pot strategy, employing sustainable heterogeneous catalysts) have received immense attention. This review aimed to emphasise recent developments in synthesising nitrogen-based fused heterocyclic ring frameworks, exploring diverse recyclable catalysts. The article focused on the synthetic protocols used between 2010 and 2020 using different single, bi- and tri-metallic materials and nanocomposites as reusable catalysts. This review designated the catalysts’ efficacy and activity in product yields, reaction time, and reusability. The MCR green methodologies (in conjunction with recyclable catalyst materials) proved eco-friendly and ideal, with a broad scope that could feasibly lead to advancements in organic synthesis.


Introduction
The strategy of using sustainable green methodologies to synthesise various heterocycles utilising heterogeneous catalysts is a continuously expanding area of interest for researchers and industries [1][2][3][4]. Over the years, synthetic organic chemists explored many heterogeneous catalysts due to their distinctive characteristics, such as thermal stability, durable absorption ability, selectivity, low toxicity, easy modification, tunable surface and textual properties [5][6][7]. Additionally, easy recovery and recyclability (compared to homogeneous catalysts) sustained interest in them [8][9][10]. The tunable strong acid and base properties and catalytic activity of heterogeneous materials played a crucial role in organic synthesis [10][11][12]. Generally, it is challenging to design and develop eco-friendly, costeffective and stable composites that show good activity. Diverse conceptualisations have proven helpful in interpreting activity associated with different heterogeneous catalysts. In supported catalyst materials, the active phase experience phase-support associations [11]. The surface free dynamics of the active phase, with catalytic support materials and the interfacial free energy between the two constituents, help such interactions. Transition metal oxides possess considerably low surface free energies, similar to support materials like alumina, titania, zirconia, and silica [9][10][11][12]. The active transition metal oxide develops a monolayer through the wetting of the support surface. As transition metals possess large surface free energy, tiny metal particles lead to aggregation, diminishing their surface area [6]. Hence, stabilising the nano-size metal particles necessitates their deposition on the support surface, enabling convenient metal-support synergies. The physical characteristics and morphology are primarily influenced by these interactions with depreciating particle size. Therefore, the nature of the support material significantly controls the catalytic behaviour of metal particles.
On the other hand, multicomponent reactions (MCRs) have steadily gained significance in synthetic organic chemistry [13][14][15][16][17][18][19]. MCRs offer many benefits-e.g., greater yields, high atom efficiency, reduced reaction time, high convergence, minimisation of purification requirements and waste generation-compared to multiple-step syntheses [20][21][22][23][24][25]. Typically, multi-step procedures require the purification of reaction products in each step and demand appropriate solvents and reagents. Hence, such processes generate more chemical waste, affecting the environment [26][27][28]. The one-pot approach, however, uses effective reusable catalysts, green solvents and eco-friendly methods [29][30][31][32]. Using efficient heterogeneous catalyst materials is a progressive approach to generate desired products with high selectivity and atom economy [33,34]. Researchers have made vast progress in designing and developing libraries of bioactive molecules comprising different heterocyclic structures utilising the MCR approach over the past two decades [35,36]. Through the choice of reactants, the MCR approach can actively introduce a chromophore into a scaffold (i.e., scaffold approach) or facilitate a chromogenic event (i.e., chromophore approach) ( Figure 1). These developments encouraged the generation of high-functional and structurally diverse molecules. Many MCRs are achievable utilising flexible and easily available starting materials to permit target compounds, and are thus proving a versatile tool in medicinal, pharmaceutical, agrochemical, computational and material sciences [37][38][39][40]. Heterocycles are important components of many natural materials and are extremely valuable in organic and medicinal chemistry [41][42][43][44][45]. Over the years, biological and therapeutic arenas recognised the importance of heterocyclic scaffolds [46][47][48]. Furthermore, combinatorial chemistry also accelerated the creation of chemical entities with elite structural units. Among the heterocyclic entities, pyranopyrazole moieties have demonstrated remarkable biochemical behaviours and activities which provide a versatile skeleton for drug innovation. Hence, many nitrogen-based, fused structures have been incorporated as building blocks of various pharmacological potent scaffolds [49][50][51]. Pyranopyrazoles are known for their anti-inflammatory, analgesic, antidiabetic, antimicrobial, cholinesteraseinhibiting, antibacterial and anticancer activities, as well as for their efficacy in treating Alzheimer's disease [52][53][54][55][56][57]. Because of this, several cost-effective synthetic protocols for synthesising pyranopyrazole derivatives-utilising less expensive substrates, reusable catalysts, and eco-friendly solvents-have been developed. This review set out to provide insight into the synthesis procedures for different pyranopyrazole analogues via the MCR approach, using various recyclable materials and nanocomposites as catalysts. This study also emphasised the catalyst's efficacy towards the precursors, conversion, product selectivity and reaction time.

Single Metal-Containing Catalysts
Several single metal-based as catalysts have been developed as catalysts for carboncarbon or carbon-heteroatom-making conversions. The cost-effective and eco-friendly supports associated with these metals further enhance their candidacy as one of the mostdesired catalysts for medicinal and chemical productions. The appeal of transitioning to metal-catalysed reactions is due to the robust activity and selectivity achievable. Another advantage of MCRs is their potential to utilise mono metal oxide catalysts and composites entirely.These mono metal oxide catalysts are pigeon-holed with the higher surface-tovolume percentages of the active metal species, improving the material's efficacy. Moreover, highly distributed metal oxide particles are presumed to perform as additional energetic and choosy catalysts more than most materials. Additionally, owing to their extraordinary surface energies, minor particles tend to cumulate easily.
Babaie et al. [59] reported a facile, efficient synthesis of dihydropyrano[2,3-c]-pyrazole derivatives (5) from the reaction of different aldehydes-(1) substituted hydrazine (2), malononitrile (3), and 3-oxoproponoate (4)-catalysed by nanosized magnesium oxide (MgO). A total of 50 mg of nanocatalyst performed well in an aqueous medium for 20 min reaction time at room temperature (RT) and afforded 88-97% yields of the desired products (Scheme 1). Compared with the commercially available MgO, the as-synthesised MgO nanocatalyst showed superior catalytic activity with yield and reaction time. The authors reported excellent yields with the electron-donating and -withdrawing substituents on the aldehydes. Hasaninejada et al. [60] synthesised a novel series of pyrano-[2,3-c]-pyrazole analogues (9) in the presence of SiO 2 supported n-propyl-4-aza-1-azoniabicyclo-[2.2.2]-octane chloride (SB-DABCO). The multicomponent reaction was conducted using various substituted aldehydes (6), different active methylene compounds (7) and 3-methyl-pyrazolone (8) in ethanol as solvent medium (Scheme 2). Excellent yields (90-98%) were obtained using 6 mol% of SB-DABCO catalyst at room temperature for 35 min, due to the relative strength of basic sites and active surface area (~160 m 2 kg −1) . Their protocol offered several benefits including simple handling, greater stability, and an easy workup, and was recyclable up to five runs without loss of catalytic activity. This protocol offered high yields with all three active methylene compounds (malononitrile, methyl cyanoacetate and ethyl cyanoacetate). Shaterian and co-workers [61] developed titanium dioxide as a nanocatalyst for the generation of dihydropyrano-[2,3-c]-pyrazoles (13) through a one-step process. The condensation was carried under solvent-free conditions at RT by reacting the substituted aldehydes (10), malononitrile (3), hydrazine hydrate (11) and ethyl acetoacetate (12)   In 2014, Paul and his co-workers [63] reported the novel synthesis of pyrano [2,3-c] pyrazole derivatives (20) and spiro-pyranopyrazoles (21) using uncapped SnO 2 quantum dots (QDs). The catalyst was synthesised by solvothermal technique, and the resultant catalyst was confirmed by XRD, TEM and SEM spectroscopy analysis. The XRD, SEM, and TEM analyses revealed that the SnO 2 QDs (with an average size of 3.9 nm) had an equally uniform nanoflower spherical shape size (with 100 nm), corresponding to the lattice plane (110). The four-component condensation reaction involved malononitrile (3), substituted hydrazine (16), dialkyl acetylenedicarboxylates (17) and aldehydes (18) or substituted isatins (19) in the aqueous medium. The high Lewis acidic character and surface area of the Sn +4 catalyst (8 mol%) performed well and provided the anticipated target molecules at room temperature for 2.5 h reaction time with excellent yields (89-98%) (Scheme 5). The catalyst material was environmentally friendly and stable for up to six cycles with sustained selectivity and activity. Both aldehyde (89-98%) and isatin (91-95%) substrates were executed well and offered significant product yields. Low catalyst-loading, eco-friendly conditions, a broad substrate scope, a simple workup and the use of a water medium were the advantages of this procedure. Borhade et al. [64] designed a ZnS nanoparticle catalyst by hydrothermal method for synthesising pyrano[2,3-c]-pyrazoles (23). P-XRD, TEM, SEM and BET microscopic spectroscopic analysis validated the structure of the subsequent ZnS nanoparticles. The prepared ZnS nanoparticle's P-XRD pattern displayed a single-phase hexagonal arrangement with crystallite size (20 nm) and was confirmed with TEM and SEM analysis. Furthermore, the BET spectrum revealed that the nanoparticle specific surface area was (84.71 m 2 .g −1 ), the pore volume was (0.0865 cc g −1 ) and diameter was (31.11 Å). The four-component reaction between aromatic aldehydes (22), hydrazine hydrate (11), ethyl acetoacetate (12), and malononitrile (3) under solvent-free and grinding conditions was efficiently accelerated by ZnS nanoparticles, affording excellent yields (87-97%) in 12 min (Scheme 6). The catalyst material could be simply separated by filtration and reused for up to five successive runs without loss of its catalytic activity. The attractive features of this procedure were the low catalyst requirement and recyclability and the mild, eco-friendly solvent-free reaction conditions. Irvani et al. [65] developed novel tin sulfide nanoparticles on activated carbon [SnS-NPs@AC] and explored them as a catalyst preparing pyrano-[2,3-c]-pyrazoles (25). The composite material and solvent influenced the optimised conditions. The spectroscopic analysis (P-XRD, TEM and SEM. TEM and SEM) of the prepared [SnS-NPs@AC] specified that the nanoparticles had a homogeneously spherical morphology and were in the range of (40-90 nm) and (30-70 nm), respectively, which was in agreement with the PXRD (64 nm) outcomes. The multicomponent reaction of 3-methyl-pyrazolinone (8), various aldehydes (24), malononitrile (3) and catalyst in ethanol solvent led to the target compounds at 80 • C for 25 min reaction time with excellent yields (85-91%) (Scheme 7). The nanocatalyst performed eight cycles with sustained activity. The mechanistic scheme comprised Knoevenagel condensation, Michael-type addition, and cyclisation to yield the target products. Zainali et al. [66] published the highly efficient, one-pot, rapid synthesis of pyrano[2,3c]-pyrazole derivatives (28) in the presence of amino-functionalised SBA-15 (SBA-Pr-NH 2 ) catalyst. The multicomponent reaction was performed using arylmethlidenemalononitrile (26), phenylhydrazine (27) and ethyl acetoacetate (12) in ethanol at RT for 8 min with excellent yields (80-95%) (Scheme 8). The possible mechanism described suggested that the intermediate formed through Knoevenagel condensation of phenylhydrazine with ethyl acetoacetate, then underwent Michael addition with arylmethlidene malononitrile to afford the target molecules. Beerappa and his colleagues [67] investigated a novel synthesis of a library of pyranopyrazole scaffolds (32) using N-methyl-morpholine N-oxide-doped silver oxide (NMO-Ag 2 O) catalyst. The condensation reaction was progressed using benzyl halide (29), active methylene compound (30), dialkylacetylenedicarboxylate (31) and hydrazine hydrate (11) in ethanol solvent medium under reflux condition for 1 h reaction time (Scheme 9). The reported mechanism involved the initial benzyl halide being converted into benzaldehyde (33) in the presence of a catalyst. It proceeded with Knoevenagel condensation (34). The obtained pyrazolone (35) involved Michael's addition (36) and was followed by cyclisation (37) to afford target compounds. Patel et al. [68] completed the preparation of pyrano[2,3-c]-pyrazoles (39) by applying a recyclable nano-SiO 2 catalyst. The nano-silica catalyst was synthesised from the agriculture waste of wheat straw via the sol-gel process. The results indicated that the prepared catalyst comprised a spherical shape with uniform distribution and crystallite size range of 100-200 nm. The BET analysis showed the surface area (215.6 m 2 g −1 ), pore volume (0.269 cm 3 g −1 ) and pore diameter (7.1 nm) for the catalyst. The multicomponent reaction involved hydrazine hydrate (11), malononitrile (3), aromatic aldehydes (38) and ethyl acetoacetate (12) in water. Additionally, 10 mol% of nanocatalyst showed the best performance and offered 87-94% yields for 40 min reaction time at 80 • C (Scheme 10). The agriculture waste catalyst was fully stable for up to five runs without significant loss of activity.  (12), substituted hydrazine (40), malononitrile (3) and aldehyde (41) or isatin (42) in the absence of solvent at RT via the grinding method (Scheme 11). Recycling investigation showed no significant reduction in the catalytic activity even after six cycles, giving excellent yields (80-95%). The reaction progressed in sequential steps, involving Knoevenagel condensation and Michael addition, followed by intramolecular cyclisation. Ghasemzadeh et al. [70] reported a novel synthesis of spiro-pyrano[2,3-c]-pyrazole derivatives (49) using Fe 3 O 4 @L-arginine as a heterogeneous catalyst via one-pot manner. The structure of the prepared nanocatalyst was analysed by P-XRD, FT-IR, SEM and VSM spectroscopy methods. SEM investigation indicated that the catalyst particles were made in circular shapes with an average size of (10-15 nm). TEM study confirmed that the morphology and nanoparticle average size (10-20 nm) was established by P-XRD analysis. The four-component condensation carried out between the substituted hydrazines (45), β-keto esters (46), various functional groups substituted isatin (47) and active methylene compound (48) under solvent-free conditions. The use of 8 mol% of nanocatalyst offered excellent yields (86-97%) of the target products at room temperature after a 60 min reaction time (Scheme 12). The nanocatalyst was recycled up to five times without significant loss of its catalytic efficiency. Active methylene compounds, malononitrile and ethyl cyanoacetate endured well, giving high yields. Mianai and co-workers [71] reported the synthesis of novel pyrano-[2,3-c]-pyrazole frameworks (52) in the presence of cobalt nanoparticles (CoNPs) as heterogeneous catalyst. The cobalt nanoparticles were prepared from the aqueous extract of zingiber. SEM analysis showed that the morphology and homogeneous nanoparticles had an average size (20-50 nm). The EDS investigation affirmed the existence of elements in the prepared catalyst. The condensation reaction was carried out between the hydrazine hydrate (11), malononitrile (3), diethyl acetylenedicarboxylate (50) and substituted aldehydes (51) in an aqueous ethanol medium. The use of 0.005 g of nanocatalyst performed well and afforded excellent yields (83-97%) of desired products after a 1 h reaction time at room temperature (Scheme 13). Mild reaction conditions, easy workup, high yields, and reusability were the essential advantages of this approach. Tabassum et al. [72] synthesised a novel series of pyrano[2,3-c]-pyrazoles (55), applying ZnO@PEG as a nanocatalyst. Various aromatic aldehydes having electron-donating/electronwithdrawing substituents (54) were reacted with ethyl acetoacetate (12), hydrazine hydrate (11), and 4-nitro phenyl acetonitrile (53) in ethanol under ultrasound-assisted conditions, affording excellent 87-97% yields in 15 min (Scheme 14). Furthermore, it was noteworthy that the nanocatalyst was recycled and reused for more than five runs with only a minor loss in its activity. Abbasabadi et al. [73] described the highly efficient sulfonic acid-mobilised Fe 3 O 4graphene oxide magnetic catalyst (Fe 3 O 4 @GO). The magnetic catalyst was evaluated for the synthesis of pyrano[2,3-c]-pyrazoles (57) through the one-step, multicomponent reaction of 3-methyl-pyrazolone (8), malononitrile (3) and substituted aldehyde (56) in green solvent ethanol at RT. The nanocatalyst performed significantly and afforded excellent product yields (90-98%) with less reaction time (30 min) (Scheme 15). Heteroaromatic and alkyl aldehydes had longer reaction times and gave lesser yields, as compared to the aromatic aldehydes. The catalyst was recovered from the reaction mixture using a magnet. The material was reused for five runs without significant activity loss Niya et al. reported [74] an efficient Fe 3 O 4 @THAM-SO 3 H material as a reusable heterogeneous catalyst for the one-pot synthesis of pyrano[2,3-c]-pyrazole derivatives (59). The resultant nanocatalyst, Fe 3 O 4 @THAM-SO 3 H, was characterised by spectroscopy systems like FT-IR, P-XRD, TGA, DTA, VSM, FE-SEM, EDS, and TEM analyses. The FESEM and TEM analyses proved that the nanocomposite was spherical and uniform, with good dispersity and average size (14 nm). The multicomponent reaction was carried out between the malononitrile (3), hydrazine hydrate (11), ethyl acetoacetate (12), various aldehydes (58) and 10 mg catalyst in an equal amount of aqueous ethanol solvent media (Scheme 16). This approach offered many benefits: simple handling, easy workup, short reaction time (25 min), the use of green, non-toxic solvents, no need for column chromatography, good-to-excellent yields (69-85%), and a catalyst that was recycled eight times with sustained activity.

With Bi-Metallic Catalysts
Bimetallic substances are well-defined as a combination of two metals, either in composites or attached metal fragments. Subsequently, the construction of bimetallic catalysts is a significant step to take towards improving their properties. These can be as deliberate as catalyst particles designed in nano-sizes ranging 10 to 100 nm. In bimetallic compounds, one element may enhance activity covering the second element's active sites. The use of bimetallic nanoparticles is quite unusual in that it avoids the use of alloy structures. Various procedures involve catalysts preparations that are eco-friendly and environmentally safe, and properties depend on metal oxide loading and scums. In rare circumstances, one metal can be stabilised in a low valence state to support the active metal. However, in highly distributed bimetallic nanoparticles, one can't ignore the partial or overall decrease of this interface when applied to diverse systems.
Maddila et al. [75] developed manganese-doped zirconia (Mn/ZrO 2 ) which was prepared via the wet impregnation method. The spherical morphology and the crystallite size (12-23 nm) of the catalyst material was established by SEM and TEM investigation. Additionally, N 2 adsorption-desorption studies showed the catalyst surface area (194.56 m 2 /g) and pore volume (0.563 cc/g). The Mn/ZrO 2 catalyst was applied for the novel synthesis of two series of pyrano[2,3-c]-pyrazoles (62 and 63) from a one-pot, multicomponent reaction of ethyl acetoacetate (12)/dimethylacetylenedicarboxylate (61), malononitrile (3), hydrazine hydrate (11), aryl aldehydes (60) and ethanol (5 mL) solvent under ultrasound irradiation at 80 • C. Excellent product yields (88-98%) were obtained in 10 min reaction time using Mn/ZrO 2 catalyst (30 mg) (Scheme 17). This reaction sequence involved Knoevenagel condensation, Michael addition and cyclisation sequence. With similar efficiency, the catalyst was reused for up to six cycles. This protocol offered reusability, eco-friendliness, a simple workup and a swift reaction time. Heravi et al. [76] reported an efficient, multicomponent and straightforward preparation of dihydropyrano [2,3-c] (66), Michael addition (67) and was followed by intramolecular cyclisation (69) to yield the desired product. The catalyst was reused five times with sustainable activity. Excellent yields, reusability, simple workup procedure and green solvents were the primary merits of this protocol.  (85-97%) in water at 60 • C for 4 h reaction time. The reaction mechanism proposed that first, a Knoevenagel condensation occurred between hydrazine and ethyl acetoacetate. In the second step, a Michael reaction occurred between malononitrile and diethyl acetylenedicarboxylate, possibly due to Cu 2+ active sites. The above two intermediates cyclised together via intramolecular action, facilitated by the Fe 3+ Lewis acidic sites and Cu 2+ active sites. Unsatisfactory yields (12-43%) of the desired products were obtained by the replacement of the ethyl acetoacetate (36) to the dialkyl acetylenedicarboxylate (46). This protocol offered several benefits, such as the simple workup, highly functional group tolerance, avoidance of harmful solvents, eco-friendly conditions, and significant yields. Zolfigol et al. [78] successfully prepared an efficient and stable nano-Fe 3 O 4 @SiO 2 @(CH 2 )3-Imidazole-SO 3 HCl as a magnetic catalyst. Using FT-IR, DTA, TGA, SEM, SEM-EDX, TEM, BET, P-XRD, and ICP analysis, the authors established the prepared catalyst structure. TGA and DTA analyses showed a 2% weight loss and thermal decomposition at 550 • C in three stages. The presence of nanocatalyst-expected elements, C, Cl, Fe, N, O, S and Si, was confirmed by EDX analysis. The nanocatalyst P-XRD pattern exhibited crystallite size (40 nm), in good agreement with TEM and SEM analysis (12.42-57.12 nm). The BET spectrum of nanoparticles showed the specific surface area (129 m 2 g −1 ), pore volume (0.281 cc g −1 ) and diameter (8.77 Å). The activity of the nanocatalyst was assessed on the three-component reaction of varieties of aldehydes (76), malononitrile (3), and 3-methyl-pyrazolineone (8) to synthesise dihydropyranopyrazole derivatives (77). Remarkably, 85-98% of the target yields were obtained under solvent-free conditions with 0.0007 g of catalyst at RT for <90 min (Scheme 20). Both aromatic and heteroaromatic aldehydes, bearing electron-donating or electron-withdrawing groups, were well tolerated and gave the products' high yields. The nanocatalyst was recovered by simple magnetic separation and reused for six cycles with only a minor loss of activity. Fatahpour et al. [80] developed a nano-thin film, Ag/TiO 2, as a recyclable catalyst for the preparation of pyrano[2,3-c]-pyrazoles (81) from the four-component reaction between ethyl acetoacetate (12), malononitrile (3), structurally substituted aldehydes (80) and hydrazine hydrate (11). The nanocatalyst performed well with various aldehydes to give 26 dihydropyrano-[2,3-c]-pyrazole derivatives with excellent yields (78-93%) at 70 • C for 55 min using aqueous ethanol (Scheme 22). The proposed reaction mechanism involved the Knoevenagel condensation, Michael addition and intramolecular cyclisation via tautomerisation to yield the desired products. Furthermore, the nano-film catalyst was stable and able to be reused ten times with sustained activity. Uderji et al. [81] reported a new, high-surface-area (509.5 m 2 /g) mesoporous catalyst (Fe 3 O 4 @FSM-16-SO 3 H) for the preparation of novel dihydropyrano-[2,3-c]-pyrazole scaffolds (83). FESEM study showed that the nanoparticles had a spherical morphology with size < 100 nm. The target molecules were prepared by a multicomponent reaction between malononitrile (3), 3-methyl-pyrazolone (8) and aldehydes (82)  A facile, three-component reaction of malononitrile (3), 3-methyl-pyrazolinone (8), and aromatic aldehydes (84) leading to pyranopyrazole derivatives (85) progressed well under a solvent-free condition in 120 min at 80 • C with the aid of a low catalytic amount (0.003 g) of Fe 3 O 4 @TiO 2 @(CH 2 ) 3 OWO 3 H via one-pot manner (Scheme 24) [82]. The prepared novel catalyst was assessed by several techniques, including SEM, EDS, FT-IR, P-XRD, and VSM analysis. SEM analysis specified that the catalyst showed uniform spherical shape particles with an average size (34-91 nm), which was in good agreement with XRD investigation. The EDX study confirmed C, Fe, O, Ti and W in the nanocomposite. Additionally, SEM and VSM showed that the deposit procedure improved particle size and reduced the catalyst material's magnetic possessions. The MCR proceeded smoothly, with a domino Knoevenagel and Michael addition via cyclisation reaction. The catalyst was stable for five cycles with no marked change in the activity. The merits of this protocol included the simple workup procedure, superior yields (78-92%), swift reaction time and reusability.
A new protocol for the synthesis of pyranopyrazole scaffolds (87) with nanomagnetic iron material [CoFe 2 O 4 ] as a reusable catalyst in aqueous solvent was described by Mishra and co-workers [83]. The one-pot approach, in the presence of a catalyst (0.05 g), involved malononitrile (3), hydrazine hydrate (11), ethyl acetoacetate (12) and substituted aldehydes (86), and used ultrasound irradiation for 5 min (Scheme 25). Both electron-withdrawing and electron-donating groups worked well and gave significant yields of the products. The probable mechanism proceeded with a tandem reaction between hydrazine hydrate and ethyl acetoacetate, resulting in prompt production of an intermediate (pyrazolone) and aromatic aldehyde and an active methylene group to produce Knoevenagel adduct. Further, Michael addition of the intermediate pyrazolone to Knoevenagel adduct, followed by intramolecular cyclisation and rearrangement, yielded the target molecule. A highly efficient and eco-friendly magnetic silica-supported propylamine/molybdate composite (Fe 3 O 4 @SiO 2 /Pr-N=Mo[Mo 5 O 18 ]) was designed by Neysi et al. [85] for the preparation of novel pyrano[2,3-c]-pyrazole analogues (91). The catalyst complex's core shell was assessed using TGA, FT-IR, SEM-EDX, VSM, and P-XRD analysis. The TEM and SEM analysis revealed a spherical particle distribution and core-shell morphology with average size (80 nm) for the prepared catalyst. Furthermore, the EDX study showed C, Fe, Mo, N, O and Si elements, all of which were homogeneously dispersed in the complex. The one-pot reaction of malononitrile (3), ethyl acetoacetate (12), hydrazine hydrate (11), and substituted aldehydes (90) was successfully catalysed by core-shell catalyst in water for reaction time (20 min) at RT (Scheme 27). The magnetic catalyst was easily recoverable and stable at 500 • C. The material was reused ten times with a minimal loss of activity.  (12), and various aldehydes (92) in a water medium at room temperature, affording excellent yields (89-99%) in 10 min (Scheme 28). The magnetic nanocatalyst was recycled and reused up to seven times without noticeable loss of its catalytic activity. Both electron-donating and electron-withdrawing groups at the ortho, meta and para positions of the aldehydes were well-endured and offered excellent yields.

With Tri-Metallic Catalysts
The design of nanomaterials, combining various elements with unique characteristics, is a crucial step towards resolving multiple problems and challenges in catalysis-as well as other applications. In recent years, novel and special features of materials combining three distinct metal elements to the alloy have attracted considerable attention in catalytic systems. These materials typically afford improved or exclusive properties due to innumerable synergistic effects. Compared to bimetallic and monometallic compounds, trimetallic materials can be made to exhibit higher degrees of selectivity, efficiency, and catalytic activity by varying their elemental composition and morphologies. The synthesis of trimetallic nanoparticles has been of great interest, due to their multiple potential applications in semiconductors, biosensors and the medicinal and catalysis fields.

With Miscellaneous Materials and Composites as Catalysts
Guo et al. [90] developed a series of pyranopyrazoles (108) and spiro[indoline-pyrano[2,3c]-pyrazole] derivatives (109) using meglumine as a biodegradable catalyst. The fourcomponent reaction, comprising malononitrile (3), hydrazine hydrate (11), β-keto ester (12) and carbonyl compound (106) or isatin (107) in EtOH-H 2 O solvent in the presence of 10 mol% meglumine at RT, gave excellent yields (85-95%) (Scheme 32). The catalyst was reusable for up to 3 cycles with trivial loss of activity. A reaction mechanism involving the Knoevenagel condensation (114), enolate formation (112) in the presence of meglumine from ethyl acetoacetate and hydrazine, Michael type addition (115), intramolecular cyclisation (116) and tautomerisation (117) was suggested, in order to deliver the desired pyranopyrazoles. Devi and her research group [95] reported an efficient one-pot synthesis of spiroindoline-pyranopyrazoles (131) in the presence of sodium dodecyl sulfate (SDS) as a micelle catalyst. The three-component condensation was carried out between the isatin (129), malononitrile (3) and 3-methyl-pyrazol-one (130) under an aqueous medium. A 2.5 mol% of SDS catalyst offered excellent (80-91%) yields at RT for 60 min (Scheme 37). The micelle catalyst was recyclable with similar activity up to four runs. The stated reaction mechanism giving the desired spiro products was involved in the Knoevenagel condensation (132) and Michael addition (133), and was followed by cyclisation (134). Mejdoubi et al. [98] described an efficient, recyclable catalyst, natural phosphate K09, which was used for synthesising pyrano[2,3-c]-pyrazoles (133). The EDX study revealed the catalyst material's elemental composition as Al, Cd, Cr, Fe, K, Na, S, Si, and Mg. The BET analysis of the K09 catalyst showed the specific surface as 13.8 m 2 .g −1 . The one-pot reaction between malononitrile (5), hydrazine hydrate (22), ethyl acetoacetate (36) and aryl aldehydes (132) in ethanol medium gave excellent results (90-98% yield) using 0.05 g of K09 catalyst at RT in 20 min (Scheme 40). The catalyst was stable up to six times, with a minute change in its efficiency. Both aromatic aldehydes and heteroaromatic aldehydes contributed excellent yields. An environmentally-benign, sulfonated carboxymethyl cellulose (CMC-SO 3 H) catalyst was synthesised by Ali et al. for the creation of novel pyrano[2,3-c]-pyrazole derivatives with good-to-excellent yields (78-90%) (145) [99]. The catalyst was investigated by a multicomponent fusion between ethyl acetoacetate (12), malononitrile (3), hydrazine hydrate (11) and various substituted aldehydes (144) in ethanol at 60 • C via a one-pot approach (Scheme 41). The reaction mechanism included Knoevenagel condensation, Michael-type addition and intramolecular cyclisation to obtain the resultant target molecules. The heterogeneous catalyst was fully stable for up to four runs with marginal loss of activity. Ganesan and his co-workers [101] reported a swift synthesis of pyranopyrazole derivatives (149) by applying nitrogen-doped graphene oxide (NGO) as a recyclable catalyst. The prepared NGO catalyst's SEM analysis showed unsystematically-aggregated, narrowlyconnected tinny sheets with various morphologies. Further, TEM displayed a well-ordered and distinct sheet and a silk-like morphology. Additionally, HR-XPS analysis strongly demonstrated the presence of multiple types of nitrogens in the NGO catalyst. The condensation reaction involved malononitrile (3), ethyl acetoacetate (12), hydrazine hydrate (11), and various functional groups of substituted aldehydes (148) under solvent-free conditions. Excellent results (80-99%) were obtained using 10 mg of NGO catalyst in 2 min through the grinding approach (Scheme 43). It is noteworthy that the stable catalyst material could be recycled and reused up to eight successive cycles with only a slight efficiency decrease. Scheme 43. Synthesis of pyranopyrazole derivatives 149 using nitrogen-doped graphene oxide.

Conclusions
This review outlined the increased available selection of recyclable catalyst materials, which are ideal for organic synthesis in general and pyranopyrazoles in particular and are expanding the scope and utility of heterogeneous catalysts. Simultaneously, the assessment of the implementation of multicomponent reactions under green techniques offers good compatibility with sustainable organic syntheses. With many green chemistry principles, the intrinsic features of the MCR approach becomes the foremost device in the synthetic chemist's toolbox. Nitrogen-based pyranopyrazole compounds are constituents of several natural products with numerous pharmaceutical applications. Thus, these emerging innovative and versatile approaches for synthesising these heterocyclic skeletons have always been challenging and rewarding. This review compiled recent literature, detailing the scope and broader choice of heterogeneous metal-based catalysts available to create the prized fused heterocycles, pyranopyrazoles. In this perspective, we emphasised the efficiency of MCRs as the ideal process for green synthesis. In most of the protocols, the employed catalysts were easily recyclable for successive runs with consistent performance. We sincerely hope this article will help synthetic chemists to develop novel heterogeneous materials and synthetic routes with greater efficiency and sustainability.