A repurposed reagent can stereoselectively insert nitrogen into C–H bonds, even those unactivated by nearby functional groups (Science 2026, DOI: 10.1126/science.aee3321). A team led by Jennifer M. Schomaker at the University of Wisconsin–Madison converted a chiral auxiliary into a nitrene transfer reagent, blending an established method of stereocontrol with a robust approach to late-stage functionalization.
Carbon-nitrogen bonds are ubiquitous in organic molecules: it’s estimated that over 75% of drugs and agrochemicals contain at least one nitrogen atom, and methods to manipulate and install amine functionality are a vital tool for the chemical industries. Nitrene transfer has already emerged as a powerful technique to insert nitrogen atoms directly into C–H bonds via a metal-stabilized intermediate, but it remains far from the perfect solution, says Derek Hu, a PhD student in Schomaker’s lab.
“Nitrene transfers often require expensive precious metals, while achieving both regio- and enantioselectivity are challenging problems as well,” Hu says. That is because the reactive metal-nitrenoid intermediate struggles to differentiate between the many similar C–H bonds typically present in organic molecules. Bulky ligand structures can help to direct the reaction toward a specific product, but this generally restricts the reaction to a handful of suitable substrates.
In a bid to address this strategic shortcoming, Schomaker’s team transformed a chiral auxiliary—a bulky structure used to direct reaction stereochemistry—into a nitrene transfer reagent, combining stereochemical control and C–H activation into a single entity.
Starting with commercially available Ellman’s sulfinamide, the researchers converted the sulfur(IV) center into its sulfur(VI) aza analog (a sulfinimidamide) to create a bulky and enantiomerically pure nitrene donor. This reagent was then treated with a silver catalyst and potent oxidant: the oxidant stripped the hydrogen atoms from the amine unit of the sulfinimidamide, while the catalyst stabilized the resulting nitrene. Upon exposure to organic substrates, this metallonitrene could insert directly into available C–H bonds to form a single amine product.
“The sterics play a really important role in funneling the reaction towards C–H insertion rather than competing processes like aziridination,” says Anh Trinh, another PhD student who was involved in the work. “The tert-butyl group also helps direct the reaction towards one of the pro-chiral C–H bonds, giving us good diastereoselectivity.”
Broadly, the reaction favors weaker C–H bonds, and the reaction conditions tolerate a wide range of functional groups and structural complexity. The team could use their reagent to aminate both unactivated hydrocarbons such as cyclohexane and intricate drug structures like sitagliptin.
“It’s elegant and profound work, and I think synthetically, this will change how we can construct complex molecules,” says catalysis chemist Martin Albrecht from the University of Bern. “We have a few mechanistic guidelines that come out of the scope, but there are lots and lots of questions, and I think it will be intriguing to explore the mechanism underlying this observed selectivity.”
Deeper mechanistic understanding, and how this could be leveraged to tailor the selectivity further, is exactly where the team hopes to take this next. “Ideally, our goal is to help develop a toolbox of different catalysts that are able to selectively aminate any desired C–H bond in either a simple feedstock or a complex, drug-like scaffold,” Hu says. “We’re currently exploring other ligand scaffolds to further improve the site- and stereoselectivity of our chemistry.”
2026 American Chemical Society
