Despite the remarkable advances witnessed in the Nazarov cyclization reactions within the past two decades, transformations that involve the analogous aza-Nazarov reaction are quite limited. We recently developed an efficient aza-Nazarov cyclization using imines and α,β-unsaturated acyl chlorides that operates via anion exchange catalysis. A broad range of α-methylene-γ-lactam products were obtained as single diastereomers and in high yields (up to 82%) when substituted 3,4-dihydroisoquinolines were reacted with α,β-unsaturated acyl chlorides in the presence of a catalytic amount of AgOTf or a hydrogen bonding catalyst. In addition, the reaction was found to work successfully with acyclic imines to give 3-methylene-2-pyrrolidinone products in good yields. The relative stereochemistry of the two newly created stereogenic centers was confirmed by the X-ray analysis of an aza-Nazarov product. Computational studies support the critical role of the –TMS group in reducing the reaction barrier of the key aza-Nazarov cyclization step via β-silicon stabilization effect.

Development of catalytic aza-Nazarov cyclization reactions

2019 Fall National Meeting

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