3344
W.-B. Wu et al. / European Journal of Medicinal Chemistry 46 (2011) 3339e3347
4.47 (1H, d, J ¼ 11 Hz), 5.02 (1H, dd, J ¼ 20, 2 Hz), 5.07 (1H, dd, J ¼ 10,
2 Hz), 5.73e5.87 (1H, m), 6.01 (1H, br), 7.68 (1H, t, J ¼ 8 Hz), 7.87
d
3.32 (1H, q, J ¼ 1.5 Hz), 3.34 (1H, q, J ¼ 1.5 Hz), 5.20 (1H, dq,
J ¼ 12.5, 2 Hz), 5.23 (1H, dq, J ¼ 12.5, 2 Hz), 5.95 (1H, m), 7.24 (1H, t,
J ¼ 1.5 Hz), 7.66 (1H, t, J ¼ 7 Hz), 7.71 (1H, dd, J ¼ 7, 1.5 Hz), 8.13 (1H,
(2H, d, J ¼ 8 Hz). 13C NMR (75 MHz, d6-DMSO)
d 43.8, 68.1, 74.1,
112.6,119.9,120.2,124.2,128.5,129.4,132.1,132.4,133.0,141.3,161.3,
173.6. FAB-MS m/z 291 [Mþ1]þ. HRMS (EI) calcd for C15H11ClO4
[Mþ1]þ: 291.0424; Found: 291.0408.
dd, J ¼ 7, 1.5 Hz). 13C NMR (75 MHz, CDCl3)
d 26.8, 105.7, 111.4, 114.1,
117.6, 123.9, 125.5, 125.9, 127.1, 128.5, 129.0, 137.5, 155.6, 167.8, 173.2.
FAB-MS m/z 273 [Mþ1]þ. HRMS (EI) calcd for C15H9ClO3 [Mþ1]þ:
273.0318; Found: 273.0313.
5.1.2.6. 3-(4-Fluorophenyl)-3-hydroxyl-9-chloro-2,3-dihydrobenzo
[de]benzopyran-7,8-dione (3f). The product was purified using flash
chromatography (CHCl3/THF ¼ 2:1) to give a orange red solid 3f
with a yield of 38%. m.p. 294e296 ꢀC. IR nmax (KBr)/cmꢁ1: 3443,
1693, 1649, 1602, 1542, 1511, 1307, 1150, 840. 1H NMR (300 MHz, d6-
5.1.3.5. 3-(4-Fluorobenzyl)-9-chlorobenzo[de]benzopyran-7,8-dione
(4f). The product was purified using flash chromatography (CHCl3/
EtOAc ¼ 15:1) to give a purple black solid 4f with a yield of 94%.
m.p. 296e297 ꢀC. 1H NMR (300 MHz, CDCl3)
d 7.21 (2H, m), 7.35
DMSO)
d
4.48 (1H, d, J ¼ 11 Hz), 4.75 (1H, d, J ¼ 11 Hz), 6.73 (1H, s),
(3H, m), 7.52 (1H, dd, J ¼ 8,1.5 Hz), 7.63 (1H, t, J ¼ 8 Hz), 8.17 (1H, dd,
J ¼ 8, 1.5 Hz). ESI-MS m/z 327 [Mþ1]þ. HRMS (EI) calcd for
C18H8ClFO3 [M þ Na]þ: 349.0044; Found: 349.0015.
7.21 (2H, m), 7.42 (2H, m), 7.48 (1H, dd, J ¼ 8, 1.5 Hz), 7.65 (1H, t,
J ¼ 8 Hz), 7.93 (1H, dd, J ¼ 8, 1.5 Hz). 13C NMR (75 MHz, d6-DMSO)
d
69.4, 75.5, 111.7, 114.5, 114.8, 124.2, 128.4, 128.1128.5, 131.9, 132.5,
137.7, 139.3, 160.3, 172.6, 176.6. FAB-MS m/z 345 [Mþ1]þ. HRMS (EI)
5.1.4. General procedure for synthesis of 3-subtituted-3-hydroxyl-
2,3-dihydrobenzo[de]-benzopyran-7,8-dione (5aec, f)
calcd for C18H10ClFO4 [M þ Na]þ: 367.0149; Found: 367.0142.
To a solution of nitro-substituted products 2 dissolved in MeOH
(50 ml), were added ammonium formate (3.15 g, 50 mmol) and
0.4 g 10% Pd/C. The reaction mixture was stirred at 40 ꢀC for 2 h.
After cooling to room temperature, the reaction mixture was
filtered, and the filtrate was evaporated under vacuum. The residue
was washed with water and dissolved in 150 ml acetone. A solution
of Fremy’s salt (3.93 g, 15 mmol) dissolved in 500 ml 0.06 M KH2PO4
solution was added under vigorous stirring, and the solution
changed from bluish violet to pale yellowish brown with solid
precipitation. After reaction for 30e50 min, the mixture was
extracted with chloroform and washed with water. The organic
layer was dried over anhydrous sodium sulfate and concentrated.
The product was purified using chromatography.
5.1.3. General procedure for synthesis of 3-subtituted-9-
chlorobenzo[de]benzopyran-7,8-dione (4bef)
A mixture of 3 (2 mmol) and PPA (2 g) was stirred at 40 ꢀC for
30 min. Then 50 ml water was added, and the resulting solution
was stirred for 30 min. The mixture was extracted with CHCl3,
washed with water, dried over anhydrous sodium sulfate, and
concentrated. The residue was purified using flash chromatography
to give the desired product.
5.1.3.1. 3-Phenyl-9-chlorobenzo[de]benzopyran-7,8-dione (4b). The
product was purified using flash chromatography (CHCl3/
EtOAc ¼ 15:1) to give a purple black solid 4b with a yield of 94%.
m.p. 197e198 ꢀC. 1H NMR (300 MHz, CDCl3)
d 7.44e7.47 (2H, m),
7.49e7.58 (4H, m), 7.77 (1H, t, J ¼ 8 Hz), 8.06 (1H, dd, J ¼ 8, 1.5 Hz).
5.1.4.1. 3-Methyl-3-hydroxyl-2,3-dihydrobenzo[de]benzopyran-7,8-
dione (5a). The product was purified with flash chromatography
(petroleum ether/EtOAc ¼ 2:1) to give a khaki solid 5a with a yield
13C NMR (100 MHz, CDCl3)
d
110.5, 121.2, 129.0, 129.2, 129.3, 129.5,
129.8, 130.6, 131.4, 131.5, 132.1, 133.2, 142.1, 160.0, 172.7, 177.9. FAB-
MS m/z 309 [Mþ1]þ. HRMS (EI) calcd for C18H9ClO3 [M þ Na]þ:
309.0318; Found: 309.0309.
of 61%. m.p. 205e209 ꢀC. 1H NMR (300 MHz, d6-DMSO)
d 1.49 (3H,
s), 4.30 (1H, d, J ¼ 11 Hz), 4.42 (1H, d, J ¼ 11 Hz), 6.06 (1H, br), 7.71
(1H, t, J ¼ 8 Hz), 7.88 (1H, dd, J ¼ 8, 1.5 Hz), 7.95 (1H, dd, J ¼ 8,
1.5 Hz). FAB-MS m/z 231 [Mþ1]þ. HRMS (EI) calcd for C13H10O4
[M þ Na]þ: 253.0477; Found: 253.0475.
5.1.3.2. 3-Benzyl-9-chlorobenzo[de]benzopyran-7,8-dione (4c). The
product was purified using flash chromatography (CHCl3/
EtOAc ¼ 15:1) to give a purple black solid 4c with a yield of 91%.
m.p. 223e225 ꢀC. IR nmax (KBr)/cmꢁ1: 1692, 1648, 1599, 1551, 1493,
5.1.4.2. 3-Phenyl-3-hydroxyl-2,3-dihydrobenzo[de]benzopyran-7,8-
dione (5b). The product was purified using flash chromatography
(petroleum ether/EtOAc ¼ 2:1) to give a flavous solid 5b with
a yield of 48%. m.p. 241e242 ꢀC. IR nmax (KBr)/cmꢁ1: 3447, 1693,
1641, 1613, 1563, 1466, 1388, 1341, 1263, 1206, 856, 722, 649. 1H
1346, 1135, 730. 1H NMR (300 MHz, CDCl3)
d 3.96 (2H, s), 7.18 (1H, t,
J ¼ 7 Hz), 7.26e7.35 (4H, m), 7.70 (2H, t, J ¼ 7 Hz), 7.67e7.75 (2H, m),
7.84 (1H, s), 7.96 (1H, d, J ¼ 7 Hz). 13C NMR (75 MHz, CDCl3)
d 33.8,
110.5, 117.0, 122.5, 127.48, 128.6, 129.2, 130.4, 130.7, 131.9, 133.4,
136.8, 142.9, 160.4, 172.6, 177.9. FAB-MS m/z 323 [Mþ1]þ. HRMS (EI)
calcd for C19H11ClO3 [Mþ1]þ: 323.0475; Found: 323.0470.
NMR (300 MHz, d6-DMSO)
d
4.37 (1H, d, J ¼ 11 Hz), 4.63 (1H, d,
J ¼ 11 Hz), 5.97 (1H, s), 6.60 (1H, br), 7.32 (5H, m), 7.48 (1H, d,
J ¼ 8 Hz), 7.65 (1H, t, J ¼ 8 Hz), 7.93 (1H, d, J ¼ 8 Hz). 13C NMR
5.1.3.3. 3-Propyl-9-chlorobenzo[de]benzopyran-7,8-dione (4d). The
product was purified using flash chromatography (CHCl3/
EtOAc ¼ 15:1) to give a purple black solid 4d with a yield of 91%.
m.p. 220e222 ꢀC. IR nmax (KBr)/cmꢁ1: 1695, 1646, 1602, 1549, 1348,
(75 MHz, d6-DMSO) d 69.6, 75.1, 107.4, 124.7, 126.3, 127.5, 127.9,
129.4, 131.9, 132.7, 139.9, 141.8, 165.7, 178.5, 178.8. FAB-MS m/z 293
[Mþ1]þ. HRMS (EI) calcd for C18H12O4 [Mþ1]þ: 293.0814; Found:
293.0818.
1270, 1227, 1157, 1141. 1H NMR (300 MHz, CDCl3)
d 1.05 (3H, t,
J ¼ 7.5 Hz), 1.65 (2H, sextet, J ¼ 7.5 Hz), 2.55 (2H, t, J ¼ 7.5 Hz), 7.23
5.1.4.3. 3-Benzyl-3-hydroxyl-2,3-dihydrobenzo[de]benzopyran-7,8-
dione (5c). The product was purified using flash chromatography
(CHCl3/EtOAc ¼ 2:1) to give a brown solid 5c with a yield of 50%.
m.p. 238e239 ꢀC. IR nmax (KBr)/cmꢁ1: 3466, 1697, 1641, 1612, 1564,
1458, 1382, 1344, 1263, 1199, 994, 776, 702. 1H NMR (300 MHz, d6-
(1H, s), 7.68 (2H, m), 8.13 (1H, dd, J ¼ 8, 1.5 Hz). 13C NMR (75 MHz,
CDCl3)
d 13.8, 21.9, 29.2, 109.9, 117.5, 122.1, 128.5129.6, 130.6, 131.5,
133.1, 141.2, 160.3, 172.2, 177.7. FAB-MS m/z 275 [Mþ1]þ. HRMS (EI)
calcd for C15H11ClO3 [Mþ1]þ: 275.0475; Found: 275.0475.
DMSO)
d
3.01 (2H, s), 4.10 (1H, d, J ¼ 11 Hz), 4.25 (1H, d, J ¼ 11 Hz),
5.1.3.4. 3-Allyl-9-chlorobenzo[de]benzopyran-7,8-dione
(4e). The
5.90 (1H, s), 5.97 (1H, br), 7.02 (2H, dd, J ¼ 7.5, 2 Hz), 7.15e7.23 (3H,
product was purified using flash chromatography (CHCl3/
EtOAc ¼ 15:1) to give an oxford blue solid 4e with a yield of 50%.
m.p. 171e172 ꢀC. IR nmax (KBr)/cmꢁ1: 1698, 1645, 1598, 1545, 1345,
1268, 1181, 1156, 1134, 867, 850, 786. 1H NMR (300 MHz, CDCl3)
m), 7.51e7.58 (2H, m), 7.84 (1H, dd, J ¼ 7, 1.5 Hz). 13C NMR (75 MHz,
d6-DMSO)
d 44.9, 67.9, 72.4, 107.4, 123.8, 126.3, 127.5, 129.3, 130.5,
131.3, 135.3, 141.1, 165.8, 178.5, 178.7. FAB-MS m/z 307 [Mþ1]þ.
HRMS (EI) calcd for C19H14O4 [Mþ1]þ: 307.0970; Found: 307.0970.