Synthesis and reactions of 4-hydroxy-8,9,10, 11-tetrahydropyrido[3,2,1-jk] carbazol-6-ones

Article abstract of DOI:10.1002/jhet.325

(Chemical Equation Presented) Tetrahydrocarbazoles 4 obtained from phenylhydrazines and cyclohexanones gave by cyclocondensation with 2-substituted malonates 5 in all cases 4-hydroxy-8,9,10,11-tetrahydropyrido [3,2,1-jk]carbazol-6-ones 6 by attack at the nitrogen and the aromatic ring of tetrahydrocarbazoles 4; the direction of the cyclization was not dependent on substituents either in the aromatic or the saturated ring; isomeric pyridocarbazoles could not be isolated. Electrophilic substitutions of pyridocarbazoles 6 under mild conditions took place exclusively at the 5-position and gave pyridocarbazolediones 9-11 with 5-nitro-, 5-hydroxy or 5-chloro-substituents. Exchange of the chloro substituent in 11 gave 5-azido- and 5-amino products 12, 14 or 16. Reactions at the aromatic ring were not observed. Chlorination of 4-hydroxypyridocarbazoles 6 with phosphoryl chloride by nucleophilic substitution took place exclusively at the 4-position and gave 4-chloropyridocarbazolones 17, which were further reacted to azides and amines 18, 19.

Full text of DOI:10.1002/jhet.325

July 2010
Synthesis and Reactions of 4-Hydroxy-8,9,10,11-
tetrahydropyrido[3,2,1-jk]carbazol-6-ones
807
Wolfgang Stadlbauer,* Hoai Van Dang, and Birgit S. Berger
Division of Organic and Bioorganic Chemistry, Department of Chemistry,
Karl-Franzens University of Graz, A-8010 Graz, Austria/Europe
*E-mail: wolfgang.stadlbauer@uni-graz.at
Received August 19, 2009
DOI 10.1002/jhet.325
Published online 4 June 2010 in Wiley InterScience (www.interscience.wiley.com).
Tetrahydrocarbazoles 4 obtained from phenylhydrazines and cyclohexanones gave by cycloconden-
sation with 2-substituted malonates 5 in all cases 4-hydroxy-8,9,10,11-tetrahydropyrido[3,2,1-jk]carba-
zol-6-ones 6 by attack at the nitrogen and the aromatic ring of tetrahydrocarbazoles 4; the direction
of the cyclization was not dependent on substituents either in the aromatic or the saturated ring; iso-
meric pyridocarbazoles could not be isolated. Electrophilic substitutions of pyridocarbazoles 6 under
mild conditions took place exclusively at the 5-position and gave pyridocarbazolediones 9-11 with 5-
nitro-, 5-hydroxy or 5-chloro-substituents. Exchange of the chloro substituent in 11 gave 5-azido- and
5-amino products 12, 14 or 16. Reactions at the aromatic ring were not observed. Chlorination of 4-
hydroxypyridocarbazoles 6 with phosphoryl chloride by nucleophilic substitution took place exclu-
sively at the 4-position and gave 4-chloropyridocarbazolones 17, which were further reacted to azides
and amines 18, 19.
J. Heterocyclic Chem., 47, 807 (2010).
INTRODUCTION
RESULTS AND DISCUSSION
Tetrahydropyrido[3,2,1-jk]carbazol-6-one A is part of
the heterocyclic skeleton of many natural products (e.g.
strychnos alkaloids such as strychninolones B [1] and
derivatives such as brucinolones [2] and vomicin [3]). It
possesses the biologically interesting combination of an
indole and a 2-pyridone structure. Moreover, some
derivatives have found interest in pharmacological
investigations [4]. Recently, we published the synthesis
and reactions of pyrido[3,2,1-jk]carbazol-6-ones C with
two aromatic rings [5]. In this article, we report about
the synthesis and reactions of tetrahydropyrido [3,2,1-
jk]carbazol-6-ones D having partial structures more sim-
ilar to the natural products (Scheme 1).
Our approach to the tetrahydro-pyridocarbazole sys-
tem started with the synthesis of 2,3,4,5-tetrahydro-1H-
carbazoles 4 with suitable substituents at the desired
positions. Despite numerous reactions and catalysts
described in the literature, such as the cyclization of
cyclohexanone phenylhydrazones [6] or 2-phenylcyclo-
hexanone oxime [7], the reaction of 2-chlorocyclohexa-
none [8] or 2-hydroxycyclohexanone with aniline [9], or
the hydrogenation of carbazole [10], we found that an
adapted version of a long-known procedure from Ref.
[11] gave the best and simplest approach. Our synthetic
approach started from phenylhydrazines 1 and cyclohex-
anones 2 in acetic acid as solvent without isolation of
C
V
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Scheme 1
Scheme 2
phenylhydrazones, and we combined this reaction with a
one-pot release of chloro- and methyl substituted phe-
nylhydrazines 1, which are commercially available only
as hydrochlorides. The cumbersome release of oily and
sensitive free phenylhydrazine bases could be skipped,
when sodium acetate was added to the reaction mixture
which gave in situ the desired phenylhydrazines. Excess
sodium acetate and formed sodium chloride was
removed at the end of the reaction during work-up by
precipitation with diethyl ether.
To study the influence of substituents at the aromatic
ring, chloro- and methyl-phenylhydrazines
1 were
reacted with cyclohexanones 2 to synthesize a series of
Scheme 3
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Scheme 4
the isolation of possibly formed isomers 7/8 was not
achieved.
6-Methyl-tetrahydrocarbazoles 4c-e formed in reason-
able yields 2-methyl-pyridocarbazoles 6k-m. 8-Methyl-
tetrahydrocarbazoles 4j-l prevented the formation of pyr-
idocarbazoles 6 by steric hindrance, but gave again no
reaction to isomeric pyridocarbazoles 7/8.
The yields of pyridocarbazoles 6a-j without substitu-
ents in the aromatic carbazole nucleus were ranging
from 20 to 80%. The cyclization reaction proceeds in
two steps via an initial malono-monoamide followed by
formation of a thermally produced ketene derivative
which cyclizes in an electrophilic substitution towards
the aromatic carbazole ring [14]. The differing yields
can be explained by both a competing malono-diamide
formation and side-reactions during the ketene reaction.
There are some other reaction sequences known using
highly reactive malonic acid derivatives, which avoid
the high temperatures of the second ketene forming
step: one of these derivatives is the well established
bis(2,4,6-trichlorophenyl) malonate (active malonate,
magic malonate) [15], another one is (chlorocarbonyl)e-
thylketene (chlorocarbonylketene, in older literature also
named as malonyldichloride) [16]. We compared the
reactions of bis(2,4,6-trichlorophenyl) 2-benzylmalonate
(5i) and 2-benzyl-2-(chlorocarbonyl)ethylketene (5j)
with tetrahydrocarbazole 4a to 5-benzyl-4-hydroxy-
8,9,10,11-tetrahydropyrido[3,2,1:jk]carbazol-6-one (6h).
Both reactions gave the desired product 6h, trichloro-
phenylester 5i in 30% and chlorocarbonylketene 5j in
55% yield, which is better than the yield of the thermal
method, but does not counterbalance the disadvantages
of time-consuming and expensive syntheses of 5i and 5j
(Scheme 3; Table 1).
tetrahydrocarbazoles with methyl- and chloro substitu-
ents in the aromatic ring and methyl substituents in the
saturated ring. The structure could be assigned to 4, as
1
evident from H NMR spectra with clear 9-NH signals
ranging between 10.4 and 10.8 ppm, and no hydrogen
signal of a 4a-proton present in the possibly formed iso-
meric structure 3. 2-Methylcyclohexanone (2, R2 ¼ 2-
Me) gives, depending on the reaction conditions, a mix-
ture of both isomers of 3 and 4, 1- or 4a-methyl-tetrahy-
drocarbazole [12]; the work on these topics is in pro-
gress [13]. 3-Methylcyclohexanone (2b) gave 2-methyl-
tetrahydrocarbazoles 4e, h, i, k, n, q, as evident from
Tetrahydro-pyridocarbazoles 6 possess besides the
biologically interesting indole structure a 4-hydroxy-pyr-
idone structure element, which is susceptible for many
reactions. It can exist in tautomeric structures: the 4-
hydroxy-6-oxo-structure as drawn in 6 is the predomi-
nant structure as evident in all spectroscopic investiga-
tions (e.g. shown by the hydroxy signal at 10.6–10.9
1
the H NMR signal of 4-CH2 at ꢂ2.6 ppm and of the 2-
CH at ꢂ1.4 ppm; the corresponding 4-methyl isomer
could not be isolated. From 3-methylphenylhydrazine
(1c) we isolated both isomers, 7-methyl-tetrahydrocarba-
zoles 4f,h and 5-methyl derivatives 4g,i in a ratio of
about 10:1 (Scheme 2).
1
The cyclocondensation reaction of 4 was performed
with ethyl 2-alkyl- and 2-phenylmalonates 5a-h. 1H
NMR spectral data revealed that in all cases the ring
closure was directed to the aromatic ring to produce 4-
hydroxy-8,9,10,11-tetrahydropyrido[3,2,1-jk]carbazol-6-
ones 6 as evident from the ratio of aromatic: aliphatic
protons and unaffected CH2 groups in position 8. 6-
Chloro-tetrahydrocarbazoles 4m-o did not show signifi-
cant influence on the synthesis and gave 2-chloro-pyri-
docarbazoles 6n-p. 7-Chloro-tetrahydrocarbazoles 4p-r
gave, probably by deactivation of the aromatic nucleus,
very low yields or unseparable mixtures which did not
allow the isolation of pure 3-chloro-pyridocarbazoles 6;
ppm in the H NMR spectra, and a single IR signal for
the amide-CO at position 6 at about 1650 cmꢁ1). A
reversed 4-oxo-6-hydroxy structure can be excluded
because of its missing 4-pyridone signal in IR spectra
[17]. However, during reactions with suitable reagents,
the molecule can react from its 4,6-dioxo tautomer giv-
ing fixed dioxo-derivatives. The carbon at position 5
behaves due to the neighborship of two carbonyl groups
as reactive CH acidic moiety, and electrophilic reactions
such as nitration are directed first to this position. There-
fore, it is possible to nitrate 6a in position 5 by a gentle
reaction with concentrated nitric acid in the presence of
sodium nitrite as catalyst in glacial acetic acid already
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at room temperature. All other aromatic positions (1,2,
and 3) remain unaffected, and 5-nitro-pyridocarbazole-
dione 9 is obtained in 75% yield. Hydroxylation of 6a
with hydrogenperoxide in buffered slightly alkaline
aqueous solution gives in good yields 5-hydroxy-pyrido-
carbazoledione 10, which contains the 3-hydroxy-2,4-
dioxoquinoline structure element present in contents of
some Pseudomonas bacteria (Scheme 4; Table 2) [18].
Electrophilic chlorination of 6 in position 5 could be
performed with sulfuryl chloride. Because of the reactiv-
ity of this reagent, 2,5-dimethyl- and 2,5,9-trimethyl
derivatives 6a and 6k had to be brought to reaction at
room temperature, otherwise polychlorinated by-products
were formed. The formed 5-chloro-pyridocarbazole-
diones 11, which were obtained in excellent yields, serve
as starting material for further substitution reactions: as
examples an azidation and aminations are shown. The
azidation of 11a proceeds by simple halogen exchange at
the aliphatic C-5 position at 50ꢀC and gives in excellent
yields 5-azido-pyridocarbazoledione 12. Amination was
performed with primary and secondary amines: 11a gave
with benzylamine (13a) the corresponding 5-benzyl-
amino-pyridocarbazoledione 14a in excellent yields;
with aniline (13b) as the amino component, the yield of
the corresponding 5-phenylamino-pyridocarbazoledione
14b was slightly lower. Reaction of 1a with secondary
amines such as morpholine (15a) or piperidine (15b)
gave in excellent yields 5-morpholino- and 5-piperidino-
pyridocarbazolediones 16a,b (Scheme 5).
Scheme 5
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Synthesis and Reactions of 4-Hydroxy-8,9,10,11-tetrahydropyrido[3,2,1-jk]carbazol-6-ones
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Scheme 6
tives give solely the 8,9,10,11-pyrido[3,2,1-jk]carbazole
system 6. Attempts to force a cyclization to 1,2,3,3a-tet-
rahydro-pyrido[3,2,1-jk]carbazole or its tautomeric ring
system (7/8) by deactivation of the aromatic nucleus by
electronic or steric influences failed. Electrophilic and
nucleophilic substitution reactions with suitable reagents
and conditions took place exclusively at the fused pyri-
done ring at position 5 or 4, respectively.
EXPERIMENTAL
General. Melting points were determined using a Stuart
SMP3 Melting Point Apparatus in open capillary tubes. IR
spectra were recorded using a Mattson Galaxy Series FTIR
7020 instrument with potassium bromide discs. NMR spectra
were recorded on a Bruker AMX 360 instrument (360 MHz
1H, 90 MHz 13C) or on a Bruker Avance DRX 500 instrument
(500 MHz 1H, 125 MHz 13C). Chemical shifts are given in
ppm (d) from the internal TMS standard. Elemental analyses
were performed at the Microanalytical Laboratory of the Uni-
versity of Vienna, Austria. Mass spectra were obtained from a
HP 1100 LC/MSD mass spectral instrument (positive or nega-
tive APCI ion source, 50–200 V, nitrogen). Dry column flash
chromatography [19] was carried out on Merck Kieselgel 60 H
(5–40 lm). All reactions were monitored by thin layer chro-
matography on 0.2 mm silica gel F 254 (Merck, Darmstadt,
Germany) plates using UV light (254 and 366 nm) for detec-
tion. Analytical HPLC was performed on a Shimadzu LC 20
system equipped with a diode array detector (215 and 254 nm)
on a Pathfinder AS reversed phase (4.6150 mm, 5 lm) col-
umn, running an acetonitrile/water gradient (30–100% acetoni-
trile). Common reagent-grade chemicals are either commer-
cially available and were used without further purification or
prepared by standard literature procedures.
In contrast to the electrophilic reactions shown above,
a nucleophilic displacement takes place at the 4-position
of the pyridocarbazolone. The 4-hydroxy group of 6 can
be easily displaced by a chloro function, using phos-
phoryl chloride as reagent, or by substituted amino
groups. Amination of 6a at position 4 can be achieved by
reaction of the reactive 4-hydroxy group with benzyl-
amine (13a) and gives 4-benzylamino-pyridocarbazo-
lones 17a in excellent yield. The amination of 6a with an-
iline (13b) needed the addition of aniline hydrochloride
as acidic catalyst and gave in exellent yields 4-anilino-
pyridocarbazolone 17b. Chlorination with phosphoryl
chloride gave 4-chloropyridocarbazolones 18 in moderate
to excellent yields. The nucleophilic exchange of the
chloro substituent in 4-chloro-5-methylpyridocarbazolone
18a against the azide group gave 4-azidopyrido[3,2,1-
jk]carbazolones 19a in only 15% yield. 4-Chloro-5-phe-
nylpyridocarbazolone 18b gave slightly better yields of
33% of the corresponding 4-azidopyrido[3,2,1-jk]carba-
zolone 19b. To improve the yield, we used our recently
developed one-pot synthesis [5] starting from 4-hydroxy-
pyridocarbazolone 6a, which reacted with a mixture of
sodium azide and phosphoryl chloride (probably via reac-
tive phosphoric esters) in dimethylformamide to obtain in
this one-pot reaction 19a in 58% yield (Scheme 6).
General methods for the Fischer indole synthesis of
2,3,4,9-tetrahydro-1H-carbazoles (4). Method
A (one pot
procedure). To a mixture of anhydrous sodium acetate (2.46 g,
30 mmol) in glacial acetic acid (40 mL) the appropriate cyclo-
hexanone 2 (30 mmol) was added at 90ꢀC, then the corre-
sponding phenylhydrazine hydrochloride 1.HCl (25 mmol)
was added in small portions during 1 h. The reaction mixture
was further heated under reflux for 1 h, cooled to room tem-
perature and diluted with diethyl ether (100 mL). The precipi-
tated solid (inorganic salts) was separated by suction filtration
and washed with diethyl ether. The combined filtrates were
taken to dryness in vacuo, the residue diluted with a mixture
of ethanol/water (7:3, 100 mL) and after standing for 3 h, the
precipitated product isolated by suction filtration. The product
was dried in vacuo at room temperature, then recrystallized
from the appropriate solvent using charcoal.
Method B (2-step procedure). The corresponding phenylhy-
drazine hydrochloride 1.HCl (27 mmol) was suspended in
0.5M aqueous sodium hydroxide (100 mL) and stirred at 70ꢀC
for 30 min. After cooling the precipitated oil was separated
(loss ꢂ5–10%) and added without further purification to a so-
lution of the appropriate cyclohexanone 2 (30 mmol) in glacial
acetic acid (70 mL) in small portions during 1 h. The reaction
mixture was then heated under reflux for 1 h and cooled to
room temperature under stirring until a solid precipitated. The
CONCLUSION
Our results show that cyclization reactions of 2,3,4,5-
tetrahydro-1H-carbazoles 1 with malonic acid deriva-
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mixture was cooled to 5ꢀC, the precipitated solid isolated by
suction filtration and the filtrate cooled again to isolate a sec-
ond crop. The combined solids were washed with water (100
mL) and ethanol/water (7:3, 100 mL), air-dried and then
recrystallized from the appropriate solvent using charcoal.
R-key and data of 4a-r: Table 1.
4a (3.75 g, 22 mmol) and bis(2,4,6-trichlorophenyl) 2-benzyl-
malonate (5i) (12.1 g, 22 mmol) was heated without solvent
for 60 min to 250ꢀC. The 2,4,6-trichlorophenol vapors were
removed via a funnel into the water pump. After cooling the
dark reaction mixture was washed with hexane until the prod-
uct became semi-solid. Then the product was stirred overnight
with aqueous sodium hydroxide solution (0.5M, 500 mL), fil-
tered, the filtrate extracted with toluene (2 ꢃ 100 mL) and the
aqueous phase acidified with concentrated hydrochloric acid.
The precipitate was washed with water, recrystallized from
glacial acetic acid/water and dried. The yield was 2.17 g
(30%).
From tetrahydrocarbazole 4a and 2-benzyl-2-(chlorocarbo-
nyl)ethylketene (5j) (Method D, ‘‘(chlorocarbonyl)ethylke-
tene’’-method [16]). 2-Benzyl-2-(chlorocarbonyl)ethylketene
(5j). To a solution of 2-benzylmalonic acid (5, R3 ¼ CH2Ph,
X ¼ OH) (38.8 g, 0.2 mol) in toluene (50 mL), thionyl chlo-
ride (59.5 g, 0.6 mol) was added dropwise under stirring in a
nitrogen atmosphere. The mixture was heated for 24 h under
reflux, then toluene and excess thionyl chloride were removed
by distillation under reduced pressure (60ꢀC, 130 mm Hg).
The residue was distilled under reduced pressure (134–140ꢀC,
15 mm Hg). The yield was 27.2 g (70%) yellowish oil; lit. bp
110–112ꢀC (1.5 mm Hg) [16b].
5-Benzyl-4-hydroxy-8,9,10,11-tetrahydropyrido[3,2,1:jk]car-
bazol-6-one (6h). To a solution of tetrahydrocarbazole 4a
(5.12 g, 30 mmol) in dry ethyl acetate (150 mL), 2-benzyl-2-
(chlorocarbonyl)ketene (5j) (6.5 g, 33 mmol) and dry triethyl-
amine (4.5 mL) was added at 40–50ꢀC. The yellow reaction
mixture turned red and viscous and a small amount of a dark
solid precipitated. The reaction mixture was kept for 30 min at
room temperature, then the precipitate was filtered off, the fil-
trate taken to dryness under reduced pressure and triturated
with xylene. The resulting precipitate was filtered by suction
and dried. The yield was 5.42 g (55%), yellowish prisms. Data
of 6h: Table 2.
General Methods for the cyclization of tetrahydrocarba-
zoles 4 to 4-hydroxy-8,9,10,11-tetrahydropyrido[3,2,1-jk]car-
bazol-6-ones (6). Method A (thermal neat method). A mixture
of the appropriate diethyl malonate 5 (30 mmol) and the corre-
sponding tetrahydrocarbazole 4 (25 mmol) was heated for 2–3 h
to 280–300ꢀC in a metal bath using a Vigreux column equipped
with a distillation bridge. During this time the first equivalent of
ethanol (25 mmol, about 0.9 mL) was liberated. When the liber-
ation of ethanol had stopped, the reaction mixture was heated
for about 30 min to a bath temperature of 330–350ꢀC; during
this time the second equivalent of ethanol (0.9 mL, 25 mmol)
was liberated. The reaction mixture was cooled to about 80ꢀC,
methanol (30 mL) was added, the mixture cooled to room tem-
perature and filtered by suction. The solid was taken up in aque-
ous sodium hydroxide solution (0.25M, 100 mL) and extracted
with toluene (100 mL). The aqueous layer was decolorized with
charcoal at 50 to 80ꢀC and filtered. Concentrated hydrochloric
acid was added to the filtrate until pH ꢂ3, the precipitate fil-
tered by suction, washed acid-free with water, dried and recrys-
tallized from the appropriate solvent.
Method B (thermal solution method). A solution of the
appropriate diethyl malonate 5 (30 mmol) and the correspond-
ing tetrahydrocarbazole 4 (25 mmol) in diphenylether (25 mL)
was heated under reflux at 250ꢀC in a metal bath using a Vig-
reux column equipped with a distillation bridge for about 12 h.
During this time, 2 equivalents of ethanol were liberated (50
mmol, about 1.8 mL). After cooling to room temperature,
diethyl ether (50 mL) was added, and the solid which precipi-
tated was filtered by suction, washed with diethyl ether and
dried. The collected solid was taken up in aqueous sodium hy-
droxide solution (0.25M, 100 mL) and filtered by suction. Con-
centrated hydrochloric acid was added to the filtrate until pH
ꢂ3, the precipitate filtered by suction, washed acid-free with
water, dried and recrystallized from the appropriate solvent.
R-key and data of 6a-p: Table 2.
5-Nitro-5-phenyl-8,9,10,11-tetrahydropyrido[3,2,1-jk]carba-
zole-4,6-dione (9). A solution of 4-hydroxy-pyridocarbazole
6a (2.00 g, 6.3 mmol) in glacial acetic acid (12 mL) was
treated with concentrated nitric acid (1.2 mL) and sodium ni-
trite (0.03 g). The mixture was stirred for 30 min at room tem-
perature, then diluted with ice/water (45 mL), the formed yel-
low precipitate separated by suction filtration and washed with
water until acid-free. The yield was 1.70 g (75%), yellow
prisms, mp 164ꢀC (methanol). IR: 2960–2860 w, 1730 s (4-
C¼¼O), 1695 s (6-C¼¼O), 1660 sh, 1625 w, 1590 w, 1570 s
5-Benzyl-4-hydroxy-8,9,10,11-tetrahydropyrido[3,2,1-jk]car-
bazol-6-one (6h). From tetrahydrocarbazole 4a and bis(2,4,6-
trichlorophenyl) 2-benzylmalonate (5i) (Method C, ‘‘active
malonate’’ method [15]):
Bis(2,4,6-trichlorophenyl) 2-benzylmalonate (5i). A mixture of
dry 2-benzylmalonic acid (5, R3 ¼ CH2Ph, X ¼ OH) (38.8 g,
0.2 mol), 2,4,6-trichlorophenol (63.2 g, 0.32 mol) and phos-
phoryl chloride (64.4 g, 0.42 mol) was heated under reflux
until the evolution of hydrogen chloride gas had stopped
(about 4–6 h). The reaction mixture was then poured onto
crushed ice (600 mL), filtered by suction, the solid washed
with ice-water, dissolved in toluene (400 mL) and washed
with aqueous sodium hydrogencarbonate solution (5%) and
water. The organic layer was dried with sodium sulfate and
the solvent removed under reduced pressure. The residue was
triturated with hexane, filtered and dried at room temperature.
The yield was 44.6 g (50%), light yellowish prisms, mp 104ꢀC
(lit. mp 106–107ꢀC [15a]).
1
cmꢁ1; H NMR (CF3COOH): d 1.80–2.10 (m, 4 H, 9-CH2, 10-
CH2), 2.70 (t, J ¼ 7.0 Hz, 2 H, 11-CH2), 3.15 (t, J ¼ 7.0 Hz,
2 H, 8-CH2), 7.25 (t, J ¼ 7.1 Hz, 1 H, 2-H), 7.35–7.50 (m, 3
H, PhH), 7.55–7.60 (m, 2 H, PhH), 7.70 (d, J ¼ 7.1 Hz, 1-H),
7.90 (d, J ¼ 7.1 Hz, 1 H, 8-H). Anal. calcd. for C21H16N2O4
(360.37): C, 69.99; H, 4.48; N, 7.77. Found: C, 70.34; H,
4.71; N, 7.45.
5-Hydroxy-5-methyl-8,9,10,11-tetrahydropyrido[3,2,1-jk]car-
bazol-4,6-dione (10). A solution of 4-hydroxy-pyridocarbazole
6a (0.68 g, 2.7 mmol) in aqueous sodium hydroxide solution
(0.25M, 60 mL) was slowly brought to pH ꢂ8 with aqueous
potassium dihydrogenphosphate solution (1M, ꢂ10 mL), then
hydrogenperoxide (30%, 20 mL) was added. The reaction mix-
ture was stirred for 6 h at 40ꢀC. After cooling to room temper-
ature, the mixture was poured onto crushed ice/water (100
5-Benzyl-4-hydroxy-8,9,10,11-tetrahydropyrido[3,2,1:jk]car-
bazol-6-one (6h). An intimate mixture of tetrahydrocarbazole
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mL), the solid filtered by suction and washed with water. The
yield was 0.52 g (72%), yellow prisms, mp 189ꢀC (ethanol).
IR: 3395 s, 2945 m, 1711 s (4-C¼¼O), 1684 s (6-C¼¼O), 1630
IR: 3430 s, 2950 m, 2920 m, 1720 s (4-C¼¼O), 1690 s (6-
1
C¼¼O), 1630 w, 1605 w cmꢁ1; H NMR (DMSO-d6): d 1.75–
1.82 and 1.85–1.92 (2 m, 4 H, 9-CH2 and 10-CH2), 2.70 (t, J
¼ 7.0 Hz, 2 H, 11-CH2), 3.05–3.08 (m, 2 H, 8-CH2), 7.35–
7.50 (m, 3 H, 3 PhH), 7.55–7.60 (m, 2 H, PhH), 7.80–8.00 (m,
2 H, 1-H, 3-H). Anal. calcd. for C21H15Cl2NO2 (384.27): C,
65.64; H, 3.93; N. 3.65. Found: C, 65.28; H, 3.95; N 3.27.
2,5-Dichloro-10-methyl-5-phenyl-8,9,10,11-tetrahydropyrido
[3,2,1-jk]carbazole- 4,6-dione (11e). From 4-hydroxy-pyrido-
carbazole 6o (1.10 g, 3 mmol) in dioxane (20 mL) and sulfuryl
chloride (0.49 g, 0.30 mL, 3.7 mmol) as described for 11b.
The yield was 1.10 g (91%), yellow prisms, mp 105ꢀC (etha-
nol). IR: 3420 s, 2940 m, 2910 m, 1715 s (4-C¼¼O), 1690 s
1
w, 1593 m cmꢁ1; H NMR (DMSO-d6): d 1.49 (s, 3 H, 5-Me),
1.82–1.88 (m, 4 H, 9-CH2, 10-CH2), 2.68 (t, J ¼ 7.0 Hz, 2 H,
11-CH2), 3.06 (t, J ¼ 7.0 Hz, 2 H, 8-CH2), 6.15 (s, 1 H, 5-
OH), 7.41 (t, J ¼ 7.6 Hz, 1 H, 2-H), 7.69 (d, J ¼ 7.6 Hz, 1 H,
1-H), 7.82 (d, J ¼ 7.6 Hz, 1 H, 3-H); MS [APCI, pos]: m/e
(%) ¼ 271 (11), 270 (M, 100). Anal. calcd. for C16H15NO3
(269.30): C, 71.36; H, 5.61; N, 5.20. Found: C, 71.20; H,
5.86; N, 5.22.
5-Chloro-5-methyl-8,9,10,11-tetrahydropyrido[3,2,1-jk]carba-
zol-4,6-dione (11a). To a suspension of 4-hydroxy-pyridocar-
bazole 6a (2.30 g, 9 mmol) in dioxane (50 mL) at 20ꢀC, sul-
furyl chloride (0.8 mL, 10 mmol) was added slowly. The reac-
tion mixture was stirred for 5 h at room temperature and then
poured onto crushed ice/water (200 mL). The solid was filtered
and washed with water. The yield was 2.00 g (76%), yellow
needles, mp 182ꢀC (ethanol). IR: 3432 s, 2936 m, 1722 s (4-
;
(6-C¼¼O), 1625 w, 1605 w cmꢁ1 1H NMR (DMSO-d6): d
1.06 (d, J ¼ 7.0 Hz, 3 H, 10-Me), 1.30–1.55 (m, 1 H, 10-H),
1.75–2.00 (m, 2 H, 9-CH2), 2.70 (t, J ¼ 7.0 Hz, 2 H, 11-CH2),
3.03–3.08 (m, 2 H, 8-CH2), 7.35–7.50 (m, 3 H, 3 PhH), 7.55–
7.60 (m, 2 H, PhH), 7.81 (d, J ¼ 2.0 Hz, 1 H, 1-H), 8.02 (d, J
¼ 7.0 Hz, 1 H, 3-H). Anal. calcd. for C22H17Cl2NO2 (398.29):
C, 66.34; H, 4.30; N, 3.52; Found: C, 66.25; H, 4.28; N, 3.24.
5-Azido-5-methyl-8,9,10,11-tetrahydropyrido[3,2,1-jk]carba-
zole-4,6-dione (12). A suspension of 5-chloropyridocarbazole
11a (1.20 g, 4.2 mmol) and sodium azide (1.00 g, 15.3 mmol)
in dimethylformamide (40 mL) was stirred and heated for 1 h
at 50ꢀC. After cooling to room temperature, the mixture was
poured onto crushed ice/water (100 mL), filtered by suction
and washed with water. The yield was 0.95 g (77 %) yellow
needles, mp 131ꢀC (ethanol). IR: 3432 s, 2929 m, 2144 sh,
2106 s (N3), 1722 s (4-C¼¼O), 1688 s (6-C¼¼O), 1626 w, 1592
C¼¼O), 1689 s (6-C¼¼O), 1629 w, 1592 w cmꢁ1
;
1H NMR
(DMSO-d6): d 1.74–1.82 and 1.86–1.94 (2 m, 4 H, 9-CH2 and
10-CH2), 1.98 (s, 3 H, 5-Me), 2.70 (t, J ¼ 7.0 Hz, 2 H, 11-
CH2), 3.06 (t, J ¼ 7.0 Hz, 2 H, 8-CH2), 7.45 (t, J ¼ 7.6 Hz, 1
H, 2-H), 7.78 (d, J ¼ 7.6 Hz, 1 H, 1-H), 7.81 (d, J ¼ 7.6 Hz,
1 H, 3-H). Anal. calcd. for C16H14ClNO2 (287.75): C, 66.79;
H, 4.90; N, 4.87. Found: C, 66.90; H, 4.92; N, 4.85.
5-Chloro-5-phenyl-8,9,10,11-tetrahydropyrido[3,2,1-jk]carba-
zole-4,6-dione (11b). To a suspension of 4-hydroxy-pyridocar-
bazole 6g (1.65 g, 5.2 mmol) in dioxane (25 mL) at 50ꢀC, sul-
furyl chloride (1.70 g ꢂ1.01 mL, 12.6 mmol) was added
slowly. The mixture was stirred for 10 min, heated to boiling
for a few min and then poured onto crushed ice/water (50
mL). The oily product was stirred and washed several times
with water until solid. The yellow-orange precipitate was
crushed, filtered by suction and washed with water. The yield
was 1.79 g (97%), yellow prisms, mp 116ꢀC (ethanol). IR:
3430 s, 2935 m, 1720 s (4-C¼¼O), 1690 s (6-C¼¼O), 1630 w
m cmꢁ1 1H NMR (DMSO-d6): d 1.70 (s, 3 H, 5-Me), 1.81–
;
1.83 and 1.85–1.88 (2 m, 4 H, 9-CH2, 10-CH2), 2.69 (t, J ¼
7.0 Hz, 2 H, 11-CH2), 3.05–3.09 (m, 2 H, 8-CH2), 7.43 (t, J ¼
7.6 Hz, 1 H, 2-H), 7.72 (d, J ¼ 7.5 Hz, 1 H, 1-H), 7.85 (d, J
¼ 7.5 Hz, 1 H, 3-H). Anal. calcd. for C16H14N4O2 (294.32):
C, 65.30; H, 4.79; N, 19.04. Found: C, 65.24; H, 4.78; N,
18.65.
5-Benzylamino-5-methyl-8,9,10,11-tetrahydropyrido[3,2,1-
jk]carbazole-4,6-dione (14a). A solution of 5-chloropyridocar-
bazole 11a (1.20 g, 4.2 mmol) and benzylamine (13a) (0.50
mL, 4.5 mmol) in dimethylformamide (3 mL) was heated and
stirred for 15 h at 50ꢀC. After cooling to room temperature,
the mixture was poured onto ice/water (100 mL), filtered by
suction and washed with water. The yield was 1.22 g (81%),
yellow prisms, mp 73ꢀC (ethanol). IR: 3395 m, 2932 m, 2853
1
cmꢁ1; H NMR (DMSO-d6): d 1.75–1.83 and 1.85–1.93 (2 m,
4 H, 9-CH2 and 10-CH2), 2.71 (t, J ¼ 7.0 Hz, 2 H, 11-CH2),
3.05–3.09 (m, 2 H, 8-CH2), 7.37–7.50 (m, 4 H, 3 PhH, 2-H),
7.55–7.60 (m, 2 H, PhH), 7.75–7.85 (m, 2 H, 1-H, 3-H). Anal.
calcd. for C21H16ClNO2 (349.82): C, 72.10; H, 4.61; N, 4.00.
Found: C, 72.36; H, 4.32; N, 4.25.
5-Chloro-2,5,9-trimethyl-8,9,10,11-tetrahydropyrido[3,2,1-jk]
carbazole-4,6-dione (11c). From 4-hydroxy-pyridocarbazole 6l
(5.06 g, 18 mmol) in dioxane (100 mL) and sulfuryl chloride
(2.7 g ꢂ1.61 mL, 20 mmol) as described for 11a. Work-up
was performed as described for 11b. The yield was 4.56 g
(80%) orange-yellow needles, mp 151ꢀC (ethanol). IR: 3435 s,
2949 m, 2923 m, 1719 s (4-C¼¼O), 1690 s (6-C¼¼O), 1630 w,
w, 1720 s (4-C¼¼O), 1681 s (6-C¼¼O), 1628 w, 1591 m cmꢁ1
;
1H NMR (DMSO-d6): d 1.50 (s, 3 H, 5-Me), 1.79–1.83 and
1.86–2.08 (2 m, 4 H, 9-CH2, 10-CH2), 2.67 (t, J ¼ 7.0 Hz, 2
H, 11-CH2), 3.04–3.14 (m, 2 H, 8-CH2), 3.51 (s, 2 H, benzyl-
CH2), 7.17–7.30 (m, 5 H, PhH), 7.43 (t, J ¼ 7.7 Hz, 1 H, 2-
H), 7.70 (d, J ¼ 7.5 Hz, 1 H, 1-H), 7.81 (d, J ¼ 7.6 Hz, 1 H,
3-H); MS [APCI, pos]: m/e (%) ¼ 360 (11), 359 (100, M).
Anal. calcd. for C23H22N2O2 (358.44): C, 77.07; H, 6.19; N,
7.82. Found: C, 77.35; H, 5.99; N, 7.54.
1
1604 w cmꢁ1; H NMR (DMSO-d6): d 1.12 (d, J ¼ 7.0 Hz, 3
H, 9-Me), 1.46–1.50 (m, 1 H, 9-H), 1.96–1.98 (m, 5 H, 5-Me,
10-CH2), 2.51 (s, 3 H, 2-Me), 2.59–2.70 and 2.72–2.83 (2 m,
4 H, 11-CH2, 8-CH2), 7.58 (s, 1 H, 1-H), 7.67 (s, 1 H, 3-H).
Anal. calcd. for C18H18ClNO2 (315.80): C, 68.46; H, 5.75; N
4.44. Found: C, 68.58; H, 5.59; N 4.39.
5-Methyl-5-phenylamino-8,9,10,11-tetrahydropyrido[3,2,1-jk]
carbazole-4,6-dione (14b). From a solution of 5-chloropyrido-
carbazole 11a (1.00 g, 3.4 mmol) and aniline (13b) (0.5 mL,
5.5 mmol) in dimethylformamide (20 mL) as described for
14a. The yield was 0.63 g (54 %), yellow prisms, mp 115ꢀC
(ethanol). IR: 3395 m, 2932 m, 2856 w, 1724 s (4-C¼¼O),
2,5-Dichloro-5-phenyl-8,9,10,11-tetrahydropyrido[3,2,1-jk]
carbazole-4,6-dione (11d). From 4-hydroxy-pyridocarbazole
6n (1.50 g, 4.3 mmol) in dioxane (25 mL) and sulfuryl chlo-
ride (0.70 g–0.42 mL, 5.2 mmol) as described for 11b. The
yield was 1.42 g (86%) yellow prisms, mp 100ꢀC (ethanol).
1686 s (6-C¼¼O), 1603 m, 1592 m cmꢁ1
;
1H NMR (DMSO-
d6): d 1.65 (s, 3 H, 5-Me), 1.83–1.91 (m, 4 H, 9-CH2, 10-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

822
W. Stadlbauer, H. V. Dang, and B. S. Berger
Vol 47
CH2), 2.73 (t, J ¼ 7.0 Hz, 2 H, 11-CH2), 3.06 (t, J ¼ 7.0 Hz,
2 H, 8-CH2), 6.12 (d, J ¼ 8.0 Hz, 2 H, PhH), 6.51 (t, J ¼ 7.3
Hz, 1 H, PhH), 6.86 (s, 1 H, NH, D2O-exchangeable), 6.94 (t,
J ¼ 7.8 Hz, 2 H, PhH), 7.51 (t, J ¼ 7.6 Hz, 1 H, 2-H), 7.76
(d, J ¼ 7.6 Hz, 1 H, 1-H), 7.93 (d, J ¼ 7.6 Hz, 1 H, 3-H).
Anal. calcd. for C22H20N2O2 (344.42): C, 76.72; H, 5.85; N,
8.13. Found: C, 76.39; H, 5.67; N, 8.36.
108.5, 113.7, 117.4, 118.5, 120.4, 122.4, 127.5, 128.1, 129.9,
131.2 (13 ArC), 137.7, 139.1, 150.2 (3 CAN), 161.6 (C¼¼O);
MS [APCI, pos]: m/e (%) ¼ 344 (25), 343 (100), 341(5), 241
(33), 108 (39). Anal. calcd. for C23H22N2O (342.44): C, 80.67;
H, 6.48; N, 8.18. Found: C, 80.38; H, 6.47; N, 8.27.
5-Methyl-4-phenylamino-8,9,10,11-tetrahydropyrido[3,2,1-jk]
carbazole-6-one (17b). From 4-hydroxy-pyridocarbazole 6a
(2.53 g, 10 mmol), aniline hydrochloride (2.50 g, 19 mmol)
and aniline (13b) (20 mL) as described for 17a. The yield was
2.10 g (64 %), yellowish prisms, mp 167ꢀC (ethanol). IR:
3462 m, 3342 m, 2934 m, 1648 m (6-C¼¼O), 1630 s, 1601 m,
5-Methyl-5-morpholino-8,9,10,11-tetrahydropyrido[3,2,1-jk]
carbazole-4,6-dione (16a). A solution of 5-chloropyridocarba-
zole 11a (1.60 g, 5.5 mmol) and morpholine (15a) (0.5 mL,
5.7 mmol) in dimethylformamide (20 mL) was stirred for 5 h
at 50ꢀC. After cooling to room temperature, the mixture was
poured into water (100 mL), the solid was filtered by suction,
washed with water and dried at room temperature in vacuo.
The yield was 1.40 g (75%), yellow prisms, mp 72ꢀC (etha-
nol). IR: 3425 m, 2936 s, 2853 s, 1713 s (4-C¼¼O), 1681 s (6-
1
1555 w cmꢁ1; H NMR(CDCl3): d 1.89–1.93 and 1.96–2.00 (2
m, 4 H, 9-CH2. 10-CH2), 2.15 (s, 3 H, 5-Me), 2.78 (t, J ¼ 6.0
Hz, 2 H, 11-CH2), 3.31 (t, J ¼ 6.0 Hz, 2 H, 8-CH2), 6.02 (s, 1
H, NH), 6.94 (d, J ¼ 7.6 Hz, 2 H, PhH), 7.01 (t, J ¼ 7.4 Hz,
1 H, 2-H), 7.15–7.29 (m, 3 H, PhH), 7.38 (d, J ¼ 7.8 Hz, 1 H,
1-H), 7.58 (d, J ¼ 7.5 Hz, 1 H, 3-H); 13C NMR (CDCl3): d
12.4, 21.3, 22.4, (C9, C10), 22.9, 24.8 (C8, C11), 42.0 (Me),
114.9, 117.8, 118.4, 118.7, 119.2, 120.5, 127.9, 129.2, 131.3
(12 ArC), 137.6, 143.5, 144.3 (3 CAN), 161.8 (C¼¼O); MS
[APCI, pos]: m/e (%) ¼ 330 (28), 329 (100). Anal. calcd. for
C22H20N2O (328.42): C, 80.46; H, 6.14; N, 8.53. Found: C,
80.20; H, 6.26; N, 8.68.
C¼¼O), 1631 w, 1591 m cmꢁ1
.
1H NMR (DMSO-d6): d 1.49
(s, 3 H, 5-Me), 1.78–1.81 and 1.86–1.89 (2 m, 4 H, 9-CH2,
10-CH2), 2.55–2.60 (m, 4 H, 2x 5-morpholino-CH2), 2.67 (t, J
¼ 7.0 Hz, 2 H, 11-CH2), 3.09 (s, J ¼ 7.0 Hz, 2 H, 8-CH2),
3.49 (t, J ¼ 4.2 Hz, 4 H, 2x 5-morpholino-CH2), 7.40 (t, J ¼
7.6 Hz, 1 H, 2-H), 7.66 (d, J ¼ 7.6 Hz, 1 H, 1-H), 7.82
(d, J ¼ 7.6 Hz, 1 H, 3-H); MS [APCI, pos]: m/e (%) ¼ 340
(28), 339 (100, M), 337 (12). Anal. calcd. for C20H22N2O3
(338.41): C, 70.99; H, 6.55; N, 8.28. Found: C, 71.24; H,
6.32; N, 8.01.
4-Chloro-5-methyl-8,9,10,11-tetrahydropyrido[3,2,1-jk]carba-
zole-6-one (18a). A solution of 4-hydroxy-pyridocarbazole 6a
(2.53g, 10 mmol) in phosphoryl chloride (30 mL) was heated
under reflux for 1 h. The excess phosphoryl chloride was
removed i. vac., the residue cooled to room temperature and
poured onto crushed ice/water (100 mL). Caution: strong exo-
thermic reaction. The product was brought to pH ꢂ4 to 6 with
2M aqueous sodium hydroxide solution, the solid filtered by
suction and washed with water. The yield was 1.40 g (51 %),
ash–grey powder, mp 165ꢀC (ethanol). IR: 3453 m, 2930 s,
5-Methyl-5-piperidino-8,9,10,11-tetrahydropyrido[3,2,1-jk]car-
bazole-4,6-dione (16b). From 5-chloropyridocarbazole 11a
(1.50 g, 5.2 mmol) and piperidine (15b) (0.6 mL, 6 mmol) in
dimethylformamide (20 mL) as described for 16a. The yield
was 1.45 g (84%), yellow prisms, mp 87ꢀC (ethanol). IR: 3421
m, 2934 s, 2851 m, 1714 s (4-C¼¼O), 1681 s (6-C¼¼O), 1630
w, 1591 m cmꢁ1
:
1H NMR (DMSO-d6): d ¼ 1.31–1.33 and
1
1.38–1.40 (2 m, 6 H, 3 5-piperidino-CH2), 1.47 (s, 3 H, 5-
Me), 1.77–1.80 and 1.85–1.87 (2 m, 4 H, 9-CH2, 10-CH2),
2.54–2.57 (m, 4 H, 5-piperidine-CH2), 2.67 (t, J ¼ 7.0 Hz, 2
H, 11-CH2), 3.09 (t, J ¼ 7.0 Hz, 2 H, 8-CH2), 7.39 (t, J ¼ 7.6
Hz, 1 H, 2-H), 7.65 (d, J ¼ 7.5 Hz, 1 H, 1-H), 7.80 (d, J ¼
7.6 Hz, 1 H, 3-H); MS [APCI, pos]: m/e (%) ¼ 338 (20%),
337 (M, 100%). Anal. calcd. for C21H24N2O2 (336.44): C,
74.97; H, 7.19; N, 8.33. Found: C, 75.35; H, 7.01; N, 8.04.
4-Benzylamino-5-methyl-8,9,10,11-tetrahydropyrido[3,2,1-jk]
carbazol-6-one (17a). A solution of 4-hydroxy-pyridocarbazole
6a (2.53 g, 10 mmol) and excess benzylamine (13a) (20 mL)
was heated for 6 h at 180ꢀC using an air condenser to remove
water formed during the reaction, cooled and the excess ben-
zylamine removed by distillation in vacuo. To the liquid resi-
due petroleum ether (bp 60–90ꢀC, 50 mL) was added and
stirred. The solid precipitated, was filtered by suction and
washed with petroleum ether (bp 60–90ꢀC). Then toluene (50
mL) was added and the solid was filtered by suction and
washed with ethanol (20 mL). The yield was 2.15 g (63 %),
yellow prisms, mp 128ꢀC (ethanol). IR: 3442 m, 3386 s, 3357
1659 s (6-C¼¼O), 1628 m, 1597 w cmꢁ1; H NMR (CDCl3): d
1.87–2.01 (m, 4 H, 9-CH2, 10-CH2), 2.41 (s, 3 H, 5-Me), 2.76
(t, J ¼ 6.0 Hz, 2 H, 11-CH2), 3.24 (t, J ¼ 6.0 Hz, 2 H, 8-
CH2), 7.42 (t, J ¼ 7.7 Hz, 1 H, 2-H), 7.63 (d, J ¼ 7.6 Hz, 1
H, 1-H), 7.73 (d, J ¼ 7.8 Hz, 1 H, 3-H); MS [APCI, pos]: m/z
(%) ¼ 274 (35), 273 (15), 272 (100, M). Anal. calcd. for
C16H14ClNO (271.75): C, 70.72; H, 5.19; N, 5.00. Found: C,
70.49; H, 5.26; N, 5.15
4-Chloro-5-phenyl-8,9,10,11-tetrahydro-pyrido[3,2,1-jk]carba-
zol-6-one (18b). From 4-hydroxy-pyridocarbazole 6g (3.15 g,
10 mmol) and phosphoryl chloride (30 mL) as described for
18a. The yield was 2.20 g (66%), light brownish needles, mp
154ꢀC (ethanol). IR: 2960–2840 w, 1660 s (6-C¼¼O), 1625 w,
1
1595 w cmꢁ1; H NMR (CDCl3): d 1.85–2.00 (m, 4 H, 9-CH2,
10-CH2), 2.75 (t, J ¼ 6.0 Hz, 2 H, 11-CH2), 3.20–3.25 (m, 2
H, 8-CH2), 7.35–7.50 (m, 4 H, 3 PhH, 2-H), 7.55–7.60 (m, 2
H, PhH), 7.65–7.75 (m, 2 H, 1-H, 3-H). Anal. calcd. for
C21H16ClNO (333.82): C, 75.56; H, 4.83; N, 4.20. Found: C,
75.39; H, 5.06; N, 4.05.
5-Benzyl-4-chloro-8,9,10,11-tetrahydropyrido[3,2,1-jk]carba-
zol-6-one (18c). From 4-hydroxy-pyridocarbazole 6h (3.29 g,
10 mmol) and phosphoryl chloride (30 mL) as described for
18a. The yield was 0.79 g (24%), yellow prisms, mp 106ꢀC
(ligroin). IR: 2950-2850 w, 1655 s (6-C¼¼O), 1615 w, 1590 w;
1H NMR (DMSO-d6): d 1.70–1.90 (m, 4 H, 2 CH2), 2.70 (s, 2
H, 11-CH2), 3.10 (s, 2 H, 8-CH2), 4.00 (s, benzyl-CH2), 7.10–
7.50 (m, 6 H, 5 benzyl-H, 2-H), 7.70 (d, J ¼ 6.0 Hz, 1-H),
8.05 (d, J ¼ 6.0 Hz, 3-H). Anal. calcd. for C22H18ClNO
1
s, 2934 m, 1642 m (6-C¼¼O), 1618 s, 1536 s cmꢁ1; H NMR
(CDCl3): d 1.89–1.90 and 1.96–1.97 (2 m, 4 H, 9-CH2, 10-
CH2), 2.18 (s, 3 H, 5-Me), 2.76 (t, J ¼ 6.0 Hz, 2 H, 11-CH2),
3.27 (t, J ¼ 6.0 Hz, 2 H, 8-CH2), 4.43 (s, 1 H, NH), 4.82 (d, J
¼ 3.8 Hz, 2 H, benzyl-CH2), 7.30–7.36 (m, 3 H, PhH, 2-H),
7.38–7.40 (m, 3 H, PhH), 7.61 (d, J ¼ 7.5 Hz, 1 H, 1-H), 7.67
(d, J ¼ 8.0 Hz, 1 H, 3-H). 13C NMR (CDCl3): d 11.2, 21.2
and 22.4 (C9, C10), 23.0 and 24.9 (C11, C8), 52.5 (Me),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2010
Synthesis and Reactions of 4-Hydroxy-8,9,10,11-tetrahydropyrido[3,2,1-jk]carbazol-6-ones
823
(347.85): C, 75.97; H, 5.22; N, 4.03. Found: C, 76.32; H,
4.91; N, 3.65.
7.62 (m, 2 H, PhH), 7.67–7.80 (m, 2 H, 1-H, 3-H). Anal.
calcd. for C21H16N4O (340.39): C, 74.10; H, 4.74; N, 16.46.
Found: C, 74.35; H, 4.52; N, 16.28.
2,4-Dichloro-10-methyl-5-phenyl-8,9,10,11-tetrahydro-pyrido
[3,2,1-jk]carbazol-6-one (18d). From 4-hydroxy-pyridocarba-
zole 6o (3.63 g, 10 mmol) and phosphoryl chloride (30 mL) as
described for 18a. The yield was 3.28 g (86%), colorless
prisms, mp 190ꢀC (ethanol). IR: 2930–2800 w, 1660 s, 1610
REFERENCES AND NOTES
[1] (a) Budavari, S., Ed. The Merck Index; Merck & Co Inc:
Rahway, 1996; Vol. 12, p 9020; (b) Smith, G. F. In The Alkaloids;
Manske, R. H. F., Ed.; Academic Press: New York, 1965; Vol. VIII, p
591; (c) Prelog, V.; Szpilfogel, S.; Battegay, J. Helv Chim Acta 1947,
30, 366; (d) Beifuss, U. Angew Chem 1994, 196, 1204.
[2] Budavari, S., Ed. The Merck Index; Merck & Co Inc: Rah-
way, 1996; Vol. 12, p 1476.
1
w, 1590 w cmꢁ1; H NMR (CDCl3): d 1.85–2.05 (m, 4 H, 9-
CH2, 10-CH2), 2.73 (t, J ¼ 6.0 Hz, 2 H, 11-CH2), 3.20–3.25
(m, 2 H, 8-CH2), 7.35–7.45 (m, 3 H, 3 PhH), 7.55–7.60 (m, 2
H, PhH), 7.65–7.75 (m, 2 H, 1-H, 3-H). Anal. calcd. for
C22H17Cl2NO (382.29): C, 69.12; H, 4.48; N, 3.66. Found: C
69.18; H, 4.81; N 3.80.
[3] Budavari, S., Ed. The Merck Index; Merck & Co Inc: Rah-
way, 1996; Vol. 12, p 10170.
4-Chloro-2,5,9-trimethyl-8,9,10,11-tetrahydropyrido[3,2,1-jk]
carbazol-6-one (18e). From 4-hydroxy-pyridocarbazole 6l
(2.81 g, 10 mmol) and phosphoryl chloride (30 mL) as
described for 18a. The yield was 1.85 g (62%), colorless
prisms, mp 157ꢀC (ethanol). IR: 3450 m, 2922 m, 1662 s (6-
[4] (a) Ziegler, E.; Rossmann, U.; Litvan, F.; Meier, H. Mon-
atsh Chem 1962, 93, 26; (b) Ziegler, E.; Litvan, F. (Geigy Chemical
Corp.), US Pat. 1959, 3,052,678; (c) Ziegler, E.; Litvan, F. Chem
Abstr 1963, 58, 3437e; (d) Geigy Chemical Corp. Brit. Pat. 1960,
912,289; (e) Geigy Chemical Corp. Chem Abstr 1963, 59, 645; (f)
Harfenist, M.; Magnien, E. J Org Chem, 1963, 28, 538.
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.
C¼¼O), 1627 m, 1588 w cmꢁ1 1H NMR (CDCl3): 1.15 (d, 3
H, 9-Me), 1.41–1.46 (m, 1 H, 9-H), 1.89–2.19 (m, 2 H, 10-
CH2), 2.41 (s, 3 H, 5-Me) 2.58 (s, 3 H, 2-CH3), 2.68–2.84 (m,
4 H, 8-CH2, 11-CH2), 7.46 (d, J ¼ 6.5 Hz, 1 H, 1-H), 7.55 (d,
J ¼ 6.5 Hz, 1 H, 3-H). Anal. calcd. for C18H18ClNO (299.80):
C, 72.11; H, 6.05; N, 4.67. Found: C, 71,81; H, 5,94; N, 4,51.
4-Azido-5-methyl-8,9,10,11-tetrahydropyrido[3,2,1-jk]carba-
zole-6-one (19a). Method A. A mixture of 4-chloro-pyridocar-
bazole 18a (1.36 g, 5 mmol) and sodium azide (0.98 g, 15
mmol) in dimethylformamide (30 mL) was intensively stirred
and heated for 36 h at 50ꢀC. After cooling to room tempera-
ture, the mixture was poured onto crushed ice/water (250 mL).
This solution was kept for 3 h at room temperature, filtered by
suction and dried in vacuum with phosphorouspentoxide. Tlc
check showed a mixture of starting 18a and azide 19a, which
were separated by dry column flash chromatography (hexane/
ethyl acetate as gradients). The yield of 19a was 0.33 g (15%).
Method B. A mixture of 4-hydroxy-pyridocarbazole 6a (0.50
g, 2 mmol) and sodium azide (0.65 g, 10 mmol) in excess
phosphoryl chloride (3 mL ꢂ5 g, 30 mmol) was intensively
stirred and heated for 12 h at 60ꢀC. The excess phosphoryl
chloride was removed by vacuum distillation. After cooling to
room temperature, the solid was poured into crushed ice/water
(50 mL), and filtered by suction. The yield was 0.32 g (58 %),
yellowish crystals, mp 104ꢀC (dec.) (methanol). IR: 3432 m,
2390 m, 2855 w, 2114 s (N3), 1661 s (6-C¼¼O), 1626 m, 1598
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1
w cmꢁ1; H NMR (CDCl3): d 1.88–1.82 and 1.87–1,89 (2 m,
4 H, 9-CH2, 10-CH2), 2.32 (s, 3 H, 5-Me), 2.72 (t, J ¼ 7.0
Hz, 2 H, 11-CH2), 3.10 (t, J ¼ 7.0 Hz, 2 H, 8-CH2), 7.48 (t, J
¼ 7.7 Hz, 1 H, 2-H), 7.72 (d, J ¼ 7.6 Hz, 1 H, 1-H), 7.78 (d,
J ¼ 7.8 Hz, 1 H, 3-H). Anal. calcd. for C16H14N4O (278.32):
C, 69.05; H, 5.07; N, 20.13. C, 69.41; H, 5.44; N, 19.75.
4-Azido-5-phenyl-8,9,10,11-tetrahydropyrido[3,2,1-jk]carba-
zol-6-one (19b). To a solution of 4-chloro-pyridocarbazole 18b
(0.60 g, 1.8 mmol) in dimethylformamide (30 mL) at 50ꢀC,
sodium azide (0.5 g, 7.2 mmol) was added and the mixture
stirred for 12 h at room temperature, and then for about 60
min at 80ꢀC until the reaction was finished (tlc check). The
yield was 0.20 g (33%), brownish prisms, mp 107ꢀC (dec.).
IR: 3430 m, 2350 m, 2850 w, 2115 s (N3), 1660 s (6-C¼¼O),
´
Shu-Kun Lin, Vazquez Tato, M. P., Eds; CD-ROM edition, ISBN 3–
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1
1625 m, 1595 w cmꢁ1; H NMR (CDCl3): d 1.85–2.05 (m, 4
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824
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