1198
J. Jacobs et al. / Tetrahedron 65 (2009) 1193–1199
evaporation of the solvent in vacuo, the crude mixture was purified
by column chromatography on silica gel to yield the 3-substituted
1-hydroxybenz[g]isoquinoline-5,10-diones 4d and 4e, along with
3-amino-2-methoxycarbonyl-1,4-naphthoquinone 9.
H-9). 13C NMR (CDCl3):
d
29.6 (3ꢁCH3), 38.8 (Cquat), 108.8 (C-4),
123.7 (]Cquat), 127.2 (CHar), 127.6 (CHar), 132.9 (]Cquat), 133.1
(]Cquat), 134.4 (]Cquat), 134.8 (CHar), 135.1 (CHar), 141.8 (]Cquat),
164.8 (]Cquat), 182.7 (C]O), 186.3 (C]O). IR (KBr): nmax 1689,
1674 cmꢂ1. MS (ES) m/z (%): 280 (M-Hþ, 100). Anal. Calcd for
C17H15NO3: C 72.58, H 5.37, N 4.98, found: C 72.36, H 5.55, N 4.84.
General procedure 3. 2-Methoxycarbonyl-1,4-naphthoquinone 6
(1.38 mmol, 0.30 g) and a pyridinium salt 5 (1.38 mmol) were
added to a previously prepared 5 wt % solution of ammonium ac-
etate in methanol (6 ml). The sealed reaction vessel was introduced
in a CEM DiscoverÒ microwave (ramp time 5 min, pmax 275 psi).
After 5 min at 115 ꢀC, the reaction mixture was cooled to room
temperature. Upon use of pyridinium salts 5c and 5d solvent
evaporation in vacuo was needed until crystallization of the target
compounds 4c and 4d was achieved. The reaction mixture was
filtered and the crystals were washed with ice-cold methanol to
yield pure 1-hydroxybenz[g]isoquinoline-5,10-diones 4.
4.4.5. 3-(4-Methoxyphenyl)-1-hydroxybenz[g]isoquinoline-5,10-
dione 4e
Column chromatography on silica gel with dichloromethane/
methanol (9:1) afforded 4e as reddish orange crystals in 53% yield,
mp 192.8 ꢀC. 1H NMR (CDCl3):
d 3.90 (3H, s, OCH3), 7.03 (2H, d,
J¼8.8 Hz, H-20 and H-60), 7.83–7.91 (2H, m, H-7 and H-8), 8.10 (1H, s,
H-4), 8.23 (2H, d, J¼8.8 Hz, H-30 and H-50), 8.31–8.37 (2H, m, H-6
and H-9). 13C NMR (CDCl3):
d 55.60 (OCH3), 107.9 (]Cquat), 108.2
(]Cquat), 109.3 (C-4), 114.5 (C-30 and C-50), 127.2 (CHar), 127.7 (CHar),
129.7 (]Cquat), 129.8 (C-20 and C-60), 133.1 (]Cquat), 133.3 (]Cquat),
134.9 (CHar), 135.1 (CHar), 141.6 (]Cquat), 162.6 (]Cquat), 166.0
(C]O), 182.3 (C]O). IR (KBr): nmax 3253, 1677 cmꢂ1. MS (ES) m/z
(%): 332 (MþHþ, 100). Anal. Calcd for C20H13NO4: C 72.50, H 3.95, N
4.23, found: C 72.67, H 4.10, N 4.13.
4.4.1. 3-(4-Fluorophenyl)-1-hydroxybenz[g]isoquinoline-
5,10-dione 4a
Column chromatography on silica gel with dichloromethane/
methanol (9:1) afforded 4a as orange crystals in 68% yield, mp 299–
302 ꢀC. 1H NMR (CDCl3):
d
7.21–7.27 (2H, m, H-30 and H-50), 7.45
(1H, s, H-4), 7.81 (1H, dꢁdꢁd, J¼1.3, 7.7, 7.7 Hz, H-7 or H-8), 7.89
(1H, dꢁdꢁd, J¼1.3, 7.7, 7.7 Hz, H-7 or H-8), 8.03–8.10 (2H, m, H-20
and H-60), 8.22 (1H, dꢁd, J¼1.3, 7.7 Hz, H-6 or H-9), 8.30 (1H, dꢁd,
4.5. Synthesis of 3-amino-2-methoxycarbonyl-1,4-
naphthoquinone 9
J¼1.3, 7.7 Hz, H-6 or H-9). 13C NMR (CDCl3):
d 96.5 (C-4), 116.9
(d, J¼23.0 Hz, C-30 and C-50), 127.0 (CHar), 127.5 (CHar), 129.4 (d,
J¼9.2 Hz, C-20 and C-60), 131.5 (]Cquat), 133.4 (]Cquat), 133.9 (CHar),
135.2 (d, J¼9.2 Hz, ]Cquat), 135.8 (CHar), 148.0 (]Cquat), 154.9 (d,
J¼211.1 Hz, C-40), 166.0 (]Cquat), 167.4 (]Cquat), 178.7 (]Cquat),
To a 10 wt % solution of ammonium acetate (1.0 g) in acetic acid
(10 ml) was added 2-methoxycarbonyl-1,4-naphthoquinone
6
(1.2 mmol, 0.25 g) and the reaction mixture was subsequently
boiled under reflux for 4 h. After cooling to room temperature, the
reaction mixture was poured in water and extracted with
dichloromethane. The combined organic extracts were washed
with a saturated aqueous solution of sodium hydrogencarbonate
and dried over magnesium(II) sulfate. Solvent evaporation in vacuo
gave 3-amino-2-methoxycarbonyl-1,4-naphthoquinone 9, which
was purified by column chromatography on silica gel with petro-
leum ether/ethyl acetate (4:1) in 83% yield.
179.4 (C]O), 182.4 (C]O). 19F NMR (CDCl3):
d
ꢂ104.1 (1F, br s,
]Cquat–F). IR (KBr): nmax 1674 cmꢂ1. MS (ES) m/z (%): 321 (Mþ2Hþ,
100). Anal. Calcd for C19H10FNO3: C 71.47, H 3.16, N 4.39, found: C
71.32, H 3.44, N 4.49.
4.4.2. 3-(4-Chlorophenyl)-1-hydroxybenz[g]isoquinoline-5,10-
dione 4b
Column chromatography on silica gel with dichloromethane/
methanol (9:1) afforded 4b as orange yellowish crystals in 76%
4.5.1. 3-Amino-2-methoxycarbonyl-1,4-naphthoquinone 9
yield, mp 277.2–277.9 ꢀC. 1H NMR (CDCl3):
d
7.48–7.57 (3H, m, H-4,
H-30 and H-50), 7.84–7.94 (2H, m, H-7 and H-8), 8.32–8.39 (2H, m,
H-6 and H-9). 13C NMR (CDCl3):
109.8 (C-4), 127.3 (CHar), 127.8
Brown crystals, mp 146 ꢀC (lit. 145–146 ꢀC28). 1H NMR
(CDCl3):
d 3.92 (3H, s, OCH3), 7.01 (1H, br s, NH), 7.64–7.70 (1H,
d
m, H-6 or H-7), 7.79–7.85 (1H, m, H-6 or H-7), 8.07–8.10 (1H, m,
H-5 or H-8), 8.22–8.24 (1H, m, H-5 or H-8), 9.15 (1H, br s, NH).
(CHar), 129.2 (2ꢁCHar), 129.3 (2ꢁCHar), 132.8 (]Cquat), 133.1
(]Cquat), 135.2 (2ꢁCHar), 135.4 (]Cquat), 137.8 (]Cquat), 141.9
(]Cquat), 162.9 (]Cquat), 165.8 (]Cquat), 182.0 (C]O), 186.7 (C]O).
IR (KBr): nmax 1674, 1634, 1586 cmꢂ1. MS (ES) m/z (%): 335/337
(MþHþ, 40). Anal. Calcd for C19H10ClNO3: C 71.47, H 3.16, N 4.39,
found: C 71.39, H 3.40, N 4.27.
13C NMR (CDCl3):
d 52.3 (OCH3), 101.5 (]Cquat), 126.4 (CHar),
127.5 (CHar), 129.6 (]Cquat), 132.5 (CHar), 134.1 (]Cquat), 136.1
(CHar), 153.2 (]Cquat), 169.5 (]Cquat), 179.1 (C]O), 180.7 (C]O).
IR (KBr): nmax 1690, 1655 cmꢂ1. MS (ES) m/z (%): 232 (MþHþ,
100). Anal. Calcd for C12H9NO4: C 62.34, H 3.92, N 6.06, found: C
62.59, H 4.04, N 5.98.
4.4.3. 3-Phenyl-1-hydroxybenz[g]isoquinoline-5,10-dione 4c
Column chromatography on silica gel with dichloromethane/
methanol (9:1) afforded 4c as brown crystals in 45% yield, mp
Acknowledgements
192.8 ꢀC. 1H NMR (CDCl3):
d
7.52–7.56 (3H, m, H-30, H-40 and H-50),
The authors are indebted to the ‘Research FoundationdFlanders
(FWO-Vlaanderen)’ and the ‘Institute for the Promotion of
Innovation through Science and Technology in Flanders (IWT-
Vlaanderen)’ for financial support of this research.
7.84–7.94 (2H, m, H-7 and H-8), 8.19 (1H, s, H-4), 8.22–8.27 (2H, m,
H-20 and H-60), 8.32–8.39 (2H, m, H-6 and H-9). 13C NMR (CDCl3):
d
110.0 (C-4), 127.2 (CHar), 127.7 (CHar), 127.9 (2ꢁCHar), 129.0
(2ꢁCHar), 131.4 (CHar), 132.8 (2ꢁ]Cquat), 133.1 (2ꢁ]Cquat), 135.0
(CHar), 135.1 (CHar), 136.9 (]Cquat), 165.8 (]Cquat), 182.1 (C]O),
186.7 (C]O). IR (KBr): nmax 1676, 1634 cmꢂ1. MS (ES) m/z (%): 302
(MþHþ, 100). Anal. Calcd for C19H11NO3: C 75.74, H 3.68, N 4.65,
found: C 75.50, H 3.86, N 4.58.
References and notes
1. Khanapure, S. P.; Biehl, E. R. Heterocycles 1988, 27, 2643–2650.
2. (a) Krapcho, A. P.; Menta, E.; Oliva, A.; Di Domenico, R.; Fiocchi, L.; Maresch, M.
E.; Gallagher, C. E.; Hacker, M. P.; Beggiolin, G.; Giuliani, F. C.; Pezzoni, G.;
Spinelli, S. J. Med. Chem. 1998, 41, 5429–5444; (b) Faivre, S.; Raymond, R.; Boige,
V.; Gatineau, M.; Buthaut, X.; Rixe, O.; Bernareggi, A.; Camboni, G.; Armand, J.-P.
Clin. Cancer Res. 2001, 7, 43–50.
3. Burckhardt, G.; Walter, A.; Triebel, H.; Storl, K.; Simon, H.; Storl, J.; Opitz, A.; Roemer, E.;
Zimmer, C. Biochemistry 1998, 37, 4703–4711; Chem. Abstr. 1998, 128, 239063.
4. (a) Gonsette, R. E. J. Neurosci. 2004, 223, 81–86; (b) Cavaletti, G.; Cavaletti, E.;
Crippa, L.; Di Luccio, E.; Oggioni, N.; Mazzanti, B.; Biagiolo, T.; Sala, F.; Frigo,
4.4.4. 3-tert-Butyl-1-hydroxybenz[g]isoquinoline-5,10-dione 4d
Column chromatography on silica gel with petroleum ether/
ethyl acetate (4:1) yielded 48% of 4d as yellowish orange crystals,
mp 149.7 ꢀC. 1H NMR (CDCl3):
H-4), 7.81–7.89 (2H, m, H-7 and H-8), 8.26–8.33 (2H, m, H-6 and
d
1.44 (9H, s, 3ꢁCH3), 7.25 (1H, s,