4H-Pyrano[2,3-c]pyrazoles: a review

This review summarizes the synthetic pathways to pyrano[2,3-c]pyrazoles which either have a hydrogen atom, aryl substituent or condensed spiro group at the 4-position. Synthesis focuses on two component or MCR’s including three, four and five components. Reaction conditions are variable including a green approach, nanoparticulate catalyst, microwave irradiation, ultrasonic irradiations and other catalysts. Most commonly used reagents are pyrazolones, benzylidenemalononitrile, hydrazines, β-ketoesters, malononitrile, aldehydes and ketones. Various substituted phenyl, naphthalene, anthracene, furan, thiophene, indole, tetrahydroquinoline have been incorporated at 4-position while amino and cyano groups at sixth and fifth position respectively and posses diverse biological properties.


Figure 3
Emphasis has been given to the various methods published in the literature, to synthesize a number of 4-arylpyranopyrazoles or 4-spiropyranopyrazoles using different reactants with/without catalyst in solvents (organic/ionic/water) or without solvent at various temperatures under changing reaction conditions together with the reported mechanism. Methods are represented based on the number of components condensed together to generate the resultant compounds. This review does not include all publications in this area, but what we consider to represent seminal articles related to the topic. To the best of our knowledge, it is the first attempt to summarize the synthetic methods of 4-spiropyrano [2,3-c]pyrazoles, as the other reviews 1,2 also includes derivatives 5 and 6 as well as their reactions.

Scheme 2
The reaction route is believed to involve tandem Michael addition of pyrazolone 16 to the α,βtrifluoromethyl ketones (17), followed by aromatization and cyclization (Scheme 3). 13

Scheme 3
Tetrahydroquinoline derivatives are well known for antibiotic, antitumor, anti-allergic, antidepressant, anti-ulcer, anticonvulsant, anti-fertility, antioxidant and herbicidal applications. 14 Hence, Pandit and Lee synthesized tetrahydroquinolines bearing pyranopyrazoles 21-23 in acetonitrile containing 10 mol% of EDDA at 60 o C for 1-2 h ( Figure 5). 15 The cis-stereochemistry of the product was confirmed by X-ray crystallography and rationalized by the mechanism outlined in Scheme 4. In the literature, various derivatives of 24 were reacted with malononitrile (14) in benzene as solvent containing triethylamine giving pyranopyrazoles 25, which were screened for fungicidal, herbicidal and insecticidal activities. 16 All compounds were inactive fungicidal and insecticidal agents however, one compound was active herbicidal agent (Scheme 5).

Scheme 5
Gogoi and Zhao carried out enantioselective synthesis by reacting pyrazol-5-one 16 and benzylidenemalononitrile (26) under catalytic action of different cinchona alkaloids including quinine, cupreine, 9-epi-cupreine and 9-epi-amino-9-deoxyquinine in various solvents (CH 2 Cl 2 , CHCl 3 , THF, ether, benzene, MeCN). 17 Cupreine gave excellent selectivities in dichloromethane and the enantioselectivity found to be highly dependent on the reaction conditions, structure of the catalysts and the substrates hence, enantioselectivity (ee c ) decreased with small changes in catalyst, solvent and with presence of substituent on

Scheme 6
Water as a green solvent, is the most environmentally friendly, safe and inexpensive choice to decrease pollution, toxicity and cost of a reaction. 19 Peng and co-workers used pure aqueous media for reaction of 5alkoxycarbonyl-2-amino-4-aryl-3-cyano-6-methyl-4H-pyrans (27) and hydrazine hydrate in the presence of a catalytic quantity of piperazine by three methods (i) heating (ii) exposing to microwave irradiation (iii) exposing to a combination of microwave and ultrasound irradiation where, the latter was found to be excellent in terms of yield within short time 20 . It was assumed that powerful ultrasound irradiation causes cavitations and high-velocity interparticle collisions, which cleaned the surface, thus mass transfer between two phases increased and the reaction completed fast without need of any organic co-solvent (Scheme 7 Trichili and co-workers allowed a solution of substituted hydroxybenzaldehyde/naphthaldehyde 29 and malononitrile in ethanol containing piperidine to stir to get 3-cyanoiminocoumarins (30). These were reacted with thiosemicarbazide at room temperature in chloroform to form benzopyrano [2,3-c]pyrazoles (31), or derivatized to 3-cyano-N-ethoxycarbonyliminocoumarin (32) which was further refluxed with 4phenylsemicarbazide or thiosemicarbazide to form 3-triazolonyliminocoumarins (33) 21 (Scheme 8). The proposed mechanism of reaction is given (Scheme 9). 29  Shestopalov and co-workers treated 3-(methyl, phenyl, t-butyl, methoxymethylene, trifluoromethyl)substituted-5-pyrazolones 34 with heterocyclic or polyalkylated benzylidemalononitrile (26) to get 4-arylpyranopyrazoles 35 in good to excellent yields. 22 Reaction was found to be successful for sterically hindered aldehydes as well as to electron-withdrawing and electron-donating substituents at the 3-position of the pyrazoles. X-Ray crystallography studies showed that these pyranopyrazoles exist in the 2-H tautomeric form rather than as 1-H (Scheme 10).

Scheme 18
The reaction mechanism is believed to involve a domino/Knoevenagel-hetero-Diels-Alder sequence including attack of TBA-HS on pyrazolone and generating a reactive tetrabutyl ammoniumpyrazolonate, which reacts with aldehydes to form the Knoevenagel adduct 56 and Knoevenagel-Michael adduct 57. 28 The synthesis of the latter, was confirmed by spectroscopic data and its conversion to Knoevenagel adduct 56 and pyrazolone 16 under the influence of heat, light, or long time storage (path c). Similarly, intermediate 57 under reflux, afforded 54 and 58 which supported the assumption that the initially formed Michael adduct is converted into the Knoevenagel intermediate on subsequent reflux (Scheme 18). Stereochemistry of reaction was predicted as endo-(path a) and exo-(path b) of dienophile but, NMR data revealed the cis-form 54 as dominant.

Scheme 20
Abdou and co-workers, in a simple procedure, refluxed various alkene derivatives 67 and pyrazolones in piperidine containing ethanolic solution to produce a variety of pyranopyrazoles bearing carbonitrile, hydroxyl or a phenyl group at the 6-position 30

Scheme 26
In addition to these methods, Maruoka et al. adopted ring transformation and cyclization procedure by treating spirocyclopropanepyrazoles 84 and chloro acetonitrile in DMF solvent containing sodium hydride either via one pot or two steps involving synthesis of intermediate, cyanomethoxypyrazole 85 which further cyclized to 6-cyano-5-disubstituted pyranopyrazoles (86)

Scheme 27
The reaction was also tried using potassium t-butoxide in N,N-dimethylformamide and potassium tbutoxide in t-butyl alcohol, but failed. 35 Spirocyclopropanepyrazoles were subjected to ring opening using either using NaH/DMF, or titanium (IV) chloride in chloroform and afforded pyrazol-3-one 87 and carboxylic acid 88 in case of butyl acetate ( Figure 6).  36 Initially, the reaction was tested in the absence of catalyst and yielded traces of product or no product as in case of 4-dimethylaminobenzaldehyde, which has strong electron donating dimethylamino group that has significant contributions of the quinoid resonance form, hence reactivity decreased 89-90 ( Figure 7). In another attempt, various PTC namely, TBAB, DBSA, sodium dodecyl sulphate (SDS) and HTMAB were tested for similar reactants where HTMAB was found best in term of yield 37 (Scheme 28 B). The reaction conditions worked equally for aromatic aldehydes with electron-withdrawing and donating substituents, but did not proceed for aliphatic aldehydes probably, due to their low reactivity. Prajapati and co workers refluxed substituted aldehydes, malononitrile and 1-(2,4-dinitrophenyl)-3-methylpyrazol-5-one in ethanol containing Page 18 © ARKAT USA, Inc piperidine catalyst to give the respective pyranopyrazoles which were found to be good antibacterial agents (Scheme 28 C). 38

Scheme 28
Pyranopyrazoles bearing a triflouromethyl group at the 3-position were obtained by reaction of aldehydes, malononitrile and trifluoromethylpyrazol-5-one, in water as solvent without catalyst at 90 o C, in good yields in 3-5 h (Scheme 29 A). 39 The yield of the product is not affected by the electronic nature of the aryl substituents. Bhavanarushi and co-workers prepared flouropyranopyrazoles by grinding similar reactants in a pestle mortar using DBU as catalyst and established the molecular mechanism for DNA binding of resultant products (Scheme 29 B). 40 Microwave irradiation to eliminate the need of heat, enhances the rate of reaction, is a widely applicable technique and has been used for the synthesis of pyranopyrazoles within 2-8 min in dry ethanol containing piperidine catalyst (Scheme 29 C). 41 Diaminopyrano[2,3-c]pyrazoles were prepared at room temperature in ethanolic solvent containing secondary amine/organic bases such as pyridine, piperidine and pyrrolidine. 42 The resultant compounds were found to be potential antibacterial agent while, some of them also exhibited antifungal activity (Scheme 29 D).

Scheme 29
Pyrazolone and aldehydes were refluxed together with malononitrile to give 6-aminopyrano[2,3c]pyrazoles (15), or with 3-oxo-3-phenylpropanenitrile (92) to afford 6-phenylpyrazolo[3,4-b]pyridine-5carboxylate (93). 43 These compounds showed remarkable anticancer activity on human tumor cell lines (Scheme 30).  Heating, irradiation and solvent-free, environmental friendly method was developed by grinding the aryl aldehydes and malononitrile with pyrazol-5-one or dimedone (72) in the presence of 5-25 mol% D,L-proline catalyst to get pyranopyrazoles 15 and benzo[b]pyrans (98)  A possible mechanism under catalytic effect of D,L-proline is proposed which, follows same sequence of steps, but the intermediates are formed by direct interaction of the catalyst with reactants 44 (Scheme 33). Some protocols developed for two component reactions were also applied to three components synthesis. Thus aromatic aldehydes, malononitrile, pyrazolone and triethylamine were heated in ethanol to give N-unsubstituted pyrano[2,3-c]pyrazoles (28) (Scheme 34 A). 22 Similarly, cinchona alkaloids were also used as catalysts at room temperature with/without drying agents (Na 2 SO 4 , MS(4 Å) e ), and gave better yield of entioselectively (ee c ) products in some reactions, but poor yields in others 17 (Scheme 34 B).
Kamble and co-workers replaced toxic, volatile solvents (MeOH, EtOH, MeCN) with thermally stable, nonvolatile, easily available, miscible and recyclable polyethylene glycol (PEG-400), which increased the yield short reaction times. 45 Bleaching earth clay, a heterogeneous base used as catalyst due to its selectivity, acidic/basic nature, thermal stability and easy separation by filtration. Substituted benzaldehyde 103 was reacted with pyrazolone and (4-chlorophenyl)acetonitrile (104)

Scheme 36
Novel heterogeneous, eco-friendly silica sodium carbonate (SSC) catalyzed synthesis of pyranopyrazoles 114 by treating pyrazolone, malononitrile, and substituted benzaldehydes/naphthaldehyde in water/ethanol mixture (1:2) ( Figure 8) has been reported. 47 At first, the catalyst is prepared by drying silica gel 60 at 120 °C, adding thionyl chloride while cooling on ice, keeping cold for 30 min, then refluxing for 48 h followed by filtration to isolate the silica chloride. Silica chloride and sodium bicarbonate were allowed to react in nhexane, and washed with water to remove remaining sodium bicarbonate. This novel catalyst was found to be effective in small quantity (1 mol%) and reusable without significant loss in activity. The reaction mechanism is represented as Scheme 37. Brønsted acidic task-specific ionic liquids, have a dual action as solvent and catalyst and possess tunable polarities, high thermal stability, and are immiscibility with a number of organic solvents, negligible vapor pressure, and are recyclable. 48,49 Khurana and Chaudhary used 1-butyl-3-methylimidazolium hydroxide, for the synthesis of pyrano[2,3-c]pyrazoles and 4H-pyran derivatives. 50 When pyrazolone, arylaldehydes and malononitrile are mixed in 20 mol% of [bmim]OH, pyranopyrazoles are produced, while, pyran derivatives were obtained by replacing pyrazolone with ethyl acetoacetate or acetylacetone (Scheme 38). In the synthesis of pyranopyrazoles, the nature of substituent has very little effect on the reaction rate and yield of the products while, aryl aldehydes with electron withdrawing groups reacted faster than those with electron donating groups to form pyran derivatives. Furthermore, other ionic liquids such as [bmim]Br and [bmim]BF 4 were also applied to pyran synthesis, but failed. were produced 116 (Scheme 39). Thus reaction is applicable for variety of aldehydes as well lactones such as coumarin. It was also observed that the catalyst is recyclable and could be used four times without any significant loss in activity. yield

Scheme 39
Similarly, Heravi and co-workers used Preyssler type heteropolyacid H 14 [NaP 5 W 30 O 110 ] under solvent free conditions, but this failed to produce any products. 52 However when used in water/ethanol mixture, excellent results were obtained, probably due to two reasons (a) the first stage of the reaction includes Knoevenagel condensation, which is faster in water, and (b) the PKa of HPA depends on the solvent. Reaction conditions found effective for pyrazolone, barbituric acid, aldehydes having electron-donating and electron withdrawing substituent but, did not work for ethyl cyanoacetate, diethyl malonate, ethyl benzoylacetate, ethyl acetoacetate and acetophenone (Scheme 40). . The synthesized compounds were tested for biological activities where all exhibited remarkable antiinflammatory, analgesic and anticonvulsant activities and most of the analogues found potential as antimicrobial agent. Some compounds showed anticonvulsant potency more than both anti-inflammatory and analgesic activities. It was also observed that presence of halo atoms increased biological action.

Scheme 45
Enders and co-workers tested different secondary amines as catalysts for reaction of α,β-unsaturated aldehydes 137 and Wittig reagent 138 to prepare enantioselective tetrahydropyranopyrazoles 139 where, MacMillan imidazolidinone showed excellent result in chloroform/toluene with a small amount of methanol (Scheme 46). 56 One pot reaction gave better yields and enantioselectivity than a two-step synthesis. Furthermore, NOESY experiments revealed that the major diastereomer shows trans configuration.

Scheme 46
Reaction is believed to be catalyzed by secondary amine to form Michael intermediate 140 which cyclized to form 6-hydroxy pyranopyrazoles 141, followed by Wittig reagent initiated ring-opening 142 and finally oxa-Michael domino reaction to give final product 139 (Scheme 47). 56 Wittig reaction with electron-rich or neutral substituents of phosphoranes showed greater enantioselectivity and yields as compare to slightly electrondeficient phosphoranes. Structure of compound was confirmed by X-ray studies.

Scheme 49
Malononitrile and ketone were treated to obtain nitrile 145 which being reactive and unstable dimerized to 148, which supported Pathway B. 57 Similarly, reaction with sterically hindered ketone named, adamantan-2one, yielded a Michael adduct 149 which did not undergo further reaction (Figure 9). Al-Thebeiti carried out a solvent-free synthesis by fusing pyrazolone and cyclic ketone 150 in the presence of anhydrous sodium acetate at 200 o C to get intermediate 151 which were refluxed with malononitrile to obtain spiropyrano[2,3-c]pyrazoles (152) and derivatized further to oxo-and amino-pyrimidines using various reagents. 58 Some of the synthesized analogues exhibited moderate antimicrobial activity against Escherichia coli and Staphylococcus aureus (Scheme 50).

Scheme 50
Riad and co-workers reacted acetoacetanilide (153) and α-cyanocinnamonitrile derivatives to produce intermediate 154 which when either treated with hydrazine hydrate to form pyrano[2,3-c]pyrazole (28) (Scheme 51) or cyclized under acidic conditions gave pyran derivatives. 59 It was also observed that these pyranopyrazoles could be converted easily to pyrazolopyridines in acetic acid and ammonium acetete. These compounds showed moderate inhibition effect on bacteria.

Scheme 51
In addition to these ketones, un/substituted isatin (155) has been widely used for synthesis of spiro-2oxindole-pyranopyrazoles. Redkin and co-workers treated isatin, with a suitable CH acid (malononitrile/cyanoacetic ester) and pyrazolones via a one pot (Scheme 52 A) or two step method involving reaction of isatin and CH acid to form intermediate 156 which further reacts with pyrazolone to form pyranopyrazoles 157 (Scheme 52 B). 60 It was assumed that the formation of the Michael adduct is common in both methods which cyclized regioselectively to pyrano[2,3-c]pyrazol bearing spiro-2-oxindole derivatives. Similarly, Dandia and co-workers ground N-unsubstituted isatin 155 and malononitrile in agate mortar or subjected to microwave irradiation at 640 W to get intermediate 156 (Scheme 52 C) which adsorbed on neutral alumina using methanol and treated with pyrazolone to get pyranopyrazoles 157 61
Mandha et al. carried out a non-catalytic synthesis in water/ethanol mixture using various carbonyl compounds such as aldehydes 91, isophthalaldehyde (170), indole-2,3-dione (49), and 9-fluorenone (171). 64 The reaction mechanism is believed to involve Knoevenagel condensation between the carbonyl compounds and malononitrile to form various benzylidemalononitrile as intermediates 26, 172-174, which underwent Michael addition with pyrazolin-5-one, followed by intramolecular cyclization to form polyfunctional Elinson and coworkers electrolyzed an ethanolic solution of isatin, malononitrile, pyrazolone and sodium bromide in an undivided cell having a magnetic stirrer. 65 Reaction was found to be successful after passing 0.04 F/mol quantity of electricity at different densities but, 2 mA/cm 2 was found optimal to obtain excellent yields of spiro[indole-3,4-pyrano [2,3-c]

Scheme 56
The reaction mechanism was proposed to involve ethoxide ion catalyzed Knoevenagel condensation of malononitrile and isatin with elimination of hydroxide ion to give electron-deficient Knoevenagel adduct 156, followed by Michael addition of pyrazolone to form Michael adduct 179 and finally cyclization to form pyran ring system (Scheme 57

Scheme 58
It was proposed that the Knoevenagel condensation between isatin and CH-acidic derivative to form alkene 156 is the first step, alkene reacts with the carbonyl compound to give the Michael adduct 185, followed by attack of enolate oxygen on the nitrile group (Thorpe-Ziegler type reaction) and finally tautomerizing to form the target compounds 67 (Scheme 59).
Zolfigol et al. catalyzed synthesis using the highly stable, readily available, metal free, less toxic and reusable organocatalysts such as isonicotinic acid and picolinic acid, where 10 mol% of isonicotinic acid at 80 o C showed better results than latter one. 69 Reaction conditions were suitable for aromatic aldehydes, aliphatic aldehydes, N-phenylhydrazine and hydrazine hydrate.

3.
Kiyani and co-workers carried out synthesis in organic solvents (THF, CHCl 3 , CH 2 Cl 2 , EtOH) or water and observed solvent effect on reaction time and yield of products. 71 Water containing 15 mol% of sodium benzoate gave best yield. Aldehydes containing donor substituents increased reactivity and yield as compare to electron withdrawing substituents. Additionally, steric hindrance also played role as evidenced by the slower reaction of 2-nitrobenzaldehyde compare to 4-nitrobenzaldehyde. But in case of hydrazine, reactions of phenylhydrazine took longer time than hydrazine hydrate to give products in good yield. Reaction mechanism is represented as Scheme 62.

4.
Vasuki and Kumaravel tested potassium carbonate and the organic bases piperidine, triethylamine, diethylamine, pyrrolidine, morpholine, piperazine for synthesis. 72 Benzaldehyde reacted well without any catalyst, while other aromatic aldehydes reacted in the presence of 5-10 mol% of piperidine in aqueous media at room temperature. Various mono, di and tri-substituted aromatic aldehydes, hetaryl aldehydes and aliphatic aldehydes used successfully. X-Ray crystallography study confirms the 2-H tautomeric form of pyranopyrazoles.

5.
Pawar and co-workers developed an inexpensive and environmental friendly method in water/ethanol mixture using 20 mol% of citric acid. 73 Various organocatalysts such as oxalic acid, picric acid, succinic acid, ptoluenesulfonic acid and sulfamic acid were also tested in different organic solvents at reflux temperature, but

6.
Madhusudana and Pasha used inexpensive, non-toxic, environmental friendly and easily available iodine catalyst in water solvent at 25 o C to get excellent yields. 74 Reaction was unsuccessful in absence of catalyst and solvent, non-polar solvent gave poor yield while increasing the polarity, increased the yield and shortened reaction time. The reaction was applied successfully for aromatic and hetaryl aldehydes. 7.
Glycine replaced iodine and reaction was carried out in various organic solvent, obtained excellent yields in water solvent within 5-20 min. 75 Substituted aldehydes containing electron-donating and electron withdrawing groups worked equally well. 8.
In water, reactants stirred in the presence of piperidine catalyst to give pyranopyrazoles, which showed inhibition to steel corrosion. 6 9.
Cetyltrimethylammonium chloride (CTACl) used as a phase transfer catalyst, which increased the hydrophobic surfaces and accelerate the reaction rates of heterogeneous multi-component reactions, to prepare pyranopyrazoles at 90 o C. 76 Aromatic aldehydes showed good results, but aliphatic aldehydes such as butanal or pentanal showed only small traces of product presumably due to competing of aldol condensation.

10.
Kanagaraj and Pitchumani compared the catalytic action of methylamine, diethylamine, triethylamine, piperidine and per-6-amino-β-cyclodextrin for pyranopyrazoles synthesis where latter, gave excellent yield without solvent in 1 min. 77 It was proposed that per-6-ABCD have seven free primary amino groups, thus behaves as an efficient supramolecular host and base catalyst. In the first step, the carbonyl compounds bind within the CD cavity then reacts with malononitrile by Knoevenagel condensation to form Page 40 © ARKAT USA, Inc ylidenemalononitrile. These intermediates have enzyme-like binding, which ensure tight fitting in cavities and facilitates further Michael addition of the ylidenemalononitrile to pyrazolone, followed by cyclization and tautomerization. To support this mechanism, an inclusion complex was formed by mixing equimolar amounts of adamantane and per-6-ABCD and used as catalyst, absence of any product confirms inculsion to per-6-ABCD cavities essential for pyranopyrazoles synthesis. 11.
An easily available, cheap, and non-toxic catalyst sodium bisulphite was used under ultrasound irradiation without any solvent. 78 It was assumed that ultrasonic cavitations created microscopic internal high pressure and high temperature. Electron donating and/or withdrawing substituents of aromatic aldehydes showed no effect on yield of pyranopyrazoles. 12.
Alumina and alumina supported reagents have well known surface properties and specific porous structures, hence the catalytic efficiency of α-alumina, basic alumina and KF-alumina examined using 30 mol% of each catalyst. 79 The order of reactivity is found to be alumina > KF-alumina > basic alumina. The higher activity of α-alumina was attributed to the amphoteric nature and the greater surface area allowing for greater adsorption of the reactants on its surface. Aromatic, poly functional and aliphatic aldehydes used under this condition.

13.
Reddy and Garcia carried out eco friendly synthesis using montmorillonite K-10 as catalyst. The reaction has an advantage of catalyst recovery and reusability for several time. 80 14.
Phenylboronic acid (5 mol%) in water at reflux temperature was used for aromatic and hetero-aromatic aldehydes. 81 Electron donating or withdrawing groups, at any position (p, m or o) of aldehyde, gave good yield, but electron withdrawing substituted aldehydes reacted slowly while aliphatic aldehydes gave poor yields. The reaction mechanism proposed to involve initial binding of PhB(OH) 2 with carbonyl oxygen. 15.
Kumar and co-workers used inexpensive, mild, water-tolerant and eco-friendly tetraethyl ammonium bromide (10 mol%) catalyst in boiling water for aromatic, hetero-aryl and aliphatic aldehydes. 82

16.
Nagarajan and Reddy synthesized pyranopyrazoles without solvent and catalyst at room temperature within 3-11 min. 83 Aldehydes bearing electron-releasing groups at the para position gave better yield than electron-withdrawing groups at the same position. Similarly, disubstituted aldehyde with electron-donating groups at para and meta positions required shorter reaction time and gave higher yield. Reaction conditions worked equally for aliphatic aldehydes. 17.
Moeinpour and Khojastehnezhad used Ni 0.5 Zn 0.5 Fe 2 O 4 nanoparticles in water to get maximum yield at room temperature. 84 Catalyst was separated easily by an external magnet, reused six times, studied by XRD patterns which showed no change in structure, weight and reactivity. Initially, nanoparticles were prepared by mixing equimolar solutions of FeCl 3 , NiCl 2 , ZnCl 2 and NaOH, then coating silica and polyphosphoric acid on the nanoparticles. The nanoparticles were found to be spherical, average size less than 70 nm in diameter and narrowly distribute. 18.
Babaie and Sheibani prepared MgO nanoparticles by treating aqueous magnesium hydroxide gels, magnesium nitrate and liquid ammonia and used these nanoparticles for pyranopyrazoles synthesis using malononitrile, aromatic aldehydes, phenyl hydrazine/hydrazine hydrate and different ethyl 3-alkyl-3oxopropanoate in acetonitrile at room temperature in 5-45 min. 85 19.
Various iron oxides such as Fe 3 O 4 , Fe 3 O 4 nanoparticles and recovered Fe 3 O 4 nanoparticles were compared for pyranopyrazoles synthesis where nanoparticles in fresh and recovered state showed excellent results. 86 Nanoparticles were prepared by treating FeCl 3 .6H 2 O, FeCl 2 .4H 2 O with NaOH. Out of different solvents, ultra pure water was found to be excellent.

20.
Saha and co-workers used 10 mol% of ZrO 2 nanoparticles for MCR pyranopyrazoles synthesis at room temperature in water/ethanol mixture (6: 1). 87 The structure of ZrO 2 was confirmed as tetragonal and 17 nm in particle size. 21.
Borhade and Uphade prepared ZnS nanoparticles by mixing and stirring together a solution of zinc nitrate, sodium dodecyl sulphate and sodium sulphide and confirmed the elemental composition by EDAX spectrum and structure by XRD, SEM, TEM techniques. 88 These particles were found to be single-phase, hexagonal with average crystallite size of 20 nm and compared with FeCl 3 , SnCl 4 , P 2 O 5 , ZnCl 2 , bulk ZnS and ZnS nanopatricles. Nanoparticles technique was found most effective catalyst for synthesis of pyranopyrazoles at room temperature.

22.
Ebrahimipour et al. Carried out condensation of 5-bromo-2-hydroxybenzaldehyde with 2-amino-4methylphenol to form a ligand, which reacted with Ni(OAc) 2 .4H 2 O and 1-Methylimidazole to form mixed ligand complex [Ni(L)(mimi)] either at reflux temperature to obtain bulk form or under ultrasonic irradiation to get nano-sized particles. 89 Both forms were tested for pyranopyrazoles synthesis and revealed that mixed ligand [Ni(L)(mimi)] in either form, gave better yields, but nanoparticles are more efficient. The structure of the nanoparticles was found to be composed of finely dispersed nanorods with average diameter 45 nm. 23.
Shinde and co-workers synthesized pyranopyrazoles in water at reflux, but obtained poor yield. 90 To increase efficiency silica gel 60 used as a catalyst, which increased the yield of product and decreased reaction time at room temperature. Reaction was found to be equally good for small scale, large scale, electron withdrawing and electron donating substituted aldehydes. 24.
Nimbalkar and co workers initially synthesized triethylammonium hydrogen sulphate[Et 3 NH][HSO 4 ] and used it to carry out multicomponenet synthesis of pyranopyrazole at room temperature. 88 The synthesized compounds were subjected to molecular docking and in vitro anticancer study where were found active against cancer cell lines. 25.

26.
Chavan and co-workers compared the catalytic activity of silicotungstic acid with FeCl 3 , ZnCl 2 , SnCl 4 , P 2 O 5 and CAN, where the former showed excellent result at 60 o C. 93 Aromatic aldehydes produced high yield as compare to aliphatic aldehydes. NOE study of pyranopyrazoles confirmed its 2-H tautomeric form.

27.
A mixture of anhydrous choline chloride and anhydrous urea in a 2:1 ratio heated at 50 o C to form a homogenous liquid that catalyses the formation of pyranopyrazoles (62-95%) under solvent free condition. 94 The reaction was found to be applicable for hydrazine hydrate, phenylhydrazine, various β-ketoestsers such as ethyl isobutyroylacetoacetate, ethyl benzoylacetoacetate, aromatic and hetero aromatic aldehydes. 28.
Devkate and co-workers also used same Bronsted acid ionic liquid in various aprotic and protic solvents, but obtained excellent results under solvent free condition. 96 30.
Amin and co-workers replaced malononitrile with 2-cyanoacetamide and refluxed with other three reactants in methanol to obtain 5-carboxamide pyranopyrazoles (204) and found to be antibacterial and antifungal agents 97 ( Figure 12). In four components synthesis, mostly reported mechanism involves the following steps (i) Reaction of hydrazine and the β-ketoester to form pyrazolone, which tautomerizes to the enol form 198. For this purpose, various β-ketoesters such as ethyl acetoacetate, phenyl acetoacetate, ethyl 3-alkyl-3-oxopropanoate, ethyl isobutyroylacetoacetate and ethyl benzoylacetoacetate have been treated with hydrazine hydrate and phenylhydrazine (ii) Synthesis of ylidenemalononitrile 26 by Knoevenagel condensation of aldehydes and malononitrile. Mono substituted aromatic aldehydes, disubstituted aromatic aldehydes, hetero-aromatic aldehydes, alicyclic aldehydes as well as ketones have been used (iii) Reaction of pyrazolone and ylidenemalononitrile to form Michael adduct 206/208 either following path a or b (iv) Cyclization  Brahmachari and Banerjee prepared pyrano [2,3-c]pyrazoles (28) and various pyran-annulated heterocycles 215 using urea (10 mol%)

Scheme 70
Koohshari and co workers carried out regio-and chemio-selective synthesis of ethyl acetate bearing pyranopyrazoles in water/ethanol (8:2) without any catalyst at temperature range of 25-82 o C. 101  Pore et al. used acetylenic esters 233 instead of β-ketoesters in water/ethanol mixture at reflux temperature to desire indolinepyranopyrazole 234. 102 The reaction protocol worked for isatin, 5-substituted isatin, N-substituted isatin, diethyl acetylenedicarboxylate (DEAD) and dimethyl acetylenedicarboxylate (DMAD) (Scheme 73). Reactivity of isatin possessing electron donating or withdrawing substituents did not show any significant difference, but product 234 obtained by only adding reactants in following sequence (i) hydrazine hydrate (ii) acetylenic ester (iii) solvent (iv) isatin (v) malononitrile. The reaction mechanism involves fast and exothermic reaction of DEAD/ DMAD with malononitrile to form ethoxypyrazolone other reaction steps are similar.

Scheme 73
Similarly, Wang and co-workers prepared spiroarylpyranopyrazoles in ethanol solvent containing triethylamine (Scheme 74). 103 Structures were confirmed by X-ray.

Scheme 74
The mechanism of both reactions is summarized and represented below 102

Scheme 75
Meglumine (10 mol%) in ethanol/water mixture was used as catalyst for the reaction of carbonyl compounds such as aldehydes, ketone, isatin or acenaphtylene-1,2-dione, to get pyranopyrazoles 28, 236-238 ( Figure 13). Ambethkar and co-workers ground reactants together in a pestle mortar using L-proline (10 mol%) as the catalyst, aryl aldehydes with the electron withdrawing groups gave better yields (Scheme 76). 105 Compounds 239 were tested for in vitro antioxidant and antimicrobial activities.

Scheme 76
Zonouz and co-workers prepared pyranopyrazoles 240 without catalyst in water at 50-60 o C in 66-88 % yield 106 (Figure 14). Triethylamine, piperidine or chitosan as catalysts were used to obtain pyranopyrazoles 241 at reflux temperature either by four components or reacting pyrazolone with benzylidemalononitrile. 107

Scheme 77
The reaction mechanism is supposed to involve 108 (i) Synthesis of pyrazolone (ii) Knoevenagel condensation of pyrazolone with aldehydes to form the Michael acceptor 245 (iii) An immediate Michael-type addition of nitroketene-N,S-acetal to give intermediate 246 (iv) Cyclization by eliminating a molecule of methanethiol 247 (v) Tautomerization. It was also proposed that intermediate 246 may undergo N-attack and by eliminating a molecule of water to yield 248, but this was not isolated (Scheme 78).

Scheme 79
Reaction was found to be effective for a variety phenyl derivatives, however electron withdrawing groups at the 2-position, resulted in the formation of oxa-aza-[3.3.3]propellanes (252) 109 (Figure 16).

Five Component Synthesis
Lu and co-workers carried out a one pot synthesis of pyranopyrazoles involving Suzuki coupling between 4bromobenzaldehyde (253) and arylboronic acid (254) under dehalogenating effect of KF.2H 2 O in the presence of Pd/C at 80 o C. 110 Firstly, 4-bromobenzaldehyde and arylboronic acid were added to form substituted biphenyl aldehydes later on, other reagents were added and allowed to react for 5-6 hr.

Scheme 81
The reaction mechanism was proposed to involve synthesis of β-ketoester in situ by nucleophilic substitution of Meldrum's acid to acetyl chloride. 111 Other steps include synthesis of pyrazolone, alkene and Michael adduct followed by cyclization and tautomerization (Scheme 82).

Biological Activities
Pyranopyrazoles in general are biologically active and have remarkable antimicrobial 53,58 , anticancer, 43 antiinflammatory, 23,53,112 analgesic, anticonvulsant, anti-platelet, vasodilator, 3 antifungal, 24,42,97 potential Chk1 inhibitors, 113,114 herbicidal 16 and molluscicidal properties. 33,34 Moreover, pyranopyrazoles were found to be effective inhibitors to steel corrosion 6 and as antioxidants for lubricant oil. 5 Since these MCRs can lead to a variety of pyrano [2,3-c]pyrazoles by virtue of aryl and hetaryl aldehydes, hydrazines and malononitriles and other reactants, the researchers from time to time have subjected the novel synthesized compounds to diverse type of biological activities which may be summed up in the following: Tetrahydroquinolines derivatives being biological active anti-HIV, antibacterial, antifungal, antimalarial, antitrypanosomal, antitumor, psychotropic, anti-allergic, anti-inflammatory, and estrogenic agents, were incorporated with pyranopyrazoles to obtain potential biologically active compounds 21-23. 15 Tacconi and co-workers prepared pyranopyrazoles 25 and screened for fungicidal, herbicidal and insecticidal activities.
Ismail and co-workers prepared benzamide based pyranopyrazoles 37 and screened for their anti-inflammatory and ulcerogenic activities. All compounds were found to be active but, compound 263 showed excellent anti-inflammatory and good prostaglandin inhibitory activity 23 (Figure 18). Some indole based pyranopyrazoles 39 were found to be active antibacterial, antifungal and anti-oxidant agents. 24 4-Hetaryl pyranopyrazoles 15 exhibited moderate molluscicidal activity against Biomphalaria alexandrina snails. 33,34 while other deivatives of 15 showed antibacterial, antifungal, anti-inflammatory and anticancer activity against liver carcinoma cells. 38,64,43 Compounds 110-113 were found active antibacterial. Moreover, derivatives containing halo group at 2 nd position of substituent exhibited both antibacterial and antifungal activities. 46