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Y. L. Janin et al. / Tetrahedron 60 (2004) 5481–5485
(CDCl3): d¼1.42 (d, 3H, J¼6.5 Hz), 2.50 (dd, 1H, J¼13.5,
14.6 Hz), 2.70 (dd, 1H, J¼5.2, 3.5 Hz), 3.61 (m, 1H), 3.71
(s, 3H), 3.89 (s, 6H), 3.84 (s, 3H), 3.91 (s, 3H), 6.73 (s, 1H),
6.79 (s, 2H), 6.80 (s, 1H). 13C NMR (CDCl3): d¼21.7, 32.2,
52.8, 56.0, 56.1, 60.8, 106.1, 110.4, 111.4, 121.2, 132.4,
134.6, 138.9, 146.9, 150.9, 152.9, 165.4. HRMS calcd for
C21H25NO5: 372.1811; found (MþHþ): 372.1802.
stirred in 70% aqueous ethanol (80 mL) containing sodium
hydroxide (0.8 g, 0.02 mol) at 50 8C for 30 min. The
resulting solution was made acid with 1 N hydrochloric
acid, saturated with sodium chloride and extracted with
dichloromethane. The organic layer was washed with brine
and dried over magnesium sulfate before concentrating to
dryness. The residue was recrystallized in toluene to give
compound 12 (0.4 g, 61%). Mp¼161 8C. 1H NMR (CDCl3):
d¼3.90 (s, 6H), 3.93 (s, 3H), 4.88 (s, 2H), 6.09 (s, 2H), 6.83
(s, 2H), 7.11 (s, 1H), 7.34 (s, 1H), 7.48 (s,1H). 13C NMR
(CDCl3): d¼56.2, 60.9, 64.7, 101.7, 102.7, 103.3, 106.8,
115.9, 123.1, 135.2, 136.0, 138.3, 148.3, 150.9, 150.95,
153.2, 158.1. HRMS calcd for C20H20NO6: 370.1291 found
(MþHþ): 370.1288.
2.1.5. 7-Methyl-5-phenyl-7,8-dihydro-[1,3]dioxolo[4,5-
g]isoquinoline (9c). From 1 equiv. of benzonitrile,
2 equiv. of safrole and 2 equiv. of 54% tetrafluoroboric
acid in ether, following the same procedure described for
9a, a 16% yield of compound 9c was obtained. In this case,
the waxy chromatographic fraction obtained was re-
dissolved in dichloromethane, washed with a 1 N sodium
hydroxide solution, water and then dried over magnesium
2.1.9. 5-(3,4,5-Trimethoxyphenyl)-[1,3]dioxolo[4,5-g]iso-
quinoline-7-carbaldehyde (13). Compound 12 (0.35 g,
0.95 mmol) and Dess–Martin periodinane26 (0.6 g,
1.42 mmol) were stirred in dichloromethane (50 mL) for
2 h. The solution was diluted with more dichloromethane
and washed with 1 N sodium hydroxide, water and dried
over magnesium sulfate before concentrating to dryness to
give aldehyde 13 (0.32 g, 91%) which could be used directly
for the next step or recrystallized in aqueous ethanol.
Mp¼145–146 8C. 1H NMR (CDCl3): d¼3.88 (s, 6H), 3.90
(s, 3H), 6.13 (s, 2H), 6.83 (s, 2H), 7.26 (s, 1H), 7.38 (s, 1H),
8.17 (s,1H), 10.20 (s, 2H). 13C NMR (CDCl3): d¼56.2,
60.9, 102.2, 103.8, 104.6, 106.8, 119.3, 126.8, 134.5, 134.8,
138.6, 145.4, 150.7, 151.2, 153.3, 159.2, 193.8. HRMS
calcd for C20H18NO6: 368.1134; found (MþHþ): 368.1127.
1
sulfate before concentrating to dryness. H NMR (CDCl3):
d¼1.41 (d, 3H, J¼7.0 Hz), 2.50 (dd, 1H, J¼12.8, 15.4 Hz),
2.72 (dd, 1H, J¼5.2, 15.4 Hz), 3.63 (m, 1H), 5.94 (s, 2H),
6.68 (s, 1H), 6.71 (s, 1H), 7.40 (m, 3H), 7.51 (m, 2H). 13C
NMR (CDCl3): d¼21.6, 33.8, 52.8, 101.2, 108.0, 108.5,
122.7, 128.1, 128.8, 129.1, 133.9, 138.3, 145.8, 149.9,
165.6. HRMS calcd for C17H15NO2: 266.1181; found
(MþHþ): 266.1184.
2.1.6. 7-Methyl-5-(3,4,5-trimethoxyphenyl)-[1,3]-
dioxolo[4,5-g]isoquinoline (10). Compound 9a (1.75 g,
4.9 mmol) and 10% palladium over charcoal (0.25 g,
0.246 mmol) were heated to reflux in decaline (80 mL) for
12 h. The suspension was diluted in dichloromethane,
filtered and concentrated to dryness under vacuum. The
residue was purified by chromatography over silica gel
eluting with a 2:3 mixture of ethyl acetate–cyclohexane to
give compound 10 (1.26 g, 72%). A small portion was
recrystallized in aqueous methanol. Mp¼149 8C lit.19 152–
2.1.10. 5-(3,4,5-Trimethoxyphenyl)-[1,3]dioxolo[4,5-
g]isoquinoline-7-carboxylic acid (2). Compound 13
(0.32 g, 0.87 mmol) was dissolved in acetonitrile (30 mL),
water (5 mL) and silver nitrate (0.7 g, 4.12 mmol) were
added to the solution followed by sodium hydroxide (0.26 g,
6.5 mmol). The blackening solution was stirred for 90 min
and made acid with 1 N hydrochloric acid. This was
saturated with sodium chloride and extracted with dichloro-
methane. The organic layer was washed with brine and dried
over magnesium sulfate before concentrating to dryness.
The residue was recrystallized in a mixture of toluene and
heptane to give acid 2 (0.24 g, 71%). Mp¼229 8C. 1H NMR
(CDCl3): d¼3.90 (s, 6H), 3.95 (s, 3H), 6.16 (s, 2H), 6.81 (s,
2H), 7.30 (s, 1H), 7.44 (s, 1H), 8.45 (s,1H). 13C NMR
(CDCl3): d¼54.4, 61.0, 102.4, 104.0, 104.4, 106.9, 121.0,
126.4, 133.7, 135.9, 137.8, 138.9, 150.8, 151.7, 153.4,
157.5, 165.1. HRMS calcd for C20H18NO7: 384.1083; found
(MþHþ): 384.1090.
1
154 8C. H NMR (CDCl3): d¼2.65 (s, 3H), 3.87 (s, 6H),
3.88 (s, 3H), 6.04 (s, 2H), 6.79 (s, 2H), 7.02 (s, 1H), 7.25 (s,
1H), 7.31 (s, 1H). 13C NMR (CDCl3): d¼24.1, 56.2, 60.9,
101.5, 102.2, 103.2, 106.8, 118.0, 121.8, 135.7, 136.0,
138.2, 147.7, 149.9, 150.6, 153.2, 158.3. HRMS calcd for
C20H20NO5: 354.1341; found (MþHþ): 354.1339.
2.1.7. 7-Methyl-5-(3,4,5-trimethoxyphenyl)-[1,3]-
dioxolo[4,5-g]isoquinoline N-oxide (11). Compound 10
(1.04 g, 2.9 mmol) was dissolved in dichloromethane
(100 mL) and 70% 3-chloroperoxybenzoic acid (2.18 g,
8.8 mmol) was added. The solution was stirred overnight,
further diluted in dichloromethane and washed with 1 N
sodium hydroxide, water and then dried over magnesium
sulfate to give compound 11 (0.98 g, 90%) pure enough for
1
the next step. Mp¼258 8C. H NMR (CDCl3): d¼2.62 (s,
3H), 3.84 (s, 6H), 3.92 (s, 3H), 6.03 (s, 2H), 6.62 (s, 2H),
6.66 (s, 1H), 6.99 (s, 1H), 7.48 (s,1H). 13C NMR (CDCl3):
d¼18.0, 56.0, 60.8, 101.6, 101.7, 102.2, 106.8, 121.5, 125.7,
126.8, 127.6, 138.2, 144.3, 145.4, 149.0, 149.3, 153.6.
HRMS calcd for C20H20NO6: 370.1291; found (MþHþ):
370.1290.
References and notes
1. Janin, Y. L.; Roulland, E.; Beurdeley-Thomas, A.; Decaudin,
D.; Monneret, C.; Poupon, M.-F. J. Chem. Soc. Perkin Trans. I
2002, 529–532.
2. Decaudin, D.; Castedo, M.; Nemati, F.; Beurdeley-Thomas,
A.; De Pinieux, G.; Caron, A.; Pouillart, P.; Wijdenes, J.;
Rouillard, D.; Kroemer, G.; Poupon, M. F. Cancer Res. 2002,
62, 1388–1393.
2.1.8. 5-(3,4,5-Trimethoxyphenyl)-[1,3]dioxolo[4,5-g]iso-
quinolin-7-yl]-methanol (12). Compound 11 (0.65 g,
1.76 mmol) and acetic anhydride (2 mL, 21.2 mmol) were
refluxed in 1,2-dichlorobenzene (60 ml) for 4 h. The
solution was concentrated to dryness and the residue was
3. Casellas, P.; Galiegue, S.; Basile, A. S. Neurochemistry Int.
2002, 40, 475–486.