18F-Labeling of Aryl-SCF3, -OCF3 and -OCHF2 with [18F]Fluoride

Article abstract of DOI:10.1002/anie.201504665

We report that halogenophilic silver(I) triflate permits halogen exchange (halex) nucleophilic ¹⁸F-fluorination of aryl-OCHFCl, -OCF₂Br and -SCF₂Br precursors under mild conditions. This Ag^I-mediated process allows for the first time access to a range of ¹⁸F-labeled aryl-OCHF₂, -OCF₃ and -SCF₃ derivatives, inclusive of [¹⁸F]riluzole. The ¹⁸F-labeling of these medicinally important motifs expands the radiochemical space available for PET applications. A halogen exchange (halex) ¹⁸F-fluorination process offers access for the first time to ¹⁸F-labeled arylOCF₃, arylOCHF₂ and arylSCF₃, three motifs of established medicinal importance in PET radiotracers. The use of silver(I) triflate is critical to permit ¹⁸F-labeling under mild conditions.

Full text of DOI:10.1002/anie.201504665

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201504665
German Edition: DOI: 10.1002/ange.201504665
18
Halex F-Fluorination
18F-Labeling of Aryl-SCF3, -OCF3 and -OCHF2 with [18F]Fluoride**
Tanatorn Khotavivattana, Stefan Verhoog, Matthew Tredwell, Lukas Pfeifer,
Samuel Calderwood, Katherine Wheelhouse, Thomas Lee Collier, and VØronique Gouverneur*
Abstract: We report that halogenophilic silver(I) triflate
permits halogen exchange (halex) nucleophilic 18F-fluorination
of aryl-OCHFCl, -OCF2Br and -SCF2Br precursors under
mild conditions. This AgI-mediated process allows for the first
time access to a range of 18F-labeled aryl-OCHF2, -OCF3 and
-SCF3 derivatives, inclusive of [18F]riluzole. The 18F-labeling of
these medicinally important motifs expands the radiochemical
space available for PET applications.
amyotropic lateral sclerosis,[4] or the CF3S-substituted 2-
phenylethylamine tiflorex, which possesses anorectic activ-
ity.[5] To date, there is no method available to label trifluoro-
methyl ethers or thioethers. The prospect of providing 18F-
labeled aryl-OCF3, -OCHF2 and -SCF3 applying a common
methodology led us to consider halogen exchange 18F-
fluorination (Figure 1). Halogen exchange (halex) applied
P
ositron emission tomography (PET) is a non-invasive
quantitative imaging technology assessing biological and
biochemical processes in living subjects.[1] This imaging
modality enhances our understanding of disease states and
drug activity during both preclinical and clinical development.
The success of PET and renewed interest in 18F-radiochem-
istry led to creative methods to incorporate 18F into molecules
of increasing complexity.[2] Despite these advances, clinically
useful radiotracers lie within a narrow accessible space with
[18F]fluoroalkanes and [18F]fluoroarenes at the forefront.
Many potentially high-value PET 18F-labeled tracers and
drugs lie outside this radiochemical space, and the ability to
test tracers not amenable to traditional or newly developed
18F-labeling intervention would be a major boost for PET
imaging. A more diverse range of 18F-tags could serve
medicinal chemists by informing the selection of lead com-
pounds much earlier in the drug discovery pipeline. Drug
developers have employed di- and trifluoromethyl ether, as
well as thioether substitution to tune conformation on
demand, or modulate physicochemical parameters such as
lipophilicity.[3] Pharmaceutical drugs that have benefited from
these substitutions are the CF3O-containing 2-amino benzo-
thiazole riluzole, the first drug approved for the treatment of
Figure 1. 18F-Labeling of aryl-SCF3, -OCF3 and -OCHF2. I.a) Thermal
activation for halex 18F-fluorination of aryl-CF2X precursors employs
harsh conditions. I.b) Thermal activation is not suitable for the 18F-
labeling of arylSCF3 or arylOCF3 by halex 18F-fluorination. II. AgIOTf
mediated 18F-halex occurs under mild conditions and allows access to
new 18F-labeled motifs of medicinal significance including [18F]aryl-
SCF3, -OCF3 and -OCHF2.
[*] T. Khotavivattana,[+] S. Verhoog,[+] Dr. M. Tredwell, L. Pfeifer,
S. Calderwood, Prof. V. Gouverneur
University of Oxford, Chemistry Research Laboratory
Mansfield Road, Oxford, OX1 3TA (UK)
to 18F-labeling relies on thermal activation only;[6] this method
has met with limited success for aryl-CF2X precursors since
the presence of two a-fluorine severely inhibits substitution
with fluoride (Figure 1, Ia).[7] In preliminary work, we found
that thermal activation does not permit 18F-incorporation to
label aryl-OCF3 or aryl-SCF3 derivatives by halogen exchange
18F-fluorination (see below and Figure 1, Ib). These difficul-
ties prompted us to identify a metal-based activation
approach for halex 18F-fluorination of RCF2X precursors
under mild reaction conditions; such an advance may be
transformational to access medicinally important 18F-labeled
motifs that are currently not within reach (Figure 1, II).
Silver is used in homogeneous catalysis owing to its Lewis
acidity, its halide affinity or as a powerful 1eÀ oxidant.[8] We
E-mail: veronique.gouverneur@chem.ox.ac.uk
Dr. T. Lee Collier
Advion BioSystems
10 Brown Road, Suite 101, Ithaca, NY 14850 (USA)
Dr. K. Wheelhouse
Medicines Discovery & Development, GlaxoSmithKline R&D
Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY (UK)
[+] These authors contributed equally to this work.
[**] Financial support was provided by the EPSRC (S.V., M.T.), GSK
(S.V.), the CRUK (M.T.), the Royal Thai Government (T.K.), the EU
(FP7-PEOPLE-2012-ITN-RADIOMI-316882 to L.P.), the MRC (S.C.)
and Advion. V.G. holds a Royal Society Wolfson Research Merit
Award (2013-2018).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201504665.
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Table 1: 18F-Fluorination of the arylSCF2Br precursor 1a.[a]
employed AgI salts and [18F]selectfluor bis(triflate)[9] for the
18F-fluorination of arylstannanes[9] and arylboronic acids,[10]
and to induce the 18F-fluorodecarboxylation of 2,2-difluoro-2-
arylacetic acid derivatives.[11] In this study, we considered that
the affinity of AgI salts for halide may facilitate halogen
exchange nucleophilic 18F-fluorination under mild reaction
conditions; this characteristic of AgI-based chemistry has
never been considered as a generic activation manifold to
promote halex 18F-fluorination.[12] Here, we report that
Entry
Solvent[b]
Additive
Temp.
RCY [%][c]
1
2
3
4
5
6
7
8
MeCN
DMF
DMA
NMP
DMSO
DCM
DCM
DCM
DCM
DCE
–
–
–
–
808C
1108C
1508C
1808C
1808C
RT
RT
RT
RT
RT
608C
RT
RT
RT
RT
RT
RT
RT
RT
0 (n=2)
0 (n=2)
0 (n=2)
0 (n=2)
0 (n=2)
0 (n=2)
0 (n=2)
0 (n=2)
60Æ4 (n=10)
79Æ3 (n=2)
81Æ3 (n=4)
34Æ9 (n=2)
31Æ2 (n=2)
44Æ3 (n=2)
0 (n=2)
À
silver(I) triflate allows for RCF2 Br bond displacement with
[18F]fluoride under mild conditions. The method offers, for the
first time, access to 18F-labeled aryl-OCF3 and -SCF3 motifs,
and was successfully extended to [18F]aryl-OCHF2 (Figure 1,
II).
–
Ag2O
AgNO3
Ag2CO3
AgOTf
AgOTf
AgOTf[d]
AgOTf[e]
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgNTf2
LiOTf
Cu(OTf)2
We focused in the first instance on the 18F-labeling of
trifluoromethyl thioethers, a class of compounds character-
ized by high lipophilicity (Hansch constant p = 1.44); for drug
discovery, this property allows effective transport of drug
molecules through lipid membranes and improves bioavail-
ability.[3] The 18F-labeling of trifluoromethyl thioethers has
not been reported despite the impressive number of methods
9
10
11
12
13[f]
14[g]
15
16
17
18
19
20
DCE
DCM
DCM
DCM
MeCN
DMF
Et2O
DCM
DCM
DCM
0 (n=2)
0 (n=2)
À
À
developed in recent years permitting arylS CF3 or aryl SCF3
bond construction.[3,13] In the context of radiochemistry, these
methods would require 18F-reagents suitable for [18F]CF3 or
[18F]SCF3 incorporation. The conversion of ArSCCl3 into
ArSCF3 with excess SbF3 is the oldest method for the
synthesis of perfluoroalkylsulfide and is still commercially
significant.[14] Recent variants of Swarts-type fluorination
74Æ3 (n=2)
0 (n=2)
RT
0 (n=2)
[a] 1a (0.04 mmol), solvent (300 mL), additive (0.04 mmol), 20 min.
[b] DMF=N,N-dimethylformamide; DMA=N,N-dimethylacetamide;
NMP=N-methyl-2-pyrrolidone; DMSO=dimethylsulfoxide; DCM=di-
chloromethane; DCE=1,2-dichloroethane. [c] Radiochemical yield
determined by radio-TLC and repeated n times. [d] 0.08 mmol.
[e] 0.004 mmol. [f] 1a (0.02 mmol), AgOTf (0.02 mmol). [g] 1a
(0.02 mmol), AgOTf (0.02 mmol), 150 mL of DCM.
À
À
create an arylSCF2 F bond from arylSCF2 Br precursors in
the presence of SbF3 at 1608C,[15] or with AgBF4.[16] These
reagents are not suitable for 18F-labeling due to the risk of
isotope exchange. For preliminary studies, we prepared
[1,1’-biphenyl]-4-yl(bromodifluoromethyl)-sulfane
(1a),[17]
a model difluorinated precursor requiring single 18F-fluorina-
tion to afford [18F]arylSCF3 (2a) (Table 1).
B, with the exception of 1i. The reaction tolerates alkyl,
ethers, esters, aryl and halogens on the aryl core, as well as
unprotected amine and alcohol positioned ortho or para with
respect to the thioether functionality (Scheme 1).
The treatment of 1a with [18F]KF/K222 in a range of
solvents and at temperatures up to 1808C did not permit 18F-
incorporation (Table 1, entries 1–5). A series of AgI salts were
considered to promote halex 18F-fluorination (entries 6–9).
The presence of AgIOTf (1 equiv) in DCM or DCE afforded
[18F]arylSCF3 2a in 60% and 79% radiochemical yield
(RCY),[18] respectively (entries 9 and 10). At 608C in DCE
with 2 equiv of AgOTf, the RCY increased to 81% (entry 11).
A lower 10 mol% loading of AgI salt permits halex 18F-
fluorination in DCM at room temperature but the RCY
dropped to 34% (entry 12). Changing the amount of pre-
cursor or concentration had no beneficial effect (entries 13
and 14). Acetonitrile, dimethylformamide or diethyl ether are
not suitable solvents for this transformation (RCY< 5%),
a result best rationalized referring to the calculated bonding
enthalpies of these solvents to Ag+ (entries 15–17).[19] The use
of AgNTf2 with a weakly coordinating triflimide counter-
anion was also effective, affording 2a in 74% RCY (entry 18).
Experiments using LiOTf or Cu(OTf)2 instead of AgIOTf
confirmed that AgI is the critical entity permitting halogen
exchange (entries 19 and 20).
The successful labeling of trifluoromethyl thioethers 2a–
i encouraged further investigation with the 18F-fluorination of
two additional motifs of medicinal importance. Trifluoro-
methyl ethers are within reach by halex fluorination upon
treatment of aryl trichloromethyl ethers with HF, SbF5, SbF3
(Swartꢀs reagent) in the presence of SbCl5 or MoF6.[20]
Alternative methods employ aryl fluoroformates or aryl
xanthates reacting with SF4/HF at 1608C or with HF·pyridine
and an oxidant, respectively.[21] These syntheses requiring
sequential fluorination are not ideal for 18F-labeling, hence 4-
(bromodifluoromethoxy)-1,1’-biphenyl 3a was selected as
model substrate for 18F-incorporation. Experiments probing
the reactivity of 3a with [18F]KF and Kryptofix.222 did not
lead to product formation in the absence of AgI salt.
Extensive optimization indicated that 18F-fluorination of this
substrate is challenging, and we were therefore delighted to
obtain 4a in RCY averaging 24% (n = 4) when the reaction
was conducted in DCE at 608C with AgOTf (2 equiv). The
reaction did not proceed in acetonitrile but gave 18% RCY in
toluene at 1008C. Decreasing the amount of AgI or the
temperature had a detrimental effect on the RCY. Other AgI
salts gave traces of the product with the exception of AgBF4
Various arylSCF3 2a–i were 18F-labeled applying reaction
conditions A (1 equiv AgOTf, DCM, RT) or B (2 equiv
AgOTf, DCE, 608C); the RCYs are higher under conditions
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Scheme 1. AgI-Mediated halex 18F-fluorination towards [18F]aryl-SCF3.
Conditions A: AgOTf (1 equiv), DCM, RT, 20 min. Conditions B: AgOTf
(2 equiv), DCE, 608C, 20 min. DCM=dichloromethane; DCE=1,2-
dichloroethane.
(9% RCY at room temperature), but this reagent was not
retained due to the risk of isotope scrambling.[22] Applying the
protocol optimized for this class of substrates (2 equiv of
AgOTf, DCE, 608C, 20 min), the labeled products 4a–g were
obtained with RCY reaching 72%. The method gave
[18F]riluzole 4h in 29% RCY from the N-unprotected
precursor 3h. For this target, the use of the mono- or bis-
protected N-Boc precursor was not advantageous (Scheme 2,
I).
The reactivity of 4-(chlorofluoromethoxy)-1,1’-biphenyl
5a, a substrate which upon 18F-fluorination could afford the
[18F]difluoromethoxy)arene 6a, was examined next
(Scheme 2, II). 4-(Bromofluoromethoxy)-1,1’-biphenyl was
not considered as this precursor was difficult to prepare and
purify. The difluoromethoxy group is an important motif for
medicinal chemists due to its non-isotropic shape and
electrostatic potential. This group can adopt two intercon-
verting conformations of different lipophilicity, a property
enabling this unit to adjust to polarity changes of the
molecular environment.[23] Early experiments reveal that 5a
responded to halex 18F-fluorination at room temperature in
the absence of AgI salt affording 6a in low RCY (19%), but
the RCY increased to 70% when AgOTf was added to the
reaction vial. The RCYs obtained with precursors 5a–i ranged
from 66% to 79%. These data indicate that halex 18F-
fluorination is more facile for this class of substrates, with
both electron withdrawing and donating substituents well
tolerated on the arene.
Scheme 2. AgI-mediated halex 18F-fluorination towards [18F]aryl-OCF3
and -OCHF2.
ArCHFCl > ArSCF2Br > ArOCF2Br (Scheme 3). This order
combined with the observation that electron withdrawing
groups on the aryl substituent of arylCF2Br precursors lead to
significantly lower RCY,[17] suggests that cationic intermedi-
ates are involved in these AgI-mediated 18F-fluorinations.[24]
The identification of a robust protocol for the isolation of
18F-labeled products starting from circa 4 GBq of radio-
activity required further tuning since increased quantities of
K2CO3 and Kryptofix had a detrimental effect on the RCY.
These limitations were overcome using potassium oxalate[25]
and dicyclohexyl-18-crown-6[26] acting as an alternative base
and [18F]KF activator, respectively. Using these modified
conditions, the labeled products 2a ([18F]arylSCF3), 4a
([18F]arylOCF3), 6b and 6 f ([18F]arylOCHF2) were isolated
Competition experiments were conducted with 1i, 3a and
5a as well as two additional precursors 4-(bromodifluoro-
methyl)-1,1’-biphenyl 7a and 4-(chlorofluoromethyl)-1,1’-
biphenyl 9a; this study provides the ensuing order of
reactivity towards 18F-fluoride: ArOCHFCl > ArCF2Br ꢀ
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within reach. This work represents a significant step in
this direction.
Experimental Section
General procedure for halogen exchange 18F-fluorination: To a V-
vial containing AgOTf (0.04 mmol) is added [18F]KF/K222
( ꢀ 30 MBq) in MeCN ( ꢀ 30 mL). This vial is heated at 1008C
for 2 min under a stream of N2. After allowing to cool, substrate
(0.04 mmol) in DCM (300 mL) is added to the vial. This mixture is
allowed to stir at RT for 20 min, after which time the reaction is
quenched by the addition of EtOH/H2O (9:1, 500 mL).
Keywords: [18F]fluoride · difluoromethyl ethers ·
halogen exchange · silver triflate · trifluoromethyl ethers
How to cite: Angew. Chem. Int. Ed. 2015, 54, 9991–9995
Angew. Chem. 2015, 127, 10129–10133
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after preparative radio-HPLC in 10% Æ 1% (n = 2), 11%
Æ 4% (n = 2), 34% Æ 1% (n = 2) and 31% Æ 2% (n = 2)
RCY, respectively. The specific activities (SA)[27] of 2a, 4a, 6b
and 6 f were found to be 0.15 GBqmmolÀ1, 0.04 GBqmmolÀ1,
0.04 GBqmmolÀ1 and 0.17 GBqmmolÀ1, respectively; these
values are comparable to those obtained for 18F-labeled aryl-
CF3 applying our [18F]CuCF3-based cross-coupling strategy,[28]
and imply that this radiochemical method is best suited to
support drug development studies. Control experiments
inform that no 18F-incorporation was detectable when sub-
jecting unlabeled 2a, 4a or 6a to the reaction condition
applied for AgI-mediated 18F-fluorination; these results
demonstrate that 19F-18F isotope exchange does not occur on
the 18F-labeled product.[29] The silver content of 18F-radio-
tracers prepared with our method was considered, although
such silver contamination concerns are very different for PET
imaging because of the small amount of radiotracer that is
required. Inductively coupled plasma atomic emission spec-
trometry (ICP-AES) analysis was performed on [18F]6b and
[18F]4a, both purified by a conventional HPLC technique.
This analysis indicated that AgIOTf can be removed effec-
tively since the Ag content was found to be < 0.05 mggÀ1 for
[18F]6b (n = 2) and 0.02 mggÀ1 for [18F]4a (n = 2); these values
are well below any levels of concern.[30]
This work demonstrates that AgOTf induces halogen
exchange nucleophilic 18F-fluorination under mild reaction
conditions and this advance permits for the first time access to
medicinally relevant 18F-labeled aryl-OCHF2, -OCF3 and
-SCF3 derivatives. In drug discovery, the concept of chemical
space describes the pool of molecules to be considered when
searching for new drugs. It is reasonable to predict that major
progresses in PET imaging will emerge from a dramatically
expanded radiochemical space enabling the synthesis and
discovery of radiotracers and radioligands currently not
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[18] RCY in this context is determined by radio-TLC (EtOAc/
Hexane, 1:1) after quenching the reactions with EtOH/H2O (9:1;
500 mL), taking in to account by radiochemical purity by radio-
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Received: May 22, 2015
Published online: July 3, 2015
Angew. Chem. Int. Ed. 2015, 54, 9991 –9995
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 9995