5-Unsubstituted pyrido[3,2,1-jk]carbazol-6-ones: Syntheses, substitution, and cyclization reactions

Article abstract of DOI:10.1002/jhet.1994

The synthesis of the 5-unsubstituted pyrido[3,2,1-jk]carbazol-6-one 4 can be achieved by the reaction of carbazole (1) and malonate derivatives, either in a three-step synthesis via 5-acetyl-pyridocarbazolone 3 or in a one-step reaction from 1 and malonic acid/phosphoryl chloride. The 5-acetyl derivative 5 can be transformed via a tosylate intermediate to 4-azido-pyridocarbazolone 11, which cyclizes by thermal decomposition to the isoxazolo-pyrido[3,2,1-jk]carbazolone 12. The thermolysis conditions were investigated by DSC. Nitration of pyridocarbazolone 4 and subsequent introduction of azide leads to azido derivative 23, which cyclizes on thermolysis to furazan-oxide derivative 24. Again, the thermolysis conditions were investigated by DSC. 5-Chloro-5-nitro-pyrido[3,2,1-jk]carbazole-4,6-dione, obtained from 4 by subsequent nitration and chlorination, forms by exchange of both 5-substituents 5,5-dihydroxy-pyridocarbazoledione 17, which acylates phenol to give 5-hydroxy-5-(p-hydroxyphenyl)- pyridocarbazoledione 20. Acid-catalyzed cyclodehydration of 20 forms a highly fused benzofuropyridocarbazole 21. Another C-C coupling at position 5 starts from 4-chloro-5-nitro-pyridocarbazolone 22 and diethyl malonate 2a, which forms the diethyl (nitrocarbazolyl)malonate 25.With dimethyl malonate 2c, the intermediate dimethyl (nitrocarbazolyl)malonate gives on thermolysis the (nitrocarbazolyl)acetate 27 by loss of one ester group.

Full text of DOI:10.1002/jhet.1994

114
5-Unsubstituted Pyrido[3,2,1-jk]carbazol-6-ones: Syntheses, Substitution,
Vol 52
and Cyclization Reactions
*
Wolfgang Stadlbauer, Van Hoai Dang, and Nikolaus Guttenberger
Department of Chemistry, Organic Synthesis Group, Karl-Franzens University of Graz, Heinrichstrasse 28, A-8010 Graz,
Austria
*
E-mail: wolfgang.stadlbauer@uni-graz.at
Received December 10, 2012
DOI 10.1002/jhet.1994
Published online 5 May 2014 in Wiley Online Library (wileyonlinelibrary.com).
The synthesis of the 5-unsubstituted pyrido[3,2,1-jk]carbazol-6-one 4 can be achieved by the reaction
of carbazole (1) and malonate derivatives, either in a three-step synthesis via 5-acetyl-pyridocarbazolone
3 or in a one-step reaction from 1 and malonic acid/phosphoryl chloride. The 5-acetyl derivative 5 can
be transformed via a tosylate intermediate to 4-azido-pyridocarbazolone 11, which cyclizes by thermal
decomposition to the isoxazolo-pyrido[3,2,1-jk]carbazolone 12. The thermolysis conditions were investi-
gated by DSC. Nitration of pyridocarbazolone 4 and subsequent introduction of azide leads to azido
derivative 23, which cyclizes on thermolysis to furazan-oxide derivative 24. Again, the thermolysis
conditions were investigated by DSC. 5-Chloro-5-nitro-pyrido[3,2,1-jk]carbazole-4,6-dione,
obtained from 4 by subsequent nitration and chlorination, forms by exchange of both 5-substituents
5,5-dihydroxy-pyridocarbazoledione 17, which acylates phenol to give 5-hydroxy-5-(p-hydroxyphenyl)-
pyridocarbazoledione 20. Acid-catalyzed cyclodehydration of 20 forms a highly fused benzofuro-
pyridocarbazole 21. Another C–C coupling at position 5 starts from 4-chloro-5-nitro-pyridocarbazolone
22 and diethyl malonate 2a, which forms the diethyl (nitrocarbazolyl)malonate 25. With dimethyl malonate
2c, the intermediate dimethyl (nitrocarbazolyl)malonate gives on thermolysis the (nitrocarbazolyl)acetate
27 by loss of one ester group.
J. Heterocyclic Chem., 52, 114 (2015).
INTRODUCTION
Recently, we published the syntheses of 5-monosubstituted
4-hydroxypyrido[3,2,1-jk]carbazol-6-ones, which were obtained
by cyclocondensation of 2-alkyl or 2-aryl malonates and
carbazole [6], and studied their reactions [7]. The approach
to 5-unsubstituted derivatives was found to require other
reaction pathways, which is shown in this contribution.
Furthermore, the substitution at C-5 of 4-hydroxypyrido
[3,2,1-jk]carbazol-6-ones and further reactions lead to new
and interesting structures.
The pyrido[3,2,1-jk]carbazol-6-one framework is part of
the heterocyclic skeleton of natural products such as
Strychnos alkaloids with the biologically interesting com-
bination of an indole and a 2-pyridone structure [2,3]. Fur-
thermore, some pyridocarbazolone derivatives have found
interest in pharmacological investigations [4] and in dye-
stuff chemistry [5].
© 2014 HeteroCorporation

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Cyclization Reactions
Scheme 1
RESULTS AND DISCUSSION
Whereas 2-substituted malonates react in a smooth
thermal 1:1 cyclocondensation reaction with carbazole
(1) in good yields to 5-substituted 4-hydroxy-pyrido
[3,2,1-jk]carbazol-6-ones [4], 5-unsubstituted derivatives
could not be obtained in such an easy way. Attempts to
perform a cyclocondensation of 2-unsubstituted diethyl
malonate 2a with carbazole (1) give in a 1:1 reaction
a mixture of compounds, which cannot be simply sepa-
rated. In a 2:1 cyclocondensation of 2a with 1, how-
ever, a single compound 3 is obtained in good yields,
which has been shown to consist of one molecule of
carbazole (1) and two molecules deriving from
malonate 2a. The structure was assigned to 7-hydroxy-
5H,8H-pyrano[20,30:4,5]pyrido[3,2,1-jk]carbazole-5,8-
dione (3), a structure similar as obtained from related
quinoline systems [8]. We could further show that the
use of boiling diphenyl ether (bp 258ꢀC) as solvent
gives the best results, when the formed four molecules
of ethanol were removed by distillation during the
reaction.
Pyrano-pyridocarbazole 3 having a lactone structure
reacts as cyclic ester with sodium or potassium hydrox-
ide by hydrolytic ring opening. Best results were
obtained when glycol was used as the solvent to obtain
a higher reaction temperature and shorter reaction time.
Acidification with hydrochloric acid results in the
formation of an acetoacetic acid fragment as substituent,
which decarboxylates spontaneously at elevated
temperatures already in weakly acidic media to give
the 5-acetyl-pyridocarbazole 5. Because strong foaming
by evolution of carbon dioxide accompanies this reac-
tion, caution must be taken when performing this
reaction.
diamide of malonic acid (from 2c and two molecules of
carbazole 1) and further accompanied with small
amounts of 4-chloro-pyridocarbazolone 7.
For mechanistic studies and to prove the structure of the
pyrone 3, we investigated also the reaction of
pyridocarbazolone 4 back to the pyrono derivative 3. The
reaction with 1 equiv of diethyl malonate 2a gave in mod-
erate yield as main product the pyrone 3, however with a
number of byproducts deriving probably from higher fused
derivatives.
A further method for the degradation of the pyrano ring
in 3 was found when pyrano-pyridocarbazole 3 was
brought to reaction with sulfuryl chloride. In contrast to
similar reactions described in the following paragraphs
(Scheme 3, reactions to 14 and 16), not only electrophilic
chlorination at the dicarbonyl-methylene group takes place
but also the ring opening of the lactone ring and decarbox-
ylation, probably caused by sulfuric acid formed during the
reaction. As product, 5-dichloroacetyl-pyridocarbazolone 6
is formed.
4-Chloro-pyridocarbazolone 7 was obtained in good
yields from 4-hydroxypyridocarbazolone 4 by reaction
with boiling phosphoryl chloride. The exchange of the
chloro atom against the azide group proceeds easily in a
nucleophilic reaction with sodium azide in DMF and pro-
duces 4-azido-pyridocarbazolone 8.
The 5-acetyl group in pyridocarbazole 5 can be
removed in a smooth reaction with 90% sulfuric acid
at 140ꢀC by ipso-substitution and results in a moderate
overall yield of highly pure 5-unsubstituted
pyridocarbazole 4 after three steps (Scheme 1).
We made several attempts to obtain 4 in a shorter
reaction sequence using several reactive malonic acid
derivatives (e.g., trichlorophenyl esters or ketene
carboxylates) and catalysts [9], but the results were dis-
appointing. The best results we obtained were by the re-
action of malonic acid 2c and carbazole (1) with
phosphoryl chloride as condensation agent. This method
was already described in the literature some decades
earlier [10] and was reported to yield 4 in about 57%
yield, but the enforcement of this reaction gave often
differing yields and purities depending on the accuracy
and workup. We adapted this method and optimized
the yield to about 70%, but the reaction remained
always somehow cumbersome, because product 4 was
always contaminated with byproducts such as the
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Scheme 2
Recently, we published a series of electrocyclization re-
actions of hetaryl azides with reactive ortho-substituents
such as acyl or nitro groups [1,8,11,12]. Acetyl-
pyridocarbazolone 5 has as precursor of one of these struc-
ture elements an acetyl group, together with a hydroxy
group in ortho-position. The conversion of the 4-hydroxy
group to a reactive intermediate was rather difficult: simple
chlorination with phosphoryl chloride or tosylation with
tosyl chloride did not work because hydrogen bondings be-
tween the acetyl group and the 4-hydroxy group prevented
a reaction. A successful way was found by a two-step reac-
tion in a similar manner as shown in [11a], first converting
the hydroxy group of 5 with sodium methanolate at room
temperature to its sodium salt 9. The salt can now easily
be tosylated under reflux to give tosylate 10, which proved
to be a very reactive intermediate. The tosyloxy group was
exchanged against the azido group with sodium azide in
DMF at room temperature to form 4-azido compound 11
in very good yields.
The thermal ring closure reaction of the azide 11 was in-
vestigated by DSC to obtain the hints on the cyclization
temperature and possible further decomposition [13]. The
DSC diagram of 11 (Fig. 1) shows that no melting point
of 11 appears, but cyclization takes place already at rather
low temperatures with an onset temperature of about
85ꢀC and a reaction peak maximum at about 101ꢀC. The
reaction enthalpy is rather low with ꢁ21 mcal/mg. A small
decomposition area is visible at about 170ꢀC, followed by
a melting area at 223ꢀC, which is already the melting area of
the cyclized species, the isoxazole 12. A further decomposi-
tion can be observed at 330ꢀC. From this information, the de-
composition of the azide was performed in refluxing
bromobenzene to obtain in good yields 6-methyl-7H-
isoxazolo[30,40:4,5]pyrido[3,2,1-jk]carbazol-7-one (12). The
DSC diagram of isoxazole 12 showed only a melting area with
a peak maximum at 226ꢀC (Scheme 2).
aromatic nuclei should be avoided, which could be
accomplished by mild reagents and low temperatures.
4-Hydroxy-pyridocarbazolone 4 reacts at room tempera-
ture with nitric acid in acetic acid in the presence of
sodium nitrite as a catalyst exclusively at position 5
to give 5-nitro-pyridocarbazolone 13. An electrophilic
chlorination of 13 with sulfuryl chloride in dioxane
at about 50ꢀC attacks again position 5 and yields
5-chloro-5-nitro-pyridocarbazoledione
16.
Another
pathway to the 5-chloro-5-nitro compound 16 was
described in the literature using a reversed order of
nitration and chlorination [14,15]. This reaction
sequence starts first by 5,5-dichlorination of
4
In the following part, electrophilic reactions at
pyridocarbazolone 4, directed regioselectively to position
5, were studied. Further electrophilic reactions at the
with sulfuryl chloride, which gives as intermediate
5,5-dichloro-pyridocarbazoledione 14. Selective re-
duction with zinc dust leads to the monochloro
derivative 15. In the nitration step to 16, in litera-
ture [14], nitric acid in acetic acid at reflux temper-
ature was applied to attack position 5, which
however gives some multinitrated byproducts,
already visible by the published melting point. By
using again our previously described mild nitration
method with sodium nitrite as catalyst at room
temperature, the attack takes place exclusively at
position
5
and gives pure 5-chloro-5-nitro-
pyridocarbazoledione 16. The total yield leading in
our new sequence in two steps from 4 ! 13 ! 16 is
53%; in the known four-step reaction according to
the literature sequence [14,15] from 4 ! 14 ! 15
! 16, only 23% is obtained. 5-Chloro-5-nitro-
pyridocarbazoledione 16 has recently found interest
Figure 1. Combined DSC diagram of 5-acetyl-4-azido-pyrido[3,2,1-jk]
carbazol-6-one (11) and 6-methyl-7H-isoxazolo[30,40:4,5]pyrido[3,2,1-jk]
carbazol-7-one (12) (dotted line).
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Cyclization Reactions
for anticancer drug development, because it shows a
strong inhibitor activity for the enzyme “vaccinia
H1-related phosphatase” among a screening of 50 000 tested
compounds. In this investigation, only 20 structures have
shown a similar strong activity as 16 [16]. Other biological
activities of 16 were found by other authors [17] (Scheme 3).
place in the manner of an electrophilic acylation at
aromatic compounds, which results in a substitution of one
hydroxy group by the aromatic ring in para-position of the
phenol group, and produces 5-p-hydroxyphenyl-5-hydroxy
derivative 20. Such structures having a 1,3-dicarbonyl unit
with a 2-alkyl/aryl-2-hydroxy substituent pattern are related
to a series of bioactive heterocycles with anti-inflammatory
[18] and antibacterial [19] properties (Scheme 4).
In earlier investigations, we could show that cyclic 1,3-
dicarbonyl units possessing a 2-aryl-2-hydroxy moiety
can be cyclodehydrated in strongly acidic media to fused
benzopyranes [20] containing then the structure of, for ex-
ample, coumestrols or aza-coumestrols. These structures
are known to have potential anti-estrogenic [21] or anti-
osteoporotic [22] activities. When 5-p-hydroxyphenyl-5-
hydroxy-pyridocarbazoledione 20 was treated with Eaton’s
reagent (methanesulfonic acid, containing 7% phosphorus
pentoxide), a cyclodehydration takes place, and 10-
hydroxy-[1]benzofuro-pyridocarbazolone 21 was formed
in low yields.
As described earlier, electrocyclization reactions of
hetaryl azides take place also with reactive ortho-
substituents such as nitro groups [1,8,12]. When 5-nitro-
pyridocarbazolone 13 as starting material was brought to
reaction with phosphoryl chloride to obtain as reactive in-
termediate 4-chloro-5-nitropyridocarbazolone 22, again
this reaction was hindered by hydrogen bondings between
the nitro and hydroxy groups, similarly as observed with
the acetyl group in 5. Addition of TEA destroyed these
bondings, and nucleophilic chlorination takes place in ex-
cellent yields in position 4 to replace the hydroxy group
of 13 against a chloro substituent and formed 4-chloro
compound 22. The exchange of the 4-chloro atom against
a 4-azido group was easily achieved with sodium azide in
a DMF suspension warming it to 60ꢀC. The isolation of
the azide 23 was somewhat cumbersome because the end
of the reaction cannot easily be determined from the
5-Chloro-5-nitro derivative 16 could be shown to be
rather sensitive to thermolysis and gives in refluxing
diphenyl ether the trioxo derivative, pyrido[3,2,1-jk]carba-
zole-4,5,6-trione 18. Reaction of 16 with water resulted
in a total exchange of both substituents at position 5,
the chloro and nitro groups, against hydroxy groups
and formed in moderate yields 5,5-dihydroxy-
pyridocarbazoledione 17. Compound 17 can be regarded
as the hydrate of the trioxo compound 18, which is also
visible from its reactions: on heating, the yellow dihydroxy
compound 17 looses one molecule of water and forms in
refluxing xylene the red trioxo compound 18 in good
yields. In turn, treating trioxo compound 18 with water
forms back the dihydroxy compound 17 nearly
quantitatively.
Reaction of morpholine with 5,5-dihydroxy-
pyridocarbazoledione 17 leads to the substitution of one
5-hydroxy group and forms the half-aminal 5-hydroxy-5-
morpholinyl-pyridocarbazoledione 19. In the reaction of
the dihydroxy compound 17 with phenol in the presence
of concd sulfuric acid as catalyst, a C–C coupling takes
Scheme 3
Scheme 4
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W. Stadlbauer, V. H. Dang, and N. Guttenberger
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Scheme 5
4-Chloroquinolines have been recently shown to react with
CH-acidic compounds such as malonates, cyanoacetates,
malononitriles, or cyclic CH-acidic derivatives (e.g.,
dimedone) in a nucleophilic C–C coupling reaction to give
4-heteroarylsubstituted 1,3-dicarbonyl compounds [23]. In a
similar way, 4-chloro-5-nitro-pyridocarbazolone 22 reacts
with diethyl malonate 2a to form (5-nitro-6-
oxopyridocarbazolyl)malonate 25. When dimethyl malonate
2c was used, (pyridocarbazolyl)malonate 26 was obtained in
excellent yields. Thermolysis of this dimethyl malonate in
refluxing dichlorobenzene formed—probably by hydrolytic
or substitutive removal of the methyl group followed by a
decarboxylation—in excellent yields and purity
(pyridocarbazolyl)acetate 27. A similar elimination with
the diethyl malonate 25 could not be observed, because at
lower temperatures, no reaction took place and, at higher
temperatures, only decomposition products were formed. At-
tempts to find out a suitable thermolysis temperature failed,
because the DSC diagram showed that starting from
150ꢀC, a series of decompositions occur (Scheme 6).
reaction mixture because both chloro compound 23 and
azide 24 have very similar Rf values.
The thermolysis of nitro compounds with ortho-azido
groups is known to lead to furoxanes. However, the ther-
mal conditions must be carefully selected; otherwise, de-
composition reactions take place [1,8,12]. The thermal
conditions for the cyclization of the azide in structure 23
to the furoxane in 24 were again determined by DSC
[13]. In this reaction, in the DSC diagram, only a strong
exothermic cyclization reaction was visible with an onset
at 140ꢀC and 165ꢀC as peak maximum and a reaction
enthalpy of ꢁ114 mcal/mg. The synthetic thermolysis re-
action was carried out in refluxing DMF and produced pure
oxadiazolo-pyridocarbazolone oxide 24 in excellent yields.
The DSC diagram of furoxane 24 does not show any
signals up to the melting area at 275–280ꢀC (Scheme 5).
CONCLUSION
This contribution shows that the rarely investigated 5-
unsubstituted pyrido[3,2,1-jk]carbazol-6-one
4 can be
obtained easily via two pathways from carbazole (1) and
malonic acid derivatives in good yields and purity. The struc-
ture of 4 shows two reactive sites: in an electrophilic substitu-
tion, position 5 can be attacked easily and regioselectively to
give, for example, 5-nitro compound 13 and 5-chloro com-
pound 14. Further reactions lead to biologically interesting
structures such as 5-chloro-5-nitro-pyridocarbazoledione 16,
5-aryl-5-hydroxy-pyridocarbazoledione 20, and 10-hydroxy-
[1]benzofuro-pyridocarbazolone 21.
Scheme 6
Position 4, which bears in 5-unsubstituted pyrido
[3,2,1-jk]carbazol-6-one 4 a reactive hydroxy group,
can be attacked in a nucleophilic substitution to form
tosyloxy, chloro, and azido compounds 10, 11, 22, and 23,
or gives with CH-acidic compounds a C–C coupling reaction
to malonates 25 and 26. The reactive azido intermediates 11
and 23 undergo thermolytic cyclizations to isoxazole 12
and furoxane 24; the cyclization conditions were investi-
gated by DSC.
EXPERIMENTAL
General.
Melting points were determined using a Stuart
SMP3 melting point apparatus (Bibby Scientific Limited, Stone,
Staffordshire, UK) in open capillary tubes. Calorimetric data
(DSC data) were obtained on a Perkin Elmer Pyris 1 DSC
instrument (Perkin Elmer Corp., Waltham, MA, USA) with the
Pyris Software for Windows (Pyris Thermal Analysis System)
version 3.72. The DSC plots were recorded between 25ꢀC and
600ꢀC, with a heating rate of 2–10ꢀC/min, and 1.5–3.0 mg of
compound in sealed aluminum crucibles (11 bar). IR spectra
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Cyclization Reactions
were recorded with a Mattson Galaxy Series FTIR 7020
instrument (Mattson Instruments, Ltd., Milton Keynes, England)
in potassium bromide (KBr) discs or with a Bruker Alpha-P
instrument (Bruker GmbH, Karlsruhe, Germany) with ATR
measurement, using a reflection method. NMR spectra were
recorded on a Bruker AMX 360 instrument (Bruker GmbH)
removed by distillation in vacuo, and the residue was poured
onto crushed ice/water (100 mL) and stirred for 3 h at 20ꢀC until
the solid precipitated. The solid was filtered by suction and
dissolved in 0.5M aq sodium hydroxide solution (250 mL), and
the remaining insoluble byproducts were filtered off. The
mother liquor was acidified with 2M hydrochloric acid to pH 2,
and the formed solid was filtered by suction, washed with water
(100 mL), and dried at 40ꢀC. The yield was 1.80 g (70%),
yellowish prisms, mp 315ꢀC (ethanol).
1
(360 MHz H, 90 MHz 13C), on a Bruker Avance III instrument
(Bruker GmbH) (300 MHz 1H), or on a Bruker Avance DRX
500 instrument (Bruker GmbH) (500 MHz 1H, 125 MHz 13C).
Chemical shifts are given in parts per million (d) from the
internal TMS standard. Elemental analyses were performed at
the Microanalytical Laboratory of the University of Vienna,
Austria. Mass spectra were obtained from an HP 1100 LC/MSD
mass spectral instrument (Agilent Technologies, Santa Clara,
CA, USA) with either positive or negative atmospheric pressure
chemical ionization (APCI) ion source, 50–200 V, nitrogen, or
atmospheric pressure electrospray method. Dry column flash
chromatography [24] was carried out on silica gel 60 H (5–
40 mm) (Merck, Darmstadt, Germany). All reactions were
monitored by TLC on 0.2-mm silica gel F254 plates (Merck)
using UV light (254 and 366 nm) for detection. Analytical
HPLC was performed on a Shimadzu LC 20 system (Shimadzu
Corp., Kyoto, Japan) equipped with a diode array detector (215
and 254 nm) on a Pathfinder AS reversed-phase (4.6150 mm,
5 mm) column, running an acetonitrile/water gradient (30–100%
acetonitrile). Common reagent-grade chemicals are either
commercially available and were used without further
purification or prepared by standard literature procedures.
7-Hydroxy-5H,8H-pyrano[20,30:4,5]pyrido[3,2,1-jk]carbazole-
5,8-dione (3).
Method B.
A solution of 5-acetyl-pyridocarbazolone 5
(1.50 g, 5.4 mmol) in sulfuric acid (86%, 60 mL) was heated for
5 min to 140ꢀC. The solution was cooled to room temperature,
poured onto crushed ice/water (500 mL), and then stirred for
2 min until a yellowish solid precipitated. The mixture was
stirred at room temperature for 3 h, and the solid was filtered by
suction and washed with water (250 mL) until the filtrate was
neutral. The yield was 0.85 g (67%), yellowish prisms, mp
321ꢀC (ethanol); lit. mp 320ꢀC (nitrobenzene) [10]. IR (KBr):
3059–2918 s, 1669 s (6-CO), 1630 s, 1547 s cmꢁ1 1H NMR
.
(360 MHz, DMSO-d6): d 5.94 (s, 1H, 5-H), 7.50, 7.61 and 7.95
(3t, J = 7.7 Hz, 3 ꢂ 1H, 2-H, 9-H, 10-H), 8.27 and 8.39 (2d,
J = 7.5 Hz, 2 ꢂ 1H, 1-H, 11-H), 8.53 (d, J = 8.0 Hz, 1H, 8-H),
12.03 (s, 1H, OH).
5-Acetyl-4-hydroxy pyrido[3,2,1-jk]carbazol-6-one (5).
A
solution of pyrano-pyridocarbazolone 3 (3.03 g, 10 mmol) in
1.6M aq sodium hydroxide solution (30 mL) and 1,2-ethanediol
(30 mL) was heated under reflux for 3 h at 180ꢀC (bath
temperature). After cooling to room temperature, the reaction
mixture was poured onto crushed ice/water (100 mL) and
neutralized with 2M hydrochloric acid (5 mL), which formed a
precipitate (attention: strong foaming occurs). The solid was
filtered by suction and washed with water until the filtrate was
acid free (~200 mL). The yield was 1.58 g (57%), brown
powder, mp 177ꢀC (ethanol/toluene). IR (ATR): 3434 s, 1672 s
Method A.
A mixture of carbazole (1) (3.34 g, 20 mmol),
diethyl malonate (2a) (9.60 g, 60 mmol), and diphenyl ether
(40 mL) was stirred for 7 h at 250–260ꢀC. The formed ethanol
(about 2 mL) was removed by distillation from the reaction
mixture. After cooling to 50ꢀC, the reaction mixture was poured
into dioxane (30 mL), and then, methanol (20 mL) was slowly
added until a solid precipitated. The product was kept 12 h at
5ꢀC, then filtered by suction, and washed with cold methanol
(~50 mL). The yield was 3.45 g (57%), orange prisms, mp
252ꢀC (1-butanol).
(6-CO), 1607 s, 1547 s cmꢁ1 1H NMR (300 MHz, CDCl3): d
.
2.94 (s, 3H, Me), 7.51 (t, J = 7.5 Hz, 1H, 2-H), 7.55–7.63 (m,
2H, 9-H, 10-H), 8.08, 8.17 and 8.26 (3d, J = 7.5 Hz, 3 ꢂ 1H, 1-
H, 3-H, 11-H), 8.71 (d, J = 8.0 Hz, 1H, 8-H). 13C NMR
(75 MHz, CDCl3): d 30.6 (acetyl-CH3), 105.6 (5-C), 115.5
(ArC), 118.6 (ArC), 123.0 (ArC), 123.1 (ArC), 124.3 (ArC),
125.6 (ArC), 128.8 (ArC), 132.6 (ArC), 135.8 (ArC), 137.0
(ArC), 138.5 (ArC), 156.0 (6-amide-CO), 175.2 (4-C–OH),
198.9 (acetyl-CO). MS [APCI, neg]: m/z (%) = 277 (15, M), 276
(100, M ꢁ 1), 234 (12). Anal. Calcd for C17H11NO3 (277.28):
C, 73.64; H, 4.00; N, 5.05. Found: C, 73.78; H, 3.97; N, 4.85.
5-(2,2-Dichloroacetyl)-4-hydroxy-6H-pyrido[3,2,1-jk]
Method B.
A mixture of 4-hydroxy-pyridocarbazolone 4
(4.70 g, 20 mmol) and diethyl malonate (2a) (4.80 g, 30 mmol)
in diphenyl ether (20 mL) was brought to reaction and worked
up as described for method A. The yield was 3.07 g (51%),
orange prisms, mp 246ꢀC (n-butanol). IR (KBr): 2955 s, 1744 s
(8-CO), 1661 s (5-CO), 1633 s, 1546 s cmꢁ1
.
1H NMR
(300 MHz, CDCl3): d 5.74 (s, 1H, 6-H), 7.59 (t, J = 7.3 Hz, 1H,
2-H), 7.63–7.74 (m, 2H, 11-H, 12-H), 8.10, 8.26, and 8.30 (3
d, J = 7.5 Hz, 3 ꢂ 1H, 1-H, 3-H, 13-H), 8.61 (d, J = 8.0 Hz, 1H,
10-H), 12.59 (s, 1H, 7-OH). MS [APCI, neg]: m/z (%) = 303
(20, M), 302 (100, M ꢁ 1). Anal. Calcd for C18H9NO4 (303.28):
C, 71.29; H, 2.99; N, 4.62. Found: C, 71.47; H, 3.29; N, 4.35.
4-Hydroxy-6H-pyrido[3,2,1-jk]carbazole-6-one (4).
carbazol-6-one (6). To a solution of pyrano-pyridoquinoline
3 (1.61 g, 5.3 mmol) in dioxane (50 mL), sulfuryl chloride
(1.35 g, 0.81 mL, 10 mmol) was slowly added. The reaction
mixture was heated for 30 min to 50ꢀC and then for 5 min to
90ꢀC. The mixture was cooled to room temperature and then
poured onto ice/water (200 mL). The obtained solid was
filtered by suction and washed with water (250 mL) until
neutral. The yield was 1.10 g (60%), yellow needles, mp
317ꢀC (ethanol/toluene). IR (KBr): 3439 s, 3040 s, 1754 s, 1730 s
Method A.
To a stirred mixture of carbazole (1) (1.83 g,
11 mmol), malonic acid (2a) (3.02 g, 29 mmol), and naphthalene
(3.00 g), phosphoryl chloride (16.8 g, 10 mL, 110 mmol) was
slowly added. The reaction mixture was heated to 70–80ꢀC
under stirring until the mixture dissolved. The solution was kept
for 45 min at this temperature, and then, the mixture was heated
for further 10 min to 120ꢀC (attention: strong foaming occurs).
The bright brown color of the reaction mixture changed to dark
brown. After cooling to 20ꢀC, excess phosphoryl chloride was
(dichloroacetyl-CO), 1672 s (6-CO), 1631s, 1580s cmꢁ1 1H
.
NMR (360 MHz, CDCl3): d 7.54 (s, 1H, CHCl2), 7.64–7.60
(m, 2H, 2-H, 9-H), 8.08 (d, J = 7.9 Hz, 2H, 10-H, 11-H), 8.20
(d, J = 7.9 Hz, 1H, 1-H), 8.31 (d, J = 7.5 Hz, 1H, 3-H), 8.70 (d,
J = 8.0Hz, 1H, 8-H), 16.02 (s, 1H, OH). 13C NMR (125MHz,
CHCl2): d 68.5 (acetyl-CHCl2), 104.5 (5-C), 112.5 (ArC), 117.2
(ArC), 121.1 (ArC), 121.8 (ArC), 123.5 (ArC), 124.4 (ArC),
Journal of Heterocyclic Chemistry
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125.4 (ArC), 127.4 (ArC), 128.9 (ArC), 130.8 (ArC), 137.0 (ArC),
138.0 (ArC), 159.5 (6-amide–CO), 189.1 (4-C–OH), 193.5
(dichloroacetyl-CO). Anal. Calcd for C17H9Cl2NO3 (346.17): C,
58.98; H, 2.62; N, 4.05. Found: C, 58.56; H, 2.47; N, 3.96.
1H, ArH), 7.94 (d, J = 8.0 Hz, 2H, ArH), 8.07 and 8.20 (2d,
J = 7.5Hz, 2 ꢂ 1H, 3-H, 11-H), 8.67 (d, J = 8.0 Hz, 1H, 8-H).
Anal. Calcd for C24H17NO5S (431.47): C, 66.81; H, 3.97; N,
3.25. Found: C, 66.58; H, 3.91; N, 3.08.
4-Chloropyrido[3,2,1-jk]carbazole-6-one (7).
A mixture
5-Acetyl-4-azido-pyrido[3,2,1-jk]carbazol-6-one (11).
A
of 4-hydroxy-pyridocarbazolone 4 (1.60 g, 6.8 mmol) in excess
phosphoryl chloride (20 mL) was heated under reflux for 1 h.
After cooling to room temperature, the reaction mixture was
poured onto ice/water (500 mL) and neutralized with 1M aq
sodium hydroxide solution. The precipitated solid was filtered
off by suction and washed with water (200mL) until neutral. The
yield was 1.35 g (78%), pale blue prisms, mp 246ꢀC (ethanol). IR
mixture of tosylate 10 (0.45 g, 1.0 mmol) and sodium azide
(0.18 g, 2.8 mmol) in DMF (15 mL) was stirred for 5 h at room
temperature and then poured onto ice/water (100 mL). The
formed precipitate was filtered by suction, washed with water,
and dried in vacuo at ambient temperature. The yield was 0.20 g
(66%), yellowish prisms, mp 206ꢀC dec (methanol). DSC:
reaction onset 84.8ꢀC, peak maximum 101.1ꢀC (ꢁ21 mcal/mg);
decomposition peak maximum 170ꢀC (ꢁ20 mcal/mg); mp onset
207.5ꢀC, peak maximum 213.6ꢀC (36 mcal/mg); decomposition
onset 330.7ꢀC, peak maximum 334.1ꢀC (ꢁ110 mcal/mg). IR
(ATR): 3433 m, 2136 s (N3), 1688 s (6-CO), 1645 s, 1640 s,
(ATR): 3447s, 1672s (6-CO), 1603 s, 1554 scmꢁ1
.
1H
NMR (300 MHz, CDCl3): d 6.69 (s, 1H, 5-H), 7.52 (t, J = 7.0 Hz,
1H, 2-H), 7.60–7.63 (m, 2H, 9-H, 10-H), 8.03 (d, J = 7.4 Hz, 1H,
11-H), 8.09 (d, J = 7.6 Hz, 1H, 1-H), 8.22 (d, J = 6.8 Hz, 1H, 3-H),
8.73 (d, J = 8.0Hz, 1H, 8-H). Anal. Calcd for C15H8ClNO
(253.69): C, 71.02; H, 3.18; N, 5.52. Found: C, 71.23; H, 3.39;
N, 5.26.
1607 s, 1536 m cmꢁ1 1H NMR (300 MHz, CDCl3): d 2.90 (s,
.
3H, Me), 7.52 (t, J = 7.6 Hz, 1H, 2-H), 7.58–7.62 (m, 2H, 9-H,
10-H), 8.04, 8.24 and 8.34 (3d, J = 7.6 Hz, 3 ꢂ 1H, 1-H, 3-H,
11-H), 8.49 (d, J = 8.0 Hz, 1H, 8-H). Anal. Calcd for
C17H10N4O2 (302.29): C, 67.55; H, 3.33; N, 18.53. Found: C,
67.91; H, 3.71; N, 18.13.
4-Azidopyrido[3,2,1-jk]carbazol-6-one (8).
Method A.
A mixture of 4-chloro-pyridocarbazolone 7
(2.03 g, 8 mmol) and sodium azide (1.04 g, 16 mmol) in DMF
(30 mL) was stirred and warmed for 12 h at 60ꢀC. Then, ice/
water (100 mL) was added, the mixture stirred for 1 h and
warmed to room temperature, and the formed precipitate filtered
by suction. The yield was 1.19 g (57%), yellowish prisms, mp
252ꢀC dec (methanol).
6-Methyl-7H-isoxazolo[30,40:4,5]pyrido[3,2,1-jk]carbazol-7-
one (12). A mixture of 4-azido-pyridocarbazolone 10 (0.10 g,
0.33mmol) in bromobenzene (3 mL) was heated under reflux for
3 h. After cooling to room temperature, the mixture was poured
onto ice/water (50 mL). The formed solid was filtered, washed
with water (50mL), and dried. The yield was 0.071g (78%),
yellow prisms, mp 223ꢀC (methanol). DSC: mp onset 224.1ꢀC;
peak maximum 225.7ꢀC (54mcal/mg). IR (ATR): 3396 m, 1694 s
Method B.
A mixture of 4-hydroxy-pyridocarbazolone 4
(0.19 g, 0.8 mmol) and sodium azide (1.00 g, 15.4 mmol) in
excess phosphoryl chloride (10 mL) was vigorously stirred and
warmed for 12 h at 60ꢀC. The excess phosphoryl chloride was
removed by vacuum distillation, the residue cooled to room
temperature, poured onto ice/water (50 mL), and stirred for 2 h,
and the precipitated solid filtered by suction. The yield was
0.12 g (60%), yellowish prisms, mp 250ꢀC dec (methanol). IR
(ATR): 3433 s, 2126 s (N3), 1673 s (6-CO), 1605 s,
(amide-CO), 1669 m, 1637s, 1612s, 1574w cmꢁ1 1H NMR
.
(300 MHz, DMSO-d6): d 2.92 (s, 3H, Me), 7.53 (t, J = 7.5 Hz, 1H,
2-H), 7.64 (t, J = 7.6 Hz, 2H, 9-H, 10-H), 8.07, 8.27 and 8.37 (3d,
J = 7.7Hz, 3 ꢂ 1H, 1-H, 3-H, 11-H), 8.52 (d, J = 8.1 Hz, 1H, 8-H).
Anal. Calcd for C17H10N2O2 (274.28): C, 74.45; H, 3.67; N,
10.21. Found: C, 74.55; H, 3.70; N, 10.03.
1555 m cmꢁ1 1H NMR (300 MHz, DMSO-d6): d 6.57 (s, 1H,
.
4-Hydroxy-5-nitropyrido[3,2,1-jk]carbazol-6-one (13).
To a stirred mixture of 4-hydroxypyridocarbazolone 4 (1.48 g,
6.3 mmol) in glacial acetic acid (50 mL) at room temperature,
concentrated nitric acid (4.0 mL, 60 mmol) was slowly added.
Then, sodium nitrite (0.25 g, 3.6 mmol) was added as catalyst,
which starts a slightly exothermic reaction. The starting material
dissolved, and then, a precipitation of the product can be
observed. The mixture was stirred for further 30 min and then
poured onto crushed ice/water (100 mL). The precipitated solid
was filtered by suction and washed with water until acid free.
The yield was 1.20 g (68%), yellow needles, mp 192ꢀC
(ethanol). IR (ATR): 3456 m, 1671 s (6-CO), 1648 s,
5-H), 7.55 (t, J = 7.0 Hz, 1H, 2-H), 7.61–7.69 (m, 2H, 9-H, 10-
H), 7.94 (d, J = 7.9 Hz, 1H, 11-H), 8.29 (d, J = 7.6 Hz, 1H, 1-H),
8.45 (d, J = 7.5 Hz, 1H, 3-H), 8.51 (d, J = 8.0 Hz, 1H, 8-H).
Anal. Calcd for C15H8N4O (260.26): C, 69.23; H, 3.10; N,
21.53. Found C, 68.85; H, 3.47; N, 21.15.
Sodium 5-acetyl-6-oxo-6H-pyrido[3,2,1-jk]carbazol-4-olate
(9).
To a mixture of 4-acetylpyridocarbazolone 5 (10.00 g,
36 mmol) and sodium methoxide (70 mL) prepared from sodium
(2.76 g, 120 mmol) and methanol (70 mL), dioxane (270 mL)
was added. The reaction mixture was stirred for 5 min at room
temperature, and the formed solid was filtered by suction and
washed with methanol (20 mL). The yield was 9.66 g (9 1%),
yellowish powder, mp > 300ꢀC (methanol). This product was
used without further purification for the synthesis of 10.
1549 m cmꢁ1 1H NMR (300 MHz, DMSO-d6): d 7.49 (t,
.
J = 7.5 Hz, 1H, 2-H), 7.57–7.62 (m, 2H, 9-H, 10-H), 8.14
(d, J = 7.8 Hz, 1H, 11-H), 8.26 (d, J = 7.7 Hz, 1H, 1-H), 8.42 (d,
J = 7.6 Hz, 1H, 3-H), 8.50 (d, J = 8.1 Hz, 1H, 8-H). MS [APCI,
pos]: m/z (%) = 282 (15, M + 2), 281 (100, M + 1), 249 (25), 233
(15). Anal. Calcd for C15H8N2O4 (280.24): C, 64.29; H, 2.88;
N, 10.00. Found: C, 64.02; H, 3.11; N, 9.74.
5,5-Dichloropyrido[3,2,1-jk]carbazole-4,6-dione (14). To
a stirred solution of 4-hydroxy-pyridocarbazolone 4 (1.50 g,
6.4 mmol) in dioxane (20 mL), sulfuryl chloride (1.35 g,
0.81 mL, 10 mmol) was slowly added. The reaction mixture was
heated for 30 min to 50ꢀC, then for 5 min to 90ꢀC. After
cooling to room temperature, the reaction mixture was poured
onto ice/water (100 mL). This solution was extracted with ethyl
5-Acetyl-6-oxo-6H-pyrido[3,2,1-jk]carbazol-4-yl 4-methylbenze
nesulfonate (10).
A mixture of the sodium salt 9 (4.94 g,
16.7 mmol) in dry acetonitrile (70 mL) and p-toluenesulfonylchloride
(4.00 g, 21 mmol) was stirred and heated under reflux for 8 h.
After cooling to room temperature, the mixture was poured onto
ice/water (100mL). A solid precipitated, which was then filtered
by suction and washed with water (200 mL). The yield was 6.34 g
(88%), yellowish needles, mp 189ꢀC (ethanol). IR (ATR): 1696s
(6-CO), 1607 m, 1560 m cmꢁ1 1H NMR (300 MHz, CDCl3): d
.
2.52 (s, 3H, tosyl-CH3), 2.67 (s, 3H, acetyl-CH3), 7.45 (d,
J = 8.0 Hz, 2H, ArH), 7.62–7.50 (m, 3H, ArH), 7.86 (d, J = 8.0 Hz,
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5-Unsubstituted Pyrido[3,2,1-jk]carbazol-6-ones: Syntheses, Substitution, and
121
Cyclization Reactions
acetate (50 mL), and the organic layer was dried with sodium
sulfate and taken to dryness in vacuo to give a solid. The yield
was 1.17 g (60%), yellow needles, mp 183ꢀC (ethanol), lit. mp
181–183ꢀC (benzene) [15]. IR (ATR): 3425 m 1733 s (4-CO),
water (50 mL) was added and the mixture kept overnight at room
temperature. Colorless needles of dihydroxy compound 17 were
formed, which were then filtered by suction. The yield was 0.52 g
(31%), colorless prisms, decomposition starting at 120–140ꢀC.
Method B. Pyridocarbazoletrione 18 (25 mg, 0.1 mmol) was
heated in water (5 mL) to 80ꢀC for 15min. The reaction mixture
was cooled to 10ꢀC, filtered by suction, and dried under reduced
pressure at 40ꢀC. The yield was 27mg (95%), colorless prisms,
decomposition starting at 120–140ꢀC, then melting between
220ꢀC and 223ꢀC dec by forming back the red tricarbonyl
compound 18; lit. mp 215–223ꢀC [15]. IR (ATR): 3435 m, 3240 s,
1708 s (6-CO), 1607 s, 1590 s cmꢁ1
CDCl3):
.
1H NMR (300 MHz,
d
7.54–7.63 (m, 3H, 2-H, 9-H, 10-H), 8.04
(d, J = 7.1 Hz, 1H, 11-H), 8.14 (d, J = 7.2 Hz, 1H, 1-H), 8.27 (d,
J = 7.1 Hz, 1H, 3-H), 8.51 (d, J = 7.8 Hz, 1H, 8-H).
5-Chloro-4-hydroxypyrido[3,2,1-jk]carbazol-6-one (15).
A
solution of 5,5-dichloro-pyridocarbazolone 14 (1.00 g,
3.3 mmol) in ethanol (30 mL) in glacial acetic acid (20 mL) was
heated under reflux. Zinc dust (0.60 g, 9.2 mmol) was slowly
added to the boiling mixture in small portions under vigorous
stirring, and then the reaction mixture heated under reflux for
further 30 min. The color of the mixture turned from yellow to
colorless greenish during this time. After cooling to room
temperature, the reaction mixture was filtered by suction and
washed with ethanol (10 mL). The filtrate was taken to dryness
under reduced pressure. To both solids, ethanol (each 20 mL)
was added, the mixtures were heated to reflux, and the insoluble
solids were filtered off while still hot. The ethanol filtrates were
combined and cooled to room temperature, which formed a
crystalline precipitate. The yield was 0.63 g (71%), pale
yellowish needles, mp 258ꢀC (ethanol), lit. mp 259–260ꢀC (1-
butanol, acetic acid, or nitrobenzene) [15]. IR (ATR): 3057 m,
1
1708 m (4-CO), 1660 s (6-CO), 1605 m, 1587 m cmꢁ1. H NMR
(300 MHz, DMSO-d6): d 7.04–7.12 (m, 3H, 2-H, 9-H, 10-H),
7.26, 7.44 and 7.58 (3 d, J=7.1 Hz, 3ꢂ 1H, 1-H, 3-H, 11-H), 7.65
(d, J = 7.8 Hz, 1H, 8-H).
Pyrido[3,2,1-jk]carbazole-4,5,6-trione (18).
Method A. A solution of 5-chloro-5-nitropyridocarbazoledione
16 (0.10 g, 0.32 mmol) in diphenyl ether (4 mL) was heated slowly
to 190–200ꢀC. The color of the reaction mixture changed from
yellow to red, and the formation of nitrous gases was observed.
The reaction mixture was cooled to 0ꢀC, and dry cyclohexane (4 mL)
was added. The formed precipitate was filtered by suction and
washed with dry cyclohexane. The yield was 37 mg (46%), red
powder, mp 218–223ꢀC.
Method B. A solution of 5,5-dihydroxy-pyridocarbazoledione
16 (86 mg, 0.32 mmol) in dry xylene (4 mL) was heated for 30 min
under reflux, and the yellow color of the reaction mixture changed
during this time to red. After cooling to 0ꢀC, a precipitate was
formed, which was then filtered by suction. The yield was 54 mg
(67%), red powder, mp 220–223ꢀC; lit. mp 215–223ꢀC [15] IR
1
2925 m, 1634 s (6-CO), 1603 s, 1512 s cmꢁ1. H NMR (DMSO-
d6): d 7.53 (t, J = 7.5 Hz, 1H, 2-H), 7.60–7.66 (m, 2H, 9-H, 10-
H), 8.12 (d, J = 7.8 Hz, 1H, 11-H), 8.28 (d, J = 7.8 Hz, 1H, 1-H),
8.41 (d, J = 5.5 Hz, 1H, 3-H), 8.53 (d, J = 8.0 Hz, 1H, 8-H). MS
[APCI, pos]: m/z (%) = 272 (45, M + 3), 270 (100, M + 1). MS
[APCI, neg]: m/z (%) = 270 (25, M + 1), 268 (100, M ꢁ 1), 234
(5). Anal. Calcd for C15H8ClNO2 (269.69): C, 66.81; H, 2.99;
N, 5.19. Found: C, 66.45; H, 3.06; N, 5.13.
(ATR): 3083 w, 1711 s (4-CO, 5-CO), 1687 s (6-CO), 1591 s cmꢁ1
.
1H NMR(300 MHz, DMSO-d6): d 7.55–7.71 (m, 3H, 2-H, 9-H,
10-H), 8.02 and 8.32 (2d, J=7.4, 2ꢂ 1H, 1-H, 11-H), 8.50 (d,
J= 7.3 Hz, 2H, 3-H, 8-H).13C NMR (75 MHz, DMSO-d6): 116.2
(ArC), 121.1 (ArC), 122.0 (ArC), 124.4 (ArC), 124.8 (ArC), 124.9
(ArC), 125.7 (ArC), 127.3 (ArC), 129.1 (ArC), 137.0 (ArC), 139.7
(ArC), 155.7 (4-CO), 170.9 (6-CO), 176.4 (5-CO).
5-Chloro-5-nitro-pyrido[3,2,1-jk]carbazole-4,6-dione (16).
Method A.
To a solution of 5-nitro-pyridocarbazolone 13
(0.50 g, 1.6mmol) in dioxane (15 mL) at 50ꢀC, sulfuryl chloride
(0.42 mL, 0.71g, 3.7 mmol) was added slowly in small portions
and the mixture kept at this temperature. The color of the mixture
changed from yellow to brown. The temperature was kept at 50ꢀC
for further 10min and the complete conversion checked by TLC
comparison. Then, the mixture was heated for 5 min to 60ꢀC and
then cooled in an ice bath. The precipitated solid was filtered by
suction and washed with a small amount of cold water. The yield
was 0.39 g (78%), yellow powder, mp 164–166ꢀC dec (ethanol).
Method B. To a stirred mixture of 5-chloro-pyridocarbazolone
15 (1.69 g, 6.3 mmol) in glacial acetic acid (50 mL) at room
temperature, concentrated nitric acid (4.0 mL, 60 mmol) was slowly
added. Then, sodium nitrite (0.25 g, 3.6 mmol) was added as
catalyst, which starts a slightly exothermic reaction. The starting
material dissolved, and then, a precipitation of the product can be
observed. The mixture was stirred for further 30 min and then
poured onto crushed ice/water (50 mL), the solid filtered by
suction, and the filtrate kept for the synthesis of 17. The solid was
washed with water until acid free. The yield was 1.05 g (53%),
yellow prisms, mp 165–166ꢀC dec (ethanol); lit. mp 135–140ꢀC
dec (benzene) [14]. IR (ATR): 3100 w, 1729 s (4-CO), 1698 s
(6-CO), 1583 s cmꢁ1. 1H NMR (300 MHz, DMSO-d6): d 7.65–7.80
(m, 3H, 2-H, 9-H, 10-H), 8.16 and 8.39 (2d, J = 8.2 Hz, 3H,
1-H, 3-H, 11-H), 8.72 (d, 1H, J = 7.7 Hz, 8-H).
5-Hydroxy-5-morpholin-4-yl-pyrido[3,2,1-jk]carbazole-4,6-
dione (19). To a solution of 5,5-dihydroxy-pyridocarbazoledione
17 (1.34 g, 5 mmol) in ethanol (10mL), morpholine (0.61 g.
7 mmol) was added, and the mixture was heated under reflux for
30min. Then, the mixture was cooled to room temperature, and
the precipitated crystals were filtered by suction and washed with
a small amount of cold ethanol. The yield was 1.51 g (90%) light
yellow-brownish prisms, mp 167ꢀC (ethanol). IR (KBr): 3450 m,
3250–2900 m, 1715s (4-CO), 1705s, 1670s (6-CO), 1620s,
1545 s cmꢁ1 1H NMR (360 MHz, DMSO-d6): d 2.60–2.70
.
(m, 4H, NCH2), 3.55–3.60 (m, 4H, OCH2), 5.60 (s, 1H, 5-OH),
7.50–7.70 (m, 3H, 2-H, 9-H, 10-H), 8.00 and 8.30 (2d, J = 7.4,
2 ꢂ 1H, 1-H, 11-H), 8.50–8.55 (m, 2H, 3-H, 8-H). Anal. Calcd for
C19H16N2O4 (336.35): C, 67.85; H, 4.79; N, 8.33. Found: C,
68.21; H, 5.12; N, 7.95.
5-Hydroxy-5-(4-hydroxyphenyl)pyrido[3,2,1-jk]carbazole-4,6-
dione (20).
A solution of 5,5-dihydroxy-pyridocarbazoledione
17 (1.34 g, 5 mmol) in glacial acetic acid (13mL) and water
(0.03 mL) was cooled to 0–5ꢀC. To this mixture, concd sulfuric
acid (2.1 mL) was added and the mixture kept at this temperature.
Then, phenol (0.94g, 10 mmol) was added in small portions and
the mixture warmed to room temperature and stirred for 2 h. A
solid precipitated, which was then filtered by suction. The yield
was 1.00g (58%), brownish prisms, mp 209–210ꢀC. IR (KBr):
5,5-Dihydroxypyrido[3,2,1-jk]carbazole-4,6-dione (17).
Method A. To the filtrate of the reaction mixture of 5-chloro-
5-nitro-pyridocarbazoledione 16 (obtained from 15 in method B),
1
3400 m, 1710s (4-CO), 1680 s (6-CO), 1610s, 1580s cmꢁ1. H
Journal of Heterocyclic Chemistry
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W. Stadlbauer, V. H. Dang, and N. Guttenberger
Vol 52
NMR (360 MHz, DMSO-d6): d 5.55 (s, 1H, 5-OH), 6.60–7.10 (m,
4H, PhH), 7.50–7.70 (m, 3H, 2-H, 9-H, 10-H), 8.00 and 8.30 (2 d,
2ꢂ 1H, J= 7.4, 2 H, 1-H, 11-H), 8.50–8.55 (m, 2H, 3-H, 8-H) 9.10
(s, 1H, 40-OH). Anal. Calcd for C21H13NO4 (343.34): C, 73.46; H,
3.82; N, 4.08. Found: C, 73.84; H, 4,19; N, 3.70.
yield was 0.08 g (89%), yellow prisms, mp 278ꢀC (methanol).
DSC: mp onset 275.1ꢀC, peak maximum 279.5ꢀC (28 mcal/mg).
IR (ATR): 3369 m, 1694 s (7-CO), 1648 m, 1608s, 1598 s cmꢁ1
.
1H NMR (300 MHz, DMSO-d6): d 7.68 (t, J = 7.6 Hz, 1H, 2-H),
7.76 and 7.83 (2t, J = 7.6 Hz, 2 ꢂ 1H, 10-H, 11-H), 8.17
(d, J = 8.0 Hz, 1H, 12-H), 8.42 (d, J = 7.6 Hz, 1H, 1-H), 8.51
(d, J = 8.0 Hz, 1H, 3-H), 8.76 (d, J = 7.6 Hz, 1H, 9-H). Anal. Calcd
for C15H7N3O3 (277.24): C, 64.99; H, 2.54; N; 15.16. Found: C,
10-Hydroxy-13H-[1]benzofuro[20,30:4,5]pyrido[3,2,1-jk]
carbazol-13-one (21).
A solution of 5-hydroxy-5-(4-
hydroxyphenyl)-pyridocarbazoledione 20 (0.034 g, 0.1 mmol) in
Eaton’s reagent (methanesulfonic acid/7% phosphorus pentoxide)
(10 mL) was heated for 20 min to 150ꢀC. Then, the reaction
mixture was poured onto crushed ice/water (50mL), and the
precipitate filtered by suction, washed with water until neutral,
dried, and recrystallized several times from DMF/methanol using
charcoal for purification. The yield was 6.3 mg (19%), yellowish
prisms, mp 285ꢀC dec mp (DMF/methanol). IR (KBr): 3380 s,
3050 w, 1655 m (13-CO), 1640 s, 1595 w cmꢁ1. 1H NMR (360 MHz,
CDCl3): d 7.30, 7.45 and 7.55 (3t, J= 7.3 Hz, 3H, 2-H, 3-H, 6-H),
7.65–7.75 (m, 2H, 9-H, 11-H), 8.30–8.40 (m, 4H, 4-H, 5-H, 7-H,
12-H), 8.77 (d, J= 8.1 Hz, 1H, 1-H), 9.02 (s, 1H, 10-OH). 13C NMR
(75 MHz, CDCl3): d 98.9 (ArC), 99.7 (ArC), 112.1 (ArC), 112.2
(ArC), 115.6 (ArC), 116.3 (ArC), 122.3 (ArC), 122.5 (ArC), 124.3
(ArC), 124.6 (ArC), 125.0 (ArC), 126.0 (ArC), 127.0 (ArC), 128.1
(ArC), 133.4 (ArC), 135.3 (ArC), 139.9 (ArC), 150.1 (4a-C–O),
155.6 (3b-C–O), 156.7 (6-C–OH), 159.7 (13-amide-CO). MS [APCI,
pos]: m/z (%) = 326 (M + 1, 80), 325 (M, 25). Anal. Calcd for
C21H11NO3 (325.33): C, 77.53; H, 3.41; N, 4.31. Found: C, 77.85;
H, 3.79; N, 3.95.
65.31; H, 2.59; N; 14.89.
Diethyl (5-nitro-6-oxopyrido[3,2,1-jk]carbazol-4-yl)malonate
(25).
To a solution of 4-chloro-5-nitro-pyridocarbazolone 22
(1.79 g, 6 mmol) in DMF (30 mL), anhydrous potassium
carbonate (2.00 g, 14mmol) and diethyl malonate (2a) (16.0 g,
100 mmol) were added. The reaction mixture was stirred for 6 h at
room temperature, poured onto crushed ice/water (100 mL), and
neutralized with concd hydrochloric acid (2mL) in crushed ice.
After standing for 3 h, the solid was filtered by suction and
washed with water until acid free. The yield was 1.99g (79%),
pale blue prisms, mp 230ꢀC (ethanol). IR (ATR): 3457 m, 1757 s
(ester-CO), 1743 s (ester-CO), 1685 s (6-CO), 1538 s cmꢁ1 1H
.
NMR (300 MHz, CDCl3): d 1.28 (t, J = 7.1 Hz, 6H, 2 Me), 4.33
(q, J = 7.1 Hz, 4H, 2 CH2), 4.95 (s, 1H, CH), 7.58 (t, J = 7.5 Hz,
1H, 2-H), 7.60–7.64 (m, 2H, 9-H, 10-H), 8.04 (d, J = 8.1 Hz, 1H,
11-H), 8.09 (d, J = 7.5 Hz, 1H, 1-H), 8.26 (d, J = 7.5 Hz, 1H, 3-H),
8.68 (d, J = 8.0 Hz, 1H, 8-H). MS [APCI, pos]: m/z (%) = 423 (85,
M + 1), 377 (30), 333 (15), 305 (30), 261 (25), 235 (100). MS
[APCI, neg]: m/z (%)= 422 (27, M), 421 (100, M ꢁ 1). Anal.
Calcd for C22H18N2O7 (422.40): C, 62.56; H, 4.30; N, 6.63.
Found: C, 62.28; H, 4.44; N, 6.57.
4-Chloro-5-nitropyrido[3,2,1-jk]carbazol-6-one (22).
A
mixture of 5-nitro-pyridocarbazolone 13 (1.29 g, 4.6 mmol) in
phosphoryl chloride (11.03 g, 6.6 mL, 72 mmol) and TEA
(0.5 mL) as catalyst was heated under reflux for 2 h. The
reaction mixture was then cooled to room temperature and
poured onto crushed ice/water (100 mL). The solid product was
filtered by suction and washed with water. The yield was 1.25 g
(91%), pale blue powder, mp 261ꢀC (ethanol). IR (ATR):
Dimethyl
malonate (26).
(5-nitro-6-oxopyrido[3,2,1-jk]carbazol-4-yl)
To solution of 4-chloro-5-nitro-
a
pyridocarbazolone 22 (1.80 g, 6 mmol) in DMF (30 mL),
anhydrous potassium carbonate (2.00 g, 14 mmol) and
dimethyl malonate (2c) (11.9 g, 90 mmol) were added. The
reaction mixture was stirred for 6 h at room temperature and
poured onto crushed ice/water (100 mL). The solution was
neutralized with concentrated hydrochloric acid (2 mL) in
crushed ice. After standing for 3 h, the solid was filtered by
suction and washed with water until acid free. The yield
was 2.05 g (85%), pale blue prisms, mp 205ꢀC (ethanol/
toluene). IR (ATR): 3478 m, 1761 s (ester-CO), 1740 s
1
1684 s (6-CO), 1604 m, 1538 s cmꢁ1. H NMR (CDCl3): d 7.60
(t, J = 7.6 Hz, 1H, 2-H), 7.67 (t, J = 7.6 Hz, 1H, 10-H), 7.75 (t,
J = 7.8 Hz, 1H, 9-H), 8.11 (m, 2H, 1-H, 11-H), 8.33 (d,
J = 7.6 Hz, 1H, 3-H), 8.65 (d, J = 8.1 Hz, 1H, 8-H). Anal. Calcd
for C15H7ClN2O3 (298.69): C, 60.32; H, 2.36; N, 9.38. Found:
C, 59.95; H, 2.55; N, 9.04.
(ester-CO), 1680 m (6-CO), 1540 s cmꢁ1 1H NMR (300MHz,
.
4-Azido-5-nitropyrido[3,2,1-jk]carbazol-6-one (23).
A
stirred mixture of 4-chloropyridocarbazolone 22 (1.20 g,
4 mmol) and sodium azide (6.00 g, 92 mmol) in DMF (40 mL)
was heated for 3 h at 60ꢀC. The reaction mixture was then
poured onto crushed ice/water (200 mL) and kept for 5 h at
room temperature. The precipitate was filtered by suction and
washed with water. The yield was 0.79 g (65%), yellow powder,
mp 210ꢀC dec (ethanol). DSC: reaction onset 139.8ꢀC, peak
maximum 164.7ꢀC (ꢁ114 mcal/mg). IR (ATR): 3435 s, 2141 s
CDCl3): d 3.83 (s, 6H, 2 Me), 4.99 (s, 1H, CH), 7.55
(t, J = 7.5Hz, 1H, 2-H), 7.60–7.65 (m, 2H, 9-H, 10-H), 8.00 (d,
J = 8.1Hz, 1H, 11-H), 8.07 (d, J = 7.5 Hz, 1H, 1-H), 8.25
(d, J = 7.5 Hz, 1H, 3-H), 8.65 (d, J = 8.1 Hz, 1H, 8-H). Anal. Calcd
for C20H14N2O7 (394.34): C, 60.92; H, 3.58; N, 7.10. Found: C,
60.96; H, 3.40; N, 7.13.
Methyl (5-nitro-6-oxopyrido[3,2,1-jk]carbazol-4-yl)acetate
(27).
A solution of dimethyl (5-nitro-pyridocarbazolyl)
(N3), 1642 s (6-CO), 1601 s cmꢁ1
.
1H NMR (300 MHz,
malonate 26 (1.00 g, 2.5 mmol) in dichlorobenzene (30 mL) was
stirred and heated under reflux for 12 h. The reaction mixture
was cooled to room temperature, and cyclohexane (50 mL) was
added. The precipitated solid was filtered by suction and
washed with cyclohexane. The yield was 0.70 g (83%), yellow
prisms, mp 210ꢀC (ethanol). IR (ATR): 3459 m, 1734 s (ester-
CDCl3): d 7.56–7.63 (m, 1H, 2-H), 7.65–7.85 (m, 2H, 9-H,
10-H), 8.00 (d, J = 7.2 Hz, 1H, 3-H), 8.10–8.14 (m, 2H, 1-H,
11-H), 8.68 (d, J = 7.7 Hz, 1H, 8-H). Anal. Calcd for
C15H7N5O3 (305.25): C, 59.02; H, 2.31; N, 22.94. Found: C,
59.34; H, 2.70; N, 22.55.
1
CO), 1686 s (6-CO), 1535 s cmꢁ1. H NMR (300 MHz, CDCl3):
7H-[1, 2, 5]Oxadiazolo[30,40: 4,5]pyrido[3,2,1-jk]carbazol-
d 3.77 (s, 3H, Me), 4.02 (s, 2H, CH2), 7.53 (t, J = 7.5 Hz, 1H,
2-H), 7.58–7.66 (m, 2H, 9-H, 10-H), 7.86 (d, J = 8.0 Hz, 1H,
11-H), 8.05 (d, J = 7.5 Hz, 1H, 1-H), 8.23 (d, J = 7.5 Hz, 1H, 3-
H), 8.62 (d, J = 8.0 Hz, 1H, 8-H). MS [APCI, pos]: m/z
(%) = 337 (32, M + 1), 235 (100), 148 (10), 112 (10). MS
7-one 6-oxide (24).
A solution of 4-azidopyridocarbazolone
23 (0.10 g, 0.32 mmol) in DMF (20 mL) was heated under
reflux for 2 h. After cooling to room temperature, the mixture
was poured onto crushed ice/water (100 mL). The formed
solid was filtered by suction, washed with water, and dried. The
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2015
5-Unsubstituted Pyrido[3,2,1-jk]carbazol-6-ones: Syntheses, Substitution, and
123
Cyclization Reactions
[APCI, neg]: m/z (%) = 336 (25, M), 335 (100, M ꢁ 1), 268 (18),
215 (15). Anal. Calcd for C18H12N2O5 (336.31): C, 64.29; H,
3.60; N, 8.33. Found: C, 64.58; H, 3.71; N, 8.12.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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