Mn-salen catalysed benzylic C-H activation for the synthesis of aryl [18F]CF3-containing PET probes

Article abstract of DOI:10.1039/c4cc05762g

The development of a Mn-salen complex catalysed oxidative benzylic fluorination of non-activated C-H bonds using [¹⁸F]fluoride is described for installation of [¹⁸F]CHRF, [¹⁸F]CR₂F and particularly [¹⁸

Full text of DOI:10.1039/c4cc05762g

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Mn–salen catalysed benzylic C–H activation for
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the synthesis of aryl [ F]CF -containing PET
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Cite this:DOI: 10.1039/c4cc05762g
probes†
Received 24th July 2014,
Accepted 11th February 2015
a
a
b
a
L. Carroll,* H. L. Evans, A. C. Spivey and E. O. Aboagye
DOI: 10.1039/c4cc05762g
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The development of a Mn–salen complex catalysed oxidative benzylic of aryl difluoromethyl compounds as an efficient approach to
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fluorination of non-activated C–H bonds using
[
F]fluoride is [ F]labelled trifluoro aryl PET probes.
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described for installation of [ F]CHRF, [ F]CR
2
F and particularly
Selecting to work with Jacobsen-type pre-catalyst (ꢀ)-1 and
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[
F]CF
3
containing groups in the presence of other functional groups. with iodosobenzene as stoichiometric oxidant due to their
commercially availability, our initial objective was to define
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PET is a non-invasive molecular imaging modality which allows optimal conditions for the benzylic oxidative [ F] fluorination
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the in vivo imaging of a variety of biological processes in of 1-ethylnapthalene 2a by [ F] fluoride (Table 1).
patients. Of the leading PET radioisotopes currently available, A combination of different solvents, temperatures durations
fluorine-18 ( F) is one of the most important, as evidenced by and protocols for addition of the PhIO were explored. Portion-wise
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the numerous clinically-deployed F radiotracers. These tracers addition of solid PhIO gave a promising radiochemical incorpora-
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0
0
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include 2-[ F]fluorodeoxyglucose ([ F]FDG), 3 -deoxy-3 -[ F]fluoro- tion of 27% within 15 minutes (n = 3; entry 1). As PhIO is only
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thymidine ([ F]FLT) and [ F]fluorodopa, which are widely sparingly soluble in most organic solvents, and full dissolution
used in the fields of oncology and neurology.
has been an increase in the number of F-containing pre- a co-solvent. Use of either MeOH or DMF as co-solvents (1 : 1 v/v)
clinical radiotracers and new methods for the attachment of allowed complete dissolution of the oxidant, but suppressed
F-containing prosthetic groups to target molecules, the initial product formation (entries 2 and 4) whereas t-BuOH was ineffec-
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–4
While there is critical for automated radiosynthesis, we explored the use of
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incorporation of [ F]fluoride is in most cases still achieved tive as a co-solvent and gave identical levels of incorporation to
by classical nucleophilic substitution reactions (i.e., via S 2 or when using MeCN alone (entry 3 cf. entry 1). Reverting to the use
N
S Ar mechanisms). Recently however, protocols for the pre-
N
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5,6
paration of [ F] aryl fluorides from aryl iodonium salts, and
by the use of Pd(IV) and Ni(II) complexes, [ F]allylic fluorides
by Pd-catalysed substitution, [ F]4-fluorophenols by oxidative
fluorination, and [ F]trifluoromethyl aromatics catalysed by
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Table 1 Optimisation of the oxidative [ F]fluorination of 1-ethylnaphthalene 2a
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copper, have been described that bypass these traditional
radiofluorination paradigms. Moreover, Groves et al. have very
recently disclosed an appealing method for direct oxidative
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c
d
[
[
F]fluorination at benzylic methylene C–H positions using
Entry
Solvent
PhIO
T/1C
Time
%RCI
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10–12
F]fluoride using a Mn(salen)OTs pre-catalyst.
This report
a
1
2
3
4
5
6
7
MeCN
P
P
P
P
P
S
S
P
60
60
60
60
60
60
90
60
15
30
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15
30
30
30
30
27
Trace
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2
72
32
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70
a
has prompted us to disclose a related procedure that we have
developed and applied with particular success for the fluorination
MeCN–MeOH
MeCN–t-BuOH
a
a
MeCN–DMF
b
MeCNb
MeCN
a
b
Comprehensive Cancer Imaging Centre, Department of Surgery and Cancer,
MeCNb
e
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MeCN
Imperial College London, Hammersmith Campus, Du Cane Road, London,
W12 0NN, UK. E-mail: l.carroll@imperial.ac.uk
a
b
c
[
substrate] = 0.3 M. [substrate] = 0.1 M. Method of PhIO addition,
either P = in equal portions at 5 min intervals, N = none used or S =
single addition. RCI = radiochemical incorporation, calculated from
radio-HPLC analysis, n = 3 in each example. Kryptofix 2.2.2. (K222)
b
Department of Chemistry, Imperial College London, South Kensington Campus,
d
UK
e
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc05762g
used instead of 18-c-6.
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Fig. 2
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F oxidative benzylic fluorination to give CF -containing compounds,
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Fig. 1 Oxidative benzylic [ F]fluorination of several different compounds
using optimised labelling conditions, n = 4.
n = 3.
the successful formation of isomeric 2- and 4-substituted biaryls
of just MeCN as solvent but with increased dilution (0.1 M cf.
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[
[
F]3m and [ F]3n and of 4-substituted biaryls [ F]3k, [ F]3l and
F]3o in 36%, 61%, 16%, 42% and 34% RCYs respectively.
Labelled bromophenyls [ F]3g and [ F]3h can also be deployed
0
3
.3 M) we were pleased to observe that after a reaction time of
0 minutes 72% radiochemical incorporation could be achieved
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(entry 5). At this dilution, addition of the PhIO solution as a single
as prosthetic groups as illustrated by the preparation of biaryl
portion gave 32% RCI after 30 min, which we considered adequate
for compound labelling (entry 6). Increasing the temperature to
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[
F]3k and [ F]3j by Suzuki coupling (Scheme 1).
The specific radioactivity of a labelled probe, quantifies the
90 1C gave no discernible improvement in incorporation (entry 7)
amount of radioactivity relative to non-labelled material present,
and constitutes an important property of the probe. For the
and replacement of 18-c-6 with Kryptofixr 2.2.2 (K222) had no
significant influence on the level of RCI (entry 8).
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synthesis of [ F]3g, the specific activity was B4 GBq mmol
,
Application of this reaction to several simple substrates was
undertaken to delineate the scope of the method (Fig. 1).
Successful labelling of compounds was achieved with moderate
to good levels of incorporation in most cases. In general, secondary
fluorides were introduced efficiently, whereas introduction at a
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starting from 190 MBq of starting [ F]fluoride. This level of
specific activity is B10 fold greater than that reported by
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Huiban et al. for their [ F]CF labelling.
We also performed ICP-MS analysis on a purified sample of
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[
F]3a which had been allowed to decay, and no manganese
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primary position gave less than 5% RCY ([ F]3c) and at a tertiary
ꢁ1
was detected (o0.01 mg l ). Unlike Pd, which has a non-
dietary limit of 100 mg per day for a 50 kg adult, Mn is essential
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position gave a more promising 14% RCY ([ F]3d). Site-selective
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labelling to give phenylalanine derivative [ F]3e gave 49% RCY
although no diastereoselectivity was observed.
for various functions in the human body and a daily intake of
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.5 mg per day is recommended for a 50 kg adult.
Notwithstanding the attraction of installing a single fluorine
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Mechanistically, we anticipate that the [ F]labelling reaction
atom site-selectively within a target molecule, labelling of CF
groups was of particular interest due to their occurrence in a
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proceeds via essentially the same catalytic cycle as proposed by Liu
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and Groves for their F labelling using Mn(salen)OTs (Fig. 3).
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number of pharmaceuticals and we anticipated that F-labelling
of a difluoromethyl group could be an attractive entry to
Thus, following initial Cl to OTf ligand exchange at Mn(III)
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effected by the AgOTf, [ F]fluoride is introduced via ligand
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labelled CF units. The benzylic difluoromethyl containing
exchange (-4). Oxidation by PhIO then gives Mn(V) oxo species 5
precursors required for this approach are readily prepared by
fluorodeoxygenation of benzaldehydes or by copper-catalysed
difluoromethylation of aryl iodides using TMS–CF CO Et
2
2
1
5–17
(or TMS–CF
2
H).
Ten benzylic difluoromethyl substrates also containing
other potentially reactive functional groups (i.e. ether, aryl
halide and carbamate groups) were investigated (Fig. 2).
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[
F]Trifluoromethylbenzene ([ F]3f) and its 4- and 2-brominated
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derivatives [ F]3g and [ F]3h were prepared in 27%, 44% and 54%
RCYs respectively whereas the more electron deficient 4-nitro
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and 3-cyano derivatives [ F]3i and [ F]3j were much less
efficiently labelled (1% and 8% RCY respectively). It appears
therefore that although strongly electron withdrawing substitu-
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ents deter [ F]fluorine trapping of the presumed radical inter-
Scheme 1 Synthesis of biaryls [ F]3k and 3o from [ F]3g by Suzuki
mediate, bulky 2-substituents are tolerated. This is consistent with coupling, n = 3.
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experimental protocol holds promise for adaption to automated
clinical PET probe production.
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We thank Imanova Ltd for [ F]fluoride and use of their
radiochemistry facilities, Dr Neil Bramall (University of Sheffield)
for ICP analysis, and CRUK/EPSRC.MRC/DoH (England) for
funding (grant C2536/A10337).
Notes and references
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Fig. 3 Proposed catalytic cycle for the F-labelling reaction, and side-reaction
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9
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1
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groups using [ F]fluoride to give aryl [ F]CF compounds.
3
1
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The labelling reactions can be achieved without extensive
investment in complex precursors and the straightforward
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