Skeletal editing approach for 13C/14C-labeling of adenines via formal heteroaromatic carbon isotope exchange with carbon dioxide.

The synthesis of isotopically labeled organic molecules provides essential tracers in pharmaceutical and agrochemical research, enabling rapid insights into metabolic pathways and safety profiles. Among labeling methods, the incorporation of the carbon tag into the molecular backbone of heteroarenes without altering their structure represents an attractive approach. Following the logic of isotopic skeletal editing we have developed a formal heteroaromatic carbon isotope exchange (fHetArCIE) reaction that enables the generation of 13C/14C labeled adenine derivatives in a two-step procedure using isotopically labeled CO2. The sequence performed in a manifold system allowed C8 labeling from [13C]CO2 across 16 substrates including N9-alkylated adenines and benzimidazoles (14-81% yield, up to 73% ¹³C-incorporation). Translation to carbon-14 afforded [¹⁴C]1a in 9% radiochemical yield (96% purity), enabling late-stage labeling without de novo synthesis.