From o ‐Phenylenediamine to Flavin Derivatives: A Potential Prebiotic Carbon Skeleton Expansion With Formaldehyde, Cyanide, and CO ₂

Molecular cofactors are vital for many enzymatic processes. Flavin derivatives mediate redox processes in biological systems, and their ubiquitous nature makes them critical for sustaining most forms of life. Due to the structural resemblance between the tricyclic core of flavin and nucleobases, it has been proposed that modern metabolism originated from flavin‐derived heterocycles, although the prebiotic origin of such heterocycles from small molecules has remained unclear. Here, we demonstrate that simple C1 precursors (formaldehyde, cyanide, and carbon dioxide), together with aromatic ortho‐diamines, can assemble into the three‐ring system of lumichrome. This constitutes a prebiotically plausible chemical route to flavin‐type heterocyclic scaffolds. A Strecker‐like reaction afforded 3,4‐dihydroquinoxalin‐2‐amines via a facile intramolecular cyclization. Subsequently, either CO ₂ ‐mediated oxidation or a photochemical C1‐cyanation followed by carboxylation with CO ₂ produces alloxazine scaffolds in good yields. Notably, we showcase a single‐vessel synthesis of lumichrome without purification of intermediates. This work shows how simple C1 precursors and aromatic diamines can assemble into complex, biologically relevant heterocycles, highlighting the chemical accessibility of alloxazine‐type scaffolds from simple feedstocks, independently of their evolutionary history.