E. Dubost et al. / Tetrahedron 70 (2014) 8413e8418
8417
suspension was heated at 80 ꢀC for 10 min and benzophenone
hydrazone (2.1 equiv) and the chosen substituted starting material
1bem (1 equiv) were added. The resulting mixture was heated at
100 ꢀC for the time depicted in Tables 1 and 2. The mixture was
poured in water (20 mL per mmol of 1bem) and CH2Cl2 (20 mL
per mmol of 1bem), filtrated on a short pad of Celite, and
extracted with CH2Cl2 (3ꢁ20 mL per mmol of 1bem). The com-
bined organic layers were washed with water (3ꢁ20 mL per mmol
of 1bem), dried over MgSO4, filtrated and evaporated. The crude
product was eluted on a short pad of silica gel using CH2Cl2 as
eluent and evaporated. The crude was introduced in a microwave
vial with p-toluenesulfonic acid (2 or 3 equiv see Tables 1 and 2)
and solvents (see Tables 1 and 2, 10 mL per mmol of 1bem). The
vial was sealed and the suspension was heated at 100 ꢀC for the
time depicted in Tables 1 and 2. The resulting mixture was poured
in water (20 mL per mmol of 1bem) and extracted with EtOAc
(3ꢁ20 mL per mmol of 1bem). The combined layers were dried
on MgSO4, filtrated, evaporated purified by silica gel
chromatography.
following general procedure A and using AcOEt/cyclohexane (1/3) as
eluent for the chromatography, 3g was obtained as brown powder
(81 mg, 50%). Mp >200 ꢀC. 1H NMR (400 MHz, CDCl3):
d¼7.02 (d,
J¼5.3 Hz,1H), 7.42 (d, J¼5.3 Hz,1H), 7.81 (s,1H), NH signal is missing.
13C NMR (100 MHz, CDCl3):
d
¼110.1, 121.9, 129.3 (2C), 132.9. HRMS
m/z (ESþ) found (MþH)þ 125.0171, requires C5H5N2S 125.0173.
4.4.7. 1H-Pyrazolo[3,4-c]pyridine
(3h). Starting
from
3-
bromopyridine-4-carboxaldehyde 1h (250 mg, 1.34 mmol), fol-
lowing general procedure A, replacing water by a 1 M NaOH solu-
tion in the last extraction and using CH2Cl2 and CH2Cl2/MeOH
(97:3) as eluents for the chromatography, 3j was obtained as
a yellow powder (73 mg, 46%). Mp 95e96 ꢀC. 1H NMR (400 MHz,
CDCl3):
d
¼7.71 (dd, J¼5.6, 0.9 Hz, 1H), 8.20 (d, J¼0.9 Hz, 1H), 8.37 (d,
J¼5.6 Hz, 1H), 9.11 (s, 1H), NH signal is missing. 13C NMR (100 MHz,
CDCl3):
d
¼115.1, 127.2, 134.3, 134.6, 137.2, 138.9. HRMS m/z (ESþ)
found (MþH)þ 120.0568, requires C6H6N3 120.0562.
4.4.8. 3-Methyl-1H-indazole (3i).5d Starting from 20-bromoaceto-
phenone 1i (0.135 mL, 1.0 mmol), following general procedure A
and using CH2Cl2 as eluent for the chromatography, 3i was obtained
as a white powder (86 mg, 65%). Mp 109e110 ꢀC. 1H NMR (400 MHz,
4.4.1. 4-Methoxy-1H-indazole (3b).18 Starting from 2-bromo-6-
methoxybenzaldehyde 1b15 (245 mg, 1.14 mmol), following general
procedure A and using CH2Cl2 as eluent for the chromatography, 3b
was obtained as a white powder (125 mg, 74%). Mp 120e121 ꢀC. 1H
CDCl3):
d
¼2.64 (s, 3H), 7.15 (t, J¼7.4 Hz, 1H), 7.38 (t, J¼7.3 Hz, 1H),
7.44 (d, J¼8.3 Hz, 1H), 7.70 (d, J¼8.1 Hz, 1H), 10.65 (s, 1H). 13C NMR
NMR (400 MHz, CDCl3):
d
¼3.97 (s, 3H), 6.47 (d, J¼7.8 Hz,1H), 7.08 (d,
(100 MHz, CDCl3):
143.2.
d¼11.9, 109.7, 120.1, 120.2, 122.7, 126.7, 141.1,
J¼7.8 Hz,1H), 7.28 (t, J¼7.8 Hz,1H), 8.20 (s,1H),11.07 (s,1H). 13C NMR
(100 MHz, CDCl3):
d¼55.3, 99.6,102.6,115.2,128.0,132.3,141.9,153.7.
4.4.9. 3-(4-Methoxyphenyl)-1H-indazole (3j).22 Starting from (2-
iodophenyl)(4-methoxyphenyl)methanone (400 mg,
1j17
1.18 mmol), following general procedure A and using CH2Cl2 and
CH2Cl2/MeOH (8:2) as eluents for the chromatography, 3j was ob-
tained as a yellow powder (224 mg, 85%). Mp 86e87 ꢀC. 1H NMR
4.4.2. 4-Bromo-1H-indazole
(3c).4c Starting
from
1,6-
dibromobenzaldehyde 1c16 (250 mg, 0.95 mmol), following
general procedure A and using AcOEt/cyclohexane (1:3) as elu-
ent for the chromatography, 3c was obtained as a yellow powder
(46 mg, 25%). Mp 170e172 ꢀC. 1H NMR (400 MHz, CDCl3):
d
¼7.26
(400 MHz, CDCl3):
1H); 7.33e7.39 (m, 2H); 7.93 (d, J¼8.8 Hz, 2H); 8.00 (d, J¼8.3 Hz,
1H), 11.02 (s, 1H). 13C NMR (100 MHz, CDCl3):
¼55.5, 110.3, 114.5
(2C), 121.0, 121.3 (2C), 126.4, 127.0, 129.0 (2C), 141.9, 145.8, 159.9.
d
¼3.88 (s, 3H); 7.06 (d, J¼8.8 Hz, 2H); 7.22 (m,
(dd, J¼8.3, 7.3 Hz, 1H), 7.34 (dd, J¼7.4, 0.7 Hz, 1H), 7.45 (dt,
J¼8.3, 0.8 Hz, 1H), 8.11 (d, J¼0.9 Hz, 1H), 10.32 (br s, 1H). 13C
d
NMR (100 MHz, CDCl3):
140.7.
d
¼109.0, 114.8, 124.2, 124.7, 128.0, 135.4,
4.4.10. 6-Fluoro-3-(4-methoxyphenyl)-1H-indazole
(3k). Starting
4.4.3. 5-Methoxy-1H-indazole (3d).19 Starting from 2-bromo-5-
methoxybenzaldehyde 1d (500 mg, 2.32 mmol), following general
procedure A and using CH2Cl2 as eluent for the chromatography, 3d
was obtained as a white powder (264 mg, 76%). Mp 171e172 ꢀC. 1H
from (2-bromo-4-fluorophenyl)(4-methoxyphenyl)methanone 1k
(0.25 g, 0.81 mmol), following general procedure A and using
AcOEt/cyclohexane (1:6) and (1:3) as the eluent for the chroma-
tography, 3k was obtained as a yellow powder (131 mg, 67%). Mp
NMR (400 MHz, CDCl3):
d
¼3.86 (s, 3H), 7.07e7.11 (m, 2H), 7.40 (d,
127e128 ꢀC. 1H NMR (400 MHz, CDCl3):
d
¼3.89 (s, 3H), 6.74 (dd,
J¼8.8 Hz, 1H), 8.02 (s, 1H), 10.58 (s, 1H). 13C NMR (100 MHz, CDCl3):
J¼9.2 Hz, J¼2.2 Hz, 1H), 6.94 (td, J¼8.9 Hz, J¼2.2 Hz, 1H), 7.07 (d,
d¼55.6, 99.9, 110.6, 119.1, 123.5, 134.4, 135.9, 154.7.
J¼8.7 Hz, 2H), 7.88 (m, 3H), NH signal is missing. 13C NMR
(100 MHz, CDCl3):
d
¼55.5, 96.0 (d, J¼26 Hz), 111.2 (d, J¼26 Hz),
4.4.4. 5-Fluoro-1H-indazole (3e).20 Starting from 2-bromo-5-
fluorobenzaldehyde 1e (500 mg, 4.46 mmol), following general
procedure A and using CH2Cl2 as eluent for the chromatography, 3e
was obtained as a white powder (320 mg, 95%). Mp 120e122 ꢀC. 1H
114.7 (2C), 118.0, 122.7 (d, J¼11 Hz), 125.7, 129.2 (2C), 142.2 (d,
J¼13 Hz), 145.9, 160.2, 166.6 (d, J¼244 Hz). HRMS m/z (ESþ) found
(MþH)þ 243.0927, requires C14H12FN2O 243.034.
NMR (400 MHz, CDCl3):
J¼1.9 Hz, J¼8.8 Hz, 1H), 7.46 (dd, J¼3.9 Hz, J¼8.8 Hz, 1H), 8.07 (s,
1H), 10.41 (s, 1H). 13C NMR (100 MHz, CDCl3):
110.8 (d, J¼9 Hz), 116.6 (d, J¼27 Hz), 123.3 (d, J¼11 Hz), 134.9, 137.0,
158.0 (d, J¼237 Hz).
d
¼7.19 (dt, J¼2.9 Hz, J¼8.8 Hz,1H), 7.39 (dd,
4.4.11. 3-(4-Chlorophenyl)-5-nitro-1H-indazole (3l). Starting from
(2-bromo-5-nitrophenyl)(4-chlorophenyl)methanone 1l (0.94 g,
2.76 mmol), following general procedure A and CH2Cl2 and CH2Cl2/
MeOH (98:2) as eluents for the chromatography, 3l was obtained as
a yellow powder (0.256 mg, 36%). Mp 201e202 ꢀC. 1H NMR
d¼104.9 (d, J¼24 Hz),
(400 MHz, DMSO):
d
¼7.60 (d, J¼8.5 Hz, 2H), 7.76 (d, J¼9.2 Hz, 1H),
4.4.5. 6-Methyl-1H-indazole (3f).21 Starting from 2-bromo-4-
methylbenzaldehyde 1f (500 mg, 2.51 mmol), following general
procedure A and using CH2Cl2 as eluent for the chromatography, 3f
was obtained as a white powder (310 mg, 94%). Mp 180e182 ꢀC. 1H
8.01 (d, J¼8.5 Hz, 2H), 8.22 (dd, J¼9.2 Hz, J¼1.6 Hz, 1H), 8.87 (d,
J¼1.6 Hz, 1H), NH signal is missing. 13C NMR (100 MHz, DMSO):
d
¼111.8, 118.6, 119.2, 121.4, 128.9 (2C), 129.4 (2C), 131.2, 133.5, 142.4,
143.6, 145.4. HRMS m/z (ESþ) found (MþH)þ 274.0371, requires
NMR (400 MHz, CDCl3):
d
¼2.50 (s, 3H), 7.01 (d, J¼8.3 Hz,1H), 7.28 (s,
C13H9ClN3O2 274.0383.
1H), 7.64 (d, J¼8.3 Hz, 1H), 8.02 (s, 1H), 10.04 (s, 1H). 13C NMR
(100 MHz, CDCl3):
d¼21.9,109.0,120.4,121.4,123.3,134.9,137.2,140.7.
4.4.12. 5-Chloro-3-(4-methoxyphenyl)-1H-indazole (3m). Starting
from (2-bromo-5-chlorophenyl)(4-methoxyphenyl)methanone 1m
(1.12 g, 3.44 mmol), following general procedure A and using
CH2Cl2 and CH2Cl2/MeOH (98:2) as eluents for the chromatography,
4.4.6. 1H-Thieno[3,2-c]pyrazole
(3g). Starting
from
3-
bromothiophene-2-carboxaldehyde 1g (250 mg, 1.3 mmol),