Naphthylcombretastatins
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 2 565
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tained in 82% yield as a nonseparable mixture (Z/E 1:2). H
NMR data for 26Z (from the spectrum of the mixture) δH
(ppm): 2.28 (s, 3H), 3.85 (s, 6H), 3.88 (s, 3H), 5.96 (d, J ) 3.3,
1H), 6.23 (d, J ) 3.3, 1H), 6.28 (s, 2H), 6.70 (s, 2H). MS of the
mixture: m/z 274 (M+, 100), 259 (71).
26E, (E)-2-Methyl-5-[2-(3,4,5-trimethoxyphenyl)vinyl]-
furan. From the mixture a small amount of pure 26E was
obtained by crystallization. Mp: 90 °C (Hex/EtOAc). 1H NMR
δH (ppm): 2.35 (s, 3H), 3.86 (s, 3H), 3.89 (s, 6H), 6.02 (d, J )
3.3, 1H), 6.23 (d, J ) 3.3, 1H), 6.68 (s, 2H), 6.73 (d, J ) 16.0,
1H), 6.89 (d, J ) 16.0, 1H). MS: m/z 274 (M+, 100), 259 (64).
27Z, (Z)-N,N-Dimethyl-2-nitro-4-[2-(3,4,5-trimethoxy-
phenyl)vinyl]aniline. Following the general method, by
reaction of 4-dimethylamino-3-nitrobenzaldehyde and triphen-
yl(3,4,5-trimethoxybenzylidene)phosphorane, compound 27Z
was isolated in 41% yield. Mp: 98 °C (CH2Cl2/ether). 1H NMR
δH (ppm): 2.87 (s, 6H), 3.72 (s, 6H), 3.85 (s, 3H), 6.38 (d, J )
12.4, 1H), 6.48 (d, J ) 12.4, 1H), 6.49 (s, 2H), 6.84 (d, J ) 8.8,
1H), 7.30 (dd, J1 ) 8.8, J2 ) 2.2, 1H), 7.73 (d, J ) 2.2, 1H).
HRMS (C19H22N2O5): calcd 358.1529, found 358.1577.
27E, (E)-N,N-Dimethyl-2-nitro-4-[2-(3,4,5-trimethoxy-
phenyl)vinyl]aniline. From the same reaction, compound
27E was obtained in 42% yield. Mp: 75 °C (CH2Cl2/ether). 1H
NMR δH (ppm): 2.90 (s, 6H), 3.86 (s, 3H), 3.90 (s, 6H), 6.70 (s,
2H), 6.90 (s, 2H), 6.98 (d, J ) 8.8, 1H), 7.53 (dd, J1 ) 2.2,
J2 ) 8.8, 1H), 7.89 (d, J ) 2.2, 1H). HRMS (C19H22N2O5): calcd
358.1529, found 358.1553.
31E, (E)-1-Methyl-3-[2-(3,4,5-trimethoxyphenyl)vinyl]-
1H-indole. From the same reaction, compound 31E was
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obtained in 52% yield. H NMR δH (ppm): 3.78 (s, 3H), 3.87
(s, 3H), 3.92 (s, 6H), 6.73 (s, 2H), 7.02 (d, J ) 16.4, 1H), 7.20
(d, J ) 16.4, 1H), 7.1-7.5 (m, 5H). MS: m/z 323 (M+, 100),
308 (85).
32Z, (Z)-1-Phenylsulfonyl-5-[2-(3,4,5-trimethoxyphenyl)-
vinyl]-1H-indole. Following the general method, by reaction
of 1-phenylsulfonyl-1H-indole-5-carbaldehyde and triphenyl-
(3,4,5-trimethoxybenzylidene)phosphorane, compound 32Z was
isolated in 18% yield. 1H NMR δH (ppm): 3.45 (s, 6H), 3.80 (s,
3H), 6.39 (s, 2H), 6.48 (d, J ) 12.1, 1H), 6.55 (d, J ) 3.6, 1H),
6.61 (d, J ) 12.1, 1H), 7.2-7.5 (m, 5H), 7.52 (d, J ) 3.6, 1H),
7.7-7.9 (m, 3H). HRMS (C25H23NO5S): calcd 449.1297, found
449.1346.
32E, (E)-1-Phenylsulfonyl-5-[2-(3,4,5-trimethoxyphen-
yl)vinyl]-1H-indole. From the same reaction, compound 24E
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was obtained in 13% yield. H NMR δH (ppm): 3.87 (s, 3H),
3.91 (s, 6H), 6.66 (d, J ) 3.8, 1H), 6.73 (s, 2H), 6.98 (d,
J ) 16.0, 1H), 7.08 (d, J ) 16.0, 1H), 7.4-7.5 (m, 4H), 7.56 (d,
J ) 3.8, 1H), 7.63 (d, J ) 1.6, 1H), 7.8-8.1 (m, 3H). HRMS
(C25H23NO5S): calcd 449.1297, found 449.1288.
33Z, (Z)-5-[2-(3,4,5-Trimethoxyphenyl)vinyl]-1H-in-
dole. By TBAF treatment of 32Z the indole derivative 33Z
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was obtained in 24% yield. H NMR δH (ppm): 3.62 (s, 6H),
3.84 (s, 3H), 6.41 (d, J ) 12.0, 1H), 6.48 (m, 1H), 6.56 (s, 2H),
6.71 (d, J ) 12.0, 1H), 7.18 (m, 1H), 7.20 (dd, J1 ) 1.5, J2 )
8.0, 1H), 7.26 (d, J ) 8.0, 1H), 7.27(d, 1H), 8.19 (s, 1H). HRMS
(C19H19NO3): calcd 309.1365, found 309.1387.
28Z, (Z)-N,N-Dimethyl-2-amino-4-[2-(3,4,5-trimethoxy-
phenyl)vinyl]aniline. By Zn in AcOH reduction of 27Z,
33E, (E)-5-[2-(3,4,5-Trimethoxyphenyl)vinyl]-1H-in-
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compound 28Z was isolated in 67% yield. H NMR δH (ppm):
dole. By TBAF treatment of 32E, the indole derivative 33E
2.63 (s, 6H), 3.68 (s, 6H), 3,84 (s, 3H), 6.38 (d, J ) 12.1, 1H),
6.51 (s, 2H), 6.53 (d, J ) 12.1, 1H), 6.60-6.75 (m, 2H), 6.91
(d, J ) 2.9, 1H). HRMS (C19H24N2O3): calcd 328.1787, found
328.1763.
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was obtained in 32% yield. H NMR δH (ppm): 3.84 (s, 3H),
3.87 (s, 6H), 6.56 (bs, 1H), 6.76 (s, 2H), 7.01 (d, J ) 16.0, 1H),
7.16 (d, J ) 16.0, 1H), 7.23 (m, 2H), 7.40 (m, 2H), 7.76 (bs,
1H). HRMS (C19H19NO3): calcd 309.1365, found 309.1358.
34Z, (Z)-1-Methyl-5-[2-(3,4,5-trimethoxyphenyl)vinyl]-
1H-indole. Following the general method, by reaction of
1-methyl-1H-indole-5-carbaldehyde and triphenyl(3,4,5-tri-
methoxybenzylidene)phosphorane, compound 34Z was isolated
in 21% yield. 1H NMR δH (ppm): 3.63 (s, 6H), 3.76 (s, 3H),
3.84 (s, 3H), 6.40 (d, J ) 2.9, 1H), 6.43 (d, J ) 12.0, 1H), 6.58
(s, 2H), 6.70 (d, J ) 12.0, 1H), 7.00 (d, J ) 2.9, 1H), 7.19 (m,
2H), 7.60 (bs, 1H). HRMS (C20H21NO3): calcd 323.1521, found
323.1562.
28E, (E)-N,N-Dimethyl-2-amino-4-[2-(3,4,5-trimethoxy-
phenyl)vinyl]aniline. By the same reduction procedure, from
the nitro derivative 27E, compound 28E was obtained in 80%
yield. Mp: 200 °C (EtOH/HCl). 1H NMR δH (ppm): 2.67 (s,
6H), 3.90 (s, 6H), 3.91 (s, 3H), 6.70 (s, 2H), 6.8-7.0 (m, 5H).
HRMS (C19H24N2O3): calcd 328.1787, found 328.1743.
29Z, (Z)-1-{3-[2-(3,4,5-Trimethoxyphenyl)vinyl]-1H-in-
dol-1-yl}ethanone. Following the general method, by reaction
of 1-acetyl-1H-indole-3-carbaldehyde and triphenyl(3,4,5-tri-
methoxybenzylidene)phosphorane, compound 29Z was isolated
in 17% yield. 1H NMR δH (ppm): 2.52 (s, 3H), 3.58 (s, 6H),
3.82 (s, 3H), 6.55 (s, 2H), 6.60 (d, J ) 12.0, 1H), 6.71 (d, J )
12.0 1H), 7.33 (s, 1H), 7.1-7.5 (m, 4H). HRMS (C21H21NO4):
calcd 351.1471, found 351.1470.
34E, (E)-1-Methyl-5-[2-(3,4,5-trimethoxyphenyl)vinyl]-
1H-indole. From the same reaction, compound 34E was
obtained in 39% yield. Mp: 110 °C (ether). 1H NMR δH (ppm):
3.81 (s, 3H), 3.87 (s, 3H), 3.93 (s, 6H), 6.49 (d, J ) 3.3, 1H),
6.76 (s, 2H), 7.00 (d, J ) 16.4, 1H), 7.05 (d, J ) 3.3, 1H), 7.16
(d, J ) 16.4, 1H), 7.31 (d, J ) 8.8, 1H), 7.47 (dd, J1 ) 8.8,
J2 ) 1.6, 1H), 7.74 (d, J ) 1.6, 1H). HRMS (C20H21NO3): calcd
323.1521, found 323.1489.
35Z, (Z)-9-Ethyl-3-[2-(3,4,5-trimethoxyphenyl)vinyl]-
9H-carbazole. Following the general method, by reaction of
9-ethyl-9H-carbazole-3-carbaldehyde and triphenyl(3,4,5-tri-
methoxybenzylidene)phosphorane, compound 35Z was isolated
in 60% yield. 1H NMR δH (ppm): 1.34 (t, J ) 7.0, 3H), 3.62 (s,
6H), 3.86 (s, 3H), 4.32 (c, J ) 7.0, 2H), 6.50 (d, J ) 12.0, 1H),
6.60 (s, 2H), 6.78 (d, J ) 12.0, 1H), 7.0-8.2 (m, 7H). MS: m/z
387 (M+, 100), 372 (71).
29E, (E)-1-{3-[2-(3,4,5-Trimethoxyphenyl)vinyl]-1H-in-
dol-1-yl}ethanone. From the same reaction, compound 29E
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was obtained in 56% yield. H NMR δH (ppm): 2.66 (s, 3H),
3.88 (s, 3H), 3.93 (s, 6H), 6.76 (s, 2H), 7.15 (s, 2H), 7.55 (s,
1H), 7.1-7.5 (m, 4H). MS: m/z 351 (M+, 100), 294 (73).
30Z, (Z)-3-[2-(3,4,5-Trimethoxyphenyl)vinyl]-1H-in-
dole. By treatment of compound 29Z with KOH in MeOH
(10%), deacetylated derivative 30Z was obtained in 18% yield.
1H NMR δH (ppm): 3.62 (s, 6H), 3.84 (s, 3H), 6.51 (d, J ) 12.6,
1H), 6.62 (s, 2H), 6.73 (d, J ) 12.6, 1H), 7.0-7.5 (m, 5H).
HRMS (C19H19NO3): calcd 320.1412, found 320.1455.
30E, (E)-3-[2-(3,4,5-Trimethoxyphenyl)vinyl]-1H-in-
dole. By the same treatment, from 29E, compound 30E was
obtained in 97% yield. Mp: 156 °C (ether). 1H NMR δH (ppm):
3.88 (s, 3H), 3.94 (s, 6H), 6.75 (s, 2H), 7.08 (d, J ) 16.4, 1H),
7.22 (d, J ) 16.4, 1H), 7.2-7.5 (m, 5H). MS: m/z 309 (M+,
100), 294 (56).
35E, (E)-9-Ethyl-3-[2-(3,4,5-trimethoxyphenyl)vinyl]-
9H-carbazole. From the same reaction, compound 35E was
obtained in 35% yield. 1H NMR δH (ppm): 1.45 (t, J ) 7.0,
3H), 3.90 (s, 3H), 3.98 (s, 6H), 4.36 (c, J ) 7.0, 2H), 6.80 (s,
2H), 7.08 (d, J ) 16.0, 1H), 7.23 (d, J ) 16.0, 1H), 7.2-8.3 (m,
7H). MS: m/z 387 (M+, 100), 372 (68).
31Z, (Z)-1-Methyl-3-[2-(3,4,5-trimethoxyphenyl)vinyl]-
1H-indole. Following the general method, by reaction of
1-methyl-1H-indole-3-carbaldehyde and triphenyl(3,4,5-tri-
methoxybenzylidene)phosphorane, compound 31Z was isolated
in 16% yield. Mp: 142°C (Hex/EtOAc). 1H NMR δH (ppm): 3.65
(s, 6H), 3.71 (s, 3H), 3.85 (s, 3H), 6.43 (d, J ) 12.0, 1H), 6.65
(s, 2H), 6.73 (d, J ) 12.0, 1H), 7.0-7.5 (m, 5H). HRMS (C20H21-
NO3): calcd 323.1521, found 323.1499.
36Z, (Z)-2-[2-(3,4-Dimethoxy-5-nitrophenyl)vinyl]naph-
thalene. Following the general method, by reaction of 3,4-
dimethoxy-5-nitrobenzaldehyde and triphenyl(2-naphthyl-
methylidene)phosphorane, compound 36Z was isolated in 26%
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yield. H NMR δH (ppm): 3.44 (s, 3H), 3.94 (s, 3H), 6.56 (d,
J ) 12.0, 1H), 6.87 (d, J ) 12.0, 1H), 6.95 (d, J ) 2.2, 1H),
7.34 (dd, J1 ) 8.6, J2 ) 1.6, 1H), 7.4-7.6 (m, 3H), 7.6-7.9 (m,
4H). HRMS (C20H17NO4): calcd 335.1157, found 335.1201.