A simple one-pot synthesis of 2,6-disubstituted 4-(polyfluoroalkyl) pyridines and -pyrimidines by reaction of 2-polyfluoroalkylchromones with aromatic methyl ketimines and amidines

Article abstract of DOI:10.1055/s-2004-822321

The reaction of 2-polyfluoroalkylchromones with ketimines, derived from aromatic methyl ketones and isopropylamine, gives 2,6-diaryl-4- polyfluoroalkylpyridines in moderate to low yields. Benzamidine and guanidine also react with 2-polyfluoroalkylchromones to afford the corresponding 2,6-disubstituted 4-polyfluoroalkylpyrimidines.

Full text of DOI:10.1055/s-2004-822321

942
PAPER
A Simple One-Pot Synthesis of 2,6-Disubstituted 4-(Polyfluoroalkyl)pyridines
and -pyrimidines by Reaction of 2-Polyfluoroalkylchromones with Aromatic
Methyl Ketimines and Amidines
S
ynthesis 4-(Polyf
y
luoroalkyl)py
a
ridines and
c
-pyrimidin
h
es eslav Ya. Sosnovskikh,* Boris I. Usachev, Aleksei Yu. Sizov, Mikhail A. Barabanov
Department of Chemistry, Ural State University, 620083 Ekaterinburg, Russian Federation
Fax +7(3432)615978; E-mail: Vyacheslav.Sosnovskikh@usu.ru
Received 4 February 2004; revised 12 February 2004
Recently,5 in continuation of our studies on the chemical
properties of 2-polyfluoroalkylchromones 1, which
turned out to be highly reactive substrates in the reactions
with N-,6a,b S-,6c,d and C-nucleophiles,6e,f we investigated
Abstract: The reaction of 2-polyfluoroalkylchromones with
ketimines, derived from aromatic methyl ketones and isopropyl-
amine, gives 2,6-diaryl-4-polyfluoroalkylpyridines in moderate to
low yields. Benzamidine and guanidine also react with 2-polyfluo-
roalkylchromones to afford the corresponding 2,6-disubstituted 4- the reactions of these compounds with 1,3,3-trimethyl-
polyfluoroalkylpyrimidines.
3,4-dihydroisoquinolines and aromatic N-substituted me-
thyl ketimines capable of reacting with electrophilic sub-
strates as 1,3-C,N-dinucleophiles due to the enamine
tautomeric form. We demonstrated that chromones 1 react
with dihydroisoquinolines and methyl ketimines to give
2,6-diaryl-4-trifluoromethylpyridines (preliminary com-
munication, see Ref.5). This result and the literature data4k
clearly showed that the present approach could be also
applicable to chromones 1 and amidines (1,3-N,N-dinu-
cleophiles), providing the corresponding 4-polyfluoro-
alkylpyrimidines. Herein, the synthesis of such
polyfluoroalkyl-substituted pyridines and pyrimidines
with 2-hydroxyaryl substituent is reported in detail.
Key words: 2-polyfluoroalkylchromones, ketimines, amidines, 4-
polyfluoroalkylpyridines and -pyrimidines
Much attention has been given to the chemistry of RF-con-
taining N-heterocycles, because they find wide use in var-
ious areas of industry, medicine, and agriculture due to
their unique physical properties, chemical reactivity, and
biological activity.1,2 In connection with this, remarkable
progress has been made in the development of new and ef-
ficient methods for the synthesis of polyfluoroalkylated
pyridine and pyrimidine derivatives using fluorinated
building blocks.
We have found that 2-RF-chromones 1a–e react with 1.5
equivalents of N-(1-arylethylidene)-2-propanamines
2a,b, prepared from acetophenone, 2-acetothienone and
isopropylamine, by refluxing in anhydrous butanol for 4
hours to afford pyridines 3a–i in 23–67% isolated yields
(Equation 1, Table 1). Similar results were obtained by
using 1-phenylethan-1-imine (the reaction takes place in a
closed flask, without solvent, at 90 °C), but the prepara-
tion of N-unsubstituted imines is more tedious. Imines
bearing phenyl group at the nitrogen atom and the imine,
prepared by action of isopropylamine on 2-hydroxyace-
tophenone, fail to undergo heterocyclization under the
same conditions. Although the reaction affords pyridines
3 in moderate yields, this approach has advantages with
regard to ease of operation and the ready availability of
starting materials. Since the method is experimentally
simple, it may be of value in RF-containing pyridines
chemistry.
2,6-Diaryl-4-(trifluoromethyl)pyridines have recently
been synthesized by the reaction of enamines, prepared
from substituted acetophenones and morpholine, with tri-
fluoromethylated b-diketones in the presence of ammoni-
um acetate.3a The condensation of CF3-containing a,b-
unsaturated ketones and b-diketones with primary
amines, such as b-aminocrotononitrile and ethyl b-amino-
crotonates, affords 2- and 4-trifluoromethylpyridines.3b,c
These compounds were also obtained from the reaction of
trifluoromethylated a,b-unsaturated ketones and b-dike-
tones with N-silyl-1-azaallyl anions3d and by Hantzsch’s
dihydropyridine synthesis.3e,f
2,6-Disubstituted 4-(polyfluoroalkyl)pirimidines were
obtained by reactions of amidines with RF-substituted
alkyl ketones,4a a,b-unsaturated ketones,4b b-diketones,4c
b-alkoxy-4d–f and b-aminovinyl ketones,4g,h N-aryl acety-
lenic imines,4i iodoalkenes,4j and 3-hetarylchromones.4k
In addition, fluoroalkyl pyrimidines have been synthe-
sized from one-pot reactions of a-fluoroalkyl carbonyl
compounds, orthoesters and ammonium carbonate.4l The
condensation of fluoro-containing nitriles with methyl
ketimines4m and enamines4n provides a simple route to py-
rimidines with two polyfluoroalkyl groups.
RF
O
Ar
Me
Pri
R
BuOH
R
Ar
N
H
N
RF
O
O
3a-j
2a,b
Ar = Ph (2a), 2-C4H3S (2b)
1a-f
SYNTHESIS 2004, No. 6, pp 0942–0948
x
x
.
x
x
.2
0
0
4
Advanced online publication: 25.03.2004
DOI: 10.1055/s-2004-822321; Art ID: Z02204SS.pdf
© Georg Thieme Verlag Stuttgart · New York
Equation 1

PAPER
Synthesis 4-(Polyfluoroalkyl)pyridines and -pyrimidines
943
Table 1 Synthesis of 2,6-Diaryl-4-polyfluoroalkylpiridines 3a–j by Reaction of Chromones 1a–f with Methylketimines 2a,b
Chromone
R
RF
Ar
Pyridine
3a
Yield (%)
Mp (°C)
134–135
138–139
133–134
193–195
198–200
227–228
237–238
192–194
215–217
185–186
1a
1a
1b
1c
1c
1d
1d
1e
1e
1f
H
CF3
Ph
35
27
23
67
54
40
36
61
38
11
H
CF3
2-C4H3S
Ph
3b
MeO
NO2
NO2
NO2
NO2
NO2
NO2
NO2
CF3
3c
CF3
Ph
3d
CF3
2-C4H3S
Ph
3e
CF2H
CF2H
(CF2)2H
(CF2)2H
H
3f
2-C4H3S
Ph
3g
3h
2-C4H3S
Ph
3i
3j
Note that the reaction is typical only for 2-polyfluoro-
J
C,F = 33.7 Hz) than that of 2-CF3-pyridines3b,d (C-2, ca.
alkylchromones and does not occur when the RF group is 149 ppm, q, JC,F ca. 35 Hz) in the 13C NMR spectrum.
replaced by the methyl or trichloromethyl group. It is like-
ly that a balance occurs between steric and electronic ef-
fects. Unsubstituted chromone does not react under these
conditions and the reaction of 6-nitrochromone 1f with N-
(1-phenylethylidene)-2-propanamine (2a) gives the corre-
sponding pyridine 3j in only 11% yield. This is probably
Most likely, the reaction includes the nucleophilic attack
of the enamine tautomer of methyl ketimine 2 at C2 atom
of 2-RF-chromone 1 followed by the opening of pyrone
ring and intramolecular cyclization at the keto group
(Scheme 1). Taking into account the results of the reaction
of chromones 1 with 1,3,3-trimethyl-3,4-dihydroisoquin-
owing to the lack of RF group, which enhances the electro-
olines,5 we could propose that the first step involves the
philicity of the substrate and encourages conjugate addi-
formation of the zwitterionic intermediate 4, bearing an
isopropyl group at the nitrogen atom, followed by elimi-
nation of propylene. In fact, in the case of compound 3e,
the zwitterionic compound 4e (RF = CF3, Ar = Ph) was
isolated as red crystals (at ca. 20 °C, 1 week in THF and 2
weeks in hexane–toluene). When 4e was heated in bu-
tanol, pyridine 3e was obtained. This result confirms the
intermediacy of 4 in the present formation of pyridines 3.
tion at the initial stage. However, 2-difluoromethyl- and
2-(1,1,2,2-tetrafluoroethyl)chromones fail to react with
imine 2a and the best yields (36–67%) of pyridines 3 were
obtained for the 6-nitro-2-RF-chromone 1c–e, because the
electron-withdrawing nitro group favors stabilization of
the leaving phenolate anion, thus facilitating the pyrone
ring opening. In contrast to the nitro group, the electron-
donating methyl and methoxy substituents afflict this re-
Moderate yields of pyridines 3 suggest that imines 2 act
action. Thus, chromone 1b provides only 23% of the
not only as a 1,3-C,N-dinucleophiles, but also as a source
product 3c; 7-trifluoromethylnorkhellin7a having two
methoxy groups in the benzene ring and 5,7-dimethyl-2-
trifluoromethylchromone7b are not converted into the cor-
responding pyridine derivatives under the action of imine
2a.
1 +
2
3
-C3H6
RF
OH
O
RF
Although much attention has been paid to the chemistry of
the RF-containing pyridine derivatives, compounds 3a–j
were not described in the literature and were unavailable
by the known 2,6-diarylpyridine syntheses.3 The struc-
tures of the pyridines 3 compare well with the results of
elemental analysis, 1H, 19F, 13C NMR and IR spectrosco-
py. The 1H NMR spectra of these compounds showed sig-
nals for the aromatic protons of the aryl substituents, two
singlets ranging between 7.74–8.17 and 7.94–8.50 ppm
for the protons of the pyridine ring, and a singlet of the OH
proton at 11.9–15.4 ppm. In the 19F NMR spectra the trif-
luoromethyl group of 3a,d manifests itself as a singlet at
–66 ppm. The CF3-substituted carbon atom of 4-CF3-py-
ridine 3a resonates at higher field (C-4, 140.8 ppm, q,
O
Ar
N
-H2O
Pri
HN
Pri
Ar
R
R
R
4
2
1
PriNH2
RF
Pri
+
ArCOMe
OH
O
HN
5
R = NO2, RF = CF3 (5a); R = NO2, RF = CF2H (5b)
Scheme 1
Synthesis 2004, No. 6, 942–948 © Thieme Stuttgart · New York

944
V. Ya. Sosnovskikh et al.
PAPER
O
of isopropylamine which destroys the starting chromones.
Further support of this hypothesis has been obtained in ex-
periments with chromones 1c,d. Thus, when these com-
pounds reacted with imine 2a by heating without solvent,
besides the desired pyridines 3d,f, a reasonable amount of
aminoenones 5a,b has been also isolated by crystalliza-
tion. Aminoenones 5 are likely the result of the in situ hy-
drolysis of imine 2a followed by the attack of
isopropylamine at the C2 atom of the corresponding
chromone. Aminoenones 5a,b were independently syn-
thesized from chromones 1c,d and isopropylamine in ex-
cellent yields.
Me
Pri
+
O
CF3
OMe
2c
N
1a
BuOH
CF3
N
CF3
5
3
6'
3'
6''
3''
5'
5''
4''
N
HBr
4'
O
HO
OH
OH
Me
Using this reaction, we were able to obtain 2-(2-hydroxy-
phenyl)-6-(2-methoxyphenyl)-4-(trifluoromethyl)pyridine
(3k) in 43% yield from 2-trifluoromethylchromone (1a)
and methylketimine 2c, prepared from 2-methoxy-
acetophenone and isopropylamine. Demethylation of 3k
to 2,6-bis(2-hydroxyphenyl)-4-(trifluoromethyl)pyridine
(3l) was achieved in 85% yield by heating with 48% hy-
drobromic acid at 200 °C in a sealed tube for 10 hours
(Scheme 2). These reactions are the most convenient and
concise route to pyridine 3l, which owing to the presence
of two ortho-OH groups is of great interest and might be
employed as an analytical reagent8a and organic electrolu-
minescence substance.8b–8d Previously, nonfluorinated
2,6-bis(2-hydroxyphenyl)pyridine was obtained by the re-
action of 2,6-dibromopyridine with the Grignard reagent
from 2-bromoanisole in the presence of NiCl2 as catalyst,
followed by demethylation in molten pyridinium chlo-
ride.8b
3k
3l
Scheme 2
RF
O
N
R1
NH2
R
R
+
N
H
R1
NH
6a,b
EtOH
O
RF
O
1
7a-k
CF3
Me
O
Me
N
N
R1
+
6a,b
EtOH
Me
N
O
CF3
Me
N
O
1g
1 = Ph (6a), R1 = NH2 (6b)
H
7l,m
Next, we examined reactions of the 2-polyfluoroalkyl-
chromones 1 with amidines 6a,b and found that substitut-
ed 2-RF-chromones with both electron-donating and
electron-withdrawing substituents are effective in this
process, thus creating a fast and efficient route to new py-
R
Scheme 3
Table 2 Synthesis of 4-Polyfluoroalkylpirimidines 7a–m by Reaction Chromones 1 with Amidines 6a,b
Chromone
R
RF
R1
Pyrimidine
Yield (%)
Mp (°C)
143–144
151–152
204–206
174–176
164–165
163–165
157–158
146–147
151–153
217–218
265–266
>270 (dec.)
>300 (dec.)
1a
1b
1c
1i
H
CF3
Ph
7a
7b
7c
7d
7e
7f
58
51
92
68
71
68
42
45
75
46
55
98
58
MeO
NO2
Me
Cl
CF3
Ph
CF3
Ph
CF3
Ph
1j
CF3
Ph
1k
1l
H
(CF2)2H
(CF2)2H
(CF2)2H
(CF2)2H
CF3
Ph
Me
MeO
Cl
Ph
7g
7h
7i
1m
1n
1a
1c
1g
1g
Ph
Ph
H
NH2
NH2
Ph
7j
NO2
-
CF3
7k
7l
CF3
-
CF3
NH2
7m
Synthesis 2004, No. 6, 942–948 © Thieme Stuttgart · New York

PAPER
Synthesis 4-(Polyfluoroalkyl)pyridines and -pyrimidines
945
rimidine derivatives. Reflux of chromones 1 with benz- (Scheme 3, Table 2). Note that 5,7-dimethyl-2-trifluoro-
amidine hydrochloride (6a) or guanidinium nitrate (6b) in methylchromone did not react with 6a and azachromone
the presence of KOH in ethanol for 3 hours yielded the py- 1g gave a complex mixture with imine 2a in boiling bu-
rimidines 7a–k as yellow solids in 45–92% yields. The tanol.
present reaction could be applicable to the 8-aza-5,7-di-
The analytical and spectral data of compounds 3 and 7
prepared are given in Tables 3 and 4, respectively.
methyl-2-trifluoromethylchromone (1g)9 and amidines
6a,b to afford the corresponding pyrimidines 7l,m with 2-
pyridone substituent in 98% and 58% yields, respectively
Table 3 Analytical and Spectral Data for Pyridines 3a–l
Pyridinea 1H NMR (CDCl3/TMS)
IR (Nujol)
(cm–1)
d, J(Hz)
3ab,c
3b
6.99 (ddd, 1 H, H-5, Ar, oJ = 8.1, 7.2, mJ = 1.2), 7.08 (dd, 1 H, H-3, Ar, oJ = 8.4, mJ = 1.2), 7.39 (ddd, 1 H, H-4, Ar,
1620, 1595,
oJ = 8.4, 7.2, mJ = 1.6), 7.51–7.58 (m, 3 H, C6H5), 7.83 (s, 1 Hpyridyl), 7.88 (dd, 1 H, H-6, Ar, oJ = 8.1, mJ = 1.6), 7.94– 1570
7.97 (m, 2 H, C6H5), 8.05 (s, 1 Hpyridyl), 14.04 (s, 1 H, OH)
6.98 (ddd, 1 H, H-5, Ar, oJ = 8.1, 7.2, mJ = 1.2), 7.09 (dd, 1 H, H-3, Ar, oJ = 8.4, mJ = 1.2), 7.19 (dd, 1 Hthienyl, H-4,
J = 5.0, 3.7), 7.39 (ddd, 1 H, H-4, Ar, oJ = 8.4, 7.2, mJ = 1.6), 7.52 (dd, 1 Hthienyl, H-5, J = 5.0, 1.1), 7.72 (dd, 1 Hthienyl
1620, 1600,
1575, 1545
,
H-3, J = 3.7, 1.1), 7.74 (s, 1 Hpyridyl), 7.84 (dd, 1 H, H-6, Ar, oJ = 8.1, mJ = 1.6), 7.94 (s, 1 Hpyridyl), 13.38 (s, 1 H, OH)
3c
3.87 (s, 3 H, CH3O), 7.02 (d, 1 H, H-3, H-4, Ar, J = 1.6), 7.35 (t, 3 H, H-6, Ar, J = 1.6), 7.52–7.58 (m, 3 H, C6H5), 7.83 1620, 1575,
(s, 1 Hpyridyl), 7.94–7.97 (m, 2 H, C6H5), 7.98 (s, 1 Hpyridyl), 13.51 (s, 1 H, OH)
1500
3dd
3e
7.14 (d, 1 H, H-3, Ar, oJ = 9.1), 7.57–7.61 (m, 3 H, C6H5), 7.93–7.95 (m, 2 H, C6H5), 7.95 (s, 1 Hpyridyl), 8.16 (s, 1
Hpyridyl), 8.27 (dd, 1 H, H-4, Ar, oJ = 9.1, mJ = 2.7), 8.86 (d, 1 H, H-6, Ar, mJ = 2.7), 15.21 (s, 1 H, OH)
1625, 1595,
1570, 1535
7.16 (d, 1 H, H-3, Ar, oJ = 9.1), 7.27 (dd, 1 Hthienyl, H-4, J = 5.0, 3.8), 7.58 (dd, 1 Hthienyl, H-5, J = 5.0, 1.1), 7.76 (dd, 1625, 1590,
1 Hthienyl, H-3, J = 3.8, 1.1), 7.86 (s, 1 Hpyridyl), 8.03 (s, 1 Hpyridyl), 8.27 (dd, 1 H, H-4, Ar, oJ = 9.1, mJ = 2.7), 8.82 (d, 1 1565, 1525
H, H-6, Ar, mJ = 2.7), 14.48 (s, 1 H, OH)
3fe
3ge
3h
3i
7.18 (d, 1 H, H-3, Ar, oJ = 9.1), 7.24 (tt, 1 H, CF2H, 2JH,F = 55.0), 7.56–7.64 (m, 3 H, C6H5), 8.12–8.14 (m, 2 H, C6H5), 1620, 1590,
8.17 (s, 1 Hpyridyl), 8.24 (dd, 1 H, H-4, Ar, oJ = 9.1, mJ = 2.9), 8.50 (s, 1 Hpyridyl), 9.01 (d, 1 H, H-6, Ar, mJ = 2.9), 13.9 1570, 1530
(br s, 1 H, OH)
7.18 (d, 1 H, H-3, Ar, oJ = 9.1), 7.21 (tt, 1 H, CF2H, 2JH,F = 55.0), 7.26 (dd, 1 Hthienyl, H-4, J = 5.0, 3.7), 7.80 (dd, 1
Hthienyl, H-5, J = 5.0, 1.1), 8.04 (dd, 1 Hthienyl, H-3, J = 3.7, 1.1), 8.15 (s, 1 Hpyridyl), 8.23 (dd, 1 H, H-4, Ar, oJ = 9.1,
mJ = 2.9), 8.38 (s, 1 Hpyridyl), 8.97 (d, 1 H, H-6, Ar, mJ = 2.9), 13.3 (br s, 1 H, OH)
1620, 1595,
1565, 1525
6.11 (tt, 1 H, CF2CF2H, 2JH,F = 53.8, 3JH,F = 1.6), 7.14 (d, 1 H, H-3, Ar, oJ = 9.1), 7.56–7.61 (m, 3 H, C6H5), 7.89 (s, 1 1620, 1590,
Hpyridyl), 7.92–7.96 (m, 2 H, C6H5), 8.09 (s, 1 Hpyridyl), 8.27 (dd, 1 H, H-4, Ar, oJ = 9.1, mJ = 2.7), 8.86 (d, 1 H, H-6, Ar, 1560
mJ = 2.7), 15.36 (s, 1 H, OH)
6.09 (tt, 1 H, CF2CF2H, 2JH,F = 53.8, 3JH,F = 1.7), 7.16 (d, 1 H, H-3, Ar, oJ = 9.1), 7.22 (dd, 1 Hthienyl, H-4, J = 5.0, 3.8), 1620, 1595,
7.57 (dd, 1 Hthienyl, H-5, J = 5.0, 1.1), 7.76 (dd, 1 Hthienyl, H-3, J = 3.8, 1.1), 7.81 (s, 1 Hpyridyl), 7.97 (s, 1 Hpyridyl), 8.27 1565, 1525
(dd, 1 H, H-4, Ar, oJ = 9.1, mJ = 2.7), 8.83 (d, 1 H, H-6, Ar, mJ = 2.7), 14.62 (s, 1 H, OH)
3j
7.10 (d, 1 H, H-3, Ar, oJ = 9.1), 7.50–7.58 (m, 3 H, C6H5), 7.77 (dd, 1 Hpyridyl, oJ = 7.3, mJ = 1.0), 7.92 (m, 2 Hpyridyl), 1600, 1560
7.99–8.06 (m, 2 H, C6H5), 8.22 (dd, 1 H, H-4, Ar, oJ = 9.1, mJ = 2.6), 8.85 (d, 1 H, H-6, Ar, mJ = 2.6), 16.16 (s, 1 H, OH)
3k
3.93 (s, 3 H, CH3O), 6.96 (ddd, 1 H, H-5¢, oJ = 8.1, 7.2, mJ = 1.2), 7.04 (dd, 1 H, H-3¢, oJ = 8.3, mJ = 1.2), 7.07 (dd, 1 1620, 1605,
H, H-3¢¢, oJ = 8.3, mJ = 1.0), 7.12 (ddd, 1 H, H-5¢¢, oJ = 7.5, 7.6, mJ = 1.0), 7.36 (ddd, 1 H, H-4¢, oJ = 8.5, 7.2, mJ = 1.6), 1590, 1570
7.47 (ddd, 1 H, H-4¢¢, oJ = 8.3, 7.5, mJ = 1.7), 7.72 (dd, 1 H, H-6¢¢, oJ = 7.6, mJ = 1.7), 7.85 (dd, 1 H, H-6¢, oJ = 8.1,
mJ = 1.6), 7.91 (s, 1 Hpyridyl), 8.00 (s, 1 Hpyridyl), 13.87 (s, 1 H, OH)
3l
7.00 (ddd, 2 H, H-5¢, H-5¢¢, oJ = 7.9, 7.2, mJ = 1.2), 7.02 (dd, 2 H, H-3¢, H-3¢¢, oJ = 8.3, mJ = 1.2), 7.37 (ddd, 2 H, H-4¢, 1625, 1600,
H-4¢¢, oJ = 8.3, 7.2, mJ = 1.6), 7.98 (dd, 2 H, H-6¢, H-6¢¢, oJ = 7.9, mJ = 1.6), 8.29 (s, 2 Hpyridyl), 11.91 (s, 2 H, 2 OH)
1595, 1565
a Satisfactory microanalyses obtained: C 0.19, H 0.42, N 0.25.
b 13C NMR (CDCl3/TMS): d = 113.29 (q, J = 3.7 Hz), 114.06 (q, J = 3.5 Hz), 118.11 (s), 118.77 (s), 119.25 (s), 122.78 (q, J = 273.8 Hz), 126.60
(s), 126.98 (s), 129.31 (s), 130.42 (s), 132.53 (s), 136.84 (s), 140.78 (q, J = 33.7 Hz), 156.53 (s), 159.15 (s), 159.93 (s).
c 19F NMR (CDCl3/CFCl3): d = –66.1 (s, CF3).
d 19F NMR (CDCl3/CFCl3): d = –66.0 (s, CF3).
e Recorded in DMSO-d6.
Synthesis 2004, No. 6, 942–948 © Thieme Stuttgart · New York

946
V. Ya. Sosnovskikh et al.
PAPER
Table 4 Analytical and Spectral Data for Pyrimidines 7a–m
Pyrimidinea 1H NMR (CDCl3/TMS) d, J(Hz)
IR (Nujol) (cm–1)
7a
7.00 (ddd, 1 H, H-5, Ar, oJ = 8.0, 7.2, mJ = 1.0), 7.10 (dd, 1 H, H-3, Ar, oJ = 8.4, mJ = 1.0), 7.46 (ddd, 1 H, H- 1590, 1575, 1540
4, Ar, oJ = 8.4, 7.2, mJ = 1.5), 7.50–7.60 (m, 3 H, C6H5), 7.87 (dd, 1 H, H-6, Ar, oJ = 7.8, mJ = 1.5), 7.97 (s, 1
Hpyrimidyl), 8.37–8.42 (m, 2 H, C6H5), 13.6 (br s, 1 H, OH)
7b
7c
7d
7e
7f
3.86 (s, 3 H, CH3O), 7.04 (d, 1 H, H-3, Ar, oJ = 9.0), 7.10 (dd, 1 H, H-4, Ar, oJ = 9.0, mJ = 2.9), 7.30 (d, 1 H, 1590, 1575, 1540
H-6, Ar, mJ = 2.9), 7.53–7.58 (m, 3 H, C6H5), 7.90 (s, 1 Hpyrimidyl), 8.37–8.40 (m, 2 H, C6H5), 13.15 (s, 1 H, OH)
7.20 (d, 1 H, H-3, Ar, oJ = 9.3), 7.54–7.63 (m, 3 H, C6H5), 8.09 (s, 1 Hpyrimidyl), 8.34 (dd, 1 H, H-4, Ar, oJ = 9.3, 1595, 1550, 1535
mJ = 2.4), 8.37–8.40 (m, 2 H, C6H5), 8.86 (d, 1 H, H-6, Ar, mJ = 2.4), 14.59 (s, 1 H, OH)
2.36 (s, 3 H, CH3), 6.98 (d, 1 H, H-3, Ar, oJ = 8.4), 7.25 (dd, 1 H, H-4, Ar, oJ = 8.4, mJ = 1.7), 7.50–7.58 (m, 1590, 1575, 1540
3 H, C6H5), 7.62 (d, 1 H, H-6, Ar, mJ = 1.7), 7.94 (s, 1 Hpyrimidyl), 8.36–8.40 (m, 2 H, C6H5), 13.37 (s, 1 H, OH)
7.03 (d, 1 H, H-3, Ar, oJ = 8.9), 7.39 (dd, 1 H, H-4, Ar, oJ = 8.9, mJ = 2.5), 7.52–7.58 (m, 3 H, C6H5), 7.80 (d, 1595, 1575, 1545
1 H, H-6, Ar, mJ = 2.5), 7.90 (s, 1 Hpyrimidyl), 8.34–8.37 (m, 2 H, C6H5), 13.56 (s, 1 H, OH)
6.50 (tt, 1 H, CF2CF2H, 2JH,F = 53.1, 3JH,F = 5.4), 7.0–8.0 (m, 6 H, Ar, C6H5), 7.90 (dd, 1 H, H-6, Ar, oJ = 7.9, 1590, 1575, 1540
mJ = 1.7), 8.04 (s, 1 Hpyrimidyl), 8.30–8.45 (m, 2 H, C6H5), 13.6 (br s, 1 H, OH)
7g
2.38 (s, 3 H, CH3), 6.52 (tt, 1 H, CF2CF2H, 2JH,F = 53.0, 3JH,F = 5.4), 7.00 (d, 1 H, H-3, Ar, oJ = 8.4), 7.28 (dd, 1590, 1570, 1540
1 H, ;-4, Ar, oJ = 8.4, mJ = 2.1), 7.53–7.60 (m, 3 H, C6H5), 7.68 (d, 1 H, H-6, Ar, mJ = 1.4), 8.04 (s, 1 Hpyrimidyl),
8.34–8.37 (m, 2 H, C6H5), 13.47 (s, 1 H, OH)
7h
7i
3.88 (s, 3 H, CH3O), 6.52 (tt, 1 H, CF2CF2H, 2JH,F = 53.0, 3JH,F = 5.4), 7.05 (d, 1 H, H-3, Ar, oJ = 9.0), 7.11
(dd, 1 H, H-4, Ar, oJ = 9.0, mJ = 2.9), 7.34 (d, 1 H, H-6, Ar, mJ = 2.9), 7.53–7.61 (m, 3 H, C6H5), 7.99 (s, 1
Hpyrimidyl), 8.34–8.38 (m, 2 H, C6H5), 13.23 (s, 1 H, OH)
1600, 1575, 1545
6.50 (tt, 1 H, CF2CF2H, 2JH,F = 53.0, 3JH,F = 5.2), 7.07 (d, 1 H, H-3, Ar, oJ = 8.9), 7.42 (dd, 1 H, H-4, Ar,
oJ = 8.9, mJ = 2.5), 7.54–7.63 (m, 3 H, C6H5), 7.87 (d, 1 H, H-6, Ar, mJ = 2.5), 8.00 (s, 1 Hpyrimidyl), 8.33–8.36
(m, 2 H, C6H5), 13.7 (br s, 1 H, OH)
1595, 1575, 1545
7jb
6.95 (ddd, 1 H, H-5, Ar, oJ = 8.1, 7.2, mJ = 1.2), 6.97 (dd, 1 H, H-3, Ar, oJ = 8.4, mJ = 1.2), 7.43 (ddd, 1 H, H- 3470, 3310, 3180,
4, Ar, oJ = 8.4, 7.2, mJ = 1.6), 7.67 (s, 1 Hpyrimidyl), 7.75 (br s, 2 H, NH2), 8.13 (dd, 1 H, H-6, Ar, oJ = 8.1,
mJ = 1.6), 13.2 (br s, 1 H, OH)
1645, 1595, 1545
7kb
7lb
7.17 (d, 1 H, H-3, Ar, oJ = 9.2), 7.82 (br s, 2 H, NH2), 7.87 (s, 1 Hpyrimidyl), 8.27 (dd, 1 H, H-4, Ar, oJ = 9.2,
mJ = 2.8), 8.90 (d, 1 H, H-6, Ar, mJ = 2.8), 13.9 (br s, 1 H, OH)
3430, 3330, 3210,
1660, 1595, 1560
2.25 (s, 3 H, CH3), 2.34 (s, 3 H, CH3), 6.16 (s, 1 Hpyridyl), 7.56–7.61 (m, 3 H, C6H5), 8.12 (s, 1 Hpyrimidyl), 8.39– 1655, 1625, 1585,
8.42 (m, 2 H, C6H5), 12.0 (br s, 1 H, NHCO) 1530
7mb
2.10 (s, 3 H, CH3), 2.18 (s, 3 H, CH3), 6.01 (s, 1 Hpyridyl), 7.01 (s, 1 Hpyrimidyl), 7.22 (s, 2 H, NH2), 11.8 (br s, 1 3500, 3310, 3200,
H, NHCO)
1650, 1630, 1590,
1540
a Satisfactory microanalyses obtained: C 0.31, H 0.30, N 0.25.
b Recorded in DMSO-d6.
Melting points are uncorrected. All solvents used were dried and
distilled per standard procedures. The starting 2-polyfluoroalkyl-
chromones 1a–f were prepared by reaction of the appropriate 2-hy-
droxyacetophenones and 3-acetyl-4,6-dimethyl-2-pyridone with
RFCO2Et according to described procedures.6a,9 The starting imines
2a–c were prepared by direct condensation of the appropriate car-
bonyl compound and isopropylamine according to described proce-
dure.10 1-Phenylethan-1-imine was obtained from benzonitrile and
CH3MgI according to known method.11 Pyridines 3k,l were de-
scribed earlier.5
In conclusion, we have demonstrated that 2-(2-hydroxyar-
yl)-6-(het)aryl-4-polyfluoroalkylpyridines can be easily
prepared from readily available 2-polyfluoroalkyl-
chromones and aromatic methyl ketimines. In spite of the
moderate yields, the method has advantages, particularly
with regard to ease of operation and applicability to the
concise synthesis of useful materials. In addition, the re-
action with benzamidine and guanidine is a simple and
convenient synthesis of 2,6-disubstituted 4-polyfluoro-
alkylpyrimidines, which are difficult to prepare by other
methods.
2,6-Diaryl-4-polyfluoroalkylpyridines (3); General Procedure
To a solution of chromone 1 (2.0 mmol) in butanol (4 mL) was add-
ed methylketimine 2 (3.0 mmol), and the mixture was refluxed for
4 h. Then, the reaction mixture was concentrated to ca. 2 mL and
cooled to r.t. The resulting precipitate was filtered, washed with
EtOH, and recrystallized from butanol or ethanol to give pyridine 3
as a yellow solid (see Tables 1 and 3).
1H, 19F, and 13C NMR spectra were recorded on a Bruker DRX-400
spectrometer (1H at 400.1 MHz, 19F at 376.5 MHz, and 13C at 100.6
MHz) with TMS and CFCl3 as internal standards. The IR spectra
were measured on an IKS-29 instrument as suspensions in Nujol.
Synthesis 2004, No. 6, 942–948 © Thieme Stuttgart · New York

PAPER
Synthesis 4-(Polyfluoroalkyl)pyridines and -pyrimidines
947
Reactions Chromones 1a,c with 1-Phenylethan-1-imine
4-Polyfluoroalkylpyrimidines (7); General Procedure
To chromone 1a or 1c (2 mmol) was added 1-phenylethan-1-imine
(0.52 g, 4.4 mmol), and the mixture was heated at 90 °C for 4 h in a
closed flask. Then the reaction mixture was diluted with 70% EtOH
(5 mL) and the crystalline material was collected by filtration to
give pyridines 3a and 3d in 29 and 32% yields, respectively.
Benzamidine or guanidine (2.0 mmol), prepared from 6a,b and
KOH, was dissolved in EtOH (5 mL). To this solution was added
chromone 1 (1.6 mmol), and the mixture was refluxed for 3 h (for
chromones 1a–n) or 1 h (for azachromone 1g). After the reaction
mixture was cooled to the r.t., the resulting precipitate was filtered,
washed with H2O, and recrystallized from toluene to give pyrimi-
dine 7 as a yellow solid (see Tables 2 and 4).
2-[1-Isopropyl-6-phenyl-4-(trifluoromethyl)pyridinium-2-yl]-
4-nitrophenolate (4e)
A mixture of chromone 1c (0.26 g, 1.0 mmol) and imine 2a (0.16 g,
1.0 mmol) in THF (1 mL) was allowed to stand with stirring for 1
week at ca. 20 °C. After evaporation of solvent at ca. 20 °C, the res-
idue was diluted with a mixture (7 mL) of hexane–toluene (1:1) and
kept again for 2 weeks at ca. 20 °C. The solid product was separated
by filtration to give the title compound as red crystals; yield: 12%;
mp 149–151 °C.
Acknowledgment
This work was financially supported by the Russian Foundation for
Basic Research (grant 02-03-32706) and by the U.S. Civilian Rese-
arch and Development Foundation and Russian Federation Ministry
of Education (grants EK-005-X1 and Y1-005-04).
IR (Nujol): 1590, 1515 cm–1.
References
1H NMR (CDCl3/TMS): d = 1.42–1.48 (m, 6 H, 2 CH3), 5.52 (sept,
1 H, CH, J = 6.9 Hz), 6.55 (d, 1 H, H-3¢, oJ = 9.6 Hz), 7.57–7.65 (m,
5 H, C6H5), 7.69 (d, 1 Hpyridyl, J = 2.0 Hz), 8.08 (d, 1 Hpyridyl, J = 2.0
Hz), 8.13 (dd, 1 H, H-4¢, oJ = 9.6 Hz, mJ = 3.0 Hz), 8.22 (d, 1 H, H-
6¢, mJ = 3.0 Hz).
(1) (a) Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications; Filler, R.; Kobayashi, Y.;
Yagupolskii, L. M., Eds.; Elsevier: Amsterdam, 1993.
(b) Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; Wiley: New York, 1991. (c) Hiyama, T.
Organofluorine Compounds. Chemistry and Application;
Springer-Verlag: Berlin, 2000.
Anal. Calcd for C21H17F3N2O3: C, 62.69; H, 4.26; N, 6.96. Found:
C, 62.46; H, 4.40; N, 6.66.
(2) (a) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992,
48, 6555. (b) Lin, P.; Jiang, J. Tetrahedron 2000, 56, 3635.
(c) Nenaidenko, V. G.; Sanin, A. V.; Balenkova, E. S. Russ.
Chem. Rev. 1999, 68, 437. (d) Sosnovskikh, V. Ya. Russ.
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4,4,4-Trifluoro-1-(2-hydroxy-5-nitrophenyl)-3-(isopropylami-
no)but-2-en-1-one (5a); Typical Procedure
A mixture of chromone 1c (1.30 g, 5.0 mmol) and imine 2a (0.90 g,
5.6 mmol) was heated in a sealed tube at 90 °C for 6 h. The reaction
mixture was cooled and diluted with MeOH (5 mL). The precipitate
formed (0.52 g) was filtered off and recrystallized from butanol to
give pyridine 3d as light yellow needles (39%). After removal of the
solvent from the filtrate, the residue was purified by recrystalliza-
tion from hexane to give aminoenone 5a as light yellow needles;
yield: 15%; mp 129–130 °C (EtOH). Treatment of chromone 1c
with isopropylamine in EtOH at ca. 20 °C for 1 h gives 5a in 90%
yield.
(3) (a) Funabiki, K.; Isomura, A.; Yamaguchi, Y.; Hashimoto,
W.; Matsunaga, K.; Shibata, K.; Matsui, M. J. Chem. Soc.,
Perkin Trans. 1 2001, 2578. (b) Katsuyama, I.; Ogawa, S.;
Yamaguchi, Y.; Funabiki, K.; Matsui, M.; Muramatsu, H.;
Shibata, K. Synthesis 1997, 1321. (c) Katsuyama, I.;
Funabiki, K.; Matsui, M.; Muramatsu, H.; Shibata, K.
Synlett 1997, 591. (d) Konakahara, T.; Hojahmat, M.;
Tamura, S. J. Chem. Soc., Perkin Trans. 1 1999, 2803.
(e) Lee, L. F.; Stikes, G. L.; Molyneaux, J. M.; Sing, Y. L.;
Chupp, J. P.; Woodard, S. S. J. Org. Chem. 1990, 55, 2872.
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Abstr. 1986, 104, 19514. (g) Xiong, W.-N.; Yang, C.-G.;
Jiang, B. Bioorg. Med. Chem. 2001, 9, 1773.
IR (Nujol): 1615, 1580 cm–1.
1H NMR (CDCl3/TMS): d = 1.37 (d, 6 H, 2 CH3, J = 6.4 Hz),), 4.02
[d sept q, 1 H, CH, JCH,NH = 10.4 Hz, J(CH,CH3) = 6.4 Hz,
J(CH,CF3) = 1.3 Hz], 6.17 (s, 1 H, =CH), 7.03 (d, 1 H, H-3, oJ = 9.2
Hz), 8.27 (dd, 1 H, H-4, oJ = 9.2 Hz, mJ = 2.7 Hz), 8.60 (d, 1 H, H-
6, mJ = 2.7 Hz), 10.56 (br s, 1 H, NH), 13.62 (s, 1 H, OH).
(4) (a) Guan, H.-P.; Hu, Q.-S.; Hu, C.-M. Synthesis 1996, 997.
(b) Funabiki, K.; Nakamura, H.; Matsui, M.; Shibata, K.
Synlett 1999, 756. (c) Sevenard, D. V.; Khomutov, O. G.;
Koryakova, O. V.; Sattarova, V. V.; Kodess, M. I.; Stelten,
J.; Loop, I.; Lork, E.; Pashkevich, K. I.; Röschenthaler, G.-
V. Synthesis 2000, 1738. (d) Zanatta, N.; Cortelini, M. de F.
M.; Carpes, M. J. S.; Bonacorso, H. G.; Martins, M. A. P. J.
Heterocycl. Chem. 1997, 34, 509. (e) Madruga, C. da C.;
Clerici, E.; Martins, M. A. P.; Zanatta, N. J. Heterocycl.
Chem. 1995, 32, 735. (f) Zanatta, N.; Fagundes, M. B.;
Ellensohn, R.; Marques, M.; Bonacorso, H. G.; Martins, M.
A. P. J. Heterocycl. Chem. 1998, 35, 451. (g) Soufyane, M.;
van den Broek, S.; Khamliche, L.; Mirand, C. Heterocycles
1999, 51, 2445. (h) Yu, H.-B.; Huang, W.-Y. J. Fluorine
Chem. 1997, 84, 65. (i) Yu, H.-B.; Huang, W.-Y. J.
Fluorine Chem. 1998, 87, 69. (j) Guan, H.-P.; Tang, X.-Q.;
Luo, B.-H.; Hu, C.-M. Synthesis 1997, 1489. (k) Frasinyuk,
M. S.; Khilya, V. P. Chem. Heterocycl. Compd. 1999, 35, 3.
(l) Luo, B.-H.; Guang, H.-P.; Hu, C.-M. Synlett 1997, 1261.
(m) Sosnovskikh, V. Ya.; Usachev, B. I.; Röschenthaler, G.-
V. Tetrahedron 2002, 58, 1375. (n) Burger, K.; Hein, F.;
Wassmuth, U.; Krist, H. Synthesis 1981, 904.
Anal. Calcd for C13H13F3N2O4: C, 49.06; H, 4.12; N, 8.80. Found:
C, 49.33; H, 4.12; N, 8.54.
4,4-Difluoro-1-(2-hydroxy-5-nitrophenyl)-3-(isopropylami-
no)but-2-en-1-one (5b)
This compound was obtained similarly to 5 in 18% yield as a light
yellow needles, mp 147–148 °C (EtOH). Treatment of chromone
1d with isopropylamine in EtOH at ca. 20 °C for 1 h gave 5b in 94%
yield.
IR (Nujol): 1610, 1580 cm–1.
1H NMR (CDCl3/TMS): d = 1.36 (d, 6 H, 2 CH3, J = 6.4 Hz), 4.06
[d sept, 1 H, CH, JCH,NH = 10.3 Hz, J(CH,CH3)= 6.3 Hz], 5.96 (s, 1
2
H, =CH), 6.28 (t, 1 H, CF2H, J = 53.2 Hz), 7.01 (d, 1 H, H-3,
oJ = 9.2 Hz), 8.24 (dd, 1 H, H-4, oJ = 9.2 Hz, mJ = 2.7 Hz), 8.60 (d,
1 H, H-6, mJ = 2.7 Hz), 10.40 (br d, 1 H, NH, JNH,CH = 8.3 Hz), 13.89
(s, 1 H, OH).
Anal. Calcd for C13H14F2N2O4: C, 52.00; H, 4.70; N, 9.33. Found:
C, 51.76; H, 4.75; N, 9.31.
Synthesis 2004, No. 6, 942–948 © Thieme Stuttgart · New York

948
V. Ya. Sosnovskikh et al.
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Synthesis 2004, No. 6, 942–948 © Thieme Stuttgart · New York