Single-step radiosynthesis of "18F-labeled click synthons" from azide-functionalized diaryliodonium salts

Article abstract of DOI:10.1002/ejoc.201200695

Positron emission tomography (PET) is an increasingly important biomedical imaging technique that relies on the development of radiotracers labeled with positron emitters to achieve biochemical specificity. Fluorine-18 (t _1/2 = 109.7 min) is an

Full text of DOI:10.1002/ejoc.201200695

Job/Unit: O20695
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Date: 03-07-12 16:13:36
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FULL PAPER
DOI: 10.1002/ejoc.201200695
Single-Step Radiosynthesis of “18F-Labeled Click Synthons” from Azide-
Functionalized Diaryliodonium Salts
Joong-Hyun Chun[a] and Victor W. Pike*[a]
Keywords: Click chemistry / Hypervalent compounds / Imaging agents / Isotopic labeling / Radiochemistry
Positron emission tomography (PET) is an increasingly im-
portant biomedical imaging technique that relies on the de-
velopment of radiotracers labeled with positron emitters to
achieve biochemical specificity. Fluorine-18 (t1/2 = 109.7 min)
is an attractive positron-emitting radiolabel for organic radio-
tracers, primarily because of its longer half-life and greater
availability relative to those of the main alternative, carbon-
11 (t1/2 = 20.4 min). Rapid, simple methods are sought for la-
beling prospective PET radiotracers with fluorine-18 from cy-
clotron-produced aqueous [18F]fluoride ion, which must often
be converted first into a suitably reactive labeling synthon
for use in a subsequent labeling reaction. The use of 18F-
labeled synthons in “click chemistry” is attracting increasing
attention for labeling PET radiotracers. Herein we describe
rapid, single-step radiosynthesis of azido- or azidomethyl-
bearing [18F]fluoroarenes from the reactions of diaryliodon-
ium salts with no-carrier-added [18F]fluoride ion within a
microfluidic apparatus to provide previously poorly access-
ible 18F-labeled click synthons in radiochemical yields of
15% for 4-[18F]fluorophenyl azide and about 40% for each
of the [18F](azidomethyl)fluorobenzenes. The radiosynthesis
of the latter synthons was possible under “wet conditions”,
so obviating the need to dry the cyclotron-produced
[
18F]fluoride ion and greatly enhancing the practicality of the
method.
[18F]Fluoroalkyl azides[5] and [18F]azidobenzyl fluor-
Introduction
ides[6] have been explored as labeling synthons in click ra-
diochemistry. Generally, these labeling synthons may be
prepared in a single efficient step from [18F]fluoride ion.
However, potential radiotracers prepared from these syn-
thons may be prone to radiodefluorination in vivo.[7] Such
radiodefluorination results in the uptake of [18F]fluoride
ion into bone, which may compromise the performance of
the radiotracer. Because aryl C–18F bonds are usually more
stable than alkyl C–18F bonds in vivo, azide synthons with
fluorine-18 attached to an aryl ring have been sought.
Hashizume et al.[8] have reported the synthesis of several
[18F]fluorophenyl azides ([18F]1a–f; Figure 1) by the iso-
topic exchange of [18F]fluoride ion with fluorophenyl az-
ides, and they used these synthons to label a protein, cyto-
chrome C, photochemically. The decay-corrected radio-
chemical yields (RCYs) of the [18F]fluorophenyl azides were
very low (0–12%). Moreover, a major disadvantage of such
exchange labeling is that the resultant specific radioactivity
of the labeled synthon and of any derived radioactive prod-
uct becomes greatly decreased from that of the no-carrier-
added (NCA) [18F]fluoride ion source. 1-(Azidomethyl)-4-
[18F]fluorobenzene ([18F]2a) has been used as a labeling
synthon to prepare 18F-labeled peptides,[9,10] sometimes in
excellent RCYs (19–90%). The potential of using this syn-
thon to label oligonucleotides quantitatively has also been
demonstrated.[11] Nonetheless, the reported radiosynthesis
of [18F]2a required four radiochemical steps from 4-formyl-
N,N,N-trimethylanilinium triflate performed over 75 min
Efficient and rapid methods for labeling organic com-
pounds with the short-lived positron emitter fluorine-18
(t1/2 = 109.7 min) are sought for producing novel radio-
tracers for biomedical imaging with positron emission tom-
ography (PET).[1] Fluorine-18 can be obtained in high
yields and with high specific radioactivity from a cyclotron
by the 18O(p,n)18F reaction with 18O-enriched water.[2] This
process provides the fluorine-18 as aqueous [18F]fluoride
ion. Methods for producing 18F-labeled radiotracers from
this source must either use the [18F]fluoride ion directly or
proceed through conversion of the [18F]fluoride ion into a
labeling synthon. 18F-Labeled organoazides are potentially
useful synthons in “click radiochemistry”, based on the
well-known mild, rapid, and efficient copper(I)-catalyzed
azide–alkyne 1,3-dipolar cycloaddition reaction[3] for at-
taching fluorine-18 to biomolecules, especially macromole-
cules.[4] Despite the attractive features of the “click reac-
tion” for radiolabeling, the prior preparation of a suitable
radioactive synthon is still necessary and radiosynthetically
demanding.
[a] Molecular Imaging Branch, National Institute of Mental
Health, National Institutes of Health,
10 Center Drive, Building 10, Room B3 C346A, Bethesda, MD
20892, USA
Fax: +1-301-480-5112
E-mail: pikev@mail.nih.gov
Homepage: http://intramural.nimh.nih.gov/mib/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200695.
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J.-H. Chun, V. W. Pike
FULL PAPER
and gave a low overall RCY (34%).[9] This type of pro- from iodoarenes and mCPBA (m-chloroperbenzoic acid) in
cedure was recently automated to give [18F]2a in RCYs of the presence of various sulfonic acids. Because this method
up to 60% and the ortho isomer [18F]2b in 30% RCY.[12]
uses a mild oxidizing agent under ambient temperature, we
were attracted to its use for preparing azide-bearing [hy-
droxy(tosyloxy)iodo]arenes that might then be converted in
situ into the target diaryliodonium tosylates by treatment
with anisole or thiophene (Scheme 2).
Figure 1. Previously reported [18F]fluoroaryl azides.
Herein, we describe the rapid one-step radiosynthesis of
various [18F]fluoroarenes bearing an azide functionality
from azide-functionalized diaryliodonium salts as access-
ible “18F-labeled click synthons”, including [18F]2a and
[18F]2b.
Scheme 2. mCPBA-mediated one-pot synthesis of azide-bearing di-
aryliodonium tosylates.
By this one-pot approach, we were successful in con-
verting iodoaryl azides into azide-bearing diaryliodonium
tosylates in moderate-to-good yields (53–74%, Scheme 3).
Many of the prepared diaryliodonium tosylates were also
conveniently converted into diaryliodonium halides in ex-
cellent yields (76–92%) by treatment with inorganic halides
in aqueous acetonitrile (Scheme 3).
Results and Discussion
Diaryliodonium salts have served as uniquely effective
precursors for introducing the [18F]fluoride ion into elec-
tron-rich as well as electron-deficient aryl rings
(Scheme 1).[13–15] Such diaryliodonium salts are gradually
gaining application in the preparation of PET radiotracers
as improved methods for the synthesis of elaborate diaryl-
iodonium salts become available.[16]
Scheme 1. Radiosynthesis of [18F]fluoroarenes from diaryliodon-
ium salts.
We considered that the use of diaryliodonium salt pre-
cursors might permit advantageous single-step radiosynth-
eses of click synthons, such as [18F]1f and [18F]2a, because
the azide group is regarded as electronically neutral and like
other electronically neutral groups might be expected to be
well tolerated in the radiofluorination of diaryliodonium
salts. An electron-rich aryl ring, such as a 4-methoxyphenyl
or 2-thienyl ring, is generally known to direct the [18F]fluor-
ide ion into a relatively electron-deficient ring in a diaryl-
iodonium salt.[13–15] Accordingly, we sought a convenient
Scheme 3. One-pot synthesis of diaryliodonium tosylates from
iodoaryl azides and subsequent conversion into their correspond-
ing halides. Reagents: (i) iodoaryl azide (1 equiv.), mCPBA
(1.1 equiv.); (ii) pTsOH·H2O (1.1 equiv.); (iii) CHCl3, ArH (excess,
5–10-fold); (iv) MX = NH4Cl (9–11, 14), KBr (12), or KI (13).
Two types of azide-bearing diaryliodonium salts (3–14)
method for preparing diaryliodonium salts with an azide were prepared, those in which the azide group is attached
group directly or indirectly attached to one aryl ring, with directly to the aryl ring (3, 4, 9, and 10) and those in which
the other ring being relatively electron-rich. Moreover, we the azide group is linked to the aryl ring by a methylene
wished to avoid highly nucleophilic or fluorine-containing group (5–8 and 11–14). Each salt was subjected to labeling
anions to prevent competing reactions or the dilution of with NCA [18F]fluoride ion in the commercial microfluidic
specific radioactivity, respectively, in the radiofluorination apparatus that we have described previously.[14] Thus, dried
process. Recently we reported success in preparing func- [18F]fluoride ion–kryptofix 2.2.2 complex (18F–-K 2.2.2-K+)
tionalized diaryliodonium tosylates by generating reactive was dissolved in the reaction solvent, either DMF or
[hydroxy(tosyl)iodo]arenes in situ for reaction with acti- MeCN. A solution of the diaryliodonium salt was prepared
vated arenes or arylstannanes.[17] Yamamoto and Togo[18] in matching solvent. Each reagent solution was then loaded
reported the synthesis of [hydroxy(sulfonyloxy)iodo]arenes into a storage loop. The reaction was implemented by infus-
2
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Radiosynthesis of “18F-Labeled Click Synthons”
ing each reagent solution into the microreactor at equal set Table 1. RCYs of radioactive products from the radiofluorination
of azide-functionalized diaryliodonium salts in DMF.
rates (4–10 μL/min) and at a fixed temperature. Effluents
were quenched with aq. MeCN and analyzed by reversed-
phase HPLC equipped with a radioactivity detector. The
reaction temperature and time were varied to obtain opti-
mal RCYs. Radioactivity adsorption is a well-known phe-
nomenon in radiofluorination with dry NCA [18F]fluoride
ion.[19] In this study, the adsorption of radioactivity within
the microfluidic apparatus was overall generally moderate
but somewhat variable (25Ϯ9%; meanϮSD, n = 22).
Entry Substrate Conditions[a]
RCY [%][b]
For substrates with an azide group attached directly to
the aromatic ring, low RCYs of 1-azido-4-[18F]fluorobenz-
ene ([18F]1f) or 1-azido-3-[18F]fluorobenzene ([18F]1g) were
obtained in DMF from the corresponding tosylates
(Table 1, entries 1 and 5). Changing solvent to acetonitrile
(Table 1, entry 3) or the anion to chloride (Table 1, entries 4
and 7) gave similar or lower RCYs. Accompanying forma-
tion of 4-[18F]fluoroanisole was relatively low. Hashizume
et al.[8] failed to produce [18F]1f by exchange of 1f with [18F]
fluoride ion, and hence these results show some benefit of
using an iodonium salt precursor. Nonetheless, the low
RCYs are surprising given that analogous diaryliodonium
salts, only differing by having a non-electron-withdrawing
substituent (e.g., Me, MeO) other than azide, give high ra-
diochemical yields of the substituted radiofluorinated ar-
enes under comparable conditions.[14,15] Inclusion of the
free radical scavenger, TEMPO (2,2,6,6-tetramethylpiper-
idine-1-oxyl) in some fluoridation reactions of diaryliodon-
ium salts has been reported to give improved yields.[20] We
found that inclusion of TEMPO improved the RCY of
[18F]1f appreciably (cf. Table 1, entries 1 and 2), but had less
effect on the RCY of [18F]1g (cf. Table 1, entries 5 and 6).
In view of the still modest RCYs for [18F]1f and [18F]1g, we
decided to explore the radiofluorination of diaryliodonium
salts with the azido group indirectly linked to an aryl ring.
The radiofluorination of the aryl(4-methoxyphenyl)-
iodonium toyslates bearing azidomethyl groups generally
proceeded rapidly in DMF to give the desired 18F-labeled
fluorobenzyl azides in useful RCYs (ca. 40%), irrespective
of the position of the azidomethyl group in the aryl ring
(Table 2, entries 1–3). Replacement of the 4-methoxyaryl
ring in the salt with a 2-thienyl ring reduced the attainable
RCY to 14% (cf. Table 2, entries 4 and 1). Variation in the
optimal RCYs with salt counterion was small (Table 2, en-
tries 1–3 and 5–8). When the radiofluorinations of the four
T
[°C]
t
[s]
[18F]Click
synthon
4-[18F]Fluoro-
anisole
1
3
3
3
9
4
4
10
160
160
160
160
160
160
180
188
188
126
188
188
188
118
[18F]1f, 10
[18F]1f, 15
[18F]1f, 12
[18F]1f, 9
0.7
1.7
0
0.6
1
2[c]
3[d]
4
5
[18F]1g, 10
[18F]1g, 12
[18F]1g, 4
6[c]
7
0.7
0
[a] The conditions are those giving optimal RCY from ca. eight
runs under various conditions. [b] The RCYs were determined
chromatographically and are corrected for radioactivity adsorption
in the apparatus. The adsorption was 29Ϯ12% (meanϮSD, n =
7). [c] The reaction mixture included 1 equiv. of TEMPO with re-
spect to the iodonium salt. [d] The reaction was performed in
MeCN.
Table 2. Single-step NCA radiofluorination of diaryliodonium salts
bearing azidomethyl groups in DMF.
Entry
Substrate
Conditions[a]
RCY [%][b]
Ar18F
T
[°C]
t
[s]
[18F]Click
synthon
1
2
3
4
5
6
7
8
5
6
7
160
180
180
160
200
200
200
180
188
188
188
188
94
94
188
157
[18F]2a, 37
[18F]2b, 41
[18F]2c, 39
[18F]2a, 14
[18F]2a, 45
[18F]2a, 40
[18F]2a, 38
[18F]2c, 35
1.8
Ͻ0.7
0.9
0
2.2
2.4
1.7
0.8
4-azidomethylphenyl(4-methoxyphenyl)iodonium salts
5
8
and 11–13 were compared under conditions of identical
temperature (160 °C) and reaction time (188 s), the chloride
salt gave the highest RCY (Table 3).
11
12
13
14
When the radiofluorinations were performed at high
temperature (Ͼ180 °C), a small amount of [18F]fluorobenz-
aldehyde (Ͻ3% RCY) was also produced, as detected by
radio-HPLC (Figure 2). This radioactive product presum-
ably arises through the aerobic oxidation of the [18F]fluoro-
benzyl azide. Otherwise, all the radiofluorinations pro-
ceeded cleanly and selectively to the desired [18F]fluoro-
[a] The conditions are those giving optimal RCY from ca. eight
runs under various conditions. [b] The RCYs were determined
chromatographically and are corrected for radioactivity adsorp-
tion; adsorption was 19Ϯ7% (meanϮSD, n = 8).
Because the [18F]fluoride ion is generally produced by
benzyl azides with only 4-[18F]fluoroanisole appearing as a proton irradiation of 18O-enriched water, the first stage in
minor byproduct.
radiotracer synthesis is virtually always the removal of
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J.-H. Chun, V. W. Pike
FULL PAPER
Table 3. Effect of counterions on the radiofluorination of 4-azido- ent iodine. These are distinct advantages over traditional
methylphenyl(4-methoxyphenyl)iodonium salts in DMF.
radiofluorination performed by aromatic nucleophilic sub-
stitution reactions.
Table 4. Radiofluorination of diaryliodonium salts under “wet”
conditions.
Entry Substrate[a]
X
RCY [%][b]
4-[18F]Fluoroanisole
[18F]2a
1
2
3
4
5
OTs
Cl
Br
I
37
51
40
36
1.8
2.7
1.6
1.7
11
12
13
[a] 5 mm substrate concentration in DMF. [b] The RCYs were de-
termined chromatographically with correction for adsorption.
Radioactivity recovery from the apparatus was 82Ϯ7%
(meanϮSD, n = 4).
Entry Substrate[a]
Conditions
RCY [%][b]
T
t
[18F]Fluoro- 4-[18F]Fluoro-
[°C]
[s]
benzyl azide
anisole
1
5
6
6
200
200
180
188
188
94
[18F]2a, 17
[18F]2b, 46
[18F]2b, 53
1
1
2
2
3[c]
[a] 5 mm in DMF. [b] Optimal RCY from 6–8 different runs under
different conditions, determined chromatographically with correc-
tion for radioactivity adsorption; adsorption in the microfluidic ap-
paratus was 29Ϯ2% (n = 3, meanϮSD). [c] Reaction performed
in MeCN.
The very rapid production of [18F]2b in moderate radio-
chemical yield under “wet” radiofluorination conditions,
avoiding the need to dry the cyclotron-produced [18F]fluor-
ide ion, is highly attractive for the application of this syn-
thon to the click labeling of macromolecules or even small
molecules. Aqueous DMF and MeCN are often used as
solvents for click chemistry, and hence conceivably the syn-
thons [18F]2a–c may be used in the solvents in which they
are prepared. The radiosyntheses and use of these labeling
synthons should be highly amenable to simple automation
for radiation safety and therefore to operation with very
high amounts of radioactivity.
Figure 2. Radio-HPLC chromatograms for the analysis of radioac-
tive products from the radiofluorination of 11 in the temperature
range 120–200 °C.
water to generate the highly nucleophilic “naked” [18F]fluor-
ide ion.[1] This can be a tedious and lengthy process that
wastes useful radioactivity. We have previously shown that
radiofluorinations of diaryliodonium salts in DMF proceed
effectively even in the presence of low concentrations of
water (0.25 vol.-% in DMF).[14] With a view to developing
a more streamlined procedure for preparing the click syn-
thons [18F]2a–c, we investigated the radiofluorination of az-
ide-functionalized diaryliodonium salts with “wet” cyclo-
tron-produced NCA [18F]fluoride ion. Thus, one of the
storage loops of the microfluidic apparatus was loaded with
a mixture of cyclotron-produced [18F]fluoride ion in [18O]-
water and a solution of potassium carbonate and K 2.2.2
in DMF. The concentration of water in this storage loop
was around 70 vol.-%. The radiofluorination of the p-azido-
methyl salt 5 in aqueous DMF in this format produced
a low but appreciable RCY (17%) of [18F]2a, whereas, re-
markably, the radiofluorination of the o-azidomethyl salt 6
produced the synthon [18F]2b in a very useful RCY (46%;
Table 4). Radiofluorination of 6 in aqueous MeCN also
gave [18F]2b in an even higher RCY (53%) in a shorter reac-
tion time and at a lower temperature. This RCY even ex-
ceeds that obtained under dry conditions (41%; Table 2, en-
try 2). These results show a tolerance of the radiofluorina-
tion of iodonium salts to the presence of high concentra-
tions of water, in this case 35 vol-%. Again, they show the
tolerance of these reactions to bulky non-electron-with-
Conclusions
Azide-bearing diaryliodonium salts have been readily
prepared. Those bearing an azidomethyl group on one aryl
ring and with a partner 4-methoxyphenyl ring were readily
radiofluorinated with cyclotron-produced NCA [18F]fluor-
ide ion, even in the presence of a high proportion of water,
to give the useful click-labeling synthons [18F]2a–c rapidly
in useful RCYs. This represents a major advance on the
previous multistep radiosyntheses[9,12] of [18F]2a and
[18F]2b, which required a drying stage and four radiochemi-
cal steps. The synthons [18F]2a–c are now readily accessible
for application in click radiochemistry.
Experimental Section
General: Anhydrous chloroform and acetonitrile were purchased in
Sure/SealTM bottles from Sigma–Aldrich (Milwaukee, WI) and
used without further treatment. Iodobenzyl bromide, fluorobenzyl
drawing substituents in the ortho position to the hyperval- bromide, mCPBA, and pTsOH·H2O were purchased from Sigma–
4
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Radiosynthesis of “18F-Labeled Click Synthons”
Aldrich and used as received. Iodobenzyl azides were prepared ac-
cording to a known procedure.[21] Fluorobenzyl azides were pre-
pared similarly from fluorobenzyl bromides. All other reagents
were purchased from either Sigma–Aldrich or Alfa Aesar (Ward
Hill, MA) and used without purification. Acetonitrile (high purity
solvent, Burdick & Jackson; Morristown, NJ) for HPLC was also
used without further treatment. QMA anionic resin cartridges were
supplied by ORTG (Oakdale, TN). NCA [18F]fluoride ion was ob-
tained through the 18O(p,n)18F nuclear reaction by irradiating
[18O]water (95 atom-%) for 90–120 min with a proton beam
(17 MeV; 20 μA) produced with a PETrace cyclotron (GE Medical
Systems; Milwaukee, MI).
8.08 (m, 2 H), 7.87–7.83 (m, 2 H), 7.68 (d, J = 8.4 Hz, 2 H), 7.49
(t, J = 8 Hz, 1 H), 7.36–7.33 (m, 1 H), 7.21 (d, J = 7.6 Hz, 2 H),
7.08–7.05 (m, 2 H), 3.84 (s, 3 H), 2.36 (s, 3 H) ppm. 13C NMR
([D4]MeOD): δ = 164.8, 144.8, 143.8, 141.8, 138.9, 134.1, 132.0,
129.9, 126.3, 124.1, 119.1, 116.9, 104.7, 56.5, 21.5 ppm. HRMS:
calcd. for C13H11N3OI [M – OTs]+ 351.9947; found 351.9951.
[4-(Azidomethyl)phenyl](4Ј-methoxyphenyl)iodonium Tosylate (5):
White solid (0.72 g, 74%). M.p. 149–151 °C. 1H NMR ([D4]-
MeOD): δ = 8.12–8.06 (m, 4 H), 7.67 (d, J = 8 Hz, 2 H), 7.48 (d,
J = 8.8 Hz, 2 H), 7.21 (d, J = 8 Hz, 2 H), 7.05 (dd, J = 2, 9.2 Hz,
2 H), 4.78 (s, 2 H), 3.84 (s, 3 H), 2.36 (s, 3 H) ppm. 13C NMR
([D4]MeOD): δ = 164.7, 143.8, 142.6, 141.8, 138.7, 136.5, 132.6,
130.0, 127.1, 119.0, 115.7, 104.7, 56.5, 54.6, 21.5 ppm. HRMS:
calcd. for C14H13N3OI [M – OTs]+ 366.0103; found 366.0107.
1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded at
room temperature with a Bruker Avance-400 spectrometer. 1H and
13C chemical shifts are reported in δ (ppm) downfield relative to
the signal for tetramethylsilane. The abbreviations br., s, d, t, and
m denote broad, singlet, doublet, triplet, and multiplet, respectively.
HRMS were acquired at the Mass Spectrometry Laboratory, Uni-
versity of Illinois at Urbana-Champaign (Urbana, IL, USA) under
electron ionization conditions with a double-focusing high-resolu-
tion mass spectrometer (Autospec; Micromass Inc., USA). Melting
points were measured with a Mel-Temp manual melting point ap-
paratus (Electrothermal; Fisher Scientific, Pitsburg, PA).
[2-(Azidomethyl)phenyl](4Ј-methoxyphenyl)iodonium Tosylate (6):
White solid (0.78 g, 73%). M.p. 167–169 °C. 1H NMR ([D4]-
MeOD): δ = 8.30 (d, J = 8.4 Hz, 1 H), 8.09 (dd, J = 2, 9.2 Hz, 2
H), 7.70–7.67 (m, 4 H), 7.49–7.45 (m, 1 H), 7.21 (d, J = 8 Hz, 2
H), 7.06 (dd, J = 2, 8.8 Hz, 2 H), 4.74 (s, 2 H), 3.84 (s, 3 H), 2.36
(s, 3 H) ppm. 13C NMR ([D4]MeOD): δ = 164.5, 143.7, 141.8,
139.3, 138.8, 138.6, 134.6, 133.3, 133.1, 129.9, 127.1, 119.8, 119.0,
104.5, 57.4, 56.5, 21.4 ppm. HRMS: calcd. for C14H13N3OI [M –
OTs]+ 366.0103; found 366.0096.
Caution! Many organoazides with high azido content are known
to be explosive.[22] Great care should be exercised during the heat-
ing needed for diaryliodonium salt synthesis (mostly at ca. 40 °C,
with up to 7 mmol of the organic azide in this study). Owing to
possible friction and impact-sensitive character, the isolation of the
final iodonium salts should be conducted in a properly shielded
hood with safety precautions. Also, the test of the complete con-
sumption of mCPBA should be performed with either aqueous po-
tassium iodide or KI starch paper to ensure the absence of organic
peracids after the reaction.[23]
[3-(Azidomethyl)phenyl](4Ј-methoxyphenyl)iodonium Tosylate (7):
White solid (0.82 g, 69%). M.p. 136–138 °C. 1H NMR ([D4]-
MeOD): δ = 8.15 (s, 1 H), 8.11–8.07 (m, 3 H), 7.71–7.64 (m, 3 H),
7.53 (t, J = 8 Hz, 1 H), 7.22 (d, J = 7.6 Hz, 2 H), 7.06 (dd, J = 2,
6.8 Hz, 2 H), 4.47 (s, 2 H), 3.84 (s, 3 H), 2.37 (s, 3 H) ppm. 13C
NMR ([D4]MeOD): δ = 164.8, 143.8, 142.1, 141.8, 138.8, 135.6,
135.4, 133.4, 133.2, 130.0, 127.1, 119.1, 116.8, 104.7, 56.5, 54.5,
21.5 ppm. HRMS: calcd. for C14H13N3OI [M – OTs]+ 366.0103;
found 366.0105.
[4-(Azidomethyl)phenyl](2Ј-thienyl)iodonium Tosylate (8): White so-
lid (0.38 g, 53%). M.p. 163–165 °C. 1H NMR ([D4]MeOD): δ =
8.17 (d, J = 8.4 Hz, 2 H), 8.01 (dd, J = 1.2, 4 Hz, 1 H), 7.88 (dd,
J = 1.2, 5.6 Hz, 1 H), 7.69 (d, J = 8 Hz, 2 H), 7.50 (d, J = 8.4 Hz,
2 H), 7.22 (d, J = 8 Hz, 2 H), 7.17 (dd, J = 5.6, 9.2 Hz, 1 H), 4.49
(s, 2 H), 2.36 (s, 3 H) ppm. 13C NMR ([D4]MeOD): δ = 143.7,
142.9, 142.4, 141.8, 138.8, 136.3, 132.7, 131.0, 130.0, 127.1, 118.1,
99.3, 54.6, 21.5 ppm. HRMS: calcd. for C11H9N3SI [M – OTs]+
341.9562; found 341.9559.
General Procedure for the Synthesis of Diaryliodonium Tosylates:
Azide-functionalized diaryliodonium tosylates were readily ob-
tained in a single step from the corresponding iodoarenes with
mCPBA/pTsOH·H2O and an electron-rich arene such as anisole
and thiophene. The procedure is exemplified by the synthesis of 3.
4-Azidophenyl(4Ј-methoxyphenyl)iodonium Tosylate (3): mCPBA
(0.49 g, 2.2 mmol, 77% max. content) was added to a stirred solu-
tion of 1-azido-4-iodobenzene (0.49 g, 2.0 mmol) in CHCl3 (20 mL)
at room temp. The mixture was stirred at room temp. until it be-
came a pale-yellow solution (ca. 15 min). pTsOH·H2O (0.42 g,
2.2 mmol) was added followed by anisole (1.08 g, 10 mmol). The
reaction mixture was gradually heated to 40 °C and held at this
temperature for about 2 h as the mixture became a yellow solution.
The consumption of 1-azido-4-iodobenzene was monitored by
TLC (Rf = 0.53, hexane) and formation of the intermediate [hy-
droxy(tosyl)iodo]arene was verified with KI starch paper. The sol-
vent was then removed in vacuo. The residual yellow oil was tritu-
rated with Et2O to give a solid that was washed with Et2O and
recrystallized from MeOH/Et2O to give 3 (white solid; 0.58 g,
Synthesis of Diaryliodonium Halides: Diaryliodonium chlorides,
bromides, and iodides were obtained from the corresponding di-
aryliodonium tosylates by anion metathesis with sat. NH4Cl (aq.),
sat. KBr (aq.), and sat. KI (aq.), respectively, as exemplified for 9.
4-Azidophenyl(4Ј-methoxyphenyl)iodonium Chloride (9): 4-Azi-
dophenyl(4Ј-methoxyphenyl)iodonium
tosylate
(3;
0.20 g,
0.38 mmol) was dissolved in MeCN/H2O (H2O10 vol.-%, 2 mL) at
room temp. and heated to 50 °C. The mixture became a clear solu-
tion and was stirred for a further 5 min at 50 °C. Sat. NH4Cl (aq.)
was added dropwise. The reaction mixture was slowly cooled to
room temp. over 30 min. A white solid precipitated out and this
was filtered off, washed with ice-cold water (2 mL) and Et2O
(20 mL), and further dried in vacuo for 3 h to give 9 (0.13 g, 84%).
M.p. 180–182 °C. 1H NMR ([D7]DMF): δ = 8.21 (d, J = 8.8 Hz, 2
H), 8.14 (d, J = 9.2 Hz, 2 H), 7.21 (d, J = 8.8 Hz, 2 H), 7.05 (d, J
= 9.2 Hz, 2 H), 3.86 (s, 3 H) ppm. 13C NMR ([D7]DMF): δ = 162.6,
143.1, 137.0, 136.6, 122.0, 117.3, 117.2, 111.7, 55.7 ppm. HRMS:
calcd. for C13H11N3OI [M – Cl]+ 351.9947; found 351.9949.
56%).
M.p.
150–151 °C.
1H
NMR
([D4]-
MeOD): δ = 8.11–8.05 (m, 4 H), 7.69 (d, J = 8 Hz, 2 H), 7.23–7.17
(m, 4 H), 7.05 (d, J = 8.8 Hz, 2 H), 3.84 (s, 3 H), 2.36 (s, 3 H) ppm.
13C NMR ([D4]MeOD): δ = 164.7, 146.6, 143.8, 141.8, 138.6, 138.0,
130.0, 127.1, 123.6, 119.0, 110.4, 105.1, 56.5, 21.4 ppm. HRMS:
calcd. for C13H11N3OI [M – OTs]+ 351.9947; found 351.9947.
The following diaryliodonium tosylates were prepared similarly.
3-Azidophenyl(4Ј-methoxyphenyl)iodonium Tosylate (4): White solid
1
(0.71 g, 68%). M.p. 143–145 °C. H NMR ([D4]MeOD): δ = 8.12– The following diaryliodonium halides were prepared similarly.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5

Job/Unit: O20695
/KAP1
Date: 03-07-12 16:13:36
Pages: 8
J.-H. Chun, V. W. Pike
FULL PAPER
3-Azidophenyl(4Ј-methoxyphenyl)iodonium Chloride (10): White so-
creasing linearly from 60 to 90% over 7 min. Radioactive products
lid (0.11 g, 91%). M.p. 182–184 °C. 1H NMR ([D6]DMSO): δ = were identified by their co-mobility with reference fluoro com-
8.12 (dd, J = 2.4, 7.2 Hz, 2 H), 7.98 (t, J = 2 Hz, 1 H), 7.02 (dt, J
= 0.8, 5.6 Hz, 1 H), 7.47 (t, J = 8.4 Hz, 1 H), 7.33–7.30 (m, 1 H),
7.03 (dd, J = 2, 6.8 Hz, 2 H), 3.79 (s, 3 H) ppm. 13CNMR
([D6]DMSO): δ = 161.5, 141.6, 136.9, 132.3, 130.7, 124.9, 121.8,
120.6, 117.1, 108.8, 55.6 ppm. HRMS: calcd. for C14H13N3OI [M –
Cl]+ 351.9947; found 351.9957.
pounds. These chromatographically determined RCYs were cor-
rected for the adsorption of radioactivity in the apparatus to give
RCYs from the total [18F]fluoride ion originally introduced into
the microreactor. The amounts of precursor, temperature, and flow
rates were varied to obtain high RCYs.
Wet Radiofluorination: Cyclotron-produced NCA [18F]fluoride ion
(3.7–7.4 MBq) in [18O]water (200 μL) from the cyclotron target was
mixed with DMF (200 μL) and K 2.2.2 (3 mg)/K2CO3 (0.5 mg)
solution in aq. MeCN (5% vol.-%, 100 μL). The solution was left
to stand for 5 min at room temp. and loaded into a storage loop
of the microfluidic apparatus. Reactions were then carried out and
analyzed as for dry radiofluorination reactions.
[4-(Azidomethyl)phenyl](4Ј-methoxyphenyl)iodonium Chloride (11):
White solid (89 mg, 76%). M.p. 163–165 °C. 1H NMR ([D6]-
DMSO): δ = 8.11 (dd, J = 7.6, 15.2 Hz, 4 H), 7.44 (d, J = 7.6 Hz,
2 H), 7.02 (d, J = 8 Hz, 2 H), 4.52 (s, 2 H), 3.78 (s, 3 H) ppm. 13C
NMR ([D6]DMSO): δ = 161.5, 139.2, 136.8, 134.9, 130.8, 119.0,
117.1, 108.5, 55.6, 52.7 ppm. HRMS: calcd. for C14H13N3OI [M –
Cl]+ 366.0103; found 366.0106.
Supporting Information (see footnote on the first page of this arti-
cle): Details of the synthesis of reference azido compounds, copies
of the 1H NMR and 13C NMR spectra for all prepared compounds,
and sample radiochromatograms.
[4-(Azidomethyl)phenyl](4Ј-methoxyphenyl)iodonium Bromide (12):
White solid (0.10 g, 77%). M.p. 176–177 °C. 1H NMR ([D6]-
DMSO): δ = 8.15 (dd, J = 8, 12.4 Hz, 4 H), 7.46 (d, J = 8 Hz, 2
H), 7.04 (d, J = 8.4 Hz, 2 H), 4.53 (s, 2 H), 3.79 (s, 3 H) ppm. 13C
NMR ([D6]DMSO): δ = 161.7, 139.5, 137.0, 135.0, 131.0, 117.9,
117.2, 107.3, 55.6, 52.3 ppm. HRMS: calcd. for C14H13N3OI [M –
Br]+ 366.0103; found 366.0104.
Acknowledgments
We thank the Intramural Research Program of the National Insti-
tutes of Health (NIMH) for the support of this research and are
grateful to the NIH Clinical PET department (Chief, Dr. P. Hersco-
vitch) for production of fluorine-18.
[4-(Azidomethyl)phenyl](4Ј-methoxyphenyl)iodonium Iodide (13):
White solid (0.15 g, 92%). M.p. 152–153 °C. 1H NMR ([D6]-
DMSO): δ = 8.17 (dd, J = 8, 10.8 Hz, 4 H), 7.48 (d, J = 8 Hz, 2
H), 7.06 (d, J = 8.8 Hz, 2 H), 4.54 (s, 2 H), 3.79 (s, 3 H) ppm. 13C
NMR ([D6]DMSO): δ = 161.8, 139.7, 137.1, 135.1, 131.1, 117.3,
117.0, 106.3, 55.7, 52.6 ppm. HRMS: calcd. for C14H13N3OI [M –
I]+ 366.0103; found 366.0105.
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[3-(Azidomethyl)phenyl](4Ј-methoxyphenyl)iodonium Chloride (14):
White solid (0.13 g, 83%). M.p. 177–179 °C. 1H NMR ([D7]DMF):
δ = 8.27 (s, 1 H), 8.19–8.15 (m, 3 H), 7.63 (d, J = 7.6 Hz, 1 H),
8.14 (t, J = 8 Hz, 1 H), 7.05 (d, J = 9.2 Hz, 2 H), 4.60 (s, 2 H),
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366.0107.
–
Cl]+ 366.0103; found
Radiochemistry
Dry Radiofluorination: Cyclotron-produced NCA [18F]fluoride ion
(3.7–7.4 GBq) in [18O]water (250–400 μL) was adsorbed onto a
QMA anionic resin cartridge within a CE module of a NanoTek
apparatus (Advion; Louisville, TN) and then released with a solu-
tion of K2CO3 (0.8 mg, 5 nmol) plus K 2.2.2 (4.5 mg; 11 nmol) in
MeCN/H2O (9:1 v/v; 450 μL) into a 2-mL V-vial. The solution was
dried by two successive cycles of azeotropic evaporation with aceto-
nitrile (0.6 mL) under nitrogen flow at 95 °C. Dried 18F–-K 2.2.2-
K+ complex (3.7–5.5 GBq) was dissolved in reaction solvent (typi-
cally, DMF or MeCN; 260 μL). A solution of diaryliodonium salt
(10 mm) was prepared in matching solvent. Each solution (260 μL)
was loaded into a separate storage loop of the microfluidic appara-
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6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O20695
/KAP1
Date: 03-07-12 16:13:36
Pages: 8
Radiosynthesis of “18F-Labeled Click Synthons”
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Received: May 23, 2012
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Job/Unit: O20695
/KAP1
Date: 03-07-12 16:13:36
Pages: 8
J.-H. Chun, V. W. Pike
FULL PAPER
Radiochemistry
[18F]Click synthons from diaryliodonium
salts: [18F]Fluorobenzyl azides have been
readily prepared through single-step radio-
fluorinations of diaryliodonium salt pre-
cursors.
J.-H. Chun, V. W. Pike* .................... 1–8
Single-Step Radiosynthesis of “18F-La-
beled Click Synthons” from Azide-Func-
tionalized Diaryliodonium Salts
Keywords: Click chemistry / Hypervalent
compounds / Imaging agents / Isotopic la-
beling / Radiochemistry
8
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Eur. J. Org. Chem. 0000, 0–0