Chemoselective Radiosyntheses of Electron-Rich [18F]Fluoroarenes from Aryl(2,4,6-trimethoxyphenyl)iodonium Tosylates

Article abstract of DOI:10.1021/acs.joc.9b00019

Hypervalent diaryliodonium salts have been used to produce various [¹⁸F]fluoroarenes. The iodonium salt approach as a labeling precursor has been established to equally afford complex ¹⁸F-fluorinated molecules. Because of the inheren

Full text of DOI:10.1021/acs.joc.9b00019

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Note
18
Chemoselective radiosyntheses of electron-rich [F]fluoroarenes
from aryl(2,4,6-trimethoxyphenyl)iodonium tosylates
Young-Do Kwon, Jeongmin Son, and Joong-Hyun Chun
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00019 • Publication Date (Web): 19 Feb 2019
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Chemoselective radiosyntheses of electron-rich [18F]fluoroarenes
from aryl(2,4,6-trimethoxyphenyl)iodonium tosylates
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Young-Do Kwon,† Jeongmin Son,‡ and Joong-Hyun Chun*,†
† Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul 03722,
Republic of Korea.
‡ Department of Nuclear Medicine, Severance Hospital, Yonsei University Health System,
Seoul 03722, Republic of Korea.
Abstract
Hypervalent diaryliodonium salts have been used to produce various [18F]fluoroarenes. The
iodonium salt approach as a labeling precursor has been established to equally afford complex
18F-fluorinated molecules. Because of the inherent two-aryl ring system connected to a central
iodine atom, safeguarding the chemoselectivity during radiofluorination using diaryliodonium
salts is important. Herein, we introduce a superior chemoselective radiosynthesis of
[18F]fluoroarenes using an aryl(2,4,6-trimethoxyphenyl)iodonium tosylate as a precursor for
18F-incorporation, even on electron-rich aryl rings.
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Fluoroaromatic compounds are an important class of organic compounds because of
their unique physiochemical and biological properties.1 Extensive effort has been devoted to
developing a reliable approach to constructing aromatic C–F bonds to exploit the inherently
strong C–F bond in fluoroaromatic systems. In radiochemistry associated with fluorine-18 for
positron emission tomography (PET) imaging modality, the aromatic C–18F bond is known to
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offer various advantages over other aliphatic F-radiotracers. One such advantage is the
metabolic stability of aromatic 18F-radiotracers, which ameliorates radiodefluorination under
physiological conditions during image acquisition.2 Widely employed methods for aromatic
radiofluorination include the use of various classes of hypervalent compounds,3 arylborons,4
arylstannanes,5 and N-arylsydnones.6 Among them, diaryliodonium salts and iodonium ylides
offer catalyst-free radiofluorination, which relieves the downstream quality-control burden of
PET tracers produced for human use.
Recently, different research groups have used diaryliodonium salts to exploit the
unique aryl-group transfer ability. This approach has encouraged synthetic chemists to focus
on developing an efficient method to chemoselectively transfer aryl groups onto the desired
chemical skeleton.7 In fluorine-18 radiochemistry, the use of diaryliodonium salts is now a
well-established approach to the single-step introduction of a [18F]fluoride ion onto electron-
rich aryl rings and complex radiopharmaceuticals with an aromatic chemical entity, which is
difficult to achieve through conventional nucleophilic aromatic fluorination.3 Simple aryl rings
can be radiofluorinated via symmetrical iodonium salts;8 however, the synthesis of symmetric
iodonium salts can be challenging, particularly when the desired ring has a complex structure.
Consequently, unsymmetrical diaryliodonium salts are widely preferred for radiotracers,
although awareness of chemoselectivity in radiofluorination is important because of the
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competition between two aryl rings for the incoming F-nucleophile. The radiofluorination
with a diaryliodonium salt can produce two 18F-fluorinated aryl rings in a non-chemoselective
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manner when the iodonium salt bears two electronically similar aryl rings. One method to
overcome this limitation is to use an electron-rich aryl ring to direct the 18F-nucleophile onto
the desired aromatic moiety; 4-anisyl-, 2-anisyl-, 2-thienyl-, 4-tolyl-, and, less frequently,
phenyl-rings have been used as spectator aryl rings.3a,9–11 DiMagno et al. demonstrated that
cyclophane efficiently modulates the direction of nucleophile incorporation.12 The synthesis of
this class of iodonium salts for routine use without adversely affecting their excellent
chemoselectivity is challenging, particularly when dealing with complex substrates.
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Scheme 1. 18F-Directing Aryl Rings Used for Diaryliodonium Salts
OMe
S
Previous
approaches
Me
Ar' =
OMe
18F
18F
Ar'-
>
Ar-
18F-
moderate to poor chemoselectivity
X
Ar
I
OMe
Ar'
The present
study
18F
18F
Ar'-
Ar' =
>>>
X = OTs, OTf, BF4, etc.
Ar-
diaryliodonium salt
MeO
OMe
convenient preparation of labeling precursor
highly chemoselective radiofluorination without catalyst
applicable to produce electron-rich [18F]fluoroarenes
Recently, 1,3,5-trimethoxybenzene (TMB) has been used as counterpart aryl rings in
iodonium salts to selectively transfer the aryl group to the desired chemical entity in an organic
synthesis, thereby enabling chemoselective arylation with nucleophiles containing C, N, O,
18
and/or S atoms.13 Because the rapid and reliable incorporation of F (t1/2 = 109.8 min) is
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required to produce F-labeled tracers, chemoselective radiofluorination is ideal to produce
clinical PET tracers for imaging purposes. In addition, facile separation of the radioactive
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byproduct is important to achieve the radiochemical purity required for PET
radiopharmaceuticals. Such facile separation might be achievable with the aryl(2,4,6-
trimethoxyphenyl)iodonium salt as a 18F-directing aryl partner. Herein, we show that,
compared with other spectator aryl rings, the 2,4,6-trimethoxyphenyl (TMP) group in a
diaryliodonium tosylate confers excellent chemoselectivity to produce electron-rich aryl
fluorides as well as improved radiochemical yield (RCY) in radiofluorinations (Scheme 1).
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Aryl(TMP)iodonium tosylates were prepared using the modified meta-
chloroperbenzoic acid (mCPBA)-mediated single-pot method established by Stuart14 and
Olofsson.15 Using symmetric TMB as the electron-rich aryl ring partner advantageously
prevents the formation of isomeric byproducts during the iodonium salt synthesis. Thus,
unsymmetrical iodonium tosylates with a TMP group as a spectator ring were obtained in 10–
90% yields and were used for subsequent radiofluorination.
Initially, we selected mesityl(TMP)iodonium tosylate (1) to gain insight into the
radiofluorination medium required to produce [18F]fluoroarenes from aryl(TMP)iodonium
tosylates. Common aprotic organic solvents–acetonitrile, N-methyl-2-pyrrolidone, 1,4-dioxane,
dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), and N,N-dimethylacetamide
(DMA)–were screened for their suitability. Different phase-transfer agents (PTAs) were also
compared to identify the ideal PTA solution for radiofluorination. The initial radiofluorination
of 1 under different reaction conditions revealed that K 2.2.2 was the best PTA for our purposes
(see Supporting Information for details); however, we subsequently found that this condition
was not generally applicable to all substrates.
Next, we examined the selectivity between electron-rich aryl rings during
radiofluorination. For comparison, we selected five electron-rich aryl rings to assess the ring
selectivity: 4-anisyl, 2-anisyl, 2-thienyl, 4-tolyl, and mesityl, the last of which is employed in
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Cu-catalyzed aromatic radiofluorination. The electron-rich aryl rings 1–4 were selectively
fluorinated against the 2,4,6-TMP ring, demonstrating excellent chemoselectivity, even among
the electron-rich aromatic systems (Table 1). Most commonly formed 4-[18F]fluoroanisole was
obtained at a 29% RCY (Entry 2, Table 1). Other electron-rich aryl rings were also efficiently
radiofluorinated with up to 89% RCY (Entries 1 and 3–5, Table 1). Oddly, [18F]fluorothiophene
was not observed in the radio-HPLC analysis of 5 (Entry 5, Table 1). The characterization of
the resulting [18F]fluorothiophene is known to be problematic when a thienyl iodonium salt is
used as a radiolabeling precursor,10 presumably because this system is too electron-dense for
the incoming [18F]fluoride ion to join either ring. Strikingly, the peak for [18F]F-TMB was
barely noticeable in the radio-HPLC chromatogram, indicating that this moiety is the ideal aryl
ring partner for controlling the chemoselectivity of 18F-incorporation into the electron-rich aryl
system. Unlike the chemically unstable [18F]fluorothiophene and somewhat volatile
[18F]fluoroanisole byproducts, the [18F]F-TMB coproduct in the fluorination mixture could be
readily traced to assess the fluorination integrity in PET radiotracer production.
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Table 1. Comparison of Fluorine-18 Incorporation among Electron-rich Aryl Ringsa,b
-OTs
18F-
OMe
OMe
I
18F
PTA/base
Ar
18F
Ar
+
Solvent
120-160 oC, 10 min
MeO
OMe
MeO
OMe
18
18
18F
1 5
-
1a 5a
F] -[ F]
[
TMB
Substratec
#; Ar
RCY (%)e
entry
conditiond
18F-Ar
89 ± 4
29 ± 9f
39 ± 6
36 ± 1
0
18F-TMB
N.O.g
<1
1
2
3
4
5
1; Mesityl
A
B
C
C
D
2; 4-MeOC6H4
3; 2-MeOC6H4
4; 4-MeC6H4
5; 2-Thienyl
N.O.
N.O.
N.O.
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a K 2.2.2. (3.7 mg, 9.7 μmol), K2CO3 (0.7 mg, 4.8 μmol); or TBAHCO3 (10 μL, 13.2 μmol;
40% aq solution). b Solvent (2 mL). c Substrate (3 mM). d A: K 2.2.2./K2CO3/DMSO/120 oC;
B: TBAHCO3/DMSO/160 oC; C: K 2.2.2./K2CO3/DMA/160 oC; D: K 2.2.2./K2CO3/DMA/160
oC. e Average ± SD (n = 2). f n = 4. g N.O. = not observed.
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After initially comparing the chemoselectivity, we radiofluorinated a series of
phenyl(aryl)iodonium tosylates with various electron-rich aryl groups to determine whether the
RCY could be improved in addition to the demonstrated selectivity. As a model compound to
produce [18F]fluorobenzene, phenyl(TMP)iodonium tosylate (11) was prepared along with
other phenyl(aryl)iodonium tosylates (aryl = 2-anisyl (6), 4-anisyl (7), 4-tolyl (8), mesityl (9),
and 2-thienyl (10)); these iodonium tosylates were radiofluorinated under the same reaction
conditions (in DMA at 140 °C for 10 min) to enable a direct comparison (Table 2). Notably,
11 gave the highest RCY with the expected excellent chemoselectivity (Entry 6, Table 2). From
these controlled experiments, we found that [18F]fluorobenzene was exclusively produced in a
selective manner over the other electron-rich aryl rings. This chemoselectivity is a substantial
improvement over that afforded by anisole and thiophene, which are often used as aryl partners
with diaryliodonium salts.
Table 2. Radiofluorination of Phenyl(aryl)iodonium Tosylates to Produce
[18F]Fluorobenzene with Different Electron-rich Aryl Ringsa
-OTs
18F
I
18F-
K 2.2.2./K2CO3/
Ar
18F
Ar
+
DMA
140 oC, 10 min
18
18
6 11
-
6a 11a
F] -[ F]
[
substrate
(#; Ar)
RCY (%)b
Selectivity for
18F-Phc
entry
1
18F-Ph
7 ± 2
18F-Ar
<1
6; 2-MeOC6H4
>7
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2
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7; 4-MeOC6H4
8; 4-MeC6H4
9; Mesityl
25 ± 0
20 ± 8
8 ± 0
<1
6 ± 3
29 ± 2
<1
>25
3.3
0.3
>6
10; 2-Thienyl
11; TMP
6 ± 3
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36 ± 7
N.O.d
>36
a Substrate (3 mM), K 2.2.2. (3.7 mg, 9.7 μmol), K2CO3 (0.7 mg, 4.8 μmol), DMA (2 mL). b
Average ± SD (n = 2). c Selectivity: 18F-Ph/18F-Ar. d N.O.= not observed.
In addition to the advantageous chemoselectivity of aryl(TMP)iodonium tosylate,
aryl(TMP)iodonium and aryl(4-anisyl)iodonium tosylates were compared to investigate
whether improved or comparable RCYs were attainable (Table 3). The selected iodonium
tosylates (TMP- and 4-anisyl-iodonium tosylates) were radiofluorinated under the same
conditions (solvent, temperature, and PTA/base) to directly compare their efficiency. In the
comparison of TMP-iodonium tosylate 1 and 4-anisyl-iodonium tosylate 12, 4-
[18F]fluoromesitylene was produced at a higher RCY when the TMP-iodonium tosylate was
radiofluorinated. 2-[18F]Fluoroanisole was also produced at a higher RCY with 3 than with the
4-anisyl-iodonium tosylate (13). Overall, the aryl(TMP)iodonium tosylates were found to
provide higher RCYs than the 4-anisyl-iodonium tosylates. Note that 4-[18F]fluoroanisole was
detected using radio-HPLC, whereas little or no [18F]F-TMB was observed in the reaction
mixture (see the radio-HPLC chromatogram in Supporting Information). In our study, all of
the radioactive products formed by radiofluorination separated well, which might improve the
implementation of this methodology for the production of PET radiotracers for clinical study.
Table 3. Comparison between Aryl(TMP)iodonium and Aryl(4-anisyl)iodonium
Tosylates for the Radiosynthesis of [18F]Fluoroarenesa
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18F-/
-OTs
K 2.2.2./K2CO3
Ar
I
18F
18F
Ar'
Ar
+
6
7
8
9
DMA
160 oC, 10 min
Ar'
Ar'
=
TMP
or 4-anisyl
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Ar’ = 4-anisyl
RCY (%)b
Ar’ = TMP
entry
Ar
RCY (%)b
#
#
18F-Ar
25 ± 2
9 ± 2
18F-anisole
<1
18F-Ar
85 ± 7
39 ± 6
48 ± 5
36 ± 1
34 ± 17
68 ± 7
42 ± 16
35 ± 9
18F-TMB
N.O.c
N.O.
1
2
3
4
5
6
7
8
Mesityl
12
13
1
3
2-MeOC6H4
4 ± 1
N.O.
6 ± 2
1.3 ± 0.8
<1
2-MeOCH2C6H4
4-MeC6H4
14
16
17
19
21
23
39 ± 21
31 ± 9
26 ± 9
53 ± 13
22 ± 5
20 ± 2
15
4
N.O.
N.O.
3-MeC6H4
18
20
22
24
N.O.
2-MeC6H4
N.O.
4-EtOCO-C6H4
3-EtOCO-C6H4
<1
N.O.
<1
N.O.
a Substrate (3 mM), K 2.2.2. (3.7 mg, 9.7 μmol), K2CO3 (0.7 mg, 4.8 μmol), DMA (2 mL). b
Average ± SD (n = 2). c N.O.= not observed.
Next, we extended the applicability of the TMP-aryl iodonium tosylates to the
synthesis of more functionalized [18F]fluoroarenes (Scheme 2). As demonstrated in the
radiofluorination of 1, one reaction condition could not be accommodated when different
substrates were used in radiofluorination. An investigation using TMP-iodonium tosylates
revealed that meta-[18F]fluoroarenes were produced with excellent chemoselectivity in
comparison with the chemoselectivity16 previous reported for anisyl- and thienyl-aryl rings.
The electron-donating methoxy (25) and ethoxy (26) groups were well tolerated to give 3-
[18F]fluoroanisole and 3-[18F]fluorophenetole at 21% and 14% RCY, respectively ([18F]25a
and [18F]26a, Scheme 2). TMP-iodonium tosylates such as CN– (27) or NO2– (28) with an
electron-withdrawing group at the meta-position produced the corresponding [18F]fluoroarenes
at 36% and 33% RCY, respectively ([18F]27a and [18F]28a, Scheme 2). Meta-[18F]fluorobenzyl
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chloride as a potential [18F]fluoro-alkylating agent was also produced in a single step with a
useful RCY ([18F]29a, Scheme 2) (see ref. 18f for para-[18F]fluorobenzyl chloride from
aryl(TMP)iodonium tosylate, which was produced in a microfluidic system). The electron-rich
ortho- or para-substituted [18F]fluoroarenes were obtained at 25–54% RCYs ([18F]30a–32a,
Scheme 2). Notably, little [18F]F-TMB was observed in any of the resultant radiofluorination
mixtures except for 32. [18F]Fluoroarenes with para-electron-withdrawing substituents were
obtained at useful RCYs ([18F]33a and [18F]34a, Scheme 2). Azide-functionalized click-
labeling synthons were produced in a single step at 16% and 35% RCY ([18F]35a and [18F]36a,
Scheme 2, respectively). Halogen-functionalized homoaromatic and heteroaromatic
[18F]fluoroarenes were produced at 23% and 31% RCY ([18F]37a and [18F]38a, Scheme 2,
respectively) as well as [18F]fluorobenzyl ether ([18F]39a, 24% RCY).
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Scheme 2. Radiosynthesis of Functionalized [18F]Fluoroarenes Using Various
Aryl(TMP)iodonium Tosylatesa,b
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18F-
PTA/base
-OTs
TMP
Ar
I
18F
+
e,f
d,i
18F
TMB
Ar
solvent
120-160 oC, 10 min
18
18
25a 39a
-[ F]
[
F]
not observed
8
25 39
-
9
18F
18F
O2N
18F
18F
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MeO
EtO
NC
18
e,f
18
18
e,g
18
e,f
25a
[
F]
, 21 3%
27a
28a
26a
[
F]
, 36 10%
(n = 6)
[
[
F]
F]
, 33 2%
(n = 4)
[
F]
, 14 2%
18F
18F
OEt
18F
18F
Cl
18
d,h
18
d,i
18
18
c,d,j
29a
30a
31a
F] , 25 3%
32a
[
F]
, 25 13%
[
F]
, 49 7%
[
, 54 4%
(n = 4)
18F
18F
18F
18F
Me
MeO
N3
N3
F]
O
O
18
d,i
18
d,i
18
c,e,j
18
d,k
36a
[
F]
, 35 18%
33a
34a
35a
, 16 1%
[
F]
, 32 5%
[
F]
, 51 7%
(n = 6)
[
18F
18F
18F
Br
N
O
Br
18
e,f
18
d,j
18
d,i
37a
38a,
31 4%
[
F]
, 23 6%
[
F]
39a,
24 13%
[
F]
a K 2.2.2. (3.7 mg, 9.7 μmol)/K2CO3 (0.7 mg, 4.8 μmol), solvent (2 mL), 10 min. b RCYs in
parenthesis are average ± SD (n = 2), otherwise specified. c TBAHCO3 (10 μL, 13.2 μmol; 40%
aq solution). d Substrate (3 mM). e Substrate (7.5 mM). f DMSO, 140 oC. g DMSO, 160 oC. h
DMA, 140 oC. i DMA, 160 oC. j DMSO, 120 oC. k DMA, 120 oC.
Lastly, the radiosynthesis of N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB;
[18F]40a)17a was demonstrated from a TMP-iodonium precursor, which was previously
established in three synthetic steps (Scheme 3). This single-step radiosynthesis17b,c of an 18F-
fluorinated labeling agent using aryl(TMP)iodonium tosylate could facilitate the subsequent
production of protein- and peptide-labeling agents.
Scheme 3. Radiofluorination to Produce the Complex Labeling Building Block [18F]SFBa
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OHC
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previously established
protocol
N
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9
3 steps
-OTs
18F
18F-
OMe
O
I
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K 2.2.2./K2CO3
18F
O
O
TMB
N
O
DMA
140 oC, 10 min
N
MeO
OMe
O
O
O
18
40
40a
[
F]
O
Not observed
single-step radiofluorination
20  3% b
a Substrate (3 mM), K 2.2.2. (3.7 mg, 9.7 μmol), K2CO3 (0.7 mg, 4.8 μmol), DMA (2 mL). b
Average ± SD (n = 3).
In conclusion, the highly chemoselective radiosynthesis of electron-rich
[18F]fluoroarenes was realized using aryl(TMP)iodonium tosylates as radiolabeling precursors.
Various unsymmetrical TMP-iodonium tosylates were prepared via single-pot mCPBA-
mediated synthesis to afford 2,4,6-trimethoxyphenyl as a spectator aryl group. The remarkable
chemoselectivity for directing the [18F]fluoride ion to electron-rich aryl rings implies that
aryl(TMP)iodonium tosylates can provide efficient and reliable radiosynthetic routes to
potential PET radiopharmaceuticals, particularly when iodonium salts are used as labeling
precursors.
EXPERIMENTAL SECTION
General Information. Reaction progress was monitored by TLC, and TLC spots were
visualized under 254 nm UV light. Crude products were purified on a column chromatography
using silica gel (0.060–0.020 mm, 60 A). Melting points were recorded using 1101D Mel-
Temp® Digital Melting Point Apparatus (Cole-Parmer Ltd, Stone, Staffordshire, UK) and
uncorrected. H and C{1H} NMR spectra were recorded on a Bruker Avance III HD 300
1
13
spectrometer (300 MHz), installed at Yonsei Center for Research Facilities (YCRF at Yonsei
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University, Seoul, Republic of Korea). The chemical shifts for 1H and 13C{1H} NMR spectra,
were reported in δ units (ppm) relative to the residual protonated solvent resonance, and the
coupling constants (J) were given in Hz. FT-IR spectra were recorded on Vertex 70 (Bruker,
Billerica, MA, USA), and only major peaks were reported. Electrospray ionization (ESI) high
resolution mass spectrometry (HRMS) using a time-of-flight mass spectrometer was performed
at Korea Basic Science Institute (KBSI), Ochang, Republic of Korea. The Ultimate 3000
spectra HPLC system (Thermo Scientific, Waltham, MA, USA) comprised a reverse phase
column (Luna®, 5 μm, C18(2), 100 Å, 250 × 4.6 mm i.d.; Phenomenex, Torrance, CA, USA)
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and a radioactivity detector (PMT; Flow-count; Bioscan, Washington, DC, USA).
Radioactivity was determined with a CRC®-712M dose calibrator (Capintec, Ramsey, NJ,
USA).
Materials. An aluminum-backed plate with silica gel 60 F254 for thin-layer
chromatography (TLC) analysis was purchased from Macherey-Nagel GmbH & Co. KG
(Düren, North Rhine-Westphalia, Germany). Sep-Pak® Light QMA cartridge (carbonate form,
part no. 186004540) was purchased from Waters (Milford, MA, USA). 2-Fluorophenetole, 3-
fluorophenetole, 3’-fluoroacetophenone, 3-iodobenzyl chloride and 1-(benzyloxy)-4-
fluorobenzene were purchased from Combi-Blocks (San Diego, CA, USA). N-Succinimidyl 4-
fluorobenzoate and 40% aq tetrabutylammonium hydrogen carbonate solution were purchased
from FutureChem (Seoul, Republic of Korea). Oxygen-18 enriched water was acquired from
Rotem (Beer Sheva, Israel). Meta-chloroperbenzoic acid (mCPBA) was obtained from Sigma-
Aldrich (St. Louis, MO, USA) and used without further treatment. mCPBA used in this study
has 70–77% active peroxy content and is stabilized with H2O and meta-chlorobenzoic acid. All
other chemicals were purchased from Sigma-Aldrich, ACROS organics (Waltham, MA, USA),
and Alfa Aesar (Ward Hill, MA, USA) and used as received.
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The following iodo- or fluoro-arenes were prepared as described previously: 2-
iodophenetole,18a 3-iodophenetole,18a 1-azido-4-iodobenzene,18b 1-azido-4-fluorobenzene,18b
4-iodobenzyl azide,18b 4-fluorobenzyl azide,18b 1-methoxymethyl-2-iodobenzene,18c 1-
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methoxymethyl-2-fluorobenzene,18d
2-iodo-1,3,5-trimethoxybenzene,18e
2-fluoro-1,3,5-
trimethoxybenzene,18f and N-succinimidyl 4-iodobenzoate.18g 2-(Diacetoxyiodo)thiophene
was prepared according to the literature method.18h The following diaryliodonium tosylates
were synthesized according to the known procedures: 2-methoxyphenyl(phenyl)iodonium
tosylate
(6),18i
4-methoxyphenyl(phenyl)iodonium
tosylate
(7),18i
4-
methylphenyl(phenyl)iodonium tosylate (8),18j 2,4,6-trimethylphenyl(phenyl)iodonium
tosylate (9),18i 2-thienyl(phenyl)iodonium tosylate (10),18i 2,4,6-trimethylphenyl(4-
methoxyphenyl)iodonium tosylate (12),18i 4-methylphenyl(4-methoxyphenyl)iodonium
tosylate (16),18k 3-methylphenyl(4-methoxyphenyl)iodonium tosylate (17),16 2-
methylphenyl(4-methoxyphenyl)iodonium tosylate (19),18k 4-ethoxycarbonylphenyl(4-
methoxyphenyl)iodonium
tosylate
(21),18k
and
3-ethoxycarbonylphenyl(4-
methoxyphenyl)iodonium tosylate (23).18l
Syntheses
of
Diaryliodonium
Tosylates.
2-Thienyl(2,4,6-
trimethoxyphenyl)iodonium tosylate (5). To a solution of 2-(diacetoxyiodo)thiophene (0.49 g,
1.5 mmol) in dichloromethane (15 mL) was added p-TsOH·H2O (0.31 g, 1.6 mmol) and 1,3,5-
trimethoxybenzene (0.29 g, 1.7 mmol). The reaction mixture was stirred at rt for 30 min, and
evaporated under reduced pressure. After removal of solvent, the crude oil was triturated with
Et2O. The solid precipitate was filtered, washed with Et2O (30 mL x 2) and dried in air to give
5 (0.080 g, 10%) as a white solid; m.p. 192–193 C. 1H NMR (300 MHz, CDCl3): δ = 7.69–
o
7.67 (m, 3 H), 7.50 (d, J = 5.3 Hz, 1 H), 7.10 (d, J = 8.0 Hz, 2 H), 6.98 (dd, J = 5.3, 3.8 Hz, 1
H), 6.12 (s, 2 H), 3.92 (s, 6 H), 3.84 (s, 3 H), 2.33 (s, 3 H). 13C{1H} NMR (75 MHz, CDCl3):
δ = 167.0, 159.9, 143.1, 139.6, 139.4, 135.2, 129.1, 128.6, 126.2, 91.7, 77.4, 57.2, 56.1, 21.6.
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IR (KBr): 2977, 2946, 1579, 1227, 1176, 1122, 1011, 679 cm-1. HRMS (ESI): calcd. for
C13H14IO3S+ [M - OTs]+ 376.9708; found 376.9708.
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2-Methoxyphenyl(4-methoxyphenyl)iodonium tosylate (13). A solution of 2-
methoxyiodobenzene (0.23 g, 1.0 mmol) and mCPBA (0.34 g, 1.5 mmol) in chloroform (15
mL) was stirred at rt for 4 h. After adding p-TsOH·H2O (0.21 g, 1.1 mmol) and anisole (0.54
g, 5.0 mmol) to the mixture, the reaction mixture was stirred at 40 oC for 2 h, and evaporated
under reduced pressure. After removal of solvent, the crude oil was triturated with Et2O. The
solid precipitate was filtered, washed with Et2O (30 mL x 2) and dried in air to give 13 (0.41
g, 80%) as a white solid; m.p. 141–143 oC. 1H NMR (300 MHz, CDCl3): δ = 7.89 (d, J = 9.0
Hz, 2 H), 7.60–7.47 (m, 4 H), 7.06 (d, J = 8.1 Hz, 2 H), 7.01–6.93 (m, 2 H), 6.87 (d, J = 9.1
Hz, 2 H), 3.92 (s, 3 H), 3.81 (s, 3 H), 2.31 (s, 3 H). 13C{1H} NMR (75 MHz, CDCl3): δ = 162.5,
156.6, 142.8, 139.3, 137.7, 135.4, 134.2, 128.5, 126.1, 123.8, 117.5, 112.4, 104.8, 101.9, 56.9,
55.7, 21.3. IR (KBr): 2946, 2843, 1573, 1480, 1298, 1256, 1187, 1120, 1009, 754, 679 cm-1.
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+
HRMS (ESI): calcd. for C14H14IO2 [M-OTs]+ 341.0038; found 341.0039.
2-Methoxymethylphenyl(4-methoxyphenyl)iodonium tosylate (14). Treating 1-
methoxymethyl-2-iodobenzene (0.37 g, 1.5 mmol) according to the synthetic procedure for
compound 13 gave compound 14 (0.53 g, 67%) as a white solid; m.p. 124–127 oC. 1H NMR
(300 MHz, CDCl3): δ = 7.92 (d, J = 8.8 Hz, 2 H), 7.58 (d, J = 8.0 Hz, 2 H), 7.43–7.20 (m, 4
H), 7.04 (d, J = 7.8 Hz, 2 H), 6.90 (d, J = 8.8 Hz, 2 H), 4.67 (s, 2 H), 3.82 (s, 3 H), 3.54 (s, 3
13
H), 2.30 (s, 3 H). C{1H} NMR (75 MHz, CDCl3): δ = 162.8, 143.1, 139.2, 138.7, 138.3,
132.5, 131.3, 131.1, 130.4, 128.5, 126.1, 117.8, 115.6, 101.8, 74.9, 58.8, 55.7, 21.3. IR (KBr):
3070, 2975, 2927, 1491, 1257, 1195, 1091, 1029, 1008, 818, 677 cm-1. HRMS (ESI): calcd. for
+
C15H16IO2 [M - OTs]+ 355.0195; found 355.0195.
General Procedure for Synthesis of Aryl(TMP)iodonium Tosylate from
Iodoarene. The following diaryliodonium tosylates were prepared by the modified synthetic
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procedure established by Stuart14 and Olofsson.15 This series of TMP-iodonium tosylates
seemed to have shelf stability for several months when stored in amber vials at 4–8 °C.
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Mesityl(2,4,6-trimethoxyphenyl)iodonium tosylate (1).15
A
solution of 2-
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iodomesitylene (0.49 g, 2.0 mmol) and mCPBA (0.52 g, 2.3 mmol) in dichloromethane (15
mL) was stirred at rt for 4 h. After adding p-TsOH·H2O (0.42 g, 2.2 mmol) and 1,3,5-
trimethoxybenzene (0.50 g, 3.0 mmol) to the mixture, the reaction mixture was stirred at rt for
30 min, and evaporated under reduced pressure. After removal of solvent, the crude oil was
triturated with Et2O. The solid precipitate was filtered, washed with Et2O (30 mL x 2) and dried
in air to give 1 (0.98 g, 84%) as a white solid; m.p. 186–188 oC. 1H NMR (300 MHz, CDCl3):
δ = 7.60 (d, J = 8.1 Hz, 2 H), 7.04 (d, J = 7.9 Hz, 2 H), 6.90 (s, 2 H), 6.12 (s, 2 H), 3.83 (s, 3
H), 3.82 (s, 6 H), 2.61 (s, 6 H), 2.31 (s, 3 H), 2.26 (s, 3 H). 13C{1H} NMR (75 MHz, CDCl3):
δ = 166.4, 160.4, 143.4, 142.6, 142.4, 138.9, 129.5, 128.3, 126.0, 122.4, 91.7, 81.9, 56.7, 56.1,
26.6, 21.3, 20.9. HRMS (ESI): calcd. for C18H22IO3 [M - OTs]+ 413.0614; found 413.0612.
+
The following compounds (2−4, 11, 15, 18, 20, 22, and 24−40) were prepared similarly
from the appropriate iodoarene and 1,3,5-trimethoxybenzene.
4-Methoxyphenyl(2,4,6-trimethoxyphenyl)iodonium tosylate (2). Yield (0.33 g, 39%)
as a white solid; m.p. 209–212 oC. 1H NMR (300 MHz, CD3OD): δ = 7.87 (d, J = 7.8 Hz, 2 H),
7.68 (d, J = 7.4 Hz, 2 H), 7.19 (d, J = 7.6 Hz, 2 H), 6.97 (d, J = 7.9 Hz, 2 H), 6.38 (s, 2 H), 3.97
(s, 6 H), 3.87 (s, 3 H), 3.80 (s, 3 H), 2.34 (s, 3 H). 13C{1H} NMR (75 MHz, CD3OD): δ = 168.6,
164.0, 161.3, 143.6, 141.6, 138.0, 129.8, 126.9, 118.3, 104.5, 92.8, 86.8, 57.7, 56.6, 56.2, 21.3.
IR (KBr): 2948, 2842, 1585, 1487, 1230, 1158, 1029, 680 cm-1. HRMS (ESI): calcd. for
+
C16H18IO4 [M - OTs]+ 401.0250; found 401.0247.
2-Methoxyphenyl(2,4,6-trimethoxyphenyl)iodonium tosylate (3). Yield (0.48 g, 84%)
as a pale yellow solid; m.p. 159–161 oC. 1H NMR (300 MHz, CDCl3): δ = 7.61 (d, J = 7.9 Hz,
2 H), 7.40 (t, J = 7.6 Hz, 1 H), 7.19 (d, J = 7.8 Hz, 1 H), 7.03 (d, J = 7.8 Hz, 2 H), 6.94 (d, J =
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8.2 Hz, 1 H), 6.87 (t, J = 7.6 Hz, 1 H), 6.16 (s, 2 H), 3.89 (s, 3 H), 3.84 (s, 3 H), 3.80 (s, 6 H),
2.29 (s, 3 H). 13C{1H} NMR (75 MHz, CDCl3): δ = 167.2, 160.7, 156.3, 143.7, 138.9, 132.9,
132.4, 128.4, 126.1, 123.7, 112.2, 103.4, 91.9, 81.3, 57.2, 57.0, 56.2, 21.4. IR (KBr): 3010,
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+
2975, 2943, 1582, 1478, 1221, 1175, 1123, 1009, 681 cm-1. HRMS (ESI): calcd. for C16H18IO4
[M - OTs]+ 401.0250; found 401.0245.
4-Methylphenyl(2,4,6-trimethoxyphenyl)iodonium tosylate (4).14 Yield (0.71 g, 64%)
as a white solid; m.p. 200–202 oC. 1H NMR (300 MHz, CD3OD): δ = 7.81 (d, J = 8.3 Hz, 2 H),
7.68 (d, J = 8.1 Hz, 2 H), 7.26 (d, J = 8.2 Hz, 2 H), 7.19 (d, J = 8.0 Hz, 2 H), 6.40 (s, 2 H), 3.96
(s, 6 H), 3.88 (s, 3 H), 2.36 (s, 3 H), 2.35 (s, 3 H). 13C{1H} NMR (75 MHz, CD3OD): δ = 168.7,
161.4, 144.3, 143.6, 141.6, 135.8, 133.4, 129.8, 126.9, 112.2, 92.8, 86.3, 57.7, 56.7, 21.29,
+
21.28. HRMS (ESI): calcd. for C16H18IO3 [M - OTs]+ 385.0301; found 385.0292.
Phenyl(2,4,6-trimethoxyphenyl)iodonium tosylate (11).15 Yield (0.72 g, 89%) as a
white solid; m.p. 214–216 oC. 1H NMR (300 MHz, CD3OD): δ = 7.94 (d, J = 7.7 Hz, 2 H), 7.68
(d, J = 8.0 Hz, 2 H), 7.60 (t, J = 7.3 Hz, 1 H), 7.45 (t, J = 7.7 Hz, 2 H), 7.20 (d, J = 7.8 Hz, 2
H), 6.40 (s, 2 H), 3.96 (s, 6 H), 3.88 (s, 3 H), 2.35 (s, 3 H). 13C{1H} NMR (75 MHz, CD3OD):
δ = 168.8, 161.4, 143.6, 141.6, 135.8, 133.0, 132.7, 129.8, 126.9, 115.9, 92.9, 86.2, 57.7, 56.7,
+
21.3. HRMS (ESI): calcd. for C15H16IO3 [M - OTs]+ 371.0144; found 371.0143.
2-Methoxymethylphenyl(2,4,6-trimethoxyphenyl)iodonium tosylate (15). Yield (0.29 g,
24%) as a white solid; m.p. 153–155 oC. 1H NMR (300 MHz, CDCl3): δ = 7.66 (d, J = 8.0 Hz,
2 H), 7.43–7.32 (m, 2 H), 7.23–7.14 (m, 2 H), 7.06 (d, J = 7.8 Hz, 2 H), 6.18 (s, 2 H), 4.69 (s,
2 H), 3.88 (s, 3 H), 3.84 (s, 6 H), 3.63 (s, 3 H), 2.31 (s, 3 H). 13C{1H} NMR (75 MHz, CDCl3):
δ = 167.3, 160.9, 144.0, 138.7, 138.2, 131.1, 130.9, 130.6, 129.7, 128.3, 126.1, 114.0, 91.9,
83.7, 74.8, 59.1, 57.2, 56.2, 21.3. IR (KBr): 3091, 2941, 2844, 1585, 1462, 1352, 1222, 1180,
1121, 1009, 681 cm-1. HRMS (ESI): calcd. for C17H20IO4 [M - OTs]+ 415.0406; found
+
415.0406.
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3-Methylphenyl(2,4,6-trimethoxyphenyl)iodonium tosylate (18). Yield (0.82 g, 74%)
as a pale yellow solid; m.p. 178–180 oC. 1H NMR (300 MHz, CDCl3): δ = 7.73–7.70 (m, 3 H),
7.62 (d, J = 8.0 Hz, 1 H), 7.25–7.15 (m, 2 H), 7.10 (d, J = 7.9 Hz, 2 H), 6.16 (s, 2 H), 3.874 (s,
6 H), 3.865 (s, 3 H), 2.32 (s, 3 H), 2.30 (s, 3 H). 13C{1H} NMR (75 MHz, CDCl3): δ = 167.1,
160.6, 143.4, 142.0, 139.1, 134.3, 132.2, 131.1, 130.8, 128.5, 126.1, 115.5, 91.7, 83.5, 57.0,
56.2, 21.4, 21.3. IR (KBr): 3090, 2942, 1584, 1238, 1183, 1119, 1009, 675 cm-1. HRMS (ESI):
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+
calcd. for C16H18IO3 [M - OTs]+ 385.0301; found 385.0300.
2-Methylphenyl(2,4,6-trimethoxyphenyl)iodonium tosylate (20).13d Yield (0.80 g, 72%)
as a white solid; m.p. 189–191 oC. 1H NMR (300 MHz, CDCl3): δ = 7.98 (dd, J = 7.8, 1.1 Hz,
1 H), 7.64 (d, J = 8.1 Hz, 2 H), 7.41–7.30 (m, 2 H), 7.08–7.03 (m, 3 H), 6.13 (s, 2 H), 3.88 (s,
6 H), 3.84 (s, 3 H), 2.68 (s, 3 H), 2.31 (s, 3 H). 13C{1H} NMR (75 MHz, CDCl3): δ = 166.8,
160.4, 143.3, 141.3, 139.1, 137.2, 132.3, 131.3, 128.7, 128.4, 126.0, 121.4, 91.7, 83.7. 56.9,
+
56.1, 25.6, 21.3. HRMS (ESI): calcd. for C16H18IO3 [M - OTs]+ 385.0301; found 385.0302.
[4-(Ethoxycarbonyl)phenyl](2,4,6-trimethoxyphenyl)iodonium tosylate (22). Yield
(0.96 g, 78%) as a white solid; m.p. 189–191 oC. 1H NMR (300 MHz, CDCl3): δ = 7.93 (s, 4
H), 7.71 (d, J = 8.1 Hz, 2 H), 7.11 (d, J = 7.9 Hz, 2 H), 6.17 (s, 2 H), 4.36 (q, J = 7.1 Hz, 2 H),
3.87 (s, 3 H), 3.86 (s, 6 H), 2.33 (s, 3 H), 1.37 (t, J = 7.1 Hz, 3 H). 13C{1H} NMR (75 MHz,
CDCl3): δ = 167.3, 165.2, 160.6, 143.1, 139.3, 133.7, 133.0, 132.1, 128.5, 126.1, 120.4, 91.7,
84.3, 61.7, 57.0, 56.1, 21.4, 14.3. IR (KBr): 3096, 2949, 1710, 1585, 1227, 1182, 1120, 677
+
cm-1. HRMS (ESI): calcd. for C18H20IO5 [M - OTs]+ 443.0355; found 443.0360.
[3-(Ethoxycarbonyl)phenyl](2,4,6-trimethoxyphenyl)iodonium tosylate (24). Yield
(0.64 g, 52%) as a white solid; m.p. 189–190 oC. 1H NMR (300 MHz, CDCl3): δ = 8.41 (s, 1
H), 8.20 (d, J = 8.1 Hz, 1 H), 8.08 (d, J = 7.8 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 2 H), 7.39 (t, J =
8.0 Hz, 1 H), 7.06 (d, J = 8.0 Hz, 2 H), 6.16 (s, 2 H), 4.34 (q, J = 7.1 Hz, 2 H), 3.88 (s, 6 H),
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3.85 (s, 3 H), 2.31 (s, 3 H), 1.36 (t, J = 7.1 Hz, 3 H). C{1H} NMR (75 MHz, CDCl3): δ =
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8
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167.2, 164.4, 160.6, 143.1, 139.3, 138.6, 134.8, 133.3, 132.1, 131.2, 128.5, 126.1, 115.8, 91.7,
84.5, 61.8, 57.0, 56.1, 21.4, 14.3. IR (KBr): 2984, 2940, 1729, 1580, 1225, 1179, 1122, 1010,
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681 cm-1. HRMS (ESI): calcd. for C18H20IO5 [M - OTs]+ 443.0355; found 443.0356.
3-Methoxyphenyl(2,4,6-trimethoxyphenyl)iodonium tosylate (25). Yield (0.75 g, 65%)
as a white solid; m.p. 156–158 oC. 1H NMR (300 MHz, CDCl3): δ = 7.70 (d, J = 8.1 Hz, 2 H),
7.54–7.52 (m, 1 H), 7.29–7.25 (m, 1 H), 7.17 (t, J = 8.2 Hz, 1 H), 7.09 (d, J = 7.9 Hz, 2 H),
6.97–6.93 (m, 1 H), 6.19 (s, 2 H), 3.87 (s, 3 H), 3.86 (s, 6 H), 3.75 (s, 3 H), 2.32 (s, 3 H). 13C{1H}
NMR (75 MHz, CDCl3): δ = 167.2, 160.9, 160.6, 143.4, 139.2, 131.8, 128.5, 126.1, 125.0,
119.0, 117.8, 115.5, 91.7, 83.5, 57.0, 56.2, 55.9, 21.3. IR (KBr): 3089, 2944, 1584, 1236, 1178,
1119, 987, 676 cm-1. HRMS (ESI): calcd. for C16H18IO4 [M - OTs]+ 401.0250; found 401.0240.
+
3-Ethoxyphenyl(2,4,6-trimethoxyphenyl)iodonium tosylate (26). Yield (0.79 g, 67%)
as a white solid; m.p. 149–151 oC. 1H NMR (300 MHz, CDCl3): δ = 7.73 (d, J = 8.1 Hz, 2 H),
7.55–7.54 (m, 1 H), 7.26–7.25 (m, 1 H), 7.18–7.10 (m, 3 H), 6.96–6.93 (m, 1 H), 6.17 (s, 2 H),
3.97 (q, J = 7.0 Hz, 2 H), 3.87 (s, 9 H), 2.33 (s, 3 H), 1.36 (t, J = 7.0 Hz, 3 H). 13C{1H} NMR
(75 MHz, CDCl3): δ = 167.2, 160.7, 160.3, 143.3, 139.2, 131.7, 128.5, 126.1, 124.9, 119.5,
118.3, 115.5, 91.7, 83.5, 64.3, 57.0, 56.2, 21.4, 14.6. IR (KBr): 2976, 2939, 1588, 1470, 1236,
1165, 1120, 1008, 680 cm-1. HRMS (ESI): calcd. for C17H20IO4 [M - OTs]+ 415.0406; found
+
415.0404.
3-Cyanophenyl(2,4,6-trimethoxyphenyl)iodonium tosylate (27).14 Yield (0.44 g, 39%)
as a pale yellow solid; m.p. 207–209 oC. 1H NMR (300 MHz, CD3OD): δ = 8.34 (t, J = 1.4 Hz,
1 H), 8.21 (d, J = 8.2 Hz, 1 H), 7.95 (d, J = 7.8 Hz, 1 H), 7.68–7.59 (m, 3 H), 7.20 (d, J = 8.0
Hz, 2 H), 6.43 (s, 2 H), 3.98 (s, 6 H), 3.90 (s, 3 H), 2.36 (s, 3 H). C{1H} NMR (75 MHz,
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CD3OD): δ = 169.1, 161.4, 143.6, 141.6, 140.0, 138.8, 136.5, 133.4, 129.8, 126.9, 117.6, 116.2,
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115.9, 93.0, 86.4, 57.8, 56.8, 21.3. HRMS (ESI): calcd. for C16H15NIO3 [M - OTs]+ 396.0097;
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found 396.0109.
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3-Nitrophenyl(2,4,6-trimethoxyphenyl)iodonium tosylate (28). Yield (0.24 g, 21%) as
a pale yellow solid; m.p. 210–212 oC. 1H NMR (300 MHz, CD3OD): δ = 8.77 (t, J = 1.9 Hz, 1
H), 8.43–8.40 (m, 1 H), 8.31–8.27 (m, 1 H), 7.73–7.64 (m, 3 H), 7.19 (d, J = 8.0 Hz, 2 H), 6.43
(s, 2 H), 3.99 (s, 6 H), 3.90 (s, 3 H), 2.35 (s, 3 H). 13C{1H} NMR (75 MHz, CD3OD): δ = 167.8,
160.1, 148.9, 142.3, 140.2, 139.8, 132.3, 129.0, 128.4, 126.2, 125.5, 114.2, 91.7, 85.1, 56.5,
55.4, 19.9. IR (KBr): 2978, 2940, 1585, 1347, 1214, 1164, 1125, 1009, 811, 681 cm-1. HRMS
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(ESI): calcd. for C15H15NIO5 [M - OTs]+ 415.9995; found 415.9996.
[3-(Chloromethyl)phenyl](2,4,6-trimethoxyphenyl)iodonium tosylate (29). Yield (0.52
g, 51%) as a white solid; m.p. 172–174 oC. 1H NMR (300 MHz, CDCl3): δ = 7.97 (t, J = 1.7
Hz, 1 H), 7.80 (d, J = 8.2 Hz, 1 H), 7.71 (d, J = 8.2 Hz, 2 H), 7.48 (d, J = 7.7 Hz, 1 H), 7.29 (t,
J = 8.0 Hz, 1 H), 7.11 (d, J = 7.9 Hz, 2 H), 6.17 (s, 2 H), 4.49 (s, 2 H), 3.88 (s, 6 H), 3.87 (s, 3
13
H), 2.33 (s, 3 H). C{1H} NMR (75 MHz, CDCl3): δ = 167.2, 160.6, 143.2, 140.9, 139.3,
134.0, 133.5, 131.6, 131.3, 128.5, 126.1, 115.7, 91.7, 83.9, 57.0, 56.1, 44.8, 21.4. IR (KBr):
3006, 2969, 1588, 1467, 1412, 1340, 1191, 1121, 1040, 692 cm-1. HRMS (ESI): calcd. for
+
C16H17IClO3 [M - OTs]+ 418.9911; found 418.9911.
2-Biphenyl(2,4,6-trimethoxyphenyl)iodonium tosylate (30). Yield (0.58 g, 47%) as a
white solid; m.p. 164–166 oC. 1H NMR (300 MHz, CD3OD): δ = 8.25 (dd, J = 8.1, 1.1 Hz, 1
H), 7.70–7.65 (m, 3 H), 7.54–7.41 (m, 5 H), 7.31–7.28 (m, 2 H), 7.20 (d, J = 7.9 Hz, 2 H), 6.23
(s, 2 H), 3.84 (s, 3 H), 3.69 (s, 6 H), 2.35 (s, 3 H). 13C{1H} NMR (75 MHz, CD3OD): δ = 168.5,
161.3, 147.0, 143.7, 142.5, 141.5, 139.0, 133.6, 132.7, 131.1, 130.4, 129.9, 129.8, 129.7, 126.9,
118.9, 92.5, 85.1, 57.4, 56.6, 21.3. IR (KBr): 2937, 2844, 1584, 1472, 1226, 1179, 1130, 1033,
+
815, 675 cm-1. HRMS (ESI): calcd. for C21H20IO3 [M - OTs]+ 447.0457; found 447.0464.
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4-Biphenyl(2,4,6-trimethoxyphenyl)iodonium tosylate (31).14 Yield (0.87 g, 71%) as a
white solid; m.p. 196–198 oC. 1H NMR (300 MHz, CDCl3): δ = 7.94 (d, J = 8.6 Hz, 2 H), 7.73
(d, J = 8.1 Hz, 2 H), 7.51–7.38 (m, 7 H), 7.10 (d, J = 8.3 Hz, 2 H), 6.18 (s, 2 H), 3.90 (s, 6 H),
3.87 (s, 3 H), 2.30 (s, 3 H). 13C{1H} NMR (75 MHz, CDCl3): δ = 167.1, 160.6, 144.4, 143.3,
139.2, 139.0, 134.4, 130.0, 129.1, 128.5, 127.2, 126.1, 114.1, 91.7, 83.9, 57.1, 56.2, 21.3.
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HRMS (ESI): calcd. for C21H20IO3 [M - OTs]+ 447.0457; found 447.0460.
2-Ethoxyphenyl(2,4,6-trimethoxyphenyl)iodonium tosylate (32). Yield (1.1 g, 90%) as
o
a white solid; m.p. 179–181 C. 1H NMR (300 MHz, CDCl3): δ = 7.65 (d, J = 8.2 Hz, 2 H),
7.43–7.37 (m, 1 H), 7.32 (dd, J = 8.0, 1.4 Hz, 1 H), 7.06 (d, J = 8.3 Hz, 2 H), 6.93–6.85 (m, 2
H), 6.16 (s, 2 H), 4.15 (q, J = 7.0 Hz, 2 H), 3.87 (s, 3 H), 3.83 (s, 6 H), 2.31 (s, 3 H), 1.46 (t, J
= 7.0 Hz, 3 H). 13C{1H} NMR (75 MHz, CDCl3): δ = 167.1, 160.6, 155.7, 143.7, 138.8, 133.0,
132.9, 128.3, 126.1, 123.5, 112.9, 103.6, 91.8, 81.3, 65.7, 57.1, 56.1, 21.3, 14.6. IR (KBr):
+
2986, 1580, 1181, 1118, 1010, 679 cm-1. HRMS (ESI): calcd. for C17H20IO4 [M - OTs]+
415.0406; found 415.0407.
4-Acetylphenyl(2,4,6-trimethoxyphenyl)iodonium tosylate (33). Yield (0.52 g, 44%) as
a white solid; m.p. 204–206 oC. 1H NMR (300 MHz, DMSO-d6): δ = 8.03 (d, J = 8.5 Hz, 2 H),
7.95 (d, J = 8.5 Hz, 2 H), 7.46 (d, J = 7.9 Hz, 2 H), 7.10 (d, J = 7.8 Hz, 2 H), 6.48 (s, 2 H), 3.94
(s, 6 H), 3.87 (s, 3 H), 2.57 (s, 3 H), 2.28 (s, 3 H). 13C{1H} NMR (75 MHz, DMSO-d6): δ =
197.4, 166.4, 159.4, 145.8, 138.8, 137.6, 134.4, 130.8, 128.0, 125.5, 120.9, 92.1, 87.1, 57.4,
56.2, 26.9, 20.8. IR (KBr): 2981, 2947, 2844, 1687, 1582, 1346, 1231, 1156, 1004, 681 cm-1.
+
HRMS (ESI): calcd. for C17H18IO4 [M - OTs]+ 413.0250; found 413.0249.
[4-(Methoxycarbonyl)phenyl](2,4,6-trimethoxyphenyl)iodonium tosylate (34).14 Yield
(0.52 g, 48%) as a white solid; m.p. 195–197 oC. 1H NMR (300 MHz, CD3OD): δ = 8.05–7.99
(m, 4 H), 7.67 (d, J = 8.2 Hz, 2 H), 7.19 (d, J = 7.9 Hz, 2 H), 6.42 (s, 2 H), 3.97 (s, 6 H), 3.91
(s, 3 H), 3.89 (s, 3 H), 2.34 (s, 3 H). 13C{1H} NMR (75 MHz, CD3OD): δ = 169.0, 166.8, 161.5,
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(ESI): calcd. for C17H18IO5 [M - OTs]+ 429.0199; found 429.0197.
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4-Azidophenyl(2,4,6-trimethoxyphenyl)iodonium tosylate (35).13b Yield (0.53 g, 44%)
as a white solid; m.p. 187–188 oC. 1H NMR (300 MHz, CDCl3): δ = 7.86 (d, J = 8.9 Hz, 2 H),
7.69 (d, J = 8.2 Hz, 2 H), 7.10 (d, J = 7.9 Hz, 2 H), 6.92 (d, J = 8.9 Hz, 2 H), 6.16 (s, 2 H), 3.88
(s, 6 H), 3.86 (s, 3 H), 2.33 (s, 3 H). 13C{1H} NMR (75 MHz, CDCl3): δ = 167.1, 160.5, 143.6,
143.2, 139.3, 135.9, 128.5, 126.1, 121.8, 109.7, 91.7, 84.5, 57.0, 56.1, 21.3. HRMS (ESI): calcd.
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for C15H15N3IO3 [M - OTs]+ 412.0158; found 412.0159.
[4-(Azidomethyl)phenyl](2,4,6-trimethoxyphenyl)iodonium tosylate (36). Yield (0.58
g, 50%) as a white solid; m.p. 177–178 oC. 1H NMR (300 MHz, CDCl3): δ = 7.87 (d, J = 8.5
Hz, 2 H), 7.67 (d, J = 8.1 Hz, 2 H), 7.24 (d, J = 8.5 Hz, 2 H), 7.08 (d, J = 7.9 Hz, 2 H), 6.16 (s,
2 H), 4.34 (s, 2 H), 3.85 (s, 9 H), 2.31 (s, 3 H). 13C{1H} NMR (75 MHz, CDCl3): δ = 167.2,
160.6, 143.2, 139.3, 134.3, 130.7, 128.5, 126.1, 115.0, 91.7, 84.0, 57.0, 56.1, 53.8, 21.4. IR
(KBr): 2945, 2093, 1581, 1228, 1177, 1118, 1009, 679 cm-1. HRMS (ESI): calcd. for
+
C16H17N3IO3 [M - OTs]+ 426.0315; found 426.0315.
3-Bromophenyl(2,4,6-trimethoxyphenyl)iodonium tosylate (37). Yield (0.53 g, 43%)
as a white solid; m.p. 175–177 oC. 1H NMR (300 MHz, CDCl3): δ = 7.92–7.89 (m, 2 H), 7.70
(d, J = 8.1 Hz, 2 H), 7.57 (d, J = 8.1 Hz, 1 H), 7.19 (t, J = 8.3 Hz, 1 H), 7.11 (d, J = 8.0 Hz, 2
H), 6.17 (s, 2 H), 3.88 (s, 6 H), 3.87 (s, 3 H), 2.33 (s, 3 H). 13C{1H} NMR (75 MHz, CDCl3):
δ = 167.2, 160.6, 143.1, 139.3, 136.0, 134.4, 132.8, 132.4, 128.6, 126.1, 123.9, 115.8, 91.8,
84.6, 57.1, 56.2, 21.4. IR (KBr): 3084, 2943, 1579, 1453, 1227, 1119, 1009, 817, 678 cm-1.
+
HRMS (ESI): calcd. for C15H15IBrO3 [M - OTs]+ 448.9249; found 448.9253.
6-Bromopyridin-3-yl(2,4,6-trimethoxyphenyl)iodonium tosylate (38). Yield (0.78 g,
63%) as a white solid; m.p. 206–208 oC. 1H NMR (300 MHz, CD3OD): δ = 8.81 (d, J = 2.4 Hz,
1 H), 8.21 (dd, J = 8.5, 2.5 Hz, 1 H), 7.69 (d, J = 8.3 Hz, 3 H), 7.22 (d, J = 7.9 Hz, 2 H), 6.44
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(s, 2 H), 4.00 (s, 6 H), 3.90 (s, 3 H), 2.37 (s, 3 H). 13C{1H} NMR (75 MHz, CD3OD): δ = 169.1,
161.3, 155.0, 146.3, 145.6, 143.5, 141.6, 132.6, 129.8, 126.9, 114.0, 93.0, 86.2, 57.8, 56.7, 21.3.
IR (KBr): 3163, 2943, 2845, 1585, 1344, 1232, 1119, 1009, 682 cm-1. HRMS (ESI): calcd. for
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C14H14NIBrO3 [M - OTs]+ 449.9202; found 449.9202.
[4-(Benzyloxy)phenyl](2,4,6-trimethoxyphenyl)iodonium tosylate (39). Yield (0.75 g,
60%) as a white solid; m.p. 191–193 oC. 1H NMR (300 MHz, CD3OD): δ = 7.87 (d, J = 9.0 Hz,
2 H), 7.68 (d, J = 8.1 Hz, 2 H), 7.41–7.29 (m, 5 H), 7.19 (d, J = 8.0 Hz, 2 H), 7.04 (d, J = 9.0
Hz, 2 H), 6.38 (s, 2 H), 5.10 (s, 2 H), 3.96 (s, 6 H), 3.87 (s, 3 H), 2.34 (s, 3 H). 13C{1H} NMR
(75 MHz, CD3OD): δ = 168.6, 163.1, 161.3, 143.6, 141.6, 138.0, 137.6, 129.8, 129.6, 129.2,
128.7, 126.9, 119.3, 104.8, 92.8, 86.7, 71.4, 57.7, 56.6, 21.3. IR (KBr): 2946, 2844, 1580, 1471,
1227, 1164, 1006, 807, 678 cm-1. HRMS (ESI): calcd. for C22H22IO4 [M - OTs]+ 477.0563;
+
found 477.0562.
{4-[(2,5-Dioxopyrrolidinyloxy)carbonyl]phenyl}(2,4,6-trimethoxyphenyl)iodonium
tosylate (40). The reaction was performed in accordance with the synthetic procedure for
compound 1 with slight modification (reaction medium: MeCN, reaction temperature: 60 oC)
to yield compound 40 (0.40 g, 30%) as a white solid; m.p. 143–145 oC. 1H NMR (300 MHz,
CD3OD): δ = 8.18–8.11 (m, 4 H), 7.69 (d, J = 8.2 Hz, 2 H), 7.22 (d, J = 7.9 Hz, 2 H), 6.45 (s,
2 H), 3.99 (s, 6 H), 3.91 (s, 3 H), 2.90 (s, 4 H), 2.36 (s, 3 H). 13C{1H} NMR (75 MHz, CD3OD):
δ = 170.1, 167.8, 160.9, 160.1, 142.2, 140.3, 134.8, 132.4, 128.4, 128.3, 125.6, 121.1, 91.7,
84.7, 56.5, 55.4, 25.2, 19.9. IR (KBr): 2945, 1741, 1585, 1208, 1163, 1122, 1008, 680 cm-1.
HRMS (ESI): calcd. for C20H19INO7 [M - OTs]+ 512.0206; found 512.0207.
+
Radiochemistry: A General Procedure. No-carrier-added [18F]fluoride ion was
produced via [18O(p,n)18F] nuclear reaction by irradiation of [18O]H2O on a GE PETtrace 16.5
MeV cyclotron (GE Healthcare, Madison, WI, USA). Typical irradiation parameters, including
40 μA for 3 min, resulted in 5.5 ± 0.7 GBq (150 ± 20 mCi) of [18F]fluoride ion in [18O]H2O
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target water. The cyclotron-produced [18F]fluoride ion (1.0–1.5 GBq) in H2 O was trapped on
a QMA cartridge preconditioned with 10 mL H2O, and the trapped [18F]fluoride ion was
released with a PTA solution (K 2.2.2. (15 mg, 39 μmol) and K2CO3 (2.7 mg, 19 μmol) in
MeCN-H2O (49:1 v/v; total 1200 μL); or TBAHCO3 (40 μL, 53 μmol; 40% aq solution) in 1.0
mL MeCN). The residual target water was removed by azeotropic evaporation with MeCN at
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110 C for 10 min, then cooled to rt for 3 min. The resulting [18F]fluoride ion complex was
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solubilized in organic solvent (DMF, DMA, or DMSO; 4.0 mL) by stirring at rt for 5 min. The
iodonium tosylate precursor solution (ca. 3.0 or 7.5 mM) in the corresponding solvent (1.0 mL)
was added to 18F-/K 2.2.2./K2CO3 or 18F-/TBAHCO3 complex solution (1.0 mL). The
radiofluorination was performed in a borosilicate glass vessel with silicone cap containing
Teflon septum using conductively heated reactor19 (Monowave 50, Anton Paar GmbH, Austria)
at different temperatures (120–160 oC) for 10 min. Then the reaction mixture was cooled to 60
oC, and an aliquot (ca. 200 μL) was diluted with MeCN-H2O (40:60 v/v, 3 mL) and subjected
to reverse-phase radio-HPLC. RCYs of the [18F]fluoroarenes were determined by radio-HPLC.
The identity of [18F]fluoroarenes was confirmed with coinjection of non-radioactive fluoro-
standards.
ASSOCIATED CONTENT
Supporting Information
Screening of conditions for radiofluorination, radio-HPLC chromatograms, and 1H and 13C{1H}
NMR spectra (PDF) are available. The material is available free of charge on the ACS
Publications website at http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Author
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* E-mail: jchun@yuhs.ac
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ORCID
Young-Do Kwon: 0000-0002-7515-6021
Joong-Hyun Chun: 0000-0002-9665-7829
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The financial support for this research was provided by the National Research Foundation of
Korea (NRF-2015R1D1A1A02061420) and a faculty research grant from Yonsei University
College of Medicine (6-2018-0100). The authors thank MID (Medical Illustration & Design)
for helping to design the TOC graphics.
REFERENCES
(1) Meanwell, N. A. Fluorine and fluorinated motifs in the design and application of
bioisosteres for drug design. J. Med. Chem. 2018, 61, 5822–5880.
(2) Preshlock, S.; Tredwell, M.; Gouverneur, V. 18F-Labeling of arenes and heteroarenes for
applications in positron emission tomography. Chem. Rev. 2016, 116, 719–766.
(3) (a) Pike, V. W. Hypervalent aryliodine compounds as precursors for radiofluorination. J.
Labelled Compd. Radiopharm. 2018, 61, 196–227. (b) Telu, S.; Siméon, F. G.; Lu, S.; Pike, V.
W. Hypervalent iodine compounds as precursors for biomedical radiotracers. In The Chemistry
of Hypervalent Halogen Compounds, Patai’s Chemistry of Functional Groups; John Wiley &
ACS Paragon Plus Environment

Page 25 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Sons, Ltd: New York, DOI: 10.1002/9780470682531.pat0955. Published online: June 13, 2018.
https://onlinelibrary.wiley.com/doi/full/10.1002/9780470682531.pat0955 (last accessed Dec
28, 2018).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4) (a) Tredwell, M.; Preshlock, S. M.; Taylor, N. J.; Gruber, S.; Huiban, M.; Passchier, J.;
Mercier, J.; Génicot, C.; Gouverneur, V. A general copper-mediated nucleophilic 18F
fluorination of arenes. Angew. Chem. Int. Ed. 2014, 53, 7751–7755. (b) Mossine, A. V.; Brooks,
A. F.; Makaravage, K. J.; Miller, J. M.; Ichiishi, N.; Sanford, M. S.; Scott, P. J. H. Synthesis of
[18F]arenes via the copper-mediated [18F]fluorination of boronic acids. Org. Lett. 2015, 17,
5780–5783.
(5) Makaravage, K. J.; Brooks, A. F.; Mossine, A. V.; Sanford, M. S.; Scott, P. J. H. Copper-
mediated radiofluorination of arylstannanes with [18F]KF. Org. Lett. 2016, 18, 5440–5443.
(6) (a) Narayanam, M. K.; Ma, G.; Champagne, P. A.; Houk, K. N.; Murphy, J. M. Synthesis
of [18F]fluoroarenes by nucleophilic radiofluorination of N-arylsydnones. Angew. Chem. Int.
Ed. 2017, 56, 13006–13010. (b) Narayanam, M. K.; Ma, G.; Champagne, P. A.; Houk, K. N.;
18
Murphy, J. M. Nucleophilic F-fluorination of anilines via N-arylsydnone intermediates.
Synlett 2018, 29, 1131–1135.
(7) (a) Merritt, E. A.; Olofsson, B. Diaryliodonium salts: a journey from obscurity to fame.
Angew. Chem. Int. Ed. 2009, 48, 9052–9070. (b) Aradi, K.; Tóth, B. L.; Tolnai, G. L.; Novák,
Z. Diaryliodonium salts in organic syntheses: a useful compound class for novel arylation
strategies. Synlett 2016, 27, 1456–1485. (c) Olofsson, B. Arylation with diaryliodonium salts.
Top. Curr. Chem. 2016, 373, 135–166. (d) Stuart, D. R. Aryl transfer selectivity in metal-free
reactions of unsymmetrical diaryliodonium salts. Chem. - Eur. J. 2017, 23, 15852–15863.
(8) (a) Gao, Z.; Gouverneur, V.; Davis, B. G. Enhanced aqueous suzuki−miyaura coupling
allows site-specific polypeptide 18F-labeling. J. Am. Chem. Soc. 2013, 135, 13612–13615. (b)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 28
1
2
3
4
5
6
7
8
9
Wüst, F. R.; Kniess, T. Synthesis of 4-[18F]fluoroiodobenzene and its application in
sonogashira cross-coupling reactions. J. Labelled Compd. Radiopharm. 2003, 46, 699–713.
(9) Selivanova, S. V.; Stellfeld, T.; Heinrich, T. K.; Müller, A.; Krämer, S. D.; Schubiger, P.
A.; Schibli, R.; Ametamey, S. M.; Vos, B.; Meding, J.; Bauser, M.; Hütter, J.; Dinkelborg, L.
M. Design, synthesis, and initial evaluation of a high affinity positron emission tomography
probe for imaging matrix metalloproteinases 2 and 9. J. Med. Chem. 2013, 56, 4912–4920.
(10) (a) Carroll, M. A.; Jones, C.; Tang, S.-L. Fluoridation of 2-thienyliodonium salts. J.
Labelled Compd. Radiopharm. 2007, 50, 450–451. (b) Ross, T. L.; Ermert, J.; Hocke, C.;
Coenen, H. H. Nucleophilic 18F-fluorination of heteroaromatic iodonium salts with no-carrier-
added [18F]fluoride. J. Am. Chem. Soc. 2007, 129, 8018–8025.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(11) (a) Moon, B. S.; Park, J. H.; Lee, H. J.; Lee, B. C.; Kim, S. E. Routine production of
[18F]flumazenil from iodonium tosylate using a sample pretreatment method: a 2.5-year
production report. Mol. Imaging Biol. 2014, 16, 619–625. (b) Moon, B. S.; Kil, H. S.; Park, J.
H.; Kim, J. S.; Park, J.; Chi, D. Y.; Lee, B. C.; Kim, S. E. Facile aromatic radiofluorination of
[18F]flumazenil from diaryliodonium salts with evaluation of their stability and selectivity.
Org. Biomol. Chem. 2011, 9, 8346–8355.
(12) (a) Wang, B.; Graskemper, J. W.; Qin, L.; DiMagno, S. G. Regiospecific reductive
elimination from diaryliodonium salts. Angew. Chem. Int. Ed. 2010, 49, 4079–4083. (b)
Graskemper, J. W.; Wang, B.; Qin, L.; Neumann, K. D.; DiMagno, S. G. Unprecedented
directing group ability of cyclophanes in arene fluorinations with diaryliodonium salts. Org.
Lett. 2011, 13, 3158–3161.
(13) (a) Lindstedt, E.; Stridfeldt, E.; Olofsson, B. Mild synthesis of sterically congested alkyl
aryl ethers. Org. Lett. 2016, 18, 4234–4237. (b) Reitti, M.; Villo, P.; Olofsson, B. One-pot C–
H functionalization of arenes by diaryliodonium salts. Angew. Chem. Int. Ed. 2016, 55, 8928–
8932. (c) Sandtorv, A. H.; Stuart, D. R. Metal-free synthesis of aryl amines: beyond
ACS Paragon Plus Environment

Page 27 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
nucleophilic aromatic substitution. Angew. Chem. Int. Ed. 2016, 55, 15812–15815. (d) Basu,
S.; Sandtorv, A. H.; Stuart, D. R. Imide arylation with aryl(TMP)iodonium tosylates. Beilstein
J. Org. Chem. 2018, 14, 1034–1038.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(14) Seidl, T. L.; Sundalam, S. K.; McCullough, B.; Stuart, D. R. Unsymmetrical aryl(2,4,6-
trimethoxyphenyl)iodonium salts: one-pot synthesis, scope, stability, and synthetic studies. J.
Org. Chem. 2016, 81, 1998–2009.
(15) Lindstedt, E.; Reitti, M.; Olofsson, B. One-pot synthesis of unsymmetric diaryliodonium
salts from iodine and arenes. J. Org. Chem. 2017, 82, 11909–11914.
(16) Chun, J.-H.; Lu, S.; Pike, V. W. Rapid and efficient radiosyntheses of meta-substituted
[18F]fluoroarenes from [18F]fluoride ion and diaryliodonium tosylates within a microreactor.
Eur. J. Org. Chem. 2011, 2011, 4439–4447.
(17) (a) Vaidyanathan, G.; Zalutsky, M. R. Synthesis of N-succinimidyl 4-
[18F]fluorobenzoate, an agent for labeling proteins and peptides with 18F. Nat. Protoc. 2006, 1,
1655–1661. [18F]SFB from diaryliodonium trifluoroacetate, see: (b) Yan, R.; Brichard, L.;
Soloviev, D.; Aigbirhio, F. I.; Carroll, M. A. The first single-step-single-post synthesis of 4-
[18F]SFB. J. Labelled Compd. Radiopharm. 2009, 52, 216. (c) Carroll, M. A.; Yan, R.
18
19
Formation of F and F fluoroarenes bearing reactive functionalities. WO2009/138763A1,
2009.
(18) (a) Richards-Taylor, C. S.; Blakemore, D. C.; Willis, M. C. One-pot three-component
sulfone synthesis exploiting palladium-catalysed aryl halide aminosulfonylation. Chem. Sci.
2014, 5, 222–228. (b) Chun, J.-H.; Pike, V. W. Single-step radiosynthesis of “18F-labeled click
synthons” from azide-functionalized diaryliodonium salts. Eur. J. Org. Chem. 2012, 2012,
4541–4547. (c) Kobayashi, Y.; Masakado, S.; Takemoto, Y. Photoactivated N-
acyliminoiodinanes applied to amination: an ortho-methoxymethyl group stabilizes reactive
precursors. Angew. Chem. Int. Ed. 2018, 57, 693–697. (d) Mazzotti, A. R.; Campbell, M. G.;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 28
1
2
3
4
5
6
7
8
9
Tang, P.; Murphy, J. M.; Ritter, T. Palladium(III)-catalyzed fluorination of arylboronic acid
derivatives. J. Am. Chem. Soc. 2013, 135, 14012–14015. (e) Reddy, V. K.; Rao, J. V.; Reddy,
L. B.; Ram, B.; Balram, B. Synthesis of chalcone derivatives of benzo[b]furan as potential
antibacterial agents. Indian J. Chem. 2015, 54B, 791–797. (f) Chun, J.-H.; Pike, V. W. Single-
step syntheses of no-carrier-added functionalized [18F]fluoroarenes as labeling synthons from
diaryliodonium salts. Org. Biomol. Chem. 2013, 11, 6300–6306. (g) Edem, P. E.; Czorny, S.;
Valliant, J. F. Synthesis and evaluation of radioiodinated acyloxymethyl ketones as activity-
based probes for Cathepsin B. J. Med. Chem. 2014, 57, 9564–9577. (h) Lee, B. C.; Lee, K. C.;
Lee, H.; Mach, R. H.; Katzenellenbogen, J. A. Strategies for the labeling of halogen-substituted
peroxisome proliferator-activated receptor γ ligands: potential positron emission tomography
and single photon emission computed tomography imaging agents. Bioconjugate Chem. 2007,
18, 514–523. (i) Altomonte, S.; Telu, S.; Lu, S.; Pike, V. W. Pd(0)-mediated 11C‑carbonylation
of aryl(mesityl)iodonium salts as a route to [11C]arylcarboxylic acids and derivatives. J. Org.
Chem. 2017, 82, 11925–11932 (j) Zhang, M.-R.; Kumata, K.; Takei, M.; Fukumura, T.; Suzuki,
K. How to introduce radioactive chlorine into a benzene ring using [*Cl]Cl–? Appl. Radiat.
Isot. 2008, 66, 1341–1345. (k) Guérard, F.; Lee, Y.-S.; Baidoo, K.; Gestin, J.-F.; Brechbiel, M.
W. Unexpected behavior of the heaviest halogen astatine in the nucleophilic substitution of
aryliodonium salts. Chem. - Eur. J. 2016, 22, 12332–12339. (l) Chun, J.-H.; Telu, S.; Lu, S.;
Pike, V. W. Radiofluorination of diaryliodonium tosylates under aqueous–organic and
cryptand-free conditions. Org. Biomol. Chem. 2013, 11, 5094–5099
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(19) Obermayer, D.; Znidar, D.; Glotz, G.; Stadler, A.; Dallinger, D.; Kappe, C. O. Design
and performance validation of a conductively heated sealed-vessel reactor for organic synthesis.
J. Org. Chem. 2016, 81, 11788–11801.
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