Reactivity of 3-substituted pyrazole-5-diazonium salts towards 3-azolyl enamines. Synthesis of novel 3-azolylpyrazolo-[5,1-c ][1,2,4]triazines

A series of novel 3-azolylpyrazolo[5,1-c ][1,2,4]triazines was synthesized by reaction of 3-substituted pyrazole-5-diazonium salts with β -azolyl enamines in an efficient fashion. The structures of the compounds prepared were characterized by NMR spectroscopy, mass-spectrometry, elemental and X-ray diffraction analyses. Plausible mechanisms were formulated.

We turned our attention to reactions of diazopyrazoles 1 with enamines because they take place in a regioselective manner to form pyrazolo [5,1-c] [1,2,4]triazines as exclusive products in good yields.Scheme 1 shows a few known examples for formation of pyrazolotriazines 2-4 by this reaction. 10,12,13,15o the best of our knowledge 3-azolylpyrazolo [5,1-c] [1,2,4]triazines are not described in the literature and reactions of β-azolyl enamines with diazo compounds and diazonium salts are not studied so far.7][28][29][30][31][32] Therefore, it is a challenging task to develop a new efficient synthetic method for their preparation.In continuation of our interest in the chemistry of diazoazoles and the synthesis of various types of triazines we have carefully studied the reactions of 3-substituted pyrazole-5-diazonium salts with enamines containing heterocyclic components.
To prepare pyrazole-5-diazonium salts 6a-d we treated 3-aryl-1H-pyrazole-5-amines 5a-d with sodium nitrite and sulfuric acid in water solution at 0-5 C.The desired compounds 6a-d were prepared in good yields as solid substances.In the case of 3-methyl-1H-pyrazole-5-amine 5e we did not manage to isolate hydrosulfate salt 6e as a solid.Therefore, it was alternatively generated from aminopyrazole 5e by reaction with sodium nitrite in an aqueous solution of HBF 4 at low temperature (Scheme 2) and tetrafluoroborate salt 6e was used in situ in further studies.Enamines 8a-f were prepared by treatment of the corresponding 5-methylthiadiazole-4carboxylate 7a,b or alkyl 5-methyl-3-arylisoxazole-4-carboxylates esters 7c-f with DMF-DMA in the presence of N-methylimidazole under reflux for six hours as has been reported earlier 33,34 (Scheme 3).
The study of the progress of the reaction mixture indicated that homogenous conditions were superior to heterogeneous ones (compare entries 2, 3 with entry 1).From the solvent screening it was found that acetonitrile was the best solvent (compare entry 3 with entries 1, 2 and entry 10 with entry 9).Furthermore, room temperature conditions performed better than heating at 45-50 ºC (compare entries 3, 10, 14 with entries 4, 11, 15, respectively).Based on the low yields of the title compounds at 50 ºC, the partial decomposition of the initial diazo compounds was assumed due to the temperature increase.Good yields of the desired pyrazolo[5,1-c][1,2,4]triazines 9 were obtained when the reaction was performed in acetonitrile at room temperature and these conditions were chosen as the optimal ones.
While triazine system formation in the two steps formally corresponds to the route A, an alternate routes B, C involving initial 1,3 union II followed by a [1,5]-sigmatropic shift and elimination of dimethyl amine or 1,7-cycloaddition of 6 to 8 to yield III, which then aromatizes to form the title compounds 9a-l are also possible. 10,12,13,15e attempted to capture the intermediate I or II at a lower temperature (Scheme 5).However, it was difficult to check the presence of any intermediate product according to TLC.NMR experiments have shown that already 5 min after beginning of the reaction between cooled solutions of diazonium salt and enamine in dry DMSO-d 6 there were no longer signals of the starting compounds.Thus, unfortunately the trials to isolate either azo coupling intermediate or acyclic hydrazones failed.
In the IR spectra of 9a-l bands are observed corresponding to the asymmetric (1544-1638 cm -1 ) absorption modes of the N=N bonds typical for a triazine structure.
The mass spectra of the 3-azolylpyrazolo[5,1-c][1,2,4]triazines 9a-l show a molecular ion peak (M + ) and decomposition under electron impact conditions with sequential cleavage of CO 2 Et or CO 2 Me thus pointing to the presence of ethoxy and methoxy carbonyl groups in the molecule, respectively.Ions with m/z 143, 177, 173, 157 point to the presence of 3-arylpyrazole fragments in the molecules bearing isoxazolyl moiety 9f-l.For thiadiazolyl derivatives 9a-e the general fragmentation is not the same.The occurrence of 1,2,3-thiazole fragment is confirmed by the characteristic processes 36 of loss of nitrogen molecule.Found together with the formation of the thiirene molecule there are also observed the pyrazole and pyrazolotriazine fragments with m/z 69 and 120, respectively.
The 1 H NMR spectra revealed the presence of the following signals: a singlet at δ H 9.91-10.13due to the H-4 proton of the triazine, a singlet at δ H 7.89-8.09due to the H-8 pyrazole proton and two multiplets in the region 7.04-8.18due to the aromatic protons of pyrazole and triazine, respectively.The absence of a signal at δ H 12.00-13.00assigned to NH pyrazole proton, shows that this part of molecule has been involved in the reaction, and moreover the 1 H spectra are free of signals characteristic for the dimethylamine protons.
The 13 C NMR spectra revealed signals for all carbons of compounds 9a-l and most significantly there is a C-4 signal at δ C 95.22-96.84,proving triazine formation.The 13 C spectrum showed aromatic signals in the region δ C 121.24-134.10 for both pyrazole and triazine aromatic carbons.At lower field one can see the signals due to the C=O group of the ester function and to quaternary carbons.The DEPT spectrum allows assigning exactly the signal at δ C 124.12-124.84 as C-8 since it is connected with a proton.
In addition, in the comparison of the 13 С spectra of diazonium salts 6а-е and pyrazolo[5,1c] [1,2,4]triazines 9а-l we have noticed that the spectra of the former compounds exhibit signals of the carbon attached to diazonium function in the region δ C 122.7-124.1 according to 2D HMBC spectra.On the other hand, the signals of the quaternary carbons of the final compounds are at lower field (δ C 130.7-147.6).As for 3-R-pyrazole-5-diazonium salts this observation can be explained by the localization of the negative charge on the carbon of the pyrazole cycle.
Additional support for the structures of compounds 9a-l as pyrazolo[5,1-c][1,2,4]triazines was given by X-ray analysis of a single crystal of 9e which was successfully obtained by crystallization from tetrahydrofuran.The compound crystallizes into the monoclinic space group P2 1 /n (Fig. 1).Both rings are planar (rms deviations 0.001 and 0.002 Å for thiadiazole and pyrazolo [

Conclusions
We have demonstrated a simple, regioselective and convenient method for the synthesis of novel 3-substituted pyrazolo[5,1-c][1,2,4]triazines by reaction of pyrazole-5-diazonium salts with βazolyl enamines.In this context, twelve new reported 3-azolylpyrazolo[5,1-c][1,2,4]triazines were isolated and characterized.The crystal data for a representative compound pointed out its planar structure and formation of the intramolecular hydrogen bonding which stabilizes the molecule.Plausible mechanisms for the formation of the title compounds were proposed.The study of scope and limitation of this reaction is in progress in our laboratories.

Experimental Section
General.Melting points were determined on a Stuart SMP30 and are uncorrected.The 1 H and 13 C NMR spectra were recorded on a Bruker Avance 400 spectrometer in DMSO-d 6 at 400 and 100 MHz, respectively.TMS was used as the internal standard.IR spectra were measured on a Bruker Alpha FT-IR spectrometer (ZnSe).The samples were examined directly as solids and ν max values were given for the main absorption bands.The results of elemental analysis for the obtained compounds correspond to calculated data (Perkin Elmer 2400 II).The reactions were monitored and the purity of the products was checked by TLC with Silufol UV-254 (silica gel STC-1A as the sorbent) using the following solvent systems: chloroform/ethanol, 5:1; hexane/ethyl acetate, 3:1.The single-crystal X-ray diffraction data for 9e were collected on an Agilent SuperNova diffractometer with Eos CCD detector, MoK α radiation, λ = 0.71073 Å.Data frames were processed (unit cell determination, intensity data integration, correction for Lorentz and polarization effects, and empirical absorption correction) using CrysAlis PRO. 37General procedure for the synthesis of 3-aryl-1H-pyrazole-5-diazonium hydrosulfates (6ad).A cooled solution of NaNO 2 (0.08 g, 1.2 mmol) in water (0.5 mL) was added dropwise to a stirring suspension of 3-aryl-5-aminopyrazole 5a-d (1.0 mmol) in 30% H 2 SO 4 (4 mL, 2 mmol) at 0 °C.The reaction mixture was stirred at this temperature for 30 min.Then, the formed precipitate was collected by filtration, washed with cold water (3 mL) and dried in vacuo.).

Figure 1 .
Figure 1.The molecular structure of 9e with displacement ellipsoids drawn at the 50% probability level and intramolecular hydrogen bond drawn as dashed line.