A ring expansion strategy towards diverse azaheterocycles
Ring expansion to “grow” larger N-heterocycles often uses cycloaddition of strained aza-rings with π-bonds. Here, we report a formal cross-dimerization between three-membered aza-heterocycles and 3- and 4-membered-ring ketones, providing a straightforward means of assembling diverse N-heterocycles.
Nitrogenated heterocycles are inextricably woven into our daily life for use as pharmaceuticals, agrochemicals, dyes, and plastics. More than half of all FDA-approved drugs contain at least one N-heterocycle. Thus, the development of innovative strategies for N-heterocycle synthesis has been the core of organic synthesis throughout the history of synthetic chemistry.
For decades, cycloaddition of strained aza-rings with π-bonds has been regarded as a powerful and straightforward ring expansion strategy to “grow” larger aza-ring systems from smaller rings. However, the product types and scopes are somewhat limited due to the difficulties in controlling the regioselectivity of electronically or sterically unbiased π-bonds and the accessibility of specific π-bond synthons in some cases.
Hence, alternative general ring expansion methods for N-heterocycle synthesis via cross-dimerization of two different strained rings would represent a significant synthetic advancement and remain highly sought after. We envisioned a strategy in which two different strained rings are selectively cross-dimerized, representing an unprecedented fundamental ring expansion reaction to access larger N-heterocycles. The key challenge for such a strategy is to identify the difference in reactivity between the two different strained rings in the reaction.
In conclusion, we have described the implementation of such ring expansion strategy involving formal cross-dimerization, enabling the modular and robust synthesis of 3-benzazepinones, dihydropyridinones and urasils. The use of synergistic bimetallic catalysis was critical to the success of the transformation. It is anticipated that this unprecedented ring expansion mode will open up new retrosynthetic approaches for complex molecule synthesis.