InCl 3-Assisted Synthesis of Pyrano[2,3-a ]carbazoles via Multicomponent Reaction

Article abstract of DOI:10.1080/00397911.2014.910526

A facile, efficient, and environmentally friendly protocol for the synthesis of pyrano[2,3-a]carbazoles has been developed by one-pot multicomponent reaction of benzaldehyde/isatin with malononitrile and 1-hydroxycarbazoles in the presence of InCl3 as catalyst.

Full text of DOI:10.1080/00397911.2014.910526

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InCl3-Assisted Synthesis of Pyrano[2,3-
a]carbazoles via Multicomponent
Reaction
Ezhumalai Yamuna a & Karnam Jayarampillai Rajendra Prasad b
a Department of Chemistry , Tamkang University , Tamsui , Taiwan
b Department of Chemistry , Bharathiar University , Coimbatore ,
India
Accepted author version posted online: 16 May 2014.Published
online: 16 Jul 2014.
To cite this article: Ezhumalai Yamuna & Karnam Jayarampillai Rajendra Prasad (2014) InCl3-Assisted
Synthesis of Pyrano[2,3-a]carbazoles via Multicomponent Reaction, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:18, 2656-2661,
DOI: 10.1080/00397911.2014.910526
To link to this article: http://dx.doi.org/10.1080/00397911.2014.910526
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Synthetic Communications1, 44: 2656–2661, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.910526
InCl3-ASSISTED SYNTHESIS OF PYRANO[2,3-a]
CARBAZOLES VIA MULTICOMPONENT REACTION
Ezhumalai Yamuna1 and
Karnam Jayarampillai Rajendra Prasad2
1Department of Chemistry, Tamkang University, Tamsui, Taiwan
2Department of Chemistry, Bharathiar University, Coimbatore, India
GRAPHICAL ABSTRACT
Abstract A facile, efficient, and environmentally friendly protocol for the synthesis of
pyrano[2,3-a]carbazoles has been developed by one-pot multicomponent reaction of benzal-
dehyde/isatin with malononitrile and 1-hydroxycarbazoles in the presence of InCl3 as catalyst.
Keywords Heterocycles; 1-hydroxy carbazoles; InCl3; multicomponent reaction;
pyrano[2,3-a]carbazoles
INTRODUCTION
Multicomponent reactions (MCRs), in which multiple reactions are combined
into one synthetic operation, have been used extensively to form carbon–carbon
bonds in synthetic chemistry.[1] Such reactions offer a wide range of possibilities
for the efficient construction of highly complex molecules in a single procedural step,
thus avoiding the complicated purification operations and allowing savings of
both solvents and reagents. In the past decade there have been tremendous develop-
ments in three- and four-component reactions and great efforts continue to be made
to develop new MCRs.[2]
The carbazole nucleus is probably the most well-known heterocycle, a common
and important feature of a variety of natural products and medicinal agents.[3]
As specific examples, pyranocarbazole alkaloids such as grinimbine, mupamine,
and mahanimbine possess mosquitocidal, antimicrobial, anti-inflammatory, and
Received January 1, 2014.
Address correspondence to K. J. R. Prasad, Department of Chemistry, Bharathiar University,
Coimbatore-641046, India. E-mail: prasad_125@yahoo.com
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
2656

PYRANO[2,3-a]CARBAZOLES
2657
Figure 1. Oxygenated carbazole alkaloids.
antioxidant activities (Fig. 1).[4] Furthermore, it has been reported that sharing of
the indole 3-carbon in the formation of spiroindoline derivatives highly enhances
biological activity.[5] The spirooxindole system is the core structure of many
pharmacological agents and natural alkaloids.[6]
In recent years, indium trihalides have emerged as mild and water-tolerant
Lewis acids, imparting high regio- and chemoselectivity in various organic transfor-
mations. They can be conveniently used in both aqueous and nonaqueous media and
in addition, they can be recovered from aqueous layer on workup and recycled for
use in subsequent reactions. Further, InCl3 has been found to be highly effective
in hetero-Diels–Alder reaction,[7] Pall–Knorr condensation,[8] Friedel–Crafts
reaction,[9] and domino reaction.[10] The need to reduce the amount of toxic waste
and by-products arising from chemical processes requires increasing emphasis on
the use of less toxic and environmentally compatible materials in the design of
new synthetic methods.
For our synthetic strategy the easily accessible 1-hydroxycarbazoles were
employed as suitable synthons for deriving 1-oxygenated pyranocarbazole
compounds. Recently we reported the synthesis of 3- and 4-substituted pyrano
[2,3-a]carbazol-2-ones[11–14] but most of the procedures suffer from limitations such
as difficult workup and poor yields.
In continuation of our research interest, herein we report a novel and multi-
component one-pot synthesis of pyrano[2,3-a]carbazoles from 1-hydroxy carbazoles
and malononitrile with benzaldehyde=isatin in the presence of InCl3.
RESULTS AND DISCUSSION
We initially examined the reaction of 1-hydroxycarbazole 1, benzaldehyde, and
malononitrile in the presence of various catalysts using the same solvent system at
varying temperatures to yield pyrano[2,3-a]carbazoles. Using p-TsOH, tin(II) chlor-
ide, zinc chloride (entries 5 and 6 of Table 1) gave only poor to moderate yields.
Morpholine, ceric ammonium nitrate (CAN), and ytterbium triflate gave reasonable
yields (entries 8, 9, and 10 of Table 1). Indium(III) chloride (entries 1–4), on the
other hand, showed promising results. Ytterbium triflate as the catalyst facilitated
the formation of pyrano[2,3-a]carbazoles in good yields (around 80%). With InCl3
as the catalyst the reactions proceeded smoothly in an even shorter reaction time
with similarly good yields, thus indicating InCl3 as the most efficient catalyst of those
tested (Table 1). To optimize the reaction conditions we evaluated the most suitable
catalyst loading. With 10, 15, 20, and 25 mol% of InCl3 the yields progressively

2658
E. YAMUNA AND K. J. R. PRASAD
Table 1. Comparison of the efficiency of InCl3 with other catalysts for the synthesis pyrano[2,3-
a]carbazoles
Yield (%)
Entry
Catalyst
Solvent
Temperature (ꢁC)
Time (h)
2a
3a
1
2
InCl3 (10 mol%)
InCl3 (15 mol%)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
90
85
90
70
70
70
70
70
70
70
8
5
80
80
85
95
45
56
54
65
60
80
82
85
85
93
46
35
38
59
52
76
3
InCl3 (20 mol%)
InCl3 (25 mol%)
6
4
1.5
24
12
15
18
14
10
5
p-TsOH (25 mol%)
SnCl2.H2O (25 mol%)
ZnCl2 (25 mol%)
Morpholine (25 mol%)
CAN (25 mol%)
6
7
8
9
10
Yb(OTf)3 (25 mol%)
improved with loading until reaching a maximum of > 90% at 25 mol%. No
additional increase was observed upon further increasing the load of InCl3.
The reaction was found to be general and use of this method with various
1-hydroxycarbazoles[15] with benzaldehyde afforded highly substituted 2-amino-4-
phenyl-4,11-dihydropyrano [2,3-a]carbazole-3-carbonitrile in good yield as shown
in Scheme 1 (Table 2, entries 1–4).
Subsequently, we also investigated the reaction of compounds 1 with isatin
instead of benzaldehyde. Reactions proceeded smoothly and gave another series of
20-amino-2-oxo-110H-spiro[indoline-3,40-pyrano[2,3-a]carbazole]-30-carbonitrile in excellent
yields (Scheme 2, Table 2, entries 5–8).
The structures of the products were deduced from their elemental analysis data
1
and from their infrared (IR), mass, H NMR, and 13C NMR spectra. The IR spec-
trum of 2a, for example, shows absorption peaks at 3472, 3413, 3313, and 2194 cmꢀ1
,
which attest to the presence of amino, indole NH, and cyano groups, respectively.
Similarly, for compound 3a the IR spectrum showed 3432, 3329, and 3290 cmꢀ1
for the NH2 and carbazole NH groups, and at 2217 cmꢀ1 for the cyano group, as
1
expected. The H NMR spectrum of compounds 2b–d is as expected. Compound
2a, for example, exhibits a series of signals in the aromatic region of the spectrum
Scheme 1. Synthesis of 2-amino-4-phenyl-4,11-dihydropyrano[2,3-a]carbazole-3-carbonitrile.

PYRANO[2,3-a]CARBAZOLES
2659
Table 2. Reaction of 1-hydroxycarbazoles with benzaldehyde=isatin and malononitrile in the presence
of InCl3
Entry
R1
R2
R3
Reactant
Product
Yield (%)
1
2
3
4
5
6
7
8
H
H
H
Benzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
Isatin
2a
2b
2c
2d
3a
3b
3c
3d
95
92
90
90
93
90
90
94
H
CH3
H
H
H
CH3
H
CH3
H
H
H
H
H
CH3
H
H
Isatin
Isatin
Isatin
H
CH3
CH3
H
H
Scheme 2. Synthesis of 20-amino-2-oxo-110H-spiro[indoline-3,40-pyrano[2,3-a]carbazole-30-carbonitrile.
at d 11.23–6.74, one singlet arising from the benzylic proton (d 4.88), and a broad
singlet for the two amine protons (d 6.69). The identities of the other compounds
2b–d and 3a–d were established in similar ways with all spectroscopic data
readily assignable.
CONCLUSION
In summary, this method offers easy access to pyrano[2,3-a]carbazoles with
varied substitution patterns in very good yields. Furthermore, good yields, simple
reaction conditions, easy purification, and economical availability of the catalyst
make this facile and superior method for the synthesis of pyrano[2,3-a]carbazoles.
Biological evaluation of these derivatives is under way.
EXPERIMENTAL
Melting points (mp) were determined on Mettler FP 51 apparatus (Mettler
Instruments, Switzerland) and are uncorrected. They are expressed in degree
centigrade (ꢁC). IR spectra were recorded on a Shimadzu FTIR-8201PC spectro-
1
photometer (Shimadzu, Japan) using KBr pellets. H and 13C NMR spectra were
recorded on Bruker AMX 400 and AMX 500 (400 MHz and 500 MHz (1H),
100 MHz and 125 MHz (13C) NMR) spectrometers at Indian Institute of Science,

2660
E. YAMUNA AND K. J. R. PRASAD
Bangalore, and Indian Institute of Technology, Chennai, using tetramethylsilane
(TMS) as an internal reference. The chemical shifts are expressed in parts per million
(ppm). Microanalyses were performed on a Vario EL III model CHNS analyzer
(Vario, Germany) at the Department of Chemistry, Bharathiar University. The purity
of the products was tested by thin-layer chromatography (TLC) with plates coated
with silica gel-G with petroleum ether and ethyl acetate as developing solvents.
Procedure for the Preparation of Pyrano[2,3-a]carbazoles (2a)
InCl3 (25 mol%) dissolved in CH3CN was added to a mixture of 1-hydroxycar-
bazole (1 mmol), malononitrile (1 mmol), and benzaldehyde (1 mmol) and subjected
to microwave irradiation (Biotage microwave oven, 70 ꢁC, 2 bar pressure) for 10 min.
The progress of the reaction was monitored by TLC. Upon cooling, the product
precipitated from the reaction mixture, which was filtered, dried, and recrystallized
from ethanol.
2-Amino-4-phenyl-4,11-dihydropyrano[2,3-a]carbazole-
3-carbonitrile (2a)
Light yellow solid (0.320 g, 95%); mp: 244 ꢁC; IR (KBr) 3472, 3413, 3313,
2194, 1646 cmꢀ1; 1H NMR (400 MHz, CDCl3): d (ppm) 4.88 (s, 1H, benzylic hydrogen),
6.69 (s, 2H, 2-NH2), 6.74 (d.,1H, 5-H, J ¼ 8.0 Hz), 7.14 (t, 1H, 9-H, J ¼ 8.0 Hz),
7.22–7.16 (m, 3H, 20-H, 40-H & 60-H), 7.28 (t, 2H, 3-H & 5-H, J ¼ 8.0 Hz), 7.36
(dt, 1H, 8-H, Jo ¼ 8.0 Hz, Jm ¼ 1.5 Hz), 7.54 (d, 1H, 10-H, J ¼ 8.0 Hz), 7.73
(d,1H, 6-H, J ¼ 8.0 Hz), 8.00 (d, 1H, 7-H, J ¼ 8.0 Hz), 11.23 (bs, 1H, 11-H);
13C NMR (CDCl3, 125 MHz) d: 41.40, 58.00, 112.26, 116.76, 119.45, 119.60,
119.68, 120.59, 120.97, 122.81, 123.76, 126.22, 127.23, 127.98, 129.10, 134.98,
140.70, 146.73, 160.46. MS: m=z (%) 337 (Mþ, 100), 260 (26), 222, (21), 165 (18),
145 (14), 141(12), 119 (9), 115 (12). Anal. calcd. for C22H15N3O: C, 78.32; H, 4.48;
N, 12.46%. Found: C, 78.36; H, 4.43; N, 12.50%.
ACKNOWLEDGMENTS
Our sincere thanks go to the chairman, NMR Research Centre, IISc,
Bangalore; SAIF, IIT Madras, Chennai; and the director, ISO Quality Assurance
Cell, Indian Institute of Chemical Technology, Hyderabad, for providing access
to their NMR and mass spectral facilities and use of a Biotage microwave oven,
Madurai Kamaraj University, Madurai.
FUNDING
We acknowledge URF, Bharathiar University, for the award of a research
fellowship.
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.

PYRANO[2,3-a]CARBAZOLES
2661
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