Synthesis of18F-labelled cyclooxygenase-2 (COX-2) inhibitors via Stille reaction with 4-[18F]fluoroiodobenzene as radiotracers for positron emission tomography (PET)

Article abstract of DOI:10.1039/b412871k

The Stille reaction with 4-[¹⁸F]fluoroiodobenzene as a novel approach for the synthesis of radiotracers for monitoring COX-2 expression by means of PET has been developed. Optimized reaction conditions were elaborated by screening of various ca

Full text of DOI:10.1039/b412871k

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A R T I C L E
Synthesis of 18F-labelled cyclooxygenase-2 (COX-2) inhibitors via
Stille reaction with 4-[18F]fluoroiodobenzene as radiotracers for
positron emission tomography (PET)
Frank R. Wu¨st,*a Aileen Ho¨hnea and Peter Metzb
a Institute of Bioinorganic and Radiopharmaceutical Chemistry, FZ-Rossendorf, PF 51 01 19,
D-01314, Dresden, Germany. E-mail: f.wuest@fz-rossendorf.de; Fax: +493512602951;
Tel: +493512602760
b Institute of Organic Chemistry, Technical University Dresden, Bergstraße 66, D-01069,
Dresden, Germany. E-mail: peter.metz@chemie.tu-dresden.de; Fax: +4935146333162;
Tel: +4935146337006
Received 20th August 2004, Accepted 15th November 2004
First published as an Advance Article on the web 22nd December 2004
The Stille reaction with 4-[18F]fluoroiodobenzene as a novel approach for the synthesis of radiotracers for monitoring
COX-2 expression by means of PET has been developed. Optimized reaction conditions were elaborated by screening
of various catalyst systems and solvents. By using optimized reaction conditions 18F-labelled COX-2 inhibitors [18F]-5
and [18F]-13 could be obtained in radiochemical yields of up to 94% and 68%, respectively, based upon
4-[18F]fluoroiodobenzene.
with regard to drug metabolism, in vivo activity and stability
Introduction
has been reviewed recently.6 Also, a hydrogen atom often can be
Positron emission tomography (PET) is a medical imaging
replaced bioisosterically with a fluorine atom.
technique using compounds labelled with short-lived positron
The development of COX inhibitors labelled with short-lived
emitting radioisotopes, also termed as radiotracers, for quantita-
positron emitters is currently a major focus of pharmaceutical
tive investigations of molecular and cellular transport processes
research.7 Cyclooxygenases control the complex conversion of
in vivo.1 Thus, in combination with appropriately labelled
arachidonic acid to prostaglandins and thromboxanes, which
radiotracers, PET offers exceptional possibilities to study phys-
trigger as autocrine and paracrine chemical messengers many
iology, metabolism, pharmacokinetics and modes of action
physiological and pathophysiological responses.8 The COXs
of novel and established drugs.2 For this purpose 11C and
exists in two distinct isoforms—a constitutive form (COX-1)
18F are the most useful positron emitters, which have half-
and an inducible form (COX-2). The COX-1 enzyme is respon-
lives measured in minutes, being 20.4 min and 109.6 min,
sible for maintaining homeostasis (gastric and renal integrity)
respectively. Consequently, time dominates all aspects of PET,
whereas COX-2 induces inflammatory conditions. Besides being
and organic chemistry with 11C and 18F differs significantly
associated with inflammation and pain, it is well documented
from conventional chemistry. In this connection syntheses
that especially COX-2 is overexpressed in many human cancer
involving short-lived positron emitting radionuclides require
entities. Although a large variety of COX-2 inhibitors, such as
fast and efficient reactions due to short half-lives. Moreover,
celecoxib and rofecoxib (Scheme 1), are among the most widely
use of submicromolar amounts of radiolabelled compounds,
used therapeutics for the treatment of pain and inflammation,
as typically found in the synthesis of PET radiotracers, results
their exact biological pathway still remains uncertain.
in an extraordinary stoichiometrical relation between labelled
and unlabelled reagents. Therefore, one has to develop an
appropriate radiosynthesis route considering the short half-life
and the submicromolar amounts of compounds labelled with
short-lived positron emitters such as 11C and 18F. The special
features encountered in organic chemistry with the short-lived
positron emitters 11C and 18F have extensively been reviewed
recently.3
In the last decade especially palladium-mediated carbon–
carbon bond forming reactions have proven to be very useful
Scheme 1 Selective COX-2 inhibitors.
for the synthesis of a wide variety of 11C-labelled radiotracers.4
However, only a few attempts have been made to adopt the recent
advances in palladium-mediated reactions to the synthesis of
18F-labelled radiotracers.5 Palladium-mediated carbon–carbon
or carbon–heteroatom bond forming reactions with organic
halides suggest the use of 18F-labelled aryl halides (e.g. 4-
[18F]fluoroiodobenzene) as ideally suited coupling partners. This
approach can be regarded as a general method for the mild
and efficient introduction of a 4-[18F]fluorophenyl group into
a wide variety of potential PET radiotracers. Moreover, the
4-fluorophenyl group is recognized as a common structural
component found in many fluorinated drugs. The beneficial
effect of a fluoroaryl group in drug design and development
Therefore, the development and in vivo investigation of
appropriately 18F- or 11C-labelled COX inhibitors would provide
pharmacological data, which may help to understand their
physiological actions and metabolic pathways. To date only a
few attempts have been reported on the radiolabelling of COX-2
inhibitors as radiotracers for PET. Therein, the radiolabelling
was accomplished via nucleophilic aromatic substitution with
[18F]fluoride or methylation with [11C]MeI.9 However, the ap-
proaches involving [18F]fluoride are restricted to aromatic rings,
which are sufficiently activated by the presence of electron-
withdrawing groups.
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 5 0 3 – 5 0 7
5 0 3
©

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On the other hand COX-2 inhibitors often represent 1,2-
diarylhetero- or carbocycles.10 This typical structural motif
suggests the selective introduction of a 4-[18F]fluorophenyl group
via transition metal-mediated carbon–carbon bond forming
reactions such as the Stille reaction.
In this paper we describe the synthesis of two selective
COX-2 inhibitors [18F]-5 and [18F]-13 via Stille reaction with 4-
[18F]fluoroiodobenzene as a novel approach for the synthesis of
radiotracers for monitoring COX-2 expression by means of PET
(Scheme 2). The radiolabelled COX-2 inhibitors differ in their
core structure, being a 2(5H)furanone unit (compound [18F]-5)
and a cyclopentene ring (compound [18F]-13), respectively. The
reaction conditions were optimized by extensive screening of
various catalyst systems and solvents.
fluoroiodobenzene as the coupling partner to provide reference
compound 5 in a very good yield of 88%.
The synthesis of 1-iodo-4-methanesulfonylbenzene 8 was
accomplished by conversion of 4-methylthioaniline 6 into the
corresponding iodo compound 7 employing a Sandmeyer anal-
ogous reaction (Scheme 4).12
Scheme 4 Reaction conditions: (i) 1. NaNO2, HCl, 0 ◦C, 2. KI, 80 ◦C;
(ii) oxone, MeOH–H2O.
Treatment of the intermediate diazonium salt generated from
6 with KI gave thioether 7, which was oxidized to sulfone 8 by
means of oxone in 58% total yield for both steps.
Synthesis of labelling precursor 12 and reference compound 13
containing a cyclopentene core
A different synthetic route was chosen for the preparation of
labelling precursor 12 and reference compound 13, which is
illustrated in Scheme 5.
Scheme 2 Synthetic route for the preparation of 18F-labelled COX-2
inhibitors [18F]-5 and [18F]-13.
Results and discussion
Synthesis of labelling precursor 4 and reference compound 5
containing a 2(5H)furanone core
The synthesis of 2(5H)furanone-based compounds 4 and 5 is
depicted in Scheme 3.
Scheme 5 Reaction conditions: (i) PdCl2(PPh3)2, DMF, Cs2CO3, 4-
(methanesulfonyl)phenylboronic acid, 100 ◦C; (ii) Sn2Bu6, PdCl2(PPh3)2,
dioxane, reflux; (iii) Pd(PPh3)4, toluene, EtOH, 2 M Na2CO3, 4-fluo-
rophenylboronic acid, reflux.
Application of a Suzuki–Stille and Suzuki–Suzuki re-
action sequence starting from commercially available 1,2-
dibromocyclopentene 10 provided labelling precursor 12 and
reference compound 13, respectively. The synthesis was modified
with respect to the literature procedure.13 It was found that
compound 11 could prepared in a single step starting from 4-
(methanesulfonyl)phenylboronic acid as the coupling partner
in the Suzuki cross-coupling reaction. Moreover, performance
of the reaction in DMF proved to be superior to the re-
ported solvent system toluene–EtOH–2 M Na2CO3. A two-
fold excess of 1,2-dibromocyclopentene 10 was treated with
4-(methanesulfonyl)phenylboronic acid in a first Suzuki cross-
coupling step to minimize the formation of symmetrically bis-
arylated product. Thus, compound 11 could be obtained in a
single step in 45% yield. A second Suzuki cross-coupling reaction
between compound 11 and 4-fluorophenylboronic acid gave
reference compound 13 in 69% yield. The required stannane
labelling precursor 12 was prepared via a Pd-catalyzed cross-
coupling reaction between monobromide 11 and hexabutylditin
in 45% yield.
Scheme 3 Reaction conditions: (i) Sn2Bu6, PdCl2(PPh3)2, THF, rt;
(ii) DOWEX 50W-X4, MeOH, 50 ◦C; (iii) Pd2(dba)3, AsPh3, CuI,
1-iodo-4-methanesulfonylbenzene 8, THF, 50 ◦C; (iv) PdCl2(PPh3)2,
CuI, 4-fluoroiodobenzene, DMF, 50 ◦C.
Methyl propynoate 1 was subjected to a bis-stannylation
reaction with hexabutylditin according to a literature procedure
to give the desired bis-stannylated methyl enoate 2 in 75%
yield.11 A THP-ether deprotection/lactone cyclization reaction
step by means of a cation exchange resin afforded compound 3
(83% yield) as a colourless oil. Stille reaction of bis-stannylated
compound 3 with 1-iodo-4-methanesulfonylbenzene 8 gave
labelling precursor 4 in 27% yield. The Stille reaction of 8
with bis-stannylated compound 3 exclusively gave the desired
3-(tributylstannyl)-4-aryl-2(5H)furanone regioisomer 4. This
observation is consistent with reports in the literature describing
analogous reactions.11 Moreover, 2D nuclear Overhauser effect
spectroscopy (NOESY) of compound 4 revealed a correlation
between aromatic protons at 7.50 ppm with methylene protons
at 5.17 ppm, which confirms the specified regiochemistry.
Compound 4 was further used for a second Stille reaction with 4-
Optimization of the Stille cross-coupling reaction between
stannane 4 and 4-[18F]fluoroiodobenzene
Stannane 4 was used for the optimization of the Stille cross-
coupling reaction conditions with 4-[18F]fluoroiodobenzene,
which was prepared via thermal decomposition of 4,4ꢀ-
diiododiphenyliodonium triflate in the presence of [18F]fluoride
5c,d,f
as reported recently (Scheme 6).
5 0 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 5 0 3 – 5 0 7

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tri-o-tolylphosphine and tri-2-furylphosphine resulted in a fur-
ther increase of radiochemical yield, reaching 93% (entry 12) and
98% (entry 13), respectively. Utilization of tri-2-furylphosphine
as co-ligand in the Stille reaction is known to increase the rate of
the transmetallation step of the stannane to palladium, which is
thought to be the rate-determining step of the catalytic cycle.14
Moreover, compared to other co-ligands that are commonly
used in Stille cross-coupling reactions the formed catalyst species
are remarkably stable when tri-2-furylphosphine is used.
However, in our experiments tri-2-furylphosphine was al-
ways co-eluted as a chemical impurity along with 18F-labelled
compound [18F]-5 as monitored by HPLC analysis. Complete
removal of the tri-2-furylphosphine ligand from the HPLC
fraction containing compound [18F]-5 was not possible even by
testing different eluents.15 This drawback may limit the use of
tri-2-furylphosphine as co-ligand in the radiosynthesis of 18F-
labelled compounds via Stille reaction, since the corresponding
radiotracers should be of pharmaceutical quality, which also
implies a sufficient chemical purity.
The beneficial effect of tri-o-tolylphosphine on the radiochem-
ical yield (entry 12) is mainly governed by steric effects, which
are thought to be responsible for an acceleration of the reaction
rate.14
The use of Pd(PPh3)4 as palladium complex diminished the
radiochemical yield to 40% and 27% (entries 14 and 15). The
lower radiochemical yields can be explained by the lower air
stability of Pd(PPh3)4 compared to the more air-stable Pd2(dba)3,
since the radiosynthesis was carried out without an inert gas
atmosphere.
Scheme 6 Reaction conditions: (i) [18F]KF, K222, K2CO3, DMF, 120 ◦C.
The reaction conditions were optimized by screening several
catalyst systems (palladium complex/co-ligand/additive), sol-
vents, reaction temperatures and reaction times. The radiochem-
ical yields (RCY) were determined by radio-HPLC of aliquots
taken from the reaction mixture representing the percentage
of cross-coupled product present in the reaction mixture. The
results are summarized in Table 1.
In a first set of reactions (entries 1–6) the influence of
different solvents on the radiochemical yield was studied by
using the catalyst system Pd2(dba)3/AsPh3/CuI. This catalyst
system has already successfully been applied in the Stille reaction
18
5d
of stannylated nucleosides with 4-[ F]fluoroiodobenzene.
The data show that in pure solvents, regardless of the different
polarity (DMF, THF or toluene), only low radiochemical yields
of up to 20% (entry 3) could be obtained, while most of the
4-[18F]fluoroiodobenzene remained unreacted in the reaction
mixture. When DMF was used as the solvent (entries 1 and
2), no effect of the reaction temperature (65 ◦C vs. 115 ◦C)
on the radiochemical yield could be observed. In contrast,
performance of the cross-coupling reaction at an elevated
reaction temperature (115 ◦C vs. 65 ◦C) resulted in a significantly
lower radiochemical yield when THF was the solvent (entry 3
vs. entry 4). The lowest radiochemical yields of 5% and 4%,
respectively, were observed with toluene as the solvent (entries 5
and 6).
These findings led us to the use of several solvent mixtures
in another set of reactions (entries 7–11). Also the effect of
reaction temperature on the radiochemical yield was studied.
The performance of the cross-coupling reaction in 1 : 1 mixtures
of DMF–THF or DMF–toluene at 65 ◦C gave the desired
product in 50% and 85% radiochemical yield, respectively
(entries 7 and 11). Application of higher reaction temperatures
led to the formation of non-determined side-products, which
reduced the radiochemical yield of product [18F]-5 (entry 8). This
tendency was also observed in DMF–dioxane as the solvent,
although radiochemical yields were much lower compared to
the results obtained by using DMF–THF or DMF–toluene as
the solvents (entries 9 and 10). So far, these results suggested
the use of DMF–toluene as the solvent system of choice
and 65 ◦C as the preferred reaction temperature. Further
optimization attempts were aimed at the variation of the used
co-ligands, being triphenylarsine, tri-o-tolylphosphine and tri-2-
furylphosphine (TFP), respectively (entries 11–13). The use of
Thus, for the Stille cross-coupling of stannane 4 with 4-
[18F]fluoroiodobenzene, reaction conditions according to entry
12 turned out to be most suitable with respect to the efficient
radiosynthesis of 18F-labelled COX-2 inhibitor [18F]-5 as radio-
tracer for PET. Optimized reaction conditions (according to
entry 12) were also applied to the synthesis of 18F-labelled COX-
2 inhibitor [18F]-13, and this compound could be obtained in
68% radiochemical yield based upon 4-[18F]fluoroiodobenzene.
Conclusions
In conclusion, we have developed a convenient method for
radiolabelling of two COX-2 inhibitors with the short-lived
positron emitter 18F via carbon–carbon bond formation with 4-
[18F]fluoroiodobenzene. This approach represents an alternative
route to the published methods involving nucleophilic aromatic
substitution with [18F]fluoride. Moreover, this novel method
will also be applicable to structurally related COX-2 inhibitors
bearing a 4-[18F]fluorophenyl-substituted 1,2-diarylhetero- or
carbocycle motif. The radiopharmacological evaluation of the
Table 1 Stille cross-coupling reaction of 4-[18F]fluoroiodobenzene with stannane 4a
Entry
Catalyst system
Solventb
Temperature/◦C
Reaction time/min
RCY (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Pd2(dba)3/AsPh3/CuI
Pd2(dba)3/AsPh3/CuI
Pd2(dba)3/AsPh3/CuI
Pd2(dba)3/AsPh3/CuI
Pd2(dba)3/AsPh3/CuI
Pd2(dba)3/AsPh3/CuI
Pd2(dba)3/AsPh3/CuI
Pd2(dba)3/AsPh3/CuI
Pd2(dba)3/AsPh3/CuI
Pd2(dba)3/AsPh3/CuI
Pd2(dba)3/AsPh3/CuI
Pd2(dba)3/P(o-tol)3/CuI
Pd2(dba)3/TFP/CuI
Pd(PPh3)4/AsPh3/CuI
Pd(PPh3)4/P(o-tol)3/CuI
DMF
DMF
THF
THF
toluene
toluene
DMF–THF
DMF–THF
DMF–dioxane
DMF–dioxane
DMF–toluene
DMF–toluene
DMF–toluene
DMF–toluene
DMF–toluene
65
115
65
115
100
100
65
115
65
90
65
65
65
65
20
30
20
30
10
20
20
30
20
30
20
20
20
20
20
7
10
20
9
5
4
50
3
8
0.2
85
93
98
40
27
65
a Molar ratios of stannane/Pd complex/co-ligand/CuI: 1 : 2 : 1.5 : 2. b Mixed solvents in a 1:1 mixture
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 5 0 3 – 5 0 7
5 0 5

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18F-labelled COX-2 inhibitors [18F]-5 and [18F]-13 for imaging
COX-2 expression in vivo by means of PET is currently in
progress.
the product was isolated as a colourless solid (4.1 g, 58%). Mp
◦
116–118 ◦C (Lit. 117–118 C),12 Rf (30% EtOAc–petrol ether):
0.35; 1H NMR (CDCl3, 400 MHz): d 3.04 (s, 3H, CH3), 7.66 and
7.94 (2d of AAꢀBBꢀ system, J = 7.8 Hz, 4H, Ar-H).
Experimental
1-(2-Bromocyclopent-1-enyl)-4-methanesulfonylbenzene (11).
A solution of 1,2-dibromocyclopentene 10 (500 mg, 2.2 mmol),
PdCl2(PPh3)2 (70 mg, 0.1 mmol), Cs2CO3 (1.08 g, 3.3 mmol)
and 4-(methanesulfonyl)phenylboronic acid (220 mg, 1.1 mmol)
in dry DMF (10 ml) was heated under nitrogen at 100 ◦C
overnight. After the addition of water (25 ml) the solu-
tion was extracted with EtOAc. The solvent was evaporated
and the residue was purified by flash chromatography (50%
EtOAc–petrol ether) to afford 150 mg (45%, based upon 4-
(methylsulfonyl)phenylboronic acid) of compound 11 as a solid.
General
1H NMR, 13C NMR and 19F NMR spectra were recorded on a
Varian Inova-400 at 400 MHz, 100 MHz and 376 MHz, respec-
tively. Chemical shifts (d) were determined relative to the solvent
and converted to the TMS scale. Melting points were determined
on a Cambridge Instruments GalenTM III melting point appara-
tus and are uncorrected. Mass spectra were obtained on a Quat-
tro/LC mass spectrometer (Micromass) by electrospray ionisa-
tion. Flash chromatography was conducted using MERCK silica
gel (mesh size 230–400 ASTM). Thin-layer chromatography
(TLC) was performed on Merck silica gel F-254 aluminium
plates, with visualization under UV light (254 nm). All chem-
icals were obtained from commercial suppliers (reagent grade)
and used without further purification. 4-(Tetrahydropyran-2-
yloxy)but-2-ynoic acid methyl ester 1,11 4-(tetrahydropyran-
2-yloxy)-2,3-bis-tributylstannanylbut-2-enoic acid methyl es-
ter 2,11 3,4-bis-tributylstannanyl-5H-furan-2-one 311 and 4-
methylthioiodobenzene 712 were prepared according to literature
procedures.
◦
◦
13a
Mp 105–106 C (Lit. 103.2–103.8 C), Rf (30% EtOAc–petrol
1
ether): 0.4; H NMR (CDCl3, 400 MHz): d 2.06 (quint., J =
7.6 Hz, 2H, CH2), 2.77 (t, J = 7.6 Hz, 2H, CH2), 2.88 (t, J =
7.6 Hz, 2H, CH2), 3.05 (s, 3H, CH3), 7.76 and 7.90 (2d of AAꢀBBꢀ
system, J = 8.4 Hz, 4H, Ar-H). 13C NMR (CDCl3, 100 MHz):
d 21.8, 35.9, 42.6, 44.4, 120.3, 127.1, 128.2, 136.8, 138.2, 141.4.
Tributyl-[2-(4-methanesulfonylphenyl)cyclopent-1-enyl]stan-
nane (12).
A solution of 1-(2-bromocyclopent-1-enyl)-4-
methanesulfonylbenzene 11 (300 mg, 1.0 mmol), PdCl2(PPh3)2
(35.1 mg, 50.0 lmol) and Sn2Bu6 (0.5 ml, 1.00 mmol) in
dioxane (10 ml) was heated under reflux for 16 h under a
nitrogen atmosphere. The solvent was evaporated, and product
12 was isolated as a colourless oil by flash chromatography
(20% EtOAc–petrol ether). Yield: 230 mg (45%). Rf (20%
EtOAc–petrol ether): 0.3; 1H NMR (CDCl3, 400 MHz): d
0.75–1.39 (m, 27H, SnBu3), 1.99 (quint., J = 7.5 Hz, 2H, CH2),
2.65, (m, 2H, CH2), 2.77 (m, 2H, CH2), 3.04 (s, 3H, CH3), 7.43
and 7.86 (2d of AAꢀBBꢀ system, J = 8.5 Hz, 4H, Ar-H). 13C
NMR (CDCl3, 100 MHz): d 10.1, 13.6, 24.8, 27.3, 29.1, 38.1,
42.3, 44.6, 127.1, 127.7, 138.3, 146.1, 147.2, 151.4. LRMS (ESI
positive): 535.3 [M + Na].
Chemical syntheses
4-(4-Methanesulfonylphenyl)-3-tributylstannanyl-5H-furan-2-
one (4). 1-Iodo-4-methanesulfonylbenzene
8
(282 mg,
1.0 mmol), 3,4-bis-tributylstannanyl-5H-furan-2-one 3, CuI
(15.5 mg, 80 lmol), AsPh3 (24.5 mg, 80 lmol) and Pd2(dba)3
(18.2 mg, 20 lmol) were dissolved in dry THF (7 ml). The
reaction mixture was stirred at 50 ◦C overnight under nitrogen.
The volume of the solution was concentrated to ∼3 ml and
loaded to a flash chromatography column. Elution with 80%
Et2O–petrol ether gave compound 4 (144 mg, 27%) as a
colourless oil. Rf (80% Et2O–petrol ether): 0.25; 1H NMR
(CDCl3, 400 MHz): d 0.78–1.48 (m, 27 H, SnBu3), 3.07 (s, 3H,
CH3), 5.06 (m, 2H, CH2), 7.53 and 8.02 (2d of AAꢀBBꢀ system,
J = 8.5 Hz, 4H, Ar-H). 13C NMR (CDCl3, 100 MHz): d 10.5,
13.5, 27.1, 28.8, 44.4, 73.8, 125.4, 127.9, 133.8, 139.3, 141.9,
171.4, 177.9. LRMS (ESI positive): 471.0 [M − Bu].
1-Fluoro-4-(2-(4-(methanesulfonyl)phenyl)cyclopent-1-enyl)-
benzene (13). To a solution of compound 11 (100 mg,
0.33 mmol) and 4-fluorophenylboronic acid (56 mg, 0.4 mmol)
in a solvent mixture containing of toluene (2 ml), ethanol
(2 ml) and 2 M Na2CO3 (2 ml) was added Pd(PPh3)4 (20 mg,
0.017 mmol). The mixture was refluxed overnight and then
concentrated in vacuo. The residue was purified by flash
chromatography (50% EtOAc–petrol ether) to afford 72 mg
(69%) of compound 13 as a solid. Mp 146–147 ◦C, Rf (50%
EtOAc–petrol ether): 0.6; 1H NMR (CDCl3, 400 MHz): d 2.09
(quint., J = 7.3 Hz, 2H, CH2), 2.91 (t, J = 7.3 Hz, 4H, CH2),
3.04 (s, 3H, CH3), 6.93 (m, 2H, Ar-H), 7.10 (m, 2H, Ar-H),
7.32 and 7.76 (2d of AAꢀBBꢀ system, J = 8.2 Hz, 4H, Ar-H).
13C NMR (CDCl3, 100 MHz): d 22.0, 38.6, 39.5, 44.4, 115.4 (d,
2J(C–F) = 21.6 Hz), 127.2, 128.9, 129.7 (d, 3J(C–F) = 8.0 Hz),
133.5 (d, 4J(C–F) = 3.2 Hz), 135.6, 138.1, 140.4, 144.0, 161.9 (d,
1J(C–F) = 245.4 Hz). 19F NMR (CDCl3, 376 MHz): d −114.8
(m).
3-(4-Fluorophenyl)-4-(4-methanesulfonylphenyl)-5H-furan-2-
one (5). 4-Fluoroiodobenzene (57 ll, 0.5 mmol), 4-(4-
methanesulfonylphenyl)-3-tributylstannanyl-5H-furan-2-one 4
(132 mg, 0.25 mmol), CuI (3.8 mg, 20 lmol), and PdCl2(PPh3)2
(3.5 mg, 5.0 lmol) were stirred in dry DMF (10 ml) at 50 ◦C
overnight under nitrogen. The volume of the solution was
concentrated to ∼3 ml and loaded to a flash chromatography
column, which was eluted with 50% EtOAc–petrol ether to
give 73 mg (88%) of compound 5 as a brownish solid. Mp
170–171 ◦C, Rf (50% EtOAc–petrol ether): 0.3; 1H NMR
(CDCl3, 400 MHz): d 3.07 (s, 3H, CH3), 5.17 (s, 2H, CH2),
7.08 (m, 2H, Ar-H), 7.39 (m, 2 H, Ar-H), 7.50 and 7.93 (2d
of AAꢀBBꢀ system, J = 8.3 Hz, 4H, Ar-H). 13C NMR (CDCl3,
2
100 MHz): d 44.2, 70.4, 116.1 (d, J(C–F) = 21.7 Hz), 125.0
Radiosyntheses
(d, 4J(C–F) = 3.1 Hz), 127.8, 128.2, 128.4, 131.1 (d, 3J(C–F) =
No-carrier added aqueous [18F]fluoride ion was produced in
a IBA CYCLONE 18/9 cyclotron by irradiation of [18O]H2O
via the 18O(p,n)18F nuclear reaction. Resolubilization of the
1
8.3 Hz), 153.5, 142.0, 136.1, 163.2 (d, J(C–F) = 250.4 Hz),
172.4. 19F NMR (CDCl3, 376 MHz): d −110.8 (m). LRMS (ESI
positive): 333.2 [M + H].
R
aqueous [18F]fluoride was accomplished with Kryptofixꢀ 2.2.2
1-Iodo-4-methanesulfonylbenzene(8). 4-Methylthioiodoben-
zene 7 was prepared by adapting the procedure reported
in the literature starting from 4-methylthioaniline 6 (3.1 ml,
25 mmol).12 Crude 7 in a 1 : 1 mixture of THF–MeOH (100 ml)
was treated with oxone (15.4 g, 25 mmol) in water (50 ml) at
0 ◦C, and the mixture was stirred at room temperature for 4 h.
The solvent was evaporated, and the residue was re-dissolved in
EtOAc. After flash chromatography (30% EtOAc–petrol ether)
and K2CO3. The radiosynthesis of 4-[18F]fluoroiodobenzene was
accomplished in an automated nucleophilic fluorination module
5d
(Nuclear Interface, Mu¨nster) as described by Wu¨st and Kniess.
HPLC analyses were carried out with a SUPELCOSIL LC-
18S column (4.6 × 250 mm, 5 lm) using an indicated isocratic
eluent (CH3CN–0.1 M ammonium formate) from a gradient
pump L2500 (Merck, Hitachi) with a flow rate of 1 ml min−1.
The products were monitored by a UV detector L4500
5 0 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 5 0 3 – 5 0 7

View Article Online
(Merck, Hitachi) at 254 nm and by c-detection with a scintil-
lation detector GABI (X-RAYTEST).
Antoni, M. Bjo¨rkman, B. H. Forngren, P. Hartvig, K. Markides, U.
Yngve and M. Ogren, Acta Chem. Scand., 1999, 53, 651.
¨
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Optimisation of the Stille reaction with 4-[18F]fluoroiodo-
benzene. To a vial containing stannane 4 (4 mg, 7.5 lmol),
palladium complex (15 lmol), co-ligand (12 lmol) and CuI
(3 mg, 15 lmol) in 0.5 ml of a solvent (DMF, THF, dioxane or
toluene) was added 4-[18F]fluoroiodobenzene (30–125 MBq in
0.5 ml of DMF, THF, dioxane or toluene). The sealed reaction
vial was heated at 65 ◦C, 90 ◦C, 100 ◦C or 115 ◦C. After the
indicated reaction times (see Table 1) aliquots (50 ll) were taken
and after dilution with acetonitrile the samples were subjected to
radio-HPLC analysis. The reaction yield was determined from
the radio-HPLC chromatogram representing the percentage of
radioactivity area of cross-coupled product [18F]-5 related to the
total radioactivity area.
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3-(4-[18F]Fluoro-phenyl)-4-(4-methanesulfonylphenyl)-5H-
furan-2-one ([18F]-5). HPLC analysis: CH3CN–0.1 M ammo-
nium formate (60 : 40), tR = 4.5 min.
Radiosynthesis of 1-[18F]fluoro-4-(2-(4-(methanesulfonyl)-
phenyl)cyclopent-1-enyl)benzene ([18F]-13) using optimised re-
action conditions. To a vial containing labelling precursor
12 (5 mg, 10 lmol), Pd2(dba)3 (18 mg, 20 lmol), tri-o-
tolylphosphine (4.5 mg, 15 lmol) and CuI (3 mg, 20 lmol) in
DMF (0.5 ml) was added 4-[18F]fluoroiodobenzene (35 MBq in
0.5 ml toluene). The sealed reaction vial was heated at 65 ◦C for
20 min and aliquots (20 ll) were taken for radio-HPLC analysis
after dilution with acetonitrile.
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1-[18F]Fluoro-4-(2-(4-(methylsulfonyl)phenyl)cyclopent-1-enyl)-
benzene ([18F]-13). HPLC analysis: CH3CN–0.1 M ammonium
formate (60 : 40), tR = 13.5 min.
8 L. J. Marnett, Curr. Opin. Chem. Biol., 2000, 4, 545.
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Acknowledgements
Financial support from the Deutsche Forschungsgemeinschaft
(to F. W.) is gratefully acknowledged. The authors wish to thank
S. Preusche for radioisotope production, and H. Kasper and
T. Krauss for technical assistance.
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5 0 7