A universal procedure for the [18F]trifluoromethylation of aryl iodides and aryl boronic acids with highly improved specific activity

Article abstract of DOI:10.1002/anie.201406221

Herein we describe a valuable method for the introduction of the [¹⁸F]CF₃ group into arenes with highly improved specific activity by the reaction of [¹⁸F]trifluoromethane with aryl iodides or aryl boronic acids. This [

Full text of DOI:10.1002/anie.201406221

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Communications
DOI: 10.1002/anie.201406221
Isotopic Labeling
A Universal Procedure for the [18F]Trifluoromethylation of Aryl
Iodides and Aryl Boronic Acids with Highly Improved Specific Activity
Dion van der Born, Claudia Sewing, J. (Koos) D. M. Herscheid, Albert D. Windhorst,
Romano V. A. Orru, and Danielle J. Vugts*
Abstract: Herein, we describe a valuable method for the
introduction of the [18F]CF3 group into arenes with highly
improved specific activity by the reaction of [18F]trifluoro-
methane with aryl iodides or aryl boronic acids. This [18F]tri-
fluoromethylation reaction is the first to be described in which
the [18F]CF3 products are generated in actual trace amounts
and can therefore effectively be used as PET tracers. The
method shows broad scope with respect to possible aryl iodide
and aryl boronic acid substrates, as well as good to excellent
conversion. In particular, the [18F]trifluoromethylation of
boronic acids was found to outperform [18F]trifluoro-
methylation reactions of halogenated aryl precursors with
regard to conversion, reaction conditions, and kinetics.
subsequent purification, formulation, and quality control of
the 18F-labeled PETradiopharmaceutical has to be completed
within 2 h. Consequently, there is an increasing demand for
new robust, reliable, and rapid radiochemical synthetic
methodology for the late-stage introduction of fluorine-18
into radiopharmaceuticals. Of particular interest are methods
that utilize [18F]fluoride, as this reagent is obtained by the
18O(p,n)18F nuclear reaction in high yields and is commer-
cially available.[4]
The CF3 group is a popular functional group in many
active pharmaceutical ingredients (APIs) and/or drug candi-
dates, because it improves binding selectivity, lipophilicity,
and metabolic stability.[5] Efficient methodology to introduce
18F-labeled CF3 groups into such compounds makes them
useful as potential PET tracers. Today, only a few methods are
available for the radiolabeling of trifluoromethyl arenes with
[18F]fluoride (Scheme 1). These methods can be divided into
Positron emission tomography (PET) is a noninvasive
molecular-imaging technique for the visualization of human
physiology by the use of biomarkers labeled with a positron-
emitting radionuclide.[1] As only trace amounts of a radiola-
beled biomarker are required for the emission of enough
positrons for a PET scan, PET is a very valuable technique for
the imaging of low-density biological targets without inducing
any biological effects. Therefore, PET has proven to be an
excellent diagnostic tool in all areas of medicine and is
frequently used to detect, characterize, and monitor cancer as
well as neurodegenerative and cardiovascular diseases; it can
even lead to diagnosis well before structural changes or
symptoms occur.[2] Furthermore, PET imaging is of added
value in drug-discovery and drug-development programs.[3]
Among the various positron-emitting isotopes available,
fluorine-18 is most commonly used. Fluorine-18 has a rela-
tively low positron energy (Emax = 634 keV) and is readily
produced with a low-energy cyclotron. This characteristic, in
combination with a half-life of 110 min, makes fluorine-18
perfectly suited for introduction in small-molecule PET
radiopharmaceuticals. Still, short synthesis times are required,
and for optimal utilization, the introduction of fluorine-18 and
Scheme 1. Reported methods for the synthesis of [18F]trifluoromethyl
arenes.
two categories: the direct treatment of [18F]fluoride with
a precursor of the type ArCF2X,[6] and the introduction of
a [18F]CF3 group by the treatment of an aryl iodide with
[18F]CuCF3 formed in situ.[7,8] Both approaches require harsh
reaction conditions and long reaction times. Furthermore, the
labeled products are not suitable as PET tracers. Owing to
degradation of the RCF2X (ArCF2X, HCF2I, COOMeCF2I)
precursors, not only radioactive 18F, but also mass amounts of
19F are incorporated into the products. In radiochemistry, the
ratio of 18F over the total mass of the product is expressed as
the specific activity (SA) in GBqmmolÀ1. The reported
specific activities of 100–139 MBqmmolÀ1 for methods based
on the use of [18F]CuCF3 make these products unsuitable for
the imaging of low-density biological targets.[9]
[*] D. van der Born, C. Sewing, Dr. J. D. M. Herscheid,
Prof. Dr. A. D. Windhorst, Dr. D. J. Vugts
Department of Radiology and Nuclear Medicine
VU University Medical Center
De Boelelaan 1085c, 1081 HV Amsterdam (The Netherlands)
E-mail: d.vugts@vumc.nl
Prof. Dr. R. V. A. Orru
Department of Chemistry and Pharmaceutical Sciences and
Amsterdam Institute for Molecules, Medicines and Systems
(AIMMS), VU University Amsterdam
De Boelelaan 1083, 1081 HV, Amsterdam (The Netherlands)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201406221.
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Recently, we reported the synthesis of [18F]HCF3 and its
application as
labeling agent for the [18F]trifluoro-
stabilization with Et3N·3HF was completed in just 2 min at
room temperature.
a
methylation of aldehydes and ketones.[10] To further extend
the application of [18F]HCF3, we focused on broadening the
scope of the reaction by exploring the labeling of aryl iodides
and aryl boronic acids. To make the products useful for PET
imaging, we also investigated the synthesis of [18F]HCF3 with
an improved SA. We suspect that all [18F]trifluoromethylation
products derived from [18F]HCF3 with an improved SA will
also be obtained with an improved SA. Herein we report the
broad applicability of [18F]HCF3 as a labeling agent with
improved SA for the aromatic [18F]trifluoromethylation of
aryl iodides and aryl boronic acids (Scheme 2).
Optimal [18F]trifluoromethylation of iodobenzene pro-
ceeded at 1308C in DMF in 10 min in the presence of CuIBr,
KOtBu, and Et3N·3HF in a molar ratio of 1:3:1 and with
a total CuIBr concentration of 10 mm. Various other CuI
sources can also be used (Table 1, entries 1–3). Of the various
bases, however, only KOtBu led to good conversion (Table 1,
entries 4 and 5), when used in 3 molar excess relative to the
amount of CuIBr. For the stabilization of the formed
[18F]CuCF3, all K+ ions had to react with Et3N·3HF; thus,
relative to KOtBu, 1 equivalent of HF, which corresponds to
0.33 equivalents of Et3N·3HF, had to be present in the
reaction mixture. A decrease in the amount of Et3N·3HF
led to a drastic reduction in conversion into the product
(Table 1, entry 6). We also found that the total concentration
of the CuIBr, KOtBu, and HF reagents is quite important.
Higher concentrations of these reagents led to lower con-
version (Table 1, entry 8).
Having optimized the reaction conditions for the
[18F]trifluoromethylation of aryl iodides, we turned our
attention to the scope of this reaction (Scheme 3). A broad
range of aryl iodides could be converted successfully into the
desired [18F]trifluoromethyl arenes. From Scheme 3, it
becomes clear that electronic effects do not have a large
impact, and a wide array of functional groups in the precursor
structure are compatible with the reaction. Even more
interesting is that both 4-iodobenzaldehyde and 4-iodoaceto-
phenone are exclusively converted into the [18F]ArCF3
products 10 and 11, with no [18F]trifluorocarbinol formation
observed. Trifluorocarbinols are known to be formed by the
reaction of the trifluoromethyl anion with aldehydes and
ketones.[10,13] However, as we did not observe any
[18F]trifluorocarbinol side products, we can conclude that no
sources of the [18F]CF3 anion were present in the reaction
mixture. Unprotected alcohols and carboxylic acids were
found to be incompatible with our method. The use of
unprotected aniline, however, did lead to product formation
with good conversion.
Scheme 2. Our strategy for [18F]trifluoromethylation by the use of
[18F]HCF3 with highly improved specific activity as a versatile labeling
agent.
First, we focused on the [18F]trifluoromethylation of aryl
iodides by using iodobenzene as a model substrate. Initial
experiments with various strong bases and CuI sources did not
lead to satisfactory yields of the desired [18F](trifluoro-
methyl)benzene, and decomposition of [18F]CuCF3 to
[18F]fluoride was observed.[11] However, the addition of
Et3N·3HF to the solution was found to stabilize the CuCF3
species owing to precipitation of the K+ cation as KF(s), as
was reported by Zanardi et al.[12] With this approach, we
obtained [18F]trifluoromethylbenzene in satisfactory yields
(Table 1). The formation of [18F]CuCF3 and subsequent
Table 1: Optimization of the [18F]trifluoromethylation of iodobenzene.[a]
To further extend the application of [18F]HCF3 as a label-
ing agent, we investigated the oxidative [18F]trifluoro-
methylation of boronic acids (Table 2).[14] The required
[18F]CuICF3 reagent was prepared as described for the [18F]tri-
fluoromethylation of aryl iodides. Next, [18F]CuICF3 was
oxidized to [18F]CuIICF3 in the presence of the boronic acid
precursor by purging the reaction mixture with air during the
first minute of the reaction. Oxidation with air is required, as
only a low conversion was found when the reaction mixture
was not purged with air (Table 2, entry 1). The preparation of
[18F]trifluoromethyl arenes by using boronic acid substrates
led to some major improvements over the [18F]trifluoro-
methylation of aryl iodides, thus making this method more
appropriate for the synthesis of PET radiopharmaceuticals.
Significant advantages over the [18F]trifluoromethylation
of aryl iodides are the reduction in the amount of the
precursor required from 100 to 50 mmol (Table 2, entries 3–6),
the completion of the synthesis in just 1 min instead of 10 min
(Table 2, entries 7 and 8), and a reaction temperature of 208C
instead of 1308C. All in all, these conditions result in less
Entry
Base
CuI
source
CuI
[mm]
Ratio[b]
t
Conversion
[%] (n=3)
[min]
1
2
3
4
5
6
7
8
9
KOtBu
KOtBu
KOtBu
NaOtBu
KHMDS
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
CuICl
CuIBr
CuII
20
20
20
20
20
20
20
40
10
10
1:3:1
1:3:1
1:3:1
1:3:1
1:3:1
1:3:0.5
1:3:1.5
1:3:1
1:3:1
1:3:1
10
10
10
10
10
10
10
10
10
5
48Æ3
56Æ3
57Æ3
3Æ3
CuIBr
CuIBr
CuIBr
CuIBr
CuIBr
CuIBr
CuIBr
12Æ5
4Æ2
46Æ3
34Æ2
61Æ2
32Æ5
10
[a] Standard reaction conditions: [18F]CuCF3 formation at 208C for
1 min; Et3N·3HF stabilization at 208C for 5 min; [18F]trifluoromethylation
at 1308C; DMF (0.5 mL). [b] CuIX/base/Et3N·3HF ratio. DMF=N,N-
dimethylformamide, HMDS=hexamethyldisilazide.
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led to the [18F]ArCF3 products
10 and 11. From the boronic
acid precursor, even the unpro-
tected [18F]trifluoromethylated
phenol 12 could be formed;
thus, acetyl protection of
phenol groups is not required.
The reaction to form aniline 14
could unfortunately not be
investigated owing to the
unsuccessful synthesis of the
boronic acid precursor; how-
ever, the N-Boc-protected ani-
line 17 and phenylamide 18
were formed with excellent
conversion. Carboxylic acid 13
could not be formed: Protec-
tion of the acid group was
required. The low conversion
in the formation of iodide 9
was attributed to the poor
solubility of 4-iodophenyl-
boronic acid in DMF.
To prove the applicability
of this method for the synthesis
of PET radiopharmaceuticals,
Scheme 3. Scope of the [18F]trifluoromethylation of aryl iodides and aryl boronic acids. Standard reaction
conditions: [18F]CuCF3 formation: 1) CuIBr (5 mmol), KOtBu (15 mmol), DMF, 208C, 1 min; 2) Et3N·3HF
(5 mmol), 208C, 1 min; method A: aryl iodide (100 mmol), 1308C, 10 min; method B: aryl boronic acid
(50 mmol), air (10 mL), 208C, 10 min. Boc=tert-butoxycarbonyl.
we
synthesized
the
[18F]trifluoromethyl-substi-
tuted estrone derivative 22 as
well as the Boc- and OMe-
protected [18F]4-trifluorome-
Table 2: Optimization of the [18F]trifluoromethylation of phenylboronic
thylphenylalanine 25 (Scheme 4). Both products are radio-
pharmaceuticals of interest for PET. Estrone has a high
binding affinity for the estrogen receptor, and this
[18F]trifluoromethylestrone derivative is therefore a poten-
tially useful tracer for the imaging of overexpression of the
estrogen receptor in breast cancer. This type of cancer relies
on estrogen hormones for growth. If overexpression is found
by the use of PET, a hormone-suppression treatment could be
started.[15] Radiolabeled amino acids, including [18F]4-fluoro-
phenylalanine, have found their application in the imaging of
upregulated amino acid incorporation by various types of
cancer cells. Methods for the synthesis of [18F]fluoro-substi-
tuted phenylalanine, however, are impractical, as they require
multistep synthetic routes and/or electrophilic labeling meth-
ods. For both estrone and phenylalanine, direct installment of
the fluorine-18 isotope at the aromatic ring by nucleophilic
substitution with [18F]fluoride is not possible owing to the high
electron density of the aromatic systems. However, as
[18F]trifluoromethylation is barely affected by electronic
effects, we reasoned that it should be possible to install the
[18F]CF3 group at the aromatic ring in these compounds. As
anticipated, both the [18F]trifluoromethylation of aryl iodides
20 and 23 and the oxidative [18F]trifluoromethylation of
boronic acids 21 and 24 led to the desired products. In
particular when the boronic acids were used as the starting
material, we observed excellent conversion in just 1 min at
208C.
acid.[a]
Entry
Phenylboronic acid
Air
t
Conversion
[mmol]
[mL]
[min]
[%] (n=3)
1
2
3
4
5
6
7
8
100
100
100
50
20
10
0
0.5
5
5
5
5
5
10
10
10
10
10
10
10
1
19Æ22
62Æ19
87Æ8
94Æ1
55Æ17
4Æ5
50
50
85Æ10
94Æ1
1
[a] Standard reaction conditions: CuIBr (5 mmol), KOtBu (15 mmol),
Et3N·3HF (5 mmol), DMF (0.5 mL); [18F]CuCF3 formation at 208C for
1 min; Et3N·3HF stabilization at 208C for 1 min;
[18F]trifluoromethylation at 208C.
degradation of the precursor. In general, improved generality
of the reaction and higher conversion were observed when
boronic acids were used instead of aryl iodide precursors
(Scheme 3). Again, electronic effects did not have a large
impact on conversion into the product, and the reaction of
boronic acids with an aldehyde or ketone functionality only
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caused by unfavorable reaction kinetics due to the lower
amounts of HCF3 present in the reaction mixture; however,
more evidence is required to support this finding.
In summary, [18F]HCF3 was found to be an excellent
labeling agent for the [18F]trifluoromethylation of aryl iodides
and aryl boronic acids with strongly improved specific
activities under mild reaction conditions. As the CF3 group
is a common moiety in drug candidates and active pharma-
ceutical ingredient, we expect that this methodology will be
widely applied in the synthesis of fluorine-18-labeled PET
tracers.
Received: June 13, 2014
Published online: August 26, 2014
Keywords: fluorine-18 · isotopic labeling · radiochemistry ·
.
specific activity · trifluoromethylation
Scheme 4. Synthesis of the [18F]trifluoromethyl-substituted estrone
derivative 22 and Boc/OMe-protected [18F]4-trifluoromethylphenyl-
alanine 25.
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Next, we investigated the specific activity (SA) of the
products obtained by the method described herein. The initial
measured SA of [18F]1-trifluoromethyl-4-nitrobenzene,
obtained by the [18F]trifluoromethylation of 1-iodo-4-nitro-
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same (see the Supporting Information for details). Since in
the reaction of benzophenone with [18F]HCF3 no addition of
Et3N·3HF is required, we thus proved indirectly that no 19F/
18F isotopic exchange occurs during the reaction of
[18F]HCF3 with 1-iodo-4-nitrobenzene and 4-nitrophenylbor-
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compounds with improved SA. From all combined experi-
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