Skeletal-editing ‘dream’ realized

A new atom-swapping reaction gives chemists a versatile tool for replacing aromatic carbons with nitrogen in complex molecules. The atomic switcheroo will help drugmakers explore how pharmaceutical leads and natural products respond to tiny structural tweaks known as skeletal editing (Science 2026, DOI: 10.1126/science.aef3511).

C-to-N cut-and-paste chemistry has been a longtime dream of University of Chicago chemist Mark D. Levin, who led the development of the new reaction. In 2023, Levin’s group reported a first- generation C-to-N transformation in aromatic rings. Although that reaction was an exciting proof of concept, Levin says it is limited because it proceeds through a singlet nitrene. That singlet nitrene tends to cross over to the triplet nitrene in electron-rich or highly conjugated systems—common systems in drug candidates—and the triplet can’t form the intermediate needed to do the swap. It’s essentially a dead end.

Levin says he didn’t know how to improve that transformation until he came across some useful reactions in the literature. First, he read about what he calls some “really beautiful work” from Ekaterina M. Chainikova’s lab at the Ufa Institute of Chemistry in which triplet nitrenes react with molecular oxygen and go on to form nitrile oxides. Not long after, he was reading about the synthesis of (−)-N-methylwelwitindolinone B isothiocyanate done by Viresh Rawal, who works in the office next to Levin’s. The synthesis uses a nitrile oxide to form an isothiocyanate.

Levin reasoned that putting those two reactions together might transform his triplet nitrene from a liability into a feature. And it worked. The resulting second-generation C-to-N reaction proceeds through an entirely different mechanism than the first generation. “The overall transformation is just bonkers,” Levin says.

Not only does the swap work with the once-problematic triplet nitrenes “but the reaction is just so much milder than anything else we had done previously,” Levin says. The reaction tolerates many functional groups, and the team was able to use it to make skeletal edits to complex natural products, such as vinpocetine.

Nick Meanwell, a veteran medicinal chemist who now runs NuArq MedChem Consulting, says that the reaction is the kind of elegant work he has come to associate with Levin’s lab and that it is a reaction medicinal chemists will embrace.

In particular, it will allow chemists to do nitrogen scans, in which they iteratively replace carbon atoms with nitrogen at each position in an aromatic ring, Meanwell says. “Typically, we have to go back and synthesize them all from scratch.”

Levin cautions that azides, which are the starting materials for making the triplet nitrene, can be explosive and toxic. The method also calls for oxygen in organic solvents, a combination which presents a flammability risk. The reaction’s biggest limitation is that—for reasons Levin and his team don’t fully understand—it requires extremely dilute conditions. The solvent volumes are reasonable for making 100 mg or less of a compound, which is common for medicinal chemists, he says. But the amount of solvent becomes unwieldy when scaled up.

“I can see now a future where this reaction is good enough for any possible C-to-N replacement that people want,” Levin says. “Even a few years ago, I think that was still very much me dreaming. Now it feels tangible. There’s still work to do for sure, but I think it’s a lot more clear now that we can turn this into a really good reaction.”