1028
Vol. 56, No. 7
ether were distilled from sodium/benzophenone.
2-(4-Benzyloxy-2-bromo-5-methoxyphenyl)-[1,3]dioxolane
3.92 (s, 3H), 3.78 (t, Jꢂ6.6 Hz, 2H), 3.27—3.92 (s, 3H) (s, 3H), 3.05 (t,
Jꢂ6.5 Hz, 2H). EI-MS m/z (%): 327 (Mꢀ, 38). HR-MS-EI (calcd for
C19H21NO4): 327.3902, found 327.3901.
(6) A
mixture of compound 5 (22.47 g, 70 mmol), ethylene glycol (8.68 g, 140
mmol), and p-TsOH (100 mg) was refluxed for 3 h with a Dean–Stark appa-
ratus. The mixture was cooled to 0 °C and NaHCO3 (300 mg) was added.
After filtering, the filtrate was concentrated in vacuo to give compound 6 as
6-Methylveratraldehyde (13) Phosphorus oxychloride (24.5 g, 160
mmol) was added to 6.08 g (40 mmol) of 3,4-dimethoxytoluene under nitro-
gen with stirring. The mixture was heated to 80 °C, and 11.7 g (160 mmol)
of DMF was added while the reaction temperature was maintained at 90—
95 °C. The mixture was stirred at 95 °C for 4 h. The dark brown syrup was
cooled to 40 °C, poured cautiously onto crushed ice, and extracted with
ether. The combined ether extracts were washed with brine, dried, and evap-
orated in vacuo to give 6-methylveratraldehyde 13 as a brown oil, which
1
a yellow solid (23.0 g, 90%). mp: 85—88 °C. H-NMR (CDCl3) d: 7.44—
7.29 (m, 5H), 7.13 (s, 3H), 7.05 (s, 1H); 5.97 (s, 1H), 5.12 (s, 2H), 4.20—
4.04 (m, 4H), 3.88 (s, 3H). EI-MS: m/z 365 (Mꢀ, 46). HR-MS-EI (calcd for
C17H17BrO4): 365.2376, found 365.2381.
5-Benzyloxy-2-[1,3]dioxolan-2-yl-4-methoxybenzonitrile (7) A mix-
ture of acetal 6 (21.9 g, 60 mmol) and CuCN (6.3 g, 70 mmol) in DMF
(20 ml) was refluxed for 2 h. The hot and dark reaction mixture was poured
into a warm solution of sodium cyanide (14.7 g, 0.3 mol) in water. The mix-
ture was shaken well and then extracted with benzene. The combined extract
was concentrated and column-purified to give benzonitrile 7 as a yellow
solid (15.86 g, 85%). mp: 75—78 °C. IR (cmꢁ1): 2220 (CN). 1H-NMR
(CDCl3) d: 7.43—7.32 (m, 5H), 7.11 (s, 3H), 7.11 (s, 1H); 5.93 (s, 1H), 5.15
(s, 2H), 4.25—4.06 (m, 4H), 3.95 (s, 3H). EI-MS: m/z 311 (Mꢀ, 100). HR-
MS-EI (calcd for C18H17NO4): 311.3468, found 311.3467.
5-Benzyloxy-2-formyl-4-methoxybenzonitrile (8) The cyano acetal 7
(15.55 g, 50 mmol) in 5% HCl (100 ml) was warmed to 50—60 °C for
15 min. The solid was collected, washed with water and dried in vacuo to
give aldehyde 8 as a pale yellow solid (12.03 g, 90%). mp: 116—118 °C. IR
(cmꢁ1): 2230 (CN). 1H-NMR (CDCl3): d 10.24 (s, 1H), 7.50 (s, 1H), 7.43—
7.36 (m, 5H), 7.20 (s, 1H); 5.24 (s, 2H), 3.99 (s, 3H). EI-MS: m/z 267 (Mꢀ,
57). HR-MS-EI (calcd for C16H13NO3): 267.2925, found 267.2929.
5-Benzyloxy-4-methoxy-2-(2-methoxyvinyl)benzonitrile (9) To a so-
lution of (methoxymethyl)triphenylphosphonium chloride (20.52 g, 60 mmol)
in dry THF (30 ml), 1.6 M n-butyl lithium (38 ml, 60 mmol) was added at
0 °C and the solution was stirred at 0 °C for 1 h. The reaction mixture was
then added to aldehyde 8 (10.68 g, 40 mmol) in THF (30 ml). The reaction
mixture was stirred at room temperature for 30 min. The reaction was
quenched with water and extracted with ethyl acetate. The organic layers
were washed with water and brine and dried over sodium sulfate. After re-
moving the solvent, the residue was purified by column chromatography
with n-hexane–ethyl acetate (3 : 1) to afford a mixture of cis/trans isomer
(2 : 1 ratio) as a yellow solid (8.97 g, 76%).1H-NMR (300 MHz, CDCl3) d
(cis): 7.71 (s, 1 H), 7.43—7.30 (m, 5H), 7.00 (s, 1 H), 6.26 (d, Jꢂ7.2 Hz,
1H), 5.55 (d, Jꢂ7.2 Hz, 1H), 5.12 (s, 2H), 3.93 (s, 3H), 3.83 (s, 3H). d
(trans): 7.43—7.30 (m, 5H), 7.13 (d, Jꢂ12.9 Hz, 1H), 6.99 (s, 1H), 6.84 (s,
1H), 6.02 (s, 2H), 6.04. (d, Jꢂ12.9 Hz, 1H), 5.11 (s, 2H), 3.93 (s, 3H), 3.73
(s, 3H).
1
crystallized on standing overnight (6.73 g, 94%). mp: 73—74 °C. H-NMR
(300 MHz, CDCl3) d: 10.32 (s, 1H), 7.45 (s, 1H), 6.82 (s, 1H), 4.06 (s, 3H),
4.03 (s, 3H), 2.76 (s, 3H). EI-MS: m/z 180 (Mꢀ, 100).
2-Methyl-4,5-dimethoxybenzoic acid (14) To a stirred mixture of alde-
hyde 13 (6.73 g, 37 mmol) in DMSO (50 ml) and NaH2PO4 (1.8 g) in water
(20 ml), a solution of 80% NaClO2 (9 g, 80 mmol) in water (60 ml) was
added at room temperature. The reaction mixture stood overnight and then
5% NaHCO3 solution was added. The aqueous layer was extracted twice
with ether and then acidified with c-HCl. The precipitated carboxylic acid
was taken up with CH2Cl2. The extracts were combined, washed with brine,
dried, and evaporated to give the benzoic acid 14 (6.94 g, 95%). mp: 139—
1
141 °C. H-NMR (300 MHz, CDCl3) d: 7.64 (s, 1H), 6.73 (s, 1H), 3.95 (s,
1H), 3.95 (s, 6H), 2.63 (s, 3H). EI-MS: m/z 196 (Mꢀ, 65).
2-Methyl-4,5-dimethoxy-N,N-diethylbenzamide (3) To a suspension
of 2-methyl-4,5-dimethoxybenzoic acid 14 (5 g) in CH2Cl2 (50 ml) contain-
ing pyridine (3.2 g), oxalyl chloride (17.8 ml) was added slowly with stirring.
After an additional 2 h of stirring, the excess oxalyl chloride was removed in
vacuo and the last trace of oxalyl chloride was removed by co-distillation
with benzene. The obtained acid chloride was dissolved in CH2Cl2 (60 ml)
and carefully treated with diethyl amine (18.65 g) at 0 °C. The reaction mix-
ture was diluted with water, the organic layer was separated and the aqueous
layer was extracted with CH2Cl2. The organic portions were washed with
water and brine, dried, and then evaporated. The residue was purified by col-
umn chromatography to give 2-methyl-4,5-dimethoxy-N,N-diethylbenza-
1
mide 3 as an oil (5.7 g, 90%). IR (cmꢁ1): 1625 (CO). H-NMR (300 MHz,
CDCl3) d: 6.68 (s, 2H), 3.97 (s, 3H), 3.94 (s, 3H), 3.75—2.90 (m, 4H), 2.23
(s, 3H), 1.50—0.85 (m, 6H). EI-MS: m/z 251 (Mꢀ, 100).
3-[5-Benzyloxy-4-methoxy-2-(2-methoxymethoxyethyl)phenyl]-6,7-
dimethoxy-2H-isoquinolin-1-one (15)
A solution of N,N-diethyltolu-
amide 3 (1.04 g, 4 mmol) and benzonitrile 4 (1.01 g, 3 mmol) in dry THF
(40 ml) were added dropwise to a solution of n-BuLi (5 ml of 1.6 M in
hexane, 8 mmol) in THF (30 ml) at ꢁ70 °C and the reaction mixture was
stirred at the same temperature for 6 h. The reaction was quenched with
water and extracted with ethyl acetate and dried over sodium sulfate. After
removing the solvent, the residue was purified by column chromatography
with n-hexane–ethyl acetate (1 : 1) to afford compound 15 as an orange oil
5-Benzyloxy-4-methoxy-2-(2-oxo-ethyl)benzonitrile (10) The reaction
mixture of cis/trans isomer 9 (8.85 g, 30 mmol) in acetone (50 ml) and 10%
HCl (20 ml) was refluxed for 3 h. The acetone was removed in vacuo, and
the reaction mixture was poured into water and extracted with ethyl acetate.
The ethyl acetate extracts were washed with water and brine and dried over
anhydrous sodium sulfate. After removing the solvent, the residue was puri-
fied by column chromatography on silica gel with n-hexane–ethyl acetate
(1 : 1) to give compound 10 as a solid (7.59 g, 90%). mp: 100—103 °C. IR
1
(507 mg, 33%). IR (cmꢁ1): 3400 (NH), 1645 (CꢂO). H-NMR (300 MHz,
CDCl3) d: 10.4 (b, 1H), 7.78 (s, 1H), 7.42—7.33 (m, 5H), 6.97 (s, 1H), 6.89
(s, 1H), 6.81 (s, 1H), 6.33 (s, 1H), 5.19 (s, 2H), 4.72 (s, 2H), 4.00 (s, 3H),
3.99 (s, 3H), 3.92 (s, 3H), 3.88 (m, 2H), 3.31 (s, 3 H), 2.88 (m, 2H). EI-MS
m/z (%): 505 (Mꢀ, 100), 414 (61), 91 (53). EI-MS m/z (%): 505 (Mꢀ, 35).
HR-MS-EI (calcd for C29H31NO7): 505.5831, found 505.5837.
(cmꢁ1): 2220 (CN), 1720 (CꢂO), 1300—1000 (C–O). H-NMR (300 MHz,
CDCl3) d: 9.79 (s, 1 H), 7.43—7.30 (m, 5H), 7.11 (s, 1H), 6.75 (s, 1H), 5.14
(s, 2H), 3.92 (s, 3H). EI-MS: m/z 281 (Mꢀ, 100). HR-MS-EI (calcd for
C17H15NO3): 281.2599, found 281.2897.
1
3-[5-Benzyloxy-2-(2-hydroxy-ethyl)-4-methoxy-phenyl]-6,7-di-
methoxy-2H-isoquinolin-1-one (16) To the mixture of compound 15
(300 mg, 0.6 mmol) in THF (15 ml), 10% HCl (5 ml) was added and the re-
action was refluxed for 2 h. The reaction mixture was poured into water and
extracted with ethyl acetate. The ethyl acetate extracts were washed with
water and brine and dried over anhydrous sodium sulfate. After removing
the solvent, the residue was purified by column chromatography on silica gel
with CH2Cl2 : MeOH (20 : 1) to give the alcohol 16 as a yellow solid (205
mg, 75%). mp: 177—179 °C. IR (cmꢁ1): 3400 (NH, OH), 1642 (CꢂO). 1H-
NMR (300 MHz, CDCl3) d: 7.71 (s, 1H), 7.42—7.33 (m, 5H), 6.92 (s, 1H),
6.88 (s, 1H), 6.82 (s, 1H), 6.36 (s, 1H), 5.11 (s, 2H), 4.13 (t, Jꢂ5.4 Hz, 2H),
4.06 (s, 3H), 3.99 (s, 3H), 2.81 (t, Jꢂ5.4 Hz, 2H). EI-MS m/z (%): 461 (Mꢀ,
38). HR-MS-EI (calcd for C27H27NO6): 461.5288, found 461.5291. Anal.
Calcd for C27H27NO6: C, 70.27; H, 5.90; N, 3.04. Found: C, 70.56; H, 5.79;
N, 3.15.
5-Benzyloxy-2-(2-hydroxyethyl)-4-methoxybenzonitrile (11) NaBH4
(1.52 g, 40 mmol) was added to a mixture of aldehyde 10 (5.62 g, 20 mmol)
in acetic acid (40 ml). After the reaction was over, acetic acid was removed
in vacuo and the resulting mixture was poured into water and extracted with
ethyl acetate. The organic solvent was evaporated off and the residue was
purified by column chromatography with n-hexane–ethyl acetate to give al-
cohol 11 as a yellow solid (4.59 g, 81%). mp: 116.5—118.5 °C. IR (cmꢁ1):
3360 (OH), 2220 (CN), 1720 (CꢂO), 1300—1000 (C–O). 1H-NMR (300
MHz, CDCl3) d: 7.43—7.32 (m, 5H), 7.06 (s, 1H), 6.85 (s, 1H), 5.12 (s,
2H), 3.92 (s, 3H), 3.90 (m, 2H), 3.01 (t, Jꢂ6.6 Hz, 2H). EI-MS: m/z 283
(Mꢀ, 79). HR-MS-EI (calcd for C17H17NO3): 283.3358, found 283.3357.
5-Benzyloxy-4-methoxy-2-(2-methoxymethoxyethyl)benzonitrile
(4)
To a mixture of alcohol 11 (4.53 g, 16 mmol) in CH2Cl2 at 0 °C, diisopropyl-
ethylamine (3.87 g, 32 mmol) and chloromethylmethyl ether (2.5 g, 32
mmol) were added. After the reaction was over, CH2Cl2 was removed in
vacuo and the residue was purified by column chromatography with n-
hexane–ethyl acetate (3 : 1) to give benzonitrile 4 as a yellow solid (4.64 g,
2-Benzyloxy-3,10,11-trimethoxy-5,6-dihydro-isoquino[3,2-a]isoquino-
lin-8-one (17) The mixture of compound 16 (170 mg, 0.36 mmol), tosyl
chloride (133 mg, 0.7 mmol) and K2CO3 (290 mg, 2.1 mmol) in DMF (10
ml) was stirred at 100 °C for 4 h. Water was added and the reaction mixture
was extracted with ethyl acetate. The ethyl acetate extracts were washed
with water and brine and dried over anhydrous sodium sulfate. After remov-
1
89%). mp: 72—74 °C. IR (cmꢁ1): 2219 (CN). H-NMR (300 MHz, CDCl3)
d: 7.42—7.33 (m, 5H), 7.05 (s, 1H), 6.86 (s, 1H), 5.11 (s, 2H), 4.60 (s, 2H),