One-step reductive etherification of 4-[18F]fluoro-benzaldehyde with decaborane

Article abstract of DOI:10.1002/jlcr.1087

Reductive coupling reactions between 4-[¹⁸F]fluoro-benzaldehyde ([¹⁸F]1) and different alcohols by use of decaborane (B ₁₀H₁₄) as reducing agent have the potential to synthesize 4-[¹⁸F]fluoro-benzylet

Full text of DOI:10.1002/jlcr.1087

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2006; 49: 745–755.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.1087
Research Article
One-step reductive etherification of
4-[18F]fluoro-benzaldehyde with decaborane
Uta Funke, Hongmei Jiay, Steffen Fischer, Matthias Scheunemann*
and Jorg Steinbachz
¨
Institute of Interdisciplinary Isotope Research, Permoserstrabe 15, 04318
Leipzig, Germany
Summary
Reductive coupling reactions between 4-[18F]fluoro-benzaldehyde ([18F]1) and
different alcohols by use of decaborane (B10H14) as reducing agent have the potential
to synthesize 4-[18F]fluoro-benzylethers in one step. [18F]1 was synthesized from 4-
trimethylammonium benzaldehyde (triflate salt) via a standard fluorination procedure
(K[18F]F/Kryptofix1 222) in dimethylformamide at 908C for 25 min and purified by
solid-phase extraction. Subsequently, reductive etherifications of [18F]1 were
performed as one-step reactions with primary and secondary alcohols, mediated by
B10H14 in acetonitrile at 608C. Various 4-[18F]fluorobenzyl ethers (6 examples are
shown) were obtained within 1–2 h reaction time in decay-corrected radiochemical
yields of 12–45%. Copyright # 2006 John Wiley & Sons, Ltd.
Received 14 March 2006; Revised 29 April 2006; Accepted 29 April 2006
Key Words: 4-[18F]fluoro-benzylether; fluorine-18; reductive etherification; decaborane;
labelling
Introduction
Tailor-made radiotracers are the key for molecular imaging by means of
positron emission tomography (PET). Radiosyntheses utilizing the short-lived
*Correspondence to: Matthias Scheunemann, Institute of Interdisciplinary Isotope Research,
Permoserstraꢀe 15, 04318 Leipzig, Germany. E-mail: scheunemann@iif-leipzig.de
y Current address: Beijing Normal University, College of Chemistry, Beijing 100875, People’s Republic of
China.
z Current address: Forschungszentrum Rossendorf, Institute of Radiopharmacy, POB 510119, 01314
Dresden, Germany.
Contract/grant sponsor: China Scholarship Council
Copyright # 2006 John Wiley & Sons, Ltd.

746
U. FUNKE ET AL.
radionuclide 18F (half-life 109.8 min) have an increased relevance in research
and radiopharmaceutical application. Because of the short half-life of 18F, it is
essential to keep the time for radiotracer production, including all radio-
synthetic and separation steps, as short as possible. A convenient access to a
variety of 18F-labelled compounds is still limited, e.g. in the case of ether
compounds. Despite the inherent benefit of a good stability regarding
metabolic defluorination, only one 18F-labelled aralkyl ether (4-[18F]fluoro-
proxyfan) has been described until now. This 4-[18F]fluoro-benzyl ether has
been prepared from 4-[18F]fluoro-benzaldehyde via a three-step procedure.1
Recently, a series of studies has been published on the application of
decaborane (B10H14) as a mild and quite stable reducing agent in methanol.2–11
The reductive etherification of aromatic aldehydes with B10H14 in methanol or
ethanol has been reported to be an efficient way to synthesize the
corresponding ethers.2 This suggests the possibility to synthesize 18F-labelled
fluoro-benzylethers from 4-[18F]fluoro-benzaldehyde in one step. However,
until now the method mentioned above has only been used to synthesize
simple compounds (ROR’: R = methyl, ethyl; R0 = aralkyl). It had to be
performed in neat alcohols acting as reactant and solvent as well, which may
be disadvantageous in some cases. Furthermore, reductive etherification of
4-fluoro-benzaldehyde has not been reported until now.
Since the reaction seems to run via an oxonium ion intermediate,2,10,12 it
would also be interesting to explore whether the electron withdrawing fluorine
substitute hampers the formation of such an oxonium ion.
Results and discussion
Non-radioactive syntheses
In order to broaden the application of this reaction for its preparative use as
well as for the subsequent 18F-labelling, non-radioactive experiments were
initially carried out. For practical reasons, a 10:1 molar ratio of alcohol to
4-fluoro-benzaldehyde was used. The demand of a solvent is evident, if we take
into account that for a common 18F-radiosynthesis the molar ratio of the
respective alcohol to 4–[18F]fluoro-benzaldehyde is expected to be higher than
1.000:1. 4-Fluoro-benzaldehyde (1) was reacted in the presence of decaborane
in acetonitrile (MeCN) at 50–608C with a series of primary and secondary
alcohols and one tertiary alcohol (2a–g), respectively (Scheme 1, Table 1).
The consumption of 4-fluoro-benzaldehyde was monitored by thin-layer
chromatography (TLC). At the end of the synthesis, acetone was added to the
solution in order to decompose unreacted decaborane. The product was
separated by extraction with hexane and washed with 1 M NaOH solution.
Further purification by column chromatography (hexane–ethyl acetate) gave
respective ethers as colourless liquids in moderate to good yields (Table 1).
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm. 2006; 49: 745–755
DOI: 10.1002/jlcr

ONE-STEP REDUCTIVE ETHERIFICATION OF 4-[18F]FLUORO-BENZALDEHYDE 747
Scheme 1. Reductive etherification of 4-fluoro-benzaldehyde (1) with alcohols
(2a–g) in the presence of decaborane in acetonitrile
Table 1. Reductive etherification of 4-fluoro-benzaldehyde with alcohols in acetonitrile
in the presence of decaborane
Entry
Alcohols
R–OH
Reaction
time (h)
Productsa,c
Yield
(%)b
RO
F
OH
1
2
3
4
5
2a
2b
2c
2d
2e
4
3ac
3bc
3cd
3d
75
46
59
64
75
F
6
OH
HO
6
OH
6
OH
15
3e
OH
6
7
2f
15
8
3f
44
50
OH
OH
2g
3gc
a All products were fully characterized by spectroscopic methods. Spectral data are consistent with the
assigned structures and data from literature as well.
b Yields of isolated products.
c 3a,13 3b,14 and 3g15 have been previously described.
d 3c: Partially etherified diol (cis-4-(4-fluoro-benzyloxy)-but-2-en-1-ol).
As shown in Table 1, not only primary (2a–c), but also secondary alcohols
(2d–f) and one tertiary alcohol (2g) can be used for the reductive etherification
of 4-fluoro-benzaldehyde. Derivatives of carboxylic acids,2–5,11 such as esters
or cyano groups have been reported to remain intact under the reaction
conditions, whereas nitro groups3,5,11 or alkenes6 can only be reduced in the
presence of palladium catalysts. The smooth conversion of the olefinic
alcohols 2b, 2c and 2f (Table 1, entries 2, 3 and 6) confirms the qualified
stability of double bonds in the presence of decaborane.
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm. 2006; 49: 745–755
DOI: 10.1002/jlcr

748
U. FUNKE ET AL.
In conclusion, the reductive coupling of 4-fluoro-benzaldehyde with
different alcohols by means of B10H14 could readily proceed in acetonitrile.
The synthetic potential of this type of reaction could be broadened to prepare
4-fluoro-benzylethers with a range of variable functional groups.
Radiosyntheses
The results of the non-radioactive syntheses encouraged us to synthesize
4-[18F]fluoro-benzylethers (Table 2) from 4-[18F]fluoro-benzaldehyde in one
step.
The labelling precursor for 4-[18F]fluoro-benzaldehyde ([18F]1), trimethyl-
ammonium benzaldehyde triflate (5, TMABA), was obtained from
N,N-dimethylamino benzaldehyde (4) via quaternization.16 In radiotracer
experiments, the preparation of [18F]1 was achieved by the nucleophilic
aromatic substitution of TMABA by [18F]fluoride ion in dry DMF instead of
DMSO16 at 908C, as shown in Scheme 2. After purification by solid-phase
extraction on reversed phase (RP-SPE), the resulting solution of [18F]1 in
Table 2. Reductive etherification of 4-[18F]fluoro-benzaldehyde with alcohols in acetoni-
trile in the presence of decaborane
Entry
Alcohols
R–OH
Products
Decay-corrected
radiochemical
TLC Rf
(C6H12/EtOAc:
yield [% (SD)]a,b
5/1 v/v)c
RO
18F
OH
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
[18F]3a
[18F]3b
[18F]3c
[18F]3d
[18F]3e
[18F]3f
18.2 (3.4)
14.9 (0.4)
31.9 (n ¼ 2)d
25.5 (5.8)
9.6 (3.5)
0.68
0.66
0.43e
0.76
0.76
0.75
F
OH
HO
OH
OH
OH
11.3 (4.0)
OH
a Reaction conditions: Solution of [18F]1 (approx. 0.7 ml, 5–215 MBq) in MeCN, corresponding alcohol
(0.5–9.5 mmol) and B10H14 (0.01–0.07mmol), 608C, argon, 60–120 min. For further details see experimental
part.
b Number of reactions: n ¼ 327 unless otherwise stated. SD = Standard deviation.
c Values are corresponding to the results of the non-radioactive substances.
d Individual numbers: 17.9, 45.8.
e Rf in cyclohexane (C6H12)/ethyl acetate (EtOAc): 1/1 v/v.
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm. 2006; 49: 745–755
DOI: 10.1002/jlcr

ONE-STEP REDUCTIVE ETHERIFICATION OF 4-[18F]FLUORO-BENZALDEHYDE 749
Scheme 2. Preparation of 4-[18F]fluoro-benzaldehyde and reductive etherifica-
tion with alcohols in the presence of decaborane in acetonitrile
acetonitrile was applied directly to synthesize the 4-[18F]fluoro-benzylethers
([18F]3a–f, Scheme 2, Table 2).
In a first series of experiments we adapted the conditions of the non-
radioactive coupling reactions for radiosynthesis by adding 0.05–0.06 mmol
solid B10H14 and 0.5–0.6 mmol of the respective alcohol to a solution of no-
carrier-added (n.c.a.) 4-[18F]fluoro-benzaldehyde ([18F]1) in MeCN. [18F]1 was
consumed within 30 min yielding only minor amounts of the desired
radiofluorinated ethers. The rapid reduction of [18F]1 to 4-[18F]fluoro-benzyl
alcohol ([18F]2a) by decaborane caused this unexpected result.
Thus, we increased the amount of alcohol and used a stock solution of
decaborane in acetonitrile to lower the concentration of B10H14, and
consequently the reductive power. The results of selected experiments with
different proportions of 2d and B10H14 are shown in Figure 1.
A large excess of alcohol and a minor amount of decaborane result in a
pseudo-first-order reaction, so the undesired reduction of 4-[18F]fluoro-
benzaldehyde to [18F]2a could be diminished. Although reaction times,
necessary for the reductive etherification of [18F]1, increased to 60–120 min,
Figure 1. Radiochemical yields of 4-[18F]fluoro-benzyl-iso-propylether ([18F]3d)
as quantified by Radio-TLC: Influence of reaction time and mass ratio of alcohol
and B10H14 (iso-propanol [mmol] / B10H14 [mmol]: b 1.3 / 0.005; ^ 1.3 / 0.01;
*
1.3 / 0.015; c 3.3 / 0.01;
$
3.3 / 0.02;
&
6.5 / 0.01;
m
6.5 / 0.02)
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm. 2006; 49: 745–755
DOI: 10.1002/jlcr

750
U. FUNKE ET AL.
the radiochemical yield of [18F]3d could be improved up to 33% (decay-
corrected, Figure 1). In the course of high-performance liquid chromato-
graphy (HPLC) analysis, 4-[18F]fluoro-benzoic acid ([18F]6) was observed as
radioactive by-product and identified by co-elution with an authentic sample
of 6. The radiochemical yields of 4-[18F]fluoro-benzylethers were not further
increased at an elevated reaction temperature of 708C.
In addition, we tried to perform one-pot synthesis, starting from TMABA/
n.c.a. [18F]fluoride, i.e. we omitted the purification of [18F]1 by RP-SPE.
Attempts in mixtures of acetonitrile/DMF with 50–100 ml of alcohol (2b, 2e)
for 1 h at 608C (starting from [18F]1) did not succeed. However, a selected one-
pot synthesis using a large excess of alcohol 2a (1 ml) resulted in 22%
radiochemical yield (decay-corrected) of [18F]3a.
Further attempts to simplify the procedure and diminish the reaction
volume were carried out by elution of [18F]1 from the RP-cartridge directly
with the corresponding alcohol instead of MeCN. Thus, applying 2a as
an eluent for RP-SPE as well as reactant gave a 14% radiochemical yield
of [18F]3a.
Identification and quantification of the 18F-labelled ethers were
accomplished by radio-TLC and radio-HPLC in comparison with their
non-radioactive analogues. Aqueous ammonium acetate solutions with
MeCN ratios of 40–60% were proven as suitable eluents for HPLC analysis,
except in the case of the more hydrophilic ether 3c ([18F]3c) as depicted in
Figure 2.
Figure 2. (I) Retention times of reference compounds in dependence on the
percentage of MeCN in eluent and (II) Radiochromatograms of selected
4-[18F]fluoro-benzylethers
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm. 2006; 49: 745–755
DOI: 10.1002/jlcr

ONE-STEP REDUCTIVE ETHERIFICATION OF 4-[18F]FLUORO-BENZALDEHYDE 751
Experimental
Material and methods
Cyclohex-3-enol (2f, Table 1) was prepared from cis/trans-cyclohexane-1,4-
diol.17 All other reagents and substrates were purchased from commercial
sources and were used without further purification. N.c.a. aqueous [18F]fluor-
ide was generated by the 18O(p,n)18F nuclear reaction at a GE PETtrace
16.5 MeV cyclotron.
1H and 13C NMR spectra were recorded at room temperature on a Varian
Gemini VXR200 or Gemini 300BB in CDCl3 or (CD3)2SO (DMSO), at
frequencies as indicated. Chemical shifts are reported in d units (ppm) relative
to the signal of the given solvents as internal reference (CHCl3: dH=7.27 ppm,
dC=77 ppm; DMSO: dH=2.49 ppm, dC=39.5 ppm). Coupling constants are
given in Hz. Low-resolution mass spectra (LRMS) were recorded on an
Applied Biosystems Mariner Biospectrometry Workstation (MS-TOF) using
direct inlet system and electron spray ionization (ESI). High-resolution mass
spectra (HRMS) were recorded on a 7 T APEX II Fourier transform ion
cyclotron resonance mass analyser (FT-ICR-MS) with ESI or on a Finnigan
MAT 8230 with electron impact (EI).
Thin-layer chromatography (TLC) was performed on Macherey-Nagel silica
gel 60F254 plates (0.2 mm on aluminium) in cyclohexane/ethyl acetate mixtures
(C6H12/EtOAc: 5/1 v/v) and n-pentane/chloroform mixtures (nP/CHCl3: 3/1 v/
v) as eluents. For calculation of the retention factors (Rf) compounds were
localized by irradiation with an UV lamp (254 and 366 nm). Autoradiograms
on Fuji imaging plates were scanned with a Fuji BAS 1800 II phosphor imager,
applying BASReader 2.26 software. Amounts of radiolabelled products were
calculated with AIDA 2.31 program. Merck Silica gel 60 and Waters SepPack
C18 cartridges were used for column chromatography. High-performance
liquid chromatography (HPLC, Figure 2) was performed on a Merck-Hitachi
LaChrom system with D-7000 interface, L-7100 pump and a CS Nucleosil 100-
5C18 AB column (250 ꢀ 4 mm) by elution with acetonitrile/aqueous ammo-
nium acetate buffer solutions (MeCN/NH4AcO: 60/40 and 50/50 v/v, Cbuffer
=
20 mmol/l, flow rate 1 ml/min). Retention times (tR, means not adjusted) were
determined by UV detector L7400 at 220 nm and by Raytest 200 Socket
81030043 and NaI 2 ꢀ 200 Pinhole radioflow detectors.
Representative procedure for reductive etherification with 4-fluoro-benzaldehyde
(entry 6, Table 1)
B10H14 (62 mg, 0.50 mmol) was added to a solution of 4-fluoro-benzaldehyde
(1, 124 mg, 1.0 mmol) and cyclohex-3-enol (2f, 980 mg, 10.0 mmol) in
acetonitrile (5 ml) at room temperature (RT) under inert atmosphere. The
resulting mixture was stirred at 508C for 15 h. Acetone (2 ml) was added and
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm. 2006; 49: 745–755
DOI: 10.1002/jlcr

752
U. FUNKE ET AL.
the mixture was stirred for 2 h. The solvent was evaporated and the residue
was extracted with hexane (20 ml). The hexane solution was washed with 1 M
NaOH (2 ml) and evaporated. The crude ether was purified by column
chromatography (n-hexane/EtOAc: 5/1 v/v) to yield 3f (44%, 91 mg) of a
colourless liquid.
Bis-(4-fluoro-benzyl)-ether (3a).13 TLC Rf ¼ 0:68, 0.46 (C6H12/EtOAc, nP/
CHCl3); HPLC tR ¼ 4:73, 6.49 min (MeCN/NH4AcO: 60/40, 50/50).
1H-NMR (CDCl3, 300 MHz): d 7.37 (m, 4 H, ArH), 7.04 (m, 4 H, ArH),
4.52 (s, 4 H, (ArCH2)2O). 13C-NMR (CDCl3, 75 MHz): d 71.7, 115.6 (d,
J ¼ 21:6 Hz), 129.8 (d, J ¼ 8:0 Hz), 134.1 (d, J ¼ 3:5 Hz), 162.7 (d,
J ¼ 244:2 Hz); LRMS (ESI) m/z 257.1 (M+Na+).
1-Allyloxymethyl-4-fluoro-benzene (3b).14 TLC Rf ¼ 0:66, 0.37 (C6H12/EtOAc,
1
nP/CHCl3); HPLC tR ¼ 6:86, 11.65min (MeCN/NH4AcO: 60/40, 50/50). H-
NMR (CDCl3, 200 MHz): d 7.33 (m, 2 H, ArH), 7.04 (m, 2 H, ArH), 5.94 (ddt,
J3 ¼ 16:9 Hz, J3 ¼ 10:3 Hz, J3 ¼ 5:9 Hz, 1 H, OCH2CHCH2), 5.32 (dq-like,
J3 ¼ 17:2 Hz, J2,4=1.7 Hz, 1 H, OCH2CHCHHcis), 5.23 (dq-like, J3 ¼ 10:3 Hz,
J2;4 ¼ 1:5 Hz, 1 H, OCH2CHCHHtrans), 4.50 (s, 2 H, ArCH2O), 4.04
(dt, J3 ¼ 5:6 Hz, J4 ¼ 1:4 Hz, 2 H, OCH2CHCH2); 13C-NMR (CDCl3,
50MHz): d 71.3, 71.5, 115.4 (d, J ¼ 21:2 Hz), 117.4, 129.6 (d, J ¼ 8:1 Hz),
134.2 (d, J ¼ 3:4 Hz), 134.8, 162.5 (d, J ¼ 244:3 Hz); LRMS (ESI) m/z 189.1
(M+Na+).
cis-4-(4-Fluoro-benzyloxy)-but-2-en-1-ol (3c). TLC Rf ¼ 0:16, 0.43 (C6H12/
EtOAc: 5/1, 1/1 v/v); HPLC tR ¼ 2:75, 3.21 min (MeCN/NH4AcO: 60/40, 50/
1
50). H-NMR (CDCl3, 200 MHz): d 7.32 (m, 2 H, ArH), 7.03 (m, 2 H, ArH),
5.68–5.87 (m, 2 H, CH=CHCH2OH), 4.47 (s, 2 H, ArCH2O), 4.15 (d,
J3 ¼ 5:5 Hz, 2 H, ArCH2OCH2CH=CH), 4.07 (d, J3 ¼ 5:4 Hz, 2 H,
CH=CHCH2OH), 2.30 (m, 1 H, OH). 13C-NMR (CDCl3, 50 MHz): d 58.7,
65.8, 71.8, 115.4 (d, J ¼ 21:3 Hz), 128.1, 129.6 (d, J ¼ 8:1 Hz), 132.6, 133.8 (d,
J ¼ 3:1 Hz), 162.5 (d, J ¼ 244:4 Hz); LRMS (ESI) m/z 219.1 (M+Na+);
HRMS (ESI) m/z C11H13FO2 ꢁ Na (M+Na+) calculated 219.07918; found:
219.07920.
1-Fluoro-4-iso-propoxymethyl-benzene (3d). TLC Rf ¼ 0:76, 0.41 (C6H12/
EtOAc, nP/CHCl3); HPLC tR ¼ 7:70, 13.34 min (MeCN/NH4AcO: 60/40,
1
50/50). H-NMR (CDCl3, 200 MHz): d 7.35 (m, 2 H, ArH), 7.05 (m, 2 H,
ArH), 4.49 (s, 2 H, ArCH2O), 3.70 (sept, J3 ¼ 6:2 Hz, 1 H, OCH(CH3)2), 1.24
(d, J3 ¼ 6:2 Hz, 6 H, OCH(CH3)2). 13C-NMR (CDCl3, 50 MHz): d 22.2, 69.5,
71.2, 115.2 (d, J ¼ 21:1 Hz), 129.3 (d, J ¼ 8:0 Hz), 135.0 (d, J ¼ 2:9 Hz), 162.3
(d, J ¼ 243:7 Hz); LRMS (ESI) m/z 191.1 (M+Na+); HRMS (EI) m/z
C10H13FO2 (M+) calculated 168.09504; found: 168.09509.
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm. 2006; 49: 745–755
DOI: 10.1002/jlcr

ONE-STEP REDUCTIVE ETHERIFICATION OF 4-[18F]FLUORO-BENZALDEHYDE 753
1-Cyclopentyloxymethyl-4-fluoro-benzene (3e). TLC Rf ¼ 0:76, 0.28 (C6H12/
EtOAc, nP/CHCl3); HPLC tR ¼ 13:16, 20.64 min (MeCN/NH4AcO: 60/40,
1
50/50). H-NMR (CDCl3, 200 MHz): d 7.31 (m, 2 H, ArH), 7.01 (m, 2 H,
ArH), 4.42 (s, 2 H, ArCH2O), 3.95–4.05 (m, 1 H, c-pentyl: CH-O), 1.50–1.80
(2 m, 8 H, c-pentyl: 4CH2). 13C-NMR (CDCl3, 50 MHz): d 23.8, 32.5, 70.2,
81.2, 115.3 (d, J ¼ 21:3 Hz), 129.5 (d, J ¼ 8:0 Hz), 135.0 (d, J ¼ 3:5 Hz), 162.4
(d, J ¼ 243:4 Hz); LRMS (ESI) m/z 217.1 (M+Na+); HRMS (ESI) m/z
C12H15FO2 ꢁ Na (M+Na+) calculated 217.09991; found: 217.10000.
1-(Cyclohex-3-enyloxymethyl)-4-fluoro-benzene (3f). TLC Rf ¼ 0:75, 0.38
(C6H12/EtOAc, nP/CHCl3); HPLC tR ¼ 12:42, 20.72 min (MeCN/NH4AcO:
1
60/40, 50/50). H-NMR (CDCl3, 300 MHz): d 7.32 (m, 2 H, ArH), 7.03 (m,
2 H, ArH), 5.60–5.65 (m, 2 H, c-hexenyl: –CH¼CH–), 4.50–4.55 (AB, 2 H,
ArCH2O), 3.65–3.68 (m, 1 H, c-hexenyl: CH-O), 2.35–2.40, 1.94–2.22,
1.62–1.80 (3 m, 6 H, c-hexenyl: 3CH2). 13C-NMR (CDCl3, 75 MHz): d 24.3,
28.1, 32.0, 69.5, 74.2, 115.4 (d, J ¼ 21:6 Hz), 124.5, 127.1, 129.5 (d,
J ¼ 8:0 Hz), 135.1, 162.5 (d, J ¼ 243:6 Hz); LRMS (ESI) m/z 229.2
(M+Na+); HRMS (ESI) m/z C13H15FO2 ꢁ Na (M+Na+) calculated
229.09991; found: 229.09997.
1-tert-Butoxymethyl-4-fluoro-benzene (3g).15 TLC Rf ¼ 0:77, 0.37 (C6H12/
1
EtOAc, nP/CHCl3). H-NMR (CDCl3, 200 MHz): d 7.31 (m, 2 H, ArH), 7.02
(m, 2 H, ArH), 4.42 (s, 2 H, ArCH2O), 1.31 (s, 9 H, -C(CH3)3). 13C-NMR
(CDCl3, 50 MHz): d 27.9, 63.6, 73.6, 115.2 (d, J ¼ 21:4 Hz), 129.1 (d,
J ¼ 7:9 Hz), 135.8, 162.2 (d, J ¼ 242:9 Hz); LRMS (ESI) m/z 205.1
(M+Na+).
(4-Formyl-phenyl)-trimethyl-ammonium trifluoro-methanesulfonate (TMABA;
5).16 Methyl trifluoro-methanesulfonate (1.1 ml, 10 mmol) was added to a
solution of N,N-dimethylamino benzaldehyde (4, 1.64 g, 11 mmol) in
dichloromethane (20 ml) at RT under argon. The dark green reaction mixture
was stirred at RT for 48 h. The resulting green solid was filtrated, washed,
recrystallized and again filtrated from hot dichloromethane to yield 5 (21%,
664 mg) of a white powdery solid. mp (Boetius): 1108C (sublimation at
100–1038C). 1H-NMR (DMSO, 200 MHz): d 3.38 (s, CH3), 3.65 (s, CH3), 8.12,
8.17, 8.19, 8.24 (dd, 4 H, CHarom, J ¼ 8:79 Hz), 10.11 (s, 1 H, CHO).
13C-NMR (DMSO, 50 MHz) d 56.43 (CH3), 121.73 (CHarom, ortho
to –N(CH3)+3 ), 130.92 (CHarom,), 136.81 (Cquart, C-CHO), 151.07 (Cquart
C-N(CH3)+3 ), 192.17 (CHO); LRMS (ESI) m/z 164.13 (M+).
,
4-[18F]Fluoro-benzaldehyde ð½18Fꢂ1Þ. An aqueous [18F]Fꢃ solution of
278–1384 MBq was transferred in a 2–3 ml reaction vial with septum. About
100–200 ml of a solution of Kryptofix1222 (K.222) in acetonitrile (100 mg/ml,
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm. 2006; 49: 745–755
DOI: 10.1002/jlcr

754
U. FUNKE ET AL.
0.027–0.053 mmol), 100–200 ml of an aqueous solution of potassium carbonate
(20 mg/ml, 0.015–0.029 mmol) and 300–500 ml of MeCN (p.a.) were added.
The reaction mixture was stirred under argon stream/vacuum and heated in a
conventional glycol bath up to 908C for 15–20 min, while 2–3 times 300–500 ml
MeCN (p.a., in proportion to the quantity of water) and one time MeCN
(puriss., absolute) were added for co-evaporation to give n.c.a. K[18F]F-
K.222-carbonate complex as a white semi-solid residue.
After addition of 6-12 mg (0.02–0.04 mmol) precursor 5, dissolved in
300–400 ml DMF, to the K[18F]F-K.222-carbonate complex, the dark green
to brown reaction mixture was stirred in a closed vial under argon at 908C for
25 min. After monitoring the reaction with HPLC and TLC, it was quenched
by addition of 10 ml 0.1 M HCl. The resulting yellowish aqueous solution was
passed through a C18 cartridge, methanol/water conditioned. Rinsing with
3 ml water, drying with air and elution of the product with 2 ml MeCN
(puriss., absolute) into a Na2SO4-filled vial (1 g) resulted in 36–59% (n ¼ 9)
decay-corrected radiochemical yield of [18F]1. 4-[18F]Fluoro-benzaldehyde
([18F]1): TLC Rf ¼ 0:50, 0.20 (C6H12/EtOAc, nP/CHCl3); HPLC tR ¼ 3:71,
4.54 min (MeCN/NH4AcO: 60/40, 50/50).
Representative procedure for reductive etherification with 4-fluoro-benzaldehyde
to obtain 4-[18F]fluoro-benzylethers ½18Fꢂ3a2f (entry 3, Table 2). A solution
of [18F]1 (0.7 ml, 41 MBq) in MeCN was retained from Na2SO4 by syringe.
Then, 500 ml of cis-but-2-ene-1,4-diol (2c, 6 mmol) and 150 ml of a decaborane
solution in MeCN (0.2 mol/l, 0.03 mmol) were added. The reaction mixture
was heated in a conventional glycol bath up to 608C and stirred in a closed vial
under argon. For 2 h, the reaction was controlled by TLC every 30 min. After
100 min reaction time, a decay-corrected radiochemical yield of 45.8% of cis-4-
(4-[18F]fluoro-benzyloxy)-but-2-en-1-ol ([18F]3c) was obtained. The product
was identified and the yield was determined by TLC and HPLC in comparison
to the non-radioactive compound 3c.
Analytical data of radioactive by-products. 4-[18F]Fluoro-benzyl alcohol
(½18Fꢂ2a). TLC Rf ¼ 0:18, 0.05 (CH/EtOAc, nP/CHCl3); HPLC tR ¼ 2:79,
3.22 min (MeCN/NH4AcO: 60/40, 50/50). 4-[18F]Fluoro-benzoic acid ([18F]6).
TLC Rf ¼ 0:07 (C6H12/EtOAc); HPLC tR ¼ 1:86, 1.90 min (MeCN/NH4AcO:
60/40, 50/50).
Conclusion
4-[18F]Fluoro-benzylethers were obtained from 4-[18F]fluoro-benzaldehyde
and primary and secondary alcohols via a one-step reductive coupling in
MeCN mediated by B10H14. This procedure could serve as a new and easy
access to 18F-labelled benzylethers. However, radiochemical yields are
dependent on the conditions applied and need to be optimized individually.
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm. 2006; 49: 745–755
DOI: 10.1002/jlcr

ONE-STEP REDUCTIVE ETHERIFICATION OF 4-[18F]FLUORO-BENZALDEHYDE 755
Acknowledgements
We are grateful to the cyclotron operators of the Clinic and Polyclinic for
Nuclear Medicine at the University of Leipzig. Furthermore, we wish to thank
the collaborators of the Institute of Analytical Chemistry on the Faculty of
Chemistry and Mineralogy at the University of Leipzig for recording the
NMR and high-resolution mass spectra. H. Jia was supported by China
Scholarship Council.
References
1. Iwata R, Horvath G, Pascali C, Bogni A, Yanai K, Kovacs Z, Ido T. J Label
Compd Radiopharm 2000; 43: 873–882.
2. Lee SH, Park YJ, Yoon CM. Tetrahedron Lett 1999; 40: 6049–6050.
3. Bae JW, Cho YJ, Lee SH, Yoon COM, Yoon CM. Chem Commun 2000; 19:
1857–1858.
4. Bae JW, Lee SH, Cho YJ, Yoon CM. J Chem Soc, Perkin Trans 1 2000; 145–146.
5. Bae JW, Cho YJ, Lee SH, Yoon CM. Tetrahedron Lett 2000; 41: 175–177.
6. Lee SH, Park YJ, Yoon CM. Tetrahedron Lett 2000; 41: 887–889.
7. Bae JW, Lee SH, Jung YJ, Yoon COM, Yoon CM. Tetrahedron Lett 2001; 42:
2137–2139.
8. Lee SH, Jung YJ, Cho YJ, Yoon COM, Hwang HJ, Yoon CM. Synth Commun
2001; 31: 2251–2254.
9. Jung YJ, Bae JW, Yoon COM, Yoo BW, Yoon CM. Synth Commun 2001; 31:
3417–3421.
10. Lee SH, Lee JH, Yoon CM. Tetrahedron Lett 2002; 43: 2699–2703.
11. Jung YJ, Bae JW, Park ES, Chang YM, Yoon CM. Tetrahedron 2003; 59:
10331–10338.
12. Jia HM, Fang DC, Scheunemann M. J Org Chem 2005; 70: 4478–4483.
13. Emert J, Goldenberg M, Chiu GL, Valeri A. J Org Chem 1977; 42: 2012–2013.
14. Fu H, Newcomb M, Wong CH. J Am Chem Soc 1991; 113: 5878–5880.
15. Cristol SJ, Bindel TH. J Org Chem 1980; 45: 951–957.
16. Haka MS, Kilbourn MR, Watkins GL, Toorongian SA. J Label Compd
Radiopharm 1989; 27: 823–833.
17. Godek CJ, Moir RY, Purves CB. Can J Chem 1951; 29: 946–948.
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm. 2006; 49: 745–755
DOI: 10.1002/jlcr