718
B. Maggio et al. / European Journal of Medicinal Chemistry 54 (2012) 709e720
3H, CH3), 5.24 (d, 1H, J ¼ 6.90 Hz, pyrazoline H-4), 6.34 (d, 1H,
J ¼ 6.90 Hz, exchangeable with D2O, pyrazoline OH), 6.11e7.78 (a
set of signals, 8H, aromatic protons). Anal. (C19H19N3O2) C, H, N.
(CH3), 119.93 (C), 121.07 (CH), 122.73 (C), 123.34 (CH), 127.077 (CH),
128.32 (CH þ C), 129.34 (CH), 130.12 (CH), 132.17 (CH), 134.60 (CH),
135.56 (C), 137.73 (C), 140.01 (C), 140.21 (C), 161.87 (CO). Anal.
(C18H14N2O2) C, N, H.
3.1.8.3. ꢂ(30SR,40RS)-40-hydroxy-2,50-dimethyl-20-(4-methylphenyl)-
2’0,40-dihydro spiro[isoindole-1,30-pyrazol]-3(2H)-one 5d. Yield:
3.1.9.3. 1-(4-Methylphenyl)-3-methylisochromeno[4,3-c]pyrazole-þ5(1H)-
22%; m.p:. 244e246 ꢀC; I.R.
n
[cmꢁ1]: 3240e3140 (OH), 1680 (CO);
one 7d. Yield: 42%; m.p.: 178e180 ꢀC; MS (m/z): 290 (M ); I.R.
1H NMR (DMSO-d6)
d
[ppm]: 2.10 (s, 6H, 2 ꢃ CH3), 2.53 (s, 3H, CH3),
(cmꢁ1): 1740, 1725 (CO). 1H NMR (DMSO-d6)
d
[ppm]: 2.35 (s, 3H,
CH3), 2.46 (s, 3H, CH3), 7.10e8.30 (a set of signals, 8H, aromatic
protons). 13C NMR (CDCl3)
[ppm]: 10.20 (CH3), 21.34 (CH3), 119.91
5.25 (d, 1H, J ¼ 6.70 Hz, pyrazoline H-4), 6.35(d, 1H, J ¼ 6.70 Hz,
exchangeable with D2O, pyrazoline OH), 6.45e7.80 (a set of signals,
8H, aromatic protons). Anal. (C19H19N3O2) C, H, N.
d
(C), 121.01 (CH), 122.78 (C), 126.33 (2 ꢃ CH), 128.30 (CH þ C), 130.22
(2 ꢃ CH), 132.14 (CH), 134.59 (CH), 135.41 (C), 137.62 (C), 137.78 (C),
139.56 (C), 161.88 (CO). Anal. (C18H14N2O2) C, N, H.
3.1.8.4. ꢂ(30SR,40RS)-40-hydroxy-2-methyl-20-phenyl-20,40-dihydrospiro
[isoindole-1,30-pyrazol]-3(2H)-one þ 5e. Yield:
(br, OH), 1690,1675 (CO); 1H NMR (DMSO-d6)
21%;
[cmꢁ1]: 3220
d [ppm]: 2.58 (s, 3H,
m.p.:
202e203 ꢀC; MS (m/z): 262 (M eCH3NH2); I.R.
n
3.1.9.4. 1-Phenylisochromeno[4,3-c]pyrazoþle-5(1H)-one 7e. Yield:
41%, m.p.: 174e176 ꢀC; MS (m/z): 262 (M ); I.R. (cmꢁ1): 1730, 1720
CH3), 5.47 (d, 1H, J ¼ 6.81 Hz, pyrazoline H-4), 6.35 (d, 1H,
J ¼ 6.81 Hz, exchangeable with D2O, pyrazoline OH), 6.33e7.78
(a set of signal, 10H, aromatic and pyrazoline H-3 protons). Anal.
(C17H15N3O2) C, H, N.
(CO); 1H NMR (DMSO-d6)
d
[ppm]: 2.51 (s, 3H, CH3), 7.07e8.32 (a
set of signal, 10H, pyrazole and phenyl protons). 13C NMR (CDCl3)
d
[ppm]: 120.02 (C), 120.89 (CH), 122.55 (C), 126.55 (2 ꢃ CH), 126.87
(CH), 127.99 (C), 128.54 (CH), 129.72 (3 ꢃ CH), 132.25 (CH), 134.67
(CH), 139.57 (C), 140.32 (C), 161.50 (CO). Anal. (C16H10N2O2) C, N, H.
3.1.8.5. ꢂ(30SR,40RS)-6-chloro-40-hydroxy-2,50-dimethyl-20-phenyl-
20,40-dihydro spiro[isoindole-1,30-pyrazol]þ-3(2H)-one 5f. Yield: 24%;
3.1.9.5. 8-Chloro-3-methyl-1-phenylisochromeno[4,3-c]pyrazole-5(1H)-
m.p.: 238e239 ꢀC; MS (m/z): 310 (M eCH3NH2); I.R.
3340e3140 (OH), 1685e1655 (CO); 1H NMR (DMSO-d6)
n
[cmꢁ1]:
[ppm]:
one 7f. Yield 74%, m.p.: 243e244 ꢀC; MS (m/z): 310 (Mþ); I.R.
d
(cmꢁ1): 1733, 1718 (CO); 1H NMR (DMSO-d6)
d [ppm]: 2.36 (s, 3H,
2.10 (s, 3H, CH3), 2.53 (s, 3H, CH3), 5.33 (d, 1H, J ¼ 6.57 Hz, pyr-
azoline H-4), 6.40 (d, 1H, J ¼ 6.57 Hz, exchangeable with D2O, pyr-
azoline OH), 6.57e7.91 (a set of signals, 8H, aromatic protons). Anal.
(C18H16ClN3O2) C, H, N.
CH3), 6.95e8.28 (a set of signals, 8H, aromatic protons). Anal.
(C17H11ClN2O2) C, N, H.
3.1.9.6. 7-Chloro-3-methyl-1-phenylisochromeno[4,3-c]pyrazole-þ5(1H)-
one 7g. Yield: 66%; m.p.: 199e200 ꢀC; MS (m/z): 310 (M ); I.R.
3.1.8.6. ꢂ(30SR,40RS)-5-chloro-40-hydroxy-2,50-dimethyl-20-phenyl-
20,40-dihydro spiro[isoindole-1,30-pyrazol]þ-3(2H)-one 5g. Yield: 25%;
(cmꢁ1): 1735, 1717 (CO). 1H NMR (DMSO-d6)
d
[ppm]: 2.36 (s, 3H,
CH3), 7.08e8.21 (a set of signals, 8H, aromatic protons). 13C NMR
(CDCl3) [ppm]: 10.17 (CH3), 121.33 (C), 122.14 (C), 122.47 (CH),
m.p.: 240e243 ꢀC; MS (m/z): 310 (M eCH3NH2); I.R.
3340e3140 (OH), 1685e1660 (CO); 1H NMR (DMSO-d6)
n
d
[cmꢁ1]:
[ppm]:
d
126.40 (2 ꢃ CH), 126.58 (C), 129.57 (CH), 129.79 (2 ꢃ CH), 131.78
(CH), 134.38 (CH), 134.91 (C), 135.88 (C), 137.79 (C), 140.05 (C),
160.71 (CO). Anal. (C17H11ClN2O2) C, N, H.
2.10 (s, 3H, CH3), 2.54 (s, 3H, CH3), 5.27 (d, 1H, J ¼ 6.50 Hz, pyr-
azoline H-4), 6.41 (d, 1H, J ¼ 6.50 Hz, exchangeable with D2O, pyr-
azoline OH), 6.57e7.85 (a set of signals, 8H, aromatic protons). Anal.
(C18H16ClN3O2) C, H, N.
3.1.9.7. 3,7-Dimethyl-1-phenylisochromeno[4,3-c]pyrazole-5(1H)-
one 7h. Yield: 76%; m.p.: 231e233 ꢀC; MS (m/z): 290 (Mþ); I.R.
3.1.8.7. ꢂ(30SR,40RS)-40-hydroxy-2,5,50-trimethyl-20-phenyl-20,40-dihydro
spiro[isoindole-1,30-pyrazol]-3(2H)-one 5h. Yield: 24%; m.p.:
(cmꢁ1): 1725, 1717 (CO). 1H NMR (DMSO-d6)
d
[ppm]: 2.35 (s, 3H,
CH3), 2.40 (s, 3H, CH3), 7.02e8.10 (a set of signals, 8H, aromatic
protons). 13C NMR (CDCl3)
[ppm]: 10.20 (CH3), 21.36 (CH3), 77.23
254e255 ꢀC; I.R.
NMR (DMSO-d6)
n
[cmꢁ1]: 3340e3140 (OH), 1680e1650 (CO). 1H
d
d
[ppm]: 2.09 (s, 3H, CH3), 2.45 (s, 3H, CH3), 2.52 (s,
(C), 119.88 (C), 120.99 (CH), 122.95 (C), 125.73 (C), 126.43 (2 ꢃ CH),
129.25 (CH), 129.61 (2 ꢃ CH), 132.12 (CH), 135.70 (CH), 137.38 (C),
138.80 (C), 140.36 (C), 162.02 (CO). Anal. (C18H14N2O2) C, N, H.
3H, CH3), 5.25 (d, 1H, J ¼ 7.40 Hz, pyrazoline H-4), 6.34 (d, 1H,
J ¼ 7.40 Hz, exchangeable with D2O, pyrazoline OH), 6.57e7.65 (a
set of signals, 8H, aromatic protons). Anal. (C19H19N3O2) C, N, H.
3.2. X-ray structure determination
3.1.9. General procedure for the preparation of compounds 7beh
0.9 mmol of 5beh were melted at 260 ꢀC for 5 min and the
obtained material was crystallized from ethanol.
Crystals of C19H19N3O.2C2H5OH (5h$C2H5OH) and C19H19N3O2
(5d) were obtained from an ethanolic solution at room tempera-
ture as yellow cubes. The intensity data were collected on Enraf
3.1.9.1. 1-(3-Chlorophenyl)-3-methylisochromeno[4,3-c]pyrazole-5(1H)-
Nonius CAD-4 diffractometer with MoK
a
(
l
¼ 0.71073 Å) radiation
one 7b. Yield: 30%; m.p.: 188e189 ꢀC; MS (m/z): 310 (Mþ); I.R.
at room temperature. The lattice parameters were determined by
least-squares refinements of 25 high angle reflections. The
structures were solved by direct methods [16] and the refine-
ments were carried out by full-matrix least-squares using SHELX-
97 [17] and WINGX [18]. All non-H-atoms were refined aniso-
tropically. The H-atoms positions of 5h$C2H5OH were detected in
a difference Fourier synthesis and refined with isotropic thermal
factors, while hydrogen atoms of the solvent molecule and of 5d
were introduced in calculated positions in their described geom-
etries and allowed to ride on the attached carbon atom with fixed
isotropic thermal parameters (1.2Ueq of the parent carbon atom).
Geometrical calculations were carried out using the program
PARST [19].
(cmꢁ1): 1745, 1718 (CO). 1H NMR (DMSO-d6)
d
[ppm]: 2.36 (s, 3H,
CH3), 7.15e8.30 (a set of signals, 8H, aromatic protons). 13C NMR
(CDCl3) [ppm]: 10.19 (CH3), 119.96 (C), 120.93 (CH), 122.73 (C),
d
124.44 (CH), 126.70 (CH), 127.91 (C), 128.63 (CH), 129.46 (CH),
130.55 (CH), 132.33 (CH), 134.76 (CH), 135.32 (C), 136.52 (C), 138.12
(C), 141.30 (C), 161.59 (CO). Anal. (C17H11ClN2O2) C, N, H.
3.1.9.2. 1-(3-Methylphenyl)-3-methylisochromeno[4,3-c]pyrazolþe-
5(1H)-one 7c. Yield: 42%; m.p.: 178e180 ꢀC; MS (m/z): 290 (M );
I.R. (cmꢁ1): 1735, 1718 (CO). 1H NMR (DMSO-d6)
d
[ppm]: 2.36
(s, 3H, CH3), 2.42 (s, 3H, CH3), 7.12e8.30 (a set of signals, 8H,
aromatic protons). 13C NMR (CDCl3)
[ppm]: 10.21 (CH3), 21.34
d