Atom-swapping reaction turns furans into pyrroles

A new photocatalytic strategy allows researchers to swap oxygen atoms for nitrogens, converting furans into pyrroles in a single step. The approach could enable drug discovery chemists to adjust heterocyclic chemical structures with ease, allowing them to study how subtle changes affect the pharmacological activity of target compounds.

‘Existing methods for this type of heterocycle conversion often require harsh conditions, such as extreme heat or ultraviolet irradiation, which limit their applicability in complex organic synthesis due to low product yields and limited substrate scope,’ says Mark Levin, an organic chemist at the University of Chicago, US, who was not involved in the study.

Heterocycles, like furans and pyrroles, play a vital role in drug design owing to their unique electronic properties that can enable precise interactions with biological targets. ‘[The new reaction] stands out as the first protocol that allows for the direct conversion of furan to pyrrole under milder conditions, making it far more practical for a wider range of applications in synthetic chemistry,’ says Levin.

The method, which was developed by researchers in South Korea, adds to the growing repertoire of skeletal editing techniques – an emerging field in synthetic chemistry focused on modifying a molecule’s core structure by adding, removing or replacing single atoms. Of all the common skeletal editing techniques, inserting nitrogen into an aromatic ring is particularly challenging and energy intensive, says Yoonsu Park from the Korea Advanced Institute of Science and Technology in Daejeon, who led the work. ‘The aromatic stabilisation energy is so high that the exchange of one atom to another is deemed impossible.’

By taking inspiration from a 1971 study that used ultraviolet light to convert furan to N-propylpyrrole in a 3% yield,² Park applied a commercially available acridinium photocatalyst and blue light to oxidise the furan ring. ‘The problem was that the starting material, the five-membered ring, is regarded as an electron-rich compound and the amine is also electron rich, so coupling between nucleophile to nucleophile is virtually impossible in the conventional sense,’ explains Park.

Park’s team’s light-driven oxidation generates a radical species, disrupting the ring’s aromaticity. A primary amine is then added, which triggers a molecular rearrangement, temporarily opening the ring to form a species containing both the nitrogen and oxygen atoms. A spontaneous ring-closing condensation then forms the final pyrrole, restoring the aromaticity and generating water as the only byproduct.

‘The clean oxidation of furan substrates is surprising, despite the presence of more electron-rich amines and pyrroles,’ comments Levin.

The team demonstrated the method’s versatility by applying it to a variety of furans and amines, including complex naturally derived medicinal compounds. Park explains that the researchers are now working on developing further ways of editing five-membered rings. ‘We want to improve the reactivity … careful optimisation of the furan substrate additive matters a lot and is the immediate challenge in this reaction,’ he adds. ‘If we want to scale this up, we need to think about the design of the reactor too.’