Synthesis of Indolo[3,2-b]carbazoles via an Anomeric-Based Oxidation Process: A Combined Experimental and Computational Strategy

Article abstract of DOI:10.1002/jhet.3077

Indolo[3,2-b]carbazole is a molecule of great biological significance, as it is formed in vivo after consumption of cruciferous vegetables. The reaction of 1H-indole and various aldehydes in the presence of a catalytic amount of N,2-dibromo-6-chloro-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine-7-sulfonamide 1,1-dioxide as an efficient and homogeneous catalyst in acetonitrile at 50°C produces 6,12-disubstituted 5,7-dihydroindolo[2,3-b]carbazole with an in good to excellent yield. The presented technique offers a fast and robust method, by the use of inexpensive commercially available starting materials toward 6,12-disubstituted 5,7-dihydroindolo[2,3-b]carbazole. A new anomeric-based oxidation was kept in mind for the final step of the indolo[2,3-b]carbazoles synthesis. The suggested anomeric-based oxidation mechanism was supported by experimental and theoretical evidences.

Full text of DOI:10.1002/jhet.3077

Month 2018
Synthesis of Indolo[3,2-b]carbazoles via an Anomeric-Based Oxidation
Process: A Combined Experimental and Computational Strategy
a
a
a
b
a
c
d
c
*
*
M. A. Zolfigol, A. Khazaei, F. Karimitabar, M. Hamidi, F. Maleki, B. Aghabarari, F. Sefat, and M. Mozafari
aDepartment of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan 6517838683, Iran
bMedical Biotechnology Research Center, Guilan University of Medical Sciences, Rasht, Iran
cNanotechnology and Advanced Materials Department, Materials and Energy Research Center (MERC), Tehran, Iran
dFaculty of Engineering and Informatics, Medical Engineering Department, University of Bradford, Bradford, UK
*
E-mail: zolfi@basu.ac.ir; mozafari.masoud@gmail.com
Received May 5, 2017
DOI 10.1002/jhet.3077
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
Indolo[3,2-b]carbazole is a molecule of great biological significance, as it is formed in vivo after
consumption of cruciferous vegetables. The reaction of 1H-indole and various aldehydes in the presence
of a catalytic amount of N,2-dibromo-6-chloro-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine-7-sulfonamide
1,1-dioxide as an efficient and homogeneous catalyst in acetonitrile at 50°C produces 6,12-disubstituted
5,7-dihydroindolo[2,3-b]carbazole with an in good to excellent yield. The presented technique offers a fast
and robust method, by the use of inexpensive commercially available starting materials toward 6,12-
disubstituted 5,7-dihydroindolo[2,3-b]carbazole. A new anomeric-based oxidation was kept in mind for
the final step of the indolo[2,3-b]carbazoles synthesis. The suggested anomeric-based oxidation mechanism
was supported by experimental and theoretical evidences.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
indolo[3,2-b]carbazoles have been reported in the
literature, most of which depend on multi-step sequences
Indolocarbazole derivatives (ICZs) are alkaloids
exhibiting attractive biological properties such as
antitumor and antibiotic activities [1,2]. Their strict and
coplanar structural features give ICZs high HOMO
levels and remarkable hole-transporting properties.
Consequently, ICZs have been introduced as key electron-
rich π-conjugated backbones in optoelectronic materials
for applications such as organic field-effect transistor
(OFET) [3–6] and organic light-emitting diode (OLED)
[7–10]. Among of five likely isomers, 5,11-
dihydroindolo[3,2-b]carbazole (referred to herein as
indolo[3,2-b]carbazole or ICZ) has shown attractive
structural and electrical properties (high charge carrier
mobility) combined with good stability under atmospheric
changes that makes them good components for use in
organic electronics [11]. Numerous synthetic procedures
for the synthesis of symmetrical and unsymmetrical
characterized by low overall yield [12–14].
A
comprehensive overview of the synthesis and
characterization of indolo[3,2-b]carbazoles can be found
in the literature [1,11,15–17].
On the other hand, organic synthetic methodology, as
rational designing philosophy for developing novel
reagent systems for organic synthesis, continuously seeks
for new reagents, best reaction conditions, and more
efficient and selective methods. In this regard, a large
group of compounds entitled N-halo reagents are
widely used as catalysts and/or reagents in fine
organic synthesis [18]. The N-halo derivatives include
of amines, amides, imides, urea, saccharines,
sulfonamides, and sulfonimides [18,19]. The synthesis
and applications of N-halo reagents have been
extensively reviewed in the literature [18–20], and the
present work is a continuation of previous studies [21]
© 2018 Wiley Periodicals, Inc.

M. A. Zolfigol, A. Khazaei, F. Karimitabar, M. Hamidi, F. Maleki,
Vol 000
B. Aghabarari, F. Sefat, and M. Mozafari
Figure 1. The presented model reaction in this study. [Color figure can be viewed at wileyonlinelibrary.com]
by the authors on the applications of N-halo reagents in
organic synthesis. This study aims to prepare 5,11-
dihydroindolo[3,2-b]carbazoles by using an N-bromo
reagent via one-pot and anomeric based oxidation.
open capillary tubes and are uncorrected. All reactions
were monitored by thin-layer chromatography using silica
gel SIL G/UV 254 plates.
Computational details.
In this research, the
computations were performed using the Gaussian 09
program [22]. Moreover, density functional theory has
been used to investigate the reactions of intermediate VI
in the presence of catalyst N,2-dibromo-6-chloro-3,4-
dihydro-2H-benzo[e][1,2,4]thiadiazine-7-sulfonamide 1,1-
dioxide (DCDBTSD). All geometry optimizations were
performed at B3LYP/SVP level of the theory. The
frequency calculations at the same level of the theory
have also been performed to identify all of the stationary
points as minima with no imaginary frequencies or
transition structures with one imaginary frequency. In
order to investigate the mechanism, the total electronic
energy (Eel + ZPE) and the Gibbs-free energies have
EXPERIMENTAL
Materials. All chemicals were purchased from Merck
Company. The known products were identified by
comparison of physical properties such as melting point
and spectral data with those reported in the literature.
Infrared spectroscopy was recorded on a Perkin Elmer
GX FT-IR spectrometer using the KBr technique. Melting
points were measured using a Büchi B-545 apparatus in
Table 1
Optimization of conditionsa.
been used. The salvation energies (ΔGsolv
) were
calculated with the solvation model based on density
(SMD) model using acetonitrile as a solvent. Then, the
Gibbs-free energies in the solution were calculated by
Amount
of catalyst/
mol%
Temp.
(°C)
Time
(min)
Yieldb
(%)
Entry
Solvent
using equation ΔG(aq)
intramolecular interactions were calculated on the basis of
natural bond orbital [23] analyses.
=
ΔGgas
+
ΔGsolv
.
The
1
2
3
4
5
6
7
8
9
MeCN
MeCN
MeCN
MeCN
H2O
CH3CH2OH
none
MeCN
MeCN
-
4
5
10
5
5
5
5
5
50
50
50
50
50
50
50
40
60
180
35
15
-
80
96
97
26
40
80
80
96
15
General procedure for synthesis of DCDBTSD.
A
180
180
50
50
15
solution of sodium hydroxide (6 mol.LÀ1, 1 mL) was
added drop-wise to a round-bottomed flask (50 mL)
containing hydrochlorothiazide (0.6 g, 2 mmol) in
distilled water (2 mL) as it was being stirred for 10 min
at room temperature. After the addition was complete, the
reaction mixture was stirred for a further 20 min.
aReaction conditions: 1H–indole (1 mmol), 4-methoxybenzaldehyde(1-
mmol), solvent (2 mL), and DCDBTSD.
bYields of isolated products.
Figure 2. The synthesis of 6,12-disubstituted 5,7-dihydroindolo [3,2-b]carbazoles. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Indolo[3,2-b]carbazoles via an Anomeric-Based Oxidation Process:
A Combined Experimental and Computational Strategy
Table 2
Synthesis of indolo[3,2-b]carbazoles in the presence of 5 mol% of DCDBTSD in acetonitrile at 50°C.
Entry
Ar
Time (min)
Yield (%)a
Mp. °C (lit.)[Ref]
1
2
3
4
5
6
7
8
C6H5
4-ClC6H4
2-OH C6H4
4-MeO C6H4
2,4-(MeO)2 C6H4
4-MeC6H4
20
50
18
15
15
20
50
20
83
90
95
90
93
91
92
95
346–348 (350–352) [24]
369–371 (364–366) [25]
342–344(>300) [24]
378–380 (383–385) [24]
400<
400 < (400<) [24]
338–340 (341–343) [24]
400 < (400<) [24]
2-ClC6H4
4-OHC6H4
aYields of isolated products.
Figure 3. Suggested mechanism for the synthesis of indolo[3,2-b]carbazole derivatives. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. A. Zolfigol, A. Khazaei, F. Karimitabar, M. Hamidi, F. Maleki,
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B. Aghabarari, F. Sefat, and M. Mozafari
Following this, bromine (0.08 mL, 3 mmol) was slowly
added to the hydrochlorothiazide solution as it was being
stirred for a period of 15 min at 0°C. The insoluble
brominated catalyst was removed by filtration and
washed with water (10 mL) to provide DCDBTSD at a
yield of 90% (0.82 g) [19].
entry 3). Notably, when this reaction was carried out in the
absence of DCDBTSD, the yield of the product was very low
(Table 1, entry 1). Several experiments were carried out at 40,
50, and 60°C in acetonitrile to determine the optimal
temperature (Table 1, entries 3, 8, and 9). It was found that
the most appropriate reaction temperature was 50°C (entry
3). In addition, the optimized conditions for the synthesis of
5,11-dihydroindolo[3,2-b]carbazoles have been depicted in
Figure 2.
To delineate this method for library construction, the
procedure was evaluated using various aromatic aldehydes
(Table 2). The 6,12-disubstituted 5,7-dihydroindolo[3,2-b]
carbazoles were selectively synthesized by condensation
General procedure for the synthesis of indolo[3,2-b]
carbazole derivatives.
In the experimental method, the
equimolar amounts of indole (2 mmol, 0.234 g), aldehyde
(2 mmol), and DCDBTSD (0.0228 g, 5 mol%) were
added to a round-bottomed 2flask containing MeCN
(2 mL). The reaction mixture was stirred at 50°C for an
appropriate time point as listed in Table 2. The desired
solid product was obtained by simple filtration, dried, and
recrystallized (DMF–CHCl3).
RESULTS AND DISCUSSION
The initial studies were carried out one equimolar
amounts of 1H–indole and 4-methoxybenzaldehyde in the
presence of a catalytic amount of DCDBTSD as a model
reaction (Fig. 1).
Figure 5. A striking example, which had been observed for an unusual
hydride transfer from tricyclic orthoamide (16) through anomeric-based
oxidation [27]. [Color figure can be viewed at wileyonlinelibrary.com]
To determine the optimal reaction solvent, this reaction
was examined in H2O, CH3CN, EtOH, and under
solvent-free systems at 50°C. Table 1 indicates that the
reaction using acetonitrile as a solvent resulted in a high
yield and shorter reaction time (Table 1, entry 3).
The effect of the amount of catalyst was investigated
through reactions carried out at DCDBTSD contents ranging
from 4 to 10 mol%. It was found that an increase in the
DCDBTSD content from 4, 5, to 10 mol% could increase
the yield from 80% to 96% and 97%, respectively (Table 1,
entries 2–4). It was found that 5 mol% of DCDBTSD in
acetonitrile is satisfactory to catalyze the reaction (Table 1,
Figure 6. Synthesis of 1,4-dihydropyrano-[2,3-c]-pyrazole derivatives
via anomeric-based oxidation [28]. [Color figure can be viewed at
wileyonlinelibrary.com]
Figure 4. The proposed mechanism for the in situ oxidation–reduction in Cannizzaro reaction through unusual hydride transfer via anomeric-based ox-
idation [26]. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
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Month 2018
Synthesis of Indolo[3,2-b]carbazoles via an Anomeric-Based Oxidation Process:
A Combined Experimental and Computational Strategy
Figure 7. The synthesis of 2,4,6-triarylpyridines through anomeric-based oxidation [29]. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 8. Energy profile calculated for synthesis of indolo[3,2-b]carbazole by catalyst DCDBTSD beginning from compound VI (see Fig. 3). The relative
Gibbs-free energies in acetonitrile and the gas phase total electronic energies (Eel + ZPE, figures in parentheses) obtained from the B3LYP/SVP calcula-
tions both are given in kcal/mol. [Color figure can be viewed at wileyonlinelibrary.com]
of 1H-indole and aromatic aldehydes to produce excellent
yields in the presence of 5 mol% of DCDBTSD in
acetonitrile at 50°C.
It was noted that substituents in the aromatic ring of the
aldehyde had a strong effect on the reaction. Electron-
withdrawing groups in the aromatic ring of the aldehyde
Journal of Heterocyclic Chemistry
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M. A. Zolfigol, A. Khazaei, F. Karimitabar, M. Hamidi, F. Maleki,
Vol 000
B. Aghabarari, F. Sefat, and M. Mozafari
decelerated that the reaction and the electron-donating
groups accelerated the reaction. Because of the previously
mentioned fact, it was not possible to synthesize indolo
[3,2-b]carbazoles of 4-nitrobenzaldehyde.
Previously reported methods for the synthesis of indolo
[3,2-b]carbazoles observed that indolo[2,3-b]carbazoles
also formed during the reaction but were difficult to
separate because of their insolubility [24]. In the present
study, the indolo[2,3-b]carbazole isomer could not form,
which makes this method more suitable for the synthesis
of indolo[3,2- b]carbazoles. A plausible mechanism for
the reaction is outlined in Figure 3.
and 2,4,6-triarylpyridine derivatives synthesis [29] (Figs 6
and 7). For approving of this aim, reaction was carried out
under nitrogen atmosphere and in the absence of any
molecular oxygen. We observed that the reaction
progressed in the absence of any oxygen molecules and
under atmosphere of nitrogen. The previously mentioned
evidence shows that the conversion of intermediate VI to
its corresponding indolo[3,2-b]carbazoles VIII (Fig. 8)
might happen via unusual hydride transfer and releasing
of molecular hydrogen (H2). The C─H bond is so weaken
via electron donation from the C─C double bond into the
anti-bonding of C─H (σ*C─H orbital), which it can be
broken via reaction with a proton to afford molecular
hydrogen. Very recently, we introduced a new term for
this phenomena entitled “anomeric-based oxidation.” The
major reason of ABO is the driving force of
It is likely that the described catalyst in situ release Br+,
which act as an electrophilic species that activates the
aldehyde for an electrophilic attack of indole to generate
intermediate III. Self-condensation occurs and results in
the formation of tetrahydro intermediate VI. Earlier
reports suggest aerobic auto-oxidation of tetrahydro
compound VI to its corresponding indolo[3,2-b]carbazole.
In contrast to the previously reported mechanistic
explanation for the final step of the previously described
organic synthesis [24,25], we believed that this step might
progress by uncommon hydride transfer as well as
Cannizzaro reaction (Fig. 4) [26] and H2 releasing from
tricyclic orthoamide (Fig. 5) [27]. Recently, we suggested
an anomeric-based oxidation (ABO) for the final step for
the synthesis of 1,4-dihydropyrano-[2,3-c]-pyrazole [28]
aromatization,
which
will
be
supported
via
stereoelectronic and/or anomeric effect.
To investigate the final step in mechanistic process for the
synthesis of indolo[3,2-b]carbazole density functional theory
has been used. Starting from VI, two different orientations of
Ph substituents and C─H groups on intermediate VI with
respect to each other give cis and trans isomers. As
illustrated in Figure 1, by addition of catalyst DCDBTSD,
intermediate VII will be formed through the formation of
transition structures, TS-cis and TS-trans, and then
removing the molecular hydrogen (H2). According to the
Figure 9. The optimized structure of all compounds involved in conversion of VI to VIII according to the mechanism suggested in Figure 8. [Color figure
can be viewed at wileyonlinelibrary.com]
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Synthesis of Indolo[3,2-b]carbazoles via an Anomeric-Based Oxidation Process:
A Combined Experimental and Computational Strategy
Table 3
has also supported the ABO in the final step of the
mechanistic pathway. It is speculated that the proposed
mechanism have a high potential for entering into the
graduate text books in the future.
The main second order perturbation energies (kcal/mol) calculated for
intermediate VI.
Isomers of
intermediate VI
Donor–acceptor
interactions
Cis
Trans
2.88
Acknowledgments. We thank Bu-Ali Sina University and Iran
National Science Foundation (INSF) for financial support (The
Grant of Allameh Tabataba’i’s Award, Grant Number: BN093)
to our research group. Also we would like to express our sincere
thanks Professor Sadegh Salehzadeh for his guidance.
π C1-C2 →σ*
C6-H1
π C1-C2 →σ*
C3-H2
π C4-C5 →σ*
C6-H1
π C4-C5 →σ*
C3-H2
2.83
3.36
3.36
2.83
3.23
3.23
2.88
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Total
12.38 12.22
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values of calculated Gibbs-free energies in acetonitrile
solution, this reaction is about 20.1 and 19.5 kcal/mol
endothermic for cis and trans isomers, respectively.
In the final step of the reaction, intermediate VII
converts into indolo[3,2-b]carbazole (VIII) through an
exothermic process (ΔG = À29.62 kcal/mol for both cis
and trans isomers). In conclusion, the process of
conversion of VI to VIII through the releasing molecular
hydrogen is exothermic (ΔG = À9.50 and À10.11 kcal/
mol for cis and trans isomers, respectively).
The important step of ABO is the direct elimination of
H2 molecule from intermediate VI and catalyst
DCDBTSD (Fig. 9) in which the C─H bond in
intermediate VI is so weakened because of the
delocalization of π electron of C─C double bonds to σ*
C─H bonds. The natural bond orbital analysis of donor–
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identified the previous delocalization for cis and trans
isomers of intermediates VI are 12.38 and 12.22 kcal/
mol, respectively.
Thus, the previous theoretical studies support our
suggested mechanism and show that the releasing
molecular hydrogen (H2) is quite possible in such
systems. The optimized structures of all compounds
involved in our suggested mechanism are shown in
Figure 2. The Cartesian atomic coordinates of all
compounds involved in our suggested mechanism are
available in the Supporting Information.
CONCLUSIONS
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novel and efficient method for the synthesis of indolo
[3,2-b]carbazole derivatives catalyzed effectively by
DCDBTSD. A new mechanistic approach is proposed for
the final step of the indolo[3,2-b]carbazole synthesis. In
addition to the experimental efforts, the theoretical study
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SUPPORTING INFORMATION
Additional Supporting Information may be found online
in the supporting information tab for this article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet