Synthesis of 2,3-Dihydro‑1<i>H</i>‑azepine and 1<i>H</i>‑Azepin-2(3<i>H</i>)‑one Derivatives From Intramolecular Condensation between Stable Tertiary Enamides and Aldehydes

A new strategy to construct 2,3-dihydro-1H-azepine and 1H-azepin-2­(3H)-one heterocyclic rings is reported based on emerging tertiary enamide synthons. Under very mild conditions employing BBr3 as a Lewis acid catalyst and P2O5 as an additive, tertiary enamides that contain a formyl group underwent highly efficient and scalable intramolecular cyclic condensation to afford diverse 2,3-dihydro-1H-azepine and 1H-azepin-2­(3H)-one derivatives in 71–96% yields. The reaction proceeded most probably through a nucleophilic addition of enamides to aldehyde, deprotonation, and dehydration cascade. Application of the method in the synthesis of dihydro-azepino­[2,1-a]­isoindol-5-ones, the core structure of naturally occurring lennoxamine, was also demonstrated.本文报道了一种基于新兴叔烯酰胺合成子（tertiary enamide synthons）构建2,3-二氢-1H-氮杂卓（2,3-dihydro-1H-azepine）与1H-氮杂卓-2(3H)-酮（1H-azepin-2(3H)-one）杂环的全新策略。在以三溴化硼（BBr3）作为路易斯酸催化剂、五氧化二磷（P2O5）作为添加剂的极温和反应条件下，带有醛基的叔烯酰胺可发生高效且可规模化的分子内环化缩合反应，以71%~96%的收率得到多种2,3-二氢-1H-氮杂卓与1H-氮杂卓-2(3H)-酮衍生物。该反应的历程大概率经由烯酰胺对醛基的亲核加成、去质子化以及脱水级联过程。本方法还被应用于二氢氮杂卓并[2,1-a]异吲哚-5-酮的合成——该类化合物是天然产物莱诺胺（lennoxamine）的核心骨架。