Sequential Ir/Cu-Mediated Method for the Meta-Selective C-H Radiofluorination of (Hetero)Arenes

Article abstract of DOI:10.1021/jacs.1c00523

This article describes a sequential Ir/Cu-mediated process for the meta-selective C-H radiofluorination of (hetero)arene substrates. In the first step, Ir-catalyzed C(sp2)-H borylation affords (hetero)aryl pinacolboronate (BPin) esters. The intermediate organoboronates are then directly subjected to copper-mediated radiofluorination with [18F]tetrabutylammonium fluoride to afford fluorine-18 labeled (hetero)arenes in high radiochemical yield and radiochemical purity. This entire process is performed on a benchtop without Schlenk or glovebox techniques and circumvents the need to isolate (hetero)aryl boronate esters. The reaction was automated on a TracerLab FXFN module with 1,3-dimethoxybenzene and a meta-tyrosine derivative. The products, [18F]1-fluoro-3,5-dimethoxybenzene and an 18F-labeled meta-tyrosine derivative, were obtained in 37 ± 5% isolated radiochemical yield and >99% radiochemical purity and 25% isolated radiochemical yield and 99% radiochemical purity, and 0.52 Ci/μmol (19.24 GBq/μmol) molar activity (Am), respectively.

Full text of DOI:10.1021/jacs.1c00523

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Sequential Ir/Cu-Mediated Method for the Meta-Selective C−H
Radiofluorination of (Hetero)Arenes
Jay S. Wright,§ Liam S. Sharninghausen,§ Sean Preshlock,§ Allen F. Brooks, Melanie S. Sanford,*
and Peter J. H. Scott*
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ABSTRACT: This article describes a sequential Ir/Cu-mediated
process for the meta-selective C−H radiofluorination of (hetero)-
arene substrates. In the first step, Ir-catalyzed C(sp2)−H borylation
affords (hetero)aryl pinacolboronate (BPin) esters. The inter-
mediate organoboronates are then directly subjected to copper-
mediated radiofluorination with [18F]tetrabutylammonium fluoride
to afford fluorine-18 labeled (hetero)arenes in high radiochemical
yield and radiochemical purity. This entire process is performed on
a benchtop without Schlenk or glovebox techniques and circum-
vents the need to isolate (hetero)aryl boronate esters. The reaction
was automated on a TracerLab FXFN module with 1,3-
dimethoxybenzene and a meta-tyrosine derivative. The products,
[18F]1-fluoro-3,5-dimethoxybenzene and an 18F-labeled meta-tyrosine derivative, were obtained in 37 5% isolated radiochemical
yield and >99% radiochemical purity and 25% isolated radiochemical yield and 99% radiochemical purity, and 0.52 Ci/μmol (19.24
GBq/μmol) molar activity (Am), respectively.
Scheme 1. (A) Radiofluorination of Prefunctionalized
Precursors, (B) Existing C−H Radiofluorination
Approaches, and (C) C−H Radiofluorination Using
Sequential Ir/Cu Mediated Processes (This Work)
INTRODUCTION
■
Positron emission tomography (PET) with 18F-labeled radio-
tracers is widely used for the detection, staging, and study of
disease.1,2 While numerous 18F-containing molecules have
been deployed in PET, those containing aromatic C−18F
bonds are particularly desirable due to their resistance to
metabolic defluorination. As such, there is a pressing need for
synthetic methods for the late-stage radiofluorination of
(hetero)arenes, particularly those that are fast (due to the
short ∼110 min half-life of 18F), use nucleophilic [18F]fluoride
(which has high molar activity and is readily available from
small medical cyclotrons), and are translatable to automated
clinical production laboratories.
Most existing protocols for the nucleophilic radiofluorina-
tion of (hetero)arenes are limited in scope and/or utilize
precursors that require multistep syntheses (Scheme 1A). For
instance, classical SNAr radiofluorination reactions require
highly electron deficient (hetero)aryl halide/pseudohalide
substrates.3 This electronic limitation has been overcome by
moving to alternative mechanistic pathways and/or precursors,
including those involving diazonium salts,4 triazenes,5 organo-
nickel6 or -palladium complexes,7 phenols,8−10 hypervalent
iodine derivatives,11−13 organoboron or stannane re-
agents,14−17 or sulfur-substituted aromatics.18,19 However,
challenges with the synthesis, handling, isolation, scalability,
and/or long-term storage of these precursors continue to limit
widespread application of many of these methods in clinical
Received: January 18, 2021
Published: April 29, 2021
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© 2021 American Chemical Society
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settings.20−23 The Cu-mediated radiofluorination (CMRF) of
organoboron precursors is a general (in terms of substrate
scope) and practical (in terms of precursor availability and
translation to automated syntheses) radiofluorination strategy
that has been widely adopted for clinical use.24 Although many
simple arylboron reagents exhibit high benchtop stability, the
purification, storage, and/or handling of highly functionalized
(hetero)arylboron compounds (for example, those derived
from the late-stage borylation of bioactive scaffolds) as well as
of 2-azaaryl and polyfluorinated aryl boron derivatives can be
quite challenging.25
Table 1. Impact of C−H Borylation Reagents on CMRF of
a
1-BPin
entry
[Cu] (μmol)
additive (μmol)
RCY (%)
1
2
3
5
5
5
none
80 10
42 10
An attractive alternative would be to directly use C(sp2)−H
substrates as precursors for nucleophilic radiofluorination. The
(hetero)arene substrates of these transformations are excep-
tionally stable and readily available. However, there are major
challenges to realizing this approach, including (1) developing
strategies for the rapid activation/radiofluorination of tradi-
tionally inert C(sp2)−H bonds and (2) controlling the
selectivity of 18F incorporation when there are multiple
C(sp2)−H sites. Several recent reports have shown the
feasibility of C(sp2)−H radiofluorination in limited contexts
(Scheme 1B). For instance, aminoquinoline directing groups
were used to control reactivity and selectivity in ortho-selective
C(sp2)−H CMRF of (hetero)arenes.26 Additionally, para-
selective electrophilic aromatic substitution (EAS) on electron
rich (hetero)arenes was employed for the in situ generation of
hypervalent iodine precursors for CMRF.27 A related para-
selective EAS reaction was leveraged to access aryl sulfonium
salts, which then undergo uncatalyzed nucleophilic radio-
fluorination.28 Finally, an organic photoredox approach was
utilized to achieve para-selective nucleophilic radiofluorination
of electron rich (hetero)arenes.29 In this report, we
demonstrate a sequential Ir/Cu-mediated C(sp2)−H radio-
fluorination with a wide substrate scope, complementary site
selectivity, and high operational simplicity compared to
existing methods (Scheme 1C). This transformation merges
the Ir-catalyzed C(sp2)−H borylation of (hetero)arenes30,31
with Cu-mediated radiofluorination to achieve meta-selective
18F-labeling of electronically diverse (hetero)arene substrates.
[Ir(COD)Cl]2 (3)
[Ir(COD)OMe]2 (3)
tmphen (6)
80
6
4
5
49 13
5
6
5
5
dtbpy (6)
TBACl (6)
58
0
3
7
8
9
10
11
12
13
14
20
20
20
20
20
20
20
20
none
tmphen (6)
dtbpy (6)
B2Pin2 (10)
92
88
91
36
43
96
83
86
1
3
3
6
9
3
5
2
HBPin (20)
n-BuOH (550)
B2Pin2 (10) and n-BuOH (550)
HBPin (10) and n-BuOH (550)
a
Unless otherwise stated, RCYs are nonisolated and are calculated by
multiplying RCC (measured via radio-TLC) by the RCP (measured
via radio-HPLC).
conversion (RCC) values obtained via radio-thin-layer
chromatography (rTLC) analysis by radiochemical purity
(RCP) values obtained via radio-high-performance liquid
chromatography (rHPLC) analysis. However, as predicted,
the addition of various C−H borylation reaction components
significantly lowers the yield of 1-18F. Iridium sources
containing chloride ligands (e.g., [Ir(COD)Cl]2, entry 2), are
particularly problematic, likely due to competing reactions of
the Cl− ion. Consistent with this proposal, the addition of 5
μmol of tetrabutylammonium chloride (TBACl, entry 6)
completely shuts down the CMRF reaction. Moving to the
halide-free Ir precursor [Ir(COD)OMe]2 restores the yield to
∼80% (entry 3).
Common ligands for Ir-catalyzed C−H borylation, 4,4′-di-
tert-butylbipyridine (dtbpy) and 3,4,7,8-tetramethyl-1,10-phe-
nanthroline (tmphen), also impede radiofluorination (entries
4, 5). We hypothesize that these ligate the Cu and render it less
reactive. To mitigate this issue, the Cu loading was increased
from 5 μmol (equimolar with the added ligands) to 20 μmol
(>3-fold excess relative to the dtbpy/tmphen). This change in
stoichiometry restores the radiofluorination yield to >80%
(entries 7−9). Finally, B2Pin2 and HBPin inhibit the
radiofluorination step (entries 10, 11). We hypothesized that
this could be addressed by using an alcohol additive to quench
reactive boron species.35,36 Indeed, the addition of 30 equiv of
n-BuOH37,38 renders the radiofluorination reaction insensitive
to boron additives (entries 13, 14).39
RESULTS AND DISCUSSION
■
Although other tandem Ir C−H borylation sequences have
been reported,32 we anticipated three major challenges for
combining Ir-catalyzed C(sp2)−H borylation and Cu-mediated
radiofluorination of the resulting (hetero)aryl boronate esters.
First, CMRF reactions are well-known to be highly sensitive to
conditions (e.g., solvent, ligands, additives),33,34 thus creating
potential compatibility issues with the Ir catalysis. Second, due
to the sensitivity of the active Ir catalyst, the Ir-catalyzed
reaction is most commonly conducted with rigorous exclusion
of air and moisture, which is not feasible in standard
radiochemistry laboratories. Third, Ir-catalyzed C(sp2)−H
borylation proceeds with modest site selectivity for certain
classes of substrates, which could ultimately result in mixtures
of radiofluorinated products.
We first probed the anticipated compatibility issues by
conducting the CMRF of 1-BPin in the presence of different
components of the Ir-catalyzed C−H borylation reaction
(Table 1). Under standard radiofluorination conditions (20
μmol of 1-BPin, 0.25 equiv of Cu(py)4(OTf)2, [18F]tetrabutyl-
ammonium fluoride ([18F]TBAF) in DMA at 120 °C for 20
min), 1-18F is formed in 80% radiochemical yield (RCY; entry
1), which was measured by multiplying radiochemical
The C−H borylation step was next evaluated using the
compatible precatalyst and ligand, [Ir(COD)OMe]2/tmphen.
Initial studies focused on identifying an operationally simple
benchtop procedure, since most radiochemistry laboratories
lack specialized equipment for air-free reactions. These studies
revealed that the ligand, catalyst, and solvent for C−H
borylation can be dispensed into a vial under ambient
conditions followed by a 2 min argon sparge of the resulting
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a
solution. Subsequent addition of HBPin and 1-H followed by
heating at 80 °C for 16 h results in the formation of 1-BPin in
82% NMR yield and 16:1 meta:ortho selectivity. This is
comparable to the 92% NMR yield and identical regioselec-
tivity obtained under rigorously dry/air-free conditions.
The two steps of the sequence were next combined by
adding n-BuOH to the crude C−H borylation mixture and
then directly subjecting this solution to radiofluorination with
Cu(py)4(OTf)2 and [18F]TBAF in DMA at 120 °C for 20 min.
As shown in Scheme 2, this sequence affords 1-18F in 88 6%
Scheme 3. Substrate Scope
a
Scheme 2. Sequence for C−H Radiofluorination of 1-H
a
See Supporting Information for complete experimental details.
Nonisolated RCY is calculated by multiplying RCC (measured via
radio-TLC) by the RCP (measured via radio-HPLC). Isolated RCY
refers to the isolated recovery of the labeled product following
semipreparative HPLC purification.
nonisolated RCY and 16:1 meta:ortho selectivity, as confirmed
by rHPLC. Importantly, the RCY is based on 18F as the
limiting reagent.40 This sequence was directly translated to
automated radiosynthesis by loading the crude C−H
borylation mixture into a TracerLab FXFN synthesis module.
Under automated conditions, 1-18F is produced in 37 5%
isolated RCY and >99% radiochemical purity (RCP, n = 3),
illustrating the potential for clinical translation (Scheme 2, see
Supporting Information for full details).
a
See Supporting Information for complete experimental details and
minor changes to the Cu mediator structure and temperature for
different substrates. Unless otherwise stated, RCYs are nonisolated
and are calculated by multiplying RCC (measured via radio-TLC) by
the RCP (measured via radio-HPLC).
NMR studies show that the selectivity enhancement in both
9 and 11 is due to facile decomposition of the ortho-borylated
intermediates under CMRF conditions. This decomposition
occurs via a combination of protodeboronation and oxidation
pathways (see Supporting Information for complete de-
tails).46,47 Notably, it is well documented that ortho-fluorine
substituents accelerate protodeboronation in various media,
supporting these conclusions.48,25a
Arenes with other substitution patterns are similarly effective
substrates for this sequence. For instance, veratrole 13-H
undergoes selective C−H borylation/radiofluorination to
afford 13-18F in 83% RCY. The C−H borylation of 1-(2-
methoxyphenyl)ethan-1-one 14-H is slow at room temperature
but proceeds efficiently at 80 °C to afford 2:1 selectivity for the
site para to the acetyl substituent. The isomer ratio is
enhanced in the CMRF step, resulting in 14-18F as a 3.4:1
mixture of isomers.49 Anisole 15-H undergoes C−H borylation
to generate a 3.3:1:trace mixture of the meta:para:ortho
boronate esters. Here again, the meta-selectivity is modestly
enhanced in the CMRF step (15-18F is generated in a 12:3:1
mixture). Notably, this meta-selectivity with 15-H is comple-
mentary to that obtained in C−H radiofluorination reactions
This optimized sequence is effective for the 18F-labeling of
electronically diverse 1,3-disubstituted arenes, affording 1-18F
to 11-18F in RCYs ranging from 8% to 88% (Scheme 3).41,42 In
these examples, the 18F-labeled product is formed with high
meta-selectivity, and regioisomers could be separated and
quantified using analytical or semipreparative HPLC (see
Supporting Information). The C−H borylation site-selectivity
is lowest for substrates bearing relatively small cyano and
fluoro substituents (9−11), as expected for the sterically
controlled C−H functionalization step.43,44 However, the
isomer ratio in the 18F-labeled products is typically higher
than that observed in the C−H borylation step. For instance,
the Ir-catalyzed C−H borylation of 9-H proceeds ortho and
meta to the nitrile substituent with 5:1 selectivity favoring the
less sterically congested meta-boronate. However, the radio-
labeling reaction affords 9-18F in 10:1 selectivity favoring the
same position.45 Even more strikingly, C−H borylation of
methyl 3-fluorobenzoate 11 affords a 2.5:1 mixture of ArBPin
isomers a and b (Scheme 4A); however, after radio-
fluorination, 11-18F is formed as a 41:1 mixture favoring the
meta-isomer a.
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Scheme 4. (A) Highly Meta-Selective CMRF Preceded by
Nonselective C−H Borylation of Fluorinated 11-H and (B)
Highly C-6 Selective CMRF of Indole 16-H via BPin Adduct
Scheme 5. Tandem C−H Radiofluorination of
a
Pharmaceutically Relevant Scaffolds
a
c
a
Yields are nonisolated RCYs and are calculated by multiplying RCC
(measured via radio-thin-layer chromatography) by the RCP
(measured via radio-HPLC).
involving EAS or radical cation pathways (where the para-
isomer is strongly favored, Scheme 1B).27,28a,50 This protocol
is also compatible with modified C−H borylation systems that
override intrinsic substrate regiochemistry.51 For example,
indole 16-H undergoes selective C−H borylation at C-6
through the in situ installation of a traceless BPin directing
group at the N−H bond to form BPin c prior to the C−H
borylation (Scheme 4B, see Supporting Information for
protocol).
a
See Supporting Information for complete experimental details and
minor changes to the Cu mediator and temperature for different
substrates. Unless otherwise stated, RCYs are nonisolated and are
calculated by multiplying RCC (measured via radio-thin-layer
chromatography) by the RCP (measured via radio-HPLC). Isolated
RCY refers to the isolated recovery of the labeled product following
semipreparative HPLC purification.
A final noteworthy feature of this sequence is that it does not
require either (1) high conversion in the C−H borylation step
or (2) the generation of isolable boronate esters. This is
exemplified by the formation of product 8-18F. The Ir-
catalyzed C−H borylation of 2-bromo-4-methylpyridine
Protected aromatic amino acid derivatives undergo high
yielding radiofluorination to afford products such as 18-18F
and 19-18F. These have potential applications for imaging
dopaminergic metabolism and tumor proliferation.55 Auto-
mated labeling was followed by semipreparative HPLC
purification to afford 18-18F in 25% isolated RCY, 99% RCP,
and 0.52 Ci/μmol (19.24 GBq/μmol) Am (n = 2). ICP-MS
analysis of 18-18F obtained from this procedure indicated an Ir
content of 13.46 ng, which is below the exposure limits (e.g.,
parenteral = 10 μg/day) stipulated for human use.56 This
analysis further emphasizes the suitability of this radiolabeling
method for use in conjunction with human PET imaging
studies. Furthermore, manual labeling of 19-H to afford
labeled phenylalanine derivatives was achieved following acidic
deprotection in HCl, and the meta- and para-regiosomers were
separated using analytical rHPLC.57 Over the C−H radio-
fluorination protocol and the subsequent deprotection 19-18F
was obtained in >99% ee as determined via chiral HPLC
analysis.
1
proceeds in low (<10%) yield as determined by H NMR
spectroscopy. Furthermore, the intermediate 2-pyridyl-sub-
stituted boronate ester is notoriously unstable.25b,c,52 None-
theless, this substrate was successfully functionalized in 8%
RCY, thereby circumventing the need to synthesize, isolate,
and store the boronate ester precursor.53
The ability to directly and selectively convert bioactive
molecules into radiofluorinated analogues offers opportunities
to streamline 18F-radiotracer synthesis and development. As
such, it is critical to evaluate this method in the context of such
scaffolds (Scheme 5). Under the standard C−H borylation/
CMRF conditions, the anesthetic lidocaine reacts to furnish
17-18F in 15 8% RCY. Notably, this radiolabeling approach
is complementary to Hooker’s synthesis of the 18F-fluoroethyl
analogue [18F]radiocaine.54
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This method is also effective for the meta-selective
radiofluorination of a protected guanidine. Deprotection of
the crude product with trifluoroacetic acid delivered 20-18F.
Notably, previous access to related imaging agents required the
multistep synthesis of prefunctionalized iodonium precur-
sors.58 Finally, the densely functionalized cannabinoid receptor
2 partial agonist GW405833 undergoes C−H radiofluorination
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c00523
Author Contributions
§J.S.W., L.S.S., and S.P. contributed equally to this work.
Notes
The authors declare no competing financial interest.
to afford 21-18F in 60
3% RCY. Multiple attempts to
chromatographically isolate the boronate ester intermediate of
this transformation led to the recovery of protodeboronated
GW405833 substrate. Our approach enables high-yielding
radiofluorination by circumventing the requirement to isolate/
store this boronate. Once again, the incorporation of 18F onto
the aromatic ring complements existing radiolabeling strategies
for this molecule, which involve the multistep installation of a
[18F]fluoroethyl group.59 Overall, these examples highlight the
broad functional group compatibility of the method, including
tolerance of esters, amines, indoles, amides, and protected
guanidines.
ACKNOWLEDGMENTS
■
This work was supported by the NIH [Award R01EB021155
(M.S.S. and P.J.H.S.) and Award F32GM136022 (L.S.S.)].
Our gratitude is extended to Angela Dial (University of
Michigan Earth and Environmental Science Department) for
performing ICP-MS analysis.
REFERENCES
■
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CONCLUSIONS
■
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c00523.
■
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AUTHOR INFORMATION
Corresponding Authors
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D’Amato, E. M.; Chen, J.; Hooker, J. M.; Ritter, T. 18F-
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[18F]Bavarostat Enabled by a Ru-Mediated Deoxyfluorination. ACS
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Melanie S. Sanford − Department of Chemistry, University of
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Peter J. H. Scott − Department of Radiology, University of
Michigan, Ann Arbor, Michigan 48109, United States;
orcid.org/0000-0002-6505-0450; Email: pjhscott@
med.umich.edu
(11) Rotstein, B. H.; Stephenson, N. A.; Vasdev, N.; Liang, S. H.
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Authors
Jay S. Wright − Department of Radiology, University of
Michigan, Ann Arbor, Michigan 48109, United States;
orcid.org/0000-0002-1350-123X
Liam S. Sharninghausen − Department of Chemistry,
University of Michigan, Ann Arbor, Michigan 48109, United
States; orcid.org/0000-0002-2249-1010
Sean Preshlock − Department of Radiology, University of
Michigan, Ann Arbor, Michigan 48109, United States
Allen F. Brooks − Department of Radiology, University of
Michigan, Ann Arbor, Michigan 48109, United States;
orcid.org/0000-0003-3773-3024
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(15) Mossine, A. V.; Brooks, A. F.; Makaravage, K. J.; Miller, J. M.;
Ichiishi, N.; Sanford, M. S.; Scott, P. J. H. Synthesis of [18F]Arenes via
the Copper-Mediated [18F]Fluorination of Boronic Acids. Org. Lett.
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(16) Tredwell, M.; Preshlock, S. M.; Taylor, N. J.; Gruber, S.;
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Journal of the American Chemical Society
pubs.acs.org/JACS
Article
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(40) This explains why the yield for the two step C−H borylation/
radiofluorination sequence (88%; determined based on 18F as limiting
reagent) is higher than that of the C−H borylation step (82%;
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(41) Electron deficient substrates afford better yields using
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(45) Since Ir is known to induce selective protodeboronation, we
considered the possibility that residual C−H borylation materials may
be responsible for this selectivity enhancement. However, comparable
regioselectivities were obtained in the CMRF of purified boronates
derived from 14-H in the presence/absence of the C−H borylation
components (see Supporting Information). See the following:
Kallepalli, V. A.; Gore, K. A.; Shi, F.; Sanchez, L.; Chotana, G. A.;
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(46) (a) Similar selectivity enhancement was observed for 9-18F and
10-18F. There was some run-to-run variability in the C−H borylation
selectivity. However, only traces of ortho-18F-labeled isomers were
detected in all runs. (b) Subjecting a 2.5:1 mixture of a:b to the Cu
radiofluorination conditions without added [18F]TBAF led to
quantitative consumption of b. In contrast, isomer a remained after
20 min (see Supporting Information for further details).
(47) We thank a reviewer for offering alternative explanations for the
regioselectivity enhancements observed in the fluoroarene substrates.
These have been examined using meta- and ortho-substituted BPin
precursors 11-BPin, which do not afford appreciable quantities of the
ortho-labeled radiofluorine under the CMRF conditions, ruling out
other pathways. These controls demonstrate that isomerization of the
radiofluorine products via a benzyne mediated by an IrH species does
not operate (see Supporting Information for details).
(48) (a) Kuivila, H. G.; Reuwer, J. F., Jr.; Mangravite, J. A.
Electrophilic Displacement Reactions: XV. Kinetics and Mechanism
of the Base-Catalyzed Protodeboronation of Areneboronic Acids. Can.
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(49) CMRF of the independently synthesized boronate regioisomers
corresponding to 14-H employed as mixtures in various ratios gave
regiochemical outcomes consistent with the tandem protocol; see the
Supporting Information for details. For a prior investigation of this
substrate under a different Ir C−H borylation system, see the
following: Tajuddin, H.; Harrisson, P.; Bitterlich, B.; Collings, J. C.;
Sim, N.; Batsanov, A. S.; Cheung, M. S.; Kawamorita, S.; Maxwell, A.
C.; Shukla, L.; Morris, J.; Lin, Z.; Marder, T. B.; Steel, P. G. Iridium-
6921
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