Regioselective protection at N-2 and derivatization at C-3 of indazoles

Article abstract of DOI:10.1021/jo060607j

Indazoles are regioselectively protected at N-2 by a 2-(trimethylsilyl) ethoxymethyl (SEM) group using novel conditions. The SEM group can efficiently direct regioselective C-3 lithiation, and the resulting nucleophile can react with a wide range of electrophiles to generate novel indazole derivatives. The SEM group can be removed by treatment with TBAF in THF or aqueous HCl in EtOH.

Full text of DOI:10.1021/jo060607j

Regioselective Protection at N-2 and
Derivatization at C-3 of Indazoles
Guanglin Luo*, Ling Chen and Gene Dubowchik
Bristol-Myers Squibb Pharmaceutical Research Institute
Department of Neurosciences Chemistry, 5 Research Parkway
Wallingford, CT 06492
Guanglin.Luo@bms.com
Supporting Information
Page S1
General Details
Page S2-S3
Preparation and spectra of 1b
Page S4-S13
Page S14 – S36
Page S37 – S39
Page S40 – S44
Page S45 – S68
Protection of indazoles using NaH/SEM-Cl in THF
Regioselctive protection of indazoles
Acylation of indazole and spectra of 8
Protection of indazole using Cychex2NMe/BOM-Cl
Selective lithiation and subsequent electrophilic reactions
Experimental procedures for the new reactions and full characterization of compounds
1
b, 2a, 2b, 3a-3i, 8-10, 12a-12h and 13.
General Details.
1
13
1
H and C NMR spectra were recorded on a 400 MHz Bruker spectrometer. In H
13
and C NMR spectra, chemical shifts were expressed in (ppm) downfield from CHCl
3
(
7.26 ppm) and CDCl (77.0 ppm), respectively. Mass spectra were recorded by electron
3
impact or chemical ionization. Column chromatography was performed on silica gel packed
in Biotage Horizon columns.
Indazoles 1a, 1c, 1e-1i, and 3-methyl pyrazole 4 were commercially available.
1
Indazole 1d was prepared by literature methods. All reagents, anhydrous grade solvents, and
(
1) Dell’Erba, C.; Novi, M; Petrillo, G.; Tavani, C. Tetrahedron 1994, 50, 3529.

Luo, et al.
p. S2
starting materials were used as received from commercial sources. Reactions that required
anhydrous conditions were conducted under an atmosphere of dry nitrogen with oven-dried
flasks.
Preparation of 7-methylindazole-5-carboxaldehyde (1b).
CH3
CH3
H
H
N
N
N
N
Br
OHC
5
-Bromo-7-methylindazole (1d) (6.10 g, 28.9 mmol) and sodium hydride (60% in
mineral oil, 1.27 g, 1.1 equiv) were weighed into a flame-dried round-bottom flask containing
a magnetic stir bar. Under a nitrogen atmosphere at room temperature, dry tetrahydrofuran
(
30 mL) was added. The mixture was stirred at room temperature for 15 min, during which
time it became homogeneous. The stirred mixture was cooled to -70°C and a solution of sec-
butyllithium in cyclohexane (1.4M, 45 mL, 2.2 equiv) was added over several minutes. After
1
h at -70°C, dimethylformamide (10 mL) was added over several minutes. The mixture was
allowed to warm to room temperature and was stirred overnight. It was then cooled to 0°C
and carefully treated with 1N hydrochloric acid (60 mL). After a few minutes, solid sodium
bicarbonate was added to basify the mixture to pH 9-10. The layers were separated and the
aqueous phase washed twice with ethyl acetate. The combined organic phases were extracted
with 0.8M sodium hydrogen sulfate (3 x 125 mL). The combined aqueous phases were
washed with ethyl acetate (100 mL) and then the pH was adjusted to ca. 10 with solid sodium
hydroxide. The resulting suspension was extracted with ethyl acetate (3 x 150 mL). The
combined organic phases were washed with brine, dried (magnesium sulfate) and evaporated
1
to give the product as a light-tan solid (3.01 g, 65%). H-NMR (MeOD-D4, 500 MHz) δ 2.58
+
(
3H, s), 7.65 (1H, s), 8.18 (1H, s), 8.24 (1H, s), 9.93 (1H, s). MS m/e 161.06 (M+H) .

Luo, et al.
p. S3
1b
Acquisition Time (sec) 3.2768
Comment
7-methylindazolealdehyde proton_d MeOD v chenling 41
Date
09 Jan 2006 18:05:41
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Number of Transients 16
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7-methylindazolealdehyde
chenling
Owner
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MeOD
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1
.00
1.981.00
3.18
1
8
16
14
12
10
8
6
4
2
0
-2
Chemical Shift (ppm)

Luo, et al.
p. S4
Protection of indazoles using NaH/SEM-Cl in THF.
1
-((2-(Trimethylsilyl)ethoxy)methyl)-1H-indazole (2a)
and 2-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (3a).
NOE (0.5%)
Si
Si
H
H
N
H
N
O
H
O
+
N
N
H
N
H
N
H
NOE (0.5%)
To an oven-dried flask was charged indazole 1a (121 mg, 1.03 mmol) and powdered
NaH (95%, 50 mg, 1.2 equiv.). Anhydrous THF (10 mL) was slowly introduced via syringe
under nitrogen. After the mixture was stirred for 5 min, SEM-Cl (0.22 mL, 1.2 equiv.) was
added via syringe. The mixture was left stirring overnight (16 h). The reaction mixture was
diluted with ethyl acetate and quenched with 0.5 N NaOH. The layers were separated and the
organic layer was washed with brine, dried over Na SO , filtered, and concentrated in vacuo.
2
4
The crude product was purified using silica gel column chromatography (linear gradient: 0-
0%, ethyl acetate/hexanes) to afford 147 mg (58% yield) of 2a and 20 mg (8% yield) of 3a
5
as colorless oils. Structures of 2a and 3a were assigned unequivocally by NOE studies.
1
2
a: NOE (0.5%) between methylene group of SEM and 7-H; H NMR (400 MHz,
3
CDCl ) 8.01(1 H, s), 7.73 (1 H, d, J = 8.8 Hz), 7.58 (1 H, d, J = 9.2 Hz), 7.40 (1 H, t, J = 8.4
Hz), 7.18 (1 H, t, J = 8.0 Hz), 5.735 (2 H, s), 3.55 (2 H, t, J = 8.0 Hz),0.88 (2 H, t, J = 8.0Hz),
1
3
0
1
.02 (9 H, s) ; C NMR (100.6 MHz, CDCl
3
)
139.8, 134.0, 126.7, 124.8, 121.3, 121.0,
+
09.7, 77.7, 66.4, 17.8, -1.2; HRMS m/e 249.1435 (M + H) , calcd. 249.1423.
3
a: NOE (0.5%) between methylene group of SEM and 3-H; analytical data was the
same as reported in the experimental section of the paper.

Luo, et al.
p. S5
2
a
Acquisition Time (sec) 4.0894
Date
Comment
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400.13
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Owner
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0
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0
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.70
.65
.60
.55
.50
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.40
.35
.30
.25
.20
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.05
0
1
.00 1.02 1.04
2.08
5.5
2.08
3.5
2.09
1.0
9.29
0
8
.5
8.0 7.5 7.0
6.5
6.0
5.0
4.5
4.0
3.0
2.5
2.0
1.5
0.5
-0.5
Chemical Shift (ppm)

Luo, et al.
p. S6
2
a
Acquisition Time (sec) 1.2976
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13C
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0
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0
0
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.00
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.90
.85
.80
.75
.70
.65
.60
.55
.50
.45
.40
.35
.30
.25
.20
.15
.10
.05
0
2
20
200
180
160
140
120
100
80
60
40
20
0
-20
Chemical Shift (ppm)

Luo, et al.
p. S7
2a - NOE experiment
4
/26/2006 9:08 AM
luogu
Acquisition Time (sec) 4.0894
Comment
57557-044-1 selnogp_d
Date
26 Jan 2004 16:27:08
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File Name
Frequency (MHz)
Origin
400.13
CDCl3
32768
Nucleus
Original Points Count 32768
Solvent CHLOROFORM-D Spectrum Offset (Hz)
1H
Number of Transients 64
Owner
v
Points Count
Sweep Width (Hz)
3201.0972
8012.82
Temperature (degree C) 27.000
0
0
0
0
0
0
0
0
0
0
0
0
.060
.055
.050
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.005
0
-0.005
-0.010
-0.015
-0.020
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-0.46
100.00
8
.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
Chemical Shift (ppm)
No.
1
(ppm)
[5.46 .. 6.14] 100.000
[7.45 .. 7.78] -0.458
Value
Absolute Value
7.08560e+9
No
1
Color
Structure
Visible
True
2
-3.24245e+7

Luo, et al.
p. S8
3
a
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Comment
57557-045-1 protonlf_d
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Owner
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CHLOROFORM-D
8012.82
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3187.5366
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0
1
.00 0.91
.0 7.5
0.92
7.0
1.92
5.5
1.99
1.96
1.0
8.75
8
6.5
6.0
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
0.5
0
-0.5
Chemical Shift (ppm)

Luo, et al.
p. S9
3
a
Acquisition Time (sec) 1.2976
Comment
57557-045-1 c13_d
Date
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13C
Number of Transients 128
Owner
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Original Points Count 32768
v
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32768
Solvent
CHLOROFORM-D
25252.53
Temperature (degree C) 27.000
11069.1318
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VerticalScaleFactor = 1
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0
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.00
.95
.90
.85
.80
.75
.70
.65
.60
.55
.50
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.40
.35
.30
.25
.20
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.10
.05
0
1
50
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
Chemical Shift (ppm)

Luo, et al.
p. S10
3a - NOE experiment
4
/26/2006 9:12 AM
luogu
Acquisition Time (sec) 4.0894
Comment
57557-045-1 selnogp_d
Date
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Frequency (MHz)
Origin
400.13
CDCl3
32768
Nucleus
Original Points Count 32768
Solvent CHLOROFORM-D Spectrum Offset (Hz)
1H
Number of Transients 64
Owner
v
Points Count
Sweep Width (Hz)
3201.0972
8012.82
Temperature (degree C) 27.000
0
0
0
0
0
0
0
0
0
0
0
0
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.06
.05
.04
.03
.02
.01
0
-
0.01
0.02
-
-0.49
100.00
8
.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
Chemical Shift (ppm)
No.
1
(ppm)
[5.49 .. 5.99] 100.000
[8.02 .. 8.22] -0.491
Value
Absolute Value
6.63464e+9
No
1
Color
Structure
Visible
True
2
-3.26045e+7

Luo, et al.
-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-carbaldehyde (2b)
p. S11
7
and 7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-5-carbaldehyde (3b).
NOE (2.7%)
CH3
Si
+
CH
3
Si
H
H
N
CH H
N
O
3
O
N
N
H
N
OHC
OHC
H
N
NOE (1.1%)
H
OHC
To an oven-dried flask was charged 7-methylindazole-5-carboxaldehyde 1b (712 mg,
4
.45 mmol) and powdered NaH (95%, 135 mg, 5.34 mmol, 1.2 equiv.). Anhydrous THF (10
mL) was slowly introduced via syringe under nitrogen. After the mixture was stirred for 5
min, SEM-Cl (0.83 mL, 1.05 equiv.) was added via syringe. The mixture was left stirring
overnight (16 h). The reaction mixture was diluted with ethyl acetate and quenched with 0.5
N NaOH. The layers were separated and the organic layer was washed with brine, dried over
Na
column chromatography (linear gradient: 5-40%, ethyl acetate/hexanes) to afford 0.50 g
39% yield) of 2b as a light yellow oil and 0.35 g (27% yield) of 3b as an off-white solid.
Structures of 2b and 3b were assigned unequivocally by NOE studies.
2 4
SO , filtered, and concentrated in vacuo. The crude product was purified using silica gel
(
2
b: NOE (2.7%) between 7-CH and methylene group of SEM; R = 0.39 (20% ethyl
3 f
1
acetate/hexanes); H NMR (400 MHz, CDCl ) 9.84 (1 H, s), 7.98 (1 H, s), 7.90 (1 H, s),
3
1
3
7
.53 (1 H, s), 5.71 (2 H, s), 3.43 (2 H, br.), 2.64 (3 H, s), 0.74 (2 H, br.), -0.20 (9 H, s); C
NMR (100.6 MHz, CDCl
3
)
191.2, 141.5, 135.6, 131.2, 126.7, 125.4, 124.8, 122.3, 79.4,
+
6
6.2, 18.6, 17.6, -1.5; MS m/e 291.16 (M + H) .
3
f
b: NOE (1.1%) between 3-H and methylene group of SEM; R = 0.23 (20% ethyl
1
acetate/hexanes); H NMR (400 MHz, CDCl
3
)
9.85 (1 H, s), 8.26 (1 H, s), 7.98 (1 H, s),
7
0
1
.47 (1 H, s), 5.68 (2 H, s), 3.62 (2 H, t, J = 8.0 Hz), 2.55 (3 H, s), 0.88 (2 H, t, J = 8.0 Hz), -
1
3
.10 (9 H, s); C NMR (100.6 MHz, CDCl
3
)
191.8, 151.1, 132.2, 129.2, 127.7, 126.1,
+
21.8, 121.2, 81.9, 67.7, 17.8, 17.0, -1.5; HRMS m/e 291.1533 (M + H) , calcd. 291.1529.

Luo, et al.
p. S12
2
b
Acquisition Time (sec) 4.0894
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Date
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Owner
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1
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1.99 1.01
2.02
2.05
3.06
2.13
8.96
1
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9
8
7
6
5
4
3
2
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Chemical Shift (ppm)

Luo, et al.
p. S13
2
b
Acquisition Time (sec) 1.2976
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Date
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11069.1318
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2
20
200
180
160
140
120
100
80
60
40
20
0
-20
Chemical Shift (ppm)

Luo, et al.
p. S14
2b- NOE experiment
5/1/2006 9:47 AM
luogu
Acquisition Time (sec) 4.0894
Comment
55624-141-1 selnogp_d
Date
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C:\Documents and Settings\luogu\My Documents\My Documents\publications\Indazoles\55624-141-1_40.jdx
File Name
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Origin
400.13
Nucleus
1H
Number of Transients 64
Owner
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Original Points Count 32768
v
Points Count
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32768
Solvent
CHLOROFORM-D
8012.82
3201.0972
Sweep Width (Hz)
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0
0
0
0
.20
.15
.10
.05
0
-
0.05
1
00.00
6.0 5.5
No
-2.67
8
.0
7.5
7.0
6.5
5.0
Color
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
Chemical Shift (ppm)
No.
1
(ppm)
[2.58 .. 2.81]
Value
Absolute Value
-4.06966e+8
Structure
Visible
True
-2.675
1
2
[5.52 .. 6.09] 100.000 1.52157e+10

Luo, et al.
p. S15
3
b
Acquisition Time (sec) 4.0894
Comment
55624-141-2 proton_d
Date
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Nucleus
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Solvent
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3187.5293
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0
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.85
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.10
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0
1
.01
1.02 0.98
1.98
2.04
2.97
2.10
9.17
0
1
0
9
8
7
6
5
Chemical Shift (ppm)
4
3
2
1

Luo, et al.
p. S16
3
b
Acquisition Time (sec) 1.2976
Comment
55624-141-2 c13_d
Date
08 Sep 2003 18:44:47
\\cruncher.wfd.pri.bms.com\nmrread1\d400a\2003\data\luogu\nmr\55624-141-2\11\55624-141-2_11.jdx
File Name
Frequency (MHz)
Origin
100.62
Nucleus
13C
Number of Transients
Owner
128
v
CDCl3
Original Points Count 32768
Points Count
Spectrum Offset (Hz)
32768
Solvent
CHLOROFORM-D
25252.53
Temperature (degree C) 27.000
11069.1318
Sweep Width (Hz)
VerticalScaleFactor = 1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
.00
.95
.90
.85
.80
.75
.70
.65
.60
.55
.50
.45
.40
.35
.30
.25
.20
.15
.10
.05
0
2
20
200
180
160
140
120
100
80
60
40
20
0
-20
Chemical Shift (ppm)

Luo, et al.
p. S17
3b- NOE experiment
5
/1/2006 10:14 AM
luogu
Acquisition Time (sec) 4.0894
Comment
55624-141-2 selnogp_d
Date
08 Sep 2003 21:58:55
C:\Documents and Settings\luogu\My Documents\My Documents\publications\Indazoles\55624-141-2_40.jdx
File Name
Frequency (MHz)
Origin
400.13
Nucleus
1H
Number of Transients 64
Owner
CDCl3
Original Points Count 32768
v
Points Count
Spectrum Offset (Hz)
32768
Solvent
CHLOROFORM-D
8012.82
3201.0972
Sweep Width (Hz)
Temperature (degree C) 27.000
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
.15
.14
.13
.12
.11
.10
.09
.08
.07
.06
.05
.04
.03
.02
.01
0
-0.01
-0.02
-0.03
-1.14
100.00
6
9
8
7
5
4
3
2
1
0
Chemical Shift (ppm)
No.
1
(ppm)
Value Absolute Value
No
1
Color
Structure
Visible
True
[5.46 .. 5.96] 99.999
[8.18 .. 8.42] -1.142
8.69008e+9
-9.92611e+7
2

Luo, et al.
p. S18
Regioselective protection of indazoles using dicyclohexylmethyl amine/SEM-Cl in THF.
2
-((2-(Trimethylsilyl)ethoxy)methyl)-1H-indazole (3a).
H
Si
N
N
N
N
O
General procedure A. See the Experimental Section in the paper.
7
-Methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-5-carbaldehyde (3b).
CH3
CH3
Si
H
N
N
O
N
N
OHC
OHC
According to general procedure A, 7-methylindazole-5-carbaldehyde 1b (185 mg,
1
.15 mmol) was allowed to react with SEM-Cl (0.29 mL) to afford, after purification, 277 mg
(
87% yield) of 3b as a white solid. Analytical data of 3a matched these of 3a previously
prepared by NaH/SEM-Cl/THF treatment..
6
-Bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (3c).
H
Si
Br
N
Br
N
O
N
N
According to general procedure A, 6-bromoindazole (1c) (153 mg, 0.78 mmol) was
allowed to react with SEM-Cl for 3 h to afford, after purification, 158 mg (62% yield) of 3c
1
as a brown oil. H NMR (400 MHz, CDCl ) 8.07 (1 H, s), 7.89 (1 H, s), 7.54(1 H, d, J =
3
8
.8 Hz), 7.15 (1 H, d, J = 9.2 Hz), 5.68 (2 H, s), 3.60 (2 H, t, J = 8.0 Hz), 0.92 (2 H, t, J = 8.0
1
3
Hz), -0.43 (9 H, s) ; C NMR (100.6 MHz, CDCl
3
)
149.5, 126.0, 123.1, 121.9, 120.8,
+
1
20.5, 120.4 81.9, 67.7, 17.8, -1.4; HRMS m/e 327.0531 (M + H) , calcd 327.0528.

Luo, et al.
p. S19
3c
Acquisition Time (sec) 3.9715
Comment
57557-090-1 proton_d CDCl3 v chenling 57
Date
15 Mar 2004 13:58:46
\\cruncher.wfd.pri.bms.com\nmrread1\d400a\2004\data\chenling\nmr\57557-090-1\10\57557-090-1_10.jdx
File Name
Frequency (MHz)
Origin
400.13
Nucleus
1H
Number of Transients 16
57557-090-1
32768
Original Points Count 32768
Solvent
Owner
chenling
2454.8384
Points Count
Sweep Width (Hz)
CHLOROFORM-D
Spectrum Offset (Hz)
8250.83
Temperature (degree C) 24.460
VerticalScaleFactor = 1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
.75
.70
.65
.60
.55
.50
.45
.40
.35
.30
.25
.20
.15
.10
.05
0
0
.96 1.02 1.01
2.09
5.5
2.10
2.11
1.0
9.21
8
.0 7.5 7.0
6.5
6.0
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
0.5
0
-0.5
Chemical Shift (ppm)

Luo, et al.
p. S20
3c
Acquisition Time (sec) 1.2976
Comment
57557-090-1 c13_d CDCl3 v chenling 57
Date
15 Mar 2004 14:06:32
\\cruncher.wfd.pri.bms.com\nmrread1\d400a\2004\data\chenling\nmr\57557-090-1\11\57557-090-1_11.jdx
File Name
Frequency (MHz)
Origin
100.62
Nucleus
13C
Number of Transients 128
57557-090-1
32768
Original Points Count 32768
Solvent
Owner
chenling
11030.1299
Points Count
Sweep Width (Hz)
CHLOROFORM-D
Spectrum Offset (Hz)
25252.53
Temperature (degree C) 26.160
VerticalScaleFactor = 1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
.85
.80
.75
.70
.65
.60
.55
.50
.45
.40
.35
.30
.25
.20
.15
.10
.05
0
1
28
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)

Luo, et al.
-Bromo-7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (3d).
p. S21
5
CH3
CH3
Si
H
N
N
O
N
N
Br
Br
According to general procedure A, 5-bromo-7-methyl-indazole (1d) (202 mg, 0.96
mmol) was allowed to react with SEM-Cl for 3 h to afford, after purification, 263 mg (81%
1
yield) of 3d . H NMR (400 MHz, CDCl
3
) 8.01 (1 H, s), 7.66 (1 H, s), 7.12 (1 H , s), 5.69
1
3
(
2 H, s), 3.61 (2 H, t, J = 8.0 Hz), 2.59 (3 H, s), 0.92 (2 H, t, J = 8.0Hz), -0.04 (9 H, s); C
NMR (100.6 MHz, CDCl
3
)
147.7, 130.3, 128.8, 123.0, 122.2 , 120.0, 115.7, 81.8, 67.5,
+
1
7.8, 16.9, -1.4; HRMS m/e 341.0696 (M + H) , calcd: 341.0607.

Luo, et al.
p. S22
3d
Acquisition Time (sec) 3.9715
Comment
57557-096-1 proton_d CDCl3 v chenling 48
Date
23 Mar 2004 14:02:08
\\cruncher.wfd.pri.bms.com\nmrread1\d400a\2004\data\chenling\nmr\57557-096-1\10\57557-096-1_10.jdx
File Name
Frequency (MHz)
Origin
400.13
Nucleus
1H
Number of Transients 16
57557-096-1
32768
Original Points Count 32768
Solvent
Owner
chenling
2454.8384
Points Count
Sweep Width (Hz)
CHLOROFORM-D
Spectrum Offset (Hz)
8250.83
Temperature (degree C) 23.960
VerticalScaleFactor = 1
0
0
0
0
0
0
0
0
.40
.35
.30
.25
.20
.15
.10
.05
0
1
.00 0.97
0.99
7.0
2.09
5.5
2.08
3.5
3.06
2.13
1.0
9.26
8
.5
8.0 7.5
6.5
6.0
5.0
4.5
4.0
3.0
2.5
2.0
1.5
0.5
0
-0.5
Chemical Shift (ppm)

Luo, et al.
p. S23
3d
Acquisition Time (sec) 1.2976
Comment
57557-096-1 c13_d CDCl3 v chenling 48
Date
23 Mar 2004 14:09:54
\\cruncher.wfd.pri.bms.com\nmrread1\d400a\2004\data\chenling\nmr\57557-096-1\11\57557-096-1_11.jdx
File Name
Frequency (MHz)
Origin
100.62
Nucleus
13C
Number of Transients 128
57557-096-1
32768
Original Points Count 32768
Solvent
Owner
chenling
11030.1299
Points Count
Sweep Width (Hz)
CHLOROFORM-D
Spectrum Offset (Hz)
25252.53
Temperature (degree C) 25.760
VerticalScaleFactor = 1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
.00
.95
.90
.85
.80
.75
.70
.65
.60
.55
.50
.45
.40
.35
.30
.25
.20
.15
.10
.05
0
2
20
200
180
160
140
120
100
80
60
40
20
0
-20
Chemical Shift (ppm)

Luo, et al.
p. S24
Ethyl 2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-5-carboxylate (3e).
H
Si
N
N
O
N
N
EtO C
2
EtO C
2
According to general procedure A, ethyl indazole-5-carboxylate (1e) (175 mg, 0.92
mmol) was allowed to react with SEM-Cl for 3 h to afford, after purification, 261 mg (89%
1
yield) of 3e as a colorless oil. H NMR (400 MHz, CDCl
3
)
8.52 (1 H, s), 8.23 (1 H, s),
7
3
.90 (1 H, d, J = 9.2 Hz), 7.70 (1 H, d, J = 9.2 Hz), 5.72 (2 H, s), 4.38 (2 H, q, J = 6.8 Hz),
1
3
.62 (2 H, t, J = 8.0 Hz), 1.38 (3 H, t, J = 7.2 Hz), 0.92 (2 H, t, J = 8.0 Hz), 0.00 (9 H, s); C
NMR (100.6 MHz, CDCl
3
)
166.9, 150.0, 126.2, 125.1, 125.0, 124.7, 121.6, 117.8, 82.0,
+
6
7.8, 60.9, 17.9, 14.4, -1.5; HRMS m/e 321.1637 (M + H) , calcd: 321.1635.

Luo, et al.
p. S25
3e
Acquisition Time (sec) 3.9715
Comment
57557-089-1 proton_d CDCl3 v chenling 14
Date
12 Mar 2004 14:07:21
\\cruncher.wfd.pri.bms.com\nmrread1\d400a\2004\data\chenling\nmr\57557-089-1\10\57557-089-1_10.jdx
File Name
Frequency (MHz)
Origin
400.13
Nucleus
1H
Number of Transients 16
57557-089-1
32768
Original Points Count 32768
Solvent
Owner
chenling
2454.8384
Points Count
Sweep Width (Hz)
CHLOROFORM-D
Spectrum Offset (Hz)
8250.83
Temperature (degree C) 24.760
VerticalScaleFactor = 1
0
0
0
0
0
0
0
0
0
0
0
0
0
.65
.60
.55
.50
.45
.40
.35
.30
.25
.20
.15
.10
.05
0
1
.02 1.04
2.12
1.96
2.18
2.98 2.23
9.25
8
7
6
5
4
3
2
1
0
Chemical Shift (ppm)

Luo, et al.
p. S26
3e
Acquisition Time (sec) 1.2976
Comment
57557-089-1 c13_d CDCl3 v chenling 14
Date
12 Mar 2004 14:15:07
\\cruncher.wfd.pri.bms.com\nmrread1\d400a\2004\data\chenling\nmr\57557-089-1\11\57557-089-1_11.jdx
File Name
Frequency (MHz)
Origin
100.62
Nucleus
13C
Number of Transients 128
57557-089-1
32768
Original Points Count 32768
Solvent
Owner
chenling
11030.1299
Points Count
Sweep Width (Hz)
CHLOROFORM-D
Spectrum Offset (Hz)
25252.53
Temperature (degree C) 26.460
VerticalScaleFactor = 1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
.00
.95
.90
.85
.80
.75
.70
.65
.60
.55
.50
.45
.40
.35
.30
.25
.20
.15
.10
.05
0
2
20
200
180
160
140
120
100
80
60
40
20
0
-20
Chemical Shift (ppm)

Luo, et al.
p. S27
6
-Nitro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (3f).
H
Si
O N
2
N
O N
2
N
O
N
N
According to general procedure A, 6-nitroindazole (1f) (162 mg, 1.0 mmol) was
allowed to react with SEM-Cl for 20 h to afford, after purification, 229 mg (78% yield) of 3f
1
as a yellow wax. H NMR (400 MHz, CDCl
3
) 8.71 (1 H, s), 8.23 (1 H, s), 7.90 (1 H, d, J =
9
.2 Hz), 7.78 (1 H, d , J = 9.2 Hz), 5.77 (2 H, s), 3.64 (2 H, t, J = 8.4 Hz), 0.94 (2 H, t, J = 8.4
1
3
Hz), 0.00 (9 H, s) ; C NMR (100.6 MHz, CDCl
3
) 146.9, 146.8, 124.5, 123.4, 121.9, 116.2,
+
1
16.1, 82.5, 68.1, 17.9, -1.5; HRMS m/e 294.1279 (M + H) , calcd: 294.1274.

Luo, et al.
p. S28
3
f
Acquisition Time (sec) 3.9715
Comment
57557-103-1 proton_d CDCl3 v chenling 18
Date
25 Mar 2004 14:53:45
\\cruncher.wfd.pri.bms.com\nmrread1\d400a\2004\data\chenling\nmr\57557-103-1\10\57557-103-1_10.jdx
File Name
Frequency (MHz)
Origin
400.13
Nucleus
1H
Number of Transients 16
57557-103-1
32768
Original Points Count 32768
Solvent
Owner
chenling
Points Count
Sweep Width (Hz)
CHLOROFORM-D
Spectrum Offset (Hz)
2454.8384
8250.83
Temperature (degree C) 24.260
VerticalScaleFactor = 1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
.70
.65
.60
.55
.50
.45
.40
.35
.30
.25
.20
.15
.10
.05
0
1
.00 1.05 2.14
2.18
2.18
2.24
1
9.81
0
9
8
7
6
5
4
3
2
Chemical Shift (ppm)

Luo, et al.
p. S29
3
f
Acquisition Time (sec) 1.2976
Comment
57557-103-1 c13_d CDCl3 v chenling 18
Date
25 Mar 2004 15:01:31
\\cruncher.wfd.pri.bms.com\nmrread1\d400a\2004\data\chenling\nmr\57557-103-1\11\57557-103-1_11.jdx
File Name
Frequency (MHz)
Origin
100.62
Nucleus
13C
Number of Transients 128
57557-103-1
32768
Original Points Count 32768
Solvent
Owner
chenling
11030.1299
Points Count
Sweep Width (Hz)
CHLOROFORM-D
Spectrum Offset (Hz)
25252.53
Temperature (degree C) 25.960
VerticalScaleFactor = 1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
.00
.95
.90
.85
.80
.75
.70
.65
.60
.55
.50
.45
.40
.35
.30
.25
.20
.15
.10
.05
0
2
20
200
180
160
140
120
100
80
60
40
20
0
-20
Chemical Shift (ppm)

Luo, et al.
p. S30
5
-Nitro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (3g).
H
N
Si
N
O
N
N
O N
2
O N
2
According to general procedure A, 5-nitroindazole (1g) (169 mg, 1.0 mmol) was
allowed to react with SEM-Cl for 20 h to afford, after purification, 228 mg (75% yield) of 3g
1
as a light yellow wax. H NMR (400 MHz, CDCl
3
) 8.73 (1 H, s), 8.39 (1 H, s), 8.06 (1 H,
d, J = 9.6 Hz), 7.75 (1 H, d, J = 9.6 Hz), 5.74 (2 H, s), 3.64 (2 H, t, J = 8.4 Hz), 0.93 (2 H, t, J
1
3
=
8.4 Hz), -0.05 (9 H, s) ; C NMR (100.6 MHz, CDCl
3
) 149.7, 143.5, 126.8, 120.6, 120.4,
+
1
19.8, 119.0, 82.3, 68.2, 17.8, -1.2; HRMS m/e 294.1276 (M + H) , calcd:296.1274.