Ultrasonic irradiation assisted efficient regioselective synthesis of CF₃-containing pyrazoles catalyzed by Cu(OTf)₂/Et₃N

Over the last two decades there has been rapid progress in synthetic organic chemistry associated with the search for new organic compound derivatives with desirable properties. Such compounds are widely used in the pharmaceutical industry. Among the several FDA approved pharmaceutical drugs, the pyrazole core is found in rimonabant (1), and celecoxib (2) (Figure 1) [1].

Pyrazoles exhibit significant biological properties such as antihyperglycemic [2], analgesic [3], anti-inflammatory [4], antipyretic [5], antibacterial [6], hypoglycemic [7] and sedative-hypnotic activities [8].

The trifluoromethyl group is a very important substituent in medicinal chemistry, due to its unique stereoelectronic properties. A trifluoromethyl group usually increases the lipophilicity of a molecule, improving its transport characteristics in vivo. Furthermore, the strength and durability of the C-F bond compared with the С-Н bond (116 and 100 kcal/mol respectively) allows undesirable metabolic transformations to be avoided. So the introduction of trifluoromethyl groups into bioactive molecules has become very important in pharmaceutical studies, stimulating work directed towards the elaboration of synthetic methodology for compounds containing trifluoromethyl groups. Because of all these factors, organofluorine chemistry has been vigorously developing during the past two decades [9].

Most of the known approaches to the synthesis of CF₃-containing organic compounds suffer from serious drawbacks. First of all, the starting materials required for these methods are rather difficult to obtain, or they are fairly toxic and inconvenient to work with. Additionally, methods for direct fluorination and trifluoromethylation do not always allow the introduction of the CF₃-group at the required position of a molecule.

It is worth mentioning that most of the reported methods for synthesis of CF₃-containing pyrazoles suffer from formation of mixures of regioisomers. Pavlik et al. studied the reactivity of CF₃-enones towards N-substituted hydrazines where a mixture of regioisomers was obtained. Also, in the reaction of β-alkoxy substituted enones with N-methyl hydrazine two isomeric dihydropyrazoles were obtained [10, 11]. Singh et al. investigated the reactivity of 3-(ethoxymethylene)1,1,1-trifluropentan-2,4-dione with various aryl and heteroaryle substituted hydrazines, and a mixure of pyrazoles formed [12].

Nenajdenko et al. obtained CF₃-conatining pyrazoles with 100% regioselectivty from the reaction of α-bromo-ethoxy-trifluromethyl enone with aryl hydrazine, but with lower yield [13].

As a result the more flexible “synthon” approach, based on the application of simple and readily available fluorine-containing compounds has gained substantial interest [14]. Nitrilimines containing a fluro or trifluoromethyl moiety (liberated in situ from the corresponding hydrazonyl halide) are easily available compounds which can be prepared by various methods [15] and fairly convenient building blocks to prepare heterocyclic compounds containing a trifluoromethyl group.

It is evident from the recent literature that copper triflate [Cu(OTf)₂] has invoked enormous interest as a green and potential Lewis acid catalyst to construct carbon–carbon and carbon– heteroatom bonds in various organic transformations [16–23]. Despite its great importance, only a few papers have reported on its catalytic application in organic synthesis [24].

Ultrasound irradiation has been utilized to accelerate a number of synthetically useful reactions during the last few years. Cavitation is the formation, growth and collapse of bubbles in an irradiated liquid. This effect induces very high local pressure and temperatures inside the bubbles and enhances mass transfer and turbulent flow in the liquid [25]. Ultrasound has been utilized to accelerate a number of synthetically useful reactions, especially in heterocyclic chemistry [26–36].

As part of our ongoing interest in sonochemistry [37–42], and in a continuation of our interest in the synthesis of a wide range of heterocyclic systems for biological screening programme in our laboratory [43–51], we will introduce here a novel and efficient regioselective synthesis of trifluromethyl containing pyrazoles under ultrasonic irradaition promoted by catalytic amount of copper triflate and triethylamine.

A wide variety of catalysts were scanned for the reaction of N-phenyltrifluromethylcarbohydrazonoyl benzenesulfonate (3) and 1,1,1-trifluoropentane-2,4-dione (4a) (Scheme 1) in ethanol under ultrasound irradiation as a model reaction (Table 1). These catalysts are sodium ethoxide, triethylamine, copper triflate, copper triflate/triethyl amine, which were selected to promote the mentioned reaction.

Absolute ethanol was selected as solvent due to the solubility of the two starting materials. Thin layer chromatography (TLC) used to follow the reaction progress.

It is clear from the results cited in Table 1, that only one isolable unique product was obtained (as examined by TLC). The best yield of 90% of the isolated product was reached using Cu(OTf)₂ and Et₃N, each of 0.05 equiv. (entry 7). The reaction gave relatively low yield when 0.05 or 0.1 equiv. of Et₃N alone was used (entry 3,4). Furthermore, sodium ethoxide base gave a trace amount of product (entry 2) and no reaction was observed in the absence of catalyst or using Cu(OTf)₂ as catalyst in 5 or 10 mol% (entry 1,5,6 respectively). Also from Table 1, the effect of loading (Mol%) on the% yield of isolated product was studied, and it is clear that 0.05:0.05 equiv. of Cu(OTf)₂ and Et₃N furnishes the respective product in a quantitative yield (Table 1, entry 7,8).

It is worth mentioning that we followed the above reaction to completion using GC-MS and the resulting products were identified from their retention times. It was found that 100% regioselectivity was attained in presence of Cu(OTf)₂ with Et₃N (Table 1, entry 7 and 8) but in the presence Et₃N only (Table 1, entry 3 and 4) there was a very small amount (traces) of other product detected by GC-MS, which completely disappeared in recrystalization of the crude product to give only pure 5a.

The isolated product was identified as the pyrazole structure 5a, although two regioisomeric cycloadducts 5a and 6a seemed possible (Scheme 1). Unambiguous structure determination of the obtained products is therefore crucial to rationalize the observed regioselectivity. Structure elucidation was conveniently achieved on the basis of the ¹H-¹³C connectivities (gHMBC) showed by methyl protons towards the carbonyl group and C-4 of pyrazole. On this basis, the analysis of gHMBC spectra of the product led us to attribute the signal at δ 191.65 ppm to the quaternary carbon (carbonyl group) owing to its correlation peaks with the methyl protons at δ 2.65 ppm; also, the signal at δ 112.11 ppm to the C-4 of the pyrazole owing to its correlation peaks with the methyl protons at δ 2.65 ppm. This observation indicated that the methyl protons correlate to carbonyl functional group and the C-4 of the pyrazole, which is in accordance to the structure 5a (Figure 2). Therefore, ¹H-¹³C HMBC of the product formed provides sharp evidence for the existence of regioisomer 5a and rules out the other alternative structure 6a. Consequently the reaction product was identified as the pyrazole structure 5a (Scheme 1).

The formation of pyrazole product 5a is in line with the well established earlier studies for β-diketones containing highly fluorinated groups, in which the enolic content predominates, as in Figure 3[52–54].

It is reasonable to propose a mechanism for formation of the pyrazole 5a under the adopted reaction conditions (Scheme 2). Pyrazole 5a was assumed to form via nitrile imine 7 (liberated in situ from 3 by the action of triethylamine and release triethyl ammonium salt) which involved a more or less concerted cycloaddition reaction. In the Cu(OTf)₂-catalyzed addition reactions it reacts with the enolized form of β-diketone 4a _II to generate copper(II) intermediate 8 and release of triflic acid (TfOH). The nitilie imine 7 reacts with intermediate 8 to give non isolable intermediate 5-hydroxy-2-pyrazoline derivative 9, and cyclizes via elimination of molecule of water to yield the desired regioselective pyrazole derivatives 5a.

Therefore, copper(II)triflate has an important role in which it activates the enolic O-H bond of β-diketone to initiate the reaction.

The scope and generality of this protocol was tested using another derivative of β-diketone 4b with N-phenyltrifluromethylcarbo-hydrazonoyl benzenesulfonate (3) as shown in the Scheme 3 under the optimized reaction conditions, and the corresponding pyrazole derivatives 5b were obtained in excellent yield.

We extended our study to find out the reactivity of β-diketone 4a,b towards the α-ketohydrazonoyl halides 10a-f under ultrasonic irradiation and/or conventional method to give the corresponding pyrazole derivatives 11a-l in 85–91% yields (Scheme 4, Table 3).

The structure of pyrazole derivatives 11a–l was assigned on the basis of their elemental analyses and spectral data. For example, the ¹H NMR spectrum of compound 11a revealed two singlet signals at δ 2.29 and 2.74 due to the two methyl groups in addition to aromatic multiplet at δ 7.31–7.71. The mass spectrum of the same compound revealed a peak corresponding to its molecular ion at m/z 296. The mechanism of the formation of compounds 11a-l is in line with those depicted in Scheme 2.

From the data cited in Table 3, it was observed that the reaction time increased considerably and the yield of the products decreased under conventional method. Thus, ultrasound was found to have beneficial effect on the synthesis of pyrazole derivatives in which decrease time of above reactions from 7 to 11 h in conventional procedure to 45 min. to 1 h. Also, there was a noticeable improvement in the yields of the reactions under ultrasonic irradiations.

The improvement induced by ultrasound in the above mentioned reactions can be attributed to the well established theory for the cavitation, The collapse of bubbles caused by cavitation produces intense local heating and high pressures [55, 56], so reaction time decreases clearly and high% yield was obtained.

An ultrasonic assisted efficient protocol for the regioselective synthesis a series of novel pyrazoles containing the trifluromthyl moiety utilizing an efficient catalytic system Cu(OTf)₂/Et₃N was reported. Cu(OTf)₂/Et₃N catalyst showed a great advantage over all the investigated catalysts and ultrasonic irradiation method offered high yields of pyrazoles in short reaction times compared with classical conditions. gHMBC spectra of the product were used to rationalize the observed regioselectivity.