Synthesis and crystal structure of (4bRS,9bRS)-5-(2,4-dimethoxyphenyl)-4b, 9b-7,7-dimethyldihydroxy-4b,5,6,7,8,9b-hexahydroindeno[1,2-b] indole-9,10-dione

Article abstract of DOI:10.3184/174751911X13015834294266

A highly regiospecific synthesis and crystal structure of (4bRS,9bRS)-5-(2,4-dimethoxyphenyl)-7,7-dimethyl-4b,9bdihydroxy-4b,5,6,7,8, 9b-hexahydroindeno[1,2-b]indole-9,10-dione is reported. It was tested in vitro against six human tumour cell lines and tw

Full text of DOI:10.3184/174751911X13015834294266

222 RESEARCH PAPER
APRIL, 222–224
JOURNAL OF CHEMICAL RESEARCH 2011
Synthesis and crystal structure of (4bRS,9bRS)-5-(2,4-dimethoxyphenyl)-
4b,9b-7,7-dimethyldihydroxy-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]
indole-9,10-dione
Gricela Loboa, Elimar Zuletaa, Katiuska Charrisa, Mario V. Capparellib, Alexander Briceñoc,
Jorge Angeld and Jaime Charrisa*
aLaboratorio de Síntesis Orgánica, Facultad de Farmacia, Universidad Central de Venezuela, Apartado 47206, Los Chaguaramos,
1041-A Caracas, Venezuela
bUnidad de Estructura Molecular, Fundación Instituto de Estudios Avanzados (IDEA), Apartado 17606, Caracas 1015-A, Venezuela
cLaboratorio de Síntesis y Caracterización de Nuevos Materiales, Instituto Venezolano de Investigaciones Científicas (IVIC) Apartado 21827,
Caracas, 1020-A, Venezuela
dLaboratorio de Síntesis Orgánica y Diseño de Fármacos, Dpto. de Química, Facultad Experimental de Ciencias, Universidad del Zulia,
Maracaibo, Venezuela
A highly regiospecific synthesis and crystal structure of (4bRS,9bRS)-5-(2,4-dimethoxyphenyl)-7,7-dimethyl-4b,9b-
dihydroxy-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-9,10-dione is reported. It was tested in vitro against six human
tumour cell lines and two nontumourogenic cell lines. Their in vitro activity against Mycobacterium tuberculosis is
also reported. In general, it was found to possess a marginal activity.
Keywords: indeno[1,2-b]indole, ninhydrin, regiospecific, crystal structure
Despite recent advances in molecular biology and the progress
in combinatorial synthetic methodology, the rate of introduc-
tion of new pharmaceutical products has decreased markedly
over the past two decades. Structural diversity in a focused
collection of potential therapeutics is believed to increase
the positive hit rate. Most pharmaceutical products in use are
still small synthetic organic molecules that often contain a
heterocyclic ring.1,2 However, the range of easily accessible
and suitably functionalised heterocyclic building blocks for
the synthesis of structurally diverse libraries is rather limited.
The development of new, rapid, and clean synthetic routes
toward focused libraries of such compounds is therefore of
great importance to both medicinal and synthetic chemists.
Polyhydroxylated alkaloids as indenoindoles are interesting
heterocycles that can act as powerful and selective inhibitors
of glycosidases and exhibit activities as powerful lipid peroxi-
dation inhibitors,3 potassium channel openers,4 DNA intercala-
tors and topoisomerase II inhibitors,5 estrogenic agents,6 or
inhibitors of protein kinase CK2,7 indicating a growing interest
in this class of compounds.
resulting amino compounds, have been published. The forma-
tion of vic-dihydroxy-indenoindolones by the reaction of
ninhydrine 1 with aliphatic, and aromatic amines, or alicyclic,
and cyclic enaminones has been reported elsewhere.11–14
As part of our investigation into the synthesis of heterocy-
clic compounds with potential antimalarial, and anticancer
activities,15 we report here the synthesis of (4bRS,9bRS)-
5-(2,4-dimethoxyphenyl)-7,7-dimethyl-4b,9b-dihydroxy-
4b,5,6,7,8,9b-hexahydroindeno-[1,2-b]-indole-9,10-dione,
and the study by X-ray diffraction analysis.
The synthesis of 3-(2,4-dimethoxyphenylamino)-5,5-
dimethylcyclohex-2-enone 2 was achieved according to litera-
ture procedures by refluxing 5,5-dimethylcyclohexane-
1,3-dione with aromatic amine and a catalytic amount of
p-toluensulfonic acid in toluene and removal of water as an
azeotrope with a Dean–Stark water trap,16 to prepare the vic-
dihydroxy-indenoindiole 3, a solution of equimolar amounts
of corresponding enaminone 2 and ninhydrin 1 in chloroform,
stirred at room temperature for 24 h. TLC (EtAc:Hx 1:1)
showed, that only one compound was produced (Scheme 1).
Spectroscopic data (1H and 13C NMR) revealed that this was
Among the existing procedures for the preparation of inde-
noindoles, the Fischer indolisation starting with an indanone,
via the respective phenylhydrazones, serves as the most
common method.8,9 Recently, two new syntheses by transfor-
mation and reduction of 2-nitrobenylidenephtalide, generated
either by intramolecular cyclisation of 2-(2-nitrophenylethyl)
benzoic acid10 or by reaction of a phthalidyl-phosphonium
bromide with 2-nitrobenzaldehyde,5 and cyclisation of the
1
a cyclisation product with two H resonances due to OH
functionalities at 5.76 and 6.99 ppm and two 13C resonances at
83.66 and 96.32 ppm.
The X-ray analysis confirmed the molecular structure of 3
(Fig. 1). The relevant bond lengths and angles are given in
Table 1.
Scheme 1 Synthesis of (4bRS,9bRS)-5-(2,4-dimethoxypheny)l-7,7-dimethyl-(4b,9b)-dihydroxy-
4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-9,10-dione 3.
* Correspondent. E-mail: jaime.charris@ucv.ve

JOURNAL OF CHEMICAL RESEARCH 2011 223
Table 1 Selected bond lengths (Å) and angles (°) for 3
Table 2 Possible hydrogen bonds for 3 (Å and °)
C1–C2
C1–N1
C2–C3
C2–O2
C3–C8
C4–O3
C6–C7
C8–N1
C9–O4
1.574(2)
1.4991(18)
1.494(2)
1.4161(18)
1.367(2)
1.2547(19)
1.540(2)
C1–C11
C1–O1
C2–C9
C3–C4
C4–C5
C5–C6
C7–C8
C9–C10
C16–N1
1.513(2)
1.3852(17)
1.544(2)
1.411(2)
1.512(2)
1.533(2)
1.483(2)
1.472(2)
1.4261(19)
D-H···A
D-H
H···A
D···A
DHA
O1–H1···O3i
O2–H2···O3
C7–H7A···O6ii
0.93(2)
0.86(2)
0.97
1.86(2)
2.12(2)
2.53
2.7912(17)
2.8886(19)
3.474(2)
174(2)
149(2)
164.5
161.6
C23–H23C···O1iii 0.96
2.59
3.511(2)
Symmetry codes: i) –x+1, –y, –z; ii) –x+1, –y, –z+1; iii) x+1, y, z
1.3468(18)
1.210(2)
C2–C1–C11
C2–C1–O1
C11–C1–N1
C1–C2–C3
C1–C2–O2
C3–C2–O2
C2–C3–C4
C4–C3–C8
C3–C4–O3
C4–C5–C6
C5–C6–C22
C7–C6–C22
C22–C6–C23
C3–C8–C7
C7–C8–N1
C2–C9–O4
C9–C10–C11
C1–C11–C10
C1–N1–C8
C8–N1–C16
105.36(12)
117.13(11)
110.10(11)
103.73(11)
111.87(12)
114.15(12)
126.75(13)
121.22(14)
122.66(15)
116.07(13)
109.21(14)
108.77(14)
109.17(14)
124.21(13)
123.35(13)
124.35(15)
110.72(14)
111.29(13)
111.29(11)
125.60(12)
C2–C1–N1
C11–C1–O1
O11–C1–N1
C1–C2–C9
C3–C2–C9
C9–C2–O2
C2–C3–C8
C3–C4–C5
C5–C4–O3
C5–C6–C7
C5–C6–C23
C7–C6–C23
C6–C7–C8
C3–C8–N1
C2–C9–C10
C10–C9–O4
C9–C10–C15
C1–C11–C12
C1–N1–C16
102.43(11)
109.87(11)
111.53(12)
104.09(11)
111.92(12)
110.45(12)
110.02(12)
116.56(14)
120.59(14)
109.57(13)
109.86(14)
110.23(13)
110.94(13)
112.33(13)
108.32(13)
127.31(15)
128.44(16)
127.75(15)
123.03(11)
two 5-membered rings are approximately planar (r.m.s. devia-
tions: 0.019 and 0.020 Å). The tetracyclic system is V-shaped,
with the two 5-membered rings making a dihedral angle of
65.20(8)°, while the N-bonded phenyl ring is perpendicular to
the heterocycle [dihedral angle 88.16(8)°]. The C3–C4–C5–
C6–C7–C8 ring displays a conformation intermediate between
boat and sofa [C3 and C6 are at 0.147(2) Å and 0.600(2) Å
from the C4, C5, C7, C8 mean plane; the puckering parame-
ters17 are: q2 = 0.4301(16) Å, q3 = -0.1918(17) Å, φ2 = 1.8(3)°,
Q = 0.4709(17) Å)]. The molecule forms an O–H···O(keto)
intramolecular hydrogen bond. In addition, in the crystal struc-
ture there are intermolecular hydrogen bonds of the types
O–H···O(keto) and (possible) weaker C–H···O(hydroxyl) and
C–H···O(methoxy) (Table 2), which link the molecules to form
a three-dimensional network.
Compound 3 was investigated for its in vitro cytotoxic
activity against 3T3, BALB/3T3 clone A31 embryonic mouse
fibroblast cells; Vero, normal African green monkey kidney
epithelial cells; H460, human large cell lung cancer; DU145,
human prostate carcinoma; MCF-7, human breast adenocarci-
noma; M-14, human melanoma; HT-29, human colon adenocar-
cinoma; K562, human chronic myelogenous leukemia cells
using previously reported methodology,18–20 (GI50 > 250 µg mL−1)
GI50 is the concentration at which 3 inhibits the growth of cells
by 50%. Evaluation of the antimicobacterial activity in vitro
against sensitive MTB H37Rv strain and multidrug-resistant
(MDR-MTB) clinical isolated was performed using the TEMA
method.21 (MIC value >25 µg mL−1) MIC is defined as the
lowest drug concentration that prevents the change in colour.
Experimental
Melting point was determined on a Thomas micro hot stage apparatus
and is uncorrected. IR spectra was determined as KBr pellet on a
1
Shimadzu model 470 spectrophotometer. The H NMR, 13C NMR
spectra were recorded using a Jeol Eclipse 270 (270 MHz/67.9 MHz)
spectrometer using DMSO-d6, and are reported in ppm downfield
from the residual DMSO. Elemental analyses was performed on a
Perkin Elmer 2400 CHN analyser, result was within 0.4% of the
predicted values. Chemical reagents were obtained from Aldrich
Chemical Co, USA. All solvents were distilled and dried in the usual
manner.
(4bRS,9bRS)-5-(2,4-dimethoxypheny)l-7,7-dimethyl-(4b,9b)-
dihydroxy-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-9,10-dione 3:
Enaminone 2 0.29g (1.35 mmol) and 1 0.2g (1.12 mmol) were dis-
solved in chloroform 5 mL and stirred at room temperature (24 h). The
solvent was evaporated in vacuo, the solid was isolated by suction,
washed with diethyl ether and recrystallised off ethanol to afford the
o
title compound, yield 87%; mp. 239–240 C; IR (KBr) cm−1: 1718
(CO), 3200 (OH). 1H NMR DMSO-d6: δ 0.79(s, 3H, CH3), 0.94(s, 3H,
CH3), 1.88(s, 2H, H6), 2.01(d, 2H, H8, J = 4.5 Hz), 3.15(s, 3H, OCH3),
3.80(s, 3H, OCH3), 5.76(s, 1H, OH), 6.57(d, 1H, H3’, J = 2.7 Hz),
6.61(d, 1H, H4, J = 7.4Hz), 6.68(dd, 1H, H5’, J = 2.7, 8.6 Hz), 6.98 (s,
1H, OH), 7.46–7.57(m, 3H, H2,3,6’), 7.69(dd, 1H, H1, J = 1.2, 8.2 Hz).
13C NMR: 28.4(2), 33.5, 36.7, 51.9, 55.4, 55.9, 83.7, 96.3, 99.4, 104.6,
105.3, 117.2, 123.4, 125.0, 130.1, 132.3, 134.8, 135.0, 148.4, 157.3,
161.1, 165.7, 189.2, 198.4. Anal. Calcd for C25H25NO6: C, 68.95; H,
5.79; N, 3.22. Found: C, 69.03; H, 5.78; N, 3.27%.
X-ray crystallography: Crystals of 3 suitable for X-ray diffraction
were obtained by slow evaporation of a solution in ethanol. Crystal
data, intensity data collection parameters and final refinement results
are summarised in Table 3.
Fig. 1 Molecular structure of compound 3 showing the atomic
numbering. The displacement ellipsoids are drawn at 50%
probability. A dashed line indicates an intramolecular hydrogen
bond.
The molecule displays two chiral centres (C4b and C9b)
with a cis ring fusion. Therefore, since the space group is
centrosymmetric, the crystal consists of an equimolar mixture
of the RR and SS configurations. The two phenyl rings are
quite planar (r.m.s. deviations: 0.0051 and 0.0071 Å) and the

224 JOURNAL OF CHEMICAL RESEARCH 2011
Table 3 Crystal data, intensity data collection parameters and
final refinement results for 3
CRYSTALCLEAR;22 structure solution, SHELXS-97;23 structure
refinement, SHELXL-97;23 geometrical calculations, PLATON;24
molecular graphics, ORTEP-3.25 The structure solution, the refine-
ment and the drawings were carried out with the aid of the WinGX26
suite of programs.
Comprehensive crystallographic data (excluding structure factors)
for the structural analysis of 3 have been deposited with the
Cambridge Crystallographic Data Centre. Copies of the data (CIF
file) and can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK, fax: +44-(0)1223-336033,
or from www.ccdc.cam.ac.uk/data_request/cif, quoting deposition
No. CCDC 804490.
CCDC deposit No.
CCDC 804490
Crystal data
Formula
C25H25NO6
435.46
MW
Colour
yellow
Morphology
Specimen size (mm)
T (K)
prism
0.45x0.36x0.25
298(2)
a (Å)
9.480(3)
18.563(4)
12.368(3)
94.249(6)
2170.5(9)
monoclinic
P21/n (No. 14)
4
b (Å)
c (Å)
We thank the IIF and CDCH-UCV (grants IIF.01-2009, PG.
06-7548-2009/1), and CYTED-RIDIMEDCHAG programmes
for financial support.
β (°)
V (Å3)
Crystal system
Space group (No.)
Z
Received 14 December 2010; accepted 12 March 2011
Paper 1000478 doi: 10.3184/174751911X13015834294266
Published online: 3 May 2011
Dc (g cm–3)
F(000)
1.333
920
µ(Mo–Kα) (mm–1)
θ range (°) for cell
No. reflections for cell
0.095
2.8–26.3
705
References
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–9, 11
h range
3
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k range
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–21, 21
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<0.1
Mean ∆I for checks (%)
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Abs. correction
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Rint
24569
4190
3544
multi–scan
0.925–0.958
0.0224
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0.001
∆/σ mean
<0.0005
–0.21, 0.42
∆ρr (min., max.) (e Å–3)
Diffraction data were measured on a RigakuAFC-7S diffractometer
with a Mercury CCD detector using graphite-monochromated Mo-Kα
radiation (λ = 0.71070 Å). The structure was solved by direct methods
and refined on F2 by full-matrix least-squares, using all reflections
and weights w = [σ2(Fo2) + (a P)2 + b P]−1, with P = (Fo2 + 2 Fc2)/3. The
C-bonded H atoms were placed in calculated positions and refined
using a riding atom model with fixed C–H distances (0.93 Å for CH,
0.97 Å for CH2, 0.96 Å for CH3), and with Uiso = p Ueq(parent atom)
(p = 1.2 for CH and CH2, 1.5 for CH3). The O-bonded H atoms were
located in difference Fourier syntheses and refined isotropically.
The following computer programs were used: data collection,
data reduction, cell refinement and absorption correction,

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