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Skeletal-editing reaction turns pyridines into substituted benzenes

The new method swaps out a nitrogen-carbon pair for 2 carbons to modify aromatic rings

by Brianna Barbu
February 2, 2024

A reaction scheme showing loratadine being converted into a derivative that contains a naphthalene instead of a pyridine ring.

Hot on the heels of reports of two skeletal-editing methods for adding nitrogen atoms into aromatic rings, chemists from the University of Münster are joining the atom-trading action. The team has devised a method for swapping out a nitrogen-carbon pair from pyridine rings to make substituted benzenes (Nat. Chem. 2024, DOI: 10.1038/s41557-023-01428-2) .

Being able to rearrange the atoms in a ring provides chemists with a way to easily modify drug candidates and create related compounds to compare their pharmacological properties.

Armido Studer, who led the work, says the method is an elegant case of reusing established chemistry to do new things. It arose from the group’s previous work adding functionality to the meta position of pyridines ; that was achieved by dearomatizing them with a cycloaddition reaction, performing C–H functionalization, and then rearomatizing the ring (Science 2022, DOI: 10.1126/science.ade6029) .

The researchers realized that the stable oxazino pyridine intermediate of that reaction contained a diene that was ripe for Diels-Alder cycloaddition. “We found a way to activate pyridine, and the activated intermediates offered more to us than just meta functionalization,” Studer says. By adding an activated alkyne to that oxazino pyridine intermediate, they were able to incorporate the atoms from the alkyne into the ring, replacing a nitrogen and one carbon from the original structure with two new, functionalized carbons.

The University of Chicago’s Mark Levin, whose team published two nitrogen-insertion reactions in the fall, says in an email that the work is “creative, interesting, and likely quite useful.” He says his favorite thing is how it built on the earlier C–H functionalization strategy to do skeletal editing. “I suspect it will get a lot of people thinking about their chemistry in a new way.”

Studer says he looks forward to seeing what the field of skeletal editing accomplishes in the near future—including what medicinal leads this boom of new reactions might generate. He also mentions that his method could be useful in materials science, for tuning the π systems of conjugated compounds. “I’m pretty sure we will see far more to come in the next few years.”



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