Nickel-mediated oxidative fluorination for PET with aqueous [ 18F] fluoride

Article abstract of DOI:10.1021/ja3084797

A one-step oxidative fluorination for carbon-fluorine bond formation from well-defined nickel complexes with oxidant and aqueous fluoride is presented, which enables a straightforward and practical ¹⁸F late-stage fluorination of complex small molecules with potential for PET imaging.

Full text of DOI:10.1021/ja3084797

Communication
pubs.acs.org/JACS
Nickel-Mediated Oxidative Fluorination for PET with Aqueous [18F]
Fluoride
Eunsung Lee,† Jacob M. Hooker,‡,§ and Tobias Ritter*,†,§
†Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United
States
‡Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School,
Charlestown,Massachusetts 02129, United States
§Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Boston,
Massachusetts 02114, United States
S
* Supporting Information
the challenges associated with 19F fluorination,3 chemistry with
18F needs to take into account the small concentration of 18F
ABSTRACT: A one-step oxidative fluorination for
(roughly 10−4 M), the impracticality to work under rigorously
anhydrous conditions, and the side product profile. We sought
to develop a practical, one-step, functional-group-tolerant,
electrophilic fluorination reaction that employs [18F]fluoride.
We had previously developed the electrophilic fluorination
reagent 4 made from high-specific activity [18F]fluoride via
reductive elimination from high-valent palladium fluoride
complexes (Scheme 1).6 Palladium complex 4 can be used
carbon−fluorine bond formation from well-defined nickel
complexes with oxidant and aqueous fluoride is presented,
which enables a straightforward and practical 18F late-stage
fluorination of complex small molecules with potential for
PET imaging.
ositron emission tomography (PET) requires synthesis of
P
molecules that contain positron-emitting isotopes, such as
11C, 13N, 15O, and 18F.1 The 18F isotope is typically the
preferred radionuclide for clinically relevant PET applications
due to its longer half-life of 110 min, which permits synthesis
and distribution of radiotracer quantities appropriate for
imaging.2 But C−F bond formation is challenging, especially
with 18F.3 Here we report a practical late-stage fluorination
reaction with high-specific activity 18F fluoride to make aryl and
alkenyl fluorides from organometallic nickel complexes. A
direct oxidative fluorination of organotransition metal com-
plexes with an oxidant and fluoride has never been reported and
enables practical one-step access to complex 18F-labeled small
molecules from [18F]fluoride. When nickel complexes 1 are
combined with an oxidant and aqueous fluoride, the organic
fluorides 2 are formed at room temperature in less than 1 min
(eq 1).
Scheme 1. Two-Step Late-Stage Fluorination via Pd(IV)
Fluoride Complex 4
for late-stage 18F fluorination of complex arenes and was the
first reagent to capture fluoride and subsequently function as an
electrophilic fluorination reagent. Yet, use of 4 requires a two-
step sequence: fluoride capture (3 → 4), followed by fluoride
transfer via electrophilic fluorination (5 → [18F]2). The two-
step sequence increases reaction time and the possibility for
error and makes the method less suitable for adoption by
Synthesis of simple 18F PET tracers is typically accomplished
with conventional nucleophilic substitution reactions with
[18F]fluoride.1,4 [18F]Fluoride is the only readily available
source of F-18. But conventional nucleophilic substitution
reactions commonly only give access to simple molecules and
have a small substrate scope. C−F bond formation is more
difficult with 18F than with the naturally occurring 19F, and
most modern, functional-group-tolerant fluorination reactions
are not currently useful for applications in PET.5 In addition to
Received: August 27, 2012
© XXXX American Chemical Society
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dx.doi.org/10.1021/ja3084797 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
nonchemists. Moreover, the fluoride must be dried azeotropi-
cally, as is common for most reactions that use [18F]fluoride.1
This manuscript reports on fluorination of arylnickel
complexes that avoid some of the limitations inherent to the
palladium chemistry shown in Scheme 1, most notably the two-
step procedure. We established the relevance of nickel aryl
complexes 1 to the direct oxidative fluorination with fluoride
through reaction of 1a with hypervalent iodine oxidant 6 and
tetrabutylammonium difluorotriphenylsilicate (TBAT) as the
fluoride source, which afforded a 65% isolated yield of aryl
fluoride 2a after chromatographic purification on silica gel (eq
2).
Table 1. Fluorination of Ni(II)−Aryl Complexes with
a
[18F]Fluoride
For radiofluorination, a solution of aqueous [18F]fluoride
(2−5 μL, 100−500 μCi) containing 2 mg of 18-cr-6 in MeCN
(200−500 μL) was added to a mixture of 1.0 mg of nickel
complex 1 and 1.0 equiv (relative to 1) of oxidant 6 at room
temperature under ambient atmosphere in a vial. After less than
1 min after addition, the fluorination reactions were analyzed by
radioTLC and HPLC for radiochemical yield and product
identity, respectively (Table 1). All reactions proceeded without
deliberate addition of [19F]fluoride (no-carrier-added). No
carrier-added 18F fluorination allows for the synthesis of 18F-
labeled molecules of high specific activity.1 For example,
compound 2g was prepared in 1.1 Ci·μmol−1. The trans-
formation is successful for the synthesis of electron-rich,
electron-poor, ortho-, meta-, and para-substituted, and densely
functionalized aryl fluorides, as well as for alkenyl fluorides.
Tertiary amines are currently not tolerated, presumably due to
the unproductive reaction of oxidant 6 with nucleophiles such
as amines.
a
Reaction conditions: 1.0 mg of nickel complex 1, 1.0 equiv of 6 (with
respect to 1), aqueous solution of [18F]fluoride (2−5 μL, 100−500
μCi; 500 μCi in 5 μL of water corresponds to a concentration of 42
nM in [18F]), and 2.0 mg of 18-cr-6 in MeCN (200−500 μL) at 23 °C.
Radiochemical yields (RCYs) were measured by radio-TLC, are based
on original aqueous [18F] content, and are averaged over n
experiments. Boc, tert-butoxycarbonyl; Bz, benzoyl; SFB, N-
succinimidyl 4-fluorobenzoate.
The ability to use aqueous fluoride solutions makes extensive
drying procedures, which are typical for radiochemistry with
[18F]fluoride,1 superfluous. Drying procedures increase the time
from [18F] production to tracer purification; for example,
drying fluoride for the reaction shown in Scheme 1 takes longer
than the 20-min reaction time. The direct use of aqueous
fluoride solution presented here avoids unproductive radio-
active decay and also increases the yield based on fluoride
because drying commonly results in significant fluorine content
being absorbed onto walls of glass reaction vessels. The
aqueous fluoride solution can be used without ion exchange
that is normally required for radiochemistry with [18F]fluoride,
which further increases practicality and reduces reaction time.
To facilitate purification subsequent to fluorination, it is
desirable to employ as little starting material (e.g., 1) as
possible for radiofluorination, and 1 mg of nickel complex (ca. 1
μmol) is a low amount compared to other [18F] radio-
fluorination reactions. For example, the method presented here
requires an order of magnitude less starting material than the
palladium-mediated method described in Scheme 1 and yet
affords generally higher radiochemical yields.6d
The synthesis of the nickel organometallics (1) is
accomplished by oxidative addition of aryl or alkenyl bromides
to commercially available Ni(COD)2 in the presence of
tetramethylethylenediamine (TMEDA), followed by addition
of silver salt 8 (Scheme 2). All reported nickel organometallics
used for fluorination in this manuscript are moisture- and air-
stable solids that can be purified by column chromatography on
silica gel or recrystallization. The nickel complexes were
prepared from the corresponding bromides in 30−92% yield
and can be stored under ambient atmosphere.
The one-step oxidative fluorination of well-defined nickel
complexes with oxidant and aqueous fluoride enables a
straightforward and practical 18F late-stage fluorination of
complex small molecules.7 Operational simplicity of the
fluorination, most notably the ability to use aqueous solutions
of [18F]fluoride, will also empower nonexperts to obtain
previously unavailable 18F-labeled molecules and showcases the
potential of modern organometallic chemistry for applications
B
dx.doi.org/10.1021/ja3084797 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(4) (a) Pike, V. W.; Aigbirhio, F. I. J. Chem. Soc., Chem. Commun.
1995, 2215−2216. (b) Chun, J. H.; Lu, S. Y.; Lee, Y. S.; Pike, V. W. J.
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Scheme 2. Synthesis of Ni(II) Aryl Complexes
(5) For the first transition metal-catalyzed C−18F bond formation,
see: (a) Teare, H.; Robins, E. G.; Kirjavainen, A.; Forsback, S.;
Sandford, G.; Solin, O.; Luthra, S. K.; Gouverneur, V. Angew. Chem.,
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bond formations, see: (b) Hollingworth, C.; Hazari, A.; Hopkinson, M.
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in PET.7 The transformation represents the first example of
fluorination with a first row transition metal organometallic and
the first example of a reaction that affords aryl fluoride by 18F−
C bond formation at room temperature within seconds using
an aqueous solution of 18F fluoride. Going forward, we will
evaluate the possibility of translating the transformation to
automated radiosyntheses as well as PET imaging applications.
(7) For metal-catalyzed C−H to C−19F bond formation with fluoride
and oxidant, see: (a) McMurtrey, K. B.; Racowski, J. M.; Sanford, M. S.
Org. Lett. 2012, 14, 4094−4097. (b) Liu, W.; Huang, X.; Cheng, M.-J.;
Nielsen, R. J.; Goddard, W. A., III; Groves, J. T. Science 2012, 337,
1322−1325. For other modern transition-metal-catalyzed and
-mediated C−F bond forming reactions with potential for applications
in PET, see: (c) Watson, D. A.; Su, M. J.; Teverovskiy, G.; Zhang, Y.;
Garcia-Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325,
1661−1664. (d) Katcher, M. H.; Doyle, A. G. J. Am. Chem. Soc. 2010,
132, 17402−17404. (e) Noel, T.; Maimone, T. J.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2011, 50, 8900−8903. (f) Fier, P. S.; Hartwig, J.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures, spectroscopic data for all
new compounds, crystallographic data for 1c (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
ritter@chemistry.harvard.edu
■
Notes
The authors declare the following competing financial
interest(s): A patent application has been filed through Harvard
on methods and reagents presented in this manuscript.
ACKNOWLEDGMENTS
■
Funding was provided by NIH-NIGMS (GM088237) and
NIH-NIBIB (EB013042), as well as for a shared instrument
grant (S10RR017208). We thank Dr. A. Kamlet for the
synthesis of material used to prepare [18F]2h. We thank S.-L.
Zheng (Harvard) for X-ray crystallographic analysis. We thank
S. Carlin (Massachusetts General Hospital) for technical
assistance with [18F]fluoride. TR is a Sloan fellow, a Lilly
Grantee, an Amgen Young Investigator, a Camille Dreyfus
Teacher-Scholar, and an AstraZeneca Awardee.
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dx.doi.org/10.1021/ja3084797 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX