US researchers have developed a chemical reaction that quenches nitrogen atoms in organic molecules, including in ring structures, and connects the carbon atoms on either side.1 In Mark Levin’s first publication by the University of Chicago Laboratory, chemists use an unusual electrophilic amide to trigger the deletion. The reaction offers “a new way of thinking about molecular editing,” says Levin.

A picture showing an exemplary nitrogen deletion reaction

The exchange of single element atoms was on the wish list of five reactions reported by organic chemists World of chemistry Levin set up his laboratory specifically to attempt single-atom skeletal manipulation, but nitrogen deletion was not his initial focus. In search of something completely different, however, he came across two decades of research on electrophilic amides by Stephen Glover of the University of New England at Armidale, Australia.2 These molecules had two oxygen atoms attached to their amide nitrogen. Glover called them anomeric amides, referring to anomeric carbon centers in carbohydrates that also have two oxygen substituents.

Levin recognized that an anomeric amide reaction with a secondary amine appeared to proceed via an isodiazene intermediate. These intermediates can react so that two carbon atoms separated by a nitrogen atom can bond directly to one another, thereby eliminating nitrous gas. “I saw the opportunity and set out to achieve nitrogen extinguishing,” says Levin.

The Chicago team developed an anomeric amide reagent that enables nitrogen deletion when heated with a variety of secondary amines. The chemists’ studies suggest that the carbon atoms adjacent to nitrogen form radicals that react quickly with one another without leaving the cage of the solvent molecules in which they live. As such, the secondary amine requires at least one radical stabilizing substituent such as a benzyl group, otherwise other reactions dominate.

A scheme showing the nitrogen deletion reaction

Levin highlights his favorite example as a deletion of a secondary amine nitrogen from the cancer drug lapatinib. “Imagine that you were on the medicinal chemistry team doing the initial optimization work and you wanted to make this derivative,” he says. “Without our method, you’d have to start your synthesis from scratch to install this other side chain. That could be a real headache. ‘

Richmond Sarpong, who also works on the processing of molecular skeletons at the University of California in Berkeley, USA, calls the approach “beautiful and powerful in its simplicity”. Levin and his team show how anomeric amides can be used “in an unusual yet practical way to achieve nitrogen deletion,” he adds. “It’s the kind of method that you can easily incorporate into the design of a synthesis, much like olefin metathesis or click chemistry,” says Sarpong. “Because of this, it will find wide use in synthesis.”

Levin’s team is working with chemical supply giant Sigma-Aldrich to scale reagent synthesis and make it widely available. “We hope that the reagent will be commercially available soon,” says Levin. ‘In the meantime, I’m happy to send you free samples. The synthesis is quite simple, with only two isolations and no chromatography. ‘


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