Comparison of pathways to the versatile synthon of no-carrier-added 1-bromo-4-[18F]fluorobenzene

Article abstract of DOI:10.1002/jlcr.830

The availability of no-carrier-added (n.c.a.) 1-bromo-4-[ ¹⁸F]fluorobenzene with high radiochemical yields is important for ¹⁸F-arylation reactions using metallo-organic 4-[¹⁸F] fluorophenyl compounds (e.g. of lithium or m

Full text of DOI:10.1002/jlcr.830

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2004; 47: 429–441.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.830
Research Article
Comparison of pathways to the versatile synthon
of no-carrier-added 1-bromo-4-[ F]fluorobenzene
18
y
Johannes Ermert*, Carsten Hocke , Thomas Ludwig, Ren e! Gail
and Heinz H. Coenen
Institut f u. r Nuklearchemie, Forschungszentrum J u. lich GmbH, J u. lich D-52425, Germany
Summary
1
The availability of no-carrier-added (n.c.a.) 1-bromo-4-[ F]fluorobenzene with high
8
1
radiochemical yields is important for F-arylation reactions using metallo-organic 4-
8
1
8
[
F]fluorophenyl compounds (e.g. of lithium or magnesium) or Pd-catalyzed
coupling. In this study, different methods for the preparation of 1-bromo-4-
1
8
[
[
F]fluorobenzene by nucleophilic aromatic substitution reactions using n.c.a.
1
8
F]fluoride were examined. Of six pathways compared, symmetrical bis-(4-
bromphenyl)iodonium bromide proved most useful to achieve the title compound in
a direct, one-step nucleophilic substitution with a radiochemical yield (RCY) of 65%
within 10 min. Copyright # 2004 John Wiley & Sons, Ltd.
1
Key Words: F-fluorination; 1-bromo-4-[ F]fluorobenzene; iodonium leaving group;
8
18
1
fluorine-18; [ F]fluoromethane
8
Introduction
Methods for the introduction of fluorine-18 into aromatic ring systems play an
important role in the development of new radiopharmaceuticals for positron
1
emission tomography. There are two common pathways for the F-labelling
8
1
8
of the arene system. However, electrophilic F-substitution leads only to
carrier-added products because of the unavoidable addition of elemental
fluorine to the target gas. In spite of several recent attempts to improve the
1
–3
electrophilic pathway by less addition of carrier the specific activity using
electrophilic substitution is often too low for labelling, e.g. of receptor ligands.
The other pathway via nucleophilic displacement of adequate leaving
+
groups (e.g. NO or N (CH ) ) which are activated by electron withdrawing
2 3 3
*
Correspondence to: J. Ermert, Institut f u. r Nuklearchemie, Forschungszentrum J u. lich GmbH, J u. lich
D-52425, Germany. Email: j.ermert@fz-juelich.de
y
Present address: Universit a. t Erlangen-N u. rnberg, Nuklearmedizinische Klinik mit Poliklinik, Teilbereich
Kopfklinik, Schwabachanlage 6, Erlangen 91054, Germany.
Copyright # 2004 John Wiley & Sons, Ltd.
Received 11 August 2003
Revised 30 October 2003
Accepted 4 November 2003

4
30
J. ERMERT ET AL.
substituents (e.g. CHO, COCH , COOMe, NO , CN, etc.) by no-carrier-
3
2
18
added (n.c.a.) [ F]fluoride is generally used for the preparation of
1
F-labelled, electron deficient arenes. However, in limited cases a direct
8
1
8
one step synthesis of n.c.a. electron rich [ F]fluoroarenes is even possible
1
8
via an
F-fluorination reaction when using substituted diphenyliodo-
1
nium salts, which was introduced into F-radiochemistry by Pike and
8
4
Aigbirhio.
1
While only a few examples are described for direct nucleophilic F-labelling
8
cf. 5–7
18
the n.c.a. F-labelling of complex radiopharma-
of complex molecules ,
ceuticals is performed in most cases starting from small, simple electron
deficient arenes being subsequently converted into complex molecules via
1
multi-step reactions (e.g. the synthesis of n.c.a. [ F]fluoroamino acids and
8
8
1
n.c.a. [ F]fluorometaraminol ).
8
9,10
1
8
Until now, there are only a few examples of synthetic methods using F-
labelled aromatic organometallic compounds. In order to enlarge the scope of
1
n.c.a. F-labelling via organometallic intermediates, the synthesis of n.c.a. 4-
8
1
8
18
F]fluorohalobenzene is an important key step. n.c.a. [ F]fluorohaloarenes,
[
1
especially the bromo and iodo derivatives, serve as synthon for F-
8
18
fluoroarylation reactions using 4-[ F]fluorphenyl lithium or magnesium
1
1,12
18
halide
lalkenes and -arenes.
The aim of this study was to examine different methods for a facile, one-pot
or for palladium-catalyzed coupling reactions to [ F]fluoropheny-
13–15
18
synthesis of 1-bromo-4-[ F]fluorobenzene.
Results and discussion
Different methods can be taken into consideration for the synthesis of n.c.a. 1-
1
bromo-4-[ F]fluorobenzene 1. Recently, Allain-Barbier et al. and Forngren
8
13
1
et al. published a two-step procedure for the synthesis of 1-bromo-4-
4
1
[
8
18
F]fluorobenzene 1. After a carbonyl activated F-for-NO substitution on
2
3
-bromo-6-nitrobenzaldehyde the aldehyde group was removed by the
Wilkinson catalyst to yield 40–66% radiochemical yield (RCY) of 1-bromo-
1
8
4
-[ F]fluorobenzene 1.
In Scheme 1 direct methods to 1-bromo-4-[ F]fluorobenzene 1 as examined
in this study are outlined, while most of these methods are also applicable for
1
8
18
the synthesis of n.c.a. 1-[ F]fluoro-4-iodobenzene.
8
1
Both [ F]fluorohalo compounds offer the possibility of use of a variety of
coupling conditions. For example, they can be converted either into
1
8
corresponding lithium or magnesium compounds useful for F-fluoroaryla-
tion reactions. Further, coupling reactions using palladium catalysts lead to
1
[
8
16
F]fluoroarylalkenes or [ F]fluoroaniline derivatives. Both methods
18
17
enlarge the scope of possibilities for the synthesis of PET radiopharmaceu-
ticals.
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 429–441

1
8
1
-BROMO-4-[ F]FLUOROBENZENE
431
1
Scheme 1. One-step reaction to n.c.a. 1-bromo-4-[ F]fluorobenzene
8
18
18
Studies of the halogen-activated F-for-halide and F-for-nitro exchange and
the Wallach reaction
1
The well-known Wallach reaction (Scheme 1, pathway A) was applied in F-
8
1
8,19
chemistry for the labelling of spiro- and haloperidol.
In case of the
decomposition of 1-piperidyldiazo-4-bromobenzene 2, however, even using a
wide variation of several parameters (temperature, concentration of precursor,
1
F-carrier, solvent, different sulfonic acids for decomposition) not more than
9
1
8
3
–4% RCY of 1-bromo-4-[ F]fluorobenzene 1 was achieved.
Former studies of a direct nucleophilic aromatic substitution reaction using
20,21
Therefore, as
1
8
an F-for-halide exchange showed contradicting results.
depicted in pathway B, a nucleophilic exchange reaction was examined using
halides simultaneously as weak activating and leaving group. The well-known
1
and efficient Kryptofix 2.2.2. phase transfer catalyst in combination
2
2
with K CO
2
served as anion activation system. However, nucleophilic
3
1
8
18
F-substitution led only to 1–2% RCY of 1-bromo-4-[ F]fluorobenzene
using DMSO at up to 160 8C reaction temperature and a concentration of
5–20 mmol/l of 1,4-dibromobenzene 3.
1
23
18
In earlier studies, Shiue et al. showed that F-labelling of bromo- and
chloronitrobenzene as precursors using Rb CO as anion activator and
2
3
temperatures higher than 160 8C for 15 min yielded 10–50% RCY of
1
8
[
F]fluoro-4-nitrobenzene. A detailed reinvestigation in this study (Pathway
18
C) of the halogen activated F-for-NO exchange on 1-bromo-4-nitroarene 4
2
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 429–441

4
32
J. ERMERT ET AL.
18
yielded likewise only 0.5% of 1-bromo-4-[ F]fluorobenzene 1 and more than
1
8
4
0% of 1-[ F]fluoro-4-nitrobenzene using the efficient Kryptofix 2.2.2/K CO
2 3
as anion activator and DMSO as solvent at less drastic conditions of 808C
within 5 min.These results are in agreement with a recently published study on
18
24
the synthesis of F-labelled 6-nitroquipazine. There, an RCY of 30% of 1-
1
8
[
F]fluoro-2-nitrobenzene was found for the nitro-activated and microwave-
1
assisted F-labelling of an ortho substituted bromo precursor.
8
1
Studies of the F-for-N (CH ) substitution; formation of [ F]fluoror-
8
+
18
3
3
methane
1
8
+
Based on earlier results an F-for-N (CH ) substitution on 4-halo-N,N,N-
3
3
trimethyl-ammonium triflates appeared to be a promising synthetic pathway
18
for the synthesis of n.c.a. 4-[ F]fluoro-1-haloarenes. At first the trimethy-
lammonium function was considered as the best leaving group for an activated
1
8
nucleophilic F-substitution reaction on arenes. In contrast to an earlier
25
2
6
18
+
publication, however, the
activating halides, e.g. in 4-bromo-N,N,N-trimethylammonium triflate 5
pathway D), led only to a radiochemical yield of 8–15% of 1-bromo-4-
F-for-N (CH ) substitution with weakly
3 3
(
1
8
27
13
[
F]fluorobenzene 1. These results were confirmed by another group and
1
could be explained by the formation of volatile methyl [ F]fluoride, which has
8
18
+
also been produced instead of the [ F]fluoroarene on ortho N (CH ) -
3
3
28
18
substituted acetophenone derivatives. Furthermore, formation of [ F]CH F
3
29
was observed by Maeda et al. when investigating the dimethylsulfonium
1
group as a leaving group for nucleophilic aromatic F-fluorination reactions.
8
Studies on-4-halophenyliodonium salts
1
The use of iodonium salts as precursors for n.c.a. [ F]fluoroarenes
8
4,30
offers
18
the possibility of direct nucleophilic F-fluorination of weakly activated
arenes. Using bromine as substituent R (see Table 1), the decomposition of the
1
corresponding iodonium salts leads to a mixture of [ F]fluorobenzene and
8
1
[
8
F]fluorobromobenzene and the corresponding iodoarenes, respectively (cf.
also Scheme 2).
As listed in Table 1, a radiochemical yield of about 50% of n.c.a. 1-
1
[
8
F]fluoro-4-bromobenzene 1 was found after 10 min reaction time in
1
8
dimethylformamide (DMF) as solvent. The formation of 1-[ F]fluoro-4-
1
bromobenzene 1 is preferred to the formation of [ F]fluorobenzene. This was
8
30
also described in the literature and reflects expectations based on the classic
SNAr mechanism for nucleophilic aromatic substitution. An increase in the
electronegativity of R causes a decrease in the electron density of the aromatic
1
8
ring, resulting in a better nucleophilic attack of the [ F]fluoride ion forming
18
preferably the 1-[ F]fluoro-4-bromobenzene 1 (Scheme 2).
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 429–441

1
8
1
-BROMO-4-[ F]FLUOROBENZENE
433
1
8
Table 1. RCY of n.c.a. bromo-[ F]fluoroarene by thermal decomposition of diarylio-
donium salts
Cpd.
R
X
Anion
RCY (%)
Ratio
Product B
Product A
6
Br
Br
Br
Br
CH
H
triflate
bromide
triflate
tosylate
triflate
50 ꢀ 5
70
100
100
100
98
30
0
0
0
2
7a
7b
7c
8
4-Br
4-Br
4-Br
3-Br
65 ꢀ 10
55 ꢀ 10
65 ꢀ 10
43 ꢀ 5
3
O
Scheme 2. General mechanism of the nucleophilic decomposition of diphenylio-
18
donium salts with [ F]fluoride
The principal drawback of the approach of a mono-substituted (4-
bromophenyl)phenyliodonium salt as precursor for the synthesis of 1-
1
bromo-4-[ F]fluorobenzene is that the maximum radiochemical yield is
8
1
limited by the additional formation of 30% [ F]fluorobenzene (cf. Table 1).
8
1
8
Thus, to simplify the synthesis of n.c.a. 1-bromo-4-[ F]fluorobenzene 1 and
to improve the RCY, symmetrically substituted bis-(4-bromophenyl)iodonium
salts 7 were used as starting material (pathway F). The major advantage of this
1
8
precursor lies in the exclusive formation of 1-bromo-4-[ F]fluorobenzene 1 as
1
F-labelled product in contrast to the (4-bromophenyl)phenyliodonium salts
8
1
8
6
. Nevertheless, the formation of F-labelled arenes using iodonium salt is
accompanied by the formation of macroscopic amounts of iodoarenes
Scheme 2), while the starting iodonium-precursor is completely decomposed
(
18
under the reaction conditions used for F-labelling.
There are different possibilities for a preparative purification of 1-bromo-4-
1
[
8
F]fluorobenzene 1. The decision for one of the purification procedures is
depending on the desired following reaction. For Pd-catalyzed reactions, like
1
Stille or Sonogashira coupling or for the magnesium- or lithium reactions
3
15
12
it is not necessary to remove the iodobenzenes formed by the decomposition of
the iodonium salt. Here, a simple purification procedure via a silica gel
cartridge is probably the easiest way to remove the solvent DMF, the phase
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 429–441

4
34
J. ERMERT ET AL.
18
transfer catalyst and [ F]fluoride. Furthermore, this method offers the best
conditions to establish a fully automated synthesis. To obtain n.c.a. 1-bromo-
1
-[ F]fluorobenzene 1 in high radiochemical and chemical purity, a GC-
8
4
procedure appears the best way for purification, but it is hard to automate and
leads to a lower yield which is due to more purification steps (see experimental
part). Nevertheless, both methods are useful when the subsequent reaction
step demands the absence of moisture. As a third method for purification a
1
4
simple distillation was introduced by Forngren et al.
1
8
In Figure 1, the time course of 1-bromo-4-[ F]fluorobenzene 1 using bis-(4-
bromophenyl)iodonium bromide 7a as precursor is depicted; the saturation
yield is reached at 10–15 min. The concentration of precursor was optimized
(
not shown here) and the best concentration was found to be ꢁ25 mmol/l.
1
Earlier used concentrations of Kryptofix 2.2.2 and potassium carbonate
26
(
molar ratio 2:1) as phase transfer catalyst proved also optimal for this
reaction.
Variation of solvent had a strong influence on the radiochemical yields of
1
8
the F-fluorinated products. It was possible to obtain n.c.a. 4-bromo-
1
[
8
F]fluorobenzene 1 in radiochemical yields of up to 65% with bromide or
tosylate as counter ion within 10 min reaction time, using DMF or DMF/
dioxane as solvent and a reaction temperature of 1308C. In the case of DMAA
the radiochemical yields obtained were found to be only half of those in DMF.
Unexpectedly, no labelling reaction was observed in dimethyl sulfoxide
1
8
(
DMSO) which may be due to redox processes during the F-labelling. In
18
30
contrast to other studies the F-fluorination in acetonitrile at 1008C yielded
only 1–5% RCY. These low yields were also found in the nucleophilic
1
00
9
8
7
6
5
4
3
2
1
0
0
0
0
0
0
0
0
0
0
0
2
4
6
8
10
12
14
16
18
20
reaction time[min]
18
Figure 1. Time course of n.c.a. [ F]fluoride substitution on bis-(4-bromophenyl)
iodonium bromide reaction conditions: [bis-(4-bromophenyl)iodonium bromi-
de]=90 mmol/l, [K ꢂ 2.2.2.]=33.25 mmol/l, [K CO ]=16.63 mmol/l, 0.55 ml
2
3
DMF, 1308C, (n=3)
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 429–441

1
8
1
-BROMO-4-[ F]FLUOROBENZENE
435
1
8
18
F-synthesis of 1-iodo-4-[ F]fluorobenzene using bis-(4-iodophenyl)iodo-
1
5
nium salts.
The influence of the counter ion of symmetrically substituted bis-(4-
bromophenyl)iodonium salts (cf. Table 1) differed from the results previously
31
described for diphenyliodonium salts, where an increasing RCY was found
in the sequence tosylate5iodide5triflate5chloride5bromide. Using sym-
metric bis-(4-bromophenyl)iodonium salts no significant difference is observed
between the sulfonate anions (tosylate and triflate) and bromide, even though
the solubility of the sulfonate derivatives in DMF is better than the solubility
of the bromide derivative.
The optimization studies described above were determined via aliquots
taken from the reaction mixture and analyzed by HPLC. Interestingly, it is
recommendable to increase the amount of precursor to 90 mmol/l and using
1
308C reaction temperature to improve the preparative yield of n.c.a. 4-
1
8
bromo-[ F]fluorobenzene 1, when using the separation by a silica gel column.
The preparative RCY after separation was found to be 40 ꢀ 5%. The GC-
procedure again delivered only 20 ꢀ 5% RCY, but a high chemical and
radiochemical purity. The specific activity was determined to >14.8 TBq/
1
8
mmol via the GC-procedure starting from 185 MBq n.c.a. [ F]fluoride.
Additionally, an alternative strategy was examined for the formation of
18
n.c.a. 1-bromo-3-[ F]fluorobenzene via unsymmetrically substituted diphe-
nyliodonium salts as precursors (cf. Scheme 3) by increasing the relative
reactivity of the bromophenyl moiety.
(3-Bromophenyl)-(4-methoxyphenyl)iodonium triflate was chosen as pre-
cursor, because the positive mesomeric and inductive effect of the methoxy
18
group was expected to direct the F-labelling reaction to the formation of 1-
1
bromo-3-[ F]fluorobenzene. Indeed, only 2–4% RCY of 4-[ F]fluoroanisole
8
18
18
and more than 40% RCY of 1-bromo-3-[ F]fluorobenzene were found using
DMF at 1008C within 6 min. However, the total yield could not compete with
6
5% RCY which is due to the twofold statistical chance in the symmetrically
substituted bis-(4-bromophenyl)-iodonium precursor.
18
Scheme 3. Preparation of n.c.a. 1-bromo-3-[ F]fluorobenzene via (3-bromophe-
nyl)-(4-methoxyphenyl)iodonium triflate
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 429–441

4
36
J. ERMERT ET AL.
Conclusion
In conclusion, six methods were compared for the one-step synthesis of n.c.a.
1
-bromo-4-[ F]fluorobenzene. The best results were obtained using bis-(4-
8
1
bromophenyl)iodonium salts as precursors yielding up to 65% RCY of the
title compound 1, whereas unsymmetrically substituted 4-bromophenyliodo-
nium and (3-bromophenyl)-(4-methoxyphenyl)iodonium salts led to only 35
and 40% RCY of the desired product accompanied with corresponding
1
[
8
F]fluorobenzenes, respectively. The other methods examined, like substi-
tution on dihalobenzenes or the Wallach reaction, were even less efficient
because of the low activation of the aromatic ring system for aro-
matic nucleophilic substitution reaction when using the weakly activating
halides. Even the use of the trimethylammonium moiety as leaving group led
18
to only 10–15% RCY of 1-bromo-4-[ F]fluorobenzene with the weakly
1
8
activating halide while more than 70% RCY was found for [ F]fluoro-
methane.
Experimental
Materials and methods
Reagents and anhydrous solvents were purchased from Aldrich (Steinheim,
Germany) or Merck (Darmstadt, Germany), N,N-dimethyl-4-fluoroaniline
from PurChem (Karlsruhe, Germany) and fluoromethane from Heraeus
(
Karlsruhe, Germany). They were used without further purification. Oxygen-
8 enriched water (>95% enriched) was supplied by Chemotrade (Leipzig,
Germany). Sep-PakTM C-18 plus-cartridges were purchased from Waters
Eschborn, Germany), EN-cartridges, glass column (LiChrolutTM
1
(
6
5 ꢃ 10 mm) and LiChrolutTM RP-18 from Merck (Darmstadt, Germany).
Thin layer chromatography (TLC) was run on precoated plates of silica gel
0F254 (Merck). The compounds were detected at 254 nm. Analytical HPLC
6
was performed on the following systems: HPLC Sykam (S1000) pump,
Knauer UV/VIS-detector (type 97) with a constant wavelength of 254 nm and
an EG&G ACE MateTM radioactivity detector. Gas chromatography was
performed on a Hewlett Packard HP 5890 Series II equipped with a TCD.
RadioTLC chromatograms were detected on a Packard Instant ImagerTM.
1
13
19
H-, C- and F-NMR spectra were recorded on a Bruker Avance 200
spectrometer with samples dissolved in CDCl or d -DMSO. All shifts are
3
6
given in d ppm using the signals of the appropriate solvent as a reference. Mass
spectra were obtained from a Finnigan Automass Multi mass spectrometer
with an electron beam energy of 70 eV. High resolution mass spectra were
recorded on a Finnigan MAT 900 ST apparatus (University of Cologne).
Melting points are uncorrected and were determined on a Mettler FP-61
apparatus in open capillaries.
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 429–441

1
8
1
-BROMO-4-[ F]FLUOROBENZENE
437
Precursor synthesis
Further compounds were synthesized according to literature methods:
1
1
1
-piperidyldiazo-4-bromobenzene 2 , (4-bromophenyl)trimethylammonium
2
6
32
triflate 5 , (4-bromophenyl)phenyliodonium triflate 6 , bis-(4-bromphenyl)
33
iodonium bromide 7a .
Bis-(4-bromphenyl)iodonium triflate 7b and (3-bromophenyl)-(4-methoxyphe-
nyl)iodonium triflate 8. 4-Bromodiacetoxyiodo(III)benzene and 3-bromodia-
3
4,35
cetoxyiodo(III)benzene were synthesized according to literature methods
and used without further purification. Trifluoromethanesulfonic acid (0.36 ml/
.07 ml) was added slowly at –208C to a stirred solution of the corresponding
4
bromodiacetoxyiodo(III)benzene (2.05 mmol) and further stirred for 1 h at
room temperature. Then, the solution was cooled to –108C and the aromatic
compound (2.2 mmol) was added dropwise. The reaction mixture was stirred
for 24 h at room temperature. After evaporation of the solvent, diethyl ether
was added to crystallize the residue. The solids were filtered, washed with
diethyl ether and recrystallized from methanol.
1
Bis-(4-bromphenyl)iodonium triflate 7b (yield 0.56 g, 43%): mp.: 1988C; H-
NMR (d -DMSO): 8.2 ppm (4 H, m, Ar-H), 7.8 ppm (4 H, m, ArH); C-NMR
1
3
6
(
d -DMSO): 116.2 ppm (=C-Br), 127.2 ppm (=C-I), 135.6 ppm (=C-H),
6
19
1
37.9 ppm (=C-H); F-NMR (d -DMSO): ꢄ78.16 ppm (3F, s, -SO CF ); IR
6
3
3
ꢄ1
(
KBr, cm ): 3075, 1553, 1471, 1273, 1165, 637; LC/MS-mode (m/z):
+ +
M =439); HR-MS (m/z): C H Br I; exact mass calculated (g/mol): [M ]
(
12 8 2
4
36.804; measured: 436.803.
3-Bromophenyl)-(4-methoxyphenyl)iodonium triflate 8 (yield 0.31 g, 39%):
(
1
mp.: 128–1298C; H-NMR (d -DMSO): 8.55 ppm (1 H, t, ArH), 8.23 ppm
6
(
(
(
3 H, d, ArH), 7.85 ppm (1 H, m, Ar-H), 7.49 ppm (1 H, t, Ar-H), 7.11 ppm
13
2 H, d, Ar-H), 3.82 ppm (3 H, s, -OCH3); C-NMR (d -DMSO): 162.97 ppm
6
=C-O), 144.88 ppm (=C-I), 138.2 ppm (=C-H), 137.48 ppm (=C-H),
1
35.68 ppm (=C-H), 134.54 ppm (=C-H), 134.24 ppm (=C-H), 123.97 ppm
1
9
=C-Br), 118.46 ppm (=C-I), 106.52 ppm (=C-H), 56.59 ppm (-CH ); F-
(
3
7
7
NMR (d -DMSO): ꢄ78.74 ppm (3F, s, -SO CF ); HR-MS (m/z): C H BrIO;
6
3
3
13 11
+
exact mass calculated (g/mol): [M ] 388.904; measured: 388.902; LC–MS-
+
Mode (m/z): (M =390).
Bis-(4-bromphenyl)iodonium tosylate 7c. Bis-(4-bromphenyl)iodonium hydro-
3
3
gensulfate (0.9 g/2 mmol) was dissolved in 15 ml methanol and mixed with
.38 g (2 mmol) toluenesulfonic acid monohydrate. The solution was heated to
0
reflux and 0.82 g (2.5 mmol) lead(II)carbonate were added. After 2 h the
reaction mixture was further stirred for 4 h at RT. After removal of the
solvent, addition of diethyl ether gave the raw product, which was crystallized
in ethanol/diethyl ether. Yield 0.6 g, 96%.
Copyright # 2004 John Wiley & Sons, Ltd.
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J. ERMERT ET AL.
1
mp: 2038C; H-NMR (d -DMSO): 8,2 ppm (4 H, m, Ar-H), 7,8 ppm (4 H,
6
m, ArH), 7.5 ppm (2 H, m Ar-H), 7.1 ppm (2 H, m Ar-H), 2.3 ppm (3 H, s, C ),
3
1
3
C-NMR (d -DMSO): 21.7 ppm (-CH ), 116.4 ppm (=C-Br), 126.4 (=CH),
6
3
1
1
27,1 ppm (=C–I), 128,9 (=CH), 135,4 ppm (=C-H), 138.0 ppm (=C-H)
ꢄ1
44.9 (=C-), 146.4 (=C-); IR (KBr, cm ): 3075, 1553, 1471, 1273, 1165, 637;
+
LC/MS-mode (m/z): (M =439); HR-MS (m/z): C H Br I; exact mass
+
calculated (g/mol): [M ] 436.804; measured: 436.803.
1
2
8
2
Radiochemistry
1
8
18
For all substitution experiments [ F]fluoride was produced by the O(p,n) F
18
1
8
nuclear reaction via bombardment of an isotopically enriched [ O]water
1.3 ml) target with a 17 MeV proton beam from the BC 1710 Baby Cyclotron.
(
1
8
The [ F]fluoride (148–222 MBq) in 10–20 ml water, 10 mg (26.5 mmol)
Kryptofix 2.2.2 and 13.25 ml of a 1 M K CO in a 5 ml Wheaton glass vial
1
2
3
were dried two times by azeotropic evaporation with 1 ml anhydrous
acetonitrile at 808C.
Studies on the Wallach reaction. The details of these studies were described
11
18
earlier in detail. In brief: to dried [ F]fluoride (37–74 MBq), 30 mg
(112 mmol) of 1-piperidyldiazo-4-bromobenzene and 350 mmol of toluenesul-
fonic acid or methanesulfonic acid together with 500 ml CCl were added and
4
heated to 1008C for 15 min. After the reaction the solution was cooled, filtered
and analyzed by HPLC.
18
Standard conditions for the F-fluorination exemplified by the synthesis
of 1-bromo-4-[ F]fluorobenzene via dibromodiphenyliodonium salt. The
18
18
closed reaction vial containing dry [ F]fluoride was heated to 1308C by
0
an oil bath and a solution of the 4,4 -dibromodiphenyliodonium salt dissolved
in 0.8 ml DMF (25 mmol/l) was added. At the appropriate time (10 min)
aliquots of the reaction mixture (20 ml) were quenched in 300 ml acetonitrile
and analyzed by reversed phase HPLC using a m-Bondapak column
(4 ꢃ 250 mm). Radioactivity measurement was performed by a Nal(Tl) well-
type scintillation detector on-line connected with the outlet of the u.v.-
photometer.
1
8
The same procedure was applied for the halogen-activated F-for-halide
studies using a precursor concentration of 15–20 mmol/l in 1 ml DMSO at
1
8
1
1
608C and for the F-for-NO exchange using 40–50 mmol/l of precursor in
2
ml DMSO at 808C.
18
GC isolation of 1-bromo-4-[ F]fluorobenzene. The organic components of the
reaction mixture were separated from the solvent and the salts by a solid phase
1
extraction on SEP-PAK C-18 cartridges. Then, the cartridge was washed
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 429–441

1
8
1
-BROMO-4-[ F]FLUOROBENZENE
439
with 10 ml water and afterwards dried by a stream of air. By rinsing the
1
8
cartridge with 2 ml diethyl ether 1-bromo-4-[ F]fluorobenzene was coeluted
with 1,4-diiodobenzene and the whole eluate was passed through a cartridge
filled with anhydrous MgSO for drying. The volume of the solution was
4
then reduced in the cold to about 1 ml by using a stream of argon. After
that, the solution was gas chromatographically separated as described
18
below, and the n.c.a. 1-bromo-4-[ F]fluorobenzene was trapped in dry
form in a nitrogen cooled trap. Afterwards the labelled product was
dissolved in 1–5 ml dry diethyl ether. From end of synthesis this separation
took 40 min.
Gas-chromatographic separation was performed on Chromosorb W-AW-
DMCS (60–80 mesh) with 6% bentone and 20% DC 200 in a glass column
(4 m ꢃ 8 mm) and with a helium gas flow of 150 ml/min. The injector was
heated to 2408C. A TCD detector was used for the detection of the reference
0
0
compounds. At the outlet of the GC, a heated 1/16 stainless steel line lead to a
Valco valve oven (HVEC-220 V, heated to 2008C) with two outlets. One outlet
was connected to a cooling trap cooled by liquid nitrogen by another heated 1/
0
0
1
6 stainless steel line to collect the labelled product. The parameters of the
temperature program were:
Starting temperature:
Start of heating:
Heating rate:
Reset:
1408C
5 min
158C/min
50 min
4.53
0
k (1-bromo-4-fluorobenzene)
1
8
Column chromatographic isolation of 1-bromo-4-[ F]fluorobenzene. After
finishing the labelling reaction the whole reaction mixture was given on top
of a small glass column (120 ꢃ 10 mm) for column chromatography. The
stationary phase consisted of silica Si-60 (0.063–0.200 mm) conditioned by dry
diethyl ether. Thereby the whole reaction mixture (0.8 ml DMF) was separated
within 10 min in which the first 2.5 ml eluate were discarded (diethyl ether).
The following 3 ml contained about 95% of the whole n.c.a. 4-bromo-
1
[
8
F]fluorobenzene. Owing to the strong adsorption of DMF on silica it was
relatively easy to separate the aromatic compounds from the dipolar aprotic
solvent.
18
18
Conditions for the examination of [ F]fluoromethane formation. The F-
labelling of bromophenyltrimethylammonium triflate (5) was carried out
according to the procedure described above using 16 mmol/l of precursor in
0.8 ml DMSO at 1208C. The reaction mixture was cooled in an ice bath, the
activity of the closed vial was measured and after that the gas phase of the vial
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 429–441

4
40
J. ERMERT ET AL.
was qualitatively analyzed by gas chromatography using the following
conditions:
Column:
4 m ꢃ 8 mm glass column
Porapack P
Material:
Temperature:
308C
2.18
0
18
k ([ F]fluoromethane)
18
For its quantification [ F]fluoromethane was removed from the organic
18
phase by a stream of argon (10 min). The F-labelled arenes were separated by
silica gel column chromatography (1 ꢃ 15 cm) using diethyl ether as solvent.
The activity of the diethyl ether solution was measured to obtain the yield of
1
[
8
18
F]fluoroarenes. The purity of the [ F]fluoroarenes was checked by reversed-
phase HPLC using a m-Bondapak column (4 ꢃ 250 mm).
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