Skip to main content
NCBI home page
JACS Au logoLink to JACS Au
. 2026 Feb 2;6(2):773–778. doi: 10.1021/jacsau.5c01545

Aryl Halide Carboxylation via Decarboxylative Metal–Halogen Exchange

Daniel J Ryder-Mahoney †, Ken Yamazaki ‡,*, Gregory J P Perry †,*
PMCID: PMC12933346  PMID: 41755871

Abstract

A unique mode of metal–halogen exchange is reported for the carboxylation of aromatic halides. The process is mediated by the potassium salt of a commercially available carboxylic acid, which acts as the source of CO2 and metalating agent. The procedure demonstrates that readily available, bench-stable carboxylic acid salts can generate metalating agents in situ for metal–halogen exchange, thus avoiding sensitive and hazardous organometallics. The carboxylation proceeds under mild conditions, shows broad substrate scope and avoids specialized apparatus such as pressurized containers or strictly inert conditions. Application to the carbon isotope labeling of biologically relevant compounds is also reported, including a late-stage carbon isotope exchange. Experimental and computational studies support our proposed mechanism of decarboxylative metal–halogen exchange in which the metalating agent and CO2 are generated in situ from the carboxylate salt.

Keywords: Carboxylation, Metal−Halogen Exchange, Carbon Isotope Labeling, Dual-Function Reagent, CO2 Transfer

graphic file with name au5c01545_0009.jpg

graphic file with name au5c01545_0008.jpg

The carboxylic acid motif is a highly valuable functional group found in a variety of important molecules. They are also key synthetic building blocks as they can be transformed into other functionalities, such as esters, amides and alcohols. Carboxylation is also the method of choice for installing carbon isotope labels. However, efficient and practical methods are needed in this area due to the high costs associated with labeled compounds.

The carboxylation of carbon–halogen (C–X) bonds is particularly useful for preparing carboxylic acids as the site of the C–X bond controls the position of carboxylation. Metal–halogen exchange is a fundamental process in organometallic chemistry and a widely adopted strategy in synthesis. Ever since the pioneering work by Wittig and Gilman, metal–halogen exchange has been closely entwined with the field of carboxylation. Indeed, Gilman’s first evidence of metal–halogen exchange involved carboxylation of aryl halide I to give benzoic acid III via metalated intermediate II (Scheme A). Of the various methods for C–X carboxylation, metal–halogen exchange has established itself among the most powerful. Significant advancements have been made in this area, but the habitual use of hazardous and difficult-to-handle organometallics can create barriers toward application.

1. (A) Classical Metal–Halogen Exchange. (B) (i) Established Reactivity: Decarboxylative Functionalization, (ii) Our Previous Work: Decarboxylative Metalation via Deprotonation, (iii) This Work: Decarboxylative Metalation via Metal–Halogen Exchange.

1

Open in a new tab

When considering reactions between carboxylic acids/carboxylates and organohalides, the simplest process involves ester formation via nucleophilic substitution. More recently, decarboxylative functionalization has emerged to enable cross-coupling between carboxylic acids and organohalides (Scheme B­(i)). These couplings have received considerable attention as they replace traditional nucleophilic organometallics, which can present hazards, are difficult-to-handle and are of limited availability, with stable and abundant carboxylic acid derivatives IV. Despite sustained investigation, this field limits the role of the in situ generated organometallic to a nucleophilic species V for coupling reactions. Though significant, this fails to tap into the wide-ranging functions that organometallics are capable of, most strikingly highly valuable metalation chemistry.

We have recently established a program to expand the capabilities of in situ formed organometallics. Previously, we revealed a process for C–H carboxylation that proceeded via decarboxylative deprotonation (Scheme B, (ii)). − In this process, carboxylate IV underwent decarboxylation to provide an in situ organometallic VI capable of deprotonating C–H bonds. Impressively, the CO2 generated during the initial decarboxylation step was captured by the deprotonated intermediate to give carboxylic acid products VII. We therefore described carboxylate IV as a dual-function reagent as it provided a combined source of base and CO2. We questioned whether an analogous process of decarboxylative metalation with aryl halides would be possible (Scheme B­(iii)). In this process, the in situ generated organometallic VIII would promote metal–halogen exchange. The resulting metalated substrate would then capture the in situ generated CO2 to give product VII. In this way, dual-function reagent IV would act as a source of metalating agent and CO2. This C–X carboxylation via decarboxylative metal–halogen exchange would augment existing CO2 transfer ,, and exchange reactions , while delivering a novel concept in organometallic chemistry and a useful tool for carbon isotope labeling.

We began our study by submitting aryl halide 1a-I to our previously reported reaction conditions (Table ). Potassium triphenylacetate 2-K, which is easily prepared from commercially available triphenylacetic acid (CAS: 595–91–5), was used as the dual source of CO2 and metalating agent. This provided the carboxylated product (isolated as the corresponding methyl ester) 3a in reasonable yield (Entry 1). The process was optimized by simply doubling the equivalents of dual-function reagent 2-K (Entry 2). The reaction was similarly efficient with aryl bromide 1a-Br (Entry 3). Poor reactivity was observed with aryl chloride 1a-Cl (Entry 4), however, engaging these substrates in metal–halogen exchange is notoriously difficult. Interestingly, whereas our previous C–H carboxylation procedure required long reaction times, this C–X carboxylation was completed in as little as 5 min (Entries 5–7), indicating the greater efficiency of metal–halogen exchange over deprotonation. , Following a solvent screen, we chose DMF as the solvent for this investigation, though DMSO was also effective (Entry 8). , The cesium and rubidium salts 2-Rb and 2-Cs (Entries 11 and 12) were also effective carboxylating agents, but diminished yields were observed for the lithium and sodium salts 2-Li and 2-Na (Entries 9 and 10). We found that the lithium and sodium salts were hygroscopic, therefore, we believe this drop in yield is likely due to the presence of water, rather than any observable reactivity difference.

1. Reaction Optimization .

graphic file with name au5c01545_0007.jpg

Entry X M time NMR yield 3a (%)
1 I K 16 h 45
2 I K 16 h 90
3 Br K 16 h 96
4 Cl K 16 h 0, 7
5 Br K 30 min 96 (91)
6 Br K 5 min 91
7 Br K 1 min trace
8 Br K 30 min 73
9 Br Li 30 min 37
10 Br Na 30 min 63
11 Br Rb 30 min 93
12 Br Cs 60 min 85
Open in a new tab
a

Reaction conditions: 1a-X (0.5 mmol), 2-M (2.0 equiv), DMF (0.2 M), 50 °C. Then MeI (8.0 equiv), 50 °C, 2 h. DMSO = dimethyl sulfoxide. DMF = N,N-dimethylformamide.

b

2-K (1.0 equiv).

c

140 °C.

d

Isolated yield.

e

DMSO instead of DMF.

We have been able to demonstrate our decarboxylative metal–halogen exchange process in the carboxylation of various heteroaromatic bromides (Scheme ). The reaction was applicable to substrates bearing electron-donating (3b, 3c) and electron-withdrawing groups (3g, 3h), and with substitution around the heteroaromatic ring (3e, 3i, 3j). We were impressed that sensitive functional groups, such as esters (3g, 3h) and aldehydes (3k) were tolerated. We also note that all reactions were carried out in DMF (N,N-dimethylformamide) but we have never observed competing formylation reactions, again highlighting the functional group tolerance and complementarity of our approach to traditional metal–halogen exchange. The compatibility of the reaction with various functional groups was further investigated by means of a robustness screen. , This revealed that ketones, alkenes, aryl triflates, alkynes, nitriles, nitro groups and alkyl chlorides are all tolerated under the reaction conditions. This improved tolerance over traditional metal–halogen exchange may be due to the electrophile (CO2) being present in the reaction mixture while the metalated intermediate (see 5, Scheme ) is formed. Conversely, traditional metal–halogen exchange requires the metalated intermediate to be formed before the addition of the desired electrophile, resulting in a greater chance of side reactions occurring. Several instances of selective C–X carboxylation are also noteworthy, for example, C–Br bonds were preferentially carboxylated in the presence of C–Cl and C–F bonds (3d, 3e). Moreover, dibrominated substrates could be selectively monocarboxylated (3f). Impressive examples of site-selective C–X carboxylation were observed, for example, 2- and 5-brominated thiazoles 1n-Br and 1o-Br gave 2- and 5-carboxylated products 3n and 3o in good yields. We also observed that carboxylation with less activated heteroaromatics, such as benzothiophenes and benzofurans, proceeded efficiently (3t, 3u). The carboxylation of less reactive substrates (see 3r and 3s) is currently outside the limits of this methodology, however, some other 6-membered rings reacted well under the standard conditions (see 3v and 3w). Overall, we have carboxylated a variety of (hetero)­aromatics, including (benzo)­thiazoles, imidazoles, oxadiazoles, benzothiophenes and benzofurans, which are among the most used ring systems in drug discovery.

2. Scope of the C–X Carboxylation .

2

Open in a new tab

a Reaction conditions: 1-Br (1.0 mmol), 2-K (2.05 equiv), DMF (0.2 M), 50 °C, 30 min. See the Supporting Information for details on the alkylation.

b 0.1 M.

c 60 °C.

d 0.05 M.

e 100 °C.

f The aryl iodide (1r-I/1s-I) was used.

g NMR yield.

3. Proposed Mechanism for C–X Carboxylation.

3

Open in a new tab

Our proposed mechanism for C–X carboxylation is provided in Scheme . Decarboxylative metalation consists of decarboxylation of 2-K to give the metalating agent 4 (step (i)), followed by metal–halogen exchange with the substrate 1-X to give metalated intermediate 5 (step (ii)). Carboxylation of 5 with the in situ formed CO2 and subsequent alkylation would then lead to the desired product 3 (step (iii)).

To gather evidence for our proposed decarboxylative metal–halogen exchange mechanism we first conducted the reaction in the presence of a radical scavenger, TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl). The reaction was largely unaffected, suggesting radical intermediates were not involved in this process (Scheme A). Next, we could isolate side product ester 6 from the reaction (Scheme B). The structure of 6 was unequivocally determined through X-ray crystallography (Scheme E). In a separate experiment, the potassium salt 2-K and trityl bromide 7 reacted to form ester 6 in similarly high yield (Scheme C). Thus, to explain the formation of 6, we believe 2-K first mediates decarboxylative metal–halogen exchange to give trityl bromide 7 (Scheme D, steps (i) and (ii), cf. Scheme , steps (i) and (ii)). Trityl bromide 7 then reacts with another equivalent of carboxylate 2-K to give ester 6. This provides indirect evidence of decarboxylative metal–halogen exchange and explains the need for two equivalents of 2-K. In this way, the process is reminiscent of metal–halogen exchange involving t-BuLi, which also requires two equivalents of the organometallic to destroy a reactive alkyl halide side product.

4. Mechanistic Studies.

4

Open in a new tab

a See the Supporting Information for further details on the reaction conditions.

b Potential energy diagram for the C–X carboxylation computed at the SMD­(DMF)/B3LYP-D3/def2-TZVPP//SMD­(DMF)/B3LYP-D3/def2-SVP level of theory. Gibbs free energies (ΔG [kcal mol–1]) and bond lengths (Å) are provided in the inset.

To provide further evidence for our proposed decarboxylative metal–halogen exchange mechanism, a density functional theory (DFT) study was conducted (Scheme F). We systematically explored the coordination of the potassium cation with multiple DMF molecules (n = 1, 2, 3) in the calculations to account for solvation of the potassium cation. The initial decarboxylation of 2-K-(DMF) 2 proceeded via the transition state TS1-(DMF)2 with an activation energy barrier of 14.8 kcal mol–1. A cation-π interaction was observed, which contributed to the stabilization of the transition state through charge delocalization. The metalating agent Int1-(DMF) 2 , formed after the release of CO2, then underwent the metal–halogen exchange with 1a-Br via the transition state TS2-(DMF) 2 (ΔG ‡ = 10.5 kcal mol–1). This process was facilitated by the interaction of the potassium cation with both the phenyl ring and the nitrogen atom of 1a-Br. Finally, carboxylation of Int2-(DMF) 2 furnished the carboxylate Int3-(DMF) 2 (ΔG = −15.7 kcal mol–1). Overall, the activation energy barrier for the rate-determining decarboxylation step is consistent with the reaction conditions employed.

Labeled compounds are key to the development of new medicines and agrochemicals, and relied upon in mechanistic studies. ,, Due to the price, hazards and scarcity of some isotopes, practical and efficient methods are of great relevance in this field, for example, 14CO2 is radioactive, costs >£1,500/mmol and only produced in select locations. , Dual-function reagent 2-K is a bench-stable and weighable solid, so offers a practical alternative for carbon isotope labeling. Our C–X carboxylation only requires 2.0 equiv of 2-K and side product 6 can undergo routine hydrolysis to regenerate the precursor to 2-K if desired. , Scheme reveals the formation of various labeled drug derivatives and precursors via C–X carboxylation. We have also demonstrated a formal carbon isotope exchange , for late-stage isotope labeling of the anti-inflammatory drug Febuxostat (Scheme ). Accordingly, Febuxostat 3aa-H underwent decarboxylative bromination to provide aryl bromide intermediate 1aa-Br. Exposure to our C–X carboxylation conditions with labeled reagent 2-K* then provided the labeled Febuxostat ester 3aa*.

5. Carbon Isotope Labeling .

5

Open in a new tab

a Reaction conditions: 1-Br (0.25 mmol), 2-K* (2.05 equiv), DMF (0.2 M), 50 °C, 30 min. See the Supporting Information for details on the alkylation and amide coupling steps.

b 1 h.

c Carboxylation performed at 140 °C.

6. Late-Stage Carbon Isotope Exchange .

6

Open in a new tab

a Reaction conditions: Bromination – 3aa (0.5 mmol), Bu4NBr3 (2.0 equiv), K3PO4 (1.0 equiv), MeCN (0.2 M), 50 °C, 16 h. Extraction/filtration. Carboxylation – 1aa-Br (0.25 mmol), 2-K* (2.05 equiv), DMF (0.2 M), 70 °C, 30 min. See the Supporting Information for details on the methylation.

In conclusion, we have introduced decarboxylative metalation as a unique mode of reactivity for metal–halogen exchange. The procedure employs carboxylate 2-K as a dual-function reagent to generate a metalating agent and CO2 in situ, thereby avoiding hazardous organometallics. This reactivity has been applied in the C–X carboxylation of various heteroaromatic substrates and shows notable functional group tolerance and selectivity in comparison to traditional metal–halogen exchange pathways. Preliminary mechanistic studies and computational analysis provide support for our proposed decarboxylative metal–halogen exchange in which the metalating agent is generated in situ. The application of this method in carbon isotope chemistry has also been demonstrated in the labeling of molecules with known bioactivity and a formal late-stage carbon isotope exchange.

Supplementary Material

au5c01545_si_001.pdf (8MB, pdf)

Acknowledgments

This work was supported by a Royal Society Research Grant (RGS\R2\242219), an RSC Researcher Collaborations Grant (C24-8914031093), an RSC Research Fund (R24-6800702932), a Daiwa Foundation Small Grant (14880/15735) and an EPSRC New Investigator Award (UKRI1101). The computational analysis was performed using the Research Center for Computational Science, Okazaki, Japan (Project: 25-IMS-C248). We thank Dr Julie M. Herniman, Dr Neil J. Wells and Dr Mark E. Light for leading the mass spectrometry, NMR spectroscopy and X-ray diffraction facilities within the University of Southampton.

Supporting Information is available free of charge via the Internet at . Small molecule crystal data is deposited with the Cambridge Crystallographic Data Centre (CCDC) with deposition numbers 2333766 (for 6) and 2371571 (for 3y). The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.5c01545.

  • Experimental details, optimization studies, scope of the C-X carboxylation of aryl halides, robustness screen, unsuccessful examples, mechanistic studies, computational studies, isotope labeling, and NMR data (PDF)

CRediT: Daniel J. Ryder-Mahoney data curation, investigation, methodology, validation, writing - review & editing; Ken Yamazaki data curation, investigation, methodology, resources, visualization, writing - review & editing; Gregory J. P. Perry conceptualization, funding acquisition, investigation, methodology, project administration, resources, supervision, writing - original draft, writing - review & editing.

The authors declare no competing financial interest.

References

  1. a Kalgutkar, A. S. ; Daniels, J. S. . Chapter 3. Carboxylic Acids and Their Bioisosteres. In Drug Discovery; Smith, D. A. , Ed.; Royal Society of Chemistry: 2010; pp 99–167. [Google Scholar]; b Lamberth, C. ; Dinges, J. . Different Roles of Carboxylic Functions in Pharmaceuticals and Agrochemicals. In Bioactive Carboxylic Compound Classes: Pharmaceuticals and Agrochemicals; Lamberth, C. , Dinges, J. , Eds.; Wiley-VCH Verlag GmbH & Co. KGaA:, 2016; pp 1–11. [Google Scholar]
  2. Carboxylic Acids and Esters (1969), 1st ed.; Patai, S. , Ed.; Wiley: 1969; PATAI’S Chemistry of Functional Groups. [Google Scholar]
  3. Bragg R. A., Sardana M., Artelsmair M., Elmore C. S.. New Trends and Applications in Carboxylation for Isotope Chemistry. J. Label. Compd. Radiopharm. 2018;61:934–948. doi: 10.1002/jlcr.3633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. For select reviews in this area see:; a Börjesson M., Moragas T., Gallego D., Martin R.. Metal-Catalyzed Carboxylation of Organic (Pseudo)­Halides with CO2 . ACS Catal. 2016;6:6739–6749. doi: 10.1021/acscatal.6b02124. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Tortajada A., Juliá-Hernández F., Börjesson M., Moragas T., Martin R.. Transition-Metal-Catalyzed Carboxylation Reactions with Carbon Dioxide. Angew. Chem., Int. Ed. 2018;57:15948–15982. doi: 10.1002/anie.201803186. [DOI] [PubMed] [Google Scholar]; c Zhang Z., Ye J.-H., Ju T., Liao L.-L., Huang H., Gui Y.-Y., Zhou W.-J., Yu D.-G.. Visible-Light-Driven Catalytic Reductive Carboxylation with CO2 . ACS Catal. 2020;10:10871–10885. doi: 10.1021/acscatal.0c03127. [DOI] [Google Scholar]; d Ye J.-H., Ju T., Huang H., Liao L.-L., Yu D.-G.. Radical Carboxylative Cyclizations and Carboxylations with CO2 . Acc. Chem. Res. 2021;54:2518–2531. doi: 10.1021/acs.accounts.1c00135. [DOI] [PubMed] [Google Scholar]; e Ran C.-K., Liao L.-L., Gao T.-Y., Gui Y.-Y., Yu D.-G.. Recent Progress and Challenges in Carboxylation with CO2 . Curr. Opin. Green Sus. Chem. 2021;32:100525. doi: 10.1016/j.cogsc.2021.100525. [DOI] [Google Scholar]; f Sun G.-Q., Liao L.-L., Ran C.-K., Ye J.-H., Yu D.-G.. Recent Advances in Electrochemical Carboxylation with CO2 . Acc. Chem. Res. 2024;57:2728–2745. doi: 10.1021/acs.accounts.4c00417. [DOI] [PubMed] [Google Scholar]
  5. Organometallics in Synthesis: Third Manual, 1st ed.; Schlosser, M. , Ed.; Wiley: 2013. [Google Scholar]
  6. a Wittig G., Pockels U., Dröge H.. Über Die Austauschbarkeit von Aromatisch Gebundenem Wasserstoff Gegen Lithium Mittels Phenyl-lithiums. Ber. Dtsch. Chem. Ges. A/B. 1938;71:1903–1912. doi: 10.1002/cber.19380710922. [DOI] [Google Scholar]; b Gilman H., Langham W., Jacoby A. L.. Metalation as a Side Reaction in the Preparation of Organolithium Compounds. J. Am. Chem. Soc. 1939;61:106–109. doi: 10.1021/ja01870a036. [DOI] [Google Scholar]
  7. a Gentner T. X., Mulvey R. E.. Alkali-Metal Mediation: Diversity of Applications in Main-Group Organometallic Chemistry. Angew. Chem., Int. Ed. 2021;60:9247–9262. doi: 10.1002/anie.202010963. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Wei B., Chen Y.-H., Knochel P.. Recent Advances in Halogen–Metal Exchange Reactions. Acc. Chem. Res. 2024;57:1951–1963. doi: 10.1021/acs.accounts.4c00242. [DOI] [PubMed] [Google Scholar]; c Anderson D. E., Tortajada A., Hevia E.. New Frontiers in Organosodium Chemistry as Sustainable Alternatives to Organolithium Reagents. Angew. Chem., Int. Ed. 2024;63:e202313556. doi: 10.1002/anie.202313556. [DOI] [PubMed] [Google Scholar]
  8. a Perry G. J. P., Larrosa I.. Recent Progress in Decarboxylative Oxidative Cross-Coupling for Biaryl Synthesis. Eur. J. Org. Chem. 2017;2017:3517–3527. doi: 10.1002/ejoc.201700121. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Moon P. J., Lundgren R. J.. Metal-Catalyzed Ionic Decarboxylative Cross-Coupling Reactions of C­(sp3) Acids: Reaction Development, Mechanisms, and Application. ACS Catal. 2020;10:1742–1753. doi: 10.1021/acscatal.9b04956. [DOI] [Google Scholar]; c Laudadio G., Palkowitz M. D., El-Hayek Ewing T., Baran P. S.. Decarboxylative Cross-Coupling: A Radical Tool in Medicinal Chemistry. ACS Med. Chem. Lett. 2022;13:1413–1420. doi: 10.1021/acsmedchemlett.2c00286. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Tibbetts J. D., Askey H. E., Cao Q., Grayson J. D., Hobson S. L., Johnson G. D., Turner-Dore J. C., Cresswell A. J.. Decarboxylative, Radical C–C Bond Formation with Alkyl or Aryl Carboxylic Acids: Recent Advances. Synthesis. 2023;55:3239–3250. doi: 10.1055/a-2081-1830. [DOI] [Google Scholar]
  9. a Wang S., Larrosa I., Yorimitsu H., Perry G. J. P.. Carboxylic Acid Salts as Dual-Function Reagents for Carboxylation and Carbon Isotope Labeling. Angew. Chem., Int. Ed. 2023;62:e202218371. doi: 10.1002/anie.202218371. [DOI] [PubMed] [Google Scholar]; b Liu X., Perry G. J. P., Kong D.. A Para-Selective Kolbe–Schmitt Reaction. Angew. Chem., Int. Ed. 2026;65:e22503. doi: 10.1002/anie.202522503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. For applications of our work see:; a Liu X., Cao S., Zhang C., Jiang Y., Kong D.. Integrating Umpolung and CO2 Shuttling Strategies for the Synthesis of 12C- and 13C-α-Ketoacids from Aldehydes. Org. Lett. 2024;26:8967–8972. doi: 10.1021/acs.orglett.4c03508. [DOI] [PubMed] [Google Scholar]; b Nakahara H., Shirai R., Nishimoto Y., Yokogawa D., Yamaguchi J.. Heteroaromatic Swapping in Aromatic Ketones. Nat. Commun. 2025;16:8998. doi: 10.1038/s41467-025-64041-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. For reports on related base-mediated carboxylation see:; a Vechorkin O., Hirt N., Hu X.. Carbon Dioxide as the C1 Source for Direct C–H Functionalization of Aromatic Heterocycles. Org. Lett. 2010;12:3567–3569. doi: 10.1021/ol101450u. [DOI] [PubMed] [Google Scholar]; b Fenner S., Ackermann L.. C–H Carboxylation of Heteroarenes with Ambient CO. Green Chem. 2016;18:3804–3807. doi: 10.1039/C6GC00200E. [DOI] [Google Scholar]; c Felten S., He C. Q., Weisel M., Shevlin M., Emmert M. H.. Accessing Diverse Azole Carboxylic Acid Building Blocks via Mild C–H Carboxylation: Parallel, One-Pot Amide Couplings and Machine-Learning-Guided Substrate Scope Design. J. Am. Chem. Soc. 2022;144:23115–23126. doi: 10.1021/jacs.2c10557. [DOI] [PubMed] [Google Scholar]; d Shigeno M., Hanasaka K., Tohara I., Izumi K., Yamakoshi H., Kwon E., Nozawa-Kumada K., Kondo Y.. Direct C–H Carboxylation Forming Polyfunctionalized Aromatic Carboxylic Acids by Combined Bro̷nsted Bases. Org. Lett. 2022;24:809–814. doi: 10.1021/acs.orglett.1c03866. [DOI] [PubMed] [Google Scholar]; e Shigeno M., Tohara I., Sasaki K., Nozawa-Kumada K., Kondo Y.. Combined Bro̷nsted Base-Promoted CO2 Fixation into Benzylic C–H Bonds of Alkylarenes. Org. Lett. 2022;24:4825–4830. doi: 10.1021/acs.orglett.2c01986. [DOI] [PubMed] [Google Scholar]
  12. a Liao L.-L., Cao G.-M., Jiang Y.-X., Jin X.-H., Hu X.-L., Chruma J. J., Sun G.-Q., Gui Y.-Y., Yu D.-G.. α-Amino Acids and Peptides as Bifunctional Reagents: Carbocarboxylation of Activated Alkenes via Recycling CO2 . J. Am. Chem. Soc. 2021;143:2812–2821. doi: 10.1021/jacs.0c11896. [DOI] [PubMed] [Google Scholar]; b Shimotai K., Sasamoto O., Shigeno M.. Carboxylations of (Hetero)­Aromatic C–H Bonds Using an Alkyl Silyl Carbonate Reagent. Org. Lett. 2025;27:352–356. doi: 10.1021/acs.orglett.4c04388. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Colella B. M., Ohata J.. Small-Molecule CO2 Donors Accelerate Three-Component Peptide/Protein Bioconjugation with Alkylazides and Phosphines in Ionic Liquids. Synlett. 2025;36:719–723. doi: 10.1055/a-2212-7816. [DOI] [Google Scholar]
  13. For reviews on this topic see:; a Babin V., Taran F., Audisio D.. Late-Stage Carbon-14 Labeling and Isotope Exchange: Emerging Opportunities and Future Challenges. JACS Au. 2022;2:1234–1251. doi: 10.1021/jacsau.2c00030. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Labiche A., Malandain A., Molins M., Taran F., Audisio D.. Modern Strategies for Carbon Isotope Exchange. Angew. Chem., Int. Ed. 2023;62:e202303535. doi: 10.1002/anie.202303535. [DOI] [PubMed] [Google Scholar]
  14. For select examples see:; a Destro G., Loreau O., Marcon E., Taran F., Cantat T., Audisio D.. Dynamic Carbon Isotope Exchange of Pharmaceuticals with Labeled CO2 . J. Am. Chem. Soc. 2019;141:780–784. doi: 10.1021/jacs.8b12140. [DOI] [PubMed] [Google Scholar]; b Kingston C., Wallace M. A., Allentoff A. J., deGruyter J. N., Chen J. S., Gong S. X., Bonacorsi S., Baran P. S.. Direct Carbon Isotope Exchange through Decarboxylative Carboxylation. J. Am. Chem. Soc. 2019;141:774–779. doi: 10.1021/jacs.8b12035. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Tortajada A., Duan Y., Sahoo B., Cong F., Toupalas G., Sallustrau A., Loreau O., Audisio D., Martin R.. Catalytic Decarboxylation/Carboxylation Platform for Accessing Isotopically Labeled Carboxylic Acids. ACS Catal. 2019;9:5897–5901. doi: 10.1021/acscatal.9b01921. [DOI] [Google Scholar]; d Destro G., Horkka K., Loreau O., Buisson D., Kingston L., Del Vecchio A., Schou M., Elmore C. S., Taran F., Cantat T., Audisio D.. Transition-Metal-Free Carbon Isotope Exchange of Phenyl Acetic Acids. Angew. Chem., Int. Ed. 2020;59:13490–13495. doi: 10.1002/anie.202002341. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Kong D., Moon P. J., Lui E. K. J., Bsharat O., Lundgren R. J.. Direct Reversible Decarboxylation from Stable Organic Acids in Dimethylformamide Solution. Science. 2020;369:557–561. doi: 10.1126/science.abb4129. [DOI] [PubMed] [Google Scholar]; f Babin V., Talbot A., Labiche A., Destro G., Del Vecchio A., Elmore C. S., Taran F., Sallustrau A., Audisio D.. Photochemical Strategy for Carbon Isotope Exchange with CO2 . ACS Catal. 2021;11:2968–2976. doi: 10.1021/acscatal.0c05344. [DOI] [Google Scholar]; g Kong D., Munch M., Qiqige Q., Cooze C. J. C., Rotstein B. H., Lundgren R. J.. Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by Organic Photoredox Catalysis. J. Am. Chem. Soc. 2021;143:2200–2206. doi: 10.1021/jacs.0c12819. [DOI] [PubMed] [Google Scholar]; h Bsharat O., Doyle M. G. J., Munch M., Mair B. A., Cooze C. J. C., Derdau V., Bauer A., Kong D., Rotstein B. H., Lundgren R. J.. Aldehyde-Catalysed Carboxylate Exchange in α-Amino Acids with Isotopically Labelled CO2 . Nat. Chem. 2022;14:1367–1374. doi: 10.1038/s41557-022-01074-0. [DOI] [PubMed] [Google Scholar]; i Talbot A., Sallustrau A., Goudet A., Taran F., Audisio D.. Investigation on the Stoichiometry of Carbon Dioxide in Isotope-Exchange Reactions with Phenylacetic Acids. Synlett. 2022;33:171–176. doi: 10.1055/s-0040-1720447. [DOI] [Google Scholar]; j Doyle M. G. J., Bsharat O., Sib A., Derdau V., Lundgren R. J.. Enantioselective Carbon Isotope Exchange. J. Am. Chem. Soc. 2024;146:18804–18810. doi: 10.1021/jacs.4c03685. [DOI] [PubMed] [Google Scholar]
  15. To the best of our knowledge, a functionalization via decarboxylative metal-halogen exchange has not been reported. The closest examples of this type of chemistry have been reported by Tunge and co-workers:; a Joseph E., Smith I., Tunge J. A.. Cobalt-Catalyzed Decarboxylative Difluoroalkylation of Nitrophenylacetic Acid Salts. Chem. Sci. 2023;14:13902–13907. doi: 10.1039/D3SC05583C. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Joseph E., Brar D. S., Stuhlsatz G., Tunge J. A.. Transition Metal-Free Decarboxylative Olefination of Carboxylic Acid Salts. Chem. Sci. 2024;15:9353–9360. doi: 10.1039/D4SC01905A. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Brar D. S., Aponte R., Tunge J.. Photoredox-Catalyzed Decarboxylative Elimination via Halogen Atom Transfer. J. Org. Chem. 2025;90:5274–5280. doi: 10.1021/acs.joc.5c00237. [DOI] [PubMed] [Google Scholar]; d Brar D. S., Tunge J. A.. Photoredox-Catalyzed Decarboxylative Nitro-Mannich Reaction. Org. Lett. 2025;27:8034–8038. doi: 10.1021/acs.orglett.5c02370. [DOI] [PubMed] [Google Scholar]
  16. See the Supporting Information for further details.
  17. Byrne F. P., Jin S., Paggiola G., Petchey T. H. M., Clark J. H., Farmer T. J., Hunt A. J., Robert McElroy C., Sherwood J.. Tools and Techniques for Solvent Selection: Green Solvent Selection Guides. Sustain. Chem. Process. 2016;4:7. doi: 10.1186/s40508-016-0051-z. [DOI] [Google Scholar]
  18. Bouveault Aldehyde Synthesis: (Bouveault Reaction). In Comprehensive Organic Name Reactions and Reagents; Wiley: 2010; pp 490–492. [Google Scholar]
  19. a Collins K. D., Glorius F.. A Robustness Screen for the Rapid Assessment of Chemical Reactions. Nat. Chem. 2013;5:597–601. doi: 10.1038/nchem.1669. [DOI] [PubMed] [Google Scholar]; b Collins K. D., Rühling A., Glorius F.. Application of a Robustness Screen for the Evaluation of Synthetic Organic Methodology. Nat. Protoc. 2014;9:1348–1353. doi: 10.1038/nprot.2014.076. [DOI] [PubMed] [Google Scholar]
  20. For examples of reduction-resistant electrophiles see:; a Fukazawa M., Takahashi F., Nogi K., Sasamori T., Yorimitsu H.. Reductive Difunctionalization of Aryl Alkenes with Sodium Metal and Reduction-Resistant Alkoxy-Substituted Electrophiles. Org. Lett. 2020;22:2303–2307. doi: 10.1021/acs.orglett.0c00490. [DOI] [PubMed] [Google Scholar]; b Ito S., Fukazawa M., Takahashi F., Nogi K., Yorimitsu H.. Sodium-Metal-Promoted Reductive 1,2- Syn -Diboration of Alkynes with Reduction-Resistant Trimethoxyborane. Bull. Chem. Soc. Jpn. 2020;93:1171–1179. doi: 10.1246/bcsj.20200110. [DOI] [Google Scholar]
  21. The reaction of 1r gave recovered starting material (93%). The reaction of 1s gave nitrobenzene (60%), suggesting decarboxylative metal-halogen exchange occurred, but subsequent carboxylation was inefficient .
  22. a Shearer J., Castro J. L., Lawson A. D. G., MacCoss M., Taylor R. D.. Rings in Clinical Trials and Drugs: Present and Future. J. Med. Chem. 2022;65:8699–8712. doi: 10.1021/acs.jmedchem.2c00473. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Roure B., Alonso M., Lonardi G., Yildiz D. B., Buettner C. S., Dos Santos T., Xu Y., Bossart M., Derdau V., Méndez M., Llaveria J., Ruffoni A., Leonori D.. Photochemical Permutation of Thiazoles. Isothiazoles and Other Azoles. Nature. 2025;637:860–867. doi: 10.1038/s41586-024-08342-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Small molecule crystal data are deposited with the Cambridge Crystallographic Data Centre (CCDC) with deposition numbers 2333766 (for 6) and 2371571 (for 3y).
  24. Aryllithium and Hetaryllithium Compounds; Gribble, G. W. , Majewski, M. , Snieckus, V. , Eds.; Georg Thieme Verlag: 2006; Science of Synthesis, p 357. [Google Scholar]
  25. a Voges, R. ; Heys, J. R. ; Moenius, T. . Preparation of Compounds Labeled with Tritium and Carbon-14, 1st ed.; Wiley: 2009. [Google Scholar]; b Elmore C. S., Bragg R. A.. Isotope Chemistry; a Useful Tool in the Drug Discovery Arsenal. Bioorg. Med. Chem. Lett. 2015;25:167–171. doi: 10.1016/j.bmcl.2014.11.051. [DOI] [PubMed] [Google Scholar]; c Derdau V., Elmore C. S., Hartung T., McKillican B., Mejuch T., Rosenbaum C., Wiebe C.. The Future of (Radio)-Labeled Compounds in Research and Development within the Life Science Industry. Angew. Chem., Int. Ed. 2023;62:e202306019. doi: 10.1002/anie.202306019. [DOI] [PubMed] [Google Scholar]
  26. Westaway K. C.. Determining Transition State Structure Using Kinetic Isotope Effects. Label. Compd. Radiopharm. 2007;50:989–1005. doi: 10.1002/jlcr.1434. [DOI] [Google Scholar]
  27. The carboxylating agent 2-K* can be prepared using 2 equivalents of CO2 gas or less. See the Supporting Information and ref .
  28. Hydrolysis of the side product 6 with trifluoroacetic acid afforded recovery of triphenylacetic acid in 76% yield .
  29. a Perry G. J. P., Quibell J. M., Panigrahi A., Larrosa I.. Transition-Metal-Free Decarboxylative Iodination: New Routes for Decarboxylative Oxidative Cross-Couplings. J. Am. Chem. Soc. 2017;139:11527–11536. doi: 10.1021/jacs.7b05155. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Quibell J. M., Perry G. J. P., Cannas D. M., Larrosa I.. Transition-Metal-Free Decarboxylative Bromination of Aromatic Carboxylic Acids. Chem. Sci. 2018;9:3860–3865. doi: 10.1039/C8SC01016A. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Quibell J. M., Duan G., Perry G. J. P., Larrosa I.. Decarboxylative Suzuki–Miyaura Coupling of (Hetero)­Aromatic Carboxylic Acids Using Iodine as the Terminal Oxidant. Chem. Commun. 2019;55:6445–6448. doi: 10.1039/C9CC01817D. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

au5c01545_si_001.pdf (8MB, pdf)

Articles from JACS Au are provided here courtesy of American Chemical Society

RESOURCES