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Scientists have achieved a new feat in molecular editing by swapping carbon for nitrogen, enabling the direct conversion of indoles into benzimidazoles. This simple switch in a offers a hassle-free and effective way of designing medicinally relevant molecules. The work is published in Nature Chemistry.

Single-atom swap reactions require the selective formation and breaking of multiple bonds at the same time, making them quite rare and challenging.

Researchers from ETH Zurich overcame these hurdles by exploiting the electron-rich indole ring's eagerness to undergo oxidative cleavage via Witkop oxidation. This step can split the electron-rich ring open to form a dicarbonyl intermediate, thereby creating an entry point for subsequent cascade reactions.

A one-step, direct C-to-N atom exchange strategy converted N-alkyl indoles into benzimidazoles using only two readily available reagents: phenyliodine(III) diacetate (PIDA) and ammonium carbamate. The transformation took place under simple conditions鈥攁t room temperature and within 30 minutes.

The researchers note that the obtained benzimidazoles showed improvements in metabolic stability, biological activity, and structural diversity, making them particularly attractive for pharmaceutical applications.

As of 2024, indoles ranked sixth among the most common nitrogen-containing heterocycles in FDA-approved drugs, a popularity likely driven by their abundance in naturally-occurring therapeutic alkaloids.

Despite their prevalence, indoles remain notoriously difficult scaffolds in drug discovery. Their tendency to undergo oxidation often triggers toxicity issues and unfavorable absorption鈥揹istribution鈥搈etabolism鈥揺xcretion pathways.

Studies have found that converting indole-containing drugs into benzimidazoles not only makes the drug molecules more stable in the body but also increases their potency. There is a lack of simple methods to achieve this conversion, as existing strategies rely on multi-step processes that are impractical for drug companies.

For instance, a common requirement for indole conversions is substrate preactivation, which involves chemically modifying a starting material prior to skeletal editing. Not only is this step difficult to achieve, but it also limits the applicability of the reaction by hindering the later-stage improvisations to drug-like molecules.

By tapping into the natural reactivity of the indole skeleton, the researchers of this study eliminated the need for preactivation and created a C-to-N swap method that was practical for pharmaceutical applications.

The transformation proceeded through a four-step cascade, the first step being the Witkop oxidation, which produces a dicarbonyl intermediate. This intermediate then underwent oxidative amidation with ammonium carbamate, introducing nitrogen functionality in the form of a primary amide.

Next, a Hofmann-type rearrangement mediated by the PIDA reagent, removed one carbon atom while inserting nitrogen in its place. Finally, cyclization restored aromaticity, resulting in a benzimidazole scaffold.

What set this strategy apart was its ability to tolerate a wide range of functional groups. By converting 15 drug-like molecules, the researchers demonstrate the immediate potential of this new atom swap strategy for drug discovery.

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