Synthesis of [18F]Arenes via the Copper-Mediated [18F]Fluorination of Boronic Acids

Article abstract of DOI:10.1021/acs.orglett.5b02875

A copper-mediated radiofluorination of aryl- and vinylboronic acids with K¹⁸F is described. This method exhibits high functional group tolerance and is effective for the radiofluorination of a range of electron-deficient, -neutral, and -rich aryl-, heteroaryl-, and vinylboronic acids. This method has been applied to the synthesis of [¹⁸F]FPEB, a PET radiotracer for quantifying metabotropic glutamate 5 receptors.

Full text of DOI:10.1021/acs.orglett.5b02875

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Letter
pubs.acs.org/OrgLett
Synthesis of [18F]Arenes via the Copper-Mediated [18F]Fluorination of
Boronic Acids
Andrew V. Mossine,† Allen F. Brooks,† Katarina J. Makaravage,‡ Jason M. Miller,§ Naoko Ichiishi,‡
Melanie S. Sanford,*,‡ and Peter J. H. Scott*,†,§
†Department of Radiology, University of Michigan Medical School, 1301 Catherine Street, Ann Arbor, Michigan 48109, United States
‡Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
§Department of Medicinal Chemistry, University of Michigan, 428 Church Street, Ann Arbor, Michigan 48109, United States
S
* Supporting Information
ABSTRACT: A copper-mediated radiofluorination of aryl- and vinylboronic
acids with K18F is described. This method exhibits high functional group
tolerance and is effective for the radiofluorination of a range of electron-
deficient, -neutral, and -rich aryl-, heteroaryl-, and vinylboronic acids. This
method has been applied to the synthesis of [18F]FPEB, a PET radiotracer for
quantifying metabotropic glutamate 5 receptors.
here are over 1.5 million positron emission tomography
(PET) scans performed annually in the US, in which
Scheme 1. Nucleophilic Fluorination of Aryl Boron Reagents
T
patients are injected with a PET tracer (a bioactive molecule
tagged with a positron-emitting radionuclide).1 The functional
information obtained from these studies can be used to diagnose
and stage disease as well as to predict and/or monitor response to
therapy.2,3 The most common PET radionuclide is 18F, due to its
convenient half-life (110 min), excellent imaging properties, and
ready availability of large amounts of no-carrier-added [18F]-
fluoride from small medical cyclotrons.4 The growing prevalence
of fluorine in pharmaceutical scaffolds5 also offers rich
opportunities for the simultaneous development of PET
radiotracers as companion diagnostics. However, despite these
benefits, the development of new 18F radiotracers is complicated
by the limited number of reactions available for the introduction
of 18F into bioactive molecules, particularly on electron-rich
aromatic rings.6
18F-labeled aromatics are most commonly prepared using
SNAr reactions.6 These reactions typically require high temper-
atures (often >150 °C) and are restricted to electron-deficient
substrates. Recent advances have expanded the scope of
nucleophilic aromatic radiofluorination using triarylsulfonium,7
diarylselenone,8 and iodonium ylide9 precursors. Complemen-
tary studies from our group10 and others11 have focused on the
transition-metal-mediated nucleophilic radiofluorination of
aromatic substrates. However, despite these advances, there are
still very few operationally simple nucleophilic radiofluorination
reactions that are effective for electron-rich aromatic substrates
and use stable, commercially available precursors.
In 2013, the Sanford group disclosed the Cu-mediated
fluorination of aryl trifluoroborates, arylboronate esters, and
arylboronic acids with KF (Scheme 1a),12 and we immediately
sought to translate this discovery to a radiofluorination of
arylboron compounds with K18F.13 Our initial studies focused on
conditions similar to those used for nonradioactive 19F
fluorination, and we found that both potassium trifluoroborate
salts and boronate esters undergo Cu-mediated radiofluorina-
tion. Preliminary optimization focused on arylpinacol ester 1-
BPin (a substrate of particular interest in connection with a
program developing radiotracers for glycogen synthase kinase-
3).14 These studies uncovered conditions for the radio-
fluorination of 1-BPin with K18F to afford 2 in ∼5% unoptimized
radiochemical conversion (RCC; % integrated area correspond-
ing to product versus 18F− in a radio-HPLC or -TLC trace)
(Scheme 1b and Scheme 2).
Concomitant with our initial studies, Gouverneur reported a
closely related radiofluorination of pinacol boronate esters and
demonstrated its application to the synthesis of a range of
[18F]arenes, including 2 in 66
6% radiochemical yield.11e
However, in our hands, exposing 1-BPin to Gouverneur’s
conditions provided 2 in just 31 13% RCC (n = 7, Scheme 2).
Received: October 4, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02875
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(aryl)iodonium salts with K18F10a were also not applicable to 1-
B(OH)2 (entry 3). A recent report by Neumaier has shown that
the use of large quantities of strongly basic K2CO3 to elute 18F−
from quaternary methylammonium (QMA) ion exchange
cartridges can be problematic for downstream copper-mediated
radiofluorination reactions.19 We therefore next evaluated 18F
elution with alternative salts.20
Scheme 2. Radiofluorination of 1-BPin To Form [18F]-4-
Fluoroacetophenone 2
We first examined elution with a solution of pyridinium p-
toluenesulfonate (PPTS), given the importance of pyridine in
these reactions. This led to recovery of 72% of the 18F− from the
QMA cartridge. The eluted 18F− was then azeotropically dried
and combined with Cu(OTf)2, 1-B(OH)2, and pyridine in DMF.
The reaction was heated at 110 °C for 20 min, after which time
radio-TLC and radio-HPLC confirmed the formation of 2 in 48
2% (n = 3) RCC (entry 4).
In addition to the modest yield and reproducibility, we noted
several other limitations of Gouverneur’s method. These include
(1) the requirement for an expensive copper salt [Cu-
(OTf)2(py)4],15 (2) incompatibility with more abundant
organoboron precursors such as boronic acids, and (3)
incompatibility with automation using a commercial radio-
chemistry synthesis module.16 The latter point is particularly
critical given that all modern radiopharmaceuticals in routine
clinical use are prepared according to current good manufactur-
ing practice (cGMP) via automated synthesis.
We report herein that these limitations have all been addressed
through the development of a copper-mediated radiofluorination
of boronic acids (Scheme 1c). These starting materials are
particularly practical given their ready availability17 and stability
(most boronic acids are white crystalline solids that can be
handled in air without special precautions and typically possess
long shelf lives).18 While the central theme of this paper is
demonstrating the first efficient nucleophilic fluorination of a
boronic acid (using 18F or 19F), the method also offers a general
approach for the radiofluorination of boronate esters.
Furthermore, we demonstrate the full automation of this
organoboron radiofluorination reaction using a commercial
radiochemistry synthesis platform.
While PPTS was effective for eluting 18F−, we noted significant
losses (50−60%) of radioactivity during azeotropic drying, which
is likely due to the formation of some volatile H18F under the
acidic conditions.21 Inspired by the work of Katsifis,21 Oh,22 and
Lemaire23 exploring alternate 18F− elution strategies, we next
examined the elution of 18F− with a weakly basic combination of
KOTf and K2CO3 (73/1 molar ratio). With this new eluent, 80%
of the 18F− was recovered from the QMA. After azeotropic drying
of K18F, PPTS and pyridine were added to the reaction mixture,
along with Cu(OTf)2 and 1-B(OH)2. This modification
eliminated loss of activity during the drying step and also
resulted in a slightly improved RCC of 51 5% (n = 3, entry 5).
We next optimized the reaction with respect to copper source.
These studies revealed that copper is essential for the reaction
(entry 6 and Table S1) and that CuI complexes do not promote
radiofluorination (Table S2). A screen of different solvents
showed that radiofluorination proceeds in DMF but not MeCN
(Tables S3 and S4). Finally, an evaluation of different pyridine
additives showed that pyridine is essential for reactivity (entry 7
and Table S1) and that many substituted pyridines afford yields
comparable to that of pyridine (Table S5). As such, pyridine was
utilized moving forward due to its low cost and ready
availability.24 Reagent concentrations and ratios were also
optimized, as well as reaction temperature (Tables S6−10),
leading to optimal conditions as follows: a 1:5:125 ratio of 1-
B(OH)2/Cu(OTf)2/pyridine at a 4 mM concentration of the
boronic acid in DMF at 110 °C for 20 min, providing 61 8%
RCC to 2 (n = 7; entry 8). Notably, the analogous reaction with
Cu(OTf)2(py)4 proceeded in 51 7% RCC (n = 3, entry 9),
confirming that the readily available and inexpensive combina-
tion of Cu(OTf)2 and pyridine promotes this reaction as
effectively as the more costly Cu(OTf)2(py)4. The process was
fully automated in one pot (entry 10), resulting in high specific
activity 2 (∼2000 Ci/mmol), albeit in lower RCC of 10 2% (n
= 2).
The radiofluorination of boronic acid 1-B(OH)2 was first
examined under the conditions developed for the corresponding
pinacol boronate ester 1-BPin. However, none of 2 was detected
under either our or Gouverneur’s conditions (Table 1, entries 1
and 2, respectively). Similarly, the conditions that we recently
reported for the Cu-catalyzed radiofluorination of (mesityl)
Table 1. Optimization of Radiofluorination of 1-B(OH)2 To
Form [18F]-4-Fluoroacetophenone 2
a
b
entry
QMA eluent
[Cu]
Cu(OTf)2
RCC (%)
1
K2CO3
0
0
0
2
K2CO3
Cu(OTf)2(py)4
(MeCN)4CuOTf
Cu(OTf)2
c
3
K2CO3
4
PPTS
48
51
2
Notably, we do observe competing formation of the
protodeboronated byproduct in HPLC traces of the crude
reaction mixtures. This byproduct is also formed in the
radiofluorination of Bpin precursors. In general, 10−20% of
the aryl boron precursor is converted to the protodeboronated
byproduct. However, in all of the reported examples, the
fluorinated products were readily separable from both the
precursor and the protodeboronated byproduct by HPLC.
We next tested the compatibility of this radiofluorination
method with water and strong bases. The reaction showed water
tolerance, with water/boronic acid ratios of 16:1 resulting in only
minor decreases in RCC (Table S11). Despite being tolerant of
pyridine, the reaction was highly sensitive to stronger bases. For
d
5
KOTf/K2CO3
KOTf/K2CO3
KOTf/K2CO3
KOTf/K2CO3
KOTf/K2CO3
KOTf/K2CO3
Cu(OTf)2
5
6
none
<1
<4
8
e
7
Cu(OTf)2
8
9
Cu(OTf)2
61
51
10
Cu(OTf)2(py)4
Cu(OTf)2
7
f
10
2
a
Conditions: 1:5:125 1-B(OH)2/Cu(OTf)2/py at 4 mM concen-
tration of the boronic acid precursor in DMF, K18F, 110 °C, 20 min.
b
c
RCC was determined by radio-TLC (n ≥ 2). Other Cu sources were
d
tested as well. See the SI. Best conditions 1:5:125:0.1 1-B(OH)2/
Cu(OTf)2/py/PPTS. Pyridine omitted. Reaction automated using a
e
f
GE TRACERLab FXFN
.
B
DOI: 10.1021/acs.orglett.5b02875
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Synthesis of [18F]FPEB
example, rapid declines in RCC were observed upon the addition
of even small amounts of K2CO3 or Hunig’s base (Table S12).
The optimized radiofluorination conditions were applied to a
series of different boronic acid substrates. As summarized in
Figure 1, this method is compatible with a range of functional
[18F]FPEB (20) in 8
2% (manual, n = 4) and 4
1%
(automated, n = 2) RCC, with specific activity of 750 Ci/mmol.
These yields are within the range of that obtained in previously
reported syntheses of [18F]FPEB (1−20%).28,29
In conclusion, this paper reports a mild and general Cu-
mediated method for the radiofluorination of organoboron
compounds with K18F. This method represents the first high-
yielding nucleophilic fluorination of boronic acids (using 18F or
19F), is compatible with aryl, heteroaryl, and vinyl boronic acids,
and thus fills an important gap in the late-stage fluorination space.
The method is also suitable for the radiofluorination of boronate
esters and potassium trifluoroborates. Finally, this process can be
automated on a commercial radiochemistry synthesis module
and applied to clinically relevant radiotracers, such as [18F]FPEB.
Validation of the method for cGMP clinical production of
[18F]FPEB and other PET tracers is currently under inves-
tigation.
Figure 1. Substrate scope. Conditions: 1:5:125 boronic acid:-
CuOTf2:pyridine at 4 mM concentration of the boronic acid precursor
in DMF, K18F, 110 °C, 20 min.
ASSOCIATED CONTENT
* Supporting Information
■
S
groups. The reaction proceeds in moderate to high RCC with
arylboronic acids bearing electron-withdrawing (2−8), electron-
neutral (9−12), and electron-donating (13−16) substituents.
Electron-rich 1-[18F]fluoro-3,4,5-trimethoxybenzene (16) was
formed in 36 11% RCC (n = 6), significantly higher than that
obtained in the corresponding copper-mediated (mesityl)
(aryl)iodonium chemistry (14 1%, n = 5).10a Meta (4, 14,
and 16) and ortho substituents (5 and 11) were tolerated,
although the latter resulted in lower RCC, likely due to slower
transmetalation of the more sterically hindered aryl boronic
acids.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02875.
Experimental procedures, optimization details, radio-
HPLC/TLC traces, and spectral data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: mssanfor@umich.edu.
*E-mail: pjhscott@umich.edu.
This method is also compatible with heteroaromatic (17) and
vinyl (18) boronic acids. While the yield of [18F]5-fluoroindole
(17) was lower than that for many of the other substrates (18
11%; n = 5), this substrate is of significant interest given the
importance of fluoroindoles as, for example, RNA analogs25 and
cannabinoid CB2 receptor ligands.26 Moreover, the formation of
[18F]5-fluoroindole (17), in addition to [18F]4-fluorophenol
(13), demonstrate that this radiofluorination reaction proceeds
without the need for protection of protic functional groups.
The radiofluorination of pinacol boronate esters and
potassium trifluoroborates was also revisited using these
optimized conditions. Using boronate esters, fluorinated
products were formed in comparable yields to the boronic acid
reactions (Table S13). For example, the radiofluorination of 1-
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the NIH (GM073836 (M.S.S.) and T32-
EB005172 (P.J.H.S.)), the US DOE (DE-SC0012484
(P.J.H.S.)), the Alzheimer’s Association (NIRP-14-305669
(P.J.H.S.)), and Merck (M.S.S. and P.J.H.S.) for financial
support.
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(20) Neumaier’s modified elution conditions (i.e., elution with 60 μg of
K2CO3) were not practical in our system, since this small quantity of
D
DOI: 10.1021/acs.orglett.5b02875
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