A new effective route for the synthesis of substituted 2H-indazoles

Article abstract of DOI:10.1007/s10593-010-0409-1

A two-stage synthesis of 2H-indazoles has been established, based on consecutive reactions of reduction of 2-alkyl-, 2-cyclopropyl-, and 2-arylcarbonylazobenzenes to phenylazo-substituted benzyl alcohols and intramolecular heterocyclization of the reducti

Full text of DOI:10.1007/s10593-010-0409-1

Chemistry of Heterocyclic Compounds, Vol. 45, No. 10, 2009
A NEW EFFECTIVE ROUTE
FOR THE SYNTHESIS OF
SUBSTITUTED 2H-INDAZOLES
S. S. Mochalov1*, M. I. Khasanov1, E. V. Trofimova1,
A. N. Fedotov1, and N. S. Zefirov1
A two-stage synthesis of 2H-indazoles has been established, based on consecutive reactions of reduction
of 2-alkyl-, 2-cyclopropyl-, and 2-arylcarbonylazobenzenes to phenylazo-substituted benzyl alcohols
and intramolecular heterocyclization of the reduction products under the influence of organic acids.
Keywords: 2-aminoacylbenzenes, 2-arylazobenzyl alcohols, 2-acylazobenzenes, intramolecular
heterocyclizations.
In recent years there has been a considerably strengthened interest in the synthesis and study of the medico-
biological properties of derivatives of 2H-indazoles, resulting from the observation in a series of compounds which
are seldom encountered in nature, a class of heterocycles with a wide range of biological activity: antiangiogenic
[1], anticarcinogenic and anti-inflammatory [2,3], antimicrobial [4], antifungal [5, 6], cytotoxic [7], and
antihelminthic [8]. In addition compounds of this class show potential as inhibitors of NO-synthetases [9, 10],
protein kinases [11, 12], tubulin [13], modulators of X-receptors of the liver [14], and they also show properties of
male contraceptives [15, 16].
The discovery of the biological activity of the 2H-indazoles caused the real problem of the synthesis of new
derivatives of this class of heterocycles. It is important to underline that at present a wide range of precursors has
been used to synthesize the 2H-indazole ring, in practice including all strategic routes for its synthesis. For example,
2H-indazoles have been synthesized from 2-azidobenzylideneamines [17] or 2-azidobenzoylamines [18,19],
oxidative cyclization from N-acylhydrazones of 2-aminoacylbenzenes [20, 21], reaction of carbenes with azobenzene
[22, 23], rearrangement of ortho-substituted azobenzenes [24, 25], and reductive heterocyclization of ortho-nitro-
benzylideneamines [26-28], and heterocyclization of ortho-nitrobenzylamines [29-33]. A variant of the formation of
the 2H-indazole system from compounds containing the pyrazole unit have been described. For example, oxidation
of 4,5-tetramethylenepyrazoles with dichlorodicyanobenzoquinone gave substituted 2H-indazoles in high yield [34].
However, despite the abundance of variants for the construction of the 2H-indazole ring, the variation of substituents
is practically limited to those in positions 2 and 3, and only in the papers [30, 31, 33] were syntheses of 2H-indazoles
containing substituents in the annelated benzene ring reported.
_______
* To whom correspondence should be addressed, e-mail: ssmoch@org.chem.msu.ru.
1 M. V. Lomonosov Moscow State University, Moscow 119992, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, 1507-1518, October, 2009. Original
article submitted December 19, 2008.
1208
0009-3122/09/4510-1208©2009 Springer Science+Business Media, Inc.

Recently [35] we have shown that 2-benzoyl-4,5-ethylenedioxiazobenzenes are converted in high yield
into 2,3-diaryl-5,6-ethylenedioxy-2H-indazoles by a two-step process (reduction to the corresponding
phenylazosubstituted benzhydrol and acid-catalyzed heterocyclization of these alcohols). In fact this was the
first example of a new variant using a compounds of a series of azobenzenes in the synthesis of 2H-indazoles.
The objective of the present work was to investigate the range of this two-stage transformation of ortho-
acylazobenzenes into the corresponding 2H-indazoles and the possibility of obtaining of 2H-indazoles with
substituents in the annelated benzene ring by this route. With this aim in mind we have synthesized a series of
asymmetrically substituted ortho-acylazobenzenes by the condensation of ortho-amino ketones 1-8 and
2-aminophenylcyclopropane 10 with nitrosobenzenes and have studied their behavior in the conditions of the
two-stage transformation.
O
O
O
O
O
O
R
R
N
AcOH
ON
X
+
20°C, 4 h
NH2
N
1–8
X
9a–j
1, 9a R = Me; 2, 9b,c R = i-Pr, 3, 9d,e R = c-Pr; 4, 9f R = Ph; 5, 9g R = 4-MeC6H4; 6, 9h R = 4-MeOC6H4;
7, 9i R = 4-ClC6H4; 8, 9j R = 3-FC6H4; 9a,b,d,g,i,j X = H, c,e,h X = Cl, f X = Ph
O
Me
Bu-t
ON
N
N
O
AcOH
+
20°С, 4 h
NH2
Me
Bu-t
10
9k
11
It should be noted that despite the presence of two groups capable of condensation in the nitroso-
compound 11, the reaction occurs with the nitroso group only to give the azobenzene 9k. It is interesting that the
5-amino-6-acyl-substituted 1,4-benzodioxanes 12 and 13, unlike their 6-amino-7-acyl-substituted isomers, do
not form the corresponding azobenzenes 9l-o.
X
NH2
O
O
O
AcOH
R
N
ON
X
O
+
N
20°C, 210 h
O
O
R
12, 13
9l–o
12, 9 l,m R = Me, 13, 9 n,o R = i-Pr; 9 l,n X = H, m,o X = Cl
1209

Table 1. Characteristics of 2-Acyl-substituted Azobenzenes 9a-k,
2-Arylazo-substituted Benzyl Alcohols 14a-k, and 2H-Indazoles 15a-k
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp*, °С
Yield, %
С
H
4
N
5
1
9a
2
3
6
7
49
C16H14N2O3
C18H18N2O3
C18H17ClN2O3
C18H16N2O3
C18H15ClN2O3
C21H16N2O3
C22H18N2O3
C22H17ClN2O4
C21H15ClN2O3
C21H15FN2O3
C21H24N2O
67.92
68.07
69.42
69.66
62.78
62.70
69.91
70.12
62.76
63.07
73.01
73.24
73.61
73.73
64.71
64.63
5.03
5.00
5.89
5.85
4.81
4.97
5.31
5.23
4.46
4.41
4.59
4.68
5.09
5.06
4.26
4.19
9.99
9.92
9.11
9.03
105-106
74-75
9b
52
9c
8.16
8.12
9.16
9.09
8.26
8.17
8.02
8.13
7.93
7.82
7.01
6.85
7.45
7.40
7.88
7.73
8.92
8.74
9.93
9.85
9.14
8.97
8.21
8.08
117-118
128-129
120-121
130-131
124-125
141-142
127-128
131-132
Sticky oil
Sticky oil
Sticky oil
105-106
90-91
48
9d
51
9e
45
9f
48
9g
54
9h
46
9i
66.28
66.58
69.37
69.61
78.51
78.71
3.91
3.99
4.22
4.17
7.31
7.55
52
9j
51
9k
53
14a
14b
14c
14d
14e
14f
14g
14h
14i
14j
14k
15a
15b
15c
15d
15e
15f
C16H16N2O3
C18H20N2O3
C18H19ClN2O3
C18H18N2O3
C18H17ClN2O3
C21H18N2O3
C22H20N2O3
C22H19ClN2O4
C21H17ClN2O3
C21H17FN2O3
C21H26N2O
67.41
67.59
69.03
69.21
62.11
62.34
69.52
69.66
62.61
62.70
72.64
72.82
73.21
73.32
64.14
64.31
66.18
66.23
68.98
69.22
78.01
78.22
72.01
72.16
73.11
73.45
65.97
65.75
73.78
73.95
65.95
66.16
5.76
5.67
6.31
6.45
5.58
5.52
5.94
5.85
4.88
4.97
5.03
5.24
5.48
5.59
4.51
4.66
4.36
4.50
4.62
4.70
8.24
8.13
5.36
5.30
6.28
6.16
5.36
5.21
5.41
5.52
4.68
4.63
87
81
86
9.21
9.03
92
8.22
8.12
7.82
8.09
7.56
7.77
6.62
6.82
7.02
7.36
7.81
7.69
8.46
8.69
10.68
10.52
9.71
9.52
8.44
8.52
9.32
9.58
8.48
8.57
115-116
115-116
61-62
87
85
86
128-129
73-74
82
95
125-126
Oil
94
83
C16H14N2O2
C18H18N2O2
C18H17ClN2O2
C18H16N2O2
C18H15ClN2O2
C21H16N2O2
118-119
124-125
151-152
78-79
85
79
79
89 (96)*2
94
118-119
199-200
76.53
76.81
4.80
4.91
8.44
8.53
91
________
* Crystallized from ethanol.
*2 The yields in brackets refer to the reaction carried out in formic acid.
1210

Table 1 (continued)
1
15g
15h
15i
2
3
4
5
6
7
C22H18N2O2
C22H17ClN2O3
C21H15ClN2O2
C21H15FN2O2
C21H24N2
76.92
77.17
67.14
67.26
69.31
69.52
73.08
72.82
5.18
5.30
4.31
4.36
3.91
4.17
4.44
4.37
8.03
8.18
7.28
7.13
7.53
7.72
7.88
8.09
184-185
208-209
179-180
201-202
146-147
95
91 (96)
94
15j
15k
88 (94)
87 (93)
82.78
82.85
8.07
7.95
9.24
9.20
Even when the reaction time was increased manifold the amino ketones 12 and 13 reacted with neither
nitrosobenzene nor 4-chloronitrosobenzene and were recovered quantitatively unchanged, whereas the
nitrosobenzenes were converted into the corresponding azoxybenzenes.
Reduction of the ortho-acylazobenzenes 9a-k to the phenylazo-substituted benzyl alcohols 14a-k,
immediately converted into the 2H-indazoles 15a-k, was carried out with NaBH4 in ethanol: the reactions
occurred in high yield (Table 2) and in no case was the transformation of the azo group observed under the
influence of the reducing agent used. This result shows that the azo group can be added to the number of groups
which do not react with NaBH4, at least when groups reducible by NaBH4 are present in the substrate.
HO
H
O
O
CF3CO2H or HCO2H
0–20°C
R
1) NaBH4, EtOH
2) H3O+
9a–j
N
N
14a–j
X
H
δ+
H O
H
R
H
R
O
+
O
O
R
–H2O
X
–H
O
O
+
X
N
δ+
N
X
N
N
N
O
N
15a–j
B
A
Heterocyclization of ortho-phenylazobenzyl alcohols into the required 2H-indazoles occurred readily in
high yield in the presence of trifluoroacetic acid (Table 3). Since this conversion occurs practically with no
complications even in the presence of a cyclopropane unit on a benzene carbon (see below), it can be assumed
that carbenium ion of benzyl type is not formed as a discrete particle during the heterocyclization*, and it occurs
as an intramolecular variant of a nucleophilic substitution of the SN2 type via the transition state A: the
intermediate B which is then formed is stabilized by the loss of a proton from the benzyl position and is
transformed into the 2H-indazole heterocycle.
Of particular interest is the heterocyclization of the alcohol 14k. This alcohol presents itself as a model
in which the reactivity of two groups in ortho-position to the azo group, possible sources of carbenium ions of
the benzyl type, capable of regioselective formation of the corresponding 2H-indazole.
_______
* A cyclopropane fragment, directly bonded to a carbon atom with a complete positive charge, is easily
isomerized [36].
1211

Me
N
t-Bu
N
OH
Me
1. NaBH4,
alcochol
15k
HCO2H
OH
Me
9k
N
+
t-Bu
N
2. H3O
20°C, 30 min
14k
N
t-Bu
N
Me
Table 2. 1H NMR Spectra of Compounds 9, 14, and 15
Com-
pound
Chemical shifts, δ, ppm (J, Hz*)
1
2
9a
2.68 (3Н, s, СН3); 4.34 (4Н, s, OCH2CH2O); 7.28 (1Н, s), 7.34 (1Н, s) – Н-5,8;
7.52 (3Н, m), 7.88 (2Н, m) – ArH
1.19 (6Н, d, J = 6.4, CH(СН3)2); 3.36 (1Н, sp, J = 6.4, CH(СН3)2);
4.33 (4Н, m, OCH2CH2O); 7.07 (1Н, s), 7.39 (1Н, s) – Н-5,8; 7.48 (3Н, m),
7.85(2Н, m) – ArH
9b
9c
9d
9e
1.17 (6Н, d, J = 6.5, CH(СН3)2); 3.31 (1Н, sp, J = 6.5, CH(СН3)2);
4.35 (4Н, s, OCH2CH2O); 7.06 (1Н, s), 7.41 (1Н, s) – Н-5,8; 7.45 (2Н, d, J = 8.4),
7.78 (2Н, d, J = 8.4) – ArH
0.99 (2Н, m), 1.31 (2Н, m), 2.51 (1Н, m) – cyclopropane protons;
4.34 (4Н, s, OCH2CH2O); 7.18 (1Н, s), 7.41 (1Н, s) – Н-5,8; 7.48 (3Н, m),
7.91 (2Н, d, J = 8.0) – ArH
0.99 (2Н, m), 1.32 (2Н, m), 2.45 (1Н, m) – cyclopropane protons;
4.35 (4Н, s, OCH2CH2O); 7.17 (1Н, s), 7.39 (1Н, s) – Н-5,8; 7.48 (2Н, d, J = 8.6),
7.84 (2Н, d, J = 8.6) – ArH
4.42 (4Н, m, OCH2CH2O); 7.17 (1Н, s), 7.42 (1Н, s) – Н-5, Н-8; 7.28 (2Н, m),
7.39 (3Н, m); 7.46 (2Н, m), 7.57 (1Н, m); 7.68 (2Н, m) – ArH
9f
2.37 (3Н, s, СН3); 4.35 (4Н, s, OCH2CH2O); 7.13 (1Н, s, Н-8);
7.19 (2Н, d, J = 8.0, Н-3',5'); 7.33 (3Н, m), 7.40 (2Н, m) – ArH''; 7.51 (1Н, s, H-5);
7.71 (2Н, d, J = 8.0, Н-2',6')
9g
3.83 (3Н, s, OСН3); 4.36 (4Н, s, OCH2CH2O); 7.10 (1Н, s), 7.48 (1H, s) – H-5,8;
6.87 (2Н, d, J = 8.6), 7.29 (2Н, d, J = 8.6), 7.38 (2Н, d, J = 8.4),
7.77 (2Н, d, J = 8.4) – ArH
9h
4.42 (4Н, m, OCH2CH2O); 7.19 (1Н, s, Н-8); 7.32 (2Н, d, J = 7.6), 7.42 (3H, m) – ArH'';
7.44 (1Н, s, H-5); 7.53 (2Н, d, J = 8.2, Н-3',5'); 7.68 (2Н, d, J = 8.2, Н-2',6')
9i
4.43 (4Н, m, OCH2CH2O); 7.19 (1Н, s, Н-8); 7.32 (2Н, d, J = 8.4),
7.39-7.51 (7H, m) – ArH; 7.44 (1Н, s, H-5)
9j
9k
0.89 (2Н, m), 1.15 (2Н, m) – СН2-cyclopropane protons; 1.40 (9Н, s, С(СН3)3);
2.51 (3Н, s, СН3); 2.93 (1Н, m, СН- cyclopropane); 7.01 (1Н, m), 7.23 (1Н, m),
7.41 (1Н, m), 7.75 (1Н, dd, J1 = 7.4, J2 = 1.6), 7.58-7.68 (2Н, m),
7.81 (1Н, d, J = 7.6) – ArH
14a
14b
14c
1.61 (3Н, d, J = 6.5, СН3); 3.90 (1Н, br. s, ОН); 4.31 (4Н, m, OCH2CH2O);
5.56 (1Н, q, J = 6.5, СНОН); 7.05 (1Н, s, Н-5); 7.40 (1Н, s, Н-8); 7.51 (3Н, m),
7.85 (2Н, d, J = 8.2) – ArH
0.82 (3Н, d, J = 6.6), 1.09 (3Н, d, J = 6.6) – CH(СН3)2; 2.03 (1Н, sp, J = 6.6, СН(СН3)2);
3.62 (1Н, d, J = 6.8, ОН); 4.34 (4Н, m, OCH2CH2O); 4.94 (1Н, m, СНОН);
6.95 (1Н, s, Н-5); 7.42 (1Н, s, Н-8); 7.48 (3Н, m), 7.83 (2Н, d, J = 8.3) – ArH
0.82 (3Н, d, J = 5.9), 1.06 (3Н, d, J = 5.9) – CH(СН3)2; 1.99 (1Н, m, СН(СН3)2);
3.35 (1Н, br. s, ОН); 4.32 (4Н, m, OCH2CH2O); 4.96 (1Н, m, СНОН);
6.99 (1Н, s, Н-5); 7.39 (1Н, s, Н-8); 7.48 (2Н, d, J = 8.6), 7.75 (2Н, d, J = 8.6) – ArH
1212

Table 2 (continued)
1
2
14d
14e
14f
14g
0.34 (1Н, m), 0.48 (1Н, m), 0.58 (1Н, m), 0.71 (1Н, m),
1.34 (1Н, m) – cyclopropane protons; 3.70 (1Н, br. s, ОН); 4.32 (4Н, m, OCH2CH2O);
4.63 (1Н, d, J = 6.4, СНОН); 7.11 (1Н, s), 7.44 (1Н, s) – Н-5,8; 7.51 (3Н, m),
7.83 (2Н, d, J = 8.3) – ArH
0.31 (1Н, m), 0.51 (1Н, m), 0.55 (1Н, m), 0.68 (1Н, m),
1.29 (1Н, m) – cyclopropane protons; 3.45 (1Н, br. s, ОН); 4.31 (4Н, m, OCH2CH2O);
4.69 (1Н, d, J = 6.4, СНОН); 7.13 (1Н, s), 7.40 (1Н, s) – Н-5,8; 7.49 (2Н, d, J = 8.4),
7.78 (2Н, d, J = 8.4) – ArH
4.27 (2H, m), 4.33 (2Н, m) – OCH2CH2O; 5.95 (1Н, d, J = 4.4, ОН);
6.58 (1Н, d, J = 4.4, СНОН); 7.15 (1Н, s), 7.19 (1Н, s) – Н-5,8; 7.13 (1Н, t, J = 7.3),
7.24 (2Н, t, J = 7.3), 7.32 (2Н, d, J = 7.3), 7.53 (1Н, t, J = 7.4), 7.59 (2Н, t, J = 7.4),
7.85 (2Н, d, J = 7.4) – ArH
2.32 (3H, s, CH3); 3.85 (1Н, br. s, ОН); 4.31 (4H, m, OCH2CH2O); 6.55 (1Н, s, СНОН);
6.97 (1Н, s, H-5); 7.12 (2Н, d, J = 8.2, H-3',5'); 7.30 (2Н, d, J = 8.2, H-2',6');
7.42 (1Н, s, H-8); 7.48 (3Н, m), 7.80 (2Н, d, J = 7.8) – ArH''
3.58 (1Н, br. s, ОН); 3.77 (3H, s, OCH3); 4.30 (4H, m, OCH2CH2O); 6.53 (1Н, s, СНОН);
7.01 (1Н, s), 7.40 (1H, s) – H-5,8; 6.84 (2Н, d, J = 8.4), 7.30 (2Н, d, J = 8.4),
7.46 (2Н, d, J = 8.2), 7.71 (2Н, d, J = 8.2) – ArH
14h
14i
4.27 (2H, m), 4.33 (2H, m) – OCH2CH2O; 6.06 (1Н, d, J = 4.5, ОН);
6.77 (1Н, d, J = 4.5, СНОН); 7.17 (2Н, s, H-5,8); 7.31 (2Н, d, J = 8.8, H-3', 5');
7.33 (2Н, d, J = 8.8, H-2',6'); 7.53 (1Н, t, J = 7.2), 7.59 (2Н, t, J = 7.2),
7.85 (2Н, d, J = 7.2) – ArH''
4.27 (2H, m), 4.33 (2H, m) – OCH2CH2O; 6.06 (1Н, d, J = 4.5, ОН);
6.77 (1Н, d, J = 4.5, СНОН); 7.17 (2Н, s, H-5,8); 7.31 (2Н, d, J = 8.8, H-3',5');
7.33 (2Н, d, J = 8.8, H-2',6'); 7.53 (1Н, t, J = 7.2), 7.59 (2Н, t, J = 7.2),
7.85 (2Н, d, J = 7.2) – ArH''
14j
0.92 (2Н, m), 1.15 (2Н, m) – СН2-cyclopropane protons; 1.37 (9Н, s, С(СН3)3);
1.63 (3Н, d, J = 6.8, СН3); 1.73 (1Н, br. s, ОН); 2.93 (1Н, m, СН- cyclopropane);
5.54 (1Н, m, СНОН); 7.05 (1Н, d, J = 7.8), 7.23 (1Н, m), 7.41 (1Н, m), 7.53 (3Н, m),
7.79 (1Н, d, J = 1.8) – ArH
14k
2.57 (3Н, s, СН3); 4.31 (4Н, m, OCH2CH2O); 6.98 (1Н, s), 7.12 (1Н, s) – H-4,7;
7.52 (5Н, m, ArH)
15a
15b
15c
1.45 (6Н, d, J = 6.4, CH(СН3)2); 3.31 (1H, sp, J = 6.4, CH(СН3)2);
4.32 (4Н, m, OCH2CH2O); 7.12 (1Н, s), 7.22 (1Н, s) – H-4,7; 7.48 (5Н, m, ArH)
1.45 (6Н, d, J = 6.4, CH(СН3)2); 3.26 (1H, sp, J = 6.4, CH(СН3)2);
4.32 (4Н, s, OCH2CH2O); 7.09 (1Н, s), 7.19 (1Н, s) – H-4,7; 7.42 (2Н, d, J = 9.1),
7.50 (2Н, d, J = 9.1) – ArH
0.82 (2Н, m), 0.97 (2Н, m), 2.09 (1Н, m) – cyclopropane protons;
4.31 (4Н, m, OCH2CH2O); 7.08 (1Н, s), 7.11 (1Н, s) – H-4,7; 7.43 (1Н, t, J = 8.0),
7.51 (2Н, t, J = 8.0), 7.67 (2Н, d, J = 8.0) – ArH
15d
15e
0.81 (2Н, m), 1.01 (2Н, m), 2.06 (1Н, m) – cyclopropane protons;
4.31 (4Н, m, OCH2CH2O); 7.06 (1Н, s), 7.08 (1Н, s) – H-4,7; 7.48 (2Н, d, J = 8.8),
7.64 (2Н, d, J = 8.8) – ArH
4.31 (4Н, m, OCH2CH2O); 7.11 (1Н, s), 7.22 (1Н, s) – H-4,7; 7.30–7.44 (10Н, m, ArH)
15f
2.38 (3Н, s, СН3); 4.33 (4Н, m, OCH2CH2O); 7.11 (1Н, s), 7.19 (1Н, s) – H-4,7;
7.18 (2Н, d, J = 8.3, H-3',5'); 7.22 (2Н, d, J = 8.3, H-2',6'); 7.38 (3H, m),
7.43 (2Н, m) – ArH"
15g
3.85 (3Н, s, OСН3); 4.30 (2H, m), 4.35 (2Н, m) – OCH2CH2O; 7.07 (1Н, s),
7.24 (1Н, s) –H-4,7; 6.94 (2Н, d, J = 8.4), 7.21 (2Н, d, J = 8.4), 7.36 (4H, m) – ArH
15h
15i
4.32 (4Н, m, OCH2CH2O); 7.06 (1Н, s), 7.19 (1Н, s) – H-4,7;
7.24 (2Н, d, J = 8.2, H-3',5'); 7.35 (2Н, d, J = 8.2, H-2',6'); 7.41 (5H, m, ArH'')
4.33 (4Н, m, OCH2CH2O); 7.01-7.10 (3Н, m, ArH); 7.11 (1Н, s), 7.22 (1Н, s) – H-4,7;
7.31-7.44 (6H, m, ArH)
15j
15k
0.65-0.85 (4Н, m), 1.36 (1Н, m) – cyclopropane protons; 1.42 (9Н, s, С(СН3)3);
2.45 (3Н, s, СН3); 6.97 (1Н, d, J = 7.8), 7.24 (1Н, d, J = 8.4), 7.28 (2Н, m),
7.43 (1Н, m), 7.61 (1Н, d, J = 8.4), 7.66 (1Н, m) – ArH
_______
* 1H NMR spectra were recorded inCDCl3 (compounds 9a-e,g,h,k, 14a-e,
g,h,k and 15a-k) and in DMSO-d6 (compounds 9f,i,j and 14f,i)
1213

Table 3. Mass Spectra of Compounds 9, 14 and 15
Com-
pound
m/z (Irel, %)
9a
282 [M]+ (56.2), 267 (6.3), 205 (12.2), 177 (25.8), 149 (30.4), 123 (8.8), 105 (17.1),
77 (100.0), 51 (46.5), 43 (42.2)
9d
9e
308 [M]+ (8.2), 280 (10.3), 203 (7.3), 175 (13.5), 163 (9.5), 147 (6.1), 131 (11.2),
119 (8.2), 103 (24.2), 91 (12.6), 77 (100.0), 51 (40.6), 39 (26.6)
342 [M]+ (8.1), 314 (7.2), 203 (8.2), 175 (16.1), 163 (12.4), 131 (13.1), 119 (12.2),
111 (100.0), 103 (30.5), 91 (16.1), 75 (52.1), 69 (13.2), 50 (51.1), 39 (52.6)
9f
344 [M]+ (46.5), 239 (45.2), 183 (16.1), 167 (11.8), 155 (18.2), 139 (34.8), 127 (22.5),
105 (36.1), 77 (100.0), 69 (15.1), 51 (80.1), 39 (11.1)
9g
358 [M]+ (35.4), 253 (14.1), 197 (6.5), 169 (9.1), 153 (13.2), 119 (13.5), 91 (40.6),
77 (100.0), 65 (30.6), 51 (52.5), 39 (18.2)
9i
378 [M]+ (40.4), 273 (10.8), 238 (23.6), 173 (6.5), 154 (9.1), 139 (13.4), 126 (14.8),
111 (21.2), 105 (14.1), 77 (100.0), 69 (11.1), 51 (40.1)
9j
362 [M]+ (72.2), 257 (68.4), 201 (16.4), 185 (15.1), 173 (19.1), 157 (34.2), 145 (14.1),
123 (19.2), 105 (34.2), 95 (48.1), 77 (100.0), 69 (20.8), 51 (51.2)
14d
14f
14g
14i
14j
310 [M]+ (11.3), 293 (9.2), 218 (16.1), 190 (18.2), 178 (11.9), 164 (11.3), 134 (24.2),
107 (12.1), 91 (14.1), 77 (100.0), 65 (19.2), 51 (63.1), 39 (37.1)
346 [M]+ (59.8), 329 (55.1), 254 (94.1), 211 (12.2), 198 (16.4), 182 (12.2), 170 (14.1),
139 (15.1), 128 (15.6), 115 (16.1), 105 (18.2), 77 (100.0), 51 (68.1), 39 (18.1)
360 [M]+ (61.1), 343 (51.1), 268 (100.0), 225 (6.1), 212 (9.1), 184 (12.2), 128 (8.1),
119 (14.2), 91 (28.2), 77 (56.1), 65 (18.1), 51 (36.2), 39 (15.4)
380 [M]+ (66.1), 363 (49.1), 288 (100.0), 253 (41.2), 197 (16.2), 139 (24.4), 111 (17.1),
77 (96.2), 65 (12.5), 51 (58.2), 39 (15.2)
364 [M]+ (62.5), 347 (50.6), 272 (100.0), 229 (16.1), 216 (17.2), 200 (14.3), 188 (14.2),
157 (13.3), 146 (13.4), 133 (14.6), 123 (18.1); 95 (32.3), 77 (86.5), 69 (19.5), 51 (68.3),
39 (17.5)
328 [M]+ (100), 271 (45.7), 255 (7.1), 243 (29.9), 204 (30.1), 150 (8.5), 77 (28.5),
50 (15.7)
15f
It has been shown [24] that 2-cyclopropylazobenzene is capable of rearrangement into 3-ethyl-2-phenyl-
2H-indazole under the influence of trifluoroacetic acid, but is unchanged under the influence of formic acid even
on heating. With the objective of retaining the three-carbon ring under the conditions of cyclization of the
azoalcohol 14k, we carried out the reaction in formic acid. However the reaction occurred regioselectively at
room temperature and only 6-tert-butyl-2-(2-cyclopropyl)phenyl-3-methyl-2H-indazole (15k) was formed.
This result shows that in the process of synthesis of 2H-indazoles by the two-step conversion of ortho-
acylazobenzenes, the step involving the heterocyclization of ortho-arylazo-substituted benzyl alcohols,
containing substituents unstable to the influence of strong acids, can be carried out with formic acid which is
much weaker than trifluoroacetic acid.
With the examples of the azo alcohols 14d,j, and h we have shown that conversion of precursors of this
type into the corresponding 2H-indazoles occurs as readily with trifluoroacetic acid as with formic acid.
Thus this type of conversion of 2-acylazobenzenes can be used to create a library of 2H-indazoles with
the objective of testing their biological activity.
EXPERIMENTAL
1H NMR spectra were recorded on a Varian VXR-400 (400 MHz) spectrometer in CDCl3 with residual
CHCl3 as internal standard, and on a Bruker DRX-500 (500 MHz) spectrometere in DMSO-d6 with TMS as
internal standard. Mass spectra were recorded on a Finnigan MAT Incos-50 machine with electron impact
ionization, 70eV. Preparative separation of the reaction mixture and monitoring of the purity of the compounds
obtained was carried by TLC with Al2O3 (activity II) with 1:1:3 ether-CH2Cl2-petroleum ether as eluant.
1214

Physicochemical and spectral characteristics of compounds 9, 14, and 15 are given in Tables 1-3.
7-Acetyl-6-Amino-1,4-benzodioxane (1). Reduced iron (17 g) was added to a solution of 6-acetyl-
7-nitro-1,4-benzodioxane (2.23 g, 10 mmol) in benzene (100 ml) heated to 75°C and stirred at this temperature
for 30 min, then water (7 ml) was added in portions over 2 h. The reaction mixture was stirred for 1 h at 80°C,
the hot benzene solution was decanted, the solvent was evaporated, and the residue was recrystallized from
ethanol. Yield 79%; mp 126-127°C [37].
Amines 2-8, 12, and 13 were made analogously by reduction of the corresponding nitro-compound.
6-Amino-7-isobutyroyl-1,4-benzodioxane, (2), yield 69%; mp 114°C [38].
6-Amino-7-cyclopropylcarbonyl-1,4-benzodioxane (3), yield 68%; mp 93-95°C [38].
6-Amino-7-benzoyl-1,4-benzodioxane (4), yield 84%; mp 134-135°C [37].
6-Amino-7-(4-methylbenzoyl)-1,4-benzodioxane (5), yield 79%; mp 136-137°C [38].
6-Amino-7-(4-methoxybenzoyl)-1,4-benzodioxane (6), yield 78%; mp 160-161°C [38].
1
6-Amino-7-(4-chlorobenzoyl)-1,4-benzodioxane (7), yield 82%; mp 123-124°C. H NMR spectrum
(DMSO-d6), δ, ppm: 4.12 (2H, m); 4.23 (2H, m) –OCH2CH2O; 6.32 (1H, s, H-5); 6.68 (1H, s, H-8); 6.85 (2H,
br. s, NH2); 7.52 (4H, m ArH'). Found, %: C 61.92; H 3.91; N 4.63. C15H12ClNO3. Calculated, %: C 62.19;
H 4.17; N 4.83.
6-Amino-7-(3-fluorobenzoyl)-1,4-benzodioxane (8), yield 82%; mp 124-125°C [38].
1
6-Acetyl-5-amino-1,4-benzodioxane (12), yield 74%; mp 115-116°C. H NMR spectrum (CDCl3), δ,
ppm (J, Hz): 2.55 (3H, s, CH3); 4.27 (4H, m, OCH2CH2O); 6.22 (1H, d, J = 9.2, H-8); 6.52 (2H, br. s, NH2);
7.24 (1H, d, J = 9.2, H-7). Found, %: C 61.93; H 5.68; N 7.29. C10H11NO3. Calculated, %: C 62.17; H 5.74;
N 7.25,
1
5-Amino-6-isobutyroyl-1,4-benzodioxane (13), yield 69%; mp 67-68°C. H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 1.19 (6H, d, J = 6.5, CH(CH3)2)); 3.51 (1H, sp, CH(CH3)2)); 4.29 (4H, m, OCH2CH2O); 6.22
(1H, d, J = 9.3, H-8); 6.61 (2H, br. s, NH2); 7.35 (1H, d, J = 9.3, H-7). Found, %: C 64.88; H 6.91; N 6.47.
C12H15NO3. Calculated, %: C 65.14; H 6.83;N 6.33.
2-Aminophenylcyclopropane was prepared as in [39]. Yield 72%; bp 103-104°C (9 mmHg),
nD20 1.5810.
2-Acetyl-5-tert-butylnitrosobenzene (11) was synthesized as described in [40]. Yield 87%; mp
140-143°C (ethanol).
2-Arylazoacylbenzenes 9a-k (General Method). The corresponding nitrosobenzene (10 mmol) was
added to a solution of the amino ketone 1-8, 10 (10 mmol) in glacial acetic acid (30 ml) over 3 min. The uniform
solution was kept for 8 h at 20°C and then poured into water (250 ml), the product was extracted with CHCl3,
the extract was dried with CaCl2, the solvent was evaporated, and the residue was chromatographed on a strip on
Al2O3.
2-Arylazobenzyl Alcohols 14a-k (General Method). A 2-arylazoacylbenzene 9a-k (10 mmol) was
added in portions to a suspension of NaBH4 (0.38 g, 10 mmol) in ethanol (30 ml), the mixture was stirred for 6-8
h at 40-50°C, the reaction mass was carefully decomposed with10% HCl solution (~2-3 ml), and the ethanolic
solution was poured into water (200 ml). The reduction products were extracted with CHCl3, the extract was
dried with MgSO4, the solvent was evaporated, and the residue was either recrystallized or chromatographed on
strips with Al2O3.
Cyclization of 2-Arylazobenzyl Alcohols 14a-k into 2H-Indazoles 15a-k under the Influence of
Trifluoroacetic Acid (General Method). An azo alcohol 14a-k (1 mmol) was added CF3COOH at 0-5°C, the
temperature was increased to 20°C, the mixture was stirred for 30 min, poured into ice water (100 ml),
neutralized with Na2CO3, extracted with CHCl3 (2×30 ml), dried over MgSO4, the solvent was evaporated, and
the residue was recrystallized from ethanol.
1215

Cyclization of 2-Arylazobenzyl Alcohols 14d, j, h, and k into 2H-Indazoles 15d, j, h, and k under
the Influence of Formic Acid (General Method). An azo alcohol 14d,j,h,k (1 mmol) was added to HCO2H
(10 ml) at 20°C, stirred for 2 h, the reaction mixture was poured into cold water (150 ml), neutralized with
Na2CO3, the residue was filtered off , washed with water and crystallized from ethanol.
This work was carried out with a financial grant "For development of the scientific school of
Academician N. S. Zefirov."
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