An Alternate Synthesis of 6H-Indolo[2,3-b]quinoline via One-Pot Alkylation–Dehydration–Cyclization–Aromatization Approach

Article abstract of DOI:10.1002/jhet.2213

A simple, straightforward and efficient synthesis of 6H-indolo[2,3-b]quinoline, a natural product isolated from leaves of Justicia betonica, is achieved through a pivalic acid-assisted one-pot alkylation–dehydration–cyclization–aromatization approach. This synthesis constitutes a formal approach toward a biologically important alkaloid neocryptolepine.

Full text of DOI:10.1002/jhet.2213

Month 2016
An Alternate Synthesis of 6H-Indolo[2,3-b]quinoline via One-Pot
Alkylation–Dehydration–Cyclization–Aromatization Approach
Hari K. Kadam and Santosh G. Tilve*
Department of Chemistry, Goa University, Taleigao Plateau, Goa 403206, India
*
E-mail: stilve@unigoa.ac.in
Received December 31, 2013
DOI 10.1002/jhet.2213
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
OHC
"
ONE-POT"
N
H
N
H
N
H N
2
6
H-Indolo[2,3-b]quinoline
Quinindoline or Norcryptotackeine
A simple, straightforward and efficient synthesis of 6H-indolo[2,3-b]quinoline, a natural product isolated
from leaves of Justicia betonica, is achieved through a pivalic acid-assisted one-pot alkylation–dehydration–
cyclization–aromatization approach. This synthesis constitutes a formal approach toward a biologically
important alkaloid neocryptolepine.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
Our group had developed a one-pot synthesis of indolo-
quinoline by reaction of indole-3-carboxaldehyde and aryl
amines in presence of iodine as a catalyst in refluxing
diphenylether [6a]. This process involves iodine-catalyzed
sequential imination, nucleophilic addition, and annulation
reactions. Thereafter, Vaghei and Malaekehpoor [6b]
reported NBS as catalyst instead of iodine for these reactions
at room temperature and synthesized various substituted
indoloquinolines. A recyclable heterogeneous Ru catalyst
is reported by Khorshidi and Tabatabaeian [6c] for these
reactions. Seidel’s group [7] explored a divergent reaction
of indole with N-methyl-2-aminobenzaldehyde using
p-TSA to obtain neocryptolepine. Similarly, Liang’s group
[8] exploited a metal-free iodine-mediated selective difunc-
tionalization of N-benzylindoles by Friedel–Craft alkyl-
Indoloquinoline alkaloids are known for their natural
occurrence and diverse biological activities [1]. 6H-Indolo
2,3-b]quinoline 1, also known as quinindoline or norcryp-
[
totackeine, was isolated from the leaves of Justicia betonica
along with 5H-indolo[2,3-b]quinolin-11(6H)-one 2 [2].
Quinindoline 1 is a recognized precursor of well-known
alkaloid 5-methyl-5H-indolo[2,3-b]quinoline 3 named as
neocryptolepine or cryptotackeine isolated from roots of
West African plant Cryptolepis sanguinolenta [3] (Fig. 1).
Decoction of C. sanguinolenta was used in the past for
treatment of infectious diseases, fever, and malaria. This
made the isolated alkaloids a subject of intense biological
screening and as medicinally important compound [4].
Neocryptolepine 3 exhibited in vitro and in vivo anti-
plasmodial activity and antibacterial activity and also
inhibited the growth of the yeast Candida albicans.
Antiproliferative study on human hepatocellular carcinoma
HepG2 and human breast carcinoma MCF-7 cells revealed
methyl substituted 6H-indolo[2,3-b]quinolines to be most
active. Many methyl derivatives of neocryptolepine 3
displayed antibacterial, antimycotic, in vitro cytotoxic ac-
tivity, in vivo antitumor properties, and DNA topoisomer-
ase II inhibition. Synthetic derivatives of neocryptolepine
ation
with
N-tosylaminobenzaldehyde
to
give
benzylindoloquinoline. This was then debenzylated to
indoloquinoline by AlCl and then regioselectively methyl-
3
ated at quinoline N-atom with dimethylsulfate to give
neocryptolepine. Pumphrey et al. [9] demonstrated a Ru
catalyzed C–H bond amination strategy for synthesis of
neocryptolepine using aryl azide. Maes’s group [10] syn-
thesized chloroneocryptolepine starting from quinolinium
triflates and chloroanilines via a one-pot condensation and
Pd-catalyzed intramolecular direct arylation strategy.
In continuation of our interest in indoloquinoline alka-
loids [1,6a,11], we herein report a simple one-pot assembly
of indoloquinoline skeleton by pivalic acid-mediated cycli-
zation between indole and o-aminobenzaldehyde.
3
displayed in vitro inhibition of β-haematin formation in
cell-free systems, indicating a potential mechanism for
their antiplasmodial activity, and also exhibited antitry-
panosomal activity. Amino-substituted neocryptolepine
derivatives exhibited schistosomicidal activity.
Potential medicinal applications have motivated many
synthetic chemists to develop methodologies for its prepa-
rations through diverse approaches [5]. One-pot approaches
RESULTS AND DISCUSSION
[
6] have become widely popular as these methods can be
In literature [7,8] as described earlier, N-tosyl-o-
aminobenzaldehyde and N-methyl-o-aminobenzaldehyde
have been reported as substrate for the synthesis of
indolo[2,3-b]quinoline system. However, direct use of
easily utilized by medicinal chemists and other applica-
tion-oriented researchers to have an easy access to this
skeleton. Here are the highlights of such one-pot
methodologies.
©
2016 Wiley Periodicals, Inc.

H. K. Kadam and S. G. Tilve
Vol 000
Figure 1. Naturally occurring indolo[2,3-b]quinolines.
unsubstituted o-aminobenzaldehyde was lacking, maybe
because of its propensity for dimerization and polymeriza-
tion. We thought that directly using o-aminobenzaldehyde
can give 6H-indolo[2,3-b]quinoline 1, and its N-alkylation
then can give neocryptolepine 3 and its analogs. Further, as
arene being not protected, additional step of removal of the
protecting group from nitrogen may not be required. Ini-
We then tried the reaction using indole 4 and freshly pre-
pared o-aminobenzaldehyde 5 and heated this mixture in
solvent at high temperature; we were delighted to observe
product formation after reflux for 6 h, but on purification,
product 1 was isolated in just 11% yield (Scheme 1; Table 1).
Then,weinvestigatedthisreactionbyemployingvariousox-
idizingreagentsthatweanticipatedmayhelpinfinaloxidation
tially, we tried the reaction using p-TSA and I condition
step. Thus, we tried MnO , Pd/C, and DDQ but were
2
2
reported for N-methylindole without success. Strong acid
like TFA is known to give 3-(2-amino-phenyl)quinolines
with indole and o-aminobenzaldehyde [7].
unsuccessful toobtain any product formation.
Pivalic acid, being a non-nucleophilic weak acid, binds
reversibly to the amino group and activates the carbonyl,
thereby increasing the electrophilicity of aldehyde 5. We
tried this for the reaction and observed product 1 formation
in moderate yield. Increasing the acid strength did not furnish
us any product formation. This one-pot reaction, although
average yielding, is very simple and efficient.
Scheme 1. One-pot cyclization.
Table 2
a
Scope of reaction (Scheme 2).
Table 1
b
Entry
1
Indoloquinoline 1a-b
% Yield
Various catalyst and reagents (Scheme 1).
56
a
Entry
Reaction condition
% Yield
1
2
3
4
5
6
7
8
p-TSA, Ph
, dioxane, reflux, 24 h
Ph O, reflux, 6 h
MnO , dioxane, reflux, 24 h
Pd/C, dioxane, reflux, 24 h
DDQ, dioxane, reflux, 24 h
2
O, reflux, 4 h
–
–
11
–
–
–
I
2
2
2
54
2
2
PivOH (1 eq.), Ph O, reflux, 6 h
PivOH, reflux, 6 h
56
–
a
4 (1 mmol), 5 (1.5 mmol), pivalic acid (1 mL), Ph
b
2
O (10 mL) reflux, 6 h.
a
Isolated yield.
Isolated yield.
Scheme 2. Substrate study.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
One-Pot Synthesis of 6H-Indolo[2,3-b]quinoline
Scheme 3. Mechanistic rationale.
Scheme 4. Formal synthesis of neocryptolepine.
We extended this methodology for synthesizing a deriv-
ative using 5-methoxyindole 4b and obtained the corre-
sponding product in 54% yield (Scheme 2; Table 2).
Based on the product formation and reaction conditions
employed, a probable mechanism is postulated (Scheme 3).
First alkylation of indole 4 with o-aminobenzaldehyde 5
takes place followed by dehydration, and cyclization fur-
nishes dihydroindoloquinoline, which oxidizes in air to
give the final product indoloquinoline 1.
chromatography with TLC silica gel 60 F254 purchased from Merck
Mumbai, India). Column chromatography was performed on silica
(
gel (60–120 mesh). Flash chromatography was performed on a
Combiflash Companion (Teledyne Isco, NE) with silica
gel (230–400 mesh). Melting points were recorded in open capillary
tubes using Thiele’s apparatus and are uncorrected. The IR spectra
were recorded on Shimadzu FTIR spectrophotometer (Kyoto, Japan).
1
13
The H (400 MHz) and C (100 MHz) NMR spectra were recorded
on a Bruker AVANCE 400 instrument (Switzerland) using CDCl3
6
and DMSO-d as solvent. Chemical shifts δ are expressed relative to
TMS or residual solvent; the coupling constant J is given in hertz.
The multiplicities of the carbon signals were obtained from
DEPT-135 experiment. The following abbreviations were used:
s = singlet, d = doublet, t = triplet, m = multiplet, br s = broad singlet,
and dd = double doublet.
The transformation of natural product indoloquinoline to
neocryptolepine is well known in literature [11,13–16]
using MeI or Me SO as methylating agents. Thus, this
2
4
synthesis formulates a formal synthesis of alkaloid
neocryptolepine 3 (Scheme 4).
o-Aminobenzaldehyde (5).
CONCLUSION
6
H-Indolo[2,3-b]quinoline 1 is successfully synthe-
sized in one pot by alkylation–dehydration–cyclization–
aromatization approach using pivalic acid with indole and
o-aminobenzaldehyde. This method provides scope for
generating a library of such compounds for various biologi-
cal applications. The overall yields in this methodology were
comparable with the other efficient syntheses known in
literature. This synthesis also constitutes the formal synthesis
of alkaloid neocryptolepine 3.
A mixture of o-aminobenzyl alcohol (0.615 g, 5 mmol) and
MnO (2.0 g) was stirred in CH Cl at room temperature. This
2
2
2
was filtered after 12 h, and removing solvent under vacuum gave
product 5 in 92% (0.557 g) yield.
Orange oil [12].
1
3
H-NMR (400 MHz, CDCl ): δ 6.05 (br s, 2 H), 6.55
(
1
d, J = 8.0 Hz, 1 H), 6.66 (t, J = 7.6 Hz, 1 H), 7.23 (t, J = 7.2 Hz,
H), 7.38 (d, J = 7.6 Hz, 1 H), 9.78 (s, 1 H) ppm.
6H-Indolo[2,3-b]quinoline (1a).
EXPERIMENTAL SECTION
Commercial reagents were purchased from Sigma-Aldrich
(Mumbai, India) and used without further purification. Solvents were
distilled prior to use. Reactions were monitored by thin layer
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. K. Kadam and S. G. Tilve
Vol 000
A mixture of indole 4a (0.117 g, 1 mmol), freshly prepared
o-aminobenzaldehyde (0.182g, 1.5mmol), and pivalic acid (1mL)
was refluxed in Ph O (10 mL) for 6 h (TLC; 10% EtOAc/hexanes).
2
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7
After cooling, the mixture was chromatographed (silica gel), Ph O
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0.122 g) yield.
mp > 300°C (Lit. mp: 342–346 °C) [6a,11]
À1
IR (KBr): 3143, 3055, 1612, 1580 cm
.
1
6
H-NMR (400 MHz, DMSO-d ): δ = 7.27 (t, J = 8.0 Hz, 1 H),
7
1
1
.46–7.53 (m, 3 H), 7.72 (t, J = 7.2 Hz, 1 H), 7.96 (d, J = 8.0 Hz,
H), 8.10 (d, J = 8.0 Hz, 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 9.05 (s,
H), 11.69 (s, 1 H) ppm.
3
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2
9
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sponding indoloquinoline 1b was obtained as light-green solid
in 54% (0.134 g) yield.
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1
H-NMR (400 MHz, DMSO-d ): δ = 3.87 (s 3 H), 7.14 (dd,
6
J = 8.4, 2.8 Hz, 1 H), 7.39 (d, J = 8.8 Hz, 1 H), 7.46 (t, J = 7.2 Hz,
1
(
1
H), 7.70 (t, J = 8.4 Hz, 1 H), 7.88 (d, J = 2.4 Hz, 1 H), 7.94
d, J = 8.8 Hz, 1 H), 8.07 (d, J = 8.0 Hz, 1 H), 9.04 (s, 1 H),
1.49 (s, 1 H) ppm.
13
C-NMR (100 MHz, DMSO-d
CH), 111.60 (CH), 116.55 (CH), 118.08 (Cq), 121.23 (Cq),
22.50 (CH), 123.37 (Cq), 126.90 (CH), 127.64 (CH), 128.63
6 3
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(
1
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2X CH), 135.82 (Cq), 146.33 (Cq), 153.26 (Cq), 153.57 (Cq) ppm.
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Acknowledgments. We are thankful to the Council for Scientific
and Industrial Research (CSIR), New Delhi, for project funding.
H. K. is also thankful to CSIR for awarding the National
Eligibility Test (NET) Senior Research Fellowship.
[
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet