Selective fluorination of pyridine and its derivatives in the presence of high-oxidation-state transition metals

Article abstract of DOI:10.1007/s11172-016-1513-x

The oxidative fluorination of pyridine and 4-ethylpyridine under chemical and electro-chemical conditions in the presence of transition metal (high-oxidation-state nickel, cobalt, and silver) salts was studied. The chemical fluorination affords 2-fluoropyridine in all cases, while the electrochemical fluorination results in 2-fluoroor 3-fluoropyridine depending on the catalyst used.

Full text of DOI:10.1007/s11172-016-1513-x

1
798
Russian Chemical Bulletin, International Edition, Vol. 65, No. 7, pp. 1798—1804, July, 2016
Selective fluorination of pyridine and its derivatives in the presence
of highꢀoxidationꢀstate transition metals*
T. V. Gryaznova, V. V. Khrizanforova, K. V. Kholin, M. N. Khrizanforov, and Yu. H. Budnikova
A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center of the Russian Academy of Sciences,
8
ul. Arbuzova, 420088 Kazan, Russian Federation.
Eꢀmail: tatyanag@iopc.ru
The oxidative fluorination of pyridine and 4ꢀethylpyridine under chemical and electroꢀ
chemical conditions in the presence of transition metal (highꢀoxidationꢀstate nickel, cobalt,
and silver) salts was studied. The chemical fluorination affords 2ꢀfluoropyridine in all cases,
while the electrochemical fluorination results in 2ꢀfluoroꢀ or 3ꢀfluoropyridine depending on
the catalyst used.
Key words: C—H functionalization, oxidation, fluorination, electrosynthesis, pyridine,
4
ꢀethylpyridine, potassium hexafluoronickelate, cobalt trifluoride, silver nitrate.
1
8
2
ꢀ[ F]ꢀFluoroꢀsubstituted pyridines are widely used
atures or using anhydrous tetrabutylammonium fluoride
(TBAF).5 The synthesis of fluoropyridines from aminopyꢀ
ridines by the Balz—Schiemann reaction uses potentially
explosive diazonium intermediates.5b It was shown that
2ꢀnitroꢀ and 2ꢀtrialkylammonium pyridines can be good preꢀ
cursors of 2ꢀfluoropyridines,5 although their wide apꢀ
a
as the fragments of radiotracers for positron emission toꢀ
mography, which is explained by simple (although often
inefficient) methods of their radiochemical synthesis and
their restricted defluorination in vivo.2
1
с,6
plication is limited by the complexity of their synthesis
7
(
Scheme 1, Eq. (2)). Recently, a new approach to the
synthesis of 2ꢀfluoropyridine based on the Chichibabin
reaction, which consists in direct fluorination of the pyriꢀ
dine C—H bond using AgF (Scheme 1, Eq. (3)), was
2
4
proposed. This method is applied successfully for subꢀ
strates with different functional groups and provides access
to a wide range of 2ꢀfluoropyridines, which in some cases
considerably improves the synthetic approaches to clinicalꢀ
ly significant compounds. It was shown that some 2ꢀsubꢀ
stituted pyridines can be obtained by the C—H bond actiꢀ
vation of pyridine Nꢀoxides with metal complex catalysts
in the presence of different nucleophiles (Cl, Br, CN,
8,9
amine, etc.). Several examples of preparation of 2ꢀpyridꢀ
yltrimethylammonium salts from pyridine Nꢀoxides were
1
0
described. The use of 2ꢀpyridyltrialkylammonium salts
for the synthesis of fluoropyridines was described in Ref. 11
In addition, nonradioactive fluorinated heterocycles
are extensively used in medicinal chemistry as both target
compounds and synthetic intermediates. Conventionꢀ
ally, 2ꢀfluoropyridines are synthesized by nucleophilic subꢀ
stitution of fluoride for a suitable leaving group in the
(
Scheme 1, Eq. (4)). The reaction is performed under
3
,4
moderately mild conditions; however, this method is multiꢀ
step and requires a large volume of solvents (including
explosive THF), as well as the excess of the activating
electrophile (3 equiv.), trifluoroacetic anhydride (TFAA) or
2
position (Scheme 1, Eq. (1)). Substitution of 2ꢀchloroꢀ
and 2ꢀbromopyridines with fluorine requires high temperꢀ
pꢀtoluenesulfonic anhydride (Ts O). In addition, the use of
2
2
ꢀ and 3ꢀphenylpyridines allows obtaining ammonium
salts in good yields (100% and 58%, respectively), but the use
of 4ꢀphenylpyridine does not afford the desired result.
The electrochemical fluorination of pyridine proceeds
inefficiently under severe conditions, typically, at high anꢀ
*
Based on the materials of the International Conference "Organoꢀ
metallic and Coordination Chemistry. Problems and Advances"
VI Razuvaev Readings) (September 18—23, 2015, Nizhny
Novgorod, Russia).
1
1
(
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1798—1804, July, 2016.
066ꢀ5285/16/6507ꢀ1798 © 2016 Springer Science+Business Media, Inc.
1

Selective fluorination of pyridines
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
1799
Scheme 1
regioselective introduction of the fluorine atom into the
pyridine ring, is still of great significance for the search of
new drugs and the design of radiotracers. In addition,
a general synthetic method which would provide access to
both nonradioactive fluoropyridines and Fꢀradioligands
via a common intermediate is in demand.
The aim of the present work was to regenerate electroꢀ
chemically the catalytic amounts of highꢀoxidationꢀstate
nickel and cobalt fluorides on the anode and to use them
for regioselective oneꢀstep monofluorination of pyridine
under mild conditions excluding the conventional excess
of oxidant (highꢀoxidationꢀstate metal fluoride or other
oxidant) and agressive hydrofluoric acid.
Nucleophilic aromatic substitution
1
8
(
1)
2)
X = Cl, Br, +N , NO , +NR3
2
2
Formation of pyridyltrimethylammonium salt
(
Results and Discussion
In the present work, we considered approaches to fluorꢀ
ination of pyridine and 4ꢀethylpyridine under different
conditions using different fluorinating agents and transiꢀ
tion metal salts. The following fluorinating reagents, cataꢀ
lysts and fluorine sources, were studied by cyclic voltamꢀ
metry (CV): K NiF , CsF, AgF, and СоF , as well as
R is an electronꢀwithdrawing group.
X = Cl, Br, +N , NO , +NR3
2
2
2
6
3
Fluorination of the C—H bond involving AgF2
Me NF in MeCN and a paste electrode (Figs 1 and 2,
4
Table 1). Since the solubility of many fluorides in acetoꢀ
nitrile is low, carbon paste electrode (CPE) based on the
phosphonium salt was used to specify their oxidation
potentials (see Fig. 2, Table 1). The oxidation potentials
of fluorides in solution and in the solid state are either
close or in some cases coincide.
AgF2 (2—3 equiv.)
(
3)
4)
1
5
Synthesis via pyridyltrialkylammonium salts
Pyridine and 4ꢀethylpyridine in the available potential
range do not oxidize on glassy carbon electrode (up to
(
3.0 V). All fluorides under study oxidize at high anode
potentials of about 2 V and higher. Since the oxidation
potentials of fluorides differ slightly (only Me NF is notaꢀ
4
I/mA
0
.02
0
ode potentials and a high power consumption; the product
yields being at best 22% based on pyridine and 10% based
on the current in a concentrated fluoride solution (0.5 M
–
0.04
1
2
3
4
Me NF•2HF in acetonitrile, 70ꢀfold excess of fluoride
4
1
2
–0.07
compared to pyridine).
As is known, chemical oxidative fluorination of organꢀ
ic compounds can proceed with the assistance of nickel
fluorides (in hydrofluoric acid) and highꢀoxidationꢀstate
silver or cobalt fluorides.1 The redoxꢀactive NiF /NiF
–0.10
3
.3
2.9
1.6
1.2
0.5 E/V
3
2
3
Fig. 1. CV curves for oxidation of K NiF (1), CsF (2), AgF (3),
and CoF (4) in MeCN. Conditions: 0.1 V s , Bu NBF , a glassy
carbon (GC) working electrode, and an Ag/AgNO3 reference
electrode.
2
6
film formed in a solution of HF and its salts was shown to
play a key role in some electrochemical fluorination
processes.1
–1
3
4
4
4
The development of reliable synthetic methods, which
would allow fast (at the final step of the synthesis) and
Note. Figures 1 and 2 are available in full color on the web page
of the journal (http://www.link.springer.com).

1
800
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
Gryaznova et al.
I/mA
4
0
0
–
–
40
80
1
2
3
4
1
000
2000
3000
4000
ΔH/G
–
120
Fig. 3. ESR spectrum for the K NiF powder.
2
6
2
.5
1.0
–0.4 E/V
Fig. 2. CV curves for oxidation of K NiF (1), AgF (2), CsF (3),
2
6
–
1
and CoF (4) in carbon paste electrode. Conditions: 0.1 V s
,
the crystal lattice. The signal intensity corresponds to the
Ni content of about 5—10% in the sample. The ESR
3
III
Bu NBF , a platinum auxiliary electrode, an Ag/AgNO referꢀ
4
4
3
ence electrode, MeCN.
spectrum also contains an additional signal, presumably,
from the highꢀspin (S = 5/2) 3d Mn ions with splitting
5
from the fluorine nuclei. The intensity of the second signal
is lower by about two orders of magnitude than that of the
first signal. Upon addition of pyridine to the K NiF powꢀ
bly more difficult to oxidize), one can assume that all of
them correspond to oxidation of fluoride ions proceeding
via the formation of fluorine radical.
2
6
3
+
der, the intensity of Ni
signal decreases with time
Highꢀoxidationꢀstate metal fluorides under certain
(
Fig. 4). No new signals, including those belonging to the
1
3,14
conditions can fluorinate organic compounds;
thereꢀ
pyridine radical cation, appear.
fore, it is necessary to consider the earlier unstudied chemꢀ
ical oxidative fluorination of pyridine, as well as to try
regeneration of the active form of metal fluoride, for exꢀ
ample, nickel or cobalt fluoride, on the anode under cataꢀ
lytic reaction conditions.
The performed electrochemical CV studies revealed
that upon addition of pyridine to potassium hexafluoroꢀ
nickelate the oxidation peak of the latter shifts to the
cathode region (Fig. 5), perhaps, due to the formation of
nickel(II) fluorides oxidizing at the earlier stages.
As noted above, substituted cyclohexanes can be fluorꢀ
inated completely on exposure to the fluorinating reagents
generated from potassium hexafluoronickelate in the presence
First, potassium hexafluoronickelate was studied as
the fluorinating agent. The CV curve for a solution of the
salt under study shows oxidation to occur at a high anode
potential of 1.85 V in both acetonitrile and a paste (see
Figs 1 and 2). Potassium hexafluoronickelate (K NiF )
1
6
of BF or anhydrous HF (in fact, RNiF and NiF ). We
3
3
4
2
6
assumed that the electrochemical oxidation of nickel(II)
fluorides which must form as the final products from
nickel(III) and nickel(IV) compounds after oxidative fluorꢀ
ination of an aromatic compound, for example, pyridine,
was studied also by ESR spectroscopy. The commercial
reagent (SigmaꢀAldrich, 99% purity), which is formally
IV
III
a Ni compound, was found to contain Ni impurities.
The ESR signal for the K NiF powder is a homogeneously
2
6
broadened line with g = 2.25 and ΔH = 230 Gs (Fig. 3).
III
Apparently, the signal belongs to impurity Ni centers in
Table 1. Oxidation peak potentials of fluorides acting as
the fluorine sources in the synthesis of fluoropyridinea
Fluorine
source
Epox/V
GC
CPE
K NiF6
CsF
AgF
CoF3
1.85 (1.33 in Py)
1.9
2.0
2.2
2.1
2
1.91
2.06
2.10 (1.40 in Py)
2.90
b
Me NF
—
—
4
c
NiF Py4
1.30
1.40
2
c
CoF Py4
—
2
1000
2000
3000
4000 ΔH/G
a
Fig. 4. Decrease in the intensity of the ESR signal for the Ni3+
Relative to Ag/AgNO , the solvent was MeCN.
No oxidation. Not recorded.
3
b
c
ions of K NiF upon addition of pyridine.
2
6

Selective fluorination of pyridines
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
1801
I/μA
40 °C); in acetonitrile, the complete conversion requires
heating at 70 °C for a long time.
1
2
0
Fluorination of 4ꢀethylpyridine with potassium hexaꢀ
fluoronickelate using either the excess of the starting pyridꢀ
ine (80 °C) or acetonitrile (70 °C, 3 days) proceeds analoꢀ
gously (the ratio of EtPy : K NiF = 3 : 1). The yield of
–
70
2
2
6
2
ꢀfluoroꢀ4ꢀethylpyridine (2) was 46% (Scheme 3).
–
–
–
100
150
200
Scheme 3
2
.5
1.8
1.0
0.3
–0.4 E/V
Fig. 5. CV curves for oxidation of K NiF in MeCN (1) and
2
6
pyridine (2). Conditions: 0.1 V s–1, Bu NBF , a platinum auxilꢀ
4
4
iary electrode, an Ag/AgNO reference electrode, MeCN.
(δ
19F
–69.82)
3
As the fluorinating agent, CoF was also studied. The
3
will make the process catalytic by nickel, for which the
available nonꢀaggressive salt, for example, CsF and thereto
similar salt, can be selected as the source of the major
fluorine portion. This helps one to avoid the use of aggresꢀ
reaction between pyridine and cobalt trifluoride was perꢀ
formed in acetonitrile at 70 °C (24 h) at the 1 : 1 ratio of
the starting reagents. In this case, pyridine is also fluoriꢀ
nated at the 2 position (see Scheme 2); however, the reacꢀ
tion under these conditions proceeds slower: according to
sive HF or BF as coreagents. We found that chemical
3
1
fluorination of pyridine using potassium hexafluoronickeꢀ
the data from H NMR spectroscopy, the degree of pyriꢀ
1
9
late proceeds selectively at 80 °C to form a single reaction
dine conversion within 24 h is about 30%. The F NMR
1
9
1
product, 2ꢀfluoropyridine (1) whose F NMR spectrum
spectrum displays a singlet at δ19F –67.4. The H NMR
contains a singlet signal at δ –65.88. The reaction was
19F
spectrum (CDCl ) coincides completely with that of
3
performed in the excess of pyridine, which served as both
a substrate and a solvent (Scheme 2). The crimson color
of the solution suggesting the presence of the starting poꢀ
tassium hexafluoronickelate in the reaction mixture disꢀ
appears after several hours; at the same time, brightꢀblue
crystals and a beige crystalline powder form.
2ꢀfluoropyridine obtained using K NiF as the fluorinating
2
6
agent (see Scheme 2). The reaction in the excess of pyrꢀ
idine also proceeds selectively to form 2ꢀfluoropyridine.
During the synthesis, precipitation of pink crystals which,
as in the case of K NiF , correspond to the complex of
2
6
cobalt difluoride and four pyridine ligands (the analogous
1
8
III
structure was described only for Co ). We failed to obꢀ
tain the spectral characteristics of this complex, since the
signals are much broadened due to the presence of paraꢀ
magnetic cobalt species.
Scheme 2
The electrooxidative fluorination of pyridine and
4ꢀethylpyridine was performed in order to regenerate elecꢀ
trochemically the catalytic amounts of highꢀoxidationꢀ
state nickel and cobalt fluorides on the anode followed by
their use for selective oneꢀstep monofluorination of pyrꢀ
idine under mild conditions. The electrolysis was perꢀ
formed in a divided cell in acetonitrile at room temperaꢀ
ture. The source of fluoride ions was cesium fluoride and
tetramethylammonium fluoride. Electricity 2 F per 1 mol
of pyridine was passed. When potassium hexafluoronickelate
was used as the catalyst (the ratio of the starting reagents
was Py : K NiF : CsF = 1 : 0.1 : 2), the electrolysis was
The beige crystalline powder is potassium fluoride. The
1
7
resulting blue crystals are the earlier described nickel
fluoride coordinated to pyridine, nickel tetrapyridine difꢀ
luoride NiF Py . The oxidation peak of NiF Py on the
2
6
performed at a potential of 2.07 V (vs. Ag/AgNO ). In
2
4
2
4
3
1
9
CV curve is close to that of K NiF in pyridine (see Table 1),
contrast to the chemical reaction, the F NMR spectrum
of the reaction mixture contains a singlet at δ19F –128.8.
According to the spectral data, in contrast to products
described in Ref. 12, the main fluorination product in this
case is 3ꢀfluoropyridine (3) (Scheme 4).
2
6
i.e., the reaction of the latter compounds, coordination,
and oxidation start quite fast. The aboveꢀdescribed reacꢀ
tion does not proceed in dichloromethane. Perhaps, this
reaction requires a higher temperature (b.p. of CH Cl is
2
2

1
802
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
Gryaznova et al.
Scheme 4
Pyridine underwent electrocatalytic fluorination using
AgNO as the catalyst and cesium fluoride as the fluorine
3
source (Py : AgNO : CsF = 1 : 0.1 : 2). The electrolysis
3
was performed without a supporting electrolyte at an anꢀ
ode potential of 0.98—1.10 V. The isolated product was
2ꢀfluoropyridine (1) (Scheme 6, Table 2). 4ꢀEthylpyridine
under these conditions is fluorinated analogously.
X = H (3), Et (4)
Scheme 6
The electrooxidative fluorination of 4ꢀethylpyridine
using potassium hexafluoronickelate as the catalyst proꢀ
ceeds analogously to form 3ꢀfluoroꢀ4ꢀethylpyridine (4)
(
δ
19F
–127.4). It should be noted that functionalization of
4
—7
pyridine typically proceeds at the 2 position.
The C—H
substitution reactions at the 3 position, for example, upon
catalytic olefination of pyridine in the presence of palladium
complexes1 or classical electrophilic substitution,20 are
known.
X = H (1), Et (2)
9
The use of tetramethylammonium fluoride as the
source of fluoride ions upon electrocatalytic fluorination
of pyridine and 4ꢀethylpyridine in the presence of potassiꢀ
um hexafluoronickelate results a dramatic decrease in the
yield of fluorinated products. The reason for such differꢀ
ence is not obvious. It seems that in this case a higher
quantity of electricity is required. It should be noted that
without catalysts, such as nickel, cobalt, or silver salts, in
the presence of CsF the electrocatalytic fluorination do
not occur under these conditions.
Thus, the electrocatalytic fluorination of pyridine and
4ꢀethylpyridine depending on the catalyst used proceeds
selectively under mild condtions at the 2 and 3 positions,
the used source of fluoride ions has no effect on the regioꢀ
chemistry of fluorination, but influences the yield of the
final product. The dependence of the reaction regioselecꢀ
tivity on the nature of the catalyst metal and the synthesis
method (chemical or electrochemical) is likely caused by
different mechanisms of oxidative fluorination whose clarꢀ
ification require additional studies.
The electrocatalytic fluorination of pyridine and 4ꢀethylꢀ
pyridine was studied also in the presence of CoF (the
3
ratio of the starting reagents was 1 : 1). In contrast to the
aboveꢀdescribed electrolysis, cobalt trifluoride acted in this
case as both the source of fluoride ions and the catalyst.
After passing 2 F of electricity per 1 mol of metal fluoride at
1
9
a potential of 1.92 V, the F NMR spectrum of the reacꢀ
tion mixture displayed two singlet signals at δ –34.8
19F
and –152.2 with identical intensities, which can suggest
the formation of the pyridinium salt 6.21 Subsequent treatꢀ
ment of salt 6 with triethylamine affords 2ꢀfluoropyridine 1
(
δ
19F
–69.8) (Scheme 5).
Scheme 5
Experimental
Acetonitrile was distilled successively over P O , KMnO ,
2
5
4
R = H (1, 5), Et (2, 6)
and molecular sieves 4 Å. Benzene was purified by distillation
Table 2. Electrochemical fluorination of pyridine and 4ꢀethylpyridine
Substrate
Pyridine
Catalyst (10%)
Source F–
Potential/V
Fluorinated product
Yield (%)
K NiF6
CsF
CsF
CoF3
CoF3
CsF
2.07
1.89
2.08
2.12
1.02
0.76
2.04
1.59
3
4
1
2
1
2
3
4
43
45
49
57
48
20
—*
7
2
4
ꢀEthylpyridine
Pyridine
ꢀEthylpyridine
Pyridine
ꢀEthylpyridine
Pyridine
K NiF6
2
CoF3
CoF3
AgNO3
AgNO3
4
4
CsF
K NiF6
Me NF
2
4
4
ꢀEthylpyridine
K NiF6
Me NF
2
4
*
Trace amounts.

Selective fluorination of pyridines
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
1803
3
JHH = 8.58 Hz, 3JHF = 9.24 Hz); 7.52 (d, 1 H, 3JHH = 7.54 Hz).
F NMR (DMSOꢀd ), δ: –128.4 (cf. Ref. 25: δ –125.6).
19F
6
over sodium metal. After purification, the solvents were stored
19
under dry argon atmosphere. The supporting salt Et NBF was
4
4
1
recrystallized from ethanol and dried for 2 days in a vacuum
cabinet at 100 °C. Pyridine and 4ꢀethylpyridine, potassium
hexafluoronickelate, and tetramethylammonium fluoride were
obtained from Aldrich, boron trifluoride was obtained from Alfa
Aesar, silver nitrate and cesium fluoride were obtained from
Strem Chemicals. All syntheses were performed under dry argon
atmosphere.
4ꢀEthylꢀ3ꢀfluoropyridine (4). H NMR (CDСl ), δ: 8.37 (d, 1 H,
3
3
3JHH = 5.05 Hz); 8.29 (m, 1 H); 7.27 (d, 1 H, J = 7.12 Hz);
2.74 (q, 2 H, CH , J
= 7.63 Hz) (cf. Ref. 26). F NMR (CDСl ), δ: –128.4.
HF
3
3
= 7.63 Hz); 1.26 (t, 3 H, CH , J
=
HH
2
HH
3
19
3
This work was financially supported by the Russian
Science Foundation (Project No. 14ꢀ23ꢀ00016).
Preparative electrolyses were performed using a B5ꢀ49 diꢀ
rectꢀcurrent power supply in a 40ꢀmL threeꢀelectrode cell. The
potential of the working electrode was recorded using a V7ꢀ27
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3
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2
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4
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1
19
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6
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2
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3
The auxiliary electrode was a platinum wire with a diameter of
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27, 381.
1
mm and a length of 10 mm. The measurements were perꢀ
formed in a temperatureꢀcontrolled (25 °C) cell in argon atmoꢀ
sphere. Cyclic voltammograms were recorded in MeCN at the
–
3
–1
substrate concentration of 5•10 mol L against Bu NBF4
4
–
1
–1
(1•10 mol L ).
Electrolysis (general procedure). Pyridine or 4ꢀethylpyridine
6.2 mmol), the source of F– ions (CsF, Ме NF, or CoF ,
(
4
3
6
.2 mmol), and the catalyst (K NiF , CoF , or AgNO , 0.62 mmol)
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2
6
3
3
in acetonitrile (20 mL) were placed in an electrochemical cell.
The electrolysis was performed with division of the anode and
cathode compartments with stirring on a magnetic stirrer under
the constant flow of argon. Electricity of 2 F per 1 mol of the
starting pyridine (333 mA h) was passed through the electrolyte.
Once the electrolysis has been completed, the reaction mixture
was passed through silica gel and the solvent was removed. The
residue was purified by column chromatography on silica gel
(
the eluents were CH Cl and pentane).
2 2
1
2
ꢀFluoropyridine (1). H NMR (DMSOꢀd ), δ: 8.29 (d, 1 H,
6
3JHH = 5.85 Hz); 8.02 (dt, 1 H, J = 7.98 Hz, J = 1.25 Hz);
3
4
HH
HF
.38 (dd, 1 H, 3J = 7.28 Hz, J = 4.91 Hz); 7.20 (dd, 1 H,
3
7
HH HH
3
JHH = 7.54 Hz, 3J
19
= 2.58 Hz) (cf. Ref. 22). F NMR
9. Pat. EU EP0619307, 1994; https://www.google.com/
patents/EP0619307A1?cl=en&hl=ru.
HF
(
19F
DMSOꢀd ), δ: –65.88 (cf. Ref. 23: δ –69.5).
6
1
4
ꢀEthylꢀ2ꢀfluoropyridine (2). H NMR (CDСl ), δ: 8.10
10. (a) E. Rivadeneira, K. Jelich, Eur. Pat. EP 556683, 1993;
https://www.google.com/patents/EP0556683A1?cl=en;
(b) E. Rivadeneira, K. Jelich, Pat. US 5502194, 1996;
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son, T. Svensson, Pat. WO/2001/070730, 2001; http://
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3
3
(
d, 1 H, J = 5.05 Hz); 6.97 (m, 1 H); 6.72 (s, 1 H); 2.67 (q, 2 H,
HH
3
3
CH , J
= 7.61 Hz); 1.24 (t, 3 H, CH , J
= 7.61 Hz)
2
HH
3
HH
19
(
cf. Ref. 24). F NMR (CDСl ), δ: –69.8.
3
1
3
ꢀFluoropyridine (3). H NMR (DMSOꢀd ), δ: 8.61 (d, 1 H,
6
3JHF = 5.85 Hz); 8.49 (d, 1 H, J
3
= 4.98 Hz); 7.72 (dd, 1 H,
HH

1
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Received January 12, 2016;
in revised form April 21, 2016