Reactions of 3-(polyfluoroacyl)chromenones with heterocyclic amines: novel synthesis of polyfluoroalkyl-containing fused pyridines P07409SS

Article abstract of DOI:10.1055/s-0029-1216995

The selectivity of the reactions of 3-(polyfluoroacyl)-4H-chromen-4-ones with a wide range of aminoheterocycles and arylamines has been evaluated. The method described facilitates access to polyfluoroalkyl-containing fused pyridines. Georg Thieme Verlag S

Full text of DOI:10.1055/s-0029-1216995

PAPER
3869
Reactions of 3-(Polyfluoroacyl)chromenones with Heterocyclic Amines:
Novel Synthesis of Polyfluoroalkyl-Containing Fused Pyridines
S
ynthesis of Polyf
n
luoroalkyl-C
t
ontaini
o
ng
F
used Py
n
idines Kotljarov,a,b Viktor O. Iaroshenko,*c,d Dmitriy M. Volochnyuk,c Roman A. Irgashev,e
Vyacheslav Ya. Sosnovskikhe
a
Formaly Fachbereich Chemie der Universität Konstanz, Fach M-720, Universitätsstr. 10, 78457 Konstanz, Germany
Institute of Organic and Bioorganic Chemistry, University of Tartu, Jakobi 2, 50014 Tartu, Estonia
Enamine Ltd., 23 A. Matrosova st., 01103 Kyiv, Ukraine
b
c
Fax +380(44)5373253; E-mail: yaroshenko@enamine.net
d
National Taras Shevchenko University, 62 Volodymyrska st., 01033 Kyiv 33, Ukraine
Department of Chemistry, Ural State University, 51 Lenina Ave., 620083 Ekaterinburg, Russian Federation
e
Received 19 May 2009; revised 13 July 2009
Dedicated to Professor Peter Langer on the occasion of his 40th birthday
ter to form stable covalent hydrates and with primary
aromatic and aliphatic amines to give 3-[(aryl/alkylami-
no)methylene]-2-hydroxy-2-(polyfluoroalkyl)chroman-
4-ones.7 Very recently we have shown that chromenones
1 are suitable for the synthesis of polyfluoroalkyl-contain-
ing pyridines,8 either by annulation of the pyridine core8a
by addition of 1 to enamines or by hetero-Diels–Alder
protocol with enol ethers followed by ammonolysis of the
thus formed adducts.8b,c The reaction of 1 with enamines
arising from active methylene compounds starts predom-
inantly with attack at the unsubstituted C2 (1,4-addition)
and is accompanied by pyrone ring-opening to form b-di-
carbonyl intermediates capable of regioselective intramo-
lecular heterocyclizations.8a Alternatively, the initial
attack can also occur at the 3-(trifluoroacetyl) group (1,2-
addition), which does not exclude the variant of recycliza-
tion due to the intramolecular Michael reaction and subse-
quent ring-opening with cleavage of the O1–C2 bond.9
Abstract: The selectivity of the reactions of 3-(polyfluoroacyl)-
4H-chromen-4-ones with a wide range of aminoheterocycles and
arylamines has been evaluated. The method described facilitates ac-
cess to polyfluoroalkyl-containing fused pyridines.
Key words: aminoheterocycles, arylamines, condensation, chro-
man-4-ones, polyfluoroalkyl, fused pyridines
Regiospecific annulation of the pyridine and pyrimidine
core to electron-rich aminoheterocycles recently became
one of the basic methods for purine (purine isosteres) as-
sembly.1 Application of this method gave rise to the syn-
thesis of many purines and their isosteres, such as
desazapurines1a–c and a numbers of different azapurines.1d
Elaboration of novel reagents in the class of 1,3-dielectro-
philes for the synthesis of purine analogues is one of the
challenges of modern heterocyclic chemistry. A special
position among purine isosteres and purine analogues is
occupied by fluorinated derivatives, which show a wide
spectrum of biological activity and have been identified as
pharmacophores of high potency. For example, some
polyfluoroalkyl-substituted purines have been recognized
as antiviral2 and phosphodiesterase inhibitory agents.3
Previously, we have reported the synthesis of many fluor-
inated purines and their analogues,4 such as 7-thiopu-
O
O
O
HO OH
CF3
H2O
CF3
1a
– H2O
O
O
Het
H2N
rines,4a
a
number of 1-desazapurines,4b 1,7-
2
desazapurines,4c azapurines,4d,e and 7-desazapurines.4c
Het
OH
O
CF3
N
3-Formyl-4H-chromen-4-ones are frequently used in or-
ganic chemistry. The majority of the reactions with these
compounds are nucleophilic additions at C2 with concom-
itant opening of the pyrone ring leading to various types
of heterocyclic compounds including pyrimidines5 and
pyridines.6 3-(Polyfluoroacyl)-4H-chromen-4-ones are
novel building blocks, the chemistry of which has not yet
been fully elaborated. Recent advances in the chemistry of
these compounds, especially 3-(trifluoroacetyl)-4H-
chromen-4-one (1a), show that they easily react with wa-
O
O
HN
OH
CF3
Het
4
3
Het
N
O
OH
O
CF3
N
OH
Het
CF3
SYNTHESIS 2009, No. 22, pp 3869–3879
x
x.
x
x
.
2
0
0
9
6
5
Advanced online publication: 08.09.2009
DOI: 10.1055/s-0029-1216995; Art ID: P07409SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 General structures of the obtained products 3–6

3870
A. Kotljarov et al.
PAPER
Table 1 Isolated Yields of Compounds 3–6
Considering these findings and the electron-withdrawing
force of a 3-(trifluoroacetyl) group, we thought that the re-
action of 1a with electron-rich heterocyclic amines and
arylamines could produce the corresponding fused py-
ridines. At the same time, we reasoned that when com-
pounds such as 1a were coupled with 1,3-C,N-
dinucleophiles 2, the similar electrophilic character of
their reactive centers would lead to a mixture of regioiso-
meric products such as 3–6 (Scheme 1). To obviate this
problem, a wide range of electron-rich aminoheterocycles
and aromatic amines bearing electron-donating substitu-
ents 2a–v were designed and various reaction conditions
were used in order to develop a simple and convenient
synthesis of novel polyfluoroalkyl-containing fused py-
ridines. In this current publication we report the applica-
tion of chromenones 1a for pyridine ring annulation to
electron-rich aminoheterocycles 2 (Figure 1).
Entry Substrate Yield (%)
3 (DMF) 4 (DMF)
5 (DMF) 6 (AcOH)
1
2
2a
2b
n.d.
–
97
n.d.
–
–
37
56 (AcOH)
85
–
5a
5a
–
–
34
60 (AcOH)
3
4
5
2c
2d
2e
–
–
94 (AcOH)
46 (AcOH)
–
–
3a
n.d.
n.d.
–
33
64
–
–
8
72 (AcOH)
6
7
2f
22
21
25
30a
74
59
64
2a
52
–
–
–
–
–
–
–
–
–
–
2g
2h
2i
32a
n.d.
n.d.
30
36
8
70
O
S
9
24
N
N
Ph
NH2
Et2N
NC
NH2
N
N
NH2
N
10
11
12
13
14
15
16
2j
n.d.
4a
H
Et
2c
2a
2b
2k
2l
5a
Me
t-Bu
N
N
96
n.d.
n.d.
n.d.
n.d.
N
NH2
NH2
S
NH2
N
N
O
O
2m
2n
2o
2p
99
n.d.
4a
2d
2e
2f
t-Bu
O
Ph
94
Me
O
76
n.d.
HN
N
NH2
EtO2C
94
–
n.d.
48 (AcOH)
n.d.
–
–
n.d.
O
O
N
N
NH2
2i
NH2
2g
2h
Me
Me
17
18
2q–v
64–98
n.d.
n.d.
34
n.d.
62
–
–
O
NH2
N
Me
2w
N
N
N
N
Me
a Identified based on the 19F NMR spectrum of the mixture; n.d. = not
detected.
N
H
NH2
N
NH2
H2N
NH2
Me
2k
2j
2l
OMe
Me
Me
N
Based on the literature data,8a the formation of four possi-
ble classes of end-products 3–6 can be anticipated, how-
ever, during 19F NMR analysis of the mixtures obtained
from reactions of 1a with 2 in anhydrous N,N-dimethyl-
formamide in the temperature range 60–100 °C, only
three products were observed. Heterocycles 2a,i–k react
with 1a to give the corresponding pyridines 4 as the main
products, while in the case of 2e–h,w the formation of
chromeno[4,3-b]pyridines 5 was preferred (a mixture of
approximately equal amounts of compounds 3g, 4g, and
5g was obtained with 2g). At the same time, aminohetero-
cycles 2b,l–o in N,N-dimethylformamide gave mainly
chromanones 3 (Table 1). Reactions of heterocycles 2a–e
and 3,5-dimethoxyaniline (2p), performed in glacial ace-
NH2
NH2
EtO2C
N
H
S
N
NH2
2m
OMe
2n
2o
CN
R1,R2
NH2
NH2
Me
NH2
MeO
2q-v
2p
2w
q: R1 = 3-NMe2, R2 = H; r: R1,R2 = 3,4-OCH2O; s: R1,R2 = 3,4-O(CH2)2O;
t: R1 = 2-OH, R2 = 5-Cl, u: R1 = 2-OH, R2 = 5-NO2; v: R1 = 2-CONH2, R2 = H
Figure 1 Structures of the used enamines 2
It was found that the ratio of the products is strongly de- tic acid yielded preferably products 4 and 6, which repre-
pendent not only on the structure of aminoheterocycle 2, sent fused pyridines with a trifluoromethyl group located
but also on the solvent used. Reacted enamines, solvents, in the a- or g-position. All products can be easily separat-
and ratios of compounds 3–6, when obtained, are listed in ed by column chromatography on silica gel. Thus,
Table 1.
chromenone 1a reacts with 2 giving four types of prod-
ucts, depending on the nature of the 1,3-C,N-dinucleo-
Synthesis 2009, No. 22, 3869–3879 © Thieme Stuttgart · New York

PAPER
Synthesis of Polyfluoroalkyl-Containing Fused Pyridines
3871
phile and the solvent. By correct choice of these to the benzoyl carbonyl group, due to which the trifluoro-
parameters the trifluoromethyl-containing pyridines 4–6 acetyl group remains free and can participate in the forma-
could be selectively obtained in moderate to good yields. tion of cyclic semiketal form 5. The improved
Arylamines 2p–v react with 1a almost exclusively as N- regioselectivity in acetic acid is probably due to the higher
nucleophiles to give the corresponding chromanones electrophilicity of the trifluoroacetyl carbonyl carbon
3p–v in 64–98% isolated yields. This finding is consistent atom, which is completely hydrated in N,N-dimethyl-
with data reported for similar compounds.7
formamide.
Electron-rich aminoheterocycles 2a–o can be considered Note that for the initial attack of the trifluoroacetyl group
as enamines with two nucleophilic centers and the initial by the internal carbon atom of enamine 2 (1,2-addition,
nucleophilic attack can proceed either at the 2-position intermediate C) the reaction through the ring-closure/
(1,4-addition) or at the trifluoroacetyl group (1,2-addi- ring-opening sequence would result in isomeric trifluo-
tion) of chromenone 1a. One might expect that the selec- romethyl-substituted pyridines 6. This direction was ob-
tivity between C- and N-attack on chromenone 1a and, served only in acetic acid medium where the
thus, the ratio between products depends on the difference trifluoroacetyl and 2,2,2-trifluoro-1,1-dihydroxymethyl
of nucleophilicity between two centers; obtaining of com- groups are activated by protonation, while the amino
pounds 3–6 can be rationalized by the reaction paths de- group becomes less nucleophilic. In all of these reactions
picted in Scheme 2.
g-(trifluoromethyl)pyridines 6 were formed in small
quantities, while a-(trifluoromethyl)pyridines 4 dominat-
ed. It is worth mentioning that the alternative cyclization,
leading to chromeno[4,3-b]pyridines 5 was not observed
in this case.
OH
O
O
CF3
NH
3
It was also found that chromenones 1a–c react with 2a in
refluxing toluene to give target products 4a, 4ba, and 4ca
in 73–92% yields. These compounds precipitate out of the
reaction solution and analytically pure products can be
isolated by simple filtration. In contrast, under the same
conditions, reaction between 1b and 2i gave a 2:1 mixture
of 4bi and 5bi (Scheme 3).
A
Het
OH
O
4
5
O
1,4-AN
CF3
1a + 2
RF
O
O
OH
O
Het
B
R
H2N
O
RF
N
2a
PhMe,
O
NH
1a–c
PhMe,
R
N
HO CF3
O
Ph
1,2-AN
2i
4a, 4ba, 4ca
6
Het
O
O
H2N
OH
O
CF2H
C
Me
N
Me
O
N
N
N
Scheme 2 Possible routes for the formation of 3–6
Me
+
N
The ambident character of enamine 2 means that nucleo-
philic attack of nitrogen or carbon on chromenone 1a
would lead to the production of intermediates A or B/C.
Formation of 3 includes nucleophilic 1,4-addition of the
amino group with concomitant opening of the pyrone ring
and subsequent intramolecular cyclization of intermediate
A with the participation of the phenolic hydroxy and tri-
fluoroacetyl groups. The first step of the reaction leading
to 4 and 5 in N,N-dimethylformamide consists apparently
of attack at C2 of chromenone 1a by the internal b-carbon
of the enamine (in general, this atom is more nucleophilic
than the primary amino group) with the pyrone ring open-
ing (1,4-addition, intermediate B), and finally, the in-
tramolecular attack at the trifluoroacetyl group or at the
carbonyl of the 2-hydroxybenzoyl group by the amino
group leads to pyridines 4 and 5, respectively. In the case
of 2e–h, the attack of the amino group is mainly directed
O
O
N
OH
Me
O
CF2H
4bi
5bi
R
F = CF3, R = H (1a); RF = CF2H, R = H (1b); RF = CF3, R = Cl (1c) .
Scheme 3 Reaction of 1a–c with 2a,i in refluxing toluene
On the whole, the most important step determining the
structure of a product is the addition to the first center of
dinucleophile. From the enamine point of view, it clearly
appears that the less aromatic heterocycles 2a–k have a
proclivity to form fused pyridines 4–6, almost indepen-
dently of the solvent. On the other hand, in aminohetero-
cycles 2l–o and arylamines 2p–v the high degree of
aromatization of the ring would be responsible for their
observed lack of reactivity. In terms of solvent, the trend
Synthesis 2009, No. 22, 3869–3879 © Thieme Stuttgart · New York

3872
A. Kotljarov et al.
PAPER
was that expected, namely in polar protic solvents like quartet (d = 137–148, 2JC,F = 34–36 Hz) due to the C–CF3;
19
glacial acetic acid the nucleophilicity of the amino group in the F NMR spectra, the singlet of the CF3 group ap-
is reduced and the C-attack onto 1 which leads to interme- peared at d = –62 to –64. In the 1H NMR spectra, a single
diates B and C is more favored.
proton in the g-position of the pyridine core situated at
d = 7.9–9.0, in the 13C NMR spectra, the carbon in the
same position appeared at d ~ 134. In the 1H NMR spectra,
the chelated OH proton appeared at d = 11–12 as a sharp
singlet. In the ROESY spectrum for 4d, the presence of
the correlation between the methyl group in the 1-posi-
tion, which was observed at d = 3.78, and g-pyridine pro-
ton (d = 8.21) is another feature supporting the structure
of type 4.
Me
N
Me
Me
O
HN
DMF
100 °C
O
OH
CF3
O
O
O
8 (80%)
Me
Me
1a
NH2
Me
N
N
Me
Me
Structures of type 5 represent systems with an annulated
Me
7
N
AcOH
reflux
13
tricyclic core. Their C NMR spectra resemble those of
O
CF3
compounds 3. The location of signals of fluorine-substi-
tuted carbon, as well as of carbon adjacent to the trifluo-
romethyl group and coupling constants JC,F are close to
observed in the case of 3 due to the sp3 hybridized carbon
9 (76%)
O
Scheme 4 Reaction of chromenone 1a with derivative 7
1
atom of the C–CF3 assembly. However, the H NMR
Finally, the reaction of chromenone 1a with 5,5-dimethyl-
3-(1-methylhydrazino)cyclohex-2-en-1-one (7) in N,N-
dimethylformamide at 100 °C led to chromanone 8, while
in refluxing acetic acid chromenone 9 was produced. This
fact demonstrates the possibility of dehydration of 2-hy-
droxy-2-(trifluoromethyl)chromanone 8 under acidic con-
ditions to give 2-(trifluoromethyl)chromenone 9, a result
which has never been achieved in N,N-dimethylform-
amide with chromanones 3 (Scheme 4).
spectra reveal the difference, the absence of the NH pro-
ton at low field. Moreover, the absence of the
[HOC6H4CO]+ and [C6H4CO]+ fragments in mass spectra
along with overall low amount of peaks confirms the tri-
cyclic structure of their core.
A peculiarity which confirms the appearance of the struc-
ture g-(trifluoromethyl)pyridine of 6, is their characteris-
tic shift of the signal for the carbon of the CF3 group in the
13C NMR spectra (d = 129.4–131.7, 2JC,F = 35–36 Hz). At
the same time, the signal of the CF3 group is located at
d = –57 in the 19F NMR spectra. This is another character-
istic feature of the structure of type 6.
Conclusive confirmation of the obtained products was ob-
tained from X-ray single crystal analyses of 3n, 4a, and 5g
(Figures 2– 4).
Figure 2 Molecular structure of compound 3n
The structures of compounds 3–6 can be easily recognized
1
by H, 19F, and 13C NMR spectroscopy. A characteristic
spectral feature of 3 is a chemical shift of the NH proton
in the range of d = 12–13 with coupling constant 3J = 12–
13 Hz on the olefinic proton, doublet of which was ob-
served at d = 7.6–8.6. In the 13C NMR spectra the signal
of the tetrahedral carbon atom adjacent to the polyfluoro-
alkyl substituent at ca. d = 97–98 is a distinctive quartet
(2JC,F = 32–34 Hz). When RF = CF3, the 19F NMR chemi-
cal shift of the CF3 group was observed at d = –84.8 to
–87.0 while the 13C NMR showed the CF3 carbon as a
quartet at d = 118.7–124.8 (1JC,F = 286–291 Hz).
Figure 3 Molecular structure of compound 4a
Compounds 4 are aromatic heteroannulated pyridines and
their spectral properties in many respects are similar to the
purine isosteres we have synthesized previously.4 Py-
ridines 4 were identified as a-(trifluoromethyl)-substitut-
ed isomers because their 13C NMR spectra show a typical
Figure 4 Molecular structure of compound 5g as a solvate with
methanol molecule
Synthesis 2009, No. 22, 3869–3879 © Thieme Stuttgart · New York

PAPER
Synthesis of Polyfluoroalkyl-Containing Fused Pyridines
3873
7.57 (d, 3J = 7.8 Hz, 1 H), 7.67 (s, 1 H, H4), 7.82 (d, 3J = 12.6 Hz,
1 H, = CH), 9.15 (s, 1 H, OH), 12.65 (d, 3J = 12.6 Hz, 1 H, NH).
In conclusion, we have shown that it is possible to prepare
a range of fluorinated heteroannulated pyridines in mod-
erate to good yields by reaction of highly reactive 3-(poly- 13C NMR (DMSO-d6): d = 29.5, 60.3, 72.3, 97.6 (q, 2JC,F = 33 Hz),
1
99.7, 103.3, 116.7, 119.6, 118.7 (q, JC,F = 289 Hz), 121.8, 125.9,
fluoroacyl)-4H-chromen-4-ones
with
electron-rich
131.5, 135.5, 136.8, 138.2, 151.2, 155.9, 180.6.
19F NMR (DMSO-d6): d = –85.4.
MS: m/z (%) = 406 (11) [M + 1]+, 405 (44) [M]+, 349 (11) [M –
CF3]+, 281 (18) [M – CF3 – C4H9 + 1]+, 280 (100) [M – CF3 –
C4H9]+, 242 (32) [M – C9H12N3]+, 173 (24) [C10H5O3]+, 121 (37)
[HOC6H4CO]+, 57 (56), 41 (19).
aminoheterocycles as 1,3-C,N-dinucleophiles. Although
four competitive routes were observed, the reaction path-
ways could be controlled with respect to prevailing fused
pyridine derivatives.
All solvents were purified and dried by standard methods. NMR
spectra were recorded on a Jeol JNM-LA 400, Varian VXR-300 or
Varian Mercury-400, Bruker 600 spectrometer: 1H and 13C signals
(300, 400 and 100 MHz, respectively) were recorded with TMS as
an internal standard; 19F (282.2 and 376.2 MHz) with CFCl3 as in-
ternal standard. Mass spectra were obtained on a Hewlett-Packard
HPGC/MS 5890/5972 instrument (EI, 70 eV) by GC inlet or on a
MX-1321 instrument (EI, 70 eV) by direct inlet. Column chroma-
tography was performed on silica gel (63–200 mesh, Merck). Silica
gel Merck 60F254 plates were used for TLC. Satisfactory microanal-
ysis obtained: C 0.33; H 0.25; N 0.25.
(Z)-3-{[(2,6-Diaminopyrimidin-4-yl)amino]methylene}-2-
hydroxy-2-(trifluoromethyl)chroman-4-one (3j)
Reaction conditions: DMF, 100 °C, 24 h; orange crystals; yield: 105
mg (30%); mp 237–238 °C; Rf = 0.55 (EtOAc).
1H NMR (DMSO-d6): d = 5.20 (s, 1 H, H5¢), 6.35 (br s, 2 H), 6.95
(d, 3J = 7.8 Hz, 1 H), 6.97 (t, 3J = 7.8 Hz, 1 H), 7.13 (t, 3J = 7.8 Hz,
1 H), 7.55 (br s, 2 H), 7.81 (d, 3J = 7.8 Hz, 1 H), 8.48 (d, 3J = 12.9
Hz, 1 H, =CH), 8.60 (s, 1 H, OH), 11.80 (d, 3J = 12.9 Hz, 1 H, NH).
2
13C NMR (DMSO-d6): d = 97.8 (q, JC,F = 33 Hz), 116.5, 119.3,
120.7 (q, 1JC,F = 288 Hz), 122.1, 125.7, 132.4, 134.4, 135.1, 136.4,
X-ray Crystallography of 3n, 4a, and 5g
145.6, 155.7, 160.2, 164.4, 180.5.
Crystallographic measurements were performed at r.t. on a Enraf-
Nonius CAD4 diffractometer operating in the w-2q scan mode (the
scanning rate ratio w/2q = 1.2). The structure was solved by direct
methods and refined by full-matrix least-squares technique in aniso-
tropic approximation using SHELXS97 and SHELXL9722 pro-
gram packages. Hydrogen atoms were placed at calculated position
and refined as ‘riding’ model.10
19F NMR (DMSO-d6): d = –85.2.
MS: m/z (%) = 367 (11) [M]+, 298 (41) [M – CF3]+, 242 (49) [M –
1 – C4H6N5]+, 174 (27) [C10H5O3 + 1]+, 173 (100) [C10H5O3]+, 125
(89) [C4H7N5]+, 121 (80) [HOC6H4CO]+, 92 (31) [OC6H4]+.
3-{[(2,6-Dimethylpyrimidin-4-yl)amino]methylene}-2-
hydroxy-2-(trifluoromethyl)chroman-4-one (3l)
Reaction conditions: DMF, 60 °C, 2 h; colorless solid; yield: 319
mg (96%); mp 195–197 °C; Rf = 0.37 (EtOAc).
Cyclization of 3-(Trifluoroacetyl)-4H-chromen-4-one (1a) with
Aminoheterocycles 2; General Procedure
1H NMR (DMSO-d6): d = 2.38 (s, 3 H), 2.52 (s, 3 H), 7.08 (d,
3J = 7.8 Hz, 1 H), 7.16 (s, 1 H, H5¢), 7.16 (t, 3J = 7.8 Hz, 1 H), 7.58
(t, 3J = 7.8 Hz, 1 H), 7.85 (d, 3J = 7.8 Hz, 1 H), 8.62 (d, 3J = 12.0 Hz,
1 H, =CH), 9.18 (s, 1 H, OH), 12.07 (d, 3J = 12.0 Hz, 1 H, NH).
13C NMR (DMSO-d6): d = 23.6, 25.6, 97.8 (q, 2JC,F = 33 Hz), 102.6,
105.1, 116.9, 119.7, 122.2, 122.7 (q, 1JC,F = 288 Hz), 126.0, 135.7,
142.8, 156.0, 156.8, 166.7, 168.1, 181.0.
Into conical flask were placed the hydrate of 1a (242 mg, 0.91
mmol), the corresponding dinucleophile (1 mmol), and the solvent
[DMF or AcOH (10 mL)]. In the case of dinucleophile hydrochlo-
rides, NaOAc (1 mmol) was added. The flask was equipped with a
reflux condenser and was heated overnight if not reported other-
wise. The solvent was removed in vacuo and the product was puri-
fied by flash chromatography (silica gel) or recrystallization. The
yield refers to amount of isolated product.
19F NMR (DMSO-d6): d = –84.8.
(Z)-3-{[(1-Ethyl-1H-pyrazol-5-yl)amino]methylene}-2-
hydroxy-2-(trifluoromethyl)chroman-4-one (3b)
Reaction conditions: DMF, 80 °C; yellow crystals; yield: 270 mg
(85%); mp 153–155 °C; Rf = 0.51 (EtOAc).
MS: m/z (%) = 365 (22) [M]+, 297 (33) [M – CF3]+, 296 (100) [M –
CF3]+, 176 (49), 173 (44) [C10H5O3]+, 123 (41) [C6H9N3]+, 121 (39)
[HOC6H4CO]+, 107 (29) [C6H7N2]+, 67 (18), 66 (23), 42 (24).
1H NMR (DMSO-d6): d = 1.37 (t, 3J = 7.4 Hz, 3 H), 4.12 (q, 3J = 7.4
2-Hydroxy-3-{[(3-methyl-1H-pyrazol-5-yl)amino]methylene}-
2-(trifluoromethyl)chroman-4-one (3m)
Reaction conditions: DMF, 60 °C; yellow solid; yield: 304 mg
(99%); mp 200–203 °C; Rf = 0.57 (EtOAc).
Hz, 2 H), 6.33 (d, 3J = 2.0 Hz, 1 H, H4¢), 7.06 (d, 3J = 7.8 Hz, 1 H),
3
3
7.15 (t, J = 7.8 Hz, 1 H), 7.40 (d, J = 2.0 Hz, 1 H, H3¢), 7.56 (t,
3J = 7.8 Hz, 1 H), 7.71 (d, 3J = 12.1 Hz, 1 H, =CH), 7.86 (d, 3J = 7.8
Hz, 1 H), 9.04 (s, 1 H, OH), 12.70 (d, 3J = 12.1 Hz, 1 H, NH).
1H NMR (CDCl3): d = 2.26 (s, 3 H), 6.09 (s, 1 H, H4¢), 7.07 (d,
13C NMR (DMSO-d6): d = 14.2, 42.6, 94.1, 97.5 (q, 2JC,F = 33 Hz),
100.1, 109.8, 120.2 (q, 1JC,F = 286 Hz), 116.5, 119.6, 122.2, 125.6,
135.2, 138.1, 138.9, 149.2, 155.7, 180.4.
19F NMR (DMSO-d6): d = –85.2.
MS: m/z (%) = 353 (51) [M]+, 285 (21) [M + 1 – CF3]+, 284 (100)
[M – CF3]+, 243 (27) [M – C5H7N3]+, 173 (39) [C10H5O3]+, 121 (41)
[HOC6H4CO]+, 111 (19) [C5H9N3]+, 83 (17).
3
3J = 7.8 Hz, 1 H), 7.15 (t, J = 7.8 Hz, 1 H), 7.55 (t, 3J = 7.8 Hz, 1
H), 7.85 (d, 3J = 7.8 Hz, 1 H), 8.07 (d, 3J = 12.8 Hz, 1 H, =CH), 8.94
(s, 1 H, OH), 12.29 (s, 1 H, H1¢), 12.36 (d, 3J = 12.8 Hz, 1 H, NH).
2
13C NMR (CDCl3): d = 10.3, 93.1, 97.9 (q, JC,F = 33 Hz), 116.4,
116.5, 120.0, 122.2, 122.9 (q, 1JC,F = 288 Hz), 125.6, 134.9, 140.6,
147.1, 148.3, 155.7, 162.3, 179.6.
19F NMR (CDCl3): d = –85.4.
MS: m/z (%) = 339 (64) [M]+, 271 (40) [M + 1 – CF3]+, 270 (100)
[M – CF3]+, 253 (30), 252 (70), 243 (26) [M – C4H6N3]+, 242 (22)
[M – 1 – C4H6N3]+, 175 (24) [C10H5O3 + 2]+, 173 (87) [C10H5O3]+,
150 (74), 121 (76) [HOC6H4CO]+, 108 (53), 97 (79) [C4H7N3]+, 94
(19), 65 (23), 53 (24).
1-tert-Butyl-5-({[2-hydroxy-4-oxo-2-(trifluoromethyl)chroman-
3-ylidene]methyl}amino)-1H-pyrrole-3-carbonitrile (3f)
Reaction conditions: DMF, 100 °C; colorless solid; yield: 81 mg
(22%); mp 200–202 °C; Rf = 0.1 (CH2Cl2).
1H NMR (DMSO-d6): d = 1.60 (s, 9 H), 7.05 (d, 3J = 7.8 Hz, 1 H),
3
7.13 (t, 3J = 7.8 Hz, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 7.55 (s, 1 H),
Synthesis 2009, No. 22, 3869–3879 © Thieme Stuttgart · New York

3874
A. Kotljarov et al.
PAPER
Ethyl 5-({[2-Hydroxy-4-oxo-2-(trifluoromethyl)chroman-3-
ylidene]methyl}amino)-3-methylthiophene-2-carboxylate (3n)
Reaction conditions: DMF, 60 °C, 2 h; colorless solid; yield: 366
mg (94%); mp 134–137 °C; Rf = 0.85 (PE–Et2O, 1:1).
13C NMR (DMSO-d6): d = 40.0 (2 C), 98.0 (q, 2JC,F = 33 Hz), 98.4,
101.6, 104.2, 109.3, 116.5, 120.1, 122.3, 122.9 (q, 1JC,F = 291 Hz),
125.7, 130.4, 135.0, 140.0, 151.5, 147.4, 155.8, 179.6.
19F NMR (DMSO-d6): d = –85.3.
MS: m/z (%) = 379 (25) [M + 1]+, 378 (81) [M]+, 310 (24) [M + 1 –
CF3]+, 309 (100) [M – CF3]+, 243 (16) [M – C8H11N2]+, 189 (19),
173 (34) [C10H5O3]+, 136 (58) [C8H12N2]+, 135 (20) [C8H11N2]+, 121
(36) [HOC6H4CO]+.
1H NMR (CDCl3): d = 1.29 (t, 3J = 7.1 Hz, 3 H), 2.41 (s, 3 H), 4.23
(q, 3J = 7.1 Hz, 2 H), 6.38 (s, 1 H, H4¢), 6.86 (d, 3J = 7.8 Hz, 1 H),
3
3
7.02 (t, J = 7.8 Hz, 1 H), 7.36 (t, J = 7.8 Hz, 1 H), 7.56 (d,
4J = 12.1 Hz, 1 H, =CH), 7.81 (d, J = 7.8 Hz, 1 H), 12.84 (d,
3
3J = 12.1 Hz, 1 H, NH).
2
13C NMR (CDCl3): d = 14.2, 16.1, 61.0, 97.3 (q, JC,F = 34 Hz),
3-{[(1,3-Benzodioxol-5-yl)amino]methylene)-2-hydroxy-2-(tri-
fluoromethyl)chroman-4-one (3r)
100.6, 116.8, 117.5, 118.2, 119.8, 122.3 (q, 1JC,F = 290 Hz), 122.8,
126.2, 135.5, 147.0, 147.1, 147.3, 155.9, 162.7, 181.7.
Reaction conditions: DMF, 60 °C; colorless solid; yield: 338 mg
(98%); mp 150–152 °C; Rf = 0.37 (PE–EtOAc, 2:1).
19F NMR (CDCl3): d = –87.0.
MS, m/z (%) = 427 (72) [M]+, 358 (100) [M – CF3]+, 330 (21), 243
(35) [M – 1 – C8H10NO2S]+, 185 (38) [C8H10NO2S + 1], 173 (51)
[C10H5O3]+, 121 (58) [HOC6H4CO]+.
1H NMR (DMSO-d6): d = 6.05 (s, 2 H, H2¢), 6.83 (d, 3J = 8.4 Hz, 1
H, H6¢), 6.94 (d, 3J = 8.4 Hz, 1 H, H7¢), 7.04 (d, 3J = 7.8 Hz, 1 H),
7.12 (d, 3J = 7.8 Hz, 1 H), 7.16 (s, 1 H, H4¢), 7.52 (t, 3J = 7.8 Hz, 1
H), 7.80 (d, 3J = 7.8 Hz, 1 H), 7.87 (d, 3J = 12.6 Hz, 1 H, =CH), 9.01
(s, 1 H, OH), 12.54 (d, 3J = 12.6 Hz, 1 H, NH).
13C NMR (DMSO-d6): d = 97.9 (q, 3JC,F = 33 Hz), 98.3, 99.7, 101.6,
108.8, 110.8, 116.4, 120.0, 122.2, 123.5 (q, 1JC,F = 289 Hz), 125.6,
134.0, 134.8, 144.8, 147.7, 148.4, 155.7, 173.3.
2-Hydroxy-3-{[(4-methoxypyridin-2-yl)amino]methylene}-2-
(trifluoromethyl)chroman-4-one (3o)
Reaction conditions: DMF, 100 °C; yellow solid; yield: 253 mg
(76%); mp 159–160 °C (i-PrOH).
3
1H NMR (DMSO-d6): d = 3.85 (s, 3 H), 6.73 (d, J = 5.8 Hz, 1 H,
19F NMR (DMSO-d6): d = –85.3.
H5¢), 7.04 (d, 3J = 7.8 Hz, 1 H), 7.07 (s, 1 H, H2¢), 7.12 (t, 3J = 7.8
Hz, 1 H), 7.52 (t, 3J = 7.8 Hz, 1 H), 7.80 (d, 3J = 7.8 Hz, 1 H), 8.14
(d, 3J = 5.8 Hz, 1 H, H6¢), 8.62 (d, 3J = 12.2 Hz, 1 H, =CH), 9.11 (s,
1 H, OH), 12.21 (d, 3J = 12.2 Hz, 1 H, NH).
13C NMR (DMSO-d6): d = 55.6, 97.8, 98.9 (q, 2JC,F = 33 Hz), 103.7,
107.5, 117.0, 122.3 (q, 1JC,F = 289 Hz), 122.4, 124.1, 125.8, 135.3,
144.5, 149.2, 155.8, 163.7, 164.4, 180.1.
MS: m/z (%) = 379 (63) [M]+, 311 (26) [M + 1 – CF3]+, 310 (100)
[M – CF3]+, 243 (15) [M – C7H6NO2]+, 190 (28) [C7H5O2 + CF3]+,
173 (31) [C10H5O3]+, 155 (22), 137 (50) [C7H7NO2]+, 121 (53)
[HOC6H4CO]+.
3-{[(2,3-Dihydro-1,4-benzodioxin-6-yl)amino]methylene}-2-
hydroxy-2-(trifluoromethyl)chroman-4-one (3s)
Reaction conditions: DMF, 100 °C, 24 h; colorless solid; yield: 351
mg (98%); mp 146 °C; Rf = 0.57 (EtOAc).
19F NMR (DMSO-d6): d = –85.1.
MS: m/z (%) = 366 (22) [M]+, 298 (20) [M + 1 – CF3]+, 297 (100)
[M – CF3]+, 177 (36), 173 (34) [C10H5O3]+, 124 (29), 121 (16)
[HOC6H4CO]+, 108 (25).
3
1H NMR (CDCl3): d = 4.26 (d, J = 8.6 Hz, 4 H), 4.45 (br s, 1 H,
3
OH), 6.60 (d, J = 8.3 Hz, 1 H, H7¢), 6.63 (s, 1 H, H5¢), 6.83 (d,
3J = 8.3 Hz, 1 H, H8¢), 6.89 (d, 3J = 7.8 Hz, 1 H), 7.06 (t, 3J = 7.8
Hz, 1 H), 7.36 (t, 3J = 7.8 Hz, 1 H), 7.78 (d, 3J = 12.4 Hz, 1 H, =CH),
7.89 (d, 3J = 7.8 Hz, 1 H), 12.70 (d, 3J = 12.4 Hz, 1 H, NH).
3-{[(3,5-Dimethoxyphenyl)amino]methylene}-2-hydroxy-2-(tri-
fluoromethyl)chroman-4-one (3p)
Reaction conditions: DMF, 60 °C; colorless solid; yield: 338 mg
(94%); mp 131–133 °C; Rf = 0.55 (CH2Cl2–MeOH, 20:1).
2
13C NMR (CDCl3): d = 64.3, 64.5, 97.7 (q, JC,F = 33 Hz), 98.1,
106.3, 110.9, 116.5, 118.2, 120.2, 122.5, 122.5 (q, 1JC,F = 289 Hz),
126.0, 133.0, 134.5, 141.5, 144.3, 147.6, 155.3, 180.4.
19F NMR (CDCl3): d = –86.7.
MS: m/z (%) = 393 (51) [M]+, 325 (21) [M + 1 – CF3]+, 324 (100)
[M – CF3]+, 173 (12) [C10H5O3]+, 121 (20) [HOC6H4CO]+, 95 (12),
69 (20).
1H NMR (DMSO-d6): d = 3.77 (s, 6 H), 6.33 (s, 1 H, H4¢), 6.59 (s,
2 H, H2¢, H6¢), 7.06 (d, 3J = 7.8 Hz, 1 H), 7.13 (t, 3J = 7.8 Hz, 1 H),
3
3
7.54 (t, J = 7.8 Hz, 1 H), 7.81(d, J = 7.8 Hz, 1 H), 7.95 (d,
3J = 12.9 Hz, 1 H, =CH), 9.12 (s, 1 H, OH), 12.47 (d, 3J = 12.9 Hz,
1 H, NH).
13C NMR (DMSO-d6): d = 55.5 (2 C), 95.9 (2 C), 97.1, 98.0 (q,
2JC,F = 33 Hz), 99.0, 116.5, 120.0, 122.3, 122.8 (q, 1JC,F = 288 Hz),
125.7, 135.1, 141.1, 147.2, 155.8, 161.5 (2 C), 180.0.
(Z)-3-{[(5-Chloro-2-hydroxyphenyl)amino]methylene}-2-
hydroxy-2-(trifluoromethyl)chroman-4-one (3t)
Reaction conditions: DMF, 60 °C; pale yellow solid; yield: 294 mg
(84%); mp 193 °C; Rf = 0.09 (PE–EtOAc, 2:1).
19F NMR (DMSO-d6): d = –85.2.
MS: m/z (%) = 395 (17) [M]+, 326 (41) [M – CF3]+, 242 (22) [M –
C8H11NO2]+, 173 (35) [C10H5O3]+, 152 (100) [C8H10NO2]+, 124 (42)
[C6H9N3 + 1]+, 120 (71) [HOC6H4CO]+, 94 (12), 93 (26)
[C6H4CO]+, 53 (29).
3
1H NMR (DMSO-d6): d = 6.91 (d, J = 8.4 Hz, 1 H, H3¢), 7.02 (d,
3J = 8.4 Hz, 1 H, H4¢), 7.05 (d, 3J = 7.8 Hz, 1 H), 7.13 (t, 3J = 7.8
Hz, 1 H), 7.53, (t, 3J = 7.8 Hz, 1 H), 7.63 (s, 1 H), 7.82 (d, 3J = 7.8
Hz, 1 H), 8.11 (d, 3J = 13.2 Hz, 1 H, =CH), 9.02 (s, 1 H, OH), 10.69
(s, ArOH, 1 H), 12.69 (d, 3J = 13.2 Hz, 1 H, NH).
3-({[3-(Dimethylamino)phenyl]amino}methylene)-2-hydroxy-
2-(trifluoromethyl)chroman-4-one (3q)
Reaction conditions: DMF, 80 °C, 4 h; colorless solid; yield: 219
mg (64%); mp 167–168 °C (i-PrOH).
2
13C NMR (DMSO-d6): d = 98.0 (q, JC,F = 32 Hz), 99.7, 114.2,
116.5, 116.8, 120.0, 122.2, 122.8 (q, 1JC,F = 289 Hz), 123.7, 124.5,
125.7, 128.4, 135.0, 145.4, 146.0, 155.8, 179.9.
3
1H NMR (DMSO-d6): d = 2.93 (s, 6 H), 6.50 (d, J = 8.2 Hz, 1 H,
19F NMR (DMSO-d6): d = –85.1.
3
H5¢), 6.63 (d, J = 8.2 Hz, 1 H, H4¢), 6.68 (s, 1 H, H2¢), 7.05 (d,
MS: m/z (%) = 385 (22) [M]+, 349 (27), 347 (72), 318 (34), 316 (88)
[M – CF3]+, 300 (21), 298 (46), 243 (24), 242 (25), 196 (15)
[HOC6H3Cl + CF3]+, 173 (97) [C10H5O3]+, 154 (24), 145 (32), 143
(85) [ClC6H3(NH2)OH]+, 121 (100) [HOC6H4CO]+, 80 (21).
3J = 7.8 Hz, 1 H), 7.13 (t, 3J = 7.8 Hz, 1 H), 7.21 (t, 3J = 8.2 Hz, 1
H, H5¢), 7.52 (t, 3J = 7.8 Hz, 1 H), 7.81 (d, 3J = 7.8 Hz, 1 H), 7.97
(d, 3J = 12.7 Hz, 1 H, =CH), 9.07 (s, 1 H, OH), 12.50 (d, 3J = 12.7
Hz, 1 H, NH).
Synthesis 2009, No. 22, 3869–3879 © Thieme Stuttgart · New York

PAPER
Synthesis of Polyfluoroalkyl-Containing Fused Pyridines
3875
3
(Z)-2-Hydroxy-3-{[(2-hydroxy-5-nitrophenyl)amino]methyl-
ene}-2-(trifluoromethyl)chroman-4-one (3u)
(d, 3J = 7.8 Hz, 1 H), 7.55 (t, J = 7.8 Hz, 1 H), 8.16 (s, 1 H, H3),
8.19 (s, 1 H, H4), 11.83 (s, 1 H, OH).
Reaction conditions: DMF, 60 °C; yellow solid; yield: 295 mg
(82%); mp 221–223 °C (i-PrOH–H2O).
13C NMR (CDCl3): d = 14.9, 42.8, 115.3, 118.6, 119.1, 119.7, 121.0
1
(q, JC,F = 275 Hz), 125.4, 131.3, 132.6, 133.3, 137.5, 143.5 (q,
3
1H NMR (DMSO-d6): d = 7.06 (d, J = 7.2 Hz, 1 H), 7.11 (d,
2JC,F = 36 Hz), 148.1, 163.3, 199.4.
19F NMR (CDCl3): d = –61.5.
MS: m/z (%): 335 (38) [M]+, 267 (20) [M + 1 – CF3]+, 266 (85) [M
– CF3]+, 242 (14) [M – HOC6H4]+, 121 (78) [HOC6H4CO]+, 120
(100) [OC6H4CO]+, 93 (26) [HOC6H4]+, 92 (21) [OC6H4], 65 (31).
3J = 8.4 Hz, 1 H, H3¢), 7.13 (t, 3J = 7.2 Hz, 1 H), 7.54 (t, 3J = 7.2 Hz,
1 H), 7.84 (d, 3J = 7.2 Hz, 1 H), 7.95 (d, 3J = 8.4 Hz, 1 H, H4¢), 8.22
(d, 3J = 12.6 Hz, 1 H, =CH), 8.33 (s, 1 H, H6¢), 9.12 (s, 1 H, OH),
12.10 (s, 1 H, ArOH), 12.68 (d, 3J = 12.6 Hz, 1 H, NH).
2
13C NMR (DMSO-d6): d = 98.2 (q, JC,F = 33 Hz), 100.4, 110.7,
115.2, 116.6, 120.0, 121.2, 122.3, 124.8 (q, 1JC,F = 289 Hz), 125.8,
2-(Diethylamino)-6-salicyloyl-5-(trifluoromethyl)thiazolo[4,5-
b]pyridine (4c)
Reaction conditions: AcOH, reflux; colorless solid; yield: 338 mg
127.8, 135.3, 140.2, 146.1, 152.9, 155.9, 180.4.
19F NMR (DMSO-d6): d = –85.0.
MS: m/z (%) = 396 (9) [M]+, 358 (47), 327 (54) [M – CF3]+, 243
(24) [M – C6H5N2O3]+, 242 (23) [M – C6H5N2O3 – 1]+, 173 (100)
[C10H5O3]+, 154 (39) [C6H6N2O3]+, 121 (86) [HOC6H4CO]+, 80.0
(19).
(94%); mp 150–151 °C; Rf = 0.42 (EtOAc).
3
1H NMR (CDCl3): d = 1.35 (t, J = 7.1 Hz, 6 H), 3.69 (br s, 4 H),
6.83 (t, 3J = 8.0 Hz, 1 H), 7.07 (d, 3J = 8.0 Hz, 1 H), 7.21 (d, 3J = 8.0
Hz, 1 H), 7.53 (t, 3J = 8.0 Hz, 1 H), 7.86 (s, 1 H, H7), 11.81 (s, 1 H,
OH).
2-({[2-Hydroxy-4-oxo-2-(trifluoromethyl)chroman-3-
ylidene]methyl}amino)benzamide (3v)
Reaction conditions: DMF, 60 °C; colorless solid; yield: 279 mg
(82%); mp 204–205 °C (MeOH–H2O).
1H NMR (DMSO-d6): d = 7.05 (d, 3J = 7.8 Hz, 1 H), 7.13 (t, 3J = 7.8
Hz, 1 H), 7.22 (t, 3J = 7.8 Hz, 1 H), 7.52 (t, 3J = 7.8 Hz, 2 H), 7.58
(t, 3J = 7.8 Hz, 1 H), 7.63 (s, 1 H), 7.75 (d, 3J = 7.8 Hz, 1 H), 7.82
(d, 3J = 7.8 Hz, 1 H), 7.90 (d, 3J = 13.2 Hz, 1 H, =CH), 8.17 (s, 1 H),
9.09 (s, 1 H, OH), 13.50 (d, 3J = 13.2 Hz, 1 H, NH).
13C NMR (CDCl3): d = 12.7 (2 C), 46.1 (2 C), 116.1, 118.4, 119.2,
119.9, 121.4 (q, 1JC,F = 277 Hz), 128.4, 131.1, 133.2, 137.4, 141.9
(q, 2JC,F = 35 Hz), 162.8, 165.0, 170.6, 199.4.
19F NMR (CDCl3): d = –63.7.
MS: m/z (%) = 395 (54) [M]+, 366 (24) [M – Et]+, 352 (16) [M + 1
– Et – Me]+, 327 (20) [M + 1 – CF3]+ (21), 326.0 (80) [M – CF3]+,
298 (19) [M + 1 – CF3 – Et]+, 246 (24), 232 (25), 205 (15), 146 (100)
[M – 2 Et – CF3 – HOC6H4CO]+, 121 (29) [HOC6H4CO]+, 120 (23)
[OC6H4CO]+, 118 (49), 97 (19), 93 (17) [HOC6H4]+, 92 (80)
[OC6H4]+.
2
13C NMR (DMSO-d6): d = 98.1 (q, JC,F = 33 Hz), 100.2, 114.3,
116.0, 116.5, 122.2, 122.6, 122.9 (q, 1JC,F = 288 Hz), 123.7, 125.8,
129.1, 132.6, 135.0, 139.5, 145.3, 155.8, 169.8, 179.1.
19F NMR (DMSO-d6): d = –85.0.
MS: m/z (%) = 378 (19) [M]+, 309 (57) [M – CF3]+, 243 (15) [M –
C7H7N2O]+, 242 (26), 173 (100) [C10H5O3]+, 172 (88) [C10H4O3]+,
136 (98) [C7H8N2O]+, 121 (92) [HOC6H4CO]+, 120 (43)
[C7H6NO]+, 119 (77) [C7H5NO]+, 92 (46), 65 (27).
1-Methyl-3-phenyl-6-salicyloyl-5-(trifluoromethyl)-1,3-di-
hydro-2H-imidazo[4,5-b]pyridine-2-thione (4d)
Reaction conditions: AcOH, reflux; colorless solid; yield: 180 mg
(46%); mp 170–173 °C (EtOH).
1H NMR (DMSO-d6): d = 3.78 (s, 3 H, Me), 6.95 (t, 3J = 7.5 Hz, 1
H), 7.02 (d, 3J = 8.0 Hz, 1 H), 7.50–7.67 (m, 7 H), 8.21 (s, 1 H, H7),
11.03 (s, 1 H, OH).
2-Phenyl-5-salicyloyl-6-(trifluoromethyl)-1,2-dihydro-3H-
pyrazolo[3,4-b]pyridin-3-one (4a)
Reaction conditions: DMF, 100 °C, 24 h; colorless solid; yield: 352
mg (97%); mp 188 °C; Rf = 0.35 (PE–EtOAc, 1:1).
13C NMR (DMSO-d6): d = 30.9, 115.6, 117.8, 119.4, 121.1, 122.1
(q, 1JC,F = 272 Hz), 128.2, 128.4, 129.2, 130.9, 132.5, 134.0, 135.0
(q, 2JC,F = 34 Hz), 137.1, 144.9, 160.1, 173.8, 195.7.
3
3
1H NMR (CDCl3): d = 6.86 (t, J = 7.8 Hz, 1 H), 7.13 (d, J = 7.8
Hz, 2 H), 7.28 (t, 3J = 7.8 Hz, 1 H), 7.45 (t, 3J = 7.8 Hz, 2 H), 7.58
(t, 3J = 7.8 Hz, 1 H), 7.80 (d, 3J = 7.8 Hz, 2 H), 8.23 (s, 1 H, H4),
9.09 (br s, 1 H), 11.67 (s, 1 H).
3-Neopentyl-5-salicyloyl-6-(trifluoromethyl)isoxazolo[5,4-b]py-
ridine (4e)
Reaction conditions: DMF, 100 °C; colorless solid; yield: 115 mg
(33%); mp 141–142 °C; Rf = 0.81 (CH2Cl2).
1H NMR (DMSO-d6): d = 6.97 (td, J = 7.8, 1.1 Hz, 1 H), 7.00 (d,
J = 8.4 Hz, 1 H), 7.34 (tt, J = 7.4, 1.0 Hz, 1 H), 7.53–7.61 (m, 4 H),
7.89–7.93 (m, 2 H), 8.46 (s, 1 H, H4), 10.88 (s, 1 H, OH), 11.7–13.5
(br s, 1 H, NH).
13C NMR (CDCl3): d = 113.1, 118.8, 119.2, 119.4, 120.4, 123.4 (q,
1JC,F = 279 Hz), 127.7, 129.6, 132.9, 135.3, 135.8, 138.0, 146.7,
148.2 (q, 2JC,F = 35 Hz), 155.6, 157.2, 163.4, 197.6.
19F NMR (CDCl3): d = –63.6.
MS: m/z (%) = 400 (17) [M + 1]+, 399 (70) [M]+, 331 (22) [M + 1 –
CF3]+, 330 (100) [M – CF3]+, 279 (25), 122 (29), 121 (94)
[HOC6H4CO]+, 93 (22) [HOC6H4]+, 77 (44), 65 (24).
1H NMR (CDCl3): d = 1.06 (s, 9 H), 2.91 (s, 2 H), 6.85 (t, 3J = 8.2
Hz, 1 H), 7.05 (d, 3J = 8.2 Hz, 1 H), 7.12 (d, 3J = 7.8 Hz, 1 H), 7.58
(t, 3J = 7.8 Hz, 1 H), 8.12 (s, 1 H, H4), 11.64 (s, 1 H, OH).
13C NMR (CDCl3): d = 29.7, 32.0, 39.4, 112.5, 116.2, 118.9, 119.4,
1
120.7 (q, JC,F = 275 Hz), 128.9, 132.8, 133.2, 138.0, 145.4 (q,
2JC,F = 34 Hz), 157.7, 163.4, 168.0, 197.8.
19F NMR (CDCl3): d = –63.0.
MS: m/z (%) = 379 (24) [M + 1]+, 378 (89) [M]+, 363 (53) [M –
CH3]+, 322 (43) [M – C4H9 + 1]+, 310 (30) [M – CF3 + 1]+, 309 (100)
[M – CF3]+, 253 (27) [M – CF3 – C4H9]+, 239 (32) [M – CF3 – C5H11
+ 1]+, 121 (61) [HOC6H4CO]+, 120 (34) [OC6H4CO]+, 65 (15), 57
(98) [C4H9]+, 55 (20), 43 (38), 41 (43).
1-Ethyl-5-salicyloyl-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]py-
ridine (4b)
Reaction conditions: AcOH, reflux; colorless solid; yield: 187 mg
(60%); mp 137–139 °C; Rf = 0.23 (PE–Et2O, 2:1).
1-tert-Butyl-5-salicyloyl-6-(trifluoromethyl)-1H-pyrrolo[2,3-
b]pyridine-3-carbonitrile (4f)
Reaction conditions: DMF, 100 °C, 32 h; colorless solid; yield: 75
mg (21%); mp 207 °C; Rf = 0.68 (CH2Cl2).
3
3
1H NMR (CDCl3): d = 1.62 (t, J = 7.0 Hz, 3 H), 4.70 (q, J = 7.0
Hz, 2 H), 6.83 (t, 3J = 7.8 Hz, 1 H), 7.10 (d, 3J = 7.8 Hz, 1 H), 7.19
Synthesis 2009, No. 22, 3869–3879 © Thieme Stuttgart · New York

3876
A. Kotljarov et al.
PAPER
1H NMR (DMSO-d6): d = 1.81 (9 H), 6.94 (t, 3J = 7.8 Hz, 1 H), 6.98
(d, 3J = 7.8 Hz, 1 H), 7.51 (d, 3J = 7.8 Hz, 1 H), 7.57 (t, 3J = 7.8 Hz,
1 H), 8.43 (s, 1 H, H2), 9.05 (s, 1 H, H4), 10.90 (s, 1 H, OH).
1H NMR (DMSO-d6): d = 2.33 (s, 3 H), 6.04 (s, 1 H, H3), 6.99 (m,
2 H), 7.57 (m, 2 H), 8.64 (s, 1 H, H8), 10.79 (s, 1 H, OH), 13.42 (s,
1 H, NH).
13C NMR (DMSO-d6): d = 28.3, 59.5, 83.0, 114.4, 117.6, 119.4,
121.6 (q, 1JC,F = 273 Hz), 121.7, 122.0, 128.2, 129.0, 132.5, 136.6
(q, 2JC,F = 34 Hz), 136.7, 144.9, 160.2, 196.0.
13C NMR (DMSO-d6): d = 14.3, 89.9, 109.5, 117.8, 119.7, 120.9 (q,
1JC,F = 286 Hz), 122.3, 128.1, 132.2, 136.7, 139.7, 142.3, 146.7 (q,
2JC,F = 35 Hz), 149.4, 154.2, 155.8, 159.8, 194.2.
19F NMR (DMSO-d6): d = –61.3.
19F NMR (DMSO-d6): d = –63.2.
MS: m/z (%) = 389 (12) [M + 1]+, 388 (54) [M]+, 320 (23) [M + 1 –
CF3]+, 319 (100) [M – CF3]+, 268 (20) [M – 1 – HOC6H4CO]+, 121
(74) [HOC6H4CO]+, 93 (17) [HOC6H4]+, 65 (18).
MS: m/z (%) = 387 (30) [M]+, 318 (29) [M – CF3]+, 262 (100) [M +
1 – CF3 – C4H9]+, 121 (21) [HOC6H4CO]+, 69 (16), 57 (39).
Ethyl 5-Salicyloyl-6-(trifluoromethyl)furo[2,3-b]pyridine-2-
carboxylate (4g)
Reaction conditions: DMF, 100 °C; colorless solid; yield: 86 mg
5,7-Dimethoxy-3-salicyloyl-2-(trifluoromethyl)quinoline (4p)
Reaction conditions: AcOH, reflux, 84 h; colorless solid; yield: 167
mg (48%); mp 141–143 °C; Rf = 0.67 (Et2O).
(25%); mp 149–150 °C; Rf = 0.57 (toluene–Et2O, 5:1).
3
3
1H NMR (CDCl3): d = 1.46 (t, J = 7.1 Hz, 3 H), 4.50 (q, J = 7.1
Hz, 2 H), 6.84 (t, 3J = 7.8 Hz, 1 H), 7.10 (d, 3J = 7.8 Hz, 2 H), 7.57
(t, 3J = 7.8 Hz, 1 H), 7.62 (s, 1 H, H3), 8.16 (s, 1 H, H4), 11.69 (s, 1
H, OH).
1H NMR (CDCl3): d = 3.94 (s, 3 H), 3.97 (s, 3 H), 6.88 (s, 1 H, H4¢),
6.95 (m, 3J = 7.8 Hz, 2 H), 7.21 (s, 1 H), 7.55 (m, 3J = 7.8 Hz, 2 H),
8.46 (s, 1 H, H4), 10.78 (s, 1 H, OH).
13C NMR (CDCl3): d = 56.5, 56.8, 100.2, 101.6, 115.9, 118.0,
119.8, 121.7 (q, 1JC,F = 275 Hz), 123.1, 128.9, 132.1, 132.4, 136.7,
144.0 (q, 2JC,F = 34 Hz), 148.0, 156.0, 160.0, 163.9, 195.7.
13C NMR (CDCl3): d = 14.1, 62.5, 111.7, 118.8, 119.4, 119.4, 121.0
1
(q, JC,F = 275 Hz), 121.4, 129.8, 132.7, 133.1, 138.0, 142.3 (q,
2JC,F = 35 Hz), 149.3, 158.2, 160.3, 163.4, 198.4.
19F NMR (CDCl3): d = –62.7.
19F NMR (CDCl3): d = –61.6.
MS: m/z (%) = 378 (12) [M + 1]+, 377 (58) [M]+, 308 (35) [M –
CF3]+, 257 (15) [M + 1 – HOC6H4CO]+, 256 (100) [M –
HOC6H4CO]+, 121 (53) [HOC6H4CO]+, 93 (15) [HOC6H4]+, 65
(14).
MS: m/z (%) = 379 (22) [M]+, 311 (19) [M + 1 – CF3]+, 310 (100)
[M – CF3]+, 282 (31) [M + 1 – CF3 – Et]+, 121 (91) [HOC6H4CO]+,
120 (17) [OC6H4CO]+, 93 (23) [HOC6H4]+, 65 (32).
1,3-Dimethyl-6-salicyloyl-7-(trifluoromethyl)pyrido[2,3-d]pyri-
midine-2,4(1H,3H)-dione (4i)
Reaction conditions: DMF, 80 °C, 30 h; colorless solid; yield: 276
2-Methyl-5-salicyloyl-6-(trifluoromethyl)pyridine-3-carbo-
nitrile (4w)
Reaction conditions: DMF, 100 °C; colorless solid; yield: 95 mg
mg (74%); mp 254–256 °C (AcOH).
(34%); mp 139 °C; Rf = 0.77 (CH2Cl2).
1H NMR (CDCl3): d = 3.53 (s, 3 H), 3.80 (s, 3 H), 6.85 (t, 3J = 7.4
Hz, 1 H), 7.10 (d, 3J = 7.4 Hz, 1 H), 7.11 (d, 3J = 7.4 Hz, 1 H), 7.58
(t, 3J = 7.4 Hz, 1 H), 8.55 (s, 1 H, H5), 11.62 (s, 1 H, OH).
1H NMR (DMSO-d6): d = 2.80 (s, 3 H), 6.94 (d, 3J = 7.8 Hz, 1 H),
6.97 (t, 3J = 7.8 Hz, 1 H), 7.56 (t, 3J = 7.8 Hz, 1 H), 7.65 (d, 3J = 7.8
Hz, 1 H), 8.65 (s, 1 H, H4), 10.71 (s, 1 H, OH).
13C NMR (CDCl3): d = 28.9, 30.0, 111.8, 118.9, 119.1, 119.5, 120.3
13C NMR (DMSO-d6): d = 22.5, 111.8, 115.5, 117.7, 119.6, 120.7
2
1
(q, 1JC,F = 276 Hz), 127.4, 132.7, 138.4, 139.2, 148.3 (q, JC,F = 35
(q, JC,F = 275 Hz), 121.5, 131.5, 134.1, 137.0, 141.2, 143.6 (q,
Hz), 150.8, 150.8, 159.7, 163.4, 197.1.
19F NMR (CDCl3): d = –64.2.
2JC,F = 34 Hz), 159.7, 161.6, 192.0.
19F NMR (DMSO-d6): d = –63.7.
MS: m/z (%) = 379 (28) [M]+, 311 (30) [M + 1 – CF3]+, 310 (100)
[M – CF3]+, 121 (51) [HOC6H4CO]+, 120 (43), 93 (14) [HOC6H4]+,
65 (14).
MS: m/z (%) = 306 (25) [M]+, 237 (100) [M – CF3]+, 121 (99)
[HOC6H4CO]+, 93 (22) [HOC6H4]+, 65 (27).
8-Neopentyl-6-(trifluoromethyl)-6H-chromeno[4,3-b]isoxazo-
lo[4,5-e]pyridin-6-ol (5e)
Reaction conditions: DMF, 100 °C; colorless solid; yield: 220 mg
6-Salicyloyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4-di-
amine (4j)
Reaction conditions: DMF, 100 °C, 24 h; colorless solid; yield: 187
mg (59%); mp 278 °C; Rf = 0.64 (EtOAc).
1H NMR (DMSO-d6): d = 6.84 (br s, 2 H), 6.95 (t, 3J = 7.7 Hz, 1 H),
6.98 (d, 3J = 7.7 Hz, 1 H), 7.53–7.58 (m, 2 H), 7.92 (br s, 2 H), 8.59
(s, 1 H, H5), 10.92 (s, 1 H, OH).
(64%); mp 137 °C; Rf = 0.68 (CH2Cl2).
1H NMR (DMSO-d6): d = 0.99 (s, 9 H), 2.99 (s, 2 H), 7.16 (d,
3
3J = 7.8 Hz, 1 H), 7.23 (t, J = 7.8 Hz, 1 H), 7.52 (t, 3J = 7.8 Hz, 1
H), 8.28 (d, 3J = 7.8 Hz, 1 H), 8.63 (s, 1 H, H7), 9.65 (s, 1 H, OH).
13C NMR (DMSO-d6): d = 29.0 (3 C), 31.9, 37.4, 96.7 (q, 1JC,F = 33
13C NMR (DMSO-d6): d = 105.7, 117.8, 119.7, 121.1 (q, 1JC,F = 278
Hz), 113.8, 116.8, 118.7, 119.7, 122.4 (q, JC,F = 289 Hz), 123.2,
125.1, 133.6, 134.0, 148.7, 153.1, 158.2, 169.4.
1
2
Hz), 121.9, 125.8, 132.6, 134.8, 136.7, 147.6 (q, JC,F = 34 Hz),
160.7, 162.6, 163.1, 164.6, 195.8.
19F NMR (DMSO-d6): d = –63.4.
MS: m/z (%) = 350 (17) [M + 1]+, 349 (89) [M]+, 280 (50) [M –
CF3]+, 256 (14) [M – HOC6H4]+, 230 (12), 229 (100), 121 (39)
[HOC6H4CO]+, 120 (30) [OC6H4CO]+, 93 (15) [HOC6H4]+, 65 (20).
19F NMR (DMSO-d6): d = –84.3.
MS: m/z (%) = 379 (24) [M + 1]+, 378 (89) [M]+, 363 (53) [M –
Me]+, 322 (43) [M + 1 – C4H9]+, 310 (30) [M + 1 – CF3]+, 309 (100)
[M – CF3]+, 253 (27) [M – CF3 – C4H9]+, 239 (32) [M + 1 – CF3 –
C5H11]+, 121 (61) [HOC6H4CO]+, 120 (34) [OC6H4CO]+, 57 (98)
[C4H9]+, 55 (20), 43 (38) [C3H7]+, 41 (43).
2-Methyl-7-salicyloyl-6-(trifluoromethyl)pyrazolo[1,5-a]pyri-
do[2,3-d]pyrimidin-9(4H)-one (4k)
Reaction conditions: DMF, 80 °C, 24 h; yield: 227 mg (64%); mp
10-tert-Butyl-6-hydroxy-6-(trifluoromethyl)-6,10-dihydro-
chromeno[4,3-b]pyrrolo[3,2-e]pyridine-8-carbonitrile (5f)
Reaction conditions: DMF, 100 °C; pale yellow solid; yield: 183 mg
(52%); mp 173–175 °C; Rf = 0.19 (CH2Cl2).
>300 °C (MeOH).
Synthesis 2009, No. 22, 3869–3879 © Thieme Stuttgart · New York

PAPER
Synthesis of Polyfluoroalkyl-Containing Fused Pyridines
3877
1H NMR (DMSO-d6): d = 1.84 (s, 9 H), 7.13 (d, 3J = 7.8 Hz, 1 H),
1H NMR (DMSO-d6): d = 2.78, (s, 3 H), 7.14 (d, 3J = 7.8 Hz, 1 H),
7.22 (t, 3J = 7.8 Hz, 1 H), 7.52 (t, 3J = 7.8 Hz, 1 H), 8.25 (d, 3J = 7.8
Hz, 1 H), 8.38 (s, 1 H, H4), 9.62 (s, 1 H, OH).
3
3
7.23 (t, J = 7.8 Hz, 1 H), 7.44 (t, J = 7.8 Hz, 1 H), 8.16 (s, 1 H,
H9), 8.27 (d, 3J = 7.8 Hz, 1 H), 8.67 (s, 1 H, H7), 9.41 (s, 1 H, OH).
2
13C NMR (DMSO-d6): d = 28.6 (3 C), 59.0, 82.6, 96.6 (q, 1JC,F = 32
13C NMR (DMSO-d6): d = 23.2, 95.7 (q, JC,F = 33 Hz), 107.7,
1
Hz), 114.9, 116.6, 117.5, 119.9, 120.2, 122.5 (q, JC,F = 262 Hz),
116.5, 116.8, 118.1, 119.8, 122.2 (q, 1JC,F = 289 Hz), 123.1, 125.0,
123.0, 123.9, 126.6, 131.8, 138.5, 142.2, 147.2, 152.1.
133.8, 139.8, 149.2, 152.9, 163.4.
19F NMR (DMSO-d6): d = –83.9.
MS: m/z (%) = 388 (11) [M + 1]+, 387 (46) [M]+, 318 (55) [M –
CF3]+, 263 (22) [M + 1 – CF3 – C4H9]+, 262 (100) [M – CF3 –
C4H9]+, 57 (32) [C4H9]+, 41 (22).
19F NMR (DMSO-d6): d = –84.2.
MS: m/z (%) = 306 (15) [M]+, 238 (17) [M + 1 – CF3]+, 237 (100)
[M – CF3]+.
2-Phenyl-5-salicyloyl-4-(trifluoromethyl)-1,2-dihydro-3H-
pyrazolo[3,4-b]pyridin-3-one (6a)
Reaction conditions: AcOH, 100 °C, 36 h; yield: 134 mg (37%); mp
Ethyl 6-Hydroxy-6-(trifluoromethyl)-6H-chromeno[4,3-b]fu-
ro[3,2-e]pyridine-9-carboxylate (5g)
Reaction conditions: DMF, 100 °C; colorless solid; yield: 124 mg
(36%); mp 133–135 °C; Rf = 0.46 (toluene–Et2O, 5:1).
188 °C; Rf = 0.24 (PE–EtOAc, 1:1).
1H NMR (DMSO-d6): d = 6.96 (t, 3J = 8.2 Hz, 2 H), 7.33 (t, 3J = 7.2
Hz, 1 H), 7.54 (m, 3 H), 7.64 (d, 3J = 7.8 Hz, 1 H), 7.89 (d, 3J = 8.2
Hz, 2 H), 8.73 (s, 1 H, H6), 10.89 (s, 1 H, OH).
13C NMR (DMSO-d6): d = 104.5, 117.5, 119.3, 120.3, 121.5 (q,
1JC,F = 275 Hz), 121.8, 125.8, 126.9, 128.8, 131.7 (q, 2JC,F = 36 Hz),
131.8, 136.4, 136.5, 151.8, 155.1, 155.7, 159.9, 194.8.
19F NMR (DMSO-d6): d = –57.0.
MS: m/z (%) = 400 (19) [M + 1]+, 399 (71) [M]+, 331 (20) [M + 1 –
CF3]+, 330 (96) [M – CF3]+, 279 (20) [M + 1 – HOC6H4CO]+, 121
(100) [HOC6H4CO]+, 93 (23) [HOC6H4]+, 77 (69) [C6H5]+, 65 (36).
3
3
1H NMR (CDCl3): d = 1.44 (t, J = 7.1 Hz, 3 H), 4.46 (q, J = 7.1
Hz, 2 H), 7.07 (d, 3J = 7.8 Hz, 1 H), 7.20 (t, 3J = 7.8 Hz, 1 H), 7.41
(t, 3J = 7.8 Hz, 1 H), 7.54 (s, 1 H, H8), 8.35 (s, 1 H, H7), 8.38 (d,
3J = 7.8 Hz, 1 H), 10.43 (s, OH).
2
13C NMR (CDCl3): d = 14.2, 62.1, 96.4 (q, JC,F = 33 Hz), 112.8,
116.6, 118.8, 119.5, 122.3 (q, 1JC,F = 279 Hz), 123.5, 123.5, 125.4,
131.8, 132.6, 146.3, 147.0, 152.2, 158.9, 162.9.
19F NMR (CDCl3): d = –85.3.
MS: m/z (%) = 379 (24) [M]+, 311 (20) [M + 1 – CF3]+, 310 (100)
[M – CF3]+, 282 (33) [M + 1 – CF3 – C2H5]+, 149 (18), 121 (21)
[HOC6H4CO]+, 69 (26).
1-Ethyl-5-salicyloyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]py-
ridine (6b)
6-Hydroxy-11-methyl-6-(trifluoromethyl)-6H-
chromeno[3¢,4¢:5,6]pyrido[2,3-d]pyrimidine-8,10(9H,11H)-di-
one (5h)
Reaction conditions: DMF, 80 °C; colorless solid; yield: 233 mg
(70%); mp 200–201 °C (MeOH).
1H NMR (DMSO-d6): d = 3.61 (s, 3 H), 7.16 (d, 3J = 7.8 Hz, 1 H),
7.24 (t, 3J = 7.8 Hz, 1 H), 7.54 (t, 3J = 7.8 Hz, 1 H), 8.31 (d, 3J = 7.8
Hz, 1 H), 8.34 (s, 1 H, H7), 9.59 (s, 1 H, OH), 11.85 (s, 1 H, NH).
Reaction conditions: AcOH, 100 °C; yield: 104 mg (34%); mp 163–
164 °C; Rf = 0.38 (PE–Et2O, 2:1).
3
3
1H NMR (CDCl3): d = 1.60 (t, J = 7.4 Hz, 3 H), 4.69 (q, J = 7.4
Hz, 2 H), 6.84 (t, 3J = 7.8 Hz, 1 H), 7.11 (d, 3J = 7.8 Hz, 1 H), 7.17
(d, 3J = 7.8 Hz, 1 H), 7.56 (t, 3J = 7.8 Hz, 1 H), 8.27 (q, J = 1.6 Hz,
1 H, H3), 8.59 (s, 1 H, H6), 11.81 (s, 1 H, OH).
13C NMR (CDCl3): d = 14.9, 42.8, 110.6 (q, JC,F = 2.4 Hz), 118.6,
1
119.3, 120.1, 122.5 (q, JC,F = 274 Hz), 125.0 (q, JC,F = 2.5 Hz),
2
2
13C NMR (DMSO-d6): d = 27.9, 95.9 (q, JC,F = 33 Hz), 110.7,
129.4 (q, JC,F = 35 Hz), 131.7 (q, JC,F = 2.4 Hz), 137.7, 147.4,
116.4, 116.8, 118.2, 123.1, 124.1 (q, 1JC,F = 285 Hz), 125.4, 133.9,
150.3, 163.2, 199.2.
135.8, 150.7, 150.7, 153.2, 160.6, 192.7.
19F NMR (DMSO-d6): d = –84.6.
19F NMR (CDCl3): d = –57.5.
MS: m/z (%) = 335 (36) [M]+, 267 (21) [M + 1 – CF3]+, 266 (100)
[M – CF3]+, 242 (12) [M – HOC6H4]+, 121 (66) [HOC6H4CO]+, 120
(95) [OC6H4CO]+, 93 (18) [HOC6H4]+, 92 (16) [OC6H4]+, 65 (19).
MS: m/z (%) = 365 (22) [M]+, 297 (34) [M + 1 – CF3]+, 296 (100)
[M – CF3]+, 197 (16), 196 (15), 152 (23).
6-Hydroxy-9,11-dimethyl-6-(trifluoromethyl)-6H-
chromeno[3¢,4¢:5,6]pyrido[2,3-d]pyrimidine-8,10(9H,11H)-di-
one (5i)
Reaction conditions: DMF, 80 °C, 30 h; yellow solid; yield: 98 mg
(24%); mp 183 °C (AcOH).
1H NMR ((DMSO-d6): d = 3.31 (s, 3 H), 3.69 (s, 3 H), 7.17 (d,
3J = 7.8 Hz, 1 H), 7.25 (t, 3J = 7.8 Hz, 1 H), 7.55 (t, 3J = 7.8 Hz, 1
H), 8.31 (d, 3J = 7.8 Hz, 1 H), 8.39 (s, 1 H, H7), 9.66 (s, 1 H, OH).
13C NMR (DMSO-d6): d = 27.8, 29.0, 95.8 (q, 2JC,F = 33 Hz), 109.7,
117.0, 118.1, 116.5, 122.1 (q, 1JC,F = 289 Hz), 122.8, 125.1, 133.6,
136.0, 150.6, 151.6, 153.0, 160.0, 205.8.
3-Neopentyl-5-salicyloyl-4-(trifluoromethyl)isoxazolo[5,4-b]py-
ridine (6e)
Reaction conditions: AcOH, 100 °C; yield: 28 mg (8%); mp 144–
145 °C; Rf = 0.53 (PE–Et2O, 2:1).
1H NMR (CDCl3): d = 1.14 (s, 9 H), 3.01 (s, 2 H), 6.86 (t, 3J = 7.8
Hz, 1 H), 7.05 (d, 3J = 7.3 Hz, 1 H), 7.11 (d, 3J = 7.8 Hz, 1 H), 7.56
(t, 3J = 7.8 Hz, 1 H), 8.65 (s, 1 H, H6), 11.61 (s, 1 H, OH).
13C NMR (CDCl3): d = 29.7, 32.1, 39.0 (q, JC,F = 3.2 Hz), 110.3 (q,
JC,F = 2.4 Hz), 118.8, 119.6, 119.8, 121.6 (q, 1JC,F = 273 Hz), 128.3
2
(q, JC,F = 2.4 Hz), 131.5 (q, JC,F = 36 Hz), 132.7, 138.1, 149.6,
156.5, 163.1, 170.0, 198.0.
19F NMR (DMSO-d6): d = –84.4.
19F NMR (CDCl3): d = –54.2.
MS: m/z (%) = 379 (15) [M]+, 311 (50) [M + 1 – CF3]+, 310 (100)
MS: m/z (%) = 378 (35) [M]+, 363 (21) [M – CH3]+, 322 (14) [M +
1 – C4H9]+, 310 (31) [M + 1 – CF3]+, 309 (100) [M – CF3]+, 252 (13)
[M – CF3 – C4H9]+, 239 (66) [M + 1 – CF3 – C5H11]+, 121(23)
[HOC6H4CO]+, 57 (22) [C4H9]+.
[M – CF3]+, 152 (10).
5-Hydroxy-2-methyl-5-(trifluoromethyl)-5H-chromeno[4,3-
b]pyridine-3-carbonitrile (5w)
Reaction conditions: DMF, 100 °C; colorless solid; yield: 173 mg
(62%); mp 146–147 °C; Rf = 0.64 (CH2Cl2).
Synthesis 2009, No. 22, 3869–3879 © Thieme Stuttgart · New York

3878
A. Kotljarov et al.
PAPER
6-(Difluoromethyl)-2-phenyl-5-salicyloyl-1,2-dihydropyrazo-
lo[3,4-b]pyridin-3-one (4ba)
243 (24) [M – C9H16N2O]+, 173 (18) [C10H5O3]+, 168 (15) [M –
C10H4F3O2]+, 121 (68) [HOC6H4CO]+, 96.0 (27).
Reaction conditions: toluene, reflux, 20 h; yield: 260 mg (80%); mp
179–180 °C.
IR (KBr): 1656, 1625, 1599, 1578 cm–1.
1H NMR (DMSO-d6): d = 6.98 (td, J = 7.8, 1.0 Hz, 1 H), 7.01 (d,
3J = 8.3 Hz, 1 H), 7.28 (t, 2JH,F = 53.7 Hz, 1 H), 7.32 (tt, 3J = 7.4, 1.0
Hz, 1 H), 7.49–7.57 (m, 4 H), 7.89–7.92 (m, 2 H), 8.26 (s, 1 H, H4),
10.67 (s, 1 H, OH), 11.6–13.6 (br s, 1 H, NH).
3-{[2-(5,5-Dimethyl-3-oxocyclohex-1-enyl)-2-methylhydra-
zono]methyl}-2-(trifluoromethyl)-4H-chromen-4-one (9)
Reaction conditions: AcOH, 100 °C; colorless solid; yield: 271 mg
(76%); mp 172–175 °C; Rf = 0.35 (PE–EtOAc, 1:1).
1H NMR (DMSO-d6): d = 0.94 (s, 6 H), 2.09 (s, 2 H, H6¢), 2.62 (s,
2 H, H4¢), 3.28 (s, 3 H), 5.50 (s, 1 H, H2¢), 7.56 (t, 3J = 7.4 Hz, 1 H),
7.71 (d, 3J = 7.4 Hz, 1 H), 7.75 (s, 1 H), 7.90 (t, 3J = 7.4 Hz, 1 H),
8.07 (d, 3J = 7.4 Hz, 1 H).
13C NMR (DMSO-d6): d = 27.9, 31.7, 31.9, 38.9, 49.6, 101.6,
118.3, 119.0 (q, 1JC,F = 274 Hz), 119.5, 122.0, 125.0, 126.5, 127.8,
135.5, 146.9 (q, 2JC,F = 37 Hz), 154.3, 160.9, 175.9, 196.2.
19F NMR (DMSO-d6): d = –64.4.
19F NMR (DMSO-d6): d = –116.1 (d, 2JF,H = 53.7 Hz, 2 F, CF2H).
MS: m/z (%) = 261 (58) [M + 1 – HOC6H4CO]+, 232 (22), 212 (17),
155 (17), 77 (69) [C6H5]+, 64 (40), 51 (32), 28 (28).
5-(5-Chloro-2-hydroxybenzoyl)-2-phenyl-6-(trifluoromethyl)-
1,2-dihydropyrazolo[3,4-b]pyridin-3-one (4ca)
Reaction conditions: toluene, reflux, 12 h; yield: 310 mg (73%); mp
260–261 °C.
MS: m/z (%) = 392 (14) [M]+, 324 (30) [M + 1 – CF3]+, 323 (100)
[M – CF3]+, 308 (17) [M – CF3 – CH3]+, 307 (21) [M – 1 – CF3 –
CH3]+, 272 (15) [M – OC6H4CO]+, 179 (13) [M – C10H4F3O2]+, 96
(17), 55 (22).
IR (KBr): 1649, 1621, 1594, 1578 cm–1.
1H NMR (DMSO-d6): d = 7.00 (d, 3J = 8.8 Hz, 1 H), 7.35 (t, 3J = 7.4
Hz, 1 H), 7.56 (t, 3J = 7.5 Hz, 2 H), 7.59 (dd, J = 8.8, 2.7 Hz, 1 H),
3
7.66 (d, J = 2.7 Hz, 1 H), 7.91 (d, J = 7.7 Hz, 2 H), 8.49 (s, 1 H,
Acknowledgment
H4), 10.85 (s, 1 H, OH), 11.5–13.5 (br s, 1 H, NH).
19F NMR (DMSO-d6): d = –62.5.
We are grateful to German Academical Exchange Service (DAAD)
for the fellowship awarded to Anton Kotljarov.
MS: m/z (%) = 279 (64) [M + 1 – HO(Cl)C6H3CO]+, 250 (30), 230
(19), 77 (68) [C6H5]+, 64 (22), 51 (23), 28 (35).
References
7-(Difluoromethyl)-1,3-dimethyl-6-salicyloylpyrido[2,3-d]pyri-
midine-2,4(1H,3H)-dione (4bi) and 6-(Difluoromethyl)-6-hy-
droxy-9,11-dimethyl-6H-chromeno[3¢,4¢:5,6]pyrido[2,3-
d]pyrimidine-8,10(9H,11H)-dione (5bi)
Reaction conditions: toluene, reflux, 22 h; yield: 300 mg (92%); mp
185–186 °C.
1H NMR (DMSO-d6): d = (4bi, 65%) 3.30 (s, 3 H), 3.63 (s, 3 H),
6.97–7.02 (m, 2 H), 7.23 (t, 2JH,F = 53.6 Hz, 1 H), 7.47–7.58 (m, 2
H), 8.40 (s, 1 H, H5), 10.64 (s, 1 H, OH).
19F NMR (DMSO-d6): d = (4bi, 65%) –116.6 (d, 2JF,H = 53.6 Hz, 2
F, CF2H).
(1) (a) Al-Shaar, A. H. M.; Gilmour, D. W.; Lythgoe, D. J.;
McClenaghan, I.; Ramsden, C. A. J. Chem. Soc., Chem.
Commun. 1989, 551. (b) Al-Shaar, A. H. M.; Gilmour, D.
W.; Lythgoe, D. J.; McClenaghan, I.; Ramsden, C. A.
J. Chem. Soc., Perkin Trans. 1 1992, 2779. (c) Al-Shaar,
A. H. M.; Chambers, R. K.; Gilmour, D. W.; Lythgoe, D. J.;
McClenaghan, I.; Ramsden, C. A. J. Chem. Soc., Perkin
Trans. 1 1992, 2789. (d) Allegretti, M.; Anacardio, R.;
Cesta, M. C.; Curti, R.; Mantovanini, M.; Nano, G.; Topai,
A.; Zampella, G. Org. Process Res. Dev. 2003, 7, 209.
(e) Dang, Q.; Gomez-Galeno, J. E. J. Org. Chem. 2002, 67,
8703.
(2) (a) Isobe, Y.; Ogita, H.; Tobe, M.; Takahisa, H.; Matsui, H.;
Tomisawa, H. JP 11,180,982, 1999. (b) Silhar, P.; Pohl, R.;
Votruba, I.; Hocek, M. Org. Biomol. Chem. 2005, 3, 3001.
(c) Oe, T.; Sueoka, H.; Terasawa, M. JP 62,010,085, 1987.
(3) (a) Sakaguchi, O.; Takeshita, M.; Izumi, T. JP 2004,217,582,
2004. (b) Lerner, A.; Tiwari, S. WO 2006,062,817, 2006.
(c) Germeyer, S.; Meade, M. C. J.; Meissner, H.;
1H NMR (DMSO-d6): d = (5bi, 35%)3.33 (s, 3 H), 3.70 (s, 3 H),
2
3
6.36 (t, JH,F = 54.5 Hz, 1 H), 7.12 (d, J = 8.2 Hz, 1 H), 7.21 (t,
3J = 7.6 Hz, 1 H), 7.52 (m, 1 H), 8.31 (dd, J = 7.8, 1.6 Hz, 1 H), 8.42
(s, 1 H, H7), 8.83 (s, 1 H, OH).
2
19F NMR (DMSO-d6): d = (5bi, 35%) –133.5 (dd, JF,F = 281.4,
2JF,H = 54.5 Hz, 1 F, CFFH), –131.5 (dd, 2JF,F = 281.4, 2JF,H = 54.5
Hz, 1 F, CFFH).
Morschhaeuser, G.; Pairet, M.; Pestel, S.; Pieper, M. P.;
Pohl, G.; Reichl, R.; Speck, G. WO 2005,013,967, 2005.
(d) Warner, J. M. WO 2004,067,006, 2004.
3-{[2-(5,5-Dimethyl-3-oxocyclohex-1-enyl)-2-methylhydrazi-
nyl]methylene}-2-hydroxy-2-(trifluoromethyl)chroman-4-one
(8)
Reaction conditions: DMF, 100 °C, 64 h; colorless solid; yield: 286
mg (80%); mp 155–157 °C; Rf = 0.3 (EtOAc).
1H NMR (DMSO-d6): d = 1.14, 1.15 (2 s, 6 H), 2.16 (s, 2 H), 2.64
(s, 2 H), 3.32 (s, 3 H), 5.21 (s, 1 H), 7.19 (d, 3J = 7.8 Hz, 1 H), 7.26
(t, 3J = 7.8 Hz, 1 H), 7.55 (d, 3J = 9.8 Hz, 1 H), 7.66 (t, 3J = 7.8 Hz,
1 H), 7.91 (d, 3J = 9.8 Hz, 1 H), 9.19 (s, 1 H, OH), 11.78 (d, 3J = 9.8
Hz, 1 H, NH).
(e) Bourguignon, J. J.; Desaubry, L.; Raboisson, P.;
Wermuth, C. G.; Lugnier, C. J. Med. Chem. 1997, 40, 1768.
(4) (a) Iaroshenko, V. O.; Volochnyuk, D. M.; Wang, Y.; Vovk,
M. V.; Boiko, V. J.; Rusanov, E. B.; Groth, U. M.;
Tolmachev, A. O. Synthesis 2007, 3309. (b) Iaroshenko, V.
O.; Wang, Y.; Sevenard, D. V.; Volochnyuk, D. M.
Synthesis 2009, 1851. (c) Iaroshenko, V. O.; Sevenard, D.
V.; Volochnyuk, D. M.; Wang, Y.; Martiloga, A.;
Tolmachev, A. O. Synthesis 2009, 1865. (d) Volochnyuk,
D. M.; Pushechnikov, A. O.; Krotko, D. G.; Sibgatulin, D.
A.; Kovalyova, S. A.; Tolmachev, A. A. Synthesis 2003,
1531. (e) Iaroshenko, V. O.; Sevenard, D. V.; Kotljarov, A.;
Volochnyuk, D. M.; Tolmachev, A. O.; Sosnovskikh, V. Ya.
Synthesis 2009, 731.
13C NMR (DMSO-d6): d = 28.0, 28.2, 32.4, 49.5, 96.9, 97.5 (q,
1
2JC,F = 34 Hz), 98.0, 99.1, 116.5, 119.5, 120.1 (q, JC,F = 290 Hz),
122.3, 124.4, 125.6, 134.9, 152.9, 155.5, 163.6, 176.6, 195.7.
19F NMR (DMSO-d6): d = –84.7.
MS: m/z (%) = 410 (21) [M]+, 342 (26) [M + 1 – CF3]+, 341 (100)
[M – CF3]+, 326 (34) [M – CF3 – CH3]+, 272 (15) [M – COC6H4O]+,
Synthesis 2009, No. 22, 3869–3879 © Thieme Stuttgart · New York

PAPER
(5) (a) Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.;
Synthesis of Polyfluoroalkyl-Containing Fused Pyridines
3879
(8) (a) Sosnovskikh, V. Ya.; Irgashev, R. A.; Kodess, M. I.
Tetrahedron 2008, 64, 2997. (b) Sosnovskikh, V. Ya.;
Khalymbadzha, I. A.; Irgashev, R. A.; Slepukhin, P. A.
Tetrahedron 2008, 64, 10172. (c) Sosnovskikh, V. Ya.;
Irgashev, R. A.; Khalymbadzha, I. A.; Slepukhin, P. A.
Tetrahedron Lett. 2007, 48, 6297.
Pipko, S. E.; Tolmachev, A. A. Heterocycles 2008, 75, 583.
(b) Randhavane, P. V.; Kale, S. B.; Jagdhani, S. G.; Karale,
B. K. Indian J. Heterocycl. Chem. 2007, 17, 153.
(c) Sonawane, S. A.; Karale, B. K.; Shingare, M. S. Indian J.
Heterocycl. Chem. 2004, 14, 155.
(6) (a) Plaskon, A. S.; Ryabukhin, S. V.; Volochnyuk, D. M.;
Gavrilenko, K. S.; Shivanyuk, A. N.; Tolmachev, A. A.
J. Org. Chem. 2008, 73, 6010. (b) Ryabukhin, S. V.;
Plaskon, A. S.; Volochnyuk, D. M.; Tolmachev, A. A.
Synthesis 2007, 1861. (c) Iaroshenko, V. O.; Groth, U.;
Kryvokhyzha, N. V.; Obeid, S.; Tolmachev, A. A.; Wesch,
T. Synlett 2008, 343.
(9) Sosnovskikh, V. Ya.; Moshkin, V. S.; Kodess, M. I.
Tetrahedron 2008, 64, 7877.
(10) Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 721116 for 3n, CCDC 721117 for 4a,
and CCDC 721118 for 5g can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: +44 (1223)336033; e-mail:
(7) Sosnovskikh, V. Ya.; Irgashev, R. A.; Barabanov, M. A.
Synthesis 2006, 2707.
deposit@ccdc.cam.ac.uk].
Synthesis 2009, No. 22, 3869–3879 © Thieme Stuttgart · New York