First straightforward synthesis of 2,4-disubstituted benz[g]isoquinoline-3,5,10(2H)-triones, 1,2,3,5-substituted naphtho[3,2,1-de]isoquinoline-4,7-diones, and 6-substituted benzo[h]pyrido[3,4,5-kl]-1,2,3,4-tetrahydroacridine-5,8-diones

Article abstract of DOI:10.1016/j.tet.2008.05.111

Structural modifications to the benz[g]isoquinoline skeleton of N-substituted benz[g]isoquinoline-3,5,10(2H)-triones were envisaged in order to make future SAR studies possible for this type of bioactive compounds. Several N-substituted benz[g]isoquinoline-3,5,10(2H)-triones were converted to novel 2,4-substituted benz[g]isoquinoline-3,5,10(2H)-triones, new tetracyclic 1,2,3,5-substituted naphtho[3,2,1-de]isoquinoline-4,7-diones, and 6-substituted benzo[h]pyrido[3,4,5-kl]-1,2,3,4-tetrahydroacridine-5,8-diones. All the synthesized target compounds represent new heterocyclic systems, which were previously undescribed in the literature.

Full text of DOI:10.1016/j.tet.2008.05.111

Tetrahedron 64 (2008) 7545–7554
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
First straightforward synthesis of 2,4-disubstituted benz[g]isoquinoline-
3,5,10(2H)-triones, 1,2,3,5-substituted naphtho[3,2,1-de]isoquinoline-4,7-diones,
and 6-substituted benzo[h]pyrido[3,4,5-kl]-1,2,3,4-tetrahydroacridine-5,8-diones
*
Jan Jacobs, Bart Kesteleyn, Norbert De Kimpe
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, B-9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Structural modifications to the benz[g]isoquinoline skeleton of N-substituted benz[g]isoquinoline-
3,5,10(2H)-triones were envisaged in order to make future SAR studies possible for this type of bioactive
compounds. Several N-substituted benz[g]isoquinoline-3,5,10(2H)-triones were converted to novel
2,4-substituted benz[g]isoquinoline-3,5,10(2H)-triones, new tetracyclic 1,2,3,5-substituted naphtho-
[3,2,1-de]isoquinoline-4,7-diones, and 6-substituted benzo[h]pyrido[3,4,5-kl]-1,2,3,4-tetrahydroacridine-
5,8-diones. All the synthesized target compounds represent new heterocyclic systems, which were
previously undescribed in the literature.
Received 13 February 2008
Received in revised form 21 May 2008
Accepted 23 May 2008
Available online 28 May 2008
Keywords:
Benz[g]isoquinoline-3,5,10(2H)-triones
2-Azaanthraquinones
Quinones
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
(MEL-28).6 Finally, benz[g]isoquinoline-3,5,10(2H)-triones 8 are
promising antitumor compounds as cytotoxic activity against mu-
Naphthoquinones with annelated N-heterocycles constitute an
important research area in organic synthesis due to the pro-
nounced biological activities of several natural products (Fig. 1). For
instance, the unsubstituted benz[g]isoquinoline-5,10-dione (1) has
been isolated from Psychotria camponutans and Mitracarpus scaber,
and is renowned for its strong activity against chloroquine-re-
sistant Plasmodium falciparum, which is responsible for malaria.1 In
addition, the 2-azaanthraquinone 1 exhibits growth inhibition
against the multi-drug resistant pathogen Staphylococcus aureus,
and its good activity against Trypanosoma congolense has also been
described.1c,2 The naturally occurring bostrycoidin (2) and ana-
logues 3–7 on the other hand have been isolated from different
fungi,3 and have been shown to possess interesting physiological
activities, amongst which is the antibiotic activity against Myco-
bacterium tuberculosis and Gram-positive bacteria.3a,4
The naturally occurring 1-azaanthraquinone cleistopholin 10,
isolated from Cleistopholis patens, and synthetic analogues 9 and 11
are very strong inhibitors of Mycobacterium intracellulare with
MIC’s equal to or less than that of rifamycin.5 Ascididemin, a natu-
rally occurring 1-azaanthraquinone related to cleistopholin 10, and
related alkaloids also showed good cytotoxic activity especially
against human cell lung carcinoma (A-549) and human melanoma
rine leukemia cells (L 1210) has been discovered.7 Therefore, these
compounds could be interesting target compounds in the search for
new bioactive compounds. As a consequence, structural modifica-
tions to the benz[g]isoquinoline-3,5,10(2H)-trione skeleton are also
of great importance for SAR studies. Keeping this in mind, the
synthesis of new different substituted benz[g]isoquinoline-
3,5,10(2H)-triones 12 is disclosed in the present article. In addition,
the synthesis of different substituted naphtho[3,2,1-de]isoquino-
line-4,7-diones 13 and benzo[h]pyrido[3,4,5-kl]-1,2,3,4-tetrahy-
droacridine-5,8-diones 14 will be discussed (Fig. 2).
2. Results and discussion
Since benz[g]isoquinoline-3,5,10(2H)-triones 158 posses a good
Michael acceptor at C-4, conjugate addition was evaluated in order
to modify their molecular skeleton in an easy and straightforward
way. After all, addition of the nucleophile followed by aromatiza-
tion by tautomerization and spontaneous oxidation by air should
yield 4-substituted benz[g]isoquinoline-3,5,10(2H)-triones.
Indeed, treatment of different benz[g]isoquinoline-3,5,10(2H)-
triones 15 with potassium cyanide in refluxing methanol resulted
in the isolation of the corresponding 4-cyano substituted
compounds 16 in 65–95% yield (Scheme 1). In the same way, 2-
alkyl-4-aminoalkylbenz[g]isoquinoline-3,5,10(2H)-triones 17 were
synthesized in 26–95% yield after reaction of the appropriate sub-
strate 15 with different amines in ethanol (Table 1). The position of
* Corresponding author. Tel.: þ32 9 264 59 51; fax: þ32 9 264 62 43.
E-mail address: norbert.dekimpe@ugent.be (N. De Kimpe).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.111

7546
J. Jacobs et al. / Tetrahedron 64 (2008) 7545–7554
R1
O
R1
O
O
O
R2
R3
N
N
N
R2
R3
O
O
1
2 R1 = R3 = OH, R2 = OMe
(Bostrycoidin)
5 R1 = OH, R2 = Me, R3 = OMe
(6-Deoxy-8-methylbostrycoidin)
6 R1 = OH, R2 = H, R3 = OMe
(6-Deoxybostrycoidin)
(Benz[g]isoquinoline-5,10-dione)
3 R1 = R2 = OMe, R3 = OH
(9-O-Methylbostrycoidin)
4 R1 = R2 = R3 = OH
(Tolypocladin)
7 R1 = R3 = OMe, R2 = H
(Scorpinone)
R3
R4
O
O
R1
R2
O
O
R
N
NH
N
O
O
O
9
8
10 R = Me (Cleistopholin)
11 R = Et
R1, R2 = H, Alkyl
R3, R4 = H, OH, OMe, OAc
Figure 1.
the isopropylamino group of compound 17a at C-4 is in accordance
with the spectral data since the chemical shift of proton H-1 moved
upfield from 8.60 ppm to 7.88 ppm due to the mesomeric electron-
donating effect of the alkylamino group at C-4, while the singlet of
proton H-4 in 2-isopropylbenz[g]isoquinoline-3,5,10(2H)-trione
(15a) had disappeared. Furthermore, irradiation of the proton H-1
of compound 17a caused a Nuclear Overhauser Effect (NOE) of 7%
on the protons of the isopropyl group at C-2, while irradiation of the
NH-proton gave only a NOE of 5% on the protons of the iso-
propylamino moiety at C-4.
O
O
O
R
O
R
1.05 equiv. KCN
N
N
MeOH, Δ, 3 h
O
CN
O
15
16a: R = i-Pr (65%)
16b: R = n-Bu (93%)
16c: R = i-Bu (95%)
Scheme 1.
However, for performing these reactions the use of absolute
ethanol is very important, as the presence of 2-butanone, used in
order to denaturate ethanol, gives rise to the formation of com-
pounds 18. The formation of these new tetracyclic compounds 18
can be explained from the reaction of enamine 20, which is formed
in situ after condensation of 2-butanone and a primary amine, by
Michael addition at C-4 to the intermediate 21, followed by intra-
molecular condensation with the C-5 carbonyl group, elimination
of water, aromatization, and spontaneous oxidation (Scheme 3).
Once the formation of these new compounds 18 had been noticed,
several attempts were made to optimize their synthesis. First,
a higher yield was obtained by adding an excess of 2-butanone and
then the effect of the reaction temperature was investigated.
However, refluxing the reaction mixture in ethanol or DMF for 1
day resulted in the isolation of a complex mixture of degradation
products along with unreacted starting material. Therefore, a set of
5-alkyl-2-aminoalkyl-3-methylnaphtho[3,2,1-de]isoquinoline-4,7-
diones 18 and 19 was prepared in isolated yields from 25% to 35% by
reaction of N-substituted benz[g]isoquinoline-3,5,10(2H)-triones
15 with an excess of different primary amines and 2-butanone in
ethanol at room temperature over a period of 3 days (Table 2,
Scheme 2). Only traces of the conjugate adducts 17 were isolated
under these reaction conditions, except for the synthesis of 5-iso-
propyl-2-isopropylamino-3-methyl-4H-dibenz[de,g]isoquinoline-
4,7(5H)-dione (18a), which was accompanied with compound 17a,
isolated in a yield of 10%. By observations from NOE experiments of
compound 18a, the structure of compounds 18 was finally con-
firmed (Fig. 3). Indeed, irradiation of the proton H-1 of compound
18a caused a NOE on the protons of the isopropyl group at C-2 and
on the protons at C-11. Furthermore, irradiation of the protons of
the C-3 methyl group gave only a NOE on the 2-aminoalkyl group,
while irradiation of the NCH-proton of the 5-aminoalkylgroup gave
only a NOE on the proton at C-6.
The extension of 2-butanone to other ketones as co-reagent
leads to the synthesis of new tetracyclic derivatives. For instance,
reaction
of
2-isopropylbenz[g]isoquinoline-3,5,10(2H)-trione
(15a) with acetone and isopropylamine resulted in the isolation
of both the conjugate adduct (17a) and 5-isopropyl-2-iso-
propylaminonaphtho[3,2,1-de]isoquinoline-4,7-dione (18d) in 21%
O
O
O
O
R1
O
R1
O
R1
O
R1
O
N
N
N
N
O
R2
N
O
R2
R4
R2
R3
14
R1, R2, R3 = alkyl
12
15
HN
R3
R
1 = alkyl
13
R1, R3 = alkyl
R2 = H, alkyl, COOR
4 = H, alkyl
R2 = CN, NHR
R
Figure 2.

J. Jacobs et al. / Tetrahedron 64 (2008) 7545–7554
7547
Table 1
Reaction of N-substituted benz[g]isoquinoline-3,5,10(2H)-triones 15 with different primary amines
O
O
O
10 equiv. R2NH2
R1
R1
O
(2.2 equiv. in case of benzylamine)
N
N
EtOH (abs.), rt, 3 d
O
HN
O
R2
15
17
Compound
R2NH2
R1
R2
Yield (%)
17a
17b
17c
17d
17e
i-PrNH2
n-PrNH2
NH3
Allylamine
Benzylamine
i-Pr
n-Pr
i-Pr
i-Pr
i-Pr
i-Pr
n-Pr
H
Allyl
Bz
44
31
95
26
56
and 28% yield, respectively (Scheme 4). The same tendency could
be noted upon the use of 2- and 3-pentanone, which resulted in the
isolation of the target compounds 18e and 18f together with 1,4-
adduct 17a in 36% and 12% (for 2-pentanone) and 16% and 38% yield
(for 3-pentanone), respectively (Scheme 4).
Table 2
Reaction of N-substituted benz[g]isoquinoline-3,5,10(2H)-triones 15 with different
primary amines in the presence of 2-butanone
O
O
10 equiv. R2NH2
R1
O
R1
O
6 equiv. 2-butanone
N
N
Upon treatment of 2-isopropylbenz[g]isoquinoline-3,5,10(2H)-
trione 15a with an excess of isopropylamine and cyclohexanone
a new reaction occurred and as a result 6-isopropylbenzo[h]-
pyrido[3,4,5-kl]-1,2,3,4-tetrahydroacridine-5,8-dione (25) was iso-
lated in 2% yield after purification by column chromatography
(Scheme 5). However, product 25 was only the minor compound of
the reaction mixture as the conjugate adduct (17a) was isolated in
64% yield. The mechanism for the formation of compound 25 can be
explained by the formation of intermediate 22 (Scheme 3). If the
intramolecular ring closure would occur via the carbon atom of
enamine 22 across the ketone at position 5, subsequent aromati-
zation would be prevented. Therefore, intramolecular ring closure
takes place directly via the nitrogen of enamine 22 across the ke-
tone at position 5. Subsequent elimination of water and deal-
kylation of the nitrogen will give rise to the formation of the
pentacyclic compound (25).
In a following step, the reaction conditions were optimized
for the synthesis of target compound 25 (Table 3). In order to avoid
the formation of the disturbing side-product 17a, N-iso-
propylcyclohexylideneamine (26) was added directly to substrate
15a in the presence of a weak, non-nucleophilic base, i.e., potas-
sium carbonate. Performing this reaction at room temperature in
ethanol as a solvent for 3 days resulted in the isolation of the target
compound 25 in 9% yield. However, since this reaction is suitable
EtOH, rt, 3 d
O
15
HN
R2
18
Compound
R2NH2
R1
R2
Yield (%)
18aa
18b
18c
i-PrNH2
n-PrNH2
n-PrNH2
i-Pr
n-Pr
i-Pr
i-Pr
n-Pr
n-Pr
35
25
26
a
During this reaction compound 17a was also isolated in 10% yield.
10 equiv.
N
H
O
O
6 equiv. 2-butanone
N
O
N
EtOH, rt, 3 d
O
O
15a
N
19 (30%)
Scheme 2.
O
O
O
R1
R1
O
R1
R2NH2
N
N
N
O
O
OH
21
O
O
O
15
N
:
HN
R2
R2
NH
R2
20
22
O
O
O
R1
O
R1
O
R1
O
N
N
-H2O
N
O2 (air)
HO
HN
R2
18
HN
HN
R2
R2
23
24
Scheme 3.

7548
J. Jacobs et al. / Tetrahedron 64 (2008) 7545–7554
7%
N
8%
10 equiv. K2CO3
6 equiv.
O
i-Pr
N
( )n
O
O
N
27a: n = 1
O
27b: n = 3
N
N
7%
6%
X
5% 7%
NH
5%
O
O
EtOH, 3 d, rt
or
EtOH, 128 °C, 3 h
(microwave)
O
( )n
15a
28a: n = 1
28b: n = 3
Figure 3. DifNOE analysis of 5-isopropyl-2-isopropylamino-3-methylnaphtho[3,2,1-
de]isoquinoline-4,7-dione (18a).
Scheme 6.
for a microwave mediated synthesis, which proved to be a valuable
method for the synthesis of naphtho[3,2,1-de]isoquinoline-4,7-
diones 30 (vide infra), the reaction was performed in ethanol as
a solvent in the microwave at 128 ꢀC for 3 h and eventually com-
pound 25 could be isolated in 16% yield.
However, extension of this reaction to higher and lower ring
homologues of compound 25 by treatment of benz[g]isoquinoline-
3,5,10(2H)-trione 15a with N-isopropylcyclopentylideneamine (27)
and N-isopropylcycloheptylideneamine (27b) in the presence of
a base failed completely as complex reaction mixtures were re-
trieved (Scheme 6).
In the final part of this research, the synthesis of functionalized
naphtho[3,2,1-de]isoquinoline-4,7-diones 30 was achieved by re-
action of N-substituted benz[g]isoquinoline-3,5,10(2H)-triones 15
with different enaminoesters 29, which could be easily prepared
from the corresponding b-ketoesters and primary amines under
Dean–Stark conditions.9 First, the reaction conditions were opti-
mized for the synthesis of compound 30d (Table 4). As no reaction
occurred in ethanol at room temperature, the reaction mixture was
subsequently heated under reflux. However, upon use of these
O
O
O
10 equiv. i-PrNH2
N
N
N
procedure A:
EtOH / acetone (1 : 1)
rt, 3 d
O
O
O
O
O
HN
R2
18d-f
R1
procedure B:
6 equiv. ketone
EtOH, rt, 3 d
15a
NH
17a
procedure A: 17a (21%), 18d: R1,R2 = H (28%)
procedure B: ketone = 2-pentanone
17a (12%), 18e: R1 = Et, R2 = H (36%)
procedure B: ketone = 3-pentanone
17a (38%), 18f: R1,R2 = Me (16%)
Scheme 4.
O
O
O
O
6 equiv. cyclohexanone
10 equiv. i-PrNH2
N
N
N
EtOH, 3 d, rt
O
O
O
O
HN
N
15a
17a (64%)
25 (2%)
Scheme 5.
Table 3
Optimization of reaction conditions for the synthesis of 6-isopropylbenzo[h]pyrido[3,4,5-kl]-1,2,3,4-tetrahydroacridine-5,8-dione (25)
6 equiv.
N
26
O
O
O
N
10 equiv. base
N
N
N
O
O
O
O
O
HN
15a
17a
25
Entry
Base
Solvent
Reaction conditions
Result (%)
17a
25
1
2
3
K2CO3
K2CO3
K2CO3
EtOH
DMF
EtOH
rt, 3 days
rt, 3 days
128 ꢀC, 3 h (microwave)
d
9
Complex mixture
d
16

J. Jacobs et al. / Tetrahedron 64 (2008) 7545–7554
7549
reaction in ethanol is twice as much as when the reaction is per-
formed in DMF.10 It has to be noted that in the case of DMF, the
substrate was not fully converted to the target compound 30d.
However, prolongation of the reaction time under microwave
conditions only resulted in the formation of more unidentifiable
degradation products. Since the best results were obtained upon
the use of ethanol as a solvent in the microwave at 128 ꢀC for 3 h,
these reaction conditions were used to synthesize a whole set of
different naphtho[3,2,1-de]isoquinoline-4,7-diones 30 in 33–42%
yield (Table 5). However, the presence of alkyl substituents at the
nitrogen of enaminoesters 29 was required for a successful
reaction.
O
O
R1
O
R1
O
N
6 equiv. enaminoester
R2
N
NH
O
O
R4
R4
COOR3
OR3
NH
R2
15
29
30
Table 4
Optimization of reaction conditions for the synthesis of 3-ethoxycarbonyl-5-iso-
propyl-2-isopropylaminonaphtho[3,2,1-de]isoquinoline-4,7-dione (30d)
Entry
R1
R2
R3
R4
Reaction conditions
Yield (%)
In conclusion, it has been proven that benz[g]isoquinoline-
3,5,10(2H)-triones are useful substrates for the synthesis of
2,4-substituted benz[g]isoquinoline-3,5,10(2H)-triones, 1,2,3,5-
1
2
3
4
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Et
Et
Et
Et
H
H
H
H
EtOH,
DMF,
D
D
, 3 days
, 2 days
22
7
38
9
EtOH, 128 ꢀC, 3 h (MW)
DMF, 203 ꢀC, 1 h (MW)
substituted
naphtho[3,2,1-de]isoquinoline-4,7-diones,
and
6-substituted benzo[h]pyrido[3,4,5-kl]-1,2,3,4-tetrahydroacridine-
5,8-diones in a one-step reaction.
MW¼microwave.
Table 5
Synthesis of substituted naphtho[3,2,1-de]isoquinoline-4,7-diones 30
3. Experimental section
Compound
Enaminoester
NH2
R1
R2
R3
R4
Yield (%)
3.1. General experimental methods
O
30a
i-Pr
H
Me
H
No reaction
34
Spectroscopic data were recorded as follows: 1H NMR spectra
were recorded at 300 or 270 MHz and 13C NMR spectra were
recorded at 75 or 68 MHz. Peak assignments were performed 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). Elemental analyses were executed with
a PerkinElmer Series II CHNS/O Analyzer 2400. 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 (Merck, silica gel 60F254). Pre-
OMe
NH
O
30b
30c
30d
i-Pr
i-Pr
i-Pr
Et
Et
Et
Et
H
H
H
OEt
NH
O
n-Pr
i-Pr
42
38
OEt
NH
O
OEt
NH
O
parative TLC was performed using silica gel plates (silica gel 60F254
,
30e
30f
n-Bu
n-Bu
n-Pr
Me
Me
H
34
33
OMe
thickness 2.0 mm). Microwave reactions were performed in a CEM
DiscoverÒ microwave.
NH
O
Et
Me
OMe
3.2. Synthesis of 2-substituted 4-cyanobenz[g]isoquinoline-
3,5,10(2H)-triones 16
conditions, the reaction took 3 days in order to complete, and as
a result a substantial amount of non-identifiable degradation
products was formed in the course of the reaction. Therefore,
several attempts were made in order to shorten the reaction time.
First, N,N-dimethylformamide (DMF) was used as a solvent instead
of ethanol, which allowed a higher reaction temperature. Although
the reaction time was decreased to 2 days, the formation of deg-
radation products became even more problematic. Since the in-
vestigated reaction concerns the use of polar compounds and
a polar solvent, it was performed using a microwave in a final at-
tempt. Indeed, the more polar a reaction mixture is, the greater is
its ability to couple with the microwave energy, which leads to
a rapid rise in temperature and faster reaction rates in comparison
with conventional methods.10 Two polar solvents, ethanol and
DMF, were used in these microwave reactions and gave rise to the
formation of the target compound 30d in 38% and 9% yield, re-
spectively (Table 4). The remarkable difference in results between
the use of these two polar solvents can be understood as follows.
First, the coupling efficiency of ethanol with the microwave energy
is higher than the coupling efficiency of DMF, which means that
DMF will require more time and energy to reach the desired tem-
perature.10,11 Moreover, as the target temperature was set to 50 ꢀC,
above the boiling point of the solvent, pressure will built up in the
reaction vessel, which is advantageous for the reaction rate. How-
ever, the pressure, which is generated while performing the
General procedure: potassium cyanide (1.49 mmol, 100 mg) was
added to
a solution of 1.42 mmol of benz[g]isoquinoline-
3,5,10(2H)-trione 15 in methanol (16 ml). The reaction mixture was
boiled under reflux for 3 h, after which it was cooled to room
temperature and poured in an aqueous solution of saturated so-
dium hydrogen carbonate. The aqueous phase was extracted with
small portions of ethyl acetate (three times) and the combined
organic extracts were dried (MgSO4). Solvent evaporation in vacuo
furnished crude 2-substituted 4-cyanobenz[g]isoquinoline-
3,5,10(2H)-triones 16.
3.2.1. 4-Cyano-2-isopropylbenz[g]isoquinoline-3,5,10(2H)-
trione (16a)
Flash chromatography on silica gel with ethyl acetate/hexane
(1:4) as eluent followed by recrystallization from methanol gave
16a as yellow crystals (yield 65%), mp 265.6–266.0 ꢀC. 1H NMR
(300 MHz, CDCl3):
J¼6.9 Hz, NCH), 7.85–7.94 (2H, m, H-7 and H-8), 8.31–8.38 (2H, m,
H-6 and H-9), 8.80 (1H, s, H-1). 13C NMR (75 MHz, CDCl3):
22.0
d
1.54 (6H, d, J¼6.9 Hz, 2ꢁCH3), 5.32 (1H, septet,
d
(2ꢁCH3), 50.7 (NCH), 101.4 (CN), 112.9 (]Cquat), 114.0 (]Cquat),
127.6 and 128.5 (C-6 and C-9), 133.2 (]Cquat), 133.6 (]Cquat), 135.1
and 135.7 (C-7 and C-8),142.4 (C-1),143.2 (]Cquat),160.0 (N–C]O),
178.5 (C]O), 179.5 (C]O). IR (KBr): nmax 2218, 1692, 1670, 1652,
1587, 1575, 1531 cmꢂ1. MS (ES) m/z (%): 310 (MþNHþ4 , 100), 293

7550
J. Jacobs et al. / Tetrahedron 64 (2008) 7545–7554
(MþHþ, 95). Anal. Calcd for C17H12N2O3: C 69.86, H 4.14, N 9.58;
J¼7.6 Hz, CH3), 1.06 (3H, t, J¼7.3 Hz, CH3), 1.75 (2H, sextet, J¼7.3 Hz,
CH2CH2CH3), 1.83 (2H, sextet, J¼7.6 Hz, CH2CH2CH3), 3.93 (2H, t,
J¼7.6 Hz, NCH2), 4.09 (2H, q, J¼6.6 Hz, NHCH2), 7.67–7.80 (2H, m, H-
7 and H-8), 7.75 (1H, s, H-1), 8.25–8.33 (2H, m, H-6 and H-9), 11.23
found: C 70.01, H 4.29, N 9.46.
3.2.2. 2-n-Butyl-4-cyanobenz[g]isoquinoline-3,5,10(2H)-
trione (16b)
(1H, br s, NH). 13C NMR (68 MHz, CDCl3):
d 11.2 (CH3), 11.5 (CH3),
Recrystallization from diethyl ether gave 16b as orange crystals
22.2 (CH2CH2CH3), 24.6 (CH2CH2CH3), 47.5 (NHCH2), 52.3 (NCH2),
108.3 (]Cquat), 113.4 (]Cquat), 126.7 (C-6 and C-9), 128.3 (C-1),
132.8 and 133.8 (C-7 and C-8), 133.7 (]Cquat), 135.9 (]Cquat), 144.4
(C-4), 158.9 (N–C]O), 181.1 (C]O), 182.5 (C]O). IR (KBr): nmax
3060, 1635, 1570, 1330, 1275 cmꢂ1. MS (70 eV) m/z (%): 324 (Mþ,
52), 295 (100), 253 (31). Anal. Calcd for C19H20N2O3: C 70.35, H 6.21,
N 8.64; found: C 70.12, H 6.24, N 8.47.
(yield 93%), mp 196.7–197.1 ꢀC. 1H NMR (300 MHz, CDCl3):
d 1.00
(3H, t, J¼7.5 Hz, CH3), 1.44 (2H, sextet, J¼7.5 Hz, CH2CH3), 1.80–1.90
(2H, m, NCH2CH2), 4.18 (2H, t, J¼7.6 Hz, NCH2), 7.86–7.93 (2H, m, H-7
and H-8), 8.31–8.38 (2H, m, H-6 and H-9), 8.73 (1H, s, H-1). 13C NMR
(75 MHz, CDCl3):
d 13.6 (CH3), 19.9 (CH2CH3), 31.0 (NCH2CH2), 52.3
(NCH2), 101.6 (CN), 112.5 (]Cquat), 113.9 (]Cquat), 127.5 and 128.5
(C-6 and C-9), 133.1 (]Cquat), 133.5 (]Cquat), 135.1 and 135.7 (C-7
and C-8), 143.9 (]Cquat), 146.0 (C-1), 160.1 (N–C]O), 178.5 (C]O),
3.3.3. 4-Amino-2-isopropylaminobenz[g]isoquinoline-3,5,10(2H)-
trione (17c)
Flash chromatography on silica gel with ethyl acetate/hexane
(3:7) as eluent followed by recrystallization from methanol gave
17c as red crystals (yield 95%), mp 197.4–198.3 ꢀC. 1H NMR
179.5 (C]O). IR (KBr): nmax 2220,1686,1663,1655,1586,1527 cmꢂ1
.
MS (ES) m/z (%): 324 (MþNHþ4 ,100), 307 (MþHþ, 70). Anal. Calcd for
C
18H14N2O3: C 70.58, H 4.61, N 9.15; found: C 70.28, H 4.81, N 8.96.
3.2.3. 4-Cyano-2-isobutylbenz[g]isoquinoline-3,5,10(2H)-
trione (16c)
(300 MHz, CDCl3):
d
1.47 (6H, d, J¼6.9 Hz, 2ꢁCH3), 5.29 (1H,
septet, J¼6.9 Hz, NCH), 6.52 (1H, br s, NH2), 7.73–7.82 (2H, m, H-7
Recrystallization from diethyl ether afforded 16c as yellow
and H-8), 7.91 (1H, s, H-1), 8.30–8.33 (2H, m, H-6 and H-9), 9.24
crystals (yield 95%), mp 227.4–227.6 ꢀC. 1H NMR (300 MHz, CDCl3):
(1H, br s, NH2). 13C NMR (75 MHz, CDCl3):
d
21.8 (2ꢁCH3), 48.8
d
1.02 (6H, d, J¼6.9 Hz, 2ꢁCH3), 2.28 (1H, septet, J¼6.9 Hz, CH(CH3)2),
(NCH), 107.4 (]Cquat), 113.8 (]Cquat), 123.2 (C-1), 126.9 and 127.2
(C-6 and C-9), 133.5 and 134.0 (C-7 and C-8), 134.3 (]Cquat), 135.4
(]Cquat), 141.8 (]Cquat), 158.5 (N–C]O), 181.1 (C]O), 184.0
(C]O). IR (KBr): nmax 3383, 3270, 1668, 1636, 1582, 1561, 1295,
1278, 1262 cmꢂ1. MS (ES) m/z (%): 283 (MþHþ, 100), 228 (20).
Anal. Calcd for C16H14N2O3: C 68.07, H 5.00, N 9.92; found: C
67.94, H 5.09, N 10.01.
3.99 (2H, d, J¼6.9 Hz, NCH2), 7.86–7.93 (2H, m, H-7 and H-8), 8.31–
8.38 (2H, m, H-6 and H-9), 8.67 (1H, s, H-1). 13C NMR (75 MHz,
CDCl3):
d
19.82 (2ꢁCH3), 27.98 (CH(CH3)2), 59.30 (NCH2), 101.64
(CN),112.21 (]Cquat),113.91 (]Cquat),127.50 and 128.46 (C-6 and C-
9),133.12 (]Cquat),133.50 (]Cquat),135.09 and 135.70 (C-7 and C-8),
143.88 (]Cquat),146.32(C-1),160.19 (N–C]O),178.46(C]O),179.50
(C]O). IR (KBr): nmax 2229, 1691, 1674, 1643, 1588, 1537 cmꢂ1. MS
(ES) m/z (%): 324 (MþNHþ4 , 100), 307 (MþHþ, 80). Anal. Calcd for
3.3.4. 4-Allylamino-2-isopropylaminobenz[g]isoquinoline-
3,5,10(2H)-trione (17d)
C
18H14N2O3: C 70.58, H 4.61, N 9.15; found: C 70.73, H 4.94, N 9.30.
Flash chromatography on silica gel with ethyl acetate/hexane
(1:9) as eluent gave 17d as red crystals (yield 26%), mp 151.7–
152.4 ꢀC. This product was found to degrade rapidly as the crystals
turned black over a period of 4 h at room temperature. 1H NMR
3.3. Synthesis of 2-alkyl-4-aminoalkylbenz[g]isoquinoline-
3,5,10(2H)-triones 17
General procedure: 18.7 mmol of a primary amine (4.11 mmol in
the case of benzylamine) was added to a solution of 1.87 mmol of
a N-substituted benz[g]isoquinoline-3,5,10(2H)-trione 15 in abso-
lute ethanol (20 ml). The reaction mixture was stirred for 3 days in
a stoppered flask at room temperature. After solvent evaporation in
vacuo, the residue was purified by column chromatography on
silica gel.
(300 MHz, CDCl3):
d
1.44 (3H, d, J¼6.9 Hz, 2ꢁCH3), 4.77 (2H, m,
NCH2), 5.16–5.25 (2H, m, CH(CH3)2 and ]CHaHb), 5.34 (1H, ddt,
J¼1.4, 3.0, 17.3 Hz, ]CHaHb), 6.07 (1H, ddt, J¼5.2, 10.3, 17.3 Hz,
]CH), 7.73 (1H, td, J¼1.8, 7.6 Hz, H-7 or H-8), 7.78 (1H, td, J¼1.8,
7.6 Hz, H-7 or H-8), 7.90 (1H, s, H-1), 8.29 (1H, dd, J¼1.8, 7.6 Hz, H-
6 or H-9), 8.33 (1H, dd, J¼1.8, 7.6 Hz, H-6 or H-9). 13C NMR
(75 MHz, CDCl3):
d
21.6 (2ꢁCH3), 47.8 (NCH2), 47.9 (NCH), 108.5
(]Cquat), 113.7 (]Cquat), 116.2 (]CH2), 124.2 (C-1), 126.7 (C-6 and
C-9), 133.0 (C-7 or C-8), 133.8 (C-7 or C-8), 135.4 (]Cquat), 135.8
(]Cquat), 143.6 (]Cquat), 158.7 (N–C]O), 180.9 (C]O), 182.8
(C]O). IR (KBr): nmax 3078, 1667, 1634, 1612 cmꢂ1. MS (ES) m/z (%):
323 (MþHþ, 100).
3.3.1. 2-Isopropyl-4-isopropylaminobenz[g]isoquinoline-
3,5,10(2H)-trione (17a)
Flash chromatography on silica gel with ethyl acetate/hexane
(1:4) as eluent gave 17a (yield 44%) as red crystals. An analytical
sample was purified by recrystallization from methanol and affor-
ded 17a as fine red needles, mp 190 ꢀC. 1H NMR (270 MHz, CDCl3):
3.3.5. 4-Benzylamino-2-isopropylaminobenz[g]isoquinoline-
3,5,10(2H)-trione (17e)
Flash chromatography on silica gel with ethyl acetate/hexane
(1:9) as eluent followed by recrystallization from methanol gave
17e as red needles (yield 56%), mp 185.3–185.7 ꢀC. 1H NMR
d
1.37 (6H, d, J¼6.3 Hz, 2ꢁCH3), 1.44 (6H, d, J¼6.9 Hz, 2ꢁCH3), 5.22
(1H, septet, J¼6.9 Hz, NCH), 5.27 (1H, septet, J¼6.3 Hz, NCH), 7.68–
7.77 (2H, m, H-7 and H-8), 7.88 (1H, s, H-1), 8.26–8.33 (2H, m, H-6
and H-9), 11.22 (1H, br s, NH). 13C NMR (68 MHz, CDCl3):
d 21.6
(2ꢁCH3), 25.0 (2ꢁCH3), 46.7 (NCH), 47.9 (NCH), 107.9 (]Cquat), 113.8
(]Cquat), 123.9 (C-1), 126.6 and 126.7 (C-6 and C-9), 132.8 and 133.8
(C-7 and C-8), 134.0 (2ꢁ]Cquat), 143.5 (C-4), 158.3 (N–C]O), 181.1
(C]O), 182.5 (C]O). IR (KBr): nmax 1630, 1560, 1325, 1290,
1250 cmꢂ1. MS (70 eV) m/z (%): 324 (Mþ, 76), 309 (51), 281 (100),
167 (42). Anal. Calcd for C19H20N2O3: C 70.35, H 6.21, N 8.64; found:
C 70.13, H 6.34, N 8.59.
(300 MHz, CDCl3):
d
1.44 (6H, d, J¼6.9 Hz, 2ꢁCH3), 5.21 (1H, septet,
J¼6.9 Hz, NCH), 5.36 (2H, d, J¼5.8 Hz, NCH2), 7.29–7.43 (5H, m,
5CHar), 7.69–7.78 (2H, m, H-7 and H-8), 7.90 (1H, s, H-1), 8.27–8.30
(H-6 and H-9), 11.38 (1H, br s, NH). 13C NMR (75 MHz, CDCl3):
d 21.6
(2ꢁCH3), 47.9 (NCH2), 49.4 (NCH), 108.7 (]Cquat), 113.7 (]Cquat),
124.4 (C-1), 126.7 and 126.8 (C-6 and C-9), 127.5 (CHar), 127.6
(2CHar),128.8 (2CHar),133.0 and 133.8 (C-7 and C-8),133.7 (]Cquat),
135.8 (]Cquat), 139.3 (]Cquat), 143.5 (]Cquat), 158.8 (N–C]O),
180.9 (C]O), 182.9 (C]O). IR (KBr): nmax 3401, 1666, 1636, 1614,
1595, 1567, 1558, 1333, 1292, 1279 cmꢂ1. MS (ES) m/z (%): 373
(MþHþ, 100). Anal. Calcd for C23H20N2O3: C 74.18, H 5.41, N 7.52;
found: C 74.30, H 5.33, N 7.67.
3.3.2. 2-n-Propyl-4-n-propylaminobenz[g]isoquinoline-3,5,10(2H)-
trione (17b)
Recrystallization from methanol gave 17b (yield 31%) as fine red
needles, mp 142–144 ꢀC. 1H NMR (270 MHz, CDCl3):
d 1.00 (3H, t,

J. Jacobs et al. / Tetrahedron 64 (2008) 7545–7554
7551
3.4. Synthesis of 5-alkyl-2-alkylamino-3-methyl-
naphtho[3,2,1-de]isoquinoline-4,7-diones 18 and 19
(NCH2), 47.3 (NCH), 110.5 (C-1), 111.1 (C-3), 122.7 (C-11), 123.0
(]Cquat), 123.7 (]Cquat), 125.2 (]Cquat), 127.7 (C-8 and C-9), 130.7
(]Cquat), 133.0 (C-10), 133.1 (C-6), 136.4 (]Cquat), 146.1 (2ꢁ]Cquat),
162.9 (N–C]O), 181.9 (C]O). IR (KBr): nmax 1660, 1630, 1580, 1330,
1310, 1255 cmꢂ1. MS (70 eV) m/z (%): 360 (Mþ, 100), 331 (41), 289
(91). Anal. Calcd for C23H24N2O2: C 76.64, H 6.71, N 7.77; found: C
76.49, H 6.97, N 7.40.
General procedure: to a solution of a N-substituted benz[g]iso-
quinoline-3,5,10(2H)-trione 15 (1.8 mmol) in absolute ethanol
(20 ml) and 2-butanone (1 ml) was added a primary or secondary
amine (18 mmol; isopropylamine, n-propylamine, pyrrolidine), and
the reaction mixture was stirred at room temperature for 3 days.
The solvent was evaporated in vacuo and the residue was chro-
matographed on silica gel using ethyl acetate/hexane (1:4) as
eluent. First, 2-alkyl-4-alkylaminobenz[g]isoquinoline-3,5,10(2H)-
triones (17) eluted from the column as a red coloured band, but
they were only isolated in the case of 2-isopropyl-4-iso-
propylaminobenz[g]isoquinoline-3,5,10(2H)-trione (17a) in a yield
of 10%. For physical and spectral data of compound 17a, vide supra.
5-Alkyl-2-aminoalkyl-3-methylnaphtho[3,2,1-de]isoquinoline-4,7-
diones 18 and 19 eluted as a yellow colored band and they were
isolated in yield of 25–35%.
3.4.4. 5-Isopropyl-3-methyl-2-pyrrolidinylnaphtho-
[3,2,1-de]isoquinoline-4,7-dione (19)
Recrystallization from methanol gave 19 as orange needles, mp
174.3–174.5 ꢀC. 1H NMR (300 MHz, CDCl3):
d
1.50 (6H, d, J¼6.9 Hz,
2ꢁCH3), 2.01–2.06 (4H, m, 2ꢁCH2), 2.87 (3H, s, CH3), 3.28–3.32 (4H,
m, 2ꢁNCH2), 5.41 (1H, septet, J¼6.9 Hz, NCH), 7.51 (1H, td, J¼1.4,
7.8 Hz, H-9), 7.72 (1H, td, J¼1.4, 7.8 Hz, H-10), 8.20 (1H, s, H-1), 8.24
(1H, dd, J¼1.4, 7.8 Hz, H-8), 8.47 (1H, dd, J¼1.4, 7.8 Hz, H-11), 8.63
(1H, s, H-6). 13C NMR (75 MHz, CDCl3):
d
19.2 (CH3), 22.1 (2ꢁCH3),
24.9 (2ꢁCH2), 47.3 (NCH), 51.6 (2ꢁNCH2), 110.9 (]Cquat), 116.9 (C-
1), 122.7 (C-11), 123.0 (]Cquat), 124.2 (]Cquat), 126.2 (]Cquat), 127.7
and 127.8 (C-9 and C-10), 130.7 (]Cquat), 133.2 (C-8), 134.7 (C-6 and
]Cquat), 136.4 (]Cquat), 149.6 (]Cquat), 162.8 (N–C]O), 181.9
(C]O). IR (KBr): nmax 1668, 1638, 1607, 1576, 1369, 1297, 1267, 1189,
1150 cmꢂ1. MS (ES) m/z (%): 373 (MþHþ, 100), 371 (8), 290 (10), 288
(42). Anal. Calcd for C24H24N2O2: C 77.39, H 6.49, N 7.52; found: C
77.54, H 6.31, N 7.70.
3.4.1. 5-Isopropyl-2-isopropylamino-3-methylnaphtho-
[3,2,1-de]isoquinoline-4,7-dione (18a)
Recrystallization from methanol gave 18a as yellow crystals, mp
178 ꢀC. 1H NMR (270 MHz, CDCl3):
d
1.37 (6H, d, J¼6.3 Hz, 2ꢁCH3),
1.49 (6H, d, J¼6.9 Hz, 2ꢁCH3), 3.85 (1H, br s, NH), 2.84 (3H, s, CH3),
3.95 (1H, septet, J¼6.3 Hz, NCH), 5.40 (1H, septet, J¼6.9 Hz, NCH),
7.51 (1H, t, J¼7.9 Hz, H-9), 7.71 (1H, t, J¼7.9 Hz, H-10), 7.87 (1H, s, H-
1), 8.21 (1H, d, J¼7.9 Hz, H-11), 8.45 (1H, d, J¼7.9 Hz, H-8), 8.53 (1H,
3.5. Reaction of 2-isopropylbenz[g]isoquinoline-3,5,10(2H)-
trione (15a) with acetone and isopropylamine (procedure A)
and with 2-pentanone or 3-pentanone and isopropylamine
(procedure B)
s, H-6). 13C NMR (68 MHz, CDCl3):
d
14.3 (CH3), 22.1 (2ꢁCH3), 23.2
(2ꢁCH3), 44.8 (NCH), 47.3 (NCH), 111.1 (C-3), 111.6 (C-1), 122.6 (C-
11), 123.0 (2]Cquat), 123.7 (]Cquat), 125.5 (]Cquat), 127.7 (C-8 and
C-9), 130.7 (]Cquat), 133.2 (C-6 and C-10), 136.4 (]Cquat), 145.3
(]Cquat), 162.9 (N–C]O), 181.9 (C]O). IR (KBr): nmax 3430, 1665,
1630, 1605, 1585, 1290, 1265 cmꢂ1. MS (70 eV) m/z (%): 360 (Mþ,
100), 345 (57), 317 (18), 303 (67), 287 (16), 275 (22). Anal. Calcd for
Procedure A. To a solution of 2-isopropylbenz[g]isoquinoline-
3,5,10(2H)-trione (15a) (3.4 mmol, 0.90 g) in acetone (15 ml) was
added dropwise a solution of isopropylamine (34 mmol, 2 g) in
absolute ethanol (15 ml) and the reaction mixture was stirred at
room temperature for 3 days. The solvent was evaporated in vacuo
and the residue was chromatographed on silica gel using ethyl
acetate/hexane (1:4) as eluent. Elution of a red coloured band gave
first 2-isopropyl-4-isopropylaminobenz[g]isoquinoline-3,5,10(2H)-
trione (17a) (230 mg, 21%). For spectral data of compound 17a, vide
supra. Using the same solvent combination, a second compound
eluted from the column as a yellow coloured band to give 5-iso-
propyl-2-isopropylaminonaphtho[3,2,1-de]isoquinoline-4,7-dione
(18d) (330 mg, 28%) as a yellow powder. Recrystallization from
methanol gave 18d as yellow crystals, mp 172.6–173.5 ꢀC.
Procedure B. The synthesis of 3-ethyl-5-isopropyl-2-iso-
propylaminonaphtho[3,2,1-de]isoquinoline-4,7-dione (18e) and
5-isobutyl-2-isopropyl-1,3-dimethylnaphtho[3,2,1-de]isoqui-
noline-4,7-dione (18f) was analogous to the synthesis of 5-alkyl-2-
alkylamino-3-methylnaphtho[3,2,1-de]isoquinoline-4,7-diones
(18a–c). Upon the use of 2-pentanone as co-reagent, the reaction
gave rise to the isolation of the conjugate adduct 17a and the target
compound 18e in 12% and 36% yield, respectively. Some of the ar-
omatic quaternary carbons remained in the noise of the 13C NMR
spectrum of compound 18e, even upon prolongation of the pulse
delay and raising the number of recorded scans. When 3-penta-
none was used as co-reagent, the conjugate adduct 17a and the
target compound 26c could be isolated after the reaction in 38% and
16% yield, respectively.
C
23H24N2O2: C 76.64, H 6.71, N 7.77; found: C 76.58, H 6.62, N 7.76.
3.4.2. 5-n-Propyl-2-n-propylamino-3-methylnaphtho-
[3,2,1-de]isoquinoline-4,7-dione (18b)
Recrystallization from methanol gave 18b as yellow crystals, mp
222 ꢀC. 1H NMR (270 MHz, CDCl3):
d
1.03 (3H, t, J¼7.3 Hz, CH2CH3),
1.12 (3H, t, J¼7.3 Hz, CH2CH3), 1.83 (2H, sextet, J¼7.3 Hz,
CH2CH2CH3), 1.89 (2H, sextet, J¼7.3 Hz, CH2CH2CH3), 2.80 (3H, s,
CH3), 3.35 (2H, t, J¼6.9 Hz, NHCH2), 4.08 (2H, t, J¼7.3 Hz, NCH2),
7.52 (1H, t, J¼7.9 Hz, H-9), 7.72 (1H, t, J¼7.9 Hz, H-10), 7.84 (1H, s, H-
1), 8.25 (1H, d, J¼7.9 Hz, H-11), 8.43 (1H, s, H-6), 8.44 (1H, d,
J¼7.9 Hz, H-8). 13C NMR (68 MHz, CDCl3):
d
11.2 (CH2CH3), 11.8
(CH2CH3), 14.0 (CH3), 22.6 (CH2CH3), 22.8 (CH2CH3), 46.2 (NHCH2),
52.4 (NCH2), 110.5 (C-1), 110.8 (C-3), 122.8 (C-11), 123.1 (]Cquat),
123.5 (]Cquat), 123.9 (]Cquat), 125.2 (]Cquat), 127.7 and 127.8 (C-8
and C-9), 130.7 (]Cquat), 133.3 (C-10), 136.5 (]Cquat), 137.4 (C-6),
146.2 (]Cquat), 163.2 (N–C]O), 182.2 (C]O). IR (KBr): nmax 3080,
1665, 1640, 1605, 1580, 1325, 1310 cmꢂ1. MS (70 eV) m/z (%): 360
(Mþ,100), 331 (73), 317 (10), 289 (34). Anal. Calcd for C23H24N2O2: C
76.64, H 6.71, N 7.77; found: C 76.50, H 6.40, N 7.49.
3.4.3. 5-Isopropyl-2-n-propylamino-3-methylnaphtho-
[3,2,1-de]isoquinoline-4,7-dione (18c)
An analytical sample was obtained by recrystallization from
methanol to give 18c as yellow crystals, mp 188.9–190.5 ꢀC. 1H NMR
(270 MHz, CDCl3):
d
1.11 (3H, t, J¼7.2 Hz, CH2CH3), 1.50 (6H, d,
J¼6.6 Hz, 2ꢁCH3), 1.80 (2H, sextet, J¼7.2 Hz, CH2CH2CH3), 2.82 (3H,
s, CH3), 3.29 (2H, t, J¼7.2 Hz, NHCH2), 3.93 (1H, m, NH), 5.38 (1H,
septet, J¼6.6 Hz, NCH), 7.49 (1H, t, J¼7.1 Hz, H-9), 7.69 (1H, t,
J¼7.1 Hz, H-10), 7.75 (1H, s, H-1), 8.17 (1H, d, J¼7.9 Hz, H-11), 8.43
(1H, d, J¼7.6 Hz, H-8), 8.52 (1H, s, H-6). 13C NMR (68 MHz, CDCl3):
3.5.1. 5-Isopropyl-2-isopropylaminonaphtho[3,2,1-de]isoquinoline-
4,7-dione (18d)
1H NMR (270 MHz, CDCl3):
d
1.32 (6H, d, J¼6.3 Hz, 2ꢁCH3), 1.50
(6H, d, J¼6.6 Hz, 2ꢁCH3), 1.57 (1H, br s, NH), 3.83–3.96 (1H, m,
NHCH), 5.44 (1H, septet, J¼6.6 Hz, NCH), 7.53 (1H, td, J¼7.4, 1.0 Hz, H-
9), 7.59 (1H, d, J¼2.3 Hz, H-3), 7.70 (1H, td, J¼1.0, 7.4 Hz, H-10), 7.74
d
11.8 (CH2CH3), 14.1 (CH3), 22.1 (2ꢁCH3), 22.8 (CH2CH3), 46.2

7552
J. Jacobs et al. / Tetrahedron 64 (2008) 7545–7554
(1H, d, J¼2.3 Hz, H-1), 8.16 (1H, d, J¼7.9 Hz, H-11), 8.45 (1H, s, H-6),
t, J¼7.3 Hz, ]CCH2), 3.45 (1H, septet, J¼6.3 Hz, NCH). IR (NaCl): nmax
3331, 1673 cmꢂ1. MS (ES) m/z (%): 126 (MþHþ, 100). Anal. Calcd for
C8H15N: C 76.74, H 12.07, N 11.19; found: C 76.49, H 11.83, N 11.01.
8.46 (1H, dd, J¼1.6, 7.6 Hz, H-8). 13C NMR (68 MHz, CDCl3):
d 22.0
(2ꢁCH3), 22.8 (2ꢁCH3), 44.4 (CH(CH3)2), 47.5 (CH(CH3)2), 109.1 and
115.4 (C-1 and C-3), 111.3 (]Cquat), 122.03 (]Cquat), 122.8 (C-11),
125.7 (]Cquat), 126.9 (]Cquat), 127.9 and 128.1 (C-8 and C-9), 131.3
(]Cquat), 131.9 and 133.1 (C-6 and C-10), 135.7 (]Cquat), 147.0 (C-2),
161.8 (N–C]O), 181.7 (C]O). IR (KBr): nmax 1661, 1629, 1608,
1263 cmꢂ1. MS (70 eV) m/z (%): 346 (Mþ, 100), 331 (77), 289 (65).
Anal. Calcd for C22H22N2O2: C 76.28, H 6.40, N 8.09; found: C 76.09, H
6.09, N 7.73.
3.6.1.2. N-n-Propylcycloheptylideneamine (27b). Distillation (42 ꢀC,
0.01 mmHg) gave 27b as a colorless oil. 1H NMR (300 MHz, CDCl3):
d
0.94 (3H, t, J¼7.4 Hz, CH3), 1.57–1.74 (10H, m, 5ꢁCH2), 2.35 (2H, t,
J¼6.9 Hz, CH2), 2.55–2.48 (2H, m, CH2), 3.14 (2H, t, J¼7.3 Hz, NCH2).
13C NMR (75 MHz, CDCl3):
12.2 (CH3), 24.3 (CH2), 25.0 (CH2), 27.1
d
(CH2), 30.1 (CH2), 30.3 (CH2), 31.9 (CH2), 41.1 (CH2), 52.4 (NCH2),
175.8 (C]N). IR (NaCl): nmax 3267, 1641 cmꢂ1. MS (ES) m/z (%): 154
(MþHþ, 100). Anal. Calcd for C10H19N: C 78.37, H 12.50, N 9.14;
found: C 78.56, H 12.07, N 8.98.
3.5.2. 3-Ethyl-5-isopropyl-2-isopropylaminonaphtho-
[3,2,1-de]isoquinoline-4,7-dione (18e)
Preparative TLC on silica gel with hexane/ethyl acetate (4:1)
(solvent elution 4ꢁ) afforded 18e as orange crystals, mp 178.2–
3.6.2. Microwave mediated synthesis of 6-isopropylbenzo-
[h]pyrido[3,4,5-kl]-1,2,3,4-tetrahydroacridine-5,8-dione (25)
N-Isopropylcyclohexylideneamine (26) (2.22 mmol, 0.31 g) was
added to a solution of 2-isopropylbenz[g]isoquinoline-3,5,10(2H)-
trione (15a) (0.37 mmol, 100 mg) and potassium carbonate
(3.7 mmol, 0.31 g) in absolute ethanol (4 ml). The reaction vessel
was introduced in a CEM microwave and the following parameters
were used: target temperature 128 ꢀC, reaction time 3 h, and
maximal pressure 275 psi. After completion of the reaction, the
solvent was removed under reduced pressure and the reaction
mixture was purified with the aid of preparative TLC on silica gel
using petroleum ether/ethyl acetate (4:1) (solvent elution 3ꢁ) in
16% yield.
179.7 ꢀC. 1H NMR (300 MHz, CDCl3):
d
1.34 (3H, t, J¼7.4 Hz, CH2CH3),
1.37 (6H, d, J¼6.4 Hz, 2ꢁCH3), 1.49 (6H, d, J¼6.9 Hz, 2ꢁCH3), 3.38
(2H, q, J¼7.4 Hz, CH2CH3), 3.96 (1H, septet, J¼6.4 Hz, NHCH), 5.40
(1H, septet, J¼6.9 Hz, NCH), 7.52 (1H, td, J¼1.0, 7.3 Hz, H-9), 7.71
(1H, ddd, J¼1.4, 7.3, 8.2 Hz, H-10), 7.91 (1H, s, H-1), 8.22 (1H, d,
J¼8.2 Hz, H-11), 8.46 (1H, dd, J¼1.4, 7.7 Hz, H-8), 8.54 (1H, s, H-6).
13C NMR (75 MHz, CDCl3):
d
12.6 (CH3), 20.9 (CH2), 22.1 (2ꢁCH3),
23.2 (2ꢁCH3), 44.8 (NCH), 47.1 (NCH),112.2 (C-1),122.7 (C-11),127.8
(C-6 and C-8), 131.3 (]Cquat), 133.2 (C-6 and C-10), 144.7 (N–C]O),
162.4 (O–C]O). IR (KBr): nmax 3426, 1667, 1638, 1607, 1584,
1260 cmꢂ1. MS (ES) m/z (%): 375 (MþHþ, 100). Anal. Calcd for
C
24H26N2O2: C 76.98, H 7.00, N 7.48; found: C 76.62, H 7.27, N 7.29.
3.5.3. 5-Isobutyl-2-isopropylamino-1,3-dimethylnaphtho-
[3,2,1-de]isoquinoline-4,7-dione (18f)
Flash chromatography on silica gel with ethyl acetate/hexane
(1:4) as eluent followed by recrystallization from methanol gave 18f
as orange crystals, mp 150.9–152.6 ꢀC. 1H NMR (300 MHz, CDCl3):
3.6.2.1. 6-Isopropylbenzo[h]pyrido[3,4,5-kl]-1,2,3,4-tetrahydroacri-
dine-5,8-dione (25). Recrystallization from methanol gave 25 as
orange needles, mp 280.9–282.7 ꢀC. 1H NMR (300 MHz, CDCl3):
d
1.50 (6H, d, J¼6.9 Hz, 2ꢁCH3), 1.94 (4H, m, CH2-2 and CH2-3), 3.18
(2H, t, J¼5.7 Hz, CH2-4), 3.54 (2H, t, J¼5.5 Hz, CH2-1), 5.35 (1H,
septet, J¼6.9 Hz, N–CH), 7.61 (1H, td, J¼1.4, 7.9 Hz, H-10), 7.78 (1H,
td, J¼1.4, 7.9 Hz, H-11), 8.39 (1H, dd, J¼1.4, 7.9 Hz, H-9), 8.62 (1H, s,
H-7), 8.86 (1H, dd, J¼1.4, 7.9 Hz, H-12). 13C NMR (75 MHz, CDCl3):
d
1.00 (6H, d, J¼6.6 Hz, CH(CH3)2),1.22 (6H, d, J¼6.3 Hz, NCH(CH3)2),
2.28 (1H, m, CH(CH3)2), 2.86 (3H, s, CH3), 2.92 (3H, s, CH3), 3.57 (1H,
septet, J¼6.3 Hz, NCH(CH3)2), 3.90 (1H, d, J¼7.4 Hz, NH), 3.92 (2H, d,
J¼7.4 Hz, NCH2), 7.50 (1H, td, J¼1.3, 7.7 Hz, H-9), 7.67 (1H, td, J¼1.3,
7.7 Hz, H-10), 8.07 (1H, d, J¼7.7 Hz, H-8), 8.44 (1H, s, H-6), 8.45 (1H,
d
22.3 (2ꢁCH3), 22.6 and 23.3 (CH2-2 and CH2-3), 28.8 (CH2-1), 34.6
(CH2-4), 48.1 (N–CH), 110.5 (]Cquat), 124.0 (]Cquat), 125.1 (C-12),
126.6 (]Cquat), 127.5 (C-9), 129.9 (C-10), 132.2 (]Cquat), 134.0 (C-
11), 134.1 (]Cquat), 136.9 (C-7), 137.2 (]Cquat), 142.6 (]Cquat), 156.2
(C]N), 162.2 (N–C]O), 181.4 (C]O). IR (KBr): nmax 1671, 1648,
1607, 1589, 1263 cmꢂ1. MS (ES) m/z (%): 345 (MþHþ, 100), 247 (25),
235 (45). Anal. Calcd for C22H20N2O2: C 76.72, H 5.85, N 8.13; found:
C 76.47, H 5.71, N 8.24.
dd, J¼1.4, 7.7 Hz, H-11). 13C NMR (75 MHz, CDCl3):
d 17.8 (CH3), 20.0
(CH(CH3)2), 21.7 (CH3), 23.8 (NCH(CH3)2), 28.0 (CH(CH3)2), 49.2
(NHCH), 57.9 (NCH2), 109.9 (]Cquat), 121.4 (]Cquat), 125.6 (]Cquat),
127.3 and 127.4 (C-9 and C-10),128.3 (]Cquat),129.3 (C-11),132.0 (C-
8), 132.1 (]Cquat), 132.3 (]Cquat), 135.1 (]Cquat), 137.7 (]Cquat),
139.1 (C-6), 147.5 (C-2), 163.1 (N–C]O), 182.3 (C]O). IR (KBr): nmax
3313, 1667, 1643, 1604, 1584, 1271 cmꢂ1. MS (ES) m/z (%): 389
(MþHþ, 75), 262 (100), 243 (30). Anal. Calcd for C24H26N2O2: C 76.98,
H 7.00, N 7.48; found: C 77.16, H 7.33, N 7.30.
3.7. Synthesis of functionalized naphtho[3,2,1-de]-
isoquinoline-4,7-diones 30
3.6. Synthesis of 6-isopropylbenzo[h]pyrido[3,4,5-kl]-
3.7.1. Synthesis of enaminoesters 29
1,2,3,4-tetrahydroacridine-5,8-dione (25)
Enaminoesters 29 were prepared from the corresponding
b-ketoesters and primary amines under Dean–Stark conditions
3.6.1. Synthesis of imines 26, 27a, and 27b
following the literature procedures.9 The spectral data of ethyl 3-
isopropylbut-2-enoate (29d) were in full accordance with the lit-
erature data.14 The spectral data of methyl 3-aminobut-2-enoate
(29a) were also in accordance with the literature data,15 and
missing 1H and 13C NMR spectral data are given below.
The synthesis of N-isopropylcyclohexylideneamine (26), N-iso-
propylcyclopentylideneamine (27a), and N-n-propylcycloheptyli-
deneamine (27b) was accomplished according to a method in the
literature utilizing titanium(IV) chloride as a Lewis catalyst for
the condensation of the cyclic ketone with the primary amine.12
Spectral data of N-isopropylcyclohexylideneamine (26) were in
accordance with the literature data.13 13C NMR of N-iso-
propylcyclopentylideneamine (27a) was in accordance with the
literature data.13a Other experimental properties are given below.
3.7.1.1. Methyl 3-aminobut-2-enoate (29a). Yellow crystals, mp 84–
85 ꢀC (lit. 89–90 ꢀC,15a 83–84 ꢀC15b). 1H NMR (300 MHz, CDCl3):
d
1.91 (3H, s, CH3), 3.64 (3H, s, OCH3), 4.52 (1H, s, ]CH). 13C NMR
(75 MHz, CDCl3):
d 22.3 (CH3), 50.1 (OCH3), 83.6 (]CH), 160.0
(]Cquat), 170.6 (C]O).
3.6.1.1. N-Isopropylcyclopentylideneamine (27a). Distillation (21 ꢀC,
3.0 mmHg) gave 27a as a yellow oil. 1H NMR (300 MHz, CDCl3):
3.7.1.2. Ethyl 3-ethylaminobut-2-enoate (29b). Yellow oil. 1H NMR
d
1.12 (6H, d, J¼6.3 Hz, 2ꢁCH3), 1.72 (2H, pentet, J¼6.6 Hz, CH2), 1.81
(300 MHz, CDCl3):
J¼7.2 Hz, OCH2CH3), 1.92 (3H, s, CH3), 3.25 (2H, qd, J¼5.8, 7.3 Hz,
d
1.22 (3H, t, J¼7.3 Hz, NHCH2CH3), 1.25 (3H, t,
(2H, pentet, J¼6.6 Hz, CH2), 2.21 (2H, t, J¼7.3 Hz, ]CCH2), 2.31 (2H,

J. Jacobs et al. / Tetrahedron 64 (2008) 7545–7554
7553
NHCH2CH3), 4.08 (2H, q, J¼7.2 Hz, OCH2CH3), 4.43 (1H, s, ]CH),
8.48 (1H, br s, NH). 13C NMR (75 MHz, CDCl3):
14.8 (OCH2CH3),
15.8 (NHCH2CH3), 19.4 (CH3), 37.8 (NHCH2), 58.4 (OCH2CH3), 81.9
(]CH), 162.0 (]Cquat), 170.8 (C]O). IR (NaCl): nmax 3286, 1650,
1615, 1268 cmꢂ1. MS (ES) m/z (%): 158 (MþHþ, 100). Anal. Calcd for
C8H15NO2: C 61.12, H 9.62, N 8.91; found: C 61.03, H 9.69, N 8.99.
H-6), 8.45 (1H, dd, J¼1.6, 7.5 Hz, H-8). 13C NMR (75 MHz, CDCl3):
d
d
13.5 (NCH2CH3), 14.5 (OCH2CH3), 22.0 (2ꢁCH3), 38.4 (NCH2), 47.7
(NCH), 62.4 (OCH2), 108.7 (C-1), 111.1 (]Cquat), 120.2 (]Cquat), 122.1
(]Cquat), 126.2 (]Cquat), 127.1 (]Cquat), 127.3 (C-9), 127.9 (C-11),
128.7 (C-6), 132.2 (C-10), 132.3 (]Cquat), 132.5 (C-8), 135.6 (]Cquat),
145.9 (]Cquat), 161.5 (N–C]O), 170.7 (O–C]O), 181.6 (C]O). IR
(KBr): nmax 3352, 1713, 1666, 1637, 1268 cmꢂ1. MS (ES) m/z (%): 405
(MþHþ, 100). Anal. Calcd for C24H24N2O4: C 71.27, H 5.98, N 6.93;
found: C 71.48, H 6.21, N 6.88.
3.7.1.3. Ethyl 3-n-propylaminobut-2-enoate (29c). Distillation (78 ꢀC,
1.0 mmHg) gave 29c as a yellow oil. 1H NMR (300 MHz, CDCl3):
d
0.97 (3H, t, J¼7.3 Hz, CH2CH3), 1.25 (3H, t, J¼7.1 Hz, OCH2CH3), 1.59
(2H, sextet, J¼7.3 Hz, NCH2CH2CH3), 1.91 (3H, s, CH3), 3.17 (2H, m,
NHCH2CH2), 4.08 (2H, q, J¼7.1 Hz, OCH2CH3), 4.43 (1H, s, ]CH), 8.58
3.7.2.2. 3-Ethoxycarbonyl-5-isopropyl-2-n-propylaminonaphtho[3,2,1-
de]isoquinoline-4,7-dione (30c). Preparative TLC analysis on silica
gel with ethyl acetate/hexane (1:4) as eluent followed by re-
crystallization from methanol gave 30c as orange crystals, mp
(1H, br s, NH). 13C NMR (75 MHz, CDCl3):
d 11.4 (CH2CH3), 14.7
(OCH2CH3),19.4 (CH3), 23.7 (CH2), 44.8 (NCH2), 58.2 (OCH2CH3), 88.7
(]CH), 162.0 (]Cquat), 170.7 (C]O). IR (NaCl): nmax 3286, 1651, 1611,
1268 cmꢂ1. MS (ES) m/z (%): 172 (MþHþ, 100). Anal. Calcd for
C9H17NO2: C 63.13, H 10.01, N 8.18; found: C 62.90, H 10.21, N 8.05.
144.1–144.4 ꢀC. 1H NMR (300 MHz, CDCl3):
d
1.06 (3H, t, J¼7.3 Hz,
CH2CH2CH3), 1.18 (3H, t, J¼7.2 Hz, OCH2CH3), 1.50 (6H, d, J¼6.9 Hz,
2ꢁCH3), 1.76 (2H, sextet, J¼7.3 Hz, CH2CH2CH3), 3.26 (2H, td, J¼5.2,
7.3 Hz, NHCH2), 4.34 (2H, q, J¼7.2 Hz, OCH2), 5.42 (1H, septet,
J¼6.9 Hz, NCH), 5.45–5.47 (1H, br s, NH), 7.53 (1H, td, J¼1.4, 7.5 Hz,
H-9), 7.60 (1H, td, J¼1.8, 7.5 Hz, H-10), 7.69 (1H, s, H-1), 7.76 (1H, dd,
J¼1.4, 7.5 Hz, H-11), 8.43 (1H, s, H-6), 8.44 (1H, dd, J¼1.4, 7.5 Hz, H-
3.7.1.4. Methyl 3-n-propylbut-2-enoate (29e). Flash chromatogra-
phy on silica gel using hexane/ethyl acetate (4:1) as eluent gave 29e
as a colorless solid, mp 120–121 ꢀC.16 1H NMR (300 MHz, CDCl3):
d
0.98 (3H, t, J¼7.3 Hz, CH2CH3), 1.59 (2H, sextet, J¼7.3 Hz,
8). 13C NMR (75 MHz, CDCl3):
d 11.7 (CH2CH2CH3), 13.6 (OCH2CH3),
NCH2CH2CH3), 1.91 (3H, s, CH3), 3.17 (2H, dt, J¼6.9, 7.3 Hz,
NHCH2CH2), 3.63 (3H, s, OCH3), 4.44 (1H, s, ]CH), 8.56 (1H, br s,
21.9 (2ꢁCH3), 22.3 (CH2CH3), 45.6 (NCH2), 47.7 (NCH), 63.2 (OCH2),
108.8 (C-1), 111.1 (]Cquat), 120.2 (]Cquat), 122.0 (]Cquat), 126.3
(]Cquat), 127.1 (]Cquat), 127.4 (C-9), 127.9 (C-11), 128.6 (C-6), 132.2
(C-10), 132.3 (]Cquat), 132.4 (C-8), 135.6 (]Cquat), 146.0 (]Cquat),
161.5 (N–C]O), 170.7 (O–C]O), 181.6 (C]O). IR (KBr): nmax 3414,
1701, 1669, 1643, 1266 cmꢂ1. MS (ES) m/z (%): 419 (MþHþ, 100).
Anal. Calcd for C25H26N2O4: C 71.75, H 6.26, N 6.69; found: C 71.91,
H 6.37, N 6.60.
NH). 13C NMR (75 MHz, CDCl3):
d 11.4 (CH2CH3), 19.4 (CH3), 23.7
(CH2), 44.8 (NCH2), 49.9 (OCH3), 81.4 (]CH), 162.2 (]Cquat), 171.0
(C]O). IR (NaCl): nmax 3290, 1649, 1611, 1238 cmꢂ1. MS (ES) m/z (%):
158 (MþHþ, 100). Anal. Calcd for C8H15NO2: C 61.12, H 9.62, N 8.91;
found: C 61.33, H 9.85, N 8.81.
3.7.1.5. Methyl 3-ethylaminopent-2-enoate (29f). Distillation (72 ꢀC,
0.8 mmHg) gave 29f as a yellow oil. 1H NMR (300 MHz, CDCl3):
3.7.2.3. 3-Ethoxycarbonyl-5-isopropyl-2-isopropylaminonaphtho[3,2,1-
de]isoquinoline-4,7-dione (30d). Flash chromatography on silica gel
with ethyl acetate/hexane (1:4) as eluent followed by re-
crystallization from methanol gave 30d as orange crystals, mp
d
1.13 (3H, t, J¼7.4 Hz, CH3), 1.23 (3H, t, J¼7.3 Hz, NHCH2CH3), 2.23
(2H, q, J¼7.4 Hz, CH2CH3), 3.25 (2H, qd, J¼5.7, 7.3 Hz, NHCH2CH3),
3.63 (3H, s, OCH3), 4.46 (1H, s, ]CH), 8.49 (1H, br s, NH). 13C NMR
(75 MHz, CDCl3):
d
12.3 (NHCH2CH3), 15.7 (CH2CH3), 25.3 (CH2),
276.2–276.8 ꢀC. 1H NMR (300 MHz, CDCl3):
d
1.41 (3H, t, J¼7.2 Hz,
37.2 (NHCH2), 49.9 (OCH3), 79.5 (]CH),167.2 (]Cquat),171.4 (C]O).
IR (NaCl): nmax 3225, 1689, 1607, 1259 cmꢂ1. MS (ES) m/z (%): 158
(MþHþ, 100). Anal. Calcd for C8H15NO2: C 61.12, H 9.62, N 8.91;
found: C 60.95, H 9.66, N 8.93.
OCH2CH3), 1.51 (6H, d, J¼6.4 Hz, CH(CH3)2), 1.53 (6H, d, J¼6.4 Hz,
CH(CH3)2), 3.30–3.50 (1H, m, NHCH), 4.52 (2H, q, J¼7.2 Hz, CH2CH3),
5.31 (1H, septet, J¼6.4 Hz, CH(CH3)2), 7.61 (1H, td, J¼1.5, 7.5 Hz, H-
9), 7.75 (1H, td, J¼1.6, 7.5 Hz, H-10), 8.09 (1H, s, H-1), 8.18 (1H, dd,
J¼1.5, 7.5 Hz, H-11), 8.46 (1H, dd, J¼1.6, 7.5 Hz, H-8), 8.58 (1H, s, H-
3.7.2. Microwave mediated synthesis of 5-alkyl-2-alkylamino-3-
alkyloxycarbonylnaphtho[3,2,1-de]isoquinoline-4,7-diones 30
General procedure: the enaminoester 29 (2.24 mmol) was added
to a solution of an N-substituted benz[g]isoquinoline-3,5,10(2H)-
trione 15 (0.36 mmol) in absolute ethanol (4 ml). The reaction
vessel was introduced in a CEM microwave and the following pa-
rameters were used: target temperature 128 ꢀC, reaction time 3 h,
and maximal pressure 275 psi. After completion of the reaction, the
solvent was removed under reduced pressure and the reaction
mixture was purified with the aid of column chromatography or
preparative TLC on silica gel. Some of the aromatic quaternary
carbons remained in the noise of the 13C NMR spectrum of com-
pound 30e, even upon prolongation of the pulse delay and raising
the number of recorded scans.
6). 13C NMR (75 MHz, DMSO-d6):
d
13.8 (CH3), 20.9 (2ꢁCH3), 21.1
(2ꢁCH3), 48.2 (NCH), 61.2 (OCH2), 109.9 (C-1), 116.9 (]Cquat), 121.4
(]Cquat), 123.1 (]Cquat), 123.9 (]Cquat), 127.3 (C-9 and C-11), 129.4
(C-6), 129.5 (]Cquat), 130.3 (C-10), 134.2 and 134.3 (C-8 and
]Cquat), 135.2 (]Cquat), 153.6 (]Cquat), 159.7 (N–C]O), 167.3 (O–
C]O),180.6 (C]O). IR (KBr): nmax 3121,1729,1675,1637,1273 cmꢂ1
.
MS (ES) m/z (%): 419 (MþHþ, 10), 378 (100). Anal. Calcd for
C25H26N2O4: C 71.75, H 6.26, N 6.69; found: C 71.50, H 6.37, N 6.86.
3.7.2.4. 5-n-Butyl-3-methoxycarbonyl-2-n-propylaminonaphtho[3,2,1-
de]isoquinoline-4,7-dione (30e). Preparative TLC analysis on silica
gel with ethyl acetate/hexane (1:4) as eluent followed by re-
crystallization from methanol gave 30e as orange crystals, mp
151.8–152.1 ꢀC. 1H NMR (300 MHz, CDCl3):
d
0.98 (3H, t, J¼7.4 Hz,
CH3), 1.06 (3H, t, J¼7.4 Hz, CH3), 1.40–1.48 (2H, m, CH2), 1.72–1.86
(4H, m, 2ꢁCH2), 3.23–3.29 (2H, m, NHCH2), 3.83 (3H, s, OCH3), 4.14
(2H, t, J¼7.4 Hz, NCH2), 5.46–5.51 (1H, m, NH), 7.54 (1H, td, J¼1.4,
7.3 Hz, H-9), 7.61 (1H, td, J¼1.6, 6.9 Hz, H-10), 7.68 (1H, s, H-1), 7.67–
7.70 (1H, m, H-11), 8.33 (1H, s, H-6), 8.45 (1H, s, dd, J¼1.6, 7.6 Hz, H-
3.7.2.1. 3-Ethoxycarbonyl-2-ethylamino-5-isopropylnaphtho[3,2,1-de]-
isoquinoline-4,7-dione (30b). Preparative TLC analysis on silica gel
with ethyl acetate/hexane (1:4) as eluent followed by re-
crystallization from methanol gave 30b as orange crystals, mp
194.0–194.6 ꢀC. 1H NMR (300 MHz, CDCl3):
d
1.18 (3H, t, J¼
8). 13C NMR (75 MHz, CDCl3):
d 11.6 (CH3), 14.1 (CH3), 19.9 (CH2),
7.2 Hz, NCH2CH3), 1.37 (3H, t, J¼7.2 Hz, OCH2CH3), 1.50 (6H, d, J¼
6.6 Hz, CH(CH3)2), 3.34 (2H, qd, J¼5.2, 7.2 Hz, NCH2), 4.34 (2H, q,
J¼7.2 Hz, OCH2), 5.33–5.36 (1H, br s, NH), 5.40 (1H, septet, J¼6.6 Hz,
NCH), 7.53 (1H, td, J¼1.4, 7.5 Hz, H-9), 7.60 (1H, td, J¼1.6, 7.5 Hz,
H-10), 7.69 (1H, s, H-1), 7.76 (1H, dd, J¼1.4, 7.5 Hz, H-11), 8.44 (1H, s,
22.2 (CH2), 31.4 (NCH2CH2), 45.6 (NCH2), 50.2 (NCH2), 52.9 (OCH3),
108.6 (C-1), 126.4 (]Cquat), 127.1 (C-9), 127.7 (]Cquat), 127.9 (C-11),
128.7 (C-6), 129.0 (]Cquat), 132.2 (]Cquat), 132.4 (C-8), 136.6 (C-10),
136.7 (]Cquat), 142.0 (]Cquat), 146.0 (]Cquat), 161.7 (N–C]O), 171.1
(O–C]O). IR (KBr): nmax 3350, 1670, 1643, 1609, 1592, 1266 cmꢂ1
.

7554
J. Jacobs et al. / Tetrahedron 64 (2008) 7545–7554
MS (ES) m/z (%): 419 (MþHþ, 100). Anal. Calcd for C25H26N2O4: C
1319–1343; (c) Okunade, A. L.; Clark, A. M.; Hufford, C. D.; Oguntimein, B. O.
Planta Med. 1999, 65, 447–448.
71.75, H 6.26, N 6.69; found: C 71.59, H 6.43, N 6.60.
2. Nok, A. J. Cell Biochem. Funct. 2002, 20, 205–212; Chem. Abstr. 2002, 636119.
3. (a) Arsenault, G. P. TetrahedronLett.1965, 6, 4033–4037andreferencestherein;(b)
Parisot, D.; Devys, M.; Barbier, M. Z. Naturforsch. 1989, 44, 1473–1474; (c) Parisot,
D.;Devys, M.;Barbier, M. Z. Phytochemistry 1990, 29, 3364–3365;(d)Gra¨fe, U.;Ihn,
W.; Tresselt, D.; Miosga, N.; Kaden, U.; Schlegel, B.; Bormann, E.-J.; Sedmera, P.;
Novak, J. Biol. Met. 1990, 3, 39–44; (e) Miljkovic, A.; Mantle, P. G.; Williams, D. J.;
Rassing, B. J. Nat. Prod. 2001, 64, 1251–1253; (f) Moriyasu, Y. K.; Miyagawa, H.;
Hamada, N.; Miyawaki, H.; Ueno, T. Phytochemistry 2001, 58, 239–241.
4. (a) Parisot, D.; Devys, M.; Barbier, M. J. Antibiot. 1989, 42, 1189–1190; (b) Steyn, P.
S.; Wessels, P. L.; Marasas, W. F. O. Tetrahedron 1979, 35, 1551–1555; (c) Visconti,
A.; Surico, G.; Iacobellis, N. S.; Bottalico, A. Phytopath. Medit. 1983, 22, 122–156.
5. (a) Waterman, P. G.; Muhammad, I. Phytochemistry 1985, 24, 523–527; (b)
Peterson, J. R.; Zjawiony, J. K.; Liu, S.; Hufford, C. D.; Clark, A. M.; Rogers, R. D.
J. Med. Chem. 1992, 35, 4069–4077.
6. (a) Kobayashi, J.; Cheng, J.; Nakamura, H.; Ohizumi, Y.; Hirata, Y.; Sasaki, T.; Ohta,
T.; Nozoe, S. Tetrahedron Lett.1988, 29,1177–1180; (b) Feliu, L.; Ajana, W.; Alvarez,
M.; Joule, J. A. Tetrahedron 1997, 53, 4511–4520; (c) Alvarez, M.; Feliu, L.; Ajana,
W.; Joule, J. A.; Fernandez-Puentes, J. L. Eur. J. Org. Chem. 2000, 849–855.
7. Carneiro do Nascimento, S.; Bouammali, B.; Boitard, M.; Pautet, F.; Soufiaoui,
M.; Fillion, H. Pharmazie 1994, 49, 702–703.
3.7.2.5. 5-n-Butyl-2-ethylamino-3-methoxycarbonyl-1-methylnaph-
tho[3,2,1-de]isoquinoline-4,7-dione (30f). Preparative TLC analysis
on silica gel with ethyl acetate/hexane (1:4) as eluent followed by
recrystallization from methanol gave 30f as orange crystals, mp
156.2–157.9 ꢀC. 1H NMR (300 MHz, CDCl3):
d
0.99 (3H, t, J¼7.3 Hz,
CH2CH2CH3), 1.13 (3H, t, J¼7.1 Hz, NCH2CH3), 1.45 (2H, sextet,
J¼7.3 Hz, CH2CH2CH3), 1.79–1.89 (2H, m, NCH2CH2), 2.92 (3H, s,
CH3), 3.05 (2H, q, J¼7.1 Hz, NHCH2CH3), 3.87 (3H, s, OCH3), 4.11 (2H,
t, J¼7.3 Hz, NCH2CH2), 7.53 (1H, td, J¼1.1, 7.6 Hz, H-9), 7.63 (1H, td,
J¼1.6, 7.6 Hz, H-10), 7.81 (1H, dd, J¼1.1, 7.6 Hz, H-11), 8.45 (1H, dd,
J¼1.6, 7.6 Hz, H-8), 8.54 (1H, s, H-6). 13C NMR (75 MHz, CDCl3):
d
13.7 (CH2CH2CH3), 16.0 (NCH2CH3), 18.1 (CH3), 20.1 (CH2CH3), 31.3
(NCH2CH2), 44.2 (NHCH2), 50.6 (NCH2), 53.1 (OCH3), 110.0 (]Cquat),
122.8 (]Cquat), 124.5 (]Cquat), 126.2 (CHar), 127.7 (CHar), 128.3
(CHar), 128.6 (]Cquat), 129.6 (]Cquat), 131.4 (]Cquat), 132.7 (CHar),
135.7 (]Cquat), 137.4 (]Cquat), 139.9 (CHar), 145.3 (]Cquat), 162.4
(N–C]O), 171.5 (O–C]O), 181.4 (C]O). IR (KBr): nmax 3383, 1712,
1670, 1648, 1287 cmꢂ1. MS (ES) m/z (%): 419 (MþHþ, 100). Anal.
Calcd for C25H26N2O4: C 71.75, H 6.26, N 6.69; found: C 71.63, H
6.38, N 6.57.
8. Jacobs, J.; Claessens, S.; Kesteleyn, B.; Huygen, K.; De Kimpe, N. Tetrahedron
2007, 63, 2503–2510.
9. Baraldi, P. G.; Simoni, D.; Manfredini, S. Synthesis 1983, 902–903.
10. Hayes, B. L. Microwave Synthesis, Chemistry at the Speed of Light; CEM: Mat-
thews, NC, 2002; pp 292.
11. Gabriel, C.; Gabriel, S.; Grant, E. H.; Halstead, B. S. J.; Mingos, D. M. P. Chem. Soc.
Rev. 1998, 27, 213–223.
12. Weingarten, H.; Chupp, J. P.; White, W. A. J. Org. Chem. 1967, 32, 3246–3249.
13. (a) Fraser, R. R.; Banville, J.; Akiyama, F.; Chuaqui-Offermanns, N. Can. J.
Chem. 1981, 59, 705–709; (b) Liao, S.; Collum, D. B. J. Am. Chem. Soc. 2003, 125,
15114–15127; (c) Ma, Y.; Lobkovsky, E.; Collum, D. B. J. Org. Chem. 2005, 70,
2335–2337.
Acknowledgements
14. (a) Brandt, C. A.; da Silva, A. C. M. P.; Pancote, C. G.; Brito, C. L.; da Silveira, M. A.
B. Synthesis 2004, 1557–1559; (b) Zhang, Z.-H.; Song, L. M. J. Chem. Res. 2005,
817–820; (c) Zhang, Z.-H.; Yin, L.; Wang, Y. M. Adv. Synth. Catal. 2006, 348, 184–
190.
The authors are indebted to the ‘Research FoundationdFlanders
(FWO-Vlaanderen)’ for financial support of this research.
15. (a) Iwanami, M.; Shibanuma, T.; Fujimoto, M.; Kawai, R.; Tamazawa, K.;
Takenaka, T.; Takahashi, K.; Murakami, M. Chem. Pharm. Bull. 1979, 27, 1426–
1440; (b) Litvic, M.; Filipan, M.; Pogoreli, I.; Cepanec, I. Green Chem. 2005, 7,
771–774; (c) AIST: Integrated Spectral Database System of Organic Compounds
(Japan).
References and notes
1. (a) Solis, P. N.; Lang’at, C.; Gupta, M. P.; Kirby, G. C.; Warhurst, D. S.; Phillipson, J.
16. Anderson, P. C.; Staskun, B. J. Org. Chem. 1965, 30, 3033–3037.
D. Planta Med. 1995, 61, 62–65; (b) Phillipson, J. D. Phytochemistry 1995, 38,