The effect of pressurized carbon dioxide on the cyclocondensation reaction between 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones and hydrazines

The synthesis of 1-unsubstituted and 1-phenyl-5-trifluoromethylpyrazoles from the reaction of 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones [CF 3 C(O)CH=C(R 1 )OR, where R = Me, Et and R 1 = H, Me, Ph] with hydrazines [NH 2 NHR 2 , where R 2 = H, Ph] in pressurized carbon dioxide is reported for the first time. Reaction conditions such as pressure, temperature and time were evaluated. The methodology developed herein was suitable to synthesize products in moderate to excellent yields (60 % - 96 %) and short reaction times (15 - 45 min).


Introduction
Supercritical fluids (SCF) are becoming increasingly important solvent systems for organic chemistry and engineering. 1,2Supercritical fluids, which are pure compounds or mixtures heated and pressurized beyond their critical points, 1 have several advantages as solvents for homogeneous catalysis.Some of these advantages are true for all SCF solvents and essentially all reactions: mass transfer is very rapid, the solvent is completely miscible with gaseous reactants, and the solvent is easy to remove from the product.Among the SCF, supercritical carbon dioxide (sc-CO2) is the most popular. 3sc-CO2 has received special attention since it is readily accessible, has a low critical temperature (Tc = 31 °C) and moderate critical pressure (Pc = 75.8bar), conditions that are easily achieved in the laboratory. 4The advantages related to the use of sc-CO2 are so numerous that they have prompted intense research to develop its potential as a solvent for synthesis. 5,6Some advantages, such as it being non-toxic, non-flammable, and non-polluting, [7][8][9] are specific to sc-CO2, and it does not cause cancer or other long-term health problems.
Over the past few years, the investigation of reactions in SCF has become an important research area for modern synthetic chemistry and has included studies of enzymatic reactions, stereoselective syntheses, polymer processing, [10][11][12][13] and homogeneously catalyzed reactions such as Baylis-Hillman coupling, and cycloaddition reactions. 14,15The study of model reactions is an efficient strategy for acquiring knowledge of the chemical reactivity in sc-CO2, as is the case for the cyclocondensation reaction, which is an important and general route to the construction of five-membered heterocyclic ring systems.There are few examples devoted to cyclocondensation reactions using SCF as the reaction media; 16 the synthesis of pyrazoles, for example, has not yet been reported.These heterocyclic systems have many derivatives with a wide range of interesting properties.Additionally, the presence of trifluoromethyl substituents in heterocyclic rings is of importance, since physiological activity is in part promoted by the increased lipophilicity of these molecules, resulting in greater cell permeability. 179][20][21] Also, our research group is continuously interested in a more environmentally benign synthesis, demonstrated by our recent papers that focus on solvent-free synthesis 22 and the use of ionic liquids as reaction media, 23 something that is associated with efficient techniques such as microwave 20,21 and ultrasound irradiation. 24Due to our sustained interest in the study of heterocyclic synthesis and the lack of cyclocondensation reactions under pressurized CO2 in the literature, herein, we wish to report a mild and efficient method for the preparation of NH-and phenyl-pyrazoles under pressurized CO2 conditions.

Results and Discussion
Enones 1a-c were synthesized from the reaction of trifluoroacetic anhydride with enol ether or acetal, in accordance with the methodology developed in our laboratory. 25Hydrazine monohydrate and phenylhydrazine were obtained commercially and used without further purification.
Initially, two sets of experiments were programmed in order to evaluate the effect of pressurized CO2 on cyclocondensation reactions.For this purpose we chose three enones (1a-c) and two different hydrazines (hydrazine monohydrate (2) and phenylhydrazine (4) which were studied under different reaction conditions and with variations in pressure, temperature, and time.These substrates were screened in order to evaluate the substituent effect, where hydrogen had no electronic effects on the structure, methyl was electron-donating, and Phenyl was electron-donating or electron-withdrawing. Similarly, these effects were considered in the choice of hydrazines, where the hydrazine monohydrate there is no substituent and phenyl hydrazine where phenyl reduced the electronic density of nitrogen of hydrazine.
The effect of pressurized CO2 was primarily evaluated for the reaction of hydrazine monohydrate with enones 1a-c, as depicted in Table 1.From this data it can be seen that the substrate 1a suffers a strong influence from the applied pressure, which is reflected in the product yield.Indeed, as the pressure was increased two-fold (entries 1 and 2), the product yield increased by more than 40 % and the NH-pyrazole 3a was furnished at 95 % yield.On the other hand, an increase in the temperature from 65 °C to 80 °C at 60 bar (entry 1 and 3) did not lead to a considerable increase in the product yield, showing that 65 °C is a suitable temperature to perform this reaction.The same set of experiments was applied for enone 1b.A pressure of 60 bar and temperature of 65 °C furnished the NH-pyrazole 3b at 77 % yield in only 15 min.The use of a longer reaction time did not lead to an improvement in the yield.Comparing this result with what was previously observed for 3a, it can be seen that enone 1b performs better in relation to 1a in terms of both reaction time as well as product yield.In the next test, we decided to maintain the temperature of 65 °C and double the pressure (entries 4 and 5).Surprisingly, this reaction condition was not as effective as expected (based on the results for enone 1a) as there was a yield decrease of 6 % (entries 4 and 5).Finally, the temperature was increased to 80 °C, which resulted in the product yield decreasing (entries 3 and 6).The last evaluated substrate, enone 1c, was strongly affected by the increase in the temperature and in the pressure.The mild condition (entry 7) led to the product being obtained at a moderate yield.However, maintaining the temperature at 65 °C and using a pressure of 120 bar (entry 8) led to the desired product 3c at an excellent yield (96 %).Although the temperature increase to 80 °C also raises the product yield (entry 7 and 9), the two-fold increase in the pressure is a prevalent factor.Thus, this methodology has been successful for the three enones studied which were obtained in good to excellent yields.In spite of pressurized CO2 being a nonpolar and aprotic solvent, it acts as a Lewis acid 16 which favors the desired pyrazole formation.
With these results in hand, we decided to investigate the reaction of phenylhydrazine 4 with enones 1a-c.Sets of experimental tests similar to that for hydrazine 2 were applied to phenylhydrazine 4. The results obtained are shown in Table 2.A condition of 65 °C and 60 bar (entry 1) led to the desired product 5a at a moderate yield (65 %).Subsequently, a two-fold increase in the pressure (entry 2) raised the product yield to 87 %, following the same behavior already found for the reaction with hydrazine 2. The last attempt involved an increase in the temperature (entry 3), however it led to a lower product yield (50 %).An interesting find was observed from the reaction between enone 1a and hydrazine 4, as the use of pressurized CO2 led to the attainment of product 5a with high regioselectivity.In previous works, using other methodologies as microwave irradiation and/or ionic liquids, this product was obtained as a mixture of 1-phenylpyrazole and the 4,5-dihydropyrazole derivative. 26,27Analyzing enone 1b, we can see that at 65 °C and 60 bar (entry 4) product 5b was obtained in 60 % yield.In an attempt to improve this result, pressure and temperature were evaluated.However, a two-fold increase in pressure (entry 5) resulted in a similar yield, demonstrating that the pressure has no influence on enone 1b, as already seen with hydrazine 2. Likewise, the increase in the temperature (entry 6) led to a lower product yield (45 %), as already observed with this enone and hydrazine 2. As expected, enone 1c resulted in a high product yield (89 %) at 65 °C and 60 bar (entry 7).A two-fold increase in pressure (entry 8) resulted in the yield decreasing to 57 % and a temperature increase (entry 9) led to a 78 % yield.Of all the cases, this is the only one where an increase in the temperature favors the product yield when compared with an increase in the pressure.
In a general analysis of the two evaluated hydrazines, it can be seen that a pressure increase is preponderant to good product yield.When a two-fold increase in the pressure was applied, product reaction with hydrazine 2 was obtained at better yields for enone 1a and 1c, but was invariable to reaction with 1b.When the same variation was applied to reactions with hydrazine 4, the best yield was observed in enone 1a, while the product yield for reaction with enone 1c was small and product yields from enone 1b were not affected by an increase in pressure.The reaction was also sensitive to the resultant temperature increase in products formed at small yields.In general, the effect of the temperature was less significant than the pressure and it had an inverse effect, in other words, the yields were better or invariable with an increase in the pressure and were smaller with a temperature increase.Taking into account the electronic effects of enone substituents, it can be seen that enones 1a and 1b led to product formation at excellent yields, while enone 1b furnished the product at a good yield, independent of hydrazine.Additionally, the CO2 pressurization is expected to have physical and/or chemical effects.The volume of a liquid phase may expand by dissolution of CO2 molecules, causing a dilution of reacting species in the liquid phase. 28Pressurization of CO2 has not only the physical effect of enhancing the dissolution of gaseous reactants but also a chemical effect as it changes polarity.
From the results described here, it is evident that there is an sc-CO2 effect in the solvent reaction, with differential solvation occurring.The solvation effect of sc-CO2 in this reaction, which is similar to ionic liquid effects, 23 can be attributed to the interaction with Lewis acid or the well-known role of sc-CO2 as Lewis acid. 29Additionally, in the case of the reaction presented in this work, the CO2 probably participates in hydrogen bonds with carbonyl compounds, 29 enhancing the solvation effects in the activated complex of the reaction.a Reaction time for all conditions to product 5 a-c was 45 min .b Isolated product.

Conclusions
In conclusion, we have developed a simple and efficient method for the synthesis of NH-and Nphenyl-pyrazoles by applying a cyclocondensation reaction between different enones and hydrazines under pressurized CO2 conditions.The notable features of this procedure are mild and green reaction conditions, good yields and reaction rates, and cleaner reaction profiles.At present, further investigations are in progress in order to find additional synthetic applications for obtaining other heterocyclic compounds under pressurized CO2 conditions.

Experimental Section
General.Unless otherwise indicated, all common reactants were used as obtained from commercial suppliers without further purification.General procedures for the cyclocondensation reactions under pressurized carbon dioxide.Preparation of pyrazoles: Firstly, the ultrathermostat bath coupled to the CO2 pump was adjusted to 5 °C.Subsequently, the enone 1a-c (1 mmol) and the hydrazine (1 mmol) were placed in the Parr reactor cell which is coupled to a pressure and temperature controller.Carbon dioxide was then introduced into the mixture directly from the cylinder at 1.8 MPa pressure at room temperature.The mixture was stirred for the appropriate time and at the appropriate temperature, as described in Tables 1 and 2. After the reaction time, the system was slowly depressurized and the products were obtained in their pure forms.

Spectroscopic data of Compounds 3 and 5
The spectroscopic data found for these compounds are in accordance with reference 26.

Table 1 .
Influence of the temperature and pressurized CO2 on the synthesis of 3a-c and 5a-c 13 and13C NMR spectra were acquired on a Bruker DPX 200 or Bruker DPX 400 spectrometer ( 1 H at 200.13 MHz or 400.13 MHz, and13C at 50.32 MHz or 100.13MHz, respectively) at 300 K, using 5 mm sample tubes, and with digital resolution of ±0.01 ppm.CDCl3, or DMSO-d6 were used as solvents containing TMS as internal standard.GC-MS EI was registered in an Agilent 6890N series connected to an Agilent G1530CN GC 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 i.d.), and He was used as the carrier gas.A Teledyne Isco syringe pump (series D, model 256D) equipped with a pump controller, a Parr Instrument Co. model 4592 micro reactor (50 mL vessel) equipped with a temperature and pressure controller (Parr instrument Co., model 4843), and a thermal bath (Nova Ética, model 521/3D, CO2 gas, cooling 5 -7 °C) were used during the experiments.