Selective synthesis and X-ray structural analysis of a pyridocarbazole derivative

Article abstract of DOI:10.1007/s10870-010-9801-z

Pyridocarbazole possesses many biological activities such as antimicrobial and antitumor properties. It also serves as a selective inhibitor for cyclic GMP phosphodiesterase (cGMP-PDE) enzyme. Since it is very similar to ellipticine and olivacine, its derivatives are endowed with DNA intercalating properties. One of the pyridocarbazoles, MCDDC, has been synthesized and its stereochemistry has been proven by X-ray crystallographic study. The crystal belongs to the monoclinic space group, P2₁/a, with cell parameters a = 11.771(3) A, b = 14.557(3) A, c = 11.869(1) A and β = 101.80(2)°. According to the X-ray structure, the entire MCDDC molecule adopts a planar conformation except for the dichlorophenyl ring, which is almost orthogonal to the pyridine ring. Molecules are tightly bound by the N-H???N type hydrogen bonds and weak C-H???π interactions also help in packing stabilization. Graphical Abstract: One of the pyridocarbazoles, MCDDC, has been synthesized and its selectivity has been proved by X-ray crystallographic study. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10870-010-9801-z

J Chem Crystallogr (2010) 40:1094–1098
DOI 10.1007/s10870-010-9801-z
ORIGINAL PAPER
Selective Synthesis and X-Ray Structural Analysis
of a Pyridocarbazole Derivative
•
N. Sampath Rita Mathews M. N. Ponnuswamy
•
Received: 5 May 2009 / Accepted: 20 May 2010 / Published online: 11 June 2010
Ó Springer Science+Business Media, LLC 2010
Abstract Pyridocarbazole possesses many biological
activities such as antimicrobial and antitumor properties. It
also serves as a selective inhibitor for cyclic GMP phos-
phodiesterase (cGMP-PDE) enzyme. Since it is very sim-
ilar to ellipticine and olivacine, its derivatives are endowed
with DNA intercalating properties. One of the pyridocar-
bazoles, MCDDC, has been synthesized and its stereo-
chemistry has been proven by X-ray crystallographic study.
The crystal belongs to the monoclinic space group, P21/a,
molecules are available in many natural products, which
are found to possess a broad range of pharmacological
properties such as anti-microbial, anti-inflammatory and
anti-implantation activities [1]. Carbazole is one of its
derivatives and it has many interesting chemical and bio-
logical activities [2]. Carbazole derivatives are widely used
in many areas of biological sciences and it has recently
been reported that oxygen substituted carbazole rings have
an increased biological activity [3]. Benzo- and pyrido-
annellated carbazoles are pharmacologically interesting
owing to their potential anti-tumour activity due to their
planar conformation. In addition to these properties the
trimers of carbazoles are useful in photo-refractive appli-
cations [4]. Pyridocarbazoles have gained an important
place in medicinal chemistry due to their anticancer and
DNA-intercalating properties.
˚
with cell parameters a = 11.771(3) A, b = 14.557(3) A,
˚
˚
c = 11.869(1) A and b = 101.80(2)°. According to the
X-ray structure, the entire MCDDC molecule adopts a
planar conformation except for the dichlorophenyl ring,
which is almost orthogonal to the pyridine ring. Molecules
are tightly bound by the N–HÁÁÁN type hydrogen bonds and
weak C–HÁÁÁp interactions also help in packing stabilization.
Compounds which have a pyridocarbazole skeleton
exhibit extremely high isozyme selectivity for inhibiting
phosphodiesterase (PDE) type V and animal model testing
has shown them to have extremely low toxicity and only
limited side effects [5]. So these skeleton compounds are
expected to be particularly effective in preventing and/or
treating pulmonary hypertension, ischemic heart diseases
or other diseases against which the cGMP-PDE inhibitory
action is effective [5]. ‘‘Pulmonary hypertension’’ is a
generic term for various diseases that manifest hyperten-
sion in the pulmonary artery. Approaches to synthesize
substituted carbazoles are of special interest and con-
temporary importance since the carbazole alkaloids show
anti-viral and cytotoxic properties against the consump-
tion of sclerotia by insects [6, 7]. Due to their pharma-
ceutical importance, the need arose to develop novel
strategies for the synthesis of nitrogen bearing heterocy-
cles. The chemical diagram of the molecule MCDDC is
shown in Fig. 1.
Keywords Pyridocarbazole Á Hydrogen bonds Á
Conformation Á Crystal structure Á C–HÁÁÁp
Introduction
Indole ring is an important scaffold which is found in many
pharmacological and medicinal compounds. Such
N. Sampath (&) Á R. Mathews
Department of Advanced Technology Fusion,
Konkuk University, 1 Hwayang dong, Gwangjin-gu,
Seoul 143-701, Korea
e-mail: sampath@konkuk.ac.kr; sams76@gmail.com
M. N. Ponnuswamy (&)
Department of Crystallography and Biophysics, University
of Madras, Guindy Campus, Chennai 600 025, India
e-mail: mnpsy@hotmail.com
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J Chem Crystallogr (2010) 40:1094–1098
1095
(2-methoxy-3-cyano-4-(2,6-dichlorophenyl)-5,6-dihydropyr-
ido [2,3a] carbazole) in powder form with 72–81% of yield
[8]. The same result was derived by microwave irradiation
also over a conical flask for 2 min.
E
Cl
Cl
C
N
D
A
B
Cl
N
(7)
A
N
H
Cl
O
N
Cl
H3C
N
H
OCH3
NC
Cl
CH3OH / NaOH
CH2(CN)2
Fig. 1 Chemical diagram of molecule MCDDC
H
O
N
H
Cl
(6)
Cl
CN
B
Experimental
N
N
H
OCH3
(8)
Synthesis of MCDDC
The target pyridocarbazole, MCDDC, was synthesized by
three consecutive step reactions. In the first step, tetra-
hydrocarbazolone (4) was synthesized using stoichiometric
amounts of compounds 1 and 2. The intermediate com-
pound 3 further undergoes a Fischer indole synthesis
reaction in acidic condition by 7 h reflux on a water bath.
The purified compound 4 [2, 3, 4, 9-tetrahydro-1H-car-
bazol-1-one] was used for further reaction.
X-Ray Data Collection and Reduction
A dark red color prismatic crystal of MCDDC (8) was
mounted on a glass fiber and used for data collection. Cell
parameters and an orientation matrix for data collection
were obtained by least-squares refinement of the diffraction
data from 25 reflections in an ENRAF-NONIUS CAD4
automatic diffractometer [9]. Data were collected at 293(2)
˚
O
K using Cu Ka radiation (k = 1.54184 A) and the data
N
N+
reduction was carried out by XCAD4 [10] program. The
intensity data were corrected for Lorentz and polarization
absorption effects.
O
Cl-
EtOH/ H2SO4
N
+
N
NH
Reflux for 7hrs
O
N
H
(4)
( 1)
(2)
(3)
Structure Solution and Refinement
In the next step, compound 6 {(2E)-2-[(2,6-dichlorophenyl)
methylidene]-2,3,4,9-tetrahydro-1H-carbazol-1-one} was syn-
thesized by condensation reaction using 2,6-dichlorobenz-
aldehyde and 2,3,4,9-tetrahydro-1H-carbazol-1-one (4) in
alcohol with NaOH facilitated by vigorous stirring for 6 h.
The structure was solved by direct-methods using the
program SHELXS97 [11], which revealed the position of all
non-hydrogen atoms, and refined on F2 by a full-matrix
least squares procedure using SHELXL97 [11]. All hydro-
gens were located from the difference Fourier maps and
were refined isotropically. The final cycle refinement
converged to R = 0.0761 and wR = 0.2142 for the
observed reflections. The maximum and minimum heights
in the final difference Fourier map were found to be 0.540
Cl
H
O
Cl
EtOH/ NaOH
H
Cl
Cl
+
O
N
H
O
N
H
Stirred for 6hrs
and -0.807 e A-3, respectively. Least-squares planes and
(6)
˚
(4)
(5)
asymmetry calculations were done using the program
PARST97 [12]. The thermal ellipsoid plot and packing
were done using ORTEP [13, 14] and PLATON [15]. Non-
bonded interaction graphics were created using the pro-
gram MERCURY [16]. The crystallographic data and
methods of data collection, solution and refinement are
shown in Table 1 and the selected bond lengths and angles
are presented in Table 2. Other relevant details are inclu-
ded in the deposited material (CCDC), as a complete list of
bond distances and angles.
Finally, the target pyridocarbazole (MCDDC) was
synthesized by refluxing a solution of 2-benzylidene-2,3,
4,9-tetrahydrocarbazole-1-ones (6, 2 mmol), malononitrile
(2 mmol) and catalytic amount of sodium hydroxide
(50 mg) in dry methanol (10–15 mL) for 30 min. After the
completion of the reaction (as evidenced by the red pre-
cipitates) the precipitates were collected and washed with
water followed by cold ethanol. The crude products were
recrystallized using ethanol to get the pure MCDDC, 8
123

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J Chem Crystallogr (2010) 40:1094–1098
˚
Table 1 Crystal data and structure refinement parameters for
MCDDC
Table 2 Selected bond lengths (A) and bond angles (°) of MCDDC
Bonds
Lengths
Parameters
MCDDC
C1–C2
1.399(4)
1.414(4)
1.373(3)
1.405(3)
1.425(4)
1.488(3)
1.534(4)
1.527(3)
1.405(3)
1.498(3)
1.386(3)
1.369(3)
1.136(4)
1.731(3)
1.734(3)
128.7(2)
134.6(3)
132.9(2)
123.2(2)
108.2(2)
125.5(2)
121.6(2)
116.8(2)
117.0(2)
117.1(2)
119.1(2)
177.7(3)
120.6(2)
122.7(3)
CCDC
CCDC 702784
C23H15Cl2N3O
420.28
C1–C6
Empirical formula
Formula weight
Crystal size
Color, shape
Temperature
Wavelength (Cu Ka)
Crystal system, space group
Unit cell dimensions
a
C1–N1
C5–C6
0.35 9 0.20 9 0.15 mm
Dark red; Prism
293(2) K
C6–C7
C7–C8
C8–C9
˚
1.54184 A
C9–C10
Monoclinic, P21/a
C10–C11
C15–C18
˚
11.771(3) A
C7–C12
˚
14.557(3) A
b
C12–N1
˚
11.869(1) A
c
C16–N3
b
101.80(2)°
1990.8(7) A
4, 1.402 Mg/m3
C23–Cl1
3
˚
Volume (V)
Z, calculated density
F(000)
C19–Cl1
C2–C1–N1
C5–C6–C7
C6–C7–C8
C9–C10–C15
C1–N1–C12
N1–C12–C11
C10–C15–C18
C11–N2–C132
C12–C11–N2
C13–O1–C17
C14–C15–C18
C14–C16–N3
C15–C18–C19
C15–C18–C23
864
Theta range
Absorption coefficient
Limiting indices
3.80°–71.90°
3.090 mm-1
0 B h B 14; 0 B k B 17;
-14 B l B 14
Reflections collected/unique
Refinement method
4044/3846 [Rint = 0.0700]
Full-matrix least-squares on F2
3846/0/323
Data/restraints/parameters
Goodness-of-fit on F2
1.040
Final R-indices [I [ 2r (I)]
R-indices (all data)
R1 = 0.0761, wR2 = 0.2142
R1 = 0.0830, wR2 = 0.2246
-3
˚
0.540 and -0.807 e A
Largest diff. peak and hole
Results and Discussion
The perspective view of the molecule MCDDC (2-meth-
oxy-3-cyano-4-(2,6-dichlorophenyl)-5,6-dihydropyrido [2,
3-a]carbazole) is shown in Fig. 2. Comparison of bond
lengths and bond angles of carbazole moiety shows similar
features with literature values [17]. A study of asymmetric
least-squares plane calculations reveal that the six-mem-
bered ring C assumes half-chair conformation and is con-
firmed by the torsion angles (Scheme 1). The atoms C8 and
˚
C9 deviate, respectively, -0.253(3) and 0.218(3) A from
the best plane of rest of the atoms C10, C11, C12 and C7.
The mean plane angles of rings between B & C and C &
D are 3.5(1)° and 4.4(1)°, respectively, and confirm that all
these rings lies almost in the same plane of carbazole
moiety. Also the orientation angle between the indole and
pyridine ring is 6.7(1)°. Based on these mean plane angles
of MCDDC, it is observed that the whole molecule adopts
almost a planar conformation except for phenyl ring E,
Fig. 2 ORTEP diagram of the molecule MCDDC showing the
thermal ellipsoids at 30% probability level. Hydrogen atoms were
removed for clarity
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J Chem Crystallogr (2010) 40:1094–1098
1097
C10 [C9–C10–C15 = 123.2(2)°] and C15 [C10–C15–
C18 = 121.6(2)°].
Packing Features
The packing of the molecules viewed down the a-axis is
shown in Fig. 3. The N–HÁÁÁN and C–HÁÁÁN intermolecular
interactions play a major role in stabilizing the molecules
in the crystal packing. The linear chain contact grows along
the b-axis through N1–H1ÁÁÁN3 hydrogen bonds with
symmetry related molecules (Fig. 4). The same carbazole
NH group has another intra molecular hydrogen bonding
Scheme 1 Puckering of the ring C with its torsion angles
which is oriented approximately perpendicular to the pyr-
idine ring D [86.2(1)°]. This planar conformation of pyri-
docarbazoles may play an important role in biological
actions such as DNA intercalating and anticancer activities
as ellipticine and olivacine.
˚
(N1–H1ÁÁÁN2 = 2.843(4) A) with neighboring pyridine
In the carbazole moiety, the angles at C11, C2 and C5
are contracted [118.4(2), 116.4(3) and 118.8(3)°] while
those at C1, C12, C6 and C7 are expanded [128.7(2),
125.5(2), 134.6(3) and 132.9(2)°] due to the effect caused
by the fusion of small pyrrole ring and benzene rings [18],
and the strain is taken up by angular distortion rather than
bond length distortion. The planar carbazole ring is
inclined at an angle of 81.9(1)° to the dichlorophenyl
group. The folding along the bonds C1–C6 and C7–C12 are
described by the torsion angles [C2–C1–C6–C5=] 0.8(5)°,
[N1–C1–C6–C7=] -0.5(3)°, [C11–C12–C7–C8=] 5.3(4)°
and [N1–C12–C7–C6=] -0.4(3)°.
ring nitrogen (N2). This H-bond proves that the alternative
isomeric molecule A (Step 3) [Compound 7] is ruled out. In
addition to the van der Waals forces, a weak C–HÁÁÁp
interaction [19, 20] is observed between the ring centroid
of dichlorophenyl [C18 through C23] and a methylene
H8b, which is also supporting the stabilization of mole-
cules in the crystal packing. Relevant details of all
hydrogen bonds and weak C–HÁÁÁp interaction are given in
Table 3.
Supplementary Material
The asymmetric exocyclic groups, nitrile and methoxy
are coplanar with pyridine ring. The bond angle at C11
[C12–C11–N2 = 117.0(2)°] is comparatively smaller than
other angles. This may be due to the short contact between
Crystallographic data (excluding structure factors) for the
structure reported in this paper has been deposited
with the Cambridge Crystallographic Database Centre as
˚
the atoms N1ÁÁÁN2 [2.843(3) A] in the molecule. This non-
bonded interaction also influences the bond angles at N2
[C11–N2–C13 = 116.8(2)°] and C13 [N2–C13–C14 =
124.0(2)°]. The short contact between H9B and C18
˚
[2.72(3) A] is due to electron–electron repulsion and
thus the dichlorophenyl ring is pushed away from the
carbazole moiety. This is reflected through the angles at
Fig. 4 Linear chain view of the molecule MCDDC through the N–
HÁÁÁN hydrogen bonds along the b-axis. The yellow dashed lines
represent the hydrogen bonds
Table 3 Hydrogen bondings and possible non-bonded interactions
˚
for MCDPC (8, A)
D–HÁÁÁA
d(D–H)
d(DÁÁÁA)
d(HÁÁÁA)
\D–HÁÁÁA
N1–H1ÁÁÁN2
0.856(4)
0.870(5)
0.990(4)
1.07(4)
1.070
2.843(4)
3.067(4)
3.882(4)
3.356(4)
3.703
2.627(4)
2.23(5)
2.94(4)
2.61(4)
2.952
95.7(2)
165.6(8)
162.0(1)
128.8(6)
128
N1–H1ÁÁÁN3i
C2–H2ÁÁÁCl1ii
C8–H8BÁÁÁN3iii
C8–H8BÁÁÁCgiv
Equivalent positions: (i) -x ? 1/2 ? 1, y ? 1/2, -z ? 2;
(ii) -x ? 2, -y ? 1, -z ? 2; (iii) x ? 1/2, -y ? 1/2, z; (iv) x - 1/
2, -y ? 3/2, z
Fig. 3 Packing of the molecules MCDDC viewed down the b-axis.
Dashed lines represent hydrogen bonds
Cg is centroid of the ring C18 through C23
123

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J Chem Crystallogr (2010) 40:1094–1098
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