Sequential MCR/Fisher indolization strategy for the construction of polycyclic carbazole derivatives

Article abstract of DOI:10.1016/j.tetlet.2017.02.047

A one-pot method for the synthesis of novel polycyclic carbazole derivatives from readily available starting materials using a sequential multicomponent reaction/Fisher indolization strategy is described.

Full text of DOI:10.1016/j.tetlet.2017.02.047

Accepted Manuscript
Sequential MCR/Fisher indolization strategy for the construction of polycyclic
carbazole derivatives
Esma Lamera, Sofaine Bouacida, Marc Le Borgne, Zouhair Bouaziz,
Abdelmalek Bouraiou
PII:
S0040-4039(17)30224-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.047
TETL 48658
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 December 2016
8 February 2017
14 February 2017
Please cite this article as: Lamera, E., Bouacida, S., Borgne, M.L., Bouaziz, Z., Bouraiou, A., Sequential MCR/
Fisher indolization strategy for the construction of polycyclic carbazole derivatives, Tetrahedron Letters (2017),
doi: http://dx.doi.org/10.1016/j.tetlet.2017.02.047
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Graphical Abstract
Sequential MCR/Fisher indolization strategy
for the construction of polycyclic carbazole
derivatives
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Esma Lamera, Sofaine Bouacida, Marc Le Borgne, Zouhair Bouaziz, Abdelmalek Bouraiou

1
Tetrahedron Letters
Sequential MCR/Fisher indolization strategy for the construction of polycyclic
carbazole derivatives
Esma Lameraa, Sofaine Bouacidaa,b, Marc Le Borgnec, Zouhair Bouazizc† and Abdelmalek Bouraioua*
a Unité de Recherche de Chimie de l’Environnement et Moléculaire Structurale, Université des Frères Mentouri, Constantine 25000, Algérie.
b Département Sciences de la Matière, Université Oum El Bouaghi, 04000 Oum El Bouaghi, Algérie
c Université Lyon 1, Faculté de Pharmacie, ISPB, EA 4446 Bioactive Molecules and Medicinal Chemistry (B2MC), SFR Santé Lyon-Est CNRS UMS3453-
INSERM US7, 8 Avenue Rockefeller, F-69373 Lyon Cedex 8, France
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A one-pot method for the synthesis of novel polycyclic carbazole derivatives from readily
available starting materials using a sequential multicomponent reaction/Fisher indolization
strategy is described.
Available online
2016 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reaction
One pot
Fischer reaction
Carbazole
Polycycle
The synthesis and application of carbazole derivatives have
been a source of great interest due to their intriguing structural
features and promising biological activities.1 To improve the
pharmacological profile of the carbazole moiety, numerous work
in the literature has reported the synthesis of heterocyclic
compounds condensed with the carbazole nucleus.2 Many
examples of compounds including cyclopentacarbazoles,3
pyridocarbazoles,4 pyrrolocarbazoles5 and indolocarbazoles6 have
shown antitumor activities.
Condensed phthalazines, containing two bridgehead nitrogen
atoms in a fused ring system, are of particular interest and
significant work has been devoted to their synthesis. Numerous
condensed phthalazine derivatives have been reported to show a
broad range of biological activities; notably anticancer,7
antimicrobial,8
anti-inflammatory,9
anticonvulsant,10
antihypertensive11 and antioxidant properties.12
The fusion of phthalazine to the carbazole heterocycle might
result in novel biological activities. In this context, herein, we
report the synthesis of new polycyclic carbazoles condensed to
pyrazolophthalazine via a one-pot reaction.
Initially, the polycyclic carbazole formation reaction was
tested
on
13-phenyl-2,3,4,13-tetrahydro-1H-indazolo[1,2-
b]phthalazine-1,6,11-trione 1a under three sets of conditions:
HCl in EtOH, H2SO4 in i-PrOH or CF3COOH in AcOH. The
desired carbazole 2a was obtained in satisfying yield (70%) using
CF3COOH (1.7 eq.) in acetic acid in the presence of
phenylhydrazine (Scheme 1). Conversely, neither of the first two
conditions gave the desired cyclized product.
Since the synthetic utility of an acidic medium for the
preparation of 1a had already been reported,13 we next explored
the multicomponent reaction (MCR)/Fisher indolization cascade
using the same conditions in order to extend this to a one-pot
processes.
Figure 1. Selected heterocyclic compounds containing the carbazole motif
* Corresponding author. bouraiou.abdelmalek@yahoo.fr .
† Corresponding author. zouhair.bouaziz@univ-lyon1.fr.

2
Tetrahedron Letters
Scheme 1. Synthesis of polycyclic carbazole 2a.
The model reaction of 2,3-phthalazine-1,4-dione (1 mmol),
benzaldehyde (1.1 mmol) and cyclohexane-1,3-dione (1.2 mmol)
at reflux in CF3COOH/AcOH was performed in order to establish
the effectiveness of this system for the synthesis of 1a. Under
these conditions, conversion to 13-phenyl-2,3,4,13-tetrahydro-
1H-indazolo[1,2-b]phthalazine-1,6,11-trione 1a was complete
after 4 h (TLC). Compound 1a was used without isolation in the
next step; under these conditions, 1a is sufficiently pure to be
used for further transformations. After the addition of
phenylhydrazine (1.7 eq.), the reaction mixture was heated at
reflux for 24 h to give 2a in 77% yield.14 A spontaneous
oxidation occurs at the end of this sequence to give the carbazole
ring instead of the dihydrocarbazole (Scheme 2).
Figure 2. ORTEP plot of the X-ray crystal structure of 2a with the DMF
molecule omitted for clarity (thermal ellipsoids drawn at the 50% probability
level).15
Bond lengths and angles were comparable to those reported
previously for the starting material 1a16 and are in the expected
range.
Table 1. Polycyclic carbazole derivatives prepared according to Scheme 2.a
Product
Yield (%)b
To demonstrate the scope of the method, the reaction was
performed using various substituted benzaldehydes. As shown in
Table 1, substrates containing aromatic rings with electron-
withdrawing groups (halide, nitro) or electron-donating groups
(alkoxy, alkyl), gave the corresponding products 2 in good to
high yield. Substituents on the aromatic ring had no obvious
effect on the yield or reaction time.
77
2a
2b
87
61
60
2c
2dc
62
75
81
2e
2fc
2g
Scheme 2. One-pot synthesis of polycyclic carbazoles 2a-i.
The structures of compounds 2a-i were confirmed by their
spectral data. For example, the 1H NMR spectrum of 2a
displayed a singlet at 11.04 ppm due to the N-H of the carbazole
ring. Signals for the two aromatic protons 6 and 7 of the
carbazole nucleus were observed as doublets at 8.35 and 8.30
ppm. The signals of the other aromatic protons appeared between
8.39 and 7.17 ppm as multiplets. The signal attributable to the
proton of the pyrazole ring was found at 7.10 ppm as a singlet.
The 13C NMR spectrum data of 2a showed signals for the two
C=O carbon at 154.2 and 154.3 ppm. The carbon of the pyrazolo
ring resonated at 64.3 ppm, while the signals for the other
aromatic carbons were between 140.9 and 106.9 ppm.
Furthermore single crystal X-ray structural analysis was used to
verify the proposed structure of 2a (Fig. 2).
56
2h

3
Farahmand, S. J. Iran. Chem. Soc. 2013, 10, 577–581; (c) Wang,
H. J.; Zhang, X. N.; Zhang, Z. H. Monatsh. Chem. 2010, 141,
425–430; (d) Soheilizad, M.; Adib, M.; Sajjadifar, S. Monatsh.
Chem. 2014, 145, 1353–1356; (e) Abedini, M.; Shirini, F.; Omran,
J. M.–A. J. Mol. Liq. 2015, 212, 405–412; (f) Tayebee, R.; Jomei,
M. Maleki, B.; Razi, M. K.; Veisi, H.; Bakherad, M. J. Mol. Liq.
2015, 206, 119–128.
62
2i
a Reagents and conditions: benzaldehyde (1.1 mmol), 1,3-cyclohexadione (1.2
mmol), phthalhydrazide (1 mmol), acetic acid (5 mL), trifluoroacetic acid (2
mL) then phenylhydrazine (1.7 eq.), trifluoroacetic acid (2 mL), reflux.
b Isolated yield from phthalhydrazide.
14. Representative procedure for the synthesis of 16-phenyl-1,16-
dihydrophthalazino[2',3':1,2]pyrazolo[4,3-a]carbazole-9,14-dione
2a: To a mixture of acetic acid (5 mL) and trifluoroacetic acid (2
mL) in a 50 mL round-bottomed flask, benzaldehyde (1.1 mmol),
1,3-cyclohexadione (1.2 mmol) and phthalhydrazide (1 mmol)
were added. The resulting mixture was magnetically stirred at
reflux for 4 h. After completion (TLC), the reaction mixture was
cooled and phenylhydrazine (1.7 eq.) and trifluoroacetic acid (2
mL) were added. The reaction mixture was heated at reflux for 24
h. Upon completion, the solvents were removed under reduced
pressure and the product was isolated by chromatography.
Compounds 2b-c, 2e, 2j-i were obtained analogously to 2a.
Compounds 2d and 2f precipitated during solvent evaporation and
were isolated by filtration then washed with AcOH.
c
Products precipitated during solvent evaporation and were isolated by
filtration then washed with AcOH.
In conclusion, we have reported an efficient and convenient
protocol for the one-potsynthesis of polycyclic carbazole
derivatives from phthalhydrazide, benzaldehyde, cyclohexane-
1,3-dione and phenylhydrazine using a sequential MCR/Fisher
indolization strategy. This method is quite general and works
with a broad range of substrates.
15. Crystal structure analysis for 2a: C27H17N3O2, Mr = 415.13 g/mol,
Orthorhombic, space group
P
212121, a=10.5723(6) Å;
Acknowledgments
b=10.7384(6)Å ; c=21.6020(11)Å; α=β=γ=90°, Z=4, V=
2452.5(2)Å3, Z=4, c=1.323, F(000)=1024, crystal size:
0.14×0.11×0.09 mm. Crystallographic data (excluding structure
factors) for compound 2a have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC 978520. This data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
We thank MESRS (Ministère de l’Enseignement Supérieur et
de la Recherche Scientifique) Algeria, for Financial support.
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