Carbon Dioxide Radical Anion by Photoinduced Equilibration between Formate Salts and [¹¹C, ¹³C, ¹⁴C]CO₂: Application to Carbon Isotope Radiolabeling

Abstract

The need for carbon-labeled radiotracers is increasingly higher in drug discovery and development (carbon-14, β − , t 1/2 = 5730 years) as well as in positron emission tomography (PET) for in vivo molecular imaging applications (carbon-11, β + , t 1/2 = 20.4 min). However, the structural diversity of radiotracers is still systematically driven by the narrow available labeled sources and methodologies. In this context, the emergence of carbon dioxide radical anion chemistry might set forth potential unexplored opportunities. Based on a dynamic isotopic equilibration between formate salts and [ 13 C, 14 C, 11 C]CO 2 , C-labeled radical anion CO 2•− could be accessed under extremely mild conditions within seconds. This methodology was successfully applied to hydrocarboxylation and dicarboxylation reactions in late-stage carbon isotope labeling of pharmaceutically relevant compounds. The relevance of the method in applied radiochemistry was showcased by the whole-body PET biodistribution profile of [ 11 C]oxaprozin in mice.

Visible-light-driven alkene dicarboxylation with formate and CO2 under mild conditions

“…In this scenario, a potential facile electron transfer/equilibration between 13 CO 2 ˙ − and the excess CO 2 gas may account for the observation of 2a as the main product in Scheme 2c . 27 Moreover, since the reduction of simple styrenes ( E 1/2 = −2.58 V vs. SCE in DMF for 3a) 28 is more demanding than 1a, direct CO 2 ˙ − addition is possibly the predominant pathway for substrates in Table 3 . The radical intermediate VI was then reduced by PC˙ − (II) to give the anion VII, which undergoes nucleophilic attack of CO 2 to afford the final product 2a after acidification of the salt intermediate VIII.…”

Formate and CO2 Enable Reductive Carboxylation of Imines: Synthesis of Unnatural α-Amino Acids

“…When the isotope-labeled 13 CO 2 was used, charge transfer from CO 2 •– and 13 CO 2 happened to give a mixture of CO 2 and 13 CO 2. Therefore, only 57% isotope labeling was observed …”

Recent Advances in Reactions Involving Carbon Dioxide Radical Anion

“…This CO 2 •– would in turn react with the alkene substrate to forge a new C–C σ-bond and a carbon radical 109 , which was quenched by HAT from the thiol to regenerate the thiyl radicals. Recently, Audisio’s group utilized this strategy to access carbon isotope labeled products through C-labeled radical anion CO 2 •– generated by a dynamic isotopic equilibration between [ 13 C, 14 C, 11 C]­CO 2 and formate salts . In 2022, Li’s group developed the similar transformation with cheap and readily available Rose Bengal as the photocatalyst, cyclohexyl mercaptan as additive and formate salt as the carbonyl source .…”