Please do not adjust margins
ChemComm
Page 2 of 4
COMMUNICATION
Journal Name
followed by reduction. Fluorination produced 3-fluoro-4- rate of displacement of nitro was 1,100-3,100VielwarAgrteicrle Othnlainne
DOI: 10.1039/C6CC02362B
nitropyridine N-oxide (9) in 37% yield (C.1: 0.5 eq. TBAF, 25 C, bromo and that the order of reactivity was 2>4>>3 position .
DMSO, 5 min) and hydrogenation of 9 (3 mg of 10% Pd/C, 1 This difference may be due to the different nature of the
atm H2, MeOH, 25 C, 10 min) produced 3-fluoro-4- nucleophile and solvation effects and constitutes a research
aminopyridine (10) quantitatively.
question of its own.
The first option consists of fluorination of Boc-protected 3-
bromo-4-aminopyridine (1) followed by acid deprotection
(Scheme 1A). Unfortunately, treatment of
tetrabutylammonium fluoride (TBAF) did not produce the
desired product even after several hours at high temperature.
1
with
Scheme 2. Fluorination of: A. 3-bromopyridine and B. 3-
bromo-pyridine N-oxide.
After obtaining compound 9, this was then reduced using
standard hydrogenation conditions to generate the desired
final product, 3-fluoro-4-aminopyridine (10) quantitatively
(Sup. Fig. 6). To our knowledge, pyridine N-oxides have not
previously been used as precursors for radiofluorination and
with the success of non-radioactive fluorination, we decided to
test this approach for the production of [18F]3-fluoro-4-
aminopyridine.
We then considered fluorination of 3-bromo-4-nitropyridine
(3) followed by reduction of the nitro group (Scheme 1B).
Treatment of 3 with 0.5 equivalents of TBAF at room
temperature produced the para- substituted product 3-bromo-
4-fluoropyridine (6) in 71.1 ± 3.6% yield (relative to TBAF, n =
4) as determined by HPLC and NMR (Sup. Figs. 1A (HPLC) and
1B (NMR)). Under these conditions, less than 0.2% of 3-fluoro-
4-nitropyridine (5) was produced demonstrating a clear
preference for the substitution to occur at the para- or nitro-
position. Similar results were obtained with 3-iodo-4-
nitropyridine (4) (Sup. Fig. 2A and 2B). This type of reactivity is
expected from previously published data on nitro-substituted
pyridines2, 13 and consistent with the results from Abrahim et
al5 who tested fluorination of a pyridine containing a nitro
group in ortho and a bromo in meta and found exclusive
substitution at the nitro/ortho position.
Radiochemical synthesis of [18F]3-fluoro-4-aminopyridine was
conducted as shown in Scheme 3. The procedure was similar
to the non-radioactive synthesis described above except that
[18F]TBAF was prepared immediately before the reaction by
trapping [18F]fluoride in a strong anion exchange cartridge and
eluting it with TBA-HCO3. The reaction was carried out in
DMSO at room temperature. After 15 min, HPLC analysis of the
reaction crude showed an early peak that elutes with the
solvent front corresponding to unreacted [18F]TBAF and a main
peak corresponding to the desired product (Sup. Fig. 7). Under
the test conditions, the isolated decay-corrected yield for the
desired product was 10.4 ± 1.8% (n = 8). Upon further
characterization, we noticed that co-injection of the reaction
crude with a small amount of reference standard (9)
consistently gave higher yields (25 ± 4%, decay corrected, n =
8) (Fig. 1A). This led us to hypothesize that the non-radioactive
3-fluoro-4-nitropyridine N-oxide (9) could be contributing to
the radiolabeling yield by 19F/18F exchange. When we tested
labeling of 3-fluoro-4-nitropyridine N-oxide with [18F]TBAF in
the absence of the bromo precursor we obtained 33.1 ± 5.4%
(n = 4) decay-corrected isolated yield (Fig. 1B). Even more
remarkable is that this reaction reaches equilibrium within
seconds. Fluorine exchange in organic compounds has been
reported before15, however, to our knowledge this is the first
example of fluoride exchange of a C-F bond in a heterocyclic
compound.
Finally, we decided to try fluorination of 3-bromo-4-
nitropyridine N-oxide (8) hoping that the N-oxide would
further increase the reactivity of the pyridine resulting in
fluorination at the meta- position (Scheme 1C). In this case,
treatment of 8 with 0.5 equivalents TBAF at room temperature
produced the meta-fluorinated compound, 3-fluoro-4-
nitropyridine N-oxide (9), as the main product in 20.7 ± 2.7%
yield (relative to TBAF, n = 4) (Sup. Fig. 3A and 3B). Under
these conditions, we detected less than 2% fluorination at the
para position indicating that the presence of the N-oxide group
favors meta fluorination.
To peek into the potential use of pyridine N-oxides as
fluorination precursors, we compared the reactivity of 3-
bromopyridine (11) and 3-bromopyridine N-oxide (13) with
TBAF (Scheme 2). Not surprisingly, 3-bromopyridine did not
undergo reaction even after treatment with 1.2 eq. of TBAF for
12h at 120 C (Sup. Figs. 4A and 4B). In contrast, over 25%
conversion of 3-bromopyridine N-oxide (13) to 3-
fluoropyridine N-oxide (14) was detected after 30 min at 120 C
(Sup. Figs. 5A and 5B). This result indicates that even though
the nitro group in para position contributes to the enhanced
reactivity of the pyridine (likely by lowering its activation
energy) it is not sufficient to explain the reactivity and
regioselectivity of the N-oxide towards fluorination. This
regioselectivity is particularly surprising given early studies on
the nucleophilic displacement of monosubstituted pyridine N-
oxides by sodium ethoxide in ethanol which found that the
O
N
O
N
N
2. H2 (1 atm)
Pd/C
1. TBA-18
DMSO
25 ºC, 15 min
HPLC
F
18F
18F
MeOH
25 ºC, 15 min
HPLC
Br
NH2
NO2
NO2
18F]9
8
[
18F]10
[
Scheme 3. Radiochemical synthesis of 3-fluoro-4-amino-
pyridine.
After obtaining the labeled intermediate ([18F]9), this product
was hydrogenated using the same conditions as the non-
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins