Friedländer condensation of 5-aminopyrazole-4-carbaldehydes with reactive α-methylene ketones: Synthesis of pyrazolo[3,4-b]pyridines

Abstract

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.

Synthesis of pyrazolo[3,4‐b]pyridines using ammonium acetate as green reagent in multi‐component reactions

“…A literature survey showed few reports on the synthesis of pyrazolo [3,4-b]pyridines using Michael addition [14,15] however with substitution patterns different from ours. As 5-amino-3-aryl-1-phenyl-1H-pyrazole was already in hand [16] we performed the one pot synthesis of the title compounds. Thus cyclocondensation of 5-amino-3-aryl-1-phenyl-1H-pyrazole 1, psubstituted benzoylacetonitriles 2 and aryl/H aldehydes 3 on fusion in ammonium acetate at 120 °C gave pyrazolo [3,4-b]pyridine derivatives 4 in 80-85 % yield (Scheme 1).…”

A novel synthesis of benzo[h]quinolines and study of their fluorescence properties

“…Found: C,75.22;H,4.60;N,11.51. 14,24,28,55,62,93,112,113,115,121,122,126,127,128,130,137,140,152,153,161,162 6.92 (dd,J = 8.4,2.3 Hz,C 9 H),7.28 (m,4H,8.26 (d,J = 8.3 Hz, C 7 H); 13 C nmr: (CDCl 3 ) 14,23,27,56,61,94,113,114,117,118,121,123,125,127,128,129,135,141,151,154,162,163. Anal.…”

An efficient synthesis of pyrazolo[3,4‐b]pyrrolo[2,3‐d]pyridines from 5‐aminopyrazoles and cyclic β‐keto ester

“…In our other previous papers [10][11][12], pyrazolo [3,4-b]pyridines were synthesized by Friendlander condensation of 5-aminopyrazole-4-carbaldehyde with various reactive methylene compounds and the heterocyclic compounds with chloroethyl side chain [13]. In literature the pyrazolo [3,4-b]pyridines have been so far obtained by condensation of aminopyrazoles with , -unsaturated compounds [14][15][16][17][18], diethylethoxymethylenemalonate [19,20], active esters [21], cyclic ketones [11,12] and amides [12].…”