2.21 (s, 3 H), 2.36 (s, 3 H), 3.78 (s, 3 H), 3.83 (s, 3 H), 6.56
(s, 1 H), 6.59 (dd, J ) 0.8, 8.9, 1 H), 7.08 (dd, J ) 0.8, 8.8,
1 H), 7.8 (d, J ) 8.8, 1 H), 7.10 (d, J ) 0.6, 1 H), 7.68 (d,
J ) 8.7, 1 H). LC-MS m/z 355 (MH+), 377 (MNa+), 313.
3-(2,4-Dihydroxyphenyl)-7-hydroxy-4-methylcouma-
rin (4).1,9 A 12-L RBF was charged with compound 3 (484.0
g, 1.367 mol) and pyridine hydrochloride (98%, 1844 g,
15.957 mol) under a nitrogen atmosphere. The solid mixture
was gradually heated to 180-210 °C (internal temperature)
and stirred for 1 h with fast agitation. After cooling to 22
°C, the reaction was diluted with water (4.0 L) and extracted
with EtOAc (4.0 L × 1, 2.0 L × 1). The combined organic
phase was washed with brine (2.0 L) and concentrated to
dryness in vacuo at 50 °C. The resulting dark gelatinous
material was placed under high vacuum (8 mmHg) at 22 °C
overnight to afford crude 4 (388 g, 99% yield), which was
8.1, 1 H), 7.69 (d, J ) 8.7, 1 H). LC-MS m/z 411 (MH+),
433 (MNa+), 369.
3-[2,4-Bis(2-trimethylsilylethoxymethoxy)phenyl]-4-
methyl-7-(2-trimethylsilanylethoxymethoxy)coumarin (6b).
A 2-L RBF was charged with crude trihydroxy coumarin 4
(41.4 g, 0.0336 mol), acetone (400 mL), and K2CO3 (23.2
g, 0.168 mol; 325 mesh) with stirring under nitrogen.
2-Trimethylsilylethoxymethyl chloride (SEM-Cl, 24 mL,
0.134 mol) was added dropwise over a 20-min period, and
then the reaction was refluxed at 59 °C for 3 h. The mixture
was cooled to 20 °C, and the solid was filtered through a
Celite pad, which was washed with acetone (200 mL); the
combined filtrate was concentrated in vacuo at 50 °C. The
resulting crude mixture (37.6 g) was purified by chroma-
tography (580 g of SiO2; EtOAc/hexane, 2%/98% (1.0 L),
8%/90% (1.0 L)). There was obtained 17.1 g (42% yield) of
1
1
used in the next step without further purification. H NMR
coumarin 6b as brown oil. H NMR (300 MHz, CDCl3) δ
(300 MHz, CD3OD) δ 2.18 (s, 3 H), 4.80 (br, 3 H), 6.36
(dd, J ) 0.3, 8.0, 1 H), 6.38 (s, 1 H), 6.72 (s, 1 H), 7.78-
6.98 (m, 2 H), 7.62 (d, J ) 8.4, 1 H). LC-MS m/z 285
(MH+), 307 (MNa+).
0.04 (s, 9 H), 0.05 (s, 9 H), 0.08 (s, 9 H), 0.78-0.85 (m, 6
H), 2.16 (s, 3 H), 3.42-3.60 (m, 6 H), 6.05 (s, 6 H), 6.30
(s, 1 H), 6.36 (d, J ) 8.6, 1 H), 6.73 (s, 1 H), 6.75 (d, J )
9.3, 1 H), 7.22 (d, J ) 8.4, 1 H), 7.55 (d, J ) 9.2, 1 H).
LC-MS m/z 675 (MH+), 697 (MNa+).
3-[(2,4-Dimethoxy)phenyl]-7-hydroxy-4-methylcouma-
rin (5). A 22-L RBF was charged with crude 7-acetoxy
coumarin 3 (2.0 kg, 5.64 mol), MeOH (9.0 L), and K2CO3
(1.01 kg, 7.28 mol; 325 mesh). The reaction was heated to
reflux at 65 °C for 1.5 h, and then the mixture was cooled
to 20 °C; one-half of the mixture was transferred to a 22-L
separatory flask and diluted with EtOAc (8.0 L). This mixture
was carefully treated with 2 N HCl (4.0 L), and the organic
phase was separated and then concentrated in vacuo at 50
°C to give a crude product. The second half of the reaction
mixture was worked up in the same fashion; the combined
crude products was triturated with ether (1.0 L) to afford
676.5 g (38% isolated yield; HPLC ) 95%, area%) of 5 as
off-white solid, which was suitable for use in the next step
without further purification. 1H NMR (300 MHz, CDCl3) δ
1.73 (s, 3 H), 2.60 (s, 1 H), 3.78 (s, 6 H), 6.29 (s, 1 H), 6.40
(d, J ) 8.6, 1 H), 7.0 (s, 1 H), 7.08 (d, J ) 9.0, 1 H), 7.22
(d, J ) 8.5, 1 H), 7.64 (d, J ) 9.1, 1 H). LC-MS m/z 313
(MH+), 335 (MNa+).
3-[2,4-Bis(methoxymethoxy)phenyl]-7-methoxymethoxy-
4-methylcoumarin (6c). A 500-mL RBF was charged with
crude trihydroxy coumarin 4 (10.1 g, 0.0084 mol) and K2-
CO3 (5.8 g, 0.042 mol). Bromomethyl methyl ether (MOM-
Br, 90%, 4 mL, 0.044 mol) was added dropwise over an
8-min period, and then the reaction was warmed to reflux at
87 °C for 3 h. The mixture was cooled to 20 °C and diluted
with EtOAc (500 mL). The organic phase was washed with
brine (300 mL × 2) and then concentrated in vacuo at 50
°C. There was obtained 10.1 g (68% yield) of coumarin 6c
as a brown tan solid. 1H NMR (300 MHz, CDCl3) δ 2.22 (s,
3 H), 3.38 (s, 3 H), 3.48 (s, 3 H), 3.50 (s, 3 H), 5.19 (s, 2
H), 5.24 (s, 2 H), 5.26 (s, 2 H), 6.78 (dd, J ) 0.3, 7.6, 1 H),
6.92 (d, J ) 0.4, 1 H), 7.01 dd, J ) 0.2, 8.0, 1 H), 7.03-
7.10 (m, 2 H) 7.58 (d, J ) 8.2, 1 H). LC-MS m/z 417
(MH+), 439 (MNa+), 385.
7-Benzoyloxy-3-[(2,4-dibenzoyloxy)phenyl]-4-methyl-
coumarin (6d). A 22-L RBF was charged with crude
trihydroxy coumarin 7 (388 g, 1.37 mol), CH2Cl2 (5.0 L),
and Et3N (946 mL, 6.78 mol) under nitrogen. The mixture
was cooled to 0 °C with stirring and was treated with benzoyl
chloride (632 mL, 5.45 mol) over a 1-h period. Additional
CH2Cl2 (1.0 L) was added, and the mixture was warmed to
20 °C and stirred for 18 h. The mixture was further diluted
with CH2Cl2 (3.0 L) and then carefully quenched with water
(2.5 L). The phases were separated, and the aqueous layer
was extracted with CH2Cl2 (1.0 L); the combined organic
extracts were washed with saturated NaHCO3 (2.0 L × 2)
and then dried over Na2SO4. The solvent was concentrated
in vacuo at 50 °C to afford the crude tribenzoate, that was
dissolved in hot EtOAc (950 mL) and then allowed to stand
at 0 °C for 16 h. The solid was collected by filtration and
washed with ether, air-dried, and dried in a vacuum oven at
50 °C overnight. There was obtained 387.6 g (48% yield)
7-Acetoxy-3-[(2,4-diacetoxy)phenyl]-4-methylcouma-
rin (6a).1 A 5-L RBF was charged with crude coumarin 4
(132.0 g, 0.464 mol) and acetic anhydride (99%, 459.6 g,
4.5 mol). The mixture was stirred under nitrogen at 22 °C,
treated with pyridine (99.8%, 113.0 g, 1.43 mol) over a 5-min
period, and then heated to 89 °C and stirred for 6 h. The
progress of the reaction was monitored by HPLC. The excess
amount of reagents was removed by distillation under
reduced pressure (160 mmHg) at 140 °C. The resulting
mixture was cooled to 22 °C, dissolved in EtOAc (2.0 L),
and washed with saturated NaHCO3 (1.0 L), 0.5 N HCl
solution (1.0 L × 2), and brine (1.0 L). Concentration of
the organic phase gave 187.7 g of crude material, which was
purified by chromatography (2.0 kg of SiO2; EtOAc/hexane,
30%/70% (8.0 L), 40%/60% (6.0 L), 50%/50% (8.0 L) to
1
afford 110.0 g (59% yield) of triacetate coumarin 6a. H
1
NMR (300 MHz, CDCl3) δ 2.8 (s, 3 H), 2.25 (s, 3 H), 2.30
(s, 3 H), 2.36 (s, 3 H), 7.08-7.18 (m, 4 H), 7.24 (d, J )
of tribenzoxy coumarin 6d as a tan solid. H NMR (300
MHz, CDCl3) δ 2.31 (s, 3 H), 7.14 (dd, J ) 0.8, 6.8, 1 H),
358
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Vol. 10, No. 2, 2006 / Organic Process Research & Development