9-Ethyl-1,4-dimethyl-6-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl) -9H-carbazole and 6-bromo-9-ethyl-1,4-dimethyl-9H-carbazole

Article abstract of DOI:10.1107/S0108270108020593

The title carbazolyl boronic ester, C22H28BNO2, (I), is a building block for the synthesis of new carbazole derivatives of potential utility as pharmaceutically active compounds. The crystal structure of (I) and of the title bromo-carbazole com-pound, C16H16BrN, (II), the synthetic precursor of (I), were solved and analysed with the aim of understanding the lack of reactivity of (I) under Suzuki cross-coupling reaction conditions. In both structures, the methyl groups are coplanar with the carbazole ring system, and the ethyl group lies out of the carbazole plane. The dioxaborolane ring of boronic ester (I) adopts a half-chair conformation but lies approximately in a planar orientation with respect of the carbazole ring system, whereas the Br atom of (II) is coplanar with the carbazole plane. In (I), the carbazole-boronic ester C - B bond length is 1.5435 (14) A, which is somewhat shorter than the usual value of 1.57 A.

Full text of DOI:10.1107/S0108270108020593

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
bromo-1,4-dimethyl-9H-carbazole (Caruso et al., 2007). Using
a similar synthesis pathway, we were able to prepare 9-ethyl-
1,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
9H-carbazole, (I), from 6-bromo-1,4-dimethyl-9H-carbazole,
with 6-bromo-9-ethyl-1,4-dimethyl-9H-carbazole, (II), as an
intermediate product. The crystal structures of the final
product (I) and the intermediate (II) are described in this
article.
ISSN 0108-2701
9-Ethyl-1,4-dimethyl-6-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)-9H-
carbazole and 6-bromo-9-ethyl-1,4-
dimethyl-9H-carbazole
a
a
´
Jana Sopkova-de Oliveira Santos, * Anna Caruso,
Jean-Franc¸ois Lohier,b Jean-Charles Lancelota and Sylvain
Raulta
a
´
´
Centre d’Etudes et de Recherche sur le Medicament de Normandie (CERMN), UPRES
´
´
EA-4258, FR CNRS INC3M, Universite de Caen, 5 rue Vaubenard, 14032 Caen,
b
´
France, and Laboratoire de Chimie Moleculaire et Thio-organique, UMR CNRS
´
6507, ENSICAEN – Universite de Caen, 14050 Caen, France
Correspondence e-mail: jana.sopkova@unicaen.fr
Received 17 June 2008
Accepted 3 July 2008
Online 19 July 2008
The title carbazolyl boronic ester, C22H28BNO2, (I), is a
building block for the synthesis of new carbazole derivatives
of potential utility as pharmaceutically active compounds. The
crystal structure of (I) and of the title bromocarbazole
compound, C16H16BrN, (II), the synthetic precursor of (I),
were solved and analysed with the aim of understanding the
lack of reactivity of (I) under Suzuki cross-coupling reaction
conditions. In both structures, the methyl groups are coplanar
with the carbazole ring system, and the ethyl group lies out of
the carbazole plane. The dioxaborolane ring of boronic ester
(I) adopts a half-chair conformation but lies approximately in
a planar orientation with respect of the carbazole ring system,
whereas the Br atom of (II) is coplanar with the carbazole
plane. In (I), the carbazole–boronic ester C—B bond length is
The boronic acids and esters constitute very interesting and
reactive intermediates for the preparation of various
compounds; for example, they can be used in metal-catalysed
´
reactions of the Suzuki type (Suzuki, 1999; Gerard et al., 2006).
Metallo-catalysed cross-coupling chemistry has considerably
upset the existing medicinal chemistry strategies, making the
majority of classical synthetic pathways obsolete. This gener-
ally convergent strategy, which is the source of great diversity,
makes possible the synthesis of a wide range of chemical
libraries starting from a few valuable scaffolds. In this context,
we are interested in the production of boronic compounds
which are directly carriers of a potent therapeutic skeleton
and have cancerology applications (de Koning et al., 2000).
However, the title boronic ester has a lower activity than
expected, and we have undertaken the crystal structure
analysis of (I) and (II) to find an explanation.
˚
1.5435 (14) A, which is somewhat shorter than the usual value
˚
of 1.57 A.
Figs. 1 and 2 show views of the molecules of (I) and (II),
respectively. The asymmetric unit of (I) contains one molecule
and that of (II) contains two molecules.
Comment
Ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole) is a well
known alkaloid with antitumor properties, acting as a DNA
intercalating agent and inhibiting the activity of topoisomer-
ase II. Many structural modifications of the original molecule
have been designed in order to obtain derivatives with a better
pharmacological profile. In particular, 9-hydroxyellipticine,
Celiptium, has been shown to possess a higher DNA affinity
than ellipticine itself, measured on L1210 mice leukaemia, and
a lack of toxicity at therapeutic doses (Le Pecq et al., 1974;
Searle et al., 1984; Poljakova et al., 2007; Ho & Hsieh, 2006).
We have described recently a general method for the
synthesis of 9-alkyl-1,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-9H-carbazoles starting from 9-alkyl-6-
Structure analysis showed that the carbazole system is
planar in both compounds. The methyl substituents are
coplanar with the aromatic rings. The ethyl group lies out of
the carbazole plane in both structures. The dihedral angle
between the carbazole plane and the plane formed by the
ethyl C and carbazole N atoms (C9A—N9—C10—C11) is
À69.9 (1)ꢀ in (I), and thus the ethyl group is oriented
‘downwards’ with respect to the carbazole plane. In (II), the
dihedral angles are 96.2 (3) and 93.7 (3)ꢀ, and the ethyl group
is oriented ‘upwards’ with respect to the carbazole ring system.
The dioxaborolane ring of (I) is in a half-chair conforma-
tion, with an O1—C14—C15—O2 torsion angle of 30.80 (9)ꢀ.
Acta Cryst. (2008). C64, o453–o455
doi:10.1107/S0108270108020593
# 2008 International Union of Crystallography o453

organic compounds
˚
spacing is 3.50–3.54 A. Columns in the b-axis direction are also
The BO2 group is rotated away from the plane of the carba-
zole ring system by 10.90 (5)ꢀ, and the angle between the
dioxaborolane ring and the carbazole plane is 16.85 (4)ꢀ. The
bond length between the carbazole system and the dioxabor-
formed in (I). However, in this case, each second ring in the
column is slipped (in the a direction) and the planes of
neighbouring carbazole ring systems in the columns are
twisted; the angle formed between the planes is about 37ꢀ.
˚
olane ring is 1.5435 (14) A, which is smaller than usual
˚
(1.57 A; Hall, 2005). Thus, it seems that the boron electron
deficiency pumps the ꢀ electrons from the carbazole ring
system, and this could be a reason for the lower reactivity of
(I).
The stacking interaction appears to be the principal inter-
action in the crystal packing of (I). The carbazole ring systems
stack in parallel planes, forming columns in the b-axis direc-
Experimental
6-Bromo-1,4-dimethyl-9H-carbazole was prepared by the reaction of
5-bromoindole (25.0 g, 127.5 mmol) with hexane-2,4-dione (16.79 g,
147.0 mmol) in the presence of p-toluenesulfonic acid (18.65 g,
98.0 mmol) in ethanol (300 ml). 6-Bromo-1,4-dimethyl-9H-carbazole
(2.0 g, 7.3 mmol) in dry dimethylformamide (60 ml) was N-ethylated
with iodoethane (1.73 ml, 21.9 mmol)/sodium hydride (0.44 g,
10.9 mmol) under standard conditions to give (II). Lithiation–bor-
onation of this intermediate (1.5 g, 4.97 mmol), at very low
temperature (183 K), using n-BuLi (2.58 ml, 6.46 mmol), triisopropyl
borate (1.26 ml, 5.47 mmol) and pinacol (0.59 g, 4.97 mmol) in dry
tetrahydrofuran (120 ml), gave (I) after a typical hydrolytic work-up.
Transparent crystals of (I) and (II) suitable for X-ray analysis were
grown from an acetonitrile solution at room temperature.
˚
tion. The interplanar spacing is between 3.50 and 3.54 A.
In (II), the carbazole ring systems stack in parallel planes,
forming columns in the b-axis direction. The interplanar
Compound (I)
Crystal data
3
˚
C22H28BNO2
Mr = 349.26
V = 1961.24 (12) A
Z = 4
Monoclinic, P21=c
Mo Kꢂ radiation
ꢃ = 0.07 mmÀ1
T = 150 (2) K
0.51 Â 0.36 Â 0.35 mm
˚
a = 8.6357 (3) A
˚
b = 8.1068 (3) A
˚
c = 28.2057 (9) A
ꢁ = 96.673 (2)ꢀ
Data collection
Bruker APEXII CCD area-detector
diffractometer
96221 measured reflections
8529 independent reflections
6728 reflections with I > 2ꢄ(I)
Rint = 0.048
Figure 1
The asymmetric unit of (I), showing the labelling of the non-H atoms.
Displacement ellipsoids are shown at the 50% probability level and H
atoms are drawn as small circles of arbitrary radii.
Refinement
R[F2 > 2ꢄ(F2)] = 0.054
wR(F2) = 0.143
S = 1.08
347 parameters
All H-atom parameters refined
À3
˚
Áꢅmax = 0.59 e A
À3
˚
8529 reflections
Áꢅmin = À0.28 e A
Compound (II)
Crystal data
3
˚
V = 1326.6 (2) A
Z = 4
C16H16BrN
Mr = 302.21
Monoclinic, P21
a = 15.3210 (14) A
b = 4.6518 (5) A
c = 18.6647 (17) A
ꢁ = 94.239 (5)ꢀ
Mo Kꢂ radiation
ꢃ = 3.08 mmÀ1
T = 150 (2) K
0.41 Â 0.36 Â 0.34 mm
˚
˚
˚
Data collection
Figure 2
Bruker APEXII CCD area-detector
diffractometer
Absorption correction: numerical
(SAINT; Bruker, 2006)
Tmin = 0.366, Tmax = 0.507
32267 measured reflections
9080 independent reflections
7897 reflections with I > 2ꢄ(I)
Rint = 0.033
One of the two molecules of the asymmetric unit of (II), showing the
labelling of the non-H atoms. Displacement ellipsoids are shown at the
50% probability level and H atoms are drawn as small circles of arbitrary
radii.
ꢁ
´
o454 Sopkova-de Oliveira Santos et al.
C22H28BNO2 and C16H16BrN
Acta Cryst. (2008). C64, o453–o455

organic compounds
Refinement
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: SK3248). Services for accessing these data are
described at the back of the journal.
R[F2 > 2ꢄ(F2)] = 0.030
wR(F2) = 0.067
S = 1.01
9080 reflections
332 parameters
1 restraint
H-atom parameteÀrs3 constrained
˚
Áꢅmax = 0.59 e A
À3
˚
Áꢅmin = À0.33 e A
Absolute structure: Flack (1983),
3979 Friedel pairs
Flack parameter: 0.265 (4)
References
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Fourier map and refined with isotropic displacement parameters [C—
˚
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˚
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´
We thank the CRIHAN, the ‘Region Haute-Normandie’
and the European Community (FEDER) for the molecular
modelling software.
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´
Acta Cryst. (2008). C64, o453–o455
Sopkova-de Oliveira Santos et al. C22H28BNO2 and C16H16BrN o455