Fluoride relay: A new concept for the rapid preparation of anhydrous nucleophilic fluoride salts from KF

Article abstract of DOI:10.1039/b614368g

Fluoride relay is used to generate exceptionally nucleophilic fluoride reagents from KF on a time scale commensurate with radiotracer synthesis. The Royal Society of Chemistry.

Full text of DOI:10.1039/b614368g

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Fluoride relay: a new concept for the rapid preparation of anhydrous
nucleophilic fluoride salts from KF
Haoran Sun and Stephen G. DiMagno*
Received (in Cambridge, UK) 3rd October 2006, Accepted 18th October 2006
First published as an Advance Article on the web 6th November 2006
DOI: 10.1039/b614368g
Fluoride relay is used to generate exceptionally nucleophilic
fluoride reagents from KF on a time scale commensurate with
radiotracer synthesis.
Positron emission tomography (PET) is a powerful in vivo imaging
technique for healthcare and drug development.1–4 Provided the
appropriately labeled radiotracers can be synthesized, the sensitiv-
ity of PET makes it useful to study physiology, pharmacokinetics
and modes of action of novel and established drugs.5,6 The most
common positron emitting radioisotopes for the labeling of
organic molecules are 11C (t1/2 = 20.4 min.) and 18F (t1/2
=
Fig. 1 Fluoride shuttling from KF to TBAF*.
109.7 min.). Nucleophilic fluorination is the reaction of choice for
[18F] radiotracer synthesis,7,8 despite the attenuated reactivity of
hydrated fluoride salts obtained after proton bombardment of the
[18O] H2O target. The convenience and high yield of the nuclear
reaction (18O(p,n)18F) outweigh the reactivity disadvantages of
working with hydrated fluoride salts.9 Potassium salts of [18F]-
fluorides so obtained are often ‘‘activated’’ by addition of
cryptands, such as Kryptofix 222, to complex the cation and to
boost fluoride nucleophilicity.
2,6-disubstituted chlorobenzenes to enhance the reaction rate.
Polyhalogenation (Fig. 1) also excludes the possibility of
detrimental arene deprotonation side reactions at the carbon
atoms adjacent to the electron-withdrawing cyano groups. The
fluorinated isophthalonitrile is simultaneously purified and dehy-
drated by flash chromatography, and then subject to a nearly
instantaneous (,5 min) SNAr reaction with tetrabutylammonium
cyanide. This final reaction generates TBAF* in good yields from
KF (.60%). Cogenerated TBACl is an innocuous byproduct
generated from this process (vide infra).
Recently we reported the synthesis of anhydrous tetrabutyl-
ammonium fluoride (TBAF*) by nucleophilic aromatic substitu-
tion of hexafluorobenzene with TBACN.10 TBAF* has proven to
be a highly efficient reagent for Halex and fluorodenitration
reactions.11 In head-to-head experiments, we have also found that
KF-Kryptofix 222 is a poor reagent compared to anhydrous
TBAF*; room-temperature aromatic fluorodenitration reactions
proceed with TBAF* at rates comparable to those conducted with
KF-Kyrptofix 222 in DMSO heated at reflux. TBAF* also offers
dramatically enhanced selectivity in substrates prone to hydrolysis.
These data suggest that [18F] anhydrous ammonium fluoride salts
could expand the scope of radiotracers available from nucleophilic
substitution reactions, provided such salts could be prepared
rapidly and efficiently.
Three examples of the use of this process for fluorination of
challenging heterocyclic substrates are shown in Fig. 2 and 3. For
each reaction, anhydrous TBAF was generated in situ and used
without isolation or purification. These reactions were conducted
using 1 : 1 molar ratios of TBAF* and substrate: 0.2 mmol of
heterocyclic aromatic precursor and TBAF* were simply mixed
together in 0.5 mL of DMSO-d6. Yields were determined by
1
integration of H NMR spectra, using the signals from the TBA
Here we describe a new concept for the synthesis of anhydrous
tetraalkylammonium fluoride salts from KF: aromatic fluoride
relay. In fluoride relay, fluoride is first transferred from KF to an
easily purified hydrophobic arene. An anhydrous fluoride salt is
subsequently generated from this fluoroarene by a SNAr reaction
with an appropriate cyanide salt.
Implementation of this concept is shown in Fig. 1. Electron-
deficient chlorobenzenes are cleanly and rapidly (10 min)
fluorinated using KF in polar aprotic solvents. Although many
electron-deficient arenes would suffice for this reaction, we selected
Department of Chemistry & Nebraska Center for Materials and
Nanoscience, University of Nebraska, Lincoln, NE, 68588-0304, USA.
E-mail: sdimagno1@unl.edu; Fax: 402 472-9402; Tel: 402 472-9895
Fig. 2 Rapid preparation of fluorinated heterocycles from KF.
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Here we have introduced the concept of fluoride relay for the
preparation of nucleophilic fluorinating agents, and demonstrated
its utility. Anhydrous fluoride salts may now be prepared on a
timescale congruent with the stringent demands of radiotracer
synthesis and 18F PET. Importantly, this technique should be
applicable for the preparation of diverse anhydrous fluoride
salts never before used in radiotracer synthesis. Consequently,
this process should expand dramatically the diversity of
readily synthesized [18F]-labeled fluorinated radiotracers and
radiopharmaceuticals.
Notes and references
{ Typical experimental procedures: 5-chloro-2,4,6-trifluoroisophthalonitrile
was synthesized by refluxing tetrachloroisophthalonitrile (1.43 g, 5 mmol)
with KF (1.16 g, 20 mmol) in 15 mL dry DMF for 10 min. The reaction
mixture was quenched with 60 mL 1 M HCl and the resulting gray
precipitate was collected, washed with deionized water (3 6 5 mL), and
dried to yield 0.92 g (85%) of product. For smaller scale reactions, the
precipitated fluoroaromatic is simply dissolved in ethyl acetate–hexane
(3 : 7) and passed through a plug of silica gel.
Generation of TBAF*: 5-chloro-2,4,6-trifluoroisophthalonitrile (21.6 mg,
0.1 mmol) in 0.1 mL DMSO was added to a DMSO solution of TBACN
(104 mg, 0.4 mmol, 0.4 mL). Anhydrous TBAF formed immediately upon
addition. This in situ generated anhydrous TBAF solution was used directly
for the fluorination reactions reported here.
5-Fluoro-1-methyl-4-nitroimidazole: this was synthesized by adding
TBAF* (65 mg, 0.25 mmol, in 0.3 mL DMSO) to a solution of
5-chloro-1-methyl-4-nitroimidazole (65 mg, 0.4 mmol) in 0.2 mL DMSO at
Fig. 3 19F NMR spectra of fluorination of methyl 2,6-dichloronicotinate
with TBAF* (top) and KF-Kryptofix 222 (bottom).
1
room temperature. H and 19F NMR spectra indicated that the reaction
was complete within 5 min (81% yield). An analytical sample of this water-
sensitive fluoroimidazole was obtained by performing the reaction in THF
(220 uC, 5 min reaction time). The THF solution was passed directly
through a short silica column to remove the salts, and the solvent was
evaporated. Characterization data: NMR (DMSO-d6): 1H: d 7.767 (1H, d,
1.52), 3.684 (3H, d, 0.61); 19F: d 2132.2; 13C (proton decoupled): d 144.68
(d, 286.65), 141.31, 129.92 (d, 4.72), 31.31. Low-resolution MS (m/z): exptl.
M + H = 146, calc. M = 145. Rf (silica gel TLC, ethyl acetate) = 0.38
(starting material, Rf = 0.32).
cation as an internal standard. For the first example in Fig. 2,
fluorination of the naphthyridine antibiotic precursor ethyl 1-(2,4-
difluorophenyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthy-
ridine-3-carboxylate,12 the product was also isolated to
confirm the NMR yield assignments.
Examples in Fig. 2 and 3 show that TBAF* generated in this
manner from KF does not cleave methyl or ethyl esters. This is an
important point, since the inherent basicity of fluoride ion often
leads to ester saponification if water is present. A comparison of
the crude 19F NMR spectra of the fluorination of methyl 2,6-
dichloronicotinate with TBAF* and KF-Kryptofix 222 (Fig. 3)
demonstrates the superiority of TBAF* in this regard.
The smooth fluorination of the commercially available com-
pound 5-chloro-1-methyl-4-nitroimidazole to form the previously
unknown, water-sensitive 5-fluoro-1-methyl-4-nitroimidazole
provides another example of the power of this technique. This
hitherto unreported compound offers access to a wide variety of
unusual 4-substituted-5-fluoroimidazoles in two steps (reduction/
diazotization).13
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Finally, while DMSO is a convenient solvent for SNAr
fluorinations, it should be noted this technique is readily
transferable to other polar aprotic solvents such as THF or
acetonitrile.{ Use of these more volatile reaction solvents is
warranted when an aqueous workup to remove DMSO is
undesirable.
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