An Investigation of (Diacetoxyiodo)arenes as Precursors for Preparing No-Carrier-Added [18F]Fluoroarenes from Cyclotron-Produced [18F]Fluoride Ion

Article abstract of DOI:10.1021/acs.joc.5b02332

Treatment of (diacetoxyiodo)arenes (1a-1u) with cyclotron-produced [¹⁸F]fluoride ion rapidly affords no-carrier-added [¹⁸F]fluoroarenes (2a-2u) in useful yields and constitutes a new method for converting substituted iodoarenes into substituted [¹⁸F]fluoroarenes in just two steps.

Full text of DOI:10.1021/acs.joc.5b02332

Note
pubs.acs.org/joc
An Investigation of (Diacetoxyiodo)arenes as Precursors for
Preparing No-Carrier-Added [18F]Fluoroarenes from Cyclotron-
Produced [18F]Fluoride Ion
Mohammad B. Haskali,† Sanjay Telu,† Yong-Sok Lee,‡ Cheryl L. Morse,† Shuiyu Lu,†
and Victor W. Pike*,†
†Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Room B3 C346A, 10
Center Drive, Bethesda, Maryland 20892-1003, United States
‡Center for Molecular Modeling, Division of Computational Bioscience, Center for Information Technology, National Institutes of
Health, Building 12A, Room 2049, 12 South Drive, Bethesda, Maryland 20892-5624, United States
S
* Supporting Information
ABSTRACT: Treatment of (diacetoxyiodo)arenes (1a−1u) with cyclo-
tron-produced [18F]fluoride ion rapidly affords no-carrier-added [18F]-
fluoroarenes (2a−2u) in useful yields and constitutes a new method for
converting substituted iodoarenes into substituted [18F]fluoroarenes in just
two steps.
seful methods for the rapid preparation of [18F]-
are also known to give the (difluoroiodo)arenes,18 presumably
via the postulated adducts. Moreover, treatment of
(diacetoxyiodo)benzene with Bu4NF has also been found to
constitute a convenient synthesis for the well-known
compound, (difluoroiodo)benzene.19 These prior observations
reinforced our interest in testing whether treatment of
(diacetoxyiodo)arenes with NCA [18F]fluoride ion would
generate ArI(18F)OAc adducts and whether they may be
converted into NCA [18F]fluoroarenes.
To explore the radiofluorination of (diacetoxyiodo)arenes,
several substituted (diacetoxyiodo)arenes (1a−1r) were readily
prepared in one step and in moderate to high yields from the
corresponding iodoarenes, generally by treatment with per-
acetic acid (see the Experimental Section).4,11,13,15,20 Excep-
tionally, oxidation of 1-iodo-4-(trifluoromethyl)benzene by
peracetic acid gave not the (diacetoxyiodo)arene but the
bridged compound μ-oxa-bis[(acetoxyiodo)-4-trifluoromethyl-
benzene] (1s; structure shown in the Supporting Information),
as characterized by NMR and MS data (see the Experimental
Section). Such bridged compounds may arise from hydrolysis
of the corresponding (diacetoxyiodo)arenes when they bear a
strong electron-withdrawing group. Iodoarenes containing a
strongly electron-withdrawing nitro substituent in position 4 or
a cyano substituent in either positions 3 or 4 were best
converted into the corresponding (diacetoxyiodo)arenes by
initial oxone oxidation in trifluoroacetic acid, followed by ligand
exchange in acetic acid (Figure 1).21
U
fluoroarenes at high specific activity from cyclotron-
produced no-carrier-added (NCA) [18F]fluoride ion (t1/2
=
109.7 min) are in high demand because of increasing interest in
the use of 18F-labeled tracers in imaging studies with positron
emission tomography (PET).1 In the context of the need for
rapidly preparing PET radiotracers for injection into animal or
human subjects with minimal separation challenge, metal-free
methods are particularly desirable. In this regard, the use of
hypervalent diaryliodonium salts2−4 or iodonium ylides5,6 as
precursors for preparing [18F]fluoroarenes has already come to
the fore in expanding substrate scope beyond those of
traditional methods, such as classical aromatic nucleophilic
substitution or the earlier Balz Schiemann and Wallach
reactions.7,8 Here, we report on the reactivity of a further
class of hypervalent precursor that also shows value for
preparing [18F]fluoroarenes, namely, the previously unexplored
(diacetoxyiodo)arenes.
(Diacetoxyiodo)arenes are often intermediates in the syn-
thesis of diaryliodonium salts9 and iodonium ylides6,10 and are
useful reagents for oxidation reactions.11 They may be prepared
from iodoarenes,12−17 do not form extended oligomeric
structures, and are readily soluble in many solvents, including
DMF. For these encouraging reasons, we were interested to
explore whether (diacetoxyiodo)arenes were themselves
amenable to radiofluorination to produce NCA [18F]-
fluoroarenes.
Upon treatment of a λ3-iodane (ArIL2), such as a
(diacetoxyiodo)arene, with an external nucleophile (Nu:),
ligand exchange may take place to form an ArI(Nu)L adduct.17
Thus, it has been postulated that an ArI(F)OAc adduct forms
when a (diacetoxyiodo)arene is treated with HF as a source of
F− ion.18 In the presence of excess HF, (diacetoxyiodo)arenes
Radiochemical experiments were performed within a micro-
fluidic apparatus (NanoTek; Advion, Ithaca, NY), which
Received: October 9, 2015
© XXXX American Chemical Society
A
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Note
significantly when the precursor concentration was decreased to
5 mM (entry 8). Therefore, the conditions listed in entry 8
were preferred for subsequent radiofluorination experiments on
a range of variously substituted (diacetoxyiodo)arenes, and also
on (diacetoxyiodo)benzene (1u).
(Diacetoxyiodo)benzene (1u) gave a modest yield (20%) of
[
18F]fluorobenzene (2u) (Figure 2), whereas 4-
(diacetoxyiodo)anisole (1a) gave no desired product. 4-
(Diacetoxyiodo)toluene (1f) also gave a modest yield of
[18F]4-fluorotoluene (2f; 20%). As already seen for 1b,
radiochemical yield improved appreciably with a weak
electron-withdrawing group (CO2Et, 1e; 43%) in the para
position (Figure 2). However, 4-(diacetoxyiodo)nitrobenzene
(1c) gave no desired product (Figure 2).
Interestingly, upon subjecting the bridged compound 1s to
the same reaction conditions, [18F]1-fluoro-4-(trifluoromethyl)-
benzene (2s) was obtained in remarkably high radiochemical
yield (51%). This indicates that modification of the substituents
bonded through oxygen to the hypervalent iodine could be
fruitful for future improvement of reaction yields. Preliminary
experiments have shown that replacements of the diacetoxy
groups with pivaloyl or trifluoroacetyl groups are tolerated
(data not shown).
Figure 1. Syntheses of (diacetoxyiodo)arenes (1a−1r) from
iodoarenes and their conversion into [18F]fluoroarenes.
allowed us to control reagent stoichiometry, temperature, and
residence time in each single experimental run of a consecutive
series on any particular (diacetoxyiodo)arene.20,22
Initially, we explored the reaction of 4-(diacetoxyiodo)-
benzonitrile (1b) with NCA [18F]fluoride ion, with TBA+ as
counterion, in DMF. Gratifyingly, [18F]4-fluorobenzonitrile
(2b) was produced rapidly (90 s) in 11% radiochemical yield at
150 °C (entry 1, Table 1) and also in much higher
Table 1. Yields of [18F]4-Fluorobenzonitrile (2b) from 1b
a
under Various Conditions
An unusual reactivity pattern was observed for ortho-
substituted (diacetoxyiodo)arenes (Figure 2). Those with
electron-withdrawing groups, such as 2-(diacetoxyiodo)-
bromobenzene (1g) and 2-(diacetoxyiodo)trifluoromethyl-
benzene (1h), gave the desired [18F]fluoroarenes, 2g and 2h,
in low radiochemical yields. By contrast, 2-(diacetoxyiodo)-
toluene (1i) gave a moderately high yield of [18F]2-
fluorotoluene (2i; 49%). This suggested that an “ortho effect”
may be operating in a manner similar to that which is well-
known for the radiofluorination of diaryliodonium salts.20
However, addition of a methyl group to the other ortho
position, or to both the other ortho and para positions,
decreased yields (2j and 2t, respectively). Nonetheless, the
tolerance of these reactions for weakly electron-donating
methyl groups is quite striking.
b
entry
1b conc. (mM)
temp. (°C)
time (s)
yield (%)
1
2
10
10
10
10
10
10
10
5
150
200
200
200
200
200
200
200
90
90
11
31
31
19
7
c
3
90
d
4
e
90
5
90
6
7
8
45
21
25
54
180
90
a
Reactions were performed by treating 1b in DMF with [18F]Bu4N+F−
b
under the stated conditions. Based on non-decay-corrected radio-
chemical conversion of [18F]fluoride ion measured with HPLC.
c
d
Reaction performed with K+-K 2.2.2 complex. Reaction in DMSO.
e
Reaction in DMA.
With regard to meta-substituted (diacetoxyiodo)arenes,
some compounds with electron-withdrawing substituents,
such as CF3 (1m), PhCO (1p), and CO2Et (1q), gave
appreciable yields of the respective substituted [18F]-
fluoroarenes (2m, 2p, and 2q), whereas the compound with
a CN substituent (1d) gave a low yield and the compounds
with a nitro (1n) or acetyl (1o) substituent gave no desired
product (Figure 3). Generally, the introduction of [18F]fluoride
ion into an aryl meta position with respect to an electron-
donating group is especially challenging. Remarkably, the
radiochemical yield (31%) at 200 °C (entry 2). Replacement
of TBA+ with K+-K 2.2.2 (entry 3), which is also commonly
used as a solubilizing counterion for NCA [18F]fluoride ion,1
gave the same radiochemical yield. Reactions performed in
either DMSO or DMA (entries 4 and 5) gave inferior
radiochemical yields to that in DMF. Optimal residence time
in the microreactor was found to be 90 s from the use of a 5
μL/min flow rate for the input of each reagent (compare entry
2 with entries 6 and 7). The radiochemical yield of 2b increased
Figure 2. Para- and ortho-substituted [18F]fluoroarenes prepared from the corresponding (diacetoxyiodo)arenes (except 2s was prepared from
bridged compound 1s). Yields represent radiochemical conversion of [18F]fluoride ion, measured with HPLC.
B
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Note
Figure 3. Meta-substituted [18F]fluoroarenes prepared from the corresponding (diacetoxyiodo)arenes. Yields represent radiochemical conversion of
[18F]fluoride ion, measured with HPLC.
Figure 4. Reaction coordinate for the interaction of fluoride ion with 1u (see the Experimental Section for quantum chemical calculation). TS-I and
TS-II represent transition states I and II, respectively. Atoms are colored as follows: white, hydrogen; gray, carbon; yellow, fluorine; purple, iodine;
red, oxygen; blue, potassium. Distances are in Å.
compound with a 3-methyl group (1l) gave 3-[18F]-
fluorotoluene (2l) with the highest radiochemical yield (63%)
of all tested compounds, and the 3,5-dimethyl compound (1k)
gave a moderately useful yield of compound (2k) (39%)
(Figure 3). The 3-methoxy compound (1r) gave very low yield
(3%).
predict that the formation of (acetoxyfluoroiodo)benzene is
thermodynamically favored with a low energy barrier of 16.4
kcal mol−1 (Figure 4). Moreover, the conversion of 1u into
fluorobenzene was calculated to have a free energy of activation
(ΔG⧧) of 33.8 kcal mol−1 with respect to the intermediate state
(II), with energetically favored formation of fluorobenzene
(relative free energy −26.6 kcal mol−1). In terms of bond
distances, the covalent Ar−I distance shortens slightly from
2.16 Å in the first stage (I) to 2.13 Å in II, while the ionic I−F
bond (2.43 Å) in I becomes covalent (2.14 Å) in II. At
transition state II (TS-II), this covalent Ar−I bond is
lengthened to 2.60 Å, and the fluorine forms a partial bond
(2.03 Å) with the ipso aryl carbon atom.
In order to gain some mechanistic insight on the reactions
observed between [18F]fluoride ion and (diacetoxyiodo)arenes,
we performed experiments to examine whether 3-
(diacetoxyiodo)toluene (1l) undergoes ligand exchange with
Bu4NF·hydrate. The latter (0.83 equiv) was added to 1l (1
equiv) in chloroform. Upon exposing this solution to slow
1
ingress of diethyl ether, crystals formed overnight. H NMR
spectroscopy revealed that these crystals were Bu4NOAc
unaccompanied by fluoride ion, as determined by the absence
of an 19F NMR signal. Furthermore, the 19F NMR spectrum of
the remaining filtrate presented a single signal (−131 ppm
relative to the signal from CFCl3) that was significantly
different from that of Bu4NF·hydrate (−122 ppm). This
experiment affirmed the ability of fluoride ion to undergo ligand
exchange at the iodine center of a (diacetoxyiodo)arene.
Encouraged by these observations, we also performed
quantum chemical calculations to assess the energetics for
ligand exchange of fluoride ion with (diacetoxyiodo)benzene
(1u) and for subsequent conversion of the postulated
intermediate adduct into fluorobenzene. These calculations
We further noted that radiochemical yields of para-
substituted [18F]fluoroarenes were not linear with substituent
Hammett σp constants23 but showed a bell-shaped relationship
(Figure 5). This may indicate that the rate-determining step of
the reaction (and/or the mechanism itself) changes with
increasing σp value. For meta-substituted [18F]fluoroarenes, no
such clear relationship was seen between radiochemical yields
and Hammett σm values. However, a weak inverse relationship
between radiochemical yield and the F (field) factors23 was
observed (Figure 6). This indicates that inductive effects are
somewhat important for the radiofluorination of (diacetoxy-
iodo)arenes with meta substituents. Overall, the mechanisms of
C
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EXPERIMENTAL SECTION
■
Materials and Methods. Fluoroarenes, 3-iodobenzophenone,
(diacetoxyiodo)benzene (1u), (diacetoxyiodo)2,4,6-trimethylbenzene
(1t), and other chemicals and solvents were purchased commercially.
1H (400 MHz), 13C (100 MHz), and 19F (376.5 MHz) NMR spectra
were recorded on an Avance 400 instrument at rt in deuterated
solvents, as later indicated. 1H and 13C NMR signals are reported as δ
(ppm) downfield from the signal for tetramethylsilane. 19F NMR
signals are reported as δ (ppm) downfield from the signal for
trichlorofluoromethane. ESI-MS spectra could not be obtained for
(diacetoxyiodo)arenes in keeping with the absence of such spectra for
all such compounds in this study that had been reported previously.
However, ESI-MS data for the bridged compound 1s were successfully
obtained. An aqueous Bu4NHCO3 solution of approximately 1 M
concentration was prepared for radiochemical experiments by passing
carbon dioxide gas through an aqueous solution of Bu4NOH (0.5 mL,
1 M). The pH of the reaction mixture was monitored. As the pH
dropped to about 8 and remained stable, the flow of carbon dioxide
through the solution mixture was ended and the volume was brought
back to 0.5 mL. Bu4NHCO3 was stored at 4 °C and discarded after 1
week of use.
Figure 5. Radiochemical yields of p-[18F]fluoroarenes show a strong
bell-shaped relationship to Hammett σp values. The line represents a
Gaussian fit of the data and r the correlation coefficient.
For radiochemical experiments with K+-kryptofix 2.2.2 (K 2.2.2) as
counterion, a solution composed of K 2.2.2 (101 mg in 1.8 mL
MeCN) and K2CO3 (10.5 mg in 0.2 mL H2O) solution was prepared.
Quantum Chemical Calculations. The X-ray structure of 1u26
was used to build 1u complexed with potassium fluoride. The
geometry and energetics of this complex were then obtained by
resorting to quantum chemical calculations at the level of B3LYP/
DGDZVP. The reaction path in the gaseous phase was constructed by
moving a fluoride ion to the ipso aryl carbon atom in increments of 0.1
Å while relaxing the rest of the geometry. At each stationary point, the
geometry was then further refined in the reaction field of MeCN with
the polarizable continuum model together with the UAKS parameters
set as implemented in the Gaussian 09 software.27 A single imaginary
frequency was obtained for each TS in Figure 4.
Figure 6. Radiochemical yields of m-[18F]fluoroarenes show a weak
linear relationship with F values. The line represents a linear fit of the
data and r the correlation coefficient.
these reactions appear complex and heterogeneous and require
deeper investigation for full understanding.
Syntheses of (Diacetoxyiodo)arenes. All (diacetoxyiodo)arenes
were obtained in ≥95% purity, before or after recrystallization from
hot ethyl acetate and hexane, as required.
Finally, we explored whether radiofluorinations of
(diacetoxyiodo)arenes could also be achieved on a conventional
automated batch-reactor platform, such as the TRACERlab
FXFN module, which is more widely used for PET radiotracer
productions than microfluidic platforms. The treatment of 1d
(5 mM) with [18F]fluoride ion-TBA+ in DMF for 5 min at 170
°C gave 2d in 20% radiochemical yield on this module. When
the bridged compound 1s was subjected to these conditions, 2s
was obtained in 63% radiochemical yield. [18F]N-Succinimidyl
4-fluorobenzoate is a useful labeling synthon for biomolecules,
which is usually prepared from [18F]ethyl 4-fluorobenzoate
(2e) as intermediate.24,25 We found that the treatment of 1e
readily gave 2e in a useful 32% radiochemical yield. Recoveries
of radioactivity from the TRACERlab FXFN module in these
reactions ranged from 60% to 79%, which are typical for other
radiofluorination procedures. Thus, reactions in the more
conventional FXFN module also rapidly gave useful practical
yields, even at lower temperature than in the microfluidic
apparatus.
In conclusion, the treatment of (diacetoxyiodo)arenes with
NCA [18F]fluoride ion proved viable for preparing several
substituted [18F]fluoroarenes in moderate to good radio-
chemical yields, especially [18F]fluoroarenes having a range of
strong para electron-withdrawing substituents and [18F]-
fluoroarenes that have methyl groups in the meta position.
This method is a useful supplement to others for preparing
NCA [18F]fluoroarenes to serve as labeling synthons or
radiotracers from hypervalent precursors. Especially, this
method constitutes a novel two-step procedure for converting
a substituted iodoarene into a substituted [18F]fluoroarene.
4-(Diacetoxyiodo)anisole (1a). Sodium perborate monohydrate
(30 mmol) was added portionwise to a solution of 4-iodoanisole (3
mmol) in AcOH:Ac2O (1:1 v/v, 60 mL) over 5 min at rt. The mixture
was then heated to 40 °C and left stirring overnight. Reaction progress
was monitored with tlc, and when complete, the reaction mixture was
filtered. The filtrate was extracted with DCM (50 mL) and washed
with water (50 mL × 3). The organic solvent was then evaporated off
under vacuum. The residual oil was triturated with ether (10 mL). The
generated solid was rinsed with diethyl ether (10 mL × 3) and dried
under vacuum to provide 1a as a fluffy white solid (0.475 g, 45%). 1H
NMR (CDCl3): δ 8.01 (d, 2H, J = 9.0 Hz), 6.97 (d, 2H, J = 9.0 Hz),
3.86 (s, 3H), 2.00 (s, 6H). These data match literature data.16
General Method A. Oxone monopersulfate (0.92 g, 3 mmol) was
added to a solution of the iodoarene in TFA:DCM (70:30 v/v; 20
mL), and the resultant mixture was stirred at rt. The reaction was
monitored with tlc and was over in less than 1 h. Solvents were then
removed under vacuum. The residual oil was extracted with DCM and
washed with water (50 mL × 3). The organic solvent was then
evaporated off under vacuum. The residual oil was resuspended in
AcOH (10 mL) for 1 h. Water (100 mL) was then added, giving a
precipitate that was washed successively with water (15 mL × 3),
diethyl ether (10 mL × 3), and hexanes (10 mL × 3), and then dried
under vacuum for 2 h.
Thus, were prepared:
4-(Diacetoxyiodo)benzonitrile (1b). 4-Iodobenzonitrile (0.69 g, 3
mmol) gave 1b as white crystals (0.781 g, 75%). 1H NMR (d6-
DMSO): δ 8.43 (d, 2H, J = 8.7 Hz), 8.04 (d, 2H, J = 8.7 Hz), 1.93 (s,
6H). 13C NMR (d6-DMSO): δ 175.8, 136.3, 134.9, 118.1, 114.9, 20.6.
These data match literature data.28
4-(Diacetoxyiodo)nitrobenzene (1c). 4-Iodonitrobenzene (0.75 g,
1
3 mmol) gave 1c as pale yellow crystals (0.80 g, 73%). H NMR (d6-
D
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Note
DMSO): δ 8.52 (d, 2H, J = 8.9 Hz), 8.34 (d, 2H, J = 9.0 Hz), 1.94 (s,
6H). 13C NMR (d6-DMSO): δ 175.2, 149.1, 136.4, 128.3, 125.7, 20.1.
These data match literature data.11
(q, J = 3.9 Hz), 131.3, 128.5 (q, J = 3.5 Hz), 122.8 (q, J = 273.1 Hz),
20.3 ppm. 19F NMR (CDCl3): δ −62.74 ppm. These data match
literature data.22
3-(Diacetoxyiodo)benzonitrile (1d). 3-Iodobenzonitrile (0.69 g, 3
mmol) gave 1d as white crystals (0.822 g, 76%). 1H NMR (d6-
DMSO): δ 8.36 (t, 1H, J = 1.3 Hz), 8.31 (dq, 1H, J = 5.4, 1.1 Hz), 7.88
(dt, 1H, J = 1.1, 5.4 Hz), 7.64 (t, 1H, J = 8.0 Hz), 2.04 (s, 6 H). 13C
NMR (d6-DMSO): δ 176.8, 138.9, 138.1, 134.9, 131.4, 120.9, 116.7,
115.1, 20.3. These data match literature data.22
3-(Diacetoxyiodo)nitrobenzene (1n). White solid (0.793 g, 72%).
1H NMR (CDCl3): δ 8.95 (t, 1H, J = 1.9 Hz), 8.44 (dd, 1H, J = 6.2,
1.0 Hz), 8.40 (dd, 1H, J = 6.4, 1.0 Hz), 7.73 (t, 1H, J = 8.2, Hz), 2.04
(s, 6H). 13C NMR (CDCl3): δ 176.8, 148.7, 140.4, 131.6, 130.1, 126.4,
120.6, 20.3. These data match literature data.22
3-(Diacetoxyiodo)acetoxybenzene (1o). Pale yellow solid (0.90 g,
1
General Method B. Peracetic acid (32 wt %; 10 mL) was added
dropwise to a solution of the appropriate iodoarene (3 mmol) in
AcOH:Ac2O (1:1 v/v; 5 mL) at −10 °C. This mixture was slowly
warmed to rt and left stirring. Reaction progress was monitored with
tlc, and when complete, water (100 mL) was added to the mixture. If a
precipitate was generated, this was then washed successively with
water (15 mL × 3), ether (10 mL × 3), and hexanes (10 mL × 3), and
then dried under vacuum for 2 h to give the product (diacetoxyiodo)-
arene. In cases of no precipitation, the aqueous mixture was extracted
with DCM (50 mL × 3), and the combined organic extracts were
evaporated under vacuum. The resultant oil was then triturated with
ether (10 mL). Any solid was then rinsed with ether (10 mL × 3) and
dried under vacuum to give the product (diacetoxyiodo)arene. In cases
where trituration gave no solid, hexane (10 mL) was added and the
mixture was cooled in a fridge until the product (diacetoxyiodo)arene
precipitated out. This precipitate was then washed with hexanes (10
mL × 3) and dried in vacuo for 2 h.
79%). H NMR (CDCl3): δ 7.95−7.92 (m, 1H), 7.89 (t, 1H, J = 1.9
Hz), 7.52 (t, 1H, J = 8 Hz), 7.36−7.33 (m, 1H), 2.34 (s, 3H), 2.02 (s,
6H). 13C NMR (CDCl3): δ 176.6, 168.6, 151.3, 132.1, 131.4, 128.3,
125.3, 120.5, 21.1, 20.4. These data match literature data.22
3-(Diacetoxyiodo)benzophenone (1p). White crystals (0.511 g,
1
40%). m.p.: 175−178 °C. H NMR (CDCl3): δ 8.49 (t, 1H, J = 1.6
Hz), 8.28 (dq, 1H, J = 1.1, 5.1 Hz), 8.02 (dt, 1H, J = 1.2, 5.2 Hz),
7.84−7.82 (m, 2H), 7.67−7.62 (m, 2H), 7.55−7.51 (m, 2H), 2.03 (s,
6H). 13C NMR (CDCl3): δ 194.1, 176.5, 139.8, 138.1, 136.4, 136.2,
133.3, 132.8, 130.8, 130.1, 128.6, 121.1, 20.4.
Ethyl 3-(Diacetoxyiodo)benzoate (1q). White crystals (0.792 g,
67%). 1H NMR (CDCl3): δ 8.74 (t, 1H, J = 1.7 Hz), 8.26 (dd, 2H, J =
1.7, 7.9 Hz), 7.59 (t, 1H, J = 7.9 Hz), 4.43 (q, 2H, J = 7.2), 2.02 (s,
6H), 1.43 (t, 3H, J = 7.1 Hz). 13C NMR (DMSO): δ 176.6, 164.5,
138.9, 136.0, 133.1, 132.6, 130.8, 121.1, 61.9, 20.4, 14.3. These data
match literature data.16
1
3-(Diacetoxyiodo)anisole (1r). Yellow crystals (0.24 g, 23%). H
Thus, were prepared:
NMR (CDCl3): δ 7.67−7.64 (m, 2H), 7.41 (t, 1H, J = 8.4 Hz), 7.10
(dd, 1H, J = 8.4, 2.4 Hz), 3.87 (s, 3H), 2.02 (s, 6H). 13C NMR
(CDCl3): δ 176.4, 160.6, 131.5, 127.1, 121.5, 120.5, 118.0, 55.8, 20.4.
These data match literature data.22
Ethyl 4-(Diacetoxyiodo)benzoate (1e). White solid (0.576 g, 56%).
m.p.: 110−113 °C. 1H NMR (CDCl3): δ 8.17−8.12 (m, 4H), 4.42 (q,
2H, J = 7.1 Hz), 2.02 (s, 6H), 1.41 (t, 3H, J = 7.1 Hz). 13C NMR
(CDCl3): δ 176.5, 165.0, 134.9, 133.5, 131.8, 125.7, 61.7, 20.3, 14.3.
4-(Diacetoxyiodo)toluene (1f). Fluffy white solid (0.323 g, 32%).
1H NMR (CDCl3): δ 7.98 (d, 2H, J = 7.3 Hz), 7.29 (d, 2H, J = 8.0
Hz), 2.44, (s, 3H), 2.00 (s, 6H). 13C NMR (CDCl3): δ 176.0, 142.9,
134.9, 131.4, 117.0, 20.2, 19.1. These data match literature data.11
2-(Diacetoxyiodo)bromobenzene (1g). White solid (0.806 g,
μ-Oxa-bis[(acetoxyiodo)-4-trifluoromethylbenzene] (1s). Applica-
tion of General Method B to 1-iodo-4-trifluoromethylbenzene gave 1s
1
as a white fluffy solid (0.427 g, 21%). m.p.: 176−178 °C. H NMR
(CDCl3): δ 7.93 (d, 2H, J = 8.3 Hz), 7.54 (d, 2H, J = 8.7 Hz), 1.94 (s,
3H). 19F NMR (CDCl3): δ −63.24 ppm. ESI-MS: calculated for
C18H14F6I2O5 m/z 677.88, found m/z 677.6. A satisfactory13C NMR
spectrum in CDCl3 was not obtained due to decomposition over the
course of the scan time.
1
67%). H NMR (d6-DMSO): δ 8.48 (d, 1H, 8.0), 8.03 (d, 1H, J =
8.0 Hz), 7.62 (t, 1H, J = 7.3 Hz), 7.53 (t, 1H, J = 7.2 Hz), 1.92 (s, 6H).
13C NMR (d6-DMSO): δ 176.2, 139.5, 134.8, 133.4, 131.0, 129.0,
127.1, 20.6. These data match literature data.20
Radiochemistry. Radiochemistry was performed in a lead-shielded
hot-cell to minimize the radiation exposure to personnel. All
radioactivity measurements were performed using a calibrated
ionization chamber and were corrected for background.
2-(Diacetoxyiodo)trifluoromethylbenzene (1h). White solid
1
(0.644 g, 55%). m.p.: 148−150 °C. H NMR (CDCl3): δ 8.48 (d,
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 μA) generated from a
biomedical cyclotron.
1H, J = 7.8 Hz), 7.95 (dd, 1H, J = 6.7, 1.1 Hz), 7.79 (t, 1H, J = 7.6
Hz), 7.67 (dt, 1H, J = 7.6, 1.0 Hz), 1.97 (s, 6H). 13C NMR (CDCl3): δ
176.9, 140.1, 134.3, 132.4, 131.4 (q, J = 32.3 Hz), 128.0 (q, J = 5.1
Hz), 122.6 (q, J = 274.4 Hz), 117.8, 20.2. 19F NMR (CDCl3): δ
−60.22.
2-(Diacetoxyiodo)toluene (1i). White solid (0.655 g, 65%). 1H
NMR (CDCl3): δ 8.17 (d, 1H, J = 7.6 Hz), 7.53−7.51 (m, 2H), 7.28−
7.25 (m, 1H), 2.72 (s, 3H), 1.99 (s, 6H). 13C NMR (CDCl3): δ 176.4,
140.6, 137.2, 132.7, 130.9, 128.4, 127.2, 25.6, 20.3. These data match
literature data.20
aq. Bu4NHCO3 solution (50 μL; 1 M) or K+-K 2.2.2 solution (50
μL) was added to the cyclotron-produced no-carrier-added [18F]-
fluoride ion (50−200 mCi) in [18O]water (200−500 μL), and four
cycles of azeotropic addition and evaporation of acetonitrile (0.65 mL
for each addition) were performed, three times at 110 °C for 4 min
and once more at 90 °C for 4 min in an oven cavity housed within a
modified Synthia29 module.
2,6-Dimethyl(diacetoxyiodo)benzene (1j). White solid (0.725 g,
1
69%). H NMR (d6-DMSO): δ 7.39 (dd, 1H, J = 6.4, 1.6 Hz), 7.31−
7.27 (m, 2H), 2.75 (s, 6H), 1.98 (s, 6H) ppm. 13C NMR (d6-DMSO):
δ 176.5, 141.4, 132.9, 132.5, 128.1, 27.0, 20.3. These data match
literature data.20
Configuration and Operation of Microfluidic Reactor
Apparatus. The microfluidic reactor apparatus was maintained and
operated as previously described.20
Radiofluorination Reactions. In a Microfluidic Apparatus. Dry
[18F]Bu4NF complex (20−50 mCi) was dissolved in reaction solvent
(0.5 mL, typically DMF). A solution of (diacetoxyiodo)arene was
prepared in a matching solvent. Each of the two solutions (255 μL)
was loaded into separate storage loops of the microfluidic apparatus.
For reactions, each solution (10−15 μL) was infused simultaneously
into the 4 m length coiled silica glass tube microreactor of the
apparatus at a set flow rate in the range of 4−100 μL/min and at a
preset temperature. The microreactor output was quenched with
MeCN−H2O (0.5 mL, 1:1 v/v) at rt. Non-decay-corrected radio-
chemical yields (RCYs) of the [18F]fluoroarenes were measured by
reverse phase radio-HPLC on a Luna C18 column (10 μm, 100 Å, 250
× 4.60 mm) eluted at 2 mL/min with a gradient of MeCN: 0.1% (w/
3,5-Dimethyl(diacetoxyiodo)benzene (1k). White crystals (0.798
1
g, 76%). H NMR (CDCl3): δ 7.74 (s, 2 H), 7.22 (s, 1H), 2.39 (s,
6H), 2.02 (s, 6H). 13C NMR (DMSO): δ 176.4, 141.1, 133.7, 132.5,
121.3, 21.3, 20.4. These data match literature data.15
3-(Diacetoxyiodo)toluene (1l). White needles (0.837 g, 83%). H
1
NMR (DMSO): δ 8.10 (s, 1H), 8.03 (d, 1H, J = 7.6 Hz), 7.50−7.43
(m, 2H), 2.37 (s, 3H), 1.91 (s, 3H). 13C NMR (DMSO): δ 175.8,
141.5, 135.9, 133.1, 132.8, 131.2, 122.3, 21.2, 20.7. These data match
literature data.22
3-(Diacetoxyiodo)trifluoromethylbenzene (1m). White crystals
1
(0.807 g, 69%). H NMR (CDCl3): δ 8.33 (s, 1H), 8.28 (d, 1H, J =
8.2 Hz), 7.85 (d, 1H, J = 7.8 Hz), 7.65 (t, 1H, J = 8.0 Hz), 2.03 (s,
6H). 13C NMR (CDCl3): δ 176.7, 138.2, 133.1 (q, J = 33.6 Hz), 131.8
E
DOI: 10.1021/acs.joc.5b02332
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
v) HCOONH4, starting at 35% MeCN for 1 min, increased to 90% B
over 5 min and maintained at 90% MeCN for 10 min.
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In a TracerLab FXFN Module. The aqueous [18F]Bu4NF reagent was
dried within the apparatus by two cycles of addition and evaporation of
acetonitrile (2.0 mL) under a nitrogen stream and reduced pressure,
first at 65 °C, and then at 88 °C. To the dried [18F]fluoride ion
complex was added a solution of the (diacetoxyiodo)arene in
anhydrous DMF (5 mM; 1.0 mL). The reaction mixture was heated
to 170 °C for 5 min, and then transferred into water (10 mL) at rt.
The mixture was then analyzed by HPLC, as described above.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02332.
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P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega,
N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.;
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1H, 13C, and 19F NMR spectra of (diacetoxyiodo)arenes,
selected radio-chromatograms, and Cartesian coordinates
of the geometry optimized structures in Figure 4 (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pikev@mail.nih.gov. Fax: +1 301 480 5112. Tel: +1
301 594 5986.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Intramural Research
Program of the National Institutes of Health (NIMH, ZIA-
MH002793; CIT, ZIA-CT000265-19). The quantum chemical
study utilized PC/linux clusters at the Center for Molecular
Modeling of the National Institutes of Health (http://cit.nih.
gov).
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DOI: 10.1021/acs.joc.5b02332
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