A scheme showing the synthesis of the new class of heterocyclic compounds

Source: © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Modern approach to classical amide activation (a) and the synthesis of alkyl-substituted oxazolium salts by amide activation in absence of a base (b). The new work shows how a novel class of seven-membered ring can be made via amide activation in the absence of keteniminium ions

Chemists in Austria have discovered a never-before-seen class of heterocycle and made it in a single reaction.

The team around Nuno Maulide from the University of Vienna was surprised to find an unusual product after combining α‐phthalimido‐amides with triflic anhydride – a strong electrophile – and a base in acetonitrile as the solvent. Although the reaction has similar ingredients to the electrophilic amide activation, it produces an entirely different product, incorporating the solvent to create a new type of heterocycle. The fused, seven-membered rings contain one oxygen and two nitrogen atoms.

While the compounds turned out to be unstable during purification – final yields were lower than the ones measured before column chromatography – 10 examples made with different α‐phthalimido‐amide derivatives were isolated.

After some mechanistic investigations – isotope labelling and experiments using enantioenriched substrates – the team concluded the ring formation doesn’t go through the keteniminium intermediate that is the hallmark of electrophilic amide activation reactions. Instead, the chemists proposed the substrate first forms a five-membered ring, which is attacked by acetonitrile. The molecule then undergoes a ring enlargement to the final product.