Syntheses of pyrazolo-, isoxazolo-, pyrido- and pyrimido-carbazoles from 2-(3′4′-dimethoxybenzylidene)-2,3,4,9-tetrahydrocarbazol-1-ones

Article abstract of DOI:10.3184/030823408X361110

Mixed aldol condensation of 2,3,4,9-tetrahydrocarbazol-1-ones with 3,4-dimethoxybenzaldehyde (veratraldehyde) yielded 2-(3′,4′- dimethoxybenzylidene)-2,3,4,9-tetrahydrocarbazol-1-ones. These enones on reaction with hydrazine hydrate, hydroxylamine hydrochloride, malononitrile and guanidinium nitrate under different conditions yielded the corresponding pyrazolo[3,4-a]-, isoxazolo[3,4-a] pyrido[2,3-a]-, and pyrimido[4,5-a]- carbazoles respectively. The molecular and crystal structure of 2-(3′,4′-dimethoxybenzylidene)-2,3/4,9-tetrahydro-1ifcarbazol-1-one resolved by single crystal X-ray diffraction is discussed.

Full text of DOI:10.3184/030823408X361110

572 RESEARCH PAPER
OCTOBER, 572–577
JOURNAL OF CHEMICAL RESEARCH 2008
Syntheses of pyrazolo-, isoxazolo-, pyrido- and pyrimido-carbazoles from
2-(3',4'-dimethoxybenzylidene)-2,3,4,9-tetrahydrocarbazol-1-ones
Makuteswaran Sridharana, Lucas K. Beagleb, Matthias Zellerb and
Karnam Jayarampillai Rajendra Prasada*
aDepartment of Chemistry, Bharathiar University, Coimbatore 641046, Tamilnadu, India
bDepartment of Chemistry, Youngstown State University, One University Plaza, Youngstown, OH 44555-3663, USA
Mixed aldol condensation of 2,3,4,9-tetrahydrocarbazol-1-ones with 3,4-dimethoxybenzaldehyde (veratraldehyde)
yielded 2-(3',4'-dimethoxybenzylidene)-2,3,4,9-tetrahydrocarbazol-1-ones. These enones on reaction with hydrazine
hydrate, hydroxylamine hydrochloride, malononitrile and guanidinium nitrate under different conditions yielded
the corresponding pyrazolo[3,4-a]-, isoxazolo[3,4-a]-, pyrido[2,3-a]-, and pyrimido[4,5-a]-carbazoles respectively.
The molecular and crystal structure of 2-(3',4'-dimethoxybenzylidene)-2,3,4,9-tetrahydro-1H-carbazol-1-one resolved
by single crystal X-ray diffraction is discussed.
Keywords: aldol condensation, 3,4-dimethoxybenzaldehyde, fused pyrazoles, isoxazoles, pyridines, pyrimidines, carbazoles,
crystal structures
Carbazoles, and in particular carbazole alkaloids, have
attracted much interest as synthetic targets since many of their
derivatives exhibit a wide range of biological activity.1-3 These
components are considered to represent potential therapeutic
agents against a variety of diseases initiated by oxygen-
derived free radicals like myocardial and cerebral ischema,
arteriosclerosis, inflammation, rheumatism, senility, cancer
and autoimmune diseases.4-10
spectroscopic details for the compounds (2b–e) are presented
in the Experimental section. For compound 2d the crystal
structure was determined by X-ray diffraction and this is
discussed below.
TheIRspectrumofcompound2ashowsstretchingvibrations
at 3252 cm-1 and 1640 cm-1 due to the presence of NH and
1
C=O groups, respectively. The H NMR spectrum exhibits a
broad singlet at d 8.97 due to the presence of the indole NH
moiety. Two singlets at d 7.75 and d 7.43 account for the C2–
H and C2'–H atoms, respectively. A pair of doublets at d 7.34
and 7.21 with J = 8.04 Hz corresponds to the C5'–H and C6'–H
units, and the presence of C7–H and C8–H is indicated by two
doublets in the region of d 7.04 and d 6.92 with J = 8.26 Hz.
A singlet at d 6.99 is due to C5–H. Two singlets at d 3.93 and
d 3.85 account for the C3'–OCH3 and C4'–OCH3 groups and a
multiplet between d 3.29 and 3.07 corresponds to the C3 and
C4 protons. A singlet at d 2.45 indicates the presence of the
methyl proton at C6. In the mass spectrum, the molecular ion
peak appears at m/z 347.
Although a large number of reports are available in the
literature describing the synthetic methods directed towards
ellipticine, olivacine and related tetracyclic compounds,11-14
the replacement of the pyridine ring in the natural structure by
other heteroaromatic systems has been only scantly reported.
Pyridocarbazole derivatives have been reported to exhibit
anti-cancer and anti-HIV activities,15-17 and replacement
of pyridine in the pyridocarbazole by other heterocyclic
rings may lead to interesting variations in the biological
activities.18-20 Hence, we aimed to devise a concise route for
synthesising pyrazolo-, isoxazolo-, pyrido-, and pyrimido-
carbazole derivatives and searched for suitable synthons
to derive these types of carbazole derivatives. From our
laboratory, we have reported the synthesis of 2-benzylidene-
2,3,4,9-tetrahydrocarbazoles from precursors of the 2,3,4,9-
tetrahydrocarbazol-1-one type and these synthons were
utilised to prepare many heteroannelated carbazoles.21-24
In continuation of this work, we here report the use of 2-(3',4'-
dimethoxybenzylidene)-2,3,4,9-tetrahydrocarbazol-1-ones
(2a–e) as effective synthons for the synthesis of pyrazolo-,
isoxazolo-, pyrido- and pyrimido-carbazoles.
Single
crystals
of
2-(3',4'-dimethoxybenzylidene)-
2,3,4,9-tetrahydro-1H-carbazol-1-one (2d) were grown
from ethanol, crystallising in the space group P-1 with two
crystallographically independent molecules per unit cell
(Fig. 1). The molecules consists of each two mostly planar
sp2 hybridized sections made up by the aromatic indole and
veratrole units with rms deviations from planarity of 0.0321
and 0.0373 Å2 for the indole and 0.0151 and 0.0072 Å2 for
the veratrole moieties. The planarity as a whole is interrupted
by two groups in the centre of the molecules, each an sp3
hybridised ethylene group, which deviates from the mean
plane of the indole unit by up to 0.864(2) Å for C9 (0.870(2)
Å for C30 in the second molecule), and by a torsional twist
between the veratrole and the adjacent C=C double bond
of 34.8(1) and 38.4(1)° in both independent molecules,
respectively. The twist angles for the molecules as a whole,
defined by the dihedral angle between the planes of the
indole and veratrole units in both molecules, are 55.64(3)
and 48.17(3)°, respectively. Crystallographic details are
Results and discussion
The preparation of the first class of synthons, 2-(3',4'-
dimethoxybenzylidene)-2,3,4,9-tetrahydrocarbazol-1-ones
(2), here given for compound 2a, is as follows: an equimolar
mixture of 6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one
(1a) and 3,4-dimethoxybenzaldehyde (veratraldehyde) is
stirred in 5% ethanolic potassium hydroxide for 24 h to yield
6-methyl-2-(3',4'-dimethoxybenzylidene)-2,3,4,9-tetrahydro-
carbazol-1-one 2a as a yellow solid melting at 110–112°C
in 90% yield. The generality of this reaction was tested with
other substituted derivatives (1b–e) to yield 2b–e (Scheme 1).
given in Table 1. Packing in the structure of 2d is facilitated
1
…
All synthons were unambiguously identified by IR and H
by a mixture of hydrogen bonding, and p–p and C–H
p
NMR spectroscopy and mass spectrometry. Representative
data for 6-methyl-2-(3',4'-dimethoxybenzylidene)-2,3,4,9-
tetrahydrocarbazol-1-one (2a) are given below. Synthetic and
contacts, as indicated in Table 2. CCDC 686840 contains the
supplementary crystallographic data for this paper. These
data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request.cif.
* Correspondent. E-mail: prasad_125@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2008 573
R1
R2
OCH3
OCH3
+
OHC
N
H
R3
O
R1
R2
R1
1a–e
OCH3
OCH3
OCH3
R2
alc. KOH
N
H
24 h, R.T.
N
H
OCH3
N2H4.H2O
Ethanol
NH2OH.HCl
C5H5N
R3
R3
O
N
NH
N
4a–e
3a–e
OCH3
R1
R2
OCH3
N
R3
guanidinium nitrate
NaH/C6H6
H
O
CH2(CN)2
2a–e
NaH/C6H6
EtOH
R1
OCH3
R1
R2
OCH3
OCH3
1–6:
a = R1 = CH3; R2 = R3 = H;
b = R2 = CH3; R1 = R3 = H;
c = R3 = CH3; R1 = R2 = H;
d = R1 = R2 = R3 = H ;
R2
OCH3
N
H
N
H
R3
N
R3
N
N
CN
OCH2CH3
e = R1 = Cl; R2 = R3 = H
NH2
6a–e
5a–e
Scheme 1
Table 1 Crystal data for 2-(3',4'-dimethoxybenzylidene)-2,3,4,9-
tetrahydrocarbazol-1-one (2d)
Chemical formula
Mr
C21H19NO3
333.37
Cell setting, space group
Temperature (K)
a, b, c (Å)
Triclinic, P-1
100(2)
8.779(2), 10.947(3), 18.846(5)
81.441(4), 86.655(4), 68.210(3)
1662.9 (7)
4
1.332
a, b, g (°)
V (Å3)
Z
Dx ( Mg m–3)
Radiation type
m (mm–1)
Mo K
a
0.09
Crystal form, colour
Crystal size (mm)
Absorption correction
Tmin and Tmax
Plate, yellow
0.61 × 0.40 × 0.09
Multi-scan
0.847 and 1.000
16824
No. of
measured
reflections independent
observed
8142
6915
Criterion for observed reflections I > 2s(I)
Fig. 1 Thermal ellipsoid representation of both independent
molecules of compound 2d with the atom labelling scheme.
Thermal ellipsoids are at the 50% probability level.
Rint
0.019
qmax (°)
28.3
Refinement on
R[F2 > 2s(F2)], wR(F2), S
No. of relections, restraints,
parameters
F2
0.044, 0.113, 1.02
8142, 0, 455
a series (compounds 3a, 4a, 5a and 6a derived from synthon
2a); details for the compounds of the b, c, d and e series are
given in the Experimental section.
Drmax, Drmin (e Å –3
)
0.37, –0.21
When 2a was treated with hydrazine hydrate in ethanol,
it afforded the expected 3-(3',4'-dimethoxyphenyl)-
2,3,3a,4,5,10-hexahydro-7-methylpyrazolo[3,4-a]carbazole
(3a) – a fused pyrazoline – in 75% yield. Its IR spectrum
revealed a band at 1596 cm-1 (C=N) and the absence of a
carbonyl moiety. The proton NMR spectrum showed a broad
singlet at d 8.60 for the indole NH, and peaks between d 7.31
and 6.59 for six aromatic protons. The pyrazoline NH proton
showed as a broad singlet at d 5.66. The methoxy groups
appeared as singlets at d 3.97 and 3.95. Multiplets were
observed at d 3.10, d 2.89, d 2.78 and d 2.52 arising from the
C3, C5, C3a and C4 protons, respectively, and a singlet at 2.47
Having obtained the key intermediates, 2-(3',4'-dimethoxy-
benzylidene)-2,3,4,9-tetrahydrocarbazol-1-ones (2a–e), our
aim was to devise a synthetic route towards the title
compounds. Compounds (2a–e) were treated with hydrazine
hydrate, hydroxylamine hydrochloride, malononitrile and
guanidine nitrate, yielding the corresponding pyrazolo[3,4-a]-
(3a–e), isoxazolo[3,4-a]- (4a–e), pyrido[2,3-a]- (5a–e), and
pyrimido[4,5-a]- (6a–e) carbazoles respectively (Scheme 1).
All the products were examined using IR and 1H NMR
spectroscopy and mass spectrometry. Again synthetic and
spectroscopic details are given here for the compounds of the

574 JOURNAL OF CHEMICAL RESEARCH 2008
…
Table 2 Hydrogen-bonding interactions, C-H p and p-p contacts (Å, °) of 2-(3',4'-dimethoxybenzylidene)-2,3,4,9-tetrahydro-
carbazol-1-one (2d)
D–H∙∙∙A
N2–H2A∙∙∙O4i
N1–H1∙∙∙O1i
D—H
0.88
0.88
0.95
0.95
0.95
0.95
0.98
0.95
0.95
0.98
0.98
0.98
0.98
H∙∙∙A
2.10
D∙∙∙A
D—H∙∙∙A
145
2.8626 (15)
2.8356 (15)
2.797(2)
2.01
156
C13–H13∙∙∙O1
C34–H34∙∙∙O2
C4–H4∙∙∙Cg1iii
C5–H5∙∙∙Cg3iii
C21–H21∙∙∙Cg8iv
C25–H25∙∙∙Cg3iii
C26–H26∙∙∙Cg1iii
C42–H42A∙∙∙Cg5v
C42–H42B∙∙∙Cg2vi
C42–H42B∙∙∙Cg6vi
C42–H42C∙∙∙Cg2vi
2.40
2.41
104
104
2.7917(19)
3.5399(19)
3.3138(18)
3.886(2)
3.2978
3.2905
3.0410
2.8661
3.0453
2.7645
3.0470
3.3476
3.1198
96.90
83.12
145.22
132.65
149.67
164.70
109.10
142.23
104.27
3.578(2)
3.8954(19)
3.7194(19)
3.4928(19)
4.166(2)
3.4928(19)
p–p contacts
Cg3∙∙∙Cg3iii
3.8243(14)
Cg8∙∙∙Cg8vii
3.6452(12)
Symmetry codes: (i) −x + 1, −y, −z + 1; (ii) −x + 2, −y + 1, −z + 2; (iii) 1–X,1–Y,1–Z; (iv) 1 + X,–1 + Y,–1 + Z;
(v) 1 + X,–1 + Y,–1 + Z; (vi) 1–X,2–Y,2–Z; (vii) –X,2–Y,2–Z
Ring centroids: Cg1 N1 C1 C6 7 C12; Cg2 N2 C22 C27 C28 C33; Cg3 C1 C2 C3 C4 C5 C6; Cg4 C7 C8 C9 C10 C11 C12; Cg5 C14 C15
C16 C17 C18 C19; Cg6 C22 C23 C24 C25 C26 C27; Cg7 C28 C29 C30 C31 C32 C33; Cg8 C35 C36 C37 C38 C39 C40
was due to C7–CH3. The mass spectrum and elemental analysis
of 3a lent further support to the assigned structure. Extension
of the above reaction under similar conditions to 2b–e yielded
the corresponding carbazole derivatives 3b–e.
oxidation of an isoxazoline intermediate can be ruled out
since 2 yielded 4 also under nitrogen atmosphere.
In consideration of their pharmacological activity27 it was
felt worthwhile to devise a simple route for the synthesis of
pyridocarbazoles. Therefore, 2-(3',4'-dimethoxybenzylidene)-
6-methyl-2,3,4,9-tetrahydrocarbazol-1-one (2a) was dissolved
in dry ethanol and reacted with malononitrile in the presence
of sodium hydride in dry benzene to give a single product.
It showed IR absorption bands at 3330 and 1595 cm-1
corresponding to NH and C=N stretching vibrations, and a
sharp band at 2214 cm-1 indicating the presence of a cyano
Treatment of 2-(3',4'-dimethoxybenzylidene)-6-methyl-
2,3,4,9-tetrahydrocarbazol-1-one (2a) with hydroxylamine
hydrochloride in dry pyridine yielded a product which was
purified by column chromatography. The IR spectrum showed
two absorptions at 3436 and 1611 cm-1, ascribable to NH and
C=N stretching vibrations respectively. The 1H NMR spectrum
registered a broad singlet at d 9.05 that showed the presence
of an NH proton. A cluster of aromatic peaks between d 7.52
and 6.80 accounted for six aromatic protons. The appearance
of methylene protons as multiplets and methoxy and methyl
protons as three singlets were observed in the proton NMR.
The molecular ion peak in the mass spectrum appeared at m/z
360 and the elemental analysis agreed well with the molecular
formula C22H20N2O3. Based on these data the structure of
the product was assigned as 4,5-dihydro-7-methyl-3-(3',4'-
dimethoxyphenyl)isoxazolo[3,4-a]carbazole (4a). The other
carbazole derivatives 2b–e were reacted similarly to yield the
corresponding isoxazoles 4b–e.
1
group. The H NMR spectrum showed a broad singlet at d
8.75 from the indole NH. Six aromatic protons appeared
as doublets and singlets in between the region d 7.44–6.87.
The methylene protons of the ethoxy group at C2 appear as
a quartet at d 4.64 with J = 7.04 Hz and this downfield shift
was attributed to the presence of the cyano group ortho to
the ethoxy group. Methoxy and methyl protons gave singlets
and further methylene protons appeared as multiplets in their
corresponding regions; a triplet at d 1.52 revealed the methyl
of the 2-OEt group. The elemental analysis and the molecular
ion peak at m/z 439 (100%) agreed well with the molecular
formula, C27H25N3O3. Based on the spectral data and elemental
analysis, the product was identified as 2-ethoxy-5,6-dihydro-
4-(3',4'-dimethoxyphenyl)-8-methyl-pyrido[2,3-a]carbazole-
3-carbonitrile (5a).The reaction was found to be applicable
to the other derivatives 2b–e, forming the corresponding
pyridocarbazole-carbonitriles 5b–e.
A plausible mechanism follows the route of Scheme 2.
Hydroxylamine liberated in situ from hydroxylamine
hydrochloride in the presence of pyridine undergoes 1,4
Michael-type addition to 2 which is followed by further
condensation with more hydroxylamine; loss of water
molecule from the alkylhydroxylamine group, then cyclisation
and finally deamination, gives the final product 4. Aerial
OCH3
+/- H+
OCH3
NH2OH
Ar
Ar
N
H
N
H
N
H
R
R
R
- H2O
O
O
N
NH-OH
NHOH
:NH2OH
OH
2
- H2O
Ar
NH2
- NH3
Ar
O
Ar
N
N
H
N
H
R
R
R
H
N
N
O
N
NH
OH
4
Scheme 2

JOURNAL OF CHEMICAL RESEARCH 2008 575
112°C. IR: νmax 3252, 2923, 2851, 1640, 1584, 1252, 803 cm-1.
1H NMR: d 8.97 (b s, 1H, N9–H), 7.75 (s, 1H, C2–H), 7.43 (s,
1H, C2'–H), 7.34 (d, 1H, C5'–H, J = 8.04 Hz), 7.21 (d, 1H, C6'–H,
J = 8.04 Hz), 7.04 (d, 1H, C7 –H, Jm = 1.56 Hz, Jo = 8.26 Hz),
6.99 (s,1H, C5–H), 6.92 (d, 1H, C8–H, J = 8.26 Hz), 3.93 (s, 3H,
C3'–OCH3), 3.85 (s, 3H, C4'–OCH3), 3.29–3.07 (m, 4H, C3–H2, C4–
H2), 2.45 (s, 3H, C6–CH3). MS: m/z (%) 347 (M+, 100), 332 (18),
272 (11), 258 (21), 183 (26), 169 (10), 115 (16), 76 (19). Anal. Calcd
for C22H21NO3: C, 76.06; H, 6.09; N, 4.03. Found: C, 76.19; H, 6.15;
N, 4.12%.
2-(3',4'-Dimethoxybenzylidene)-2,3,4,9-tetrahydro-7-
methylcarbazol-1-one (2b): Yellow solid (1.49 g, 86%), m.p. 103–
105°C. IR: νmax 3264, 2927, 2855, 1637, 1580, 1254, 802 cm-1.
1H NMR: d 8.85 (b s, 1H, N9–H), 7.74 (s, 1H, C2–H), 7.53 (d,
1H, C5'–H, J = 8.16 Hz), 7.21 (s, 1H, C2'–H), 7.08 (d, 1H, C5–H,
J = 7.64 Hz), 7.01 (d, 1H, C6–H, J = 7.64 Hz), 6.98 (s, 1H, C8–H),
6.91(d, 1H, C6'–H, J = 8.16 Hz), 3.93 (s, 3H, C3'–OCH3), 3.85 (s, 3H,
C4'–OCH3), 3.30–3.08 (m, 4H, C3–H2, C4–H2), 2.48 (s, 3H, C7–CH3).
MS: m/z (%) 347 (M+, 100), 332 (20), 269 (16), 212 (19), 195 (16),
183 (22), 169 (11), 115 (20), 76 (10). Anal. Calcd for C22H21NO3: C,
76.06; H, 6.09; N, 4.03. Found: C, 76.10; H, 6.05; N, 4.01%.
2-(3',4'-Dimethoxybenzylidene)-2,3,4,9-tetrahydro-8-
methylcarbazol-1-one (2c): Yellow solid (1.63 g, 94%), m.p. 145–
147°C. IR: νmax 3237, 2924, 2847, 1643, 1583, 1251, 807 cm-1.
1H NMR: d 8.94 (b s, 1H, N9–H), 7.77 (s, 1H, C2–H), 7.52 (d, 1H, C5'–
H, J = 7.64 Hz), 7.21–7.18 (m, 2H, C5–H, C6–H), 7.09 (s, 1H, C2'–
H), 6.96 (d, 1H, C7–H, J = 8.04 Hz), 6.92 (d, 1H, C6'–H, J = 7.64 Hz),
3.94 (s, 3H, C3'–OCH3), 3.90 (s, 3H, C4'–OCH3), 3.32–3.09 (m, 4H,
C3–H2, C4–H2), 2.52 (s, 3H, C8–CH3). MS: m/z (%) 347 (M+, 86), 332
(11), 302 (14), 272 (19), 196 (16), 183 (20), 137 (18), 115 (16), 107
(11), 86 (17).Anal. Calcd for C22H21NO3: C, 76.06; H, 6.09; N, 4.03.
Found: C, 76.21; H, 5.98; N, 4.07%.
Amino derivatives of carbazoles have potential to be
significantly active in the treatment of both Alzheimer’s
disease and cancer.28 Incorporation of amino of groups into
the carbazole systems would enhance the hydrophilicity of
the molecules and therefore increase their water solubility.29
In addition to this, a large number of reports are available in
which heterocyclic pyrimidines with an amino group have
pharmacological as well as chemotherapeutic properties;30
we therefore decided to synthesise several new amino
substituted pyrimidocarbazoles. To achieve our target we
treated the 2-(3',4'-dimethoxybenzylidene)-6-methyl-2,3,4,9-
tetrahydrocarbazol-1-one (2a) with guanidine nitrate in
the presence of sodium hydride/benzene under reflux for
about 18 h, to afford 2-amino-4-(3',4'-dimethoxyphenyl)-
8-methylpyrimido[4,5-a]carbazole (6a) in 69% yield after
purification through a silica gel column. The IR spectrum
showed absorptions at 3443, 3189 and 3157 cm-1 which were
1
assigned to N–H and NH2 groups. The H NMR spectrum
showed a broad singlet at d 9.55 due to the presence of the
NH group. The disappearance of the methylene protons in the
aliphatic region and the appearance of further peaks in the
aromatic region clearly indicated that the system was fully
aromatised. From a broad singlet at d 5.42 we inferred the
presence of an amino group in the substrate. Methoxy and
methyl protons appeared as singlets in their respective regions.
The elemental analysis and mass spectral data were compatible
with the molecular formula C23H20N4O2. A series of similar
reactions were carried out with 2b–e and similar results were
obtained. Mechanistically the amino group of the guanidine
nitrate reacts with the carbonyl group of the enone to give the
Schiff’s base which subsequently undergoes intramolecular
1,4-Michael addition followed by aerial oxidation in presence
of NaH/benzene to yield the aromatised product 6. It should
be noted that we have carried out a relatively similar type of
reaction with CH3ONa/EtOH and in that case we isolated 5,6-
dihydropyrimidines31 but in the present case we obtained the
fully aromatised product.
2-(3',4'-Dimethoxybenzylidene)-2,3,4,9-tetrahydrocarbazol-1-one
(2d): Yellow solid (1.53 g, 92%), m.p. 108–111°C. IR: νmax 3240,
2925, 2843, 1643, 1587, 1258, 1022, 805 cm-1. 1H NMR: d 8.87
(b s, 1H, N9–H), 7.75 (s, 1H, C2–H), 7.68 (d, 1H, C5'–H, J = 8.16
Hz), 7.39–7.10 (m, 4H, C5, C6, C7, C8–H), 6.99 (s, 1H, C2'–H), 6.92
(d, 1H, C6'–H, J = 8.16 Hz), 3.95 (s, 3H, C3'–OCH3), 3.92 (s, 3H,
C4'–OCH3), 3.31–3.09 (m, 4H, C3–H2, C4–H2). MS: m/z (%) 333
(M+, 100), 302 (16), 271 (18), 257 (10), 195 (12), 182 (13), 137 (16),
114 (26), 105 (22), 77 (18). Anal. Calcd for C21H19NO3: C, 75.66; H,
5.74; N, 4.20. Found: C, 75.40; H, 5.85; N, 4.09%.
6-Chloro-2-(3',4'-dimethoxybenzylidene)-2,3,4,9-tetrahydro-
carbazol-1-one (2e): Yellow solid (1.63 g, 89%), m.p. 117–119°C.
In conclusion, pyrazolo[3,4-a]-, isoxazolo[3,4-a], pyrido
[2,3-a]- and pyrimido[4,5-a]- carbazoles were synthesised
from the newly developed synthons 2-(3',4'-dimethoxy-
1
IR: νmax 3252, 2923, 2851, 1640, 1584, 1252, 803 cm-1. H NMR:
d 8.96 (b s, 1H, N9–H), 7.76 (s, 1H, C2–H), 7.38 (s, 1H, C2'–H), 7.64
(d, 1H, C5'–H, J = 8.32 Hz), 7.34 (d, 1H, C6'–H, J = 8.32 Hz), 7.10
(d, 1H, C7 –H, Jm = 1.92 Hz, Jo = 8.16 Hz), 7.01 (s, 1H, C5–H), 6.94
(d, 1H, C8–H, J = 8.16 Hz), 3.94 (s, 3H, C3'–OCH3), 3.92 (s, 3H,
C4'–OCH3), 3.30–3.08 (m, 4H, C3–H2, C4–H2). MS: m/z (%) 369/367
(M+, 31/100), 332 (19), 302 (13), 272 (26), 197 (19), 183 (21), 169
(18), 115 (22), 103(11), 77 (12). Anal. Calcd for C21H18ClNO3: C,
68.57; H, 4.93; N, 3.81. Found: C, 68.45; H, 4.85; N, 3.92%.
benzylidene)-2,3,4,9-tetrahydrocarbazol-1-ones
2,
thus
opening an easy access to fused carbazoles with hoped-for
biological and pharmacological activities. Compound 2d was
also analysed by single crystal X-ray diffraction, providing
knowledge of the exact geometry of the molecule.
Experimental
Preparation of 3-(3',4'-dimethoxyphenyl)-2,3,3a,4,5,10-hexahydro-
pyrazolo[3,4-a]carbazoles (3): general procedure
Melting points were determined using a Mettler FP 51 apparatus
(Mettler Instruments, Switzerland). IR spectra were recorded using
KBr pellets on
(Shimadzu, Japan). NMR spectra were recorded in CDCl3 on a
Varian AMX 400 FT-NMR (Varian Australia) using TMS as internal
standard. Mass spectra were recorded on a JEOL-D-300 mass
spectrometer. Microanalyses were done on a Vario EL III model
CHNS analyser (Vario, Germany). The purity of the products was
tested by TLC using plates coated with silica gel G using petroleum
ether and ethyl acetate (85:15) as eluent.
The respective 2-(3',4'-dimethoxybenzylidene)-2,3,4,9-tetrahydro-
carbazol-1-one (2a–e, 0.001 mol) was dissolved in absolute ethanol
(20 ml). Hydrazine hydrate (0.5 ml, 0.01 mol) was added to this
mixture, which was then refluxed for 6 h, while the progress of the
reaction was monitored by TLC. After completion of the reaction,
the solvent was removed under reduced pressure. The crude mixture
was poured into ice cold water and extracted with ethyl acetate,
then washed with water and the combined organic layers dried over
anhydrous sodium sulfate. Evaporation of the solvent followed
by silica gel column chromatography using petroleum ether: ethyl
acetate (95:5) as eluent yielded 2,3,3a,4,5,10-hexahydro-3-(3',4'-
dimethoxyphenyl)pyrazolo[3,4-a]carbazole (3a–e). The product was
recrystallised from ethanol.
a Shimadzu FTIR-8201PC spectrophotometer
Preparation of 2-(3',4'-dimethoxybenzylidene)-2,3,4,9-tetrahydro-
carbazol-1-ones (2): general procedure
An equimolar mixture of the respective substituted 2,3,4,9-
tetrahydrocarbazol-1-one (1a–e, 0.005 mol) and 3,4-dimethoxy-
benzaldehyde (0.005 mol) was treated with 5% ethanolic potassium
hydroxide (25 ml) and stirred for 24 h at room temperature. The
product, precipitating as a yellow crystalline mass, was filtered
off and washed with 50% ethanol. A further crop was obtained
on neutralisation with acetic acid and dilution with water. The
product was recrystallised from methanol to yield the 2-(3',4'-
dimethoxybenzylidene)-2,3,4,9-tetrahydrocarbazol-1-ones (2a–e).
2-(3',4'-Dimethoxybenzylidene)-2,3,4,9-tetrahydro-6-
methylcarbazol-1-one (2a): Yellow solid (1.56 g, 90%), m.p. 110–
3-(3',4'-Dimethoxyphenyl)-2,3,3a,4,5,10-hexahydro-7-methylpyrazolo
[3,4-a]carbazole (3a): Yellow solid (0.270 g, 75%), m.p. 155–157°C.
1
IR: νmax 3440, 1596, 1515, 1456, 1358, 1262, 805 cm-1. H NMR:
d 8.60 (b s, 1H, N10–H), 7.31 (d, 1H, C5'–H, J = 8.52 Hz), 7.29 (s,
1H, C2'–H), 7.14(d, 1H, C6'–H, J = 8.52 Hz), 6.77 (d, 1H, C8 –H,
J = 8.40 Hz), 6.61 (d, 1H, C9–H, J = 8.40 Hz), 6.59 (s,1H, C6–H),
5.66 (b s,1H, pyrazolo NH), 3.97 (s, 3H, C3'–OCH3), 3.95 (s, 3H,
C4'–OCH3), 3.10 (m, 1H, C3–H2), 2.89 (m, 2H, C5–H2), 2.78 (m,
1H, C3a–H), 2.52 (m, 2H, C4–H2), 2.47 (s, 3H, C7-CH3). MS: m/z (%)
361(M+, 82), 346 (23), 224 (27), 218 (14), 197 (24), 168 (11), 143

576 JOURNAL OF CHEMICAL RESEARCH 2008
(15), 107 (14), 91 (19).Anal. Calcd for C22H23N3O2: C, 73.11; H,
6.47; N, 11.63. Found: C, 73.09; H, 6.35; N, 11.52%.
H), 3.78 (s, 3H, C3'–OCH3), 3.77 (s, 3H, C4'–OCH3), 3.02 (m, 2H,
C4–H2), 2.78 (m, 2H, C5–H2), 2.50 (s, 3H, C9–CH3). MS: m/z (%)
360 (M+,100), 345 (19), 307 (18), 268 (17), 237 (14), 211 (18), 114
(18), 103 (10). Anal. Calcd for C22H20N2O3: C, 73.32; H, 5.59; N,
7.77. Found: C, 73.17; H, 5.46; N, 7.61%.
3-(3',4'-Dimethoxyphenyl)-4,5-dihydroisoxazolo[3,4-a]carbazole
(4d): Pale yellow solid (0.261 g, 75%), m.p. 194–196°C. IR: νmax
3431, 1601, 1515, 1456, 1358, 1142, 795 cm-1. 1H NMR: d 9.85 (b s,
1H, N10–H), 7.62–6.91 (m, 7H, C6, C7, C8, C9, C2', C5', C6'–H), 3.83
(s, 3H, C3'–OCH3), 3.81 (s, 3H, C4'–OCH3), 2.95 (m, 2H, C4–H2),
2.19 (m, 2H, C5–H2). MS: m/z (%) 346 (M+, 100), 315 (14), 301 (11),
284 (17), 167 (18), 119 (17), 115 (10), 76 (11), 43 (14). Anal. Calcd
for C21H18N2O3: C, 72.82; H, 5.24; N, 8.09. Found: C, 72.97; H,
5.36; N, 8.21%.
3-(3',4'-Dimethoxyphenyl)-2,3,3a,4,5,10-hexahydro-8-methyl-
pyrazolo[3,4-a]carbazole (3b): Pale yellow solid (0.249 g, 69%),
m.p. 159–161°C. IR: νmax 3390, 1617, 1513, 1336, 1261, 806 cm-1.
1H NMR: d 8.72 (b s, 1H, N10–H), 7.74 (d, 1H, C5'–H, J = 8.04 Hz),
7.51 (s, 1H, C2'–H), 7.42 (d, 1H, C6'–H, J = 8.04 Hz), 6.92 (d, 1H,
C6 –H, J = 7.08 Hz), 6.86 (d, 1H, C7–H, J = 7.08 Hz), 6.82 (s,1H,
C9–H), 5.45 (b s, 1H, pyrazolo NH), 3.95 (s, 3H, C3'–OCH3), 3.92 (s,
3H, C4'–OCH3), 2.82 (m, 1H, C3–H), 2.74 (m, 2H, C5–H2), 2.69 (m,
1H, C3a–H), 2.65 (m, 2H, C4–H2), 2.47 (s, 3H, C8-CH3). MS: m/z (%)
361(M+, 96), 346 (24), 218 (11), 195 (13), 197 (22), 168 (16), 115
(10), 103 (11). Anal. Calcd for C22H23N3O2: C, 73.11; H, 6.47; N,
11.63. Found: C, 73.04; H, 6.45; N, 11.71%.
3-(3',4'-Dimethoxyphenyl)-2,3,3a,4,5,10-hexahydro-9-methyl-
pyrazolo[3,4-a]carbazole (3c): Pale yellow solid (0.252 g, 70%),
m.p. 141–143°C. IR: νmax 3424, 1597, 1513, 1377, 1263, 1026 cm-1.
1H NMR: d 8.89 (b s, 1H, N10–H), 8.01 (s, 1H, C2'–H), 7.76–6.89 (m,
5H, C6,C7, C8, C5', C6'–H), 5.60 (b s, 1H, pyrazolo NH), 3.88 (s, 3H,
C3'–OCH3), 3.85 (s, 3H, C4'–OCH3), 2.95–2.83 (m, 6H, C3–H, C3a–
H, C4–H2, C5–H2), 2.52 (s, 3H, C9–CH3). MS: m/z (%) 361(M+, 100),
346 (19), 312 (10), 276 (18), 210 (17), 195 (22), 114 (11), 107 (14),
91 (12). Anal. Calcd for C22H23N3O2: C, 73.11; H, 6.47; N, 11.63.
Found: C, 73.21; H, 6.52; N, 11.54%.
7-Chloro-3-(3',4'-dimethoxyphenyl)-4,5-dihydroisoxazolo[3,4-a]
carbazole (4e): Pale yellow solid (0.254 g, 67%), m.p. 119–121°C.
IR: νmax 3423, 1609, 1514, 1455, 1358, 1262, 1024, 804 cm-1.
1H NMR: d 9.86 (b s, 1H, N10–H), 7.64-6.86 (m, 6H, C6, C8, C9, C2',
C5', C6'–H), 3.91 (s, 3H, C3'–OCH3), 3.89 (s, 3H, C4'–OCH3), 3.08
(m, 2H, C4–H2), 2.91 (m, 2H, C5–H2). MS: m/z (%) 382/380 (M+,
12/47), 351 (12), 345 (13), 243 (19), 209 (12), 195 (14), 167(15), 107
(20), 43 (12). Anal. Calcd for C21H17 ClN2O3: C, 66.23; H, 4.50; N,
7.36. Found: C, 66.37; H, 4.56; N, 7.27%.
3-(3',4'-Dimethoxyphenyl)-2,3,3a,4,5,10-hexahydropyrazolo
[3,4-a]carbazole (3d): Pale yellow solid (0.236 g, 68%), m.p. 137–
139°C. IR: νmax 3313, 1620, 1531, 1456, 1378, 1265, 1025, 806 cm-1.
1H NMR: d 9.04 (b s, 1H, N10–H), 8.82 (s, 1H, C2'–H), 7.73–6.94 (m,
6H, C6,C7, C8, C9, C5', C6'–H), 5.72 (b s, 1H, pyrazolo NH), 3.89 (s, 3H,
C3'–OCH3), 3.86 (s, 3H, C4'–OCH3), 2.95-2.63 (m, 6H, C3–H, C3a–H,
C4–H2, C5–H2). MS: m/z (%) 347 (M+, 100), 286 (16), 210 (20), 168
(14), 137 (24), 114 (18), 105 (11), 78 (17).Anal. Calcd for C21H21N3O2:
C, 72.60; H, 6.09; N, 12.10. Found: C, 72.41; H, 6.05; N, 12.17%.
7-Chloro-3-(3',4'-dimethoxyphenyl)-2,3,3a,4,5,10-hexahydro-
pyrazolo[3,4-a]carbazole (3e): Yellow solid (0.243 g, 64%), m.p.
143–145°C. IR: νmax 3414, 1617, 1513, 1454, 1379, 1025, 1144, 807
Preparation of 4-(3',4'-dimethoxyphenyl)-2-ethoxy-5,6-dihydropyrido
[2,3-a]carbazole-3-carbonitriles (5): general procedure
A solution of the respective 2-(3',4'-dimethoxybenzylidene)-2,3,4,9-
tetrahydrocarbazol-1-one (2a–e, 1 mmol) in dry ethanol (20 ml) was
added to an ice-cooled solution of sodium hydride (1.00 g, degreased
with petroleum ether) in dry benzene (10 ml). To this mixture
malononitrile (5 mmol) was added and the mixture was refluxed on a
water bath for five hours. After the reaction was complete, the excess
of solvent was removed by distillation and the mixture was poured
into ice-water. The reaction mixture was then neutralised with ice-
cold 6N HCl and extracted with ethyl acetate (3 ¥ 50 ml). The organic
layer was thoroughly washed with water and dried over anhydrous
sodium sulfate. Upon removal of the solvent a brown crude mixture
was obtained. It was purified by column chromatography over silica
gel using petroleum ether: ethyl acetate (95:5) mixture as eluent to
afford 4-(3',4'-dimethoxyphenyl)-2-ethoxy-5,6-dihydropyrido[2,3-a]
carbazole-3-carbonitrile (5) as the product, which was recrystallised
from ethanol to obtain yellow prisms.
1
cm-1. H NMR: d 8.98 (b s, 1H, N10–H), 8.74 (s, 1H, C2'–H), 7.94–
6.89 (m, 5H, C6, C8, C9, C5', C6'–H), 5.72 (b s, 1H, pyrazolo NH),
3.86 (s, 3H, C3'–OCH3), 3.84 (s, 3H, C4'–OCH3), 3.34-3.05 (m, 6H,
C3–H, C3a–H, C4–H2, C5–H2), MS: m/z (%) 383/381 (M+, 18/62), 346
(27), 319 (20), 210 (12), 195 (24), 114 (11), 91 (19). Anal. Calcd for
C21H20 ClN3O2: C, 66.05; H, 5.28; N, 11.00. Found: C, 65.91; H, 5.15;
N, 11.11%.
4-(3',4'-Dimethoxyphenyl)-2-ethoxy-5,6-dihydro-8-methylpyrido
[2,3-a]carbazole-3-carbonitrile (5a): Yellow prisms (0.325 g, 74%),
m.p. 203–205°C. IR: νmax 3330, 2214, 1595, 1454, 1368, 1024,
804 cm-1. 1H NMR: d 8.75 (b s, 1H, N11–H), 7.44 (d, 1H, C9–H,
Jm = 1.97 Hz, Jo = 8.68 Hz), 7.35 (s, 1H, C2'–H), 7.14 (d, 1H, C6'–H,
J = 7.20 Hz), 7.05 (d, 1H, C10–H, J = 8.68 Hz), 6.95 (d, 1H, C5'–H,
J = 7.20 Hz), 6.87 (s, 1H, C7–H), 4.64 (q, 2H, C2–OCH2CH3,
J = 7.04 Hz), 3.93 (s, 3H, C3'–OCH3), 3.89 (s, 3H, C4'–OCH3), 2.91-
2.85 (m, 4H, C5–H2, C6–H2), 2.45 (s, 3H, C8–CH3), 1.52 (t, 3H, C2–
OCH2CH3, J = 7.04 Hz). MS: m/z (%) 439 (M+,100), 424 (16), 302
(19), 288 (21), 277 (14), 233 (17), 219 (12), 181 (18), 167 (11), 114
(20). Anal. Calcd for C27H25N3O3: C, 73.78; H, 5.73; N, 9.56. Found:
C, 73.67; H, 5.85; N, 9.60%.
4-(3',4'-Dimethoxyphenyl)-2-ethoxy-5,6-dihydro-9-methylpyrido
[2,3-a]carbazole-3-carbonitrile (5b): Yellow solid (0.308 g, 70%),
m.p. 106–108°C. IR: νmax 3328, 2217, 1588, 1355, 1213, 798 cm-1.
1H NMR: d 8.64 (b s, 1H, N11–H), 7.46 (d, 1H, C7 –H, J = 7.76 Hz),
7.36 (s, 1H, C2'–H), 7.15 (d, 1H, C5'–H, J = 8.60 Hz), 7.01 (d, 1H,
C6'–H, J = 8.60 Hz), 6.99 (s, 1H, C10–H), 6.85 (d, 1H, C8–H, J = 7.76
Hz), 4.59 (q, 2H, C2–OCH2CH3, J = 7.16 Hz), 3.93 (s, 3H, C3'–
OCH3), 3.91 (s, 3H, C4'–OCH3), 2.93–2.88 (m, 4H, C5–H2, C6–H2),
2.49 (s, 3H, C9-CH3), 1.56 (t, 3H, C2–OCH2CH3, J = 7.16 Hz). MS: m/z
(%) 439 (M+,100), 424 (22), 372 (14), 288 (12), 274 (14), 226 (18),
219 (18), 181 (12), 107 (10). Anal. Calcd for C27H25N3O3: C, 73.78;
H, 5.73; N, 9.56. Found: C, 73.87; H, 5.81; N, 9.49%.
4-(3',4'-Dimethoxyphenyl)-2-ethoxy-5,6-dihydro-10-methylpyrido
[2,3-a]carbazole-3-carbonitrile (5c): Yellow prisms (0.335 g, 76%),
m.p. 109–111°C. IR: νmax 3430, 2218, 1596, 1358, 1258, 1022 cm-1.
1H NMR: d 8.59 (b s, 1H, N11–H), 7.33–7.26 (m, 3H, C7, C8, C9–H),
7.06 (d, 1H, C6'–H, J = 8.04 Hz), 6.93 (d, 1H, C5'–H, J = 8.04 Hz),
6.85 (s, 1H, C2'–H), 4.61 (q, 2H, C2–OCH2CH3, J = 7.00 Hz), 3.95 (s,
3H, C3'–OCH3), 3.93 (s, 3H, C4'–OCH3), 2.96–2.89 (m, 4H, C5–H2,
C6–H2), 2.58 (s, 3H, C10–CH3),1.53(t,3H,C2–OCH2CH3,J = 7.00 Hz).
MS: m/z (%) 439 (M+, 76), 380 (16), 355 (11), 288 (14), 212 (14),
195 (10), 181 (17), 114 (11). Anal. Calcd for C27H25N3O3: C, 73.78;
H, 5.73; N, 9.56. Found: C, 73.48; H, 5.59; N, 9.42%.
Preparation of 3-(3',4'-dimethoxyphenyl)-4,5-dihydroisoxazolo[3,4-a]
carbazoles (4): general procedure
The respective 2-(3',4'-dimethoxybenzylidene)-2,3,4,9-tetrahydro-
carbazol-1-one (2a–e, 0.001 mol) was treated with hydroxylamine
hydrochloride (1 g, 0.014 mol) in pyridine (5 ml) at 130°C for 8 h.
After completion of the reaction, the crude mixture was poured into
ice cold water and neutralised with 5N HCl, and the resulting semi-
solid separated was extracted with chloroform. The combined organic
layers were dried over anhydrous sodium sulfate. After the removal
of solvent it was purified by silica gel column chromatography using
petroleum ether:ethyl acetate (98:2) as eluent to yield 4,5-dihydro-
3-(3',4'-dimethoxyphenyl)isoxazolo[3,4-a]carbazole (4a–e). The
product thus obtained was recrystallised from ethanol.
3-(3',4'-Dimethoxyphenyl)-4,5-dihydro-7-methylisoxazolo[3,4-a]
carbazole (4a): Pale yellow solid (0.252 g, 70%), m.p. 121–123°C.
IR: νmax 3436, 1611, 1512, 1453, 1329, 1256, 1026, 789 cm-1.
1H NMR: d 9.05 (b s, 1H, N10–H), 7.52 (s, 1H, C2'–H), 7.44–6.80
(m, 5H, C6, C8, C9, C5', C6'–H), 3.86 (s, 3H, C3'–OCH3), 3.83 (s, 3H,
C4'–OCH3), 3.15 (m, 2H, C4–H2), 2.97 (m, 2H, C5–H2), 2.52 (s, 3H,
C7-CH3). MS: m/z (%) 360 (M+, 100), 345 (19), 223 (19), 209 (18),
137 (20), 115 (16), 103 (18), 95 (11). Anal. Calcd for C22H20N2O3: C,
73.32; H, 5.59; N, 7.77. Found: C, 73.14; H, 5.45; N, 7.67%.
3-(3',4'-Dimethoxyphenyl)-4,5-dihydro-8-methylisoxazolo[3,4-a]
carbazole (4b): Pale yellow solid (0.259 g, 72%), m.p. 132–135°C.
1
IR: νmax 3400, 1604, 1509, 1457, 1357, 1246, 759 cm-1. H NMR:
d 9.13 (b s, 1H, N10–H), 7.46–6.87 (m, 6H, C6, C7, C9, C2', C5', C6'–
H), 3.91 (s, 3H, C3'–OCH3), 3.88 (s, 3H, C4'–OCH3), 3.22 (m, 2H,
C4–H2), 2.92 (m, 2H, C5–H2), 2.47 (s, 3H, C8–CH3). MS: m/z (%)
360 (M+, 86), 345 (27), 268 (11), 214 (19), 223 (16), 209 (11), 114
(22), 87 (16). Anal. Calcd for C22H20N2O3: C, 73.32; H, 5.59; N,
7.77. Found: C, 73.11; H, 5.44; N, 7.61%.
3-(3',4'-Dimethoxyphenyl)-4,5-dihydro-9-methylisoxazolo[3,4-a]
carbazole (4c): Pale yellow solid (0.266 g, 74%), m.p. 180–182°C.
1
IR: νmax 3426, 1614, 1512, 1456, 1380, 1260, 805 cm-1. H NMR:
d 10.26 (b s, 1H, N10–H), 7.44-6.93 (m, 6H, C6, C7, C8, C2', C5', C6'–

JOURNAL OF CHEMICAL RESEARCH 2008 577
4-(3',4'-Dimethoxyphenyl)-2-ethoxy-5,6-dihydropyrido[2,3-a]
carbazole-3-carbonitrile (5d): Yellow solid (0.344 g, 81%), m.p.
212–213°C. IR: νmax 3382, 2214, 1597, 1336, 1253, 1025, 802 cm-1.
1H NMR: d 8.77 (b s, 1H, N11–H), 7.59–6.85 (m, 7H, C7, C8, C9, C10,
C2' C5', C6'–H), 4.63 (q, 2H, C2–OCH2CH3, J = 7.20 Hz), 3.95 (s, 3H,
C3'–OCH3), 3.92 (s, 3H, C4'–OCH3), 2.98–2.88 (m, 4H, C5–H2, C6–
H2), 1.51 (t, 3H, C2–OCH2CH3, J = 7.20 Hz).MS: m/z (%) 425 (M+,
100), 394 (18), 369 (12), 325 (10), 219 (16), 197 (13), 195 (11), 137
(19), 115 (14), 43 (16). Anal. Calcd for C26H23N3O3: C, 73.79; H,
5.45; N, 9.88. Found: C, 73.48; H, 5.55; N, 9.75%.
d 9.11 (b s, 1H, N11–H), 7.80–7.22 (m, 8H, C5, C6, C7, C9, C10, C2',
C5', C6'–H), 5.89 (b s, 2H, NH2), 3.88(s, 3H, C3'–OCH3), 3.86 (s, 3H,
C4'–OCH3). MS: m/z (%) 406/404 (M+, 16/54), 354 (16), 324 (37),
369 (22), 294 (11), 233 (20), 187 (14), 156 (16), 114(18). Anal. Calcd
for C22H17ClN4O2: C, 65.27; H, 4.23; N, 13.86. Found: C, 65.55; H,
4.39; N, 13.49%.
We acknowledge UGC, New Delhi, India, for the award
of Major Research Project Grant No.F.No.31-122/2005.
M.S. thanks UGC, New Delhi for the award of a research
fellowship. Our sincere thanks go to the Director, ISO Quality
Assurance Cell, IICT, Hyderabad, and the Chairman, NMR
Research Centre, IISc, Bangalore, for providing access
to their Mass and NMR spectral facilties, respectively.
The diffractometer was funded by NSF grant 0087210, by the
Ohio Board of Regents grant CAP-491, and by Youngstown
State University.
8-Chloro-4-(3',4'-dimethoxyphenyl)-2-ethoxy-5,6-dihydropyrido
[2,3-a]carbazole-3-carbonitrile (5e): Yellow solid (0.326 g, 71%),
m.p. 179–181°C. IR: νmax 3381, 2217, 1567, 1348, 1253, 1043,
1
801 cm-1. H NMR: d 8.25 (b s, 1H, N11–H), 7.52–6.88 (m, 6H, C7,
C9, C10, C2' C5', C6'–H), 4.62 (q, 2H, C2–OCH2CH3, J = 7.00 Hz),
3.96 (s, 3H, C3'–OCH3), 3.92 (s, 3H, C4'–OCH3), 2.79–2.74 (m, 4H,
C5–H2, C6–H2), 1.54 (t, 3H, C2–OCH2CH3, J = 7.00 Hz). MS: m/z (%)
461/459 (M+, 22/79), 424 (12), 394 (17), 369 (21), 325 (11), 269
(10), 219 (18), 137 (11), 114 (11). Anal. Calcd for C26H22ClN3O3: C,
67.90; H, 4.82; N, 9.14. Found: C, 67.68; H, 4.75; N, 9.32%.
Received 4 May 2008; accepted 20 August 2008
Paper 08/5259 doi:10.3184/030823408X361110
Published online: 10 October 2008
Preparation of 2-amino-4-(3',4'-dimethoxyphenyl)pyrimido[4,5-a]-
carbazoles (6): general procedure.
To 1.00 g of sodium hydride (degreased with petroleum ether) in
dry benzene (10 ml), the respective 2-(3',4'-dimethoxybenzylidene)-
2,3,4,9-tetrahydrocarbazol-1-one (2a–e, 1 mmol) and guanidine
nitrate (10 mmol) were added and the mixture was refluxed for
18 h. The reaction was monitored by TLC. After completion of the
reaction, the excess of solvent was boiled off and the residue was
poured onto crushed ice. The reaction mixture was then neutralised
and extracted with chloroform (3 ¥ 40 ml). The organic layer was
washed with water and dried over anhydrous sodium sulfate. Upon
removal of the solvent a brown mass was obtained. It was purified by
column chromatography over silica gel using petroleum ether:ethyl
acetate (80:20) mixture as eluent to afford a yellow solid which was
recrystallised from ethanol to yield the 2-amino-4-(3',4'-dimethoxy-
phenyl)pyrimido[4,5-a]carbazoles (6a–e).
2-Amino-4-(3',4'-dimethoxyphenyl)-8-methylpyrimido[4,5-a]
carbazole (6a): Yellow solid (0.264 g, 69%), m.p. 218–220°C. IR:
νmax 3443, 3189, 3157, 1607, 1534, 1379, 1257, 801 cm-1. 1H NMR:
d 9.55 (b s, 1H, N11–H), 7.87(d, 1H, C9–H, J = 8.72 Hz), 7.70 (d, 1H,
C10–H, J = 8.72 Hz), 7.45–7.26 (m, 6H, C7, C9, C10, C2', C5', C6'–H),
5.42 (b s, 2H, NH2), 3.99 (s, 3H, C3'–OCH3), 3.95 (s, 3H, C4'–OCH3),
2.56 (s, 3H, C8–CH3). MS: m/z (%) 384 (M+, 62), 369 (14), 360 (11),
354 (22), 298 (11), 218 (14), 195 (10), 165 (12), 114 (17). Anal.
Calcd for C23H20N4O2: C, 71.86; H, 5.24; N, 14.57. Found: C, 71.79;
H, 5.45; N, 14.32%.
References
1
2
3
D.P. Chakraborty, The Alkaloids, A. Brossi, ed., Academic Press,
New York, 1993, Vol. 44, pp. 257-282.
H.J. Knolker, Advances in nitrogen heterocycles, C.J. Moody, ed.,
JAI Press, Greenwich (CT), 1986, Vol. 1, 273.
R.S. Kapil, The Alkaloids, R.H.F. Manske, ed., Academic Press,
New York, 1971, Vol. 13, 273.
4
5
H.J. Knolker and K.R. Reddy, Chem. Rev., 2002, 102, 4303.
H. Biere, H. Ahrens, C. Rufer, E. Schroeder and H. Koch, German Pat.,
1975, 2 154 337; Chem Abstr., 1975, 82, 156 068j.
A. Mooradian, U.S. Patent, 3 959 309, 1976. Chem. Abstr., 1976,
85,123 759 s
6
7
A. Mooradian, P.E. Dupont, A.G. Hlavac, M.D. Aceto and J. Pearl, J Med
Chem., 1977, 20, 487.
8
9
D.P. Chakraborty, Tetrahedron Lett., 1966, 661.
K. Rastogi, R.S. Kapil and S.P. Popli, Phytochemistry, 1980, 19, 545.
10 E. Lescot, G. Muzard, J. Markovits, J. Belleney, B.P. Roques and
J.B. Le Pecq, J. Med. Chem., 1986, 29, 1731.
11 L.K. Dalton, S. Demerac, B.C. Elmes, J.W. Loder, J.M. Swan and
T. Teitei, Aust. J. Chem., 1967, 20, 2715.
12 G.H. Svoboda, G.A. Poore and M.L. Monfort, J. Pharm. Sci., 1968,
57, 1720.
13 M. Sainsbury, Synthesis, 1977, 43.
14 S. Blechert, R. Knier, H. Schroers and T. Wirth, Synthesis, 1995, 592.
15 G.B. Marini-Bottolo and J. Schutz, Helv. Chim. Acta, 1959, 42, 2146.
16 S. Goodwin, A.F. Smith and H.C. Horning, J. Am. Chem. Soc., 1959,
81, 1903
17 K. Hirata, C. Ito, H. Furukawa, M. Itoigawa, L.M. Cosentino and
K.H. Lee, Bioorg. Med. Chem. Lett., 1999, 9, 119.
18 A. Agarwal, S.K. Agarwal and D.S. Bhakuni, Indian J. Chem., 1992, 44,
373.
19 S. Mahboobi, S. Kuhr and M. Koller, Tetrahedron, 1993, 34, 1347.
20 D. Joseph, L. Martello and G. Kirsch, J. Chem. Res., (S), 1995, 350;
J. Chem. Res., (M), 1995, 2001.
21 D. Sowmithran and K.J. Rajendra Prasad, Heterocycles, 1986, 24, 711.
22 R. Balamurali and K.J. Rajendra Prasad, Indian J. Chem., 2001, 40B,
139.
23 T. Vandana and K.J. Rajendra Prasad, Indian J. Chem., 2003, 42B, 3131.
24 I.A. Danish and K.J. Rajendra Prasad, Z. Naturforsch., 2004, 59b, 106.
25 Bruker Advanced X-ray Solutions, Apex2 v2.1-4, Bruker AXS Inc.,
Madison, Wisconsin, USA, 2000.
26 Bruker Advanced X-ray Solutions SHELXTL (Version 6.14), Bruker AXS
Inc., Madison, Wisconsin: USA, 2000-2003.
27 A.K. Shanazarov, V.G. Granik, N.I. Andreeva, S.M. Golovina, and
M.D. Mashkovskii, Pharm. Chem. J., 1989, 23, 807.
28 J.T. Klein, L. Davis, G.E. Oslen, G.S. Wong, F.P. Huger, C. Smith
W. Petko, M. Cornfeldt, J.C. Wilker, R.D. Blitzer, E. Landau,
V.H. Lawrence, L. Martin and R.C. Effland, J. Med. Chem., 1996,
39, 570.
29 C. Ducrocq, F. Wendling, M. Toyrbez-Perrin, C. Rivalle, P. Tambourin,
F. Pochon, E. Bisagni and J.C. Chermann, J. Med. Chem., 1980, 23,1212.
30 S. Kothari, M. Singhal, D. Vijayvexgia, R. Vyas and B.L. Verma, J. Indian
Chem. Soc., 2000, 77, 329.
2-Amino-4-(3',4'-dimethoxyphenyl)-9-methylpyrimido[4,5-a]
carbazole (6b): Yellow solid (0.253 g, 69%), m.p. 222–225°C.
IR: νmax 3374, 3204, 3194, 1598, 1380, 1259, 1027, 758 cm-1.
1H NMR: d 8.98 (b s, 1H, N11–H), 8.01–7.06 (m, 8H, C5, C6, C7, C8,
C10, C2', C5', C6'–H), 5.56 (b s, 2H, NH2), 3.91 (s, 3H, C3'–OCH3),
3.89 (s, 3H, C4'–OCH3), 2.58 (s, 3H, C9–CH3). MS: m/z (%) 384 (M+,
100), 369 (22), 354 (19), 294 (18), 218 (11), 195 (16), 165 (14), 114
(11), 54 (15). Anal. Calcd for C23H20N4O2: C, 71.86; H, 5.24; N,
14.57. Found: C, 71.43; H, 5.35; N, 14.39%.
2-Amino-4-(3',4'-dimethoxyphenyl)-10-methylpyrimido[4,5-
a]carbazole (6c): Yellow solid (0.276 g, 72%), m.p. 212–214°C.
1
IR: νmax 3371, 3150, 3142, 1604, 1384, 1258, 807 cm-1. H NMR:
d 8.92 (b s, 1H, N11–H), 7.98–7.25 (m, 8H, C5, C6, C7, C8, C9, C2',
C5', C6'–H), 5.59 (b s, 2H, NH2), 3.99 (s, 3H, C3'–OCH3), 3.96 (s, 3H,
C4'–OCH3), 2.68 (s, 3H, C10–CH3). MS: m/z (%) 384 (M+, 100), 376
(27), 369 (12), 276 (15), 233 (34), 197 (10), 195 (16), 114 (10). Anal.
Calcd for C23H20N4O2: C, 71.86; H, 5.24; N, 14.57. Found: C, 71.95;
H, 5.34; N, 14.49%.
2-Amino-4-(3',4'-dimethoxyphenyl)pyrimido[4,5-a]carbazole (6d):
Yellow solid (0.240 g, 65%), m.p. 138–140°C. IR: νmax 3435, 3172,
1
3166, 1595, 1457, 1259, 754 cm-1. H NMR: d 9.01 (b s, 1H, N11–
H), 7.88–7.20 (m, 9H, C5, C6, C7, C8, C9, C10, C2', C5', C6'–H), 5.92
(b s, 2H, –NH2), 3.96(s, 3H, C3'–OCH3), 3.94 (s, 3H, C4'–OCH3).
MS: m/z (%) 370 (M+, 100), 354 (26), 339 (16), 309 (21), 233 (11),
218 (18), 195 (12), 176 (14), 115 (19), 104 (17), 79 (10). Anal. Calcd
for C22H18N4O2: C, 71.34; H, 4.90; N, 15.13. Found: C, 71.55; H,
5.01; N, 14.98%.
2-Amino-8-chloro-4-(3',4'-dimethoxyphenyl)pyrimido[4,5-a]
carbazole (6e): Yellow solid (0.251 g, 62%), m.p. 189–191°C. IR:
νmax 3439, 3186, 3182, 1593, 1459, 1383, 1043, 804 cm-1. 1H NMR:
31 T. Vandana and K.J. Rajendra Prasad, Heterocyclic Comm., 2003, 9, 579.