Rapid and efficient radiosyntheses of meta-substituted [ 18F]fluoroarenes from [18F]fluoride ion and diaryliodonium tosylates within a microreactor

Article abstract of DOI:10.1002/ejoc.201100382

Effective methods for the introduction of the short-lived positron-emitter fluorine-18 (t_1/2 = 109.7 min) at high specific radioactivity into fluoroarenes are valuable for the development of radiotracers for molecular imaging with positron emis

Full text of DOI:10.1002/ejoc.201100382

FULL PAPER
DOI: 10.1002/ejoc.201100382
Rapid and Efficient Radiosyntheses of meta-Substituted [18F]Fluoroarenes from
[18F]Fluoride Ion and Diaryliodonium Tosylates within a Microreactor
Joong-Hyun Chun,[a] Shuiyu Lu,[a] and Victor W. Pike*[a]
Keywords: Isotopic labeling / Fluorine-18 / Hypervalent compounds / Microreactors / Iodonium salts
Effective methods for the introduction of the short-lived posi-
tron-emitter fluorine-18 (t1/2 = 109.7 min) at high specific
radioactivity into fluoroarenes are valuable for the develop-
ment of radiotracers for molecular imaging with positron
rinations were achieved in unsymmetrical diaryliodonium to-
sylates (ArI+ArЈTsO–), in which Ar carried either a meta elec-
tron-withdrawing (CN, NO2, CF3) or electron-donating (Me
or MeO) group, and in which the partner aryl group (ArЈ)
emission tomography. We have explored the scope of the ra- was relatively electron-rich, such as Ph, 3-MeC6H4, 4-Me-
diofluorination of diaryliodonium salts with no-carrier-added
(NCA) [18F]fluoride ion for the preparation of otherwise diffi-
cult to access meta-substituted [18F]fluoroarenes. A micro-
OC6H4, 2-thienyl, or 5-Me-2-thienyl. The radiofluorination of
appropriate diaryliodonium tosylates is therefore a generally
useful method for the preparation of simple [18F]m-fluoro-
fluidic reaction platform was used to establish optimal radio- arenes ([18F]ArF).
chemical yields. Rapid, high yielding and selective radiofluo-
half-life also allows this isotope to be distributed over dis-
Introduction
tances that may be covered in a few hours to sites where a
production cyclotron is unavailable. Hence, some useful
18F-labeled radiotracers, such as [18F]FDG, have become
commercially available for clinical application through a
network of regional distribution centers.
The short-lived positron-emitter, fluorine-18 (t1/2
=
109.7 min), has gained great importance as a radiolabel for
probes used with positron emission tomography (PET)[1]
–
a molecular imaging technique that is widely applied both
in clinical research[2] and in drug development.[3–8] Expan-
sion of the utility of PET depends on the development and
availability of radioactive probes that are specific to par-
ticular biochemical targets or pathways. Radioligands bind
to specific protein targets such as enzymes, channels, recep-
tors, or transporters to enable their concentrations to be
determined in vivo.[9] Yet other radiotracers may act as en-
zyme substrates and so permit other types of measurement,
such as [18F]2-fluoro-2-deoxy-d-glucose ([18F]FDG) for me-
asuring glucose metabolism.[10] Fluorine-18 is attractive as
a radiolabel for several reasons. These include that (i) fluor-
ine may to some extent mimic a hydrogen atom or hydroxy
group in an organic molecule, (ii) the half-life of fluorine-
18 is well suited to monitoring kinetics in vivo over an ac-
ceptably short scanning session, and (iii) fluorine-18 can be
produced with a moderate energy cyclotron in very high
activities and specific activities through the 18O(p,n)18F re-
action on 18O-enriched water.[11,12] The ease of production
of high amounts of fluorine-18 coupled with its almost 2 h
The 18O(p,n)18F reaction on 18O-enriched water provides
the fluorine-18 as aqueous fluoride ion. Therefore, all ra-
diochemistry with fluorine-18 from this method of pro-
duction must first involve a reaction of fluoride ion. In ge-
neral, this usually implies an aliphatic or aromatic nucleo-
philic substitution reaction.[13] Labeling at aliphatic carbon
atoms can be accomplished efficiently. However, fluorine-
18 bonded to aliphatic carbon may be prone to defluorina-
tion in vivo, giving rise to [18F]fluoride ion, which then
binds avidly to bone. Defluorination can be problematic for
PET scanning. For example, the uptake of [18F]fluoride ion
by skull may compromise PET measurements with the par-
ent radiotracer in nearby brain. For this reason, attachment
of fluorine-18 to an aryl carbon atom is often more attract-
ive, since tendency for radiodefluorination is usually greatly
reduced.
Several methods for preparing 18F-labeled aryl fluorides
have been evaluated and applied. These include the Balz–
Schiemann reaction,[14] the Wallach reaction,[15] and classi-
cal aromatic nucleophilic substitution[13,16,17] (Scheme 1).
The Balz–Schiemann reaction suffers from low maximal
theoretical radiochemical yield (25%), which in practice
may be very much lower on complex substrates, and also
dilution of specific radioactivity due to the co-production
on non-radioactive fluoro product from the usual tetrafluo-
roborate anion. The latter problem may be circumvented by
[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
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100382.
Eur. J. Org. Chem. 2011, 4439–4447
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4439

J.-H. Chun, S. Lu, V. W. Pike
FULL PAPER
use of non-fluorine-containing anions, but the process is
difficult, and radiochemical yields remain low.[18] The Wal-
lach reaction may be performed at high specific radioactiv-
ity but again radiochemical yields tend to be very low on
complex substrates. Over recent decades, classical aromatic
nucleophilic substitution has become the most established
and popular method for preparing [18F]fluoroarenes at high
specific radioactivity.[13,16,17] High radiochemical yields can
be obtained, especially when deploying nitro or trimeth-
ylamino as the leaving group. Nevertheless, this method
also has some limitations. In particular, an electron-with-
drawing group, generally in ortho or para position to the
leaving group, is required on the ring to be fluorinated.
Results and Discussion
Our aim was to study the reactivity of no-carrier-added
(NCA) [18F]fluoride ion towards diaryliodonium salts
(ArI+ArЈX–) bearing one of five meta substituents (OMe,
Me, CN, CF3, or NO2) in one ring (Ar), where this ring is
partnered in the salt with another relatively electron-rich
ring (ArЈ) selected from Ph, 3-MeC6H4, 4-MeOC6H4, 2-thi-
enyl, or 5-Me-2-thienyl. It was necessary to prepare each of
these salts, with poorly nucleophilic tosylate as the pre-
ferred counter anion (X– = TsO–).
Synthesis of Diaryliodonium Salts
Essentially three methods were used to prepare the di-
aryliodonium salts required for this study. These methods
are based on the use of an isolated or in-situ generated
meta-substituted [hydroxy(tosyloxy)iodo]arene (HTIA)
with (i) an electron-rich arene, (ii) an arylboronic acid,[32]
or (iii) an aryltri-n-butylstannane[33] (Scheme 3).
The meta-substituted (diacetoxyiodo)arenes 3–7, re-
quired to prepare HTIAs as reactive intermediates, were ob-
tained by oxidation of the corresponding iodoarenes with
peracetic acid in acetic acid in generally moderate to high
yields (16–75%). The required meta-substituted HTIAs
were then prepared by treating the appropriate substituted
(diacetoxyiodo)arene with tosic acid monohydrate in aceto-
nitrile. The HTIAs bearing a meta-Me (8), -CN (9), or
-CF3 (10) substituent were isolated in high yields (72–91%),
and in some examples these were also prepared and used in
situ. HTIAs with a meta-NO2 or -MeO group were pre-
pared and used in situ only. Regiospecific control was re-
quired for the synthesis of unsymmetrically substituted di-
aryliodonium salts, in which each aromatic ring is dif-
ferently substituted. The direct treatment of reactive elec-
tron-rich arenes, such as anisole, thiophene and 2-methyl-
thiophene, with HTIAs was found to be regiospecific and
produced the 4-methoxyphenyl, 2-thienyl and 5-methyl-2-
thienyl aryliodonium tosylates, respectively. In this manner,
we produced the diaryliodonium tosylates 16–21 from iso-
lated HTIAs in moderate to high yields (36–86%) and 22–
28 from in-situ generated HTIAs in high yields (81–98%).
In the syntheses of other diaryliodonium salt, regioselectiv-
ity was conferred by treatment of a substituted arylboronic
acid or a substituted aryltri-n-butylstannane with the ap-
propriate HTIA.[32,33] Thus, (3-methylphenyl)(phenyl)-
iodonium tosylate (11) was obtained from 3-tolylboronic
acid in low but useful yield (20%). Aryltri-n-butylstannanes
gave the iodonium tosylates 12–15 in low to moderate yields
(25–59%). The requisite 1-cyano-3-(tri-n-butylstannyl)ben-
zene (1) and 1-methoxy-3-(tri-n-butylstannyl)benzene (2)
were readily obtained from the corresponding iodoarenes
with hexabutylditin in moderately high yields (73%). All
prepared diaryliodonium salts were stable to long-term
storage at 4–5 °C under argon.
Scheme 1. Well-explored approaches to the radiosyntheses of [18F]-
fluoroarenes from [18F]fluoride ion.
A more recently explored method for the preparation of
[18F]fluoroarenes is the reaction of [18F]fluoride ion with
diaryliodonium salts (Scheme 2).[19–23] This method permits
the introduction of [18F]fluoride ion not only into electron-
deficient but also into electron-rich rings, and into ortho,[24]
meta or para position to substituents. A mechanism that is
wholly distinct from classical aromatic nucleophilic substi-
tution probably accounts for these useful features.[24,25] De-
spite the great potential of this labeling method, its scope
has not been studied systematically. Here, we take advan-
tage of the benefits of a microfluidic apparatus[26–29] for
performing sequential small-volume radiofluorination reac-
tions under well-controlled conditions as we described pre-
viously,[24,30,31] in order to study the reactions of diaryl-
iodonium salts with [18F]fluoride ion to prepare meta-sub-
stituted [18F]fluoroarenes. We show that these [18F]fluoroar-
enes can be obtained rapidly and in high radiochemical
yield regardless of the electron-donating or withdrawing na-
ture of the meta substituent, provided that the partner ring
in the diaryliodonium salt is relatively electron-rich.
Scheme 2. Synthesis of [18F]fluoroarenes from the radiofluorina-
tion of diaryliodonium salts.
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Radiosyntheses of meta-Substituted [18F]Fluoroarenes
Scheme 3. Preparation of meta-substituted diaryliodonium tosylates 11–28. Reagents, conditions and yields: (i) peracetic acid, AcOH,
room temp., 4 h for 3 (46%), 14 h for 4 (75%), 6 h for 5 (59%), 6 h for 6 (43%), 1 h for 7 (16%); (ii) TsOH·H2O, MeCN; (iii) CHCl3,
reflux, 3 h for 22 (87%), 23 (82%), 24 (90%), 25 (98%), 26 (90%), 27 (86%), 28 (81%); (iv) TsOH·H2O, MeCN for 8 (72%), 9 (79%),
10 (91%); (v) Sn2Bu6, Pd(PPh3)4, toluene, reflux, 14 h for 1 (73%), 2 (73%); (vi) CH2Cl2, reflux, 4 h for 14 (25%), 15 (59%); (vii) CHCl3,
reflux, 4 h for 16 (54%), 17 (69%), 18 (36%), 19 (85%), 20 (86%), 21 (85%); (viii) Koser’s reagent, CH2Cl2; 30 min, room temp. for 11
(20%), 4 h, reflux for 12 (32%), 13 (59%).
Radiochemistry
The microfluidic apparatus allows radiofluorination re-
actions to be performed in rapid sequence under very con-
trolled conditions of reagent concentrations, residence time
and temperature. Therefore, we tested each reaction under
different conditions, in a search for the optimal radiochemi-
cal yield of [18F]m-fluoroarenes. Usually, between 10 and 14
different conditions were tried, involving several different
reaction temperatures. Decay-corrected radiochemical
yields are reported for conditions found to give the highest
incorporation of [18F]fluoride ion into [18F]fluoroarenes.
The diaryliodonium tosylates were adequately soluble in
acetonitrile, and this was chosen as a suitable polar aprotic
reaction medium. Acetonitrile is widely used for reactions
with [18F]fluoride ion, particularly aliphatic nucleophilic
substitution reactions, since the [18F]fluoride ion is readily
solubilized in the presence of K+-K 2.2.2 (K 2.2.2 =
4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane)
as counter anion. In general, acetonitrile solutions of di-
aryliodonium salts were infused into the reactor at a con-
centration of 10 mm and at an infusion rate equal to that
of the acetonitrile solution of NCA [18F]fluoride ion K+-
K 2.2.2 complex. Thus, the concentration of salt within the
micro-reactor was generally 5 mm. These concentrations are
similar to those used in our preceding study of the radioflu-
orination of ortho-substituted diaryliodonium salts.[24] Re-
action times were generally less than 5 min.
All radiochemistry was performed in a microfluidic ap-
paratus. We have recently described the construction and
operation of this apparatus.[24] In essence, the apparatus has
a coiled silica glass capillary tube micro-reactor with an in-
ternal volume of 31.4 μL. This reactor is housed in a heater
which can be thermostatted to any set temperature up to
200 °C. The reactor can be infused simultaneously with two
solutions, a solution of diaryliodonium salt and a solution
of the [18F]fluoride ion reagent, each from a separate reser-
voir at a set flow rate. The reaction time is taken to equate
to the residence time of reagents in the micro-reactor, which
is the internal volume of the reactor divided by its effluent
flow rate. Decay-corrected radiochemical yields (RCYs)
were estimated from the reverse-phase HPLC analysis of
reactor effluent based on the percentage of radioactivity in
the radiochromatogram represented by radioactive product.
All injected radioactivity was found to elute from the
HPLC column. The HPLC measurement was subsequently
corrected for the proportion of used radioactivity not reco-
vered from the micro-reactor apparatus, which was assumed
to be adsorbed [18F]fluoride ion. Radioactivity recovery
was moderate and variable (48Ϯ27%, n = 19). Adsorption
is a common phenomenon in reactions of dry NCA [18F]-
fluoride ion, regardless of reactor material (e.g., glass,
glassy carbon or platinum).[34]
Eur. J. Org. Chem. 2011, 4439–4447
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J.-H. Chun, S. Lu, V. W. Pike
FULL PAPER
Table 1. RCYs of [18F]m-fluoroarenes (Ar18F) from the NCA radiofluorination of diaryliodonium tosylates bearing a meta electron-
withdrawing substituent.
Entry
Diaryliodonium salt (ArI+ArЈTsO–)
T
t[a]
RCY of [18F]fluoroarene [%][b]
Selectivity for Ar18F
Ar
ArЈ
[°C]
[s]
Total
Ar18F
ArЈ18F
1
2
3
4
5
6
7
8
9
15
12
16
14
17
18
22
23
24
19
20
25
3-NCC6H4
3-NCC6H4
3-NCC6H4
3-NCC6H4
3-NCC6H4
3-NCC6H4
3-O2NC6H4
3-O2NC6H4
3-O2NC6H4
3-F3CC6H4
3-F3CC6H4
3-F3CC6H4
3-NCC6H4
Ph
4-MeOC6H4
3-MeC6H4
2-thienyl
5-Me-2-thienyl
4-MeOC6H4
2-thienyl
5-Me-2-thienyl
4-MeOC6H4
2-thienyl
160
130
130
160
160
180
130
130
160
190
180
190
189
146
146
189
189
189
191
140
189
189
236
189
55
26
93
81
60
79
65
35
39
54
66
57
55
n.a.
Ͼ 25
7
15
29
78
8
8
19
25
82
76
58
78
58
31
37
53
66
57
Ͻ 1
11
5
2
1
7
4
2
Ͻ 1
0
10
11
12
Ͼ 53
Ͼ 66
Ͼ 57
5-Me-2-thienyl
0
[a] Residence time in micro-reactor. [b] Decay-corrected, optimized yield chosen from 10–14 different runs. n.a. = not applicable.
Micro-reactor effluents were quenched by dilution in ace- stantially improved RCYs (58–82%) of [18F]m-fluorobenzo-
tonitrile/water (1:1, v/v) at room temperature and then ana- nitrile were obtained with generally high selectivities
lyzed by reverse-phase HPLC with radioactivity detection. (Table 1, Entries 3–6). The radiofluorination of diaryl-
Radiochromatograms were in all cases simple, showing only iodonium salts having an electron-rich aryl ring (4-Me-
separated [18F]fluoride ion at or near the solvent front and OC6H4, 2-thienyl, or 5-Me-2-thienyl) and a phenyl ring
either one or two later-eluted [18F]fluoroarenes. The [18F]m- bearing a meta-NO2 (22–24) or -CF3 group (19, 20, 25) also
fluoroarenes were identified by their comobility in HPLC produced meta-substituted [18F]fluoroarenes in moderate to
with reference fluoroarenes.
quite high RCYs (31–66%) and with high selectivities
We first investigated whether the radiofluorination of di- (Table 1, Entries 7–12). RCYs varied somewhat with the na-
aryliodonium salts was a viable route to [18F]fluoroarenes ture of the electron-rich ring, especially for the m-nitro salts.
bearing an electron-withdrawing meta substituent (Table 1). Overall, these results showed that diaryliodonium tosylates
The reactions of 12 salts were studied (Scheme 4). These can be effective precursors for the rapid (Ͻ 5 min) prepara-
carried a meta-CN, -NO2, or -CF3 group on one ring. The tion of [18F]fluoroarenes bearing meta electron-withdrawing
other ring was relatively electron-rich: phenyl, 3-tolyl, substituents. Hence, this method is a useful adjunct to clas-
4-anisyl, 2-thienyl, or 5-Me-2-thienyl, or in one case 3- sical aromatic nucleophilic substitution with [18F]fluoride
NCC6H4 in a symmetrical salt.
ion in arenes carrying a leaving group in meta position to
a nitro group.[35–37]
We next studied the radiofluorination of diaryliodonium
tosylates bearing meta electron-donating methyl or methoxy
substituents in one ring, and in which the partner ring was
electron-rich Ph, 2-thienyl, or 4-methoxyphenyl (Table 2).
The reactions of 6 salts were studied (Scheme 4). RCYs of
[18F]m-fluoroarenes and product selectivities greatly de-
pended on the nature of the non-meta-substituted electron-
rich ring. Where this ring was phenyl as in 11, the RCY of
[18F]m-fluorotoluene was low (12%) and less than that of
[18F]fluorobenzene (15%) (Table 2, Entry 1). By contrast,
the RCY of [18F]m-fluoroanisole from the phenyl com-
Scheme 4. Preparation of [18F]m-fluoroarenes from NCA radio-
fluorination of diaryliodonium salts within a micro-reactor.
Radiofluorination of the symmetrical salt (15) produced pound 13 was exceptionally high (87%), and co-production
[18F]m-fluorobenzonitrile as the only radioactive product at of [18F]fluorobenzene was low (6% RCY) (Table 2, En-
160 °C in 55% RCY in just over 3 min (Table 1, Entry 1). try 5). Use of 2-thienyl as the electron-rich ring partner gave
Use of the unsymmetrical salt in which one ring was phenyl low RCYs of the target meta-substituted [18F]fluoroarenes
(12) reduced the RCY of [18F]m-fluorobenzonitrile to 25% but with acceptable selectivity (Table 2, Entries 3 and 6).
at 130 °C (Table 1, Entry 2). The selectivity for this product Use of 4-methoxyphenyl as electron-rich ring partner gave
was, however, very high (Ͼ 25). When the m-cyanophenyl [18F]m-fluorotoluene from 21 in moderately high RCY
ring was partnered with a more electron-rich aryl ring, sub- (47%) and good selectivity (Table 1, Entry 2), and gave
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Radiosyntheses of meta-Substituted [18F]Fluoroarenes
Table 2. RCYs of [18F]m-fluoroarenes (Ar18F) from the NCA radiofluorination of diaryliodonium tosylates bearing a meta electron-
donating substituent.
Entry
Diaryliodonium salt (ArI+ArЈTsO–)
T
t[a]
RCY of [18F]fluoroarene [%][b]
Selectivity for Ar18F
Ar
ArЈ
[°C]
[s]
Total
Ar18F
ArЈ18F
1
2
11
21
26
26
13
27
28
3-MeC6H4
3-MeC6H4
3-MeC6H4
3-MeC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
Ph
160
180
190
200
150
200
180
236
236
236
236
236
314
236
27
52
27
82
93
10
37
12
47
26
82
87
9
15
5
Ͻ 1
0
6
1
1
9
4-MeOC6H4
2-thienyl
2-thienyl
Ph
2-thienyl
4-MeOC6H4
3
Ͼ 26
Ͼ 82
15
9
36
4[c]
5
6
7
36
1
[a] Residence time in micro-reactor. [b] Decay-corrected, optimized yield chosen from 10–14 different runs. [c] Reaction performed in
DMF.
[18F]m-fluoroanisole from 28 in moderately high RCY which ArЈ is 3-MeC6H4, 4-MeOC6H4, 2-thienyl, or 5-Me-
(36%) with very high selectivity (Table 2, Entry 7). These 2-thienyl, is a rapid and effective method for producing sim-
results show that the treatment of diaryliodonium salts with ple NCA [18F]m-fluoroarenes with either electron-with-
[18F]fluoride ion can rapidly produce simple [18F]m-fluo- drawing or electron-donating meta substituents from
roarenes with electron-donating substituents in impressively [18F]fluoride ion.
high yields under selected conditions. Diaryliodonium
tosylates that have 4-methoxyphenyl as one of the aryl rings
gave generally moderate to high RCYs with high product
Experimental Section
General Methods: 1H NMR spectra were recorded at 400 MHz, 13
selectivity. Thus, the reactions of appropriately designed di-
aryliodonium salts with [18F]fluoride ion is a uniquely effec-
tive method for the rapid preparation of NCA [18F]fluo-
roarenes bearing meta electron-donating groups, such as
Me or OMe.
C
NMR at 100 MHz and 19F NMR at 376 MHz. No-carrier-added
(NCA) [18F]fluoride ion was obtained through the 18O(p,n)18F nu-
clear reaction by irradiating [18O]water (95 atom-%) for 90–120 min
with a proton beam (17 MeV; 20 μA) produced by a PETrace cyclo-
tron. MP-1 or QMA anion exchange cartridges for [18F]fluoride
ion trapping and release were supplied by ORTG (Oakdale, TN).
Precaution: Peracetic acid (32 wt.-%) is a strong oxidant and may
In this study, we did not systematically study the influ-
ence of solvent on RCY; the vast majority of reactions were
conducted in acetonitrile, which in the microfluidic appara-
tus could be used well above its boiling point. The RCY of cause explosions in the presence of reducing agents and organic
[18F]m-fluoroanisole from the 2-thienyl salt 26 was dramati-
materials.
cally improved to 82% when the reaction was conducted in
DMF instead of acetonitrile (Table 2, Entry 4). Thus, reac-
tion outcomes might well be influenced by solvent (com-
pare Entries 4 and 3 in Table 2), and this may warrant a
Syntheses of Arylstannanes
3-(Tri-n-butylstannyl)benzonitrile (1): 3-Iodobenzonitrile (2.2 mmol,
0.50 g) was mixed with hexabutylditin (2.5 mmol, 1.45 g) and a
catalytic amount of tetrakis(triphenylphosphane)palladium
(0.5 mol-%, 15 mg) in anhydrous toluene (20 mL) under argon. The
resulting mixture was refluxed overnight (ca. 14 h). Palladium cata-
lyst was filtered off and toluene was removed in a rotary evapora-
tor. The crude oily product was purified by column chromatog-
raphy on silica gel (10% EtOAc/hexane; Rf = 0.42) to give 1 as a
further detailed study. In our previous study on the radio-
fluorination of ortho-substituted diaryliodonium salts, we
mainly used DMF (with trace water) as a solvent with im-
pressive results.[24]
In a previous study, the free radical scavenger TEMPO
was reported to be beneficial for improved yield and repro-
ducibility in the reactions of fluoride ion with diaryliodon-
ium salts.[23] As in our previous study of the radiofluorina-
tion of ortho-substituted diaryliodonium salts with NCA
[18F]fluoride ion in the same microfluidic apparatus,[24] here
we observed high and consistent RCYs in the absence of
TEMPO; this is possibly because photoinitiated decomposi-
tion of the salt is avoided.
1
pale yellow oil (0.63 g, 73%). H NMR (CDCl3): δ = 7.72 (t, J =
0.8 Hz, 1 H), 7.68 (dt, J = 0.8, 4.4 Hz, 1 H), 7.57 (dt, J = 1.6,
5.6 Hz, 1 H), 7.40 (t, J = 7.8 Hz, 1 H), 1.48–1.54 (m, 6 H), 1.27–
1.36 (m, 6 H), 1.01–1.05 (m, 6 H), 0.88 (t, J = 7.2 Hz, 9 H) ppm.
13C NMR (CDCl3): δ = 144.2, 140.5, 139.6, 131.4, 128.1, 119.5,
112.1, 28.9, 27.3, 13.6, 9.7 ppm.
1-Methoxy-3-(tri-n-butylstannyl)benzene (2): 3-Iodoanisole (3 mmol,
0.7 g) was mixed with hexabutylditin (3.5 mmol, 2.1 g) and tetrakis-
(triphenylphosphane)palladium (0.5 mol-%, 17 mg) in anhydrous
toluene (20 mL) under argon. The reaction mixture was refluxed
overnight (ca. 12 h). Palladium catalyst was filtered off and toluene
was removed in a rotary evaporator. Crude product was separated
by column chromatography on silica gel (10% EtOAc/hexane; Rf
Conclusions
This study demonstrates that the radiofluorination of un-
symmetrical diaryliodonium tosylates (ArI+ArЈTsO–), in = 0.46) to give 2 as a colorless oil (0.87 g, 73%). 1H NMR (CDCl3):
Eur. J. Org. Chem. 2011, 4439–4447
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4443

J.-H. Chun, S. Lu, V. W. Pike
FULL PAPER
δ = 7.29–7.22 (m, 1 H), 7.01–6.96 (m, 2 H), 6.85–6.82 (m, 1 H), δ = 176.5, 160.5, 131.6, 127.1, 121.4, 120.5, 118.0, 55.8, 20.4 ppm.
3.80 (s, 3 H), 1.57–1.52 (m, 6 H), 1.38–1.28 (m, 6 H), 1.07–1.03 (m,
Synthesis of [Hydroxy(tosyloxy)iodo]arenes
6 H), 0.89 (t, J = 7.2 Hz, 9 H) ppm. 13C NMR (CDCl3): δ = 158.9,
3-[Hydroxy(tosyloxy)iodo]toluene (8): Prepared according to a pub-
143.4,128.8, 128.7, 122.1, 112.9, 55.0, 29.1, 27.4, 13.7, 9.6 ppm.
lished method[41] (0.74 g, 72%); m.p. 126–129 °C. H NMR ([D6]-
1
Syntheses of (Diacetoxyiodo)arenes
DMSO): δ = 9.75 (br. s, 1 H), 8.06–8.00 (m, 2 H), 7.51–7.47 (m, 4
H), 7.12 (dd, J = 0.4, 8.4 Hz, 2 H), 2.38 (s, 3 H), 2.29 (s, 3 H) ppm.
13C NMR ([D6]DMSO): δ = 145.4, 141.1, 137.8, 134.7, 133.1,
131.7, 130.8, 128.1, 125.5, 123.4, 20.8, 20.7 ppm.
3-(Diacetoxyiodo)toluene (3): Peracetic acid (33 mmol; 32 wt.-%, di-
luted in AcOH, 7 mL) was added dropwise to 3-iodotoluene
(8.0 mmol, 1.74 g) at 0 °C. The reaction mixture was then slowly
warmed to room temp. and stirred for ca. 4 h; H2O (ca. 1 mL) was
then added, and the white precipitate was filtered off, washed with
Et2O, and dried in air to give 3 as a white solid (1.25 g, 46%); m.p.
156–159 °C (ref.[38] m.p. 150–152 °C). 1H NMR (CDCl3): δ = 7.92–
7.89 (m, 2 H), 7.40–7.38 (m, 2 H), 2.43 (s, 3 H), 2.01 (s, 6 H) ppm.
13C NMR (CDCl3): δ = 176.6, 141.6, 135.6, 132.9, 132.3, 130.9,
121.7, 21.6, 20.6 ppm.
1-Cyano-3-[hydroxy(tosyloxy)iodo]benzene
(9):
pTsOH·H2O
(1.1 mmol, 0.2 g) in MeCN (10 mL) was added portion-wise to a
solution of 4 (1.0 mmol, 0.35 g) in hot MeCN (10 mL) to give a
yellow solution. A white solid precipitated when the solution was
cooled to room temp. The precipitate was filtered off, washed with
Et2O (20 mL), and dried to give 4 as a slightly yellow solid (0.328 g,
1
79%); m.p. 142–144 °C. H NMR ([D6]DMSO): δ = 9.98 (s, 1 H,
br.), 8.72 (s, 1 H), 8.50 (d, J = 8 Hz, 1 H), 8.16 (d, J = 7.6 Hz, 1
H), 7.80 (t, J = 7.6 Hz, 1 H), 7.47 (d, J = 7.6 Hz, 2 H), 7.12 (d, J
= 7.6 Hz, 2 H), 2.29 (s, 3 H) ppm. 13C NMR ([D6]DMSO): δ =
145.3, 138.7, 137.9, 137.5, 135.9, 131.9, 128.2, 125.5, 123.4, 117.2,
113.5, 20.8 ppm. HRMS: calcd. for C7H5INO [M
245.9416; found 245.9411.
1-Cyano-3-(diacetoxyiodo)benzene (4): Peracetic acid (9.5 mmol; 32
wt.-%, diluted in AcOH, 2 mL) was added dropwise to 3-iodoben-
zonitrile (3.0 mmol, 0.68 g) while cooled in an ice bath. The reac-
tion mixture was then slowly warmed to room temp. and stirred
overnight (ca. 14 h). The resulting white precipitate was filtered off,
washed with Et2O, and dried in air to give 4 as a white solid (0.78 g,
75%); m.p. 188–190 °C (ref.[39] m.p. 188–189 °C). 1H NMR
(CDCl3): δ = 8.37 (t, J = 1.4 Hz, 1 H), 8.31 (dt, J = 1.2, 6.4 Hz, 1
H), 7.89 (dt, J = 1.0, 8.8 Hz, 1 H), 7.66 (t, J = 7.8 Hz, 1 H), 2.04
(s, 6 H) ppm. 13C NMR (CDCl3): δ = 176.8, 138.9, 138.1, 137.1,
131.3, 120.9, 116.7, 115.1, 20.4 ppm.
–
OTs]+
1-[Hydroxy(tosyloxy)iodo]-3-(trifluoromethyl)benzene (10): Pre-
pared according to a published method[42] (1.67 g, 91%); m.p. 154–
1
156 °C (ref.[42] m.p. 158–162 °C). H NMR ([D6]DMSO): δ = 9.94
(br. s, 1 H), 8.60 (s, 1 H), 8.49 (d, J = 8 Hz, 1 H), 8.06–8.04 (m, 1
H), 7.83 (t, J = 7.6 Hz, 1 H), 7.49 (dd, J = 1.6, 6.4 Hz, 2 H), 7.13
(d, J = 8 Hz, 2 H), 2.29 (s, 3 H) ppm. 13C NMR ([D6]DMSO): δ
= 145.0, 138.1, 132.1, 131.1, 130.7 (q, J = 3 Hz), 128.9 (q, J =
3 Hz), 128.2, 125.5, 124.5, 123.7, 121.8, 20.8 ppm. 19F NMR ([D6]-
DMSO): δ = –61.2 ppm. HRMS: calcd. for C7H5F3IO [M – OTs]+
288.9337; found 288.9345.
1-(Diacetoxyiodo)-3-nitrobenzene (5): Peracetic acid (33 mmol; 32
wt.-%, diluted in AcOH, 7 mL) was added dropwise with vigorous
stirring to 1-iodo-3-nitrobenzene (7.0 mmol, 1.74 g) cooled in an
ice bath. The reaction mixture was stirred below 5 °C for 1 h and
then gradually warmed to room temp. Reaction progress was moni-
tored by TLC. After 6 h, the white precipitate was filtered off,
washed with H2O (20 mL) followed by Et2O (20 mL), and dried in
air to give 5 as a white solid (1.5 g, 59%); m.p. 155–158 °C (ref.[39]
Synthesis of Diaryliodonium Salts
By Reaction of [Hydroxy(tosyloxy)iodo]arenes with an Arylboronic
Acid [32]
1
m.p. 148–150 °C). H NMR (CDCl3): δ = 8.95 (t, J = 2 Hz, 1 H),
8.44 (m, 1 H), 8.40 (m, 1 H), 7.23 (t, J = 8 Hz, 1 H), 2.04 (s, 6 H)
ppm. 13C NMR (CDCl3): δ = 176.8, 148.7, 140.4, 131.5, 130.1,
126.3, 120.6, 20.3 ppm.
(3-Methylphenyl)(phenyl)iodonium Tosylate (11): 3-Tolylboronic
acid (4 mmol, 0.54 g) was added portion-wise to a suspension of
Koser’s reagent {[hydroxy(tosyloxy)iodo]benzene; 4.0 mmol, 1.57 g}
in CH2Cl2 (20 mL) at 0 °C. The resulting mixture became a yellow
solution at room temp. over 30 min. CH2Cl2 was removed in vacuo,
and the resulting brown oil was treated with Et2O (20 mL). The
resulting solid was filtered off, washed with Et2O, air-dried and
recrystallized from MeOH/Et2O to give 11 as a white solid (0.36 g,
20%); m.p. 182–184 °C (ref.[43] m.p. 169–170 °C). 1H NMR
(CDCl3): δ = 7.94 (d, J = 7.6 Hz, 2 H), 7.77 (s, 1 H), 7.72 (d, J =
8 Hz, 1 H), 7.51–7.48 (m, 3 H), 7.51–7.27 (m, 3 H), 7.21 (t, J =
7.6 Hz, 1 H), 7.02 (d, J = 7.6 Hz, 2 H), 2.30 (s, 3 H), 2.28 (s, 3 H)
ppm. 13C NMR (CDCl3): δ = 142.2, 139.3, 135.5, 135.1, 132.5,
132.2, 131.6, 131.5, 131.3, 128.4, 126.0, 115.3, 115.1, 21.3,
21.2 ppm. HRMS: calcd. for C13H12I [M – OTs]+ 294.9984; found
294.9986.
1-(Diacetoxyiodo)-3-(trifluoromethyl)benzene (6): The procedure
described for 5 was applied; 1-iodo-3-(trifluoromethyl)benzene
(10 mmol, 2.72 g) with peracetic acid (23.7 mmol; 32 wt.-%, diluted
in AcOH, 5 mL) gave 6 as a white solid (1.69 g, 43%); m.p. 138–
1
139 °C (ref.[40] m.p. 146–147 °C). H NMR (CDCl3): δ = 8.33 (br.
s, 1 H), 8.28 (d, J = 8.4 Hz, 1 H), 7.85 (dd, J = 0.4, 8 Hz, 1 H),
7.65 (t, J = 8 Hz, 1 H), 2.03 (s, 6 H) ppm. 13C NMR (CDCl3): δ =
176.6, 138.1, 133.0 (q, J = 34 Hz), 131.8 (q, J = 4 Hz), 131.2, 131.0,
128.5 (q, J = 4 Hz), 124.2, 121.4, 121.0, 20.3 ppm. 19F NMR
(CDCl3): δ = –62.8 ppm.
1-(Diacetoxyiodo)-3-methoxybenzene (7): Peracetic acid (33 mmol;
32 wt.-%, diluted in AcOH, 7 mL) was added dropwise to 3-
iodoanisole (15 mmol, 3.51 g) in an ice/salt bath (ca. –10 °C). The
reaction mixture was gradually warmed to room temp. and became
a strong yellow solution over 1 h. H2O (10 mL) was added to
quench the reaction, and the aqueous mixture was extracted with
CH2Cl2 (3ϫ 10 mL). The organic layer was dried with MgSO4 and
concentrated in vacuo. The resulting yellow oil was triturated with
Et2O, and the generated white solid was filtered off, washed with
Et2O, and dried in air to give 7 as a pale yellow solid (0.84 g, 16%);
By Reaction of [Hydroxy(tosyloxy)iodo]arenes with Aryltri-n-butyl-
stannanes
(3-Cyanophenyl)(phenyl)iodonium Tosylate (12): The 3-cyano deriv-
ative of Koser’s reagent (9; 1.0 mmol, 0.39 g) was added portion-
wise to a solution of 1 (1.0 mmol, 0.39 g) in CH2Cl2 (20 mL) at
room temp. The mixture was refluxed for 4 h. Solvent was removed
in vacuo, and the resulting yellow oil was triturated with Et2O
(10 mL). The solid was filtered off, washed with Et2O, dried in air
and recrystallized from MeOH/Et2O to give 12 as a white solid
1
m.p. 128–130 °C (ref.[38] m.p. 129–131 °C). H NMR (CDCl3): δ =
7.68–7.64 (m, 2 H), 7.42 (t, J = 8.4 Hz, 1 H), 7.11 (dq, J = 0.8,
2.8 Hz, 1 H), 3.87 (s, 3 H), 2.02 (s, 6 H) ppm. 13C NMR (CDCl3):
(0.15 g, 32%); m.p. 154–155 °C. H NMR ([D6]DMSO): δ = 8.86
1
4444
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4439–4447

Radiosyntheses of meta-Substituted [18F]Fluoroarenes
(s, 1 H), 8.58 (d, J = 8.4 Hz, 1 H), 8.29 (d, J = 7.6 Hz, 2 H), 8.15
(d, J = 8 Hz, 1 H), 7.75–7.68 (m, 2 H), 7.56 (t, J = 8 Hz, 2 H),
7.47 (d, J = 8 Hz, 2 H), 7.15 (d, J = 8 Hz, 2 H), 2.29 (s, 3 H) ppm.
13C NMR ([D6]DMSO): δ = 139.7, 138.4, 137.9, 137.3, 135.7,
135.3, 132.4, 132.3, 131.9, 128.0, 125.5, 117.0, 115.8, 113.9,
20.8 ppm. HRMS: calcd. for C13H9IN [M – OTs]+ 305.9780; found
305.9775.
7.05–6.99 (m, 3 H) ppm. 13C NMR (CDCl3): δ = 141.0, 140.1,
138.7, 137.2, 136.2, 134.5, 131.6, 129.6, 128.7, 125.8, 118.9, 116.5,
114.9, 100.0, 21.3 ppm. HRMS: calcd. for C11H7INS [M – OTs]+
311.9344; found 311.9352.
(3-Cyanophenyl)(5-methyl-2-thienyl)iodonium Tosylate (18): The
procedure described for 16 was applied; 2-methylthiophene
(0.7 mmol, 68 mg) with 9 (0.50 mmol, 0.21 g) gave 18 as a white
1
(3-Methoxyphenyl)(phenyl)iodonium Tosylate (13): The procedure
described for 12 was applied; 2 (2.2 mmol, 0.87 g) with Koser’s rea-
gent (2.5 mmol, 0.98 g) gave 13 as a white solid (0.63 g, 59%); m.p.
solid (90 mg, 36%); m.p. 146–148 °C. H NMR ([D6]DMSO): δ =
8.23 (s, 1 H), 8.57 (d, J = 7.6 Hz, 1 H), 8.12 (d, J = 6.8 Hz, 1 H),
7.95 (s, 1 H), 7.72 (t, J = 7.2 Hz, 1 H), 7.47 (d, J = 7.2 Hz, 2 H),
7.12 (d, J = 6.8 Hz, 2 H), 6.92 (s, 1 H), 2.56 (s, 3 H), 2.29 (s, 3 H)
ppm. 13C NMR ([D6]DMSO): δ = 151.7, 145.5, 141.3, 139.1, 137.8,
135.6, 132.3, 128.3, 128.1, 125.5, 119.7, 117.0, 113.6, 97.4, 20.8,
15.0 ppm. HRMS: calcd. for C12H9NSI [M – OTs]+ 325.9500;
found 325.9503.
1
136–139 °C (ref.[33] m.p. 147–152 °C). H NMR (CDCl3): δ = 7.96
(dd, J = 1.2, 8.4 Hz, 2 H), 7.59 (t, J = 2 Hz, 1 H), 7.50–7.47 (m, 3
H), 7.41 (dd, J = 0.4, 7.2 Hz, 1 H), 7.33 (t, J = 7.6 Hz, 2 H), 7.21
(t, J = 8.4 Hz, 1 H), 7.02–6.97 (m, 3 H), 3.73 (s, 3 H), 2.30 (s, 3 H)
ppm. 13C NMR (CDCl3): δ = 141.6, 138.3, 134.2, 130.9, 130.5,
127.4, 125.9, 124.9, 119.1, 117.7, 114.4, 114.3, 54.8, 20.3 ppm.
HRMS: calcd. for C13H12IO [M – OTs]+ 310.9933; found 310.9926.
(4-Methoxyphenyl)[3-(trifluoromethyl)phenyl]iodonium
Tosylate
(19): The procedure described for 16 was applied; anisole
(2.7 mmol, 0.3 mL) in chloroform (2 mL) with 10 (1.5 mmol,
0.69 g) gave 19 as a white solid (0.70 g, 85%); m.p. 174–175 °C. 1H
NMR (CDCl3): δ = 8.17 (d, J = 8 Hz, 1 H), 8.03 (s, 1 H), 7.84 (dd,
J = 2, 6.8 Hz, 1 H), 7.59 (d, J = 8 Hz, 1 H), 7.36–7.30 (m, 3 H),
6.91 (d, J = 8 Hz, 1 H), 6.74 (dd, J = 2, 7.2 Hz, 2 H), 3.71 (s, 3
H), 2.22 (s, 3 H) ppm. 13C NMR (CDCl3): δ = 162.4, 142.0, 139.6,
138.3, 137.6, 133.0 (q, J = 34 Hz), 131.6, 131.1 (q, J = 4 Hz), 128.5,
127.9 (q, J = 4 Hz), 125.8, 121.4, 117.4, 116.3, 104.6, 55.5,
21.2 ppm. 19F NMR (CDCl3): δ = –62.7 ppm. HRMS: calcd. for
C14H11F3IO [M – OTs]+ 378.9807; found 378.9804.
By Reaction of Isolated HTIAs with Aryltri-n-butylstannanes
(3-Cyanophenyl)(3-methylphenyl)iodonium Tosylate (14): Isolated
HTIA 8 (1.7 mmol, 0.69 g) was added portion-wise to a solution
of 1 (1.7 mmol, 0.70 g) in CH2Cl2 (20 mL). The reaction mixture
was refluxed for 4 h, and solvent was removed in vacuo. The re-
sulting crude oil was triturated with Et2O and the generated solid
washed with Et2O and dried in air to give 14 as a white solid
1
(0.21 g, 25%); m.p. 185–188 °C. H NMR ([D6]DMSO): δ = 8.84
(t, J = 1.6 Hz, 1 H), 8.57 (dq, J = 0.8, 8.4 Hz, 1 H), 8.15–8.13 (m,
2 H), 8.09 (dd, J = 0.4, 8 Hz, 2 H), 7.72 (t, J = 8 Hz, 1 H), 7.51–
7.42 (m, 4 H), 7.11 (d, J = 7.6 Hz, 2 H), 2.35 (s, 3 H), 2.29 (s, 3 H)
ppm. 13C NMR ([D6]DMSO): δ = 145.8, 141.9, 139.6, 138.4, 137.5,
135.6, 135.4, 133.0, 132.4, 132.3, 131.6, 128.0, 125.5, 116.9, 116.7,
116.5, 113.8, 20.8 ppm. HRMS: calcd. for C14H11IN [M – OTs]+
319.9936; found 319.9931.
(2-Thienyl)[3-(Trifluoromethyl)phenyl]iodonium Tosylate (20): The
procedure described for 16 was applied; thiophene (6.0 mmol,
0.5 mL) with 10 (1.5 mmol, 0.69 g) at room temp. (ca. 14 h) gave
20 as a white solid (0.68 g, 86%); m.p. 151–152 °C. 1H NMR
(CDCl3): δ = 8.24 (d, J = 8.4 Hz, 1 H), 8.15 (s, 1 H), 7.85 (dd, J =
1.2, 3.6 Hz, 1 H), 7.66 (d, J = 8 Hz, 1 H), 7.53 (dd, J = 1.2, 5.2 Hz,
1 H), 7.42 (t, J = 7.6 Hz, 1 H), 7.32 (d, J = 8.4 Hz, 2 H), 7.00–6.97
(m, 3 H), 2.29 (s, 3 H) ppm. 13C NMR (CDCl3): δ = 141.7, 140.8,
139.8, 138.0, 136.0, 133.0 (q, J = 31 Hz), 131.6, 130.9 (q, J = 3 Hz),
129.5, 128.5, 128.0 (q, J = 4 Hz), 125.7, 121.2, 118.8, 100.0,
21.2 ppm. 19F NMR (CDCl3): δ = –62.8 ppm. HRMS: calcd. for
C11H7F3IS [M – OTs]+ 354.9265; found 354.9254.
Bis(3-cyanophenyl)iodonium Tosylate (15): The procedure described
for 14 was applied; 1 (1.0 mmol, 0.39 g) with 9 (1.0 mmol, 0.42 g)
1
gave 15 as a white solid (0.63 g, 59%); m.p. 219–220 °C. H NMR
([D6]DMSO): δ = 8.86 (t, J = 1.6 Hz, 2 H), 8.60 (dq, J = 0.8,
5.6 Hz, 2 H), 8.17 (dd, J = 1.2, 6 Hz, 2 H), 7.75 (t, J = 8 Hz, 2 H),
7.46 (d, J = 8 Hz, 2 H), 7.11 (d, J = 8 Hz, 2 H), 2.29 (s, 3 H) ppm.
13C NMR ([D6]DMSO): δ = 139.8, 138.6, 137.6, 135.9, 132.5,
128.0, 125.5, 117.0, 116.9, 114.0, 20.8 ppm. HRMS: calcd. for
C14H8IN2 [M – OTs]+ 330.9732; found 330.9734.
(4-Methoxyphenyl)(3-methylphenyl)iodonium Tosylate (21): The
procedure described for 16 was applied; anisole (2.7 mmol, 0.3 mL)
with 8 (0.7 mmol, 0.28 g) gave 21 as a white solid (0.70 g, 85%);
m.p. 122–126 °C. 1H NMR (CDCl3): δ = 7.88 (d, J = 9.2 Hz, 2 H),
7.75 (s, 1 H), 7.70 (d, J = 8 Hz, 1 H), 7.50 (d, J = 8 Hz, 2 H), 7.27–
7.16 (m, 2 H), 7.02 (d, J = 8 Hz, 2 H), 6.81 (d, J = 8.4 Hz, 2 H),
2.30 (s, 3 H), 2.26 (s, 3 H) ppm. 13C NMR (CDCl3): δ = 162.2,
142.4, 142.0, 139.4, 137.3, 135.0, 132.3, 131.6, 131.2, 128.4, 126.0,
117.3, 115.5, 103.6, 55.5, 21.2 ppm. HRMS: calcd. for C14H14IO
[M – OTs]+ 325.0089; found 325.0078.
By Reaction of Isolated HTIAs with Electron-Rich Arenes
(3-Cyanophenyl)(4-methoxyphenyl)iodonium Tosylate (16): A mix-
ture of anisole (0.5 mL, 4.6 mmol) and 9 (0.25 mmol, 0.11 g) in
chloroform (10 mL) was refluxed for 4 h. After evaporation of sol-
vent under vacuum, the resulting oil was treated with Et2O. The
generated solid was filtered off, washed with Et2O and dried in air
to give 16 as a white solid (69 mg, 56%); m.p. 172–175 °C. 1H
NMR ([D6]DMSO): δ = 8.80 (s, 1 H), 8.52 (d, J = 8 Hz, 1 H), 8.20
(d, J = 8.8 Hz, 2 H), 8.12 (d, J = 7.6 Hz, 1 H), 7.71 (t, J = 8 Hz,
1 H), 7.47 (d, J = 8 Hz, 2 H), 7.10 (t, J = 6.8 Hz, 4 H), 3.80 (s, 3
H), 2.28 (s, 3 H) ppm. 13C NMR ([D6]DMSO): δ = 162.1, 145.7,
139.4, 138.1, 137.6, 137.4, 135.5, 132.3, 128.0,125.5, 117.6, 117.1,
117.0, 113.7, 105.8, 55.7, 20.8 ppm. HRMS: calcd. for C14H11INO
[M – OTs]+ 335.9885; found 335.9894.
By Reaction of In situ Generated HTIAs with Electron-Rich Arenes
(4-Methoxyphenyl)(3-nitrophenyl)iodonium
Tosylate
(22):
pTsOH·H2O (0.50 mmol, 95 mg) was added to a suspension of 5
(0.50 mmol, 0.18 g) in MeCN (5 mL). A yellow solution developed
instantly and then a precipitate. Chloroform (15 mL) was added,
followed by anisole (2.7 mmol, 0.3 mL). The mixture was refluxed
for 3 h. MeCN/chloroform was then removed in vacuo, and the
resulting brown oil was triturated with Et2O (10 mL). The gener-
ated solid was filtered off, washed with Et2O (20 mL), and dried in
air to give 22 as a white solid (0.23 g, 87%); m.p. 167–169 °C
(ref.[43] m.p. 175–180 °C). 1H NMR ([D6]DMSO): δ = 9.13 (s, 1 H),
8.61 (d, J = 8 Hz, 1 H), 8.44 (d, J = 8 Hz, 1 H), 8.27 (d, J = 9.2 Hz,
(3-Cyanophenyl)(2-thienyl)iodonium Tosylate (17): The procedure
described for 16 was applied; thiophene (50 mg, 6 mmol) with 9
(0.50 mmol, 0.21 g) gave 17 as a white solid (0.19 g, 78%); m.p.
151–152 °C. 1H NMR (CDCl3): δ = 8.29 (d, J = 8.4 Hz, 1 H), 8.12
(t, J = 1.2 Hz, 1 H), 7.87 (dd, J = 1.2, 4 Hz, 1 H), 7.67 (d, J =
1.2 Hz, 1 H), 7.56 (dd, J = 1.2, 4 Hz, 1 H), 7.42–7.35 (m, 3 H),
Eur. J. Org. Chem. 2011, 4439–4447
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4445

J.-H. Chun, S. Lu, V. W. Pike
FULL PAPER
2 H), 7.79 (t, J = 8 Hz, 1 H), 7.47 (d, J = 8 Hz, 2 H), 7.12–7.09 125.5, 120.1, 119.3, 117.8, 100.9, 55.9, 20.8 ppm. HRMS: calcd. for
(m, 4 H), 3.80 (s, 3 H), 2.29 (s, 3 H) ppm. 13C NMR ([D6]DMSO):
δ = 162.2, 148.2, 145.6, 140.9, 137.7, 132.7, 129.5, 128.1, 126.5,
125.5, 117.6, 116.9, 105.9, 55.7, 20.8 ppm. HRMS: calcd. for
C13H11INO3 [M – OTs]+ 355.9784; found 355.9778.
C11H10IOS [M – OTs]+ 316.9497; found 316.9492.
(3-Methoxyphenyl)(4-methoxyphenyl)iodonium Tosylate (28): The
procedure described for 22 was applied; 7 (0.3 mmol, 0.13 g) with
anisole (4.6 mmol, 0.5 mL) in the presence of pTsOH·H2O
(0.4 mmol, 76 mg) gave 28 as a white solid (0.15 g, 81%); m.p. 131–
(3-Nitrophenyl)(2-thienyl)iodonium Tosylate (23): The procedure de-
scribed for 22 was applied; 5 (0.50 mmol, 0.18 g) with thiophene
(1.2 mmol, 0.1 mL) in the presence of pTsOH·H2O (0.50 mmol,
95 mg) gave 23 as a white solid (0.21 g, 82%); m.p. 143–146 °C. 1H
NMR ([D6]DMSO): δ = 9.18 (s, 1 H), 8.66 (d, J = 7.6 Hz, 1 H),
8.44 (d, J = 8 Hz, 1 H), 8.17 (d, J = 3.2 Hz, 1 H), 8.00 (d, J =
4.8 Hz, 1 H), 7.81 (t, J = 8.4 Hz, 1 H), 7.46 (d, J = 7.6 Hz, 2 H),
7.21 (t, J = 3.6 Hz, 1 H), 7.11 (d, J = 7.6 Hz, 2 H), 2.29 (s, 3 H)
ppm. 13C NMR ([D6]DMSO): δ = 148.2, 145.6, 141.1, 140.6, 137.9,
137.7, 132.7, 129.8, 129.3, 128.1, 126.7, 125.5, 119.2, 101.3,
20.8 ppm. HRMS: calcd. for C10H7INO2S [M – OTs]+ 331.9242;
found 331.9242.
1
133 °C. H NMR (CDCl3): δ = 7.89 (dd, J = 2, 6.8 Hz, 2 H), 7.58
(t, J = 2 Hz, 1 H), 7.54 (dd, J = 1.6, 6.4 Hz, 2 H), 7.41 (dt, J =
0.8, 7.2 Hz, 1 H), 7.20 (t, J = 8 Hz, 1 H), 7.21 (d, J = 8 Hz, 2 H),
6.96 (dd, J = 0.8, 2.4 Hz, 1 H), 6.83 (dd, J = 2, 7.2 Hz, 2 H), 3.79
(s, 3 H), 3.74 (s, 3 H), 2.31 (s, 3 H) ppm. 13C NMR (CDCl3): δ =
162.4, 161.0, 142.7, 139.3, 137.4, 131.9, 128.5, 126.2, 126.0, 119.5,
118.2, 117.4, 115.7, 103.6, 55.9, 55.6, 21.3 ppm. HRMS: calcd. for
C14H14IO2 [M–OTs]+ 341.0039; found 341.0045.
Microfluidic NCA Radiofluorination of Diaryliodonium Salts
The detailed configuration and operation of the microfluidic device
are described in our previous publications.[24,30] Cyclotron-pro-
duced NCA [18F]fluoride ion (100–200 mCi) in [18O]water (225–
350 μL) was first adsorbed onto an anion exchange resin (i.e., MP-1
or QMA) cartridge within the CE module of a NanoTek apparatus
(Advion) and then released with a solution of K2CO3 (0.8 mg;
5 μmol) plus K 2.2.2 (4.5 mg; 11 μmol) in MeCN/H2O (9:1 v/v;
150 μL) into a 5 mL V-vial. The solution was dried by two cycles
of azeotropic evaporation with MeCN (0.45 mL) at 100 °C. Dry
18F–-K 2.2.2-K+ complex (70–150 mCi) was dissolved in MeCN or
DMF (350 μL). A 10 mm solution of diaryliodonium salt was pre-
pared in the same solvent. Each of the two solutions (255 μL) was
loaded into a separate storage loop of the microfluidic apparatus.
For radiofluorination reactions, each solution (10–15 μL) was in-
fused simultaneously into the 4 m long coiled silica glass tube
micro-reactor of the apparatus at a set flow rate in the range 5–
10 μL/min and at different temperatures. The reaction product exit-
ing the micro-reactor was quenched with MeCN/H2O (1:1, v/v;
1 mL). Amounts of precursor, temperature and flow rates were var-
ied to optimize RCYs. RCYs of [18F]m-fluoroarenes were measured
(5-Methyl-2-thienyl)(3-nitrophenyl)iodonium Tosylate (24): The pro-
cedure described for 22 was applied; 5 (0.50 mmol, 0.18 g) with 2-
methylthiophene (0.7 mmol, 68 mg) in the presence of pTsOH·H2O
(0.50 mmol, 95 mg) gave 24 as a white solid (0.23 g, 90%); m.p.
142–144 °C. 1H NMR ([D6]DMSO): δ = 9.15 (s, 1 H), 8.64 (d, J =
7.6 Hz, 1 H), 8.43 (d, J = 8 Hz, 1 H), 7.99 (d, J = 3.6 Hz, 1 H),
7.80 (t, J = 8 Hz, 1 H), 7.46 (d, J = 7.6 Hz, 2 H), 7.11 (d, J =
7.6 Hz, 2 H), 6.93 (d, J = 2.4 Hz, 1 H), 2.56 (s, 3 H), 2.29 (s, 3 H)
ppm. 13C NMR ([D6]DMSO): δ = 151.8, 148.2, 145.5, 141.5, 140.5,
137.7, 132.7, 129.2, 128.3, 128.1, 126.7, 125.5, 119.4, 20.8,
15.0 ppm. HRMS: calcd. for C11H9NO2SI [M – OTs]+ 345.9399;
found 345.9409.
(5-Methyl-2-thienyl)[3-(trifluoromethyl)phenyl]iodonium
Tosylate
(25): The procedure described for 22 was applied; 6 (2.0 mmol,
0.78 g) with 2-methylthiophene (2.5 mmol, 0.24 g) in the presence
of pTsOH·H2O (2.2 mmol, 0.42 g) gave 25 as a white solid (1.03 g,
98%); m.p. 140–142 °C. 1H NMR (CDCl3): δ = 8.22 (d, J = 8.4 Hz,
1 H), 8.10 (s, 1 H), 7.68–7.63 (m, 2 H), 7.75–7.27 (m, 3 H), 7.01
(d, J = 4.4 Hz, 2 H), 6.65 (dd, J = 1.2, 3.6 Hz, 1 H), 2.53 (s, 3 H),
2.31 (s, 3 H) ppm. 13C NMR (CDCl3): δ = 152.0, 141.8, 141.4,
139.7, 137.6, 132.9 (q, J = 34 Hz), 131.5, 130.6 (q, J = 3 Hz), 128.5,
128.0, 125.8, 123.9, 121.2, 118.9, 21.2, 15.4 ppm. 19F NMR
(CDCl3): δ = –62.8 ppm. HRMS: calcd. for C12H9F3IS [M –
OTs]+ 368.9422; found 368.9412.
by reverse-phase radio-HPLC on
a
Luna C18 column
(250ϫ4.6 mm i.d.; 10 μm) eluted at 1.75 mL/min with a gradient
of MeCN/H2O with the percentage of MeCN increased linearly
from 60 to 90% over 7 min. Retention times were 4.5, 5.6, 3.3,
4.0, 6.2, 5.4, 4.3, 5.0 and 5.1 min for [18F]fluorobenzene, [18F]3-
fluorotoluene, [18F]3-fluorobenzonitrile, [18F]3-fluoronitrobenzene,
[18F]1-fluoro-3-(trifluoromethyl)benzene, [18F]3-fluoroanisole, [18F]-
4-fluoroanisole, [18F]2-fluorothiophene, [18F]2-fluoro-5-methylthio-
phene, respectively. When the gradient was altered to increase
MeCN from 20 to 90% over 11 min, [18F]fluorobenzene and [18F]-
3-fluoroanisole eluted with retention times of 10.9 and 12.2 min,
respectively, and when altered to increase MeCN from 55 to 90%
over 7 min, [18F]3-fluoroanisole and [18F]4-fluoroanisole eluted at
5.4 and 5.0 min, respectively. These products were identified by
their comobility with the respective reference fluoro compounds.
(3-Methylphenyl)(2-thienyl)iodonium Tosylate (26): The procedure
described for 22 was applied; 3 (0.5 mmol, 0.17 g) with thiophene
(1.2 mmol, 0.1 mL) in the presence of pTsOH·H2O (0.5 mmol,
95 mg) gave 26 as a white solid (0.21 g, 90%); m.p. 146–147 °C
1
(ref.[44] m.p. 151–154 °C). H NMR (CDCl3): δ = 7.77–7.76 (m, 2
H), 7.73 (d, J = 8 Hz, 1 H), 7.56 (dd, J = 1.2, 5.6 Hz, 1 H), 7.51
(d, J = 8 Hz, 2 H), 7.28 (s, 1 H), 7.21 (t, J = 8 Hz, 1 H), 7.06–7.01
(m, 3 H), 2.32 (s, 3 H), 2.29 (s, 3 H) ppm. 13C NMR (CDCl3): δ =
142.3, 142.2, 140.3, 139.5, 135.9, 134.4, 132.4, 131.2, 131.1, 129.6,
128.5, 126.0, 118.9, 21.4, 21.3 ppm. HRMS: calcd. for C11H10IS
[M – OTs]+ 300.9548; found 300.9539.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H, 13C and 19F NMR spectroscopic data and sam-
ple radiochromatograms.
(3-Methoxyphenyl)(2-thienyl)iodonium Tosylate (27): The procedure
described for 22 was applied; 7 (1 mmol, 0.35 g) with thiophene
(6.0 mmol, 0.5 mL) in the presence of pTsOH·H2O (1 mmol, 0.19 g)
gave 27 as a white solid (0.42 g, 86%); m.p. 155–157 °C (ref.[45] m.p.
161 °C). 1H NMR ([D6]DMSO): δ = 8.08 (dd, J = 1.6, 4 Hz, 1 H),
7.97 (dd, J = 1.6, 7.6 Hz, 1 H), 7.94–7.93 (m, 1 H), 7.79 (dt, J =
0.4, 2 Hz, 1 H), 7.79–7.42 (m, 3 H), 7.21–7.16 (m, 2 H), 7.13 (d, J
= 7.60 Hz, 2 H), 3.79 (s, 3 H), 2.29 (s, 3 H) ppm. 13C NMR ([D6]-
DMSO): δ = 160.3, 145.6, 140.4, 137.7, 132.4, 129.6, 128.1, 126.6,
Acknowledgments
This research was supported by the Intramural Research Program
of the National Institutes of Health (NIMH). The authors are
grateful to the NIH Clinical Center PET Department (Chief, Dr.
Peter Herscovitch) for the cyclotron production of fluorine-18.
[1] M. E. Phelps, Proc. Natl. Acd. Sci. USA 2000, 97, 9226–9233.
4446
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4439–4447

Radiosyntheses of meta-Substituted [18F]Fluoroarenes
[2]
[3]
[23] M. A. Carroll, J. Nairne, G. Smith, D. A. Widdowson, J. Fluor-
ine Chem. 2007, 128, 127–132.
[24] J.-H. Chun, S. Lu, Y.-S. Lee, V. W. Pike, J. Org. Chem. 2010,
75, 3332–3338.
[25] Y.-S. Lee, M. Hodosˇcˇek, J.-H. Chun, V. W. Pike, Chem. Eur. J.
2010, 16, 10418–10423.
[26] S. Y. Lu, P. Watts, F. T. Chin, J. Hong, J. L. Musachio, E. Bri-
a r d , V. W. P i ke, Lab Chip 2004, 4, 523–525.
[27] C. C. Lee, G. D. Sui, A. Elizarov, C. Y. J. Shu, Y. S. Shin, A. N.
Dooley, J. Huang, A. Daridon, P. Wyatt, D. Stout, H. C. Kolb,
O. N. Witte, N. Satyamurthy, J. R. Heath, M. E. Phelps, S. R.
Quake, H. R. Tseng, Science 2005, 310, 1793–1796.
[28] A. M. Elizarov, Lab Chip 2009, 9, 1326–1333.
[29] P. W. Miller, A. J. deMello, A. D. Gee, Curr. Radiopharm. 2010,
3, 254–262.
D. F. Wong, G. Gründer, J. R. Brasˇic´, Int. Rev. Psychiatry 2007,
19, 541–558.
R. E. Gibson, H. D. Burns, T. G. Hamill, W. S. Eng, B. E.
Francis, C. Ryan, Curr. Radiopharm. Des. 2000, 6, 973–989.
C. M. Lee, L. Farde, Trends Pharmacol. Sci. 2006, 27, 310–316.
H. D. Burns, T. G. Hamill, W. Eng, B. Francis, C. Fioravanti,
R. E. Gibson, Curr. Opin. Chem. Biol. 1999, 3, 388–394.
J. M. Miller, D. Kumar, J. J. Mann, R. V. Parsey, Curr. Ra-
diopharm. 2008, 1, 12–16.
C. Halldin, B. Gulyás, O. Langer, L. Farde, Q. J. Nucl. Med.
2001, 45, 139–152.
S. M. Ametamey, M. Honer, P. A. Schubiger, Chem. Rev. 2008,
108, 1501–1516.
D. Guilloteau, S. Chalon, Curr. Pharm. Des. 2005, 11, 3237–
3245.
J. S. Fowler, T. Ido, in Handbook of Radiopharmaceuticals, Ra-
diochemistry and Applications (Eds.: M. J. Welch, C. S.
Redvanly), Wiley, Chichester, 2003, chapter 9, pp. 307–321.
T. J. Ruth, A. P. Wolf, Radiochim. Acta 1979, 26, 21–24.
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[30] S. Lu, A. M. Giamis, V. W. Pike, Curr. Radiopharm. 2009, 2,
49–55.
[31] S. Lu, V. W. Pike, J. Fluorine Chem. 2010, 131, 1032–1038.
[32] M. A. Carroll, V. W. Pike, D. A. Widdowson, Tetrahedron Lett.
2000, 41, 5393–5396.
[11]
[12] M. Guillaume, A. Luxen, B. Nebeling, M. Argentini, J. C. [33] V. W. Pike, F. Butt, A. Shah, D. A. Widdowson, J. Chem. Soc.
Clark, V. W. Pike, Appl. Radiat. Isot. 1991, 42, 749–762.
[13] L. S. Cai, S. Y. Lu, V. W. Pike, Eur. J. Org. Chem. 2008, 17,
2853–2873.
Perkin Trans. 1 1999, 245–248.
[34] J. W. Brodack, M. R. Kilbourn, M. J. Welch, J. A. Katzenellen-
bogen, Appl. Radiat. Isot. 1986, 37, 217–221.
[35] M. Constantinou, A. Shah, V. W. Pike, J. Label. Compd. Ra-
diopharm. 2001, 44 (Suppl. 1), S889–S891.
[14] G. Balz, G. Schiemann, Ber. Dtsch. Chem. Ges. 1927, 60, 1186–
1190.
[15] O. Wallach, Justus Liebigs Ann. Chem. 1886, 235, 233–255.
[16] H. H. Coenen, in PET Chemistry – The Driving Force in Molec-
ular Imaging (Eds.: P. A. Schubiger, L. Lehman, M. Friebe),
Ernst Schering Research Foundation Workshop 62, Springer-
Verlag, Berlin, 2007, chapter 1, pp. 15–50.
[36] N. Lazarova, F. G. Siméon, J. L. Musachio, S. Y. Lu, V. W.
Pike, J. Labelled Compd. Radiopharm. 2007, 50, 463–465.
[37] T. G. Hamill, S. Krause, C. Ryan, C. Bonnefous, S. Govek, T. J.
Seiders, N. D. P. Cosford, J. Roppe, T. Kamenecka, S. Patel,
R. E. Gibson, S. Sanabria, K. Riffel, W. S. Eng, C. King, X.
Yang, M. D. Green, S. S. O’Malley, R. Hargreaves, H. D.
Burns, Synapse 2005, 56, 205–216.
[38] A. Zielinska, L. Skulski, Molecules 2002, 7, 806–809.
[39] P. Kaz´mierczak, L. Skulski, Synthesis 1998, 1721–1723.
[40] M. D. Hossain, T. Kitamura, Synthesis 2005, 1932–1934.
[41] C. S. Carman, G. F. Koser, J. Org. Chem. 1983, 48, 2534–2539.
[42] T. Nabana, H. Togo, J. Org. Chem. 2002, 67, 4362–4365.
[43] M. C. Caserio, D. L. Glusker, J. D. Roberts, J. Am. Chem. Soc.
1959, 81, 336–342.
[17] F. Wuest, in, PET Chemistry – The Driving Force in Molecular
Imaging (Eds.: P. A. Schubiger, L. Lehman, M. Friebe), Ernst
Schering Research Foundation Workshop 62, Springer-Verlag,
Berlin, 2007, chapter 2, pp. 51–78.
[18] A. Knochel, O. Zwernemann, Appl. Radiat. Isot. 1991, 42,
1077–1080.
[19] V. W. Pike, F. I. Aigbirhio, J. Chem. Soc., Chem. Commun.
1995, 21, 2215–2216.
[20] A. Shah, V. W. Pike, D. A. Widdowson, J. Chem. Soc. Perkin
Trans. 1 1998, 2043–2046.
[44] A. J. Margida, G. F. Koser, J. Org. Chem. 1984, 49, 3643–3646.
[45] T. L. Ross, J. Ermert, C. Hocke, H. H. Coenen, J. Am. Chem.
Soc. 2007, 129, 8018–8025.
[21] M. R. Zhang, K. Kumata, K. Suzuki, Tetrahedron Lett. 2007,
48, 8632–8635.
[22] L. Ross, J. Ermert, C. Hocke, H. H. Coenen, J. Am. Chem. Soc.
2007, 129, 8018–8025.
Received: March 18, 2011
Published Online: June 15, 2011
Eur. J. Org. Chem. 2011, 4439–4447
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4447