Combretastatin Analogues
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 3 733
1
light petroleum 2:3; oil; yield 69% (270 mg); H NMR 3.84 (s,
9H), 3.91 (s, 6H), 4.19 (d, J ) 9.2, 1H), 5.38 (d, J ) 9.2, 1H),
5.69 (s, 1H), 6.54 (s, 2H), 6.69-6.74 (m, 1H), 6.84-6.88 (m,
2H). Anal. (C20H23NO7) C, H, N.
6.6, 1H), 5.55 (d, J ) 6.6, 1H), 5.57 (br, 1H), 6.39 (s, 2H), 6.56-
6.58 (m, 2H), 6.62 (d, J ) 2.1, 1H), 6.71 (d, J ) 8.1, 1H), 7.37-
7.44 (m, 2H), 7.55-7.59 (m, 1H), 7.70 (dd, J ) 2.1, J ) 8.1,
1H). Anal. (C25H25NO8S) C, H, N, S.
General Procedure for Preparation of the Isoxazoline
Derivatives 20b and 21b. To a solution of appropriate
isoxazoline 18a or 19a (40 mg, 0.07 mmol) in THF (7 mL),
methyllithium (1.6 M in Et2O) (63 mL, 0.1 mmol) was added
portionwise at -70 °C. After the mixture was stirred at -70
°C for 30 min, THF (4 mL) and water (0.5 mL) were added,
and the mixture was allowed to warm to room temperature.
The reaction mixture was added to water (5 mL) and extracted
with CH2Cl2 (3 × 10 mL). The organic phases were washed
with brine, dried, and evaporated under reduced pressure. The
residue was chromatographed on silica gel.
Suzuki Coupling: General Procedure for the Prepa-
ration of Biphenyls 24a-c and Terphenyl Derivatives
(26a-c). To a suspension of Pd[(PPh)3]4 (10 mg, 0.08 mmol)
in toluene, the appropriate aryl halide derivative 23 or 24a-c
(0.3 mmol) was added, and the mixture was stirred for 10 min
at room temperature. To this suspension was added sequen-
tially the arylboronic acid 22 or 25 (0.3 mmol) solubilized in a
minimum volume of EtOH containing Na2CO3 (260 mg, 2.4
mmol), and the mixuture was refluxed for 3 h, cooled, and
filtered. The filtrate was evaporated to dryness, and the
residue was diluted with CH2Cl2 (30 mL) and washed with a
saturated NaCl (15 mL) solution. Standard workup, followed
by column chromatography, gave biphenyls 24a-c and ter-
phenyls 26a-c.
2-Methoxy-5-[3-methyl-4-(3,4,5-trimethoxy-phenyl)-4,5-
dihydro-isoxazol-5-yl]-phenol (20b). Eluent ethyl acetate/
1
light petroleum 4:6; oil; yield 65% (170 mg); H NMR 1.86 (s,
3H), 3.84 (s, 9H), 3.92 (s, 3H), 4.15 (d, J ) 7.8, 1H), 5.32 (d, J
) 7.8, 1H), 5.69 (s, 1H), 6.50 (s, 2H), 6.68 (dd, J ) 2.2, J )
8.2, 1H), 6.81 (d, J ) 2.2, 1H), 6.86 (d, J ) 8.2, 1H). Anal.
(C20H23NO6) C, H, N.
3-Benzyloxy-2′-bromo-4-methoxy-biphenyl (24a). Elu-
ent diethyl ether/light petroleum 0.2:9.8; oil; yield 90% (100
mg); 1H NMR 3.93 (s, 3H), 5.17 (s, 2H), 6.95 (s, 2H), 7.25-
7.39 (m, 9H), 7.62 (d, J ) 8.0, 1H). Anal. (C20H17BrO2) C, H.
3-Benzyloxy-3′-bromo-4-methoxy-biphenyl (24b). Elu-
ent diethyl ether/light petroleum 1:4; oil; yield 60% (66 mg);
1H NMR 3.91 (s, 3H), 5.19 (s, 2H), 6.95 (d, J ) 8.4, 1H), 7.09
(s 2 H), 7.26 (d, J ) 7.8, 1H), 7.38-7.46 (m, 7 H), 760 (s, 1H).
Anal. (C20H17BrO2) C, H.
2-Methoxy-5-[3-methyl-3-(3,4,5-trimethoxy-phenyl)-4,5-
dihydro-isoxazol-4-yl]-phenol (21b). Eluent ethyl acetate/
1
light petroleum 4:6; oil; yield 60% (160 mg); H NMR 1.88 (s,
3H), 3.85 (s, 9H), 3.94 (s, 3H), 4.03 (d, J ) 7.0, 1H), 5.32 (d, J
) 7.0, 1H), 5.66 (br, 1H), 6.39 (s, 2H), 6.83 (s, 2H), 6.89 (s,
1H). Anal. (C20H23NO6) C, H, N.
3-Benzyloxy-4′-bromo-4-methoxy-biphenyl (24c). Elu-
ent diethyl ether/light petroleum 1:4; oil; yield 63% (70 mg);
1H NMR 3.92 (s, 3H), 5.20 (s, 2H), 6.97-7.03 (m, 1H), 7.08 (d,
J ) 1.9, 1H), 7.25-7.52 (m, 10H). Anal. (C20H17BrO2) C, H.
3-Benzyloxy-4,3′′,4′′,5′′-tetramethoxy-[1,1′,2′,1′′]terphe-
nyl (26a). Eluent diethyl ether/light petroleum 1:4; oil; yield
General Procedure for Removal of the TBDMS Pro-
tecting Group. A solution of the appropriate silyl ether 9a,
10a, 13a, 14a, 18a, or 19a (0.11 mmol) in dry tetrahydrofuran
(6 mL) was treated with tetrabutylammonium fluoride (37.8
mg, 0.12 mmol). Stirring was continued for 20 min, and then
ice (10 g) was added, followed by diethyl ether. The ethereal
layer was washed with water (3 × 40 mL) and dried. Removal
of solvent in vacuo was followed by filtration through a short
column of silica gel.
1
55% (75 mg); H NMR 3.62 (s, 6H), 3.83 (s, 3H), 3.88 (s, 3H),
4.89 (s, 2H), 6.37 (s, 2H), 6.80-6.87 (m, 3H), 7.28-7.45 (m,
9H). Anal. (C29H28O5) C, H.
3-Benzyloxy-4,3′′,4′′,5′′-tetramethoxy-[1,1′,3′1′′]terphe-
nyl (26b). Eluent diethyl ether/light petroleum 1:4; oil; yield
96% (131 mg); 1H NMR 3.93 (s, 3H), 3.97 (s, 9H), 5.13 (s, 2H),
6.83 (s, 2H), 7.02 (d, J ) 8.0, 1H), 7.21-7.30 (m, 2H), 7.31-
7.44 (m, 3H), 7.44-7.51 (m, 5H), 7.53-7.65 (m, 1H). Anal.
(C29H28O5) C, H.
3-Benzyloxy-4,3′′,4′′,5′′-tetramethoxy-[1,1′,4′,1′′]terphe-
nyl (26c). Eluent diethyl ether/light petroleum 1:4; oil; yield
79% (108 mg); 1H NMR 3.90 (s, 3H), 3.93 (s, 9H), 5.23 (s, 2H),
6.80 (s, 2H), 6.98 (d, J ) 8, 1H), 7.18 (s, 2H), 7.22-7.45 (m,
9H). Anal. (C29H28O5) C, H.
2-Bromo-3-(3,4,5-trimethoxy-phenyl)-pyridine (29). Com-
pound 28 (300 mg, 1.1 mmol) was added to a suspension of
Pd[(PPh)3]4 (10 mg, 0.08 mmol) in toluene, and the mixture
was stirred for 10 min at room temperature. To this solution
were added sequentially 25 (250 mg, 1.2 mmol) solubilized in
a minimum volume of EtOH and Na2CO3 (260 mg, 2.4 mmol),
and the mixuture was refluxed for 3h, cooled, and filtered. The
filtrate was evaporated to dryness, and the residue was diluted
with CH2Cl2 (30 mL) and washed with saturated NaCl solution
(15 mL). Standard workup was followed by column chroma-
tography .
Eluent ethyl acetate/light petroleum 1:2; oil; yield 53% (189
mg); 1H NMR 3.88 (s, 6H), 3.91 (s, 3H), 6.62 (s, 2H), 7.30 (dd,
J ) 4.8, J ) 7.6, 1H), 7.63 (dd, J ) 1.9, J ) 7.5, 1H), 8.36 (dd,
J ) 2.0, J ) 4.8, 1H). Anal. (C14H14 BrNO3) C, H, N.
3-Benzyloxy-4-methoxy-phenyl-boronic Acid (30). To
a 1 M THF solution of the 5-iodo-2-methoxy-benzyl-phenol (23)
(350 mg, 1 mmol) under argon at -78 °C was added dropwise
a 1.6 M solution of n-BuLi (0.7 mL, 1.1 mmol) in hexanes over
15-30 min. The reaction mixture was stirred for an additional
15 min at -78 °C, treated with B(OiPr)3 (0.4 mL, 3 mmol),
and allowed to warm to room temperature over 12 h. The
reaction was cooled to 0 °C and acidified to pH 6.5 with 5%
HCl, then extracted with CH2Cl2 (2 × 20 mL). The organic
layer was washed with saturated brine (20 mL) solution, dried
(Na2SO4), and evaporated to dryness to yield a foamy material,
which was used immediately in the cross-coupling reaction.
2-Methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-
isoxazol-5-yl]-phenol (9b). Eluent ethyl acetate/light petro-
1
leum 1:1; white solid, mp 141-144 °C; yield 90% (36 mg); H
NMR 3.30 (dd, J ) 8.2, J ) 16.2, 1H), 3.74 (dd, J ) 10.9, J )
16.2, 1H), 3.89 (s, 12H), 5.65 (dd, J ) 8.2, J ) 10.9, 1H), 5.63
(br, 1H), 6.85-6.95 (m, 5H). Anal. (C19H21NO6) C, H, N.
2-Methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-
yl]-phenol (10b). Eluent ethyl acetate/light petroleum 1:4;
white solid, mp 183-184 °C; yield 99% (39 mg); 1H NMR 3.91
(s, 3H), 3.95 (s, 9H), 5.80 (br, 1H), 5.82 (s, 1H), 6.94 (d, J )
8.9, 1H), 7.08 (s, 2H), 7.37-7.41 (m, 2H). Anal. (C19H19NO6)
C, H, N.
2-Methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-
isoxazol-3-yl]-phenol (13b). Eluent diethyl ether/light pe-
troleum 2:3; white solid, mp 129-133 °C; yield 90% (36 mg);
1H NMR 3.30 (dd, J ) 8.4, J ) 16.4, 1H), 3.75 (dd, J ) 10.4,
J ) 16.4, 1H), 3.86 (s, 3H), 3.90 (s, 6H), 3.96 (s, 3H), 5.65 (dd,
J ) 8.4, J ) 10.4, 1H), 5.68 (br, 1H), 6.62 (s, 2H), 6.90 (d, J )
8.1, 1H), 7.22 (dd, J ) 2.1, J ) 8.1, 1H), 7.28 (d, J ) 2.1, 1H).
Anal. (C19H21NO6) C, H, N.
2-Methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-
yl]-phenol (14b). Eluent ethyl acetate/light petroleum 1:4;
white solid, mp 197-200 °C; yield 64% (25 mg); 1H NMR 3.90
(s, 3H), 3.95 (s, 9H), 5.80 (br, 1H), 6.70 (s, 1H), 6.93 (d, J )
8.3, 1H), 7.04 (s, 2H), 7.36 (d, J ) 1.9, 1H), 7.43 (dd, J ) 1.9,
J ) 8.3, 1H). Anal. (C19H19NO6) C, H, N.
5-[3-Benzenesulfonyl-4-(3,4,5-trimethoxy-phenyl)-4,5-
dihydro-isoxazol-5-yl]-2-methoxy-phenol (18b). Eluent
ethyl acetate/light petroleum 3.5:6.5; oil; yield 99% (55 mg);
1H NMR 3.67 (s, 6H), 3.82 (s, 3H), 3.91 (s, 3H), 4.58 (d, J )
6.5, 1H), 5.56 (d, J ) 6.5, 1H), 5.62 (br, 1H), 6.15 (s, 2H), 6.79-
6.84 (m, 3H), 7.37-7.43 (m, 2H), 7.55 (d, J ) 8.1, 1H), 7.61-
7.65 (m, 2H). Anal. (C25H25NO8S) C, H, N, S.
5-[3-Benzenesulfonyl-5-(3,4,5-trimethoxy-phenyl)-4,5-
dihydro-isoxazol-4-yl]-2-methoxy-phenol (19b). Eluent
ethyl acetate/light petroleum 3.5:6.5; oil; yield 69% (38 mg);
1H NMR 3.82 (s, 6H), 3.84 (s, 3H), 3.89 (s, 3H), 4.56 (d, J )