SnCl2/RSH: A versatile catalytic system for the synthesis of 4-Alkylsulfanyl-indazole derivatives

Article abstract of DOI:10.1080/17415993.2014.966105

The treatment of alkylated nitro derivatives of indazole with stannous chloride in alkanethiol gave after coupling of the obtained amines with 4-methoxybenzenesulfonyl chloride in pyridine the new N-(4-Alkylsulfanylindazol-7-yl)-4-methoxybenzene sulfonamides via the nucleophilic substitution of hydrogen in position 4 of indazole, together with the expected 4-methoxy-N-(indazol-7-yl)-benzenesulfonamides. All the newly synthesized compounds have been characterized by elemental analysis and spectroscopic data.

Full text of DOI:10.1080/17415993.2014.966105

This article was downloaded by: [Gebze Yuksek Teknoloji Enstitïsu ]
On: 24 December 2014, At: 12:44
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Journal of Sulfur Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/gsrp20
SnCl /RSH: a versatile catalytic system
2
for the synthesis of 4-alkylsulfanyl-
indazole derivatives
a
a
a
Assoman Kouakou , Hakima Chicha , El Mostapha Rakib , Ahmed
a
a
a
Gamouh , Abdellah Hannioui , Mohammed Chigr & Maurizio
b
Viale
a
Laboratoire de Chimie Organique et Analytique, Faculté des
Sciences et Techniques, Université Sultan Moulay Slimane, B.P.
5
23, Béni-Mellal, Morocco
b
IRCCS, Azienda Ospedaliera Universitaria San Martino–IST Istituto
Click for updates
Nazionale per la Ricerca sul Cancro, U.O.C. Bioterapie, L.go R.
Benzi 10, 16132 Genova, Italy
Published online: 07 Oct 2014.
To cite this article: Assoman Kouakou, Hakima Chicha, El Mostapha Rakib, Ahmed Gamouh,
Abdellah Hannioui, Mohammed Chigr & Maurizio Viale (2015) SnCl /RSH: a versatile catalytic system
2
for the synthesis of 4-alkylsulfanyl-indazole derivatives, Journal of Sulfur Chemistry, 36:1, 86-95,
DOI: 10.1080/17415993.2014.966105
To link to this article: http://dx.doi.org/10.1080/17415993.2014.966105
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“
Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,

systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Journal of Sulfur Chemistry, 2015
Vol. 36, No. 1, 86–95, http://dx.doi.org/10.1080/17415993.2014.966105
SnCl /RSH: a versatile catalytic system for the synthesis of
2
4
-alkylsulfanyl-indazole derivatives
a
a
a∗
a
Assoman Kouakou , Hakima Chicha , El Mostapha Rakib , Ahmed Gamouh , Abdellah
a
a
b
Hannioui , Mohammed Chigr and Maurizio Viale
a
Laboratoire de Chimie Organique et Analytique, Faculté des Sciences et Techniques, Université Sultan
b
Moulay Slimane, B.P. 523, Béni-Mellal, Morocco IRCCS, Azienda Ospedaliera Universitaria San
Martino–IST Istituto Nazionale per la Ricerca sul Cancro, U.O.C. Bioterapie, L.go R. Benzi 10, 16132
Genova, Italy
(Received 9 July 2014; accepted 11 September 2014)
The treatment of alkylated nitro derivatives of indazole with stannous chloride in alkanethiol gave after
coupling of the obtained amines with 4-methoxybenzenesulfonyl chloride in pyridine the new N-(4-
alkylsulfanylindazol-7-yl)-4-methoxybenzene sulfonamides via the nucleophilic substitution of hydrogen
in position 4 of indazole, together with the expected 4-methoxy-N-(indazol-7-yl)-benzenesulfonamides.
All the newly synthesized compounds have been characterized by elemental analysis and spectroscopic
data.
R1
S
1
) SnCl /R SH
2 1
N
N
+
N
2
) 4-MeOPhSO Cl H CO
H CO
3
2
3
N
N
N
pyridine
R
R
R
NO2
NH
NH
S
S
O
O
O
O
Keywords: N-alkyl-7-nitroindazole; stannous chloride; alkanethiol; reduction; N-(4-alkyl sulfanylindazol-
-yl)arylsulfonamide
7
1. Introduction
Recently, stannous chloride dihydrate has gained special attention as a mild and highly chemose-
lective reducing agent for various organic transformations.[1–5] 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 the facile synthesis of different heterocyclic
compounds employing the catalytic reduction of nitro derivatives with stannous chloride. For
example, Kurth and co-workers reported a one-step synthesis of 2,3-dihydro-1H-quinazolin-4-
ones from 2-nitrobenzamides with stannous chloride in different alcohols.[6] In 2002, Bates and
Li [7] described cyclization products produced for nitroarene reduction to ami-noarene using
*
Corresponding author. Email: elmostapha1@ymail.com
ꢀ
c 2014 Taylor & Francis

Journal of Sulfur Chemistry 87
SnCl2,2H2O. In 2006, Roy and co-workers reported that a one-step reductive transformation
of 2-(2-nitro-phenyl)-3H-quinazolin-4-one in various alcohols furnished the desired tetracyclic
product with SnCl2,2H2O.[8] The method of reductive cyclization of 2-nitrobenzamides with
haloketones or keto acids mediated by SnCl2,2H2O was reported recently by Shi.[9] Previously
our group has reported the reduction of some nitroindazoles with anhydrous SnCl2 in various
alcohols, in the presence of arylsulfonyl chlorides and pyridine.[10–12] Thus, we observed a
new kind of transformation: 4-, 6- and 7-nitroindazoles, by the action of SnCl2/EtOH, gave 4-
or 7-alkoxyaminoindazoles, probably via an oxidative nucleophilic substitution of hydrogen,
together with the expected 4-, 6- and 7-aminoindazoles (Scheme 1).
X
R
O
X
X
1
) SnCl /ROH
2
N
R2
N
R2
+
N
R2
2
) ArSO Cl, Pyridine
2
N
O N
N
N
2
HN
SO2
HN
SO2
R1
R1
R1
X = H, Cl, Br, I
Ar
Ar
R= CH , C H ,C H , C H
3
2
5
3
7
4
9
R or R =H, CH , CH CHCH ,CH Ph,CH CH COOC H
1
2
3
2
2
2
2
2
2
5
Ar = 4-CH Ph-, 4-CH OPh-
3
3
Scheme 1. Reduction of nitroindazoles with SnCl2 in various alcohols.
More recently, we have described an efficient synthesis of some new alkyl 1-aryl-
sulfonyl-1,3-dihydro-3-oxo-2,1-benzisoxazole-4-carboxylates and 4-arylsulfonamido-1,3-iso-
benzofurandiones by simple reduction of 3-nitrophthalic anhydride with anhydrous SnCl2 in
different alcohols, and protection with arylsulfonyl chloride (Scheme 2).[13]
O
O
N
O
O
S
S
NO2
O
NH
R'
O
O
O
O
1
2
) SnCl ,ROH
2
+
R'
O
O
R
) R'C H SO Cl,pyridine
6
4
2
O
O
O
R= CH -,C H -,C H -,C H -
3
2
5
3
7
4
9
R' = CH -,CH O-
3
3
Scheme 2. Reduction of 3-nitrophtalic anhydride with SnCl2 in various alcohols.
Based on our experience on the conversion of the nitro group of nitroindazole derivatives
into the corresponding amino group with SnCl2, in alcoholic solution, we decided to extend this
original method, on the reduction of N-alkyl-7-nitroindazole 2a,b and 3a,b with SnCl2 by using
alkanethiol as the solvent.
2. Results and discussion
Our substrate compounds 2a,b and 3a,b were prepared as follows (Scheme 3). The alkylation
of 7-nitroindazole with RX (methyl iodide, ethyl iodide) as the alkylating agent in dry acetone

8
8 A. Kouakou et al.
and hydroxide potassium provided an expected mixture of N1 and N2 alkylation products with a
poor selectivity in favor of the N1 product.
KOH/acetone
N
N
N
R
+
RX, r.t.
N
N
N
H
R
NO2
NO2
2 aR = CH ,56%
NO2
3aR= CH ,40%
1
3
3
b R= CH -CH ,60%
3
2
b R = CH -CH , 38%
3 3
Scheme 3. Synthesis of 1-alkyl- and 2-alkyl-7-nitroindazole derivatives.
After chromatographic separation and isolation of each isomer, we studied the reduction of
the nitro group of N-alkyl-7-nitroindazoles. Thus, we observed that reduction of 1-alkyl-7-
nitroindazoles 2a,b with SnCl2 in RSH as the solvent gave two different compounds, that is,
the desired amine and the amine substituted with alkylsulfanyl group in the 4-position. It is note-
worthy that significant degradation of aromatic primary amine was observed. Consequently, we
immediately protected this amine by using 4-methoxybenzenesulfonyl chloride in pyridine. This
reaction afforded a mixture of N-(7-indazolyl)-4-methoxybenzenesulfonamide 5a,b with the cor-
responding 4-alkylsulfanylsubstituted indazole 4a–d (Scheme 4). In this case, we observed that
N-alkylation of 7-nitroindazole at N-1 position provided 4a–d functionalized in position 4 by the
alkylsulfanyl group with a moderate selectivity (Table 1).
R
1
S
1
) SnCl /R1SH
2
N
N
+
N
2
) 4-MeOPhSO Cl H CO
pyridine
H3CO
2
3
N
N
N
R
R
R
NO2
aR= CH3
NH
NH
S
S
2
b R= CH CH
O
O
O
O
3
2
4
aR= CH , R1=CH CH
3 3 2
5 aR=CH3
b R= CH CH
b R=CH , R1= CH CH CH
3
3
2
2
3
2
c R=CH CH , R1= CH CH
3
2
3
2
d RR=CH CH , R = CH CH CH
3
2
1
3
2
2
Scheme 4. Reduction of 2a,b with SnCl2 in RSH and protection with 4-MeOPhSO2Cl.
We chose the protection of 7-aminoindazole by arylsulfonyl chlorides because in our previ-
ous studies we have found that indazoles bearing a sulfonamide moiety possess an important
antiproliferative activity against some human and murine cell lines.[14,15]
Table 1. Reduction of 2a,b with SnCl2 in RSH and protection with 4-MeOPhSO2Cl.
R
R1
Time of reduction
Yield of 4a–d
Yield of 5a,b
CH3
CH3
CH3CH2
CH3CH2
CH3CH2
CH3CH2CH2
CH3CH2
3 h 30 min
4a (45%)
4b (43%)
4c (48%)
4d (52%)
5a (32%)
5a (29%)
5b (34%)
5b (31%)
4 h
5 h
6 h
CH3CH2CH2
Note: Isolated yields over the two steps after separation by flash chromatography.

Journal of Sulfur Chemistry 89
The structures of products 4a–d and 5a,b were deduced from their H NMR, 13C NMR and
1
mass spectra (MS) and by elemental analysis.
1
The assignment of the structure of compounds 4a–d was unambiguously supported by the H
and 1 C NMR spectra, in particular by the evaluation of the multiplet pattern of the C-ring proton
signals: two doublets were observed at δ 6.36–6.50 ppm and 6.64–6.81 ppm due to 6-H and 5-H
protons of indazole.
3
It is noteworthy that when using indium or iron dust as the catalytic system for the reduction
of nitroindazole derivatives, we obtained only the compounds 5a,b.
A plausible mechanism was proposed to explain the introduction of alkylsulfanyl group at
position 4 of indazole 4a–d. First, the usual partial reduction of the nitro group generates the
corresponding hydroxylamine. Hence, we assume that the nucleophilic attack of alkylthiolate
anion present in the reaction mixture occurs via the lone sulfur pair and leads to the intermedi-
ate A. Aromatization and coupling of the corresponding amine give the product 4a–d (Scheme
5). The nucleophilic attack of alkylthiolate anion takes place not directly on the nitroinda-
zole derivatives because we performed reaction between 7-nitroindazole 2a and alkylthiolate
in RSH at 60°C. Unfortunately, no reaction was observed, and we isolated only the starting
substance 2a.
R SH
1
SnCl2
N
N
N
N
N
N
R
R
R
N
HN
H
NO2
aR= CH3
O
OH
2
b R= CH -CH2
-H O
3
2
R
1
RS
S
4
-MeOPhSO Cl
2
N
4a-d
N
pyridine
N
N
R
R
NH
NH2
A
Scheme 5. Proposed mechanism for the formation of 4a–d.
It is noteworthy that reduction of aromatic nitro compounds with metals in protic solvents such
as alcohols is usually presumed to proceed by way of hydroxylamine-like intermediates.[16–19]
When we applied the same reduction conditions as previously described for 2-
alkyl-7-nitroindazole 3a,b, we obtained a mixture of two products, N-(4-ethyl(propyl)
sulfanyl-2-alkyl-2H-indazol-7-yl)-4-methoxybenzenesulfonamides 6a–c and 4-methoxy-N-(2-
alkyl-2H-indazol-7-yl)-benzenesulfonamides 7a,b (Scheme 6). This result indicates that
N-alkylation of 7-nitroindazole at N-2 position leads to a moderate selectity in favor of unsubsti-
tuted indazole derivatives 7a,b (Table 2). These results show that N-alkylation of 7-nitroindazole
at position 1 plays an important role in the introduction of the group RS in 4-position of indazole.
1
13
The structures of all newly synthesized compounds were confirmed by H NMR, C NMR
and mass spectral data.

9
0 A. Kouakou et al.
R1
S
1
) SnCl /R1SH
2
N
R
N
R
+
N
R
H CO
H CO
N
2) 4-MeOPhSO Cl,
pyridine
2
3
N
3
N
NO2
aR = CH3
NH
NH
S
S
3
O
O
O
O
b R =CH CH
3
2
6
aR = CH , R = CH CH
7 a R = CH3
bR= CH H
3
1
3
2
bR =CH , R = CH CH CH
3
2
3
1
3
2
2
c R= CH CH , R1= CH CH
3
2
3
2
Scheme 6. Reduction of 3a,b with SnCl2 in RSH and protection with 4-MeOPhSO2Cl.
Table 2. Reduction of 3a,b with SnCl2 in RSH and protection with 4-MeOPhSO2Cl.
R
R1
Time of reduction
Yield of 6a–c
Yield of 7a,b
CH3
CH3
CH3CH2
CH3CH2
CH3CH2CH2
CH3CH2
3 h
4 h 30 min
5 h
6a (35%)
6b (30%)
6c (43%)
7a (48%)
7a (45%)
7b (45%)
Note: Isolated yields over the two steps after separation by flash chromatography.
3. Conclusions
We have developed an efficient approach to generate diversified functionalized indazoles by
using anhydrous stannous chloride in alkanethiol as a method for the reduction of N-alkyl-7
nitroindazole. We investigated the N-alkylation effect of 7-nitroindazole to generate selectively
7
7
-alkylsulfanyl-7-aminoprotected-indazoles. A selective way to N-(4-alkylsulfanyl indazol-
-yl)-4-methoxybenzene sulfonamides was developed through N-alkylation of N-1 position.
Further biological evaluations of these compounds are currently under way in our laboratory.
4. Experimental
Melting points were determined using a Büchi–Tottoli apparatus. H and 13C NMR spectra were
1
recorded in CDCl3, DMSO-d6 and solution (unless otherwise specified) with TMS as an internal
1
13
reference using a Bruker AC 300 ( H) or 75 MHz ( C) instruments. Chemical shifts are given
in d parts per million (ppm) downfield from TMS. Multiplicities of 13C NMR resources were
assigned by distortionless enhancement by polarization transfer experiments. Low-resolution MS
were recorded on a Perkin-Elmer Sciex API 3000 spectrometer. Column chromatography was
carried out on SiO2 (silica gel 60 Merck 0.063–0.200 mm). Thin-layer chromatography was
carried out on SiO2 (silica gel 60, F 254 Merck 0.063–0.200 mm), and the spots were located
with UV light. Commercial reagents were used without further purification unless stated.
4.1. General procedure for the synthesis of N-alkyl-7-nitroindazoles 2a–c and 3a–c
To a solution of 7-nitroindazole 1 (6.13 mmol) in acetone (25 mL), KOH (6.8 mmol) was
added. After 15 min at room temperature, alkyl halide (12.26 mmol) was added dropwise.
The solution was stirred for 24 h. The resulting mixture was evaporated. The crude material
was dissolved with EtOAc (50 mL), washed with water and brine, dried over MgSO4 and the

Journal of Sulfur Chemistry 91
solvent was evaporated in vacuo. The resulting residue was purified by column chromatography
(EtOAc/hexane 3 : 7).
4.1.1. 1-Methyl-7-nitro-1H-indazole (2a)
1
Yield: 56%, Mp: 98–100°C; H NMR (DMSO-d6): δ 4.10 (s, 3H, CH3), 7.28 (dd, 1H, J = 7.8
1
3
Hz), 8.15 (dd, 1H, J = 7.8, 1.0 Hz), 8.21 (dd, 1H, J = 7.8, 1.0 Hz), 8.35 (s, 1H, H-3).
C
NMR (DMSO-d6): δ 40.9 (CH3), 120.1 (CH-5), 124.5 (CH-6), 128.5 (C-3a), 128.9 (CH-4),
130.8 (C-7a), 134.6 (CH-3), 135.0 (C-7).
4.1.2. 2-Methyl-7-nitro-2H-indazole (3a)
1
Yield: 40%, Mp: 132–134°C; H NMR (DMSO-d6): δ 4.25 (s, 3H, CH3), 7.23(dd, 1H, J = 7.8
13
Hz), 8.20 (dd, 1H, J = 7.8, 1.2 Hz), 8.26 (dd, 1H, J = 7.8, 1.2 Hz), 8.68 (s, 1H, H-3).
NMR (DMSO-d6): δ 40.5 (CH3), 119.5 (CH-5), 124.7 (CH-6), 125.6 (C-3a), 127.6 (CH-3), 129.5
CH-4), 136.2 (C-7), 139.4 (C-7a).
C
(
4.1.3. 1-Ethyl-7-nitro-1H-indazole (2b)
1
Yield: 60%, Mp: 53–55°C; H NMR (DMSO-d6): δ 1.31 (t, 3H, CH3, J = 7.0 Hz), 4.48 (q,
2
H, CH2O, J = 7.0 Hz), 7.31 (t, 1H, J = 7.8 Hz), 8.16 (dd, 1H, J = 7.8, 0.9 Hz), 8.22 (dd, 1H,
13
J = 7.8, 0.9 Hz), 8.40 (s, 1H, H-3). C NMR (DMSO-d6): δ 15.8 (CH3), 47.8 (NCH2), 120.6
(CH-5), 125.2 (CH-6), 129.0 (C), 129.2 (CH-4), 129.8 (C), 135.3 (C), 135.4 (CH-3).
4.1.4. 2-Ethyl-7-nitro-2H-indazole (3b)
1
Yield: 38%, Mp: 56–58°C; H NMR (DMSO-d6): δ 1.52 (t, 3H, CH3, J = 7.5 Hz), 4.55 (q,
2
H, CH2O, J = 7.5 Hz), 7.23 (t, 1H, J = 8.1 Hz), 8.24 (dd, 1H, J = 8.1, 0.9 Hz), 8.28 (dd, 1H,
13
J = 7.8, 1.0 Hz), 8.78 (s, 1H, H-3). C NMR (DMSO-d6): δ 16.1 (CH3), 48.9 (NCH2), 120.1
(CH-5), 125.1 (CH-6), 125.7 (C), 126.8 (CH-3), 130.5 (CH-4), 137.0 (C), 139.9 (C).
4.2. General procedure for the synthesis of N-(4-alkylsulfanylindazol-7-yl)arylsulfonamides
and N-(indazol-7-yl)arylsulfonamides
A mixture of N-alkyl-7-nitroindazole (1.22 mmol) and anhydrous SnCl2 (1.1 g, 6.1 mmol) in
5 mL of RSH was heated at 60°C. After reduction, the starting material disappeared and the
2
solution was allowed to cool down. The pH was made slightly basic (pH 7–8) by the addi-
tion of 5% aqueous potassium bicarbonate before being extracted with EtOAc. 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
4-methoxybenzenesulfonyl chloride (0.26 g, 1.25 mmol) at room temperature for 24 h. After
the reaction mixture was concentrated in vacuo, the resulting residue was purified by flash
chromatography (eluted with EtOAc/hexane 1:9).
4.2.1. N-(4-Ethylsulfanyl-1-methyl-1H-indazol-7-yl)-4-methoxybenzenesulfonamide (4a)
1
Yield: 45%, Mp: 96–98°C; H NMR (DMSO-d6): δ 1.21 (t, 3H, CH3, J = 7.2 Hz), 3.02 (q, 2H,
CH2S, J = 7.2 Hz), 3.82 (s, 3H, OCH3), 4.20 (s, 3H, NCH3), 6.37 (d, 1H, J = 7.8 Hz), 6.81

9
2 A. Kouakou et al.
(
1
d, 1H, J = 7.8 Hz), 7.08 (d, 2H, J = 9.0 Hz), 7.58 (d, 2H, J = 9.0 Hz), 8.00 (s, 1H), 9.79 (s,
13
H, NH). C NMR (DMSO-d6): δ 14.4 (CH3), 25.8 (CH2S), 38.9 (NCH3), 56.1 (OCH3), 114.8
(
2CH), 118.0 (C), 118.2 (CH), 125.4 (C), 126.9 (CH), 129.7 (2CH), 129.8 (C), 131.4 (CH), 131.6
+
(C), 136.8 (C), 162.9 (C). EI-MS (m/z): 378 (M +H) . Anal. Calcd for C17H19N3O3S2: C, 54.09;
H, 5.07; N, 11.13; S, 16.99. Found: C, 53.94; H, 5.01; N, 11.25; S, 17.08.
4.2.2. 4-Methoxy-N-(1-methyl-4-propylsulfanyl-1H-indazol-7-yl)-benzenesulfonamide (4b)
1
Yield: 43%, Mp: 118–120°C; H NMR (DMSO-d6): δ 0.94 (t, 3H, CH3, J = 7.2 Hz), 1.53–1.61
(
m, 2H, CH2), 2.98 (t, 2H, CH2S, J = 7.2 Hz), 3.82 (s, 3H, OCH3), 4.20 (s, 3H, NCH3), 6.36 (d,
1
8
3
H, J = 8.1 Hz), 6.81 (d, 1H, J = 8.1 Hz), 7.08 (d, 2H, J = 9.0 Hz), 7.58 (d, 2H, J = 9.0 Hz),
.00 (s, 1H), 9.81 (s, 1H, NH). 1 C NMR (DMSO-d6): δ 13.6 (CH3), 22.3 (CH2), 33.6 (CH2S),
3
8.9 (NCH3), 56.1 (OCH3), 114.8 (2CH), 118.4 (CH), 120.6 (C), 125.4 (C), 126.8 (CH), 129.7
+
(
2CH), 129.8 (C), 131.4 (CH), 131.7 (C), 136.8 (C), 162.9 (C). EI-MS (m/z): 392 (M + H) .
Anal. Calcd for C18H21N3O3S2: C, 55.22; H, 5.41; N, 10.73; S, 16.38. Found: C, 55.08; H, 5.36;
N, 10.85; S, 16.51.
4.2.3. 4-Methoxy-N-(1-methyl-1H-7-indazolyl)-benzenesulfonamide (5a)
1
Yield: 32%, Mp: 163–165°C; H NMR (DMSO-d6): δ 3.82 (s, 3H, OCH3), 4.22 (s, 3H, NCH3),
6
.42 (d, 1H, J = 7.4 Hz), 6.88 (dd, 1H, J = 7.4 Hz), 7.08 (d, 2H, J = 9.0 Hz), 7.58 (d, 2H,
13
J = 9.0 Hz), 7.63 (dd, 1H, J = 7.4, 0.9 Hz), 8.05 (s, 1H), 9.83 (s, 1H, NH). C NMR (DMSO-
d6): δ 38.9 (NCH3), 56.1 (OCH3), 114.7 (2CH), 120.4 (C), 120.8 (CH), 121.1 (CH), 126.4 (CH),
+
1
26.7(C), 129.7 (2CH), 131.6 (C), 133.0 (CH), 137.1 (C), 162.9 (C). EI-MS (m/z): 318 (M + H) .
Anal. Calcd for C15H15N3O3S: C, 56.77; H, 4.76; N, 13.24; S, 10.10. Found: C, 56.68; H, 4.67;
N, 13.35; S, 10.21.
4.2.4. N-(1-Ethyl-4-ethylsulfanyl-1H-indazol-7-yl)-4-methoxybenzenesulfonamide (4c)
1
Yield: 48%, Mp: 121–123°C; H NMR (CDCl3): δ 1.35 (t, 3H, CH3, J = 7.2 Hz), 1.51 (t, 3H,
CH3, J = 7.0 Hz), 3.02 (q, 2H, CH2S, J = 7.0 Hz), 3.88 (s, 3H, OCH3), 4.88 (q, 2H, CH2N,
J = 7.2 Hz), 6.49 (d, 1H, J = 7.5 Hz), 6.76 (d, 1H, J = 7.5 Hz), 6.80 (s, 1H, NH), 6.94 (d, 2H,
13
J = 8.7 Hz), 7.64 (d, 2H, J = 8.7 Hz), 8.21 (s, 1H). C NMR (CDCl3): δ 14.1 (CH3), 15.8
(CH3), 26.7 (CH2S), 46.1 (NCH2), 55.7 (OCH3), 114.3 (2CH), 116.7 (C), 118.8 (CH), 125.0 (C),
1
3
5
29.1 (C), 129.3 (CH), 130.1 (2CH), 130.7 (CH), 132.9 (C), 136.1 (C), 163.4 (C). EI-MS (m/z):
+
92 (M + H) . Anal. Calcd for C18H21N3O3S2: C, 55.22; H, 5.41; N, 10.73; S, 16.38. Found: C,
5.10; H, 5.32; N, 10.88; S, 16.48.
4.2.5. N-(1-Ethyl-4-propylsulfanyl-1H-indazol-7-yl)-4-methoxybenzenesulfonamide (4d)
1
Yield: 52%, Mp: 128–130°C; H NMR (CDCl3): δ 1.21 (t, 3H, CH3, J = 7.0 Hz), 1.45–1.56 (m,
5
H, CH2 and CH3), 2.95 (q, 2H, CH2S, J = 7.5 Hz), 3.88 (s, 3H, OCH3), 4.88 (q, 2H, CH2N,
J = 7.2 Hz), 6.50 (d, 1H, J = 7.8 Hz), 6.64 (d, 1H, J = 7.8 Hz), 6.75 (s, 1H, NH), 6.92 (d, 2H,
13
13
J = 9.0 Hz), 7.64 (d, 2H, J = 9.0 Hz), 8.21 (s, 1H). C NMR (CDCl3): C NMR (CDCl3):
δ 14.1 (CH3), 15.8 (CH3), 24.5 (CH2), 35.4 (CH2S), 46.1 (NCH2), 55.7 (OCH3), 114.4 (2CH),
1
19.6 (CH), 120.4 (C), 123.4 (CH), 125.8 (C), 128.9 (C), 130.0 (2CH), 132.0 (CH), 131.8 (C),
+
137.2 (C), 161.5 (C). EI-MS (m/z): 406 (M +H) . Anal. Calcd for C19H23N3O3S2: C, 56.27; H,
5
.72; N, 10.36; S, 15.81. Found: C, 55.12; H, 5.80; N, 10.46; S, 16.90.

Journal of Sulfur Chemistry 93
4.2.6. N-(1-Ethyl-1H-indazol-7-yl)-4-methoxybenzenesulfonamide (5b)
1
Yield: 34%, Mp: 114–116°C; H NMR (CDCl3): δ 1.41 (t, 3H, CH3, J = 7.2 Hz), 3.88 (s, 3H,
OCH3), 4.78 (q, 2H, CH2N, J = 7.2 Hz), 6.52 (d, 1H, J = 7.2 Hz), 6.89–7.04 (m, 3H), 7.60 (d,
1
3
2
H, J = 9.0 Hz), 7.71 (d, 1H, J = 7.4 Hz), 8.10 (s, 1H), 8.18 (s, 1H, NH). C NMR (CDCl3):
δ 15.8 (CH3), 46.3 (NCH2), 55.7 (OCH3), 114.3 (2CH), 119.7 (C), 120.6 (CH), 122.3 (CH),
1
3
5
27.5(C), 128.1 (CH), 129.8 (C), 130.0 (2CH), 131.9 (CH), 136.5 (C), 163.5 (C). EI-MS (m/z):
+
32 (M + H) . Anal. Calcd for C16H17N3O3S: C, 57.99; H, 5.17; N, 12.68; S, 9.68. Found: C,
8.10; H, 5.09; N, 12.57; S, 9.57.
4.2.7. N-(4-Ethylsulfanyl-2-methyl-2H-indazol-7-yl)-4-methoxybenzenesulfonamide (6a)
1
Yield: 35%, Mp: 88–90°C; H NMR (DMSO-d6): δ 1.15 (t, 3H, CH3, J = 7.2 Hz), 2.92 (q, 2H,
CH2S, J = 7.2 Hz), 3.75 (s, 3H, OCH3), 4.10 (s, 3H, NCH3), 6.82 (d, 1H, J = 7.8 Hz), 6.93
(
1
d, 1H, J = 7.8 Hz), 6.99 (d, 2H, J = 9.0 Hz), 7.78 (d, 2H, J = 9.0 Hz), 8.32(s, 1H), 10.11 (s,
13
H, NH). C NMR (DMSO-d6): δ 14.8 (CH3), 26.7 (CH2S), 40.5 (NCH3), 56.0 (OCH3), 114.6
(
2CH), 115.2 (CH), 120.9 (C), 121.4 (CH), 123.0 (C), 125.2 (CH), 129.5 (2CH), 129.8 (C), 132.6
+
(C), 142.6 (C), 162.8 (C). EI-MS (m/z): 378 (M +H) . Anal. Calcd for C17H19N3O3S2: C, 54.09;
H, 5.07; N, 11.13; S, 16.99. Found: C, 54.20; H, 5.14; N, 11.18; S, 17.12.
4.2.8. 4-Methoxy-N-(2-methyl-4-propylsulfanyl-2H-indazol-7-yl)-benzenesulfonamide (6b)
1
Yield: 30%, Mp: 58–60°C; H NMR (CDCl3): δ 0.99 (t, 3H, CH3, J = 7.5 Hz), 1.58–1.65 (m,
2
2
H, CH2), 2.88 (t, 2H, CH2S, J = 7.5 Hz), 3.77 (s, 3H, OCH3), 4.14 (s, 3H, NCH3), 7.83 (d,
H, J = 9.0 Hz), 6.94 (d, 1H, J = 7.8 Hz), 6.96 (s, 1H, NH), 7.31 (d, 1H, J = 7.8 Hz), 7.86
13
(
4
d, 2H, J = 9.0 Hz), 7.92 (s, 1H). C NMR (CDCl3): δ 13.4 (CH3), 22.5 (CH2), 35.1 (CH2S),
0.5 (NCH3), 55.5 (OCH3), 112.7 (CH), 114.1 (2CH), 121.4 (C), 121.4 (CH), 123.7 (CH), 124.3
+
(
C), 129.5 (2CH), 130.0 (C), 131.0 (C), 141.6 (C), 163.1 (C). EI-MS (m/z): 392 (M + H) . Anal.
Calcd for C18H21N3O3S2: C, 55.22; H, 5.41; N, 10.73; S, 16.38. Found: C, 55.14; H, 5.50; N,
10.64; S, 16.48.
4.2.9. 4-Methoxy-N-(2-methyl-2H-7-indazolyl)-benzenesulfonamide (7a)
1
Yield: 48%, Mp: 103–105°C; H NMR (DMSO-d6): δ 3.75 (s, 3H, OCH3), 4.11 (s, 3H, NCH3),
6
.88 (t, 1H, J = 7.8 Hz), 6.95–7.01 (m, 3H), 7.32 (dd, 1H, J = 7.8, 0.9 Hz), 7.81 (d, 2H, J = 9.0
13
Hz), 8.25 (s, 1H), 10.07 (s, 1H, NH). C NMR (DMSO-d6): δ 40.4 (NCH3), 56.0 (OCH3), 114.1
(
1
5
CH), 114.5 (2CH), 116.5 (CH), 121.5 (CH), 122.9 (C), 125.6 (CH), 126.9(C), 129.5 (2CH),
+
32.6 (C), 142.7 (C), 162.7 (C). EI-MS (m/z): 318 (M+ H) . Anal. Calcd for C15H15N3O3S: C,
6.77; H, 4.76; N, 13.24; S, 10.10. Found: C, 56.64; H, 4.65; N, 13.32; S, 10.24.
4.2.10. N-(2-Ethyl-4-ethylsulfanyl-2H-indazol-7-yl)-4-methoxybenzenesulfonamide (6c)
1
Yield: 43%, Mp: 124–126°C; H NMR (CDCl3): δ 1.36 (t, 3H, CH3, J = 7.2 Hz), 1.52 (t, 3H,
CH3, J = 7.5 Hz), 2.98 (q, 2H, CH2S, J = 7.2 Hz), 3.77 (s, 3H, OCH3), 4.61 (q, 2H, CH2N,
J = 7.2 Hz), 6.84 (d, 2H, J = 9.0 Hz), 6.89 (s, 1H, NH), 7.10 (d, 1H, J = 8.1 Hz), 6.65 (d, 1H,
13
J = 8.1 Hz), 7.94 (d, 2H, J = 9.0 Hz), 8.16 (s, 1H). C NMR (CDCl3): δ 13.4 (CH3), 15.2
(
(
CH3), 28.0 (CH2S), 49.1 (NCH2), 55.5 (OCH3), 114.0 (2CH), 118.5 (C), 119.3 (CH), 124.8
CH), 125.3 (C), 126.5 (CH), 129.7 (C), 129.8 (2CH), 131.1 (C), 140.1 (C), 163.1 (C). EI-MS

9
4 A. Kouakou et al.
+
(
m/z): 392 (M + H) . Anal. Calcd for C18H21N3O3S2: C, 55.22; H, 5.41; N, 10.73; S, 16.38.
Found: C, 55.13; H, 5.35; N, 10.85; S, 16.50.
4.2.11. N-(2-Ethyl-1H-indazol-7-yl)-4-methoxybenzenesulfonamide (7b)
1
Yield: 45%, Mp: 146–148°C; H NMR (CDCl3): δ 1.52 (t, 3H, CH3, J = 7.2 Hz), 3.82 (s, 3H,
OCH3), 4.37 (q, 2H, CH2N, J = 7.2 Hz), 6.83–6.90 (m, 3H), 7.65 (d, 1H, J = 8.0 Hz), 7.76
1
3
(
(
1
d, 1H, J = 8.4 Hz), 8.20 (s, 1H), 9.30 (s, 1H, NH). C NMR (CDCl3): δ 15.4 (CH3), 48.8
NCH2), 55.6 (OCH3), 113.6 (2CH), 119.6 (CH), 121.7 (CH), 124.7 (CH), 126.5 (CH), 123.6(C),
+
30.1 (2CH), 130.8 (C), 131.1 (C), 163.1 (C). EI-MS (m/z): 332 (M+ H) . Anal. Calcd for
C16H17N3O3S: C, 57.99; H, 5.17; N, 12.68; S, 9.68. Found: C, 58.09; H, 5.11; N, 12.60; S, 9.54.
Acknowledgements
We thank the University of Sultan Moulay Slimane, Béni-Mellal for financial support and the National Centre for
Scientific and Technical Research (CNRST), Rabat, for providing the NMR and Mass spectrums.
References
[
[
[
1] Singh OM, Sushuma Devi N. Application of β-oxodithioesters in domino and multicomponent reactions: facile
route to dihydropyrimidines and coumarins. J Org Chem. 2009;74:3141–3144.
2] Suresh R, Muthusubramanian S, Senthilkumaran R, Manickam G. SnCl2-catalyzed selective atom economic Imino
Diels–Alder reaction: synthesis of 2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)quinolines. J Org Chem. 2012;77:1468–1476.
3] Selvam NP, Hari Babu T, Perumal PT. A simple and convenient approach to the Friedländer synthesis of pyrano[2,3-
b]pyridines. Tetrahedron. 2009;65:8524–8530.
[
[
4] Bez G, Gogoi D. A rapid and efficient method for 1,3-dithiolane synthesis. Tetrahedron Lett. 2006;47:5155–5157.
5] Tang L, Ding L, Chang W-X, Li J. SnCl2-mediated carbonyl allylation of aldehydes and ketones in ionic liquid.
Tetrahedron Lett. 2006;47:303–306.
[
[
[
6] Yoo CL, Fettinger JC, Kurth MJ. Stannous chloride in alcohol: a one-pot conversion of 2-nitro-N-arylbenzamides
to 2,3-dihydro-1H-quinazoline-4-ones. J Org Chem. 2005;70:6941–6943.
7] Bates DK, Li K. Stannous chloride-mediated reductive cyclization-rearrangement of nitroarenyl ketones. J Org
Chem. 2002;24:8662–8665.
8] Roy AD, Subramanian A, Roy RJ. Auto-redox reaction: tin(II) chloride-mediated one-step reductive cyclization
leading to the synthesis of novel biheterocyclic 5,6-dihydro-quinazolino[4,3-b]quinazolin-8-ones with three-point
diversity. Org Chem. 2006;71:382–385.
[
9] Wang M, Dou G, Shi D. Efficient and convenient synthesis of pyrrolo[1,2-a]quinazoline derivatives with the aid of
tin(II) chloride. J Comb Chem. 2010;12:582–586.
[
10] Abbassi N, Rakib EM, Hannioui A, Alaoui M, Benchidmi M, Essassi EM, Geffken D. Alkylation and reduc-
tion of N-alkyl-4-nitroindazoles with anhydrous SnCl2 in ethanol: synthesis of novel 7-ethoxy-N-alkylindazole
derivatives. Heterocycles. 2011;83:891–900.
[11] Abbassi N, Rakib EM, Bouissane L, Hannioui A, Khouili M, El Malki A, Benchidmi M, Essassi EM. Studies
on the reduction of the nitro group in 4-Nitroindazole by anhydrous SnCl2 in different alcohols. Synth Commun.
2
011;41:999–1005.
[12] Bouissane L, El Kazzouli S, Leger J-M, Jarry C, Rakib EM, Khouili M, Guillaumet G. New and efficient synthesis
of bi- and trisubstituted indazoles. Tetrahedron. 2005;61:8218–8225.
[
13] Chicha H, Abbassi N, Rakib EM, Khouili M, El Ammari L, Spinelli D. Reduction of 3-nitrophthalic anhydride
by SnCl2 in different alcohols: a simple synthesis of alkyl 3-oxo-1,3-dihydro-2,1-benzoxazole-4-carboxylates.
Tetrahedron Lett. 2013;54:1569–1571.
[
[
[
14] Abbassi N, Rakib EM, Chicha H, Bouissane L, Hannioui A, Aiello C, Gangemi R, Castagnola P, Rosano C,
Viale M. Synthesis and antitumor activity of some substituted indazole derivatives. Arch Pharm Chem Life Sci.
2
014;347:423–431.
15] Abbassi N, Chicha H, Rakib, EM, Hannioui A, Alaoui M, Hajjaji A, Geffken D, Aiello C, Gangemi R, Rosano C,
Viale M. Synthesis, antiproliferative and apoptotic activities of N-(6(4)-indazolyl)-benzenesulfonamide derivatives
as potential anticancer agents. Eur J Med Chem. 2012;57:240–249.
16] Chauhan J, Fletcher S. One-pot synthesis of 2,1-benzisoxazoles (anthranils) by a stannous chloride-mediated tan-
dem reduction–heterocyclization of 2-nitroacylbenzenes under neutral conditions. Tetrahedron Lett. 2012;53:4951–
4
954.

Journal of Sulfur Chemistry 95
[17] Uchuskin MG, Molodtsova NV, Abaev VT, Trushkov IV, Butin AV. Furan ring opening–indole ring closure:
SnCl2-induced reductive transformation of difuryl(2-nitroaryl)methanes into 2-(2-acylvinyl)indoles. Tetrahedron.
2
012;68:4252–4258.
[18] Xing W-K, Ogata Y. Effet of meta- and para-substituents on the stannous chloride reduction of nitrobenzenes in
aqueous ethanol. J Org Chem. 1983;48:2515–2520.
[
19] McAllister LA, Bechle BM, Dounay AB, Evrard E, Gan X, Ghosh S, Kim J-Y, Parikh VD, Tuttle JB, Verhoest
PR. A general strategy for the synthesis of cyclic N-aryl hydroxamic acids via partial nitro group reduction. J Org
Chem. 2011;76:3484–3497.