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

Abstract

The reaction of 5,6-dialkyl-2-halopyridine-3,4-dicarbonitriles with alcoholic ammonia under elevated pressure gave 5,6-dialkyl-2-aminopyridine-3,4-dicarbonitriles as a result of nucleophilic replacement of the halogen atom by amino group. 6,7-Dialkyl-4-halo-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diimines were formed in analogous reaction at room temperature in the presence of potassium carbonate.II, R 1 = R 2 = Me (a), R 1 R 2 = (CH 2 ) 4 (b); I, III, R 1 = R 2 = Me, Hlg = Cl (a), Br (b), I (c); R 1 R 2 = (CH 2 ) 4 , Hlg = Cl (d), Br (e).Molecules of 5,6-dialkyl-2-halopyridine-3,4-dicarbonitriles [1-4] possess several reaction centers, namely halogen atom, cyano groups, and alkyl groups. 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. 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). Replacement of the chlorine atom in compounds Ia and Id by amino group required a shorter time than analogous reactions with bromo-and iodo-substituted derivatives Ib, Ic, and Ie. Presumably, the formation of the corresponding intermediate from chloropyridine derivatives is more favorable for steric reasons, as well as from the viewpoint of its better stabilization due to higher electronegativity of chlorine as compared to bromine and iodine. The observed pattern is consistent with the assumed addition-elimination mechanism of aromatic nucleophilic replacement (S N Ar).With a view to accelerate halogen replacement in 5,6-dialkyl-2-halopyridine-3,4-dicarbonitriles Ia-Ie in the reaction with ammonia, we added potassium carbonate to the reaction mixture. The use of K 2 CO 3 as catalyst in nucleophilic substitution reactions of 2-halopyridine-3-carbonitriles with various amines was reported in [7,8]. However, the reaction of compounds NH HN NH Scheme 1.

Synthesis, solution and solid-state fluorescence of 2-diethylaminocinchomeronic dinitrile derivatives

“…An addition of metal carbonates as a catalyst did not increase a yield of compounds 3 but led to the formation of byproducts obtaining as a result of the addition of diethylamine to cyano group. 19 According to the developed facile protocol a series of 2-diethylaminocinchomeronic dinitrile derivatives 3 were synthesized containing alkyl, cycloalkyl and aryl substituents, including the moieties with electron-donating methoxy groups (Table 1). Compounds 3b-h are new and were not described in the literature.…”