Metal-free18F-labeling of aryl-CF2H via nucleophilic radiofluorination and oxidative C-H activation

Article abstract of DOI:10.1039/c6cc07913j

A metal-free and selective method to form [¹⁸F]aryl-CF₂H through nucleophilic radiofluorination of benzyl (pseudo)halides and oxidative C-H activation of benzylic C-H bonds has been developed. The method is operationally simple and tolerates a variety of electron-neutral/deficient arenes and heteroarenes.

Full text of DOI:10.1039/c6cc07913j

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Metal-free F-labeling of aryl-CF2H via
nucleophilic radiofluorination and oxidative
C–H activation†
Cite this:DOI: 10.1039/c6cc07913j
Received 29th September 2016,
Accepted 18th November 2016
Gengyang Yuan,ab Feng Wang,c Nickeisha A. Stephenson,‡a Lu Wang,a
Benjamin H. Rotstein,§a Neil Vasdev,a Pingping Tangc and Steven H. Liang*a
DOI: 10.1039/c6cc07913j
www.rsc.org/chemcomm
A metal-free and selective method to form [18F]aryl-CF2H through
nucleophilic radiofluorination of benzyl (pseudo)halides and oxidative
C–H activation of benzylic C–H bonds has been developed. The
method is operationally simple and tolerates a variety of electron-
neutral/deficient arenes and heteroarenes.
Fluorine bearing functionalities are found in a wide range of
materials and biologically active molecules.1 Incorporation of
fluorine-18 radionuclide into these molecules facilitates the
application of noninvasive positron emission tomography (PET)
imaging in quantifying biochemical and pharmacological processes.
As a result, continuous efforts have been made to develop novel
radiofluorination methods that provide a diverse range of 18F-labeled
vectors to support molecular imaging research and drug discovery.2
Isosteric replacement of phenolic hydroxyl group with an aromatic
Scheme 1 Aryl-CF2H containing bioactive molecules.
difluoromethyl functionality (Ar-CF2H) has been demonstrated as a reduced hydrophilicity.4 Compared with recent advances in the
useful medicinal chemistry approach, leading to the discovery of preparation of non-radioactive Ar-CF2H,5 18F-labeling of this
bioactive molecules, including thiazopyr, fluxapyroxad, deracoxib, group has not yet been fully exploited. Initial methods relied
ZSTK474 etc. (Scheme 1).1d,3
on the silver(I)-mediated fluorodecarboxylation of a-fluorarylacetic
The success of this substitution has been attributed to the acids with [18F]Selectfluor bis(triflate), an electrophilic fluorinating
similar acidic and isopolar characteristics of CF2H and OH. reagent derived from [18F]F2.6 An alternative 18F-incorporation
Moreover, CF2H functionality features hydrogen-bond-donating method employed a silver(I)-mediated halogen exchange strategy
capability comparable to that of OH and NH groups, but much with readily available [18F]fluoride under mild reaction conditions,
but required aryl-CHFCl precursors prepared by multi-step
synthesis.7 Our recent work disclosed a more practical method,
a Gordon Center for Medical Imaging & Division of Nuclear Medicine and Molecular
starting from easily accessible aryl (pseudo)halides, via activation
Imaging, Massachusetts General Hospital and Department of Radiology,
of a benzoyl auxiliary, to form [18F]Ar-CF2H functionality with an
Harvard Medical School, 55 Fruit St., Boston, MA, 02114, USA.
E-mail: liang.steven@mgh.harvard.edu; Tel: +1-617-726-6107
b Department of Chemistry & Chemical Biology, Northeastern University,
360 Huntington Ave., Boston, MA, 02115, USA
c State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai
University, Collaborative Innovation Center of Chemical Science and Engineering,
Tianjin, 300071, China
excellent substrate scope.8 However, to date, syntheses of [18F]aryl-
CF2H have been restricted to low-to-moderate specific activity
radiotracers, which may have limited their application in PET
imaging studies, particularly for low density biological targets.
Recently we demonstrated the capability of silver-catalyzed
† Electronic supplementary information (ESI) available. See DOI: 10.1039/ oxidative activation of benzylic C–H bonds of aryl-CH3 for the
c6cc07913j
synthesis of aryl-CF2H, which was further adapted to transition-
metal-free conditions.9 Inspired by these discoveries, we speculated
‡ Current address: Department of Chemistry, University of the West Indies,
Mona, Kingston 7, Jamaica.
that a similar protocol could be applicable to the transforma-
§ Current address: Department of Biochemistry, Microbiology and Immunology,
tion of benzylic C–H to C–18F bond formation in the context of
University of Ottawa & University of Ottawa Heart Institute, 40 Ruskin Street,
Ottawa, Ontario, USA.
[18F]aryl-CFH2 intermediates, which could be easily obtained
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Table
1
Optimization for the synthesis of 4-([18F]fluoromethyl)-1,10-
biphenyl ([18F]2a)
Entry 1a (mg) Base (mg) Time (min) Temp. (1C) 2a RCCa (%)
1
2
3
4
2.0
2.0
2.0
2.0
TBAH (3.1) 10
TEAB (0.5) 10
TEAB (1.0) 10
TEAB (2.0) 10
130
130
130
130
49 ꢀ 3 (n = 2)
50 ꢀ 2 (n = 2)
85 ꢀ 2 (n = 2)
98 ꢀ 2 (n = 10)
a
Determined by radio-TLC integration.
Scheme 2 Radiolabeling of [18F]aryl-CF2H.
Table 2 Optimization for the preparation of 4-([18F]difluoromethyl)-1,10-
biphenyl ([18F]3a)
via nucleophilic radiofluorination of benzyl-(pseudo)halides with
[18F]fluoride (Scheme 2). Herein, we report a general and metal-
free method to radiolabel [18F]aryl-CF2H groups via a sequential
nucleophilic radiofluorination of benzyl (pseudo)halides, followed
by oxidative C–H activation.
The feasibility of our method was experimentally confirmed,
and further optimized by the radiosynthesis of 4-([18F]difluoro-
methyl)-1,10-biphenyl ([18F]3a). An illustrative workflow is depicted
in Scheme 3. Near quantitative radiochemical conversion (RCC; 98
ꢀ 2%, n 4 10) of 1a (8.09 mmol) to [18F]2a was achieved in 10 min
in MeCN with tetraethylammonium bicarbonate (TEAB, 10.4 mmol)
at 130 1C (Table 1). Under these conditions, the milder base
used herein, compared with tetra-n-butylammonium hydroxide
(TBAH),10 resulted in a 2-fold increase in RCC. Isolated [18F]2a
was subsequently subjected to oxidative reaction conditions to
install the benzyl 18F-fluoride. This step was optimized by varying
the temperature and stoichiometry of reagents including AgNO3,
Na2S2O8, and Selectfluor (Table 2). Under the initial optimal
reaction conditions (Table 2, entry 3, RCC = 41 ꢀ 6%), removal
of AgNO3 gave superior RCC (50 ꢀ 5%, entry 7), indicating that
such C–H activation can be achieved under transition-metal-free
conditions.9b Finally, compound [18F]3a was obtained in 50 ꢀ 5%
RCC with Na2S2O8 (33.6 mmol) and Selectfluor (56.5 mmol) at 120 1C
for 10 min (Table 2, entry 7).
AgNO3 Na2S2O8 Selectfluor Time Temp.
Entry (mg)
(mg)
(mg)
(min) (1C)
RCCa (%)
1
2
3
4
5
6
7
8.0
4.0
4.0
4.0
4.0
4.0
0.0
4.0
4.0
8.0
12.0
8.0
8.0
20.0
20.0
20.0
20.0
5.0
15.0
20.0
10
10
10
10
10
10
10
120
120
120
120
120
120
120
20 ꢀ 2 (n = 2)
38 ꢀ 5 (n = 2)
41 ꢀ 6 (n = 2)
23 ꢀ 3 (n = 2)
0 (n = 2)
33 ꢀ 3 (n = 2)
8.0
50 ꢀ 5 (n = 2)
a
Determined by radio-HPLC integration of product peaks, relative to
[
18F]fluoride and 18F-side products.
The scope of this methodology was then explored with more
challenging substrates (Scheme 4). Under the optimized reaction
conditions, all 18F-monofluorinated products were synthesized
quantitatively, except [18F]2e (85 ꢀ 5%) and [18F]2f (70 ꢀ 3%).
The isolated 18F-labeled compounds ([18F]2b–2i) were then sub-
jected to the second step under optimized reaction conditions as
described above. The final products [18F]3b–3h were obtained
with moderate-to-good RCCs, ranging from 10% to 45%. As
shown in Scheme 4, para-substituted electron-deficient ketone
Scheme 3 Synthesis of [18F]2a and [18F]3a. Synthesis of [18F]2a: (a) trap
and release 18Fꢁ into a V-vial via a solution of TEAB in 1 mL MeCN/H2O
(v/v 7 : 3); (b) azeotropic drying with anhydrous MeCN (3 ꢂ 1 mL, 3 min for
each cycle); (c) addition of 1a, MeCN, 130 1C, 10 min; (d) dilution and
subsequent purification of the reaction mixture (B12 min); (e) concentration
of the eluent via a C-18 cartridge (B2 min); (f) release of [18F]2a via 1 mL
MeCN (B1 min). Synthesis of [18F]3a: (g) addition of Na2S2O8, Selectfluor
and EtOH (B1 min); (h) 120 1C, 10 min; (i) dilution and subsequent
purification of the reaction mixture (B12 min).
Scheme 4 Scope of oxidative benzylic C–H activation in preparing the
[
18F]aryl-CF2H products.
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substrates [18F]2b and [18F]2c gave 10% and 15% RCCs, respec-
tively. Ester substitution in the para-position of [18F]2d also
yielded 12% RCC. Substrate [18F]2e exemplified the applicability of
this method for a multi-substituted, sterically hindered compound
with 28% RCC. In addition, a bromide motif in the product [18F]3e
could allow further coupling reactions with various counterparts to
provide more complex molecules. This method was also found to
give good conversion for substrate [18F]2f (RCC = 45%) possessing a
primary amide. The success of 2-arylpyridine substrate [18F]2g
showed the compatibility of this labeling strategy for N-heteroatom
bearing compounds. It is also noteworthy that substrate [18F]2h
demonstrated the introduction of a second fluorine atom onto
a tertiary carbon. Furthermore, product [18F]3h, bearing a
(1,1-difluoroethyl)benzene fragment, is a key structural motif in a
series of potent kidney urea transporter inhibitors,11 analogous to
the compound shown in Scheme 1. The electron-rich arene 1i led to
no desired product [18F]3i, as [18F]2i immediately decomposed
to [18F]fluoride under our standard oxidative conditions as well
as alternative oxidation reagents, for example 1-chloromethyl-4-
fluoro-1,4-diazoniabicyclo [2.2.2] octane bis(hexafluorophosphate)
(F-TEDA-PF6).12 It is possible that the increased reactivity brought
by the electron donating groups makes [18F]2i more vulnerable to
the fluorinating reagents and/or radical defluorination.
A plausible reaction mechanism is shown in Scheme 5. Homolytic
cleavage of a peroxydisulfate anion produces two sulfate radical
anions at elevated temperature, which oxidizes the benzylic
C–H bond of [18F]aryl-CFH2 (A) to a benzylic radical (B). Then,
Selectfluor reacts through a radical mechanism,13 providing a
fluorine radical for bond formation with the benzylic radical (B)
to produce the desired [18F]aryl-CF2H (C).
Specific activity is a very critical parameter which should be
considered in both radiolabeling methods and PET imaging
studies.14 Obtaining high specific activity is still a challenge for
18F-labeling of many multi-fluorinated compounds.6a,7,8 As
shown in Scheme 6, we measured the specific activity of the
aryl-CF2H product [18F]3a by our protocol (see the ESI† for
details). Briefly, compound [18F]2a was synthesized and isolated
using a commercial automated radiofluorination unit (GE
TRACERlabt FXFN; Fig. S1, ESI†), starting from 1.7 GBq of
[18F]fluoride, in 61% radiochemical yield (non-decay corrected)
with 499% radiochemical purity and 51.8 GBq mmolꢁ1 specific
activity at the end-of-synthesis (B60 min synthesis time from
[18F]fluoride). The isolated intermediate [18F]2a was formulated
and eluted from a C-18 cartridge with 1 mL of MeCN. It was
diluted with 1 mL of sterile water, from which 0.4 mL was used
Scheme 6 Specific activity determination for 4-([18F]difluoromethyl)-
1,10-biphenyl ([18F]3a).
for the second step. Under the optimized conditions, the mixture
was heated for 10 min, cooled and diluted using a mobile phase.
The reaction mixture was injected into semi-preparative HPLC
for purification. The purified [18F]3a was isolated in 38% radio-
chemical yield (non-decay corrected, based on the added activity
of [18F]2a) with a specific activity of 22.2 GBq mmolꢁ1 at the end-
of-synthesis (B25 min synthesis time from the addition of
[18F]2a). As shown in Table 3, the current method gives superior
specific activity over other reported syntheses of [18F]aryl-
CF2H.6a,7,8 Efforts were also made to further improve the specific
activity by changing the counterion of the current fluorinating
ꢁ
reagents to PF6 (F-TEDA-PF6) and OTfꢁ (1-chloromethyl-4-fluoro-
1,4-diazoniabicyclo [2.2.2]octane bis(trifluoromethane sulfonate;
F-TEDA-OTf; see the ESI† for its preparation), though none of them
gave the desired product [18F]3a. Since the tetrafluoroborate anion
(BF4ꢁ) has been proven to give high specific activity comparable to
that of OTfꢁ in an analogous radiosynthesis of aryl-[18F]fluoride
from (mesityl)(aryl)iodonium salt precursors,15 it is reasonable
to postulate that there were limited exchange reactions between
19F and 18F under the present radiolabeling conditions.
In conclusion, we have investigated a metal-free oxidative
C–H activation strategy for the synthesis of [18F]aryl-CF2H with
good radiochemical yields and reasonably high specific activity.
This method was successfully applied to mono- or multi-substituted
electron-neutral and electron-deficient substrates, among which the
amide group, N-containing heterocycle, and tertiary benzylic C–H
bond were well tolerated. Further ongoing improvement resides in
applying this method to electron-rich substituted arenes.
We would like to thank the staff at the radiochemistry
program, Gordon Center for Medical Imaging, Nuclear Medicine
and Molecular Imaging, Massachusetts General Hospital, MA,
and Department of Chemistry & Chemical Biology, Northeastern
University for their generous support. We also thank Drs Lee
Table 3 Summary of the radiolabeling of [18F]aryl-CF2H
Starting
radioactivity activity
(GBq) )
(GBq mmolꢁ1
Specific
Reaction
18F]aryl-CF2H type
Ref.
[
Gouverneur
Electrophilic —
Nucleophilic 3.5
Nucleophilic 1.4
2.5a
0.03
et al.6a
Gouverneur
et al.7
Liang,
Vasdev,
3.0
Ritter et al.8
This work
Radical
1.7
22.2
a
Scheme 5 Proposed mechanism for the radiosynthesis of [18F]aryl-CF2H.
Specific activity after radioactive decay correction.
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