Photochemical Skeletal Editing for Pyridine-to-Pyrrole, -Furan, and -Thiophene Conversion

Objective

Heteroaromatic like pyridines, pyrroles, furans, and thiophenes are privileged scaffolds in pharmaceuticals & agrochemicals. While functional group modifications are routine, direct interconversion between heteroaromatic rings typically requiring de novo synthesis . “Ring replacement” strategies could transform drug discovery by enabling late-stage modulations, yet no general methods exist for converting abundant pyridines into other heterocycles. This project will pioneer a photochemical platform to directly convert pyridines into pyrroles, furans, and thiophenes. The approach exploits pyridine N-oxidation followed by visible-light-mediated deconstruction to nitrile-containing dienes. These intermediates will undergo divergent [4+1] cycloadditions with nitrenes, singlet oxygen, or sulfur to yield pyrroles, furans, and thiophenes, respectively. The methodology will progress through: (1) development of pyridine-to-pyrrole transformation via Cu-catalysed nitrene insertion and rearrangement, (2) mechanistic elucidation, (3) extension to pyridine-to-furan and pyridine-to-thiophene conversions using singlet oxygen and elemental sulfur, and (4) demonstration of synthetic utility in late-stage ring replacement of drug molecules. This disruptive strategy introduces the first general method for heteroaromatic-to-heteroaromatic replacement, a conceptually novel retrosynthetic paradigm. It transforms pyridines from static scaffolds into versatile precursors, enabling access to new heterocyclic space of high biological and industrial value. Completion of this ambitious project at RWTH Aachen University will be supported by advanced mechanistic expertise, knowledge transfer, and dissemination, equipping the Researcher with unique skills at the interface of photochemistry, catalysis, and heteroaromatic synthesis and strongly enhancing her career trajectory toward independence.