Synthesis of no-carrier-added 4-[18F]fluorophenol from 4-benzyloxyphenyl-(2-thienyl)iodonium bromide

Article abstract of DOI:10.3390/molecules16097621

4-[¹⁸F]Fluorophenol is a versatile synthon for the synthesis of more complex radiopharmaceuticals bearing a 4-[¹⁸F]fluorophenoxy moiety. In order to prepare 4-[¹⁸F]fluorophenol in no-carrier-added (n.c.a.) form only a nucl

Full text of DOI:10.3390/molecules16097621

Molecules 2011, 16, 7621-7626; doi:10.3390/molecules16097621
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
Synthesis of No-Carrier-Added 4-[18F]Fluorophenol from
4-Benzyloxyphenyl-(2-thienyl)iodonium Bromide
Tobias L. Ross †, Johannes Ermert * and Heinz H. Coenen
Institute of Neuroscience and Medicine, INM-5: Nuclear Chemistry, Forschungszentrum Jülich
GmbH, 52425 Jülich, Germany
†
Current address: Institute of Nuclear Chemistry, Johannes Gutenberg-University Mainz,
55128 Mainz, Germany.
* Author to whom correspondence should be addressed; E-Mail: j.ermert@fz-juelich.de;
Tel.: +49-2461-613110; Fax: +49-2461-612119.
Received: 11 August 2011; in revised form: 24 August 2011 / Accepted: 31 August 2011 /
Published: 6 September 2011
Abstract: 4-[18F]Fluorophenol is a versatile synthon for the synthesis of more complex
radiopharmaceuticals bearing a 4-[18F]fluorophenoxy moiety. In order to prepare
4-[18F]fluorophenol in no-carrier-added (n.c.a.) form only a nucleophilic labelling method
starting from [18F]fluoride is suitable. In this paper a new, two step radiosynthesis starting
from 4-benzyloxyphenyl-(2-thienyl)iodonium bromide and [18F]fluoride with subsequent
deprotection is described, yielding n.c.a. [18F]fluorophenol in 34 to 36% radiochemical yield.
Keywords: fluorine-18; 4-[18F]fluorophenol; diaryl iodonium salts; radiosynthesis;
positron emission tomography
1. Introduction
The introduction of fluorine into organic molecules plays an important role in the development of
new as well as in routine production of established pharmaceuticals [1]. The use of the positron emitter
fluorine-18 in molecular imaging via positron emission tomography (PET) has led to a constant
increase in the development of radiotracers using this radionuclide with almost ideal nuclear physical
18
properties for PET studies. Obtaining those molecules in F-labelled form is often a great challenge.
Especially, the introduction of no-carrier-added (n.c.a.) [18F]fluoride into an aromatic ring is difficult,

Molecules 2011, 16
7622
especially if it is not activated for a nucleophilic substitution reaction [2]. In those cases, multi-step
18
reactions are required to obtain the desired F-labelled radiotracer. However, starting from electron
deficient small arenes like benzaldehydes, phenylketones or benzonitriles as precursors for
radiofluorination, functional [18F]fluorobenzenes can easily be formed as intermediates and
subsequently transformed by as few as possible steps to the desired radiotracer.
A further versatile primary 18F-labelled intermediate is n.c.a. 4-[18F]fluorophenol, which has
proven its suitability in various radiosyntheses of biological relevant molecules or potential
radiopharmaceuticals [3,4]. During the last decade, several attempts have been made to improve the
synthesis of n.c.a. 4-[18F]fluorophenol [5,6]. The originally applied diazonium route or the recently
more common radiosynthesis via Baeyer-Villiger oxidation using benzophenones as precursors require
three step radiosyntheses [7] which are difficult to perform in a remotely controlled apparatus.
Therefore, a more direct and convenient pathway that also minimizes any loss of radioactivity by
shortening the synthesis time was examined in this work. Aryl(2-thienyl)iodonium salts have been
18
shown as suitable F-labelling precursors even for electron rich arenes [8]. This offers the possibility
of a simplified synthesis of n.c.a. 4-[18F]fluorophenol.
2. Results and Discussion
The need of aprotic conditions for substitution with n.c.a. [18F]fluoride excludes a direct 18F-introduction
into an unprotected phenol-substituted iodonium compound. Since the benzyl protective group offers
an easy and gentle way of deprotection, it was chosen for this purpose. Thus, 4-benzyloxyphenyl-(2-
thienyl)iodonium bromide (1c) was examined as precursor. This precursor was prepared staring
from 4-benzyloxy-1-iodobenzene (1a), which was oxidized by sodium periodate to 4-benzyloxy-1-
(diacetoxyiodo)benzene (1b) within 2 h with a yield of 66%, as described in the literature [8]. The
(diacetoxyiodo)arene and thiophene undergo an electrophilic aromatic substitution in the presence of
concentrated sulphuric acid as catalyst to yield aryl(2-thienyl)iodonium hydrogen sulphate. This was
subsequently converted by metathesis to its bromide salt 1c, which was obtained in a good overall
yield of 55% (Scheme 1).
Scheme 1. Synthesis of 4-benzyloxyphenyl-(2-thienyl)iodonium bromide (1c).
OAc
OAc
NaIO4
thiophene
S
I+
O
O
I
I
O
+, KBr
H
Br
1a
1b
1c
Starting from dry Kryptofix©2.2.2/K2CO3 as anion activator system, 1c was added to the reaction
vial using DMF as solvent. The n.c.a. 18F-labelling reaction was carried out under the optimized
conditions described recently [8]. While in that mechanistic study only the analytical radiochemical
yield (RCY) of the intermediate product 1d was reported, here the preparative radiosynthesis of
4-[18F]fluorophenol is further elaborated, including the debenzylation step and work-up process. Due
to the deactivating effect of the para-benzyloxy group on nucleophilic substitution, the reaction rate
was expectedly moderate. However, the 18F-labelling reaction led regiospecifically within 20 to 30 min

Molecules 2011, 16
7623
to n.c.a. 4-benzyloxy-[18F]fluorobenzene ([18F]1d) with a RCY of 38 ± 4% as the only observed
radioactive product. Before carrying out the deprotection procedure, a quick purification via Sep-Pak©
Plus C18 and ALOX cartridges was done. Consequently, a solvent change to methanol was easily
implemented and the system was freed from polar substances and particularly from water, which had
been added to enable trapping of [18F]1d on the reversed phase cartridge and to remove DMF.
Methanol proved to be a suitable eluent and, moreover, also a favourable solvent in the following
deprotection step.
For subsequent removal of the benzyl-moiety a reductive deprotection, applying ammonium
formate and palladium black as catalyst in methanol, was elaborated. First attempts with ammonium
formate and palladium on activated charcoal led to the desired n.c.a. 4-[18F]fluorophenol [18F]1, but
difficulties were found in removing the fine charcoal particles during subsequent filtration. In addition,
the system with palladium on activated charcoal resulted in a smaller RCY of 75 to 80% within 15 min
at 100 °C, whereas the palladium black system yielded 90 to 95% RCY of n.c.a. 4-[18F]fluorophenol
under the same conditions. By filtration of the reaction suspension via a LiChrolut© glass column
containing a PTFE frit, n.c.a. 4-[18F]fluorophenol was obtained in an anhydrous methanol system. A
flow chart of the radiosynthesis is depicted in Table 1.
Table 1. Synthetic sequence of the two step radiosynthesis of n.c.a 4-[18F]fluorophenol.
Time (min)
Structures
Compounds & Conditions RCY (%)
Br
I+
S
0
O
1c
[K⊂2.2.2.]2CO3,
c(1c) = 25 mmol/L, DMF,
130 °C, 1100 mbar Argon
18F
20
O
[18F]1d
34–38
cartridge purification
eluent: MeOH (2 mL)
HCOONH4; Pd (black)
MeOH; 100 °C; filtration
18F
4-[18F]Fluorophenol
34–36
40
(90–95) *
OH
* RCY related to deprotection step.

Molecules 2011, 16
7624
In comparison to the so far best alternative procedure for the preparation of n.c.a.
4-[18F]fluorophenol, described by Ludwig et al. [7], the route with 1c offers two major improvements.
First, the radiosynthesis is more convenient, since instead of three synthetic and two purification steps,
the developed process starting from 1c provides a less complex radiosynthesis with two synthetic and
one purification steps. This offers great advantages for automation or remotely controlled
radiosyntheses. Secondly, the new route saves 20 min of total synthesis time which is one of the
18
primary concerns with F-radiosyntheses. Additionally, the resulting 4-[18F]fluorophenol is obtained
in an anhydrous methanol system which allows for direct further radiosynthetic steps including
compounds susceptible to moisture without time-consuming drying procedures. On the other hand, an
unfavourable aspect is the overall lower RCY of 35 ± 1% compared to 55% with the benzophenone
method. This, however, is in part compensated by the shorter synthesis time.
3. Experimental
3.1. General
All chemicals and solvents were purchased from Aldrich (Germany), Fluka (Switzerland), KMF
(Germany), Acros Organics (Belgium), or Merck (Germany). They were reagent grade or better and
were used without further purification. Sep-Pak© Plus C18 and ALOX cartridges were obtained from
Waters (USA) and LiChrolut© glass columns and appropriate PTFE frits (porosity 10 μm) from Merck
(Germany). Column chromatography was performed with Merck silica gel 60 (0.063–0.200 mm) and
flash-chromatography with Fluka silica gel 60 (mesh 220–440). The eluent mixtures are given as v:v
ratios. Thin-layer chromatography (TLC) was carried out with Macherey-Nagel (Germany) precoated
silica gel plates (PolyGram SIL G/UV254, 40 × 80 mm) visualized under an UV-lamp (254 nm).
Radio-TLC was performed on the same precoated silica gel plates. The developed radio-TL-chromato-
grams were measured on an Instant ImagerTM (Packard, USA) autoradiography system. The employed
high performance liquid chromatography (HPLC) system consists of a Knauer WellChrom Mini-Star
K-500 HPLC pump, a Rheodyne-Injector block 7125 and a Merck/Hitachi UV/Vis photometer L4000.
HPLC was performed on a Phenomenex© Luna 5 μm C18 column (3 × 250 mm) and various eluent
mixtures of methanol/water or acetonitrile/water all given as v:v ratios. Radio-HPLC was performed
on the same system as described for HPLC. For measurement of radioactivity the outlet of the UV/Vis
detector was connected to a NaI(Tl) well-type scintillation detector (EG&G ACE MateTM). The
syntheses of 4-benzyloxy-1-fluorobenzene, 4-benzyloxy-1-iodobenzene, 4-benzyloxy-1-(diacetoxy-
iodo)benzene and 4-benzyloxyphenyl-(2-thienyl)iodonium bromide were performed as described in the
literature [8,9] and their identity was confirmed by comparison of NMR-data and/or melting points.
3.2. Production of n.c.a. [18F]Fluoride
The production of n.c.a. [18F]fluoride is routinely carried out at the JSW BC 1710 Cyclotron
(Forschungszentrum Jülich) by bombardment of a 96% isotopically enriched [18O]water target (1.3 mL,
18
titanium body) with a 17 MeV proton beam using the O(p,n)18F nuclear reaction [10]. The n.c.a.
[18F]fluoride was separated from the enriched [18O]water by an electrochemical cell [11]. By this
procedure up to 55 GBq n.c.a. [18F]fluoride can be produced within 1 h at a nominal beam current of
25 μA.

Molecules 2011, 16
7625
3.3. Synthesis of n.c.a. 4-[18F]Fluorophenol
A 5 mL Wheaton© glass vial equipped with a triangle stirring bar and a silicone septum sealed lid
was connected to a vacuum line and an argon gas line, evacuated, and three times flushed with argon.
From the aqueous n.c.a. [18F]fluoride solution 30 to 50 MBq (10–50 μL) were added to Kryptofix©
2.2.2 (26 μmol) and a 1 M potassium carbonate solution (13 μL). After adding anhydrous acetonitrile
(0.8 mL) the mixture was transferred through the septum into the prepared vial by a 1 mL syringe. For
azeotropic distillation the vial was heated in an oil bath to 82 °C under a constant flow of argon
adjusted at 750–850 mbar until no acetonitrile/water mixture had been left. This step was repeated by
adding acetonitrile (1 mL × two times) which was subsequently followed by 5 min of full vacuum
(~10 mbar). After argon flushing and pressure balancing the resulting dry n.c.a. [18F]fluoride-cryptate
complex was ready for the nucleophilic 18F-labelling reaction.
4-Benzyloxyphenyl(2-thienyl)iodonium bromide (25 μmol) was dissolved in anhydrous DMF (1.0 mL)
and added by a syringe through the silicone septum into the vial containing the dry n.c.a. [18F]fluoride-
cryptate complex and then stirred under 1,100 mbar argon at 130 °C. At appropriate times aliquots
(10 μL) were taken with a micro-syringe (Hamilton©) via the septum and added to cold acetonitrile
(50 μL). These samples were analyzed by radio-HPLC and/or radio-TLC. After 15 to 20 min the whole
reaction mixture was added into water (10 mL) using a 20 mL syringe. This solution was passed
through a SepPak© C18 plus cartridge preconditioned with ethanol (3 mL) and water (5 mL). The
cartridge was washed with water (3 mL) and dried by an argon flow for 5 min. Before elution, the
cartridge was connected to a dry SepPak© ALOX cartridge. The product absorbed on the C18 phase
was eluted with methanol (3 mL) and transferred through both cartridges into a new reaction vial.
4-Benzyloxy-[18F]fluorobenzene ([18F]1d) was analyzed by radio-HPLC [k’ = 3.39, acetonitrile/water
(40:60), flow 1.0 mL/min] and radio-TLC [Rf = 0.79, n-hexane/ether (2:1); Rf = 0.91, n-hexane/ethyl
acetate (3:1)]. Ammonium formate (~5 mmol) and palladium black (~0.15 mmol) were added to the
methanol solution. For debenzylation the mixture was stirred at 80 °C for 15–20 min. The whole
reaction mixture was filtered through a Merck LiChrolut© glass column (65 × 10 mm) containing only
a PTFE frit (porosity 10 μm) which was washed with 0.5 mL of methanol. The obtained n.c.a.
4-[18F]fluorophenol was analyzed by radio-TLC [Rf = 0.59, n-hexane/ethyl acetate (3:1)] and radio-HPLC
([k’ = 1.93] acetonitrile/water (40:60), flow 0.7 mL/min).
4. Conclusions
In conclusion, the reported preparation of n.c.a. 4-[18F]fluorophenol from 4-benzyloxyphenyl(2-
thienyl)iodonium bromide (1c) presents an improved radiosynthesis of this primary 18F-labelled
synthon, especially in terms of practicability of labelling and applicability of coupling chemistry in
subsequently radiosynthesis steps. Thus, n.c.a. 4-[18F]fluorophenol was synthesised by nucleophilic
substitution on 4-benzyloxyphenyl(2-thienyl)iodonium bromide and subsequent debenzylation within
18
40 min and an overall RCY of 34% to 36%. This new approach towards the versatile F-labelling
synthon 4-[18F]fluorophenol offers a short and very convenient two synthetic and one purification step
procedure. In addition, the final 4-[18F]fluorophenol is obtained in an anhydrous methanol solution
which facilitates a broad variety of following coupling steps, even with moisture sensitive molecules.
Preparation of the useful 4-[18F]Fluorophenol via the 4-benzyloxyphenyl(2-thienyl)iodonium bromide

Molecules 2011, 16
7626
precursor thus requires a far less complex radiosynthesis which enables an easy transfer to a remotely
controlled synthesis device.
Acknowledgements
The authors thank M. Holschbach and D. Bier for helpful discussions.
References
1. Hagmann, W.K. The many roles for fluorine in medicinal chemistry. J. Med. Chem. 2008, 51,
4359-4369.
2. Ermert, J.; Coenen, H.H. No-carrier-added [18F]fluorobenzene derivatives as intermediates for
built-up radiosyntheses. Curr. Radiopharm. 2010, 3, 127-160.
3. Stoll, T.; Ermert, J.; Oya, S.; Kung, H.F.; Coenen, H.H. Application of n.c.a. 4-[18F]fluorophenol
in diaryl ether syntheses of 2-(4-[18F]fluorophenoxy)-benzylamines. J. Label. Compd.
Radiopharm. 2004, 47, 443-455.
4. Mühlhausen, U.; Ermert, J.; Coenen, H.H. Synthesis, labelling and first evaluation of [18F]R91150
as a serotonin 5-HT2A receptor antagonist for PET. J. Label. Compd. Radiopharm. 2009, 52, 13-22.
5. Barré, L.; Barbier, L.; Lasne, M.-C. Investigation of possible routes to no-carrier added
4-[18F]fluorophenol. J. Label. Compd. Radiopharm. 1993, 32, 101-102.
6. Ekaeva, I.; Barré, L.; Lasne, M.-C.; Gourand, F. 2- and 4-[18F]Fluorophenols from Baeyer-
Villiger Oxidation of [18F]Fluorophenylketones and [18F]Fluoro-benzaldehydes. Appl. Radiat.
Isot. 1995, 46, 777-782.
7. Ludwig, T.; Ermert, J.; Coenen, H.H. 4-[18F]Fluoroarylalkylethers via an improved synthesis of
n.c.a. 4-[18F]fluorophenol. Nucl. Med. Biol. 2002, 29, 255-262.
18
8. Ross, T.L.; Ermert, J.; Hocke, C.; Coenen, H.H. Nucleophilic F-fluorination of heteroaromatic
iodonium salts with no-carrier-added [18F]fluoride. J. Am. Chem. Soc. 2007, 129, 8018-8025.
9. Jones, B. The halogenation of phenolic ethers and anilides. Part IX. The influence of fluorine and
of alkyl groups. J. Chem. Soc. 1938, 1414-1417.
10. Qaim, S.M.; Clark, J.C.; Crouzel, C.; Guillaume, M.; Helmecke, H.J.; Nebeling, B.; Pike, V.W.;
Stöcklin, G. Radiopharmaceuticals for PET; Pike, V.W., Stöcklin, G., Eds; Kluwer Academic
Publishers: Dordrecht, The Netherlands, 1993; pp. 15-26.
11. Hamacher, K.; Hirschfelder, T.; Coenen, H.H. Electrochemical cell for separation of [18F]fluoride
from irradiated 18O-water and subsequent no carrier added nucleophilic fluorination. Appl. Radiat.
Isot. 2002, 56, 519-523.
© 2011 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).