Synthesis of 18F-difluoromethylarenes using aryl boronic acids, ethyl bromofluoroacetate and [18F]fluoride

Article abstract of DOI:10.1039/c8sc05096a

Herein, we report the radiosynthesis of ¹⁸F-difluoromethylarenes via the assembly of three components, a boron reagent, ethyl bromofluoroacetate, and cyclotron-produced non-carrier added [¹⁸F]fluoride. The two key steps are a copper-catalysed cross-coupling reaction, and a Mn-mediated ¹⁸F-fluorodecarboxylation.

Full text of DOI:10.1039/c8sc05096a

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Gouverneur, Chem. Sci., 2019, DOI: 10.1039/C8SC05096A.
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DOI: 10.1039/C8SC05096A
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ARTICLE
Synthesis of 18F-Difluoromethylarenes Using Aryl Boronic Acids,
Ethyl bromofluoroacetate and [18F]Fluoride
Received 00th January 20xx,
Accepted 00th January 20xx
Jeroen B. I. Sap,[a] Thomas C. Wilson,[a] Choon Wee Kee,[a] Natan J. W. Straathof,[a] Christopher W.
amEnde,[b] Paramita Mukherjee,[b] Lei Zhang,[b] Christophe Genicot[c] and Véronique
Gouverneur*[a]
DOI: 10.1039/x0xx00000x
www.rsc.org/
Herein, we report the radiosynthesis of 18F-difluoromethylarenes via the assembly of three components, a boron reagent,
ethyl bromofluoroacetate, and cyclotron-produced non-carrier added [18F]fluoride. The two key steps are a copper-catalysed
cross-coupling reaction, and a Mn-mediated 18F-fluorodecarboxylation.
applicability for radioligand synthesis. We therefore opted to
develop a method using pre-functionalised aryl boron reagents;
Introduction
these
are
amenable
to
18F-fluorination
and
18F-
Positron emission tomography (PET) is
technique that requires molecules labelled with a positron-emitting
radionuclide. Fluorine-18 is
a molecular imaging
trifluoromethylation,10 so extension to 18F-difluoromethylation was
viewed as a valuable development. Building on our Ag(I)-mediated
18F-fluorodecarboxylation towards [18F]ArCF2H,5 a reaction requiring
[18F]Selectfluor (bis)triflate (Scheme 1A),11 and on the Mn-mediated
a
widely used positron emitting
radionuclide in part due to its favourable decay properties, and the
numerous clinical applications of 2-deoxy-2-[18F]fluoro-D-glucose,
a
radiopharmaceutical prepared from [18F]fluoride.1 While
fluorodecarboxylation reported by Groves and co-workers,
a
radiochemists have in recent years focused their efforts on methods
enabling 18F-fluorination2 and 18F-trifluoromethylation of
(hetero)arenes,2,3 18F-difluoromethylation reactions have been less
studied despite the importance of the CF2H motif4 in radioligand
design for drug discovery programmes. In 2013, we reported a Ag(I)-
mediated 18F-fluorodecarboxylation of 2-fluoro-2-arylacetic acids
with [18F]Selectfluor (bis)triflate leading to [18F]ArCF2H.5
Subsequently, we disclosed a Ag(I)-mediated halogen exchange
reaction using [18F]fluoride.6 In 2016, a multi-step method to label
[18F]ArCF2H from aryl (pseudo)halides was disclosed by Ritter and co-
workers.7 Later, Liang and co-workers demonstrated that halogen
exchange of benzyl (pseudo)halides with [18F]fluoride followed by
oxidative benzylic C–H fluorination with Selectfluor afforded
[18F]ArCF2H with improved molar activity.8 Despite these advances,
18F-difluoromethylation remains a challenging problem, especially
for structurally complex targets. We initially considered adapting
difluoromethylation reactions operating via C–H functionalisation.9
Whilst this strategy is ideal for (hetero)arenes with innate reactivity
leading to site-selective 18F-difluoro-methylation, substrates that are
not reactive or too reactive would be unsuitable, thereby limiting
reaction using [18F]fluoride (Scheme 1B),12,13 we envisaged that the
18F-fluorodecarboxylation of 2-fluoro-2-arylacetic acids with
[18F]fluoride could afford [18F]ArCF2H. The beneficial effect of
fluorine substitution on radical stabilisation would be favorable for
this process.5,14 This approach would require a robust method to
cross-couple the aryl boron reagent with ethyl bromofluoroacetate
followed by hydrolysis to access the carboxylic acid precursor; we
gave preference to a coupling methodology applying Cu-catalysis
instead of Pd or Ni, a decision driven by guidelines for residual metals
in (radio)pharmaceuticals.15 The proposed strategy therefore relies
on three readily available components, the boron reagent, ethyl
bromofluoroacetate, and [18F]fluoride (Scheme 1C).16
F
F
A
Ag-mediated with [18F]Selectfluor (bis)triflate
CO2
H
18F
Gouverneur
18F
B
Mn-mediated with [18F]F-
Groves
CO2
H
This Work
Et
C
F
H
Et
Et
18F-fluorination
CO2Et
N+
cross-coupling
B(OH)2
boronic acids
18F-
Br
Et
[
18F]TEAF
F
F
Cu-mediated
arene coupling
Mn-mediated
fluorodecarboxylation
B(OH)2
CO2
H
18F
aChemistry Research Laboratory, Department of Chemistry, Oxford University, OX1 3TA
Oxford (UK). E-mail: veronique.gouverneur@chem.ox.ac.uk; Fax: +44 (0)1865 285002
bPfizer Inc., Medicine Design, Eastern Point Road, Groton, Connecticut 06340, and 1
Portland Street, Cambridge, Massachusetts 02139 (USA)
then hydrolysis
Scheme 1. (A) Ag(I)-mediated 18F-fluorodecarboxylation with [18F]Selectfluor (bis)triflate.
(B) Mn(III)-mediated 18F-fluorodecarboxylation with [18F]fluoride towards [18F]ArCH2F.
(C) Synthetic plan towards [18F]ArCF2H from boron reagents and [18F]fluoride.
cGlobal Chemistry, UCB New Medicines, UCB Biopharma sprl, 1420 Braine-L’Alleud
(Belgium)
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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the presence of 4,4’,4’’-tri-tert-butyl-2,2’:6’,2’’-terpyridine (L3) in
DOI: 10.1039/C8SC05096A
toluene instead of dioxane 7a was obtained in 63% yield (Table 1,
Results and Discussion
View Article Online
Preliminary experiments demonstrated that the model fluoro-
substituted carboxylic acid 1a is amenable to fluorodecarboxylation
with fluoride. When an equimolar mixture of 1a and 2a was treated
with Mn(tmp)Cl (2.5 mol%), Et3N·3HF (1.2 equiv.) and PhIO (3.3
equiv.) in MeCN at 50 oC, 3a and 4a were obtained in 44% and 20%
yield, respectively. This result indicates that the fluorine-substituted
precursor 1a is more reactive than non-fluorinated 2a towards
fluorodecarboxylation (Scheme 2A). We verified that product 4a did
not undergo fluorination via C–H functionalisation under these
conditions.17 When an excess of 1a (1 equiv.) was treated with TBAF
(0.1 equiv.), PhIO (0.5 equiv.) and Mn(tmp)Cl (0.2 equiv.) in MeCN,
3a was obtained in 50% yield (determined by 19F NMR based on TBAF
consumption) (Scheme 2B). Notably, quantitative fluoride
incorporation was observed applying similar reaction conditions to
the preformed hypervalent iodine complex 5a (Scheme 2C). These
preliminary data boded well for 18F-labeling with [18F]fluoride as the
limiting reagent, and prompted the development of a robust
protocol to convert aryl boron reagents into 2-fluoro-2-arylacetic
acids.
entry 3). Further optimisation increasing the concentration led to the
optimal protocol consisting of treating 6a (0.1 mmol) with ethyl ethyl
bromofluoroacetate (0.2 mmol), Cs2CO3 (0.2 mmol), CuI (20 mol%)
and L3 (20 mol%) in toluene (0.4 M) at 100 oC. Under these reaction
conditions, 7a was isolated in 82% yield (Table 1, entry 4). A one-pot
sequence involving cross-coupling followed by hydrolysis with MeOH
and aqueous K2CO3 afforded 8a isolated in 75% yield (Table 1, entry
5). In the absence of ligand and/or copper source (Table 1, entries 6-
7), no product formation was observed. Furthermore, no reaction
was observed with CuCl2 (Table 1, entry 8), or when the reaction
solvent was DMF or DMSO (Table 1, entry 9).
Table 1. Optimisation of the Cu-catalysed cross-coupling of aryl boronic acid 6a with
ethyl bromofluoroacetate towards ester 7a and the corresponding carboxylic acid 8a.
BrCFHCO2Et
L
OH
B
CuI/ (20 mol %)
F
then
Cs2CO3
7a, R = Et
8a, R = H
K2CO3 (10 equiv.)
MeOH/H2O, r.t. 5 h
OH
CO2R
toluene
100 °C, 18 h
Ph
Ph
6a
t-Bu
t-Bu
t-Bu
N
N
N
N
N
N
N
N
Et3N·3HF (1.2 equiv.)
PhIO (3.3 equiv.)
Mn(tmp)Cl (2.5 mol %)
A
F
F
L1
L2
L3
+
:
Ar
F
Entry
1b
2b
3
Solvent
Cu-Source
Ligand
L1
L2
L3
L3
L3
-
Product
Yielda
7%
Ar
CO2H
Ar
F
Ar
CO2H
MeCN (0.1M)
50 °C C, 1.5 h
44%
20%
4a
1a
2a
(0.1 mmol)
(0.1 mmol)
Dioxane (0.2 M)
CuI
CuI
CuI
CuI
CuI
CuI
-
7a
7a
7a
7a
8a
7a
7a
7a
7a
Ar = 1,1'-biphenyl
3a
Me
Dioxane (0.2 M)
Toluene (0.2 M)
Toluene (0.4 M)
Toluene (0.4 M)
Toluene (0.4 M)
Toluene (0.4 M)
Toluene (0.4 M)
58%
63%
82%d
75%d,e
0%
Me
Me
B
PhIO (0.5 equiv.)
Mn(tmp)Cl (0.2 equiv.)
TBAF (0.1 equiv.)
Me
F
F
Me
Me
N
Mn
Cl
N
Me
Me
N
Ar
1a
CO2H
(0.1 mmol)
Ar
F
N
MeCN (0.1M)
50 °C, 20 min.
3a
Me
4c
50% yielda
Me
Ar = 1,1'-biphenyl
Me
Mn(tmp)Cl
Me
5c
C
6c
O
O
O
F
Mn(tmp)Cl (0.2 equiv.)
TBAF (0.1 equiv.)
PhIO (0.5 equiv.) ArFHC
CFHAr
F
Ar
CO2H
O
I
7c
-
0%
MeCN (0.1M)
50 °C, 10 min.
no purification
MeCN (0.1M)
50 °C, 10 min.
F
Ar
1a
(0.1 mmol)
3a
Ar = 1,1'-biphenyl
8c
CuCl2
CuI
L2
L3
0%
>99% yield
9c
DMF or DMSO (0.2 M)
0%
Scheme 2. A. Competition studies evaluating the effect of fluorine substitution on
fluorodecarboxylation. B. Reaction with sub-stoichiometric fluoride. C. Reaction of
iodine(III) complex 5a with sub-stoichiometric fluoride. Yields of isolated products.
Screening reactions performed on 0.1 mmol scale. aYield determined by 19F-NMR using
α,α,α-trifluorotoluene as internal standard. b2 equiv. of 6a and 1 equiv. of ethyl
bromofluoroacetate. c1 equiv. of 6a, and 2 equiv. of ethyl bromofluoroacetate. dYield of
isolated product. eOne-pot procedure towards 8a.
Mn(tmp)Cl
determined by 19F NMR using α,α,α-trifluorotoluene as internal standard.
=
Mn(III) meso-tetra(2,4,6-trimethylphenyl)porphyrin chloride. aYield
These optimised conditions gave access to a range of 2-fluoro-2-
arylacetic acids (Scheme 3). The reaction is broad in scope and
tolerates various functional groups, for example alkyl 8c-8e and 8s-
8u, alkoxy 8f-8g, trifluoromethyl 8h, bromo 8p-8q, iodo 8r, and
aldehyde 8i all performed well. Substrates featuring heterocycles
such as dibenzofuran 8j, pyridine 8k, triazole 8l, and pyrazoles 8m-
8n are also suitable coupling partners applying our optimised
protocol affording the desired products in 40% to 70% yield.
Additionally, this cross-coupling chemistry afforded 8o, a derivative
of fenofibrate, in 72% yield. Finally, the reaction was amenable to
scale-up to 5 mmol (Scheme 3, 8m).
The
cross-coupling
of
arylboronic
acids
and
ethyl
bromofluoroacetate has been reported using an excess of boron
reagent under Ni or Pd catalysis, but has not been accomplished
under Cu catalysis.18-22 Initial studies reacting [1,1'-biphenyl]-4-
ylboronic acid 6a (2 equiv.) with ethyl bromofluoroacetate (1 equiv.)
in the presence of 1,10-phenanthroline (L1, 20 mol%), CuI (20 mol%)
and Cs2CO3 (2 equiv.) in dioxane (0.2 M) under N2 at 100 °C afforded
7a in 7% yield (Table 1, entry 1). When 2,2′:6′,2′′-terpyridine (L2) was
used as the ligand, the yield was significantly improved to 58% yield
(Table 1, entry 2). When the stoichiometry was altered to 1
equivalent of 6a and 2 equivalents of ethyl bromofluoroacetate in
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J. Name., 2013, 00, 1-3 | 2
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Table 2. Optimisation studies for the [18F]fluorodecarboxylation of 8b.
L3
CuI/ (20 mol %)
View Article Online
Cs2CO3 (2 equiv.)
toluene (0.4 M)
100 °C , 18 h
OH
B
F
DOI: 10.1039/C8SC05096A
F
F
F
Protocol A
]TEAF (20-30 MBq)
OH
CO2H
+
18F
R
Br
CO2Et
R
[
then K2CO3 (10 equiv.)
CO2H
18F
(2 equiv.)
MeOH/H2O, r.t. 5 h
8a - 8v
PhIO, Mn(tmp)Cl (0.002 mmol)
Solvent, 50 °C, 20 min
6a - 6v
PhO
PhO
F
CO2H
[
18F]3b
8a
(R = 4-Ph), 75%
(R = 4-OPh), 69%
(R = 3,5-diMe), 63%
(R = 2,5-diMe), 52%
(R = 4-tBu), 70%
(R = 2-OMe), 30%
(R = 3-OMe), 56%
(R = 4-CF3), 60%
8b
O
F
8b
8c
8d
8e
8f
F
O
O
O
O
O
H
CO2H
R
R
CO2H
Protocol B
then one-pot
R
MeO
I
18F
8g
8h
PhIO (0.5 equiv.)
[
]TEAF (20-30 MBq)
Mn(tmp)Cl (2 mg),
DMF, 50 °C, 20 min
a
a
8i
, 53%
F
MeCN, 50 °C, 10 min
8j
, 52%
Me
5b
F
F
O
CO2H
Me
CO2H
N
N
CO2H
Entry
Starting
Material
(mmol)
Protocol
Solvent
PhIO
(mmol)
RCCa (n
=2)b
N
N
F3C
N
a
8l
, 40%
N
a
8k
, 70%
, 60%a (55%)a,b
F
8m
Me
1
2
3
4
5
6
7
8
8b (0.11)
8b (0.11)
8b (0.11)
8b (0.055)
5b (0.014)
5b (0.014)
8b (0.014)
5b (0.014)
A
A
A
A
B
B
A
B
MeCNc
MeCNd
DMFd
0.33
0.02
0.02
0.02
3% ± 1%
6% ± 1%
7% ± 2%
22% ± 7%
CO2H
R
O
N
N
F3C
Me Me
O
8p
8q
8r
8s
8t
(R = 3-Br), 58%
(R = 4-Br), 52%
(R = 3-I), 50%
(R = 3-Me), 74%
(R = 4-Me), 72%
(R = 2-Me), 30%
(R = H), 59%
Me
CO2Et
O
CO2H
Me
O
From Fenofibrate
F
DMFd,e
DMFd,e
DMFd,e
MeCNd
DMFd,e
8u
8v
F
a
8o
, 72%
a
8n
, 41%
-
40% ± 10%f
0% ± 0%g
0%± 0%h
0% ± 0%i
Scheme 3. Scope of Cu-catalysed cross-coupling. The reactions were performed on a 0.3
mmol scale. Conditions: CuI (20 mol%), L3 (20 mol%), aryl boronic acid (1 equiv.), ethyl
bromofluoroacetate (2 equiv.), Cs2CO3 (2 equiv.), toluene (0.4M) at 100 °C for 18 h then
one-pot hydrolysis with K2CO3 (10 equiv.), MeOH/H2O (1:1), 5 h. aHydrolysis performed
as a subsequent step with K2CO3 (5 equiv.). bReaction run on 5 mmol scale. All yields are
of isolated products.
-
0.02
-
The key 18F-fluorodecarboxylation step was studied next (Table 2).
We started our investigation applying Protocol A that consists of
reacting in one-pot 8b (0.11 mmol) with PhIO (0.33 mmol),
Mn(tmp)Cl (2 mg) and [18F]TEAF (20-30 MBq) in MeCN (600 µL) at 50
°C; this protocol led to only traces of [18F]3b (Table 2, entry 1). When
the loading of PhIO (0.02 mmol) and MeCN (300 µL) was reduced,
[18F]3b was obtained in 6% ± 1% radiochemical conversion (RCC)
(Table 2, entry 2). Similar results were obtained in DMF (Table 2,
entry 3). Reducing the stoichiometry of 8b led to a significant
increase in RCC (22% ± 7%) (Table 2, entry 4). When applying Protocol
B which consists of mixing 8b with PhIO, a process generating
complex 5b, prior to the addition of Mn(tmp)Cl (2 mg) and [18F]TEAF
(20-30 MBq) and DMF (300 µL), a drastic improvement was observed,
and [18F]3b was obtained in 40% ± 10% RCC (n = 10) (Table 2, entry
5). When the reaction was run at 100 °C, the formation of [18F]3b was
not observed (Table 2, entry 6). No 18F-labelled product was obtained
when Mn(tmp)OTs was used as catalyst, or in the absence of
Mn(tmp)Cl (Table 2, entries 7 and 8).
aRadiochemical conversion. bn = number of reactions.c600 µL of MeCN. d300 µL of MeCN.
eMeCN removed at 100 °C after dispensing [18F]TEAF. f(n = 10). gReaction temperature =
100 °C. hCatalyst is Mn(tmp)OTs. iNo Mn Catalyst.
The
fluorine
substituent
is
advantageous
for
competition
18F-
fluorodecarboxylation as demonstrated with
a
experiment subjecting equimolar amount of pre-formed hypervalent
iodine(III) complexes 9a and 5a to 18F-fluorination with [18F]TEAF,
Mn(tmp)Cl at 50 °C in DMF. Difluoromethylarene [18F]3a was the only
product observed in the crude reaction mixture (Scheme 4A).
Furthermore, an additional competition experiment showed that the
iodine(III) complex 5a is formed preferentially to 9a (Scheme 4B).
Fluorine substitution therefore facilitates the two steps of the
process leading to fluorodecarboxylation.
A
O
O
O
O
O
O
O
O
F
ArH2
C
CH2Ar
ArFHC
CFHAr
[
18F]TEAF (20-30 MBq)
I
I
+
+
18F
18F]4a
Ar
18F
18F]3a
29% ± 1% (n = 2)
Ar
Mn(tmp)Cl (2 mg)
DMF, 50 °C, 20 min
[
[
Ar = 1,1'-biphenyl
5a
0% (n = 2)
(0.014 mmol)
9a (0.014 mmol)
O
O
O
O
O
O
O
B
ArFHC
CFHAr ArH2
C
CH2Ar
F
I
O
I
CO2
H
PIDA (0.1 mmol)
CDCl3, 50 °C
+
+
CO2
H
Ph
Ph
1a (0.2 mmol)
2a (0.2 mmol)
5a, 60%
Ar = 1,1'-biphenyl
9a, 40%
Scheme 4. A. Competition experiment subjecting equimolar amount of 9a and 5a to
18F]fluorodecarboxylation. B. Competition experiment reacting equimolar amount of 1a
and 3a with PIDA.
[
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Protocol B was applied to a selection of arenes using 20-30 MBq of 18F-recovery. Lowering the starting material stoichiometry to 0.007
View Article Online
[18F]fluoride (Scheme 5). Ether, alkyl, aldehyde, ketone, pyridine, mmol of 5b and changing the solvent from DMF to DCE afforded the
DOI: 10.1039/C8SC05096A
triazole, pyrazole, dibenzofuran motifs were all tolerated. The cartridge-purified [18F]3b in a decay corrected RCY of 12% and a
highest RCCs were obtained for electron rich arenes. [18F]3o derived molar activity of 3.0 GBq/µmol in a total synthesis time of 30
from a boronic acid analogue of Fenofibrate was successfully labelled minutes.23
in 23% ± 4% (n = 4). The boronic acid derivative of the COX-II inhibitor
ZA140 6z was transformed into the labelled difluoromethylated Pleasingly, 18F-fluorodecarboxylation also enabled access to the
product [18F]3z in 15% ± 2% RCC (n = 3).
[18F]ArOCF2H motif. The only known route to label this motif was
reported by our group, and required a multi-step synthesis of the
ArOCHFCl precursors which were themselves prepared from
ArOCHFCO2H.24 The reaction of estrone (1.0 equiv.) with ethyl
bromofluoroacetate (1.5 equiv.) and K2CO3 (2.5 equiv.) in DMF (2 mL)
at room temperature followed by a subsequent hydrolysis with
aqueous NaOH (2.5 equiv.) in 1:1 H2O/Et2O afforded the precursor
required for fluorodecarboxylation. 18F-Labelling applying protocol B
afforded [18F]11a in 21% ± 6% RCC (n = 3).
F
F
Protocol B
CO2H
18F
R
R
CHF18F
Me
CHF18F
Me
CHF18F
PhO
[
18F]3b
Ph
Me
Me
CHF18F
18F]3a
RCC = 40% ± 9%
(n = 10)a
[
[
18F]3d
[
18F]3c
RCC = 13% ± 5%
RCC = 34% ± 3%
(n = 6)a
(n = 4)a
RCC = 21% ± 3%
RCY = 12%b
(n = 4)a
MA = 3.0 GBq/µmol
CHF18F
CHF18F MeO
CHF18F
CHF18F
Conclusions
tBu
OMe
F3C
[
18F]3e
[
18F]3f
[
18F]3g
[
18F]3h
In summary, a novel method was developed to transform aryl
boronic acids to [18F]ArCF2H. Prior to labelling, the cross-coupling
with ethyl bromofluoroacetate was accomplished under Cu
catalysis followed by in situ hydrolysis. The radioisotope 18F is then
RCC = 28% ± 10%
RCC = 16% ± 7%
RCC = 21% ± 5%
RCC = 4% ± 1%
(n = 2)a
(n = 4)a
(n = 4)a
(n = 4)a
F3C
CHF18F
N
OHC
MeO
CHF18F
O
N
N
N
introduced in the last step applying
a
Mn-mediated
O
CHF18F
18F]3i
fluorodecarboxylation with readily available [18F]fluoride. This study
has unveiled three key features for this last transformation. Firstly,
the fluorine substituent on the carboxylic acid precursor is
advantageous for fluorodecarboxylation; secondly, the benefit of
preforming the hypervalent iodine complex prior to 18F-fluorination;
and thirdly, we have established that Mn-mediated
fluorodecarboxylation enables access to [18F]ArOCF2H in addition to
[18F]ArCF2H.
[
[
18F]3l
18F]3j
[
18F]3k
[
CHF18F
RCC = 9% ± 1%
RCC = 12% ± 4%
(n = 4)a
RCC = 32% ± 6%
RCC = 16% ± 4%
(n = 4)a
(n = 4)a
(n = 4)a
Me
Me
O
N
N
Me
Me Me
Me
O
F3C
CHF18F
O
CHF18F
N
N
Me
O
from Fenofibrate
18F]3o
CHF18F
[
18F]3m
[
18F]3n
[
RCC = 23% ± 4%
(n = 4)a
RCC = 21% ± 6%
RCC = 14% ± 5%
(n = 4)a
(n = 4)a
MeO
N
CHF18F
CHF18F
Conflicts of interest
MeO
There are no conflicts to declare.
CHF18F
[
18F]3x
[
18F]3y
[
18F]3w
RCC = 30% ± 8%
RCC = 36% ± 10%
(n = 4)a
RCC = 24% ± 11%
(n = 4)a
(n = 4)a
Acknowledgements
O
O
O
ZA140
[COX II inhibitor]
Me
H
S
Me
This work was supported by Pfizer, and the Engineering and
Physical Sciences Research Council (EP/N509711/1) (studentship
to J.B.I.S.). We also acknowledge the financial support from the
Cancer Research UK (C5255/A16466) (T.C.W.), The Agency for
Science, Technology and Research (A*STAR, Singapore)
(fellowship to C.W.K.), and UCB (N.J.W.S).
10z, R' = CF3
N
N
F3C
H
H
6z, R' = B(OH)2
18FFHC
O
[
18F]3z from 6z
from Estrone
RCC = 15% ± 2%
[
18F]11a, RCC = 21% ± 6%
(n = 3)a
(n = 3)a
R'
Scheme 5. Scope of [18F]fluorodecarboxylation applying Protocol B: aArCHFCO2H (0.028
mmol), PhIO (0.5 equiv.), MeCN (1 mL), 50 °C, 10 min then addition of [18F]TEAF (20-30
MBq) Mn(tmp)Cl (2 mg), DMF (300 µL), 50 °C, 20 min. bArCHFCO2H (0.014 mmol), PhIO
(0.5 equiv.), MeCN (1 mL), 50 °C, 10 min then addition of [18F]Mn(tmp)F (841 MBq) DCE
(300 µL), 60 °C, 20 min.
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