Light and acid clip carbon out of azaarenes

Chemists can now quickly downsize certain azaarenes from six-membered rings to five-membered rings in a reaction that’s driven by light and acid. The transformation, which turns quinoline N-oxides into N-acylindoles (example shown), offers a way to remodel a complex molecule’s core without changing its substituents. Such reactions provide a simple way for medicinal chemists to make an array of molecule derivatives when looking for drug candidates.

The reaction was developed by chemists in Mark D. Levin’s group at the University of Chicago and at Merck & Co. Last year, Levin reported a reaction that expanded indoles by one carbon to make quinolines. When graduate student Jisoo Woo was looking for a project, Levin suggested trying the reverse—contracting heterocycles by one carbon. “I wasn’t 100% sure of how to even tackle it,” Levin says. Woo found publications that used photochemistry with a mercury lamp to turn quinoline N-oxides into N-acylindoles, but the reaction only worked on certain starting materials. Woo was able to develop the reaction to make it generally applicable (Science 2022, DOI: 10.1126/science.abo4282).

“We had to really reengineer the chemistry to solve the problems with it,” Levin says. One key insight was to switch from using the mercury lamp, which put out multiple wavelengths of light, to a 390 nm light-emitting diode. This change made the reaction much cleaner because it only initiated a single photochemical reaction.

Chemists can easily replace the core structure of a potential drug candidate in computer software through a process called “scaffold hopping,” says Jürgen Bajorath, a University of Bonn professor who studies such modifications. While it’s easy to change core structures with a computer, such scaffold hops can be difficult to implement synthetically. “The photochemical approach reported by Levin and colleagues enables carbon atom deletions in aromatic heterocycles and the generation of new scaffolds in easier ways than has been possible so far,” Bajorath says in an email.

Next, Levin hopes to find reactions that clip other carbons out from the quinoline core.