A new class of SN2 reactions catalyzed by protic solvents: Facile fluorination for isotopic labeling of diagnostic molecules

Article abstract of DOI:10.1021/ja0646895

Aprotic solvents are usually preferred for the S_N2 reactions, because nucleophilicity and hence S_N2 reactivity are severely retarded by the influence of the partial positive charge of protic solvents. In this work, we introduce a remarkable effect of using tertiary alcohols as a reaction medium for nucleophilic fluorination with alkali metal fluorides. In this novel synthetic method, the nonpolar protic tert-alcohol enhances the nucleophilicity of the fluoride ion dramatically in the absence of any kind of catalyst, greatly increasing the rate of the nucleophilic fluorination and reducing formation of byproducts (such as alkenes, alcohols, or ethers) compared with conventional methods using dipolar aprotic solvents. The great efficacy of this method is a particular advantage in labeling radiopharmaceuticals with [¹⁸F]fluorine (t_1/2 = 110 min) for positron emission tomographic (PET) imaging, and it is illustrated by the synthesis of four [ ¹⁸F]fluoride-radiolabeled molecular imaging probes-[ ¹⁸F]FDG, [¹⁸F]FLT, [¹⁸F]FP-CIT, and [ ¹⁸F]FMISO-in high yield and purity and in shorter times compared to conventional syntheses.

Full text of DOI:10.1021/ja0646895

Published on Web 11/23/2006
A New Class of SN2 Reactions Catalyzed by Protic Solvents:
Facile Fluorination for Isotopic Labeling of Diagnostic
Molecules
Dong Wook Kim,† Doo-Sik Ahn,‡ Young-Ho Oh,‡ Sungyul Lee,‡ Hee Seup Kil,†,|
Seung Jun Oh,§ Sang Ju Lee,§ Jae Seung Kim,§ Jin Sook Ryu,§
Dae Hyuk Moon,§ and Dae Yoon Chi*,†,|
Contribution from the Department of Chemistry, Inha UniVersity, 253 Yonghyundong Namgu,
Inchon 402-751, Korea, College of EnVironmental Science and Applied Chemistry (BK21),
Kyunghee UniVersity, Kyungki 449-701, Korea, Department of Nuclear Medicine, Asan Medical
Center, UniVersity of Ulsan College of Medicine, 388-1 Pungnap-2-dong, Songpa-gu, Seoul
138-736, Korea, and Research Institute of Labeling, FutureChem Co. Ltd., 388-1
Pungnap-2-dong, Songpa-gu, Seoul 138-736, Korea
Received July 2, 2006; E-mail: dychi@inha.ac.kr
Abstract: Aprotic solvents are usually preferred for the SN2 reactions, because nucleophilicity and hence
SN2 reactivity are severely retarded by the influence of the partial positive charge of protic solvents. In this
work, we introduce a remarkable effect of using tertiary alcohols as a reaction medium for nucleophilic
fluorination with alkali metal fluorides. In this novel synthetic method, the nonpolar protic tert-alcohol
enhances the nucleophilicity of the fluoride ion dramatically in the absence of any kind of catalyst, greatly
increasing the rate of the nucleophilic fluorination and reducing formation of byproducts (such as alkenes,
alcohols, or ethers) compared with conventional methods using dipolar aprotic solvents. The great efficacy
of this method is a particular advantage in labeling radiopharmaceuticals with [18F]fluorine (t1/2 ) 110 min)
for positron emission tomographic (PET) imaging, and it is illustrated by the synthesis of four [18F]fluoride-
radiolabeled molecular imaging probess[18F]FDG, [18F]FLT, [18F]FP-CIT, and [18F]FMISOsin high yield
and purity and in shorter times compared to conventional syntheses.
Introduction
for imaging studies to nearby hospitals and laboratories that
are not equipped with particle accelerators for radionuclide
Noninvasive imaging of molecular and biological processes
in living subjects with positron emission tomography (PET)
provides exciting opportunities to monitor metabolism and detect
diseases in humans and in small-animal models.1 Measuring
these processes with PET requires the preparation of specific
molecular imaging probes labeled with positron-emitting ra-
dioisotopes. In this regard, fluorine is particularly useful: (a)
Because fluorine can replace hydrogen with minimal steric
interference, labeling pharmaceuticals with [18F]fluorine often
enables the fluorine-substituted analogue to be used to trace
biochemical processes while maintaining favorable interaction
with the target; (b) fluorine is also often used as a substituent
in pharmaceuticals because it can increase the activity, potency,
and stability of biologically active compounds;2 (c) finally,
because of its relatively long half-life of 110 min, [18F]labeled
radiopharmaceuticals can be produced regionally and shipped
production.
The typical method for introducing fluorine at a specific
aliphatic molecular site is the nucleophilic displacement of the
corresponding sulfonate or halide by fluoride ion.3 Although
alkali metal fluorides have traditionally been used for this
purpose, fluorination with these reagents is known to proceed
only under vigorous conditions due to their limited solubility
in organic solvents and low nucleophilicity. As an alternative,
a “naked” fluoride ion, which is not solvated tightly by bulky
cations or solvent molecules, is usually used to improve these
reactions,4 and over the past several decades, numerous kinds
of phase-transfer type protocols, such as crown ether and
quaternary ammonium fluoride derivatives, have been developed
to enhance the nucleophilicity and solubility of fluoride ions in
organic media and to accelerate this substitution reaction.5
Although the naked fluoride ion generated from phase transfer
† Inha University.
‡ Kyunghee University.
(3) For reviews on nucleophilic fluorination, see: (a) Gerstenberger, M. R.
C.; Haas, A. Angew. Chem., Int. Ed. Engl. 1981, 20, 647-667. (b)
Mascaretti, O. A. Aldrichim. Acta 1993, 26, 47-58.
§ University of Ulsan College of Medicine.
| FutureChem Co. Ltd.
(1) (a) Phelps, M. E. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 9226-9233. (b)
Marx, V. Chem. Eng. News 2005, 83, 25.
(4) (a) Forche, D. In Methoden der Organischen Chemie; Mueller, E., Ed.;
Thieme-Verlag: Stuttgart, 1962; Vol. 5/3. (b) CRC Handbook of Chemistry
and Physics, 71st ed.; CRC Press: Boston, 1990-1991.
(2) (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1990, 29, 1320-1367. (b)
Filler, R. In Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications; Filler, R., Ed.; Studies in Organic Chemistry 48;
Elservier; New York, 1993; pp 1-23.
(5) (a) Gokel, G. W. In Crown Ethers and Cryptands; Royal Society of
Chemistry: Cambridge, 1991. (b) Dehmlow, E. V.; Dehmlow, S. S. In
Phase Transfer Catalysis, 3rd ed.; VCH: New York, 1993.
9
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J. AM. CHEM. SOC. 2006, 128, 16394-16397
10.1021/ja0646895 CCC: $33.50 © 2006 American Chemical Society

SN2 Reactions Catalyzed by Protic Solvents
A R T I C L E S
Table 1. Fluorinations of Mesylate 1 with Metal Fluoride under
Table 2. Fluorinations of Various Alkyl Halides and Mesylates
Various Reaction Conditionsa
Using CsF in tert-Amyl Alcohola
yield of productb (%)
temp time
entry
solvent
MF
(°C)
(h)
1
2a
2b
2c
2d
1
2
3
4
5
6
7
8
9
t-BuOH
CsF
CsF
CsF
CsF
CsF
CsF
80
80
80
80
80
80
80
90
6
6
6
6
6
6
6
2.5
6
trace 92
-
-
-
-
-
7
30
-
-
-
-
n-BuOH
CH3CN
DMF
1,4-dioxane
benzene
tert-amyl alcohol CsF
tert-amyl alcohol CsF
t-BuOH
4c
91
33
94
97
-
64
7c
trace
48
-
-
93
94
4d
8c 9c
-
-
-
-
-
-
-
-
-
-
5(5c)
4(5c)
trace
-
-
-
-
CsBr 80
CsBr 80
94
68
13
90
10 CH3CN
11 tert-amyl alcohol RbF 90 24
12 tert-amyl alcohol KF 90 24
6
32d
76
trace
9
7c
a All reactions were carried out on a 1.0 mmol reaction scale of mesylate
1 using 3 mmol of metal fluoride in 4.0 mL of solvent. b Isolated yield.
c Yield determined by NMR. d Yield of 2-(3-bromopropoxy)naphthalene.
methods (e.g., tetrabutylammonium fluoride, TBAF, or KF-
kryptfix complex) is a good nucleophile, its synthetic utility
can be limited by its strong basicity.6 When alkali metal salts
are used, it is also well-known that polar aprotic solvents, such
as acetonitrile and dimethylformamide (DMF), are much better
than protic solvents for nucleophilic displacement; in polar
aprotic solvents, the nucleophilicity of the anions is enhanced
by selective solvation of the cation, whereas, in protic solvents,
anion nucleophilicity is reduced by interaction with the partial
positive charge of protic solvents.7 Recently, it was found that
nucleophilic fluorination with a metal fluoride may be catalyzed
by a fluorinase enzyme. In this enzymatic reaction, hydrogen
bonding among the enzyme, fluoride, and substrate plays a
crucial role in synthesis of C-F bonds.8
In this report, we introduce the phenomenal efficiency of
using tertiary alcohols as a reaction media for the nucleophilic
fluorination with alkali metal fluoride. In this method, the
nonpolar, protic tert-alcohol mediasin the absence of any kind
of catalystsactually enhances the nucleophilicity of the alkali
metal fluoride dramatically, increasing the rate of nucleophilic
fluorination compared with conventional methods and reducing
formation of typical byproducts (e.g., alkenes, alcohols, or
ethers).3,6,9
a Unless otherwise noted, all reactions were carried out under the same
conditions as those for entry 8 in Table 1, and an ether compound was
detected in the all reactions in 4-5% yield, except entry 7. b Isolated yield.
c Yield determined by NMR.
poxy)naphthalene product (2a) in low to very low yields, with
alcohol 2b and alkene 2c being formed as byproducts; this was
the case not only in polar aprotic solvents such as CH3CN and
DMF (7 and 48%, respectively, entries 3 and 4) but also in
nonpolar aprotic solvent such as 1,4-dioxane and benzene (zero
yield, entries 5 and 6). The same reaction in t-BuOH, however,
proceeded almost to completion within 6 h, providing the
fluoroalkane 2a in very high yield (92%, entry 1), together with
only small amounts of the ether byproduct 2d (7%). It is of
note that under these conditions, the reaction mixture forms a
solid at 30 min. A denser solid formed in the reaction of entry
1, Table 2 compared to the reaction of entry 8, Table 1.
Comparison of Table 1 entries 3 and 10 shows that CsBr is
much more reactive for nucleophilic displacement than CsF in
a polar aprotic solvent such as CH3CN, presumably due to
weaker ionic bonding in CsBr compared to CsF, as well as to
the greater nucleophilicity of the bromide ion compared to the
fluoride ion. By contrast, the nucleophilic bromination reaction
using CsBr proceeded remarkably slowly in t-BuOH, converting
only 4% of mesylate 1 to the corresponding bromide (2-(3-
bromopropoxy)naphthalene) in 6 h at 80 °C (entry 9). These
results should be compared with the fluorination reactions with
CsF in tert-butyl or tert-amyl alcohols, which were complete
within 6 h and produced the fluoroalkane 2a in very high yield
(92-94%, entries 1 and 7). The other alkali metal fluorides,
RbF and KF, exhibit lower reactivity for fluorination in tert-
alcohol media, with either 76% and trace yields being obtained,
respectively (entries 11 and 12, respectively), after extended
reaction times (24 h). tert-Amyl alcohol, which has a large steric
hindrance as well as a high boiling point, was found to be the
best solvent among alcohols examined for this reaction; the
Results and Discussion
Table 1 presents the results of the fluorination of a model
compound, 2-(3-methanesulfonyloxypropoxy)naphthalene (1),
with various alkali metal fluorides under various reaction
conditions. The fluorination of mesylate 1 with 3 equiv of CsF
under typical reaction conditions produced the 2-(3-fluoropro-
(6) Pilcher, A. S.; Ammon, H. L.; DeShong, P. J. Am. Chem. Soc. 1995, 117,
5166-5167.
(7) Smith, M. D.; March, J. In AdVanced Organic Chemistry, 5th ed.; Wiley-
Interscience: New York, 2001; pp 462-674.
(8) (a) Zechel, D. L.; Reid, S. P.; Nashiru, O.; Mayer, C.; Stoll, D.; Jakeman,
D. L.; Warren, P. A. J.; Withers, S. G. J. Am. Chem. Soc. 2001, 123, 4350-
4351. (b) O’Hagan, D.; Schaffrath, C.; Cobb, S. L.; Hamilton, J. T. G.;
Murphy, C. D. Nature 2002, 416, 279. (c) Dong, C.; Huang, F.; Deng, H.;
Schffrath, C.; Spencer, J. B.; O’Hagan, D.; Naismith, J. H. Nature 2004,
427, 561-565.
(9) (a) Kim, D. W.; Song, C. E.; Chi, D. Y. J. Am. Chem. Soc. 2002, 124,
10278-10279. (b) Kim, D. W.; Chi, D. Y. Angew. Chem., Int. Ed. 2004,
43, 483-485.
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A R T I C L E S
Kim et al.
product fluoroalkane was produced in 94% yield (entry 8) with
a reaction time of only 2.5 h.10 The importance of alcohol steric
hindrance is evident from comparisons of reactions run with
CsF in the tert-alcohols (entries 1, 7, and 8) compared to
n-butanol (entry 2).
latter sequence being that predicted by simply considering the
differential solvation of the nucleophile. Fourth, the effect of
the leaving group seems to be much larger than that for the
conventional SN2 reactions, suggesting that some sort of
interaction between the leaving group and the other constituents
of the reaction (the nucleophile, cation, or the solvent molecule)
is affecting the reaction rate.
Table 2 illustrates further characteristics of this fluorination
reaction with various primary and secondary halide or sulfonate
precursors using 3 equiv of CsF in tert-amyl alcohol (entries
1-5). In all cases, the corresponding fluorine-substituted
compounds are produced in comparable or greater yields than
previously reported by other methods. The fluorination of
haloethyl or alkanesulfonyloxyethyl aromatic compounds using
“naked” fluoride, which is a strong base as well as a strong
nucleophile, is known to be difficult because of the competing
elimination to give the vinylarene by product. The merit of this
method is evident in the fluorination of 2-(2-mesyloxyethyl)-
naphthalene to 2-(2-fluoroethyl)naphthalene, which proceeds
almost to completion, producing the corresponding fluoroalkane
in 92% yield with only trace quantities of alkene byproduct
(Table 2, entry 6).
The fluorination reaction of mesylates or tosylates has been
reported to be less than twice as fast as that of iodides.
Comparison of entries 1 and 2, however, shows that the
fluorination rate of a tosylate is approximately 12 times faster
than that of the corresponding iodide. This result suggests that
the reaction rate is determined not only by the nature of the
leaving group but also by other types of interactions, such as
those between the solvent (tert-alcohol) and the leaving group.
For example, H-bonding between the alcohol solvent and the
oxygen atoms in the alkanesulfonate leaving group may enhance
its nucleofugic (leaving group) character. Remarkably, using
this fluorination procedure, we were able to prepare a fluoro-
proline derivative in good yield after only 1.5 h at room
temperature from the corresponding triflate precursor (Table 2,
entry 7). It is notable that a triflate has six sites for H-bonding
with the solvent alcohol (three oxygens and three fluorines).
By contrast, fluorination of reactants with halide groups in the
tert-amyl alcohol media required long reaction times as well as
vigorous conditions, although the reactions did eventually
produce the fluorine-substituted product in high yields, as shown
in entries 3 and 4 (72 and 88%, respectively).
To test the practical utility of this new fluorination method
in an important application where speed and efficiency are
critical, namely, F-18 radiolabeling of important PET radiop-
harmaceuticals, we selected as targets the widely used and
commercially available agent 2-[18F]fluoro-2-deoxyglucose
([18F]FDG) as well as three other promising candidate radiop-
harmaceuticals that are challenging to label. The results are given
in Table 3, and overall, we obtained high radiochemical yields
under favorable reaction conditions.
3′-Deoxy-3′-[18F]fluorothymidine ([18F]FLT) is under clinical
trial (phase III) in Korea (July 2004 by Asan Medical Center)
and the United States (December 2004 by NCI and GE) for
PET imaging of tumor cell proliferation. Previously, [18F]FLT
was prepared from the [18F]fluoride ion in a radiochemical yield
of 50 ( 5.2%, under conventional conditions using a large
amount of precursor (40 mg) and reaction at 150 °C; a 15 (
5.4% yield was obtained at 110 °C with 20 mg of precursor.11
As automated synthesis modules that typically use plastic valves
and tubes do not tolerate temperatures of 150 °C, these systems
cannot be utilized for routine synthesis. During the optimization
of [18F]FLT using an automatic module, we have found that
the tetrabutylammonium cation is generally better than the
cesium cation in a tert-alcohol system. In this study, we obtained
higher radiochemical yields (65.5 ( 5.4%) of [18F]FLT with a
small amount of precursor at 120 °C (Table 3, entry 2) using
TBAHCO3. This condition enabled us to use an automated
synthesis system.
N-[18F]Fluoropropyl-2â-carbomethoxy-3â-(4-iodophenyl)nor-
tropane ([18F]FP-CIT) is a well-known radiopharmaceutical for
PET imaging of dopamine transporters. It has not been used
routinely, however, because of difficulties in its preparation
(only 1% yields have been obtained).12 In Europe, the radio-
iodine-labeled analogue of CIT, namely [123I]FP-CIT, has been
used in place of [18F]FP-CIT for single photon emission
imaging. Using our new [18F]fluorination method, we prepared
[18F]FP-CIT in 35.8 ( 5.2% yield at 100 °C for 20 min in one
step (Table 3, entry 3). Thus mass production of [18F]FP-CIT
can enable us to begin clinical trials (phase III) in Korea (June
2006 by Asan Medical Center). [18F]FDG is the only com-
mercially available radiopharmaceutical and by far the most
widely used one. The new fluorination method could facilitate
its commercial production (Table 3, entry 1) and advance the
availability of this important fluorinated radiopharmaceutical,
as well as that of other ones to be developed in the future, for
routine clinical use.
The characteristics of the nucleophilic substitution reaction
with fluoride in tert-alcohol, described above, are striking. First,
hindered protic solvents (tert-butanol and tert-amyl alcohol in
the present work) are much better than aprotic solvents,
indicating a catalytic activity of the protic solvent. This finding
is striking, because in SN2 reactions polar, aprotic solvents are
known to be much more efficient. Second, product yield is
highly dependent on the cation (Cs+ is much better than K+),
which provides experimental evidence for an important influence
of Coulombic interactions by the cation on the reaction. Third,
the relative reactivity of the halide ion nucleophile appears to
be reversed (F- much more reactive than Br-) from that typical
for halide ions in protic solvents (F- < Cl- < Br-, etc), the
(11) Oh, S. J.; Mosdzianowski, C.; Chi, D. Y.; Kim, J. Y.; Kang, S. H.; Ryu,
J. S.; Yeo, J. S.; Moon, D. H. Nucl. Med. Biol. 2004, 31, 803-809.
(12) Chaly, T.; Dhawan, V.; Kazumata, K.; Antonini, A.; Margouleff, C.; Dahl,
J. R.; Belakhlef, A.; Margouleff, D.; Yee, A.; Wang, S. Y.; Tamagnan, G.;
Neumeyer, J. L.; Eidelgerg, D. Nucl. Med. Biol. 1996, 23, 999-1004.
(13) Oh, S. J.; Chi, D. Y.; Mosdzianowski, C.; Kim, J. Y.; Kil, H. S.; Kang, S.
H.; Ryu, J. S.; Moon, D. H. Fully automated synthesis of [18F]fluoromi-
sonidazole using a conventional [18F]FDG module. Nucl. Med. Biol. 2005,
32, 899-905.
(10) Typical Procedure in Table 1: CsF (290 mg, 3.0 mmol) was added to the
mixture of 2-(3-methanesulfonyloxypropoxy)naphthalene (1, 280 mg, 1.0
mmol) in tert-amyl alcohol (3.0 mL). The mixture was stirred over 2.5 h
at 90 °C. After evaporation of solvent, the reaction mixture was extracted
with ethyl ether (7 mL × 3). The organic layer was dried over anhydrous
sodium sulfate and evaporated under a reduced pressure. The residue was
purified by flash column chromatography (20% CH2Cl2/hexanes) to obtain
192 mg (94%) of 2-(3-fluoropropoxy)naphthalene (2a).
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SN2 Reactions Catalyzed by Protic Solvents
A R T I C L E S
Table 3. Automatic Preparations of the Key Fluorine-18 Labeled PET Radiopharmaceuticals Using Alcohol Solvent System
a Radiochemical yield after [18F]fluorination in the manual synthesis (n ) 10). The product was 2-[18F]fluoro-2-deoxyglucose. b 3′-Deoxy-3′-
[18F]fluorothymidine ([18F]FLT), radiochemical yield after HPLC purification in the automatic synthesis with GE TracerLab FX module (n ) 10). c N-2-
[18F]Fluoropropyl-2â-carbomethoxypropyl-3â-(4-iodophenyl)nortropane ([18F]FP-CIT), radiochemical yield after HPLC purification in the automatic synthesis
with GE TracerLab FX module (n ) 14). d 1-[18F]Fluoro-3-(2-nitroimidazol-1-yl)propan-2-ol ([18F]FMISO), radiochemical yield after HPLC purification in
the automatic synthesis with GE TracerLab MX module (n ) 1).
Conclusions
mechanism, elucidating the mechanism of the presented reac-
tions in tert-alcohol would be of keen interest.
In summary, we have described a novel method for the
nucleophilic fluorination of some halo- and alkanesulfonyloxy
alkane systems to the corresponding fluoroalkanes using alkali
metal fluorides in tert-alcohol media. The nonpolar protic
solvent enhances the reactivity of alkali metal fluorides tre-
mendously, which facilitates the synthesis of organofluorine
compounds by enabling efficient, high yielding SN2 substitution
that is rapid and proceeds under relatively mild conditions. These
characteristics are especially important in the labeling of PET
radiopharmaceuticals with [18F]fluoride, where the short half-
life of the radionuclide (t1/2 ) 110 min) and its availability at
high specific activity only at the tracer level place a premium
on reaction speed and efficiency. Since our findings are in
marked contrast with the predictions made from the conventional
Acknowledgment. We gratefully acknowledge the National
Research and Development Program of MOST, Korea (2005-
03184, D.Y.C.), Real-time Molecular Imaging Program (S.J.O.),
and the KOSEF for financial support (R01-2005-000-10117-0,
S.Y.L.). We also thank Professors John A. Katzenellenbogen
and Peter Beak for helpful discussions.
Supporting Information Available: Experimental procedures
of labeling for [18F]FDG, [18F]FLT, [18F]FP-CIT, [18F]FMISO,
and a picture of solid formations. This material is available free
of charge via a Internet at http://pubs.acs.org.
JA0646895
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