Conversions of 7-aryl-7h-pyrazolo[3,4-d]-[1,2,3]triazin-4-ols by the action of phosphorus pentoxide, pentasulfide, and oxychloride

Article abstract of DOI:10.1007/s10593-012-1128-6

The interaction of 7-aryl-7H-pyrazolo[3,4-d][1,2,3]triazin-4-ols with phosphorus pentoxide or pentasulfide leads to the formation of 6-(5-amino-1-aryl-1H-pyrazol-4-yl)-1-aryl-1H,4H-pyrazolo[3,4-d][1,3] oxazin-4-ones and 6-(5-amino-1-aryl-1H-pyrazol-4-yl)-

Full text of DOI:10.1007/s10593-012-1128-6

Chemistry of Heterocyclic Compounds, Vol. 48, No. 8, November, 2012 (Russian Original Vol. 48, No. 8, August, 2012)
CONVERSIONS OF 7-ARYL-7H-PYRAZOLO[3,4-d]-
[1,2,3]TRIAZIN-4-OLS BY THE ACTION OF PHOSPHORUS
PENTOXIDE, PENTASULFIDE, AND OXYCHLORIDE
B. M. Khutova1, S. V. Klyuchko1, A. O. Gurenko1, A. N. Vasilenko1,
A. G. Balya1, E. B. Rusanov2, and V. S. Brovarets1*
The interaction of 7-aryl-7H-pyrazolo[3,4-d][1,2,3]triazin-4-ols with phosphorus pentoxide or pentasulfide
leads to the formation of 6-(5-amino-1-aryl-1H-pyrazol-4-yl)-1-aryl-1H,4H-pyrazolo[3,4-d][1,3]oxazin-4-ones
and 6-(5-amino-1-aryl-1H-pyrazol-4-yl)-1-aryl-1H,4H-pyrazolo[3,4-d][1,3]thiazine-4-thiones, respectively.
Reaction with phosphorus oxychloride leads to 1-aryl-5-chloro-1H-pyrazole-4-carbonyl chlorides, from which
the corresponding amides, hydrazides, and substituted 1,3,4-oxadiazoles were synthesized.
Keywords: phosphorus pentoxide, phosphorus pentasulfide, phosphorus oxychloride, pyrazolooxazines,
pyrazolothiazines, pyrazolotriazines.
Multifunctional heterocycles containing a 1,2,3-triazine fragment possess a broad spectrum of biological
activity [1-4], which in its turn stimulates development of methods for the synthesis of new types of
heterocyclic systems based on them. The present work is devoted to the investigation of the synthetic
possibilities of the poorly studied 7H-pyrazolo[3,4-d][1,2,3]triazin-4-ols 2a,b, in particular products formed in
reactions of these compounds with phosphorus-containing electrophiles: phosphorus pentoxide, phosphorus
pentasulfide, and phosphorus oxychloride. Compounds 2a,b were obtained by the diazotation of 5-amino-
1-aryl-1H-pyrazole-4-carboxamides 1a,b with an aqueous solution of sodium nitrite in a mixture of acetic and
hydrochloric acids [5], or in a dilute hydrochloric acid [6, 7].
O
OH
NH2
NaNO2
H+
N
N
N
N
NH2
N
N
N
Ar
a Ar = Ph, b Ar = 4-MeC6H4
2a,b
Ar
1a,b
_______
*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.
2Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska St., Kyiv 02094,
Ukraine; e-mail: rusanov@ioch.kiev.ua.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1344-1355, August, 2012.
Original article submitted December 22, 2011.
0009-3122/12/4808-1251©2012 Springer Science+Business Media New York
1251

Heating pyrazolotriazinols 2a,b with phosphorus pentoxide in refluxing dioxane leads to the formation
of substituted pyrazolo[3,4-d][1,3]oxazin-4-ones 3a,b in 35-38% yield (Table 1). A similar reaction is known
for 3,4-dihydro-1,2,3-benzotriazinones [8, 9].
The formation of oxazines 3a,b may be represented as the result of a series of sequential processes:
elimination of a nitrogen molecule, formation of ketenes B, dimerization into intermediates C as a result of
[4+2] cycloaddition, and then prototropic isomerization.
O
O
O
C
+
O
P2O5, 
N
Dimerization
(slowly)
2a,b
_
N
N
–N2
(fast)
N
N
N
N
NH
NH
H
N
Ar
N
N
HN
Ar
B
Ar
Ar
A
C
O
N
O
N
N
N
Ar
H2N
Ar
3a,b
a Ar = Ph, b Ar = 4-MeC6H4
Phosphorus pentoxide is apparently needed in this process for the stabilization of ketenes B as a result
of the formation of type D intermediates, which slowly convert to the final products 3a,b.
O
O
C
C
.
.
.
.
.
.
.
.
.
.
O
P
O
P
N
N
.
.
N
N
N
H
N
H
O
O
O
Ar
Ar
D
The structure of compounds 3a,b was demonstrated by X-ray structural analysis and NMR
1
spectroscopy. In the H NMR spectra (Table 2) of 6-(5-amino-1-aryl-1H-pyrazol-4-yl)-1-arylpyrazolo[3,4-d]-
[1,3]oxazin-4(1H)-ones 3a,b signals were present for the aromatic protons, a broadened signal of the NH2 group
protons at 6.78-6.93 ppm, and the signals of the pyrazole fragment protons (singlets at 7.94-8.02 and 8.32-8.41
ppm). In the 13C NMR spectra of oxazine 3b there were signals of the pyrazole ring carbon nuclei, the exocyclic
C=O group (160.3 ppm), and also signals of the aliphatic and aromatic carbon nuclei.
Complex NMR analysis (NOESY, COSY, HSQC, HMBC) (Fig. 1, Table 3) was also used for
compound 3b. The signals of 2D spectroscopy NOESY 7.45 (H-2",6") ↔ 6.78 (NH2), 7.75 (H-2"',6"') ↔ 6.78
(NH2) and HMBC 7.94 (H-3') → 95.0 (C-4'), 7.94 (H-3') → 154.7 (C-5'), 8.32 (H-3) → 99.0 (C-3a), 8.32 (H-3)
→ 149.5 ppm (C-7a) were in agreement with the proposed structure.
The X-ray structural investigation of compound 3b (Fig. 2) showed that the 1,3-oxazin-6-one fragment
on the whole has geometric characteristics similar to those of previously investigated compounds containing this
ring [10, 11].
1252

The N(3)=C(4) bond length was 1.288(5) Å, which is characteristic for a standard C=N double bond. At
the same time, the N(3)–C(3) bond length was 1.360(5) Å, which is typical of conjugated aromatic systems.
Overall the values of the bond lengths and valence angles in the pyrazole rings correspond to the standard
values.
TABLE 1. Physicochemical Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield,
%
Mp*, °С
C
H
Cl
N
S
88
2a
C10H7N5O
56.61
56.34
3.38
3.31
—
32.56
32.85
—
140-142
(decomp.)
(136 (decomp.) [6])
2b
3a
3b
4a
4b
5a
C11H9N5O
58.23
58.15
64.65
64.86
66.55
66.32
59.45
59.68
3.92
3.99
3.93
3.81
4.71
4.55
3.60
3.51
4.08
4.21
2.31
2.51
—
—
—
—
—
30.93
30.82
22.43
22.69
21.13
21.09
—
—
—
144-145
221-223
236-237
84
38
35
34
36
65
C20H14N6O2
C22H18N6O2
C20H14N6S2
C22H18N6S2
20.67 16.20 254-256
20.88 15.93
19.83 15.16 283-284
19.52 14.89
61.18
61.37
C10H6Cl2N2O 50.15
49.82
29.43 11.73
29.41 11.62
—
133-134
(134 [14])
93–94
5b
6a
6b
6c
7a
7b
7c
C11H8Cl2N2O 51.98
51.79
C17H13ClN4O2 60.21
59.92
C18H15ClN4O2 61.12
60.94
C15H11ClN4O2S 52.11
51.95
C17H11ClN4O 63.48
63.26
C18H13ClN4O 63.90
64.20
C15H9ClN4OS 55.03
54.80
3.28
3.16
4.01
3.85
4.24
4.26
3.24
3.20
3.43
3.44
3.90
3.89
3.01
2.76
27.77 10.71
27.79 10.98
10.67 16.78
10.40 16.44
10.21 15.65
9.99
10.01 15.87
10.22 16.16
10.89 17.42
10.98 17.36
10.71 16.70
10.53 16.64
—
—
—
63
70
67
62
74
77
51
206–208
216–217
236-238
109-110
112-113
15.79
8.98
9.23
—
—
10.56 16.83 10.04 149-150
10.78 17.04
9.75
8
C10H9ClN4O
50.48
50.75
3.63
3.83
2.48
2.53
3.48
3.61
4.06
3.95
5.46
5.35
4.68
4.84
4.28
4.53
5.86
5.81
15.13 23.43
14.98 23.67
13.01 19.89 11.32 210-212
12.72 20.10 11.50
11.88 18.54 10.66 Oil
11.56 18.26 10.45
—
177-179
78
88
88
62
73
58
66
89
68
79
9
C11H7ClN4OS 47.08
47.40
C13H11ClN4OS 51.04
50.90
C19H15ClN4OS 59.85
59.60
C13H14ClN3O 59.39
59.21
C12H12ClN3O 57.53
57.72
C17H14ClN3O 65.18
65.49
C14H16ClN3O 60.71
60.54
C13H14ClN3O 59.48
59.21
10a
10b
11a
11b
11c
11d
11e
11f
9.56
9.26
14.97
14.63
8.49
8.37
73-75
13.72 15.66
13.44 15.93
14.03 16.98
14.20 16.83
11.18 13.18
11.37 13.48
12.98 15.07
12.76 15.13
13.61 15.68
13.44 15.93
10.80 12.78
10.88 12.90
—
—
—
—
—
—
113-114
83-84
96-99
104-105
98-99
5.58
5.35
5.07
4.95
C18H16ClN3O 66.59
66.36
181-182
_______
*Solvents for crystallization: MeCN (compounds 3a,b, 4a,b 7a-c), hexane
(compounds 5a,b, 11a,b,d), EtOH (compound 8), petroleum ether (fraction 60-
95°C, compounds 10b, 11e), C6H6 (compounds 11c,f).
1253

TABLE 2. 1H NMR Spectra of the Synthesized Compounds
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
2b
3a
2.40 (3H, s, CH3); 7.41 (2H, d, J = 6.0, H Ar); 7.90 (2H, d, J = 6.0, H Ar);
8.57 (1H, s, H-5); 15.31 (1Н, br. s, ОН)
6.93 (2H, s, NH2); 7.48 (2H, t, J = 7.5, H Ar); 7.55-7.68 (6H, m, H Ar);
7.89 (2H, d, J = 7.5, H Ar); 8.02 (1H, s, H-3'); 8.41 (1H, s, H-3)
2.38 (3H, s, CH3); 2.39 (3H, s, CH3); 6.78 (2H, s, NH2); 7.36 (2H, d, J = 7.5, H Ar);
3b
4a
4b
7.37 (2H, d, J = 7.0, H Ar); 7.45 (2H, d, J = 7.0, H Ar); 7.75 (2H, d, J = 7.5, H Ar);
7.94 (1H, s, H-3'); 8.32 (1H, s, H-3)
7.19 (2H, s, NH2); 7.49 (1H, t, J = 7.0, H Ar); 7.50 (1H, t, J = 7.6, H Ar);
7.54 (2H, d, J = 7.6, H Ar); 7.56 (2H, t, J = 7.6, H Ar); 7.58 (2H, t, J = 7.0, H Ar);
7.79 (2H, d, J = 7.0, H Ar); 8.06 (1H, s, H-3'); 8.42 (1H, s, H-3)
2.42 (6H, s, 2CH3); 7.15 (2H, s, NH2); 7.34-7.50 (6H, m, H Ar);
7.72 (2H, d, J = 7.0, H Ar); 8.10 (1H, s, H-3'); 8.49 (1H, s, H-3)
5b
6a
2.43 (3H, s, CH3); 7.31 (2H, d, J = 8.0, H Ar); 7.49 (2H, d, J = 8.0, H Ar); 8.20 (1H, s, H-3)
7.47-7.72 (8H, m, H Ar); 7.94 (2H, d, J = 6.5, H Ar); 8.38 (1H, s, H-3); 10.35 (1H, s, NH);
10.53 (1H, s, NH)
6b
6c
2.39 (3H, s, CH3); 7.41 (2H, d, J = 4.2, H Ar); 7.51-7.66 (5H, m, H Ar);
7.68-7.80 (2H, m, H Ar); 8.37 (1H, s, H-3); 10.33 (1H, s, NH); 10.46 (1H, s, NH)
7.21 (1H, t, J = 4.0, H thiophene); 7.48-7.70 (5H, m, H Ar);
7.85 (1H, d, J = 4.0, H thiophene); 7.89 (1H, d, J = 4.0, H thiophene); 8.34 (1H, s, H-3);
10.28 (1H, s, NH); 10.48 (1H, s, NH)
7a
7b
7.55-7.75 (8H, m, H Ar); 8.15 (2H, d, J = 7.6, H Ar); 8.39 (1H, s, H-3)
2.44 (3H, s, CH3); 7.48 (1H, d, J = 7.5, H Ar); 7.53 (1H, t, J = 7.5, H Ar);
7.60 (1H, t, J = 7.0, H Ar); 7.65 (2H, t, J = 7.0, H Ar); 7.69 (2H, d, J = 7.0, H Ar);
7.90 (1H, d, J = 7.5, H Ar); 7.93 (1H, br. d, J = 7.5, H Ar); 8.55 (1H, s, H-3)
7c
7.34 (1H, t, J = 4.0, H thiophene); 7.60 (1H, t, J = 7.0, H Ar); 7.64 (2H, t, J = 7.0, H Ar);
7.69 (2H, d, J = 7.0, H Ar); 7.91 (1H, d, J = 4.0, H thiophene);
7.99 (1H, d, J = 4.0, H thiophene); 8.51 (1H, s, H-3)
8
4.46 (2H, br. s, NH2); 7.49-7.62 (5H, m, H Ar); 8.19 (1H, s, H-3); 9.53 (1H, s, NH)
7.52-7.72 (5H, m, H Ar); 8.39 (1H, s, H-3); 14.70 (1H, br. s, SH)
9
10a
1.52 (3H, t, J = 8.0, CH2CH3); 3.33 (2H, q, J = 8.0, CH2CH3); 7.50-7.76 (5H, m, H Ar);
8.19 (1H, s, H-3)
2.24 (3H, s, CH3); 4.53 (2H, s, CH2); 7.15 (2H, d, J = 7.8, H Ar);
7.35 (2H, d, J = 7.8, H Ar); 7.50-7.76 (5H, m, H Ar); 8.40 (1H, s, H-3)
0.92 (3H, t, J = 7.2, CH2CH2CH3); 1.52-1.55 (2H, m, CH2CH2CH3);
3.19 (2H, q, J = 7.2, NCH2); 7.42-7.68 (5H, m, H Ar); 8.13 (1H, t, J = 7.2, NH);
8.18 (1H, s, H-3)
10b
11a
11b
11c
2.99 (3H, s, NCH3); 3.08 (3H, s, NCH3); 7.48-7.65 (5H, m, H Ar); 7.97 (1H, s, H-3)
2.28 (3H, s, CH3); 7.16 (2H, d, J = 7.8, H Ar); 7.48-7.75 (7H, m, H Ar); 8.42 (1H, s, H-3);
10.00 (1H, s, NH)
11d
0.90 (3H, t, J = 7.2, CH2CH2CH3); 1.51-1.55 (2H, m, CH2CH2CH3); 2.40 (3H, s, ArCH3);
3.19 (2H, q, J = 7.2, NCH2); 7.38 (2H, d, J = 7.6, H Ar); 7.43 (2H, d, J = 7.6, H Ar);
8.18 (1H, t, J = 7.2, NH); 8.21 (1H, s, H-3)
11e
11f
2.40 (3H, s, ArCH3); 2.99 (3H, s, NCH3); 3.07 (3H, s, NCH3); 7.38 (2H, d, J = 7.6, H Ar);
7.47 (2H, d, J = 7.6, H Ar); 7.99 (1H, s, H-3)
2.29 (3H, s, CH3); 2.42 (3H, s, CH3); 7.16 (2H, d, J = 7.8, H Ar);
7.41 (2H, d, J = 7.6, H Ar); 7.47 (2H, d, J = 7.6, H Ar); 7.60 (2H, d, J = 7.8, H Ar);
8.41 (1H, s, H-3); 9.98 (1H, s, NH)
The bicyclic N(1,2)O(1)C(1-5) fragment is planar within the limits of 0.0156(26) Å, the pyrazole ring
N(4,5)C(6-8) is practically coplanar and is twisted by merely 2.21(19)o, while the phenyl ring C(9-14) is twisted
by 28.35(12)o. The 4-methylphenyl substituent C(16)–C(22) is twisted relative to the pyrazole ring by
48.55(11)o. In the crystal both intra- (N(6)–H(1)…N(3)) and intermolecular (N(6)–H(2)…O(2)_ $1) hydrogen
bonds are formed with the following parameters: N(6)–H(1) 0.97(6), N(6)…N(3) 2.910(5), N(6)–H(1)–N(3)
125(4)o; N(6)–H(2) 1.08(7), N(6)…O(2)_$1 2.950(5), N(6)–H(2)–O(2)_$1 1.44(6)o (the symbol $1 denotes an
atom linked with the main atoms by the symmetry operation x+0.5, 1-y, z).
6-(5-Amino-1-aryl-1H-pyrazol-4-yl)-1-arylpyrazolo[3,4-d][1,3]thiazin-4(1H)-thiones 4a,b were formed
in 34-36% yield as a result of the reaction of compounds 2a,b with phosphorus pentasulfide.
1254

S
S
N
P2S5, 
2a,b
N
N
–N2
N
Ar
N
H2N
Ar
4a,b
8.32
138.3
O
H
160.3
7.94
139.5
O
100.0
H
N
N
151.2
N
7.75
149.5
N
95.0
122.7
N
H
138.0
7.45
154.7
124.1
7.36
130.3
H
H
H
N
H
137.8
H
6.78
7.37
130.4
135.4
H
H
H
H
H
135.7
H
H
2.38
21.1
H
2.39
21.1
H
H
HMBC
NOESY
1
13
Fig. 1. Main correlations and assignment of signals (ppm) in the H and C NMR spectra
of compound 3b.
Fig. 2. General view of the compound 3b molecule with atoms represented by thermal
vibration ellipsoids of 50% probability.
It may be proposed that compounds 3a,b are formed initially and are then converted by the action of
phosphorus pentasulfide into thiazines 4a,b. Similar conversions of benzoxazines into benzothiazines have been
described in the literature [12, 13]. Comparison of the 13C NMR spectra of compounds 3a,b and 4a,b
1255

TABLE 3. Correlations Found in the COSY, NOESY, HSQC, and
HMBC Spectra of Compound 3b*
1H, δ
13C, δ
1H, δ
COSY
7.37
NOESY
HSQC
HMBC
2.39
7.37
7.45
7.94
6.78
8.32
7.75
7.36
2.38
7.37
21.1
130.4
124.1
139.5
—
130.4
2.39; 7.45
7.37
—
2.39; 7.45
7.37; 6.78
7.75
21.1; 130.4; 137.8
124.1; 135.7
95.0; 151.2; 154.7
—
—
7.45; 7.75
—
—
138.3
122.7
130.3
21.1
100.0; 149.5
122.7; 135.4
21.1; 130.3; 138.0
130.3
7.36
7.75
7.36
7.36; 7.94
7.75; 2.38
7.36
_______
*For assignment of signals, see Fig. 1.
indicate the presence of C=S groups in the latter (197.7 and 194.6 ppm for compounds 4a and 4b, respectively).
In addition, NMR analysis (NOESY, COSY, HSQC, HMBC) was used for compound 4a (Fig. 3, Table 4). The
NOESY signals 7.79 (H-2",6") ↔ 7.19 (NH2) and HMBC 8.06 (H-3') → 100.9 (C-4'), 8.42 (H-3) →117.2
(C-3a), 8.42 (H-3) → 146.6 ppm (C-7a) were similar to the signals of oxazine 3b, which unequivocally proves
the structure of compounds 4a,b.
N
O
R
O
H
N
O
O
N
Cl
POCl3
DMF
O
N
H
R
R
NHNH2
SOCl2
2a,b
Et3N
(Ar = Ph)
N
Cl
5a,b
N
N
N
Cl
Cl
N
N
Ar
Ph
Ph
6a–c
7a–c
5 a Ar = Ph, b Ar = 4-MeC6H4; 6, 7 a R = Ph, b R = 3-MeC6H4, c R = 2-thienyl
8.42
137.5
S
H
197.7
8.06
139.4
S
117.2
H
N
147.8
100.9
N
7.53
124.4
146.6
N
N
H
137.5
7.79
166.6
124.2
N
7.54
130.0
H
H
H
N
137.9
H
7.19
7.58
H
129.9
H
H
H
H
7.50
128.8
H
7.49
128.5
H
HMBC
NOESY
Fig. 3. Main correlations and assignments of signals (ppm) in the 1H and 13C NMR spectra of
compound 4a.
1256

TABLE 4. Correlations Found in the COSY, NOESY, HSQC, and HMBC
Spectra of Compound 4a*
1H, δ
13C, δ
1H, δ
COSY
7.58
NOESY
HSQC
HMBC
7.49
7.58
7.79
8.06
7.19
8.42
7.53
7.54
7.50
7.58
128.5
128.9
124.2
139.4
—
124.2
7.49; 7.79
7.58
7.49; 7.79
7.58; 7.19
—
129.9; 137.9
124.2; 128.5
100.9; 147.8
100.9; 139.4
117.2; 146.6
124.4; 128.8
130.0; 137.5
124.4
—
—
7.79
—
—
137.5
124.4
130.0
128.8
7.54
7.54
7.53; 7.50
7.54
7.53; 7.50
7.54
_______
*For assignments of signals, see Fig. 3.
On interacting 7-aryl-7H-pyrazolo[3,4-d][1,2,3]triazin-4-ols 2a,b with phosphorus oxychloride, the
corresponding 4-chloro derivatives were not formed. 1-Aryl-5-chloro-1H-pyrazole-4-carbonyl chlorides 5a,b
were formed as a result of the reaction. Compound 5a was converted into compounds 6a-c and then into
1,3,4-oxadiazoles 7a-c. The physicochemical and spectral characteristics of acyl chloride 5a were identical to
those of the same product described in [14].
1
The H NMR spectra of the obtained products given in Table 2 confirmed the structures of compounds
5b, 6a-c, 7a-c. The characteristic signals of the proton at the C-3 carbon atom of the pyrazole fragment were at
8.20-8.55 ppm.
An X-ray structural investigation of compound 7a (Fig. 4) was carried out by us in order to consider the
spatial structure of 2-(5-chloro-1-phenyl-1H-pyrazol-4-yl)-5-R-1,3,4-oxadiazoles 7a-c. The 1,3,4-oxadiazole
ring has geometric characteristics usual for heterocycles with two nitrogen atoms, lying in a plane (mean
deviation of atoms from the plane was 0.0096 Å), but the distribution of bond lengths and valence angles in it
was close to the related compound investigated previously [15]. The pyrazole ring also has the structure usual
for the same type of compound [16], and is twisted relative to the oxadiazole ring by 14.9(1)o. The phenyl
substituents C(6-11) and C(12-17) are twisted relative to the pyrazole and oxadiazole heterocycles by 42.7(1)
and 6.0(2)o, respectively. In the crystal, slightly shortened intermolecular contacts were detected in the form of
endless chains along the y crystallographic axis between the atoms of chlorine Cl(1) and nitrogen N(2) at a
distance of 3.228(2) Å (this value is somewhat less than the sum of the van der Waals radii of these atoms,
which is 3.38 Å [17]). No other shortened intermolecular contacts were found in the crystal.
Fig. 4. General form of the molecule of compound 7a with atoms represented by thermal
vibration ellipsoids of 50% probability.
1257

The acyl chloride 5a interacts smoothly with hydrazine hydrate with the formation of hydrazide 8. The
latter was used by us to obtain 5-(5-chloro-1-phenyl-1H-pyrazol-4-yl)-1,3,4-oxadiazole-2-thiol (9). The
cyclization of hydrazide 8 by the action of carbon disulfide was evidenced by the disappearance from the IR
spectra of the C=O group absorption band at 1655 cm-1, of the NHNH2 fragment at 3212-3286 cm-1, and the
appearance of a weak absorption band for the stretching vibrations of the SH group at 2782 cm-1. In addition, in
1
the H NMR spectrum of oxadiazole 9 the signals of the NHNH2 fragment protons at 4.46 and 9.53 ppm,
characteristic for hydrazide 8, were absent, and a signal appeared for the SH group proton as a broadened singlet
at 14.70 ppm. Alkylation of the thio derivative 9 with ethyl iodide was carried out in DMF in the presence of
K2CO3 at 20-25°C, and alkylation with 4-methylbenzyl chloride was carried out on refluxing in EtOH in the
presence of Et3N. Compounds 10a,b were isolated in this way in 88 and 62% yield, respectively.
N
N
SH
SR
O
NH2
N
N
N
H
CS2
O
O
H2NNH2
RX
5a
Et3N
N
Cl
N
N
Cl
Cl
N
N
N
Ph
Ph
Ph
10a,b
8
9
10 a R = Et, b R = 4-MeC6H4CH2
It should be noted that similar compounds which contain a 1,3,4-oxadiazole heterocycle in the position
4 of the 5-chloro-1H-pyrazole fragment, were previously unknown. They may be of interest as biologically
active substances (see by analogy [18-20]).
Pyrazolecarboxylic acid amides 11a-f were formed on reacting 1-aryl-5-chloro-1H-pyrazole-4-carbonyl
chlorides 5a,b with amines.
R1
O
N
R2
R1R2NH
Et3N
5a,b
N
Cl
N
Ar
11a–f
11 a–c Ar = Ph, d–f Ar = 4-MeC6H4;
a, d R1 = H, R2 = n-Pr; b, e R1 = R2 = Me; c, f R1 = H, R2 = 4-MeC6H4
The composition and structure of products 8, 9, 10a,b, 11a-f were confirmed by the results of elemental
analysis (Table 1) and by spectral data (Table 2). The signal of the proton at the C-3 atom of the pyrazole
fragment at 7.97-8.42 ppm in the 1H NMR spectra was a characteristic of them.
We have therefore investigated some conversions of 7-aryl-7H-pyrazolo[3,4-d][1,2,3]triazin-4-ols under
the action of phosphorus pentoxide, pentasulfide, and oxychloride, and it has been shown that the products
formed in this way may be used to obtain various heterocyclic compounds.
EXPERIMENTAL
The IR spectra were recorded on a Vertex 70 spectrometer in KBr pellets. The 1H and 13C NMR spectra
were acquired on a Bruker Avance DRX-500 instrument (500 and 125 MHz, respectively) in DMSO-d6 solution
(compounds 2b, 3a,b, 4a,b, 6a-c, 7a-c, 8, 9, 10b, 11a-f) and CDCl3 (compounds 5b, 10a), standard was TMS.
1258

The COSY, NOESY, HSQC, and HMBC spectra were recorded using standard procedures with gradient
separation of the signal. For the NOESY spectra τmix was 500 msec, for HMBC spectra τmix was 166 msec.
Chromato-mass spectra were recorded using a liquid chromato-mass spectrometry system consisting of an
Agilent 1100 series chromatograph with a fitted diode matrix with an Agilent LC\MSD SL mass selective
detector. The parameters for chromato-mass spectrometry analysis were: column Zorbax SB-C18, 4.6×15 mm,
1.8 μm; solvents A) MeCN–H2O, 95:5, 0.1% CF3COOH, B) 0.1% aqueous CF3COOH; eluent flow rate 3
ml/min; injection volume 1 μl; UV detectors 215, 254, 285 nm; chemical ionization at atmospheric pressure.
Elemental analysis was carried out in the analytical laboratory of the Institute of Bioorganic Chemistry and
Petrochemistry of the National Academy of Sciences of Ukraine. Melting points were determined on a Fisher-
Johns instrument. A check on the progress of reactions and the purity of the synthesized compounds was
performed by TLC on Silufol UV-254 plates in a 10:1 CHCl3–MeOH system.
The spectral characteristics of compound 2a corresponded to literature values [5].
7-Aryl-7H-pyrazolo[3,4-d][1,2,3]triazin-4-ols 2a,b (General Method). A solution of NaNO2 (13.8 g,
20 mmol) in water (50 ml) was added dropwise over 40 min at -3°C to a solution of pyrazole 1a [6] or 1b [21]
(10 mmol) in conc. HCl (600 ml). The reaction mixture was stirred at the same temperature for 2 h, then at 20°C
for 10 h. The precipitated solid was filtered off, washed with H2O, EtOH, and dried. Analytically pure
compounds 2a,b were obtained, which were used for subsequent conversions without further purification.
6-(5-Amino-1-aryl-1H-pyrazol-4-yl)-1-arylpyrazolo[3,4-d][1,3]oxazin-4(1H)-ones 3a,b (General
Method). A mixture of compound 2a or 2b (10 mmol), P2O5 (2.98 g, 21 mmol) in abs. dioxane (50 ml) was
refluxed for 3 h with vigorous stirring, during which a rapid evolution of gas and resinification were observed.
The mixture was cooled to 20-25°C, the solution decanted, and the solvent removed at reduced pressure.
2-PrOH (2 ml) was added, the solid was filtered off, and purified by recrystallization.
Compound 3a. IR spectrum, , cm-1: 3456, 3343 (NH2); 1777 (C=O); 1627, 1585, 1541, 1506.
Compound 3b. 13C NMR spectrum, δ, ppm: 21.1 (2CH3); 95.0 (C-4 pyrazole); 99.0 (C-3a); 122.7,
124.1, 130.3, 130.4, 135.4, 135.7, 137.8, 138.0 (C 2Ar); 138.3 (C-3 pyrazolooxazine); 139.5 (C-3 pyrazole);
149.5 (C-7a); 151.2 (C-6 pyrazolooxazine); 154.7 (C-5 pyrazole); 160.3 (C=O). Mass spectrum, m/z (Irel, %):
397 [M-H]+ (85).
6-(5-Amino-1-aryl-1H-pyrazol-4-yl)-1-arylpyrazolo[3,4-d][1,3]thiazine-4(1H)-thiones 4a,b (General
Method). A mixture of compound 2a or 2b (2 mmol) and P2S5 (0.533 g, 2.4 mmol) in abs. dioxane (20 ml) was
refluxed for 3 h with vigorous stirring, then cooled to 20-25°C. The solution was decanted, the solvent was
removed under reduced pressure, 2-PrOH (2 ml) was added, the solid was filtered off, dried, and recrystallized.
Compound 4a. 13C NMR spectrum, δ, ppm: 100.9 (C-4 pyrazole); 117.2 (C-3a); 124.2, 124.4, 128.5,
128.8, 129.9, 130.0, 137.5, 137.9 (C 2Ph); 137.5 (C-3 pyrazolothiazine); 139.4 (C-3 pyrazole); 146.6 (C-7a);
147.8 (C-6); 166.6 (C-5 pyrazole); 197.7 (C=S). Mass spectrum, m/z (Irel, %): 402 [M]+ (100).
13
Compound 4b. IR spectrum, , cm-1; 3428, 3309 (NH2); 1604, 1551, 1512, 1478. C NMR spectrum,
δ, ppm: 21.2 (2CH3); 100.8 (C-4 pyrazole), 117.2 (C-3a); 124.0, 124.5, 130.3, 130.4, 135.1, 135.5, 138.2, 138.3
(C 2Ar); 138.3 (C-3 pyrazolothiazine); 139.1 (C-3 pyrazole); 146.5 (C-7a); 147.7 (C-6); 166.7 (C-5 pyrazole);
194.6 (C=S).
1-Aryl-5-chloro-1H-pyrazole-4-carbonyl Chlorides 5a,b (General Method). Abs. DMF (5 ml) was
added dropwise to a mixture of compound 2a or 2b (20 mmol) and POCl3 (50 ml) at a rate sufficient to boil the
mixture. The solution was then refluxed for 2 h, and the excess of POCl3 was removed at reduced pressure. The
oily residue was extracted with hot abs. benzene (700 ml). The benzene was removed at reduced pressure and
the residue was purified by recrystallization.
Compound 5b. IR spectrum, , cm-1: 1770 (C=O), 1511, 1409.
N'-Acyl-5-chloro-1-phenyl-1H-pyrazole-4-carbohydrazides 6a-c (General Method). A mixture of
compound 5a (0.482 g, 2 mmol), the hydrazide of the appropriate acid (2 mmol), and Et3N (0.202 g, 2 mmol) in
abs. EtOH (10 ml) was refluxed for 2 h. The precipitated solid was filtered off, dried, and analyzed without
further purification.
1259

13
Compound 6a. C NMR spectrum, δ, ppm: 113.4 (C-4 pyrazole); 129.8 (C-5 pyrazole); 126.2, 128.0,
129.0, 129.8, 129.9, 132.4, 133.0, 137.6 (C 2Ph); 140.4 (C-3 pyrazole); 160.5 (C=O); 166.4 (C=O). Mass
spectrum, m/z (Irel, %): 339 [M-H]+ (98).
Compound 6b. IR spectrum, , cm-1: 3212, 3008 (NHNH2), 1674 (C=O), 1640 (C=O), 1561, 1499.
5-R-2-(5-Chloro-1-phenyl-1H-pyrazol-4-yl)-1,3,4-oxadiazoles 7a-c (General Method). Compound
6a-c (1 mmol) was refluxed for 2 h with SOCl2 (5 ml). The excess of SOCl2 was removed under reduced
pressure. The residue was treated with water, the solid was filtered off, and purified by recrystallization.
Compound 7a. Mass spectrum, m/z (Irel, %): 323 [M+H]+ (97).
Compound 7b. IR spectrum, , cm-1: 1623, 1595, 1551, 1501, 1424, 1397.
5-Chloro-1-phenyl-1H-pyrazole-4-carbohydrazide (8). A mixture of compound 5a (0.964 g, 4 mmol)
and N2H4·H2O (10 ml) was stirred at 20-25°C for 12 h. The solid was filtered off, washed with water, dried, and
purified by recrystallization. IR spectrum, , cm-1: 3286, 3212 (NHNH2), 1655 (C=O), 1624, 1554, 1503, 1458.
13C NMR spectrum, δ, ppm: 114.3 (C-4 pyrazole); 126.1 (C-2,6 Ph); 128.5 (C-5 pyrazole); 129.6 (C-1 Ph);
129.8 (C-3,5 Ph); 137.7 (C-4 Ph); 140.1 (C-3 pyrazole); 160.9 (C=O).
5-(5-Chloro-1-phenyl-1H-pyrazol-4-yl)-1,3,4-oxadiazole-2-thiol (9). A mixture of compound 8
(0.592 g, 2.5 mmol), Et3N (0.505 g, 5.0 mmol), and CS2 (0.570 g, 7.5 mmol) in abs. MeCN (25 ml) was heated
for 4 h at 50°C. The solvent was removed under reduced pressure, the residue was treated with H2O (10 ml), the
precipitated solid was filtered off, and compound 9 was obtained in an analytically pure state. IR spectrum, ,
cm-1: 2782 (S–H); 1638, 1504, 1424, 1403. 13C NMR spectrum, δ, ppm: 105.3 (C-4 pyrazole); 126.0 (C-2,6 Ph);
127.9 (C-5 pyrazole); 130.0 (C-3,5 Ph); 130.1 (C-1 Ph); 137.4 (C-4 Ph); 140.2 (C-3 pyrazole); 155.1 (C-5
pyrazole); 177.2 (C–S). Mass spectrum, m/z (Irel, %): 277 [M-H]+ (100).
2-(5-Chloro-1-phenyl-1H-pyrazol-4-yl)-5-ethylsulfanyl-1,3,4-oxadiazole (10a).
A
mixture of
compound 9 (0.557 g, 2 mmol), K2CO3 (0.828 g, 6 mmol), and EtI (1.248 g, 8 mmol) in abs. DMF (5 ml) was
stirred at 20-25°C for 16 h. The mixture was poured onto ice and extracted with CH2Cl2 (320 ml). The solvent
was removed under reduced pressure, petroleum ether (bp 60-95°C) (50 ml) was added, the solvent was
evaporated to dryness, and a yellow oil was obtained, which was analyzed without further purification.
2-(5-Chloro-1-phenyl-1H-pyrazol-4-yl)-5-{[(4-methylphenyl)methyl]sulfanyl}-1,3,4-oxadiazole
(10b). A mixture of compound 9 (0.139 g, 0.50 mmol), Et3N (0.076 g, 0.75 mmol), and 4-methylbenzyl chloride
(0.085 g, 0.70 mmol) in abs. EtOH (7 ml) was refluxed for 3 h. The solvent was removed at reduced pressure,
the residue was treated with H2O, the resulting precipitate was filtered off, and purified by recrystallization.
N-R1R2-5-Chloro-1-phenyl-1H-pyrazole-4-carboxamides 11a-f (General Method). A mixture of
compound 5a,b (2 mmol), the corresponding amine (2 mmol), and Et3N (0.202 g, 2 mmol) in abs. benzene (5 ml)
was stirred at 20-25°C for 12 h, and the solvent was removed at reduced pressure. Water (30-50 ml) was added
to the residue, the precipitated solid was filtered off, dried, and purified by recrystallization.
13
Compound 11a. C NMR spectrum, δ, ppm: 11.9 (CH3); 21.2 (NCH2CH2CH3); 40.9 (NCH2CH2CH3);
115.6 (C-4 pyrazole); 126.0 (C-2,6 Ph); 128.3 (C-5 pyrazole); 130.2 (C-3,5 Ph); 135.4 (C-1 Ph); 139.4 (C-4 Ph);
140.3 (C-3 pyrazole); 160.7 (C=O).
Compound 11d. IR spectrum, , cm-1: 3277 (N–H), 1639 (C=O), 1567, 1517. Mass spectrum, m/z
(Irel,%): 278 [M]+ (100).
Compound 11e. IR spectrum, , cm-1: 3109 (N–H), 1620 (C=O), 1543, 1515, 1403. Mass spectrum, m/z
(Irel, %): 264 [M]+ (100).
Compound 11f. IR spectrum, , cm-1: 3257 (N–H), 1645 (C=O), 1600, 1551, 1516, 1402. Mass
spectrum, m/z (Irel, %): 326 [M]+ (100).
X-Ray Structural Investigation of Compound 3b. Monocrystal with linear dimensions
0.39×0.35×0.15 mm. Investigation was carried out at room temperature on a Bruker Smart Apex II
diffractometer (λMoKα radiation, graphite monochromator, θmax 27.5o, segment of sphere -23 ≤ h ≤ 23, -5 ≤ k ≤
5, -20 ≤ l ≤ 35). Overall 10414 reflections were taken, of which 3035 were independent (average R factor
1260

0.0834). A correction for absorption was introduced with the SADABS program by the multiscanning method
(Tmin/Tmax 0.1527), and a correction was also introduced for isotropic extinction (0.0084(10)). Crystals of
compound 3b (C22H18N6O2, M 398.42) were rhombic, space group Pca21, a 17.815(4), b 3.8805(10),
c 27.377(7) Å; V 1892.6(8) Å3; Z 4; dcalc 1.398 g/cm3, μ 0.094 mm-1, F(000) 832. The structure was solved by
the direct method and refined by least squares in a full-matrix anisotropic approximation using the Bruker
SHELXTL set of programs [22]. Hydrogen atoms H(1) and H(2), which participate in the formation of
hydrogen bonds, were found and refined isotropically, the positions of the remaining hydrogen atoms were
determined geometrically. In the refinement 1660 reflections were used with I > 2σ(I), 280 parameters were
refined, number of reflections per parameter was 5.9. A weighting scheme was used ω = 1/(σ2(Fo2) +
(0.0467P)2), where P = (Fo2 + 2Fc2)/3, the ratio of the maximum (mean) displacement to the error in the last
cycle was 0.002 (0.000). The final values of the probability factors were R1(F) 0.0476, wR2(F2) 0.094 for
reflections with I > 2σ(I), R1(F) 0.1128, wR2(F2) 0.1204, GOOF 0.967 at each independent reflection. The
residual electron density from the Fourier difference series after the final refinement cycle was 0.16 and
-0.17 e/Å3.
X-Ray Structural Investigation of Compound 7a. Monocrystal with linear dimensions
0.43×0.27×0.10 mm. Investigation was carried out at room temperature on a Bruker Smart Apex II diffractometer
(λMoKα radiation, graphite monochromator, θmax 26.93o, segment of sphere –9 ≤ h ≤ 9, -16 ≤ k ≤ 16, -18 ≤ l ≤ 19).
Overall 15082 reflections were gathered, of which 3225 were independent (mean R factor 0.0463). A correction
was introduced for absorption with the SADABS program by the multiscanning method (Tmin/Tmax 0.774319).
The crystals of compound 7a (C17H11ClN4O, M 322.75) were rhombic, space group P212121; a 7.4094(3),
b 12.9429(5), c 15.6245(6) Å; V 1498.38(10) Å3; Z 4; dcalc 1.431 g/cm3; μ 0.265 mm-1, F(000) 664. The
structure was solved by the direct method and refined by least squares in a full-matrix anisotropic
approximation using the Bruker SHELXTL set of programs [22]. The positions of all hydrogen atoms were
determined geometrically. In the refinement 2384 reflections were used with I > 2σ(I), 208 parameters were refined ,
number of reflections per parameter 11.4, the weighting scheme used was ω = 1/(σ2(Fo2) + (0.0296P)2 + 0.1849P),
where P = (Fo2 + 2Fc2)/3, the ratio of the maximum (mean) displacement to the error in the last cycle was
0.002(0.000). The final values of the probability factors were R1(F) 0.0376, wR2(F2) 0.0709 on reflections with
I > 2σ(I), and R1(F) 0.0681, wR2(F2) 0.0805, GOOF 1.02 at each independent reflection. The Flack parameter
was 0.04(7). The residual electron densities from a Fourier difference series after the last cycle of refinement
were 0.14 and -0.16 e/Å3,
The coordinates of atoms, the geometric parameters of the molecules, and the crystallographic data have
been deposited at the Cambridge Crystallographic Data Center (deposit CCDC 857126 for compound 3b and
CCDC 857127 for compound 7a).
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