InCl3 promoted synthesis of pyrano[3,2-h]quinolines via microwave irradiation

Article abstract of DOI:10.1002/jhet.2067

An efficient and economical method has been developed for the synthesis of pyrano[3,2-h]quinolines via an indium trichloride-catalyzed one-pot three-component reaction of 8-hydroxyquinoline with aromatic aldehydes and malononitrile/ethyl cyanoacetate unde

Full text of DOI:10.1002/jhet.2067

Month 2014
InCl3 Promoted Synthesis of Pyrano[3,2-h]quinolines via
Microwave Irradiation
Gopal Senthil Kumar, Matthias Zeller, Michael A. Frasso, and Karnam Jayarampillai Rajendra Prasad
a
b
b
a
*
aDepartment of Chemistry, Bharathiar University, Coimbatore 641046, India
bDepartment of Chemistry, Youngstown State University, One University Plaza, Youngstown, OH 44555, USA
*
E-mail: prasad_125@yahoo.com
Additional Supporting Information may be found in the online version of this article.
Received July 3, 2012
DOI 10.1002/jhet.2067
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
R
CHO
CN
X
InCl3\ Ethanol
MW, 7 min
N
R
O
N
X
OH
NH2
X = CN, COOCH2CH3
R = C6H5, 4-Cl-C6H4, 4-CH3O-C6H4, 4-CH3-C6H4, 3-NO2-C6H4,
benzo[d][1,3]dioxal-5'-yl, 2-chloroquinolin-3'-yl
An efficient and economical method has been developed for the synthesis of pyrano[3,2-h]quinolines via
an indium trichloride-catalyzed one-pot three-component reaction of 8-hydroxyquinoline with aromatic
aldehydes and malononitrile/ethyl cyanoacetate under microwave irradiation.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
higher yield, there is an increasing trend to wherever possi-
ble replace multi-step reaction sequences by multi-compo-
nent reactions in both academic and industrial settings.
This is especially factual for the synthesis of bioactive mol-
ecules, which are often quite complex and require substan-
tial numbers of synthetic transformations even under the
best of circumstances.
Pyranoquinoline scaffolds are an important class of
compounds widely distributed in nature. Notably, they
are found in the plants of the Rutaceae family, commonly
known as the rue or citrus family. The pyranoquinoline
moiety naturally occurring in several plants, Simulenoline
(1), peroxysimulenoline (2), and benzosimuline (3), for
example, were isolated from the roots of Zanthoxylum
simulans [1], (À)-ribalinine (4) was isolated from the stem
bark of Araliopsis tabouensis [2], acetylribalinine (5) and
ribaliprenylene (6) were found in the leaves of Skimmia
laureola [3], and (+)-orixalone D (7) was isolated from
the stem of Orixa japonica [4] (Fig. 1). Pyranoquinolines
have attracted considerable attention because of a broad
spectrum of pharmacological and biological properties that
many of them exhibit [5]. Compounds with the
pyranoquinoline motif possess a wide range of biological
activities. They can be psychotropic [6], antiallergic [7],
anti-inflammatory [8], estrogenic [9], antibacterial [10,11],
antimalarial [12], antifungal [13], and anticancer [14] as
well as inhibit calcium signaling [15]. Considering all of
these potentially beneficial properties, they are currently
tested as candidates for potential pharmaceuticals [16].
The advantages of a multi-component methodology
are numerous. For example, procedures typically exhibit
higher efficiency and operational simplicity, higher overall
yield, use of fewer resources, and as a consequence, lower
cost and a reduced environmental impact. Because of the
increasing public concern toward environmental issues
and the obvious advantages of shorter reaction time and
Numerous synthetic methodologies have been devel-
oped for the construction of pyranoquinolines [17,14,18].
Particularly, hydroxyquinolines are commonly used as
reactants [19]. Recently, 2-amino-4H-pyrano[3,2-h]quinolines
had been obtained by refluxing of reactive methylene
compounds (i.e., malononitrile or ethyl cyanoacetate) with
aldehydes and 8-hydroxyquinoline using an organic base
as a catalyst. Catalysts that have been used in this reaction
include piperidine [20], pyridine [21], and KF/Al2O3 [22].
El-Agrody et al. reported a similar kind of reaction leading
to 2-styryl-8-hydroxyquinolines, the compounds with signif-
icant antitumor activity [23]. Each of these reported proce-
dures has its own merit, but all suffer from limitation of the
synthesis to only a narrow range of pyrano[3,2-h]quinolines,
a difficulty to isolate products or long reaction time and harsh
reaction conditions. Thus, there is a need to develop a more
general procedure applicable for the preparation of a wide
range of pyranoquinolines that at the same time is environ-
mentally benign, rapid, and efficient. Recently, the efficacy
of indium(III) as a Lewis acid catalyst [24] has received
attention for a range of organic transformations because of
the relatively low toxicity indium(III) compounds, their
stability in air and water, and their recyclability. These
features encouraged our interest in exploring the synthetic
© 2014 HeteroCorporation

G. S. Kumar, M. Zeller, M. A. Frasso, and K. J. R. Prasad
Vol 000
O
O
O
R
OH
CH3
1 R=OH
2 R=OOH
N
O
N
O
N
O
CH3
CH3
CH3
1, 2
3
4
OH
SH
O
O
O
OH
OAc
N
O
N
O
N
O
O
CH3
CH3
CH3
6
5
7
Figure 1. Naturally occurring pyranoquinoline alkaloids.
utility of indium(III) chloride as a catalyst for the synthe-
sis of pyranoquinolines, and herein, we report a simple,
high-yielding, convenient, and elegant procedure for the
synthesis of 2-amino-4-aryl-4H-pyrano[3,2-h]quinolines.
microwave vessel, mixed thoroughly, and kept in a Biotage
microwave oven for 7 min. The completeness of the reaction
was monitored by thin layer chromatography, which
revealed one single spot of the desired product 5a. After
completion of the reaction, the reaction mixture was concen-
trated and dried in beaker. Subsequently, the reaction
mixture was washed with ethanol to recover the catalyst.
The recovered catalyst has been reused for the second time
with the same reactivity of InCl3. When the catalyst has been
reused more than two times, the reactivity of InCl3 was
slightly decreased. To optimize the reaction condition, we
evaluated the most appropriate catalyst loading. With the
use of 5–25 mol %, increasing in 5 mol% increment of
InCl3 at 70°C, the yield steadily increased with a maximum
of >85% at 25mol% of catalyst (Table 2). No additional
improvement in the yield was observed upon further increas-
ing the quantity of InCl3.
RESULTS AND DISCUSSION
In an initial experiment, we investigated the reaction
of 1 eq. of each benzaldehyde and malononitrile with 8-
hydroxyquinoline in the presence of 20 mol% of various
catalysts in refluxing ethanol. Using triethyl amine, dimethyl
amino pyridine, L-proline, zinc(II) chloride, and indium
triflate or chloride gave yield of only 20–55% of the
expected product after recrystallization from ethanol. Several
representative results are summarized in Table 1. After
systematic screening of the results, indium(III) chloride in
ethanol was selected as the most promising among the tested
catalysts. In an attempt to improve the yield of the reaction
and acknowledging the benefits of an ecologically friendly
synthetic pathway, the same reaction was carried out using
microwave irradiation. All reactants were sealed in a
We then explored the scope and limitations of the
reaction involving aromatic aldehydes and malononitrile
with 8-hydroxyquinoline, which gave the corresponding
2-amino-4-aryl-4H-pyrano[3,2-h]quinolines
5 in good
Table 1
Screening of various catalysts on the one-pot reaction.
Table 2
Yield (%)b
Evaluation of most appropriate loading of indium(III) chloride.
Catalyst
(20 mol%)
Yield (%)b
Entry
Time (h)a
5a
6a
Amount of
InCl3 (mol%)
Time
1
2
3
4
5
6
7
—
Et3N
DMAP
L-proline
ZnCl2
5
5
5
5
5
5
5
d
d
Entry
(min)a
5a
6a
34
20
36
27
52
54
29
17
34
21
43
48
1
2
3
4
5
5
10
15
20
25
7
7
7
7
7
23
45
69
86
90
18
39
63
81
87
In(OTf)3
InCl3
Reaction conditions: 8-hydroxyquinoline (1 mmol), malononitrile/ethyl
cyanoacetate (1 mmol), benzaldehyde (1 mmol) in 20 mL ethanol at reflux
temperature. d, trace amounts.
Reaction condition: 1 mmol eq. of each 8-hydroxyquinoline,
malononitrile/ethyl cyanoacetate, and benzaldehyde in ethanol at 70°C in
a Biotage microwave oven.
aTime duration of reaction in hours.
aNo increase of yield after 7 min.
bIsolated pure product.
bIsolated pure product.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
InCl3 Promoted Synthesis of Pyrano[3,2-h]quinolines via Microwave Irradiation
Scheme 1 [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
R
CHO
CN
X
InCl3\ Ethanol
MW, 7 min
N
R
O
N
X
OH
NH2
5a-g, 6a-e
4
1
2, 3
2) X = CN,
5a-g) X = CN,
6a-e) X = COOCH2CH3
3) X = COOCH2CH3
R = a) C6H5
b) 4-Cl-C6H4
c) 3-NO2-C6H4
d) benzo[d][1,3]dioxal-5'-yl
e) 2-chloroquinolin-3'-yl
f) 4-CH3O-C6H4
g) 4-CH3-C6H4
Table 3
Synthesis of 2-amino-4H-pyrano[3,2-h]quinoline derivatives.
Table 3
(Continued)
Time
(min)
Yield
(%)
Time
(min)
Yield
(%)
Entry
1
R
X
Product
Entry
7
R
X
Product
CN
5a
7
90
CN
5g
7
88
2
CN
5b
7
88
8
9
COOEt
COOEt
6a
6b
7
7
87
84
3
4
CN
CN
5c
7
7
89
85
5d
10
11
COOEt
COOEt
6c
7
7
85
81
5
6
CN
CN
5e
5f
7
7
86
87
6d
12
COOEt
6e
7
81
(Continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

G. S. Kumar, M. Zeller, M. A. Frasso, and K. J. R. Prasad
Vol 000
Figure 2. X-ray crystal structure of compound 5a, thermal ellipsoid rep-
resentation at the 50% probability level. [Color figure can be viewed in the
online issue, which is available at wileyonlinelibrary.com.]
Figure 3. X-ray crystal structure of compound 6a, thermal ellipsoid
representation at the 50% probability level. [Color figure can be viewed
in the online issue, which is available at wileyonlinelibrary.com.]
Scheme 2. Initially, an InCl3 mediated Knoevenagel type
condensation of the aryl aldehyde 4 with the active
methylene compounds 2 or 3 affords the arylidene adduct
A. Then, Michael addition of 8-hydroxyquinoline 1 to the
Knoevenagel adduct A yields intermediate B, which un-
dergoes aromatization followed by intramolecular cycliza-
tion facilitated by InCl3 to the C–N triple bond to give
the cyclic intermediate D through intermediate C. Finally,
the pyrano[3,2-h]quinolines 5/6 are formed in situ by
tautomerization of the imino group to an amino group as
shown in Scheme 2.
yields as shown in Scheme 1. These results indicated
that this one-pot reaction is quite general and has a very
broad substrate scope (Table 3). All compounds were iso-
lated by crystallization only, and no chromatographic
work-up was required to obtain pure products. The struc-
tures of the 2-amino-4-aryl-4H-pyrano[3,2-h]quinolines 5
1
were confirmed by IR, mass spectrometry, H and 13C
NMR spectroscopy, and elemental analysis. Additionally,
the structure of one of the products was also determined
by single crystal X-ray diffraction. The IR spectrum of
compound 5a shows absorption peaks at 3443, 3324, and
2192 cmÀ1, which attest to the presence of amino and
1
cyano groups, respectively. The H NMR spectrum of 5a
CONCLUSION
exhibits a broad singlet at δ 7.18, which is the characteristic
representation of the amino group protons. The proton at
the 4-position of the pyrano[3,2-h]quinoline appears at δ
4.96. Finally, the structure of the compound 5a was
confirmed by single crystal X-ray analysis (Figure 2).
To further explore the potential of this protocol for
heterocyclic synthesis, we investigated the one-pot reaction
involving 8-hydroxyquinoline with aromatic aldehydes
and using ethyl cyanoacetate as a third component, to
give another series of pyrano[3,2-h]quinolines 6 in good
yield as shown in Scheme 1. The IR spectrum of
compound 6a shows absorption peaks at 3389, 3285,
and 1676 cmÀ1, which attest to the presence of amino
and ester groups, respectively. The two most distinctive
1H NMR signals of 6a are shifted slightly upfield from
those of 5a to δ 7.88 and 5.08, respectively. Finally,
the structure of compound 6a was also confirmed by
single crystal X-ray analysis (Figure 3). These results
showed that a one-pot reaction for the efficient synthesis
of versatile functionalized pyrano[3,2-h]quinolines has
been successfully established.
A systematic study on the synthesis and structural
elucidation of pyrano[3,2-h]quinolines has been presented.
We developed a mild and efficient method for the synthesis
of pyrano[3,2-h]quinolines via a one-pot three-component
reaction of 8-hydroxyquinoline with aromatic aldehydes
and malononitrile/ethyl cyanoacetate using InCl3 as a
catalyst to afford 2-amino-4-aryl-4H-pyrano[3,2-h]quinoline-
3-carbonitriles/carboxylates. The features of this procedure
are mild reaction conditions, good to high yield, and
operational simplicity.
Acknowledgment. Our sincere thanks go to the Director, ISO
Quality Assurance Cell, IICT, Hyderabad, SAIF, IIT Madras,
Chennai, for providing access to their mass and NMR spectral
facilities. The diffractometer was funded by NSF grant
0087210, by the Ohio Board of Regents grant CAP-491, and
by Youngstown State University.
SUPPLEMENTARY DATA
On the basis of the aforementioned experimental results
together with related reports [25,26], a plausible mechanism
for this multi-component one-pot reaction is suggested in
Complete cif files for compound 5a and 6a have been
deposited with the Cambridge Crystallographic Data Centre
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
InCl3 Promoted Synthesis of Pyrano[3,2-h]quinolines via Microwave Irradiation
Scheme 2 [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
N
OH
Michael
additon
1
N
Ar
N
C
X
O
Ar HC
C
X
5 & 6
A
NH2
H
Ar
H+ transfer
-InCl3
N
Knoevenagel
condensation
C
O
InCl3
C
X
H
N
B
Ar
H
CN
N
H2C
2 , 3
Ar-CHO
Aromatisation
InCl3
O
X
4
X
HN
InCl3
D
Ar
N
O
X
C
H
InCl3
N
C
[11] Fujita, Y.; Oguri, H.; Oikawa, H. J Antibiot 2005, 58, 425.
[12] Isaka, M.; Tanticharoen, M.; Kongsaeree, P.; Thebtaranonth,
Y. J Org Chem 2001, 66, 4803.
[13] Cantrell, C. L.; Schrader, K. K.; Mamonov, L. K.; Sitpaeva,
G. T.; Kustova, T. S.; Dunbar, C.; Wedge, D. E. J Agric Food Chem
2005, 53, 7741.
as CCDC number 859185 and 871328. Copies of the data
can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge, CB2 1EZ, UK. [Fax: +44(0)-
1223-336033 or e-mail: deposit@ccdc.cam.ac.uk
[14] Magedov, I. V.; Manpadi, M.; Ogasawara, M. A.; Dhawan,
A. S.; Rodeli, S.; Slambrouck, S. V.; Steelant, W. F. A.; Evdokimov, N. M.;
Uglinskii, P. V.; Elias, E. M.; Knee, E. J.; Tongwa, P.; Antipin, M. Y.;
Kornienko, A. J Med Chem 2008, 51, 2561.
REFERENCES AND NOTES
[15] Koizumi, F.; Fukumitsu, N.; Zhao, J.; Chanklan, R.; Miyakawa,
T.; Kawahara, S.; Iwamoto, S.; Suzuki, M.; Kakita, S.; Rahayu, E. S.;
Hosokawa, S.; Tatsuta, K.; Ichimura, M. J Antibiot 2007, 60, 455.
[16] Mohamed, E. A. Chem Pap 1994, 48, 261; (Chem. Abstr.
1995, 123, 9315x).
[17] Sekar, M.; Rajendra Prasad, K. J. J Nat Prod 1998, 61, 294.
[18] Maiti, G.; Kundu, P. Tetrahedran Lett 2006, 47, 5733.
[19] El-Agrody, A. M.; Al-Ghamdi, A. M. Arkivoc 2011,
11, 134.
[20] Kemnitzer, W.; Drewe, J.; Jiang, S.; Zhang, H.; Zhao, J.;
Crogen-Grundy, C.; Xu, L.; Lamothe, S.; Gourdeau, H.; Denis, R.; Tseng,
B.; Kasibhatla, S.; Xiang Coi, S. J Med Chem 2007, 50, 2858.
[21] Al-Mousawi, S. M.; Elkholy, Y. M.; Mohammad, M. A.;
Elnagdi, M. H. Org Prep Proced Int 1999, 31, 305.
[22] Wang, X. -S.; Shi, D. -Q.; Tu, S. -J. Chinese J Chem 2003, 21, 1114.
[23] El-Agrody, A. M.; Khattab, E. S. A. E. H.; Fouda, A. M.;
Al-Ghamdi, A. M. Med Chem Res 2011. doi: 10.1007/s00044-011-9965-x.
[24] (a) Frost, C. G.; Chauhan, K. K. J Chem Soc, Perkin Trans 1
2000, 3015; (b) Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. Curr
Org Chem 2003, 7, 1661; (c) Frost, C. G.; Hartley, J. P. Mini-Rev Org
Chem 2004, 1, 1.
[1] Chen, I. -S.; Tsai, I. -W.; Teng, C. -M.; Chen, J. -J.; Chang,
Y. -L.; Ko, F. -N.; Lu, M. C.; Pezzuto, J. M. Phytochemistry 1997, 46, 525.
[2] Wabo, H. K.; Tane, P.; Connolly, J. D.; Okunji, C. C.;
Schuster, B. M.; Iwu, M. M. Natur Prod Res 2005, 19, 591.
[3] Sultana, N.; Afza, N.; Atta-ur-Rahman. Sci. Int. (Lahore, Pak.)
2004, 16, 271; (Chem.Abstr. 2006, 144, 57041).
[4] Feng, X.; Dong, Y.; Wang, M.; Zhao, Y. Zhongcaoyao 2004,
35, 1336; (Chem. Abstr. 2006, 144, 11245).
[5] (a) Mabire, D.; Coupa, S.; Adelinet, C.; Poncelet, A.; Simonnet,
Y.; Venet, M.; Wouters, R.; Lesage, A. S. J.; Beijsterveldt, L. V.; Bischoff,
F. J Med Chem 2005, 48, 2134; (b) Michael, J. P. Nat Prod Rep 2002, 19,
742; (c) Michael, J. P. Nat Prod Rep 2003, 20, 476; (d) Michael, J. P. Nat
Prod Rep 2004, 21, 650; (e) Michael, J. P. Nat Prod Rep 2005, 22, 627.
[6] Nesterova, I. N.; Alekseeva, L. M.; Andreeva, L. M.;
Andreeva, N. I.; Golovira, S. M.; Granik, V. G. Khim-Farm Zh 1995,
29, 31 (Russ); (Chem. Abstr. 1996, 124, 117128t).
[7] (a) Cairns, H.; Cox, D.; Gould, K. J.; Ingall, A. H.; Suschitzky,
J. L. J Med Chem 1985, 28, 1832; (b) Yamada, N.; Kadowaki, S.;
Takahashi, K.; Umezu, K. Biochem Pharmacol 1992, 44, 1211.
[8] Chen, J. J.; Chen, P. H.; Liao, C. H.; Huang, S. Y.; Chen, I. S. J
Nat Prod 2007, 70, 1444.
[25] Shanthi, G.; Subbulakshmi, G.; Perumal, P. T. Tetrahedron
2007, 63, 2057.
[26] Yamuna, E.; Zeller, M.; Rajendra Prasad, K. J. Tetrahedron
Lett 2011, 52, 6805.
[9] Akhmed Kkodzhaeva, Kh. S.; Bessonsva, I. A. Dokl Akad
Nauk UZH SSR 1982, 34. (Russ); (Chem. Abstr. 1983, 98, 8372q).
[10] Hanawa, F.; Fokialakis, N.; Skaltsounis, A. L. Planta Med
2004, 70, 531.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet