Direct arene C–H fluorination with 18F? via organic photoredox catalysis

Article abstract of DOI:10.1126/science.aav7019

Positron emission tomography (PET) plays key roles in drug discovery and development, as well as medical imaging. However, there is a dearth of efficient and simple radiolabeling methods for aromatic C–H bonds, which limits advancements in PET radiotracer

Full text of DOI:10.1126/science.aav7019

RESEARCH
have sought to generalize the arene scope for
this transformation. Current strategies include
18F-deoxyfluorination of phenols via uronium
(11) and N-arylsydnone (12) intermediates; dis-
placement of sulfonium salts (13); fluorodemetal-
ation of preformed palladium or nickel arene
complexes from the requisite aryl halides or
boronic acids (14, 15); and copper-mediated
cross-coupling of preformed or in situ–generated
aryliodoniums (16, 17), aryl boronic acids (18),
esters (19), and arylstannanes (20) (Fig. 1A). De-
spite the advances in radiofluorination, these
approaches can be technically challenging for
radiochemists. Moreover, the use of metal re-
agents, especially in stoichiometric or super-
stoichiometric amounts, can complicate the
quality control process for translational studies
because additional analysis on residual metal
levels is required.
RADIOTRACER CHEMISTRY
Direct arene C–H fluorination with
18F− via organic photoredox catalysis
Wei Chen1*, Zeng Huang1*, Nicholas E. S. Tay2*, Benjamin Giglio1, Mengzhe Wang1,
Hui Wang1, Zhanhong Wu1, David A. Nicewicz2†, Zibo Li1†
Positron emission tomography (PET) plays key roles in drug discovery and development,
as well as medical imaging. However, there is a dearth of efficient and simple radiolabeling
methods for aromatic C–H bonds, which limits advancements in PET radiotracer
development. Here, we disclose a mild method for the fluorine-18 (18F)–fluorination of
aromatic C–H bonds by an [18F]F− salt via organic photoredox catalysis under blue light
illumination. This strategy was applied to the synthesis of a wide range of 18F-labeled
arenes and heteroaromatics, including pharmaceutical compounds. These products can
serve as diagnostic agents or provide key information about the in vivo fate of the labeled
substrates, as showcased in preliminary tracer studies in mice.
With these challenges in mind, we sought to
develop an arene C–H fluorination method com-
patible with [18F]F− (Fig. 1B). The Nicewicz lab
has developed a research program using organic
single-electron photooxidants to catalytically gen-
erate arene radical cations as reactive intermedi-
ates for arene C–H functionalization reactions.
Thus, we applied this strategy for direct C–H to
C–18F bond conversion. Considering the low
molar amount of no-carrier-added [18F]F−, radi-
ation exposure, and the potentially high cost of
[18F]F− production, we decided to first use 19F-
fluoride for the development of a photoredox-
catalyzed method for arene C–H fluorination.
Using diphenyl ether as the aromatic substrate,
we were able to obtain 17% of fluorinated adducts
in a 13:1 para:ortho ratio using an acridinium-
based photooxidant (1), cesium fluoride (CsF),
the phase-transfer reagent tetrabutylammonium
bisulfate (TBA-HSO4) and 2,2,6,6-tetramethyl-1-
piperidine 1-oxyl (TEMPO) as a redox co-mediator
under aerobic conditions for 24 hours (Fig. 2
and table S1). We attribute the low yields to the
relative recalcitrance of fluoride, which is a
Brønsted base and can form strong hydrogen
luorine-18 (18F) is one of the most impor-
tant radioisotopes in the radiopharmaceutical
industry because it has a relatively long
half-life (t1/2 = 110 min) and decays with
high efficiency by positron emission (97%)
mole of compound) as a result of its production
methods (6–8). Most modern methods for C–H to
C–F bond conversion require electrophilic fluorine
in the form of relatively expensive but bench-stable
reagents such as N-fluorobenzenesulfonimide
(NFSI) and 1-chloromethyl-4-fluoro-1,4-diazo-
niabicyclo[2.2.2]octane-bis(tetra-fluoroborate)
(Selectfluor). However, their utility for 18F radio-
labeling via electrophilic fluorination is dimin-
ished because [18F]NFSI and [18F]Selectfluor are
prepared from [18F]F2 (9), which results in even
lower molar activities of the 18F-labeled tracers.
Therefore, a method for direct conversion of a
C–H to a C–18F bond via a nucleophilic arene
fluorination strategy is highly attractive because
the synthesis of 18F-radiolabeled pharmaceu-
tical compounds can be accomplished with high
molar activity fluoride ([18F]F−). Furthermore,
direct C–H to C–18F conversion should alleviate
synthetic burdens associated with the synthesis
of radiotracer precursors (10) and allow for the
recovery of precious, unreacted starting material.
However, the primary hurdle for this approach is
the lack of reactivity for a majority of simple
aromatics with [18F]F−.
F
(1). A primary application of this radioisotope
is in the form of 2-[18F]fluorodeoxyglucose
([18F]FDG), which is used for oncological diag-
noses, neuroimaging, and studying glucose metab-
olism (2). Uptake of [18F]FDG and other 18F-labeled
agents is monitored by positron emission tomog-
raphy (PET) imaging, which quantifies spatial
distributions and metabolic perturbations, as
well as site-specific chemical reactivity and en-
suing in vivo biological processes (3).
Many small-molecule pharmaceuticals and
therapeutics contain aromatic or heteroaromatic
systems within their framework, thus presenting
a common organic subunit for the installation of
radioisotopes to yield radiotracers with imaging
utility. In particular, the direct conversion of
arene C–H into C–18F bonds is ideal owing to the
prevalence of aromatic C–H bonds and the in-
creasing importance of C(sp2)–F bonds in small-
molecule therapeutics and probes (4, 5). Direct
18F-fluorination of aromatics currently requires
the use of electrophilic fluorine sources, the sim-
plest of which is [18F]F2; however, this gaseous
reagent is incompatible with many common or-
ganic functional groups and suffers from low
molar activity (the measured radioactivity per
1Biomedical Research Imaging Center, Department of
Radiology, and UNC Lineberger Comprehensive Cancer
Center, University of North Carolina–Chapel Hill, Chapel Hill,
NC 27514, USA. 2Department of Chemistry, University of
North Carolina–Chapel Hill, Chapel Hill, NC 27599, USA.
*These authors contributed equally to this work.
Nucleophilic aromatic substitution of electron-
deficient arenes has been the standard method
for [18F]F− incorporation (1), but prefunctionali-
zation of the aromatic subunit with electron-
withdrawing groups is required for this strategy
(3). Thus, modern radiofluorination methods
†Corresponding author. Email: nicewicz@unc.edu (D.A.N.);
ziboli@med.unc.edu (Z.L.)
Fig. 1. An organic photoredox approach to 18F labeling of arenes for PET studies. (A) Prior work relies on the isolation of aryl organometallic
species. (B) This study obviates the need for metalation by using organic photoredox catalysis.
Chen et al., Science 364, 1170–1174 (2019)
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Fig. 2. Reaction scope of 18F-fluorination of aromatics. All RCYs are
decay-corrected and averaged over three experiments unless otherwise
noted. Asterisk indicates yield averaged over five experiments. Single-dagger
symbol indicates that 24.8% RCY of the 2-fluoro dechlorinated product is
formed. Double-dagger symbol indicates that the RCYs listed are based on
the product deprotection yields (see SM5.6). Bu, butyl; MeCN, acetonitrile;
hex, hexyl; iPr, isopropyl; t-Bu, tert-butyl; Me, methyl; Ph, phenyl; OTf,
trifluoromethanesulfonate; Et, ethyl; Boc, butoxycarbonyl.
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Fig. 3. Examples of PET tracers synthesized via arene C–H
radiofluorination. (A) Maximum intensity projection (MIP) PET images
of [18F]-fenoprofen (42) demonstrate higher uptake in TPA-treated
mouse ear (A-1) compared with control (A-2) mouse ear. (B) PET/CT
images demonstrate preferential tumor (MCF-7) accumulation of 39,
compared with longer blood circulation and higher nonspecific binding of
41 at 1 hour after injection. (C) Structures of the tracers used in the
preceding panels are shown.
bonds in aqueous environments (21). Despite
lower yields for the aryl C–H fluorination with
19F–, C–H fluorination was feasible and thus we
decided to extend our method to radiofluorination.
In this new system, [18F]F− is employed as the
limiting reagent, and we envisioned that the
relatively higher concentration of arene radical
cation would efficiently capture [18F]F−. Tran-
sitioning from F− to [18F]F− necessitated a re-
examination of fluoride sources and irradiation
method while aiming to achieve reasonable
18F-labeling yields on 30 min to 1 hour time scales,
given the fleeting half-life of the fluorine radio-
isotope. High molar activity aqueous [18F]F− is pre-
pared via proton bombardment of [18O] water
and subsequent elution of 18F-fluoride with tetra-
butylammonium bicarbonate to yield [18F]TBAF,
or potassium carbonate complexed with the
aminopolyether cryptand Kryptofix 2.2.2 to form
[18F]KF-K222 (1). In both of these systems, excess
tetrabutylammonium bicarbonate and potassium
carbonate are present. Although the initial radio-
chemical yields (RCYs) were relatively low (0.57%),
[18F]TBAF was the most effective 18F-fluorinating
agent in the synthesis of [18F]2 [see section 5.5
of the supplementary materials and methods
(SM5.5)]. Initial RCYs using 455-nm light-emitting
diodes were relatively low (0.57%), which prompted
us to reevaluate the light flux for the transfor-
mation. Using top-down irradiation with a 3.5-W
laser (450 nm) (22) for 30 min (cooled to 0°C to
prevent solvent loss from laser-generated heat)
under an aerobic atmosphere afforded a marked
increase in the yields of the 18F-fluorinated ad-
ducts of diphenyl ether (25.8 and 2.0% for the
para and ortho adducts, respectively). After ex-
tensive optimization (SM5.5), we identified a sys-
tem that afforded the para and ortho fluorinated
adducts (37.1 and 2.0% yield, respectively) but
observed a drop in the molar activity of [18F]-
TBAF. We attributed this inconsistency to the
turn lowers the net molar activity of [18F]-TBAF.
To circumvent this problem, we synthesized an
bearing substitution at the para position. We
found that these 4-substituted congeners (15 to
19) were compatible fluorination partners, al-
though the RCYs observed were significantly
lower than their 2-substituted counterparts.
Nevertheless, the isolated yields for these 4-
substituted methoxyarenes are acceptable for
PET imaging applications. Preliminary compu-
tational studies (figs. S97 and S98) suggest that
there is little correlation between the calculated
electrophilicities of the cation radical for the
2- and 4-substituted arenes and the observed
yields, thus suggesting a greater contribution
of steric effects in determining site selectivity.
When 3-methoxyacetophenone was subjected
to the radiofluorination conditions, a 2:1 ratio
of 18F-labeled adducts was obtained with a pref-
erence for fluorination para to the methoxy
group (20). Computational studies suggest that
the 6-position gains the most electrophilic char-
acter relative to the 2- and 4-positions (fig. S99)
upon single electron oxidation; however, only
the latter products are observed. Taken together,
these results demonstrate a strong preference
for the para functionalization of methoxyarenes
except in cases where the para position is oc-
cupied, and they suggest that steric effects may
play a role in dictating site selectivity for C–H
fluorination.
Arenes containing guaiacol motifs are found
in numerous plant and animal metabolites; thus,
the application of our C–H radiofluorination strat-
egy could enable the facile synthesis of 18F radio-
tracers from renewable sources. We found that
ethylguaiacol (21), vanillylamine (22), noniva-
mide (23), and zingerone (24) derivatives were
all successfully fluorinated to provide single regio-
isomers of the 18F analogs. Furthermore, this
reaction is not limited to methoxyarenes, as dem-
onstrated by mesitylene undergoing fluorination
(<9%) under aerobic conditions to give 25. This
isolated RCY was improved to 50% by employing
a modified anaerobic system (using TEMPO as a
acridinium containing a perchlorate (ClO4−) coun-
terion and found that 18F-labeled diphenyl ether
(2) adducts could be isolated with a molar ac-
tivity of 1.37 Ci/mmol (compared with 0.39 Ci/mmol
with BF4− counterion) and comparable RCYs of
38.2 and 1.8% for the para and ortho products,
respectively.
Having identified the optimal catalytic con-
ditions for the transformation, we turned our
attention to evaluating the scope of this method
with a range of aromatic and heteroaromatic
substrates. Biphenyl (3) and naphthalene (4)
were fluorinated at the 4- and 1-positions, re-
spectively, in good RCY. 2-Substituted methox-
yarenes (5 to 11) were also efficiently fluorinated
at the C–H site para to the methoxy group, fol-
lowing a similar trend to the amination (23)
and cyanation (24) methods from our laboratory.
Halogenated and pseudohalogenated methoxy-
arenes 2-bromoanisole (5), 2-chloroanisole (6),
and 2-OTf-anisole (7) were all fluorinated at the
4-position in good RCY, thus demonstrating the
compatibility of halogenated and pseudohalo-
genated arenes with our system, as these func-
tional groups are typically susceptible to oxidative
addition in transition metal–catalyzed meth-
ods. A range of carbonyl-containing functional
groups, such as esters (8), ketones (9), nitriles
(10), aldehydes (11), and amides (12), were all
compatible with this method, affording sin-
gle regioisomers of the 18F adducts. Methoxy-
substituted biphenyl systems (13 and 14) were
also competent substrates for fluorination, af-
fording the single regioisomers in moderate
RCY. We did not observe significant ortho fluo-
rination for 2-substituted anisoles, which we
attribute to a greater gain in positive charge
density on the para position of the arene cation
radical (25) and potential steric hindrance. Thus,
we were curious to explore the amenability of
our radiofluorination protocol to methoxyarenes
exchange of [18F]F− with fluoride from the BF4
−
counterion of the acridinium catalyst, which in
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net oxidant in MeCN with N2 bubbling). Fluo-
rinated heterocycles are privileged and highly
desirable motifs in pharmaceutical and agro-
chemical research, and substantial resources are
directed toward measuring the pharmacokinetics
of these compounds (26). Our radiofluorination
protocol was applied to several heterocyclic clas-
ses: We found that 2,5-dimethoxypyridine (26),
2-chloro-6-methoxyquinoline (27), and N,N-
dihexylquinazolinedione (28) were all success-
fully fluorinated in good to moderate RCY.
Benzazoles common to many therapeutics, such
as N-methylindazole (29), benzoxazole (30), and
benzimidazole (31), all underwent fluorination
at the most electrophilic positions of their re-
spective cation radicals. Selective late-stage arene
C–H fluorination is an attractive synthetic strategy,
as it circumvents the need for complicated labeling
precursors and enables the straightforward con-
version of bioactive molecules and drugs into PET
agents for in vitro companion diagnosis or for
pharmacodynamic and pharmacokinetic studies.
We chose to apply our 18F radiofluorination
method to several nonsteroidal anti-inflammatory
drugs (NSAIDs), which are an important class of
pharmaceuticals that alleviate pain and inflam-
mation by inhibiting the activity of cyclooxygenase
enzymes (COX-1 and COX-2). Although there
have been recent advances in the radiolabeling
of COX-1 and COX-2 inhibitors, many examples
use 11C as the radionuclide, which has the dis-
advantage of a shorter half-life (t1/2 = 20.2 min)
than 18F (27). Existing 18F-labeled COX inhibitors
typically incorporate 18F in the radioprobe as
part of a phenol-appended fluorinated alkyl
chain (28). However, these functional groups are
prone to metabolic degradation and thus may be
less-effective radiotracers (27, 29). Fluorination
of the aromatic ring is a strategy typically used to
study drug metabolism, as fluorine is a hydrogen
bioisostere and its substitution slows the meta-
bolic degradation of drug molecules by cyto-
chrome P450 (29). Fluorinated aromatics can
also act as metabolic tracers because hydrox-
ylated fluoroarene metabolites undergo a 1,2-
fluoride shift (NIH shift), thus allowing for the
detection and quantification of metabolic by-
products (30, 31). Furthermore, the introduction
of fluorine into the aromatic system can improve
the potency and cell permeability of drug mol-
ecules through noncovalent interactions (5). The
development of the NSAID celecoxib is an in-
structive example, in which the substitution of
various aryl C–H bonds for aryl C–F bonds was
used to bias in vitro COX-2 selectivity (32).
However, routes for the analogous synthesis of
C(sp2)–18F bonds in COX inhibitors with aro-
matic moieties are underexplored because of dif-
ficulties with designing late-stage precursors for
18F radiolabeling (33). Thus, we envisioned that
our method would enable the introduction of 18F
into known COX inhibitors. The NSAID deriva-
tives fenoprofen methyl ester (32), flurbiprofen
methyl ester (33), and O-methyl methyl salicy-
late (8) were all fluorinated in good to moderate
RCYs. Given the ubiquitous use of these commer-
cial NSAIDs (34), the synthesis of their radio-
tracer counterparts could provide researchers
with a method for visualizing their immediate
in vivo metabolic fates that is complementary
to the longitudinal metabolism studies enabled
by 3H- and 14C-labeling strategies (35).
and our method provides facile access to radio-
fluorinated 39 and 41. In vivo PET studies of
mice containing MCF7 (breast cancer) and
U87MG (glioblastoma) tumor xenografts dem-
onstrate prominent uptake of 39 with minimal
accumulation in other organs except the pancreas
and bladder (Fig. 3B and fig. S95) (see supple-
mentary materials and methods for more details).
Conversely, 41 displayed low uptake in similar
tumor models with significantly higher reten-
tion in the mouse circulatory system. On the basis
of these preliminary studies, 39 shows promise
as a selective amino acid radioprobe for tumor
detection, and further studies will be needed to
examine its biological activity and pharmacology.
These results further demonstrate the potential
of our radiofluorination method for the discov-
ery of new PET agents that circumvents the need
for prefunctionalized (hetero)arenes.
The hypolipidemic agents clofibrate (34) and
fenofibrate (35), as well as a derivative of the
biological neurotransmitter precursor DL-DOPA
(36), were selectively fluorinated in moderate RCY
after 30 min. We found that the fluorination
protocol was influenced by reaction times, as
extending the runtime to 1 hour increased the
RCY of the fluorinated DOPA derivative to 21.2%.
This result is especially noteworthy because
[
18F]DOPA is an important radioprobe for the
PET imaging of CNS disorders (36), but pub-
lished routes to it typically require extensive
and sensitive synthesis with 18F precursors (37)
or the fluorination of prefunctionalized DOPA
analogs (16, 19). This fluorinated DOPA deriv-
ative was then subjected to facile global depro-
tection to yield [18F]-DOPA (37) in 12.3% RCY.
Other aromatic amino acids, such as the pro-
tected variants of O-Me-ortho-tyrosine and 4-
phenyl-phenylalanine, were also successfully
radiofluorinated (38 and 40, respectively), and
their deprotected forms (39 and 41, respectively)
were accessed with relative ease.
A major objective of our synthetic methodol-
ogy was to develop clinically relevant PET tracers
from readily available bioactive molecules with-
out first requiring arene prefunctionalization. To
test this concept, we examined the feasibility of
converting the NSAID fenoprofen into a PET
agent by direct C–H fluorination. Fenoprofen
has notable anti-inflammatory activity (38), but
there have been minimal studies with its fluo-
rinated analogs. Given the widely exploited hy-
drogen bioisosterism of fluorine in medicinal
chemistry (5), we were interested in examining
the viability of the radiofluorinated analog for
PET studies. [18F]-Fenoprofen (42) was readily
accessed from 32, which was then used to detect
inflammation induced by 12-o-tetradecanoylphorbol-
13-acetate (TPA) in mouse ears (Fig. 3A and fig.
S94) (see supplementary materials and methods
for more details) (39). Preliminary ex vivo PET
studies (Fig. 3A) show significantly higher up-
take of [18F]-fenoprofen in the ear inflammation
model relative to the control 30 min after in-
travenous introduction of the radioprobe. These
data suggest that 42 is a potential PET agent that
demonstrates preferential accumulation in in-
flamed tissue. Additional biological evaluations
for 42 are needed but are currently beyond the
scope of this Report.
18F radiolabeling is an important tool for
noninvasive studies of biological systems, and
we anticipate that the applicability of our radio-
fluorination method to commercial pharmaceu-
ticals and metabolites will enable direct access to
new classes of translationally relevant 18F radio-
tracers, either as diagnostic agents or as target
probes for elucidating the in vivo fate of metab-
olites or pharmaceuticals.
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ACKNOWLEDGMENTS
SUPPLEMENTARY MATERIALS
Funding: Financial support was provided in part by the National
Institutes of Health (NIGMS) awards R01GM120186 (D.A.N.)
and 5R01EB014354 (Z.L.) and by the UNC Department of
Radiology, Biomedical Research Imaging Center, and UNC
Lineberger Comprehensive Cancer Center (start-up fund to Z.L.).
N.E.S.T. is grateful for an NSF Graduate Research Fellowship.
PET instrumentation was supported via an NIH High-End
Instrumentation Grant (1S10OD023611-01). Author contributions:
W.C. established the final labeling conditions and conducted
the majority of the aromatic labeling experiments. Z.H. established
the initial labeling conditions and ran a portion of the aromatic
labeling scope. N.E.S.T. identified the 19F-fluorination conditions and
science.sciencemag.org/content/364/6446/1170/suppl/DC1
Materials and Methods
Figs. S1 to S101
Tables S1 to S58
Spectral Data
Radio-HPLC Traces
References (48–81)
Movies S1 to S3
11 October 2018; resubmitted 6 February 2019
Accepted 29 May 2019
10.1126/science.aav7019
Chen et al., Science 364, 1170–1174 (2019)
21 June 2019
5 of 5

Direct arene C−H fluorination with 18F− via organic photoredox catalysis
Wei Chen, Zeng Huang, Nicholas E. S. Tay, Benjamin Giglio, Mengzhe Wang, Hui Wang, Zhanhong Wu, David A. Nicewicz
and Zibo Li
Science 364 (6446), 1170-1174.
DOI: 10.1126/science.aav7019
A metal-free route to PET probes
Positron emission tomography (PET) is a widely used imaging technique for medical diagnostics and
pharmaceutical development. As the name implies, it requires tracers that emit positrons, typically through labeling with
fluorine or carbon radioisotopes. W. Chen et al. devised a versatile technique to incorporate radioactive fluoride into
aromatic rings. The metal-free photochemical method directly substitutes aryl carbon-hydrogen bonds with [ 18F]fluoride
and so is particularly well suited to late-stage transformation of complex molecules into tracers.
Science, this issue p. 1170
ARTICLE TOOLS
http://science.sciencemag.org/content/364/6446/1170
SUPPLEMENTARY
MATERIALS
http://science.sciencemag.org/content/suppl/2019/06/19/364.6446.1170.DC1
REFERENCES
This article cites 73 articles, 3 of which you can access for free
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