1446
R.M. Claramunt et al. / European Journal of Medicinal Chemistry 46 (2011) 1439e1447
for C7H2F4N2: C, 44.23; H, 1.06; N, 14,74. Found: C, 44.34; H, 1.17; N,
4.2.4. 3-Hydroxy-4,6-difluoro-1H-indazole (20)
14.62. 1H NMR (CDCl3)
d
10.79 (br s, 1H, NH), 8.24 (d, 5JF7 ¼ 3.1, 1H,
In a three-neck round-bottom flask equipped with a reflux
condenser, methyl 2,4,6-trifluorobenzoate (49) (0.20 g, 1.1 mmol)
was dissolved in tetrahydrofuran (20 mL); then, a solution of 98%
hydrazine monohydrate (0.15 g, 3.0 mmol) in ethanol (10 mL) was
added dropwise. The mixture was heated at 70 ꢃC for 24 h. After
cooling at room temperature, the solution was decanted and the
organic solvent evaporated under vacuum. The solid residue was
washed with dichloromethane and dried to afford 20 (0.13 g, 76%)
as a white solid. Mp 293.5 ꢃC. Anal. Calcd for C7H4F2N2O: C, 49.42;
H, 2.37; N, 16.47. Found: C, 49.44; H, 2.49; N, 16.27. 1H NMR
3
5
H3); 19F NMR (CDCl3)
d
ꢀ145.5 (dd, JF5 ¼18.9, JF7 ¼ 18.9, F4),
3
3 4
ꢀ165.5 (ddd, JF4 ¼18.9, JF6 ¼ 18.9, JF7 ¼ 2.2, F5), ꢀ156.9 (dd,
3JF5 ¼18.9, JF7 ¼ 18.9, F6), ꢀ159.0 (dd, JF6 ¼ 18.9, JF4 ¼18.9, F7);
3
3
5
13C NMR (THF-d8)
d
132.2 (d, 1J ¼ 194.9, C3), 111.4 (dd, 2J ¼ 20.8,
3J ¼ 3.2, C3a), 139.6 (dddd, 1J ¼ 250.1, 2J ¼ 11.4, 3J ¼ 4J ¼ 3.8, C4),
135.8 (ddd, 1J ¼ 242.7, 2J ¼ 2J ¼ 15.5, C5), 139.8 (dddd, 1J ¼ 247.6,
2J ¼ 2J ¼ 15.1, 3J ¼ 2.5, C6), 132.7 (ddd, 1J ¼ 250.9, 2J ¼ 14.7, 3J ¼ 4.1,
C7), 126.3 (ddd, 2J ¼ 15.4, 3J ¼ 6.6, 3J ¼ 3.5, C7a); 15N NMR (THF-d8,
T ¼ 207 K)
d
ꢀ201.1 (N1), ꢀ58.6 (N2).
2,3,5,6-Tetrafluoro-4-(hydrazonomethyl)phenylhydrazine (45)
was obtained as a yellow solid. Mp > 300 ꢃC. Exact mass (ESIþ) calc
(DMSO-d6) d 11.8 (br s, 1H, NH), 10.9 (br s, 1H, OH), 6.71 (ddd,
4
3
4
3JF4 ¼ 3JF6 ¼ 10.3, JH7 ¼ 1.9, 1H, H5), 7.09 (dd, JF6 ¼ 9.2, JH5 ¼1.9,
for C7H6F4N4 222.0529, found 222.0527. 1H NMR (DMSO-d6)
d
7.62
1H, H7); 19F NMR (DMSO-d6)
d
ꢀ115.9 (dd, JH5 ¼ 9.6, JF6 ¼ 8.4,
3
4
(s, 1H, eCH]Ne), 7.11 (s, 2H, H2NeNHeC1), 6.94 (s, 1H, eNHe),
F4), ꢀ111.6 (br s, F6); 13C NMR (DMSO-d6)
d 153.6 (s, C3), 98.9
4.46 (br s, 2H, ]NeNH2); 19F NMR (DMSO-d6)
d
ꢀ147.9 (m, F3 and
(d, 2J ¼ 20.2, C3a), 155.7 (dd, 1J ¼ 253.3, 3J ¼ 16.7, C4), 94.4 (dd,
2J ¼ 30.5, 2J ¼ 23.3, C5), 161.8 (dd, 1J ¼ 242.7, 3J ¼ 11.7, C6), 92.0
(dd, 2J ¼ 26.1, 4J ¼ 4.7, C7), 143.6 (dd, 3J ¼ 15.1, 3J ¼ 10.3, C7a); 15N
F5), ꢀ159.3 (m, F2 and F6); 13C NMR (DMSO-d6)
d
143.9 (ddd,
1J ¼ 246.6, 2J ¼ 12.7, 3J ¼ 3.4, C3 and C5), 136.8 (ddd, 1J ¼ 239.2,
2J ¼ 15.3, 3J ¼ 3.8, C2 and C6), 129.8 (dd, 2J ¼ 2J ¼ 10.0, C1), 126.1
(eCH]), 103.5 (dd, 2J ¼ 2J ¼ 13.2, C4).
NMR (THF-d8, T ¼ 207 K)
d
ꢀ224.1 (N1, 1J ¼ 107.1), ꢀ117.9 (N2).
Reaction of 2,3,4,5,6-pentafluorobenzaldehyde (40) with hydra-
zine monohydrate in toluene leads to 2-bis(perfluorobenzylidene)
hydrazine (42), obtained after purification by column chromatog-
raphy on silica gel with hexane/ethyl acetate 40:1 and crystallization
in chloroform as yellow needles (62%). Mp 124e130 ꢃC (lit. [22]
4.2.5. 3-Hydroxy-6,7-difluoro-1H-indazole (21)
In a three-neck round-bottom flask equipped with a reflux
condenser, methyl 2,3,4-trifluorobenzoate (50) (0.21 g, 1.1 mmol)
was dissolved in toluene (10 mL), then, a solution of 98% hydrazine
monohydrate (0.24 g, 4.7 mmol) in ethanol (10 mL) was added
dropwise. The mixture was heated at 80 ꢃC for 24 h. After cooling at
room temperature 5 mL of toluene were added, the solution was
decanted and the organic solvent evaporated under vacuum. The
solid residue was washed with pentane and 0.16 g of a crude solid
was obtained. After silica gel chromatography with (hexane/ethyl
acetate 3:1), 21 was obtained (0.11 g, 60%) as a white solid. Mp
237.3 ꢃC (DSC). Anal. Calcd for C7H4F2N2O: C, 49.42; H, 2.37; N,
131 ꢃC). 1H NMR (CDCl3)
d
8.76 (s, 1H, eCH]Ne); 13C NMR (CDCl3)
d
108.9 (m, C1), 137.9 (dm, C3 and C5), 142.9 (dm, C2 and C6), 146.0
(dm, C4), 152.3 (d, eCH]Ne); 19F NMR (CDCl3)
d
ꢀ161.5 (m, F3, F30,
F5 and F50), ꢀ148,9 (m, F4 and F40), ꢀ139,0 (m, F2, F20, F6 and F60). If
the reaction of 2,3,4,5,6-pentafluorobenzaldehyde (40) was carried
out with hydrazine monohydrate in ethanol/water at low tempera-
ture and high-dilution, perfluorobenzylidenehydrazine (41) was
obtained as awhite solid (89%). Mp 68e69 ꢃC (lit. [22] 68 ꢃC).1H NMR
16.47. Found: C, 49.43; H, 2.61; N, 16.01. 1H NMR (DMSO-d6)
d 12.1
3
4
(CDCl3)
d
6.00 (s, 2H, NH2), 7.70 (s, 1H, eCH]Ne); 13C NMR (CDCl3)
(br s, 1H, NH), 11.0 (br s, 1H, OH), 7,43 (ddd, JH5 ¼ 8.8, JF6 ¼ 4.4,
3 3 4
d
110.4 (m, C1), 128.7 (d, eCH]Ne), 137.8 (dm, C3 and C5), 140.5
5JF7 ¼ 0.7, 1H, H4), 6.99 (ddd, JF6 ¼ 11.0, JH4 ¼ 8.8, JF7 ¼6.6, 1H,
(dm, C2 and C6),144.5 (dm, C4); 19F NMR (CDCl3)
d
ꢀ163.2 (m, F3 and
H5); 19F NMR (DMSO-d6)
d
ꢀ145.2 (ddd, JF7 ¼ 20.3, JH5 ¼10.9,
3 4
3
3
F5), ꢀ155.7 (m, 1F, F4), ꢀ144.2 (m, F2 and F6).
4JH4 ¼ 3.1, F6), e158.7 (dd, JF6 ¼ 20.3, JH5 ¼ 6.5, F7); 13C NMR
(DMSO-d6)
d
155.9 (s, C3), 112.7 (d, 3J ¼ 4.3, C3a), 116.5 (dd, 2J ¼ 9.6,
4.2.2. 3,7-Dinitro-1H-indazole (18)
3J ¼ 4.5, C4),109.1 (d, 2J ¼ 21.0, C5),148.2 (dd, 1J ¼ 241.2, 3J ¼ 9.0, C6),
135.0 (dd, 1J ¼ 247.3, 3J ¼ 16.3, C7), 131.7 (dd, 2J ¼ 11.6, 3J ¼ 3.6, C7a);
This compound was prepared according to Ref. [25] and
obtained as a yellow solid. Mp 220e222 ꢃC (lit. [25] 220 ꢃC). 1H
15N NMR (THF-d8, T ¼ 207 K)
d
ꢀ234.4 (N1), ꢀ115.1 (N2).
NMR (CD3CN)
d
12.83 (br s,1H, NH), 7.65 (t,1H, 3J ¼ 8.0, H5), 8.48 (d,
1H, 3J ¼ 7.9, H6), 8.62 (d, 1H, 3J ¼ 8.1, H4); 13C NMR (CD3CN)
d
151.5
4.2.6. 3-Hydroxy-4,6-difluoro-7-nitro-1H-indazole (24)
(m, C3), 120.2 (d, 2J ¼ 9.5, C3a), 130.3 (dd, 1J ¼ 171.7, 3J ¼ 8.6, C4),
126.4 (d, 1J ¼ 168.7, C5), 126.8 (ddd, 1J ¼ 168.5, 2J ¼ 2.3, 3J ¼ 8.6, C6),
134.9 (m, C7), 135.4 (dd, 3J ¼ 3J ¼ 6.7, C7a); 15N NMR (CD3CN)
A round-bottomed flask containing 3-hydroxy-4,6-difluoro-
1H-indazole (20) (0.06 g, 0.35 mmol) and potassium nitrate
(0.04 g, 0.4 mmol) was placed in an iceewater bath. Then,
concentrated sulphuric acid 95e98% conc. (0.8 mL, d ¼ 1.84 g/mL)
was added dropwise, and the mixture kept at 0e4 ꢃC for 1 h. The
mixture was stirred at room temperature for 24 h and poured into
iceewater (5 mL). The solution was extracted with ethyl acetate
(3 ꢁ 20 mL), dried with anhydrous sodium sulfate and solvent was
removed under reduced pressure to afford a yellow solid. The
product was purified by silica gel chromatography with (hexane/
ethyl ether 4:1), to afford 24 (0.045 g, 60%) as a yellow solid. Mp
217.4 ꢃC (DSC). Anal. Calcd for C8H6F2N3O2: C, 39.08; H, 1.41; N,
d
ꢀ14.2 (NO2), the other nitrogen atoms were not detected.
4.2.3. General procedure for esterifications
A solution of 2,4,6-trifluorobenzoic acid (47) or 2,3,4-tri-
fluorobenzoic acid (48) (0.3 g, 1.7 mmol) in dry methanol (10 mL)
was prepared in a three-necked, round-bottom flask fitted with
a reflux condenser and a calcium chloride tube. The flask was
placed in an ice/water bath, thionyl chloride (1.4 mL) was then
added dropwise, and the mixture was heated at 60e65 ꢃC for three
days under argon. After removal of solvent, the resulting residue
was purified by extraction with pentane in the case of 49 and using
column chromatography on silica gel (hexane/diethyl ether 6:1)
for 50.
19.53; Found: C, 39.36; H, 1.61; N, 19.00. 1H NMR (DMSO-d6)
d 12.8
(br s, 1H, NH), 11.7 (br s, 1H, OH), 7.13 (dd, 3JF6 ¼ 12.4, 3JF4 ¼ 9.9, 1H,
4
3
H5); 19F NMR (DMSO-d6)
d
ꢀ101.2 (dd, JF6 ¼ 17.7, JH5 ¼ 9.8,
F4), ꢀ110.3 (br s, F6); 13C NMR (DMSO-d6)
d 154.6 (s, C3), 101.5 (d,
Methyl 2,4,6-trifluorobenzoate (49): Colorless oil, yield 85% (lit.
2J ¼ 20.1, C3a), 159.2 (dd, 1J ¼ 265.4, 3J ¼ 16.8, C4), 96.4 (dd,
2J ¼ 28.7, 2J ¼ 25.5, C5), 158.4 (dd, 1J ¼ 265.9, 3J ¼ 14.4, C6), 118.6
(dd, 2J ¼ 8.8, 4J ¼ 5.0, C7), 136.2 (dd, 3J ¼ 11.3, 3J ¼ 2.5, C7a); 15N
[41] Bp 105e110 ꢃC/15 mmHg). 1H NMR (CDCl3)
6.72 (dd, 3J ¼ 3J ¼ 8.3, 2H, H3 and H5).
d 3.94 (s, 3H, OCH3),
Methyl 2,3,4-trifluorobenzoate (50): Colorless oil, yield 81%. 1H
NMR (THF-d8, T ¼ 207 K)
d
ꢀ216.3 (1J ¼ 112.3, N1), ꢀ112.4 (N2), the
NMR (CDCl3) d 3.95 (s, 3H, OCH3), 7.03 (m, 1H, H6), 7.74 (m, 1H, H5).
NO2 signal was not detected.