A general protocol for Cu-mediated fluoro-deamination: Sandmeyer fluorination of diverse aromatic substrates

Article abstract of DOI:10.1021/acs.orglett.0c04209

A Cu(I)-mediated fluoro-deamination method for nucleophilic radiofluorination was devised. The method affords fluorinated aromatic products directly from anilines under both no-carrier added and stoichiometric conditions. Isolated radiochemical yields ran

Full text of DOI:10.1021/acs.orglett.0c04209

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Letter
A General Protocol for Cu-Mediated Fluoro-deamination:
Sandmeyer Fluorination of Diverse Aromatic Substrates
́
R. Manuel Perez-García, Gaute Grønnevik, and Patrick J. Riss*
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ABSTRACT: A Cu(I)-mediated fluoro-deamination method for
nucleophilic radiofluorination was devised. The method affords
fluorinated aromatic products directly from anilines under both no-
carrier added and stoichiometric conditions. Isolated radio-
chemical yields range from 11% to 81% with high radiochemical
purities and a molar activity of 58 MBq/nmol. The reaction
conditions were implemented successfully in an automated process
for production of (S)-4[18F]fluorogluthetimide on a radiosynthesis
module.
he availability of methods for introduction of fluorine-18
Tinto a scaffold of interest is regarded as a critical
bottleneck in the development of radiopharmaceuticals for
positron emission tomography (PET). In recent years,
methods for late-stage radiolabeling of drug scaffolds with
short-lived nuclides (>2 h half-life) became a focus of research.
In this paradigm, existing molecules are subjected to
transformations appropriate to incorporate a radionuclide
post haste. Metal-mediated reactions with a [18F]fluoride ion
are a critical advancement that reshaped the chemical toolkit
radiochemists utilize in practice. Transition metal organyls,1,2,8
quasi-metallic main group elements like iodanes,3 boro-
nates,4−6,9−12 and main group metal organyls7 have been
added to the landscape of suitable precursors for radio-
chemistry. Radiolabeling of a wide range of substrates,
including access to radiopharmaceuticals that were all but
impossible to synthesize using established fluorine-18 radio-
chemistry, has now become possible. Consequently, pushing
the limits of late stage fluorination has, nowadays, been
directed at functional group transformations that are neither
obvious nor without considerable challenge. One such
transformation is the direct conversion of amines, specifically
aminoarenes, into fluorides to tap the rationale of NH2−F
bioisosterism and a pool of existing bioactive molecules. In
light of our research interests in biomedical imaging with PET,
the possibility to convert bioactive aminoarenes directly to
their fluoroarene bioisosteres is particularly attractive to readily
achieve proof-of-principle with potential PET radiotracers. In
contrast to heavier halides, fluoro-deamination of anilines in
practically useful yields with fluoride ion has been elusive to
the synthetic community. The only means to convert anilines
to aryl fluorides are the acidolysis of triazene intermediates as
described by Wallach and the Balz−Schiemann reactions,
respectively. Both of these reactions do not proceed well with
H[18F]F, [18F]fluoride, or [18F]tetrafluoroborate salts and may
not be obtained under no-carrier-added (n.c.a.) condi-
tions.13−19 Nonetheless, if achieved such a functional group
transformation may provide the means for straightforward
exchange of the NH2-group for a fluorine atom in accordance
with the concept of late-stage fluorination. Direct fluoro-
deamination in analogy to the Sandmeyer reaction could
produce fluoroarenes from both activated and nonactivated
substrates.13−19 Unfortunately, disproportionation of Cu(I) by
the fluoride ion into Cu and insoluble CuF2 impedes
Sandmeyer fluorination.
The earliest report to achieve no-carrier-added nucleophilic
fluorination of diazonium salts was published in 1995, using
two steps via p-toluenediazonium salts. Radiolabeled 4-
[18F]fluorotoluene was made from 4-toluenediazonium 2,4,6-
tri-isopropylbenzenesulfonate (Scheme 1a).18 This was refined
by using ion-exchange resin-bound aryldiazionium salts to
obtain 18F-labeled fluoroarenes in 1−8% radiochemical yield
(RCY) (Scheme 1b).19 Recently, Murphy et al. reported
another indirect method via arylsydnones (Scheme 1c), an
exotic leaving group for SNAr reactions.20 Despite these efforts,
there has been a lack of a fluorinating Sandmeyer reaction,
wherein diazonium precursors are prepared in situ to produce
fluorinated products in one step. Herein, we describe the Cu-
mediated direct conversion of anilines into aryl fluorides
(Scheme 1d).
Received: December 20, 2020
Published: January 25, 2021
© 2021 The Authors. Published by
American Chemical Society
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Org. Lett. 2021, 23, 1011−1015
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was reached (entry 3). When other substrates were employed,
it was found that only 2-, 3-, and 4-nitroaniline gave any
product.21−24 Fortunately, a negative control experiment
conducted while exploring oxidation of Cu(I) to Cu(II) in
solution provided new insight.25 While oxidation practically
extinguished the reactivity (6% ([18F]1)), an RCY of 46.5%
was observed when the Cu(I)OTf acetonitrile complex was
used in the absence of the oxidizing agent (Table 1, entry 4).25
Substitution of tBuONO for AmylONO further increased the
yield, in particular when combined with degassing of the
reaction mixtures (Table 1 entry 5).25b Furthermore, successful
elution of the [18F]fluoride from ion exchange cartridges with a
mixture of alkyl nitrite and aniline in MeCN indicated the
presence of diazonium ions rather than smooth production of
radicals. Qualitative azocoupling-tests confirmed this and
provided a means for optimizing temperature and time by
observing degradation of the diazonium intermediate.
Combined with the disappointing substrate screen the
discovery of a working Cu(I)-mediated reaction gave rise to
a new hypothesis. We reasoned that trace Cu(I) formed in situ
from Cu(II)OTf2 may have somehow mediated the fluorina-
tion reaction. The particular effectiveness of MeCN would
then relate to protection of the Cu(I) oxidation state in tetrakis
acetonitrile complexes. Indeed, Cu(I) was able to transform a
broader spectrum of anilines to fluorides. In the absence of Cu-
catalyst, only trace yields were observed and diazonium ions
remained stable. A compound formed via N2−CuF binding has
been described which suggests the involvement of a direct N−
CuF interaction in the reaction mechanism;32 however, we
consider a collaborative mechanism between Cu and Cu(II),
formed by disproportionation from Cu(I) by fluoride, more
plausible.25d,26 Cu is effective for forming aryl radicals from
arenediazonium salts, and Cu(II) readily oxidizes aryl radicals
to cations to be captured by nucleophilic fluoride. Since the
disproportionation is likely to involve a biatomic mechanism
requiring two Cu atoms in close proximity, and since the low F
concentration in n.c.a. radiochemistry (the n.c.a. F−Cu ratio is
about 1:1.2 × 105) disfavors formation of insoluble CuF2,
fluoride ions are not removed from the liquid phase but
capture aryl carbocations formed from Cu/Cu(II)-couples.
Collaborative Cu/Cu(II)-catalysis could even be plausible for
other Cu-mediated fluorinations perhaps explaining the large
excess of [Cu] employed in these reports. Radical
intermediates would also explain the ubiquitous proto
analogue formed in all radiofluorination reactions based on
Cu-salts.
Scheme 1. Modern Methods for Fluoro-deamination
Reactions (SAX, Strong Anion Exchanger; SCX, Strong
Cation Exchanger)
The starting point for this investigation was the attempt to
employ the Cu(II)-mediated fluorination conditions in a direct
conversion of anilines.3−6 We surmised that radicals formed by
reaction of alkyl nitrites with anilines in the absence of acid
would be readily oxidized in a single electron transfer to Cu(II)
allowing for fluoride to capture the aryl cation.15,21−24 Table 1
summarizes the key steps of method development.
Table 1. Influence of the Cu- and F-Source on RCY of [18F]
a
1
b
no.
[Cu]
solvent
F-source
RONO
RCY
1
2
3
4
5
6
7
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuOTf
CuOTf
CuOTf
DMF
[18F]TBAF
[18F]TBAF
[18F]KF
tBuONO
tBuONO
tBuONO
tBuONO
AmylONO
AmylONO
tBuONO
0.75%
22.5%
39.9%
44.0%
61.9%
73.9%
56.1%
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
In order to validate the disproportionation hypothesis of a
Cu/Cu(II) couple in action, we performed a control
experiment with Cu(II) in the presence of copper powder.
Indeed, these conditions furnished [18F]3 and [18F]8 in
radiochemical yields of 24.5% and 38.7%, respectively, strongly
supporting the hypothesis. To test the role of disproportiona-
tion, we added a carrier in the form of KF to both Cu sources
to see if the resultant increase in disproportionation would
benefit the outcome. Indeed, addition of substoichiometric
amounts of KF carrier (0.45 equiv, 13.5 mM) had a positive
effect on the Cu(I) reaction (Table 1 entry 6, 73.9% RCY) but
did not have an effect on the Cu(II) reaction (entry 7, 38.8%).
This indicates an interaction of Cu(I) and fluoride, such as
disproportionation to produce Cu as explained above. Since
KF is poorly soluble in MeCN, the fluoride source functions as
a phase transfer catalyst, which limits the total amount of
fluoride ions in solution at any time. As long as the fluoride
[18F]KF
[18F]KF
[18F]KF
c
c
Cu(OTf)2
[18F]KF
a
Conditions: Aniline (30 mmol), RONO (45 mmol), [Cu] 4 equiv,
KOTf or TBAOTf (36 mmol), n.c.a. [18F]fluoride ion, 1 mL volume.
b
c
Isolated RCY, averages of two duplicate experiments. With 0.45
equiv of KF carrier.
Initial trials with Cu(II) in DMF and other polar solvents
(Table S1) gave a very low RCY; only MeCN afforded over
20% of 1-fluoro-4-nitrobenzene [18F]1 from model substrate 4-
nitroaniline (Table 1, entries 1 and 2). Following a
methodological optimization a combination of KOTf and 15-
crown-5 was found to form the most active fluoride source in
the labeling reaction. A practically useful RCY of nearly 40%
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a
Table 2. Substrate Scope of the Reaction
a
RCP radiochemical purity of the isolated radioactive product, RCY “radiochemical yield” (product activity counted by dose calibrator and
corrected for HPLC purity after quality control). n.c.a.: No-carrier added conditions. c.a.: in the presence of 0.45 equiv of KF. *Cu-mediated
oxidation to a quinoide system.
concentration remains low, precipitation of CuF2 will not
withdraw fluoride ions from the liquid phase, and thus the
reaction is not impeded. Therefore, the major issue of a
Sandmeyer fluorination is circumvented under these reaction
conditions. Carrier addition improved yields to a considerable
extent although reaction times for complete consumption of
the additional fluoride nucleophile did not increase at all,
indicating a higher rate of reaction, i.e. through increase of
disproportionation, production of aryl cation captured by
fluoride. This may allow for translation of the conditions to
stoichiometric fluorination. Tables S1−S7 give an overview of
over 200 individual reagent combinations tested during
optimization. The following final conditions were developed:
Aniline (30 mM), 1.5 equiv of alkyl nitrite, 1.2 equiv of phase
transfer catalyst, 4 equiv of [Cu], 120 °C, 20 min, MeCN (1
mL), n.c.a. [18F]fluoride ion (20−150 MBq). Under these
conditions, no-carrier added [18F]1 was obtained in 61.9%
RCY and carrier-added [18F]1 in 73.9% yield with stoichio-
metric KF.33 To elucidate the substrate scope, the method was
applied to a diverse selection of anilines (Table 2) with good
results.
this is not necessarily due to an SNAr mechanism but indicative
of the individual stabilities of the corresponding diazonium
ions and radical intermediates.31 The method is highly ipso-
selective; no ortho-isomers were detected. This suggests that
the mechanism follows the proposed single electron transfer
mechanism of the Sandmeyer reaction.27 A variety of
functional groups are tolerated, including acetals, alkyl chains,
amides, aryl halides, cyanides, esters, ethers, ketones, ureas, and
others. In all cases, we observed moderate to excellent
conversion of the starting material and most products were
obtained in high radiochemical purity and good yields (37.7−
81.6%) without optimization of the workup. All but one
reaction (6 was the major component of a product mixture)
afforded a single major labeled product. The major limitations
are known intramolecular reactions of diazonium intermedi-
ates, e.g. cyclization with ortho-substituents or formation of
immines with carbonyl compounds ([18F]9). Thus, ortho-
substituted nitroaniline was only labeled in 7.3% RCY and
benzaldehyde [18F]14 was made from the acetal protected
aniline precursor. In some hydroquinone substrates, oxidation
by Cu(II) is a prevalent side reaction producing strongly
colored quinoneimines and p-quinonediimines. This is
illustrated by obtaining [18F]12 in only 20.1% RCY and
In general, the substrate scope shows some minor preference
of the new protocol on electron-withdrawing groups, although
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[18F]15 in 4% RCY. Nevertheless, nonactivated substrates
([18F]2, 40.2−68.0% RCY) including those with electron
donating substituents ([18F]3, 40.7−57.2% RCY, [18F]4,
37.7−56.0% RCY, [18F]11 39.6−75.9% RCY) proved
accessible. Notably, freshly opened Cu(MeCN)4OTf produced
about 15% higher yields than the material employed in most
runs. Although the available aniline was consumed before
complete conversion of the [18F]fluoride was achieved,
fluoroarenes were obtained in practically useful yields to
facilitate late-stage labeling of existing compounds, which
makes this method very useful for initial biological tests.
Preparation of the secondary labeling reagents 4-[18F]-
fluorophenyl iodide ([18F]3), [18F]fluorobenzoic acid methyl
ester ([18F]7), and [18F]fluorobenzaldehyde ([18F]14)
(Scheme 2) further corroborates the utility of the method.
58.7 MBq/nmol, which is an excellent result. The isolated
product (>99% RCP) obtained in the automation experiments
contained less than 1 nmol radiotracer per mL, which
principally bodes well for achieving high molar activities in
high activity productions (37 GBq/1 Ci or more).
In conclusion, the fluorinating Sandmeyer reaction, a
generally useful Cu-catalyzed deamino-fluorination of anilines,
was devised and translated into radiotracer production. This
rapid methodology applies to both activated and nonactivated
aromatic systems, producing practically useful yields of a single
fluorinated product in one step. Given the bioisosterism and
hydrogen-bonding tendencies of −NH2 and −F substituents,
this new method is an attractive means to conveniently obtain
close analogues of drug candidates or even existing drugs for
biological tests. Radiosynthesis of fluorine bioisosteres of
established drugs demonstrates the potential of this late-stage
fluorination method for radiotracer development. Further
translation of this methodology with [18F]18 is in progress.
Scheme 2. Synthesis of Labelled Aldehyde [18F]14 and the
Radiotracer Candidate [18F]18
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04209.
Supplementary procedures, data tables for individual
runs, azocoupling procedures, analytical data for radio-
chemical runs, starting materials and products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Patrick J. Riss − Section of Organic Chemistry, Department of
Chemistry, University of Oslo, 0371 Oslo, Norway;
orcid.org/0000-0002-3887-7065; Email: Patrick.Riss@
kjemi.uio.no
In order to demonstrate the late-stage fluorination on drug
molecules as realistic substrates, (−)-4-[18F]fluorogluthetimide
[18F]18 (41.4%−65.1% RCY) (Scheme 2) and the fluorinated
carbutamide derivative [18F]17 (RCY = 21%) were labeled.
Product [18F]18 is under investigation for monitoring
mitochondrial CYP2D6 in midbrain dopamine neurons in
the context of movement disorders.28−30
Authors
́
R. Manuel Perez-García − Section of Organic Chemistry,
Department of Chemistry, University of Oslo, 0371 Oslo,
Norway
The fluoride-mediated disproportionation of soluble Cu(I)
provides a way to harness the cooperative activity of a Cu/
Cu(II) couple while avoiding solid Cu-powder.25c Heteroge-
neous mixtures and suspensions, in particular dense, metallic
solids, are a notorious challenge for automation of labeling
processes. Homogeneous solutions permit rapid liquid transfer
in typical automated radiotracer productions. Labeling
conditions must be suitable for development of automated
processes on a state-of-the-art radiosynthesis platform to be
translated into (pre)clinical application. A Synthra RN plus
synthesis module was charged with a mixture of aniline and
amyl nitrite in MeCN and CuOTf/pyridine in MeCN at room
temperature. These mixtures were added to the reaction after
processing of the [18F]fluoride obtained from the cyclotron
target without notable loss in reactivity allowing for batch
production of [18F]18 for preclinical tests. Similar to other
transition-metal mediated radiofluorination reactions, a side
product formed by protonation instead of fluorination was
observed, necessitating the use of pentafluorophenyl-function-
alized HPLC stationary phases for separation to achieve high
chemical purities of radioactive products. Molar activities
achieved with the novel protocol were similar to those
routinely obtained for nucleophilic aromatic fluorination
reactions; e.g., starting with 2.2 GBq, [18F]3 was obtained in
Gaute Grønnevik − Section of Organic Chemistry,
Department of Chemistry, University of Oslo, 0371 Oslo,
Norway
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04209
Funding
Funding from the research council of Norway (NFR ES
231553 to P.J.R.) is gratefully acknowledged.
Notes
The authors declare no competing financial interest.
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