1-(2-Quinoxalyl)-, 1-[3,5-di-(trifluoromethyl)phenyl]-, 1-(2-carboxyphenyl)-, and 1-ethoxycarbonyl-4-oxo-4,5,6,7-tetrahydroindazoles

Article abstract of DOI:10.1023/A:1016079221645

The corresponding 1-(2-quinoxalyl)-, 1-[3,5-di(tridluoromethyl)phenyl]-, and 1-ethoxycarbonyl-3-methyl-4-oxo-4,5,6,7-tetrahydroindazoles have been obtained from reactions of 2-acetyl-1,3-cyclohexanedione, its 5,5-dimethyl and 5-(2-furyl) derivatives, with 2-hydrazinoquinoxaline, 3,5-di(trifluoromethyl)phenylhydrazine, and ethoxycarbonylhydrazine. On interaction with ethoxycarbonylhydrazine the intermediate 2-[1-(β-ethoxycarbonyl)hydrazino]ethylidene-1,3-cyclohexanediones were also isolated. From the potassium salt of 2-formyldimedone and 2-carboxyphenylhydrazine hydrochloride, 2-(2-carboxyphenyl)hydrazinomethylene-5,5-dimethyl-1,3-cyclohexanedione was obtained, the cyclization of which in ethanol in the presence of HCl led to 1-(2-carboxyphenyl)- and 1-(2-ethoxycarbonylphenyl)-6,6-dimethyl-4-oxo-4,5,6,7 -tetrahydroindazole.

Full text of DOI:10.1023/A:1016079221645

Chemistry of Heterocyclic Compounds, Vol. 38, No. 4, 2002
1-(2-QUINOXALYL)-, 1-[3,5-DI-
(TRIFLUOROMETHYL)PHENYL]-,
1-(2-CARBOXYPHENYL)-, AND
1-ETHOXYCARBONYL-4-OXO-
4,5,6,7-TETRAHYDROINDAZOLES
I. Strakova, A. Strakovs, and M. Petrova
The corresponding 1-(2-quinoxalyl)-, 1-[3,5-di(trifluoromethyl)phenyl]-, and 1-ethoxycarbonyl-3-
methyl-4-oxo-4,5,6,7-tetrahydroindazoles have been obtained from reactions of 2-acetyl-1,3-
cyclohexanedione, its 5,5-dimethyl and 5-(2-furyl) derivatives, with 2-hydrazinoquinoxaline,
3,5-di(trifluoromethyl)phenylhydrazine, and ethoxycarbonylhydrazine. On interaction with
ethoxycarbonylhydrazine
the
intermediate
2-[1-(β-ethoxycarbonyl)hydrazino]ethylidene-1,3-
cyclohexanediones were also isolated. From the potassium salt of 2-formyldimedone and
2-carboxyphenylhydrazine hydrochloride, 2-(2-carboxyphenyl)hydrazinomethylene-5,5-dimethyl-1,3-
cyclohexanedione was obtained, the cyclization of which in ethanol in the presence of HCl led to
1-(2-carboxyphenyl)- and 1-(2-ethoxycarbonylphenyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazole.
Keywords: 1-(2-carboxyphenyl)-, 1-[3,5-di(trifluoromethyl)phenyl]-, 1-(2-quinoxalyl)-, and
1-(ethoxycarbonyl)-4-oxo-4,5,6,7-tetrahydroindazoles.
Derivatives of indazole hydrogenated in the carbocyclic part attract attention for several reasons, the
principal of which their biological activity [1-6]. Consequently, developing our studies on the modification of
indazoles, particularly on the synthesis of indazoles with a heterocyclic [7-9] or a substituted phenyl group
[6,10,11] at nitrogen, we have carried out the reactions of 2-acetyl-1,3-cyclohexanedione (1a), its 5,5-dimethyl
(1b) and 5-(2-furyl) (1c) derivatives with 2-hydrazinoquinoxaline (2), 3,5-di(trifluoromethyl)phenylhydrazine
(3), and ethoxycarbonylhydrazine (4).
Refluxing equimolar quantities of acetyl derivatives 1 with hydrazine 3 in ethanol for 2 h leads directly
to the indazole 6 in 85-90% yield. Isolation of the intermediate 2-(1-hydrazinoethylidene) product was
unsuccessful. The formation of 1-(2-quinoxalyl)indazoles 5 requires more rigid reaction conditions, viz.
refluxing in ethanol in the presence of catalytic amounts of acid for 5 h, but also in this case isolation of the
intermediate products of the first condensation was unsuccessful. Indazoles 7 from acetyl derivatives 1 and
ethoxycarbonylhydrazine 4 may be obtained only on extended refluxing (20 h) in ethanol in the presence of
p-toluenesulfonic acid. Refluxing the same reactants for 5 min gives 2-[1-(β-ethoxycarbonylhydrazino)-
ethylidene]-1,3-cyclohexanediones 8, which are cyclized into indazoles 7 on refluxing for 20 h in ethanol in the
presence of acid.
__________________________________________________________________________________________
Riga Technical University, Riga LV-1658, Latvia; e-mail: marina@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 4, pp. 494-498, April, 2002. Original article submitted December 9, 1999.
0009-3122/02/3804-0429$27.00©2002 Plenum Publishing Corporation
429

N
N
N
R
N
H2NNH
R1
N
N
2
O
CH3
5a–c
CF3
CF3
R
R1
O
R
R1
CF3
H2NNH
CF3
3
N
COCH3
N
O
1a–c
O
CH3
6
H2NNH–COOC2H5
4
R
R1
O
R
R1
COOC2H5
H
N
N
N
H+
NHCOOC2H5
O
CH3
O
CH3
8a–c
7
1, 5–8 a R = R1= H; b R = R1= CH3; c R =
R1 = H
,
O
O
.
.
COOH
O
.
H
+
N
NHNH2
N
H
CHO
O
11
H
O
9
HOOC
10
N
N
EtOH + H+
N
N
COOC2H5
11
+
COOH
O
O
13
12
2-(2-Carboxyphenyl)hydrazinomethylene-5,5-dimethyl-1,3-cyclohexanedione (11) was obtained from
the potassium salt of 2-formyldimedone (9) and 2-hydrazinobenzoic acid hydrochloride (10). Refluxing
compound 11 in ethanol in the presence of HCl leads to a mixture of 1-(2-carboxyphenyl)- (12) and
1-(2-ethoxycarbonylphenyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazoles (13), which is readily separated by
dissolving acid 12 in alkali.
The structures of the compounds synthesized were confirmed by the data of IR and 1H NMR spectra. In
the IR spectra the keto group of indazoles 5-7, 12, and 13 is characterized by an intense maximum at 1662-1682,
and the ester group of indazoles 7 by a band at 1747-1752 cm-1. The IR spectra of 2-hydrazinoethylidene-1,3-
cyclohexanediones 8 remind the spectra of arylhydrazones of 2-acetyl-1,3-cyclohexanediones [12] with a low
1
intensity maximum at 1628-1633 and a broad intense absorption band at 1560-1590 cm-1. In the H NMR
430

spectra of the hydrazinoethylidene derivatives 8 a signal for the proton of the NH group was present in contrast
to that of the indazoles 5-7. The spectrum of the hydrazinomethylene derivative 11 was characterized by the
presence of signals for the protons of the trans-fixed =CH–NH– fragment and of signals for the protons of the
NH and COOH groups.
EXPERIMENTAL
The IR spectra were taken on a Specord IR 75 spectrometer for suspensions of substances in nujol
(1500-1800 cm-1) and hexachlorobutadiene (2000-3600 cm-1). The frequencies of the stretching vibrations of the
C–H bonds at 2800-3050 cm-1 are not given. The 1H NMR spectra were taken on a Bruker WH 90/DS (90 MHz)
spectrometer in CDCl3 and DMSO-d6 (internal standard TMS).
3-Methyl-1-(2-quinoxalyl)- (5a), 3,6,6-Trimethyl-1-(2-quinoxalyl)- (5b), and 6-(2-Furyl)-3-methyl-
1-(2-quinoxalyl)- (5c) 4-Oxo-4,5,6,7-tetrahydroindazoles. 2-Hydrazinoquinoxaline 2 (about 5 mmol) and the
corresponding 2-acetyl-1,3-cyclohexanedione 1 in abs. ethanol (40 ml) were refluxed for 2 h, p-toluenesulfonic
acid (0.02 g) was added and the mixture refluxed for a further 3 h. The reaction mixture was cooled, the solid
was filtered off, and recrystallized. Before crystallization compound 5a was maintained in a flask with a
fractionating column in an oil bath at 200-220°C (bath temperature) for 1 h.
1
5a. Yield 56%; mp 182-184°C (acetic acid). IR spectrum, cm-1: 1670 (C=O). H NMR spectrum
(DMSO-d6), δ, ppm, J (Hz): 2.12 (2H, m, C(6)H2); 2.48 (3H, s, C(3)–CH3); 2.50 (2H, m, C(5)H2); 3.52 (2H, t,
3J = 6, C(7)H2); 7.98 (4H, br m, C6H4); 9.45 (1H, s, CHquinoxaline). Found, %: C 69.22; H 5.01; N 20.20.
C16H14N4O. Calculated, %: C 69.05; H 5.07; N 20.13.
1
5b. Yield 92%; mp 200-202°C (DMF). IR spectrum, cm-1: 1667 (C=O). H NMR spectrum (CDCl3),
δ, ppm: 1.12 (6H, s, 2CH3); 2.41 (2H, s, C(5)H2); 2.56 (3H, s, C(3)–CH3); 3.41 (2H, s, C(7)H2); 7.68-8.25 (4H, m,
C6H4); 9.61 (1H, s, CHquinoxaline). Found, %: C 70.66; H 5.81; N 18.18. C18H18N4O. Calculated, %: C 70.57;
H 5.92; N 18.29.
5c. Yield 88%; mp 189-191°C (DMF). IR spectrum, cm-1: 1677 (C=O). 1H NMR spectrum (DMSO-d6),
δ, ppm: 2.45 (3H, s, C(3)–CH3); 2.76 (1H, m, C(6)H); 3.5-4.11 (4H, m, C(5)H2, C(7)H2); 6.20 (1H, m, C4H3O); 7.56
(1H, m, C4H3O); 7.89 (4H, br. m, C6H4); 9.42 (1H, s, CHquinoxaline). Found, %: C 69.82; H 4.60; N 16.11.
C20H16N4O2. Calculated, %: C 69.75; H 4.68; N 16.27.
1-[3,5-Di(trifluoromethyl)phenyl]-3-methyl-4-oxo-4,5,6,7-tetrahydroindazole (6a). A solution of
compound 1a (5 mmol) and hydrazine 3 (5 mmol) in abs. ethanol (20 ml) was refluxed for 2 h. Water (10 ml)
was added to the hot reaction mixture, which was then cooled. The solid was filtered off, and recrystallized
1
from 60% ethanol. Yield 89%; mp 112-113°C. IR spectrum, cm-1: 1682 (C=O). H NMR spectrum (CDCl3),
δ, ppm, J (Hz): 2.21 (2H, m, C(6)H2); 2.50 (2H, m, C(5)H2); 2.52 (3H, s, C(3)–CH3); 3.03 (2H, t, 3J = 6.5, C(7)H2);
4
4
7.82 (1H, m, J < 1.5, C6H3); 8.01 (2H, m, J < 1.5, C6H3). Found, %: C 52.90; H 3.30; N 7.60. C16H12F6N2O.
Calculated, %: C 53.04; H 3.34; N 7.73.
3,6,6-Trimethyl- (6b) and 6-(2-Furyl)-3-methyl- (6c) [1-(3,5-Di(trifluoromethyl)phenyl]-4-oxo-
4,5,6,7-tetrahydroindazoles were obtained analogously to compound 6a from equimolar amounts of hydrazine
1
3 and compounds 1b,c. 6b. Yield 54%; mp 128-130°C (ethanol). IR spectrum, ν, cm-1: 1676 (C=O). H NMR
spectrum (CDCl3), δ, ppm: 1.14 (6H, s, 2CH3); 2.41 (2H, s, C(5)H2); 2.54 (3H, s, C(3)–CH3); 2.83 (2H, s, C(7)H2);
7.89 (1H, m, C6H3); 8.01 (2H, m, C6H3). Found, %: C 55.19; H 4.02; N 7.11. C18H16F6N2O. Calculated, %:
C 55.39; H 4.13; N 7.18.
1
6c. Yield 86%; mp 101-102°C (60% ethanol). IR spectrum, ν, cm-1: 1677 (C=O). H NMR spectrum,
(CDCl3), δ, ppm, J (Hz): 2.53 (3H, s, C(3)–CH3); 2.86 (2H, m, (C(5)H2); 3.25 (2H, m, C(7)H2); 3.67 (1H, m, C(6)H);
4
6.09 (1H, m, C4H3O); 6.32 (1H, m, C4H3O); 7.32 (1H, m, C4H3O); 7.89 (1H, m, J < 1.5, C6H3); 8.01 (2H, m,
4J = 1.5, C6H3). Found, %: C 55.90; H 3.13; N 6.39. C20H14F6N2O2. Calculated, %: C 56.08; H 3.29; N 6.54.
431

3-Methyl- (7a), 3,6,6-Trimethyl- (7b), and 6-(2-Furyl)-3-methyl- (7c) 1-Ethoxycarbonyl-4-oxo-
4,5,6,7-tetrahydroindazoles. A. A solution of compound 1a-c (5 mmol), hydrazine 4 (5 mmol), and
p-toluenesulfonic acid (0.05 g) in abs. ethanol (20 ml) was refluxed for 20 h. The reaction mixture was cooled,
the solid filtered off, and recrystallized from ethanol.
B. A solution of the hydrazinoethylidene derivative 8 (5 mmol) and p-toluenesulfonic acid (0.05 g) in
abs. ethanol (20 ml) was refluxed for 20 h. The reaction mixture was cooled, the solid was filtered off, and
recrystallized from ethanol.
The yield of products obtained by method A is indicated below.
1
7a. Yield of product was 83%; mp 123-125°C. IR spectrum, ν, cm-1: 1752, 1664 (C=O). H NMR
3
3
spectrum (CDCl3), δ, ppm, J (Hz): 1.42 (3H, t, J = 7, CH3CH2); 2.16 (2H, m, C(6)H2); 2.47 (2H, t, J = 7,
3
4
C(5)H2); 2.49 (3H, s, C(3)–CH3); 3.21 (2H, t, J = 7, C(7)H2); 4.49 (2H, q, J = 7, CH3CH2). Found, %: C 58.48;
H 6.47; N 12.78. C11H14N2O3. Calculated, %: C 59.45; H 6.35; N 12.60.
7b. Yield 52%; mp 109-111°C. IR spectrum, ν, cm-1: 1747, 1677 (C=O). H NMR spectrum (CDCl3),
1
3
δ, ppm, J (Hz): 1.09 (6H, s, 2CH3); 1.47 (3H, t, J = 7, CH3CH2); 2.34 (2H, s, C(5)H2); 2.47 (3H, s, C(3)–CH3);
3
3.09 (2H, s, C(7)H2); 4.49 (2H, q, J = 7, CH3CH2). Found, %: C 62.19; H 7.11; N 11.11. C13H18N2O3.
Calculated, %: C 62.38; H 7.25; N 11.19.
7c. Yield 61%; mp 127-128°C. IR spectrum, ν, cm-1: 1747, 1677 (C=O). H NMR spectrum (CDCl3),
1
δ, ppm, J (Hz): 1.45 (3H, t, 3J = 7, CH3CH2); 2.49 (3H, s, C(3)–CH3); 2.78 (4H, m, C(5)H2, C(7)H2); 3.61 (1H, m,
3
3
3
3
C(6)H); 4.54 (2H, q, J = 7, CH3CH2); 6.09 (1H, d, J = 6, C4H3O); 6.29 (1H, d d, J = 6, J = 2, C4H3O); 7.34
3
(1H, d, J = 2, C4H3O. Found, %: C 61.53; H 5.61; N 10.43. C15H16N2O4. Calculated, %: C 62.49; H 5.59;
N 9.72.
5,5-H- (8a), 5,5-Dimethyl- (8b), and 5-(2-Furyl)- (8c) 2-[1-(β-Ethoxycarbonyl)hydrazine]-
ethylidene-1,3-cyclohexanediones. A solution of hydrazine 4 (5 mmol) in abs. ethanol (5 ml) heated to
70-75°C was poured into a solution of acetyl derivative 1 (5 mmol) in abs. ethanol (15 ml) heated to the same
temperature, and the reaction mixture was refluxed for 5 min. The mixture was cooled, the solid was filtered off,
and recrystallized from ethanol, without extended refluxing.
1
8a. Yield 61%; mp 118-119°C. IR spectrum, ν, cm-1: 1752, 1628 (C=O); 3200-3240 (N–H). H NMR
3
spectrum (CDCl3), δ, ppm, J (Hz): 1.23 (3H, t, J = 7, CH3CH2); 1.91 (2H, m, C(5)H2); 2.49 (4H, m, C(4)H2,
C(6)H2); 2.61 (3H, s, C(2′)–CH3); 4.24 (2H, q, 3J = 7, CH3CH2); 8.21 (1H, br s, NH–CO); 14.80 (1H, br. s, NH–C(2′)).
Found, %: C 55.17; H 6.80; N 11.51. C11H16N2O4. Calculated, %: C 54.99; H 6.71; N 11.66.
1
8b. Yield 63%; mp 93-94°C. IR spectrum, ν, cm-1: 1742, 1632 (C=O); 3180-3200 (NH). H NMR
3
spectrum (CDCl3), δ, ppm, J (Hz): 0.99 6H, s, 2CH3); 1.27 (3H, t, J = 7, CH3CH2); 2.33 (4H, br. s, C(4)H2,
C(6)H2); 2.57 (3H, s, C(2)–CH3); 4.27 (2H, q, 3J = 7, CH3CH2); 8.22 (1H, br s, NH-CO); 16.63 (1H, br. s, NH–C(2′)).
Found, %: C 58.38; H 7.52; N 10.30. C13H20N2O4. Calculated, %: C 58.19; H 7.51; N 10.44.
8c. Yield 80%; mp 149-150°C. IR spectrum, ν, cm-1: 1724, 1641 (C=O); 3290-3310, 3130 (NH).
3
1H NMR spectrum (CDCl3), δ, ppm, J (Hz): 1.24 (3H, t, J = 7, CH3CH2); 2.02 (3H, s, C(2′)CH3); 2.23 (4H, m,
C(4)H2, C(6)H2); 3.38 (1H, m, C(5)H); 4.19 (2H, q, 3J = 7, CH3CH2); 6.05 (1H, m, C4H3O); 6.27 (1H, m, C4H3O);
7.33 (1H, m, C4H3O); 7.94 (1H, br. s, NH–CO); 14.72 (1H, br. s, NH–C(2′)). Found, %: C 58.65; H 5.80; N 9.11.
C15H18N2O5. Calculated, %: C 58.81; H 5.92; N 9.14.
2-(2-Carboxyphenyl)hydrazinomethylene-5,5-dimethyl-1,3-cyclohexanedione (11). A solution of
2-hydrazinobenzoic acid hydrochloride (1.89 g, 10 mmol) heated to 60-70°C was poured into a solution of
2-formyldimedone potassium salt (9) (2.06 g, 10 mmol) in water (20 ml) at the same temperature. The reaction
mixture was cooled, the solid was filtered off, and recrystallized from ethanol. Yield 84%; mp 223-225°C.
IR spectrum, ν, cm-1: 1635 (C=O). 1H NMR spectrum (CDCl3), δ, ppm, J (Hz): 1.07 (6H, s, 2CH3); 2.34 (2H, s,
C(4,6)H2); 2.41 (2H, s, C(4,6)H2); 4.5 (1H, br. s, COOH); 6.94 (2H, m, C6H4); 7.48 (1H, m, C6H4); 7.98 (1H, dd,
3J = 8, 4J = 1.5, C6H4); 8.27 (1H, d, 3J = 9, =CH–); 10.29 (1H, br. s, NH–C6H4); 12.34 (1H, d, 3J = 9, NH–CH=).
Found, %: C 63.25; H 5.88; N 9.12. C16H18N2O4. Calculated, %: C 63.56; H 6.00; N 9.27.
432

1-(2-Carboxyphenyl)- (12) and 1-(2-Ethoxycarbonylphenyl)- (13) 6,6-Dimethyl-4-oxo-4,5,6,7-
tetrahydroindazoles. A solution of compound 11 (3.02 g, 10 mmol) and conc. hydrochloric acid (3 ml) in
ethanol (70 ml) was refluxed for 5 h, ethanol was evaporated off to half volume, and water (100 ml) was added
to the hot remainder. The oily residue which rapidly hardened was filtered off, and thoroughly ground with 1%
aqueous KOH solution. The insoluble solid was filtered off, recrystallized from ethanol, and ester 13 (1.10 g,
36%) was obtained. The filtrate was acidified with conc. HCl, the precipitated solid was filtered off,
recrystallized from 50% ethanol, and acid 12 (0.90 g: 31%) was obtained. Refluxing acid 11 for 2 h in ethanol in
the presence of catalytic amounts of acid leads exclusively to indazole 12 in 35% yield.
1
12. Mp 183-185°C. IR spectrum, ν, cm-1: 1703, 1681, 1651 (C=O); 2500-2650 (COOH). H NMR
spectrum (CDCl3), δ, ppm: 1.03 (6H, s, 2CH3); 2.36 (2H, s, C(5,7)H2); 2.47 (2H, s, C(5,7)H2); 7.32 (1H, m, C6H4);
7.62 (2H, m, C6H4); 7.89 (1H, s, C(3)H); 8.05 (1H, m, C6H4); 8.81 (1H, br. s, COOH). Found, %: C 67.80;
H 5.60; N 9.73. C16H16N2O3. Calculated, %: C 67.59; H 5.67; N 9.85.
1
13. Mp 127-128°C. IR spectrum, ν, cm-1: 1721, 1662 (C=O). H NMR spectrum (CDCl3), δ, ppm,
J (Hz): 1.05 (6H, s, 2CH3); 1.07 (3H, t, 3J = 7, CH3CH2); 2.36 (2H, s, C(5,7)H2); 2.52 (2H, s, C(5,7)H2); 4.09 (2H,
q, 3J = 7, CH3CH2); 7.32 (1H, m, C6H4); 7.56 (2H, m, C6H4); 7.96 (1H, m, C6H4); 7.98 (1H, s, C(3)H). Found, %:
C 69.03; H 6.40; N 8.81. C18H20N2O3. Calculated, %: C 69.21; H 6.45; N 8.97.
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