Photochemical Strategy for Carbon Isotope Exchange with CO2

Article abstract of DOI:10.1021/acscatal.0c05344

A photocatalytic approach for carbon isotope exchange is reported. Utilizing [13C]CO2 and [14C]CO2 as primary C1 sources, this protocol allows the insertion of the desired carbon isotope into phenyl acetic acids without the need for structural modifications or prefunctionalization in one single step. The exceptionally mild conditions required for this traceless transformation are in stark contrast with those for previous methods requiring the use of harsh thermal conditions.

Full text of DOI:10.1021/acscatal.0c05344

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Research Article
Photochemical Strategy for Carbon Isotope Exchange with CO2
Victor Babin, Alex Talbot, Alexandre Labiche, Gianluca Destro, Antonio Del Vecchio, Charles S. Elmore,
Frédéric Taran, Antoine Sallustrau, and Davide Audisio*
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ABSTRACT: A photocatalytic approach for carbon isotope
exchange is reported. Utilizing [13C]CO2 and [14C]CO2 as primary
C1 sources, this protocol allows the insertion of the desired carbon
isotope into phenyl acetic acids without the need for structural
modifications or prefunctionalization in one single step. The
exceptionally mild conditions required for this traceless trans-
formation are in stark contrast with those for previous methods
requiring the use of harsh thermal conditions.
KEYWORDS: isotope labeling, carbon-14, photoredox catalysis, carbon dioxide, decarboxylation
in human and veterinary absorption, distribution, metabolism,
and excretion (ADME) determination, and agrochemical and
environmental fate studies.8 While 14C has traditionally been
introduced into biologically relevant target compounds in a
multistep fashion, drawbacks related to the limited availability
of raw materials, their prohibitive costs ([14C]CO2: 1860 $
per mmol), and the generation of long-lasting waste are
upstanding challenges.9
INTRODUCTION
■
Developments in visible light photoredox catalysis have led to
the invention of an ample array of chemical transformations,
which would be either challenging or even impossible to
perform under thermal conditions. Carbon−carbon bond
formation represents an ongoing challenge in photocatalysis
and, particularly, in the context carbon dioxide (CO2)
valorization. Indeed, the functionalization of this one-carbon
(C1) building block has implications that go far behind the
scientific community and affect the environment and our
society as a whole.1,2 Recently, successful examples of
photocatalytic CO2 functionalization appeared (Figure
1A).3−5 In particular, UV or visible light photoinduced Csp2
and Csp3 carboxylations have been investigated in combina-
tion with transition-metal catalysts such as nickel,4a−d
copper,4e and palladium4f−j from aromatic and aliphatic
In the last couple of years, late-stage 14C-labeling has
undergone sudden growth.10 In particular, carbon isotope
exchange (CIE), which allows for the 12C−12C bond cleavage
and 12C−14C bond formation in one single step, emerged as a
privileged strategy (Figure 1B).11 Mostly focused on [12C]/
[14C]CO2 exchange,12−15 these methodologies are mainly
based on the use of transition metals. In 2019, the groups of
Baran and Martin independently reported a two-step aliphatic
carboxylic acid exchange catalyzed by nickel based on N-
hydroxyphthalimide (NHPI)-activated esters.12 While the first
procedure utilized stoichiometric amounts of metal,12a the
second group was able to implement a catalytic version of the
transformation.12b The same year, our group described the
direct CIE of (hetero)aromatic carboxylic acids using catalytic
copper catalysis and thermal activation.13 Exchange of
[12C/14C]CO was published by Gauthier and co-workers,
who developed a palladium-catalyzed CIE on aliphatic and
benzoic acid chlorides.14
bromides and triflates, and by the activation of Csp2−H and
3
̈
Csp −H bonds. In 2019, the group of Konig reported visible-
light-mediated carboxylation of benzylic C−H bonds under
metal-free conditions in the presence of an organic photo-
catalyst (4CzIPN).5c More recently, the same group reported
a redox-neutral photocatalytic C−H carboxylation of arenes
and styrenes.5d In addition, the transition-metal-free photo-
catalytic difunctionalization of styrenes to the corresponding
Csp3−COOH attracted much attention.6 Finally, examples of
Csp3 photoinduced carboxylation generating CO2 radical
anion species using the flow chemistry technology have
been reported by the group of Jamison.5g,6d Besides valorizing
this abundant greenhouse gas and the virtues of mild
conditions and facile operations, these transformations are
relevant in the field of carbon isotope labeling and particularly
for carbon-14 (14C), where [14C]CO2 represents the primary
source of radioisotope.7 14C (β− emitter, half-life 5730 years)
is the gold standard for the preparation of radiotracers utilized
Received: December 6, 2020
Revised: January 20, 2021
Published: February 19, 2021
https://dx.doi.org/10.1021/acscatal.0c05344
© 2021 American Chemical Society
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Figure 1. State of the art. (A) Current strategies for photocarboxylation. (B) Reported implementations of CIE. (C) This work: photocatalyzed
CIE on PAA. Blue circles represent the positions of isotopically labeled carbon. PC, photocatalyst; SET, single electron transfer. (a) ref 14, (b) ref
12a, (c) ref 13, (d) ref 12b, (e) ref 16a, and (f) ref 16b.
Table 1. Optimization of the Reaction
a
b
a
entry
deviation from std. cdtns.
none
4CzlPN (12 mol%)
4CzBnBN instead of 4CzlPN
K2CO3 instead of K3PO4
CsOAc instead of K3PO4
no base
DMSO instead of DMF
N2 instead of [13C]CO2
no photocatalyst
[13C]1: yield (%) /IE (%)
yield 1b (%)
c
1
2
3
4
5
6
7
8
9
10
80(72 )/51
17
47
17
7
8
0
57
85
traces
0
43/62
80/44
89/32
92/26
>90/0
c
44(21 )/66
traces / 0
>90/0
no light
>90/0
a
b
Yields were determined from the crude 1H NMR spectra using 1,3,5-trimethoxybenzene as an internal standard. Isotopic enrichments (IEs) were
c
1
determined by H NMR and mass spectrometry (see the SI for details). Isolated yield. The temperature of the reaction was 42 2 °C.
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Figure 2. Photocatalyzed CIE labeling of phenyl acetic acids and pharmaceutical compounds. Green colored circles and numbers denote the
positions of the carbon atoms labeled and the percent incorporation of the carbon isotope. DMF, N,N-dimethylformamide. Reaction conditions:
[a]
substrate (0.1 mmol, 1 equiv.), PC (6 mol%), K3PO4 (1 equiv.), [13C]CO2 (3 equiv.), DMF (0.6 mL), 6 h.
Using 2 equiv. of K3PO4 and
DMSO instead of DMF. [b] 1H NMR yield determined using DMF-d7 instead of DMF and 1,3,5-trimethoxybenzene as the internal standard.
[c]
Reaction time: 3 h instead of 6 h. The temperature of the reaction: 42 2 °C.
In 2020, our group and Lundgren’s independently reported
the transition-metal-free thermal CIE of phenyl acetic acids
(PAAs).16 By heating the corresponding cesium or potassium
carboxylates in the presence of labeled CO2, reversible
decarboxylation/carboxylation takes place and the desired
acids are obtained with good isotope incorporation. While
appealing, the requirement of harsh thermal heating is
compulsory for nonactivated PAAs. Prolonged heating at
160 °C for 48 hrs was required to label a series of well-known
nonsteroidal anti-inflammatory drugs (NSAIDs), such as
ibuprofen, fenoprofen, ketoprofen, naproxen, and diclofenac.17
Drastic conditions for an extended period of time are
generally unsuitable, especially when handling of radioactive
materials is involved.
The invention of a reversible carboxylation process under
mild conditions still constitutes a fundamental challenge.
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13C. Investigation with stronger electron-withdrawing groups
led to successful labeling of various substrates such as
trifluoromethyl [13C]17−19 (IE = 33−70%), m-nitrile
[13C]20 (IE = 64%), and ester derivatives [13C]21 (IE =
63%). Importantly, on these electron-poor substrates, no
background reactions were observed in the absence of PC.16b
Labeling of dicarboxylic acids [13C]22−23 required using
DMSO in place of DMF, for solubility reasons, and 2 equiv. of
base. It is worth noting that isotope incorporation was also
possible in the presence of labile protons such as amide or
alcohol [13C]27−29 (IE = 30−70 and 21−72% yield).
Pleasingly, functionalization in the benzylic position was not
detrimental for the reaction and applying the procedure to
such substrates could afford the expected labeled phenyl acetic
acids. The presence of alkyl substituents α to the carboxylic
acid was tolerated [13C]30−33. While the gem-dimethyl 31
was effectively labeled, the presence of a cyclopropyl ring
allowed only low exchange ([13C]32 IE <5%) even in the
presence of 4CzBnBN PC. CIE was also performed on
particularly challenging non-natural protected amino acids
[13C]35−36 and successfully enabled the exchange in 39−
52% IE. It is worth noting that under our previous thermal
CIE conditions, these amino acids were unsuccessful, thus
highlighting the superiority of this photocatalytic approach.16a
Next, we turned our attention to the labeling of
pharmaceutically relevant derivatives; felbinac [13C]37 was
labeled with an isotopic enrichment of 63 and 51% yields.
Diclofenac [13C]38 and fenclofenac [13C]39 were obtained,
respectively, in 49 and 57% of recovered products with 10 and
35% of isotope incorporation.
The structural similarity of these drugs shows that the
presence of an amine in the ortho position to the acid has a
deleterious effect on both IE and yield. Fenoprofen [13C]40
was labeled with 68% of IE and a correct isolated yield of
57%. To obtain labeled [13C]41 and [13C]42 in useful
recovered amounts and avoid extensive protodecarboxylation,
a slight modification of the conditions was required. Reducing
the time of the reaction from 6 to 3 hours allowed us to
isolate flurbiprofen [13C]41 and naproxen [13C]42 with 46
and 68% of isotopic incorporations and 55 and 30% yields,
respectively.
An optimization of the reaction was performed to effectively
label the most notorious NSAID in the market, ibuprofen
[13C]43. It was found that the use of 12 mol % of PC allowed
an enhancement of the isotopic incorporation with a minor
modification of the final isolated yield (IE = 56, 46%). The
utilization of other polar nonprotic solvents (DMSO and
DMA) drastically reduced the isolated yield. As a comparison
with our previously developed metal-free thermal CIE, in
addition to the milder photocatalyzed conditions of this
methodology, we observed an improvement in the IE of
naproxen by a factor of 2.3, diclofenac IE by 1.7, and
ibuprofen by 1.75. Yields have also been improved in the case
of flurbiprofen by a factor of 1.6 and fenclofenac by 1.4.
Understanding the Mechanism of the Transforma-
tion. We next looked at the potential reaction mechanism of
this CIE. During the optimization (Table 1) and substrate
scope (Figure 2), we observed that the transformation was
systematically affected by the competing formation of the
protodecarboxylation byproduct and the quality of the solvent
(DMF) dramatically influenced the outcome of the reaction.24
When the reaction with substrate 7 was monitored overtime
in the presence of 3 equiv. of labeled [13C]CO2, optimal
Inspired by pioneering works on transition-metal-free photo-
catalyzed carboxylation4 and the wealth of knowledge on the
photocatalyzed radical decarboxylation of Csp3 carboxylic
acids,18 we report the first photocatalytic approach for CIE
(Figure 1B). This protocol allows the insertion of the desired
isotope into phenyl acetic acids, including non-natural phenyl
glycine amino acids (Figure 1C), at 42 °C only and without
the need for structural modifications or prefunctionalization.
These exceptionally mild conditions stand in stark contrast
with previous methods requiring the use of brutal thermal
force.19,20
RESULTS AND DISCUSSION
■
Optimization of the Photocatalytic Isotope Ex-
change and Study of the Scope. The optimized reaction
conditions for the photocatalytic CIE of carboxylic acids are
shown in Table 1. The model substrate 2-phenyl acetic acid 1
was labeled in a 72% isolated yield and 51% isotopic
enrichment (IE) in the presence of the photocatalyst (PC)
4CzIPN (6 mol %), K3PO4, and [13C]CO2 as a convenient
surrogate for [14C]CO2 in dry DMF within 6 h. The reactions
were performed employing 0.1 mmol of substrate and 0.3
mmol of [13C]CO2, which were precisely delivered using the
RC Tritec manifold.21 A higher IE of 62% was obtained by
increasing the catalyst load to 12 mol% (entry 2), but the
isolated yield diminished to 43%, while protodecarboxylation
side product 1b was formed in a 47% yield.
Under the reaction conditions, we noticed that PC 2 was
entirely converted into 3 (4CzBnBN), which is likely to be
the active PC in the reaction, in agreement with previous
22
̈
reports by Konig and Tunge. Notably, the use of other
photocatalysts resulted in low isotope incorporation (Table
S4), while only 3 provided comparable results (entry 3). To
exclude PC degradation over the reaction conditions, 3 was
isolated from the crude mixture and successfully re-engaged in
photocatalytic CIE (see page S12 for details). Other bases
such as K2CO3 and CsOAc were also compatible but gave
lower IE (Table 1, entries 4 and 5, and Table S3), while the
absence of the base resulted in no reaction (Table 1, entry 6).
Importantly, the use of carbonate bases could lead to potential
isotope dilution, providing a source of unlabeled [12C]CO2, as
previously reported.23 When the reaction was performed
starting from the corresponding potassium carboxylate, [13C]1
was obtained in 50% IE and a 94% yield (see the SI).
The use of other polar aprotic solvents such as DMSO
provided [13C]1 in 66% IE but drastically eroded the yield
(entry 7 and Table S2). When [13C]CO2 was replaced by
nitrogen, complete protodecarboxylation was observed (Table
1, entry 8). Finally, removing 4CzIPN from the reaction or
the absence of light resulted in no isotope incorporation,
showcasing that no background reaction occurs (Table 1,
entries 9 and 10).
With these optimized conditions in hand, we directed our
studies toward the scope (Figure 2). Regardless of the
position, in the presence of electron-donating groups on the
aromatic ring, isotopic enrichment was observed in substituted
phenyl acetic acids bearing alkyl [13C]4−5 or methoxy
[13C]6−9 moieties. It is worth noting that higher incorpo-
ration was achieved with ortho substitution but a lower
isolated yield was obtained ([13C]8, IE = 71%, 29% yield).
Halogens were also tolerated, and [13C]10−16 were labeled in
29−70% IE and good yields. Only substrate 13 could not be
labeled, and deiodination occurred without the insertion of
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Figure 3. Mechanistic investigations. Green colored circles and numbers denote the positions of the 13C atoms labeled and the percent
1
incorporation of the isotope. Yields were determined from the crude H NMR spectra using 1,3,5-trimethoxybenzene as an internal standard.
[a]
Yields of 7 refer to the inseparable mixture of [12C]7 and [13C]7 isotopomers.
Isolated yield. (A) Effect of the reaction time on 13C
incorporation. (B) Effect of [13C]CO2 equivalents on 13C incorporation. (C) Competition experiment. (D) E1cB-elimination reaction. (E)
Radical clock experiment. (F) Reaction with styrene. (G, H) Deuterium labeling experiments. (I) Proposed mechanism. (J) Photocatalytic CIE
radiolabeling with [14C]CO2. Molar activities for 14C in MBq mmol−1; see the SI for details. Blue colored circles and numbers denote the
positions of the 14C atoms labeled and the percent incorporation of the isotope.
isotope incorporation was observed after 6 hours (Figure 3A).
Longer reaction times did not provide a significant improve-
ment on the % IE.
Then, the effect of the number of equiv. of [13C]CO2 on
the reaction was monitored. The precise amount of CO2
required for carboxylation reactions is most often a neglected
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parameter and poorly investigated. As shown in Figure 3B, in
the absence of sufficient amounts of [13C]CO2, the
protodecarboxylation product 7a was predominant (up to
0.5 equiv.). When 1 equiv. of electrophile was added, the
isotope incorporation observed started to converge toward the
expected theoretical value (38% in place of 50% theoretical).
Nonetheless, tolyl 7a was still the major product observed
with a 65% yield. Only when more than 1.5 equiv. of
[13C]CO2 was added, the yield of 7 was satisfying. When
more than 3 equiv. of CO2 was utilized, the costs of the
labeled reagent were not compensated by the limited benefit
over IE and yield.25 Such observations seem to point toward
the need for a minimal amount of DMF saturation to achieve
optimal yield and isotope incorporation.26 Taking advantage
of these results, an iterative approach was explored aiming to
maximize the %IE and minimize the amount of [13C]CO2, the
costly limiting reagent of the overall process (see the SI for
details).
To confirm this, a competition experiment was performed
(Figure 3H). These results in addition to those of the
competition experiment in Figure 3C point toward a reaction
mechanism that involves a direct nucleophilic attack, of the in
situ generated anion, to [13C]CO2 and exclude the
concomitant deprotonation of the potassium carboxylate.
On the basis of this series of mechanistic studies and the
literature reports,5c,22a a plausible catalytic cycle is presented
in Figure 3I. After deprotonation, the potassium carboxylate II
undergoes photocatalytic oxidation to III and rapid
decarboxylation to provide benzyl radical IV, which is further
reduced to carbanion V. When sufficient [13C]CO2 is present
in the solution (> 1 equiv.), carboxylation will provide the
desired labeled material labeled I. A parallel scenario is
plausible, as carbanion V is sufficiently basic to deprotonate
the carboxylate II.30 In the process, a dienolate species would
be formed that could undergo carboxylation to a malonate
intermediate and subsequently labeled I.16 However, the
results of the competition experiment between 6 and 17
(Figure 3C), as well as the deuterium labeling reactions
(Figure 3G,H), seem to point against such a parallel
mechanism. Nonetheless, substrate dependency cannot be
excluded at present.
Photocatalytic Carbon-14 Radiolabeling with
[14C]CO2. Isotope exchange procedures have revolutionized
the way tritium radiolabeling is performed nowadays in the
pharmaceutical industry.31 On the other hand, carbon-14 has
not benefited from such exceptional advances and the concept
of CIE has only very recently appeared. To take advantage of
this technology, we aimed to validate it on 14C radiolabeling.
As a first proof-of-concept, 7 was selected as a model
substrate. In the presence of exactly 0.3 mmol of [14C]CO2 (3
equiv. cost 580 $), [14C]7 was effectively labeled in a 47%
yield and 62% IE, which corresponds to a molar activity (Am)
of 1434 MBq mmol−1, which is fully in line with the possible
application of ADME and biodistribution studies routinely
performed by pharmaceutical companies in drug development
programs. Finally, ibuprofen [14C]43 was obtained in a
satisfying 29% yield and 53% IE (Am 1225 MBq mmol−1),
using 12% of PC 2.
When the transformation was performed on a 1:1 mixture
of PAAs 6 and 17 bearing opposite electronic substitution
patterns, only electron-rich [13C]6 was labeled in 43% IE. In
contrast, negligible labeling was observed for 17, which was
recovered almost quantitatively (Figure 3C). This result
indicates that photocatalytic oxidation occurs exclusively on
ox
ox
the carboxylate of 6 (E1/2 = +0.99 V), while 17 (E1/2
=
+1.39 V) does not participate in the process.27 This result
paves the way for the development of selective CIE
̈
transformations. In agreement with previous work by Konig
and co-workers,22a when tropic acid 44 was subjected to the
reaction conditions, [13C]44 was isolated in a 49% yield and a
moderate IE of 18%, together with 19% of styrene product 45
formed through the E1cB-elimination reaction, thus support-
ing the formation of a carbanion intermediate in the reaction
(Figure 3D).
A radical clock experiment was performed in the presence
of allylic acid 4628 bearing a terminal olefin at the 5-exo
position and provided [13C]46 in a 39% yield and 64% IE,
along with tolyl derivative 46a in a 37% yield (Figure 3E). No
traces of the cyclized product 47a or b could be observed,
thus suggesting that the radical species would be rapidly
reduced to the corresponding anion intermediate. When the
radical trap TEMPO (1 equiv.) was added, its incorporation
onto the tolyl motif was observed in the reaction crude (see
the SI for details). This result supports the formation of
radicals along the reaction pathway.
Besides its exceptionally mild and safe conditions, a major
advantage of this photoredox radiolabeling over competing
transition-metal-catalyzed procedures is the absence of a
transition-metal catalyst. This is a very attractive point for
safety in animal and human ADME studies, as no residual
metal traces are released in the transformation.
Finally, when 6 was subjected to the reaction conditions in
the presence of excess of styrene (3 equiv.), the labeled
[13C]6 was obtained in a moderate enrichment (24% IE)
together with acid [13C]48, in a 2.5:1 ratio. Interestingly, the
product of the radical addition to styrene, [13C]48, was
formed with high enrichment (80% IE) close to the
theoretical 12/13CO2 ratio. No other products were observed
during the reaction, suggesting that 48 was not able to
undergo photodecarboxylation under the tested conditions
and can be considered as an end product. As 48 is a product
of different structure than the substrate, the IE is not diluted
by the starting phenyl acetic substrate, explaining the higher
IE observed when compared to other experiments.29
When deuterium-labeled 1d2 was subjected to standard
reaction conditions (Figure 3G), the formation of the desired
product [13C]-1d2 was observed in the crude mixture with
identical efficiency with respect to the unlabeled isotopomer 1
(Table 1).
CONCLUSIONS
■
In summary, we developed the first photocatalytic carbon
isotope procedure for the carbon labeling of phenyl acetic
acids. This reaction proceeds under exceptionally mild
reaction conditions compared to previous CIE technologies
and provides a complementary approach to the challenging
carbon labeling of pharmaceuticals. In the process, mecha-
nistic insights into the transformation were unveiled and the
precise addition of [13C]CO2 showed a strong dependency of
reaction outcome in terms of both isotope incorporation and
product formation. Finally, it was shown that the implemen-
tation of this transformation toward radioactive 14C radio-
labeling is possible under safe and cost-sustainable conditions.
In the presence of 3 equiv. of [14C]CO2, [14C]7 and ibuprofen
[14C]43 were labeled in high molar activities in line with the
possible application for ADME studies.
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ASSOCIATED CONTENT
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■
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.0c05344.
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AUTHOR INFORMATION
■
Corresponding Author
Davide Audisio − Service de Chimie Bio-organique et
Marquage (SCBM), CEA/DRF/JOLIOT, Université Paris
Saclay, F-91191 Gif-sur-Yvette, France; orcid.org/0000-
0002-6234-3610; Email: davide.audisio@cea.fr
́
dioxide functionalization. Chem. Sci. 2019, 10, 3905−3926. (f) Julia-
́
Hernandez, F.; Gaydou, M.; Serrano, E.; van Gemmeren, M.; Martin,
R. Ni- and Fe-catalyzed Carboxylation of Unsaturated Hydrocarbons
with CO2. Top. Curr. Chem. 2016, 374, 45.
Authors
(3) For recent reviews, see: (a) Yeung, C. S. Photoredox Catalysis
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Acids from a Renewable Feedstock. Angew. Chem., Int. Ed. 2019, 58,
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(SCBM), CEA/DRF/JOLIOT, Université Paris Saclay, F-
91191 Gif-sur-Yvette, France
Alex Talbot − Service de Chimie Bio-organique et Marquage
(SCBM), CEA/DRF/JOLIOT, Université Paris Saclay, F-
91191 Gif-sur-Yvette, France
Alexandre Labiche − Service de Chimie Bio-organique et
Marquage (SCBM), CEA/DRF/JOLIOT, Université Paris
Saclay, F-91191 Gif-sur-Yvette, France
Gianluca Destro − Service de Chimie Bio-organique et
Marquage (SCBM), CEA/DRF/JOLIOT, Université Paris
Saclay, F-91191 Gif-sur-Yvette, France
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Antoine Sallustrau − Service de Chimie Bio-organique et
Marquage (SCBM), CEA/DRF/JOLIOT, Université Paris
Saclay, F-91191 Gif-sur-Yvette, France
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c05344
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by CEA and the European Union’s
Horizon 2020 research and innovation program under the
Marie Sklodowska-Curie grant agreement No. 675071, the
European Research Council (ERC-2019-COG, 864576), and
FET-OPEN No. 862179. The authors thank A. Goudet, S.
Lebrequier, and D.-A. Buisson (DRF-JOLIOT-SCBM, CEA)
for their excellent analytical support.
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