Skeletal editing strategy makes room for more nitrogen

One small atom can make a big difference in a molecule’s pharmacological properties. Especially if that atom is a nitrogen.

Over 80% of small-molecule drugs approved by the US Food and Drug Administration between 2013 and 2023 had a nitrogen-containing ring somewhere in the structure. And the evolving suite of skeletal editing reactions that can add, delete, or swap the nitrogens in a molecule with precision is giving chemists more ways to explore the atom’s influence in drug discovery.

Chemists at the University of Oklahoma have now unveiled a new strategy for expanding 5-membered aromatic rings that already contain a nitrogen, by slipping in an extra nitrogen atom as the ring’s sixth member (Science 2025, DOI: 10.1126/science.adp0974). The reagent they developed works without additives, does not require protection on the original nitrogen in the ring, and doesn’t mess with easily oxidized groups elsewhere in a molecule—all helpful for making delicate late-stage adjustments to drug leads.

“We wanted to develop a general approach which is applicable with all functional groups,” says Indrajeet Sharma, who led the work. To accomplish that, he and his team turned to sulfenylnitrenes, which contain a reactive nitrogen atom bound to a sulfur atom. The sulfur acts both as a stabilizer and a leaving group.

The researchers developed several bench-stable reagents designed to fall apart into reactive sulfenylnitrenes when they’re heated. By making alterations to the aromatic ring bound to the sulfur, they found that it’s possible to adjust how much heat is required to activate the nitrene, depending on how temperature-sensitive the molecule to be modified is. Sharma says they’re working on making the reagents commercially available.

In the reaction, the nitrene binds to an electron-rich double bond near the existing nitrogen atom. Then the sulfur group breaks off and the ring rearranges to incorporate the new nitrogen two spots over from the original one. If there are two heterocycles in a molecule, the nitrogen atom will go into the more electron-rich one.

The researchers found that their sulfenylnitrene strategy could stick nitrogen into almost any five-membered aromatic N-heterocycle. It works for pyrroles, indoles, azaindoles, and imidazoles—the latter two of which other nitrogen-insertion reactions don’t typically work on. The researchers demonstrated their method’s broad functional-group compatibility by expanding a variety of drugs and other complex molecules, including amino acid derivatives and oxidation-sensitive thioethers.

Sharma says he and his team are working on expanding the method to rings that don’t already contain nitrogen. They’re also looking at ways to boost the reaction yields in the safer solvents that industry laboratories prefer—currently it works best in toxic chlorobenzene.

Richmond Sarpong of the University of California, Berkeley, who also researches skeletal editing but was not involved in this work, calls it “a wonderful addition to the growing armamentarium of single atom skeletal editing methods” in an email to C&EN. He adds that having reagents that work for a range of temperatures is “a creative and practical alternative” that he expects many chemists will want to try out.

Sharma says he’d like to see a future where chemists use artificial intelligence predictions and skeletal-editing chemistry together to solve drug development problems. For example, if a drug candidate is failing, researchers could pinpoint what parts of the structure are responsible and then make strategic alterations to get the campaign back on track, he says. “Rather than building something from scratch . . . we can do a renovation.”