392
C. Neagoie et al. / European Journal of Medicinal Chemistry 49 (2012) 379e396
1073, 766; 1H NMR (CDCl3, 250 MHz)
d
1.19 (t, J ¼ 7.0 Hz, 3H, CH3),
(diamond-ATR, cmꢀ1
NMR (CDCl3, 250 MHz)
)
n
2952, 1697, 1624, 1503, 1453, 1326 cmꢀ1; 1H
d 3.29 (s, 3H, OCH3), 3.53 (s, 3H, OCH3), 3.75
1.42 (d, J ¼ 6.0 Hz, 6H, 2CH3), 3.23 (s, 3H, OCH3), 3.86 (s, 3H, OCH3),
4.25 (q, J ¼ 7.0 Hz, 2H, OCH2), 4.57e4.62 (m, 1H, CH), 4.87 (d, 2H,
OCH2), 5.07 (s, 2H, CH2), 6.80 (s, 1H, HAr), 6.92 (s, 1H, HAr), 6.96 (d,
J ¼ 2.0 Hz, 1H, HAr), 7.08 (dd, J ¼ 2.0 Hz, J ¼ 9.0 Hz, 1H, HAr),
7.25e7.34 (m, 6H, HAr), 9.05 (br s, 1H, NH); 13C NMR (CDCl3,
(s, 3H, OCH3), 4.94e5.07 (m, 2H, CH2), 5.10 (s, 2H, OCH2), 5.22 (s, 2H,
OCH2), 6.79 (dd, J ¼ 8.4 Hz, J ¼ 2.4 Hz, 1H), 6.83e6.87 (m, 2H), 6.96
(d, J ¼ 2.4 Hz, 1H), 7.23e7.47 (m, 7H), 8.88 (br s, 1H); 13C NMR
(CDCl3, 62.9 MHz)
d 51.5 (OCH3), 56.0 (OCH3), 56.1 (OCH3), 70.3
62.9 MHz)
d
14.1 (CH3), 22.2 (2CH3), 55.9 (OCH3), 56.6 (OCH3), 60.7
(CH2), 94.6 (OCH2), 94.8 (CH), 95.3 (OCH2), 104.3 (CH), 108.7 (CH),
112.4 (CH), 117.3 (Cq), 120.5 (Cq), 122.5 (Cq), 122.9 (CH), 123.0 (Cq),
127.4 (2xCH), 127.9 (CH), 128.6 (2xCH), 132.4 (CH), 136.5 (Cq), 136.9
(Cq), 156.3 (Cq), 157.9 (Cq), 158.1 (Cq), 162.3 (CO). HRMS (ESIþ)
Calcd for C27H27NO7Na: 500.16851. Found: 500.1697.
(OCH2), 70.6 (CH2), 96.6 (OCH2), 103.4 (CH), 106.2 (CH), 112.8 (CH),
115.6 (CH), 116.6 (Cq), 117.7 (CH), 119.5 (Cq), 124.6 (Cq), 125.9 (Cq),
127.6 (2CH), 127.9 (CH), 128.6 (2CH), 131.3 (Cq), 137.4 (Cq), 145.3
(Cq), 147.4 (Cq), 149.8 (Cq), 153.9 (Cq), 162.1 (CO); MS (ISþ) m/z 520
[M þ H]þ.
6.11.18. Methyl 3-(2,5-bis(methoxymethoxy)phenyl)-6-methyl-1H-
indole-2-carboxylate (63)
6.11.14. Methyl 3-(2,5-bis(methoxymethoxy)phenyl)-5-
(trifluoromethyl)-1H-indole-2-carboxylate (59)
Compound 63 was synthesized using the general procedure for
Suzuki reaction from 32 and 43 and isolated after 7 h as a beige
solid in 90% yield. Rf 0.2 (petroleum ether/EtOAc 9/1); Mp 127 ꢁC; IR
Compound 59 was synthesized using the general procedure for
Suzuki reaction from 29 and 43 and isolated after 7 h as an orange
solid in a 40% yield. Rf 0.2 (PE/EtOAc 8/2); mp 131 ꢁC; IR (Ge-ATR,
(Ge-ATR, cmꢀ1
) n
3366, 3303, 3020, 3000, 1713, 1468, 1077, 802; 1H
cmꢀ1
)
n
3336, 3020, 3000, 1700, 1507, 1345, 1154; 1H NMR (CDCl3,
NMR (DMSO-d6, 250 MHz) d : 2.47 (s, 3H, CH3), 3.25 (s, 3H, CH3),
250 MHz)
d
3.27 (s, 3H, OCH3), 3.50 (s, 3H, OCH3), 3.80 (s, 3H, OCH3),
3.49 (s, 3H, CH3), 3.77 (s, 3H, CH3), 4.91 (d, 2H, CH2, J ¼ 15.0 Hz), 5.14
(s, 2H, CH2); 6.95e7.07 (m, 3H), 7.18 (d, J ¼ 7.5 Hz, 2H); 7.39 (d,
4.92 (d, J ¼ 7.5 Hz, 1H, OCH2), 4.99 (d, J ¼ 7.5 Hz, 1H, OCH2), 5.16 (s,
2H, CH2), 7.06e7.08 (m, 2H, HAr), 7.20e7.25 (m, 1H, HAr), 7.48e7.57
(m, 2H, HAr), 7.81 (s, 1H, HAr), 9.31 (s, 1H, NH); 13C NMR (CDCl3,
J ¼ 10.0 Hz, 2H); 8.85 (s, 1H, NH); 13C NMR (CDCl3, 62.9 MHz)
d 21.9
(CH3), 51.6 (CH3), 55.8 (CH3), 55.9 (CH3), 95.2 (CH2), 96.0 (CH2),111.2
(CH), 116.5 (CH), 119.6 (Cq), 120.2 (CH), 121.5 (CH), 122.8 (CH), 123.0
(Cq), 125.2 (C), 126.0 (Cq), 135.8 (Cq), 136.0 (Cq), 150.6 (Cq), 151.8
(Cq), 162.4 (CO); MS (ISþ) m/z 386 [M þ H]þ.
100.6 MHz)
d 52.0 (OCH3), 55.8 (OCH3), 95.1 (OCH2), 95.7 (OCH2),
112.2 (CH), 116.4 (CH), 117.1 (CH), 120.2 (CH), 120.3 (q, J ¼ 270 Hz,
CF3), 121.9 (CH), 122.0 (CH), 122.7 (Cq), 122.9 (Cq), 123.4 (Cq), 123.5
(Cq), 125.2 (Cq), 127.3 (Cq), 136.6 (Cq), 150.4 (Cq), 151.7 (Cq), 162.0
(Cq); MS (ISþ) m/z 440 [M þ H]þ.
6.11.19. Methyl 3-(2,5-bis(methoxymethoxy)phenyl)-6-(4-
methoxyphenyl)-1H-indole-2-carboxylate (64)
6.11.15. Ethyl 3-(2,5-bis(methoxymethoxy)phenyl)-5-fluoro-1H-
indole-2-carboxy late (60)
Compound 65 was synthesized using the general procedure for
Suzuki reaction from 40 and 43 and isolated after 7 h as a beige
solid in 60% yield. Rf 0.2 (petroleum ether/EtOAc 8/2); Mp 134 ꢁC; IR
Compound 60 was synthesized using the general procedure for
Suzuki reaction from 34 and 42 and isolated after 7 h as a brown
solid in 82% yield. Rf 0.2 (petroleum ether/EtOAc 8/2); Mp 74 ꢁC; IR
) n
(Ge-ATR, cmꢀ1 3307, 3020, 3000, 1717, 1560, 1073, 829; 1H NMR
(CDCl3, 250 MHz)
d
3.27 (s, 3H, OCH3), 3.50 (s, 3H, OCH3), 3.79 (s,
(Ge-ATR, cmꢀ1
)
n
3333, 3020, 3000, 1717,1548, 1235, 1077; 1H NMR
3H, OCH3), 3.86 (s, 3H, OCH3), 4.93 (d, J ¼ 12.5 Hz, 2H, OCH2), 5.11 (s,
2H, OCH2), 6.98e7.10 (m, 4H, HAr), 7.16e7.27 (m, 1H, HAr), 7.33e7.37
(m, 1H, HAr), 7.52e7.60 (m, 4H, HAr), 8.97 (br s, 1H, NH); 13C NMR
(CDCl3, 250 MHz, F decoupled)
d
1.17 (t, J ¼ 7.5 Hz, 3H, CH3), 3.25 (s,
3H, OCH3), 3.49 (s, 3H, OCH3), 4.24 (q, J ¼ 7.5 Hz, 2H, OCH2), 4.88 (d,
J ¼ 7.5 Hz, 1H, OCH2), 4.94 (d, J ¼ 7.5 Hz, 1H, OCH2), 5.15 (s, 2H,
OCH2), 7.02e7.19 (m, 5H, HAr), 7.34e7.39 (m, 1H, HAr), 8.96 (s, 1H,
(CDCl3, 62.9 MHz)
d 51.7 (OCH3), 55.3 (OCH3), 55.8 (OCH3), 55.9
(OCH3), 95.2 (OCH2), 96.0 (OCH2), 109.2 (CH), 114.2 (2CH), 116.9
(CH), 119.6 (Cq), 120.2 (CH), 120.3 (Cq), 120.6 (Cq), 122.1 (CH), 123.5
(Cq), 123.9 (Cq), 124.5 (Cq), 125.3 (Cq), 127.0 (Cq), 128.3 (CH), 134.1
(Cq), 136.2 (Cq), 138.7 (Cq), 150.6 (Cq), 151.8 (Cq), 159.1 (CO); MS
(ISþ) m/z 478 [M þ H]þ.
NH); 13C NMR (CDCl3, 100 MHz)
d 13.9 (CH3), 55.9 (2OCH3), 60.8
(OCH2), 95.2 (OCH2), 95.8 (OCH2), 106.1 (CH), 106.3 (CH), 112.5 (CH),
112.6 (Cq), 114.5 (CH), 114.7 (Cq), 116.6 (CH), 120.1 (CH), 124.7 (Cq),
125.5 (Cq), 128.5 (Cq), 132.0 (Cq), 150.4 (Cq), 151.8 (Cq), 161.6 (CO);
MS (ISþ) m/z 404 [M þ H]þ.
6.11.20. Ethyl 7-(2,5-Bis(methoxymethoxy)phenyl)-5H- [1,3]dioxolo
[4,5-f]indole-6-carboxylate (65)
6.11.16. Methyl 3-(2,5-dimethoxyphenyl)-6-(benzyloxy)-1H-indole-
2-carboxylate (61)
Compound 64 was synthesized using the general procedure for
Suzuki reaction from 36 and 43 and isolated after 7 h as a grey solid
in 60% yield. Rf 0.2 (petroleum ether/EtOAc 8/2); Mp 112 ꢁC; IR (Ge-
Compound 61 was synthesized using the general procedure for
Suzuki reaction from 31 to 2,5-dimethoxyphenyl boronic acid C and
isolated after 7 h as a white solid in 60% yield. Rf 0.2 (petroleum
ATR, cmꢀ1
) n
3336, 3301, 3020, 3000, 1712, 1547, 1077; 1H NMR
ether/EtOAc 9/1); Mp 185 ꢁC; IR (Ge-ATR, cmꢀ1
)
n
3328, 3020, 3000,
(CDCl3, 250 MHz)
d
1.15 (t, J ¼ 7.5 Hz, 3H, CH3), 3.26 (s, 3H, CH3),
1719, 1579, 1507, 1438, 733; 1H NMR (CDCl3, 250 MHz)
d
3.68 (s, 3H,
3.49 (s, 3H, CH3), 4.24 (q, J ¼ 7.5 Hz, 2H, CH2), 4.88 (d, J ¼ 7.5 Hz, 1H,
CH2); 4.94 (d, J ¼ 7.5 Hz, 1H, CH2), 5.14 (s, 2H, CH2), 5.94 (s, 2H, CH2),
6.79 (s, 1H, HAr), 6.82 (s, 1H, HAr), 6.99e7.04 (m, 2H, HAr), 7.14e7.17
OCH3), 3.79 (s, 3H, OCH3), 4.16 (s, 3H, OCH3), 5.13 (s, 2H, CH2),
6.85e6.94 (m, 5H, HAr), 7.32e7.47 (m, 6H, HAr), 8.82 (br s, 1H, NH);
13C NMR (CDCl3, 100.6 MHz)
d
55.7 (OCH3), 56.1 (OCH3), 60.4
(m, 1H, HAr), 9.07 (s, 1H, NH); 13C NMR (CDCl3, 62.9 MHz)
d 13.9
(OCH3), 70.3 (OCH2), 94.9 (CH), 111.8 (CH), 112.5 (CH), 113.4 (CH),
117.8 (CH), 119.9 (Cq), 122.6 (Cq), 122.7 (CH), 123.0 (Cq), 123.7 (Cq),
127.3 (2CH), 127.9 (CH), 128.5 (2CH), 136.5 (Cq), 136.9 (Cq), 151.7
(Cq), 153.0 (Cq), 158.0 (Cq), 161.9 (CO); MS (ISþ) m/z 478 [M þ H]þ
(CH3), 55.8 (2CH3), 60.4 (CH2), 91.5 (CH), 95.1 (CH2), 95.9 (CH2), 99.2
(CH), 100.9 (CH2), 116.4 (CH), 116.9 (CH), 120.1 (CH), 120.2 (Cq),
122.4 (Cq), 122.8 (Cq), 125.4 (Cq), 131.4 (Cq), 144.1 (Cq), 148.0 (Cq),
150.4 (Cq), 151.8 (Cq), 162.4 (CO); MS (ISþ) m/z 430 [M þ H]þ.
6.11.17. Methyl 6-(benzyloxy)-3-(2,4-bis(methoxymethoxy)
phenyl)-1H-indole-2-carboxylate (62)
6.12. General procedure for ether deprotection and lactonizations
Compound 62 was synthesized using the general procedure for
Suzuki reaction from 31 and 45 and isolated after 7 h as pale brown
oil in 68% yield. Rf 0.40 (petroleum ether/EtOAc: 60/40); IR
Method A: A mixture of ether derivative (1.0 mmol) in brom-
hydric solution in acetic acid (30%, 15 mL) was refluxed for the
appropriate time. After cooling at room temperature, the mixture