Synthesis of novel N-Aryl-1H-indazolamines from amino-1H-indazoles and arylboronic acids

Article abstract of DOI:10.14233/ajchem.2014.16794

An efficient and high-yielding synthesis of N-aryl-1H-indazolamines from amino-1H-indazole and arylboronic acids are described. In this study a series of novel N-aryl-1H-indazolamines (1a-i) were synthesized using arylboronic acids and amino-1 H-indazoles

Full text of DOI:10.14233/ajchem.2014.16794

Asian Journal of Chemistry; Vol. 26, No. 22 (2014), 7539-7543
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.16794
Synthesis of Novel N-Aryl-1H-indazolamines from Amino-1H-indazoles and Arylboronic Acids
1,*
2
3
UDUTHA KUMARA SWAMY , H. RAMA MOHAN and U. VIPLAVA PRASAD
1
2
3
Laurus Labs Private Limited, IKP Knowledge Park, Turkapally, Shameerpet, Hyderabad-500 078, India
Advinus Therapeutics Limited, Peenya Industrial Area, Bangalore-560 058, India
Department of Organic Chemistry, Foods, Drugs and Water, Andhra University, Visakhapatnam-530 003, India
Corresponding author: Fax: +91 40 23480480; Tel: +91 40 30413370; E-mail: kumarudutha@gmail.com
Received: 30 November 2013; Accepted: 9 June 2014; Published online: 6 November 2014;
*
AJC-16180
An efficient and high-yielding synthesis of N-aryl-1H-indazolamines from amino-1H-indazole and arylboronic acids are described. In
this study a series of novel N-aryl-1H-indazolamines (1a-i) were synthesized using arylboronic acids and amino-1H-indazoles (3a-c).
Keywords: Amino-1H-indazole, Arylboronic acid.
INTRODUCTION
EXPERIMENTAL
Indazoles constitute an important class of heterocycles
that display interesting biological properties such as anti-
Melting points of newly synthesized compounds were
determined in an open glass capillary tubes using buchi/polman
melting point apparatus and are uncorrected. Infrared spectra
were recorded as potassium bromide pellets with a Perkin IR
spectrometer.All H NMR and C NMR spectra were recorded
on a BRUCKER 300 and 75 MHz, respectively. Chemical shifts
were quoted relative to residual solvent [7.26 ppm (1H) and
1,2
3
4,5
6
depressant , antiinflammatory , analgesic and antipyretic ,
7
8
9
dopamine antagonist , antitumor , antiemetic , and anti-HIV
activities . The indazole ring system is also present in many
other compounds such as herbicides, dyes or sweeteners like
guanidine-1H-indazole . Indazole derivatives have been
tested in various biological test systems and some of them
have shown to have important pharmacological activities.
Aromatic amines are important compounds found through-
10
1
13
1
,2,11
77.0 ppm (13 C) for CHCl , 2.54 ppm (1 H) and 39.5 ppm (13
3
C) for DMSO, 3.31 ppm (1 H) and 49 ppm (13 C) for MeOH]
and coupling constants (J) were given in Hz to the nearest 0.5
Hz. Chemical shifts were expressed in δ (ppm) values with
tetramethylsilane as an internal standard. Mass spectra was
12
13
out the pharmaceutical and agro chemical industries. Uses
14
for aromatic amines can range from conducting polymers in
material science to ligands for asymmetric homogeneous
+•
recorded onAgilent-LC-MS instrument giving only M values
15
•+
chemistry .
The formation of carbon-hetero atom bonds using metal
using (M + 1) mode. Analytical TLC was performed with
Silica gel GF-254 from Merck & Co., (Germany). Spots were
detected under UV-light or in iodine. All reactions were carried
out with continuous stirring under an atmosphere of dry nitrogen.
Column chromatography was carried out using commercial
silica gel (100-200 mesh). The following general experimental
procedures were followed for the synthesis of all compounds.
Typical experimental procedure for arylboronic acid
coupling 2a-i: A suitable arylboronic acid (0.20 mol) and
N-BOC-amino-1H-indazole 3a-c (0.10 mol) were dissolved
in N,N-dimethylformamide subsequently added N,N-diisopro-
pylethylamine (0.40 mol) and stirred the reaction for 10 to
12 h at room temperature. After completion of the reaction,
reaction mixture was filtered and to the filtrate added water.
Product was extracted with ethyl acetate and solvent dried over
catalysis is emerging as one of the most significant classes of
cross-coupling reactions. Copper-mediated C-N bond forma-
tion via cross coupling of arylboronic acids and nitrogen-based
nucleophiles have become an important synthetic strategy since
16
the initial reports by Chan et al. and Lam et al. . Under the
17
conditions, reported N-arylation of nitrogen-based nucleo-
philes by arylboronic acids occurs using a stoichiometric
amount of Cu salt and several equivalents of an external base/
ligand.A variety of amines, anilines and nitrogen heterocycles
have been N-arylated, both in the liquid phase and on solid
18
support .As discussed above, indazole moiety shows activities
in multiple therapeutic areas, hence an attempt was made at
first for the synthesis of novel N-aryl-1H-indazolamines.

7
540 Swamy et al.
Asian J. Chem.
1
anhydrous sodium sulfate. Solvent was evaporated under
reduced pressure the crude product was further chromato-
graphed on a silica gel column eluted with a mixture of ethyl
acetate: hexane (0 to 20 %) afforded desired compound 2a-i.
tert-Butyl-4-anilino-1H-1-indazole carboxylate (2a):
H NMR (300 MHz, CDCl
3
): δ 7.98 (s, 1H, Ar-H), 7.56 (s,
1H, Ar-H), 7.49, (d, 1H, J = 8.61 Hz, Ar-H), 7.18 (dd, 2H, J =
2.19, 4.41 Hz, Ar-H), 6.92 (dd, 2H, J = 1.95, 4.44 Hz, Ar-H),
6.84 (dd, 1H, J = 2.01, 6.60 Hz, Ar-H), 5.80 (bs, 1H, -NH-), 3.82
+
(s, 3H, -CH
3
), 1.68 (s, 9H, -CH3); ESI-MS: m/z 340 [M + H] .
1
Yield: 68 %; Brown colour syrupy mass; H NMR (300 MHz,
tert-Butyl-5-[4-(ethoxycarbonyl)aniline]-1H-1-
indazole carboxylate (6): Yield: 76 %; Light brown colour
solid; m.p.: 162-168 °C; H NMR (300 MHz, CDCl
(s, 1H, -NH-), 8.30 (s, 1H, Ar-H), 8.02 (d, 1H, J = 8.91 Hz,
Ar-H), 7.80 (d, 2H, J = 8.37 Hz, Ar-H), 7.62 (s, 1H, Ar-H),
7.40 (d, 1H, J = 8.94 Hz, Ar-H), 7.03 (d, 2H, J = 8.43 Hz, Ar-
H), 4.23 (q, 2H, J = 6.99, 14.07 Hz, -CH
1.26 (t, 3H, J = 6.99, 14.07 Hz, -CH
t-butyl] .
Typical experimental procedure for de-protection of
BOC group: The compound 2a-i (10 mmol) was dissolved in
methanol (30 mL) at room temperature followed by addition
of methanolic. HCl (10 mL). The mixture was stirred around
1 to 2 h at room temperature.After completion of the reaction,
solvent was evoparated under reduced pressure to get residue.
Residue was further diluted with 5 % sodium bicarbonate to
afford the solid, which filtered and washed with water. Dried
the product under reduce pressure at 50 °C to gave desired
compound.
CDCl
.26-7.40 (m, 3H, Ar-H), 7.16 (t, 2H, J = 7.53 Hz, Ar-H), 7.01
dd, 2H, J = 7.35, 7.08 Hz, Ar-H), 6.14 (s, 1H, -NH-), 1.71 (s,
3
): δ 8.06 (s, 1H, Ar-H), 7.70 (d, 1H, J = 8.34 Hz, Ar-H),
1
7
3
): δ 8.88
(
9
+
H, -CH
3
); ESI-MS: m/z 310 [M + H] .
tert-Butyl-4-(4-toluidino)-1H-1-indazole carboxylate
1
(
2b):Yield: 72 %; Brown colour syrupy mass; H NMR (300
MHz, CDCl ): δ 8.01 (s, 1H, Ar-H), 7.65 (d, 1H, J = 8.31 Hz,
Ar-H), 7.36 (t, 1H, J = 8.04 Hz, Ar-H), 7.13 (dd, 4H, J = 8.40,
.81 Hz, Ar-H), 6.89 (d, 1H, J = 7.71 Hz, Ar-H), 6 (bs, 1H,
NH-), 2.21 (s, 3H, -CH ), 1.72 (s, 9H, -CH ); ESI-MS: m/z
2
-), 1.62 (s, 9H, -CH
3
),
3
3
); ESI-MS: m/z 326 [M-
+
9
-
3
3
3
+
24 [M + H] .
tert-Butyl-4-(4-methoxyanilino)-1H-1-indazole-
carboxylate (2c): Yield: 76 %; Light brown colour powder;
1
m.p.: 176-181°C; H NMR (300 MHz, CDCl ): δ 7.94 (s, 1H,
3
Ar-H), 7.60 (d, 1H, J = 8.31 Hz, Ar-H), 7.33 (t, 1H, J = 7.95
Hz, Ar-H), 7.16 (dd, 2H, J = 2.16, 4.62 Hz, Ar-H), 6.91 (dd,
2
5
H, J = 2.34, 4.41 Hz, Ar-H), 6.73 (d, 1H, J = 7.80 Hz, Ar-H),
.90 (bs, 1H, -NH-), 3.82 (s, 3H, -CH ), 1.71 (s, 9H, -CH );
3
3
+
ESI-MS: m/z 340 [M + H] .
tert-Butyl-5-anilino-1H-1-indazole carboxylate (2d):
N-4-Phenyl-1H-4-indazolamine (1a):Yield: 92 %; Light
-1
brown colour solid; m.p.: 205-209 °C; IR (KBr, νmax, cm ):
3397, 3290, 2813, 1595, 1164, 768; H NMR (300 MHz,
1
1
Yield: 75 %; Brown colour syrupy mass; H NMR (300 MHz,
CDCl
Hz, Ar-H), 7.30-7.25 (m, 4H, Ar-H), 7.06 (dd, 2H, J = 1.11,
.59 Hz, Ar-H), 6.93 (s, 1H, Ar-H), 5.77 (bs, 1H, -NH-), 1.72
3
): δ 8.07 (t, 1H, J = 9 Hz, Ar-H), 7.39 (d, 1H, J = 1.8
DMSO-d
6.93-6.86 (m, 2H, Ar-H), 6.76 (d, 1H, J = 7.38 Hz, Ar-H); C
NMR (75 MHz, DMSO-d ): δ 177.18, 172.26, 168.32, 151.16,
6
) δ: 8.17 (s, 1H, Ar-H), 7.28-7.11 (m, 5H, Ar-H),
13
7
6
+
(
s, 9H, CH
3
); ESI-MS: m/z 310 [M + H] .
tert-Butyl-5-(4-toluidino)-1H-1-indazole carboxylate
148.62, 145.70, 139.41, 133.01 126.47, 125.88, 125.49,
+
122.66, 118.88, 117.60; ESI-MS: m/z 210 [M + H] .
1
(
2e): Yield: 68 %; Brown colour syrupy mass; H NMR (300
N-4-(4-Methylphenyl)-1H-4-indazolamine (1b):Yield:
MHz, CDCl
7
6
3
): δ 8.02 (s, 1H, Ar-H), 7.89 (s, 1H, Ar-H), 7.35-
.25 (m, 4H, Ar-H), 7.09 (dd, 2H, J = 1.11, 7.59 Hz, Ar-H),
.96 (s, 1H, -NH-), 2.24 (s, 3H, -CH ), 1.74 (s, 9H, -CH );
86 %; Light brown colour solid; m.p.: > 225 °C; IR (KBr,
-1
1
ν
max, cm ): 3393, 3290, 2678, 1602, 1527, 1099; H NMR
(300 MHz, DMSO-d ): δ 8.13 (s, 1H, Ar-H), 7.08 (dd, 5H, J =
8.46, 0.93 Hz,Ar-H), 6.86 (d, 1H, J = 8.16 Hz, Ar-H), 6.64 (d,
3
3
6
+
ESI-MS: m/z 324 [M + H] .
tert-Butyl-5-(4-methoxyanilino)-1H-1-indazole
13
1H, J = 7.56 Hz, Ar-H), 2.23 (s, 3H, -CH
3
); C NMR (75
1
carboxylate (2f):Yield: 73 %; Brown colour syrupy mass; H
MHz, DMSO-d ): δ 141.81, 140.04, 138.38, 131.75, 130.57,
6
NMR (300 MHz, CDCl
3
): δ 7.99 (d, 2H, J = 10.12 Hz, Ar-H),
.25-7.05 (m, 4H, Ar-H), 6.88 (d, 2H, J = 8.91 Hz, Ar-H),
.80 (s, 3H, CH ), 1.71 (2, 9H, -CH ); ESI-MS: m/z 340 [M +
130.21, 129.88, 128.76, 123.10, 120.08, 114.82, 102.26,
100.73, 20.73; ESI-MS: m/z 224 [M + H] .
N-4-(4-Methoxyphenyl)-1H-4-indazolamine (1c):
+
7
3
H] .
3
3
+
Yield: 88 %; Brown colour solid; m.p.: 160-165 °C; IR (KBr,
-1
1
tert-Butyl-6-anilino-1H-1-indazolecarboxylate (2g):
ν
max, cm ): 3387, 3291, 2827, 2730, 1603, 1508, 1108; H
1
Yield: 65 %; Brown colour solid; m.p.: 156-159 °C; H NMR
300 MHz, CDCl ): δ 8.02 (s, 1H, Ar-H), 7.80 (s, 1H, Ar-H),
.54 (d, 1H, J = 8.55 Hz, Ar-H), 7.35-7.30 (m, 2H, Ar-H),
.21 (dd, 2H, J = 1.14, 7.50 Hz, Ar-H), 7.05-6.95 (m, 2H, Ar-
); ESI-MS: m/z 310 [M
NMR (300 MHz, DMSO-d ): δ 8.12 (s, 1H, Ar-H), 7.15 (dd,
6
(
3
2H, J = 2.16, 4.53 Hz, Ar-H), 7.06 (t, 1H, J = 7.8 Hz, Ar-H),
6.89 (dd, 2H, J = 2.19, 4.59 Hz, Ar-H), 6.80 (d, 1H, J = 8.22
Hz, Ar-H), 6.48 (d, 1H, J = 7.47 Hz, Ar-H), 3.75 (s, 3H, -NH-);
7
7
13
H), 6.01 (bs, 1H, -NH-), 1.66 (s, 9H, -CH
3
C NMR (75 MHz, DMSO-d ): δ 155.09, 141.79, 139.50,
6
+
+
H] .
tert-Butyl-6-(4-toluidino)-1H-1-indazolecarboxylate
2h):Yield: 69 %; Light brown colour solid; m.p.: 136-139 °C;
135.35, 131.67, 128.80, 125.56, 122.92, 155.05, 144.81,
+
144.33, 101.06, 99.98, 55.60; ESI-MS: m/z 240 [M + H] .
(
1
N-5-Phenyl-1H-5-indazolamine (1d):Yield: 90 %; Light
-1
H NMR (300 MHz, CDCl
Ar-H), 7.51 (d, 1H, J = 8.61 Hz, Ar-H), 7.11 (dd, 4H, J = 2.55,
.18 Hz, Ar-H), 6.92 (dd, 1H, J = 1.98, 6.63 Hz, Ar-H), 5.92
bs, 1H, -NH-), 2.33 (s, 3H, -CH ), 1.65 (s, 9H, -CH ); ESI-MS:
3
): δ 8 (s, 1H, Ar-H), 7.71 (s, 1H,
brown colour solid; m.p.: >225 °C; IR (KBr, νmax, cm ): 3414,
1
2669, 1639, 1598, 1082; H NMR (300 MHz, DMSO-d
6
): δ
6
7.91 (s, 1H, Ar-H), 7.41 (dd, 2H, J = 12.30, 1.47 Hz, Ar-H),
7.18-7.12 (m, 3H, Ar-H), 6.96 (d, 2H, J = 7.62 Hz, Ar-H),
(
3
3
+
13
m/z 324 [M + H] .
tert-Butyl-6-(4-methoxyanilino)-1H-1-indazolecarbo-
6.72 (t, 1H, J = 7.26 Hz, Ar-H); C NMR (75 MHz, DMSO-
6
d ): δ 144.77, 137.03, 136.62, 131.91, 129.52, 123.21, 123.10,
+
xylate (2i):Yield: 71 %; Light brown solid; m.p.: 155-161 °C;
119.82, 116.43, 111.69, 107.24; ESI-MS: m/z 210 [M + H] .

Vol. 26, No. 22 (2014)
Synthesis of Novel N-Aryl-1H-indazolamines from Amino-1H-indazoles and Arylboronic Acids 7541
N-5-(4-Methylphenyl)-1H-5-indazolamine (1e):Yield:
The residue was dissolved in water and acidified with conc.
HCl and product was filtered and washed with water followed
by methanol to give desired compound 8. Yield: 91 %; Light
9
ν
4 %; Light brown color solid; m.p.: 188-193 °C; IR (KBr,
-1
1
max, cm ): 3329, 2992, 2643, 1644, 1512, 1081; H NMR
300 MHz, DMSO-d ): δ 7.94 (s, 1H, Ar-H), 7.44 (d, 1H, J =
.85 Hz, Ar-H), 7.35 (d, 1H, J = 1.50 Hz, Ar-H), 7.15 (dd, 1H,
1
(
8
6
yellow colour solid; m.p.: > 225 °C; H NMR (300 MHz,
CDCl ): δ 8.58 (s, 1H, -NH-), 7.97 (s, 1H, Ar-H), 7.73 (d, 2H,
3
J = 2.01, 6.84 Hz, Ar-H), 7 (dd, 4H, J = 8.37, 13.62 Hz, Ar-
J = 8.70 Hz, Ar-H), 7.50 (dd, 2H, J = 3.60, 1.80 Hz, Ar-H),
7.17 (dd, 1H, J = 1.80, 7.20 Hz, Ar-H), 6.89 (d, 2H, J = 8.70
Hz, Ar-H); ESI-MS: m/z 254 [M + H] .
13
H), 2.18 (s, 3H, -CH
3
); C NMR (75 MHz, DMSO-d ): δ
6
+
1
41.70, 137.26, 136.64, 132.07, 130.00, 129.50, 123.28, 122.45,
+
117.58, 111.64, 106.68, 20.63; ESI-MS: m/z 224 [M + H] .
Typical procedure for amide formation 9a-c: The com-
pound 8 (10 mmol) and amine (11) (20 mmol) were dissolved
in dimethyl sulfoxide at room temperature and followed by
the addition of N,N-diisopropylethylamine (40 mmol) and
TBTU (13.5 mmol) under stirring and reaction mixture was
kept as such for 3 to 6 h at room temperature.After completion
of the reaction as indicated by TLC, water was added. Product
was extracted into ethyl acetate and organic layer was washed
with water, brine and dried over anhydrous sodium sulfate.
Organic layer was concentrated in vacuo to get residue. The
residue was chromatographed on a silica gel column and eluted
with a mixture of ethyl acetate: hexane (1:9) to afford desired
compound 9a-c.
N-5-(4-Methoxyphenyl)-1H-5-indazolamine (1f):Yield:
8
4 %; Light brown colour solid; m.p.: 142-149 °C; IR (KBr,
-1
1
ν
max, cm ): 3394, 2634, 1605, 1509, 1026; H NMR (300 MHz,
): δ 7.95 (s, 1H, Ar-H), 7.44 (d, 1H, J = 8.82 Hz, Ar-
H), 7.32 (s, 1H, Ar-H), 7.15-7.05 (m, 3H, Ar-H), 6.85 (d, 2H, J =
DMSO-d
6
13
8.85 Hz,Ar-H), 3.68 (s, 3H, -CH
3
); C NMR (75 MHz, DMSO-d ):
6
δ 155.97, 137.15, 136.71, 135.28, 132.24, 122.96, 122.30, 121.77,
+
1
15.15, 112.01, 107.75, 55.73; ESI-MS: m/z 240 [M + H] .
N-6-Phenyl-1H-6-indazolamine (1g): Yield: 95 %;
-1
Brown colour solid; m.p.: 175-181 °C; IR (KBr, νmax, cm ):
1
3
d
270, 2782, 1643, 1598, 1026; H NMR (300 MHz, DMSO-
): δ 8.15 (s, 1H, Ar-H), 7.63 (d, 1H, J = 8.79 Hz,Ar-H), 7.28
6
(
7
t, 2H, J = 8.37 Hz, Ar-H), 7.16 (t, 2H, J = 7.50 Hz, Ar-H),
N-1-Benzyl-4-(1H-5-indazolylamino)benzamide (9a):
Yield: 76 %; Cream colour solid; m.p.: 160-165 °C; IR (KBr,
13
.06 (d, 1H, J = 0.39 Hz, Ar-H), 6.96-6.89 (m, 2H, Ar-H); C
): δ 143.09, 142.34, 141.77, 131.07,
29.63, 122.80, 121.90, 119.38, 117.06, 115.64, 91.22; ESI-
-1
NMR (75 MHz, DMSO-d
1
MS: m/z 210 [M + H] .
6
ν
max, cm ): 3295, 3063, 2631, 1606, 1557, 1525, 1365, 798;
1
H NMR (300 MHz, CDCl ): δ 8.69 (t, 1H, J = 5, 40 Hz, Ar-
3
+
H), 7.95 (d, 1H, J = 0.90 Hz, Ar-H), 7.43 (d, 2H, J = 8.70 Hz,
N-6-(4-Methylphenyl)-1H-6-indazolamine (1h):Yield:
Ar-H), 7.48 (t, 2H, J = 8.70 Hz, Ar-H), 7.15-7.29 (m, 5H, Ar-H),
-1
13
8
3
8
9 %; White color solid; m.p.: 217-221 °C; IR (KBr, νmax, cm ):
6.91 (d, 2H, J = 9 Hz,Ar-H), 4.43 (d, 2H, J = 6 Hz, -CH
NMR (75 MHz, CDCl
2
-); C
1
292, 2911, 2693, 1640, 805; H NMR (300 MHz, CDCl
3
): δ
3
): δ 166.30, 148.54, 140.54, 137.08,
.22 (dd, 1H, J = 8.7, 1.83 Hz, Ar-H), 7.90 (s, 1H,Ar-H), 7.55
135.53, 132.53, 129.23, 128.53, 127.51, 126.91, 123.91, 123.38,
113.63, 111.61, 109.74, 42.79; ESI-MS: m/z 343 [M + H] .
N-1-(4-Methoxybenzyl)-4-(1H-5-indazolylamino)-
+
(
d, 1H, J = 8.76 Hz, Ar-H), 7.02-7.09 (m, 4H, Ar-H), 6.97 (d,
13
1
H, J = 0.75 Hz, Ar-H), 2.22 (s, 3H, -CH
): δ 145.40, 141.89, 140.12, 132.12, 130.60,
30.06, 122.18, 119.57, 116.25, 115.68, 91.32, 20.72; ESI-MS:
3
); C NMR (75
MHz, DMSO-d
1
6
benzamide (9b):Yield: 84 %; Brown colour solid; m.p.: 148-
-1
153 °C; IR (KBr, νmax, cm ): 3287, 3094, 2925, 1604, 1508,
+
1
m/z 224 [M + H] .
764; H NMR (300 MHz, CDCl ): δ 12.94 (s, 1H, -NH-), 8.61
3
N-6-(4-Methoxyphenyl)-1H-6-indazolamine (1i):Yield:
(t, 1H, J = 5.70 Hz, 6 Hz, Ar-H), 8.39 (s, 1H, Ar-H), 7.95 (s,
1H, Ar-H), 7.70 (d, 2H, J = 8.70 Hz, Ar-H), 7.47 (d, 2H, J =
8.70 Hz, Ar-H), 7.15-7.21 (m, 3H, Ar-H), 6.82-6.93 (m, 3H,
-1
9
3
1 %; brown colour solid; m.p.: > 225 °C; IR (KBr, νmax, cm ):
1
274, 3121, 1641, 1592, 1023; H NMR (300 MHz, DMSO-d ):
6
13
δ 8.04 (s, 1H, Ar-H), 7.55 (d, 1H, J = 9.54 Hz, Ar-H), 7.12
dd, 2H, J = 2.22, 4.47 Hz, Ar-H), 6.91 (dd, 2H, J = 2.22, 4.53
Hz, Ar-H), 6.80 (t, 2H, J = 7.92 Hz, Ar-H), 3.71 (s, 3H, -CH );
): δ 155.57, 148.25, 142.03,
34.57, 130.68, 123.17, 122.96, 116.92, 115.02, 88.86, 55.62;
Ar-H), 4.35 (d, 3.69 (s, 3H, -CH
3
); C NMR (75 MHz, CDCl ):
3
(
δ 166.42, 158.43, 148.74, 134.98, 132.92, 132.28, 129.02,
128.75, 123.77, 123.64, 122.68, 113.72, 113.31, 111.02,
110.44, 55.19, 42.38; IR ESI-MS: m/z 373 [M + H]+.
N-1-(4-Fluorobenzyl)-4-(1H-5-indazolylamino)-
benzamide (9c): Yield: 68 %; White powder; m.p.: 208-215
3
13
C NMR (75 MHz, DMSO-d
6
1
+
ESI-MS: m/z 240 [M + H] .
-1
Ethyl-4-(1H-5-indazolylamino)benzoate (7): Yield:
°C; IR (KBr, νmax, cm ): 3297, 3064, 2633, 1607, 1528, 1366,
1
9
0 %; Light brown colour solid; 111-115 °C; IR (KBr, νmax
,
799; H NMR (300 MHz, CDCl ): δ 8.77 (br, 3H, -NH-), 8 (d,
3
-1
1
cm ): 3349, 3070, 2926, 2559, 1678, 1596, 1284, 773; H
NMR (300 MHz, DMSO-d ): δ 7.97 (d, 1H, J = 0.93 Hz),
.73 (dd, 2H, J = 1.89, 5.07 Hz), 7.49-7.52 (m, 2H), 7.17 (dd,
H, J = 1.86, 7.02 Hz), 6.93 (dd, 2H, J = 1.89, 5.04 Hz), 4.21
1H, J = 0.60 Hz, Ar-H), 7.75 (d, 2H, J = 8.70 Hz, Ar-H), 7.49
(dd, 2H, J = 8.70, 0.60 Hz, Ar-H), 7.29-7.33 (m, 2H, Ar-H),
7.20 (dd, 1H, J = 2.10, 6.90 Hz, Ar-H), 7.07-7.13 (m, 2H, Ar-
6
7
1
(
H), 6.95 (d, 2H, J = 8.70 Hz, Ar-H), 4.39 (d, 2H, J = 4,20 Hz,
13
13
q, 2H, J = 7.08 Hz), 1.25 (t, 3H, J = 7.11 Hz); C NMR (75
MHz, DMSO-d ): δ 14.69, 60.10, 111.39, 111.49, 113.24,
18.71, 123.29, 123.58, 131.38, 133.06, 134.40, 137.46,
-CH
2
-); C NMR (75 MHz, CDCl
3
): δ 166.31, 163, 159.80,
6
148.29, 136.91, 136.72, 136.68, 135.93, 132.01, 129.54,
129.43, 129.25, 123.98, 123.13, 115.34, 115.06, 113.84,
1
1
+
+
50.51, 165.99; ESI-MS: m/z 282 [M + H] .
111.81, 109.31, 42.13; ESI-MS: m/z 361 [M + H] .
Typical procedure for ester hydrolysis (8): The com-
pound 7 (2.6 mmol) and lithium hydroxide monohydrate (3.9
RESULTS AND DISCUSSION
mmol) in THF (10 mL) and water (0.5 mL) was refluxed for
Here in we report the synthesis, starting from 1H-indazole
of several indazole derivatives substituted at the 4 , 5 and 6
positions with substituted phenyl groups. Nitroindazole
th
th
th
2
h. After completion of the reaction, as indicated by TLC,
the reaction mixture was concentrated in vacuo to get residue.

7
542 Swamy et al.
Asian J. Chem.
19
derivatives were prepared according to the literature reports .
We now wish to report a new set of reaction conditions, opti-
mized for the cross-coupling of BOC protected 4, 5 and 6-
amino-1H-indazoles, with aryl boronic acids in the presence
indazolecarboxylate 6, followed by BOC group deprotection
in presence of acid medium i.e., MeOH. HCl in methanol to
gave compound 7. Upon ester hydrolysis in presence of LiOH.
2
H O to give acid compound 8. The acid compound 8 was
of Cu(OAc)
amine or pyridine as a base.
2
and either with diisopropylethylamine/triethyl-
coupled with various amines in presence of coupling reagents
like HATU/TBTU/HBTU/Py-BOP to give amide product 9a-c
(Scheme-II, Tables 2 and 3).
Reaction of nitroindazoles 5a-c treated with BOC anhydride
in presence of potassium carbonate in acetone at room tempe-
rature for 12 h, gave known BOC protected nitroindazole 4a-c.
The latter compound was reduced with Pd/C in the presence
of hydrogen gas in ethanol resulted BOC amino indazole 3a-c,
which was purified by column chromatography. Further, it was
H
N
H N
2
N
N
O
N
i
N
ii
O
O
O
O
O
6
coupled with phenylboronic acid in the presence of Cu(OAc)
2
3b
and TEA as base at room temperature, followed by processing
gave a coupled product BOC-N-aryl-1H-indazole 2a-i. Further
deprotection BOC in methanolic HCl gave N-aryl-1H-indazole
H
H
N
N
N
iii
N
O
N
H
HO
N
H
1
a-i. Similar results were obtained when DIPEA or pyridine
O
7
O
8
used in the presence of 4 Å molecular sieves instead of TEA.
The above reaction proceeded very smoothly and it has been
extended to other aryl boronic acid such as 4-methylphenyl
boronic acid and 4-methoxyphenyl boronic acid (Scheme-I,
Table-1).
H
N
iv
H
N
N
N
H
R
O
9
a-c
Conditions: (i) 4-Ethoxycarbonylphenyl boronic acid 10, Cu(OAc) , TEA (16-24
2
O N
h) or pyridine, MS A° (14-20 h); (ii) MeOH·HCl/MeOH/RT/6-12 h; (iii) LiOH.
2
H N
2
H O, THF, H O, reflux, 6 h; (iv) RNH (11a) R = Bn, (11b) 4-MeOBn, (11c
)
2
2
2
O N
N
4-FBn), HATU, DMSO,DIPEA, rt, 6h
2
N
i
N
ii
iii
N
Scheme-II
N
N
H
O
O
O
O
TABLE-2
5
a-c
COUPLING WITH 4-ETHOXYCARBO-
NYLPHENYLBORONIC ACID (10)
4
a-c
3
a-c
Entry
1
Substrate
Product
Time
Yield (%)
O
H
N
H
N
NH
2
R
O
R
iv
NH
N
N
N
24 h No reaction
N
N
O
N
N
N
O
O
N
H
O
O
H
2
N
H
N
1
a-i
O
N
N
O
N
2
3
16 h
76
2
a-i
O
O
O
O
O
Conditions: (i) BOC anhydride, K CO , acetone; (ii) 10 % Pd/C (50 %
O
2
3
N
O
wet), H2 gas, ethanol, 35 to 45 °C; (iii) Ar-B(OH)2 (Ar=Ph, 4-MePh, 4-
N
2
H N
N
N
H
N
24 h No reaction
MeOPh), Cu(OAc) ,TEA(16-24 h) or pyridine, MSA°(14-20 h);(iv)MeOH.
O
O
2
O
O
HCl, RT/2h
Scheme-I
TABLE-3
COUPLING WITH ARYL AMINES
TABLE-1
Entry
Substrate
Product
9a
9b
Time
4 h
6 h
Yield (%)
Entry
1
2
3
4
5
6
7
Substrate
R
H
Time (h)
18
Yield (%)*
1
2
3
8
8
8
76
84
68
3a
3a
3a
3b
3b
3b
3c
3c
3c
68
72
76
75
68
73
65
69
71
4-MeO
4-MeO
H
4-MeO
4-MeO
H
20
20
16
18
18
20
22
19
9c
5 h
Conclusion
The work presented here demonstrates a method which
is operationally straight forward, mild and selective, utilizing
the commercial reagents and also demonstrated an efficient
preparation of novel N-aryl indazole amines via Chan-Lam
mediated coupling conditions. We have also successfully
demonstrated the synthesis of the positional isomers of amino-
H-indazoles (4-6 positions) in good yields. The high pharma-
cological importance of indazole amines prompted us to synthe-
size these derivatives.
8
9
4-MeO
4-MeO
*
Isolated yield
In similar manner, 4, 5 and 6-amino indazoles (3a-c) were
coupled with 4-ethoxycarbonyl phenyl boronic acid (10) using
Cu(OAc) in the presence of TEA or pyridine/MS resulted in
the formation of tert-butyl-5-[4-(ethoxycarbonyl)aniline]-1H-
1
2

Vol. 26, No. 22 (2014)
Synthesis of Novel N-Aryl-1H-indazolamines from Amino-1H-indazoles and Arylboronic Acids 7543
8
9
.
.
V.G. Kharitonov, V.S. Sharma, D. Magde and D. Koesling, Biochemistry,
8, 10699 (1999).
(a) J.D. Rodgers, B.L. Johnson, H. Wang, R.A. Greenberg, S. Erickson-
Viitanen, R.M. Klabe, B.C. Cordova, M.M. Rayner, G.N. Lam and C.-H.
Chang, Bioorg. Med. Chem. Lett., 6, 2919 (1996); (b) J.-H. Sun, C.A.
Teleha, J.-S. Yan, J.D. Rodgers and D.A. Nugiel, J. Org. Chem., 62,
ACKNOWLEDGEMENTS
3
The authors thank Dr. C. Satyanarayana, CEO, Laurus
Labs, for his cooperation and encouragement.
5
627 (1997).
0. (a) T. Morie, H. Harada and S. Kato, Synth. Commun., 27, 559 (1997);
b) J. Bermudez, C.S. Fake, G.F. Joiner, K.A. Joiner, F.D. King, W.D.
Miner and G.J. Sanger, J. Med. Chem., 33, 1924 (1990).
1. C. Nofre, J.M. Tinti and F. Quar, FR Patent 26099603 (1988).
2. M. Negwer, In Organic-Chemical Drugs and their Synonyms: (An Inter-
national Survey), Akademie Verlag GmbH: Berlin, edn. 7 (1994).
3. J.H. Montgomery, In Agrochemicals Desk Reference: Environmental
Data, Lewis Publishers, Chelsea, MI (1993).
REFERENCES
1
(
1
.
(a) J. Elguero, in eds.: A.R. Katritzky and C.W. Rees, Comprehensive
Heterocyclic Chemistry, Pyrazoles and their Benzo Derivatives,
Pergamon Press: Oxford, Vol. 5, pp. 167-303 (1984); (b) J. Elguero, in
eds.: A.R. Katritzky, C.W. Rees and E.F.V. Scriven, Comprehensive
Heterocyclic Chemistry II: Pyrazoles, Pergamon Press: Oxford, Vol.
1
1
1
1
1
1
3, pp. 1-75 (1996).
2
3
.
.
(a) W. Stadlbauer, in ed.: E. Schaumann, In Houben-Weyl, Methoden der
Organischen Chemie: Indazole (Benzopyrazole); Georg-Thieme-Verlag
Stuttgart: New York, Hetarenes, Vol. E8b, III, p. 764 (1994); (b) W.
Stadlbauer, in ed.: R. Neier, Science of Synthesis: Indazoles, Georg-Thieme-
Verlag Stuttgart: NewYork,Vol. 2.12.4 (Hetarenes), pp. 227-324 (2002).
Y. Ikeda, N. Takano, H. Matsushita,Y. Shiraki, T. Koide, R. Nagashima,
Y. Fujimura, M. Shindo, S. Suzuki and T. Iwasaki, Arzneimittel-
Forschung, 29, 511 (1979).
G. Picciola, F. Ravenna, G. Carenini, P. Gentili and M. Riva, Farmaco
Ed. Sci., 36, 1037 (1981).
The Merck Index, edn. 12, S. Budavari, Ed., Merck & Co., Rahway,
New Jersey (1996).
4. G. D'Aprano, M. Leclerc, G. Zotti and G. Schiavon, Chem. Mater., 7, 33
(
1995).
5. F. Fache, E. Schulz, M.L. Tommasino and M. Lemaire, Chem. Rev., 100,
159 (2000).
2
6. (a) D.M.T. Chan, K.L. Monaco, R.P. Wang and M.P. Winters, Tetrahe-
dron Lett., 39, 2933 (1998); (b) P.Y.S. Lam, C.G. Clark, S. Saubern, J.
Adams, M.P. Winters, D.M.T. Chan and A. Combs, Tetrahedron Lett.,
3
9, 2941 (1998).
4
5
6
7
.
.
.
.
1
1
7. F.Y. Kwong and S.L. Buchwald, Org. Lett., 5, 793 (2003).
8. J.P. Finet, A.Y. Fedorov, S. Combes and G. Boyer, Curr. Org. Chem.,
6, 597 (2002).
1
9. A.J. Souers, J. Gao, D. Wodka, A.S. Judd, M.M. Mulhern, J.J. Napier,
M.E. Brune, E.N. Bush, S.J. Brodjian, B.D. Dayton, R. Shapiro, L.E.
Hernandez, K.C. Marsh, H.L. Sham, C.A. Collins and P.R. Kym, Bioorg.
Med. Chem. Lett., 15, 2752 (2005).
L. Mosti, G. Menozzi, P. Fossa, P. Schenone, E. Lampa, C. Parrillo, M.
D'Amisco and F. Rossi, Farmaco, 47, 567 (1992).
S. Andronati, V. Sava, S. Makan and G. Kolodeev, Pharmazie, 54, 99
(
1999).