Original synthesis of 2-substituted-4,11-dimethoxy-1-(phenylsulfonyl)-2,3- dihydro-1H-naphtho[2,3-f]indole-5,10-diones using TDAE and Cu-catalyzed reaction strategy

Article abstract of DOI:10.1016/j.tet.2011.06.069

We report herein an original and rapid synthesis of 2-substituted-4,11- dimethoxy-1-(phenylsulfonyl)-2,3-dihydro-1H-naphtho[2,3-f]indole-5,10-diones by TDAE mediated synthesis of N-benzylsulfonamides followed by an intramolecular N-arylation using Cu-catalyzed system.

Full text of DOI:10.1016/j.tet.2011.06.069

Tetrahedron 67 (2011) 6173e6180
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Original synthesis of 2-substituted-4,11-dimethoxy-1-(phenylsulfonyl)-2,3-
dihydro-1H-naphtho[2,3-f]indole-5,10-diones using TDAE and Cu-catalyzed
reaction strategy
*
Omar Khoumeri, Gamal Giuglio-Tonolo, Maxime D. Crozet, Thierry Terme, Patrice Vanelle
ꢀ
ꢀ
Laboratoire Chimie Provence LCP, UMR CNRS 6264, Universites d’Aix-Marseille I, II et III, Equipe Pharmaco-Chimie Radicalaire, Faculte de Pharmacie,
27 Boulevard Jean Moulin, 13385 Marseille Cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 May 2011
Received in revised form 8 June 2011
Accepted 21 June 2011
Available online 28 June 2011
We report herein an original and rapid synthesis of 2-substituted-4,11-dimethoxy-1-(phenylsulfonyl)-
2,3-dihydro-1H-naphtho[2,3-f]indole-5,10-diones by TDAE mediated synthesis of N-benzylsulfonamides
followed by an intramolecular N-arylation using Cu-catalyzed system.
Ó 2011 Elsevier Ltd. All rights reserved.
Dedicated to the memory of Pr Franc¸ ois
Tillequin
Keywords:
TDAE
N-(Benzenesulfonyl)benzylimine
Cu-catalyzed reaction
Naphtho[2,3-f]indole-5,10-dione
1. Introduction
OH
O
O
C
O
OH
B
O
OR1
B
R2
Anthracycline derivatives, such as daunomycin and adriamycin
possess high antitumor activity due to their capability of inter-
calating DNA double helix to result dramatic changes in DNA con-
formation1 and, furthermore, can also inhibit DNA replication and
transcription.2 Unfortunately, the clinical use is limited by both
dose-related cumulative cardiotoxicity and development of drug-
resistance.3 Several synthesis of heterocyclic anthracycline analogs
were developed by replacing the cyclohexane ring (A) of anthra-
OH
D
A
D
A
C
O
N
H
O
O
OH
OR1
H3C
O
Adriamycin
H3C
NH2
OH
cycline by
a
heterocycle.4 Interesting activity against drug
Fig. 1. Adriamycin and heterocyclic anthracycline analogs.
resistant cells has been obtained by modification of the 4,11-
dihydroxynaphtho[2,3-f]indole-5,10-dione skeleton (Fig. 1).5 On
the other hand, the compounds possessing a furano or pyrano ring
fused to polycyclic, aromatic system, such as furanoxanthone,6
benzopyranoxanthone,7 and coumarin8 have exhibited interesting
antitumor9 and anti-inflammatory properties.10
Pd-catalyzed and Cu-catalyzed CeN bond forming reactions
are extensively used in the medicinal chemistry. Cu-mediated
systems have proven their effectiveness under mild conditions in
N-arylation of amino derivatives (anilines,11 amides,12 hydrazides,13
alkylamines14) and nitrogen heterocycles15 using various ligands
(diamines, diols,.). Among them, Buchwald has developed an
extremely efficient and general catalyst system for the amidation of
aryl halides and the N-arylation of a wide variety of heterocycles.
This catalyst system is based on the use of chelating nitrogen li-
gands (N,N0-dimethylated 1,2-diamine ligands) with air stable CuI
in the presence of base (K3PO4, K2CO3, Cs2CO3,.).14
Tetrakis(dimethyl-amino)ethylene (TDAE) is an organic reducing
agent,16 which reacts with haloalkyl derivatives to generate a carb-
anion under mild conditions.17 Since 2003, we have introduced
* Corresponding author. Tel.: þ33 4 9183 5580; fax: þ33 4 9179 4677; e-mail
address: patrice.vanelle@univmed.fr (P. Vanelle).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.069

6174
O. Khoumeri et al. / Tetrahedron 67 (2011) 6173e6180
a new program directed toward the development of original syn-
thetic methods using TDAE methodology in medicinal chemistry.18
We have shown that from o- and p-nitrobenzyl chloride, tetra-
kis(dimethyl-amino)ethylene (TDAE) could generate a nitrobenzyl
carbanion, which is able to react with various electrophiles as aro-
matic aldehydes, a-ketoester, ketomalonate, and a-ketolactam de-
rivatives. We have recently reported the extension of this reactivity
in anthraquinone series with aromatic aldehyde and nitro-
derivative 2.24 After methylation using dimethylsulfate, the
obtained 2-chloro-1,4-dimethoxy-3-methylanthracene-9,10-dione
(3) was brominated using N-bromosuccinimide (NBS) giving the
bromomethyl derivative 4 (Scheme 1).24 The substituted N-(ben-
zenesulfonyl)benzylimine 7aei have been prepared by condensa-
tion of various benzaldehydes 5aei and benzenesulfonamide 6 in
the presence of AlCl3 in a solvent free procedure as described by
Sharghi (Scheme 2) (Table 1).25
O
OCH3
O
OCH3
O
O
OH
OH
O
O
OH
OH
Cl
Cl
Cl
MnO2, HCl
DMS
NBS
Br
CH3
CH3
CH3
O
OCH3
O
OCH3
1
2
81%
3
57%
4
84%
Scheme 1.
Ph
X
AlCl3, 80 °C
solvent free
N SO2
X
+
H2N SO2
Ph
CHO
7a-i
74-92%
5a-i
6
Scheme 2.
a
-ketoester derivatives.19
Table 1
Synthesis of the substituted N-(benzenesulfonyl)benzylimines 7aei
anthraquinonic with ketomalonate and
However, few studies have been reported concerning the nucleo-
philic additions of carbanion, formed via TDAE strategy, on Car-
boneNitrogen double bond and their synthetic applications.20
In order to develop pharmacomodulation studies, our team is
interested in the metal-catalyzed reactions, such as Suzu-
kieMiyaura,21 Sonogashira, Buchwald and Heck reactions. Recently,
we reported the synthesis of new 2-substituted-4,11-dimethoxy-
anthra[2,3-b]furan-5,10-diones by an intramolecular Pd-catalyzed
CeO bond forming reaction of halide alcohol derivatives via intra-
molecular Buchwald reaction.22 In connection with our program
centered on the synthesis of new quinonic compound using the
electron transfer methodology and the preparation of new poten-
tially bioactive compounds as anticancer agents,23 we report herein
an original and efficient synthesis of new 2-substituted-4,11-
dimethoxy-1-(phenylsulfonyl)-2,3-dihydro-1H-naphtho[2,3-f]in-
dole-5,10-diones (9aei) by an intramolecular Cu-catalyzed CeN
bond forming reaction of N-[1-arylethyl-2-(3-chloro-1,4-dimethoxy-
9,10-dioxo-9,10-dihydroanthracen-2-yl)]-benzenesulfonamide de-
rivatives (8aei) prepared by the TDAE methodology.
X
Aldehyde
N-(Benzenesulfonyl)benzylimine
Yield %a
H
5a
5b
5c
5d
5e
5f
7a
7b
7c
7d
7e
7f
84
92
75
74
75
75
88
83
90
4-CH3
2,5-(CH3)2
4-OCH3
4-CF3
4-F
3-F
2-F
2-Cl
5g
5h
5i
7g
7h
7i
a
All yields refer to chromatographically isolated pure products and are relative to
aldehyde 5aei.
2.2. TDAE reactivity
Among the CarboneNitrogen double bonds, we have chosen
the sulfonylaldimines, which are able to react with TDAE in
fluorine chemistry as described by Dolbier20 and Medebielle.20
To extend the reactivity of the sulfonylaldimines with non-
fluorine compounds, we have considered our TDAE conditions
described in anthraquinonic series. The reaction of 2-chloro-3-
bromomethyl-1,4-dimethoxy-anthracene-9,10-dione (4) with
the substituted N-(benzenesulfonyl)benzylimines 7aei in the
presence of TDAE at ꢀ20 ꢁC for 1 h, followed by 2 h at rt led to the
corresponding N-substituted benzenesulfonamides 8aei in good
yields (75e88%) as shown in Scheme 3 and Table 2. These several
compounds 8aei were synthesized for the investigation of the
intramolecular Cu-catalyzed substitution of an aryl chloride with
an arylsulfonamide.
2. Results and discussion
2.1. Preparation of starting materials
The required starting material for TDAE-initiated reaction in
anthraquinonic series, 2-chloro-3-bromomethyl-1,4-dimethoxy-
anthracene-9,10-dione (4), was synthesized in three steps from 1,4-
dihydroxy-2-methylanthracene-9,10-dione 1 as previously descri-
bed.19a The chloration via oxidation of 1 furnished the chloro
Ph
SO2
O
O
OCH3
Cl
HN
O
O
OCH3
Cl
Ph
SO2
TDAE
DMF
+
N
Br
X
OCH3
OCH3
75-88%
4
7a-i
8a-i
X
Scheme 3.

O. Khoumeri et al. / Tetrahedron 67 (2011) 6173e6180
6175
Table 2
2.3. Intramolecular Buchwald reaction
Reaction of 2-chloro-3-bromomethyl-1,4-dimethoxy-anthracene-9,10-dione 4 with
substituted N-(benzenesulfonyl)benzylimines 7aei using TDAE strategya
As observed in compounds 8aei, an intramolecular CeN bond
forming reaction corresponds to a reaction between an ortho
substituted aryl chloride and an arylsulfonamide, which are limited
in Pd-catalyzed chemistry.15a So, we directed our investigations to
the efficient and general catalyst system developed by Buchwald
for amidation of aryl halide. We studied the intramolecular re-
activity of compounds 8a using Cu-diamine catalyst system.
Moreover, we envisaged the use of microwave irradiation for
heating to decrease reaction time.
We started this study by an adaptation of the conditions de-
fined by Buchwald12 for amidation of aryl chloride with CuI
(10 mol %), N,N0-dimethylcyclohexyl-1,2-diamine (15 mol %) as
ligand and K2CO3 (2 equiv) as base at 110 ꢁC in toluene for 1.5 h
under microwave irradiation. The reaction of compound 8a
under these conditions furnished the awaited 2-phenyl-4,11-
dimethoxy-1-(phenylsulfonyl)-2,3-dihydro-1H-naphtho[2,3-f]in-
dole-5,10-dione 9a (Scheme 4, Table 3, entry 1) in 81% yield. We
have used the air stable CuI with the three more efficient diamine
ligands (N,N0-dimethylethane-1,2-diamine, N,N0-dimethylcyclo-
hexyl-1,2-diamine, cyclohexyl-1,2-diamine), in the presence of
base (K3PO4, K2CO3, Cs2CO3), in various solvent (toluene, DMF, 1,4-
dioxane). The main results of this optimization are reported in
Table 3.
Entry
X
N-Substituted benzenesulfonamide
Yield (%)b
Ph
SO
O
OCH
3
Cl
2
HN
1
H
8a
8b
78
O
OCH
3
Ph
SO
O
OCH
3
Cl
2
HN
2
3
4-CH3
76
76
O
OCH
3
CH
3
O
OCH
3
Ph
Cl
HN
SO
2
2,5-(CH3)2
8c
CH
3
O
OCH
3
CH
3
4
5
4-OCH3
8d
8e
75
81
Ph
SO2
Ph
SO2
O
O
OCH3
Cl
HN
O
O
OCH3
CuI, ligand
base
N
solvent, Δ
OCH3
OCH3
9a
8a
4-CF3
Scheme 4.
The best yield of compound 9a (84%) was observed in entry 3
(Table 3) using 10 mol % of CuI, 15 mol % of N,N0-dimethylethane-
1,2-diamine as ligand, 2 equiv of K2CO3 as base in toluene at 110 ꢁC
for 1.5 h under microwave irradiation. The same reaction conducted
under classical heating furnished the compound 9a in 73% yield
after 5 h.
These encouraging results led us to generalize this Cu-catalyzed
CeN bond forming reaction with the other N-substituted benze-
nesulfonamides 8aei to prepare a new series of 2-substituted-4,
11-dimethoxy-1-(phenylsulfonyl)-2,3-dihydro-1H-naphtho[2,3-f]
indole-5,10-dione 9aei in good yields (80e89%) as reported in
Scheme 5 and Table 4. From the general protocol, an adaptation of
the reaction time has been realized especially with derivatives
8gei, which require 3 h of reaction.
6
7
4-F
3-F
8f
84
88
8g
3. Conclusion
8
2-F
8h
85
In conclusion, we expand the TDAE methodology to the reaction
of 2-chloro-3-bromomethyl-1,4-dimethoxy-anthracene-9,10-dione
(4) with various N-(benzenesulfonyl)benzylimines, leading to the
corresponding N-substituted benzenesulfonamides 8aei in good
yields (75e88%). This reaction is the first example of nucleophilic
addition of a carbanion, generated by TDAE methodology, on
a CarboneNitrogen double bond as electrophile in non-fluorine
series. The obtained products were good candidates for intra-
molecular Cu-catalyzed CeN bond forming reaction to synthesize
2-substituted-4,11-dimethoxy-1-(phenylsulfonyl)-2,3-dihydro-1H-
naphtho[2,3-f]indole-5,10-dione compounds 9aei in good yields
(80e89%). These results constitute the first example of intra-
molecular Cu-catalyzed CeN bond forming reaction in
9
2-Cl
8i
80
a
All the reactions are performed using 3 equiv of substituted N-(benzenesulfonyl)
benzylimines 7aei, 1 equiv of bromide 4 and 1 equiv of TDAE in anhydrous DMF
stirred at e20 ꢁC for 1 h and then warmed up to rt for 2 h.
b
All yields refer to chromatographically isolated pure products and are relative to
bromide 4.

6176
O. Khoumeri et al. / Tetrahedron 67 (2011) 6173e6180
Table 3
Optimization study of Cu-catalyzed CeN bond forming reactiona
Entry
Heating conditions
Base
Ligand
Solvent
Yield % (9a)b
1
2
3
4
5
6
7
8
MW, 110 ꢁC, 1.5 h
MW, 110 ꢁC, 1.5 h
MW, 110 ꢁC, 1.5 h
MW, 101 ꢁC, 1.5 h
MW, 120 ꢁC, 1.5 h
MW, 110 ꢁC, 1.5 h
MW, 110 ꢁC, 1.5 h
Classical, 110 ꢁC, 5 h
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
K2CO3
trans-N,N0-Dimethylcyclohexyl-1,2-diamine
Cyclohexyl-1,2-diamine
Toluene
Toluene
Toluene
1,4-Dioxane
DMF
Toluene
Toluene
Toluene
81
79
84
63
0
62
67
73
N,N0-Dimethylethane-1,2-diamine
N,N0-Dimethylethane-1,2-diamine
N,N0-Dimethylethane-1,2-diamine
N,N0-Dimethylethane-1,2-diamine
N,N0-Dimethylethane-1,2-diamine
N,N0-Dimethylethane-1,2-diamine
a
All the reactions are performed using 10 mol % CuI, 15 mol % ligand, 2 equiv of base.
All yields refer to chromatographically isolated pure products and are relative to substrate 8a.
b
Table 4
a
Cu-catalyzed CeN bond forming reaction of compounds 8aei
Entry
Substrate
2-Substituted-4,11-dimethoxy-1-(phenylsulfonyl)-
Yield (%)b
2,3-dihydro-1H-naphtho[2,3-f]indole-5,10-dione
1
8a
9a
9b
9c
9d
9e
83
2
3
4
5
8b
8c
8d
8e
80
82
80
80
6
7
8
8f
9f
89
8g
8h
8i
9g
9h
9i
86c
80c
85c
9
a
All the reactions are performed using 10 mol % CuI, 15 mol % N,N0-dimethylethane-1,2-diamine, 2 equiv of K2CO3 in toluene at 110 ꢁC for 1.5 h.
All yields refer to chromatographically isolated pure products and are relative to substrate 8aei.
Reaction time: 3 h.
b
c

O. Khoumeri et al. / Tetrahedron 67 (2011) 6173e6180
6177
anthraquinone series under microwave irradiation. The pharma-
cological evaluation of these compounds is under active
investigation.
2-chloro-3-bromomethyl-1,4-dimethoxy-anthracene-9,10-dione
(4) (0.4 g, 1.01 mmol) and corresponding N-(benzenesulfonyl)
benzylimines 7aei (3 equiv). The solution was stirred and main-
Ph
SO2
Ph
SO2
O
O
OCH3
Cl
O
O
OCH3
CuI(10%), (MeNHCH2)2 (15%)
K2CO3 (2 equiv)
HN
N
X
toluene, 110 °C
Microwave 800 W
OCH3
OCH3
X
9a-i
8a-i
Scheme 5.
4. Experimental section
4.1. General
tained at this temperature for 30 min and then was added dropwise
(via a syringe) the TDAE (0.15 g, 0.75 mmol). A red color immedi-
ately developed with the formation of a white fine precipitate. The
solution was vigorously stirred at ꢀ20 ꢁC for 1 h and then warmed
up to rt for 8 h. After this time, TLC analysis (CH2Cl2) clearly showed
that compound (4) was totally consumed. The solution was filtered
(to remove the octamethyl-oxamidinium dibromide) and hydro-
lyzed with 70 mL of H2O. The aqueous solution was extracted with
chloroform (3ꢂ40 mL), the combined organic layers washed with
H2O (2ꢂ40 mL) and dried over MgSO4. Evaporation of the solvent
furnished an orange viscous liquid as crude product. Purification by
silica gel chromatography (CH2Cl2) and recrystallization from iso-
propanol gave corresponding N-substituted benzenesulfonamide
derivatives (8aei).
€
Melting points were determined on a Buchi melting point B-540
apparatus and are uncorrected. Element analyses were performed
on a Thermo Finnigan EA1112 at the spectropole of the University of
Aix-Marseille III. Both 1H and 13C NMR spectra were determined on
a Bruker AC 200 spectrometer. The 1H the 13C chemical shifts are
reported from CDCl3 peaks: 1H (7.26 ppm) and 13C (76.9 ppm).
Multiplicities are represented by the following notations: s, singlet;
d, doublet; t, triplet; q, quartet; m, a more complex multiplet or
overlapping multiplets. The following adsorbents were used for
column chromatography: silica gel 60 (Merck, particle size
0.063e0.200 mm, 70e230 mesh ASTM). TLC was performed on
5 cmꢂ10 cm aluminum plates coated with silica gel 60 F254 (Merck)
in an appropriate solvent.
4.3.1. N-[2-(3-Chloro-1,4-dimethoxy-9,10-dioxo-9,10-
dihydroanthracen-2-yl)-1-phenylethyl]-benzenesulfonamide
(8a). Yellow solid; mp 200 ꢁC, 1H NMR (CDCl3, 200 MHz)
d 3.15
(1H, dd, J¼13.5, 4.5 Hz, CH2), 3.26 (1H, dd, J¼13.5, 10.7 Hz, CH2),
3.90 (3H, s, OCH3), 3.94 (3H, s, OCH3), 4.67e4.78 (1H, m, CH), 5.66
(1H, d, J¼6.7 Hz, NH), 6.91e6.96 (3H, m, Ar), 7.28e7.48 (7H, m, Ar),
7.81e7.87 (2H, m, Ar), 8.20e8.26 (2H, m, Ar). 13C NMR (CDCl3,
4.2. Preparation of substituted N-(benzenesulfonyl)
benzylimines
The substituted N-(benzenesulfonyl)benzylimine 7aei have
50 MHz)
d 36.4, 57.6, 61.8, 62.8, 125.0, 125.9, 126.1, 126.6, 126.7,
been prepared as previously described by Sharghi.25 New products:
127.7, 127.8, 128.5, 128.7, 131.7, 133.6, 133.8, 134.0, 134.1, 137.8,
138.8, 140.2, 142.0, 152.9, 154.9, 181.5, 181.8. Anal. Calcd for
C30H24ClNO6S: C, 64.11; H, 4.30; N, 2.49. Found: C, 64.03; H, 4.46;
N, 2.46.
4.2.1. (E)-N-(4-Fluorobenzylidene)benzenesulfonamide (7f). White
solid; mp 108 ꢁC, 1H NMR (CDCl3, 200 MHz)
d
7.18 (t, J¼5.0 Hz, 2H, Ar),
7.51e7.61 (m, 3H, Ar), 7.92e8.02 (m, 4H, Ar), 9.03 (s,1H, eCH]Ne).13C
NMR (CDCl3, 50 MHz)
d
116.7 (d, J¼22.3 Hz), 128.0, 129.2, 133.6, 133.8,
4.3.2. N-[2-(3-Chloro-1,4-dimethoxy-9,10-dioxo-9,10-
dihydroanthracen-2-yl)-1-p-tolylethyl]-benzenesulfonamide
134.0,138.1,166.1 (d, J¼258.0 Hz),169.0. Anal. Calcd for C13H10FNO2S C,
59.30; H, 3.83; N, 5.32. Found: C, 58.90; H, 3.90; N, 5.43.
(8b). Yellow solid; mp 215 ꢁC, 1H NMR (CDCl3, 200 MHz)
d 2.35
(3H, s, CH3), 3.14 (1H, dd, J¼13.5, 9.0 Hz, CH2), 3.28 (1H, dd, J¼13.5,
4.7 Hz, CH2), 3.91 (3H, s, OCH3), 3.95 (3H, s, OCH3), 4.63e4.74 (1H,
m, CH), 5.58 (1H, d, J¼6.7 Hz, NH), 6.90e6.96 (3H, m, Ar), 7.18 (2H,
d, J¼7.9 Hz, Ar), 7.36 (2H, d, J¼7.9 Hz, Ar), 7.43e7.48 (2H, m, Ar),
7.81e7.86 (2H, m, Ar), 8.20e8.26 (2H, m, Ar).13C NMR (CDCl3,
4.2.2. (E)-N-(3-Fluorobenzylidene)benzenesulfonamide (7g). White
solid; mp 94 ꢁC, 1H NMR (CDCl3, 200 MHz)
d
7.47e7.70 (m, 7H, Ar),
8.00e8.03 (m, 2H, Ar), 9.03 (s, 1H, eCH]Ne). 13C NMR (CDCl3,
50 MHz)
d
116.6, (d, J¼22.3 Hz), 122.1 (d, J¼21.6 Hz), 126.4, 128.1,
129.2, 130.8 (d, J¼7.7 Hz), 134.4 (d, J¼7.7 Hz), 137.8, 162.3 (d,
J¼249.2 Hz), 169.2. Anal. Calcd for C13H10FNO2S C, 59.30; H, 3.83; N,
5.32. Found: C, 59.01; H, 3.86; N, 5.38.
50 MHz)
d 21.1, 36.4, 57.4, 61.8, 62.8, 125.0, 125.8, 126.2, 126.6,
126.7, 127.4, 128.4, 129.4, 131.7, 133.6, 133.8, 134.0, 134.1, 137.5,
137.8, 138.9, 139.1, 140.2, 152.9, 154.9, 181.6, 181.8. Anal. Calcd for
C31H26ClNO6S: C, 64.63; H, 4.55; N, 2.43. Found: C, 64.40; H, 4.59;
N, 2.36.
4.2.3. (E)-N-(2-Fluorobenzylidene)benzenesulfonamide (7h). White
solid; mp 130 ꢁC, 1H NMR (CDCl3, 200 MHz)
d
7.13e7.24 (m, 2H, Ar),
7.53e7.65 (m, 5H, Ar), 8.00e8.04 (m, 2H, Ar), 9.39 (s,1H, eCH]Ne).
13C NMR (CDCl3, 50 MHz)
4.3.3. N-[2-(3-Chloro-1,4-dimethoxy-9,10-dioxo-9,10-
dihydroanthracen-2-yl)-1-(2,5-dimethyl-phenyl)ethyl]benzenesulfo-
namide (8c). Yellow solid; mp 139 ꢁC, 1H NMR (CDCl3, 200 MHz)
d
116.4 (d, J¼20.5 Hz), 120.4 (d, J¼8.8 Hz),
124.8 (d, J¼3.6 Hz),126.4,128.1,129.2,133.7,137.1 (d, J¼9.1 Hz),137.8,
164.1 (d, J¼6.2 Hz), 164.3. Anal. Calcd for C13H10FNO2S C, 59.30; H,
3.83; N, 5.32. Found: C, 59.11; H, 3.88; N, 5.32.
d
2.28 (3H, s, CH3), 2.42 (3H, s, CH3), 3.05 (1H, dd, J¼13.6, 4.3 Hz, CH2),
3.27 (1H, dd, J¼13.6, 11.2 Hz, CH2), 3.93 (3H, s, OCH3), 3.94 (3H, s,
OCH3), 4.89e5.00 (1H, m, CH), 4.75 (1H, d, J¼7.3 Hz, NH), 6.92e7.02
(5H, m, Ar), 7.2 (1H, s, Ar), 7.41e7.45 (2H, m, Ar), 7.77e7.86 (2H, m,
4.3. General procedure for TDAE reaction
Ar), 8.19e8.26 (2H, m, Ar).13C NMR (CDCl3, 50 MHz)
d 18.7, 21.0, 35.4,
53.9, 61.7, 62.8, 124.9, 126.1, 126.5, 126.6, 126.7, 127.3, 128.3, 128.4,
130.5,131.2,131.6,133.6,133.8,134.0,134.1,136.0,137.8,138.8,139.8,
Into a two-necked flask equipped with a drying tube (silica gel)
and a nitrogen inlet was added 10 mL of anhydrous DMF solution of

6178
O. Khoumeri et al. / Tetrahedron 67 (2011) 6173e6180
140.3, 152.8, 155.2, 181.6, 181.8. Anal. Calcd for C32H28ClNO6S: C,
65.13; H, 4.78; N, 2.37. Found: C, 65.63; H, 4.31; N, 3.02.
J¼3.3 Hz), 124.9, 126.2, 126.6 (2C), 126.7, 127.5, 128.4 (d, J¼4.4 Hz),
128.5, 128.7 (d, J¼12.8 Hz), 129.6, (d, J¼8.4 Hz), 131.8, 133.7, (d,
J¼8.4 Hz), 134.0, 134.1, 138.1, 138.5, 140.1, 152.8, 155.2, 160.2 (d,
J¼246.2 Hz), 181.6, 181.9. Anal. Calcd for C30H23ClFNO6S: C, 62.12; H,
4.00; N, 2.41. Found: C, 62.12; H, 3.95; N, 2.40.
4.3.4. N-[2-(3-Chloro-1,4-dimethoxy-9,10-dioxo-9,10-
dihydroanthracen-2-yl)-1-(4-methoxy-phenyl)ethyl]benzenesulfona-
mide (8d). Yellow solid; mp 208 ꢁC, 1H NMR (CDCl3, 200 MHz)
d
3.13 (1H, dd, J¼13.6, 4.4 Hz, CH2), 3.25 (1H, dd, J¼13.6, 10.8 Hz,
4.3.9. N-[2-(3-Chloro-1,4-dimethoxy-9,10-dioxo-9,10-
dihydroanthracen-2-yl)-1-(2-chlorophenyl)-ethyl]benzenesulfona-
CH2), 3.81 (3H, s, OCH3), 3.91 (3H, s, OCH3), 3.94 (3H, s, OCH3),
4.63e4.74 (1H, m, CH), 5.58 (1H, d, J¼6.6 Hz, NH), 6.89 (2H, d,
J¼8.7 Hz, Ar), 6.95 (2H, dd, J¼5.4, 1.9 Hz, Ar), 7.38 (2H, d, J¼8.7 Hz,
Ar), 7.43e7.48 (2H, m, Ar), 7.52e7.60 (1H, m, Ar), 7.81e7.85 (2H, m,
mide (8i). Yellow solid; mp 203 ꢁC, 1H NMR (CDCl3, 200 MHz)
d 3.20
(1H, dd, J¼13.5, 4.8 Hz, CH2), 3.36 (1H, dd, J¼13.5,10.8 Hz, CH2), 3.92
(3H, s, OCH3), 3.93 (3H, s, OCH3), 5.05e5.16 (1H, m, CH), 5.99 (1H, d,
J¼7.5 Hz, NH), 6.93e7.04 (3H, m, Ar), 7.16e7.34 (3H, m, Ar),
7.47e7.48 (3H, m, Ar), 7.79e7.84 (2H, m, Ar), 8.19e8.24 (2H, m, Ar).
Ar), 8.20e8.26 (2H, m, Ar). 13C NMR (CDCl3, 50 MHz)
d 36.4, 55.3,
57.2, 61.8, 62.8, 114.1, 126.2, 126.4, 126.6, 126.7, 127.1, 128.5, 129.1,
131.7, 133.6, 133.8, 134.0, 134.1, 134.2, 137.8, 138.9, 140.2, 152.8,
154.9, 159.1, 181.6, 181.8. Anal. Calcd for C31H26ClNO7S: C, 62.89; H,
4.43; N, 2.37. Found: C, 62.60; H, 4.47; N, 2.34.
13C NMR (CDCl3, 50 MHz)
d 34.1, 55.2, 61.7, 62.8, 124.9, 126.2, 126.6,
126.7, 127.4, 127.5, 128.5, 128.6, 129.0, 130.0, 131.8, 132.0, 133.6,
133.8, 134.0, 134.1, 138.2, 138.3, 139.0, 139.9, 152.8, 155.2, 181.6,
181.8. Anal. Calcd for C30H23Cl2NO6S: C, 60.41; H, 3.89; N, 2.35.
Found: C, 60.00; H, 3.98; N, 2.29.
4.3.5. N-{2-(3-Chloro-1,4-dimethoxy-9,10-dioxo-9,10-
dihydroanthracen-2-yl)-1-[4-(trifluoro-methyl)phenyl]ethyl}benze-
nesulfonamide (8e). Yellow solid; mp 198 ꢁC, 1H NMR (CDCl3,
4.4. General procedure for intramolecular Buchwald reaction
200 MHz)
d
3.13 (1H, dd, J¼13.6, 4.4 Hz, CH2), 3.23 (1H, dd, J¼13.6,
10.7 Hz, CH2), 3.91 (3H, s, OCH3), 3.94 (3H, s, OCH3), 4.68e4.79 (1H,
m, CH), 5.78 (1H, d, J¼6.2 Hz, NH), 6.93e6.98 (3H, m, Ar), 7.42e7.47
(2H, m, Ar), 7.63 (4H, s, Ar), 7.82e7.86 (2H, m, Ar), 8.21e8.27 (2H, m,
Into a two-necked flask equipped with an argon inlet, CuI
(10 mol %), N,N0-dimethylethane-1,2-diamine (15 mol %) and K2CO3
(2 equiv) were added. Then the halogenated amine (8aei) (0.20 g,
1 equiv) dissolved in toluene (10 mL) was added to the flask. The
resulting mixture was heated at 110 ꢁC in microwave (800 W) until
the disappearance of the starting material as monitored by TLC. The
reaction mixture was filtered through Celite. The filtrate was con-
centrated in vacuo, diluted with chloroform, washed with H2O
(3ꢂ40 mL) and dried over MgSO4. After evaporation, the crude
product was purified by silica gel chromatography (CH2Cl2) and
recrystallized from isopropanol.
Ar). 13C NMR (CDCl3, 50 MHz)
d 36.0, 57.4, 61.9, 62.9, 124.0 (q,
J¼271.1 Hz), 125.1, 125.7 (q, J¼4.0 Hz), 126.1, 126.5, 126.7, 126.8,
127.7, 128.6, 130.0 (q, J¼32.6 Hz), 131.9, 133.6, 133.7, 134.1, 134.2,
137.7, 138.1, 139.8, 146.0, 146.1, 152.9, 154.6, 181.4, 181.7. Anal. Calcd
for C31H23ClF3NO6S: C, 59.10; H, 3.68; N, 2.22. Found: C, 58.55; H,
3.84; N, 2.21.
4.3.6. N-[2-(3-Chloro-1,4-dimethoxy-9,10-dioxo-9,10-
dihydroanthracen-2-yl)-1-(4-fluorophenyl)-ethyl]benzenesulfona-
mide (8f). Yellow solid; mp 201 ꢁC, 1H NMR (CDCl3, 200 MHz)
d
3.11
4.4.1. 4,11-Dimethoxy-2-phenyl-1-(phenylsulfonyl)-2,3-dihydro-1H-
(1H, dd, J¼13.6, 4.3 Hz, CH2), 3.22 (1H, dd, J¼13.6,10.7 Hz, CH2), 3.91
(3H, s, OCH3), 3.94 (3H, s, OCH3), 4.63e4.74 (1H, m, CH), 667 (1H, d,
J¼7.6 Hz, NH), 6.91e7.10 (5H, m, Ar), 7.42e7.49 (4H, m, Ar),
7.82e7.86 (2H, m, Ar), 8.20e8.26 (2H, m, Ar). 13C NMR (CDCl3,
naphtho[2,3-f]indole-5,10-dione (9a). Yellow solid; mp 182 ꢁC, 1H
NMR (CDCl3, 200 MHz)
d
3.21 (1H, dd, J¼17.2, 2.3 Hz, CH2), 3.29 (3H,
s, OCH3), 3.80 (1H, dd, J¼17.2, 9.8 Hz, CH2), 3.89 (3H, s, OCH3), 6.20
(1H, dd, J¼9.8, 2.3 Hz, CH), 7.30e7.43 (7H, m, Ar), 7.49e7.56 (1H, m,
Ar), 7.62e7.66 (2H, m, Ar), 7.70e7.75 (2H, m, Ar), 8.12e8.18 (2H, m,
50 MHz)
d
36.4, 57.1, 61.8, 62.9, 115.6 (d, J¼21.6 Hz), 125.1, 1261,
126.6, 126.8, 127.6 (d, J¼8.0 Hz), 128.5, 131.8, 133.6, 133.7, 134.1,
134.2, 137.7 (d, J¼5.8 Hz), 137.9, 138.5, 140.0, 152.9, 154.7 (2C), 162.2
(d, J¼245.9 Hz), 181.5, 181.8. Anal. Calcd for C30H23ClFNO6S: C,
62.12; H, 4.00; N, 2.41. Found: C, 62.29; H, 4.11; N, 2.34.
Ar). 13C NMR (CDCl3, 50 MHz)
d 35.6, 61.1, 61.2, 66.0, 124.9, 125.9,
126.5, 126.6, 127.2, 128.0, 128.4, 128.6, 129.1, 132.6, 133.5, 133.6,
133.8, 134.0, 135.6, 140.5, 141.8, 143.2, 147.3, 153.6, 182.3, 182.7. Anal.
Calcd for C30H23NO6S: C, 68.56; H, 4.41; N, 2.67. Found: C, 68.23; H,
4.56; N, 2.61.
4.3.7. N-[2-(3-Chloro-1,4-dimethoxy-9,10-dioxo-9,10-
dihydroanthracen-2-yl)-1-(3-fluorophenyl)-ethyl]benzenesulfona-
4.4.2. 4,11-Dimethoxy-1-(phenylsulfonyl)-2-p-tolyl-2,3-dihydro-1H-
mide (8g). Yellow solid; mp 193 ꢁC, 1H NMR (CDCl3, 200 MHz)
d
3.13
naphtho[2,3-f]indole-5,10-dione (9b). Yellow solid; mp 143 ꢁC, 1H
(1H, dd, J¼13.8, 4.9 Hz, CH2), 3.27 (1H, dd, J¼13.8,10.0 Hz, CH2), 3.91
(3H, s, OCH3), 3.94 (3H, s, OCH3), 4.64e4.75 (1H, m, CH), 5.68 (1H, d,
J¼6.5 Hz, NH), 6.89e7.03 (5H, m, Ar), 7.17e7.36 (2H, m, Ar),
7.43e7.45 (2H, m, Ar), 7.81e7.86 (2H, m, Ar), 8.20e8.26 (2H, m, Ar).
NMR (CDCl3, 200 MHz) d 2.35 (3H, s, CH3), 3.23 (3H, s, OCH3), 3.24
(1H, dd, J¼17.4, 2.1 Hz, CH2), 3.23 (3H, s, OCH3), 3.76 (1H, dd, J¼17.4,
9.7 Hz, CH2), 3.88 (3H, s, OCH3), 6.15 (1H, dd, J¼9.7, 2.1 Hz, CH),
7.12e7.21 (4H, m, Ar), 7.36e7.52 (3H, m, Ar), 7.63e7.74 (4H, m, Ar),
13C NMR (CDCl3, 50 MHz)
d
36.1, 57.2, 57.3, 62.9, 113.1 (d, J¼22.3 Hz),
8.11e8.17 (2H, m, Ar). 13C NMR (CDCl3, 50 MHz)
d 21.1, 35.6, 61.1,
114.7 (d, J¼21.2 Hz), 121.6 (d, J¼2.54 Hz), 125.1, 126.1, 126.6, 126.8,
127.6, 128.5, 130.4 (d, J¼8.4 Hz), 131.8, 133.7 (d, J¼8.4 Hz), 134.1,
134.2, 137.7, 138.3, 140.0, 144.6, 144.7, 152.9, 154.7, 163.0 (d,
J¼240.0 Hz),181.5, 181.8. Anal. Calcd for C30H23ClFNO6S: C, 62.12; H,
4.00; N, 2.41. Found: C, 62.03; H, 4.04; N, 2.42.
61.2, 65.9, 124.9, 125.8, 126.4, 126.5, 127.2, 128.0, 128.6, 129.7, 132.6,
133.5, 133.6, 133.8, 134.0, 135.8, 138.2, 138.8, 140.5, 143.1, 147.4,
153.6, 182.2, 182.7. Anal. Calcd for C31H25NO6S: C, 69.00; H, 4.67; N,
2.60. Found: C, 68.45; H, 4.53; N, 2.74.
4.4.3. 2-(2,5-Dimethylphenyl)-4,11-dimethoxy-1-(phenylsulfonyl)-
4.3.8. N-[2-(3-Chloro-1,4-dimethoxy-9,10-dioxo-9,10-
2,3-dihydro-1H-naphtho[2,3-f]indole-5,10-dione (9c). Yellow solid;
dihydroanthracen-2-yl)-1-(2-fluorophenyl)-ethyl]benzenesulfona-
mp 109 ꢁC, 1H NMR (CDCl3, 200 MHz)
d 2.15 (3H, s, CH3), 2.44 (3H, s,
mide (8h). Yellow solid; mp 209 ꢁC,1H NMR (CDCl3, 200 MHz)
d
3.22
CH3), 2.99 (1H, dd, J¼17.2, 2.9 Hz, CH2), 3.26 (3H, s, OCH3), 3.87 (3H,
s, OCH3), 3.88 (1H, dd, J¼17.2, 10.0 Hz, CH2), 6.43 (1H, dd, J¼10.0,
2.9 Hz, CH), 6.89 (1H, s, Ar), 6.96e7.17 (3H, m, Ar), 7.38e7.58 (3H, m,
Ar), 7.69e7.74 (3H, m, Ar), 8.11e8.18 (2H, m, Ar). 13C NMR (CDCl3,
(1H, dd, J¼13.5, 4.6 Hz, CH2), 3.37 (1H, dd, J¼13.5, 11.1 Hz, CH2), 3.92
(3H, s, OCH3), 3.94 (3H, s, OCH3), 4.86e4.98 (1H, m, CH), 5.72 (1H, d,
J¼7.7 Hz, NH), 6.93e7.03 (4H, m, Ar), 7.08e7.16 (2H, m, Ar), 7.44e7.49
(3H, m, Ar), 7.80e7.85 (2H, m, Ar), 8.20e8.26 (2H, m, Ar). 13C NMR
(CDCl3, 50 MHz) 34.3, 53.6, 61.8, 62.7, 115.8 (d, J¼21.6 Hz), 124.5 (d,
50 MHz)
d 19.0, 21.1, 35.7, 61.1, 61.2, 63.2, 124.8, 125.6, 126.4, 126.6,
127.53, 127.9, 128.4, 128.6, 131.1, 131.3, 132.6, 133.5, 133.6, 133.8,

O. Khoumeri et al. / Tetrahedron 67 (2011) 6173e6180
6179
134.0, 135.1, 135.7, 139.9, 140.6, 143.9, 147.0, 153.9, 182.3, 182.7. Anal.
Calcd for C32H27NO6S: C, 69.42; H, 4.92; N, 2.53. Found: C, 68.99; H,
5.05; N, 2.62.
182.3, 182.7. Anal. Calcd for C30H22FNO6S: C, 66.29; H, 4.08; N, 2.58.
Found: C, 66.21; H, 4.12; N, 2.55.
4.4.9. 2-(2-Chlorophenyl)-4,11-dimethoxy-1-(phenylsulfonyl)-2,3-
4.4.4. 4,11-Dimethoxy-2-(4-methoxyphenyl)-1-(phenylsulfonyl)-2,3-
dihydro-1H-naphtho[2,3-f]indole-5,10-dione (9d). Yellow solid; mp
dihydro-1H-naphtho[2,3-f] indole-5,10-dione (9i). Yellow solid; mp
114 ꢁC, 1H NMR (CDCl3, 200 MHz)
d
3.06 (1H, dd, J¼17.4, 2.6 Hz,
100 ꢁC, 1H NMR (CDCl3, 200 MHz)
d
3.18 (1H, dd, J¼17.2, 2.2 Hz,
CH2), 3.41 (3H, s, OCH3), 3.85 (3H, s, OCH3), 3.88 (1H, dd, J¼17.4,
9.9 Hz, CH2), 6.53 (1H, dd, J¼9.9, 2.6 Hz, CH), 7.13e7.32 (3H, m, Ar),
7.41e7.60 (4H, m, Ar), 7.68e7.79 (4H, m, Ar), 8.12e8.18 (2H, m, Ar).
CH2), 3.20 (3H, s, OCH3), 3.75 (1H, dd, J¼17.2, 9.7 Hz, CH2), 3.80 (3H,
s, OCH3), 3.89 (3H, s, OCH3), 6.13 (1H, dd, J¼9.7, 2.2 Hz, CH), 6.87
(2H, d, J¼8.6 Hz, Ar), 7.22 (2H, d, J¼8.6 Hz, Ar), 7.36e7.52 (3H, m,
Ar), 7.61e7.65 (2H, m, Ar), 7.69e7.76 (2H, m, Ar), 8.11e8.17 (2H, m,
13C NMR (CDCl3, 50 MHz)
d 35.7, 61.2, 61.3, 63.9, 125.1, 126.4, 126.6,
126.9, 127.0, 127.5, 128.0, 128.6, 129.4, 130.4, 132.0, 132.9, 133.5,
133.6,133.7,133.9,135.2,138.9,140.1,143.6,147.3,153.8,182.2,182.7.
Anal. Calcd for C30H22ClNO6S: C, 64.34; H, 3.96; N, 2.50. Found: C,
63.51; H, 3.95; N, 2.46.
Ar). 13C NMR (CDCl3, 50 MHz)
d 35.5, 55.3, 61.1, 61.2, 65.7, 114.3,
124.8, 126.3, 126.4, 126.6, 127.1, 127.3, 128.0, 128.6, 129.0, 132.6,
133.5, 133.6, 133.8, 134.0, 135.8, 140.6, 143.0, 147.3, 153.6, 159.6,
182.2, 182.7. Anal. Calcd for C31H25NO7S: C, 67.01; H, 4.54; N, 2.52.
Found: C, 66.30; H, 4.61; N, 2.48.
Acknowledgements
4.4.5. 4,11-Dimethoxy-1-(phenylsulfonyl)-2-[4-(trifluoromethyl)phe-
nyl]-2,3-dihydro-1H-naphtho-[2,3-f]indole-5,10-dione (9e). Yellow
This work is supported by the Centre National de la Recherche
Scientifique. We express our thanks to V. Remusat for 1H and 13C
NMR spectra recording.
solid; mp 207 ꢁC, 1H NMR (CDCl3, 200 MHz)
d
3.16 (1H, dd, J¼17.4,
2.3 Hz, CH2), 3.34 (3H, s, OCH3), 3.81 (1H, dd, J¼17.4, 9.8 Hz, CH2),
3.88 (3H, s, OCH3), 6.24 (1H, dd, J¼9.8, 2.3 Hz, CH), 7.40e7.47 (4H,
m, Ar), 7.53e7.78 (7H, m, Ar), 8.13e8.18 (2H, m, Ar). 13C NMR (CDCl3,
References and notes
50 MHz)
d
35.6, 61.2, 61.3, 65.4,123.8 (q, J¼272.2 Hz),125.2,126.1 (q,
1. (a) Lin, A. J.; Cosby, L. A.; Shansky, C. W.; Sartorelli, A. C. J. Med. Chem. 1972, 15,
1247e1252; (b) Moore, H. W. Science 1977, 197, 527e532; (c) Arcamone, F.
Cancer Res. 1985, 45, 5995e5999; (d) Monneret, C. Eur. J. Med. Chem. 2001, 36,
483e493.
2. Molina, A.; Vaquero, J. J.; Garcia-Navio, J. L.; Alvarez-Builla, J.; de Pascual-Teresa,
B.; Gago, F.; Rodrigo, M. M.; Ballesteros, M. J. Org. Chem. 1996, 61, 5587e5599.
3. Menna, P.; Salvatorelli, E.; Gianni, L.; Minotti, G. Top. Curr. Chem. 2008, 283,
21e44.
J¼3.7 Hz), 126.3, 126.5, 126.6, 127.3, 128.2, 128.8, 129.0, 130.1 (q,
J¼32.6 Hz), 133.0, 133.6, 133.7, 133.9, 135.0, 140.1, 142.8, 145.6, 147.5,
153.6, 182.2, 182.6. Anal. Calcd for C31H22F3NO6S: C, 62.73; H, 3.74;
N, 2.36. Found: C, 62.78; H, 3.97; N, 2.34.
4.4.6. 2-(4-Fluorophenyl)-4,11-dimethoxy-1-(phenylsulfonyl)-2,3-
4. Shchekotikhin, A. ,E.; Buyanov, V. N.; Preobrazhenskaya, M. N. Bioorg. Med.
Chem. 2004, 12, 3923e3930.
dihydro-1H-naphtho[2,3-f] indole-5,10-dione (9f). Yellow solid; mp
185 ꢁC, 1H NMR (CDCl3, 200 MHz)
d
3.17 (1H, dd, J¼17.4, 2.4 Hz,
5. (a) Shchekotikhin, A. ,E.; Shtil, A. A.; Luzikov, Y. N.; Bobrysheva, T. V.; Buyanov,
V. N.; Preobrazhenskaya, M. N. Bioorg. Med. Chem. 2005, 13, 2285e2291; (b)
Shchekotikhin, A. ,E.; Dezhenkova, L. G.; Susova, O. Y.; Glazunova, V. A.; Luzikov,
Y. N.; Sinkevich, Y. B.; Buyanov, V. N.; Shtil, A. A.; Preobrazhenskaya, M. N. Bi-
oorg. Med. Chem. 2007, 15, 2651e2659.
6. (a) Habib, A. M.; Ho, D. K.; Masuda, S.; MacCloud, T.; Reddy, K. S.; Aboushoer,
M.; MacKenzie, A.; Byrn, S. R.; Chang, C. J.; Cassady, J. M. J. Org. Chem. 1987, 52,
412e418; (b) Hansen, M.; Lee, S. J.; Cassady, J. M.; Hurley, L. M. J. Am. Chem. Soc.
1996, 118, 5553e5561; (c) Iinuma, M.; Tosa, H.; Tanaka, T.; Riswan, S. Phyto-
chemistry 1996, 42, 245e247.
CH2), 3.25 (3H, s, OCH3), 3.78 (1H, dd, J¼17.4, 9.7 Hz, CH2), 3.89 (3H,
s, OCH3), 6.17 (1H, dd, J¼9.7, 2.4 Hz, CH), 7.00e7.09 (2H, m, Ar),
7.26e7.32 (2H, m, Ar), 7.38e7.46 (2H, m, Ar), 7.51e7.58 (1H, m, Ar),
7.62e7.66 (2H, m, Ar), 7.71e7.75 (2H, m, Ar), 8.12e8.19 (2H, m, Ar).
13C NMR (CDCl3, 50 MHz)
d
35.6, 61.1, 61.2, 65.3, 116.0 (d, J¼21.6 Hz),
125.0, 126.5 (d, J¼6.6 Hz), 127.2, 127.7, 127.8, 128.1, 128.7, 132.8,
133.5, 133.6, 133.7, 133.9, 135.3, 137.7 (d, J¼3.3 Hz) 140.4, 142.9,
147.4, 153.6, 162.5 (d, J¼247.4 Hz), 182.2, 182.6. Anal. Calcd for
C30H22FNO6S: C, 66.29; H, 4.08; N, 2.58. Found: C, 66.19; H, 4.22; N,
2.53.
7. Sittisombut, C.; Costes, N.; Michel, S.; Koch, M.; Tillequin, F.; Pfeiffer, B.; Renard,
ꢀ
P.; Pierre, A.; Atassi, G. Chem. Pharm. Bull. 2001, 49, 675e679.
ꢀ
8. Magiatis, P.; Melliou, E.; Skaltsounis, A.-L.; Mitaku, S.; Leonce, S.; Renard, P.;
ꢀ
Pierre, A.; Atassi, G. J. Nat. Prod. 1998, 61, 982e986.
9. (a) Fellows, I. M.; Schwaebe, M.; Dexheimer, T. S.; Vankayalapati, H.; Gleason-
Guzman, M.; Whitten, J. P.; Hurley, L. H. Mol. Cancer Ther. 2005, 4, 1729e1739;
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4.4.7. 2-(3-Fluorophenyl)-4,11-dimethoxy-1-(phenylsulfonyl)-2,3-
dihydro-1H-naphtho[2,3-f] indole-5,10-dione (9g). Yellow solid; mp
195 ꢁC, 1H NMR (CDCl3, 200 MHz)
d
3.15 (1H, dd, J¼17.3, 2.2 Hz,
CH2), 3.30 (3H, s, OCH3), 3.79 (1H, dd, J¼17.3, 9.7 Hz, CH2), 3.89 (3H,
s, OCH3), 6.19 (1H, dd, J¼9.7, 2.3 Hz, CH), 6.95e7.22 (3H, m, Ar),
7.29e7.60 (4H, m, Ar), 7.67e7.75 (4H, m, Ar), 8.13e8.18 (2H, m, Ar).
13C NMR (CDCl3, 50 MHz)
d
35.6, 61.1, 61.2, 65.4 (d, J¼1.5 Hz), 112.9
(d, J¼22.3 Hz), 115.4 (d, J¼21.2 Hz), 121.6 (d, J¼2.9 Hz), 125.1, 125.3,
126.4, 126.6, 127.3, 128.7, 130.8 (d, J¼8.0 Hz), 132.9, 133.6, 133.7,
133.8 (d, J¼10.2 Hz), 135.2, 140.2, 142.9, 144.2, 144.3, 147.4, 153.6,
163.0 (d, J¼247.7 Hz), 181.2, 181.6. Anal. Calcd for C30H22FNO6S: C,
66.29; H, 4.08; N, 2.58. Found: C, 65.90; H, 4.18; N, 2.54.
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4.4.8. 2-(2-Fluorophenyl)-4,11-dimethoxy-1-(phenylsulfonyl)-2,3-
dihydro-1H-naphtho[2,3-f] indole-5,10-dione (9h). Yellow solid; mp
193 ꢁC, 1H NMR (CDCl3, 200 MHz)
d
3.15 (1H, dd, J¼17.4, 2.0 Hz,
ꢀ
17. (a) Takechi, N.; Ait-Mohand, S.; Medebielle, M.; Dolbier, W. R., Jr. Tetrahedron
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s, OCH3), 6.41 (1H, dd, J¼10.1, 2.0 Hz, CH), 7.06e7.17 (2H, m, Ar),
7.24e7.58 (5H, m, Ar), 7.66e7.74 (4H, m, Ar), 8.10e8.19 (2H, m, Ar).
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35.3, 61.1, 61.2, 61.5 (d, J¼2.2 Hz), 116.2
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