Synthetic utility of 4-bromo-2,3,5,6-tetrafluoropyridine

Article abstract of DOI:10.1016/j.jfluchem.2008.01.004

The regiochemistry of nucleophilic substitution of 4-bromo-2,3,5,6-tetrafluoropyridine has been investigated. Efficient, regioselective reactions occur with alkylamine, benzylamine and alkoxide nucleophiles, yielding products where substitution occurs ortho to the ring nitrogen. The resulting 2-substituted-4-bromo-3,5,6-trifluoropyridines can be functionalised further, either by a second regioselective nucleophilic displacement or palladium catalysed elaboration at the 4-position. Reactions with aromatic N-nucleophiles yield mixtures of ortho- and para-substituted products.

Full text of DOI:10.1016/j.jfluchem.2008.01.004

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Journal of Fluorine Chemistry 129 (2008) 447–454
www.elsevier.com/locate/fluor
Short communication
Synthetic utility of 4-bromo-2,3,5,6-tetrafluoropyridine
a
a
a
John A. Christopher a, , Laura Brophy , Sean M. Lynn , David D. Miller ,
*
Lisa A. Sloan a, Graham Sandford b
a GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
b Department of Chemistry, University of Durham, South Road, Durham DH1 3LE, UK
Received 4 December 2007; received in revised form 2 January 2008; accepted 10 January 2008
Available online 19 January 2008
Abstract
The regiochemistry of nucleophilic substitution of 4-bromo-2,3,5,6-tetrafluoropyridine has been investigated. Efficient, regioselective reactions
occur with alkylamine, benzylamine and alkoxide nucleophiles, yielding products where substitution occurs ortho to the ring nitrogen. The
resulting 2-substituted-4-bromo-3,5,6-trifluoropyridines can be functionalised further, either by a second regioselective nucleophilic displacement
or palladium catalysed elaboration at the 4-position. Reactions with aromatic N-nucleophiles yield mixtures of ortho- and para-substituted
products.
# 2008 Elsevier B.V. All rights reserved.
Keywords: Heterocyclic; Scaffold; Perfluoroheterocycle; 4-Bromo-2,3,5,6-tetrafluoropyridine; Suzuki reaction; Nucleophilic aromatic substitution
1. Introduction
interested in developing the chemistry of 4-bromo-tetrafluor-
opyridine 1, a building block which could complement the
synthetic versatility of pentafluoropyridine. In principle, the
presence of a bromine atom attached to the pyridine ring would
allow further synthetic possibilities such as, for example, a
variety of palladium catalysed processes, in addition to
nucleophilic aromatic substitution reactions of either the
fluorine or bromine atoms.
The use of perfluorinated heteroaromatic molecules as
synthetically versatile building blocks for the creation of new
molecular scaffolds for drug discovery is a growing area of
research, stimulated by the enhanced reactivity to nucleophiles
that results from their electron-deficient nature [1,2]. For
example, the use of pentafluoropyridine in the synthesis of
pentasubstituted pyridine derivatives [3], tetrahydropyrido[3,4-
b]pyrazines [4], imidazopyridines and pyrimidinopyridines [5],
and in the creation of polyfunctional tetrahydropyrido[2,3-
b]pyrazines from a range of tetrafluoropyridine derivatives
[6,7] has recently been published, demonstrating some of the
possibilities that exist for creating multi-functional heterocyclic
scaffolds from such a readily available and simple fluorinated
heteroaromatic substrate.
To our surprise, little precedent for reactions involving 1 has
been reported, although nucleophilic substitution reactions with
diethylamine [7] and methoxide [8] have been published.
In this paper, we describe our initial investigations which
demonstrate regiocontrolled nucleophilic substitution of 1 with
a wide range of nucleophiles and highlight how the resulting
products can be elaborated further via a second sequential
nucleophilic displacement step or a palladium catalysed
Suzuki–Miyuara coupling process.
Whilst pentafluoropyridine has been used very successfully
as a core scaffold for the synthesis of various drug-like systems,
its reactivity largely involves nucleophilic aromatic substitution
processes. In order to further extend the range of scaffolds for
drug discovery that could be accessed from highly fluorinated
pyridine derivatives by our general strategy, we became
2. Results and discussion
Our initial investigations centred on the use of alkylamines
and benzylamines as nucleophiles. Reactions of several 4-
substituted 2,3,5,6-tetrafluoropyridines, including 1, with
diethylamine as a model nucleophile have shown a preference
for nucleophilic attack at the position ortho to the ring nitrogen
* Corresponding author. Tel.: +44 1438 763578; fax: +44 1438 768232.
E-mail address: John.A.Christopher@gsk.com (J.A. Christopher).
0022-1139/$ – see front matter # 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.01.004

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J.A. Christopher et al. / Journal of Fluorine Chemistry 129 (2008) 447–454
Table 1
Reaction of 1 with amine nucleophiles
Nucleophlie
Conditions
Product (yield %)
100 8C, 3 h
100 8C, 3 h
100 8C, 3 h
100 8C, 3 h
100 8C, 1 h
100 8C, 4 h
[7] and we sought to understand the generality of this
regioselectivity with a wider range of nucleophiles. Typically,
a slight excess of nucleophile was reacted with 1 in the presence
of diisopropylethylamine in THF at elevated temperature in a
microwave reactor, Table 1, until analysis of the crude reaction
mixtures by 19F NMR indicated substantial conversion to
products.
Universally, substitution was observed only at the position
ortho to the ring nitrogen, as assessed by 19F NMR of the crude
Fig. 1. HMBC and nOe confirmation of regiochemistry of products 2 and 6.

J.A. Christopher et al. / Journal of Fluorine Chemistry 129 (2008) 447–454
449
Table 2
Reaction of 1 with nucleophiles
Nucleophlie
Conditions
Product (yield %)
DIPEA, DMSO, microwave 160 8C, 3 h
DIPEA, DMSO, microwave 160 8C, 1 h
Et3N, MeCN, rt, 2 days
EtONa
PhONa
PhSH
DIPEA, THF, rt, 2 h
DIPEA, THF, 0 8C–rt, 7 h
K2CO3, THF, rt, 12 h
reaction mixtures and of isolated compounds 2–7 which
showed three inequivalent fluorine resonances. The regiochem-
istry of 2–7 was assigned by reference to previous discussions
[4,7] and by extensive heteronuclear multiple bond correlation
(HMBC) and heteronuclear nOe evaluation of 2 and 6, Fig. 1.
HMBC confirmed a 3JCH correlation between the C-2 pyridine
carbon (identified as such by chemical shift and a lack of a
methylene carbon proximal to the nucleophile nitrogen in
3
each case. N15 HMBC on compound 2 showed a JNH
correlation between the pyridine nitrogen and the nucleophile
amine NH (6 was not evaluated in this fashion). Irradiation of
the fluorine resonances at ꢀ137.1 and ꢀ136.9 ppm of 2 and 6
respectively in heteronuclear nOe experiments yielded an
enhancement of the NH proton signal, allowing the fluorines at
the 3- and 5-positions of the pyridine ring to be assigned.
1
characteristically large JCF coupling) to protons on the

450
J.A. Christopher et al. / Journal of Fluorine Chemistry 129 (2008) 447–454
Scheme 1. Reaction of 3 and 12a with sodium ethoxide.
Compounds 3–5 and 7 have very similar 19F NMR spectra, and
analogous fluorine assignments have been made.
hard/soft nucleophiles, such as anilines, give mixtures arising
from competing substitution of both fluorine and bromine.
Consequently, these results provide encouraging guidance
regarding the synthetic utility of 1 for new scaffold generation
and elaboration.
In all cases, the unoptimised yields were good to moderate,
Table 1. For convenience, reactions were performed using
microwave heating, and the isolated yields compare favourably
with that reported for the attack of diethylamine upon 1 under
conventional heating conditions [7], indicating that either
synthetic mode is applicable.
2-Substituted-4-bromo-3,5,6-trifluoropyridine products 2–7
and 8a–12a have the potential to be reacted further via the
remaining fluoro- or bromo-substituents and initial studies
concerning the regioselectivity of a second nucleophilic
displacement step were carried out. 4-Bromo-N-cyclopropyl-
3,5,6-trifluoro-2-pyridinamine 3 was reacted with sodium
ethoxide and was cleanly converted to 2,6-disubstituted
bromopyridine 14 in 81% isolated yield, Scheme 1. Disap-
pearance of the characteristic 19F resonance at approximately
ꢀ90 ppm was indicative of displacement of the fluorine ortho
to the pyridine nitrogen. Similarly, fluorine displacement from
4-bromo-2,3,5-trifluoro-6-(phenyloxy)pyridine 12a by sodium
ethoxide at room temperature produced 15 in 52% isolated
yield. The regiochemistry of this second displacement
complements the well established order of attack of nucleo-
philes upon pentafluoropyridine (4 > 2 > 3) [1–4] and the
hard/soft principles outlined above.
With these successful and clean reactions in hand, we then
proceeded to investigate other nucleophiles, Table 2. Here, in
some cases, mixtures of products were obtained, resulting from
competing substitution at the positions ortho and para to the
ring nitrogen. Aromatic N-nucleophiles (entries 1 and 2)
required elevated temperatures and extended reaction times or
excess nucleophile to proceed to completion, and 19F NMR
analysis of the crude reaction mixtures indicated substantially
less selective reactions than those in Table 1. In each of these
cases mixtures of products were obtained, which could
be separated by column chromatography, with substitution at
the position para to the ring nitrogen appearing to dominate.
Benzimidazole, sodium ethoxide and sodium phenoxide gave
clean conversions to the ortho substituted products exclusively,
albeit in poor, unoptimised, yield for benzimidazole. The use of
thiophenol resulted in regiospecific displacement at the para-
position, yielding 13b [9] in 80% yield.
These results suggest that the regiochemistry of nucleophilic
attack for system 1 is, in general, governed by the hard/soft
nature of the nucleophile/electrophile [10] whereby hard
nucleophiles, such as alkoxides, preferentially attack at the
‘hard’ activated carbon–fluorine bond ortho to ring nitrogen
whilst soft nucleophiles, such as thiophenol, prefer to attack at
the ‘soft’ carbon bromine bond at the 4-position. ‘Borderline’
The 4-bromo substituent can also be utilised as a synthetic
handle. For example, 2 was reacted with phenylboronic acid
under Suzuki–Miyuara coupling conditions, and produced 16 in
acceptable yield, Scheme 2. There was no evidence to suggest
that the fluorine atoms present in 2 significantly participated in
deleterious nucleophilic substitution side-reactions.
In conclusion, we have shown that 4-bromo-2,3,5,6-
tetrafluoropyridine can be successfully reacted with a variety
of nucleophiles. With alkylamines, benzylamines, alkoxides
and benzimidazole, nucleophilic aromatic substitution occurs
Scheme 2. Suzuki–Miyaura coupling reaction of 2.

J.A. Christopher et al. / Journal of Fluorine Chemistry 129 (2008) 447–454
451
5
4
cleanly at the position ortho to the ring nitrogen whilst clean
substitution occurs at the para position with thiophenol. In
contrast, aromatic N-nucleophiles gave a mixture of ortho- and
para-substituted products. These results have been rationalised
by using hard/soft principles. We have established that the
functionality remaining in the mono-substituted products can
be exploited in a regiocontrolled second nucleophilic displace-
ment or a Suzuki–Miyaura coupling. These initial investiga-
tions indicate that 4-bromo-2,3,5,6-tetrafluoropyridine is a
reactive, versatile and controllable building block with great
potential to be exploited in drug discovery and other arenas.
25.0, F-6), ꢀ137.1 (1F, dd, JFF 28.0, JFF 9.0, F-3), ꢀ155.9
3
4
(1F, dd, JFF 25.0, JFF 9.0, F-5); m/z (Electrospray) 285.2/
287.1 (1:1 ratio, [M+H]+, 10); M+ 284.98441. C8H8BrF3N2O
requires 284.98449.
3.2.2. 4-Bromo-N-cyclopropyl-3,5,6-trifluoro-2-
pyridinamine 3
mp 49–50 8C; 1H NMR (400 MHz, DMSO-d6) d 0.50 (2H,
m, CH2), 0.69 (2H, m, CH2), 2.65 (1H, m, CH), 7.41 (br. s, NH);
13C NMR (101 MHz, CDCl3) d 7.2 (2C, s, CH2), 23.7 (s, CH),
109.2 (td, 2JCF 21.0, 3JCF 5.0, C-4), 133.7 (ddd, 1JCF 249.6, 2JCF
33.0, 3JCF 1.5, C-5), 140.7 (ddd, 1JCF 249.0, 3JCF 6.0, 4JCF 2.5,
2
3
4
3. Experimental
C-3), 142.2 (ddd, JCF 16.5, JCF 14.0, JCF 2.5, C-2), 145.7
4
(ddd, JCF 234.0, JCF 15.0, JCF 3.0, C-6); 19F NMR
1
2
5
3
3.1. General
(377 MHz, MeOD-d4) d ꢀ92.5 (1F, dd, JFF 28.0, JFF 23.0,
F-6), ꢀ137.3 (1F, dd, 5JFF 28.0, 4JFF 8.0, F-3), ꢀ154.3 (1F, dd,
4
4-Bromo-2,3,5,6-tetrafluoropyridine was obtained from
Aldrich. All other starting materials were obtained commer-
cially. Microwave reactions were performed in a Biotage
Initiator 60 EXP. NMR spectra were obtained in the deuterated
solvents indicated, on Bruker DPX400, AV400 or AVII600
spectrometers with referencing to tetramethylsilane and CFCl3
for proton and fluorine spectra, respectively. Elemental
analyses were performed by Butterworth Laboratories Limited,
Teddington, UK. Mass spectra (LC/MS) were recorded in
electrospray positive and negative ion modes on a Waters ZQ
Mass Spectrometer coupled to a Waters Acquity HPLC system.
Accurate mass measurements were performed on Bruker
Daltonics 7T FTICR-MS or Micromass Q-Tof 2 hybrid
quadrupole mass spectrometers, operating in electrospray
positive ion mode. Melting points were recorded on a
Gallenkamp apparatus and are uncorrected.
3JFF 23.0, JFF 8.0, F-5); m/z (Electrospray) 267.0/269.0 (1:1
ratio, [M+H]+, 100); Anal. Calcd for C8H6BrF3N2: C, 36.4; H,
1.8, N, 7.1. Found: C, 36.5; H, 1.7; N, 6.8%.
3.2.3. N0-(4-Bromo-3,5,6-trifluoro-2-pyridinyl)-N,N-
dimethyl-1,2-ethanediamine formate 4
1
mp 108–110 8C; H NMR (400 MHz, DMSO-d6) d 2.33
(6H, s, CH2NMe2), 2.63 (2H, t, J 6.5, CH2NMe2), 3.41 (2H, q, J
6.5, NHCH2), 7.21 (1H, br. s, NH), 8.24 (1H, br. s, HCO2H);
13C NMR (101 MHz, DMSO-d6) d 37.6 (s, NHCH2), 44.3 (2C,
s, NMe2), 56.9 (s, CH2NMe2), 109.2 (td, 2JCF 20.8, 3JCF 4.8, C-
1
2
1
4), 131.4 (dd, JCF 243.7, JCF 33.6, C-5), 140.3 (ddd, JCF
250.9, 3JCF 5.6, 4JCF 2.4, C-3), 142.0 (td, 2JCF 16.4, 3JCF 16.4,
4JCF 2.0, C-2), 144.7 (ddd, 1JCF 229.3, 2JCF 15.2, 4JCF 2.4, C-6),
164.2 (s, HCO2H); 19F NMR (377 MHz, DMSO-d6) d ꢀ93.3
5
3
5
(1F, dd, JFF 28.0, JFF 25.0, F-6), ꢀ137.6 (1F, dd, JFF 28.0,
4JFF 9.0, F-3), ꢀ156.3 (1F, dd, JFF 25.0, JFF 9.0, F-5); m/z
(Electrospray) 298.2/300.2 (1:1 ratio, [M+H]+, 100); Anal.
Calcd for C9H11BrF3N3ꢁCH2O2: C, 34.9; H, 3.8, N, 12.2.
Found: C, 35.1; H, 3.6; N, 11.8%.
3
4
3.2. General procedure for reaction of alkylamine and
benzylamine nucleophiles with 4-bromo-2,3,5,6-
tetrafluoropyridine
A mixture of 4-bromo-2,3,5,6-tetrafluoropyridine (2.5–
6.9 mmol), nucleophile (1.1–1.2 equiv.) and diisopropylethy-
lamine (3.0 equiv.) in THF (8–10 mL) was heated in a
microwave reactor at the temperature and time indicated in
Table 1. After concentration in vacuo, the material was
partitioned between water and CH2Cl2, the phases separated,
and the aqueous phase extracted with CH2Cl2. The combined
organic phases were concentrated in vacuo and purified by flash
column chromatography.
3.2.4. 4-(4-Bromo-3,5,6-trifluoro-2-pyridinyl)morpholine 5
mp 69–71 8C; 1H NMR (400 MHz, CDCl3) d 3.45 (4H, t, J
4.8, CH2NCH2), 3.80 (4H, t, J 4.8, CH2OCH2); 13C NMR
4
(101 MHz, CDCl3) d 48.2 (2C, d, JCF 5.6, CH2NCH2), 67.0
(2C, s, CH2OCH2), 112.3 (td, 2JCF 20.0, 2JCF 20.0, 3JCF 4.8, C-
1
2
2or3
4), 136.3 (dd, JCF 254.1, JCF 32.8, C-5), 142.7 (ddd,
J
CF
11.8, 2or3JCF 10.2, 4JCF 3.0, C-2), 143.6 (ddd, 1JCF 254.8, 3JCF
6.4, 4JCF 3.2, C-3), 144.9 (ddd, 1JCF 235.7, 2JCF 15.2, 4JCF 2.4,
C-6); 19F NMR (377 MHz, CDCl3) d ꢀ90.0 (1F, dd, 5JFF 28.0,
5
4
3JFF 25.0, F-6), ꢀ125.9 (1F, dd, JFF 28.0, JFF 6.0, F-3),
3
4
3.2.1. 4-Bromo-3,5,6-trifluoro-N-[2-(methyloxy)ethyl]-2-
pyridinamine 2
ꢀ145.9 (1F, dd, JFF 25.0, JFF 6.0, F-5); m/z (Electrospray)
297.1/299.2 (1:1 ratio, [M+H]+, 100); [M+H]+ 296.98420.
C9H9BrF3N2O requires 296.98449.
mp 92–93 8C; 1H NMR (400 MHz, DMSO-d6) d 3.25 (3H, s,
OMe), 3.35–3.47 (4H, m (CH2)2), 7.22 (1H, br. s, NH); 13C
NMR (101 MHz, DMSO-d6) d 40.0 (br. s, CH2CH2OMe), 57.9
(s, CH2(OMe)), 70.0 (s, CH2(OMe)), 109.2 (td, 2JCF 21.0, 3JCF
3.2.5. 4-Bromo-3,5,6-trifluoro-N-{[4-
(methyloxy)phenyl]methyl}-2-pyridinamine 6
1
2
1
5.0, C-4), 131.4 (dd, JCF 243.0, JCF 33.0, C-5), 140.3 (ddd,
3
mp 72–74 8C; H NMR (400 MHz, CDCl3) d 3.81 (3H, s,
4
2
3
1JCF 251.0, JCF 5.5, JCF 1.5, C-3), 142.1 (t, JCF 16.5, JCF
OMe), 4.52 (2H, d, J 5.5, NHCH2), 4.89 (1H, br. s, NH), 6.89
(2H, d, J 8.5, Ar), 7.28 (2H, d, J 8.5, Ar); 13C NMR (101 MHz,
DMSO-d6) d 44.7 (1C, s, CH2Ar), 55.1 (1C, s, OMe), 109.4
16.5, C-2), 144.7 (ddd, 1JCF 229.0, 2JCF 15.0, 4JCF 2.5, C-6); 19
F
5
3
NMR (377 MHz, DMSO-d6) d ꢀ92.8 (1F, dd, JFF 28.0, JFF

452
J.A. Christopher et al. / Journal of Fluorine Chemistry 129 (2008) 447–454
(1C, td, 2JCF 21.0, 3JCF 5.0, C-4), 114.0 (2C, s, Ar), 129.1 (2C, s,
Ar), 130.1 (1C, Ar), 133.2 (1C, dd, 1JCF 244.9, 2JCF 33.2, C-5),
140.1 (1C, ddd, 1JCF 250.9, 3JCF 6.0, 4JCF 2.0, C-3), 141.8 (1C,
ddd, 2JCF 16.4, 3JCF 16.4, 4JCF 1.6, C-2), 144.6 (1C, ddd, 1JCF
80–82 8C; 1H NMR (400 MHz, DMSO-d6) d 7.14–7.22 (4H, m,
Ar), 9.39 (1H, s, NH); 13C NMR (101 MHz, DMSO-d6) d 115.2
2
3
(2C, d, JCF 22.4, Ar), 123.6 (2C, d, JCF 8.0, Ar), 132.5 (2C,
dm, 1JCF 252.2, C-3/C-5), 134.9 (1C, m, C-4), 135.7 (1C, Ar),
143.7 (2C, dm, 1JCF 234.9, C-2/C-6), 159.0 (1C, d, 1JCF 240.5,
Ar); 19F NMR (377 MHz, DMSO-d6) d ꢀ95.7 (2F, m, F-2/F-6),
ꢀ119.1 (1F, s, ArF), ꢀ155.1 (2F, m, F-3/F-5); m/z (Electro-
spray) 259.3 ([MꢀH]ꢀ, 100); [M+H]+ 261.04447. C11H6F5N2
requires 261.04457.
2
4
229.1, JCF 14.6, JCF 2.6, C-6), 158.2 (1C, s, Ar); 19F NMR
(377 MHz, DMSO-d6) d ꢀ92.7 (1F, dd, 5JFF 28.0, 3JFF 25.0, F-
5
4
6), ꢀ136.9 (1F, dd, JFF 28.0, JFF 9.0, F-3), ꢀ155.6 (1F, dd,
4
3JFF 25.0, JFF 9.0, F-5); m/z (Electrospray) 347.1/349.0 (1:1
ratio, [M+H]+, 18); Anal. Calcd for C13H10BrF3N2: C, 45.0; H,
2.9 N, 8.1. Found: C, 44.6; H, 2.8; N, 7.7%.
3.3.2. Preparation of 4-bromo-3,5,6-trifluoro-N-(3-
methylphenyl)-2-pyridinamine 9a and 2,3,5,6-tetrafluoro-
N-(3-methylphenyl)-4-pyridinamine 9b
3.2.6. Preparation of 4-bromo-N-[(2-
bromophenyl)methyl]-3,5,6-trifluoro-2-pyridinamine 7
mp 91–93 8C; 1H NMR (400 MHz, MeOD-d4) d 4.60 (2H, s,
CH2), 7.15 (1H, br. t, J 7.5, Ar), 7.28 (1H, t, J 7.5, Ar), 7.34 (1H,
br. d, J 7.5, Ar), 7.56 (1H, d, J 7.5, Ar); 13C NMR (101 MHz,
DMSO-d6) d 44.6 (1C, s, CH2Ar), 109.9 (1C, td, 2JCF 21.0, 3JCF
5.3, C-4), 122.6 (1C, s, Ar), 128.1 (1C, s, Ar), 128.8 (1C, s, Ar),
A mixture of 4-bromo-2,3,5,6-tetrafluoropyridine (1.13 g,
4.93 mmol), m-toluidine (793 mL, 7.40 mmol) and DIPEA
(2.58 mL, 14.8 mmol) in DMSO (9 mL) was heated at 160 8C
in a microwave reactor for 1 h, before cooling to room
temperature and concentration in vacuo. Water and CH2Cl2
(50 mL each) were added, the phases were separated, and the
aqueous phase was extracted with CH2Cl2 (2ꢂ 25 mL). The
combined organic phases were concentrated in vacuo, and
purification by reverse-phase flash chromatography (gradient
elution; 40–95% MeCN (+0.1% CF3CO2H) in water (+0.1%
CF3CO2H)) on a C18 column yielded 9a (591 mg, 2.31 mmol)
as a ginger solid; mp 110–111 8C; 1H NMR (400 MHz, CDCl3)
d 2.38 (3H, s, Me), 6.49 (1H, br. s, NH), 6.93 (1H, br. d, J 8.0,
Ar), 7.24 (1H, d, J 8.0, Ar), 7.33 (1H, br. s, Ar), 7.41 (1H, br. d, J
8.0, Ar); 13C NMR (101 MHz, DMSO-d6) d 20.6 (1C, s, Me),
109.5 (1C, td, 2JCF 21.2, 3JCF 4.8, C-4), 116.3 (1C, s, Ar), 119.7
(1C, s, Ar), 122.8 (1C, s, Ar), 127.8 (1C, s, Ar), 132.9 (1C, dd,
1
2
129.2 (1C, s, Ar), 132.4 (1C, dd, JCF 244.1, JCF 32.4, C-5),
132.7 (1C, s, Ar), 137.9 (1C, s, Ar), 140.8 (1C, ddd, 1JCF 250.1,
3JCF 5.6, 4JCF 2.4, C-3), 142.1 (1C, br. td, 2JCF 16.0, 4JCF 1.6, C-
1
2
4
2), 145.1 (1C, ddd, JCF 230.0, JCF 15.2, JCF 2.4, C-6); 19F
5
3
NMR (377 MHz, MeOD-d4) d ꢀ95.2 (1F, dd, JFF 28.0, JFF
5
4
23.0, F-6), ꢀ140.4 (1F, dd, JFF 28.0, JFF 9.0, F-3), ꢀ156.8
3
4
(1F, dd, JFF 23.0, JFF 9.0, F-5); m/z (Electrospray) 392.8/
394.7/396.6 (approx 1:2:1 ratio, [M+H]+, 100); Anal. Calcd for
C12H7BrF3N2: C, 36.4; H, 1.8, N, 7.1. Found: C, 36.5; H, 1.7; N,
6.8%.
3.3. Reaction of 4-bromo-2,3,5,6-tetrafluoropyridine with
other nucleophiles
2
1JCF 248.1, JCF 33.2, C-5), 137.1 (1C, s, Ar), 137.7 (1C, dd,
2JCF 15.6, 3JCF 3.2, C-2), 138.5 (1C, s, Ar), 140.4 (1C, ddd, 1JCF
254.0, 3JCF 6.4, 4JCF 2.4, C-3), 143.3 (1C, ddd, 1JCF 230.3, 2JCF
15.4, 4JCF 2.6, C-6); 19F NMR (377 MHz, DMSO-d6) d ꢀ92.0
3.3.1. Preparation of 4-bromo-3,5,6-trifluoro-N-(4-
fluorophenyl)-2-pyridinamine 8a and 2,3,5,6-tetrafluoro-N-
(4-fluorophenyl)-4-pyridinamine 8b
5
3
5
(1F, dd, JFF 28.0, JFF 26.0, F-6), ꢀ132.6 (1F, dd, JFF 28.0,
3
4
A mixture of 4-bromo-2,3,5,6-tetrafluoropyridine (1.03 g,
4.49 mmol), 4-fluoroaniline (446 mL, 4.71 mmol) and DIPEA
(2.35 mL, 13.5 mmol) in DMSO (15 mL) was heated at 160 8C
in a microwave reactor for 3 h, before cooling to room
temperature and concentration in vacuo. Purification by
reverse-phase flash chromatography (gradient elution; 40–
95% MeCN (+0.05% HCO2H) in water (+0.1% HCO2H)) on a
C18 column yielded 8a (439 mg, 1.69 mmol) as a brown solid;
mp 97–99 8C; 1H NMR (400 MHz, MeOD-d4) d 7.03 (2H, t, J
8.5, Ar), 7.56–7.60 (2H, m, Ar); 13C NMR (101 MHz, DMSO-
d6) d 110.2 (1C, td, 2JCF 21.2, 3JCF 4.8, C-4), 115.2 (2C, d, 2JCF
22.4, Ar), 121.7 (2C, d, 3JCF 7.2, Ar), 133.5 (1C, dd, 1JCF 247.2,
2JCF 33.2, C-5), 135.5 (1C, d, 4JCF 2.4, Ar), 138.3 (1C, td, 2JCF
15.6, 4JCF 2.4, C-2), 140.9 (1C, ddd, 1JCF 253.4, 3JCF 6.2, 4JCF
4JFF 7.0, F-3), ꢀ150.6 (1F, dd, JFF 26.0, JFF 7.0, F-5); m/z
(Electrospray) 314.8/316.8 (approx. 1:1 ratio, [MꢀH]ꢀ, 100);
[M+H]+ 316.98956 C12H9BrF3N2 requires 316.98957; and 9b
(551 mg, 1.74 mmol) as a cream solid; mp 97–99 8C; 1H NMR
(400 MHz, CDCl3) d 2.38 (3H, s, Me), 6.27 (1H, br. s, NH), 6.92
(1H, d, J 8.0, Ar), 6.93 (1H, s, Ar), 7.04 (1H, d, J 8.0, Ar), 7.26
(1H, t, J 8.0, Ar); 13C NMR (151 MHz, DMSO-d6) d 20.9 (1C,
s, Me), 118.3 (1C, s, Ar), 121.6 (1C, s, Ar), 124.7 (1C, s, Ar),
1
128.4 (1C, s, Ar), 132.9 (2C, dm, JCF 249.5, C-3/C-5), 134.6
(1C, m, C-4), 137.9 (1C, s, Ar), 139.3 (1C, s, Ar), 143.7 (2C, br.
1
2
dt, JCF 234.8, JCF 16.0, C-2/C-6); 19F NMR (377 MHz,
CDCl3) d ꢀ99.9 (2F, m, F-2/F-6), ꢀ156.2.1 (2F, m, F-3/F-5); m/
z (Electrospray) 255.0 ([MꢀH]ꢀ, 100); [M+H]+ 257.06953.
C12H9F4N2 requires 257.06964.
1
2
4
2.2 C-3), 143.8 (ddd, JCF 230.7, JCF 15.4, JCF 2.6, C-6),
157.9 (1C, d, 1JCF 238.9, Ar); 19F NMR (377 MHz, DMSO-d6)
d ꢀ92.1 (1F, dd, 5JFF 28.0, 3JFF 25.0, F-6), ꢀ133.2 (1F, dd, 5JFF
3.3.3. Preparation of 1-(4-bromo-3,5,6-trifluoro-2-
pyridinyl)-1H-benzimidazole 10a
4
28.0, JFF 7.0, F-3), ꢀ120.6 (1F, br. s, ArF), ꢀ150.6 (1F, dd,
A mixture of 4-bromo-2,3,5,6-tetrafluoropyridine (1.00 g,
4.35 mmol), benzimidazole (514 mg, 4.35 mmol) and triethy-
lamine (1.82 mL, 13.1 mmol) in acetonitrile (20 mL) was
stirred at room temperature for 2 days before concentration in
vacuo. Water (15 mL) and CH2Cl2 (25 mL) were added, the
4
3JFF 25.0, JFF 7.0, F-5); m/z (Electrospray) 319.2/321.2
(approx. 1:1 ratio, [MꢀH]ꢀ, 89); Anal. Calcd for
C11H5BrF4N2: C, 41.2; H, 1.6, N, 8.7. Found: C, 41.3; H,
1.5; N, 8.4%; and 8b (283 mg, 0.88 mmol) as a brown solid; mp

J.A. Christopher et al. / Journal of Fluorine Chemistry 129 (2008) 447–454
453
phases were separated, and the aqueous phase was extracted
with CH2Cl2. The combined organic phases were concentrated
in vacuo, and purification by flash chromatography on silica
(gradient elution; 10–50% EtOAc in cyclohexane) yielded the
title compound (352 mg, 1.07 mmol) as a white solid; mp 213–
31.2, C-5), 142.7 (1C, ddd, 1JCF 254.8, 3JCF 6.4, 4JCF 1.6, C-3),
143.2 (1C, ddd, 1JCF 238.1, 2JCF 16.8, 4JCF 3.2, C-6), 143.4 (1C,
ddd, 2JCF 15.2, 3JCF 12.4, 4JCF 2.8, C-2), 152.7 (1C, s, Ph); 19
F
NMR (377 MHz, CDCl3) d ꢀ89.8 (1F, dd, 5JFF 28.0, 3JFF 22.0,
F-6), ꢀ133.0 (1F, dd, 5JFF 28.0, 4JFF 4.5, F-3), ꢀ140.4 (1F, dd,
1
4
215 8C; H NMR (400 MHz, DMSO-d6) d 7.40 (2H, m, Ar),
3JFF 22.0, JFF 4.5, F-5); m/z (Electrospray) 304.0/306.0 (1:1
7.82 (2H, m, Ar), 8.68 (1H, d, J 2.8, Ar); 13C NMR (151 MHz,
DMSO-d6) d 112.4 (1C, s, Ar), 114.1 (1C, ddd, 2JCF 24.6, 2JCF
20.7, 3JCF 4.4, C-4), 120.0 (1C, s, Ar), 123.6 (1C, s, Ar), 124.3
(1C, s, Ar), 129.4 (1C, td, 2JCF 15.5, 4JCF 4.4, C-2), 132.1 (1C, s,
ratio, [M+H]+, 59). Anal. Calcd for C11H5BrF3NO: C, 43.5; H,
1.7, N, 4.6. Found: C, 43.3; H, 1.6; N, 4.5%.
3.3.6. Preparation of 2,3,5,6-tetrafluoro-4-
(phenylthio)pyridine 13b
1
2
Ar), 141.9 (1C, dd, JCF 259.9, JCF 32.1, C-5), 142.6 (1C, d,
4or5
1
7.7, Ar), 142.9 (1C, s, Ar), 145.0 (1C, dd, JCF 238.8,
J
4-Bromo-2,3,5,6-tetrafluoropyridine (213 mg, 0.93 mmol),
thiophenol (90 mL, 0.88 mmol) and potassium carbonate
(345 mg, 2.5 mmol) in anhydrous THF (5 mL) were stirred
at room temperature for 12 h. 2 M aqueous sodium hydroxide
(10 mL) was added to the reaction mixture, the phases were
separated, the aqueous phase was extracted with CH2Cl2 (3ꢂ
5 mL) and the combined organic phases were dried (MgSO4)
and concentrated in vacuo. Purification by silica column
chromatography (CH2Cl2/cyclohexane, 1:4) yielded the title
compound (181 mg, 0.70 mmol) as a yellow oil. NMR data
were in accordance with the literature [9].
CF
2JCF 17.7, C-6), 146.8 (1C, dd, 1JCF 257.6, 3JCF 4.4, C-3); 19
F
5
3
NMR (377 MHz, DMSO-d6) d ꢀ88.9 (1F, dd, JFF 28.0, JFF
24.5, F-6), ꢀ123.2 (1F, d, 5JFF 28.0, F-3), ꢀ133.3 (1F, d, 3JFF
24.5, F-5); m/z (Electrospray) 327.8/329.8 (1:1 ratio, [M+H]+,
100); [M+H]+ 327.96913. C12H6BrF3N3 requires 327.96917.
3.3.4. Preparation of 4-bromo-2-(phenyloxy)-3,5,6-
trifluoropyridine 11a
A mixture of 4-bromo-2,3,5,6-tetrafluoropyridine (2.12 g,
9.24 mmol), sodium ethoxide (21 wt.% in EtOH, 3.62 mL,
9.70 mmol) and DIPEA (4.83 mL, 27.7 mmol) in anhydrous
THF (9.0 mL) was stirred at rt for 2.5 h, before concentration in
vacuo. Water and CH2Cl2 (50 mL each) were added, the phases
were separated, and the aqueous phase was extracted with
CH2Cl2 (2ꢂ 50 mL). The combined organic phases were
concentrated in vacuo, and the title compound (1.33 g,
5.19 mmol) was isolated by short-path distillation (bp 55–
57 8C/3 mbar) as a clear oil; 1H NMR (400 MHz, CDCl3) d 1.43
(3H, t, J 7.0, Me), 4.40 (2H, q, J 7.0, CH2); 13C NMR
(101 MHz, CDCl3) d 14.6 (1C, s, CH2Me), 64.4 (1C, s,
CH2Me), 112.1 (1C, td, 2JCF 20.7, 3JCF 4.3, C-4), 137.0 (1C, dd,
3.4. Reactions of 2-substituted 4-bromo-
tetrafluoropyridines
3.4.1. Preparation of 4-bromo-N-cyclopropyl-6-(ethyloxy)-
3,5-difluoro-2-pyridinamine 14
4-Bromo-2-cyclopropyl-3,5,6-trifluoropyridine (100 mg,
0.37 mmol), sodium ethoxide (21 wt.% in EtOH, 225 mL,
0.51 mmol) and DIPEA (190 mL, 1.11 mmol) in anhydrous
THF (1 mL) were stirred at room temperature for 30 min before
heating in a microwave reactor at 100 8C for 15 min. After
cooling to room temperature water (1 mL) was added, the
phases were separated, the aqueous layer was extracted with
CH2Cl2 (3ꢂ 2 mL) and the combined organic phases were dried
(MgSO4) and concentrated in vacuo. Purification by silica
column chromatography (Et2O/cyclohexane, 1:19) yielded the
2
1
3
1JCF 253.2, JCF 31.2, C-5), 142.4 (1C, ddd, JCF 258.0, JCF
7.2, 4JCF 2.4, C-3), 144.5 (1C, ddd, 1JCF 239.0, 2JCF 16.2, 4JCF
3.4, C-6), 146.2 (1C, br. td, 2JCF 13.4, 4JCF 2.7, C-2); 19F NMR
(377 MHz, CDCl3) d ꢀ92.5 (1F, dd, 5JFF 28.0, 3JFF 21.0, F-6),
ꢀ135.5 (1F, dd, 5JFF 28.0, 4JFF 6.0, F-3), ꢀ145.5 (1F, dd, 3JFF
4
1
21.0, JFF 6.0, F-5); m/z (Electrospray): failed to ionise in
title compound (88.7 mg, 0.30 mmol) as a colourless oil; H
positive or negative ion modes; Anal. Calcd for C7H5BrF3NO:
C, 32.8; H, 2.0, N, 5.5. Found: C, 32.6; H, 1.8; N, 5.3%.
NMR (400 MHz, MeOD) d 0.49 (2H, td, J 7.0, 5.0, CH2), 0.70
(2H, td, J 7.0, 5.0, CH2), 1.37 (3H, t, J 7.0, Me), 2.65 (1H, m,
CH), 4.40 (2H, q, J 7.0, OCH2); 13C NMR (101 MHz, MeOD) d
7.2 (2C, s, CyPr), 15.1 (1C, s, OCH2Me), 24.5 (1C, s, CyPr),
63.3 (1C, s, OCH2Me), 108.3 (1C, t, 2JCF 20.4, C-4), 136.3 (1C,
dd, 1JCF 246.1, 3JCF 2.4, C-3), 138.5 (1C, dd, 1JCF 245.7, 3JCF
2.8, C-5), 143.6 (1C, dd, 2JCF 13.6, 4JCF 3.2, C-2), 147.6 (1C,
3.3.5. Preparation of 4-bromo-2-(ethyloxy)-3,5,6-
trifluoropyridine 12a
Sodium phenoxide (562 mg, 4.84 mmol) was added to a
solution of 4-bromo-2,3,5,6-tetrafluoropyridine (1.06 g,
4.61 mmol) and DIPEA (2.41 mL, 13.8 mmol) in anhydrous
THF (20 mL) at 0 8C. The reaction was allowed to warm to
room temperature and stirred for 17 h before concentration in
vacuo. Purification by reverse-phase flash chromatography
(gradient elution; 35–85% MeCN (+0.1% HCO2H) in water
(+0.05% HCO2H)) on a C18 column yielded the title compound
(842 mg, 2.77 mmol) as a white solid; mp 53–55 8C; 1H NMR
(400 MHz, CDCl3) d 7.15 (2H, br. d, J 8.0, Ph), 7.25–7.29 (1H,
m, Ph), 7.43 (2H, t, J 8.0, Ph); 13C (101 MHz, DMSO-d6) d
113.2 (1C, td, 2JCF 21.6, 3JCF 3.7, C-4), 120.4 (2C, s, Ph), 125.5
2
4
dd, JCF 11.6, JCF 2.8, C-6); 19F NMR (376 MHz, MeOD) d
4
ꢀ155.4 (1F, apparent d, JFF 11.5, F-3 or F-5), ꢀ149.6 (1F,
4
apparent d, JFF 11.5, F-3 or F-5); m/z (Electrospray) 292.9/
294.9 (1:1 ratio, [M+H]+, 100); [M+H]+ 293.00930.
C10H11BrF2N2O requires 293.00956.
3.4.2. Preparation of 4-bromo-2-(ethyloxy)-3,5-difluoro-6-
(phenyloxy)pyridine 15
4-Bromo-2-(phenyloxy)-3,5,6-trifluoropyridine (96.0 mg,
0.32 mmol), sodium ethoxide (21 wt.% in EtOH, 124 mL,
0.33 mmol) and DIPEA (165 mL, 0.95 mL) in anhydrous THF
1
2
(1C, s, Ph), 129.9 (2C, s, Ph), 138.4 (1C, dd, JCF 253.3, JCF

454
J.A. Christopher et al. / Journal of Fluorine Chemistry 129 (2008) 447–454
(1.0 mL) were stirred at room temperature for 17 h. After
concentration in vacuo water and CH2Cl2 (10 mL each) were
added, the phases were separated, and the aqueous phase was
extracted with CH2Cl2 (2ꢂ 5 mL). The combined organic
phases were concentrated in vacuo and purified by mass-
directed preparative HPLC (50–98% aqueous MeCN gradient),
yielding the title compound (54.6 mg, 0.17 mmol) as an off-
white solid; mp 61–62 8C; 1H NMR (400 MHz, CDCl3) d 1.27
(3H, t, J 7.0, Me), 4.15 (2H, q, J 7.0, CH2), 7.12 (2H, br. d, J 8.0,
Ph), 7.20 (1H, t, J 8.0, Ph), 7.38 (2H, t, J 8.0, Ph); 13C NMR
(101 MHz, DMSO-d6) d 14.4 (1C, s, CH2Me), 63.5 (1C, s,
CH2Me), 111.3 (1C, t, 2JCF 21.2, C-4), 120.2 (2C, s, Ph), 125.1
3.66 (4H, m, CH2CH2OMe), 4.98 (1H, br. s, NH), 7.47–7.52
(5H, m, Ph); 13C NMR (101 MHz, DMSO-d6) d 39.7 (1C, s,
NHCH2), 57.9 (1C, s, OMe), 70.2 (1C, s, CH2OMe), 127.1 (1C,
br. t, 3JCF 2.4, Ph), 128.1 (1C, td, 2JCF 15.6, 3JCF 3.5, C-4), 128.7
(2C, s, Ph), 129.6 (1C, s, Ph), 129.6 (2C, s, Ph), 130.5 (1C, dd,
1JCF 243.3, 2JCF 30.8, C-5), 138.7 (1C, dd, 1JCF 250.1, 3JCF 4.8,
C-3), 142.4 (1C, dd, 2JCF 17.2, 3JCF 15.6, C-2), 145.2 (1C, ddd,
1JCF 227.5, JCF 15.4, JCF 2.6, C-6); 19F NMR (377 MHz,
CDCl3) d ꢀ95.2 (1F, dd, 5JFF 29.5, 3JFF 24.0, F6), ꢀ148.7 (1F,
br. d, 5JFF 29.5, F-3), ꢀ162.4 (1F, dd, 3JFF 24.0, 4JFF 4.0, F-5);
m/z (Electrospray) 283.2 ([M+H]+, 100); [M+H]+ 283.10499.
C14H14F3N2O requires 283.10527.
2
4
1
3
(1C, s, Ph), 130.0 (2C, s, Ph), 139.6 (1C, dd, JCF 250.1, JCF
1.6, C-3 or C-5), 140.4 (1C, dd, 1JCF 252.8, 3JCF 2.0, C-3 or C-
5), 143.1 (1C, dd, 2JCF 14.0, 4JCF 3.6, C-6), 145.8 (1C, dd, 2JCF
Acknowledgements
4
13.6, JCF 2.4, C-2), 154.0 (1C, s, Ph); 19F NMR (377 MHz,
CDCl3) d ꢀ139.5 (1F, br. d, 4JFF 6.0, F-3 or F-5), ꢀ142.2 (1F, d,
4JFF 6.0, F-3 or F-5); m/z (Electrospray) 330.1/332.1 (1:1 ratio,
[M+H]+, 44); [M+H]+ 329.99359. C13H11BrF2NO2 requires
329.99357.
Bill Leavens is thanked for HRMS analysis and purification
support from Helen Dawson is gratefully acknowledged. Karen
E. Lackey is thanked for advice and support.
References
3.4.3. Preparation of 3,5,6-trifluoro-N-[2-
(methyloxy)ethyl]-4-phenyl-2-pyridinamine 16
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A
mixture of 4-bromo-3,5,6-trifluoro-N-[2-(methylox-
y)ethyl]-2-pyridinamine (99.5 mg, 0.35 mmol), phenyl boronic
acid (298 mg, 2.44 mmol), dichloro(1,10-bis(diphenylphosphi-
no)ferrocene)palladium(II)-dichloromethane adduct (28.5 mg,
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microwave reactor at 160 8C for 40 min. After filtration and
concentration in vacuo, water and CH2Cl2 (20 mL each) were
added and the phases were separated. The aqueous phase was
extracted with CH2Cl2 (2ꢂ 15 mL) and the combined organic
phases were concentrated in vacuo and purified by preparative
HPLC (35–85% aqueous MeCN gradient), yielding the title
compound (59.4 mg, 0.21 mmol) as an off-white solid; mp 65–
67 8C; 1H NMR (400 MHz, CDCl3) d 3.41 (3H, s, OMe), 3.59–
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