5564 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 22
Lee et al.
compound 20 (12 mg, 68%) as a white solid. mp 202-204 °C;
1H NMR (CDCl3) δ 4.14 (s, 3H), 6.08 (s, 2H), 6.71 (s, 1H), 6.75
(s, 1H), 7.51 (m, 3H), 7.86 (m, 2H); MS (EI) m/z 296 [M]+, 268
(base), 250.
34%) and 33 (12 mg, 12%) as a yellow powder, respectively.
(32): mp 190-192 °C; 1H NMR (CDCl3) δ 1.55 (t, 3H, J ) 6.9
Hz), 4.23 (q, 2H, J ) 6.9 Hz), 6.60 (s, 1H), 6.68 (s, 1H), 7.53
(m, 3H), 7.89 (m, 2H), 12.50 (s, 1H); 13C NMR (CDCl3) δ 14.04,
64.57, 90.44, 104.87, 105.42, 125.67, 128.50, 129.05, 130.91,
131.17, 145.08, 150.12, 151.56, 163.46, 182.10; MS (EI) m/z
298 ([M]+, base), 283, 270, 269, 254. HRMS for C17H14O5 [M -
H]+: calculated, 297.0763; found, 297.0762. (33): mp 132-
133 °C; 1H NMR (CDCl3) δ 1.41, 1.53 (t, 6H, J ) 7.2 Hz), 4.13,
4.19 (q, 4H, J ) 7.2 Hz), 6.55 (s, 1H), 6.67 (s, 1H), 7.54 (m,
3H), 7.89 (m, 2H,), 12.65 (s, 1H); 13C NMR (CDCl3) δ 15.01,
15.94, 65.18, 69.30, 91.65, 106.03, 106.55, 126.66, 129.50,
131.83, 132.08, 132.19, 153.69, 153.79, 159.08, 164.24, 183.13;
MS (EI) m/z 326 [M]+, 311, 297 (base), 269. HRMS for C19H18O5
[M]+: calculated, 326.1154; found, 326.1155.
5-Hyd r oxy-6,7-(d ioctyloxy)fla von e (34). A mixture of 1
(81 mg, 0.3 mmol), 1-iodooctane (0.16 mL), and anhydrous K2-
CO3 (166 mg) in acetone (25 mL) was refluxed with stirring
for 30 h. The reaction mixture was concentrated under reduced
pressure, diluted with water (50 mL), and extracted with CH2-
Cl2 (50 mL × 3). The extract was washed with water and dried
over MgSO4, and the solvent was evaporated in vacuo. The
residue was purified by flash chromatography on a column of
silica gel and eluted with CH2Cl2/MeOH (100:1 to 50:1) to give
compound 34 (122 mg, 82%) as a pale yellow powder. mp 85-
86 °C; 1H NMR (CDCl3) δ 0.89, 0.90 (t, 6H, J ) 6.9 Hz), 1.31-
1.52 (m, 20H), 1.79, 1.89 (t, 4H, J ) 6.9 Hz), 4.03, 4.07 (t, 4H,
J ) 6.9 Hz), 6.53 (s, 1H), 6.64 (s, 1H), 7.51 (m, 3H), 7.86 (m,
2H), 12.45 (s, 1H); MS (EI) m/z 494 [M]+, 382, 270 (base).
5-Hyd r oxy-7-m eth oxy-6-p r op yloxyfla von e (21) a n d 5,7-
Dim eth oxy-6-p r op yloxy-fla von e (22). To a stirred solution
of 17 (19 mg, 0.06 mmol) in a mixture of MeOH (4 mL) and
THF (8 mL) was added TMSCHN2 (2 M in hexanes, 0.2 mL,
0.4 mmol). The reaction mixture was stirred at room temper-
ature for 24 h and evaporated. Flash chromatography of the
residue, eluting with CH2Cl2/MeOH (30:1), gave compound 21
(4 mg, 20%) as a yellow powder and compound 22 (9.2 mg,
45%) as a pale yellow powder. (21): mp 112-113 °C; 1H NMR
(CDCl3) δ 1.12 (t, 3H, J ) 7.5 Hz), 1.95 (sextet, 2H, J ) 7.5
Hz), 3.93 (s, 3H), 4.09 (t, 2H, J ) 7.5 Hz), 6.57 (s, 1H), 6.69 (s,
1H), 7.55 (m, 3H), 7.90 (m, 2H); 13C NMR (CDCl3) δ 10.91,
22.73, 61.23, 71.13, 91.77, 106.02, 106.54, 126.66, 129.49,
131.81, 132.19, 133.30, 153.55, 153.73, 159.00, 164.28, 183.11;
MS (EI) m/z 326 ([M]+, base), 283, 269. HRMS for C19H18O5
[M]+: calculated, 326.1154; found, 326.1149. (22): mp 135-
136 °C; 1H NMR (CDCl3) δ 1.13 (t, 3H, J ) 7.5 Hz), 1.96 (sextet,
2H, J ) 7.5 Hz), 3.92, 4.01 (s, 6H), 4.09 (t, 2H, J ) 7.5 Hz),
6.73 (s, 1H), 6.82 (s, 1H), 7.52 (m, 3H), 7.89 (m, 2H); 13C NMR
(CDCl3) δ 10.93, 22.71, 58.92, 61.86, 62.63, 71.10, 97.28, 108.62,
113.62, 115.71, 121.02, 126.43, 129.38, 130.02, 131.72, 132.00,
141.00, 153.05, 155.02, 157.98, 161.66, 177.67; MS (EI) m/z
340 [M]+, 325 (base), 283. HRMS for C20H20O5 [M]+: calcu-
lated, 340.1311; found, 340.1316.
5-Meth oxy-6,7-d ip r op yloxyfla von e (23). To a stirred
solution of 18 (28 mg, 0.08 mmol) in a mixture of MeOH (4
mL) and THF (8 mL) was added TMSCHN2 (2 M in hexanes,
0.32 mL, 0.64 mmol). The reaction mixture was stirred at room
temperature for 24 h and evaporated. Flash chromatography
of the residue, eluting with CH2Cl2/acetone (15:1), gave
compound 23 (23 mg, 78%) as a pale yellow powder. mp 109-
110 °C; 1H NMR (CDCl3) δ 1.08, 1.12 (t, 6H, J ) 7.5 Hz), 1.82,
1.95 (sextet, 4H, J ) 7.5 Hz), 3.99 (s, 3H), 4.00, 4.06 (t, 4H, J
) 7.5 Hz), 6.72 (s, 1H), 6.81 (s, 1H), 7.52 (m, 3H), 7.89 (m,
2H); 13C NMR (CDCl3) δ 10.95, 22.76, 23.89, 62.46, 71.00,
76.28, 97.19, 108.75, 113.16, 126.38, 129.36, 131.61, 132.11,
140.26, 153.17, 154.90, 158.13, 161.47, 177.69.; MS (EI) m/z
368 [M]+, 325 (base), 283. HRMS for C22H24O5 [M]+: calcu-
lated, 368.1624; found, 368.1630.
6-Eth oxy-5-h yd r oxy-7-m eth oxyfla von e (38). To a stirred
solution of 32 (10 mg, 0.034 mmol) in a mixture of MeOH (3
mL) and THF (6 mL) was added TMSCHN2 (2 M in hexanes,
0.02 mL, 0.04 mmol). The reaction mixture was stirred at room
temperature for 24 h and evaporated. Flash chromatography
of the residue, eluting with CH2Cl2/MeOH (50:1), afforded
compound 38 (7.4 mg, 70%) as a pale yellow powder. mp 133-
1
134 °C; H NMR (CDCl3) δ 1.55 (t, 3H, J ) 6.9 Hz), 3.93 (s,
3H), 4.21 (q, 2H, J ) 6.9 Hz), 6.57 (s, 1H), 6.69 (s, 1H), 7.56
(m, 3H), 7.90 (m, 2H), 12.68 (s, 1H); 13C NMR (CDCl3) δ 15.01,
61.19, 65.25, 91.72, 106.04, 106.58, 126.66, 129.49, 131.81,
132.19, 133.29, 153.55, 153.72, 158.75, 164.30, 183.11; MS (EI)
m/z 312 ([M]+, base), 283. HRMS for C18H16O5 [M]+: calculated,
312.0998; found, 312.0997.
6,7-Dia cetoxy-8-br om o-5-h yd r oxyfla von e (24). A mix-
ture of 4 (84 mg, 0.21 mmol) and N-bromosuccinimide (NBS,
56 mg, 0.32 mmol) in THF (8 mL) and concd H2SO4 (10 µL)
was stirred at room temperature for 48 h. The reaction mixture
was extracted with EtOAc, washed with 10% aqueous NaHSO4
solution and water, dried over MgSO4, and then concentrated
in vacuo. The residue was recrystallized from MeOH to give
compound 24 (50 mg, 55%) as a yellow powder. mp 244-246
°C; 1H NMR (CDCl3) δ 2.38, 2.44 (each s, 6H), 6.82 (s, 1H),
7.59 (m, 3H), 8.01 (m, 2H); MS (EI) m/z 434 [M + 2]+, 432
[M]+, 390, 348 (base), 270, 269.
5-Hyd r oxy-6,7-(d ip en tyloxy)fla von e (40). A mixture of
1 (51 mg, 0.19 mmol), 1-iodopentane (0.076 mL), and anhy-
drous K2CO3 (110 mg) in acetone (20 mL) was refluxed with
stirring for 24 h. The reaction mixture was concentrated under
reduced pressure, diluted with water (40 mL), and extracted
with CH2Cl2 (40 mL × 3). The extract was washed with water
and dried over MgSO4 and the solvent evaporated in vacuo.
The residue was purified by flash chromatography on a column
of silica gel and eluted with CH2Cl2/MeOH (60:1) to give
compound 40 (68 mg, 87%) as a pale yellow powder. mp 111-
112 °C; 1H NMR (CDCl3) δ 0.94, 0.97 (t, 6H, J ) 6.6 Hz), 1.39-
1.52 (m, 8H), 1.81, 1.91 (quintet, 4H, J ) 6.6 Hz), 4.05, 4.09
(t, 4H, J ) 6.6 Hz), 6.56 (s, 1H), 6.68 (s, 1H), 7.54 (m, 3H),
7.90 (m, 2H); MS (EI) m/z 410 [M]+.
8-Br om o-5,6,7-tr ih yd r oxyfla von e (25). A mixture of 1 (35
mg, 0.13 mmol) and NBS (33 mg, 0.19 mmol) in THF (4 mL)
and concd H2SO4 (5 µL) was stirred at room temperature for
12 h. The reaction mixture was extracted with EtOAc, washed
with 10% aqueous NaHSO4 solution and water, dried over
MgSO4, and then concentrated in vacuo. The residue was
recrystallized from MeOH to give compound 25 (26 mg, 57%)
5-Met h oxy-6,7-(d ip en t yloxy)fla von e (41). To a stirred
solution of 40 (33 mg, 0.08 mmol) in a mixture of MeOH (4
mL) and THF (8 mL) was added TMSCHN2 (2 M in hexanes,
0.32 mL, 0.64 mmol). The reaction mixture was stirred at room
temperature for 24 h and evaporated. Flash chromatography
of the residue, eluting with CH2Cl2/acetone (20:1), gave
compound 41 (32.6 mg, 98%) as a white solid. mp 107-108
1
as a yellow powder. mp 263-265 °C; H NMR (DMSO-d6) δ
7.07 (s, 1H), 7.59 (m, 3H), 8.12 (m, 2H), 9.58, 10.92, 12.76 (s,
3H); MS (EI) m/z 350 [M + 2]+, 348 ([M]+, base), 270.
1
°C; H NMR (CDCl3) δ 0.95, 0.97 (t, 6H, J ) 6.6 Hz), 1.39-
6-Eth oxy-5,7-d ih yd r oxyfla von e (32) a n d 6,7-Dieth oxy-
5-h yd r oxyfla von e (33). A mixture of 1 (81 mg, 0.3 mmol),
ethyl iodide (0.07 mL), and anhydrous K2CO3 (166 mg) in
acetone (25 mL) was refluxed with stirring for 18 h. The
reaction mixture was concentrated under reduced pressure,
diluted with water (50 mL), and extracted with CH2Cl2 (50
mL × 3). The extract was washed with water and dried over
MgSO4 and the solvent evaporated in vacuo. The residue was
purified by flash chromatography on a column of silica gel and
eluted with CH2Cl2/MeOH (50:1) to give compounds 32 (30 mg,
1.54 (m, 8H), 1.81, 1.93 (quintet, 4H, J ) 6.6 Hz), 3.99 (s, 3H),
4.03, 4.10 (t, 4H, J ) 6.6 Hz), 6.78 (s, 1H), 6.81 (s, 1H), 7.53
(m, 3H), 7.90 (m, 2H); MS (EI) m/z 424 [M]+.
6,7-(Dih exyloxy)-5-h yd r oxyfla von e (42). A mixture of 1
(54 mg, 0.2 mmol), 1-bromohexane (0.084 mL), and anhydrous
K2CO3 (110 mg) in acetone (20 mL) was refluxed with stirring
for 24 h. The reaction mixture was concentrated under reduced
pressure, diluted with water (40 mL) and extracted with CH2-
Cl2 (40 mL × 3). The extract was washed with water and dried