Fluoridation of 2-thienyliodonium salts

Full text of DOI:10.1002/jlcr.1189

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 450–451.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1189
Short Research Article
Fluoridation of 2-thienyliodonium saltsy
MICHAEL A. CARROLL1,*, CLARE JONES2 and SHU-LING TANG1
1 School of Natural Sciences}Chemistry, Newcastle University, Newcastle Upon Tyne NE1 7RU, UK
2 GE Healthcare, The Grove Centre, White Lion Road, Amersham, Buckinghamshire HP7 9LL, UK
Received 12 October 2006; Revised 21 November 2006; Accepted 21 November 2006
Keywords: fluorinated aromatics; fluorine-18; hypervalent iodine
Introduction
electron-deficient ring. We have found that the electro-
nic factors take precedence over the ortho effect.2
Following our initial report3 on the fluoridation of
heteroaromatic iodonium salts and the potential of the
2-thienyl substituent as a non-participating aromatic
ring,4 in the formation of fluorine-18 labelled radio-
pharmaceuticals, the synthesis and fluoridation of a
range of 2-thienyliodonium salts was investigated.
The importance of fluoridation has come to the fore due
to the recent renewed interest in the medical imaging
technique}Positron Emission Tomography. This re-
quires new methodologies for the fluoridation of
compounds as radiotracers and radiopharmaceuticals,
allowing us to use PET for diagnosis and to increase our
knowledge of in vivo pharmacokinetics.
TsO
I
X
S
X
S
CsF
+
Results and discussion
1a
2a
2b
2c
X = F
X = I
X= OTs
3a
3b
3c
Diaryliodonium salts have been shown to be suitable
precursors for the preparation of fluorine-18 labelled
aromatics1 and there are several distinct advantages
over many conventional procedures.
Scheme 1
The fluoridation of salt 1a gave fluorobenzene 2a, as
the sole fluoroarene (Scheme 1). However analysis of
the crude reaction mixture, by GC-MS, indicated that
both aryl iodides (2b, 3b) were present suggesting that
both possible fluoroarene products should also be
present. Also both possible products (2c, 3c) from the
nucleophilic substitution by the counter-ion were
present. These results suggest that the fluoridation
result}lack of 3a}was misleading in terms of selec-
tivity of the process. The other products were in similar
amounts suggesting that the phenyl and 2-thienyl
substituents were similar in electronic profile as would
be expected.
The use of [18F]fluoride, which may be produced in
*
much higher amounts and higher specific radio-
activity than
[
18F]F2 and derived reagents (cf.
fluorodestannylation).
*
Iodonium salts place little or no restriction on the
nature and pattern of aromatic substituents of the
target (cf. SNAr processes).
The outcome of the fluoridation has been shown to be
dependent on both steric and electronic factors. The
ortho effect states that if an aromatic ring on the
iodonium salt is substituted at the ortho position then
it is this ring that undergoes fluoridation. The electro-
nic effect results in the fluoridation of the most
CF3COO
S
I
X
X
S
CsF
+
*Correspondence to: Michael A. Carroll, School of Natural Scien-
ces}Chemistry, Newcastle University, Newcastle Upon Tyne NE1 7RU,
UK. E-mail: m.a.carroll@ncl.ac.uk
MeO
MeO
1b
4a X = F
3a
3b
5c
4b
4c
X = I
y
X = O C O C F 3
Proceedings of the Ninth International Symposium on the Synthesis
and Applications of Isotopically Labelled Compounds, Edinburgh,
16–20 July 2006.
Scheme 2
Copyright # 2007 John Wiley & Sons, Ltd.

FLUORIDATION OF 2-THIENYLIODONIUM SALTS 451
The fluoridation of the 4-methoxyphenyl(2-thienyl)
iodonium salt 1b (Scheme 2) was also investigated.
Again both possible aryliodides (4b, 3b) were present in
the crude reaction mixture as were both possible
products (4c, 5c) from counter-ion addition}this
suggested that both possible fluoroarenes were pro-
duced however the only fluoroarene detected was 4-
fluoroanisole 4a (in trace amounts)}this is again
consistent with the electronic nature of the 2-thienyl
substituent.
sample was prepared by lithiation of thiophene and a
quench with NFSI6).
In summary the detection, characterization and
isolation of 2-fluorothiophene is extremely problematic.
In addition the analysis of the non-fluorinated products
from the fluoridation of 2-thienyliodonium salts
strongly suggests that the process is not as selective
as would appear from the fluoroarene products only.
Acknowledgement
In these reactions both fluoroarenes should be
present, however in both cases 2-fluorothiophene was
not detected. These results suggest that 2-thienyl may
not be the ideal non-participating ring for the produc-
tion of fluoroarenes by the fluoridation of diaryliodo-
nium salts and that it is the analysis/detection of
2-fluorothiophene that may be a problem. This lack
of detection may be due to the highly volatile nature
of 2-fluorothiophene (boiling point 828C5) which may be
lost under the reaction conditions (T > b:p:) or on work-
up/analysis. It may also be unstable}e.g. subject to
hydrolysis leading to only fluoride being detected. In
addition it may also co-elute by HPLC and GC due to
very similar properties to other components (e.g. PhF,
b.p. 808C) or co-elute or pre-run the solvent.
2-Fluorothiophene also has limited UV activity making
detection by TLC and HPLC difficult/inconsistent.
Analysis of the radiofluoridation of 2-thienyl(phenyl)
iodonium tosylate initially gave a single peak by radio
HPLC however after extensive method development
(following our concerns, in this case about co-elution)
this was found to actually consist of two compo-
nents}the first fluorobenzene was as expected, the
second appeared to be 2-fluorothiophene (an authentic
We thank the EPSRC and GE-Healthcare (CTA award to
SLT) for funding and the EPSRC for provision of the
Swansea Mass Spectrometry Service.
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Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 450–451
DOI: 10.1002.jlcr