Tailored Nitrone [3+2] Dipolar Cycloaddition Enables the Elusive Synthesis of Structurally Complex Seven-Membered Heterocycles

Intramolecular [3+2] nitrone cycloadditions have seldom been used to construct 7-membered heterocycles as the formation of the competing 6-membered heterocycles is favored almost exclusively. Herein, we report an intramolecular nitrone cycloaddition that proceeds with a strong preference for the formation of seven-membered 2-benzazepines. The reaction tolerates electronically diverse substrates, including heterocyclic variants, delivering a variety of structurally diverse and synthetically challenging 2-benzazepines in yields up to 76% with diastereomeric ratios up to 20:1. DFT calculations provide mechanistic rationale for both the observed regio- and diastereoselectivity and reveal the interplay of the Pauli repulsion and distortion as key selectivity-driving structural effects. The utility of the cycloadducts, especially by exploiting the N−O bond to increase molecular complexity further, is demonstrated through a concise total synthesis of (±)-caulophine A.