One-Pot Knoevenagel/Imination/6π-Azaelectrocyclization Sequence for the Synthesis of Disubstituted Nicotinonitriles

We report on a copper-catalyzed three-component reactionfor thesynthesis of disubstituted nicotinonitriles using 3-bromopropenals,benzoylacetonitriles, and ammonium acetate (NH4OAc). TheKnoevenagel-type condensation of 3-bromopropenals with benzoylacetonitrilesgives & delta;-bromo-2,4-dienones that contain strategically placedfunctional groups that react with the ammonia generated insitu to give the corresponding azatrienes. These azatrienescan then be transformed into trisubstituted pyridines under the reactionconditions via a reaction sequence involving 6 & pi;-azaelectrocyclizationand aromatization.

Automated summary

We have developed a copper-catalyzed three-component reaction for the synthesis of disubstituted nicotinonitriles. This reaction involves the condensation of 3-bromopropenals with benzoylacetonitriles, followed by in situ generation of ammonia and transformation into trisubstituted pyridines via a reaction sequence involving 6π-azaelectrocyclization and aromatization.