Copper-catalyzed Aldol-type Addition Of Ketones To Aromatic Nitriles

Enaminones are important synthetic intermediates and building blocks for drug development and natural product synthesis. And it has similar properties of both ketenes and enamines because of its special structure(N-C=C-C=O), so enaminones can occur various chemical transformation. Besides, as a synthetic intermediates, enaminones are playing an important role in the synthesis of various heterocycles.In this paper, we will describe the Aldol-type addition of ketones to aromatic nitriles catalyzed by copper. The main contents are shown as follows:The aldol-type addition reaction of acetophenone (la) to benzonitrile (2a) was chosen as a model to optimize the reaction conditions such as catalyst, solvent, base, and temperature. We found that the best result was obtained when the reaction was treated with10mol%Cul as catalyst,11mol%2,2’-bipyridine as ligand, N,N-dimethylacetamide as solvent, and NaO’Bu as base at80℃. Under optimized conditions, the aldol-type addition of ketones to aromatic nitriles proceeded selectively with the yield of enaminone achieving82%and the yield of self-condensation product droping to12%. Next, we expanded the scope of ketone and nitrile substrates and found the catalytic system was suitable for aliphatic ketones, aromatic ketones, heterocyclic ketones, aromatic nitriles and heterocyclic nitriles. At the same time, we have achieved many new enaminones by this addition reaction.