Synthesis of novel pyrazolo[3,4-d][1,2,3]Triazines

Article abstract of DOI:10.1007/s10593-014-1503-6

Studies have been conducted of the reactions of 7-phenyl-3,7-dihydro-4H- pyrazolo[3,4-d]-[1,2,3]triazin-4-one with alkyl halides and formaldehyde, that occurred with retention of the pyrazolotriazine structure. Ethyl 2-(4-oxo-7-phenyl-4,7-dihydro-3H-pyrazolo[3,4-d][1,2,3]triazin-3-yl)-acetate was prepared by the reaction of 7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3] triazin-4-one with ethyl chloroacetate. It was used to synthesize the corresponding hydrazide with the aim of introducing the pyrazole or 1,3,4-oxadiazole fragments in the side chain of a bicyclic system.

Full text of DOI:10.1007/s10593-014-1503-6

Chemistry of Heterocyclic Compounds, Vol. 50, No. 4, July, 2014 (Russian Original Vol. 50, No. 4, April, 2014)
SYNTHESIS OF NOVEL PYRAZOLO[3,4-d][1,2,3]TRIAZINES
A. O. Gurenko1, B. M. Khutova1, S. V. Klyuchko1,
A. N. Vasilenko1, and V. S. Brovarets1*
Studies have been conducted of the reactions of 7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d]-
[1,2,3]triazin-4-one with alkyl halides and formaldehyde, that occurred with retention of the
pyrazolotriazine structure. Ethyl 2-(4-oxo-7-phenyl-4,7-dihydro-3H-pyrazolo[3,4-d][1,2,3]triazin-3-yl)-
acetate was prepared by the reaction of 7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one
with ethyl chloroacetate. It was used to synthesize the corresponding hydrazide with the aim of
introducing the pyrazole or 1,3,4-oxadiazole fragments in the side chain of a bicyclic system.
Keywords: hydrazide, 1,3,4-oxadiazole, pyrazole, pyrazolotriazine, alkylation.
Azole-annelated 1,2,3-triazines have attracted attention due to their structural similarity to purine bases.
Hence they can be efficient antiviral and antitumor agents. Several azole-annelated 1,2,3-triazines are already
used as herbicides or pesticides and as medicinal compounds [1-5]. Inhibitors of protoporphyrinogen oxidase
[6], antispasmodic medications [2], diuretics [7], and compounds which can be used in the prevention or relief
of ischemia and gout [8] are known amongst pyrazolo[3,4-d][1,2,3]triazines. 7-Aryl-3,7-dihydro-4H-pyr-
azolo[3,4-d][1,2,3]triazin-4-ones are promising precursors of such compounds. It has previously been shown
that several such reactions of these compounds are accompanied by opening of the triazine ring with the
evolution of a molecule of nitrogen and the formation of pyrazole derivatives [9-11]. None the less reactions
with preservation of the pyrazolotriazine system are also of value and these have not been studied up to our
investigations.
Our work related to the alkylation of 3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-ones. It is known
that the alkylation of their analogs, 3,4-dihydro-1,2,3-benzotriazin-4-ones, gives N-2-, N-3-, and O-alkyl
products or their mixture depending on the reagents used and the reaction conditions [12-15]. We first have
studied the alkylation of the 7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (1). Formation of the
five products A-E might be expected.
O
OAlk
O
O
O
Alk
N
N
N
N
N
N
N
N
N
N
N
N
Alk N
N
N
N+
N
N
N
N
N
N
N
N
Alk
N
Ph
Ph
Ph
Ph
Ph
Alk
A
B
C
D
E
_______
*To whom correspondence should be addressed, e-mail: brovarets@bpci.kiev.ua.
1Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, 1
Murmanska St., Kyiv 02660, Ukraine.
____________________________________________________________________________________________________________________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 577-585, April, 2014. Original
article submitted January 27, 2014.
528
0009-3122/14/5004-0528©2014 Springer Science+Business Media New York

In fact, it was found that compound 1 is alkylated regioselectively at the N-3 atom of the triazine
fragment under mild conditions (K2CO3, DMF, 20-25C) to give the 3-alkyl-3,7-dihydro-4H-pyrazolo[3,4-d]-
[1,2,3]triazin-4-ones 2a-c in 70-91% yield. The reaction of the pyrazolotriazine 1 with bromochloromethane
does not stop at the monoalkylation stage but finishes with the formation of 3,3'-methylenebis(7-phenyl-3,7-di-
hydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one) (3) in 67% yield.
O
RCH2Hal
K2CO3, DMF
N
N
R
N
20–25°C, 12 h
O
N
N
N
Ph
2a–c
NH
N
N
N
O
O
N
BrCH2Cl
K2CO3, DMF
Ph
1
N
N
N
N
N
40–50°C, 4 h
N
N
N
N
Ph
a R = Me, b R = Ph, c R = COOEt
Ph
3
The composition and structure of compounds 2a-c, 3 were confirmed by elemental analysis (Table 1)
and from spectroscopic data (Table 2). Hence the IR spectra of these compounds show the presence of
absorption bands for a C=O group at 1708-1729 cm-1 and so does not agree with the participation of the oxygen
atom in the alkylation reaction (i.e., the formation of structure A).
Unambiguous exclusion of structures C and E and a final choice of structure B could only be made
using a complex NMR analysis of one of the products of the alkylation of compound 1 (the 3-benzyl-7-phenyl-
3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (2b)). The results of the 1H and 13C NMR signal
assignments are given in Figure 1 and the full correlation listing in Table 3.
Cross peaks in the NOESY spectra of compound 2b (5.64↔7.37) and also in the HMBC spectra
(5.64↔152.9, 5.64↔128.3, 8.62↔107.6, 8.62↔148.1) identified the structure of this compound. It should be
13
noted that the signal at 135.9 ppm in the C NMR spectrum of compound 2b decreases with time and a signal
appears at 135.1 ppm; moreover the intensity of the signal at 8.62 ppm in the 1H NMR spectrum corresponding
to the H-5 proton also decreases. This may be due to exchange of the proton by the solvent deuterium.
O
N
O
N
CH2O, H2O
SOCl2, CH2Cl2
20–25°C, 20 h
N
N
OH
N
N
Cl
1
N
N
, 3 h
N
N
Ph
Ph
4
5
N
O
a R =
b R =
R
O
N
RSH, K2CO3, DMF
20–25°C, 19 h
N
N
S
N
N
N
N
N
Ph
Me
6a,b
529

TABLE 1. Physicochemical Characteristics of the Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp*, °С
Yield, %
C
H
N
S
2а
2b
2с
3
C12H11N5O
C17H13N5O
C14H13N5O3
C21H14N10O2
C11H9N5O2
C11H8ClN5O
C18H12N6O2S
59.55
59.74
4.76
4.60
28.85
29.03
―
―
―
―
―
―
93-94
85
70
91
67
79
83
86
67.12
4.10
22.88
154-156
125-128
250-252
142-145
180-181
142-144
67.32
4.32
23.09
56.64
56.18
4.52
4.38
22.34
23.40
57.38
3.41
32.06
57.53
3.22
31.95
4
54.38
54.32
3.63
3.73
28.64
28.79
5*2
50.61
3.02
26.54
50.49
3.08
26.76
6а
57.18
57.44
2.91
3.21
22.00
22.33
8.58
8.52
9.51
9.42
―
6b
C14H12N8OS
49.19
49.40
3.28
3.55
32.97
32.92
195-197
94
7а
7b
8
C13H14N6O
C16H18N6O
C12H11N7O2
C17H17N7O3
C17H15N7O2
C13H9N7O2S
C15H13N7O2S
57.50
57.77
5.21
5.22
31.14
31.09
94-96
62
64
85
77
38
76
52
62.05
6.01
26.97
―
―
―
―
128-130
234-236
227-229
241-243
221-223
120-121
61.92
5.85
27.08
50.50
50.53
3.71
3.89
34.47
34.37
9
55.31
4.82
26.50
55.58
4.66
26.69
10
11
12
58.07
58.45
4.13
4.33
27.86
28.07
47.76
2.58
29.51
10.04
9.80
47.70
2.77
29.95
50.53
50.70
3.75
3.69
27.25
27.59
8.84
9.02
_______
*Solvents for the recrystallization: petroleum ether (70-100C fraction, compounds 2a-c),
MeCN (compounds 3, 4, 7a,b), CCl4 (compounds 5, 12), EtOAc (compounds 6a,b),
dioxane (compounds 8, 9, 10).
*2Found, %: Cl 13.77. Calculated, %: Cl 13.55.
In contrast to compound 1 [9-11], the products 2a-c and 3 are stable, are unchanged with prolonged
refluxing in alcohol or dioxane, and do not react with thionyl chloride. We have also obtained other products of
the N-alkylation of the pyrazolo[3,4-d][1,2,3]triazin-4-one 1 which were used for the synthesis of novel
pyrazolotriazines. Thus, refluxing compound 1 with excess 37% aqueous formaldehyde solution gave the
3-hydroxymethyl-7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (4) which yields the chloro-
methyl derivative 5 when treated with thionyl chloride.
3-Chloromethyl-7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (5) was used by us in the
preparation of the products 6a,b via a nucleophilic substitution of the chlorine for heterocyclic thiols. The
reaction was carried out at room temperature in DMF in the presence of K2CO3. It should be noted that the
chlorine atom could not be substituted by an N-nucleophilic fragment. According to chromato-mass
spectrometry of the reaction mixture, a complex mixture of products is formed which could not be separated.
Hence to introduce aminomethyl fragments, we carried out the reaction of the pyrazolotriazine 1 with secondary
amines (dimethylamine and piperidine) in the presence of an excess of 37% aqueous formaldehyde solution to
give the 3-aminomethyl-7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-ones 7a,b in 62-64% yield.
530

O
NR1R2
CH2O, R1R2NH
20–25°C, 12 h
N
N
N
1
a R1R2N = Me2N,
b R1R2N = (CH2)5N
N
N
Ph
7a,b
TABLE 2. 1H NMR Spectra of the Compounds Synthesized
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
2а
1.38 (3H, t, J = 6.9, NCH2СH3); 4.46 (2H, q, J = 6.9, NCH2CH3); 7.50 (1H, t, J = 7.6, H Ph);
7.65 (2H, t, J = 7.6, H Ph); 8.10 (2H, d, J = 7.6, H Ph); 8.62 (1Н, s, Н-5)
2b
2c
5.64 (2H, s, CH2); 7.24-8.06 (10H, m, H Ph); 8.62 (1H, s, H-5)
1.22 (3H, t, J = 7.2, ОСH2СH3); 4.22 (2H, q, J = 7.2, ОСH2СH3); 5.35 (2H, s, NCH2);
7.05 (1H, t, J = 7.4, H Ph); 7.16 (2H, t, J = 7.4, H Ph); 8.07 (2Н, d, J = 7.4, H Ph);
8.74 (1H, s, H-5)
3
4
5
7.04 (2H, s, CH2); 7.54 (2H, t, J = 7.2, H Ph); 7.65 (4H, t, J = 7.2, H Ph);
8.02 (4H, d, J = 7.2, H Ph); 8.71 (2H, s, H-5,5')
5.88 (2H, s, CH2); 7.05 (1H, br. s, ОH); 7.55 (1H, t, J = 7.2, H Ph);
7.67 (2H, t, J = 7.2, H Ph); 8.03 (2H, d, J = 7.2, H Ph); 8.64 (1H, s, H-5)
6.35 (2H, s, CH2); 7.56 (1H, t, J = 7.4, H Ph); 7.82 (2H, t, J = 7.4, H Ph);
8.10 (2H, d, J = 7.4, H Ph); 8.76 (1H, s, H-5)
6a
6b
6.36 (2H, s, CH2); 7.38-8.01 (9H, m, H Ar, H Ph); 8.71 (1H, s, H-5)
3.63 (3H, s, NCH3); 5.91 (2H, s, CH2); 7.54 (1H, t, J = 7.4, H Ph);
7.66 (2H, t, J = 7.4, H Ph); 8.01 (2H, d, J = 7.4, H Ph); 8.68 (1H, s) and
8.72 (1H, s, H-5, Н-5 triazole)
7а
7b
8
2.36 (6H, s, N(CH3)2); 5.31 (2H, s, CH2); 7.53 (1H, t, J = 7.3, H Ph);
7.66 (2H, t, J = 7.3, H Ph); 8.06 (2H, d, J = 7.3, H Ph); 8.66 (1H, s, H-5)
1.31-2.63 (10H, m, (CH2)5 piperidine); 5.33 (2H, s, NCH2); 7.53 (1H, t, J = 7.2, H Ph);
7.66 (2H, t, J = 7.2, H Ph); 8.09 (2H, d, J = 7.2, H Ph); 8.66 (1H, s, H-5)
4.33 (2H, br. s, NH2); 5.06 (2H, s, CH2); 7.53 (1H, t, J = 7.2, H Ph);
7.65 (2H, t, J = 7.2, H Ph); 8.04 (2H, d, J = 7.2, H Ph); 8.67 (1H, s, H-5);
9.41 (1H, br. s, NH)
9
1.76 (3H, s, CH3); 1.95 (3H, s, CH3); 2.87 (1H, d, J = 18.1) and
2.98 (1H, d, J = 18.1, 4-CH2 pyrazoline); 5.45 (2H, s, NCH2); 6.57 (1H, s, ОH);
7.54 (1H, t, J = 7.3, H Ph); 7.67 (2H, t, J = 7.3, H Ph); 8.08 (2H, d, J = 7.3, H Ph);
8.70 (1H, s, H-5)
10
2.28 (3H, s, CH3); 2.46 (3H, s, CH3); 6.04 (2H, s, CH2); 6.35 (1H, s, H-4 pyrazole);
7.56 (1H, t, J = 7.3, H Ph); 7.69 (2H, t, J = 7.3, H Ph); 8.09 (2H, d, J = 7.3, H Ph);
8.75 (1H, s, H-5)
11
12
5.80 (2H, s, CH2); 7.55 (1H, t, J = 7.4, H Ph); 7.65 (2H, t, J = 7.4, H Ph);
8.03 (2H, d, J = 7.4, H Ph); 8.72 (1H, s, H-5); 14.48 (1H, br. s, SH)
1.38 (3H, t, J = 7.6, SCH2CH3); 3.24 (2H, q, J = 7.6, SCH2СН3); 5.94 (2H, s, NCH2);
7.56 (1H, t, J = 7.3, H Ph); 7.67 (2H, t, J = 7.3, H Ph); 8.05 (2H, d, J = 7.3, H Ph);
8.72 (1H, s, H-5)
5.64
52.7
7.37
H128.3
O
8.62
135.9
H
H
H
152.9
7.34
H
H
129.0
N
136.5
107.6
N
N
N
7.28
128.2
148.1
N
8.03
122.9
H
137.7
7.62
129.9
H
HMBC
7.49
128.7
H
NOESY
Fig. 1. Basic correlations and signal assignments (ppm) in the 1H and 13C NMR spectra of compound 2b.
531

TABLE 3. Correlations Found in the COSY, NOESY, HSQC, and HMBC
Spectra of Compound 2b*
1H signals,
δ, ppm
1H signals, δ, ppm
COSY NOESY
13С signals, δ, ppm
HSQC
HMBC
5.64
7.28
7.34
7.37
7.49
7.62
8.03
8.62
7.37
7.34
7.37
7.34
52.7
152.9; 136.5; 128.3
128.3
128.2
129.0
128.3
128.7
129.9
122.9
135.9
7.37; 7.28
7.34; 5.64
7.62
8.03; 7.49
7.62
7.37; 7.28
7.34; 5.64
7.62
8.03; 7.49
7.62
136.5; 129.0
128.3; 128.2
122.9
137.7; 129.9
128.7; 122.9
148.1; 107.6
—
—
_______
*For signal assignments, see Fig 1.
1
The H NMR spectra of compounds 4-7 showed signals for the methylene protons in the range
5.31-6.36 ppm and also singlet signals for the H-5 proton at 8.64-8.76 ppm.
The ethyl 2-(4-oxo-7-phenyl-4,7-dihydro-3H-pyrazolo[3,4-d][1,2,3]triazin-3-yl)acetate (2c) is of
particular interest amongst the N-alkylated pyrazolotriazine derivatives because of the presence of the ester
group which allows modification of the structure of this compound.
Pyrazolotriazine 2c reacts readily with hydrazine hydrate to form the 2-(4-oxo-7-phenyl-4,7-dihydro-
3H-pyrazolo[3,4-d][1,2,3]triazin-3-yl)acetohydrazide (8) in 85% yield. With acetylacetone the latter initially
forms compound 9 with a pyrazoline ring and this loses a molecule of water when heated to form the pyrazole
derivative 10. We have used the reaction of hydrazide 8 with carbon disulfide to prepare the pyrazolotriazine 11
OH
Me
O
N
O
Me
Me
Me
N
N
N
N
EtOH
N
N
N
N
N
N
O
O
, 16 h
N
N
N
Ph
Ph
10
9
MeCOCH2COMe 20–25°C
EtOH 17 h
O
H
N
N2H4, H2O
N
N
NH2
N
2c
20–25°C
17 h
O
N
N
Ph
8
20–25°C
24 h
CS2, Et3N
MeCN
O
O
EtBr, K2CO3
DMF
O
O
N
N
SH
SEt
N
N
20–25°C
16 h
N
N
N
N
N
N
N
N
N
N
Ph
Ph
12
11
532

which contains a (5-sulfanyl-1,3,4-oxadiazol-2-yl)methyl fragment at the N-3 atom. The cyclization of
compound 8 is supported by the disappearance in the IR spectra of the NHNH2 group absorption at 3323 and
3170 cm-1 and the appearance of a weak SH group stretching absorption at 2738 cm-1. In the 1H NMR spectra of
compounds 9-11, the signals for the protons of the NHNH2 fragment at 4.33 and 9.41 ppm (characteristic of the
hydrazide 8) are absent and there are found two methyl group proton signals (compounds 9 and 10) and an SH
group proton signal as a broad singlet at 14.48 ppm (compound 11). The 1H NMR spectra of compound 9 show
two unsymmetrical AB type system doublets for the 4-CH2 methylene protons of the dihydropyrazole ring
(Table 2), the overall intensity of which amounts to two protons. The signal at 6.57 ppm corresponds to the
hydroxyl group and disappears upon addition of D2O. The signals for the 4-CH2 and OH groups of the
dihydropyrazole ring disappear upon transformation of compound 9 to pyrazole 10, and a singlet signal at 6.35
ppm for the H-4 proton of the pyrazole ring appears. Alkylation of oxadiazole 11 using ethyl bromide in DMF
in the presence of K2CO3 at 20-25ºC gave the 3-[(5-ethylsulfanyl-1,3,4-oxadiazol-2-yl)methyl-7-phenyl-3,7-di-
1
hydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (12) in 52% yield. The H NMR spectrum of compound 12 is
reported in Table 2 and agrees with its structure.
Thus, we have shown that the reaction of 7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one
with alkylating agents, formaldehyde, and formaldehyde in the presence of secondary amines occurs with the
retention of the bicyclic structure. Modification of the compounds prepared has led to potentially biologically
active compounds.
EXPERIMENTAL
1
IR spectra were recorded on a Vertex 70 spectrometer for KBr pellets. H and 13C NMR spectra were
recorded on a Bruker Avance DRX-500 instrument (500 and 125 MHz, respectively) using DMSO-d6 with TMS
as internal standard. Chromato-mass spectra were recorded using an Agilent 1100 series diode array with an
Agilent LC/MSD SL mass selective detector. The chromato-mass spectrometric parameters were: Zorbax SB-
C18 column 4.6×15 mm, 1.8 m; solvent systems A) MeCN–H2O, 95:5, 0.1% CF3COOH, B) 0.1% aqueous
CF3COOH; flow rate 3 ml/min; injection volume 1 l; UV detectors 215, 254, 285 nm; atmospheric pressure
chemical ionization. Elemental analysis was carried out in the analytical laboratories of the Institute of
Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine. The carbon and
hydrogen content was determined by the Pregl gravimetric method, nitrogen by the Dumas gasometric
micromethod, and sulfur and chlorine by Schöniger titrimetry [16]. Melting points were measured on a Fisher–
Johns apparatus. Monitoring of the reaction course and the purity of the products was carried out by TLC on
Silufol UV-254 plates using the system CHCl3MeOH (50:1).
The starting 7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (1) was prepared using
method [10] and the 1,3-benzoxazole-2-thiol by method [17]. The 4-methyl-4H-1,2,4-triazole-3-thiol was a
commercial reagent from Aldrich.
Alkylation of 7-Phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (1) (General Method).
A mixture of compound 1 (1.28 g, 6 mmol), K2CO3 (2.49 g, 18 mmol), and EtI, PhCH2Cl, or ClCH2COOEt (24
mmol) in DMF (10 ml) was stirred at 20-25C for 12 h. The mixture was poured onto ice, and the precipitate
formed was filtered off, washed with water (20 ml), dried in air, and purified by recrystallization to give
compounds 2a-c.
3-Ethyl-7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (2a). IR spectrum, ν, cm-1:
13
3113, 2976, 1708 (С=О), 1599, 1549, 1502, 1458, 1422, 1308, 1000. С NMR spectrum, δ, ppm: 14.3 (CH3);
44.8 (CH2); 107.2 (C-4 pyrazole); 122.4; 128.4; 129.6; 135.5; 137.5; 148.0; 152.5. Mass spectrum, m/z: 242
[М+H]+.
3-Benzyl-7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (2b). IR spectrum, ν, cm-1:
3136, 2965, 1712 (С=О), 1550, 1458, 1423, 1047. Mass spectrum, m/z: 304 [М+H]+.
533

Ethyl 2-(4-Oxo-7-phenyl-4,7-dihydro-3H-pyrazolo[3,4-d][1,2,3]triazin-3-yl)acetate (2c). IR
spectrum, ν, cm-1: 3119, 3003, 1715 (2С=О, broad band with a shoulder), 1549, 1501, 1423, 1376, 1237, 1066.
Mass spectrum, m/z: 300 [M+Н]+.
3,3'-Methylenebis(7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one) (3). A mixture of
compound 1 (1.07 g, 5 mmol) and K2CO3 (1.52 g, 11 mmol) in DMF (10 ml) was stirred at 20-25C for 10 min
until a solution was formed, and BrCH2Cl (0.65 g, 5 mmol) was added dropwise. The mixture was stirred at
40-50C for 4 h and cooled to 20-25C. The product was poured onto ice, and the precipitate formed was
washed with water (30 ml), dried in air, and purified by recrystallization. IR spectrum, ν, cm-1: 3120, 1729
(2С=О, broad band with a shoulder), 1552, 1499, 1425, 1238, 1169. Mass spectrum, m/z: 439 [M+H]+.
3-Hydroxymethyl-7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (4). A mixture of
compound 1 (1.07 g, 5 mmol), 37% aqueous formaldehyde solution (10 ml, 137 mmol), and water (20 ml) was
refluxed for 3 h, cooled to 20-25C, and the precipitate formed was filtered off, dried in air, and purified by
recrystallization. IR spectrum, ν, cm-1: 3432 (ОН, broad band), 3108, 2970, 1694 (2С=О, broad band), 1548,
1495, 1426, 1080. 13С NMR spectrum, δ, ppm: 72.0 (СН2); 107.4 (С-4 pyrazole); 122.7; 128.5; 129.7; 135.8;
137.4; 147.9; 152.6. Mass spectrum, m/z: 244 [М+H]+.
3-Chloromethyl-7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (5). SOCl2 (10 ml)
was added to a suspension of compound 4 (2.43 g, 10 mmol) in CH2Cl2 (30 ml). The mixture was stirred at
20-25C for 20 h, and the solution formed was evaporated to dryness. The residue was crystallized from
petroleum ether (70-100C fraction). IR spectrum, ν, cm-1: 3101, 3063, 1717 (С=О), 1549, 1494, 1425, 1250,
1059.
Reaction of 3-Chloromethyl-7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (5) with
Thiols (General Method). A mixture of compound 5 (3.92 g, 15 mmol), K2CO3 (2.76 g, 20 mmol), and
1,3-benzoxazole-2-thiol (3.02 g, 20 mmol) or 4-methyl-4H-1,2,4-triazole-3-thiol (2.30 g, 20 mmol) in DMF
(5 ml) was stirred at 20-25C for 19 h. The mixture was poured onto ice, and the precipitate formed was filtered
off, washed with water (20 ml), dried in air, and purified by recrystallization to give compounds 6a,b.
3-[(1,3-Benzoxazol-2-ylsulfanyl)methyl]-7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one
(6a). IR spectrum, ν, cm-1: 3099, 3031, 1717 (С=О), 1548, 1501, 1451, 1424, 1134, 1060. Mass spectrum, m/z:
377 [M+Н]+.
3-{[(4-Methyl-4H-1,2,4-triazol-3-yl)sulfanyl]methyl}-7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]-
triazin-4-one (6b). IR spectrum, ν, cm-1: 3120, 3012, 1703 (C=O), 1502, 1427, 1241, 1001. Mass spectrum,
m/z: 341 [M+Н]+.
Reaction of 7-Phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (1) with Formaldehyde
in the Presence of Secondary Amines (General Method). An 37% aqueous solution of formaldehyde (15 ml)
was added dropwise to a mixture of compound 1 (2.13 g, 10 mmol) and piperidine or an 33% aqueous solution
of Me2NH (10 mmol) in water (15 ml) at 20-25C. The mixture was stirred for 12 h, and the precipitate was
filtered off, washed with water, dried in air, and recrystallized to give compounds 7a,b.
3-[(Dimethylamino)methyl]-7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (7a). IR
spectrum, ν, cm-1: 3103, 2946, 2835, 2791, 1709 (С=О, broad band with a shoulder), 1551, 1503, 1436, 1189,
1054.
7-Phenyl-3-(piperidin-1-ylmethyl)-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (7b). IR
spectrum, ν, cm-1: 3099, 3001, 2878, 2800, 1705 (С=О, broad band with a shoulder), 1545, 1501, 1415, 1148,
1030.
2-(4-Oxo-7-phenyl-4,7-dihydro-3H-pyrazolo[3,4-d][1,2,3]triazin-3-yl)acetohydrazide (8). A mixture
of compound 2c (2.01 g, 6.7 mmol) and hydrazine hydrate (4.00 g, 80 mmol) in water (16 ml) was stirred at
20-25C for 17 h. The precipitate was filtered off, dried in air, and purified by recrystallization. IR spectrum, ν,
cm-1: 3323, 3170 (NH, NH2), 3113, 2998, 1715 (С=О, broad band with a shoulder), 1599, 1551, 1500, 1255,
1096. Mass spectrum, m/z: 286 [М+H]+.
534

3-[2-(5-Hydroxy-3,5-dimethyl-4,5-dihydro-1H-pyrazol-1-yl)-2-oxoethyl]-7-phenyl-3,7-dihydro-4H-
pyrazolo[3,4-d][1,2,3]triazin-4-one (9). A mixture of hydrazide 8 (0.40 g, 1.4 mmol) and acetylacetone
(0.39 g, 3.9 mmol) in EtOH (5 ml) was held at 20-25C for 17 h. The solvent was evaporated under reduced
pressure, and the residue was purified by recrystallization. IR spectrum, ν, cm-1: 3446 (ОН, broad band), 3112,
2923, 1710 (С=О), 1668 (С=О), 1596, 1548, 1501, 1461, 1378, 1301, 1274, 1119, 1074. 13С NMR spectrum, δ,
ppm: 16.0 (CH3); 25.8 (CH3); 51.8 (CH2); 52.1 (СН2); 90.8 (С–ОН); 107.0; 122.7; 128.6; 129.7; 135.7; 137.4;
147.9; 152.7; 156.6; 163.0. Mass spectrum, m/z: 386 [М-1]-.
3-[2-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]-
triazin-4-one (10). A solution of compound (9) (0.29 g, 1 mmol) in EtOH (5 ml) was refluxed for 16 h, cooled,
and the precipitate formed was filtered off and purified by recrystallization. IR spectrum, ν, cm-1: 3111, 2970,
1709, (2С=О, broad band with a shoulder), 1591, 1550, 1502, 1424, 1322, 1063. 13С NMR spectrum, δ, ppm:
13.6 (CH3); 13.7 (CH3); 52.4 (CH2); 107.0; 112.1; 122.9; 128.7; 129.7; 135.8; 137.3; 144.1; 147.8; 152.7;
153.3; 166.6. Mass spectrum, m/z: 350 [М+Н]+.
7-Phenyl-3-[(5-sulfanyl-1,3,4-oxadiazol-2-yl)methyl]-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-
4-one (11). A mixture of hydrazide 8 (0.86 g, 3 mmol), CS2 (0.53 g, 7 mmol), and Et3N (1.21 g, 12 mmol) in
absolute MeCN (10 ml) was stirred at 20-25C for 24 h. The solvent was evaporated under reduced pressure,
and the residue was treated with a mixture of H2O (10 ml) and AcOH (1 ml). The precipitate formed was filtered
off to give compound 11 in an analytically pure state. IR spectrum, ν, cm-1: 3115, 2944, 2738 (S–H), 1694
(С=О), 1547, 1492, 1428, 1259, 1168, 1049. Mass spectrum, m/z: 328 [М+Н]+.
3-[(5-Ethylsulfanyl-1,3,4-oxadiazol-2-yl)methyl]-7-phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]-
triazin-4-one (12). A mixture of compound 11 (0.49 g, 1.5 mmol), K2CO3 (0.83 g, 6.0 mmol), and EtBr (0.44 g,
4.0 mmol) in absolute DMF (5 ml) was stirred at 20-25C for 16. The mixture was poured onto ice and
extracted with CH2Cl2 (3×20 ml). Solvent was removed under reduced pressure, and the residue was purified by
recrystallization. IR spectrum, ν, cm-1: 3092, 2898, 1710 (С=О), 1535, 1502, 1413, 1240, 1152, 1038. Mass
spectrum, m/z: 356 [М+Н]+.
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