Cu(i)-mediated 18F-trifluoromethylation of arenes: Rapid synthesis of 18F-labeled trifluoromethyl arenes

Article abstract of DOI:10.1039/c4cc01641f

This report is concerned with an efficient, Cu^I-mediated method for the radiosynthesis of [¹⁸F]trifluoromethyl arenes, abundant motifs in small molecule drug candidates and potential radiotracers for positron emission tomography. Thr

Full text of DOI:10.1039/c4cc01641f

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
18
Cu(I)-mediated F-trifluoromethylation of arenes:
18
Rapid synthesis of F-labeled trifluoromethyl
arenes†
Cite this: Chem. Commun., 2014,
50, 6056
Received 4th March 2014,
Accepted 15th April 2014
T. Ruhl,a W. Rafique,a V. T. Lienb and P. J. Riss*ab
¨
DOI: 10.1039/c4cc01641f
www.rsc.org/chemcomm
This report is concerned with an efficient, CuI-mediated method for the arene-trifluoromethylation methodology has become a key focus
radiosynthesis of [18F]trifluoromethyl arenes, abundant motifs in small in current organic chemistry.4 Radiolabelling these CF3 groups is
molecule drug candidates and potential radiotracers for positron attractive to reposition known drug molecules for PET.5
emission tomography. Three 18F-labelled radiotracer candidates were
synthesised from [18F]fluoride ions as proof of principle. The new fluoromethyl arenes starting from [18F]fluoride ions within our
protocol is widely applicable for the synthesis of novel radiotracers in radiotracer development program. Radiosynthesis of the 18F-labelled
We, hence, sought an efficient method for producing [18F]tri-
high radiochemical yields.
aryl trifluoromethane scaffold has been reported, however, mostly
through the use of rare and unavailable electrophilic fluorinating
Molecular imaging with positron emission tomography (PET) allows agents or harsh conditions.5 A more recent breakthrough employed
for non-invasive, quantitative studies of radiotracer distribution in CuI in combination with aryl iodides.5a We have explored a new
living subjects. In consequence of its maturation, PET is being route inspired by a recent report on [18F]fluoroform by Vugts et al.6
increasingly used in routine clinical diagnosis, commercial drug
For successful outcomes, reactions involving [18F]fluoroform
development, and in biomedical research. Novel radiotracers for require diligent control of the gaseous intermediate, including low
imaging a variety of biological targets are continually needed to fully temperature distillation and trapping of the product at ꢀ80 1C in a
exploit the potential of PET.1 18F is the most frequently employed secondary reaction vessel. These conditions and technical require-
PET nuclide, due to the extensive use of 2-[18F]fluoro-2-deoxy-D- ments are limiting factors with respect to the automated synthesis of
glucose ([18F]FDG) for clinical diagnosis.2,3 The relevance of 18F is high activity batches using automated synthesiser systems. Few
based on its expedient half-life (109.7 min) rendering it suitable commercially available systems provide more than one reactor and
for multi-step reactions, transport of radiotracers over moderate generally disfavour low temperature processes. We surmised that
distances, convenient handling of the tracer in imaging studies widespread adoption of trifluoromethylation reactions would strongly
and high-yield cyclotron production of no-carrier-added (n.c.a) benefit from a straightforward nucleophilic one-pot method generally
[18F]fluoride ions. The ability to form stable C–F bonds promotes the applicable to latest generation synthetic hardware. Such a methodol-
straight introduction of F atoms into most small organic molecules.
ogy would, furthermore, feature direct installation of nucleophilic
Despite the strong demand for novel radiotracers for a variety of [18F]fluoride ions into candidate radiotracers to avoid loss of radio-
disease related biological mechanisms, radiotracer development is a activity, conserve specific radioactivity and achieve rapid and
complex process. Researchers and clinicians often struggle to obtain operationally simple radiosynthesis.6 To achieve this we focused our
a desired radiotracer within a reasonable time frame because efforts on the in situ formation of a suitable 18F-trifluoromethylating
discovery of suitable molecular structures that can be labelled by reagent from an appropriate precursor and its direct conversion into
established procedures often require time-consuming iterative cycles the title compounds in the same reaction vessel (Scheme 1).
of candidate synthesis and biological evaluation.
Difluoroiodomethane (CHF2I) was selected as the starting mate-
Due to its properties, a wide portfolio of synthetic drug rial to provide a convenient source of Cu[18F]CF3. Our choice of
molecules and derivatives contain the metabolically stable CF3 Cu[18F]CF3 was encouraged by the work of Grushin et al.,7a,b who
group, and consequently an operationally simple and direct provided comprehensive insights into the formation and use of
CuCF3 for trifluoromethylation reactions using fluoroform, which
a Kjemisk Institutt, Universitetet I Oslo, Sem Sælands vei 26, 0371, Oslo, Norway.
we attempted to implement at first, albeit without success.†
E-mail: Patrick.Riss@kjemi.uio.no
To our dismay, the published reaction conditions translated
poorly into radiochemistry.7a † This is most likely due to the crucial
presence of phase transfer catalysts in the radiofluorination reaction
b Norsk Medisinsk Syklotronsenter AS, Postboks 4950 Nydalen, 0424, Oslo, Norway
† Electronic supplementary information (ESI) available: Experimental details and
analytical data. See DOI: 10.1039/c4cc01641f
6056 | Chem. Commun., 2014, 50, 6056--6059
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
Table 1 Effect of the base/ligand on the RCY of [18F]1b. The concen-
tration of the ligand in the reaction mixture was 200 mM
RCYb (%)
Entry
Liganda
[
18F]1b
Scheme 1 Strategy for the radiosynthesis of [18F]trifluoromethyl arenes.
1
2
3
4
5
6
7
8
None
tBuOK
Triphenylphosphine
Pyridine
0
2
1
2
9
8
5
2
mixture to activate the [18F]fluoride ion. Such reagents are known to
increase the basicity and reactivity when combined with strong,
anionic bases like KOtBu in dipolar aprotic solvents.7d–f Although
such strong bases were deemed crucial to deprotonate fluoroform
(pKa = 27 in DMSO) in previous reports,7 only rapid discoloration
along with low yields was observed in our radiochemical experi-
ments. Grushin and co-workers described that the use of KOtBu in
excess would even permit omission of a supporting ligand and
added triethylamine HF-complex to stabilise the Cu–CF3 reagent.
Addition of non-radioactive fluoride ions to the labelling reaction is
prohibitive in the context of the tracer principle, a prerequisite for
PET imaging. A second issue may be the fact that CuF is only stable
as a complex in solution and otherwise disproportionates to Cu0 and
CuF2. Since the development of a one-pot method would require both
species, n.c.a. [18F]fluoride ions and Cu+, to coexist, this mechanism
may deprive the reaction mixture of 18F, which is only present in very
low concentrations (mM). Hence, obtaining the short-lived [18F]CF3-
source in situ prior to trifluoromethylation in the same reaction vessel
is rather challenging and, unfortunately, the Grushin method did not
furnish the desired labelled products in useful radiochemical yields.
Given this apparent incompatibility of reagents a methodological
optimisation of various parameters became inevitable.
This prompted us to test our working hypothesis. We surmised
that KOtBu may not be required since the formation of difluoro-
carbene via a-elimination of HI from CHF2I in the presence of
4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo [8.8.8]hexacosan (crypt-222),
K2CO3, and 18Fꢀ facilitates the formation of Cu–[18F]CF3. In addition
we considered that a supporting ligand may be beneficial to address
the sensitivity of the reaction to Cu-disproportionation and potentially
stabilise a Cu–difluorocarbene complex.7g † Consequently, we chose
the screening for the most efficient Cu–ligand system in combination
with the most frequently used source of reactive 18F-fluoride; crypt-
222, K2CO3, and 18Fꢀ as the starting point for our investigations, as we
now report here.
We initially aimed to discover a simple CuI–ligand system capable
of mediating the trifluoromethylation reaction without impeding the
nucleophilic radiofluorination with the [18F]fluoride ion. In a model
reaction, we chose to use CHF2I, CuI, and a ligand in a 1 : 1 : 1 molar
ratio (see Table 1) and a model substrate, iodoarene 4-iodo benzonitrile
1a (B40 mmol) in DMF (0.3 mL). In preliminary experiments (not
shown) we found that a temperature of 145 1C was necessary to achieve
rapid conversion. Attempts to substitute the low boiling starting
material CHF2I (b.p. 22 1C) by a higher boiling difluoromethyl sulfo-
nate, in order to permit better control of the reaction stoichiometry and
for easy handling of the reagent, were not successful. Neither difluor-
omethyl tosylate nor difluoromethyl triflate were found to react to give
the desired product under a variety of conditions. Consequently, we
resorted to using CHF2I for all further experiments. Despite this minor
inconvenience, an activity balance of the reaction did not reveal any loss
DMAP
2,20-Bipyridine
Phenanthroline
IPrꢁCuBF4
TMEDA
9
19
3
28
42
10
11
12
DBU
NEt3
DIPEA
a
Abbreviations: DBU = 1,8-diazabicyclo[5.4.0]undecene; IPrꢁCuBF4
=
bis(1,3-(2,6-diisopropylphenyl)imidazol-2-ylidene)copper(I) tetrafluoro-
borate; DMAP = 4-(dimethylamino)pyridine; TMEDA = N,N,N0,N0-tetra-
methyl ethylenediamine; NEt3 = triethylamine; DIPEA = N,N-diisopropyl-N-
ethylamine. b Decay-corrected radiochemical yield in % of dispensed 18F
determined by radioHPLC or radioTLC.
of the gaseous radioactive material. In control experiments upon
omitting either ligand, or CHF2I no 18F-labelled product was obtained
(Table 1, entries 1 and 2), likewise, the use of triphenylphosphine gave
only traces of the product (Table 1, entry 3). Surprisingly, none of the
screened pyridine derivatives gave significant yields of [18F]1b (Table 1,
entries 4–7). When the commercially available Cu–NHC complex
bis(1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)copper tetrafluoro-
borate was used, [18F]1b was formed in about 2% yield (Table 1, entry 8).
At this point we deducted that a slightly more basic ligand would be
required in dipolar aprotic media and turned our attention to aliphatic,
tertiary amines. This hypothesis was rewarded with the first double-
figured yield when tetramethylethylenediamine (TMEDA), a ligand that
had proved its value previously, was used.8 Under these conditions
(Table 1, entry 9) [18F]1b was obtained in 19% radiochemical yield after
10 min at 145 1C. Encouraged by these positive findings we briefly
considered DBU (3%, Table 1, entry 10) which turned out to be inferior
to TMEDA. Further improved, albeit not yet satisfactory, yield (28%,
Table 1, entry 11) was achieved through the use of NEt3 in combination
with 1a. Further screening of ligand–catalyst combinations (Table 1,
entry 12) revealed N,N-diisopropyl-N-ethylamine (DIPEA) to be very
effective with regard to the formation of [18F]1b; without further
optimisation a radiochemical yield of 42% was achieved. We hence
refrained from further ligand screening and focussed further efforts on
the CuI–DIPEA system. Although the majority of [18F]fluoride ions had
been consumed within 10 minutes of the reaction time, a considerable
amount of residual [18F]fluoride ions left in the reaction mixture
indicated further potential for improvement. In order to boost the
conversion of [18F]fluoride, which we surmised would lead to further
improvements in RCY, we considered that alternative sources of naked
[18F]fluoride ions might prove to be beneficial. Sources of the [18F]fluor-
ide ion were obtained by trapping [18F]fluoride ions on a strong anion
exchange resin followed by elution of the trapped radioactive material
using an appropriate base in aqueous acetonitrile (MeCN–H2O, 9 : 1).
Through this protocol, reactive [18F]fluoride ion complexes are obtained
that have found widespread application in PET chemistry.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 6056--6059 | 6057

View Article Online
ChemComm
Communication
Table 2 Effects of the fluoride ion source on the RCY of [18F]1ba
Table 4 Effects of the copper source on the RCY of [18F]1b
Entry
1
Base
Ligand
[
18F]1ba (%) Entry
Catalysta
RCYb (%)
K2CO3/crypt-222
DIPEA
TMEDA
42
19
1
2
CuI
None
83
0
3
4
5
6
7
8
9
10
11
CuCl
CuBr
CuCN
CuOAc
CuFꢁPPh3
CuOTfꢁ(MeCN)4
CuOTfꢁbenzene
CuOTfꢁtoluene
CuOTfꢁ(MeCN)4
40
89
60
10
0b
5b
0b
0b
93
2
3
K2CO3/18-crown-6
TBAOH
DIPEA
49
DIPEA
TMEDA
2
18
4
5
TEAHCO3
Cs2CO3
DIPEA
56
DIPEA
TMEDA
DBU
83
38
27
a
Abbreviations: CuOTfꢁ(MeCN)4 = tetrakisacetonitrile copper(I) triflate;
CuOTfꢁbenzene
=
copper(I) trifluoromethane sulfonate benzene
complex; CuOTfꢁtoluene = copper(I) trifluoromethane sulfonate toluene
6
KHCO3/crypt-222
DIPEA
TMEDA
DBU
83
48
47
b
complex; CuFꢁPPh3 = fluorotris(triphenylphosphine)copper(I). DIPEA
was omitted.
a
Abbreviations: TBAOH = tetrabutylammonium hydroxide; TEAHCO3 =
tetraethylammonium bicarbonate.
Substitution of DMF with DMSO or THF was detrimental (Table 3,
entries 2 and 4), both of these solvents were ineffective. However,
substitution of DMF with MeCN provided a viable alternative
and similar yields were obtained. The main disadvantage of
using MeCN under these conditions is the fairly pronounced
pressure build-up in the reactor, which may result in difficulties
during automation. Moreover, a loss of activity was observed
using acetonitrile as the solvent.
Variation of the copper catalyst source. We tested whether CuI
was the preferred source of the copper catalyst by changing the
copper salt in the promising reaction example that used DIPEA–
CuI (Table 4, entry 1). The reaction did not occur when CuI was
omitted (Table 4, entry 2). Equimolar replacement of CuI with
CuCl, CuOAc, CuCN, or fluorotristriphenylphosphine CuI led to
diminished radiochemical yields (Table 4, entries 3–7). Also arene
complexes of CuOTf (Table 4, entries 8–10) were not effective in
the absence of DIPEA or gave only traces of the 18F-labelled
product (Table 4, entry 8). Tetrakis acetonitrile CuOTf and CuBr
provided the highest yields (Table 3, entry 4). In our case CuBr was
established as the preferred copper source.
General conditions, as optimised above, were used to investi-
gate the substrate scope of the 18F-trifluoromethylation. A variety of
commercially available aryl halides were screened (Table 5). In
essence, aryl iodides were confirmed to be the most appropriate
halides for our purpose (Table 5, entry 1), a steep decline in
radiochemical yield occurred upon switching to the corresponding
bromide 3a or chloride 4a (Table 5, entries 3 and 4). Most assayed
functional groups were found to be compatible with the reaction
conditions. Potentially sensitive substrates such as 4-cyano or
4-methoxycarbonylbenzenes, which may be sensitive to exposure
to carbanionic forms of trifluoromethylating reagents, gave the
desired radioactive products in high to excellent yields. Even 12a
containing a protic hydroxyl group was tolerated to some extent.
The protic carboxamide 10a gave low yield and two unidentified by-
products were observed. Electron deficient substrates globally
resulted in slightly higher radiochemical yields compared to
electron-rich arenes.
In the context of our one-pot approach we conducted control experi-
ments with DBU and TMEDA alongside DIPEA to avoid overlooking
synergies in between the 18F-complex, ligand and CuI. However, under
the screened conditions, DIPEA was generally found to be superior to
TMEDA and DBU. Substitution of the cryptand crypt-222 (Table 2,
entry 1) by the corresponding crown ether 18-crown-6 (Table 2, entry 2)
led to a slightly improved radiochemical yield of about 49%. Whereas
the use of tetrabutylammonium hydroxide (TBAOH) to form tetra-
butylammonium fluoride (TBA[18F]F) (Table 2, entry 3) did not have
any effect, the use of tetraethylammonium carbonate (TEAHCO3) to
essentially obtain tetraethylammonium fluoride (TEA[18F]F) (Table 2,
entry 4) had a remarkable impact (56%). The use of Cs2CO3 as a base,
led to a significant increase in the radiochemical yield in the
formation of [18F]1b (up to 83%, Table 2, entry 5). In the end, these
conditions were equivalent to the combination of KHCO3, crypt-222
and DIPEA which resulted in up to 83% RCY after 10 min at 145 1C
(Table 2, entry 6).
Notably, screening of various combinations of inorganic bases
and phase transfer catalysts used to activate the [18F]fluoride ion in
the next step indeed facilitated a duplication of the radiochemical
yield even when a milder base was used, highlighting the strong
influence of these reagents under our conditions. These conditions
were used in all further experiments. In order to further optimise the
reaction outcome, we focussed our attention on the contribution of
the reaction time. Increasing the reaction time beyond 10 minutes
did not improve the yield, instead it became apparent, that the
bulk of the [18F]fluoride ions had already been consumed within
10 minutes of the reaction time under our optimised conditions and
the yield did not improve, but only degraded further from this point.
Table 3 Effects of the reaction time and solvent on the RCY of [18F]1b
Entry
Solvent
Time (minutes)
RCY (%)
1
2
3
4
5
DMF
DMSO
MeCN
THF
10
10
10
10
20
83
0
78
8
Translation of the method: Radiotracer synthesis. Having confirmed
that we were able to prepare a variety of [18F]trifluoromethyl arenes
DMF
82
6058 | Chem. Commun., 2014, 50, 6056--6059
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
Table 5 Substrate scope of the 18F-trifluoromethylation reaction
yield and deprotected with TFA in a second step to obtain the
prospective 5-HT receptor radiotracer 17c.
In this report, we have shown that CuI mediated 18F-trifluoro-
methylation reactions are highly efficient in the presence of a simple
combination of DIPEA, CuBr and iodoarenes. We extended
this methodology to three examples of a single-pot synthesis of
candidate radioligands for PET imaging (Scheme 2). The resulting
[18F]trifluoromethyl arenes were obtained in sufficient yields by
using an operationally convenient protocol, suitable for straightfor-
ward automation. This direct and rapid conversion of iodoarenes is
tolerant to diverse functional groups and consequently provides
convenient access to a variety of drug molecules containing the CF3-
group. Given the high prevalence of the CF3-group and its prominent
role in drug development, paired with the availability of 18F at most
PET centres, we expect this novel methodology to be widely adapted
for the development of PET radiotracers in particular from known
and well characterised drug molecules.
Substrate
R
X
Product
RCYa,b (%)
1a
2a
3a
4a
5a
6a
7a
8a
4-Cyano
4-t-Butyl
4-t-Butyl
4-t-Butyl
4-Methoxycarbonyl
4-Nitro
4-Pyridinyl
3-Methoxycarbonyl
4-Phenyl
4-Carboxamido
4-Benzyloxy
4-Hydroxy
3,5-Dimethyl
2,6-Dimethyl
I
I
Br
Cl
I
I
I
I
I
I
I
I
I
[
[
[
[
[
[
[
[
[
[
[
[
[
[
18F]1b
18F]2b
18F]2b
18F]2b
18F]5b
18F]6b
18F]7b
18F]8b
18F]9b
18F]10b
18F]11b
18F]12b
18F]13b
18F]14b
93 ꢂ 3
69 ꢂ 8
1
1
86 ꢂ 7
89 ꢂ 4
58 ꢂ 17
86 ꢂ 8
84 ꢂ 2
44 ꢂ 14
85 ꢂ 6
12 ꢂ 1
63 ꢂ 6
75 ꢂ 6
9a
10a
11a
12a
13a
14a
I
a
Screening conditions: 100 MBq scale, CuBr (58 mmol), CHF2I
(169 mmol), KHCO3 (13 mM), crypt-222 (35 mmol), aryl halide (41 mmol),
Notes and references
b
DIPEA (59 mmol), 145 1C, 10 min, DMF (300 mL). RCY values are
mean ꢂ S.D.
1 L. Cai, S. Lu and V. W. Pike, Eur. J. Org. Chem., 2008, 2853–2873.
2 (a) P. W. Miller, N. J. Long, R. Vilar and A. D. Gee, Angew. Chem., Int.
Ed., 2008, 47, 8998–9033; (b) P. J. H. Scott, Angew. Chem., Int. Ed.,
2009, 48, 6001–6004.
`
3 G. J. Meyer, S. L. Waters, H. H. Coenen, A. Luxen, B. Maziere and
¨
B. Långstrom, Eur. J. Nucl. Med., 1995, 22, 1420–1432.
4 (a) D. A. Nagib and D. W. C. MacMillan, Nature, 2011, 480, 224–228;
(b) A. Deb, S. Manna, A. Modak, T. Patra, S. Maity and D. Maiti, Angew.
Chem., Int. Ed., 2013, 52, 9747–9750; (c) S. Mizuta, K. M. Engle, S. Verhoog,
O. Galicia-Lopez, M. O’Duill, M. Medebielle, K. Wheelhouse, G. Rassias,
A. Thompson and V. Gouverneur, Org. Lett., 2013, 15, 1250–1253;
(d) T. Furuya, A. S. Kamlet and T. Ritter, Nature, 2011, 473, 470–477;
(e) S. Mizuta, S. Verhoog, K. M. Engle, T. Khotavivattana, M. O’Duill,
K. Wheelhouse, G. Rassias, M. Medebielle and V. Gouverneur, J. Am. Chem.
Soc., 2013, 135, 2505–2508.
5 (a) M. Huiban, M. Tredwell, S. Mizuta, Z. Wan, X. Zhang, T. L. Collier,
V. Gouverneur and J. Passchier, Nat. Chem., 2013, 5, 941–944; (b) L. Zhu,
K. Ploessl and H. F. Kung, Science, 2013, 342, 429–430; (c) S. Mizuta,
I. Stenhagen, M. O’Duill, J. Wolstenhulme, A. Kirjavainen, S. Forsback,
M. Tredwell, G. Sandford, P. Moore, M. Huiban, S. Luthra, J. Passchier,
O. Solin and V. Gouverneur, Org. Lett., 2013, 15, 2648–2651;
(d) M. Tredwell and V. Gouverneur, Angew. Chem., Int. Ed., 2012, 51,
11426–11437; (e) P. J. Riss, V. Ferrari, L. Brichard, P. Burke, R. Smith and
F. I. Aigbirhio, Org. Biomol. Chem., 2012, 10, 6980–6986; ( f ) P. J. Riss and
F. I. Aigbirhio, Chem. Commun., 2011, 47, 11873–11875; (g) M. R.
Kilbourn, M. R. Pavia and V. E. Gregor, Int. J. Radiat. Appl. Instrum., Part
´
A, 1990, 41, 823–828; (h) O. Josse, D. Labar, B. Georges, V. Gregoire and
Scheme 2 Direct radiosynthesis of [18F]trifluoromethyl arenes.
J. Marchand-Brynaert, Bioorg. Med. Chem., 2001, 9, 665–675; (i) W. R.
Dolbier Jr, A.-R. Li, C. J. Koch, C.-Y. Shiue and A. V. Kachur, Appl. Radiat.
Isot., 2001, 54, 73–80.
6 D. van der Born, J. D. M. Herscheid, R. V. A. Orru and D. J. Vugts,
Chem. Commun., 2013, 49, 4018–4020.
efficiently within only 10 min, we investigated the feasibility of
synthesising prospective radiotracer candidates bearing mole-
cular structures common for small molecule drugs (Scheme 2).
Treatment of precursor 15a with 18F under our standard
conditions afforded the potential subtype selective cannabinoid
receptor agonist [18F]15b in 85% RCY. Likewise, we investigated
the direct radiosynthesis of trifluorothymine 16b from the
corresponding iodide precursor 16a in order to provide this
compound for our ongoing cancer imaging efforts in rodent
´
7 (a) A. Lishchynskyi, M. A. Novikov, E. Martin, E. C. Escudero-Adan,
´
P. Novak and V. V. Grushin, J. Org. Chem., 2013, 78, 11126–11146;
(b) O. A. Tomashenko and V. V. Grushin, Chem. Rev., 2011, 111, 4475;
(c) E. A. Symons and M. J. Clermont, J. Am. Chem. Soc., 1981, 103,
3127–3130; (d) M. Halpern, Phase-Transfer Catalysis, Ullmann’s
Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, 2002;
(e) E. V. Dehmlow and S. S. Dehmlow, Phase Transfer Catalysis,
VCH, Weinheim, 3rd edn, 1993; ( f ) C. M. Starks, C. L. Liotta and
M. E. Halpern, Phase-Transfer Catalysis, Chapman & Hall, New York,
1994; (g) W. Kirmse, Carbene Chemistry, Academic Press, Inc. LTD,
New York-London, 2nd edn, 1971, vol. 1.
models of peripheral tumours.9 [18F]16b was obtained in a 8 P. J. Riss, S. Lu, S. Telu, F. I. Aigbirhio and V. W. Pike, Angew. Chem.,
Int. Ed., 2012, 51, 2698–2702.
9 K. Virdee, P. Cumming, D. Caprioli, B. Jupp, A. Rominger,
F. I. Aigbirhio, T. D. Fryer, P. J. Riss and J. W. Dalley, Neurosci.
Biobehav. Rev., 2012, 36, 1188–1216.
radiochemical yield of 73%. In an extension of our concept
the BOC-protected piperazine 17a was converted into the
18F-trifluoromethylated BOC-protected piperazine 17b in 85%
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 6056--6059 | 6059