Syntheses of mGluR5 PET radioligands through the radiofluorination of diaryliodonium tosylates

Article abstract of DOI:10.1039/c1ob05555k

3-Fluoro-1-((thiazol-4-yl)ethynyl)benzenes constitute an important class of high-affinity metabotropic glutamate subtype 5 receptor (mGluR5) ligands, some of which have been labeled with fluorine-18 (t_1/2 = 109.7 min), to provide radioligands for molecular imaging of brain mGluR5 in living animal and human subjects with positron emission tomography (PET). Labeling in the 3-fluoro position of such ligands can be achieved through aromatic nucleophilic substitution of a halide leaving group with [¹⁸F]fluoride ion when a weakly activating m-nitrile group is present, but is generally very low yielding (<8%). Here we used a microfluidic reaction platform to show that greatly enhanced (up to 6-fold) radiochemical yields can be achieved from suitably synthesized diaryliodonium tosylate precursors. The presence of a m-nitrile or other activating group is not required. Similar conditions were adopted in a more conventional automated radiochemistry platform having a single-pot reactor, to produce mGluR5 radioligands with useful radioactivities for PET imaging.

Full text of DOI:10.1039/c1ob05555k

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Organic &
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PAPER
Syntheses of mGluR5 PET radioligands through the radiofluorination of
diaryliodonium tosylates†
Sanjay Telu, Joong-Hyun Chun, Fabrice G. Sime´on, Shuiyu Lu and Victor W. Pike*
Received 7th April 2011, Accepted 19th May 2011
DOI: 10.1039/c1ob05555k
3-Fluoro-1-((thiazol-4-yl)ethynyl)benzenes constitute an important class of high-affinity metabotropic
glutamate subtype 5 receptor (mGluR5) ligands, some of which have been labeled with fluorine-18
(t1/2 = 109.7 min), to provide radioligands for molecular imaging of brain mGluR5 in living animal and
human subjects with positron emission tomography (PET). Labeling in the 3-fluoro position of such
ligands can be achieved through aromatic nucleophilic substitution of a halide leaving group with
[18F]fluoride ion when a weakly activating m-nitrile group is present, but is generally very low yielding
(<8%). Here we used a microfluidic reaction platform to show that greatly enhanced (up to 6-fold)
radiochemical yields can be achieved from suitably synthesized diaryliodonium tosylate precursors. The
presence of a m-nitrile or other activating group is not required. Similar conditions were adopted in a
more conventional automated radiochemistry platform having a single-pot reactor, to produce
mGluR5 radioligands with useful radioactivities for PET imaging.
Ideally, radioligand syntheses should require only one such
step.
Introduction
We have developed 3-fluoro-5-((2-([18F]fluoromethyl)thiazol-4-
yl)ethynyl)benzonitrile ([18F]1, [18F]SP203, Chart 1) as an effective
PET radioligand for quantifying metabotropic glutamate subtype
5 receptors (mGluR5) in human brain.3,4 This radioligand is
potentially useful for studying the involvement of mGluR5 in
various neuropsychiatric disorders, such as autism (especially
Fragile X syndrome) and drug addiction, and also for the
development of drugs targeting mGluR5. The study of mGluR5 in
living animal brain is also of related biomedical interest. However,
[18F]SP203 has the radiolabel in an aliphatic position. Whereas
this radiolabel adequately resists radiodefluorination in human
subjects,4 this is not the case in rat and monkey.3 In rat, this
radiodefluorination occurs through a mercapturic acid pathway5
and results in avid uptake of [18F]fluoride ion by bone, including
skull. The proximity of radioactivity in skull to that in brain
can compromise the PET measurement of animal brain mGluR5
The short-lived positron-emitter, fluorine-18 (t1/2 = 109.7 min),
attracts intense interest because of its utility as a radiolabel in
probes for molecular imaging in living animal and human subjects
with positron emission tomography (PET).1 Many of these probes,
commonly called radioligands, are targeted at low concentration
protein targets, such as brain neurotransmitter receptors, neu-
rotransmitter transporters, channels and enzymes.1 In order to
avoid saturation of these generally low concentration binding
sites with accompanying non-radioactive probe (carrier) and to
avoid possible pharmacological effects, the radioligands must be
prepared and administered with a high specific radioactivity i.e.,
with a high amount of radioactivity per unit mass of carrier.1
Useful specific radioactivities typically exceed 1 Ci of radioligand
per mmol of carrier. The source of fluorine-18 used to produce the
probes must therefore have a specific radioactivity of at least this
order of magnitude.
The cyclotron-promoted 18O(p,n)18F reaction on 18O-enriched
water is the most attractive and popular route for producing high
activities of fluorine-18 in high specific activities.2 This process
provides the fluorine-18 as [18F]fluoride ion. Hence, the first step
in producing an 18F-labeled PET radioligand has generally been
either an aliphatic or aromatic nucleophilic substitution reaction.
Molecular Imaging Branch, National Institute of Mental Health, National
Institutes of Health, Rm. B3 C346A, 10 Center Drive, Bethesda, MD, 20892-
1003, USA. E-mail: pikev@mail.nih.gov; Fax: +1 301 480 5112; Tel: +1 301
594 5986
† Electronic supplementary information (ESI) available: Copies of 1H, 13
C
and 19F NMR spectra of 5a–e, 6a–c, 7a–c and 8a–c; preparative and analyt-
ical HPLC chromatograms for [18F]2a–c. See DOI: 10.1039/c1ob05555k
Chart 1 Structures of [18F]SP203 and target radioligands.
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densities with [18F]1. Hence, we sought an equivalent radioligand
that does not suffer such radiodefluorination. Compound 1 with
the radiolabel switched to the aryl fluoro position, which we call
[18F]SP203B ([18F]2c, Chart 1), would be expected to meet this
need, since most aryl C–F bonds are stable in vivo.
[18F]3-Fluoro-5-((2-methylthiazol-4-yl)ethynyl)benzonitrile
([18F]F-MTEB, [18F]2a) is a known mGluR5 radioligand6 that has
very similar structure to [18F]2c (Chart 1). [18F]2a was prepared
by Hamill et al. through nucleophilic substitution of a chloro
leaving group with cyclotron-produced [18F]fluoride ion, but only
in low decay-corrected radiochemical yield (RCY; 4 0.9%).6 The
meta-nitrile group is expected to impart only weak activation for
aromatic nucleophilic substitution with [18F]fluoride ion1 and this
likely accounts for the reported low radiochemical yield. Thus, we
predicted that a similar labeling approach would also give a low
radiochemical yield for [18F]2c.
Simple diaryliodonium salts usefully allow efficient introduc-
tion of high specific radioactivity [18F]fluoride ion into aryl
rings, whether electron-rich or poorly activated for conventional
aromatic nucleophilic substitution reactions.7–9 It is increasingly
evident8 that these reactions occur by a mechanism that is dis-
tinct from classical aromatic nucleophilic substitution. Secondary
bonding of the incoming [18F]fluoride ion to the hypervalent iodine
atom before transfer to either of the aryl carbon atoms bonded
to the same iodine atom likely occurs.8 Recently, we have also
shown that diaryliodonium salts may be used to prepare simple
meta-substituted [18F]fluoroarenes.9 We considered that the use of
diaryliodonium salt precursors might deliver higher radiochemical
yields of [18F]2c and related radioligands, and thereby allow
adequate amounts to be prepared regularly for mGluR5 imaging
in animal or human subjects with PET. Therefore we set out to
prepare and test diaryliodonium tosylates as precursors to [18F]2c
and to the two closely related radioligands [18F]2a6 and [18F]2b.3
Here we describe the successful syntheses of appropriate
diaryliodonium tosylates and their use to synthesize [18F]2a–c
in usefully high radiochemical yields, whether in a microfluidic
apparatus8–10 or in a more conventional radiotracer production
platform having a single-pot reactor (Synthia).11
Scheme 1 Syntheses of bromo-precursors 5d and 5e, and the di-
aryliodonium tosylates 7a–c and 8a–c. Reagents and conditions: (a)
Pd(PPh3)4 or Pd(PPh3)2Cl2, CuI, Et3N, DME; (b) 1 M (n-Bu)4NF in THF,
80 ◦C; (c) Sn2(n-Bu)6, Pd(PPh3)4, toluene, 115 ◦C, 16–24 h; (d) Koser’s
reagent, CH2Cl2, r.t., 24–48 h; (e) 1-(diacetoxyiodo)-4-methoxybenzene,
p-TsOH·H2O, MeCN, CH2Cl2, r.t., 24 h.
c were needed as precursors for the tri(n-butyl)stannylarenes, 6a–
c. These iodo compounds were synthesized through Sonogashira
cross-coupling reactions between the trimethylsilyl synthons 3a
or 3b and the iodoarenes, 4a or 4b in 32–42% yields. The
tri(n-butyl)stannylarenes 6a–c were obtained in 39–57% yield by
treating the iodo compounds 5a–c, respectively, with hexa-n-
butylditin.13
In the radiofluorination of diaryliodonium salts that do not
carry ortho substituents, the [18F]fluoride ion usually prefers to
enter the least electron-rich ring.7 We therefore aimed to prepare
diaryliodonium salt precursors to the target radioligands in which
one of the aryl rings would be either a phenyl or 4-methoxyphenyl
group, since these are electron-rich either to a similar or to
a greater extent relative to the aryl ring progenitors of the
radioligands. Treatment of compound 6a with Koser’s reagent
in dichloromethane at room temperature for two days gave the
phenyl(aryl)iodonium tosylate 7a in high purity after double
recrystalization in 14% yield. Similarly, treatment of 6b and 6c
gave the phenyl(aryl)iodonium salts 7b and 7c in 36% and 18%
isolated yields, respectively.
For the syntheses of the required 4-methoxyphenyl-
(aryl)iodonium salts, the required iodine(III) reagent [4-MeO-
C6H4I+(OH)TsO-] was prepared by adding a solution of p-
TsOH·H2O in MeCN to a solution of 4-MeO-C6H4I(OAc)2
in MeCN at room temperature. Formation of the iodine(III)
reagent was indicated by the immediate appearance of a bright
yellow color, sometimes quickly accompanied by a bright yellow
precipitate. This reagent is unstable under solvent-free conditions14
and was therefore used in situ to treat the tri(n-butyl)stannylarenes
6a–c in MeCN–dichloromethane. This method gave the target
4-methoxyphenyl(aryl)iodonium tosylates 8a–c in high purity
after double recrystalization in 22, 50 and 23% isolated yields,
Results and discussion
The main objective of this study was to develop an adequately high
yielding radiosynthesis of 18F-labeled mGluR5 radioligands, based
on a 3-fluoro-1-((thiazol-4-yl)ethynyl)benzene scaffold, in which
the fluorine-18 label is incorporated rapidly into the aryl ring. The
target radioligands were [18F]2a–c (Chart 1). Each of these ligands
is known to have high affinity for mGluR5 in the nanomolar or
sub-nanomolar range,3,6 and one ([18F]2a) is already known to be
an effective imaging agent.6 Our aim was accomplished through
the reaction of novel diaryliodonium salt precursors with high
specific radioactivity [18F]fluoride ion.
Chemistry
Six diaryliodonium salts were required for this study (Scheme 1).
Treatment of tri(alkyl)stannylarenes with Koser’s reagent
[PhI(OH)OTs] is a useful and established approach for the
preparation of diaryliodonium tosylates.12 To make use of this
approach, three iodo analogs (5a–c) of the fluoro compounds 2a–
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respectively. All prepared diaryliodonium salts were stable for at
least 12 months when stored at 4–5 ◦C, in the dark and under
argon.
Additionally, we wished to compare the radiofluorination of
diaryliodonium salt precursors with the radiofluorination of halo-
precursors for conventional aromatic nucleophilic substitution
(SN Ar). Therefore, two bromo compounds, 5d and 5e, were
prepared as potential precursors for the radiosyntheses of [18F]2a
and [18F]2c, respectively. These compounds were obtained through
cross-coupling of the trimethylsilyl synthons 3a or 3b with 3,5-
dibromobenzonitrile (4c) (Scheme 1).
Scheme 3 Radiosyntheses of target radioligands [18F]2a–c from di-
aryliodonium tosylates.
Radiochemistry
DMF in the presence of potassium-K 2.2.2 complex produced
The radiosynthesis of [18F]2a has been achieved previously by
classical aromatic nucleophilic substitution in a chloro-precursor
with [18F]fluoride ion under microwave heating. However, the
isolated RCY was very low (RCY; 4 0.9%).6 We prepared the
corresponding bromo precursor, 5d, and also obtained a low
isolated RCY from its use to prepare [18F]2a (7–8%). Similarly,
the microwave-assisted radiofluorination of the bromo compound
5e in DMSO gave [18F]2c, but the isolated RCY was again very
low (4.0 0.7%, n = 3) (Scheme 2). The RCY did not improve
when DMF was used as solvent. We considered that further
optimization of such radiosyntheses with conventional reaction
platforms would be challenging because of the consumption of
appreciable amounts of precursor and the need to manipulate
radioactive solutions safely.
[18F]2c with RCY increasing up to 19% over the temperature
◦
range 60–160 C (Fig. 1). The selectivity for producing [18F]2c
over [18F]fluorobenzene was very high (~35-fold) across the whole
temperature range (60–200 ◦C). Changing the aryl partner in
the iodonium salt from phenyl to the more electron-rich 4-
methoxyphenyl, as in 8c, gave [18F]2c in an improved RCY of 25 to
◦
28% between 140 and 200 C, with complete product specificity.
The RCY of [18F]2c from 8c increased two-fold between 120 and
140 ◦C but did not improve much more at still higher temperatures
(Fig. 1).
Scheme 2 Syntheses of [18F]2a and [18F]2c via nucleophilic substitution
in bromo precursors 5d and 5e, respectively.
Fig. 1 Effects of aryl partner and TEMPO on RCY of [18F]2c in the
microfluidic apparatus from precursors 7c (aryl partner: Ph) and 8c (aryl
partner: 4-MeOC6H4).
We have recently shown that a NanoTek apparatus equipped
with a microfluidic reactor (internal volume, ~31.4 mL) is an
excellent platform for optimizing radiofluorination reactions.8,9
This apparatus allows sequential radiofluorination reactions to
be carried out remotely with small amounts of non-radioactive
precursor and with very controlled reagent concentrations, re-
action times and reaction temperature. Therefore, we used this
apparatus to test whether the RCY of [18F]2c from 5e could
be improved. Only reactions conducted above 180 ◦C produced
[18F]2c and the highest RCY (just 6%), was obtained when
the reaction was performed at 220 ◦C in DMF. Thus, overall
our results confirmed that halo-precursors are poorly reactive
in SN Ar reactions to produce either [18F]2a or [18F]2c, and
that they would be unsuitable for producing these radioligands
in adequate activities for PET studies in human subjects. We
therefore proceeded to explore diaryliodonium salts as potentially
more promising precursors for the target radioligands, [18F]2a–c
(Scheme 3).
High concentrations of radical scavengers, and especially
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), have been re-
ported to improve the yields and reproducibility of the fluori-
nations of diaryliodonium salts.15 The radiofluorination of 7c in
the presence of 2 equivalents of TEMPO gave appreciable RCYs
of [18F]2c, even at moderate temperature (Fig. 1). Between 60 and
200 ◦C the RCYs of [18F]2c were between 1.9- and 2.5-fold greater
for reactions conducted in the presence of TEMPO over reactions
without TEMPO, and high product selectivity was retained.
The radiofluorination of 4-methoxyphenyl(aryl)iodonium salt
8c in the presence of TEMPO also gave◦an appreciable RCY (14%)
of [18F]2c at moderate temperature (80 C) and this yield increased
to 37% at 160 ◦C. Overall, the presence of TEMPO led to a modest
1.4-fold increase in RCYs between 140 and 200 ◦C.
In our previous studies on the radiofluorination of relatively
simple diaryliodonium salts, in the same micro-reactor, we did
not observe any great effect of added TEMPO on RCY.8,9 Thus,
the benefit of added TEMPO may depend on the structure of
In the micro-reactor, brief (251 s) treatment of the
phenyl(aryl)iodonium salt precursor 7c with [18F]fluoride ion in
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Table 1 Productions of [18F]2c from diaryliodonium tosylate 7c in a microfluidic reactora
Flow rate (mL min-1)
Infused conc’n. (mM)
Specific activity
Methodb 7c
TEMPO 7c [18F]F--K+-K 2.2.2 Residence time (s) RCY (%)c Selectivity for [18F]2c over [18F]PhF (Ci mmol-1)d
A (n = 3)
B (n = 1)
C (n = 2)
D (n = 2)
6
5.7
7
0
0
0
14
0
15
13
10
10
10
10
10
10
75
82
94
94
188
10
10
15 1.4
14 0.7
10 0.7
4
22
18
15
20
23
5
3.4 0.5
4.2
4.8 0.3
8.7 2.4
6.4 1.4
4
2
2
7
E (n = 2) 10
10
a All the reactions were carried out in DMF at 180 ◦C. b Methods A–D infused precursor and radioactive solutions separately. Method E used infusion
of a premixed solution of precursor and [18F]F--K+-K 2.2.2. c Based on radioactivity infused into the reactor. d Decay-corrected to end of radionuclide
production.
the diaryliodonium salt and perhaps its consequent susceptibility
to free radical-induced decomposition. The photosensitivity of
diaryliodonium salts is well-known16 and in some cases they have
been developed as photoinitiators of polymerization reactions.17
Reactions in the micro-reactor occur in the dark and this may be
a factor in suppressing any free radical-induced decomposition of
diaryliodonium salt precursors.
We also examined the radiofluorination of precursors 8a and
8b to synthesize the two other target mGluR5 ligands, [18F]2a and
[18F]2b (Fig. 2). In the radiofluorination of 8a, the RCY of [18F]2a
gradually increased from 10% to 25% between 80 and 140 ◦C
and increased slightly at higher temperature. No unwanted 4-
[18F]fluoroanisole was detected. In the radiofluorination of 8b,
the highest RCY of [18F]2b (42%) was obtained at 180 ◦C. The
selectivity for producing [18F]2b over 4-[18F]fluoroanisole was also
very high (92 48; n = 5).
To test whether [18F]2c could be produced from the microfluidic
apparatus in useful activities for imaging, we also worked with
higher amounts of rad◦ioactivity (120–200 mCi). Reactions were
first performed at 180 C with 7c as precursor in the absence of
TEMPO and were conducted in two ways, either with separate
continuous infusion of precursor and [18F]F--K+-K 2.2.2 reagent
solutions or continuous infusion of a premixed solution of precur-
sor and [18F]F--K+-K 2.2.2 reagent. The RCY of [18F]2c ranged
from 10–15% (Table 1). From these sub-optimal reactions, 7–10
mCi of radiochemically and chemically pure [18F]2c were isolated
after preparative HPLC. These amounts are adequate for clinical
PET experiments. The product had a high specific radioactivity of
>3.4 Ci mmol-1 corrected to the end of radionuclide production.
Inclusion of TEMPO in the reaction gave no significant increase
in RCY.
In our laboratory, the production of 18F-labeled radioligands
from [18F]fluoride ion for clinical use is usually carried out
on a more conventional reaction platform. This consists of a
semi-robotic apparatus (Synthia) configured with a capped glass
vial (1 mL), housed within a microwave heating cavity.11 We
therefore tested whether the useful RCYs obtained for the targeted
radioligands in the microfluidic apparatus could also be obtained
in this more conventional apparatus (Table 2). We first studied
the production of [18F]2c from 7c in which the reaction mixture
was subjected to four successive 2-min microwave irradiations. An
aliquot was taken from the reaction mixture after each irradiation
and analyzed by HPLC. RCY did not improve after the second
microwave irradiation. Based on this observation, we conducted
two 2-min irradiations in all further radiofluorination reactions.
The radiofluorination of 7c (5 mmol) in DMF gave [18F]2c in quite
Fig. 2 Temperature dependence of RCYs of [18F]2a–c from 8a–c,
respectively, in the microfluidic apparatus. Residence times were 251 ( ),
᭺
188 (♦) and 251 s (ꢀ).
Table 2 Productions of [18F]2a–c from diaryliodonium tosylates 7a–c and 8a–c in a Synthia apparatus under microwave conditionsa
Without TEMPO
RCY (%)
With 2 eq. of TEMPO
RCY (%)
Precursor
Product
SA (Ci mmol-1)b
SA (Ci mmol-1)b
7c
8c
7b
8b
7a
8a
[18F]2c
[18F]2c
[18F]2b
[18F]2b
[18F]2a
[18F]2a
8
4
2 (n = 6)
1 (n = 4)
4.5 1.2
1.6 1.7
30 1.5
7.8 1.9
6.8 3.0
NDc
7.5 6.6
6.5 0.3
4.8 2.3
33
8
20 13
40
7
20 1.1
8
2 (n = 2)
a All the experiments were performed in triplicate, except where specified. b Decay-corrected to end of radionuclide production. c HPLC conditions led to
co-elution of [18F]2b along with a non-radioactive impurity with strong UV-absorbance, and therefore SA was not determined (ND).
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low isolated RCY (8%) but with high selectivity for [18F]2c over
[18F]fluorobenzene byproduct (~30-fold). Under the same reaction
conditions, [18F]2c was also obtained in a low RCY (4%) as the
single radioactive product from 8c.
and used without further purification unless otherwise indicated.
HPLC-grade MeCN was purchased from Burdick & Jackson
(Morristown, NJ). MP-1 or QMA anionic resin cartridges were
supplied by ORTG (Oakdale, TN).
TEMPO had a dramatic effect on the RCYs of these microwave-
promoted reactions (Table 2). Thus, inclusion of 2 equivalents of
TEMPO in the reaction mixtures increased the RCY of [18F]2c
from 7c about 4-fold. Selectivity for [18F]2c over [18F]fluorobenzene
was again above 30-fold. Up to 15 mCi of [18F]2c in a formulated
dose ready for intravenous injection were prepared from 200 mCi
of [18F]fluoride ion. In a separate experiment, where the precursor
amount was halved to 2.5 mmol of 7c, the RCY was not greatly
diminished. The radiofluorination of 8c in the presence of TEMPO
gave [18F]2c as the only radioactive product in 8-fold improved
RCY (33%).
General methods
1H- (400 MHz), 13C- (100 MHz) and 19F- (376.5 MHz) NMR
spectra were acquired on an Advance-400 spectrometer (Bruker,
Billerica, MA). For 1H-NMR spectra, chemical shifts of residual
deuterated solvents were used as internal standards. Chemical
shifts (d) for proton and carbon resonances are reported in parts
per million (ppm) downfield from tetramethylsilane (TMS, d = 0
ppm). 19F-NMR spectra were referenced to external CFCl3 (d = 0
ppm) in the indicated solvent.
The radiofluorinations of 7a, 7b, 8a and 8b were also per-
formed with added TEMPO under these conditions (Table 2).
The phenyl(aryl)iodonium salt 7a gave [18F]2a in low RCY
(7%) with 30-fold selectivity over [18F]fluorobenzene. Use of
the corresponding 4-methoxyphenyl(aryl)iodonium salt 8a as
precursor increased the RCY of [18F]2a 3-fold to 20% and
gave no radioactive byproduct. The radiofluorination of the
phenyl(aryl)iodonium salt 7b gave [18F]2b in 20% RCY, with 2.4-
fold selectivity over [18F]fluorobenzene. Use of the corresponding
4-methoxyphenyl(aryl)iodonium salt 8b almost doubled the RCY
of [18F]2b to 40% and also greatly increased selectivity for
this product to ~50-fold. These results highlight the benefit of
using the highly electron-rich 4-methoxyphenyl ring to direct
radiofluorination to the opposite aryl ring, especially when the
target ring is also quite electron-rich. In the case of 8b, where
the target ring is not activated, it is extremely unlikely that useful
activities of [18F]2b could have been obtained by classical SNAr
reactions.
Finally, specific radioactivities of the radioligands [18F]2a–c were
high at the end of radiosyntheses (Tables 1 & 2). A fluorine atom
bonded to an aliphatic carbon could be a potential source of
carrier fluoride in classic SNAr reactions. The presence of such a
fluorine atom in the diaryliodonium salt precursors in this work
did not adversely affect the specific radioactivities of the generated
radioligands.
All reactions were monitored with either thin layer chromatog-
raphy (TLC) or KI/starch paper. Plastic-backed silica gel layers
with fluorescent indicator (250 mm, type 60, UV254; Alltech,
Deerfield, IL) were used for TLC. The absence of a violet color
when a reaction sample was exposed to KI/starch paper dipped
in aqueous acetic acid (50% v/v) was taken to confirm complete
consumption of iodine(III) reagent. Flash chromatography was
performed on silica gel (200 mesh; EM Science, Gibbstown, NJ)
with a hexane–ethyl acetate mixture as mobile phase. The purities
of compounds 5a–e, 7a–c and 8a–c were determined by HPLC
with a Gold 126 solvent module and 166 UV detector (Beckman
Coulter) equipped with a Luna C18 column (5 mm, 4.6 ¥ 250 mm,
Phenomenex, Torrance, CA), eluted with HCOONH4 (10 mM)
in MeCN : H2O (60 : 40 v/v) at 1.75 mL min-1 for 5a–e and at
1.1 mL min-1 for 7a–c and 8a–c. HPLC eluates were monitored
for absorbance at 254 nm.
All iodonium salts were stored in amber vials under argon
in a refrigerator (4–5 ◦C). Melting points were recorded on a
Mel-Temp apparatus (Thermo Fisher Scientific Corp., Waltham,
MA) and are uncorrected. LC-MS was performed on a LCQ
Deca instrument (Thermo Fisher Scientific) equipped with a Luna
C18(2) column (3 mm, 2 ¥ 50 mm) eluted at 200 mL min-1 with
a gradient of A (H2O–MeOH–AcOH; 90 : 10 : 0.5 v/v) and B
(MeOH–AcOH; 100 : 0.5 v/v), initially composed of 20% B and
linearly reaching 80% B over 3 min. High resolution mass spectra
(HRMS) were obtained at the Mass Spectrometry Laboratory,
University of Illinois (Urbana, IL).
Experimental section
Materials
Syntheses of aryl halides through Sonogashira cross-coupling
reactions3
3-Fluoro-5-((2-methylthiazol-4-yl)ethynyl)benzonitrile (2a),6 2-(fl-
uoromethyl)-4-((3-fluorophenyl)ethynyl)thiazole (2b),3 3-fluoro-
5-((2-(fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile (2c),3 2-
methyl-4-((trimethylsilyl)ethynyl)thiazole (3a),18 2-(fluoromethyl)-
4-((trimethylsilyl)ethynyl)thiazole (3b),3 and 1-(diacetoxyiodo)-4-
methoxybenzene19 were synthesized as previously reported.
3-Iodo-5-((2-methylthiazol-4-yl)ethynyl)benzonitrile (5a). Ar-
gon was bubbled into a stirred mixture of 3a (0.98 g, 5.0 mmol),
3,5-diiodobenzonitrile (4b, 2.13 g, 6.0 mmol), Pd(PPh3)4 (194 mg,
168 mmol), CuI (64 mg, 340 mmol) and Et3N (3.5 mL, 25.1 mmol) in
anhydrous 1,2-dimethoxyethane (DME, 25 mL) while the solution
was heated to 80 ◦C. After 10 min, (n-Bu)4NF in THF (1 M;
10 mL) was added dropwise to the reaction mixture under argon
over 10 min. The resulting dark solution was stirred at 80 ◦C
until TLC analysis showed complete consumption of starting
material (~15 min). The reaction mixture was cooled to r.t.,
filtered through a pad of Celite and evaporated to dryness. The
dark residue was dissolved in dichloromethane (50 mL) and then
washed successively with water (2 ¥ 50 mL) and brine (1 ¥ 50 mL).
[Hydroxy(tosyloxy)iodo]benzene
(Koser’s
reagent),
1,3-
diiodobenzene (98%) and 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) were purchased from Sigma-Aldrich (Milwaukee,
WI). 3,5-Diiodobenzonitrile (98%) was supplied by Spectra
Group Ltd. (Millbury, OH). 3-Bromo-5-fluorobenzonitrile and 1-
bromo-3-fluorobenzene were purchased from Oakwood Products,
Inc. (West Columbia, SC). Other reagents and solvents were
purchased from Sigma–Aldrich or Alfa Aesar (Ward Hill, MA)
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The organic phase was dried over MgSO4, filtered and the solvent
evaporated off under reduced pressure. The residue was purified
on a silica gel column eluted successively with 10, 15 and 25% (v/v)
EtOAc in hexane to give 5a as a white solid (0.72 g, 41%); mp 207–
210 ◦C; 1H-NMR (CDCl3): d 8.11 (t, J = 1.6 Hz, 1H), 7.93 (t, J =
1.6 Hz, 1H), 7.67 (t, J = 1.6 Hz, 1H), 7.45 (s, 1H), 2.75 (s, 3H); 13C-
NMR (CDCl3): d 166.3, 144.3, 139.9, 135.7, 133.9, 125.7, 124.0,
116.4, 114.3, 93.5, 87.1, 84.8, 19.3; GC-MS (M+): 350; HRMS
(ESI, [M + H]+): calc’d for C13H8IN2S 350.9453; found, 350.9447;
HPLC: tR, 8.3 min; purity, >99%.
1.0 mmol) and 3,5-dibromobenzonitrile (4c, 0.31 g, 1◦.2 mmol) gave
5e as a white solid (0.095 g, 30%); mp 118.5–120.5 C; 1H-NMR
(CDCl3): d 7.92 (s, 1H), 7.76 (d, J = 1.6 Hz, 2H), 7.68 (s, 1H), 5.65
(d, J = 46.8 Hz, 2H); 13C-NMR (CDCl3): d 165.3 (d, J = 24.1 Hz),
138.6, 136.5, 134.5, 133.5, 125.5, 125.4 (d, J = 1.0 Hz), 122.9,
116.5, 114.5, 86.4, 85.5, 80.6 (d, J = 171.1 Hz); 19F-NMR (CDCl3,
1H-decoupled): d -211.7; GC-MS (M+): 320; HRMS (ESI, [M +
H]+): calc’d for C13H779BrFN2S 320.9497; found, 320.9498; HPLC:
tR, 7.9 min; purity, >99%.
Syntheses of tributylstannanes (6a–c)13
2-(Fluoromethyl)-4-((3-iodophenyl)ethynyl)thiazole (5b). Use
of the procedure described for 5a with 3b (1.0 g, 4.7 mmol) and
1,3-diiodobenzene (4a, 1.85 g, 5.62 mmol) gave 5b as a white solid
3 - ((2 - Methylthiazol - 4 - yl)ethynyl) - 5 - (tri(n - butyl)stannyl) -
benzonitrile (6a). Argon was bubbled into a stirred mixture of
5a (0.38 g, 1.1 mmol), hexa-n-butylditin (1.27 g, 2.2 mmol) and
Pd(PPh3)4 (0.13 g, 0◦.11 mmol) in toluene (20 mL) while the mixture
was heated to 115 C (~15 min). Stirring and heating were then
continued until TLC analysis showed complete consumption of 5a
(~24 h). The reaction mixture was cooled to r.t., filtered through
a column of Celite and evaporated to dryness. Unreacted hexa-n-
butylditin was removed from the dark residue on silica gel column
with hexane as mobile phase. Further elution of the column with
hexane–EtOAc (95 : 5 v/v) gave 6a as a pale yellow oil (0.22 g,
◦
1
(0.67 g, 42%); mp 81–82 C; H-NMR (CDCl3): d 7.92 (t, J =
1.6 Hz, 1H), 7.72–7.68 (m, 1H), 7.60 (s, 1H), 7.51 (dt, J1 = 7.6 Hz,
J2 = 1.2 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 5.64 (d, J = 46.8 Hz,
2H, CH2); 13C-NMR (CDCl3): d 164.8 (d, J = 25.2 Hz), 140.3,
137.9, 137.3, 130.8, 129.9, 124.17, 124.15, 93.7, 87.7, 84.0, 80.6 (d,
J = 170.0 Hz); 19F-NMR (CDCl3, 1H-decoupled): d -211.3; GC-
MS [M+]: 343; HRMS (ESI, [M + H]+): calc’d for C12H8FINS,
343.9406; found, 343.9412; HPLC: tR, 11.3 min; purity, >99%.
3-((2-(Fluoromethyl)thiazol-4-yl)ethynyl)-5-iodobenzonitrile
(5c). Use of the procedure described for 5a with 3b (1.0 g,
4.7 mmol) and 3,5-diiodobenzonitrile (4b, 2.13 g, 6.0 mmol) gave
5c as a white solid (0.55 g, 32%); mp 184–186 ◦C; 1H-NMR
(CDCl3): d 8.12 (t, J = 1.6 Hz, 1H), 7.95 (t, J = 1.6 Hz, 1H),
7.78 (t, J = 1.6 Hz, 1H), 7.68 (s, 1H), 5.65 (d, J = 46.8 Hz, 2H,
CH2); 13C-NMR (CDCl3): d 165.3 (d, J = 25.2 Hz), 144.3, 140.1,
136.5, 133.9, 125.4 (d, J = 1.0 Hz), 125.3 116.3, 114.4, 93.6, 86.4,
1
39%). H-NMR (CDCl3): d 7.87 (s, 1H), 7.73 (s, 1H), 7.67 (s,
2H), 7.44 (s, 1H), 2.75 (s, 3H), 1.64–1.41 (m, 6H), 1.33 (sextet, J =
7.2 Hz, 6H), 1.21–1.02 (m, 6H), 0.90 (t, J = 7.2 Hz, 9H); 13C-NMR
(CDCl3): d 166.0, 144.8, 143.2, 139.1, 136.3, 134.2, 123.2, 123.1,
118.7, 112.3, 87.0, 85.5, 28.9, 27.3, 19.3, 13.7, 9.9.
2-(Fluoromethyl)-4-((3-(tri(n-butyl)stannyl)phenyl)ethynyl)thia-
zole (6b). Use of the procedure described for 6a with 5b (0.43 g,
1.26 mmol) and hexa-n-butylditin (1.46 g, 2.52 mmol) gave 6b as a
colorless oil (0.32 g, 51%). The reaction time was 16 h. 1H-NMR
(CDCl3): d 7.66 (s, 1H), 7.58 (s, 1H), 7.52–7.43 (m, 2H), 7.33–7.28
(m, 1H), 5.64 (d, J = 46.8 Hz, 2H, CH2), 1.64–1.43 (m, 6H), 1.33
(sextet, J = 7.2 Hz, 6H), 1.18–0.98 (m, 6H), 0.89 (t, J = 7.2 Hz, 9H);
13C-NMR (CDCl3): d 164.6 (d, J = 24.1 Hz), 142.4, 139.6, 138.1,
136.8, 131.4, 127.6, 123.4, 121.8, 90.2, 82.7, 80.7 (d, J = 172.1 Hz),
29.1, 27.4, 13.7, 9.6; 19F-NMR (CDCl3, 1H-decoupled): d -211.3.
1
85.4, 80.6 (d, J = 170.0 Hz); 19F-NMR (CDCl3, H-decoupled):
d -211.8; GC-MS [M+]: 368; HRMS (ESI, [M + H]+): calc’d for
C13H7FIN2S, 368.9359; found, 368.9374; HPLC: tR, 8.7 min; purity
>99%.
3-Bromo-5-((2-(methyl)thiazol-4-yl)ethynyl)benzonitrile
(5d).
Compound 3a (1.14 g, 5.7 mmol), 3,5-dibromobenzonitrile (4c,
1.5 g, 5.7 mmol), CuI (219 mg, 1.14 mmol), Pd(PPh3)2Cl2 (420 mg,
0.57 mmol), and Et3N (1.65 mL, 12 mmol) were placed in a
50-mL two-necked round-bottom flask with DME (10 mL) under
argon. Argon was bubbled into the resulting dark solution for
30 min while it was heated to 80 ◦C. A solution of (n-Bu)4NF
(1.0 M) in THF (6.5 mL) was added via syringe over 15 min. The
reaction mixture was stirred at 80 ◦C. After 2 h, TLC showed
that no starting material was present. The reaction mixture was
then cooled to r.t. and poured into aqueous NH4OH (1.0 M;
100 mL) and extracted with methyl tert-butyl ether (3 ¥ 35 mL).
The combined organic fractions were dried over MgSO4, and
evaporated to dryness in vacuo. Chromatography of the residue on
silica gel (EtOAc–hexane, 10 : 90 to 50 : 50, v/v) gave the desired
product as a white powder (955 mg; 55%); mp 128–130 ◦C;
1H-NMR: d 7.90 (t, J = 1.6 Hz, 1H), 7.77–7.73 (m, 2H), 7.46
(s, 1H), 2.75 (s, 3H); 13C-NMR: d 166.3, 138.6, 135.6, 134.3,
133.5, 125.9, 124.1, 122.8, 116.6, 114.4, 87.2, 84.9, 19.3; LC-MS
[M + H]+, m/z: 303.1 and 305.1; HRMS (EI, M+): calc’d for
C13H779BrN2S, 301.9513; found, 301.9504; HPLC: tR, 7.7 min;
purity, >99%.
3 - ((2 - (Fluoromethyl)thiazol - 4 - yl)ethynyl) - 5 - (tri(n - butyl) -
stannyl)benzonitrile (6c). Use of the procedure described for
6a with 5c (0.28 g, 0.75 mmol) and hexa-n-butylditin (0.87 g,
1.5 mmol) gave 6c as colorless oil (0.23 g, 57%). The reaction time
1
was 17 h. H-NMR (CDCl3): d 7.86–7.81 (m, 1H), 7.74 (t, J =
1.6 Hz, 1H), 7.70–7.68 (m, 1H), 7.65 (s, 1H), 5.65 (d, J = 46.8 Hz,
2H, CH2), 1.59–1.48 (m, 6H), 1.33 (sextet, J = 7.2 Hz, 6H), 1.16–
1.08 (m, 6H), 0.90 (t, J = 7.2 Hz, 9H); 13C-NMR (CDCl3): d
165.1 (d, J = 26.2 Hz), 145.0, 143.2, 139.4, 137.2, 134.3, 124.6
(d, J = 2.0 Hz), 122.8, 118.6, 112.4, 87.7, 84.8, 80.6 (d, J =
171.1 Hz), 28.9, 27.3, 13.6, 9.9; 19F-NMR (CDCl3, 1H-decoupled):
d -211.5.
Syntheses of diaryliodonium tosylates (7a–c) through treatment of
6a–c with Koser’s reagent
(3 - Cyano - 5 - ((2 - methylthiazol - 4 - yl)ethynyl)phenyl)(phenyl) -
iodonium tosylate (7a). Koser’s reagent (0.084 g, 0.21 mmol) was
added to a solution of 6a (0.11 g, 0.21 mmol) in dichloromethane
(3 mL). The mixture was stirred under argon at r.t. until TLC anal-
ysis and KI/starch paper test showed reaction was complete (48 h).
3-Bromo-5-((2-(fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile
(5e). Use of the procedure described for 5a with 3b (0.21 g,
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Evaporation of solvent gave a yellow oil. Diethyl ether (15 mL)
was added to this oil and the resulting mixture was sonicated for
5 min. The precipitate was filtered off and recrystallized, first from
MeCN–Et2O and then from MeOH–Et2O, to give 7a as a white
solid (17 mg, 14%). mp 217–220 ◦C (dec.); 1H-NMR (CD3OD): d
8.66 (t, J = 1.6 Hz, 1H), 8.63 (t, J = 1.6 Hz, 1H), 8.27 (d, J = 7.2 Hz,
2H), 8.21 (t, J = 1.6 Hz, 1H), 7.82 (s, 1H), 7.75 (t, J = 7.6 Hz, 1H),
7.69 (d, J = 8.4 Hz, 2H), 7.59 (t, J = 8.0 Hz, 2H), 7.22 (d, J =
7.6 Hz, 2H), 2.73 (s, 3H), 2.36 (s, 3H); 13C-NMR (d6-DMSO): d
166.4, 145.7, 141.6, 138.2, 137.9, 137.5, 135.3, 134.0, 132.4, 131.9,
128.0, 126.7, 125.4, 125.3, 117.1, 116.7, 116.2, 114.4, 88.2, 84.3,
20.7, 18.7; LC-MS (ESI, [M - OTs]+): 426.9; HRMS (ESI, [M -
OTs]+): calc’d for C19H12IN2S, 426.9766; found, 426.9759; HPLC:
tR, 2.9 min; purity >99%.
to precipitate within 5 min. A solution of 6a (0.071 g, 0.14 mmol)
in dichloromethane (3 mL) was added dropwise to the mixture,
which was then stirred under argon at r.t. until TLC analysis
and KI/starch paper test indicated completion of reaction (24 h).
Solvent removal under reduced pressure gave a yellow oil. Diethyl
ether (15 mL) was added to this oil and the resulting mixture was
sonicated for 5 min. The precipitate was collected by filtration and
recrystallized, first from MeCN–Et2O and then MeOH–Et2O, to
give 8a as a white solid (19 mg, 22%). mp 206 ◦C (dec.); 1H NMR
(CD3OD): d 8.59 (t, J = 1.2 Hz, 1H), 8.55 (t, J = 1.2 Hz, 1H),
8.21–8.13 (m, 3H), 7.82 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.21
(d, J = 7.6 Hz, 2H), 7.09 (d, J = 9.2 Hz, 2H), 3.86 (s, 3H), 2.73
(2, 3H), 2.36 (s, 3H); 13C NMR (CD3OD): d 169.1, 164.9, 143.5,
142.2, 141.8, 139.2, 139.0, 138.7, 136.1, 129.9, 128.1, 127.1, 127.0,
119.2, 116.9, 116.8, 116.6, 105.0, 89.0, 85.3, 56.5, 21.4, 18.8; LC-
MS (ESI, [M - OTs]+): 456.9; HRMS (ESI, [M - OTs]+): calc’d
for C20H14IN2OS, 456.9872; found, 456.9872; HPLC: tR, 3.0 min;
purity, >99%.
(3-((2-(Fluoromethyl)thiazol-4-yl)ethynyl)phenyl)(phenyl)iodo-
nium tosylate (7b). Use of the procedure described for 7a with
6b (0.13 g, 0.26 mmol) and Koser’s reagent (0.10 g, 0.26 mmol)
with a reaction time of 24 h gave 7b as a white solid (55 mg, 36%)
after two crystallizations, first from MeCN–Et2O and then from
MeOH–Et2O. mp 175–177 ◦C (dec.); 1H-NMR (CD3OD): d 8.41
(t, J = 1.6 Hz, 1H), 8.27–8.16 (m, 3H), 8.00 (s, 1H), 7.84 (dt, J1 =
7.6 Hz, J2 = 1.2 Hz, 1H), 7.75–7.67 (m, 3H), 7.60–7.52 (m, 3H),
7.22 (d, J = 8.0 Hz, 2H), 5.65 (d, J = 46.8 Hz, 2H, CH2), 2.36 (s,
3H); 13C-NMR (CD3OD): d 167.1 (d, J = 23.1 Hz), 143.6, 141.7,
138.9, 137.8, 136.6, 136.4, 133.9, 133.3, 133.1, 130.9, 129.9, 127.6
(d, J = 2.0 Hz), 127.2, 127.0, 116.3, 115.9, 87.3, 86.6, 81.2 (d, J =
168.0 Hz), 21.3; 19F-NMR (CD3OD, 1H-decoupled): d -211.6; LC-
MS (ESI, [M - OTs]+): 419.9, HRMS (ESI, [M - OTs]+): calc’d for
C18H12FINS, 419.9719; found, 419.9724; HPLC: tR 3.0 min; >99%
purity.
(3-((2-(Fluoromethyl)thiazol-4-yl)ethynyl)phenyl)(4-methoxy-
phenyl)iodonium tosylate, (8b). Use of the procedure described
for 8a with 6b (0.26 g, 0.5 mmol) and in situ generated
[hydroxy(tosyloxy)iodo]arene (HTIA; 0.5 mmol) gave 8b as a
white solid (155 mg, 50%) after recrystallization from MeCN–
Et2O and MeOH–petroleum ether. The reaction time was 24 h.
mp 161–164 ◦C (dec.); 1H-NMR (CD3OD): d 8.33 (s, 1H), 8.20–
8.08 (m, 3 H), 8.00 (s, 1 H), 7.80 (d, J = 7.6 Hz, 1H), 7.68 (d,
J = 8.0 Hz, 2H), 7.52 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz,
2H), 7.06 (d, J = 8.8 Hz, 2H), 5.64 (d, J = 46.8 Hz, 2H, CH2),
3.84 (s, 3H), 2.34 (s, 3H); 13C-NMR (CD3OD): d 167.0 (d, J =
23.1 Hz), 164.7, 143.6, 141.7, 138.8, 138.4, 137.8, 136.2, 136.16,
133.0, 129.9, 127.6 (d, J = 2.0 Hz), 127.1, 127.0, 119.0, 116.4, 104.7,
87.4, 86.5, 81.2 (d, J = 168.0 Hz), 56.4, 21.4; 19F-NMR (CD3OD,
1H-decoupled): d -211.7; LC-MS (ESI, [M - OTs]+): 449.9; HRMS
(ESI, [M - OTs]+): calc’d for C19H14FINOS, 449.9825; found,
449.9825; HPLC: tR, 3.2 min; purity, 98.9%.
(3 - Cyano - 5 - ((2 - (fluoromethyl)thiazol - 4 - yl)ethynyl)phenyl) -
(phenyl)iodonium tosylate (7c). Use of the procedure described
for 7a with 6c (0.55 g, 1.04 mmol) and Koser’s reagent (0.41 g,
1.04 mmol), with a reaction time of 48 h in dichloromethane
(15 mL), gave 7c as a white solid (118 mg, 18%) after crystallizati◦on
from MeCN–Et2O and then from MeOH–Et2O. mp 205–208 C
(dec.); 1H-NMR (CD3OD): d 8.69 (t, J = 1.6 Hz, 1H), 8.65 (t, J =
1.6 Hz, 1H), 8.27 (dt, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H), 8.23 (t, J =
1.2 Hz, 1H), 8.07 (s, 1H), 7.75 (t, J = 7.2 Hz, 1H), 7.69 (d, J =
8.0 Hz, 2H), 7.59 (t, J = 7.6 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 5.65
(d, J = 46.8 Hz, 2H, CH2), 2.36 (s, 3H); 13C-NMR (d6-DMSO):
d 165.0 (d, J = 22.1 Hz), 145.7, 141.7, 138.5, 138.0, 137.6, 135.4,
134.9, 132.4, 132.0, 128.6 (d, J = 2.0 Hz), 128.1, 125.5, 125.1,
117.2, 116.8, 116.2, 114.4, 87.4, 84.8, 80.1 (d, J = 165.0 Hz), 20.8;
19F-NMR (CD3OD, 1H-decoupled): d -211.9; LC-MS (ESI, [M -
OTs]+): 444.9. HRMS (ESI, [M - OTs]+): calc’d for C19H11FIN2S,
444.9672; found, 444.9689; HPLC: tR, 2.9 min; purity,
>99%.
(3-Cyano-5-((2-(fluoromethyl)thiazol-4-yl)ethynyl)phenyl)(4-
methoxyphenyl)iodonium tosylate (8c). Use of the procedure
described for 8a with 6c (0.23 g, 0.43 mmol) and in situ generated
HTIA (0.43 mmol) gave 8c as a white solid (64 mg, 23%) after
double recrystallization from MeCN–Et2O. The reaction time was
◦
1
24 h. mp 196–198 C (dec.); H-NMR (CD3OD): d 8.61 (t, J =
1.6 Hz, 1H), 8.57 (t, J = 1.6 Hz, 1H), 8.23–8.14 (m, 3H), 8.07 (s,
1H), 7.68 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.14–7.06
(m, 2H), 5.65 (d, J = 46.8 Hz, 2H, CH2), 3.86 (s, 3H), 2.36 (s, 3H);
13C-NMR (d6-DMSO): d 164.9 (d, J = 22.1 Hz), 162.1, 145.5,
141.4, 138.2, 137.8, 137.5, 137.3, 134.9, 128.5, 128.0, 125.4, 124.9,
117.6, 117.2, 116.2, 114.2, 106.0, 87.2, 84.8, 80.0 (d, J = 164.0 Hz),
55.6, 20.7; 19F-NMR (CD3OD, 1H-decoupled): d -211.8; LC-MS
(ESI, [M - OTs]+): 475.0; HRMS (ESI, [M - OTs]+) calc’d for
C20H13FIN2OS, 474.9777; found, 474.9765; HPLC: tR, 3.1 min;
purity, >99%.
Syntheses of diaryliodonium tosylates (8a–c) through treatment of
6a–c with in situ generated [4-(hydroxy(tosyloxy))iodo]anisole
(3-Cyano-5-((2-methylthiazol-4-yl)ethynyl)phenyl)(4-methoxy-
phenyl)iodonium tosylate (8a). A solution of p-toluenesulfonic
acid monohydrate (0.027 g, 0.14 mmol) in MeCN (1 mL)
was added to a solution of 1-(diacetoxyiodo)-4-methoxybenzene
(0.053 g, 0.14 mmol) in MeCN (1 mL) under argon. The resulting
pale yellow solution was stirred at r.t. A pale yellow solid started
Radiochemistry
For radiation safety to personnel, radiochemistry was performed
in a lead-shielded hot-cell. Radioactivity was measured with
an Atomlab 300 ionization calibrator (Biodex Medical Systems,
Shirley, NY), and corrected for background and physical decay.
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Radiofluorinations were performed on either a NanoTek microflu-
idic apparatus8a (Advion, Ithaca, NY) or in an in-house modified
Synthia module, equipped with a microwave cavity.11
Radiofluorination reactions in a micro-reactor
Details of the microfluidic apparatus and its operation have been
given in our earlier publication.8a Essentially, the apparatus is
composed of a 4-m long coiled silica capillary glass reactor
with an internal volume of 31.4 mL which may be heated to
any set temperature. The reactor may be fed with two separate
reagents from their respective storage loops at set flow rates
(10–15 mL min-1) controlled by motorized syringes. All reactions
resulted in some adsorption of radioactivity to PEEK, silica glass
tubing or syringe surfaces of the apparatus. RCYs were measured
with HPLC and were corrected for adsorbed radioactivity i.e., the
computed RCY is based on the decay-corrected activity of labeled
product as a percentage of radioactivity infused into the reactor.
The amount of radioactivity lost through absorption was variable
and averaged 20% (n = 32).
Production of [18F]fluoride ion reagents. No-carrier-added
(NCA) [18F]fluoride ion was obtained 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 mA) generated with a
PETrace cyclotron (GE Medical Systems, Milwaukee, WI).
For reactions in the microfluidic apparatus, the [18F]fluoride ion
(50–200 mCi) was adsorbed from the [18O]H2O (90–400 mL) onto
anion resin (either MP-1 or QMA) held within a small cartridge,
and then released with a solution of K2CO3 (1.24 mg, 9 mmol) plus
K 2.2.2 (6.77 mg, 18 mmol) in MeCN–H2O (450 mL, 9 : 1 v/v) into
a V-vial (2-mL, Alltech). The solution was dried by two cycles of
MeCN (0.5 mL) addition and evaporation. The dry [18F]F--K+-K
2.2.2 reagent was then dissolved in DMF (400 mL) and loaded into
a storage loop (315 mL) in the apparatus.
For high activity radiofluorinations, such as those for radio-
tracer production, the [18F]fluoride ion was dried by microwave
heating in a modified Synthia apparatus.11 Thus, a solution of
K2CO3 (0.28 mg, 2 mmol) plus K 2.2.2 (1.50 mg, 4 mmol) in MeCN–
H2O (100 mL, 9 : 1 v/v) and MeCN (200–400 mL) was added to a V-
vial (1-mL, Alltech) containing [18F]fluoride ion (160–300 mCi) in
[18O]H2O (200–500 mL). The vial was then placed in the microwave
cavity and heated with microwaves (90 W in 2 ¥ 2 min pulses) under
N2 gas flow (200 mL min-1) to remove water–MeCN azeotrope.
Three further cycles of MeCN (650 mL) addition and evaporation
were then performed. The dried [18F]F--K+-K 2.2.2 reagent was
dissolved in a solvent of choice, then loaded into a storage loop of
the apparatus.
With separate infusion of halo precursor and [18F]fluoride reagent.
Solutions of bromo precursor 5e (10 mM) in DMF and [18F]F--
K+-K 2.2.2 reagent in DMF (~0.4 mCi mL-1) were loaded into
their respective storage loops (315-mL each). The precursor
solution (15 mL) and [18F]F--K+-K 2.2.2 reagent (10 mL) were
simultaneously infused into the micro-reactor at set flow rates of
6 and 4 mL min-1, respectively, while the micro-reactor was kept
at a fixed temperature of 180 ◦C. Reaction (residence) time was
188 s. The reactor outputs were quenched with H2O–MeCN (1 : 1
v/v, 1 mL). An aliquot of the reaction mixture was analyzed with
HPLC (Method D), revealing [18F]2c with the same retention time
as reference 2c. Reactions were repeated using different infusion
volume, flow rate and temperature.
With separate infusion of iodonium salt precursor and [18F]fluoride
reagent. DMF solutions of diaryliodonium salt precursor
(10 mM) and [18F]F--K+-K 2.2.2 reagent (0.3 mCi mL-1) were
loaded into the respective storage loops (315 mL each). Precur-
sor solution (15 mL) and [18F]F--K+-K 2.2.2 reagent (10 mL)
were simultaneously infused into the micro-reactor at 4.5 and
3 mL min-1, respectively with the micro-reactor held at 160 ◦C. The
residence time was 251 s. Reaction outputs were quenched with
H2O–MeCN (1 : 1 v/v, 1 mL). An aliquot of the reaction mixture
was analyzed with HPLC (Method D). The radioactive products
were identified by comparison of their HPLC retention times
with those of reference 2a–c, fluorobenzene and 4-fluoroanisole.
Each product fraction was also collected for confirmation of its
identity with LC-MS or LC-MS/MS analysis of its associated
carrier. In some radiofluorination reactions with precursors 7c
and 8c, TEMPO (10 mmol) was included in the precursor solution.
Reactions were repeated using different infusion volume, flow rate
and temperature.
HPLC methods for the separation and analysis of radiofluorina-
tion products. HPLC systems were equipped with radioactivity
and UV absorbance detectors (lmax = 310 nm).
Method A: The radioactive product was separated on a Luna
C18 column (5 mm, 10 ¥ 250 mm) eluted at 4 mL min-1 with a
mixture of H2O (A) and MeCN (B). Mobile phase composition
started at 45% B for 2 min, increased linearly to 75% B over 20 min
and finally was held at 75% B for 30 min.
Method B: The radioactive product was separated on a Luna
C18 column (5 mm, 10 ¥ 250 mm), eluted at 3.5 mL min-1 with a
mixture of 25 mM aqueous HCOONH4 (A) and MeCN : 25 mM
HCOONH4 (3 : 1 v/v; B). Mobile phase composition started at
68% B for 2 min, increased linearly to 78% B over 12 min and
finally was held at 78% B for 20 min.
Method C: This method was similar to Method B, except that
mobile phase composition started at 68% B for 35 min, increased
linearly to 100% B over 2 min, and was then held at 100% B for
10 min.
Method D: The radioactive product was analyzed on a Luna
C18 column (10 mm, 4.6 ¥ 250 mm), eluted at 1.75 mL min-1
with a mixture of H2O (A) and MeCN (B). Mobile phase
composition started at 60% B and increased linearly to 90% B over
7 min.
Method E: The radioactive product was analyzed on a Luna C18
column (5 mm, 4.6 ¥ 250 mm) eluted at 1.75 mL min-1 with a mobile
phase of HCOONH4 (10 mM) in MeCN : H2O (60 : 40 v/v).
With separate infusion of iodonium salt precursor and [18F]fluoride
reagent on production activity scale. DMF solutions of 7c
(14 mM) and [18F]F--K+-K 2.2.2 reagent (0.4 mCi mL-1) were
separately loaded into their respective storage loops. These
solutions (254 mL) were simultaneously infused into the micro-
reactor at a flow rate of 10 mL min-1 with the micro-reactor held
at 180 ◦C. The reaction mixture was diluted with H2O (3 mL) and
injected on to HPLC (Method B) ([18F]2c, tR = 22.5 min).
With infusion of premixed reagents. A DMF solution of
precursor 7c (10 mM) was added to dried [18F]F--K+-K 2.2.2
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reagent (0.48 mCi mL-1) and the solution was loaded into one
storage loop. A portion of this solution (195 mL) was infused at
demonstrate the potential of diaryliodonium salts as precursors
for previously poorly accessible 18F-labeled targets.
◦
10 mL min-1 into the micro-reactor held at 180 C. The reaction
outputs were quenched with H2O (3 mL) and the product [18F]2c
separated with HPLC (Method B).
Acknowledgements
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.
Microwave-assisted radiofluorination reactions in a Synthia
apparatus
Radiofluorination of bromo precursor 5d to produce [18F]2a.
A
solution of the bromo precursor 5d (3.0 mg) in DMSO (750 mL)
was added to a closed glass V-vial (1-mL internal volume)
containing dried [18F]F--K+-K 2.2.2 reagent (94 mCi) and heated
at 150 ◦C (100 W in five pulses of 2 min). The temperature reached
~150 ◦C during microwave irradiation and decreased to ~50 ◦C
between microwave pulses. The reaction mixture was diluted with
H2O (0.7 mL) and [18F]2a separated with HPLC (Method A, tR =
25.0 min).
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in DMF (0.5 mL) was added to a closed V-vial containing
dried [18F]F--K+-K 2.2.2 reagent (25–160 mCi). This solution was
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©