Silver-Mediated 18F-Labeling of Aryl-CF3 and Aryl-CHF2 with 18F-Fluoride

Article abstract of DOI:10.1055/s-0035-1560592

We report the synthesis of [¹⁸F]arylCF₃ and [¹⁸F]arylCHF₂ derivatives from arylCF₂Br and arylCHFCl precursors applying a silver-mediated halogen exchange with [¹⁸F]fluoride. In the absence of Ag(I)OTf, no reaction takes place at room temperature for both classes of substrates; this result demonstrates the beneficial role of silver(I) as a means to induce ¹⁸F-incorporation under very mild conditions.

Full text of DOI:10.1055/s-0035-1560592

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, 25–28
letter
25
S. Verhoog et al.
Letter
Synlett
Silver-Mediated 18F-Labeling of Aryl-CF3 and Aryl-CHF2 with
18F-Fluoride
Stefan Verhooga,1
Lukas Pfeifera,1
CF218F
CF2Br
[
18F]KF/K222
Tanatorn Khotavivattanaa
Samuel Calderwooda
Thomas Lee Collierb
Katherine Wheelhousec
Matthew Tredwella,d
Véronique Gouverneur*a
RCC up to 80%
R
R
r.t., CH2Cl2
[
18F]KF/K222
Ag(I)OTf
CHF18F
RCC up to 39%
CHFCl
r.t., CH2Cl2
R
R
a University of Oxford, Chemistry Research laboratory, 12 Mansfield Road, OX1 3TA, Oxford, UK
veronique.gouverneur@chem.ox.ac.uk
b Advion BioSystems, 10 Brown Road, Suite 101, Ithaca, NY 14850, USA
c Medicines Discovery & Development, GlaxoSmithKline, R&D, Gunnels Wood Road, Stevenage,
Hertfordshire, SG1 2NY, UK
d Max-Planck-Institut für Kohlenforschung,
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
In celebration of Prof. Steven Ley’s 70th birthday
Received: 16.10.2015
Accepted after revision: 03.11.2015
Published online: 20.11.2015
strategy using readily available [18F]fluoride. Recently, we
reported that silver(I)-mediated halogen exchange (halex)
with [18F]F– affords three novel 18F-labeled motifs of medic-
inal relevance, specifically [18F]arylSCF3, [18F]arylOCF3, and
[18F]arylOCHF2.7 In this Letter, we report that this silver(I)-
mediated halogen-exchange strategy is applicable to a
range of arylCF2Br and arylCHFCl precursors affording
[18F]arylCF3 and [18F]arylCHF2 in good radiochemical con-
versions (RCC);8 a notable characteristic of this process is
the very mild reaction conditions applied for 18F-incorpora-
tion compared to alternative methods (Scheme 1).
DOI: 10.1055/s-0035-1560592; Art ID: st-2015-d0820-l
Abstract We report the synthesis of [18F]arylCF3 and [18F]arylCHF2 de-
rivatives from arylCF2Br and arylCHFCl precursors applying a silver-me-
diated halogen exchange with [18F]fluoride. In the absence of Ag(I)OTf,
no reaction takes place at room temperature for both classes of sub-
strates; this result demonstrates the beneficial role of silver(I) as a
means to induce 18F-incorporation under very mild conditions.
Key words radiochemistry, halogen exchange, silver, fluoride, trifluo-
romethylarenes, difluoromethylarenes
18F]F+, Ag(I)
[
[
18F]ArCF3
18F]ArCF2H
[
ArCF2CO2H
ArCHFCO2H
The importance of positron emission tomography (PET)
as a noninvasive imaging technique for the assessment of
disease state and for drug development has caused a great
demand for novel strategies enabling 18F incorporation.2 As
a result, numerous methods for 18F-labeling have been de-
veloped in recent years,3 and their value discussed in au-
thoritative reviews.4 Despite these advances, radiochemists
could benefit from a much more diverse range of 18F-tags
and 18F-labeling methods to support their (pre)clinical pro-
grams. With these considerations in mind, one approach is
to develop radiochemical methods that are applicable to
the synthesis of various 18F-labeled motifs. One such exam-
ple is the silver(I)-mediated decarboxylative 18F-fluorina-
tion with [18F]Selectfluor bis(triflate) of α,α-difluoro- and
α-fluoroarylacetic acids, a process leading to [18F]arylCF3
and [18F]arylCF2H, respectively;5 this method requires ac-
cess to [18F]F2 to prepare [18F]Selectfluor bis(triflate),6 a lim-
itation encouraging the development of an alternative
[
[
[
18F]ArSCF3
18F]ArOCF3
18F]ArOCF2H
ArSCF2Br
ArOCF2Br
ArOCHFCl
[
18F]F-, Ag(I)
18F]ArCF3
18F]ArCF2H
[
18F]F-, Ag(I)
ArCF2Br
ArCHFCl
[
[
this work
Scheme 1 Silver(I)-mediated radiochemical methods using [18F]F+ and
[
18F]F– sources allow access to a range of diverse 18F-motifs
Halex reactions for the synthesis of arylCF3 derivatives
require harsh reaction conditions.9 α-Bromo-α,α-difluoro-
toluene precursors do not react with [18F]fluoride at room
temperature; however, 18F-incorporation occurs with
[18F]KF/K222 in sulfolane at 160 °C or with [18F]TBAF in
DMSO at 135 °C. We consider metal activation with
Ag(I)OTf as an alternative to thermal activation which may
allow for this process to proceed under much milder condi-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 25–28

26
S. Verhoog et al.
Letter
Synlett
tions. Pleasingly, we found that the treatment of 4-(bromo-
difluoromethyl)-1,1′-biphenyl (1a) with [18F]KF/K222 and
one equivalent of AgOTf in CH2Cl2 at room temperature af-
forded [18F]4-(trifluoromethyl)-1,1′-biphenyl {[18F]2a} in
75% (n = 27) RCC (Scheme 2).10 This method proved suc-
cessful for arylCF2Br precursors 2b–f with alkyl, aryl, and
methoxy substituents located ortho, meta, or para relative
to the CF3 group being tolerated. For the most challenging
substrates 1g–j bearing electron-withdrawing substituents,
no or only trace amount of product could be detected at
room temperature; 18F-labeling was, however, observed by
employing [18F]KF/K222 and Ag(I)OTf (2 equiv) in DCE at 60
°C. The m-bromoarene 1f led to [18F]2f in 10% RCC, and the
ester-substituted precursors 1h–j responded to 18F-fluori-
nation in RCC in the range of 25%. The ester-substituted
arenes 1h and 1j were more problematic as [18F]2h and
[18F]2j were formed along labeled side products, possibly
18F-labeled acyl fluoride (vide infra), and nucleophilic par-
ticipation of the ortho-positioned ester functionality for
[18F]2j. Finally, this set of conditions increased the yield of
the m-methoxy-substituted product [18F]2f. Control experi-
ments with 1a confirm that, in the absence of Ag(I)OTf, no
18F-labeling takes place at room temperature in CH2Cl2, and
a trace of product [18F]2a (< 5%, complex mixture) was de-
tected at 60 °C in DCE.10 These results suggest that the use
of Ag(I)OTf is beneficial for 18F-incorporation for this class
of brominated substrates.
In order to determine the specific activity (SA), an isola-
tion experiment starting from 4.00 GBq of activity was per-
formed using precursor 1a. Due to the detrimental effect of
increased quantities of K2CO3 and Kryptofix on the radio-
11
chemical yield (RCY), alternative conditions using K2C2O4
as base and dicyclohexyl-18-crown-612 as the [18F]KF acti-
vator were applied. Thereupon, [18F]arylCF3 2a was isolated
in 7% RCY with a specific activity of 0.25 GBq μmol–1
(Scheme 3).10
[
18F]KF/diCy-18-crown-6
(4.00 GBq)
CF218F
AgOTf (0.04 mmol)
CF2Br
CH2Cl2, r.t., 20 min
Ph
Ph
2a
1a
RCY = 7% (272 MBq)
SA = 0.25 GBq/μmol
0.04 mmol
(8 mg)
Scheme 3 Specific activity of [18F]2a
These values are comparable to those obtained for 18F-
labeled arylCF3 applying our [18F]CuCF3-based cross-cou-
pling strategy,13 and in the same range as those determined
for the silver(I)-mediated halex process leading to 18F-la-
beled arylOCHF2, arylOCF3, and arylSCF3.7 The low specific
activity indicates release of 19F from the substrate. The pres-
ence of [18F][1,1′-biphenyl]-4-carbonyl fluoride (<5%) in the
crude reaction mixture suggests that a plausible path ac-
counting for 19F release is the attack of adventitious water
onto the in situ putatively formed cationic intermediate fol-
lowed by loss of HF.10
CF2Br conditions A or B
CF218F
R
R
2a–j
1a–j
Having investigated the value of this protocol for the
synthesis of 18F-labeled arylCF3 groups prompted us to ex-
tend this methodology further to arylCHF2, a functionality
for which few methods are available for labeling.5 In drug
discovery, the difluoromethyl group (CF2H) is of interest as
it is a bioisostere of carbinol,14 thiol,15 or hydroxamic acid
hydroxyl group.16 The difluoromethyl group can also act as
lipophilic hydrogen-bond donor improving binding selec-
tivity and cell-membrane permeability.17 The radiosynthe-
sis was undertaken with arylCHFCl precursors which are
easier to handle than arylCHFBr (Scheme 4).
The reaction of 4-(chlorofluoromethyl)-1,1′-biphenyl 3a
with [18F]KF/K222 in CH2Cl2 at room temperature led to trace
of the desired product 4-(difluoromethyl)-1,1′-biphenyl
(4a, 1% RCC, n = 2). When the 18F-labeling was carried out in
the presence of Ag(I)OTf, the reaction was successful with
alkyl, ether, and bromo substituents all well tolerated; elec-
tron-neutral and electron-rich substrates 3a–e are most
suitable for these mild conditions. To the best of our knowl-
edge, this method represents the first labeling approach to-
wards [18F]arylCHF2 from [18F]fluoride. Conditions B con-
sisting of using Ag(I)OTf in DCE at 60 °C were beneficial for
the bromo-substituted precursor 3f increasing the RCC of
CF218F
CF218F
tBu
CF218F
Ph
tBu
2a
A: 75 1% (n = 27)
2b
2c
A: 54 3% (n = 4)
A: 80 3% (n = 4)
OMe
CF218F
CF218F
MeO
CF218F
Br
CF218F
MeO
2d
2e
2f
2g
A: 0% (n = 4)
B: 10 3% (n = 4)a
A: 69 1% (n = 4) A: 44 3% (n = 4) A: 25 5% (n = 4)
B: 49 2% (n = 4)
CF218F
CF218F
MeO2C
CF218F
MeO2C
CO2Me
2i
2h
2j
A: 4 1% (n = 4)
B: 36 4% (n = 4)
A: 0% (n = 4)
A: 3 0% (n = 4)
B: 16 2% (n = 4)a
B: 26 4% (n = 4)a
Scheme 2 Silver(I)-mediated halex 18F fluorination towards [18F]aryl-
CF3. Conditions A: [18F]KF/K222, AgOTf (1.0 equiv), CH2Cl2, r.t., 20 min.
Conditions B: [18F]KF/K222, AgOTf (2.0 equiv), DCE, 60 °C, 20 min. a RCC
of 18F-labeled product shown; this reaction leads to 18F-labeled side
products. n = number of experiments.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 25–28

27
S. Verhoog et al.
Letter
Synlett
In conclusion, we have studied the silver(I)-mediated
halex 18F-fluorination for the synthesis of [18F]arylCF3 and
[18F]arylCHF2. The use of AgOTf is most beneficial for the la-
beling of arylCF2Br precursors, a class of compunds less re-
active than arylCHFCl. The current limitation remains the
low specific activity, which narrows the range of applica-
tions for PET to drug-development activities. The advantage
of this process is the mildness of the reaction conditions
since 18F-labeling occurs at room temperature for a range of
substrates.
CHFCl
CHF18F
conditions A or B
R
R
3a–h
4a–h
CHF18F
CHF18F
CHF18F
Ph
tBu
4b
A: 39 3% (n = 4)
4c
A: 37 3% (n = 4)
4a
A: 30 4% (n = 4)
CHF18F
OMe
CHF18F
MeO
CHF18F
Br
Acknowledgment
4e
4f
4d
A: 24 6% (n = 2)
A: 17 1% (n = 4)a
A: 27 2% (n = 4)
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-PEO-
PLE-2012-ITN-RADIOMI-316882 to L.P.), the MRC (S.C.), and Advion
(S.C.). V.G. holds a Royal Society Wolfson Research Merit Award
(2013–2018).
B: 26 3% (n = 4)
CHF18F
CO2Me
CHF18F
Cl
4h
4g
A: 0% (n = 2)
B: 17 3% (n = 4)a
A: 0% (n = 2)
B: 17 1% (n = 4)a
Supporting Information
Scheme 4 Silver(I)-mediated halex 18F-fluorination towards [18F]aryl-
CHF2. Conditions A: [18F]KF/K222, AgOTf (1.0 equiv), CH2Cl2, r.t., 20 min.
Conditions B: [18F]KF/K222, AgOTf (2.0 equiv), DCE, 60 °C, 20 min. a RCC
of 18F-labeled product shown; this reaction leads to 18F-labeled side
products.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560592.
S
u
p
p
o
nrtIo
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f
rmoaitn
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p
p
ortiInfogrmoaitn
References and Notes
[18F]4f from 17% to 26%. For this substrate, whereas condi-
tions A gave multiple 18F-labeled side products, a clean re-
action was observed under conditions B; electron-poor
substrates 3g and 3h that did not react with [18F]KF/K222 in
the presence of Ag(I)OTf at room temperature were also
subjected to heating at 60 °C in DCE. The desired products
[18F]4g and [18F]4h were formed in addition to labeled side
products, a factor limiting the radiosynthetic scope of this
process. Notably, a control experiment treating 3a with
[18F]KF/K222 at 60 °C in DCE in the absence of Ag(I)OTf gave
[18F]4a in 42% ± 3% (n = 2); this result indicates that for this
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ture only. The specific activity was determined for product
4b (Scheme 5) starting from 3.48 GBq of activity following
the isolation protocol described for 2a (vide supra).
[18F]ArylCHF2 4b was isolated in 10% RCY with a specific ac-
tivity of 0.03 GBq μmol–1.10
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[
18F]KF/diCy-18-crown-6
(3.48 GBq)
CHF18F
CHFCl
AgOTf (0.04 mmol)
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0.04 mmol
(8 mg)
RCY = 10% (363 MBq)
SA = 0.03 GBq/umol
Scheme 5 Specific activity of [18F]4b
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 25–28

28
S. Verhoog et al.
Letter
Synlett
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 25–28