Transition-metal-free, mild and efficient ring expansion of amino acid derivatives: facile access to densely functionalized azepines

Abstract

Azepines are important structural motifs in drug discovery possessing valuable biological and medicinal properties. However, the approaches for the preparation of these versatile skeletons are limited and still challenging. Herein, we disclose a concise, practical and efficient protocol for the rapid access to azepines by the ring expansion of easily accessible amino acid derivatives under mild conditions. The method possesses noteworthy features such as a broad substrate scope, good functional group tolerance, good scalability and efficient modification of several popular marketed drugs, highlighting the practicability of this reaction. Preliminary bioactivity studies indicated that 2p and 2s showed good anticancer activity against Ramos, HeLa and A549 cells. Moreover, the facile operation and catalyst- and additive-free conditions make it one of the most convenient and straightforward methods to afford the azepine-based building blocks, which would gain great utility in medicinal chemistry and synthetic chemistry.