Synthesis of Novel 1-[(2,6-Dichloro-4-trifluoromethyl)phenyl]-3-aryl-1H-pyrazole-4-carbaldehydes

A series of novel 1-[(2,6-dichloro-4-trifluoromethyl)phenyl]-3-aryl-1H-pyrazole-4-carbaldehydes 6a-i were synthesized using the Vilsmeier-Haack reagent. The structures of all the title compounds have been confirmed by elemental analysis, 1H-NMR and 13C-NMR and in addition, the structure of intermediate 5b was investigated by X-ray crystallography.


Introduction
The application of the Vilsmeier-Haack (VH) reagent (POCl 3 /DMF) for formylation of a variety of both aromatic and heteroaromatic substrates is well documented [1]. Besides this, the reagent has also been extensively used for effecting various chemical transformations with other classes of compounds. Many of these reactions have led to novel and convenient routes for the synthesis of various heterocyclic compounds [2]. A notable example that finds significant application in heterocyclic OPEN ACCESS chemistry is the synthesis of 4-formylpyrazoles from the double formylation of hydrazones with the VH reagent [3,4]. These observations, coupled with the recent developments in the simple synthesis of pyrazole derivatives [5], especially 4-functionalized 1,3-diphenylpyrazoles as antibacterial [6], antiinflammatory [7], antiparasitic [8], and antidiabetic drugs [9], prompted us to undertake the synthesis of pyrazole-4-carbaldehyde derivatives using the VH reagent.
It has been known for some time that fluorine atoms can lead to unexpected biological activity results due to the special properties of the fluorine atom, such as the high electronegativity of fluorine and the high carbon-fluorine bond energy [10]. As a consequence, trifluoromethyl-containing molecules have been found considerable utilization in the agrochemical and pharmaceutical industries [10][11][12], for example, pyrazole derivatives bearing trifluoromethyl groups, such as fipronil and analogs [13,14] are widely used phenylpyrazole insecticides applied in granular or bait form for residential and commercial control of turf grass pests, and celecoxib [15], widely prescribed to treat acute or chronic inflammation by providing symptomatic pain relief, are examples of such compounds. In this paper, we show a simple and efficient synthetic method using the VH reagent [4,16,17] that affords a series of novel 1-[(2,6-dichloro-4-trifluoromethyl)phenyl]-3-aryl-1H-pyrazole-4-carbaldehydes.

Results and Discussion
Phenylhydrazine 3 was synthesized from 2,6-dichloro-4-trifluoromethylphenylamine (1) through diazotization, reduction and hydration (Scheme 1). The reducing reagent plays an important role in the reaction. When the intermediate 2 was reduced by SnCl 2 , an almost quantitative yield of product was obtained. Use of Na 2 S 2 O 3 or Zn as reducing reagents led to lower yields. Phenylhydrazones 5 were next synthesized in almost quantitative yields by the reaction between the phenylhydrazine 3 and 3 or 4-substituted aryl methyl ketones, regardless of whether the ketones contained electron-withdrawing or electron-donating groups (Scheme 2).

X-ray diffraction
To verify the structural assignment compound 5b was selected as an example for an X-ray diffraction study ( Figure 1 and Table 1). The purified product 5b was dissolved in 50 % ethanol/acetone (1:1 v/v) and kept at room temperature for 5 days and single crystals of 5b were thus formed. CCDC 685556 contains the supplementary crystallographic data for this comound [18].  The Vilsmeier cyclization of hydrazones could provide an efficient route for the preparation of 1Hpyrazole-4-carbaldehydes. The reaction was carried out at 80-90 °C for 4 h using 3 equiv. of the VH reagent, affording a series of novel 1-[(2,6-dichloro-4-trifluoromethyl)phenyl]-3-aryl-1H-pyrazole-4carbaldehydes in good yields (Scheme 3). The results are shown in Table 2. 1H-Pyrazole-4carbaldehydes 6 cannot be obtained if the DMF used is not anhydrous.

General
All melting points were determined on an XT-4A apparatus and are uncorrected. TLC was performed using precoated silica gel GF 254 (0.25mm), column chromatography was performed using silica gel (200-300 mesh). The 1 H-and 13 C-NMR spectra were measured at 25 °C at 300 and 75 MHz, respectively, on a Bruker Advance 300 spectrometer, using TMS as internal standard. J-values are given in Hz. The IR spectra were taken on a Bruker Vector 55 spectrometer. Elemental analyses were carried out with an EA 1112 elemental analyzer. All the reagents used were AR grade. (3) 2,6-Dichloro-4-trifluoromethylphenylamine (1, 1.73 g, 7.5 mmol) was dissolved in concentrated HCl (10 mL) and water (10 mL) and cooled to 0 °C, sodium nitrite (0.62 g, 9.0 mmol) was added and the yellow solution was stirred at 0 °C for 2 h to get a solution of diazotizated compound 2. SnCl 2 (2.85 g, 15 mmol) was dissolved in concentrated HCl (10 mL) and cooled to 7 °C, then the diazotizated solution of 2 was added slowly dropwise. After 1 h of reaction, the precipitate was filtered, washed with water and air-dried. The precipitate was neutralized by 25% NaOH in water to pH 8, the light yellow sediment was collected and air-dried to afford a brown solid 3 (1.53 g, 83%), m.p. 65-67 °C. 1

General procedure for synthesis of N-(2,6-Dichloro-4-trifluoromethyl)phenyl-N'-(1-phenylethylidene) hydrazines 5a-i
To a solution of compound 3 (12 mmol) in absolute C 2 H 5 OH (30 mL) was added substituted acetophenone 4 (10 mmol). Two drops of concentrated HCl were added to a stirred solution, and the mixture was refluxed for 1 h. The solid obtained on cooling was filtered, dried and recrystallized from C 2 H 5 OH to give compounds 5a-i .

General procedure for synthesis of 1-[(2,6-dichloro-4-trifluoromethyl)phenyl]-3-aryl-1Hpyrazole-4-carbaldehydes 6a-i
POCl 3 (0.5 g, 3.0 mmol) was added dropwise to an ice-cold stirred solution of hydrazone 5 (1.0 mmol) in dry DMF (4 mL), the reaction mixture was allowed to attain room temperature and then heated at 80 °C for 4 h. The resulting mixture was poured onto crushed ice, neutralized with dilute sodium hydroxide and left standing overnight. The pale yellow precipitate obtained was purified by flash column chromatography with ethyl acetate-petroleum ether mixture to yield the products 6a-i.   for the synthesis in good yields of a series of 1-[(2,6-dichloro-4-trifluoromethyl)phenyl]-3-aryl-1Hpyrazole-4-carbaldehydes 6a-i using the Vilsmeier-Haack reagent. The structures of all the title compounds have been confirmed by elemental analysis, 1 H-NMR and 13 C-NMR and in addition, the structure of intermediate 5b was confirmed by X-ray crystallography.