Simple, catalyst-free, one-pot procedure for the synthesis of 2-amino-3-cyano-1,4,5,6-tetrahydropyrano[3,2-c]quinolin-5-one derivatives

Article abstract of DOI:10.1080/00397911.2012.686647

A one-pot, three-component reaction of 4-hydroxyquinolin-2(1H)-one, malononitrile, and various aldehydes for the synthesis of 2-amino-3-cyano-1,4,5, 6-tetrahydropyrano[3,2-c]quinolin-5-one derivatives is reported. The reaction is performed without any catalysts in a mixed solvent of water and ethanol to give products in good yields. The present method provided a clean, simple, and economical alternative for the synthesis of potential biologically active pyranoquinoline derivatives. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2012.686647

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Simple, Catalyst-Free, One-
Pot Procedure for the Synthesis
of 2-Amino-3-cyano-1,4,5,6-
tetrahydropyrano[3,2-c]quinolin-5-one
Derivatives
Meng-Jian Yao a , Zhi Guan a & Yan-Hong He a
a School of Chemistry and Chemical Engineering, Southwest
University, Chongqing, P. R. China
Accepted author version posted online: 22 Jan 2013.Published
online: 28 Apr 2013.
To cite this article: Meng-Jian Yao , Zhi Guan & Yan-Hong He (2013): Simple, Catalyst-Free, One-
Pot Procedure for the Synthesis of 2-Amino-3-cyano-1,4,5,6-tetrahydropyrano[3,2-c]quinolin-5-
one Derivatives, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 43:15, 2073-2078
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Synthetic Communications1, 43: 2073–2078, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.686647
SIMPLE, CATALYST-FREE, ONE-POT PROCEDURE
FOR THE SYNTHESIS OF 2-AMINO-3-CYANO-1,4,5,6-
TETRAHYDROPYRANO[3,2-c]QUINOLIN-5-ONE
DERIVATIVES
Meng-Jian Yao, Zhi Guan, and Yan-Hong He
School of Chemistry and Chemical Engineering, Southwest University,
Chongqing, P. R. China
GRAPHICAL ABSTRACT
Abstract A one-pot, three-component reaction of 4-hydroxyquinolin-2(1H)-one, malononi-
trile, and various aldehydes for the synthesis of 2-amino-3-cyano-1,4,5,6-tetrahydropyrano
[3,2-c]quinolin-5-one derivatives is reported. The reaction is performed without any cata-
lysts in a mixed solvent of water and ethanol to give products in good yields. The present
method provided a clean, simple, and economical alternative for the synthesis of potential
biologically active pyranoquinoline derivatives.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Catalyst-free; multicomponent reaction; pyranoquinoline derivative; synthesis
INTRODUCTION
As safety, health, and environmental issues are key drivers for process improve-
ments in the chemical industry,[1] the development of environmentally benign reactions
or pathways is a major focus. In recent years, the multicomponent reaction (MCR)
has attracted remarkable attention from chemists for the preparation of chemicals
following environmentally friendly and less expensive strategies.[2] MCRs are con-
vergent reactions, in which three or more starting materials react to form a product
in one pot without isolation of any intermediate, where basically all or most of the
atoms contribute to the newly formed product. MCRs have merits over conventional
Received December 15, 2011.
Address correspondence to Yan-Hong He, School of Chemistry and Chemical Engineering,
Southwest University, Chongqing 400715, P. R. China. E-mail: heyh@swu.edu.cn
2073

2074
M.-J. YAO, Z. GUAN, AND Y.-H. HE
linear-type syntheses in several aspects including high atom economy, simple proce-
dures, possible structural variations, resource efficiencies (time and cost), and rapid
access to complex molecules.[3]
Pyranoquinoline derivatives are of significant importance because of their
presence in many natural products possessing significant biological activities.[4–6]
Pyranoquinoline derivatives possess antiplatelet aggregation, antiallergic activity,
insecticidal, antifungal, antibacterial, analgesic, antimicrobial, antipyretic, cytotoxic,
and antihistaminic properties and are used for the treatment of proliferate diseases
such as cancer.[4–8] Moreover, pyranoquinolines are starting materials for the synthesis
of quinolylhydantions.[9] There have been several methods of synthesizing pyranoqui-
noline derivatives, including the three-component reaction of 4-hydroxyquinolin-2
(1H)-one, malononitrile, and various aldehydes for the synthesis of 2-amino-3-cyano-
1,4,5,6-tetrahydropyrano[3,2-c]quinolin-5-one derivatives catalyzed by Et3N,[10] KF-
Al2O3,[11] TEBA (benzyltriethylammonium chloride),[12] piperidine,[13] and ammonium
acetate.[14] However, these methods have limitations such as the use of toxic reagents,
large amounts of catalysts, and tedious workup procedures. From the viewpoint of
green chemistry, there is still an urgent need to develop new and environmentally benign
strategies for the preparation of potential biologically active pyranoquinoline deriva-
tives. In the course of development of new catalyst systems for the synthesis of these
compounds, we unexpectedly found that 2-amino-3-cyano-1,4,5,6-tetrahydropyrano
[3,2-c]quinolin-5-one derivatives could be prepared without catalyst in a mixed solvent
of ethanol and water. This catalyst-free approach offers a less expensive, much simpler,
and more environmentally friendly way to pyranoquinoline derivatives. Herein, we
report this catalyst-free, one-pot, three-component condensation reaction.
RESULTS AND DISCUSSION
In our initial study, the one-pot, three-component condensation reaction of
4-hydroxyquinolin-2(1H)-one (1), benzaldehyde (2j), and malononitrile (3) was used
as a model reaction. Different solvents were tested for the reaction, and the results
are listed in Table 1. The model reaction in water at reflux temperature for 5 h gave
the product in the yield of 78% (Table 1, entry 1). However, reactant dispersion was
very bad and easy caked in water. Furthermore, the intermediate arylmethylidene-
malononitrile was easy to sublimate. It was observed that a large amount of colorless
needle-shaped crystals appeared in the condenser when refluxing in water. To over-
come these disadvantages, we used ethanol as a solvent. Although the problems of
dispersion and sublimation did not exist in ethanol, the reaction took a long reaction
time (21 h) to get the product in a yield of 83% (Table 1, entry 2). We then tested the
mixed solvents of H2O–EtOH (Table 1, entries 3–5). The reactant dispersion was not
much better in H2O–EtOH (3:1), and a yield of 84% was obtained after 4 h (Table 1,
entry 3). However, almost any obstacle could be overcome in H2O–EtOH (1:1), and
the reaction was rapid and yield was slightly better (Table 1, entry 4). Further
increasing the ratio of ethanol in the mixed solvent to H2O–EtOH (1:3) led to
a decrease of yield (Table 1, entry 5). Therefore, H2O–EtOH (1:1) was used as the
optimal solvent system for the catalyst-free, one-pot synthesis of 2-amino-3-cyano-
1,4,5,6-tetrahydropyrano[3,2-c]quinolin-5-one derivatives.

SYNTHESIS OF PYRANOQUINOLINE DERIVATIVES
2075
Table 1. Effect of solvents on the catalyst-free, three-component reactiona
Entry
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
H2O
EtOH
5
21
4
78
83
84
85
78
H2O-EtOH (3:1)
H2O-EtOH (1:1)
H2O-EtOH (1:3)
2.5
2.5
aReaction conditions: 4-hydroxyquinolin-2(1H)-one 1 (1.0 mmol), benzaldehyde 2j (1.2 mmol), and
malononitrile 3 (1.2 mmol) in solvent (2 ml) at the reflux temperature.
bIsolated yields.
Encouraged by these results, we tried to extend the scope of the present proto-
col for condensation of different aldehydes, 4-hydroxyquinolin-2(1H)-one, and
malononitrile to afford 2-amino-3-cyano-1,4,5,6-tetrahydropyrano[3,2-c]quinolin-5-one
derivatives in H2O–EtOH (1:1) at reflux temperature. The results are summarized
in Table 2. It was very clear that aromatic aldehydes containing electron-
withdrawing groups (such as nitro group, cyano group, and halide) or electron-
donating groups (such as hydroxyl group, methyl group and alkoxyl group) could
react smoothly to give the corresponding products 4 in good to excellent yields
(77–95%). No clear electronic effect of the aromatic aldehydes on the reaction
was observed. Moreover, 2-substitution on the aromatic aldehydes did not appear
to deter the condensation process. The best yield of 95% was obtained with
2,4-dichlorobenzaldehyde (Table 2, entry 6), and 2-chlorobenzaldehyde gave an
excellent yield of 93% (Table 2, entry 2), but 3- and 4-chlorobenzaldehyde
gave lower yields after longer reaction times (Table 2, entries 3 and 4). This con-
densation reaction was applicable to the hydroxyl group substituted aromatic
aldehydes and good yields were obtained (Table 2, entries 11 and 14). In addition,
furfural could react smoothly with 4-hydroxyquinolin-2(1H)-one and malononi-
trile under the optimized reaction conditions to give a good yield (Table 2, entry
15). We also attempted the reaction with aliphatic aldehydes but failed. Finally,
the procedure was simple, and products 4 could be obtained merely by filtration
from the reaction medium.
Considering the structure of products 4 and based on the previous
reports about the catalytic synthesis of 2-amino-3-cyano-1,4,5,6-tetrahydropyrano
[3,2-c]quinolin-5-one derivatives,[11,14] we think the condensation of 4-hydroxyquino-
lin-2(1H)-one 1, aldehyde 2, and malononitrile 3 may occur by a sequential reaction
of the Knoevenagel condensation, Michael addition, intramolecular cyclization,
and isomerization, as shown in Scheme 1. First, the Knoevenagel condensation of

2076
M.-J. YAO, Z. GUAN, AND Y.-H. HE
Table 2. Catalyst-free, one-pot condensation of 4-hydroxyquinolin-2(1H)-one, aldehyde, and
malononitrilea
Entry
R
Time (h)
Product
Yieldb (%)
1
2
4-FC6H4 2a
2-ClC6H4 2b
6.5
4
4a
4b
4c
4d
4e
4f
81
93
77
82
81
95
84
90
80
85
84
85
84
83
88
3
3-ClC6H4 2c
4-ClC6H4 2d
4-BrC6H4 2e
5
4
13
13
9
5
6
2,4-Cl2C6H3 2f
3-NO2C6H4 2g
4-NO2C6H4 2h
4-CNC6H4 2i
C6H5 2j
7
4
4g
4h
4i
8
5
9
4
10
11
12
13
14
15
2.5
9
4j
4-OHC6H4 2k
4-CH3C6H4 2l
4-OCH3C6H4 2m
3-OCH3-4-OHC6H3 2n
2-Furyl 2o
4k
4l
10
13
8
4m
4n
4o
9
aReaction conditions: 4-hydroxyquinolin-2(1H)-one
malononitrile 3 (1.2 mmol) in H2O–EtOH (1:1) (2 mL) under reflux.
1
(1.0 mmol), aldehyde
2
(1.2 mmol), and
bIsolated yields.
aldehyde 2 and malononitrile 3 gives intermediate A. Second, the Michael addition
of intermediate A and 4-hydroxyquinolin-2(1H)-one 1 results in the formation of B.
Subsequently, the tandem intramolecular cyclization of C and isomerization of D
afford the final product 4.
Scheme 1. Possible sequential reaction for the catalyst-free, one-pot synthesis of 4.

SYNTHESIS OF PYRANOQUINOLINE DERIVATIVES
2077
CONCLUSION
In summary, we describe here a new and facile catalyst-free method for the
synthesis of 2-amino-3-cyano-1,4,5,6-tetrahydropyrano[3,2-c]quinolin-5-one derivatives.
The one-pot, three-component condensation of various aldehydes, 4-hydroxyquinolin-
2(1H)-one, and malononitrile could be performed without any catalysts in a mixed
solvent of water–ethanol (1:1) at reflux temperature. The salient advantages of the
methodology are clean reaction conditions, no workup procedure, easy isolation, and
good yields of the products. Undoubtedly, by removing the catalyst from the reaction
system, the present method provided a more environmentally benign, much simpler,
and more economical alternative for the synthesis of potential biologically active
compounds 2-amino-3-cyano-1,4,5,6-tetrahydropyrano[3,2-c]quinolin-5-one derivatives.
Typical Procedure for the Synthesis of 2-Amino-3-cyano-1,4,5,6-
tetrahydropyrano[3,2-c]quinolin-5-one Derivatives 4 (4j as an
Example)
A 10-mL, round-bottom flask was charged with 4-hydroxyquinolin-2-one 1
(1.0 mmol), phenyl aldehyde 2j (1.2 mmol), malononitrile 3 (1.2 mmol), and a mixed
solvent of H2O–EtOH (1:1) (2 mL). The mixture was stirred at reflux temperature for
2.5 h (Table 2, entry 10). After completion (by thin-layer chromatography, TLC),
H2O–EtOH (1:1) (1.5 mL) was added, and the mixture was stirred for 5 min. Then
the reaction mixture was cooled to rt, and the solid was collected by filtration.
The crude product was purified by recrystallization from methanol to give the pure
product 4j (269 mg, 85% yield).
2-Amino-5-oxo-4-phenyl-5,6-dihydro-4H-pyrano[3,2-c]quinoline-
3-carbonitrile (4j)[14]
1H NMR (300 MHz, DMSO-d6) d 11.75 (s, 1H), 7.90 (d, 1H, J¼ 7.9 Hz), 7.56 (t, 1H,
J¼ 7.5 Hz), 7.18–7.34 (m, 9H), 4.48 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d 161.03,
159.37, 151.74, 144.63, 137.95, 131.72, 128.83, 127.71, 127.24, 122.63, 122.28, 120.29,
115.75, 112.35, 109.83, 58.27, 36.99; IR (cmꢀ1): 3464, 3336, 3182, 2191, 1676, 1379,
1117, 1022, 847, 760, 586; MS (ESI): m=z¼ 315.0 (Mþ), 311.8, 297.7, 286.8, 273.7, 247.7.
Please see the Supplemental Material, available online, for complete experi-
mental details.
ACKNOWLEDGMENT
Financial support from the Natural Science Foundation Project of CQ CSTC
(2009A5051) is gratefully acknowledged.
REFERENCES
1. Wohlgemuth, R. The locks and keys to industrial biotechnology. New Biotechnol. 2009,
25, 204–213.
2. Ballini, R.; Bigi, F.; Conforti, M. L.; Santis, D. D.; Maggi, R.; Oppici, G.; Sartori, G.
Multicomponent reactions under clay catalysis. Catal. Today 2000, 60, 305–309.

2078
M.-J. YAO, Z. GUAN, AND Y.-H. HE
3. (a) Do¨mling, A.; Ugi, I. Multicomponent reactions with isocyanides. Angew. Chem. Int.
Ed. 2000, 39, 3168–3210; (b) Ugi, I. K.; Ebert, B.; Horl, W. Formation of 1,10-
¨
iminodicarboxylic acid derivatives, 2,6-diketo-piperazine and dibenzodiazocine-2,6-dione
by variations of multicomponent reactions. Chemosphere 2001, 43, 75–81.
4. Chen, I. S.; Tsai, I. W.; Teng, C. M.; Chen, J. J.; Chang, Y. L.; Ko, F. N.; Lu, M. C.;
Pezzuto, J. M. Pyranoquinoline alkaloids from zanthoxylum simulans. Phytochem.
1997, 46, 525–529.
5. Wabo, H. K.; Tane, P.; Connolly, J. D.; Okunji, C. C.; Schuster, B. M.; Iwu, M. M.
Tabouensinium chloride, a novel quaternary pyranoquinoline alkaloid from Araliopsis
tabouensis. Nat. Prod. Res. 2005, 19, 591–595.
6. (a) Michael, J. P. Quinoline, quinazoline, and acridone alkaloids. Nat. Prod. Rep. 2002,
19, 742–760; (b) Michael, J. P. Quinoline, quinazoline, and acridone alkaloids. Nat. Prod.
Rep. 2003, 20, 476–493; (c) Michael, J. P. Quinoline, quinazoline, and acridone alkaloids.
Nat. Prod. Rep. 2004, 21, 650–668; (d) Michael, J. P. Quinoline, quinazoline, and acridone
alkaloids. Nat. Prod. Rep. 2005, 22, 627–646.
7. (a) Nahas, N. M.; Abdel-Hafez, A. A. Synthesis and antibacteriala ctivities of fused
pyranoquinoline derivatives. Heterocycl. Commun. 2005, 11, 263–272; (b) Amin, K. M.
New pyrano[3,2 -f]quinolines of possible H1-antihistamine and mast cell-stabilizing
properties. Egypt. J. Pharm. Sci. 1993, 34, 741–750; (c) Magesh, C. J.; Makesh, S. V.;
Perumal, P. T. Highly diastereoselective inverse electron demand (IED) Diels–Alder reac-
tion mediated by chiral salen–AlCl complex: The first, target-oriented synthesis of pyrano-
quinolines as potential antibacterial agents. Bioorg. Med. Chem. Lett. 2004, 14, 2035–2040.
8. Schiemann, K.; Emde, U.; Schlueter, T.; Saal, C.; Maiwald, M. Preparation of poly-
morphic forms of pyranoquinolines for treatment of proliferative diseases. WO Patent
2007147480A2, 2007, Chem. Abstr. 2007, 148, 85962.
9. Schnur, R. C. Spiro-quinolylhydantoins. U.S. Patent 4,176,185, 1979, Chem. Abstr. 1980,
92, 111015c.
10. (a) Abd EI-Nabi, H. A. A novel one-step synthesis of pyrano[3,2-c]quinolines and a trans-
formation into 3,3-bis(4-hydroxy-2-oxoquinolinyl)arylmethanes. Pharmazie. 1997, 52, 28–
32; (b) Narsinh, D.; Anamik, S. New heterocycles from substituted 2-amino-5-oxo-
4-phenyl-6-hydro-4H-pyrano[3,2-c]quinoline-3-carbonitriles. Indian J. Heterocycl. Chem.
2000, 10, 155–156; (c) Dodia, N.; Shah, A. Synthesis of some tricyclic and tetracyclic ring
systems built on 4-hydroxy-2-quinolones. Heterocycl. Commun. 2001, 7, 289–294.
11. Wang, X. S.; Zeng, Z. S.; Shi, D. Q.; Wei, X. Y.; Zong, Z. M. One-step synthesis of
2-amino-3-cyano-4-aryl-1,4,5,6-tetrahydropyrano[3,2-c]quinolin-5-one derivatives using
KF–Al2O3 as catalyst. Synth. Commun. 2004, 34, 3021–3027.
12. Wang, X. S.; Zheng, Z. S.; Li, Y. L.; Shi, D. Q.; Tu, S. J.; Wei, X. Y.; Zong, Z. M.
Synthesis of 2-amino-4-aryl-5,6-dihydro-4H-pyrano[3,2-c]quinolin-5-one derivatives in
water. Chin. J. Org. Chem. 2006, 26, 228–232.
13. (a) Sowellim, S. I. A.; EI-Taweel, F. M. A.; Elagamey, A. A. Cyclization reactions of a,
b-unsaturated nitriles with quinoline and cinnoline derivatives: New approaches for syn-
theses of 4H-pyrano[3,2-c]quinoline and 4H-pyrano[3,2-c]cinnoline derivatives. Egypt. J.
Chem. 1995, 38, 511–522; (b) Wang, X. S.; Zeng, Z. S.; Shi, D. Q.; Tu, S. J.; Wei, X. Y.;
Zong, Z. M. Study on the reaction of arylmethylidenemalononitriles with 4-hydroxy-
1,2-dihydroquinolin-2-one. Chin. J. Org. Chem. 2004, 24, 1595–1597.
14. Lei, M.; Ma, L.; Hu, L. H. A green, efficient, and rapid procedure for the synthesis of
2-amino-3-cyano-1,4,5,6-tetrahydropyrano[3,2-c]quinolin-5-one derivatives catalyzed by
ammonium acetate. Tetrahedron Lett. 2011, 52, 2597–2600.