Chemistry of acyl(imidoyl)ketenes. 8. Thermolysis of 3-alkoxycarbonyl-5- phenyl-1,2,4,5-tetrahydropyrrolo[1,2-a]-quinoxaline-1,2,4-triones. Structure of 2-(3-oxo-4-phenyl-3,4-dihydro-2-quinoxalinyl)-2,4-di(ethoxycarbonyl)-6-phenyl-2, 3,5,6-tetrahydro-1H-p

Article abstract of DOI:10.1007/s10593-005-0061-3

3-Alkoxycarbonylmethylene-1-phenyl-1,2,3,4-tetrahydro-2-quinoxalones, obtained by the interaction of dialkyl esters of oxaloacetic acid and N-phenyl-o-phenylenediamine, react with oxalyl chloride with the formation of 3-alkoxycarbonyl-5-phenyl-1,2,4,5-tet

Full text of DOI:10.1007/s10593-005-0061-3

Chemistry of Heterocyclic Compounds, Vol. 40, No. 11, 2004
NEW DERIVATIVES OF 3-AMINOINDOLE.
SYNTHESIS OF 2-ARYL(HETARYL)-
3-(3,5-DIMETHYL-1-PYRAZOLYL)INDOLES
N. M. Przheval'skii, N. S. Skvortsova, and I. V. Magedov
The interaction of arylhydrazines with ω-(3,5-dimethyl-1-pyrazolyl)acetophenones and acetyl(2-
thiophene) leads to arylhydrazones, which are converted by Fischer cyclization into 2-aryl(thienyl)-3-
(3,3-dimethyl-1-pyrazolyl)indoles with substituents in positions 1, 5, and 7.
Keywords: arylhydrazines, arylhydrazones, pyrazolylindoles.
In a continuation of investigations on the synthesis of 3-aminoindole derivatives [1, 2] we have
developed a method for obtaining new systems containing pyrazole nucleus in position 3 (for a preliminary
communication see [3]). These compounds are promising from the point of view of biological activity, since
indoles and pyrazoles are widely known in this field [4].
Boiling a mixture of a small excess of arylhydrazines 1 with ketones 2 in ethanol in the presence of
catalytic quantities of AcOH leads to arylhydrazones 3, which were converted without isolation into indoles 4 by
heating in ethanol with three moles of thionyl chloride (Fischer indolization).
Ketones 2 were synthesized by the alkylation of 3,5-dimethylpyrazole with ω-haloacetophenones and
ω-chloro-2-acetylthiophene by the procedure of [5] (Table 1).
Me
Me
Me
N
N
+
N
H
+
O
N
NH2
N
Me
N
N
R
R
Ar
Ar
R1
R1
1
2a–c
3
Me
Me
N
N
+
–NH4
.
HCl
Ar
N
R
R1
4a–o
2a, 4a-d Ar = Ph, 2b, 4e-i Ar = p-chlorophenyl, 2c, 4j-o Ar = 2-thienyl; 4 a,e,j R = H,
b,f,k R = 5-Me, c,h,l R = Cl, d,m R = 5-F, g R = 5-Br, i,n R = 5-OMe, o R = 7-Me,
a-h, j-o R1 = H, i R1 = CH2Ph
__________________________________________________________________________________________
Moscow K. A. Timiryazev Agricultural Academy, Moscow 127550, Russia; e-mail: ibs@ibisc.msk.ru.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1662-1669, November, 2004. Original
article submitted July 5, 2002; revision submitted October 10, 2002.
0009-3122/04/4011-1435©2004 Springer Science+Business Media, Inc.
1435

TABLE 1. Physicochemical and Spectral Characteristics of Compounds 2a-c
Found, %
Calculated, %
1Н NMR spectrum, δ, ppm (J, Hz)
Pyrazole ring
——————
Com-
pound*
Empirical
formula
mp, °С
(i-PrOH)
Yield,
%
CH2
C
H
N
Ar
(2H, s)
2a
52.50
52.90
5.07
5.12
9.41
9.49
162-163
8.05 (2H, d, J = 8.3, H-2,6);
7.72 (1H, t, J = 7.2, J = 1.3, H-4);
7.59 (2H, t, J = 8.3, J = 7.2, H-3,5)
6.01 (1H, s, H-4); 2.33 (3H, s,
CH3-3); 2.15 (3H, s, CH3-5)
5.76
61
C13H14N2O·HBr
2b
2c
47.42
47.37
4.31
4.28
8.29
8.50
193-194
212-213
8.18 (2H, d, J = 8.8, H-2,6);
7.72 (2H, d, J = 8.8, H-3,5)
6.28 (1H, s, H-4); 2.35 (3H, s,
CH3-3); 2.31 (3H, s, CH3-5)
6.13
6.04
60
54
C13H13ClN2O
·
HBr
43.92
43.86
4.33
4.35
9.18
9.30
8.25 (1H, d, J = 3.8, H-3); 8.21 (1H, d, 6.27 (1H, s, H-4); 2.37 (3H, s,
J = 4.9, H-5); 7.38 (1H, m, H-4) CH3-3); 2.31 (3H, s, CH3-5)
C11H12N2OS·HBr
_______
* (3,5-Dimethyl-1H-1-pyrazolyl)methyl phenyl ketone hydrobromide (2a), (3,5-dimethyl-1H-1-pyrazolyl)methyl
4-chlorophenyl ketone hydrobromide (2b), (3,5-dimethyl-1H-1-pyrazolyl)methyl 2-thienyl ketone hydrobromide (2c).

TABLE 2. 1H NMR Spectral Characteristics of Compounds 4a-o
Com-
pound
Chemical shifts, δ, ppm. (J, Hz)*
Indole ring
2
Ar
3
R1
4
R
5
Pyrazole ring
6
1
4a
7.51 (1H, s, H-7); 7.23 (1H, m, H-6);
7.16 (1H, m, H-4); 7.08 (1H, m, H-5)
7.40-7.30 (5H, m, Harom
)
)
)
11.91 (1H, br. s)
11.80 (1H, br. s)
12.68 (1H, br. s)
10.17 (1H, br. s)
12.35 (1H, br. s)
—
6.18 (1H, s, H-4); 2.26 (3H, s, CH3-3);
1.86 (3H, s, CH3-5)
4b
4c
4d
4e
7.44 (1H, m, H-7); 7.07 (1H, d, J = 8.3, H-6); 7.42-7.39 (5H, m, Harom
7.00 (1H, s, H-4)
2.28
(3H, s, CH3)
6.14 (1H, s, H-4); 2.38 (3H, s, CH3-3);
1.91 (3H, s, CH3-5)
7.68 (1H, d, J = 8.3, H-7); 7.28 (1H, s, H-4);
7.26 (1H, d, J = 8.3, H-6)
7.44 (1H, m, H-7); 7.00 (1H, td, JH-H = 8.3,
7.49-7.40 (5H, m, Harom
—
—
—
6.31 (1H, s, H-4); 2.36 (3H, s, CH3-3);
1.96 (3H, s, CH3-5)
6.07 (1H, s, H-4); 2.25 (3H, s, CH3-3);
1.87 (3H, s, CH3-5)
7.32 (2H, d, J = 8.7, H-2,6);
JH-F = 9.4, H-6); 6.88 (1H, dd, JH-F = 9.4, H-4) 7.20 (3H, m, H-3,4,5.)
7.61 (1H, d, J = 7.7, H-4); 7.28 (1H, m, H-5); 7.49 (2H, d, J = 8.8, H-2,6);
7.26 (1H, d, J = 7.7, H-7); 7.14 (1H, t,
J = 7.7, H-6)
6.29 (1H, s, H-4); 2.33 (3H, s, CH3-3);
1.98 (3H, s, CH3-5)
7.46 (2H, d, J = 8.8, H-3,5)
4f
7.47 (1H, m, H-7); 7.03 (1H, d, J = 8.2, H-6); 7.47 (2H, m, H-2,6);
12.00 (1H, br. s)
12.10 (1H, br. s)
12.08 (1H, br. s)
2.38
(3H, s, CH3)
6.22 (1H, s, H-4); 2.31 (3H, s, CH3-3);
1.95 (3H, s, CH3-5)
6.10 (1H, s, H-4)
7.41 (2H, d, J = 8.8, H-3,5)
4g
4h
7.47 (1H, d, J = 8.8, H-7); 7.34 (1H, d,
J = 8.8, H-6); 7.24 (1H, s, H-4)
7.48 (2H, d, J = 8.8, H-2,6);
7.26 (2H, d, J = 8.8, H-3,5)
—
6.10 (1H, s, H-4); 2.23 (3H, s, CH3-3);
1.83 (3H, s, CH3-5)
7.57 (1H, d, J = 8.8, H-7); 7.23 (1H, d,
J = 8.8, H-6); 7.10 (1H, s, H-4)
7.48 (2H, d, J = 8.8, H-2,6);
7.27 (2H, d, J = 8.8, H-3,5)
—
6.10 (1H, s, H-4); 2.23 (3H, s, CH3-3);
1.83 (3H, s, CH3-5)

TABLE 2 (continued)
1
2
3
4
5
6
4i
7.43 (1H, d, J = 8.3, H-7); 6.86 (1H, m, H-6); 7.43 (2H, d, J = 8.8, H-2,6);
6.60 (1H, s, H-4) 7.27 (2H, d, J = 8.8, H-3,5)
7.25-7.21 (3H, m, H-3,4,5);
6.90 (2H, m, H-2,6);
5.45 (2H, s, CH2)
3.70
(3H, s, OCH3)
5.93 (1H, s, H-4); 2.16 (3H, s, CH3-3);
1.79 (3H, s, CH3-5)
4j
4k
4l
7.26 (1H, m, H-7); 7.12-7.00 (3H, m, H-4,5,6) 7.05 (1H, d, J = 4.4, H-5);
6.63 (1H, d, J = 3.3, H-3);
10.09 (1H, br. s)
11.79 (1H, br. s)
12.23 (1H, br. s)
—
6.10 (1H, s, H-4); 2.32 (3H, s, CH3-3);
2.04 (3H, s, CH3-5)
6.55 (1H, m, H-4)
7.35 (1H, m, H-7); 7.02 (1H, d, J = 8.3, H-6); 7.53 (1H, d, J = 4.9, H-5);
2.33
(3H, s, CH3)
6.14 (1H, s, H-4); 2.22 (3H, s, CH3-3);
1.90 (3H, s, CH3-5)
7.32 (1H, m, H-3); 7.10 (1H, t,
J = 4.9, J = 3.9, H-4)
6.85 (1H, s, H-4)
7.48 (1H, d, J = 8.3, H-7); 7.21 (1H, d, J = 8.3, 7.59 (1H, d, J = 3.9, H-5);
—
—
6.17 (1H, s, H-4); 2.23 (3H, s, CH3-3);
1.91 (3H, s, CH3-5)
H-6); 7.04 (1H, s, H-4)
7.38 (1H, d, J = 3.3, H-3);
7.13 (1H, t, J = 3.9,
J = 3.3, H-4)
4m
4n
4o
7.56 (1H, m, H-7); 7.00 (1H, td, JH-H = 8.3,
JH-F = 9.4, H-6); 6.88 (1H, d. d,
7.64 (1H, d, J = 4.9, H-5);
7.54 (1H, d, J = 3.9, H-3);
7.16 (1H, t, J = 4.9,
J = 3.9, H-4)
12.40 (1H, br. s)
11.90 (1H, br. s)
11.85 (1H, br. s)
6.26 (1H, s, H-4); 2.30 (3H, s, CH3-3);
2.02 (3H, s, CH3-5)
J
H-F = 9.4, H-4)
7.42 (1H, m, H-7); 6.88 (1H, d, J = 8.8, H-6); 7.57 (1H, d, J = 4.9, H-5);
3.77
(3H, s, OCH3)
6.19 (1H, s, H-4); 2.27 (3H, s, 3-CH3);
2.00 (3H, s, CH3-5)
6.85 (1H, s, H-4)
7.39 (1H, d, J = 3.9, H-3);
7.13 (1H, t, J = 4.9,
J = 3.9, H-4)
7.10-7.04 (3H, m, H-4,5,6)
7.76 (1H, d, J = 3.9, H-3);
7.61 (1H, d, J = 4.9, H-5);
7.16 (1H, t, J = 4.9,
J = 3.9, H-4)
2.63
(3H, s, CH3)
6.33 (1H, s, H-4); 2.34 (3H, s, CH3-3);
2.03 (3H, s, CH3-5)
_______
1
* The H NMR spectra were taken in DMSO (compounds 4a,g-i,k,l), DMF (compounds 4b,s,e,f,m-o), CD3CN
(compound 4d), and CDCl3 (compound 4j).

TABLE 3. Characteristics of Indoles 4
Found, %
Calculated, %
H
——————
Com-
pound*
Empirical
formula
Name
mp, °С
Yield, %
C
N
4a
4b
4c
4d
4e
4f
3-(3,5-Dimethyl-1H-1-pyrazolyl)-2-phenyl-1H-indole
hydrochloride
70.54
70.47
5.70
5.60
12.72
12.98
189-190
(aq. EtOH)
46
48
38
40
38
57
25
40
38
46
56
24
38
29
32
C19H17N3
·
HCl
HCl
3-(3,5-Dimethyl-1H-1-pyrazolyl)-5-methyl-2-phenyl-
1H-indole hydrochloride
71.20
71.10
5.90
5.97
12.16
12.44
290-291
(aq. EtOH)
C20H19N3
·
5-Chloro-3-(3,5-dimethyl-1H-1-pyrazolyl)-2-phenyl-
1H-indole hydrochloride
63.61
63.70
4.74
4.78
11.70
11.73
292-293
(aq. EtOH)
C19H16ClN3
C19H16FN3
C19H16ClN3
C20H18ClN3
·HCl
5-Fluoro-3-(3,5-dimethyl-1H-1-pyrazolyl)-2-phenyl-
1H-indole
74.86
74.74
5.26
5.28
13.48
13.76
242-243
(aq. EtOH)
2-(4-Chlorophenyl)-3-(3,5-dimethyl-1H-1-pyrazolyl)-
1H-indole hydrochloride
2-(4-Chlorophenyl)-3-(3,5-dimethyl-1H-1-pyrazolyl)-5-methyl-
1H-indole hydrochloride
63.73
63.70
4.70
4.78
11.52
11.73
209-210
(aq. i-PrOH)
·
HCl
HCl
64.39
64.52
5.18
5.14
10.96
11.29
310-311
(aq. EtOH)
·
5-Bromo-2-(4-chlorophenyl)-3-(3,5-dimethyl-1H-1-pyrazolyl)-
1H-indole hydrochloride
4g
4h
4i
C19H15BrClN3
·
HCl
52.27
52.20
3.74
3.69
9.55
9.61
307-308
(aq. i-PrOH)
5-Chloro-2-(4-chlorophenyl)-3-(3,5-dimethyl-1H-1-pyrazolyl)-
1H-indole hydrochloride
58.80
58.11
4.07
4.11
10.53
10.70
302-303
(aq. EtOH)
195-196
(aq. EtOH)
C19H15Сl2N3
C27H24ClN3
C17H15N3S
C18H17N3S
·HCl
1-Benzyl-2-(4-chlorophenyl)-5-methoxy-3-(3,5-dimethyl-
1H-1-pyrazolyl)-1H-indole
73.46
73.38
5.39
5.47
9.47
9.51
4j
3-(3,5-Dimethyl-1H-1-pyrazolyl)-2-(2-thienyl)-1H-indole
69.47
69.60
5.11
5.15
14.30
14.32
230-231
(C6H6–C6H14)
4k*
4l
3-(3,5-Dimethyl-1H-1-pyrazolyl)-5-methyl-2-(2-thienyl)-
1H-indole
70.47
70.33
5.66
5.57
13.51
13.67
263-264
(aq. EtOH)
5-Chloro-3-(3,5-dimethyl-1H-1-pyrazolyl)-2-(2-thienyl)-
1H-indole hydrochloride
55.92
56.05
4.25
4.15
11.20
11.53
280-281
(aq. EtOH)
C17H14СlN3S
C17H14FN3S HCl
C18H17N3OS HCl
C18H17N3S HCl
·HCl
4m
4n
4o
·
5-Fluoro-3-(3,5-dimethyl-1H-1-pyrazolyl)-2-(2-thienyl)-
1H-indole hydrochloride
58.79
58.70
4.35
4.35
11.87
12.08
230-231
(aq. CH3CN)
5-Methoxy-3-(3,5-dimethyl-1H-1-pyrazolyl)-2-(2-thienyl)-
1H-indole hydrochloride
3-(3,5-Dimethyl-1H-1-pyrazolyl)-7-methyl-2-(2-thienyl)-
1H-indole hydrochloride
60.25
60.09
5.00
5.04
11.34
11.68
257-258
(aq. i-PrOH)
227-228
(aq. i-PrOH)
·
63.10
62.87
5.33
5.28
12.08
12.22
·
_______
* Compounds 4d,i-k are bases.

1
The structures of indoles 4 were demonstrated by H NMR method (Table 2) and confirmed by data of
elemental analysis (Table 3).
The influence of the substituents in the benzene ring of arylhydrazines 1 on the yield of pyrazolylindoles
4 was on the whole as described previously for 2-phenyl-3-(N-acylamino)indoles [2]. A methyl group increases
the yield of indoles somewhat compared with unsubstituted phenylhydrazine (cf. 4b and 4a, 4f and 4e, 4k and
4j). Other substituents (Cl, Br, F, MeO) reduce the yield, which was discovered for the three groups of the
studied indoles containing various aromatic groups in position 2 [cf. for example, for R = Cl and R = H: 4c and
4a (38 and 46%, phenyl), 4h and 4e (40 and 57%, p-chlorophenyl), 4l and 4j (24 and 46%, 2-thienyl)]. The
indicated aromatic substituents (Ar) in ketones 2 , as might have been expected, had little effect on the yield of
pyrazolylindole (4), 4a-d, 38-46% (phenyl); 4e-i, 24-57% (p-chlorophenyl); 4j-o, 24-56% (2-thienyl).
The proposed scheme enables the preparation of compounds containing three of the most important
pharmacophoric groups, indole, pyrazole, and thiophene, in one molecule (4j-o). Attempts to introduce an
imidazole ring into indole position
3
proved to be unsuccessful. The reaction between
ω-(1-imidazolyl)acetophenone and phenylhydrazine under various conditions (thionyl chloride in EtOH, PPA
[polyphosphoric acid], or HBr in EtOH) led to complex mixtures of unidentified products.
EXPERIMENTAL
The 1H NMR spectra of compounds 2 and 4 were recorded on a Bruker WM 250 (250 MHz) instrument.
A check on the progress of reactions was effected by TLC on Sorbfil plates in the system CCl4—EtOAc, 6 : 1.
Commercial arylhydrazines (from Lancaster and Aldrich) were used in the work. The sodium salt of
2-(4-methoxyphenyl)hydrazinesulfonic acid was synthesized by the procedure of [6].
ω-(3,5-Dimethyl-1-pyrazolyl)acetophenones and (3,5-Dimethyl-1-pyrazolyl)methyl 2-Thienyl
Ketone (2a-c) were synthesized by the procedure given in [5] for pyrazole.
1H-1-Imidazolylmethyl Phenyl Ketone Hydrobromide was obtained by the alkylation of imidazole
1
with ω-bromoacetophenone in alcohol at 0°C, yield 55%, mp 245-246°C (EtOH). H NMR spectrum (DMSO),
δ, ppm (J, MHz): 9.07 (1H, s, H-2 Imid); 8.07 (2H, d, J = 7.8, H-2,6 Phe); 7.78 (3H, m, H-4,5 Imid, H-4 Phe);
7.65 (2H, t, J = 7.8, J = 7.1, H-3,5 Phe). Found, %: C 49.29; H 4.00; N 10.16. C11H10N2O.HBr. Calculated, %:
C 49.46; H 4.15; N 10.49.
Hydrazones (3) (General Procedure). Glacial AcOH (several drops) or AcONa (6.3 mmol) was added
to solution of phenylhydrazine base or hydrochloride 1 (3.3 mmol) respectively and ketone hydrobromide 2
(3.0 mmol) in the minimum volume of EtOH (10 ml). The mixture was boiled under reflux for 3 h. The resulting
precipitate of NaCl and NaBr was removed from the solution by hot filtration. Alcohol was evaporated, the
resulting oil was used without further purification to prepare indoles 4.
Indoles 4a-m,o (General Procedure). Solution of thionyl chloride (9.0 mmol) in EtOH (5 ml) was
added to solution of hydrazone 3a-m,o (3.0 mmol) in EtOH (5 ml), and the mixture was boiled under reflux for
3-4 h. Alcohol was evaporated, the residue washed from the NH4Cl formed with water, then either crystallized to
obtain hydrochlorides of pyrazolylindoles (4a-c,e-h,l,m,o) or pyrazolylindoles were isolated as bases (4d,i-k) by
column chromatography (silica gel L 100 × 250 µm, eluent CCl4–EtOAc, 8:1).
5-Methoxy-3-(3,5-dimethyl-1H-1-pyrazolyl)-2-(2-thienyl)-1H-indole (4n). Solution of thionyl
chloride (9.0 mmol) in EtOH (5 ml) was added to solution of 2-(4-methoxyphenyl)hydrazinesulfonic acid
sodium salt (4.0 mmol) and ketone hydrobromide 2c (3.0 mmol) in EtOH (10 ml) and the mixture was boiled
under reflux for 16 h. Alcohol was evaporated, and the residue washed with water to remove ammonium salt
formed. The residue was recrystallized from 2-PrOH.
1440

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Vysoke Tatry, Slovak Republic (2002), p. 198.
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1441