N-Arylation of indoles with 4-[18F]fluoroiodobenzene: Synthesis of 18F-labelled σ2 receptor ligands for positron emission tomography (PET)

Article abstract of DOI:10.1002/jlcr.893

The palladium-mediated N-arylation of indoles with 4-[¹⁸F] fluoroiodobenzene as a novel radiolabelling method has been developed. Optimized reaction conditions were elaborated by variation of different catalyst systems (CuI/1,2-diamines and Pd2

Full text of DOI:10.1002/jlcr.893

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2005; 48: 31–43.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.893
Research Article
N-Arylation of indoles with 4-[18F]fluoroiodobenzene:
synthesis of F-labelled r2 receptor ligands
for positron emission tomography (PET)
18
.
Frank R. Wust* and Torsten Kniess
Institut fu.r Bioanorganische und Radiopharmazeutische Chemie, FZ-Rossendorf e.V.,
Dresden, Germany
Summary
The palladium-mediated N-arylation of indoles with 4-[18F]fluoroiodobenzene as a
novel radiolabelling method has been developed. Optimized reaction conditions were
elaborated by variation of different catalyst systems (CuI/1,2-diamines and Pd2(dba)3/
phosphine ligands), bases and solvents in the reaction of indole with 4-[18F]fluor-
oiodobenzene. Optimized reaction conditions (Pd2(dba)3/(2-(dicyclohexyl-phosphi-
no)-20-(N,N-dimethylamino)-biphenyl, NaOBut, toluene, 1008C for 20 min) were
applied for the synthesis of 18F-labelled s2 receptor ligands [18F]-11 and [18F]-13 which
were obtained in 91 and 84% radiochemical yields, respectively. Copyright # 2004
John Wiley & Sons, Ltd.
Key Words: N-arylation; 4-[18F]fluoroiodobenzene; s2 ligands
Introduction
N-Arylindoles are central structural motifs in many drugs and other
pharmaceutically important compounds. Popular examples of pharmaceuti-
cals with a N-arylindole moiety comprise antipsychotic drugs,1 melatonin
receptor MT1 agonists2 and angiotensin II-1 antagonists.3 Moreover,
numerous N-arylindoles bearing a 4-fluorophenyl group are among the
highest affinity and most selective s2 receptor ligands reported in the
literature.4,5
Sigma receptors represent a distinct class of receptor proteins consisting of
two subtypes, termed s1 and s2.6 They are found in the central nervous system
as well as in various peripheral tissues such as liver, kidney, and endocrine
.
*Correspondence to: F. R. Wust, Institute of Bioinorganic and Radiopharmaceutical Chemistry, FZ-
Rossendorf, PF 51 01 19, 01314 Dresden, Germany. E-mail: f.wuest@fz-rossendorf.de
Contract/grant sponsor: Deutsche Forschungsgemeinschaft
Copyright # 2004 John Wiley & Sons, Ltd.
Received 2 August 2004
Revised 6 September 2004
Accepted 8 September 2004

¨
F. R. WUST AND T. KNIESS
32
organs. Furthermore, recent findings also imply s2 receptors in the induction
of cell death consistent with apoptosis.7 However, the exact functional role of
s2 receptors is not yet clearly defined. Over the last decade several studies have
shown an overexpression of both s receptor subtypes in many human and
non-human tumours, including those of the breast, lung, colon, brain, and
prostate.7–9 The particularly high expression of s2 receptors in rapidly
proliferating tumour cells and the need for a more defined characterization of
their functional role have prompted research on s2 receptors as potential
targets for non-invasive diagnostic imaging techniques such as positron
emission tomography (PET).9
PET is a powerful imaging methodology in biomedical research which
provides functional information of physiological, biochemical and pharma-
cological processes in vivo.10,11 PET uses compounds labelled with short-
lived positron emitting radioisotopes such as 11C (t1/2=20.4 min), 13N (t1/2
=
9.9 min), 15O (t1/2=2 min) and 18F (t1/2=109.6 min). Chemistry with short-
lived positron emitters differs significantly from conventional chemistry, and
the special features encountered in organic chemistry with short-lived positron
emitters such as 11C and 18F have been reviewed recently.11
For in vivo PET imaging of receptor proteins like s2 receptors an appropriate
compound should primarily be labelled with 11C or 18F at high specific
radioactivity. Hence, radiolabelled s2 receptor ligands may serve as molecular
probes to assess the proliferative status of certain tumour entities and to study
the distinct functional role of s2 receptors in vivo by means of PET.
The fluorine atom in the 4-fluorophenyl part found in a series of high
affinity and selective s2 receptor ligands such as Lu 28-179 represents a
potential site for isotopic substitution with 18F (Figure 1). Thus, the isotopic
labelling with 18F will lead to a PET radiotracer indistinguishable from the
parent compound, which can be used as a molecular probe to study
biochemical processes associated with s2 receptors in vivo.
Direct incorporation of 18F as readily available [18F]fluoride into the phenyl
ring of the N-aryl moiety is not feasible since the aromatic ring is not
sufficiently activated for nucleophilic aromatic substitution with [18F]fluoride.
O
N
N
F
Lu 28-179
Figure 1. High affinity and selective r2 receptor ligand Lu 28-179
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N-ARYLATION OF INDOLES
33
An alternative route for the introduction of 18F into an aryl moiety
comprises the utilization of 18F-labelled prosthetic groups such as
4-[18F]fluorohalobenzenes. In this connection especially 4-[18F]fluoroiodoben-
zene is ideally suited for the selective introduction of a 4-[18F]fluorophenyl
group into various molecules via transition metal-mediated cross-coupling
reactions.
Recently we have described a convenient synthesis of 4-[18F]fluoroiodo-
benzene via thermal decomposition of symmetrical iodonium salts in the
presence of no-carrier-added [18F]fluoride.12,13 We and other groups have
successfully applied 4-[18F]fluoroiodobenzene as a useful 18F-labelling
precursor in several C–C bond-forming reactions, such as Sonogashira12 and
Stille reactions.13–16 Moreover, 4-[18F]fluoroiodobenzene can also be used in
cross-coupling reaction involving heteroatoms. The first application of an
N-arylation reaction in 18F chemistry was exemplified by the synthesis of
the selective 5-HT2A receptor ligand [18F]RP 62203 via palladium-assisted
N-arylation of the piperazine moiety with 4-[18F]bromofluorobenzene
(Figure 2).17
Br
O
O
O
O
N
N
N
NH
S
N
S
N
18F
18F
Pd2(dba)3/P(o-tolyl)3
NaOBut, toluene
Figure 2. Synthesis of 5-HT2A receptor ligand [18F]RP 62203
In recent years several research groups have demonstrated very efficient
synthetic methods for the preparation of N-arylated compounds including
indoles.18–21 The reported palladium mediated22,23 and copper-mediated24,25
reactions of several aryl halide electrophiles with indoles gave the correspond-
ing N-aryl-substituted indoles in high yields under mild reaction conditions.
These approaches represent a major breakthrough in the formation of
N-arylindoles in terms of a more general route when compared with other
methods such as Fischer indole synthesis and Ullmann-type couplings.
However, the transition-mediated N-arylation of indoles has not been adapted
yet to organic chemistry with the short-lived positron emitter 18F for the
synthesis of PET radiotracers.
In this paper we describe the synthesis of two s2 selective ligands via
N-arylation of the indole moiety with 4-[18F]fluoroiodobenzene. The reaction
conditions were optimized by using the reaction of indole 1 with 4-[18F]fluoro-
iodobenzene as a model reaction, and optimized reaction conditions were
applied for the synthesis of 18F-labelled s2 receptor ligands [18F]-11 and
[18F]-13 (Figure 3).
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F. R. WUST AND T. KNIESS
34
O
N
N
N
N
N
18F
[18F]-13
[18F]-11
18F
Figure 3. 18F-labelled r2 receptor ligands [18F]-11 and [18F]-13
Results and discussion
Typically, N-arylations of indoles are carried out upon completion during a
12–24 h reaction time period while using almost equimolar amounts of indoles
and aryl halides or triflates as the coupling partners.22–25 However, direct
application of these reaction conditions for palladium- and copper-catalysed
N-arylations of indoles as reported in the literature is not possible when
4-[18F]fluoro-iodobenzene is used as the electrophile in the amination reaction.
The short half-life of 18F (t1/2=109.6 min) prevents such long reaction
times and the use of submicromolar amounts of 18F-labelled compounds,
as typically found in the synthesis of PET radiotracers, results in an
extraordinary stoichiometrical relation between labelled and unlabelled
reagents in the coupling reaction. Therefore, one has to develop an
appropriate radiosynthesis route considering the short half-life of 18F and
the submicromolar amounts of 18F-labelled species. For that purpose we
set up the reaction of indole with 4-[18F]fluoroiodobenzene to give 1-(4-
[18F]fluorophenyl)-1H-indole [18F]-2 as a model reaction (Figure 4) in order
to optimize reaction conditions by screening different catalyst systems, bases
and solvents.
18F
N
I
Catalyst system
N
H
18F
[18F]-2
1
Figure 4. N-arylation of indole with 4-[18F]fluoroiodobenzene
The radiochemical yield of the desired 1-(4-[18F]fluorophenyl)-1H-indole
[18F]-2, which was determined by radio-HPLC, refers to the percentage of
radioactivity area of the desired product [18F]-2 relative to the total
radioactivity area. The results are given in Table 1.
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N-ARYLATION OF INDOLES
35
Table 1. N-Arylation of indole with [18F]fluoroiodobenzene
Entry
Catalyst system
Base
Solventc
Radiochemical
yield (%)a,b
1
2
3
4
5
6
7
8
9
CuI/trans 1,2-diaminocyclohexane
CuI/trans 1,2-diaminocyclohexane
CuI/ethylendiamine
CuI/ethylendiamine
Pd2(dba)3/Xantphos
Pd2(dba)3/Xantphos
Pd2(dba)3/Xantphos
Pd2(dba)3/Xantphos
Pd2(dba)3/Xantphos
Pd2(dba)3/Xantphos
Pd2(dba)3/2-(dicyclohexyl-phosphino)
-20-(N,N-dimethylamino)-biphenyl
Pd2(dba)3/2-(dicyclohexyl-phosphino)
-20-(N,N-dimethylamino)-biphenyl
Pd2(dba)3/2-(dicyclohexyl-phosphino)
-20-(N,N-dimethylamino)-biphenyl
K3PO4
K3PO4
K3PO4
K3PO4
NaOBut
KOBut
NaOBut
Cs2CO3
K3PO4
NaOBut
NaOBut
THF/toluene
Toluene
THF/toluene
Toluene
THF
0
0
7
36
5
6
13
0
16
28
22
THF
THF/toluene
THF/toluene
THF/toluene
Toluene
10
11
THF/toluene
12
13
NaOBut
NaOBut
DMF
0
Toluene
25 (10 min),
69 (20 min)
71 (30 min),
70 (60 min)
3d
14
15
Pd2(dba)3/2-(dicyclohexyl-phosphino)
-20-(N,N-dimethylamino)-biphenyl
Pd2(dba)3/2-(dicyclohexyl-phosphino)
-20-(N,N-dimethylamino)-biphenyl
NaOBut
NaOBut
Toluene
Toluene
70e
a Radiochemical yield determined by radio-HPLC representing the percentage of radioactivity area of cross-
coupled product [18F]-2 related to the total radioactivity area.
b All reactions were conducted at 1008C for 30 min.
c Solvents in a 1:1 mixture.
d Reaction was carried out at 658C.
e Reaction was carried out at 1408C.
In a first set of reactions we studied several copper-mediated reactions for
the synthesis of 1-(4-[18F]fluorophenyl)-1H-indole [18F]-2 (entry 1–4). The use
of copper catalysts consisting of CuI and a 1,2-diamine ligand were found to
be very efficient for the amidation of aryl halides and the N-arylation of
nitrogen heterocycles.24,25
In our experiments we used K3PO4 exclusively as the base as it is known to
be the best base in the performance of copper-mediated N-arylations.24
Trans-1,2-diaminocyclohexane (entry 1 and 2) and ethylendiamine (entry 3
and 4) were used as 1,2-diamine ligands. In the case of trans-1,2-
diaminocyclohexane as bidentate ligand for copper chelation no product
formation was observed, neither using a 1:1 mixture of THF/toluene nor pure
toluene as the solvent (entry 1 and 2). On the other hand, the use of
ethylendiamine gave 7% of the desired product [18F]-2 when a mixture of
THF/toluene was used (entry 3). The radiochemical yield could further be
increased to 36% when the reaction was carried out in pure toluene as the
solvent (entry 4).
Copyright # 2004 John Wiley & Sons, Ltd.
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F. R. WUST AND T. KNIESS
36
In the following reactions (entry 5–15) we investigated several palladium-
based catalyst systems in the reaction of indole with 4-[18F]fluoroiodobenzene.
First (entry 5–10) we used Pd2(dba)3 and Xantphos as catalyst system while
varying the base and the solvent. The system Pd/Xantphos has been shown in
the literature to promote several C–N bond forming processes in good to
excellent yields while displaying good functional group compatibility.26,27
When NaOBut (entry 5) and KOBut (entry 6) were used as bases and THF as
the solvent only low radiochemical yields of 5 and 6%, respectively, could be
obtained. The radiochemical yield could be increased to 13% when a 1:1
mixture of THF/toluene was used (entry 7). Thus, a 1:1 mixture of THF and
toluene is a superior solvent to the use of THF alone. In entries 7–9 we studied
the effect of different bases, namely NaOBut, Cs2CO3 and K3PO4, on the
radiochemical yield while using a 1:1 mixture of THF/toluene as the solvent.
The obtained radiochemical yields clearly show a significant effect of the base
on the reaction. When NaOBut (entry 7) or K3PO4 (entry 9) is used as the
base, 13 and 16% of N-4-[18F]fluorophenylindole could be detected in the
reaction mixture. On the other hand, no product formation was found when
Cs2CO3 was used as the base (entry 8). The finding that NaOBut and K3PO4
are suitable bases is consistent with results reported in the literature dealing
with various N-arylation reactions.22,24 The beneficial effect of pure toluene as
the solvent of choice was demonstrated in entry 10. The radiochemical yield
could further be increased to 28% by using Pd2(dba)3/Xantphos as the catalyst
system, NaOBut as the base and pure toluene as the solvent.
In another set of reactions involving palladium-based catalyst systems
(entry 11–15) we tested 2-(dicyclohexyl-phosphino)-20-(N,N-dimethylamino)-
biphenyl as an electron-rich phosphine ligand. Several electron-rich phos-
phines were demonstrated to be excellent ligands in many palladium-mediated
N-arylation reactions.22,28 As we have learnt from the reactions employing the
catalyst system Pd2(dba)3/Xantphos (entry 5–10), NaOBut seems to be the
base of choice. Thus, in the following set of reactions (entry 11–15) we further
studied the effect of different solvents on the radiochemical yield while using
NaOBut as the base. The use of a 1:1 mixture of THF/toluene (entry 11) gave
22% of the desired product. This result reflects the superior properties of
2-(dicyclohexyl-phosphino)-20-(N,N-dimethylamino)-biphenyl as phosphine
ligand in the catalyst system when compared to Xantphos (entry 7, 13%).
No product formation was observed when the polar solvent DMF was tested
(entry 12).
On the other hand, we were very pleased to find a radiochemical yield of
71% when toluene was used as the solvent (entry 13). This finding further
confirms toluene as the solvent of choice in the N-arylation of indole 1 with
4-[18F]fluoroiodobenzene as already observed in entry 4 and 10. So far all
reactions were carried out for 30 min. However, optimization of reaction time
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N-ARYLATION OF INDOLES
37
is a very important aspect in the synthesis of 18F-labelled compounds. For this
purpose we determined the radiochemical yield dependent on the reaction time
after 10, 20, 30 and 60 min (entry 13). Cross-coupled product [18F]-2 was
formed in 25% after 10 min, and the radiochemical yield could be increased
significantly to 69% after 20 min. Extension of the reaction time to 30 and
60 min did not further improve the radiochemical yield, being 71 and 70%,
respectively.
The effect of temperature on the radiochemical yield was studied as shown
in entry 14 and 15. Lowering the reaction temperature to 658C (entry 14) was
accompanied by a drastic decrease of radiochemical yield and only 3% of the
desired product was formed. On the other hand, performance of the reaction
at 1408C did not further improve radiochemical yield of product [18F]-2 when
compared with the reaction at 1008C (entry 15 vs 13).
In conclusion, we optimized the reaction conditions by screening different
catalyst systems, bases, and solvents, enabling rapid cross-coupling of indole
with [18F]fluoroiodobenzene.
The found optimized reaction conditions (Pd2(dba)3/(2-(dicyclohexyl-
phosphino)-20-(N,N-dimethylamino)-biphenyl, NaOBut, toluene, 1008C for
20 min) were now applied to the synthesis of 18F-labelled s2-receptor ligands
by the reaction of indoles 10 and 12 with 4-[18F]fluoroiodobenzene.
The synthesis of labelling precursors 10 and 12 and the synthesis of reference
compounds 11 and 13 is depicted in Figure 5.
CO2H
ii
i
OH
N
H
N
R
4 R = H
5 R = 4-FC6H5
iii
3
HN
8
O
N
N
R
O
10 R = H
OMs
iv
11 R = 4-FC6H5
N
R
HN
N
N
9
6 R = H
7 R = 4-FC6H5
N
N
R
12 R = H
13 R = 4-FC6H5
Figure 5. Synthesis of labelling precursors (10 and 12) and reference compounds
(11 and 13). Reagents and conditions: (i) LiAlH4, THF, 08C-r.t.; (ii) MsCl,
TEA, CH2Cl2, 08C; (iii) 4-fluoroidobenzene, CuI, ZnO, K2CO3 NMP, 1608C;
(iv) amine 8 or 9, Na2CO3, acetone, r.t.
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F. R. WUST AND T. KNIESS
38
The synthesis started with reduction of commercially available 4-(3-indolyl)-
butyric acid 3 by means of LiAlH4 to give the corresponding alcohol 4 in 57%
yield. 4-(1H-Indol-3-yl)-1-butanol 4 was converted into methanesulfonate
ester 6 followed by N-alkylation reactions with amines 829 and 9 to give
labelling precursors 10 and 12 in 59 and 67% yield, respectively, for the two
steps. For the synthesis of reference compounds 11 and 13 alcohol 4 was
subjected to an Ullmann arylation reaction with 4-fluoroiodobenzene to give
1-(4-fluorophenyl)-substituted compound 54 in 44% yield prior to conversion
into methanesulfonate ester 7. N-alkylation was carried out using the same
procedure as was used for the synthesis of labelling precursors 10 and 12 using
amines 829 and 9. Following this procedure reference compounds 11 and 13
could be obtained in 52 and 62% yield relative to methanesulfonate ester 7.
The radiolabelling of sigma-2 receptor ligands [18F]-11 and [18F]-13 via
N-arylation with 4-[18F]fluoroiodobenzene is depicted in Figure 6.
I
18F
Catalyst system
N
N
NaOBut, toluene
N
H
N
O
20 min, 100°C
O
91%
[18F]-11
10
18F
I
18F
N
Catalyst system
N
NaOBut, toluene
N
N
N
N
H
20 min, 100°C
84%
12
[18F]-13
18F
Catalyst system: Pd2(dba)3 /2-(dicyclohexyl-phosphino)-2'-(N,N-dimethylamino)-biphenyl
Figure 6. Radiolabelling of r2 receptor ligands [18F]-11 and [18F]-13 via N-
arylation with 4-[18F]fluoroiodobenzene
Starting from labelling precursors 10 and 12 the desired compounds [18F]-11
and [18F]-13 could be obtained in excellent radiochemical yields of 91 and
84%, respectively, relative to 4-[18F]fluoroiodobenzene.
In summary, we have developed a convenient radiolabelling method for the
synthesis of 4-[18F]fluorophenyl-substituted indoles via N-arylation with
4-[18F]fluoroiodobenzene. Optimized reaction conditions were obtained by
Copyright # 2004 John Wiley & Sons, Ltd.
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N-ARYLATION OF INDOLES
39
screening different catalyst systems, bases and solvents, and the effectiveness of
the reaction was demonstrated by the radiosynthesis of two sigma-2 receptor
ligands [18F]-11 and [18F]-13. This novel radiosynthesis method further
expands the arsenal of 18F-labelled PET radiotracers to compounds exhibiting
a 4-[18F]fluorophenyl-substituted indole motif.
Experimental
General
1H-NMR spectra were recorded on a Varian Inova-400 spectrometer at
400 MHz. Chemical shifts (d) were determined relative to the solvent and
converted to the TMS scale. Mass spectra were obtained on a Quattro/LC
mass spectrometer (Micromass) by electrospray ionization. Flash chromato-
graphy was conducted according to Still et al.30 using MERCK silica gel (mesh
size 230–400 ASTM). Thin-layer chromatography (TLC) was performed on
Merck silica gel F-254 plastic plates, with visualization under UV (254 nm).
All chemicals were obtained from commercial suppliers of reagent grade
and used without further purification. 4-[1-(4-fluorophenyl)-1H-indol-3-yl]-1-
butanol 54 and amine 829 were prepared according to literature procedures.
Chemical synthesis
4-(1H-Indol-3-yl)-1-butanol 4. A suspension of indole 3 (2.5 g, 12.3 mmol) in
THF (40 ml) was cooled to 08C. LiAlH4 (20 ml, 20 mmol, 1 M in THF) was
added at such rate that the temperature was kept below 308C. The reaction
mixture was warmed up to room temperature and stirring continued for an
additional 4 h. After cooling to 08C water (20 ml) and 4 M NaOH (20 ml) were
added carefully. The resulting suspension was filtered to remove inorganic
salts. CH2Cl2 (100 ml) was added and the solution thoroughly washed with
water. The CH2Cl2 layer was evaporated to yield 1.3 g (57%) of compound 4,
which was directly used without further purification. 1H-NMR (CDCl3) d 1.66
(m, 2H, CH2), 1.79 (m, 2H, CH2), 2.80 (t, J=7.3 Hz, 2H, CH2), 3.66 (t,
J=6.6 Hz, 2H, CH2), 6.94 (s, 1H), 7.13 (m, 1H, Ar-H), 7.20 (m, 1H, Ar-H),
7.33 (d, J=8.0 Hz, 1H, Ar-H), 7.62 (d, J=7.8 Hz, 1H, Ar-H), 8.10 (bs, 1H).
LRMS (ESI positive) 190 [M+H].
General procedure for the synthesis of methansulfonates 6 and 7. A solution of
alcohol 4 or 5 (3.2 mmol) in CH2Cl2 (10 ml) was treated with triethylamine
(0.7 ml) and methanesulfonylchloride (4.2 mmol) at 08C. Stirring was
continued for 30 min at 08C and for one additional hour at room temperature.
Water (25 ml) was added to the reaction mixture and the aqueous layer was
extracted several times with CH2Cl2. After drying the organic layer the solvent
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F. R. WUST AND T. KNIESS
40
was evaporated to give the desired methanesulfonate esters 6 or 7, which were
used without further purification.
1
4-(1H-Indol-3-yl)butyl Methanesulfonate 6. Yield: 96%. H-NMR (CDCl3) d
1.84 (m, 4H, CH2), 2.82 (m, 2H, CH2), 2.95 (s, 3H, CH3), 4.24 (m, 2H, CH2),
6.99 (s, 1H), 7.12 (m, 1H, Ar-H), 7.20 (m, 1H, Ar-H), 7.36 (d, J = 8.1 Hz, 1H,
Ar-H), 7.59 (d, J=7.7 Hz, 1H, Ar-H), 8.05 (bs, 1H). LRMS (ESI positive) 268
[M+H].
4-[1-(4-Fluorophenyl)-1H-Indol-3-yl]butyl methanesulfonate 7. Yield: 92%.
1H-NMR (CDCl3) d 1.89 (m, 4H, CH2), 2.87 (m, 2H, CH2), 2.98 (s, 3H, CH3),
4.28 (m, 2H, CH2), 7.10 (s, 1H), 7.16–7.24 (m, 4H, Ar-H), 7.43–7.48 (m, 3H,
Ar-H), 7.66 (d, J=7.0 Hz, 1H, Ar-H). LRMS (ESI positive) 362 [M+H].
General procedure for the N-alkylation of methansulfonates 6 and 7 with amines
8 and 9 to give compounds 10, 11, 12 and 13. Amine 829 or 9 (10 mmol) and
Na2CO3 (4.7 mmol) were placed with water (2.5 ml) in a flask. Mesylate 6 or 7
in acetone (15 ml) was added to the amine/Na2CO3 slurry while stirring. The
mixture was stirred overnight at 508C. 10% NaHCO3-solution was added and
the mixture extracted with ethyl acetate. After removal of the solvent the
residue was purified by flash-chromatography (10% MeOH/CHCl3).
10-[4-(1H-Indol-3-yl)-1-butyl]spiro[isobenzofuran-1(3H),40-piperidine] 10. Yield:
1
59%. H-NMR (CDCl3) d 1.66 (m, 2H, CH2), 1.76 (m, 4H, CH2), 2.00 (td,
J=12.9, 4.2 Hz, 2H, CH2), 2.38 (t, J=10.9 Hz, 2H, CH2), 2.48 (m, 2H, CH2), 2.80
(t, J=7.3 Hz, 2H, CH2), 2.88 (m, 2H, CH2), 5.07 (s, 2H, CH2), 6.99 (s, 1H), 7.12
(m, 2H, Ar-H), 7.20 (m, 2H, Ar-H), 7.27 (m, 2H, Ar-H), 7.36 (d, J = 8.1Hz, 1H,
Ar-H), 7.59 (d, J = 7.7 Hz, 1H, Ar-H), 7.98 (bs, 1H). LRMS (ESI positive) 361
[M+H].
10-[4-[1-(4-Fluorophenyl)-1H-indol-3-yl]-1-butyl]spiro[isobenzofuran-1(3h),40-
1
piperidine] 11. Yield: 52%. H-NMR (CDCl3) d 1.71 (m, 2H, CH2), 1.79 (m,
4H, CH2), 2.05 (m, 2H, CH2), 2.42 (m, 2H, CH2), 2.51 (m, 2H, CH2), 2.85 (t,
J=7.0 Hz, 2H, CH2), 2.91 (m, 2H, CH2), 5.07 (s, 2H, CH2), 7.10 (s, 1H), 7.15
(m, 1H, Ar-H), 7.17 (m, 1H, Ar-H), 7.18–7.22 (m, 4H, Ar-H), 7.26–7.29 (m, 2H,
Ar-H), 7.43–7.47 (m, 3H, Ar-H), 7.66 (d, J=7.3 Hz, 1H). LRMS (ESI positive)
455 [M+H].
1
3-[4-(4-Phenyl-1-piperazinyl)-1-butyl]-1H-indole 12. Yield: 67%. H-NMR
(CDCl3) d 1.68 (m, 2H, CH2), 1.80 (m, 2H, CH2), 2.48 (m, 2H, CH2), 2.64 (m,
4H, CH2), 2.83 (t, J=7.3 Hz, 2H, CH2), 3.24 (m, 4H, CH2), 6. 89 (t, J=7.3 Hz,
1H, Ar-H), 6.96 (m, 2H, Ar-H), 6.97 (s, 1H), 7.15 (m, 1H, Ar-H), 7.21 (m, 1H,
Ar-H), 7.65 (d, J=7.7 Hz, 1H), 8.13 (bs, 1H). LRMS (ESI positive) 334
[M+H].
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 31–43

N-ARYLATION OF INDOLES
41
1-(4-Fluorophenyl)-3-[4-(4-phenyl-1-piperazinyl)-1-butyl]-1H-indole 13. Yield:
1
62%. H-NMR (CDCl3) d 1.71 (m, 2H, CH2), 1.80 (m, 2H, CH2), 2.52 (m,
2H, CH2), 2.67 (m, 4H, CH2), 2.85 (t, J=6.9 Hz, 2H, CH2), 3.28 (m, 4H, CH2),
6.88 (t, J=7.3 Hz, 1H, Ar-H), 6.94 (m, 2H, Ar-H), 7.10 (s, 1H), 7.15–7.22
(m, 4H, Ar-H), 7.26–7.29 (m, 2H, Ar-H), 7.43–7.47 (m, 3H, Ar-H), 7.65
(d, J=7.7 Hz, 1H, Ar-H). LRMS (ESI positive) 428 [M+H].
Radiochemical synthesis
No-carrier-added aqueous [18F]fluoride ion was produced in a IBA
CYCLONE 18/9 cyclotron by irradiation of [18O]H2O via the 18O(p,n)18F
nuclear reaction. Synthesis of 4-[18F]fluoroiodobenzene was performed in an
.
automated nucleophilic fluorination module (Nuclear Interface, Munster) as
12,13
.
described by Wust and Kniess.
Radio-HPLC analyses were carried out with a SUPELCOSIL LC-18S
column (4.6 ꢀ 250 mm, 5 mm) column using an indicated isocratic eluent
(CH3CN/0.1 M NH4-formiate) from a gradient pump L2500 (Merck, Hitachi)
with a flow rate of 1 ml/min. The products were monitored by an UV detector
L4500 (Merck, Hitachi) at 254 nm and by g-detection with a scintillation
detector GABI (X-RAYTEST).
Optimization of N-arylation of indole 1 with 4-[18F]fluoroiodobenzene via
copper-mediated reaction (entries 1–4)
To a vial containing indole 1 (7 mg, 60 mmol), CuI (3 mg, 15 mmol), 1,2-diamine
(5 ml) and K3PO4 (10 mg, 47 mmol) in THF or toluene (0.5 ml) was added
4-[18F]fluoroiodobenzene (15–35 MBq in 0.5 ml of toluene). The sealed
reaction vial was heated at 1008C for 30 min. Aliquots (50 ml) were taken and
after dilution with acetonitrile the samples were subjected to radio-HPLC
analysis.
Optimization of N-arylation of indole 1 with 4-[18F]fluoroiodobenzene via
palladium-mediated reactions (entries 5–15)
To a vial containing indole 1 (7 mg, 60 mmol), Pd2(dba)3 (3 mg, 15 mmol),
phosphine ligand (5 mg), the base (10 mg) in THF, DMF or toluene (0.5 ml)
was added 4-[18F]fluoroiodobenzene (15–35 MBq in 0.5 ml of THF, DMF or
toluene). The sealed reaction vial was heated (65, 100 and 1408C) for 10, 20, 30
or 60 min. Aliquots (50 ml) were taken and after dilution with acetonitrile the
samples were subjected to radio-HPLC analysis.
1-(4-[18F]Fluorophenyl)-1H-indole ½18Fꢁ-2. HPLC-analysis: CH3CN/0.1 M
NH4-formiate (70/30), tR=6.8 min.
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 31–43

¨
F. R. WUST AND T. KNIESS
42
Radiosynthesis of 10-[4-[1-(4-[18F]Fluorophenyl)-1H-indol-3-yl]-1-butyl]spir-
o[iso-benzofuran-1(3H),40-piperidine] ½18Fꢁ-11 and 1-(4-[18F]fluorophenyl)-
3-[4-(4-phenyl-1-piperazinyl)-1-butyl]-1H-indole ½18Fꢁ-13 using optimized
reaction conditions
To a vial containing labelling precursors 10 or 12 (7 mg), Pd2(dba)3 (4 mg,
3.75 mmol), NaOBut (9 mg, 83 mmol) and 2-(dicyclohexyl-phosphino)-20-(N,
N-di-methylamino)-biphenyl (3 mg, 7.6 mmol) in 0.5 ml of toluene was added
4-[18F]fluoroiodobenzene (50 MBq in 0.5 ml toluene). The sealed reaction vial
was heated at 658C for 20 min and aliquots (50 ml) were taken for radio-HPLC
analysis after dilution with acetonitrile.
10-[4-[1-(4-[18F]Fluorophenyl)-1H-Indol-3-yl]-1-butyl]spiro[isobenzofuran-1(3H),
40-piperidine] ½18Fꢁ-11. Yield: 91% (relative to 4-[18F]fluoroiodobenzene). HPLC-
analysis: CH3CN/0.1 M NH4-formiate (70/30), tR=9.6 min.
1-(4-[18F]Fluorophenyl)-3-[4-(4-phenyl-1-piperazinyl)-1-butyl]-1H-indole [18F]-
13. Yield: 84% (relative to 4-[18F]fluoroiodobenzene). HPLC-analysis:
CH3CN/0.1 M NH4-formiate (70/30), tR=10.3 min.
Acknowledgements
Financial support from the Deutsche Forschungsgemeinschaft (to F. W.) is
gratefully acknowledged. The authors wish to thank S. Preusche for
radioisotope production, and H. Kasper and T. Krauss for the technical
assistance.
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