Nucleophilic 18F-fluorination of heteroaromatic iodonium salts with no-carrier-added [18F]fluoride

Article abstract of DOI:10.1021/ja066850h

Diaryliodonium salts containing the 2-thienyl group as an example of an electron-rich heteroaromatic moiety proved to be very potent precursors for the nucleophilic, regioselective no-carrier-added (nca) radiofluorination of various arenes. It even allowe

Full text of DOI:10.1021/ja066850h

Published on Web 05/31/2007
Nucleophilic 18F-Fluorination of Heteroaromatic Iodonium
Salts with No-Carrier-Added [18F]Fluoride
Tobias L. Ross, Johannes Ermert, Carsten Hocke,† and Heinz H. Coenen*
Contribution from the Institut fu¨r Nuklearchemie, Forschungszentrum Ju¨lich GmbH,
D-52425 Ju¨lich, Germany
Received September 27, 2006; E-mail: h.h.coenen@fz-juelich.de
Abstract: Diaryliodonium salts containing the 2-thienyl group as an example of an electron-rich heteroaro-
matic moiety proved to be very potent precursors for the nucleophilic, regioselective no-carrier-added (nca)
radiofluorination of various arenes. It even allowed the nucleophilic introduction of nca [18F]fluoride into
electron-rich arene compounds in one step. The influences of the substitution pattern, of counteranions,
and of different reaction conditions were studied. Effects of counterions could be explained by the influence
of solvent on ion pair separation of precursor salts. Different aryl(2-thienyl)iodonium salts were used as
precursors, where the homoaromatic group systematically varied from bearing electron-deficient to electron-
rich substituents. Relative rates of exchange kinetics correlated linearly with Hammett constants of the
appropriate substituents confirming a nucleophilic aromatic substitution reaction of high reactivity and low
selectivity.
1. Introduction
Since diaryliodonium salts have allowed efficient nucleophilic
substitution on arenes,6 they have also been shown to be suitable
for a single-step introduction of fluoride into various arenes7-11
and gain more and more interest for direct radiofluorination of
electron-rich arenes. The introduction of nca [18F]fluoride into
one aryl substituent of dihomoaryliodonium salts via an SNAr
mechanism accordingly leads to nca [18F]fluoroarenes and the
corresponding iodoarenes (cf. Scheme 1).
The nucleophilic attack on the diaryliodonium salt occurs
preferably at the more electron-deficient ring. Furthermore, a
steric influence of substituents, especially for ortho-substituents,
could be observed. This so-called ortho-effect is attributed to a
iodine-centered trigonal bipyramidal intermediate with the
sterically more demanding ortho-substituted ring in the equato-
rial position upon attack of a nucleophile which favors its
introduction into this moiety.12,13 This mechanistic model was
also used to explain increasing radiofluorination yields with
increasing numbers of (electronically deactivating) methyl
substituents9 and also accepted in other studies on nucleophilic
18F-fluorination via iodonium salts.10,14,15 Hence, both param-
Radiopharmaceuticals labeled with short-lived positron emit-
ters play an important role for in ViVo studies using positron
emission tomography (PET).1,2 This molecular imaging method
allows the quantitative determination of the biodistribution of
those radiotracers and hence that of physiological parameters.
Because of its suitable decay properties (t1/2 ) 109.7 min, â+-
energy ) 635 keV) fluorine-18 is an ideal radionuclide for PET.
However, no-carrier-added (nca) procedures available for
introducing fluorine-18 into organic molecule systems, espe-
cially needed when high molar activities are demanded in order
to avoid pharmacological or toxicological effects of the labeled
compound, are limited to nucleophilic methods. In contrast to
electrophilic fluorination agents like [18F]F2 or [18F]acetylhy-
pofluorite, only [18F]fluoride is available with sufficient high
molar activity (>75 TBq/mmol). Therefore, the labeling reac-
tions of aromatic target molecules with nca [18F]fluoride so far
are generally limited to substitution on electron-deficient arenes.
Accessory activating groups, which decrease the electron density
in arenes, enlarge the scope of the nucleophilic 18F-labeling
approach, but the additional groups have to be eliminated or
converted after the 18F-intoduction (see for example refs 3-5).
(5) Langer, O.; Dolle´, F.; Valette, H.; Halldin, C.; Vaufrey, F.; Fuseau, C.;
Coulon, C.; Ottaviani, M.; Någren, K.; Bottlaender, M.; Mazie`re, B.;
Crouzel, C. Bioorg. Med. Chem. 2001, 9, 677-694.
(6) Beringer, F. M.; Brierley, A.; Drexler, M.; Gindler, E. M.; Lumpkin, C. C.
J. Am. Chem. Soc. 1953, 75, 2708-2712.
† Present adress: Universita¨t Erlangen-Nu¨rnberg, Nuklearmedizinische
Klinik mit Poliklinik, Teilbereich Kopfklinik, Schwabachanlage 6, 91054
Erlangen, Germany.
(1) Coenen, H. H. New radiohalogenation methods: An overview. In Progress
in Radiopharmacy; Cox, Mather, Sambson, Lazarus, Eds.; Development
in Nuclear Medicine 10; Martinus Nijhoff Publishers: Dordrecht, 1986;
pp 196-220.
(2) Coenen, H. H. In Clinical Molecular Anatomic Imaging: PET, PET/CT
and SPECT/CT, Chapter 16: PET-radiopharmaceuticals: fluorinated
compounds; Lippincott Williams & Wilkins: 2003.
(7) Pike, V. W.; Aigbirhio, F. I. J. Chem. Soc., Chem. Commun. 1995, 21,
2215-2216.
(8) Pike, V. W.; Aigbirhio, F. I. J. Labelled Compd. Radiopharm. 1995, 37,
120-122.
(9) Gail, R.; Hocke, C.; Coenen, H. H. J. Labelled Compd. Radiopharm. 1997,
40, 50-52.
(10) Shah, A.; Pike, V. W.; Widdowson, D. A. J. Chem. Soc., Perkin Trans. 1
1998, 2043-2046.
(11) Ermert, J.; Hocke, C.; Ludwig, T.; Gail, R.; Coenen, H. H. J. Labelled
Compd. Radiopharm. 2004, 47, 429-441.
(3) Ermert, J.; Hamacher, K.; Coenen, H. H. J. Labelled Compd. Radiopharm.
2000, 43, 1345-1363.
(4) Sobrio, F.; Amokhtari, M.; Gourand, F.; Dhilly, M.; Dauphin, F.; Barre´,
L. Bioorg. Med. Chem. 2000, 8, 2511-2518.
(12) Le Count, D. J.; Reid, J. A. J. Chem. Soc. 1967, C 14, 1298-1301.
(13) Yamada, Y.; Okawara, M. Bull. Chem. Soc. Jpn. 1972, 45, 1860-1863.
(14) Hostetler, E. D.; Jonson, S. D.; Welch, M. J.; Katzenellenbogen, J. A. J.
Org. Chem. 1999, 64, 178-185.
9
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J. AM. CHEM. SOC. 2007, 129, 8018-8025
10.1021/ja066850h CCC: $37.00 © 2007 American Chemical Society

18F-Fluorination of Heteroaromatic Iodonium Salts
A R T I C L E S
Scheme 1. Reaction of nca [18F]Fluoride with
Dihomoaryliodonium Salts
of the corresponding diaryliodonium salt.16,17 This route has the
advantage of achieving reliable and good yields with electron-
rich molecules. Additionally, it is a comfortable way to get the
bromide or iodide salts of iodonium compounds. Other described
methods mostly lead to tosylates, triflates, tetrafluoroborates,
or further salts with complex counteranions.18-22 However, these
methods imply problems with electron-rich arenes, especially
for purification, and only enable moderate yields due to many
side products.21
All aryl(2-thienyl)iodonium bromides and iodides used for
this study are prepared starting from their diacetoxyiodoarenes
and thiophene in acetic acid anhydride with sulfuric acid as
catalyst. The necessary diacetoxyiodoarenes are synthesized
from the appropriate iodoarenes by oxidation with sodium
perborate or periodate in acetic acid.17,23,24 Exceptionally, for
1-iodo-4-(diacetoxyiodo)benzene, equimolar peracetic acid is
the oxidant, because it is necessary to oxidize only one iodine
of the 1,4-diiodobenzene and to leave the other one unaltered.25
The tosylates and triflates of the iodonium precursors for [18F]-
fluoroanisoles are suitably obtained from the bromides by an
oxidative anion metathesis with hydrogen peroxide and the
corresponding organic acid in very high yields.26 All diacetoxy-
iodoarenes are prepared in sufficient yields of 42 to 74% as
well as the corresponding aryl(2-thienyl)iodonium salts in 30
to 67% yield. The oxidative anion metathesis results in nearly
quantitative conversion with yields of 90 to 98%.
2.2. Reaction Conditions of the 18F-Substitution on 2-Meth-
oxyphenyl(2-thienyl)iodonium Bromide. The Kryptofix 2.2.2/
K2CO3 system was used to activate the nca [18F]fluoride in all
labeling reactions.27 For the optimization of the general condi-
tions the 18F-labeling reactions were carried out with 2-meth-
oxyphenyl(2-thienyl)iodonium bromide as the model precursor.
This precursor enables very high radiochemical yields and is
an example of an electron-rich molecule.
The radiochemical yields (RCYs) were determined by radio-
HPLC or radio-TLC (autoradiographically) and are decay
corrected. In case of [18F]fluoroanisoles, 4-[18F]fluorotoluene,
and [18F]fluorobenzene, the RCY could not be exactly deter-
mined by radio-TLC systems due to their volatility. Thus, the
RCY for these compounds were acquired only by radio-HPLC.
All 18F-labeled products were identified by comparison with
the Rf- or k-values of their nonradioactive reference molecules.
2-Fluorothiophene, a possible product of the substitution reac-
tion, was not available as a reference compound. However, given
the facts that all fluoroanalogues exhibit a slightly slower
retention than their corresponding arenes (k-value within 10%
higher) and that no radioactivity is coeluted with thiophene
which is well separated from all fluoroarenes examined here,
Scheme 2. Aryl(2-thienyl)iodonium Salts Used as Model
Precursors for nca Radiofluorination of Homoarenes of Different
Electron Densities
eters, the electron density and the steric structure of a iodonium
precursor, determine the orientation of the substitution.
So far, reactions of symmetric and asymmetric diaryliodonium
salts with nca [18F]fluoride were studied with homoaryl groups
only. However, a more electron-rich aryl substituent like a
heteroaromatic moiety in the iodonium salt should allow the
direct single-step nucleophilic 18F-labeling of a second aryl
group which is lesser but still electron-rich.13,15 Indeed, various
reactions of nonradioactive nucleophiles, including fluoride, with
mixed arylheteroaryliodonium salts are described and show a
very high regioselectivity up to regiospecificity.13,15,16
In this study, the 2-thienyl group was used as a highly
electron-rich heteroaromatic group. As a model reaction for
optimization studies the formation of the electron-rich target
molecule ortho-[18F]fluoroanisole was studied using the precur-
sors 2-methoxyphenyl(2-thienyl)iodonium bromide, iodide, to-
sylate, and triflate. Further, the influence of the steric confor-
mation by comparison with the meta- and para-derivates and
the influence of the electronic character were examined. Using
different para-substituted aryl(2-thienyl)iodonium bromides (R
) 4-CH3, 4-OBn, H, 4-I, 4-Br, 4-Cl) with systematic variation
of the electron density in the homoaromatic moiety, the
mechanistic features and the chemoselectivity of the reaction
toward 18F-substituted homoarenes were tested (cf. Scheme 2).
2. Results and Discussion
2.1. Synthesis of Precursors. With respect to the principally
high reactivity of diaryliodonium salts with nucleophiles, the
preparation of these precursors is a crucial step to exploit this
concept for radiofluorination of arenes. Several methods are
known for the synthesis of diaryliodonium salts. In a classical
way, the reaction of a diacetoxyiodoarene with an aromatic
compound is catalyzed with concentrated sulfuric acid to yield
the iodonium hydrogensulphate. Subsequent addition of aqueous
potassium bromide or iodide solution leads to the precipitation
(17) Kryska, A.; Skulski, L. Molecules 2001, 6, 875-880.
(18) Beringer, F. M.; Bachofner, E. H.; Falk, R. A.; Leff, M. J. Am. Chem.
Soc. 1958, 80, 4279-4281.
(19) Koser, G. F.; Wettach, R. H. J. Org. Chem. 1980, 45, 1542-1543.
(20) Kitamura, T.; Matsuyuki, J.; Taniguchi, H. Synthesis 1994, 147-148.
(21) Carroll, M. A.; Pike, V. W.; Widdowson, D. A. Tetrahedron Lett. 2000,
41, 5393-5396.
(22) Varvoglis, A. Topics in Current Chemistry; Springer-Verlag: Berlin, 2003;
Vol. 224, pp 69-98.
(23) McKillop, A.; Kemp, D. Tetrahedron 1989, 45, 3299-3306.
(24) Kazmierczak, P.; Skulski, L.; Kraszkiewicz, L. Molecules 2001, 6, 881-
891.
(25) Wu¨st, F. R.; Kniess, T. J. Labelled Compd. Radiopharm. 2003, 46, 699-
(15) Martin-Santamaria, S.; Caroll, M. A.; Caroll, C. M.; Carter, C. D.; Pike,
V. W.; Rzepa, H. S.; Widdowson, D. A. Chem. Commun. 2000, 8, 649-
650.
(16) Yamada, Y.; Okawara, M. Bull. Chem. Soc. Jpn. 1972, 45, 2515-2519.
713.
(26) Kazmierczak, P.; Skulski, L. Synthesis 1995, 1027-1032.
(27) Coenen, H. H.; Klatte, B.; Kno¨chel, A.; Schu¨ller, M.; Sto¨cklin, G. J. Lab.
Compd. Radiopharm. 1986, 23, 455-466.
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A R T I C L E S
Ross et al.
Figure 2. Dependence of RCY of the nucleophilic 18F-substitution on
2-methoxyphenyl(2-thienyl)iodonium salts on the counterion (130 °C in
DMF).
Figure 1. Temperature dependence of the nucleophilic 18F-substitution on
2-methoxyphenyl(2-thienyl)iodonium bromide.
formation of 2-[18F]fluorothiophene can be excluded. This is
in agreement with reactions on an equimolar scale.15
in Figure 1. At temperatures higher than 132 °C the rate is still
increasing, whereas the radiochemical yields decrease.
The decreasing yields may be a result of the thermal
instability of the precursor, and its decomposition competes with
the 18F-substitution. At higher temperatures diaryliodonium salts
are known to be cleaved by an internal nucleophilic attack of
the counteranion, which leads here to 2-bromoanisole and
2-iodothiophene.13,31 Thus, the highest radiochemical yields of
2-[18F]fluoroanisole could be obtained in a narrow range of 129
to 133 °C, and 130 °C was selected as the most suitable reaction
temperature.
Raising the concentration of Kryptofix 2.2.2 (ratio Kryptofix
2.2.2 and K2CO3: 2:1) to more than 26 µmol does not affect
the RCY or the reaction rate. However, less than 26 µmol
considerably reduces the RCY of 2-[18F]fluoroanisole. Very high
concentrations of 52 µmol and above surprisingly lead to traces
of an unidentified radioactive side product (<5%) with higher
polarity than that of 2-fluoroanisole. This, however, originates
obviously from labeling of an impurity in Kryptofix as was
confirmed by control experiments without the presence of the
iodonium precursor.
2.3. Influence of Counteranions on Iodonium Salts. Dif-
ferent counteranions of iodonium salts are known to strongly
effect their reaction with nucleophiles. Earlier studies show
slightly differing results,8,11 but all found the highest RCY by
using an inorganic counterion. An advantage of the inorganic
counterions is the effective ion pair separation of iodonium salts
in polar solvents,31,32 but there are also indications for partially
dimeric and trimeric structures of the iodonium salt with
inorganic counterions, even in polar solvents.33,34 On one side,
the nucleophilic attack of [18F]fluoride is favored by a dissoci-
ated iodonium salt and hence a “naked” iodonium cation. On
the other side, anions with a high nucleophilicity compete with
[18F]fluoride for the substitution reaction. Considering their low
nucleophilicity, organic counterions appear attractive under this
aspect. Otherwise their bond to the iodine exhibits a more
pronounced covalent character which causes a steric and
electronic hindrance. Hence an additional step becomes neces-
The solvent used for the labeling reaction has a strong
influence on the RCY. The SNAr reaction generally demands
aprotic, polar solvents. In the majority of cases, dimethylsul-
foxide (DMSO) is the most suitable one and a highly effective
medium for nucleophilic 18F-labeling reactions. According to
previous studies,9,11,25 however, it does not work for the reaction
type studied here, and with 2-methoxyphenyl(2-thienyl)iodo-
nium bromide as the model compound, it led only to an RCY
of 1 to 2%. There are two possible explanations for this outcome.
On one hand, the low reduction potential of DMSO presumably
causes redox processes between iodine(III) species and DMSO
molecules. On the other hand, the S-O bond in DMSO has a
semipolar character in favor of a S+-O- polarization and shows
distinct nucleophilicity and a strong solvation of cations,28 what
would lower or even prevent their reactivity. Furthermore, there
is evidence that DMSO affects diaryliodonium cations in a way
that the oriented oxygen atom partially neutralizes the positive
charge of the iodine(III).29,30 Likely, a combination of both
processes with a preliminary strong solvation and subsequent
redox process is assumed for the nonsuitability of DMSO in
18F-labeling reactions with diaryliodonium salts.
Acetonitrile (ACN) and dimethylacetamide (DMAA) give
only low RCYs of 5 to 15%. The best results were received by
using dimethylformamide (DMF), where RCYs up to 60% could
be obtained. These effects of the solvent on the nucleophilic
18F-fluorination of iodonium salts are comparable to findings
in other studies.11,25
The concentration of the precursor 2-methoxyphenyl(2-
thienyl)iodonium bromide was varied in a range from 6 mmol/L
to 75 mmol/L DMF. More than 25 mmol/L did not notably
improve the RCY of 2-[18F]fluoroanisole, thus a concentration
of 25 mmol/L was kept as optimal. Further on, higher
concentrations caused problems of solubility and led to suspen-
sions, which however cleared within seconds when the mixture
was added to the warm reaction vial.
The same precursor was used to examine the influence of
the reaction temperature, which strongly affects the RCYs. The
yields increased from 90 to 130 °C as it is graphically depicted
(31) Beringer, F. M.; Mausner, M. J. Am. Chem. Soc. 1958, 80, 4535-4536.
(32) Ochiai, M.; Kida, M.; Sato, K.; Takino, T.; Goto, S.; Donkai, N.; Okuyama,
T. Tetrahedron Lett. 1999, 40, 1559-1562.
(33) Carroll, M. A.; Mart´ın-Santamar´ıa, S.; Pike, V. W.; Rzepa, H. S.;
Widdowson, D. A. J. Chem. Soc., Perkin Trans. 2 1999, 2707-2714.
(34) Mart´ın-Santamar´ıa, S.; Carroll, M. A.; Pike, V. W.; Rzepa, H. S.;
Widdowson, D. A. J. Chem. Soc., Perkin Trans. 2 2000, 2158-2161.
(28) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry, 5th ed.;
John Wiley & Sons: 2001.
(29) Beringer, F. M.; Galton, S. A. J. Org. Chem. 1966, 31, 1648-1651.
(30) Fraenkel, G. J. Chem. Phys. 1963, 39, 1614-1615.
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18F-Fluorination of Heteroaromatic Iodonium Salts
A R T I C L E S
Table 1. Proton Shifts δ (ppm) of 2-Methoxyphenyl(2-thienyl)iodonium Cations in d6-DMF
δ
[ppm]
2-methoxyphenyl ring
H4
thienyl ring
H4
counterion
OCH3
H3
H5
H6
H3
H5
bromide (nondissociated, 92%)
bromide (dissociated, 8%)
iodide (nondissociated, 87%)
iodide (dissociated, 13%)
tosylate
4.166
4.014
4.104
4.016
4.199
4.223
7.437
b
7.451
7.280
7.521
7.549
7.736
7.522
7.770
7.525
7.820
7.846
7.169
6.901
7.198
6.903
7.242c
7.267
8.432
b
8.466
b
8.513
8.531
7.973a
b
7.209
b
7.242
7.039
7.313
7.342
7.973a
7.939
8.036a
7.939
8.184
8.214
8.036a
7.829
8.142
8.172
triflate
a Signals are overlaid and show a multiplet. b Signals are too small or overlaid completely. c Signals show a multiplet with tosylates’ H2 + H6.
sary in which [18F]fluoride must replace the organic counter-
anion before it can form the trigonal-bipyramial transition
complex via which aromatic substitution proceeds as generally
accepted.33,34 In this study the effects of different counterions
were examined in DMF at 130 °C with 2-methoxyphenyl(2-
thienyl)iodonium bromide, iodide, tosylate, and triflate. The
following order of increasing RCY was obtained: tosylates <
iodides < triflates < bromides (cf. Figure 2).
Here, the bromides prove the aforementioned assumptions
for inorganic counteranions just as the tosylates do for the
organic counteranions. Only the triflates stand out and show a
slightly higher RCY than that of iodides, which may be caused
by their very high reactivity as leaving group. Nevertheless,
the sequence is in agreement with previous studies of nucleo-
philic 18F-fluorination of diaryliodonium salts.8
In terms of kinetics, the triflates and iodides exhibit the
highest reaction rates and a different series was attained for the
increasing reaction rates: tosylates < bromides < iodides <
triflates (cf. Figure 2). The tosylates show the lowest rates as
well as the lowest yields, this may be attributed to the fact that
their rather covalent bond combines with a major steric demand.
However, the triflates give the fastest rates, which correlates
with their high quality and reactivity as a leaving group. The
iodide shows a slightly higher rate than the bromide, although
bromide is the better leaving group considering the highest RCY
obtainable.35,36
The strong influence of the character of counteranions argues
for incomplete dissociated diaryliodonium salts, even with
iodides and bromides. Evidence for the grade of dissociation
can be received from NMR spectra of these solutions. Although
the 18F-fluorination was examined in DMF at 130 °C, the proton
shifts in NMR spectra of ortho-methoxyphenyl substituted
iodonium salts, measured in d6-DMF at room temperature,
diverge (cf. Table 1). In the case of fully dissociated iodonium
salts, the proton shifts of the cations would be identical,
regardless of the nature of the anions.37,38
signals of the dissociated salts are very small and largely
overlaid, they are significant for the free iodonium cation and
similar for both counteranions as expected.
The tosylate and the triflate present more similarities of their
proton shifts. This is likely not a result of dissociated ion pairs
but rather the fact that both counteranions are sulfonic acids,
and consequently the immediate vicinity of the iodine(III) is
the same. Consequently, their inductive effects on the proton
shifts are nearly the same. The grade of dissociation for the
bromide and iodide was determined by integration of the peak
areas; the results are given in Table 1. The variations in both
the proton shifts and the outcome of the nucleophilic 18F-
fluorination reactions are in favor of nonfully dissociated aryl-
(2-thienyl)iodonium salts with all anions examined. In the case
of the iodide and the bromide, a disagreement in RCYs and
reaction rates occurs. Presumably, this is an effect of the
aforementioned thermal instability and tendency of the precur-
sors to decompose. As a result, the iodide is more reactive to
both the 18F-introduction and the decomposition, which causes
a faster initial reactivity but also loss of reactive precursor and
in the net result leads to a lower RCY.
2.4. Influence of the Substitution Pattern of Methoxy-
phenyl(2-thienyl)iodonium Bromide. In general, the influence
of the substitution pattern in the SNAr reaction is very predictable
for common arenes. Making a rough estimate for the reactivity,
the effects of ortho- and para-position are approximately
comparable and differ from those of the meta-position. This is
explainable by the character of the SNAr mechanism and the
corresponding resonance structures. In the nucleophilic attack
on the ipso-carbon, a so-called Meisenheimer complex with a
negative charge is formed as an intermediate. Those negatively
charged intermediates can be stabilized by electron-accepting
groups in the ortho- and para-position by resonance. Such
resonance stabilization cannot occur in the meta-position.
The nucleophilic attack on diaryliodonium salts is strongly
affected by the substitution pattern. Especially a huge difference
between ortho- and para-substituted rings is not explainable by
the regular character of the SNAr mechanism and is due to the
influence of the ortho-effect mentioned above.
The clear differences between the proton shifts disprove the
presence of fully dissociated iodonium salts. Between the
bromide and tosylate, the deviations are very notable. Especially
for the bromide and the iodide, the spectra show both proton
shifts of nondissociated salt and proton shifts of the free aryl-
(2-thienyl)iodonium cations. The signals of the latter are
identical with signals obtained from spectra in d6-DMSO (cf.
analytical data in the Experimental Section). Although the
Ortho-, meta-, and para-methoxyphenyl(2-thienyl)iodonium
bromides were labeled under the optimized conditions, viz
130 °C in DMF (cf. Figure 3). The results correspond to the
expectations, and indeed a strong ortho-effect could be observed.
The para-derivative shows moderate RCYs of 25-30%, and
the meta-derivative only reaches RCYs of ∼20%.
(35) Ayers, P. W.; Anderson, J. S. M.; Rodriguez, J. I.; Jawed, Z. Phys. Chem.
Chem. Phys. 2005, 7, 1918-1925.
The ortho-derivative gave a 2-fold higher RCY of ∼60% than
the para-derivative after a reaction time of 35 min. Obviously,
this rise results from the ortho-effect alone. Considering kinetics,
(36) Suhr, H. Chem. Ber. 1964, 97, 3268-3276.
(37) Beringer, F. M.; Galton, S. A. J. Org. Chem. 1966, 31, 1648-1651.
(38) Petrosyan, V. S.; Reutov, O. A. Chem. Abstr. 1968, 68, 7940u.
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A R T I C L E S
Ross et al.
Figure 4. Hammett diagram for the 18F-substitution on substituted aryl-
(2-thienyl)iodonium bromides (130 °C in DMF).
Figure 3. Dependence of the RCY on the substitution pattern of
methoxyphenyl(2-thienyl)iodonium bromide (130 °C in DMF).
Table 2. RCY and the First-Order Reaction Rates of Nucleophilic
18F-Fluorination of Aryl(2-thienyl)iodonium Bromides in
Dependence on Substituents (R) and Their Hammett Constants
all precursors show relatively fast rates. The meta-derivative
shows even a slightly higher initial reaction rate than the ortho-
and para-derivative but ends in a lower RCY.
The methoxy group is obviously not able to stabilize a
negatively charged transition state due to its electron-donating
character. However, the aryl(2-thienyl)iodonium cation repre-
sents a positively charged initial state and can be stabilized by
conjugation with ortho- and para-methoxy substituents. As a
result, both positions show slower initial reaction rates but also
a smaller tendency for decomposition. In contrast, the meta-
derivative is more activated for the radiofluorination as well as
for the decomposition by an ipso-attack of the counteranion,
which reduces the amount of the precursor and results in low
RCYs.
2.5. Influence of the Phenyl Substituents. The attack of the
nca [18F]fluoride on the diaryliodonium salt depends on the
electronic character of the aromatic rings. If differences in
electron density are present, the outcome will generally be a
product ratio with a preference for the electron-poor group.7-11
In this study the 2-thienyl group represents a highly electron-
rich group, which directs the nucleophilic attack to the second,
less electron-rich ring in the iodonium salt. A detailed insight
in the influence of the electronic character on the nucleophilic
18F-fluorination should be obtained by comparison of aryl(2-
thienyl)iodonium bromides with substituted phenyl rings of
systematically differing electron densities.
All aryl(2-thienyl)iodonium bromides were labeled under the
above-mentioned optimal conditions. Expectedly, the RCY
generally increases with a decrease of the electron density, with
the ortho-methoxy derivative being an exception, which reaches
an RCY of 61% (Table 2). This is probably due to the strong
ortho-effect as discussed above. Based on the RCY the following
series of substituents was obtained: 4-Br > H > 4-Cl > 2-OCH3
> 4-I > 4-OBn > 4-CH3 > 4-OCH3 > 3-OCH3. The differences
of the substituents’ effect on the reaction are more visible from
a kinetic approach. A quantitative treatment of the total
electronic effects (resonance and field) of a substituent is
represented by the Hammett constant σ, a characteristic
parameter for each substituent when attached to a benzene
ring.39-41
1
R
σ41
RCY [%]
ki [min-
]
4-OBn
4-OMe
4-Me
H
3-OMe
4-Cl
-0.42
-0.28
-0.17
0.00
0.12
0.23
0.23
0.27
-
36 ( 3
29 ( 3
32 ( 2
64 ( 4
20 ( 3
62 ( 4
70 ( 5
60 ( 8
61 ( 5
0.0305 ( 0.004
0.0263 ( 0.001
0.0480 ( 0.004
0.0860 ( 0.001
0.1072 ( 0.006
0.1437 ( 0.017
0.2325 ( 0.045
0.1750 ( 0.020
0.0518 ( 0.002
4-Br
4-I
2-OMe
The Hammett constant is part of the Hammett equation, which
is a linear free-energy relationship.
ki
log ) σF (Hammett equation)
k0
k0 is the rate constant or equilibrium constant for R ) H, ki is
the constant for the substituent R, F is a constant for a given
reaction under a given set of conditions (reaction parameter),
and σ is the Hammett constant for the substituent R. The
application of the Hammett treatment generally fails for the
ortho-position because no steric aspects can be taken into
account.
Therefore the reaction rate ki values of the 18F-fluorinations
of the aryl(2-thienyl)iodonium bromides were determined by
linear regression of the diagram ln(A0/A0 - At) versus time,
where A0 is the starting activity of the nca [18F]fluoride and At
is the activity of the [18F]fluoroarene product at time t. The
corresponding log k′/k0 values were plotted against the Hammett
substituent constants (cf. Figure 4).
The relationship in the Hammett diagram shows a reasonable
good linear fit, which corresponds to the implication of the
expected SNAr mechanism of the 18F-substitution on aryl(2-
thienyl)iodonium salts. Furthermore, since F is larger than unity,
the reaction is positively influenced by electron-withdrawing
groups. Thus, the reaction parameter (slope) with F ) +1.2 (
(39) Hammett, L. P. J. Am. Chem. Soc. 1937, 59, 96-102.
(40) Jaffe´, H. H. Chem. ReV. 1953, 53, 191-261.
(41) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165-195.
9
8022 J. AM. CHEM. SOC. VOL. 129, NO. 25, 2007

18F-Fluorination of Heteroaromatic Iodonium Salts
A R T I C L E S
0.2 confirms the nucleophilic mechanism over the range of the
investigated substituents, even for electron-donating groups. The
low absolute value of F implies a high reactivity, which causes
a relatively low sensitivity with respect to substituent effects.42
The high reactivity can be understood due to the high energetic
level of the iodonium reaction center and is crucial for this
reaction type. Consequently, the influence of substituents in the
para-position has only a relatively marginal effect.
the high reactivity of this reaction type with aryl(2-thienyl)-
iodonium salts led to a relatively low sensitivity to substituent
effects.
In the case of electron-rich [18F]fluoroarenes the 2-methox-
yphenyl(2-thienyl)iodonium bromide gave the best result with
60% RCYs within 20-30 min. Based on the comparison of all
precursors examined, the 4-bromophenyl(2-thienyl)iodonium
bromide enabled the highest RCY of ∼70% forming 4-bromo-
[18F]fluorobenzene within 5-10 min.
Besides the 4-methoxy group, the 4-bromo substituent gives
the widest deviations. For the former this is presumably caused
by its strong resonance stabilization of the initial state. The
deviation of the 4-bromo derivative cannot completely be
understood.
4. Experimental Section
4.1. General. Unless otherwise noted all reagents and anhydrous
solvents were purchased from Aldrich (Steinheim, Germany), Fluka
(Buchs, Switzerland), or Merck (Darmstadt, Germany). They were used
without further purification. Oxygen-18 enriched water (>95% en-
riched) was purchased from Chemotrade (Leipzig, Germany).
The syntheses of 4-benzyloxy-1-fluorobenzene,43 2-(diacetoxyiodo)-
anisole,24 3-(diacetoxyiodo)anisole,24 4-(diacetoxyiodo)anisole,24 4-
(diacetoxyiodo)toluene,24 4-iodo-1-(diacetoxyiodo)benzene,25 4-
bromo-1-(diacetoxyiodo)benzene,24 4-chloro-1-(diacetoxyiodo)ben-
zene,24 4-methoxyphenyl(2-thienyl)iodonium bromide,16 4-methox-
yphenyl(2-thienyl)iodonium iodide,16 4-methylphenyl(2-thienyl)-
iodonium bromide,16 phenyl(2-thienyl)iodonium bromide,16 and 4-
chlorophenyl(2-thienyl)iodonium bromide16 were performed as de-
scribed in the literature, and the identity was confirmed by comparison
of NMR data and/or melting points.
1H NMR and 13C NMR spectra were recorded on a Bruker Avance-
200. The chemical shifts δ are in ppm relative to the solvents. Mass
spectra were obtained on an Automass Multi III mass spectrometer.
Melting points are uncorrected and were determined on a Mettler FP-
61 and a Bu¨chi Melting Point B-540, respectively. Elemental analyses
(EA, microanalyses) were performed on a Leco CHNS-932 CHNS
analyzer (Zentralabteilung fu¨r chemische Analysen, Forschungszentrum
Ju¨lich).
3. Summary
In a systematic approach 18 aryl(2-thienyl)iodonium salts
were prepared and used as model precursors for nucleophilic
nca 18F-labeling of arenes. For the first time the highly electron-
rich heteroaromatic 2-thienyl group was used in iodonium
precursors for nca 18F-fluorination reactions.
The 2-thienyl group offers the possibility of one-step 18F-
introduction into electron-rich arenes, e.g., [18F]fluoroanisoles.
It proved that the 2-thienyl group directs the nca [18F]fluoride
to a regiospecific attack of the ipso-carbon of the arylgroup,
and consequently only the desired [18F]fluoroarenes without any
other radioactive side product were formed.
Optimization of the general reaction conditions shows a strong
dependence on reaction parameters. In the case of different
solvents, especially for DMSO the nonsuitability of this reaction
type is explained with an electronic and a steric deactivation of
the iodonium cation. For the 18F-labeling via aryl(2-thienyl)-
iodonium salts the following conditions are suggested: DMF,
25 mmol/L concentration of precursor, 130 °C. The necessary
reaction time depends on the precursor molecule and ranges
from 5 to 20 min.
4.2. Syntheses. 4.2.1. 4-Benzyloxy-1-(diacetoxyiodo)benzene. The
4-benzyloxy-1-(diacetoxyiodo)benzene was synthesized by an oxidation
of 4-benzyloxy-1-iodobenzene with sodium periodate.24
Yield: 2.83 g (66%). Melting point: 113 °C. 1H NMR (CDCl3): δ
) 2.03 (s, 6H, CH3), 5.15 (s, 2H, CH2), 7.07 (d, 2H, H2 + H6), 7.39
- 7.47 (m, 5H, CHPh, H9 - H13), 8.03 (d, 2H, H3 + H5). 13C NMR
(CDCl3): δ ) 20.8 (2C, CH3), 70.8 (CH2), 112.3 (C, C1), 117.9 (2C,
CH, C3 + C5), 127.9 (2C, CH, C9 + C13), 128.9 (CH, C11), 129.2
(2C, CH, C10 + C12), 136.2 (C, C8), 137.6 (2C, CH, C2 + C6), 161.8
(C, C4), 176.8 (2C, CO). MS: m/z 369 [M+, 100]. C17H17IO5
calculated: C, 47.7; H, 4.00. Found: C, 45.6; H, 3.71.
4.2.2. Aryl-2-thienyliodonium Bromides and Iodides. (Diacetoxy-
iodo)arene (2 mmol) and thiophene (6 mmol) were stirred in 10 mL of
acetic acid anhydride at -30 °C. Concentrated sulfuric acid (0.5 mL)
was added dropwise over 1 h. The mixture was allowed to warm up to
5 °C and further stirred at this temperature for 3 h.
The influence of counteranions was determined with bro-
mides, iodides, tosylates, and triflates. The strong dependence
on the counteranions indicated that the iodonium salts are not
fully dissociated in the reaction mixture. At this point, the grade
of dissociation was determined for the inorganic anions in d6-
DMF by NMR investigations. The bromides showed the highest
dissociation and hence gave the best labeling results.
Investigations of the effect of the substitution pattern of the
target arenes were made. Expectedly, ortho-substituted mol-
ecules showed a strong ortho-effect, which considerably en-
hanced the RCY even for these electron-rich molecules. In terms
of kinetics, the meta-derivatives showed a faster initial reaction
rate than the ortho- and para-derivative with almost similar rates.
With regard to the ortho-effect and the SNAr mechanism, ortho-
substituted arenes appeared as ideal target molecules for this
reaction type.
In terms of kinetics, the initial reaction rates of the 18F-
labeling reaction for all precursor bromide salts were quantified
and correlated in a Hammett relationship. The Hammett diagram
exhibited a linear relationship and a reaction parameter F )
+1.2 ( 0.2, which confirmed an expected nucleophilic aromatic
substitution mechanism. Due to the activated ipso-aryl carbon,
The dark solution was poured into 15 mL of ice water. The organic
compounds were extracted with ether and discarded. The aqueous layers
were treated with activated coal for 10 min at 40 °C to become a clear
solution.
To the filtered, clear solution 10 mL of a potassium bromide or a
potassium iodide solution (25%) were added. After 1 h of storage in
the refrigerator precipitates were collected and washed with acetone
(small portion) and ether. The product was dried and stored in an
exsiccator. The so stored precursors could be used for the 18F-labeling
without any further purification. For a recrystallization the compounds
were dissolved in hot methanol and precipitated with ether.12,17
4.2.3. 2-Methoxyphenyl(2-thienyl)iodonium Bromide. Yield: 0.31
1
g (39%). Melting point: 174 °C. H NMR (DMSO-d6): δ ) 3.91 (s,
(42) Exner, O. In AdVances in Linear Free Relationships; Chapman, N. B.,
Shorter, J., Eds.; Plenum: London, 1972; Chapter 1.
(43) Jones, B. J. Chem. Soc. 1938, 1414-1417.
9
J. AM. CHEM. SOC. VOL. 129, NO. 25, 2007 8023

A R T I C L E S
Ross et al.
3H, OCH3), 6.99 (t, 1H, 5-ar), 7.03 (t, 1H, 4-th), 7.23 (d, 1H, 3-ar),
7.55 (t, 1H, 4-ar), 7.78 (d, 1H, 5-th), 7.80 (d, 1H, 3-th), 8.21 (d, 1H,
6-ar). 13C NMR (DMSO-d6): δ ) 57.3 (OCH3), 104.9 (2-th), 112.3
(1-ar), 113.2 (3-ar), 123.6 (5-ar), 129.4 (4-th), 134.8 (4-ar), 136.0 (3-
th), 137.2 (6-ar), 139.1 (5-th), 156.1 (2-ar). MS 317 [M+, 100]. C11H10-
BrIOS, calculated: C, 33.3; H, 2.54. Found: C, 32.9; H, 2.46.
4.2.4. 2-Methoxyphenyl(2-thienyl)iodonium Iodide. Yield: 0.51
4.2.11. 2-Methoxyphenyl(2-thienyl)iodonium Tosylate. Yield: 0.9
g (76%). Melting point: 140 °C. H NMR (DMSO-d6): δ ) 2.24 (s,
1
3H, CH3-Ots), 3.94 (s, 3H, OCH3), 7.03 (t, 1H, 5-ar), 7.10 (2H, 2-Ots),
7.11 (1H, 4-th), 7.28 (d, 1H, 3-ar), 7.44 (d, 2H, 3-Ots), 7.60 (t, 1H,
4-ar), 7.89 (d, 1H, 3-th), 7.90 (d, 1H, 5-th), 8.27 (d, 1H, 6-ar). 13C
NMR (DMSO-d6): δ ) 21.2 (CH3-Ots), 57.5 (OCH3), 100.5 (2-th),
109.7 (1-ar), 113.4 (3-ar), 123.8 (5-ar), 125.9 (2C, 2-Ots), 128.6 (2C,
3-Ots), 129.8 (4-th), 135.5 (4-ar), 137.2 (6-ar), 137.3 (3-th), 138.3 (4-
Ots), 140.5 (5-th), 145.8 (1-Ots), 156.3 (2-ar). MS 317 [M+, 100].
C18H17IO4S2, calculated: C, 44.3; H, 3.51. Found: C, 43.6; H, 3.39.
4.2.12. 2-Methoxyphenyl(2-thienyl)iodonium Triflate. Yield: 2.03
g (98%). Melting point: 170-175 °C. 1H NMR (DMSO-d6): δ ) 3.95
(s, 3H, OCH3), 7.04 (t, 1H, 5-ar), 7.10 (1H, 4-th), 7.28 (d, 1H, 3-ar),
7.61 (t, 1H, 4-ar), 7.89 (d, 1H, 3-th), 7.90 (d, 1H, 5-th). 13C NMR
(DMSO-d6): δ ) 57.4 (OCH3), 100.4 (2-th), 109.6 (1-ar), 113.4 (3-
ar), 121.1 (CF3), 123.8 (5-ar), 129.8 (4-th), 135.5 (4-ar), 137.17 (6-ar),
137.23 (3-th), 140.5 (5-th), 156.3 (2-ar). MS 317 [M+, 100]. C12H10F3-
IO4S2, calculated: C, 30.9; H, 2.16. Found: C, 30.7; H, 2.13.
1
g (58%). Melting point: 183 °C. H NMR (DMSO-d6): δ ) 3.93 (s,
3H, OCH3), 7.01 (t, 1H, 5-ar), 7.06 (t, 1H, 4-th), 7.25 (d, 1H, 3-ar),
7.58 (t, 1H, 4-ar), 7.84 (d, 1H, 3-th), 7.84 (d, 1H, 5-th), 8.24 (d, 1H,
6-ar). 13C NMR (DMSO-d6): δ ) 57.4 (OCH3), 102.6 (2-th), 111.1
(1-ar), 113.3 (3-ar), 123.7 (5-ar), 129.6 (4-th), 135.1 (4-ar), 136.5 (3-
th), 137.2 (6-ar), 139.7 (5-th), 156.2 (2-ar). MS 317 [M+, 100]. C11H10I2-
OS, calculated: C, 29.8; H, 2.27. Found: C, 29.5; H, 2.21.
4.2.5. 3-Methoxyphenyl(2-thienyl)iodonium Bromide. Yield: 0.54
1
g (67%). Melting point: 161 °C. H NMR (DMSO-d6): δ ) 3.79 (s,
3H, OCH3), 7.11 (t, 1H, 4-th), 7.16 (d, 1H, 4-ar), 7.39 (t, 1H, 5-ar),
7.74 (d, 1H, 2-ar), 7.88 (d, 1H, 5-th), 7.89 (d, 1H, 3-th), 7.96 (d, 1H,
6-ar). 13C NMR (DMSO-d6): δ ) 56.7 (OCH3), 107.7 (2-th), 117.8
(1-ar), 121.0 (4-ar), 123.2 (2-ar), 127.3 (5-ar), 130.0 (4-th), 132.8 (6-
ar), 136.6 (3-th), 139.7 (5-th), 160.9 (3-ar). MS 317 [M+, 100]. C11H10-
BrIOS, calculated: C, 33.3; H, 2.54. Found: C, 33.6; H, 2.47.
4.2.6. 3-Methoxyphenyl(2-thienyl)iodonium Iodide. Yield: 0.32
4.2.13. 3-Methoxyphenyl(2-thienyl)iodonium Tosylate. Yield: 1.1
1
g (93%). Melting point: 161 °C. H NMR (DMSO-d6): δ ) 2.07 (s,
3H, CH3-Ots), 3.57 (s, 3H, OCH3), 7.01 (d, 2H, 3-Ots), 7.06 (t, 1H,
4-th), 7.09 (t, 1H, 4-ar), 7.33 (t, 1H, 5-ar), 7.38 (d, 2H, 2-Ots), 7.68 (d,
1H, 6-ar), 7.81 (s, 1H, 2-ar), 7.85 (d, 1H, 3-th), 7.96 (d, 1H, 5-th). 13
C
1
NMR (DMSO-d6): δ ) 20.7 (CH3-OTs), 55.8 (OCH3), 100.7 (2-th),
117.7 (4-ar), 119.2 (1-ar), 120.0 (2-ar), 125.4 (2C, 2-Ots), 126.5 (6-
ar), 128.1 (2C, 3-Ots), 129.5 (4-th), 132.3 (5-ar), 137.1 (3-th), 137.8
(4-Ots), 140.3 (5-th), 145.1 (1-Ots), 160.2 (3-ar). MS 317 [M+, 100].
C18H17IO4S2, calculated: C, 44.3; H, 3.51. Found: C, 44.6, H, 3.61.
4.2.14. 3-Methoxyphenyl(2-thienyl)iodonium Triflate. Yield: 0.94
g (36%). Melting point: 155 °C. H NMR (DMSO-d6): δ ) 3.79 (s,
3H, OCH3), 7.11 (t, 1H, 4-th), 7.17 (d, 1H, 4-ar), 7.39 (t, 1H, 5-ar),
7.74 (d, 1H, 2-ar), 7.87 (d, 1H, 5-th), 7.89 (d, 1H, 3-th), 7.96 (d, 1H,
6-ar). 13C NMR (DMSO-d6): δ ) 56.7 (OCH3), 107.6 (2-th), 117.8
(1-ar), 121.0 (4-ar), 123.2 (2-ar), 127.3 (5-ar), 129.4 (4-th), 132.2 (6-
ar), 136.6 (3-th), 139.7 (5-th), 160.9 (3-ar). MS 317 [M+, 100]. C11H10I2-
OS, calculated: C, 29.8; H, 2.27. Found: C, 30.2; H, 2.56.
4.2.7. 4-Benzyloxyphenyl(2-thienyl)iodonium Bromide. Yield:
0.52 g (55%). Melting point: 202 °C. 1H NMR (DMSO-d6): δ ) 5.08
(s, 2H, CH2), 7.05 (2H, 3-ar), 7.06 (1H, 4-th), 7.25-7.40 (m, 5H,
phenyl), 7.83 (d, 1H, 3-th), 7.89 (d, 1H, 5-th), 8.01 (d, 2H, 2-ar). 13C
NMR (DMSO-d6): δ ) 70.07 (CH2), 104.6 (2-th), 110.4 (1-ar), 118.3
(2C, 3-ar), 128.3 (2C, 9-ar), 128.6 (11-ar), 128.9 (2C, 10-ar), 129.7
(4-th), 136.5 (8-ar), 136.7 (3-th), 137.0 (3-th), 139.6 (5-th), 161.1 (4-
ar). MS 393 [M+, 100]. C17H14BrIOS, calculated: C, 43.2; H, 2.98.
Found: C, 43.2; H, 2.93.
1
g (81%). Melting point: 88 °C. H NMR (DMSO-d6): δ ) 3.73 (s,
3H, OCH3), 7.11 (t, 1H, 4-th), 7.14 (t, 1H, 4-ar), 7.38 (t, 1H, 5-ar),
7.72 (d, 1H, 6-ar), 7.85 (s, 1H, 2-ar), 7.89 (d, 1H, 3-th), 7.99 (d, 1H,
5-th). 13C NMR (DMSO-d6): δ ) 56.3 (OCH3), 101.1 (2-th), 118.3
(4-ar), 119.5 (1-ar), 120.5 (CF3), 126.9 (6-ar), 130.0 (4-th), 132.8 (5-
ar), 137.7 (3-th), 140.8 (5-th), 160.7 (3-ar). MS 317 [M+, 100]. C12H10F3-
IO4S2, calculated: C, 30.9; H, 2.16. Found: C, 30.6; H, 2.21.
4.2.15. 4-Methoxyphenyl(2-thienyl)iodonium Tosylate. Yield: 1.01
1
g (93%). Melting point: 185 °C. H NMR (DMSO-d6): δ ) 2.21 (s,
3H, CH3-Ots), 3.72 (s, 3H, OCH3), 6.98 (d, 2H, 3-ar), 7.04 (d, 2H,
3-Ots), 7.08 (t, 1H, 4-th), 7.41 (d, 2H, 2-Ots), 7.87 (d, 1H, 3-th), 7.94
(d, 1H, 5-th), 8.10 (d, 2H, 2-ar). 13C NMR (DMSO-d6): δ ) 21.2 (CH3-
Ots), 56.1 (OCH3), 101.8 (2-th), 108.7 (1-ar), 117.7 (2C, 3-ar), 125.9
(2C, 2-Ots), 128.5 (2C, 3-Ots), 129.9 (4-th), 137.2 (2C, 2-ar), 137.3
(3-th), 138.1 (4-Ots), 140.2 (5-th), 145.1 (1-Ots), 162.3 (4-ar). MS 317
[M+, 100]. C18H17IO4S2, calculated: C, 44.3; H, 3.51. Found: C, 43.8;
H, 3.50.
4.2.8. 4-Iodophenyl(2-thienyl)iodonium Bromide. Yield: 0.17 g
1
(18%). Melting point: 162 °C. H NMR (DMSO-d6): δ ) 7.04 (t,
1H, H4Th), 7.56 (d, 2H, H3Ar + H5Ar), 7.81 (d, 1H, H3Th), 7.88 (d, 1H,
H5Th), 8.14 (d, 2H, H2Ar + H6Ar). 13C NMR (DMSO-d6): δ ) 97.1
(C, C4ar), 106.3 (C, C2Th), 120.8 (C, C1ar), 129.7 (CH, C4Th), 136.0
(2C, CH, C3ar + C5ar), 136.4 (CH, C3th), 137.2 (2C, CH, C2ar + C6ar),
139.6 (CH, C5th). MS 413 [M+, 100]. C10H7BrI2S, calculated: C, 24.4;
H, 1.43. Found: C, 23.8; H, 1.39.
4.2.16. 4-Methoxyphenyl(2-thienyl)iodonium Triflate. Yield: 0.44
1
g (37%). Melting point: 93 °C. H NMR (DMSO-d6): δ ) 3.72 (s,
4.2.9. 4-Bromophenyl(2-thienyl)iodonium Bromide. Yield: 0.33
1
3H, OCH3), 7.00 (d, 2H, 3-ar), 7.10 (t, 1H, 4-th), 7.86 (d, 1H, 3-th),
7.93 (d, 1H, 5-th), 8.10 (d, 2H, 2-ar). 13C NMR (DMSO-d6): δ ) 56.1
(OCH3), 101.6 (2-th), 108.6 (1-ar), 117.8 (2C, 3-ar), 121.0 (CF3), 129.9
(4-th), 137.2 (2C, 2-ar), 137.3 (3-th), 140.2 (5-th), 162.4 (4-ar). MS
317.2 [M+, 100]. C12H10F3IO4S2, calculated: C, 30.9; H, 2.16. Found:
C, 31.1; H, 2.26.
g (36%). Melting point: 162 °C. H NMR (DMSO-d6): δ ) 7.05 (t,
1H, 4-th), 7.61 (d, 2H, 3-ar), 7.81 (d, 1H, 3-th), 7.88 (d, 1H, 5-th),
8.06 (d, 2H, 2-ar). 13C NMR (DMSO-d6): δ ) 106.3 (2-th), 120.9
(1-ar), 125.9 (4-ar), 129.7 (4-th), 134.6 (2C, 3-ar), 136.6 (3-th), 136.9
(2C, 2-ar), 139.6 (5-th). MS 366 [M+, 100], 365 (97). C10H7Br2IS
calculated: C, 26.9; H, 1.58. Found: C, 26.7; H, 1.65.
4.2.10. Aryl-2-thienyliodonium Tosylates and Triflates. An ap-
propriate aryl-2-thienyliodonium bromide (2.5 mmol) and cyclo-hexene
(2.5 mmol) were suspended in 8 mL in pure methanol. p-Toluene-
sulfonic acid monohydrate (3 mmol) or trifluoromethane sulfonic acid
(3 mmol) was added while the mixture stirred. Finally, 30% aqueous
hydrogen peroxide solution (3.4 mmol) was added. The mixture was
heated to reflux until complete dissolution. The reflux was continued
for 15 min further.
Under reduced pressure the solvent and most of the water were
removed. The crude product was dissolved in methanol at 60 °C, and
the solution quickly cooled down. The product was precipitated with
addition of ether and n-hexane.26
4.3. Radioactive Synthesis. For all radioactive experiments no-
carrier-added [18F]fluoride was produced by the 18O(p,n)18F nuclear
reaction via bombardment of an isotopically enriched [18O]water target
(1.3 mL) with a 17 MeV proton beam at the JSW BC 1710 cyclotron
(Forschungszentrum Ju¨lich). Nca [18F]fluoride (30-50 MBq) in 10-
50 µL of water, 10 mg (26.5 µmol) of Kryptofix 2.2.2, and 13.25 µL
of a 1 M aqueous K2CO3 solution in a 5-mL Wheaton glass vial were
dried three times by azeotropic evaporation with 0.8 mL anhydrous
acetonitrile at 80 °C and 800 mbar under a constant argon flow.
4.4. General 18F-Labeling Procedure. The appropriate precursor
(25 µmol) was dissolved in 1.0 mL anhydrous DMF. This solution
was added by a syringe through a silicone septum into a closed vial
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8024 J. AM. CHEM. SOC. VOL. 129, NO. 25, 2007

18F-Fluorination of Heteroaromatic Iodonium Salts
A R T I C L E S
Table 3. Rf-Values and Solvent Systems (given as v/v Ratios) of
the Relevant Reference Compounds for Radio-TLC on Silica Gel
Plates
quenched with 50 µL of cold HPLC-eluent. The aliquots were analyzed
by reversed-phase radio-HPLC using a Phenomenex Luna 5µ C18
column (3 mm × 250 mm) and acetonitrile/water (40/60) as eluent.
RCYs of nonvolatile products were also determined by radio-TLC.
All 18F-labeled products were identified by their nonradioactive
reference compounds via comparison of their UV signals with the
radioactive signals. Since [18F]fluoroanisoles, 4-[18F]fluorotoluene, and
[18F]fluorobenzene are volatile and their RCYs are not determinable
by radio-TLC, these products were only analyzed by radio-HPLC.
Analytical radio-HPLC was performed on a system consisting of a
Knauer WellChrom Mini-Star K-500 HPLC pump connected with a
Rheodyne-Injector block 7125 and a Merck/Hitachi UV/vis photometer
L4000. Radioactivity was measured by an NaI(Tl) well-type scintillation
detector (EG&G ACE Mate) connected to the outlet of the UV detector.
Radio-TLC was carried out on Merck silica gel TLC sheets with the
solvent mixture of n-hexane/diethylether in various v/v ratios. The radio-
TL-chromatograms were measured on an Instant Imager (Packard,
USA). The k- and Rf-values of the appropriate fluoro compounds are
listed in Tables 3 and 4 .
compound
solvent system (v/v)
Rf
4-benzyloxy-1-fluorobenzene
n-hexane/ether (2:1)
n-hexane/ethyl acetate (3:1)
n-hexane
n-hexane/ether (1:1)
n-hexane/ether (1:1)
0.79
0.91
0.52
0.85
0.78
1-chloro-4-fluorobenzene
1-bromo-4-fluorobenzene
1-fluoro-4-iodobenzene
Table 4. k-Values, Solvent Systems (in v/v Ratios), and Flow
Rates of the Relevant Reference Compounds for Radio-HPLC
solvent system (v/v);
compound
flow [ml/min]
k′
2-fluoroanisole
3-fluoroanisole
4-fluoroanisole
4-benzyloxy-1-fluorobenzene
4-methyl-1-fluorobenzene
fluorobenzene
1-chloro-4-fluorobenzene
1-bromo-4-fluorobenzene
4-iodo-1-fluorobenzene
acetonitrile/water (40:60); 0.7
acetonitrile/water (40:60); 0.7
acetonitrile/water (40:60); 0.7
acetonitrile/water (60:40); 1.0
acetonitrile/water (40:60); 0.7
acetonitrile/water (40:60); 0.7
acetonitrile/water (40:60); 0.7
acetonitrile/water (40:60); 0.7
acetonitrile/water (40:60); 0.7
2.44
3.82
3.32
3.39
4.81
3.00
5.30
6.65
8.84
Acknowledgment. The authors thank Ms. Dr. S. Willbold,
M. Michulitz (Zentralabteilung fu¨r chemische Analysen, For-
schungszentrum Ju¨lich GmbH), Dr. M. Holschbach, and Dr.
D. Bier for recording NMR and MS spectra and elemental
analysis.
containing the dry nca [18F]fluoride and stirred at 130 °C under 1100
mbar of argon. The light overpressure was necessary to avoid losses
of volatile products (e.g., [18F]fluoroanisoles). At the appropriate times
aliquots (10 µL) of the reaction mixture were taken by syringe and
JA066850H
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J. AM. CHEM. SOC. VOL. 129, NO. 25, 2007 8025