Synthesis of 4-[18F]fluoroiodobenzene and its application in Sonogashira cross-coupling reactions

Article abstract of DOI:10.1002/jlcr.709

The first application of a Sonogashira cross-coupling reaction in ¹⁸F chemistry has been developed. The reaction was exemplified by the cross-coupling of terminal alkynes (ethynylcyclopentyl carbinol 6, 17α-ethynyl-3,17β-estradiol 7 and 17α-ethynyl-3-methoxy-3,17β-estradiol 8) with 4-[¹⁸F]fluoroiodobenzene. 4,4′-Diiododiaryliodonium salts were used as precursors for the synthesis of 4-[¹⁸F]fluoroiodobenzene, enabling the convenient access to 4-[¹⁸F]fluoroiodobenzene in 13-70% yield using conventional heating or microwave activation. The Sonogashira cross-coupling of 4-[¹⁸F]fluoroiodobenzene with terminal alkynes gave the corresponding 4-[¹⁸F]fluorophenylethynyl-substituted compounds [¹⁸F]-9, [¹⁸F]-10 and [¹⁸F]-13 in yields up to 88% within 20min of starting from 4-[¹⁸F]fluoroiodobenzene. Copyright

Full text of DOI:10.1002/jlcr.709

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2003; 46: 699–713.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.709
Research Article
Synthesis of 4-[18F]fluoroiodobenzene and its
application in sonogashira cross-coupling reactions
.
Frank R. Wust* and Torsten Kniess
Institut fu.r Bioanorganische und Radiopharmazeutische Chemie, FZ-Rossendorf
e.V., Dresden, Germany
Summary
The first application of a Sonogashira cross-coupling reaction in 18F chemistry
has been developed. The reaction was exemplified by the cross-coupling of
terminal alkynes (ethynylcyclopentyl carbinol 6, 17a-ethynyl-3,17b-estradiol 7
and 17a-ethynyl-3-methoxy-3,17b-estradiol 8) with 4-[18F]fluoroiodobenzene.
4,40-Diiododiaryliodonium salts were used as precursors for the synthesis of 4-
[18F]fluoroiodobenzene, enabling the convenient access to 4-[18F]fluoroiodo-
benzene in 13–70% yield using conventional heating or microwave activation.
The Sonogashira cross-coupling of 4-[18F]fluoroiodobenzene with terminal
alkynes gave the corresponding 4-[18F]fluorophenylethynyl-substituted com-
pounds [18F]-9, [18F]-10 and [18F]-13 in yields up to 88% within 20 min of
starting from 4-[18F]fluoroiodobenzene. Copyright # 2003 John Wiley & Sons,
Ltd.
Key Words: [18F]fluoroiodobenzene; sonogashira cross-coupling; 18F-labelled
steroids
Introduction
The extensive development of novel radiolabelling techniques with the
short-lived positron emitters 11C and 18F represents a fundamental but
challenging task. With regard to the special requirements encountered
.
*Correspondence to: F. R. Wust, Institut fur Bioanorganische und Radiopharmazeutische Chemie,
FZ-Rossendorf e.V., Dresden, Germany. E-mail: f.wuest@fz-rossendorf.de
.
Contract/grant sponsor: Deutsche Forschungsgemeinschaft
Copyright # 2003 John Wiley & Sons, Ltd.
Received 13 January 2003
Revised 19 February 2003
Accepted 26 February 2003

¨
F. R. WUST AND T. KNIESS
700
by the synthesis of PET radiotracers special attention has to be paid to
rapid, selective and functional group-tolerating reactions. In this
connection the use of catalysts such as enzymes or transition metal
complexes have proved to be particularly valuable tools in the rapid and
efficient syntheses of a wide variety of 11C-labelled radiotracers.1–6
Hence, the application of copper- and palladium-mediated cross-
coupling reactions for distinct 11C–C bond forming reactions has
significantly extended the number of 11C-labelled compounds.
However, only a few attempts have been made to adopt the recent
advances in transition-metal catalysed reactions to the synthesis of 18F-
labelled radiotracers.7–10 The palladium-catalysed cross-coupling reac-
tions of organometallic compounds like Grignard reagents, tin, or
boron derivatives with organic halides suggests the use of 18F-labelled
aryl halides as the 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 complex functionalized
target molecules. The 4-fluorophenyl group is a common structural
component found in many fluorinated drugs. The beneficial effect of a
fluoroaryl group in drug design and development with regard to drug
metabolism, in vivo activity and stability has been reviewed re-
cently.11,12 The first few reports on the synthesis of 18F-labelled
radiotracers via palladium-mediated cross-coupling reactions have
mainly exploited the Stille reaction7–9 and in one case a Hartwig–
Buchwald N-arylation reaction.10 The reaction of vinyl or aryl tin
reagents with 4-[18F]fluoro-bromobenzene or 4-[18F]fluoroiodobenzene
led to the formation of 4-[18F]fluorostyrenes, 4-[18F]fluoro-biphenyls
and the nicotinic acetylcholine receptor ligand 9-(40-[18F]fluoro-phe-
nyl)cytisine.7–9 The reaction of
4-[18F]fluorobromobenzene according to
a
piperazine derivative with
Hartwig-Buchwald
a
N-arylation protocol provided the 5-HT2A receptor antagonist
[18F]RP 62203.10 (Figure 1).
The synthesis of 4-[18F]fluorohalobenzenes can be accomplished via
three different routes. The one-step synthesis of 4-[18F]fluoroiodoben-
zene starting from 4-iodophenyltrimethylammonium triflate only gives
low yields (5–10%, decay-corrected) due to the formation of large
amounts of [18F]fluoromethane originating from a competitive nucleo-
philic aliphatic substitution reaction.7 Alternatively, 4-[18F]fluorobro-
mobenzene can be synthesized in a two-step process comprising the
nucleophilic fluorination of 5-bromo-2-nitrobenzaldehyde and subse-
quent reductive decarbonylation with Wilkinson catalyst.7,13 A third
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 699–713

SYNTHESIS OF 4-[18F]FLUORO
701
HN
Stille-
reaction
N
O
18F
9-(4´-[18F]fluorophenyl)cytisine
X
18F
X = Br, I
O
O
N
N
N-arylation
S
N
18F
[
18F]RP 62203
Figure 1. Cross-coupling reactions with 4-[18F]fluorohalobenzenes
approach for the synthesis of 4-[18F]fluorohalobenzenes consists of the
thermal decomposition of diaryliodonium salts in the presence of
[18F]fluoride.14–17 This route was shown to be very efficient in the
synthesis of several [18F]fluoroarenes in moderate to high radiochemical
yields.
Recently we have developed a modified Sonogashira-like reaction for
the cross-coupling of terminal alkynes with the readily available 11C
labelling precursor [11C]MeI.18 In this paper we describe for the first
time Sonogashira cross-coupling reactions in 18F chemistry. For this
purpose we have developed a convenient route to 4-[18F]fluoroiodo-
benzene via symmetrical diiododiphenyliodonium salts in order to
circumvent the regioselectivity problems encountered in the 18F-
labelling when non-symmetrical iodonium salts are used.14–16 The
Sonogashira reaction19 was exemplified by reacting 4-[18F]fluoroiodo-
benzene with terminal alkynes (ethynylcyclopentyl carbinol 6, 17a-
ethynyl-3,17b-estradiol 7 and 17a-ethynyl-3,17b-estradiol-3-methylether
8) to form the corresponding 4-[18F]fluorophenylethynyl-substituted
compounds [18F]-9, [18F]-10 and [18F]-13.
Results and discussion
Synthesis of 4,40-diiododiphenyliodonium salts 2, 3 and 5
The syntheses of symmetrical 4,40-diiododiphenyliodonium salts 2, 3
and 5 were accomplished via two different routes, being the coupling of
iodobenzene with iodyl sulfate 120,21 in sulfuric acid and the
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 699–713

¨
F. R. WUST AND T. KNIESS
702
condensation of 4-iodo-1-(diacetoxyiodo)benzene 4 with iodobenzene in
the presence of trifluoromethane sulfuric acid (Figure 2).
I
-
-
I
OTs
Cl
I
+
AgOTs
+
(IO)2SO4
HCl
I
I
I
I
3
2
1
I
-
OTf
I
I(OAc)2
I
+
CH3CO3H
TfOH
I
I
I
I
4
5
Figure 2. Synthesis of 4,40-diiododiphenyliodonium salts
The first approach started from iodyl sulfate 1 and its subsequent
reaction with iodobenzene followed by HCl to form 4,40-diiododiphe-
nyl-iodonium chloride 2 in 37% yield. The chloride ion was replaced
with the tosylate anion by refluxing the chloride salt 2 in methanol with
silver tosylate to yield 25% of 4,40-diiododiphenyliodonium tosylate 3.
An alternative route was employed by refluxing 1,4-diiodobenzene with
peracetic acid to give 4-iodo-1-(diacetoxyiodo)benzene 4 in 63%
isolated yield. This compound was treated with trifluorosulfonic acid
and iodobenzene to give 4,40-diiodo-diphenyliodonium triflate 5 in 32%
yield.
Synthesis of reference compounds
The syntheses of the 4-fluorophenylethynyl-substituted compounds 9,
10 and 13 were accomplished by employing a Sonogashira cross-
coupling reaction of 4-fluoroiodobenzene with the corresponding
terminal alkynes 6, 7 and 8 in the presence of CuI and Pd[PPh3]4 as
catalysts and triethylamine as the base. The desired cross-coupled
products 9, 10 and 13 could be obtained in high yields of 78–94% after
purification by flash chromatography.
The thermal decomposition of the diiododiphenyliodonium salts in
the presence of [18F]fluoride to form 4-[18F]fluoroiodobenzene leads to
rather large amounts of iodobenzene and 1,4-diiodobenzene as non-
radioactive by-products. Therefore, we also set up the syntheses of 17a-
phenylethynyl-3,17b-estradiol 11 and 17a-(4-iodophenylethynyl)-3,17b-
estradiol 12 to prove the expected competitive reaction of iodobenzene
and 1,4-diiodobenzene in the Sonogashira cross-coupling of 17a-
ethynyl-3,17b-estradiol 8 with 4-[18F]fluoroiodobenzene. The reaction
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 699–713

SYNTHESIS OF 4-[18F]FLUORO
703
of iodobenzene and 1,4-diiodobenzene with 17a-ethynyl-3,17b-estradiol
8 was accomplished according to a similar Sonogashira reaction
employed for the synthesis of compounds 8, 9 and 10, yielding 96%
of 11 and 59% of 12, respectively.
The syntheses of all reference compounds via a Sonogashira cross-
coupling reaction are depicted in Figure 3.
I
HO
OH
F
F
Pd[PPh3]4, CuI
THF, TEA
6
9
X
OH
OH
I
X
Pd[PPh3]4, CuI
THF, TEA
RO
RO
R = H, X = F 10
R = H, X = H 11
R = H, X = I 12
R = Me, X = F 13
R = H
R = Me 8
7
Figure 3. Synthesis of reference compounds
Synthesis of 4-[18F]fluoroiodobenzene
The symmetrical 4,40-diiododiphenyliodonium salts 2, 3 and 5 were used
as precursors for radiofluorinations with [18F]fluoride to yield 4-
[18F]fluoroiodobenzene as the only radioactive product along with
non-reacted [18F]fluoride. The conventional heating was carried out in a
sealed vial containing the iodonium salt (20 mg) and resolubilized
[18F]KF in an aprotic solvent (DMF, DMSO or acetonitrile) using an
oil bath at different temperatures for 40 min. Alternatively, microwave
activation at 120 W for 5 min was used (Figure 4).
X-
18F
K2CO3, K222, [18F]F-
I
I
I
+
+
+
I
I
I
I
X = Cl
2
X = OTs 3
X = OTf 5
Figure 4. Radiosynthesis of 4-[18F]fluoroiodobenzene
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 699–713

¨
F. R. WUST AND T. KNIESS
704
By varying the counter anion (chloride, tosylate and triflate) of the
diiododiphenyliodonium salts, the reaction temperature (80, 100, 120,
140, 1608C and microwave activation) and the solvent (acetonitrile,
DMF and DMSO) the radiochemical yield of 4-[18F]fluoroiodobenzene
could reach up to 70%. The yield of 4-[18F]fluoroiodobenzene was
determined by radio-TLC. The results are given in Table 1.
Table 1. Reaction conditions for the synthesis of 4-[18F]fluoroiodobenzene.
Run
Precursor
X
Solvent
Temperature/
microwave
(MW) (8C)
Yield of 4-[18F]
fluoroiodobenzene
(%)
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
3
3
5
5
5
5
2
5
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
OTs
OTs
OTf
OTf
OTf
OTf
Cl
CH3CN
CH3CN
CH3CN
DMF
DMF
DMF
DMF
DMSO
CH3CN
DMF
CH3CN
CH3CN
DMF
80
100
120
100
120
140
160
140
100
140
80
100
140
140
MW
MW
0.5–1.0
1.6–3.0
1.3–2.8
3–12
8–19
13–63
15–52
0.5–1.0
0.5–2.5
21–46
0.5–1.0
2.5–5
11–22
0.5–1.0
15–70
16–37
9
10
11
12
13
14
15
16
DMSO
DMF
DMF
OTf
The summary clearly shows the important influence of temperature
and solvent on the radiochemical yield, showing a maximum at 1408C
with DMF as the solvent (runs 4–7,10,13). This finding agrees with the
16
results obtained by Gail et al. since high reaction temperatures seem
to be essential for an efficient thermal decomposition of diaryliodonium
salts in a highly polar aprotic solvent. However, the reported high
radiochemical yields of several [18F]fluoroarenes in the reaction of
[18F]fluoride with diaryliodonium salts in acetonitrile as the solvent
using lower reaction temperatures (80–1008C)15 could not be repro-
duced (runs 1, 2, 9, 11 and 12). In our experiments acetonitrile always
gave considerable lower yields than DMF. Surprisingly, DMSO as an
otherwise very efficient polar aprotic solvent gave only very low
radiochemical yields of 4-[18F]fluoroiodobenzene (runs 8 and 14), being
less than 1%.
The influence of the diiododiphenyliodonium salt counter anion
(chloride, tosylate and triflate) on the radiochemical yield was also
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 699–713

SYNTHESIS OF 4-[18F]FLUORO
705
studied. Despite the better solubility of tosylate precursor 3 and triflate
precursor 5 in DMF the obtained radiochemical yields are in the same
range or even slightly higher when the less DMF-soluble chloride
precursor 2 was used (runs 6, 10 and 13). However, starting from
chloride precursor 2 the radiochemical yields are obtained over a wide
range, from 13 to 63% (run 6). The obtained radiochemical yields using
tosylate precursor 3 (run 10) and triflate precursor 5 (run 13) are more
reproducible, ranging from 21–46% and 11–22%, respectively.
Microwave activation did not further improve the radiochemical yield
of 4-[18F]fluoroiodobenzene (runs 15 and 16), but the reduction of
reaction time from 40 to 5 min is of great advantage in the work with the
short-lived positron emitter 18F. Again, the radiochemical yields
obtained with chloride precursor 2 vary widely, from 15 to 70%.
The 4-[18F]fluoroiodobenzene was purified by solid phase extraction
(SPE) to provide a radiochemically pure product (>95%) suitable for
subsequent Sonogashira cross-coupling reactions with terminal alkynes.
It is of great importance to mention that in all our experiments with
symmetrical diiododiphenyl iodonium salts 2, 3 and 5 the formation of
1,4-diiodobenzene and iodobenzene as non-radioactive by-products was
observed. This finding has not been reported yet in the literature dealing
with the synthesis of [18F]fluoroarenes via thermal decomposition of
non-symmetrical diaryliodonium salts. Therefore, we also set up an
experiment using the non-symmetrical iodonium salt 4-iodophenyl(to-
lyl) triflate in the radiolabelling with [18F]fluoride in DMF at 1408C for
40 min. As expected we found [18F]fluoroiodobenzene as the only
radioactive product (10–15% yield) along with 1,4-diiodobenzene,
iodobenzene and 4-iodotoluene as non-radioactive by-products origi-
nating from thermal decomposition of the iodonium salt.
The non-radioactive iodoarene by-products could not be removed by
solid phase extraction. Since we were starting from symmetrical
diiododiphenyliodonium salts the formation of 1,4-diiodobenzene and
iodobenzene as by-products is inevitable. Hence, they will act as
competitive ligands in the subsequent Sonogashira cross-coupling
reaction of terminal alkynes 6, 7 and 8 with 4-[18F]fluoroiodobenzene.
Sonogashira cross-coupling reactions with 4-[18F]fluoroiodobenzene
SPE-purified 4-[18F]fluoriodobenzene (50–150 MBq) was used in the
palladium–copper catalysed Sonogashira cross-coupling with terminal
alkynes 6, 7 and 8 (Figure 5).
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 699–713

¨
F. R. WUST AND T. KNIESS
706
HO
18F
6
[
18F]-9
Pd[PPh3]4, CuI
I
18F
THF, TEA
18F
OH
7, 8
RO
X = H
X = Me [18F]-13
[
18F]-10
Figure 5. Sonogashira cross-coupling with 4-[18F]fluoroiodobenzene
The reactions were performed in a sealed vial at 1108C for 20 min
using THF as the solvent and triethylamine as the base. The obtained
radiochemical yields were determined by monitoring the conversion of
4-[18F]fluoroiodobenzene into the corresponding cross-coupled pro-
ducts. 85% of 4-[18F]fluoroiodobenzene was converted into cross-
coupled product [18F]-9, 65–88% into [18F]-10 and 34–64% into [18F]-13,
respectively. Lowering the reaction temperature to 608C did not lead to
any product formation. Also the use of triethylamine as the solvent and
the base gave no cross-coupled products. The optimum amount of
components in the cross-coupling reaction was found to be about 3 mg
for each component. Higher amounts of catalyst (CuI and Pd[PPh3]4)
and terminal alkynes did not further improve the radiochemical yields.
The competitive cross-coupling reaction of 1,4-diiodobenzene and
iodobenzene originating from the synthesis of 4-[18F]fluoroiodobenzene
was studied by the reaction of 4-[18F]fluoroiodobenzene with 17a-
ethynyl-3,17b-estradiol 8. The corresponding cross-coupled products 11
and 12 could be identified by comparing the retention times of pure
reference compounds with the HPLC-trace of the reaction mixture. As
expected, the phenylethynyl compound 11 and 4-iodophenylethynyl
compound 12 could be found in the UV-trace of the HPLC-
chromatogram of the reaction mixture, showing retention times of 8.7
and 14.7 min, respectively. The retention time of the desired 18F-labelled
cross-coupling product [18F]-10 was found to be 9.1 min.
The strong electron-withdrawing effect of the fluorine atom and the
trace amounts of 4-[18F]fluoroiodobenzene make this ligand probably
the most reactive partner in the Sonogashira cross-coupling cycle
resulting in moderate to high radiochemical yields of 34–88%. However,
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 699–713

SYNTHESIS OF 4-[18F]FLUORO
707
when the presented Sonogashira reaction is aimed at 18F-labelled
receptor-binding ligands, the effective specific radioactivity24 will
probably be low, since the exact separation of the [18F]fluoropheny-
lethynyl compound from the non-radioactive phenylethynyl compound
was found to be very challenging. All our attempts to achieve a sufficient
separation of [18F]-10 from 11 by varying the RP-HPLC-separation
conditions have failed.
To circumvent that problem it will be necessary to develope an
approach to synthesize radiochemically and chemically pure 4-
[18F]fluoroiodobenzene. In this respect the substitution of 4-[18F]fluor-
oiodobenzene with [18F]fluorobromobenzene could be an attractive
alternative. [18F]fluorobromobenzene can be synthesized in high radio-
chemical and chemical purity.7,13 Investigations on the application of
[18F]fluorobromobenzene in the Sonogashira reaction are currently in
progress.
Conclusions
We have developed a novel approach for a transition-metal mediated
carbon–carbon bond formation in 18F chemistry, being the Sonogashira
cross-coupling of terminal alkynes with 4-[18F]fluoroiodobenzene. The
reaction proceeds in sufficient radiochemical yields in short reaction
times, and the reaction is compatible with functional groups such as
hydroxyl. However, the utilized 4-[18F]fluoroiodobenzene is contami-
nated with 1,4-diiodobenzene and iodobenzene, causing competitive
cross-coupling reactions which result in the formation of non-radio-
active by-products which interfere with the separation process. An
alternative approach using radiochemically and chemically pure 4-
[18F]fluorobromobenzene is currently under investigation.
Experimental
General
1H-NMR, 13C-NMR and 19F-NMR spectra were recorded on a Varian
Inova-400 at 400, 100 and 376 MHz, respectively. Chemical shifts (d) are
determined relative to the solvent and converted to the TMS scale. The
13C-NMR data of steroids are reported as: chemical shift (assignment of
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 699–713

¨
F. R. WUST AND T. KNIESS
708
carbon atom according to steroid numbering). Elemental analysis were
obtained on a LECO CHNS 932 elemental analyser. Mass spectra were
obtained on a Quattro/LC mass spectrometer (Micromass) by electro-
spray ionisation. Melting points were determined on a Galen III melting
point apparatus (Cambridge Instruments) and are uncorrected. Flash
chromatography was conducted according to Still et al.22 using
MERCK silica gel (mesh size 230–400 ASTM). Thin-layer chromato-
graphy (TLC) was performed on Merck silica gel F-254 plastic plates,
with visualization under UV (254 nm).
All chemicals were obtained from commercial suppliers of reagent
grade and used without further purification. Reactions using microwave
activation were performed with a MICROWELL 10 oven (Labwell
AB).
Chemical synthesis
4; 40-Diiododiphenyliodonium chloride 2. A mixture of concentrated
sulfuric acid (15 ml) and 30% fumic sulfuric acid (30 ml) was added to
iodine (12.7 g, 50 mmol) under stirring. Then a mixture of concentrated
sulfuric acid (4 ml), 65% fumic sulfuric acid (2 ml), and 100% fumic
nitric acid (6.5 ml) was slowly added. The reaction mixture was stirred at
70–808C for 1.5 h, at which time yellow crystals of iodyl sulfate 1
precipitated. The mixture was then cooled to 08C, and iodobenzene
(51 g, 250 mmol) was slowly added. The mixture was stirred at 458C for
2 h and then cooled to 08C. Water was very carefully added in small
portions. The nitrogen oxides were removed by a gentle stream of
nitrogen. The product, a brown oil, was collected, dissolved in
methanol, and crystallized as the chloride salt 2 by dropwise addition
of concentrated hydrochloric acid. Yield: 52.6 g (37%). Melting point
198–2008C. Analytically calculated for C12H8ClI3: C, 25.36; H, 1.42.
Found: C, 24.93; H, 1.18.
4; 40-Diiododiphenyliodonium tosylate 3. 4; 40-Diiododiphenyiodonium
chloride 2 (2.84 g, 5.0 mmol) and AgOTs (1.4 g, 5.0 mmol) were refluxed
in methanol (100 ml) for 30 min. The mixture was filtered hot, and the
filtrate was evaporated to a final volume of 5 ml. Diethyl ether was
added, and the white precipitate was filtered off and dried under vacuum
1
to give 0.9 g (25%) of 3 as a white solid. Melting point 152–1548C. H-
NMR (DMSOd6): d 3.84 (s, 3H; CH3), 7.06 (d, J ¼ 8:2 Hz, 2H; Ar-H),
7.43 (d, J ¼ 8:2 Hz, 2H; Ar-H), 7.81 (d, J ¼ 8:7 Hz, 4H; Ar-H), 7.93 (d,
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 699–713

SYNTHESIS OF 4-[18F]FLUORO
709
J ¼ 8:7 Hz, 4H; Ar-H). 13C-NMR (DMSOd6): d 21.14, 100.62, 116.50,
125.80, 128.46, 137.15, 138.18, 140.64, 145.57. Analytically calculated
for C19H15I3O3S: C, 32.41; H, 2.15; S 4.55. Found: C, 31.96; H, 2.49; S,
4.76.
4-Iodo-1-(diacetoxyiodo)-benzene 4. 1,4-diiodobenzene (3.29g, 10mmol)
was suspended under stirring in 40% peracetic acid (19ml). The mixture
was carefully warmed up to 408C and after refluxing a yellow precipitate
was formed. After cooling the precipitate was filtered off and washed with
acetic acid. The product was re-crystallized from acetic acid/acetic
anhydride (4:1) to give 2.84g (63%) of 4 as a white solid. Melting point
1
170–1728C. H-NMR (DMSOd6): d 1.89 (s, 6H; CH3), 7.49 (m, 4H; Ar-
H). Analytically calculated for C10H10I2O4: C, 26.81; H, 2.25. Found: C,
26.50; H, 2.47.
4; 40-Diiododiphenyliodonium triflate 5. 4-Iodo-1-(diacetoxyiodo)-ben-
zene 4 (582 mg, 1.3 mmol) was suspended in dry dichloromethane
(20 ml) and cooled to ꢀ308C while stirring under nitrogen. Then
trifluoro-methane sulfonic acid (230 ml, 2.6 mmol) was added dropwise
over 2 h. The mixture was warmed up to 08C and stirring was continued
for 1 h at 08C. During this time a clear yellow solution was produced.
After re-cooling to ꢀ308C iodobenzene (265 mg, 1.3 mmol) in dichlor-
omethane (1 ml) was added, and the mixture was stirred at ambient
temperature overnight. The yellow solution was evaporated under
vacuum and the residue was treated with diethyl ether. The white solid
was filtered off, washed with diethyl ether and dried to give 287 mg
1
(32%) of 5. Melting point 185–1878C. H-NMR (DMSOd6): d 7.88 (d,
4H; Ar-H), 7.98 (m, 4H; Ar-H), 13C-NMR (DMSOd6): 131.81, 135.18,
136.77, 140.40. Analytically calculated for C13H8F3I3O3S: C, 22.90; H,
1.18; S, 4.70. Found: C, 22.48; H, 1.05; S, 4.57. LRMS (ESI positive)
532.6 [M-OTf].
General procedure for the Sonogashira cross-coupling reaction to give
compounds 9; 10; 11; 12 and 13. A solution of the terminal alkyne (6, 7
and 8, 1 mmol), the iodoarene (1,4-fluoroiodobenzene, iodobenzene
or 1,4-diiodobenzene, 1 mmol), CuI (0.04 mmol) and Pd[PPh3]4
(0.02 mmol) was refluxed in THF (5 ml) and triethylamine (5 ml) for
3 h under an argon atmosphere. After cooling the solvent was
evaporated and the residue was purified by flash chromatography
(50% EtOAc/hexane) to give the corresponding cross-coupled products.
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 699–713

¨
F. R. WUST AND T. KNIESS
710
4-fluorophenylethynyl-cyclopentylcarbinol 9. Yield: 88%. Melting point
1
39-418C. H-NMR (CDCl3): d 1.75-1.90 (m, 4H; 2 ꢁ CH2), 2.00–2.06
(m, 4H; 2 ꢁ CH2), 6.98 (m, 2H; Ar–H), 7.39 (m, 2H; Ar–H). 13C-NMR
(CDCl3): 23.48, 42.49, 74.84, 82.03, 92.51, 115.47 (d, JCF ¼ 21:4 Hz),
118.92 (d, JCF ¼ 3:0 Hz), 133.44 (d, JCF ¼ 9:2 Hz), 162.38 (d,
JCF ¼ 250:2 Hz). 19F-NMR (CDCl3): d -111.65 (dt, J ¼ 18:9 Hz,
J ¼ 5:4 Hz).
17a-(4-fluorophenylethynyl)-3,17b-estradiol 10. Yield: 94%. Melting
1
point 85–888C. H-NMR (CDCl3): 0.93 (s, 3H; 18-CH3), 2.81 (m, 2H;
6a/6b-H), 6.56 (d, J ¼ 2:5 Hz, 1H; 4-H), 6.63 (dd, J ¼ 8:6 Hz,
J ¼ 2:5 Hz, 1H; 2-H), 7.00 (m, 2H; Ar–H), 7.16 (d, J ¼ 8:6 Hz, 1H; 1-
H), 7.42 (m, 2H; Ar–H). 13C-NMR (CDCl3): 12.86(18), 22.56(15),
26.20(11) 26.95(7), 29.19(8), 32.89(12), 39.04(16), 39.44(6) 43.33(9),
47.20(13), 49.33(14), 78.54(17), 82.96(C ꢂ C), 94,72(C ꢂ C), 112.70(2),
114.88(4), 115.64 (d, JCF ¼ 22:0 Hz), 119.32, 126.05(1), 130.21(10),
133.42 (d, JCF ¼ 8:3 Hz), 137.10(5), 154.87(3), 162.84 (d,
JCF ¼ 245:8 Hz). 19F-NMR (CDCl3): -111.48 (quint. J ¼ 5:4 Hz).
Analytically calculated for C26H27FO2: C, 79.97; H, 6.97. Found: C,
80.06; H, 6.84. LRMS (ESI positive) 413.0 [M+Na].
17a-(phenylethynyl)-3,17b-estradiol 11. Yield: 96%. Melting point 155-
1578C. 1H-NMR (DMSOd6): 0.81 (s, 3H; CH3), 2.70 (m, 2H; 6a/6b-H),
5.46 (s, 1H; 17-OH), 6.43 (d, J ¼ 2:5 Hz, 1H; 4-H), 6.51 (dd, J ¼ 8:6 Hz,
J ¼ 2:5 Hz, 1H; 2-H), 7.06 (d, J ¼ 8:6 Hz, 1H; 1-H), 7.34–7.37 (m, 3H;
Ar–H), 7.38–7.42 (m, 2H; Ar–H), 8.99 (s, 1H; 3-OH), 13C-NMR
(DMSOd6): 12.83(18), 22.51(15), 26.16(11), 26.91(7), 29.13(8), 32.84(12),
38.84(16), 39.21(6), 43.31(9), 47.17(13), 49.29(14), 78.50(17),
83.94(CꢂC), 94.97(CꢂC), 112.65(2), 114.81(4), 122.85, 126.03(1),
128.06, 128.53, 130.40, 131.11(10), 137.04(5), 154.82(3). Analytically
calculated for C26H28O2: C,83.83; H,7.58. Found: C,83.21; H,7.32.
LRMS (ESI positive) 373.5 [M+H].
17a-(4-iodophenylethynyl)-3,17b-estradiol 12. Yield: 59%. Melting
1
point 219–2228C. H-NMR (DMSOd6): 0.79 (s, 3H; CH3), 2.69 (m,
2H; 6a/6b-H), 5.48 (s, 1H; 17-OH), 6.42 (d, J ¼ 2:2 Hz, 1H; 4-H), 6.50
(dd, J ¼ 8:3 Hz, J ¼ 2:2 Hz, 1H; 2-H), 7.05 (d, J ¼ 8:3 Hz, 1H; 1-H),
7.19 and 7.71 (2d of AA0BB0system, J ¼ 8:3 Hz, 4H; Ar–H), 8.97 (s, 1H;
3-OH), 13C-NMR (DMSOd6): 12.88(18), 22.58(15), 26.20(11), 26.98(7),
29.20(8), 32.92(12), 38.73(16), 39.19(6), 43.35(9), 47.25(13), 49.39(14),
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 699–713

SYNTHESIS OF 4-[18F]FLUORO
711
78.62(17), 83.25(CꢂC), 94.58(CꢂC), 96.51, 112.73(2), 114.91(4), 122.37,
126.10(1), 130.20, 132.96(10), 137.13(5), 137.44, 154.89(3). Analytically
calculated for C26H27O2I: C, 62.66; H, 5.46. Found: C, 62.61; H, 5.55.
LRMS (ESI positive) 520.9 [M+H].
17a-(4-fluorophenylethynyl)-3,17b-estradiol-3-methylether 13. Yield: 78%.
Melting point 52–548C. 1H-NMR (CDCl3): 0.94 (s, 3H; 18-CH3), 2.87 (m,
2H; 6a/6b-H), 3.78 (s, 3H; OCH3), 6.65 (d, J ¼ 2:9 Hz, 1H; 4-H), 6.74 (dd,
J ¼ 8:6 Hz, J ¼ 2:9 Hz, 1H; 2-H), 7.01 (m, 2H; Ar–H), 7.23 (d,
J ¼ 8:6 Hz, 1H; 1-H), 7.45 (m, 2H; Ar–H), 13C-NMR (CDCl3):
12.86(18), 22.89(15), 26.44(11), 27.23(7), 29.81(8), 33.06(12), 39.01(16),
39.44(6), 43.62(9), 47.57(13), 49.76(14), 55.15(3-OCH3), 80.27(17),
85.14(CꢂC), 92.68(CꢂC), 111.45(2), 113.74(4), 115.66 (d, JCF=22.0 Hz),
118.99, 126.59(1), 132.70(10), 133.80 (d, JCF = 8.3 Hz) 138.19(5),
157.66(3), 161.44 (d, JCF = 248,1 Hz). 19F-NMR (CDCl3): -111.42 (m).
Analytically calculated for C27H29O2F: C, 80.17; H, 7.23. Found: C, 79.91;
H, 6.93. LRMS (ESI positive) 426.9 [M+H].
Radiochemical syntheses
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 aqueous [18F]fluor-
ide (300–700 MBq) was accomplished as described by Coenen et al.23
with Kryptofix1 2.2.2 and K2CO3 in a conical vial and azeotropically
removing water with acetonitrile in a stream of nitrogen. Finally the
dried [18F]KF was resolubilized in an appropriate volume of anhydrous
solvent (acetonitrile, DMSO or DMF). HPLC analyses were carried out
with a Phenomenex RP 18 column (LUNA C18(2) 4.6 ꢁ 250 mm, 5 mm)
using an indicated isocratic eluent with a flow rate of 1.0 ml/min. The
products were monitored by UV detector L4500 (Merck, Hitachi) at
254 nm and by g-detection with a scintillation detector GABI (X-
RAYTEST). For radio-TLC detection a BAS 2000 scanner (FUJIX)
was used.
General procedure for the synthesis of 4-[18F]fluoroiodobenzene
The dried [18F]KF (300–700 MBq) in 1 ml of solvent (acetonitrile, DMF
or DMSO) was heated in a sealed conical vial in the presence of 4,40-
diiododiphenyliodonium salts 2, 3 or 5 (20 mg) by means of an oil bath
at the indicated temperatures for 40 min or mirowaved for 5 min at
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 699–713

¨
F. R. WUST AND T. KNIESS
712
120 W. The mixture was diluted with water (10 ml) and passed through a
Chromafix RP18 cartridge (200 mg, pre-conditioned with 5 ml ethanol
and 10 ml water). The cartridge was washed with water (5 ml), dried
with
a
stream of nitrogen and the 4-[18F]fluoroiodobenzene
(50–150 MBq) was eluted from the cartridge using THF (2 ml). Radio-
TLC: Rf ¼ 0:420:5, hexane). HPLC-analysis: acetonitrile/water (80/20),
tR ¼ 6:5 min, acetonitrile/water (70/30), tR ¼ 9:8 min.
General procedure for the Sonogashira reaction with 4-[18F]fluoroiodo-
benzene
A vial containing the terminal alkyne 6, 7 or 8 (3 mg), CuI (3 mg),
Pd[PPh3]4 (3 mg), triethylamine (1 ml) and 4-[18F]fluoroiodobenzene
(50–150 MBq in 2 ml THF) was sealed and heated in an oil bath (1108C)
for 20 min. After cooling aliquots were taken for radio-HPLC analysis.
4-[18F]fluorophenylethynyl-cyclopentylcarbinol [18F]-9. Yield: 85%,
radio-HPLC-analysis: acetonitrile/water (70/30), tR ¼ 3:1 min.
17a-(4-[18F]fluorophenylethynyl)-3,17b-estradiol
[18F]-10. Yield:
65–88%, radio-HPLC-analysis: acetonitrile/water (70/30), tR ¼ 9:1 min.
17a-(4-[18F]fluorophenylethynyl)-3,17b-estradiol-3-methylether [18F]-
13. Yield: 34–64%. radio-HPLC-analysis: acetonitrile/water (80/20),
tR ¼ 14:2 min.
Acknowledgements
Financial support from the Deutsche Forschungsgemeinschaft (to F.
W.) is gratefully acknowledged. The authors wish to thank S. Preusche
for radioisotope production and T. Krauss for technical assistance.
References
(
1. Langstrom B, Kihlberg T, Bergstrom M, Antoni G, Bjorkmann M,
.
.
¨
¨
Forngren BH, Hartvig P, Markides K, Yngve U, Ogren M. Acta Chim
Scand 1999; 53: 651–669.
(
2. Neu H, Bonasera TA, Langstrom B. J Label Compd Radiopharm 1997; 41:
.
227–234.
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 699–713

SYNTHESIS OF 4-[18F]FLUORO
713
.
3. Wust F, Dence CS, McCarthy TJ, Welch MJ. J Label Compd Radiopharm
2000; 43: 1289–1300.
(
.
4. Karimi F, Langstrom B. J Label Compd Radiopharm 2002; 45: 423–434.
5. Hostetler ED, Fallis S, McCarthy TJ, Welch MJ, Katzenellenbogen JA. J
Org Chem 1998; 63: 1348–1351.
(
6. Kihlberg T, Langstrom B. J Org Chem 1999; 64: 9201–9205.
.
!
7. Allain-Barbier L, Lasne M-C, Perrio-Huard C, Moreau B, Barre L. Acta
Chem Scand 1998; 52: 480–489.
!
8. Marriere E, Rouden J, Tadino V, Lasne M-C. Org Lett 2000; 2:
1121–1124.
(
9. Forngren T, Andersson Y, Lamm B, Langstrom B. Acta Chem Scand 1998;
.
52: 475–479.
!
10. Marriere E, Chazalviel L, Dhilly M, Toutain J, Perrio C, Dauphin F,
Lasne M-C. J Label Compd Radiopharm 1999; 42: S69–S71.
11. Ismail FMD. J Fluorine Chem 2002; 118: 27–33.
12. Park BK, Kitteringham NR, O’Neil PM. Annu Rev Pharmacol Toxicol
2001; 41: 443–470.
13. Plevenaux A, Lemaire C, Palmer AJ, Damhaut P, Comar D. Appl Radiat
Isot 1992; 43: 1035–1040.
14. Pike VW, Aigbirhio FI. J Label Compd Radiopharm 1995; 37: 120–122.
15. Shah A, Pike VW, Widdowson DA. J Chem Soc, Perkin Trans 1998; 1:
2043–2046.
16. Gail R, Hocke C, Coenen HH. J Label Compd Radiopharm 1997; 40:
50–52.
17. Shah A, Pike VW, Widdowson DA, J Chem Soc, Perkin Trans, 1997; 1:
2463–2465.
.
18. Wust F, Zessin J. J Label Compd Radiopharm, 2003; 46: 333–342.
19. Sonogashira K, Tohda Y, Hagihara N. Tetrahedron Lett 1975; 4467–4470.
(
20. Marsh G, Hu J, Jakobsson E, Rahm S, Bergman A. Environ Sci Technol
1999; 33: 3033–3037.
21. Beringer FM, Falk RA, Karniol M, Lillien I, Masulo G, Mausner M,
Sommer E. J Am Chem Soc 1959; 81: 342–351.
22. Still WC, Kahn M, Mitra A. J Org Chem 1978; 43: 2923–2925.
.
23. Coenen HH, Klatte B, Knochel A, Schuller M, Stocklin G. J Label Compd
.
.
Radiopharm 1986; 23: 455–462.
24. Senderoff SG, McElvany KD, Carlson KE, Heimann DF, Katzenellenbo-
gen JA, Welch MJ. Int J Appl Radiat Isot 1982; 33: 545–551.
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 699–713