Chemists revive an old route to amides, making it safer

Chemists have been using the Schmidt reaction, which transforms aldehydes and ketones into amides, for nearly 100 years. But the reaction has a downside that prevents it from being widely used: it requires azides, which can be volatile, toxic, and potentially explosive. Ning Jiao and colleagues at Peking University discovered they could replace these dangerous azides with the common industrial solvent nitromethane in a Schmidt-like transformation. Amides made in this manner could be used as drugs, agrochemicals, or commodity chemicals.

“Jiao and colleagues have found a way of making an incredibly useful reaction—the insertion of a single nitrogen atom in between two carbons—into a safer and more accessible process,” says Jeffrey Bode, a chemist at the Swiss Federal Institute of Technology (ETH), Zurich, who develops new reactions.

“The classic approach to synthesizing amides is centered on the activation of carboxylic acids using exotic reagents to enable nucleophilic substitution,” Jiao explains. The Schmidt reaction, which is essentially a nitrogen insertion reaction, offers an efficient alternative approach to making these chemicals, but it is limited because it requires azides, he says.

Jiao and his team reasoned that they could use a cascade reaction to transform nitromethane into a nitroxyl species, which could then form a hydroxylamine derivative that would react as an azide does in a Schmidt-type process. The strategy overcomes the long-standing challenge of using azides in the traditional Schmidt reaction, and it also unlocks novel reactivity in nitroalkanes, which are typically used as carbon nucleophiles.

The new Schmidt-type reaction creates amides from ketones (example shown), alkynes, and even simple alkylbenzenes, which are often inert to this type of reaction. Depending on the conditions used, the reaction can also transform aldehydes into either primary amides or nitriles (Science 2019, DOI: 10.1126/science.aay9501).

Chemists have long sought alternative methods to working with azides, says Jeff Aubé, a chemist at the University of North Carolina at Chapel Hill who develops new synthetic techniques. “The safety of this regimen for larger scale reactions remains to be worked out, but for now it looks very attractive for lab-scale work. We’ll certainly give it a try.”