Copper(II) triflate-mediated synthesis of 1,3,5-triarylpyrazoles in [bmim][PF6] ionic liquid and evaluation of their anticancer activities

A simple, efficient, and environmentally friendly protocol for the synthesis of 1,3,5-triarylpyrazole in [bimm][PF6] ionic liquid mediated by Cu(OTf)2 is described. The reaction protocol gave 1,3,5-triarylpyrazoles in good to high yields (71-82%) via a one-pot addition–cyclocondensation between hydrazines and chalcones, and oxidative aromatization without requirement for an additional oxidizing reagent. The catalyst can be reused up to four cycles without much loss in the catalytic activity. The pyrazoles (4a-o) and pyrazolines (3a-n) were evaluated for antiproliferative activity in SK-OV-3, HT-29, and HeLa human cancer cells lines. Among all compounds, 3b inhibited cell proliferation of HeLa cells by 80% at a concentration of 50 μM. Pyrazoles and their derivatives are well recognized as an important class of heterocyclic compounds that have been found with extensive use in the pharmaceutical, material, and agrochemical industries. Compounds containing pyrazole moiety have exhibited diverse biological activities. For example, 4-substituted 1,5-diaryl-1H-pyrazole-3-carboxylate derivatives can act as cannabinoid-1 (CB1) receptor antagonists, Iκβ kinase β (IKKβ or IKK-2) inhibitors, and antiinflammatory agents. Pyrazole derivatives have been shown to have good binding affinity towards estrogen receptor. Some of the pyrazole derivatives have been reported to possess antidepressant, anticonvulsant, anti-inflammatory, and arthritics activities. Pyrazole scaffold constitutes the basic framework of several drug molecules such as celecoxib (a non-steroidal anti-inflammatory drug) and rimonabant (an anorectic antiobesity drug) (Figure 1). Figure 1. Chemical structures of drug molecules, celecoxib and rimonabant containing pyrazole scaffold. Because of their diverse bioactivities, pyrazoles have received considerable attention of chemists. Thus, a number of synthetic strategies have been developed for their synthesis. 16 The most common approach for synthesis of substituted pyrazoles is the condensation of α,β-unsaturated carbonyl compounds with hydrazines. However, this strategy results in the formation of 4,5dihydro-1H-pyrazoles (pyrazolines) that need to be further oxidized to corresponding pyrazoles. For this oxidative aromatization of pyrazolines to pyrazoles, various reagents have been employed such as I2 , Bi(NO3)3. 5H2O , MnO2 , DDQ, Pd/C, NaOEt, PhI(OAc)2 , and TBBDA. However, many of these oxidative methods suffer from relatively high oxidant loading, use of strong oxidants and chlorinated organic solvents, harsh conditions, poor yields, and longer reaction time. Thus, the development of environmentally benign processes with the use of alternative solvents such as ionic liquids in place of organic solvent and a catalytic amount of ecofriendly catalysts that avoid harsh oxidizing reagents are desirable. As part of our ongoing work on the development of novel reaction methodologies using metal triflates, and evaluation of small molecules as anticancer agents, herein we report copper (II) triflate-mediated protocol for the synthesis of pyrazoles by one-pot reaction of hydrazines with α,β-unsaturated ketones in 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF6]) ionic liquid (Scheme 1) and evaluation of antiproliferative activity against different cancer cell lines. In the standardization experiment, when 4-tertbutylphenylhydrazine hydrochloride (2) and 1,2diphenylprop-2-en-1-one (1) were reacted in ethanol at 130 °C in the presence of Cu(OTf)2 (20 mole %), 1-(4tert-butylphenyl)-3,5-diphenyl-4,5-dihydro-1H-pyrazole (3a) was obtained in 62% yield (Table 1, entry 8). Further optimization of reaction condition was carried out by changing solvents, catalysts, and catalyst loading. As shown in Table 1, the use of 20 mol% Cu(OTf)2 in [bmim][PF6] gave the desired product 4a in excellent yield (82%) (Table 1, entry 2). When Cu(OTf)2 was changed with other catalysts such as pTSA, Sc(OTf)3, Ce(OTf)3, Zn(OTf)2, AgOTf, or Yb(OTf)3, a mixture of 3a and 4a was observed. Use of Ce(OTf)3 in [bmim][PF6] resulted in 75% of 3a along with 10% of 4a whereas pTSA in [bmim][PF6] gave 69% of 3a (Table 1, entry 11-12). There was not much increase in yield of 4a on changing the amount of Cu(OTf)2 from 20 mol% to 30 mol%. However, reducing the amount of Cu(OTf)2 to 10 mol% decreased the yield of 4a to 64% along with the formation of 3a in 15% (Table 1, entries 1-3). These data indicate that Cu(OTf)2 was involved in aerobic oxidation of 3a to 4a. It is necessary to mention that 4a was not formed in the absence of Cu(OTf)2 in [bmim[PF6] ionic liquids, and only 3a was isolated along with starting material.