A Facile Synthesis of Pyrido[2,3:3,4]pyrazolo[1,5-a]pyrimidine and Pyrido[2,3:3,4]pyrazolo[5,1-c][1,2,4]triazine Bearing a Thiophene Moiety

1 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia 2Department of Pharmaceutical Chemistry, College of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt 3 Department of Applied Organic Chemistry, National Research Center, Dokki, Giza 12622, Egypt 4 Pharmaceutical and Drug Industries Research Division, Department of Medicinal and Pharmaceutical Chemistry, National Research Centre, Dokki, Giza 12622, Egypt 5 Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt


Introduction
Thiophene moiety is present in a large number of bioactive molecules having diverse biological activities such as antiinflammatory [1], anticonvulsant [2], antibacterial [3], and antitumor [4] activities. Moreover, thiophene moiety is a wellknown isostere for benzene; for example, the replacement of benzene ring of the antidepressant drug, Viloxazine, (I, Figure 1) led to a prolongation of half-life [5].

General Procedure for the Synthesis of Compounds 14 and 15.
To a solution of compound 11 (0.24 g, 1 mmol) in glacial acetic acid (25 mL), acetyl acetone (12a) and/or ethyl acetoacetate (12b) (1 mmol) were added. The mixture was refluxed for 14 h and then allowed to cool to rt. The solid formed was filtered, washed with ethanol, and recrystallized from EtOH/DMF to afford the corresponding pyrido [
The reaction of the pyrazolo[3,4-b]pyridine derivative 11 with acetylacetone (12a) or ethyl acetoacetate (12b) in glacial acetic acid gave, in both cases, a single product. The reaction products were identified as pyrido [2 ,3 :3,4]pyrazolo[1,5a]pyrimidines 14 and 15, respectively (Scheme 2). The structures of the latter compounds were established on the basis of their spectral data. For example, the 1 H NMR of compound 14 showed four singlet signals of methyl groups in the region 2.29-2.81 in addition to a singlet signal due to the pyrimidine proton around 7.27, while its 13 C NMR exhibited four signals in the region 16.47-25.17 due to four methyl groups. The mass spectrum of 14 showed a peak corresponding to its molecular ion at m/z 308. 9 [M] + .
The hydrazones 19a,b and 22a-c underwent intramolecular cyclization in boiling pyridine to yield the fused systems 21a,b and 24a-c, respectively (Scheme 3). The IR spectra lack the characteristic bands of NH groups for products 21a and 21b and the nitrile absorption bands for compounds 24a and 24c. On the other hand, the mass spectra of compounds 21a,b and 24a-c showed a peak corresponding to their molecular ions. Mechanistically, compounds 19a and 19b underwent an intramolecular cyclization via loss of a water molecule from the intermediates 20a and 20b to give compounds 21a and 21b, respectively. Michael-addition of the endocyclic NH of the hydrazones 22a-c to their nitrile functionality gave the corresponding compounds 24a-c, as reported in the literature for an analogous system [16].

Conclusion
Pyrazolo [3,4-b]pyridine derivative 11 acts as a key intermediate for the straightforward synthesis of the title compounds 14, 15, 17, 21a,b, and 24a-c. These derivatives were synthesized starting from readily available reagents using convenient procedures. Further chemical and biological studies on such compounds will be reported in a due course.