Efficient Routes to Pyrazolo[3,4-e][1,2,4]triazines and a New Ring System: [1,2,4]Triazino[5,6-d][1,2,3]triazines

Arylhydrazonomalononitriles 1a,b react with phenylhydrazine to yield amidrazones 2a,b that cyclize to give 2-aryl-5-phenylhydrazono-2,5-dihydro-[1,2,4]-triazine-6-carbonitriles 5a,b upon reaction with dimethylformamide dimethylacetal (DMFDMA). Refluxing 5a,b in glacial acetic acid resulted in the formation of the pyrazolo-1,2,4-triazines 6a,b. Compounds 6a,b were also formed upon treatment of 3-amino-4-phenylhydrazono-1-phenyl-2-pyrazolin-5-ones 7a,b with DMFDMA. Reacting these triazinyl arylhydrazononitriles 5a,b with hydroxylamine hydrochloride in ethanolic sodium acetate afforded amidrazones 8a,b that are readily cyclized in refluxing dimethylformamide into [1,2,4]triazino[1,2,3]triazines 10a,b.


Results and Discussion
Reacting 2-arylhydrazonomalononitriles 1a,b with phenylhydrazine at room temperature in ethanol afforded 3-amino-2-arylhydrazono-3-phenylhydrazonopropanenitriles 2a,b. This is in contrast to the reported formation of 3a,b upon extended refluxing of 1a,b and phenylhydrazine in ethanol (Scheme 1) [3]. Although 2a,b may also exist in other tautomeric forms, only 2a,b were produced, as indicated from the 1 H-NMR spectra that revealed D 2 O exchangeable amino signals at δ 6.09, 4.03 ppm and two hydrazone NH signals at δ 8.87, 9.67 and δ 11.10, 12.48 ppm, respectively. Compounds 2a,b, so formed, reacted readily and smoothly with dimethylformamide dimethylacetal (DMFDMA) to yield the products of condensation with elimination of two molecules of methanol and one molecule of dimethylamine. These can thus be formulated as the 2-aryl-5-phenylhydrazono-1,2,4-triazines 5a,b or the isomeric 1,2,4-triazoles 4a,b. Structures 5a,b could be established for these products based on the 1 H-NMR spectra which revealed characteristic C-H signals at δ 9.67 and 8.76 ppm, respectively. If the products were 4a,b these signals should have appeared at higher field (δ ~ 8 ppm) [12]. Moreover the reaction product 5a,b cyclized upon refluxing in acetic acid to yield 6a,b. Heterocyclic ring systems similar to 6a,b were prepared by reacting 7 with acetic anhydride to give the methyl derivatives of 6 [13]. If the reaction products were 4a,b they should be recovered unreacted under these conditions. Compounds 6a,b could also be obtained via reaction of 7a,b with (DMFDMA) (cf. Scheme 1).
Compounds 5a,b reacted with hydroxylamine hydrochloride in ethanolic sodium acetate to yield 1,2,4-triazine-6-carboximidamides 8a,b. Refluxing the latter in dimethylformamide (DMF) resulted in cyclization via water elimination to yield the [1,2,4]triazino [5,6- Possible Tiemann rearrangement of 8a,b prior to cyclization as reported earlier [14] for similar systems could be discounted as irradiation of the NH 2 signal at δ 6.12 ppm did not enhance the integration of the aromatic multiplet at δ 7.44 -8.02 ppm, as would be the case if the products were 9a,b. HMBC 15 N-NMR indicated the amino protons at δ 6.14 ppm to have a 4 J cross peak with the sp 2 nitrogen at δ 280 ppm. A Tiemann rearrangement product should show such a cross peak with the sp 3 nitrogen at δ 230 ppm (cf. Scheme 2).

General procedures
Melting points were recorded on Gallenkamp apparatus and are uncorrected. Infrared spectra (KBr) were determined on a Perkin-Elmer 2000 FT-IR system. NMR measurements were determined on a Bruker DPX spectrometer, at 600 MHz for 1 H-NMR and 125 MHz for 13 C-NMR, in DMSO-d 6 as solvent and using TMS as internal standard. Mass spectra were measured on MS 30 and MS 9 (AEI) spectrometers, with EI 70 eV. Elemental analyses were performed by using of LECO CHNS-932 Elemental Analyzer. Copies of the original data can be provided upon request.

Synthesis of arylhydrazonomalononitriles 1a,b
These compounds were prepared following the literature procedure [6]. A cold solution of aryldiazonium salt (10 mmol) was prepared by adding a sodium nitrite solution (1.4 g dissolved in 10 mL water) to a pre-cooled solution of arylamine hydrochloride (10 mmol of arylamine in 6 mL of 6 M HCl) with continuous stirring. The resulting solution of aryldiazonium salts were then added carefully to a cold ethanolic solution (50 mL) of malononitrile (0.66 g, 10 mmol) and sodium acetate trihydrate (2.8 g, 20 mmol). The mixture was stirred at room temperature for 1 h and the solid product formed was collected by filtration, washed with water and recrystallized from ethanol.

Reaction of 1a,b with phenylhydrazine
A mixture of arylhydrazonomalononitrile 1a,b (10 mmol) and phenylhydrazine (1.08 g, 10 mmol) was dissolved in ethanol (50 mL) and the reaction progress was followed by TLC till completion after 24 h. The reaction mixture was cooled and the solid product, so formed, was then collected by filtration and recrystallized from ethanol.

Reaction of 2a,b with DMFDMA
A mixture of 2a,b (10 mmol) and DMFDMA (1.2 g, 10 mmol) was dissolved in xylene (50 mL) and the reaction mixture was refluxed for 8 h, then concentrated under reduced pressure to the half of its original volume, cooled and the solid product, so formed, was then filtered and recrystallized from ethanol.

Cyclization of phenylhydrazono-1,2,4-triazines 5a,b upon refluxing in AcOH
A mixture of 5a,b (10 mmol) was dissolved in glacial acetic acid (30 mL) and the reaction was refluxed for 6 h while the reaction was followed to completion by TLC. The reaction mixture was neutralized with Na 2 CO 3 solution whereby a solid product was formed. The solid was collected by filtration and recrystallized from ethanol.

Alternate route to 6a,b by refluxing pyrazolones 7a,b with DMFDMA (chemical evidence)
A mixture of 7a,b (10 mmol) and DMFDMA (1.2 g, 10 mmol) was dissolved in dry xylene (50 mL) and the solution was refluxed for 8 h. The reaction mixture was triturated as usual and the solid product, so formed, was then filtered and recrystallized from ethanol. Elemental analysis and NMR spectra matched those of 6a,b.

Cyclization of 1,2,4-triazine-6-carboximidamides 8a,b upon refluxing with DMF
A solution of 8a,b (10 mmol) in DMF (30 mL) was refluxed for 4 h. The reaction mixture was poured on HCl/ice mixture. The solid product, so formed, was then filtered and recrystallized from ethanol to give 10a,b.