Synthesis and cytotoxic activity of heterocyclization products of 1,1-dicyano-2-hetaryl-2-trifluoromethylethylenes

Article abstract of DOI:10.1007/s11172-010-0058-7

Methods for the synthesis of novel fluorinated compounds by reaction of 1,1-dicyano-2-hetaryl-2-trifluoromethylethylenes with a variety of nitrogen heterocycles have been developed. Cyctotoxicity of the obtained organofluorine heterocycles were studied in vitro at the U.S. National Cancer Institute (NCI) in the framework of the International Program for Development of Effective Antitumor Drugs. Cytotoxic activity in the series of fluorinated pyrazolo[1,5-a]pyrimidines has been observed for the first time, this strongly depending on the nature and position of the substituents.

Full text of DOI:10.1007/s11172-010-0058-7

Russian Chemical Bulletin, International Edition, Vol. 59, No. 1, pp. 162—176, January, 2010
162
Synthesis and cytotoxic activity of heterocyclization products
of 1,1ꢀdicyanoꢀ2ꢀhetarylꢀ2ꢀtrifluoromethylethylenes
Yu. E. Pavlova,a A. F. Shidlovskii,a D. B. Gusev,a A. S. Peregudov,a Yu. N. Bulychev,b and N. D. Chkanikova
aA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 6471. Eꢀmail: nchkan@ineos.ac.ru
bResearch institute of Experimental Diagnostics and Tumor Therapy
N. N. Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences,
24 Kashirskoe sh., 115478 Moscow, Russian Federation.
Fax: +7 (495) 324 6037. Eꢀmail: ybulychev@hotmail.com
Methods for the synthesis of novel fluorinated compounds by reaction of 1,1ꢀdicyanoꢀ2ꢀ
hetarylꢀ2ꢀtrifluoromethylethylenes with a variety of nitrogen heterocycles have been develꢀ
oped. Cyctotoxicity of the obtained organofluorine heterocycles were studied in vitro at the
U.S. National Cancer Institute (NCI) in the framework of the International Program for
Development of Effective Antitumor Drugs. Cytotoxic activity in the series of fluorinated
pyrazolo[1,5ꢀa]pyrimidines has been observed for the first time, this strongly depending on the
nature and position of the substituents.
Key words: cyano(hetaryl)ethylenes, heterocyclizarion, in vitro cytotoxicity.
Fluorinated cyanoethylenes are convenient precursors
Results and Discussion
for heterocyclic compounds such as 3ꢀtrifluoromethꢀ
ylpyrazoles, 4ꢀtrifluoromethylpyrimidines, and others.1
Heterocyclization of 1,1ꢀdicyanoꢀ2,2ꢀbis(trifluoromeꢀ
thyl)ethylene has previously been studied in our laboraꢀ
tory.2 Further, these conversions were extended to 1,1ꢀdiꢀ
cyanoethylenes with other fluorinated substituents and
functional groups.3,4 Several 1,4ꢀdihydropyridine deriꢀ
vates, which were synthesized from the corresponding diꢀ
cyanoehtylenes according to the method developed by us,
have been patented as biologically active agents.5 An esꢀ
sential part of the modern antitumor agents represent fluꢀ
orinated pharmaceuticals.6 Currently, a search for the anꢀ
titumor agents in this direction is regarded as a very topiꢀ
cal task. Thus about 100 structural types of fluorinated
anticancer agents is given in a review,7 most of which
being heterocycles.
In continuation of this research, it was of interest to
develop synthetic pathways towards 1,1ꢀdicyanoꢀ2ꢀhetarꢀ
ylꢀ2ꢀtrifluoromethylethylenes where one of the CF3 groups
is replaced by a heteroaromatic core and to study the cycliꢀ
zation of these novel compounds. This direction of the
research can increase significantly the chemical diversity
of the heterocyclic structures, which could be derived on
the base of fluorinated 1,1ꢀdicyanoethylenes, which is esꢀ
sential for the search for novel practically useful comꢀ
pounds. Pyrazole and thiophene derivatives were selected
for functionalization of cyanoethylenes.
2ꢀChloroꢀ1,1ꢀdicyanoꢀ2ꢀtrifluoromethylethylene (1)
was used as a starting compound for the synthesis of the
target cyanoethylenes. Compound 1 was synthesized by
condensation of ethyl trifluoroacetate with malononitrile
in the presence of sodium ethoxide followed by treatment
of the resulted alkoxide with phosphorus oxycloride.8 It is
known that alkene 1 readily reacts with nucleophiles to
give cyanovinylation products, the chloride anion acting
as a leaving group.8,9 The mobility of the chlorine atom in
alkene 1, which is abnormal for vinyl chlorides, was disꢀ
cussed.10 The initial step of the reaction of alkene 1 with
RHꢀnucleophiles involved presumably the addition to the
double bond of the alkene followed by elimination of
HCl.10 Similarly, tetracyanoethylene reacts with nucleoꢀ
philes with elimination of hydrogen cyanide. In the present
work, we extended this reaction to heteroaromatic comꢀ
pounds of πꢀdonating nature. NꢀMethylpyrrole underwent
noncatalyzed 2ꢀcyanovinylation with alkene 1 at room
temperature (Scheme 1). The target dicyanoethylene 2
was isolated in 77% yield by vacuum distillation. Indole,
as well as its 2ꢀmethyl and 2ꢀphenyl derivatives, underꢀ
went 3ꢀsubstitution upon refluxing with alkene 1 in benzꢀ
ene to give cyanoethylenes 3—5. The most stable 2ꢀpheꢀ
nylindole gave the highest yield (95%) of the reaction prodꢀ
uct, derivative 5. It was also found that anilines readily
react with alkene 1 to give the corresponding 4ꢀCꢀvinylꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 160—173, January, 2010.
1066ꢀ5285/10/5901ꢀ0162 © 2010 Springer Science+Business Media, Inc.

Cytotoxicity of trifluromethylpyrazolopyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
163
Scheme 1
Scheme 3
Compound
R
2
3
4
5
6
7
8
Nꢀmethylpyrrolꢀ2ꢀyl
Indolꢀ3ꢀyl
2ꢀMethylindolꢀ3ꢀyl
2ꢀPhenylindolꢀ3ꢀyl
pꢀDiethylaminophenyl
pꢀMorpholinophenyl
4ꢀAminoꢀ3,5ꢀdiisopropylphenyl
ation products 6—8. It is of note that in the case of
2,6ꢀdiisopropylaniline this reaction, and not Nꢀvinylation,
proceeded in high yield (75%), which can probably be
attributed to steric hindrance at the amino group due to
the isopropyl groups.
Compound
R
R´
Me
Ph
Me
Ph
Me
Ph
Me
Ph
10
11
12
13
14
15
16
17
NꢀMethylpyrrolꢀ2ꢀyl
NꢀMethylpyrrolꢀ2ꢀyl
Indolꢀ3ꢀyl
An attempt of cyanovinylation of thiophene with alkꢀ
ene 1 was unsuccessful. No reaction was observed even at
elevated temperature. The use of the Lewis acids (AlCl3,
SnCl4, ZnCl2) as the catalysts led to the resinification of
the reaction mixture. An alternative pathway for the synꢀ
thesis of alkenylthiophenes was developed, which involved
condensation of 2ꢀtrifluoroacetylthiophene with malonoꢀ
nitrile in benzene in the presence of piperidine and acetic
acid (Scheme 2). The target compound 9 was isolated by
vacuum distillation in 68% yield. The obtained conjugated
systems 2—9 are brightꢀcolored compounds. Their color
allowed visual monitoring of their transformations, which
involved addition at the double bond.
Indolꢀ3ꢀyl
2ꢀMethylindolꢀ3ꢀyl
2ꢀMethylindolꢀ3ꢀyl
2ꢀPhenylindolꢀ3ꢀyl
2ꢀThienyl
signals for each of the characteristic nuclei (Table 2). Thus
compound 11 showed two signals for the N—CH3 group
(δH 3.53 and 3.46), two signals for the NH2 group (δH 6.69
and 6.87), two signals for each of three pyrrole СН groups,
and two signals for the CF3 group at δF 3.19 and 5.92. The
intensity ratio of the signals in each pair is the same, 2 : 1.
The signal intensity ratio for compounds 13, 15, and 16 is
3 : 1, 4 : 1, and 1 : 1, respectively.
Scheme 2
In the case of substituted 1,4ꢀdihydropyrimidines
(R´ = methyl, compounds 10, 12 and/or R = methyl in
the position 2 of the indole moiety, compound 14), the 1H
NMR spectra exhibited single set of signals for the methyl
groups and broadened single signals for the NHꢀprotons
of the NH2 groups and the heterocyclic core (Table 2).
The 19F NMR spectra of these compounds also contained
markedly broadened single signal of the CF3 group.
This spectral pattern, apparently, could be explained
by the fact that compounds 10—17 can exist in solution in
two tautomeric forms (see Scheme 3).
For compounds 11, 13, 15, and 16, tautomerization
occurred slowly on the NMR time scale. The tautomeric
equilibrium constant КТ could be determined from the
intensity ratio of the characteristic signals. It could be
expected, that in the 19F NMR spectra the signals for the
СF3 group of tautomer А will appear at the lower fields
than that of tautomer B due to stronger electronꢀwithꢀ
drawing effect of the C=N fragment as compared with the
MeC—NH fragment. On the base of this assumption,
КТ values was calculated approximately 4, 9, 16, and 1 for
We have previously shown that 1,1ꢀdicyanoꢀ2,2ꢀbisꢀ
(trifluoromethyl)ethylene and 1,1ꢀdicyanoethylenes bearꢀ
ing other fluoromethylꢀsubstituents or an ester function
instead of the CF3 group react with amidines to give
1,4ꢀdihydropyrimidines.4,5 The reaction of synthesized
alkenes 2—5 and 9 with Nꢀunsubstituted carboxamidines
(acetamidine and benzamidine) led to the corresponding
1,4ꢀdihydropyrimidines (Scheme 3, Table 1).
The H and 19F NMR spectra of synthesized 1,4ꢀdiꢀ
1
hydropyrimidines bearing the phenyl groups as the R´ꢀsubꢀ
stituents (compounds 11, 13, and 15) or in the position 2
of the indole moiety (compound 16) exhibited two sets of

164
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Pavlova et al.
Table 1. Yields, physicochemical parameters, and elemental analysis data of compounds 10—61
Comꢀ Yield M.p.
pound (%) /°C
Found
Calculated
Molecular
formula
Comꢀ Yield M.p.
pound (%) /°C
Found
Calculated
Molecular
formula
(%)
N
(%)
N
С
H
С
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
48 225— 50.86 4.29 24.71
226 50.88 4.27 24.72
67 249— 56.45 3.76 21.95
250 56.43 3.79 21.93
C12H12F3N5
C15H12F3N5
C16H14F3N5
C17H14F3N5
C20H14F3N5
C21H16F3N5
C21H16F3N5
C16H11F3N4S
C16H14F3N5
C16H14F3N5
C20H18F3N5O
C20H20F3N5
C18H12F3N5
C19H14F3N5
C19H14F3N5
C19H14F3N5
C15H11F3N4S
C15H11F3N4S
C13H11F3N6
C14H13F3N6
C18H17F3N6O
C25H23F3N6O2
C24H20ClF3N6O
C18H19F3N6
C25H25F3N6O
C24H22ClF3N6
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
49 222— 59.40 5.73 20.78
224 59.39 5.75 20.77
66 110— 63.52 5.73 16.46 C27H29F3N6O
115 63.50 5.78 16.46
60 255— 60.64 5.09 16.32 C26 H26ClF3N6
C20H23F3N6
65
59
58
>240 57.63 4.21 21.03
decomp. 57.66 4.23 21.01
>240 59.10 4.08 20.24
разл. 59.13 4.09 20.28
>240 62.97 3.71 18.39
decomp. 62.99 3.70 18.36
257
*
60.69 5.07 16.32
55.83 3.21 24.45 C16H11F3N6
55.82 3.22 24.47
56
46
53
61
58
56
59
42
44
67
83
86
52
44
41
45
40
50
53
51
52
55
43
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
56.90 3.68 23.44 C17H13F3N6
56.98 3.66 23.45
58.13 3.16 18.49 C22H14ClF3N6
58.10 3.10 18.48
61.30 3.77 18.13 C23H17F3N6O
61.33 3.80 18.16
56.93 3.64 23.47 C17H13F3N6
56.98 3.66 23.45
58.03 4.02 22.55 C18H15F3N6
58.06 4.06 22.57
62.69 3.63 19.95 C22H15F3N6
62.86 3.60 19.99
51.23 2.61 16.58 C18H11ClF3N5S
51.25 2.63 16.60
54.65 3.40 16.76 C19H14F3N5OS
54.67 3.38 16.78
51.18 2.79 14.92 C20H13F6N5S
51.16 2.81 14.85
53.40 4.30 20.74 C15H14F3N5O
53.41 4.18 30.76
57.58 3.65 16.80 C20H15F3N5O
57.56 3.62 16.78
55.35 3.47 16.16 C20H15ClF3N5O
55.37 3.49 16.14
58.82 3.24 14.89 C23H15ClF3N5O
58.80 3.22 14.91
58.82 3.24 14.89 C23H15ClF3N5O
58.80 3.22 14.91
52.20 2.75 12.85 C19H13ClF3N4OS
52.24 2.77 12.83
58.08 4.12 14.28 C19H16ClF3N4
58.10 4.11 14.26
52 221— 63.76 4.07 17.74
222 63.79 4.08 17.71
68 190— 63.73 4.09 17.75
191 63.79 4.08 17.71
38 110— 55.19 3.16 16.07
111
*
55.17 3.18 16.08
57.63 4.22 21.03
57.66 4.23 21.01
57.64 4.21 21.02
57.66 4.23 21.01
59
53
*
48 100— 59.85 4.52 17.45
105
*
59.76 4.54 17.43
62.01 5.20 18.08
62.00 5.23 18.12
60.88 3.42 19.73
60.85 3.40 19.71
61.81 3.81 18.95
61.79 3.82 18.96
61.77 3.83 18.98
61.79 3.82 18.96
61.80 3.80 18.94
61.79 3.82 18.96
53.56 3.31 16.64
53.57 3.30 16.66
53.58 3.32 16.68
53.57 3.30 16.66
50.63 3.61 27.25
50.65 3.60 27.26
52.16 4.10 26.06
52.17 4.07 26.08
55.38 4.39 21.53
55.32 4.47 21.48
60.48 4.67 16.93
60.56 4.67 16.86
57.55 4.02 16.78
57.49 4.06 16.84
57.44 5.09 22.33
57.32 5.03 22.22
57
61
75
63
54
49
47
61
54
47
65
58
45
*
*
*
*
*
*
*
*
*
*
*
*
58.09 4.09 14.25 C19H16ClF3N4
58.10 4.11 14.26
66.69 4.72 12.43 C25H21F3N4O
66.66 4.70 12.44
68.22 5.03 13.25 C24H21F3N4
68.24 5.01 13.26
61.63 3.74 13.07 C22H16ClF3N4
61.62 3.76 13.06
65.10 4.49 13.23 C23H19F3N4O
65.09 4.51 13.20
6166 4.67 10.78 C20H18F3N3S
61.68 4.66 10.79
67 204— 62.23 5.22 17.42
205
*
62.17 5.17 17.35
59.20 4.55 17.26
59.21 4.59 17.29
56
* Viscous glassy substance.

Cytotoxicity of trifluromethylpyrazolopyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
165
Table 2. 1H and 19F NMR spectral data (DMSOꢀd6, δ, (J/Hz)) of compounds 1—47
Comꢀ
pound
1H NMR
19F NMR
(s, 3 F, CF3)
10
11
8.86 (br.s, 1 H, NH); 6.84 (1 H, s, NH); 6.47 (br.s, 2 H, NH2); 6.06 (s, 1 H, CH);
5.96 (m, 1 H, CH); 3.50 (s, 3 H, CH3); 1.99 (s, 3 H, CH3)
3.6
9.62 (s, 1 H, NH); 7.92 (d, 2 H, CH, J = 8); 7.58—7.46 (m, 3 H, CH);
6.69 (br.s, 2 H, NH2); 6.50 (s, 1 H, CH); 6.15 (s, 1 H, CH);
5.99 (s, 1 H, CH); 3.53 (s, 3 H, CH3)
3.19
11´
10.17 (s, 1 H, NH); 7.85 (m, 2 H, CH); 7.58—7.46 (m, 3 H); 6.87 (br.s, 2 H, NH2);
6.71 (s, 1 H, CH); 6.08 (s, 1 H, CH); 5.93 (s, 1 H, CH); 3.46 (s, 3 H, CH3)
5.92
3.37
12
9.87 (br.s, 1 H, NH); 7.44 (d, 1 H, CH, J = 8); 7.39 (d, 1 H, CH, J = 8);
7.29 (s, 1 H, CH); 7.14 (t, 1 H, CH, J = 8); 7.03 (t, 1 H, CH, J = 8);
6.33 (br.s, 2 H, NH2); 1.99 (s, 3 H, CH3)
13
11.31 (s, 1 H, NH); 9.44 (s, 1 H, NH); 7.91 (d, 2 H, CH, J = 8);
7.66—7.31 (m, 5 H, CH); 7.12 (d, 1 H, CH, J = 8); 6.99 (t, 1 H, CH, J = 8);
6.52 (br.s, 2 H, NH2)
3.06
13´
14
11.16 (s, 1 H, NH); 10.07 (s, 1 H, NH); 7.85 (d, 2 H, CH, J = 8);
7.66—7.31 (m, 5 H, CH); 7.07 (t, 1 H, CH, J = 8); 6.94 (t, 1 H, CH, J = 8);
6.41 (br.s, 2 H, NH2)
6.62
9.61 (br.s, 1 H, NH); 7.45—7.41 (m, 1 H, CH); 7.29 (d, 1 H, CH, J = 8);
7.03 (d, 1 H, CH, J = 8); 6.95 (t, 1 H, CH, J = 8); 6.92 (br.s, 2 H, NH2);
2.34 (s, 3 H, CH3); 1.98 (s, 3 H, CH3)
5.10 (br.s)
15
11.61 (s, 1 H, NH); 9.07 (s, 1 H, NH); 7.50 (d, 1 H, CH, J = 8);
7.40—7.36 (m, 6 H, CH); 7.17—7.07 (m, 2 H, CH); 6.11 (br.s, 2 H, NH2);
1.71 (s, 3 H, CH3)
5.24
8.83
15´
11.23 (s, 1 H, NH); 9.30 (s, 1 H, NH); 7.92 (d, 2 H, CH, J = 8);
7.70—7.36 (m, 5 H, CH); 7.17—7.07 (m, 2 H, CH); 5.82 (br.s, 2 H, NH2);
1.43 (s, 3 H, CH3)
16
9.09 (s, 1 H, NH); 7.53—7.07 (m, 9 H, CH); 11.64 (br.s, 1 H, NH);
6.13 (br.s, 2 H, NH2); 1.71 (s, 3 H, CH3)
1.03
2.63
0.57
8.79
16´
17
11.25 (br.s, 1 H, NH); 9.34 (s, 1 H, NH); 7.53—7.07 (m, 9 H, CH);
5.87 (br.s, 2 H, NH2); 1.41 (s, 3 H, CH3)
10.16 (s, 1 H, NH); 7.88—7.87 (m, 2 H); 7.62—7.53 (m, 4 H, CH);
7.26 (d, 1 H, CH, J = 4); 7.09—7.07 (m, 1 H, CH); 6.53 (br.s, 2 H, NH2)
18
7.48 (d, 1 H, CH, J = 8); 7.13 (br.s, 2 H, NH2); 6.70 (s, 1 H, CH);
6.00 (br.s, 2 H, CH); 5.90 (t, 1 H, CH, J = 4); 3.52 (s, 3 H, N—CH3);
2.04 (s, 3 H, CH3)
19
7.35 (s, 1 H, CH); 7.11 (br.s, 2 H, NH2); 6.91 (d, 1 H, CH, J = 8);
6.69 (br.s, 1 H, CH); 6.51 (d, 1 H, CH, J = 8); 6.00 (br.s, H, CH);
5.90—5.89 (t, 1 H, CH, J = 4); 3.51 (s, 3 H, N—CH3); 1.95 (s, 3 H, CH3)
8.82
20
21
22
7.36 (m, 3 H, CH); 7.07 (br.s, 2 H, NH2); 6.95 (m, 3 H, CH); 6.65 (br.s, 1 H, CH);
6.05 (m, 1 H, CH); 3.71 (br.s, 4 H, 2 CH2); 3.10 (br.s, 4 H, 2 CH2)
3.57
3.68
2.25
7.39 (s, 1 H, CH); 7.25 (m, 2 H, CH) 7.03 (br.s, 2 H, NH2); 6.98 (m, 1 H, CH);
6.60 (m, 3 H, CH); 6.06 (m, 1 H, CH); 3.29 (m, 4 H, 2 CH2); 1.06 (m, 6 H, 2 CH3)
11.13 (s, 1 H, NH); 7.66 (d, 1 H, CH, J = 8); 7.43 (d, 1 H, CH, J = 8);
7.36 (d, 1 H, CH, J = 8); 7.20 (s, 1 H, CH); 7.08—6.94 (m, 3 H, CH);
7.06 7.11 (br.s, 2 H, NH2); 5.57 (d, 1 H, CH, J = 8); 6.06 (br.s, 1 H, CH);
23
24
11.11 (s, 1 H, NH); 7.67 (d, 1 H, CH, J = 8); 7.35 (d, 1 H, CH, J = 8);
7.25 (s, 1 H, CH); 7.18 (s, 1 H, CH); 7.06 (t, 1 H, CH, J = 8);
2.35
1.98
6.98 (br.s, 2 H, NH2); 6.95 (m, 1 H, CH); 6.83 (d, 1 H, CH, J = 8);
6.55 (d, 1 H, CH, J = 8); 1.91 (s, 3 H, CH3)
11.10 (s, 1 H, NH); 7.65 (d, 1 H, CH, J = 8); 7.40—7.35 (m, 2 H, CH);
7.07 (t, 1 H, CH, J = 8); 6.97 (br.s, 2 H, NH2); 7.19 (s, 1 H, CH);
6.96—6.94 (m, 1 H, CH); 6.37 (s, 1 H, CH); 5.94 (d, 1 H, CH, J = 8);
(to be continued)

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Pavlova et al.
Table 2 (continued)
Comꢀ
pound
1H NMR
19F NMR
(s, 3 F, CF3)
25
11.11 (s, 1 H, NH); 7.73 (d, 1 H, CH, J = 8); 7.37—7.33 (m, 2 H, CH);
7.21 (s, 1 H, CH); 2.03 (s, 3 H, CH3) 7.06 (t, 1 H, CH, J = 8); 6.97 (br.s, 2 H, NH2);
6.96—6.94 (m, 1 H, CH); 6.85 (br.s, 1 H, CH); 5.99 (br.s, 1 H, CH);
2.03 (s, 3 H, CH3)
2.51
26
7.52 (d, 1 H, CH, J = 5); 7.35 (br.s, 1 H, CH); 7.15—7.13 (m, 1 H, CH);
7.13 (br.s, 2 H, NH2); 7.04 (t, 1 H, CH, J = 5); 6.94 (d, 1 H, CH, J = 8);
6.59 (d, 1 H, CH, J = 8); 1.96 (s, 3 H, CH3)
0.24
27
28
29
7.61—7.53 (m, 2 H, CH); 7.22 (br.s, 2 H, NH2); 7.09 (m, 2 H); 6.54 (br.s, 1 H, CH);
6.15 (br.s, 1 H, CH); 2.15 (s, 3 H, CH3)
0.26
–0.41
–0.37
8.38 (s, 1 H, NH); 7.51 (br.s, 2 H, NH2); 7.50 (s, 1 H, CH); 6.89 (s, 1 H, CH);
6.13 (s, 1 H, CH); 5.98 (t, 1 H, CH, J = 4); 5.35 (s, 1 H, CH); 3.60 (s, 3 H, CH3)
8.26 (s, 1 H, NH); 7.34 (br.s, 2 H, NH2); 6.88 (br.s, 1 H, CH);
6.11 (bt.s, 1 H, CH); 5.97 (t, 1 H, CH, J = 4); 5.21 (s, 1 H, CH);
2.11 (s, 3 H, CH3)
30
31
8.33 (s, 1 H, NH); 7.45 (m, 5 H, CH + NH2); 7.00 (d, 2 H, CH); 5.39 (s, 1 H, CH);
3.74 (br.s, 4 H, 2 CH2); 3.15 (br.s, 4 H, 2 CH2)
2.72
2.69
8.42 (s, 1 H, NH); 7.79 (d, 2 H, CH); 7.47 (d, 2 H, CH); 7.38 (br.s, 2 H, NH2);
7.00 (m, 4 H, CH); 5.79 (s, 1 H, CH); 3.77 (m, 7 H, 2 CH2 + OCH3);
3.15 (br.s, 4 H, 2 CH2)
32
33
34
8.51 (s, 1 H, NH); 7.89 (d, 2 H, CH); 7.51 (m, 6 H, CH + NH2); 7.01 (d, 2 H, CH);
5.89 (s, 1 H, CH); 3.74 (br.s, 4 H, 2 CH2); 3.15 (br.s, 4 H, 2 CH2)
2.59
2.69
2.65
8.23 (s, 1 H, NH); 7.49 (s, 1 H, CH); 7.36 (m, 4 H, CH + NH2); 6.69 (d, 2 H, CH);
5.37 (s, 1 H, CH); 3.35 (m, 4 H, 2 CH2); 1.08 (m, 6 H, 2 CH3)
8.37 (s, 1 H, NH); 7.83 (d, 2 H, CH); 7.39 (m, 4 H, CH + NH2); 7.03 (d, 2 H, CH);
6.74 (d, 2 H, CH); 5.81 (s, 1 H, CH); 3.84 (s, 3 H, OCH3); 3.39 (m, 4 H, 2 CH2);
1.13 (m, 6 H, 2 CH3)
35
36
37
8.41 (s, 1 H, NH); 7.89 (d, 2 H, CH); 7.49 (d, 2 H, CH); 7.38 (m, 4 H, CH + NH2);
6.69 (d, 2 H, CH); 5.86 (s, 1 H, CH); 3.36 (m, 4 H, 2 CH2); 1.08 (m, 6 H, 2 CH3)
2.58
2.79
2.87
8.22 (s, 1 H, NH); 7.48 (s, H, CH); 7.26 (br.s, 2 H, NH2); 7.14 (s, 2 H, CH);
5.39 (s, 1 H, CH); 4.84 (br.s, 2 H, NH2); 3.04 (m, 2 H, CH); 1.14 (m, 12 H, 4 CH3)
8.32 (s, 1 H, NH); 7.78 (d, 2 H, CH); 7.26 (br.s, 2 H, NH2); 7.16 (s, 2 H, CH);
6.97 (d, 2 H, CH); 5.77 (s, 1 H, CH); 4.85 (br.s, 2 H, NH2); 3.79 (s, 3 H, OCH3);
3.04 (m, 2 H, CH); 1.14 (m, 12 H, 4 CH3)
38
39
8.40 (s, 1 H, NH); 7.87 (d, 2 H, CH); 7.47 (d, 2 H, CH); 7.35 (br.s, 2 H, NH2);
7.15 (s, 2 H, CH); 5.86 (s, 1 H, CH); 4.85 (br.s, 2 H, NH2); 3.04 (m, 2 H, CH);
1.14 (m, 12 H, 4 CH3)
2.84
11.30 (s, 1 H, NH); 8.22 (br.s, 1 H, NH); 7.51 (s, 1 H, CH);
7.49 (d, 1 H, CH, J = 8); 7.45 (d, 1 H, CH, J = 8); 7.34 (s, 1 H, CH);
7.33 (br.s, 2 H, NH2); 7.14 (t, 1 H, CH, J = 8); 7.01 (t, 1 H, CH, J = 8);
5.34 (s, 1 H, CH)
–0.70
40
41
42
11.30 (s, 1 H, NH); 8.15 (br.s, 1 H, NH); 7.49 (d, 1 H, СH, J = 8); 7.45 (d, 1 H,
CH, J = 8); 7.33 (br.s, 1 H, CH); 7.22 (br.s, 2 H, NH2); 7.14 (t, 1 H, CH, J = 8);
7.01 (t, 1 H, CH, J = 8); 5.20 (s, 1 H, CH);2.13 (s, 3 H, CH3)
–0.69
–0.62
–0.59
11.33 (s, 1 H, NH); 8.44 (br.s, 1 H, NH); 7.92 (d, 2 H, CH, J = 8);
7.74—47 (m, 6 H); 7.45 (br.s, 2 H, NH2); 7.37 (br.s, 1 H, CH);
7.15 (t, 1 H, CH, J = 8); 7.01 (t, 1 H, CH, J = 8); 5.82 (s, 1 H, CH)
11.31 (s, 1 H, NH); 8.33 (br.s, 1 H, NH); 7.82 (d, 1 H, CH, J = 8);
7.54 (d, 1H, CH, J = 8); 7.46 (d, 1 H, CH, J = 8); 7.36 (br.s, 1 H, CH);
7.34 (br.s, 2 H, NH2); 7.15 (t, 1 H, CH, J = 8); 7.01 (t, 1 H, CH, J = 8);
7.00 (d, 2 H, CH, J = 8); 5.75 (s, 1 H, CH); 3.80 (s, 3 H, OCH3)
(to be continued)

Cytotoxicity of trifluromethylpyrazolopyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
167
Table 2 (continued)
Comꢀ
pound
1H NMR
19F NMR
(s, 3 F, CF3)
43
11.27 (s, 1 H, NH); 8.17 (br.s, 1 H, NH); 7.51 (d, 1 H, CH, J = 1);
7.41 (d, 1 H, CH, J = 8); 7.32 (d, 1 H, CH, J = 8); 7.27 (br.s, 2 H, NH2);
7.05 (t, 1 H, CH, J = 8); 6.95 (t, 1 H, CH, J = 8); 5.33 (d, 1 H, CH, J = 1);
2.38 (s, 3 H, CH3)
0.44
44
45
11.28 (s, 1 H, NH); 8.10 (br.s, 1 H, NH); 7.39 (d, 1 H, CH, J = 8);
7.31 (d, 1 H, CH, J = 8); 7.17 (br.s, 2 H, NH2); 7.04 (t, 1 H, CH, J = 8);
6.94 (t, 1 H, CH, J = 8); 5.18 (s, 1 H, CH); 2.37 (s, 3 H, CH3); 2.11 (s, 3 H, CH3)
0.74
0.25
10.44 (s, 1 H, NH); 7.98 (s, 1 H, CH); 7.58 (s, 1 H, CH); 7.37 (d, 1 H, CH, J = 8);
7.24—7.70 (m, 4 H); 7.22 (br.s, 2 H, NH2); 7.11—7.07 (m, 1 H, CH);
6.93 (t, 1 H, CH, J = 8); 6.84 (t, 1 H, CH, J = 8); 6.59 (d, 1H, CH, J = 8);
6.54 (d, 1 H, CH, J = 2)
46
47
8.88 (s, 1 H, NH); 7.90 (d, 2 H, CH, J = 8.7); 7.71—7.70 (m, 1 H, CH);
7.55 (br.s, 2 H, NH2); 7.50 (d, 2 H, CH, J = 8.7); 7.25 (br.s, 1 H, CH);
7.11—7.09 (m, 1 H, CH); 5.93 (s, 1 H, CH)
0.16
0.19
8.79 (s, 1 H, NH); 7.80 (d, 2 H, CH, J = 8.7); 7.70 (d, 1 H, CH, J = 5);
7.64 (br.s, 2 H, NH2); 7.25 (br.s, 1 H, CH);7.10—7.08 (m, 1 H, CH);
6.99 (d, 2 H, CH, J = 8.7); 3.80 (s, 3 H, OCH3)
Scheme 4
compounds 11, 13, 15, and 16, respectively. The comparꢀ
ison of КТ values of compounds 13 and 15 indicated that
the increase in the steric hindrance near the nitrogen atom
in the position 6 of 1,4ꢀdihydropyrimidines resulted in
a decrease in the concentration of the tautomer A.
For compounds 10, 12, and 14, the tautomerization is
a considerably fast process on the NMR time scale, which
results in averaging of the shielding of the characteristic
groups. In this work, no detailed study of tautomerization
was carried out. However, preliminary kinetic study by the
dynamic NMR spectroscopy showed that in the 19F NMR
spectra the signal width at half height depends on the
concentration. For example, the decrease in the conꢀ
centration of compound 12 in DMSO from 0.02 to
0.005 mol L–1 broadened the signal of the fluorine atom
from 100 to 295 Hz, which reflected the nonꢀfirstꢀorder
kinetics of the tautomerization with respect to dihydropyꢀ
rimidine derivatives. Since the change in the concentraꢀ
tion led to the change in the width of NHꢀproton signals
as well as in the width of the proton signals for water
presented in DMSO, it could be assumed that all mobile
protons of the system participated in the process, and the
mechanism involved the formation of cyclic and acyclic
associates as it has been shown for the known system of
galvinoxyl (Coppinger's radical) with a spatially remote
cationꢀacceptor centers.
Comꢀ
pound
18
19
20
21
22
23
24
R
R´
R″
R″′
NꢀMethylpyrrolꢀ2ꢀyl
NꢀMethylpyrrolꢀ2ꢀyl
pꢀMorpholinophenyl
pꢀDiethylaminophenyl
Indolꢀ3ꢀyl
Me
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
Indolꢀ3ꢀyl
Indolꢀ3ꢀyl
Indolꢀ3ꢀyl
2ꢀThienyl
Me
H
H
Me
H
H
Me
H
H
Me
H
H
Me
H
H
25
26
27
2ꢀThienyl
It have been found that alkenes 2, 3, 6, 7, and 9 readily
react with 2ꢀaminopyridines to give pyrido[1,2ꢀа]pyꢀ
rimidine derivatives 18—27 (Scheme 4, Tables 1 and 2).
The highest yields were observed in the heterocyclizaꢀ
tion reaction of alkene 3 with the corresponding amiꢀ
nopyridines.
The reaction of 3ꢀaminopyrazoles with dicyanotrifluꢀ
oromethylethylenes has earlier been studied in our laboraꢀ
tory.2—4 It was found that the reaction of alkenes 2—9
with 3ꢀaminopyrazoles proceeded as cycloaddition to give
pyrazolo[1,5ꢀa]pyrimidines 28—47 (Scheme 5, Tables 1, 2).

168
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Pavlova et al.
Scheme 6
The reaction of 3ꢀaminoꢀ2ꢀarylꢀ5ꢀmethylpyrazole with
alkene 9 resulted in substituted dihydroꢀ1Нꢀpyrazoloꢀ
[3,4ꢀb]pyridine 48 (Scheme 5, Table 1, 3).
Scheme 5
49—54
Compound
R
R´
49
50
51
52
53
54
NꢀMethylpyrrolꢀ2ꢀyl
NꢀMethylpyrrolꢀ2ꢀyl
NꢀMethylpyrrolꢀ2ꢀyl
Indolꢀ3ꢀyl
Me
pꢀFC6H4
mꢀClC6H4
oꢀClC6H4
pꢀClC6H4
mꢀClC6H4
Indolꢀ3ꢀyl
2ꢀThienyl
The reaction of 1,1ꢀdicyanoꢀ2,2ꢀbis(trifluoromethyl)ꢀ
ethylene with anilines in the presence of an enolizable
ketone, which furnished 1ꢀarylꢀ1,4ꢀdihydropyridines, has
been studied earlier.11
It has been found that the threeꢀcomponent condenꢀ
sation of ethylenes 2 and 3 with diverse anilines and aceꢀ
tone at room temperature led to 1,4ꢀdihydropyridine deꢀ
rivatives 55—60 (Scheme 7, Table 1, 4).
Scheme 7
Comꢀ
pound
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
R
R´
NꢀMethylpyrrolꢀ2ꢀyl
NꢀMethylpyrrolꢀ2ꢀyl
pꢀMorpholinophenyl
pꢀMorpholinophenyl
pꢀMorpholinophenyl
pꢀDiethylaminophenyl
pꢀDiethylaminophenyl
pꢀDiethylaminophenyl
4ꢀAminoꢀ3,5ꢀdiisopropylphenyl
4ꢀAminoꢀ3,5ꢀdiisopropylphenyl
4ꢀAminoꢀ3,5ꢀdiisopropylphenyl
Indolꢀ3ꢀyl
H
Me
H
pꢀMeOC6H4
pꢀClC6H4
H
pꢀMeOC6H4
pꢀClC6H4
H
pꢀMeOC6H4
pꢀClC6H4
H
Comꢀ
pound
55
56
57
58
59
60
61
R
R´
NꢀMethylpyrrolꢀ2ꢀyl
NꢀMethylpyrrolꢀ2ꢀyl
NꢀMethylpyrrolꢀ2ꢀyl
Indolꢀ3ꢀyl
mꢀClC6H4
pꢀClC6H4
pꢀOPhC6H4
2,6ꢀMe2C6H3
pꢀClC6H4
Indolꢀ3ꢀyl
Indolꢀ3ꢀyl
2ꢀThienyl
Indolꢀ3ꢀyl
Indolꢀ3ꢀyl
Indolꢀ3ꢀyl
Me
pꢀOMeC6H4
3,4ꢀMe2C6H3
pꢀClC6H4
pꢀMeOC6H4
H
Me
H
pꢀClC6H4
pꢀMeOC6H4
2ꢀMethylindolꢀ3ꢀyl
2ꢀMethylindolꢀ3ꢀyl
2ꢀMethylindolꢀ3ꢀyl
2ꢀThienyll
It should be noted that the oneꢀstep threeꢀcomponent
condensation of alkene 9 under conditions described above
failed. The target 1,4ꢀdihydropyridine 61 was synthesized
by the reaction of ethylene 9 with the Schiff base derived
from 3,4ꢀdimethylaniline and acetone.12
The study of the cytotoxic activity of the synthesized
trifluoromethylꢀcontaining heterocycles was carried out
in vitro against a standard panel consisting of 60 human
tumor cell lines at the U.S. National Cancer Institute
2ꢀThienyl
The reactions of the ethylenes 2, 3, and 9 with a variety
of 2ꢀarylꢀ5ꢀmethylpyrazolꢀ3ꢀone derivates were systemꢀ
atically studied. All reactions yielded the corresponding
1,4ꢀdihydropyrano[2,3ꢀc]pyrazoles 49—54 (Scheme 6,
Tables 1, 3).

Cytotoxicity of trifluromethylpyrazolopyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
169
Table 3. 1H and 19F NMR spectral data (CDCl3, δ, (J/Hz)) of compounds 48—54
Compound
1H NMR
19F NMR
48
7.85—7.80 (m, 4 H); 7.69 (d, 1 H, СH, J = 5); 7.23 (s, 1 H, CH);
7.07—7.05 (m, 1 H, CH); 5.50 (br.s, 2 H, NH2); 1.52 (s, 3 H, CH3)
17.58 (s, 3 F, CF3);
2.07 (s, 3 F, CF3)
49
50
51
6.58 (t, 1 H, CH, J = 2); 6.43 (t, 1 H, CH, J = 2);
6.11—6.09 (m, 1 H, CH); 5.08 (br.s, 2 H, NH2); 3.74 (s, 3 H, NCH3);
3.19 (s, 3 H, NCH3); 1.59 (s, 3 H, CH3)
4.30 (s, 3 F, CF3)
7.65—7.61 (m, 2 H, CH); 7.21—7.17 (m, 2 H, CH); 6.62 (s, 1 H, CH);
6.65 (br.s, 1 H , CH); 6.14—6.12 (m, 1 H, 2 H, CH);
5.08 (br.s, 2 H, NH2); 3.29 (s, 3 H, NCH3); 1.77 (s, 3 H, CH3)
4.40 (s, 3 F, CF3);
–35.0 (1 F, CF)
7.72 (t, 1 H, CH, J = 2); 7.61—7.59 (m, 1 H, CH);
4.38 (s, 3 F, CF3)
7.42 (t, 1 H, CH, J = 8); 7.33 (d, 1 H, CH, J = 8); 6.62 (br.s, 1 H, CH);
6.46 (m, 1 H, CH); 6.13 (m, 1 H, CH); 5.14 (br.s, 2 H, NH2);
3.23 (s, 3 H, NCH3); 1.78 (s, 3 H, CH3)
52
9.91 (s, 1 H, NH); 7.49—7.46 (m, 2 H, CH); 7.36—7.33 (m, 2 H, CH);
7.30 (d, 1 H, CH, J = 8); 7.01 (t, 1 H, CH, J = 8);
6.91 (d, 1 H, CH, J = 8); 6.79 (t, 1 H, CH, J = 8);
5.86 (br.s, 2 H, NH2); 1.53 (s, 3 H, CH3)
4.35 (s, 3 F, CF3)
53
54
8.48 (s, 1 H, NH); 7.66 (m, 2 H); 7.46—7.44 (m, 2 H, CH);
7.36 (d, 1 H, CH, J = 8); 7.16—7.13 (m, 1 H, CH); 6.93 (s, 2 H, CH);
5.13 (br.s, 2 H, NH2); 1.65 (s, 3 H, CH3)
4.35 (s, 3 F, CF3)
5.62 (s, 3 F, CF3)
7.72 (br.s, 1 H, CH); 7.57 (d, 1 H, CH, J = 8); 7.42 (s, 1 H, CH);
7.40—7.37 (m, 1 H, CH); 7.34—7.30 (m, 2 H, CH); 7.04—7.02 (m, 1 H, CH);
5.17 (br.s, 2 H, NH2); 1.94 (s, 3 H, CH3)
Table 4. 1H and 19F NMR spectral data (DMSOꢀd6, δ, (J/Hz)) of compounds 55—61
Comꢀ
pound
H NMR
19F NMR
(s, 3 F, CF3)
55
56
57
58
7.60 (m, 2 H, CH); 7.43 (br.s, 1 H, CH); 7.23 (d, 1 H, CH, J = 8);
5.95—5.91 (m, 2 H, CH); 5.72 (br.s, 2 H, NH2); 4.67 (s, 1 H, CH);
3.65 (s, 3 H, N—CH3); 1.54 (s, 3 H, CH3)
3.58
3.58
3.37
3.32
7.57 (d, 2 H, СH, J = 8); 7.30 (d, 2 H, СH, J = 8); 6.76 13 (m, 1 H, CH); 5.94 (m, 2 H);
5.67 (br.s, 2 H, NH2); 4.66 (d, 1 H, CH, J = 1); 3.64 (s, 3 H, N—CH3);
1.52 (s, 3 H, CH3)
7.46—7.42 (m, 2 H, CH); 7.28—7.19 (m, 3 H, CH); 7.15—7.08 (m, 4 H, CH);
6.75 (s, 1 H, CH); 5.94—5.91 (m, 2 H); 5.63 (br.s, 2 H, NH2); 4.65 (s, 1 H, CH);
3.65 (s, 3 H, N—CH3); 1.54 (s, 3 H, CH3)
11.11 (s, 1 H, NH); 7.23 (d, 1 H, CH, J = 8); 7.42 (d, 1 H, CH, J = 8);
7.34—7.26 (m, 3 H); 7.12 (br.s, 1 H, CH); 7.11 (t, 1 H, CH, J = 8);
7.70 (t, 1 H, CH, J = 8); 5.28 (br.s, 2 H, NH2); 4.75 (s, 1 H, CH);
2.35 (s, 3 H, CH3); 2.17 (s, 3 H, CH3); 1.41 (s, 3 H, CH3)
59
60
61
11.12 (s, 1 H, NH); 7.66 (d, 1 H, CH, J = 8); 7.62 (s, 1 H, CH); 7.59 (s, 1 H, CH);
7.42—7.37 (m, 3 H); 7.20 (br.s, 1 H, CH); 7.13 (t, 1 H, CH, J = 8);
7.04 (t, 1 H, CH, J = 8); 5.55 (br.s, 2 H, NH2); 4.48 (s, 1 H, CH); 1.54 (s, 3 H, CH3)
3.48
3.47
11.12 (s, 1 H, NH); ); 7.67 (d, 1 H, CH, J = 8); 7.42 (d, 1 H, CH, J = 8);
7.34 (s, 1 H, CH); 7.20 (s, 1 H, CH); 7.15—7.02 (m, 5 H, CH); 5.36 (br.s, 2 H, NH2);
4.63 (s, 1 H, CH); 3.81 (br.s, 3 H, OCH3)
7.32 (d, 1 H, CH, J = 5); 7.25—7.23 (m, 2 H, CH); 7.07—6.97 (m, 3 H, CH);
4.50 (s, 1 H, CH); 4.34 (br.s, 2 H, NH2); 2.33 (s, 3 H, CH3); 2.31 (s, 3 H, CH3);
1.69 (s, 3 H, CH3)
–1.71

170
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Pavlova et al.
(NCI) in the framework of the International Program for
Screening and Development of Effective Antitumor Drugs
in accordance with the known procedure.13 This set of the
cell lines have previously been used for the study of the
cytotoxicity of heterocyclization products of cyano(triꢀ
fluoromethyl)vinylphosphonates.14
Tables 5 and 6. The values above 100% indicated the
growth stimulation of the cell cultures. The negative valꢀ
ues indicated the cell death in percent to the control. This
test revealed six compounds of the pyrazolo[1,5ꢀа]pyriꢀ
midine series that were subjected to further research
(Table 7).
The protocol used for the study of the mentioned group
of the compounds has been slightly modified. The study
was carried out in two steps. Initially, all compounds were
studied against the full panel of the human tumor cells
with incubation period of 24 h and with the use of the
single concentration for all compounds (10–5 mol L–1).
The compounds that exhibited cytotoxic activity were subꢀ
jected to further in vitro investigation against the same
panel of cells with the use of five logarithmic concentraꢀ
The cytotoxic activity of fourteen compounds including
four pyrido[1,2ꢀа]pyrimidines and ten pyrazolo[1,5ꢀa]ꢀ
pyrimidines were studied. In general, compounds of the
pyrazolo[1,5ꢀa]pyrimidine series turned to be more active
as compared with substituted pyrido[1,2ꢀа]pyrimidines.
None of CF3ꢀsubstituted pyrido[1,2ꢀа]pyrimidines (comꢀ
pounds 19, 20, 21, and 24) possessed cytotoxic activity
sufficient for further study in five concentrations. No inꢀ
fluence of the nature of the substituent at the position 2 on
the cytotoxicity was found. On the contrary, for several
cell lines the growth stimulation was observed.
Six compounds from ten of the pyrazolo[1,5ꢀa]pyꢀ
rimidine series were selected and studied in a complete
in vitro screening program, namely, at five different conꢀ
centrations. It should be noted, that all active compounds
have 4ꢀchlorophenyl of 4ꢀmethoxyphenyl group in the poꢀ
sition 2 of the pyrazole moiety. In terms of cytotoxicity,
the presence of this type of substituent could be regarded
as more important than the variation of the substituents in
tions 10–4, 10–5, 10–6, 10–7, and 10–8 mol L–1
.
The results of the study of the cytotoxic activity are
given in Tables 5—7.
The presented data should be considered as the results
of the first step of the investigation in the group of comꢀ
pounds, which allowed identification of promising clusꢀ
ters or individual compounds for subsequent research. The
residual growth values of the cell cultures after incubation
with the assayed compounds at the concentration of
10–5 mol L–1 in percent to the control are presented in
Table 5. The in vitro cytotoxicity of CF3ꢀsubstituted pyrido[1.2ꢀа]pyrimidines 19—21, 24 and pyrazolo[1.5ꢀa]pyrimidines
29—31 at concentration of 10–5 mol L–1
Cell culture
Residual growth of the cell culture (% to control)
19
20
21
24
29
30
31
Nonꢀsmall cell lung cancer
A549/ATCC
EKVX
HOPꢀ62
113.91
105.83
111.87
99.44
107.98
101.60
97.99
107.33
105.61
98.29
90.93
95.48
99.58
99.91
113.16
91.31
80.39
112.13
95.41
90.35
94.17
93.50
107.67
116.81
79.27
82.08
108.42
92.91
77.52
93.60
90.42
97.53
108.46
76.34
92.28
108.78
94.55
103.59
106.15
98.58
88.76
109.83
67.65
104.06
108.06
102.48
98.03
98.19
98.98
100.73
117.23
89.86
46.75
72.78
90.58
75.64
60.01
71.76
90.48
83.47
58.78
HOPꢀ92
NCIꢀH226
NCIꢀH23
NCIꢀH322M
NCIꢀH460
NCIꢀH522
114.64
93.95
Colon cancer
COLO 205
HCCꢀ2998
HCTꢀ116
HCTꢀ15
HT 29
123.22
113.87
108.21
109.19
115.58
109.42
115.88
119.84
77.94
105.14
94.28
118.96
109.03
106.26
129.45
88.59
93.47
111.99
87.22
95.57
106.22
88.05
112.98
88.55
95.88
87.58
57.58
61.01
54.64
93.09
99.37
101.79
114.30
101.19
106.59
108.98
104.97
104.14
110.85
108.77
112.98
99.66
59.64
119.45
110.65
116.09
104.77
106.25
111.44
KM 12
SWꢀ620
Breast cancer
BTꢀ549
HS578T
120.27
127.48
97.13
113.02
99.73
122.35
101.91
113.22
125.12
139.21
106.73
121.20
90.15
127.38
(to be continued)

Cytotoxicity of trifluromethylpyrazolopyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
171
Table 5 (continued)
Cell culture
Residual growth of the cell culture (% to control)
19
20
21
24
29
30
31
Breast cancer
MCF7
MDAꢀMBꢀ231/
ATCC
106.81
127.87
92.87
90.36
112.26
99.47
88.86
97.66
104.57
101.72
98.95
90.71
76.07
83.64
MDAꢀMBꢀ435
NCI/ADRꢀRES
Tꢀ47D
103.14
102.68
110.27
104.28
90.74
108.37
103.46
94.27
82.68
98.11
91.27
91.73
99.58
98.43
98.20
101.45
93.76
108.29
77.42
80.09
32.61
Ovarian cancer
IGROV1
75.88
121.81
111.57
105.86
94.87
66.31
114.39
104.43
87.97
99.95
99.37
59.11
110.72
106.43
105.91
80.42
60.37
100.21
95.58
95.79
93.26
86.34
–57.34
110.01
98.79
93.02
92.91
99.16
103.81
127.45
103.40
78.99
102.59
99.20
54.53
97.54
75.30
97.97
73.68
99.06
OVCARꢀ3
OVCARꢀ4
OVCARꢀ5
OVCARꢀ8
SKꢀOVꢀ3
112.27
105.13
Leukemia
CCRFꢀ CEM
HLꢀ60(TB)
Kꢀ562
MOLTꢀ4
RPMIꢀ8226
SR
81.22
91.85
85.14
57.71
111.61
88.96
187.72
84.70
97.43
83.57
112.50
105.48
93.42
86.98
82.25
58.44
101.76
93.44
79.25
108.41
91.60
96.14
85.60
89.05
123.73
121.47
—
149.13
120.31
185.74
191.35
89.50
90.90
97.31
113.13
115.02
67.71
28.18
42.04
35.44
4.59
52.41
Renal cancer
768ꢀ0
A 498
100.81
118.47
113.87
99.93
–22.09
113.24
112.76
47.41
100.99
94.03
102.95
115.61
112.88
99.13
–20.55
106.45
123.56
69.01
96.16
89.40
79.03
91.62
2.08
110.12
92.74
35.57
102.36
136.85
115.57
99.74
7.37
80.72
103.83
75.02
101.47
96.56
116.79
99.79
–0.78
90.40
129.13
84.45
74.13
70.66
100.97
73.98
–15.50
71.43
87.33
ACHN
CAKIꢀ1
RXFꢀ393
SN12C
TKꢀ10
UOꢀ31
108.10
101.45
–3.01
103.60
125.56
71.76
57.99
Melanoma
LOX IMVI
M14
104.25
107.49
114.61
88.04
128.32
100.54
117.24
105.07
101.39
106.16
121.22
62.10
118.11
87.40
96.42
105.43
120.77
52.63
121.86
98.87
76.96
108.09
106.27
55.13
113.45
93.21
97.39
102.40
107.98
55.27
112.80
114.09
97.35
105.43
109.74
117.29
96.84
130.11
104.32
105.21
89.89
90.23
88.66
98.08
48.93
106.01
49.70
54.68
64.15
MALMEꢀ3M
SKꢀMELꢀ2
SKꢀMELꢀ28
SKꢀMELꢀ5
UACCꢀ257
UACCꢀ62
115.64
86.93
98.66
86.92
112.01
93.67
93.57
Prostate cancer
DUꢀ145
PCꢀ3
121.63
98.41
120.86
98.74
116.91
103.88
110.45
99.57
137.60
107.54
126.71
107.23
98.92
75.50
CNS cancer
SFꢀ268
SFꢀ295
SFꢀ539
SNBꢀ19
SNBꢀ75
U251
110.41
105.32
107.35
106.47
98.32
98.57
102.16
105.12
96.02
90.50
103.48
108.80
99.81
109.16
104.43
92.75
101.15
99.01
108.75
101.56
84.36
109.99
107.47
110.12
96.31
60.54
106.58
104.50
94.02
108.13
106.98
102.87
108.39
79.20
75.73
97.09
80.00
109.08
80.22
114.46
102.00
55.48

172
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Pavlova et al.
Table 6. The in vitro cytotoxicity of CF3ꢀsubstituted pyrido[1.2ꢀа]pyrimidines 32—38 at concentration
of 10–5 mol L–1
Cell culture
Residual growth of the cell culture (% to control)
32
33
34
35
36
37
38
Nonꢀsmall cell lung cancer
A549/ATCC
EKVX
HOPꢀ62
46.72
57.8
82.98
50.4
72.12
71.01
72.21
57.85
66.54
1.57
26.01
47.7
79.7
93.41
94.89
77.7
79.08
104.2
95.31
103.91
88.72
37.45
47.74
80.61
43.08
52.34
47.39
68.58
52.2
98.16
109.72
100.16
95.73
93.91
99.51
86.5
10.72
26.65
47.54
–33.49
40.71
35.6
57.88
30.39
25.45
41.11
38.89
55.25
20.62
56.18
44.9
33.55
10.88
41.91
HOPꢀ92
6.23
NCIꢀH226
NCIꢀH23
NCIꢀH322M
NCIꢀH460
NCIꢀH522
32.76
24.65
40.85
11.66
–7.04
107.32
27.34
85.91
Colon cancer
COLO 205
HCCꢀ2998
HCTꢀ116
HCTꢀ15
HT 29
56.59
81.56
48.54
52.13
20.96
74.54
74.3
–33.84
32.91
17.17
19.24
–9.04
21.92
19.87
98.06
74.49
81.36
50.13
88.37
120.86
107.85
55.07
72.98
42.86
92.47
43.3
108.58
84.21
95.37
95.75
106.07
99.08
114.14
0.58
5.85
29.71
41.01
30.06
31.15
40.78
5.78
32.83
24.37
40.09
28.33
44.37
KM 12
SWꢀ620
51.0
70.82
56.56
Breast cancer
BTꢀ549
HS578T
MCF7
MDAꢀMBꢀ231/
ATCC
91.18
98.69
37.64
82.1
42.26
69.68
1.86
109.75
119.53
84.65
73.1
100
21.62
69.45
115.38
128.64
100.93
100.97
44.61
37.69
24.55
25.43
61.03
56.51
26.14
20.2
5.69
77.64
MDAꢀMBꢀ435
NCI/ADRꢀRES
Tꢀ47D
65.13
78.82
38.24
27.69
27.73
ꢀ8.45
77.63
78.47
74.64
44.39
49.27
37.55
107.08
96.02
82.19
24.84
30.85
33.0
35.48
–15.19
22.52
Ovarian cancer
IGROV1
8.2
—
49.17
–0.47
65.29
45.23
93.51
48.23
79.53
21.62
116.03
91.51
95.29
95.97
94.14
30.87
24.55
22.77
55.03
31.06
62.27
26.07
46.01
48.02
71.78
30.62
75.07
OVCARꢀ3
OVCARꢀ4
OVCARꢀ5
OVCARꢀ8
SKꢀOVꢀ3
81.24
54.08
90.21
70.61
88.25
30.88 111.17
17.1 79.27
46.04 100.34
11.62
49.25
92.22
98.08
Leukemia
CCRFꢀ CEM
HLꢀ60(TB)
Kꢀ562
MOLTꢀ4
RPMIꢀ8226
SR
32.31
–17.5
28.38
11.56
33.41
35.35
19.59
–35.41
7.24
–21.45
–23.49
8.67
69.78
65.69
83.54
42.81
63.79
78.36
38.71
–6.4
26.19
13.38
17.65
43.81
93.77
88.81
83.37
75.26
92.1
—
32.43
–4.58
23.77
19.24
14.03
9.31
–9.4
19.67
9.45
–40.88
10.53
89.92
Renal cancer
768ꢀ0
A 498
85.86
71.92
82.29
69.45
–31.85
78.8
38.89 101.41
69.01
40.51
99.73
61.44
–1.37
63.15
62.72
11.9
103.22
109.11
109.08
108.57
19.87
87.09
119.6
73.3
43.46
27.36
21.49
39.13
1.58
40.72
40.84
13.36
41.83
42.98
33.67
43.16
–16.3
41.67
28.95
20.47
–4.87
22.14
35.29
60.98
62.81
98.92
ACHN
CAKIꢀ1
RXFꢀ393
SN12C
TKꢀ10
UOꢀ31
–47.29 –18.7
28.05
44.43
1.51
94.14
93.55
35.24
92.83
32.09
(to be continued)

Cytotoxicity of trifluromethylpyrazolopyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
173
Table 6 (continued)
Cell culture
Residual growth of the cell culture (% to control)
32
33
34
35
36
37
38
Melanoma
LOX IMVI
M14
78.5
66.68
76.29
36.91
103.32
31.32
29
26.36
33.23 104.51
29.19 111
–9.31
57.16 121.1
–30.57
–21.66
45.12
58.62
87.59
72.43
63.53
21.08
97.87
21.86
45.1
89.03
118.99
99.36
28.91
55.16
61.12
–11.23
61.87
38.72
46.26
45.18
37.58
49.06
12.92
6.82
76.93
49.45
74.3
MALMEꢀ3M
SKꢀMELꢀ2
SKꢀMELꢀ28
SKꢀMELꢀ5
UACCꢀ257
UACCꢀ62
49.22
71.49
128.69
106.32
99.19
80.23
92.53
79.63
75.21
60.11
77.84
59.03
Prostate cancer
DUꢀ145
PCꢀ3
85.21
55.46
62.99 101.93
88.83
50.07
124.13
106.03
72.92
ꢀ2.49
80.55
34.34
23.17
83.85
CNS cancer
SFꢀ268
SFꢀ295
SFꢀ539
SNBꢀ19
SNBꢀ75
U251
73.69
50.92
86.92
84.41
77.03
74.37
31.88
–18.29
60.41 108.41
27.01
33.71
28.21
74.16
75.99
59.35
21.21
84.21
68.22
77.79
88.63
102.77
91.47
106.51
88.01
55.51
100.43
37.26
–18.09
43.62
29.47
8.48
37.17
3.12
51.17
40.55
49.81
42.76
91.09
89.42
48.56
15.63
the position 5. Thus compound 30 with unsubstituted pyraꢀ
zole ring and bearing a 4ꢀmorpholinophenyl group in the
position 5 as in compounds 31 and 32 exhibited no cytoꢀ
toxic activity. At the same time, compounds 31 and 32
with 4ꢀmethoxyphenyl and 4ꢀchlorophenyl groups in the
position 2 exhibited significant cytotoxicity of the same
level against the majority of the cell lines. The similar
conclusions can be drawn from the consideration of comꢀ
pounds 36 and 37 bearing the same 4ꢀaminoꢀ3,5ꢀdiisoꢀ
propylphenyl group in the position 5. Compound 36 unꢀ
substituted in the position 2 exhibited no cytotoxic activity.
Compounds 37 and especially 38 with 4ꢀmethoxyphenyl
and 4ꢀchlorophenyl groups in the position 2, respectively,
exhibited the strongest nonselective cytotoxic activity
against the majority of the cell cultures of all subpanels.
The above described pattern was also fully confirmed
for compounds 33, 34, and 35 bearing the same 4ꢀdiethyꢀ
laminophenylꢀsubstituent in the position 5. Compound
33 without substituent in the position 2 showed no cytoꢀ
toxicity. At the same time, compounds 34 and 35 with
4ꢀmethoxyphenyl and 4ꢀchlorophenyl groups in the posiꢀ
tion 2, respectively, exhibited significant nonselective cyꢀ
totoxic activity. The importance of the substituent in the
position 2 followed from the lack of cytotoxic activity of
compound 29 with the methyl substituent in the position 2.
In summary, for the first time data on the in vitro
cytotoxic activity of fourteen novel CF3ꢀsubstituted pyꢀ
razolo[1,5ꢀa]pyrimidines and pyrido[1,2ꢀа]pyrimidines
against broad range of human cancer cells of diverse origin
have been obtained. It has been shown that pyrido[1,2ꢀа]ꢀ
pyrimidines exhibited no cytotoxic activity. In the series
of pyrazolo[1,5ꢀa]pyrimidines, several highly active cytoꢀ
toxic agents were found. The strong dependence of cytoꢀ
toxicity on the nature of the substituent in the position 2
has been found. The 4ꢀmethoxyphenyl or 4ꢀchlorophenyl
groups favor significant increase in the nonselective cytoꢀ
toxicity against the majority of the cell lines. Hence, variꢀ
ation of the substituents in the position 2 could lead to
discovery of new and more effective cytotoxic agents. For
the identification of compounds with the highest cytotoxꢀ
ic activity in the series under study, the stateꢀofꢀtheꢀart
in silico screening should be applied. Synthesis of pyrꢀ
azolo[1,5ꢀa]pyrimidine derivatives with 4ꢀaminophenyl,
4ꢀhydrohyphenyl, 4ꢀalkylaminophenyl, and hetaryl groups
as well as their possible combinations is also the point
of interest.
Experimental
The 1H and 19F NMR spectra were recorded on a Bruker
AMXꢀ400 instrument at 400.13 MHz and 376.50 MHz, respecꢀ
tively. Chemical shifts were determined relative to the residual
signal of the deuterated solvent and refined relative to Me4Si.
The 19F NMR spectra were referenced to CF3COOH as the
external standard. Mass spectra were obtained on a Cratos
MSꢀ890 mass spectrometer (EI, 70 eV). The starting compounds
5ꢀmethylꢀ2,3ꢀdihydropyrazolꢀ3ꢀones and 3ꢀaminopyrazoles
were synthesized by the known procedures.15,16

174
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Pavlova et al.
Table 7. Cytotoxicity of compounds 31, 32, 34, 35, 37, 38
Cell culture
GI50/μmol L–1
34 35
Cell culture
GI50/μmol L–1
34 35
31
32
37
38
31
32
37
38
Leukemia
2.41 2.96 1.98 1.7
SKꢀMELꢀ2
SKꢀMELꢀ28
SKꢀMELꢀ5
UACCꢀ257
UACCꢀ62
5.06 4.62 2.97 4.03 1.01 1.38
>100 5.27 8.05 4.67 2.96 1.88
CCRFꢀ CEM
HLꢀ60(TB)
Kꢀ562
MOLTꢀ4
RPMIꢀ8226
SR
3.33 2.2
6.05 3.49 2.9
0.869 1.42 1.48
3.05 3.44 2.14
1.65 1.02 0.596
4.24 1.32 2.28
2.09 1.29 1.78
—
—
—
1.47 1.26
1.58 1.49
1.69 1.52
15
3.42 5.8
>100 36.8
7.64 2.84 3.19 2.21
2.28 2.15 0.101 2.72 0.801 0.36
1.17 1.7 1.22 1.38 0.236
Ovarian cancer
—
IGROV1
OVCARꢀ3
>100
63.9
6.98 7.4
4.11 5.52 3.48 1.97 1.63
2.56 2.13 1.86
Nonꢀsmall cell lung cancer
A549/ATCC
EKVX
HOPꢀ62
7.36
3.35
>100 28.2
7.35
>100 24.6
>100 11.7
1.75 11.2
8.52 5.18 3.57 3.5
3.03
Ovarian cancer
2.77 2.11 3.5
7.67 5.4
3.93 2.19
2.15 1.29
OVCARꢀ4
OVCARꢀ5
OVCARꢀ8
SKꢀOVꢀ3
7.09 3.88 3.96 7.87 4.1
4.28
6.58 2.99
>100 34.6 65.1 20.7
>100 5.87 8.1
HOPꢀ92
3.67 2.94 1.29 0.261 2.53
3.66 3.23 3.13
NCIꢀH226
NCIꢀH23
NCIꢀH322M
NCIꢀH460
NCIꢀH522
8.64 5.93 4.38 2.4
5.11 3.84 2.57 1.81
>100 18.7 30.5 24.1
3.86 2.55
Renal cancer
8.03 15
4.74 4.42
8.28
3.94 4.88 2.01 2.11 1.66
768ꢀ0
A 498
10.2 29.9
0.567 3.4
2.49 1.07
>100 5.59 4.27 3.15 2.48 1.82
41.1 17.3 13.1
2.69 1.38 1.6
ACHN
CAKIꢀ1
RXFꢀ393
SN12C
TKꢀ10
UOꢀ31
>100 15.2
>100 6.59 8.29 3.14 2.01 1.35
10.1 12.7 8.19 3.52 2.03 1.27
>100 18.7 28.4 3.93 2.6 3.05
9.13 12.2 4.15 2.98
1.77 1.5 1.56
5.98 4.37 3.01 2.62
Colon cancer
COLO 205
HCCꢀ2998
HCTꢀ116
HCTꢀ15
HT 29
4.57 5.15 4.03 3.16 1.98 1.68
56.2
53.1
3.51 1.51 4.74 3.21 1.7
2.98 4.07 2.52 5.7 1.44
2.91 2.43 1.58
2.93 4.99 2.88 4.58 3.11
3.52 10.1 3.49 1.6
4.06 3.67 2.55 2.15
1.65 15
4.13 3.13 3.9
5.48 3.51 2.8
4.6
39.8
>100
Prostate cancer
KM 12
SWꢀ620
3
—
PCꢀ3
3.09 3.38 0.528 3.81 4.43 1.58
DUꢀ145
>100 6.35 70.8
6.28 3.82 2.31
CNS cancer
7.24 8.24 4.02 2.79 2.08
2.09 3.85 3.01 1.55
SFꢀ268
SFꢀ295
SFꢀ539
SNBꢀ19
SNBꢀ75
U251
>100
Breast cancer
2.88 1.6
>100 40.5 11.9
>100 19.8 8.4
MCF7
6.2
1.08 2.63 2.11 2.28 1.69
4.11 2.34 1.7
7.81 2.25 1.8
NCI/ADRꢀRES >100 9.34 4.75 3.51 2.75 2.36
MDAꢀ
MBꢀ231/A
HS 578T
>100 11.8 34.4
>100 3.78 25.7
2.49 1.93 1.44
>100 12.4 11.8 11.6
2.17 1.81
>100 22.1
7.92 4.65 2.9 1.75
2.73 2.3
1.61
2.07
—
Melanoma
6.62 3.5
MDAꢀMBꢀ435 8.06 4.71 4.15 3.22
3
LOX IMVI
MALMEꢀ3M
M14
>100 10.9
3.51 1.62
MDAꢀN
BTꢀ549
Tꢀ47D
4.26 2.89 2.54
1.42 3.08 3.65 6.39 1.73 2.27
3.66 2.35 5.41 4.27 2.72 1.6
—
0.467
3.16 4.53 5.49 5.11 2.56 2.53
>100 6.8 6.93 3.65 2.23 2.09
Note. GI50 (growth inhibition) is the concentration of compound causing 50% retardation of the cell growth rates.
1,1ꢀDicyanoꢀ2ꢀ(Nꢀmethylpyrrolꢀ2ꢀyl)ꢀ2ꢀtrifluoromethylethꢀ
ylene (2). To a solution of Nꢀmethylpyrrole (1 g) in diethyl ether
(10 mL), a solution of compound 1 (1.11 g) in diethyl ether
(5 mL) was added with stirring at room temperature. After 1 h of
stirring, the precipitate that formed was filtered off, the solvent
was evaporated in vacuo and the residue was redistilled to give
compound 2 in a yield of 1.06 g (77%), b.p. 92—93 °С (1 Torr).
1Н NMR (acetoneꢀd6), δ: 7.46 (m, 1 Н, СН); 6.97 (m, 1 Н,
СН); 6.44 (m, 1 Н, СН); 3.85 (s, 3 H, CH3). 19F NMR (aceꢀ
toneꢀd6), δ: –17.2 (s, CF3). Found (%): C, 53.39; H, 2.70;
F, 25.32. C10H6F3N3. Calculated (%): C, 53.34; H, 2.69; F, 25.31.
1,1ꢀDicyanoꢀ2ꢀ(indolꢀ3ꢀyl)ꢀ2ꢀtrifluoromethylethylene (3). To
a solution of indole (1.6 g) in benzene (20 mL), a solution of
compound 1 (2.5 g) in benzene (10 mL) was added dropwise
with stirring. The mixture was refluxed until evolution of HCl
ceased (5 h), then the solvent was removed in vacuo and
the residue was recrystallized from hexane—benzene mixture
(5 : 1) to give brownꢀcolored compound 3 (2.7 g, 75%), m.p.
127—128 °С. 1Н NMR (CD3CN), δ: 10.70 (br.s, 1 Н, NH); 8.08
(s, 1 H, CH); 7.71 (m, 2 Н, СН); 7.42 (m, 2 Н, СН). 19F NMR
(CD3CN), δ: –16.7 (s, CF3). Found (%): C, 59.55; H, 2.31;
F, 21.57. C13H6F3N3. Calculated (%): C, 59.32; H, 2.28; F, 21.67.

Cytotoxicity of trifluromethylpyrazolopyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
175
1,1ꢀDicyanoꢀ2ꢀ(2ꢀmethylindolꢀ3ꢀyl)ꢀ2ꢀtrifluoromethylethylꢀ
ene (4) was synthesized as described above for compound 3 in
a yield of 47%, m.p. 168—170 °С. 1Н NMR (acetoneꢀd6), δ:
11.50 (br.s, 1 Н, NH); 7.50 (m, 2 Н, СН); 7.24 (m, 2 Н, СН);
2.65 (s, 3 H, CH3). 19F NMR (acetoneꢀd6), δ: –17.7 (s, CF3).
Found (%): C, 61.05; H, 2.91; F, 20.77. C14H8F3N3. Calculatꢀ
ed (%): C, 61.09; H, 2.91; F, 20.73.
1,1ꢀDicyanoꢀ2ꢀ(2ꢀphenylindolꢀ3ꢀyl)ꢀ2ꢀtrifluoromethylethylꢀ
ene (5) was synthesized as described above for compound 3 in
a yield of 93%, m.p. 211—213 °С. 1Н NMR (CD3CN), δ: 10.80
(br.s, 1 Н, NH); 7.68 (m, 1 Н, СН); 7.64 (s, 5 H, СН); 7.39
(m, 3 H, СН). 19F NMR (CD3CN), δ: –17.6 (s, CF3).
Found (%): C, 67.60; H, 2.98; F, 16.94. C19H10F3N3. Calculatꢀ
ed (%): C, 67.66; H, 2.97; F, 16.91.
1,1ꢀDicyanoꢀ2ꢀ(pꢀdiethylaminophenyl)ꢀ2ꢀtrifluoromethylꢀ
ethylene (6). To a solution of N,Nꢀdiethylaniline (3.1 g) in diꢀ
ethyl ether (25 mL), a solution of compound 1 (1.9 g) in diethyl
ether (5 mL) was added dropwise with stirring at room temperaꢀ
ture. After 1 h of stirring, the precipitate that formed was filtered
off, the mother liquor was concentrated in vacuo and the residue
was recrystallized from hexane—benzene mixture (3 : 1) to give
crimsonꢀcolored compound 6 (2.4 g, 78%), m.p. 45—46 °С.
1Н NMR (acetoneꢀd6), δ: 7.72 (d, 2 Н, CH, J = 9 Hz); 7.21 (d, 2 Н,
CH, J = 9 Hz); 4.02 (q, 4 H, CH2, J = 7 Hz); 1.28 (t, 6 Н, CH3,
J = 7 Hz). 19F NMR (acetoneꢀd6), δ: 17.5 (s, CF3). Found (%):
С, 61.25; Н, 4.73; F, 19.43. С15H14F3N3. Calculated (%):
С, 61.43; Н, 4.81; F, 19.43
1,1ꢀDicyanoꢀ2ꢀ(pꢀmorpholinophenyl)ꢀ2ꢀtrifluoromethylethylꢀ
ene (7) was synthesized in accordance with the procedure deꢀ
scribed for 6 to give compound 7 (85%), crimson crystals, m.p.
143—144 °С. 1Н NMR (acetoneꢀd6) δ: 7.68 (d, 2 Н, СН, J = 9 Hz);
7.14 (d, 2 Н, СН, J = 9 Hz); 3.82 (t, 4 Н, СН2, J = 5 Hz); 3.47
(t, 4 Н, СН2, J = 5 Hz). 19F NMR (acetoneꢀd6), δ: 17.8 (s, CF3).
Found (%): С, 58.61; Н, 4.00; F, 18.51. C15H12F3N3O. Calcuꢀ
lated (%): С, 58.63; Н, 3.94; F, 18.55.
Compounds 11—17 were synthesized analogously from alkꢀ
enes 2—5, 9 and the corresponding amidines. Physicochemical
data, the 1Н and 19F NMR spectral data, and elemental analysis
data of compounds 10—17 are given in Tables 1 and 2.
4ꢀAminoꢀ3ꢀcyanoꢀ7ꢀmethylꢀ2ꢀ(Nꢀmethylpyrrolꢀ2ꢀyl)ꢀ2ꢀtriꢀ
fluoromethylꢀ2Нꢀpyrido[1,2ꢀa]pyrimidine (18). To a solution of
2ꢀaminoꢀ5ꢀmethylpyridine (0.11 g, 1 mmol), a solution of comꢀ
pound 2 (0.23 g, 1 mmol) in MeCN (5 mL) was added dropwise
at room temperature. After 8 h of stirring, the reaction mixture
was concentrated in vacuo. Purification by column chromatogꢀ
raphy (silica gel, carbon tetrachloride : acetone, 4 : 1) yielded
compound 18 (0.20 g, 59%).
Compounds 19—27 were synthesized as described above for
18 from alkenes 2, 3, 6, 7, and 9 and the corresponding amiꢀ
nopyridines. Physicochemical data, the 1Н and 19F NMR specꢀ
tral data, and elemental analysis data of compounds 18—27 are
given in Tables 1 and 2.
7ꢀAminoꢀ6ꢀcyanoꢀ5ꢀ(Nꢀmethylpyrrolꢀ2ꢀyl)ꢀ5ꢀtrifluoromethꢀ
ylꢀ4,5ꢀdihydropyrazolo[1,5ꢀа]pyrimidine (28). To a solution of
3ꢀaminopyrazole (0.08 g, 1 mmol) in diethyl ether (20 mL),
a solution of compound 2 (0.23 g, 1 mmol) in diethyl ether
(10 mL) was added dropwise at ∼20 °С. The reaction mixture
was stirred for 12 h and concentrated in vacuo. Purification of
the residue by column chromatography (silica gel, chloroꢀ
form : acetone, 3 : 1) yielded compound 28 (0.19 g, 61%).
Compounds 29—47 were synthesized as described above for
28 from alkenes 2—9 and the corresponding aminopyrazoles.
1
Physicochemical data, the Н and 19F NMR spectral data, and
elemental analysis data of compounds 28—47 are given in
Tables 1 and 2.
6ꢀAminoꢀ5ꢀcyanoꢀ3ꢀmethylꢀ4ꢀ(2ꢀthienyl)ꢀ4ꢀtrifluoromethylꢀ
1ꢀ(4ꢀtrifluoromethylphenyl)ꢀ4,7ꢀdihydroꢀ1Нꢀpyrazolo[3,4ꢀb]pyꢀ
ridine (48). To a solution of 5ꢀaminoꢀ3ꢀmethylꢀ1ꢀ(4ꢀtrifluoroꢀ
methylphenyl)pyrazole (0.24 g, 1 mmol) in MeCN (15 mL),
a solution of alkene 9 (0.23 g, 1 mmol) in MeCN (5 mL)
was added dropwise. The reaction mixture was refluxed for
20 h and then the solvent was removed in vacuo. Purification by
column chromatography (silica gel, carbon tetrachloride : aceꢀ
tone, 3 : 1) afforded compound 48 in a yield of 0.32 g (67%).
Physicochemical data, the 1Н and 19F NMR spectral
data, and elemental analysis data of compound 48 are given in
Tables 1 and 3.
2ꢀ(4ꢀAminoꢀ3,5ꢀdiisopropylphenyl)ꢀ1,1ꢀdicyanoꢀ2ꢀtrifluoꢀ
romethylethylene (8) was synthesized as described above for comꢀ
pound 6 in a yield of 75% as a red amorphous substance. 1Н NMR
(CDCl3) δ: 7.34 (s, 2 Н, СН); 4.57 (br.s, 2 Н, NH2); 2.88 (m, 2 Н,
СН); 1.31 (d, 12 Н, СН3, J = 6.5 Hz). 19F NMR (CDCl3), δ: 16.2
(s, CF3). Found (%): С, 63.41; Н, 5.65; F, 17.69. C17H18F3N3.
Calculated (%): С, 63.54; Н, 5.65; F, 17.74.
1,1ꢀDicyanoꢀ2ꢀ(2ꢀthienyl)ꢀ2ꢀtrifluoromethylethylene (9). To
a solution of 2ꢀtrifluoroacetylthiophene (1.27 g) in benzene
(1 mL), a solution of malononitrile (0.47 g) in benzene (10 mL),
glacial acetic acid and piperidine (3 drops of each) were
added with stirring. The reaction mixture was refluxed for 5 h,
the solvent was removed in vacuo and the residue was disꢀ
tilled to give compound 9 in a yield of 1.1 g (68%) as yellow
oil, b.p. 64—65 °С (2.5 Torr). 1Н NMR (CDCl3) δ: 7.95 (br.s,
1 Н, CH); 7.94 (br.s, 1 Н, CH); 7.31 (t, 1 Н, CH, J = 5 Hz).
19F NMR (CDCl3), δ: 17.98 (s, CF3). Found (%): С, 47.35,
H, 1.35, N, 12.27. C9H3F3N2S. Calculated (%): С, 47.37, H, 1.33,
N, 12.28.
6ꢀAminoꢀ5ꢀcyanoꢀ2ꢀmethylꢀ4ꢀ(Nꢀmethylpyrrolꢀ2ꢀyl)ꢀ4ꢀtriꢀ
fluoromethylꢀ1,4ꢀdihydropyrimidine (10). To a solution of acetꢀ
amide (0.06 g, 1 mmol) in MeCN (7 mL), a solution of comꢀ
pound 2 (0.23 g, 1 mmol) in MeCN (5 mL) was added at ∼20 °С.
The reaction mixture was stirred for 8 h, the precipitate that
formed was filtered off and recrystallized from diethyl ether to
give compound 10 in a yield of 0.12 g (48%).
6ꢀAminoꢀ1ꢀ(3ꢀchlorophenyl)ꢀ5ꢀcyanoꢀ3ꢀmethylꢀ4ꢀ(Nꢀmethꢀ
ylpyrrolꢀ2ꢀyl)ꢀ4ꢀtrifluoromethylꢀ1,4ꢀdihydropyrano[2,3ꢀс]pyroꢀ
zole (49). To a solution of 5ꢀmethylꢀ2,3ꢀdihydropyrazolone
(0.12 g, 1 mmol), a solution of alkene 2 (0.23 g, 1 mmol) in
anhydrous MeCN (10 ml) was added dropwise. The reaction
mixture was refluxed for 36 h, solvent was removed in vacuo.
Purification of the residue by column chromatography (silica
gel, ethyl acetate : hexanes, 3 : 1) afforded compound 49 in a yield
of 0.29 g (83%).
Compounds 50—54 were synthesized as described above for
49 from alkenes 2, 3, 9 and the corresponding 5ꢀmethylꢀ2,3ꢀ
dihydropyrazolones. Physicochemical data, the 1Н and 19F NMR
spectral data, and elemental analysis data of compounds 49—54
are given in Tables 1 and 3.
2ꢀAminoꢀ1ꢀ(3ꢀchlorophenyl)ꢀ3ꢀcyanoꢀ6ꢀmethylꢀ4ꢀ(Nꢀmethꢀ
ylpyrrolꢀ2ꢀyl)ꢀ4ꢀtrifluoromethylꢀ1,4ꢀdihydropyridine (55). A soꢀ
lution of compound 2 (0.23 g, 1 mmol) and 3ꢀchloroaniline
(0.13 g, 1 mmol) in acetone (4 mL) was stirred for 10 h. The
solvent was removed in vacuo. Purification of the residue by

176
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Pavlova et al.
column chromatography (silica gel, carbon tetrachloride : aceꢀ
tone, 5 : 1) yielded compound 55 (0.25 g, 40%).
ours Co., WO Pat., 1996, 97, 11057 [Chem. Abstr., 1997, 126,
305586f].
Compounds 56—60 were synthesized as described above for
55 from alkenes 2, 3 and the corresponding anilines. Physicoꢀ
chemical data, the 1Н and 19F NMR spectral data and elemental
analysis data of compounds 55—60 are given in Tables 1 and 4.
2ꢀAminoꢀ1ꢀ(3ꢀchlorophenyl)ꢀ3ꢀcyanoꢀ6ꢀmethylꢀ4ꢀ(2ꢀthieꢀ
nyl)ꢀ4ꢀtrifluoromethylꢀ1,4ꢀdihydropyridine (61). A solution of
3,4ꢀdimethylaniline (0.05 g) and pꢀtoluenesulfonic acid (0.01 g)
in a mixture of benzene (20 mL) and acetone (2 mL) was reꢀ
fluxed with azeotropic distillation for 1 h, then alkene 9 (0.09 g,
0.4 mmol) was added. After stirring for 8 h, the solvent was
removed in vacuo. Purification of the residue by column chroꢀ
matography (silica gel, carbon tetrachloride : acetone, 6 : 1) afꢀ
forded compound 61 in a yield of 0.06 g (43%). Physicochemical
data, the 1Н and 19F NMR spectral data, and elemental analysis
data of compound 61 are given in Tables 1 and 4.
6. A. M. Thayer, Chem. Eng. News., 2006, 84, 15.
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Received October 19, 2009