Aza-Nazarov cyclization reactions using anion exchange strategy

Abstract

Although Nazarov reaction is a synthetically useful route for the synthesis of five-membered rings, there are a very limited number of studies on its analogous process producing N-heterocycles; aza-Nazarov reaction, and an effective methodology that proceeds under mild conditions has yet to be developed. In consideration of the importance of nitrogen containing heterocyclic compounds in organic and pharmaceutical chemistry, developing a new aza-Nazarov reaction will have the potential to be beneficial in many synthetic applications. In this work, a novel catalytic aza-Nazarov reaction between 3,4-dihydroisoquinolines and α,β-unsaturated acyl chlorides, that can be used for a broad range of substrates, has been developed. By taking advantage of the stabilizing β-silicon effect and the anion exchange strategy, the proposed reaction proceeds under much better conditions with respect to reaction yield, reaction conditions and environmental issues. Our initial efforts focused on the use of achiral anion exchange strategy employing silver trifluoromethanesulfonate (AgOTf) as the anion source to develop a novel aza-Nazarov reaction. To demonstrate that the reaction has a wide substrate scope, the substituents on the starting materials have been changed with electron withdrawing and donating groups. Several attempts have been made to render the developed reaction enantioselective using chiral catalysts, nevertheless asymmetric aza-Nazarov reactions could not be achieved.