Highly hindered 2-(aryl-di-tert -butylsilyl)- N -methyl-imidazoles: A new tool for the aqueous 19F- and 18F-fluorination of biomolecule-based structures

Article abstract of DOI:10.1039/c8cc01782d

A new class of silicon-based fluoride acceptors with a C-linked heterocycle as the leaving group was synthesized in one step from commercial chemicals, and linked to biomolecules. The resulting conjugates were efficiently ¹⁹F-fluorinated in aqu

Full text of DOI:10.1039/c8cc01782d

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Highly hindered 2-(aryl-di-tert-butylsilyl)-N-
methyl-imidazoles: a new tool for the aqueous
Cite this:DOI: 10.1039/c8cc01782d
19F- and F-fluorination of biomolecule-based
18
Received 5th March 2018,
Accepted 22nd April 2018
structures†
b
Marion Tisseraud,a Jurgen Schulz,
Philippe Fernandez,
Delphine Vimont,b Murielle Berlande,a
DOI: 10.1039/c8cc01782d
¨
Philippe Hermange*a and Eric Fouquet
*
b
a
rsc.li/chemcomm
A new class of silicon-based fluoride acceptors with a C-linked hetero-
cycle as the leaving group was synthesized in one step from commercial
chemicals, and linked to biomolecules. The resulting conjugates were
efficiently 19F-fluorinated in aqueous mixtures, and switching to
18F-labelling provided nucleoside- and peptide-based bioconjugates
with excellent molar activities suitable for biological applications.
Among the various radionuclides suitable for positron emission
tomography, 18F decays in 97% via b+ emission (635 keV positrons),
presents a convenient half-life of 109.8 min, and [18F]fluoride anion
can be produced with a high molar activity (Am).1 These interesting
Scheme 1 18F-Fluorination of silicon-based fluoride acceptors.
properties have stimulated researchers to develop new synthetic structure for silicon-based fluoride acceptors (SiFA).10a,11a
methods for the efficient introduction of this radioisotope onto Various leaving groups were explored in order to fluorinate
molecules of biological interest.2 Despite the possibilities offered by these highly hindered compounds via nucleophilic substitution
multistep radiosyntheses,3 late-stage 18F-fluorination remains one using [18F]FÀ (Scheme 1). For example, simple isotopic exchange
of the most attractive strategies to ensure the highest overall with fluorine-19 was extremely efficient,9 and even compatible with
radiochemical yields from the native radioelement.4 Important water as the co-solvent in some cases.9a,d Unfortunately, the
progresses have been realized in this field,2,4 but complex bio- products are inseparable from the nonradioactive precursors,
molecules with numerous unprotected functionalities (peptides, which results in low to moderate molar activities (typically from 1
oligonucleotides, etc.) still remain challenging substrates. In this to 60 GBq mmolÀ1, i.e. 0.03 to 1.6 Ci mmolÀ1), whereas ideal
case, the ‘‘click’’ conjugation with radioactive prosthetic groups values for biological applications would be preferentially higher
demonstrated its efficiency, but mainly relies on advanced than 100 GBq mmolÀ1 (E3 Ci mmolÀ1).9c In contrast, starting from
18F-fluorinated precursors.5 On the other hand, last-step labelling aryl-di-tert-butyl-silane11a–f or aryl-di-tert-butyl-alkoxysilane11a,g,h
of bioconjugates using [18F]FÀ was achieved during the last decade produces 18F-fluorinated molecules with higher molar activities
by designing specific tags suitable for enzymatic fluorination6 (60–500 GBq mmolÀ1, i.e. 1.6–13.5 mCi mmolÀ1), but it requires in
or possessing heteroelements with high affinities for fluoride most cases strictly anhydrous organic solvents and/or counter-
ions,7 i.e. Al,8 B9 or Si atoms.10,11 In this latter case, the steric anion cryptands to enhance the nucleophilicity of the fluoride ion.
shielding of the silicon centre proved to be crucial to avoid Thus, new methods without drying steps and toxic reagents would
in vivo hydrolysis of the newly created silicon–fluorine-18 bond, greatly shorten and simplify these radiolabelling procedures. For
and the aryl-di-tert-butyl-silyl moiety became a privileged example, new aryl-di-tert-butyl-acetoxysilane SiFAs have recently
appeared as a promising approach in this regard, but are still only
scarcely described in the literature.11i,j
a
´
Univ. Bordeaux, Institut des Sciences Moleculaires, UMR-CNRS 5255,
´
351 Cours de la Liberation, 33405 Talence Cedex, France.
In this context, we decided to investigate novel potential
leaving groups that would provide highly stable, fluoride-
selective precursors. Indeed, such molecules would allow further
modification and bioconjugation of the SiFA moiety without any
restriction in the reaction conditions, and might be fluorinated
efficiently in aqueous media. Inspired by the reactivity of
E-mail: philippe.hermange@u-bordeaux.fr, eric.fouquet@u-bordeaux.fr
b
´
Department Institut des Neurosciences Cognitives et Integratives d’Aquitaine,
´
UMR-CNRS 5287, 146 Rue Leo Saignat, 33076 Bordeaux Cedex, France
† Electronic supplementary information (ESI) available: General experimental
procedures and analysis/spectroscopic data (1H NMR, 13C NMR and radio-HPLC
chromatograms). See DOI: 10.1039/c8cc01782d
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Table 1 19F-Fluorination of precursor 3e
1H NMR
yield (%)
Entrya
3
‘‘FÀ’’ (x equiv.)
Acid (y equiv.)
1
2
3e TBAF (1.5 equiv.)
3h TBAF (1.5 equiv.)
AcOH (10 equiv.)
AcOH (10 equiv.)
85
30
90
20
0
3
3e KF/Kryptofixs (1.5 equiv.) AcOH (10 equiv.)
4b
5
3e TBAF (1.5 equiv.)
3e TBAF (1.5 equiv.)
3e TBAF (1.5 equiv.)
3e TBAF (1.5 equiv.)
3e TBAF (1.5 equiv.)
3e 0.1 M HFaq (1.5 equiv.)
3e 0.1 M HFaq (0.5 equiv.)
AcOH (10 equiv.)
—
NH4Cl (10 equiv.)
6
50
7
CH3SO3H (1.5 equiv.) 100
8c
9
PS-SO3H (1.5 equiv.)d
93
90
88
—
—
10d
11
12
3e 0.1 M NaFaq (0.5 equiv.) 1.0 M HClaq (0.5 equiv.) 90
3e 0.1 M NaFaq (0.5 equiv.) AcOH (10 equiv.) 100
a
Reactions were carried out on a 33 mmol scale in 1 mL of solvent using
mesitylene as the internal standard. 1H NMR yields were determined
via 1H NMR analysis of an aliquot of the mixture. See the ESI for
Scheme 2 Syntheses and bioconjugations of 2-(aryl-di-tert-butylsilyl)-N-
methyl-imidazoles (isolated yields after column chromatography on silica gel).
b
evolution in time of the 1H NMR yields. DMSO-d6 was used as the
c
solvent. PS-SO3H = sulfonic acid functionalized polystyrene resin
d
(1.18 mmol gÀ1). A 1 : 1 mixture of H2O and THF-d8 was used as the
solvent, and trimethoxybenzene was used as the internal standard.
trimethylsilyl-imidazoles and trimethylsilyl-imidazoliums towards
fluoride and hydroxide ions,12 we hypothesised that these hetero-
cycles could generate a new class of SiFA compounds with carbon- 1H NMR under various conditions (Table 1 and ESI†). A first reaction
based leaving groups. Firstly, a method for the preparation of the was realized in deuterated-THF at 70 1C, using TBAF as a convenient
highly hindered 2-(aryl-di-tert-butylsilyl)-N-methyl-imidazole struc- fluoride source and 10 equivalents of acetic acid (a common
tures was needed, and many strategies were studied. However, the additive for aryl-di-tert-butyl-silane or aryl-di-tert-butyl-alkoxy-
one-pot sequential double nucleophilic substitution of di-tert- silane fluorinations)11 in order to protonate the imidazole
butylsilylbis(trifluoromethanesulfonate) by 2-N-methylimidazolyl- moiety.15 In this case, compound 4e was produced smoothly in
lithium and phenyllithium was identified as the only successful 85% 1H NMR yield within 2 hours (entry 1), whereas starting
procedure (Scheme 2A), leading to the desired compound 2a with an from the silane 3h gave only 30% of 4e under the exact same
excellent yield of 84%. In order to obtain a SiFA group suitable for conditions (entry 2), suggesting an increase of the kinetics of
further functionalisation, 1-bromo-4-(methoxymethyl)-benzene was fluorination with the imidazolium leaving group.
added instead of phenyllithium, and lithiated in situ by Li-halogen
Encouraged by this promising result, the fluoride source was
exchange using n-butyllithium. With this optimised set of conditions, switched to a mixture of KF and Kryptofixs 2.2.2. (a privileged
compound 2b was synthesized in good yields up to 70%.13 The combination for nucleophilic 18F-labelling), and a 90% 1H NMR
removal of the methoxymethyl group was achieved by treatment with yield of 4e was also reached under these conditions (entry 3).
a mixture of H2SO4/H2O/CH3OH (1:3:8), producing the desired 2c in Changing the solvent to DMSO-d6 was detrimental (entry 4) and
90% yield after 24 h at 50 1C. Interestingly, it also demonstrated the THF was kept for further studies. Adding an acid proved to be
complete stability of this 2-(aryl-di-tert-butylsilyl)-N-methyl-imidazole crucial, as no reaction was observed in the absence of AcOH
group towards highly acidic conditions (Scheme 2B). Then, the (entry 5). Ammonium chloride was sufficient to achieve 50% of the
terminal alkyne functionality needed for the conjugation with bio- fluorination after 2 h (entry 6), but the best results with 4e were
molecules was introduced via O-alkylation of the phenol with a obtained using 1.5 equivalents of a strong acid, i.e. methanesulfonic
modified triethyleneglycol chain residue (compound 2d). Finally, acid (entry 7). Interestingly, a resin-supported sulfonic acid was
bioconjugates 3a–g were synthesized in moderate to good yields using almost similarly efficient, allowing an easier manipulation when
copper-catalysed Huisgen cycloadditions14 under microwave irradia- working on a small scale (entry 8). Finally, the direct use of aqueous
tion (35–74%, Scheme 2C).
HF was explored, and a similar result to the anhydrous conditions
Despite having established a synthetic access to bioconjugated was obtained (90% 1H NMR yield, entry 9). Gratefully, increasing the
2-(aryl-di-tert-butylsilyl)-N-methyl-imidazole precursors, their fluori- H2O/THF ratio to 1 : 1 and introducing HF as the limiting reagent
nation abilities were still undetermined at this point. Thus, the (0.5 equiv.) only impacted slightly the kinetics of the reaction (entry
thymidine derivative 3e was selected as a model substrate, and its 10, 88% 1H NMR yield). Moreover, its in situ generation from
reactivity towards [19F]fluoride was monitored over time using aqueous solutions of sodium fluoride and hydrogen chloride/acetic
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fluorinated products 4a–g were isolated in order to fully confirm
1
their structures using H, 13C, 19F and 29Si NMR, as well as mass
analysis (see the ESI† for details).16
Thus, having demonstrated the compatibility of this methodology
with alkaloid-, biotin-, carbohydrate-, nucleoside- and peptide-based
bioconjugates, the 18F-labelling was envisaged. Precursor 3e was
again selected as the benchmark and engaged for further studies
(Table 2). After proton bombardment of an 18O-water target, the
[18F]FÀ produced (typically 80–100 GBq) was trapped onto an anion
exchange resin cartridge bearing quaternary ammonium function-
alities (QMA). Then, elution by 300 mL of an aqueous solution of
NaCl (0.9% w/w) provided the desired saline solution of [18F]NaF,
which was further injected in the reaction vial previously loaded with
a THF solution of the precursor and the acid. After heating for
15 min, the crude mixture was transferred into the HPLC loop and
further eluted onto the C18 column. The desired product was
collected into the collecting vial, its activity determined and the
radiochemical purity of the sample was checked using analytical
radio-HPLC. After a first disappointing experiment at 70 1C for
15 min (Table 2, entry 1), it became quickly clear that a slight
Scheme 3 Fluorination of precursors 3a–g: reaction time and 1H NMR
yield (isolated yields after column chromatography on silica gel). Reactions
were carried out on the 7–33 mmol scale in 1 mL of solvent using
mesitylene as the internal standard. 1H NMR yields were determined via
1H NMR analysis of an aliquot of the mixture. See the ESI† for details.
a
Isolated yield after purification by preparative HPLC.
acid was also possible (entries 11 and 12, 90% and 100%, respec- increase in the reaction temperature was needed to achieve better
tively), which could enable the use of the more readily available radiochemical conversions. Indeed, a promising radiochemical yield
aqueous solutions of [18F]NaF for the further radiolabelling of this (RCY) of 17.5 Æ 0.1% and an excellent molar activity (higher than
2-(aryl-di-tert-butylsilyl)-N-methyl-imidazole bioconjugate. The scope 180 GBq mmolÀ1) were obtained when 3e, aqueous HCl (1 equiv.)
of these aqueous conditions (i.e. at 70 1C in THF with 1.5 equivalents and [18F]FÀ were heated in a THF/NaClaq (1 : 1) mixture at 100 1C for
of a 0.1 M aqueous solution of hydrogen fluoride) was tested on the 15 min (n = 2, Table 2, entry 2). Interestingly, despite a higher
substrates 3a–g previously synthesized (Scheme 3). In most cases, dilution, dividing by two the amount of precursor 3e under the same
1
complete conversion and excellent H NMR yields were obtained, reaction conditions allowed the production of the desired [18F]4e in
despite few precursors required to prolong the reaction times to 34.4 Æ 7.0% RCY, while maintaining the molar activity up to 130 Æ
achieve completion (from 3 to 5 h, compounds 3b, 3d, 3f and 3g). All 31 GBq mmolÀ1 (n = 3, Table 2, entry 3). The use of a supported
Table 2 18F-Fluorination of precursors 3e and 3g
Entry
(number of runs)
Substrate
(quantity)
Molar activityb
Conditions
RCYa (%)
(GBq mmolÀ1
)
1c (n = 1)
2 (n = 2)
3 (n = 3)
4 (n = 1)
5 (n = 2)
6 (n = 4)
3e (13.3 mmol)
3e (13.3 mmol)
3e (6.6 mmol)
3e (6.6 mmol)
3e (6.6 mmol)
3g (3.3 mmol)
THF (400 mL), HClaq (1 M, 1 equiv.), H2O (82.7 mL), 70 1C, 15 min
THF (300 mL), HClaq (1 M, 1 equiv.), 100 1C, 15 min
THF (300 mL), HClaq (1 M, 1 equiv.), 100 1C, 15 min
THF (300 mL), PS-SO3Hd (1 equiv.), 100 1C, 15 min
THF (300 mL), AcOH (10 equiv.), 100 1C, 15 min
THF (300 mL), AcOH (2 equiv.), 100 1C, 30 min
3.7
6
17.5 Æ 0.1
34.4 Æ 7.0
28.0
188 Æ 5
130 Æ 31
61
34.9 Æ 2.8
89 Æ 20
20.4 Æ 7.7
129 Æ 37
a
Calculated as the activity in the collected vial corrected by the decay, divided by the activity at the end of bombardment (Â100), mean Æ standard
b
deviation of n experiments. Molar activity determined by HPLC/radio-HPLC, mean Æ standard deviation of n experiments; see the ESI for details.
c
d
Starting activity of 24 GBq. PS-SO3H = sulfonic acid functionalised polystyrene resin (1.18 mmol gÀ1). QMA: quaternary ammonium anion
exchange column.
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7 For selected reviews, see: (a) O. Jacobson, D. O. Kiesewetter and X. Chen,
Bioconjugate Chem., 2015, 26, 1; (b) J.-L. Zeng, J. Wang and J.-A. Ma,
Bioconjugate Chem., 2015, 26, 1000; (c) V. Bernard-Gauthier, J. J.
sulfonic acid instead of HCl also led to the formation of the
radioactive product, but both radiochemical yields and molar
activities decreased in this case (28.0% and 61 GBq mmolÀ1
,
¨
¨
Bailey, Z. Liu, B. Wangler, C. Wangler, K. Jurschat, D. M. Perrin and
R. Schirrmacher, Bioconjugate Chem., 2016, 27, 267; (d) H. S. Krishnan,
L. Ma, N. Vasdev and S. H. Liang, Chem. – Eur. J., 2017, 23, 15553.
8 For selected examples, see: (a) C. A. D’Souza, W. J. McBride, R. M.
Sharkey, L. J. Todaro and D. M. Goldenberg, Bioconjugate Chem., 2011,
22, 179; (b) W. Wang, Z. Liu and Z. Li, Bioconjugate Chem., 2015, 26, 24.
9 For selected examples, see: (a) R. Ting, M. J. Adam, T. J. Ruth and D. M.
Perrin, J. Am. Chem. Soc., 2005, 127, 13094; (b) Z. Liu, M. Pourghiasian,
respectively, Table 2, entry 4).
Using 10 equivalents of acetic acid proved to be as efficient as
1 equivalent of aqueous HCl (34.9 Æ 2.8% RCY, 89 Æ 20 GBq mmolÀ1
MA, n = 2, Table 2, entry 5), and could be more suitable for sensitive
molecules with multiple basic sites (i.e. peptides, ...). It should be
noted that control experiments under the conditions of entry 3 of
Table 2 with both 3h or [19F]4e only lead to limited amounts of the
radioactive [18F]4e (less than 1% RCY, see the ESI†).17 Finally,
radiofluorination of the highly functionalised cycloRGD-based pre-
cursor 3g was examined. In this case, 2 equivalents of AcOH and a
reaction time of 30 min proved to be the best conditions (see the
ESI†). Indeed, a good RCY of 20.4 Æ 7.7% could be obtained with an
excellent molar activity of 129 Æ 37 GBq mmolÀ1, which would be
fully suitable for biological applications with high specificity require-
ments (n = 4, Table 2, entry 6).
´
M. A. Radtke, J. Lau, J. Pan, G. M. Dias, D. Yapp, K.-S. Lin, F. Benard and
D. M. Perrin, Angew. Chem., Int. Ed., 2014, 53, 11876; (c) D. M. Perrin, Acc.
Chem. Res., 2016, 49, 1333; (d) B. Brizet, V. Goncalves, C. Bernhard,
P. D. Harvey, F. Denat and C. Goze, Chem. – Eur. J., 2014, 20, 12933;
¨
(e) K. Chansaenpak, M. Wang, Z. Wu, R. Zaman, Z. Li and F. P. Gabbaı,
Chem. Commun., 2015, 51, 12439; ( f) K. Chansaenpak, H. Wang, M. Wang,
B. Giglio, X. Ma, H. Yuan, S. Hu, Z. Wu and Z. Li, Chem. – Eur. J., 2016,
22, 12122; (g) E. A. Rodriguez, Y. Wang, J. L. Crisp, D. R. Vera, R. Y. Tsien
and R. Ting, Bioconjugate Chem., 2016, 27, 1390.
10 For selected isotopic exchange examples, see: (a) R. Schirrmacher,
¨
G. Bradtmoller, E. Schirrmacher, O. Thews, J. Tillmanns, T. Siessmeier,
¨
H. G. Buchholz, P. Bartenstein, B. Wangler, C. M. Niemeyer and
¨
K. Jurkschat, Angew. Chem., Int. Ed., 2006, 45, 6047; (b) C. Wangler,
S. Niedermoser, J. Chin, K. Orchowski, E. Schirrmacher, K. Jurkschat,
To conclude, we designed and synthesized new 2-(aryl-di-tert-
butylsilyl)-N-methyl-imidazole structures that can be easily conjugated
to biomolecules. While being highly stable under various conditions,
such moieties were very reactive and selective towards fluoride upon
¨
L. Iovkova-Berends, A. P. Kostikov, R. Schirrmacher and B. Wangler, Nat.
Protoc., 2012, 7, 1946; (c) S. Lindner, C. Michler, S. Leidner, C. Rensch,
¨
¨
C. Wangler, R. Schirrmacher, P. Bartenstein and B. Wangler, Bioconjugate
Chem., 2014, 25, 738; (d) M. Glaser, P. Iveson, S. Hoppmann, B. Indrevoll,
A. Wilson, J. Aruke, A. Danikas, R. Bhalla and D. Hiscock, J. Nucl. Med.,
2013, 54, 1981.
¨
activation by strong or weak Bronsted acids, even in aqueous
mixtures. After observing the excellent functional tolerance in model
19F-fluorinations, the reaction conditions were easily transferred to
the radioactive [18F]FÀ by slightly increasing the reaction temperature.
18F-Labelled nucleoside- and peptide-based bioconjugates were
obtained from an aqueous saline solution of [18F]NaF in good RCY
with high molar activities perfectly suitable for potential preclinical/
clinical applications. Thus, these compounds opened the way to a
new class of SIFA precursors using heterocyclic moieties as carbon-
based leaving groups. Further developments to improve the procedure
and the radiochemical yields (microwave heating,18...), as well as
detailed mechanistic investigations, are currently in progress.
This study was supported by a public grant from the French
Agence Nationale de la Recherche within the context of the
Investments for the Future Program, referenced ANR-10-LABX-57
and named TRAIL (SUPSIFLU project).
11 For selected other nucleophilic substitution examples, see: (a) L. Mu,
¨
A. Hohne, P. A. Schubiger, S. M. Ametamey, K. Graham, J. E. Cyr,
L. Dinkelborg, T. Stellfeld, A. Srinivasan, U. Voigtmann and U. Klar,
¨
Angew. Chem., Int. Ed., 2008, 47, 4922; (b) A. Hohne, L. Yu, L. Mu,
M. Reiher, U. Voigtmann, U. Klar, K. Graham, P. A. Schubiger and
S. M. Ametamey, Chem. – Eur. J., 2009, 15, 3736; (c) J. Schulz, D. Vimont,
T. Bordenave, D. James, J.-M. Escudier, M. Allard, M. Szlosek-Pinaud and
E. Fouquet, Chem. – Eur. J., 2011, 17, 3096; (d) E. Amigues, J. Schulz,
M. Szlosek-Pinaud, P. Fernandez, S. Silvente-Poirot, S. Brillouet,
F. Courbon and E. Fouquet, ChemPlusChem, 2012, 77, 345;
(e) P. P. Hazari, J. Schulz, D. Vimont, N. Chada, M. Allard, M. Szlosek-
Pinaud, E. Fouquet and A. K. Mishra, ChemMedChem, 2014, 9, 337;
( f ) B. Rugeri, H. Audi, P. Jewula, R. Koudih, R. Malacea-Kabbara,
´
D. Vimont, J. Schulz, P. Fernandez and S. Juge, Eur. J. Org. Chem.,
2017, 5399; (g) M. H. Al-huniti, S. Lu, V. W. Pike and S. D. Lepore,
J. Fluorine Chem., 2014, 158, 48; (h) S. Jana, M. H. Al-huniti, B. Y. Yang,
S. Lu, V. W. Pike and S. D. Lepore, J. Org. Chem., 2017, 82, 2329; (i) S. H.
Kim, V. M. Carroll, D. Zhou, C. S. Dence and J. A. Katzenellenbogen,
J. Labeled Compd. Radiopharm., 2013, 56, S157; ( j) N. Yasui, S. H. Kim,
V. M. Carroll, D. Zhou, C. S. Dence and J. A. Katzenellenbogen, J. Labeled
Compd. Radiopharm., 2013, 56, S158.
12 R. S. Brown, H. Slebocka-Tilk, J. M. Buschek and J. G. Ulan, J. Am.
Chem. Soc., 1984, 106, 5979.
Conflicts of interest
13 Yields are dependent on the purity of the commercial tert-butylsilyl
bis(trifluoromethanesulfonate) employed, which often contains
hydrolysis products (the ratio can be determined using 1H NMR).
All our attempts to purify it prior to use were unsuccessful.
14 (a) V. V. Rostovtsev, L. G. Green, V. V. Fokin and K. B. Sharpless, Angew.
Chem., Int. Ed., 2002, 41, 2596; (b) C. W. Tornøe, C. Christensen and
M. J. Meldal, J. Org. Chem., 2002, 67, 3057.
There are no conflicts to declare.
Notes and references
1 S. M. Ametamey, M. Honer and P. A. Schubiger, Chem. Rev., 2008,
108, 1501.
15 The pKa of [2b + H]+/2b was determined to be 6.26 in H2O. See the
ESI† for details.
2 (a) S. Preshlock, M. Tredwell and V. Gouverneur, Chem. Rev., 2016,
116, 719; (b) M. G. Campbell, J. Mercier, C. Genicot, V. Gouverneur, 16 The differences between the 1H NMR yields and the isolated yields
J. M. Hooker and T. Ritter, Nat. Chem., 2017, 9, 1.
3 S. H. Liang and N. Vasdev, Aust. J. Chem., 2015, 68, 1319.
4 C. N. Neumann and T. Ritter, Angew. Chem., Int. Ed., 2015, 54, 3216.
after purification using column chromatography on silica gel can be
explained by the difficulties encountered when working with such
small amounts of highly polar compounds.
5 (a) K. Chen and P. S. Conti, Adv. Drug Delivery Rev., 2010, 62, 1005; 17 Anhydrous conditions from ref. 11c with 3h led to a higher RCY of
(b) C. L. Charron, A. L. Farnsworth, P. D. Roselt, R. J. Hicks and
C. A. Hutton, Tetrahedron Lett., 2016, 57, 5119.
6 For a review, see: (a) D. O’Hagan and H. Deng, Chem. Rev., 2015,
[
18F]4e (46.3%), but the activity yield (AY) was lower than the best AY
obtained with 3e, due to the additional time needed for the
azeotropic drying of [18F]fluoride. See the ESI† for details.
115, 634. For a recent example, see: (b) Q. Zhang, S. Dall’Angelo, 18 Microwaving in F-18 Chemistry: Quirks and Tweaks. in PET Chemistry,
I. N. Fleming, L. F. Schweiger, M. Zanda and D. O’Hagan,
Chem. – Eur. J., 2016, 22, 10998.
ed. P. A. Schubiger, L. Lehmann and M. Friebe, Springer, Berlin,
Heidelberg, 2007, pp. 243–269.
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