Facile convergent route to indoloquinolines

Article abstract of DOI:10.1080/00397911.2017.1359303

A convergent route to indoloquinolines is developed through aldol condensation. This two-step method utilizes commercially available 2-oxoindole and o-nitrobenzaldehyde as starting materials. Chromatography-free method is accomplished for preparing several derivatives of indoloquinolines with desirable aromatic substitutions on indole as well as quinoline ring.

Full text of DOI:10.1080/00397911.2017.1359303

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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A facile convergent route to indoloquinolines
Hari K. Kadam, Deesha D. Malik, Lalitprabha Salgaonkar, Ketan Mandrekar &
Santosh G. Tilve
To cite this article: Hari K. Kadam, Deesha D. Malik, Lalitprabha Salgaonkar, Ketan Mandrekar &
Santosh G. Tilve (2017): A facile convergent route to indoloquinolines, Synthetic Communications,
DOI: 10.1080/00397911.2017.1359303
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1359303
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Date: 30 July 2017, At: 03:06

A facile convergent route to Indoloquinolines
Hari K. Kadam
Department of Chemistry, St. Xavier’s College, Mapusa, Goa, India
Deesha D. Malik
Department of Chemistry, Goa University, Taleigao Plateau, Goa, India
Center for Biomimetic Systems, Ewha Womans University, Seoul, Korea
Lalitprabha Salgaonkar
Department of Chemistry, St. Xavier’s College, Mapusa, Goa, India
Ketan Mandrekar
Department of Chemistry, Goa University, Taleigao Plateau, Goa, India
Santosh G. Tilve
Department of Chemistry, Goa University, Taleigao Plateau, Goa, India
Address correspondence to Hari K. Kadam, Department of Chemistry, St. Xavier’s College,
Mapusa, Goa – 403507, India. Fax: + 91-832-2262356. E-mail: harikadam05@gmail.com
1

Supporting Information
Full Experimental details are available via the Supplementary Content section of this article’s
webpage.
ABSTRACT
A convergent route to indoloquinolines is developed via Aldol condensation. This two step
method utilizes commercially available 2-oxoindole and o-nitrobenzaldehyde as starting materials.
Chromatography-free method is accomplished for preparing several derivatives of
indoloquinolines with desirable aromatic substitutions.
KEYWORDS: aldol reaction, indoloquinoline, natural product, oxoindole, synthesis
Introduction
Nitrogen containing heterocyclic compounds is a noble class of chemical entities
incorporated in medicinal studies. The diverse biological responses of such compounds in
antiviral, anticancer, antibacterial, and other studies make them a challenging target of synthetic
development for organic chemists.[1] Indoloquinoline alkaloids belong to one such class. 6H-
indolo[2,3-b]quinolone 1, a natural product isolated from isolated from the leaves of Justicia
betonica, (Figure 1) exhibit promising biological properties.[2]4-methyl-6H-indolo[2,3-
2

b]quinoline (I) exhibited excellent antiproliferative activity against human hepatocellular
carcinoma HepG2 and human breast carcinoma MCF-7 cells.[3a] Neocryptoepine (II) or 5-methyl-
5H-indolo[2,3-b]quinoline is a natural product isolated from roots of the West African plant
Cryptolepis sanguinolenta and exhibits antiplasmodial, antitumor activity and DNA binding
properties.[3b]
N,N-Diethyl-N-(5-methyl-5H-indolo[2,3-b]quinolin-8-yl)pentane-1,4-diamine
(III), 1-(3-(2-Chloro-5-methyl-5H-indolo[2,3-b]quinolin-11-ylamino)-propyl)-3-phenylurea (IV)
and 1-(3-(2-Methoxy-5-methyl-5H-indolo[2,3-b]quinolin-11-ylamino)propyl)-3-phenylurea (V)
showed excellent antimalarial activity.[4]
The useful biological properties and potential medicinal use of these indoloquinolines have
resulted in several synthetic methods being developed and reviews in literature.[3–7] In this paper,
we report a two step method using commercially available 2-oxoindole and o-nitrobenzaldehyde
as starting materials for synthesis of indoloquinolines via Aldol condensation.
Results and Discussion
At the onset, we contemplated that 2-oxoindole 3 and o-nitrobenzaldehyde 4 can give us
olefinic condensed product as described in scheme 1 via Aldol reaction which can further be
converted to indoloquinolines via method involving reduction[6] and cyclisation.
3

In view of this, 2-oxoindole 3 and o-nitrobenzaldehyde 4 were reacted in Aldol reaction
conditions using piperidine as base to give required condensed olefinic Aldol product 2 as
geometrical isomeric mixture[8] inꢀ moderate yield. This reaction was further optimised to provide
maximum yield by precisely tuning the reaction condition and time. We were successful in
avoiding the uneconomic, environmentally harmful and time consuming column chromatography
to obtain the required product from this step.
The Aldol reaction used here provided us a convenient and efficient alternative to other
costly, tedious and laborious processes by avoiding preparation of any unstable precursors, use of
toxic reagents and metals and ultimately giving condensed olefinic compounds. Further the Aldol
product 2 was subjected to nitroreduction[6] and cyclisation which was further optimised with
EtOH-AcOH (1:3) at 120 °C for 48hꢀ to give indoloquinoline in good yield. The overall yield in
this two step method as described in Scheme 2 was far more comparable with the one step or one
pot methods available in literature.[7]
Having established a short two step chromatography free route from easily available
starting materials, we further extended it to prepare derivatives of indoloquinolines with desired
aromatic substitutions. Dimethoxy-indoloquinoline, Methylenedioxy-indoloquinoline and Chloro-
4

indoloquinoline derivatives were obtained in around 73-78% overall yields in two steps as
described in Table 1.
Experimental
General procedure for Aldol product 2a-d: In a dry 100mLꢀ round bottom flask, 2-oxindole
3a-b (1 mmol), o-nitrobenzaldehydes 4a-c (1.2 mmol) and EtOH (25mLꢀ) were mixed with stirring
and Piperidine (0.85mgꢀ, 0.01 mmol) in EtOH (2mLꢀ) was added dropwise while stirring at r.t.
Mixture was then refluxed with stirring for 1hꢀ. On completion of reaction (monitored by TLC),
solvent was removed under vacuum and Et2O was added, insoluble solid Aldol product 2a-d
separated out and was isolated by filtration.
3-(2-nitrobenzylidene)indolin-2-one (geometrical isomeric mixture);[6] 2a; Orange solid;
1
M.P. 224-226 °C. IR (KBr):  1201, 1342, 1470, 1624, 1686, 1732, 3254, 3332cmꢀ-1. H NMR
(DMSO-d6): δ 6.14 (d, J = 6.8Hzꢀ, 1H), 6.59 (s, 1H), 6.64 (t, J = 8.0Hzꢀ, 1H), 6.77 (m, 2H), 7.00
(t, J = 7.6Hzꢀ, 1H), 7.11 (t, J = 8.0Hzꢀ, 1H), 7.26 (t, J = 8.0Hzꢀ, 1H), 7.47 (m, 1H), 10.35 (s, 1H)
ppm. LCMS: m/z [M + H] +: 267.1
General Procedure for indoloquinolines 1a-d: In a dry 100mLꢀ round bottom flask, Aldol
product 2a-d (0.8 mmol), Fe powder (0.280gꢀ, 5 mmol), EtOH (5mLꢀ), AcOH (15mLꢀ) and conc.
HCl (1mLꢀ) were mixed. Mixture was then stirred at 120 °C for 48hꢀ. On completion of reaction
5

(monitored by TLC), mixture was filtered and washed with CHCl3. Solvent was removed under
vacuum. 2Nꢀ NaOH (100mLꢀ) was added and product was extracted in CHCl3 (50mLꢀ X 3). Extract
was dried with anhy. Sodium sulfate, filtered and solvent was removed under vacuum to give
indoloquinoline product 1a-d.
6H-indolo[2,3-b]quinoline;[5],[6] 1a; Brown solid. M.P. > 300 °C. 1H NMR (DMSO-d6,): δ
7.27 (t, J = 6.8Hzꢀ, 1H), 7.52 (m, 3H), 7.72 (t, J = 8.4Hzꢀ, 1H), 7.97 (d, J = 8.0Hzꢀ, 1H), 8.10 (d, J
= 8.0Hzꢀ, 1H), 8.26 (d, J = 8.0Hzꢀ, 1H), 9.06 (s, 1H), 11.71 (s, 1H) ppm. 13Cꢀ NMR (DMSO-d6): δ
110.9 (CH), 117.8 (Cq), 119.6 (CH), 120.2 (Cq), 121.8 (CH), 122.7 (CH), 123.6 (Cq), 126.9 (CH),
127.5 (CH), 128.2 (CH), 128.62 (CH), 128.65 (CH), 141.4 (Cq), 146.3 (Cq), 152.8 (Cq) ppm.
Conclusion
In conclusion, a two step efficient method is developed for synthesis of indoloquinolines
via Aldol reaction using commercially available starting materials. The method is optimised to
achieve affordable overall yields and avoiding chromatography purification. The general utility of
this method is demonstrated by preparing several derivatives of indoloquinolines with desirable
aromatic substitutions.
Acknowledgments
We thank Science & Engineering Research Board (SERB), New Delhi for funding.
6

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Table 1. Derivatives of indoloquinolines prepared using scheme 2
Entry Aldol
(geometrical
mixture)
products
2 %
Indoloquinolines 1
%
Overall
isomeric Isolated
Isolated yield
Yield
Yield
86
over 2
steps
NO2
1
2
3
4
91
78.3%
N
H
N
N
H
O
1a
2a
NO2
OMe
OMe
89
82
84
84
73.0%
73.9%
75.6%
N
H
N
OMe
OMe
N
H
O
1b
2b
NO2
O
O
88
N
H
N
N
H
O
1c
O
O
2c
NO2
Cl
90
Cl
N
H
N
N
H
O
1d
2d
9

Figure 1. Indoloquinoline 1 and similar medicinally important entities.
10

Scheme 1. Retrosynthetic analysis of Indoloquinoline 1 via Aldol condensation.
11

Scheme 2. Two step route to indoloquinolines.
12