Syntheses based on 4-chloro-1-[3,5-di(trifluoromethyl)phenyl]-, 4-chloro-1-(2,4-difluorophenyl)-5-formyl-3-methyl-6,7-dihydroindazoles, and 4-chloro-5-formyl-3-methyl-1-(2-pyridyl)-6,7-dihydroindazoles

Article abstract of DOI:10.1007/s10593-005-0196-2

Vilsmeier formylation of 1-[3,5-di(trifluoromethyl)phenyl]- and 1-(2,4-difluorophenyl)-3-methyl-4-oxo-4,5,6,7-tetrahydroindazoles gave the corresponding 1-aryl-4-chloro-5-formyl-3-methyl-6,7-dihydroindazoles. Reaction of the latter with amidines, o-phenyl

Full text of DOI:10.1007/s10593-005-0196-2

Chemistry of Heterocyclic Compounds, Vol. 41, No. 5, 2005
SYNTHESES BASED ON 4-CHLORO-1-[3,5-DI(TRIFLUORO-
METHYL)PHENYL]-, 4-CHLORO-1-(2,4-DIFLUOROPHENYL)-
5-FORMYL-3-METHYL-6,7-DIHYDROINDAZOLES, AND 4-CHLORO-
5-FORMYL-3-METHYL-1-(2-PYRIDYL)-6,7-DIHYDROINDAZOLES
I. Strakova, A. Strakovs, and M. Petrova
Vilsmeier formylation of 1-[3,5-di(trifluoromethyl)phenyl]- and 1-(2,4-difluorophenyl)-3-methyl-4-oxo-
4,5,6,7-tetrahydroindazoles
gave
the
corresponding
1-aryl-4-chloro-5-formyl-3-methyl-6,7-
dihydroindazoles. Reaction of the latter with amidines, o-phenylenediamine, hydrazine, or
hydroxylamine gave a series of 1-aryl-3-methyl-6,6-dihydroindazoles annelated at positions 4 and 5.
The reaction of 4-chloro-5-formyl-3-methyl-1-(2-pyridyl)-6,7-dihydroindazole with substituted anilines
gave 5-arylaminomethylene-4-oxo- or 5-arylaminomethylene-4-arylimino-3-methyl-1-(2-pyridyl)-
4,5,6,7-tetrahydroindazoles depending on the molar ratio of reagents and the nucleophilicity of the
amines.
Keywords: β-arylaminovinyl ketones, β-arylaminovinylarylimines, 4,5-dihydro-7H-benzo[b]indazolo-
[4,5-e]diazepines, 4,5-dihydro-1H-pyrazolo[3,4-e]indazoles, 3,8-substituted 4,5-dihydropyrazolo[5,4-h]-
quinazolines, β-chlorovinylaldehydes.
Modification of indazoles hydrogenated in the carbocycle is mostly carried out with the aim of finding
biologically active compounds [1-6]. Continuing our research in this direction [7-11] we report in this work the
synthesis of a series of novel compounds of the group indicated. Hence the Vilsmeier formylation of
1-[3,5-di(trifluoromethyl)phenyl]- (1) and 1-(2,4-difluorophenyl)-3-methyl-4-oxo-4,5,6,7-tetrahydroindazole (2)
gave the corresponding β-chlorovinylaldehydes 3 (75%) and 4 (86%). The method is given in [7].
The starting indazole 1 is reported in [10] and the indazole 2 has been synthesized for the first time from
2-acetyl-1,3-cyclohexanedione and 2,4-difluorophenylhydrazine. The structure of the products 3 and 4 is
confirmed from spectroscopic data (Table 1). In the IR spectra of compounds 3 and 4 the carbonyl group band is
1
seen at 1653 and 1659 cm-1 and in the H NMR spectra the aldehyde proton signals are observed at 10.40 and
10.20 ppm respectively. Refluxing the aldehydes 3, 4 with guanidine carbonate, benzamidine,
4-pyridylcarbamidine, 5-trifluoromethyl-2-pyridylcarbamidine hydrochlorides, or the hydrobromides of
1-pyrrolidinyl- and 4-morpholinylcarbamidines in ethanol in the presence of sodium ethylate (or KOH in the
case of the pyrrolidine and morpholine carbamidines) gave the corresponding 3,8-disubstituted 1-methyl-4,5-
dihydropyrazolo[5,4-h]quinazolines 5-13.
Refluxing the aldehydes 3 and 4 for a short time with o-phenylenediamine in ethanol in the presence of
conc. HCl gave the corresponding 3-substituted 1-methyl-4,5-dihydro-7H-benzo[b]indazolo[4,5-e][1,4]diazepine
1
hydrochlorides 14, 15, the H NMR spectra of which showed an N+H group proton signal at 9.50 and 10.32 or
9.36 and 10.30 ppm respectively.
__________________________________________________________________________________________
Riga Technical University, Riga LV-1658, Latvia, e-mail: marina@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 5, pp. 740-750, May, 2005. Original article submitted May 14, 2003.
0009-3122/05/4105-0637©2005 Springer Science+Business Media, Inc.
637

Scheme 1
Ar
Ar
N
N
N
N
H
O
Me
O
Cl
3, 4
Me
1, 2
Ar
_
N
N
Ar
N
N
+
HN
NH
Me
Cl
N
N
Me
R
5–13
14, 15
Ar
Ar
N
N
N
N
3, 4
H
N
Cl
18–22
Me
R1
Me
N
NH
16, 17
Ar
Ar
N
N
N
N
H
H
Me
OCOMe
O
Cl
COOEt
23, 24
Me
NC
25, 26
1, 3, 5-9, 14, 16, 18, 19, 23, 25 Ar = 3,5-(CF3)2C6H3; 2, 4, 10-13, 15, 17, 20-22, 24, 26 Ar = 2,4-F2C6H3; 5, 10 R = NH2;
6, 12 R = 4-C5H4N; 7 R = 4-CF3C5H3N-2; 8, 13 R = (CH2)4N; 11 R = Ph; 9 R = O(CH2CH2)2N; 18, 20 R1= OH;
19, 21 R1 = 3,5-(CF3)2C6H3NH; 22 R1 = EtOOCNH
Refluxing the aldehydes 3 and 4 with hydrazine hydrochloride in the presence of potassium carbonate in
ethanol for 3 h gave the 6-substituted 4,5-dihydro-1H-pyrazolo[3,4-e]indazoles 16 and 17 respectively, refluxing
with hydroxylamine hydrochloride in pyridine the oximes 18 and 20, with 3,5-di(trifluoromethyl)-
phenylhydrazine in ethanol the hydrazones 19 and 21, and refluxing aldehyde 4 with carbethoxyhydrazine the
hydrazone 22.
Treatment of the aldehydes 3 and 4 with ethyl cyanoacetate in absolute ethanol in the presence of
diethylamine at 20°C gave the corresponding 1-substituted 4-chloro-5-(2-cyano-2-carbethoxyethenyl)-3-methyl-
6,7-dihydroindazoles 23 and 24. The ester groups of these compounds show characteristic bands for C=O groups
at 1713 and 1717 cm-1, a CN group at 2220 cm-1, and an ethylene proton at 8.58 ppm.
638

Refluxing the aldehydes 3 and 4 in acetic anhydride gave the 4-acetoxy derivatives 25 and 26, the
carbonyl function frequencies of which appear at 1777 and 1681 and 1775 and 1685 cm-1 respectively.
To extend the investigation of 4-chloro-5-formyl-3-methyl-1-(2-pyridyl)-6,7-dihydroindazole (27) [7, 8]
we have now studied the reaction with aniline derivatives of different nucleophilicities 28a-l.
When carrying out the reactions both with an equimolar amount of reagents and also with an excess of
+
amine, the anilines of lower basicity 28a-h (pKBH < 3.5) gave the corresponding 5-arylaminomethylene-3-
methyl-4-oxo-1-(2-pyridyl)-4,5,6,7-tetrahydroindazoles 29a-h. Under these reaction conditions the equimolar
amount of water separated in the reaction of the formyl group with the amine is sufficient to hydrolyze the
C(4)–Cl bond.
With a twofold excess of more nucleophilic amines 28i-l relative to the indazole 27 the
5-arylaminomethylene-4-arylimino-4,5,6,7-tetrahydroindazole hydrochlorides 30i-l are formed. Reaction of
compound 27 with amines 28a,b in the molar ratio 1:2 also gives the corresponding hydrochlorides 30a,b.
Treatment of a suspension of the hydrochlorides 30a,b,i-l in ethanol with a 10% aqueous solution of NaHCO3
gave the 4-arylamino-5-arylaminomethylene-4,5,6,7-tetrahydroindazoles 31a,b,i-l.
Scheme 2
Py
(2)
(2)
Py
H2N–Ar
N
N
N
N
28a–h
H
N
O
Me
O
Cl
Me
Ar
H
27
H2N–Ar
28i–l
29
Py (2)
N
N
+
Me
NH
H
N
–
Ar Ar
Cl
30
(2)
Py
Py
(2)
(2)
Py
N
N
N
N
N
N
H
H
N
Me
NH
Ar
Me
N
N
Me
N
NH
Ar
Ar
Ar
Ar
Ar
31C
31B
31A
28-31 a Ar = C6H4Cl-2; b Ar = C6H4CF3-3; c Ar = C6H4COOH-2; d Ar = C6H4COO Me-2;
e Ar = C6H2Br3-2,4,6; f Ar = C6H2Cl3-2,4,6; g Ar = C6H4NO2-3; h Ar = C6H4NO2-4; i Ar = C6H5; j Ar = C6H4OMe-4;
k Ar = C6H4Me-4; l Ar = C6H4Br-4
Characteristic carbonyl group frequencies for the carbonyl groups of the ketones 29 are found in the
region 1665-1646 and NH stretching vibrations at 3300-2800 cm-1. In the IR spectra of the bases 31 the latter is
1
of low intensity and detecting it is difficult. In the H NMR spectra of the bases 31 the NH group proton has a
chemical shift of 9-13 ppm and this confirms the presence of an H-chelated ring stabilized by intramolecular
hydrogen bonding. The N+–H group protons of the hydrochlorides 30 are also characterized by a low field
chemical shifts (11-12 ppm) (Table 2).
Several of the synthesized arylaminomethylene ketones 29 (29c,d,e) are a mixture of isomers relative to
the C(5)=CHNH– double bond with the corresponding spectroscopic features.
639

TABLE 1. Characteristics of the Compounds Synthesized
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
Yield, %
mp, °С
С
H
4
N
5
Cl (Br)
6
1
2
3
7
8
2
С14Н12F2N2O
64.02
64.11
50.01
49.95
58.30
58.35
52.13
52.30
58.04
58.11
52.92
53.05
56.40
56.53
54.49
54.66
61.11
61.33
70.42
70.58
67.02
67.18
65.30
65.38
55.20
55.37
63.09
63.24
52.65
52.85
62.77
62.93
48.07
48.18
47.40
47.30
55.49
55.65
51.52
51.65
54.58
54.76
52.30
52.44
59.33
59.48
52.61
52.79
61.30
61.44
65.93
65.84
63.10
63.31
67.10
67.37
67.86
68.03
42.14
42.36
4.55
4.61
2.66
2.71
3.50
3.59
3.20
3.17
3.03
3.18
2.55
2.60
4.06
4.10
3.82
3.96
4.25
4.18
4.22
4.31
4.09
4.03
5.10
5.21
3.34
3.44
4.20
4.30
3.01
3.13
4.19
4.23
2.80
2.86
2.31
2.38
3.62
3.74
2.70
2.83
4.25
4.34
3.08
3.20
4.04
3.99
3.20
3.26
4.14
4.25
4.81
4.70
4.22
4.30
4.90
4.85
5.16
5.19
2.70
2.67
10.53
10.69
6.69
6.85
8.99
9.07
16.82
16.95
14.60
14.73
12.92
12.89
15.09
14.99
14.52
14.49
22.43
22.36
15.14
14.97
18.55
18.66
18.97
19.06
11.11
11.23
14.13
14.05
14.40
14.50
19.42
19.57
9.79
9.92
8.70
8.83
13.03
12.98
10.41
10.48
14.08
14.19
8.20
8.34
10.30
10.41
6.33
6.48
8.35
8.43
15.23
15.35
14.14
14.06
14.73
14.96
14.42
14.42
10.02
9.88
88-89
72
75
86
61
66
48
51
43
57
63
62
50
79
66
49
53
83
88
80
85
77
69
66
70
77
66
50
75
64
46
3
С17Н11ClF6N2O
С15Н11ClF2N2O
С18Н13F6N5
8.50
8.67
11.40
11.48
117-118
139-141
191-192
235-237
247-249
207-209
225-226
232-234
120-121
238-239
133-134
315-320
310-314
171-172
218-220
225-226
225-226
200-202
192-193
155-156
163-164
163-164
160-161
152-153
152-153
174-175
269-271
138-140
222-224
4
5
6
С23Н15F6N5
7
С24Н14F9N5
8
С22Н19F6N5
9
С22Н19F6N5O
С16Н13F2N5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
29a
29b
29c
29d
29e
С22Н16F2N4
С21Н15F2N5
С20Н19F2N5
С23Н17ClF6N4
С21Н17ClF2N4
С17Н12F6N4
6.90
7.11
8.70
8.89
С15Н12F2N4
С17Н12ClF6N3O
С25Н15ClF12N4
С15Н12ClF2N3O
С23Н15ClF8N4
С18Н17ClF2N4O2
С22Н16ClF6N3O2
С20Н16ClF2N3O2
С19Н14F6N2O3
С17Н14F2N2O3
C20H17ClN4O
C21H17F3N4O
C21H18N4O3
8.20
8.37
5.40
5.58
10.80
10.95
6.50
6.63
8.80
8.98
7.00
7.04
8.60
8.78
9.50
9.72
C22H20N4O3
C20H15Br3N4O
42.40
42.27
640

TABLE 1 (continued)
1
29f
29g
29h
30a
30b
30i
2
C20H15Cl3N4O
C20H17N5O3
C20H17N5O3
C26H22Cl3N5
C28H22ClF6N5
C26H24ClN5
C28H28ClN5O2
C28H28ClN5
C26H22Br2ClN5
C26H21Cl2N5
C28H21F6N5
C26H23N5
3
4
5
6
7
8
55.55
55.39
64.16
63.99
63.77
63.99
61.01
61.13
58.16
58.19
70.70
70.66
67.05
66.99
71.35
71.55
51.94
52.07
65.60
65.83
61.91
62.11
77.17
77.01
72.02
72.24
77.40
77.57
55.44
55.44
3.40
3.49
4.51
4.57
4.50
4.57
4.14
4.34
3.82
3.83
5.51
5.47
5.61
5.62
5.93
6.00
3.58
3.70
4.41
4.46
3.90
3.91
5.70
5.72
5.78
5.84
6.11
6.28
3.64
3.76
12.70
12.92
18.66
18.66
18.71
18.66
13.50
13.71
12.12
12.12
15.78
15.84
14.03
13.95
14.90
14.90
11.58
11.68
14.58
14.76
12.81
12.93
17.13
17.27
14.95
15.04
16.03
16.15
12.37
12.43
24.30
24.52
195-197
256-259
271-273
195-205
230-235
207-210
235-240
235-240
226-230
161-162
145-147
133-135
209-210
133-135
198-200
62
94
67
47
40
95
90
75
83
78
71
78
98
99
79
20.60
20.82
8.20
8.02
7.10
7.06
7.60
7.54
30j
30k
30l
31a
31b
31i
15.20
14.95
31j
31k
31l
C28H27N5O2
C28H27N5
C26H21Br2N5
28.10
28.37
TABLE 2. IR and 1H NMR Spectra of the Compounds Synthesized
IR
spectrum,
Com-
pound
ν, cm-1
(C=O, NH,
OH)
1Н NMR spectrum, δ, ppm (SSCC, J, Hz)
1
2
3
2
1667
CDCl3. 2.14 (2H, m, CH2); 2.47 (2H, m, CH2); 2.51 (3H, s, CH3);
2.74 (2H, m, CH2); 7.03 (2H, center m, НAr); 7.47 (1Н, center m, НAr)
3
4
5
6
7
8
1653
1659
CDCl3. 2.58 (3H, s, CH3); 2.85 (4H, center m, 2CH2); 7.90 (1H, br. s, НAr);
7.93 (2Н, br. s, НAr); 10.40 (1Н, s, СНО)
CDCl3. 2.50 (3H, s, CH3); 2.72 (4H, center m, 2CH2);
6.89-7.54 (3H, m, НAr); 10.20 (1Н, s, СНО)
3480, 3290, CDCl3. 2.63 (3H, s, CH3); 2.94 (4H, m, 2CH2); 5.09 (2H, br. s, NН2);
3160-3100
7.81 (1Н, br. s, НAr); 7.98 (2H, br. s, НAr); 8.03 (1Н, s, Н-6)
1622
DMSO-d6. 2.74 (3H, s, CH3); 3.13 (4H, center m, 2CH2);
8.27 (5H, m, 3НAr, 2Hpyr); 8.76 (3Н, m, 2Hpyr, Н-6)
DMСО-d6. 2.67 (3H, s, CH3); 3.28 (4H, center m, 2CH2);
8.26-9.21 (7H, m, 3НAr, 3H , Н-6)
CDCl3. 2.01 (4H, center m, 2CH2); 2.72 (3H, s, CH3);
2.96 (4H, center m, 2СН2); 3.63 (4H, center m, N(СН2)2);
7.85 (1Н, br. s, НAr); 7.98 (2H, br. s, НAr); 8.12 (1Н, s, Н-6)
9
CDCl3. 2.67 (3H, s, CH3); 2.96 (4H, center m, 2CH2); 3.81 (8H, center m,
N(CH2СН2)2O); 7.92 (1Н, br. s, НAr); 8.00 (2H, br. s, НAr); 8.16 (1Н, s, Н-6)
10
11
3400, 3300, CDCl3 + DMSO-d6. 2.61 (3H, s, CH3); 2.78 (4H, m, 2CH2); 5.05 (2H, br. s,
3150-3100
NH2); 7.01 (2Н, center m, НAr); 7.49 (1H, center m, НAr); 8.05 (1Н, s, Н-6)
CDCl3. 2.85 (3H, s, CH3); 2.92 (4H, center m, 2CH2); 7.01 (2Н, m, НAr);
7.52 (3H, m, НPh); 7.56 (1Н, m, НAr); 8.45 (1Н, s, Н-6); 8.46 (2Н, m, НPh)
641

TABLE 2 (continued)
1
2
3
12
CDCl3. 2.78 (3H, s, CH3); 2.94 (4H, br. s, 2CH2); 7.05 (2Н, center m, НAr);
7.61 (1H, center m, НAr); 8.34 (2Н, m, 3J = 6.0, Hpyr); 8.54 (1Н, s, Н-6);
8.74 (2Н, m, 3J = 6.0, Нpyr
)
13
14
CDCl3. 1.98 (4H, center m, 2CH2); 2.67 (3H, s, CH3); 2.81 (4Н, m, 2СН2);
3.64 (4H, center m, N(СН2)2); 7.01 (2Н, center m, HAr);
7.52 (1Н, center m, НAr); 8.07 (1Н, s, Н-6)
2850-2750
2850-2750
DMСО-d6. 2.45 (2H, m, CH2); 2.58 (3H, s, CH3); 2.89 (2Н, m, СН2);
6.69 (2H, m, НAr); 6.85 (1Н, d, 3J = 8.0, H-6); 7.01 (2Н, m, НAr);
8.22 (3Н, m, НAr); 9.50 (1Н, br. s, NH); 10.32 (1Н, br. d, 3J = 8.0, NH)
15
16
17
18
19
DMSO-d6. 2.61 (3H, s, CH3); 2.45 (4H, m, 2CH2); 6.72-7.74 (8Н, m,
2НAr, H-6); 9.36 (1H, br. s, NH); 10.30 (1Н, d, 3J = 8.0, NН)
3200, 3120 CDCl3. 2.58 (3H, s, CH3); 3.01 (4H, m, 2CH2); 7.38 (1Н, s, H-6);
7.81 (1H, br. s, HAr); 8.01 (2Н, br. s, НAr); 10.20 (1Н, br. s, NН)
3200, 3100 CDCl3. 2.53 (3H, s, CH3); 2.77 (4H, center m, 2CH2); 6.97 (2Н, center m,
HAr); 7.28 (1H, s, H-3); 7.46 (1Н, center m, НAr); 11.67 (1Н, br. s, NН)
3280-3160
3330-3200
1722
CDCl3. 2.54 (3H, s, CH3); 2.98 (4H, m, 2CH2); 7.85 (1Н, br. s, НAr);
7.96 (2H, br. s, HAr); 8.34 (1Н, s, N=CН–); 10.81 (1Н, s, OН)
CDCl3. 2.53 (3H, s, CH3); 3.01 (4H, m, 2CH2); 7.21 (1Н, br. s, НAr);
7.49 (2H, br. s, HAr); 7.83 (1Н, br. s, НAr); 7.98 (2Н, br. s, НAr);
8.16 (1Н, s, N=CН–); 10.20 (1Н, br. s, NН)
20
CDCl3 + DMSO-d6. 2.49 (3H, s, CH3); 2.76 (4H, center m, HAr);
7.03 (2Н, center m, НAr); 7.49 (1Н, center m, НAr); 8.38 (1H, s, N=CН);
10.34 (1Н, br. s, OН)
21
22
CDCl3. 2.52 (3H, s, CH3); 2.89 (4H, center m, 2CH2);
6.81-7.35 (6Н, m, НAr); 8.07 (2H, br. s, NH, N=CH–)
CDCl3. 1.27 (3H, t, 3J = 7.0, CH3); 2.52 (3H, s, CH3); 2.65-3.01 (4Н, m,
2СН2); 4.29 (2H, q, 3J = 7.0, CH2); 6.96 (2Н, center m, НAr); 7.63 (1Н,
center m, НAr); 8.07 (1Н, br. s, N=СН–); 8.09 (1Н, br. s, NН)
23
24
1713; 2220 CDCl3. 1.36 (3H, t, 3J = 7.0, CH3); 2.56 (3H, s, CH3); 3.21 (4Н, center m,
2СН2); 4.34 (2H, q, 3J = 7.0, CH2); 7.92 (1Н, br. s, НAr); 7.95 (2Н, br. s,
НAr); 8.58 (1Н, s, =СН–)
1717; 2220 CDCl3. 1.35 (3H, t, 3J = 7.0, CH3); 2.55 (3H, s, CH3); 2.79 (2Н, t, 3J = 7.0,
CH2); 3.22 (2H, t, 3J = 7.0, CH2); 4.35 (2Н, q, 3J = 7.0, CH2); 7.02 (2Н,
center m, НAr); 7.48 (1Н, center m, НAr); 8.58 (1Н, s, =СН–)
CDCl3. 2.25 (3H, s, CH3); 2.58 (3H, s, CH3); 3.03 (4Н, center m, 2CH2);
7.89 (1H, br. s, HAr); 7.96 (2Н, br. s, НAr); 8.27 (1Н, s, СНО)
25
26
1777; 3100
1775, 1685 CDCl3. 2.23 (3H, s, CH3); 2.52 (3H, s, CH3); 2.85 (4Н, center m, 2CH2);
7.02 (2H, center m, HAr); 7.47 (1Н, center m, НAr); 8.25 (1Н, s, СНО)
29а
29b
29c
29d
1655;
DMSO-d6. 2.53 (3Н, s, СН3); 2.78 (2Н, t, 3J = 7, СН2); 3.41 (2Н, t, 3J = 7,
СН2); 6.98 (1Н, dt, 3J = 8, 4J = 1.5, С6Н4); 7.25-8.09 (7Н, m, С6Н4, С5Н4N,
3200-2800
=CH–); 8.52 (1H, m, 3 = 5, С5Н4N); 11.65 (1Н, d, 3J = 13.5, NH)
J
1658;
3200-2800
DMSO-d6. 2.61 (3Н, s, СН3); 2.79 (2Н, t, 3J = 7, СН2);
3.46 (2Н, t, 3J = 7, СН2); 7.13-7.98 (8Н, m, С6Н4, С5Н4N, =CH–);
8.42 (1H, m, 3J =5, С5Н4N); 11.49 (1Н, d, 3J = 11.4, NH)
1680, 1656; DMSO-d6. 2.50 (3Н, s, СН3); 2.82 (2Н, m, СН2); 3.45 (2Н, m, СН2);
3200-2900
7.08-8.05 (8Н, m, С6Н4, С5Н4N, =CH–); 8.45 (1H, m, 3J = 5, С5Н4N);
10.65 and 12.58 (1Н, d, 3J = 13, NH); 13.2 (1Н, br. s, СООН)
1716, 1665; CDCl3. 2.61 and 2.67 (3Н, s, СН3); 2.80 and 2.95 (2Н, t, 3J = 7, СН2);
3300-3200
3.45 and 3.58 (2Н, t, 3J = 7, СН2); 3.92 and 4.01 (3Н, s, СООСН3);
6.93 (1Н, t, 3
J = 7, C6H4); 7.22-8.40 (8Н, m, С6Н4, С5Н4N, =CH–);
10.61 and 12.95 (1Н, d, 3J = 13, NH)
29e
29f
1646;
3200-2800
CDCl3. 2.63 (3Н, s, СН3); 2.72 (2Н, t, 3J = 7, СН2); 3.46 (2Н,
t, 3 = 7, СН2); 7.06 (1Н, d, 3J = 11, =CH–); 7.20 (1Н, m, С5Н4N);
J
7.49 (2Н, s, С6Н2); 7.81 (1Н, d, 3J = 8.4, 4J = 1.7, C5H4N);
7.93 (1H, dt, 3J = 8.4, 4.5J = 1, C5H4N); 8.42 (1Н, m, 3J = 5, C5H4N);
11.40 (1H, d, 3J = 11, NH)
1650;
3200-2800
DMSO-d6. 2.52 (3Н, s, СН3); 2.81 (2Н, m, СН2); 3.43 (2Н, m, СН2);
7.29-8.09 (6Н, m, С6Н2, С5Н4N, =CH–); 8.50 (1H, m, 3J = 5, С5Н4N);
9.07 and 11.21 (1Н, d, 3J = 13, NH)
642

TABLE 2 (continued)
1
2
3
29g
1656; 3100 DMSO-d6. 2.51 (3Н, s, СН3); 2.94 (2Н, m, СН2); 3.47 (2Н, m, СН2);
7.43-8.14 (8Н, m, С6Н4, С5Н4N, =CH–); 8.54 (1H, m, 3J = 5, С5Н4N);
9.27 (1Н, d, 3J = 13, NH)
29h
30а
30b
30i
1656;
3200-2800
DMSO-d6. 2.50 (3Н, s, СН3); 2.98 (2Н, t, 3J = 7, СН2); 3.46 (2Н, t,
3J = 7, СН2); 7.31-8.20 (8Н, m, С6Н4, С5Н4N, =CH–);
8.51 (1H, m, 3J = 5, С5Н4N); 9.56 and 11.43 (1Н, d, 3J = 13, NH)
3000-2750
3000-2800
DMSO-d6. 1.35 (3Н, s, СН3); 2.75 (2Н, m, СН2); 3.68 (2Н, m, СН2);
6.87-8.02 (12Н, m, 2С6Н4, С5Н4N, =CH–); 8.72 (1H, m, 3J = 5, С5Н4N);
12.62 (1Н, d, 3J = 10, NH); 12.80 (1Н, br. s, NH)
DMSO-d6. 1.45 (3Н, s, СН3); 2.95 (2Н, m, СН2); 3.22 (2Н, m, СН2);
7.44-8.21 (11Н, m, 2С6Н4, С5Н4N); 8.60 (1H, m, 3J = 5, С5Н4N);
9.15 (1Н, br. s, =СH–); 11.30 (1Н, br. s, NH); 12.25 (1Н, br. s, NH)
1634;
3000-2750
CDCl3. 1.45 (3Н, s, СН3); 2.56 (2Н, t, 3J = 7, СН2); 3.27 (2Н, t, 3J = 7,
СН2); 6.78-7.35 (9Н, m, 2С6Н5, С5Н4N); 7.87 (4H, m, С6Н5, С5Н4N);
8.46 (1Н, dt,3J = 4.9, 4J = 1.4, С5Н4N); 8.97 (1H, d, 3J = 14.3, =СН–);
11.62 (1Н, d, 3J = 14.3, NH); 11.75 (1Н, br. s, NH)
30j
1632;
3000-2750
CDCl3. 1.49 (3Н, s, СН3); 2.54 (2Н, m, СН2); 3.22 (2Н, m, СН2);
3.48 (3Н, s, СН3); 3.76 (3Н, s, СН3); 6.61 (2Н, m, 3J = 9, С6Н4);
6.80 (2H, m, 3J = 9, С6Н4); 7.26 (4Н, m, С6Н4, С5Н4N); 7.84 (4H, m, С6Н4,
С5Н4N); 8.45 (1H, m, 3J = 5, С5Н4N); 8.81 (1H, d, 3J = 16, =СН–);
11.50 (1Н, br. s, NH); 11.53 (1Н, d, 3J = 16, NH)
1
Compounds 31 can exist in the tautomeric forms 31A-C. The H NMR spectroscopic data conclusively
points to the absence of the 31B form due to the presence of NH proton signals in them. The predominance of
form 31A is confirmed only for compound 31a since its spectrum shows proton signals for the fragment
=CH–NH– with a characteristic spin-spin coupling of 3JCHNH = 9.5 Hz.
In the spectra of the remaining compounds 31b,i-l the proton signals for the =CH– and NH groups are
→
broad singlets and this can be a result of both tautomeric conversions of 31A
31C and of hindered rotation
←
around the C(5')–N bond (31A). Exchange of the 4-carbonyl group (compound 29) for arylimino (compound 31)
is accompanied by a marked low field shift of the 3-methyl group proton signal (∆δ > 1 ppm) due to the
anisotropic effect of the aromatic substituent.
EXPERIMENTAL
IR spectra were recorded on a Specord IR-75 instrument for suspensions in vaseline oil (1800-1500 cm-1
region) or in hexachlorobutadiene (3600-2000 cm-1 region). The C–H bond stretching vibrations in the region
1
3050-2800 cm-1 are not listed. H NMR spectra were recorded on Bruker WH-90/DS (90 MHz) and Varian
Mercury BB (200 MHz) instruments using CDCl3 and DMSO-d6 with TMS as internal standard.
1
The characteristics of the compounds synthesized are given in Table 1 and IR and H NMR
spectroscopic data in Table 2.
The amidines and hydrazines used in this work were obtained from Acros and Maybridge.
1-(2,4-Difluorophenyl)-3-methyl-4-oxo-4,5,6,7-tetrahydroindazole (2). A refluxing mixture of
2,4-difluorophenylhydrazine hydrochloride (2.88 g, 16 mmol) in water (15 ml) and KOH (0.9 g) in ethanol
(15 ml) was added to a hot solution of 2-acetyl-1,3-cyclohexanedione (2.46 g, 16 mmol) in ethanol (15 ml). The
reaction product was refluxed for 30 min, conc. HCl (0.5 ml) was added, and the refluxing was continued for a
further 2 h. Without cooling, the product was treated with water (50 ml) and held for 1 day in the fridge. The
precipitated product 2 was filtered off and recrystallized from 50% ethanol.
643

1-[3,5-Di(trifluoromethyl)phenyl]- (3) and 4-Chloro-1-(2,4-difluorophenyl)-5-formyl-3-methyl-6,7-
dihydroindazole (4). A solution of phosphorus oxychloride (1.1 ml, 12.0 mmol) in DMF (4 ml) was added with
stirring to a solution of 4-oxo-4,5,6,7-tetrahydroindazole 1 or 2 (4 mmol) in DMF (4 ml). The mixture was held
for 1 h on a boiling water bath, cooled, poured into ice, and the precipitated compound 3 or 4 was filtered off and
recrystallized from ethanol.
3-[3,5-Di(trifluoromethyl)phenyl]- (5) and 8-Amino-3-(2,4-difluorophenyl)-1-methyl-4,5-dihydro-
pyrazolo[5,4-h]quinazoline (10). The chloro aldehyde 3 or 4 (20 mmol) and guanidine carbonate (2.5 mmol) in
a solution of sodium ethylate prepared from sodium (10 mmol) in absolute ethanol (15 ml) was refluxed for 10 h.
The reaction mixture was cooled, diluted with water (20 ml), and the precipitated compound 5 or 10 was
recrystallized from ethanol.
3-[3,5-Di(trifluoromethyl)phenyl]-8-(4-pyridyl)-
(6),
3-[3,5-Di(trifluoromethyl)phenyl]-8-(4-
trifluoromethyl-2-pyridyl)- (7), 3-(2,4-Difluorophenyl)-8-phenyl- (11), and 3-(2,4-Difluorophenyl)-1-
methyl-8-(4-pyridyl)-4,5-dihydropyrazolo[5,4-h]quinazoline (12). The chloro aldehyde 3 or 4 (2 mmol) were
refluxed for 11 h with an equimolar amount of the appropriate amidine hydrochloride in a solution of sodium
ethylate prepared from sodium (4 mmol) in absolute ethanol (30 ml). The reaction mixture was cooled, diluted
with water (50 ml), and the precipitated compound 11 or 12 was filtered off and recrystallized from ethanol (or
from DMF in the case of the pyrimidine 7).
3-[3,5-Di(trifluoromethyl)phenyl]-8-(1-pyrrolidyl)- (8), 3-[3,5-Di(trifluoromethyl)phenyl]-8-(4-
morpholinyl)- (9), and 3-(2,4-Difluorophenyl)-1-methyl-8-(1-pyrrolidyl)-4,5-dihydropyrazolo[5,4-h]-
quinazoline (13). The corresponding amidine hydrobromide (2 mmol) and a solution of the chloro aldehyde 3 or
4 (2 mmol) in absolute ethanol was added to a suspension of finely pulverized KOH (4 mmol) in absolute
ethanol (10 ml). The mixture was refluxed for 11 h, cooled, diluted with water (100 ml), and held for 1 day in
the fridge. The oily material which had solidified in this way was recrystallized from a mixture of DMF and
water (1:1).
3-[3,5-Di(trifluoromethyl)phenyl]- (14) and 3-(2,4-Difluorophenyl)-1-methyl-4,5-dihydro-7H-
benzo[b]indazolo[4,5-e][1,4]diazepine (15) Hydrochlorides. Separately prepared (and brought to reflux)
solutions of the aldehyde 3 or 4 (2 mmol) in absolute ethanol (10 ml) and o-phenylenediamine (2 mmol) in
absolute ethanol (10 ml) were mixed, refluxed for 5 min, and conc. HCl (0.8 ml) was added without cooling. The
reaction product was held for 1 day in the fridge and the black crystalline hydrochlorides 14 and 15 were filtered
off and washed on the filter with a small amount of hot absolute ethanol and then ether.
6-[3,5-Di(trifluoromethyl)phenyl]- (16) and 6-(2,4-Difluorophenyl)-8-methyl-4,5-dihydro-1H-
pyrazolo[3,4-e]indazole (17). The chloro aldehyde 3 or 4 (2 mmol), hydrazine hydrochloride (4 mmol), and
potassium carbonate (8 mmol) in absolute ethanol (20 ml) were refluxed for 3 h. After cooling, water (50 ml)
was added and after 1 day compound 16 or 17 was filtered off and recrystallized from 70% ethanol.
1-[3,5-Di(trifluoromethyl)phenyl]- (18) and 4-Chloro-1-(2,4-difluorophenyl)-5-hydroxyimino-
methyl-3-methyl-6,7-dihydroindazole (20). The chloro aldehyde 3 or 4 (2 mmol) and an equimolar amount of
hydroxylamine hydrochloride in pyridine (6 ml) were refluxed for 3 h. After cooling, the mixture was treated
with water (50 ml) and the precipitate was filtered off and recrystallized from ethanol.
1-[3,5-Di(trifluoromethyl)phenyl]- (19) and 4-Chloro-1-(2,4-difluorophenyl)-5-[3,5-di(trifluoro-
methyl)phenylhydrazonomethyl]-3-methyl-6,7-dihydroindazole (21). Separately prepared solutions of the
aldehyde 3 or 4 (1 mmol) in absolute ethanol (5 ml) and 3,5-ditrifluoromethylphenylhydrazine (1 mmol) in
absolute ethanol (5 ml) were heated to reflux, mixed together, and refluxed for 15 min. The hydrazones 19 and
21 which precipitated on cooling were recrystallized from ethanol.
5-Carbethoxyhydrazonomethyl-4-chloro-1-(2,4-difluorophenyl)-3-methyl-6,7-dihydroindazole (22).
Solutions of the aldehyde 4 (0.31 g, 1.1 mmol) in ethanol (10 ml) and carbethoxyhydrazine (0.10 g, 1.1 mmol) in
ethanol (5 ml) were brought to reflux and mixed. A catalytic amount of p-touenesulfonic acid was added and the
mixture obtained was refluxed for 1-2 min. Water (40 ml) was added without cooling and the product was held
for 1 day in the fridge. The precipitated hydrazone 22 was filtered off and recrystallized from 50% ethanol.
644

1-[3,5-Di(trifluoromethyl)phenyl]- (23) and 5-(2-Carbethoxy-2-cyanoethenyl)-4-chloro-1-(2,4-
difluorophenyl)-3-methyl-6,7-dihydroindazole (24). A mixture of the chloro aldehyde 3 or 4 (2.0 mmol),
diethylamine (2 mmol), and ethyl cyanoacetate (2 mmol) was stirred for 2 h at 20°C, held for 1 day in the fridge,
and the precipitated compound 23 or 24 was filtered off and recrystallized from ethanol.
1-[3,5-Di(trifluoromethyl)phenyl]- (25) and 4-Acetoxy-1-(2,4-difluorophenyl)-5-formyl-3-methyl-
6,7-dihydroindazole (26). The chloro aldehyde 3 or 4 (2 mmol) in acetic anhydride (10 ml) was refluxed for 3 h
and the reaction mixture was cooled and poured into crushed ice. After 1 day compound 25 or 26 was filtered off
and recrystallized from 90% ethanol.
5-(2-Chlorophenylaminomethylene)- (29a), 5-(3-Trifluoromethylphenylaminomethylene)- (29b), 5-
(2-Hydroxycarbonylphenylaminomethylene- (29c), 5-(2-Carbomethoxyphenylaminomethylene- (29d), 5-
(2,4,6-Tribromophenylaminomethylene)-
(29e),
5-(3,4,5-Trichlorophenylaminomethylene)-
(29f),
5-(3-Nitrophenylaminomethylene)- (29g)-, and 5-(4-Nitrophenylaminomethylene)-3-methyl-4-oxo-1-(2-
pyridyl)-4,5,6,7-tetrahydroindazole (29h). Separately prepared solutions of the indazole 27 (2 mmol) in
absolute ethanol (10 ml) and the corresponding amine (2 mmol) in absolute ethanol (20 ml) were taken to reflux.
The hot solutions were combined and refluxed for 2 h. The precipitation of the compound 29 began even at
reflux. The reaction mixture was held for 1 day at room temperature, filtered off, and crystallized from absolute
ethanol.
5-(2-Chlorophenylaminomethylene)-4-(2-chlorophenylimino)- (30a), 5-(3-Trifluoromethylphenyl-
aminomethylene)-4-(3-trifluoromethylphenylimino)- (30b), 5-Phenylaminomethylene-4-phenylimino-
(30i), 5-(4-Methoxyphenylaminomethylene)-4-(4-methoxyphenylimino)- (30j), 5-(4-Methylphenylamino-
methylene)-4-(4-methylphenylimino)-
(30k),
and
5-(4-Bromophenylaminomethylene)-4-(4-bromo-
phenylimino)-3-methyl-1-(2-pyridyl)-4,5,6,7-tetrahydroindazole (30l) Hydrochlorides. Separately prepared
solutions of the indazole 27 (2 mmol) in absolute ethanol (10 ml) and the corresponding amine (4 mmol) in
absolute ethanol (30 ml) were taken to reflux, combined, and refluxed for 2 h. The precipitation of the compound
30 began even at reflux. The reaction mixture was held for 1 day at room temperature and the precipitated 30
hydrochloride was filtered off. Compounds 30b,i were recrystallized from absolute ethanol and compounds 30c-
h,j-l were carefully washed with absolute ethanol.
5-(2-Chlorophenylaminomethylene)-4-(2-chlorophenylimino)- (31a), 5-(3-Trifluoromethylphenyl-
aminomethylene)-4-(3-trifluoromethylphenylimino)- (31b), 5-Phenylaminomethylene-4-phenylimino-
(31i), 5-(4-Methoxyphenylaminomethylene)-4-(4-methoxyphenylimino)- (31j), 5-(4-Methylphenylamino-
methylene)-4-(4-methylphenylimino)-
(31k),
and
5-(4-Bromophenylaminomethylene)-4-(4-bromo-
phenylimino)-3-methyl-1-(2-pyridyl)-4,5,6,7-tetrahydroindazole (31l). A solution of NaHCO3 (10% aqueous)
was added dropwise with stirring to a suspension of the hydrochloride 30 (2 mmol) in ethanol (10 ml) to pH 8-9.
The precipitated base 31 was filtered off and recrystallized from absolute ethanol.
REFERENCES
1.
2.
J. Zadykowicz and P. G. Potvin, J. Heterocycl. Chem., 36, 623 (1999).
A. J. Angel, A. E. Finefrock, A. R. Williams, J. D. Townsend, T.-H. V. Nguyen, D. R. Hurst,
F. J. Heldrich, C. F. Beam, and I. T. Badejo, J. Heterocycl. Chem., 36, 1231 (1999).
T. Lorand, B. Kocsis, L. Emody, and P. Sohar, Eur. J. Med. Chem., 34, 1009 (1999).
R. F. Kaltenbach, R. M. Klabe, B. C. Cordova, and S. P. Seitz, Bioorg. Med. Chem. Lett., 9, 2259
(1999).
3.
4.
5.
6.
K. Y. Avenell, I. Boyfield, M. S. Hadley, Ch. N. Johnson, D. J. Nash, G. J. Riley, and G. Stemp, Bioorg.
Med. Chem. Lett., 9, 2715 (1999).
Wei-Xu, L.-F. Huang, L. Bauer, H. N. Bhargava, and W. J. Dunr, Bioorg. Med. Chem. Lett., 9, 3375
(1999).
645

7.
8.
9.
I. A. Strakova, L. G. Delyatitskaya, M. V. Petrova, and A. Ya. Strakovs, Khim. Geterotsikl. Soedin., 768
(1998).
I. A. Strakova, L. G. Delyatitskaya, M. V. Petrova, and A. Ya. Strakovs, Khim. Geterotsikl. Soedin.,
1209 (1998).
I. A. Strakova, A. Ya. Strakovs, M. V. Petrova, and L. G. Delyatitskaya, Khim. Geterotsikl. Soedin., 533
(2000).
10.
11.
I. A. Strakova, A. Ya. Strakovs, and M. V. Petrova, Khim. Geterotsikl. Soedin., 494 (2002).
I. A. Strakova, A. Ya. Strakovs, and M. V. Petrova, Khim. Geterotsikl. Soedin., 962 (2000).
646