No carrier-added nucleophilic aromatic radiofluorination using solid phase supported arenediazonium sulfonates and 1-(aryldiazenyl)piperazines

Article abstract of DOI:10.1016/j.tetlet.2012.01.082

This Letter concerns the investigation of a solid phase based method for no carrier-added nucleophilic [¹⁸F]fluorination of aromatic compounds via de-diazofluorination. Initial screening of reaction conditions was conducted using soluble analog

Full text of DOI:10.1016/j.tetlet.2012.01.082

Tetrahedron Letters 53 (2012) 1717–1719
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Tetrahedron Letters
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No carrier-added nucleophilic aromatic radiofluorination using solid phase
supported arenediazonium sulfonates and 1-(aryldiazenyl)piperazines
Patrick J. Riss a, , Sonja Kuschel a,b, Franklin I. Aigbirhio a
⇑
a Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
b Department of Chemistry, Pharmacy and Geosciences, University of Mainz, Fritz-Strassmann-Weg 2, 55128 Mainz, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter concerns the investigation of a solid phase based method for no carrier-added nucleophilic
[
18F]fluorination of aromatic compounds via de-diazofluorination. Initial screening of reaction conditions
Received 23 October 2011
Revised 6 January 2012
Accepted 20 January 2012
Available online 28 January 2012
was conducted using soluble analogues, that is, substituted benzenediazonium tosylates and 1-(phen-
yldiazenyl)piperazines in solution. This was followed by translation of the principle conditions to solid
phase bound analogues. A variety of substituted aryldiazonium cations were immobilised using a
sulfonate functionalised ion exchange resin and labelled with [18F]fluoride ion by Balz–Schiemann like
thermal decomposition in the presence of no carrier-added [18F]fluoride ion. Likewise, a chloromethyl-
bearing (Merrifield-) resin was modified using piperazine to provide the means for covalent immobilisa-
tion of diazonium ions. The resin bound 1-(aryldiazenyl)piperazines obtained were used as substrates for
a Wallach reaction with hydrogen [18F]fluoride.
Keywords:
Nucleophilic aromatic radiofluorination
Fluorine-18
Solid phase
Wallach reaction
Ó 2012 Elsevier Ltd. All rights reserved.
Balz–Schiemann reaction
No carrier-added (NCA) nucleophilic aromatic radiofluorination
of electron rich aromatic compounds with [18F]fluoride ion is a
highly challenging task in radiopharmaceutical chemistry.1 There
is a need to develop novel methods to access a wider range of prod-
ucts or improve the radiosynthesis of key radiopharmaceuticals. Still
required are straightforward methodsfor the PET-tracers, 2-[18F]flu-
radiochemical yields (RCY), low specific radioactivity and exten-
sive by-product formation.3
Our initial experiments were focussed on the investigation of
the utility of aryldiazonium tosylates as precursors for 18F-labelling.
A set of diversely functionalised model substrates were prepared
using a modification of previously published methods2a (Scheme 1).
In our laboratory, diazonium salts were obtained under mild
conditions by using solid-supported nitrite ions and toluenesul-
fonic acid as a proton source in 30–60% yields.
oro-L
-DOPA and 6-[18F]fluoro-meta-tyrosine whichare clinicallyrel-
evant radiotracers for neurodegenerative diseases, to be produced
with high specific radioactivity and high yield. Moreover, a traceless,
direct nucleophilic labelling method which does not require the use
of toxic metals and catalysts would ease quality control and valida-
tion in radiotracer productions for human application significantly.1
Recent reports of very stable solid-supported aryldiazonium sul-
fonates and resin-bound triazenes2 motivated our effort to re-inves-
tigate de-diazofluorination in NCA nucleophilic radiofluorination
using solid phase bound substrates. In both cases, only the labelled
product would be cleaved off the resin upon the formation of a C–
F bond with [18F]fluoride ion whereas the unlabelled precursor
would remain on the resin. Thereby, the purification of the product
is simplified remarkably.
Despite the high interest in a simple and straightforward meth-
odology for 18F-labelling of aromatic substrates, solid phase meth-
ods have not been investigated in aromatic 18F-labelling reactions.
Fluorination of aromatic compounds by Balz–Schiemann and Wal-
lach reactions has been reported in good yields, however their
translation into 18F-radiochemistry has been hampered by low
Immobilisation on a solid phase was achieved by stirring the
commercially available cation exchange resin Amberlyst A15 (Na+-
form) in a solution of the desired aryldiazonium tosylate in metha-
nol. To maximise the loading of the resin, this step was repeated
three times to allow for a maximum loading of 1–1.5 mmol/g.4
We chose the conditions elaborated by Knöchel and Zwerne-
mann5 as the starting point for labelling experiments. Precursors
1a–e were reacted with either Cs[18F]F or [Na+/18-C-6][18F]FÀ at
120 °C in toluene for 30 min. The commonly used polyether [K+/
18-C-6]18FÀ and the cryptate [K+/K222]18FÀ were largely omitted
due to low radiochemical yields being obtained, supposedly due
to host–guest interactions between the diazonium cation and the
larger complexing agents 18-crown-6 and K2224,6a which are not
possible with the smaller analogue 15-crown-5.6b Under these
conditions radiolabelled fluoroarenes were obtained in 0.5–7%
yields after 30 min at 120 °C in toluene (Table 1). Precursor-loaded
Amberlyst A15 resins 2a,b were then used under essentially the
same conditions to obtain 18F-labelled products in a radiochemical
yield of 6% (Table 1).
⇑
Corresponding author.
E-mail address: pr340@wbic.cam.ac.uk (P.J. Riss).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.082

1718
P. J. Riss et al. / Tetrahedron Letters 53 (2012) 1717–1719
N
N
NO2-, 3 eq
O
S
N
NH2
R2
C
s
O
O
F
1
/
8
t
o
F
l
TsOH, 3 eq
MeOH, rt, 15 min
u
e
o
r
R4
R2
n
e
N
a
R4
F
1
/
,
1
2
R3
8
0
°
F
C
[
,
1
5
R3
3
0
-
C
mi
-
1a-e
5
n
]
30-60%
2
3
4
1a
: R =H, R =H, R =O-CH3
18F
R2
F
1b: R2=H, R3=H, R4=CH3
1c: R2=H, R3=H, R4=I
R2
R4
O
O
O
R4
MeOH,
20 min, rt
1d: R2=H, R3=H, R4=H
1e: R2=O-C5H6, R3=H, R4=H
R3
S
Na
R3
4
5
max. RCY
6%
max. yield
]
5
-
8%
R2
C
-
5
1
[
N
n
i
F
,
R3
R4
8
1
/
m
N
O
O
O
0
F
3
a
S
N
r
C
°
o
0
8
F
2
1
/
1
2a,b
F
s
C
0.8 - 1.08 mmol/g
toluene,
2
3
4
2a
: R =H, R =H, R =O-CH3
2b: R2=O-C5H6, R3=H, R4=H
Scheme 1. Synthesis and radiosynthesis of fluoroarenes from aryl tosylates and solid-supported arenediazonium ions.
At this point we attempted to improve the radiochemical yields
by screening a variety of solvents, metal additives, temperatures
and reaction times.4 However, this effort did not give any signifi-
cant improvement in the labelling outcome. A detailed radioactiv-
ity balance furthermore revealed that after removal of the reaction
mixture followed by three subsequent washing steps (2.5 ml) more
than 90% of the 18F-radioactivity was irreversibly bound to the so-
lid phase containing the resin.4 We concluded that de-
diazo[18F]fluorination of resin-bound diazonium sulfonates is fea-
sible but does not give sufficient yields for further investigation.
We therefore turned our interest to triazene analogues which
can be readily decomposed in the presence of strong acids to yield
diazonium ions.3d
N
N
O
N
N
N
N
O
3a
Figure 1. 1-(Aryldiazenyl)piperazines.
3b
Table 2
18F]Fluorination of 1-(aryldiazenyl)piperazines 3a,b under different reaction condi-
[
tions in CCl4 at 90 °C
Prior to the use of a solid phase bound precursor, the reaction
conditions were investigated using 1-(aryldiazenyl)piperazines
3a and 3b.
Substrate
Reaction conditions
RCY7
3a
3a
3a
3a
3b
3b
3b
3b
3b
C18F, H3CSO3H (5 equiv)
3%
3%
2%
5%
Trace
3%
6%
3%
23%
C18F, F3CSO3H (5 equiv)
Compounds 3a and 3b (Fig. 1) were synthesised by a standard
method8 and radiofluorinated by a method similar to that of Pages
et al.3f The strong acids methanesulfonic acid, sulfuric acid and tri-
flic acid were used for acid-induced decomposition of 3a and 3b in
the presence of Cs[18F]F or [Na+/15-C-5]18FÀ (Table 2). Carbon tet-
rachloride was used as the solvent. Up to 23% RCYs were obtained
for substrate 3b using [Na+/15-C-5]18FÀ and triflic acid after heat-
ing for 30 min.
[Na+/15-C-5]18FÀ, H3CSO3H (5 equiv)
[Na+/15-C-5]18FÀ, F3CSO3H (5 equiv)
Cs18F, H2SO4 (5 equiv)
Cs18F, H3CSO3H (5 equiv)
Cs18F, F3CSO3H (5 equiv)
[Na+/15-C-5]18FÀ, H3CSO3H (5 equiv)
[Na+/15-C-5]18FÀ, F3CSO3H (5 equiv)
Similar conditions were used to synthesise the non-radioactive
reference compound 7, however only trace amounts (0.3%) of fluo-
rinated product were isolated (Scheme 2).
N
N
NH2
O
1. 1 M HCl
1 eq NaNO2
N
2. 1.1 eq piperidine
O
0 °C, 30 min
Table 1
[
sulfonates 2a,b after 30 min
3b
30%
18F]Fluorination of aryldiazonium tosylates 1a–e and solid-supported aryldiazonium
Na18F[15-C-5], F3CSO3H,
CCl4, 90 °C, 30 min
CsF,F3CSO3H,2eq
CCl4, 90 °C,18 h
Substrate
Reaction conditions
RCY7
1a
1a
1c
1e
1e
1a
1a
2a
2b
2b
Cs18F, toluene, 120 °C
1%
Trace
1%
7%
1%
Trace
Trace
trace
6%
18F
[Na+/15-C-5] 18FÀ, toluene, 120 °C
[Na+/15-C-5] 18FÀ, toluene, 120 °C
Cs18F, toluene, 120 °C
O
F
[Na+/15-C-5] 18FÀ, toluene, 120 °C
[K+/18-C-6] 18FÀ, toluene, 120 °C
[K+/K222] 18FÀ, toluene, 120 °C
[Na+/15-C-5] 18FÀ, toluene, 120 °C
[Na+/15-C-5] 18FÀ, toluene, 120 °C
Cs18F, toluene, 120 °C
O
6
RCY7 23%
7
0.3% isolated yield
6%
Scheme 2. Synthesis and fluorination of 3b.

P. J. Riss et al. / Tetrahedron Letters 53 (2012) 1717–1719
1719
N
N
-
BF4
O
piperazine 10 eq
Et3N 11 eq
4.5 eq
N
9
N
N
Cl
N
N
NH
THF, rt, 45 min
DMF, 60 °C, 48 h
10
0.2 mmol/g
8
O
Na18F[15-C-5], F3CSO3H,
CCl4, 90 °C, 30 min
18F
O
6
14% RCY
Scheme 3. Synthesis and [18F]fluorination of polymer functionalised triazene 10.
In addition, about 10% of diphenyl ether was formed in the
reaction, with 20% of the triazene recovered from the reaction
mixture even after a prolonged reaction time of 18 h under reflux.
We therefore synthesised this non-commercially available refer-
ence compound from 2-fluorophenol and diphenyliodonium
tosylate.4
Acknowledgements
The authors gratefully acknowledge funding from the MRC
(G0900903) and the German academic exchange service (DAAD).
Supplementary data
A commercially available ‘Merrifield’-type polymer resin bear-
ing chloromethylene functional groups for covalent attachment
was modified with piperazine according to a published procedure
in order to establish an anchoring point, that is, secondary amine
functionalised resin 8, to allow for triazene formation on the resin.8
Polymer functionalised triazene 10 was synthesised using 8 and
diazonium tetrafluoroborate 9 (Scheme 3) following the procedure
of Bräse et al.9
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.082.
References and notes
1. (a) Wester, H. J. In Handbook of Nuclear Chemistry; Kluwer Academic Publishers:
Amsterdam, 2003; Vol. 4, pp 167–21; (b) Miller, P. W.; Long, N. J.; Vilar, R.; Gee,
A. D. Angew. Chem. 2008, 120, 9136–9210. Angew. Chem. Int. Ed. 2008, 47, 8998–
9110; (c) Cai, L.; Lu, S.; Pike, V. W. Eur. J. Org. Chem. 2008, 2853–2863.
2. (a) Filimonov, V.; Trusova, M. Org. Lett. 2008, 10, 3961–3964; (b) Merrington, J.;
James, M.; Bradley, M. Chem. Commun. 2002, 1, 140–141; (c) Döbele, M.;
Vanderheiden, S.; Jung, N.; Bräse, S. Angew. Chem. 2010, 122, 6122–6125.
3. (a) Hoyte, R. M.; Lin, S. S.; Christman, D. R.; Atkins, H. L.; Hauser, W.; Wolf, A. P.
J. Nucl. Med. 1971, 12, 280–286; (b) Atkins, H. L.; Christman, D. R.; Fowler, J. S.;
Hauser, W.; Hoyte, R. M.; Klopper, J. F.; Lin, S. S.; Wolf, A. P. J. Nucl. Med. 1972,
13, 713–719; (c) Knochel, A.; Zwernemann, O. Appl. Radiat. Isot. 1991, 42, 1077–
1080; (d) Tewson, T. J.; Welch, M. J. J. Chem. Soc. Chem. Commun. 1979, 1149–
1150; (e) Ng, J. S.; Katzenellenbogen, J. A.; Kilbourn, M. R. J. Org. Chem. 1981, 46,
2520–2528; (f) Pages, T.; Langlois, B. R.; Le Bars, D.; Landais, P. J. Fluorine Chem.
2001, 107, 329–335.
The triazene bound polymer was obtained with a maximum
loading of 0.2 mmol/g.4
Resin 10 was reacted using the optimised conditions from Table
2. Within 30 min at 90 °C, 18F-labelled ether 6 was obtained in up
to 14% RCY.4,10
Contrary to the ion exchange resin, the activity balance of this
reaction has shown that more than 60% of the 18F-radioactivity
can be recovered by filtering the resin. Only 18% of the radioactiv-
ity was still adsorbed on the resin and the reaction vessel after
three subsequent washing steps (2.5 ml).4
4. See Supplementary data for details.
We conclude that solid phase supported de-diazofluorination
using arenediazonium cations ionically bound to a sulfonate func-
tionalised ion exchange resin is not suitable for nucleophilic 18F-
labelling of aromatic compounds. Very low RCYs due to poor con-
version are further augmented by extensive adsorption of 18F-
radioactivity to the resin. This methodology does not promise util-
ity in radiotracer synthesis.
5. Knöchel, A.; Zwernemann, O. J. Lab. Compd. Radiopharm. 1995, 38, 325–336.
6. (a) Krane, J.; Skjetne, T. Tetrahedron Lett. 1980, 21, 1775–1778; (b) Bartsch, R.
A.; Chen, H.; Haddock, N. F.; Juri, P. N. J. Am. Chem. Soc. 1976, 98, 6753–6754.
7. Radiochemical yields (RCY) were determined by radioTLC and calculated as the
percentage of the product radioactivity from the total radioactivity.
8. Patrick, T. B.; Willaredt, R. P.; DeGonia, D. J. J. Org. Chem. 1985, 50, 2232–2235.
9. Schroen, M.; Bräse, S. Tetrahedron 2005, 61, 12186–12192. Compound 10: FT-
IR,
m
in cmÀ1 = 1668 (w, N = Nval), 1222 (m, Ar–O–Ar), 1119 (s, C–Ndef, sek.).
10. An aliquot of [18F]fluoride ion in H2O (10–20 MBq) was added to a solution of
On the other hand, 1-(phenyldiazenyl)piperazines 3a and 3b
were radiofluorinated within 30 min at 90 °C using [Na+/15-C-
5]18FÀ in CCl4 in the presence of trifluoromethanesulfonic acid with
up to 23% RCY. The analogous reaction using solid supported tria-
zene 10 afforded the 18F-labelled product 6 in a reasonable radio-
chemical yield. This novel solid phase method has proven to be
suitable for 18F-radiolabelling of aromatic compounds, in particular
since no electron-withdrawing group was necessary in order to
facilitate the synthesis of [18F]6.
CsCO3 or a mixture of Na2CO3 and 2.5 equiv 15-C-5 (100 ll, 0.08 mmol/ml) in a
V-shaped reaction vessel (Wheaton 5 ml reactivialÒ) and heated to 90 °C in a
stream of nitrogen to evaporate the liquid. Residual traces of H2O were
removed by co-evaporation with MeCN (3 Â 0.8 ml).
Resin 10 was allowed to swell in CCl4 for 1.5 h prior to the labelling reaction.
An aliquot (equivalent to a dry mass of 100 mg) was added to the dried [Na+/
15-C-5]18FÀ and then anhydrous CCl4 (500
l
l) was added. The vessel was
cooled in an ice bath to 0 °C prior to the addition of trifluoromethanesulfonic
acid (10 l). The reaction vessel was briefly vortexed and heated to 90 °C for
l
30 min. Radiochemical yields were determined by radioTLC on silica gel
(hexanes–EtOAc, 19:1).