when diaryliodonium salts are fluorinated with cyclotron-
derived 18F-fluoride ion.1
Table 2. Yields of Fluorinated Arenes Obtained from
Decomposition of Salts 1-7 after Removal of TMAPF6
In addition to reducing the solvent polarity, the use of
benzene as the reaction solvent effectively removes the
inorganic spectator ions (tetramethylammonium and hexaflu-
orophosphate) from solution. While these salts are not
expected to participate directly in the thermal decomposition
reaction, their presence might facilitate ligand exchange
reactions and increase the I-F dissociation rate and dis-
sociation constants. To probe whether the observed improve-
ment in fluorination yield was a function of solvent polarity
or extraneous salt, the thermal decomposition of the diaryli-
odonium fluorides was also conducted under “salt-free”
conditions in both solvents.
Salt removal was performed by a simple solvent exchange
process; compounds 2-7 were dissolved in CH3CN and
treated with TMAF, and the solvent was evaporated. The
remaining salts were dissolved in benzene and passed through
a 0.20 µm PTFE syringe filter (Scheme 1). Upon evaporation
(ArF + 4FA)a “salt-free” conditions
compound
C6D6
CD3CN
1
2
3
4
5
6
7
86
43
(77 + 14)
(49 + 23)
(78 + 12)
(57 + 20)
(85 + 10)
(89 + 0)
(30 + 8)
(40 + 20)
(49 + 32)
(40 + 15)
(68 + 0)
(78 + 0)
a The numbers inside the parentheses indicate the percentage yields of
the desired fluorinated arene followed by the amount of 4-fluoroanisole
(4FA) produced during the reaction. All solutions were heated at 140 °C
for 15 min in sealed NMR tubes.
yields and selectivities for formation of fluorinated arenes
from 1-7 (Table S1, Supporting Information) were es-
sentially identical to those obtained for reactions conducted
in C6D6, indicating that a wide range of nonpolar aromatic
solvents might be readily used for this process.
Scheme 1. Salt Removal by Solvent Exchange Process
Compounds 8 and 9, suitably protected precursors of
previously investigated radiotracers 18F-6-fluorodopamine18
and 18F-2-fluoroestradiol,19 respectively, were decomposed
to the corresponding fluorinated arenes in excellent (80%
for 8) and fair (42% for 9) yields in benzene. The reduced
fluorination yield for the latter compound is accompanied
by a concomitant increase in the amount of 4-fluoroanisole
produced, consistent with the similar “directing group”
abilities of the 2-methoxy and 4-methoxy substituted arenes.
(Recently, our laboratory reported a potential solution to this
directing group problem.20) Successful fluorination of these
arenes indicates that the methodology is sufficiently broad
to tolerate suitably protected alcohol and amine functionality.
of the benzene, clean samples of the diaryliodonium salts
1
were obtained. H and 19F NMR spectra of the isolated
diaryliodonium fluorides showed no residual TMAPF6 in the
samples of diaryliodonium fluorides prepared using this
solvent exchange method.
The results of thermal decomposition reactions (140 °C,
15 min) of the salt-free diaryliodonium fluorides are sum-
marized in Table 2. For reactions conducted in benzene, salt-
free conditions were associated with a modest enhancement
in the yields of fluorinated arenes. In contrast, the yields of
reactions conducted in CD3CN improved dramatically after
the salt was removed; in some instances the yields obtained
for the thermal decomposition of salt-free diaryliodonium
fluorides in acetonitrile approached those seen for reactions
conducted in benzene. These results suggest that fluoride ion
dissociation may be responsible for some degradation of the
arene fluorination efficiency observed in polar aprotic sol-
vents.
Deuterated benzene is a particularly convenient and
relatively inexpensive solvent for conducting these iodonium
salt decomposition experiments, but its carcinogenicity makes
benzene unattractive for practical preparations. Thus, we also
investigated the thermal decomposition reactions of com-
pounds 1-7 in d8-toluene under salt-free conditions. The
Figure 4. Syntheses of compounds 8 and 9. Reagents and
conditions: (a) Br2, AcOH, rt, KOH; (b) diisopropylethylamine,
phthaloyl dichloride, CH3CN, rt; (c) Pd2(dba)3, t-Bu3P, benzene,
Sn2Bu6, 100 °C; (d) p-OMePhI(OTs)(OH), CH3CN; (e) H2O,
NaPF6; (f) NBS, CH3CN/CCl4 (3:7); (g) n-BuLi, Bu3SnCl, THF,
-78 °C to rt.
(14) Kitamura, T.; Matsuyuki, J.; Taniguchi, H. Synthesis 1994, 147–
148.
(15) Shah, A.; Pike, V. W.; Widdowson, D. A. J. Chem. Soc., Perkin
Trans. 1 1997, 2463–2465.
(16) Koser, G. F.; Wettach, R. H.; Smith, C. S. J. Org. Chem. 1980,
45, 1543–1544.
To more closely mimic the conditions of radiotracer
synthesis, we examined the thermal decomposition reactions
of 1 at three concentrations (1 mM, 5 µM, and 5 nM);
(17) Pike, V. W.; Butt, F.; Shah, A.; Widdowson, D. A. J. Chem. Soc.,
Perkin Trans. 1 1999, 245–248.
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Org. Lett., Vol. 12, No. 15, 2010