Studies on the acetylation of 3,6‐diamino‐1H‐pyrazolo[3,4‐b]pyridine‐5‐carbonitrile derivatives

Abstract

in Wiley InterScience (www.interscience.wiley.com).The acetylation reaction of the differently substituted 3,6-diamino-1H-pyrazolo [3,4-b]pyridine-5-carbonitrile derivatives 1-6 is reported. The structure of the resulting acetamides has been investigated and confirmed by analytical, spectroscopic, and chemical transformations. From these studies, we conclude that, in general, under mild conditions, and using acetic anhydride, when free, the N(1)H moiety is a more reactive center respect to the C(3)NH 2 and C(6)NH 2 groups. This trend is reversed when no steric hindrance due to presence of a phenyl group at C4 drives the preferred acetylation to C(3)NH 2 , as it is evident by comparing the observed results from precursor 1 with 3. When N1 is blocked, the (C3)NH 2 group undergoes preferential acetylation over the (C6)NH 2 site, which only has been mono (or diacetylated) at reflux. Computational analyses based on DFT studies have been extensively used to explain the observed reactivities.

Regioselective reaction of 5,6-dialkyl-2-halopyridine-3,4-dicarbonitriles with ammonia

“…Depending on the substrate and reagent nature, these transformations may be catalyzed by the reacting nucleophile [5,6] or other base such as potassium [7,8] or cesium carbonate [9, 10], sodium hydrogen carbonate [11,12], triethylamine [13,14], ethyl(diisopropyl)amine [15,16], etc. Taking into account reduced nucleophilicity and high volatility of ammonia compared to primary and secondary amines, 2-aminopyridine-3-carbonitriles are synthesized under pressure [12,17, 18] or microwave irradiation [19].The halogen atom in 5,6-dialkyl-2-halopyridine-3,4-dicarbonitriles Ia-Ie was not replaced by amino group on prolonged heating in aqueous ammonia or in organic solvents saturated with ammonia (ethanol, propan-2-ol, 1,4-dioxane, acetonitrile). We succeeded in obtaining 5,6-dialkyl-2-aminopyridine-3,4-dicarbonitriles IIa and IIb in 72-82% yield by carrying out the reaction under elevated pressure in ethanol saturated with ammonia (Scheme 1).…”

“…The halogen atom in 2-halopyridine-3-carbonitriles is activated by the neighboring cyano group, and it can be readily replaced under mild conditions, e.g., by nitrogen-containing nucleophiles [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Depending on the substrate and reagent nature, these transformations may be catalyzed by the reacting nucleophile [5,6] or other base such as potassium [7,8] or cesium carbonate [9,10], sodium hydrogen carbonate [11,12], triethylamine [13,14], ethyl(diisopropyl)amine [15,16], etc.…”