700
M. J. Piggott and D. Wege
stirring was continued for 3 h. The methanol was evaporated and the
residue was subjected to rapid silica filtration. Elution with ethyl
acetate/petroleum (4 : 1) gave methyl (3-acetyl-5-methoxynaphthalen-
1,4-dion-2-yl)acetate (30) as a yellow solid (119 mg, 30%), which
crystallized from dichloromethane/petroleum as yellow needles, mp
130–138◦C (Found C, 63.7; H, 5.0. C16H14O6 requires C, 63.6; H,
4.7%). Mass spectrum m/z 302 (M, 23%), 272 (42), 271 (32), 270
(74), 255 (33), 244 (47), 243 (100), 242 (70), 229 (48), 115 (29). δH
2-Acetyl-3-bromomethyl-8-methoxynaphthalene-1,4-dione (34)
A mixture of 2-acetyl-8-methoxy-3-methylnaphthalene-1,4-dione (33)
(514 mg, 2.1 mmol), NBS (410 mg, 2.3 mmol), and a catalytic amount
of AIBN in carbon tetrachloride (50 mL) under argon, was heated
under reflux whilst being irradiated with a 150W tungsten lamp. After
3 h, TLC (dichloromethane) indicated that starting material was still
present so another equivalent of NBS (0.41 g, 2.3 mmol) and a fresh
portion of AIBN was added to the reaction mixture. After 13 h the
carbon tetrachloride was evaporated and the residue was subjected to
rapid silica filtration. Elution with ethyl acetate/petroleum (4 : 1) gave
fractions containing the desired product and a by-product. The crude
material was dissolved in dichloromethane (50 mL) and washed with
water (3 × 100 mL).The aqueous washes were back extracted with ether
(2 × 20 mL) and the combined organic solution was washed with water
(50 mL) and brine (2 × 50 mL), dried and evaporated to give the title
bromide (34) as a yellow solid (609 mg, 90%), which crystallized from
dichloromethane/petroleum as yellow needles, mp 108◦C (dec.) (Found
C, 52.0; H, 3.3. C14H11BrO4 requires C, 52.0; H, 3.4%). Mass spec-
trum: m/z 324 ([M + 2], 1.6%), 322 (M, 1.6), 244 (40), 243 (100), 229
(23), 201 (27). δH (500 MHz) 7.79 (dd, J5,6 7.7, J5,7 1.1, 1 H, H5),
7.73 (dd, J6,7 8.4, J6,5 7.7, 1 H, H6), 7.35 (dd, J7,6 8.4, J7,5 1.1, 1 H,
H7), 4.28 (s, 2 H, CH2), 4.01 (s, 3 H, CH3O), 2.55 (s, 3 H, COCH3).
δC (125.8 MHz)† 201.0 (COCH3), 182.7 (C4), 182.5 (C1), 159.8 (C8),
147.4 (C2), 138.4 (C3), 135.8 (C6), 133.3 (C4a), 119.7 (C5), 118.9
(C8a), 118.4(C7), 56.5(CH3O), 31.6(COCH3), 20.1(CH2). νmax/cm−1
1701, 1669, 1647.
(500 MHz) 7.67 (dd (overlapping), J8 ,7 7.6, J8 ,6 1.9, 1 H, H8ꢀ), 7.65
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
(dd (apparent t overlapping), J7 ,8 = J7 ,6 7.6, 1 H, H7 ), 7.29 (dd, J6 ,7
7.6, J6 ,8 1.9, 1 H, H6ꢀ), 3.96 (s, 3 H, CH3O), 3.65 (s, 3 H, CO2CH3),
3.53 (s, 2 H, CH2), 2.45 (s, 3 H, CH3). δC (125.8 MHz) 201.6 (COCH3),
184.2 (C1ꢀ), 182.5 (C4ꢀ), 169.4 (C1), 159.6 (C5ꢀ), 148.0 (C3ꢀ), 136.3
(C2ꢀ), 135.4 (C8ꢀ), 133.2 (C8aꢀ), 119.4 (C7ꢀ), 118.8 (C4aꢀ), 118.2 (C6ꢀ),
56.4 (CH3O), 52.3 (CO2CH3), 31.5 (COCH3), 31.3 (C2). νmax/cm−1
1748, 1709, 1658, 1644.
ꢀ
ꢀ
2-Acetyl-8-methoxy-3-methylnaphthalene-1,4-diol (32)
A stirred solution of diisopropylamine (2.36 mL, 16.8 mmol) in anhy-
drous THF (20 mL) at −78◦C under argon, was treated with a 1.3 M
hexane solution of BunLi (13.0 mL, 16.9 mmol). After 30 min a solu-
tion of 4-methoxy-3-oxo-1,3-dihydroisobenzofuran-1-carbonitrile (23)
(2.90 g, 15.3 mmol) in anhydrous THF (60 mL) was added dropwise
over 25 min, whereupon the bright orange cyanophthalide anion formed.
Stirring was continued for 45 min during which time the orange lithium
salt precipitated from solution. The slurry was treated dropwise with
a solution of (E)-pent-3-en-2-one (31) (1.32 g, 15.7 mmol) in anhy-
drous THF (30 mL) and the reaction mixture was allowed to slowly
warm to room temperature overnight. The dark red solution was diluted
with ice-cold 1 M hydrochloric acid (500 mL) whereupon it turned yel-
low. Extraction with ethyl acetate (4 × 200 mL) gave a yellow solution
which was washed with water (200 mL) and brine (2 × 200 mL), dried
and evaporated to give a brown tar which was subjected to rapid silica
filtration. Elution with ethyl acetate/petroleum (4 : 1) gave the title com-
pound (32) as a brown solid (2.98 g, 79%), containing a trace of the
oxidized 2-acetyl-8-methoxy-3-methylnaphthalene-1,4- dione (33). As
the quinone (33) was required, the mixture was used in the next step.The
pure hydroquinone (32) crystallized from dichloromethane/petroleum
as large translucent yellow needles, mp 132–133◦C (Found C, 68.3; H,
5.5. C14H14O4 requires C, 68.3; H, 5.7%). Mass spectrum m/z 246 (M,
78%), 232 (14), 231 (100), 215 (15). δH (300 MHz) 9.16 (s, 1 H, OH),
7.64 (dd, J5,6 8.6, J5,7 0.9, 1 H, H5), 7.30 (dd, J6,5 8.6, J6,7 7.8, 1 H,
H6), 6.72 (br d, J7,6 7.8, H7), 5.23 (br s, OH), 4.00 (s, 3 H, CH3O), 2.60
(s, 3 H, COCH3), 2.20 (s, 3 H, CH3). δC (75.5 MHz) 206.6 (CO), 156.3
(C), 145.5 (C), 141.3 (C), 127.8 (C), 126.3 (CH), 124.4 (C), 116.4 (C),
115.3 (CH), 113.3 (C), 104.3 (CH), 56.1 (CH3O), 32.4 (COCH3), 12.6
(CH3). νmax/cm−1 3400, 1676, 1653.
2-Acetoxymethyl-3-acetyl-5-methoxynaphthalene-1,4-dione (35)
A stirred solution of 2-acetyl-3-bromomethyl-8-methoxynaphthalene-
1,4-dione (34) (200 mg, 0.62 mmol) in anhydrous DMF (20 mL) under
argon, was cooled in an ice/brine bath before being treated with anhy-
drous sodium acetate (5.1 g, 62 mmol). After 4 h, the reaction mixture
was diluted with ether (20 mL), vacuum filtered through a short col-
umn of silica and washed through with ether (150 mL). The filtrate
was evaporated and the residue was dissolved in ethyl acetate (50 mL)
and washed with water (3 × 40 mL). The aqueous washes were back
extracted with ethyl acetate (2 × 50 mL). The combined ethyl acetate
solution was washed with brine (2 × 50 mL), dried and evaporated to
give the title acetate (35) as an orange oil (171 mg, 91%), which crystal-
lized from ether as orange crystals, mp 115–117◦C (Found C, 63.6; H,
4.7. C16H14O6 requires C, 63.6; H, 4.7%). Mass spectrum m/z 302 (M,
< 2%), 260 (100), 242 (35), 232 (37), 218 (19), 217 (91). δH (300 MHz)
7.72 (m, AB part of ABX, 2 H, H7/H8), 7.33 (dd, J6,7 7.4, J6,8 2.3, 1 H,
H6), 5.07 (s, 2 H, CH2), 4.00 (s, 3 H, CH3O), 2.51 (s, 3 H, COCH3),
2.05 (s, 3 H, CH3). δC (75.5 MHz) 200.7 (COCH3), 183.9 (CO), 182.6
(CO), 169.7 (CO2), 159.8 (C5), 147.5 (C), 136.3 (C), 135.7 (C2), 133.4
(C), 119.4 (CH), 118.8 (C), 118.3 (CH), 57.9 (CH2), 56.5 (CH3O), 31.8
(COCH3), 20.4 (CH3). νmax/cm−1 1735, 1740, 1653.
2-Acetyl-8-methoxy-3-methylnaphthalene-1,4-dione (33)
2-Acetyl-3-formyloxymethyl-8-methoxynaphthalene-1,4-dione (36)
A stirred solution of 2-acetyl-8-methoxy-3-methylnaphthalene-1,4-diol
(32) (50 mg, 0.20 mmol) in methanol (5 mL) was treated with a solu-
tion of iron(iii) chloride (0.07 g, 0.43 mmol) in methanol (5 mL).
The reaction mixture was stirred at room temperature for 1 h during
which time a white precipitate formed. The methanol was evapo-
rated and the residue was washed through a plug of silica with
dichloromethane. The filtrate was evaporated to give the title quinone
(33) as a bright yellow crystalline solid (50 mg, 100%), which crys-
tallized from dichloromethane/petroleum as yellow-brown rectangular
plates, mp 170–172◦C (Found C, 68.7; H, 4.9. C14H12O4 requires C,
68.8; H, 4.9%). Mass spectrum m/z 244 (M, 100%), 231 (17), 229 (68),
202 (19), 201 (56), 115 (17). δH (300 MHz) 7.75 (dd, J5,6 7.7, J5,7 1.3,
1 H, H5), 7.68 (dd (apparent t), J6,5 = J6,7 8, 1 H, H6), 7.31 (dd, J7,6
8.3, J7,5 1.2, 1 H, H7), 4.00 (s, 3 H, CH3O), 2.47 (s, 3 H, COCH3), 2.04
(s, 3 H, CH3). δC (75.5 MHz) 201.9 (COCH3), 185.3 (CO), 182.7 (CO),
159.7(C), 147.2(C), 139.9(C), 135.3(C5), 133.8(C), 119.4(CH), 119.0
(C), 118.0 (CH), 56.5 (CH3O), 31.6 (COCH3), 12.6 (CH3). νmax/cm−1
1713, 1653, 1642.
A stirred solution of 2-acetyl-3-bromomethyl-8-methoxynaphthalene-
1,4-dione (34) (53 mg, 0.16 mmol) in anhydrous DMF (5 mL), in an
ice/brine bath under argon, was treated with anhydrous sodium for-
mate (1.10 g, 16.2 mmol). Stirring was continued for 4 h after which
time TLC showed the reaction to be complete. The reaction mixture
was diluted with ether (20 mL) and filtered through a small plug of sil-
ica with ether (50 mL) and ethyl acetate (50 mL) washes. The filtrate
was concentrated and diluted with ethyl acetate (60 mL), then washed
with water (3 × 20 mL) and brine (3 × 40 mL), dried and evaporated to
give the title formate (36) as an orange gum, which precipitated from
dichloromethane/petroleum as an orange solid (48 mg, 100%) and crys-
tallized from ether as red-brown crystals, mp 150–155◦C (Found C,
62.4; H, 4.4. C15H12O6 requires C, 62.5; H, 4.2%). Mass spectrum m/z
288 (M, 4%), 260 (71), 244 (69), 242 (80), 232 (58), 229 (51), 217
(100), 199 (75), 171 (67), 127 (53). δH (300 MHz) 8.02 (t, J 0.9, 1 H,
CHO), 7.75 (m, AB part of ABX, 2 H, H5/H6), 7.35 (dd, J5,6 7.3, J5,7
2.4, 1 H, H7), 5.14 (d, J 0.9, 1 H, CH2), 4.01 (s, 3 H, CH3O), 2.52 (s,