Radiosynthesis of 4-[18F]fluoro-l-tryptophan by isotopic exchange on carbonyl-activated precursors

Article abstract of DOI:10.1016/j.bmc.2015.06.073

Several ¹⁸F-labeled aromatic amino acids have been developed primarily for tumor imaging with positron-emission-tomography (PET). Also, ¹⁸F-labeled tryptophan derivatives were synthesized by electrophilic ¹⁸F-fluorination or by introducing a [¹⁸F]fluoroalkyl group. Here, a 3-step method for a nucleophilic radiosynthesis of 4-[¹⁸F]fluoro-l-tryptophan was developed. A carbonyl activated precursor containing a chiral amino acid building block was radiofluorinated by isotopic exchange, followed by removal of the activating formyl group by reductive decarbonylation and subsequent cleavage of the building block under acidic conditions. The title compound was obtained within 100 min with a radiochemical yield of about 13%, a molar activity of >70 MBq/mmol and an enantiomeric excess of >99%.

Full text of DOI:10.1016/j.bmc.2015.06.073

Bioorganic & Medicinal Chemistry 23 (2015) 5856–5869
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Radiosynthesis of 4-[18F]fluoro-L-tryptophan by isotopic exchange on
carbonyl-activated precursors
⇑
Philipp S. Weiss, Johannes Ermert , Johnny Castillo Meleán, Dominique Schäfer, Heinz H. Coenen
Institut für Neurowissenschaften und Medizin, INM-5: Nuklearchemie, Forschungszentrum Jülich, 52425 Jülich, Germany
a r t i c l e i n f o
a b s t r a c t
Several 18F-labeled aromatic amino acids have been developed primarily for tumor imaging with
positron-emission-tomography (PET). Also, 18F-labeled tryptophan derivatives were synthesized by
electrophilic 18F-fluorination or by introducing a [18F]fluoroalkyl group. Here, a 3-step method for a
Article history:
Received 15 April 2015
Revised 27 June 2015
Accepted 29 June 2015
Available online 6 July 2015
nucleophilic radiosynthesis of 4-[18F]fluoro-
L-tryptophan was developed. A carbonyl activated precursor
containing a chiral amino acid building block was radiofluorinated by isotopic exchange, followed by
removal of the activating formyl group by reductive decarbonylation and subsequent cleavage of the
building block under acidic conditions. The title compound was obtained within 100 min with a
radiochemical yield of about 13%, a molar activity of >70 MBq/mmol and an enantiomeric excess of >99%.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Aromatic amino acids
4-Fluoro-L-tryptophan
Fluoroindoles
Fluorine-18
Radiofluorination
Isotopic exchange
1. Introduction
18F-fluorination.9 Recently, a more efficient radiolabeling has been
performed by 18F-fluoroalkylation in different positions of trypto-
The indole moiety is one of the most frequently occurring hete-
rocycles in natural products.1 It is, for example, part of the essential
phan.10–12
The major aim of this study was to find out, whether an activa-
amino acid
L
-tryptophan, its metabolite skatol, the plant growth
tion of the carbocycle of the indole moiety is possible in such a way
that isotopic 18F-exchange via a nucleophilic aromatic substitution
(SNAr) becomes possible. For this, the influence of the substitution
pattern of the fluorine and the activating carbonyl group on the
RCY and chemical stability were of high interest. To examine the
influence of the position of activating carbonyl function and of
the fluorine leaving group on the exchange rate, indole derivatives
with various protecting groups at the indole nitrogen were synthe-
sized and labeled with fluorine-18. Further, a corresponding pre-
factor 3-indolylacetic acid (heteroauxin) and the neurotransmitter
serotonin.2 There is also a broad variety of plant alkaloids that con-
tain indole, for example, strychnine and ellipticin. Many of those
plant alkaloids are highly toxic but may also have properties that
are very valuable for special medicinal considerations.
Recent studies revealed that many tumors up-regulate the
enzyme tryptophan dioxygenase to stimulate the consumption of
tryptophan. Hence, the uptake of tryptophan of those tumor cells
increases. This is because the primary product of tryptophan
dioxygenase is kyneurine which is known to be an endogenous
ligand for the aryl hydrocarbon receptor and as mediator of inva-
sive tumor growth.3
cursor for the radiosynthesis of 4-[18F]fluoro-
L-tryptophan had to
be designed and prepared and the radiosynthesis had to be
optimized.
Furthermore, tryptophan is the precursor for serotonin4 which
is involved in a series of neurological regulations and diseases such
as depression5 and migraine.6
Hitherto, only a few tryptophan derivatives have been radiola-
beled with positron emitters.7 First radiofluorinated tryptophan
derivatives were realized by the Balz-Schiemann reaction,8
but with low radiochemical yield (RCY), or by electrophilic
2. Results and discussion
2.1. Radiolabeling of indole derivatives with fluorine-18
2.1.1. Synthesis of precursors for labeling of indole-1H-
carbaldehydes
Four different ortho- and para substituted indolecarbaldehydes
1–4 (Scheme 1) were prepared following a modified procedure
from lit.2
⇑
Corresponding author. Tel.: +49 2461 61 3110; fax: +49 2461 61 2119.
E-mail address: j.ermert@fz-juelich.de (J. Ermert).
http://dx.doi.org/10.1016/j.bmc.2015.06.073
0968-0896/Ó 2015 Elsevier Ltd. All rights reserved.

P. S. Weiss et al. / Bioorg. Med. Chem. 23 (2015) 5856–5869
5857
O
F
O
F
F
a: PG = none (H)
b: PG = benzyl
c: PG = methyl
d: PG = boc
e: PG = tosyl
f: PG = TIPS
N
PG
N
PG
N
PG
N
PG
O
F
O
1a-f
2a,b,d,f
3a,e,f
4b
Scheme 1. Fluoro-1H-indole-carbaldehydes (PG: protecting group).
In the first step the amino group of the ortho-substituted
indolecarbaldehydes 1–3 was protected by the triisopropylsilyl-
group (TIPS) which proceeded quantitatively. This was the protect-
ing group of choice, since TIPS is a bulky group that is able to avoid
the ordinary deprotonation of the intrinsically most acidic 2-posi-
tion of indoles by the consecutive lithiation reaction.2 Next, the for-
myl group was introduced in ortho position to the fluorine (1–3).
This was accomplished by N,N-dimethylformamide (DMF) as elec-
trophile instead of carbon dioxide, referring to the procedure from
lit.2 The formylation gave yields of about 65% with all fluoro-1H-in-
dole derivatives. Hereby, it was essential to use at least four equiv-
alents of DMF, otherwise much lower yields were obtained. The
removal of TIPS from the nitrogen was performed with tetrabuty-
lammonium fluoride (TBAF) giving yields of >90%. Finally, different
protecting groups were then attached to the indole nitrogen of the
fluoro-1H-indolecarbaldehydes, namely the benzyl, the methyl, the
tert-butoxycarbonyl (Boc) and the tosyl group.
Except for the N-benzylation, all protection procedures were
performed as described in lit.13–15 Accordingly, N-benzylations of
indoles proceeded in good yields when tetrahydrofuran (THF) or
dimethylsulfoxide (DMSO) was used as solvent. However, the use
of DMF as solvent for the benzylation of all indole compounds
described here (1a–3a) was essential otherwise a decomposition
of the final product was observed. With DMF as solvent the benzy-
lation succeeded in good yields of about 85%. The methylation gave
moderate yields of about 58% while tosylation and Boc-protection
led to the desired products in 80% and 90% yields, respectively. The
total synthetic pathway for derivatives of compounds 1 to 3 is
shown in Scheme 2, with 6-fluoro-1H-indole-5-carbaldehyde
(1b–e) as an example.
compounds 1b–3b, giving the desired product in yields of about
81%. The formylation was here the final step, carried out in THF
with n-butyllithium and DMF and providing finally the precursor
4b with about 39% yield.
2.1.2. Isotopic exchange with [18F]fluoride and subsequent
decarbonylation
The first step in the preparation of radiofluorinated indoles was
an 18F-for-19F isotopic exchange reaction. Previous work on nucle-
ophilic aromatic substitution had shown that DMF as solvent and
temperatures above 100 °C gave the best radiochemical yield
(RCY) with fluorobenzaldehydes.17,18 These conditions were
adapted to study the influence of different protecting groups on
the radiolabeling reaction. For this purpose, the 18F-fluorination
was carried out with different protected 6-fluoro-indole-1H-5-car-
baldehydes 1a–e (cf. Scheme 4) using [18F]TBAF at 130 °C for
15 min. All reactions were analyzed by radio HPLC and the results
obtained are listed in Table 1.
The radiolabeling was not possible at all when the nitrogen of
the 6-fluoro-1H-indole-5-carbaldehyde (1a) was not protected or
when it was protected with a tosyl group. The latter is not surpris-
ing since de-tosylation of indoles is commonly carried out with
TBAF.19 The best radiochemical yields were obtained with the ben-
zyl- and methyl-protected indole derivatives 1b and 1c (25% and
20%, respectively). Due to higher RCY the benzyl group was there-
fore preferred to the methyl group for further reactions.
Next, the dependence of radiolabeling on the temperature was
examined. For this, the benzyl-protected precursors (1b–4b) were
first radiofluorinated at 150 °C for 15 min using DMF as solvent.
Since the RCY at this temperature was higher than 90% for 1-ben-
zyl-4-fluoro-1H-indole-5-carbaldehyde (2b), it was tested out how
far the temperature could be reduced until the RCY would decrease
significantly. That happened at 60 °C. Alternatively, DMSO and ace-
tonitrile were tested as solvents, but a RCY higher than 8–10%
could not be obtained. Moreover, reaction times longer than
15 min did not increase the RCY. The other benzyl-protected
indolecarbaldehydes (1b, 3b, and 4b) were also tested at
The para-substituted precursor 4b was differently synthesized,
following a three-step linear pathway starting from 1-bromo-4-
fluoro-2-nitrobenzene. The total synthetic route is shown in
Scheme 3. The first step therein was the formation of the indole
via a Bartoli reaction16 giving 7-bromo-4-fluoro-1H-indole in 52%
yield. The subsequent benzylation reaction was carried out with
NaH and benzyl bromide under similar conditions as for the indole
O
1) sec-BuLi
2) DMF
1) n-BuLi
2) TIPS-Cl
N
H
F
THF, -78 °C
N
TIPS
THF, -78 °C
N
TIPS
F
F
1f
1b: PG = benzyl
1c: PG = methyl
1d: PG = Boc
1e: PG = tosyl
1f: PG = TIPS
O
F
O
F
TBAF
THF
protection
N
H
N
PG
1a
1b - 1e
Scheme 2. Synthetic pathway for the preparation of the ortho-substituted indole precursors, exemplified for 6-fluoro-1H-indole-5-carbaldehyde.

5858
P. S. Weiss et al. / Bioorg. Med. Chem. 23 (2015) 5856–5869
F
F
F
F
1) n
-BuLi
1)
MgBr
1) NaH
2) BnBr
2) DMF
THF, -78 °C
THF, -78 °C
N
N
DMF, 0 °C
2) NH4Cl aq
N
H
NO2
Br
O
Br
Br
5
4b
Scheme 3. Synthetic pathway for the preparation of 1-benzyl-4-fluoro-1H-indole-7-carbaldehyde (4b).
described by Castillo et al.21 giving a RCY of 85 2%. Increasing
O
F
O
the amount of Wilkinson’s catalyst to 3 equiv and the reaction time
to 120 s, however, led to optimum conditions with a RCY of 95%.
The results are summarized in Table 2. Those latter conditions
were then applied to all indole compounds 1b–4b leading to sim-
ilar RCYs.
[
18F]TBAF
DMF, 130 °C
N
18F
N
PG
PG
Following debenzylation reactions were studied using ammo-
nium formate (NH4HCO2)22 and hydrogen gas23 with palladium
on charcoal, respectively, or AlCl3 in benzene.24 The use of triphos-
gene also proved to convert the benzylamine into the correspond-
ing carbamoyl chloride that should be hydrolyzed under acidic
conditions.25 However, all methods tested gave no debenzylated
indole derivative, only the AlCl3 method gave radiolabeled side
products. Since all of these attempts failed for the debenzylation
of the indole compounds, the 4-fluoro-1H-indole-5-carbaldehyde
(2a) which gave the best results regarding RCY and chemical stabil-
ity was also protected with a Boc-group. Although the isotopic
exchange reaction with the Boc-protected derivative 1d gave a
RCY of only 6% (cf. Table 1), the Boc-group offers, in principle,
the possibility of its easy removal. Therefore, 1-boc-4-fluoro-1H-
indole-5-carbaldehyde (2d) was labeled with fluorine-18 at tem-
peratures between 70 °C and 110 °C, showing a maximum RCY of
28% at a reaction temperature of 80 °C after 15 min. The deprotec-
tion of this compound proceeded quantitatively with 2 M HCl at
room temperature (cf. Scheme 5).
18F]1a-e
1a-e
[
Scheme 4. Radiofluorination of 6-fluoro-indole-1H-5-carbaldehydes 1a–e.
temperatures between 60 and 150 °C. Surprisingly, the 1-benzyl-
fluoro-1H-indolecarbaldehydes with different ortho- and para-sub-
stitution patterns gave a varying RCY. They also showed a very dif-
ferent chemical stability toward elevated temperatures.
The maximum RCYs were found in the range of 55–94% depend-
ing on the substitution pattern of the used fluoro-1H-indolecar-
baldehydes. The RCY of 1-benzyl-4-[18F]fluoro-1H-indole-7-
carbaldehyde (4b) and 1-benzyl-7-[18F]fluoro-1H-indole-6-
carbaldehyde (3b) was maximum at 80 °C and 95 °C, respectively,
and decreased with increasing temperatures due to decomposition
of the compounds. In contrast, 1-benzyl-4-[18F]fluoro-1H-indole-
5-carbaldehyde (2b) and 1-benzyl-6-[18F]fluoro-1H-indole-5-
carbaldehyde (1b) did not show any decomposition at all, even at
temperatures as high as 150 °C. The results are graphically shown
in Figure 1.
It can be concluded that the substitution pattern has an influ-
ence on the results of the corresponding isotopic exchange reac-
tions. However, not only the position of the fluorine influences
the isotopic exchange, but also the position of the formyl group,
a fact significantly exemplified by the different results found with
the compounds examined. Both 2b and 4b have the fluorine atom
attached in the 4-position, while the compounds 1b and 2b both
have the formyl group in the 5-position with a different substitu-
tion pattern of the other substituent, respectively.
2.2. Radiosynthesis of 4-[18F]fluoro-
L-tryptophan
A previous report on the labeling of aromatic amino acids
described the radiosynthesis of 2-[18F]fluoro-
-phenylalanine and
2-[18F]fluoro- -tyrosine in a three step synthesis.21 The concept
L
L
of this synthesis was adapted to the precursor 16 described above,
following the same synthetic procedures: isotopic exchange,
reductive decarbonylation, and cleavage of the amino acid auxil-
iary (Scheme 6).
The subsequent reductive decarbonylation was performed with
chlorotris(triphenylphosphine)rhodium(I) (‘Wilkinson’s catalyst’,
Rh(PPh3)3Cl). Due to the fact that during this reaction the forma-
tion of stable Rh(PPh3)2(CO)Cl occurs as a secondary product it is
necessary to use stoichiometric amounts of Wilkinson’s catalyst.
This reaction was at first tested with 1-benzyl-6-[18F]fluoro-1H-in-
dole-5-carbaldehyde ([18F]1b) under conditions previously
described.18,20,21 Good results were obtained using the method
2.2.1. Precursor synthesis
The above described results on [18F]fluoroindolecarbaldehydes
have shown that indoles should preferably be radiofluorinated in
the 4-position. Therefore, a synthetic route was developed to pre-
pare a suitable precursor for the radiosynthesis of 4-[18F]fluoro-
L-
tryptophan. The selected precursor was synthesized in an 11 step
linear synthesis starting from 4-fluoroindole with an overall yield
of 8% (see Scheme 7) following a modified route to the one
described by Konas et al.15
As the first step, 4-fluoroindole was N-protected with TIPS-Cl
(94%). A regioselective iodination of 6 was performed as previously
described by Schlosser et al.2 using diiodoethane instead of ele-
mental iodine followed by deprotection with TBAF, giving ca. 65%
of the deprotected iodoindole 8. The formylation in the 3-position
was carried out under standard Vilsmeier-Haack conditions.26
The resulting aldehyde (9) was isolated in 88% yield by filtration
and used as obtained without further purification. A tosyl-group
was introduced (83%) and the protected aldehyde (10) reduced
quantitatively by NaBH4 yielding the corresponding alcohol (11)
Table 1
Dependence of the radiochemical yield of 6-[18F]fluoro-indole-1H-5-carbaldehydes
1a–e on different protecting groups (n = 3)
Compound
Protecting group
RCY [%]
0
1a
1b
1c
1d
1e
None
Benzyl
Methyl
Boc
25
20
6
7
4
2
Tosyl
0
Conditions: 1 mL DMF, TBAHCO3 [18 lmol], reaction time 15 min 130 °C.

P. S. Weiss et al. / Bioorg. Med. Chem. 23 (2015) 5856–5869
5859
Figure 1. Influence of the temperature on the isotopic 18F-exchange on fluoro-1H-indolecarbaldehydes with an ortho- and para-substitution pattern. Conditions: precursors
1b–4b [20 lmol], 1 mL DMF, TBAHCO3 [18 lmol], reaction time 15 min, (n = 3). Each solid curve is an eye-guide.
2.2.2. Isotopic exchange with [18F]fluoride
Table 2
Reductive decarbonylation of 1-benzyl-6-[18F]fluoro-1H-indole-carbaldehyde (1e)
(n = 3)
The first step in the radiosynthetic pathway is again the isotopic
18F-for-19
F exchange. The previous studies on nucleophilic
exchange of indoles indicated, that the use of DMF as solvent and
temperatures between 80 °C and 130° gave the highest RCY.
Thus, the optimum temperature for the isotopic exchange of pre-
cursor 16 was tested by heating the reaction mixture to tempera-
tures between 60 and 120 °C for 15 min (see Fig. 2).
The temperature range is very narrow, over which a good RCY of
above 40% could be obtained and extends from 75 to 85 °C, with an
optimum RCY of 51% at about 80 °C. At temperatures higher than
90 °C the precursor decomposed rapidly. The exchange radiolabel-
ing was also tested in DMSO and MeCN, but the desired compound
could not be obtained in both solvents. Furthermore, a kinetic mea-
surement of the isotopic exchange was performed at the optimum
temperature of 80 °C. The maximum RCY was reached between 10
and 15 min, while again decomposition of the labeled intermediate
occurred with reaction times longer than 20 min. As it is known
from literature that only highly activated aromatic systems will
Solvent
Equivalents of
Wilkinson
catalyst
Conditions
Conversion RCY
(%)
(%)
Benzonitrile
3
150 °C,
>99
95
6
20 min18
100 W, 50 s21
100 W, 120 s
150 °C,
Benzonitrile
Benzonitrile
Dioxane
3
3
2
85
>99
29
2
4
85
95
6
2
3
3
20 min20
which was brominated in an Appel reaction with PPh3 and CBr4
(78%).27 The resulting bromide (12) was immediately coupled with
Seebach’s chiral amino acid auxiliary (73%). The imidazolidinone
(13) obtained was formylated via an iodine formyl exchange in a
Grignard like reaction using i-PrMgBr and DMF, providing 72% of
the corresponding benzaldehyde 14. Further, the tosyl-group was
removed and replaced by a Boc-group, since it is known that N-to-
sylindoles can be easily detosylated by nucleophilic fluoride. The
subsequent removal of the tosyl-group was performed with TBAF
leading to the unprotected indolecarbaldehyde 15 in 53% yield,19
and eventually the introduction of the Boc-group (94%)14 led to
the desired precursor benzyl (2S,5S)-2-tert-butyl-5-[(1-boc-4-flu-
oro-5-formyl-1H-indol-3-yl)methyl]-3-methyl-4-oxoimidazo-
lidine-1-carboxylate (16) with an overall yield of about 8%.
allow
[
a
nucleophilic aromatic substitution reaction with
18F]fluoride at room temperature,28 the reaction here was not
studied under room temperature conditions.
Furthermore, in order to improve the process of the isotopic
exchange, a microwave assisted reaction was tested. Microwave
O
F
O
18F
[
18F]TBAF
DMF
N
N
BOC
BOC
2d
18F
18F
HCl
Rh(PPh3)3Cl
benzonitrile
N
H
N
BOC
Figure 2. Influence of temperature on the isotopic 18F-exchange on precursor 16.
Conditions: 1 mL DMF, TBAHCO3 [18
out at least in triplicate. The solid curve is an eye-guide.
lmol], 15 min, each experiment was carried
Scheme 5. Reaction sequence to 4-[18F]fluoro-1H-indole.

5860
P. S. Weiss et al. / Bioorg. Med. Chem. 23 (2015) 5856–5869
O
N
O
O
N
O
O
F
O
18F
TBA18
DMF
F
N
N
O
O
N
N
BOC
BOC
18F]16
16
[
O
N
O
NH2
OH
18F
18F
N
Rh(PPh3)3Cl
benzonitrile
HCl
O
O
N
BOC
N
H
18F]17
[
18F]18
[
Scheme 6. Synthetic route for the radiosynthesis of 4-[18F]fluoro-
L-tryptophan.
irradiation produces efficient internal heating (in-core volumetric
heating) by direct coupling of microwave energy with the mole-
cules (solvents, reagents, catalysts) that are present in the reaction
mixture, resulting in an inverted temperature gradient compared
to conventional thermal heating.29 While the total RCY could not
be increased by the use of this technique in comparison to conven-
tional heating, the reaction time could be reduced to 1 min. The
best results using a microwave assisted reaction were obtained
by a power of 40 W and a reaction time of 1 min with a RCY of
about 49%.
approximately 34% for this deprotection reaction. Each experiment
was carried out at least in triplicate. The final purification was per-
formed by HPLC using 10% ethanol in water which can directly be
used for first animal experiments.
The reactions performed under conventional heating yielded
the desired product in an overall RCY of [18F]18 of approximately
8%. The application of a microwave assisted synthesis increased
the total RCY to about 13% due to the higher yields that were
obtained for the decarbonylation reaction with microwave heating.
Furthermore, the total preparation time of 4-[18F]fluoro-
L-trypto-
phan ([18F]18) could be reduced to 27 min, yielding the product
in an enantiomeric purity of >99%. None of the D-enantiomer could
be observed by chiral HPLC.
2.2.3. Reductive decarbonylation and hydrolysis
The aldehyde function was removed with the help of
Wilkinson’s catalyst. This reaction was tested under the conditions
that gave the best RCY with the indoles (1b–4b) as described
above, and it was optimized regarding the equivalents of catalyst,
solvent, temperature and time. The reaction was also carried out
under microwave assisted heating. It turned out that under con-
ventional heating (CH) only a moderate RCY of [18F]17 of about
45% could be achieved which is probably due to decomposition.
Under microwave assisted heating (MH) a RCY of about 75% was
obtained. However, the formation of a polar side product could
not be avoided, but be limited to about 20%, when using 3 or
4 equiv of Wilkinson’s catalyst. Under microwave heating it could
also not be accomplished to get the decarbonylated intermediate
without removing the Boc-group from the indole-nitrogen which,
however, is not a problem in this case. Moreover, the use of micro-
wave assisted heating led to almost quantitative chemical conver-
sion of [18F]17, whereas 35 9% of [18F]17 were left unchanged
under conditions of conventional heating. The fractions of non-
converted intermediate [18F]17 were examined by HPLC analysis.
The conversions were examined by HPLC analysis. The results are
summarized in Table 3.
The specific activity obtained by isotopic exchange reactions is a
function of both the amount of precursor and the amount of
radioactivity of [18F]fluoride. The maximum amount of carrier is
limited by the quantity of precursor that is used; in this study here
9 lmol. When a starting activity of approximately 250 MBq was
used the molar activity was always >70 MBq/mmol which is in
the region of specific activities obtained under electrophilic fluori-
nation conditions. Thus, it can be expected that with a higher start-
ing activity of [18F]fluoride the molar activity of the product would
increase considerably and will thereby be much higher than that
obtained with electrophilic 18F-fluorination. An animal toxicologi-
cal study of 4-[18F]fluoro-
L-tryptophan is in progress, however, in
earlier tests with bacteria no toxicity of the compound was
observed.31
3. Summary
An influence of the positions of fluorine and of the formyl group
on the isotopic exchange in the carbocyclic ring of indole was
observed with several fluoro-1H-indolecarbaldehydes, each bear-
ing a different protecting group at the indole nitrogen. The best
results regarding radiochemical yield and chemical stability were
obtained with 1-benzyl-4-fluoro-1H-indole-5-carbaldehyde (2e).
However, it was not possible to remove the benzyl protection
group from this compound. Thus, the Boc-protected derivative
The amide bond in Seebach’s auxiliary requires harsh condi-
tions for hydrolysis. In previous studies this was done using con-
centrated HBr or HI and temperatures as high as 150 °C or even
200 °C.17,30 In another work concentrated HCl and heating to
150 °C for 30 min proved sufficient for the hydrolysis of the Boc-
protected derivative of Seebach’s auxiliary.21 In the study here,
those conditions were adapted to give a RCY of [18F]18 of
4-[18F]fluoro-
radiosynthesis, consisting of an isotopic exchange, a reductive
L-tryptophan was best prepared by the three step

P. S. Weiss et al. / Bioorg. Med. Chem. 23 (2015) 5856–5869
5861
F
F
F
1) n-BuLi
2) TIPS-Cl
1) sec-BuLi
2) Diiodethane
I
THF, -78 °C
THF, -78 °C
N
TIPS
N
TIPS
N
H
6
7
O
O
F
F
F
H
1) NaH
2) Tos-Cl
H
DMF, POCl3
DMF
I
TBAF
I
I
THF, 0 °C
THF, RT
N
N
N
H
H
Tos
8
9
10
74 %
65 %
89 %
O
N
F
OH
F
Br
F
1) LDA, Z-BMI
2) THF, -78 °C
N
I
CBr4 , PPh3
DCM, 0 °C
I
I
NaBH4
O
O
N
THF/EtOH
N
N
Tos
Tos
Tos
11 97 %
12 63 %
13 73 %
O
N
O
N
O
1) iPrMgBr
O
F
O
F
TBAF
2) DMF
N
N
O
O
O
THF, 80 °C
THF, 0 °C
N
N
H
Tos
14 73 %
15 42 %
O
N
O
O
F
N
Boc2O, DMAP
THF, RT
O
N
Boc
16 86 %
Scheme 7. Synthesis pathway of precursor 16 for radiosynthesis of 4-[18F]fluoro-
L-tryptophan.
decarbonylation with Rh(PPh3)3Cl and the hydrolysis of the
protecting groups with HCl. After optimization of this procedure,
1-(triisopropylsilyl)-1H-indole, 7-bromo-4-fluoroindole, 7-fluoro-
1-(triisopropylsilyl)-1H-indole and 4-fluoro-1-triisopropyl-1H-in-
dole (6) were prepared as described in lit.2
4-[18F]fluoro-
L-tryptophan could be isolated in a total radiochemi-
cal yield of about 13%, an enantiomeric excess of >99% and a molar
activity of >70 MBq/mmol within about 100 min total synthesis
time. Hence, a new and more efficient nucleophilic radiosynthesis
Experiments under microwave heating were performed using a
CEM Discover (Matthews, USA) single-mode microwave reactor
system. Thin layer chromatography (TLC) was performed on pre-
coated plates of silica gel 60 F254 (Merck, Darmstadt, Germany)
and the compounds were detected at 254 nm. Radioactivity on
radio-TLC was detected on a Raytest minigita device (Raytest,
Straubenhardt, Germany). High-performance liquid chromatogra-
phy (HPLC) separations were achieved with a Knauer pump, a
Knauer K-2500 UV/VIS detector (Knauer, Berlin, Germany), a
of 4-[18F]fluoro-
L-tryptophan was developed which makes the tra-
cer now available for preclinical evaluation studies.
4. Experimental
4.1. General
manual Rheodyne injector (20 lL or 1.0 mL loop), and a NaI(Tl)
Chemicals were purchased from Sigma-Aldrich (Taufkirchen),
Merck (Darmstadt), and ABCR (Karlsruhe) (all Germany).
1-Triisopropylsilyl-6-fluoro-1H-indole-5-carbaldehyde, 4-fluoro-
well-type scintillation detector (EG&G Ortec; model 276
Photomultiplier Base) with an ACE Mate Amplifier and BIAS supply
(all from Ortec Ametek, Meerbusch, Germany) for radioactivity

5862
P. S. Weiss et al. / Bioorg. Med. Chem. 23 (2015) 5856–5869
Table 3
detection. Data acquisition and interpretation were performed
with Gina software (Raytest, Version 2.18).
Conditions and results for the reductive decarbonylation of precursor 16
1H, 13C and 19F NMR spectra were recorded on a Varian Inova
400 MHz spectrometer using CDCl3 or d6-DMSO as solvents. All
chemical shifts are given below in d ppm using the signals of the
appropriate solvent as a reference. HRMS spectra were obtained
on an FTICR ‘LTQ FT Ultra’ (Thermo Fisher Scientific, Germany).
Optical rotation was measured using a Perkin Elmer (Rodgau,
Germany) Model 341 Polarimeter at a wavelength of 589 nm.
Conditions
Equivalents of
Rh(PPh3)3Cl
Time
(min)
Conversion
(%)
RCY
(%)
CH, 150 °C
CH, 150 °C
CH, 150 °C
MH, 100 W
MH, 100 W
MH, 100 W
MH, 100 W
2
3
4
1
2
3
4
20
20
20
2
2
2
22
65
45
8
9
6
15
45
35
6
8
3
>99
>99
>99
>99
58 11
69
75
78
9
7
6
2
4.2. Chromatographic systems
CH: conventional heating; MH: microwave assisted heating; Each experiment was
carried out at least in triplicate.
System A
Analytical HPLC of the 18F-labeled indole derivatives was per-
formed with
a
Kromasil 5
l
m
C18 column (250 ꢀ 4 mm; CS
Chromatographieservice Langerwehe, Germany). Elution was per-
formed at a constant flow rate of 1 mL minꢁ1 with an acetonitrile
water mixture (65:35).
Table 4
k0-Values of the labeled compounds analyzed by radio-HPLC
Compound
HPLC System
k0
5.18
System B
[
[
[
[
[
[
[
[
[
18F]1b
18F]2b
18F]3b
18F]4b
18F]16
18F]17
18F]18
18F]18
18F]18
A
A
A
A
A
A
B
C
D
Semi-preparative HPLC was carried out with a Synergi 4
lm
5.26
5.38
6.60
14.68
5.18
3.44
6.18
2.99
Hydro-RP 80 Å column Phenomenex,
(250 ꢀ 10 mm;
Aschaffenburg, Germany). The mobile phase was 10% ethanol in
water, and the flow rate was 4 mL minꢁ1
.
System C
The enantiomeric purity of the radiolabeled compounds was
determined by HPLC using a Supelco chirobiotic™ T column,
250 ꢀ 4.6 mm (Sigma-Aldrich, Diedenhofen, Germany). Elution
was performed with a methanol-water mixture (30:70) at a con-
stant flow rate of 1 mL minꢁ1
.
acetate (EA)/petroleum ether (PE), Rf = 0.30) giving 2.5 g (7.8 mmol,
64%) of the desired product as a colorless oil.
1H NMR (CDCl3) d 10.38 (s, 1H), 8.17 (d, 3J = 7.0 Hz, 1H), 7.32 (d,
4J = 3.3 Hz, 1H), 7.24 (dd, 3J = 12.6 Hz, 4J = 0.7, 1H), 6.74 (dd,
4J = 2.4 Hz, 4J = 0.9 Hz, 1H), 1.72 (hept, 3J = 7.6 Hz, 3H), 1.19 (d,
System D
Analytical HPLC was carried out with a Synergi 4 lm Hydro-RP
80 Å column (250 ꢀ 4 mm; Phenomenex). The mobile phase was
10% ethanol in water, and the flow rate was 1 mL minꢁ1. The k0-
values of important radiolabelled compounds together with the
corresponding separation systems are summarized in Table 4.
3
3J = 7.4 Hz, 18H); 13C NMR (CDCl3) 187.1 (d, JCF = 6.4 Hz), 161.13
1
3
4
(d, JCF = 247), 144.8 (d, JCF = 12 Hz), 133.4 (d, JCF = 3 Hz), 128.2
5
4
3
(d, JCF = 1 Hz), 121.7 (d, JCF = 4Hz), 118.4 (d, JCF = 11Hz), 106.5,
100.4 (d, JCF = 25.2 Hz), 18.0(6C), 12.7(3C); 19F NMR (CDCl3) d
2
ꢁ130.1; HRMS: C18H26FNOSi [M+H]+ calcd: 320.1840; found:
4.3. Precursor syntheses
320.1839.
Following 10 fluoroindole carbaldehydes were synthesized
according to Schlosser et al.2
4.3.2. 1-Triisopropylsilyl-4-fluoro-1H-indol-5-carbaldehyd (2f)
4.3.1. 1-Triisopropylsilyl-6-fluoro-1H-indole-5-carbaldehyde
(1f)
F
O
N
O
TIPS
N
F
TIPS
Analogously prepared as the aldehyde 1f, while starting from 4-
fluoro-1-(triisopropylsilyl)-1H-indole giving the desired product as
a colorless solid in 66% yield.
A
solution of 6-fluoro-1-(triisopropylsilyl)-1H-indole (4.0 g,
Mp: 61–63 °C.
1H NMR (DMSO-d6) d 10.26 (s, 1H), 7.51–7.48 (m, 3H), 6.85 (d,
4J = 3.2 Hz), 1.73 (hept, 3H, 3J = 7.6 Hz), 1.02 (d, 18H, 3J = 7.6 Hz);
14 mmol) in 30 mL tetrahydrofuran was cooled to ꢁ78 °C, and a
1.4 M solution of sec-butyllithium in hexanes (14 mmol) was
added dropwise. The resulting mixture was stirred for 2 h at
ꢁ78 °C before 5 mL dimethylformamide were added slowly. The
reaction was allowed to warm up to room temperature and stirred
for 2 more hours. Water was added and the aqueous phase was
extracted with Et2O. The combined organic extracts were dried
over Na2SO4, filtered and the solvents were evaporated in vacuo.
The crude residue was purified by flash chromatography (2% ethyl
13C NMR (DMSO-d6)
d
187.3 (d, 3JCF = 6 Hz), 158.9 (d,
2
1JCF = 259 Hz), 147.3 (d, JCF = 12 Hz), 134.2, 120.9, 119.7 (d,
2JCF = 19 Hz), 115.8 (d, JCF = 5 Hz), 111.5, 102.3, 18.1 (6C),
3
12.2(3C); 19F NMR (DMSO-d6) d ꢁ128,78; HRMS: C18H26FNOSi
[M+H]+ calcd 320.1840; found: 320.1842; elemental analysis calcd
for C18H26FNOSi: C, 67.67; H, 8.20; N, 4.38; found: C, 67.68; H,
8.25; N, 4.35.

P. S. Weiss et al. / Bioorg. Med. Chem. 23 (2015) 5856–5869
5863
4.3.3. 1-Triisopropylsilyl-7-fluoro-1H-indol-5-carbaldehyd (3f)
Mp: decomposition at 61–67 °C.
1H NMR (DMSO-d6) d 11.89 (s, 1H), 10.27 (s, 1H), 7.49 (t, 2H,
3J = 6.8 Hz), 7.33 (d, 1H, 3J = 8.4 Hz), 6.68 (s, 1H); 13C NMR
3
1
(DMSO-d6) d 187.2 (d, JCF = 7 Hz), 159.5 (d, JCF = 26 Hz), 142.8
2
2
(d, JCF = 13 Hz), 128.2, 120.5, 116.2 (d, JCF = 21 Hz), 115.2 (d,
4
3JCF = 5 Hz), 109.4 (d, JCF = 3 Hz), 99.33; 19F NMR (DMSO-d6) d
N
TIPS
ꢁ129,01; HRMS: C9H6FNO [M+H]+ calcd 164.0506; found:
164.0506; elemental analysis calcd for C9H6FNO: C, 66.26; H,
3.71; N, 8.59; found: C, 65.76; H, 3.73; N, 8.54.
O
F
Analogously prepared as the aldehyde 1f, but starting from 7-
fluoro-1-(triisopropylsilyl)-1H-indole giving the desired product
as colorless oil in 63% yield.
4.3.6. 7-Fluoro-1H-indole-6-carbaldehyde (3a)
1H NMR (DMSO-d6) d 10.32 (s, 1H), 7.71 (d, 1H, 4J = 2.6 Hz), 7.52
(dd, 1H, 3J = 8.2 Hz, 3J = 12.6 Hz), 7.51 (d, 1H, 3J = 7.1 Hz), 6.82 (s,
1H), 1.69 (sept, 3H, 3J = 7.2 Hz), 1.07 (d, 18H, 3J = 7.5 Hz); 13C
N
H
3
1
NMR (DMSO-d6) d 187.5 (d, JCF = 8.3 Hz), 153.1 (d, JCF = 257 Hz),
O
F
140.9 (d, JCF = 8 Hz), 138.4, 126.9 (2JCF = 9 Hz), 119.6, 117.4,
3
106.8, 18.3(6C), 13.1 (3C) (5JCF = 5 Hz); 19F NMR (DMSO-d6) d
ꢁ133.15; HRMS: C18H26FNOSi [M+H]+ calcd 320.1840; found:
320.1840; elemental analysis calcd for C18H26FNOSi: C, 67.67; H,
8.20; N, 4.38; found: C, 67.42; H, 8.24; N, 4.35.
Analogously prepared as aldehyde 1a, but starting from 1-tri-
isopropylsilyl-7-fluoro-1H-indol-5-carbaldehyd (3f) giving the
desired product as a colorless solid in 88% yield.
4.3.4. 6-Fluoro-1H-indole-5-carbaldehyde (1a)
Mp: 132 °C.
1H NMR (DMSO-d6) d 10.28 (s, 1H), 7.67–7.34 (m, 2H), 7.41–
7.37 (m, 1H), 6.59 (s, 1H); 13C NMR (DMSO-d6) d 187.3 (d,
3JCF = 7 Hz), 152.7 (d, JCF = 259 Hz), 137.0 (d, JCF = 8 Hz), 131.6,
1
3
O
2
4
123.2 (d, JCF = 11 Hz), 117.9, 117.0 (d, JCF = 3 Hz), 116.5 (d,
4JCF = 3 Hz), 103.7 (d, JCF = 1 Hz); 19F NMR (DMSO-d6) d ꢁ140.48;
4
HRMS: C9H6FNO [M+H]+ calcd 164.0506; found: 164.0505; ele-
mental analysis calcd for C9H6FNO: C, 66.26; H, 3.71; N, 8.59;
found: C, 65.89; H, 3.75; N, 8.62.
N
H
F
4.3.7. 1-Benzyl-6-fluoro-1H-indole-5-carbaldehyde (1b)
4.1 mL of a 1.0 M solution of TBAF in THF were added to a solu-
tion of 1.3 g (4.0 mmol) of 1-triisopropylsilyl-6-fluoro-1H-indole-
5-carbaldehyde (1f) in 5 mL THF. The reaction mixture was stirred
for 5 min at room temperature, quenched by the addition of water
and extracted repeatedly with Et2O. The combined organic layers
were dried over Na2SO4, filtered and the solvent was removed in
vacuo. Purification by column chromatography (PE/EA = 3:2) deliv-
ered 560 mg (3.4 mmol, 86%) of the desired 6-fluoro-1H-indole-5-
carbaldehyde (1d) as a colorless solid.
O
N
F
Mp: decomposition at 125–128 °C.
1H NMR (DMSO-d6) d 11.60 (s, 1H), 10.16 (s, 1H), 8.06 (d, 1H,
3J = 6.8 Hz), 7.47 (t, 1H, 3J = 3.0 Hz), 7.28 (d, 1H, 3J = 12.0 Hz), 6.61
3
(s, 1H); 13C NMR (DMSO-d6) d 188.2 (d, JCF = 5 Hz), 160.2 (d,
A solution of 270 mg (1.7 mmol) of 6-fluoro-1H-indole-5-car-
baldehyde (1a) in 5 mL DMF was cooled to 0 °C, and 100 mg
(2.5 mmol) of a 60% dispersion of NaH in mineral oil were added.
The resulting solution was stirred for 20 min at 0 °C before
1JCF = 246 Hz), 139.7 (d, JCF = 13 Hz), 128.8 (d, JCF = 3 Hz), 124.9,
3
4
4
3
123.2 (d, JCF = 4 Hz), 117.9 (d, JCF = 11 Hz), 103.7, 98.4 (d,
2JCF = 25 Hz); 19F NMR (DMSO-d6) d ꢁ130.24; HRMS: C9H6FNO
[M+H]+ calcd 164.0506; found: 164.0506; elemental analysis calcd
for C9H6FNO: C, 66.26; H, 3.71; N, 8.59; found: C, 65.80; H, 3.75; N,
8.55.
296 lL (2.5 mmol) benzyl bromide were added. Then, the reaction
mixture was warmed to room temperature and stirred for 12 h.
Water was added, followed by repeated extraction with Et2O. The
combined organic layers were dried over Na2SO4, and the solvent
was evaporated in vacuo. Purification by column chromatography
gave 371 mg (1.46 mmol, 86%) of 1-benzyl-6-fluoro-1H-indole-5-
carbaldehyde (1e) as a colorless solid.
4.3.5. 4-Fluoro-1H-indole-5-carbaldehyde (2a)
Mp: 100–101 °C.
O
F
1H NMR (DMSO-d6) d 10.17 (s, 1H), 8.08 (d, 1H, 3J = 6.8 Hz), 7.63
(d, 1H, 4JCF = 3.1 Hz), 7.54 (d, 1H, 3JCF = 12.5 Hz), 7.32–7.22 (m, 5H),
5.43 (s, 2H); 13C NMR (DMSO-d6) d 188.1 (d, JCF = 5 Hz), 160.3 (d,
3
N
H
1JCF = 246 Hz), 139.6 (d, JCF = 13 Hz), 137.9, 132.7 (d, JCF = 3 Hz),
2
4
4
129.1, 128.1(2C), 127.6(2C), 125.3, 123.6 (d, JCF = 4 Hz), 118.0 (d,
3JCF = 11 Hz), 104.1, 97.7 (d, JCF = 26 Hz), 49.8; 19F NMR (DMSO-
2
d6) d ꢁ128.90; HRMS: C16H12FNO [M+H]+ calcd 254.0976; found:
254.0975; elemental analysis calcd for C16H12FNO: C, 75.88; H,
4.78; N, 5.53; found: C, 75.27; H, 4.86; N, 5.27.
Analogously prepared as compound 1a, while starting from 1-
triisopropylsilyl-4-fluoro-1H-indol-5-carbaldehyd (2f); colorless
solid; yield 89%.

5864
P. S. Weiss et al. / Bioorg. Med. Chem. 23 (2015) 5856–5869
4.3.8. 1-Benzyl-4-fluoro-1H-indole-5-carbaldehyd (2b)
(0.75 mmol) of a 60% dispersion of NaH in mineral oil were added.
The resulting solution was allowed to stir for 20 min at 0 °C, before
100 lL (1.6 mmol) iodomethane were added. The reaction mixture
was allowed to reach room temperature and then stirred for fur-
ther 12 h. Water was added, followed by repeated extraction with
Et2O. The combined organic layers were dried over Na2SO4, and the
solvent was evaporated in vacuo. Purification by column chro-
matography gave 52 mg (0.29 mmol, 58%) of 1-methyl-6-fluoro-
1H-indole-5-carbaldehyde (1c) as an off-white solid.
Mp: 108–110 °C.
O
F
N
1H NMR (DMSO-d6) d 10.21 (s, 1H), 8.09 (d, 1H, 3J = 6.8 Hz),
7.52–7.46 (m, 2H), 6.67 (dd, 1H, 4J = 3.2 Hz, 5J = 0.9 Hz), 3.82 (s,
3
3H); 13C NMR (DMSO-d6)
d
188.2 (d, JCF = 5 Hz), 160.3 (d,
Analogously prepared as the aldehyde 1b, while starting from
4-fluoro-1H-indole-6-carbaldehyde (2a) giving the desired product
as a colorless solid in 88% yield.
1JCF = 246 Hz), 140.2 (d, JCF = 13 Hz), 133.1 (d, JCF = 3 Hz), 125.1
2
4
5
3
3
(d, JCF = 1 Hz), 123.5 (d, JCF = 4 Hz), 117.8 (d, JCF = 11 Hz), 103.4,
97.3 (dd, JCF = 25, 33 Hz); 19F NMR (DMSO-d6) d ꢁ129.49; HRMS:
2
Mp: 96–97 °C.
C10H8FNO [M+Na]+ calcd 200.0482; found: 200.0482; elemental
analysis calcd for C10H8FNO: C, 67.79; H, 4.55; N, 7.91; found: C,
66.42; H, 4.61; N, 7.61.
1H NMR (DMSO-d6) d 10.26 (s, 1H), 7.68 (d, 1H, 4J = 3.2 Hz), 7.49
(dd, 1H, 3J = 8.8 Hz, 3J = 8.4 Hz), 7.30–7.20 (m, 5H), 6.75 (d, 1H,
4J = 2.8 Hz), 5.47 (s, 2H); 13C NMR (DMSO-d6)
d
187.2 (d,
3JCF = 6 Hz), 159.2 (d, JCF = 260 Hz), 142.3 (d, JCF = 13 Hz), 137.8,
1
3
2
3
4.3.11. 1-Boc-6-fluoro-1H-indole-5-carbaldehyde (1d),
132.0 (2C), 129.0 (d, JCF = 21 Hz), 128.1 (d, JCF = 8 Hz), 127.5
2
3
according to de Koning et al.14
(2C), 116.8 (d, JCF = 21 Hz), 115.4 (d, JCF = 5 Hz), 108.2 (d,
4JCF = 3 Hz), 99.6, 49.9; 19F NMR (DMSO-d6) d ꢁ128.90; HRMS:
C
16H12FNO [M+H]+ calcd 254.0976; found: 254.0975; elemental
O
analysis calcd for C16H12FNO: C, 75.88; H, 4.78; N, 5.53; found: C,
75.27; H, 4.86; N, 5.27.
N
Boc
F
4.3.9. 1-Benzyl-7-fluoro-1H-indole-6-carbaldehyd (3b)
7.3 mg (0.06 mmol) DMAP and 152 mg (0.7 mmol) Boc2O were
added to a solution of 100 mg (0.61 mmol) of 6-fluoro-1H-indole-
5-carbaldehyde (1a) in 7 mL THF. The resulting solution was stirred
for 4 h at room temperature. Water was added, followed by repeated
extraction with Et2O. The combined organic layers were dried over
Na2SO4 and the solvent was evaporated in vacuo. Purification by col-
umn chromatography gave 136 mg (0.48 mmol, 72%) of 1-Boc-6-
fluoro-1H-indole-5-carbaldehyde (1d) as a colorless solid.
Mp: 91–93 °C.
N
O
F
Analogously prepared as the aldehyde 1b, but starting from 7-
fluoro-1H-indole-6-carbaldehyde (3a) giving the desired product
as a colorless solid in 82% yield.
1H NMR (DMSO-d6) d 10.38 (s, 1H), 8.05 (d, 1H, 3J = 6.7 Hz), 7.95
(d, 1H, 3J = 11.2 Hz), 7.62 (d, 1H, 4J = 3.6 Hz), 6.63 (d, 1H,
Mp: 90–91 °C.
1H NMR (CDCl3) d 10.36 (s, 1H), 7.52 (dd, 1H, 3J = 5.9 Hz,
4J = 2.1 Hz), 7.39 (d, 1H, 3J = 8.3 Hz), 7.33–7.24 (m, 4H), 7.13 (d,
2H, 3J = 7.0 Hz), 6.58 (s, 1H), 5.51 (s, 2H); 13C NMR (CDCl3) d
187.0 (d, JCF = 9 Hz), 153.7 (d, JCF = 259 Hz), 137.8 (d, JCF = 7 Hz),
137,4, 133.9, 128.9, 128(2C), 126.7(2C), 123 (d, JCF = 8 Hz), 118.4,
4J = 3.8 Hz), 1.68 (s, 9H); 13C NMR (DMSO-d6)
d 187.4 (d,
3JCF = 6.8 Hz), 162.6 (d, 1JCF = 249.8 Hz), 149, 139.1 (d,
3JCF = 13.2 Hz), 128.0 (d, 4JCF = 3.1 Hz), 127.0, 121.3 (d,
4JCF = 3.1 Hz), 120.8 (d, 3JCF = 10.1 Hz), 107.8, 102.9 (d,
2JCF = 28.1 Hz), 85.0, 28.1(3C); 19F NMR (DMSO-d6) d ꢁ126.44;
HRMS: C16H12FNO3S [M+Na]+ calcd 286.0849; found: 286.0849;
elemental analysis calcd for C16H12FNO3S: C, 63.87; H, 5.36; N,
5.32; found: C, 63.71; H, 5.38; N, 5.23.
3
1
3
3
4
4
4
117.6 (d, JCF = 5 Hz), 117.1 (d, JCF = 3 Hz), 103.7 (d, JCF = 1 Hz),
52.7 (d, JCF = 6 Hz); 19F NMR (CDCl3)
d
ꢁ148.05; HRMS:
4
C
16H12FNO [M+H]+ calcd 254.0976; found: 254.0976; elemental
analysis calcd for C16H12FNO: C, 75.88; H, 4.78; N, 5.53; found: C,
75.57; H, 4.80; N, 5.49.
4.3.12. 1-Boc-4-fluoro-1H-indole-5-carbaldehyde (2d),
according to Koning et al.14
4.3.10. 1-Methyl-6-fluoro-1H-indole-5-carbaldehyde (1c)
O
F
O
N
Boc
N
CH3
F
Analogously prepared as the aldehyde 1d, but starting from 7-
fluoro-1H-indole-6-carbaldehyde (3a), giving the desired product
as a colorless solid in 82% yield.
A solution of 80 mg (0.5 mmol) of 6-fluoro-1H-indole-5-car-
baldehyde (1a) in 5 mL DMF was cooled to 0 °C, and 30 mg

P. S. Weiss et al. / Bioorg. Med. Chem. 23 (2015) 5856–5869
5865
Mp: 112–114 °C.
(100% PE Rf = 0.29) yielding 711 mg (2.4 mmol, 81%) of 1-benzyl-
7-bromo-4-fluoro-1H-indole (4d) as colorless oil.
Mp: 65 °C.
1H NMR (CDCl3) d 10.48 (s, 1H), 8.06 (d, 3J = 8.7 Hz, 1H), 7.82
(dd, 3J = 8.7 Hz, 3J = 6.5 Hz, 1H), 7.67 (d, 4J = 3.8 Hz, 1H), 6.81 (d,
4J = 3.8 Hz, 1H), 1.73 (s, 9H); 13C NMR (CDCl3)
d
186.9 (d,
1H NMR (DMSO-d6) d 7.33–7.25 (m, 4H), 7.12–7.03 (m, 3H), 6.71
(dd, 2H, 3J = 10.5 Hz, 3J = 9.4 Hz), 5.87 (s, 2H); 13C NMR (DMSO-d6) d
3JCF = 7 Hz), 158.7 (d, JCF = 247), 149.8, 141.6, 127.3, 123.6 (d,
1
4JCF = 2 Hz), 119.3 (d, JCF = 21 Hz), 118.2 (d, JCF = 6 Hz), 111.9 (d,
4JCF = 4 Hz), 103.4, 85.2, 28.1(3C); 19F NMR (CDCl3) d ꢁ129.58;
HRMS: C16H12FNO3S [M+Na]+ calcd 286.0849; found: 286.0850;
elemental analysis calcd for C16H12FNO3S: C, 62.77; H, 5.36; N,
5.32; found: C, 63.31; H, 5.22; N, 5.21.
159.9 (d, JCF = 243 Hz), 139.7, 134.4 (d, JCF = 11 Hz), 133.6, 129.0,
2
3
1
3
3
2
127.6(2C), 127.1 (d, JCF = 8), 126.2(2C), 120.4 (d, JCF = 24 Hz),
2
4
106.4 (d, JCF = 20 Hz), 98.0 (d, JCF = 3), 98.1, 50.8; 19F NMR
(DMSO-d6) d ꢁ124.11; E.A.: calcd C, 63.87; H, 5.36; N, 5.32; found:
C, 63.71; H, 5.38; N, 5.23.
4.3.13. 1-Tosyl-6-fluoro-1H-indole-5-carbaldehyde (1e),
4.3.15. 1-Benzyl-4-fluoro-1H-indole-7-carbaldehyde (4b)
according to Konas et al.15
F
O
N
N
Tos
F
O
A solution of 420 mg (1.4 mmol) of 4d in 5 mL THF was cooled
to ꢁ78 °C, and 560
hexane were added. The mixture was stirred for 30 min, before
500 L DMF were added, followed by warming to room tempera-
ture and stirring for 3 h. Water was added, and the aqueous phase
was repeatedly extracted with Et2O. The combined organic frac-
tions were dried over Na2SO4, and the solvent was evaporated in
vacuo. The crude product was purified by column chromatography
yielding 134 mg (0.5 mmol, 39%) of 1-benzyl-4-fluoro-1H-indole-
7-carbaldehyde (4e) as a colorless solid.
lL (1.4 mmol) of a 2.5 M solution of n-BuLi in
A solution of 150 mg (0.92 mmol) of 6-fluoro-1H-indole-5-
carbaldehyde (1a) in 5 mL DMF was cooled to 0 °C, and 55 mg
(1.38 mmol) of a 60% dispersion of NaH in mineral oil were added.
The resulting solution was allowed to stir for 20 min at 0 °C, before
263 mg (1.38 mmol) of tosyl chloride were added. The reaction
mixture was allowed to reach room temperature and stirred for
further 12 h. Water was added, followed by repeated extraction
with Et2O. The combined organic layers were dried over Na2SO4,
and the solvent was evaporated in vacuo. Purification by column
chromatography gave 239 mg (0.75 mmol, 82%) of 1-tosyl-6-flu-
oro-1H-indole-5-carbaldehyde (1e) as an off-white solid.
Mp: 130–132 °C.
l
Mp: 75–77 °C.
1H NMR (DMSO-d6) d 10.05 (s, 1H), 7.81 (dd, 3J = 8.4 Hz, 4J = 5.7 Hz,
1H), 7.71 (d, 3J = 3.2 Hz, 1H), 7.21–7.10 (m, 6H), 6.98 (d, 3JFH = 21.0 Hz,
1H), 6.90 (d, 4J = 1.3 Hz), 6.82 (d, 3J = 3.3 Hz), 5.97 (s, 2H); 13C NMR
1H NMR (DMSO-d6) d 10.15 (s, 1H), 8.06 (d, 1H, 3J = 6.8 Hz), 7.94
(d, 2H, 3J = 8.4 Hz), 7.90 (d, 1H, 3J = 3.5 Hz), 7.81 (d, 1H, 3J = 11.4 Hz),
7.37 (d, 1H, 3J = 8.0 Hz), 6.93 (d, 1H, 3J = 3.4 Hz), 2.27 (s, 3H); 13C NMR
(DMSO-d6) d 187.9 (d, 3JCF = 5 Hz), 161.4 (d, 1JCF = 251 Hz), 146.6(2C),
1
(DMSO-d6)
d
190.3, 159.9 (d, JCF = 154 Hz), 138.6, 136.2 (d,
3
3JCF = 13 Hz), 132.1, 132.1 (d, JCF = 10 Hz), 129.1, 127.7(2C),
126.5(2C), 120.5, 105.4 (d, JCF = 20 Hz), 98.9, 53.7, 28.5; 19F NMR
2
3
4
(DMSO-d6) d ꢁ111.47; elemental analysis calcd for C16H12FNO: C,
137.6 (d, JCF = 13 Hz), 134.1, 130.9, 129.4 (d, JCF = 4 Hz), 127.4 (d,
4
3
4JCF = 4 Hz), 127.4(2C), 123.7 (d, JCF = 4 Hz), 121.0 (d, JCF = 11 Hz),
110.2, 101.4 (d, 2JCF = 27 Hz), 21.5; 19F NMR (DMSO-d6) d ꢁ124.12;
HRMS: C16H12FNO3S [M+H]+ calcd 318.0595; found: 318.0594; ele-
mental analysis calcd for C16H12FNO3S: C, 60.56; H, 3.81; N, 4.41;
found: C, 60.35; H, 3.95; N, 4.46.
63.87; H, 5.36; N, 5.32; found: C, 63.71; H, 5.38; N, 5.23.
4.3.16. 4-Fluoro-5-iodo-1H-indole (8)
F
4.3.14. 1-Benzyl-7-bromo-4-fluoro-1H-indole (5)
I
N
H
F
sec-BuLi in hexane (20 ml, 28 mmol, 1.4 M) was added to solu-
tion of 8.0 g (27.5 mmol) 4-fluoro-1-triisopropylsilyl-1H-indole (7)
and 5.8 mL N,N,N0,N00,N00-pentamethyldiethylenetriamine (4.9 g,
27.5 mmol) in 40 mL THF at ꢁ78 °C. The solution was stirred at this
temperature for 6 h before 7.8 g (27.5 mmol) of diiodoethane were
added. The reaction mixture was slowly warmed to room temper-
ature and stirred overnight. Water was added and the aqueous
phase was extracted with Et2O. The combined organic layers were
dried over Na2SO4, filtered and concentrated in vacuo. The crude
product, a brownish oil, was dissolved in 30 mL THF and 7.1 g
(27.1 mmol) TBAFꢂH2O were added. The mixture was stirred for
30 min at room temperature before water was added. The aqueous
phase was extracted with Et2O and the organic layer dried over
Na2SO4, filtered and the solvent evaporated in vacuo. The crude
residue was purified by flash chromatography (PE/EA = 4:1;
N
Br
A solution of 612 mg (2.9 mmol) of 7-bromo-4-fluoro-1H-in-
dole in dry DMF was cooled to 0 °C, and 173 mg (4.3 mmol) of a
60% dispersion of NaH in mineral oil were added. After 20 min
510 lL (735 mg, 4.3 mmol) benzyl bromide were added and the
reaction mixture was allowed to warm up to room temperature
and stirred overnight. Water was added, and the aqueous phase
was repeatedly extracted with Et2O. The combined organic layers
were dried over Na2SO4 and the solvent was removed in vacuo.
The crude product was purified by column chromatography

5866
P. S. Weiss et al. / Bioorg. Med. Chem. 23 (2015) 5856–5869
Rf = 0.45) giving 4.7 g (17.9 mmol, 65%) of the desired product as a
light green solid.
3J = 8.1 Hz), 2.39 (s, 3H); 13C NMR (CDCl3) d 184.7, 159.5 (d,
1JCF = 242 Hz), 4JCF = 3 Hz),
146.6(2C), 136.5 (d, 135.3
(3JCF = 11.2 Hz), 133.7(2C), 132.6 (4JCF = 2.8 Hz), 130.5, 127.1,
Mp: 58–60 °C.
1H NMR (CDCl3) d 8.30 (broad s, 1H), 7.42 (dd, 3J = 8.4 Hz,
4J = 6.0 Hz, 1H), 7.14 (t, 3J = 2.7 Hz, 1H), 6.99 (d, 3J = 8.5 Hz, 1H),
124.2 (d, JCF = 2 Hz), 120.9 (d, JCF = 1 Hz), 100.7 (d, JCF = 31 Hz),
4
5
2
2
78.4 (d, JCF = 27 Hz), 21.6; 19F NMR (CDCl3) d ꢁ89.70; HRMS:
1
6.61 (t, 3J = 2.0 Hz, 1H); 13C NMR (CDCl3) d 155.2 (d, JCF = 245 Hz),
C
16H11FINO3S [M+H]+ calcd 443.9561; found: 443.9561; elemental
3
2
138.3 (d, JCF = 11 Hz), 131.1, 124.7, 117.9 (d, JCF = 24 Hz), 109.2
analysis calcd for C16H11FINO3S: C, 43.36; H, 2.50; N, 3.16; found:
C, 43.05; H, 2.59; N, 3.11.
(d, JCF = 4 Hz), 98.8 (d, JCF = 6 Hz), 68.3 (d, JCF = 23 Hz); 19F NMR
(CDCl3) d ꢁ101.74; elemental analysis calcd for C8H5FIN: C, 36.81;
H, 1.93; N, 5.37; found: C, 37.64 H, 2.17; N, 5.14.
4
3
2
4.3.19. (4-Fluoro-5-iodo-1-tosyl-1H-indol-3-yl)methanol (11)
4.3.17. 4-Fluoro-5-iodo-1H-indole-3-carbaldehyde (9)
F
OH
I
O
F
H
N
I
Tos
N
H
541 mg (14.3 mmol) NaBH4 were added to a solution of 4.2 g
(9.5 mmol) of 9 in 150 mL THF/EtOH (2:1) at 0 °C. The resulting
solution was warmed to room temperature and stirred for
30 min. Saturated NH4Claq was added and the mixture was
extracted with Et2O. The combined organic extracts were washed
with brine and dried over Na2SO4. Evaporation of the solvent gave
the desired product as a colorless solid (97%, 4.1 g, 9.2 mmol).
Mp: 131–132 °C.
5.7 mL POCl3 (35.5 mmol) were added to 16.0 mL DMF at 0 °C.
The mixture was stirred at this temperature for 15 min before 4.1
g (15.6 mmol) of 4-fluoro-5-iodo-1H-indole (7) were added in
37 mL of DMF. The solution was warmed to room temperature
and stirred until it became an opaque paste (approximately 1 h). It
was added 10% NaOHaq until the pH of the solution was greater than
10. The suspension was heated to reflux for 10 min before it was
cooled to 0 °C. The precipitate was filtered and washed with water
and Et2O. After drying under reduced pressure at 50 °C, the desired
product was obtained as an off-white solid (89%, 4.03 g, 13.9 mmol).
Mp: decomposition at 246–249 °C.
1H NMR (DMSO-d6)
d
7.87 (d, 3J = 8.4 Hz, 2H), 7.70 (dd,
3J = 8.6 Hz, 3J = 6.0 Hz, 1H), 7.63 (s, 1H), 7.61 (d, 3J = 8.7 Hz, 1H),
7.40 (d, 3J = 8.2 Hz, 2H), 5.26 (t, 3J = 5.4 Hz, 2H), 4.63 (s, 1H), 2.33
1
(s, 3H); 13C NMR (DMSO-d6) d 154.6 (d, JCF = 245 Hz), 145.9 (2C),
3
136.7 (d, JCF = 10 Hz), 134.3, 133.7(2C), 130.4, 126.8, 124.4, 121.7
1H NMR (DMSO-d6) d 12.60 (s, 1H), 10.02 (d, 4J = 3.3 Hz, 1H),
8.30 (d, 4J = 2.9 Hz, 1H), 7.60 (dd, 3J = 8.6 Hz, 3J = 5.8 Hz, 1H), 7.23
3
2
4
(d, JCF = 5 Hz), 118.0 (d, JCF = 23 Hz), 111.6 (d, JCF = 4 Hz), 74.9
2
4
(d, JCF = 24 Hz), 55.5 (d, JCF = 2 Hz), 21.0; 19F NMR (DMSO-d6) d
ꢁ100.88; HRMS: C16H13FINO3S [M+Na]+ calcd 467.9537; found:
467.9539; elemental analysis calcd for C16H13FINO3S: C, 43.16; H,
2.94; N, 3.15; found: C, 43.40; H, 3.03; N, 3.15.
4
(d, 3J = 8.5 Hz, 1H); 13C NMR (DMSO-d6) d 184.1 (d, JCF = 2 Hz),
1
3
155.1 (d, JCF = 245 Hz), 140.1 (d, JCF = 11 Hz), 136.8, 132,8, 116.8
3
2
4
(d, JCF = 7 Hz), 113.8 (d, JCF = 25 Hz), 111.7 (d, JCF = 4 Hz), 73.2
(d, JCF = 24 Hz); 19F NMR (DMSO-d6) d ꢁ92.94; HRMS: C9H5FINO
2
[MꢁH]+ calcd 289.9473; found: 289.9477; elemental analysis calcd
for C9H5FINO: C, 37.40; H, 1.74; N, 4.85; found:: C, 37.86; H, 1.84;
N, 5.22.
4.3.20. (3-(Bromomethyl)-4-fluoro-5-iodo-1-tosyl)-1H-indole
(12)
4.3.18. 4-Fluoro-5-iodo-1-tosyl-1H-indole-3-carbaldehyde (10)
F
Br
I
O
N
F
H
Tos
I
N
Tos
A solution of the alcohol 10 (2.0 g, 4.5 mmol) was cooled to 0 °C
before PPh3 (1.3 g, 5.0 mmol) and CBr4 (1.7 g, 5.0 mmol) were
added subsequently. The mixture was stirred at 0 °C and the pro-
gress of reaction monitored by TLC (PE/EA = 4:1, Rf = 0.72). After
approximately 30 min the reaction was finished and the solvent
was partially removed in vacuo at room temperature. The oily resi-
due was applied to a silica column eluted with a mixture of PE/EE
(4:1). Removal of the solvents under reduced pressure gave the
desired product as a colorless solid (63%, 1.4 g, 2.8 mmol).
Mp: decomposition at 166–168 °C.
A solution of 3.8 g (13.3 mmol) 4-fluoro-5-iodo-1H-indole-3-
carbaldehyde (8) in 40 mL of THF was cooled to 0 °C and 480 mg
(20 mmol) of a 60% dispersion of NaH in mineral oil was added.
The resulting solution was stirred for 20 min at 0 °C.
Subsequently, 3.8 g (20 mmol) of Tos-Cl was added. The reaction
mixture was warmed to room temperature and stirred for another
2 h. Water was added and the aqueous phase was extracted with
Et2O. The combined organic extracts were dried over Na2SO4 and
the solvent was removed in vacuo. Purification by flash chromatog-
raphy (PE/EA = 4:1 Rf = 0.38) gave the desired product as a colorless
solid (74%, 4.4 g, 9.8 mmol).
1H NMR (DMSO-d6) d 8.08 (s, 1H), 7.88 (d, 3J = 8.4 Hz, 2H), 7.75
(dd, 3J = 8.7 Hz, 3J = 6.0 Hz, 1H), 7.62 (d. 3J = 8.8 Hz, 1H), 7.42 (d,
3J = 8.2 Hz, 2H), 4.82 (s, 2H), 2.33 (s, 3H); 13C NMR (DMSO-d6) d
1
3
Mp: decomposition at 148–153 °C.
154.3 (d, JCF = 247 Hz), 146.2(2C), 136.3 (d, JCF = 9 Hz), 134.9,
1H NMR (CDCl3) d 10.02 (s, 1H), 8.65 (d, 1H, 3J = 6.2 Hz), 8.19 (s,
1H), 7.83 (d, 2H, 3J = 8.1 Hz), 7.69 (d, 1H, 3J = 8.3 Hz), 7.32 (d, 2H,
2
133.3, 130.4, 126.7(2C), 124.3, 117.4 (d, JCF = 23 Hz), 117.0 (d,
4
2
4JCF = 4 Hz), 111.6 (d, JCF = 4 Hz), 75.6 (d, JCF = 24 Hz), 55.4 (d,

P. S. Weiss et al. / Bioorg. Med. Chem. 23 (2015) 5856–5869
5867
4JCF = 2 Hz), 20.9; 19F NMR (DMSO-d6)
C
mental analysis calcd for C16H12BrFINO2S: C, 37.82; H, 2.38; N,
2.73; found: C, 38.12; H, 2.38; N, 2.64.
d
ꢁ102.l3; HRMS:
1.7 mL of a 2.9 M solution of isopropyl magnesium bromide in
THF was added to a solution of the iodide 12 (1.8 g, 2.5 mmol) in
5 mL of THF at 0 °C. The resulting solution was stirred for 1 h at
16H12BrFINO2S [MꢁBr]ꢁ calcd 427.9617; found: 427.9636; ele-
0 °C before 770 lL of DMF (10 mmol) were added. The reaction
was warmed to room temperature and stirred for another 3 h.
Saturated NH4Claq was added, and the aqueous phase was
extracted with Et2O. The combined organic extracts were dried
over Na2SO4 and the solvent removed under reduced pressure.
Flash chromatography (PE/EA = 7:3, Rf = 0.27) of the crude mix-
ture gave the desired product as a colorless solid (73%, 1.1 g,
1.8 mmol).
4.3.21. Benzyl (2S,5S)-2-tert-butyl-5-[(4-fluoro-5-iodo-1-tosyl-
1H-indol-3-yl)methyl]-3-methyl-4-oxoimidazolidine-1-
carboxylate (13)
O
Mp: 73–75 °C.
O
N
1H NMR (CDCl3) d 10.34 (s, 1H), 7.81–7.71 (m, 4H), 7.31 (d,
3J = 7.7 Hz, 2H), 7.02–6.87 (m, 6H), 5.16 (s, 1H), 4.93 (s, 2H),
4.45 (s, 1H), 4.16 (d, 3J = 7.1 Hz, 1H), 3.53 (d, 4J = 17.2 Hz, 1H),
3.05 (s, 3H), 2.37 (s, 3H), 1.06 (s, 9H); 13C NMR (CDCl3) d 186.6
F
N
I
O
3
1
(d, JCF = 8 Hz), 171.0, 160.0 (d, JCF = 264 Hz), 145.8(2C), 140.0
N
Tos
3
(d, JCF = 11 Hz), 134.9, 134.6(2C), 130.2, 128.4(2C), 128.3(2C),
127.2, 123.9, 119.5 (d, JCF = 17 Hz), 118.8 (4JCF = 5 Hz), 116.0,
2
109.9 (d, JCF = 4 Hz), 81.3, 67.6, 40.8, 32.1, 26.6, 21.3(3C); 19F
4
n-BuLi in hexane (1.24 mL, 3.1 mmol) was added to a solution of
NMR (CDCl3) d ꢁ129.12, HRMS: C33H34FN3O6S [M+Na]+ calcd
diisopropylamine (435
lL, 3.1 mmol) in 3 mL of THF at ꢁ78 °C. The
642.2044; found: 642.2030, elemental analysis calcd for
resulting solution was stirred for 30 min before a solution of Z-BMI
(772 mg, 2.7 mmol) in 3 mL of THF was added. After another
30 min of stirring at -78 °C a solution of bromide 11 in 4.5 mL
THF was added. The reaction was slowly warmed to room temper-
ature and stirred overnight. The reaction was quenched with satu-
rated NH4Claq. Water was added and the aqueous phase was
extracted with diethyl ether. The combined organic extracts were
dried over Na2SO4, and the solvent was removed under reduced
pressure. Purification of the crude product by flash chromatogra-
phy (PE/EA = 7:3; Rf = 0.4) gave the desired product as a colorless
solid (73%, 1.4 g, 2.0 mmol).
C
33H34FN3O6S: C, 63.96; H, 5.53; N, 6.78; found: C, 63.91; H,
5.63; N, 6.48.
4.3.23. Benzyl (2S,5S)-2-tert-butyl-5-[(4-fluoro-5-formyl-1H-
indol-3-yl)methyl]-3-methyl-4-oxo-imidazolidine-1-
carboxylate (15)
O
O
N
Mp: 76–78 °C.
1H NMR (CDCl3) d 7.73 (broad s, 2H), 7.52 (dd, 3J = 8.7 Hz,
4J = 5.7 Hz, 1H), 7.47 (d, 3J = 8.6 Hz, 1H), 7.25 (broad s, 2H), 7.15–
6.60 (broad m, 6H), 5.18 (broad s, 1H), 4.84 (d, 4J = 6.1 Hz, 2H),
4.38 (s, 1H), 3.76 (broad s, 1H), 3.40 (d, 3J = 14.4 Hz, 1H), 3.06 (s,
3H), 2.32 (s, 3H), 1.02 (s, 9H); 13C NMR (CDCl3) d 171.1, 155.4 (d,
O
F
N
O
N
H
3
1JCF = 249 Hz), 145.5(2C), 136.5 (d, JCF = 9 Hz), 134.9(2C), 134.7,
134.2, 130.1, 128.5(2C), 128.3(2C), 128.3, 127.1, 122.2, 120.2 (d,
4
4
2JCF = 21 Hz), 115.0 (d, JCF = 3 Hz), 111.2 (d, JCF = 4 Hz), 81.2, 73.8
3.5 mL of 1.0 M solution of TBAF in THF was added to a solution
of 432 mg (0.7 mmol) of 13 in 10 mL THF. The resulting mixture
was heated to reflux for 3 h, then cooled to room temperature
and the solvent was evaporated in vacuo. Flash chromatography
of the crude mixture gave the desired product as a colorless solid
(42%, 140 mg, 0.3 mmol). The compound decomposed rapidly, as
a result of which the data of elemental analysis were not in
agreement.
2
(d, JCF = 24 Hz), 67.6, 60.4, 58.3, 40.9, 32.1, 26.3, 21.6, 21.1(3C);
19F NMR (CDCl3) d ꢁ100.94; HRMS: C33H32FIN3O5S [M+Na]+ calcu-
lated 740.1061; found: 740.1053; elemental analysis calcd for
C
33H32FIN3O5S: C, 53.56; H, 4.64; N, 5.86; found: C, 53.83; H,
20
4.84; N, 5.60, [
a
]
D
+57 (c 10mg/mL, MeOH).
4.3.22. Benzyl (2S,5S)-2-tert-butyl-5-[(4-fluoro-5-formyl-1-
tosyl-1H-indol-3-yl)methyl]-3-methyl-4-oxoimidazolidine-1-
carboxylate (14)
1H NMR (DMSO-d6) d 11.53 (s, 1H), 10.27 (s, 1H), 7.48 (dd,
3J = 8.4 Hz, 3J = 6.2 Hz, 1H), 7.27 (d, 3J = 8.5 Hz, 1H), 7.19–7.14 (m,
3H), 7.08 (d, 3J = 7.2 Hz, 2H), 6.72 (s, 1H), 5.19 (s, 1H), 5.00 (d,
2J = 12.3 Hz, 1H), 4.79 (d, 2J = 12.3 Hz, 1H), 4.50 (d, 3J = 4.4 Hz,
1H), 3.97–3.94 (broad s, 1H), 3.38 (d, 4J = 15.4 Hz, 1H), 2.93 (s,
O
3
O
N
3H), 0.93 (s, 9H); 13C NMR (DMSO-d6) d 187.2 (d, JCF = 8 Hz),
1
2
171.0, 160.8 (d, JCF = 263 Hz), 142.6 (d, JCF = 14 Hz), 136.3,
O
F
2
N
128.6(2C), 128.3(2C), 123.6, 120.5, 115.8 (d, JCF = 16 Hz), 115.2
(d, JCF = 5 Hz), 109.9, 109.2, 80.4, 66.9, 58.7, 31.8, 26.5; 19F NMR
3
O
(DMSO-d6) d ꢁ130.47; HRMS: C26H28FN3O4 [M+Na]+ calculated
N
S
488.1956; found: 488.1992; elemental analysis calcd for
O
O
C26H28FN3O4: C, 67.08; H, 6.06; N, 9.03; found: C, 65.20; H, 5.92;
N, 8.60.

5868
P. S. Weiss et al. / Bioorg. Med. Chem. 23 (2015) 5856–5869
4.3.24. Benzyl (2S,5S)-2-tert-butyl-5-[(1-boc-4-fluoro-5-formyl-
1H-indol-3-yl)methyl]-3-methyl-4-oxoimidazolidine-1-
carboxylate (16)
4.4.3. General procedure for the radiosynthesis of 1-benzyl-
18F]fluoro-1H-indoles ([18F]1-4b) under microwave heating
A solution of 20 mol of the corresponding precursor was dis-
[
l
solved in 1.0 mL DMF and added to a Reacti-Vial™ containing the
dried residue of [18F]TBAF. The reaction mixture was irradiated
with 50 W microwaves during 1 min. After labeling, the solution
was diluted with 10.0 mL water and passed through a previously
conditioned LiChrolut RP-18e cartridge (Merck). Then, the
adsorbed labeled compound was eluted with 2.0 mL acetonitrile
into a second Reacti-Vial™ and the solvent subsequently evapo-
rated. A solution containing 3 equiv of Wilkinson’s catalyst in
1.0 mL benzonitrile was added, and the mixture was irradiated
with 120 W microwaves during 2 min.
O
O
N
O
F
N
O
N
Boc
4.4.4. General procedure for the radiosynthesis of 4-[18F]fluoro-
L
-tryptophan ([18F]18)
60 mg (0.27 mmol) of Boc2O was added to a solution of 14
(110 mg, 0.23 mmol) and of DMAP (3 mg, 24 mol) in 5 mL THF.
Conventional heating.
A solution of 8–9 lmol of the corre-
l
sponding precursor was dissolved in 1.0 mL DMF and added to a
Reacti-Vial™ containing the dried residue of [18F]TBAF. The reaction
mixture was heated to 80 °C for 15 min. After labeling, the reaction
mixture was diluted with 1.0 mL acetonitrile and 9.0 mL water and
passed through a previously conditioned LiChrolut RP-18e cartridge
(Merck, Germany). Thereafter the cartridge was eluted with 2.0 mL
acetonitrile and the solvent was evaporated. A solution containing
2 equiv of Wilkinson’s catalyst in 1.0 mL benzonitrile was added
and the reaction mixture was heated to 150 °C for 20 min. The mix-
ture was diluted with 1.0 mL of a solution of ethyl acetate in petro-
leum ether (5% EA/PE) and filtered through a silica cartridge (600–
The resulting solution was stirred for 1 h at room temperature.
The solvent was evaporated under reduced pressure. Purification
of the crude mixture by flash chromatography yielded the desired
product as a colorless solid (86%, 112 mg, 0.20 mmol).
Mp: 133–136 °C.
1H NMR (CDCl3) d 10.37 (s, 1H), 7.92 (d, 3J = 8.8 Hz, 1H), 7.74
(dd, 3J = 8.7 Hz, 4J = 6.5 Hz, 1H), 7.39–7.03 (m, 5H), 6.98 (s, 1H),
5.14–4.89 (m, 3H), 4.49 (d, 4J = 1.2 Hz, 1H), 4.03 (d, 2J = 16.8 Hz,
1H), 3.59 (d, 2J = 17.2 Hz), 3.11 (s, 3H), 1.58 (s, 9H), 0.99 (s, 9H);
3
13C NMR (CDCl3)
d
187.5 (d, JCF = 7 Hz), 170.9, 160.6 (d,
2
1JCF = 261 Hz), 148.5(2C), 140.5 (d, JCF = 12 Hz), 136.3, 128.3 (d,
3JCF = 5 Hz), 124.6(2C), 123.2, 118.8, 118.5, 118.4, 114.5 (d,
4JCF = 3 Hz), 111.9, 85.5, 80.8, 66.8, 58.1, 32.0, 28.0, 26.4(3C); 19F
700 mg silica gel in
a 3 mL polyethylene filtration tube).
Subsequently the desired compound was eluted with a solution of
ethyl acetate in petroleum ether (60% EA/PE). The solvents were
evaporated, then 0.5 mL of concentrated hydrochloric acid was
added, and the reaction mixture was heated to 150 °C for 30 min.
The product was purified by semi-preparative HLPC (System B).
NMR (CDCl3)
d
ꢁ130.61; HRMS C31H36FN3O4 [M+Na]+ calcd
588.2480; found: 588.2461; elemental analysis calcd for
C
31H36FN3O4: C, 65.83; H, 6.42; N, 7.43; found: C, 66.10; H, 6.57;
20
N, 7.26, [
a
]
D
ꢁ3.1 (c 10 mg/mL, CHCl3).
Microwave heating.
A solution of 8–9 lmol of the correspond-
4.4. Radiochemistry
ing precursor was dissolved in 1.0 mL DMF and added to a vial con-
taining the dried residue of [18F]TBAF. The reaction mixture was
irradiated with 40 W microwaves for 1 min. After labeling, the
reaction mixture was diluted with 1.0 mL acetonitrile and 9.0 mL
water and passed through a previously conditioned LiChrolut RP-
18e cartridge (Merck, Germany). Thereafter the cartridge was
eluted with 2.0 mL acetonitrile and the solvent was evaporated.
A solution containing 2 equiv of Wilkinson’s catalyst in 1.0 mL ben-
zonitrile was added and the reaction mixture irradiated with
100 W microwaves during 2 min. The mixture was diluted with
1.0 mL of a solution of ethyl acetate in petroleum ether (5%
EA/PE) and filtered through a silica cartridge (600–700 mg silica
gel in a 3 mL polyethylene filtration tube). Subsequently, the
desired compound was eluted with a solution of ethyl acetate in
petroleum ether (60% EA/PE). The solvents were evaporated, then
0.5 mL of concentrated hydrochloric acid was added, and the reac-
tion mixture was heated to 150 °C for 30 min. The product was
purified by semi-preparative HLPC (System B).
4.4.1. Preparation of [18F]TBAF
N.c.a. [18F]fluoride was produced via the 18O(p,n)18F nuclear
reaction by bombardment of an isotopically enriched [18O]water
target with 17 MeV protons at the JSW cyclotron BC 1710 (INM-
5, Forschungszentrum Jülich).32 An aliquot of the aqueous
[
18F]fluoride was added to a solution containing 150
lL of a
0.13 M tetrabutylammonium bicarbonate (TBAHCO3) solution.33
1.0 mL of dry acetonitrile was added to the mixture. The solvent
was evaporated under a stream of argon at 75 °C and 600 mbar.
The azeotropic evaporation was repeated twice with each 1.0 mL
of acetonitrile and followed by evacuating the vial for 5 min at
10–20 mbar.
4.4.2. General procedure for the radiosynthesis of 1-benzyl-
[
18F]fluoro-1H-indoles ([18F]1-4b) under conventional heating
A solution of 20 lmol of the corresponding precursor was dis-
solved in 1.0 mL DMF and added to a Reacti-Vial™ containing the
dried residue of [18F]TBAF. The reaction mixture was heated to
the optimum temperature for 15 min. After labeling the solution
was diluted with 10.0 mL of water and passed through a previ-
ously conditioned LiChrolut RP-18e cartridge (Merck).
Thereafter, the adsorbed labeled compound was eluted with
2.0 mL acetonitrile into a second vial and the solvent subse-
quently evaporated. A solution containing 3 equiv of Wilkinson’s
catalyst in 1.0 mL benzonitrile was added, and the mixture was
heated to 150 °C for 20 min.
Acknowledgements
The authors wish to thank Dr. Dirk Bier and Dr. Marcus
Holschbach (INM-5), Dr. Patrick Bongen (Institut für Bio-und
Geowissenschaften, Biotechnologie (IBG-1)) and Dr. Sabine
Willbold (Zentralinstitut für Engineering, Elektronik und Analytik,
ZEA-3), all Forschungszentrum Jülich, for recording the spectro-
scopic data.

P. S. Weiss et al. / Bioorg. Med. Chem. 23 (2015) 5856–5869
15. Konas, D. W.; Seci, D.; Tamimi, S. Synth. Commun. 2012, 42, 144.
5869
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