Ionic liquid [Et3NH] [HSO4]-catalyzedMulticomponent Synthesis of 6-amino-4- (substituted phenyl)-3-methyl-2,4-dihydropyrano[2,3-c] pyrazole-5-carbonitrile

A series of 6-amino-4-substituted-3-methyl-2,4-dihy ropyrano[2,3-c] pyrazole-5-carbonitriles(5a5j) as a potent anticancer agent were synthesized v ia one-pot, four-component condensation reaction of aryl aldehydes, ethyl acetoacetate, malononitrile, and h y razine hydrate in solvent-free conditions using i onic liquid[Et3NH] [HSO4] as an efficient, eco-friendly and reusable cataly st. The Multicomponent coupling reactions (MCRs) indicate a highly appreciated synt hetic tool for the establishment of novel and compl ex molecular scaffold with a minimum number ofsyntheti c steps with the advantage like shorter reaction times, lower costs, high degrees of atom economy etc.With the literature survey it is found that d ihydropyrano[2,3c]pyrazole derivatives possess very important biolo gical activities, including anticancer, antiinflamm atory, antimicrobial, inhibitors of human Chk1 kinase, mol luscicidal, and insecticidal activities. The solven t used in conventional organic synthesis are suffered by many disadvantage like environmental hazards, toxicity, volatile nature, expensive etc. A new term ‘designer solvent s’ refers to Ionic liquids because of their adjusta ble physical and chemical properties with the change in selected ationic and anionic combination. Ionic liquids ha ve become a promising alternative media for various ch emical processes due to their properties including good solvating capability, negligible vapour pressure, n on-inflammability, ease of recyclability,controlled miscibility and high thermal stability. Herein we are introducing first time the use of ac idic Bronsted ionic liquid(ABILs)[Et3NH][HSO4] triethyl ammonium sulphate for the synthesis of bio logically important scaffold 6-amino-4-(substituted phenyl)-3-methyl-2,4-dihydro pyrano[2,3-c]pyrazole-5-carbonitrile,the synthesise d derivatives subjected to anticancer activity. Compared to other methods, this new method consist e tly has advantages, including excellent yields, a short rea ction time, mild reaction conditions and catalyst r eusability.

green chemistry.In modern era, academicians and industrialist are looking for green protocols for the synthesis of chemical processes to conquer eco-friendliness [3]To replace conventional media or solvents used for organic synthesis is very essential as they shows some side effects including toxicity, flammable and volatile nature so research is progressing in finding alternative greener media for commonly used organic synthesis [4],research and development of room-temperature ionic liquids are acting as best replacement to conventional media with the advantages such as chemo selectivity and facile condensation reactions [5,6,7] In organic synthesis green chemistry is now a days acting as boon with the use of deliberately important solvents so called a 'designer solvents' referring to Ionic liquids because of their adjustable physical and chemical properties with the change in selected cationic and anionic combination.Ionic liquids have become a promising alternative media for various chemical processes due to their properties including good solvating capability, negligible vapour pressure, non-inflammability, ease of recyclability, controlled miscibility and high thermal stability.[8,9].Hence acting as very excellent catalysts, as well as solvents, for many organic transformations [10] Acidic Bronsted Ionic Liquids (ABILs) are of special importance, because they simultaneously possess proton acidity and the characteristic properties of ionic liquids.ABILs offer environmental friendly catalyst properties due to the combination of the advantages of liquid acids and solid acids, such as uniform acid sites, stability in water and air, easy separation and reusability.[11].In recent times, the value of Acidic Bronsted Ionic Liquid (ABIL), mainly [Et 3 NH][ HSO 4 ] has acknowledged as a catalyst and solvent of choice for organic transformation with excellent yield.[Et 3 NH][HSO 4 ] ionic liquid posses advantages as non-toxic, inexpensive ,easy preparation with readily available starting reactants .[12,13].

Synthesis of dihydropyrano
Theresidual ionic liquid was washed with diethyl ether, dried under vacuum at 60and reused for subsequent reactions.The recovered ionic liquid could be used for four times without much loss of catalytic activity.After 15 min of stirring, the reaction mixture was cooled to room temperature.125 Then, it was extracted using ethylacetate.The reaction mixture was quenched with crushed ice and extracted with ethyl acetate.
The solvent was evaporated under reduced pressure to afford the corresponding crude compounds.The obtained crude compounds were recrystallized using ethanol.An important feature of this method is that both electronreleasing and withdrawing groups give excellent yields.

4 .
Conclusion: In conclusion we have tried to developed an efficient, greener and prompt synthetic protocol for substituted dihydropyrano[2,3-F]pyrazoles via one pot cyclocondensation of various aromatic aldehydes, ethyl acetoacetate, hydrazine hydrate, and malononitrile by using[Et3NH][HSO4] catalyst.This technique overcomes some of the problems associated with excessive or wasteful refluxing procedure.Remarkable advantages of this synthetic strategy are reaction performs at ambient room temperature in very less reaction time with nontoxic and economically viable catalyst by avoiding the use of solvent and lastly shortened work-up procedure.As far our knowledge this is the first report on the use of [Et 3 NH] [HSO 4 ] catalyst for the syntheses of substituted dihydropyrano[2,3-F]pyrazoles.SUPPLIMENTRY DATA Table1 Physical characterization of 6-amino-4-(substituted phenyl)-3-methyl-2,4-dihydropyrano[2

Table 2
Screening of reaction media for the synthesis of compound 5a-5j reaction was carried out in the absence of the catalyst; no product is obtained so catalyst is added increasing amount to determine the appropriateconcentration of the catalyst and solvent [Et3NH][HSO4], we investigated the model reaction atdifferent concentrations of [Et 3 NH][HSO 4 ], such as 0,5, 10, 15, 20 and 25 mol%.The dihydropyrano[2,3-c]pyrazole formed in 0,50,65,70,94 and 85 % yields, respectively(Table2).The increase in concentration of catalyst from 20 to 25 mol% does not increase the yield of product.This indicates that 20 mol% of [Et 3 NH] [HSO 4 ] is sufficient forthe reaction by considering the product yield.

Table 3
Effect of ionic liquid concentration on reaction time and yieldEntry [Et 3 NH][HSO 4 ] mol%Time in minutes Yield(%)

Table 4
Reusability of ionic liquid for model reaction Bruker, Billerica, MA, USA)fitted with an Aspect 3000 computer and all the chemical shifts (δppm) were referred to internal TMSfor 1 H and DMSO-d6 for 13 C-NMR.
With extreme high literature survey of all available method of multi component one pot cyclo condensation synthesis of 6-amino-4-(substituted phenyl)-3-methyl-2,4-dihydropyrano[2,3-c] pyrazole-5-carbonitrile herein as far as our genuine knowledge first time we are introducing the use of this green medium i.e.Acid Bronsted Ionic Liquid [Et3NH] [HSO4]as solvent and catalyst in 20mol% at room temperature in 10 to 15 minutes with excellent yield up to 94%.1H-NMR data are reported in the order of chemical shift,multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; br, broad; br s, broad singlet; m, multiplet and/or multiple resonance), number of protons.A Micro TOF-Q-II (Bruker Daltonics, Billerica, MA, USA with electron spray ionization (ESI) was used to obtain the HRMS data.