SnCl2/EtOH-mediated Synthesis of Novel 4-Ethoxy-and 4-Chloroindazoles Bearing Sulfonamide Moieties

Article abstract of DOI:10.1080/00397911.2015.1061670

The treatment of N-alkyl-5-nitroindazole with stannous chloride in ethanol, aftercoupling of the obtained amines with arylsulfonyl chloride in pyridine, gave the new 4-ethoxy-and 4-chloroindazoles bearing sulfonamide in moderate to good yields. Chlorinati

Full text of DOI:10.1080/00397911.2015.1061670

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SnCl /EtOH-Mediated Synthesis of Novel 4-Ethoxy- and
2
4
-Chloroindazoles Bearing Sulfonamide Moiety
a a b b
c
Hakima Chicha , Latifa Bouissane , Lahcen El Ammari , Mohamed Saadi , Michel Baltas &
a
Rakib El Mostapha
a
Laboratoire de Chimie Organique et Analytiques, Faculté des Sciences et Techniques,
Université Sultan Moulay Slimane, Béni-Mellal, Morocco
b
Laboratoire de Chimie du Solide Appliquée, Faculté des Sciences, Université Mohammed V-
Agdal, Rabat, Morocco
c
Université Paul Sabatier, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt
Biologique, Toulouse cedex 9, France
Accepted author version posted online: 16 Jun 2015.
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To cite this article: Hakima Chicha, Latifa Bouissane, Lahcen El Ammari, Mohamed Saadi, Michel Baltas & Rakib El
Mostapha (2015): SnCl /EtOH-Mediated Synthesis of Novel 4-Ethoxy- and 4-Chloroindazoles Bearing Sulfonamide Moiety,
2
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:
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SnCl /EtOH-Mediated Synthesis of Novel 4-Ethoxy- and 4-Chloroindazoles Bearing
2
Sulfonamide Moiety
1
1
2
2
Hakima Chicha , Latifa Bouissane , Lahcen El Ammari , Mohamed Saadi , Michel
3
1
Baltas , Rakib El Mostapha
1
Laboratoire de Chimie Organique et Analytiques, Faculté des Sciences et Techniques,
2
Université Sultan Moulay Slimane, Béni-Mellal, Morocco Laboratoire de Chimie du
Solide Appliquée, Faculté des Sciences, Université Mohammed V-Agdal, Rabat,
3
Morocco Université Paul Sabatier, Laboratoire de Synthèse et Physico-Chimie de
Molécules d’Intérêt Biologique, Toulouse cedex 9, France
Corresponding author. Rakib El Mostapha E-mail: elmostapha1@ymail.com
Abstract
The treatment of N-alkyl-5-nitroindazole with stannous chloride in ethanol gave after
coupling of the obtained amines with arylsulfonyl chloride in pyridine the new 4-ethoxy-
and 4-chloroindazoles bearing sulfonamide in moderate to good yields. Chlorination and
ethoxylation of indazole is observed during the reduction of the nitro group with
anhydrous SnCl in ethanol. The influence of the N-alkylation in N-1 and N-2 position of
2
5
-nitroindazole on the reduction is investigated. The presence of ethoxy group and
chlorine atom at position C-4 of indazole is confirmed by X-ray diffraction analysis of
compounds 7a and 8a
KEYWORDS: N-alkyl-5-nitroindazoles, stannous chloride, reduction, arylsulfonyl
chloride, N-(4-ethoxyindazol-5-yl)-arylsulfonamides, N-(4-chloroindazol-5-yl)-
arylsulfonamides
1

INTRODUCTION
In recent years, stannous chloride has been receiving increasing interest as reducing agent
[
1-5]
due to its applications in organic transformations
. In view of its inherent properties
such as reusability, greater selectivity, operational simplicity, non-corrosiveness, low cost
and ease of isolation, several groups have accomplished efficient syntheses of different
heterocyclic compounds employing the reduction of nitro derivatives with stannous
[
6-9]
chloride
. Our research program during the last ten years has been focused on the
[
10-17]
synthesis of heterocyclic compounds using anhydrous SnCl as reductive reagent
.
2
We thus, have reported the synthesis of 7-alkoxy- and 4-alkoxyindazole derivatives via
the reduction of 4-, 6- and 7-nitroindazoles in the presence of anhydrous SnCl in various
2
alcohol solvents, followed by the coupling of the newly formed amine with arylsulfonyl
[
10-17]
chlorides in pyridine
. We selected arylsulfonyl chloride as a protective agent of
aminoindazole because in our previous study, we observed significant degradation of
aromatic primary amine. Interestingly, several indazoles bearing arylsulfonamide showed
an important antiproliferative activity against human (colon and prostate) and murine
[
14-16]
(leukemia) cell lines
.
Along these lines, and searching for the synthesis of new substituted indazoles bearing
sulfonamide, which are useful for biological screening, we examined the reduction of N-
alkyl-5-nitroindazoles 2a,b and 3a,b with SnCl in ethanol, followed by coupling of the
2
obtained amines with arylsulfonyl chlorides in pyridine. This method provides a route for
the construction of 4-ethoxy- and 4-chloroindazoles described for the first time. The N-
2

alkyl-5-nitroindazoles 2a,b and 3a,b have been synthesized starting from simple
[
15]
alkylation of 5-nitroindazole 1 according to our previously described procedure . The
mixture of N1- and N2- alkylation was purified by column chromatography on silica gel
using EtOAc/hexane to afford the desired products, 1-alkyl-5-nitroindazoles 2a,b
followed by 2-alkyl-5-nitroindazoles 3a,b.
RESULTS AND DISCUSSION
In order to optimize this sequence and considering that the presence of the NH group in
5
-nitroindazole could be the limiting factor; we decided to investigate the influence of the
N-alkylation in N-1 and N-2 position of 5-nitroindazole on the nitro group reduction.
Thus, treatment of 1-alkyl-5-nitroindazoles 2a,b with SnCl in ethanol gave after
2
coupling of the corresponding amine with arylsulfonyl chlorides in pyridine the novel
sulfonamides 4a-d substituted by a chlorine atom in position C-4 of the indazole, together
with the N-(1-alkyl-4-ethoxy-5-indazolyl)arylsulfonamides 5a-d functionalized in
position 4 with an ethoxy group and unsubstituted sulfonamides 6a-d (Scheme 1, Table
1
). The ability of SnCl , in alcoholic solution, to form the corresponding 4-
2
chloroindazoles 4a-d, was observed for the first time during the reduction of 1-alkyl-5-
nitroindazole. In the course of our previous studies on the reduction of 4-, 6- and 7-
[10-13]
nitroindazoles
observed.
with stannous chloride in different alcohols the chlorination was not
1
13
The structures of 4a-d, 5a-d and 6a-d were confirmed by IR, H NMR, and C NMR.
[
18-21]
The structures of 6a-d were further confirmed by X-ray analysis
.
3

These results induced us to test the same reaction on other substrates, the isomeric
compounds 5-nitroindazole substituted at the N-2 position 3a,b. Furthermore, when 2-
alkyl-5-nitroindazoles 3a,b was treated under the same experimental conditions, only 4-
chloroindazoles 7a-d and 4-ethoxyindazoles 8a-d were isolated in excellent combined
yields (Scheme 2 and Table 2). In this case we observed favorable yields of 4-chlorinated
derivatives 7a-d (31-38%) and 4-ethoxyindazoles 8a-d (60-67%). These results show that
N-alkylation of 5-nitroindazole at position N-2 plays an important role in the introduction
of the ethoxy group and chlorine atom in 4-position of indazole. We are now
investigating cyclic voltammetry (CV), electron spin resonance (ESR), NMR, and ab-
initio calculations of some N-alkyl-5-nitroindazoles in order to gain information
concerning the electronic distribution on the different atoms of the indazole system,
especially looking at the effect of the presence of an alkyl on nitrogen 1 or 2.
1
13
The structures of all newly synthesized compounds were confirmed by H NMR, C
NMR and mass spectral data. The presence of chlorine atom and ethoxy group in position
C-4 of indazole was unambiguously confirmed by X-ray crystallographic analysis of
compounds 7a and 8a (Figures 1 and 2).
Crystal structure data for compound 7a: The title compound was recrystallized from
ethanol. Crystals of C H ClN O S belong to the P2(1)2(1)2(1) space group [a = 4.9585
1
5
14
3
2
3
(
1), b = 12.2442 (3), c = 25.8587 (8) A; Z = 4; V = 1569.96 (7) A ]. The 16328 room
temperature diffraction data were measured on a Bruker X8 diffractometer using Mo Ka
4

radiation up to a 2Ɵ max of 59.14 °. The crystal structure was refined to a final R-index
of 0.0424 for 3579 unique reflections and 200 least squares parameters. The
crystallographic information file has been deposited with the Cambridge Crystallographic
Data Centre, CCDC 1031265.
Crystal structure data for compound 8a: The title compound was recrystallized from
ethanol. Crystals of C H N O S belong to the P2(1)/c space group [a = 13.5102 (5), b =
1
7
19
3
3
3
9
.0587 (3), c = 14.1624 (5) A, β = 92.089 (2)°; Z = 4; V = 1732.11 (7) A ]. The 26283
room temperature diffraction data were measured on a Bruker X8 diffractometer using
Mo Ka radiation up to a 2Ɵ max of 54.20°. The crystal structure was refined to a final R-
index of 0.0439 for 2912 unique reflections and 217 least squares parameters. The
crystallographic information file has been deposited with the Cambridge Crystallographic
Data Centre, CCDC 1031266.
A plausible mechanism was proposed to explain the introduction of ethoxy group at
position 4 of 2-alkyl-5-nitroindazole 3a,b. First, the usual partial reduction of the nitro
group generates the corresponding hydroxylamine. Hence, we assume that the
nucleophilic attack of ethanol present in the reaction mixture occurs via the lone oxygen
pair and leads to the intermediate A. Aromatization and coupling of the corresponding
amine gives the products 8a-d (Scheme 3).
The nucleophilic attack of ethanol takes place not directly on the nitroindazole
derivatives because we performed reaction between 2-methyl-5-nitroindazole 3a and
5

sodium ethoxide in ethanol at 60°C, no reaction was observed and we isolated only the
starting substance 3a.
The reduction of aromatic nitro compounds with metals in protic solvents such as
alcohols is usually presumed to proceed by way of hydroxylamine-like intermediates
[
13,22-25]
.
Thus, the formation of the chlorinated products 7a-d could be explained probably by the
presence of the chlorine anion in the reaction mixture, followed by the nucleophilic
substitution on position 4 of indazole.
CONCLUSIONS
We have developed an efficient approach to generate diversified functionalized indazoles
by using anhydrous stannous chloride in ethanol as a method for the reduction of N-alkyl-
5
nitroindazole. We investigated the N-alkylation effect of 5-nitroindazole to generate
selectively 4-ethoxy- and 4-chloroindazoles. A selective way to 4-ethoxy- and 4-
chloroindazoles was developed through N-alkylation of 5-nitroindazole at position N-2.
The substituted indazoles bearing sulfonamides described in this paper will serve as
interesting compounds in medicinal chemistry. Biological evaluation of these compounds
is currently under way.
EXPERIMENTAL
6

1
13
Melting points were determined using a Büchi-Tottoli apparatus. H and C NMR
spectra were recorded in CDCl , DMSO-d and solution (unless otherwise specified) with
3
6
1
13
TMS as an internal reference using a Bruker AC 300 ( H) or 75MHz ( C) instruments.
Chemical shifts are given in d parts per million (ppm) downfield from TMS.
13
Multiplicities of C NMR resources were assigned by distortionless enhancement by
polarization transfer (DEPT) experiments. Low-resolution mass spectra (MS) were
recorded on a Perkin-Elmer Sciex API 3000 spectrometer. Column chromatography was
carried out on SiO (silica gel 60 Merck 0.063–0.200 mm). Thin-layer chromatography
2
(
TLC) was carried out on SiO (silica gel 60, F 254 Merck 0.063–0.200 mm), and the
2
spots were located with UV light. Commercial reagents were used without further
purification unless stated.
General Procedure For The Synthesis Of N-Alkyl-5-Nitroindazoles 2a,B And 3a,B
To a solution of 5-nitroindazole 1 (6.13 mmol) in THF (25 mL) cooled at 0 °C was added
cesium carbonate (12.26 mmol). After 15 mn at 0°C, MeI or allyl bromide (6.13 mmol)
was added dropwise. Upon disappearance of the starting material as indicated by TLC,
the resulting mixture was evaporated. The crude material was dissolved with EtOAc (50
mL), washed with water and brine, dried over MgSO and the solvent was removed in
4
vacuo. The resulting residue was purified by column chromatography on silica gel using
EtOAc/hexane (3:7) to afford the desired products, 1-alkyl-5-nitroindazole followed by
2
-alkyl-5-nitroindazole.
7

1
1
-Allyl-5-nitro-1H-indazole (2b). Yield: 54%; yellow solid; mp 59-61 °C; H NMR
(
CDCl ): δ 5.05-5.13 (m, 2H, NCH ), 5.18-5.31 (m, 2H, =CH ), 5.97-6.01 (m, 1H, =CH),
3
2
2
7
1
1
.45 (d, 1H, J = 9.0 Hz), 8.21 (s, 1H, H-3), 8.25 (dd, 1H, J = 9.3, 2.4 Hz), 8.72 (d, 1H, J =
13
.8 Hz); C NMR (CDCl ): δ 52.2 (NCH ), 109.6 (CH), 118.6 (=CH ), 119.0 (CH),
3
2
2
21.5 (CH), 123.4 (C), 131.8 (CH), 135.9 (CH-3, =CH), 141.2 (C), 142.4 (C).
1
2
-Allyl-5-nitro-2H-indazole (3b). Yield: 39%; Yellow solid; mp 46-48 °C; H NMR
(
CDCl ): δ 5.07-5.11 (m, 2H, NCH ), 5.34-5.43 (m, 2H, =CH ), 6.07-6.12 (m, 1H, =CH),
3 2 2
7
.73 (d, 1H, J = 9.2 Hz), 8.07 (dd, 1H, J = 9.2 Hz, 1.8 Hz), 8.24 (s, 1H, H-3), 8.70 (d, 1H,
13
J = 1.8 Hz); C NMR (CDCl ): δ 56.7 (NCH ), 118.4 (CH), 119.4 (CH), 120.4 (CH),
3
2
1
20.8 (=CH ), 121.2 (C), 126.8 (CH-3, =CH), 131.1 (CH), 143.2 (C), 149.7 (C).
2
General Procedure For The Synthesis Of Compounds 4a-D, 5a-D And 6a-D
A mixture of 1-alkyl-5-nitroindazole 2a or 2b (0.66 mmol) and anhydrous SnCl (3.3
2
mmol) in 25 mL of absolute ethanol was heated at 60 °C. After reduction the solution
was allowed to cool down. The pH was made slightly basic (pH 7–8) by addition of 5%
aqueous potassium bicarbonate before being extracted with ethyl acetate. The organic
phase was washed with brine and dried over magnesium sulfate. The solvent was
removed to afford the amine, which was immediately dissolved in pyridine (5 mL) and
then reacted with arylsulfonyl chloride (0.72 mmol) at room temperature overnight. After
the reaction mixture was concentrated in vacuo, the resulting residue was purified by
flash chromatography (eluted with EtOAc/hexane).
8

N-(4-Chloro-1-methyl-1H-indazol-5-yl)-4-methylbenzene sulfonamide (4a). White
1
solid; mp 159-161°C; H NMR (CDCl ): δ 2.34 (s, 3H, CH ), 4.05 (s, 3H, NCH ), 6.85
3
3
3
(s, 1H, NH), 7.14 (d, 2H, J = 8.1 Hz), 7.29 (d, 1H, J = 9.0 Hz), 7.54 (d, 2H, J = 8.1 Hz),
1
3
7
.74 (d, 1H, J = 8.1 Hz), 7.87 (s, 1H, H-3); C NMR (CDCl ): δ 21.6 (CH ), 35.9
3 3
(
NCH ), 108.4 (CH), 118.6 (C), 122.9 (C), 124.5 (CH), 126.4 (C), 127.2 (2CH), 129.6
3
3
5
(
2CH), 130.8 (C), 131.4 (CH), 135.7 (C), 138.7 (C), 144.1 (C); EI-MS (m/z) = 336 ( Cl)
+
37
+
[
M+1] , 338 ( Cl) [M+3] ; Anal. Calcd for C H ClN O S; C, 53.65; H, 4.20; N,
15 14 3 2
1
2.51. Found: C, 53.77; H, 4.09; N, 12.64.
N-(4-Ethoxy-1-methyl-1H-indazol-5-yl)-4-methylbenzene sulfonamide (5a). White
1
solid; mp 125-127 °C; H NMR (CDCl ): δ 1.20 (t, 3H, CH , J = 7.2 Hz), 2.31 (s, 3H,
3
3
CH ), 4.01 (s, 3H, NCH ), 4.20 (q, 2H, CH O, J = 7.2 Hz), 6.81 (s, 1H, NH), 6.97 (d, 1H,
3
3
2
J = 9.0 Hz), 7.14 (d, 2H, J = 8.4 Hz), 7.51 (d, 2H, J = 8.4 Hz), 7.67 (d, 1H, J = 9.0 Hz),
1
3
7
.92 (s, 1H, H-3); C NMR (CDCl ): δ 15.3 (CH ), 21.5 (CH ), 35.7 (NCH ), 67.8
3 3 3 3
(
CH O), 102.2 (CH), 113.0 (CH), 118.1 (C), 122.9 (C), 124.6 (CH), 126.4 (C), 127.2
2
(2CH), 129.2 (2CH), 130.2 (CH), 136.1 (C), 140.4 (C), 143.5 (C); EI-MS (m/z) = 346
+
[
M+1] ; Anal. Calcd for C H N O S; C, 59.11; H, 5.54; N, 12.16. Found: C, 59.27; H,
17
19
3
3
5
.41; N, 12.08.
4
1
1
9
-Methyl-N-(1-methyl-1H-indazol-5-yl)-benzene sulfonamide (6a). White solid; mp
1
82-184 °C; H NMR (DMSO-d ): δ 2.27 (s, 3H, CH ), 3.94 (s, 3H, NCH ), 7.09 (dd,
6
3
3
H, J = 9.0, 2.1 Hz), 7.25 (d, 2H, J = 8.1 Hz), 7.38 (d, 1H, J = 1.8 Hz), 7.46 (d, 1H, J =
1
3
.0 Hz), 7.55 (d, 2H, J = 8.1 Hz), 7.92 (s, 1H, H-3), 10.01 (s, 1H, NH); C NMR
9

(
DMSO-d ): δ 21.4 (CH ), 35.8 (NCH ), 110.6 (CH), 113.2 (CH), 122.5 (CH), 123.8 (C),
6 3 3
1
27.2 (2CH), 130.0 (2CH), 130.9 (C), 132.6 (CH), 136.1 (C), 136.9 (C), 137.8 (C), 143.5
+
(
C); EI-MS (m/z) = 302 [M+1] ; Anal. Calcd for C H N O S; C, 59.78; H, 5.02; N,
15
15
3
2
1
3.94. Found: C, 59.64; H, 5.13; N, 13.78.
Synthesis Of Compounds 7a-D And 8a-D
These compounds were prepared from 2-alkyl-5-nitroindazoles 3a,b using the same
procedure applied to 1-alkyl-5-nitroindazole.
SUPPLEMENTARY MATERIALS
1
13
Full characterization data, H and C NMR spectra, and X-ray crystallographic materials
for this article can be accessed on the publisher’s website.
ACKNOWLEDGEMENTS
We thank the University of Sultan Moulay Slimane, Beni-Mellal for financial support
and the National Centre for Scientific and Technical Research (CNRST), Rabat, for
providing the NMR and X-ray crystallography of our compounds
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1
2

Table 1. Yields, melting points and reaction times of compounds 4a-d, 5a-d and 6a-d.
Entry R1
R
Substituent at C-4 of
Time of reduction
Mp (°C) Yield
(%)
indazole
Cl
(h)
4
5
6
4
5
6
4
5
6
4
5
6
a
a
a
b
b
b
c
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
3
3
3
CH
3
3
3
3
3
3
4h
159-161 18
125-127 35
182-184 56
134-136 20
157-159 28
148-150 55
105-107 18
109-111 26
100-102 64
106-108 16
130-132 25
CH
C
H
5
H
5
H
5
H
5
O
O
O
O
4h
2
CH
H
4h
O CH
O CH
O CH
Cl
4h
C
4h
2
H
4h
allyl Cl
allyl C
4h30mn
4h30mn
4h30mn
4h30mn
4h30mn
4h30mn
c
2
c
allyl H
d
d
d
O allyl Cl
O allyl C
O allyl H
2
96-98
66
Note: Isolated yields over the two steps after separation by flash chromatography
1
3

Table 2. Yields, melting points and reaction times of compounds 7a-d and 8a-d.
Entry R1
R
Substituent at C-4 of
Time of reduction Mp
Yield
(%)
34
indazole
Cl
(h)
(°C)
113-
7
8
7
8
7
8
a
a
b
b
c
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
CH
3
3
3
3
5h15mn
1
15
103-
05
104-
06
108-
10
147-
49
115-
17
98-100 31
103- 65
05
Note: Isolated yields over the two steps after separation by flash chromatography
CH
C
H
O
O
5h15mn
5h15mn
5h15mn
6h
67
35
64
38
60
2
5
1
O CH
O CH
Cl
1
C
H
5
2
1
allyl Cl
1
c
allyl C
2
H
5
O
O
6h
1
7
8
d
d
CH
3
3
O allyl Cl
O allyl C
6h
6h
CH
H
5
2
1
1
4

Scheme 1. Reduction of 2a,b in ethanol and protection with arylsulfonyl chlorides in
pyridine.
1
5

Scheme 2. Reduction of 3a,b in ethanol and protection with arylsulfonyl chlorides in
pyridine
1
6

Scheme 3. Proposed mechanism for the formation of 4-ethoxyindazoles 8a-d
1
7

Figure 1. ORTEP diagram of N-(4-Chloro-2-methyl-2H-indazol-5-yl)-4-methyl-benzene
sulfonamide 7a
1
8

Figure 2. ORTEP diagram of N-(4-ethoxy-2-methyl-2H-indazol-5-yl)-4-methyl-benzene
sulfonamide 8a
1
9