Synthesis of N-substituted 1,2-dihydrobenz[g]isoquinoline-5,10-diones

Article abstract of DOI:10.1016/j.tet.2008.03.084

The synthesis of N-substituted 1,2-dihydrobenz[g]isoquinoline-5,10-diones was envisaged as part of?our?research on structural modifications of pentalongin, the active principle of Pentas longiflora Oliv.?Therefore, a synthesis of the 2-aza analogues of this natural pyranonaphthoquinone with an acid-mediated intramolecular cyclization of different N-protected 2-(((2,2-dimethoxyethyl)amino)methyl)-1,4-naphthoquinones in the key step was conducted. The synthesized 1,2-dihydrobenz[g]isoquinoline-5,10-diones represent a new class of compounds, which has been undescribed in organic chemistry.

Full text of DOI:10.1016/j.tet.2008.03.084

Tetrahedron 64 (2008) 4985–4992
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of N-substituted 1,2-dihydrobenz[g]isoquinoline-5,10-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:
The synthesis of N-substituted 1,2-dihydrobenz[g]isoquinoline-5,10-diones was envisaged as part
of our research on structural modifications of pentalongin, the active principle of Pentas longiflora
Oliv. Therefore, a synthesis of the 2-aza analogues of this natural pyranonaphthoquinone with an
acid-mediated intramolecular cyclizationofdifferentN-protected2-(((2,2-dimethoxyethyl)amino)methyl)-
1,4-naphthoquinones in the key step was conducted. The synthesized 1,2-dihydrobenz[g]isoquinoline-
5,10-diones represent a new class of compounds, which has been undescribed in organic chemistry.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 16 November 2007
Received in revised form 20 March 2008
Accepted 26 March 2008
Available online 29 March 2008
Keywords:
1,2-Dihydrobenz[g]isoquinoline-5,10-diones
2-Azaanthraquinones
Pyranonaphthoquinones
Pentalongin
Friedel–Crafts cyclization
1. Introduction
dihydrobenz[g]isoquinoline-5,10-diones 9 have never been repor-
ted in literature and as this structure was totally new, an extra
Although pyranonaphthoquinones represent a large class of
natural products, their naturally occurring 2-aza analogues, all of
which have been isolated as the aromatic 2-azaanthraquinones,
have rarely been found in nature. So far, only a few naturally
occurring 2-azaanthraquinones have been reported: bostrycoidin
(1),1 9-O-methylbostrycoidin (2),2 tolypocladin (3),3 6-deoxy-8-
methylbostrycoidin (4),4,5 6-deoxybostrycoidin (5),6 scorpinone
(6),4 and benz[g]isoquinoline-5,10-dione (7).7 Nevertheless, also
these compounds have been found to possess interesting physio-
impetus was given to the synthesis of such novel compounds. As
part of an explanation for the lack of occurrence of 1,2-dihy-
drobenz[g]isoquinoline-5,10-diones 9 in nature, this might be due
to their tendency to spontaneously aromatize to the corresponding
2-azaanthraquinones. Since there is no doubt that the N-unsub-
stituted compound 9 (R¼H) cannot be synthesized as it would
oxidatively aromatize to benz[g]isoquinoline-5,10-dione 7, the in-
clusion of N-protection for the synthesis of the targeted 1,2-dihy-
drobenz[g]isoquinoline-5,10-diones 9 will be necessary.
logical activities. For instance, bostrycoidin (1),
a
2-azaan-
Retrosynthetic analysis suggested that the target compounds
thraquinone isolated from several fungi of the Fusarium species,1
has been shown to possess significant in vitro antibiotic activity
against Mycobacterium tuberculosis.8 9-O-Methylbostrycoidin (2)
revealed antibiotic activity against Gram-positive bacteria2,9 and
benz[g]isoquinoline-5,10-dione (7), isolated form Psychotria cam-
ponutans, has been found active against the multi-drug resistant
Plasmodium falciparum.7
9
could be prepared starting from 1,4-dimethoxy-2-for-
mylnaphthalene (11). Condensation with aminoacetaldehyde di-
methyl acetal, followed by reduction of the imine and N-protection
should give tertiary amines 10. Oxidative demethylation of
compounds 10 to the corresponding 1,4-naphthoquinones and
acid-mediated intramolecular ring closure should give the target
1,2-dihydrobenz[g]isoquinoline-5,10-diones 9.
In view of interesting physiological properties of pentalongin
(8),10 the active principle of the medicinal plant Pentas longiflora,
and naturally occurring 2-azaanthraquinones 1–7, and as a part
of our research on the structural modifications of pentalongin
(8),11 the synthesis of N-substituted 1,2-dihydrobenz[g]isoquino-
2. Results and discussion
N-((1,4-Dimethoxynaphth-2-yl)methylene)-N-(2,2-dimeth-
oxyethyl)amine (12) was prepared in 97% yield by condensation
of 1,4-dimethoxy-2-formylnaphthalene (11)12 with amino-
acetaldehyde dimethyl acetal in dichloromethane in the presence
of magnesium(II) sulfate (Scheme 1). Reduction of this aldimine
12 with sodium borohydride in methanol at room temperature
line-5,10-diones
9 as direct 2-aza analogues of this natural
pyranonaphthoquinone was envisaged. Remarkably, 1,2-
gave
N-(2,2-dimethoxyethyl)-N-((1,4-dimethoxynaphth-2-yl)-
* Corresponding author. Tel.: þ32 9 264 59 51; fax: þ32 9 264 62 43.
E-mail address: norbert.dekimpe@ugent.be (N. De Kimpe).
methyl)amine (13) in 90% yield. At this stage of the reaction sequence,
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.084

4986
J. Jacobs et al. / Tetrahedron 64 (2008) 4985–4992
R1
R3
O
O
R1
O
O
R2
R3
N
N
R2
1 R1 = R3 = OH, R2 = OMe (Bostrycoidin)
2 R1 = R2 = OMe, R3 = OH (9-O-Methylbostrycoidin)
3 R1 = R2 = R3 = OH (Tolypocladin)
4 R1 = OH, R2 = Me, R3 = OMe
(6-Deoxy-8-methylbostrycoidin)
5 R1 = OH, R2 = H, R3 = OMe
(6-Deoxybostrycoidin)
6 R1 = R3 = OMe, R2 = H
(Scorpinone)
O
O
O
O
O
R
N
O
N
O
7 (Benz[g]isoquinoline-5,10-dione)
8 (Pentalongin)
9 (R = H, alkyl, aryl)
O
OMe
OMe O
H
R
N
OMe
OMe
N
R
O
OMe
OMe
9
10
11
several different types of N-protecting groups were then in-
troduced in order to (1) avoid the oxidation of the nitrogen atom
during the next oxidative demethylation step with cerium(IV)
ammonium nitrate and (2) to test the stability of the different
N-protecting groups during the final acid-catalyzed cyclization
step. In this way, secondary amine 13 was converted into its N-t-
Boc, N-methanesulfonyl, N-p-toluenesulfonyl, and N-acetyl de-
rivatives 10a–d in 55–85% yield by reaction with di-tert-butyl
dicarbonate, methanesulfonyl chloride, p-toluenesulfonyl chlo-
ride, and acetic anhydride, respectively (Scheme 1). However,
it was not possible to introduce more electron-rich N-sub-
stituents on secondary amine 13, since reaction with iodo-
methane in dichloromethane in the presence of silver(I) oxide or
potassium carbonate resulted in unaltered starting material. All
attempts to cyclize amino acetal 13 and N-protected analogues
10 directly under Friedel–Crafts conditions failed completely.
Therefore, cerium(IV) ammonium nitrate mediated oxidative
demethylation afforded the corresponding 1,4-naphthoquinone
OMe O
H
OMe
11
MeO
NH2
1 equiv.
OMe
2 equiv. MgSO4
CH2Cl2, rt, 2 h
H
OMe
OMe
OMe
OMe
OMe
N
2 equiv. NaBH4
MeOH, rt, 16 h
N
H
OMe
OMe
OMe
12 (97%)
13 (90%)
(t-Boc)2O, Et3N, CH2Cl2, rt, 16 h (for 10a)
MesCl, Et3N, CH2Cl2, rt, 16 h (for 10b)
TosCl, pyridine, rt, 16 h (for 10c)
Ac2O, pyridine, rt, 16 h (for 10d)
O
O
OMe
OMe
OMe
OMe
N
N
R
3 equiv. CAN
R
OMe
CH3CN/H2O 1/2,
0 °C, 30 min
OMe
14a: R = t-Boc (100%)
14b: R = Mes (94%)
14c: R = Tos (83%)
14d: R = Ac (81%)
10a: R = t-Boc (85%)
10b: R = Mes (55%)
10c: R = Tos (84%)
10d: R = Ac (81%)
Scheme 1.

J. Jacobs et al. / Tetrahedron 64 (2008) 4985–4992
4987
acetals 14a–d, which were then also evaluated in the cyclization
protocol.
complete conversion to benz[g]isoquinoline-5,10-dione (7). How-
ever, the hydrolysis of the N-methanesulfonyl group could be di-
minished using less concentrated solutions of hydrobromic acid
and a shorter reaction time. Even upon reaction of aldehyde 15 in
5% HBr in acetic acid at room temperature for 1 h, the desired 2-
methanesulfonyl-1,2-dihydrobenz[g]isoquinoline-5,10-dione (9b)
was still obtained in a mixture together with 2-azaanthraquinone 7
in a ratio of 73:27 (1H NMR). It was found, however, that the
intramolecular cyclization of 1,4-naphthoquinone acetal 14b could
be accomplished using a mixture of 12 M aqueous hydrochloric
acid in diethyl ether to afford 2-methanesulfonyl-1,2-dihy-
drobenz[g]isoquinoline-5,10-dione (9b) in 62% yield as the sole
reaction product without any hydrolysis of the N-methanesulfonyl
group. Mechanistically, the acetal function of compound 14b was
hydrolyzed by 12 M aqueous hydrochloric acid to the correspond-
ing aldehyde. The protonated aldehyde function then gave rise to
an intramolecular 6-endo-trig ring closure, which was followed by
elimination of water and tautomerization to give the target com-
pound 9b.
Curiously, similar treatment of the N-p-toluenesulfonyl pro-
tected 1,4-naphthoquine acetal 14c with 12 M aqueous hydro-
chloric acid for 16 h at room temperature afforded the desired
2-(p-toluenesulfonyl)-1,2-dihydrobenz[g]isoquinoline-5,10-dione (9c)
in only 8% yield, together with the 4-hydroxy-2-(p-toluene-
sulfonyl)-1,2,3,4-tetrahydro-benz[g]isoquinoline-5,10-dione (16),
which was isolated in 38% after purification by flash chromatog-
raphy. It has been reported that N-p-toluenesulfonyl protected
(benzylamino)acetaldehyde acetals selectively afford 4-hydroxy-
1,2,3,4-tetrahydroisoquinolines upon treatment with concentrated
hydrochloric acid.13 The complete conversion of 1,4-naph-
thoquinone acetal 14c to 3,4-dehydro derivative 9c could be
accomplished after a reaction time of 5 days in a mixture of
12 M aqueous hydrochloric acid and diethyl ether and afforded
the pure compound 9c in 84% yield after recrystallization from
ethanol (Scheme 4).
The acid-catalyzed intramolecular cyclization of the N-t-Boc
protected 1,4-napthoquinone acetal 14a was found only to proceed
upon treatment with a saturated solution of dry hydrogen chloride
in diethyl ether at room temperature for 16 h (Scheme 2). In a first
step, the acetal function of compound 14a was protonated and after
elimination of methanol, the corresponding stabilized carbenium
ion was formed, which gave rise to an intramolecular 6-endo-trig
ring closure. It seems that the electron-poor double bond of the
quinone system is reactive enough to bring about this cyclization.
Then, elimination of methanol and deprotection of the N-t-Boc
group, followed by spontaneous oxidation in air gave rise to the
formation of benz[g]isoquinoline-5,10-dione (7), which was
obtained in 38% yield after isolation by flash chromatography. Al-
though the deprotection of the N-t-Boc group was not targeted, it
could not be prevented using the above-mentioned severe reaction
conditions. However, treatment of 14a with diluted aqueous solu-
tions of hydrochloric acid or oxalic acid resulted only in the hy-
drolysis of the acetal function and no cyclization was observed in
these cases. Thus, the conversion of 14a to the corresponding 1,2-
dihydrobenz[g]isoquinoline-5,10-dione 9 (R¼t-Boc) failed due to
removal of the N-protecting group, which was followed by spon-
taneous oxidation to the aromatic compound 7. This conversion
was best performed by treatment of the reaction mixture with
aqueous sodium hydrogen carbonate at room temperature after the
acid-mediated intramolecular cyclization.
O
O
(1) HClg
OMe
t-Boc OMe
Et2O, rt, 16 h
N
N
(2) NaHCO3 (aq.)/
CH2Cl2 1/1,
rt, 16 h
O
O
7 (38%)
14a
Scheme 2.
Finally, also the N-acetyl protected 1,4-naphthoquinone 14d was
treated with 12 M aqueous hydrochloric acid (Scheme 5). In this
case, the reaction conditions seemed to be too strong for the acetyl
group to survive and only complex reaction mixtures were
obtained.
As it is clear from the above presented results, the synthesis of
the targeted N-protected benz[g]isoquinoline-5,10-diones 9 as di-
rect 2-aza analogues of the natural product pentalongin (8) is
subject to some severe limitations. First of all, only electron-with-
drawing protecting groups could be introduced at nitrogen of
Using N-methanesulfonyl protected 1,4-naphthoquinone acetal
14b as a substrate for the Lewis acid-catalyzed intramolecular cy-
clization, treatment with excess aluminum(III) chloride in
dichloromethane afforded aldehyde 15 in 87% yield (Scheme 3). The
intramolecular cyclization of this aldehyde 15 was first attempted
using different concentrations of hydrobromic acid. The outcome of
the cyclization reaction was observed to be dependent upon the
applied concentration of hydrobromic acid. Treatment of aldehyde
15 with 33% HBr in acetic acid for 16 h at room temperature gave
O
O
1) 10 equiv. AlCl3
CH2Cl2, 0 °C, 2 h
2) aq. work up
OMe
Mes OMe
O
N
N
Mes
H
O
O
14b
15 (87%)
Procedure B
Procedure A
33% HBr in AcOH, 5% HBr in AcOH,
12 M HCl (aq.)/Et2O 1/1,
rt, 16 h
rt, 16 h
rt, 1 h
O
O
O
O
Mes
Mes
N
N
N
O
O
7
9b
9b (62%)
A: 7/9b 100/0 (1H NMR), yield = 64%
B: 7/9b 73/27 (1H NMR)
Scheme 3.

4988
J. Jacobs et al. / Tetrahedron 64 (2008) 4985–4992
4.2. Synthesis of N-((1,4-dimethoxynaphth-2-yl)methylene)-
(2,2-dimethoxyethyl)amine (12)
O
O
12 M HCl (aq.)/Et2O 2/7,
rt, 5 d
OMe
Tos OMe
Tos
N
N
1,4-Dimethoxy-2-formylnaphthalene (11)12 (0.016 mol, 3.5 g),
aminoacetaldehyde dimethyl acetal (0.016 mol, 1.68 g), and mag-
nesium(II) sulfate (0.032 mol, 3.84 g) were dissolved in dichloro-
methane in a flask, which was fitted with a calcium chloride tube,
and the mixture was stirred for 2 h. Filtration and evaporation of
the solvent in vacuo gave the crude imine 12 (4.7 g, 97% yield),
which was used without purification in the next step (purity by 1H
NMR>95%). An analytical sample was obtained by recrystallization
from methanol to give N-((1,4-dimethoxynaphth-2-yl)methylene)-
N-(2,2-dimethoxyethyl)amine (12) as yellow flakes, mp 68 ꢀC.
O
O
14c
9c (84%)
12 M HCl (aq.)/Et2O 1/2,
rt, 16 h
O
O
O
Tos
Tos
N
N
OH
O
4.2.1. N-((1,4-Dimethoxynaphth-2-yl)methylene)-N-
(2,2-dimethoxyethyl)amine (12)
16 (38%)
9c (8%)
1H NMR (CDCl3): d 3.42 (6H, s, CH(OCH3)2), 3.88 (2H, d, J¼5.3 Hz,
NCH2), 3.92 (3H, s, OCH3), 3.99 (3H, s, OCH3), 4.73 (1H, t, J¼5.3 Hz,
CH(OCH3)2), 7.48–7.52 (2H, m, H-6 and H-7), 7.35 (1H, s, H-3), 8.06–
8.25 (2H, m, H-5 and H-8). 13C NMR (CDCl3): d 53.9 (CH(OCH3)2),
55.7 (OCH3), 63.9 (OCH3), 64.1 (NCH2), 100.0 (C-3), 103.8
(CH(OCH3)2), 122.3 and 122.6 (C-5 and C-8), 124.3 (]Cquat), 126.8
and 126.9 (C-6 and C-7), 128.4 (]Cquat), 128.5 (]Cquat), 151.6 (]C–
Scheme 4.
N-(2,2-dimethoxyethyl)-N-((1,4-dimethoxynaphth-2-yl)methyl)-
amine (13). Eventually, two derivatives 9b and 9c could be syn-
thesized bearing the desired enamine functionality, which is not as
straightforward as it seems since in other cases cleavage caused by
oxidative aromatization with this type of protecting groups has
been established.14
O), 152.0 (]C–O), 159.6 (C]N). IR (KBr): n
1624, 1592, 1449,
max
1365, 1265 cmꢁ1. MS (ES) m/z (%): 303 (Mþ, 11), 216 (6), 199 (6), 75
(100). Anal. Calcd for C17H21NO4: C, 67.31; H, 6.98; N, 4.62. Found: C,
67.48; H, 6.96; N, 4.52.
3. Conclusion
4.3. Synthesis of N-(2,2-dimethoxyethyl)-N-
((1,4-dimethoxynaphth-2-yl)methyl)amine (13)
A synthetic program was directed toward the synthesis of N-
protected benz[g]isoquinoline-5,10-diones 9, which represent
a new class of compounds in organic chemistry. The synthesis to-
ward these 2-aza analogues of pentalongin (8) was achieved by the
synthesis of different 1,4-naphthoquinone aminoacetals 14, which
could be converted into the target compounds with an acid-
mediated intramolecular cyclization.
To a cooled (0 ꢀC) solution of N-((1,4-dimethoxynaphth-2-
yl)methylene)-N-(2,2-dimethoxyethyl)amine (12) (3 mmol, 0.91 g)
in methanol (20 ml) was added sodium borohydride (6 mmol,
0.20 g) and the reaction mixture was stirred for 16 h at room
temperature in a flask fitted with a calcium chloride tube. The re-
action was quenched by careful addition of water (1 ml) and the
solution was concentrated in vacuo to 5 ml. After the addition of
water, the aqueous solution was extracted with small portions of
dichloromethane. The combined organic extracts were washed
with brine, dried (MgSO4), and evaporated in vacuo. Flash
chromatography on silica gel using a solution of 2% methanol in
chloroform as eluent gave N-(2,2-dimethoxyethyl)-N-((1,4-dime-
thoxynaphth-2-yl)methyl)amine (13) (0.82 g, 90% yield) as an oil.
4. Experimental section
4.1. General experimental methods
Spectroscopic data were recorded as follows: 1H NMR spectra
were recorded at 270 MHz and 13C NMR spectra were recorded at
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 Perkin Elmer
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). Diethyl ether was freshly distilled over
sodium benzophenone ketyl and dichloromethane was distilled
over calcium hydride.
4.3.1. N-(2,2-Dimethoxyethyl)-N-((1,4-dimethoxynaphth-
2-yl)methyl)amine (13)
1H NMR (CDCl3): d 2.80 (2H, d, J¼5.6 Hz, NCH2CH), 3.36 (6H, s,
CH(OCH3)2), 3.90 (3H, s, OCH3), 3.99 (3H, s, OCH3), 4.00 (2H, s,
ArCH2), 4.52 (1H, t, J¼5.6 Hz, CH(OCH3)2), 6.81 (1H, s, H-3), 7.43–
7.56 (2H, m, H-6 and H-7), 8.02–8.05 (1H, m, H-5 or H-8), 8.20–8.23
(1H, m, H-5 or H-8). 13C NMR (CDCl3): d 48.3 (ArCH2), 50.5
(NCH2CH), 53.8 (CH(OCH3)2), 55.6 (OCH3), 62.3 (OCH3), 103.8
(CH(OCH3)2), 104.8 (C-3), 121.8 and 122.4 (C-5 and C-8), 125.2 and
126.5 (C-6 and C-7), 126.0 (]Cquat), 127.7 (]Cquat), 128.5 (]Cquat),
O
O
O
OMe
Ac
or
N
N
N
X
Ac OMe
12 M HCl (aq.)/Et2O 1/2,
rt, 16 h
O
O
O
14d
9d
7
Scheme 5.

J. Jacobs et al. / Tetrahedron 64 (2008) 4985–4992
4989
147.5 (]C–O), 152.0 (]C–O). IR (NaCl): nmax 3337, 1629, 1596, 1455,
1372, 1266 cmꢁ1. MS (ES) m/z (%): 305 (Mþ, 11), 216 (32), 201 (100),
75 (93). Anal. Calcd for C17H23NO4: C, 66.86; H, 7.59; N, 4.59. Found:
C, 66.70; H, 7.44, N, 4.31.
(]Cquat), 128.3 (]Cquat), 148.0 (]C–O), 152.3 (]C–O). IR (NaCl):
nmax 1625, 1595, 1458, 1332, 1146 cmꢁ1. MS (ES) m/z (%): 383 (Mþ,
9), 201 (28), 75 (100). Anal. Calcd for C18H22NO6S: C, 56.38; H, 6.57;
N, 3.65. Found: C, 56.06; H, 6.29; N, 3.82.
4.4. Synthesis of N-(tert-butoxycarbonyl)-N-(2,2-dimethoxy-
ethyl)-N-((1,4-dimethoxy-naphth-2-yl)methyl)amine (10a)
4.6. Synthesis of N-(p-toluenesulfonyl)-N-(2,2-dimethoxy-
ethyl)-N-((1,4-dimethoxynaphth-2-yl)methyl)amine (10c)
A
solution of N-(2,2-dimethoxyethyl)-N-((1,4-dimethoxy-
p-Toluenesulfonyl chloride (0.01 mol, 2.00 g) was added por-
tionwise over a period of 30 min to a solution of N-(2,2-dime-
naphth-2-yl)methyl)amine (13) (3 mmol, 0.92 g), di-tert-butyldi-
carbonate (3 mmol, 0.65 g), and triethylamine (3 mmol, 0.30 g) in
dichloromethane (20 ml) was stirred for 16 h at room temperature
under nitrogen atmosphere. The solution was poured in 2 M HCl
and the aqueous solution was extracted with dichloromethane,
dried (MgSO4), and evaporated in vacuo. Flash chromatography on
silica gel using ethyl acetate/hexane (1:4) as eluent gave N-(tert-
butoxycarbonyl)-N-(2,2-dimethoxyethyl)-N-((1,4-dimethoxy-
naphth-2-yl)methyl)amine (10a) (1.03 g, 85% yield) as an oil.
Product 10a occurred as a 1:1 mixture of rotamers (CDCl3).
thoxyethyl)-N-((1,4-dimethoxynaphth-2-yl)methyl)amine
(13)
(0.01 mol, 3.05 g) in pyridine (10 ml) and the reaction mixture was
stirred for 16 h at room temperature in a flask, which was fitted
with a calcium chloride tube. Water was added and the aqueous
solution was extracted with small portions of diethyl ether. The
combined organic extracts were washed with 2 M HCl and sub-
sequently with a saturated aqueous solution of sodium hydrogen
carbonate, dried (MgSO4), and evaporated in vacuo. Flash chro-
matography on silica gel with ethyl acetate/hexane (1:4) as eluent
gave N-(p-toluenesulfonyl)-N-(2,2-dimethoxyethyl)-N-((1,4-dime-
thoxynaphth-2-yl)methyl)amine (10c) (3.87 g, 84% yield) as yellow
crystals.
4.4.1. N-(tert-Butoxycarbonyl)-N-(2,2-dimethoxyethyl)-N-((1,4-
dimethoxynaphth-2-yl)methyl)amine (10a)
1H NMR (CDCl3): d 1.47 and 1.54 (9H, each s, C(CH3)3), 3.26 and
3.36 (2H, each d, J¼4.7 Hz, NCH2CH), 3.87 (3H, s, OCH3), 3.94 (3H, s,
OCH3), 4.50 and 4.61 (1H, each t, J¼4.7 Hz, CH(OCH3)2), 4.76 and
4.79 (2H, each s, ArCH2), 5.35 and 5.38 (6H, each s, CH(OCH3)2), 6.67
and 6.75 (1H, each s, H-3), 7.42–7.55 (2H, m, H-6 and H-7), 8.01–
8.04 (1H, m, H-5 or H-8), 8.20–8.23 (1H, m, H-5 or H-8). 13C NMR
(CDCl3): d 28.5 (C(CH3)3), 45.1 and 46.3 (ArCH2), 48.1 and 48.3
(NCH2CH), 54.2 (CH(OCH3)2), 55.5 (OCH3), 62.0 (OCH3), 62.4
(OCH3), 80.0 (C(CH3)3), 102.9 and 103.1 (CH(OCH3)2), 103.5 and
103.9 (C-3), 121.81 and 122.83 (C-5 and C-8), 125.3 and 126.6 (C-6
and C-7), 126.2 (]Cquat), 128.5 (]Cquat), 147.0 and 147.5 (N–C]O),
152.1 (]C–O), 156.2 (]C–O). IR (NaCl): nmax 1693, 1629, 1597, 1460,
1369 cmꢁ1. MS (ES) m/z (%): 405 (Mþ, 1), 152 (35), 121 (17), 86 (63),
84 (100). Anal. Calcd for C22H31NO6: C, 65.17; H, 7.71; N, 3.45.
Found: C, 64.84; H, 7.46; N, 3.25.
4.6.1. N-(p-Toluenesulfonyl)-N-(2,2-dimethoxyethyl)-N-
((1,4-dimethoxynaphth-2-yl)methyl)amine (10c)
An analytical sample was obtained by recrystallization from
ethanol and afforded 10c as fine yellow needles, mp 80 ꢀC. 1H NMR
(CDCl3): d 2.42 (3H, s, CH3), 3.18 (6H, s, CH(OCH3)2), 3.28 (2H, d,
J¼5.6 Hz, NCH2CH), 3.83 (3H, s, OCH3), 3.86 (3H, s, OCH3), 4.40 (1H,
t, J¼5.6 Hz, CH(OCH3)2), 4.69 (2H, s, ArCH2), 6.72 (1H, s, H-3), 7.30
(2H, d, J¼8.3 Hz, 2ꢂCHar), 7.73–7.55 (2H, m, H-6 and H-7), 7.78 (2H,
d, J¼8.3 Hz, 2ꢂCHar), 7.87–8.01 (1H, m, H-5 or H-8), 8.18–8.21 (1H,
m, H-5 or H-8). 13C NMR (CDCl3): d 21.5 (CH3), 47.1 (ArCH2), 49.4
(NCH2CH), 54.3 (CH(OCH3)2), 55.6 (OCH3), 62.4 (OCH3), 103.3
(CH(OCH3)2), 103.9 (C-3), 121.9 and 122.4 (C-5 and C-8), 124.2
(]Cquat), 125.6 and 126.7 (C-6 and C-7), 126.3 (]Cquat), 127.3
(2ꢂCHar), 128.3 (]Cquat), 129.7 (2ꢂCHar), 137.6 (]Cquat), 143.3
(]Cquat), 147.6 (]C–O), 152.1 (]C–O). IR (KBr):
n
1613,
max
4.5. Synthesis of N-methanesulfonyl-N-(2,2-dimethoxyethyl)-
N-((1,4-dimethoxynaphth-2-yl)methyl)amine (10b)
1156 cmꢁ1. MS (ES) m/z (%): 459 (Mþ, 1), 216 (12), 187 (10), 75 (100).
Anal. Calcd for C24H29NO6S: C, 62.73; H, 6.36; N, 3.05. Found: C,
62.58; H, 6.41; N, 2.96.
A solution of methanesulfonyl chloride (2 mmol, 0.23 g) in an-
hydrous dichloromethane (2 ml) was added dropwise to a solution
4.7. Synthesis of N-acetyl-N-(2,2-dimethoxyethyl)-N-
of
N-(2,2-dimethoxyethyl)-N-((1,4-dimethoxynaphth-2-yl)me-
((1,4-dimethoxynaphth-2-yl)-methyl)amine (10d)
thyl)amine (13) (2 mmol, 0.61 g) and triethylamine (2 mmol,
0.20 g) in anhydrous dichloromethane (20 ml) and the reaction
mixture was stirred for 16 h at room temperature. The solution was
concentrated in vacuo to 5 ml and was poured in 2 M HCl. The
aqueous solution was extracted with small portions of dichloro-
methane and the combined organic extracts were washed with
a saturated aqueous solution of sodium hydrogen carbonate, dried
(MgSO4), and evaporated in vacuo. Flash chromatography on silica
gel using ethyl acetate/hexane (1:1) as eluent gave N-meth-
anesulfonyl-N-(2,2-dimethoxyethyl)-N-((1,4-dimethoxynaphth-2-
yl)methyl)amine (10b) (0.41 g, 55% yield) as a colorless oil.
A
solution of N-(2,2-dimethoxyethyl)-N-((1,4-dimethoxy-
naphth-2-yl)methyl)amine (13) (3 mmol, 0.92 g) in pyridine
(10 ml) and acetic anhydride (30 mmol, 3.06 g) was stirred for 16 h
at room temperature in a flask, fitted with a calcium chloride tube.
The reaction mixture was poured in water and the aqueous solution
was extracted with small portions of diethyl ether. The combined
organic extracts were washed with 2 M HCl and then with a satu-
rated aqueous solution of sodium hydrogen carbonate, dried
(MgSO4), and evaporated in vacuo. Flash chromatography on silica
gel with ethyl acetate/hexane (4:1) as eluent gave N-acetyl-N-(2,2-
dimethoxyethyl)-N-((1,4-dimethoxynaphth-2-yl)-methyl)amine
(10d) (0.95 g, 87%) as an oil. Product 10d occurred as a 1:1 mixture
of rotamers (CDCl3).
4.5.1. N-Methanesulfonyl-N-(2,2-dimethoxyethyl)-N-
((1,4-dimethoxynaphth-2-yl)methyl)amine (10b)
1H NMR (CDCl3): d 3.00 (3H, s, SO2CH3), 3.31 (2H, d, J¼5.3 Hz,
NCH2CH), 3.35 (6H, s, CH(OCH3)2), 3.89 (3H, s, OCH3), 3.99 (3H, s,
OCH3), 4.54 (1H, t, J¼5.3 Hz, CH(OCH3)2), 4.70 (2H, s, ArCH2), 6.92
(1H, s, H-3), 7.46–7.58 (2H, m, H-6 and H-7), 8.01–8.04 (1H, m, H-5
or H-8), 8.22–8.25 (1H, m, H-5 or H-8). 13C NMR (CDCl3): d 39.7
(SO2CH3), 45.9 (ArCH2), 47.8 (NCH2CH), 54.4 (CH(OCH3)2), 55.8
(OCH3), 62.6 (OCH3),103.0 (CH(OCH3)2),104.4 (C-3),121.9 and 122.5
(C-5 and C-8), 123.8 (]Cquat), 125.8 and 126.8 (C-6 and C-7), 126.6
4.7.1. N-Acetyl-N-(2,2-dimethoxyethyl)-N-((1,4-dimethoxynaphth-
2-yl)-methyl)amine (10d)
1H NMR (CDCl3): d 2.19 and 2.24 (3H, each s, CH3), 3.32 and 3.41
(6H, each s, CH(OCH3)2), 3.35 and 3.54 (2H, each d, J¼5.3 Hz,
NCH2CH), 3.88 and 3.89 (3H, each s, OCH3), 3.94 and 3.95 (3H, each
s, OCH3), 4.33 and 4.64 (1H, each t, J¼5.3 Hz, CH(OCH3)2), 4.85 and
4.90 (2H, each s, ArCH2), 6.50 and 6.72 (1H, each s, H-3), 7.45–7.59

4990
J. Jacobs et al. / Tetrahedron 64 (2008) 4985–4992
(2H, m, H-6 and H-7), 8.00–8.05 (1H, m, H-5 or H-8), 8.20–8.25 (1H,
m, H-5 or H-8). 13C NMR (CDCl3): d 21.8 and 21.9 (CH3), 43.0 and
48.5 (ArCH2), 48.0 and 50.2 (NCH2CH), 54.6 and 55.2 (CH(OCH3)2),
55.7 (OCH3), 61.9 (OCH3), 62.6 (OCH3), 101.8 and 104.4 (C-3), 103.1
and 103.5 (CH(OCH3)2), 121.7 and 121.8 and 122.4 and 122.5 (C-5
and C-8), 124.7 and 125.7 (]Cquat), 125.5 and 125.6 and 126.7 and
126.9 (C-6 and C-7), 126.1 and 126.3 (]Cquat), 128.3 and 128.5
(]Cquat), 147.0 and 147.8 (]C–O), 152.3 and 152.5 (]C–O), 171.7
and 172.1 (C]O). IR (NaCl): nmax 1637, 1594 cmꢁ1. MS (ES) m/z (%):
347 (Mþ, 36), 284 (8), 257 (7), 201 (30), 75 (100). Anal. Calcd for
J¼1.7 Hz, ArCH2), 4.45 (1H, t, J¼5.3 Hz, CH(OCH3)2), 7.04 (1H, t,
J¼1.7 Hz, H-3), 7.24–7.31 (2H, m, 2ꢂCHar), 7.69–7.76 (4H, m, 2ꢂCHar,
H-6 and H-7), 8.04–8.09 (2H, m, H-5 and H-8). 13C NMR (CDCl3):
d 21.51 (CH3), 48.45 (ArCH2), 51.59 (NCH2CH), 54.70 (CH(OCH3)2),
103.95 (CH(OCH3)2), 126.23 and 126.32 (H-5 and H-8), 127.28
(2ꢂCHar), 129.92 (2ꢂCHar), 132.04 (]Cquat), 133.71 and 133.96 and
135.24 (C-3, C-6 and C-7), 136.15 (]Cquat), 143.93 (]Cquat), 146.22
(]Cquat), 184.69 (C]O), 184.90 (C]O). IR (KBr): nmax 1652, 1628,
1590, 1157 cmꢁ1. MS (ES) m/z (%): 429 (Mþ, 2), 274 (100), 242 (47),
227 (65). Anal. Calcd for C22H23NO6S: C, 61.52; H, 5.40; N, 3.26.
Found: C, 61.32; H, 5.22; N, 3.22.
C
19H25NO5: C, 65.69; H, 7.25; N, 4.03. Found: C, 65.50; H, 7.10; N,
4.25.
4.8.4. N-Acetyl-2-(((2,2-dimethoxyethyl)amino)methyl)-
4.8. Cerium(IV) ammonium nitrate mediated oxidative
1,4-naphthoquinone (14d)
demethylation of N-protected amines 10
Flash chromatography on silica gel with ethyl acetate/hexane
(4:1) gave 14d (81% yield) as a yellow oil. Product 14d occurred as
a 1:1 mixture of rotamers. 1H NMR (CDCl3): d 2.11 and 2.24 (3H,
each s, CH3), 3.39 and 3.42 (6H, each s, CH(OCH3)2), 3.46 and 3.48
(2H, d, J¼5.6 Hz, NCH2CH), 4.44 and 4.54 (1H, t, J¼5.6 Hz,
CH(OCH3)2), 4.58–4.61 (2H, d, J¼1.7 Hz, ArCH2), 6.65–6.72 (1H, t,
J¼1.7 Hz, H-3), 7.73–7.79 (2H, m, H-6 and H-7), 8.04–8.12 (2H, m, H-
5 and H-8). 13C NMR (CDCl3): d 20.83 and 21.10 (CH3), 45.19 and
48.34 (ArCH2), 48.07 and 51.34 (NCH2CH), 54.38 and 54.59
(CH(OCH3)2), 102.61 and 102.97 (CH(OCH3)2), 125.54 and 125.75
and 125.84 (C-5 and C-8), 131.38 and 131.48 (]Cquat), 131.54
(]Cquat), 132.97 and 133.10 (C-3), 133.24 and 133.41 and 133.48 and
133.68 (C-6 and C-7), 145.36 and 145.55 (]Cquat), 171.07 and 171.23
General procedure. A solution of cerium(IV) ammonium nitrate
(3 mmol) in water (10 ml) was added dropwise to a cooled (0 ꢀC)
solution of an N-protected amine 10 (1 mmol) in acetonitrile (5 ml)
and the resulting mixture was stirred for 30 min at room temper-
ature. The reaction mixture was poured in water and the aqueous
solution was extracted with ethyl acetate. The combined organic
extracts were washed with brine, dried (MgSO4), and evaporated in
vacuo to afford the crude 1,4-naphthoquinones 14.
4.8.1. N-(tert-Butoxycarbonyl)-2-(((2,2-dimethoxyethyl)amino)-
methyl)-1,4-naphthoquinone (14a)
Oil, crude yield: 100%. The product decomposed upon flash
chromatography on silica gel with ethyl acetate/hexane (1:4)
as eluent. The product occurred as a 1:1 mixture of rotamers
(CDCl3). 1H NMR (CDCl3): d 1.41 and 1.51 (9H, each s, C(CH3)3),
3.35 and 3.42 (2H, each d, J¼5.3 Hz, NCH2CH), 3.38 and 3.39 (6H,
each s, CH(OCH3)2), 4.43–4.54 (3H, m, ArCH2 and CH(OCH3)2),
6.66 and 6.72 (1H, each s, H-3), 7.72–7.77 (2H, m, H-6 and H-7),
8.04–8.11 (2H, m, H-5 and H-8). 13C NMR (CDCl3): d 27.4 and 28.3
(C(CH3)3), 47.0 and 47.4 (ArCH2), 49.7 and 50.0 (NCH2CH), 54.6
(CH(OCH3)2), 80.6 and 80.7 (C(CH3)3), 103.4 and 104.0
(CH(OCH3)2), 126.09 and 126.16 and 126.27 and 126.32 (C-5 and
C-8), 132.0 (]Cquat), 132.1 and 132.2 (]Cquat), 133.2 and 133.3 and
133.7 and 133.8 and 133.9 (C-3, C-6 and C-7), 146.8 and 147.3 (N–
C]O), 155.25 and 155.34 (]Cquat), 184.7 and 184.8 (C]O), 185.0
(N–C]O), 183.77 (C]O), 184.20 and 184.46 (C]O). IR (NaCl): n
max
1661, 1628, 1595 cmꢁ1. MS (ES) m/z (%): 317 (Mþ, 1), 201 (15), 75
(100). Anal. Calcd for C17H19NO5: C, 64.34; H, 6.03; N, 4.41. Found: C,
64.02; H, 5.88; N, 4.39.
4.9. Reaction of N-(tert-butoxycarbonyl)-2-(((2,2-dimethoxy-
ethyl)amino)methyl)-1,4-naphthoquinone (14a) with HCl(g)
N-(tert-Butoxycarbonyl)-2-(((2,2-dimethoxyethyl)amino)-
methyl)-1,4-naphthoquinone (14a) (2.5 mmol, 1 g) was added to
a saturated solution of dry HCl gas in dry diethyl ether (50 ml) and
the mixture was stirred for 16 h in a stoppered flask. A precipitate
was gradually formed during the course of the reaction and was
dissolved in dichloromethane (50 ml) after isolation by filtration.
The solution was stirred vigorously for 16 h at room temperature
with a saturated aqueous solution of sodium hydrogen carbonate
(50 ml) in an open flask. The organic phase was separated, dried
(MgSO4), and evaporated in vacuo. Flash chromatography on silica
gel using ethyl acetate/hexane (1:4) as eluent gave benz[g]isoqui-
noline-5,10-dione (7) (200 mg, 38% yield) as white crystals. Spectral
data were in accordance with the literature data.15
(C]O). IR (NaCl): n
1695, 1662, 1593 cmꢁ1. MS (ES) m/z (%):
max
375 (Mþ, 1), 75 (100).
4.8.2. N-Methanesulfonyl-2-(((2,2-dimethoxyethyl)amino)methyl)-
1,4-naphthoquinone (14b)
Oil, yield: 94%. The product was used without purification in the
next step (purity by 1H NMR>95%). An analytical sample was
obtained by recrystallization from ethanol to give 14b as brown
crystals, mp 118–119 ꢀC. 1H NMR (CDCl3): d 3.02 (3H, s, SO2CH3),
3.37 (6H, s, CH(OCH3)2), 3.40 (2H, d, J¼5.0 Hz, NCH2CH), 4.47–4.51
(3H, m, ArCH2 and CH(OCH3)2), 7.06 (1H, t, J¼1.7 Hz, H-3), 7.74–7.77
(2H, m, H-6 and H-7), 8.08–8.11 (2H, m, H-5 and H-8). 13C NMR
(CDCl3): d 39.03 (SO2CH3), 47.42 (ArCH2), 49.77 (NCH2CH), 54.81
(CH(OCH3)2), 103.66 (CH(OCH3)2), 126.34 and 126.38 (C-5 and C-8),
132.02 (]Cquat), 132.07 (]Cquat), 133.83 and 134.10 (C-6 and C-7),
135.34 (C-3), 145.77 (]Cquat), 184.62 (C]O), 185.03 (C]O). IR
(NaCl): nmax 1651, 1613, 1590, 1143 cmꢁ1. MS (ES) m/z (%): no Mþ, 75
(100). Anal. Calcd for C16H19NO6S: C, 54.38; H, 5.42; N, 3.96. Found:
C, 54.71; H, 5.44; N, 3.81.
4.10. Synthesis of N-methanesulfonyl-(((1,4-dioxonaphth-
2-yl)methyl)amino)acetaldehyde (15)
Aluminum(III) chloride (6 mmol, 0.80 g) was added portionwise
to a cooled (0 ꢀC) solution of N-methanesulfonyl-2-(((2,2-dime-
thoxyethyl)amino)methyl)-1,4-naphthoquinone (14b) (0.6 mmol,
212 mg) in dichloromethane (20 ml) and the resulting mixture was
stirred for 2 h at 0 ꢀC. The reaction was quenched by careful addi-
tion of water (5 ml) and then 2 M HCl was added. The mixture was
extracted with dichloromethane and the combined organic extracts
were washed with water, dried (MgSO4), and evaporated in vacuo.
Flash chromatography on silica gel using ethyl acetate/hexane (1:1)
as eluent gave N-methanesulfonyl-(((1,4-dioxonaphth-2-yl)me-
thyl)amino)acetaldehyde (15) (160 mg, 87%) as a brown oil, which
was found to decompose rapidly.
4.8.3. N-(p-Toluenesulfonyl)-2-(((2,2-dimethoxyethyl)amino)-
methyl)-1,4-naphthoquinone (14c)
Recrystallization from ethanol gave 14c (83% yield) as yellow
crystals, mp 98–100 ꢀC. 1H NMR (CDCl3): d 2.41 (3H, s, CH3), 3.30
(6H, s, CH(OCH3)2), 3.32 (2H, d, J¼5.3 Hz, NCH2CH), 4.39 (2H, d,

J. Jacobs et al. / Tetrahedron 64 (2008) 4985–4992
4991
4.10.1. N-Methanesulfonyl-(((1,4-dioxonaphth-2-yl)methyl)-
amino)acetaldehyde (15)
room temperature in a stoppered flask, which was protected from
light with aluminum foil. The suspension was poured in water,
extracted with dichloromethane, dried (MgSO4), and evaporated in
vacuo. Recrysallization form ethanol gave 2-methanesulfonyl-1,2-
dihydrobenz[g]isoquinoline-5,10-dione (9b) (250 mg, 62% yield) as
fine red needles, mp 161–163 ꢀC. For spectral data of 2-meth-
anesulfonyl-1,2-dihydrobenz[g]isoquinoline-5,10-dione (9b) vide
supra.
1H NMR (CDCl3): d 3.08 (3H, s, SO2CH3), 4.37 (2H, s, CH2CHO),
4.40 (2H, d, J¼1.7 Hz, ArCH2), 7.06 (1H, t, J¼1.7 Hz, H-3), 7.75–7.81
(2H, m, H-6 and H-7), 8.07–8.11 (2H, m, H-5 and H-8), 9.60 (1H, s,
CHO). 13C NMR (CDCl3): d 40.0 (SO2CH3), 47.0 (ArCH2), 57.8
(CH2CHO), 126.4 and 126.5 (C-5 and C-8), 131.9 (]Cquat), 132.0
(]Cquat), 134.0 and 134.3 (C-6 and C-7), 135.8 (C-3), 144.9 (]Cquat),
185.5 (C]O), 185.1 (C]O), 196.7 (CHO).
4.14. Synthesis of 2-(p-toluenesulfonyl)-1,2-dihydrobenz[g]-
isoquinoline-5,10-dione (9c) and 4-hydroxy-2-(p-toluenesul-
fonyl)-1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-dione (16)
4.11. Reaction of N-methanesulfonyl-(((1,4-dioxonaphth-2-yl)-
methyl)amino)acetaldehyde (15) with 33% HBr in acetic acid
N-Methanesulfonyl-(((1,4-dioxonaphth-2-yl)methyl)amino)-
acetaldehyde (15) (0.3 mmol, 100 mg) was mixed with 33% HBr in
acetic acid and stirred for 16 h at room temperature in a stoppered
flask. Water was added and the aqueous solution was extracted
with dichloromethane. The combined organic extracts were
washed with a saturated aqueous solution of sodium hydrogen
carbonate, dried (MgSO4), and evaporated in vacuo. Flash chro-
matography on silica gel with ethyl acetate/hexane (1:4) as eluent
gave benz[g]isoquinoline-5,10-dione (7) (40 mg, 64% yield) as
white crystals. Spectral data were in accordance with the literature
data.15
Procedure 1. To a cooled (0 ꢀC) solution of N-(p-toluenesulfonyl)-
2-(((2,2-dimethoxyethyl)amino)methyl)-1,4-naphthoquinone (14c)
(2 mmol, 0.86 g) in diethyl ether (40 ml) was added dropwise 12 M
HCl (20 ml) and the reaction mixture was stirred vigorously for 16 h
at room temperature in a stoppered flask, which was protected from
light with aluminum foil. The mixture was poured in water,
extracted with dichloromethane, dried (MgSO4), and evaporated in
vacuo. Flash chromatography on silica gel using ethyl acetate/hex-
ane (1:4) as eluent gave 2-(p-toluenesulfonyl)-1,2-dihydrobenz[g]-
isoquinoline-5,10-dione (9c) (60 mg, 8% yield) as red crystals. A
second fraction was collected by elution with ethyl acetate/hexane
(1:1) as eluent to give 4-hydroxy-2-(p-toluenesulfonyl)-1,2,3,4-
tetrahydrobenz[g]isoquinoline-5,10-dione (16) (290 mg, 38% yield)
as yellow crystals, mp 178 ꢀC.
4.12. Reaction of N-methanesulfonyl-(((1,4-dioxonaphth-2-
yl)methyl)amino)acetaldehyde (15) with 5% HBr in acetic acid
Procedure 2. To a cooled (0 ꢀC) solution of N-(p-toluenesulfonyl)-
2-(((2,2-dimethoxyethyl)amino)methyl)-1,4-naphthoquinone (14c)
(2.8 mmol,1.20 g) in diethyl ether (70 ml) was added dropwise 12 M
HCl (20 ml) and the reaction mixture was stirred vigorously for 5
days at room temperature in a stoppered flask, which was protected
from light with aluminum foil. Water was added and the suspension
was extracted with dichloromethane, dried (MgSO4), and evapo-
rated in vacuo. Recrystallization from ethanol gave 2-(p-toluene-
sulfonyl)-1,2-dihydrobenz[g]isoquinoline-5,10-dione (9c) (0.86 g,
84% yield) as red needles, 154 ꢀC.
To a cooled (0 ꢀC) solution of N-methanesulfonyl-(((1,4-dioxo-
naphth-2-yl)methyl)amino)acetaldehyde (15) (0.6 mmol, 200 mg)
in glacial acetic acid (5 ml) was added dropwise a solution of 33%
HBr in acetic acid (1 ml) and the reaction mixture was stirred for 1 h
at room temperature. The mixture was poured in water and
extracted with dichloromethane. The combined organic extracts
were washed with a saturated aqueous solution of sodium hydro-
gen carbonate, dried (MgSO4), and evaporated in vacuo to give
a mixture of benz[g]isoquinoline-5,10-dione (7) and 2-meth-
anesulfonyl-1,2-dihydrobenz[g]isoquinoline-5,10-dione (9b) in
a ratio of 73:27 (1H NMR). Spectral data of benz[g]isoquinoline-
5,10-dione (7) were in accordance with the literature data.15
4.14.1. 2-(p-Toluenesulfonyl)-1,2-dihydrobenz[g]isoquinoline-5,
10-dione (9c)
1H NMR (CDCl3): d 2.41 (3H, s, CH3), 4.61 (2H, s, CH2), 6.07 (1H, d,
J¼7.6 Hz, H-4), 7.26 (1H, d, J¼7.6 Hz, H-3), 7.35 (2H, d, J¼8.3 Hz,
2ꢂCHar), 7.68–7.72 (2H, m, H-7 and H-8), 7.75 (2H, d, J¼8.3 Hz,
2ꢂCHar), 8.02–8.07 (2H, m, H-6 and H-9). 13C NMR (CDCl3): d 21.6
(CH3), 41.1 (CH2), 100.0 (C-4), 126.1 and 126.6 (C-6 and C-9), 126.4
(]Cquat), 127.5 (2ꢂCHar), 130.2 (2ꢂCHar), 131.4 (]Cquat), 132.3
(]Cquat), 133.5 and 134.1 (C-7 and C-8), 133.6 (]Cquat), 134.8 (C-3),
136.9 (]Cquat), 145.1 (]Cquat), 181.7 (C]O), 181.8 (C]O). IR (KBr):
4.12.1. 2-Methanesulfonyl-1,2-dihydrobenz[g]isoquinoline-5,
10-dione (9b)
An analytical sample was prepared by recrystallization from
ethanol and afforded 9b as fine red needles, mp 161–163 ꢀC. 1H
NMR (CDCl3): d 3.04 (3H, s, SO2CH3), 4.84 (2H, s, CH2), 6.17 (1H, d,
J¼7.4 Hz, H-4), 7.12 (1H, d, J¼7.4 Hz, H-4), 7.74–7.77 (2H, m, H-7 and
H-8), 8.08–8.13 (2H, m, H-6 and H-9). 13C NMR (CDCl3): d 39.0
(SO2CH3), 41.3 (CH2), 100.6 (C-4), 126.2 and 126.7 (C-6 and C-9),
126.3 (]Cquat), 131.4 (]Cquat), 132.3 (]Cquat), 133.7 and 134.2 (C-7
and C-8), 134.4 (C-3), 137.1 (]Cquat), 181.7 (C]O), 181.9 (C]O). IR
n
1670, 1646, 1616, 1594, 1564, 1163 cmꢁ1. MS (ES) m/z (%): 365
max
(Mþ, 12), 210 (100). Anal. Calcd for C20H15NO4S: C, 65.74; H, 4.14; N,
(KBr): n
1661, 1646, 1634, 1613, 1583, 1563, 1157 cmꢁ1. MS (ES)
max
3.83. Found: C, 65.50; H, 4.27; N, 3.68.
m/z (%): 289 (Mþ, 9), 210 (100), 182 (8), 154 (7), 127 (19). Anal. Calcd
for C14H11NO4S: C, 58.12; H, 3.83; N, 4.84. Found: C, 57.89; H, 3.79;
N, 4.72.
4.14.2. 4-Hydroxy-2-(p-toluenesulfonyl)-1,2,3,4-tetrahydrobenz[g]-
isoquinoline-5,10-dione (16)
1H NMR (CDCl3): d 2.43 (3H, s, CH3), 3.04 (1H, dꢂd, J¼2.6,
13.2 Hz, CHH-3), 3.72 (1H, dꢂd, J¼1.3, 19.8 Hz, CHH-1), 4.24 (1H, m,
CHH-3), 4.69 (1H, d, J¼19.8 Hz, CHH-1), 5.26 (1H, d, J¼1.3 Hz, H-4),
7.36 (2H, d, J¼7.9 Hz, 2ꢂCHar), 7.68–7.81 (4H, m, H-7 and H-8,
2ꢂCHar), 8.06–8.13 (2H, m, H-6 and H-9). 13C NMR (CDCl3): d 21.6
(CH3), 42.5 (C-1), 46.6 (C-4), 49.3 (C-3), 126.6 and 126.9 (C-6 and C-
9), 127.9 (2ꢂCHar), 128.1 (]Cquat), 130.0 (2ꢂCHar), 130.2 (]Cquat),
131.5 (]Cquat), 133.3 (]Cquat), 134.3 and 134.5 (C-7 and C-8), 139.9
(]Cquat), 140.8 (]Cquat), 144.4 (]Cquat), 181.0 (C]O), 182.9 (C]O).
IR (KBr): nmax 1667, 1638, 1593, 1162 cmꢁ1. MS (ES) m/z (%): 365
4.13. Synthesis of 2-methanesulfonyl-1,2-dihydrobenz[g]-
isoquinoline-5,10-dione (9b) from N-methanesulfonyl-2-
(((2,2-dimethoxyethyl)amino)methyl)-1,4-naphthoquinone
(14b)
To a cooled (0 ꢀC) solution of N-methanesulfonyl-2-(((2,2-
dimethoxyethyl)amino)methyl)-1,4-naphthoquinone
(14b)
(1.4 mmol, 0.49 g) in diethyl ether (20 ml) was added portionwise
12 M HCl (20 ml) and the mixture was stirred vigorously for 16 h at

4992
J. Jacobs et al. / Tetrahedron 64 (2008) 4985–4992
(MþꢁH2O, 1), 210 (18), 209 (100), 181 (35). Anal. Calcd for
5. Nguyen Van, T.; Verniest, G.; Claessens, S.; De Kimpe, N. Tetrahedron 2005, 61,
2295–2300.
6. Parisot, D.; Devys, M.; Barbier, M. Z. Naturforsch. 1989, 44, 1473–1474.
7. (a) Solis, P. N.; Lang’at, C.; Gupta, M. P.; Kirby, G. C.; Warhurst, D. S.; Phillipson,
J. D. Planta Med. 1995, 61, 62–65; (b) Phillipson, J. D. Phytochemistry 1995, 38,
1319–1343.
8. Parisot, D.; Devys, M.; Barbier, M. J. Antibiot. 1989, 42, 1189–1190.
9. Visconti, A.; Surico, G.; Iacobellis, N. S.; Bottalico, A. Phytopath. Medit. 1983, 22,
122–156.
C
20H17NO5S: C, 62.65; H, 4.47; N, 4.47. Found: C, 62.43; H, 4.27; N,
3.62.
Acknowledgements
The authors are indebted to the ‘Research FoundationdFlanders
10. For a recent review on the isolation and the synthesis of pentalongin and re-
lated pyranonaphthoquinones, see: Claessens, S.; Verniest, G.; Jacobs, J.; Van
Hende, E.; Habonimana, P.; Nguyen Van, T.; Van Puyvelde, L.; De Kimpe, N.
Synlett 2007, 829–850.
(FWO-Vlaanderen)’ for financial support of this research.
References and notes
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