Direct Carbon Isotope Exchange through Decarboxylative Carboxylation

Abstract

A two-step degradation-reconstruction approach to the carbon-14 radiolabeling of alkyl carboxylic acids is presented. Simple activation via redox-active ester formation was followed by nickelmediated decarboxylative carboxylation to afford a range of complex compounds with ample isotopic incorporations for drug metabolism and pharmacokinetic studies. The practicality and operational simplicity of the protocol was demonstrated by its use in an industrial carbon-14 radiolabeling setting.

Transition‐Metal‐Free Carbon Isotope Exchange of Phenyl Acetic Acids

“…We described a copper‐catalyzed decarboxylative‐carboxylation of (hetero)aromatic carboxylic acid salts with [ 14 C]CO 2 . In 2019, Baran and Martin independently reported a nickel‐catalyzed approach utilizing [ 14 C]CO 2 . Gauthier et al.…”

“…The green colored circles and numbers denote the positions of the atoms labeled and the percent incorporation of the isotope. Reaction conditions: substrate (0.1 mmol, 1 equiv), 13…”

“…[28,29] Next, we examined the scope of the reaction. A series of electron-rich derivatives was screened: labeled PAAs [ 13 (25), Naproxen (26), and Ketoprofen (27), though a higher temperature (190 8C) was necessary to achieve reasonable carbon-13 incorporations (26 % to 32 % IE). Flurbiprofen (28) did not perform effectively under standard conditions; further optimization allowed to label [ 13 C]28 in 51 % IE (33 % yield) at 190 8C in only 30 minutes.…”

The Emergence of Carbon Isotope Exchange

“…Using more convenient [ 14 C]CO 2 gas as the isotope source, a method to generate carbon‐14 radiolabelled aliphatic acids has been developed by Baran and co‐workers (Figure b). This strategy is based on a nickel‐mediated transformation of activated acids in the presence of an excess of [ 14 C]CO 2 (5–32 equiv).…”

Carbon-11 carboxylation of trialkoxysilane and trimethylsilane derivatives using [11C]CO2

“…4 a Recently, a dynamic carbon isotope exchange (isotopic enrichment) of carboxylates using [ 13 C]CO 2 and [ 14 C]CO 2 has been reported; however, the applicability of this methodology to carbon-11 chemistry would require an extensive study on the range of molar activity that could be obtained. 5 …”