Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3 1205
HNO3 (0.75 mL) and AcOH (6 drops) were added at room
temperature, and the reaction was stirred for 4 h. The reaction
was then diluted with EtOAc (20.0 mL), washed with brine,
dried over MgSO4, filtered, and condensed. The red oil was then
purified by flash chromatography (2:3 Et2O:hexanes 0.5%
AcOH), followed by recrystallization from Et2O/hexanes to
afford 1 (0.443 g, 42%) as a red solid. Rf = 0.16 (2:3 Et2O:
hexanes 0.5% AcOH); mp=56-57 °C (lit. 68 °C).5 1H NMR
(CDCl3): δ 0.84 (t, 3H), 1.18 (bs, 14H), 1.39 (bs, 2H), 1.94 (d,
3H), 2.09 (t, 3H,), 3.99 (s, 3H), 4.02 (s, 3H), 7.26 (d, 1H).
(E)-3-(5,6-Dimethoxy-3-methyl-1,4-dioxocyclohexa-2,5-dienyl)-
propenoic Acid (5a). Following the method used for the synthesis
of 1, the Emmons condensation was performed with 4 (0.323 g,
1.34 mmol) to provide ethyl (E)-3-(6-methyl-2,3,4,5-trimethoxy-
phenyl)-propenoate (0.343 g, 83%) as a pale-yellow oil following
chromatography (CH2Cl2 to 1:19 EtOAc:CH2Cl2). Rf = 0.17
(CH2Cl2). H NMR (CDCl3): δ 1.32 (t, 3H), 2.26 (s, 3H), 3.76
(s, 3H), 3.78 (s, 3H), 3.88 (s, 3H), 3.94 (s, 3H), 4.24 (q, 2H), 6.52 (d,
1H), 7.77 (d, 1H).
The ethyl ester (0.066 g, 0.21 mmol) was hydrolyzed (KOH,
EtOH) to provide the unsaturated acid (0.046 g, 78%) as a light-
tan solid following flash chromatography (2:3 Et2O:hexanes
0.5% AcOH) or recrystallization from Et2O/hexanes. Rf=0.16
(2:3 Et2O:hexanes 0.5% AcOH); mp = 96-97 °C. 1H NMR
(CDCl3): δ 3.77 (s, 3H), 3.81 (s, 3H), 3.89 (s, 3H), 3.95 (s, 3H),
6.59 (d, 1H), 7.90 (d, 1H).
The unsaturated acid (0.010 g, 0.033 mmol) was then oxidized
to provide 5c (0.003 g, 32%) as a red solid following flash
chromatography (1:1 Et2O:hexanes 0.5% AcOH) and recrystal-
lization from Et2O/hexanes. Rf =0.10 (2:3 Et2O:hexanes 0.5%
AcOH); mp=124-131 °C. 1H NMR (CDCl3): δ 1.01 (t, 3H), 1.94
(d, 3H), 2.12 (q, 2H), 3.99 (s, 3H), 4.01 (s, 3H), 7.23 (d, 1H).
(E)-3-(4,5-Dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dienyl)-
2-propylpropenoic Acid (5d). Following the method used for the
synthesis of 1, the Emmons condensation was performed with 4
(0.437 g, 1.82 mmol) to provide ethyl (E)-3-(6-methyl-2,3,4,
5-trimethoxyphenyl)-2-propylpropenoate (0.275 g, 43%) as a
colorless oil following chromatography (1:3 EtOAc:hexanes).
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Rf = 0.52 (1:3 EtOAc:hexanes). H NMR (CDCl3): δ 0.75 (t,
3H, J=7.2 Hz), 1.33 (t, 3H, J=7.2 Hz), 1.35 (m, 2H), 2.03 (s, 3H),
2.11 (m, 2H), 3.69 (s, 3H), 3.78 (s, 3H), 3.88 (s, 3H), 3.93 (s, 3H),
4.25 (q, 2H, J=7.2 Hz), 7.38 (s, 1H).
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The ethyl ester (0.034 g, 0.098 mmol) was then hydrolyzed
(KOH, EtOH) to provide the unsaturated acid (0.029 g, 92%) as
a gold oil following flash chromatography (2:3 Et2O:hexanes
1
0.5% AcOH). Rf = 0.18 (2:3 Et2O:hexanes 0.5% AcOH). H
NMR (CDCl3): δ 0.77 (t, 3H), 1.41 (m, 2H), 2.04 (s, 3H), 2.13
(m, 2H), 3.70 (s, 3H), 3.79 (s, 3H), 3.89 (s, 3H), 3.93 (s, 3H),
7.55 (s, 1H).
The unsaturated acid (0.029 g, 0.090 mmol) was then oxidized
to provide 5d (0.016 g, 59%) as a red solid following flash
chromatography (1:1 Et2O:hexanes 0.5% AcOH) and recrys-
tallization from Et2O/hexanes. Rf = 0.12 (2:3 Et2O:hexanes
The unsaturated acid (0.089 g, 0.31 mmol) was then oxidized
to provide 5a (0.024 g, 57%) as a red solid following flash
chromatography (1:1 Et2O:hexanes 0.5% AcOH) and subse-
quent recrystallization from Et2O/hexanes. Rf=0.06 (2:3 Et2O:
1
0.5% AcOH); mp=95-99 °C. H NMR (CDCl3): δ 0.76 (t,
3H), 1.41 (m, 2H), 1.91 (d, 3H), 2.04 (m, 2H), 3.95 (s, 3H), 3.98
(s, 3H), 7.24 (s, 1H).
1
(E)-3-(5,6-Dimethoxy-3-methyl-1,4-dioxocyclohexa-2,5-dienyl)-
2-butylpropenoic Acid (5e). Following the method used for the
synthesis of 1, the Emmons condensation was performed with 4
(0.650 g, 2.71 mmol) to provide ethyl (E)-3-(6-methyl-2,3,4,5-
trimethoxyphenyl)-2-butylpropenoate (0.484 g, 49%) as a yellow
oil following chromatography (1:9 EtOAc:hexanes). Rf=0.54 (1:3
EtOAc:hexanes). 1H NMR (CDCl3): δ 0.73 (t, 3H), 1.12 (m, 2H),
1.29 (m, 2H), 1.32 (t, 3H), 2.03 (s, 3H), 2.13 (m, 2H), 3.69 (s, 3H),
3.78 (s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 4.25 (q, 2H), 7.37 (s, 1H).
The ethyl ester (0.166 g, 0.453 mmol) was then hydrolyzed
(KOH, EtOH) to provide the unsaturated acid (0.144 g, 94%) as
a yellow amorphous solid following flash chromatography
(2:3 Et2O:hexanes 0.5% AcOH) and recrystallization from
Et2O/hexanes. Rf1= 0.26 (2:3 Et2O:hexanes 0.5% AcOH);
mp = 70-85 °C. H NMR (CDCl3): δ 0.74 (t, 3H), 1.19 (m,
4H), 2.04 (s, 3H), 2.15 (m, 2H), 3.70 (s, 3H), 3.79 (s, 3H), 3.89 (s,
3H), 3.93 (s, 3H), 7.53 (s, 1H).
hexanes 0.5% AcOH); mp=116-125 °C. H NMR (CDCl3):
δ2.19 (s, 3H), 4.00 (s, 6H), 6.76 (d, 1H), 7.60 (d, 1H).
(E)-3-(5,6-Dimethoxy-3-methyl-1,4-dioxocyclohexa-2,5-dienyl)-
2-methylpropenoic Acid (5b). Following the method used for the
synthesis of 1, the Emmons condensation was performed with 4
(0.569 g, 2.37 mmol) to provide ethyl (E)-3-(6-methyl-2,3,4,
5-trimethoxyphenyl)-2-methylpropenoate (0.674 g, 88%) as a
pale-yellow oil following chromatography (1:3 EtOAc:hexanes).
Rf=0.48 (1:3 EtOAc:hexanes). 1H NMR (CDCl3): δ1.31 (t, 3H),
1.71 (d, 3H), 2.01 (s, 3H), 3.67 (s, 3H), 3.77 (s, 3H), 3.87 (s, 3H),
3.91 (s, 3H), 4.24 (q, 2H), 7.47 (d, 1H).
The ethyl ester (0.156 g, 0.481 mmol) was hydrolyzed (KOH,
EtOH) to provide the unsaturated acid (0.121 g, 85%) as a light-
yellow solid following flash chromatography (2:3 Et2O:hexanes
0.5% AcOH) and recrystallization from Et2O/hexanes. Rf=0.16
1
(2:3 Et2O:hexanes 0.5% AcOH); mp=98-102 °C. H NMR
(CDCl3): δ 1.76 (d, 3H, J=1.2 Hz), 2.05 (s, 3H), 3.69 (s, 3H), 3.79
(s, 3H), 3.90 (s, 3H), 3.93 (s, 3H), 7.64 (d, 1H).
The unsaturated acid (0.015 g, 0.044 mmol) was then oxidized
to provide 5e (0.005 g, 40%) as a red solid following flash
chromatography (1:1 Et2O:hexanes 0.5% AcOH) and recrys-
tallization from Et2O/hexanes. Rf = 0.12 (2:3 Et2O:hexanes
The unsaturated acid (0.057 g, 0.19 mmol) was then oxidized
to provide 5b (0.016 g, 31%) as a red solid following flash
chromatography (1:1 Et2O:hexanes 0.5% AcOH) and recrys-
tallization from Et2O/hexanes. Rf = 0.06 (2:3 Et2O:hexanes
0.5% AcOH); mp=134-136 °C. 1H NMR (CDCl3): δ1.77 (d,
3H, J=1.2 Hz), 1.95 (d, 3H, J=1.2 Hz), 4.01 (s, 3H), 4.03 (s, 3H),
7.39 (s, 1H).
(E)-3-(5,6-Dimethoxy-3-methyl-1,4-dioxocyclohexa-2,5-dienyl)-
2-ethylpropenoic acid (5c). Following the method used for the
synthesis of 1, the Emmons condensation was performed with 4
(0.437 g, 1.82 mmol) to provide ethyl (E)-3-(6-methyl-2,3,4,
5-trimethoxyphenyl)-2-ethylpropenoate (0.258 g, 42%) as a color-
less oil following chromatography (1:3 EtOAc:hexanes). Rf=0.50
(1:3 EtOAc:hexanes). 1H NMR (CDCl3): δ 0.94 (t, 3H), 1.33 (t,
3H), 2.02 (s, 3H), 2.15 (q, 2H), 3.69 (s, 3H), 3.78 (s, 3H), 3.89 (s,
3H), 3.92 (s, 3H), 4.26 (q, 2H), 7.36 (s, 1H).
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0.5% AcOH); mp=54-55 °C. H NMR (CDCl3): δ 0.82 (t,
3H), 1.22 (m, 2H), 1.39 (m, 2H), 1.95 (d, 3H), 2.10 (m, 2H), 3.99
(s, 3H), 4.02 (s, 3H), 7.24 (s, 1H).
2-Chloro-3,4,5,6-tetramethoxybenzaldehyde (6). According to
a general aryl chlorination procedure by Lopez-Alvarado,22
2,3,4,5-tetramethoxybenzaldehyde (0.767 g, 3.39 mmol) was
dissolved in CH2Cl2 (10 mL) at room temperature and then
SO2Cl2 (neat, 0.31 mL, 3.7 mmol) was added at room tempera-
ture. The reaction was stirred for 1 h and monitored by 1H NMR
for completion. The reaction was then diluted with CH2Cl2,
washed with brine, dried over MgSO4, filtered, and condensed.
The resulting oil was then purified by flash column chromato-
graphy (1:4 Et2O:hexanes) to provide 6 (0.861 g, 97%) as a
1
colorless oil. Rf=0.27 (1:4 Et2O:hexanes). H NMR (CDCl3):
δ 3.84 (s, 3H), 3.89 (s, 3H), 3.90 (s, 3H), 4.02 (s, 3H), 10.34
(s, 1H).
The ethyl ester (0.041 g, 0.12 mmol) was then hydrolyzed to
provide the unsaturated acid (0.010 g, 27%) as a gold oil
following flash chromatography (2:3 Et2O:hexanes 0.5%
1
AcOH). Rf =0.16 (2:3 Et2O:hexanes 0.5% AcOH). H NMR
(CDCl3): δ 0.98 (t, 3H), 2.04 (s, 3H), 2.18 (q, 2H), 3.70 (s, 3H),
3.79 (s, 3H), 3.90 (s, 3H), 3.93 (s, 3H), 7.53 (s, 1H).
(E)-3-(3-Chloro-5,6-dimethoxy-1,4-dioxocyclohexa-2,5-dienyl)-
2-methylpropenoic Acid (7). Following the method used for the
synthesis of 1, the Emmons condensation was performed in