New synthesis of N-substituted benz[g]isoquinoline-3,5,10(2H)-triones

Article abstract of DOI:10.1016/j.tet.2006.12.052

Various N-substituted benz[g]isoquinoline-3,5,10(2H)-triones 7 were prepared starting from vitamin K₃ (menadione) 9. The key steps involve substitution of a benzylic bromide by a primary amine and intramolecular condensation across the ester mo

Full text of DOI:10.1016/j.tet.2006.12.052

Tetrahedron 63 (2007) 2503–2510
New synthesis of N-substituted benz[g]isoquinoline-
3,5,10(2H)-triones
Jan Jacobs,a Sven Claessens,a Bart Kesteleyn,a Kris Huygenb and Norbert De Kimpea,
*
aDepartment of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, B-9000 Ghent, Belgium
bPasteur Institute, Engelandstraat 642, B-1180 Brussels, Belgium
Received 27 October 2006; revised 14 December 2006; accepted 15 December 2006
Available online 20 December 2006
Abstract—Various N-substituted benz[g]isoquinoline-3,5,10(2H)-triones 7 were prepared starting from vitamin K3 (menadione) 9. The key
steps involve substitution of a benzylic bromide by a primary amine and intramolecular condensation across the ester moiety of a (3-bromo-
methyl-naphth-2-yl)acetate 8 followed by oxidation with cerium(IV) ammonium nitrate (CAN) and spontaneous dehydrogenation, resulting
in the title compounds 7. A selection of the synthesised new compounds was tested in vitro against Mycobacterium tuberculosis.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
benz[g]isoquinoline-3,5,10(2H)-triones 6 are promising
antitumour compounds, since they were described for their
cytotoxic activity against murine leukaemia cells (L 1210).5
Therefore, benz[g]isoquinoline-3,5,10(2H)-triones could be
interesting target compounds in the search for new drugs.
Naphthoquinones with annelated N-heterocycles constitute
an important research area in organicsynthesis due to the pro-
nounced biological activities of several natural products.
Mimosamycin 1, an antibiotic isolated from Streptomyces
lavendulae, shows antituberculous activity.1 Bostrycoidin
2, a 2-aza-anthraquinone isolated from several fungi of the
Fusarium species,2 also possesses significant in vitro anti-
biotic activity against Mycobacterium tuberculosis.3 The
naturally occurring 1-aza-anthraquinone cleistopholin 3, iso-
lated from Cleistopholis patens, and synthetic analogues 4
and 5 arevery strong inhibitors of Mycobacterium intracellu-
lare with MIC’s equal to or less than rifamycin.4 Moreover,
In the present article, a new strategy for the synthesis of
benz[g]isoquinoline-3,5,10(2H)-triones will be disclosed.
According to literature these compounds have only been
synthesised by a Diels–Alder reaction between disilylated
2-aza-1,3-butadienes and 1,4-naphthoquinones.6 However,
for substituted 1,4-naphthoquinones, these cycloadditions
are generally unsatisfactory in terms of yields and separation
of the different regioisomers.
O
O
OH
OH
O
R3
O
R1
MeO
CH3
O
N
N
NH
MeO
O
O
R4
O
R2
1
2
6
R1, R2 = H, Alkyl
R3, R4 = H, OH, OMe, OAc
O
O
R
N
N
O
O
3: R = CH3
4: R = CH2CH3
5
Keywords: Benz[g]isoquinoline-3,5,10(2H)-triones; 2-Aza-anthraquinon-3-ones; Quinones; Mimosamycin; Mycobacterium tuberculosis.
* Corresponding author. Tel.: +32 9 264 59 51; fax: +32 9 264 62 43; e-mail: norbert.dekimpe@ugent.be
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.12.052

2504
J. Jacobs et al. / Tetrahedron 63 (2007) 2503–2510
O
OMe Br
O
due to hydrolysis of the ester function, the formation of the
naphthofuran side-product 12 could be prevented and as a
result, (1,4-dimethoxy-3-methyl-naphth-2-yl)acetic acid 13
was the only reaction product obtained in a yield of 80%.
The esterification of carboxylic acid 13 was accomplished
upon reflux in ethanol with a catalytic amount of con-
centrated sulfuric acid to afford the desired ethyl (1,4-di-
methoxy-3-methyl-naphth-2-yl)acetate 11 in 79% yield.
Reaction of the ethyl ester 11 with a slight excess of N-bro-
mosuccinimide and 0.1 equiv of benzoyl peroxide in carbon
tetrachloride gave ethyl (3-bromomethyl-1,4-dimethoxy-
naphth-2-yl)acetate 8 in quantitativeyield as a result of selec-
tive radical bromination at the C-3 methyl group (Scheme 1).
R
O
N
O
OEt
O
OMe
O
9
7
8
Retrosynthetic analysis suggested that benz[g]isoquinoline-
3,5,10(2H)-triones 7 can be synthesised starting from mena-
dione 9, deploying a strategy, which is comparable to the
synthesis of mimosamycin developed by our department.7
Introduction of an alkyl side chain, followed by a reductive
O-methylation and radical bromination at the benzylic posi-
tion results in the formation of compound 8. Subsequent
reaction of this intermediate with primary amines and oxi-
dative demethylation should yield the target compounds 7.
Ethyl (3-bromomethyl-1,4-dimethoxy-naphth-2-yl)acetate 8
was then reacted with ammonia or with a primary amine
(propylamine, isopropylamine, butylamine, isobutylamine,
sec-butylamine, aniline, benzylamine, allylamine) in ethanol
for 2–3 days at room temperature to give, via substitution of
the benzylic bromide and intramolecular condensation with
the ester group, the corresponding 5,10-dimethoxy-1,4-di-
hydrobenz[g]isoquinoline-3(2H)-ones 14a–i in yields of
30–86% (Scheme 2). This reaction proceeded slowly as
only 66% of conversion was achieved after 36 h at room
temperature when isopropylamine was used. However, in
the case of the more sterically hindered tert-butylamine
and the less nucleophilic aniline, only nucleophilic substitu-
tion of the benzylic bromidewas observed, giving the (3-ami-
nomethyl-naphth-2-yl)acetates 15a and 15b in yields of 83%
and 45%, respectively. However, 2-phenyl-5,10-dimethoxy-
1,4-dihydrobenz[g]isoquinoline-3(2H)-one 14g could be
obtained in a yield of 39% when ethyl (3-bromomethyl-
1,4-dimethoxy-naphth-2-yl)acetate 8 was heated under re-
flux for 3 days in the presence of an excess of 5 equiv of
aniline. On the other hand, the cyclisation of the tert-butyl
derivative 15a could not be accomplished even after the
addition of potassium carbonate as a base under reflux in
ethanol for several days. In order to obtain the desired N-alkyl
and N-aryl substituted benz[g]isoquinoline-3,5,10(2H)-
triones 7, 5,10-dimethoxy-1,4-dihydrobenz[g]isoquinoline-
3(2H)-ones 14a–i were treated with 3 equiv of cerium(IV)
ammonium nitrate in aqueous acetonitrile, but this procedure
2. Results and discussion
Ethyl (3-methyl-1,4-dioxo-naphth-2-yl)acetate 10 was pre-
pared according to literature methods involving the reaction
of menadione 9 with the pyridinium ylide obtained by
treating ethyl pyridin-1-ylacetate with triethylamine.8–10
Reduction of the naphthoquinone ethyl ester 10 to ethyl
(1,4-dimethoxy-3-methyl-naphth-2-yl)acetate 11 was per-
formed with tin(II) chloride in concentrated hydrochloric
acid/ethanol (1:10). Subsequent dimethylation of the inter-
mediate hydroquinone ethyl ester using dimethyl sulfate
and potassium carbonate in refluxing acetone afforded ethyl
(1,4-dimethoxy-3-methyl-naphth-2-yl)acetate 11 in 45%
yield (Scheme 1). However, this procedure was found to be
only satisfactory in small scale experiments (<2 g). When
larger amounts of starting material were used, the naphtho-
[1,2-b]furan 12, resulting from the intramolecular cyclisation
of the phenolic hydroxyl group with the ester function,
became a disturbing side-product of the reaction (up to 33%,
depending from batch to batch). Therefore, on a large scale,
ethyl (1,4-dimethoxy-3-methyl-naphth-2-yl)acetate 11 was
prepared in a two-step procedure using a large excess of
potassium hydroxide for the methylation of the intermediate
hydroquinone ethyl ester with dimethyl sulfate. In this case,
(1) 3.5 equiv. SnCl2
O
OMe
OMe
12 M HCl, EtOH
rt, 30 min
O
O
+
(2) 5 equiv. Me2SO4
5 equiv. K2CO3
acetone, , 16 h
OEt
OEt
O
O
OMe
OMe
10
11 (26-45%)
12 (0-33%)
(1) 3.5 equiv. SnCl2
12 M HCl, EtOH
(2) 40 equiv. KOH
20 equiv. Me2SO4
80 °C, 2 h
+
(3) H3O
OMe
OMe
OMe
OMe Br
O
1.05 equiv. NBS
0.10 equiv. BPO
H2SO4 (cat.)
EtOH, , 8 h
O
O
CCl4, , 4 h
OEt
OH
OEt
OMe
13 (80%)
OMe
11 (79%)
8 (100%)
Scheme 1. Synthesis of ethyl (1,4-dimethoxy-3-methyl-naphth-2-yl)acetate 11 and ethyl (3-bromomethyl-1,4-dimethoxy-naphth-2-yl)acetate 8.

J. Jacobs et al. / Tetrahedron 63 (2007) 2503–2510
2505
(R = H, n-Pr, i-Pr, n-Bu, i-Bu,
2-n-butyl-5,10-dimethoxy-1,4-dihydrobenz[g]isoquinoline-
3(2H)-one 14d, 2-isobutyl-5,10-dimethoxy-1,4-dihydro-
benz[g]isoquinoline-3(2H)-one 14e and 2-n-propylbenz-
[g]isoquinoline-3,5,10(2H)-trione 7b was tested in vitro
against M. tuberculosis, in a luciferase screening assay. Two
concentration levels (10 mM and 1 mM) were tested on their
ability to stop or slow down growing the luminescent
M. tuberculosis. Streptomycin, which has a strong bacteri-
cidal activity, was used as a negative control. Compounds
14a and 7b showed a weak, not significant activity against
M. tuberculosis, whereas the use of compounds 14d and
14e resulted in a slight bacteriostatic effect at a concentration
of 10 mM (29% of growth with regard to the positive control
on day 3). However, in the search for novel antituberculosis
drugs, quinones with a better antimycobacterial activity are
needed. Therefore, further research in this respect is going
on presently.
OMe Br
sec-Bu, Bn, allyl)
(R = t-Bu, Ph)
RNH2 (excess)
EtOH, rt, 3d
RNH2 (excess)
O
EtOH, rt, 3d
OEt
OMe
8
R
O
MeO HN
OMe
R
(R = Ph)
EtOH, , 3d
N
OEt
O
MeO
OMe
15a R = t-Bu (83%)
15b R = Ph (45%)
14a R = H (86%)
14f R = sec-Bu (34%)
14b R = n-Pr (74%) 14g R = Ph (39%)
14c R = i-Pr (62%) 14h R = Bn (33%)
14d R = n-Bu (35%) 14i R = allyl (62%)
14e R = i-Bu (30%)
3 equiv. cerium(IV) ammonium nitrate (CAN)
CH3CN/H2O 2/1
rt, 30 min
O
O
O
3. Conclusions
R
O
R
air, K2CO3
N
N
A synthetic programme was directed towards the synthesis
of N-alkyl and N-arylbenz[g]isoquinoline-3,5,10(2H)-
triones 7. The synthesis was accomplished by reaction of
ethyl (3-bromomethyl-1,4-dimethoxy-naphth-2-yl)acetate
8 with a primary amine and subsequent oxidative demethyl-
ation with cerium(IV) ammonium nitrate. In vitro testing
against M. tuberculosis revealed a slight, not significant
antimycobacterial activity of the synthesised benz[g]iso-
quinoline-3,5,10(2H)-trione 7b and 5,10-dimethoxy-1,4-di-
hydrobenz[g]isoquinoline-3(2H)-one 14a. 2-n-Butyl-5,10-
dimethoxy-1,4-dihydrobenz[g]isoquinoline-3(2H)-one 14b
and 2-isobutyl-5,10-dimethoxy-1,4-dihydrobenz[g]isoqui-
noline-3(2H)-one 14e revealed a moderate bacteriostatic
effect at a concentration of 10 mM.
MeOH
rt, 6-8 h
O
O
16
7a R = H (0%)
7f R = sec-Bu (42%)
7b R = n-Pr (67%) 7g R = Ph (4%)
7c R = i-Pr (45%)
7h R = Bn (25%)
7d R = n-Bu (41%) 7i R = allyl (74%)
7e R = i-Bu (58%)
Scheme 2. Synthesis of N-substituted benz[g]isoquinoline-3,5,10(2H)-
triones 7.
gave mixtures of the desired benz[g]isoquinoline-3,5,
10(2H)-triones 7 together with the intermediate 1,4-dihydro-
benz[g]isoquinoline-3,5,10(2H)-triones 16. The intermediate
N-substituted 1,4-dihydrobenz[g]isoquinoline-3,5,10(2H)-
triones 16 could not be isolated in pure form, since they grad-
ually oxidised over a period of several hours—by oxidation
in air—into the corresponding N-substituted benz[g]isoqui-
noline-3,5,10(2H)-triones 7. To stimulate the spontaneous
oxidation of these intermediates 16, the reaction mixtures ob-
tained from the oxidation with cerium(IV) ammonium nitrate
were dissolved in methanol. After addition of potassium
carbonate, air was bubbled through the solution and afforded
N-substituted benz[g]isoquinoline-3,5,10(2H)-triones 7b–i
in 25–74% yields after purificationby means of flash chroma-
tography or recrystallisation. The low yield of 4% that was
obtained for the N-phenyl derivative 7g can be explained
by the oxidative reactions of the N-phenyl group with
cerium(IV) ammonium nitrate. The N-unsubstituted benz[g]-
isoquinoline-3,5,10(2H)-trione 7a could not be obtained
from the oxidation of the corresponding 1,4-dihydrobenz[g]-
isoquinoline-3(2H)-one 14a with cerium(IV) ammonium
nitrate probably due to the formation of inseparable disturb-
ing side-products, resulting in complex reaction mixtures.
Also treatment of 14a with silver(II) oxide in dioxane and
6 M HNO3, which is a frequently used alternative for the
oxidative demethylation of 1,4-dimethoxynaphthalenes
into their corresponding 1,4-naphthoquinones, only resulted
in a complex reaction mixture.
4. Experimental section
4.1. General experimental methods
Spectroscopic data were recorded as follows. 1H NMR spec-
tra were recorded at 270 MHz or 300 MHz and 13C NMR
spectra were recorded at 68 MHz or 75 MHz. Peak assign-
ments were made with the aid of the DEPT technique, 2D-
COSY and HETCOR spectra. Mass spectra were recorded
using a direct inlet system (70 eV) with a VL detector (ES,
4000 V). High resolution mass spectra were recorded on
a tandem mass spectrometer. The reported melting points
are not corrected. Flash chromatography was carried out
using a glass column with silica gel (particle size 0.035–
0.07 mm, pore diameter ca. 6 nm). Solvent systems were
determined via initial TLC analysis.
4.2. Synthesis of ethyl (1,4-dimethoxy-3-methyl-naphth-
2-yl)acetate 11 from ethyl (3-methyl-1,4-dioxo-naphth-
2-yl)acetate 10
To a stirred solution of ethyl (3-methyl-1,4-dioxo-naphth-
2-yl)acetate 108 (1.9 mmol, 0.5 g) in 95% ethanol (20 ml)
was added dropwise a solution of tin(II) chloride (6.7 mmol,
1.26 g) in 12 M HCl (2 ml), and the reaction mixture was
kept at room temperature for 30 min. The solvent was
In the second part of this research, the bioactivity of 5,10-
dimethoxy-1,4-dihydrobenz[g]isoquinoline-3(2H)-one 14a,

2506
J. Jacobs et al. / Tetrahedron 63 (2007) 2503–2510
concentrated in vacuo to a volume of 5 ml, and cold water
(50 ml) was added, which caused the hydroquinone to
precipitate. After 30 min, the white precipitate, obtained
by filtration, was dissolved in acetone (20 ml). To this solu-
tion was first added dimethyl sulfate (9.5 mmol, 1.2 g) and
then potassium carbonate (9.5 mmol, 1.31 g) and the mix-
ture was heated under reflux for 16 h. Most of the acetone
was evaporated in vacuo and the residue was dissolved in
water and extracted with diethyl ether. The combined or-
ganic phases were washed with brine, dried (MgSO4) and
evaporated in vacuo. Flash chromatography on silica gel
with ethyl acetate/hexane (1:9) as eluent gave ethyl (1,4-di-
methoxy-3-methyl-naphth-2-yl)acetate 11 as an oil. When
the experiment was repeated, using more than 2 g of ethyl
(3-methyl-1,4-dioxo-naphth-2-yl)acetate 10, a solid crystal-
lised from the crude oil. This crystalline compound was
obtained in pure form by recrystallisation from diethyl ether
to give 2,5-dimethoxy-4-methylnaphtho[1,2-b]furan 12 in
yields up to 33% as yellow cubes, mp 124.7–126.0 ꢀC.
to give (1,4-dimethoxy-3-methyl-naphth-2-yl)acetic acid
13 (8.30 g, 80%). The crude product (purity about 98%)
was used without further purification in the next step. An
analytical sample was purified by means of flash chromato-
graphy on silica gel with 2% methanol in chloroform as
eluent, mp 124–125 ꢀC.
4.3.1. (1,4-Dimethoxy-3-methyl-naphth-2-yl)acetic acid
13. 1H NMR (270 MHz, CDCl3): d 2.37 (s, 3H, CH3), 3.87
(s, 3H, MeO), 3.91 (s, 3H, MeO), 3.95 (s, 2H, CH2), 7.46–
7.50 (m, 2H, H-6 and H-7), 8.01–8.08 (m, 2H, H-5 and H-
8), 10.8 (br s, 1H, COOH). 13C NMR (68 MHz, CDCl3):
d 12.7, 32.7, 61.5, 62.4, 122.3, 122.5, 123.3, 125.6, 126.2,
126.5, 127.0, 128.5, 150.3, 150.8, 177.3. IR (KBr): nmax
1695 cmꢁ1. MS (70 eV) m/z (%): 260 (M+, 100), 245 (18),
213 (30), 201 (48), 199 (13), 185 (22), 157 (22), 141 (11),
129 (12), 128 (18), 115 (12). Anal. Calcd for C15H16O4: C
69.22, H 6.20, found C 69.14, H 6.08.
4.4. Synthesis of ethyl (1,4-dimethoxy-3-methyl-naphth-
2-yl)acetate 11 from (1,4-dimethoxy-3-methyl-naphth-
2-yl)acetic acid 13
4.2.1. Ethyl (1,4-dimethoxy-3-methyl-naphth-2-yl)-
acetate 11. H NMR (270 MHz, CDCl3): d 1.25 (t, 3H,
1
J¼7.1 Hz, OCH2CH3), 2.35 (s, 3H, CH3), 3.86 (s, 3H,
MeO), 3.90 (s, 3H, MeO), 3.92 (s, 2H, CH2C]O), 4.18
(q, 2H, J¼7.1 Hz, OCH2CH3), 7.44–7.48 (m, 2H, H-6 and
H-7), 8.03–8.08 (m, 2H, H-5 and H-8). 13C NMR (68 MHz,
CDCl3): d 12.6, 14.2, 33.1, 60.9, 61.4, 62.3, 122.2, 122.5,
124.1, 125.8, 126.1, 126.6, 127.0, 128.3, 150.1, 150.8,
171.7. IR (NaCl): nmax 1725 cmꢁ1. MS (70 eV) m/z (%):
288 (M+, 100), 273 (44), 227 (22), 215 (22). Anal. Calcd
for C17H20O4: C 70.81, H 6.99, found: C 70.69, H 7.12.
To a solution of (1,4-dimethoxy-3-methyl-naphth-2-yl)-
acetic acid 13 (4 mmol, 1.04 g) in 95% ethanol (20 ml)
was added concentrated sulfuric acid (five drops) and the
reaction mixture was heated under reflux for 8 h. The
solution was concentrated in vacuo to 5 ml, water was added
and the aqueous solution was extracted with dichloro-
methane. The combined extracts were washed with a satu-
rated solution of sodium hydrogen carbonate and then with
brine. The organic solution was dried (MgSO4) and evapo-
rated in vacuo to give (1,4-dimethoxy-3-methyl-naphth-
2-yl)acetate 11 (0.91, 79%) as an oil, which was used in the
next step. An analytical sample was purified by means of
flash chromatography on silica gel with ethyl acetate/hexane
(1:9) as eluent and resulted in the isolation of a brown oil.
The spectral data are in accordance with the previously
reported data (vide supra).
4.2.2. 2,5-Dimethoxy-4-methylnaphtho[1,2-b]furan 12.
1H NMR (270 MHz, CDCl3): d 2.48 (s, 3H, CH3), 3.89 (s,
3H, MeO), 3.98 (s, 3H, MeO), 5.62 (s, 1H, H-3), 7.36–
7.50 (m, 2H, H-7 and H-8), 8.06–8.11 (m, 2H, H-6 and
H-9). 13C NMR (68 MHz, CDCl3): d 12.3, 58.0, 61.3,
76.5, 119.0, 119.2, 120.1, 122.6, 123.7, 124.4, 125.6, 126.2,
139.0, 149.4, 163.6. IR (KBr): nmax 1600, 1580, 1330, 1265,
1035 cmꢁ1. MS (70 eV) m/z (%): 242 (M+, 88), 227 (100),
212 (47). Anal. Calcd for C15H14O3: C 74.36, H 5.82, found:
C 74.48, H 5.91.
4.5. Synthesis of ethyl (3-bromomethyl-1,4-dimethoxy-
naphth-2-yl)acetate 8
4.3. Synthesis of (1,4-dimethoxy-3-methyl-naphth-2-yl)-
acetic acid 13
A mixture of ethyl (1,4-dimethoxy-3-methyl-naphth-2-yl)-
acetate 11 (1.7 mmol, 0.5 g), N-bromosuccinimide
(1.78 mmol, 0.32 g) and benzoyl peroxide (0.17 mmol,
40 mg) in carbon tetrachloride (20 ml) was heated under
reflux for 4 h. The reaction mixture was allowed to cool to
room temperature with additional cooling using an ice-
bath for 1 h. The succinimide was separated by filtration
and the filtrate was evaporated in vacuo to give crude
ethyl (3-bromomethyl-1,4-dimethoxy-naphth-2-yl)acetate 8
(0.71 g, 100%). Flash chromatography on silica gel using
ethyl acetate/hexane (1:20) as eluent resulted in the isolation
of a green oil and gave rise to a substantial degree of decom-
position. Therefore, the crude product—purity >95% (1H
NMR)—was used as such in the next step.
To a solution of ethyl (3-methyl-1,4-dioxo-naphth-2-yl)ace-
tate 108 (40 mmol, 10.3 g) in 95% ethanol (200 ml) was
added dropwise a solution of tin(II) chloride (140 mmol,
26.6 g) in concentrated hydrochloric acid (25 ml). Stirring
was continued for 0.5 h and the reaction mixture was
concentrated in vacuo until most of the ethanol was evapo-
rated. Upon the addition of cold water (500 ml), a white solid
precipitated and after 30 min the precipitate was isolated
by filtration and mixed together with dimethyl sulfate
(800 mmol, 100.8 g). A solution of potassium hydroxide
(1.6 mol, 89.6 g) in water (200 ml) was added at 0 ꢀC over
a period of 1 h. Stirring was continued for 2 h at 70–80 ꢀC
and the reaction mixture was poured in ice-water (800 ml).
The aqueous solution was acidified with concentrated hydro-
chloric acid until precipitation of 13 was completed. The
precipitate was obtained by filtration and dissolved in
acetone (150 ml), dried (MgSO4) and evaporated in vacuo
4.5.1. Ethyl (3-bromomethyl-1,4-dimethoxy-naphth-2-
yl)acetate 8. 1H NMR (270 MHz, CDCl3): d 1.25 (t, 3H, J¼
7.1 Hz, OCH2CH3), 3.90 (s, 3H, MeO), 4.04 (s, 3H, MeO),
4.08 (s, 2H, CH2C]O), 4.18 (q, 2H, J¼7.1 Hz, OCH2CH3),
4.85 (s, 2H, CH2Br), 7.48–7.52 (m, 2H, H-6 and H-7),

J. Jacobs et al. / Tetrahedron 63 (2007) 2503–2510
2507
8.03–8.09 (m, 2H, H-5 and H-8). 13C NMR (68 MHz,
CDCl3): d 14.2, 26.4, 32.0, 61.1, 62.3, 62.5, 122.7, 123.0,
126.5, 127.0, 128.1, 128.8, 128.9, 129.7, 151.5, 151.7,
171.4. IR (NaCl): nmax 1725 cmꢁ1. MS (70 eV) m/z (%):
366/368 (M+, 30), 287 (100), 258 (20), 241 (60). Anal. Calcd
for C17H19BrO4: C 55.60, H 5.21, found: C 55.40, H 4.99.
299 (M+, 100), 268 (51), 256 (25), 226 (50). Anal. Calcd
for C18H21NO3: C 72.22, H 7.07, N 4.68, found: C 72.13,
H 6.59, N 4.49.
4.6.4. 2-n-Butyl-5,10-dimethoxy-1,4-dihydrobenz[g]-
isoquinoline-3(2H)-one 14d. Flash chromatography on
silica gel with ethyl acetate/hexane (1:1) as eluent gave 14d
(yield: 35%) as a yellow-brown powder, mp 76.1–76.7 ꢀC.
1H NMR (300 MHz, CDCl3): d 0.95 (t, 3H, J¼7.4 Hz,
CH3), 1.37 (sextet, 2H, J¼7.4 Hz, N(CH2)2CH2CH3),
1.58–1.68 (m, 2H, NCH2CH2CH2CH3), 3.58 (t, 2H,
J¼7.4 Hz, NCH2(CH2)2CH3), 3.80 (s, 2H, CH2N), 3.91 (s,
3H, MeO), 3.94 (s, 3H, MeO), 4.77 (s, 2H, CH2C]O),
7.51–7.54 (m, 2H, H-7 and H-8), 8.05–8.12 (m, 2H, H-6
and H-9). 13C NMR (75 MHz, CDCl3): d 13.9, 20.1, 29.6,
32.7, 45.7, 46.9, 61.9, 62.2, 121.9, 122.2, 122.3, 126.1,
126.3, 127.3, 128.3, 147.4, 148.5, 168.8. IR (KBr): nmax
1659, 1360 cmꢁ1. MS (ES) m/z (%): 314 (M+H+, 100).
HRMS calcd for (C19H23NO3$H)+: 314.17507, found
314.17598. Anal. Calcd for C19H23NO3: C 72.82, H 7.40,
N 4.47, found: C 72.66, H 7.28, N 4.40.
4.6. Reaction of ethyl (3-bromomethyl-1,4-dimethoxy-
naphth-2-yl)acetate 8 with ammonia or primary amines
General procedure: to a stirred solution of ethyl (3-bromo-
methyl-1,4-dimethoxy-naphth-2-yl)acetate 7 in 95% ethanol
(5% solution) was added at once 10 equiv of a primary
amine (2.2 equiv was used in the case of benzylamine and
aniline; for the reaction with ammonia 10 equiv of an aque-
ous solution of 25% NH3 was used), and the solution was
stirred for 2–3 days. The reaction mixture was concentrated
in vacuo until most of the ethanol was evaporated and water
was added to the residue. This mixture was extracted three
times with dichloromethane, washed with 1 M HCl and
then with brine, dried (MgSO4) and evaporated in vacuo.
4.6.1. 5,10-Dimethoxy-1,4-dihydrobenz[g]isoquinoline-
3(2H)-one 14a. Recrystallisation from methanol gave 13a
4.6.5. 2-Isobutyl-5,10-dimethoxy-1,4-dihydrobenz[g]-
isoquinoline-3(2H)-one 14e. Flash chromatography on
silica gel with ethyl acetate/hexane (1:3) and then diethyl
ether as eluent gave 14e (yield: 30%) as yellow needles,
1
(yield: 86%) as a yellow powder, mp 196.5–197 ꢀC. H
NMR (270 MHz, CDCl3): d 3.79 (s, 2H, CH2C]O), 3.91
(s, 3H, MeO), 3.92 (s, 3H, MeO), 4.72 (d, 2H, J¼2.6 Hz,
CH2N), 6.64 (br s, 1H, NH), 7.51–7.55 (m, 2H, H-7 and
H-8), 8.06–8.11 (m, 2H, H-6 and H-9). 13C NMR (68 MHz,
CDCl3): d 31.5, 40.5, 61.8, 62.0, 121.4, 121.7, 122.2,
122.3, 126.2, 126.3, 127.4, 128.1, 147.8, 148.89, 172.3. IR
(KBr): nmax 3170, 1670 cmꢁ1. MS (70 eV) m/z (%): 257
(M+, 100), 242 (25), 227 (27). Anal. Calcd for C15H15NO3:
C 70.02, H 5.88, N 5.44, found: C 69.75, H 5.85, N 5.30.
1
mp 104.8–105.6 ꢀC. H NMR (300 MHz, CDCl3): d 0.94
(d, 6H, J¼6.9 Hz, CH(CH3)2), 2.02 (m, 1H, CH(CH3)2),
3.40 (d, 2H, J¼7.7 Hz, NCH2CH), 3.77 (s, 2H, CH2N),
3.91 (s, 3H, MeO), 3.93 (s, 3H, MeO), 4.66 (s, 2H,
CH2C]O), 7.51–7.55 (m, 2H, H-7 and H-8), 8.05–8.13
(m, 2H, H-6 and H-9). 13C NMR (75 MHz, CDCl3):
d 20.0, 26.9, 32.8, 46.1, 54.3, 61.9, 62.3, 122.0, 122.2,
122.3, 126.1, 126.3, 127.3, 128.3, 147.4, 148.5, 169.3. IR
(KBr): nmax 1660, 1359 cmꢁ1. MS (ES) m/z (%): 314
(M+H+, 100). Anal. Calcd for C19H23NO3: C 72.82, H
7.40, N 4.47, found: C 72.91, H 7.58, N 4.49.
4.6.2. 2-n-Propyl-5,10-dimethoxy-1,4-dihydrobenz[g]-
isoquinoline-3(2H)-one 14b. Flash chromatography on
silica gel with ethyl acetate/hexane (3:1) as eluent gave
1
14b (yield: 74%) as a pale yellow powder, mp 50 ꢀC. H
4.6.6. 2-sec-Butyl-5,10-dimethoxy-1,4-dihydrobenz[g]-
isoquinoline-3(2H)-one 14f. Flash chromatography on
silica gel with ethyl acetate/hexane (7:3) and then diethyl
ether as eluent gave 14f (yield: 34%) as yellow crystals,
NMR (270 MHz, CDCl3): d 0.94 (t, 3H, J¼7.6 Hz, CH3),
1.68 (sextet, 2H, J¼7.6 Hz, NCH2CH2CH3), 3.54 (t, 2H,
J¼7.6 Hz, NCH2CH2CH3), 3.79 (s, 2H, CH2C]O), 3.91
(s, 3H, MeO), 3.93 (s, 3H, MeO), 4.66 (s, 2H, CH2N),
7.50–7.54 (m, 2H, H-7 and H-8), 8.06–8.11 (m, 2H, H-6
and H-9). 13C NMR (68 MHz, CDCl3): d 11.3, 20.8, 32.7,
45.8, 48.7, 61.9, 62.2, 122.0, 122.2, 122.3, 122.4, 126.1,
126.3, 127.3, 128.3, 147.5, 148.6, 168.8. IR (KBr): nmax
1655 cmꢁ1. MS (70 eV) m/z (%): 299 (M+, 100), 284 (12),
268 (51). Anal. Calcd for C18H21NO3: C 72.22, H 7.07, N
4.68, found: C 72.03, H 7.55, N 4.50.
1
mp 100.1–100.5 ꢀC. H NMR (300 MHz, CDCl3): d 0.84
(t, 3H, J¼7.2 Hz, CH2CH3), 1.22 (d, 3H, J¼7.2 Hz,
CHCH3), 1.58 (qꢂt, 2H, J¼7.2 Hz, J¼7.2 Hz, CH2CH3),
3.77 (d, 1H, J¼18.3 Hz, CH2N), 3.86 (d, 1H, J¼18.3 Hz,
CH2N), 3.92 (s, 3H, MeO), 3.95 (s, 3H, MeO), 4.49 (s,
2H, CH2C]O), 4.77 (qꢂt, 1H, J¼7.2 Hz, J¼7.2 Hz,
NCH), 7.50–7.56 (m, 2H, H-7 and H-8), 8.05–8.13 (m,
2H, H-6 and H-9). 13C NMR (75 MHz, CDCl3): d 11.1,
17.9, 26.8, 33.4, 38.4, 49.8, 62.0, 62.3, 122.3, 122.4,
122.5, 122.6, 126.1, 126.3, 127.3, 128.4, 147.4, 148.5,
169.4. IR (KBr): nmax 1657, 1359 cmꢁ1. MS (ES) m/z (%):
314 (M+H+, 100). Anal. Calcd for C19H23NO3: C 72.82, H
7.40, N 4.47, found: C 72.67, H 7.24, N 4.37.
4.6.3. 2-Isopropyl-5,10-dimethoxy-1,4-dihydrobenz[g]-
isoquinoline-3(2H)-one 14c. Flash chromatography on
silica gel with ethyl acetate/hexane (3:1) as eluent gave
14c (yield: 62%) as a white powder, mp 88–90 ꢀC. 1H
NMR (270 MHz, CDCl3): d 1.23 (d, 6H, J¼6.9 Hz,
CH(CH3)2), 3.78 (s, 2H, CH2C]O), 3.90 (s, 3H, MeO),
3.94 (s, 3H, MeO), 4.53 (s, 2H, CH2N), 5.01 (septet, 1H,
J¼6.9 Hz, CH(CH3)2), 7.48–7.54 (m, 2H, H-7 and H-8),
8.04–8.12 (m, 2H, H-6 and H-9). 13C NMR (68 MHz,
CDCl3): d 19.6, 33.4, 38.4, 44.0, 62.0, 62.3, 122.2, 122.3,
122.5, 122.6, 126.1, 126.3, 127.3, 128.3, 147.4, 148.5,
168.7. IR (KBr): nmax 1640 cmꢁ1. MS (70 eV) m/z (%):
4.6.7. 2-Phenyl-5,10-dimethoxy-1,4-dihydrobenz[g]-
isoquinoline-3(2H)-one 14g. This compound was prepared
according to the general procedure. However, 5 equiv of
aniline was used and the reaction mixture was heated under
reflux for 3 days. Flash chromatography on silica gel with
ethyl acetate/hexane (1:1) as eluent gave 14g (yield: 39%)
1
as a yellow powder, mp 160–161 ꢀC. H NMR (270 MHz,

2508
J. Jacobs et al. / Tetrahedron 63 (2007) 2503–2510
CDCl3): d 3.88 (s, 3H, MeO), 3.95 (s, 3H, MeO), 3.98 (s,
2H, CH2C]O), 5.06 (s, 2H, CH2N), 7.25–7.46 (m, 5H,
5ꢂ]CH–phenyl), 7.52–7.57 (m, 2H, H-7 and H-8), 8.06–
8.14 (m, 2H, H-6 and H-9). 13C NMR (68 MHz, CDCl3):
d 33.7, 49.0, 62.1, 62.5, 122.1, 122.3, 122.4, 125.8, 126.3,
126.5, 127.1, 127.5, 128.5, 129.2, 142.4, 147.6, 148.8,
169.1. IR (KBr): nmax 1647 cmꢁ1. MS (70 eV) m/z (%):
333 (M+, 100), 302 (38). Anal. Calcd for C21H19NO3: C
75.66, H 5.74, N 4.20, found: C 75.54, H 5.65, N 4.15.
3H, J¼7.1 Hz, OCH2CH3), 3.93 (s, 3H, MeO), 3.94 (s, 2H,
CH2C]O), 3.95 (s, 3H, MeO), 4.12 (q, 2H, J¼7.1 Hz,
OCH2CH3), 4.43 (s, 2H, CH2N), 6.69–6.77 (m, 3H,
3ꢂ]CH–phenyl), 7.19–7.25 (m, 2H, 2ꢂ]CH–phenyl),
7.52–7.56 (m, 2H, H-7 and H-8), 8.06–8.14 (m, 2H, H-6
and H-9). 13C NMR (68 MHz, CDCl3): d 14.1, 32.5, 40.6,
61.1, 62.2, 63.5, 112.7, 117.5, 122.6, 122.9, 124.0, 126.4,
126.5, 127.0, 128.4, 128.4, 129.3, 148.3, 151.5, 172.7. IR
(KBr): nmax 3379, 1717 cmꢁ1. MS (70 eV) m/z (%): 379
(M+, 99), 334 (12), 286 (100). Anal. Calcd for C23H25NO4:
C 72.80, H 6.64, N 3.69, found: C 72.03, H 6.71, N 3.65.
4.6.8. 2-Benzyl-5,10-dimethoxy-1,4-dihydrobenz[g]-
isoquinoline-3(2H)-one 14h. Flash chromatography on
silica gel using ethyl acetate/hexane (1:1) as eluent gave
4.7. Synthesis of N-alkyl and N-arylbenz[g]isoquinoline-
3,5,10(2H)-triones 7
1
14h (yield: 33%) as an oil. H NMR (270 MHz, CDCl3):
d 3.61 (s, 3H, MeO), 3.87 (s, 2H, CH2C]O), 3.89 (s, 3H,
MeO), 4.55 (s, 2H, CH2N), 4.78 (s, 2H, CH2N), 7.22–7.29
(m, 5H, 5ꢂ]CH–phenyl), 7.44–7.52 (m, 2H, H-7 and H-
8), 7.98–8.09 (m, 2H, H-6 and H-9). 13C NMR (68 MHz,
CDCl3): d 32.4, 44.9, 49.8, 61.7, 61.7, 121.6, 122.0,
122.07, 122.14, 125.9, 126.1, 127.2, 127.5, 127.9, 128.1,
128.6, 136.6, 147.3, 148.4, 168.9. IR (NaCl): nmax
1650 cmꢁ1. MS (70 eV) m/z (%): 347 (M+, 88), 316 (21),
256 (35), 91 (100). Anal. Calcd for C22H21NO3: C 76.06,
H 6.09, N 4.03, found: C 75.88, H 6.01, N 3.89.
General procedure: to a cooled (0 ꢀC) solution of an
N-substituted 5,10-dimethoxy-1,4-dihydrobenz[g]isoquino-
line-3(2H)-one 14 (0.34 mmol) in acetonitrile (10 ml) was
added dropwise a solution of cerium(IV) ammonium nitrate
(1.02 mmol) in water (5 ml) and stirring was continued for
30 min at room temperature. The solution was poured in
water and extracted two times with ethyl acetate. The
combined organic extracts were washed with brine, dried
(MgSO4) and evaporated in vacuo. The intermediate
N-substituted 1,4-dihydrobenz[g]isoquinoline-3,5,10(2H)-
triones 16 could not be isolated in pure form by recrystalli-
sation from methanol, since they gradually oxidised over
a period of several hours—by oxidation in air—into the cor-
responding N-substituted benz[g]isoquinoline-3,5,10(2H)-
triones 7. To stimulate the spontaneous oxidation, the crude
products 16 were dissolved in methanol and after the addi-
tion of potassium carbonate (1 g), air was bubbled through
the solution for 3–5 h. Filtration and evaporation in vacuo
afforded crude benz[g]isoquinoline-3,5,10(2H)-triones 7.
4.6.9. 2-Allyl-5,10-dimethoxy-1,4-dihydrobenz[g]isoqui-
noline-3(2H)-one 14i. Flash chromatography on silica gel
using hexane/ethyl acetate (3:7) as eluent gave 14i (yield:
62%). Recrystallisation from ethanol afforded an analytical
1
sample of 14i as orange crystals, mp 90.2 ꢀC. H NMR
(300 MHz, CDCl3): d 3.82 (s, 2H, CH2C]O), 3.90 (s, 3H,
MeO), 3.91 (s, 3H, MeO), 4.21 (dꢂt, 2H, J¼6.0 Hz, J¼
1.4 Hz, ]CHCH2), 4.63 (s, 2H, CH2N), 5.23 (dꢂt, 1H, J¼
17.3 Hz, J¼1.4 Hz, ]CHaHb), 5.23 (dꢂt, 1H, J¼9.9 Hz,
J¼1.4 Hz, ]CHaHb), 5.82 (dꢂdꢂt, 1H, J¼17.3 Hz,
J¼9.9 Hz, J¼1.4 Hz, ]CH), 7.50–7.55 (m, 2H, H-7 and
H-8), 8.03–8.11 (m, 2H, H-6 and H-9). 13C NMR (CDCl3,
75 MHz): d 32.7, 45.2, 49.2, 62.0, 62.3, 118.0, 121.9, 122.3
(C and CH), 122.4, 126.2, 126.4, 127.4, 128.4, 132.6,
147.6, 148.6, 168.9. IR (KBr): nmax 1660, 1359 cmꢁ1. MS
(ES) m/z (%): 595 (2M+H+, 100), 298 (M+H+, 35) Anal.
Calcd for C18H19NO3: C 72.71, H 6.44, N 4.71, found: C
72.56, H 6.29, N 4.58.
4.7.1. 2-n-Propylbenz[g]isoquinoline-3,5,10(2H)-trione
7b. Flash chromatography on silica gel using ethyl acetate/
hexane (3:7) as eluent gave 7b (yield: 67%) as a yellow pow-
der. An analytical sample was obtained by recrystallisation
from methanol to give 7b as yellow needles, mp 221 ꢀC.
1H NMR (270 MHz, CDCl3): d 1.02 (t, 3H, J¼7.4 Hz,
CH3), 1.86 (sextet, 2H, J¼7.4 Hz, NCH2CH2CH3), 4.07 (t,
2H, J¼7.4 Hz, NCH2), 7.31 (s, 1H, H-4), 7.78–7.89 (m,
2H, H-7 and H-8), 8.29–8.35 (m, 2H, H-6 and H-9), 8.52
(s, 1H, H-1). 13C NMR (68 MHz, CDCl3): d 11.0, 22.5,
52.6, 112.7, 118.0, 127.4, 127.7, 133.9, 134.2, 134.3,
135.0, 139.9, 143.1, 162.1, 179.6, 181.7. IR (KBr): nmax
1670, 1585, 1325, 1290, 1260 cmꢁ1. MS (70 eV) m/z (%):
267 (M+, 89), 252 (15), 225 (100), 197 (57). Anal. Calcd
for C16H13NO3: C 71.90, H 4.90, N 5.24, found: C 71.68,
H 4.75, N 5.05.
4.6.10. Ethyl (3-((tert-butylamino)methyl)-1,4-dimeth-
oxy-naphth-2-yl)acetate 15a. Flash chromatography on
silica gel using 4% methanol in chloroform as eluent gave
15a (yield: 83%) as a brown oil. 1H NMR (270 MHz,
CDCl3): d 1.21 (s, 9H, C(CH3)3), 1.27 (t, 3H, J¼7.3 Hz,
OCH2CH3), 3.87 (s, 2H, CH2C]O), 3.91 (s, 3H, MeO),
3.96 (s, 3H, MeO), 4.09 (s, 2H, CH2N), 4.19 (q, 2H, J¼
7.3 Hz, OCH2CH3), 7.47–7.51 (m, 2H, H-6 and H-7), 8.03–
8.08 (m, 2H, H-5 and H-8). 13C NMR (68 MHz, CDCl3):
d 14.3, 28.8, 32.3, 38.7, 50.8, 60.7, 62.1, 63.1, 122.6,
124.5, 125.9, 128.0, 129.2, 150.9, 151.3, 172.4. IR (NaCl):
nmax 1730 cmꢁ1. MS (70 eV) m/z (%): 359 (M+, 38), 344
(57), 302 (54), 287 (100). Anal. Calcd for C21H29NO4: C
70.17, H 8.13, N 3.90, found: C 69.98, H 7.83, N 3.98.
4.7.2. 2-Isopropylbenz[g]isoquinoline-3,5,10(2H)-trione
7c. Flash chromatography on silica gel using ethyl acetate/
hexane (1:1) as eluent gave 7c (yield: 45%) as a yellow
powder. Recrystallisation from methanol afforded 7c as
yellow needles, mp 208–209 ꢀC. 1H NMR (270 MHz,
CDCl3): d 1.49 (d, 6H, J¼6.6 Hz, CH(CH3)2), 5.30 (septet,
1H, J¼6.6 Hz, CH(CH3)2), 7.29 (s, 1H, H-4), 7.78–7.88
(m, 2H, H-7 and H-8), 8.28–8.35 (m, 2H, H-6 and H-9),
8.60 (s, 1H, H-1). 13C NMR (68 MHz, CDCl3): d 22.7,
48.4, 113.0, 117.7, 127.4, 127.6, 133.9, 134.2, 134.3,
135.0, 139.1, 139.3, 162.2, 179.5, 181.8. IR (KBr): nmax
4.6.11. Ethyl (1,4-dimethoxy-3-((phenylamino)methyl)-
naphth-2-yl)acetate 15b. Recrystallisation from ethanol
gave 15b (yield: 45%) as orange-yellow needles, mp
1
130.5–131.3 ꢀC. H NMR (270 MHz, CDCl3): d 1.18 (t,

J. Jacobs et al. / Tetrahedron 63 (2007) 2503–2510
2509
1675, 1585, 1335, 1295, 1265 cmꢁ1. MS (70 eV) m/z (%):
267 (M+, 87), 225 (100), 197 (63). Anal. Calcd for
C16H13NO3: C 71.90, H 4.90, N 5.24, found: C 71.66, H
4.86, N 5.08.
129.6, 129.7, 134.0, 134.3, 134.4, 135.1, 139.5, 140.2,
143.5, 162.1, 179.6, 181.5. IR (KBr): nmax 1673, 1647,
1584, 1271 cmꢁ1. MS (70 eV) m/z (%): 301 (M+, 100),
273 (62), 170 (34). Anal. Calcd for C19H11NO3: C 75.74,
H 3.68, N 4.65, found: C 75.82, H 3.74, N 4.49.
4.7.3. 2-n-Butylbenz[g]isoquinoline-3,5,10(2H)-trione
7d. Flash chromatography on silica gel with ethyl acetate/
hexane (3:7) as eluent and then recrystallisation from meth-
anol gave 7d as an orange powder (yield: 41%), mp 156.8–
4.7.7. 2-Benzylbenz[g]isoquinoline-3,5,10(2H)-trione 7h.
Flash chromatography on silica gel with ethyl acetate/
hexane (3:7) as eluent gave 7h (yield: 25%) as a yellow pow-
der. Recrystallisation from methanol afforded an analytical
1
157.3 ꢀC. H NMR (300 MHz, CDCl3): d 0.99 (t, 3H, J¼
1
7.4 Hz, CH3), 1.43 (sextet, 2H, J¼7.4 Hz, N(CH2)2CH2CH3),
1.82 (quintet, 2H, J¼7.4 Hz, NCH2CH2CH2CH3), 4.10 (t,
2H, J¼7.4 Hz, NCH2(CH2)2CH3), 7.31 (s, 1H, H-4), 7.81–
7.86 (m, 2H, H-7 and H-8), 8.31–8.34 (m, 2H, H-6 and H-
9), 8.52 (s, 1H, H-1). 13C NMR (75 MHz, CDCl3): d 13.7,
19.9, 31.3, 50.8, 112.6, 117.8, 127.3, 127.6, 133.9, 134.2,
134.2, 135.0, 139.8, 143.1, 162.3, 179.5, 181.7. IR (KBr):
nmax 1690, 1674, 1645, 1330, 1305, 1297 cmꢁ1. MS (ES)
m/z (%): 282 (M+H+, 100). Anal. Calcd for C17H15NO3: C
72.58, H 5.37, N 4.98, found: C 72.34, H 5.26, N 4.87.
sample of 7h as fine yellow needles, mp 201–202 ꢀC. H
NMR (270 MHz, CDCl3): d 5.27 (s, 2H, CH2N), 7.32 (s,
1H, H-4), 7.33–7.40 (m, 5H, 5ꢂ]CH–phenyl), 7.78–7.85
(m, 2H, H-7 and H-8), 8.26–8.29 (m, 2H, H-6 and H-9),
8.56 (s, 1H, H-1). 13C NMR (68 MHz, CDCl3): d 53.3,
113.0, 118.2, 127.0, 127.4, 127.7, 128.6, 128.8, 129.2,
133.9, 134.2, 134.8, 135.0, 139.9, 142.8, 162.4, 179.4,
181.6. IR (KBr): nmax 1675, 1645, 1585, 1535, 1330, 1315,
1295, 1265 cmꢁ1. MS (70 eV) m/z (%): 315 (M+, 28), 209
(12), 91 (100). Anal. Calcd for C20H13NO3: C 76.18, H
4.16, N 4.44, found: C 75.98, H 4.08, N 4.33.
4.7.4. 2-Isobutylbenz[g]isoquinoline-3,5,10(2H)-trione
7e. Flash chromatography on silica gel with ethyl acetate/
hexane (3:7) as eluent and then recrystallisation from
methanol gave 7e as an orange powder (yield: 58%),
4.7.8. 2-Allylbenz[g]isoquinoline-3,5,10(2H)-trione 7i.
Flash chromatography on silica gel using hexane/ethyl ace-
tate (7:3) as eluent gave 7i (yield: 74%) as an orange oil. 1H
NMR (300 MHz, CDCl3): d 4.72 (dꢂt, 2H, J¼6.1 Hz,
J¼1.4 Hz, CH2), 5.33–5.42 (m, 2H, ]CH2), 6.01 (dꢂdꢂt,
1H, J¼16.9 Hz, J¼10.2 Hz, J¼6.1 Hz, ]CH), 7.34 (s,
1H, H-4), 7.80–7.88 (m, 2H, H-6 and H-7), 8.30–8.35 (m,
2H, H-5 and H-8), 8.53 (1H, s, H-1). 13C NMR (75 MHz,
CDCl3): d 52.3, 113.0, 118.1, 120.8, 127.5, 127.8, 131.0,
134.0, 134.4, 135.1, 140.0, 142.8, 162.2, 179.6, 181.8. IR
(NaCl): nmax 1687, 1674, 1646 cmꢁ1. MS (ES) m/z (%):
266 (M+H+, 100). Anal. Calcd for C16H11NO3: C 72.45, H
4.18, N 5.28, found: C 72.27, H 4.06, N 5.13.
1
mp 193.9–194.2 ꢀC. H NMR (300 MHz, CDCl3): d 1.00
(d, 6H, J¼6.6 Hz, NCH2CH(CH3)2), 2.18–2.32 (m, 1H,
NCH2CH(CH3)2), 3.92 (d, 2H, J¼7.4 Hz, NCH2CH(CH3)2),
7.32 (s, 1H, H-4), 7.79–7.89 (m, 2H, H-7 and H-8), 8.30–
8.35 (m, 2H, H-6 and H-9), 8.47 (s, 1H, H-1). 13C NMR
(75 MHz, CDCl3): d 19.8, 28.0, 57.9, 112.3, 117.8, 127.3,
127.6, 133.8, 134.1, 134.2, 134.9, 139.7, 143.4, 162.4,
179.4, 181.6. IR (KBr): nmax 1683, 1640, 1588, 1327,
1288, 1263 cmꢁ1. MS (ES) m/z (%): 282 (M+H+, 100),
262 (35), 184 (10). HRMS calcd for (C17H15NO3$H)+:
282.11247, found 282.11214. Anal. Calcd for C17H15NO3:
C 72.58, H 5.37, N 4.98, found: C 72.52, H 5.27, N 4.86.
4.8. Biotesting
4.7.5. 2-sec-Butylbenz[g]isoquinoline-3,5,10(2H)-trione
7f. Flash chromatography on silica gel with ethyl acetate/
hexane (3:7) as eluent and then recrystallisation from meth-
anol gave 7f as an orange powder (yield: 42%), mp 137.4–
138.1 ꢀC. 1H NMR (300 MHz, CDCl3): d 0.93 (t, 3H,
J¼7.2 Hz, CH2CH3), 1.46 (d, 3H, J¼7.2 Hz, CHCH3),
1.84 (quintet, 2H, J¼7.2 Hz, CH2CH3), 5.13 (sextet, 1H,
J¼7.2 Hz, NCH), 7.32 (s, 1H, H-4), 7.79–7.89 (m, 2H,
H-7 and H-8), 8.29–8.36 (m, 2H, H-6 and H-9), 8.52 (s,
1H, H-1). 13C NMR (75 MHz, CDCl3): d 10.6, 20.1, 29.2,
53.6, 113.0, 117.7, 127.4, 127.6, 133.9, 134.1, 134.3,
135.0, 139.1, 139.3, 162.5, 179.5, 181.7. IR (KBr): nmax
1692, 1673, 1642, 1591, 1338, 1295, 1283 cmꢁ1. MS (ES)
m/z (%): 282 (M+H+, 100). Anal. Calcd for C17H15NO3: C
72.58, H 5.37, N 4.98, found: C 72.70, H 5.49, N 5.10.
Compounds were tested in vitro against luminescent
M. tuberculosis H37Rv using a luciferase screening assay
as described before.11 Briefly, compounds were dissolved
in DMSO and diluted in Sauton–5% FCS medium. The final
DMSO concentration did not exceed 0.1% (toxic level).
Luminescent mycobacteria were grown at 10 mM and 1 mM
solution in 200 ml volumes in 96 microwell plates and incu-
ꢀ
bated at 37 C and 5% CO2 atmosphere. Measure points
were day 1, day 3 and day 7 and each time the growth was
compared with that of untreated (0 mM) bacteria and of
bacteria treated with streptomycin as a positive control. A
1%solutionofn-undecanalinethanol was usedasasubstrate.
Luminescence was measured in a Turner Design Lumino-
meter for 15 s after a delay of 5 s and expressed in Relative
Light Units (RLU, 1 mRLU¼2 CFU). Mean values were
calculated from triplicate cultures.
4.7.6. 2-Phenylbenz[g]isoquinoline-3,5,10(2H)-trione 7g.
Flash chromatography on silica gel using ethyl acetate/
hexane (1:4) as eluent, followed by recrystallisation from
ethanol gave 7g (yield: 4%) as a yellow powder, mp
Acknowledgements
1
265.6–266.1 ꢀC. H NMR (270 MHz, CDCl3): d 7.43–7.46
The authors are indebted to the ‘Research Foundation—
Flanders (FWO-Vlaanderen)’ and the ‘Institute for the
Promotion of Innovation through Science and Technology
in Flanders (IWT-Vlaanderen)’ for financial support of this
research.
(m, 3H, H-4 and 2ꢂ]CH–phenyl), 7.49–7.61 (m, 3H,
3ꢂ]CH–phenyl), 7.81–7.91 (m, 2H, H-7 and H-8), 8.32–
8.36 (m, 2H, H-6 and H-9), 8.60 (s, 1H, H-1). 13C NMR
(68 MHz, CDCl3): d 113.0, 119.1, 126.2, 127.5, 127.8,

2510
J. Jacobs et al. / Tetrahedron 63 (2007) 2503–2510
Soc. Chim. Belg. 1992, 101, 337–338; (d) Bouammali, B.;
References and notes
Pautet, F.; Carneiro do Nascimento, S.; Boitard, M.; Fillion,
H. Arch. Pharm. 1993, 326, 547–550; (e) Ghosez, L.; Jnoff,
E.; Bayard, P.; Sainte, F.; Beaudegnies, R. Tetrahedron 1999,
55, 3387–3400.
1. Arai, T.; Yazawa, K.; Mikami, Y. J. Antibiot. 1976, 29, 398–407.
2. Arsenault, G. P. Tetrahedron Lett. 1965, 6, 4033–4037 and
references therein.
7. Kesteleyn, B.; De Kimpe, N. J. Org. Chem. 2000, 65,
635–639.
3. Parisot, D.; Devys, M.; Barbier, M. J. Antibiot. 1989, 42, 1189–
1190.
8. Aldersley, M. F.; Dean, F. M.; Nayyir-Mazhir, R.; Hamzah,
A. S. J. Chem. Soc., Perkin Trans. 1 1983, 1753–1757.
9. Aldersley, M. F.; Dean, F. M.; Hamzah, A. S. Tetrahedron Lett.
1986, 27, 255–258.
4. (a) Peterson, J. R.; Zjawiony, J. K.; Liu, S.; Hufford, C. D.;
Clark, A. M.; Rogers, R. D. J. Med. Chem. 1992, 35, 4069–
4077; (b) Waterman, P. G.; Muhammad, I. Phytochemistry
1985, 24, 523–527.
10. Aldersley, M. F.; Chishti, S. H.; Dean, F. M.; Douglas,
M. E.; Ennis, D. S. J. Chem. Soc., Perkin Trans. 1 1990,
2163–2174.
11. Walburger, A.; Koul, A.; Ferrari, G.; Nguyen, L.; Prescianotto-
Baschong, C.; Huygen, K.; Klebl, B.; Thompson, C.; Bacher,
G.; Pieters, J. Science 2004, 304, 1800–1804.
5. CarneirodoNascimento,S.;Bouammali,B.;Boitard,M.;Pautet,
F.; Soufiaoui, M.; Fillion, H. Pharmazie 1994, 49, 702–703.
6. (a) Sainte, F.; Serckx-Poncin, B.; Hesbain-Frisque, A.-M.;
Ghosez, L. J. Am. Chem. Soc. 1982, 104, 1428–1430;
(b) Bouammali, B.; Pautet, F.; Fillion, H. Heterocycles 1991,
32, 915–922; (c) Bouammali, B.; Pautet, F.; Fillion, H. Bull.