Synthesis and structural characterization of 1- and 2-substituted indazoles: Ester and carboxylic acid derivatives

Article abstract of DOI:10.3390/11110867

A series of indazoles substituted at the N-1 and N-2 positions with estercontaining side chains -(CH₂)_nCO₂R of different lengths (n = 0-6, 9, 10) are described. Nucleophilic substitution reactions on halo esters (X(CH₂)_nCO₂R) by 1H-indazole in alkaline solution lead to mixtures of N-1 and N-2 isomers, in which the N-1 isomer predominates. Basic hydrolysis of the ester derivatives allowed the synthesis of the corresponding indazole carboxylic acids. All compounds were fully characterised by multinuclear NMR and IR spectroscopies, MS spectrometry and elemental analysis; the NMR spectroscopic data were used for structural assignment of the N-1 and N-2 isomers. The molecular structure of indazol-2-yl-acetic acid (5b) was determined by X-ray diffraction, which shows a supramolecular architecture involving O2-H...N1 intermolecular hydrogen bonds.

Full text of DOI:10.3390/11110867

Molecules 2006, 11, 867-889
molecules
ISSN 1420-3049
http://www.mdpi.org
Full Paper
Synthesis and Structural Characterization of 1- and 2-
Substituted Indazoles: Ester and Carboxylic Acid Derivatives
1
,
1
1
1
Fátima C. Teixeira *, Hélène Ramos , Inês F. Antunes , M. João M. Curto ,
2
3
M. Teresa Duarte and Isabel Bento
1
INETI - Departamento de Tecnologia de Indústrias Químicas, Estrada do Paço do Lumiar, 22, 1649-
38 Lisboa, Portugal
0
2
3
Instituto Superior Técnico, Centro de Química Estrutural, Complexo I, Av. Rovisco Pais, 1049-001
Lisboa, Portugal
Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Apartado 127, 2781-901
Oeiras, Portugal
*
Author to whom correspondence should be addressed; E-mail: fatima.teixeira@ineti.pt
Received: 4 October 2006; in revised form: 30 October 2006 / Accepted: 13 November 2006 /
Published: 14 November 2006
Abstract: A series of indazoles substituted at the N-1 and N-2 positions with ester-
containing side chains -(CH
2
)
n
CO
2
R of different lengths (n = 0-6, 9, 10) are described.
CO R) by 1H-indazole in
Nucleophilic substitution reactions on halo esters (X(CH
2
)
n
2
alkaline solution lead to mixtures of N-1 and N-2 isomers, in which the N-1 isomer
predominates. Basic hydrolysis of the ester derivatives allowed the synthesis of the
corresponding indazole carboxylic acids. All compounds were fully characterised by
multinuclear NMR and IR spectroscopies, MS spectrometry and elemental analysis; the
NMR spectroscopic data were used for structural assignment of the N-1 and N-2 isomers.
The molecular structure of indazol-2-yl-acetic acid (5b) was determined by X-ray
diffraction, which shows a supramolecular architecture involving O2-H...N1
intermolecular hydrogen bonds.
Keywords: Indazole, N-1 and N-2 isomers, Spectroscopic characterization, X-ray
diffraction studies.

Molecules 2006, 11
868
Introduction
Indazoles constitute an important class of heterocycles that display interesting biological properties
1,2], such as anti-depressant [3], anti-inflammatory [4,5], analgesic and antipyretic [6], dopamine
[
antagonistic [7], anti-tumor [8], anti-emetic [9] and anti-HIV activities [10]. The indazole ring system
is also present in many other compounds such as herbicides, dyes or sweeteners like guanidine-1H-
indazole [1,2,11]. Despite the many useful applications of indazole derivatives, indazole chemistry
remains less studied compared to other heteroaromatic compounds, such as indole or benzimidazole.
Indazole is a ten-π electron aromatic heterocyclic system. Like the pyrazole molecule, indazole
resembles both pyridine and pyrrole and its reactivity reflects this dual behaviour [1]. The indazole
ring has two nitrogen atoms and presents annular tautomerism with regards to the position of the NH
hydrogen atom. Due to the difference in energy between the tautomers, the 1H-tautomer (the
benzenoid form 1a) predominates in the gas-phase, solution and solid state, and its derivatives are
usually thermodynamically more stable than the corresponding 2H-forms (the quinonoid form 1b)
(
Figure 1) [1,2,12,13].
Figure 1. Annular tautomerism of indazole (1a: benzenoid 1H-indazole tautomer; 1b:
quinonoid 2H-indazole tautomer).
N
N
N H
N
H
1
a
1b
Several studies concerning the alkylation of 1H-indazole (1) reveal that the acidity or basicity of
the medium, use of protic or aprotic solvents, as well as electronic and steric effects all affect the ratio
of N-1 and N-2 alkylated isomers formed. Generally, the N-1 isomers are thermodynamically more
stable, whereas the N-2 isomers are kinetically favoured [14]. Yamazaki [15] and Elguero [16] have
reported the formation of both N-1 and N-2-acyl indazole derivatives, but they readily isomerize to
afford the most stable isomer after equilibration. The regioselectivity of the reaction is also dependent
on the nature of the alkylating agents used; recently Cheung et al. reported an efficient and
regioselective synthesis of N-2 alkylated isomers using trimethyloxonium tetrafluoroborate or
triethyloxonium hexafluorophosphonate as alkylating agents [17].
NMR spectroscopy is very useful to assign the structures of 1- and 2-substituted indazoles, as the
1
13
H-NMR and C-NMR spectra of the two isomers are usually sufficiently different to be used as
1
3
diagnostic tools to establish the position of substitution. C-NMR spectroscopy is usually a
particularly good method to perform this assignment [1,2,14,16-18].
As part of a continuing effort to develop novel heterocyclic compounds with potential therapeutic
biological activity, we are currently involved in the synthesis of a large number of indazole
derivatives. The substitution at the different atoms of the six- and five membered rings with side
chains with different length and functionalisation, can afford a large number of indazole derivatives,
presenting a promising field to provide new derivatives with biological/therapeutical properties.

Molecules 2006, 11
869
Here we report the synthesis, starting from 1H-indazole (1), of several indazole derivatives
substituted at the N-1 and N-2 positions with side chains of different lengths and functionalised with
ester or carboxylic acid groups. Their full characterization was achieved by IR and multinuclear NMR,
mass spectrometry, mp and elemental analysis. The recrystallization of indazol-2-yl-acetic acid 5b
afforded crystals suitable for X-ray diffraction studies, which confirm the proposed structure.
Application of these compounds to the synthesis of novel biologically active compounds is under
investigation and will be reported in due course.
Results and Discussion
Synthesis
The indazole ester derivatives 2 and 3 were obtained in different yields and ratios starting from
1
H-indazole (1) by nucleophilic substitution reactions of the corresponding halo esters with different
hydrocarbon chain lengths (Table 1).
Table 1. Synthesis of indazole derivatives substituted at N-1 and N-2 (2 and 3).
4
3
3
a
5
6
i) Base
N
N
+
N
(CH2)nCO2R
7
a
N
H
ii) X(CH )nCO R
N
N
2
2
7
(CH2)nCO2R
1
2
3
X(CH
2
)
n
CO
2
R
R
2
3
2 + 3
(%)
Series
a
n
Base (solvent)
(
%)
(%)
X
0
Kt-BuO (THF)
Kt-BuO (THF)
Kt-BuO(THF)
K CO (DMF)
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
99
-
99
[
a]
[a]
(45)
(10)
13
b
c
1
2
3
55
67
68
89
2
3
22
[
a]
a]
[a]
Kt-BuO (THF)
NaH (THF)
(15)
47
(15)
39
86
95
K CO (DMF)
49
46
2
3
[
[a]
Kt-BuO (THF)
(26)
49
(18)
12
[
b]
[c]
d
Kt-BuO (DMSO)
61
K
2
CO
3
(DMF)
59
37
96
90
[
b]
e
4
5
K CO (DMF)
59
31
2
3
[
b]
[a]
[a]
f
Kt-BuO (THF)
CO (DMF)
(39)
62
(39)
34
K
2
3
96
97
97
98
g
6
9
K CO (DMF)
61
36
2
2
2
3
3
3
h
i
K
K
CO
CO
(DMF)
63
34
10
(DMF)
60
38
[
a]
1
[b]
Determined from the H-NMR spectra;
For the same reagents, the reactions were also
performed using bases such as NaH (THF) (n = 3-5), nBuLi (THF) (n = 3, 5), KOH (MeOH) (n =
[
c]
3
) and pyridine (n = 3), but indazole 1 remained unreacted; A complex mixture of products was
also obtained.

Molecules 2006, 11
870
For best results, the reaction was carried out on the anionic form of the 1H-indazole, readily
obtained in situ by the action of a base (Kt-BuO, NaH, nBuLi, KOH, pyridine or K CO ), in different
2
3
solvents (THF, DMSO, MeOH or DMF). Compounds 2 and 3 were separated by column
chromatography to provide the pure compounds, usually as pale yellow oils, in good to excellent yield.
The N-1 isomers 2 were eluted first in each case and in all cases the N-1 isomers were the major
isomers formed.
In these common nucleophilic displacement reactions, X in the compounds X(CH ) CO R
2
n
2
corresponds to chloro or bromo atoms. When n≥1, the reactivity of chloroesters was lower than that of
the corresponding bromoesters, so the latter were used. For n> 3 only the use of K CO as base in
2
3
2
DMF allows complete reactions. The reaction of indazole 1 with ClCO Me in the presence of Kt-BuO,
at room temperature, gave only the N-1 isomer 2a in excellent yield (99%). The synthesis of 2a was
previously reported by Kingsbury et al. [19], who showed that the reaction of ClCO Me with indazole
2
1
in the presence of an amine, such as pyridine or triethylamine, gave the N-1 isomer 2a (57%) at
room temperature and the N-2 isomer at -78 ºC. The synthesis of 2b, 2c, 3b and 3c, using also a
nucleophilic displacement reactions with bromo esters, was first reported by Auwers in 1926 [20], but
no spectroscopic characterisation has been described. During the course of this work, a patent referring
to compounds 2d, 2e, 3d and 3e was published, but no spectroscopic data was given [21].
The esters 2 and 3 were subject to basic hydrolysis to afford the corresponding N-1 and N-2
indazole carboxylic acid derivatives (compounds 4 and 5, respectively), as white crystalline solids in
good to excellent yields (Table 2 and 3). Indazol-2-yl-acetic acid 5b gave crystals suitable for an X-ray
structural analysis (see Figure 2, below).
Table 2. Physical-chemical characteristics and elemental analysis of indazole carboxylic acids 4b-i.
i) NaOH
N
N
N
N
(
CH ) CO R
(CH ) CO H
2 n 2
2
n
2
2
4
Analysis (%)
Yield
Nº
n
R
mp (ºC)
Formula
Calcd.
H
Found
H
(
%)
C
N
C
N
1
4
b
1
2
3
4
5
6
9
Et
Et
97
98
93
99
186-188
106-107
60-62
C
9
H
H
H
H
H
H
H
H
8
N
2
O
2
61.36 4.58 15.90 61.32
63.15 5.30 14.73 62.96
64.69 5.92 13.72 64.71
66.04 6.47 12.84 66.11
67.22 6.94 12.06 67.42
68.27 7.37 11.37 68.46
4.52
5.34
5.97
6.58
6.99
7.25
8.49
8.91
15.85
14.49
13.74
12.86
11.97
11.36
9.65
2
4
c
C
10
11
12
13
14
17
18
10
12
14
16
18
24
26
N
2
2
2
2
2
2
2
O
O
O
O
O
O
O
2
2
2
2
2
2
2
4
d
Et
C
C
C
C
C
C
N
N
N
N
N
N
4
e
Et
82-83
4
f
Et
100
74
69-70
4
g
Et
54-58
4
h
Me
93
78-81
70.80 8.39
71.49 8.67
9.71
9.26
70.67
71.39
4
i
10 Me
95
73-74
9.29
1
2
(
(
Lit. [20] (H
2
O) 185-186 ºC)
Lit. [20] (C
6
6
H /petroluem ether 105.5-106.5 ºC)

Molecules 2006, 11
871
Table 3. Physical-chemical characteristics and elemental analyses of indazole carboxylic acids 5a-i.
i) NaOH
N
(CH ) CO R
N
(CH ) CO H
2
n
2
2 n
2
N
N
3
5
Analysis (%)
Yield
Nº
n
R
mp (ºC)
Formula
Calcd.
H
Found
H
(
%)
C
N
C
N
1
5
b
1
2
3
4
5
6
9
Et
Et
96
98
97
98
59
62
90
93
254-256
147-149
C
9
H
8
N
2
O
2
61.36 4.58
63.15 5.30
64.69 5.92
66.04 6.47
67.22 6.94
68.27 7.37
70.80 8.39
71.49 8.67
15.90
14.73
61.24
63.05
64.71
65.92
66.97
68.15
70.69
71.53
4.51 15.90
5.37 14.70
5.99 13.64
6.18 12.74
7.31 11.66
7.38 11.27
2
5
c
C
10
C
11
C
12
C
13
C
14
C
17
C
18
H
H
H
H
H
H
H
10
12
14
16
18
24
26
N
N
N
N
N
N
N
2
2
2
2
2
2
2
O
O
O
O
O
O
2
5
d
Et
132-134
112-114
86-87
77-78
68
2
2
2
2
2
2
13.72
5
e
Et
12.84
5
f
Et
12.06
5
5
g
Et
11.37
h
Me
9.71
8.68
8.68
9.76
9.15
5
i
10 Me
82
O
9.26
1
2
(
Lit. [20] dec. 257 ºC) ; (Lit. [20] (H
2
O) 148 ºC)
Spectroscopic Characterization
The unambiguous assignment of indazole derivatives substituted at N-1 and N-2 was carried out by
1
13
H- and C-NMR spectroscopy, DEPT and two-dimensional NMR techniques. The main resonances
1
in the H-NMR spectra of 1H-indazole ester derivatives 2b-i in CDCl
3
are: i) three resonances in the
δ = 7.12-7.73 ppm region, usually as a two proton multiplet, a one proton doublet and a one proton
triplet, which correspond to the 4-H to 7-H protons, ii) a singlet (or a doublet with J = 0.6 Hz) at δ =
7
5
.98-8.04 ppm, which corresponds to the 3-H proton, iii) a triplet for the the NCH
2
protons at δ = 4.36-
1
.13 ppm, and iv) resonances at δ = 1.22-3.65 ppm for the CH
2
protons. The H-NMR spectrum of 1H-
indazole ester derivative 2a (n = 0), with the ester carbonyl group bonded to the nitrogen atom of the
indazole, shows all the resonances at higher frequency than those of compounds 2b-i, in particular the
resonance of the 7-H proton, which appears at δ = 8.26 ppm, due to the deshielding effect of the ester
carbonyl group.
1
The H-NMR spectra of the N-1 and N-2 isomers are very different. Spectral comparison shows
that the resonances of the 3-H to 6-H protons in the N-2 isomers appear at lower frequency than in the
corresponding 1N-isomers, but the resonance of the 7-H proton of the N-2 isomers appears at higher
frequency, due to the deshielding effect of the N-1 lone pair. The 3-H proton in the N-2 isomers is
shielded relative to the same proton in the N-1 isomer. The main resonances of the N-2 ester
derivatives 3 are: i) four resonances in the δ = 7.06-7.71 ppm region, usually as two one proton
doublets (4-H and 7-H) and two one proton triplets (5-H and 6-H), ii) a singlet (or a doublet, J = 0.6
Hz) at δ = 7.88-8.00 ppm, which corresponds to the 3-H proton, iii) a triplet for the the NCH protons
2
2
at δ = 4.39-5.19 ppm, and iv) resonances at δ = 1.35-3.65 ppm for the CH protons.
The chemical shifts of the indazole protons in carboxylic acids 4 and 5 do not differ substantially
from those in the corresponding esters 2 and 3, respectively. This is also the case for the side-chain
protons.

Molecules 2006, 11
872
1
The main resonances in the H-NMR spectra of the 1H-indazole carboxylic acid derivatives 4 in
MeOD are: i) four resonances at δ = 7.12-7.76 ppm, usually as two one proton doublets (4-H and 7-H)
and two one proton triplets (5-H and 6-H), ii) a singlet (or a doublet with J = 0.6 Hz) at δ = 7.98-8.04
ppm corresponding to the 3-H proton, iii) a triplet for the NCH protons at δ = 4.38-5.22 ppm, and iv)
2
1
resonances at δ = 1.23-2.91 ppm for the CH
2
protons. The H-NMR spectra of compounds 4d, 4e and
4
f were also recorded in CDCl . It was observed that the chemical shifts depend on solvents used, in
3
3
particular the resonance of 7-H: in MeOD, it appears as a doublet at δ ≈ 7.53 ppm and in CDCl it
appears as a two proton multiplet at δ ≈ 7.40 ppm (with the same chemical shift as the 6-H proton).
1
The H-NMR spectrum of compound 4f was also recorded in DMSO and it showed no significant
differences compared to the spectrum recorded in MeOD.
1
The main resonances in the H-NMR spectra of the 2H-indazole carboxylic acid derivatives 5c-i in
MeOD are: i) four resonances in the δ = 7.03-7.74 ppm region, usually as two one proton doublets (4-
H and 7-H) and two one proton triplets (5-H and 6-H), ii) a singlet (or a doublet with J = 0.6 Hz) at δ =
8
.16-8.36 ppm, corresponding to the 3-H proton, iii) a triplet for the NCH protons at δ = 4.40-5.28
2
1
ppm, and iv) resonances at δ = 1.27-3.00 ppm for the CH protons. The H-NMR spectrum of
2
carboxylic acid 5b was recorded in DMSO, but comparison with the spectra of 5c-i recorded in MeOD
showed no significant differences. As observed for the N-1 isomer, the N-2 carboxylic acid derivatives
1
5
present H-NMR spectra similar to those of the corresponding ester derivatives 3, with the exception
of the 3-H proton which is deshielded compared to the corresponding esters and N-1 isomers.
1
3
3
The main resonances in the C-NMR spectra in CDCl of 1H-indazole ester derivatives 2b-i (with
the exception 2a) are: i) the resonances of C4 and C5 appear at δ ≈ 120-121 ppm, ii) C6 has a chemical
shift of δ = 126 ppm, iii) C7 is the more shielded atom, with a chemical shift at δ = 108-109 ppm, iv)
C3 appears at higher frequency, with a chemical shift at δ = 132-134 ppm; v) the quaternary C3a and
C7a carbon atoms present different chemical shifts, with C7a at higher frequency (δ = 139 ppm) than
2
C3a (δ = 123-125 ppm), vi) the CH carbon atom resonances appear at δ = 22.2-34.5 ppm, as expected,
and vii) the CO carbon atom has a chemical shift of δ = 167-174 ppm and becomes more deshielded in
compounds with longer hydrocarbon chains. In the case of compound 2a (n = 0), the chemical shift of
carbon C7 is deshielded relative to the free indazole due to the ester group (Table 4).
1
3
Table 4. C-NMR chemical shifts (δ in ppm) of 1H-indazole 1, 1H-indazole esters 2a-i
and 2H-indazole esters 3b-i in CDCl3.
Nº
1
n
R
C7
C4
C5
C6
C3
C3a
C7a
CO NCH
2
CH
2
OCH
2
CH
3
OCH
3
110.0 120.4 120.1 125.8 133.4 122.8 139.9
2
2
a
0
1
2
3
4
5
Me 114.3 121.1 124.0 129.2 140.2 125.7 139.7 151.0
Et 108.6 121.1 120.8 126.6 134.1 124.1 140.0 167.8 50.1
Et 109.0 120.9* 120.5* 126.3 133.5 123.9 139.5 171.1 44.1
Et 108.8 121.0* 120.4* 126.1 133.0 123.9 139.4 172.7 47.6
Et 108.9 121.1* 120.4* 126.1 132.8 124.0 139.3 173.2 48.4
Et 108.8 121.0* 120.3* 126.0 132.7 123.9 139.3 173.4 48.5
54.3
b
61.6, 13.9
60.8, 14.0
60.4, 14.1
2
c
34.5
2
d
24.9, 30.9
2
e
22.2, 29.2, 33.7 60.3, 14.2
24.5, 26.3, 29.4, 60.1, 14.1
2
f
3
4.0

Molecules 2006, 11
873
Table 4. Cont.
Nº
n
R
C7
C4
C5
C6
C3
C3a
C7a
CO NCH
2
CH
2
OCH
2
CH
3
OCH
3
2
2
g
6
Et 108.9 121.1* 120.3* 126.0 132.7 123.9 139.3 173.7 48.7
24.7, 26.5, 28.7, 60.2, 14.2
9.6, 34.2
24.8, 26.8, 29.0,
9.1, 29.2, 29.8,
4.0
i 10 Me 109.0 121.1* 120.3* 126.0 132.6 124.0 139.3 174.3 48.9 24.9, 26.8, 29.05,
9.13, 29.26,
2
h
9
Me 108.9 121.0 120.3 126.0 132.6 123.9 139.3 174.2 48.8
51.4
51.4
2
3
2
2
2
9.31, 29.8, 34.1
3
b
1
2
3
4
Et 117.6 120.3 122.1 126.4 124.4 122.2 149.2 167.2 54.5
Et 117.1 120.1 121.51 125.9 123.5 121.5 148.9 170.7 48.7
Et 117.2 119.9 121.47 125.7 122.8 121.5 148.8 172.4 52.3
Et 117.2 120.0 121.5 125.7 122.6 121.6 148.7 173.0 53.2
62.2, 14.1
60.8, 13.9
60.4, 14.0
3
c
34.9
3
d
25.5, 30.7
3
e
21.9, 29.8, 33.5 60.3, 14.1
2
4.3, 26.0, 30.2,
3.9
4.7, 26.3, 28.5,
0.4, 34.1
4.8, 26.6, 28.96,
Me 117.3 120.0* 121.4* 125.6 122.4 121.7 148.7 174.2 53.7 28.98, 29.0, 29.1,
0.6, 34.0
3
f
5
6
Et 117.3 119.9 121.5 125.7 122.5 121.6 148.8 173.4 53.4
60.2, 14.1
60.2, 14.2
3
2
3
g
Et 117.3 120.0 121.5 125.7 122.5 121.7 148.8 173.6 53.6
3
2
3
h
9
51.4
51.4
3
2
4.9, 26.6, 29.04,
29.12, 29.24,
3
i 10 Me 117.4 120.0* 121.5* 125.7 122.5 121.7 148.8 174.3 53.8
2
9.28, 30.6, 34.1
*
These assignments may be reversed. The NMR assignment of the other compounds was done
using two-dimensional NMR techniques.
2
Compared to the N-1 isomer 2 the N-2 isomers 3 present similar chemical shifts for CH , CO, C6,
C4 and C5 (Table 4). Other carbon atoms present large differences that allow the unequivocal
assignment of both isomers: i) C7 (δ ≈ 117 ppm) and C7a (δ ≈ 148-149 ppm) are more deshielded in
the N-2 isomer, with ∆δ ≈ 8-9 and 9-10 ppm, respectively, ii) C3 (δ ≈ 122-124 ppm) and C3a (δ ≈ 121-
1
22 ppm) are more shielded in these N-2 isomers, with ∆δ ≈ 10 ppm (C3) and ∆δ ≈ 2-3 ppm (C3a).
1
3
In the C-NMR spectra in MeOD, the differences between the N-1 and N-2 indazole carboxylic
acids 4 and 5 are similar to those observed in the spectra of the ester derivatives: i) CH , CO, C6, C5
2
and C4 have similar chemical shifts in both isomers, ii) C7 and C7a are deshielded in the N-2 isomers
with ∆δ ≈ 7 ppm (C7) and ∆δ ≈ 10-11 ppm (C7a), iii) the C3 (δ ≈ 135 ppm in N-1 and δ ≈ 125 ppm in
N-2 isomer) and C3a (δ ≈ 125 ppm in N-1 and δ ≈ 122-123 ppm in N-2 isomer) are more shielded in
the N-2 than in the N-1 isomers (Table 5).
1
3
The C-NMR spectra in different deuterated solvents show similar patterns, with small differences
in the chemical shifts, as were observed at higher frequencies in MeOD. Comparison of the spectra of
indazole carboxylic acid derivatives 4d, 4e and 4f and indazole esters 2d, 2e and 2f in the same solvent
1
3
(
3
CDCl ), reveal no differences between their C-NMR spectra, with the exception of the CO carbon
atom. These observations confirm that, despite the change in the functional groups of indazole
derivatives (with no mesomeric effect towards the indazole ring) the chemical shifts of indazole ring
carbon atoms remain constant, which allows the assignment of N-1 and N-2 isomers of carboxylic acid
1
3
derivatives by C-NMR spectroscopy.

Molecules 2006, 11
874
1
3
These spectroscopic data are in agreement with the C-NMR spectra of 1N- and 2N-substituted
indazoles reported in the literature [1,2,8,11,12]. The structural assignments were ultimately confirmed
by X-ray crystal structure analysis of compound 5b.
1
3
Table 5. C-NMR chemical shifts (δ in ppm) of 1H-indazole carboxylic acids 4b-i and
H-indazole carboxylic acids 5b-i.
2
Nº
n
Solvent
C7
C4
C5
C6
C3
C3a C7a CO NCH
2
CH
2
4
b
1
2
3
3
4
4
5
5
5
6
MeOD 110.4 122.1
122.1 128.1 135.0 125.4 141.8 171.5 50.6
4
c
MeOD 110.6 122.0* 121.9* 127.8 134.5 125.2 141.0 174.6 45.2
MeOD 110.3 122.2* 121.9* 127.8 134.1 125.2 141.0 174.6 48.6
35.1
4
4
d
d
26.2, 31.6
CDCl
MeOD 110.3 122.1* 121.8* 127.7 133.8 125.2 140.9 177.0 49.2
CDCl 108.8 121.2* 120.5* 126.4 132.7 123.7 139.3 178.3 48.2
MeOD 110.4 122.2
CDCl 108.9 121.2
DMSO 109.6 120.8
108.9 121.3* 120.7* 126.6 132.9 123.7 139.4 177.6 47.4
24.7, 30.8
3
4
4
e
e
23.3, 30.3, 34.3
21.9, 29.0, 33.4
3
4
4
4
f
f
f
121.8 127.7 133.8 125.1 140.9 177.4 49.3 25.6, 27.3, 30.6, 34.7
120.5 126.3 132.7 123.8 139.3 178.9 48.5 24.2, 26.2, 29.4, 33.8
120.3 125.9 132.4 123.4 139.2 174.4 47.9 24.1, 25.8, 29.2, 33.6
3
4
g
MeOD 110.4 122.1* 121.8* 127.7 133.7 125.1 140.9 177.5 49.4 25.8, 27.4, 29.7, 30.7,
4.7
3
4
h
9
MeOD 110.4 122.2* 121.8* 127.7 133.7 125.1 140.9 177.7 49.5
26.0, 27.7, 30.11,
3
0.18, 30.2, 30.3, 30.9,
3
4.9
4
i 10 MeOD 110.4 122.1
121.8 127.7 133.7 125.1 140.9 177.7 49.5
26.0, 27.7, 30.1,
0.27, 30.34, 30.4,
3
3
0.9, 34.9
5
b
1
2
3
4
5
6
DMSO 117.0 120.8
MeOD 117.4 121.6
121.2 125.8 125.5 121.6 148.2 169.3 54.2
122.7 127.6 125.9 122.9 150.1 174.0 49.9
5
c
35.6
5
d
MeOD 117.4 121.6* 122.7* 127.5 125.5 123.1 150.1 176.2 53.4
MeOD 117.3 121.5* 122.6* 127.5 125.4 123.1 149.9 176.9 53.9
27.0, 31.5
5
e
23.0, 31.0, 34.2
5
f
MeOD 117.3 121.5
MeOD 117.3 121.5* 122.6* 127.4 125.3 123.0 149.9 177.5 54.2 25.8, 27.2, 29.6, 31.4,
4.7
122.6 127.4 125.3 123.1 149.9 177.7 54.3 26.0, 27.5, 30.0, 30.1,
0.2, 30.3, 31.6, 34.9
i 10 MeOD 117.3 121.5* 122.6* 127.4 125.3 123.1 149.9 177.7 54.3 26.1, 27.5, 30.1, 30.2,
0.3, 30.38, 30.41,
1.6, 35.0
122.6 127.4 125.4 123.1 149.9 177.3 54.1 25.5, 27.1, 31.3, 34.6
5
5
5
g
3
h
9
MeOD 117.3 121.5
3
3
3
*
These assignments may be reversed. The NMR assignment of the other compounds was done using
two-dimensional NMR techniques.
-
1
The IR spectra of compounds 2 and 3 show ν(C=O) stretching bands in the range of 1731-1748 cm
-1
and ν(C-O) stretching bands in the 1171-1212 cm region. The ν(C=O) stretching band frequencies are
similar in both the N-1 and N-2 isomers. The absence of the NH stretching band confirmed the

Molecules 2006, 11
875
substitution on the nitrogen atom. The IR spectra of indazole carboxylic acids 4 and 5 show broad
-1
bands in the 3500-2300 cm region, corresponding to the hydrogen-bonded O-H characteristic of
-1
carboxylic acids. These bands overlap the C-H stretching region around 3000 cm . The spectra also
showed ν(C=O) stretching bands at the usually lower frequency than the corresponding esters, in the
-1
1
689-1736 cm region. In general, the ν(C=O) stretching bands reveal a shift to lower wavenumber with
an increasing alkyl side chain directly linked to the nitrogen atom of indazole.
+
The electron impact (EI) mass spectra of all compounds show the [M] ions with relative
abundances varying from 5 to 100% of the respective base peaks, with small molecular peaks for
compounds with longer side chains. In most of the spectra, the ions with m/z values corresponding to
+
+
[
IndzCH ] and [IndzH] (IndzH-Indazole) are either the base peaks or have high relative abundances.
2
The mass spectra of 1H- and 2H-indazole ester derivatives 2 and 3 are similar and their fragmentation
+
+
+
generally involves the formation of [M-OR] , [M-COOR] and [M-(CH ) COOR] ions. Mass spectra
2
n
of the 1H- and 2H-indazole carboxylic acid derivatives 4 and 5 are also similar. Their fragmentation
+
+
involves the formation of [M-COOH] and [M-(CH
2 n
) COOH] ions.
Molecular and crystal structure of 2-indazol-2-yl-acetic acid (5b)
2
-Indazol-2-yl-acetic acid (5b, n = 1) was recrystallized from acetone/water solution to afford
crystals suitable for X-ray diffraction studies. Compound 5b crystallizes in the centrosymetric space
group P2 /n, with one molecule per asymmetric unit. The ORTEP [23] view of the molecule, with the
1
atomic numbering scheme, is given in Figure 2. Detailed bond distances and angles and other
structural parameters, are given in Table 6.
Figure 2. ORTEP [23] view of compound 5b showing the atomic labelling scheme and
the relative positioning of the indazole ring and the carboxylic moiety.
Table 6. Bond lengths [Å], angles [º] and other structural parameters for compound 5b.
N1-C7a
N1-N2
N2-C3
1.349(2)
1.3526(19)
1.334(2)
1.446(2)
1.413(2)
1.413(3)
1.384(3)
C3a-C4
C8-C9
C5-C4
C5-C6
C7-C6
C9-O1
C9-O2
1.421(2)
1.516(2)
1.355(3)
1.408(3)
1.360(3)
1.200(2)
1.307(2)
N2-C8
C7a-C3a
C7a-C7
C3a-C3

Molecules 2006, 11
876
Table 6. Cont.
C7a-N1-N2
C3-N2-N1
C3-N2-C8
104.08(12)
N2-C8-C9
C4-C5-C6
C5-C4-C3a
C6-C7-C7a
N2-C3-C3a
C7-C6-C5
O1-C9-O2
O1-C9-C8
O2-C9-C8
112.22(14)
121.66(18)
118.2(2)
113.32(14)
127.88(16)
118.73(14)
111.07(15)
128.05(17)
120.86(16)
104.44(14)
135.92(18)
119.64(17)
N1-N2-C8
N1-C7a-C3a
N1-C7a-C7
C3a-C7a-C7
C3-C3a-C7a
C3-C3a-C4
C7a-C3a-C4
117.5(2)
107.08(16)
122.1(2)
125.35(16)
124.33(15)
110.32(14)
Angle between planes
C3a-C3-N1-N2-C7a and C9-O1-O2
87.2(1)
Torsion angles
N2-C8-C9-O1
N2-C8-C9-O2
10.0(3)
N1-N2-C8-C9
C3-N2-C8-C9
87.99(19)
-88.9(2)
-169.98(15)
Hydrogen bond
D-H…A
D-H H...A D...A D-H..A
1.02(3) Å 1.68(3) Å
[
a]
o
O2-H2...N1
2.677(2) Å
164(3)
[
a]
-
symmetry operation 1/2-x,1/2+y,3/2-z
The molecular structure of the indazole is similar to that of related compounds reported in the
literature [24]. As expected, the indazole moiety is planar, with maximum deviations of 0.0052(9) Å in
the N1 atom. Atom C8 is still within the indazole least square plane, but the carboxyl group (COOH) is
oriented perpendicularly, forming an angle of 87.2(1)° with the five membered pyrazole ring. The
plane containing the COOH group bisects the indazole almost as a mirror plane, but no disorder was
found in the molecule. The values of the torsion angles N2-C8-C9-O1 [10.0(3)º] and N2-C8-C9-O2
[
-169.98(15)º], showing the planarity of the fragment, as well as N1-N2-C8-C9 [87.99(19)º] and C3-
N2-C8-C9 [-88.9(2)º] support the relative orientation of the carboxy moiety described above.
The secondary structure of compound 5b presents a one dimensional zigzag chain, due to the short
O2-H...N1 intermolecular hydrogen bond [2.677(2) Å with an angle of 164(3)°], which is preferably
2
observed, instead of the R (8) main pattern found in carboxylic acid derivatives (C-O-H…O-C-O-
2
H…O contacts) [25]. The one-dimensional zigzag chain along the b axis obtained with a C(6) synthon
as well as the weak π…π contacts [~ 2.75(4) Å] within neighbouring chains are shown in the packing
diagrams of Figure 3 (a, b and c, respectively). The supramolecular motif found in the crystal structure
of compound 5b agrees with the data in the literature, either for 1H-unsubstituted indazoles [26] where
N-H…N hydrogen bonds are responsible for the supramolecular pattern, or with pyrazole [27] or even
2
with pyrazole carboxylic acid derivatives [28] where the usual hydrogen bond ring pattern R (8) [25]
2
is not found, due to the strength of this heteromeric intermolecular interaction [29].

Molecules 2006, 11
Figure 3. (a) and (b) View along axis a and b respectively, showing the C(6) hydrogen
877
bond synthon, responsible for the zigzag chain. (c) Packing diagram along axis c shows
the weak interaction between the zigzag neighbouring chains, due to the π…π contacts
(
drawings done with Mercury) [24b].
(
b)
(
a)
(
c)
Conclusions
A series of seventeen esters and sixteen carboxylic acids with side chains with different length
derived from indazole substituted at N-1 and N-2, is reported. General synthetic routes to these
compounds have been described and their full spectroscopic characterization and structural features
have been presented. Spectroscopic data were used to assign the substitution patterns and the major
differences in these data are pointed out. Recrystallization of compound 5b (n = 1) gave crystals
suitable for X-ray crystal structure analysis. Application of these compounds to the synthesis of novel
biologically active compounds will be described in a subsequent paper.
Acknowledgements
We thank Fundação para a Ciência e a Tecnologia (POCTI, POCI and FEDER programs) for
provision of funding (Projects POCTI/QUI/39368/ 2001 and POCI/QUI/55508/2004).
Experimental
General
Reagents were used as purchased and were purified when necessary according to standard
procedures [30]. 7-Bromoheptanoic acid ethyl ester was a gift from CU Chemie Uetikon GmbH
(
Germany). Column chromatography was performed on silica gel (230-400 Mesh) under a positive
pressure of nitrogen. Melting points were determined on a Reichert Thermovar melting point apparatus
1
and are uncorrected. NMR spectra were recorded on a Bruker AMX 300 spectrometer ( H at 300 MHz,
1
3
C at 75 MHz). Chemical shifts (δ) are reported in ppm and coupling constants (J) in Hz. The

Molecules 2006, 11
878
1
13
assignment of H- and C- multiplicities was done using a DEPT sequence, two-dimensional NMR
(
HETCOR and COSY) and irradiations techniques (Tables 4 and 5). Infrared spectra were recorded on
a Perkin Elmer FT-IR 1725xIR Fourier Transform spectrophotometer using either thin films on NaCl
-1
plates (film) or KBr discs (KBr) as stated. Only the characteristic bands are quoted in cm . Low-
resolution mass spectra (MS) were recorded on a Kratos 25 RF or a Thermo Quest model GCQplus
spectrometer. High-resolution mass spectra (HRMS) were obtained on a VG AutoSpect M instrument.
Elemental analyses were performed on a CE instrument EA 1110CHNS-O or a Fisons EA-1108
elemental analyser (for compounds 4 and 5 see Table 2 and 3). Although compounds 2a-e [19-21],
3
b-e [20,21], 4b-e [20,21,31] and 5b-e [20,21] have been noted previously in the literature, no full
spectroscopic characterisation has been reported, therefore the full characterisation of these
compounds is described herein.
General procedure 1 (using Kt-BuO as base). Kt-BuO (1.6 eq.) was added to a solution of indazole 1
o
(
o
1 eq.) in THF at 0 C. The reaction mixture was warmed to r.t., stirred over 1 h. and then recooled to 0
2 n 2
C. After 15 min., excess X(CH ) CO R was added and the reaction mixture was allowed to warm to
r.t. and stirred for 0.5-4 h. The solvent was removed under reduced pressure and the residue was
redissolved in EtOAc, washed successively with water and brine and dried over anhydrous MgSO
4
.
After filtration, the solvent was evaporated in vacuo. The resulting oil was purified by column
chromatography (2:3 ether/petroleum ether).
General procedure 2 (using K
2
CO
3
as base): A mixture of indazole 1 (1 eq.) and K
2
CO
3
(3-10 eq.) in
o
DMF was stirred at 80 C. After 30 min., excess X(CH
2
)
n
CO
2
R was added and the reaction mixture
o
was stirred for 4-24 h. at 80 C. Upon cooling, the mixture was acidified with 10% aqueous HCl
solution and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed
4
with brine and dried over anhydrous MgSO . After filtration, the solvent was removed in vacuo and
the resulting oil was purified by column chromatography (2:3 ether/petroleum ether).
Indazole-1-carboxylic acid methyl ester (2a)
Following general procedure 1, reaction of indazole 1 (200 mg, 1.69 mmol) in THF (10 mL), Kt-
2 3
BuO (260 mg, 2.73 mmol) and ClCO CH (0.13 mL, 1.69 mmol) for 30 min. gave compound 2a (290
mg, 99%) as a white solid, mp 56-58 ºC (Lit. [19] 58-60 ºC); IR (KBr): 3013 (C-H)Ar, 2958 (C-H),
-
1 1
1
1
3
736 (C=O), 1611, 1457 (C=C, C=N) cm ; H NMR (CDCl ): δ 4.13 (s, 3 H, OCH ), 7.36 (t, J = 7.8,
3
3
H, 5-H or 6-H), 7.58 (dt, J = 7.8 and 0.9, 1 H, 5-H or 6-H), 7.76 (d, J = 7.8, 1 H, 4-H), 8.20 (s, 1 H,
+
+
-H), 8.26 (d, J = 8.4, 1 H, 7-H); MS (EI): m/z (%)= 176 (100) [M] , 145 (4) [M-OMe] , 118 (19)
+
+
[IndzH] , 117 (9) [M-CO
2 9 8 2 2
Me] ; Anal. Calcd. for C H N O : C 61.36, H 4.58, N 15.90. Found: C
61.31, H 4.61, N 15.74.
Indazol-1-yl-acetic acid ethyl ester (2b) and indazol-2-yl-acetic acid ethyl ester (3b)
Following general procedure 1, reaction of indazole 1 (500 mg, 4.23 mmol) in THF (10 mL), Kt-
2 2
BuO (665 mg, 5.93 mmol) and BrCH CO Et (0.56 mL, 5.08 mmol) for 2 h. gave compounds 2b (474

Molecules 2006, 11
879
mg, 55%) and 3b (110 mg, 13%) as pale yellow oils. Compound 2b: IR (film): 3064 (C-H)Ar, 2983,
-
1 1
2
1
1
940 (C-H), 1748 (C=O), 1619, 1504, 1470, 1435 (C=C, C=N), 1210 (C-O) cm ; H-NMR (CDCl
3
): δ
.21 (t, J = 7.2, 3 H, OCH CH ), 4.18 (q, J = 7.2, 2 H, OCH CH ), 5.13 (s, 2 H, NCH CO Et), 7.15 (m,
2
3
2
3
2
2
H, 5-H), 7.33 (m, 2 H, 6-H and 7-H), 7.72 (dd, J = 8.1 and 0.6, 1 H, 4-H), 8.04 (d, J = 0.9, 1 H, 3-H);
+
+
+
MS (EI): m/z (%) = 204 (27) [M] , 131 (100) [M-CO
2
Et] , 118 (2) [IndzH] ; HRMS (EI): calcd. for
+
[
M] (C H N O ): 204.0899, found 204.0893. Compound 3b: IR (film): 3121, 3065 (C-H)Ar, 2984,
1
1
12
2
2
-1 1
2
1
941 (C-H), 1746 (C=O), 1630, 1520, 1475, 1429 (C=C, C=N), 1212 (C-O) cm ; H-NMR (CDCl
3
):
.28 (t, J = 7.2, 3 H, OCH CH ), 4.25 (q, J = 7.2, 2 H, OCH CH ), 5.19 (s, 2 H, NCH CO Et), 7.09 (t,
2
3
2
3
2
2
J = 7.2, 1 H, 5-H), 7.29 (m, 1 H, 6-H), 7.66 (d, J = 8.4, 1 H, 4-H), 7.68 (dd, J = 8.7 and 0.6, 1 H, 7-H),
+
+
+
8
.00 (s, 1 H, 3-H); MS (EI): m/z (%) = 204 (64) [M] , 131 (100) [M-CO Et] , 118 (11) [IndzH] ;
2
+
HRMS (EI) calcd. for [M] (C11
H
12
N
2
O
2
): 204.0899, found 204.0903. Following general procedure 2,
indazole 1 (3.00 g, 25.4 mmol) in DMF (10 mL), K CO (10.53 g, 76.18 mmol) and BrCH CO Et (4.2
2
3
2
2
mL, 38.1 mmol) gave compound 2b (3.49 g, 67%) and compound 3b (1.16 g, 22%) after reacting for
2
4 h.
3
-Indazol-1-yl-propionic acid ethyl ester (2c) and 3-indazol-2-yl-propionic acid ethyl ester (3c)
Following general procedure 2, reaction of indazole 1 (3.00 g, 25.4 mmol) in DMF (10 mL),
K
2
3 2 2 2
CO (10.53 g, 76.18 mmol) and Br(CH ) CO Et (4.9 mL, 38.1 mmol) for 4 h. gave compounds 2c
(
2.72g, 49%) and 3c (2.53 g, 46%) as pale yellow oils. Compound 2c: IR (film): 3062 (C-H)Ar, 2982,
-1 1
2
938 (C-H), 1734 (C=O), 1616, 1500, 1466, 1447 (C=C, C=N), 1192 (C-O) cm ; H-NMR (CDCl
.16 (t, J = 7.2, 3 H, OCH CH ), 2.96 (t, J = 6.9, 2 H, CH CH CO Et), 4.08 (q, J = 7.2, 2 H,
CH ), 4.67 (t, J = 6.9, 2 H, NCH ), 7.13 (t, J = 7.5, 1 H, 5-H), 7.38 (dt, J = 7.5 and 1.2, 1 H, 6-
H), 7.48 (dd, J = 8.7 and 0.6, 1 H, 7-H), 7.70 (d, J = 8.1, 1 H, 4-H), 8.00 (s, 1 H, 3-H); MS (EI): m/z
3
): δ
1
2
3
2
2
2
OCH
2
3
2
+
+
+
+
(
%) = 218 (90) [M] , 173 (58) [M-OEt] , 145 (31) [M-CO
2
Et] , 131 (100) [M-CH
): 218.1055, found 218.1054. Compound 3c: IR
film): 3121, 3062 (C-H)Ar, 2982, 2938 (C-H), 1733 (C=O), 1628, 1517, 1471, 1446 (C=C, C=N),
2 2
CO Et] , 118 (45)
+
+
14 2 2
[IndzH] ; HRMS (EI) calcd. for [M] (C12H N O
(
-1
1
1
201 (C-O) cm ; H- NMR (CDCl
CH CO Et), 4.11 (q, J = 7.2, 2 H, OCH
H), 7.27 (t, J = 8.7, 1 H, 6-H), 7.63 (d, J = 8.4, 1 H, 4-H), 7.68 (d, J = 8.7, 1 H, 7-H), 7.99 (s, 1 H, 3-
3
): 1.21 (t, J = 7.2, 3 H, OCH
2
CH
3
), 3.03 (t, J = 6.6, 2 H,
CH
2
2
2
2
CH ), 4.69 (t, J = 6.6, 2 H, NCH
3
2
), 7.06 (t, J = 7.5, 1 H, 5-
+
+
+
H); MS (EI): m/z (%) = 218 (75) [M] , 173 (24) [M-OEt] , 145 (45) [M-CO Et] , 131 (42) [M-
2
+
+
+
CH
2
CO
2
Et] , 118 (100) [IndzH] ; HRMS (EI) calcd. for [M] (C12
H
14
N
2
O
2
): 218.1055, found
1
2
18.1047. The reaction was also performed using general procedure 1. Analysis of the H-NMR
spectrum of the crude product indicated the presence of 2c, 3c and 1 in the ratio 15:15:70.
4
-Indazol-1-yl-butyric acid ethyl ester (2d) and 4-indazol-2-yl-butyric acid ethyl ester (3d)
Following general procedure 2, reaction of indazole 1 (3.00 g, 25.4 mmol) in DMF (10 mL),
K
2
3 2 3 2
CO (10.53 g, 76.18 mmol) and Br(CH ) CO Et (5.4 mL, 38.1 mmol) for 24 h. gave compounds 2d
(
3.49 g, 59%) and 3b (2.16 g, 37%) as pale yellow oils. Compound 2d: IR (film): 3063 (C-H)Ar, 2981,
-1 1
2
1
939 (C-H), 1731 (C=O), 1616, 1500, 1466, 1447 (C=C, C=N), 1190 (C-O) cm ; H-NMR (CDCl ): δ
3
2 3 2 2 2 2 3
.21 (t, J = 7.2, 3 H, OCH CH ), 2.19-2.32 (m, 4 H, CH CH CO Et), 4.10 (q, J = 7.2, 2 H, OCH CH ),

Molecules 2006, 11
.45 (t, J = 6.6, 2 H, NCH
880
4
2
), 7.13 (dt, J = 7.5 and 0.9, 1 H, 5-H), 7.38 (m, 2 H, 6-H and 7-H), 7.71 (d, J
+
+
=
8.1, 1 H, 4-H), 7.99 (s, 1 H, 3-H); MS (EI): m/z (%) = 232 (75) [M] , 187 (100) [M-OEt] , 159 (9)
+
+
+
+
[M-CO Et] , 145 (22) [M-CH CO Et] , 131 (76) [M-(CH ) CO Et] , 118 (20) [IndzH] ; HRMS (EI)
2 2 2 2 2 2
+
16 2 2
calcd. for [M] (C13H N O ): 232.1212, found 232.1212. Compound 3d: IR (film): 3119, 3061 (C-
-
1 1
H)Ar, 2982, 2980 (C-H), 1730 (C=O), 1628, 1515, 1469, 1445 (C=C, C=N), 1186 (C-O) cm ; H-
NMR (CDCl ): δ 1.22 (t, J = 7.2, 3 H, OCH CH ), 2,30 (m, 4 H, CH CH CO Et), 4.10 (q, J = 7.2, 2 H,
3
2
3
2
2
2
OCH
2
CH
3
2
), 4.46 (t, J = 6.6, 2 H, NCH ), 7.06 (dt, J = 7.5 and 0.6, 1 H, 5-H), 7.27 (m, 1 H, 6-H), 7.63
(
d, J = 8.7, 1 H, 4-H), 7.70 (dd, J = 8.7 and 0.9, 1 H, 7-H), 7.88 (s, 1 H, 3-H); MS (EI): m/z (%) = 232
+
+
+
+
+
(
68) [M] , 187 (47) [M-OEt] , 159 (7) [M] , 145 (17) [M-CH CO Et] , 131 (100) [M-(CH ) CO Et] ,
2 2 2 2 2
+
+
1
18 (36) [IndzH] ; HRMS (EI) calcd. for [M] (C13
H
16
N
2
O
2
): 232.1212, found 232.1218. The reaction
1
was also performed using general procedure 1. Analysis of the H-NMR spectrum of the crude product
indicated the presence of 2d, 3d and 1 in the ratio 26:18:56.
5
-Indazol-1-yl-pentanoic acid ethyl ester (2e) and 5-indazol-2-yl-pentanoic acid ethyl ester (3e)
Following general procedure 2, reaction of indazole 1 (3.00 g, 25.4 mmol) in DMF (10 mL),
K CO (10.53 g, 76.18 mmol) and Br(CH ) CO Et (4.7 mL, 33.02 mmol) for 24 h. gave compounds 2e
2
3
2 4
2
(
3.67 g, 59%) and 3e (1.95 g, 31%) as pale yellow oils. Compound 2e: IR (film): 3062 (C-H)Ar, 2982,
-1 1
2
1
2
939 (C-H), 1732 (C=O), 1616, 1500, 1466, 1447 (C=C, C=N), 1184 (C-O) cm ; H-NMR (CDCl
.22 (t, J = 7.2, 3 H, OCH CH ), 1.60-1.70 (m, 2 H, CH CH CO Et), 1.93-2.03 (m, 2 H, NCH CH
.32 (t, J = 7.2, 2 H, CH CO Et), 4.10 (q, J = 7.2, 2 H, OCH CH ), 4.40 (t, J = 7.2, 2 H, NCH ), 7.13
3
): δ
2
3
2
2
2
2
2
),
2
2
2
3
2
(
dt, J = 7.2 and 1.8, 1 H, 5-H), 7.39 (m, 2 H, 6-H and 7-H), 7.73 (td, J = 8.1 and 0.9, 1 H, 4-H), 7.99
+
+
+
(
d, J = 0.9, 1 H, 3-H); MS (EI): m/z (%) = 246 (27) [M] , 201 (56) [M-OEt] , 173 (10) [M-CO
2
Et] ,
+
+
+
1
31 (100) [M-(CH ) CO Et] , 118 (30) [IndzH] ; HRMS (EI) calcd. for [M] (C14H N O ): 246.1368,
2 3 2 18 2 2
found 246.1362. Compound 3e: IR (film): 3119, 3061 (C-H)Ar, 2980, 2942 (C-H), 1731 (C=O), 1630,
-1
1
1
516, 1469, 1446 (C=C, C=N), 1186 (C-O) cm ; H-NMR (CDCl
OCH CH ), 1.59-1.69 (m, 2 H, CH CH CO Et), 2.00-2.10 (m, 2 H, NCH
CH CO Et), 4.10 (q, J = 7.2, 2 H, OCH CH ), 4.41 (t, J = 6.9, 2 H, NCH ), 7.06 (dt, J = 7.5 and 0.9, 1
3
): δ 1.22 (t, J = 7.2, 3 H,
2
3
2
2
2
2
CH ), 2.32 (t, J = 7.2, 2 H,
2
2
2
2
3
2
H, 5-H), 7.27 (m, 1 H, 6-H), 7.63 (td, J = 8.4 and 0.9, 1 H, 4-H), 7.70 (dd, J = 8.7 and 0.9, 1 H, 7-H),
+
+
+
7
.89 (s, 1 H, 3-H); MS (EI): m/z (%) = 246 (62) [M] , 201 (63) [M-OEt] , 173 (35) [M-CO
2
Et] , 159
+
+
+
+
(
4) [M-CH
2
CO
2
Et] , 145 (11) [M-(CH
2
)
2
CO
2
Et] , 131 (100) [M-(CH
2
)
3
CO
2
Et] , 118 (62) [IndzH] ;
+
HRMS (EI) calcd. for [M] (C14
H
18
N
2
O
2
): 246.1368, found 246.1367.
6
-Indazol-1-yl-hexanoic acid ethyl ester (2f) and 6-indazol-2-yl-hexanoic acid ethyl ester (3f)
Following general procedure 2, reaction of indazole 1 (200 mg, 1.69 mmol) in DMF (2 mL),
K CO (2.34 g, 16.93 mmol) and Br(CH ) CO Et (0.6 mL, 3.39 mmol) for 5 h. gave compounds 2f
2
3
2 5
2
(
276 g, 62%) and 3f (150 mg, 34%) as pale yellow oils. Compound 2f: IR (film): 3061 (C-H)Ar, 2979,
-1
1
2
938, 2865 (C-H), 1731 (C=O), 1616, 1499, 1465, 1446 (C=C, C=N), 1181 (C-O) cm ; H-NMR
(
CDCl ): δ 1.22 (t, J = 7,2, 3 H, OCH CH ), 1.34 (m, 2 H, CH ), 1.65 (m, 2 H, CH CH CO Et), 1.94
3
2
3
2
2
2
2
(
m, 2 H, NCH
2
CH
2
), 2.27 (t, J = 7.5, 2 H, CH
2
CO
2
2 3
Et), 4.09 (q, J = 7.2, 2 H, OCH CH ), 4.38 (t, J =
7
.2, 2 H, NCH
2
), 7.13 (dt, J = 7.2 and 1.8, 1 H, 5-H), 7.37 (m, 2 H, 6-H and 7-H), 7.73 (dd, J = 8.4 and

Molecules 2006, 11
881
+
+
0
.9, 1 H, 4-H), 7.98 (s, 1 H, 3-H); MS (EI): m/z (%) = 260 (11) [M] , 215 (20) [M-OEt] , 187 (4) [M-
+
+
+
+
CO
2
Et] , 173 (14) [M-CH
2
CO
2
Et] , 131 (100) [M-(CH
2
)
4
CO
2
Et] , 118 (14) [IndzH] ; HRMS (EI)
+
calcd. for [M] (C H N O ): 260.1525, found 260.1526. Compound 3f: IR (film): 3119, 3062 (C-
1
5
20
2
2
-1
1
H)Ar, 2980, 2938 (C-H), 1732 (C=O), 1628, 1516, 1465 (C=C, C=N), 1186 (C-O) cm ; H-NMR
(CDCl
3
2 3 2 2 2 2
): δ 1.29 (t, J = 7.2, 3 H, OCH CH ), 1.35 (m, 2 H, CH ), 1.67 (m, 2 H, CH CH CO Et), 2.03
(
m, 2 H, NCH CH ), 2.28 (t, J = 7.5, 2 H, CH CO Et), 4.10 (q, J = 7.2, 2 H, OCH CH ), 4.40 (t, J =
2
2
2
2
2
3
7
.2, 2 H, NCH
2
), 7.07 (t, J = 7.8, 1 H, 5-H), 7.27 (t, J = 7.8, 1 H, 6-H), 7.64 (d, J = 8.4, 1 H, 4-H), 7.70
+
+
(
(
(
d, J = 8.7, 1 H, 7-H), 7.89 (s, 1H, 3-H); MS (EI): m/z (%) = 260 (67) [M] , 215 (61) [M-OEt] , 187
+
+
+
+
28) [M-CO Et] , 173 (78) [M-CH CO Et] , 131 (100) [M-(CH ) CO Et] , 118 (61) [IndzH] ; HRMS
2
2
2
2 4
2
+
EI) calcd. for [M] (C15
H
20
N
2
O
2
): 260.1525, found 260.1525. The reaction was also performed using
1
general procedure 1. Analysis of the H-NMR spectrum of the crude product indicated the presence of
2
f, 3f and 1 in the ratio 39:39:22.
7
-Indazol-1-yl-heptanoic acid ethyl ester (2g) and 7-indazol-2-yl-heptanoic acid ethyl ester (3g)
Following general procedure 2, reaction of indazole 1 (500 mg, 4.23 mmol) in DMF (5 mL), K CO3
2
(
2.92 g, 21.20 mmol) and Br(CH
2
)
6
2
CO Et (1.64 mL, 8.46 mmol) for 5 h. gave compounds 2g (714 mg,
6
2
1
1%) and 3g (422 mg, 36%) as pale yellow oils. Compound 2g: IR (film): 3061 (C-H)Ar, 2979, 2936,
-1 1
859 (C-H), 1731 (C=O), 1615, 1499, 1465, 1424 (C=C, C=N), 1180 (C-O) cm ; H-NMR (CDCl
.23 (t, J = 7.2, 3 H, OCH CH ), 1.33 (m, 4 H, 2×(CH )), 1.57 (m, 2 H, CH ), 1.93 (m, 2 H, CH ), 2.25
CO Et), 4.10 (q, J = 7.2, 2 H, OCH CH ), 4.37 (t, J = 6.9, 2 H, NCH ), 7.13 (dt, J
3
): δ
2
3
2
2
2
(
t, J = 7.5, 2 H, CH
2
2
2
3
2
=
7.2 and 1.5, 1 H, 5-H), 7.39 (m, 2 H, 6-H and 7-H), 7.72 (d, J = 8.1, 1 H, 4-H), 7.98 (s, 1 H, 3-H);
+
+
+
MS (EI): m/z (%) = 274 (7) [M] , 229 (11) [M-OEt] , 187 (17) [M-CH
2
CO
2
Et] , 173 (6) [M-
+
+
+
+
(
(
(
(
2 2 2 2 5 2
CH ) CO Et] , 131 (100) [M-(CH ) CO Et] , 118 (22) [IndzH] ; HRMS (EI) calcd. for [M]
16 22 2 2
C H N O ): 274.1681, found 274.1680. Compound 3g: IR (film): 3061 (C-H)Ar, 2979, 2933, 2859
-1 1
C-H), 1731 (C=O), 1628, 1515, 1466, 1446 (C=C, C=N), 1185 (C-O) cm ; H-NMR (CDCl
t, J = 7.2, 3 H, OCH CH ), 1.35 (m, 4 H, 2×(CH )), 1.61 (m, 2 H, CH CH CO Et), 2.02 (m, 2 H,
), 2.27 (t, J = 7.2, 2 H, CH CO Et), 4.11 (q, J = 7.2, 2 H, OCH CH ), 4.40 (t, J = 7.2, 2 H,
), 7.07 (t, J = 7.2, 1 H, 5-H), 7.27 (m, 1 H, 6-H), 7.64 (d, J = 8.4, 1 H, 4-H), 7.64 (dd, J = 8.4 and
3
): δ 1.24
2
3
2
2
2
2
NCH
2
CH
2
2
2
2
3
NCH
2
+
+
0
.9, 1 H, 7-H), 7.89 (d, J = 0.9, 1 H, 3-H); MS (EI): m/z (%) = 274 (15) [M] , 229 (21) [M-OEt] , 187
+
+
+
+
(
27) [M-CH
2
CO
2
Et] , 173 (5) [M-(CH
2
)
2
CO
2 2 5 2
Et] , 131 (100) [M-(CH ) CO Et] , 118 (21) [IndzH] ;
+
HRMS (EI) calcd. for [M] (C16
H
22
N
2
O
2
): 274.1681, found 274.1679.
1
0-Indazol-1-yl-decanoic acid methyl ester (2h) and 10-indazol-2-yl-decanoic acid methyl ester (3h)
Following general procedure 2, reaction of indazole 1 (1.00 g, 8.46 mmol) in DMF (10 mL), K CO3
2
(
5.85 g, 42.30 mmol) and Br(CH ) CO Me (2.96 mL, 12.69 mmol) for 12 h. gave compounds 2h (1.53
2 9 2
g, 63%) and 3h (825 mg, 34%) as pale yellow oils. Compound 2h: IR (film): 3061 (C-H)Ar, 2928,
-
1 1
2
1
3
855 (C-H), 1739 (C=O), 1616, 1499, 1465, 1435 (C=C, C=N), 1196 (C-O) cm ; H-NMR (CDCl
3
): δ
.26 (m, 10 H, 5×(CH )), 1.56 (m, 2 H, CH ), 1.94 (m, 2 H, CH ), 2.28 (t, J = 7.2, 2 H, CH CO CH ),
2
2
2
2
2
3
.65 (s, 3 H, OCH
3
), 4.36 (t, J = 6.9, 2 H, NCH
2
), 7.12 (dt, J = 7.2 and 1.5, 1 H, 5-H), 7.39 (m, 2 H, 6-
+
H and 7-H), 7.72 (d, J = 8.1, 1 H, 4-H), 7.98 (d, J = 0.3, 1 H, 3-H); MS (EI): m/z (%) = 302 (20) [M] ,

Molecules 2006, 11
882
+
+
+
+
2
1
71 (15) [M-OMe] , 243 (2) [M-CO
2
Me] , 229 (23) [M-CH
2
+
CO
2
Me] , 187 (12) [M-(CH
2
)
4
CO
2
Me] ,
+
+
73 (16) [M-(CH
2
)
5
CO
2
Me] , 131 (100) [M-(CH
2
)
8
CO
2
Me] , 118 (34) [IndzH] ; HRMS (EI) calcd.
+
for [M] (C H N O ): 302.1994, found 302.1985. Compound 3h: IR (film): 3060 (C-H)Ar, 2928,
1
8
26
2
2
-1 1
2
1
3
8
2
855 (C-H), 1739 (C=O), 1628, 1515, 1466, 1436 (C=C, C=N), 1196 (C-O) cm ; H-NMR (CDCl
.27 (m, 10 H, 5×(CH )), 1.59 (m, 2 H, CH ), 2.00 (m, 2 H, CH ), 2.28 (t, J = 7.2, 2 H, CH CO CH
.65 (s, 3 H, OCH ), 4.39 (t, J = 7.2, 2 H, NCH ), 7.06 (m, 1 H, 5-H), 7.26 (m, 1 H, 6-H), 7.64 (d, J =
3
): δ
2
2
2
2
2
3
),
3
2
+
.4, 1 H, 4-H), 7.70 (dd, J = 8.7 and 0.9, 1 H, 7-H), 7.89 (s, 1 H, 3-H); MS (EI): m/z = 302 (68) [M] ,
+
+
+
71 (35) [M-OMe] , 229 (54) [M-CH
2
CO
2
Me] , 187 (42) [M-(CH
2
)
4
CO
2
Me] , 173 (37) [M-
+
+
+
+
(
CH ) CO Me] , 131 (100) [M-(CH ) CO Me] , 118 (91) [IndzH] ; HRMS (EI) calcd. for [M]
2
5
2
2 8
2
(
C
18
H
26
N
2
O
2
): 302.1994, found 302.1992.
1
1-Indazol-1-yl-undecanoic acid methyl ester (2i) and 11-indazol-2-yl-undecanoic acid methyl ester
(
3i)
Following general procedure 2, reaction of indazole 1 (1.02 g, 8.61 mmol) in DMF (10 mL), K CO3
2
(
5.85 g, 42.33 mmol) and Br(CH
2
)
10CO
2
Et (3.06 mL, 12.68 mmol) for 7 h. gave compounds 2i (1.64 g,
6
0%) as a white solid and 3i (1.04 g, 38%) as a pale yellow oil. Compound 2i: mp 52-54 °C; IR (KBr):
-
3
058 (C-H)Ar, 2914, 2847 (C-H), 1741 (C=O), 1617, 1495, 1466, 1438 (C=C, C=N), 1176 (C-O) cm
1
1
;
H-MR (CDCl
3
): δ 1.28 (m, 12 H, 6×(CH
2
)), 1.60 (m, 2 H, CH
2
2
), 1.92 (m, 2 H, CH ), 2.29 (t, J =
7
.5, 2 H, CH
2
CO
2
CH ), 3.66 (s, 3 H, OCH ), 4.37 (t, J = 7.2, 2 H, NCH
3
3
2
), 7.13 (t, J = 7.2, 1 H, 5-H),
7
.38 (m, 2 H, 6-H and H-7), 7.72 (d, J = 8.1, 1 H, 4-H), 7.98 (s, 1 H, 3-H); MS (EI): m/z (%) = 316 (6)
+
+
+
+
[M] , 243 (11) [M-(CH
2
+
)CO
2
Me] , 187 (7) [M-(CH
2
)
5
CO
2
Me] , 173 (11) [M-(CH
2 6 2
) CO Me] , 131
+
(
100) [M-(CH
2
)
9
CO
2
Me] , 118 (41) [IndzH] . Anal. Calcd. for C19
H
28
N
2
O
2
: C 72.12, H 8.92, N 8.85.
Found: C 72.15, H 8.87, N 8.79. Compound 3i: IR (film): 3060 (C-H)Ar, 2922, 2855 (C-H), 1732
-1 1
(
C=O), 1628, 1515, 1465, 1435 (C=C, C=N), 1771 (C-O) cm ; H-NMR (CDCl
×(CH )), 1.60 (m, 2 H, CH ), 2.00 (m, 2 H, CH ), 2.29 (t, J = 7.5, 2 H, CH CO
OCH ), 4.40 (t, J = 7.2, 2 H, NCH ), 7.06 (m, 1 H, 5-H), 7.26 (m, 1 H, 6-H), 7.64 (td, J = 8.7 and 0.9,
3
): δ 1.25 (m, 12 H,
6
2
2
2
2
2
CH ), 3.65 (s, 3 H,
3
3
2
1
H, 4-H), 7.70 (dd, J = 8.7 and 0.6, 1 H, 7-H), 7.90 (d, J = 0.6, 1 H, 3-H); MS (EI): m/z = 316 (78)
+
+
+
+
[
(
(
M] , 285 (40) [M-OMe] , 243 (72) [M-CH
2
CO
2
Me] , 187 (42) [M-(CH
2
)
5
CO
2
Me] , 173 (39) [M-
+
+
+
+
CH ) CO Me] , 131 (100) [M-(CH ) CO Me] , 118 (90) [IndzH] ; HRMS (EI) calcd. for [M]
2
6
2
2 9
2
C
19
H
28
N
2
O
2
): 316.2151, found 316.2154.
General procedure 3: Indazole ester derivative (2 or 3) (1 eq.) and excess aqueous NaOH solution (10
M) was stirred at reflux for 1-5 h. After cooling, the mixture was acidified with 10% aqueous HCl
solution and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed
4
with brine, dried over anhydrous MgSO , filtered and the solvent removed in vacuo. The resulting
solid was purified by recrystallisation from ethyl acetate/petroleum ether. The following compounds
were prepared following this procedure:

Molecules 2006, 11
883
Indazol-1-yl-acetic acid (4b)
Reaction of compound 2b (2.42 g, 11.86 mmol) in aqueous NaOH solution (10 M, 10 mL) for 5 h.
gave compound 4b (2.02 g, 97%) as white crystals, mp 186-188 ºC (Lit. [20] 185-186 ºC (H O)); IR
2
(
KBr): 3300-2300 (COO-H), 3112 (C-H)Ar, 2943 (C-H) 1736 (C=O), 1618, 1507, 1464 (C=C, C=N)
-1 1
cm ; H-NMR (MeOD): δ 5.22 (s, 2 H, NCH ), 7.17 (dt, J = 7.5 and 0.9, 1 H, 5-H), 7.42 (dt, J = 7.2
2
and 0.9, 1 H, 6-H), 7.51 (dd, J = 8.4 and 0.9, 1 H, 7-H), 7.76 (d, J = 7.5, 1 H, 4-H), 8.04 (d, J = 0.6, 1
+
+
H, 3-H); MS (EI): m/z (%) = 176 (33) [M] , 131 (100) [M-CO
2
H] .
3
-Indazol-1-yl-propionic acid (4c)
Reaction of compound 2c (2.72 g, 12.45 mmol) in aqueous NaOH solution (10 M, 10 mL) for 3 h.
gave compound 4c (2.32 g, 98%) as white crystals, mp 106-107 ºC (Lit. [20] 105.5-106.5 ºC
(
C H /petroleum ether)); IR (KBr): 3300-2300 (COO-H), 2932 (C-H), 1718 (C=O), 1655, 1618, 1502,
6 6
-1 1
1
466 (C=C, C=N) cm ; H-NMR (MeOD): δ 2.91 (t, J = 6.9, 2 H, CH CO H), 4.65 (t, J = 6.6, 2 H,
2
2
2
NCH ), 7.13 (t, J = 7.8, 1 H, 5-H), 7.39 (t, J = 7.8, 1 H, 6-H), 7.59 (d, J = 8.1, 1 H, 7-H), 7.71 (d, J =
+
+
8
2 2
.1, 1 H, 4-H), 8.00 (s, 1 H, 3-H); MS (EI): m/z (%) = 190 (20) [M] , 131 (100) [M-CH CO H] , 118
+
(
9) [IndzH] .
4
-Indazol-1-yl-butyric acid (4d)
Reaction of compound 2d (3.49 g, 15.02 mmol) in aqueous NaOH solution (10 M, 15 mL) for 3 h.
gave compound 4d (2.85 g, 93%) as white crystals, mp 60-62 ºC; IR (KBr): 3300-2400 (COO-H),
-
1 1
3
2
057 (C-H)Ar, 2948 (C-H), 1690 (C=O), 1616, 1497, 1463 (C=C, C=N) cm ; H-NMR (MeOD): δ
.10-2.27 (m, 4 H, CH
2
CH
2
), 4.45 (t, J = 6.9, 2 H, NCH
2
), 7.13 (t, J = 7.8, 1 H, 5-H), 7.39 (m, 1 H, 6-
1
H), 7.54 (d, J = 8.4, 1 H, 7-H), 7.73 (dd, J = 8.1 and 0.9, 1 H, 4-H), 8.00 (s, 1 H, 3-H); H NMR
(CDCl
3
): δ 2.23 (m, 2 H, NCH
2
CH
2
), 2.35 (t, J = 7.2, 2 H, CH
2
2 2
CO H), 4.49 (t, J = 6.6, 2 H, NCH ),
7
.13 (dt, J = 7.2 and 0.9, 1 H, 5-H), 7.39 (m, 2 H, 6-H and 7-H), 7.72 (d, J = 8.1, 1 H, 4-H), 8.02 (s, 1
+
+
+
H, 3-H); MS (EI): m/z (%) = 204 (14) [M] , 131 (100) [M-(CH
2
)
2
2
CO H] , 118 (9) [IndzH] .
5
-Indazol-1-yl-pentanoic acid (4e)
Reaction of compound 2e (216 mg, 0.879 mmol) in aqueous NaOH solution (10 M, 1 mL) for 2 h.
gave compound 4e (189 mg, 99%) as white crystals, mp 82-83 ºC; IR (KBr): 3500-2400 (COO-H),
-
1 1
3
1
6
108 (C-H)Ar, 2931 (C-H), 1712 (C=O), 1617, 1501, 1454 (C=C, C=N) cm ; H-NMR (MeOD): δ
.55 (m, 2 H, CH CH CO H), 1.92 (m, 2 H, NCH CH ), 2.27 (t, J = 7.2, 2 H, CH CO H), 4.40 (t, J =
2
2
2
2
2
2
2
.9, 2 H, NCH ), 7.12 (t, J = 7.5, 1 H, 5-H), 7.38 (t, J = 8.1, 1 H, 6-H), 7.53 (d, J = 8.7, 1 H, 7-H), 7.72
2
1
(
d, J = 8.1, 1 H, 4-H), 7.98 (s, 1 H, 3-H); H-NMR (CDCl
3
): δ 1.66 (m, 2 H, CH
2 2
), 1.99 (m, 2 H, CH ),
2
.37 (t, J = 7.2, 2 H, CH
2
CO
2
H), 4.41 (t, J = 6.9, 2 H, NCH
2
), 7.14 (dt, J = 7.2 and 2.1, 1 H, 5-H), 7.40
(
[
m, 2 H, 6-H and 7-H), 7.73 (d, J = 8.1, 1 H, 4-H), 8.02 (s, 1 H, 3-H); MS (EI): m/z (%) = 218 (16)
+
+
+
M] , 131 (100) [M-(CH ) CO H] , 118 (19) [IndzH] .
2
3
2

Molecules 2006, 11
-Indazol-1-yl-hexanoic acid (4f)
884
6
Reaction of compound 2f (1.35 g, 5.19 mmol) in aqueous NaOH solution (10 M, 5 mL) for 2 h.
gave compound 4f (1.20 g, 100%) as white crystals, mp 69-70 °C; IR (KBr): 3500-2350 (COO-H),
-
1
3
058, 3042 (C-H)Ar, 2969, 2936, 2871 (C-H), 1691 (C=O), 1638, 1617, 1498, 1438 (C=C, C=N) cm ;
1
H-NMR (MeOD): δ 1.30 (m, 2 H, CH
2 2 2 2 2 2
), 1.60 (m, 2 H, CH CH CO H), 1.92 (m, 2 H, NCH CH ), 2.22
(
t, J = 7.2, 2 H, CH CO H), 4.40 (t, J = 7.2, 2 H, NCH
2
2
2
), 7.13 (t, J = 7.1, 1 H, 5-H), 7.39 (dt, J = 7.8
1
and 0.9, 1 H, 6-H), 7.53 (d, J = 8.7, 1 H, 7-H), 7.73 (d, J = 8.1, 1 H, 4-H), 7.98 (s, 1 H, 3-H); H-NMR
(
CDCl ): δ 1.38 (m, 2 H, CH ), 1.67 (m, 2 H, CH CH CO H), 1.95 (m, 2 H, NCH CH ), 2.33 (t, J =
3
2
2
2
2
2
2
7
.2, 2 H, CH
2
CO
2
H), 4.40 (t, J = 7.2, 2 H, NCH
2
), 7.14 (dt, J = 6.9 and 2.1, 1 H, 5-H), 7.40 (m, 2 H, 6-
1
H and 7-H), 7.72 (d, J = 8.1, 1 H, 4-H), 8.00 (s, 1 H, 3-H); H-NMR (DMSO): δ 1.22 (m, 2 H, CH
2
),
1
6
8
.49 (m, 2 H, CH CH CO H), 1.80 (m, 2 H, NCH CH ), 2.14 (t, J = 7.2, 2 H, CH CO H), 4.37 (t, J =
2 2 2 2 2 2 2
2
.9, 2 H, NCH ), 7.10 (dt, J = 6.9 and 0.9, 1 H, 5-H), 7.35 (dt, J = 7.8 and 0.9, 1 H, 6-H), 7.63 (dd, J =
.4 and 0.9, 1 H, 7-H), 7.73 (d, J = 8.1, 1 H, 4-H), 8.03 (d, J = 0.9, 1 H, 3-H); MS (EI): m/z (%) = 232
+
+
+
+
(
13) [M] , 173 (19) [M-CH CO H] , 131 (100) [M-(CH ) CO H] , 118 (25) [IndzH] .
2 2 2 4 2
7
-Indazol-1-yl-heptanoic acid (4g)
Reaction of compound 2g (720 mg, 2.61 mmol) in aqueous NaOH solution (10 M, 2.5 mL) for 2 h.
gave compound 4g (474 mg, 74%) as white crystals, mp 54-58 °C; IR (KBr): 3350-2400 (COO-H),
-1 1
3
041 (C-H)Ar, 2929, 2908, 2855 (C-H), 1701 (C=O), 1614, 1561, 1462 (C=C, C=N) cm ; H-NMR
MeOD): δ 1.30 (m, 4 H, 2×(CH )), 1.51 (m, 2 H, CH ), 1.90 (m, 2 H, CH ), 2.22 (t, J = 7.2, 2 H,
H), 4.39 (t, J = 6.9, 2 H, NCH ), 7.13 (dt, J = 7.8 and 0.9, 1 H, 5-H), 7.39 (dt, J = 7.8 and 0.9,
(
2
2
2
CH
2
CO
2
2
1
H, 6-H), 7.53 (dd, J = 8.4 and 0.9, 1 H, 7-H), 7.73 (d, J = 8.1, 1 H, 4-H), 7.98 (d, J = 0.6, 1 H, 3-H);
+
+
+
MS (EI): m/z (%) = 246 (12) [M] , 187 (21) [M-CH
2
CO
2
H] , 131 (100) [M-(CH
2
)
5
CO
2
H] , 118 (31)
+
[IndzH] .
1
0-Indazol-1-yl-decanoic acid (4h)
Reaction of compound 2h (1.02 g, 3.36 mmol) in aqueous NaOH solution (10 M, 3.0 mL) for 2 h.
gave compound 4h (913 mg, 93%) as white crystals, mp 78-81 °C; IR (KBr): 3360-2400 (COO-H),
-1 1
3
041 (C-H)Ar, 2932, 2915, 2845 (C-H), 1689 (C=O), 1615, 1497, 1467, 1428 (C=C, C=N) cm ; H-
NMR (MeOD): δ 1.24 (m, 10 H, 5×(CH )), 1.54 (m, 2 H, CH ), 1.87 (m, 2 H, CH ), 2.23 (t, J = 7.5, 2
2
2
2
H, CH
2
CO
2
2
H), 4.39 (t, J = 6.9, 2 H, NCH ), 7.13 (t, J = 7.5, 1 H, 5-H), 7.38 (t, J = 7.5, 1 H, 6-H), 7.52
(
(
(
d, J = 8.4, 1 H, 7-H), 7.73 (dd, J = 8.4 and 0.9, 1 H, 4-H), 7.98 (s, 1 H, 3-H); MS (EI): m/z (%) = 288
+
+
+
+
13) [M] , 229 (11) [M-CH
2
CO
2
H] , 187 (9) [M-(CH
2
)
4
CO
2
H] , 173 (14) [M-(CH
2
)
5
CO
2
H] , 131
+
+
100) [M-(CH ) CO H] , 118 (51) [IndzH] .
2
8
2
1
1-Indazol-1-yl-undecanoic acid (4i)
Reaction of compound 2i (755 mg, 2.39 mmol) in aqueous NaOH solution (10 M, 3 mL) for 2 h.
gave compound 4i (686 mg, 95%) as white crystals, mp 73-74 °C; IR (KBr): 3350-2400 (COO-H),

Molecules 2006, 11
885
-
1 1
3
041 (C-H)Ar, 2921, 2849 (C-H), 1691 (C=O), 1615, 1497, 1464, 1428 (C=C, C=N) cm ; H-NMR
MeOD): δ 1.23 (m, 12 H, 6×(CH )), 1.54 (m, 2 H, CH CH CO H), 1.86 (m, 2 H, NCH CH ), 2.24 (t,
J = 7.5, 2 H, CH CO H), 4.38 (t, J = 6.9, 2 H, NCH ), 7.12 (dt, J = 7.8 and 0.9, 1 H, 5-H), 7.38 (dt, J =
(
2
2
2
2
2
2
2
2
2
7
.8 and 1.2, 1 H, 6-H), 7.51 (dd, J = 8.4 and 0.6, 1 H, 7-H), 7.72 (dd, J = 8.1 and 0.9, 1 H, 4-H), 7.98
+
+
(
(
d, J = 0.9, 1 H, 3-H); MS (EI): m/z (%) = 302 (6) [M] , 243 (7) [M-CH
2
CO
2
H] , 187 (6) [M-
+
+
+
+
CH ) CO H] , 173 (10) [M-(CH ) CO H] , 131 (100) [M-(CH ) CO H] , 118 (59) [IndzH] .
2
5
2
2 6
2
2 9
2
Indazol-2-yl-acetic acid (5b)
Reaction of compound 3b (100 mg, 0.49 mmol) in aqueous NaOH solution (10 M, 1 mL) for 2 h.
gave compound 5b (83 mg, 96%) as white crystals, mp 254-256 ºC (Lit. [20] 257 ºC (dec.)); IR (KBr):
3
300-2300 (COO-H), 3130 (C-H)Ar, 2986, 2944 (C-H), 1719 (C=O), 1628, 1517, 1481 (C=C, C=N)
-1 1
cm ; H-NMR (DMSO): δ 5.29 (s, 2 H, NCH
2
), 7.03 (t, J = 7.5, 1 H, 5-H), 7.24 (t, J = 8.7, 1 H, 6-H),
7
1
.58 (d, J = 8.7, 1 H, 7-H), 7.71 (d, J = 8.4, 1 H, 4-H), 8.36 (d, J = 0.9, 1 H, 3-H); MS (EI): m/z (%) =
+
+
+
76 (5) [M] , 131 (100) [M-CO H] , 118 (34) [IndzH] .
2
3
-Indazol-2-yl-propionic acid (5c)
Reaction of compound 3c (2.53 g, 11.61 mmol) in aqueous NaOH solution (10 M, 10 mL) for 2.5
h. gave compound 5c (2.16 g, 98%) as white crystals, mp 147-149 ºC (Lit. [20] 148-149 ºC (H
2
O)); IR
(
KBr): 3300-2300 (COO-H), 3128 (C-H)Ar, 2927 (C-H), 1708 (C=O), 1626, 1516, 1476 (C=C, C=N)
-1 1
cm ; H-NMR (MeOD): δ 3.00 (t, J = 6.6, 2 H, CH
2
CO
2
H), 4.68 (t, J = 6.6, 2 H, NCH
2
), 7.04 (t, J
=
7.5, 1 H, 5-H), 7.26 (m, 1 H, 6-H), 7.57 (dd, J = 8.9 and 0.9, 1 H, 7-H), 7.64 (d, J = 8.4, 1 H, 4-H),
+
+
+
8
1
.18 (s, 1 H, 3-H); MS (EI): m/z (%) = 190 (29) [M] , 145 (7) [M-CO
2
H] , 131 (13) [M-CH
2
CO
2
H] ,
+
18 (100) [IndzH] .
4
-Indazol-2-yl-butyric acid (5d)
Reaction of compound 3d (143 mg, 0.62 mmol) in aqueous NaOH solution (10 M, 1 mL) for 2 h.
gave compound 5d (122 mg, 97%) as white crystals, mp 132-134 ºC; IR (KBr): 3450-2300 (COO-H),
-
1 1
3
2
1
=
119 (C-H)Ar, 2937 (C-H), 1698 (C=O), 1626, 1508, 1474, (C=C, C=N) cm ; H-NMR (MeOD): δ
2 2 2 2
.26 (m, 4 H, CH CH CO H), 4.49 (t, J = 6.6, 2 H, NCH ), 7.06 (t, J = 7.8, 1 H, 5-H), 7.28 (t, J = 8.1,
H, 6-H), 7.58 (d, J = 8.7, 1 H, 7-H), 7.67 (d, J = 8.4, 1 H, 4-H), 8.19 (s, 1 H, 3-H); MS (EI): m/z (%)
+
+
+
204 (28) [M] , 131 (100) [M-(CH ) CO H] , 118 (55) [IndzH] .
2
2
2
5
-Indazol-2-yl-pentanoic acid (5e)
Reaction of compound 3e (168 mg, 0.68 mmol) in aqueous NaOH solution (10 M, 2 mL) for 2 h.
gave compound 5e (134 mg, 90%) as white crystals, mp 112-114 ºC; IR (KBr): 3450-2300 (COO-H),
-1 1
3
1
6
129 (C-H)Ar, 2944 (C-H), 1701 (C=O), 1636, 1508, 1458 (C=C, C=N) cm ; H-NMR (MeOD): δ
.55 (m, 2 H, CH CH CO H), 2.00 (m, 2 H, NCH CH ), 2.30 (t, J = 7.2, 2 H, CH CO H), 4.41 (t, J =
.9, 2 H, NCH ), 7.05 (t, J = 8.1, 1 H, 5-H), 7.26 (t, J = 8.7, 1 H, 6-H), 7.58 (d, J = 8.7, 1 H, 7-H), 7.66
2
2
2
2
2
2
2
2

Molecules 2006, 11
886
+
(
d, J = 8.4, 1 H, 4-H), 8.16 (d, J = 1.5, 1 H, 3-H); MS (EI): m/z (%) = 218 (5) [M] , 173 (3) [M-
+
+
+
2 2 3 2
CO H] , 131 (24) [M-(CH ) CO H] , 118 (11) [IndzH] , 61 (100).
6
-Indazol-2-yl-hexanoic acid (5f)
Reaction of compound 3f (1.05 mg, 4.04 mmol) in aqueous NaOH solution (10 M, 3 mL) for 2 h.
gave compound 5f (553 mg, 59%) as white crystals, mp 86-87 °C; IR (KBr): 3330-2400 (COO-H),
-1 1
3
131 (C-H)Ar, 2948, 2867 (C-H), 1717 (C=O), 1626, 1517, 1466, 1451 (C=C, C=N) cm ; H-NMR
(
MeOD): δ 1.31 (m, 2 H, CH ), 1.62 (m, 2 H, CH CH CO H), 1.98 (m, 2 H, NCH CH ), 2.25 (t, J =
2
2
2
2
2
2
7
.2, 2 H, CH
2
CO
2
2
H), 4.41 (t, J = 7.2, 2 H, NCH ), 7.04 (t, J = 7.2, 1 H, 5-H), 7.26 (t, J = 7.2, 1 H, 6-
H), 7.57 (d, J = 8.7, 1 H, 7-H), 7.66 (d, J = 8.4, 1 H, 4-H), 8.16 (s, 1 H, 3-H); MS (EI): m/z (%) = 232
+
+
+
+
(
23) [M] , 173 (50) [M-CH CO H] , 131 (100) [M-(CH ) CO H] , 118 (82) [IndzH] .
2 2 2 4 2
7
-Indazol-2-yl-heptanoic acid (5g)
Reaction of compound 3g (251 mg, 1.28 mmol) in aqueous NaOH solution (10 M, 1.5 mL) for 30
min. gave compound 5g (195 mg, 62%) as white crystals, mp 77-78 °C; IR (KBr): 3350-2400 (COO-
-1 1
H), 3127 (C-H)Ar, 2934, 2857 (C-H), 1707 (C=O), 1629, 1515, 1465, 1433 (C=C, C=N) cm ; H-
NMR (MeOD): δ 1.32 (m, 4 H, 2×(CH )), 1.56 (m, 2 H, CH ), 1.96 (m, 2 H, CH ), 2.24 (t, J = 7.2, 2
H, CH CO H), 4.40 (t, J = 7.2, 2 H, NCH ), 7.05 (t, J = 7.5, 1 H, 5-H), 7.27 (t, J = 7.5, 1 H, 6-H), 7.58
2
2
2
2
2
2
(
[
[
d, J = 8.7, 1 H, 7-H), 7.66 (d, J = 8.4, 1 H, 4-H), 8.16 (s, 1 H, 3-H); MS (EI): m/z (%) = 246 (26)
+
+
+
+
M] , 187 (51) [M-CH
2
CO
2
H] , 173 (18) [M-(CH
2
)
2
CO
2
H] , 131 (100) [M-(CH
2
)
5
CO
2
H] , 118 (78)
+
IndzH] .
1
0-Indazol-2-yl-decanoic acid (5h)
Reaction of compound 3h (710 mg, 2.35 mmol) in aqueous NaOH solution (10 M, 2.5 mL) for 2 h.
gave compound 5h (611 mg, 90%) as white crystals, mp 68 °C; IR (KBr): 3350-2400 (COO-H), 3128
-1
1
(
C-H)Ar, 2922, 2850, (C-H), 1711 (C=O), 1627, 1515, 1469, 1432 (C=C, C=N) cm ; H-NMR
(
MeOD): δ 1.27 (m, 10 H, 5×(CH )), 1.55 (m, 2 H, CH ), 1.97 (m, 2 H, CH ), 2.24 (t, J = 7.2, 2 H,
2
2
2
CH
2
CO
2
H), 4.41 (t, J = 6,9, 2 H, NCH
2
), 7.05 (t, J = 7.5, 1 H, 5-H), 7.27 (t, J = 7.2, 1 H, 6-H), 7.58 (d,
+
J = 8.7, 1 H, 7-H), 7.67 (d, J = 8.4, 1 H, 4-H), 8.18 (s, 1 H, 3-H); MS (EI): m/z (%) = 288 (33) [M] ,
+
+
+
2
29 (20) [M-CH CO H] , 187 (20) [M-(CH ) CO H] , 173 (21) [M-(CH ) CO H] , 131 (97) [M-
2 2 2 4 2 2 5 2
+
+
(CH
2
)
8
CO
2
H] , 118 (100) [IndzH] .
1
1-Indazol-1-yl-undecanoic acid (5i)
Reaction of compound 3i (311 mg, 0.98 mmol) in aqueous NaOH solution (10 M, 1.5 mL) for 2 h.
gave compound 5i (276 mg, 93%) as white crystals, mp 82 °C; IR (KBr): 3500-2390 (COO-H), 3127
-1 1
(
(
C-H)Ar, 2935, 2916, 2848 (C-H), 1708 (C=O), 1629, 1515, 1462, 1434 (C=C, C=N) cm ; H-NMR
MeOD): δ 1.27 (m, 12 H, 6×(CH )), 1.56 (m, 2 H, CH ), 1.98 (m, 2 H, CH ), 2.25 (t, J = 7.5, 2 H,
CO H), 4.42 (t, J = 7.2, 2 H, NCH ), 7.05 (t, J = 7.2, 1 H, 5-H), 7.27 (t, J = 7.5, 1 H, 6-H), 7.57 (d,
2
2
2
CH
2
2
2

Molecules 2006, 11
887
J = 8.7, 1 H, 7-H), 7.67 (dd, J = 8.1 and 0.6, 1 H, 4-H), 8.19 (s, 1 H, 3-H); MS (EI): m/z (%) = 302 (18)
+
+
+
+
[
M] , 243 (16) [M-CH
2
CO
2
H] , 187 (17) [M-(CH
2
)
5
CO
2
H] , 173 (18) [M-(CH
2
)
6
CO
2
H] , 131 (98)
+
+
[
M-(CH ) CO H] , 118 (100) [IndzH] .
2
9
2
X-ray data analysis of compound 5b
Data were collected in a CAD-4, equipped with a rotating anode, using Cu radiation (λ=1.5418 Å).
Cell dimensions were determined from the setting angles of 25 reflections. Data were corrected for
Lorentz and polarization effects. The structure was solved by direct methods using SIR97 [32] and
refined using SHELXL [33] within the WinGX suite of programs [34]. Non-hydrogen atoms were
refined anysotropically and H atoms were identified from the Fourier difference map and allowed to
refine freely. The crystal data and refinement parameters are summarized in Table 7.
CCDC 279230 contains the supplementary crystallographic data on this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge, CB2 1EZ, UK; E-mail: deposit@ccdc.cam.ac.uk.
Table 7. Crystal data and structure refinement for compound 5b.
Empirical formula
Formula weight
9 8 2 2
C H N O
176.17
Temperature
293(2) K
Wavelength
1.54184 A
Crystal system, space group
Unit cell dimensions
Monoclinic, P2 /n
1
a = 9.615(2) Å
b = 8.524(2) Å β = 92.420(10)º
c = 10.109(6) Å
3
Volume
827.8(6) A
3
Z, Calculated density
Absorption coefficient
F(000)
4, 1.414 Mg/m
-
1
0.855 mm
368
Crystal size
0.5 x 0.4 x 0.2 mm
6.80 to 59.39 deg.
-10<=h<=0, -9<=k<=0, -11<=l<=11
1281 / 1201 [R(int) = 0.0134]
99.2%
Theta range for data collection
Limiting indices
Reflections collected / unique
Completeness to theta = 59.39
Absorption correction
Refinement method
Data / restraints / parameters
None
2
Full-matrix least-squares on F
1201 / 0 / 151
2
Goodness-of-fit on F
1.134
Final R indices [I>2sigma(I)]
R indices (all data)
R = 0.0411, wR = 0.0980
1
2
R = 0.0571, wR = 0.1054
1
2
Extinction coefficient
0.017(2)
-
3
Largest diff. peak and hole
0.210 and -0.223 e. Å

Molecules 2006, 11
888
References
1
2
.
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(
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4
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2
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1
924-1929.
1
1
1. Nofre, C.; Tinti, J. M.; Quar, F. FR Patent 26099603, 1988.
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1
3. (a) Escande, A.; Lapasset, J.; Faure, R.; Vicenta, E.-J.; Elguero, J. Tetrahedron 1974, 30, 2903-
2
909; (b) Faure, R.; Vicent, E. J.; Elguero, J. Heterocycles 1983, 20, 1713-1716; (c) Catalán, J.;
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1
4. (a) Black, P. J.; Heffernan, M. L. Aust. J. Chem. 1963, 14, 1051-1055; (b) Jaffari, G. A.; Nunn, A.
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