Highly Regioselective Synthesis of Novel 1 , 4 ’-Bipyrazoles

Este trabalho descreve a síntese de 1,4’-bipirazóis inéditos pela da reação de ciclocondensação de novas b-dimetilaminoenonas com as monoidrato de hidrazina, tert-butil hidrazina, fenil hidrazina, carboximetilhidrazina. Os produtos foram obtidos com alta regiosseletividade em rendimentos de bons a moderados (50-80%). A técnica de cristalografia de raios-X foi utilizada para a elucidação da regiosseletividade da formação dos produtos. 1,4’-Bipirazolilisoxazóis também foram descritos.


Introduction
Many heterocyclic compounds have interesting biological activities.Pyrazoles and isoxazoles figure prominently in this regard. 1The recent success of a pyrazole COX-II inhibitor has further highlighted the importance of these heterocycles in medicinal chemistry. 2The past few years have also witnessed explosive developments in combinatorial chemistry and solid-phase synthesis.0][11] A literature survey turned up a few reports on 1,4'-bipyrazole and isoxazole synthesis and structure. 12The most promising method is a four-steps synthesis via the cyclization of an a-oxo-a-(3,5-dimethyl-1H-pyrazole-1-yl ketene dithioacetal with hydrazine monohydrate or phenylhydrazine in refluxing ethanol. 13,4'-Bipyrazoles have been also prepared by the reaction of 2-pyrazolyl-3-dimethylamino acrylate and acrylonitrile with hydrazine monohydrate and phenylhydrazine hydrochloride under microwave irradiation conditions. 14ur research group has been dedicated to the development of synthetic routes to heterocyclic compounds for around twenty years. 15We have extensively explored the potential of enones such as: 4-alkoxy-1,1,1-trihalo-3-alken-2-ones 15 and enaminones 16 as building blocks in cyclocondensation reactions.Our results have shown that the obtainment of heterocycles with high regioselectivity is generally dependent on the structure of the building block and sometimes it is dependent on the reaction conditions.Now we are interested in finding an alternative route to 1,4'-bipyrazoles and 1,4'-bipyrazoylisoxazoles. In view of the formation of new bonds C-C or C-N especially in the 4-position of the pyrazolyl ring, herein we reported our investigation in the regioselectivity of the cyclocondensation reactions of b-dimethylaminoenones with different 1,2-dinucleophiles such as hydrazine monohydrate, tert-butylhydrazine hydrochloride, phenylhydrazine hydrochloride, carboxymethylhydrazine and hydroxylamine hydrochloride by a three-steps procedure (alkylation, condensation and cyclocondensation reactions, respectively) to obtain the respective azoles in good yields.(Scheme 1).
Although carbanions resulting from proton abstraction from N-alkylpyrazoles might also be stabilized by the electron-attracting inductive effect of the ring nitrogen, the reactivity of such a species towards N,N-dimethylformamide dimethylacetal was demonstrated.The structure of the compounds was determined by 1 H NMR and 13 C NMR spectroscopy, MS espectrometry, and HRMS analysis.Moreover, X-ray crystallography data confirmed the structure of compound 3b.By carrying out a single crystal X-ray analysis, E-configutation of the products was unequivocaly determined, showing that a single isomer was obtained (Figure 1).
In the last step, the b-dimethylaminoenones were converted to 1,4'-bipyrazoles by treatment with hydrazine monohydrate, tert-butylhydrazine hydrochloride, phenylhydrazine hydrochloride and carboxymethylhydrazine.When the b-dimethylaminoenones 3a-b reacted with hydrazine monohydrate in ethanol at room temperature for 5 h, the corresponding 1,4'-bipyrazoles 4a (in 71% yield) and 4b (in 80% yield) were obtained; and when reacted with tert-butylhydrazine hydrochloride or phenylhydrazine hydrochloride in ethanol at 60 °C for 5 h, 1,4'-bipyrazoles 5a-b and 6a-b were obtained, respectively.After an initial screen of solvents and reaction temperatures, the 1,4'-bipyrazole 7a was synthesized by the cyclocondensation reaction of the b-dimethylaminoenone 3a with carboxymethylhydrazine and the use of one equivalent of BF 3 • OEt 2 in anhydrous MeOH under reflux for 10 h in 72% yield.On the other hand, the reaction of the b-dimethylaminoenone 3b with carboxymethylhydrazine using these conditions did not give the expected 1,4'-bipyrazole 7b.Our preparative results are summarized in Scheme 1 and Table 1.The highly regioselective cyclocondensation reactions of the b-dimethylaminoenones 3a-b with different hydrazines gave 1,5-regioisomer rather than the potential 1,3-regioisomer.Moreover, the regiochemistry of the compound 5b was unequivocally determined by single crystal X-ray diffraction data, 18 confirming the formation of the 1,5-regioisomer as a single product (Figure 2).
Thus, the b-dimethylaminoenones 3a-b reacted with different hydrazines to afford, in each case, only one of the two possible regioisomers.Similarly, when the b-dimethylaminoenone 3a reacted with hydroxylamine hydrochloride in ethanol at 60 °C for 5 h, the 1,5-regioisomer of the 1,4'-bipyrazoylisoxazole (8a) was obtained with high regioselectivity in 61% yield.When the b-dimethylaminoenone 3b reacted with hydroxylamine hydrochloride in ethanol at 60 °C for 5 h, the 1,5-regioisomer of the 1,4'-bipyrazoylisoxazole (8b) was obtained in 50% yield.Therefore, we can say that the cyclocondensation reactions of the b-dimethylaminoenones 3a and 3b with hydroxylamine hydrochloride in these conditions are highly regioselective in both cases.Our preparative results are summarized in Scheme 2.
Thus, the compound 2c was synthesized by the alkylation reaction of 3,5-dimethyl-1H-pyrazole with chloroacetone 1c in the presence of triethylamine under reflux of anhydrous toluene for 5 h in 67% yield.Then the compound 2c condensed with 1.2 equivalents of neat DMFDMA under reflux of toluene for 48 h.After removal of the excess reagent, the 4-dimethylamino-3-(3,5-dimethyl-1H-1-pyrazolyl)-3-buten-2-one 3c was obtained in 94% yield.Although the condensation reaction with two equivalents of DMFDMA may in theory lead to a mixture of 3c and 3c' (Figure 3), in our experiment only 3c was formed.The 1 H NMR spectra of 3c revealed the presence of a singlet corresponding to methyl at d 2.25, and the absence of the two olefinic doublets, which would be observed in the 1 H NMR spectra of 3c'.The b-dimethylaminoenone 3c was used as starting material for the synthesis of the 1,4'-bipyrazole 4c through the cyclocondensation reaction with hydrazine monohydrate in ethanol at room temperature for 5 h resulting in the product with 71% yield.

Conclusions
The b-dimethylaminoenones 3a-c were synthesized via highy regioselective condensation reactions.A convenient synthetic route to 1,4'-biazoles, containing a variety of neutral, electron-donating and electron-withdrawing substituents, by a simple procedure from the b-dimethylaminoenones 3a-c is now available.Studies on the syntheses of other heterocyclic rings from 3a-c are in progress.

Experimental
Unless otherwise indicated, all common reagents and solvents were used as obtained from commercial suppliers without further purification.The indicated solvents were dried and purified according to recommended procedures. 19he 1 H and 13 C NMR spectra were acquired on a Bruker DPX 200 or Bruker DPX 400 spectrometer ( 1 H at 200.13 MHz or 400.13 MHz and 13 C at 50.32 MHz or 100.61MHz, respectively), in 5 mm tube, and CDCl 3 was used as solvent, containing TMS as internal standard at 298 K (digital resolution of ± 0.01 ppm).The mass spectra were registered in a HP 5973 MSD connected to a HP 6890 GC and interfaced by a Pentium PC.The GC was equipped with a split-splitless injector, autosampler, cross-linked to a HP-5 capillary column (30 m, 0.32 mm of internal diameter), and helium as carrier gas.The high-resolution mass spectrum were obtained from a MicroTOF Ic Bruker Daltonics (Instituto de Química, Universidade de São Paulo, Brazil).The melting points were measure using a Microquímica MQAPF 301.The melting points were not corrected.

General procedure for synthesis of 2a-b
A m i x t u r e o f 2 -b r o m o a c e t o p h e n o n e 1 a o r 3-bromopropiophenone 1b (20 mmol), 3,5-dimethyl-1Hpirazole (20 mmol) and potassium carbonate (20 mmol) was stirred at reflux temperature of anhydrous acetone (20 mL) for 5 h.Then the mixture was filtered, extracted with dichloromethane (20 mL) and washed with water (3 × 20 mL).The organic layer was dried with anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.The products 2a-b were purified by recrystallization in hexane as solvent.

Procedure for synthesis of 2c
A mixture of chloroacetone 1c (10 mmol), 3,5-dimethyl-1H-pirazole (10 mmol) and triethylamine (10 mmol) was stirred at reflux temperature of anhydrous toluene (3 mL) for 5 h.Then the mixture was extracted with dichloromethane (10 mL) and washed with water (3 × 10 mL).The organic layer was dried with anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.The product 2c was purified by recrystallization in hexane as solvent.

Experimental procedure for synthesis of b-dimethylaminoenone 3c
A mixture of (3,5-dimethyl-1H-1-pyrazolyl)acetone 2c (3 mmol) and DMFDMA (3.6 mmol) was stirred at reflux temperature of anhydrous toluene (1 mL) for 48 h.Then the mixture was submitted at reduced pressure for 1 h.The product 3c was purified by filtration in a column chromatographic silica gel with dichloromethane as an eluent.

General Procedure for synthesis of 1,4'-bipyrazoles 4a-c
A mixture of b-dimethylaminoenone 3a, 3b or 3c (1 mmol), hydrazine monohydrate (1.2 mmol) and ethanol (1 mmol) was stirred at room temperature for 5 h.Then the mixture was extracted with dichloromethane (3 mL) and washed with water (3 × 3 mL).The organic layer was dried with anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.The products 4a-c were purified by filtration in a column chromatographic silica gel with dichloromethane as an eluent.

General procedure for synthesis of 1,4'-biazoles 5a-b, 6a-b and 8a-b
A mixture of b-dimethylaminoenone 3a or 3b (1 mmol), tert-butylhydrazine hydrochloride, phenylhydrazine hydrochloride or hydroxylamine hydrochloride (1.2 mmol) and ethanol was stirred at 60 °C for 5 h.Then the mixture Vol.21, No. 2, 2010 was extracted with dichloromethane (3 mL) and washed with water (3 × 3 mL).The organic layer was dried with anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.The oil products were purified by filtration in a column chromatographic silica gel with dichloromethane as an eluent, and the product 5b was purified by recrystallization in hexane as solvent.

Experimental procedure for synthesis of 1,4'-bipyrazole 7a
A mixture of b-dimethylaminoenone 3a (1 mmol), carboxymethylhydrazine (1.2 mmol) and BF 3 .OEt 2 (1.2 mmol) was stirred at reflux temperature of methanol (1 mL) for 10 h.Then the mixture was extracted with dichloromethane (3 mL) and washed with water (3 × mL).The organic layer was dried with anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.The product 7a was purified by filtration in a column chromatographic silica gel with dichloromethane as an eluent.

Table 1 .
Reaction conditions to synthesis of the 1,4'-