Solid-Supported Iodonium Salts for Fluorinations

Article abstract of DOI:10.1002/ejoc.201500992

Solid-supported iodonium salt precursors have been prepared and used for the production of fluoroarenes. The importance of the resin functionality for the attachment of the iodonium salt moieties has been demonstrated. Furthermore, the production of new i

Full text of DOI:10.1002/ejoc.201500992

FULL PAPER
DOI: 10.1002/ejoc.201500992
Solid-Supported Iodonium Salts for Fluorinations
Richard Edwards,[a] Wilke de Vries,[a] Andrew D. Westwell,[b] Stephen Daniels,[c] and
Thomas Wirth*[a]
Keywords: Solid-phase synthesis / Radiochemistry / Fluorine / Fluorination / Iodine / Hypervalent iodine
Solid-supported iodonium salt precursors have been pre- method with respect to those previously described. The suc-
pared and used for the production of fluoroarenes. The im-
portance of the resin functionality for the attachment of the
iodonium salt moieties has been demonstrated. Furthermore,
the production of new iodonium salt precursors for fluorin-
ation has been achieved by an alternative and improved
cessful radiofluorination of a simple solid-supported precur-
sor with no-carrier-added (n.c.a.) [18F]fluoride shows the suit-
ability of the method for the production of useful PET syn-
thons.
110 min). Such compounds find utility in positron emission
tomography (PET) imaging. This highly sensitive and versa-
tile imaging technique allows for the pharmacokinetics and
biodistribution of positron emitters to be studied in vivo.[5]
Diaryliodonium salt precursors can be used for the nu-
cleophilic incorporation of fluoride into electron-rich aro-
matic compounds.[6] The use of diaryliodonium salts for the
formation of 18F-labelled aromatic compounds was first re-
ported by Pike et al., who used both symmetrical and un-
symmetrical diaryliodonium precursors.[7] If an unsymmet-
rical diaryliodonium salt is used, selective fluorination can
be achieved by tuning the steric and electronic properties of
the second aryl substituent.[8] Small, electron-rich aryl
groups (commonly 2-thienyl and 4-methoxyphenyl) are
used as “non-participating” aryl rings to direct fluorination
to the desired aromatic moiety. Other non-participating
groups include a [2,2]paracyclophane moiety.[9]
Adaption of this methodology to solid-supported iodon-
ium salts for the introduction of fluorine combines the ra-
pid and selective fluorination of diaryliodonium salts with
the facile purification available to solid-supported precur-
sors. Work in this area includes radiofluorination of solid-
supported iodonium salt precursors for the production of
[18F]fluorobenzene and [18F]fluorouracil reported by Brady
et al.[10] Furthermore, a patent published by Carroll et al.
shows the synthesis of diaryliodonium salt precursors for
radiofluorination linked to an aminomethyl resin through
amide linkages.[11]
Introduction
Solid-phase organic synthesis is “synthesis in which the
starting material and synthetic intermediates are linked to
an insoluble support”.[1] The use of a solid support for syn-
thesis was first reported by Merrifield in 1963.[2] Merrifield
utilised chloromethyl-functionalised resin for the pro-
duction of peptides.
Since this pioneering work, the use of polymer-bound
precursors and reagents has become widespread in organic
synthesis.[3] The general advantage provided by the method-
ology is the ability to separate intermediates from reagents
and solvents mechanically.[1] Most commonly used are
polystyrene supports.[3c]
The cleavage of the polymer-bound molecule is a key step
in solid-supported organic synthesis and is not only used to
cleave the product from the resin but can also be used to
introduce functionality into the molecule being cleaved.
This includes the introduction of halogens such as fluor-
ine.[3b] The use of solid-supported precursors for the intro-
duction of the 18F isotope during this cleavage step has
been described.[4] Here, the solid-supported methodology
offers an opportunity for rapid purification of radiolabelled
compounds. This is a highly desirable feature when produc-
ing compounds with a short half-life time (18F: t1/2
=
[a] School of Chemistry, Cardiff University,
Main Building, Park Place, Cardiff CF10 3AT, UK
E-mail: wirth@cf.ac.uk
http://blogs.cardiff.ac.uk/wirth/
[b] School of Pharmacy and Pharmaceutical Sciences, Cardiff
University,
Here we report the synthesis and evaluation of polysty-
rene-supported diaryliodonium salts for fluorination and
radiofluorination. Different methods for the production of
the resin-bound precursors are investigated. Key factors in
optimising the functionalisation of the resin and iodonium
salt formation are discussed.
Cardiff CF10 3NB, UK
[c] Wales Research & Diagnostic PET Imaging Centre (PETIC),
School of Medicine, Cardiff University,
Cardiff CF14 4XN, UK
Supporting Information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500992.
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FULL PAPER
Results and Discussion
Investigation begun with the attempted production of so-
lid-supported diaryliodonium salts previously reported in
a patent by Carroll et al.[9] The strategy uses amide bond
formation as the key step, linking the precursor to the resin.
Aminomethyl-functionalised polystyrene resin is used for
coupling to carboxylic acids 1 and 2(TFA) (Figure 1).
Figure 1. Iodoaryl-functionalised carboxylic acid 1, for amide cou-
pling followed by oxidation to the iodonium salt, and iodonium
salt functionalised linker 2(TFA), ready for amide coupling to the
amine resin.
The two carboxylic acids 1 and 2(TFA) provide the start-
ing materials for two possible routes to the same resin-
bound precursor. As shown in Scheme 1 on the right-hand
side, compound 1 is attached to a polymer and then takes
part in subsequent transformations to produce the polymer-
supported iodonium salt 6(TFA). In the second route
(Scheme 1, left-hand side), the iodonium salt 8(TFA) is
formed first and is then, after hydrolysis to 2, bound
through an amide linkage to the aminomethyl resin.
Scheme 1. Two routes for the synthesis of resin-bound iodonium
salt 6 from 1 or 3 (DIPEA = diisopropylethylamine, DPPC = di-
phenylphosphoryl chloride, TFA = trifluoroacetic acid).
The right-hand route starting from 1 in Scheme 1 was
chosen for initial investigations because a higher loading
with regard to iodine was reported for this method by ele-
Scheme 2. Synthesis of iodoaryl linker 1.
mental analysis (11.59% I for right-hand route vs. 7.49% I could be attained under the reported conditions, and repro-
for left-hand route). ducibility was a problem (Table 1, Entries 1–3). A number
The synthesis of the iodoaryl linker 1 was very successful of different conditions were used to obtain higher loadings
in our hands, with both the formation and the hydrolysis of (Table 1). The procedure was carried out under inert condi-
ethyl 6-(4-iodophenoxy)hexanoate (3) proceeding with ex- tions, which gave an increased loading as determined by
cellent yields (Scheme 2).
weight increase of the polymer (Entry 4). All future experi-
However, the functionalisation of the aminomethyl resin ments were carried out under inert conditions (Entries 5–
with the linker 1 proved to be difficult. Only a low loading 11). Despite some improvement, yields were still unaccept-
Table 1. Optimisation for amide coupling of linker 1 to amino-functionalised resin.
Entry
Resin
Coupling agent
Time
[h]
DIPEA Solvent
[equiv.]
Loading
Yield[a]
[%]
Elemental analysis
(% I)
[mmolg–1]
1
2
3
4
5
6
7
8
aminomethyl
aminomethyl
aminomethyl
aminomethyl
aminomethyl
aminomethyl
aminomethyl
aminomethyl
aminomethyl
tris(aminoethyl)
tris(aminoethyl)
DPPC
DPPC
DPPC
DPPC
DPPC
DPPC
T3P
T3P
T3P
T3P
DPPC
18
18
18
18
25
25
48
25
25
65
43
2.25
2.25
2.25
2.25
3
3
2
2
2
2
2.25
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
EtOAc
DMF
CH2Cl2
EtOAc
CH2Cl2
0.36
0.27
0.17
0.66
0.49
0.07
0.33
0.19
0.29
1.73
2.11
37
18
12
44
33
4
37
13
19
69
85
3.5
–
–
–
–
–
–
–
–
9
10
11
12.3
13.6
[a] Yields based on gain in mass of resin or by elemental analysis when available (see the Supporting Information for details).
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Solid-Supported Iodonium Salts for Fluorinations
able and repeats of the experiment again gave inconsistenc- Oxidation of the supported iodoaryl moiety in 10 with per-
ies in the observed loadings.
acetic acid proceeded to give diacetate 11 in 55% yield, af-
Increasing the equivalents of diisopropylethylamine did ter which addition of tri-n-butylphenyltin and TFA afforded
not change the loading (Entry 5). The use of anhydrous the solid-supported diaryliodonium salt 12(TFA) in quanti-
DMF as the solvent was also investigated because such po- tative yield.
lar aprotic solvents can give beneficial “swelling” of the
Fluorination of the solid-supported salt 12(TFA) with
support.[1] However, this was detrimental to the reaction no-carrier-added (n.c.a.) [18F]fluoride produced [18F]fluoro-
(Entry 8). The use of T3P (propylphosphonic anhydride) as benzene (13, Scheme 5). TLC showed a radiochemical con-
a coupling agent also failed to improve the functionalis- version (RCC) of 3%. Identity of the radiolabelled com-
ation of the polystyrene support in a number of solvents pound was confirmed by radio-HPLC and co-elution with
(Entries 7–9).
a “cold” standard.
The poor results prompted a test reaction in which an
amide linkage was introduced between the 6-(4-iodo-
phenoxy)hexanoic acid (1) and aniline to give 9 in excellent
yield (Scheme 3).
Scheme 5. “Hot” fluorination of polymer-supported iodonium salt
12.
To achieve the maximum potential of the solid-supported
methodology, it was proposed that solid-supported
Scheme 3. Amide coupling between carboxylic acid 1 and aniline.
These results implied that complications had originated TEMPO could be used in conjunction with the solid-sup-
from the solid-supported amine, and a solution was ported precursor 12(TFA). This meant that in the event of
achieved by the use of a different resin. Coupling reactions a clean and selective reaction it should be possible to isolate
with tris(aminoethyl) resin gave substantially higher load- pure product by means of a simple cartridge purification.
ings with both coupling agents (Table 1, Entries 10 and 11). The reaction, however, was not as successful as reported for
This suggested that a steric effect from the resin may have the unsupported TEMPO. The extra resin in the reaction
inhibited penetration of the reagents to the functionalised mixture resulted in an increase in the amount of activity
sites.
retained by the resin (12% with unsupported TEMPO, 19%
The reaction under the optimised conditions for iodoaryl with supported TEMPO), and radio-TLC showed a re-
functionalisation of the resin is shown below (Scheme 4). duction in the radiochemical conversion to Ͻ1%. Further-
Scheme 4. Amide coupling between 1 and tris(2-aminoethyl)amine resin and synthesis of solid-supported iodonium salt 12(TFA).
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R. Edwards, W. de Vries, A. D. Westwell, S. Daniels, T. Wirth
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more, radio-HPLC analysis showed a significant increase in
impurities (see the Supporting Information).
However, the reaction to produce 18(Br) proceeded po-
orly. The initial conditions, with the diacetate 19 and a
The successful production of [18F]fluorobenzene boron-trifluoride-catalysed reaction with the boronic acid,
prompted an expansion of the methodology to the pro- provided the iodonium salt 18(Br) in poor yield. It should
duction of fluorinated aromatic compounds with applica- also be noted that the obtained iodonium salt could not be
tion in PET. Two compounds considered for their valuable isolated with a high purity. Attempts to improve the yield
application were [18F]4-fluorobenzaldehyde and [18F]4- by tuning the reaction conditions were unsuccessful (see the
fluorophenol.
Supporting Information for a full Table of conditions used
[18F]4-Fluorobenzaldehyde ([18F]FBA) is a prosthetic in attempts to improve the yield). This is presumably due
group used for the 18F labelling of peptides. The labelling to the electron-rich nature of the hypervalent iodine com-
is achieved under mild conditons by chemoselective oxime pound, because reaction with (diacetoxyiodo)benzene as
formation between an aminooxy-functionalised peptide and described by Richarz et al.[14] proceeds well.
the [18F]FBA.[12]
Arylstannanes can also be used in the synthesis of di-
The second target, [18F]4-fluorophenol, is an important aryliodoium salts[15] and offer an alternative to the boronic
18F-labelled synthon for the production of labelled mol- acid protocol. Therefore, the appropriate stannane – 4-(tri-
ecules bearing the [18F]4-fluorophenoxy functionality. The methylstannyl)benzaldehyde – was produced for utility in
labelled species is employed in the synthesis of a number of the synthesis of diaryliodonium salt 18(Br). However, reac-
valuable tracers of biological interest.[13] With these targets tions with 4-methoxy Koser reagent, produced in situ under
in mind, the solid-supported precursors 14(Br) and 16(Br), conditions adapted from those reported by Wirth et al.,[16]
based on the tris(aminoethyl) resin, were investigated failed to produce the iodonium salt 18(Br) (see the Support-
(Scheme 6).
ing Information for all attempted conditions).
Attempts to produce the resin-bound precursor were also
unsuccessful. The reaction gave a very small increase in the
mass of the resin, thus suggesting a low level of conversion
of the diacetate into the diaryliodonium salt. Fluorination
of the supported precursor did not produce the desired
fluorinated product, providing further evidence of the lack
of success in forming the iodonium salt (see the Supporting
Information for details).
Precursors for 4-Fluorophenol Synthesis
As well as the solid-supported precursor 16(Br), the solu-
tion-phase precursor 20(Br) was targeted for comparison.
Protected linker iodonium salt 21(Br) was also synthesised
in order to investigate whether the linker moiety had any
effect on the fluorination reaction (Figure 2).
Scheme 6. Solid-supported precursors 14(Br), for 4-fluorobenzalde-
hyde production, and 16(Br), for 4-fluorophenol production.
Precursors for 4-Fluorobenzaldehyde Synthesis
As well as solid-supported iodonium salt 14(Br), the
solution-phase precursor 18(Br) was also targeted, for com-
parison with the solution-phase approach.
Initial investigation began with the solution-phase reac-
tion in order to probe the iodonium-salt-forming reaction
(Scheme 7).
Figure 2. Precursors for [18F]4-fluorobenzaldehyde production.
Iodonium salt 21(Br) was synthesised first, in order to
probe the reactivity of the linker moiety. Furthermore, sub-
sequent transformation would provide a carboxylic acid for
linkage to the aminomethyl resin.
Firstly, aryl-BPin moiety 22 was synthesised by benzyl
protection of 4-iodophenol and subsequent coupling with
bis(pinocolato)diboron as shown in Scheme 8. Subsequent
treatment with diacetate 7 produced the desired product
21(Br) but in poor yields, so an alternative approach was
investigated.
Scheme 7. Synthesis of solution-phase [18F]FBA precursor 18(Br).
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Solid-Supported Iodonium Salts for Fluorinations
Scheme 8. Synthesis of iodonium salt 21(Br) via aryl BPin moiety 22.
It was found that significant improvements to the yield Optimisation for the oxidation of aryl iodide to diacetate
could be made by using a slightly altered synthesis strategy 24 is shown in Table 2.
(Scheme 9). Rather than oxidation of iodophenol ether 3,
Table 2. Optimisation for the oxidation of O-benzyl-4-iodophenol
to diacetate 24.
oxidation of the O-benzyl-4-iodophenol 23 was conducted.
Entry Reagents and solvent
Time
[h]
Temp.
[°C]
Yield
[%]
1
2
3
4
NaIO4, NaOAc, AcOH, Ac2O
2
24
2
120
80
r.t.
r.t.
impure
48
0
NaIO4, NaOAc, AcOH, Ac2O
AcOOH, CH2Cl2
Selectfluor®, AcOH, MeCN
5
95
The use of Selectfluor® as an oxidant in acetonitrile and
acetic acid proved optimal, giving an excellent yield of the
corresponding diacetate 24. This method showed improve-
ments on those previously reported.[17]
Conversion of the diacetate into the Koser reagent deriv-
ative 25 followed by treatment with electron-rich aromatic
26 gave the desired iodonium tosylate 21(TsO) in good
yields. The iodonium salt 21(TsO) could then be hydrolysed
with trifluoroacetic acid (TFA) in water to yield 27(TsO).
Interestingly, the tosylate counterion in acid 27(TsO) was
not exchanged to a trifluoroacetate counterion after the hy-
Scheme 9. Synthesis of iodonium salt precursor 21(TsO) via diacet-
ate 24 (TFE = 2,2,2-trifluoroethanol).
1
drolysis as confirmed by H NMR spectroscopy. Coupling
Scheme 10. Synthesis of solid-supported precursor 16(Br).
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R. Edwards, W. de Vries, A. D. Westwell, S. Daniels, T. Wirth
FULL PAPER
to the solid support was achieved under the standard condi- yields obtained dropped to 7% and 8%, respectively.
tions to produce 16(TsO/Cl), which was converted into Decreasing the concentration of the iodonium bromide was
16(Br) as shown in Scheme 10.
detrimental to the reaction, yields could be improved by
Synthesis of the solution-phase iodonium bromides was increasing the equivalents of TMAF, with use of 2 equiv.
also successful (Scheme 11). Iodonium tosylate 20(TsO) was increasing the yield to 20% and use of 4 equiv. giving 22%.
produced by an analogous procedure for reaction with anis-
Interestingly, when the fluorination reaction was per-
ole. The isolated iodonium tosylates 20(TsO) and 21(TsO) formed with precursor 21(Br) under optimised reaction
were then converted into their corresponding iodonium conditions, the yields of the desired fluorinated product 17
bromides by washing with saturated aqueous KBr.
were improved to 30% as analysed by GC (Scheme 12).
Scheme 12. Fluorination of linker-derived iodonium salt 21(Br).
This showed that the linker moiety was beneficial for the
fluorination reaction. Fluorination of the solid-supported
precursor was successful as well, giving yields between 22%
and 24% depending on the scale of the reaction
(Scheme 13). The results show that the reaction is reproduc-
ible and scalable.
Scheme 11. Synthesis of iodonium bromides 20(Br) and 21(Br).
After the synthesis of the iodonium precursors 16(Br),
20(Br) and 21(Br) it was important to test their efficacy in
the fluorination reaction. Optimisation was conducted with
iodonium salt 20(Br) and tetramethylammonium fluoride
(TMAF) as fluoride source (Table 3).
Table 3. Fluorination of solution-phase iodonium salt 20(Br).
Scheme 13. Fluorination of solid-supported iodonium salt 16(Br).
The high number of equivalents used for the cold fluorin-
ation reactions means that conditions are far from emulat-
ing those used for the “hot” fluorination with [18F]fluoride.
Investigations of the solid-supported precursor under radio-
fluorination conditions will be conducted in the future, be-
cause this is the application in which such a precursor
would be of greatest value.
Entry
Solvent
Conc. of 20(Br)
TMAF
[equiv.]
Yield[a]
[%]
[molcm–3]
Conclusions
1
2
3
4
5
6
7
MeCN
DMF
DMSO
MeCN
MeCN
MeCN
MeCN
5
5
5
2.5
1.25
5
1
1
1
1
1
2
4
13
7
8
5
5
20
22
A number of synthetically relevant iodonium salt precur-
sors have been synthesised on a solid support. The utility
of these compounds has been shown for the production of
19F-bearing aromatics as well as for the production of [18F]-
fluorobenzene. The successful radiofluorination represents
a proof of concept for the production of valuable 18F-lab-
elled synthons/prosthetic groups by this method. Further-
more, the importance of the resin functionality has been
5
[a] Yields determined by GC analysis.
Optimal conditions were found by GC analysis of the demonstrated. Limitations of aminomethyl-functionalised
reaction mixture subsequent to the thermal breakdown of resin for amide linkage were discovered. The problem was
the iodonium salt. Of the solvents tested, acetonitrile pro- addressed by the use of a resin with improved amine avail-
vided the best result, giving a 13% yield (Table 3, Entry 1). ability for a much improved loading through amide bond
When the reaction was performed in DMF or DMSO, the formation.
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Solid-Supported Iodonium Salts for Fluorinations
Procedure for the Formation of Diacetate 24: A solution of O-
benzyl-4-iodophenol (23, 5.0 mmol, 1.0 equiv.) and Selectfluor®
(25.0 mmol, 5.0 equiv.) in MeCN/AcOH (3:1, 200 mL) was stirred
for 5 h at room temperature. The acetonitrile was evaporated in
vacuo, and water was added to the residue before extraction with
CH2Cl2. The combined organic layers were washed with water and
dried with MgSO4. Removal of the solvent gave the crude product
as a yellow solid. Trituration with hexane gave the pure product as
Production of a solid-supported precursor for O-benzyl-
4-fluorophenol was achieved by an alternative approach to
those previously reported. The method used provides a
promising alternative strategy to those previously reported
for the synthesis of polymer-supported iodonium salts.
Fluorination of the precursor was successful, providing ac-
ceptable yields of the fluorinated product. Adaption of this
procedure for the incorporation of [18F]fluoride could pro-
vide a suitable method for the production of valuable PET
synthons.
1
a colourless solid (2.13 g, 95%), m.p. 61 °C. H NMR (400 MHz,
CDCl3): δ = 8.04–7.97 (m, 2 H), 7.45–7.32 (m, 5 H), 7.07–7.03 (m,
2 H), 5.11 (s, 2 H), 2.00 (s, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 176.5 (2 C), 161.4, 137.3 (2 C), 135.8, 128.9 (2 C),
128.6, 127.6 (2 C), 117.5 (2 C), 111.8, 70.5, 20.6 ppm. Spectral data
are in agreement with the literature.[18]
Experimental Section
Procedure for the Formation of 4-Benzyloxy Koser Reagent 25: Di-
acetate 24 (4.44 mmol, 1.0 equiv.) was dissolved in MeCN (50 mL)
and cooled to 0 °C before the addition of pTsOH·H2O (4.44 mmol,
1.0 equiv.). The product began to precipitate immediately. After
10 min, Et2O was added to the slurry and the product was filtered
off and washed with Et2O. The pure product was dried under a
flow of nitrogen to give the product as a pale yellow solid (2.09 g,
95%). The compound was stored under nitrogen at –20 °C. If the
compound was subjected to high vacuum it decomposed to a
brown solid. 1H NMR (400 MHz, CDCl3): δ = 8.27–8.23 (m, 2 H),
7.67–7.63 (m, 2 H), 7.44–7.39 (m, 2 H), 7.38–7.27 (m, 3 H), 7.24–
7.16 (m, 4 H), 5.2 (s, 2 H), 2.32 (s, 4 H) ppm. 13C NMR (100 MHz,
MeOD): δ = 164.7, 143.3, 141.8, 140.3, 137.4, 129.8 (2 C), 129.7
(2 C), 129.4, 128.8 (2 C), 126.9 (2 C), 119.3 (2 C), 71.6, 21.3 ppm.
Procedure for the Functionalisation of Tris(aminoethyl)amine Resin:
Under argon, tris(2-aminoethyl)amine-polymer resin (0.25 g,
0.88 mmol, 0.75 equiv.) in freshly distilled CH2Cl2 (7 mL) was
treated with 6-(4-iodophenoxy)hexanoic acid (0.39 g, 1.17 mmol,
1 equiv.), diisopropylethylamine (0.34 g, 2.63 mmol, 2.25 equiv.)
and diphenylphosphoryl chloride (0.31 g, 1.17 mmol, 1 equiv.). The
reaction mixture was kept under agitation for 43 h. It was then
filtered and washed thoroughly with CH2Cl2 (100 mL) and water
in methanol (20%, 100 mL). The resin was then dried under vac-
uum to give a beige, sand-like product (0.47 g, 1.73 mmolg–1, 85–
100%). Found C 68.12%, H 6.34%, N 3.57%, I 13.6%.
Procedure for the Oxidation of 11: 6-(4-Iodophenoxy)hexanoic
acid–tris(2-aminoethyl)amine-polymer resin amide (0.25 g,
0.52 mmol) in CH2Cl2 (7 mL) was treated with peracetic acid (48
wt.-%, 2 mL). The reaction mixture was agitated at room tempera-
ture for 18 h, after which it was filtered and washed with CH2Cl2.
The resin was then dried under vacuum to give a sand-like solid
(0.284 g, 1.16 mmolg–1, 55%). Found C 66.34%, H 6.62%, N
3.67%, I 9.53%.
General Procedure for the Formation of Diaryliodonium Salts from
4-Benzyloxy Koser Reagent 25: Koser reagent 25 (0.401 mmol,
1.0 equiv.) was dissolved in CH2Cl2 (3 mL) and cooled to 0 °C be-
fore addition of the electron-rich arene (anisole or 26, 0.405 mmol,
1.01 equiv.). 2,2,2-Trifluoroethanol (TFE) (0.3 mL) was added to
the solution and the reaction mixture was allowed to warm to room
temperature over 2 h. The solvents were removed in vacuo and the
product was triturated with Et2O. Filtration gives the iodonium
salt, which may be recrystallised from CH2Cl2 and Et2O if neces-
sary.
Procedure for the Formation of Resin-Bound Iodonium Salt
12(TFA): 6-(4-Iodophenoxy)hexanoic acid–aminomethyl polysty-
rene resin amide (0.15 g, 0.174 mmol, 1 equiv.) in CH2Cl2 (5 mL)
was cooled in a acetonitrile and dry ice bath to –41 °C and treated
with tri-n-butylphenyltin (128 mg, 0.348 mmol, 2 equiv.). The reac-
tion mixture was agitated, trifluoroacetic acid (79 mg, 0.696 mmol,
4 equiv.) was added, and the mixture was allowed to warm to room
temperature over 2 h. The resin was then washed with CH2Cl2 to
give a beige, sand-like solid (0.244 g, 1.16 mmolg–1, 100%). Found
C 62.55%, H 6.16%, N 3.29%, I 9.97%, F 5.99%.
General Procedure for n.c.a. [18F]Fluoride Incorporation with Resin-
Bound Iodonium Salt 12(TFA): [18F]Fluoride, delivered from the
cyclotron as an aqueous solution, was trapped on a pretreated
QMA cartridge to remove the 18O-enriched water. The [18F]fluoride
was eluted with a Kryptofix 2.2.2 carbonate solution [0.6 mL,
MeCN (0.3 mL), H2O (0.3 mL), Kr-2.2.2 (22.8 mg), K2CO3
(8.4 mg)] into a 5 mL V-shaped vial. The mixture was dried under
a flow of nitrogen and reduced pressure at 120 °C for 440 seconds.
The residue was azeotropically dried twice with the addition of
acetonitrile (2ϫ 1 mL). Distillation was achieved by heating at
120 °C under a flow of nitrogen for 440 seconds. The dried [18F]
KF·Kr222·K2CO3 salt was redissolved in acetonitrile and transfer-
red to a sealed vial containing the supported iodonium precursor
12(TFA) [0.103 g, 0.12 mmol (1.16 mmolg–1), 1.0 equiv.] and
TEMPO (6.56 mg, 0.042 mmol, 0.35 equiv.). The reaction mixture
was then heated at 90 °C for 15 min on a hot plate. The product
solution was removed from the support by filtration. Analysis by
radio-TLC showed a RCC of 3%. Product identity was confirmed
by radio-HPLC.
General Procedure for the Fluorination of Solution-Phase Iodonium
Salt Precursors: In a glovebox, tetramethylammonium fluoride
(TMAF) was added to a NMR tube, after which the tube was se-
aled with a rubber septum and removed from the glovebox. Iodon-
ium salt precursor was dissolved in the appropriate dry deuterated
solvent and added to the TMAF by injecting the solution through
the septum that was equipped with . The reaction mixture was
heated in a silicon oil bath at 90 °C for 1 h before being removed
and allowed to cool to room temperature. The reaction was moni-
tored by 19F NMR and GC.
General Procedure for the Fluorination of Solid-Supported Iodonium
Salt Precursors: In a glovebox, tetramethylammonium fluoride
(TMAF) was added to a reaction vessel containing supported
iodonium salt 16(Br), after which the tube was sealed with a rubber
septum and removed from the glovebox. The appropriate dry deu-
terated solvent was added to the TMAF and precursor by injection
through the septum that was equipped with a balloon filled with
argon. The reaction mixture was heated in a silicon oil bath at
90 °C for 1 h before being removed and allowed to cool to room
temperature. The reaction was monitored by 19F NMR and GC.
Supporting Information (see footnote on the first page of this arti-
cle): All synthetic methods including spectroscopic data and analyt-
ical data are included in the supporting information.
Eur. J. Org. Chem. 2015, 6909–6916
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6915

R. Edwards, W. de Vries, A. D. Westwell, S. Daniels, T. Wirth
FULL PAPER
Angew. Chem. Int. Ed. 2012, 51, 11426–11437; Angew. Chem.
2012, 124, 11590.
Acknowledgments
[7] V. W. Pike, F. I. Aigbirhio, J. Chem. Soc., Chem. Commun.
1995, 2215–2216.
[8] J.-H. Chun, S. Lu, Y.-S. Lee, V. W. Pike, J. Org. Chem. 2010,
75, 3332–3338.
[9] a) B. Wang, J. W. Graskemper, L. Qin, S. G. DiMagno, Angew.
Chem. Int. Ed. 2010, 49, 4079–4083; Angew. Chem. 2010, 122,
4173; b) J. W. Graskemper, B. Wang, L. Qin, K. D. Neumann,
S. G. DiMagno, Org. Lett. 2011, 13, 3158–3161.
[10] F. Brady, S. K. Luthra, E. G. Robins, WO2003002489 A2,
2004.
Support from the Schools of Chemistry, Pharmacy and Medicine
of Cardiff University and from the Erasmus Exchange Program
(grant to W. d. V.) is gratefully acknowledged. The authors thank
the Engineering and Physical Sciences Research Council (EPSRC),
National Mass Spectrometry Facility, Swansea, for mass spectro-
metric data.
[11] H. J. Wadsworth, D. A. Widdowson, E. Wilson, M. A. Carroll,
WO2005061415 A1, 2004.
[12] T. Poethko, M. Schottelius, G. Thumshim, U. Hersel, M. Herz,
G. Henriksen, H. Kessler, M. Schwaiger, H. J. Wester, J. Nucl.
Med. 2004, 45, 892–902.
[13] a) U. Muehlhausen, J. Ermert, H. H. Coenen, J. Labelled
Compd. Radiopharm. 2009, 52, 13–22; b) T. Stoll, J. Ermert, S.
Oya, H. F. Kung, H. H. Coenen, J. Labelled Compd. Ra-
diopharm. 2004, 47, 443–455.
[14] R. Richarz, P. Krapf, F. Zarrad, E. A. Urusova, B. Neumaier,
B. D. Zlatopolskiy, Org. Biomol. Chem. 2014, 12, 8094–8099.
[15] E. A. Merritt, B. Olofsson, Angew. Chem. Int. Ed. 2009, 48,
9052–9070; Angew. Chem. 2009, 121, 9214.
[16] R. Edwards, A. D. Westwell, S. Daniels, T. Wirth, Eur. J. Org.
Chem. 2015, 625–630.
[17] T. L. Ross, J. Ermert, H. H. Coenen, Molecules 2011, 16, 7621–
7626.
[18] T. L. Ross, J. Ermert, C. Hocke, H. H. Coenen, J. Am. Chem.
Soc. 2007, 129, 8018–8025.
[1]
F. Z. Dörwald, Organic Synthesis on Solid Phase, Wiley-VCH,
Weinheim, Germany, 2000.
R. B. Merrifield, J. Am. Chem. Soc. 1963, 85, 2149–2154.
a) S. V. Ley, I. R. Baxendale, R. N. Bream, P. S. Jackson, A. G.
Leach, D. A. Longbottom, M. Nesi, J. S. Scott, R. I. Storer,
S. J. Taylor, J. Chem. Soc. Perkin Trans. 1 2000, 3815–4195; b)
S. Boldon, I. Stenhagen, J. Moore, S. Luthra, V. Gouverneur,
Synthesis 2011, 3929–3953; c) F. Guillier, D. Orain, M. Bradley,
Chem. Rev. 2000, 100, 2091–2157; d) A. Kirschning, H.
Monenschein, R. Wittenberg, Angew. Chem. Int. Ed. 2001, 40,
650–679; Angew. Chem. 2001, 113, 670.
[2]
[3]
[4] a) L. J. Brown, D. R. Bouvet, S. Champion, A. M. Gibson, Y.
Hu, A. Jackson, I. Khan, N. Ma, N. Millot, H. Wadsworth,
R. C. D. Brown, Angew. Chem. Int. Ed. 2007, 46, 941–944; An-
gew. Chem. 2007, 119, 959; b) S. K. Luthra, F. Brady, H. J.
Wadsworth, WO2003002489 A2, 2003.
[5] P. M. Matthews, E. A. Rabiner, J. Passchier, R. N. Gunn, Br. J.
Clin. Pharmacol. 2012, 73, 175–186.
[6] a) M. S. Yusubov, Y. Svitich, M. S. Larkina, V. V. Zhdankin,
ARKIVOC 2013, i, 364–395; b) M. Tredwell, V. Gouverneur,
Received: July 27, 2015
Published Online: October 1, 2015
6916
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Eur. J. Org. Chem. 2015, 6909–6916