Page 9 of 14
The Journal of Organic Chemistry
taken not to let the column go dry. If the column runs dry, or is
locally concentrated, the product may precipitate. If this occurs,
1
2
3
4
5
6
7
8
(Z)-4-(2-Bromo-3,4,5-trimethoxybenzylidene)-2-phenyloxazol-
5-one (S9): To a three neck round bottomed flask equipped with
the compound will streak heavily on the column. The product
will appear on the column as a bright yellow band. The product
was eluted with a sharp gradient of 0 to 25% acetone in
dichloromethane.35 Fractions containing the product were pooled
and concentrated in vacuo to afford an orange gel (1.405 g). The
gel was stirred vigorously with hexanes (10 mL) until completely
converted to a light yellowꢀorange powder. The powder was
collected by filtration and dried at ambient temperature under
vacuum (100 torr) until a constant weight was achieved affording
1 as a light yellowꢀorange powder (912 mg, 94%) which was
identical in all respects with the previously reported literature.6,9
Solid samples of (+)ꢀduocarmycin SA (1) are stored under
nitrogen at –20 °C. Rf (30% acetone in dichloromethane, silica
gel): 13 0.16 (UV), 1 0.51 (UV, visual, yellow spot). M.p.
a
thermocouple
was
added
2ꢀbromoꢀ3,4,5ꢀ
trimethoxybenzaldehyde (S8, 40.00 g, 145.4 mmol, 1.00 equiv.),
freshly powdered potassium acetate (7.14 g, 72.7 mmol, 0.50
equiv.), THF (200 mL) and acetic anhydride (41.2 mL, 436.2
mmol, 3.00 equiv.). The light slurry was placed under nitrogen
and heated to an internal temperature of 60 °C. Solid NꢀBzꢀ
glycine (29.54 g, 159.9 mmol, 1.10 equiv.) was added in small
(~2.0 g) portions though a funnel, against a slight nitrogen flow
from the round bottom flask, at a rate that maintained the internal
temperature at 60±3 °C (~5 min, minor delayed exotherm). The
light brown slurry becomes a red/orange slurry and is allowed to
stir for 2 h at 60 °C. An addition funnel was attached, filled with
a 10 v% solution of water in isopropanol (400 mL) and the
solution was added at a rate that maintained the internal
temperature at 55 °C (~1.25 h). The yellow/orange slurry was
cooled to room temperature, then to an internal temperature of 5
°C, and held for 30 min. The crystals were isolated by filtration,
then dried in a vacuum oven at 50 °C until constant weight, to
afford oxazolone S9 as dense, yellow prisms (51.58 g, 85%). Rf
(20% ethyl acetate in hexanes, silica gel): bromide S8 0.53 (UV),
oxazolone S9 0.39 (UV, visual, yellow spot). M.p. (THF/aqueous
isopropanol): 167–168 °C. 1H NMR (400 MHz, CDCl3) δ: 8.54
(s, 1H), 8.12 (d, J=7.8 Hz, 2H), 7.73 (s, 1H), 7.64 (t, J=7.4 Hz,
1H), 7.54 (t, J=7.7 Hz, 2H), 4.04 (s, 3H), 4.00 (s, 3H), 3.92 (s,
3H). 13C NMR (101 MHz, CDCl3) δ:37 167.2, 163.9, 152.5,
151.0, 145.8, 133.6, 129.4, 129.1, 128.3, 128.2, 125.4, 115.6,
111.9, 61.3, 61.0, 56.1. 1H NMR (400 MHz, THFꢀd8) δ: 8.60 (s,
1H), 8.13ꢀ8.16 (m, 2H), 7.65 (tt, J=7.3, 1.6 Hz, 1H), 7.59 (s, 1H),
7.53ꢀ7.58 (m, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 3.86 (s, 3H). 13C
NMR (101 MHz, THFꢀd8) δ: 167.3, 165.4, 154.0, 152.2, 147.1,
135.1, 134.6, 130.1, 129.24, 129.16, 128.5, 126.9, 115.7, 112.9,
61.4, 61.3, 56.6. IR (thin film) (cm˗1): 1797 (s), 1648 (m), 1482
(m), 1327 (s), 1170 (m). HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd
for C19H17O5NBr 418.0285; Found 418.0290.
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11
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15
16
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19
20
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25
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33
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36
37
38
39
40
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42
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(dichloromethane/acetone/hexanes): >250 °C, at 200 °C
1
22
darkens. [α]D
:
+188.39 ° (c = 0.34 mg/mL, methanol). 1H
NMR (400 MHz, DMSOꢀd6) δ: 9.95 (br s, 1H), 9.34 (br s, 1H),
7.05 (s, 1H), 6.97 (d, J=2.3 Hz, 1H), 6.80 (s, 1H), 6.62 (d, J=2.3
Hz, 1H), 4.49 (dd, J=10.4, 4.8 Hz, 1H), 4.41 (d, J=10.4 Hz, 1H),
4.09 (s, 3H), 3.96 (s, 3H), 3.93 (s, 3H), 3.91 (s, 3H), 2.81 (app dt,
J=7.6, 4.8 Hz, 1H), 1.76 (dd, J=7.6, 4.6 Hz, 1H), 1.59 (app t,
J=4.7 Hz, 1H). 13C NMR (101 MHz, DMSOꢀd6) δ: 177.9, 161.5,
161.1, 160.9, 150.3, 141.0, 138.8, 131.5, 129.9, 128.4, 126.7,
126.3, 123.2, 112.5, 107.7, 107.5, 97.5, 61.4, 61.1, 56.2, 54.9,
52.1, 31.3, 26.0, 23.5. IR (thin film) (cm˗1): 3415 (br w), 3190 (br
w), 1713 (m), 1640 (m), 1271 (s). HRMS (ESIꢀTOF) m/z:
[M+H]+ Calcd for C25H24N3O7 478.1609; Found 478.1613.
Synthesis of 11:
2-Bromo-3,4,5-trimethyoxybenzaldehyde (S8)36: To a three
neck round bottomed flask equipped with a thermocouple was
added 3,4,5ꢀtrimethoxybenzaldehyde (14, 50.00 g, 249.7 mmol,
1.00 equiv.) and acetonitrile (500 mL) then was allowed to stir
until a homogeneous solution formed (~5 min). The flask was
placed under nitrogen and Nꢀbromosuccinimide (47.14 g, 262.2
mmol, 1.05 equiv.) was added in one portion. The mixture was
heated to an internal temperature of 50 °C for 1 h, cooled to room
temperature, and diluted with toluene (500 mL). The solution
was washed with a half saturated, aqueous solution of sodium
thiosulfate (500 mL), then with a saturated aqueous solution of
brine (250 mL). The organic layer was dried over sodium sulfate,
filtered and concentrated in vacuo to afford a dark solid. The
solid was dissolved in a 25 v% solution of isopropanol in hexane
(200 mL) at 50 °C, then cooled to 38–40 °C, and seeded with
product (250 mg). The seed bed was stirred for 1 h, then cooled
to room temperature (23 °C) and held for 15 h. The slurry was
then further cooled to an internal temperature of 5 °C and held for
1 h. The crystals were isolated by filtration and the cake was
washed with a 25 v% solution of isopropanol in hexanes (100
mL) then dried in a vacuum oven at 50 °C until constant weight,
to afford bromide S8 as offꢀwhite needles (57.62 g, 84%) which
was identical in all respects with the previously reported
literature.36 Rf (20% ethyl acetate in hexanes, silica gel): 14 0.26
(UV), bromide S8 0.53 (UV). M.p. (isopropanol/hexanes): 58.5–
59.5 °C. 1H NMR (400 MHz, CDCl3) δ: 10.30 (s, 1H), 7.31 (s,
1H), 3.99 (s, 3H), 3.92 (s, 3H), 3.91 (s, 3H). 13C NMR (101
MHz, CDCl3) δ: 191.0, 153.0, 150.8, 148.7, 128.8, 115.6, 107.4,
61.24, 61.17, 56.2. IR (thin film) (cm˗1): 2942 (m), 2866 (m),
1691 (s), 1579 (m), 1107 (s). HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C10H12O4Br 274.9914; Found 274.9919.
Methyl
(Z)-2-Benzamido-3-(2-bromo-3,4,5-
To a three neck round
trimethoxyphenyl)acrylate (15):
bottomed flask equipped with a thermocouple was added the
oxazolone S9 (40.00 g, 95.65 mmol, 1.00 equiv.), methanol (200
mL) and triethylamine (1.33 mL, 9.57 mmol, 0.10 equiv.). The
yellow suspension was heated to an internal temperature of 60 °C,
then held for 0.5 h, whereupon a light yellow homogeneous
solution formed. Heptane (200 mL) was added, maintaining an
internal temperature >50 °C. The biphasic mixture was cooled to
an internal temperature of 40 °C, seeded with product (200 mg),
and the mixture was stirred for 30 min before being cooled to
room temperature. The solvents were concentrated in vacuo to
approximately 200 mL, additional heptane (200 mL) was added,
and the solvents were again concentrated to approximately 200
mL. The slurry was cooled to an internal temperature of 5 °C,
held for 30 min, then the crystals were isolated by filtration and
dried in a vacuum oven at 50 °C until constant weight, to afford
the product 15 as dense, light yellow rods (42.3 g, 98%). Rf (40%
ethyl acetate in hexanes, silica gel): oxazolone S9 0.61 (UV,
visual, yellow spot), 15 0.41 (UV). M.p. (methanol/heptane):
139–140 °C. 1H NMR (400 MHz, CDCl3) δ: 7.82 (app d, J=7.3
Hz, 2H), 7.78 (br s, 1H), 7.60 (s, 1H), 7.54 (app tt, J=7.5, 1.4 Hz,
1H), 7.44 (app t, J=7.6 Hz, 2H), 6.92 (s, 1H), 3.89 (s, 3H), 3.88
(br s, 6H), 3.55 (s, 3H). 13C NMR (101 MHz, CDCl3) δ: 165.8,
165.4, 152.4, 150.9, 143.6, 133.2, 132.3, 130.2, 129.4, 128.8,
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