Hetarenium salts from pentafluoropyridine. Syntheses, spectroscopic properties, and applications

Article abstract of DOI:10.1002/jhet.5570440326

(Chemical Equation Presented) Reaction of pentafluoropyridine with nucleophilic heteroaromatics such as 4-(dimethylamino)pyridine, 4-(pyrrolidin-1-yl)pyridine, 4-(morpholin-4-yl)pyridine, 4-aminopyridine, and 3,4-diaminopyridine resulted in the formation of 4-hetarenium substituted tetrafluoropyridines. The 4-(dimethylamino)-pyridinium derivative underwent substitution reactions with isopropanolate, isopropanethiolate, and benzylthiolate to F²,F³,O⁴,F⁵,F ⁶- and O²,F³,O⁴,F⁵,F ⁶-pentasubstituted pyridines as well as their sulfur analogs. N-Propylamine, isopropylamine, and piperidine formed 4-amino-N ²,F³,F⁵,F⁶-pentasubstituted pyridines in the presence of sodium amide as base, whereas morpholine gave the 4-amino-2,6-bismorpholino-substituted 3,5-difluoropyridine, ¹⁹F, ¹⁵N, ¹³C, and ¹H nmr spectrocopy was performed to elucidate the structures of the substitution products.

Full text of DOI:10.1002/jhet.5570440326

May-Jun 2007
679
Hetarenium Salts from Pentafluoropyridine.
Syntheses, Spectroscopic Properties, and Applications
Andreas Schmidt,* Thorsten Mordhorst, Jan Christoph Namyslo, and Werner Telle
Clausthal University of Technology, Institute of Organic Chemistry, Leibnizstrasse 6,
D-38678 Clausthal-Zellerfeld, Germany
Received October 9, 2006
R1
R2
R
F
N
N
Z
F
F
F
F
F
F
F
F
F
F
F
Z
(R1 = NMe2
R2 = H)
R
N
N
R1 = NMe2, NH2, pyrrolidin-1-yl,
morpholin-4-yl
Z = NH, O, S
R2 = H, NH2
Reaction of pentafluoropyridine with nucleophilic heteroaromatics such as 4-(dimethylamino)pyridine,
4-(pyrrolidin-1-yl)pyridine, 4-(morpholin-4-yl)pyridine, 4-aminopyridine, and 3,4-diaminopyridine
resulted in the formation of 4-hetarenium substituted tetrafluoropyridines. The 4-(dimethylamino)-
pyridinium derivative underwent substitution reactions with isopropanolate, isopropanethiolate, and
benzylthiolate to F2,F3,O4,F5,F6- and O2,F3,O4,F5,F6-pentasubstituted pyridines as well as their sulfur
analogs. N-Propylamine, isopropylamine, and piperidine formed 4-amino-N2,F3,F5,F6-pentasubstituted
pyridines in the presence of sodium amide as base, whereas morpholine gave the 4-amino-2,6-bis-
morpholino-substituted 3,5-difluoropyridine. 19F, 15N, 13C, and 1H nmr spectrocopy was performed to
elucidate the structures of the substitution products.
J. Heterocyclic Chem., 44, 679 (2007).
O2,Cl3,S4,Cl5,O6-pentasubstituted pyridines can be
prepared starting from 4-(dimethylaminopyridinium)-
activated chloropyridines. In view of the current interest
in pentafluoropyridine as valuable building block in
sequential controlled substitution reactions [22,23], we
report here our results on syntheses of pyridinium salts
prepared from pentafluoropyridine, and some reactions of
the 4-(4-dimethylamino)pyridinio substituted tetrafluoro-
pyridine.
INTRODUCTION
4-(Dimethylamino)pyridine (DMAP) and other nucleo-
philic heteroaromatics such as 4-(pyrrolidin-1-yl)pyridine
and 1-methylimidazole are very versatile reagents in
organic chemistry due to catalyzing, stabilizing, and
activating properties. Catalysis of acylations [1-4], Baylis-
Hillman [5] and Dakin-West reactions [6], silylations [7],
and many other syntheses by DMAP is widely applied in
organic synthesis. Stabilization of reactive species such as
allyl anions [8], allyl radicals [9], uracilates [10,11],
pyrimidinium-olates [12-14] as well as -aminides [15,16],
pyridinium-olates [17] and heteroaromatics with up to ten
positive charges within a common ꢀ-electron system by
4-(dimethylamino)-pyridinium and other hetarenium
substituents [18] was reported. The activation of
perhalogenated heteroaromatics by hetarenium substi-
tuents can be applied for the preparation of otherwise
unavailable functionalized heteroaromatics. We reported
that activation of pentachloropyridine by 4-(dimethyl-
amino)pyridinium substituents enables the synthesis of
Cl2,Cl3,O4,Cl5,Cl6- and O2,Cl3,O4,Cl5,Cl6-pentasubstituted
pyridines [19] as well as their sulfur analogs [20].
Similarly, first examples of O2,Cl3,O4,Cl5,O6- [17] and
N2,Cl3,S4,Cl5,N6- [21] substitution patterns, biologically
RESULTS AND DISCUSSION
Reaction of pentafluoropyridine with 4-(dimethyl-
amino)pyridine, 4-(pyrrolidin-1-yl)pyridine, 4-(morpho-
lin-4-yl)pyridine, 4-aminopyridine, and 3,4-diamino-
pyridine gave the 2',3',5',6'-tetrafluoro-[1,4]bipyridinyl-1-
ylium fluorides 2a-e (Scheme 1). Best yields were
obtained when ethyl acetate was used as the solvent, and
when reaction times of approximately 6 hours at room
temperature were allowed. Heating in 1,2-dichloro-
benzene and excessive heteroarene did not improve the
yields, but caused the formation of by-products which
were difficult to separate.
Whereas the structure elucidation of 2a-c is
unambiguous, alternative structures for 2d and 2e had
to be taken into consideration. 4-Aminopyridine and
3,4-diaminopyridine are N,N-bis- and N,N,N-tris-
interesting S2,Cl3,S4,Cl5,S6- [20], and
a variety of

680
A. Schmidt, T. Mordhorst, J. C. Namyslo, W. Telle
Vol 44
Scheme 1
R1
R2
R1
R2
F
N
F
F
F
F
F
F
F
F
F
N
N
N
1
2a - 2e
Compound
R1
R2
Mp
Yield
%
Molecular
Formula
HR-ESI-MS
Calcd/Found
(°C)
+
2a
2b
2c
2d
2e
N(CH3)2
pyrrolidin-1-yl
morpholin-1-yl
NH2
H
H
H
158
126
62
93
79
99
75
88
C12H10N3F5
C14H12N3F5
C14H12N3OF5
C10H6N3F5
C10H7N4F5
272.0811 (C12H10N3F4 ) / 272.0811
+
298.0967 (C14H12N3F4 ) / 298.0976
+
314.0917 (C14H12N3OF4 ) / 314.0918
+
H
NH2
216
102
244.0491 (C10H6N3F4 ) / 244.0498
+
NH2
259.0610 (C10H7N4F4 ) / 259.0607
(dec.)
nucleophiles, respectively, and amines are known to
react smoothly with pentafluoropyridine in the 4-
position. The pyridinium salts 2a-e, however, behave
very similar under electrospray ionization mass
spectrometry (ESIMS) conditions, which is the method
of choice to detect cationic molecules. Thus, the base
peaks in the high-resolution ESI mass spectra of all
compounds 2a-e are the molecular peaks. Sodium
adducts, which are often observed on measurement of
uncharged compounds, are not detected. The formation
of pyridinium salts was moreover confirmed by an
HMBC spectrum of 2e which unambiguously
displayed the CH-coupling of C-4 to H-2' and H-6' of
the 3,4-diaminopyridinium ring.
Reaction of pentafluoropyridine with five equiva-
lents of 4-(dimethylamino)pyridine and trimethylsilyl
trifluoromethanesulfonate (TMSOTf) in 1,2-dichloro-
benzene resulted in the formation of the pentacationic
species 3 in 90% yield (Scheme 2) which is also
available starting from pentachloropyridine applying
analogous reaction conditions [18].
We then tested some nucleophilic substitutions on
the 4-(dimethylamino)pyridinio substituted 2,3,5,6-
tetrafluoropyridine 2a. This salt is stable toward water
over a period of 10 hours at reflux temperature.
Whereas pentafluoropyridine reacts with sodium
hydroxide to 4-hydroxytetrafluoropyridin [24], the
pyridinium salt 2a gives 3,5,6-trifluoro-2,4-dihydro-
xypyridine. No reaction was observable on treatment
of 2a with 2-propanolate at room temperature. At
reflux temperature, however, a mixture of compounds
was obtained after a reaction time of 2 hours.
Performing the reaction at 45°C over a period of six
hours resulted in the formation of 2,3,5-trifluoro-4,6-
di-(2-propoxy)pyridine 5 which was isolated in 45%
yield after chromatographic work-up (Scheme 3).
2,3,5,6-Tetrafluoro-4-(2-propoxy)pyridine
4 was
found as by-product in 12% yield. This compound is
the major product of the reaction of pentafluoro-
pyridine with 2-propanol in dimethylformamide in the
presence of triethylamine at room temperature [25].
According to a GCMS analysis of the crude reaction
mixture, an additional by-product of this reaction is
tris-(2-propoxy)-substituted difluoropyridine, as peaks
at m/z 289 (M, 51), and characteristic fragmentation
patterns at m/z 247, 203, and 160 are detectable. In 19F
nmr spectroscopy in deuteriochloroform, signals of
the monopropoxy derivative 4 were detected at ꢀ -
158.8 ppm and ꢀ -91.4 ppm, which were assigned to
3/5-F and 2/6-F, respectively. The value of the FF
coupling constants through five, three, and four bonds
were measured as ꢀ –34.3, –17.5 Hz, and –4.6 Hz,
respectively. As expected, the bispropoxy derivative 5
gave three distinct 19F nmr resonance frequencies
Scheme 2
N(CH3)2
5 OTf
N(CH3)2
N(CH3)2
N
5 DMAP
5 TMSOTf
N
N
N
N
1
1,2-dichloro-
benzene
N
N(CH3)2
N(CH3)2
3

May-Jun 2007
Hetarenium Salts from Pentafluoropyridine.
681
Syntheses, Spectroscopic Properties, and Applications
which were detected at ꢀ -167.1, -159.1, and -94.4
ppm. The measurement yielded characteristic
coupling constants (see Experimental). This reaction
is similar to the preparation of 2,4-di-tert-butoxy-
3,5,6-trifluoropyridine from pentafluoropyridine and
the potassium salt of tert-butyl alcohol which is quite
temperature-sensitive [26].
mono- and 4,6-bis-sulfanyls 6b and 7b, which was
separated chromatographically, in 68% yield.
According to the Beilstein CrossFire database, 7b is the
first representative of a S2,F3,S4,F5,F6-pentasubstituted
pyridine.
Scheme 4
R
R
S
S
Scheme 3
F
F
F
S
F
F
F
F
RSH
+
2a
CH3
CH3
R
N
N
CH3
F
O
CH3
F
O
7
6
iPrONa
iPrOH
F
F
F
CH3
CH3
+
6a,7a: R = iPr
6b,7b: R = CH2Ph
2a
F
N
O
F
N
5
1-Propylamine, 2-propylamine, and piperidine afforded
the 2-NR2-substituted 4-amino-3,5,6-trifluoropyridines
8a-c on reaction with 2a (Scheme 5), when the reaction is
conducted in the presence of sodium amide as base. The
13C nmr spectra clearly indicated non-symmetric
structures in agreement with an ꢁ, ꢂ-disubstitution pattern
of the former pentafluoropyridine ring. Ten protons in 8a
4
2-Propanethiole and benzylthiole were chosen as S-
nucleophiles. The former mentioned thiole replaced the
4-(dimethylamino)pyridinium ring of 2a in a mixture
of acetone and methanol within 18 hours at room
temperature to give the 4-(2-propanesulfanyl)-tetra-
fluoropyridine 6a which is a known compound [27]
(Scheme 4). Benzylthiole reacted to a mixture of 4-
1
and 8b were detected by H nmr spectroscopy, and the
mass spectra confirmed one amino group plus one
Figure 1. 1H-15N-HMBC spectrum of 8b in [D6]-DMSO.

682
A. Schmidt, T. Mordhorst, J. C. Namyslo, W. Telle
Vol 44
A priori, two mechanisms for the formation of 8a-c
and 9 have to be considered. Thus, substitution of the
4-(dimethylamino)pyridinium ring by amide yielded
Scheme 5
NH2
F
F
F
the observed products. In
a control experiment,
R-NH-R´
2a
however, the pyridinium salt 2a did neither react with
sodium amide (DMF, reflux, 6 h), nor with ammonia
(dioxane/water, 30 h at rt or 4 h at 90°C) to 4-amino-
tetrafluoropyridine. Therefore, we assume a dealkyl-
ation mechanism (Scheme 7), which we proved in a
reaction of the tetrachloro derivative of 2a in an
analogous series of reactions before [28].
R
NaNH2
N
N
R´
8a-c
R-NH-R´
NH2
8a:
8b:
Me
NH2
NH
Scheme 7
R
8c:
R
R
R´N
H
H
N
N
N
N
RCH2NHR´
NaNH2
F
F
F
F
F
F
propylamino group attached to the trifluoropyridine ring,
respectively. In the 13C nmr spectrum taken in deuterio-
chloroform the resonance frequency of C3 of 8b is
diagnostically important, as it shows the splitting
expected for a N2,F3,N4,F5,F6-substitution pattern, and the
characteristic magnitudes of the coupling constants (dd,
N
R
N
R
R´
R´
R
R
N
3
1JCF = 236.6 Hz; JCF = 4.4 Hz). Halogen dance reactions
R´
were therefore excluded from consideration. The 15N nmr
spectrum taken in [D6]-DMSO displayed three signals at ꢀ
-327.7 (NH2), -294.7 (NH), and -181.7 ppm (Npyr). In
NH2
N
HN
N
work-
up
F
F
F
F
F
F
1
contrast to the H nmr spectrum taken in deuteriochloro-
form, separated resonance frequencies of the secondary
amine proton at ꢀ 5.9 ppm and the methine proton at ꢀ 3.9
ppm were measured in deuteriodimethylsulfoxide, and
after some variation of the concentration of the solution of
N
R
N
R
R´
R´
In summary, we present new (tetrafluoro-4-yl)pyri-
dinium salts which can serve as starting materials for the
synthesis of highly functionalized pyridines.
1
8b we were able to measure an H-15N-HMBC spectrum
3
which is shown in Figure 1. The JNH-coupling between
the nitrogen atom of the pyridine ring and the secondary
NH proton proves that the isopropylamino group is
attached to C2 of the pyridine ring. In accordance with the
assigned structure, three 19F nmr resonance frequencies
appear at ꢀ –177.1, -164.4, and 97.0 ppm, respectively.
Under analogous reaction conditions, morpholine
gave the 2,6-bis-morpholino-substituted 4-amino-3,5-
difluoropyridine 9 (Scheme 6). In accordance to the
assigned structure, only one 19F nmr resonance
frequency is detectable at ꢀ = -160.0 ppm as a singlet.
EXPERIMENTAL
The nmr spectra were recorded on a Bruker Avance 400 at
400 MHz (1H nmr), 100 MHz (13C nmr), 376 MHz (19F nmr) and
40 MHz (15N nmr), respectively. The chemical shifts of the H
1
and 13C nmr spectra are reported in ppm relative to internal
tetramethylsilane (ꢀ = 0.00 ppm). The exact reference for the 19
F
nmr spectra was trichlorofluoromethane (Cl3CF) in deuterio-
chloroform (ꢀ = 0.0 ppm), and for the 15N nmr measurements
nitromethane (CH3NO2) in deuteriochlorofom (ꢀ = 0.0 ppm). FT-
IR spectra were obtained on a Bruker Vector 22 in the range of
400 to 4000 cm-1 (2.5 % pellets in KBr). The GC-MS spectra
were recorded on a GC Hewlett-Packard 5980, Serie II in
combination with a MS Hewlett-Packard 5989 B, and on a
Varian GC3900 with SAT2100T mass spectrometer. Melting
points are uncorrected. The fluorine contents prevented us from
performing CHN analyses.
Scheme 6
O
NH2
N
F
F
H
2a
General procedure for the synthesis of the 2',3',5',6'-
tetrafluoro-[1,4]bipyridinyl-1-ylium fluorides (2a-e).
Pentafluoropyridine (1.69 g, 10 mmol) and the heteroarene [4-
(dimethylamino)pyridine (1.22 g, 10 mmol), 4-(pyrrolidin-1-
NaNH2
N
N
N
O
O
9

May-Jun 2007
Hetarenium Salts from Pentafluoropyridine.
683
Syntheses, Spectroscopic Properties, and Applications
yl)pyridine (1.48 g, 10 mmol), 4-(morpholin-4-yl)-pyridine
(1.64 g, 10 mmol), 4-aminopyridine (0.94 g, 10 mmol), 3,4-
diaminopyridine (1.09 g, 10 mmol), respectively] were
suspended in 100 mL of ethyl acetate. The suspensions were
stirred for 6 h, respectively. The precipitates were filtered off
and dried in vacuo.
2,3,5,6-Tetrafluoro-4-isopropoxypyridine (4). This
compound was isolated as a by-product in the synthesis of 5 and
was isolated as colorless oil (Rf 0.44, petrol), yield 231 mg
1
3
(12%). H nmr (deuteriochlorofom): 1.48 (d, J = 6.1 Hz, 6H;
CH3), 5.06 (sept, 3J = 6.1 Hz, 1H; CH); 19F nmr (trichlorofluoro-
methane): ꢀ -91.4 (ddd, badly resolved; 2/6-F), -158.0 (ddd, 5J3,6
5
3
3
4
4
4-(Dimethylamino)-2',3',5',6'-tetrafluoro-[1,4]bipyridinyl-
1-ylium fluoride (2a). This salt was isolated as a yellow solid,
= J5,2 = -34.3 Hz, J3,2 = J5,6 = -17.5 Hz, J3,5 = J5,3 = -4.6 Hz;
3/5-F); 13C nmr (deuteriochlorofom) ꢀ 22.6 (CH3), 78.4 (CH),
1
mp 155 – 158°C. H nmr ([D6]-DMSO): ꢀ 8.45 (d, 3J = 7.8 Hz,
1
1
135.7 (d, JCF = 255.2 H, C-3/5), 144.3 (d, JCF = 239.9 Hz, C-
2/6), 146.6 (C-4); ir (sodium chloride): 2932, 2361, 1719, 1643,
1503, 1472, 1389, 1258, 1092, 977, 904, 739, 589, cm-1; ms: m/z
= 210 ([M+H]+, 100).
3
2H; H-2'), 7.36 (d, J = 7.8 Hz, 2H; H-3'), 3.35 (s, 6H; CH3)
1
3
ppm; H nmr (CD3OD): ꢀ 8.24 (d, J = 8.0 Hz, 2H, H-2'), 7.19
(d, 3J = 8.0 Hz, 2H, H-3'), 3.31 (s, 6H, N(CH3)2); 13C nmr
(CD3OD): ꢀ 39.8 (CH3), 108.2 (C-3'), 130.9 (m, C-4), 137.9 (d,
1J = 256.2 Hz, C-2), 141.4 (C-2'), 143.6 (ddd, 1J = 244.7 Hz, 2J =
2,3,5-Trifluoro-4,6-di-(2-propoxy)-pyridine (5). Sodium 2-
propanolate (0.82 g, 10 mmol) and 4-(dimethylamino)-2',3',5',6'-
tetrafluoro-[1,4]bipyridinyl-1-ylium fluoride 2a (2.91 g, 10
mmol) in 50 mL of 2-propanol were heated at 45°C over a
period of 5 h. After cooling, the alcohol was distilled off in
vacuo. The residue was chromatographed on silica gel with ethyl
acetate/petrol = 1:8. The pyridine 5 was obtained as colorless
solid in 45% yield (1.05 g); Rf = 0.42 (petrol/ethyl acetate =
8:1). 1H nmr (deuteriochloroform): ꢀ 5.20 (sept, 3J = 6.2 Hz, 1H;
4
14.3 Hz, J = 4.4 Hz, C-2) 157.2 (C-4'); ir (potassium bromide):
3442, 3033, 2360, 1651, 1585, 1492, 1233, 1164, 970, 847 cm-1.
2',3',5',6'-Tetrafluoro-4-(pyrrolidin-1-yl)-[1,4]bipyridinyl-
1-ylium fluoride (2b). This compound was isolated as a yellow
solid. 1H nmr (DMSO-d6): ꢀ 8.46 (d, 3J = 7.9 Hz, 2H; H-2'), 7.22
3
(d, J = 7.9 Hz, 2H; H-3'), 3.51 – 3.75 (m, 4H; N-CH2-), 1.95 –
2.15 (m, 4H; -CH2-) ppm; 13C nmr (DMSO-d6): ꢀ 153.5 (C-4'),
143.7 (dtd, 1JCF = 245.0 Hz, 2JCF = 14.7 Hz, 3JCF = 4.4 Hz, 2C, C-
2), 141.2 (C-2'), 137.1 (ddd, 1JCF = 262.6 Hz, 2JCF = 29.7 Hz, 3JCF
= 5.8 Hz, 2C, C-3), 130.9 (m, 1C, C-4), 109.2 (C-3'), 49.2 (N-
CH2-), 24.5 (-CH2-) ppm; ir (potassium bromide): 3088, 3030,
2880, 1648, 1574, 1508, 1477, 1227, 1164, 972, 848 cm-1.
2',3',5',6'-Tetrafluoro-4-(morpholin-4-yl)-[1,4]bipyridinyl-
1-ylium fluoride (2c). This salt was obtained as a yellow solid.
1H nmr (D2O): ꢀ 8.11 (d, 3J = 7.2 Hz, 2H; H-2'), 7.18 (d, 3J = 7.2
Hz, 2H; H-3'), 3.60 – 3.90 (m, 8H; -CH2-) ppm; 13C nmr (D2O): ꢀ
156.6 (C-4'), 143.6 (dtd, 1JCF = 243.6 Hz, 2JCF = 15.4 Hz, 3JCF = 2.9
Hz, 2C, C-2), 141.8 (C-2'), 137.6 (ddd, 1JCF = 261.2 Hz, 2JCF = 32.2
Hz, 3JCF = 4.4 Hz, 2C, C-3), 130.9 (m, 1C, C-4), 108.3 (C-3'), 65.7
(-OCH2-), 46.9 (NCH2-) ppm; ir (potassium bromide): 3443, 1645,
1565, 1490, 1233, 1163, 1114, 972, 932 cm-1.
3
3
CH), 4.87 (sept, J = 6.2 Hz, 1H; CH), 1.40 (d, J = 6.2 Hz, 6H;
CH3), 1.37 (d, 3J = 6.2 Hz, 6H; CH3) ppm; 19F nmr
(trichlorofluoromethane): ꢀ -94.4 (dd, 3JFF = 25.2 Hz; 5JFF = 22.9
3
5
Hz; 6-F), -159.1 (d, JFF = 25.2 Hz; 5-F), -167.1 (d, JFF = 22.9
Hz; 3-F); 13C nmr (deuteriochloroform): ꢀ 21.9 (CH3), 22.6
1
2
(CH3), 70.4 (CH), 77.5 (CH), 132.5 (dd, JCF = 251.3 Hz, JCF
=
1
3
30.4 Hz; C-5), 137.2 (dd, JCF = 252.7 Hz, JCF = 7.0 Hz; C-3),
144.6 (ddd, 1JCF = 233.3 Hz, 2JCF = 13.6 Hz, JCF = 3.3 Hz; C-6),
4
144.8 (m, C-2), 145.7 (m, C-4); ir (potassium bromide): 1568,
1531, 1436, 1398, 1319, 1299, 1165, 1132, 1095 cm-1; ms: m/z =
249 (M+, 56); 189 (M - C3H7O, 100).
2,3,5,6-Tetrafluoro-4-(2-propylsulfanyl)-pyridine (6a). A
sample of the pyridinium fluoride 2a (2.91 g, 10 mmol) was
dissolved in 100 mL of methanol and acetone (1:10), before 2-
propanethiol (0.76 g, 10 mmol) was added. Then, the mixture
was stirred at room temperature for 18 h. The solvent mixture
was then distilled off in vacuo, and the residue was
chromatographed (silica gel, ethyl acetate/petrol = 1:1) to give a
yellow oil in 40% yield (0.90 g); Rf = 0.86 (ethyl acetate/petrol
= 1:1). 1H nmr (deuteriochloroform): ꢀ 3.95 (h, 3J = 6.7 Hz, 1H;
4-Amino-2',3',5',6'-tetrafluoro-[1,4]bipyridinyl-1-ylium
1
fluoride (2d). This salt was isolated as a yellow solid. H nmr
([D6]-DMSO): ꢀ 9.62 (s, br, NH2), 8.31 (d, 3J = 7.6 Hz, 2H; H-
2'), 7.08 (d, 3J = 7.6 Hz, 2H; H-3') ppm; 13C nmr ([D6]-DMSO):
ꢀ 160.2 (C-4'), 142.3 (C-2'), 110.0 (C-3') ppm; the C-atoms of
the fluoropyridine moiety gave very small signals; ir (potassium
bromide): 3063, 1638, 1475, 1158, 972, 867, 835, 747 cm-1.
3,4-Diamino-2',3',5',6'-tetrafluoro-[1,4]bipyridinyl-1-ylium
3
CH), 1.37 (d, J = 6.7 Hz, 6H; CH3) ppm. 13C nmr (deuterio-
chloroform): ꢀ 145.8 (ddd, J = 229.4 Hz, J = 14.0 Hz, J = 2.9
Hz, C-3), 141.0 (ddd, J = 231.4 Hz, J = 14.0 Hz, J = 2.9 Hz, C-
2), 130.9 (tt, J = 18.1 Hz, J = 2.9 Hz, C-4), 38.3 (CH), 23.3
(CH3) ppm; ms: m/z = 226 (MH+, 100), 181 (M - C3H7, 18).
4-Benzylsulfanyl-2,3,5,6-tetrafluoropyridine (6b) and 4,6-
Bisbenzylsulfanyl-2,3,5-trifluoropyridine (7b). A sample of
the pyridinium fluoride 2a (2.91 g; 10.0 mmol) and 1.24 g (10.0
mmol) of benzylthiol was dissolved in 100 mL of acetone and
methanol (5:1) and stirred at room temperature for 36 h. A small
portion of silica gel was added to the reaction mixture, and then
the solvent was evaporated in vacuo. The residue was then
chromatographed (silica gel, petrol).
1
fluoride (2e). This salt was isolated as a yellow solid. H nmr
(D2O): ꢀ 7.69 (dd, 3J = 6.5 Hz, 4J = 1.1 Hz, 1H; H-6'), 7.64 (d, 4J
= 1.1 Hz, 1H; H-2'), 6.81 (dd, 3J = 6.5 Hz, 4J = 1.1 Hz, 1H; H-5')
1
ppm; 13C nmr (D2O): ꢀ 151.4 (C-4'), 143.7 (ddd, JCF = 245.5
2
4
1
Hz, JCF = 14.7 Hz, JCF = 3.4 Hz, 2C, C-2), 137.7 (ddd, JCF
=
2
4
265.2 Hz, JCF = 37.8 Hz, JCF = 2.5 Hz, 2C, C-3), 136.3 (C-3'),
132.5 (C-6'), 131.5 (t, JCF = 12.1 Hz, 1C, C-4), 122.8 (C-2'),
2
107.6 (C-5') ppm; ir (potassium bromide): 1618, 1581, 1476,
1333, 1147, 972, 850 cm-1.
1,1',1'',1''',1''''-Pentakis[4-(dimethylamino)-(pyridine-2,3,
4,5,6-pentayl)pyridinium]pentakis(trifluoromethanesulfonate)
(3). Pentafluoropyridine (1.68 g, 10 mmol), 4-(dimethylamino)-
pyridine (6.1 g, 50 mmol) and trimethylsilyl trifluoromethan-
sulfate (12.22 g, 55 mmol) were dissolved under nitrogen in 200
mL of 1,2-dichlorobenzene and heated at 180°C. After one hour,
the solution was cooled to room temperature, and the crude
reaction product was filtered off, washed several times with
petrol and dried in vacuo. Analytical and spectroscopic data are
in total agreement with those reported earlier [18].
4-Benzylsulfanyl-2,3,5,6-tetrafluoropyridine (6b). This
compound was isolated as yellow oil, Rf = 0.33 (petrol), yield:
1
936 mg (34%). H nmr (deuteriochloroform): ꢀ 4.31 (s, 2H;
CH2), 7.15 – 7.35 (m, 5H; HPh); 13C nmr (deuteriochloroform): ꢀ
1
43.4, 127.4, 128.3, 128.9, 135.3, 137.4, 141.2 (d, JCF = 254.2
1
Hz, C3/5), 143.4 (d, JCF = 244.3 Hz); ir (sodium chloride):
3031, 1629, 1460, 1070, 1027, 949, 892, 765, 698, 580, 565,
cm-1 ms: m/z = 181 (M-CH2C6H5; 20%).

684
A. Schmidt, T. Mordhorst, J. C. Namyslo, W. Telle
Vol 44
1
2,4-Bisbenzylsulfanyl-3,5,6-trifluoropyridine (7b). This
compound was isolated as yellow oil, Rf 0.08 (petrol), yield: 910
mg (34%). H nmr (deuteriochloroform): ꢀ 4.12 (s, 2H; CH2),
4.23 (d, J = 5.7 Hz, 2H; CH2), 6.99 – 7.40 (m, 10H; HPh); 13C
nmr (deuteriochloroform): ꢀ 34.0, 38.2, 135.9, 137.0, 127.6 –
129.8 (10 C, overlapped); ir (sodium chloride): 3063, 3030,
1596, 1560, 1495, 1454, 1432, 1385, 1356, 1316, 1265, 1239,
1205, 1155, 1071, 1029, 999, 909, 842, 802, 767, 739, 700, 563
cm-1 ; ms: m/z = 377 (M+, 100%).
(5:1) to give 8b in 32% yield. H NMR (deuteriochloroform): ꢀ
3.36 (m, 8H; -N(CH2)2-), 3.84 (m, 8H; O(CH2)2-), 4.17 (s, 1H;
NH2); 4.19 (s, 1H; NH2); 19F nmr (trichlorofluoromethane) ꢀ -
160.0 (s); 13C nmr (deuteriochloroform): ꢀ 48.3 (-N(CH2)2), 66.9
(O(CH2)2-), 133.0 (C-4), 134.1 (d, J = 221 Hz; C-3/5), 141.9 (C-
2/6); ir (potassium bromide) = 3218, 2964, 2857, 1639, 1603,
1476, 1446, 1371, 1350, 1289, 1263, 1160, 1114, 1068, 939; ms:
m/z = 300 (M+, 100%).
1
Acknowledgement. The Deutsche Forschungsgemeinschaft is
gratefully acknowleged for the financial support. We thank Dr.
Gerald Dräger, University of Hannover, for measuring the HR-
ESI-MS spectra.
4-Amino-3,5,6-trifluoro-2-propylamino-pyridine (8a).
A
sample of 0.7 g of pyridinium fluoride 2a (2.4 mmol) and 0.47 g
of sodium amide (12 mmol) in 30 mL of n-propylamine was
heated at 35°C for 5 h. A small amount of silica gel was added
and the excess amine was evaporated in vacuo. The residue was
then chromatographed (silica gel, ethyl acetate/petrol = 1:7). The
product was isolated as a brown oil (Rf 0.24; ethyl acetate/petrol
= 1:7), mp. 137 – 141°C. 1H nmr (deuteriochloroform): ꢀ 0.96 (t,
J = 7.3 Hz, 3H; CH3), 1.60 (m, 2H, CH3CH2CH2), 3.32 (m, 2H,
CH3CH2CH2); 13C nmr (deuteriochloroform): ꢀ 11.4, 23.1, 42.9;
the resonance frequencies of the pyridine ring were too small to
be assigned; ms: m/z = 205 (M+, 80%), 176 (M+-C2H5, 100%).
4-Amino-3,5,6-trifluoro-2-(2-propylamino)-pyridine (8b).
A sample of the pyridinium salt 2a (0.3 g; 1.37 mmol) and
sodium amide (0.27 g; 6.9 mmol) in 15 mL of 2-propylamine
was heated at reflux temperature for 5 h. A small amount of
silica gel was added and the excess amine was distilled off in
vacuo. The residue was then chromatographed (petrol/ethyl
acetate = 5:1) to give 8b as brown oil (Rf = 0.38; petrol/ethyl
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1
3
acetate = 5:1). H nmr (deuteriochloroform): ꢀ 1.23 (d, J = 6.3
Hz, 6H; CH3), 4.10 (s, br, NH), 4.12 (sept, 3J = 6.6 Hz, 1H; CH),
4.31 (s, br, 2H, NH2); 19F nmr (trichlorofluoromethane): ꢀ -97.0
(dd, 3JFF = -26.7 Hz, 5JFF = -24.4 Hz; 6-F), -164.4 (d, 5JFF = -24.4
[9] DiMagno, S. G.; Waterman, K. C.; Speer, D. V.; Streitwieser,
A. J. Am. Chem. Soc. 1991, 113, 4679.
[10] Schmidt, A.; Kindermann, M. K.; Vainiotalo, P.; Nieger, M.
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1325.
3
Hz; 3-F), -177.1 (dd, JFF = -26.7 Hz; 5-F); 13C nmr (deuterio-
1
chloroform): ꢀ 23.2 (CH3), 42.5 (CH), 126.2 (ddd, JCF = 240.0
2
3
1
Hz, JCF = 34.0 Hz, JCF = 1.2 Hz; C-5), 131.8 (dd, JCF = 236.6
3
2
3
Hz, JCF = 4.4 Hz; C-3), 133.1 (ddd, JCF = 13.3 Hz, JCF = 6.6
3
2
3
Hz, JCF = 4.5 Hz; C-4), 140.2 (ddd, JCF = 18.5 Hz, JCF = 11.6
Hz, 4JCF = 1.9 Hz; C-2), 145.7 (ddd, 1JCF = 224.7 Hz, 2JCF = 11.6
4
Hz, JCF = 2.1 Hz; C-6); ms: m/z = 205 (M+, 62%), 190 (M+ -
NH2, 100%).
[16] Schmidt, A. J. Heterocycl. Chem. 2002, 39, 949.
[17] Schmidt, A.; Mordhorst, T.; Habeck, T. Org. Lett. 2002, 4,
1375.
[18] Schmidt, A.; Mordhorst, T.; Nieger, M. Org. Biomol. Chem.,
2005, 3, 3788.
[19] Schmidt, A.; Mordhorst, T. Synthesis 2005, 781.
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Chem. 1996, 76, 67.
2,3,5-Trifluoro-6-(N-piperidino)-4-amino-pyridine (8c). A
solution of pyridinium fluoride 2a (2.91 g, 10 mmol) and sodium
amide (0.59 g, 15 mmol) in 100 mL of piperidine was heated at
reflux temperature for 4 h. The piperidine was then distilled off
and the residue was chromatographed (silica gel, ethyl
acetate/petrol = 1:1) to give a grey solid, mp 59 °C, in 66% yield
1
(Rf = 0.81; ethyl acetate / petrol = 1:1). H nmr (deuteriochloro-
form): ꢀ 4.53 (s, 2H; CH2), 3.25 – 3.30 (m, 4H; CH2), 1.55 – 1.73
(m, 6H; CH2) ppm; 13C nmr (deuteriochloroform): ꢀ 48.8, 25.7,
24.5 ppm; the signals of the pyridine are too small; ir (potassium
bromide): 3512, 3395, 2933, 2850, 1639, 1487, 1464, 1450, 1249,
1118, 1091, 932 cm-1; ms: m/z = 232 (MH+, 100).
4-Amino-3,5-difluoro-2,6-dimorpholino-pyridine (9). A
sample of pyridinium salt 2a (0.73 g; 2.5 mmol) and sodium
amide (0.49 g; 12.5 mmol) in 25 mL of morpholine was heated at
reflux temperature for 5 h. A small amount of silica gel was added
to the solution and then the excess amine was distilled off in
vacuo. The residue was then chromatographed (silica gel; petrol /
ethyl acetate = 2/1). The product (Rf = 0.20; petrol/ethyl acetate =
2:1) was finally recrystallized from hexane/dichloromethane
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2006, 62, 6893.