Revolutionizing Nitrogen Utilization: The Power of Skeletal Editing Strategy

A single tiny atom can create a significant impact on a molecule’s medicinal characteristics. Particularly when that atom is nitrogen.

Researchers at the University of Oklahoma have recently introduced a novel technique for enlarging 5-membered aromatic rings that already feature a nitrogen, by incorporating an additional nitrogen atom as the ring’s sixth participant (Science 2025, DOI: 10.1126/science.adp0974). The reagent they created operates without any additives, does not need protective measures on the initial nitrogen in the ring, and avoids interference with easily oxidizable groups located elsewhere in the molecule—all advantageous for making sensitive late-stage modifications to drug candidates.

“Our goal was to establish a universal method applicable to all functional groups,” states Indrajeet Sharma, who spearheaded the project. To achieve this, he and his team utilized sulfenylnitrenes, which comprise a reactive nitrogen atom connected to a sulfur atom. The sulfur functions both as a stabilizer and as a leaving group.

The scientists devised several stable reagents intended to decompose into reactive sulfenylnitrenes upon heating. By modifying the aromatic ring linked to the sulfur, they discovered it was possible to regulate the amount of heat necessary to activate the nitrene, based on the temperature sensitivity of the molecule destined for modification. Sharma mentions they are focused on making the reagents accessible in the market.

During the reaction, the nitrene attaches to an electron-rich double bond located near the pre-existing nitrogen atom. Subsequently, the sulfur group detaches, and the ring rearranges to incorporate the new nitrogen two positions away from the original one. In cases where two heterocycles exist within a molecule, the nitrogen atom will enter the more electron-rich one.

The researchers observed that their sulfenylnitrene approach could insert nitrogen into nearly any five-membered aromatic N-heterocycle. It is effective for pyrroles, indoles, azaindoles, and imidazoles—the latter two of which other nitrogen-insertion reactions do not commonly succeed with. They validated their method’s broad compatibility with various functional groups by expanding an assortment of drugs and other complex compounds, encompassing amino acid derivatives and oxidation-sensitive thioethers.

Sharma indicates that he and his team aspire to broaden the technique to rings that do not currently contain nitrogen. They are also exploring methods to enhance the reaction yields in safer solvents that are favored by industrial laboratories—currently, it performs optimally in toxic chlorobenzene.

Richmond Sarpong from the University of California, Berkeley, who is also engaged in skeletal editing research but was not part of this study, refers to it as “a fantastic addition to the expanding repertoire of single atom skeletal editing techniques” in an email to C&EN. He further notes that having reagents that operate across a range of temperatures is “an inventive and practical alternative” that he anticipates many chemists will be eager to test.

Sharma expresses his desire to envision a future where chemists integrate artificial intelligence predictions with skeletal editing chemistry to tackle drug development challenges. For instance, if a drug candidate is underperforming, researchers could identify which areas of the structure are contributing to the issue and then implement strategic modifications to redirect the project back on course, he explains. “Instead of constructing something anew . . . we can carry out renovations.”