Copper-catalyzed [18F]fluorination of (Mesityl)(aryl)iodonium salts

Article abstract of DOI:10.1021/ol501243g

A practical, rapid, and highly regioselective Cu-catalyzed radiofluorination of (mesityl)(aryl)iodonium salts is described. This protocol utilizes [¹⁸F]KF to access ¹⁸F-labeled electron-rich, -neutral, and -deficient aryl fluorides under a single set of mild conditions. This methodology is applied to the synthesis of protected versions of two important radiotracers: 4-[¹⁸F]fluorophenylalanine and 6-[ ¹⁸F]fluoroDOPA.

Full text of DOI:10.1021/ol501243g

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed [18F]Fluorination of (Mesityl)(aryl)iodonium Salts
Naoko Ichiishi,† Allen F. Brooks,‡ Joseph J. Topczewski,† Melissa E. Rodnick,‡ Melanie S. Sanford,*,†
and Peter J. H. Scott*,#,‡
†Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
‡Department of Radiology, University of Michigan Medical School, 1301 Catherine, Ann Arbor, Michigan 48109, United States
#Interdepartmental Program in Medicinal Chemistry, University of Michigan, 428 Church Street, Ann Arbor, Michigan 48109, United
States
S
* Supporting Information
ABSTRACT: A practical, rapid, and highly regioselective Cu-
catalyzed radiofluorination of (mesityl)(aryl)iodonium salts is
described. This protocol utilizes [18F]KF to access 18F-labeled
electron-rich, -neutral, and -deficient aryl fluorides under a single
set of mild conditions. This methodology is applied to the synthesis
of protected versions of two important radiotracers: 4-[18F]-
fluorophenylalanine and 6-[18F]fluoroDOPA.
Scheme 1. Radiofluorination of Diaryliodonium Salts
ositron emission tomography (PET) is a powerful and
Pminimally invasive medical imaging technique that provides
kinetic physiochemical information.1 The most commonly used
radioisotope for PET is 18F, which offers the advantages of high-
resolution imaging, a relatively long lifetime (t1/2 = 110 min), and
minimal perturbation of radioligand binding. Despite these
advantages, the development of novel 18F radiotracers is
currently impeded by a paucity of general and effective
radiofluorination methods. There are currently few robust
synthetic procedures for the incorporation of 18F into organic
molecules with sufficient speed, selectivity, yield, radiochemical
purity, and reproducibility to provide clinical imaging materials.
Direct methods for the late stage nucleophilic [18F]fluorination
of electron-rich aromatic substrates remains an especially long-
standing challenge.2 A target of particular interest in this regard is
6-[18F]fluoroDOPA.3,4
The classical radiofluorination methods for electron-rich aryl
rings utilize electrophilic fluorinating reagents derived from
[18F]F2.2 However, [18F]F2 production typically requires 19F2 as a
carrier gas, which leads to low specific activity (SA) radiotracers
(typically <1.0 Ci/mmol) and requires specialized facilities. The
development of [18F]KF production from [18O]water has
provided the means to synthesize high SA radiotracers (>1000
Ci/mmol) through nucleophilic substitution (typically SN2 or
SNAr).1 However, the use of [18F]KF is generally limited to the
formation of primary sp3-C−F bonds or sp2-C−F bonds on
electron-deficient (hetero)aromatics.
Two main strategies have been used to address these
limitations. The first involves radiofluorination of powerful
electrophiles such as diaryliodonium salts.5 Diaryliodonium salts
bearing the 2-thienyl group have been shown to react with
[18F]KF at elevated temperatures (often ≥150 °C) to afford
[18F]fluororarenes (Scheme 1a).6 In these systems, the 2-thienyl
group directs radiofluorination to the other aromatic ligand on
iodine with moderate to good selectivity.6 However, the
[(thienyl)(aryl)I+] starting materials are often challenging to
prepare, suffer from low stability, and have a limited shelf life.7
Furthermore, with electron-neutral or -rich substrates, these
transformations frequently require high temperatures, exhibit
modest regioselectivity, demonstrate limited functional group
tolerance, and provide low radiochemical yields.6 With the
exception of recent work by DiMagno,8 it has proven challenging
to access many important radiotracers using this method.
A second strategy applies transition metal catalysts and/or
reagents to achieve radiofluorination with [18F]KF.9,10 Tran-
sition-metal catalysis offers opportunities for accelerating
radiofluorination reaction rates as well as enhancing selectivity
and reactivity. For instance, Hooker and Ritter have made
progress in the radiofluorination of arenes using Pd9a,b and Ni9c
complexes.
Received: April 30, 2014
Published: June 3, 2014
© 2014 American Chemical Society
3224
dx.doi.org/10.1021/ol501243g | Org. Lett. 2014, 16, 3224−3227

Organic Letters
Letter
We sought to develop a general, mild, high-yielding, and user-
friendly procedure for the radiofluorination of diverse aromatic
substrates by merging transition-metal catalysis with the
fluorination of diaryliodonium reagents (Scheme 1b). We have
recently demonstrated that Cu salts catalyze the fluorination of
stable and synthetically accessible mesityl-substituted diary-
liodonium salts.11 Here, the mesityl group directs oxidative
addition and fluorination to the smaller aryl group on iodine,
regardless of its electronic properties. In this paper, we
demonstrate that this Cu-catalyzed fluorination method can be
translated to a high specific activity radiofluorination of electron-
rich, -neutral, and -deficient arene substrates. Furtheremore, this
protocol enables the radiofluorination of protected versions of 4-
[18F]fluorophenylalanine, and 6-[18F]fluoroDOPA.
Our initial studies focused on the Cu-catalyzed radio-
fluorination of [4-OMePh-I-Mes]BF4 (1). This substrate was
selected because the radiosynthesis of electron-rich fluoroarenes
such as [18F]fluoroanisole remains a challenge.12 Gratifyingly,
the use of Cu(OTf)2 as the catalyst, DMF as the solvent, and
[18F]KF-18-crown-6 as the fluoride source resulted in 36%
radiochemical conversion (RCC) to 4-[18F]fluoroanisole in 20
min (Table 1, entry 1). High selectivity was observed for 4-
(Tables S1−S4, Supporting Information). Optimal conditions
were as follows: 6 μmol loading of 1, 1:1 molar ratio of CuOTf to
1, 85 °C, 20 min, in a total volume of 750 μL of DMF. Under
these conditions, 1 was obtained in 79
8% radiochemical
conversion (n = 38, entry 6). Notably, >50% RCC was obtained
under most of the conditions examined, indicating that this
transformation is remarkably insensitive to the reaction
conditions (a particularly attractive attribute when translating
this chemistry to use by nonexperts).
One concern in the radiofluorination of 1 is the possibility for
isotopic dilution via 18F/19F exchange between the BF4
counterion and the [18F]KF.13 In principle, this issue can be
addressed by changing the counterion;14 however, an evaluation
of different [4-OMePh-I-Mes]X salts (X = TsO, PF6, TfO)
showed that the best conversion was obtained with BF4 (Table 1,
entries 6−9). To test whether isotopic dilution from the BF4
counterion is, indeed, a problem, we compared the specific
activity (SA) of the 4-[18F]fluoroanisole product obtained from
[4-OMePh-I-Mes]BF4 to that from [4-OMePh-I-Mes]OTs.
Automated syntheses were conducted in a standard module
with 1500 mCi initial activity of 18F. Under automated
conditions, [4-OMePh-I-Mes]BF4 afforded a RCC of 40
10% and a SA of 1800 800 Ci/mmol (n = 3), while [4-OMePh-
I-Mes]OTs afforded 10 2% RCC with a comparable SA of
Table 1. Optimization of Radiofluorination of 1 To Form 4-
[18F]Fluoroanisole
3000
1000 Ci/mmol (n = 3). These results indicate that
isotopic dilution is not a significant problem under these reaction
conditions.15
Importantly for the user, this transformation is performed
under ambient conditions without the requirement for a drybox
or extensive drying of reagents and glassware. The reaction
mixture is homogeneous, and the remainder of 18F appears to be
sequestered as inorganic fluoride salts. The copper catalyst is
commercially available and is stable in solution over at least 4 h;
for instance, a 77% RCC was obtained using a solution of
(CH3CN)4CuOTf in DMF that was allowed to stand for 4 h
under ambient conditions prior to use. Finally, 1 and the other
(mesityl)(aryl)iodonium salts described herein are colorless,
free-flowing solids that are shelf stable for months under ambient
conditions when protected from intense light. Thus, this method
is highly practical and amenable to routine automated synthesis.
These radiofluorination conditions were next applied to a
diverse series of (mesityl)(aryl)iodonium tetrafluoroborate salts
(Table 2). In all cases, modest to excellent radiochemical
conversion was obtained without further optimization of the
reaction conditions. All of the reactions in Table 2 were highly
selective for a single 18F-containing product, with ≤2%
fluoromesitylene detected. Furthermore, for all of the substrates
examined, ≤2% of the corresponding fluoroarene product was
observed in the absence of Cu catalyst, confirming that Cu is vital
for accelerating the reaction rate as well as controlling selectivity.
This protocol can be used for the radiofluorination of arenes
containing multiple electron-donating methoxy substituents
(Table 2, entries 2 and 3). Remarkably, even the highly
electron-rich product 1-[18F]fluoro-3,4,5-trimethoxybenzene
(4) was obtained in 14% RCC using this nucleophilic
fluorination protocol. Steric factors do impact the radiochemical
conversion; for instance, while 4-[18F]fluoroanisole was obtained
in 79% RCC, the corresponding 2-[18F]fluoroanisole was formed
in 30% RCC.
a
entry
[Cu]
Cu(OTf)2
X
RCC 2 (%)
b
1
BF4
BF4
BF4
BF4
BF4
BF4
PF6
OTs
OTf
36 19 (n = 15)
10 6 (n = 3)
43 15 (n = 3)
70 11 (n = 11)
<1
b
2
CuCO3·Cu(OH)2
CuOTf·toluene
(CH3CN)4CuOTf
none
b
3
b
4
b
5
c
6
(CH3CN)4CuOTf
(CH3CN)4CuOTf
(CH3CN)4CuOTf
(CH3CN)4CuOTf
79 8 (n = 38)
53 7 (n = 3)
45 26 (n = 3)
15 12 (n = 3)
c
7
c
8
c
9
a
Radiochemical conversion was determined by radio-TLC (average of
n runs). The identity of 4-[18F]fluoroanisole was confirmed by HPLC.
b
Conditions: [4-OMePh-I-Mes]BF4 (6 μmol), [Cu] (3 μmol),
[18F]KF·18-crown-6·K2CO3 complex in DMF (250 μL, 300−700
c
μCi), total volume 750 μL. Conditions: [4-OMePh-I-Mes]X (6
μmol), [Cu] (6 μmol). [18F]KF·18-crown-6·K2CO3 complex in DMF
(250 μL, 300−700 μCi), total volume 750 μL.
[18F]fluoroanisole, and <1% of [18F]fluoromesitylene was
detected by radio-TLC or radio-HPLC. While the radiochemical
conversion was reasonable, the reaction showed modest
reproducibility ( 19% yield over n = 15). To address this
issue, we sought an alternate Cu precursor to catalyze the
radiofluorination. A variety of CuI and CuII complexes were
examined (for examples, see entries 2−4). Commercially
available and bench stable (CH3CN)4CuOTf proved optimal,
providing high radiochemical conversion and improved
reproducibility (70 11% RCC over n = 11, entry 4). A control
experiment in the absence of Cu provided no detectable 4-
[18F]fluoroanisole and only 6% RCC to [18F]fluoromesitylene
(entry 5). A number of other variables were examined to
optimize the radiofluorination including the ratio of [Cu] to 1,
concentration of 1, temperature, counterion, and reaction time
Electron-neutral and electron-deficient aryl rings also under-
went radiofluorination in high yield and selectivity using this
method (entries 6−10). A variety of functional groups, including
amide NH bonds (6), ketones (8), aryl iodides (9), esters (10),
3225
dx.doi.org/10.1021/ol501243g | Org. Lett. 2014, 16, 3224−3227

Organic Letters
Letter
b
Table 2. [18F]Fluorination of (Mesityl)(aryl)iodonium Salts
Scheme 2. Amino Acid Derived Substrates
sample count rates.”21b,20 The current protocol affords protected
F-PHE (13) in 23% RCC (eq 1).
Finally, protected 6-[18F]fluoroDOPA 15 was prepared in 17
6% RCC with a tosylate counterion and 30 3% RCC with a
tetrafluoroborate counterion (eq 2). While there has been much
activity in the radiofluorination community aimed at accessing 6-
[18F]fluoro-L-DOPA,21,22 current methods suffer from draw-
backs that limit routine production of this material. This
molecule has been of great interest to the PET community
since the 1970s due to its numerous clinical applications.3,4
However, despite decades of research, there is no routine automated
synthesis of 18F-DOPA in clinical use.5,6 To further demonstrate
the utility of this method, we have performed the automated
synthesis of 15 from the shelf stable salt 14-OTs. Under our
standard conditions, 14-OTs afforded 17 2% RCC of 15 with a
SA of 4000 2000 Ci/mmol (n = 2).23,24
In summary, this paper demonstrates a general, practical, and
rapid Cu-catalyzed radiofluorination of diaryliodonium salts
using [18F]KF. This method is compatible with a wide range of
functional groups, is competent for electronically diverse aryl
groups, and uniformly affords good selectivity for a single 18F-
containing product. The synthesis of protected versions of
clinically relevant tracers, 4-[18F]fluorophenylalanine and 6-
[18F]fluoroDOPA, has been demonstrated. Application of this
methodology to other molecules of clinical interest is ongoing
and will be disclosed in due course.
a
Radiochemical conversion were determined by radio-TLC (average
of n runs). The identity of each product was confirmed by HPLC.
b
Reaction conditions: precursor (6 μmol), Cu catalyst (6 μmol).
[18F]KF·18-crown-6·K2CO3 complex in DMF (250 μL, 300−700
μCi). Total reaction volume 750 μL.
ASSOCIATED CONTENT
■
S
* Supporting Information
and aldehydes (11), were well tolerated. This enabled the
preparation of several known PET prosthetic groups, including
4-[18F]fluoroiodobenzene (entry 8),16 methyl [18F]-
fluorobenzoate (entry 9),17 and [18F]fluorobenzaldehyde
(entry 10).18
Experimental procedures, optimization details, radio-TLC traces,
HPLC traces, and spectral data for all new compounds. This
material is available free of charge via the Internet at http://pubs.
acs.org.
Having demonstrated that a diverse range of [18F]arylfluorides
can be accessed via this methodology, the radiofluorination of
several molecules of clinical relevance was investigated. Two
(mesityl)(aryl)iodonium salts derived from aromatic amino acids
(12 and 14) were prepared and subjected to the radio-
fluorination protocol (Scheme 2). Without any substrate-specific
optimization, the radiolabeled products 13 and 15 were obtained
in acceptable yields. Importantly, 13 is a protected version of 4-
[18F]fluorophenylalanine (F-PHE), a radiotracer originally
developed in the 1970s as a probe of pancreatic and cerebral
protein synthesis.19 However, clinical applications of F-PHE to
tumor imaging have not been realized partially due to the lack of
an acceptable radio-synthesis. The original doses of F-PHE were
prepared in low specific activity (<0.01 Ci/mmol) and required a
dose “approaching toxic levels in order to obtain adequate
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: mssanfor@umich.edu.
*E-mail: pjhscott@umich.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge the NIH (GM073836 (MSS) and T32-
EB005172 (PJHS)) for financial support.
■
REFERENCES
■
(1) (a) Cai, L.; Lu, S.; Pike, V. W. Eur. J. Org. Chem. 2008, 2853.
(b) Ametamey, S. M.; Honer, M.; Schubiger, P. A. Chem. Rev. 2008, 108,
3226
dx.doi.org/10.1021/ol501243g | Org. Lett. 2014, 16, 3224−3227

Organic Letters
Letter
1501. (c) Miller, P. W.; Long, N. J.; Vilar, R.; Gee, A. D. Angew. Chem.,
Int. Ed. 2008, 47, 8998. (d) Littich, R.; Scott, P. J. H. Angew. Chem., Int.
Ed. 2012, 51, 1106.
(17) (a) Basuli, F.; Wu, H.; Griffiths, G. L. J. Labelled Compd.
Radiopharm. 2011, 54, 224. (b) Vaidyanathan, G.; Zalutsky, M. R. Nucl.
Med. Biol. 1992, 19, 275. (c) Hoehne, A.; Behera, D.; Parsons, W. H.;
James, M. L.; Shen, B.; Borgohain, P.; Bodapati, D.; Prabhakar, A.;
Gambhir, S. S.; Yeomans, D. C.; Biswal, S.; Chin, F. T.; Bois, J. D. J. Am.
Chem. Soc. 2013, 135, 18102.
(18) (a) Lemaire, C.; Guillaume, M.; Christiaens, L.; Palmer, A. J.;
Cantineau, R. Appl. Radiat. Isot. 1987, 38, 1033. (b) Haka, M. S.;
Kilbourn, M. R.; Watkins, G. L.; Toorongian, S. A. J. Labelled Compd.
Radiopharm. 1989, 27, 823. (c) Poethko, T.; Schottelius, M.;
Thumshirn, G.; Hersel, U.; Herz, M.; Henriksen, G.; Kessler, H.;
Schwaiger, M.; Wester, H.-J. J. Nucl. Med. 2004, 45, 892.
(2) For a recent review on [18F]fluoroaryl synthesis, see: Tredwell, M.;
Gouverneur, V. Angew. Chem., Int. Ed. 2012, 51, 11426.
(3) (a) Garnett, E. S.; Firnau, G.; Chan, P. K. H.; Sood, S.; Belbeck, L.
W. Proc. Natl. Acad. Sci. U.S.A. 1978, 75, 464. (b) Garnett, E. S.; Firnau,
G.; Nahmias, C. Nature 1983, 305, 137. (c) Luxen, A.; Guillaume, M.;
Melega, W. P.; Pike, V. W.; Solin, O.; Wagner, R. Int. J. Nucl. Med. Biol.
1992, 19, 149. (d) Rakshi, J. S.; Uema, T.; Ito, K.; Bailey, D. L.; Morrish,
P. K.; Ashburner, J.; Dagher, A.; Jenkins, I. H.; Friston, K. J.; Brooks, D. J.
Brain 1999, 122, 1637.
(4) For the application of 6-[18F]F -DOPA to tumor imaging, see:
(a) Hoegerle, S.; Altehoefer, C.; Ghanem, N.; Koehler, G.; Waller, C. F.;
Scheruebl, H.; Moser, E.; Nitzsche, E. Radiology 2001, 220, 373.
(19) (a) Goulding, R. W.; Palmer, A. J.; Thakur, M. L. Radioisotopy
1971, 12, 1045. (b) Cottrall, M. F.; Taylor, D. M.; McElwain, T. J. Br. J.
Radiol. 1973, 46, 277. (c) Bodsch, W.; Coenen, H. H.; Stocklin, G.;
̈
Takahashi, K.; Hossmann, K. A. J. Neurochem. 1988, 50, 979.
́
(b) Becherer, A.; Szabo, M.; Karanikas, G.; Wunderbaldinger, P.;
(20) Since then, O-(2-[18F]fluoroethyl)-L-tyrosine has been utilized as
a less than ideal but accessible surrogate for phenylalanine. See:
(a) Wester, H. J.; Herz, M.; Weber, W.; Heiss, P.; Senekowitsch-
Angelberger, P.; Raderer, M.; Kurtaran, A.; Dudczak, R.; Kletter, K. J.
Nucl. Med. 2004, 45, 1161. (c) Chen, W.; Silverman, D. H. S.; Delaloye,
S.; Czernin, J.; Kamdar, N.; Pope, W.; Satyamurthy, N.; Schiepers, C.;
Cloughesy, T. J. Nucl. Med. 2006, 47, 904.
Schmidtke, R.; Schwaiger, M.; Stocklin, G. J. Nucl. Med. 1999, 40, 205.
̈
(b) Langen, K.-J.; Hamacher, K.; Weckesser, M.; Floeth, F.; Stoffels, G.;
Bauer, D.; Coenen, H. H.; Pauleit, D. Nucl. Med. Biol. 2006, 33, 287.
(21) For 6-[18F]F-DOPA syntheses using [18F]F2 or a derivative
thereof, see: (a) Firnau, G.; Chirakal, R.; Garnett, E. S. J. Nucl. Med.
1984, 25, 1228. (b) Chirakal, R.; Firnau, G.; Couse, J.; Garnett, E. S.
Appl. Radiat. Isot. 1984, 35, 651. (c) Coenen, H. H.; Franken, K.; Kling,
(5) (a) Grushin, V. V.; Kantor, M. M.; Tolstoya, T. P.; Shcherbina, T.
M. Russ. Chem. Bull. 1984, 33, 2130. (b) Shah, A.; Pike, V. W.;
Widdowson, D. A. J. Chem. Soc., Perkin Trans. 1 1998, 2043. (c) Chun, J.;
Telu, S.; Lu, S.; Pike, V. W. Org. Biomol. Chem. 2013, 11, 5094.
(d) Chun, J.; Pike, V. W. Org. Biomol. Chem. 2013, 11, 6300.
(e) Yusubov, M. S.; Svitich, D. Y.; Larkina, M. S.; Zhdankin, V. V.
ARKIVOC 2013, 364.
(6) (a) Martín-Santamaría, S.; Carroll, M. A.; Carroll, C. M.; Carter, C.
D.; Rzepa, H. S.; Widdowson, D. A.; Pike, V. W. Chem. Commun. 2000,
649. (b) Ross, T. L.; Ermert, J.; Hocke, C.; Coenen, H. H. J. Am. Chem.
Soc. 2007, 129, 8018. (c) Carroll, M. A.; Jones, C.; Tang, S.-L. J. Labelled
Compd. Radiopharm. 2007, 50, 450. (d) Jang, K. S.; Jung, Y.-W.; Gu, G.;
Koeppe, R. A.; Sherman, P. S.; Quesada, C. A.; Raffel, D. M. J. Med.
Chem. 2013, 56, 7312.
P.; Stocklin, G. Appl. Radiat. Isot. 1988, 39, 1243. (d) Namavari, M.;
̈
Bishop, A.; Satyamurthy, N.; Bida, G.; Barrio, J. R. Appl. Radiat. Isot.
1992, 43, 989. (e) Stenhagen, I. S. R.; Kirjavainen, A. K.; Forsback, S. J.;
Jørgensen, C. G.; Robins, E. G.; Luthra, S. K.; Solin, O.; Gouverneur, V.
Chem. Commun. 2013, 49, 1386.
(22) For syntheses of 6-[18F]F-DOPA from 18F−, see: (a) Ding, Y. S.;
Shiue, C. Y.; Fowler, J. S.; Wolf, A. P.; Plenevaux, A. J. Fluorine Chem.
1990, 48, 189. (b) Lemaire, C.; Damhaut, P.; Plenevaux, A.; Comar, D. J.
Nucl. Med. 1994, 35, 1996. (c) Lemaire, C.; Gillet, S.; Guillouet, S.;
Plenevaux, A.; Aerts, J.; Luxen, A. Eur. J. Org. Chem. 2004, 2899.
(d) Wagner, F. M.; Ermert, J.; Coenen, H. H. J. Nucl. Med. 2009, 50,
1724.
(7) In our hands, (2-thienyl)(aryl)iodonium derivatives exhibit modest
stability; for example, [(4-OMePh)(2-thienyl)I]Br was found to
decompose within 2 weeks under ambient conditions.
(8) Only one report in the patent literature has described accessing F-
DOPA from diaryliodonium salts: DiMagno, S. Fluorination of
Aromatic Ring Systems. WO2010/048170A2, April 29, 2010.
(9) For transition metal-catalyzed aryl radiofluorination, see: (a) Lee,
E.; Kamlet, A. S.; Powers, D. C.; Neumann, C. N.; Boursalian, G. B.;
Furuya, T.; Choi, D. C.; Hooker, J. M.; Ritter, T. Science 2011, 334, 639.
(b) Kamlet, A. S.; Neumann, C. N.; Lee, E.; Carlin, S. M.; Moseley, C.
K.; Stephenson, N.; Hooker, J. M.; Ritter, T. PLoS One 2013, 8, e59187.
(c) Lee, E.; Hooker, J. M.; Ritter, T. J. Am. Chem. Soc. 2012, 134, 17456.
(10) For metal catalyzed sp3 radiofluorination, see: (a) Topczewski, J.
J.; Tewson, T. J.; Nguyen, H. M. J. Am. Chem. Soc. 2011, 133, 19318.
(b) Benedetto, E.; Tredwell, M.; Hollingworth, C.; Khotavivattana, T.;
Brown, J. M.; Gouverneur, V. Chem. Sci. 2013, 4, 89. (c) Graham, T. J.
A.; Lambert, R. F.; Ploessl, K.; Kung, H. F.; Doyle, A. G. J. Am. Chem. Soc.
2014, 136, 5291. (d) Huang, X.; Liu, W.; Ren, H.; Neelamegam, R.;
Hooker, J. M.; Groves, J. T. J. Am. Chem. Soc. 2014, 136, 6842.
(11) Ichiishi, N.; Canty, A. J.; Yates, B. F.; Sanford, M. S. Org. Lett.
2013, 15, 5134.
(23) An unoptimized and uncorrected isolated RCY of 1.1% of 15
(16.5 mCi) was obtained via automated synthesis using 14-BF4 as
starting material. This material had a specific activity of 290 Ci/mmol.
(24) Salts 12 and 14 were prepared from L-PHE and L-DOPA
respectively. Optimization of the radiosynthesis is ongoing and to date
ee’s have not yet been determined.
(12) To achieve an acceptable yield, bis(p-methoxyphenyl)iodonium
salts are required, which produces iodoanisole as a byproduct: Pike, V.
W.; Aigbirhio, F. I. J. Chem. Soc., Chem. Commun. 1995, 2215.
(13) Jauregui-Osoro, M.; Sunassee, K.; Weeks, A. J.; Berry, D. J.; Paul,
R. L.; Cleij, M.; Banga, J. P.; O’Doherty, M. J.; Marsden, P. K.; Clarke, S.
E. M.; Ballinger, J. R.; Szanda, I.; Cheng, S.-Y.; Blower, P. J. Eur. J. Nucl.
Med. Mol. Imaging 2010, 37, 2108.
(14) Chun, J.-H.; Lu, S.; Pike, V. W. Eur. J. Org. Chem. 2011, 4439.
(15) If 18F/19F exchange were rapid, the expected specific activity of 4-
[18F]fluoroanisole would be <1 Ci/mmol.
(16) (a) Gail, R.; Coenen, H. H. Appl. Radiat. Isot. 1994, 45, 105.
(b) Steiniger, B.; Wuest, F. R. J. Labelled Compd. Radiopharm. 2006, 49,
817. (c) Gao, Z.; Gouverneur, V.; Davis, B. G. J. Am. Chem. Soc. 2013,
135, 13612.
3227
dx.doi.org/10.1021/ol501243g | Org. Lett. 2014, 16, 3224−3227