300
Md.I. Hossain et al. / European Journal of Medicinal Chemistry 69 (2013) 294e309
Table 4
5.2.6. 7-(4-Bromophenyl)-2,3-dimethyl-7,8-dihydro-2H-3,8a-
epidioxypyrano[4,3-b]pyran-5(3H)-one (5a)
Antiproliferative activity of 10aed against human leukemia MV4-11 cell line.
White solids in 94% yield, mp: 169e170 ꢀC (ethyl acetateehex-
ane); IR (KBr) nmax ¼ 3072, 2982, 2937, 2899, 1732, 1649, 1595, 1491,
Entry Compound
R1
R2
Yield (%) MV4-11
IC50 M)
(m
1381, 1276, 1188 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 7.58e7.50 (m,
Cisplatin
2.820 ꢁ 0.450
0.501 ꢁ 0.062
1
2
10a
10b
86
85
2H), 7.40e7.35 (m, 1H), 7.33e7.21 (m, 2H), 5.42 (dd, J ¼ 9.0, 5.0 Hz)
and 5.32 (dd, J ¼ 12.3, 1.9 Hz) (total 1H), 4.37 (dq, J ¼ 16.3, 6.6 Hz,
1H), 2.50e2.33 (m) and 2.32e2.22 (m) (total 1H), 1.57 (s, 1H) and
1.50 (s, 2H), 1.48e1.41 (m, 1H), 1.03 (dt, J ¼ 6.6, 3.3 Hz, 2H); 13C NMR
0.661 ꢁ 0.332
(101 MHz, CDCl3)
d 140.3 (duplicated), 136.0, 132.0, 131.7 (dupli-
cated), 127.7 (duplicated), 123.0, 95.2, 94.8, 78.5, 78.3, 76.2, 75.4,
36.8, 36.4, 17.3 (duplicated), 16.98. Anal. Calcd for C16H15BrO5: C,
52.34; H, 4.12. Found: C, 52.40; H, 3.92.
3
4
10c
10d
87
84
0.517 ꢁ 0.009
1.045 ꢁ 0.438
5.2.7. 7-(3-Chlorophenyl)-2,3-dimethyl-7,8-dihydropyrano[4,3-b]
pyran-5(2H)-one (5b)
White solids in 92% yield, mp: 152e154 ꢀC (ethyl acetateehex-
ane); IR (KBr) nmax ¼ 3063, 2978, 2931, 2890, 1728, 1647, 1593, 1438,
halogen lamps for 1e2 h at 0 ꢀC. The solution was brought to room
temperature and solvent was removed in vacuum to afford the
crude residue, which was purified by flash column chromatography.
1383, 1276, 1190 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 7.40 (d,
J ¼ 9.1 Hz, 2H), 7.37e7.33 (m, 2H), 7.28e7.22 (m, 1H), 5.33 (dd,
J ¼ 12.3, 1.8 Hz, 1H), 4.36 (q, J ¼ 6.6 Hz, 1H), 2.45 (dd, J ¼ 15.4,
12.3 Hz, 1H), 2.29 (dd, J ¼ 15.3, 2.0 Hz, 1H), 1.58 (s, 1H), 1.51 (s, 2H),
1.49e1.42 (m, 1H), 1.03 (d, J ¼ 6.6 Hz, 2H); 13C NMR (101 MHz,
5.2.2. Methyl 1-ethyl-4-methyl-6-propyl-2,3,5-trioxabicyclo[2.2.2]
oct-7-ene-8-carboxylate (3a) [24]
CDCl3)
d 160.8, 141.9, 140.4, 138.9, 134.8, 131.7, 130.1, 129.1, 126.3,
White solids in 85% yield, mp: 137e138 ꢀC (ethyl acetateehex-
124.1, 95.1, 78.5, 76.2 (duplicated), 36.8 (duplicated), 17.2 (dupli-
cated), 16.9, 15.0. Anal. Calcd for C16H15ClO5: C, 59.54; H, 4.68.
Found: C, 59.12; H, 4.20.
ane); 1H NMR (600 MHz, CDCl3)
d
0.89 (t, J ¼ 7.2 Hz, 3H), 1.03 (m,
1H), 1.04 (t, J ¼ 7.2 Hz, 3H), 1.30 (m, 2H), 1.45 (m, 1H), 1.76 (s, 3H),
1.79 (m, 1H), 1.92 (m, 1H), 3.81 (s, 3H), 4.20 (dd, J ¼ 10.2, 2.4 Hz, 1H),
7.17 (s, 1H); 13C NMR (150.8 MHz, CDCl3)
d 6.8, 13.9, 18.0, 19.6, 24.8,
5.2.8. 7-(3-Methoxyphenyl)-2,3-dimethyl-7,8-dihydro-2H-3,8a-
epidioxypyrano[4,3-b]pyran-5(3H)-one (5c)
33.3, 51.9, 76.8, 78.7, 97.0, 136.4, 138.9, 162.5.
White solids in 85% yield, mp: 128e129 ꢀC (ethyl acetatee
hexane); IR (KBr) nmax ¼ 3074, 2980, 2937, 2835, 1732, 1645, 1600,
5.2.3. Methyl 1-ethyl-4-phenyl-6-propyl-2,3,5-trioxabicyclo[2.2.2]
1494, 1373, 1274, 1188 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 7.39 (s,
oct-7-ene-8-carboxylate (3b) [24]
Yield 82%; 1H NMR (600 MHz, CDCl3)
1.11 (t, J ¼ 7.2 Hz, 3H), 1.19 (m, 1H), 1.44 (m, 2H), 1.62 (m, 1H), 1.88
(m, 1H), 2.00 (m, 1H), 3.54 (s, 3H), 4.41 (d, d, J ¼ 10.8, 2.4 Hz, 1H),
7.23 (s, 1H), 7.39 (m, 3H), 7.54 (m, 2H); 13C NMR (150.8 MHz, CDCl3)
d
0.97 (t, J ¼ 7.2 Hz, 3H),
1H), 7.32 (t, J ¼ 7.9 Hz, 1H), 6.93 (ddd, J ¼ 10.7, 6.6, 4.8 Hz, 3H), 5.34
(dd, J ¼ 12.3, 2.0 Hz, 1H), 4.37 (q, J ¼ 6.7 Hz, 1H), 3.83 (d, J ¼ 1.5 Hz,
3H), 2.49 (dd, J ¼ 15.4, 12.3 Hz) and 2.36e2.26 (m) (total 1H), 1.59
(s) and 1.52 (s) (total 3H),1.49e1.42 (m) and 1.05 (t, J ¼ 7.3 Hz) (total
3H); 13C NMR (101 MHz, CDCl3)
d 161.2, 159.9, 140.1, 138.4, 131.9,
d
6.9,13.9,18.1, 24.9, 33.3, 51.9, 77.3, 79.4, 97.4,126.3 (2C),127.7 (2C),
129.2, 134.5, 138.36, 138.43, 162.4.
129.9, 118.2 (duplicated), 114.7, 111.4, 95.3, 78.5, 76.2, 73.8, 55.3,
36.9, 17.3 (duplicated), 16.9. Anal. Calcd for C17H18O6: C, 64.14; H,
5.70. Found: C, 64.24; H, 5.24.
5.2.4. Methyl 2-methyl-2,5,6,7,8,8a-hexahydro-2,4a-
epidioxychromene-3-carboxylate (3c) [24]
Yield 78%; 1H NMR (600 MHz, CDCl3)
d 0.87e1.69 (m, 4H), 1.73
5.2.9. 7-(4-Fluorophenyl)-2,3-dimethyl-7,8-dihydro-2H-3,8a-
epidioxypyrano[4,3-b]pyran-5(3H)-one (5d)
(s) and 1.75 (s) (total 3H), 1.80e2.11 (m, 4H), 3.77 (s) and 3.79 (s)
(total 3H), 3.40 and 4.09 (dd, J ¼ 12.0, 5.4 Hz) (total 1H), 7.13 (s) and
White solids in 90% yield, mp: 145e147 ꢀC (ethyl acetateehex-
ane); IR (KBr) nmax ¼ 3074, 2985, 2937, 2832, 1736, 1649, 1606, 1516,
7.22 (s) (total 1H); 13C NMR (150.8 MHz, CDCl3)
d 19.5, 19.7, 20.0,
1383, 1286, 1188 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d 7.4e7.3 (m, 3H),
22.5, 22.8, 23.1, 28.4, 29.2, 30.2, 30.3, 51.9, 73.3, 73.7, 75.8, 76.7, 97.1,
98.2, 134.9, 136.1, 139.2, 140.3, 162.4, 162.7.
7.10 (td, J ¼ 8.6, 1.5 Hz, 2H), 5.44 (dd, J ¼ 8.2, 5.9 Hz) and 5.34 (dd,
J ¼ 12.3, 1.8 Hz) (total 1H), 4.37 (dt, J ¼ 19.9, 6.6 Hz, 1H), 2.5e2.3 (m)
and 2.27 (ddd, J ¼ 9.4, 2.1, 1.1 Hz) (total 2H), 1.58 (s) and 1.52 (s)
(total 3H), 1.40 (m) and 1.04 (t, J ¼ 6.5 Hz) (total 3H); 13C NMR
5.2.5. Methyl 1,4-dimethyl-6-phenyl-2,3,5-trioxabicyclo[2.2.2]oct-
7-ene-8-carboxylate (3d) [24]
Yield 85%; 1H NMR (600 MHz, CDCl3)
d
1.32 (s, 3H), 1.91 (s, 3H),
3.86 (s, 3H), 5.18 (s, 1H), 7.03 (s, 1H), 7.11 (m, 2H), 7.32 (m, 3H); 13
NMR (150.8 MHz, CDCl3) 17.8, 19.5, 52.1, 77.1, 80.1, 98.2, 127.4 (2C),
128.3 (2C), 128.7, 136.1, 136.7, 139.7, 162.5.
(151 MHz, CDCl3)
d 163.7, 162.1, 161.0, 141.8, 140.3, 140.1, 132.8
C
(duplicated), 131.82, 128.1e127.9 (m), 115.9, 115.7, 95.2, 94.94
(duplicated), 78.5, 76.30 (duplicated), 75.4, 73.8, 36.8 (duplicated),
36.4, 17.3 (duplicated), 16.9, 15.0. HRMS (FAB) calcd for [M þ H]þ
d
Scheme 5. Synthesis of 2,3,7,8-tetrahydro-3,8a-epidioxychromen-5(6H)-one 13. Reagents and conditions: (i) ethylenediammonium diacetate (EDDA, 5 mol%), MeOH, 2e3 h, 60 ꢀC.
(ii) Rose bengal, O2, h
, MeOH, 0 ꢀC, 1 h.
n