Synthesis of 18F-labelled biphenyls via SUZUKI cross-coupling with 4-[18F]fluoroiodobenzene

Article abstract of DOI:10.1002/jlcr.1099

The SUZUKI reaction of organoboron compounds with 4-[¹⁸F] fluoroiodobenzene has been developed as a novel radiolabelling technique in ¹⁸F chemistry. The cross-coupling reaction of p-tolylboronic acid with 4-[¹⁸F]fluoroiodobenzene was used to screen different palladium complexes, bases and solvents. Optimized reaction conditions (Pd ₂(dba)₃, Cs₂CO₃, acetonitrile, 60°C for 5 min) were further applied to the synthesis of various ¹⁸F-labelled biphenyls bearing different functional groups. The reaction proceeded in excellent radiochemical yields of up to 94% within 5 min while showing good compatibility to many functional groups. Copyright

Full text of DOI:10.1002/jlcr.1099

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2006; 49: 817–827.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.1099
Research Article
1
Synthesis of F-labelled biphenyls via SUZUKI cross-
8
1
coupling with 4-[ F]fluoroiodobenzene
8
¨
Bjorn Steiniger and Frank R. Wuest*
Institut fu¨r Radiopharmazie, FZ-Rossendorf e.V., Dresden, Germany
Summary
1
8
The Suzuki reaction of organoboron compounds with 4-[ F]fluoroiodobenzene has
been developed as a novel radiolabelling technique in F chemistry. The cross-
1
8
1
8
coupling reaction of p-tolylboronic acid with 4-[ F]fluoroiodobenzene was used to
screen different palladium complexes, bases and solvents. Optimized reaction
conditions (Pd (dba) , Cs CO , acetonitrile, 608C for 5 min) were further applied to
2
3
2
3
1
8
the synthesis of various F-labelled biphenyls bearing different functional groups.
The reaction proceeded in excellent radiochemical yields of up to 94% within 5 min
while showing good compatibility to many functional groups. Copyright # 2006
John Wiley & Sons, Ltd.
Received 10 May 2006; Accepted 31 May 2006
1
8
18
Key Words: Suzuki cross-coupling; 4-[ F]fluoroiodobenzene; F-labelled biphenyls
Introduction
The 4-fluorophenyl group is a common structural motif found in many
fluorinated drugs, and the beneficial effect of a fluoroaryl group in drug design
and development with regard to drug metabolism, in vivo activity and stability
1
has been reviewed recently. The mild and efficient introduction of a
18
4
-[ F]fluorophenyl group into a distinct position of a given molecule would
lead to potential PET radiotracers. In this line, the use of palladium-mediated
1
8
C–C and C–N bond forming reactions with F-labelled aryl halides can be
regarded as a general method for the versatile synthesis of a wide variety of
1
8
F-labelled radiotracers.
¨
*Correspondence to: Frank R. Wuest, Institute fur Radiophamazie, FZ-Rossendorf e.V., Dresden,
Germany. E-mail: f.wuest@fz-rossendorf.de
Copyright # 2006 John Wiley & Sons, Ltd.

8
18
B. STEINIGER AND F. R. WUEST
Various palladium-mediated C–C and C–N cross-coupling reactions with
18
18
-[ F]fluoroiodobenzene and 4-[ F]bromofluorobenzene have been reported in
4
18
the literature for the synthesis of F-labelled compounds. The most commonly
employed reaction is the Stille cross-coupling utilizing several organostannane
derivatives as the organometallic component. Other methods make use of the
2–6
7
8,9
Sonogashira reaction and the Buchwald N-arylation reaction.
However, within the class of palladium-mediated cross-coupling reactions
the organoboron compound-based Suzuki reaction has not been used for the
1
8
synthesis of F-labelled radiotracers yet. The mild reaction conditions, the
extensive functional group compatibility and the circumvention of toxic tin
by-products would make the Suzuki reaction an attractive alternative to the
frequently employed Stille reaction. Moreover, the Suzuki reaction has
already proved to be a reliable and robust synthetic method in the synthesis of
1
1
10,11
several C-labelled compounds.
In this report, we describe the synthesis of various F-labelled biphenyls via
18
18
Suzuki cross-coupling reaction with 4[ F]fluoroiodobenzene. The reaction
conditions were optimized by screening various palladium complexes, bases and
18
solvents. Optimized reaction conditions were used to synthesize several F-
labelled biphenyls to study the functional group compatibility of the reaction.
Results and discussion
The Suzuki reaction follows the typical catalytic cycle proposed for
palladium-mediated carbon–carbon bond forming reactions. Several different
palladium complexes, bases and solvents have been utilized to give the desired
1
2,13
cross-coupled products in high yields.
coupling reaction in radiosyntheses with the short-lived positron emitter
one has to adapt the reaction conditions to the short physical half-life
However, to use the Suzuki cross-
1
8
F
18
(
t =109.6 min) of F and the extraordinary stoichiometrical relation
1/2
typically found in syntheses using tracer amounts. For this purpose we set
up the reaction of commercially available p-tolyl boronic acid with
0
18
18
4
-[ F]fluoroiodobenzene to give 4 -[ F]fluoro-4-methyl biphenyl as a model
reaction to explore optimized reaction conditions by screening different
palladium complexes, bases and solvents (Figure 1).
0
18
The radiochemical yield of 4 -[ F]fluoro-4-methyl biphenyl was determined
by radio-TLC referring to the percentage of the radioactivity area of the
desired cross-coupled product related to the total radioactivity area. The
results are summarized in Table 1.
In a first set of reactions (entry 1–10) the influence of different palladium
complexes and bases on the radiochemical yield was studied when acetonitrile
as the solvent was used. A wide variety of palladium complexes can be used for
Suzuki cross-coupling reactions. Palladium(0) complexes Pd(PPh3)4 and
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm. 2006; 49: 817–827
DOI: 10.1002/jlcr

1
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SYNTHESIS OF F-LABELLED BIPHENYLS VIA SUZUKI CROSS-COUPLING
819
18F
1
8
F
B(OH)2
I
H C
3
Palladium complex,
base, solvent
H C
3
1
Figure 1. SUZUKI cross-coupling of p-tolyl boronic acid with 4-[ F]fluoroiodo-
8
benzene
1
Table 1. Optimization of SUZUKI reaction with 4-[ F]fluoroiodobenzene
8
a
b
Entry
Palladium complex
Base
Solvent
Radiochemical yield (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
Pd(PPh3)4
Pd(PPh3)4
Cs CO
2
CH CN
3
CH CN
3
90
3
3
3
f
K PO
3
55(87)f
86(95)
89
91
90
54(76)
4
Pd(PPh
Pd (dba)
Pd (dba)
3
)
4
KOAc
Cs CO
K PO
CH
CH
3
3
CN
CN
2
3
2
CH CN
3
2
3
3
3
4
Pd
2
(dba)
KOAc
Cs CO
PO
KOAc
CH
CH
CH
3
3
3
CN
CN
CN
f
Pd(PPh
Pd(PPh
3
3
)
2
Cl
Cl
2
2
2
2
)
2
K
3
4
82
88
88
88
Pd(PPh ) Cl
3
CH CN
3
CH CN
3
2
1
1
1
1
1
1
1
1
1
1
Pd(OAc)
Pd (dba)
Pd (dba)
2
2
3
3
3
/PPh
3
Cs
Cs
Cs CO
2
2
CO
CO
3
3
3
2
2
DMF
DMF
DMF
DMF
toluene
toluene
c
91
85
c
Pd (dba)
2
K PO
3
3
3
4
4
4
c
Pd(PPh
Pd(PPh
3
3
)
4
K
K
PO
PO
90
68
c
)
2
Cl
2
c
Pd (dba)
2
Cs CO
2
32
74
3
3
3
3
3
d
Pd
Pd
Pd
2
(dba)
2
(dba)
2
(dba)
3
3
3
Cs
2
Cs
2
Cs
2
CO
CO
CO
CH
CH
3
3
CN
CN
e
27
28
e
DMF
a
Molar ratio of p-tolyl boronic acid/Pd-complex/base:10/1/25.
b
All reactions were carried out at 608C for 5 min.
Reaction was carried out at 808C for 5 min.
c
d
Reaction was carried out at 408C for 5 min.
e
18
-[ F]Fluoroidodobenzene was added to the solution containing the base and the palladium complex prior
4
to the addition of p-tolyl boronic acid.
In parenthesis: reaction time of 20 min.
f
Pd (dba) are frequently used, but Pd(PPh ) Cl and Pd(OAc) plus PPh are
2
2
3
3 2
2
3
also known to be efficient.
When Pd(PPh ) as the palladium complex is used high radiochemical (90
3
4
and 86%) yields are obtained when Cs CO or KOAc as the base are used
2
3
(entry 1 and 3), whereas only a moderate radiochemical yield of 55% is
achieved when K PO is used (entry 2). Prolongation of the reaction time from
3
4
5
to 20 min increased the radiochemical yield to 87%. Comparable high
radiochemical yields of 89–91% are obtained independently from the used
base with Pd (dba) as the palladium(0) complex (entries 4–6).
2
3
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm. 2006; 49: 817–827
DOI: 10.1002/jlcr

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20
B. STEINIGER AND F. R. WUEST
The use of Pd(PPh ) Cl as palladium(II) complex gave radiochemical yields
3
2
2
of 82 and 88%, when K PO or KOAc was used (entries 8 and 9). Lower
3
4
radiochemical yields (54%) are observed when Cs CO is used as the base
2
3
(entry 7). However, prolongation of the reaction time to 20 min increased the
radiochemical yield to 76%. Palladium(II) complex Pd(OAc) plus PPh as
3
2
co-ligand (ratio 1:2) afforded high radiochemical yield of 88% with Cs CO as
2
3
the base (entry 10).
In a second set of reactions the effect of DMF as the solvent was tested
entries 11–14). High radiochemical yields of 88 and 91%, respectively, were
(
obtained with Pd (dba) and Cs CO at 608C (entry 11) and 808C (entry 12).
2
3
2
3
Thus, increase of the reaction temperature did not further improve the
radiochemical yield. No significant differences in the radiochemical yields
(85 and 90%) were observed for palladium(0) complexes Pd (dba) and
2 3
Pd(PPh ) when K PO as the base was used and the reaction was carried out
4
3
4
3
at 808C (entries 13 and 14).
In entries 15 and 16 lower radiochemical yields of 68 and 32% were achieved
when toluene as the solvent was used. Thus, toluene seems to be a less suitable
18
solvent for Suzuki reactions with 4-[ F]Fluoroidodobenzene when compared
with acetonitrile or DMF.
Lowering the reaction temperature from 60 to 408C resulted in a decrease of
the radiochemical yield from 89 to 74% (entries 4 and 17).
In all reactions (entries 1–17) a polar by-product could be detected at the
start of the TLC plates. We assume that the by-product consists of a complex
18
between the palladium complex and 4-[ F]fluoroiodobenzene.
In a last set of reactions (entries 18 and 19) we studied the influence of the
order of reagent addition. Examples in the literature describing Suzuki and
1
1
Sonogashira cross-coupling reactions with CH I report on the importance
3
of the order of reagent addition to provide reasonable and reproducible
11,14
radiochemical yields.
However, in our case addition of p-tolyl boronic acid
1
8
to a pre-formed solution consisting of palladium complex, 4-[ F]fluoroiodo-
benzene and base gave significantly lower radiochemical yields of 28 and 27%,
respectively (entries 18 and 19) while forming several unspecified side-products.
The data summarized in Table 1 clearly demonstrate the favourable
1
8
characteristics of the Suzuki reaction involving 4-[ F]fluoroiodobenzene as a
coupling partner. The reaction proceeds very fast (5 min) under mild
conditions (608C), and the reaction seems to be quite tolerable to different
palladium complexes and bases when polar solvents like acetonitrile or DMF
are used. However, the reaction proceeds in much lower radiochemical yields
when an non-polar solvent like toluene is used. Thus, we chose Pd (dba) as
2
3
the palladium complex, Cs CO as the base and acetonitrile as the solvent in
2
3
the following experiments to test the functional group compatibility of the
18
Suzuki reaction with 4-[ F]fluoroiodobenzene.
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm. 2006; 49: 817–827
DOI: 10.1002/jlcr

1
8
SYNTHESIS OF F-LABELLED BIPHENYLS VIA SUZUKI CROSS-COUPLING
821
For this purpose we subjected various functionalized organoboron
1
compounds to a cross-coupling reaction with 4-[ F]fluoroiodobenzene to
8
18
18
18
give the corresponding F-labelled biphenyls [ F]15-[ F]28 (Figure 2).
The results are summarized in Table 2.
We were very pleased to find that application of the found optimized
18
Suzuki reaction conditions with 4-[ F]fluoroiodobenzene gave in most cases
high radiochemical yields of 77–94% within the array of different functiona-
lized organoboron compounds. The reaction tolerates ester groups (entry 8),
OMe and SMe groups (entries 10 and 11), methanesulfonyl groups (entry 12),
hydroxy groups (entry 13) and nitro groups (entry 14). This observation is in
agreement with the known functional group compatibility of the Suzuki
1
2,13
reaction.
However, the reaction is not limited to boronic acids. As exemplified in entry
4, boronic acid esters gave comparable radiochemical yields, hence offering
Most compounds tested were boronic acids (entries 1–13).
1
an even broader range of starting materials.
For most reactions a reaction time of 5 min at 608C gave sufficient
radiochemical yields. Prolongation of the reaction time to 20 min did not
significantly improve the radiochemical yields (entries 10 and 14).
The influence of sterically more hindered aryl boronic acids was tested by
using 2-methyl-phenyl boronic acid 2 and 3-methyl-phenyl boronic acid 3 in
18
the cross-coupling reaction with 4-[ F]fluoroiodobenzene (entries 2 and 3).
The obtained high radiochemical yields of 91 and 90%, respectively, for both
reactions confirm the suitability of the Suzuki reaction to form sterically
13
hindered biaryls.
In contrast to carboxylic acid esters (entry 8), carboxylic acids seem to be
not tolerated very well (entry 9), and reaction of carboxylic acid-containing
18
boronic acid 9 with 4-[ F]fluoroiodobenzene gave only low to moderate
radiochemical yields of 37% after 5 min and 45% after 20 min.
B(OH)2
R
18F
18F
1-13
I
R
Pd (dba) , Cs CO ,
2
3
2
3
O
B
CH CN, 5 min, 60 ˚C
3
[18
F]15-[ F]28
18
O
O N
2
14
R = H, Me, F, Cl, Br, CO Me, CO H,
2
2
OMe, SMe, SO Me, OH, NO
2
2
Figure 2. SUZUKI cross-coupling of several organoboron compounds 1–14 with
1
8
18
18
18
-[ F]fluoroiodobenzene to give F-labelled biphenyls [ F]15-[ F]28
4
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm. 2006; 49: 817–827
DOI: 10.1002/jlcr

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22
B. STEINIGER AND F. R. WUEST
1
8
Table 2. SUZUKI reaction of several organoboron compounds with 4-[ F]fluoro-
iodobenzene
Entry
Organoboron compound
Product
Radio-
chemical
yield (%)
a,b
1
8
1
2
B(OH)2
F
90
91
1
8
1
[ F]15
CH3
CH3
1
8
B(OH)2
F
18
2
[ F]16
H C
H C
3
3
3
18
90
B(OH)2
F
18
3
[ F]17
1
8
4
5
6
7
8
9
H3C
F
B(OH)2
H3C
F
F
90
82
77
1
8
4
[ F]18
1
8
B(OH)2
F
1
8
5
[ F]19
1
8
Cl
B(OH)2
Cl
F
1
8
6
[ F]20
18F
c
Br
B(OH)
Br
30(34)
2
1
8
7
[ F]21
1
8
MeO2C
HO2C
O
B(OH)2
MeO2C
HO2C
O
F
89
1
8
8
[ F]22
1
8
c
B(OH)2
F
37(45)
1
8
9
[ F]23
1
8
c
1
1
1
1
0
1
2
3
4
B(OH)2
B(OH)2
F
82(85)
1
8
1
0
1
[ F]24
S
S
18F
94
84
93
1
8
1
[ F]25
1
8
MeO2S
HO
B(OH)2
MeO2S
HO
F
1
8
12
[ F]26
18F
B(OH)2
1
8
1
3
[ F]27
O
B
O
18F
c
1
O N
O2N
88(90)
2
18
[ F]28
1
4
a
The radiochemical yields were determined by radio-TLC referring to the percentage of the
18
radioactivity area of the F-labelled biphenyl related to the total radioactivity area.
b
All reactions were carried out at 608C for 5 min.
In parenthesis: reaction time of 20 min.
c
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm. 2006; 49: 817–827
DOI: 10.1002/jlcr

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8
SYNTHESIS OF F-LABELLED BIPHENYLS VIA SUZUKI CROSS-COUPLING
823
An interesting trend is notable within the reaction of halogen-substituted
18
boronic acids with 4-[ F]fluoroiodobenzene (entries 5–7). Fluorine- and
chlorine-containing boronic acids 5 and 6 afforded high radiochemical
yields of 82 and 77%, respectively (entries 5 and 6), whereas bromine-
1
8
containing compound 7 gave the corresponding biphenyl compound [ F]21 in
only 30% radiochemical yield after 5 min and 34% after 20 min. This low
radiochemical yield might be explained by a competing homo-coupling
reaction of 4-bromo-phenyl boronic acid 7 according to a Suzuki reaction.
The tendency of an increasing rate of competitive homo-coupling correlates
with the increasing susceptibility of aryl halides to undergo an oxidative
addition to the reactive palladium(0) species, being Br >Cl>F. Thus,
1
8
4
-bromo-phenyl boronic acid 7 successfully competes with 4-[ F]fluoroiodo-
benzene to undergo the oxidative addition leading to substantial amounts of
homo-coupled product rather than to form the desired cross-coupled product
1
8
[
F]21 in high radiochemical yields.
In summary, we have developed a novel radiolabelling method for the
18
synthesis of 4-[ F]fluorophenyl-substituted biaryls via the Suzuki cross-
coupling reaction between organoboron compounds with 4-[ F]fluoroiodo-
benzene. Optimized reaction conditions (Pd (dba) , Cs CO , acetonitrile,
1
8
2
3
2
3
18
6
08C) usually afforded the desired F-labelled biphenyls in excellent radio-
chemical yields (>80%) within 5 min. The found broad tolerance towards
various functional groups along with the mild and efficient reaction conditions
make the Suzuki a promising novel radiolabelling technique for the
18
convenient synthesis of F-labelled radiotracers.
Experimental
General
1
H-NMR spectra were recorded on a Varian Inova-400 at 400 MHz. Chemical
shifts (d) are determined relative to the solvent and converted to the TMS
scale. Melting points were determined on a Galen III melting point apparatus
(
Cambridge Instruments) and are uncorrected. Flash-chromatography was
15
conducted according to Still et al. Thin-layer chromatography (TLC) was
performed on Merck silica gel F-254 plastic plates, with visualization under
UV (254 nm). Compounds 1–14 were purchased from Aldrich.
Chemical syntheses
General procedure for the synthesis of biphenyls 15228. To a solution
containing the aryl boronic acid (0.74 mmol) in DMF (5 ml) was added
4
-fluoro-iodobenzene (0.57 mmol), Pd(PPh ) Cl (0.03 mmol) and caesium
3 2 2
carbonate (1.13 mmol). The mixture was stirred at 608C until TLC analysis
showed consumption of fluoroiodobenzene. Then, ethyl acetate (50 ml) was
Copyright # 2006 John Wiley & Sons, Ltd.
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B. STEINIGER AND F. R. WUEST
added and the solution was filtered through Celite. Evaporation of the solvent
gave the crude product, which was purified by flash-chromatography (EtOAc/
petroleum ether 40–60).
1
4
-fluoro-biphenyl (15). Yield: 99%. H-NMR (CDCl ) d 7.18 (m, 1H; Ar-H),
3
7
.41 (m, 2H, Ar-H), 7.48–7.53 (m, 2H, Ar-H), 7.58–7.62 (m, 4H, Ar-H).
Melting point 71–748C.
0
4
-fluoro-2-methyl-biphenyl (16). Instead of Pd(PPh ) Cl Pd (dba) was used
3 2 2 2 3
1
as catalyst. Yield: 99%. H-NMR (CDCl ) d 2.27 (s, 3H; CH ), 7.08–7.14
3
3
(m, 2H; Ar-H), 7.20–7.25 (m, 2H; Ar-H), 7.27–7.32 (m, 4H; Ar-H).
0-fluoro-3-methyl-biphenyl (17). Yield: 64%. H-NMR (CDCl ) d 2,44
s, 3H; CH ), 7.14–7.20 (m, 3H; Ar-H), 7.33–7.62 (m, 5H; Ar-H).
1
4
3
(
3
0-fluoro-4-methyl-biphenyl (18). Yield: 70%. H-NMR (CDCl ) d 2.44
s, 3H; CH ), 7.15 (m, 2H; Ar-H), 7.28 (m, 2H, Ar-H), 7.46–7.60 (m, 4H;
1
4
3
(
3
Ar-H). Melting point 73–768C.
0
1
4
,4 -difluoro-biphenyl (19). Yield: 91%. H-NMR (CDCl ) d 7.12 (m, 4H;
3
Ar-H), 7.46–7.52 (m, 4H; Ar-H). Melting point 67–688C.
0
1
4
-chloro-4 -fluoro-biphenyl (20). Yield: 91%. H-NMR (CDCl ) d 7.11–7.17
3
(m, 2H; Ar-H), 7.39–7.44 (m, 2H; Ar-H), 7.45–7.54 (m, 4H; Ar-H). Melting
point 83–88 8C.
0
1
4
-bromo-4 -fluoro-biphenyl (21). Yield: 58%. H-NMR (CDCl ) d 7.10–7.16
3
(m, 2H; Ar-H), 7.39–7.53 (m, 4H; Ar-H), 7.54–7.58 (m, 2H; Ar-H). Melting
point 86–918C.
0
1
-fluoro-4-biphenyl-carboxylic acid methyl ester (22). Yield: 79%. H-NMR
4
(
CDCl ) d 3,94 (s, 3H; CH ), 7.13–7.18 (m, 2H; Ar-H), 7.57–7.62 (m, 4H;
3
3
Ar-H), 8.08–8.11 (m, 2H; Ar-H). Melting point 99–1008C.
4
0-fluoro-biphenyl-4-carboxylic acid (23). Yield: 64%. 1H-NMR (DMSO)
d 7.32 (m, 2H; Ar-H), 7.77–7.80 (m, 4H; Ar-H), 8.01 (m, 2H; Ar-H), 12.88
(b, 1H, COOH). Melting point 234–2368C.
0
1
4
-fluoro-4-methoxy-biphenyl (24). Yield: 86%. H-NMR (CDCl ) d 3.85
3
(s, 3H; CH ), 6.98 (m, 2H; Ar-H), 7.10 (m, 2H; Ar-H), 7.46–7.51 (m, 4H;
3
Ar-H). Melting point 83–858C.
0-fluoro-4-methylsulfanyl-biphenyl (25). Yield: 73%. H-NMR (CDCl3)
1
4
d 2.53 (s, 3H; CH ), 7.09–7.15 (m, 2H; Ar-H), 7.31–7.34 (m, 2H; Ar-H),
3
7
.42–7.54 (m, 4H; Ar-H). Melting point 122–1238C.
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm. 2006; 49: 817–827
DOI: 10.1002/jlcr

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SYNTHESIS OF F-LABELLED BIPHENYLS VIA SUZUKI CROSS-COUPLING
825
0
1
4
-fluoro-4-(methanesulfonyl)-biphenyl (26). Yield: 80%. H-NMR (CDCl )
3
d 3.10 (s, 3H; CH ), 7.18 (m, 2H; Ar-H), 7.59 (m, 2H; Ar-H), 7.73 (m, 2H;
3
Ar-H), 8.01 (m, 2H; Ar-H). Melting point 144–1468C.
0
1
4
-fluoro-biphenyl-4-ol (27). Yield: 54%. H-NMR (DMSO) d 6.83 (m, 2H;
Ar-H), 7.22 (m, 2H; Ar-H), 7.46 (m, 2H; Ar-H), 7.59 (m, 2H; Ar-H), 9.55
(s, 1H; OH). Melting point 143–1508C.
0
1
4
-fluoro-4-nitro-biphenyl (28). Yield: 61%. H-NMR (CDCl ) d 7.16-7.22
3
(
(
m, 2H; Ar-H), 7.57–7.62 (m, 2H; Ar-H), 7.67–7.71 (m, 2H; Ar-H), 8.28
m, 2H; Ar-H). Melting point 122–1258C.
Radiochemical syntheses
No-carrier-added aqueous [ F]fluoride ion was produced in a IBA CYCLONE
18
1
8
18
18
1
8/9 cyclotron by irradiation of [ O]H O via the O(p,n) F nuclear reaction.
2
18
Synthesis of 4-[ F]fluoroiodobenzene was performed in an automated
nucleophilic fluorination module (Nuclear Interface, Munster) as described by
¨
5
,9
18
Wuest et al. Purified 4-[ F]fluoroiodobenzene was eluted from the RP18
cartridge (Merck LiChrolut) with acetonitrile, DMF or toluene. Radio-TLC
analysis was performed on Merck silica gel F-254 plastic plates using petroleum
ether (b.p. 40–608C) or mixtures of petroleum ether/ethyl acetate as eluent. For
reading the radio-TLC plates a Bas2000 scanner (Fujix) was used.
1
8
General procedure for the Suzuki reaction with 4-[ F]fluoroiodobenzene
To an Eppendorf plastic vial containing the boronic acid (18 mmol), the
palladium complex (1.8 mmol) and the base (45 mmol) in 300 ml of solvent
1
8
(
acetonitrile, DMF or toluene) was added 10 ml of 4-[ F]fluoroiodobenzene
(0.8–2.0 MBq) in acetonitrile, DMF or toluene. The sealed vial was heated and
vortexed in a Thermocycler comfort (Eppendorf) at the indicated temperature.
Progress of the reaction was monitored by analysing aliquots (1.5 ml) on TLC
plates after 5 and 20 min.
1
8
4
-[ f]fluoroiodobenzene. Radio-TLC: R =0.53, petroleum ether; R =0.64,
f f
1
0% EtOAc/petroleum ether; R =0.69, 30% EtOAc/petroleum ether;
f
R =0.75, 50% EtOAc/petroleum ether.
f
1
8
18
4
-[ f]fluoro-biphenyl (½ Fꢀ15). Radio-TLC: R =0.29, petroleum ether.
f
0
18
18
-[ f]fluoro-2-methyl-biphenyl (½ Fꢀ16). Radio-TLC: R =0.30, petroleum ether.
4
f
0
18
18
-[ f]fluoro-3-methyl-biphenyl (½ Fꢀ17). Radio-TLC: R =0.24, petroleum
4
f
ether.
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm. 2006; 49: 817–827
DOI: 10.1002/jlcr

8
26
B. STEINIGER AND F. R. WUEST
0
18
18
-[ f]fluoro-4-methyl-biphenyl (½ Fꢀ18). Radio-TLC: R =0.26, petroleum
4
f
ether.
0
18
,4 -[ f]difluoro-biphenyl (½ Fꢀ19). Radio-TLC: R =0.29, petroleum ether.
18
4
f
0
18
-chloro-4 -[ f]fluoro-biphenyl (½ Fꢀ20). Radio-TLC: R =0.28, petroleum
18
4
f
ether.
0
18
18
4
-bromo-4 -[ f]fluoro-biphenyl (½ Fꢀ21). Radio-TLC: R =0.30, petroleum ether.
f
0
18
18
4
-[ f]fluoro-4-biphenyl-carboxylic acid methyl ester (½ Fꢀ22). Radio-TLC:
R =0.22, 10% EtOAc/petroleum ether.
f
0
18
18
-[ f]fluoro-biphenyl-4-carboxylic acid (½ Fꢀ23). Radio-TLC: R =0.19,
0% EtOAc/petroleum ether.
4
f
5
0
18
18
-[ f]fluoro-4-methoxy-biphenyl (½ Fꢀ24). Radio-TLC: R =0.35, 10%
EtOAc/petroleum ether.
4
f
0
18
18
-[ f]fluoro-4-methylsulfanyl-biphenyl (½ Fꢀ25). Radio-TLC: R =0.42,
0% EtOAc/petroleum ether.
4
f
1
0
18
18
-[ f]fluoro-4-(methanesulfonyl)-biphenyl (½ Fꢀ26). Radio-TLC: R =0.18,
0% EtOAc/petroleum ether.
4
f
3
0
18
18
-[ f]fluoro-biphenyl-4-ol (½ Fꢀ27). Radio-TLC: R =0.35, 30% EtOAc/
petroleum ether.
4
f
0
18
18
-[ f]fluoro-4-nitro-biphenyl (½ Fꢀ28). Radio-TLC: R =0.33, 10% EtOAc/
petroleum ether.
4
f
Acknowledgements
The authors wish to thank S. Preusche for radioisotope production and
T. Krauss for technical assistance.
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