A series of 1,3,6-trisubstituted and 1,3,5,6-tetrasubstituted pyrazolo[3,4-b]pyridines 5 has been synthesized by Friedländer condensation of 5-aminopyrazole-4-carbaldehydes 3 with α-methylene ketones such as acetone (4a) or acetophenones 4b-f with potassium hydroxide as basic catalyst. Condensation of 5-aminopyrazole-4-carbaldehydes 3 and unsymmetric dialkylketones 6 yielded mixtures of isomeric pyrazolo [3,4-b]pyridine derivatives 7 and 8. Condensation of 5-aminopyrazole-4-carbaldehydes 3 with CHacidic acylacetonitriles 9 and acylacetates 11 with piperidine as basic catalyst yielded pyrazolo [3,4-b] [7]. o-Aminoaldehydes are the key intermediates for the synthesis of various biologically active heterocycles e.g. [8,9] using the Friedländer reaction with ketones in a 4+2 cyclocondensation [10], which prompted us to investigate the reaction pathway of 5-aminopyrazole-4-carbaldehydes with α-methylene ketones to new 1,3,6-trisubstituted and 1,3,5,6-tetrasubstituted pyrazolo [3,4-b]pyridines, especially to 1,3,6-triarylpyrazolo[3,4-b]pyridines. A literature survey shows a few reports on the synthesis of pyrazolo [3,4-b]pyridines using the Friedländer condensation [11], however with substitution patterns different to ours.The required starting materials for the intendedFriedländer condensation, 5-aminopyrazole-4-carbaldehydes 3, were synthesized by cyclocondensation of p-substituted aroylacetonitriles, a class of compounds which was studied recently by us for other cyclization reactions [12]. p-Substituted aroylacetonitriles cyclize as 1,3-dicarbonyl synthons with arylhydrazines already on heating without catalysts according to known methods [13] and furnished in good to excellent yields 5-aminopyrazoles 1, which afforded on Vilsmeier-Haack formylation with excess dimethylformamide and phosphoryl chloride 4-formyl-pyrazolyl-dimethylimidoformamides 2. Thermal analysis of formamides 2 by differential scanning calorimetry (DSC) revealed that they are thermally stable compounds which showed thermal decomposition only above 350 °C. Hydrolysis of formamides 2 with refluxing ethanolic sodium hydroxide yielded the required 5-aminopyrazole-4-carbaldehydes 3 in good yield.
