Synthetic Strategies for Azepine Derivatives

The azepine scaffold represents a versatile seven-membered nitrogen heterocycle which features prominently in pharmaceutically relevant molecules and natural products. Owing to inherent ring-strain and conformational flexibility, the construction of azepine cores has long posed a synthetic challenge. Classical approaches to azepine frameworks encompass ring-expansion processes, pericyclic rearrangements and cycloaddition strategies. Beckmann and Schmidt rearrangements of ketoximes and hydrazones permit the scaffold elongation of six-membered precursors, while sigmatropic rearrangements such as Stevens and Meisenheimer variants allow direct annulation of isoquinoline-derived ylides and N-oxides into benzazepine-type systems. Meanwhile, cycloadditions—including (4+3) annulations of donor–acceptor cyclopropanes with azadienes—have emerged as convergent routes to densely functionalised azepanes under mild conditions, often employing Lewis acids to ensure high stereoselectivity. Transition-metal-catalysed C–H activation and oxidative ring-closure methodologies have further expanded the diversity of accessible substitution patterns. Contemporary efforts increasingly focus on asymmetric catalysis, practical scalability and late-stage functionalisation, enabling rapid generation of complex azepine libraries for medicinal chemistry. The global significance of azepine derivatives spans anticancer agents, central-nervous-system modulators and enzyme inhibitors, highlighting the enduring importance of innovative synthetic routes in this field.

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Synthetic Strategies for Azepine Derivatives publication trend

The graph below shows the total number of articles in synthetic strategies for azepine derivatives across all publications each year (not limited to Nature Index journals).

Technical terms

Azepine: A seven-membered unsaturated heterocycle containing one nitrogen atom.

Azepane: A fully saturated seven-membered heterocycle with one nitrogen atom.

Ring-expansion: A transformation that increases ring size, often via rearrangement of smaller cyclic precursors.

Sigmatropic rearrangement: A pericyclic reaction in which a σ-bond migrates adjacent to a π-system, reorganising ring connectivity.

(4+3) Annulation: A cycloaddition between a four-atom component and a three-atom component to construct seven-membered rings.

Donor–acceptor cyclopropane: A cyclopropane bearing both electron-donating and electron-withdrawing substituents that facilitate ring opening and cycloaddition.

Azadiene: A conjugated diene system containing at least one nitrogen atom within the π framework.

References

1. Ring-Expansion Reaction of Oximes with Aluminum Reductants. Molecules (2012).
2. Synthesis and X-ray Structural Studies of a Substituted 2,3,4,5-Tetrahydro-1H-3-benzazonine and a 1,2,3,5-Tetrahydro-4,3-benzoxazonine. Molecules (2014).
3. (4+3) Annulation of Donor‐Acceptor Cyclopropanes and Azadienes: Highly Stereoselective Synthesis of Azepanones. Angewandte Chemie (2022).