Alkylation and reduction of N-alkyl-4-nitroindazoles with anhydrous SnCl2 in ethanol: Synthesis of novel 7-ethoxy-N-alkylindazole derivatives

Article abstract of DOI:10.3987/COM-11-12149

New series of indazoles substituted at the N-1 and N-2 positions and their 7-ethoxy derivatives have been synthesis starting from alkylation of 4-nitroindazole and reduction of alkyl-nitro-derivatives with anhydrous SnCl2 in ethanol. The structures of the

Full text of DOI:10.3987/COM-11-12149

HETEROCYCLES, Vol. 83, No. 4, 2011
891
HETEROCYCLES, Vol. 83, No. 4, 2011, pp. 891 - 900. © The Japan Institute of Heterocyclic Chemistry
Received, 22nd January, 2011, Accepted, 21st February, 2011, Published online, 3rd March, 2011
DOI: 10.3987/COM-11-12149
ALKYLATION AND REDUCTION OF N-ALKYL-4-NITROINDAZOLES
WITH ANHYDROUS SnCl2 IN ETHANOL: SYNTHESIS OF NOVEL
7-ETHOXY-N-ALKYLINDAZOLE DERIVATIVES
Najat Abbassi,a El Mostapha Rakib,a* Abdellah Hannioui,a Mdaghri Alaoui,a
Mohamed Benchidmi,b El Mokhtar Essassi,b and Detlef Geffkenc
aLaboratory of Organic and Analytical Chemistry, Faculty of Sciences and
Techniques, University Sultan Moulay Slimane, B.P. 523, Beni-Mellal, Morocco
bLaboratory of Heterocyclic Chemistry, Faculty of Sciences, University Mohamed
V, Rabat, Morocco
cDepartment of Pharmaceutical Chemistry, Institute of Pharmacy, University of
Hamburg, Hamburg, Germany
*E-mail: elmostapha1@ymail.com
Abstract – New series of indazoles substituted at the N-1 and N-2 positions and
their 7-ethoxy derivatives have been synthesis starting from alkylation of
4-nitroindazole and reduction of alkyl-nitro-derivatives with anhydrous SnCl2 in
ethanol. The structures of the products obtained were characterized using 1H NMR,
13C NMR, MS spectrometry and elemental analysis; the NMR spectroscopic data
were used for structural assignment of the N-1 and N-2 isomers.
Substituted indazoles are recently being increasingly reported as bioactive molecules. Some recent
examples of substituted indazoles are granisetron used in CNS disorder,1 7-substituted indazoles
developed as neuronal-NOS inhibitors,2 5-nitroindazole and its derivatives have been found to possess
wide spectrum of activities like antiprotozoal,3 antimalarial4 and cytotoxic,5 N2-(substituted
benzyl)-3-(4-methylphenyl)-2H-indazoles
exhibit
antiangiogenic
activity6
and
N-[4-(3-amino-1H-indazol-4-yl)-phenyl]-N’-(3-methylphenyl)-urea (ABT-869) has shown significant
tumor growth inhibition in multiple preclinical animal models.7 Moreover, other indazole derivatives are
found to exhibit significant levels of activity as HIV protease inhibitors, serototonin 5-HT1α, 5-HT2 and
5-HT3 receptor antagonists and aldol reductase inhibitors.8,9 Recently, our research group has reported the
synthesis and the antiproliferative activities of new N-(7-indazolyl) benzenesulfonamide derivatives.

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Some of these compounds exhibited significant cytotoxicity against human (colon and prostate) and
murine (leukemia) cell lines.10 In our ongoing research programme for new polyfunctionalised
indazoles,10-13 we report herein the synthesis of new series of di- and trisubstituted indazole derivatives,
which were obtained by alkylation of 4-nitroindazole followed by reduction of alkyl-nitro-derivatives
with anhydrous SnCl2 in ethanol.
The indazole ring has two nitrogen atoms (N-1, N-2) and presents annular tautomerism with regards to the
position of the NH hydrogen atom. Several studies concerning the alkylation of 1H-indazole 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 In the present work
we examined alkylation of 4-nitroindazole by different alkylating conditions. These reactions gave a
mixture of isomers 2 and 3, with a moderate selectivity in favour of compound 2 (Scheme 1). The use of
t-BuOK /THF instead of KOH/acetone led to the more interesting result, with a smooth selectivity in
favour of the isomer 2. The benzylation of 4-nitroindazole in the presence of t-BuOK /THF give only N-1
isomers.
1b
NO2
1b
NO2
1b
NO2
i) base
ii) RX
+
N R
N
N
N
N
N
H
1b
R
3
a R = CH2CH=CH2
b R = CH2Ph
2
1
c R = CH2CH2Br
Scheme 1. Synthesis of 1-alkyl- and 2-alkyl-4-nitroindazole derivatives
Table 1. Synthesis of 4-nitroindazole derivatives substituted at N-1 and N-2 (2 and 3)
Alkyl halide RX Base(solvent) Ratio 2/3a Yield of 2b Yield of 3b Yield of 2+3
a BrCH2CH=CH2 KOH/acetone
68/32
80/20
62/38
100/0
58/42
60/40
49%
57%
52%
78%
33%
45%
24%
15%
31%
0
25%
29%
73%
72%
83%
78%
58%
74%
t-BuOK /THF
b ClCH2Ph
KOH/acetone
t-BuOK /THF
KOH/acetone
t-BuOK /THF
c BrCH2CH2Br
a Ratio determined by 1H NMR spectroscopy of the reaction mixture.
b Yields of isolated products after flash chromatograph
13
The 1-alkyl and 2-alkyl isomers could be differentiated from their C chemical shifts. The chemical
shifts of CH-3 could differentiate between the two alkyl isomeric classes. Thus, the related signals
appeared at δ 132.8-133.7 ppm for the 1-alkyl isomers 2, whereas the values were δ 124.2-125.5 ppm for

HETEROCYCLES, Vol. 83, No. 4, 2011
893
13
the 2-alkyl derivatives 3. C-NMR spectroscopy is usually a particularly good method to perform this
assignment.
After separation of compounds 2 and 3 by column chromatography, we studied the reduction of the nitro
group of N-alkylindazoles. Thus, we observed that reduction of the compound 3a with SnCl2 in ethanol as
solvent gave two different compounds, that is, the desired amine and the amine substituted with ethoxy
1
group in the 7-position, according to H NMR of crude product. It is noteworthy that significant
degradation of aromatic primary amine was observed. Consequently, we immediately protected this
amine by using 4-methylbenzenesulfonyl chloride in pyridine. This reaction afforded a mixture of
N-(4-indazolyl)-benzenesulfonamide 5a with the corresponding 7-ethoxysubstituted indazole 4a. The
same method was used to obtain compounds 4b and 5b from isomer 3b (Scheme 2). The
7-ethoxyindazoles 4a and 4b were obtained in 53% and 45% yields respectively.
O
O
O
O
S
S
NO2
1b
NH
NH
1) SnCl2, EtOH, 60°C
Me
Me
N
R
N
R
N
R
+
N
N
2) 4-MeC6H4SO2Cl
pyridine
N
3a R = CH2CH=CH2
3b R = CH2Ph
OEt
4a R = CH2CH=CH2 53%
4b R = CH2Ph 45%
5a R = CH2CH=CH2 44%
5b R = CH2Ph 38%
Scheme 2. Reduction of 2-alkyl-4-nitroindazole with SnCl2 in ethanol
The yields of isolated products were determined after flash chromatography. The assignment of the
structure of 7-ethoxy-N-(4-indazolyl)-4-methylbenzenesulfonamides 4a and 4b was unambiguously
1
13
supported by the H and C NMR spectra, in particular by the evaluation of the multiplet pattern of the
C-ring proton signals: two doublets were observed at δ 6.33-6.40 ppm and 6.55-6.56 ppm due to 6-H and
5-H protons of indazole. These results showed that the nitro group of indazole plays an important role for
the orientation of the nucleophilic substitution of ethoxy group in indazole. Due to its
electron-withdrawing effect the nitro group in nitroarene activates in ortho and para for addition of
nucleophilic agents.15–17 Thus, the formation of the compound substituted by an ethoxy group in
7-position could be explained by the presence of the ethoxy anion in the reaction mixture, followed by the
nucleophilic substitution on 2-alkyl-4-nitroindazole.
When we applied the same condition of the reduction as previously described to 6-nitroindazole 7, we
obtained exclusively the corresponding sulfonamide 9 in 75% yield (Scheme 3). No trace of nucleophilic
substitution was observed. This result show the important role played by position of nitro group in
indazole for the preparation of ethoxyindazole derivatives. The N-alkylated indazoles 7 and 8 were
obtained by alkylation of 6-nitroindazole 6 with allyl bromide in the presence of K2CO3 in THF.

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1b
1b
K2CO3/THF
N
N
N
+
N
N
N
O2N
O2N
O2N
Br
H
1b
6
8
49%
7 43%
1) SnCl2, EtOH, 60°C
2) 4-MeC6H4SO2Cl
pyridine
75%
1b
O
O
N
N
S
N
H
Me
9
Scheme 3. Alkylation and reduction of 1-allyl-6-nitroindazole 7 with SnCl2 in ethanol
To generalize our results obtained in the series of 4-nitroindazole to other analogue structure, we
investigated the reduction of 4-nitroindole 10 with SnCl2 in ethanol. In this reaction, only the
corresponding amine 11 was isolated in good yield (Scheme 4). No trace of the aminoethoxyindole was
identified. Compound 10 was prepared according to method described in the literature.18
NH2
NO2
SnCl2, EtOH, 60°C
Me
Me
74%
N
H
N
H
11
10
Scheme 4. Reduction of 4-nitroindole 10 with SnCl2 in ethanol
These results show that the nature of the structure and the position of nitro group are factors important for
the synthesis of the new series of alkoxyheterocycle derivatives.
In summary, we have developed an efficient method for the synthesis of new series of indazoles
substituted at the N-1 and N-2 positions as well as their 7-ethoxyindazole derivatives starting from
alkylation of 4-nitroindazole and reduction of alkyl-nitro-derivatives with anhydrous SnCl2 in ethanol.
This methodology of reduction is a valuable and general method for the preparation of new functionalized
indazoles such as 7-alkoxy-4-aminoprotectedindazoles.
EXPERIMENTAL
1
13
Melting points were determined using a Büchi-Tottoli apparatus and are uncorrected. H and C NMR
spectra were recorded in CDCl3 or DMSO-d6 and solution (unless otherwise specified) with TMS as an

HETEROCYCLES, Vol. 83, No. 4, 2011
895
internal reference using a Bruker AC 300 (1H) or 75MHz (13C) instruments. Chemical shifts are given in δ
parts per million (ppm). Multiplicities of 13C 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
SiO2 (silica gel 60 Merck 0.063–0.200 mm). Thin-layer chromatography (TLC) was carried out on SiO2
(silica gel 60, F 254 Merck 0.063–0.200 mm), and the spots were located with UV light (254 nm).
Commercial reagents were used without further purification unless stated.
4-Nitroindazole (1)19: In a 500 mL round bottomed flask were introduced (5 g, 33 mmol) of 2-
methyl-3-nitroaniline and 200 mL of AcOH. The solution was warmed under stirring until completed
dissolution. Addition drop by drop of a solution of (2.3 g, 37.70 mmol) of NaNO2 in 5 mL of water led to
diazonium salt precipitation. The solution was stirred until this precipitate redisolved and the mixture was
concentrated to the third of its initial volume. Then hot water (250 mL) was added to yield an
orange-yellow product. The mixture was warmed and filtered hot. After cooling the obtained precipitate
was filtered, washed with cold water and dried to yield 1: 85%, mp 198-200 °C. 1H NMR (DMSO-d6): δ
7.54 (t, 1H, H-6, J = 7.9 Hz), 7.87 (d, 1H, H-7, J = 7.5 Hz), 7.94 (d, 1H, H-5, J = 7.9 Hz), 8.46 (s, 1H),
13
13.98 (s, 1H, NH). C NMR (DMSO-d6): δ 110.6 (C-3a), 118.1 (CH-5), 119.3 (CH-7); 125.9 (CH-6),
141.4 (C-4), 143.4 (C-7a).
General procedure for the synthesis of 1-alkyl- and 2-alkyl-4-nitroindazole derivatives
General procedure 1 (using t-BuOK as base). To a solution of 4-nitroindazole 1 (6.13 mmol) in THF
(30 mL) cooled at 0 °C was added potassium t-butoxide (9.2 mmol). After 15 min at 0 °C, RX (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 MgSO4 and the solvent was evaporated in vacuo. The resulting residue was
purified by column chromatography (EtOAc/hexane 3/7).
General procedure 2 (using KOH as base). To a solution of 4-nitroindazole 1 (6.13 mmol) in acetone
(15 mL) cooled at 0 °C was added potassium hydroxide (9.2 mmol). After 15 mn at 0 °C, RX (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 MgSO4 and the solvent was evaporated in vacuo. The resulting residue was
purified by column chromatography (EtOAc/hexane 3/7).
1
1-Allyl-4-nitro-1H-indazole (2a). This compound was obtained as yellow solid, mp 63-65 °C. H NMR
(CDCl3): δ 5.07-5.10 (m, 2H, NCH2), 5.15-5.26 (m, 2H, =CH2), 5.95-6.08 (m, 1H, =CH), 7.44 (t, 1H,
13
J=7.8 Hz), 7.75 (d, 1H, J = 8.4 Hz), 8.04 (d, 1H , J = 7.8 Hz), 8.51 (s, 1H). C NMR (CDCl3): δ 52.2
(NCH2), 116.5 (CH-5), 117.1 (C-3a), 118.2 (CH-7), 118.5 (=CH2), 125.4 (CH-6), 132.0 (=CH), 132.8

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(CH-3), 140.6, 141.0 (C-4, C-7a). Anal. Calcd for C10H9N3O2: C, 59.11; H, 4.46; N, 20.68. Found: C,
59.03; H, 4.52; N, 20.56.
1
2-Allyl-4-nitro-2H-indazole (3a).This compound was obtained as yellow solid, mp 68-70 °C. H NMR
(CDCl3): δ 5.10-5.13 (m, 2H, NCH2), 5.35-5.42 (m, 2H, =CH2), 6.09-6.22 (m, 1H, =CH), 7.37 (t, 1H,
13
J=7.8 Hz), 8.07 (d, 1H, J = 8.4 Hz), 8.15 (d, 1H, J = 7.8 Hz), 8.56 (s, 1H). C NMR (CDCl3): δ 56.7
(NCH2), 115.0 (C-3a), 120.4 (=CH2), 120.6 (CH-5), 124.2 (CH-3), 124.4 (CH-7), 126.0 (CH-6), 131.4
(=CH), 140.6 (C-4), 149.9 (C-7a). Anal. Calcd for C10H9N3O2: C, 59.11; H, 4.46; N, 20.68. Found: C,
58.96; H, 4.50; N, 20.59.
1
1-Benzyl-4-nitro-1H-indazole (2b). This compound was obtained as yellow solid, mp 75-77 °C. H
NMR (CDCl3): δ 5.69 (s, 2H, NCH2), 7.20-7.24 (m, 2H, ArH), 7.28-7.36 (m, 3H, ArH), 7.43 (t, 1H, J =
13
7.8 Hz), 7.72 (d, 1H, J = 7.8 Hz), 8.11 (d, 1H, J = 8.1 Hz), 8.66 (s, 1H). C NMR (CDCl3): δ 53.6
(NCH2), 116.5 (CH-5), 117.4 (C-3a), 118.3 (CH-7), 125.6 (CH-6), 127.2 (2CH), 128.2 (CH), 129.0
(2CH), 133.0 (CH-3), 135.9 (C), 140.7, 141.1 (C-4, C-7a). Anal. Calcd for C14H11N3O2: C, 66.40; H,
4.38; N, 16.59. Found: C, 66.56; H, 4.27; N, 16.52.
1
2-Benzyl-4-nitro-2H-indazole (3b). This compound was obtained as yellow solid, mp 106-108 °C. H
NMR (CDCl3): δ 5.69 (s, 2H, NCH2), 7.35-5.41 (m, 6H, ArH), 8.10 (d, 1H, J = 8.5 Hz), 8.17 (d, 1H, J =
13
7.8 Hz), 8.57 (s, 1H). C NMR (CDCl3): δ 58.2 (NCH2), 115.2 (C-3a), 120.7 (CH-5), 124.3 (CH-7),
124.6 (CH-3), 126.2 (CH-6), 128.2 (2CH), 128.8 (CH), 129.2 (2CH), 134.9 (C), 140.7 (C-4), 150.0
(C-7a). Anal. Calcd for C14H11N3O2: C, 66.40; H, 4.38; N, 16.59. Found: C, 66.62; H, 4.30; N, 16.48.
1-(2-Bromoethyl)-4-nitro-1H-indazole (2c). This compound was obtained as yellow solid, mp 78-80 °C.
1H NMR (CDCl3): δ 3.85 (t, 2H, J = 6.3 Hz, BrCH2), 3.93 (t, 2H, J = 6.3 Hz, NCH2), 7.51 (t, 1H, J = 7.8
Hz), 7.85 (d, 1H, J = 8.4 Hz), 8.10 (d, 1H, J = 7.8 Hz), 8.62 (s, 1H). 13C NMR (CDCl3): δ 29.9 (BrCH2),
50.6 (NCH2), 116.3 (CH-5), 116.9 (C-3a), 118.5 (CH-7), 125.8 (CH-6), 133.7 (CH-3), 140.6, 141.7 (C-4,
C-7a). Anal. Calcd for C9H8BrN3O2: C, 40.02; H, 2.99; N, 15.56. Found: C, 40.24; H, 3.14; N, 15.45.
2-(2-Bromoethyl)-4-nitro-2H-indazole (3c). This compound was obtained as yellow solid, mp
104-110 °C, 1H NMR (CDCl3): δ 3.93 (t, 2H, J = 6.3 Hz, BrCH2), 4.88 (t, 2H, J = 6.3 Hz, NCH2), 7.38 (t,
13
1H, J = 7.5 Hz), 8.04 (d, 1H, J = 8.3 Hz), 8.13 (d, 1H, J = 7.5 Hz), 8.61 (s, 1H). C NMR (CDCl3): δ
29.7 (BrCH2), 55.5 (NCH2), 114.6 (C-3a), 120.3 (CH-5), 125.5 (CH-3), 125.8 (CH-7), 126.1 (CH-6),
141.7 (C-4), 150.2 (C-7a). Anal. Calcd for C9H8BrN3O2: C, 40.02; H, 2.99; N, 15.56. Found: C, 40.26; H,
3.22; N, 15.48.
General method for the synthesis of 7-ethoxy-N-(-2-alkyl-4-indazolyl)-4-methylbenzene
sulfonamides
and
N-(2-alkyl-4-indazolyl)-4-methylbenzenesulfonamides.
A
mixture of
2-alkyl-4-nitroindazole (3a-b) (1.22 mmol) and anhydrous SnCl2 (1.1 g, 6.1 mmol) in 25 mL of absolute
EtOH is heated at 60 °C. After reduction, the starting material has disappeared and the solution is allowed

HETEROCYCLES, Vol. 83, No. 4, 2011
897
to cool down. The pH is made slightly basic (pH 7–8) by addition of 5% aqueous potassium bicarbonate
before being extracted with EtOAc. The organic phase is 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-methylbenzenesulfonyl 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).
N-(2-Allyl-7-ethoxy-2H-indazol-4-yl)-4-methylbenzenesulfonamide (4a). Yield: 53%, colorless solid,
1
mp 143-145 °C. H NMR (DMSO-d6): δ 1.33 (t, 3H, CH3, J = 7.0 Hz), 2.28 (s, 3H, CH3), 4.05 (q, 2H,
CH2O, J = 7.0 Hz), 4.95-4.98 (m, 2H, NCH2), 5.08-5.24 (m, 2H, =CH2), 5.95-6.05 (m, 1H, =CH), 6.40 (d,
1H, H-6, J = 8.1 Hz), 6.55 (d, 1H, H-5, J = 8.1 Hz), 7.24 (d, 2H, ArH, J = 7.8 Hz), 7.53 (d, 2H, ArH, J =
13
7.8 Hz), 8.08 (s, 1H, H-3), 9.86 (s, 1H, NH). C NMR (DMSO-d6): δ 15.1 (CH3), 21.4 (CH3), 55.6
(NCH2), 63.7 (CH2O), 103.8 (CH), 115.5 (CH), 118.9 (=CH2), 120.3 (C), 122.0 (C), 123.4 (CH-3), 127.2
(2CH), 129.8 (2CH), 133.8 ( =CH), 137.4 (C), 142.0 (C), 143.3 (C), 147.3 (C). MS: m/z 372 (M + 1)+.
Anal. Calcd for C19H21N3O3S: C, 61.44; H, 5.70; N, 11.31. Found: C, 61.70; H, 5.54; N, 11.51.
N-(2-Allyl-2H-indazol-4-yl)-4-methylbenzenesulfonamide (5a). Yield: 44% , colorless solid, mp
1
150-152 °C. H NMR (DMSO-d6): δ 2.25 (s, 3H, CH3), 4.96-5.01 (m, 2H, NCH2), 5.13-5.23 (m, 2H,
=CH2), 5.96-6.06 (m, 1H, =CH), 6.77 (d, 1H, J = 7.2 Hz), 7.04 (t, 1H, J = 7.3 Hz), 7.23 (d, 1H, J = 7.2
Hz), 7.55 (d, 2H, ArH, J = 7.4 Hz), 7.65 (d, 2H, ArH, J = 7.4 Hz), 8.37 (s, 1H, H-3), 10.34 (s, 1H, NH).
13C NMR (DMSO-d6): δ 21.3 (CH3), 55.7 (NCH2), 111.0 (CH) 113.6 (CH), 119.1 (=CH2), 120.3 (C),
122.0 (C), 123.2 (CH-3), 126.1 (CH), 127.2 (2CH), 129.8 (2CH), 133.8 (=CH), 137.3 (C), 142.0 (C),
149.4 (C). MS: m/z 328 (M + 1)+. Anal. Calcd. for C17H17N3O2S: C, 62.37; H, 5.23; N, 12.83. Found: C,
62.52; H, 5.08; N, 12.95.
N-(2-Benzyl-7-ethoxy-2H-indazol-4-yl)-4-methylbenzenesulfonamide (4b). Yield: 45%, colorless
solid, mp 156-158 °C. 1H NMR (CDCl3): δ 1.47 (t, 3H, CH3, J = 7.1 Hz), 2.32 (s, 3H, CH3), 4.15 (q, 2H,
CH2O, J = 7.1 Hz), 5.54 (s, 2H, NCH2), 6.33 (d, 1H, H-6, J = 7.9 Hz), 6.56 (d, 1H, H-5, J = 7.9 Hz), 7.10
(d, 2H, ArH, J = 7.7 Hz), 7.23-7.35 (m, 5H, ArH), 7.53 (d, 2H, ArH, J = 7.7 Hz), 7.82 (s, 1H, H-3), 8.96
(s, 1H, NH). 13C NMR (CDCl3): δ 14.6 (CH3), 21.5 (CH3), 57.5 (NCH2), 64.0 (CH2O), 103.3 (CH), 118.4
(CH), 120.3 (C), 121.2 (C), 122.9 (CH-3), 127.4 (2CH), 128.2 (2CH), 128.5 (CH), 128.9 (2CH), 129.4
(2CH), 135.2 (C), 136.0 (C), 142.0 (C), 143.6 (C), 148.2 (C). MS: m/z 422 (M + 1)+. Anal. Calcd for
C23H23N3O3S: C, 65.54; H, 5.50; N, 9.97. Found: C, 65.68; H, 5.42; N, 10.11.
N-(2-Benzyl-2H-indazol-4-yl)-4-methylbenzenesulfonamide (5b). Yield: 38%, colorless solid, mp
180-182 °C, 1H NMR (CDCl3): δ 2.31 (s, 3H, CH3), 5.60 (s, 2H, NCH2), 6.84 (d, 1H, J = 7.8 Hz), 7.13 (d,
2H, ArH, J = 7.8 Hz), 7.28-7.41 (m, 7H, ArH), 7.66 (d, 2H, ArH, J = 7.8 Hz), 7.82 (s, 1H, H-3), 8.85 (s,
13
1H, NH). C NMR (CDCl3): δ 21.5 (CH3), 57.3 (NCH2), 113.0 (CH), 114.1 (CH), 117.3 (C), 124.7

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(CH-3), 126.4 (CH), 127.3 (2CH), 128.4 (2CH), 128.8 (CH), 129.0 (2CH), 129.6 (2CH), 129.7 (C), 134.2
(C), 135.8 (C), 144.0 (C), 147.1 (C). MS: m/z 378 (M + 1)+. Anal. Calcd for C21H19N3O2S: C, 66.82; H,
5.07; N, 11.13. Found: C, 66.69; H, 5.12; N, 10.98.
Preparation of N-alkylated indazoles (7) and (8). To a solution of 6-nitroindazole (6) (6.13 mmol) in
THF (30 mL) cooled at 0 °C was added K2CO3 (9.2 mmol). After 15 mn at 0 °C, allyl bromide (6.13
mmol) was added dropwise. The solution was stirred for 16 h and the resulting mixture was evaporated.
The crude material was dissolved with EtOAc (50 mL), washed with water and brine, dried over MgSO4
and the solvent was evaporated in vacuo. The resulting residue was purified by column chromatography
(EtOAc/hexane 3/7).
1-Allyl-6-nitro-1H-indazole (7). Yield: 43%, yellow solid, mp 56-58 °C. 1H NMR (CDCl3): δ 5.10-5.13
(m, 2H, NCH2), 5.16-5.30 (m, 2H, =CH2), 6.01-6.10 (m, 1H, =CH), 7.84 (d, 1H, J = 9.1 Hz), 8.01 (dd, 1H,
13
J = 9.1 Hz , 1.8 Hz), 8.13 (s, 1H), 8.37 (d, 1H , J = 1.6 Hz). C NMR (CDCl3): δ 52.3 (NCH2), 106.1
(CH-7), 115.5 (CH-5), 118.7 (=CH2), 121.9 (CH-4), 127.3 (C-3a), 131.9, 133.6 (CH-3, =CH), 138.2
(C-7a), 146.5 (C-6). Anal. Calcd for C10H9N3O2: C, 59.11; H, 4.46; N, 20.68. Found: C, 59.23; H, 4.58; N,
20.61.
2-Allyl-6-nitro-1H-indazole (8). Yield: 49%, yellow solid, mp 48-50 °C. 1H NMR (CDCl3): δ 5.10-5.12
(m, 2H, NCH2), 5.34-5.43 (m, 2H, =CH2), 6.13-6.18 (m, 1H, =CH), 7.75 (d, 1H, J = 9.3 Hz), 7.88 (dd, 1H,
13
J = 9.3 Hz , 2.1 Hz), 8.08 (s, 1H), 8.68 (d, 1H , J = 1.8 Hz). C NMR (CDCl3): δ 56.8 (NCH2), 115.5,
115.9 (CH-5, CH-7), 120.7 (=CH2), 121.5 (CH-4), 123.7 (CH-3), 124.4 (C-3a), 131.2 (=CH), 146.6,
146.8 (C-6, C-7a). Anal. Calcd for C10H9N3O2: C, 59.11; H, 4.46; N, 20.68. Found: C, 59.18; H, 4.50; N,
20.57.
Synthesis of N-(1-allyl-1H-indazol-6-yl)-4-methylbenzenesulfonamide (9). This compound was
prepared from 1-Allyl-6-nitro-1H-indazole 7 by using the same procedure applied to (3a-b).
1
Yield: 75%, colorless solid, mp 95-97 °C. H NMR (CDCl3): δ 2.34 (s, 3H, CH3), 4.97-5.00 (m, 2H,
NCH2), 5.06-5.22 (m, 2H, =CH2), 5.91-5.97 (m, 1H, =CH), 6.82 (d, 1H, J = 8.4 Hz), 7.18 (d, 2H, ArH, J
= 7.8 Hz), 7.28 (s, 1H), 7.55 (d, 1H, J = 8.4 Hz), 7.64 (s, 1H, NH); 7.70 (d, 2H, ArH, J = 7.8 Hz), 8.00 (s,
1H, H-3). 13C NMR (CDCl3): δ 21.5 (CH3), 51.7 (NCH2), 100.7 (CH), 116.3 (CH), 118.2 (=CH2), 121.3
(C), 122.3 (CH), 127.4 (2CH), 129.7 (2CH), 132.1 (CH), 132.7 (CH), 135.8 (C), 136.0 (C), 139.7 (C),
144.1 (C); MS: m/z 328 (M + 1)+ ; Anal. Calcd for C17H17N3O2S: C, 62.37; H, 5.23; N, 12.83. Found: C,
62.48; H, 5.12; N, 13.01.
Synthesis of 4-Amino-2-methyl-1H-indole (11). A mixture of 2-methyl-4-nitroindole (10) (1.22 mmol)
and anhydrous SnCl2 (1.1 g, 6.1 mmol) in 25 mL of absolute EtOH is heated at 60 °C. After reduction,
the starting material has disappeared and the solution is allowed to cool down. The pH is made slightly
basic (pH 7–8) by addition of 5% aqueous potassium bicarbonate before being extracted with EtOAc. The

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organic phase is washed with brine and dried over magnesium sulfate. The solvent was removed under
vacuum and the residue was purified by flash chromatography (eluted with EtOAc/hexane 3/7). Yield:
74%, brown solid, mp 192-194 °C. 1H NMR (DMSO-d6): δ 2.35 (s, 3H, CH3), 4.01 (s, 2H, NH2), 6.21 (s,
1H, H-3), 6.58 (d, 1H, J = 7.4 Hz), 6.88 (t, 1H, J = 7.4 Hz), 7.70 (d, 1H, J = 7.4 Hz), 11.00 (s, 1H, NH).
13C NMR (DMSO-d6): δ 13.8 (CH3), 96.9 (CH), 106.7 (CH), 108.8 (CH), 116.1 (C), 121.0 (CH), 129.6
(C), 135.4 (C), 137.5 (C).
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