Synthesis and Electrophilic Substitutions of Novel Pyrazolo[1,5-c]-1,2,4-triazolo[4,3-a]pyrimidines

5-Aryl-7-hydrazino-2-phenylpyrazolo[1,5-c]pyrimidines 1 were used as precursors for the preparation of a new series of 5-aryl-8-phenylpyrazolo[1,5-c]-1,2,4- triazolo[4,3-a]pyrimidines 2. The reactions of 2 with certain electrophilic reagents gave the respective 6-substituted derivatives 3-5 rather than the 7-isomeric products. Formylation of the key compounds 1 with ethyl formate yielded the formyl derivatives 6. Furthermore, boiling of compounds 1 with acetic acid afforded 7-acetylhydrazino-5-aryl-2-phenylpyrazolo[1,5-c]pyrimidines 7. Bromination of 7 yielded the dibromo- derivatives 8, while their iodination and nitration gave the monosubstituted derivatives 9 and 10, respectively. Also, treatment of 1 with boiling acetic anhydride yielded the triacetyl derivatives 11. The structure of synthesized products was confirmed by elemental analyses, IR, 1H NMR and MS spectra.


Results and Discussion
Much work from our laboratory has utilized hydrazino heterocycles as raw materials for the synthesis of various types of heterocyclic compounds [18][19][20][21]. In the present investigation, the target pyrazolotriazolopyrimidine compounds were synthesized from 5-aryl-7-hydrazino-2-phenylpyrazolo [1,5-c]pyrimidines 1a-d that were prepared via a sequence of reactions from ethyl phenylpropiolate [2,22]. Heating of 1a-d with formic acid under reflux yielded a novel series of 5-aryl-8-phenylpyrazolo[1,5-c]-1,2,4-triazolo[4,3-a]pyrimidines 2a-d (Scheme 1). The structures of 2a-d were deduced from their spectral analyses. Thus, the 1 H-NMR spectra revealed the presence of three singlets for the pyrazole ring proton at δ H 6.91- 7.33 ppm, of the pyrimidine ring proton at δ H 7.43- 7.44 ppm and of triazole ring proton at δ H 8.53- 9.00 ppm, in addition to the aromatic ring protons and the absence of NH signals. The MS spectra also showed a molecular ion peak as a base peak that indicated the stability of this ring.
Treatment of 1a-d with boiling ethyl formate afforded 5-aryl-7-formylhydrazino-2phenylpyrazolo [1,5-c]pyrimidines 6a-d. Their 1 H-NMR spectra showed a new characteristic signal at δ H 7.98-8.08 ppm corresponding to the formyl proton, in addition to the aromatic ring protons at δ H 7.20-7.99 ppm, with other characteristic signals; a singlet for the exchangeable two NH protons which were assigned at δ H 4.73-4.80 ppm, a singlet at δ H 6.68-6.72 ppm for the pyrazole ring proton and a singlet at δ H 7. 19-7.29 ppm for the pyrimidine ring proton. Boiling of hydrazine derivatives 1a-d with acetic acid under reflux afforded 7-acetylhydrazino-5aryl-2-phenylpyrazolo[1,5-c]pyrimidines 7a-d (Scheme 2). The structures of 7a-d were confirmed by their 1 H-NMR spectra, which revealed an acetyl group proton singlet at δ H 2.04-2.36 ppm, in addition to the characteristic signals of pyrazole and pyrimidine ring protons, two exchangeable NH protons and aromatic ring protons. The mass spectra of 7a-d which showed their molecular ion peaks as a base peak also confirmed the structures.
Next, the electrophilic substitution reaction of 7a-d via bromination with bromine in acetic acid gave the unexpected dibromo derivatives 8a-d rather than the monobromo derivatives. Their 1 H-NMR spectra showed the absence of the signals of both pyrazole and pyrimidine ring protons and the presence of acetyl group protons, in addition to the other characteristic signals. These unexpected obtained products may be due to the excess bromine added to obtain a homogenous reaction mixture.
Furthermore, acetylation of 1a-d with boiling acetic anhydride afforded the triacetyl derivatives 11a-d. Their 1 H-NMR spectra revealed the absence of the NH protons of the starting hydrazine derivatives and the presence of signals at δ H 2.42-2.56 ppm corresponding to the three acetyl groups protons, as well as a singlet at δ H 6.87-7.28 ppm for the pyrazole ring proton and a singlet at δ H 7.70- 8.24 ppm for the pyrimidine ring proton, in addition to the aromatic ring protons at δ H 6.98-8.05 ppm. The structures of 11a-d were also confirmed by their MS spectra which showed fragmentation process involving a sequential elimination of two ketene molecules to give the most stable one (M .+ -2CH 2 CO) as a base peak.

General
Melting points were determined on a Kofler Block and are uncorrected. Elemental analyses were carried out in the Microanalytical Laboratory of the Faculty of Science, Cairo University. The IR spectra of compounds were recorded on a Bruker Tensor 37 Fourier Transform infrared 8400 spectrophotometer using potassium bromide pellets and frequencies are reported in cm −1 . The 1 H-NMR spectra were recorded on a JEOL JNM ECA 500 MHZ instrument and chemical shifts δ H are given in ppm relative to tetramethylsilane used as internal standard. Mass spectra were recorded at 70 ev with a GCMS-QP 1000 EX spectrometer. Reactions were routinely followed by thin layer chromatography (TLC; Merck Kieselgel60-F254 precoated plastic plates). The spots were detected by iodine. 5-Aryl-7-hydrazino-2-phenylpyrazolo[1,5-c]pyrimidines 1 were prepared from the respective acetylenic β-diketones as described earlier [2,22].

Conclusions
In summary, the strategy for constructing the target compounds started by 5-aryl-7-hydrazino-2phenylpyrazolo[1,5-c]pyrimidines 1a-d where the hydrazine moiety can be readily heterocyclized with one-carbon inserting agents to give the triazole ring fused to the pyrazolopyrimidine skeleton has been successfully demonstrated.