The Emergence of Carbon Isotope Exchange

Abstract

Significant progress in C−C bond activation with transition metals has recently enabled the development of several carbon isotope exchange reactions. These methods are based on C−C bond decarboxylative carboxylation reactions in the presence of selected transition metals and labelled carbon monoxide or carbon dioxide.

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

“…Recent breakthroughs in late‐stage 14 C labeling have challenged this traditional approach and showcased direct access to complex scaffolds from [ 14 C]CO 2 . In addition, the first examples of transition‐metal‐catalyzed carbon isotope exchange (CIE) have recently emerged . Such technology enable selective replacement of molecular moieties into complex organic molecules, by reversible molecular deconstruction/reconstruction thus providing access to 14 C labeled compounds in a single operation, directly from the end‐use molecules.…”

“…[10] In addition, the first examples of transition-metal-catalyzed carbon isotope exchange (CIE) have recently emerged. [11] Such technology enable selective replacement of molecular moieties into complex organic molecules, by reversible molecular deconstruction/reconstruction thus providing access to 14 C labeled compounds in a single operation, directly from the end-use molecules. We described a copper-catalyzed decarboxylativecarboxylation of (hetero)aromatic carboxylic acid salts with [ 14 C]CO 2 .…”

Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by Organic Photoredox Catalysis

“…Arylacetates substituted with a-alkyl, a-alkoxy, and a-NH benzoyl groups were productive substrates (23)(24)(25), as were molecules featuring an alkene or terminal alkyne (26)(27). Alkylated (Fig 3, 43-50).…”

Late-Stage Carbon Isotope Exchange of Aryl Nitriles through Ni-Catalyzed C–CN Bond Activation

“…23 Herein we report a novel CIE strategy which is the first to employ Ar-CN exchange and demonstrate its utility for incorporating 13 C or 14 C labels (Figure 2B). This one-step approach offers broad substrate scope (vide infra) and uses both a common, solid 13 C/ 14 C source and air-stable catalyst precursor. Taken together, this CIE method delivers a robust and practical radiolabeling strategy for nitrile-containing pharmaceuticals and intermediates in drug development, and addresses a critical gap in the assembly of carbon isotope labeling methods.…”

“…Late-stage CIE, akin to more common and facile hydrogen isotope exchange (HIE), allows for the streamlined production of the labeled compounds, and has become an emerging concept and an active area of research. 14 The pioneering methods from Gauthier, 15 Baran, 16 and Cantat/Audisio 17 using 13 CO or 13 CO2, to facilitate CIE showed the power of utilizing transition metal catalysts to achieve C-C bond activation, allowing for a sustainable late-stage carbon isotope enrichment strategy for pharmaceutically relevant small molecules. Despite added progress in this arena [18][19][20][21][22] , CIE labeling approaches are limited to carboxylic acids, revealing the unmet need for new CIE methods to address the diverse functional groups present in pharmaceuticals and natural products, and ideally employing easily handleable solid labeling sources (Figure 2A).…”