New and efficient synthesis of bi- and trisubstituted indazoles

Article abstract of DOI:10.1016/j.tet.2005.06.038

In this paper, the synthesis of bi- and trisubstituted indazoles was described. 4-Alkoxy-7-aminoprotected-indazole or 7-aminoprotected-indazole derivatives were prepared selectively using SnCl₂ in alcohol or SnCl₂ in ethyl acetate, r

Full text of DOI:10.1016/j.tet.2005.06.038

Tetrahedron 61 (2005) 8218–8225
New and efficient synthesis of bi- and trisubstituted indazoles
a,b
c
c
Latifa Bouissane,a,b Saıd El Kazzouli, Jean-Michel Leger, Christian Jarry,
´
El Mostapha Rakib, Mostafa Khouili and Gerald Guillaumet
¨
b
b
a,
*
´
a
´ ´ ´
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Universite d’Orleans, BP 6759, 45067 Orleans Cedex 2, France
b
´ ´
Faculte des Sciences et Techniques de Beni-Mellal, Universite Cadi-Ayyad, BP 523, 23000 Beni-Mellal, Morocco
´ ´
EA 2962, Pharmacochimie, Universite Victor Segalen Bordeaux II, 146, rue Leo Saignat, 33076 Bordeaux Cedex, France
c
Received 7 March 2005; revised 30 May 2005; accepted 9 June 2005
Available online 11 July 2005
Abstract—In this paper, the synthesis of bi- and trisubstituted indazoles was described. 4-Alkoxy-7-aminoprotected-indazole or 7-amino-
protected-indazole derivatives were prepared selectively using SnCl2 in alcohol or SnCl2 in ethyl acetate, respectively. The effects of the
halogen atom in position 3 and of the N-alkylation in N-1 position of 7-nitroindazoles were investigated.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Recently, considerable importance has been attached to
synthetic methods leading to indazole derivatives because
of their biological activities.1–9 Various indazole deriva-
tives, such as 3-substituted indazoles obtained via different
cross-coupling reactions,10–15 are common components of
drugs and are generally found to be of pharmaceutical
interest in a variety of therapeutic areas.16
One of the simplest ways to prepare 7-aminoindazole
derivatives consists of the reduction of 7-nitroindazole
derivatives with SnCl2 in alcoholic solution. However, we
observed that reduction of the compounds 1(a–d) with
SnCl2 in ethanol as solvent gave two different compounds,
that is, the desired amine and the amine substituted with
1
ethoxy group in the 4-position, according to H NMR of
crude product. It is noteworthy that significant degrada-
tion of aromatic primary amine was observed. Conse-
quently, we immediately protected this amine by using
4-methoxybenzenesulfonyl chloride in pyridine. This
reaction afforded a mixture of N-(3-substituted-7-indazolyl)-
benzenesulfonamides 3(a–d) with the corresponding
4-ethoxysubstituted derivatives 2(a–d) (Scheme 2).
One of our research targets is to develop simple and
inexpensive synthetic procedures for heterocyclic com-
pounds that are of interest for medical purpose. Here, we
present the simple and efficient synthetic procedures
developed to obtain 4- and 7-bisubstituted indazole
derivatives. During the synthesis of sulfonamides from
7-nitroindazoles, we noticed that the conversion of the nitro
group into a corresponding amino group with SnCl2 in the
presence of ethanol gave a product functionalized in the
4-position. Afterward we generalized this sequence by using
other alcohols as solvent followed by a coupling reaction of
amines achieved with various protecting groups (Scheme 1),
in order to prepare new bi-and trisubstituted indazoles.
Scheme 1.
Keywords: Indazoles; Cross-coupling reaction; Alcohols; Nucleophilic
addition.
*
Corresponding author. Tel.: C33 2 38 41 70 73; fax: C33 2 38 41 70 78;
e-mail: gerald.guillaumet@univ-orleans.fr
Scheme 2.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.038

L. Bouissane et al. / Tetrahedron 61 (2005) 8218–8225
8219
Table 2. Effect of atom nature in 3-position on the synthesis of N-(4-
ethoxy-1H-1-methyl-7-indazolyl)benzenesulfonamides 5 and C(4) nonsub-
stituted indazole 6
The structure of the N-(4-ethoxy-3-iodo-7-indazolyl)-4-
methoxybenzenesulfonamide 2d, was unambiguously
established by X-ray crystallography (Fig. 1). Indeed, the
ethoxy group is bound to the C-4 of the aromatic ring.
Moreover, a chelate was found between N(1) bound to H(1)
Y
Time of
reduction
Ratio 5/6a
Yield of 5b
67/33c
100/0
100/0
100/0
—
˚
and O(16) with N(1)–O(16)Z2.994(5) A and the angle
H
Cl
Br
I
4 h
2 h
2 h 15 min
1 h 50 min
76%
78%
80%
N(1)–H(1)/O(16)Z114.88, inducing a bent shape for 2.
On the other hand, bond lengths and angles do not show
surprising features.
1
a Ratio determined by H NMR spectroscopy of the reaction mixture.
b Compounds 5(b–d) were isolated by flash chromatography.
c Compounds 5a and 6a were not separable by flash chromatography,
global yield: 76%.
4a gave a mixture of the compound 5a with the C(4)-
nonsubstituted indazole (6a) (Scheme 3). In this last case,
by comparing the 2/3 and 5/6 ratios, it is clear that SNH is
improved by N-alkylation of the N-1 position (see Tables 1
and 2).
Figure 1. X-ray crystal structure of 2d.
As it was noticed in Table 1, the nature of the substituent in
the 3-position on the indazolyl ring in 1 led to different
ratios of N-(4-ethoxy-1H-7-indazolyl)benzenesulfonamides
2(a–d) and of corresponding 4-unsubstituted derivatives
3(a–d). From the iodine-substituted 1d, only the N-(4-
ethoxy-1H-7-indazolyl)benzenesulfonamide 2d was iso-
lated, whereas 1a, 1b and 1c afforded a mixture of
compounds 2(a–c) and 3(a–c) (Table 1).
In the case of palladium-catalyzed reactions achieved with
indazole, it was demonstrated the necessity of a protecting
group in the N-1 position.12,13 In order to optimize this
sequence and considering that the presence of the NH group
in 3-substituted-7-nitroindazoles 1(a–d) could be the limit-
ing factor, we decided to investigate the reactivity of the N-
methyl-3-substituted-7-nitroindazoles 4(a–d). Hence, the
preliminary protection of compounds 1(a–d) by iodo-
methane gave the corresponding 1-methyl-3-substituted-7-
nitroindazoles 4(a–d).17,18 Then, compounds 4(a–d) were
reduced as previously described, and subsequent coupling
was achieved with 4-methoxybenzenesulfonyl chloride. We
noticed that 4(b-d) afforded only the N-(4-ethoxy-3-
halogeno-1-methyl-7-indazolyl)benzene-sulfonamides
5(b–d) functionalized in position 4 (Table 2). Conversely,
Scheme 3.
Finally, the reduction-protection of 7-nitro-indazole 4a and
3-bromo-1-methyl-7-nitro-1H-indazole (4c) was performed
with SnCl2 by using ethyl acetate as solvent. As expected,
we obtained exclusively the corresponding amines 6a and
6c in 92 and 82% yields, respectively. No trace of SNH
substitution was observed (Scheme 4).
These results could be related to the important role played
by nitro groups of 7-nitro-indazole with regards to the
introduction of the substituent in 4-position. Due to its
Table 1. Influence of the atom nature in the 3-position in 1(a–d) on the synthesis of N-(4-ethoxy-1H-7-indazolyl)benzenesulfonamides 2(a–d) and
4-unsubstituted derivatives 3(a–d)
Y
Time of reduction (h)
Ratio 2/3a
Yield of 2b
Yield of 3b
Yield of 2C3c (%)
c
c
H
Cl
Br
I
4
5
9
2
52/48
72
65
78
76
44/56
63/37
100/0
28%
56%
76%
37%
22%
0%
a Ratio determined by 1H NMR spectroscopy of the reaction mixture.
b Yields of isolated products after flash chromatography.
c Compounds 2a and 3a were not separable by flash chromatography.

8220
L. Bouissane et al. / Tetrahedron 61 (2005) 8218–8225
Scheme 4.
Scheme 6.
electron-withdrawing effect the nitro group in nitroarene
activates in ortho and para for addition of nucleophilic
agents.19–23 Thus, the formation of the compound substituted
by an ethoxy group in 4-position could be explained by the
presence of the C2H5OK anion in the reaction mixture, fol-
lowed by the SNH on 7-nitroindazole. To study this hypothesis
we performed reactions between compounds 1a or 4a and
C2H5OK in ethanol at 60 8C. Unfortunately, no reaction was
observed, and we isolated only the starting substances 1a or 4a
in 92 and 95%, respectively. In addition to the mechanism
proposed, we can supposed that the introduction of ethoxy
group proceeds on the intermediate stage in reduction of NO2
namely protonated hydroxylamine compound. Introduction
of nucleophilic substituents via reactions of protonated
arylhydroxylamines is a well known process.24
In order to use other secondary amine protecting groups, we
also studied the coupling reaction with pivaloyl chloride or
benzyl chloroformate achieved in pyridine, with 4d as an
example. The desired products 9(a–b) were obtained in
good yields (Scheme 7).
Scheme 7.
The reduction of the 3-iodo-7-nitroindazole 4d was
achieved with SnCl2 in different alcohols, in order to
introduce various alkoxy groups in the 4-position. In all
cases, only compounds 7(a–e) were obtained in good yields,
illustrating the ability to introduce various alkoxy groups
(Scheme 5). The results are collected in Table 3.
For deep investigations, we used the N-(4-ethoxy-3-iodo-1-
methyl-1H-indazol-7-yl)-2,2-dimethyl-propionamide 9a for
Suzuki cross-coupling reaction with 3-thiopheneboronic
acid in presence of catalytic amount of tetrakis(triphenyl-
phosphine)palladium(0). As expected, the sequence gave
the N-(4-ethoxy-1-methyl-3-thiophen-3-yl-1H-indazol-7-
yl)-2,2-dimethylpropionamide 10 in a very good yield
(Scheme 8).
Scheme 5.
Scheme 8.
Table 3. Synthesis of N-(4-alkoxy-3-iodo-1-methyl-7-indazolyl)benzene-
sulfonamides 7(a–e)
In conclusion, we present simple and efficient synthetic
procedures of reduction-protection reaction developed to
obtain bi- and tri-bisubstituted indazole derivatives. We
determined experimental conditions to generate selectively
4-alkoxy-7-aminoprotected-indazoles by using various
alcohols as solvent and different reactants in presence of
SnCl2. A selective way to 3-, 4-, 7-trisubstituted indazoles
was developed through N-alkylation of N-1 position and by
substitution of hydrogen in the 3-position by various
halogens.
R
Time of reduction
Yield (%)a
CH3
3 h
1 h 30 min
1 h
1 h
45 min
67
77
79
75
78
CH3(CH2)2
(CH3)2CH
CH3(CH2)3
(CH3)3SiCH2CH2
a Yields of isolated products after flash chromatography.
Moreover, it is noteworthy that the method developed here,
permits, after simple transformation, to obtain other types of
functionalization, which presents a potential utility for
further developments in medicinal chemistry. For example,
after a simple treatment in refluxing TFA, the ether function
of compound 7e was transformed into the corresponding
phenol group (product 8) in good yield (Scheme 6).
The reduction-protection conducted with ethyl acetate as
solvent allowed us to generate exclusively 7-aminoprotected-
indazoles. No trace of SNH substitution was observed.
Finally, potentiality of the functionalization ability in the

L. Bouissane et al. / Tetrahedron 61 (2005) 8218–8225
8221
3-position of 3-iodoindazolylbenzenamide by a Suzuki
cross-coupling reaction with various aromatic derivatives
was established. This appears to be a general method to
prepare new building blocks of interest in medicinal
chemistry.
(1 g, 6.13 mmol) was dissolved in 25 mL of MeOH and 2 N
aqueous sodium hydroxide (20 mL), and then sodium
hypochlorite (6 mL, 98.2 mmol) was added to the solution.
The mixture was refluxed for 1 h. After cooling, the solution
acidified with acetic acid. The solid was filtered, washed
with water and dried in vacuo to give a yellow solid (98%
yield): mp 167–168 8C (lit.23 mp 166–168 8C). IR (KBr,
cmK1): 3210 (NH), 1610 (CN), 1520, 1310 (NO2). 1H NMR
(DMSO-d6) d 7.45 (t, JZ7.8 Hz, 1H), 8.20 (d, JZ7.8 Hz,
1H), 8.44 (d, JZ7.8 Hz, 1H), 14.13 (s, 1H, NH). 13C NMR
(DMSO-d6) d 121.3, 125.1, 127.8 (3CH), 123.4, 132.5,
133.2, 134.7 (4C). MS m/zZ198 (35Cl) [MC1]C, 200
(37Cl) [MC3]C.
3. Experimental
3.1. General
Melting points were determined with Bu¨chi SMP-20
1
melting point apparatus and were uncorrected. H NMR
and 13C NMR were recorded on a Bruker Avance DPX250
spectrometer (250.19 MHz 1H, 62.89 MHz 13C) using
tetramethylsilane as the internal standard, multiplicities
were determined by the DEPT 135 sequence. Chemical
shifts were reported in parts per million (ppm, d units).
Coupling constants were reported in units of hertz (Hz).
Splitting patterns were designated as s, singlet; d, doublet, t,
triplet. IR spectra were obtained on Perkin-Elmer Paragon
1000 PC FT-IR. Infrared spectra were recorded using NaCl
film or KBr pellets. Low-resolution mass spectra (MS) were
recorded on a Perkin-Elmer SCIEX API 3000 spectrometer.
All commercial solvents were used without further puri-
fication. The following solvents and reagents have been
abbreviated: dimethylformamide (DMF), dimethyl sulf-
oxide (DMSO), ethyl acetate (EtOAc), methanol (MeOH),
trifluoroacetic acid (TFA), ethylene glycol dimethyl ether
(DME) and petroleum ether (EP). Thin layer chromato-
graphy (TLC) was carried out on Merck silica gel 60F254
precoated plates. Visualization was made with ultraviolet
light.
3.2.3. 3-Bromo-7-nitro-1H-indazole (1c). To a solution
of 7-nitroindazole (1 g, 6.13 mmol), (1.2 g, 6.74 mmol) of
N-bromosuccinimide in acetonitrile was heated at reflux for
30 min. The solvent was removed in vacuo and the residue
was taken up in 50 mL of ethyl acetate, washed with 2!
100 ml of water, 100 mL of 10% sodium thiosulfate, brine
and then dried. The solvent was removed in vacuo and the
residue was purified by flash chromatography on silica gel
eluting with EtOAc/hexane to provide 1.3 g (90%) of 3 as a
yellow solid: mp 175–176 8C (lit.18 mp 176–178 8C). IR
(KBr, cmK1): 3180 (NH), 1620 (CN), 1500, 1310 (NO2). 1H
NMR (DMSO-d6) d 7.46 (t, JZ7.9 Hz, 1H); 8.13 (d, JZ
7.9 Hz, 1H); 8.45 (d, JZ7.9 Hz, 1H), 14.25 (s, 1H, NH). 13C
NMR (DMSO-d6) d 121.3, 124.9, 128.3, (3CH), 123.1,
126.1, 133.3, 133.1 (4C). MS m/zZ242 (79Br) [MC1]C,
244 (81Br) [MC3]C.
3.2.4. 3-Iodo-7-nitro-1H-indazole (1d). Iodine (3.1 g,
12.26 mmol) and potassium hydroxide pellets (1.28 g,
23 mmol) were successively added into a DMF solution
(60 mL) of 7-nitroindazole (1 g, 6.13 mmol) at room
temperature under stirring. After 1 h, the reaction mixture
was poured into 10% aqueous NaHSO3 (200 mL) and
extracted with Et2O (2!150 mL). The combined organic
layers were washed with water and brine, dried over MgSO4
and the solvent evaporated to give a light yellow solid (95%
yield): mp 188–189 8C. IR (KBr, cmK1): 3110 (NH), 1600
(CN), 1520, 1300 (NO2). 1H NMR (DMSO-d6) d 7.44
(t, JZ7.8 Hz, 1H), 8.00 (d, JZ7.8 Hz, 1H), 8.46 (d, JZ
7.8 Hz, 1H), 14.32 (s, 1H, NH). 13C NMR (DMSO-d6) d
120.9, 124.6, 130.8 (3CH), 96.8, 130.8, 132.1, 132.6 (4C).
MS m/zZ290 [MC1]C. Anal. Calcd for C7H4IN3O2; C,
29.09; H, 1.39; I, 43.91; N, 14.54. Found: C, 29.16; H, 1.53;
I, 44.08; N, 14.46.
3.2. Crystal structure analysis of 2d
The crystal structure of compound 2d has been determined
by single-crystal X-ray diffraction techniques and refined by
full-matrix least-squares procedures, to give a final R value
of 0.0479. The crystals are triclinic, space group P-1, with
˚
˚
˚
aZ7.924(1) A, bZ9.130(2) A, cZ12.3056(1) A, aZ
90.23(2)8, bZ92.89(1)8, gZ96.71(2)8, and ZZ2. A crystal
0.25!0.10!0.05 mm was chosen. The data were collected
on a CAD4 Enraf-Nonius diffractometer with graphite
monochromatized Cu Ka radiation. Full crystallographic
results have been deposited at the Cambridge Crystallo-
graphic Data Centre (CCDC), UK, as Supplementary
Materials.25a The position of non-H atoms were determined
by the program SHELXS25b and the position of the H atoms
were deduced from coordinates of the non-H atoms and
confirmed by Fourier synthesis. H atoms were included for
structure factor calculations but not refined.
3.3. General method for alkylation of 7-nitroindazole
derivatives
3.2.1. 7-Nitro-1H-indazole (1a). This compound was
prepared according to method described in the lit.26 (65%
yield): mp 185–186 8C (lit.26 mp 186 8C). IR (KBr, cmK1):
3180 (NH), 1620 (CN), 1500, 1290 (NO2). 1H NMR
(DMSO-d6) d 7.32 (t, JZ7.8 Hz, 1H), 8.32 (d, JZ7.8 Hz,
1H), 8.35 (d, JZ7.8 Hz, 1H), 8.41 (s, 1H), 13.94 (s, 1H,
NH). 13C NMR (DMSO-d6) d 120.2, 123.5, 129.9, 135.6
(4CH), 127.1, 131.9, 132.1 (3C). MS m/zZ164 [MC1]C.
To a solution of 7-nitroindazole derivatives (6.13 mmol) in
acetone (15 mL) cooled at 0 8C was added potassium
hydroxide (9.2 mmol). After 15 mn at 0 8C, iodomethane
(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 removed in vacuo to give the
corresponding compounds. Spectral data for representative
compounds are as follows:
3.2.2. 3-Chloro-7-nitro-1H-indazole (1b). 7-Nitroindazole

8222
L. Bouissane et al. / Tetrahedron 61 (2005) 8218–8225
3.3.1. 1-Methyl-7-nitro-1H-indazole (4a). Chromato-
graphy using EtOAc/hexane give a yellow solid (93%
yield): mp 99–100 8C (lit.26 mp 98 8C). IR (KBr, cmK1):
1620 (CN), 1510, 1290 (NO2). 1H NMR (DMSO-d6) d 4.16
(s, 3H, CH3), 7.40 (t, JZ7.7 Hz, 1H), 7.90 (d, JZ7.7 Hz,
1H), 8.29 (d, JZ7.7 Hz, 1H), 8.32 (s, 1H). 13C NMR
(DMSO-d6) d 40.3 (NCH3), 120.1, 124.5, 128.6, 134.3
(4CH), 125.4, 128.4, 130.4 (3C). MS m/zZ178 [MC1]C.
(q, 2H, JZ6.9 Hz, CH2O), 6.38 (d, JZ8.1 Hz, 1H), 6.76
(d, JZ8.1 Hz, 1H), 7.00 (d, JZ8.9 Hz, 2H), 7.62 (d, JZ
8.9 Hz, 2H), 8.52 (s, 1H, NH), 12.08 (s, 1H, NH). 13C NMR
(acetone-d6) d 14.8 (CH3), 56.0 (OCH3), 64.7 (CH2O),
101.7, 114.8, 126.5, 130.3 (4CH), 113.1, 114.3, 131.8,
133.4, 141.2, 152.6, 163.9 (7C). MS m/zZ382 (35Cl)
[MC1]C, 384 (37Cl) [MC3]C. Anal. Calcd for C16H16-
ClN3O4S; C, 50.33; H, 4.22; Cl, 9.29; N, 11.00, S, 8.40.
Found: C, 50.30; H, 4.16; Cl, 9.45; N, 11.17, S, 8.49.
3.3.2. 3-Chloro-1-methyl-7-nitro-1H-indazole (4b). This
compound was similarly prepared from 3-chloro-7-nitro-
indazole in 96% yield as a yellow solid: mp 150–151 8C
(lit.18 mp 148–150 8C). IR (KBr, cmK1): 1615 (CN), 1490,
1300 (NO2). 1H NMR (DMSO-d6) d 4.11 (s, 3H, CH3), 7.42
(t, JZ7.8 Hz, 1H), 8.11 (d, JZ7.8 Hz, 1H), 8.28 (d, JZ
7.8 Hz, 1H). 13C NMR (DMSO-d6) d 40.9 (NCH3), 121.2,
126.1, 126.5 (3CH), 124.6, 132.0, 132.8, 135.1 (4C).
MS m/zZ212 (35Cl) [MC1]C, 214 (37Cl) [MC3]C.
3.4.2. N-(3-Bromo-4-ethoxy-1H-7-indazolyl)-4-methoxy-
benzenesulfonamide (2c). Violet solid, yield 56%: mp
114–115 8C. IR (KBr, cmK1): 3342, 3142 (NH), 1596 (CN),
1342, 1160 (SO2), 1258, 1018 (ArOCH). 1H NMR (acetone-
d6) d 1.44 (t, JZ7.2 Hz, 3H, CH3), 3.85 (s, 3H, OCH3), 4.12
(q, JZ7.2 Hz, 2H, CH2O), 6.38 (d, JZ8.1 Hz, 1H), 6.76
(d, JZ8.1 Hz, 1H), 6.99 (d, JZ9.1 Hz, 2H), 7.61 (d, JZ
9.1 Hz, 2H), 8.53 (s, 1H, NH), 12.25 (s, 1H, NH). 13C NMR
(acetone-d6) d 14.8 (CH3), 56.0 (OCH3), 64.7 (CH2O),
101.8, 114.8, 126.4, 130.3 (4CH), 109.7, 114.2, 131.8, 152.5,
153.0, 154.8, 164.0 (7C). MS m/zZ426 (79Br) [MC1]C, 428
(81Br) [MC3]C. Anal. Calcd for C16H16BrN3O4S; C, 45.08;
H, 3.78; Br, 18.74; N, 9.86, S, 7.52. Found: C, 45.20; H, 3.70;
Br, 18.60; N, 10.09, S, 7.66.
3.3.3. 3-Bromo-1-methyl-7-nitro-1H-indazole (4c). This
compound was similarly prepared from 3-bromo-7-nitro-
indazole in 92% yield as a yellow solid: mp 158–159 8C
(lit.18 mp 160–162 8C). IR (KBr, cmK1): 1610 (CN), 1520,
1310 (NO2). 1H NMR (DMSO-d6) d 4.22 (s, 3H, CH3), 7.45
(t, JZ7.8 Hz, 1H), 8.02 (d, JZ7.8 Hz, 1H), 8.27 (d, JZ
7.8 Hz, 1H). 13C NMR (DMSO-d6) d 41.4 (NCH3), 121.8,
126.6, 126.7 (3CH), 122.0, 127.8, 128.8, 130.1 (4C).
MS m/zZ256 (79Br) [MC1]C, 258 (81Br) [MC3]C.
3.4.3. N-(3-Chloro-1H-7-indazolyl)-4-methoxybenzene-
sulfonamide (3b). Colorless solid, yield 37%: mp 201–
202 8C. IR (KBr, cmK1): 3338, 3242 (NH), 1596 (CN),
1337, 1170 (SO2), 1254, 1017 (ArOCH). 1H NMR (DMSO-
d6) d 3.78 (s, 3H, OCH3), 6.95 (d, JZ7.5 Hz, 1H), 7.01 (dd,
JZ7.5, 7.8 Hz, 1H), 7.07 (d, JZ8.7 Hz, 2H), 7.24 (d, JZ
7.8 Hz, 1H), 7.67 (d, JZ8.7 Hz, 2H), 10.02 (s, 1H, NH),
13.00 (s, 1H, NH). 13C NMR (DMSO-d6) d 55.6 (OCH3),
114.3, 115.7, 120.0, 121.8, 129.2 (5CH), 120.1, 121.5, 130.5,
132.5, 136.2, 162.6 (6C). MS m/zZ338 (35Cl) [MC1]C,
340 (37Cl) [MC3]C. Anal. Calcd for C14H12ClN3O3S; C,
49.78; H, 3.58; Cl, 10.50; N, 12.44; S, 9.49. Found: C,
49.86; H, 3.44; Cl, 10.75; N, 12.40; S, 9.39.
3.3.4. 3-Iodo-1-methyl-7-nitro-1H-indazole (4d). This
compound was similarly prepared from 3-iodo-7-nitro-
indazole in 97% as a yellow solid: mp 171–172 8C. IR (KBr,
1
cmK1): 1610 (CN), 1530, 1300 (NO2). H NMR (DMSO-
d6) d 4.16 (s, 3H, CH3), 7.40 (t, JZ7.7 Hz, 1H), 7.9 (d, JZ
7.7 Hz, 1H), 8.29 (d, JZ7.7 Hz, 1H). 13C NMR (DMSO-d6)
d 40.8 (NCH3), 120.8, 125.7, 128.6 (3CH), 95.1, 131.4,
132.1, 134.7 (4C). MS m/zZ304 [MC1]C. Anal. Calcd for
C8H6IN3O2; C, 31.71; H, 2.00; I, 41.87; N, 13.87. Found: C,
31.80; H, 2.13; I, 41.77; N, 13.72.
3.4.4. N-(3-Bromo-1H-7-indazolyl)-4-methoxybenzene-
sulfonamide (3c). Colorless solid, yield 22%: mp 193–
194 8C. IR (KBr, cmK1): 3317, 3228 (NH), 1596 (CN),
1340, 1146 (SO2), 1252, 1002 (ArOCH). 1H NMR (acetone-
d6) d 3.83 (s, 3H, OCH3), 7.01 (d, JZ9.1 Hz, 2H), 7.10
(d, JZ7.2 Hz, 1H), 7.43 (dd, JZ7.2, 8.8 Hz, 1H), 7.53 (d,
JZ8.8 Hz, 1H), 7.66 (d, JZ9.1 Hz, 2H), 8.90 (s, 1H, NH),
12.33 (s, 1H, NH). 13C NMR (acetone-d6) d 56.0 (OCH3),
115.0, 118.1, 122.7, 122.8, 130.3 (5CH), 114.4, 122.2, 125.4,
126.7, 131.6, 164.1 (6C). MS m/zZ382 (79Br) [MC1]C,
384 (81Br) [MC3]C. Anal. Calcd for C14H12BrN3O3S; C,
43.99; H, 3.16; Br, 20.90; N, 10.99; S, 8.39. Found: C,
43.90; H, 3.25; Br, 20.85; N, 11.18; S, 8.21.
3.4. Synthesis of compounds 2(a–d) and 3(a–d)
General method. A mixture of 3-halogeno-7-nitroindazole
1(a–d) (0.66 mmol) and anhydrous SnCl2 (0.62 g,
3.3 mmol) in 25 mL of absolute ethanol is heated at 60 8C.
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 ethyl
acetate. 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-methoxybenzenesulfonyl
chloride (0.15 g, 0.72 mmol) at room temperature over-
night. After the reaction mixture was concentrated in vacuo,
the resulting residue was purified by flash chromatography
(eluted with EtOAc/EP).
3.4.5. N-(4-Ethoxy-3-iodo-1H-7-indazolyl)-4-methoxy-
benzenesulfonamide (2d). Violet solid, yield 76%: mp
171–172 8C. IR (KBr, cmK1): 3304, 3260 (NH), 1600 (CN),
1338, 1156 (SO2), 1270, 1024 (ArOCH). 1H NMR (acetone-
d6) d 1.38 (t, JZ6.9 Hz, 3H, CH3), 3.79 (s, 3H, OCH3), 4.05
(q, JZ6.9 Hz, 2H, OCH2), 6.33 (d, JZ8.4 Hz, 1H), 6.58 (d,
JZ8.4 Hz, 1H), 7.03 (d, JZ8.7 Hz, 2H), 7.60 (d, JZ
8.7 Hz, 2H), 9.56 (s, 1H, NH), 13.20 (s, 1H, NH). 13C NMR
(acetone-d6) d 14.3 (CH3), 55.6 (OCH3), 63.5 (CH2O),
100.8, 114.1, 123.8, 129.1 (4CH), 88.2, 112.9, 116.9, 130.8,
3.4.1. N-(3-Chloro-4-ethoxy-1H-7-indazolyl)-4-methoxy-
benzenesulfonamide (2b). Rose solid, yield 28%: mp 104–
105 8C. IR (KBr, cmK1): 3342, 3229 (NH), 1596 (CN),
1341, 1160 (SO2), 1244, 1025 (ArOCH). 1H NMR (acetone-
d6) d 1.43 (t, JZ6.9 Hz, 3H, CH3), 3.84 (s, 3H, OCH3), 4.12

L. Bouissane et al. / Tetrahedron 61 (2005) 8218–8225
8223
138.9, 150.4, 162.3 (7C). MS m/zZ474 [MC1]C. Anal.
Calcd for C16H16IN3O4S; C, 40.60; H, 3.41; I, 26.81; N,
8.88; S, 6.77. Found C, 40.42; H, 3.66; I, 26.76; N, 8.94; S,
6.59.
acetate is heated at 60 8C. 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 ethyl acetate. 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-methoxybenzenesulfonyl chloride (0.15 g, 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/EP).
3.5. Synthesis of 5(a–d) and 6a
These compounds were prepared from 3-halogeno-1-
methyl-7-nitroindazole 4(a–d) by using the same procedure
applied to 1(a–d).
3.5.1. N-(3-Chloro-4-ethoxy-1-methyl-1H-7-indazolyl)-
4-methoxybenzenesulfonamide (5b). Colorless solid,
yield 76%: mp 168–169 8C. IR (KBr, cmK1): 3261 (NH),
3.6.1. 4-Methoxy-N-(1-methyl-1H-7-indazolyl)-benzene-
sulfonamide (6a). Colorless solid, yield 92%: mp 163–
164 8C. IR (KBr, cmK1): 3274 (NH), 1598 (CN), 1304,
1
1590 (CN), 1340, 1154 (SO2), 1260, 1054 (ArOCH). H
NMR (acetone-d6) d 1.39 (t, JZ6.9 Hz, 3H, CH3), 3.87
(s, 3H, OCH3), 4.08 (q, JZ6.9 Hz, 2H, CH2O), 4.20 (s, 3H,
NCH3), 6.28 (d, JZ8.1 Hz, 1H), 6.43 (d, JZ8.1 Hz, 1H),
7.04 (d, JZ9.1 Hz, 2H), 7.59 (d, JZ9.1 Hz, 2H), 8.39
(s, 1H, NH). 13C NMR (acetone-d6) d 14.7 (CH3), 39.2
(NCH3), 56.1 (OCH3), 64.8 (CH2O), 101.4, 114.9, 130.5,
130.6 (4CH), 113.8, 114.3, 126.7, 132.2, 141.1, 153.6, 164.1
(7C). MS m/zZ396 (35Cl) [MC1]C, 398 (37Cl) [MC3]C.
Anal. Calcd for C17H18ClN3O4S; C, 51.58; H, 4.58; Cl,
8.96; N, 10.61; S, 8.10. Found: C, 51.66; H, 4.48; Cl, 9.11;
N, 10.51; S, 8.23.
1
1160 (SO2), 1258, 1023 (ArOCH). H NMR (DMSO-d6) d
3.48 (s, 3H, OCH3), 4.23 (s, 3H, NCH3), 6.43 (d, JZ7.5 Hz,
1H), 6.90 (dd, JZ7.5, 7.9 Hz, 1H), 7.10 (d, JZ8.5 Hz, 2H),
7.59 (d, JZ8.5 Hz, 2H), 7.65 (d, JZ7.9 Hz, 1H), 8.06 (s,
1H), 9.83 (s, 1H, NH). 13C NMR (DMSO-d6) d 38.7,
(NCH3) 55.7 (OCH3), 114.0, 114.3, 120.2, 120.6, 123.1,
125.4, 127.6, 129.6, 133.7, 137.8, 162.8. MS m/zZ318
[MC1]C. Anal. Calcd for C15H15N3O3S; C, 56.77; H, 4.76;
N, 13.24; S, 10.10. Found: C, 56.58; H, 4.93; N, 13.36; S,
9.96.
3.6.2. N-(3-Bromo-1-methyl-1H-7-indazolyl)-4-methoxy-
benzenesulfonamide (6c). Colorless solid, yield 82%: mp
184–185 8C. IR (KBr, cmK1): 3440, 3232 (NH), 1644 (CN),
1318, 1154 (SO2), 1278, 1076 (ArOCH). 1H NMR (acetone-
d6) d 3.90 (s, 3H, OCH3), 4.33 (3H, NCH3), 6.66 (dd, JZ
1.6, 7.2 Hz, 1H), 6.99–7.09 (m, 3H), 7.52 (dd, JZ1.6,
7.2 Hz, 1H), 7.62 (d, JZ9.1 Hz, 2H), 8.71 (s, 1H, NH). 13C
NMR (acetone-d6) d 39.6 (NCH3), 56.2 (OCH3), 115.0,
119.8, 120.5, 121.7, 122.2 (5CH), 126.8, 130.7, 131.9,
139.4, 164.2 (5C). MS m/zZ396 (79Br) [MC1]C, 398
(81Br) [MC1]C. Anal. Calcd for C15H14BrN3O3S; C, 45.47;
H, 3.56; Br, 20.16; N, 10.60; S, 8.09. Found: C, 45.38; H,
3.69; Br, 20.04; N, 10.77; S, 8.23.
3.5.2. N-(3-Bromo-4-ethoxy-1-methyl-1H-7-indazolyl)-4-
methoxybenzenesulfonamide (5c). Colorless solid, yield
78%: mp 158–159 8C. IR (KBr, cmK1): 3240 (NH), 1590
1
(CN), 1332, 1146 (SO2), 1254, 1060 (ArOCH). H NMR
(acetone-d6) d 1.40 (t, JZ6.9 Hz, 3H, CH3), 3.86 (s, 3H,
OCH3), 4.08 (q, JZ6.9 Hz, 2H, CH2O), 4.23 (s, 3H, NCH3),
6.28 (d, JZ8.1 Hz, 1H), 6.43, (d, JZ8.1 Hz, 1H), 7.04
(d, JZ9.1 Hz, 2H), 7.60 (d, JZ9.1 Hz, 2H), 8.38 (s, 1H,
NH). 13C NMR (acetone-d6) d 14.7 (CH3), 39.3 (NCH3),
56.1 (OCH3), 64.8 (CH2O), 101.5 114.9, 130.3, 130.6
(4CH), 113.6, 116.4, 117.3, 132.1, 141.0, 153.5, 164.0 (7C).
MS m/zZ440 (79Br) [MC1]C, 442 (81Br) [MC3]C. Anal.
Calcd for C17H18BrN3O4S; C, 46.37; H, 4.12; Br, 18.15; N,
9.54; S, 7.28. Found: C, 46.44; H, 4.03; Br, 18.32; N, 9.59;
S, 7.40.
3.7. Synthesis of 7(a–e)
These compounds were synthesized as described for 1(a–d)
by using the appropriate alcohol.
3.5.3. N-(4-Ethoxy-3-iodo-1-methyl-1H-7-indazolyl)-4-
methoxybenzenesulfonamide (5d). Colorless solid, yield
80%: mp 183–184 8C. IR (KBr, cmK1): 3290 (NH), 1590
1
(CN), 1332, 1154 (SO2), 1260, 1018 (ArOCH). H NMR
3.7.1. N-(3-Iodo-4-methoxy-1-methyl-1H-7-indazolyl)-4-
methoxybenzenesulfonamide (7a). Green solid, yield
67%: mp 203–204 8C. IR (KBr, cmK1): 3276 (NH), 1590
(acetone-d6) d 1.47 (t, JZ7.2 Hz, 3H, CH3), 3.90 (s, 3H,
OCH3), 4.12 (q, JZ7.2 Hz, 2H, CH2O), 4.30 (s, 3H, NCH3),
6.30 (d, JZ8.1 Hz, 1H), 6.44 (d, JZ8.1 Hz, 1H), 7.07
(d, JZ8.7 Hz, 2H), 7.62 (d, JZ8.7 Hz, 2H), 8.42 (s, 1H,
NH). 13C NMR (acetone-d6) d 14.7 (CH3), 39.3 (NCH3),
56.1 (OCH3), 64.8 (CH2O), 101.4, 114.9, 130.0, 130.6
(4CH), 85.5, 113.4, 126.7, 132.2, 143.2, 153.2, 164.0 (7C).
MS m/zZ488 [MC1]C. Anal. Calcd for C17H18IN3O4S; C,
41.90; H, 3.72; I, 26.04; N, 8.62; S, 6.58. Found: C, 41.96;
H, 3.88; I, 26.00; N, 8.49; S, 6.43.
1
(CN), 1326, 1154 (SO2), 1254, 1060 (ArOCH). H NMR
(acetone-d6) d 3.82 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.19
(s, 3H, NCH3), 6.33 (d, JZ8.5 Hz, 1H), 6.37 (d, JZ8.5 Hz,
1H), 7.19 (d, JZ8.7 Hz, 2H), 7.58 (d, JZ8.7 Hz, 2H), 9.56
(s, 1H, NH). 13C NMR (acetone-d6) d 35.9 (NCH3), 55.6,
55.7 (2OCH3), 100.4, 114.3, 128.4, 129.2 (4CH), 86.4,
112.7, 118.7, 131.1, 139.1, 152.1, 162.4 (7C). MS m/zZ474
[MC1]C. Anal. Calcd for C16H16IN3O4S; C, 40.60; H,
3.41; I, 26.81; N, 8.88; S, 6.77. Found: C, 40.54; H, 3.61; I,
26.92; N, 8.70; S, 6.50.
3.6. General procedure for the preparation of com-
pounds 6a and 6c
3.7.2. N-(3-Iodo-4-propoxy-1-methyl-1H-7-indazolyl)-4-
methoxybenzenesulfonamide (7b). Colorless solid, yield
77%: mp 139–140 8C. IR (KBr, cmK1): 3226 (NH), 1582
A mixture of 3-halogeno-7-nitroindazole 4a, c (0.66 mmol)
and anhydrous SnCl2 (0.62 g, 3.3 mmol) in 25 mL of ethyl

8224
L. Bouissane et al. / Tetrahedron 61 (2005) 8218–8225
1
(CN), 1326, 1146 (SO2), 1254, 1026 (ArOCH). H NMR
(acetone-d6) d 1.10 (t, JZ7.5 Hz, 3H, CH3), 1.75–1.81 (m,
2H, CH2); 3.84 (s, 3H, OCH3), 3.97 (t, JZ6.3 Hz, 2H,
CH2O), 4.18 (s, 3H, NCH3), 6.29 (d, JZ7.9 Hz, 1H), 6.34
(d, JZ7.9 Hz, 1H), 7.10 (d, JZ8.8 Hz, 2H), 7.58 (d, JZ
8.8 Hz, 2H), 9.60 (s, 1H, NH). 13C NMR (acetone-d6) d 10.8
(CH3), 38.4 (NCH3), 21.8 (CH2), 55.6 (OCH3), 69.4
(CH2O), 112.2, 114.4, 128.6, 129.2 (4CH), 86.6, 100.7,
114.7, 118.5, 131.0, 151.7, 162.4 (7C). MS m/zZ502
[MC1]C. Anal. Calcd for C18H20IN3O4S; C, 43.12; H,
4.02; I, 25.31; N, 8.38; S, 6.40. Found: C, 43.01; H, 4.23; I,
25.55; N, 8.19; S, 6.56.
The mixture was refluxed for 2 h. After cooling, solvent was
removed. The crude material was dissolved with EtOAc,
washed with sodium hydrogen carbonate and brine, dried
over MgSO4 and the solvent removed in vacuo. The residue
was purified by flash chromatography on silica gel eluting
with EtOAc/EP to provide 80% of 8 as colorless solid: mp
227–228 8C. IR (KBr, cmK1): 3310 (OH), 3246 (NH), 1602
(CN), 1344, 1143 (SO2). 1H NMR (acetone-d6) d 3.89
(s, 3H, OCH3), 4.30 (s, 3H, NCH3), 6.24 (d, JZ7.9 Hz, 1H),
6.35 (d, JZ7.9 Hz, 1H), 7.06 (d, JZ8.9 Hz, 2H), 7.62 (d,
JZ8.9 Hz, 2H), 8.34 (s, 1H, NH), 9.26 (s, 1H, OH). 13C
NMR (acetone-d6) d 39.2 (NCH3), 56.1 (OCH3), 104.9,
114.8, 130.0, 130.6 (4CH), 85.5, 112.4, 119.7, 132.2, 140.9,
151.9, 163.9 (7C). SM: m/zZ460 [MC1]C. Anal. Calcd for
C15H14IN3O4S; C, 39.23; H, 3.07; I, 27.63; N, 9.15; S, 6.98.
Found: C, 39.36; H, 3.28; I, 27.43; N, 9.05; S, 6.84.
3.7.3. N-(3-Iodo-4-isopropoxy-1-methyl-1H-7-indazolyl)-
4-methoxybenzenesulfonamide (7c). Colorless solid, yield
79%: mp 101–102 8C. IR (KBr, cmK1): 3018 (NH), 1582
1
(CN), 1326, 1154 (SO2), 1218, 1082 (ArOCH). H NMR
(acetone-d6) d 1.37 (d, JZ6.0 Hz, 6H, 2CH3), 3.90 (s, 3H,
OCH3), 4.29(s, 3H, NCH3), 4.69–4.78 (m, 1H, (CH3)2CH–O),
6.33 (d, JZ8.3 Hz, 1H), 6.44 (d, JZ8.3 Hz, 1H), 7.08
(d, JZ8.9 Hz, 2H), 7.63 (d, JZ8.9 Hz, 2H), 8.41 (s, 1H,
NH). 13C NMR (acetone-d6) d 21.5, 22.1 (2CH3), 39.3
(NCH3), 56.1 (OCH3), 71.5 (CHO), 102.5, 114.9, 126.7,
130.0, 130.6 (5CH), 85.7, 113.0, 120.4, 132.3, 140.6, 152.1,
164.0 (7C). MS m/zZ502 [MC1]C. Anal. Calcd for
C18H20IN3O4S; C, 43.12; H, 4.02; I, 25.31; N, 8.38; S,
6.40. Found: C, 43.01; H, 4.23; I, 25.55; N, 8.19; S, 6.56.
3.8. General procedure for the preparation of com-
pounds 9(a,b)
A mixture of 3-halogeno-7-nitroindazole 1(a–d) (0.66 mmol)
and anhydrous SnCl2 (0.62 g, 3.3 mmol) in 25 mL of
absolute ethanol is heated at 60 8C. 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 ethyl acetate. 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 CH2Cl2 (5 mL) and then Et3N (1.5 equiv) and
trimethylacethyl chloride(1.1 equiv) or benzyl chloro-
formate (1.1 equiv) were added. The reaction mixture was
stirred at room temperature overnight. After the reaction
mixture was concentrated in vacuo, the resulting residue
was purified by flash chromatography (eluted with EtOAc/
EP).
3.7.4. N-(4-Butoxy-3-iodo-1-methyl-1H-7-indazolyl)-4-
methoxybenzenesulfonamide (7d). Colorless solid, yield
75%: mp 91–92 8C. IR (KBr, cmK1): 3228 (NH), 1590
1
(CN), 1332, 1146 (SO2), 1234, 1060 (ArOCH). H NMR
(acetone-d6) d 0.94 (t, JZ7.2 Hz, 3H, CH3), 1.52–1.61
(m, 2H, CH2), 1.73–1.77 (m, 2H, CH2), 3.84 (s, 3H, OCH3),
4.01 (t, JZ6.6 Hz, 2H, CH2O), 4.18 (s, 3H, NCH3), 6.31
(d, JZ8.3 Hz, 1H), 6.35 (d, JZ8.3 Hz, 1H), 7.10 (d, JZ
8.8 Hz, 2H), 7.58 (d, JZ8.8 Hz, 2H), 9.60 (s, 1H, NH). 13C
NMR (acetone-d6) d 13.7 (CH3), 38.4 (NCH3), 18.8, 30.5
(2CH2), 55.6 (OCH3), 67.5 (CH2O), 100.7, 112.2, 114.2,
129.2 (4CH), 119.5, 125.4, 128.6, 131.1, 139.0, 151.6,
162.4 (7C). MS m/zZ516 [MC1]C. Anal. Calcd for
C19H22IN3O4S; C, 44.28; H, 4.30; I, 24.62; N, 8.15; S,
6.22. Found: C, 44.45; H, 4.21; I, 24.43; N, 8.38; S, 6.41.
3.8.1. N-(4-Ethoxy-3-iodo-1-methyl-1H-7-indazolyl)-2,2-
dimethyl-propionamide (9a). Colorless solid, yield 81%:
mp 161–162 8C. IR (KBr, cmK1): 3268 (NH), 1640 (CO),
1
1602 (CN), 1246, 1016 (ArOCH). H NMR (acetone-d6) d
1.28 (s, 9H, 3CH3), 1.45 (t, JZ6.9 Hz, 3H, CH3), 4.04
(s, 3H, NCH3), 4.12 (q, JZ6.9 Hz, 2H, OCH2), 6.40 (d, JZ
8.1 Hz, 1H), 6.92 (d, JZ8.1 Hz, 1H), 8.57 (s, 1H, NH). 13C
NMR (acetone-d6) d 14.8 (CH3), 27.8 (3CH3), 38.3 (NCH3),
39.5 (C(CH3)3), 64.6 (OCH2), 101.6, 128.6 (2CH), 85.1,
115.5, 119.6, 139.8, 152.1 (5C), 179.2 (CO). SM m/zZ402
[MC1]C. Anal. Calcd for C15H20IN3O2; C, 44.90; H, 5.02;
I, 31.63; N, 10.47. Found: C, 44.97; H, 4.89; I, 31.44; N,
10.56.
3.7.5. N-(3-Iodo-4-(2-trimethylsilanyl-ethoxy)-1-methyl-
1H-7-indazolyl)-4-methoxybenzene sulfonamide (7e).
Colorless solid yield 78%: mp 172–173 8C. IR (KBr, cmK1):
3254 (NH), 1590 (CN), 1334, 1146 (SO2), 1246, 1040
1
(ArOCH). H NMR (acetone-d6) d 0.10 (s, 9H, CH3), 1.29
(t, JZ8.5 Hz, 2H, CH2), 3.91 (s, 3H, OCH3), 4.19 (t, JZ
8.5 Hz, 2H, CH2), 4.29 (s, 3H, NCH3), 6.33 (d, JZ8.1 Hz,
1H), 6.44 (d, JZ8.1 Hz, 1H), 7.08 (d, JZ8.9 Hz, 2H), 7.63
(d, JZ8.9 Hz, 2H), 8.41 (s, 1H, NH). 13C NMR (acetone-d6)
d K1.3 (3CH3), 18.0 (CH2), 39.3 (NCH3), 56.1 (OCH3),
66.8 (CH2O), 101.6, 114.9, 130.0, 130.6 (4CH), 85.5, 113.2,
119.8, 132.2, 140.4, 153.2, 164.0 (7C). MS m/zZ560
[MC1]C. Anal. Calcd for C20H26IN3O4SSi; C, 42.94; H,
4.68; I, 22.68; N, 7.51; S, 5.73, Si, 5.02. Found: C, 42.77; H,
4.51; I, 22.59; N, 7.73; S, 5.90, Si, 4.96.
3.8.2. (4-Ethoxy-3-iodo-1-methyl-1H-7-indazolyl)-car-
bamic acid benzyl ester (9b). Colorless solid, yield 74%: mp
167–168 8C. IR (KBr, cmK1): 3254 (NH), 1682 (CO), 1604
1
(CN), 1240, 1054 (ArOCH). H NMR (acetone-d6) d 1.45
(t, JZ7.2 Hz, 3H, CH3), 4.03 (s, 3H, NCH3), 4.14 (q, JZ
7.2 Hz, 2H, OCH2), 5.14 (s, 2H, CH2), 6.44 (d, JZ8.1 Hz, 1H),
7.08 (d, JZ8.1 Hz, 1H), 7.34 (m, 5H), 8.25 (s, 1H, NH). 13C
NMR (acetone-d6) d 14.8 (CH3), 38.1 (NCH3), 64.7 (OCH2),
67.2 (OCH2), 101.7, 114.9, 121.4, 128.8, 129.2 (5CH), 85.4,
119.8, 138.0, 139.7, 152.4, 158.6 (6C), 177.1 (CO). SM m/zZ
452 [MC1]C. Anal. Calcd for C18H18IN3O3; C, 47.91; H, 4.02;
I, 28.12; N, 9.31. Found: C, 47.86; H, 3.92; I, 28.30; N, 9.15.
3.7.6. N-(4-Hydroxy-3-iodo-1-methyl-1H-7-indazolyl)-4-
methoxy-benzenesulfonamide (8). Compound 7e (100 mg,
0.18 mmol) was dissolved in 5 mL of trifluoroacetic acid.

L. Bouissane et al. / Tetrahedron 61 (2005) 8218–8225
8225
S.; Nikulin, V.; Levin, J.; Sprankle, K. G.; Tedder, M. E.;
Almassy, R.; Appelt, K.; Yager, K. M. J. Med. Chem. 2003,
46, 5663.
3.8.3. N-(4-Ethoxy-1-methyl-3-thiophen-3-yl-1H-7-inda-
zolyl)-2,2-dimethyl-propionamide (10). Under argon
atmosphere, a mixture of 9a (100 mg, 0.24 mmol) and
3-thiopheneboronic acid (mZ40 mg, 0.28 mmol) in DME
(8 mL), sodium carbonate (80 mg, 0.72 mmol) in H2O
(4 mL) was added followed by the addition of Pd(PPh3)4
(30 mg, 0.043 mmol). The reaction mixture was refluxed
with vigorous stirring for 2 h. It was then evaporated to
dryness under reduced pressure. Ethyl acetate (5 mL) was
added; the organic phase was washed with a saturated
solution of sodium chloride (10 mL), dried over MgSO4 and
the solvent removed in vacuo. The residue was purified by
flash chromatography (EtOAc/EP) yielding 72 mg (81%) of
10 as a colorless solid: mp 132–133 8C. IR (KBr, cmK1):
3320 (NH), 1644 (CO), 1602 (CN), 1258, 1048 (ArOCH).
1H NMR (acetone-d6) d 1.36 (s, 9H, 3CH3), 1.48 (t, JZ
7.2 Hz, 3H, CH3), 4.13 (s, 3H, NCH3), 4.20 (q, JZ7.2 Hz,
2H, CH2O), 6.98 (d, JZ8.1 Hz, 1H), 7.22 (d, JZ8.1 Hz,
1H), 7.58 (dd, JZ6.2, 4.0 Hz, 1H), 7.90 (d, JZ6.2 Hz, 1H),
8.34 (d, JZ4.0 Hz, 1H), 8.60 (s, 1H, NH). 13C NMR
(acetone-d6) d 14.8 (CH3), 27.9 (3CH3), 38.2 (NCH3), 39.6
(C(CH3)3) 64.7 (OCH2), 101.2, 124.7, 126.7, 128.1, 129.7
(5CH), 114.7, 115.9, 135.8, 141.1, 153.0 (5C), 179.1 (CO).
SM m/zZ358 [MC1]C. Anal. Calcd for C19H23IN3O2S; C,
63.84; H, 6.49; N, 11.75, S, 8.97. Found: C, 63.78; H, 6.30;
N, 11.96, S, 9.18.
10. Arnautu, A.; Collot, V.; Ros, J. C.; Alayrac, C.; Witulski, B.;
Rault, S. Tetrahedron Lett. 2002, 43, 2695.
11. Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron Lett. 2000, 41,
9053.
12. Collot, V.; Varlet, D.; Rault, S. Tetrahedron Lett. 2000, 41,
4363.
13. Collot, V.; Dallemagne, P.; Bovy, P. R.; Rault, S. Tetrahedron
1999, 55, 6917.
14. Gordon, D. W. Synlett 1998, 1065.
15. Welch, W. M.; Hanau, C. E.; Whalen, W. M. Synthesis 1992,
937.
16. Steffan, R. J.; Matelan, E.; Ashwell, M. A.; Moore, W. J.;
Solvibile, W. R.; Trybulski, E.; Chadwick, C. C.; Chippari, S.;
Kenney, T.; Eckert, A.; Borges-Marcucci, L.; Keith, J. C.; Xu,
Z.; Mosyak, L.; Harnish, D. C. J. Med. Chem. 2004, 47, 6435.
17. Gamage, S. A.; Spicer, J. A.; Rewcastle, G. W.; Milton, J.;
Sohal, S.; Dangerfield, W.; Mistry, P.; Nicker, N.; Charlton, P.
A.; Denny, W. A. J. Med. Chem. 2002, 45, 740.
18. Benchidmi, M.; Bouchet, P.; Lazaro, R. J. Heterocycl. Chem.
1979, 16, 1599.
19. Terrier, F. Nucleophilic Aromatic Displacement: The Influence
of the Nitro Group; VCH: New York, 1991.
20. (a) Makosza, M.; Wojciechowski, K. Heterocycles 2001, 54,
445. (b) Makosza, M.; Winiarski, J. Acc. Chem. Res. 1987, 20,
282. (c) Makosza, M.; Stalewski, J. Tetrahedron 1995, 51,
7277. (d) Makosza, M.; Sienkiewiez, K. J. Org. Chem. 1998,
63, 4199.
References and notes
21. Buncel, E.; Crampton, M. R.; Strauss, M. J.; Terrier, F.
Electon-Defficient Aromatic- and Heteroaromatic-Base Inter-
actions; Elsevier: Amsterdam, 1984.
1. Caron, S.; Vazquez, E. Synthesis 1999, 588 and references
cited therein.
22. Chupakhin, O. N.; Charushin, V. N.; van der Plas, H. C.
Nucleophilic Aromatic Substitution of Hydrogen; Academic:
San Diego, 1994.
2. Yeu, J.-P.; Yeh, J.-T.; Chen, T.-Y.; Uang, B.-J. Synthesis 2001,
1775 and references cited therein.
3. Sun, J.-H.; Teleha, C. A.; Yan, J.-S.; Rodgers, J. D.; Nugiel, D.
A. J. Org. Chem. 1997, 62, 5627.
23. Miller, J. Aromatic Nucleophilic Substitution; Elsevier:
Amsterdam, 1968.
4. Rodgers, J. D.; Johnson, B. L.; Wang, H.; Greenberg, R. A.;
Erickson-Viitanen, S.; Klabe, R. M.; Cordova, B. C.; Rayner,
M. M.; Lam, G. N.; chang, C.-H. Bioorg. Med. Chem. Lett.
1996, 6, 2919.
24. (a) Okamoto, T.; Shudo, K.; Ohta, T. J. Am. Chem. Soc. 1975,
97, 7184. (b) Hays, J. T.; Young, H. L.; Espy, H. H. J. Org.
Chem. 1967, 32, 158. (c) Makosza, M.; Wojciechowski, K.
Chem. Rev. 2004, 104, 2631.
5. Norman, M. H.; Navas, F., III; Thompson, J. B.; Rigdon, G. C.
J. Med. Chem. 1996, 39, 4692.
¨
25. (a) Sheldrick, G. M.; Kroger, C.; Goddard, R. SHELX 86 in
Crystallographic Computing 3; Oxford University Press: New
York, 1985, 175–189(b) Supplementary X-ray Crystallo-
graphic data: Cambridge Crystallographic Data Centre,
University Chemical Lab; Lensfield Road Cambridge, CB2
1EW, UK, http://www.deposit@chemcrys.cam.ac.uk
26. Noelting, E. Ber. 1904, 37, 2556.
6. Yoshida, T.; Matsuura, N.; Yamamoto, K.; Doi, M.; Shimada,
K.; Morie, T.; Kato, S. Heterocycles 1996, 43, 2701.
7. Robertson, D. W.; Bloomquist, W.; Cohen, M. L.; Reid, L. R.;
Schenck, K.; Wong, D. T. J. Med. Chem. 1990, 33, 3176.
8. Keppler, B. K.; Hartmann, M. Met. Based Drugs 1994, 1, 145.
9. Li, X.; Chu, S.; Feher, V. A.; Khalili, M.; Nie, Z.; Margosiak,