Peculiarities of cyclization of ethyl 2-ethoxymethylene-3-oxo-3- (polyfluoroalkyl)propionates with 3-amino-5-hydroxypyrazole

Article abstract of DOI:10.1016/j.jfluchem.2013.01.005

The reactions of ethyl 2-ethoxymethylene-3-oxo-3-(polyfluoroalkyl) propionates with 3-amino-5-hydroxypyrazole result in ethyl 2,7-dihydroxy-7- (polyfluoroalkyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-carboxylates under mild conditions. These products undergo recyclization in refluxing ethanol to form ethyl 3-hydroxy-4-(polyfluoroalkyl)-1H-pyrazolo[3,4-b]pyridin-5-carboxylates, whereas in refluxing glacial acetic acid they are dehydrated to ethyl 2-hydroxy-7-(polyfluoroalkyl)pyrazolo[1,5-a]pyrimidin-6-carboxylates. The non-fluorinated ethyl 2-ethoxymethylene-3-oxo esters in the reactions with 3-amino-5-hydroxypyrazole in ethanol (or glacial acetic acid) under reflux form only ethyl 2-hydroxy-7-phenyl(hydroxy)pyrazolo[1,5-a]pyrimidin-6-carboxylates.

Full text of DOI:10.1016/j.jfluchem.2013.01.005

Journal of Fluorine Chemistry 147 (2013) 15–21
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Peculiarities of cyclization of ethyl 2-ethoxymethylene-3-oxo-3-
(polyfluoroalkyl)propionates with 3-amino-5-hydroxypyrazole
*
Marina V. Goryaeva , Yanina V. Burgart, Viktor I. Saloutin
I.Ya. Postovsky Institute of Organic Synthesis, Russian Academy of Sciences (Ural Branch), 620990 Ekaterinburg, Russian Federation
A R T I C L E I N F O
A B S T R A C T
Article history:
The reactions of ethyl 2-ethoxymethylene-3-oxo-3-(polyfluoroalkyl)propionates with 3-amino-5-
hydroxypyrazole result in ethyl 2,7-dihydroxy-7-(polyfluoroalkyl)-4,7-dihydropyrazolo[1,5-a]pyrimi-
din-6-carboxylates under mild conditions. These products undergo recyclization in refluxing ethanol to
form ethyl 3-hydroxy-4-(polyfluoroalkyl)-1H-pyrazolo[3,4-b]pyridin-5-carboxylates, whereas in
refluxing glacial acetic acid they are dehydrated to ethyl 2-hydroxy-7-(polyfluoroalkyl)pyrazolo[1,5-
a]pyrimidin-6-carboxylates. The non-fluorinated ethyl 2-ethoxymethylene-3-oxo esters in the reactions
with 3-amino-5-hydroxypyrazole in ethanol (or glacial acetic acid) under reflux form only ethyl 2-
hydroxy-7-phenyl(hydroxy)pyrazolo[1,5-a]pyrimidin-6-carboxylates.
Received 13 November 2012
Received in revised form 29 December 2012
Accepted 2 January 2013
Available online 23 January 2013
Keywords:
Ethyl 2-ethoxymethylene-3-oxo-3-
(polyfluoroalkyl)propionates
3-Amino-5-hydroxypyrazole
Pyrazolo[1,5-a]pyrimidines
Pyrazolo[3,4-b]pyridines
Recyclization
ß 2013 Elsevier B.V. All rights reserved.
1. Introduction
pyrazolo[3,4-b]pyridines. In the latter case, N(1)-substituted
aminopyrazoles behave as N,C-binucleophiles.
Pyrazolo[1,5-a]pyrimidines and pyrazolo[3,4-b]pyridines re-
main to be tremendously attractive compounds for drug discovery
since they exhibit a wide range of biological and pharmaceutical
activities. Among their derivatives there are anti-leishmania drugs
[1], analgesics [2], selective inhibitors of PDE5 [3], PDE4 [4], HCV
polymerase [5], CHK1 [6], cyclin-dependent kinase [7] and B-Raf
kinase [8] as well as A1 adenosine [9], glucocorticoid [10] and CRF1
[11] receptor antagonists, antimicrobial [12], anti-tumor [13], anti-
proliferative [14], and antitubercular agents [15]. The search for new
compounds bearing these ring systems seems rather promising.
Cyclocondensation of 1,3-dicarbonyl compounds with amino-
pyrazoles is of particular value for the synthesis of pyrazolo[1,5-
a]pyrimidines [16]. The use of 2-ethoxymethylene-3-oxo esters
[17,18] and diethyl-2-ethoxymethylenemalonate [18,19] allows
obtaining functionalized pyrazolo[1,5-a]pyrimidines, which can
undergo further transformations. Aminopyrazoles were shown to
react as N,N-binucleophiles in these cyclizations. N(1)-Substituted
aminopyrazoles react with 2-ethoxymethylene-3-oxo esters [7,20]
and diethyl-2-ethoxymethylenemalonate [1,3,4,9,10,20] to yield
Previously, we have shown that ethyl 2-ethoxymethylene-3-
oxo-3-(polyfluoroalkyl)propionates are very suitable building
blocks for the synthesis of azaheterocycles, including condensed
pyrimidines [21]. The reactions of ethyl 2-ethoxymethylene-3-
oxo-3-(polyfluoroalkyl)propionates with aminoazoles were found
to differ from those of non-fluoroalkylated substrates. They react
with aminoazoles (including 3-amino-5-methylpyrazole and ethyl
3-aminopyrazole-4-carboxylate) to give stable dihydroazolo[1,5-
a]pyrimidines bearing
a gem-aminoalcohol fragment at the
polyfluoroalkyl substituent. Polyfluoroalkylated dihydroa-
zolo[1,5-a]pyrimidines can be subjected to ring-chain isomeriza-
tion in solutions [21c].
However, the reactions of ethyl 2-ethoxymethylene-3-oxo-3-
(polyfluoroalkyl)propionates with aminopyrazoles bearing both
the NH-groups and an activated C-center have not been studied
previously. In this case, while using such binucleophiles, one can
expect a change of the cyclization pathways. The present paper
focuses on the cyclization of ethyl 2-ethoxymethylene-3-oxo-3-
(polyfluoroalkyl)propionates with 3-amino-5-hydroxypyrazole
bearing an additional nucleophilic reaction C-center.
2. Results and discussion
* Corresponding author at: I.Ya. Postovsky Institute of Organic Synthesis, Russian
Academy of Sciences (Ural Branch), 22/20, S. Kovalevskoy/Akademicheskaya St.,
GSP-147, 620990 Ekaterinburg, Russian Federation. Tel.: +7 343 3623229;
fax: +7 343 3745954.
It has been established that ethyl 2-ethoxymethylene-3-oxo-3-
(polyfluoroalkyl)propionates 1a–c react with 3-amino-5-hydroxy-
pyrazole in tetrahydrofuran or dimethylformamide under mild
E-mail address: pmv@ios.uran.ru (M.V. Goryaeva).
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.01.005

16
M.V. Goryaeva et al. / Journal of Fluorine Chemistry 147 (2013) 15–21
OEt
OEt
H2N
R
iii or iv
N
+
OH
N
H
O
O
R= OEt, Ph
1
R= CF3
H(CF2)2
i or ii
C3F7
HO
H
N
H
O
O
R
N
N
EtO
N
N
OH
H
O
in solution
R> CF3
N
H
O
2
iv
OEt R
iii
2' (E, Z)
R
R
N
N
OH
N
EtO2C
+
EtO2C
HO2C
N
OH
4
N
N
minor
H
4
3
v
v
CF3
R
OH
N
HO2C
N
N
OH
N
N
N
H
5
6
1: R= CF3 (a), (CF2)2H (b), C3F7 (c), OEt (d), Ph (e);
2, 3: R= CF3 (a), (CF2)2H (b), C3F7 (c);
4: R= CF3 (a), (CF2)2H (b), C3F7 (c); OH (d); Ph (e);
6: R= (CF2)2H (a), OH (b); Ph (c).
Conditions: (i): THF, r.t.; (ii): DMF, r.t.; (iii): EtOH, reflux;
(iv): AcOH, reflux; (v): NaOH, EtOH/H2O, reflux.
Scheme 1. Synthesis of pyrazolo[1,5-a]pyrimidines 2, 4, 6 and pyrazolo[3,4-b]pyridines 3, 5.
˚
˚
˚
conditions to give ethyl 2,7-dihydroxy-7-(polyfluoroalkyl)-4,7-
dihydropyrazolo[1,5-a]pyrimidin-6-carboxylates 2a–c (Scheme 1).
Nevertheless, the similar synthesis of dihydropyrazolo[1,5-a]pyr-
imidines from 3-amino-5-methylpyrazole and ethyl 3-aminopyr-
azole-4-carboxylate required more drastic conditions [21c].
X-ray diffraction analysis of crystalline compound 2c (Fig. 1)
confirmed its structure as ethyl 2,7-dihydroxy-7-heptafluoropro-
pyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-carboxylate with one
intermolecular hydrogen bond between the atoms O(1). . .H(3)–
O(3). The parameters of this hydrogen bond are as follows:
O(1). . .H(3) 2.80(2) A, H(3)–O(3) 0.82(2) A, O(1). . .O(3) 3.133(3) A,
O(1). . .H(3)–O(3) 162(2)8.
The comparison of the IR spectra of compounds 2a–c did not
reveal considerable differences in their structure.
The 1H NMR spectra of compounds 2a–c recorded in (CD3)2SO
contained the signals corresponding to the resonance of protons in
dihydropyrazolo[1,5-a]pyrimidines. However, in the 1H and 19F
NMR spectra of compound 2c in (CD3)2SO, besides a set of signals of
heterocyclic form 2 (93%), we observed two additional sets of
signals corresponding to 20 (Z) (3%) and 20 (E) (4%) isomers of the

M.V. Goryaeva et al. / Journal of Fluorine Chemistry 147 (2013) 15–21
17
Table 2
The NMR monitoring data for the heterocycle 2a recyclization in CD3OD.
Reaction conditions
Content of the starting material and the
reaction products (%)
2a
3a
4a
10 min, rt
6 h, rt
99
86
28
56
–
ꢀ1
14
70
43
97
–
–
ꢀ1
1
2 weeks, rt
5 min, reflux
30 min, reflux
3
an inseparable mixture of the products, in which we did not
detected pyrazolo[3,4-b]pyridines 3.
While investigating the ring-chain isomerism of dihydropyr-
azolo[1,5-a]pyrimidines 2 in CD3OD, the open forms were not
found (see Table 1). However, the recyclization of dihydropyr-
azolo[1,5-a]pyrimidines 2a–c into pyrazolo[3,4-b]pyridines 3a–c
takes place only in alcohols.
Fig. 1. The general view of compound 2c (thermal ellipsoids of 50% probability).
open-chain ethyl 4,4,5,5,6,6,6-heptafluoro-2-[(5-hydroxy-1H-pyr-
azol-3-yl)aminomethylene-3-oxohexanoate (Scheme 1).
The ability of dihydropyrazolo[1,5-a]pyrimidine 2c to undergo
ring-chain isomerism in (CD3)2SO encouraged us to register the 1H
and 19F NMR spectra of compounds 2a–c in various solvents. The
results of this investigation are presented in Table 1. It turned out
that the tendency of heterocycles 2a–c toward opening the
pyrimidine ring and formation of the open-chain isomers increases
with elongation of the polyfluoroalkyl substituent. Besides,
methanol stabilizes the cyclic form regardless of the length of
polyfluoroalkyl substituent.
It should be noted that the ring-chain isomerism is not typical
for the non-fluorinated analogs viz. 2-Azolylaminomethylene-3-
oxoalkanoates. These compounds exhibited irreversible intramo-
lecular condensation with the formation of azolopyrimidines
[18a].
Surprisingly, the attempts to crystallize compounds 2a–c from
ethanol led to the formation of pyrazolo[3,4-b]pyridines 3a–c as
the main products. We did not observe such transformations when
crystallizing other dihydroazolo[1,5-a]pyrimidines, including the
pyrazolo derivatives [21a,c]. Obviously, it became possible due to
the presence of a competitive nucleophilic C-center activated by
the hydroxy group in 3-amino-5-hydroxypyrazole. These recycli-
zation reactions are regioselective and the pyrazolo[3,4-b]pyr-
idines 3 were the predominant products (64–86%), whereas
dehydrated pyrazolopyrimidines 4a–c were isolated as by-
products (5–14%) (Scheme 1).
For the recyclization of dihydropyrazolo[1,5-a]pyrimidines 2a–
c into pyrazolo[3,4-b]pyridines 3a–c, it is possible to use boiling
methanol in addition to ethanol. However, a mixture of products
3a–c and 4a–c with the predominance of the latter is formed in n-
butanol under reflux. The refluxing of heterocycles 2 in polar
aprotic solvents such as acetonitrile and dimethylformamide led to
To study this reaction in detail, the recyclization of the
heterocycle 2a in CD3OD was monitored by NMR, but no
intermediates were found (see Table 2). The recyclization
proceeded in CD3OD at room temperature; however, complete
conversion of 2a into 3a did not occur even after 2 weeks of
stirring. When the same reaction was carried out in refluxing
CD3OD, the yield of 3a was 43% in 5 min. The complete conversion
was achieved after refluxing for 30 min.
When ethanol was used as a solvent, the recyclization did not
proceed at room temperature. However, refluxing did promote the
process, and the TLC monitoring showed complete conversion of
2a into 3a in 30 min. Replacement of methanol and ethanol for
higher boiling n-butanol led to a change in the reaction pathway
yielding the dehydrated product 4a.
A peculiarity of these transformations in alcohols is likely to be
due to the solvation effects (hydrogen bonding and others) typical
for such polar protic solvents. Solvation effects can lead to
redistribution of the electron density in a dissolved compound,
which contributes to either the weakening or strengthening of
chemical bonds [22].
From the experimental results it can be assumed that an
intermediate activated complex of heterocycle 3a with solvent is
formed in methanol and ethanol. The formation of such a complex
stabilizes the cyclic form and prevents a fast dihydropyrimidine
cycle opening. Therefore, we did not find an open-chain form
immediately after dissolution in methanol. However, under the
influence of alcohol solvation effects there is the redistribution of
electronic density in an intermediate complex resulting in the
cleavage of C(7)–N(8) bond. Then, the open-chain form undergoes
fast recyclization into a pyridine derivative with a new C(3a)–C(4)
bond. Hence, methanol having the smallest size and the greatest
dielectric constant compared to other alcohols (MeOH
e 32.6, EtOH
e
24.3, BuOH 17.1) is considered to be a more suitable solvent for
e
this recyclization. It is obvious that the recyclization process
proceeds faster under the temperature.
Table 1
The structure of pyrazolo[3,4-b]pyridine 3c was proved by the
X-ray diffraction analysis (Fig. 2).
Content (%) of isomeric forms of compounds 2 in various solvents according to the
NMR spectroscopy data.
Dehydration of dihydropyrazolo[1,5-a]pyrimidines 2a–c into
pyrazolo[1,5-a]pyrimidines 4a–c was successfully performed in
glacial acetic acid under reflux for 2–3 days (Scheme 1). The X-ray
diffraction analysis proved the structure of heterocycle 4a (Fig. 3).
The 1H NMR spectra of compounds 3a–c are characterized by
Compound
RF
Solvent
(CD3)2SO
2a, 100
2b, 100
CD3CN
(CD3)2CO
CD3OD
2a, 100
2b, 100
2a
2b
CF3
2a, 100
2a, 100
(CF2)2H
2b, 96
20b (E), 4
2b, 94
20b (Z), 1
20b (E), 5
the singlet of the methine proton H-6 (
d 8.69–8.74 ppm) and two
broadened low-field singlets of NH ( 11.36–11.62 ppm) and OH (
d
d
13.10–13.21 ppm) protons. These data are in contrast to those
2c
C3F7
2c, 93
2c, 92
2c, 82
2c, 100
published for heterocycles 4a–c. Their 1H NMR spectra contained
20c (Z), 3
20c (E), 4
20c (Z), 3
20c (E), 5
20c (Z), 8
20c (E), 10
two singlets of methine protons H-3 (d 6.27–6.32 ppm) and H-5 (d

18
M.V. Goryaeva et al. / Journal of Fluorine Chemistry 147 (2013) 15–21
recyclization of dihydropyrazolo[1,5-a]pyrimidines into pyra-
zolo[3,4-b]pyridines was found. The recyclization became possible
when 3-amino-5-hydroxypyrazoles with a C-nucleophilic center
activated by a hydroxy group were used. The revealed recyclization
is typical for polyfluoroalkyl-containing pyrazolo[1,5-a]pyrimidines
and was not found with non-fluorinated analogs.
4. Experimental
4.1. General
Melting points were measured in the open capillaries on a Stuart
SMP3 melting point apparatus. The IR diffuse reflectance spectra
were recorded on a Perkin Elmer Spectrum One Fourier transform
infrared spectrometer in the range from 400 to 4000 cmꢁ1. The 1H
(400 MHz) and 19F (376 MHz) NMR spectra were recorded on a
Bruker DRX-400 spectrometer with SiMe4 and C6F6 as internal
standards, respectively. The 13C (100 MHz) NMR spectra were
recorded on a Bruker AVANCE 500 spectrometer with SiMe4 as
internal standards. The chemical shifts were converted from C6F6 to
CCl3F (ꢁ162.9 ppm). The microanalyses were carried out on a Perkin
Elmer PE 2400 series II elemental analyzer. The column chromatog-
raphy was performed on Merck silica gel 60 (0.063–0.200 mm).
Fig. 2. The general view of compound 3c (thermal ellipsoids of 50% probability).
Ethyl
2-ethoxymethylene-3-oxo-3-(polyfluoroalkyl)propio-
nates 1a–c were prepared according to the reported procedure
[24], 3-amino-5-hydroxypyrazole is commercially available from
Alfa Aesar.
4.2. Reactions of esters 1a–e with 3-amino-5-hydroxypyrazole
Method A. A mixture of the corresponding ester (1a–c) (3 mmol)
and 3-amino-5-hydroxypyrazole (3 mmol) in dimethylformamide
(20 mL) was stirred at room temperature for 2 h. After completion
of the reaction, the reaction mixture was poured into water
(50 mL). The resulting precipitate was filtered off and crystallized
from acetone (or acetonitrile) to give dihydropyrazolo[1,5-
a]pyrimidine (2a–c).
Fig. 3. The general view of compound 4a (thermal ellipsoids of 50% probability).
8.51–8.57 ppm), as well as a broadened singlet of the OH proton (
d
7.62–9.60 ppm) [23]. The difference in the spectral parameters for
heterocycles 3a–c and 4a–c allowed us to identify all these
products even without X-ray diffraction analysis in each case.
The opportunity to obtain three heterocyclic products 2, 3 and 4
in the reactions of fluoroalkyl esters 1 with 3-amino-5-hydro-
xypyrazole encouraged us to examine these transformations under
various conditions. It has been found that these reactions carried
out in ethanol, acetonitrile, 1,4-dioxane, glacial acetic acid or
dimethylformamide under reflux are not regioselective and result
in inseparable mixtures of the products.
For comparison, we also investigated the reactions of non-
fluorinated esters 2d,e with 3-amino-5-hydroxypyrazole.
Attempts to implement these transformations under similar mild
conditions (tetrahydrofuran or dimethylformamide, at room
temperature) were unsuccessful due to the formation of an
inseparable mixture of products and an incomplete conversion of
the starting reagents. The use of ethanol (or glacial acetic acid)
under reflux gave only pyrazolo[1,5-a]pyrimidines 4d,e similarly
as described in [17b] (Scheme 1).
Method B. A mixture of the corresponding ester (1a–c) (3 mmol)
and 3-amino-5-hydroxypyrazole (3 mmol) in tetrahydrofuran
(20 mL) was stirred for 3–5 days at room temperature. After
completion of the reaction, the solvent was evaporated, the residue
was crystallized from acetone (or acetonitrile) to give dihydropyr-
azolo[1,5-a]pyrimidines (2a–c).
Method C. A mixture of the corresponding ester (1d,e) (3 mmol)
and 3-amino-5-hydroxypyrazole (3 mmol) in glacial acetic acid
(10 mL) was refluxed for 4 h (1d) and for 3 days (1e). After
completion of the reaction and cooling the reaction mixture, the
resulting precipitate was filtered off and washed with water, then
crystallized from dimethyl sulfoxide to give pyrazolo[1,5-a]py-
rimidine 4d. In the case of product 4e the reaction mixture was
poured into water (30 mL) and neutralized to pH 7 with sodium
hydrogen carbonate. The resulting precipitate was filtered off and
crystallized from 50% ethanol.
Method D. A mixture of the corresponding ester (1d,e) (3 mmol)
and 3-amino-5-hydroxypyrazole (3 mmol) in ethanol (15 mL) was
refluxed for 2–3 days. After completion of the reaction and cooling
the reaction mixture, the resulting precipitate was filtered off and
crystallized from dimethyl sulfoxide to give pyrazolo[1,5-a]py-
rimidine 4d. In the case of product 4e the solvent was evaporated
and the residue was crystallized from 50% ethanol.
The ester substituent in heterocycles 3,4 made it possible to
obtain pyrazolo[3,4-b]pyridin-5-carboxylic acid
5 and pyra-
zolo[1,5-a]pyrimidin-6-carboxylic acids 6a–c by alkaline hydroly-
sis (Scheme 1).
3. Conclusion
4.2.1. Ethyl 2,7-dihydroxy-7-trifluoromethyl-4,7-
dihydropyrazolo[1,5-a]pyrimidin-6-carboxylate (2a)
Yield (method A) 580 mg (66%), (method B) 739 mg (84%),
Two types of heterocycles were obtained in the reactions of ethyl
2-ethoxymethylene-3-oxo-3-(polyfluoroalkyl)propionates with 3-
amino-5-hydroxypyrazole. In addition, the first example of
white powder, mp 191–192 8C. IR:
n 3323, 3283, 3189 (N–H, O–H),
2985 (C–H), 1680 (C55O), 1609, 1536 (N–C55C–C55N), 1239–1174

M.V. Goryaeva et al. / Journal of Fluorine Chemistry 147 (2013) 15–21
19
(C–F) cmꢁ1
4.12 (2H, m, CH2), 5.11 (1H, s, H-3), 7.68 (1H, s, OH), 7.79 (1H, s, H-
5), 10.18 (1H, br s, OH), 10.73 (1H, br s, NH). 13C NMR ((CD3)2SO):
14.2 (s, CH3), 59.4 (s, CH2), 75.4 (s, C-3), 82.4 (q, C-7, JCF = 33.4 Hz),
93.6 (s, C-6), 123.5 (q, CF3, JCF = 293.0 Hz), 137.8 (s, C-3a), 138.7 (s,
.
1H NMR ((CD3)2SO):
d
1.22 (3H, t, JHH = 7.1 Hz, CH3),
4.2.5. Ethyl 2-hydroxy-7-phenylpyrazolo[1,5-a]pyrimidine-6-
carboxylate (4e)
Yield (method C) 697 mg (82%), yield (method D) 646 mg
(76%), light yellow powder, mp 234–236 8C. IR: 3131, 3100 (O–
H), 3012, 2980 (C–H), 1704 (C55O), 1625, 1539 (C55C–C55N) cmꢁ1
1H NMR ((CD3)2SO):
0.91 (3H, t, JHH = 7.1 Hz, CH3), 4.00 (2H, q,
JHH = 7.1 Hz, CH2), 6.09 (1H, s, H-3), 7.45–7.54 (5H, m, Ph), 8.80
(1H, s, H-5), 11.46 (1H, s, OH). 13C NMR ((CD3)2SO):
13.4 (s,
d
n
.
C-5), 161.4 (s, C-2), 164.8 (s, C55O). 19F NMR ((CD3)2SO):
(s, CF3). Anal. calcd. for C10H10F3N3O4: C, 40.96; H, 3.41; N, 14.33.
Found: C, 40.98; H, 3.20; N, 14.47.
d
ꢁ78.45
d
d
CH3), 60.6 (s, CH2), 82.2 (s, C-3), 109.3 (s, C-6), 128.0 (s, Co), 128.7
(s, Cm), 129.5 (s, Cp), 131.0 (s, Ci), 148.2 (s, C-3a), 149.6 (s, C-5),
149.8 (s, C-7), 164.0 (s, C-2), 167.9 (s, C55O). Anal. calcd. for
4.2.2. Ethyl 2,7-dihydroxy-7-(1,1,2,2-tetrafluoroethyl)-4,7-
dihydropyrazolo[1,5-a]pyrimidin-6-carboxylate (2b)
Yield (method A) 517 mg (53%), (method B) 693 mg (71%),
C15H13N3O3: C, 63.60; H, 4.63; N, 14.83. Found: C, 63.44; H, 4.53;
white powder, mp 175–176 8C. IR:
2990 (C–H), 1673 (C55O), 1614, 1542 (N–C55C–C55N), 1242–1082
(C–F) cmꢁ1 1H NMR ((CD3)2SO):
1.22 (t, 3H, CH3, JHH = 7.1 Hz),
n
3305, 3153 (N–H, O–H), 3089,
N, 14.82.
.
d
4.3. Recyclization of 4,7-dihydropyrazolo[1,5-a]pyrimidines 2a–c
4.12 (2H, m, CH2), 5.12 (1H, s, H-3), 6.70 (1H, ddd, JHF = 54.5, 51.8,
11.7 Hz, CF2H), 7.57 (1H, br s, OH), 7.78 (1H, s, H-5), 10.15 (1H, br s,
Dihydropyrazolo[1,5-a]pyrimidine (2a–c) (1 mmol) in ethanol
(30 mL) was refluxed for 30–40 min. After completion of the
reaction, the solvent was evaporated. The residue was washed with
chloroform (2 ꢂ 20 mL) and crystallized from acetone (or acetoni-
trile) to give the pyrazolo[3,4-b]pyridines (3a–c). The chloroform
filtrate was evaporated, and the residue was crystallized from
hexane to give a small amount (5–14%) of pyrazolo[1,5-a]pyr-
imidines (4a–c).
OH), 10.68 (1H, br s, NH). 13C NMR ((CD3)2SO):
d 14.1 (s, CH3), 59.39
(s, CH2), 75.4 (s, C-3), 83.8 (t, C-7, JCF = 28.8 Hz), 93.9 (s, C-6), 109.8
(tm, HCF2, JCF = 251.1 Hz), 114.8 (tm, CF2, JCF = 266.0 Hz), 138.2 (s,
C-3a), 138.3 (s, C-5), 161.4 (s, C-2), 165.4 (s, C55O). 19F NMR
((CD3)2SO):
d
ꢁ137.02 (1F, ddt, JFF = 292.0, 9.7 Hz, JFH = 54.5 Hz,
CF2H), ꢁ131.07 (1F, dm, JFF = 258.5 Hz, CF2), ꢁ130.74 (1F, ddd,
JFF = 292.0, 10.7 Hz, JFH = 51.8 Hz, CF2H), ꢁ120.72 (1F, dd,
JFF = 258.5, 10.7 Hz, CF2). Anal. calcd. for C11H11F4N3O4: C, 40.62;
H, 3.41; N, 12.96. Found: C, 40.56; H, 3.31; N, 12.75.
4.3.1. Ethyl 3-hydroxy-4-trifluoromethyl-1H-pyrazolo[3,4-b]pyridin-
5-carboxylate (3a)
4.2.3. Ethyl 2,7-dihydroxy-7-(1,1,2,2,3,3,3-heptafluoropropyl)-4,7-
dihydropyrazolo[1,5-a]pyrimidin-6-carboxylate (2c)
Yield 237 mg (86%), light yellow powder, mp 229–231 8C. IR:
3171, 3136 (N–H, O–H), 3098, 3989 (C–H), 1714 (C55O), 1590,
1566, 1514 (N–C55C–C55N), 1221–1143 (C–F) cmꢁ1 1H NMR
((CD3)2SO): 1.32 (3H, t, JHH = 7.1 Hz, CH3), 4.36 (2H, q,
JHH = 7.1 Hz, CH2), 8.74 (1H, s, H-6), 11.47 (1H, br s, NH), 13.16
(1H, br s, OH). 13C NMR ((CD3)2SO):
13.7 (s, CH3), 62.1 (s, CH2),
n
Yield (method A) 578 mg (49%), (method B) 766 mg (65%), white
.
powder, mp 174–176 8C. IR:
1651 (C55O), 1629, 1609, 1546 (N–C55C–C55N), 1218–1121 (C–
F) cmꢁ1 1H NMR ((CD3)2SO):
2c (93%): 1.22 (3H, t, JHH = 7.1 Hz,
n
3319, 3194 (N–H, O–H), 2991 (C–H),
d
.
d
d
CH3), 4.12 (2H, m, CH2), 5.14 (1H, s, H-3), 7.77 (1H, s, OH), 7.81 (1H, d,
JHH = 6.0 Hz, H-5), 10.13 (1H, br s, OH), 10.81 (1H, br d, JHH = 6.0 Hz,
NH), 2c0 (E) (4%): 1.06 (3H, t, JHH = 7.1 Hz, CH3), 4.17 (2H, q,
JHH = 7.1 Hz, CH2), 5.59 (1H, s, H-40), 8.61 (1H, d, JHH = 14.6 Hz, CH),
11.01 (1H, s, OH), 11.76 (1H, br d, JHH = 14.6 Hz, NH), 12.16 (1H, br s,
NH-10), 2c0 (Z): (3%) 1.28 (3H, t, JHH = 7.0 Hz, CH3), 4.24 (2H, q,
JHH = 7.0 Hz, CH2), 5.50 (1H, s, H-40), 8.61 (1H, d, JHH = 14.5 Hz, CH),
10.86 (1H, s, OH), 10.96 (1H, br d, JHH = 14.5 Hz, NH), 12.06 (1H, br s,
98.0 (s, C-5), 121.0 (q, C-3a, JCF = 2.9 Hz), 121.9 (q, CF3,
JCF = 274.9 Hz), 128.7 (q, C-4, JCF = 34.9 Hz), 149.2 (s, C-6), 152.5,
153.0 (two s, C-3, C-7a), 166.0 (s, C55O). 19F NMR ((CD3)2SO):
d
ꢁ56.91 (s, CF3). Anal. calcd. for C10H8F3N3O3: C, 43.65; H, 2.93; N,
15.27. Found: C, 43.64; H, 3.05; N, 15.34.
4.3.2. Ethyl 3-hydroxy-4-(1,1,2,2-tetrafluoroethyl)-1H-pyrazolo[3,4-
b]pyridin-5-carboxylate (3b)
NH-10). 13C NMR ((CD3)2SO):
C-3), 84.3 (t, C-7, JCF = 26.6 Hz), 93.8 (s, C-6), 109.1 (tq,
JCF = 37.6, 268.3 Hz), 114.4 (tt, -CF2, JCF = 30.7, 269.9 Hz), 117.7 (qt,
CF3, JCF = 35.0, 289.0 Hz), 137.6 (s, C-3a), 138.5 (s, C-5), 161.2 (s, C-2),
165.4 (s, C55O). 19F NMR ((CD3)2SO):
2c (93%): ꢁ126.55 (1F, ddd,
JFF = 288.6, 13.7, 5.4 Hz,
-CFB), ꢁ125.08 (1F, ddd, JFF = 288.6, 12.8,
4.7 Hz,
dm, JFF = 278.0 Hz,
(4%): ꢁ123.26 (2F, m,
d
2c 14.1 (s, CH3), 59.5 (s, CH2), 75.6 (s,
-CF2,
a
Yield 218 mg (71%), yellow powder, mp 230–233 8C. IR:
3137 (N–H, O–H), 3098, 3067 (C–H), 1732 (C55O), 1595, 1555, 1506
(N–C55C–C55N), 1231–1072 (C–F) cmꢁ1. 1H NMR ((CD3)2SO):
1.31
(3H, t, JHH = 7.1 Hz, CH3), 4.35 (2H, q, JHH = 7.1 Hz, CH2), 6.92 (1H, tt,
JHF = 52.0, 5.8 Hz, CF2H), 8.69 (1H, s, H-6), 11.62 (1H, br s, NH),
n 3168,
b
d
d
b
13.10 (1H, br s, OH). 19F NMR ((CD3)2SO):
d
ꢁ136.40 (2F, dm,
JFH = 52.0 Hz, CF2H), ꢁ109.63 (2F, m, CF2). Anal. calcd. for
C11H9F4N3O3: C, 43.01; H, 2.95; N, 13.68. Found: C, 42.80; H,
b
-CFA), ꢁ117.41 (1F, dm, JFF = 278.0 Hz, -CFB), ꢁ115.53 (1F,
a
a
-CFA), ꢁ80.58 (t, 3F, JFF = 11.7 Hz, CF3), 2c0 (E):
b
-CF2), ꢁ113.11 (2F, m,
a
-CF2), ꢁ79.95 (3F, t,
3.01; N, 13.55.
JFF = 9.4 Hz, CF3), 2c0 (Z):(3%): 0124.47(2F, m,
b
-CF2), ꢁ112.49(2F, m,
a-CF2), ꢁ79.90 (3F, t, JFF = 9.4 Hz, CF3). Anal. calcd. forC12H10F7N3O4:
4.3.3. Ethyl 3-hydroxy-4-(1,1,2,2,3,3,3-heptafluoropropyl)-1H-
pyrazolo[3,4-b]pyridin-5-carboxylate (3c)
C, 36.65; H, 2.65; N, 10.69. Found: C, 36.63; H, 2.59; N, 10.75.
Yield 240 mg (64%), light yellow powder, mp 251–253 8C. IR:
n
4.2.4. Ethyl 2,7-dihydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate
(4d)
3186, 3126 (N–H, O–H), 3049 (C–H), 1736 (C55O), 1592, 1559, 1500
(N–C55C–C55N), 1239–1110 (C–F) cmꢁ1. 1H NMR ((CD3)2SO):
1.29
d
Yield (method C) 395 mg (59%), yield (method D) 308 mg (46%),
(3H, t, JHH = 7.1 Hz, CH3), 4.35 (2H, q, JHH = 7.1 Hz, CH2), 8.73 (1H, s,
yellow powder, mp 300–302 8C. IR:
H), 3001, 2984, 2939 (C–H), 1715 (C55O), 1661, 1621, 1581, 1551
(C55C–C55N) cmꢁ1 1H NMR ((CD3)2SO):
1.27 (3H, t, JHH = 7.1 Hz,
CH3), 4.20 (2H, q, JHH = 7.1 Hz, CH2), 5.58 (1H, s, H-3), 8.44 (1H, s, H-
5), 11.04, 12.77 (both 1H, two br s, 2 OH). 13C NMR ((CD3)2SO):
n
3277, 3205, 3147, 3100 (O–
H-6), 11.36 (1H, br s, NH), 13.21 (1H, br s, OH). 13C NMR ((CD3)2SO):
d
13.6 (s, CH3), 62.2 (s, CH2), 98.9 (s, C-5), 108.2 (tq,
b-CF2,
.
d
JCF = 266.4, 38.8 Hz), 114.9 (tt, -CF2, JCF = 258.7, 34.6 Hz), 117.9
a
(qt, CF3, JCF = 287.6, 35.9 Hz), 121.0 (t, C-3a, JCF = 4.4 Hz), 126.8 (t,
C-4, JCF = 26.2 Hz), 148.9 (s, C-6), 151.9, 153.1 (two s, C-3, C-7a),
d
14.3 (s, CH3), 59.9 (s, CH2), 77.8 (s, C-3), 99.0 (s, C-6), 140.9 (s, C-3a),
144.2 (s, C-5), 152.2 (s, C-7), 163.7 (s, C-2), 164.1 (s, C55O). Anal.
calcd. for C9H9N3O4: C, 48.43; H, 4.06; N, 18.83. Found: C, 48.34; H,
3.98; N, 18.70.
166.1 (s, C55O). 19F NMR ((CD3)2SO):
d
ꢁ122.28 (2F, m,
b-CF2),
ꢁ102.79 (2F, m,
a-CF2), ꢁ79.87 (3F, t, JFF = 10.1 Hz, CF3). Anal.
calcd. for C12H8F7N3O3: C, 38.41; H, 2.15; N, 11.20. Found: C, 38.43;
H, 2.10; N, 11.18.

20
M.V. Goryaeva et al. / Journal of Fluorine Chemistry 147 (2013) 15–21
4.4. Dehydration of 4,7-dihydropyrazolo[1,5-a]pyrimidines 2a–c
(N–C55C–C55N), 1224–1124 (C–F) cmꢁ1. 1H NMR ((CD3)2SO):
(1H, s, H-6), 11.68, 13.09, 13.40 (all of 1H, three br s, 2 OH, NH). 19
NMR (CDCl3):
d 8.73
F
Dihydropyrazolo[1,5-a]pyrimidine (2a–c) (1 mmol) in glacial
acetic acid (10 mL) was refluxed for 2–3 days. After the completion
of the reaction, the reaction mixture was poured into water
(20 mL) and neutralized to pH 7 by sodium hydrogen carbonate.
The resulting precipitate was filtered off and crystallized from
hexane to give corresponding pyrazolo[1,5-a]pyrimidine (4a,c). In
the case of product 4b after neutralization, the reaction mixture
was extracted with chloroform (2 ꢂ 50 mL). The organic layer was
concentrated and the residue was purified by column chromatog-
raphy (eluent–chloroform).
d
ꢁ56.87 (s, CF3). Anal. calcd. for C8H4F3N3O3: C,
38.88; H, 1.63; N, 17.00. Found: C, 38.93; H, 1.66; N, 16.94.
4.5.2. 2-Hydroxy-7-(1,1,2,2-tetrafluoroethyl)pyrazolo[1,5-
a]pyrimidine-6-carboxylic acid (6a)
Yield 80 mg (96%), white powder, mp 291–293 8C. IR:
n
3162,
(O–H), 3095 (C–H), 1698 (C55O), 1649, 1625, 1578, 1564 (C55C–
C55N), 1234–1101 (C–F) cmꢁ1. 1H NMR (CDCl3):
5.73 (1H, s, H-3),
7.10 (1H, tt, JHF = 52.6, 5.8 Hz, CF2H), 8.58 (1H, s, H-5), 11.27, 13.59
(both 1H, two br s, 2 OH). 13C NMR ((CD3)2SO):
80.0 (s, C-3), 103.9
d
d
(s, C-6), 109.3 (tt, HCF2, JCF = 249.8, 29.1 Hz), 110.7 (tt, CF2,
JCF = 260.3, 26.3 Hz), 133.8 (t, C-7, JCF = 27.1 Hz), 140.7, 146.7 (two
s, C-3a, C-5), 152.8 (s, C-2), 164.6 (s, C55O). 19F NMR (CDCl3):
d
4.4.1. Ethyl 2-hydroxy-7-trifluoromethylpyrazolo[1,5-a]pyrimidin-6-
carboxylate (4a)
Yield 245 mg (89%), yellow powder, mp 139–141 8C. IR:
(O–H), 3008, 2971 (C–H), 1741 (C55O), 1629, 1534 (C55C–C55N),
1266–1163 (C–F) cmꢁ1. 1H NMR (CDCl3):
1.41 (3H, t, JHH = 7.1 Hz,
CH3), 4.59 (2H, q, JHH = 7.1 Hz, CH2), 6.32 (1H, s, H-3), 8.57 (1H, s, H-
5), 9.60 (1H, br s, OH). 19F NMR (CDCl3):
n
3159
ꢁ137.89 (2F, dm, JFH = 52.6 Hz, HCF2), ꢁ121.99 (2F, m, CF2). Anal.
calcd. for C9H5F4N3O3: C, 38.72; H, 1.81; N, 15.05. Found: C, 38.77;
H, 1.84; N, 14.98.
d
d
ꢁ65.64 (s, CF3). Anal.
4.5.3. 2,7-Dihydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid
calcd. for C10H8F3N3O3: C, 43.65; H, 2.93; N, 15.27. Found: C, 43.58;
H, 2.82; N, 15.47.
(6b)
Yield 57 mg (98%), beige powder, mp 293–295 8C. IR:
(O–H), 3063, 2934 (C–H), 1693 (C55O), 1629, 1580, 1544 (C55C–
C55N) cmꢁ1. 1H NMR ((CD3)2SO):
5.72 (1H, s, H-3), 8.59 (1H, s, H-
5), 11.37, 13.37 (both 1H, two br s, 2 OH). 13C NMR ((CD3)2SO):
n 3149
4.4.2. Ethyl 2-hydroxy-7-(1,1,2,2-tetrafluoroethyl)pyrazolo[1,5-
d
a]pyrimidin-6-carboxylate (4b)
d
Yield 258 mg (84%), yellow powder, mp 129–131 8C. IR:
(O–H), 3050, 2986 (C–H), 1728 (C55O), 1629, 1538 (C55C–C55N),
1257–1086 (C–F) cmꢁ1. 1H NMR (CDCl3):
1.40 (3H, t, JHH = 7.1 Hz,
CH3), 4.44 (2H, q, JHH = 7.1 Hz, CH2), 6.27 (1H, s, H-3), 6.95 (1H, tt,
JHF = 53.3, 5.8 Hz, CF2H), 7.62 (1H, s, OH), 8.53 (1H, s, H-5). 19F NMR
n
3140
78.90 (s, C-3), 97.57 (s, C-6), 141.50, 144.58 (two s, C-3a, C-5),
157.21 (s, C-7), 164.65 (s, C-2), 165.18 (s, C55O). Anal. calcd. for
C7H5N3O4: C, 43.09; H, 2.58; N, 21.53. Found: C, 42.92; H, 2.56; N,
21.45.
d
(CDCl3):
d
ꢁ138.13 (2F, dm, JFH = 53.3 Hz, HCF2), ꢁ118.55 (2F, m,
4.5.4. 2-Hydroxy-7-phenylpyrazolo[1,5-a]pyrimidine-6-carboxylic
CF2). Anal. calcd. for C11H9F4N3O3: C, 43.01; H, 2.95; N, 13.68.
Found: C, 43.17; H, 2.99; N, 13.60.
acid (6c)
Yield 76 mg (99%), light yellow powder, mp 283–285 8C. IR:
3454, 3129 (O–H), 3059, 2972 (C–H), 1699 (C55O), 1615, 1598
(C55C–C55N) cmꢁ1 1H NMR ((CD3)2SO):
6.07 (1H, s, H-3), 7.49
(5H, m, C6H5), 8.82 (1H, s, H-5), 11.39, 12.89 (both 1H, two br s, 2
OH). 13C NMR ((CD3)2SO):
81.9 (s, C-3), 109.9 (s, C-6), 127.95 (s,
n
4.4.3. Ethyl 7-(1,1,2,2,3,3,3-heptafluoropropyl)-2-
.
d
hydroxypyrazolo[1,5-a]pyrimidin-6-carboxylate (4c)
Yield289 mg(77%), yellowpowder, mp 130–131 8C. IR:
H), 3049, 2938 (C–H), 1737 (C55O), 1625, 1530 (C55C–C55N), 1243–
1124 (C–F) cmꢁ1 1H NMR (CDCl3):
1.38 (3H, t, JHH = 7.1 Hz, CH3),
4.42 (2H, q, JHH = 7.1 Hz, CH2), 6.29 (1H, s, H-3), 8.19 (1H, br s, OH),
8.51 (1H, s, H-5). 13CNMR (CDCl3):
13.7 (s, CH3), 63.2 (s, CH2), 66.0 (s,
C-3), 83.3 (s, C-6), 109.3 (tq, -CF2, JCF = 269.6, 36.7 Hz), 113.4 (tt, a-
n
3151 (O–
d
Co), 128.8 (s, Cm), 129.4 (s, Cp), 131.1 (s, Ci), 148.2 (s, C-7), 149.8,
150.2 (two s, C-3a, C-5), 165.3 (s, C-2), 167.7 (s, C55O). Anal. calcd.
for C13H9N3O3: C, 61.18; H, 3.55; N, 16.46. Found: C, 60.99; H, 3.57;
N, 16.39.
.
d
d
b
CF2, JCF = 263.4, 36.0 Hz), 117.7 (qt, CF3, JCF = 288.4, 33.9 Hz), 131.5 (t,
C-7, JCF = 27.4 Hz), 147.7(s, C-5), 150.4 (s, C-3a), 164.0 (s, C-2), 167.3 (s,
4.6. Crystallographic details
C55O). 19F NMR (CDCl3):
d
ꢁ122.61 (2F, m,
b
-CF2), ꢁ109.81 (2F, m,
a
-
The single crystals of compounds 2c, 3c and 4a were obtained
by crystallization from acetone–ethanol 2:1, acetone and CHCl3
respectively. The X-ray studies were performed on an Xcalibur 3
CF2), ꢁ81.59 (3F, t, JFF = 8.8 Hz, CF3). Anal. calcd. for C12H8F7N3O3: C,
38.41; H, 2.15; N, 11.20. Found: C, 38.21; H, 2.10; N, 11.22.
CCD diffractometer at 295(2) K (Mo Ka irradiation, graphite
4.5. Hydrolysis of ethyl pyrazolo[3,4-b]pyridin-5-carboxylate 3a and
ethyl pyrazolo[1,5-a]pyrimidin-6 carboxylates 4b,d,e
monochromator, CCD detector, /2 scanning). The crystal
v u
structures were solved by direct methods followed by Fourier
synthesis with SHELXS-97 and refined with full-matrix least
squares methods for all non-hydrogen atoms with SHELXL-97
software packages [25].
Pyrazolo[3,4-b]pyridine
3 (or pyrazolo[1,5-a]pyrimidine 4)
(0.3 mmol) and sodium hydroxide (0.6 mmol) in the mixture of
ethanol–water 3:2 (15 mL) were refluxed for 6–8 h. After
completion of the reaction, the reaction mixture was poured into
water (40 mL) and acidified to pH 3–4 with 10% hydrochloric acid.
The resulting precipitate was filtered off, washed with water and
crystallized from ethanol to give acid (6a–c). In the case of product
5 after acidification, the reaction mixture was extracted with
acetonitrile (2 ꢂ 50 mL). The solvent was removed under reduced
pressure; the residue was crystallized from ethanol.
4.6.1. Crystallographic data for 2c
C12H10F7N3O4 (M =393.23) are triclinic, space group P-1,
˚
˚
˚
a =6.8890(9) A, b =10.3836(17) A, c =11.3313(10) A,
=100.022(10)8, = 108.867(12),
Dcalc = 1.726 g/cm3,m(Mo K
a
=96.243(13)8,
3
˚
b
g
V =756.75(17) A ,
Z = 2,
a
) = 0.183 mmꢁ1, F(0 0 0) =396, 5346
reflections measured, 2562 unique reflections which were used in
all calculations. The final R is 0.0473, number of refined parameters
285.
4.5.1. 3-Hydroxy-4-trifluoromethyl-1H-pyrazolo[3,4-b]pyridin-5-
carboxylic acid (5)
4.6.2. Crystallographic data for 3c
Yield 71 mg (96%), light yellow powder, mp 290–292 8C. IR:
3261, 3213 (O–H, N–H), 3058, 2985 (C–H), 1702 (C55O), 1592, 1558
n
C12H8F7N3O3 (M = 375.21) are triclinic, space group P-1,
˚
˚
˚
a = 5.3342(13) A, b = 9.125(2) A, c = 15.453(4) A,
a = 86.80(3)8,

M.V. Goryaeva et al. / Journal of Fluorine Chemistry 147 (2013) 15–21
21
3
(b) X. Wang, D.M. Berger, E.J. Salaski, N. Torres, M. Dutia, C. Hanna, Y. Hu, J.I. Levin,
D. Powell, D. Wojciechowicz, K. Collins, E. Frommer, J. Lucas, J. Med. Chem. 53
(2010) 7874–7878.
˚
b
= 81.50(2)8,
g
= 75.953(18),
V = 721.5(3) A ,
Z = 2,
Dcalc = 1.727 g/cm3,
m
(Mo
Ka
) = 0.183 mmꢁ1
,
F(0 0 0) = 376,
6788 reflections measured, 2960 unique reflections which were
used in all calculations. The final R is 0.0353, number of refined
parameters 238.
[9] T. Tuccinardi, S. Schenone, F. Bondavalli, C. Brullo, O. Bruno, L. Mosti, A.T. Zizzari, C.
Tintori, F. Manetti, O. Ciampi, M.L. Trincavelli, C. Martini, A. Martinelli, M. Botta,
ChemMedChem 3 (2008) 898–913.
[10] J. Rimland, A. Dunne, S.S. Hunjan, R. Sasse, I. Uings, D. Montanari, M. Caivano, P.
Shah, D. Standing, D. Gray, D. Brown, W. Cairns, R. Trump, P.W. Smith, N.
Bertheleme, P. D’Alessandro, S. Gul, M. Vimal, D.N. Smith, S.P. Watson, Bioorg.
Med. Chem. Lett. 20 (2010) 2340–2343.
[11] T. Saito, T. Obitsu, C. Minamoto, T. Sugiura, N. Matsumura, S. Ueno, A. Kishi, S.
Katsumata, H. Nakai, M. Toda, Bioorg. Med. Chem. 19 (2011) 5955–5966.
[12] (a) K. Senga, T. Novinson, R.H. Springer, R.P. Rao, D.E. O’Brien, R.K. Robins, H.R.
Wilson, J. Med. Chem. 18 (1975) 312–314;
(b) R. Aggarwal, G. Sumran, N. Garg, A. Aggarwal, Eur. J. Med. Chem. 46 (2011)
3038–3046.
[13] O.M. Ahmed, M.A. Mohamed, R.R. Ahmed, S.A. Ahmed, Eur. J. Med. Chem. 44
(2009) 3519–3523.
[14] (a) D. Powell, A. Gopalsamy, Y.D. Wang, N. Zhang, M. Miranda, J.P. McGinnisb, S.K.
Rabindran, Bioorg. Med. Chem. Lett. 17 (2007) 1641–1645;
4.6.3. Crystallographic data for 4a
C10H8F3N3O3 (M = 275.19) are monoclinic, space group P21,
˚
˚
˚
˚
a = 4.9635(6) A, b = 11.4886(16) A, c = 10.1451(16) A,
b
m
a
= g = 908,
= 95.690(11)8, V = 575.66(14) A , Z = 2, Dcalc = 1.588 g/cmꢁ3
,
3
(Mo Ka
) = 0.150 mmꢁ1, F(0 0 0) = 280, 4259 reflection measured,
1482 unique reflections which were used in all calculations. The
final R is 0.0377, number of refined parameters 184.
CCDC Nos. 869663, 869664 and 869662 contain the supple-
mentary crystallographic data for 2c, 3c and 4a, respectively. These
data can be obtained free of charge via http://www.ccdc.cam.a-
c.uk/conts/retrieving.html (or from the CCDC, 12 Union Road,
(b) Y.D. Wang, E. Honores, B. Wua, S. Johnson, D. Powell, M. Miranda, J.P.
McGinnis, C. Discafani, S.K. Rabindran, W. Cheng, G. Krishnamurthy, Bioorg.
Med. Chem. 17 (2009) 2091–2100.
Cambridge CB2 1EZ, UK; fax: +44 1223 336033;
deposit@ccdc cam ac uk.
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This research was financially supported by the Ministry of
Education and Science of the Russian Federation (Project 8430), the
Program of the Ural Branch of RAS (Project 12-P-3-1030), the State
Program for Supporting of Leading Scientific Schools of the Russian
Federation (Grant 5505.2012.3) and the Russian Foundation for
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