Reaction of-Alkoxyvinyl Halomethyl Ketones with Cyanoacetohydrazide

Este trabalho apresenta a síntese de uma série de treze 1-cianoacetil-5-hidroxi-5-halometil1H-4,5-diidropirazóis a partir da reação de condensação entre cianoacetohidrazida e 4-alcoxi-3alquen-2-onas [RC(O)C(R)=C(R)(OR), onde R = CF 3 , CCl 3 , CHCl 2 , CO 2 Et; R = H, Me; R = H, Me, Et, Pr, Pentil, c-Hexil, Ph, e R = Me, Et]. Reações de desidratação e derivatização destes compostos também são apresentadas com o objetivo de demonstrar a versatilidade de pirazóis 1-cianoacetil-substituídos como blocos precursores em síntese orgânica.


Introduction
Among several commercially available substituted hydrazines, cyanoacetic acid hydrazide has received the most attention recently. 1Cyanoacetic acid hydrazide is a versatile and convenient intermediate for the synthesis of wide variety of heterocyclic compounds.This substrate can act as an ambident nucleophile, that is, as both an N-and a C-nucleophile.Upon treatment of cyanoacetic acid hydrazide with various reactants, the attack can take place at five possible sites; the nucleophile is able to attack the carbon atom of the carbonyl group (position-3) and the carbon atom of the nitrile function (position-5).In addition, the carbon atom of the active methylene group (position-4) and the nitrogen atoms of the hydrazine portion (position-1 and position-2) are able to attack electrophiles (Scheme 1).The reactions of cyanoacetic acid hydrazide with numerous reactants (nucleophiles and electrophiles) are used in the synthesis of a variety of polyfunctional heterocyclic compounds of biological interest. 1The main reaction reported involves the cyclocondensation reaction of cyanoacetic acid hydrazide with 1,3-dicarbonyl compounds.It has been demonstrated in the literature that the product of this cyclocondensation reaction is dependent on the reaction conditions. 1 The results obtained reveal that there is a delicate compromise between the reaction conditions, starting materials and products formed.[8] Alternatively, when , -unsaturated ketones and -ketoaldehyde were reacted with cyanoacetic acid hydrazide under basic conditions, pyrazolopyrimidines were formed.In addition, for 1,3-dicarbonyl compounds, when acetic acid was employed instead of concentrated HCl, pyrazolopyrimidin-2-ols were obtained. 9,10heme 1.

Results and Discussion
The enones 1-4 (Scheme 2) were synthesized from the reaction of the respective acyl chloride or anhydride with enol ether or acetal, in accordance with the methodology developed in our laboratory. 12Cyanoacetic acid hydrazide was obtained commercially.We started our study from the reaction of enone 1b with cyanoacetic acid hydrazide by evaluating the best reaction conditions (Table 1).
The first reaction condition evaluated was based on a report from the literature, in which the authors synthesized pyrazoles from 1,3-dicarbonyl compounds. 17However, for the synthesis we used, two hours were not enough to obtain the 4,5-dihydropyrazole 5b and the starting material remained in part, unchanged (entry 1).However, in 3 hours the conversion to the expected 4,5-dihydropyrazole (5b) was completed with 80% yield (entry 2).When reflux was employed, under the same reaction conditions, in 2 hours, the formation of 3-methyl-5-trifluoromethyl-1H-pyrazole (9b, see Scheme 5) from the loss of the cyanoacetyl group was detected (entry 3).The use of ethanol as solvent without HCl led to an increase in the reaction time, and in 16 hours at room temperature the 4,5-dihydropyrazole 5b was also obtained with 80% yield (entry 4).The addition of a catalytic amount of conc.HCl resulted in a mixture of pyrazoles, 5b and 9b (entry 5).When reflux was used under these conditions, the ratio of 5b:9b was reduced (entry 6).On the other hand, when the reaction was performed under basic conditions (KOH), while pyridone derivatives were expected, surprisingly, pyrazole 9b was obtained, although in low yield (entry 7).The reactions performed in piperidine led to reduced yields of the products (entries 8,9).However, when pyridine was used, 5b was formed as the main product, but in low yields (entries 10,11).Furthermore, the results found in the Table 1 show that for all the reaction conditions tested, pyrazoles 5b or 9b were the only products formed.These results indicate that trihalomethylated , -unsaturated ketones always reacted with cyanoacetic acid hydrazide to form pyrazoles, different from those products described in the literature where 1,3-dicarbonyl compounds, alkylidenemalononitriles and cyanobutanoates reacted with this same reactant.Based on the results shown in the Table 1, we developed an efficient general method to produce the 4,5-dihydropyrazoles 5-8 (Scheme 2).Thus, the cyclocondensation reactions were performed in water as solvent with a catalytic amount of concentrated HCl, with a reaction time of 3 hours (to obtain products 5) or 8 hours (to obtain products 6-8) at room temperature, and a series of 1-cyanoacetyl-5-hydroxy-5halomethyl-1H-4,5-dihydropyrazoles 5-8 was obtained in reasonable to good yields (Scheme 2).Although the 4,5-dihydropyrazoles 5a-c,f-g are commercially available, however, their synthesis and spectral characterization are not reported in literature.4,5-Dihydropyrazoles 5-8 showed sets of 1 H and 13 C NMR data that correspond to the proposed structures.Compounds 5a-c,e-g, 6a-d, 7b and 8b showed 1 H NMR chemical shifts of the diastereotopic methylene protons (H-4a and H-4b) as a characteristic AB system and as a doublet at the range of 3.26-3.70,respectively, with a geminal coupling constant at the range of 2 J 18-20 Hz.The same compounds showed the 13  Although the attainment of two pairs of diastereoisomers for compounds 5f and 5h was expected from the synthetic procedure, the 1 H and 13 C NMR data of these compounds showed that only one pair of diastereoisomers was obtained.Semi-empirical AM1 calculations 18 showed that the diastereoisomer pair 3R3aS/3S3aR of 5f compound was 1.12 kcal mol -1 more stable than the diastereoisomer pair 3S3aS/3R3aR and the diastereoisomer pair 4S5R/4R5S of compound 5h was 1.48 kcal mol -1 more stable than the diastereoisomer pair 4R5R/4S5S.These data are supported by previously reported crystallographic studies for analogous compounds. 19The difference in energy between the two pairs of diastereoisomers for compounds 5f and 5h indicates that the preferable formation of the diastereoisomer pair (> 90%) of compounds is that where the hydroxyl and methylene group (5f) and/or methyl group (5h) are situated cis to each other.The structure of compound 5f was also confirmed by crystal X-ray diffraction (Figure 1). 20e mechanism of formation of 4,5-dihydropyrazoles involves a cyclocondensation reaction, which is depict in Scheme 3. The reaction proceeds by a Michael addition/ Scheme 2. During the study of the reaction between enones 1 and cyanoacetic acid hydrazide, we found that a small increase in the reaction temperature (50 °C) resulted in elimination of water, with simultaneous loss of the cyanoacetyl group and the subsequent formation of 3-methyl-5-trifluoromethyl-1H-pyrazole (9b).In previous studies, we had obtained similar trihalomethylated 4,5-dihydropyrazoles containing a strong electron-withdrawing group attached to the N1atom, where it was possible to eliminate a water molecule and to obtain the aromatic pyrazole without the loss of the N1-group, 14,22 by stirring the reaction mixture in ethanol, for 24 hours, at 45 °C.To obtain the 1H-pyrazole a subsequent step was necessary, which involved the use of reflux in the presence of sulphuric acid for 4 hours.14,22 Thus, we decided to investigate the possibility of dehydrating 4,5-dihydropyrazoles 5 to obtain the aromatic 1-cyanoacetylpyrazoles.In Table 2 the attempts of dehydratation are described.
In a strategy for dehydratation of 5b acetic acid and dichloromethane as solvent were used, but only the starting material was recovered.In another attempt, with sulfonyl chloride, pyridine and benzene as solvent, we observed 3-methyl-5-trifluoromethyl-1H-pyrazole (9b) as a single product.Therefore, we understood that our attempts of dehydratation of 4,5-dihydropyrazole 5b were unsuccessful since the acetic acid conditions were mild while the sulfonyl chloride conditions were harsh.The formation of product 9b can be explained through the mechanism showed in Scheme 4.
When the base catalyst was used, the carbanion was obtained and than, from the ketene elimination, the NHpyrazole was formed.However, when acidic catalyst was used, the pyrazole formation occurred through dehydratation and acyl cation elimination.
The scope of this work are not limited to synthesis of 4,5-dihydropyrazoles from the cyclocondensation of cianoacetohydrazide and halomethylated , -unsaturated ketones.But it was broad to derivate of these compounds.Thus, with the objective of showing the importance of this heterocycle as new precursor and considering that pyrazoles contain poli-functionalized substituents, we decided react the 1-cyanoacetyl-portion of product 5b with dimethylformamide dimethyl acetal (DMFDMA).The condensation reaction of 5b with DMFDMA was carried out in solvent free conditions, at 50 °C, with a reaction time of 2 hours (Scheme 5).All the isolated products were well characterized by their melting points, 1 H and 13 C NMR, and MS spectral data (see Experimental section).

Conclusions
In summary, we demonstrated that the products obtained from the reaction of cyanoacetic acid hydrazide with trihalomethylated , -unsaturated ketones were different from those described in the literature for similar 1,3-dielectrophile substrates.In addition, we developed an efficient and regiospecific preparation of 1-cyanoacetyl-5halomethyl [carboxyethyl]-4,5-dihydropyrazoles under mild conditions by a conventional procedure in good yields.

Experimental
Unless otherwise indicated, all common reagents and solvents were used as obtained from commercial supplies without further purifications. 1 H and 13 C NMR spectra were recorded on a Bruker DPX 400 (1H 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 5973 MSD connected to a HP 6890 GC and interfaced by a Pentium PC.The CG was equipped with a split-splitless injector, autosampler, cross-linked to a HP-5 capillary column (30 m length 0.32 internal diameter), and He was used as the carrier gas.All melting points were determined on a Reichert Thermovar apparatus.Elemental Analyses were performed on a Perkin Elmer CHN elemental analyser.The refractive index was obtained from a refractometer, using water as reference at 20 °C.X-ray data were collected on a Bruker SMART CCD diffractometer. 23The crystallographic structure was solved by direct methods (SHELXS-97). 24efinements were carried out with the SHELXL-97 package. 25he ORTEP 26 diagram of the molecule indicating atom numbering scheme with thermal ellipsoids at 50% probability is illustrated in Figure 1.

Table 1 .
Reaction conditions of enone 1b with cyanoacetic acid hydrazide