Removal of fluorine from and introduction of fluorine into polyhalopyridines: An exercise in nucleophilic hetarenic substitution

Article abstract of DOI:10.1002/chem.200400837

Starting from six industrially available fluorinated pyridines, an expedient access to all three tetrafluoropyridines (2-4), all six trifluoropyridines (5-10), and the five non-commercial difluoropyridines (11-14 and 16) was developed. The methods employed for the selective removal of fluorine from polyfluoropyridines were the reduction by metals or complex hydrides and the site-selective replacement by hydrazine followed by dehydrogenation-dediazotation or dehydrochlorination-dediazotation. To introduce an extra fluorine atom, a suitable precursor was metalated and chlorinated before being subjected to a chlorine/ fluorine displacement process.

Full text of DOI:10.1002/chem.200400837

FULL PAPER
Removal of Fluorine from and Introduction of Fluorine into
Polyhalopyridines: An Exercise in Nucleophilic Hetarenic Substitution
Carla Bobbio, Thierry Rausis, and Manfred Schlosser*[a]
Abstract: Starting from six industrially
available fluorinated pyridines, an ex-
pedient access to all three tetrafluoro-
pyridines (2–4), all six trifluoropyri-
dines (5–10), and the five non-commer-
cial difluoropyridines (11–14 and 16)
was developed. The methods employed
for the selective removal of fluorine
from polyfluoropyridines were the re-
duction by metals or complex hydrides
and the site-selective replacement by
hydrazine followed by dehydrogena-
tion–dediazotation or dehydrochlorina-
tion–dediazotation. To introduce an
extra fluorine atom, a suitable precur-
sor was metalated and chlorinated
before being subjected to a chlorine/
fluorine displacement process.
Keywords: fluorine
·
hydrazino
compounds · hydrogenation · metal-
ation · nucleophilic substitution
Introduction
described in easily reproducible literature procedures, we
set about convenient improved methods of preparation, and
providing a suitable route to the missing difluoropyridines
and, by extension, trifluoropyridines, and tetrafluoropyridines.
The most critical issue concerned the logistics. We decided
to rely on just a few technically or commercially available
substances as starting materials. Thus we selected 2- and 3-
fluoropyridine which, like the unstable 4-isomer, can be
readily prepared from the corresponding aminopyridines by
fluorodediazotation (Scheme 1).[7–11] In addition, we picked
Fluorine is a marvelous tool for engineering biorelevant
properties such as acidity, lipophilicity, and metabolic stabili-
ty.[1] This creates a demand for novel fluorinated compounds
equipped with suitable functionality, which can be incorpo-
rated as attractive building blocks into potential lead struc-
tures. Unlike the abundantly documented fluorinated benzo-
ic acids, benzaldehydes, or areneboronic acids, heterocyclic
analogues thereof are yet rather rare.
By using our toolbox methods,[2] we have functionalized
2-fluoropyridine,[3] 3-fluoropyridine,[4] and 2,6-difluoropyri-
dine[5] in a regiochemically exhaustive fashion. This means
each vacant position is selectively made amenable to substi-
tution.
Since the key intermediates in the reaction sequences are
polar organometallic species, they can be trapped by all
kinds of electrophilic reagents. The choice is embarrassingly
wide indeed. Virtually any imaginable functional entity can
be attached to the core compound. Carboxylation, our stan-
dard derivatization method, represents just one out of
dozens, if not hundreds, of possibilities.
When we began to extend our studies to 2,3-, 2,4-, and
2,5-difluoropyridines,[3,6] we faced a practical problem. As
none of these new substrates is commercially supplied nor
Scheme 1.
[a] C. Bobbio, T. Rausis, Prof. M. Schlosser
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale, BCh
1015 Lausanne (Switzerland)
5-chloro-2,3-difluoropyridine,[12–14] which is made from 2,3,5-
trichloropyridine (Scheme 1) and serves as an important in-
dustrial intermediate for the manufacture of a herbicide,
E-mail: manfred.schlosser@epfl.ch
Chem. Eur. J. 2005, 11, 1903 – 1910
DOI: 10.1002/chem.200400837
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1903

Scheme 2. Synopsis of the “downstream and upstream” modes of access to oligofluoropyridines. A: Defluorination using metals or complex metal hy-
drides; B: catalytic hydrogenation; C1: reaction with hydrazine followed by dehydrochlorinative dediazotation; C2: reaction with hydrazine followed by
dehydrogenative dediazotation; C3: like C2 but preceded by metalation and trialkylsilylation and terminated by protodesilylation; D: metalation and
chlorination (or bromination); E: chlorine(bromine)/fluorine displacement.
and finally we resorted to 3,5-dichlorotrifluoropyridine, 3-
chlorotetrafluoropyridine, and pentafluoropyridine, the
three latter being concomitantly produced by chlorine/fluo-
rine displacement (“halex”) from pentachloropyridine.[15,16]
1904
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Nucleophilic Hetarenic Substitution
FULL PAPER
2-Fluoropyridine is particularly inexpensive (50E per mol)
and the retail price of the other compounds is still moderate
(150–250E per mol).
Our results will be subdivided into work aimed at the in-
troduction of one additional fluorine atom into insufficiently
halogenated precursors and removal of one or several fluo-
rine atoms from excessively halogenated precursors. As one
can easily recognize, the “upstream” and “downstream”
modes are complementary. Only by applying them conjoint-
ly, the fixed objectives could be attained (see Scheme 2).
(see Scheme 4) 3-chlorotetrafluoropyridine (17) was cleanly
converted into 2,3,4,6-tetrafluoropyridine (4; 89%), 3-
chloro-2,5,6-trifluoropyridine (19) into 2,3,6-trifluoropyri-
dine (8; 74%), 3,5-dichlorotrifluoropyridine (20) into 2,4,6-
trifluoropyridine (10; 85%), 5-chloro-2,3-difluoropyridine
(24) into 2,3-difluoropyridine (13; 75%), 3-chloro-2,5-di-
fluoropyridine (25) into 2,5-difluoropyridine (14; 70%) and
3-chloro-2,4-difluoropyridine (26) into 2,4-difluoropyridine
(16; 77%).
In a single instance the discrimination between the heavi-
er and the lighter halogen proved imperfect. The catalytic
hydrogenation of 3-chloro-4,5-difluoropyridine (22) provid-
ed a 5:95 mixture of 3-fluoropyridine (4%), evidently
formed through 3-chloro-5-fluoropyridine (29), and 3,4-di-
fluoropyridine (12; 75%; Scheme 5).
Results and Discussion
Removal of chlorine or fluorine from polyhalopyridines:
The selective reduction of pentafluoropyridine (1) to 2,3,5,6-
tetrafluoropyridine (2) by catalytic hydrogenation[17] or with
lithium aluminum hydride[18] has been reported (Scheme 3).
Scheme 5.
Scheme 3.
Our only case of a non-hydrogenolytic dechlorination
concerns 3-chloro-2,5,6-trifluoropyridine (20) as the sub-
strate. Hydrazine was found to displace with amazing selec-
tivity the fluorine atom accommodated at the 6- rather than
that at the 2-position. Arylhydrazines and hetarylhydrazines
being extremely versatile intermediates, they can undergo
dediazotation in various ways.[6,20] When the 3-chloro-2,5-di-
fluoro-6-hydrazinopyridine (32) was heated with an aqueous
solution of sodium hydroxide under reflux, the nitrogen and
chlorine atoms were lost simultaneously thus giving rise to
2,5-difluoropyridine (14; 75%; Scheme 6). The dehydrohalo-
We achieved a much higher yield (90% rather than 60%)
under more convenient conditions when we used zinc
powder in aqueous ammonia as the reagent at 08C rather
than at +258C, as recommended.[19] The analogous removal
of the fluorine atom from the 4-position of 3-chlorotetra-
fluoropyridine (17) proceeded most readily with sodium bor-
ohydride in ethanol affording 3-chloro-2,5,6-trifluoropyri-
dine (19; 92%) as the sole product (Scheme 3).
With one exception, the replacement of chlorine was
always accomplished by transfer hydrogenation using palla-
dium on charcoal as the catalyst and ammonium formate as
the hydrogen source. The reaction temperature and time
(generally 258C for 6 h) and the solvent (mostly 1-octanol)
were adapted to the situation when appropriate. In this way
Scheme 6.
genation/dediazotation sequence obviously involves a (het)-
arylhydrazine tautomer[21,22] which suffers consecutive 1,6-
elimination of hydrogen chloride and 1,2-elimination of dini-
trogen. On the other hand, when the hydrazinopyridine 32
was treated with cupric sulfate, dehydrogenation generated
directly a hetaryldiazene which collapsed to 3-chloro-2,5-di-
fluoropyridine (25; 67%; Scheme 6).
Scheme 4.
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M. Schlosser et al.
The dehydrogenation/dediazotation method was applied
to several other hydrazinopyridines (Scheme 7). Thus, 2,3,5-
trifluoropyridine (6, 65%) was made from 2,3,5,6-
tetrafluoropyridine (2) through the hydrazine derivative 33
(88%), 3,5-difluoropyridine (11; 79%) from 2,3,5-trifluoro-
pyridine (6) through intermediate 34 (68%) and 3-chloro-5-
fluoropyridine (29; 72%) from 5-chloro-2,3-difluoropyridine
(24) through intermediate 35 (87%) and 2,3,6-trifluoropyri-
dine (8; 73%) from 2,3,4,6-tetrafluoropyridine (49) through
intermediate 36 (90%).
with the respective chlorotrialkylsilane (Scheme 8).[19,20] In
that way, the silanes 37, 39, and 41 (91, 82, and 91%) fur-
nished a set of silylated 2-hydrazinopyridines 38, 40, and 42
(96, 96, and 98%) which were converted into the defluori-
nated pyridines 9, 12, and 16 (65, 60, and 51%) by protode-
silylation performed with tetrabutylammonium fluoride hy-
drate (TBAF) and oxidation with cupric sulfate or manga-
nese dioxide.
Introduction of chlorine into pyridines and its displacement
by fluorine: The “upstream” strategy consists of the site-spe-
cific insertion of a heavier halogen, in particular chlorine,
and its subsequent displacement by fluorine in a “halex” op-
eration. As with the silylation described in the preceding
paragraph, organometallic species generated by permuta-
tional hydrogen/metal interconversion acted as the crucial
intermediates to which the extra halogen was delivered.
Thus, 2,3,5-trifluoropyridine (6), 3,5-difluoropyridine (11),
and 2,3-difluoropyridine (13) were all deprotonated by bu-
tyllithium at the 4-position. Treatment with molecular bro-
mine and hexachloroethane or 1,1,2-trichloro-1,2,2-trifluoro-
ethane provided 4-bromo-2,3,5-trifluoro-pyridine (18; 78%),
4-chloro-3,5-difluoropyridine (21; 73%) and 4-chloro-2,3-di-
fluoropyridine (23; 81%; Scheme 9). These compounds re-
Scheme 7.
When both 2-(6-) and 4-positions of a pyridine bear fluo-
rine atoms, hydrazine invariably attacks the latter site. How-
ever, the nucleophilic substitution can be redirected to the
2-(6-)position by screening the 4-halogen with a bulky trial-
kylsilyl group which can be readily attached to halopyridines
such as 4, 7, and 10 by lithiation followed by condensation
Scheme 9.
acted with spray-dried potassium fluoride in anhydrous di-
methyl sulfoxide and in the presence of small amounts of
tetramethylammonium chloride to give 2,3,4,5-tetrafluoro-
pyridine (3; 70%), 3,4,5-trifluoropyridine (5; 51%) and
2,3,4-trifluoropyridine (7; 75%), respectively.
The access to 3,4-difluoropyridine (12) starting from 3-flu-
oropyridine (deprotonated by lithium diisopropylamide,
LIDA) through 4-chloro-3-fluoropyridine (27; 68%) was
hampered by very poor yields at the halogen exchange
stage. A far superior route (Scheme 10) departs from 3-
chloro-5-fluoropyridine (29; made from 5-chloro-2,3-
difluoropyridine (24) by dehydrogenation–dediazotation of
the 2-hydrazino derivative; see above) and passes through
3,4-dichloro-5-fluoropyridine (28; 78%) and 3-chloro-4,5-di-
fluoropyridine (22; 71%) before being terminated with the
catalytic hydrogenation of the latter intermediate (see above).
Scheme 8.
1906
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Nucleophilic Hetarenic Substitution
FULL PAPER
amount of a reference substance (“internal standard”) and correction of
the ratios thus obtained by means of separately established calibration
factors. The stationary phases employed are encoded as DB-23 (silicone
type) and DB-WAX (polyethylene glycol type).
Defluorinations using metals or complex hydrides
2,3,5,6-Tetrafluoropyridine (2): Pentafluoropyridine (1; 55 mL, 85 g,
0.50 mol) and zinc powder (0.13 kg, 2.0 mol) were stirred in a 20% aque-
ous solution (0.50 L) of ammonia at 08C. After 6 h, the mixture was di-
luted with water (1.0 L) and the product was purified by steam distilla-
tion. Distillation at atmospheric pressure afforded 2 as a colorless liquid
(68.2 g; 90%)
;
b.p. 101.5–1028C (ref. [18] 1028C). 1H NMR: d=
7.73 ppm (quint, J=7.1 Hz, 1H).
Scheme 10.
3-Chloro-2,5,6-trifluoropyridine (19): 3-Chloro-2,4,5,6-tetrafluoropyridine
(17; 93 g, 0.50 mol) was slowly added to sodium borohydride (29 g,
0.75 mol) in anhydrous ethanol (0.25 L) keeping the internal temperature
between À108C and 08C, the first third of the reagent was added in the
course of 1 h, the rest over about 15 min. At 08C, the mixture was treated
with 1.5% sulfuric acid (0.80 L). The lower phase was separated to afford
19 (68.1 g; 81%). An additional amount of 19 (9.1 g; 11%) was obtained
by extraction of the aqueous phase with pentanes (3ꢂ40 mL); b.p. 134–
1358C (ref. [26] 718C/99 Torr). 1H NMR: d=7.78 ppm (q, J=7.3 Hz,
1H).
Catalytic hydrogenation was also the last step in the se-
quence leading from 2-fluoropyridine to 2,4-difluoropyridine
(16; 77%; Scheme 11). This time the temporary help of
even two chlorine atoms was required. The first one was in-
Catalytic hydrogenation of chlorofluoropyridines
2,3,4,6-Tetrafluoropyridine (4): The slurry containing 5-chloro-2,3,4,6-tet-
rafluoropyridine (17; 93 g, 0.50 mol), ammonium formate (32 g,
0.50 mol), 10% palladium on charcoal (13 g, 12 mmol), and octanol
(0.25 L) was stirred at 258C for 6 h. The product was directly flash distil-
led from the reaction mixture under reduced pressure and redistilled at
atmospheric pressure; colorless liquid; b.p. 94–968C (ref. [17] 89–908C);
yield: 67.2 g (89%). 1H NMR: d=6.73 ppm (dddd, J=8.0, 4.5, 2.9,
1.6 Hz, 1H).
2,3,6-Trifluoropyridine (8): Prepared analogously from 3-chloro-2,5,6-tri-
fluoropyridine (19; 84 g, 0.50 mol); colorless liquid; b.p. 115–1178C (ref.
[17] 115–1168C); yield: 49.2 g (74%). 1H NMR: d=7.71 (tdd, J=9.0, 8.0,
6.1 Hz, 1H), 6.84 ppm (ddd, J=8.6, 3.2, 2.2 Hz, 1H).
Scheme 11.
2,4,6-Trifluoropyridine (10): Prepared analogously from 3,5-dichloro-
2,4,6-trifluoropyridine (20; 0.10 kg, 0.50 mol) by using 63 g (1.0 mol) of
ammonium formate; colorless liquid; b.p. 988C (ref. [17] 94–958C); yield:
troduced after prior metalation into the 3-position and the
second analogously into the 4-position. The 3,4-dichloro-2-
fluoropyridine (28; 78%) thus obtained was subjected to the
standard “halex” procedure to afford the required 3-chloro-
2,4-difluoropyridine (26; 79%).
1
56.6 g (85%). H NMR: d=6.60 ppm (dt, J=7.7, 1.0 Hz, 2H).
3,4-Difluoropyridine (12): Prepared analogously from 3-chloro-4,5-di-
fluoropyridine (22; 22 g, 0.15 mol) using ammonium formate (9.5 g,
0.15 mol, added in three portions in 1 h intervals) under heating to 458C
for 6 h; colorless liquid; b.p. 101–1038C; yield: 13.6 g (79%). According
to gas chromatography (30 m; DB-WAX; 358C; DB-23; 358C), the prod-
uct contained 4% of 3-fluoropyridine. See later for analytical and spec-
tral data of the pure compound.
Conclusion
2,3-Difluoropyridine (13): 5-Chloro-2,3-difluoropyridine (23; 75 g,
0.50 mol), ammonium formate (63 g, 1.0 mol) and 10% palladium on
charcoal (27 g, 25 mmol) were stirred in 80% acetic acid (0.25 L) at 258C
for 6 h. After filtration and washing with water (0.25 L), the filtrate was
neutralized before being steam distilled; colorless liquid; b.p. 119–1218C
(ref. [27] 1188C); yield: 43.2 g (75%). 1H NMR: d=7.99 (dt, J=4.9,
1.5 Hz, 1H), 7.57 (dtd, J=9.4, 8.1, 1.5 Hz, 1H), 7.19 ppm (ddd, J=8.0,
4.9, 3.3 Hz, 1H).
Using inexpensive starting materials, we have developed
simple and expedient protocols that make all non-commer-
cial di-, tri-, and tetrafluoropyridines readily available. The
synthetic approach is once more tributary to the interven-
tion of selective organometallic methods. The results dis-
closed are of practical importance and, at the same time,
mirror mechanistically fascinating facets.
2,5-Difluoropyridine (14): Prepared analogously starting from 3-chloro-
2,5-difluoropyridine (25; 22 g, 0.15 mol) and stirring for 2 h at 258C; col-
orless liquid; b.p. 113–1158C (ref. [28] 115–1178C); m.p. À35 to À338C;
n2D0 1.4431; yield: 12.1 g (70%). 1H NMR: d=8.06 (dd, J=2.9, 1.6 Hz,
1H), 7.5 (symm. m, 1H), 6.93 ppm (dt, J=9.0, 3.5 Hz); 13C NMR: d=
159.2 (d, J=236 Hz), 157.4 (dd, J=251, 5 Hz), 134.6 (dd, J=28, 17 Hz),
128.2 (dd, J=22, 9 Hz), 110.5 ppm (dd, J=42, 5 Hz); elemental analysis
calcd (%) for C5H3F2N (115.08): C 52.18, H 2.63; found: C 52.20, H 2.68.
Experimental Section
Generalities: Details concerning standard operations and abbreviations
can be found in previous publications from this laboratory.[23–25] 1H and
(1H-decoupled) 13C NMR spectra were recorded at 400 and 101 MHz, re-
spectively, samples having been dissolved in CDCl3 or, if marked by an
asterisk (*), in [D6]acetone. Whenever possible and appropriate, yields
and purities of products were determined, prior to isolation, by gas chro-
2,4-Difluoropyridine (16): 3-Chloro-2,4-difluoropyridine (26; 22 g,
0.15 mol), 10% palladium on charcoal (8.0 g, 7.5 mmol) and ammonium
formate (19 g, 0.30 mol, added in two portions in 2 h intervals), were
heated at 758C in octanol (75 mL) for 4 h. The product was flash-distilled
from the reaction mixture under reduced pressure and redistilled at at-
matographic comparison of their peak areas with that of
a known
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M. Schlosser et al.
mospheric pressure; colorless liquid; b.p. 105–1068C (ref. [29] 1078C);
yield: 13.3 g (77%). 1H NMR: d=8.22 (dd, J=8.6, 5.6 Hz, 1H), 6.96
(dddd, J=7.8, 5.9, 2.3, 0.6 Hz, 1H), 6.67 ppm (dt, J=8.6, 2.1 Hz, 1H).
6 Hz), 128.9 (dd, J=24, 6 Hz), 111.0 ppm (td, J=25, 18 Hz); elemental
analysis calcd (%) for C5H5F2N3 (145.11): C 41.39, H 3.47; found: C
41.69, H 3.27.
Dehalogenation through hydrazino derivatives
5-Chloro-3-fluoro-2-hydrazinopyridine (35): Prepared analogously from
5-chloro-2,3-difluoropyridine (24; 60 g, 0.40 mol) but heating under
reflux for 20 h; colorless prisms (from ethanol); m.p. 173–1748C; yield:
56.2 g (87%); 1H NMR: d=7.95 (d, J=2.0 Hz, 1H), 7.22 (dd, J=10.4,
2.0 Hz, 1H), 5.9 (s, br., 1H), 3.9 ppm (s, br., 2H); 13C NMR: d=148.7 (d,
J=12 Hz), 145.7 (d, J=259 Hz), 140.9 (d, J=6 Hz), 121.4 (d, J=18 Hz),
119.8 (d, J=3 Hz); elemental analysis calcd (%) for C5H5ClFN3 (161.57):
C 37.17, H 3.12; found: C 37.43, H 3.13.
Fluoro(trialkylsilyl)pyridines:
2,3,4,6-Tetrafluoro-5-(trimethylsilyl)pyridine
(37):
Diisopropylamine
(28 mL, 20 g, 0.20 mol), 2,3,4,6-tetrafluoropyridine (4; 30 g, 0.20 mol) and
chlorotrimethylsilane (25 mL, 22 g, 0.20 mol) in tetrahydrofuran (0.10 L)
were consecutively added to a solution containing butyllithium (0.20 mol)
in tetrahydrofuran (0.25 L) and hexanes (0.15 L) cooled in a dry ice/
methanol bath. After 45 min at À758C, the mixture was treated with
water (0.10 L). Upon distillation, a colorless liquid (40.6 g; 91%) was col-
lected; b.p. 67–698C/20 Torr (reference [30] 71–738C/20 Torr).
2,3,6-Trifluoro-4-hydrazinopyridine (36): Prepared analogously from
2,3,4,6-tetrafluoropyridine (4; 15 g, 0.10 mol) at 508C for 2 h; colorless
platelets (from ethyl acetate); m.p. 149–1518C; yield: 14.7 g (90%);
1H NMR: d=8.9 (s, br., 1H), 6.89 (d, J=4.2 Hz, 1H), 3.0 ppm (s, br.,
2H); 13C NMR: d=158.1 (ddd, J=234, 17, 2 Hz), 150.5 (ddd, J=233, 20,
13 Hz), 148.6 (ddd, J=13, 8, 6 Hz), 131.2 (ddd, J=244, 29, 6 Hz),
91.9 ppm (dd, J=46, 5 Hz); elemental analysis calcd (%) for C5H4F3N3
(163.10): C 36.82, H 2.47; found: C 37.14, H 2.33.
2,3,4-Trifluoro-5-(triethylsilyl)pyridine (39): Diisopropylamine (28 mL,
20 g, 0.20 mol) and 2,3,4-trifluoropyridine (7; 27 g, 0.20 mol) were added
consecutively to a solution of butyllithium (0.20 mol) in hexanes (0.15 L)
and tetrahydrofuran (0.35 L) cooled in a dry ice/methanol bath. After 2 h
at À758C, the mixture was treated with chlorotriethylsilane (33 mL, 30 g,
0.20 mol) and, 1 h later, with water (50 mL). The organic phase was
washed with 5% hydrochloric acid (4ꢂ70 mL) and dried. Upon distilla-
tion, a colorless liquid was collected (40.6 g; 82%); b.p. 129–1308C/30
Torr. 1H NMR: d=7.88 (ddd, J=6.7, 1.6, 0.9 Hz, 1H), 0.9 ppm (m, 15H);
13C NMR: d=161.7 (dt, J=258, 6 Hz), 154.4 (ddd, J=238, 17, 5 Hz),
147.0 (m), 134.9 (ddd, J=266, 29, 17 Hz), 120.7 (ddd, J=27, 6, 4 Hz), 7.1,
3.3 ppm; elemental analysis calcd (%) for C11H16F3NSi (247.34): C 53.42,
H 6.52; found: C 53.38, H 6.45.
3,4-Difluoro-2-hydrazinopyridine: Tetrabutylammonium fluoride trihy-
drate (63 g, 0.20 mol) and 3,4-difluoro-2-hydrazino-5-(triethylsilyl)pyri-
dine (40; 52 g, 0.20 mol) in tetrahydrofuran (0.20 L) were kept for 2 h at
258C. The solvent was evaporated and the residue triturated with water
(0.25 L). After filtration and washing with hexanes (3ꢂ20 mL), 20.9 g
(72%) of a pink solid were obtained; colorless cotton-like needles (from
chloroform); m.p. 154–1558C; 1H NMR: d=7.89 (t, J=6.3 Hz, 1H), 6.54
(dt, J=9.4, 5.6 Hz, 1H), 6.0 (s, br., 1H), 3.9 ppm (s, br., 2H); 13C NMR:
d=154.5 (dd, J=259, 8 Hz), 152.0 (dd, J=8, 4 Hz), 143.6 (t, J=8 Hz),
134.8 (dd, J=254, 12 Hz), 104.3 ppm (dd, J=16, 3 Hz); elemental analy-
sis calcd (%) for C5H5F2N3 (145.11): C 41.39, H 3.47; found: C 41.58, H
3.46.
2,4,6-Trifluoro-3-(triethylsilyl)pyridine (41): At À1008C, butyllithium
(0.20 mol) in hexanes (0.15 L) and, 45 min later, chlorotriethylsilane
(34 mL, 30 g, 0.20 mol) were added to a solution of 2,4,6-trifluoropyridine
(10; 27 g, 0.20 mol) in tetrahydrofuran (0.35 L). After 1 h at À758C, the
mixture was poured into water (0.15 L). The organic phase was washed
with brine (2ꢂ50 mL). Distillation afforded a colorless liquid (45.1 g;
91%); b.p. 65–678C/1.6 Torr; n2D0 =1.4630; 1H NMR: d=6.50 (dd, J=7.6,
1.9 Hz, 1H), 0.9 ppm (m, 15H); 13C NMR: d=178.2 (ddd, J=259, 16,
12 Hz), 166.5 (ddd, J=243, 22, 18 Hz), 164.0 (ddd, J=245, 20, 17 Hz),
102.3 (ddd, J=50, 35, 6 Hz), 94.8 (ddd, J=37, 30, 7 Hz), 7.1, 3.8 ppm (t,
J=2.1 Hz); elemental analysis calcd (%) for C11H16F3NSi (247.34): C
53.42, H 6.52; found: C 53.46, H 6.48.
4,6-Difluoro-2-hydrazinopyridine: Prepared analogously from 4,6-di-
fluoro-5-triethylsilyl-2-hydrazinopyridine (42; 52 g, 0.20 mol). After evap-
oration of the solvent, the residue was partitioned between water
(50 mL) and diethyl ether (50 mL). The aqueous phase was extracted
with diethyl ether (2ꢂ20 mL) and the combined organic layers were
evaporated. Upon trituration from hexanes, an orange precipitate was
collected by filtration; colorless cotton-like needles (from chloroform
and hexanes); m.p. 101–1038C; yield: 12.3 g (85%). 1H NMR: d=6.37
(dd, J=10.0, 1.6 Hz, 1H), 6.3 (s, br., 1H), 5.98 (dt, J=8.4, 1.7 Hz),
3.8 ppm (s, br., 2H); 13C NMR: d=172.6 (dd, J=257, 14 Hz), 163.9 (dd,
J=236, 17 Hz), 162.0 (dd, J=20, 14 Hz), 89.7 (dd, J=24, 5 Hz), 86.5 ppm
(dd, J=41, 25 Hz); elemental analysis calcd (%) for C5H5F2N3 (145.11):
C 41.39, H 3.47; found: C 41.69, H 3.27.
Halo(hydrazino)pyridines:
5-Chloro-3,6-difluoro-2-hydrazinopyridine (32): Hydrazine monohydrate
(39 mL, 40 g, 0.80 mol) was slowly added to a solution of 3-chloro-2,5,6-
trifluoropyridine (19; 67 g, 0.40 mol) in ethanol (70 mL) kept at À58C.
After 20 h, the mixture was poured into water (0.35 L). The precipitate,
collected by filtration and dried, proved to be sufficiently pure for further
transformations; yield: 58.9 g (82%); yellow needles (from ethanol); m.p.
120–1218C; 1H NMR: d=7.34 (dd, J=8.8, 6.8 Hz, 1H), 6.2 (s, br., 1H),
3.9 ppm (s, br., 2H); 13C NMR: d=153.6 (d, J=233 Hz), 146.8 (t, J=
14 Hz), 142.4 (dd, J=251, 5 Hz), 125.5 (d, J=19 Hz), 101.2 ppm (dd, J=
38, 4 Hz); elemental analysis calcd (%) for C5H4ClF2N3 (179.56): C 33.45,
H 2.24; found: C 33.65, H 2.20.
Fluorohydrazino(trialkylsilyl)pyridines:
3,4,6-Trifluoro-2-hydrazino-5-(trimethylsilyl)pyridine (38): A solution of
2,3,4,6-tetrafluoro-5-(trimethylsilyl)pyridine (37; 45 g, 0.20 mol) and hy-
drazine (0.40 mol) in tetrahydrofuran (0.40 L) was kept at 08C for 2 h.
Filtration and evaporation afforded a yellow oil (45.2 g; 96%) which
proved to be sufficiently pure for further transformations.
3,4-Difluoro-2-hydrazino-5-(triethylsilyl)pyridine (40): 5-Triethylsilyl-
2,3,4-trifluoropyridine (39; 50 g, 0.20 mol) and hydrazine monohydrate
(19 mL, 20 g, 0.40 mol) in tetrahydrofuran (0.20 L) were heated at 508C
for 20 h. After evaporation of the solvent, hexanes (70 mL) were added
and the salt precipitated was filtered. The filtrate, after evaporation, af-
forded 49.8 g (96%) of an orange oil which proved to be sufficiently pure
for further transformations. 1H NMR: d=7.82 (d, J=6.4 Hz, 1H),
0.9 ppm (m, 15H); 13C NMR: d=158.4 (dd, J=253, 6 Hz), 152.7 (dd, J=
9, 4 Hz), 148.9 (dd, J=14, 9 Hz), 134.6 (dd, J=255, 16 Hz), 110.5 (dd, J=
27, 5 Hz), 7.2, 3.5 ppm.
3,5,6-Trifluoro-2-hydrazinopyridine (33): 2,3,5,6-Tetrafluoropyridine (2;
30 g, 0.20 mol) and hydrazine monohydrate (20 mL, 20 g, 0.40 mol) in
ethanol (70 mL) were heated under reflux for 2 h. Upon addition of
water (0.20 L), a slightly yellow solid precipitated; yellow needles (from
ethanol); m.p. 101–1048C; yield: 28.7 g (88%); 1H NMR: d=7.23 (dd,
J=15.8, 8.7 Hz, 1H), 5.9 (s, br., 1H), 3.8 ppm (s, br., 2H); 13C NMR: d=
145.7 (ddd, J=234, 15, 3 Hz), 143.6 (ddd, J=14, 13, 2 Hz), 141.3 (ddd,
J=252, 5, 3 Hz), 135.1 (ddd, J=250, 30, 5 Hz), 114.8 ppm (td, J=21,
4 Hz); elemental analysis calcd (%) for C5H4F3N3 (163.10): C 36.82, H
2.47; found: C 37.14, H 2.43.
4,6-Difluoro-2-hydrazino-5-(triethylsilyl)pyridine (42): Prepared analo-
gously from 2,4,6-trifluoro-3-(triethylsilyl)pyridine (41; 50 g, 0.20 mol),
but reducing the reaction time to 2 h; slightly yellow oil; yield: 50.8 g
3,5-Difluoro-2-hydrazinopyridine (34): Prepared analogously from 2,3,5-
trifluoropyridine (6; 27 g, 0.20 mol) but heating under reflux in ethanol
(0.20 L) for 6 h. At 258C, addition of water (0.40 L) and filtration afford-
ed 19.7 g (68%) of a white precipitate; colorless prisms (from ethanol);
m.p. 146–1488C; 1H NMR: d=7.91 (d, J=2.5 Hz, 1H), 7.09 (ddd, J=
10.1, 7.7, 2.4 Hz, 1H), 5.9 (s, br., 1H), 3.9 ppm (s, br., 2H); 13C NMR:
d=152.6 (dd, J=249, 3 Hz), 146.9 (d, J=11 Hz), 145.5 (dd, J=260,
1
(98%). H NMR: d=6.30 (d, J=10.0 Hz, 1H), 6.3 (s, br., 1H), 3.8 (s, br.,
2H), 0.9 ppm (m, 15H); 13C NMR: d=177.4 (dd, J=255, 18 Hz), 167.6
(dd, J=233, 22 Hz), 163.1 (dd, J=20, 15 Hz), 90.7 (dd, J=51, 36 Hz),
89.3 (dd, J=30, 5 Hz), 7.5, 4.0 ppm (t, J=2.0 Hz); elemental analysis
1908
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 1903 – 1910

Nucleophilic Hetarenic Substitution
FULL PAPER
calcd (%) for C11H19F2N3Si (259.37): C 50.94, H 7.38; found: C 51.21, H
7.31.
water (0.14 L) were heated under reflux for 25 min. Dilution with water
and steam distillation afforded 16 (see above) as a colorless liquid
(4.11 g; 51%).
Reaction of a chlorohydrazinopyridine with sodium hydroxide:
Metalation and subsequent introduction of chlorine (or bromine)
2,5-Difluoropyridine (14): 5-Chloro-3,6-difluoro-2-hydrazinopyridine (32;
18 g, 0.10 mol) was heated in a 3.0m aqueous solution (66 mL) of sodium
hydroxide (8.0 g, 0.20 mol) under reflux for 45 min. Steam distillation
gave 14 as a colorless liquid (8.63 g; 75%). For spectral and analytical
data, see above.
4-Bromo-2,3,5-trifluoropyridine (18): At À758C, 2,3,5-trifluoropyridine
(6; 27 g, 0.20 mol) was added to butyllithium (0.20 mol) in a mixture of
hexanes (0.15 L) and tetrahydrofuran (0.25 L). After 2 h, the mixture was
treated with bromine (10 mL, 32 g, 0.20 mol) and kept at À758C for 1 h,
before being poured into a saturated solution (0.10 L) of sodium thiosul-
fate. The organic phase was dried and evaporated. Upon distillation, a
colorless liquid was collected; b.p. 59–608C/27 Torr; yield: 33.1 g (78%).
1H NMR: d=7.9 ppm (s, br., 1H); 13C NMR: d=154.9 (ddd, J=258, 5,
3 Hz), 148.1 (ddd, J=239, 15, 3 Hz), 143.8 (dd, J=267, 33 Hz), 128.2
(ddd, J=28, 15, 7 Hz), 111.3 ppm (ddd, J=24, 19, 5 Hz); elemental analy-
sis calcd (%) for C5HBrF3N (211.97): C 28.33, H 0.48; found: C 28.01, H
0.49.
Reactions of hydrazinopyridines with oxidants:
3-Chloro-2,5-difluoropyridine (25): 5-Chloro-3,6-difluoro-2-hydrazinopyr-
idine (32; 18 g, 0.10 mol) and copper(ii) sulfate pentahydrate (50 g,
0.20 mol) in water (0.20 L) were heated under reflux for some 2 h until
the gas evolution ceased. Upon steam distillation a colorless liquid was
collected; m.p. 10–128C; b.p. 136–1378C; n2D0 =1.4786; yield: 10.0 g
(67%). 1H NMR: d=7.98 (t, J=2.3 Hz, 1H), 7.64 ppm (td, J=6.9,
2.6 Hz, 1H); 13C NMR: d=156.6 (dd, J=256, 5 Hz), 154.8 (dd, J=236,
2 Hz), 132.3 (dd, J=27, 14 Hz), 128.3 (dd, J=24, 2 Hz), 117.6 ppm (dd,
J=39, 6 Hz); elemental analysis calcd (%) for C5H2ClF2N (149.53): C
40.16, H 1.35; found: C 40.13, H 1.44.
4-Chloro-3,5-difluoropyridine (21): Prepared analogously from 3,5-di-
fluoropyridine (11; 23 g, 0.20 mol) by using hexachloroethane (47 g,
0.20 mol) instead of bromine. Distillation (b.p. 120–1258C) afforded a
colorless liquid containing compound 21 and tetrachloroethylene. The
liquid was diluted in pentanes (0.15 L) and, at 08C, was treated with a sa-
turated solution (65 mL) of 4.5m hydrogen chloride in diethyl ether. The
precipitate formed was collected by filtration, washed with pentanes (2ꢂ
20 mL) and dissolved in water (30 mL). After neutralization at 08C and
distillation of the organic phase, a colorless liquid was obtained; m.p. 7–
98C; b.p. 129–1318C; yield: 10.9 g (73%); n2D0 =1.4794; 1H NMR: d=
8.4 ppm (s, br., 2H); 13C NMR: d=155.6 (d, J=263 Hz, 2 C), 134.3 (dd,
J=22, 5 Hz, 2 C), 118.6 ppm (t, J=18 Hz); elemental analysis calcd (%)
for C5H2ClF2N (149.53): C 40.16, H 1.35; found: C 40.16, H 1.18.
2,3,5-Trifluoropyridine (6): Prepared analogously from 3,5,6-trifluoro-2-
hydrazinopyridine (33; 25 g, 0.15 mol); colorless liquid; b.p. 101.58C (ref.
[29] 101–1028C); yield: 13.0 g (65%). 1H NMR: d=7.89 (t, J=2.5 Hz,
1H), 7.40 ppm (dtd, J=9.8, 8.5, 2.6 Hz, 1H).
3,5-Difluoropyridine (11): Prepared analogously from 3,5-difluoro-2-hy-
drazinopyridine (34; 15 g, 0.10 mol); colorless liquid; b.p. 92–938C (ref.:
[31] 92.58C); yield: 9.07 g (79%). 1H NMR: d=8.36 (d, J=2.4 Hz, 2H),
7.22 (tt, J=8.6, 2.4 Hz, 1H) ppm.
3-Chloro-5-fluoropyridine (29): Prepared analogously from 5-chloro-3-
fluoro-2-hydrazinopyridine (35; 49 g, 0.30 mol); colorless platelets (from
4-Chloro-2,3-difluoropyridine (22): Prepared as described in the preced-
ing paragraph from 2,3-difluoropyridine (13; 23 g, 0.20 mol) but using
1,1,2-trichloro-2,2,1-trifluoroethane (48 mL, 75 g, 0.40 mol) instead of
hexachloroethane. Distillation at atmospheric pressure afforded a color-
less liquid; b.p. 139–1418C; m.p. À23 to À258C; n2D0 =1.4726; yield: 24.2 g
(81%); 1H NMR: d=7.91 (d, J=5.4 Hz, 1H), 7.34 ppm (t, J=4.9 Hz,
1H); 13C NMR: d=152.8 (dd, J=240, 14 Hz), 143.0 (dd, J=263, 31 Hz),
141.6 (dd, J=15, 8 Hz), 133.6 (d, J=13 Hz), 124.0 ppm (t, J=4 Hz); ele-
mental analysis calcd (%) for C5H2ClF2N (149.53): C 40.16, H 1.35;
found: C 40.25, H 1.36.
1
methanol); m.p. 26–278C; b.p. 132–1348C; yield: 28.4 g (72%); H NMR:
d=8.43 (s, br., 1H), 8.40 (d, J=2.5 Hz, 1H), 7.47 ppm (dt, J=8.1, 2.4 Hz,
1H); 13C NMR: d=158.6 (d, J=262 Hz), 144.6 (d, J=4 Hz), 136.0 (d, J=
23 Hz), 131.8 (d, J=4 Hz), 123.1 ppm (d, J=21 Hz); elemental analysis
calcd (%) for C5H3ClFN (131.54): C 45.65, H 2.30; found: C 45.69, H
2.22.
2,3,6-Trifluoropyridine (8): Prepared analogously starting from 2,3,6-tri-
fluoro-4-hydrazinopyridine (36; 8.2 g, 50 mmol) under reflux for 45 min.
A steam distillation followed by an ordinary distillation afforded a color-
less liquid; yield: 4.86 g (73%). For the physical and spectral data of this
compound, see above.
3,4-Dichloro-5-fluoropyridine (23): Prepared analogously from 3-chloro-
5-fluoropyridine (28; 26 g, 0.20 mol); colorless liquid; m.p. À5 to À28C;
b.p. 78–798C/29 Torr; n2D0 =1.5292; yield: 23.3 g (78%); 1H NMR: d=8.5
(s, br., 1H), 8.4 ppm (s, br., 1H); 13C NMR: d=155.9 (d, J=263 Hz),
145.8 (d, J=5 Hz), 136.5 (d, J=23 Hz), 131.7 (d, J=3 Hz), 129.9 ppm (d,
J=17 Hz); elemental analysis calcd (%) for C5H2Cl2FN (165.98): C 36.18,
H 1.21; found: C 35.99, 1.22.
2,4,5-Trifluoropyridine (9): At 258C, 3,4,6-trifluoro-2-hydrazino-5-(tri-
methylsilyl)pyridine (37; 24 g, 0.10 mol) and tetrabutylammonium fluo-
ride trihydrate (32 g, 0.10 mol) were dissolved in tetrahydrofuran
(0.20 L). After 2 h, the mixture was evaporated and water (0.10 L) was
added. The aqueous phase was extracted with diethyl ether (3ꢂ0.10 L),
and the combined organic layers were evaporated. The residue, copper(ii)
sulfate pentahydrate (50 g, 0.20 mol) and water (0.20 L) were heated for
45 min under reflux. Upon steam distillation followed by an ordinary dis-
tillation, a colorless liquid was isolated; b.p. 99–1018C; n2D0 =1.4201; yield:
8.65 g (65%); 1H NMR: d=8.15 (dt, J=9.6, 1.3 Hz, 1H), 6.83 ppm (ddd,
J=8.0, 4.8, 2.9 Hz, 1H); 13C NMR: d=159.2 (ddd, J=237, 11, 2 Hz),
158.2 (dt, J=267, 13 Hz), 146.7 (ddd, J=254, 11, 6 Hz), 135.9 (ddd, J=
21, 19, 2 Hz), 99.3 ppm (dd, J=46, 19 Hz); elemental analysis calcd (%)
for C5H2F3N (133.07): C 45.13, H 1.51; found: C 45.27, H 1.61.
4-Chloro-3-fluoropyridine (27): Diisopropylamine (28 mL, 20 g, 0.20 mol)
and 3-fluoropyridine (19 g, 0.20 mol) were added consecutively to a so-
lution of butyllithium (0.20 mol) in hexanes (0.15 L) and tetrahydrofuran
(0.35 L) cooled in a dry ice/methanol bath. After 2 h at À758C, the mix-
ture was treated with 1,1,2-trichloro-2,2,1-trifluoroethane (48 mL, 75 g,
0.40 mol) and, 1 h later, with water (80 mL). The organic phase was treat-
ed with 5% hydrochloric acid (4ꢂ30 mL), dried and concentrated. The
residue was distilled affording a colorless liquid; m.p. À27 to À248C; b.p.
81–828C/97 Torr; n2D0 =1.5033; yield: 17.9 g (68%). 1H NMR: d=8.5 (s,
br., 1H), 8.34 (d, J=5.3 Hz, 1H), 7.39 ppm (dd, J=6.5, 5.5 Hz, 1H);
13C NMR: d=155.8 (d, J=259 Hz), 146.2 (d, J=6 Hz), 139.1 (d, J=
23 Hz), 130.5 (d, J=15 Hz), 125.5 ppm; elemental analysis calcd (%) for
C5H3ClFN (131.54): C 45.66, H 2.30; found: C 45.74, H 2.23.
3,4-Difluoropyridine (12): 3,4-Difluoro-2-hydrazinopyridine (see above,
22 g, 0.15 mol) was added in three portions (at 15 min interval) to a mix-
ture of manganese(iv) oxide (13 g, 0.15 mol) in octanol (75 mL) at 158C,
and then the mixture was allowed to reach 258C. After flash distillation
of the crude reaction mixture, the product was redistilled; colorless
liquid; b.p. 102–1038C; n2D0 =1.4426; yield: 10.4 g (60%). 1H NMR: d=
8.59 (dd, J=9.9, 2.3 Hz, 1H), 8.39 (t, J=6.2 Hz, 1H), 7.17 ppm (dt, J=
10.0, 6.1 Hz, 1H); 13C NMR: d=156.0 (dd, J=265, 11 Hz), 148.6 (dd, J=
259, 10 Hz), 147.7 (t, J=6 Hz), 140.8 (d, J=19 Hz), 113.3 ppm (d, J=
13 Hz); elemental analysis calcd (%) for C5H3F2N (115.08): C 52.18, H
2.63; found: C 51.97, H 2.69.
3-Chloro-2-fluoropyridine (31): Prepared analogously from 2-fluoropyri-
dine (17 mL, 19 g, 0.20 mol); colorless liquid; b.p. 68–708C/32 Torr (ref.
[32] 94–958C/100 Torr); yield: 22.4 g (85%); 1H NMR: d=8.12 (dd, J=
4.8, 1.4 Hz, 1H), 7.82 (ddd, J=8.2, 7.6, 1.5 Hz, 1H), 7.17 ppm (ddd, J=
7.9, 4.8, 1.4 Hz, 1H).
3,4-Dichloro-2-fluoropyridine (30): At À758C, 3-chloro-2-fluoropyridine
(31; 26 g, 0.20 mol) was added to butyllithium (0.20 mol) in a mixture of
hexanes (0.15 L) and tetrahydrofuran (0.25 L). After 2 h, the mixture was
2,4-Difluoropyridine (16): 4,6-Difluoro-2-hydrazinopyridine (see above,
10 g, 70 mmol) and copper(ii) sulfate pentahydrate (35 g, 0.14 mol) in
Chem. Eur. J. 2005, 11, 1903 – 1910
www.chemeurj.org
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1909

M. Schlosser et al.
treated with 1,1,2-trichloro-2,2,1-trifluoroethane (48 mL, 75 g, 0.40 mol)
and kept at À758C for 1 h. Upon distillation, a colorless liquid was col-
lected; m.p. 17–198C; b.p. 62–638C/10 Torr; yield: 26.6 g (80%);
1H NMR: d=8.03 (dd, J=5.5, 0.9 Hz, 1H), 7.32 ppm (d, J=5.5 Hz, 1H);
13C NMR: d=159.7 (d, J=239 Hz), 145.7 (d, J=3 Hz), 144.5 (d, J=
24 Hz), 123.4 (d, J=5 Hz), 117.0 ppm (d, J=36 Hz); elemental analysis
calcd (%) for C5H2Cl2FN (165.98): C 36.18, H 1.21; found: C 36.54, H
0.93.
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[Chem. Abstr. 1934, 28, 59577].
Halogen/fluorine displacement
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435–438.
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(to Asahi Glass Co.; filed on 26 Oct. 1990; issued on 9 June 1992).
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Soc. 1965, 575–581.
2,3,4,5-Tetrafluoropyridine (3): 4-Bromo-2,3,5-trifluoropyridine (18; 21 g,
0.10 mol), potassium fluoride (12 g, 0.20 mol) and tetramethylammonium
chloride (2.2 g, 20 mmol) were heated in dimethyl sulfoxide (0.20 L) at
1508C for 2 h. Steam distillation followed by an ordinary distillation gave
3 as a colorless liquid (10.6 g; 70%); b.p. 92–92.58C (ref. :[17] 87–888C).
1H NMR: d=7.96 ppm (dt, J=8.7, 2.1 Hz, 1H).
3,4,5-Trifluoropyridine (5): Prepared analogously from 4-chloro-3,5-di-
fluoropyridine (21; 15 g, 0.10 mol), but extending the reaction time to
6 h; colorless liquid; b.p. 85–878C; yield: 6.74 g (51%); 1H NMR: d=
8.42 ppm (d, J=7.4 Hz, 2H); 13C NMR: d=148.5 (dd, J=263, 8 Hz, 2 C),
144.7 (dt, J=268, 13 Hz), 136.0 ppm (symm. m, 2 C); elemental analysis
calcd (%) for C5H2F3N (133.07): C 45.13, H 1.51; found: C 45.47, H 1.19.
2,3,4-Trifluoropyridine (7): As described for compound 3 starting from 4-
chloro-2,3-difluoropyridine (23; 15 g, 0.10 mol); colorless liquid; b.p. 107–
107.58C (ref. [28] 104.5–1068C); yield: 9.95 g (75%); 1H NMR: d=7.95
(tm, J=6.3 Hz, 1H), 7.09 ppm (dt, J=8.6, 5.3 Hz, 1H).
3-Chloro-4,5-difluoropyridine (22): As described for compound 3 starting
from 3,4-dichloro-5-fluoropyridine (28; 17 g, 0.10 mol) and heating at
1258C for 6 h; colorless liquid; m.p. 4–68C; b.p. 70–728C/98 Torr; nD20
=
1.4760; yield: 10.7 g (71%); 1H NMR: d=8.46 ppm (t, J=8.0 Hz, 2H);
13C NMR: d=152.6 (dd, J=267, 12 Hz), 148.7 (dd, J=263, 10 Hz), 147.2
(d, J=5 Hz), 138.8 (d, J=19 Hz), 120.9 ppm (d, J=12 Hz); elemental
analysis calcd (%) for C5H2ClF2N (149.53): C 40.16, H 1.35; found: C
40.17, H 1.17.
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3-Chloro-2,4-difluoropyridine (26): As described for compound 3 starting
from 3,4-dichloro-2-fluoropyridine (30; 17 g, 0.10 mol); colorless liquid;
m.p. 5–88C; b.p. 146–1478C; nD201.4782; yield: 11.8 g (79%); 1H NMR:
d=8.10 (dd, J=6.8, 5.8 Hz, 1H), 7.07 ppm (dd, J=7.4, 5.7 Hz, 1H);
13C NMR: d=166.5 (dd, J=265, 5 Hz), 160.5 (dd, J=237, 5 Hz), 146.1
(dd, J=17, 10 Hz), 111.2 (dd, J=18, 5 Hz), 106.0 ppm (dd, J=38, 19 Hz);
elemental analysis calcd (%) for C5H2ClF2N (149.53): C 40.16, H 1.35;
found: C 40.37, H 1.28.
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Acknowledgement
This work was supported by the Schweizerische Nationalfonds zur Fçr-
derung der wissenschaftlichen Forschung, Bern (grant 20–100’336–02).
The authors are further indebted to Dr. F. Dorn and Dr. P. Maienfisch of
Syngenta, Basle, for a generous gift of 5-chloro-2,3-difluoropyridine.
[32] G. C. Finger, L. D. Starr, D. R. Dickerson, H. S. Gutowsky, J.
Hamer, J. Chem. Soc. 1963, 28, 1666–1668.
Received: August 13, 2004
[1] F. Leroux, P. Jeschke, M. Schlosser, Chem. Rev. 2005, 105, in press.
Published online: February 1, 2005
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