Novel 2,4,5-trisubstituted pyridines as key intermediates for the preparation of the TSPO ligand 6-F-PBR28: Synthesis and full 1H and 13C NMR characterization

Article abstract of DOI:10.1002/jhet.1723

As part of our ongoing research for molecular structures binding to the translocator protein (TSPO 18 kDa), we investigated the preparation of a number of new 2,4,5-trisubstituted pyridines as novel building blocks. In particular, 5-amino-2-halo-4-phenoxypyridines (11, 12, 13) were designed as key intermediates for the synthesis of the recently developed TSPO ligand 6-F-PBR28 and its fluorine-18-labeled version for positron emission tomography, 6-[ ¹⁸F]F-PBR28. We hereby report the chemical preparation as well as the ¹H and ¹³C NMR spectroscopic data of polysubstituted pyridines 2, 3, 4, 5, 6, 7, 7b, 8, 9, 10, 11, 12, 13, 14. The latter demonstrates dramatic changes in electron density repartition of the aromatic ring upon substitution.

Full text of DOI:10.1002/jhet.1723

404
Novel 2,4,5-Trisubstituted Pyridines as Key Intermediates for the
Preparation of the TSPO Ligand 6-F-PBR28: Synthesis and
Vol 51
1
Full H and 13C NMR Characterization
*
Annelaure Damont, Frédéric Lemée, Guillaume Raggiri, and Frédéric Dollé
CEA, I²BM, Service Hospitalier Frédéric Joliot, Orsay, France
*
E-mail: annelaure.damont@cea.fr
Received February 9, 2012
DOI 10.1002/jhet.1723
Published online 18 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
As part of our ongoing research for molecular structures binding to the translocator protein (TSPO
18 kDa), we investigated the preparation of a number of new 2,4,5-trisubstituted pyridines as novel building
blocks. In particular, 5-amino-2-halo-4-phenoxypyridines (11–13) were designed as key intermediates for
the synthesis of the recently developed TSPO ligand 6-F-PBR28 and its fluorine-18-labeled version for
positron emission tomography, 6-[18F]F-PBR28. We hereby report the chemical preparation as well as the
1H and 13C NMR spectroscopic data of polysubstituted pyridines 2–14. The latter demonstrates dramatic
changes in electron density repartition of the aromatic ring upon substitution.
J. Hetercyclic Chem., 51, 404 (2014).
INTRODUCTION
(a few minutes) and often reported to proceed with high
yields (>70%), these reactions lead to a positioning of
the radioactive atom in the probe that is relatively stable
metabolically (C(sp2)-F bond), a considerable advantage
when compared with the traditionally dominating aliphatic
nucleophilic radiofluorination methodology (C(sp3)-F
bond formation) [6–8]. For these reasons, we have a long-
standing interest in molecules bearing a 2-fluoropyridine
moiety, and we have already reported several 2-[18F]
fluoropyridinyl-containing structures, for use either as radioli-
gands [9–16] or as reagents dedicated to the radiolabeling of
more complex structures such as oligonucleotides, peptides,
or proteins [17–20] by prosthetic conjugation approaches.
The development of such fluorine-18-labeled compounds
constructed around a pyridine core usually requires the prior
synthesis of their a-halo-, a-nitro-, or a-trimethylammonium-
counterparts as labeling precursors for aromatic nucleophilic
radiofluorination as well as the a-fluoro—fluorine-19
(stable)—derivative as standard reference. The present
For many years, our laboratory has been interested in the
preparation and use of positron-emitting radiolabeled probes
(or radiotracers) for in vivo imaging using the powerful
positron emission tomography tool [1]. In the positron
emission tomography community, there has recently been a
strong interest for the discovery of new radioligands targeting
the translocator protein (TSPO 18 kDa) [2,3], formerly
known as the peripheral benzodiazepine receptor (PBR), as
radiomarkers of neuroinflammation and potential useful
probes for early detection of neurodegenerative disorders
and, in particular, radioligands labeled with the short-lived
positron emitter fluorine-18 (half-life = 109.8 min). PBR-28
[4], a compound belonging to one of the most promising
TSPO radiotracer families, has attracted much of our atten-
tion because it features a pyridine motif that is of particular
interest when designing novel radiofluorinated probes.
Indeed, this small heterocycle opens up the option of a
fluorine-18 introduction at an a-position to the ring nitrogen
using the well-established nucleophilic ortho–heteroaromatic
radiofluorination methodology [5]. Besides being rapid
1
paper aims at detailing the synthesis as well as the H and
13C NMR signal assignments of some new 2,4,5-trisubstituted
pyridines that have been recently prepared in our laboratory
© 2013 HeteroCorporation

March 2014 Novel 2,4,5-Trisubstituted Pyridines as Key Intermediates for the Preparation of the TSPO
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Ligand 6-F-PBR28: Synthesis and Full H and 13C NMR Characterization
as scaffolds for the preparation of the recently developed
TSPO 18 kDa radioligand 6-[18F]F-PBR28 [16]. Most of them
are halogenated pyridines and might also be useful building
blocks for the design of more complex heteroaromatic
compounds by means of cross-coupling reactions for instance.
Throughout this paper, a, b, and g designate the positions
relative to the ring nitrogen.
generated with phenol and NaH in THF. Indeed, leaving
groups at 4-position relative to the pyridine ring nitrogen
are usually more reactive than those at 2-position [23]. The
general order of reactivity of each position of pyridine
halides, C4>C2>>C3, has been observed for many SNAr
displacements. In our particular case, 4-position is even more
reactive because the nitro group diminishes also inductively
the electron density at the vicinal C4 position. Thus, selective
displacement of 4-Cl with phenolate anion was successfully
achieved, and compound 4 was exclusively obtained (68%)
over its C2-regioisomer whose formation was not observed
(Scheme 1, route A). Nevertheless, formation of a non-
negligible amount of 2,4-diphenoxy-5-nitropyridine 5
(9%), whose polarity is very close to the one of the desired
molecule, prompted us to find an alternative way, more
adequate to the gram scale, of preparing compound 4.
A more efficient route for the preparation of 2-chloro-5-
nitro-4-phenoxypyridine (4) was then developed by carrying
out the displacement of the 4-chlorine with the phenolate
anion prior to the a-functionalization (2-hydroxy introduction)
of the pyridine ring, avoiding the formation of undesired 2,4-
diphenoxy-5-nitropyridine (5). Thus, treatment of 4-chloro-3-
nitropyridine (1) with phenol and NaH in THF at room
temperature gave quantitatively the 3-nitro-4-phenoxypyridine
(6), which was selectively hydroxylated at the C6 position with
tert-butyl hydroperoxide via vicarious nucleophilic substitution
of hydrogen in presence of t-BuOK as a base. Despite the low
RESULTS AND DISCUSSION
We started with the preparation of 2-chloro-5-nitro-4-
phenoxypyridine 4 (Scheme 1) as key intermediate. Two
synthetic routes were explored for the generation of this
compound. In the first route (route A), hydroxylation at
the C6 position of the commercially available 4-chloro-3-
nitropyridine (1) was performed prior to the displacement
of the 4-chlorine by the phenolate anion. Thus, selective
hydroxylation of 4-chloro-3-nitropyridine (1) at the position
para to the nitro group was performed in DMF using tert-
butyl hydroperoxide (t-BuOOH) in the presence of
potassium tert-butoxide (t-BuOK) as a base [21,22] to
afford 4-chloro-5-nitropyridin-2-ol (2) in 51% yield. This
intermediate was then treated with phosphorus oxychloride
in refluxing toluene to provide 2,4-dichloro-5-nitropyridine
(3) in good yield (72%). The 4-chlorine was then displaced,
with preference over the 2-chlorine, by the phenolate anion
Scheme 1. Synthetic approaches for the preparation of various 2,4,5-trisubstituted pyridines.
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nucleophilicity of t-BuOK and the low reaction temperature
(À50 to À30ꢀC), compound 7 was obtained in only moderate
yield (38–45%) because of side-products formation. In
particular, displacement of the very labile C4 phenoxy
group, because of activation by both the ring nitrogen
atom and the ortho nitro group, was concomitantly
observed resulting in the formation of undesired 5-nitro-
4-tert-butoxypyridin-2-ol (7b) (15%) that was easily
isolated from the crude because of its poor solubility in
dichloromethane. Hydroxypyridine 7 was then converted
to the corresponding 2-chloro-5-nitro-4-phenoxypyridine
(4) in 64% yield with POCl3 in refluxing toluene. 2-bromo-
5-nitro-4-phenoxy-pyridine (8) was exclusively prepared
following the second strategy (route B, Scheme 1) using
POBr3 as brominating agent in the third step (81% yield) of
the synthetic sequence.
The preparation of the 2-fluoro-counterpart (9) of com-
pounds 4 and 8 was first attempted from the chloro-analog
4 using the well-known potassium fluoride (KF) exchange
technique [24]. Thus, 2-chloro-5-nitro-4-phenoxypyridine
(4) was treated with KF in DMF at 90ꢀC, and the reaction
was monitored by TLC. Unfortunately, fluorination of
4 failed to provide any expected product, and all efforts
(temperature, solvent, or fluorine salt changes) to introduce
the fluorine atom by substituting the chlorine were
unsuccessful. Possibly, the phenoxy group was the first
displaced because of the predominant attractive effect of
the ortho–nitro substituent on 4-position [23]. Therefore, an
alternative strategy was considered to obtain compound 9.
We observed that the 2-hydroxy group of pyridinol 7 could
be successfully replaced with fluorine when reacted with
DAST (N,N-diethylaminosulfur trifluoride) in acetonitrile at
75ꢀC (44% yield). Direct fluorination of hydroxyl group on
an activated heteroaromatic ring using DAST or a similar
deoxo-fluorinating agent has not been reported in the
literature [16].
formation, commonly known as the Buchwald–Hartwig
amination reaction [26,27], was envisaged for the introduction
of a dimethylamino group regioselectively at the 2-position.
The reaction was carried out as described by Wagaw et al
[28] for the synthesis of aminopyridines. Substituted 2-
bromopyridine 8 was reacted with dimethylamine and
t-BuOK in the presence of palladium acetate and 1,3-bis
(diphenylphosphino)propane (dppp) in toluene at 75ꢀC to
afford 2-dimethylamino-4-phenoxy-5-nitropyridine (10) in
low to moderate yields (10–46%, method A). Chemical
yields were not reproducible following this procedure and
direct nucleophilic substitution was therefore examined:
compound 8 was reacted with dimethylamine under various
reaction conditions. In short, although mild SNAr conditions
(NHMe2, THF, or DMF, rt) afforded a mixture of C2/C4
isomers and disubstituted product in a nearly 1:1:1 ratio
(CCM analyses), acid-catalyzed conditions and elevated
reaction temperature (NHMe2.HCl, DMF, 120ꢀC, method B)
allowed regioselective and almost exclusive nucleophilic
substitution of the bromine atom that means without
concomitant/competitive displacement of the phenoxy group
at C4 (Scheme 1). Indeed, it is well established [29,30] that
nucleophilic attack on basic a-halo-heterocycles is most
often facilitated by acid-catalysis, presumably because it
proceeds via the N-protonated iminium ion. In our case, even
if the presence of an acid dramatically decreases the nucleo-
philicity of dimethylamine and that elevated temperature
(120ꢀC) was needed for completion of the reaction, the
acid-catalyzed process proceeded in high yield and strongly
favored the C2-isomer (10) formation.
Eventually, the preparation of 5-amino-2-chloro-4-
phenoxypyridine (11), 5-amino-2-bromo-4-phenoxypyridine
(12), 5-amino-2-fluoro-4-phenoxypyridine (13), and N2,
N2-dimethyl-4-phenoxypyridine-2,5-diamine (14) was
envisaged. Thus, reduction of nitropyridines 4, 8, 9, and 10
by means of iron dust in acetic acid at room temperature gave
aminopyridines 11, 12, 13, and 14, respectively, in good to
excellent yields (Scheme 1).
Introduction of a dimethylamino group at the 2-position
of the pyridine ring was envisaged via displacement of
the 2-bromine atom in compound 8. Considering that the
2-position and 4-position in pyridine 8 are both highly
activated [25] because of the presence of the ring nitrogen
(a and g activation) and the nitro group (ortho and para
activation) with a higher inductive effect at the 4-position
(Scheme 2), a palladium-catalyzed carbon–nitrogen bond
1H NMR spectra of pyridines 1–14 were recorded, and
the data obtained for these disubstituted and trisubstituted
pyridines is gathered in Table 1.
Assuming that there is no substantial shift difference
between NMR experiments measured in CDCl3 and in
CD2Cl2, the following observations can be made. Hydrogen
Scheme 2. Possible regioisomers formed with reaction of dimethylamine on bromopyridine 8.
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Ligand 6-F-PBR28: Synthesis and Full H and 13C NMR Characterization
Table 1
1H NMR chemical shift assignments of pyridines (1–14).
Structure
Chemical shifts (d, ppm)b
Compounda
R2
R4
R5
H-6
H-3
H-2
Others
—
1 [a]
2 [b]
3 [a]
4 [a]
5 [a]
H
Cl
Cl
Cl
OPh
OPh
NO2
NO2
NO2
NO2
NO2
9.06 (s)
8.72 (s)
8.96 (s)
8.95 (s)
8.83 (s)
7.53 (d)c
6.69 (s)
7.59 (s)
6.75 (s)
6.27 (s)
8.63 (d)c
OH
Cl
Cl
—
—
—
—
12.90 (bs, OH)
—
7.53 (t, 2H)f, 7.39 (t, 1H)f, 7.16 (d, 2H)f
7.50 (t, 2H)f, 7.41 (t, 2H)f, 7.35 (t, 1H)f, 7.25 (t, 1H)f,
7.22 (d, 2H)f, 7.10 (d, 2H)f
OPh
6 [a]
7 [b]
7b [b]
8 [a]
9 [g]
10 [a]
11 [g]
12 [a]
13 [g]
14 [g]
H
OPh
OPh
OtBu
OPh
OPh
OPh
OPh
OPh
OPh
OPh
NO2
NO2
NO2
NO2
NO2
NO2
NH2
NH2
NH2
NH2
9.12 (s)
8.70 (s)
8.66 (s)
8.90 (s)
8.86 (s)
8.99 (s)
7.86 (s)
7.87 (s)
7.62 (s)
7.77 (s)
6.77 (d)d
5.27 (s)
7.59 (s)
6.90 (s)
6.33 (s)
5.65 (s)
6.52 (s)
6.64 (s)
6.13 (d)e
5.95 (s)
8.53 (d)d
—
7.49 (t, 2H)f, 7.34 (t, 1H)f, 7.15 (d, 2H)f
OH
OH
Br
12.50 (bs, OH), 7.52 (t, 2H)f, 7.35 (t, 1H)f, 7.25 (d, 2H)f
12.20 (bs, OH), 1.28 (s, 9H)
—
—
—
—
—
—
—
—
7.52 (t, 2H)f, 7.39 (t, 1H)f, 7.15 (d, 2H)f
7.50 (t, 2H)f, 7.40 (t, 1H)f, 7.19 (d, 2H)f
7.45 (t, 2H)f, 7.27 (t, 1H)f, 7.13 (d, 2H)f, 3.05 (s, 6H)
7.45 (t, 2H)f, 7.28 (t, 1H)f, 7.11 (d, 2H)f
7.44 (t, 2H)f, 7.27 (t, 1H)f, 7.09 (d, 2H)f
7.46 (t, 2H)f, 7.29 (t, 1H)f, 7.13 (d, 2H)f
7.39 (t, 2H)f, 7.17 (t, 1H)f, 7.07 (d, 2H)f, 2.86 (s, 6H)
F
NMe2
Cl
Br
F
NMe2
aDeuterated solvent used: [a] CDCl3, [b] DMSO-d6, [g] CD2Cl2.
bSignal multiplicity in parentheses.
c(3JH2–H3 = 5.2 Hz).
d(3JH2–H3 = 6.0 Hz).
e(3JH–F = 1.6 Hz).
f(3JH–H = 8.0 Hz).
atoms at the 6-position are systematically the most
deshielded with H NMR signals ranging from 7.62 to
In most cases, C-2 and C-4 positions in pyridines are the
most deshielded (quaternary phenoxy carbon signal excluded).
C-4 resonances occur in a low field window ranging from
162.3 to 137.6 ppm and the C-2 chemical shifts average
155 ppm with the exception of compound 12 whose C-2 is
significantly more shielded with a signal at 129.6 ppm. C-3
signals appear invariably at the lowest frequencies with
chemical shifts below 130.9 ppm. The carbon atom C-5
bearing the nitro group is consistently observed as a character-
istic low-intensity broad signal around 135–130 ppm.
Replacement of the electron withdrawing nitro group with
the amino substituent, which is p-electron releasing in the
ortho and para positions, at C-5 of the pyridine mainly
influences the C-6 chemical shift with a shielding effect
(showing behavior similar to that found for H-6) and, to a
lesser extent, generates a C-4 signal upfield displacement.
Although modifications at position 2 have almost no influence
on the C-4 resonance signal, great chemical shift variability is
observed for C-2 and C-3 peaks. It is worth noting that,
for pyridines bearing a phenoxy at position 4, the more the
C-2 signal is shielded, the higher the C-3 signal frequency is.
1
9.12ppm, because of the vicinal influence of the heterocyclic
nitrogen. As expected, the 5-nitro substitution in pyridines
leads to H-6 signals much less shielded than those of the
corresponding 5-amino pyridines (shift downfield of
1
1.14 Æ 0.09 ppm). H NMR signals of hydrogen atoms at
the 3-position are detected with great resonance variability.
A small shift towards higher fields, of 0.20 to 0.26ppm, is
observed for H-3 signals when the 5-nitro substituent is
replaced by a 5-amino group for 2-halo-4-phenoxypyridines
(compare 4, 8, and 9 to 11, 12, and 13, respectively). The
opposite effect was observed in the case of 2-dimethylamino-
4-phenoxypyridines 10 and 14.
Chemical shift values of the ring carbons belonging to
synthesized disubstituted and trisubstituted pyridines are
listed in Table 2. The NMR signals were assigned
unambiguously by sequential analysis of 1D (normal 13C
and DEPT135 sequences) and 2D (heteronuclear single
quantum correlation HSQC and heteronuclear multiple-bond
correlation HMBC) experiments.
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Table 2
13C NMR chemical shift assignments of pyridines (1–14).
Structure
Chemical shifts (d, ppm)
Compounda
R2
R4
R5
C-2
C-3
C-4
C-5
C-6
Others
1 [a]
2 [b]
3 [a]
4 [a]
5 [a]
H
OH
Cl
Cl
OPh
Cl
Cl
Cl
OPh
OPh
NO2 146.3
NO2 160.5
NO2 155.3
NO2 156.4
NO2 167.3
126.5
119.9
126.6
111.8
97.8
137.6
138.6
139.4
159.5
161.3
144.4 153.0
129.5 140.7
143.2 146.6
135.9 147.4
133.1 147.3
—
—
—
152.2 (C), 130.8 (2CH), 127.2 (CH), 120.8 (2CH)
152.8 (C), 152.5 (C), 130.6 (2CH), 129.7 (2CH), 126.7
(CH), 125.8 (CH), 121.3 (2CH), 121.0 (2CH)
152.6 (C), 130.6 (2CH), 126.7 (CH), 120.8 (2CH)
153.1 (C), 131.0 (2CH), 126.7 (CH), 121.2 (2CH)
80.9 (C), 28.1 (3CH3)
152.2 (C), 131.8 (2CH), 127.2 (CH), 120.8 (2CH)
153.8 (C), 130.8 (2CH), 127.1 (CH), 120.8 (2CH)
152.3 (C), 130.1 (2CH), 125.7 (CH), 120.5 (2CH), 38.1
(2CH3)
6 [a]
7 [b]
7b [b]
8 [a]
9 [g]
H
OPh
OPh
NO2 154.5
NO2 163.0
111.8
100.7
130.9
115.6
97.0c
91.1
158.1
160.7
148.3
158.9
136.8 147.4
125.8 141.3
138.7 137.1
136.3 147.4
OH
OH
Br
OtBu NO2 166.6
OPh
OPh
OPh
NO2 147.0
NO2 165.9b
NO2 161.8
F
162.3d 135.3 146.7e
10 [a]
NMe2
160.1
127.8 149.4
11 [g]
12 [a]
13 [g]
14 [g]
Cl
Br
F
OPh
OPh
OPh
OPh
NH2 140.0
NH2 129.6
NH2 157.2f
NH2 155.5
110.0
113.6
153.3
153.0
133.5 135.7
133.6 136.6
153.8 (C), 130.2 (2CH), 125.5 (CH), 120.3 (2CH)
153.7 (C), 130.3 (2CH), 125.6 (CH), 120.3 (2CH)
153.8 (C), 130.2 (2CH), 125.6 (CH), 120.4 (2CH)
155.2 (C), 129.8 (2CH), 124.0 (CH), 119.0 (2CH), 38.4
(2CH3)
95.4g 155.4h 132.0 132.1i
NMe2
94.7
153.7
125.4 136.2
aDeuterated solvent used: [a] CDCl3, [b] DMSO-d6, [g] CD2Cl2.
b(d, JC2-F = 243 Hz).
c(d, JC3-F = 43 Hz).
d(d, JC4-F = 13 Hz).
e(d, JC6-F = 20 Hz).
f(d, JC2-F = 240 Hz).
g(d, JC3-F = 46 Hz).
h(d, JC4-F = 10 Hz).
i(d, JC6-F = 18 Hz).
CONCLUSION
interesting building blocks for the preparation of a broad
range of chemicals. The experimental 1H and 13C chemical
shifts of pyridines 1–14 collected and reported herein
constitute a valuable database for, as an example, testing
the accuracy of different NMR chemical shift calculation
programs by comparison of the predicted and experimental
values [31].
A series of disubstituted and trisubstituted pyridines has
been synthesized (2–14) and fully characterized by 1H and
13C NMR experiments. It was shown that when dimethyla-
mine is used as nucleophile on 2,4-disubstituted-5-nitro-
pyridines, it is possible to regioselectively favor the C-2
substitution over the C-4 displacement even if the latter
carbon is the most activated position. The observed
changes in the chemical shifts upon substitution are rather
significant and might be interpreted in terms of inductive
and mesomeric effects. The electron-density distribution
in these pyridine systems can also give some insight in
the reactivity of the different substituted carbons toward
nucleophilic displacements. The halo-pyridines synthesized
may offer cross-coupling reaction opportunities, whereas
the 5-amino substituent provide the possibility to design
more complex structures via, for example, reductive
amination or peptide bond formation and thus constitute
EXPERIMENTAL
Chemicals were purchased from Aldrich France and were used
without further purification, unless otherwise stated. Flash
chromatographies were conducted on silica gel or alumina gel
(0.63–0.200 mm, VWR) columns. TLCs were run on precoated
plates of silica gel 60F254 (VWR). The compounds were localized
at 254 nm using a UV lamp and/or by dipping the TLC plates in a
1% ethanolic ninhydrin solution, a basic KMnO4 aqueous solution
or a 1% MeOH/H2O (1/1, v:v) FeCl3 solution and heating on a
1
hot plate. H and 13C NMR spectra were recorded on a Bruker
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Ligand 6-F-PBR28: Synthesis and Full H and 13C NMR Characterization
(Wissembourg, France) Avance 400MHz apparatus, and chemical
shifts were referenced to the hydrogenated residue of the deuterated
solvent (d[CDHCl2] = 5.32 ppm and d[CHCl3] = 7.23ppm) for H
solution of K2CO3 and extracted twice with EtOAc. The combined
organic layers were successively washed with water and brine, dried
over Na2SO4, and evaporated to dryness. The resulting brownish
residue was purified by silica gel column chromatography (heptane/
EtOAc 9/1) to afford expected compound 4 (371 mg, 64%) as white
crystals.
1
NMR and to the deuterated solvent (d[CD2Cl2] = 53.5 ppm and
d[CDCl3] = 77.0ppm) for 13C NMR experiments. The standard
concentration of the analyzed samples was 20mg/mL. The
chemical shifts are reported in ppm, downfield from TMS (s, d, t,
and b for singlet, doublet, triplet, and broad, respectively). Complete
1H and 13C NMR spectra assignments for compounds 1–14 are
summarized in Tables 1 and 2, respectively. The high resolution
mass spectrometry (HRMS) analyses were performed by Imagif
(ICSN-CNRS, Gif-sur-Yvette) by electrospray with positive (ESI
+) or negative (ESI-) ionization mode.
3-Nitro-4-phenoxypyridine (6).
Starting from commercial
4-chloro-3-nitropyridine (1) (5.0 g, 31.6mmol), the synthesis was
performed in the same manner as described for the preparation of
4 (method A). Compound 6 was obtained quantitatively (6.8g,
100%) as a white solid and was pure enough to be used in the
next step without further purification. Rf 0.22 (heptane/EtOAc 2/1);
HR-ESI(+)-MS m/z Calcd for C11H8N2O3: 217.0613 [M + H]+,
found 217.0608.
5-Nitro-4-phenoxypyridin-2-ol (7). Starting from 3-nitro-4-
phenoxypyridine (6) (6.8 g, 31.5mmol), the synthesis was
performed in the same manner as for the preparation of compound
2. Compound 7 (3.28 g, 45%) was isolated as a beige powder and
trituration of the evaporated filtrate with CH2Cl2 afforded an
insoluble beige solid that was isolated and identified as 5-nitro-4-
tert-butoxypyridin-2-ol (7b) (217mg, 15%). Compound 7: Rf 0.18
(CH2Cl2/acetone 8/2); HR-ESI(À)-MS m/z Calcd for C11H8N2O4:
231.0406 [MÀ H]À, found 231.0414. Compound 7b: Rf 0.07
(CH2Cl2/acetone 8/2); HR-ESI(+)-MS m/z Calcd for C9H12N2O4:
213.0875 [M+ H]+, found 213.0865.
4-Chloro-5-nitropyridin-2-ol (2). A cold solution (0–5ꢀC)
of commercial 4-chloro-3-nitropyridine (1) (2 g, 12.6 mmol) and
t-BuOOH (2.53 mL, 6 M solution in decane, 15.2mmol) in DMF
(10 mL) was added slowly via cannula to a solution of t-BuOK
(37.8 mmol) in DMF (10 mL) at À35ꢀC. The reaction mixture
was stirred for 2 h at À35ꢀC and diluted with a saturated aqueous
solution of NH4Cl (50mL). Stirring was prolonged for 30min at
room temperature, and the solution basified to pH 8–9 with a
saturated aqueous solution of K2CO3 and washed with Et2O. The
aqueous layer was acidified to pH 1 and extracted twice with
Et2O. The combined organic layers were evaporated to dryness,
and the residue triturated in MeOH. The precipitate was filtered
to afford pure compound 2 (1.12g, 51%) as yellow crystals.
Rf 0.14 (CH2Cl2/acetone 9/1); HR-ESI(À)-MS m/z Calcd for
C5H3ClN2O3: 172.9754 [MÀ H]À, found 172.9751.
2-Bromo-5-nitro-4-phenoxypyridine (8).
Phosphorous
oxybromide (6.10 g, 16.0 mmol) was added to a suspension of
5-nitro-4-phenoxypyridin-2-ol 7 (1.24 g, 5.34 mmol) in toluene
(60 mL), and the heterogeneous mixture was refluxed for 2 h.
The reaction was cooled to 0ꢀC and carefully diluted with a
saturated aqueous solution of K2CO3 and extracted twice with
EtOAc. The combined organic layers were successively washed
with water and brine, dried over Na2SO4, and evaporated to
dryness. The resulting brownish residue was purified by silica
gel column chromatography (heptane/EtOAc 9/1) to afford
expected compound 8 (1.28 g, 81%) as white crystals. Rf 0.73
(CH2Cl2/acetone 9/1); HR-ESI(+)-MS m/z Calcd for
C11H7BrN2O3: 294.9718 [M + H]+, found 294.9717.
2-Fluoro-5-nitro-4-phenoxypyridine (9). To a solution of
5-nitro-4-phenoxypyridin-2-ol (7) (680 mg, 2.93mmol) in
acetonitrile (25mL) was added dropwise a 1 M solution of
(diethylamino)sulfur trifluoride (DAST, 1.55mL, 11.7mmol) in
CH2Cl2. The resulting mixture was stirred for 6 h at 75ꢀC and was
then diluted with water and extracted twice with EtOAc. The
organic layers were combined and washed with brine, dried over
Na2SO4, filtered, and evaporated to dryness. The crude was
purified by silica gel column chromatography (petroleum ether/
EtOAc 9/1) to give expected compound 9 (300 mg, 44%) as a
light-yellow syrup and recovered starting material (230mg). Rf
0.62 (petroleum ether/Et2O 2/1); HR-ESI(+)-MS m/z Calcd for
C11H7FN2O3: 235.0519 [M+ H]+, found 235.0522.
2,4-Dichloro-5-nitropyridine (3). Phosphorous oxychloride
(2.61 mL, 28.4 mmol) was added to a suspension of 4-chloro-5-
nitropyridin-2-ol (2) (1.65 g, 9.5 mmol) in toluene (50mL), and
the heterogeneous mixture was refluxed for 6 h. The reaction was
cooled to 0ꢀC, and a saturated aqueous solution of K2CO3 was
carefully added. The resulting mixture was extracted twice with
ethyl acetate. The combined organic layers were successively
washed with water and brine, dried over Na2SO4 and evaporated
to dryness. The resulting syrup was purified by silica gel column
chromatography (heptane/EtOAc 16/1) to afford expected
compound 3 (1.32 g, 72%) as light-yellow crystals. Rf 0.81
(CH2Cl2/acetone 9/1); ESI(+)-MS (m/z): not detected.
2-Chloro-5-nitro-4-phenoxypyridine (4).
Method A (from 2,4-dichloro-5-nitropyridine (3)).
To a
solution of 2,4-dichloro-5-nitropyridine (3) (0.89 g, 4.62 mmol) and
NaH (133 mg, 5.54 mmol) in THF (30 mL) was added dropwise a
solution of phenol (454 mg, 5.54 mmol) in THF (10 mL). The
reaction mixture was stirred overnight at room temperature, diluted
with EtOAc, and washed successively with a saturated aqueous
solution of K2CO3 (twice), water, and brine. The organic layer was
dried over Na2SO4, evaporated to dryness, and the resulting
residue purified by silica gel column chromatography (CH2Cl2
100%) to afford undesired 2,4-diphenoxy-5-nitropyridine (5)
(128 mg, 9%) and desired compound 4 (786 mg, 68%) as white
crystalline solids. Compound 4: Rf 0.59 (heptane/EtOAc 2/1); HR-
ESI(+)-MS m/z Calcd for C11H7ClN2O3: 251.0223 [M + H]+,
found 251.0216. Compound 5: Rf 0.62 (heptane/EtOAc 2/1); HR-
ESI(+)-MS m/z Calcd for C17H12N2O4: 309.0875 [M + H]+, found
309.0877.
N,N-Dimethyl-5-nitro-4-phenoxypyridin-2-amine (10).
Method A (Buchwald–Hartwig amination). A mixture of
2-bromo-5-nitro-4-phenoxypyridine (8) (500 mg, 1.69mmol), Pd
(OAc)2 (38mg, 0.17 mmol), 1,3-bis(diphenylphosphino)propane
(140 mg, 0.34 mmol), dimethylamine (1.02mL, 2.03mmol, 2 M
solution in THF), t-BuOK (266 mg, 2.37 mmol), and toluene
(10 mL) was stirred and heated to 70ꢀC until complete
disappearance of compound 8. The mixture was then poured into
water and extracted twice with EtOAc. The combined organic
layers were successively washed with a saturated aqueous solution
of K2CO3, a 1 M aqueous HCl solution, and brine before being
Method B (from 5-nitro-4-phenoxypyridin-2-ol (7)). Phosphorous
oxychloride (1.07 g, 6.96 mmol) was added to a suspension of 5-nitro-
4-phenoxypyridin-2-ol (7) (538 mg, 2.32 mmol) in toluene (10 mL),
and the heterogeneous mixture was refluxed for 2 h. The reaction
was cooled to 0ꢀC and carefully diluted with a saturated aqueous
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

410
A. Damont, F. Lemée, G. Raggiri, and F. Dollé
Vol 51
[2] Dollé, F.; Luus, C.; Reynolds, A.; Kassiou, M. Curr Med
Chem 2009, 16, 2899.
[3] Roeda, D.; Kuhnast, B; Damont, A; Dollé, F. J Fluorine Chem
2012, 134, 107.
[4] Briard, E.; Zoghbi, S. S.; Imaizumi, M.; Gourley, J. P.; Hong, J.;
Cropley, V.; Fujita, M.; Innis, R. B.; Pike, V. W. J Med Chem 2008, 51, 17.
[5] Dollé, F. Curr Pharm Des 2005, 11, 3221.
dried over Na2SO4, filtered and evaporated to dryness. The dark
residue was purified by silica gel column chromatography
(Petroleum ether/EtOAc 9/1) to afford compound 10 (200 mg,
46%) as yellow needles. Rf 0.26 (petroleum ether/Et2O 7/3);
HR-ESI(+)-MS m/z Calcd for C13H13N3O3: 260.1035 [M + H]+,
found 260.1030.
Method B (amination via acid-catalyzed/elevated temperature
conditions). To a solution of 2-bromo-5-nitro-4-phenoxypyridine
(8) (2.15 g, 7.29mmol) in DMF (40mL) was added NHMe2.HCl
(713mg, 8.75 mmol) in one portion, and the reaction mixture was
stirred at 120ꢀC for 16h. The mixture was partitioned between
EtOAc and water, the organic layer was collected and washed
with brine before being dried over Na2SO4, filtered, and
evaporated to dryness. The crude product was purified by silica
gel column chromatography (heptane/EtOAc 7/3) to afford
desired compound 10 (1.55 g, 82%) as yellow needles.
[6] Lasne, M.-C.; Perrio, C.; Rouden, J.; Barré, L.; Roeda, D.;
Dollé, F.; Crouzel, C. Eds.; Springer-Verlag: Berlin Heidelberg, 2002;
Vol 222, pp 201–258.
[7] Dollé, D.; Roeda, D.; Kuhnast, B.; Lasne, M-C. In Fluorine
and Health: Molecular Imaging, Biomedical Materials and Pharmaceuti-
cals; Tressaud, A.; Haufe, G., In Topics in current chemistry; Krause
W., Ed.; Elsevier: Amsterdam-Boston-Heidelberg-London-New York-
Oxford-Paris-San Diego-San Francisco-Singapore-Sydney-Tokyo, 2008,
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[8] Banister, S.; Roeda, D.; Dollé, F.; Kassiou, M. Curr Radiopharm
2010, 3, 68.
[9] Dollé, F.; Valette, H.; Bottlaender, M.; Hinnen, F.; Vaufrey, F.;
Guenther, I.; Crouzel, C. J Labelled Compd Radiopharm 1998, 41, 451.
[10] Dollé, F.; Dolci, L.; Valette, H.; Hinnen, F.; Vaufrey, F.;
Guenther, I.; Fuseau, C.; Coulon, C.; Bottlaender, M.; Crouzel, C. J
Med Chem 1999, 42, 2251.
[11] Dolci, L.; Dollé, F.; Valette, H.; Vaufrey, F.; Fuseau, C.; Bot-
tlaender, M.; Crouzel, C. Bioorg Med Chem 1999, 7, 467.
[12] Roger, G.; Lagnel, B.; Rouden, J.; Besret, L.; Valette, H.;
Demphel, S.; Gopisetti, J.; Coulon, C.; Ottaviani, M.; Wrenn, L.A.; Letchworth,
S.R.; Bohme, G.A.; Benavides, J.; Lasne, M.-C.; Bottlaender, M.; Dollé,
F. Bioorg Med Chem 2003, 11, 5333.
2-Chloro-4-phenoxypyridin-5-amine (11).
A mixture of
2-chloro-5-nitro-4-phenoxypyridine (4) (200 mg, 0.80mmol) and
powdered Fe (270 mg, 2.40mmol) in acetic acid (4mL) was
stirred for 30 min at 90ꢀC. The resulting mixture was diluted with
water and extracted twice with EtOAc. The combined organic
layers were dried over Na2SO4, filtered, and evaporated to
dryness. The resulting syrup was purified by silica gel column
chromatography (heptane/EtOAc 3/1) to afford desired compound
11 (170 mg, 96%) as a light-yellow oil. Rf 0.20 (petroleum ether/
Et2O 2/1); HR-ESI(+)-MS m/z Calcd for C11H9ClN2O: 221.0482
[M+ H]+, found 221.0482.
[13] Karramkam, M.; Hinnen, F.; Berrehouma, M.; Hlavacek, C.;
Vaufrey, F.; Halldin, C.; McCarron, J.A.; Pike, V.W.; Dollé, F. Bioorg
Med Chem 2003, 11, 2769.
2-Bromo-4-phenoxypyridin-5-amine (12).
Starting from
2-bromo-5-nitro-4-phenoxypyridine (8) (240 mg, 0.81 mmol),
the synthesis was performed in the same manner as for the
preparation of compound 11. Compound 12 (210 mg, 98%) was
isolated after silica gel column chromatography (heptane/EtOAc
3/1) as a light-yellow syrup. Rf 0.19 (petroleum ether/Et2O 7/3);
HR-ESI(+)-MS m/z Calcd for C11H9BrN2O: 264.9976 [M + H]+,
found 264.9979.
2-Fluoro-4-phenoxypyridin-5-amine (13). Starting from 2-
fluoro-5-nitro-4-phenoxypyridine (9) (300 mg, 1.28mmol), the
synthesis was performed in the same manner as for the
preparation of compound 11. Compound 13 (185 mg, 71%) was
isolated after silica gel column chromatography (heptane/EtOAc
3/1) as a light-yellow oil. Rf 0.24 (petroleum ether/Et2O 2/1); HR-
ESI(+)-MS m/z Calcd for C11H9FN2O: 205.0777 [M+ H]+, found
205.0788.
[14] Roger, G.; Hinnen, F.; Valette, H.; Saba, W.; Bottlaender, M.;
Dollé, F. J Labelled Compd Radiopharm 2006, 49, 489.
[15] Roger, G.; Saba, W.; Valette, H.; Hinnen, F.; Coulon, C.;
Ottaviani, M.; Bottlaender, M.; Dollé, F. Bioorg Med Chem 2006, 14,
3848.
[16] Damont, A.; Boisgard, R.; Kuhnast, B.; Lemée, F.; Raggiri,
G.; Scarf, A.M.; Da Pozzo, E.; Selleri, S.; Martini, C.; Tavitian, B.;
Kassiou, M.; Dollé, F. Bioorg Med Chem Lett 2011, 21, 4819.
[17] Kuhnast, B.; de Bruin, B.; Hinnen, F.; Tavitian, B.; Dollé, F.
Bioconjugate Chem 2004, 15, 617.
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Amessou, M.; Johannes, L.; Samson, A.; Boisgard, R.; Tavitian, B.;
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N2,N2-Dimethyl-4-phenoxypyridine-2,5-diamine (14).
Starting from N,N-dimethyl-5-nitro-4-phenoxypyridin-2-amine
(10) (200 mg, 0.77 mmol), the synthesis was performed in the
same manner as for the preparation of compound 11.
Compound 14 (130 mg, 74%) was isolated after silica gel
column chromatography (Petroleum ether/EtOAc 1/1) as pink
crystals. Rf 0.30 (toluene/acetone 1/1); HR-ESI(+)-MS m/z
Calcd for C13H15N3O: 230.1293 [M + H]+, found 230.1295.
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Acknowledgment. The authors also wish to thank Dr Dirk
Roeda for proof reading the manuscript and suggesting
linguistic corrections. This work was supported in part by the
EC-FP6-project DiMI (LSHB-CT-2005-512146).
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet