A broadly applicable [ 18 F]trifluoromethylation of aryl and heteroaryl iodides for PET imaging

Article abstract of DOI:10.1038/nchem.1756

Molecules labelled with the unnatural isotope fluorine-18 are used for positron emission tomography. Currently, this molecular imaging technology is not exploited at its full potential because many 18 F-labelled probes are inaccessible or notoriously difficult to produce. Typical challenges associated with 18 F radiochemistry are the short half-life of 18 F (<2 h), the use of sub-stoichiometric amounts of 18 F, relative to the precursor and other reagents, as well as the limited availability of parent 18 F sources of suitable reactivity ([ 18 F]F - and [ 18 F]F 2). There is a high-priority demand for general methods allowing access to [ 18 F]CF 3 -substituted molecules for application in pharmaceutical discovery programmes. We report the development of a process for the late-stage [ 18 F]trifluoromethylation of (hetero)arenes from [ 18 F]fluoride using commercially available reagents and (hetero)aryl iodides. This [ 18 F]CuCF 3 -based protocol benefits from a large substrate scope and is characterized by its operational simplicity.

Full text of DOI:10.1038/nchem.1756

ARTICLES
PUBLISHED ONLINE: 8 SEPTEMBER 2013 | DOI: 10.1038/NCHEM.1756
A broadly applicable [18F]trifluoromethylation of
aryl and heteroaryl iodides for PET imaging
Mickael Huiban1, Matthew Tredwell2, Satoshi Mizuta2, Zehong Wan3, Xiaomin Zhang3,
4
2
Thomas Lee Collier , Veronique Gouverneur and Jan Passchier1
´
*
*
Molecules labelled with the unnatural isotope fluorine-18 are used for positron emission tomography. Currently, this
molecular imaging technology is not exploited at its full potential because many 18F-labelled probes are inaccessible or
notoriously difficult to produce. Typical challenges associated with 18F radiochemistry are the short half-life of 18F (<2 h),
the use of sub-stoichiometric amounts of 18F, relative to the precursor and other reagents, as well as the limited
availability of parent 18F sources of suitable reactivity ([18F]F– and [18F]F2). There is a high-priority demand for general
methods allowing access to [18F]CF3-substituted molecules for application in pharmaceutical discovery programmes. We
report the development of a process for the late-stage [18F]trifluoromethylation of (hetero)arenes from [18F]fluoride using
commercially available reagents and (hetero)aryl iodides. This [18F]CuCF3–based protocol benefits from a large substrate
scope and is characterized by its operational simplicity.
I
a
b
CF3
Transition metal
catalysis
ositron emission tomography (PET) is a non-invasive quantitat-
ive imaging technology that can detect pre-symptomatic bio-
chemical changes in body tissues where no evidence of
R
R
R
X
X
CF3 source
P
abnormality is available using computed tomography (CT) or mag-
netic resonance imaging (MRI), or before structural changes occur
from disease1,2. This technology helps researchers in understanding
diseases and can assist clinicians in the selection of the best treatment
for an individual patient, provided that competent biomarkers are
available. The unrivalled sensitivity of PET also makes this technique
suitable for addressing questions fundamental to drug development
for oncology, cardiology, neurosciences and inflammatory diseases3,4.
For these studies, 18F is one of the most commonly used positron-
emitting radioisotopes5,6, in part due to the extensive use of
2-deoxy-2-[18F]fluoroglucose ([18F]FDG) in the clinicand the impor-
tance of fluorine substitution in the context of drug discovery7,8.
Despite the success of PET and the consequent upsurge of inter-
est in [18F]radiochemistry9–11, no general method is available to
radiolabel trifluoromethyl arenes and heteroarenes12–15. Today,
there is a pressing need for such methodology as these compounds
are notoriously important pharmacophores present in a large
number of prescribed drugs, so their potential for PET imaging as
F
F
F
F
18F
Halex exchange
X
18F]F– source
R
[
X = F, Cl, Br
F
F
c
F
F
F
Fluorodecarboxylation
18F
CO2H
[
18F]F+ source
R
R
R
F
d
e
ClCF2CO2Me
18F]F– source
Cu(I), Ligand
I
[
18F
R
X
X
Cu(I)
TMEDA
Cu(I)I
[
18F]FCF2Cu
ClCF2CO2Me
CF2
–MeI, –CO2
[
18F]F–
Ar-I
[
18F]FCF2Cu
[
18F]FCF2-Ar + Cu(I)I
a tool to facilitate drug discovery is unquestionable. Here we Figure 1 | Direct trifluoromethylation of aryl and heteroaryl iodides.
report a new strategy for the direct [18F]trifluoromethylation of a, Modern methodology to prepare non-labelled trifluoromethylated
aryl and heteroaryl iodides using methyl chlorodifluoroacetate and (hetero)arenes using transition metal-catalysed cross-coupling chemistry and
[18F]fluoride through a copper-mediated cross-coupling reaction. commercially available pre-made CF3 reagents. b, Halex exchange with
We demonstrate the broad utility of this multicomponent trans- [18F]fluoride is a known protocol to access [18F]CF3 arenes; this strategy is
formation with the [18F]labelling of functionalized trifluoromethyl severely limited in scope and uses starting materials that require multistep
arenes and heteroarenes including pharmaceutical agents.
synthesis. c, This [18F]fluorodecarboxylation process uses the electrophilic
This radiochemistry based on in situ generated [18F]CuCF3 is reagent [18F]Selectfluor, which is prepared from [18F]F2. d, Our strategy offers
operationally simple and uses [18F]fluoride and commercially avail- a direct route to [18F]CF3 (hetero)arenes from [18F]fluoride and (hetero)aryl
able reagents. This advance enlarges considerably the range of [18F] iodides. The broad scope of this reaction and its logistical simplicity allows
molecules available for PET studies and can accelerate both drug access to [18F]CF3 (hetero)arenes not within reach using known
discovery and development. The short half-life of 18F (110 min) dic- methodologies. e, The multicomponent assembling of [18F]fluoride, methyl
tates a preference for protocols based on late-stage fluorination. chlorodifluoroacetate and CuI towards [18F]CuCF3 is the breakthrough
Classically, the CF3 motif is installed on arenes and heteroarenes advance paving the road to [18F]CF3-based cross-coupling radiochemistry.
1Imanova, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK, 2Chemistry Research
Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK, 3GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai
201203, China, 4Advion BioSystems, 10 Brown Road, Suite 101, Ithaca, New York 14850, USA. e-mail: jan.passchier@imanova.co.uk;
*
veronique.gouverneur@chem.ox.ac.uk
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1756
ARTICLES
a
ClCF2CO2Me (1.5 equiv.)
CuI (1.5 equiv.)
TMEDA (1.5 equiv.)
CF218F
I
CF218F
Het
or
I
or
Het
[
18F]KF/kryptofix
DMF, 150 ºC, 20 min
[
18F]CF3 arenes
[
18F]CF3 heteroarenes
Aryl iodide
Heteroaryl iodide
O
O
H
O
O
18FF2C
O
NO2
CO2H
18FF2C
OEt
OEt
OEt
18FF2C
18FF2C
63% 5% (n = 3)
Br
18FF2C
46% 3% (n = 3)
OPiv
18FF2C
18FF2C
0% (n = 3)
1
2
3
4
5
6
7
87% 3% (n = 3)
59% 9% (n = 3)
80% 2% (n = 3)
48% 4% (n = 3)
CN
Ph
OAc
OH
OBn
18FF2C
18FF2C
18FF2C
18FF2C
18FF2C
18FF2C
18FF2C
8
9
10
41% 13% (n = 3)
11
12
13
5% 4% (n = 3)
14
55% 11% (n = 3)
71% 4% (n = 3)
49% 4% (n = 3)
11% 2% (n = 3)
39% 9% (n = 3)
O
HN
H
N
CF218F
NHBoc
CONH2
MeO
MeO
NH2
O
18FF2C
18FF2C
18FF2C
18FF2C
18FF2C
15
16
17
0% (n = 3)
18
19
20
55% 3% (n = 3)
11% 7% (n = 3)
44% 8% (n = 3)
41% 18% (n = 3)
45% 9% (n = 3)
O
c
b
O
O
N
H
CF218F
O
Me
Me
BocHN
OMe
BOM
O
CF218F
O
N
CF218F
N
N
CF218F
N
O
Me
Me
H
O
O
O
N
24
Cl
N
O
18FF2C
BOM
25
26
23
48% 5% (n = 3)
64% 12% (n = 3)
67% 8% (n = 3)
21
36% 2% (n = 3)
BOM (benzyloxyl-
methyl acetal)
45% 7% (n = 3)
22
CF218F
18FF2C
50% 8% (n = 3)
N
S
Me
CF218F
18FF2C
Me
Cl
N
S
NHCOtBu
CF218F
NHCOtBu
d
27
28
29
38% 10% (n = 3)
40% 12% (n = 3)
17% 5% (n = 3)
via direct C–H
functionalization from
N
N
Me
30
19% 2% (n = 3)
Me
31
Figure 2 | Cu(I)-mediated [18F]trifluoromethylation of arenes, heteroarenes and pyrimidine-2,4(1H,3H)-dione with [18F]fluoride. a, Arenes bearing a variety
of functional groups are efficiently labelled with [18F]CF3. b, Substrate scope includes a dipeptide, carbohydrate and a uracil derivative. c, A variety of
heteroarenes are within reach using this new radiochemistry. d, Direct C–H functionalization of an indole derivative. The RCYs are indicated below
each product.
by means of cross-coupling technologies catalysed by transition [18F]trifluoromethylation would, in a single operation, build the
metals (Fig. 1a)16–18. These reactions, which employ either a nucleo- (hetero)aryl–CF218F linkage directly from (hetero)aryl iodide precur-
philic or electrophilic source of CF3, have not been considered for sors through consecutive (hetero)aryl–CF2–18F two bond construc-
radiochemistry as [18F]labelling of the CF3 sources is required tion using [18F]fluoride and a reagent acting as a difluorocarbene
before the cross-coupling event. To date, access to [18F]CF3 arenes source (Fig. 1d). Specifically, we sought to take advantage of the
relies on arylCF2–18F bond formation, typically via halex exchange reactivity of methyl chlorodifluoroacetate known to undergo, in
processes12–15. This radiochemistry is low yielding, limited in scope the presence of fluoride, halide-promoted decarboxylation to give
and requires harsh reaction conditions due to the low reactivity of trifluoromethide, an intermediate that can be captured with
aryl difluoromethylene precursors armed with a halide-based copper iodide22–25. In our design plan, if the reaction is performed
leaving group (Fig. 1b). More recently, the Ag(I)-mediated with [18F]fluoride, the resulting in situ generated [18F]CuCF3
[18F]fluorodecarboxylation19 of arylCF2COOH was successfully species could undergo cross-coupling with the aryl or heteroaryl
implemented using [18F]Selectfluor bis(triflate)20, an electrophilic iodide with release of [18F]labelled trifluoromethyl (hetero)arene
fluorinating reagent prepared from high specific activity [18F]F2 (Fig. 1e). We were poised to test the proposed ‘difluorocarbene–flu-
(Fig. 1c)21. These strategies suffer from either a lack of operational oride–CuI’ multicomponent strategy towards [18F]CuCF3 because
simplicity or broad applicability, hampering translational studies the value of unligated and ligated trifluoromethylcopper complex
and rapid progress of PET imaging.
for trifluoromethylation of (hetero)aryl iodides is amply demon-
To address this challenge, we reasoned that a more direct instal- strated in the literature26–28. We recognized that the proposed
lation of a [18F]CF3 group to a biomarker candidate would obviate transient formation of CF2-carbene may lead to side reactions,
the need to prepare an ‘arylCF2’ precursor armed with a leaving but considered that the short reaction time imposed by
group
amenable
to
[18F]fluoride
displacement.
This [18F]radiochemistry
could
bypass
these
complications.
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1756
ARTICLES
CF218F
I
Overcoming these challenges unveils a new reactivity space unex-
plored for [18F]trifluoromethylation.
a
ClCF2CO2Me (1.5 equiv.)
CuI (1.5 equiv.)
TMEDA (1.5 equiv.)
O
O
Boc
Boc
N
Me
N
[
18F]KF/kryptofix
Results
Me
32
33
DMF, 150 ºC, 20 min
Our initial studies began with the validation of the difluorocarbene–
[18F]fluoride–CuI strategy to access [18F]CuCF3 and the identifi-
cation of a robust protocol for aryl [18F]trifluoromethylation
(Supplementary page S12). p-Iodonitrobenzene served as model
substrate for optimization studies. All reactions were conducted
without deliberate addition of [19F]fluoride (no carrier added).
The [18F]trifluoromethylation requires the presence of CuI and a
ligand to proceed. CuBr or CuCl were less efficient than CuI and
the reaction was best performed in the presence of N,N,N′,N′-tetra-
methylethylenediamine (TMEDA). Notably, 1,10-phenanthroline
was not suitable as a replacement for TMEDA, a result contrasting
with the well-established reactivity of (phen)CuCF3 (refs 26,27), a
complex allowing for the conversion of aryl iodides into trifluoro-
methylated arenes. The [18F]trifluoromethylation proceeded at
150 8C using [18F]KF/K222 in dimethylformamide (DMF) or in
N-methylpyrrolidone, but higher radiochemical yields (RCYs)
were obtained in DMF. [18F]Tetraethylammonium fluoride was
also a competent [18F]fluoride source. Stoichiometric amounts of
aryl iodide, methyl chlorodifluoroacetate, CuI and TMEDA (ratio
1:1.5:1.5:1.5) were used for the reaction. When the quantity of
aryl iodide was increased with respect to the other reagents, the
RCY decreased significantly. The optimized protocol started with
the preparation of a vial containing CuI (11 mg), to which was
added [18F]KF/K222 in MeCN. The solvent was evaporated under
N2 at 100 8C (2 min). The vial was removed from heat, and a sol-
ution of methyl chlorodifluoroacetate (6 ml), TMEDA (9 ml) and
aryl (or heteroaryl) iodide (0.037 mmol) in DMF (300 ml) was
added via syringe. The sealed vial was heated at 150 8C for
20 min. The reaction was quenched by addition of water (100 ml)
and analysed by radioactive thin-layer chromatography
(radioTLC) and radioactive high-performance liquid chromato-
graphy (HPLC) to identify the RCY and derive the product identity,
respectively. Applying these conditions, [18F]trifluoromethyl nitro-
benzene was obtained in 87% RCY within 30 min.
37% 4% (n = 3)
CF218F
b
O2N
18FF2C
O
O
TFA
H
N
·TFA
N
H
150 ºC
5 min
35
Me
34
Flutamide (Eulexin)
Oncology (prostate cancer)
>95% (n = 3)
Fluoxetin (Prozac)
antidepressant
55% 3% (n = 3)
Figure 3 | [18F]Labelling of fluoxetine and flutamide. Biologically active
molecules were subjected to the standard reaction conditions. a, The
antidepressant fluoxetine was [18F]labelled in a two-step protocol within
25 min. b, [18F]Flutamide could be accessed in a single step in 55% RCY.
underwent direct C–H oxidative [18F]trifluoromethylation under
our standard [18F]labelling conditions30,31. The indole with the
[18F]CF3-substituent installed at the C2 position was formed as
the predominant regioisomer. This transformation is a unique
example of direct CH functionalization in the context of 18F-radio-
chemistry. This transformation may be mediated by oxygen or CuI
present in the system (Fig 2d).
An additional major benefit of our [18F]trifluoromethylation
procedure is its amenability to labelling biologically active molecules
and widely prescribed drugs (Fig. 3). For instance, N-Boc protected
[18F]fluoxetine32 was readily prepared in 37% RCY by applying this
direct [18F]trifluoromethylation. The subsequent N-Boc deprotec-
tion delivered [18F]fluoxetine (trifluoroacetic salt) within 5 min at
150 8C (.95% conversion) (Fig. 3a). [18F]Flutamide33 was obtained
with an RCY of 55% (Fig. 3b). Easy access to non-steroidal 18F-
labelled radiopharmaceutical such as [18F]flutamide can encourage
the development of a wide spectrum of specific prostate cancer PET
imaging agents and facilitate image-guided treatment.
As illustrated in Fig. 2, we found that this new [18F]CF3Cu-
mediated protocol allows for the direct incorporation of [18F]CF3 Discussion
into a broad range of arenes and heteroarene rings. A wide range Specific activity is an important consideration when reviewing
of arenes and functional groups are tolerated, including esters, new radiochemistry. The mass dose of the tool compound defines
nitro and cyano groups, and aryl halides other than iodide, ethers the extent of applications and dictates the level of toxicology
and amides. The [18F]trifluoromethylation occurred with good to required to support human use. The specific activity of
excellent RCY and regioselectivity, the attachment of the [18F]CF3 [18F]4-trifluoromethyl nitrobenzene was found to be
group occurring through cross-coupling at the iodo-substituted 0.1 GBq mmol21 (ref. 34). The method reported here is therefore
carbon. Unprotected alcohols, amines and carboxylic acids are not of particular value to support drug development activities. For
compatible with this protocol, probably due to competing alkylation translational preclinical and clinical studies, the potential toxicity
with methyl chlorodifluoroacetate or in situ generated methyl halide of CuI was considered, although such concerns are very different
(Fig. 2a). A dipeptide, DNA base analogue (N-benzyloxyl-methyl for PET imaging because of the small amount of radiotracer that
acetal (BOM) protected uracil derivative)29 and carbohydrate all is required. In fact, various radiotracers containing a Cu(I)-based
responded to [18F]trifluoromethylation with RCYs exceeding 30% chelate35 or employing a copper(I)-mediated reaction for their prep-
(Fig. 2b). We next turned our attention to heteroarenes with the aration, for example the azide-alkyne 1,3-dipolar cycloaddition
knowledge that there is an unmet pressing need for CF3 (CuAAC), are used for clinical studies on a regular basis36. For com-
[18F]labelling technologies for these valuable pharmacophores. As pleteness, inductively coupled plasma mass spectrometry (ICP-MS)
shown in Fig. 2c, we found that pyrazine, quinoline, pyridine, analysis was performed on [18F]4-trifluoromethyl nitrobenzene
indoles, thiophene and benzothiazole are compatible with this purified by a conventional HPLC technique. This analysis indicated
new [18F]labelling approach. For these heterocyclic motifs, the that the labelled material contained 217 ppb Cu-63 residue, a clear
RCY ranged from 17% to 67%. Notably, 2-chloropyridine under- demonstration that CuI can be removed effectively.
went selective [18F]trifluoromethylation with no side reaction,
In this work, we have introduced an efficient no-carrier-
resulting from direct substitution of the chloro substituent with added multicomponent protocol that allows for facile
[18F]fluoride. For these reactions, radio-HPLC analysis of the [18F]trifluoromethylation of aromatic and heteroaromatic systems
crude
reaction
mixtures
typically
showed
the using (hetero)aryl iodide, and [18F]CF3Cu generated in situ from
[18F]trifluoromethylated arene or heteroarene as a single product methyl chlorodifluoroacetate, CuI, TMEDA and [18F]fluoride.
together with unreacted [18F]fluoride. An additional development This technology may find ample applications in [18F]tri-
is the demonstration that C3-substituted N-methyl indole fluoromethylation of pharmaceutical candidates to facilitate drug
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1756
ARTICLES
19. Mizuta, S. et al. Catalytic decarboxylative fluorination for the synthesis of tri-
and difluoromethyl arenes. Org. Lett. 15, 2648–2651 (2013).
development, especially for CNS diseases. Previously unavailable
18F-PET tracers for clinical studies may also come within reach.
This radiochemistry does not necessitate the preparation of
complex organometallic precursors and can be performed with
commercially available reagents in a reaction vessel exposed to air.
Therefore, this [18F]trifluoromethylation process should be suitable
for automated synthesizers and microfluidic development. Its oper-
ational simplicity allows for immediate use by most establishments,
provided they have access to basic PET chemistry infrastructure.
20. Teare, H. et al. Radiosynthesis and evaluation of [18F]selectfluor bis(triflate).
Angew. Chem. Int. Ed. 49, 6821–6824 (2010).
21. Bergman, J. & Solin, O. Fluorine-18-labeled fluorine gas for synthesis of
tracer molecules. Nucl. Med. Biol. 24, 677–683 (1997).
22. MacNeil, J. G. Jr & Burton, D. J. Generation of trifluoromethylcopper from
chlorodifluoroacetate. J. Fluor. Chem. 55, 225–227 (1991).
23. Su, D-B., Duan, J-X., Yu, A-J. & Chen, Q-Y. Synthesis of functionalized
long-chain perfluoroalkanes from methyl halofluoroacetates: a process of
difluorocarbene insertion into copper–carbon bonds. J. Fluor. Chem. 65,
11–14 (1993).
24. Duan, J-X., Su, D-B. & Chen, Q-Y. Trifluoromethylation of organic halides
with methyl halodifluoroacetates—a process via difluorocarbene and
trifluoromethide intermediates. J. Fluor. Chem. 61, 279–284 (1993).
25. Duan, J-X., Su, D-B., Wu, J-P. & Chen, Q-Y. Synthesis of trifluoromethyl aryl
derivatives via difluorocarbene precursors and nitro-substituted aryl chlorides.
J. Fluor. Chem. 66, 167–169 (1994).
Methods
General radiochemical procedure for [18F]trifluoromethylation. [18F]KF/K222 in
MeCN was added to a V-vial containing CuI (11 mg) and a magnetic stirrer bar. The
solvent was evaporated under N2 at 100 8C (2 min). The vial was removed from heat,
and a solution of methyl chlorodifluoroacetate (6 ml), TMEDA (9 ml) and aryl (or
heteroaryl) iodide (0.037 mmol) in DMF (300 ml) was added via syringe. The sealed
vial was heated at 150 8C for 20 min. The reaction was quenched by the addition of
water (100 ml). An aliquot was removed for analysis by radioTLC and HPLC to
obtain the RCY and product identity, respectively.
26. Oishi, M., Kondo, H. & Amii, H. Aromatic trifluoromethylation catalytic in
copper. Chem. Commun. 1909–1911 (2009).
27. Morimoto, H., Tsubogo, T., Litvinas, N. D. & Hartwig, J. F. A broadly applicable
copper reagent for trifluoromethylations and perfluoroalkylations of aryl
iodides and bromides. Angew. Chem. Int. Ed. 50, 3793–3798 (2011).
28. Chu, L. & Qing, F-L. Copper-catalyzed direct C–H oxidative
trifluoromethylation of heteroarenes. J. Am. Chem. Soc. 134, 1298–1304 (2012).
29. Naimi, E., Duan, W., Wiebe, L. I. & Knaus, E. E. Synthesis of unnatural 7-
substituted-1-(2-deoxy-b-D-ribofuranosyl)isocarbostyrils: ‘thymine
replacement’ analogs of deoxythymidine for evaluation as antiviral and
anticancer agents. Nucleosides Nucleotides Nucleic Acids 20, 1533–1553 (2001).
30. Nagib, D. A. & MacMillan, D. W. C. Trifluoromethylation of arenes and
heteroarenes by means of photoredox catalysis. Nature 480, 224–228 (2011).
31. Ji, Y. et al. Innate C–H trifluoromethylation of heterocycles. Proc. Natl Acad. Sci.
USA 108, 14411–14415 (2011).
Received 29 June 2013; accepted 12 August 2013;
published online 8 September 2013
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Acknowledgements
Financial support was provided by Imanova, GlaxoSmithKline, the European Union
(grant PIIF-GA-20100274903 to S.M.), the Engineering and Physical Sciences Research
Council (M.T.) and the Cancer Research UK (M.T.). The authors thank P. Holdship
(Department of Earth Sciences, University of Oxford) for the ICP-MS measurements.
V.G. is a recipient of a Royal Society Wolfson Research Merit Award.
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Author contributions
M.H., M.T. and S.M. performed and analysed experiments. All authors contributed to the
design of experiments to develop this reaction and probe its utility. V.G. and J.P. prepared
the manuscript.
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Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Correspondence and requests for materials should be addressed to
V.G. and J.P.
16. Furuya, T., Kamlet, A. S. & Ritter, T. Catalysis for fluorination and
trifluoromethylation. Nature 473, 470–477 (2011).
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Competing financial interests
The authors declare no competing financial interests.
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