General procedure to prepare the ketones \8 and 9
To a stirred solution of methyl 3,5-dimethoxyphenylacetate (
7) [
9] (1.0 mmol) in toluene (1.5 mL) was added the appropriate anhydride (2.0 mmol) along with perchloric acid (70%, 2 drops initially followed by 1 drop after 18 h). After stirring for 72 h the solution was concentrated
in vacuo and subjected to flash chromatography (an efficient method to hydrolyze excess anhydride) on a silica column (Pet. Sp/EtOAc 25:75) to give one main fraction containing the product and the appropriate carboxylic acid, which was concentrated
in vacuo and then extracted with ether, aqueous NaHCO
3 (5%; 3×30 mL) and then H
2O (30 mL). The organic phase was dried (MgSO
4) and concentrated
in vacuo to return
8 (96%), or
9 (92%) as orange oils.
3,5-Dimethoxy-2-hexanoyl-phenylacetic acid methyl ester (
8): TLC: R
f 0.65 [EtOAc/Pet. Sp, 30:70
(v/v)]. IR: ν (cm
-1): 2935 s, 2858 m, 1738 s, 1682 m, 1605 s, 1583 m, 1455 m, 1428 m, 1318 s, 1293 w, 1257 w, 1205 m, 1156 s, 1086 m, 1058 m, 1012 m, 954 w, 835 m. EIMS
m/z: 308 (M
+⋅, 26%), 277 (M-OCH
3, 17%), 237 (M-(CH
2)
4CH
3, 100%), 209 (M-C(O)(CH
2)
4CH
3, 88%). HREI-MS
m/z: found 308.1624 (C
17H
24O
5 requires 308.1624). UV (MeOH) λ
max (log ε): 201 (3.46), 266 (2.93).
1H-NMR (CDCl
3): 6.39 (1H, d, 2.2 Hz, 4-H), 6.37 (1H, d, 2.2Hz, 6-H), 3.81 (3H, s, 3-OCH
3)*, 3.80 (3H, s, 5-OCH
3)*, 3.67 (3H, s, -CO
2CH
3), 3.62 (2H, s, -C
H2CO
2CH
3), 2.81 (2H, t, 7.2 Hz, 2'-H), 1.64 (2H, m, 3'-H), 1.31 (4H, m, 4'&5'-H), 0.89 (3H, t, 6.9 Hz, 6'-H).
13C APT-NMR (CDCl
3): 206.8 (C-1'), 171.6 (-
CO
2CH
3), 161.2 (C-3)*, 158.8 (C-5)*, 134.3 (C-1), 123.9 (C-2), 107.8 (C-6), 97.4 (C-4), 55.5 (C-3-OCH
3)
∞, 55.3 (C-5-OCH
3)
∞, 51.9 (-CO
2CH
3), 44.3 ( C-2'), 38.7 (-
CH
2CO
2CH
3), 31.4 (C-4'), 23.7 (C-3'), 22.4 (C-5'), 13.9 (C-6'). Shifts with identical superscripts (*,
∞) within a data set are interchangeable.
3,5-Dimethoxy-2-pentanoyl-phenylacetic acid methyl ester (
9): TLC: R
f 0.55 [EtOAc/ Pet. Sp, 30:70
(v/v)]. IR: ν (cm
-1): 2957 s, 2871 m, 1740 s, 1686 m, 1603 s, 1460 m, 1433 m, 1319 s, 1294 w, 1263 w, 1205m, 1157 s, 1099 m, 1082 m, 1013 m, 948 w, 835 m. EIMS
m/z: 294 (M
+⋅, 15%), 293 (52%), 275 (14%), 261 (35%), 250 (24%), 234 (100%), 206 (71%), 202 (33%), 176 (20%), 162 (28%), 148 (21%). HREI-MS
m/z: found 294.1467 (C
16H
22O
5 requires 294.1467). UV (MeOH) λ
max (log ε): 202 (3.45), 263 (2.90).
1H-NMR (CDC
l3): 6.39 (1H, d, 2.2 Hz, 4-H), 6.36 (1H, d, 2.2Hz, 6-H), 3.80 (3H, s, 3-OCH
3)*, 3.79 (3H, s, 5-OCH
3)*, 3.67 (3H, s, -CO
2CH
3), 3.62 (2H, s, -C
H2CO
2CH
3), 2.82 (2H, t, 7.3 Hz, 2'-H), 1.61 (2H, m, 3'-H), 1.36 (2H, m, 4'-H), 0.91 (3H, t, 7.3 Hz, 5'-H).
13C APT-NMR (CDCl
3): 206.5 (C-1'), 171.4 (-
CO
2CH
3), 161.1 (C-3)*, 158.6 (C-5)*, 134.2 (C-1), 123.7 (C-2), 107.8 (C-6), 97.2 (C-4), 55.4 (C-3-OCH
3)
∞, 55.3 (C-5-OCH
3)∞, 51.7 (-CO
2CH
3), 43.9 ( C-2'), 38.5 (-
CH
2CO
2CH
3), 26.0 (C-3'), 22.2 (C-4'), 13.7 (C-5'). Shifts with identical superscripts (*,
∞) within a data set are interchangeable.
Cyclization of 3,5-dimethoxy-2-hexanoyl-phenylacetic acid methyl ester (8) with ethoxide, to give the naphthol (10) and the naphthoquinone (11) by auto-oxidation.
A solution of 3,5-dimethoxy-2-hexanoyl-phenylacetic acid methyl ester (8, 95mg, 0.31 mmol) in dry EtOH (10 mL), was added dropwise, over 7 min, to a refluxing solution of sodium ethoxide (prepared from Na (0.42 g) in 10 mL of dry EtOH) under N2. After a further 10 min at reflux the reaction mixture was cooled, diluted with ether (30 mL), neutralized with HCl (1M) and then extracted with aqueous NaHCO3 (5%; 3×30 mL) giving a light pink aqueous phase and a yellow organic phase. The ethereal phase was dried (MgSO4) and concentrated in vacuo to give a crude mixture, which was purified by flash chromatography on a silica column (r = 6 mm, l = 20 cm, silica gel 0.040-0.063 mm; Pet. Sp/EtOAc 25:75), giving 3-butyl-2-hydroxy-5,7-dimethoxy-1,4-naphthoquinone (11) (47 mg, 0.16 mmol, 52%) as a bright yellow solid and 2-butyl-6,8-dimethoxy-naphthalene-1,3-diol (10) (21 mg, 0.076 mmol, 25%) as a yellow oil, which auto-oxidized to the naphthoquinone (11) over several days on exposure to air.
Butyl-6,8-dimethoxy-naphthalene-1,3-diol (
10): TLC: R
f 0.48 [EtOAc/ Pet. Sp, 25:75 (v/v)]. IR: ν
(cm
-1): 3402 (s, br), 2932 s, 2858 m, 2362 w, 1636 s, 1597 s, 1448 m, 1404 m, 1371 s, 1338 w, 1246 w, 1209 m, 1150 m, 1107 m, 1041 m. ESI-MS (+ve ion, cv 50V)
m/z: 277 (M+H, 100%), 263 (M-CH
3+H, 10%), 220 (2%), 205 (2%). UV (MeOH) λ
max (log ε): 245 (4.90), 292 (3.91).
1H-NMR (CDCl
3): 9.43 (1H, s, 1-OH), 6.55 (1H, s, 4-H), 6.50 (1H, d, 2.1 Hz, 5-H), 6.28 (1H, d, 2.1 Hz, 7-H), 3.98 (3H, s, 8-OCH
3), 3.85 (3H, s, 6-OCH
3), 2.74 (2H, t, 7.5 Hz, 1'-H), 1.58 (2H, m, 2'-H), 1.44 (2H, m, 3'-H), 0.94 (3H, t, 7.2 Hz, 4'-H).
13C APT-NMR (CDCl
3): 157.5 (C-6)*, 157.0 (C-8) *, 154.6 (C-3)
∞, 152.9 (C-1)
∞, 135.9 (C-4a), 112.1 (C-2), 106.2 (C-8a), 100.8 (C-4) 98.0 (C-5), 95.4 (C-7), 56.0 (C-8-OCH
3), 55.3 (C-6-OCH
3), 31.5 (C-2'), 22.9 (C-1')
Δ, 22.8 (C-3')
Δ, 14.1 (C-4'). Shifts with identical superscripts (*,
∞,Δ) are interchangeable.
Butyl-2-hydroxy-5,7-dimethoxy-1,4-naphthoquinone (
11): TLC: R
f 0.28 [EtOAc/ Pet. Sp, 25:75
(v/v)]. mp: 160∞C. IR: ν (cm
-1): 3209 m, 2932 m, 2359 m, 1655 m, 1638 s, 1595 m, 1460 m, 1321 s, 1209 s, 1157 m, 1126 w, 1034 w. EIMS
m/z: 290 (M
+∞, 100%), 248 (M-C
3H
6, 43%), 233 (M-(CH
2)
3CH
3, 13%), 219 (35%), 165 (22%). HREI-MS
m/z: found 290.1163 (C
16H
18O
5 requires 290.1154). UV (MeOH) λ
max (log ε): 212 (4.68), 261 (4.51), 304 (4.29).
1H-NMR (CDCl
3): 7.25 (1H, d, 2.4 Hz, 8-H), 6.75 (1H, d, 2.4 Hz, 5-H), 3.96 (3H, s, 5-OCH
3)*, 3.93 (3H, s, 7-OCH
3)*, 2.56 (2H, t, 7.5 Hz, 1'-H), 1.50 (2H, m, 2'-H), 1.40 (2H, m, 3'-H), 0.92 (3H, t, 7.2 Hz, 4'-H).
13C APT-NMR (CDCl
3): 183.6 (C-4)*, 181.7 (C-1)*, 163.7 (C-7)∞, 161.7 (C-5)∞, 150.9 (C-2), 133.2 (C-8a), 126.2 (C-3), 114.2 (C-4a), 105.2 (C-6), 103.0 (C-8), 56.4 (C-5-OCH
3)
Δ, 55.8 (C-7-OCH
3)
Δ, 30.5 (C-2'), 23.2 (C-1'), 22.9 (C-3'), 13.8(C-4'). Shifts with identical superscripts (*,
∞,Δ) within a data set are interchangeable.
Synthesis of 6,8-dimethoxy-1,3-bis-(2-methoxy-ethoxymethoxy)-2-propyl-naphthalene (12)
To a stirred solution of 3,5-dimethoxy-2-pentanoyl-phenylacetic acid methyl ester (9, 12.5 mg, 43.1 μmol) in dry DMF (1 mL) under N2, was added NaH (50% dispersion in mineral oil; 3.2 mg, 130 μmol). After stirring for 10 min MEM-Cl (35 μL, 38 mg, 0.30 mmol) was added and the solution left stirring overnight before being extracted with ether and water. The ethereal phase was dried (MgSO4) and concentrated in vacuo to give a crude orange oil, which was purified by flash chromatography (r = 3 mm, l = 5 cm, silica gel 0.040-0.063 mm; Pet. Sp/EtOAc 70:30), to give 6,8-dimethoxy-1,3-bis-(2- methoxy-ethoxymethoxy)-2-propyl-naphthalene (12) (5.1 mg, 12 μmol, 27%, unoptimized) as an orange oil.
6,8-Dimethoxy-1,3-bis-(2-methoxy-ethoxymethoxy)-2-propyl-naphthalene (
12): TLC: R
f 0.22 [EtOAc/
Pet. Sp, 30:70 (v/v)]. IR: ν (cm
-1): 2932 s, 1622 s, 1580m, 1458 m, 1389 m, 1337 m, 1252 w, 1204 m, 1155 s, 1119 m, 1097 m, 1036 s, 847 w. ESI-MS (+ve ion, cv 50V)
m/z: 461 (M+Na, 100%), 239 (M+H, 11%), 373 ([M-MEM]+Na), 28%), 221 (22%). HREI-MS
m/z: found 438.2258 (C
23H
34O
8 requires 438.2254). UV (MeOH) λ
max (log ε): 216 (4.25), 242 (4.46), 288 (3.74).
1H-NMR (CDCl
3): 7.14 (1H, s, 4-H), 6.65 (1H, d, 2.2 Hz, 5-H), 6.37 (1H, d, 2.2 Hz, 7-H), 5.38 (2H, s, 1'''-H), 5.12 (2H, s, 1'-H), 4.00-3.57 (8H, m, {3'-H, 4'-H, 3'''-H, 4'''-H}), 3.90 (3H, s, 8-OCH
3)*, 3.86 (3H, s, 6-OCH
3)*, 3.40 (3H, s, 6'-H)
∞, 3.39 (3H, s, 6'''-H)
∞, 2.80 (2H, t, 7.5 Hz, 1''-H), 1.60 (2H, m, 2''-H), 0.97 (3H, t, 7.3 Hz, 3''-H).
13C APT-NMR (CDCl
3): 157.6 (C-8), 156.4 (C-6), 154.9 (C-3), 151.5 (C-1), 136.6 (C-4a), 123.4 (C-2), 111.3 (C-8a), 105.2 (C-4), 100.2 (C-1')∗, 98.5 (C-5), 97.0 (C-7), 93.3 (C-1''')∗, 71.7 (C-4')
Δ, 71.6 (C-4''')
Δ, 69.2 (C-3'), 67.6 (C-3'''), 59.1 (C-6')
Ψ, 59.0 (C-6''')
Ψ, 55.8 (C-8-OCH
3)
Ω, 55.2 (C-6-OCH
3)
Ω, 26.5 (C-2''), 23.2 (C-1''), 14.5 (C-3''). Shifts with identical superscripts (*,
∞,Δ,Ψ,Ω) within a data set are interchangeable.
NBS Bromination of 12: Synthesis of 5-Bromo-6,8-dimethoxy-1,3-bis-(2-methoxy-ethoxymethoxy)-2- propyl-naphthalene (13)
To a solution of 6,8-dimethoxy-1,3-bis-(2-methoxy-ethoxymethoxy)-2-propyl-naphthalene (12) (10 mg, 0.023 mmol) in CCl4 (4 mL) was added N-bromosuccinimide (5.1 mg, 0.031 mmol) and a catalytic amount of AIBN. The solution was refluxed until all the starting material had been consumed (TLC), and was then extracted with ether (30 mL) and aqueous NaHCO3 (5%; 30 mL). The ethereal phase was concentrated in vacuo and the resulting crude oil was purified on a short flash chromatography column (r = 2.5 mm, l = 5 cm, silica gel 0.040-0.063 mm; 2% MeOH in DCM), to give the ring-brominated naphthalene (13), (4 mg, 8 μmol, 34%).
5-Bromo-6,8-dimethoxy-1,3-bis-(2-methoxy-ethoxymethoxy)-2-propyl-naphthalene (
13): TLC: R
f 0.32
[MeOH/ DCM, 2:98 (v/v)]. ESI-EIMS (+ve ion, cv 20 V)
m/z: 541 (M+Na,
81Br, 100%), 539 (M+Na,
79Br, 100%), 519 (M+H,
81Br, 55%), 517 (M+H,
79Br, 55%). HREI-MS
m/z: found 516.1356 (C
23H
33O
879Br
1 requires 516.1359).
1H-NMR (CDCl
3): 7.65 (1H, s, 7-H), 6.55 (1H, s, 4-H), 5.43 (2H, s, 1'''-H), 5.10 (2H, s, 1'-H), 4.00 (3H, s, 8-OCH
3)*, 3.97 (3H, s, 6-OCH
3)*, 3.87 (4H, m, (3'-H, 3'''-H))
∞, 3.61 (4H, m, (4'-H, 4'''-H))
∞, 3.40 (6H, s (coincident), 6'-H & 6'''-H), 2.82 (2H, t, 7.8 Hz, 1''-H), 1.58 (2H, m, 2''-H), 0.98 (3H, t, 7.4 Hz, 3''-H). Shifts with identical superscripts (*,
∞) within a data set are interchangeable.