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Letter
Cite This: ACS Catal. 2019, 9, 5897−5901

pubs.acs.org/acscatalysis

Catalytic Decarboxylation/Carboxylation Platform for Accessing
Isotopically Labeled Carboxylic Acids
Andreu Tortajada,†,§ Yaya Duan,†,⊥ Basudev Sahoo,†,⊥ Fei Cong,†,§,⊥ Georgios Toupalas,†,⊥
Antoine Sallustrau,∥ Olivier Loreau,∥ Davide Audisio,∥ and Ruben Martin*,†,‡
†

Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països Catalans 16,
43007 Tarragona, Spain
‡
ICREA, Passeig Lluís Companys, 23, 08010 Barcelona, Spain
§
Departament de Química Analítica i Química Orgànica, Universitat Rovira i Virgili, C/Marcel·lí Domingo, 1, 43007 Tarragona,
Spain
∥
Service de Chimie Bio-Organique et Marquage (SCBM), CEA-DRF-JOLIOT-SCBM, Université Paris-Saclay, 91191 Gif sur Yvette,
France

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from https://pubs.acs.org/doi/10.1021/acscatal.9b01921.

S
* Supporting Information

ABSTRACT: An integrated catalytic decarboxylation/carboxylation for accessing isotopically labeled carboxylic acids with
13
CO2 or 14CO2 is described. The method shows a wide scope
under mild conditions, even in the context of late-stage
functionalization, and does not require stoichiometric organometallics, thus complementing existing carbon-labeling techniques en route to carboxylic acids.
KEYWORDS: carboxylation, nickel, isotopic labeling, carbon dioxide, carboxylic acid

T

resonance have allowed the latter to be used for similar
purposes,7 thus improving the practicality of these studies by
employing stable 13C probes.
Prompted by the prevalence of carboxylic acids in
biologically active molecules (Scheme 1, bottom),8 carboxylation reactions with isotopically labeled CO2 have attracted
considerable attention.9,10 At present, high levels of 13C- and
14
C-incorporation can be achieved with stoichiometric and
polarized organometallics;11 however, their high reactivity and
low chemoselectivity severely limit the synthetic application of
these processes (Scheme 2, top left). Although decarboxylation
allows carbon isotopes of carboxylic acids in drug molecules to
be rapidly interchanged without modifying the established
route to the drug molecule (Scheme 2, top middle/right),12
such techniques require stoichiometric nickel species13a or
harsh conditions.13b In addition, modest C-labeling exchange is
observed due to competitive hydrolysis of the starting
precursor or in situ carboxylation with initially extruded
12
CO2.13 Taken together, these features contribute to the
perception that designing a mild, robust, and modular catalytic
decarboxylation/carboxylation that enables the access to Clabeled aliphatic and aromatic carboxylic acids in high specific
activities is deemed necessary. As part of our interest in
catalytic carboxylation reactions,14 we report the successful

he evaluation of the metabolic profile of lead compounds
through preclinical testing is of utmost importance in
drug discovery.1 Although these studies require isotopically
labeled active pharmaceutical ingredients (APIs), their synthesis is oftentimes more problematic than that of the parent
compound, reinforcing the need for strategies that rapidly and
reliably incorporate isotopes into molecules.2 Among different
scenarios, carbon labeling is often preferred due to its high
sensitivity and lower risk of label metabolic cleavage, rendering
the interpretation of preclinical data easy.3 While 11C is utilized
for positron emitting tomography (PET) imaging,4 its short
half-life precludes long-term studies. However, 13C- and 14Clabeling are appropriate for evaluating drug profiles, including
absorption, distribution, metabolism, and excretion (ADME),
and pharmacokinetic studies (Scheme 1).5,6 Although radioactive 14C has oftentimes displaced 13C as metabolic tracers,
recent advances in mass spectrometry and nuclear magnetic
Scheme 1. Carbon Isotope Labeling

Received: May 9, 2019
Revised: May 24, 2019
Published: May 29, 2019
© XXXX American Chemical Society

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Table 1. 12C/13C-Isotopic Exchange of Carboxylic Acidsa

Scheme 2. 13C- and 14C-Labeling Carboxylations with CO2

realization of a catalytic carbon isotope exchange by merging
decarboxylative events with carboxylation protocols with
13
CO2 or 14CO2 via the intermediacy of halogenated species
or activated esters (Scheme 2, bottom). Our protocols are
distinguished by their mild conditions, versatility, excellent
chemoselectivity profile, and high isotopic incorporations (up
to >99% C-labeling), thus expediting the design of radiolabeling techniqueseven in the context of late-stage
functionalizationen route to labeled carboxylic acids while
obviating the need for stoichiometric organometallic species.
Our investigations began by evaluating the feasibility of the
approach highlighted in Scheme 2 (bottom) with easy-tohandle 13CO2 in lieu of radioactive 14CO2 and the Nhydroxyphthalimido ester 1a, readily available in a single step
from octanoic acid.15 A judicious optimization of all reaction
parameters revealed that a combination of NiCl2·dme (10 mol
%) and 6,6′-dimethyl-4,4′-diphenyl-2,2′-bipyridine L1 (25 mol
%) in DMF:MeOH (3:1) at 0 °C with Mn as reducing agent
under an atmospheric pressure of 13CO2 provided the best
results, affording [13C]2a in 55% yield and 56% 12C/13Cexchange.15 In line with our expectations, bipyridine and
phenanthroline ligands possessing substituents adjacent to the
nitrogen atom were critical for success.16 Indeed, the absence
of the latter resulted in negligible conversions, if any, to
[13C]2a, thus showing the structural intricacies on the ligand
backbone. Likewise, solvents and reducing agents other than
DMF:MeOH or Mn had a deleterious effect on reactivity and
specificity, whereas control experiments revealed that all
reaction parameters were essential for the catalytic carboxylation to occur.15
With a set of conditions in hand, we turned our attention to
study the generality of our Ni-catalyzed decarboxylative/
carboxylation of N-hydroxyphthalimido esters. As shown in
Table 1, an array of linear (2a−2f, 2i−2m) or α-branched (2g,
2h) labeled carboxylic acids could easily be within reach from
their parent analogues. The chemoselectivity of our 12C/13Ccarbon-labeling exchange posed no problems, as nitriles (2i),
alkenes (2j), carbamates (2m), or nitrogen-containing heterocycles (2d) could all be well-accommodated. Interestingly, not
even traces of competitive Ni-catalyzed carboxylation at the
C−Cl terminus was observed in 2b and 2k,17 thus leaving
ample room for further functionalization via conventional

NHP-ester (0.1 mmol), NiCl2·dme (10 mol %), L1 (25 mol %), Mn
(2 equiv), 13CO2 (1 atm) in DMF:MeOH (3:1, 0.06 M) at 0 °C.
a

cross-coupling reactions.18 Particularly noteworthy was the
ability to enable the targeted 12C/13C-exchange at late-stages
with advanced carboxylic acid intermediates such as citronellic
acid (2j), MCPB (2k), lithocholic acid (2l), or pregabalin
(2m), thus showing the potential that our catalytic protocol
might have in preclinical studies for drug discovery.19 Putting
these results into perspective, the examples shown in Table 1
represent a powerful alternative to existing methodologies
based on the utilization of stoichiometric amounts of
organometallics11 or Ni complexes.13a
The data shown in Scheme 3 (top) illustrates the
prospective impact of our 12C/13C-exchange by converting
3a and 3b into their [13C]5a and [13C]5b congeners without
chromatographic purification.15 However, a number of
daunting challenges remain. Among these, a seemingly trivial
extension to 13C-labeled phenyl acetic acids or benzoic acids
events still constitutes terra incognita; substantial homodimerization is observed in the former whereas a difficult
decarboxylation of aryl NHP-esters prevents a 12C/13Cexchange in the latter. More importantly, modest isotope
exchange was observed for all substrates shown in Table 1 due
to unavoidable hydrolysis of the parent NHP-ester and
competitive carboxylation with 12CO2. These observations
are particularly problematic due to the prevalence of carboxylic
acids in APIs as well as the need for maximizing the 12C/13Cexchange for preclinical testing. To this end, we anticipated
that the merger of decarboxylative halogenation with the
robustness of catalytic carboxylation of organic halides might
offer a powerful platform for obtaining otherwise inaccessible
carboxylic acids with >99% 13C-content. As shown in Scheme
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ACS Catalysis
Scheme 3. Direct 12C/13C-Exchange of Carboxylic Acidsa

Table 2. Decarboxylative Halogenation/Carboxylation

a
Ni/L1, Table 1; Ni/L2, NiBr2·dme (10 mol %), L2 (24 mol %), Mn
(2 equiv), TBAB (1 equiv), 13CO2 (1 atm) in DMF (0.17 M), at 60
°C; Ni/L3, NiBr2·diglyme (10 mol %), L3 (24 mol %), Mn (3 equiv),
LiCl (1 equiv), 13CO2 (1 atm) in DMF (0.40 M), at 90 °C.

3 (bottom), this turned out to be the case. Indeed, a Agcatalyzed decarboxylative halogenation20 followed by Ni/L2or Ni/L3-catalyzed carboxylation afforded [13C]5a and
[13C]5b in slightly lower overall yields to those shown for
NHP-esters but with >99% 13C-labeling. Encouraged by these
results, we examined the 13C-carboxylation of a host of benzyl,
aryl, or unactivated alkyl chlorides obtained via decarboxylative
halogenation of the parent carboxylic acids (Table 2). Notably,
nitriles (5c), esters (5d−5f), or nitrogen-containing heterocycles (5e) do not interfere, obtaining in all cases >99% 13Clabeling. Albeit in lower yields, secondary and tertiary alkyl
carboxylic acids such as 5b, 5g, or 5h were within reach, with
5g being obtained as a single diastereoisomer. Importantly,
13
C-labeled aryl acetic acids (5i, 5j) and (hetero)aryl
carboxylic acids (5k−5m)compounds that were beyond
reach from NHP-esterscould also be coupled under Ni/
neocuproine or Ni/PPh3 regimes, thus representing an
opportunity to improve upon existing C-labeling techniques.
Aimed at extending the applicability of our carbon isotope
exchange, we next focused our attention on converting αbranched carboxylic acids into their labeled linear analogues
via chain-walking scenarios,14a,21 a transformation that has
proven elusive in related labeling approaches.13a Although in
low yields, the preparation of [13C]2a,5a,6 with >99% 13Clabeling not only demonstrates the successful realization of this
goal (Scheme 4) but also sets the basis for designing siteselective radiolabeling techniques at remote sp3 C−H sites.22
Given the key role of 14C-radiolabeling in pharmacokinetic and
ADME studies,5 the ability to access 14C-labeled molecules was
then explored. Preliminary results successfully highlighted the
applicability of this method under otherwise similar conditions.15 It is particularly noteworthy that [14C]5i and
[14C]5k are obtained in high molar activities (≥2.04 GBq
mmol−1)23 with negligible isotope dilution, thus opening a
gateway to study the metabolic activity of drugs containing
carboxylic acid motifs.
In conclusion, we have developed a simple, efficient, and
highly versatile catalytic decarboxylation/carboxylation for
carbon isotope exchange of carboxylic acids with 13CO2 or

a
As Scheme 4, Ni/L2. bNi/L3. cUsing 4g with a 1:1 diastereomeric
ratio. dAs Scheme 4, Ni/L3, TBAB (2 equiv), DMA (0.4 M) at 80 °C.
e
NiCl2·dme (10 mol %), PCp3·HBF4 (20 mol %), MgCl2 (2 equiv),
Zn (5 equiv), DMF (0.5 M) at room temperature. fNiBr2·dme (10
mol %), neocuproine (20 mol %), Mn (2 equiv), DMA (0.2 M) at 50
°C. gNiCl2(PPh3)2 (5 mol %), PPh3 (10 mol %), TEAI (10 mol %),
Mn (3 equiv), DMA (0.25 M) at room temperature.

Scheme 4. Chain-Walking

13

C-Exchange and 14C-Labeling

a

NiI2 (2.5 mol %), L4 (4.4 mol %), Mn (2 equiv), DMF (1.0 M), 25
°C, 20 h. bReactions performed with 4i and 4k as substrates.

14

CO2. This route enables access to labeled aliphatic or
aromatic carboxylic acids, even at late-stages, without changing
the already established sequence en route to the parent
compound, thus offering a robust and economical gateway for
rapidly and reliably obtaining preclinical data for lead

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Bennati, M. Dynamic Nuclear Polarization of 13C Nuclei in the Liquid

generation in drug discovery. Further work on radiolabeling
techniques is ongoing.

■

ASSOCIATED CONTENT

S
* Supporting Information

The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.9b01921.
Experimental procedures and characterization data
including 1H, 13C, and 19F NMR, HRMS, and IR
(PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: rmartinromo@iciq.es.
ORCID

Andreu Tortajada: 0000-0002-2635-8030
Basudev Sahoo: 0000-0002-9746-9555
Davide Audisio: 0000-0002-6234-3610
Ruben Martin: 0000-0002-2543-0221
Author Contributions
⊥

Y.D., B.S., F.C., and G.T. contributed equally.

Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS
We thank ICIQ, European Research Council (ERC-PoC-2016755251), and MINECO (CTQ2015-65496-R) for financial
support. A.T. and F.C. thank MECD (FPU program) and
China Scholarship Council (CSC) for predoctoral fellowships,
and B.S. thanks European Union’s Horizon 2020 under the
Marie Sklodowska-Curie grant agreement (795961). We thank
Dr. Noemi Cabello (ICIQ-HRMS department) for mass
analysis and Dr. Yasuhiro Okuda for conducting initial
experiments.

■

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(13) This work was funded by the European Research Council
(ERC-PoC-2016-755251) and presented at the 2018-Hirata Award
Symposium. While this manuscript was under preparation, Baran and
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DOI: 10.1021/acscatal.9b01921
ACS Catal. 2019, 9, 5897−5901