Synthesis of substituted 1H-indazoles by pyrazole annelation to an arene

Article abstract of DOI:10.1007/s10593-013-1244-y

Substituted 1H-indazoles have been synthesized by reductive intramolecular heterocyclization of 2,4-di-aroyl-N-nitrosomethylanilines and 2,4-diacetyl-N-nitrosomethylaniline. The N-nitrosoanilines were obtained by nitrosation of N-methyl-2,4-diaroyl- and 2

Full text of DOI:10.1007/s10593-013-1244-y

Chemistry of Heterocyclic Compounds, Vol. 49, No. 2, May, 2013 (Russian Original Vol. 49, No. 2, February, 2013)
SYNTHESIS OF SUBSTITUTED 1H-INDAZOLES
BY PYRAZOLE ANNELATION TO AN ARENE
A. K. Garkushenko1, O. P. Sorokina1, G. A. Kryuchkova1, A. A. Zmeev1,
M. A. Makarova1, M. A. Vorontsova1, and G. P. Sagitullina1*
Substituted 1H-indazoles have been synthesized by reductive intramolecular heterocyclization of 2,4-di-
aroyl-N-nitrosomethylanilines and 2,4-diacetyl-N-nitrosomethylaniline. The N-nitrosoanilines were
obtained by nitrosation of N-methyl-2,4-diaroyl- and 2,4-diacetylanilines, the products of quaternary
3,5-diaroyl- and 3,5-diacetylpyridinium salt recyclization.
Keywords: 5-aroyl-3-aryl-1,6-dimethyl-1H-indazoles, 5-amino-1,3,6-trimethyl-1H-indazole, 3,5-bis-
(cyclopropylcarbonyl)-2,6-dimethyl-1,4-dihydropyridine, 3,5-bis(cyclopropylcarbonyl)-2,6-dimethyl-
pyridine, substituted ortho-aroyl-N-methylanilines, substituted N-methyl-N-nitrosobenzenes, Hantzsch
synthesis.
Indazoles (azaindoles) are heterocyclic compounds structurally related to indoles, and can be viewed as
indole (bio)isosteres [1]. Unlike indoles, indazole derivatives are rare in nature. The first alkaloids of the
indazole series, nigellicine, nigellidine, and nigeglanine were isolated during the past three decades from the
plants Nigella sativa and Nigella glandulifera belonging to the Ranunculaceae family [2-6].
Interest in the chemistry of indazoles is explained by the wide spectrum of their biological activity. In
particular, indazoles display antitumor, antifungal, and anti-inflammatory activity; they possess antiseptic and
antipyretic properties, and are antagonists of dopamine receptors and regulators of CNS activity [7-9].
Medications of the indazole series, bendazac, benzydamine, lonidamine, bindarit, and granisetron, are
used as anticancer, anti-inflammatory, immunosuppressive, and serotoninergic agents [10-18]. In 2010, clinical
trials of axitinib, a new anticancer drug of this series was completed by Pfizer. Its effectiveness in the therapy of
carcinoma cells of kidney epithelium was established [19].
The classical methods of 1H-indazole synthesis are mainly based on closing the pyrazole ring by
intramolecular heterocyclization of ortho-methyl-N-nitroso- and diazoaromatic compounds, by the reaction of
ortho-halo- and ortho-hydroxyacyl benzenes, and substituted esters of 2-azidobenzoic acid with hydrazine [7,
20, 21]. The synthesis of indazoles by annelation of the benzene ring to pyrazole is limited to the cycloaddition
reaction of 1-phenyl-4(5)-vinylpyrazoles and 1-aryl-3-phenyl-1,6-dihydropyrano[2,3-c]pyrazoles with various
dienophiles [22-24].
_______
*To whom correspondence should be addressed, e-mail: sagitullina@orgchem.univer.omsk.su.
1F. M. Dostoevskii Omsk State University, 55a Mira Ave., Omsk 644077, Russia.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 297-304. February, 2013. Original
article submitted July 25, 2012.
0009-3122/13/4902-0273©2013 Springer Science+Business Media New York
273

Polyfluoro-substituted indazoles, obtained by the recyclization of 5-tetrafluorophenyl-1,2,4-oxadiazoles
by the action of hydrazine, are also avaible [25].
Other methods of 1H-indazole synthesis with lesser synthetic value are also known [7, 20].
The methods of 3-arylindazole synthesis are represented by the cycloaddition reaction of
tosylhydrazones and 1,1-dialkylhydrazones to an aryne [26, 27], N-acetyl-4-styrylpyrazoles to N-methyl- and
N-phenylmaleimide [28], the intramolecular Pd-catalyzed amination reaction of ortho-bromobenzophenone
hydrazones [29], cyclization of ortho-hydroxybenzophenone hydrazones [30, 31], and by the nucleophilic
substitution of hydrogen in nitroarenes by the anion of para-nitrobenzaldehyde hydrazone [32].
The aim of the present work was the synthesis of the previously unknown 5-aroyl-3-aryl-1H-indazoles
and 5-acetyl-3-methyl-1H-indazole from 2,4-diaroyl-N-methylanilines and 2,4-diacetyl-N-methylaniline,
respectively, obtained by the recyclization of quaternary 3,5-diaroylpyridinium salts and 3,5-diacetylpyridinium
salts [33].
Alkylation of 3,5-diaroylpyridines 1a-g, characterized by low basicity, was carried out using the methyl
ester of fluorosulfonic acid. Rearrangement of the quaternary pyridinium salts 2a-g on heating with an aqueous
alcoholic solution of sodium hydroxide led to 2,4-diaroyl-N-methylanilines 3a-g. The complete recyclization
scheme for quaternary pyridinium salts 2 was presented by us previously [34].
COAr
Me
COAr
ArOC
Me
ArOC
Me
COAr
ArOC
Me
MeSO3F
10% NaOH
+
N
EtOH–H2O, 
C2H4Cl2
0°C
Me_
N
NH
Me
SO3F
Me
1a–g
2a–g
3a–g
1–3 a Ar = Ph, b Ar = 4-ClC6H4, c Ar = 1-naphthyl, d Ar = 4-MeOC6H4,
e Ar = 3-MeOC6H4, f Ar = 4-BrC6H4, g Ar = 2-naphthyl
The two-stage scheme for the synthesis of substituted indazoles 4a-g by building up the pyrazole ring
involved N-nitrosation of N-methylanilines 3a-g and a stage of intramolecular reductive heterocyclization of
N-nitroso-N-methylanilines 5a-g. The formation of the pyrazole nucleus of indazoles 4a-g proceeded by
intramolecular condensation of arylmethylhydrazine, formed in situ on reduction of the N-nitroso group, with an
aroyl group. All the stages in the synthesis of indazoles were performed in preparative yields.
Ar
NaNO2,
AcOH
ArOC
Me
COAr
ArOC
Me
Zn, AcOH
DMF
O
3a–g
O
N
N
NH2
N
Me
Me
5a–g
Ar
N
ArOC
– H2O
N
Me
Me
4a–g
3–5 a Ar = Ph, b Ar = 4-ClC6H4, c Ar =1-naphtyl, d Ar = 4-MeOC6H4,
e Ar = 3-MeOC6H4, f Ar = 4-BrC6H4, g Ar = naphtyl
274

Synthesized by an analogous scheme were 5-acetylindazole 6 from N-nitroso-N-methylaniline 7, the
starting material for which was 2,4-diacetyl-N-methylaniline 8, itself the product of a 3,5-diacetylpyridinium
salt rearrangement [33]. The 5-aminoindazole 9 was obtained in 80% yield by converting the acetyl group in
position 5 of indazole 6 by the Schmidt reaction.
Ac
Ac
Ac
Ac
NaNO2, AcOH
Me
Me
NH
Me
N
NO
Me
7
8
Me
Me
N
Ac
H2N
NaN3, H2SO4
Zn, AcOH
N
N
N
Me
Me
Me
6
Me
9
It should be mentioned that the two-stage synthesis of 3,5-diacetylpyridine from acetylacetone by the
Hantzsch reaction was characterized by high yields both at the stage of obtaining 3,5-diacetyl-1,4-di-
hydropyridine (87%) and also at the stage of its aromatization (81%). The yields of the remaining compounds of
the 3,5-dialkanoylpyridine series, beginning with 3,5-dipropionylpyridine, did not exceed 40% at the stage of
1,4-dihydropyridine synthesis [35]. For this reason, the syntheses of 3,5-dialkanoylpyridines and the
rearrangement of their quaternary salts were stopped at 3,5-dipropionylpyridine [33].
In the present study, we have obtained for the first time 3,5-bis(cyclopropylcarbonyl)-2,6-dimethyl-1,4-di-
hydropyridine (10) by a modified Hantzsch synthesis [35]. Oxidation of the dihydropyridine 10 with sodium
nitrite in acetic acid led to a complex mixture of reaction products, from which the crystalline pyridine 11 could
not be isolated. Oxidation of dihydropyridine 10 with chloranil on heating in benzene led to pyridine 11 in 64%
yield.
O
O
O
O
HCHO
+
EtOH, 
Me
O
N
H
Me
Me
O
O
NH3
Me
10
O
Chloranil
C6H6, 
Me
N
Me
11
It should be noted that the recyclization of symmetrical 4-aryl-3,5-diacetylpyridinium salts into the
corresponding 2,4-diacetyl-3-aryl-N,5-dimethylanilines occurred in yields of 19-40%, consequently we did not
consider them as promising materials in the synthesis of indazoles [33].
The structures of compounds 2d-g, 3d-g, 4d-g, 5d-g, 6, 7, and 9-11, which were synthesized for the first
time, were confirmed by IR, 1H NMR spectroscopy and by data of elemental analysis. The physicochemical and
spectral characteristics of the compounds are given in Tables 1 and 2.
An effective synthesis of new substituted 1H-indazoles is therefore proposed, based on annelation of
pyrazole ring onto the available ortho-aroyl-N-methylanilines. The obtained compounds hold promise for the
study of their biological activity.
275

TABLE 1. Physicochemical Characteristics of the Synthesized
Compounds 2d-g, 3d-g, 4d-g, 5d-g, 6, 7, 9-11
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp, °С
Yield, %
С
H
N
2d
2e
2f
2g
3d
3e
3f
3g
4d
4e
4f
4g
5d
5e
5f
5g
6
C24H24FNO7S
C24H24FNO7S
C22H18Br2FNO5S
C30H24FNO5S
C24H23NO4
58.80
58.89
58.85
58.89
45.07
45.00
68.07
68.04
74.06
74.02
74.00
74.02
54.29
54.24
83.95
83.89
74.63
74.59
74.58
74.59
54.59
54.57
84.50
84.48
68.93
68.89
68.87
68.89
51.22
51.19
78.64
78.59
4.96
4.94
4.90
4.94
3.12
3.09
4.55
4.57
5.98
5.95
5.94
5.95
3.55
3.52
5.36
5.40
5.72
5.74
5.77
5.74
3.30
3.33
5.23
5.20
5.34
5.30
5.33
5.30
3.15
3.12
4.80
4.84
2.85
2.86
2.80
2.86
2.43
2.39
2.70
2.64
3.67
3.60
3.56
3.60
2.80
2.88
3.30
3.26
7.30
7.25
7.33
7.25
5.86
5.79
6.53
6.57
6.73
6.69
6.71
6.69
5.48
5.43
6.12
6.11
230-231
227-228
266-267
248-249
133-134
142-143
170-171
191-192
157-158
102-103
176-177
194-195
158-159
126-127
207-208
203-204
126-127
94-95
91
85
92
95
86
75
98
77
63
50
79
81
86
82
93
80
74
88
80
85
64
C24H23NO4
C22H17Br2NO2
C30H23NO2
C24H22N2O3
C24H22N2O3
C22H16Br2N2O
C30H22N2O
C24H22N2O5
C24H22N2O5
C22H16Br2N2O3
C30H22N2O3
C12H14N2O
71.13
71.26
61.42
61.53
68.62
68.54
73.50
73.44
7.07
6.98
6.04
6.02
7.54
7.48
7.83
7.81
13.99
13.85
12.06
11.96
24.08
23.98
5.79
5.71
7
C12H14N2O3
C10H13N3
9
183-184
176-177
51-52
10
11
C15H19NO2
C15H17NO2
74.10
74.05
7.09
7.04
5.86
5.76
EXPERIMENTAL
The IR spectra were recorded on a Simex FT-801 spectrometer (with an attachment for a frustrated total
1
internal reflection). H NMR spectra were recorded on a Bruker Avance DRX-400 instrument (400 MHz).
Chemical shifts were measured relative to the residual signals of the solvents: CHCl3 (δ 7.26 ppm), DMSO
(δ 2.50 ppm). Elemental analysis was carried out on a PerkinElmer CHN analyzer. Melting points were
determined on a Boetius hot stage apparatus. Column chromatography was performed on Merck 60 Å, 0.060-
0.200 mm silica gel. A check on the progress of reactions and the purity of the obtained substances was
effected by TLC on Silufol UV-254 plates with visualization in UV light.
276

277

Syntheses of pyridinium salts 2a-c, 2,4-diaroylanilines 3a-c, and indazoles 4a-c have been described
previously [34]. The starting 3,5-diaroylpyridines 1a-g were obtained previously by a modified Hantzsch
synthesis [36]. 1-Cyclopropylbutane-1,3-dione was synthesized in 60% yield by ester condensation of methyl
cyclopropyl ketone and ethyl acetate, as described in the work [37], with replacement of NaNH2 and solvent
methyl tert-butyl ether by NaH and diethyl ether.
3,5-Diaroyl-1,2,6-trimethylpyridinium Fluorosulfonates 2d-g (General Method). A solution of
methyl fluorosulfonate (3.42 g, 30 mmol) in abs. dichloroethane (12 ml) was added dropwise with stirring to a
solution of the corresponding pyridine 1d-g [36] in abs. dichloroethane (24 ml) at 0°C. The mixture was stirred
for 30 min at 0°C and for 2 days at room temperature. The precipitated solid was filtered off and recrystallized
from ethanol.
2,4-Diaroyl-N,5-dimethylanilines 3d-g (General Method). A suspension of quaternary salt 2d-g
(5 mmol) in ethanol (10 ml) and 10% NaOH solution (10 ml) was heated at 80°C for 1 h, cooled, diluted with
water, and yellow crystals of diaroylanilines 3d-g were filtered off. The products were purified by column
chromatography (eluent chloroform) and recrystallized from ethanol.
N-Nitrosoanilines 5d-g, 7 (General Method). NaNO2 (0.97 g, 14 mmol) was added in portions at
room temperature to a solution of aniline 3d-g and 8 [33] (7 mmol) in acetic acid (14 ml). The reaction mixture
was stirred for 1 h at room temperature and poured into water. White crystals of nitrosoanilines 5d-g and 7 were
filtered off and recrystallized from ethanol.
5-Aroyl-3-aryl-1,6-dimethyl-1H-indazoles 4d-g (General Method). Zinc dust (3.2 g, 50 mmol) was
added in portions with stirring to a solution of nitrosoaniline 5d-g (10 mmol) in DMF (30 ml) and acetic acid
(30 ml), maintaining the temperature at or below 10°C. The mixture was stirred for 30 min at room temperature,
heated to 100°C, the inorganic solids were filtered off and washed with hot acetic acid. The filtrate was cooled,
diluted with water, colorless crystals of indazoles 4d-g were filtered off and recrystallized from ethanol.
1-(1,3,6-Trimethyl-1H-indazol-5-yl)ethanone (6). Zinc dust (1.60 g, 25 mmol) was added in portions
with stirring to a solution of nitrosoaniline 7 (1.34 g, 5 mmol) in acetic acid (10 ml), maintaining the
temperature at or below 10°C. The mixture was stirred for 1 h at room temperature, the inorganic solids were
filtered off, and washed with acetic acid. The filtrate was cooled, diluted with water, neutralized with potassium
carbonate solution, and indazole 6 was filtered off. Yield 0.75 g (74%). Colorless crystals; mp 126-127°C (2-
PrOH).
1,3,6-Trimethyl-1H-indazol-5-amine (9). NaN3 (0.43 g, 6.6 mmol) was added in portions with
vigorous stirring to a solution of 5-acetylindazole 6 (1.21 g, 6.0 mmol) in conc. H2SO4 (3 ml), so that the
temperature did not exceed 40°C. (Caution! Risk of explosion!) The reaction mixture was stirred for 12 h, ice
(12 g) was added, the mixture was refluxed for 12 h, cooled, diluted with water (30 ml), and neutralized with
aqueous ammonia. Aminoindazole 9 was filtered off. Yield 0.65 g (80%). White crystals; mp 183-184°C (CCl4).
3,5-Bis(cyclopropylcarbonyl)-2,6-dimethyl-1,4-dihydropyridine (10) was obtained by a modified
Hantzsch synthesis [35]. Yield 74%. Yellow crystals; mp 176-177°C (EtOH).
3,5-Bis(cyclopropylcarbonyl)-2,6-dimethylpyridine (11). Oxidation of 1,4-dihydropyridine 10 with
chloranil was carried out by heating in benzene according to the procedure of [38]. After purification by column
chromatography (eluent chloroform–ethyl acetate, 9:1), the pyridine 11 was obtained in 64% yield as colorless
crystals, mp 51-52°C (petroleum ether).
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