Microwave-Assisted Synthesis of Novel 5-Trichloromethyl-4,5-dihydro-1H-1-pyrazole Methyl Esters under Solvent Free Conditions

A preparação, com bons rendimentos (70–98%), de doze novos ésteres etílicos de 5-triclorometil-4,5-diidro-1H-1-pirazóis, usando-se ambientalmente boas técnicas induzidas por microondas, é descrita. Estes compostos foram sintetizados a partir da reação de ciclocondensação de 1,1,1-tricloro-4-alcoxi-3-alquen-2-onas [CCl 3 C(O)C(R)=C(R)OR, onde R, R = H, alquila; R = H, alquila e arila] com metil carboxilato hidrazina. As vantagens obtidas pelo uso de irradiações de microondas na ausência de solventes, em relação ao método convencional foram demonstradas.


Introduction
Trihalomethyl substituted pyrazoles belong to an important class of compounds, which possess a wide variety of pharmaceutical and agrochemical properties. 1,2 The main synthetic method used to prepare trihalomethylpyrazoles involves a [3+2] cyclization such as the classical 1,3-diketone with hydrazines. 3 In recent years, we have developed a general synthesis of 1,1,1-trihalo-4-alkoxy-3-alken-2-ones, 4,5 important halogen-containing building blocks and their use in heterocyclic preparations (e.g. isoxazoles, pyrazoles, pyrazolium chlorides, pyrrolidines, pyrimidines, thiazines, diazepines, thiazoles, selenazoles, and quinolines) has been extensively described. 5 In particular, trichloromethyl substituted azoles are important as synthons and reagents in organic synthesis. These compounds have also been used as precursors for the synthesis of carbonyl-azole derivatives 6 in a one-pot procedure. Moreover, the pharmaceutical properties of trichloromethyl substituted pyrazolines have been reported by our research group. 7 Recently, we reported the application of microwave irradiation for the synthesis of halomethylsubstituted azoles. 8 The beneficial effects of microwave irradiation are playing an increasing role in process chemistry, especially in cases where classical methods require forcing conditions or prolonged reaction times. When processes involve sensitive reagents, or there is the possibility of compound decomposition under prolonged reactions conditions, microwaves have also shown an advantage. The use of focused microwave irradiation to decrease reaction times and improve yields has been demonstrated. 9 Microwave irradiation (MW), using commercial domestic ovens, has been recently used to accelerate organic reactions, due to its high heating efficiency, giving remarkable rate enhancement and dramatic reduction in reaction times. In recents papers were reported the application of microwave irradiation with great results for the synthesis of heterocycles, an eco-friendly methodology to prepare indazoles, pyrazolopyridines, bipyrazoles, aziridines, benzimidazoles and 2-oxazolines in solvent free conditions. 10,11 Thus, the aim of this work is to demonstrate the advantages obtained by the use of microwave irradiation for the synthesis of novel 5trichloromethyl-4,5-dihydro-1H-1-pyrazole methyl esters 2 by the reaction of 1,1,1-trichloro-4-alkoxy-3-alken-2ones 1 with methyl hydrazino carboxylate under solvent free conditions and in good yields (Scheme 1).

Experimental
Unless otherwise indicated, all common reagents and solvents were used as obtained from commercial supplies without further purifications. The melting points were taken on a melting point microscope Reichert-Thermovar and are uncorrected. 1 H and 13 C NMR spectra were recorded on a Bruker DPX 400 ( 1 H at 400.13 MHz and 13 C at 100.62 MHz) in 5 mm sample tubes at 298 K (digital resolution ±0.01 ppm) in CDCl 3 /TMS solutions. Mass spectra were registered in a HP 6890 GC connected to a HP 5973 MSD and interfaced by a Pentium PC. The GC was equipped with a split-splitless injector, autosampler, cross-linked HP-5 capillary column (30 m, 0.32 mm of internal diameter), and helium was used as the carrier gas.
Microwave irradiations were conducted in a Panasonic M720 at a frequency of 2450 MHz, with an average energy in the sample of 45 W and the temperature measured after the completion of the reaction in the range of 50-55 °C. The measure of average energy in the sample is in agreement with methodology presented in reference 9.

Synthesis of 5-trichloromethyl-4,5-dihydro-1H-1-pyrazole ethyl esters 2a-l (microwave method)
A mixture of 1,1,1-trichloro-4-alkoxy-3-alken-2-ones 1 (2 mmol) and methyl hydrazino carboxylate (2.5 mmol) was stirred for a few minutes, and then the mixture was irradiated in a microwave oven at 45 W for 6 min, at 50-55 o C (temperature after the completion of the reaction). A10% HCl solution (30 mL) was added to the reaction mixture, and the product 2 was extracted with chloroform (2 × 20 mL), washed with distilled water (2 × 30 mL) and dried with MgSO 4 . The solvent was removed in a rotaevaporator, and the product was obtained in high purity. When necessary the product was recrystallized from cyclohexane.

Synthesis of 5-trichloromethyl-4,5-dihydro-1H-1-pyrazole ethyl esters 2a-l (conventional method)
A solution of 1 (2 mmol) and NH 2 NHCO 2 Me ( 2.5 mmol) in methanol (30 mL) was stirred under reflux for 24 hours. Water was added (60 mL) and the organic phase was extracted with CHCl 3 (2 × 20 mL). The organic extract was dried (MgSO 4 ) and the solvent was removed under reduced pressure. The work-up was carried out as described for the microwave method.