Synthesis of new hydroxybenzo[a]carbazoles

Article abstract of DOI:10.1055/s-2008-1078599

An investigation of the alkylation sites of 4,7-dihydroxybenzo[a]pyrrolo[3, 4-c]carbazole-1,3(2H,8H)-dione, as well as the site of reduction in the maleimide upper ring, was carried out which resulted in the synthesis of diversely substituted 4-hydroxyben

Full text of DOI:10.1055/s-2008-1078599

PAPER
2569
Synthesis of New Hydroxybenzo[a]carbazoles
Synthesis of
N
e
l
w Hyd
i
roxybe
s
nzo[
a
]carb
a
azoles beth Conchon, Fabrice Anizon, Bettina Aboab, Michelle Prudhomme*
Laboratoire SEESIB, UMR 6504 CNRS, Université Blaise Pascal, 63177 Aubière, France
Fax +33(4)73407717; E-mail: michelle.prudhomme@univ-bpclermont.fr
Received 8 April 2008; revised 5 May 2008
the synthesis of 4,7-dihydroxybenzo[a]pyrrolo[3,4-c]car-
bazole and its derivatives (Figure 1).7,8 In this paper, we
report synthetic studies aimed at investigating the alkyla-
tion sites of 4,7-dihydroxybenzo[a]pyrrolo[3,4-c]carba-
Abstract: An investigation of the alkylation sites of 4,7-dihydrox-
ybenzo[a]pyrrolo[3,4-c]carbazole-1,3(2H,8H)-dione, as well as the
site of reduction in the maleimide upper ring, was carried out which
resulted in the synthesis of diversely substituted 4-hydroxyben-
zo[a]pyrrolo[3,4-c]carbazoles. Moreover, the synthesis of 5,6-dicy- zole-1,3(2H,8H)-dione, as well as the site of reduction in
ano-1,4-dihydroxy-11H-benzo[a]carbazole was performed in
which the maleimide ring of the above scaffold is missing and is re-
placed by electron-withdrawing nitrile groups.
the maleimide upper ring. For this purpose, two alkyl
groups were introduced and the alkylation sites were de-
termined by 2D NMR experiments. Then, the site of re-
duction in the maleimide upper ring was investigated
Key words: fused-ring systems, Diels–Alder reactions, alkyla-
tions, reductions, nitriles
using several reducing agents. The synthesis of a ben-
zo[a]carbazole 9 without the maleimide ring but bearing
two nitrile groups instead of the carbonyl groups of the
previous scaffold was also carried out (Figure 1).
A number of biologically active compounds possess a
benzo[a]carbazole framework. According to their substit-
uents, these compounds can exhibit antifungal and antitu-
mor activities,1–4 antiestrogenic properties,5 or kinase
inhibitory activities.6–8 Various approaches have been re-
ported for the synthesis of benzo[a]carbazoles including
photocyclization, palladium-catalyzed cross-coupling re-
actions, Fischer indolization, Diels–Alder reactions, and
irradiation of a benzotriazole derivative.9,10 In the course
of studies on benzo[a]carbazoles, we were interested in
2-Benzyl-7-(benzyloxy)-4-hydroxybenzo[a]pyrrolo[3,4-
c]carbazole-1,3(2H,8H)-dione (1) and 4-hydroxy-7-meth-
oxy-2-methylbenzo[a]pyrrolo[3,4-c]carbazole-1,3(2H,8H)-
dione (2) were obtained by reaction of diphenol C with 4–
5 equivalents of benzyl bromide or methyl iodide in the
presence of potassium carbonate (Scheme 1). Diphenol C
was synthesized from indolylmaleimide A via a Diels–
Alder cycloaddition/oxidation with 1,4-benzoquinone fol-
lowed by reduction using sodium dithionite.7 Despite a
H
N
H
H
N
O
O
O
O
N
O
O
OH
OH
11
R
OH
N
N
N
H
HO
H
O
O
OH
Ref. 8
Ref. 7
R = H, Me, OH
Ref. 7
HO
R
N
HO
OH
X
X'
Y'
NC
CN
Y
OH
OH
N
H
N
HO
H
RO
9
1 R = Bn, X,Y = O, X',Y' = O
2 R = Me, X,Y = O, X',Y' = O
3 R = Bn, X,Y = O, X' = H, Y' = OH
4 R = Bn, X = H, Y = OH, X',Y' = O
5 R = Me, X,Y = O, X' = H, Y' = OH
6 R = Me, X,Y = O, X' = Y' = H
Figure 1
SYNTHESIS 2008, No. 16, pp 2569–2574
x
x.
x
x
.
2
0
0
8
Advanced online publication: 17.07.2008
DOI: 10.1055/s-2008-1078599; Art ID: Z08108SS
© Georg Thieme Verlag Stuttgart · New York

2570
E. Conchon et al.
PAPER
O
O
H
N
H
H
N
N
O
O
O
O
O
O
OH
O
aq Na2S2O4
THF
N
N
H
N
H
H
HO
O
A
B
C
K2CO3
Bn
N
OH
BnBr or MeI
O
OH
R
N2
LiAlH4, THF
–78 °C
O
3
O
N
1
H
OH
4
BnO
12
1
11
10
3
Bn
5
6
Bn
NaBH4, THF
r.t.
N
O
N
OH
N
H
HO
8
7
O
9
RO
OH
OH
1 R = Bn
2 R = Me
+
N
N
H
BnO
H
BnO
3
4
Me
Me
N
N
OH
O
O
LiAlH4, THF
–78 °C
OH
OH
H2, Pd/C
2
EtOH, DMF
55 psi
N
N
H
H
MeO
MeO
6
5
Scheme 1 Synthetic scheme for compounds 1–6
large excess of the base and the alkyl halide, substitution
of diphenol C with benzyl and methyl groups occurred on
the imide nitrogen and on the hydroxy group at the 7-po-
sition, but not on the hydroxy group at the 4-position,
probably because of a hydrogen bond between the hy-
droxy group and the oxygen of the carbonyl at the 3-posi-
tion.
To confirm the hypothesis of a hydrogen bond between
the oxygen of the carbonyl at the 3-position and the hydro-
gen of the hydroxy group at the 4-position, that prevents
alkylation of this hydroxy group, conformational analysis
was performed using the Monte Carlo Multiple Method
with MM3 force field of Macromodel 7.0 program. In-
deed, two intramolecular hydrogen bonds were found in
compound C (Figure 2), one between the indolic NH and
the oxygen of the hydroxy group at the 7-position (1.98 Å)
and a second between the hydrogen of the hydroxy group
at the 4-position and the carbonyl at the 3-position (1.79
Å).
Figure 2 Conformational analysis of compound C: hydrogen bonds
are shown as thin solid lines
quantitative yield, whereas reduction of 1 with sodium
borohydride at room temperature yielded regioisomers 3
and 4 in 60% and 28% yield, respectively (Scheme 1).
The structures of compounds 3 and 4 were assigned from
NMR experiments (1H,1H-COSY, HSQC, HMBC, 2D-
NOESY) (Figure 3). The position of the benzyl group on
one of the phenol functions was determined by NOESY
The structure of compound 1 has been confirmed by 2D
NMR experiments after the reduction step leading to 3
and/or 4. Reduction of compound 1 using lithium alumi-
num hydride at –78 °C provided only compound 3 in a
Synthesis 2008, No. 16, 2569–2574 © Thieme Stuttgart · New York

PAPER
Synthesis of New Hydroxybenzo[a]carbazoles
2571
OMe
H5.18
H 5.09
H4.65
O
H4.48
OH
Br
6.38H
7.34HO
N
N
OMe
O
170.7
1)
167.6
115.4
8.38H
OH
142.2
toluene, EtOH
Pd(PPh3)4,
Na2CO3
OH
OMe
112.5
H6.88
B(OH)2
N
N
N
N
2) TFA, CH2Cl2
12.12
H
NOE
H
11.85
H
H
Boc
O
O
MeO
5.72H2C
5.70 H2C
7.57 H
7
NOE
H 7.56
H7.57
1) BBr3, CH2Cl2
2) DDQ, MeOH
H
7.56
CN
5
CN
NC
6
NC
4
3
OH
O
4
7
Na2S2O4
THF
Figure 3 Assignment of the structures of compounds 3 and 4
8
3
9
11
N
2
N
1
H
H
10
experiments. NOE effects were observed between the in-
dole NH proton at 12.12 ppm in compound 4 and at 11.85
ppm in compound 3 and the aromatic protons in the ortho
position of the benzyl group at 7.56 ppm in compound 4
and at 7.57 ppm in compound 3, indicating that the benzyl
group was fixed to the oxygen at the 7-position. NOE ef-
fects were also observed between these aromatic protons
and the methylenic protons of the benzyl group at 5.72
and at 5.70 ppm in compounds 4 and 3, respectively.
1H,13C-HMBC experiments showed that the second ben-
zyl group was attached to the nitrogen of the hydroxylac-
HO
O
9
8
Scheme 2 Synthetic scheme for compound 9
mer. With sodium borohydride, a weaker complexation
leads to the formation of both regioisomers.
Reduction of compound 2 using lithium aluminum hy-
dride in tetrahydrofuran at –78 °C gave hydroxylactam 5
in a quantitative yield. Reduction of 5 by catalytic hydro-
genation on Pd/C at 55 psi in an ethanol–N,N-dimethyl-
formamide mixture yielded lactam 6 (Scheme 1).
3
tam. Indeed, J couplings were observed between the
methylenic protons of the benzyl group (at 4.48 and 5.18
ppm in compound 3 and at 4.65 and 5.09 ppm in com-
pound 4) and the carbonyl of the hydroxylactam at 167.6
and at 170.7 ppm in compounds 3 and 4, respectively.
Moreover, the orientation of the hydroxy group of the hy-
For the synthesis of 5,6-dicyano-1,4-dihydroxy-11H-ben-
zo[a]carbazole (9), we first tried a Suzuki coupling reac-
tion between N-Boc-1H-indol-2-ylboronic acid and 2-
bromo-1,4-benzoquinone. The N-Boc-1H-indol-2-ylbo-
ronic acid was prepared by reaction of N-Boc-1H-indole
with lithium diisopropylamide, then quenching with tri-
isopropyl borate, according to the method described by
Vazquez and co-workers.11 The Suzuki coupling with 2-
bromo-1,4-benzoquinone failed, probably because of oxi-
dation of the catalyst by the quinone. Therefore, the
Suzuki coupling was carried out using commercially
available 2-bromo-1,4-dimethoxybenzene, followed by
removal of the Boc protecting group with trifluoroacetic
acid, which gave the coupling product 7 (Scheme 2).
Demethylation was performed using boron tribromide,
then reaction with a large excess of 2,3-dichloro-5,6-di-
cyano-1,4-benzoquinone (DDQ) led to quinone 8 which
was further reduced to hydroquinone 9 using aqueous so-
dium dithionite. The proposed mechanism leading to the
formation of compound 8 is outlined in Scheme 3. After
demethylation of compound 7 and oxidation to the qui-
none, a second molecule of DDQ could give rise to a Diels–
Alder reaction12,13 leading to intermediate 7a. Then, after
oxidation to 7b, a retro-Diels–Alder reaction could lead to
compound 8. The presence of C≡Nbonds was confirmed
by a large absorption band at 2228 cm–1 in the IR spectrum
of intermediate 8 and at 2225 cm–1 in the IR spectrum of
compound 9.
1
droxylactam was determined by H,13C-HMBC experi-
ments on compound 4 based on several couplings:
3
(i) J Couplings were observed between the quaternary
carbon at 112.5 ppm and the CH proton of the hydroxylac-
tam at 6.38 ppm and the aromatic proton of the indole
moiety at 8.38 ppm.
(ii) The quaternary carbon at 142.2 ppm could be assigned
on account of 3J coupling with the proton of the hydroxy
at 7.34 ppm, 2J coupling with the proton of the hydroxy-
lactam at 6.38 ppm, and 4J coupling (weak) with the NH
indolic proton at 12.12 ppm. It can be noticed that if the
structure of compound 4 was that of its regioisomer 3,
coupling between the indolic NH proton and this quater-
nary carbon would be a 5J coupling that is rarely observed.
(iii) Two couplings were also found with the quaternary
carbon at 115.4 ppm: a 3J coupling with the proton of the
hydroxylactam at 6.38 ppm and a 4J coupling (weak) with
the aromatic proton of the phenolic moiety at 6.88 ppm.
When lithium aluminum hydride or sodium borohydride
is used, a complex could be formed between the carbonyl
at the 3-position, the metal, and the oxygen atom at the 4-
position, that could guide the approach of the hydride to-
ward the carbon of the carbonyl at the 3-position, leading
to hydroxylactam 3 as the unique or the major regioiso-
In conclusion, this work was focused on an examination
of the sites of alkylation and reduction of maleimido-4,7-
Synthesis 2008, No. 16, 2569–2574 © Thieme Stuttgart · New York

2572
E. Conchon et al.
PAPER
Cl
Cl
Cl
Cl
O
O
O
O
CN
O
NC
CN
OMe
O
NC
1) BBr3, CH2Cl2
2) DDQ, MeOH
Diels–Alder
N
N
H
N
H
H
MeO
O
O
7
7a
oxidation
Cl
Cl
CN
NC
O
O
O
retro-Diels–Alder
CN
O
NC
N
H
O
N
H
O
8
7b
Scheme 3 Proposed mechanism for the formation of compound 8
Due to the insolubility of 1, its 13C NMR spectrum could not be re-
corded.
dihydroxybenzo[a]carbazoles. The results give an insight
into the possible chemical modifications compatible with
the interaction with biological targets. 5,6-Dicyano-1,4- HRMS (ESI+): m/z [M + H]+ calcd for C32H23N2O4: 499.1658;
found: 499.1635.
dihydroxy-11H-benzo[a]carbazole, possessing two nitrile
groups instead of the two carbonyl groups of the previous
framework, was synthesized via a Diels–Alder cycloaddi-
tion between DDQ and 2-(2,5-dimethoxyphenyl)-1H-in-
dole obtained by a Suzuki coupling reaction.
4-Hydroxy-7-methoxy-2-methylbenzo[a]pyrrolo[3,4-c]carba-
zole-1,3(2H,8H)-dione (2)
To a soln of diphenol C7 (200 mg, 0.63 mmol) in acetone (6 mL)
were added K2CO3 (348 mg, 2.52 mmol) and MeI (150 mL, 2.52
mmol). The mixture was refluxed for 3 h. After cooling, aq 1 N HCl
was added until acidic pH. After extraction with EtOAc (3 ×), the
organic phase was dried (MgSO4). The solvent was removed and
the residue was purified by flash chromatography (cyclohexane–
EtOAc, 8:2 Æ1:1) to give 2 (193 mg, 0.56 mmol, 89% yield) as a
red solid; mp >280 °C.
IR spectra were recorded on a Perkin–Elmer Paragon 500 spectrom-
eter. NMR spectra were recorded on a Bruker Avance 400 and
Avance 500 (for the HMBC experiments) instruments (chemical
shifts d in ppm); the following abbreviations are used: singlet (s),
broad signal (br s), doublet (d), doublet of doublets (dd), triplet (t),
doublet of triplets (dt), multiplet (m), tertiary carbons (C tert), qua-
ternary carbons (C quat). High-resolution mass spectra (ESI+) were
determined on a high-resolution Waters Micro Q-Tof apparatus.
Chromatographic purifications were performed using silica gel
[Geduran SI 60 (Merck), 0.040–0.063 mm] flash column chroma-
tography.
IR (KBr): 1610 (C=C), 1669 and 1751 (C=O), 3300–3600 cm–1
(NH, OH).
1H NMR (400 MHz, DMSO-d6): d = 3.08 (s, 3 H), 4.07 (s, 3 H), 6.93
(d, J = 8.5 Hz, 1 H), 7.10 (d, J = 8.5 Hz, 1 H), 7.37 (t, J = 7.5 Hz, 1
H), 7.57 (t, J = 7.5 Hz, 1 H), 7.89 (d, J = 8.0 Hz, 1 H), 8.88 (d, J =
8.0 Hz, 1 H), 11.58 (s, 1 H), 11.93 (s, 1 H).
Conformational analysis was performed using the Monte Carlo
Multiple Method14 with MM3 force field15 of Macromodel 7.0 pro-
gram (Macromodel 7.0, Schrödinger Inc., 1500 SW First Ave, Suite
1180, Portland, OR 97201, USA).
13C NMR (100 MHz, DMSO-d6): d = 24.0 and 55.9 (CH3), 108.7,
112.5, 112.9, 120.7, 123.7, and 126.4 (C tert), 112.0, 114.2, 116.4,
117.7, 119.7, 127.2, 139.6, 139.7, 146.9, and 148.6 (C quat), 168.3
and 173.7 (C=O).
HRMS (ESI+): m/z [M + H]+ calcd for C20H15N2O4: 347.1032;
found: 347.1031.
2-Benzyl-7-(benzyloxy)-4-hydroxybenzo[a]pyrrolo[3,4-c]car-
bazole-1,3(2H,8H)-dione (1)
To a soln of diphenol C7 (70 mg, 0.22 mmol) in acetone (1.5 mL)
were added K2CO3 (181 mg, 1.32 mmol) and BnBr (124 mL, 1.06
mmol). The mixture was refluxed for 3 h. After cooling, aq 1 N HCl
was added until acidic pH. After extraction with EtOAc (3 ×), the
organic phase was dried (MgSO4). The solvent was removed and
the residue was purified by flash chromatography (cyclohexane–
EtOAc, 9:1 Æ7:3) to give 1 (88 mg, 0.18 mmol, 80% yield) as a red
solid; mp >280 °C.
2-Benzyl-7-(benzyloxy)-3,8-dihydro-3,4-dihydroxyben-
zo[a]pyrrolo[3,4-c]carbazol-1(2H)-one (3)
To a soln of compound 1 (100 mg, 0.20 mmol) in THF (9 mL) at
–78 °C was added 2 M LiAlH4 in THF (500 mL). The mixture was
stirred at –78 °C for 3 h, then aq 1 N HCl was added until acidic pH.
After extraction with EtOAc (3 ×), the organic phase was washed
with brine, then dried (MgSO4). The solvent was removed to give 3
(100 mg, 0.20 mmol, 100% yield) as a beige solid; mp >280 °C.
IR (KBr): 1670 (C=O), 3400–3600 cm–1 (NH, OH).
1H NMR (400 MHz, DMSO-d6): d = 4.48 (d, J = 15.5 Hz, 1 H), 5.18
(d, J = 15.5 Hz, 1 H), 5.70 (s, 2 H), 6.36 (d, J = 7.0 Hz, 1 H, CHOH),
IR (KBr): 1668 and 1752 (C=O), 3300–3600 cm–1 (NH, OH).
1H NMR (400 MHz, DMSO-d6): d = 4.95 (s, 2 H), 5.73 (s, 2 H),
6.98–7.63 (m, 14 H), 7.97 (d, J = 8.0 Hz, 1 H), 9.03 (d, J = 8.0 Hz,
1 H), 11.70 (br s, 1 H), 12.33 (s, 1 H).
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Synthesis of New Hydroxybenzo[a]carbazoles
2573
6.40 (d, J = 7.0 Hz, 1 H, CHOH), 6.88 (d, J = 8.5 Hz, 2 H), 7.07 (t,
J = 8.5 Hz, 1 H), 7.29–7.45 (m, 8 H), 7.49 (dt, J1 = 7.0 Hz, J2 = 1.0
Hz, 1 H), 7.57 (d, J = 7.0 Hz, 2 H), 7.88 (d, J = 8.0 Hz, 1 H), 9.29
(d, J = 8.0 Hz, 1 H), 9.98 (s, 1 H), 11.85 (s, 1 H).
10% Pd/C (19 mg). The mixture was filtered over Celite®, then the
solvent was removed. The residue was purified by flash chromatog-
raphy (cyclohexane–EtOAc, 1:1) to give compound 6 (30 mg, 0.09
mmol, 50% yield) as a brown solid; mp >280 °C.
13C NMR (100 MHz, DMSO-d6): d = 42.2 and 69.1 (CH2), 81.6,
109.7, 110.1, 111.8, 119.3, 124.7, 125.0, 127.1, 127.2 (2 C), 127.6
(3 C), 128.4 (2 C), and 128.5 (2 C) (C tert), 112.2, 115.6, 118.6,
120.9, 124.9, 133.8, 135.4, 137.5, 138.2, 138.8, 146.8, and 147.8 (C
quat), 167.6 (C=O).
IR (KBr): 1619, 1640, and 1697 (C=C, C=O), 3300–3600 cm–1
(NH, OH).
1H NMR (400 MHz, DMSO-d6): d = 3.39 (s, 3 H), 4.15 (s, 3 H), 5.09
(s, 2 H), 7.01 (d, J = 8.5 Hz, 1 H), 7.13 (d, J = 8.5 Hz, 1 H), 7.26 (t,
J = 7.5 Hz, 1 H), 7.44 (t, J = 8.0 Hz, 1 H), 7.85 (d, J = 8.0 Hz, 1 H),
9.32 (d, J = 8.0 Hz, 1 H), 10.07 (s, 1 H), 11.65 (s, 1 H).
HRMS (ESI+): m/z [M + H – H2O]+ calcd for C32H23N2O3:
483.1709; found: 483.1703.
13C NMR (100 MHz, DMSO-d6): d = 29.0 and 55.8 (CH3), 54.9
(CH2), 107.1, 109.0, 111.7, 118.9, 124.5, and 124.8 (C tert), 112.6,
114.7, 118.4, 121.1, 125.6, 131.5, 134.0, 138.5, 148.5, and 148.7 (C
quat), 168.5 (C=O).
2-Benzyl-7-(benzyloxy)-1,8-dihydro-1,4-dihydroxyben-
zo[a]pyrrolo[3,4-c]carbazol-3(2H)-one (4)
To a soln of compound 1 (50 mg, 0.10 mmol) in THF (2 mL) at 0 °C
was added NaBH4 (4 mg, 0.10 mmol). The mixture was stirred at r.t.
for 4 h. Aq 1 N HCl was added until acidic pH. After extraction with
EtOAc (3 ×), the organic phase was washed with brine, then dried
(MgSO4). The solvent was removed and the residue was purified by
flash chromatography (cyclohexane–EtOAc, 9:1 Æ1:1). Both re-
gioisomers were isolated as beige solids: compound 3 (30 mg, 0.060
mmol, 60% yield) and compound 4 (14 mg, 0.028 mmol, 28%
yield); mp >280 °C.
HRMS (ESI+): m/z [M + H]+ calcd for C20H17N2O3: 333.1233;
found: 333.1233.
2-(2,5-Dimethoxyphenyl)-1H-indole (7)
To a mixture of 2-bromo-1,4-dimethoxybenzene (1.00 g, 4.62
mmol) and Pd(PPh3)4 (432 mg, 0.37 mmol) in toluene (27 mL) was
added N-Boc-1H-indol-2-ylboronic acid (2.35 g, 9.24 mmol) in
EtOH (13 mL). Then, a soln of Na2CO3 (3.61 g) in H2O (6.7 mL)
was added and the mixture was refluxed for 3 h. After cooling, H2O
was added. After extraction with EtOAc (3 ×), the organic phase
was dried (MgSO4). The solvent was removed and the residue was
purified by flash chromatography (cyclohexane Æ cyclohexane–
EtOAc, 9:1). The coupling product mixed with 2-bromo-1,4-
dimethoxybenzene (850 mg) was dissolved in CH2Cl2 (9 mL) and
stirred at r.t. for 18 h in the presence of TFA (8 mL). H2O was add-
ed. After extraction with CH2Cl2 (3 ×), the organic phase was dried
(MgSO4). The solvent was removed and the residue was purified by
flash chromatography (cyclohexane–EtOAc, 9:1) to give com-
pound 7 (407 mg, 1.61 mmol, 35% yield) as a beige solid; mp
85 °C.
IR (KBr): 1670 (C=O), 3300–3600 cm–1 (NH, OH).
1H NMR (400 MHz, DMSO-d6): d = 4.65 (d, J = 15.5 Hz, 1 H), 5.09
(d, J = 15.5 Hz, 1 H), 5.72 (s, 2 H), 6.38 (d, J = 10.0 Hz, 1 H,
CHOH), 6.88 (d, J = 8.5 Hz, 1 H), 7.15 (d, J = 8.5 Hz, 1 H), 7.28–
7.43 (m, 8 H), 7.47 (d, J = 7.5 Hz, 2 H), 7.53–7.57 (m, 3 H), 7.93
(d, J = 8.0 Hz, 1 H), 8.38 (d, J = 8.0 Hz, 1 H), 12.12 (s, 1 H), 13.22
(s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 43.0 and 69.2 (CH2), 81.1,
109.9, 112.2, 112.4, 120.3, 122.5, 125.3, 127.1 (2 C), 127.3, 127.6,
127.7 (2 C), 128.5 (2 C), and 128.6 (2 C) (C tert), 112.5, 114.4,
115.4, 118.5, 120.3, 137.3, 137.5, 137.9, 139.0, 142.2, 146.5, and
148.8 (C quat), 170.7 (C=O).
IR (KBr): 1617 and 1638 (C=C), 3300–3600 cm–1 (NH).
HRMS (ESI+): m/z [M + H]+ calcd for C32H25N2O4: 501.1814;
found: 501.1805.
1H NMR (400 MHz, CDCl3): d = 3.86 (s, 3 H), 3.98 (s, 3 H), 6.85
(dd, J1 = 9.0 Hz, J2 = 3.0 Hz, 1 H), 6.91 (dd, J1 = 1.0 Hz, J2 = 0.5
Hz, 1 H), 6.97 (d, J = 9.0 Hz, 1 H), 7.12 (dt, J1 = 7.0 Hz, J2 = 1.0
Hz, 1 H), 7.20 (dt, J1 = 7.0 Hz, J2 = 1.0 Hz, 1 H), 7.40 (d, J = 3.0
Hz, 1 H), 7.43 (dd, J1 = 8.5 Hz, J2 = 0.5 Hz, 1 H), 7.65 (d, J = 8.0
Hz, 1 H), 9.75 (br s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 55.8 and 56.6 (CH3), 99.9, 111.0,
113.3, 113.4, 113.7, 119.8, 120.3, and 122.0 (C tert), 121.4, 128.0,
135.8, and 136.2 (C quat), 150.3 and 154.2 (C–O).
3,8-Dihydro-3,4-dihydroxy-7-methoxy-2-methylbenzo[a]pyr-
rolo[3,4-c]carbazol-1(2H)-one (5)
To a soln of compound 2 (70 mg, 0.20 mmol) in THF (9 mL) at
–78 °C was added 2 M LiAlH4 in THF (500 mL). The mixture was
stirred at –78 °C for 20 min, then aq 1 N HCl was added until acidic
pH. After extraction with EtOAc (3 ×), the organic phase was
washed with brine, then dried (MgSO4). The solvent was removed
to give 5 (70 mg, 0.20 mmol, 100% yield) as a beige solid; mp
>280 °C.
HRMS (ESI+): m/z [M + H]+ calcd for C16H16NO2: 254.1181;
found: 254.1190.
IR (KBr): 1619, 1637, 1679, and 1697 (C=C, C=O), 3300–3600
cm–1 (NH, OH).
5,6-Dicyano-1,4-dihydroxy-11H-benzo[a]carbazole (9)
A 1 M soln of BBr3 in CH2Cl2 (800 mL) was added dropwise to a
soln of compound 7 (50 mg, 0.20 mmol) in CH2Cl2 (5 mL) at –78 °C.
The mixture was stirred at r.t. for 12 h. The mixture was cooled to
0 °C and H2O was added. After extraction with EtOAc (3 ×), the or-
ganic phase was dried (MgSO4). The solvents were removed, the
residue was dissolved in MeOH (5 mL), and the solution was re-
fluxed for 30 min in the presence of DDQ (816 mg, 3.6 mmol). The
solvent was removed and EtOAc was added to the residue. The mix-
ture was filtered and the solid was washed with EtOAc to yield in-
termediate 8. A soln of Na2S2O4 (70 mg, 0.40 mmol) in H2O (500
mL) was added to a soln of quinone 8 in THF (2 mL). The mixture
was stirred at r.t. for 4 h. The solvent was removed and the residue
was purified by flash chromatography (EtOAc–cyclohexane, 7:3) to
give 9 (31 mg, 0.10 mmol, 52% yield) as a beige solid; mp >280 °C.
1H NMR (400 MHz, DMSO-d6): d = 3.14 (s, 3 H), 4.16 (s, 3 H), 6.43
(d, J = 7.5 Hz, 1 H), 6.48 (d, J = 7.5 Hz, 1 H), 7.05 (d, J = 8.5 Hz, 1
H), 7.16 (d, J = 8.5 Hz, 1 H), 7.28 (dt, J1 = 6.5 Hz, J2 = 1.0 Hz, 1 H),
7.47 (dt, J1 = 8.0 Hz, J2 = 1.0 Hz, 1 H), 7.87 (d, J = 8.0 Hz, 1 H),
9.25 (d, J = 8.0 Hz, 1 H), 10.06 (s, 1 H), 11.74 (s, 1 H).
Due to the insolubility of 5, its 13C NMR spectrum could not be re-
corded.
HRMS (ESI+): m/z [M + H – H2O]+ calcd for C20H15N2O3:
331.1083; found: 331.1089.
3,8-Dihydro-4-hydroxy-7-methoxy-2-methylbenzo[a]pyrro-
lo[3,4-c]carbazol-1(2H)-one (6)
A soln of hydroxylactam 5 (63 mg, 0.18 mmol) in EtOH–DMF (50
mL:5 mL) was hydrogenated for 24 h (55 psi) in the presence of
IR (KBr): 1618, 1638, and 1657 (C=C), 2225 (C≡N), 3000–3600
cm–1 (NH, OH).
Synthesis 2008, No. 16, 2569–2574 © Thieme Stuttgart · New York

2574
E. Conchon et al.
PAPER
1H NMR (400 MHz, DMSO-d6): d = 7.08 (d, J = 8.0 Hz, 1 H), 7.20
(d, J = 8.0 Hz, 1 H), 7.46 (dt, J1 = 7.0 Hz, J2 = 1.0 Hz, 1 H), 7.61 (dt,
J1 = 8.0 Hz, J2 = 1.0 Hz, 1 H), 8.03 (d, J = 8.0 Hz, 1 H), 8.47 (d, J =
8.0 Hz, 1 H), 10.49 (s, 1 H), 10.84 (s, 1 H), 12.31 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 101.3, 110.2, 113.5, 114.6,
116.7, 118.2, 119.4, 120.4, 136.9, 139.4, 145.6, and 146.6 (C quat),
112.5, 113.4, 113.5, 119.0, 121.1, and 126.4 (C tert).
(4) Cruces, J.; Martinez, E.; Treus, M.; Martinez, L. A.; Estévez,
J. C.; Estévez, R. J.; Castedo, L. Tetrahedron 2002, 58,
3015.
(5) von Angerer, E.; Prekajac, J. J. Med. Chem. 1986, 29, 380.
(6) Routier, S.; Mérour, J. Y.; Dias, N.; Lansiaux, A.; Bailly, C.;
Lozach, O.; Meijer, L. J. Med. Chem. 2006, 49, 789.
(7) Conchon, E.; Anizon, F.; Aboab, B.; Prudhomme, M.
J. Med. Chem. 2007, 50, 4669.
HRMS (ESI+): m/z [M + H]+ calcd for C18H10N3O2: 300.0773;
found: 300.0775.
(8) Conchon, E.; Anizon, F.; Aboab, B.; Golsteyn, R. M.;
Léonce, S.; Pfeiffer, B.; Prudhomme, M. Bioorg. Med.
Chem. 2008, 16, 4419.
(9) Knölker, H. J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303.
(10) Cai, X.; Snieckus, V. Org. Lett. 2004, 6, 2293.
(11) Vazquez, E.; Davies, I. W.; Payack, J. F. J. Org. Chem.
2002, 67, 7551.
Acknowledgment
The authors are grateful to Bertrand Légeret, University Blaise
Pascal, Clermont-Ferrand, for recording the mass spectra.
(12) Prinzbach, H.; Knothe, L.; Schneider, H.-W. Angew. Chem.,
Int. Ed. Engl. 1973, 12, 1009.
(13) Beck, A.; Hunkler, D.; Prinzbach, H. Tetrahedron Lett.
1983, 24, 2151.
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1989, 111, 4379.
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Synthesis 2008, No. 16, 2569–2574 © Thieme Stuttgart · New York