Efficient palladium-catalyzed electrocarboxylation enables late-stage carbon isotope labelling

The study addresses the challenge of incorporating carbon isotopes (¹³C and ¹⁴C) into pharmaceutically relevant molecules, particularly aryl carboxylic acids, which are key motifs in many drugs and agrochemicals. Traditional labelling routes (e.g., carboxylation of preformed organometallics, nitrile substitution followed by hydrolysis) often require harsh conditions and exhibit poor functional group tolerance, limiting their utility for late-stage labelling. Modern transition metal-catalysed carboxylations expanded scope but typically require excess CO₂ and/or sensitive catalysts, which is incompatible with carbon-14 labelling where only stoichiometric or sub-stoichiometric labelled CO₂ can be used. The research aim is to develop a robust, low-loading palladium-catalysed electrocarboxylation that operates efficiently with near-stoichiometric CO₂ (including CO₂ released from Ba¹⁴CO₃), enabling late-stage single-step isotope incorporation into complex molecules.

Classical labelling strategies for aryl carboxylic acids include carboxylation of reactive organometallics or conversion of nitriles followed by hydrolysis, but their harsh conditions limit functional group compatibility. Transition metal-catalysed carboxylations using Pd, Co, Cu, and Ni have broadened scope but often require sacrificial reductants and elevated CO₂ pressures to suppress side reactions such as hydrodehalogenation or undesired couplings. Photoredox-Pd and Ni CRC methods have demonstrated efficacy but rely on amines or metals as reductants and typically excess CO₂ (1–20 bar), and higher catalyst loadings (often 2.5–10 mol%). Dynamic carbon isotope exchange (CIE) on carboxylates can be elegant but rarely achieves full isotope incorporation due to equilibration with unlabelled CO₂. Labelled CO has been used in stoichiometric or substoichiometric amounts for carbonylation, but generating ¹⁴CO from Ba¹⁴CO₃ adds a radioactive step. Early electrochemical CRC by Fauvarque, Jutand, and Torii (Pd/Ni catalysts) showed feasibility but required high catalyst loadings and atmospheric CO₂ with simple substrates. More recent electro-Ni CRC also employed high catalyst loadings and excess CO₂, limiting suitability for radiochemistry with limited labelled CO₂. Prior Pd- and Ni-based CRC protocols under low equivalents of CO₂ show diminished performance, underscoring the need for a system that is effective at low CO₂ concentration and tolerant of complex substrates.

The authors developed a Pd-catalysed electrocarboxylation using (BINAP)PdCl₂ (1.0 mol%) in a divided H-cell. Optimised conditions: TBABF₄ (0.2 M) as supporting electrolyte in DMF (3 mL per chamber), carbon paper electrodes (2 cm²), room temperature, and constant current of −4 mA (2.2 F total). An additive in the anodic chamber (ascorbic acid, ethanol, or triethylamine) is essential to provide a lower-potential oxidation process, improving yields by maintaining appropriate cathodic potentials; without an anodic electron donor yields drop significantly. CO₂ is supplied either at 1 atm or ex situ (1.5 equivalents) generated from BaCO₃ using camphorsulfonic acid in a three-chamber electro-glassware. The protocol was tested on aryl fluorosulfates (from phenols) and aryl bromides. For double carboxylations, current was reduced (e.g., −1 mA) to obtain bis-carboxylated products. For amide-free conditions, mechanistic CV analyses indicated DMF acts as the sacrificial anodic reductant; switching to acetonitrile required triethylamine as an electron donor and TBABr (0.2 equiv) in combination with TBABF₄ to enable solvent exchange while maintaining performance. Mechanistic studies included DFT (B3LYP-D3[IEFPCM]) to evaluate CO₂ migratory insertion barriers into Pd(II) intermediates with different ligands (tBuXPhos, PPh₃, BINAP), stoichiometric tests of an aryl-Pd(II) complex (32) with CO₂, and cyclic voltammetry of pre-catalysts and intermediates under Ar/CO₂. Comparative experiments applied previously reported CRC methods under restricted CO₂ (1.5 equiv) to benchmark performance.

• The Pd(BINAP)Cl₂-catalysed electrocarboxylation operates with only 1 mol% catalyst and near-stoichiometric CO₂, avoiding stoichiometric metallic or organic reductants.
• Optimised conditions in DMF/TBABF₄ at −4 mA afford high yields: model substrate gave 93% yield at 1 atm CO₂ and 85% yield with 1.5 equiv CO₂ released ex situ from BaCO₃. Without an anodic electron donor, yield dropped to 37%. Bench-top setup using 96% ethanol as anodic additive delivered 87%.
• Alternative electrolytes (NaI, NaBr, KI, NaBF₄, LiBF₄) were ineffective (no reaction observed under tested conditions).
• Under 1.5 equiv CO₂ in a two-chamber reactor, several published CRC protocols performed poorly: Ni/Mn (Tsuji 2012) 0%; Ni/PC (König 2017) 0%; Ni (Yu 2021) 0%; Pd/Ir (Iwasawa 2017) 68%; Pd/Ir (Jana 2019) 26%; Pd/Et₂Zn (Martin 2009) 19%.
• Substrate scope: both aryl fluorosulfates and aryl bromides were competent electrophiles. Electron-rich/hindered aryl bromides gave lower yields (slower oxidative addition), whereas electron-rich/hindered aryl fluorosulfates performed well. Electron-poor aryl bromides reacted readily; electron-poor aryl fluorosulfates had reduced yields due to competitive substrate reduction to phenols. The method tolerated various functional groups (e.g., chloride, tosylate), and enabled double carboxylation (bisphenol-A derivative) in 95% yield at −1 mA.
• Heteroaryl substrates and late-stage derivatizations of natural products proceeded in good yields. Late-stage stable-isotope labelling: adapalene 50%, bexarotene 28%. A two-step decarboxylative bromination followed by electrocarboxylation enabled labelling of probenecid (carboxylation step 57%).
• Radiolabelling with ¹⁴CO₂: direct use of Ba¹⁴CO₃ with ex situ CO₂ release enabled single-step labelling. Tamibarotene (RARα agonist) was prepared in 63% radiochemical yield; an olaparib precursor in 67% yield; compound 2 showed good ¹⁴C labelling yields. Full ¹⁴C incorporation is achieved when using only Ba¹⁴CO₃; molar activity can be tuned by diluting Ba¹⁴CO₃ with Ba¹²CO₃.
• Mechanistic insights: DFT indicates CO₂ migratory insertion into a Pd(II) aryl complex (III) is too high in energy (computed barriers: tBuXPhos ~51.5 kcal/mol; PPh₃ ~35.0 kcal/mol; BINAP ~34.5 kcal/mol), ruling out Pd(II) insertion under the conditions. Stoichiometric reaction of aryl–Pd(II) complex 32 with CO₂ in DMF at rt gave 0% carboxylation. CV of (BINAP)PdCl₂ shows two one-electron reduction events (−0.85, −1.35 V vs Ag/AgCl), consistent with access to Pd(I); (PPh₃)₂PdCl₂ shows a single two-electron reduction. Data support carboxylation from a reduced Pd species within the coordination sphere. DMF serves as the sacrificial anodic reductant; ethanol likely traps oxidized DMF-derived intermediates, improving efficiency. Amide-free conditions in acetonitrile are feasible with Et₃N and TBABr/TBABF₄.

The developed Pd-catalysed electrocarboxylation directly addresses the core challenge in radiolabelling aryl carboxylic acids: achieving efficient carboxylation at low CO₂ equivalents compatible with ¹⁴C sources. By using only 1 mol% (BINAP)PdCl₂ and controlling anodic and cathodic processes in a divided cell, the method minimizes side reactions (hydrodehalogenation, undesired couplings) and maintains catalyst activity even at low CO₂ concentration. The ex situ generation of CO₂ from BaCO₃ enables practical benchtop handling and full ¹⁴C incorporation, eliminating additional radioactive steps (e.g., CO₂-to-CO conversion). Mechanistic studies clarify that a reduced Pd species (Pd(I)/Pd(0)) is responsible for CO₂ insertion, informing ligand and solvent choices. Demonstrated tolerance to diverse electrophiles and functional groups, successful late-stage labelling of complex APIs and precursors, and adaptability to amide-free solvent conditions underscore the method’s relevance to pharmaceutical radiochemistry and stable isotope applications.

This work presents a practical, low-loading (1 mol%) Pd(BINAP)Cl₂-catalysed electrocarboxylation that enables late-stage carbon isotope labelling of aryl (pseudo)halides using only near-stoichiometric CO₂, including ¹⁴CO₂ released ex situ from Ba¹⁴CO₃. The method avoids stoichiometric reactive reductants, employs simple electrochemical equipment, and exhibits broad functional group tolerance and substrate scope. Mechanistic investigations identify a reduced Pd species as the active carboxylating intermediate and reveal DMF acts as the sacrificial anodic reductant, insights that facilitated translation to acetonitrile using Et₃N and bromide. The approach provides single-step access to fully ¹⁴C-labelled targets with tunable molar activity and is poised for immediate impact in drug development. Future work could expand scope to additional electrophile classes, optimize conditions for challenging electron-rich aryl bromides and electron-poor aryl fluorosulfates, and scale the process for industrial implementation.

• Electron-rich or sterically hindered aryl bromides give lower yields due to more demanding oxidative addition.
• Electron-poor aryl fluorosulfates can undergo competitive reduction, forming phenols and reducing carboxylation yields, reflecting sensitivity to substrate reduction potentials.
• The reaction performance depends on solvent and supporting electrolyte; several alternative electrolytes failed under the tested conditions, and DMF serves as a sacrificial anodic reductant (requiring additives or specific conditions). Translation to acetonitrile requires added Et₃N and TBABr.
• While many complex molecules are tolerated, some late-stage radiolabellings afforded modest yields (e.g., bexarotene 28%), indicating potential substrate-dependent limitations.
• Control of proton inventory and compartmentalisation (H-cell) are important to suppress side reactions (e.g., hydrodehalogenation), which may complicate setup if not properly managed.