Green Synthesis of Pyrazoles: Recent Developments in Aqueous Methods

Organic syntheses by adopting green protocols such as sonochemical procedures, microwave technologies, solvent-free conditions, green solvents, heterogeneous catalysis particularly nanocata-lysts, ionic liquids have replaced traditional procedures due to concerns pertaining especially to the environment. The heterocycle, pyrazole, due to its multifaceted applications, has been the target of chemists and therefore various synthetic approaches have been developed to synthesize pyrazole-containing molecules. In the present compilation, we have summarized recent water-based research work on the synthesis of pyrazoles


Introduction
There is great concern in the utilization of chemicals and polymers for production processes, which have detrimental effects on public health and the global environment.For the wellbeing of society and humans, various environmentally benign organic transformations are being devised with advantages such as chemical waste minimization, atom economy, energy saving, easy workup, alternative catalysts and procedures, and chromatography-free isolation of the products.][3][4][5] The green approaches that are generally considered for organic synthetic reactions are: (i) the use of green solvents, such as nature's solvent water, as a reaction medium instead of organic solvents, (ii) reactions in the solid state without the use of solvent, (iii) using catalytic amount of organometallic reagents instead of stoichiometric amounts, and (iv) biosynthetic processes.For the synthesis of heterocyclic compounds, many green methods have been applied, [6][7][8][9] performing the reactions at ambient temperature and using alternative energy sources are the methods of choice.
Organic reactions are mainly performed in organic solvents thus giving rise to large amounts of solvent waste that are hazardous to aquatic organisms and pollute underground water.The use of aqueous media, a non-polluting abundant solvent, for organic syntheses is a very important S. Singh et al.
This review compiles recent work on the water-based syntheses of pyrazole derivatives (from 2015 till 2022) to facilitate scientists working, or intending to work, in this important field.

Review SynOpen
presence of PTSA, Et 3 N, CeO 2 /CuO, CeO 2 /CuO@GQDs, and CeO 2 /CuO@GQDs@NH 2 nanocomposite, the use of different concentrations of the catalyst under different solvents was also examined.The best results were obtained using CeO 2 /CuO@GQDs@NH 2 nanocomposite catalyst in water.
Also in 2021, Bansal and co-workers reported an environment friendly aqueous synthesis of tetrasubstituted pyrazoles 10 in the presence of cetyltrimethylammonium bromide (CTAB) by using arylaldehydes, ethyl acetoacetate, and PhNHNH 2 or NH 2 NH 2 •H 2 O in one pot (Scheme 5). 41This is green and efficient synthetic protocol that can be used to prepare sulfinic esters which will have good applications in the future.
The preparation and application of nanostructured diphosphate, Na 2 CaP 2 O 7 , was performed by Maleki, Khojastehnezhad, and co-workers in 2016 for the synthesis of dihydropyrano[2,3-c]pyrazoles 12 and spiro[indoline-3,4-pyrano[2,3-c]pyrazole]s 15 (Scheme 14). 53All the reactions were performed under reflux with water as the solvent.The catalytic approach is efficiently extendable to a wide variety of aromatic aldehydes to produce only the expected product.
Similarly, the Hazeri group applied Ag/TiO 2 nano films as heterogeneous catalysts in this reaction (Scheme 20). 62horbani-Vaghei and co-workers studied the use of Fe 3 O 4 @SiO 2 Scheme 15 Use of BSA biocatalyst for the synthesis of pyranopyrazoles and spiropyranopyrazoles

Review SynOpen
-Casein has also been used for the synthesis of pyrazoles 12 and 15 in EtOH/H 2 O at 60 °C by Maghsoodlou and co-workers in 2019 (Scheme 33). 78heme 33 Cyclocondensation in the presence of -casein Also in 2019, Abouzari-lotf and co-workers used phosphoric acid functionalized graphene oxide (GO-PO 3 H 2 -II) to catalyze the aqueous reaction of arylaldehydes, ethyl acetoacetate, and malononitrile with hydrazine or PhNHNH 2 (Scheme 34).79 The nanocatalyst was compatible with various meta-and para-substituted arylaldehyde substrates.

Review SynOpen
In 2020, Sangshetti and co-workers reported titanium dioxide (10 mol%) for the one-pot, four-component synthesis of methyl 6-amino-5-cyano-4-aryl-2,4-dihydropyrano[2,3-c]pyrazole-3-carboxylates 12 in 85-90% yield in water at r.t. in 30 min (Scheme 37). 82izam and co-workers, in 2020, used 18-crown-[6]ether for the four-component synthesis of pyranopyrazoles 12 in 89-96% yield in water using ultrasonication within 10 min (Scheme 38). 83The use of various solvents, such as MeOH, MeCN, DMF, DMSO, DCM, was examined but water was found to be the best. 83 two-component synthesis of pyrano[2,3-c]pyrazoles 12 was achieved using the natural waste, water extract of banana peels (WEB) by Chowhan and co-workers, in 2020, starting from arylidenemalononitriles and 3-methyl-1,4-dihydro-5H-pyrazol-5-one (Scheme 39). 84The reaction was efficiently performed with various substituted arylidenemalononitriles possessing ortho-, meta-, or para-substituted aryl or hetaryl groups at room temperature and the products were obtained in excellent 91-96% yield. 84heme 39 Water extract of banana peels in the synthesis of fused pyrazoles In 2017, Moosavi-Zare and co-workers utilized boric acid catalyst for the four-component reaction of arylaldehydes, ethyl acetoacetate, and malononitrile with NH 2 NH 2 •H 2 O to give pyrano [2,3-c]pyrazole 12 at 70 °C within 20 min (Scheme 40). 85The reaction is compatible with many electron-releasing and -withdrawing substituents on the arylaldehydes and also with halogen substituents Scheme 40 Pyrano[2,3-c]pyrazole formation using boric acid catalyst Zahoor and co-workers, in 2020, heated the aqueous ethanolic solution (9:1) of arylaldehydes, malononitrile, ethyl acetoacetate, and NH 2 NH 2 •H 2 O at 90 °C with the natural catalyst L-cysteine (0.5 mol) to produce pyrano[2,3c]pyrazoles 12 in excellent yields (Scheme 41). 86hakar and co-workers applied sodium lauryl sulfate (SLS) (15 mol%) in their work towards the four-component synthesis of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]s 15 using water as solvent (Scheme 42). 87This micelle-promot-Scheme 37 TiO 2 -catalyzed one-pot synthesis of methyl pyrano [2,3-c]  In 2016, Daraie and Heravi reported a simple and ecofriendly approach for the multicomponent production of many derivatives of pyrazolo[4′,3′:5,6]pyrido [2,3-d]pyrimidinediones 22 from the reactants ethyl acetoacetate, arylaldehyde, NH 2 NH 2 •H 2 O, and 6-amino-1,3-dimethyluracil catalyzed by triethylamine or L-proline in water as solvent (Scheme 48).The generality of this method was established by using various substituted arylaldehydes possessing either electron-donating or electron-withdrawing groups to successfully give products 22 in excellent yields (82-92% with TEA and 75-90% with L-proline).Polyfunctionalized pyrazolo[4′,3′:5,6]pyrido [2,3-d]pyrimidines 23 were conveniently obtained in aqueous medium by applying the multi-reactant approach.Derivatives of arylglyoxal, uracil, -aminocrotonitrile, and PhNHNH 2 underwent the reaction efficiently in the presence of triethylamine catalyst under refluxing condition (Scheme 49).The protocol offered easy isolation and high yield of the products. 94heme 49 TEA-mediated synthesis of polyfunctionalized tricyclic derivatives Siddiqui and co-workers reported that the iodine (10 mol%) catalyzed reaction in aqueous medium of ethyl benzoylacetate, isatin, and 6-amino-1-methyluracil with NH 2 NH 2 •H 2 O or PhNHNH 2 efficiently gave various substituted pyridopyrimidines 24 (Scheme 50).95 Many Brønsted and Lewis acid catalysts, such as FeCl 3 , I 2 , CoCl 2 , Cu(OAc) 2 , HCl, and PTSA, were screened for this process.Among all the tested catalysts, molecular iodine was found to be best.The use of many solvents, such as CHCl 3 , THF, MeOH, EtOH, MeCN, and water was also examined at various temperatures.The solvents MeOH, EtOH, MeCN, and water were successful, but water was the preferred solvent both in terms of environmental compatibility and yield.Furthermore, performing the reaction in the aqueous medium was also advantageous for the separation of the product as it was obtained just by filtration because of the solubility difference of the product and the reactants.Various isatin derivatives containing electron-donating or electron-withdrawing groups smoothly gave the products.The workup of the reaction involved only filtration, and chromatography or recrystallization was not needed.95 Scheme 50 Molecule iodine in the synthesis of substituted pyrazolopyridopyrimidines Halloysite clay nanotubes (HNTs) were functionalized by -aminopropyltriethoxysilane and then immobilized by using phosphotungstic acid.The hybrid catalyst was used for the synthesis of fused tricyclic system containing pyrimidines, pyrans, and pyrazoles. Ths reaction was performed by refluxing ethyl acetoacetate, arylaldehydes, uracils, and hydrazine in water under microwave and ultrasonic conditions (Scheme 51).Using microwaves, the reaction was complete in 5 min, but the yield was low with many byproducts.Under ultrasonication, the reaction was complete within 15 min at 60 °C and the yield was excellent.96

Conclusion
The review is towards summarizing the literature on the synthesis of pyrazole derivatives (pyranopyrazole, spiro-pyranopyrazole, furopyrazole, pyrazolopyrimidine) using water as green solvent.The synthetic work on pyrazoles under water is mainly performed in the presence of catalysts.A wide variety of catalysts such as nanoparticles, nanothin films, Brønsted and Lewis acid catalysts, bases, amino acids, and natural catalysts have been applied to achieve the formation of the pyrazole nucleus.A little work has also been carried out under ultrasonication and microwave.It is to highlight that the reported work is inclined towards the synthesis of two fused pyrazole systems, furo[2,3-c]-and pyrano [2,3-c]pyrazoles.It is also found that the majority of the reactions are performed involving multicomponent reaction system.Surely, there is good deal of scope to work in this particular area and this focused compilation will be very advantageous for scientists interested in working in the area of green synthesis of pyrazoles.
. degree in 2007 from Guru Jambheshwar University of Science & Technology, Hisar (GJUS&T), Haryana.She completed a Ph.D. in 2014 at Kuruk-shetra University, Kurukshetra under the guidance of Prof. Om Prakash and Dr. Rashmi Pundeer.Presently she is working as assistant professor in Govt.College Hisar (Department of High-er Education, Panchkula Haryana, since 2011).Her area of interest in research is exploring new techniques in the synthesis of heterocyclic compounds.