Original and efficient synthesis of substituted 3,4-dihydronaphtho[2,3-g] quinoline-2,6,11(1H)-triones

Article abstract of DOI:10.1055/s-0029-1217001

We report an original and short synthesis of substituted 3,4-dihydronaphtho[2,3-g]quinoline-2,6,11(1h)-triones by using the tetrakis(dimethylamino)ethylene or malonate substitution strategies, followed by a one-pot reduction-cyclization reaction.

Full text of DOI:10.1055/s-0029-1217001

PAPER
3677
Original and Efficient Synthesis of Substituted 3,4-Dihydronaphtho[2,3-g]
quinoline-2,6,11(1H)-triones
3
, 4-Dihydronaphth
m
o[2,3-
g
]quinoline-2
a
,6,11(1
H
)-
r
triones Khoumeri, Thierry Terme, Patrice Vanelle*
Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Universités d’Aix-Marseille I, II et III – CNRS, UMR 6264,
Laboratoire Chimie Provence, 27 Bd. J. Moulin, 13385 Marseille Cedex 05, France
Fax +33(491)794677; E-mail: patrice.vanelle@pharmacie.univ-mrs.fr
Received 15 June 2009; revised 7 July 2009
with various electrophiles, such as aromatic aldehydes, a-
keto esters, keto malonates, a-keto lactams, or a-diketone
derivatives. We have recently reported an extension of
this reactivity with aromatic aldehydes in the anthraquino-
ne series.7
Abstract: We report an original and short synthesis of substituted
3,4-dihydronaphtho[2,3-g]quinoline-2,6,11(1H)-triones by using
the tetrakis(dimethylamino)ethylene or malonate substitution strat-
egies, followed by a one-pot reduction–cyclization reaction.
Key words: quinones, electron transfer, cyclization, malonate,
naphthoquinolinetriones
In connection with our program centered on the synthesis
of new quinonic compounds by using the single-electron-
transfer methodology and on the preparation of new, po-
tentially bioactive, compounds as anticancer agents, we
report an original and efficient synthesis of substituted
naphtho[2,3-g]quinoline-2,6,11-triones by a reduction–
cyclization reaction8 of nitroanthraquinonic ester deriva-
tives prepared by the TDAE or malonate substitution
strategies.
Anthracycline derivatives such as daunomycin and adria-
mycin (Figure 1) possess high antitumor activity because
of their ability to intercalate the DNA double helix, there-
by producing dramatic changes in the conformation of the
DNA;1 furthermore, these compounds can inhibit DNA
replication and transcription.2 Unfortunately, their clinical
use is limited by dose-related cumulative cardiotoxicity
and the development of drug resistance.3 Several synthe-
sis of heterocyclic anthracycline analogs have been devel-
oped in which the cyclohexane ring (A) of anthracycline
is replaced by a heterocycle.4 Interesting activity against
drug-resistant cells is obtained by modifying the 4,11-di-
In our attempts to apply these strategies in preparing nit-
roquinonic ester derivatives with nitro and ester groups in
the appropriate relative positions, we began by focusing
on a retrosynthetic pathway in which TDAE reactions are
succeeded by a nitration reaction. We therefore prepared,
as previously described,7 the 2-(bromomethyl)-1,4-
dimethoxy-9,10-anthraquinone (1).
hydroxynaphtho[2,3-f]indole-5,10-dione
scaffold
(Figure 1).5
Reaction of quinone 1 with 3 equivalents of various a-
keto esters in N,N-dimethylformamide containing TDAE
at –20 °C for one hour and then at room temperature for
two hours gave the corresponding a-hydroxy ester deriv-
atives 2a–c in good yields (Scheme 1). As described in
our previous study,6b this reaction is regioselective: only
the oxo group of the keto ester reacted with the quinonic
anion.
OH
O
OR1
B
O
C
O
OH
B
O
R2
A
N
H
OH
D
A
D
C
O
OR1
O
OMe
OH
O
The second step was the nitration of the a-hydroxy ester
derivatives 2a–c with nitric acid in acetic acid at 0 °C.
This reaction was accompanied by demethylation of the
methoxy group in the 4-position of the anthraquinonic
moiety9 to give the nitro a-hydroxy ester derivatives 3a–c
in moderate yields (Scheme 1).
adriamycin
Me
NH2
OH
Figure 1 Adriamycin and the 4,11-dihydroxynaphtho[2,3-f]indole-
5,10-dione scaffold
Since 2003, we have pursued a new program directed at
the development of original synthetic methods in medici-
The last step was the reduction of the nitro aromatic group
by iron in acetic acid at 65 °C. This reduction was fol-
lowed by a cyclization reaction in which nucleophilic at-
tack by the amino group onto the ester carbonyl group led
to the corresponding 3,12-dihydroxy-5-methoxy-3,4-di-
hydronaphtho[2,3-g]quinoline-2,6,11(1H)-triones 4a–c
in moderate yields (39–63%).
nal chemistry by using
a
strategy based on
N1,N1,N1,N1,N2,N2,N2,N2-octamethylethene-1,1,2,2-tetra-
mine [tetrakis(dimethylamino)ethylene; TDAE].6 We
have shown that TDAE can generate a nitrobenzyl carb-
anion from 2- or 4-nitrobenzyl chloride, which can react
To avoid the demethylation that accompanied the nitra-
tion reaction, we modified the synthesis strategy to start
from the 1-hydroxy-4-methoxy-3-methyl-2-nitro-9,10-
SYNTHESIS 2009, No. 21, pp 3677–3683
Advanced online publication: 08.09.2009
DOI: 10.1055/s-0029-1217001; Art ID: Z12509SS
x
x.
x
x
.
2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

3678
O. Khoumeri et al.
PAPER
O
O
OMe
O
O
O
OMe
OMe
O
OH
O
O
OH
H
NO2
O
N
R
CO2Et
OH
OH
Fe
HNO3
Br
TDAE, DMF
R
AcOH
0 °C
AcOH
65 °C
R
OH
R
–20 °C, 1 h
r.t., 2 h
CO2Et
CO2Et
OMe
O
OMe
OMe
1
2a R = H
b R = Me
c R = CO2Et
85%
82%
88%
3a R = H
b R = Me
c R = CO2Et
4a R = H
b R = Me
c R = CO2Et
50%
39%
63%
67%
65%
66%
Scheme 1 Synthesis of 3,12-dihydroxy-5-methoxy-3,4-dihydronaphtho[2,3-g]quinoline-2,6,11(1H)-triones 4a–c
anthraquinone (5),9 which gave, after methylation and hydronaphtho[2,3-g]quinoline-2,6,11(1H)-triones 9a and
bromation, the 2-bromomethyl derivative 7. 9b in good yields (Scheme 2).
We studied the reactivity of bromide 7 under TDAE con- In order to prepare other nitroquinonic ester derivatives,
ditions with a-keto ester derivatives. The absence of reac- we envisaged the use of the bromide 7 as an electrophile
tivity or poor reactivity of 7 toward a-keto esters in N,N- in a nucleophilic substitution reaction with various alkyl
dimethylformamide as solvent led us to perform the reac- malonate anions. The reaction of bromide 7 with alkylma-
tion in tetrahydrofuran (another solvent for TDAE reac- lonate derivatives (3 equiv) and sodium hydride (3 equiv)
tions).10 The reaction of quinone 7 with a-keto ester in dimethyl sulfoxide under an inert atmosphere for 15
derivatives in the presence of TDAE in tetrahydrofuran at minutes gave the corresponding ester derivatives 10a–d in
–20 °C for one hours and then at room temperature for good yields (60–71%), as shown in Scheme 3 and listed in
four hours gave the corresponding a-hydroxy ester deriv- Table 1.
atives 8a and 8b. In contrast to the reaction of 2-bromo-
These substituted products 10a–d are good candidates for
further cyclization reactions. Reduction of the nitro aro-
matic group with iron under the same conditions as de-
scribed above led to the corresponding alkyl 5,12-
dimethoxy-1,2,3,4,6,11-hexahydro-2,6,11-trioxonaph-
tho[2,3-g]quinoline-3-carboxylates 11a–d in good yields
(73–90%), as shown in Scheme 3 and listed in Table 2.
methyl-1,4-dimethoxy-9,10-anthraquinone (1) with a-
keto ester derivatives, which gave a-hydroxy esters 2a–c
in good yields (82–88%), 2-bromomethyl-1,4-dimethoxy-
3-nitro-9,10-anthraquinone (7) gave 8a and 8b in moder-
ate yields (38% and 63%, respectively; Scheme 2), prob-
ably because the quinonic carbanion is more stabilized by
the nitro group. The second step was the reduction of the
In conclusion, we developed a synthesis of new substitut-
nitro group with iron in boiling acetic acid, which gave,
ed nitroanthraquinonic esters or malonates by the TDAE
after cyclization, the 3-hydroxy-5,12-dimethoxy-3,4-di-
O
OH
O
OMe
O
OMe
O
OMe
O
NO2
Me
NO2
NO2
Me
NO2
Br
DMS, K2CO3
acetone
88%
R
CO2Et
Br2
OH
CCl4
60%
TDAE, THF
–20 °C, 1 h
r.t., 4 h
R
CO2Et
O
OMe
O
OMe
OMe
O
OMe
O
OMe
5
6
7
8a R = CO2Et
b R = Me
63%
38%
O
O
OMe
H
NO2
N
O
OH
Fe
OH
R
AcOH
117 °C
CO2Et
R
O
OMe
O
OMe
8a,b
9a R = CO2Et 86%
b R = Me 70%
Scheme 2 Synthesis of 3-hydroxy-5,12-dimethoxy-3,4-dihydronaphtho[2,3-g]quinoline-2,6,11(1H)-triones 9a and 9b
O
OMe
O
OMe
O
OMe
H
NO2
CO2R2
CO2R2
N
O
NO2
Br
CO2R2
CO2R2
R1
NaH
Fe
R1
+
AcOH
117 °C
DMSO
N2
CO2R2
R1
O
OMe
O
OMe
O
OMe
10a–d
11a–d
7
Scheme 3 Synthesis of alkyl 5,12-dimethoxy-1,2,3,4,6,11-hexahydro-2,6,11-trioxonaphtho[2,3-g]quinoline-3-carboxylates 11a–d
Synthesis 2009, No. 21, 3677–3683 © Thieme Stuttgart · New York

PAPER
3,4-Dihydronaphtho[2,3-g]quinoline-2,6,11(1H)-triones
3679
Reaction of 2-Bromomethyl-1,4-dimethoxy-9,10-anthraquin-
one (1) and a-Keto Ester Derivatives in the Presence of TDAE;
General Procedure
Table 1 Reaction of Bromide 7 with Malonate Derivatives
R
R1
Et
Producta
10a
Yield (%)b
A two-necked flask equipped with a drying tube (silica gel) and a
N2 inlet was charged with a soln of anthraquinone 1 (0.4 g, 1.10
mmol) and the appropriate a-keto ester (3 equiv) in anhyd DMF (10
mL) at –20 °C. The soln was stirred and maintained at –20 °C for
30 min and then TDAE (0.22 g, 1.10 mmol) was added dropwise
from a syringe. A red color immediately developed with the forma-
tion of a fine white precipitate. The soln was stirred vigorously at
–20 °C for 1 h and then warmed to r.t. for 2 h, when TLC analysis
(CH2Cl2) clearly showed that compound 1 was totally consumed.
The soln was filtered and H2O (80 mL) was added. The aq soln was
extracted with chloroform (3 × 40 mL) and the combined organic
layers were washed with H2O (2 × 40 mL), dried (MgSO4), and con-
centrated to give a viscous orange liquid as a crude product. This
was purified by chromatography [silica gel (CH2Cl2–Et2O, 95:5)]
and recrystallization (EtOH) to give the a-hydroxy ester derivatives
2a–c.
H
76
69
63
71
H
Me
Et
10b
Me
Ph
10c
Et
10d
a All reactions were performed at r.t. under N2 for 15 min using 7 (1
equiv) and malonate (3 equiv) in DMSO.
b Yields of chromatographically isolated pure products relative to bro-
mide 7.
Table 2 Reduction–Cyclization Reactions of 10a–d
R
R1
Et
Producta
11a
Yield (%)b
H
90
87
75
73
Ethyl 3-(1,4-Dimethoxy-9,10-dioxo-9,10-dihydroanthracen-2-
yl)-2-hydroxypropanoate (2a)
Yellow solid; yield: 85%; mp 154 °C.
H
Me
Et
11b
1H NMR (200 MHz, CDCl3): d = 1.27 (t, J = 7.1 Hz, 3 H, CH3),
3.03 (dd, J = 13.9, 8.2 Hz, 1 H, CH2), 3.12 (br s, 1 H, OH), 3.33 (dd,
J = 13.9, 5.8 Hz, 1 H, CH2), 3.90 (s, 3 H, OCH3), 3.99 (s, 3 H,
OCH3), 4.24 (q, J = 7.1 Hz, 2 H, CH2), 4.51 (dd, J = 8.2, 4.2 Hz, 1
H, CH), 7.32 (s, 1 H, Ar-H), 7.68–7.75 (m, 2 H, Ar-H), 7.12–7.18
(m, 2 H, Ar-H).
13C NMR (50 MHz, CDCl3): d = 14.2, 35.6, 56.8, 62.1, 62.2, 70.3,
121.6, 121.7, 126.4, 126.5, 127.0, 133.2, 133.6, 133.8, 134.3, 140.9,
152.7, 156.2, 174.0, 182.8, 183.3.
Me
Ph
11c
Et
11d
a All the reactions were performed by using Fe (30 equiv) in boiling
AcOH for 2 h.
b Yields of chromatographically isolated pure products relative to the
nitro ester derivatives 10a–d.
or malonate substitution strategies that involves the reac-
tion of 2-bromomethyl-1,4-dimethoxy-3-nitro-9,10-an-
thraquinone (7) with a-keto ester or malonate derivatives.
These two strategies are complementary in that the bro-
mide 7 reacts as a nucleophile in the TDAE method and as
an electrophile in the malonate method. Moreover, we
present an example of the use of the TDAE strategy to
generate a quinonic anion that cannot be generated effec-
tively by the conventional organometallic strategy. Final-
ly, the reduction–cyclization reaction of the nitroquinonic
Anal. Calcd for C21H20O7: C, 65.62; H, 5.24. Found: C, 65.20;
H, 5.47.
Ethyl 3-(1,4-Dimethoxy-9,10-dioxo-9,10-dihydroanthracen-2-
yl)-2-hydroxy-2-methylpropanoate (2b)
Yellow solid; yield: 82%; mp 142 °C.
1H NMR (200 MHz, CDCl3): d = 1.24 (t, J = 7.2 Hz, 3 H, CH3),
1.51 (s, 3 H, CH3), 3.13 (d, J = 13.7, 1 H, CH2), 3.27 (d, J = 13.7 Hz,
1 H, CH2), 3.45 (br s, 1 H, OH), 3.88 (s, 3 H, OCH3), 4.00 (s, 3 H,
OCH3), 4.18 (q, J = 7.2 Hz, 2 H, CH2), 7.38 (s, 1 H, Ar-H), 7.69–
ester derivatives gave new substituted 3,4-dihydronaph- 7.74 (m, 2 H, Ar-H), 8.13–8.19 (m, 2 H, Ar-H).
13C NMR (50 MHz, CDCl3): d = 14.0, 26.1, 39.9, 56.7, 62.1, 62.2,
74.7, 121.8, 122.2, 126.4, 126.5, 126.9, 133.2, 133.5, 133.9, 134.3,
140.1, 152.9, 155.9, 176.0, 182.9, 183.2.
tho[2,3-g]quinoline-2,6,11(1H)-triones. The pharmaco-
logical properties of these compounds are under active
investigation.
Anal. Calcd for C22H22O7: C, 66.32; H, 5.57. Found: C, 66.11;
H, 5.79.
Melting points were determined on a Buchi capillary melting point
apparatus and are uncorrected. Elemental analyses were performed
by the Centre de Microanalyses of the Spectropole (Aix-Marseille
Diethyl [(1,4-Dimethoxy-9,10-dioxo-9,10-dihydroanthracen-2-
yl)methyl](hydroxy)malonate (2c)
Yellow solid; yield: 88%; mp 87 °C.
1
University). Both H and 13C NMR spectra were determined on a
Bruker AC 200 spectrometer. The 1H chemical shifts are reported as
parts per million downfield from TMS whereas the 13C chemical
shifts are referenced to the solvents peaks for CDCl3 (76.9 ppm) or
DMSO-d6 (39.6 ppm). Absorptions are reported with the following
notations: s, singlet; d, doublet; t, triplet; q, quartet; m, complex
multiplet or overlapping multiplets. Column chromatography was
performed on silica gel 60 (Merck, particle size 0.063–0.200 mm,
70–230 mesh ASTM). TLC was performed using an appropriate
solvent on 5 × 10 cm aluminum plates coated with silica gel 60 F-
254 (Merck).
1H NMR (200 MHz, CDCl3): d = 1.27 (t, J = 7.1 Hz, 6 H, 2 CH3),
3.56 (s, 2 H, CH2), 3.89 (s, 3 H, OCH3), 3.98 (s, 3 H, OCH3), 4.26
(q, J = 7.1 Hz, 4 H, 2 CH2), 7.44 (s, 1 H, Ar-H), 7.69–7.74 (m, 2 H,
Ar-H), 8.12–8.19 (m, 2 H, Ar-H).
13C NMR (50 MHz, CDCl3): d = 13.9 (2 C), 34.6, 56.7, 62.2, 62.9
(2 C), 78.5, 121.9, 122.2, 126.3, 126.5, 126.9, 133.2, 133.5, 133.9,
134.3, 138.8, 152.9, 155.9, 169.8 (2 C), 182.8, 183.1.
Anal. Calcd for C24H24O9: C, 63.15; H, 5.30. Found: C, 62.92;
H, 5.58.
Synthesis 2009, No. 21, 3677–3683 © Thieme Stuttgart · New York

3680
O. Khoumeri et al.
PAPER
Nitration of a-Hydroxy Derivatives 2a–c; General Procedure
Fuming HNO3 (2.5 mL) was added dropwise to a soln of a-hydroxy
derivative 2a–c (0.4 g, 1 equiv) in glacial AcOH (3 mL) at 0 °C. The
soln was maintained at 0 °C for 10 min then poured into crushed ice.
The precipitate was filtered off, washed with H2O, dried, and re-
crystallized (EtOH) to give the corresponding nitro a-hydroxy ester
derivative 3a–c.
1H NMR (200 MHz, DMSO-d6): d = 1.22 (br s, 1 H, OH), 2.90 (dd,
J = 16.7, 10.3 Hz, 1 H, CH2), 3.24 (dd, J = 16.7, 5.7 Hz, 1 H, CH2),
3.77 (s, 3 H, OCH3), 4.20–4.28 (m, 1 H, CH), 5.81 (d, J = 4.5 Hz, 1
H, OH), 7.88–7.97 (m, 2 H, Ar-H), 8.14–8.22 (m, 2 H, Ar-H), 10.20
(s, 1 H, NH).
13C NMR (50 MHz, DMSO-d6): d = 29.2, 61.7, 65.8, 115.1, 118.2,
126.8, 127.0, 127.6, 132.7, 134.6 (2 C), 135.4, 136.2, 147.4, 153.3,
171.4, 180.4, 189.4.
Ethyl 2-Hydroxy-3-(4-hydroxy-1-methoxy-3-nitro-9,10-dioxo-
9,10-dihydroanthracen-2-yl)propanoate (3a)
Yellow solid; yield: 67%; mp 181 °C.
Anal. Calcd for C18H13NO6: C, 63.72; H, 3.86; N, 4.13. Found: C,
62.40; H, 4.04; N, 3.85.
1H NMR (200 MHz, CDCl3): d = 1.27 (t, J = 7.1 Hz, 3 H, CH3),
1.57 (br s, 1 H, OH), 3.00 (br s, 1 H, OH), 3.07 (dd, J = 13.5, 8.9 Hz,
1 H, CH2), 3.19 (dd, J = 13.5, 5.1 Hz, 1 H, CH2), 3.96 (s, 3 H,
OCH3), 4.26 (q, J = 7.1 Hz, 2 H, CH2), 4.48 (dd, J = 8.9, 5.1 Hz, 1
H, CH), 7.83–7.87 (m, 2 H, Ar-H), 8.28–8.32 (m, 2 H, Ar-H).
13C NMR (50 MHz, CDCl3): d = 14.1, 32.2, 62.4, 62.6, 69.3, 116.6,
124.7, 126.9, 127.8, 131.9, 134.2, 134.4, 135.4, 135.6, 145.2, 150.7,
152.8, 173.3, 180.6, 188.0.
3,12-Dihydroxy-5-methoxy-3-methyl-3,4-dihydronaphtho[2,3-
g]quinoline-2,6,11(1H)-trione (4b)
Yellow solid; yield: 39%; mp 260 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.22 (br s, 1 H, OH), 1.30 (t,
J = 7.1 Hz, 3 H, CH3), 2.90 (d, J = 7.2 Hz, 1 H, CH2), 3.11 (d,
J = 7.2 Hz, 1 H, CH2), 3.75 (s, 3 H, OCH3), 5.68 (br s, 1 H, OH),
7.80–7.91 (m, 2 H, Ar-H), 8.10–8.20 (m, 2 H, Ar-H), 10.12 (s, 1 H,
NH).
Anal. Calcd for C20H17NO9: C, 57.83; H, 4.13; N, 3.37. Found: C,
57.53; H, 4.08; N, 3.48.
13C NMR (50 MHz, DMSO-d6): d = 24.7, 34.9, 61.3, 68.2, 114.5,
117.7, 126.5, 127.0, 127.2, 132.3, 134.1 (2 C), 135.0, 135.7, 146.8,
152.9, 172.2, 180.0, 189.0.
Ethyl 2-Hydroxy-3-(4-hydroxy-1-methoxy-3-nitro-9,10-dioxo-
9,10-dihydroanthracen-2-yl)-2-methylpropanoate (3b)
Yellow solid; yield: 65%; mp 159 °C.
Anal. Calcd for C19H15NO6: C, 64.59; H, 4.28; N, 3.96. Found: C,
63.94; H, 4.41; N, 3.84.
1H NMR (200 MHz, CDCl3): d = 1.32 (t, J = 7.1 Hz, 3 H, CH3),
1.46 (s, 3 H, CH3), 3.23 (d, J = 13.5 Hz, 1 H, CH2), 3.35 (d, J = 13.5
Hz, 1 H, CH2), 3.89 (s, 3 H, OCH3), 4.24 (q, J = 7.1 Hz, 2 H, CH2),
7.83–7.87 (m, 2 H, Ar-H), 8.27–8.31 (m, 2 H, Ar-H).
13C NMR (50 MHz, CDCl3): d = 14.0, 25.9, 36.4, 62.3, 62.6, 74.0,
116.6, 124.6, 126.8, 127.7, 131.9, 134.2, 134.3, 135.2, 135.6, 146.0,
151.0, 152.9, 175.4, 180.5, 188.0.
Ethyl 3,12-Dihydroxy-5-methoxy-2,6,11-trioxo-1,2,3,4,6,11-
hexahydronaphtho[2,3-g]quinoline-3-carboxylate (4c)
Yellow solid; yield: 63%; mp 226 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.14 (t, J = 7.1 Hz, 3 H, CH3),
3.22 (d, J = 17.2, 1 H, CH2), 3.44 (d, J = 17.2 Hz, 1 H, CH2), 3.76
(s, 3 H, OCH3), 4.12 (q, J = 7.1 Hz, 2 H, CH2), 6.78 (br s, 1 H, OH),
7.87–7.93 (m, 2 H, Ar-H), 8.10–8.21 (m, 2 H, Ar-H), 10.62 (s, 1 H,
NH).
Anal. Calcd for C21H19NO9: C, 58.74; H, 4.46; N, 3.26. Found: C,
58.21; H, 4.42; N, 3.21.
13C NMR (50 MHz, DMSO-d6): d = 14.8, 32.0, 61.8, 62.4, 74.5,
115.1, 118.5, 125.9, 126.9, 127.6, 132.5, 133.9, 134.5, 135.2, 136.1,
147.3, 153.1, 168.0, 171.2, 180.3, 189.3.
Diethyl Hydroxy[(4-hydroxy-1-methoxy-3-nitro-9,10-dioxo-
9,10-dihydroanthracen-2-yl)methyl]malonate (3c)
Yellow solid; yield: 66%; mp 157 °C.
1H NMR (200 MHz, CDCl3): d = 1.31 (t, J = 7.1 Hz, 6 H, 2 CH3),
3.68 (s, 2 H, CH2), 3.79 (br s, 1 H, OH), 3.87 (s, 3 H, OCH3), 4.28
(q, J = 7.1 Hz, 4 H, 2 CH2), 7.75–7.84 (m, 2 H, Ar-H), 8.20–8.28
(m, 2 H, Ar-H).
13C NMR (50 MHz, CDCl3): d = 13.9 (2 C), 31.1, 62.4, 63.1 (2 C),
77.2, 116.8, 124.6, 126.8, 127.6, 131.9, 134.0, 134.2, 134.3, 135.6,
146.3, 150.9, 152.8, 169.5 (2 C), 180.3, 188.1.
Anal. Calcd for C21H17NO8: C, 61.31; H, 4.17; N, 3.40. Found: C,
60.81; H, 4.21; N, 3.26.
2-(Bromomethyl)-1,4-dimethoxy-3-nitro-9,10-anthraquinone
(7)
A soln of Br2 (3.28 mL, 64 mmol) in CCl4 (10 mL) was added drop-
wise to a soln of nitroanthraquinone 6 (0.7 g, 3 mmol) in CCl4 (140
mL) at 80 °C. The soln was kept at 80 °C for 4 h and then cooled.
The organic layer was washed with sat. aq Na2SO3 (100 mL), dried
(MgSO4) and concentrated. Purification of the residue by chroma-
tography (silica gel, CH2Cl2) and recrystallization (EtOH) gave a
yellow solid; yield: 60%; mp 177 °C.
Anal. Calcd for C23H21NO11: C, 56.68; H, 4.34; N, 2.87. Found: C,
56.55; H, 4.35; N, 2.79.
Reduction–Cyclization of a-Hydroxy Derivatives 3a–c; General
Procedure
1H NMR (200 MHz, CDCl3): d = 4.04 (s, 3 H, OCH3), 4.12 (s, 3 H,
OCH3), 4.51 (s, 2 H, CH2Br), 7.79–7.84 (m, 2 H, Ar-H), 8.19–8.27
(m, 2 H, Ar-H).
13C NMR (50 MHz, CDCl3): d = 18.9, 63.8, 64.7, 126.8, 126.9,
128.4, 128.8, 131.9, 133.3, 133.4, 134.3, 134.4, 147.8, 150.7, 155.7,
180.7, 181.2.
Fe powder (6 equiv) was added portionwise to a stirred soln of 3a–
c (0.2 g) in glacial AcOH (40 mL) at 65 °C. The soln was main-
tained at 65 °C for 30 min then filtered through Celite. The solvent
was evaporated under reduced pressure and the residue was extract-
ed with CHCl3 (3 × 40 mL). The combined organic layers were
washed with H2O (2 × 40 mL), dried (MgSO4), and concentrated.
The residue was purified by chromatography [silica gel (CH2Cl2–
Et2O, 90:10)] and recrystallization (EtOH) to give the correspond-
ing quinoline derivative 4a–c.
Anal. Calcd for C17H12BrNO6: C, 50.27; H, 2.98; N, 3.45. Found: C,
50.14; H, 2.96; N, 3.46.
Reaction of 2-(Bromomethyl)-1,4-dimethoxy-3-nitro-9,10-an-
thraquinone (7) with a-Keto Ester Derivatives in the Presence
of TDAE; General Procedure
A two-necked flask equipped with a drying tube (silica gel) and a
N2 inlet was charged with a soln of nitroanthraquinone 7 (0.3 g, 0.73
mmol) and diethyl oxomalonate (1 g, 5.9 mmol) or ethyl 2-oxopro-
3,12-Dihydroxy-5-methoxy-3,4-dihydronaphtho[2,3-g]quino-
line-2,6,11(1H)-trione (4a)
Yellow solid; yield: 50%; mp 294 °C.
Synthesis 2009, No. 21, 3677–3683 © Thieme Stuttgart · New York

PAPER
3,4-Dihydronaphtho[2,3-g]quinoline-2,6,11(1H)-triones
3681
panoate (0.68 g, 5.9 mmol) in anhyd THF (3 mL) at –20 °C. The
soln was stirred and maintained at –20 °C for 30 min and then
TDAE (0.15 g, 0.73 mmol) was added dropwise from a syringe. A
red color immediately developed with the formation of a white fine
precipitate. The soln was stirred vigorously at –20 °C for 1 h and
then warmed to r.t. for 4 h, when TLC (CH2Cl2) clearly showed that
compound 7 was totally consumed. The soln was filtered to remove
the octamethyloxamidinium dibromide, and H2O (80 mL) was add-
ed. The aqueous mixture was extracted with CHCl3 (3 × 40 mL) and
the combined organic layers were washed with H2O (2 × 40 mL),
dried (MgSO4), and concentrated. The resulting viscous orange liq-
uid was purified by chromatography [silica gel (CH2Cl2–Et2OH,
95:5)] and recrystallization (EtOH) to give the corresponding nitro-
quinonic ester 8a or 8b.
13C NMR (50 MHz, CDCl3): d = 14.8, 32.0, 62.2, 62.3, 62.5, 74.5,
121.6, 124.4, 126.6, 126.9, 127.0, 134.3, 134.5 (2 C), 134.9, 139.3,
143.9, 155.5, 168.6, 171.2, 181.7, 182.8.
Anal. Calcd for C22H19NO8: C, 62.12; H, 4.50; N, 3.29. Found: C,
61.57; H, 4.63; N, 3.19.
3-Hydroxy-5,12-dimethoxy-3-methyl-3,4-dihydronaphtho[2,3-
g]quinoline-2,6,11(1H)-trione (9b)
Yellow solid; yield: 70%; mp 240 °C.
1H NMR (200 MHz, CDCl3): d = 1.37 (s, 3 H, CH3), 2.30 (br s, 1 H,
OH), 3.04 (d, J = 16.8 Hz, 1 H, CH2), 3.55 (d, J = 16.8 Hz, 1 H,
CH2) 3.93 (s, 3 H, OCH3), 3.97 (s, 3 H, OCH3), 7.74–7.23 (m, 2 H,
Ar-H), 8.17–8.21 (m, 2 H, Ar-H), 8.22 (s, 1 H, NH).
13C NMR (50 MHz, CDCl3): d = 24.8, 34.8, 61.7, 62.1, 68.2, 120.8,
125.6, 125.8, 126.5, 126.6, 133.9, 134.0, 134.2, 134.4, 139.4, 143.3,
155.2, 172.7, 181.3, 182.5.
Diethyl 2-[(1,4-Dimethoxy-3-nitro-9,10-dioxo-9,10-dihydroan-
thracen-2-yl)methyl](hydroxy)malonate (8a)
Yellow solid; yield: 63%; mp 172 °C.
1H NMR (200 MHz, CDCl3): d = 1.30 (t, J = 7.1 Hz, 6 H, 2 CH3),
3.61 (s, 2 H, CH2), 3.89 (s, 3 H, OCH3), 3.98 (s, 3 H, OCH3), 4.27
(q, J = 7.1 Hz, 4 H, 2 CH2), 7.75–7.82 (m, 2 H, Ar-H), 8.13–8.20
(m, 2 H, Ar-H).
13C NMR (50 MHz, CDCl3): d = 13.8 (2 C), 31.1, 62.8, 63.0 (2 C),
64.4, 76.7, 126.7, 126.8, 127.4, 127.8, 130.7, 133.5, 133.6, 134.1,
134.2, 148.1, 152.9, 156.5, 169.5 (2 C), 181.0, 181.4.
Anal. Calcd for C20H17NO6: C, 65.39; H, 4.66; N, 3.81. Found: C,
64.50; H, 4.84; N, 3.66.
Reaction of 2-(Bromomethyl)-1,4-dimethoxy-3-nitro-9,10-an-
thraquinone (7) with Malonate Derivatives; General Procedure
A soln of 60% NaH (3 equiv) in DMSO under an inert atmosphere
was treated with the appropriate dialkyl malonate (3 equiv) and
stirred for 40 min. A soln of 7 (1 equiv) in DMSO was then added
and the mixture was stirred for 15 min. The mixture was poured into
cold H2O (80 mL), and the soln was extracted with CHCl3 (3 × 30
mL). The organic layers were washed with H2O (50 mL), dried
(MgSO4), and concentrated under reduced pressure. Purification by
chromatography [silica gel (CH2Cl2–Et2O, 95:5)] and recrystalliza-
tion (i-PrOH) gave the corresponding quinonic malonate derivative
10a–d.
Anal. Calcd for C24H23NO11: C, 57.49; H, 4.62; N, 2.79. Found: C,
57.21; H, 4.69; N, 2.74.
Ethyl 3-(1,4-Dimethoxy-3-nitro-9,10-dioxo-9,10-dihydroan-
thracen-2-yl)-2-hydroxy-2-methyl Propanoate (8b)
Yellow solid; yield: 38%; mp 128 °C.
1H NMR (200 MHz, CDCl3): d = 1.32 (t, J = 7.2 Hz, 3 H, CH3),
1.46 (s, 3 H, CH3), 3.15 (d, J = 13.8 Hz, 1 H, CH2), 3.27 (d, J = 13.8
Hz, 1 H, CH2), 3.91 (s, 3 H, OCH3), 4.00 (s, 3 H, OCH3), 4.25 (q,
J = 7.2 Hz, 2 H, CH2), 7.77–7.82 (m, 2 H, Ar-H), 8.17–8.23 (m, 2
H, Ar-H).
Diethyl [(1,4-Dimethoxy-3-nitro-9,10-dioxo-9,10-dihydroan-
thracen-2-yl)methyl]malonate (10a)
Yellow solid; yield: 76%; mp 128 °C.
1H NMR (200 MHz, CDCl3): d = 1.22 (t, J = 7.1 Hz, 6 H, 2 CH3),
3.23 (d, J = 7.3 Hz, 2 H, CH2), 3.80 (t, J = 7.3 Hz, 1 H, CH), 3.95
(s, 3 H, OCH3), 3.99 (s, 3 H, OCH3), 4.18 (q, J = 7.1 Hz, 4 H, CH2),
7.72–7.73 (m, 2 H, Ar-H), 8.16–8.20 (m, 2 H, Ar-H).
13C NMR (50 MHz, CDCl3): d = 14.0, 26.0, 36.5, 62.6, 62.8, 64.5,
73.8, 126.8, 126.9, 127.5, 127.6, 131.9, 133.5, 133.7, 134.2, 134.3,
148.2, 152.7, 156.6, 175.5, 181.1, 181.6.
Anal. Calcd for C22H21NO9: C, 59.59; H, 4.77; N, 3.16. Found: C,
59.35; H, 4.85; N, 3.15.
13C NMR (50 MHz, CDCl3): d = 13.9 (2 C), 26.1, 50.9, 61.9 (2 C),
62.9, 64.6, 126.8, 126.9, 127.6, 127.7, 133.1, 133.4, 133.6, 134.2,
134.3, 147.8, 151.8, 156.5, 168.0 (2 C), 180.9, 181.6.
Reduction–Cyclisation of a-Hydroxy Derivatives 8a–b; General
Procedure
Anal. Calcd for C24H23NO10: C, 59.38; H, 4.78; N, 2.89. Found: C,
59.47; H, 4.84; N, 2.84.
Fe powder (30 equiv) was added over 0.5 h to a stirred soln of 8a or
8b (0.1 g) in glacial AcOH (25 mL) at 117 °C. The soln was main-
tained at 117 °C for 2 h then filtered through Celite. The solvent was
evaporated under reduced pressure and the residue was extracted
with CHCl3 (3 × 40 mL). The combined organic layers were washed
with H2O (2 × 40 mL), dried (MgSO4), and concentrated. The resi-
due was purified by chromatography [silica gel (CH2Cl2–Et2O,
90:10)] and recrystallization (EtOH) to give the corresponding
quinoline derivatives 9a and 9b.
Dimethyl [(1,4-Dimethoxy-3-nitro-9,10-dioxo-9,10-dihydroan-
thracen-2-yl)methyl]malonate (10b)
Yellow solid; yield: 69%; mp 137 °C.
1H NMR (200 MHz, CDCl3): d = 3.21 (d, J = 7.3 Hz, 2 H, CH2),
3.73 (s, 6 H, 2 CH3), 3.82 (t, J = 7.3 Hz, 1 H, CH), 3.95 (s, 3 H,
OCH3), 3.99 (s, 3 H, OCH3), 7.77–7.82 (m, 2 H, Ar-H), 8.17–8.21
(m, 2 H, Ar-H).
13C NMR (50 MHz, CDCl3): d = 26.2, 50.6, 52.9 (2 C), 63.0, 64.6,
126.8, 126.9, 127.6, 127.7, 132.8, 133.5, 133.6, 134.2, 134.3, 147.8,
151.8, 156.4, 168.4 (2 C), 180.9, 181.6.
Ethyl 3-Hydroxy-5,12-dimethoxy-2,6,11-trioxo-1,2,3,4,6,11-
hexahydronaphtho[2,3-g]quinoline-3-carboxylate (9a)
Yellow solid; yield: 86%; mp 242 °C.
1H NMR (200 MHz, CDCl3): d = 1.22 (t, J = 7.1 Hz, 3 H, CH3),
1.59 (br s, 1 H, OH), 3.24 (d, J = 17.3 Hz, 1 H, CH2), 3.81 (d,
J = 17.3 Hz, 1 H, CH2), 3.96 (s, 3 H, OCH3), 3.97 (s, 3 H, OCH3),
4.24 (q, J = 7.1 Hz, 2 H, CH2), 7.73–7.78 (m, 2 H, Ar-H), 8.17–8.24
(m, 2 H, Ar-H), 8.36 (s, 1 H, NH).
Anal. Calcd for C22H19NO10: C, 57.77; H, 4.19; N, 3.06. Found: C,
57.51; H, 4.25; N, 2.81.
Diethyl [(1,4-Dimethoxy-3-nitro-9,10-dioxo-9,10-dihydroan-
thracen-2-yl)methyl](methyl)malonate (10c)
Yellow solid; yield: 63%; mp 133 °C.
1H NMR (200 MHz, CDCl3): d = 1.24 (s, 3 H, CH3), 1.25 (t, J = 7.2
Hz, 6 H, 2 CH3), 3.40 (s, 2 H, CH2), 3.85 (s, 3 H, OCH3), 3.97 (s, 3
Synthesis 2009, No. 21, 3677–3683 © Thieme Stuttgart · New York

3682
O. Khoumeri et al.
PAPER
Ethyl 5,12-Dimethoxy-3-methyl-2,6,11-trioxo-1,2,3,4,6,11-
H, OCH3), 4.18 (q, J = 7.2 Hz, 4 H, 2 CH2), 7.73–7.82 (m, 2 H, Ar-
H), 8.14–8.20 (m, 2 H, Ar-H).
hexahydronaphtho[2,3-g]quinoline-3-carboxylate (11c)
Yellow solid; yield: 75%; mp 169 °C.
13C NMR (50 MHz, CDCl3): d = 13.9 (2 C), 19.5, 31.5, 53.2, 61.9
(2 C), 62.6, 64.5, 126.7, 126.9, 127.3, 127.6, 132.3, 133.4, 133.6,
134.1, 134.2, 147.7, 152.7, 157.0, 171.2 (2 C), 180.9, 181.4.
1H NMR (200 MHz, CDCl3): d = 1.13 (t, J = 7.2 Hz, 3 H, CH3),
1.22 (s, 3 H, CH3), 2.90 (d, J = 16.8 Hz, 1 H, CH2), 3.74 (d, J = 16.8
Hz, 1 H, CH2), 3.93 (s, 6 H, 2 OCH3), 4.12 (q, J = 7.2 Hz, 2 H, CH2),
3.69–7.73 (m, 2 H, Ar-H), 8.14–8.16 (m, 2 H, Ar-H), 8.52 (s, 1 H,
NH).
Anal. Calcd for C25H25NO10: C, 60.12; H, 5.05; N, 2.80. Found: C,
59.87; H, 5.10; N, 2.67.
Diethyl [(1,4-Dimethoxy-3-nitro-9,10-dioxo-9,10-dihydroan-
thracen-2-yl)methyl](phenyl)malonate (10d)
Yellow solid; yield: 71%; mp 127 °C.
13C NMR (50 MHz, CDCl3): d = 13.9, 20.3, 31.3, 48.5, 61.9, 62.0,
62.1, 121.5, 123.9, 126.1, 126.4, 126.6, 133.4, 133.5, 133.8, 133.9,
137.8, 142.6, 155.1, 169.2, 171.0, 181.5, 182.5.
1H NMR (200 MHz, CDCl3): d = 1.26 (t, J = 7.2 Hz, 6 H, 2 CH3),
3.80 (s, 3 H, OCH3), 3.81 (s, 2 H, CH2), 3.82 (s, 3 H, OCH3), 4.23
(q, J = 7.1 Hz, 4 H, 2 CH2), 7.05–7.18 (m, 5 H, Ar-H), 7.76–7.81
(m, 2 H, Ar-H), 8.16–8.20 (m, 2 H, Ar-H).
13C NMR (50 MHz, CDCl3): d = 13.8 (2 C), 34.2, 62.3 (2 C), 62.4,
63.1, 64.2, 126.7, 126.8, 126.9, 127.3, 127.7, 127.9 (2 C), 128.3 (2
C), 132.9, 133.5, 133.6, 134.1, 134.2, 135.4, 147.6, 152.1, 157.3,
169.6 (2 C), 180.9, 181.4.
Anal. Calcd for C23H21NO7: C, 65.24; H, 5.00; N, 3.31. Found: C,
65.14; H, 5.06; N, 3.29.
Ethyl 5,12-Dimethoxy-2,6,11-trioxo-3-phenyl-1,2,3,4,6,11-
hexahydronaphtho[2,3-g]quinoline-3-carboxylate (11d)
Yellow solid; yield: 73%; mp 250 °C.
1H NMR (200 MHz, CDCl3): d = 1.21 (t, J = 7.1 Hz, 3 H, CH3),
3.78 (d, J = 16.8 Hz, 1 H, CH2), 3.88 (s, 3 H, OCH3), 3.92 (d,
J = 16.8 Hz, 1 H, CH2), 3.97 (s, 3 H, OCH3), 4.24 (q, J = 7.1 Hz, 2
H, CH2), 7.29–7.34 (m, 5 H, Ar-H), 7.70–7.77 (m, 2 H, Ar-H),
8.12–8.20 (m, 2 H, Ar-H), 8.56 (s, 1 H, NH).
Anal. Calcd for C30H27NO10: C, 64.17; H, 4.85; N, 2.49. Found: C,
64.06; H, 4.98; N, 2.37.
Reduction–Cyclization of Quinonic Malonate Derivatives
10a–d; General Procedure
13C NMR (50 MHz, CDCl3): d = 13.9, 29.9, 58.0, 62.0, 62.1, 62.5,
121.7, 124.3, 126.1, 126.4, 126.6, 127.3 (2 C), 128.3, 128.6 (2 C),
133.4, 133.5, 133.8, 133.9, 134.6, 137.2, 142.6, 155.1, 167.8, 169.6,
181.6, 182.5.
Fe powder (30 equiv) was added over 30 min to a stirred soln of
10a–d (0.2 g) in glacial AcOH (50 mL) at 117 °C. The soln was
maintained at 117 °C for 2 h then filtered through Celite. The sol-
vent was evaporated under reduced pressure and the residue was ex-
tracted with CHCl3 (3 × 40 mL). The combined organic layers were
washed with H2O (2 × 40 mL), dried (MgSO4), and concentrated.
The residue was purified by chromatography [silica gel (CH2Cl2–
Et2O, 90:10)] and recrystallization (EtOH) to give the correspond-
ing quinoline derivatives 11a–d.
Anal. Calcd for C28H23NO7: C, 69.27; H, 4.78; N, 2.89. Found: C,
68.90; H, 4.92; N, 2.84.
Acknowledgment
This work supported by the Centre National de la Recherche Scien-
tifique and the Université de la Méditerranée. We express our
thanks to Dr V. Remusat for recording the NMR spectra.
Ethyl 5,12-Dimethoxy-2,6,11-trioxo-1,2,3,4,6,11-hexahydro-
naphtho[2,3-g]quinoline-3-carboxylate (11a)
Yellow solid; yield: 90%; mp 243 °C.
1H NMR (200 MHz, CDCl3): d = 1.27 (t, J = 7.1 Hz, 3 H, CH3),
3.33 (dd, J = 15.8, 5.6 Hz, 1 H, CH2), 3.54 (dd, J = 15.8, 8.4 Hz, 1
H, CH2), 3.66 (m, 1 H, CH), 3.95 (s, 6 H, 2 OCH3), 4.23 (q, J = 7.1
Hz, 2 H, CH2), 7.72–7.73 (m, 2 H, Ar-H), 8.16–8.20 (m, 2 H, Ar-
H), 8.34 (s, 1 H, NH).
References
(1) (a) Lin, A. J.; Cosby, L. A.; Shansky, C. W.; Sartorelli, A. C.
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Bobrysheva, T. V.; Buyanov, V. N.; Preobrazhenskaya,
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13C NMR (50 MHz, CDCl3): d = 14.1, 23.4, 46.3, 62.0, 62.1, 62.2,
121.8, 123.5, 126.2, 126.5, 126.7, 133.5, 133.6, 133.9, 134.0, 137.6,
142.8, 155.3, 165.7, 168.3, 181.6, 182.5.
Anal. Calcd for C22H19NO7: C, 64.54; H, 4.68; N, 3.24. Found: C,
64.48; H, 4.76; N, 3.36.
(4) Shchekotikhin, A. E.; Buyanov, V. N.; Preobrazhenskaya,
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Methyl 5,12-Dimethoxy-2,6,11-trioxo-1,2,3,4,6,11-hexahydro-
naphtho[2,3-g]quinoline-3-carboxylate (11b)
Yellow solid; yield: 87%; mp 272 °C.
1H NMR (200 MHz, CDCl3): d = 3.33 (dd, J = 16.4, 7.8 Hz, 1 H,
CH2), 3.68 (dd, J = 16.4, 6.1 Hz, 1 H, CH2), 3.72 (dd, J = 7.8 Hz,
J = 6.1 Hz, 1 H, CH), 3.79 (s, 3 H, OCH3), 3.95 (s, 3 H, OCH3), 3.96
(s, 3 H, OCH3), 7.74–7.81 (m, 2 H, Ar-H), 8.17–8.22 (m, 2 H, Ar-
H), 8.33 (s, 1 H, NH).
(5) Shchekotikhin, A. E.; Dezhenkova, L. G.; Susova, O. Y.;
Glazunova, V. A.; Luzikov, Y. N.; Sinkevich, Y. B.;
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G.; Terme, T.; Médebielle, M.; Vanelle, P. Tetrahedron Lett.
2004, 45, 5121. (c) Amiri-Attou, O.; Terme, T.; Vanelle, P.
Molecules 2005, 10, 545. (d) Montana, M.; Terme, T.;
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(f) Montana, M.; Crozet, M. D.; Castera-Ducros, C.; Terme,
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13C NMR (50 MHz, DMSO-d6): d = 23.2, 46.1, 52.9, 61.8, 62.1,
121.1, 124.8, 126.1, 126.5, 126.6, 133.8, 134.1 (2 C), 134.5, 139.3,
143.7, 154.7, 166.7, 169.9, 181.3, 182.4.
Anal. Calcd for C21H17NO7: C, 63.80; H, 4.33; N, 3.54. Found: C,
63.84; H, 4.52; N, 3.44.
(7) Khoumeri, O.; Montana, M.; Terme, T.; Vanelle, P.
Tetrahedron 2008, 64, 11237.
Synthesis 2009, No. 21, 3677–3683 © Thieme Stuttgart · New York

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Synthesis 2009, No. 21, 3677–3683 © Thieme Stuttgart · New York