Targeted fluorination with the fluoride ion by manganese-catalyzed decarboxylation

Article abstract of DOI:10.1002/anie.201500399

We describe the first catalytic decarboxylative fluorination reaction based on the nucleophilic fluoride ion. The reported method allows the facile replacement of various aliphatic carboxylic acid groups with fluorine. Moreover, the potential of this method for PET imaging has been demonstrated by the successful ¹⁸F labeling of a variety of carboxylic acids with radiochemical conversions up to 50-%, representing a targeted decarboxylative ¹⁸F labeling method with no-carrier-added [¹⁸F]fluoride. Mechanistic probes suggest that the reaction proceeds through the interaction of the manganese catalyst with iodine(III) carboxylates formed in situ from iodosylbenzene and the carboxylic acid substrates. Nucleophile first: An efficient manganese porphyrin catalyzed decarboxylative fluorination reaction based on a nucleophilic fluorine source is described. The potential of the described method for use in PET imaging has been demonstrated by the successful ¹⁸F labeling of various aliphatic carboxylic acids, representing the first decarboxylative ¹⁸F labeling method with no-carrier-added [¹⁸F]fluoride.

Full text of DOI:10.1002/anie.201500399

Angewandte
Chemie
DOI: 10.1002/anie.201500399
Decarboxylative Fluorination
Hot Paper
Targeted Fluorination with the Fluoride Ion by Manganese-Catalyzed
Decarboxylation**
Xiongyi Huang, Wei Liu, Jacob M. Hooker, and John T. Groves*
Abstract: We describe the first catalytic decarboxylative
fluorination reaction based on the nucleophilic fluoride ion.
The reported method allows the facile replacement of various
aliphatic carboxylic acid groups with fluorine. Moreover, the
potential of this method for PET imaging has been demon-
strated by the successful 18F labeling of a variety of carboxylic
acids with radiochemical conversions up to 50%, representing
a targeted decarboxylative 18F labeling method with no-carrier-
added [18F]fluoride. Mechanistic probes suggest that the
reaction proceeds through the interaction of the manganese
catalyst with iodine(III) carboxylates formed in situ from
iodosylbenzene and the carboxylic acid substrates.
tions with fluoride-based reagents (FÀ),[3a] only a handful of
reactions have been developed, which allow the synthesis of
aryl fluorides,[4] alkenyl fluorides,[5] allylic fluorides,[6] fluo-
rohydrins,[7] 18F-labeled trifluoromethyl arenes,[8] and benzylic
fluorides.[9]
À
A general catalytic method for constructing aliphatic C F
bonds with simple nucleophilic fluoride remains a challenging
task.[10] In 2012, our laboratory reported an efficient aliphatic
À
C H fluorination reaction that employed manganese tetra-
mesitylporphyrin [Mn(tmp)]Cl as the catalyst and silver
fluoride/tetrabutylammonium
fluoride
trihydrate
(TBAF·3H2O) as the fluoride source.[11] The reaction was
shown to proceed via a novel trans-difluoromanganese(IV)
porphyrin complex that served as the fluorine transfer agent.
O
rganofluorine compounds are of significant importance
for the agrochemical and pharmaceutical industries as well as
for PET imaging applications.[1] Despite the broad impact of
organofluorine compounds and the intrinsic strength of the
Insights gained from the facile capture of substrate carbon
IV
À
À
radicals by F Mn F species led to the development of
À
benzylic C H fluorination reactions using manganese salen
C F bond, the incorporation of fluorine into organic mole-
catalysts.[12] Very recently, we reported the first 18F labeling
À
cules remains challenging.[2] Conventional fluorination meth-
ods typically involve harsh reaction conditions, displaying
poor functional-group tolerance and low selectivity.[2] These
limitations have inspired the development of a number of new
methods, especially catalytic approaches, for constructing
reaction of aliphatic C H bonds with no-carrier-added
À
[18F]fluoride and Mn(salen) catalysts.[13]
À
We have sought a complementary Mn F fluorination
protocol that would employ a ubiquitous and easily managed
target functional group. A possible approach was suggested
by reports of Mn-catalyzed oxidative decarboxylations from
the 1990s.[14] This decarboxylative hydroxylation reaction is
fast and has a wide functional-group tolerance. Functional-
À
C F bonds.
During the past ten years, remarkable advances have been
made in the field of catalytic fluorination.[2,3] The majority of
these newly developed methods are based on electrophilic
fluorination reagents (F+), such as Selectfluor and other N-
fluoroammonium analogues, N-fluoropyridinium salts
(NFPs), and N-fluorosulfonamides.[3b] For catalytic fluorina-
=
À
ities like olefinic C C bonds and reactive C H bonds, which
are reactive under common metalloporphyrin-catalyzed oxi-
dative conditions, were well tolerated. Driven by these
appealing features, we aimed to develop a catalytic fluorode-
carboxylation reaction based on nucleophilic fluoride (FÀ)
(Scheme 1).
[*] X. Huang, Dr. W. Liu, Prof. J. T. Groves
Department of Chemistry, Princeton University
Princeton NJ 08544 (USA)
E-mail: jtgroves@princeton.edu
Prof. J. M. Hooker
Athinoula A. Martinos Center for Biomedical Imaging, Department
of Radiology, Massachusetts General Hospital, Harvard Medical
School (USA)
[**] This research was supported by the US National Science Founda-
tion award CHE-1148597 (J.T.G.) and in part by the Center for
Catalytic Hydrocarbon Functionalization, an Energy Frontier
Research Center, U.S. Department of Energy, Office of Science,
Basic Energy Sciences, under Award No. DE SC0001298 (J.T.G.). A
portion of this research was carried out at the Martinos Center for
Biomedical Imaging using resources provided by the Center for
Functional Neuroimaging Technologies, P41EB015896, and shared
instrumentation grants S10RR017208 and S10RR023452. X.H.
thanks the Howard Hughes Medical Institute for fellowship
support. W.L. thanks Merck, Inc. for fellowship support.
Scheme 1. The concept of manganese-catalyzed decarboxylative fluori-
nation.
The concept of decarboxylative fluorination was first
demonstrated by Grakauskas with fluorine gas in 1969 and
later by Patrick et al. with XeF2.[15] Applications of these
reactions were severely limited however, due to the highly
reactive, electrophilic fluorination reagents. Several catalytic
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201500399.
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
decarboxylative fluorination methods have been developed
recently based on modern electrophilic fluorination reagents
such as Selectfluor[16] that have enabled transformations of
various types of carboxylic acids to the corresponding
fluorides under mild conditions.
A decarboxylative fluorination using the fluoride ion has
not been described until this report. The major advantages of
using fluoride for PET imaging applications are the signifi-
cantly higher specific activities that can be achieved with
[18F]fluoride compared to [18F]F+ reagents, as well as the ease
of preparing and handling [18F]fluoride salts.[1b,4b] Moreover,
decarboxylative fluorination may enable easier purifications
given the marked difference (polarity/charge) in the precur-
sor carboxylic acid and the fluorinated product.
catalyst, iodosylbenzene (PhIO) as the oxidant, DCE as
solvent and 0.5 equiv benzoic acid as the additive (Table 1,
entry 9). No fluorination products were detected in control
experiments with the catalyst or oxidant omitted.
Having identified the optimal conditions, we then exam-
ined the substrate scope of this reaction. As shown in
Scheme 2, a variety of functional groups, including hetero-
With ibuprofen (1a) as an initial model substrate,
exploratory reaction conditions afforded fluorination product
1 in a promising 13% yield (Table 1, entry 1). The modest
Table 1: Optimization of the reaction conditions.[a]
Entry Catalyst[b]
Oxidant
[Mn(tmp)]Cl PhIO
FÀ (equiv)
Solvent[c] Yield [%]
1
2
3
4
5
6
7
8
9
AgF/
ACN/
DCM
ACN/
DCM
DCE
13
TBAF·3H2O
Et3N·3HF
(1.2)
Et3N·3HF
(1.2)
Et3N·3HF
(1.2)
Et3N·3HF
(1.2)
[Mn(tmp)]Cl PhIO
[Mn(tmp)]Cl PhIO
[Mn(ttp)]Cl PhIO
53
61
DCE
DCE
DCE
DCE
DCE
DCE
43
[Mn(tdcpp)]Cl PhIO
[Mn(tpfpp)]Cl PhIO
16
Et3N·3HF
(1.2)
trace
45
[Mn(tmp)]Cl PhI(OPiv)2 Et3N·3HF
(1.2)
[Mn(tmp)]Cl PhI(OAc)2 Et3N·3HF
(1.2)
50
65[d]
Scheme 2. Substrate scope and functional-group tolerance. [a] Stan-
dard conditions: substrate (0.5 mmol), [Mn(tmp)]Cl (2.5 mol%),
Et3N·3HF (1.2 equiv), benzoic acid additive (0.5 equiv), DCE (1 mL).
PhIO (3.3 equiv) was added in small portions within 45 min to 1.5 h at
458C under N2 protection. The reported yields are those of isolated
products unless otherwise noted. [b] Yields were determined by
19F NMR spectroscopy. [c] Iodosylmesitylene was used as the oxidant.
[d] 2 equiv of oxidant were used.
[Mn(tmp)]Cl
PhIO
Et3N·3HF
(1.2)
[a] Reaction conditions: Nitrogen atmosphere, 1a (103 mg, 0.5 mmol),
catalyst (10 mg, 2.5 mol%), oxidant (370 mg, 3.3 equiv), and solvent
(1 mL). Yields were determined by 19F NMR spectroscopy with 20 mL
fluorobenzene as standard. [b] tmp: tetramesitylporphyrin; ttp:
5,10,15,20-tetrakis(p-tolyl)porphyrin; tdcpp: 5,10,15,20-tetrakis(2,6-
dichlorophenyl)porphyrin; tpfpp: 5,10,15,20-tetrakis(pentafluorophe-
nyl)porphyrin. [c] ACN: acetonitrile; DCM: dichloromethane; DCE: 1,2-
dichloroethane. [d] 0.5 equiv benzoic acid as additive.
cycle, amide, imide, ester, ketone, ether, nitrile, halogen, and
even alkene and alkyne, are well tolerated. Higher yields were
generally observed for substrates bearing electron-donating
substituents. Molecules containing strongly electron-rich
aromatic rings, which are challenging substrates for Select-
fluor-based decarboxylative fluorination methods because of
the competing aryl fluorination,[16d] were readily fluorinated
without any ring fluorination (11–13). The tolerance to
yield is likely due to the formation of insoluble silver
carboxylates that were observed during the reaction. We
thus turned to a less basic fluoride source, triethylamine
trihydrofluoride (Et3N·3HF),[17] with which the yield
increased to 53% (Table 1, entry 2). After extensive screen-
ing a 65% yield was obtained with [Mn(tmp)]Cl as the
2
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
reactive functional groups like halogens (10) and alkynes (7)
further broadens the application of the present method, as
various structural motifs can be accessed through these
functionalities by well-established methods such as cross
coupling or “click” reactions. Surprisingly, no epoxidation or
À
C H activation products were observed with substrates
=
containing olefinic C C bonds (e.g., 11 and 26), despite the
well-known [Mn(tmp)]Cl/PhIO catalytic system that effi-
ciently performs these reactions.[18] While the present method
efficiently fluorinated benzylic and aryloxy carboxylic acids,
tertiary, secondary, and primary acids were less reactive (22–
25). The same trend was observed for the related Mn-
catalyzed decarboxylative hydroxylation reaction.[19] The
results suggest a free-radical pathway, as the reactivity pattern
À
is consistent with variations of the C COOH bond dissoci-
ation energies.[20]
The mildness of the fluorination conditions prompted us
to test its application to fluorinating molecules with structures
of biological importance (Scheme 2). Fluorinated benzyl
cinnamate and a fluorinated estrone derivative could be
obtained in 56% and 65% yield, respectively, from the
corresponding acids. Moreover, this procedure could be
applied to fragile, complex structures like artemisinin, for
which the decarboxylative fluorination proceeded smoothly
to afford 28 in 61% yield in 1 h. These results clearly
demonstrate the significant potential of the reported method
for late-stage fluorination of bioactive molecules.
Scheme 3. a) Decarboxylative fluorination with KF as fluoride source.
b) Adapting the manganese-catalyzed decarboxylative fluorination to
18F labeling. Radiochemical conversions (RCCs) are averaged over
n experiments.
A proposed reaction mechanism is shown in Figure 1.
There are two likely pathways for the activation of the
carboxylic acid. The first involves the preformation of an
iodine(III) carboxylate ester that oxidizes the manganese(III)
Compared to current decarboxylative fluorination meth-
ods that are based on F+ reagents, the major advantage of this
fluoride-based decarboxylative fluorination reaction is its
applicability to 18F labeling with [18F]fluoride. To demonstrate
this potential, we first tested the reaction with limiting
amounts of K19F, since a functional reaction for 18F labeling
should be able to incorporate sub-stoichiometric amounts of
fluoride into substrate molecules.[1b,4d,21] Thus, treating acid
16a with [Mn(tmp)]Cl, PhIO, and only 0.05 equiv of K19F in
ACN for 10 min afforded the fluorinated product 16 in 56%
yield based on the amount of fluoride (Scheme 3a). Inspired
by this promising result, we further evaluated the efficacy of
this method for radiofluorination with no-carrier-added
[18F]fluoride (Scheme 3b). We found that carboxylic acids
underwent efficient decarboxylative 18F-fluorination with
RCCs ranging from 20% to 50% under similar reaction
conditions to those used with K19F. Less reactive acids under
19F conditions, such as secondary carboxylic acid 25a, could be
readily 18F-labeled (40% RCC for 18F-25), which is presum-
ably due to the very low concentration of [18F]fluoride and the
large excess of other reactants. In our previous work, we
demonstrated that the tedious azeotropic K18F drying step
could be eliminated by directly eluting [18F]fluoride from the
ion exchange cartridge with a solution of the [Mn(salen)]OTs
catalyst. With a similar protocol, 18F-19 was obtained with
a non-decay-corrected radiochemical yield (RCY) of 10%.
The specific activity was determined to be 1.78 CimmolÀ1 (at
end of bombardment; EOB). This transformation represents
the first general decarboxylative 18F labeling method with no-
carrier-added [18F]fluoride. Efforts are ongoing to expand the
substrate scope of this novel 18F labeling method and adapt it
to PET imaging applications.
Figure 1. Mechanistic probes of the fluorine-transfer step.
porphyrin to a fluoromanganese(IV) intermediate with con-
current decarboxylation (pathway A). The second pathway
proceeds through a direct hydrogen abstraction from the
hydroxy group of the carboxylic acid by an oxomanganese(V)
porphyrin intermediate (pathway B). Although further work
is needed to differentiate the two pathways, current evidence
suggests pathway A, since both PhI(OPiv)2 and PhI(OAc)2
were efficient oxidants for decarboxylative fluorination in the
absence of water (Table 1, entries 7 and 8).
To explore whether iodine(III) carboxylates could react
with manganese(III) porphyrins to afford the fluorination
products, iodobenzene dicarboxylate 29 was synthesized and
subjected to a DCE solution of [Mn(tmp)]Cl and Et3N·3HF
(Scheme 4a). Heating the reaction mixture at 458C for 1 h
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
roiodane 33 first forms an adduct with the manganese(III)
porphyrin, which is thermodynamically favored by 1.6 kcal
molÀ1. This adduct then undergoes a facile dissociation at the
iodine center with a barrier of 18.2 kcalmolÀ1. In the
transition state, the frontier orbital interaction involves the
À À
d
yz orbital of [Mn(PorH)]F and the s* orbital of the O I F
bond with bonding interactions between fluorine and man-
À
ganese. Significant elongations of both the I O bond (from
À
2.11 ꢀ in Q-1 to 2.36 ꢀ in Q-TS1) and the I F bond (from
2.08 ꢀ to 2.51 ꢀ) are observed with a concurrent contraction
À
of the Mn F bond (from 2.32 ꢀ to 1.90 ꢀ). These results are
consistent with a dissociation of the carboxyl radical from
iodine and a synchronous F-atom transfer to MnIII to afford
IV
À
À
F Mn F.
For the fluorine-transfer step, the radical nature of the
reaction was demonstrated by adding 5 equiv CCl3Br as an
alkyl radical trap (Scheme 5, top). The major product was the
alkyl bromide 1b. Since the rate constant for bromine transfer
Scheme 5. Mechanistic studies of the fluorine-transfer step.
from BrCCl3 to alkyl radicals is known to be about
108 mÀ1 sÀ1,[22] the 1:2 fluorination/bromination (1/1b) ratio
corresponds to a nanosecond radical lifetime, which is
comparable to the rate of the manganese porphyrin catalyzed
Scheme 4. a) Fluorination of iodine(III) dicarboxylate 29. b) 19F NMR
spectrum of a solution of [Mn(tmp)]Cl, Et3N·3HF, and acid 30a.
c) Potential energy surfaces (kcalmolÀ1) for the formation of carboxyl
radicals through the interaction of an iodine(III) carboxylate complex
and a manganese(III) porphyrin. T and Q refer to triplet and quintet
states, respectively.
À
C H fluorination reaction. When a chiral manganese salen
complex was used as the catalyst, fluorination of acid 16a
afforded 16 in 11% ee (Scheme 5, bottom). This low but
mechanistically informative ee value provides strong addi-
tional support for a manganese-bound fluoride in the
intermediate of the fluorine-transfer step.
afforded (1-fluoroethyl)benzene (30) in 80% yield, demon-
strating that the iodine(III) carboxylate complex is highly
reactive toward the manganese(III) porphyrin. The formation
of an iodine(III) carboxylate was further indicated by NMR
spectroscopy (Scheme 4b). Adding 0.3 equiv of PhIO to
a CD2Cl2 solution of acid 30a and Et3N·3HF (1.0 equiv) led to
immediate dissolution of solid PhIO. The 19F NMR spectrum
of this clear solution revealed the resonances of Et3N·3HF
(À160 ppm) and PhIF2 (À177 ppm),[9] as well as a new
resonance at À132 ppm, which was identified as belonging
to fluoroiodane 31 from the titration experiment between 29
and Et3N·3HF (Figure S1 in the Supporting Information).
Adding 2 mol% [Mn(tmp)]Cl catalyst to this clear solution
afforded fluoroethylbenzene in 40% yield, which, again,
demonstrates that an iodine(III) carboxylate complex can
react productively with the manganese porphyrin catalyst.
The formation of carboxyl radicals through the interaction
between the iodine(III) carboxylate and the manganese
porphyrin is also supported by DFT calculations (Scheme 4c).
The lowest-energy reaction profile was on the quintet energy
surface, as expected for a manganese(III) porphyrin. Fluo-
In summary, we have described a catalytic decarboxyla-
tive fluorination based on nucleophilic fluoride. This Mn-
catalyzed transformation is characterized by its high rate,
wide functional-group tolerance and high specificity. The
potential of this method for PET imaging applications has
been demonstrated by successful 18F labeling of a variety of
target carboxylic acids, which represents the first decarbox-
ylative 18F labeling method based on no-carrier-added
[18F]fluoride. Ongoing work will focus on expanding the
substrate scope of this novel 18F labeling method and adapting
it to PET imaging applications.
Experimental Section
An oven-dried 5 mL Schlenk flask was placed under an atmosphere of
N2. [Mn(tmp)]Cl (10 mg, 2.5 mol%), acid substrate (0.5 mmol),
Et3N·3HF (100 mL, 1.2 equiv), benzoic acid (30 mg, 0.5 equiv), and
DCE (1.0 mL) were added to the vial and heated to 458C. Under
a stream of N2, PhIO (370 mg, 1.6 mmol, 3.3 equiv) was added to the
4
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
reaction mixture in small portions over a period of 45 min–1.5 h. The
reaction was monitored by GC/MS with naphthalene (0.195 mmol) as
an internal standard. After the reaction was complete, the products
were isolated by silica gel column chromatography.
H. F. Kung, A. G. Doyle, J. Am. Chem. Soc. 2014, 136, 5291 –
5294.
[8] a) M. Huiban, M. Tredwell, S. Mizuta, Z. Wan, X. Zhang, T. L.
Collier, V. Gouverneur, J. Passchier, Nat. Chem. 2013, 5, 941 –
944; b) T. Rꢁhl, W. Rafique, V. T. Lien, P. J. Riss, Chem.
Commun. 2014, 50, 6056 – 6059; c) D. van der Born, C. Sewing,
J. D. M. Herscheid, A. D. Windhorst, R. V. A. Orru, D. J. Vugts,
Angew. Chem. Int. Ed. 2014, 53, 11046 – 11050; Angew. Chem.
2014, 126, 11226 – 11230.
[9] K. B. McMurtrey, J. M. Racowski, M. S. Sanford, Org. Lett. 2012,
14, 4094 – 4097.
[10] H. Dang, M. Mailig, G. Lalic, Angew. Chem. Int. Ed. 2014, 53,
6473 – 6476; Angew. Chem. 2014, 126, 6591 – 6594.
[11] W. Liu, X. Y. Huang, M. J. Cheng, R. J. Nielsen, W. A. Goddard,
J. T. Groves, Science 2012, 337, 1322 – 1325.
[12] a) W. Liu, J. T. Groves, Angew. Chem. Int. Ed. 2013, 52, 6024 –
6027; Angew. Chem. 2013, 125, 6140 – 6143; b) W. Liu, X. Huang,
J. T. Groves, Nat. Protoc. 2013, 8, 2348 – 2354.
[13] X. Y. Huang, W. Liu, H. Ren, R. Neelamegam, J. M. Hooker,
J. T. Groves, J. Am. Chem. Soc. 2014, 136, 6842 – 6845. A no-
carrier-added preparation is a preparation of a radioactive
isotope which is essentially free from stable isotopes of the
element in question.
Received: January 19, 2015
Published online: && &&, &&&&
Keywords: decarboxylation · fluoride · fluorination ·
.
labeling with 18F · manganese porphyrins
[1] a) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc.
Rev. 2008, 37, 320 – 330; b) P. W. Miller, N. J. Long, R. Vilar,
A. D. Gee, Angew. Chem. Int. Ed. 2008, 47, 8998 – 9033; Angew.
Chem. 2008, 120, 9136 – 9172.
[2] T. Furuya, A. S. Kamlet, T. Ritter, Nature 2011, 473, 470 – 477.
[3] a) C. Hollingworth, V. Gouverneur, Chem. Commun. 2012, 48,
2929 – 2942; b) T. Liang, C. N. Neumann, T. Ritter, Angew.
Chem. Int. Ed. 2013, 52, 8214 – 8264; Angew. Chem. 2013, 125,
8372 – 8423; c) A. F. Brooks, J. J. Topczewski, N. Ichiishi, M. S.
Sanford, P. J. H. Scott, Chem. Sci. 2014, 5, 4545 – 4553.
[4] a) D. A. Watson, M. Su, G. Teverovskiy, Y. Zhang, J. Garcia-
Fortanet, T. Kinzel, S. L. Buchwald, Science 2009, 325, 1661 –
1664; b) E. Lee, A. S. Kamlet, D. C. Powers, C. N. Neumann,
G. B. Boursalian, T. Furuya, D. C. Choi, J. M. Hooker, T. Ritter,
Science 2011, 334, 639 – 642; c) A. Casitas, M. Canta, M. Sola, M.
Costas, X. Ribas, J. Am. Chem. Soc. 2011, 133, 19386 – 19392;
d) E. Lee, J. M. Hooker, T. Ritter, J. Am. Chem. Soc. 2012, 134,
17456 – 17458; e) Y. Ye, S. D. Schimler, P. S. Hanley, M. S.
Sanford, J. Am. Chem. Soc. 2013, 135, 16292 – 16295; f) T.
Truong, K. Klimovica, O. Daugulis, J. Am. Chem. Soc. 2013, 135,
9342 – 9345; g) N. Ichiishi, A. F. Brooks, J. J. Topczewski, M. E.
Rodnick, M. S. Sanford, P. J. H. Scott, Org. Lett. 2014, 16, 3224 –
3227; h) M. Tredwell, S. M. Preshlock, N. J. Taylor, S. Gruber, M.
Huiban, J. Passchier, J. Mercier, C. Genicot, V. Gouverneur,
Angew. Chem. Int. Ed. 2014, 53, 7751 – 7755; Angew. Chem.
2014, 126, 7885 – 7889.
[14] M. Komuro, T. Higuchi, M. Hirobe, Bioorg. Med. Chem. 1995, 3,
55 – 65.
[15] a) V. Grakauskas, J. Org. Chem. 1969, 34, 2446 – 2450; b) T. B.
Patrick, K. K. Johri, D. H. White, J. Org. Chem. 1983, 48, 4158 –
4159.
[16] a) F. Yin, Z. T. Wang, Z. D. Li, C. Z. Li, J. Am. Chem. Soc. 2012,
134, 10401 – 10404; b) M. Rueda-Becerril, C. C. Sazepin, J. C. T.
Leung, T. Okbinoglu, P. Kennepohl, J. F. Paquin, G. M. Sammis,
J. Am. Chem. Soc. 2012, 134, 4026 – 4029; c) M. Rueda-Becerril,
O. Mahe, M. Drouin, M. B. Majewski, J. G. West, M. O. Wolf,
G. M. Sammis, J. F. Paquin, J. Am. Chem. Soc. 2014, 136, 2637 –
2641; d) J. C. T. Leung, C. Chatalova-Sazepin, J. G. West, M.
Rueda-Becerril, J. F. Paquin, G. M. Sammis, Angew. Chem. Int.
Ed. 2012, 51, 10804 – 10807; Angew. Chem. 2012, 124, 10962 –
10965; e) S. Mizuta, I. S. R. Stenhagen, M. OꢂDuill, J. Wolsten-
hulme, A. K. Kirjavainen, S. J. Forsback, M. Tredwell, G.
Sandford, P. R. Moore, M. Huiban, S. K. Luthra, J. Passchier,
O. Solin, V. Gouverneur, Org. Lett. 2013, 15, 2648 – 2651.
[17] R. Franz, J. Fluorine Chem. 1980, 15, 423 – 434.
[18] a) J. T. Groves, W. J. Kruper, R. C. Haushalter, J. Am. Chem.
Soc. 1980, 102, 6375 – 6377; b) J. T. Groves, M. K. Stern, J. Am.
Chem. Soc. 1987, 109, 3812 – 3814; c) J. T. Groves, J. Porphyrins
Phthalocyanines 2000, 4, 350 – 352; d) C. M. Che, V. K. Y. Lo,
C. Y. Zhou, J. S. Huang, Chem. Soc. Rev. 2011, 40, 1950 – 1975.
[19] M. Komuro, Y. Nagatsu, T. Higuchi, M. Hirobe, Tetrahedron
Lett. 1992, 33, 4949 – 4952.
[5] a) D. S. Laitar, P. Muller, T. G. Gray, J. P. Sadighi, Organo-
metallics 2005, 24, 4503 – 4505; b) B. C. Gorske, C. T. Mbofana,
S. J. Miller, Org. Lett. 2009, 11, 4318 – 4321.
[6] a) A. Hazari, V. Gouverneur, J. M. Brown, Angew. Chem. Int.
Ed. 2009, 48, 1296 – 1299; Angew. Chem. 2009, 121, 1322 – 1325;
b) M. H. Katcher, A. G. Doyle, J. Am. Chem. Soc. 2010, 132,
17402 – 17404; c) J. J. Topczewski, T. J. Tewson, H. M. Nguyen, J.
Am. Chem. Soc. 2011, 133, 19318 – 19321; d) A. M. Lauer, J. Wu,
Org. Lett. 2012, 14, 5138 – 5141; e) Z. Zhang, F. Wang, X. Mu, P.
Chen, G. Liu, Angew. Chem. Int. Ed. 2013, 52, 7549 – 7553;
Angew. Chem. 2013, 125, 7697 – 7701; f) M.-G. Braun, A. G.
Doyle, J. Am. Chem. Soc. 2013, 135, 12990 – 12993.
[20] J. Shi, X. Y. Huang, J. P. Wang, R. Li, J. Phys. Chem. A 2010, 114,
6263 – 6272.
[7] a) Y. Hamashima, M. Sodeoka, Synlett 2006, 1467 – 1478; b) M.
Althaus, A. Togni, A. Mezzetti, J. Fluorine Chem. 2009, 130,
702 – 707; c) J. A. Kalow, A. G. Doyle, J. Am. Chem. Soc. 2010,
132, 3268 – 3269; d) T. J. A. Graham, R. F. Lambert, K. Ploessl,
[21] L. Li, M. N. Hopkinson, R. L. Yona, R. Bejot, A. D. Gee, V.
Gouverneur, Chem. Sci. 2011, 2, 123 – 131.
[22] L. Mathew, J. Warkentin, Can. J. Chem. 1988, 66, 11 – 16.
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Decarboxylative Fluorination
X. Huang, W. Liu, J. M. Hooker,
Nucleophile first: An efficient manganese
porphyrin catalyzed decarboxylative fluo-
rination reaction based on a nucleophilic
fluorine source is described. The poten-
tial of the described method for use in
PET imaging has been demonstrated by
the successful 18F labeling of various
aliphatic carboxylic acids, representing
the first decarboxylative 18F labeling
method with no-carrier-added
J. T. Groves*
&&&& — &&&&
Targeted Fluorination with the Fluoride
Ion by Manganese-Catalyzed
Decarboxylation
[18F]fluoride.
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!