A Novel Synthetic Approach for the Synthesis of Pyridocarbazole Alkaloids

Article abstract of DOI:10.1002/jhet.5570400608

The synthesis of 11-methyl-6H-pyrido[4,3-b]carbazole-1(2H)-one (5), which can be important for the synthesis of other pyridocarbazole alkaloids and especially 1-substituted ellipticines, is described. Construction of the tetracyclic structure was achieved by a new route and two important precursor compounds (4a and 4b) for the synthesis of pyridocarbazole alkaloids and also many new tetrahydrocarbazole derivatives (7, 8, 9, 10, 11, 12, 13) were synthesized.

Full text of DOI:10.1002/jhet.5570400608

Nov-Dec 2003
1005
A Novel Synthetic Approach for the Synthesis of
Pyridocarbazole Alkaloids
a
b
a
Yavuz Ergün , Süleyman Patir and Gürol Okay
a
Hacettepe University, Faculty of Science, Department of Chemistry, 06532 Beytepe-Ankara, TURKEY
b
Hacettepe University, Faculty of Education, Department of Chemistry,
06532 Beytepe-Ankara, TURKEY
Received July 24, 2003
The synthesis of 11-methyl-6H-pyrido[4,3-b]carbazole-1(2H)-one (5), which can be important for the
synthesis of other pyridocarbazole alkaloids and especially 1-substituted ellipticines, is described.
Construction of the tetracyclic structure was achieved by a new route and two important precursor
compounds (4a and 4b) for the synthesis of pyridocarbazole alkaloids and also many new tetrahydrocar-
bazole derivatives (7, 8, 9, 10, 11, 12, 13) were synthesized.
J. Heterocyclic Chem., 40, 1005 (2003).
The 6H-pyrido[4,3-b]carbazole alkaloids, ellipticine
plays a role between pyrano[3,4-b]indol-3-one and arynes
[16]. The B+C type of synthesis covers an intramolecular
Diels-Alder cycloaddition of an acetylenic vinyl-
keteneimine as a key step in constructing the B+C ring of
the ellipticine or its derivatives simultaneously [17]. In the
D type of synthesis, ellipticine and its derivatives are syn-
thesized by the intramolecular aromatic electrophilic sub-
stitution reaction with suitable carbazole derivatives
[18,19].
(1a), olivacine (1b) and their derivatives such as janetine
(2a) and guatambuine (2b), occur in the genera Ochrasia,
Aspidosperma, Tabernaemontana which are members of
the family Apocynnaceae [1]. These alkaloids display pro-
nounced antitumor activity in several animal and human
tumor systems [2-4]. Especially 1-substituted ellipticines
with dialkylamino-alkylamino side chain such as com-
pound 3 have higher antitumor activity on L1210
leukaemia in mice with lower cardiovascular effect com-
pared with the parent ellipticines [5-7]. Therefore, many
chemists have paid great attention to the synthesis of 6H-
pyrido[4,3-b]carbazole alkaloids [8-12]. The 6H-
pyrido[4,3-b]carbazole alkaloids are tetracyclic. The syn-
thetic strategies for the preparation of the tetracyclic 6H-
pyrido[4,3-b]carbazole alkaloids are classified in four
main groups, such as B type, C type, B+C type and D type,
based upon the last ring to be constructed [13,14].
In this work, we used a D type of synthetic strategy and
developed a novel approach. All of the previous studies on
D type of synthesis construct the D ring in the final step
using the intramolecular aromatic electrophilic substitu-
tion reaction. In the present work we first achieved the
construction of the D ring both with an intramolecular con-
densation reaction between an ester and a ketone group on
the tetrahydrocarbazole derivative (Scheme 1) and with
intramolecular aldol condensation reaction between an
aldehyde and ketone group on the tetrahydrocarbazole
derivative (Scheme 2). Thus we synthesized two new pre-
cursor compounds 4a and 4b which can be a useful key
intermediate for the synthesis of 6H-pyrido[4,3-b]car-
bazole alkaloids using a new synthetic approach. Finally
we accomplished the synthesis of 11-methyl-6H-
pyrido[4,3-b]carbazole-1(2H)-one (5) which can be
important for the synthesis of other pyridocarbazoles and
especially 1-substituted ellipticines from these closely
related compounds 4a and 4b with a novel synthetic
approach. Previously some 6H-pyrido[4,3-b]carbazole-
1(2H)-ones similar to compound 5 were synthesized and
used efficiently for the synthesis of 1-substituted ellip-
ticines [20-25].
In our study we selected a 1,2-dihydrocarbazole 6 as the
starting material (Scheme1) [26]. Compound 6 was hydro-
genated with Pd/C (10 %) in tetrahydrofuran to give
tetrahydrocarbazole 7 [27]. Tetrahydrocarbazole ester 7
was then refluxed with sodium hydroxide solution (30 %)
in methanol-water (1:1) yielding tetrahydrocarbazole car-
boxylic acid 8 [28]. Compound 8 was then converted to
amide 9 using ethyl chloroformate, triethyl amine and
The B type synthesis includes Goldberg's coupling of
substituted nitro anilines with a bromo isoquinoline deriv-
ative. The B ring is constructed with the subsequent reac-
tions [15]. In the C type of synthesis, Diels-Alder reaction

1006
Y. Ergün, S. Patir and G. Okay
Vol. 40
Scheme 1
Reagents and conditions: i) Pd/C (10%), H , THF, 24h, 92%; ii) NaOH (30%), metanol-water (1:1), reflux, 2h, 96%; iii)
2
ClCO C H , (C H ) N, CH Cl , stirred, 2h, 0°C, then methyl glycinate hydrochloride, stirred, 12h, 75%; iv) periodic acid,
2
2
5
2
5 3
2
2
0°C, 2h, 67%; v) NaH, THF, reflux, 5h, 62%; vi) NaBH , MeOH-THF, 0°, 3h; vii) p-TsOH, Pd/C (10%), decalin, ∆, 6h, 34%.
4
bazole amide 11 at position 1 with periodic acid in
methanol-water (1:1) yielded compound 12 [33].
Compound 12 was treated with boron tribromide in
dichloromethane at -78° in order to convert the acetal
group to aldehyde to afford the compound 13 [34]. Then
we treated compound 13 with sodium hydride in anhy-
drous tetrahydrofuran under nitrogen atmosphere and
obtained the tetracyclic compound 4b as a mixture of the
epimeric alcohols with intramolecular aldol condensa-
tion reaction which as a new precursor compound with
potential biological activity for the synthesis of the pyri-
docarbazole alkaloids.
methyl glycinate hydrochloride [29]. Oxidation of the
amide 9 at position 1 with periodic acid yielded the 1-oxo-
tetrahydrocarbazole derivative 10 [30]. Then we treated
compound 10 with sodium hydride in anhydrous
tetrahydrofuran under nitrogen atmosphere and obtained
the tetracyclic intermediate 4a with a condensation reac-
tion which as a new precursor compound with potential
biological activity for the synthesis of the pyridocarbazole
alkaloids [31].
Alternatively we constructed the D ring via intramole-
cular aldol condensation. First compound 8 was con-
verted to tetrahydrocarbazole amide 11 with ethyl chlo-
roformate, triethyl amine and aminoacetaldehyde
dimethylacetal [32]. Oxidation of the tetrahydrocar-
Finally the reduction of these similar compounds 4a and
4b at 5 position in order to change ketone to alcohol with

Nov-Dec 2003
A Novel Synthetic Approach for the Synthesis of Pyridocarbazole Alkaloids
1007
Scheme 2
Reagent and conditions: i) ClCO C H , (C H ) N, 0°C, stirred, 2h, then aminoacetaldehyde dimethylacetal,
2
2
5
2 5 3
stirred, 12h, 68%; ii) periodic acid, MeOH-H O, stirred, 6h, 45%; iii) BBr , CH Cl , -78°C, stirred, 2h, 63%; iv)
2
3
2
2
NaH, THF, stirred, 5h, 57%; v) NaBH , MeOH-THF, 0°, 3h; vi) p-TsOH, Pd/C (10%), decalin, ∆, 6h, 34%.
4
spectrometer. Column chromatography was carried out using 70-
230 mesh silica gel (0.063-0.2 mm, Merck).
sodium borohydride yielded intermediate 14 [35,36].
Compound 14 treated with p-toluene sulfonic acid and pal-
ladium-charcoal (10 %) in decalin without isolation
afforded 11-methyl-6H-pyrido[4,3-b]carbazole-1(2H)-one
(5) [37,38].
We used two different routes to synthesize compound 5
shown in Scheme 1 and Scheme 2. Compound 8 is a com-
mon compound in two synthetic paths. If we compared
two synthetic plan, it is seen that the reaction steps in
Scheme 1 is one step less than in Scheme 2 and also the
yield in first route (Scheme 1) is higher than the second
route (Scheme 2).
Ethyl 4-Methyl-1,2,3,4-tetrahydro-9H-carbazole-3-carboxylate
(7).
A mixture of 5 g (19.6 mmoles) of ethyl 4-methyl-1,2-dihydro-
carbazole-3-carboxylate, 250 mg of palladium-charcoal (10%)
and 5 ml of acetic acid in 100 ml of tetrahydrofuran was hydro-
genated at atmospheric pressure. After the cessation of hydrogen
uptake the mixture was filtered and the filtrate evaporated. The
crude product was filtered through a short silica gel column with
ethyl acetate. After evaporation of the solvent, the residue was
crystallized from methanol to yield 4.64 g (92 %) of 7; mp: 105-
106°; ir (potassium bromide): ν 3350 (NH), 2945 (CH), 1710
-1
1
(C=O, ester) cm ; H nmr (deuteriochloroform): δ 1.22 (3H, d,
J=6.92 Hz, CHCH ), 1.37 (3H, t, J=7.30 Hz, OCH CH ), 2.14-
EXPERIMENTAL
3
2
3
2.19 (2H, m, CH ), 2.77-2.82 (2H, m, CH ), 2.89-2.94 (1H, m,
2
2
CH), 3.61-3.66 (1H, m, CH), 4.28 (2H, q, J=7.21 Hz, OCH CH ),
All melting points were measured in sealed tubes using an
electrothermal digital melting point apparatus (Gallenkamp) and
are uncorrected. Infrared spectra were recorded on an Hitachi
2
3
7.05-7.15 (2H, m, aromatic protons), 7.30 (1H, d, J=7.44 Hz, aro-
matic proton), 7.52 (1H, d, J=7.43 Hz, aromatic proton), 7.71 (1H,
1
+
+
270-30 infrared spectrometer. H NMR spectra were obtained on
s, NH); ms: m/z 257 (100) [M] , 212 (11.30) [M-C H O] , 184
2 5
+
+
a high resolution fourier transform Bruker WH-400 NMR spec-
trometer with tetramethylsilane as an internal stantard. Mass
spectra were recorded on a Micromass UK Platform II LC-MS
(14.62) [M-C H O ] , 169 (17.12) [M-C H O ] .
3 5 2 4 8 2
Anal. Calcd. for C H NO : C 74.71; H 7.39; N 5.45. Found:
16 19
2
C 74.76; H 7.30; N 5.49.

1008
Y. Ergün, S. Patir and G. Okay
Vol. 40
4-Methyl-1,2,3,4-tetrahydro-9H-carbazole-3-carboxylic acid (8).
The residue was chromotographed on silica gel using ethyl
acetate and crystallized from methanol, yielded 2.63 g (67 %) of
10; mp: 182-183°; ir (potassium bromide): ν 3450 (NH), 3380
(NH), 2945 (CH), 1735 (C=O, ester), 1670 (C=O, ketone), 1635
A solution of 2.5 g (9.70 mmoles) of 7 and 20 ml of 30 %
sodium hydroxide solution in methanol-water was refluxed for 3
hours. The solvent was removed under reduced pressure and the
residue was diluted with water and acidified with hydrochloric
acid. The solution was extracted with ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate and the sol-
vent was evaporated. The residue was crystallized from
dichloromethane-cyclohexane yielding 2.13 g (96 %) of 8; mp:
173.5-174.2°; ir (potassium bromide): ν 3410 (NH), 2935 (CH),
-1 1
(C=O, amide) cm ; H nmr (deuteriochloroform): δ 1.58 (3H, d,
J=6.98 Hz, CHCH ), 2.90 (1H, dd, J=3.61 and 17.21 Hz,
3
COHCHCH), 3.40 (1H, dd, J=13.36 and 17.21 Hz, COHCHCH),
3.50-3.60 (1H, m, CH), 3.83-3.97 (1H, m, CH), 4.06 (3H, s,
OCH ), 4.35 (1H, dd, J=5.35 and 18.31 Hz, HNHCHCO CH ),
3
2
3
4.46 (1H, dd, J=5.44 and 18.31 Hz, HNHCHCO CH ), 6.55 (1H,
2
3
s, NH), 7.41 (1H, t, J=7.55 Hz, aromatic proton), 7.62 (1H, t,
J=7.74 Hz, aromatic proton), 7.68 (1H, d, J=8.31 Hz, aromatic
proton), 7.85 (1H, d, J=8.10 Hz, aromatic proton), 9.36 (1H, s,
-1
1
1715 (C=O, acid) cm ; H nmr (dimethylsulfoxide-d ): δ 1.15
6
(3H, d, J=6.84 Hz, CHCH ), 1.90-2.10 (2H, m, CH ), 2.62-2.75
3
2
(3H, m, CH and CH ), 3.40-3.45 (1H, m, CH), 6.90-7.05 (2H, m,
2
+
+
NH); ms: m/z 314 (38.40) [M] , 198 (65.30) [M-C H NO ] ,
4
6
3
aromatic protons), 7.20 (1H, d, J=7.78 Hz, aromatic proton), 7.22
(1H, d, J=7.58 Hz, aromatic proton), 10.12 (1H, s, NH), 11.95
+
+
183 (33.40) [M-C H NO ] , 167 (26.40) [M-C H NO ] , 154
(100) [M-C H NO ] , 115 (57.40) [M-C H NO ] .
5
9
3
5
9
4
+
+
+
+
6
10
4
9
13
4
(1H, s, CO H); ms: m/z 229 (100) [M] , 184 (8.10) [M-CH O] ,
2
2
Anal. Calcd. for C
H N O : C 64.97; H 5.73; N 8.92.
+
+
17 18 2 4
169 (14.83) [M-C H O ] , 167 (19.20) [M-C H O ] .
2
4
2
2 6 2
Found: C 64.89; H 5.77; N 8.90.
Anal. Calcd. for C H NO : C 73.36; H 6.55; N 6.11. Found:
14 15
2
C 73.30; H 6.52; N 6.15.
4-Hydroxy-11-methyl-1,2,3,5,11,11a-hexahydro-6H-pyrido[4,3-
b]carbazole-1,5-dione (4a).
3-(N-Methoxycarbonylmethyl)-4-methyl-1,2,3,4-tetrahydro-9H-
carbazole-3-carboxamide (9).
A solution of 1.5 g (4.78 mmoles) of 10 and 0.63 g (15.75
mmoles) sodium hydride (60 % dispersion in oil) in anhydrous
tetrahydrofuran was refluxed under nitrogen atmosphere for 5
hours. Then the mixture was cooled in an ice bath and 20 ml of 10
% hydrochloric acid was added. After extraction with chloro-
form, the organic layer was washed with 10 ml of 10% sodium
carbonate solution, dried with anhydrous magnesium sulfate and
the solvent was evaporated. After purification of the residue by
column chromatography using silica gel and ethyl acetate-
methanol (1:1) and crystallized from diethyl ether, yielded 0.84 g
(62 %) of the tetracyclic compound 4a; mp: 249-251°; ir (potas-
sium bromide): ν 3445 (NH), 3350 (NH), 2942 (CH), 1675
To a solution of 1.09 g (10 mmoles) of ethyl chloroformate in
25 ml of dichloromethane at 0° was added dropwise a solution of
2.29 g (10 mmoles) of 8 followed by 3.10 g (30.69 mmoles) of
triethyl amine in 25 ml of dichloromethane. The solution was
stirred for 2 hours at 0° and 1.26 g (10 mmoles) of methylglyci-
nate hydrochloride was added. After 12 hours at room tempera-
ture, the mixture was diluted with ethyl acetate and washed first
with 50 ml of 10 % hydrochloric acid and then with 50 ml of 10
% sodium carbonate solutions. The organic layer was dried with
anhydrous magnesium sulfate and the solvent was evaporated
under reduced pressure. The residue was chromatographed on sil-
ica gel using ethyl acetate and crystallized from diethyl ether
yielding 2.25 g (75 %) of the amide 9; mp: 149.5-150.5°; ir
(potassium bromide): ν 3400 (NH), 3350 (NH), 2940 (CH), 1755
-1
1
(C=O, ketone), 1637 (C=O, amide) cm ; H nmr (dimethylsul-
foxide-d ): δ 1.23 (3H, d, J=6.94 Hz, CHCH ), 3.15-3.20 (1H, m,
6
3
CH), 3.35 (1H, d, J=5.35 Hz, CH), 3.70 (1H, dd, J=5.70 and
17.42 Hz, HNHCH), 3.85 (1H, dd, J=5.86 and 17.44 Hz,
HNHCH), 7.10 (1H, t, J=7.49 Hz, aromatic proton), 7.31 (1H, t,
J=7.30 Hz, aromatic proton), 7.41 (1H, d, J=8.26 Hz, aromatic
proton), 7.70 (1H, d, J=7.99 Hz, aromatic proton), 8.35 (1H, t,
J=5.42 Hz, NH, amide), 11.59 (1H, s, NH), 12.48 (1H, bs, OH,
-1
1
(C=O, ester), 1634 (C=O, amide) cm ; H nmr (deuteriochloro-
form): δ 1.27 (3H, d, J=6.92 Hz, CHCH ), 2.07-2.25 (2H, m,
3
CH ), 2.70-2.85 (3H, m, CH and CH ), 3.42-3.52 (1H, m, CH),
2
2
3.80 (3H, s, OCH ), 4.10 (1H, dd, J=5.21 and 18.25 Hz,
3
HNHCHCO CH ), 4.17 (1H, dd, J=5.38 and 18.22 Hz,
2
3
+
+
enol); ms: m/z 282 (4.31) [M] , 254 (2.76) [M-CO] , 225 (10.81)
HNHCHCO CH ), 6.17 (1H, t, J=4.84 Hz, NH), 7.07-7.14 (2H,
2
3
+
+
[M-C H NO] , 199 (7.10) [M-C HNO ] , 198 (80.35) [M-
C H NO ] , 197 (10.37) [M-C H NO ] , 184 (33.62) [M-
C H NO ] , 183 (24.89) [M-C H NO ] , 167 (22.71) [M-
C H NO ] , 115 (17.65) [M-C H NO ] .
m, aromatic protons), 7.29 (1H, d, J=7.49 Hz, aromatic proton),
7.51 (1H,d, J=7.42 Hz, aromatic proton), 7.86 (1H, s, NH); ms:
2
3
3
2
+
+
3
2
2
3
3
2
+
+
+
+
m/z 300 (48.14) [M] , 285 (4.65) [M-CH ] , 269 (2.41) [M-
4
4
2
4
5
2
3
+
+
+
+
CH O] , 212 (5.59) [M-C H NO ] , 184 (11.30) [M-
4
5
3
8
9
3
3
3
6
2
+
+
Anal. Calcd. for C
H N O : C 68.08; H 4.96; N 9.93.
C H NO ] , 167 (34.31) [M-C H NO ] .
16 14 2 3
4
6
3
5
11
3
Found: C 68.13; H 4.98; N 9.89.
Anal. Calcd. for C
H N O : C 68.00; H 6.67; N 9.33.
17 20 2 3
Found: C 68.07; H 6.62; N 9.38.
[N-(2,2-Dimethoxyethyl)]-4-methyl-1,2,3,4-tetrahydro-9H-car-
bazole-3-carboxamide (11).
3-(N-Methoxycarbonylmethyl)-4-methyl-1-oxo-1,2,3,4-tetrahy-
dro-9H-carbazole-3-carboxamide (10).
To a solution of 1.09 g (10 mmoles) of ethyl chloroformate in
15 ml of dichloromethane at 0° was added dropwise a solution of
2.29 g (10 mmoles) of 8 followed by 3.10 g (30.69 mmoles) of
triethyl amine in 25 ml of dichloromethane. The solution was
stirred for 2 hours at 0° and 1.05 g (10 mmoles) of aminoac-
etaldehyde dimethylacetal was added. After 12 hours at room
temperature, the mixture was diluted with ethyl acetate and
washed first with 50 ml of 10 % hydrochloric acid and then with
50 ml of 10 % sodium carbonate solutions. The organic layer was
dried with anhydrous magnesium sulfate and the solvent was
To a solution of 5.7 g (25 mmoles) of periodic acid in 100 ml
of methanol-water (1:1) was added dropwise 3.75 g (12.5
mmoles) of 9 in 25 ml of methanol at 0°. The reaction mixture
was stirred for 1 hour at 0°, then stirring was continued for one
more hour at room temperature. The solvent was evaporated,
then the residue was dissolved in chloroform and washed first
with 50 ml of 10 % sodium carbonate and then with 50 ml of 10
% sodium bisulfide solutions. The organic layer was dried over
anhydrous magnesium sulfate and the solvent was evaporated.

Nov-Dec 2003
A Novel Synthetic Approach for the Synthesis of Pyridocarbazole Alkaloids
1009
-1 1
evaporated under reduced pressure. The residue was chro-
matographed on silica gel using ethyl acetate and crystallized
from diethyl ether to yield 2.15 g (68 %) of amide 11; mp: 145-
146°; ir (potassium bromide): ν 3425 (NH), 3285(NH), 2934
amide) cm ; H nmr (deuteriochloroform): δ 1.22 (3H, d, J=7.11
Hz, CHCH ), 2.61 (1H, dd, J=16.30 and 3.78 Hz, CH), 2.83 (1H,
3
dd, J=16.35 and 13.85 Hz, CH), 3.15-3.25 (1H, m, CH), 3.30-
3.40 (1H, m, CH), 3.54-3.62 (2H, m, NHCH CHO), 7.11 (1H, t,
J=7.70 Hz, aromatic proton), 7.24 (1H, t, J=7.90 Hz, aromatic
proton), 7.37 (1H, d, J=8.20 Hz, aromatic proton), 7.52 (1H, d,
J=8.10 Hz, aromatic proton), 7.75 (1H, t, J=5.65 Hz,
NHCH CHO), 11.10 (1H, s, NH), 11.90 (1H, sb, CHO); ms: m/z
284(8.43) [M] , 255 (22.56) [M-CHO] , 242 (48.20) [M-
C H O] , 198(100) [M-C H NO ] , 183 (100) [M-C H NO ] ,
167 (19.52) [M-C H NO ] , 115 (52.37) [M-C H NO ] .
2
-1
1
(CH), 1665(C=O, amide) cm ; H nmr (deuteriochloroform): δ
1.24 (3H, d, J=6.93 Hz, CHCH ), 2.06-2.11 (1H, m, CH), 2.13-
3
2.19 (1H, m, CH), 2.62-2.69 (1H, m, CH), 2.73-2.84 (3H, m, CH
and CH ), 3.44 (3H, s, OCH ), 3.45 (3H, s, OCH ), 3.52 (2H, t,
2
3
3
2
+
+
J=5.56 Hz, NHCH CH(OCH ) ), 4.45 (1H, t, J=5.26 Hz,
2
3 2
+
+
+
CH(OCH ) ), 5.84 (1H, t, J=5.48 Hz, NH), 7.08-7.16 (2H, m,
3 2
2
2
3
4
2
4
7
2
+
+
aromatic protons), 7.30 (1H, d, J=7.49 Hz, aromatic proton), 7.51
(1H, d, J=7.50 Hz, aromatic proton), 7.84 (1H, s, NH); ms: m/z
4
7
3
8
11
3
Anal. Calcd. for C H N O : C, 67.60; H, 5.63; N, 9.86.
Found: C, 68.08; H, 5.70; N, 10.18.
16 16
2 3
+
+
+
317 (18.08) [M+1] , 316 (100) [M] , 285 (36.16) [M-CH O] ,
3
+
+
253 (3.04) [M-C H O ] , 212 (7.53) [M-C H NO ] ,184
2
7
2
4
10
2
4-Hydroxy-11-methyl-1,2,3,4,4a,5,11,11a-octahydro-6H-pyrido-
[4,3-b]carbazole-1,5-dione (4b).
+
+
(29.28) [M-C H NO ] , 168 (40.11) [M-C H NO ] .
5
10
3
6
14
3
Anal. Calcd. for C H N O : C, 68.35; H, 7.59; N, 8.86.
18 24
2 3
Compound 13 (2 g, 7.40 mmoles) of was treated with 0.89 g
(22.2 mmoles; 60% dispersion in oil) of sodium hydride in 25 ml
of anhydrous tetrahydrofuran and the mixture was stirred under
nitrogen atmosphere for 5 hours at 50°. Then the mixture was
cooled in an ice bath and hydrochloric acid was added slowly.
After extraction with chloroform, the organic layer was washed
with 10 ml of 5 % sodium carbonate, dried with anhydrous mag-
nesium sulfate and the solvent was evaporated. After purification
of residue by column chromatography using silica gel and ethyl
acetate-methanol (1:1) and crystallization from ether 1.2 g (57 %
yield) of compound 4b was obtained as a mixture of epimeric
alcohols; mp: 223-224°; ir (potassium bromide): ν 3500 (OH),
3375 (NH), 3260 (NH), 2945 (CH), 1665 (C=O), 1630 (C=O,
Found: C, 68.85; H, 7.70; N, 8.45.
[N-(2,2-Dimethoxyethyl)]-4-methyl-1-oxo-1,2,3,4-tetrahydro-
9H-carbazole-3-carboxamide (12).
To a solution of 3.60 g (16.55 mmoles) of periodic acid in 100
ml of methanol-water (1:1) was added dropwise 2.5 g (7.91
mmoles) of 11 in 25 ml of methanol at 0°. The reaction mixture
was stirred for 1 hour at 0°, then stirring was continued for one
more hour at room temperature. The solvent was evaporated then
the residue was dissolved in chloroform and washed first with 50
ml of 10 % sodium carbonate and then with 50 ml of 10 %
sodium bisulfide solutions. The organic layer was dried over
anhydrous magnesium sulfate and the solvent was evaporated.
The residue was chromotographed on silica gel using ethyl
acetate and crystallized from methanol to yield 1.18 g (45 %) of
compound 12; mp: 189-189°; ir (potassium bromide): ν 3380
(NH), 3250 (NH), 2950 (CH), 1660 (C=O), 1640 (C=O, amide)
-1 1
amide) cm ; H nmr (deuteriochloroform): δ 1.05 (3H, d, J=7.02
Hz, CHCH ), 2.22-2.28 (1H, m, CH), 2.35-2.45 (1H, m, CH),
3
2.54-2.63 (1H, m, CH), 3.05 (1H, bs, OH), 3.10-3.17 (1H, m,
CH), 3.59 (2H, t, J=5.30 Hz, NHCH CH), 6.05 (1H, bs, amide-
2
-1
1
cm ; H nmr (deuteriochloroform): δ 1.32 (3H, d, J=7.03 Hz,
NH), 6.85-7.05 (2H, m, aromatic protons), 7.18 (1H, d, J=7.72
Hz, aromatic proton), 7.33 (1H, d, J=7.51 Hz, aromatic proton),
CHCH ), 2.64 (1H, dd, J=16.92 and 3.44 Hz, CH), 3.14 (1H, dd,
3
+
J= 16.95 and 13.48 Hz, CH), 3.23-3.29 (1H, m, CH), 3.45 (3H, s,
OCH ), 3.46 (3H, s, OCH ), 3.51 (2H, t, J=5.62 Hz,
9.87 (1H, s, NH); ms: m/z 284 (12.43) [M] , 266 (23.42) [M-
+
+
+
H O] , 197 (24.17) [M-C H NO ] , 183 (100) [M-C H NO ] ,
3
3
2
3
5
2
4
7
2
+
+
NHCH CH(OCH ) ), 3.63-3.68 (1H, m, CH), 4.47 (1H, t, J=5.40
167 (71.18) [M-C H NO ] , 115 (52.14) [M-C H NO ] .
2
3 2
4
7
3
8
11
3
Hz, CH(OCH ) ), 5.95 (1H, t, J=5.35 Hz, amide-NH), 7.18 (t,
Anal. Calcd. for C H N O : C, 67.60; H, 5.63; N, 9.86.
3 2
16 16
2 3
1H, J=7.05 Hz, aromatic proton), 7.40-7.45 (2H, m, aromatic
protons), 7.64 (1H, d, J=8.06 Hz, aromatic proton), 9.15 (1H, s,
Found: C, 67.96; H, 5.32; N, 9.68.
11-Methyl-6H-pyrido[4,3-b]carbazole-1(2H)-one (5).
+
+
NH); ms: m/z 331 (1.82) [M+1] , 330 (6.19) [M] , 298 (10.59)
+
+
[M-CH O] , 267 (1.91) [M-C H O ] , 197 (100) [M-
A solution of 1 g (3.5 mmoles) of 4a (4b) in 15 ml of tetrahy-
drofuran-methanol (1:1) was cooled 0° and treated with 400 mg
(10.67 mmoles) of sodium borohydride and the reaction mixture
stirred for 3 hours at room temperature. The reaction mixture was
diluted with water and extracted with chloroform. The organic
layer was dried with anhydrous magnesium sulfate. The solvent
was evaporated to yield 0.72 g of the crude product 14. After that,
a solution of 0.72 g (2.5 mmoles) of 14, 250 mg of palladium-
charcoal (10 %) and 100 mg of p-toluene sulfonic acid in 15 ml
of decalin was refluxed under nitrogen atmosphere for 6 hours.
The catalyst was separated and the solvent was removed under
reduced pressure. The crude product was dissolved in chloroform
and extracted with 20 ml of 5 % sodium bicarbonate solution.
The organic layer was dried with anhydrous magnesium sulfate
and the solvent was evaporated. The crude product was chro-
matographed with silica gel and ethyl acetate. The solvent was
removed under reduced pressure and the product was crystallized
from diethyl ether to yield 300 mg (34 %) of 5 as a yellow solids,
mp: 236-237°; ir (potassium bromide): ν 3350 (NH), 3275 (NH),
4
2
7
2
+
C H NO ] .
5
11
3
Anal. Calcd. for C H N O : C, 65.45; H, 6.67; N, 8.48.
18 22
2 4
Found: C, 64.85; H, 6.37; N, 8.57.
N-Formylmethyl-4-methyl-1-oxo-1,2,3,4-tetrahydro-9H-carbazole-
3-carboxamide (13).
To a stirred solution of 1.57 g (4.75 mmoles) of 12 in 25 ml of
chloroform under nitrogen at -78° was added via syringe 3.57 g
(14.25 mmoles) of boron tribromide in chloroform. After 1 hour
at -78°, the reaction mixture was allowed to warm to room tem-
perature over 2 hours. Then the reaction mixture was poured into
ice-water mixture slowly and extracted with chloroform. The
organic phase was washed with 25 ml of 10 % sodium carbonate
and dried with anhydrous magnesium sulfate. The solvent was
evaporated and the residue was chromatographed on silica gel
using ethyl acetate and crystallized from ether to yield 0.85 g (63
%) of 13; mp: 131-132°; ir (potassium bromide): ν 3320 (NH),
3250 (NH), 2948 (CH), 1680 (C=O), 1660 (C=O), 1640 (C=O,

Y. Ergün, S. Patir and G. Okay
Vol. 40
1010
[14] M. Sainsbury, Synthesis, 437 (1977).
[15] R. B. Miller and J. G. Stowel, J. Org. Chem., 48, 886 (1983).
[16] C. May and C. J. Moody, J. Chem. Soc. Chem. Commun., 926
-1 1
1670 (C=O, amide) cm ; H nmr (deuteriodimethylsulfoxide): δ
2.80 (3H, s, CH ), 6.09 (1H, dd, J=10.02 and 4.09 Hz, 3-CH),
3
6.26 (1H, d, J=10.05 Hz, 4-CH), 7.18 (1H, t, J=7.94 Hz, aromatic
proton), 7.37 (1H, t, J=7.10 Hz, aromatic proton), 7.44-7.50 (2H,
m, aromatic protons), 7.68 (1H, d, J=8.25 Hz, aromatic proton),
8.31 (1H, d, J=4.15 Hz, amide-NH), 10.90 (1H, s, NH); ms: m/z
248 (8.41) [M] , 220 (13.42) [M-CO] , 179 (60.35) [M-
C H NO] , 165 (40.37) [M-C H NO] , 115 (100) [M-
(1984).
[17] E. Differding and L. Ghosez, Tetrahedron Letters, 26, 1647
(1985).
[18] Y. Murakami, Y. Yokoyama and N. Okuyama, Tetrahedron
Letters, 24, 2189 (1983).
[19] Y. Yokoyama, N. Okuyama, S. Iwadate, T. Mowoi and Y.
Murakami, J. Chem. Soc. Perkin Trans 1, 1319 (1990).
[20] E. Bisagni, C. Ducrocq, J. M. Lhoste, C. Rivalle and A.
Civier, J. Chem. Soc. Perkin Trans. I, 1706 (1979).
[21] C. Ducrocq, E. Bisagni, C. Rivalle and J. M. Lhoste, J. Chem.
Soc. Perkin Trans. I, 142 (1979),
[22] A. Langendoen, G. J. Koomen and U. K. Bandit,
Heterocycles, 26, 91 (1987).
[23] A. Langendoen, G. J. Koomen and U. K. Bandit, Tetrahedron,
44, 3627 (1988).
[24] L. Larue, C. Rivalle, G. Muzard, C. Paoletti, E. Bisagni and J.
Paoletti, J. Med. Chem., 31, 1951 (1988).
[25] E. Bisagni, M. Rautureau and C Huel, Heterocycles, 27, 1671
(1988).
+
+
+
+
3
3
4
5
+
C H NO] .
8
7
Anal. Calcd. for C H N O: C, 77.42; H, 4.84; N, 11.29.
16 12
2
Found: C, 77.19; H, 4.97; N, 11.41.
Acknowledgement.
The authors wish to express their gratitute to The Scientific
and Technical Research Council of Turkey (TUBITAK Grant
No:2024) for financial support.
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