C-to-N atom swap enables direct access to benzimidazoles from drug-like indoles
3 days ago
- #heterocycles
- #skeletal-editing
- #medicinal-chemistry
- A method for converting N-alkyl indoles to benzimidazoles via a carbon-to-nitrogen (C-to-N) atom swap was developed.
- The reaction uses commercially available phenyliodine(III) diacetate (PIDA) and ammonium carbamate as the nitrogen source.
- The process involves oxidative cleavage, oxidative amidation, Hofmann-type rearrangement, and cyclization in a single step.
- The reaction shows broad functional group tolerance and was successfully applied to 15 drug-like molecules.
- This method enables late-stage diversification of pharmaceuticals and agrochemicals without prefunctionalization.
- The transformation improves pharmacokinetic properties by converting metabolically labile indoles to more stable benzimidazoles.
- Control experiments confirmed the reaction mechanism and intermediate steps.
- The reaction was optimized to achieve good yields and demonstrated scalability.
- X-ray crystallography confirmed the structures of key products.
- The method has immediate applications in drug discovery and lead optimization programs.