Investigation towards an efficient synthesis of benzo[g]isoquinoline-1,5, 10(2H)-triones

Article abstract of DOI:10.1016/j.tet.2011.09.021

As part of our research on 2-aza analogues of pentalongin, the active principle of Pentas longiflora Oliv., the first synthesis of 2,3-disubstituted benzo[g]isoquinoline-1,5,10(2H)-triones via 3,4-disubstituted 6-hydroxybenzo[g]furo[4,3,2-de]isoquinoline-

Full text of DOI:10.1016/j.tet.2011.09.021

Tetrahedron 67 (2011) 8747e8756
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Investigation towards an efficient synthesis of benzo[g]isoquinoline-
1,5,10(2H)-triones
,
Blaise Mavinga Mbala a, Jan Jacobs a, Pieter Claes a, Virima Mudogo b, Norbert De Kimpe a
*
a Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, B-9000 Ghent, Belgium
b Department of Chemistry, Faculty of Sciences, University of Kinshasa, PO Box 190, Kin XI, Kinshasa, Democratic Republic of Congo
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 June 2011
Received in revised form 6 September 2011
Accepted 8 September 2011
Available online 12 September 2011
As part of our research on 2-aza analogues of pentalongin, the active principle of Pentas longiflora Oliv.,
the first synthesis of 2,3-disubstituted benzo[g]isoquinoline-1,5,10(2H)-triones via 3,4-disubstituted 6-
hydroxybenzo[g]furo[4,3,2-de]isoquinoline-2,5(4H)-diones as the key intermediates is reported. The
latter compounds have been prepared by treating 2-methoxycarbonyl-1,4-naphthoquinone with N-
substituted enaminoesters under acidic conditions. These reagents are easily accessible from readily
available 1,4-dihydroxy-2-naphthoic acid, b-ketoesters and primary amines. Finally, a short synthesis of
Keywords:
substituted benzo[g]isoquinoline-1,5,10(2H)-triones is achieved by an oxidative addition of N-substituted
enaminoesters onto methyl 1,4-dihydroxynaphthalene-2-carboxylate.
Ó 2011 Elsevier Ltd. All rights reserved.
Benzo[g]furo[4,3,2-de]isoquinoline-2,5(4H)-
diones
Benzo[g]isoquinoline-1,5,10(2H)-triones
Pentalongin
Nenitzescu reaction
O
O
1. Introduction
R1
R3
O
O
R2
R1
N
N
2-Azaanthraquinones can be considered as 2-aza analogues of
pyranonaphthoquinones to which belong eleutherin 1,1 ven-
tiloquinone L 22 and pentalongin 3,3 the naturally occurring pyr-
anonaphthoquinone and active principle of Pentas longiflora Oliv,3
which suggests their potential value as lead structures for the de-
velopment of new pharmaceuticals and agrochemicals.
R2
O
4
5
6
R1 = R3 = OH, R2 = OMe (bostrycoidin)
R1 = R2 = R3 = OH (tolypocladin)
R1 = R2 = OMe, R2 = H (scorpinone)
7
O
OMe O
OH
O
However, the synthesis of 2,3-disubstituted benzo[g]isoquino-
O
O
O
line-1,5,10(2H)-triones 7, the partial structural pattern found in kib-
delone A 8, has only been synthesized to a very limited extend.12a
Kibdelone A 8 belongs to a novel family of bioactive heterocyclic
polyketides produced by a rare soil actinomycete Kibdelosporangium
sp. (MST-108465) and exhibits potent selective cytotoxicity against
a panel of human tumour cell lines as well as significant antibiotic
and nematocidal activity.12
MeO
O
O
O
2 ventiloquinone L
3 pentalongin
1 eleutherin
Unlike pyranonaphthoquinones, their nitrogen analogues are
scarcelyfoundinnatureandarereportedtoexhibitseveralinteresting
bioactivities, including antimicrobial, cytotoxic and insecticidal ac-
tivities.4 Examples of naturally occurring 2-azaanthraquinones in-
clude bostrycoidin 4,5,7 tolypocladin 56 and scorpinone 6.5f,7 Several
research groups8 including ours, disclosed different synthetic strate-
gies for the preparation of 2-azaanthraquinone derivatives, such as N-
substituted benzo[g]isoquinoline-5,10-diones,9 N-substituted benzo
[g]isoquinoline-3,5,10(2H)-triones10 and 2,4-disubstituted benzo[g]
isoquinoline-3,5,10(2H)-triones.11
OH
OH
O
HO
O
OH
O
O
CH3
MeO
N
8 kibdelone A
O
Cl
* Corresponding author. E-mail address: Norbert.Dekimpe@UGent.be (N. De Kimpe).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.021

8748
B.M. Mbala et al. / Tetrahedron 67 (2011) 8747e8756
In this manuscript, an investigation towards the first synthesis of
disclosed on this addition reaction under acidic conditions15 de-
spite the fact that experiments14,15 and ab initio calculations16
showed that quinones behave better as electrophiles under acidic
substituted benzo[g]isoquinoline-1,5,10(2H)-triones 9 is reported.
Retrosynthetic analysis suggested that three possible routes could
lead to the synthesis of the targeted alkyl 2,3-dialkylbenzo[g]iso-
quinoline-1,5,10(2H)-trione-4-carboxylates 9 (Scheme 1). Two routes
rely on the synthesis of 3,4-dialkyl-6-hydroxybenzo[g]furo[4,3,2-de]
isoquinoline-2,5(4H)-diones 10 as key intermediates, which may
most likely be prepared by treating 2-methoxycarbonyl-1,4-
conditions. Therefore, the addition of
b-ketoesters 13 to 2-
methoxycarbonyl-1,4-naphthoquinone 1117 was conducted under
acidic conditions in order to avoid the formation of the kinetic
product of the reaction, i.e., ethyl 5-hydroxy-4-methoxycarbonyl-2-
methylnaphtho[1,2-b]furan-3-carboxylate 17 and its subsequent
decarboxylated derivative 18, which would divert the course of the
naphthoquinone 11 with either
b-ketoesters 13 and primary
R1NH2
O
O
O
12
Route A
OMe
+
O
O
O
OH
O
O
R2
OR3
OR3
R2
R1
O
N
11
13
O
O
R1
R2
NH
O
O
10
OMe
9
6
10
1
R1
R2
2
N
+
Route B
8
7
3
O
5
4
14
11
O
COOR3
Route C
OH
O
9
R1
OMe
NH
O
+
R2
OR3
OH
15
14
Scheme 1.
amines 12 (Scheme 1, route A) or ready-made N-alkyl enaminoesters
14 (Scheme 1, route B). A third route, which will be investigated,
concerns the oxidative addition reaction of N-alkyl enaminoesters 14
with methyl 1,4-dihydroxynaphthalene-2-carboxylate 15 (Scheme 1,
route C) as entries towards the synthesis of substituted benzo[g]
isoquinoline-1,5,10(2H)-triones 9.
synthesis.15 The naphtho[1,2-b]furan 17 arises from the intra-
molecular nucleophilic attack of the intermediate phenol of the
adduct 16a across the ketone function of the acetonyl moiety
(Scheme 2). Therefore, test reactions were conducted under dif-
ferent reaction conditions treating the activated naphthoquinone
11 with ethyl acetoacetate 13a. The desired naphtho[1,2-b]furan-
2(3H)-one 19a was obtained in 54% yield when using a mixture of
toluene and acetic acid (5:1) under reflux for 4 h (Scheme 3).
Extending the optimized reaction conditions for the synthesis of
2. Results and discussion
2.1. Route A
other
derivatives
19bed
from
2-methoxycarbonyl-1,4-
naphthoquinone 11 and higher
low (17%) to moderate yield (54%) except for compound 19e due to
the steric hindrance of the bulky tert-butyl group, which afforded
b
-ketoesters 13 was successful in
The addition of
b
-ketoesters to quinones under basic13 and
radical14 conditions has been well described, but few reports are
1.0 equiv
O
O
OH
O
Me
OEt
O
O
OH
OH
O
13a
OMe
O
OMe
OMe
COOEt
0.05 equiv Yb(OTf)3
CH3CN, 0°C, 90 min
- H2O
OEt
O
O
Me
O
Me
17 (75 %)
(2) decarboxylation
11
Ref. 15
16a
(1) hydrolysis
OH
O
OMe
O
Me
18
Scheme 2.

B.M. Mbala et al. / Tetrahedron 67 (2011) 8747e8756
8749
Scheme 3.
a very complex mixture without a trace of the targeted compound
19e as checked by NMR and LCeMS analysis.
dihydro-5-hydroxy-2-oxonaphtho[1,2-b]furan-4-carboxylate 19a
with 2 equiv of n-propylammonium acetate, which was generated
in situ by the reaction of n-propylamine and acetic acid at 0 ꢀC for
30 min, in boiling toluene-acetic acid (5:1) resulted in the forma-
tion of methyl 2,3-dihydro-5-hydroxy-2-oxonaphtho[1,2-b]furan-
4-carboxylate 21 in 53% yield instead of the targeted 2,3-dialky-
lbenzo[g]furo[4,3,2-de]isoquinoline-2,5(4H)-dione 10a (Scheme 5).
Facing this drawback, different attempts were made to insert the
nitrogen atom using an excess of ammonium acetate in different
solvents in order to reduce the eventual steric effect that might be
exhibited by an alkyl group.
In a following part, a one-pot synthesis of benzo[g]furo[4,3,2-de]
isoquinoline-2,5(4H)-diones 10 was investigated by reaction of the
activated naphthoquinone 11 with ethyl acetoacetate 13a and
ammonium acetate in boiling acetic acid. However, no trace of
compound 10b was observed while the naphtho[1,2-b]furan 18 was
isolated in 13% yield together with methyl 1,4-dihydro-
xynaphthalene-2-carboxylate 15 and 3-amino-2-methoxy-
carbonyl-1,4-naphthoquinone 20 in 6% and 41% yield, respectively
(Scheme 4).
Scheme 4.
The formation of the tricyclic compound 18 arose from a con-
densation reaction outlined in Scheme 2. The formation of methyl
1,4-dihydroxynaphthalene-2-carboxylate 15 and 3-amino-2-
methoxycarbonyl-1,4-naphthoquinone 20 was also observed re-
cently by the reaction of the activated naphthoquinone 11 with an
excess of ammonium acetate in boiling acetic acid.9a Therefore, the
outcome of the competitive addition of ammonia and of the enolate
of
ethyl
acetoacetate
13a
to
2-methoxycarbonyl-1,4-
naphthoquinone 11 led favourably towards the facile ammonia
addition compared to that of the ethyl acetoacetate 13a. Under
these conditions, the ammonia adduct 20 is formed preferentially
in comparison with compound 18, which is supported by the re-
spective isolated yields of each addition product, and as a conse-
quence, treatment of the activated naphthoquinone 11 with
b-
ketoesters 13 and ammonium acetate in boiling acetic acid did not
appear to be the right condition to set an efficient one-pot synthesis
of benzo[g]furo[4,3,2-de]isoquinoline-2,5(4H)-diones 10. Thus, an
alternative synthesis was to be envisaged in order to prepare the
target intermediates 10 from methyl 3-acyl-2,3-dihydro-5-
hydroxy-2-oxonaphtho[1,2-b]furan-4-carboxylates 19 and pri-
mary amines 12. Unfortunately, treatment of methyl 3-acetyl-2,3-
Scheme 5.

8750
B.M. Mbala et al. / Tetrahedron 67 (2011) 8747e8756
However, all the attempts failed to afford compound 10a
The first mode implies a nucleophilic attack of the amino group of
compound 24 across the ketone moiety leading to an annelated
indole 26, while the second mode implies a nucleophilic attack of
the amino group of intermediate 25 across the ester carbonyl
(Table 1, entries 2e4) and provided the same unexpected methyl
2,3-dihydro-5-hydroxy-2-oxonaphtho[1,2-b]furan-4-carboxylate
21 in 46e67% yield. An attempt to increase the substrate electro-
philicity of the carbonyl group by substitution of the methyl group
in methyl 3-acetyl-2,3-dihydro-5-hydroxy-2-oxonaphtho[1,2-b]
furan-4-carboxylate 19a with a phenyl group in methyl 3-benzoyl-
2,3-dihydro-5-hydroxy-2-oxonaphtho[1,2-b]furan-4-carboxylate
19d improved the yield of the same product 21 to 91% (Table 1,
entry 5), probably by limiting side reactions.
group leading to benzo[g]isoquinoline-1,5,10(2H)-triones
9
(Scheme 7).
OH
O
OH
O
- H2O
OMe
OMe
O
O
COOR3
COOR3
OMe
N
R1
O
R2
O
HN
R2
Table 1
Route a
R1
24
Reaction conditions for the conversion of methyl 3-acyl-2,3-dihydro-5-hydroxy-2-
oxonaphtho[1,2-b]furan-4-carboxylates 19a,d to methyl 2,3-dihydro-5-hydroxy-2-
oxonaph-tho[1,2-b]furan-4-carboxylate 21
26
O
11
+
R3O
R2
O
Route b
O
OH
R1NH2.HOAc
R1
N
OH
O
OH
O
O
14
HN
OMe
1
R1
(1) - CH3OH
(2) O2 air
(R1 = n-Pr, 2 equiv.)
(R1 = H, 12 equiv.)
:
NHR
R2
OMe
O
OMe
R2
O
COOR3
COOR3
OH
Toluene:AcOH (5:1),
9
R2
Δ, 3-4 h
O
O
25
O
O
19
21
Scheme 7.
Entry
1
Substrate
Equiv of R1NH2
$HOAc
Solvent and
reaction
conditions
Isolated
yield
of 21 (%)
The reaction of the activated naphthoquinone 11 with N-n-
propyl- and N-ethylamino-2-butenoates 14a and 14d in boiling
toluene/acetic acid (5:1), as previously established in the case of b-
19a
2 (R1¼n-Pr)
Toluene/AcOH (5:1),
, 3 h
Toluene,
AcOH, , 4 h
Toluene/AcOH (5:1),
, 4 h
Toluene/AcOH (5:1),
, 4 h
53
D
2
3
4
19a
19a
19a
12 (R1¼H)
12 (R1¼H)
12 (R1¼H)
D
, 4 h
46
54
67
ketoesters, furnished the hydroquinone adducts 25, which cyclized
to compounds 10 (Scheme 8, Table 2). Structure determination of
the compounds, which were isolated from the reaction crudes,
excluded annelated indoles 26 as a possible structure for these
compounds, since the 13C NMR spectra showed the presence of an
amide as well as an ester function (Scheme 7). However, the para-
quinone system of the alternative compound 9 was not present in
the 13C NMR and the IR showed the presence of a hydroxyl group. In
this way, the molecular structure of the isolated compounds was
determined to be 6-hydroxy-3-methylbenzo[g]furo[4,3,2-de]iso-
quinoline-2,5(4H)-diones 10. Amending the above mentioned re-
actions, the hydroquinone adducts 25 were found to cyclize hardly
to 6-hydroxy-4-n-propyl-3-methylbenzo[g]furo[4,3,2-de]isoquino-
line-2,5(4H)-dione 10a and 4-ethyl-6-hydroxy-3-methyl-benzo[g]
furo[4,3,2-de]isoquinoline-2,5(4H)-dione 10d (Table 2, entries 1
and 2). Nevertheless, the use of N-ethylamino-2-pentenoate 14e
resulted in a spontaneous cyclization to the targeted benzo[g]furo
[4,3,2-de]isoquinoline-2,5(4H)-dione 10e upon boiling in toluene:
acetic acid (5:1) for 4 h (Table 2, entry 3). Other substituent com-
binations utilizing enaminoesters 14feg gave intractable mixtures
of compounds, from which the targeted compounds could not be
isolated by column chromatography and/or recrystallization. This
can be ascribed to a difficult cyclization of intermediate naphtho
[1,2-b]furans 28, even upon prolongation of the reaction time to
48 h, which results in a partial degradation of the compounds
(Table 2, Scheme 8).
D
D
5
19d
12 (R1¼Ph)
91
D
The formation of methyl 2,3-dihydro-5-hydroxy-2-oxonaphtho
[1,2-b]furan-4-carboxylate 21 can be explained by a nucleofuge
group expulsion of intermediate 22, which is formed after the ad-
dition of the amine across the acyl or benzoyl group of naph-
thofuran derivatives 19, and subsequent keto-enol tautomerism
(Scheme 6). The difficult access to the key intermediates 10 by re-
action of naphthofurans 19 with amines put a serious impediment
to this first route A towards the targeted benzo[g]isoquinoline-
1,5,10(2H)-triones 9 and prompted us to work out the second route
B, which calls upon N-substituted enaminoesters 14.
R2CONHR1
O
OH
O
OH
O
OH
OMe
OMe
O
OMe
H
R2
O
+
R1NH2
R1
R2
O
N
O
O
12
H
O
H
O
O
O
19
23
22
OH
Finally,
4-ethyl-6-hydroxy-3-methylbenzo[g]furo[4,3,2-de]
OMe
isoquinoline-2,5(4H)-dione 10d and 3,4-diethyl-6-hydroxybenzo
[g]furo[4,3,2-de]isoquinoline-2,5(4H)-dione 10e were hydro-
lyzed to 2-ethyl-3-methyl-1,2,5,10-tetrahydro-1,5,10-trioxobenzo
[g]isoqui-noline-4-carboxylic acid 30d and 2,3-diethyl-1,2,5,10-
tetrahydro-1,5,10-trioxobenzo[g]isoquinoline-4-carboxylic acid
30e in 40 and 98% of crude yield, respectively, using 4 M NaOH/
THF/MeOH (2:1:1) at 50 ꢀC for 1.5 h and subsequent spontaneous
air oxygen oxidation. However, hydrolysis of 6-hydroxy-3-
methyl-4-n-propylbenzo[g]furo[4,3,2-de]isoquinoline-2,5(4H)-
dione 10a under the same conditions gave a complex mixture of
reaction products (Scheme 8). All attempts to purify compounds
30d and 30e by chromatography and recrystallization techniques
failed.
O
O
21
Scheme 6.
2.2. Route B
The reaction of enaminoesters with simple quinones is known
in the literature as the Nenitzescu reaction.17 In case of 2-
methoxycarbonyl-1,4-naphthoquinone 11 as the substrate,
enaminoesters 1418 add to this activated quinone to form tauto-
meric intermediates 24 and 25, which can cyclize in two modes.

B.M. Mbala et al. / Tetrahedron 67 (2011) 8747e8756
8751
Scheme 8.
Table 2
Reaction of different N-substituted enaminoesters 14 with 2-methoxycarbonyl-1,4-
naphthoquinone 11 in boiling toluene: acetic acid (5:1) to afford 3,4-dialkyl-6-
hydroxybenzo[g]furo[4,3,2-de]isoquinoline-2,5(4H)-diones 10
1.05 equiv.
OH
O
O
O
Toluene:AcOH
(5:1)
R1
R1
R2
NH
O
N
OMe
R2
OEt
Δ, 4-48 h
+
O
O
11
O
14
10
Entry
Enaminoester
R1
R2
Reaction
time (h)
Isolated
product
Yield
(%)
1
2
3
4
5
6
14a
14d
14e
14f
14g
14h
n-Pr
Et
Et
i-Pr
Et
n-Pr
Me
Me
Et
Me
Ph
Ph
36
36
4
36
48
48
10a
10d
10e
d
19
33
47
d
d
d
Scheme 9.
d
d
Therefore, the crude extracts of the hydrolysis reactions con-
taining 2-ethyl-3-methyl-1,2,5,10-tetrahydro-1,5,10-trioxobenzo[g]
isoquinoline-4-carboxylic acid 30d and 2,3-diethyl-1,2,5,10-
tetrahydro-1,5,10-trioxobenzo[g]isoquinoline-4-carboxylate
9e
was isolated as the sole product in an excellent yield of 97% directly
after the treatment of compound 29e with diazomethane in the
presence of air. An attempt to obtain methyl 2,3-diethyl-1,2-
dihydro-5,10-dihydroxy-1-oxobenzo[g]isoquinoline-4-carboxylate
31e by running the reaction with diazomethane under nitrogen
atmosphere and quickly performing the workup of the reaction
gave methyl 2,3-diethyl-1,2,5,10-tetrahydro-1,5,10-trioxobenzo[g]
isoquinoline-4-carboxylate 9e in 28% yield and a complex fraction,
which revealed the presence of very minute quantity of methyl 2,3-
diethyl-1,2-dihydro-5,10-dihydroxy-1-oxobenzo[g]isoquinoline-4-
carboxylate 31e upon LCeMS analysis.
The remarkable differences observed in the chemical behaviour
of compound 31d in comparison with compound 31e on the one
hand and of benzo[g]isoquinoline-1,5,10(2H)-trione 9d in compar-
ison with compound 9e on the other hand, were clues for the de-
velopment of a short alternative procedure, such as the direct
reaction of methyl 1,4-dihydroxynaphthalene-2-carboxylate 15
with enaminoesters 14 under oxidative conditions.
tetrahydro-1,5,10-trioxobenzo[g]isoquinoline-4-carboxylic
acid
30e, respectively, have been converted to the corresponding methyl
esters by treatment with a solution of diazomethane in anhydrous
diethyl ether at room temperature (Scheme 9). In the first case,
methyl 2-ethyl-3-methyl-1,2,5,10-tetrahydro-1,5,10-trioxobenzo[g]
isoquinoline-4-carboxylate 9d was isolated together with methyl
2-ethyl-1,2-dihydro-5,10-dihydroxy-3-methyl-1-oxobenzo[g]iso-
quinoline-4-carboxylate 31d in 14% and 22% yield, respectively.
Different attempts to purify compound 31d by preparative TLC and
recrystallization failed. In order to get full conversion of in-
termediate hydroquinone 31d to benzo[g]isoquinoline-1,5,10(2H)-
trione 9d, the workup extract of the diazomethane reaction was
stirred with magnesium sulfate or silica gel for 24 h in the presence
of air oxygen. Unfortunately, this operation failed to fully convert
the reaction substrate to the targeted benzo[g]isoquinoline-
1,5,10(2H)-trione 9d. Secondly, methyl 2,3-diethyl-1,2,5,10-

8752
B.M. Mbala et al. / Tetrahedron 67 (2011) 8747e8756
Table 4
2.3. Route C
Synthesis of 2,3-disubstituted alkyl 1,2,5,10-tetrahydro-1,5,10-trioxobenzo[g]iso-
quinoline-4-carboxylates 9 by a two-steps procedure involving oxidative addition of
enaminoesters 14 to methyl 1,4-dihydroxynaphthalene-2-carboxylate 15
First, the reaction of methyl 1,4-dihydroxynaphthalene-2-
carboxylate 15 with enaminoester 14e was screened in order to
optimize the oxidative addition reaction for these reaction sub-
strates. An excess of oxidant was needed to assure the oxidation of
hydroquinone 15 before the addition reaction and of the adduct
after the addition of enaminoester 14e. Therefore, methyl 1,4-
dihydroxynaphthalene-2-carboxylate 15 and enaminoester 14e
were reacted using manganese oxide as the oxidant of choice. At
the end, methyl 2,3-diethyl-1,2,5,10-tetrahydro-1,5,10-trioxobenzo
[g]isoquinoline-4-carboxylate 9e was obtained in 69% yield over
two steps using 6 equiv of manganese dioxide and 10 equiv of
magnesium sulfate in anhydrous dichloromethane for 3.5 h at room
temperature to afford a mixture of the targeted benzo[g]isoquino-
line-1,5,10(2H)-trione 9e and its precursor 32, which was converted
subsequently in the target compound 9e by boiling in a mixture of
toluene/acetic acid (5:1) (Table 3, entry 1). In the absence of acetic
acid in the second step, the yield of the reaction was lowered (Table
3, entry 2). The attempts to prepare methyl 2,3-diethyl-1,2,5,10-
tetrahydro-1,5,10-trioxobenzo[g]isoquinoline-4-carboxylate 9e in
a single step resulted in lower yields (Table 3, entries 3 and 4). It
was noticed that the presence of acetic acid was detrimental to this
direct one-step procedure.
1
(1) 1.05 equiv.
R
NH
O
O
O
OH
O
R2
OR3
R1
R2
14
N
OMe
6 equiv. MnO2
10 equiv. MgSO4
CH2Cl2, rt, 3.5 h
O
COOR3
OH
(2) Toluene:AcOH (5:1), Δ, 1.5 h
15
9
Entry
Enaminoester
R1
R2
R3
Isolated
product
Yield
(%)
1
2
3
4
5
6
14a
14e
14g
14h
14i
n-Pr
Et
Et
n-Pr
n-Pr
n-Pr
Me
Et
Ph
Ph
Me
Et
Me
Me
Et
Et
Et
9a
9e
9g
9h
9i
46
69
32
56
29
71
14j
Me
9j
Table 3
Test reactions towards the direct synthesis of methyl 2,3-diethyl-1,2,5,10-tetrahydro-1,5,10-trioxobenzo[g]isoquinoline-4-carboxylate 9e
Et
NH
O
OMe
O
O
O
OH
O
14e
COOMe
NHEt
Et
6 equiv. MnO2
N
OMe
+
10 equiv. MgSO4
O
COOMe
O
COOMe
OH
9e
32
15
Δ
O
O
O
Et
N
COOMe
9e(69%)
Entry
1
Scale (mmol)
1.15
Reaction conditions
(1) CH2Cl2, rt, 3.5 h,
(2) , Toluene/AcOH (5:1), 1 h
(1) CH2Cl2, rt, 3.5 h,
(2) , Toluene, 1 h
Yield 9e (%)
69
D
2
2.30
59
D
3
4
2.30
2.30
D
D
, Toluene, 1.5 h
, Toluene/AcOH (5:1), 1.5 h
44
12
Referring to the overall yield of each route, the two-steps pro-
cedure appeared to be the best entry towards benzo[g]isoquino-
line-1,5,10(2H)-triones 9 compared to the direct one-step oxidative
addition (Table 3, entries 3 and 4) and the multistep procedures
previously elaborated and described earlier in this manuscript
(routes A and B). Having in hand this two-steps procedure, other
derivatives (9a,eej) were prepared accordingly in 29e71% yields
(Table 4).
achieved
in
two
steps
by
reacting
methyl
1,4-
dihydroxynaphthalene-2-carboxylate with enaminoesters in the
presence of 6 equiv of manganese dioxide and 10 equiv of mag-
nesium sulfate in anhydrous dichloromethane for 3.5 h and sub-
sequent boiling in a mixture of toluene/acetic acid (5:1).
4. Experimental section
4.1. General experimental methods
3. Conclusion
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
recorded with a Jeol NMR spectrometer. Peak assignments were
performed with the aid of the DEPT technique, 2D COSY and HSQC
A short and efficient synthesis of 2,3-disubstituted alkyl 1,2,5,10-
tetrahydro-1,5,10-trioxobenzo[g]isoquinoline-4-carboxylates was

B.M. Mbala et al. / Tetrahedron 67 (2011) 8747e8756
8753
spectra. Mass spectra were recorded using a direct inlet system
(70 eV) with a VL detector (ES, 4000 V). IR spectra were recorded
with a Perkin Elmer FT-IR spectrometer. Elemental analyses were
executed with a PerkineElmer Series II CHNS/O Analyzer 2400.
Although numerous attempts were executed for the recrystallized
compounds, the results were found to be unsatisfactory to date.
Therefore, HRMS were recorded using a tandem spectrometer
Agilent 6220 TOF-LC/MS. Melting points were recorded on a Buchi
melting point B-540 apparatus and are not corrected. Flash chro-
matography was carried out using a glass column with silica gel
(particle size 0.035e0.070 mm, pore diameter ca. 6 nm). Solvent
systems for column chromatography were determined via initial
TLC analysis (silica gel).
52.47 (C-3), 59.65 (OCH3), 101.92 (Cquat), 114.37 (Cquat), 121.12 (CH),
123.51 (Cquat), 124.89 (CH), 125.53 (Cquat), 127.42 (CH), 130.82 (CH),
143.12 (Cquat), 159.13 (]CeO), 170.05 (O]CeO), 170.25 (O]CeO),
202.94 (C]O). IR (ATR): nmax 3790, 2980, 2921, 1798, 1716, 1660,
1598 cmꢂ1. MS m/z (%): 327 ([MꢂH]þ, 100). Anal. Calcd for C18H16O6:
C 65.85, H 4.91; found: C 65.60, H 4.26. HRMS (ESI) for C18H18O6:
327.0947 [MꢂH]þ, found 327.0867.
4.2.4. Methyl 3-benzoyl-2,3-dihydro-5-hydroxy-2-oxo-naphtho[1,2-
b]furan-4-carboxylate 19d. Green crystals, mp: 219.1e220.3 ꢀC
(EtOH). 1H NMR (CDCl3):
d 3.44 (3H, s, MeO), 6.11 (1H, s, H-3),
7.59e7.71 (3H, m, H-30, H-40 and H-50), 7.72e7.77 (1H, m, H-7 or H-
8), 7.77e7.99 (1H, m, H-7 or H-8), 8.00 (1H, d, J¼8.3 Hz, H-6 or H-9),
8.17e8.20 (2H, m, H-20 and H-60), 8.50 (1H, d, J¼8.3 Hz, H-6 or H-9),
4.2. Synthesis of methyl 3-acyl-2,3-dihydro-5-hydroxy-2-
11.89 (1H, s, OH). 13C NMR (CDCl3):
d 52.10 (C-3), 55.68 (OCH3),
oxonaphtho[1,2-b]furan-4-carboxylates 19
101.49 (Cquat), 115.56 (Cquat), 121.15 (CH), 123.62 (Cquat), 124.87 (CH),
125.54 (Cquat), 127.34 (CH), 129.18 (2ꢁ CH), 129.51 (2ꢁ CH), 130.83
(CH), 134.31 (CH), 135.77 (Cquat), 143.57 (Cquat), 159.23 (]CeO),
169.68 (O]CeO), 170.65 (O]CeO), 190.61 (C]O). IR (ATR): nmax
3056, 1798, 1688, 1660, 1649, 1597 cmꢂ1. MS m/z (%): 361 ([MꢂH]þ,
100). Anal. Calcd for C21H14O6: C 69.61, H 3.89; found: C 69.09, H
3.16. HRMS (ESI) for C21H14O6: 361.0790 [MꢂH]þ, found 361.0695.
General procedure: To a solution of 2-methoxycarbonyl-1,4-
naphthoquinone 11 (2.4 mmol, 0.5 g)9a in toluene (16.7 ml) were
added acetic acid (3.3 ml) and 1.05 equiv of b-ketoesters 13aee,
respectively. The reaction mixture was subsequently boiled under
reflux for 4 h. After cooling to room temperature, the reaction
mixture was poured in a saturated aqueous solution of sodium
bicarbonate. The organic phase was separated and the remaining
aqueous phase was extracted with 3ꢁ20 ml of dichloromethane.
The combined extracts were dried over magnesium(II) sulfate.
Solvent evaporation in vacuo furnished a crude solid, which was
recrystallized from ethanol.
4.3. Synthesis of methyl 5-hydroxy-2-methylnaphtho[1,2-b]
furan-4-carboxylate 18
To a 10 wt % solution of ammonium acetate (1.0 g) in acetic acid
(10 ml) were added 2-methoxycarbonyl-1,4-naphthoquinone 11
(2.4 mmol, 0.50 g) and ethyl acetoacetate 13a (2.5 mmol, 0.32 g),
and the reaction mixture was subsequently boiled under reflux for
4 h. After cooling to room temperature, the reaction mixture was
poured in water. The organic phase was separated and the aqueous
phase was extracted twice with 5 ml of dichloromethane. The
combined organic extracts were washed with a saturated aqueous
solution of sodium bicarbonate and then dried over magnesium(II)
sulfate. Solvent evaporation in vacuo furnished a mixture of three
compounds. Purification by column chromatography on silica gel
with hexane/ethyl acetate (9:1) gave methyl 5-hydroxy-2-
methylnaphthofuran-4-carboxylate 18 (0.08 g, 13%), methyl 1,4-
dihydroxynaphthalene-2-carboxylate 15 (0.03 g, 6%) and 3-
amino-2-methoxycarbonyl-1,4-naphthoquinone 20 (0.23 g, 41%).
Spectral data of compounds 15 and 20 correspond to the experi-
mental data in the literature.9a
4.2.1. Methyl 3-acetyl-2,3-dihydro-5-hydroxy-2-oxonaphtho[1,2-b]
furan-4-carboxylate 19a. Green crystals, mp: 180.9e181.8 ꢀC (EtOH).
1H NMR (CDCl3):
d 2.46(3H, s, CH3), 3.93(3H, s, MeO), 5.17 (1H, s, H-3),
7.60e7.67 (1H, m, H-7orH-8), 7.70e7.77 (1H, m, H-7 or H-8), 7.94 (1H,
d, J¼8.3 Hz, H-6 orH-9), 8.46(1H, d, J¼8.3 Hz, H-6orH-9),11.84 (1H, s,
OH). 13C NMR (CDCl3):
d 29.34 (CH3), 52.49 (C-3), 61.17 (OCH3), 101.62
(Cquat), 114.26 (Cquat), 121.10 (CH), 123.51 (Cquat), 124.87 (CH), 125.56
(Cquat),127.47 (CH),130.86 (CH),143.22 (Cquat),159.07 (]CeO),169.74
(O]CeO), 170.18 (O]CeO), 197.06 (C]O). IR (ATR): nmax 3099, 1806,
1721, 1667, 1644, 1600 cmꢂ1. MS m/z (%): 301 ([MþH]þ, 100). Anal.
Calcd forC16H12O6:C 64.00, H4.03; found:C 63.83, H 3.98. HRMS(ESI)
for C16H12O6: 299.0634 [MꢂH]þ, found 299.0563.
4.2.2. Methyl
2,3-dihydro-5-hydroxy-3-(1-oxo-n-propyl)naphtho
[1,2-b]furan-4-carboxylate 19b. Green crystals, mp: 154.7e156.0 ꢀC
White crystals, mp:136.0e136.9 ꢀC. 1H NMR (CDCl3):
d 2.55 (3H,
(EtOH). 1H NMR (CDCl3):
d
1.15 0(3H, t, J¼7.2 Hz, CH2CH3), 2.65 (1H,
s, CH3), 4.07 (3H, s, MeO), 6.82 (1H, s, H-3), 7.47 (1H, m, H-7 or H-8),
7.68 (1H, m, H-7 or H-8), 8.14 (1H, m, H-6 or H-9), 8.44 (1H, m, H-6
qd, J¼7.2, 8.9 Hz, CHaHbCH3 ), 3.03 (1H, qd, J¼7.2, 8.9 Hz,
CHaHbCH3), 3.91 (3H, s, MeO), 5.17 (1H, s, H-3), 7.60e7.68 (1H, m, H-
7 or H-8), 7.75-7.78 (1H, m, H-7 or H-8), 7.95 (1H, d, J¼8.3 Hz, H-6 or
H-9), 8.47 (1H, d, J¼8.3 Hz, H-6 or H-9), 11.86 (1H, s, OH). 13C NMR
or H-9), 12.21 (1H, s, OH). 13C NMR (CDCl3):
d 14.27 (CH3), 52.28
(CH), 99.50 (Cquat), 119.52 (Cquat), 120.50 (Cquat), 122.20 (Cquat),
124.50 (CH), 124.51 (Cquat), 124.75 (Cquat), 124.99 (CH), 130.00 (CH),
155.09 (Cquat), 158.96 (Cquat), 172.05 (O]CeO). IR (ATR): nmax 3027,
1638, 1600 cmꢂ1. MS m/z (%): 257 ([MþH]þ, 100). Anal. Calcd for
C15H12O4: C 70.31, H 4.72, found: C 71.00, H 5.15. HRMS (ESI) for
C15H12O4: 257.0736 [MþH]þ, found 257.0350.
(CDCl3):
d 7.58 (CH2CH3), 35.74 (CH2), 52.42 (C-3), 60.53 (OCH3),
101.60 (Cquat), 114.41 (Cquat), 121.10 (CH), 123.56 (Cquat), 124.89 (CH),
125.53 (Cquat), 127.40 (CH), 130.86 (CH), 143.28 (Cquat), 159.13 (]
CeO), 169.76 (O]CeO), 170.48 (O]CeO), 199.85 (C]O). IR (ATR):
nmax 3078, 1804, 1745, 1724, 1660, 1646, 1646, 1598 cmꢂ1. MS m/z
(%): 313 ([MꢂH]þ, 100). Anal. Calcd for C17H14O6: C 64.97, H 4.49;
found: C 64.54, H 4.00. HRMS (ESI) for C17H14O6: 313.0790 [MꢂH]þ,
found 313.0715.
4.4. Synthesis of methyl 2,3-dihydro-5-hydroxy-2-
oxonaphtho[1,2-b]furan-4-carboxylate 21
To a solution of compound 19a or 19d (0.25 g) in toluene (10 ml)
and acetic acid (2 ml) was added 12 equiv of ammonium acetate,
and the reaction mixture was heated under reflux for 4 h. After
cooling to room temperature, the reaction mixture was poured in
water. The organic phase was separated and the aqueous phase was
extracted with 3ꢁ8 ml of dichloromethane. The combined organic
extracts were washed with a saturated solution of sodium bi-
carbonate, brine and dried over magnesium(II) sulfate. Solvent
evaporation in vacuo furnished a solid, which was recrystallized
4.2.3. Methyl
[1,2-b]furan-4-carboxylate 19c. Green crystals, mp: 178.6e179.4 ꢀC
(EtOH). 1H NMR (CDCl3):
2,3-dihydro-5-hydroxy-3-(1-oxoisobutyryl)naphtho
d
1.15 (3H, d, J¼6.6 Hz, CH(CH3)(CH3)), 1.25
(1H, d, J¼6.6 Hz, CH(CH3)(CH3)), 3.20 (1H, sept, J¼6.6 Hz, CH(CH3)2),
3.91 (3H, s, MeO), 5.30 (1H, s, H-3), 7.64e7.67 (1H, m, H-7 or H-8),
7.72e7.77 (1H, m, H-7 or H-8), 7.96 (1H, d, J¼8.3 Hz, H-6 or H-9), 8.48
(1H, d, J¼8.3 Hz, H-6 or H-9), 11.96 (1H, s, OH). 13C NMR (CDCl3):
d
17.58 (CH(CH3)(CH3)), 19.31 (CH(CH3)(CH3)), 39.42 (CH(CH3)2),

8754
B.M. Mbala et al. / Tetrahedron 67 (2011) 8747e8756
from ethanol to furnish methyl 2,3-dihydro-5-hydroxy-2-
oxonaphtho[1,2-b]furan-4-carboxylate 21.
NMR (CDCl3):
d
1.41 (3H, t, J¼7.2 Hz, CH2CH3), 1.49 (3H, t, J¼7.2 Hz,
NCH2CH3), 3.22 (2H, q, J¼7.2 Hz, CH2CH3), 4.22 (2H, q, J¼7.2 Hz,
NCH2CH3), 7.46 (1H, ddd, J¼1.4, 7.0, 8.8 Hz, H-7 or H-8), 7.65 (1H,
ddd, J¼1.4, 7.0, 8.8 Hz, H-7 or H-8), 7.94e7.99 (1H, dm, J¼8.8 Hz,
H-6 or H-9), 8.38e8.43 (1H, m, H-6 or H-9), 10.20 (1H, s, OH). 13C
Brown crystals, mp: 172.5e173.3 ꢀC (EtOH). 1H NMR (CDCl3):
d
4.03 (3H, s, MeO), 4.07 (2H, s, H-3), 7.60 (1H, dd, J¼7.9, 8.2 Hz, H-7),
7.73 (1H, dd, J¼7.7, 7.9 Hz, H-8), 7.96 (1H, J¼7.7 Hz, H-9), 8.45 (1H, d,
J¼8.2 Hz, H-6), 11.93 (1H, s, OH). 13C NMR (CDCl3):
d
36.79 (CH2),
NMR (CDCl3): d 13.91 (CH3), 14.90 (CH3), 22.84 (CH2CH3), 38.68
52.74 (CH), 101.93 (Cquat), 114.79 (Cquat), 120.90 (CH), 123.71 (Cquat),
124.72 (CH), 126.78 (CH), 130.63 (CH), 142.75 (Cquat), 158.61 (Cquat),
170.78 (O]CeO), 174.86 (O]CeO). IR (ATR): nmax 3566, 3118, 3028,
2958, 1788, 1670, 1644, 1599 cmꢂ1. MS m/z (%): 257 ([MꢂH]þ, 100).
Anal. Calcd for C15H12O4: C 65.12, H 3.90; found: C 64.70, H 2.62.
HRMS (ESI) for C15H12O4: 257.0528 [MꢂH]þ, found 257.0450.
(NCH2), 100.70 (Cquat), 100.90 (Cquat), 120.18 (CH), 120.76 (Cquat),
122.14 (Cquat), 122.72 (Cquat), 124.35 (CH), 124.58 (CH), 129.73
(CH), 134.37 (Cquat), 153.00 (Cquat), 156.38 (]CeO), 165.34 (O]
CeN), 166.57 (O]CeO). IR (ATR): nmax 3170, 1793, 1754, 1676,
1636, 1610, 1225 cmꢂ1. MS m/z (%): 310 ([MþH]þ, 100). Anal. Calcd
for C18H15NO4: C 69.89, H 4.89, N 4.53; found: C 69.39, H 4.47, N
4.40. HRMS (ESI) for C18H15NO4: 308.1001 [MꢂH]þ, found
308.0920.
4.5. Synthesis of 3,4-dialkyl-6-hydroxybenzo[g]furo[4,3,2-de]
isoquinoline-2,5(4H)-diones 10
4.6. Synthesis of 2,3-dialkyl-1,2,5,10-tetrahydro-1,5,10-
General procedure: To
a
solution 2-methoxycarbonyl-1,4-
trioxobenzo[g]isoquinoline-4-carboxylic acids 30
naphthoquinone 11 (2.40 mmol, 0.50 g) in toluene (16.7 ml) were
added acetic acid (3.3 ml) and 1.05 equiv of the appropriate
enaminoester 14aeh, respectively. The reaction mixture was sub-
sequently boiled under reflux for 4e48 h (Table 2). The reaction
was followed to completion by TLC and LCeMS. After cooling to
room temperature, the target compounds 10a, 10d and 10e pre-
cipitated as yellow-orange solids from the reaction mixture. After
filtration of the crystals, the filtrate was poured in a saturated
aqueous solution of sodium bicarbonate. The organic phase was
separated and the aqueous phase was extracted with 3ꢁ20 ml of
dichloromethane. The combined organic extracts were dried over
magnesium(II) sulfate. Solvent evaporation in vacuo furnished
crude solids, which were mixed with the isolated yellow-orange
precipitate and were then recrystallized from ethanol.
General procedure: 100 mg of 3,4-dialkyl-6-hydroxybenzo[g]
furo[4,3,2-de]isoquinoline-2,5(4H)-diones 10d (0.34 mmol) and
10e (0.32 mmol) were added to a solution of 2 ml of 4 M NaOH,1 ml
of THF and 1 ml of MeOH. This reaction mixture was stirred for 1.5 h
in an oil bath, which was preheated to 50 ꢀC, and then it was cooled
to room temperature. The reaction mixture was poured in 8 ml of
1 M HCl and extracted with 3ꢁ5 ml of chloroform. The combined
organic extracts were washed with brine and concentrated in vacuo
to afford the target compounds 30d and 30e (purity 81e83%). All
attempts to purify the latter compounds by column chromatogra-
phy and/or recrystallization techniques failed as it resulted in
degradation of the products.
4.6.1. 2-Ethyl-3-methyl-1,2,5,10-tetrahydro-1,5,10-trioxobenzo[g]iso-
4.5.1. 6-Hydroxy-3-methyl-4-n-propylbenzo[g]furo[4,3,2-de]iso-
quinoline-4-carboxylic
acid
30d. Brown
powder,
mp:
quinoline-2,5(4H)-dione 10a. Orange crystals, mp: 241.7e242.9 ꢀC
190.6e191.8 ꢀC. 1H NMR (DMSO-d6):
d
1.24e1.28 (3H, t, J¼7.1 Hz,
(EtOH). 1H NMR (CDCl3):
d
1.08 (3H, t, J¼7.1 Hz, NCH2CH2CH3),
NCH2CH3), 2.51 (3H, s, CH3), 4.12 (2H, q, J¼7.1 Hz, NCH2CH3),
7.82e7.987 (1H, dd, J¼6.3 and 7.1 Hz, H-7 or H-8), 7.90e7.95 (1H,
dd, J¼6.6 and 7.1 Hz, H-7 or H-8), 8.02 (1H, d, J¼7.1 Hz, H-6 or H-9),
1.85e1.75(2H, m, NCH2CH2CH3),2.86(3H, s,CH3),4.10(2H, t,J¼7.2 Hz,
NCH2CH2CH3), 7.49 (1H, ddd, J¼1.4, 7.0, 8.8 Hz, H-7 or H-8), 7.68 (1H,
ddd, J¼1.4, 7.0, 8.8 Hz, H-7 or H-8), 7.98e8.01 (1H, dm, J¼8.8 Hz, H-6
or H-9), 8.42e8.45 (1H, m, H-6 or H-9), 10.26 (1H, s, OH). 13C NMR
8.07 (1H, d, J¼7.1 Hz, H-6 or H-9). 13C NMR (DMSO):
d 13.40 (CH3),
18.65 (CH3), 79.74 (NCH2), 111.89 (Cquat), 116.66 (Cquat), 126.58 (CH),
126.72 (CH), 131.8 (Cquat), 134.00 (2ꢁ CH), 135.80 (Cquat), 141.29
(Cquat), 153.56 (Cquat), 157.56 (Cquat), 168.91 (O]CeN and O]CeO),
180.34 (C]O), 183.76 (C]O). IR (ATR): nmax 3352, 3164, 3071, 2922,
2853, 2626, 2360, 2341, 1716, 1682, 1616, 1521, 1285 cmꢂ1. MS m/z
(%): 312 ([MþH]þ, 100). Purity (LCeMS): 83%.
(CDCl3): d11.43(CH3),16.13(CH3),22.84(NCH2CH2CH3),45.37(NCH2),
100.67 (Cquat),101.94 (Cquat),120.31 (CH),120.63 (Cquat),122.32 (Cquat),
122.86 (Cquat), 124.44 (CH), 124.67 (CH), 129.82 (CH), 134.13 (Cquat),
150.72 (Cquat), 153.16 (]CeO), 165.36 (O]CeN), 166.51 (O]CeO). IR
(ATR): nmax 3170,1793,1754,1676,1636,1610,1225 cmꢂ1. MS m/z (%):
310 ([MþH]þ,100). Anal. Calcd for C18H15NO4: C 69.89, H 4.89, N 4.53;
found: C 68.89, H 4.30, N 4.36. HRMS (ESI) for C18H15NO4: 308.1001
[MꢂH]þ, found 308.0930.
4.6.2. 2,3-Diethyl-1,2,5,10-tetrahydro-1,5,10-trioxobenzo[g]isoquino-
line-4-carboxylic acid 30e. Brown powder, mp: 192.1e193.9 ꢀC. 1H
NMR (CDCl3):
d
1.43 (6H, 2ꢁt, J¼7.1 Hz, CH2CH3 and NCH2CH3), 2.94
4.5.2. 4-Ethyl-6-hydroxy-3-methylbenzo[g]furo[4,3,2-de]isoquino-
(2H, q, J¼7.1 Hz, CH2CH3), 4.28 (2H, q, J¼7.1 Hz, NCH2CH3),
7.71e7.76 (1H, dd, J¼7.1 and 7.1 Hz, H-7 or H-8), 7.80e7.85 (1H, dd,
J¼7.7 and 7.7 Hz, H-7 or H-8), 8.10 (1H, d, J¼7.7 Hz, H-6 or H-9), 8.26
line-2,5(4H)-dione 10d. Orange crystals, mp: 243.1e244.6 ꢀC
(EtOH). 1H NMR (CDCl3):
d
1.40 (3H, t, J¼7.1 Hz, NCH2CH3), 2.86 (3H,
s, CH3), 4.23 (2H, q, J¼7.1 Hz, NCH2CH3), 7.49 (1H, ddd, J¼1.4, 7.0,
8.8 Hz, H-7 or H-8), 7.68 (1H, ddd, J¼1.4, 7.0, 8.8 Hz, H-7 or H-8),
7.98e8.02 (1H, dm, J¼8.8 Hz, H-6 or H-9), 8.27e8.46 (1H, m, H-6 or
(1H, d, J¼7.7 Hz, H-6 or H-9). 13C NMR (DMSO-d6):
d 14.15 (CH3),
14.39 (CH3), 25.28 (CH2CH3), 79.94 (NCH2), 111.65 (Cquat), 117.10
(Cquat), 126.60 (CH), 126.72 (CH), 131.81 (Cquat), 134.02 (CH), 134.03
(Cquat), 135.82 (CH), 141.52 (Cquat), 157.67 (Cquat), 157.76 (CH), 168.75
(O]CeN and O]CeO), 180.39 (C]O), 183.76 (C]O). IR (ATR): nmax
H-9), 10.23 (1H, s, OH). 13C NMR (CDCl3):
d 14.27 (CH3), 16.01 (CH3),
38.96 (NCH2), 100.67 (Cquat), 101.97 (Cquat), 120.32 (CH), 120.32
(Cquat), 122.18 (Cquat), 122.87 (Cquat), 124.46 (CH), 124.69 (CH),
129.84 (CH), 140.35 (Cquat), 150.55 (Cquat), 153.16 (]CeO), 165.21
(O]CeN), 167.09 (O]CeO). IR (ATR): nmax 3170, 1793, 1754, 1676,
1636, 1610, 1225 cmꢂ1. MS m/z (%): 296 ([MþH]þ, 100). Anal. Calcd
for C17H13NO4: C 69.15, H 4.44, N 4.74; found: C 68.16, H 3.54, N
4.49. HRMS (ESI) for C17H13NO4: 294.0845 [MꢂH]þ, found
294.0768.
3342, 3165, 3073, 3025, 2963, 2700, 1750, 1678, 1606, 1528 cmꢂ1
.
MS m/z (%): 326 ([MþH]þ, 100). Purity (LCeMS): 81%.
4.7. Synthesis of alkyl 2,3-disubstituted alkyl 1,2,5,10-
tetrahydro-1,5,10-trioxobenzo[g]isoquinoline-4-carboxylates 9
Procedure A: To a solution of 2,3-diethyl-1,2,5,10-tetrahydro-
1,5,10-trioxobenzogisoquinoline-4-carboxylic acid 30e (200 mg,
0.62 mmol) in 2 ml of THF and 8 ml of acetonitrile was added
4.5.3. 3,4-Diethyl-6-hydroxybenzo[g]furo[4,3,2-de]isoquinoline-
2,5(4H)-dione 10e. Yellow crystals, mp: 200.7e201.6 ꢀC (EtOH). 1H
a freshly-prepared solution of 5 equiv of diazomethane in

B.M. Mbala et al. / Tetrahedron 67 (2011) 8747e8756
8755
anhydrous diethyl ether at room temperature. The reaction was run
to completion after 2 h. Then the reaction mixture was poured in
10 ml of water and extracted with 3ꢁ10 ml of ethyl acetate. The
combined organic extracts were washed with brine and dried over
magnesium sulfate. The filtrate was concentrated under reduced
pressure to form a crude solid, which was purified by preparative
thin layer chromatography on silica gel using a mixture of hexane/
ethyl acetate (1:4) as eluents to afford 203 mg (97%) of the target
compound 9e.
Procedure B, Oxidative addition: To a mixture of methyl 1,4-
dihydroxynaphthalene-2-carboxylate 15 (0.5 g, 1.15 mmol), man-
ganese oxide (1.34 g, 6.90 mmol) and magnesium(II) sulfate (2.76 g,
11.50 mmol) was added a solution of an appropriate enaminoester
14 (1.05 equiv in 20 ml of anhydrous dichloromethane). The re-
action mixture was stirred at room temperature for 3.5 h, after
which it was filtered and concentrated in vacuo. The resulting
residue was dissolved in 15 ml of toluene and 3 ml of acetic acid,
and this mixture was subsequently boiled under reflux for 1e1.5 h.
After cooling to room temperature, the reaction mixture was
poured in water and extracted with ethyl acetate (3ꢁ20 ml). The
combined organic extracts were washed with aqueous saturated
sodium bicarbonate and brine, after which they were dried
(MgSO4) and concentrated in vacuo. The obtained target com-
pounds were recrystallized from methanol for compounds 9a,e and
from ethanol for compounds 9gej.
and H-50), 7.49e7.56 (3H, m, H-30, H-40 and H-50), 7.73 (1H, t,
J¼6.0 Hz, H-7 or H-8), 7.83 (1H, t, J¼6.0 Hz, H-7 or H-8), 8.10 (1H, d,
J¼6.0 Hz, H-6 or H-9), 8.28 (1H, d, J¼6.0 Hz, H-6 or H-9). 13C NMR
(CDCl3):
d 13.66 (NCH2CH3), 13.94 (OCH2CH3), 43.13 (NCH2CH3),
61.77 (OCH2CH3), 111.88 (Cquat), 119.02 (Cquat), 126.67 (CH), 127.27
(CH), 128.49 (2ꢁ CH), 128.75 (2ꢁ CH), 130.47 (CH), 131.44 (Cquat),
131.57 (Cquat), 133.44 (CH), 133.77 (Cquat), 135.29 (CH), 141.42 (Cquat),
154.69 (Cquat), 157.89 (O]CeN), 166.45 (O]CeO), 180.63 (C]O),
183.21 (C]O). IR (ATR): nmax 2991, 1735, 1658, 1628, 1591, 1523,
1488, 1444, 1400, 1327, 1223, 1182, 1150, 1047, 977, 916 cmꢂ1. MS m/
z (%): 402 ([MþH]þ, 100). Anal. Calcd for C24H19NO5: C 71.81, H 4.77,
N 3.49; found: C 71.39, H 4.02, N 3.49. HRMS (ESI) for C24H19O5:
402.1263 [MþH]þ, found 402.1344.
4.7.4. Ethyl 3-phenyl-2-n-propyl-1,2,5,10-tetrahydro-1,5,10-
trioxobenzo[g]isoquinoline-4-carboxylate 9h. Orange crystals, mp:
169.0e169.4 ꢀC (EtOH). 1H NMR (CDCl3):
d
0.75 (3H, t, J¼7.4 Hz,
NCH2CH2CH3), 1.00 (3H, t, J¼7.1 Hz, OCH2CH3), 1.66 (2H, sext,
J¼7.4 Hz, NCH2CH2CH3), 3.82 (2H, q, J¼7.4 Hz, NCH2CH2CH3), 4.02
(2H, q, J¼7.1 Hz, OCH2CH3), 7.36e7.41 (2H, m, H-20 and H-50),
7.49e7.56 (3H, m, H-30, H-40 and H-50), 7.73 (1H, t, J¼6.0 Hz, H-7
or H-8), 7.83 (1H, t, J¼6.0 Hz, H-7 or H-8), 8.10 (1H, d, J¼6.0 Hz,
H-6 or H-9), 8.28 (1H, d, J¼6.0 Hz, H-6 or H-9). 13C NMR (CDCl3):
d
11.31 (NCH2CH2CH3), 13.66 (OCH2CH3), 22.09 (NCH2CH2CH3),
49.30 (NCH2CH2CH3), 61.77 (OCH2H3), 111.80 (Cquat), 118.98
(Cquat), 126.67 (CH), 127.28 (CH), 128.57 (2ꢁ CH), 128.67 (2ꢁ CH),
130.46 (CH), 131.47 (Cquat), 131.57 (Cquat), 133.42 (CH), 133.79
(Cquat), 135.27 (CH), 141.39 (Cquat), 154.66 (Cquat), 158.00 (O]
CeN), 166.47 (O]CeO), 180.59 (C]O), 183.23 (C]O). IR (ATR):
nmax 2980, 1688, 1628, 1593, 1524, 1492, 1446, 1406, 1320, 1285,
1177, 1166, 1024, 977, 928 cmꢂ1. MS m/z (%): 416 ([MþH]þ, 100).
Anal. Calcd for C25H21NO5: C 72.28, H 5.10, N 3.37; found: C 71.39,
H 4.55, N 8.21. HRMS (ESI) for C25H21NO5: 416.1419 [MþH]þ,
found 416.1502.
4.7.1. Methyl 2-n-propyl-3-methyl-1,2,5,10-tetrahydro-1,5,10-
trioxobenzo[g]isoquinoline-4-carboxylate 9a. Greenish brown pow-
der, mp: not observed due to compound decomposition at 256 ꢀC.
1H NMR (CDCl3):
d
1.01 (3H, t, J¼7.4 Hz, CH2CH2CH3), 1.77 (2H, sext,
J¼7.4 Hz, NCH2CH2CH3), 3.19 (3H, s, CH3), 4.00 (3H, s, OCH3), 4.11
(2H, br s, NCH2CH2CH3), 7.76 (1H, t, J¼7.7 Hz, H-7 or H-8), 7.83 (1H,
t, J¼7.7 Hz, H-7 or H-8), 8.08 (1H, d, J¼7.7 Hz, H-6 or H-9), 8.25 (1H,
d, J¼7.7 Hz, H-6 or H-9). 13C NMR (CDCl3):
d 11.17 (NCH2CH2CH3),
22.67 (NCH2CH2CH3), 30.73 (CH3), 47.07 (NCH2CH2CH3), 53.91
(OCH3), 110.75 (Cquat), 118.86 (Cquat), 126.77 (CH), 127.28 (CH),
131.39 (Cquat), 133.59 (Cquat), 133.59 (CH), 135.47 (CH), 141.82 (Cquat),
151.41 (Cquat), 159.06 (O]CeN), 168.40 (O]CeO), 180.20 (C]O),
183.24 (C]O). IR (ATR): nmax 2961,1717,1688,1631,1592,1513,1437,
1415,1283,1254,1164, 969 cmꢂ1. MS m/z (%): 340 ([MþH]þ,10), 699
(100). Anal. Calcd for C19H17NO5: C 67.25, H 5.05, N 4.13; found: C
66.39, H 3.78, N 4.93. HRMS (ESI) for C19H17O5: 340.1107 [MþH]þ,
found 340.1181.
4.7.5. Ethyl 3-methyl-2-n-propyl-1,2,5,10-tetrahydro-1,5,10-
trioxobenzo[g]isoquinoline-4-carboxylate 9i. Brown crystals, mp:
128.6e129.0 ꢀC (EtOH). 1H NMR (CDCl3):
d
1.12 (3H, t, J¼7.4 Hz,
CH2CH2CH3), 1.40 (3H, J¼7.4 Hz, OCH2CH3), 1.77 (2H, sext, J¼7.4 Hz,
NCH2CH2CH3), 3.18 (3H, s, CH3), 4.26 (2H, br s, NCH2CH2CH3), 4.48
(2H, q, J¼7.4 Hz, OCH2CH3), 7.75 (1H, t, J¼7.7 Hz, H-7 or H-8), 7.84
(1H, t, J¼7.7 Hz, H-7 or H-8), 8.09 (1H, d, J¼7.7 Hz, H-6 or H-9),
8.26 (1H, d, J¼7.7 Hz, H-6 or H-9). 13C NMR (CDCl3): To date,
a decent 13C NMR spectrum of this derivative could not be
recorded even upon prolongation of the relaxation delay and in-
creasing the number of recorded scans. IR (ATR) nmax: 2968, 1725,
1688, 1629, 1592, 1511, 1440, 1417, 1415, 1327, 1282, 1254, 1210,
1174, 1058, 1011, 968 cmꢂ1. MS m/z (%): 354 ([MþH]þ, 10%), 705
(100%). Anal. Calcd for C20H19NO5: C 67.98, H 5.42, N 3.96; found: C
67.66, H 4.71, N 6.61. HRMS (ESI) for C20H19NO5: 354.1263 [MþH]þ,
found 354.1326.
4.7.2. Methyl 2-3-diethyl-1,2,5,10-tetrahydro-1,5,10-trioxobenzo[g]
isoquinoline-4-carboxylate
9e. Red
orange
crystals,
mp:
183.1e184.2 ꢀC (MeOH). 1H NMR (CDCl3):
d
1.37 (3H, t, J¼7.0 Hz,
CH2CH3), 1.41 (3H, t, J¼7.0 Hz, NCH2CH3), 2.80 (2H, q, J¼7.0 Hz,
CH2CH3), 4.00 (3H, s, OCH3), 4.28 (2H, q, J¼7.0 Hz, NCH2CH3), 7.72
(1H, d, J¼7.7 Hz, H-7 or H-8), 7.82 (1H, d, J¼7.7 Hz, H-7 or H-8), 8.09
(1H, d, J¼7.7 Hz, H-6 or H-9), 8.25 (1H, d, J¼7.7 Hz, H-6 or H-9). 13C
NMR (CDCl3):
d 13.86 (CH2CH3), 14.13 (NCH2CH3), 25.35 (CH2CH3),
40.88 (NCH2CH3), 53.28 (OCH3), 109.01 (Cquat), 117.60 (Cquat), 126.66
(CH), 127.19 (CH), 131.45 (Cquat), 133.36 (Cquat), 133.74 (CH), 135.30
(CH), 141.73 (Cquat), 157.36 (Cquat), 158.29 (O]CeN), 168.28 (O]
CeO), 180.46 (C]O), 183.46 (C]O). IR (ATR): nmax 2946, 1731, 1693,
1632, 1514, 1434, 1283, 1260, 1153, 1087, 994, 749 cmꢂ1. MS m/z (%):
340 ([MþH]þ, 100). Anal. Calcd for C19H17NO5: C 67.25, H 5.05, N
4.13; found: C 67.04, H 4.47, N 5.53. HRMS (ESI) for C19H17NO5:
340.1107 [MþH]þ, found 340.1201.
4.7.6. Methyl 3-ethyl-2-n-propyl-1,2,5,10-tetrahydro-1,5,10-
trioxobenzo[g]isoquinoline-4-carboxylate 9j. Orange crystals, mp:
128.6e129.0 ꢀC (EtOH). 1H NMR (CDCl3):
d
1.05 (3H, t, J¼7.4 Hz,
CH2CH2CH3), 1.36 (3H, J¼7.4 Hz, CH2CH3), 1.79 (2H, sext, J¼7.4 Hz,
NCH2CH2CH3), 2.80 (2H, q, J¼7.4 Hz, CH2CH3), 4.00 (3H, s, OCH3),
4.11 (2H, q, J¼7.4 Hz, NCH2CH3), 7.72 (1H, t, J¼7.7 Hz, H-7 or H-8),
7.81 (1H, t, J¼7.7 Hz, H-7 or H-8), 8.09 (1H, d, J¼7.7 Hz, H-6 or H-9),
8.25 (1H, d, J¼7.7 Hz, H-6 or H-9). 13C NMR (CDCl3):
d 11.52 (CH3),
13.80 (CH3), 22.35 (CH2CH3), 25.41 (NCH2CH2CH3), 47.16
(NCH2CH2CH3), 53.26 (OCH3), 109.96 (Cquat), 117.57 (Cquat), 126.66
(CH), 127.21 (CH), 131.47 (Cquat), 133.35 (Cquat), 133.76 (CH), 135.29
(CH), 141.71 (Cquat), 157.41 (Cquat), 158.42 (O]CeN), 168.29 (O]
CeO), 180.43 (C]O), 183.47 (C]O). IR (ATR): nmax 2966, 1728, 1691,
1633, 1593, 1516, 1415, 1330, 1282, 1255, 1148, 1064, 979 cmꢂ1. MS
4.7.3. Ethyl 2-ethyl-3-phenyl-1,2,5,10-tetrahydro-1,5,10-trioxobenzo
[g]isoquinoline-4-carboxylate 9g. Yellow-orange crystals, mp:
193.4e194.2 ꢀC (EtOH). 1H NMR (CDCl3):
d
1.00 (3H, t, J¼7.1 Hz,
NCH2CH3), 1.21 (3H, t, J¼6.9 Hz, OCH2CH3), 3.97 (2H, q, J¼7.1 Hz,
NCH2CH3), 4.02 (2H, q, J¼6.9 Hz, OCH2CH3), 7.37e7.40 (2H, m, H-20

8756
B.M. Mbala et al. / Tetrahedron 67 (2011) 8747e8756
m/z (%): 354 ([MþH]þ, 100). Anal. Calcd for C20H19NO5: C 67.98, H
5.42, N 3.96; found: C 67.73, H 4.92, N 12.35. HRMS (ESI) for
C20H19NO5: 354.1262 [MþH]þ, found 354.1262.
References and notes
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4.8. Synthesis of methyl 1,2-dihydro-5,10-dihydroxy-2-ethyl-
3-methyl-1-oxobenzo[g]isoquinoline-4-carboxylate 31d
To a solution of 1,2-dihydro-5,10-dihydroxy-2-ethyl-3-methyl-
1-oxobenzo[g]isoquinoline-4-carboxylic acid 29d (200 mg,
0.64 mmol) in 2 ml of THF and 8 ml of acetonitrile was added
a freshly-prepared solution of 5 equiv of diazomethane in anhy-
drous diethyl ether at room temperature. The reaction was run to
completion, after which the reaction mixture was poured in 10 ml
of water and extracted with 3ꢁ10 ml of ethyl acetate. The combined
organic extracts were washed with brine and dried over magne-
sium(IV) sulfate in a flask, which was open to air and which was
stirred vigorously for 1 h. After filtration, the solvent was evapo-
rated in vacuo to form a crude solid, which was purified by pre-
parative thin layer chromatography on silica gel using a mixture of
hexane/ethyl acetate (1:4) as eluents to afford compound 31d and
compound 9d in 22% and 14%, respectively.
4. Plubrukarn, A.; Yuenyongsawad, S.; Thammasaroj, T.; Jitsue, A. Pharm. Biol.
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4.8.1. Methyl 1,2-dihydro-5,10-dihydroxy-2-ethyl-3-methyl-1-
oxobenzo[g]isoquinoline-4-carboxylate 31d. Green sticky solid, 1H
NMR (CDCl3):
d
1.40 (3H, t, J¼7.5 Hz, NCH2CH3), 2.90 (3H, s, CH3),
4.18 (3H, s, OCH3), 4.25 (2H, q, J¼7.5 Hz, NCH2CH3), 7.53 (1H, t,
J¼9.0 Hz, H-7 or H-8), 7.67 (1H, t, J¼9.0 Hz, H-7 or H-8), 8.08 (1H, d,
J¼9.0 Hz, H-6 or H-9), 8.45 (1H, d, J¼9.0 Hz, H-6 or H-9). 13C NMR
ꢀ
Rebstock, A. S.; Mongin, F.; Trecourt, F.; Queguiner, G. Org. Biomol. Chem. 2004,
2, 291e295.
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Kimpe, N. Tetrahedron 2008, 64, 6364e6371; (c) Jacobs, J.; Kesteleyn, B.; De
Kimpe, N. Tetrahedron 2008, 64, 4985e4992; (d) Jacobs, J.; Deblander, J.; Kes-
teleyn, B.; Abbaspour Tehrani, K.; De Kimpe, N. Tetrahedron 2008, 64,
5345e5353; (e) Claessens, S.; Jacobs, J.; De Kimpe, N. Synlett 2007, 741e744.
10. Jacobs, J.; Claessens, S.; Kesteleyn, B.; Huygen, K.; De Kimpe, N. Tetrahedron
2007, 63, 2505e2510.
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Chem., Int. Ed. 2011, 50, 2511e2515; (b) Ratnayake, R.; Lacey, E.; Tennant, S.; Gill,
J. H.; Capon, R. J. Chem.dEur. J. 2007, 13, 1610e1619.
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Chem. 2003, 11, 4791e4796; (b) Makosza, M.; Nizamov, S. Tetrahedron 2001, 57,
9615e9621; (c) Aleman, J.; Richter, B.; Jorgensen, J. A. Angew. Chem. 2007, 46,
5515e5518; (d) Reynolds, G. A.; Van Allan, J. A.; Adel, R. E. J. Org. Chem. 1965, 30,
3819e3824; (e) Widmer, E.; Meyer, J. W.; Walser, A.; Hardegger, E. Helv. Chim.
Acta 1965, 48, 538e555.
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Tseng, C. M.; Wu, Y. L.; Chuang, C. P. Tetrahedron 2002, 58, 7625e7633; (c) Tsai,
A. I.; Wu, Y. L.; Chuang, C. P. Tetrahedron 2001, 57, 7829e7837; (d) Wang, S. F.;
Chuang, C. P.; Lee, J. H. Heterocycles 1999, 50, 489e497; (e) Chuang, C. P.; Wang,
S. F. Tetrahedron 1998, 54, 10043e10052; (f) Murphy, W. S.; Neville, D.; Fer-
guson, G. Tetrahedron Lett. 1996, 37, 7615e7618.
(CDCl3): d 14.12 (CH3), 16.09 (CH3), 39.65 (NCH2CH3), 63.72 (OCH3),
99.91 (Cquat), 109.13 (Cquat), 120.58 (CH), 122.00 (Cquat), 122.54
(Cquat), 125.04 (CH), 125.70 (CH), 128.05 (Cquat), 129.27 (CH), 138.31
(Cquat), 151.70 (Cquat), 153.48 (Cquat), 160.13 (O]CeN), 166.95 (O]
CeO). IR (ATR): nmax 3347, 2944, 2358, 1751, 1672, 1638, 1440, 1396,
1366, 1237, 1044 cmꢂ1. MS m/z (%): 328 ([MþH]þ, 100).
4.8.2. Methyl 2-ethyl-3-methyl-1,2,5,10-tetrahydro-1,5,10-
trioxobenzo[g]isoquinoline-4-carboxylate 9d. Orange red powder,
mp: not observed due to decomposition of the compound at 280 ꢀC.
1H NMR (CDCl3):
d
1.42 (3H, t, J¼7.4 Hz, CH2CH3), 3.19 (3H, s, CH3),
4.09 (3H, s, OCH3), 4.24 (2H, br s, NCH2), 7.74 (1H, t, J¼7.7 Hz, H-7 or
H-8), 7.83 (1H, t, J¼7.7 Hz, H-7 or H-8), 8.09 (1H, d, J¼7.7 Hz, H-6 or
H-9), 8.25 (1H, d, J¼7.7 Hz, H-6 or H-9). 13C NMR (CDCl3):
d 14.27
(CH2CH3), 30.66 (CH3), 41.32 (NCH2), 53.79 (OCH3), 110.74 (Cquat),
118.83 (Cquat), 126.61 (CH), 127.20 (CH), 131.28 (Cquat), 133.23 (Cquat),
135.43 (CH), 136.91 (CH), 141.78 (Cquat), 151.67 (Cquat), 157.94 (O]
CeN),168.33 (O]CeO),180.36 (C]O),183.32 (C]O). IR (ATR): nmax
1735, 1687, 1508, 1416, 1281, 1259, 994 cmꢂ1. MS m/z (%): 326
([MþH]þ, 100).
15. Mudiganti, N. V. S.; Claessens, S.; De Kimpe, N. Tetrahedron 2009, 65,
1716e1723.
16. Irikura, K. K.; Meot-Ner, M.; Sieck, L. W. J. Org. Chem. 1996, 61, 3167e3171.
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Weiss, M. J. J. Org. Chem. 1968, 33, 198e200; (c) Schenck, L. W.; Sippel, A.; Kuna,
K.; Frank, W.; Albert, A.; Kucklaender, U. Tetrahedron 2005, 61, 9129e9139; (d)
Kucklander, U.; Pitzler, H.; Kuna, K. Arch. Pharmacol. 1994, 327, 137e142; (e)
Lyubchanskaya, V. M.; Alekseeva, L. M.; Savina, S. A.; Shashkov, A. S.; Granik, V.
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Acknowledgements
The authors are indebted to the Belgian Technical Cooperation
(BTC) and the Research FoundationdFlanders (FWO-Vlaanderen)
for financial support of this research.