An eco-friendly synthesis of 2-aminochromenes and indolyl chromenes catalyzed by InCl3 in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2007.07.102

A simple and convenient method for the synthesis of new 2-aminochromenes and indolyl chromenes via an indium trichloride catalyzed, three-component reaction in aqueous media is described.

Full text of DOI:10.1016/j.tetlet.2007.07.102

Tetrahedron Letters 48 (2007) 6785–6789
An eco-friendly synthesis of 2-aminochromenes and indolyl
chromenes catalyzed by InCl3 in aqueous media
Gnanamani Shanthi and Paramasivan T. Perumal*
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, India
Received 31 May 2007; revised 5 July 2007; accepted 12 July 2007
Available online 25 July 2007
Abstract—A simple and convenient method for the synthesis of new 2-aminochromenes and indolyl chromenes via an indium tri-
chloride catalyzed, three-component reaction in aqueous media is described.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Multicomponent reactions (MCRs) by virtue of their
convergence, productivity, facile execution and gener-
ally high yields of products have attracted considerable
attention from the point of view of combinatorial chem-
istry.1 The first MCR was described by Strecker in 1850
for the synthesis of amino acids.2 However, in the past
decade there have been tremendous developments in
three- and four-component reactions and great efforts
have been and still are being made to find and develop
new MCRs.3 In this context, dihydropyridines (DHPs)
show interesting features that make them attractive for
use in MCRs.
except for some chiral NAD(P)H models.11 Hence, the
use of NAD(P)H model compounds as a class of mild
reducing agents in synthetic organic chemistry is of con-
siderable interest.1
2-Aminochromenes are widely employed as pigments,12
cosmetics, agrochemicals13 and represent an important
class of chemical entities being the main constituents
of many natural products. Fused chromenes exhibit a
wide spectrum of biological applications as antimicro-
bial, antiviral,14 mutagenic, antiproliferative, sex phero-
mone, antitumour15 and central nervous system agents.
The most straightforward synthesis of this heterocyclic
nucleus involves the MCR of araldehyde, malononitrile
and an activated phenol in the presence of piperidine16
using acetonitrile or ethanol as solvent. However, most
of the reported methods require prolonged reaction
times, reagents in stoichiometric amounts, and toxic
solvents and generate moderate yields of the product.
Due to the unique pharmacological properties of 2-
aminochromenes, the development of synthetic methods
enabling facile access to this heterocycle is desirable.
The reduced form of the nicotinamide adenine dinucleo-
tide coenzyme [NAD(P)H] plays a vital role in many
bioreductions by transferring a hydride ion or an elec-
tron to substrates.4 1-Benzyl-1,4-dihydronicotinamide
(BNAH), Hantzsch 1,4-dihydro pyridines (DHP), 10-
methyl-9,10-dihydroacridine (AcrH2) and many other
1,4-dihydropyridine derivatives have been used widely
as models of NAD(P)H to mimic the reductions of var-
ious unsaturated compounds such as quinones,5
ketones,6 aldehydes,7 imines8 and alkenes.9 Garden
et al.10 have reported the reduction of certain electron-
withdrawing conjugated olefins using the Hantzsch
1,4-dihydropyridine ester. To our best knowledge, very
little effort has been made towards the application of
these NAD(P)H models in synthetic organic chemistry
Lately, the utility of indium(III) Lewis acids17 in organic
synthesis has received a great deal of interest due to their
relatively low toxicity, stability in air and water and
recyclability. As part of our current studies on the
design of new routes for the preparation of biologically
active heterocyclic compounds and in the application of
18
InCl3 in organic synthesis, we herein disclose a simple
and convenient method for the synthesis of 2-amino-
chromenes from the Hantzsch ester using a catalytic
amount of InCl3 in aqueous media at room temperature
(Scheme 1).
Keywords: 2-Aminochromenes; Three-component reaction; Indium(III)
chloride.
*
Corresponding author. Tel.: +91 44 24913289; fax: +91 44
24911589; e-mail: ptperumal@gmail.com
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.102

6786
G. Shanthi, P. T. Perumal / Tetrahedron Letters 48 (2007) 6785–6789
H
H
CHO
+
OH
EtO2C
+
H3C
CO2Et
CH3
InCl3 (20 mol%)
H2O:EtOH, 1:1
CN
CN
CN
N
H
3
O
NH2
———
1
4a
2
Scheme 1.
H H
5
8
4
CHO
OH
X
X
CN
EtO2C
+
H3C
CO2Et
CH3
InCl3(20 mol%)
H2O:EtOH, 1:1
CN
6
7
3
+
CN
O
2
NH2
N
H
1
3
4a-e
2
1
Scheme 2.
In order to study the scope and limitations of the three-
The structures of compounds 4a–e were confirmed by
1
component reaction, various Lewis acid catalysts,
including SnCl2Æ2H2O, NH2SO3H, CAN, In(OTf)3 and
InCl3 and different solvent systems were investigated.
The best overall yield (86%) was obtained with InCl3
in water:ethanol (1:1). Optimum results were obtained
using 20 mol % of InCl3.
IR, H and 13C NMR spectroscopy, mass spectrometry
and elemental analysis. The mass spectrum of 4a21 dis-
played the molecular ion (M+) peak at m/z 172. The
1H NMR spectrum of 4a exhibited a singlet at d 3.41
for H-4 and a broad singlet at d 6.77 (D2O exchange-
able) due to the –NH2 protons. A distinguishing reso-
nance at d 24.1 for C-4 and d 161.4 for C-2 were
observed in the 13C NMR spectrum.
The reactions were carried out by first mixing salicyl-
aldehyde 1, malononitrile 2 and Hantzsch dihydro-
pyridine ester19 3 in H2O:ethanol (1:1). Then, a
catalytic amount of InCl3 (20 mol %) was added.20
The reaction proceeded spontaneously at ambient
temperature and was complete within 30 min (Scheme
2 and Table 1).
We propose a plausible mechanism to account for the
formation of 4 (Scheme 3).
Encouraged by these results, we have examined this
transformation using 2-hydroxynaphthalene-1-carbox-
aldehyde 6 and obtained the fused chromenes 7 in good
yields (Scheme 4).22
Table 1. Synthesis of 2-aminochromenes
The indole moiety23 is probably the most common and
important feature, of a variety of natural products and
medicinal agents with significant biological activities
including antimicrobial, antiviral and antitumour.24
However, there have been no examples of indolyl
chromenes reported. Thus, we investigated a three-
component reaction involving salicylaldehyde and mal-
ononitrile with indole replacing the Hantzsch dihydro-
pyridine ester in order to synthesize new indolyl
chromenes 9a–g. The presence of two or more different
heterocyclic moieties in a single molecule often enhances
the biocidal profile remarkably (Scheme 5).25
Entry
X(1)
Product (4)
Time
(min)
Yielda
(%)
CN
1
H
25
86
O
NH2
4a
H3C
CN
2
3
CH3
35
40
84
82
O
O
NH2
4b
MeO
Br
CN
The structures of compounds 9a–g were confirmed by
spectroscopic and elemental data. The 1H NMR of
9b26 displayed a singlet at d 4.97 (H-4) and a broad sin-
glet due to –NH2 at d 6.83 (D2O exchangeable). Signals
at d 32.8 (C-4) and d 160.6 (C-2) in the 13C spectrum
confirmed the formation of the product.
OMe
NH2
4c
CN
4
Br
30
30
88
87
O
NH2
Similarly, the protocol was extended to synthesize indole
with fused chromenes 10 in good yield by reaction of
2-hydroxynaphthalene-1-carboxaldehyde and malono-
nitrile with indole (Scheme 6).27
4d
Cl
CN
5
Cl
O
NH2
4e
In conclusion, we have developed a simple and clean
method for the synthesis of novel 2-aminochromenes
a Isolated yield.

G. Shanthi, P. T. Perumal / Tetrahedron Letters 48 (2007) 6785–6789
6787
CHO
X
X
CN
NH
InCl3
CN
CN
2
+
OH
H2O:EtOH
O
1
5
H
H
EtO2C
CO2Et
CH3
CN
X
X
CN
NH
EtO2C
+
H3C
CO2Et
CH3
InCl3
+
H3C
N
H
H2O:EtOH
O
NH2
O
N
InCl3
5
3
4a-e
Scheme 3.
CN
CHO
NH2
H
H
OH
EtO2C
CO2Et
CH3
CN
CN
InCl3 (20 mol%)
H2O:EtOH, 1:1
O
+
+
H3C
N
H
3
6
2
7
Scheme 4.
O1
H2N
2
NC
3
R3
X
CHO
OH
R3
CN
CN
4
InCl3 (20 mol%)
H2O
R2
+
+
R2
N
N
R1
R1
1
2
8
9a-g
R1
R3
R2
Time (hr) Yield (%)
X
9a
H
H
H
H
H
H
H
H
1.2
1.0
1.0
84
86
CH3
9b
9c
H
H
H
87
87
80
H
H
CH3
9d
9e
H
H
H
OCH3
Br
1.1
2.0
H
H
9f
H
Cl
H
2.0
1.2
81
84
9g
CH3
Br
H
Scheme 5.
H2N
NC
O
CHO
OH
+
InCl3 (20 mol%)
H2O
CN
CN
+
N
H
8
N
H
2
10
6
Scheme 6.
and indolyl chromenes catalyzed by indium(III) chloride
in aqueous media at room temperature. Advantages of
this method are its generality, short reaction times and
easy work-up. Biological evaluation of these derivatives
is underway.
Acknowledgment
One of the authors, G.S. thanks the Council of Scientific
and Industrial Research, New Delhi, India, for the
research fellowship.

6788
G. Shanthi, P. T. Perumal / Tetrahedron Letters 48 (2007) 6785–6789
18. (a) Babu, G.; Perumal, P. T. Aldrichim. Acta 2000, 33, 16–
Supplementary data
22; (b) Babu, G.; Perumal, P. T. Tetrahedron Lett. 1997,
38, 5025–5026; (c) Babu, G.; Perumal, P. T. Tetrahedron
1998, 54, 1627–1638; (d) Babu, G.; Nagarajan, R.;
Natarajan, R.; Perumal, P. T. Synthesis 2000, 661–667;
(e) Shanthi, G.; Subbulakshmi, G.; Perumal, P. T.
Tetrahedron 2007, 2057–2063.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2007.
07.102.
References and notes
19. Several Hantzsch dihydropyridine derivatives were syn-
thesized and applied in this reaction. Other 4,4-dihydro
derivatives afforded the products, but the yields were
slightly lower than with 3. 4-Substituted (alkyl or aryl)
Hantzsch dihydropyridines did not react under the
conditions.
20. General procedure for the synthesis of 2-amino-4H-chro-
mene-3-carbonitrile: To a stirred mixture of appropriate
salicylaldehyde (1 mmol), malononitrile (1 mmol) and
Hantzsch dihydropyridine ester (1 mmol) in water:ethanol
(1:1) (10 mL), a catalytic amount of indium(III) chloride
(20 mol %) was added and the mixture was stirred at room
temperature for the appropriate time (Table 1). After
complete conversion as indicated by TLC, the product was
extracted with ethyl acetate (2 · 15 mL). The combined
extracts were dried over anhydrous Na2SO4 and concen-
trated in vacuo. The resulting product was purified by
column chromatography on silica gel (Merck, 60–120
mesh, ethyl acetate–hexane, 2:8) to afford pure product
(4a–e).
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21. 2-Amino-4H-chromene-3-carbonitrile 4a (Table 1, entry 1):
white solid; mp: 125 ꢁC. mmax (KBr): 3447, 3335, 2190,
1
1661, 1412, 1267, 1229, 753 cmÀ1. H NMR (DMSO-d6,
500 MHz): d 3.41 (s, 2H), 6.77 (br s, 2H, NH2), 6.91 (d,
1H, J = 7.65 Hz), 7.05 (t, 1H, J = 6.15 Hz), 7.14 (d, 1H,
J = 7.65 Hz), 7.17 (t, 1H, J = 7.6 Hz). 13C NMR (DMSO-
d6, 125 MHz): d 24.1, 49.4, 116.4, 120.1, 121.6, 124.9,
128.4, 129.3, 149.8, 161.4. MS (m/z): 172 (M+). Anal.
Calcd for C10H8N2O: C, 69.76; H, 4.68; N, 16.27. Found:
C, 69.70; H, 4.64; N, 16.23.
22. 3-Amino-1H-benzo[f]chromene-2-carbonitrile 7: light yel-
low solid; mp: 196 ꢁC. mmax (KBr): 3444, 3314, 2190, 1674,
8. (a) Lu, Y.; Liu, B.; Cheng, J.-P. Chem. J. Chin. Univ. 1997,
18, 391–394; (b) Merjer, J. P.; Van Niel, J. C. G.; Pandit,
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1588, 1409, 1236, 808, 739 cmÀ1 1H NMR (DMSO-d6,
.
500 MHz): d 3.74 (s, 2H), 6.84 (br s, 2H, NH2), 7.14 (d,
1H, J = 9.15 Hz), 7.46 (t, 1H, J = 6.9 Hz), 7.56 (t, 1H,
J = 6.85 Hz), 7.79 (t, 2H, J = 8.4 Hz), 7.89 (d, 1H,
J = 8.4 Hz).13C NMR (DMSO-d6, 125 MHz): d 22.2,
49.8, 112.4, 117.2, 121.8, 123.5, 125.6, 127.8, 128.8,
129.2, 130.7, 131.3, 146.8, 160.8. MS (m/z): 222 (M+).
Anal. Calcd for C14H10N2O: C, 75.66; H, 4.54; N, 12.60.
Found: C, 75.62; H, 4.49; N, 12.52.
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Part I; Wiley: New York, NY, 1992.
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25. General procedure for the synthesis of indolyl chromenes:
To a stirred mixture of salicylaldehyde (1 mmol), malono-
nitrile (1 mmol) and indole (1 mmol) in water (10 mL), a
catalytic amount of indium(III) chloride (20 mol %) was
added and the mixture was stirred at room temperature
for the appropriate time (Scheme 5). After complete
conversion as indicated by TLC, the product was
extracted with ethyl acetate (2 · 15 mL). The combined
extracts was dried over anhydrous Na2SO4 and concen-
trated in vacuo. The resulting product was purified by
column chromatography on silica gel (Merck, 60–120
mesh, ethyl acetate–hexane, 3:7) to afford pure product
(9a–g).
17. For reviews on indium Lewis acids see: (a) Frost, C. G.;
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G. Shanthi, P. T. Perumal / Tetrahedron Letters 48 (2007) 6785–6789
6789
26. 2-Amino-4-(1-methyl-1H-indol-3yl)-4H-chromene-3-carbo-
nitrile 9b (Scheme 5): yellow solid; mp: 202 ꢁC. mmax (KBr):
27. 3-Amino-1-(1H-indol-3yl)-1H-benzo[f]chromene-2-carbo-
nitrile 10: white solid; mp: 216 ꢁC. mmax (KBr): 3435, 3331,
1
1
3452, 3340, 2192, 1654, 1403, 1226, 743 cmÀ1. H NMR
2185, 1661, 1483, 1230, 759 cmÀ1. H NMR (DMSO-d6,
(DMSO-d6, 500 MHz): d 3.69 (s, 3H), 4.97 (s, 1H), 6.83 (br
s, 2H, NH2), 6.88 (t, 1H, J = 7.65 Hz), 6.94 (t, 1H,
J = 7.65 Hz), 7.02 (t, 1H, J = 9.2 Hz), 7.08 (d, 2H,
J = 7.65 Hz), 7.14 (t, 1H, J = 8.4 Hz), 7.23 (s, 1H), 7.27
(d, 1H, J = 8.4 Hz), 7.33 (d, 1H, J = 7.65 Hz). 13C NMR
(DMSO-d6, 125 MHz): d 32.7, 32.8, 56.7, 110.5, 116.3,
118.7, 119.2, 121.4, 121.7, 124.2, 124.9, 126.1, 127.8, 128.4,
129.8, 137.7, 148.9, 160.6. MS (m/z): 301 (M+). Anal.
Calcd for C19H15N3O: C, 75.73; H, 5.02; N, 13.94. Found:
C, 75.68; H, 4.95; N, 13.89.
500 MHz): d 5.54 (s, 1H), 6.78 (t, 1H, J = 7.65 Hz), 6.93 (t,
1H, J = 7.6 Hz), 7.18 (d, 1H, J = 7.65 Hz), 7.25 (d, 1H,
J = 8.4 Hz), 7.30 (t, 2H, J = 9.15 Hz), 7.35 (t, 2H,
J = 6.85 Hz), 7.82 (t, 2H, J = 7.6 Hz), 8.07 (d, 1H,
J = 8.4 Hz), 10.87 (s, 1H, NH). 13C NMR (DMSO-d6,
125 MHz): d 31.0, 58.3, 112.2, 116.2, 117.2, 118.7, 119.0,
121.4, 123.6, 124.2, 125.3, 125.7, 127.3, 128.9, 129.6, 131.1,
131.3, 137.2, 147.0, 160.3. MS (m/z): 337 (M+). Anal.
Calcd for C22H15N3O: C, 78.32; H, 4.48; N, 12.45. Found:
C, 78.27; H, 4.42; N, 12.38.