CuCF3: A [18F]trifluoromethylating agent for arylboronic acids and aryl iodides

Article abstract of DOI:10.1002/chem.201403630

Positron emission tomography has emerged as the leading method for medical imaging with fluorine-18 as the most widely used radioactive isotope. Here we report a semi-automated method for the preparation of valuable [ ¹⁸F]trifluoromethylcopper, as well as its use for the radiosynthesis of [¹⁸F]trifluoromethylarenes and heteroarenes. Mild conditions of [¹⁸F]trifluoromethylation make this method particularly useful for the radiosynthesis of pharmacologically relevant [¹⁸F] trifluoromethylarenes and heteroarenes. ¹⁸F Radiochemistry: A semi-automated method for the fast preparation of radiolabelled (trifluoromethyl)copper is reported (see scheme), thus making [ ¹⁸F]CuCF₃ almost as accessible as [¹⁸F]fluoride itself for the preparation of radiolabelled trifluoromethylated probes. It can be used for the preparation of radiolabelled trifluoromethylarenes from arylboronic acids and aryliodides. This methodology is clean, efficient and consistent with the specific requirements of radiochemistry.

Full text of DOI:10.1002/chem.201403630

DOI: 10.1002/chem.201403630
Communication
&
Radiolabelling
[18F]CuCF3: A [18F]Trifluoromethylating Agent for Arylboronic
Acids and Aryl Iodides
Pavel Ivashkin,[a] Gꢀrald Lemonnier,[a] Jonathan Cousin,[a] Vincent Grꢀgoire,[b] Daniel Labar,*[b]
Philippe Jubault,*[a] and Xavier Pannecoucke[a]
severely underrepresented among the 18F-labelled PET probes.
Abstract: Positron emission tomography has emerged as
the leading method for medical imaging with fluorine-18
This is obviously due to the difficulty of assembling the radio-
labelled CF3 group through either nucleophilic or electrophilic
as the most widely used radioactive isotope. Here we
reactions involving fluorine-18. Until recently [18F]CF3-labelled
report a semi-automated method for the preparation of
18
compounds have been prepared through CÀ F bond forma-
valuable [18F]trifluoromethylcopper, as well as its use for
tion either by oxidative fluorination of dithioesters,[5] a halo-
the radiosynthesis of [18F]trifluoromethylarenes and het-
gen-exchange reaction from a suitable trihalomethylarene pre-
eroarenes. Mild conditions of [18F]trifluoromethylation
cursor,[6] or the decarboxylative electrophilic fluorination of di-
make this method particularly useful for the radiosynthesis
fluorinated aryl carboxylic acids.[7] However, harsh conditions
of pharmacologically relevant [18F]trifluoromethylarenes
are often required and the scope is mainly limited to electron-
and heteroarenes.
deficient substrates. A different approach based on the direct
formation of the CÀCF218F bond was proposed very recently by
the research groups of Gouverneur[8] and Riss[9] (Scheme 1).
Positron emission tomography (PET) is a powerful imaging
method widely used in clinic, notably for diagnostics in oncol-
ogy.[1] Among radioactive isotopes available for PET, fluorine-18
is the most commonly used.[2] Indeed, its half-life (t1/2 110 min)
offers a good compromise between high radioactivity and con-
venience of synthetic manipulations, while the low positron
energy associated with fluorine 18 decay leads to high imaging
resolution. Typically, the radioactive fluorine atom is introduced
into a probe as late as possible in order to minimize the dura-
tion of radiosynthesis, thus preserving the maximum amount
of initial activity. 18F-Labelled radiotracers are usually produced
through the nucleophilic substitution of a suitable leaving
group by [18F]fluoride.[2,3]
Scheme 1. Radiolabelled trifluoromethylarenes. DIPEA=N,N-diisopropyl-
ethylamine, TMEDA=N,N,N’,N’-tetramethylethylenediamine.
Trifluoromethylarenes are key moieties for the development
of bioactive compounds, especially in medicinal chemistry.[4]
A
general method for radiolabelling such moieties that complies
with the specific constraints inherent to radiochemistry, has
great potential for the efficient study of the pharmacological
properties of active trifluoromethylated compounds and, more
generally, for drug discovery. However, such compounds are
Aryl iodides were successfully converted into the correspond-
ing radiolabelled trifluoromethylarenes by using a difluorome-
thylated precursor and [18F]fluoride. The reaction is believed to
occur via the in situ formation of a radiolabelled trifluorometh-
ylating agent, presumably [18F]CuCF3. Although harsh condi-
tions are required (1508C), the subsequent reaction of
[18F]CuCF3 with aryl iodides demonstrated moderate to good
radiochemical yields and a wide substrate scope.
[a] Dr. P. Ivashkin, Dr. G. Lemonnier, J. Cousin, Prof. Dr. P. Jubault,
Prof. Dr. X. Pannecoucke
Normandie Univ., COBRA, UMR 6014 et FR 3038
Univ. Rouen; INSA Rouen; CNRS
In the present work, we report an efficient method for pre-
paring well-defined radiolabelled trifluoromethylcopper
([18F]CuCF3), allowing us to then [18F]trifluoromethylate arylbor-
onic acids and aryliodides under mild conditions. Key inter-
mediate [18F]CuCF3 was prepared as a ready-to-use solution in
DMF through a semi-automated procedure and the subse-
quent radiolabelling of arylboronic acids is characterized by
conditions that involve a quasineutral solution, room tempera-
ture, and air atmosphere.
1 rue Tesniꢀre, 76821 Mont Saint-Aignan Cedex (France)
E-mail: philippe.jubault@insa-rouen.fr
[b] Prof. Dr. V. Grꢁgoire, Dr. D. Labar
Centre for Molecular Imaging, Radiotherapy and Oncology (MIRO)
Institute of Experimental and Clinical Research (IREC)
Universitꢁ Catholique de Louvain
Av. Hippocrate, 54, 1200-Brussels (Belgium)
E-mail: daniel.labar@uclouvain.be
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403630.
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Communication
At the onset of our project, we were inspired by Grushin’s
pioneering work concerning the cupration of fluoroform and
the use of the resulting CuCF3 reagent in various trifluorome-
thylation reactions.[10] In addition to the high synthetic poten-
tial of the CuCF3 reagent, high rate of cupration and unusually
rapid trifluoromethylation of boronic acids, even at room tem-
perature, were observed, thus suggesting that this approach
could be well-adapted to the radiochemistry constraints.
Table 1. Optimization of [18F]CuCF3 preparation from 1.
Entry 18FÀ Source[a]
1
Cu/1
X
[Cu]
[molLÀ1
RCY transfer RCY
[%][b]
[mmol]
]
[%][c]
In that context, efficient generation of [18F]CHF3 under condi-
tions that are compatible with the cupration chemistry is of
primary importance. CHF3 is a usual byproduct in reactions in-
volving a difluorocarbene (CF2), for example, the industrial pro-
duction of polytetrafluoroethylene (PTFE), as well as a number
of difluoromethylation and cyclopropanation reactions.[11]
Therefore, we decided to generate [18F]CHF3 from [18F]fluoride
and a suitable source of CF2.[12] Among several CF2 precursors,
difluoromethylsulfonium salt 1[13] provided the best yield and
the highest purity of CHF3, when it was treated with tetra-n-
butylammonium fluoride (TBAF·3H2O) or KF/18-C-6 in acetoni-
trile under nonradioactive conditions.[14] Its structure was con-
firmed by X-ray analysis (Figure 1). Sulfonium salt 1·CH2Cl2 is an
easy-to-manipulate and bench-stable crystalline solid, which
are essential characteristics for a precursor that would have
widespread use for the preparation of PET radiotracers.
1
2
3
4
5
6
7
KF/K222
KF/K222
KF/K222
TBAF
TBAF
TBAF
17
50
50
13
79
50
50
1:3
1:5
1:3
Cl 0.06
Cl 0.25
62
47
61
29
40
10
10
33
36
36[e]
I
0.18
1:40 Cl 0.25
1:13 Cl 0.25
1:3
1:3
ND[d]
ND[d]
93
I
I
0.18
0.03
TBAF
94[e]
[a] TBAF and KF/K222 were released from the anion exchange cartridge
with TBAHCO3 and K2CO3/K222, respectively. [b] RCY of fluoride transfer
from the drying reactor onto 1. Calculated from activity remaining in
[18F]FÀ drying reactor. [c] Calculated from activity of [18F]CuCF3 solution
and initial activity eluted from the anion exchange cartridge. [d] No rele-
vant quantity of activity was detected in the drying reactor. [e] Average
of two experiments.
[18F]CuCF3 was obtained with 29% radiochemical yield (RCY;
Table 1, entry 1). Increasing the amount of reactants to 50
mmol of 1 and 5 equivalents of copper salt resulted in 40%
RCY (Table 1, entry 2). However, in our next trials to optimize
the stoichiometry of the reaction and the copper source, some
reproducibility issues emerged (Table 1, entry 3). In particular,
using [18F]KF/K222, we had difficulties in controlling the efficien-
cy of activity transfer (that is, 18FÀ anions) from the drying reac-
tor to the reactor containing precursor 1.[16]
In mmol-scale experiments with non-radioactive fluoride, we
confirmed that the whole sequence of reactions was feasible:
Table 2. Optimization of coupling reactions.[a]
Figure 1. Crystal structure of 1·CH2Cl2.
Entry
Substrate
n
CuX[b]
T [8C]
t [min]
RCY [%][c]
1
2a
2a
2a
2a
2a
2a
3a
3a
3a
2
2
0.14
1.4
1.4
2
1
3
1
CuCl
CuCl
CuCl
CuCl
CuCl
CuI
CuCl
CuCl
CuI
RT
RT
RT
RT
60
RT
100
100
100
27
23
38
16
16
25
25
50
15
40
120
25
75
78
22
22
CHF3 was instantaneously generated from 1[14] in CH3CN,
pulled out with a stream of N2, and trapped in a solution of
K[Cu(OtBu)2].[10a] The resulting CuCF3 solution could be immedi-
ately used for the trifluoromethylation of aryl iodides and aryl-
boronic acids.[15] Radiochemical synthesis of [18F]CuCF3 was suc-
2[d]
3
4
5
6
7
8
9
29
80[e]
30
cessfully realized by using
a
semi-automated module.[16]
24
63
79
79
78[e]
[18F]Fluoride anions previously dried according to the usual
procedure were solubilized in PhCN; the solution was then
transferred onto neat 1 and the resulting [18F]CHF3 formed was
pulled out using a flow of He and trapped in a solution of
K[Cu(OtBu)2] in DMF (prepared form either CuI or CuCl and
tBuOK) as [18F]CuCF3.
10
3a
2
CuI
100
[a] Performed by adding [18F]CuCF3 solution in DMF to the corresponding
substrate under air for 2a and under N2 for 3a. [b] Copper source used to
generate CuOtBu. [c] Calculated from activities of organic and aqueous
layers. Radiochemical purity confirmed by radio-HPLC analysis. [d] AgOTf
was used as an additive (1 equiv). [e] Average of two experiments.
At first, [18F]KF/K222 was used as the fluoride source. With 17
mmol of precursor
1
and 3 equivalents of K[Cu(OtBu)2],
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Consequently, we turned our attention to [18F]TBAF as the
fluoride source (Table 1, entries 4–7). The better solubility of
[18F]TBAF in PhCN ensured the efficient transfer of 18FÀ anions
from the drying reactor into precursor 1. Indeed, by using 13
mmol of 1 and 40 equivalents of CuCl, [18F]CuCF3 was produced
with only 10% RCY but no relevant remaining quantity of ac-
tivity was detected in the drying reactor (Table 1, entry 4). By
increasing the loading of 1, we were pleased to get [18F]CuCF3
with 33% RCY (Table 1, entry 5). The amount of precursor
1 was adjusted to 50 mmol along with 3 equivalents of copper
salt without loss in yield (Table 1, entry 6). Finally, the sequence
was reproduced under more dilute conditions to facilitate fur-
ther use of the [18F]CuCF3 solution (Table 1, entry 7). At the end
of [18F]CHF3 distillation, trimethylborate was added to the DMF
solution to neutralize the excess of tBuOK. Although the pres-
ent approach requires distillation of [18F]CHF3, it compares fa-
vorably to the recently reported
pling reaction of 2a and the corresponding trifluoromethylat-
ed product was obtained in 80% yield (Table 2, entry 6).
The same enhancing effect of the use of CuI on the coupling
reaction rate was observed for the trifluoromethylation of aryl
iodide 3a. Indeed, using CuCl as copper source along with
1 equivalent of 3a, the coupling reaction gave the desired
product with only 30% yield after 25 min at 1008C (Table 2,
entry 7). No improvement was observed when 3 equivalents of
3a were used (Table 2, entry 8). However, using CuI as
a copper source, the rate of the trifluoromethylation reaction
of 3a was notably increased. Indeed, with 1 equivalent of aryl
iodide, 63% of the coupling product was obtained after
15 min, reaching a maximum of 79% after 40 min (Table 2,
entry 9). Finally, the best compromise between rate and stoi-
chiometry was found with 2 equivalents of 3a and 25 min re-
action time (Table 2, entry 10).
one-pot procedures, because it
allows the fast and room-tem-
Table 3. Scope the [18F]trifluoromethylation.[a]
perature preparation (2 min) of
a neutral solution of [18F]CuCF3.
Having developed an efficient
and reproducible method for the
preparation of [18F]CuCF3, we
moved on to the coupling reac-
tion. In the case of boronic
acids, our preliminary studies
under nonradiochemical condi-
tions showed that the addition
of an AgI salt dramatically im-
proved the rate of the reac-
tion.[15] Surprisingly, under radio-
Entry
Substrate
Product
RCY
Radio-HPLC
[%][c]
[%][b]
1
2
2a
2b
4a
4b
80
82
99.8
100
3
2c
4c
88
100
chemical
conditions,
AgOTf
seemed to have no effect at all
(Table 2, entries 1 and 2). Indeed,
by using 2 equivalents of boron-
ic acid 2a (with respect to initial
copper loading), we observed
rapid formation of the desired
coupling product in the pres-
ence or absence of AgOTf (75%
versus 78%). Using a substoichio-
metric amount of 2a resulted in
poor yield (Table 2, entry 3); we
assumed that the excess of
copper salt used for the prepara-
tion of [18F]CuCF3 reacts with the
substrate. With 1.4 equivalent of
2a, only 22% of the desired
product was detected (Table 2,
entry 4). Raising the temperature
to 608C had no effect (Table 2,
entry 5). Finally, the replacement
of CuCl for CuI[17] for the genera-
tion of K[Cu(OtBu)2] had a very
positive effect on the rate and
the reproducibility of the cou-
4
5
2d
2e
4d
4e
86
86
99.9
99.9
6
7
2 f
4 f
87
78
100
100
2g
4g
8
2h
4h
85
100
9
3a
3b
4i
4j
78
18
100
10
98.9
[a] Reactions performed on 0.05 mmol scale of substrate (1:CuX=2:1). [b] Calculated from activities of organic
and aqueous layers after extraction with EtOAc:H2O. Average of two experiments. [c] Radiochemical purity de-
termined by radio-HPLC analysis of the crude organic phase.
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These optimized conditions were successfully applied to a va-
riety of arylboronic acids and aryl iodides (Table 3). Electron-
rich arene 2a gave the corresponding product in a very good
80% yield along with excellent radiochemical purity (99.8%;
Table 3, entry 1). We were pleased to observe that all other
boronic acids tested gave similar results regarding yields (78–
88%) and radiochemical purities (>99.8%). Phenylboronic acid
2b (Table 3, entry 2) and electron poor arenes 2c–e were suita-
ble substrates in this process (Table 3, entries 3–5). It is note-
worthy that ketone and ester functions are compatible with
this reaction, as well as benzothiophene and pyridine heterocy-
cles 2 f and 2g (Table 3, entries 6 and 7). Fluoxetine precursor
2h furnished valuable radiolabelled N-Boc-fluoxetine 4h with
a very good yield (85%).[18] Aryl iodide 3a bearing an electron-
withdrawing group was efficiently engaged in this process
leading to the expected trifluoromethylated compound in
78% yield and excellent radiochemical purity. Finally, this pro-
cess allowed us to prepare [18F]leflunomide 4j with 18% yield
and excellent radiochemical purity. We assume that this mod-
erate result, which was already observed under nonradiochem-
ical conditions, is due to the incompatibility between the
amide function and the harsher conditions (1008C) used to
convert aryl iodides.
fluoromethylarenes and heteroarenes, such as [18F]leflunomide
or [18F]fluoxetine precursor. We have developed a rapid (2 min)
and semi-automated preparation of [18F]CuCF3 from dried
[18F]TBAF and the precursor 1, thus making [18F]CuCF3 almost
as accessible as [18F]fluoride itself. The resulting [18F]CuCF3 is
suitable for the efficient and clean trifluoromethylation of both
arylboronic acids and aryl iodides. This two-step procedure
allows the coupling reaction to proceed at much lower tem-
perature and neutral conditions than methods previously de-
scribed and can therefore potentially be applied to larger
classes of substrates possessing various functions.
Acknowledgements
This work was supported by MESR (Ministꢂre de l’Enseigne-
ment Supꢀrieur et de la Recherche), CNRS, University of Rouen,
INSA of Rouen, Labex SYNORG (ANR-11-LABX-0029) and the
Rꢀgion Haute-Normandie through MATT Program (Dispositif de
Maturation Acadꢀmique et de Transfert de Technologie Haut-
Normand), CRUNCH program and SEINARI. This work was also
supported by ERDF funding through the IS:CE-Chem project
and Interreg IV A France -(Channel)- England Program and AI-
Chem Channel Program. We thank Dr. Frꢀdꢀric Dollꢀ (CEA,
chemistry and radiochemistry group) for initial fruitful
discussions.
The specific activity of the [18F]trifluoromethylarenes pre-
pared with our process (100 MBqmmolÀ1 for 4i) is of the same
level as that reported by Gouverneur et al.[9] by using in situ
generated [18F]CuCF3. This range of specific activity is adequate
for numerous applications in PET, but it is still 103 times lower
than the typical values obtained in SN2 [18F]fluorination reac-
tions of the nonfluorinated substrates. As illustrated on
Scheme 2, and based on control experiments,[15] we suppose
that the observed isotopic dilution originates from the partial
hydrolysis of CF2 by traces of water and the excess of carrier
base (such as TBAHCO3). That can in principle be improved
Keywords: arylboronic acid
·
copper
·
fluorine
·
radiochemistry · trifluoromethylation
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through development of
technique.
a
better [18F]fluoride drying
In conclusion, we report here the first method for preparing
well-defined [18F]CuCF3 as a radiolabelling agent and demon-
strate its utility through the preparation of radiolabelled tri-
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Scheme 2. Proposed origin of isotopic dilution.
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[9] T. Rꢃhl, W. Rafique, V. T. Lien, P. J. Riss, Chem. Commun. 2014, 50, 6056.
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[14] Compound 1 free of CH2Cl2 can be obtained as a white powder. See
the Supporting Information.
[15] See the Supporting Information for details.
[16] See the Supporting Information for detailed semi-automated process.
[17] The effect of X in CuX on the stability of CuCF3 was discussed in: A.
´
´
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we tested several combinations of sulfonium cations and counter
anions (see the Supporting Information), only 1 provided a bench-
stable crystalline solid.
[18] This compound can be easily deprotected to furnish [18F]fluoxetine; see
ref. [9].
Received: May 21, 2014
Published online on && &&, 0000
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COMMUNICATION
&
Radiolabelling
P. Ivashkin, G. Lemonnier, J. Cousin,
V. Grꢁgoire, D. Labar,* P. Jubault,*
X. Pannecoucke
&& – &&
18F Radiochemistry: A semi-automated
method for the fast preparation of ra-
diolabelled (trifluoromethyl)copper is re-
ported (see scheme), thus making
[18F]CuCF3 almost as accessible as
[18F]fluoride itself for the preparation of
radiolabelled trifluoromethylated
probes. It can be used for the prepara-
tion of radiolabelled trifluoromethyl-
arenes from arylboronic acids and aryl-
iodides. This methodology is clean, effi-
cient and consistent with the specific re-
quirements of radiochemistry.
[18F]CuCF3: A [18F]Trifluoromethylating
Agent for Arylboronic Acids and Aryl
Iodides
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