48
S. Malik et al. / European Journal of Medicinal Chemistry 84 (2014) 42e50
The crude product was purified using column chromatography
with hexane/EtOAc (25:2) as the eluting solvent. Fractions con-
taining the desired compound were combined and dried under
vacuum to give 3 as colorless oil. Rf ¼ 0.70 (hexane e EtOAc, 5:1);
7d/0.60 mL, 8a/0.63 g, 8b/0.55 g, 8c/0.80 g, 8d/0.50 mL, 9ae9c/
0.5 g, 5.0 mmol) in 20 ml of water. The flask was heated in a mantle
until the temperature of the contents reached 210 ꢀC. The residue
was cooled somewhat and dissolved in 50 ml of hot 95% ethyl
alcohol. After mixing with a moderate amount of activated charcoal
and filtering, the yellowish filtrate was cooled thoroughly in an ice-
bath. The white product was filtered off and dried in vacuo. The
obtained product was crystallized from anhydrous ethanol.
Yield: 82%; 1H NMR (CDCl3, ppm)
d
: 7.70 (d, 1H, J ¼ 7.10 Hz, Ar-H),
7.60e7.55 (m, 2H, Ar-H), 7.31 (m, 1H, Ar-H), 2.30 (s, 3H, CH3); 13C
NMR (CDCl3, ppm) : 162.8 (C), 154.5 (C), 130.5 (CH), 123.5 (CH),
d
122.2 (C), 121.6 (CH), 108.5 (CH), 12.8 (CH3); ESI-MS: 134.10(C8H7NO
[M þ H]þ).
4.1.7.1. 3-(Benzo[d]isoxazol-3-yl)-1-ethylpyrrolidine-2, 5-dione (7a).
4.1.4. Benzo[d]isoxazole-3-carbaldehyde (4)
1H NMR (CDCl3, ppm)
d
: 7.68 (d, 1H, J ¼ 7.10 Hz, benzisoxazole-H),
A mixture of selenium dioxide (1.10 g,10 mmol), 5 mL water, and
20 mL of dioxane was heated with stirring until dissolution, and 3-
methylbenzo[d]isoxazole (3)(2.66 mL, 20 mmol) in 10 mL of
dioxane were added and refluxed for 48 h with stirring. The sele-
nium (about 80%, 0.88 g) was filtered off after cooling at room
temperature, 2 mL of conc. HCl was added and solvent removed in
vacuo on water bath below 50 ꢀC. To the dark oily residue was
added excess of potassium carbonate and ether, the ethereal layer
was dried over sodium sulfate, after removal of solvent the residue
was fractioned to give colorless oil. Rf ¼ 0.65 (hexane e EtOAc, 9:1);
7.58e7.53 (m, 2H, benzisoxazole-H), 7.31 (m, 1H, benzisoxazole-H),
4.45 (q,1H, J ¼ 5.90 Hz, Hc imide), 3.80 (t, 3H, J ¼ 7.50 Hz, eCH2CH3),
3.30 (dd, 1H, J ¼ 9.90 Hz, J ¼ 15.70 Hz, Ha imide), 2.85 (dd, 1H,
J ¼ 6.50 Hz, J ¼ 18.70 Hz, Hb imide), 1.10 (q, 2H, J ¼ 7.50 Hz,
eCH2CH3); 13C NMR (CDCl3, ppm)
d: 177.4 (C]O), 174.4 (C]O),
160.5 (C), 145.5 (C), 135.3 (CH), 131.1 (CH), 125.3 (CH), 122.2 (C),
121.1 (CH), 109.5 (CH), 36.3 (CH2), 30.2 (CH2), 12.5 (CH3); ESI-MS:
245.25 (M þ H)þ.
4.1.7.2. 3-(benzo[d]isoxazol-3-yl)-1-propylpyrrolidine-2, 5-dione
Yield: 85%; 1H NMR (CDCl3, ppm)
d
: 9.50 (s, 1H, CHO), 7.75 (d, 1H,
(7b). 1H NMR (CDCl3, ppm)
d: 7.64e7.57 (m, 2H, benzisoxazole-
J ¼ 7.10 Hz, Ar-H), 7.66e7.55 (m, 2H, Ar-H), 7.25 (m, 1H, Ar-H); 13C
H), 7.42 (t, 1H, J ¼ 6.90 Hz, benzisoxazole-H), 7.15 (t, 1H,
J ¼ 7.00 Hz, benzisoxazole-H), 4.40 (q, 1H, J ¼ 5.50 Hz, Hc imide),
4.10 (q, 2H, J ¼ 7.20 Hz, eCH2CH2CH3), 3.33 (dd, 1H, J ¼ 9.50 Hz,
J ¼ 18.70 Hz, Ha imide), 2.80 (dd, 1H, J ¼ 5.65 Hz, J ¼ 15.70 Hz, Hb
imide), 1.40e1.55 (m, 2H, J ¼ 7.20 Hz, eCH2CH2CH3), 0.90e0.85 (t,
NMR (CDCl3, ppm) d: 190.2 (C), 161.5 (C), 147.5 (C), 130.6 (CH), 124.1
(CH), 121.9 (C), 120.6 (CH), 108.8 (CH); ESI-MS:148.04 (C8H5NO2
[M þ H]þ).
4.1.5. Methyl 3-(benzo[d]isoxazol-3-yl)-2, 3-dicyanopropanoate (5)
To a solution of benzo[d]isoxazole-3-carbaldehyde (4) (1.50 mL,
10 mmol) and methyl cyanoacetate (1.0 g, 10 mmol) in 3 mL of 60%
ethyl alcohol was added 0.5 mL of piperidine. The temperature was
slowly increased to 60 ꢀC. Then the mixture had cooled to 25 ꢀC it
was diluted with 100 mL of water and potassium cyanide (1.30 g,
20 mmol) was added portion wise over a period of 20 min. Stirring
was continued until a clear solution was obtained. After dilution
with 100 mL of water, the mixture was acidified to congo red and
conc. HCl(sp. gr. 1.18). The oil which precipitated was stirred until
solidification and then filtered. Rf ¼ 0.55 (hexane e EtOAc, 9:1);
3H, J ¼ 7.20 Hz, eCH2CH2CH3); 13C NMR (CDCl3, ppm)
d: 178.5 (C]
O), 174.5 (C]O), 160.2 (C), 144.6 (C), 134.8 (CH), 131.6 (CH), 125.6
(CH), 121.8 (C), 120.8 (CH), 109.9 (CH), 38.5 (CH2), 35.8 (CH2), 18.5
(CH2), 11.2 (CH3); ESI-MS: 259.15 (M þ H)þ.
4.1.7.3. 3-(Benzo[d]isoxazol-3-yl)-1-butylpyrrolidine-2, 5-dione (7c).
1H NMR (CDCl3, ppm)
d
: 7.70 (d, 1H, J ¼ 8.10 Hz, benzisoxazole-H),
7.65e7.50 (m, 2H, benzisoxazole-H), 7.25 (m, 1H, benzisoxazole-H),
4.40 (q, 1H, J ¼ 5.60 Hz, Hc imide), 4.11e3.95 (q, 2H, J ¼ 7.10 Hz,
eCH2(CH2)2CH3), 3.25 (dd, 1H, J ¼ 9.20 Hz, J ¼ 16.50 Hz, Ha imide),
2.88 (d, 1H, J ¼ 6.75 Hz, Hb imide), 1.50e1.40 (m, 2H, J ¼ 7.10 Hz,
eCH2CH2 CH2CH3), 1.35e1.20 (m, 2H, J ¼ 7.10 Hz, eCH2CH2
CH2CH3), 0.95e0.80 (t, 3H, J ¼ 7.10 Hz, eCH2(CH2)2CH3); 13C NMR
Yield: 83%; mp 128e130 ꢀC; 1H NMR (CDCl3, ppm)
d: 7.71 (d, 1H,
J ¼ 8.50 Hz, Ar-H), 7.60e7.55 (m, 2H, Ar-H), 7.30 (m, 1H, Ar-H), 4.11
(d, 1H, J ¼ 9.50 Hz, CH), 3.50 (s, 3H, OCH3), 3.20 (d, 1H, J ¼ 9.50 Hz,
(CDCl3, ppm) d: 176.6 (C]O), 173.5 (C]O), 161.1 (C), 145.6 (C), 133.8
CH); 13C NMR (CDCl3, ppm)
d
: 164.8 (C]O), 161.1 (C), 148.6 (C),
(CH), 131.5 (CH), 125.5 (CH), 122.2 (C), 120.9 (CH), 108.9 (CH), 40.5
(CH2), 33.3 (CH2), 25.5 (CH2), 18.9 (CH2), 13.5 (CH3); ESI-MS: 273.30
(M þ H)þ.
130.5 (CH), 125.0 (CH), 121.6 (C), 120.6 (CH), 118.8 (CN), 115.4 (CN),
107.9 (CH), 51.4 (CH3), 34.3 (CH), 22.5 (CH); ESI-MS:
256.25(C13H9N3O3 [M þ H]þ).
4.1.7.4. 3-(Benzo[d]isoxazol-3-yl)-1-cyclohexylpyrrolidine-2, 5-dione
4.1.6. 2-(Benzo[d]isoxazol-3-yl)succinic acid (6)
(7d). 1H NMR (CDCl3, ppm)
d:
7.71 (d, 1H,
J
¼
7.80 Hz,
The
solid
methyl
3-(benzo[d]isoxazol-3-yl)-2,
3-
benzisoxazole-H), 7.34 (t, 1H, J ¼ 6.70 Hz, benzisoxazole-H), 7.11 (d,
1H, J ¼ 7.80 Hz, benzisoxazole-H), 6.99 (t, 1H, J ¼ 6.70 Hz,
benzisoxazole-H), 4.48 (q, 1H, J ¼ 5.50 Hz, Hc imide), 3.62e3.50 (m,
1H, cyclohexyl), 3.20 (dd, 1H, J ¼ 8.90 Hz, J ¼ 17.75 Hz, Ha imide),
2.80 (dd, 1H, J ¼ 6.75 Hz, J ¼ 16.80 Hz, Hb imide), 1.94e1.75 (m, 2H,
cyclohexyl), 1.73e1.48 (m, 3H, J ¼ 10.10 Hz, J ¼ 12.0 Hz, cyclohexyl),
1.42e1.25 (m, 3H, J ¼ 10.10 Hz, J ¼ 12.0 Hz, cyclohexyl), 1.20e1.02
(m, 3H, J ¼ 10.10 Hz, J ¼ 12.0 Hz, cyclohexyl); 13C NMR (CDCl3, ppm)
dicyanopropanoate (5) (2.55 g, 10 mmol) was refluxed with
100 mL of conc. HCl(sp. gr. 1.18) for six hours or until solution was
complete. On cooling to 25 ꢀC a solid precipitated which was
filtered off and washed with 50 mL of water and dried. . Rf ¼ 0.75
(hexane e EtOAc, 9:1); Yield: 81%; mp 160e162 ꢀC; 1H NMR (CDCl3,
ppm) d: 12.30 (s, 1H, eCHCOOH), 12.05 (s, 1H, eCH2COOH), 7.61 (d,
1H, J ¼ 7.00 Hz, Ar-H), 7.58e7.54 (m, 2H, Ar-H), 7.20 (m, 1H, Ar-H),
3.90 (t, 1H, J ¼ 6.20 Hz, J ¼ 9.50 Hz, J ¼ 22.20 Hz, CH), 2.95 (dd, 1H,
J ¼ 4.40 Hz, J ¼ 13.80 Hz CH2), 2.45 (dd, 1H, J ¼ 8.40 Hz, J ¼ 13.80 Hz
d: 178.1 (C]O), 175.4 (C]O), 162.2 (C), 145.5 (C), 132.5 (CH), 130.7
(CH), 125.1 (CH), 122.6 (C), 120.5 (CH), 109.5 (CH), 45.5 (CH), 36.6
(CH2), 31.2 (CH2), 30.4 (CH2), 25.7 (CH2), 24.8 (CH2), 20.5 (CH2); ESI-
MS: 299.25 (M þ H)þ.
CH2); 13C NMR (CDCl3, ppm)
d: 188.8 (C), 184.4 (C), 161.8 (C), 148.1
(C), 130.7 (CH), 124.4 (CH), 121.3 (C), 120.5 (CH), 109.2 (CH), 41.2
(CH), 25.4 (CH2); ESI-MS: 236.50(C11H9NO5 [M þ H]þ).
4.1.7.5. 3-(Benzo[d]isoxazol-3-yl)-1-(4-fluorophenyl) pyrrolidine-2,
4.1.7. General procedure for the synthesis of 3-(benzo[d]isoxazol-3-
yl)-1N-substituted pyrrolidine-2, 5-dione (7ae7d, 8ae8d, 9ae9c)
2-(benzo[d]isoxazol-3-yl)succinic acid (6) (2.35 g, 10 mmol) was
added in small portions to amines (7a/0.22 g, 7b/0.45 mL, 7c/0.36 g,
5-dione (8a). 1H NMR (CDCl3, ppm)
d
: 8.20 (d, 2H, J ¼ 8.80 Hz,
Ar-H), 7.78e7.57 (m, 2H, benzisoxazole-H), 7.55 (d, 2H, J ¼ 8.80 Hz,
Ar-H), 7.35 (t, 1H, J ¼ 7.00 Hz, benzisoxazole-H), 7.10 (t, 1H,
J ¼ 7.50 Hz, benzisoxazole-H), 4.10 (q, 1H, J ¼ 5.65 Hz, Hc imide),