Catalytic aza-Nazarov cyclization reactions to access α-methylene-γ-lactam heterocycles

We have developed a catalytic aza-Nazarov reaction of N-acyliminium salts generated in situ from the reaction of a variety of cyclic and acyclic imines with alpha,13-unsaturated acyl chlorides to afford substituted alpha-methylene-gamma-lactam heterocycles. The reactions proceed effectively in the presence of catalytic (20 mol %) amounts of AgOTf as an anion exchange agent or hydrogen-bond donors such as squaramides and thioureas as anion-binding organocatalysts. The aza-Nazarov cyclization of 3,4-dihydroisoquinolines with alpha,13-unsaturated acyl chlorides gives tricyclic lactam products 7 in up to 79% yield with full diastereocontrol (dr = >99:1). The use of acyclic imines in a similar catalytic aza-Nazarov reaction with 20 mol % of AgOTf results in the formation of alpha-methylene-gamma-lactam heterocycles 19 in up to 76% yield and with good to high diastereoselectivities (4.3:1 to 16:1). We have demonstrated the scalability of the reaction with a gram-scale example. The relative stereochemistry of the alpha-methylene-gamma-lactam products 19 has been determined via the single-crystal X-ray analysis of lactam 19l. In order to shed light on the details of the reaction mechanism, we have performed carefully designed mechanistic studies which consist of experiments on the effect of 13-silicon stabilization, the alkene geometry of the alpha,13-unsaturated acyl chloride reactants, and adventitious water on the success of the catalytic aza-Nazarov reaction.

Automated summary

We have developed a catalytic aza-Nazarov reaction to synthesize substituted alpha-methylene-gamma-lactam heterocycles. The reaction can be effectively conducted using AgOTf or hydrogen-bond donors as catalysts. Both cyclic and acyclic imines can be used as starting materials, resulting in high yields and diastereoselectivities. Mechanistic studies have been performed to understand the reaction details.