Heterocycle-Based Combretastatin A-4 Analogues
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 8 1707
for 6 h. After it was cooled to room temperature, the reaction
mixture was concentrated in vacuo, diluted with EtOAc,
washed with water and brine, dried (MgSO4), filtered, and
concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel eluting with EtOAc to
afford 0.341 g (90%) of 1-methyl-4-(3,4,5-trimethoxyphenyl)-
5-(N-methyl-indol-5-yl)imidazole (24h ) as a white solid. 1H
NMR (CDCl3): δ 7.63 (s, 1H), 7.60 (s, 1H), 7.43 (d, J ) 8.5 Hz,
1H), 7.20 (dd, J ) 7.8, 1.3 Hz, 1H), 7.12 (d, J ) 3.1 Hz, 1H),
6.81 (s, 2H), 6.51 (d, J ) 3.1 Hz, 1H), 3.85 (s, 3H), 3.78 (s,
3H), 3.53 (s, 6H), 3.48 (s, 3H). ESI (+)/MS: 378 (M + H)+.
Anal. Calcd for C22H23N3O3‚HCl: C, 63.84; H, 5.84; N, 10.15.
Found: C, 63.61; H, 5.96; N, 10.10.
4-(3,4,5-Tr im et h oxyp h en yl)-5-(4-N,N-d im et h yla m in o-
p h en yl)oxa zole (27c). Compound 27c was prepared in a
similar manner as described for the preparation of 27b. 1H
NMR (CDCl3): δ 7.88 (s, 1H), 7.53 (d, J ) 8.9 Hz, 2H), 6.95 (s,
2H), 6.72 (d, J ) 8.8 Hz, 2H), 3.83 (s, 3H), 3.80 (s, 6H), 3.01
(s, 6H). ESI (+)/MS: 355 (M
+
H)+. Anal. Calcd for
C20H22N2O4: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.83; H,
6.32; N, 7.84.
4-(3,4,5-Tr im eth oxyp h en yl)-5-(N-m eth yl-in d ol-5-yl)ox-
a zole (27d ). Compound 27d was prepared in a similar manner
1
as described for the preparation of 27b. H NMR (CDCl3): δ
7.95 (m, 2H), 7.50 (dd, J ) 8.4, 1.4 Hz, 1H), 7.34 (d, J ) 8.8
Hz, 1H), 7.10 (d, J ) 3.4 Hz, 1H), 7.00 (s, 2H), 6.51 (d, J ) 2.9
Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.74 (s, 6H). ESI (+)/MS:
357 (M + H)+, 379 (M + Na)+. Anal. Calcd for C21H20N2O4: C,
69.22; H, 5.53; N, 7.69. Found: C, 69.14; H, 5.55; N, 7.61.
1-Methyl-4-(3,4,5-trimethoxyphenyl)-5-(3-amino-4-methoxy-
p h en yl)im id a zole (25f). Compound 24f, 1-methyl-4-(3,4,5-
trimethoxyphenyl)-5-(3-nitro-4-methoxyphenyl)imidazole, was
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prepared in a similar way to that of 24h . H NMR (CDCl3): δ
4-(3,4,5-Tr im e t h oxyp h e n yl)-5-(3-a m in o-4-m e t h oxy-
p h en yl)oxa zole (28a ). Compound 28a was prepared in a
similar manner as described for the preparation of 28b. 1H
NMR (DMSO-d6): δ 8.40 (s, 1H), 6.95-6.97 (m, 3H), 6.88 (d,
J ) 8.5 Hz, 1H), 6.80 (dd, J ) 8.2, 2.1 Hz, 1H), 4.98 (s, 2H),
6.51 (d, J ) 2.9 Hz, 1H), 3.80 (s, 3H), 3.70 (s, 6H), 3.69 (s,
3H). ESI (+)/MS: 357 (M + H)+, 379 (M + Na)+. Anal. Calcd
for C19H20N2O5: C, 64.04; H, 5.66; N, 7.86. Found: C, 63.95;
H, 5.55; N, 7.82.
4-(3-Am in o-4-m e t h oxyp h e n yl)-5-(3,4,5-t r im e t h oxy-
p h en yl)oxa zole (30a ). Compound 30a was prepared in a
similar manner as described for the preparation of 28b. 1H
NMR (CDCl3): δ 7.90 (s, 1H), 7.16 (d, J ) 1.0 Hz, 1H), 7.11
(d, J ) 8.1 Hz, 1H), 6.88 (s, 2H), 6.81 (d, J ) 8.5 Hz, 1H), 3.88
(s, 6H), 3.79 (s, 6H). ESI (+)/MS: 357 (M + H)+, 379 (M +
Na)+. Anal. Calcd for C19H20N2O5: C, 64.04; H, 5.66; N, 7.86.
Found: C, C, 63.97; H, 5.53; N, 7.80.
7.89 (d, J ) 1.7 Hz, 1H), 7.62 (s, 1H), 7.52 (dd, J ) 8.8, 2 Hz,
1H), 7.21 (d, J ) 8.5 Hz, 1H), 6.72 (s, 2H), 4.02 (s, 3H), 3.82
(s, 3H), 3.69 (s, 6H), 3.54 (s, 3H). ESI (+)/MS: 400 (M + H)+.
A mixture of 24f (11.0 g, 27 mmol), SnCl2‚2H2O (12.43 g,
55.0 mmol), and 100 mL of concentrated HCl in 300 mL of
EtOH was refluxed for 6 h. The solvent was removed under
reduced pressure. The residue was diluted with 1 L of water,
neutralized with 50% NaOH, and extracted with EtOAc. The
combined organic layers were then washed with brine, dried
(MgSO4), and concentrated in vacuo. The crude product was
recryststallized from MeCN to afford pure 6.8 g (68%) of 25f.
1H NMR (HCl salt, in MeOH-d4): δ 9.14 (s, 1H), 7.68-7.56
(m, 4H), 6.65 (s, 2H), 4.07 (s, 3H), 3.79 (s, 3H), 3.74 (s, 3H),
3.70 (s, 3H), 3.69 (s, 3H). ESI (+)/MS: 370 (M + H)+, 392 (M
+ Na)+. Anal. Calcd for C20H23N3O4‚HCl: C, 59.18; H, 5.96;
N, 10.35. Found: C, 58.85; H, 5.81; N, 10.23.
1-Meth yl-4-(3,4,5-tr im eth oxyph en yl)-5-(N-m eth yl-3-ch lo-
r o-in d ol-5-yl)im id a zole (26). A mixture of 24h (0.377 g, 1
mmol) and NCS (0.16 g, 1.2 mmol) in 10 mL of acetonitrile
was stirred for 20 h. The solvent was removed in vacuo, and
the residue was purified by flash chromatography on silica gel
eluting with 100:3 EtOAc/methanol to give 0.240 g (58%) of
4-(3-Am in o-4-m eth oxyp h en yl)-5-(3-m eth oxy-4,5-m eth -
ylen ed ioxyp h en yl)oxa zole (30b). Compound 30b was pre-
pared in a similar manner as described for the preparation of
28b. 1H NMR (CDCl3): δ 7.86 (s, 1H), 7.01-7.05 (m, 2H), 6.85
(d, J ) 1.0 Hz, 1H), 6.77-6.81 (m, 2H), 6.00 (s, 2H), 3.88 (s,
3H), 3.82 (s, 3H). ESI (+)/MS: 341 (M + H)+. Anal. Calcd for
C18H16N2O5: C, 63.54; H, 4.74; N, 8.23. Found: C, 63.43; H,
4.49; N, 8.15.
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26 as a white solid. H NMR (CDCl3): δ 7.66 (m, 1H), 7.59 (s,
1H), 7.40 (dd, J ) 8.5, 0.7 Hz, 1H), 7.22 (dd, J ) 8.5, 1.7 Hz,
1H), 7.11 (s, 1H), 6.81 (s, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 3.56
(s, 6H), 3.48 (s, 3H). ESI (+)/MS: 378 (M + H)+. Anal. Calcd
for C22H22N3O3Cl: C, 64.15; H, 5.38; N, 10.20. Found: C, 64.28;
H, 5.52; N, 10.06.
1-Me t h yl-4-(4-m e t h oxy-3-n it r op h e n yl)-5-(3,4,5-t r i-
m eth oxyp h en yl)im id a zole (31a ). Compound 31a was pre-
pared in a similar manner as described for the preparation of
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24h . H NMR (CDCl3): δ 8.05 (d, J ) 2 Hz, 1H,), 7.72 (d, J )
Gen er a l P r oced u r e for th e F or m a tion of 4,5-Disu bsti-
tu ted Oxa zoles. The representative procedure for the forma-
tion of 4,5-disubstituted oxazoles is as follows. A mixture of
21a (0.43 g, 1.2 mmol), 3-benzyloxy-4-methoxybenzaldehyde
6c (0.242 g, 1 mmol), and potassium carbonate (0.1.34 g, 2.4
mmol) in 10 mL of methanol and 3 mL of DME was refluxed
for 2 h. After it was cooled to room temperature, the solution
was concentrated in vacuo and diluted with EtOAc. The
solution was washed with water and brine, dried (MgSO4),
filtered, and concentrated in vacuo. The residue was purified
by flash chromatography on silica gel eluting with 1:1 EtOAc/
hexane to give 0.40 g (89%) of 4-(3,4,5-trimethoxyphenyl)-5-
(3-benzyloxy-4-methoxyphenyl)oxazole (27b) as a white solid.
1H NMR (CDCl3): δ 7.89 (s, 1H), 7.18-7.34 (m, 6H), 6.92-
6.89 (m, 4H), 5.06 (s, 2H), 3.92 (s, 3H), 3.89 (s, 3H), 3.79 (s,
6H). ESI (+)/MS: 448 (M + H)+.
A mixture of 27b (0.28 g, 0.63 mmol), ammonium formate
(0.400 g, 6.3 mmol), 5% palladium on carbon (0.1 g), and 30
mL of methanol was heated under reflux for 2 h. After it was
cooled to room temperature, the solution was filtered through
a pad of Celite and concentrated in vacuo. The residue was
purified by flash chromatography on silica gel eluting with 3:2
EtOAc/hexane to give 0.202 g (90%) of 4-(3,4,5-trimethoxy-
phenyl)-5-(3-hydroxy-4-methoxyphenyl)oxazole (28b) as a white
solid. 1H NMR (CDCl3): δ 7.91 (s, 1H), 7.26 (d, J ) 2.3 Hz,
1H), 7.16 (dd, J ) 8.1, 1.9 Hz, 1H), 6.94 (s, 2H), 6.86 (d, J )
8.5 Hz, 1H), 5.5 (br, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.809 (s,
6H). ESI (+)/MS: 358 (M + H)+. Anal. Calcd for C19H19NO6:
C, 63.86; H, 5.36; N, 3.92. Found: C, 63.93; H, 5.37; N, 3.88.
8.8 Hz, 1H), 7.61 (d, J ) 1.1 Hz, 1H), 6.96 (d, J ) 8.8 Hz, 1H),
6.54 (s, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.83 (s, 6H), 3.54 (s,
3H). ESI (+)/MS: 400 (M + H)+.
1-Meth yl-4-(4-n itr o-3-m eth ylph en yl)-5-(3,4,5-tr im eth ox-
yp h en yl)im id a zole (31b). Compound 31b was prepared from
19a , tosmic agent 21c, and methylamine in a similar manner
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as described for the preparation of 24h . H NMR (CDCl3): δ
7.84 (d, J ) 8.9 Hz, 1H), 7.71 (s, 1H), 7.63 (s, 1H), 7.32 (d, J
) 8.9 Hz, 1H), 6.54 (s, 2H), 3.96 (s, 3H), 3.83 (s, 6H), 3.53 (s,
3H). ESI (+)/MS: 384 (M + H)+.
1-Met h yl-4-(N-m et h yl-in d ol-5-yl)-5-(3,4,5-t r im et h ox-
yp h en yl)im id a zole (32). Compound 32 was prepared from
31b in a similar manner as described for the preparation of
compound 10. 1H NMR (CDCl3): δ 7.85 (d, J ) 1.0 Hz, 1H),
7.57 (s, 1H), 7.43 (dd, J ) 8.8, 1.6 Hz, 1H), 7.16 (d, J ) 8.5
Hz, 1H), 6.98 (d, J ) 3.1 Hz, 1H), 6.58 (s, 2H), 6.38 (dd, J )
3.1, 0.3 Hz, 1H), 3.94 (s, 3H), 3.78 (s, 3H), 3.75 (s, 6H), 3.52 (s,
3H). ESI (+)/MS: 378 (M + H)+. Anal. Calcd for C22H23N3O3:
C, 70.01; H, 6.14; N, 11.13. Found: C, 69.71; H, 6.30; N, 11.10.
1-Me t h yl-4-(3-a m in o-4-m e t h oxyp h e n yl)-5-(3,4,5-t r i-
m eth oxyp h en yl)im id a zole (33). Compound 33 was prepared
from 31a in a similar manner as described for the preparation
1
of 25f. H NMR (HCl salt, in MeOH-d4): δ 9.14 (1H, s), 7.63
(dd, j ) 8.4, 2.2 Hz, 1H), 7.53 (d, J ) 1.9 Hz, 1H), 7.44 (d, J )
8.8 Hz, 1H), 6.65 (s, 2H), 4.07 (s, 3H), 3.79 (s, 3H), 3.74 (s,
3H), 3.68 (s, 6H). APCI (+)/MS: 370 (M + H)+. Anal. Calcd
for C20H23N3O4‚1.1HCl: C, 58.66; H, 5.93; N, 10.26. Found:
C, 58.51; H, 5.95; N, 10.25.