An efficient one-pot synthesis of pyrano[3,2-c]quinolin-2,5-dione derivatives catalyzed by l-proline

Article abstract of DOI:10.3390/molecules171213856

A series of 4-Aryl-6-methyl-3,4-dihydro-2H-pyrano[3,2-c]quinolin-2,5(6H)- diones were synthesized via the three-component reactions of aromatic aldehydes, 4-hydroxy-1- methylquinolin-2(1H)-one, and Meldrum's acid catalyzed by L-proline. The structures of the products were identified by spectroscopic analysis. A mechanism for this three-component reaction catalyzed by L-proline was proposed.

Full text of DOI:10.3390/molecules171213856

Molecules 2012, 17, 13856-13863; doi:10.3390/molecules171213856
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
An Efficient One-Pot Synthesis of Pyrano[3,2-c]quinolin-2,5-dione
Derivatives Catalyzed by L-Proline
Songlei Zhu 1,2,†,*, Jing Wang 2,†, Zhou Xu 2 and Jie Li 3
1
Key Laboratory of Biological Cancer Therapy of Jiangsu Province, Xuzhou Medical College,
Xuzhou 221004, China
2
Department of Chemistry, Xuzhou Medical College, Xuzhou 221004, China
3
School of Pharmacy, Xuzhou Medical College, Xuzhou 221004, China
†
These authors contributed equally to this work.
* Author to whom correspondence should be addressed; E-Mail: songleizhu@xzmc.edu.cn;
Tel./Fax: +86-516-8397-9800.
Received: 5 November 2012; in revised form: 17 November 2012 / Accepted: 20 November 2012 /
Published: 22 November 2012
Abstract: A series of 4-aryl-6-methyl-3,4-dihydro-2H-pyrano[3,2-c]quinolin-2,5(6H)-diones
were synthesized via the three-component reactions of aromatic aldehydes, 4-hydroxy-1-
methylquinolin-2(1H)-one, and Meldrum’s acid catalyzed by L-proline. The structures of
the products were identified by spectroscopic analysis. A mechanism for this three-component
reaction catalyzed by L-proline was proposed.
Keywords: pyrano[3,2-c]quinolin-2,5(6H)-dione; multi-component reaction; L-proline
1. Introduction
Multicomponent reactions (MCRs) play an increasingly important role in organic and medical
chemistry for their high degree of atom economy, convergence, productivity, easy execution, generally
excellent yields and broad applications in combinatorial chemistry [1]. MCRs are highly efficient strategies
to achieve the rapid assembly of complex products, especially sequential carbon-carbon and carbon-
heteroatom bond-forming reactions in the area of heterocycles and natural products [2–4].
Pyranoquinolines and their derivatives have been reported to possess antidiabetic activities [5] and
pure calcium channel blocking activities [6]. A few methods have been reported for the synthesis

Molecules 2012, 17
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of pyranoquinoline derivatives from 3-oxopropanoic acid [7], or by a MCRs of malononitrile
(or cyanoacetate) with aldehydes and 4-hydroxyl-1,2-dihydroquinolin-2-one (or 8-hydroxyquinoline)
in the presence of KF-Al2O3 [8–10], TEA [11] and NEt3 [12] as catalysts under reflux or microwave
irradiation conditions.
In recent years, the use of L-proline in different organic reactions has drawn much interest because
of its experimental simplicity, ease of handing, cost effectiveness, and excellent solubility in water and
organic solvents [13–17]. L-proline is a very efficient catalyst in transformations such as enamine-based
direct catalytic asymmetric aldol condensations [18,19], Mannich reactions [20,21], Diels-Alder
reactions [22] and Michael additions [23]. Proline has also been used as a catalyst for two-carbon
homologation and in various one-pot multicomponent reactions [24–26]. As continuation of our
interest in developing new methodologies for the preparation of heterocyclic compounds, herein we
report a mild and highly efficient protocol for the synthesis of 3,4-dihydro-2H-pyrano[3,2-c]quinolin-
2,5(6H)-diones catalyzed by L-proline.
2. Results and Discussion
Initially, the three-component reaction of 4-methoxybenzaldehyde (1a), 4-hydroxy-1-methylquinolin-
2(1H)-one (2), and Meldrum’s acid (3) was investigated as a model reaction to establish the feasibility
of the strategy and to optimize the reaction conditions (Scheme 1). The effects of solvents and catalyst
loading were evaluated for this model reaction, and the results are summarized in Table 1.
Scheme 1. The model reaction.
Table 1. Optimization of reaction conditions.
Entry Solvents Catalyst (mol%) Temperature (°C) Time (h) Yield (%)
1
2
EtOH
EtOH
CH3CN
CHCl3
HOAc
DMF
No
reflux
reflux
reflux
reflux
100
5
1
2
2
2
2
4
2
1
1
45
91
70
63
80
52
45
75
90
91
L-proline (10%)
L-proline (10%)
L-proline (10%)
L-proline (10%)
L-proline (10%)
L-proline (10%)
L-proline (5%)
L-proline (15%)
L-proline (20%)
3
4
5
6
100
7
H2O
reflux
reflux
reflux
reflux
8
EtOH
EtOH
EtOH
9
10
It was found that when the reaction was carried out without any catalyst, only a modest amount of
product was obtained, even after 5 h (Table 1, entry 1). When the reaction was conducted in the

Molecules 2012, 17
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presence of L-proline (10 mol%) in ethanol, the target compound 4a was obtained in 91% yield (Table 1,
entry 2). Other solvents were also used in this reaction. The results indicated that ethanol provided
much better results than acetonitrile, chloroform, acetic acid, N,N-dimethylformamide (DMF), and
water (Table 1, entries 2–7).
To optimize the catalyst loading, 5 mol%, 10 mol%, 15 mol%, and 20 mol% of L-proline were
tested in the reactions, respectively (Table 1, entries 2, and 8–10). A 10 mol% loading of L-proline was
sufficient to efficiently push the reaction forward, while 5 mol% of L-proline was not enough. Higher
amounts of L-proline did not lead to significant changes in the reaction yields. With these optimum
conditions in hand, a series of 4-aryl-6-methyl-3,4-dihydro-2H-pyrano[3,2-c]quinolin-2,5(6H)-dione
derivatives were synthesized via three-component reactions of aromatic aldehydes 1, 4-hydroxy-1-
methylquinolin-2(1H)-one (2), and Meldrum’s acid (3) in ethanol in the presence of L-proline (Scheme 2).
The results sare summarized in Table 2.
Scheme 2. Synthesis of 4-aryl-6-methyl-3,4-dihydro-2H-pyrano[3,2-c]quinolin-2,5(6H)-diones 4.
O
O
OH
O
O
O CH3
O CH3
L-proline (10 mol %)
EtOH, reflux 1-2.5 h
Ar
ArCHO
+
+
N
O
N
O
CH3
CH3
1
2
3
4
Table 2. Synthesis of pyrano[3,2-c]quinoline-2,5-diones 4 catalyzed by L-proline
Entry
Ar
Product Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
4-CH3OC6H4
4-BrC6H4
4a
4b
4c
4d
4e
4f
2
1
91
94
95
93
92
95
92
90
91
4-HOC6H4
4-(CH3)2NC6H4
Thiophen-2-yl
3-ClC6H4
1
1.5
2
1.5
1
4-ClC6H4
4g
4h
4i
4-FC6H4
2
3,4-(CH3)2C6H3
2.5
As shown in Table 2, this protocol could be applied not only to the aromatic aldehydes with
electron-withdrawing groups (such as halides), but also to the aromatic aldehydes with electron-donating
groups (such as alkyl and hydroxy groups) therefore, we concluded that the electronic nature of the
substituents of aromatic aldehydes has no significant effect on this reaction.
The structures of the compound 4 were identified by their spectroscopic analysis. Thus, the infrared
(IR) spectra of compound 4 measured in potassium bromide pellets showed two bands for the stretching
1
vibrations of the C=O groups at 1,653–1,658 and 1,773–1,783 cm−1, respectively. In the H-NMR
spectra of compounds 4 measured in dimethyl sulfoxide-d6, the quinoline N-CH3 proton signals at
3.64–3.69 ppm, the CH2 proton signals at 2.89–3.11 and 3.42–3.55 ppm, the CH proton signals at
4.44–4.81 ppm, and the aromatic proton signals at 6.64–7.95 ppm were observed.

Molecules 2012, 17
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Although the detailed mechanism of above reaction remains to be fully clarified, the formation of
compounds 4 could be explained by a reaction sequence presented in Scheme 3. We propose that the
reaction procees via a reaction sequence of condensation, addition, cyclization, and elimination. We
suggest that L-proline may catalyze the formation of iminium ion 5 in a reversible reaction with
aldehydes 1. The higher reactivity of the iminium ion compared with the carbonyl species could
facilitate Knovenagel condensation between aldehyde 1 and Meldrum’s acid (3) via intermediate 6,
and after elimination of L-proline, compound 7 might be produced as an intermediate. Then,
intermediate 7 is attacked via Michael addition of 4-hydroxy-1-methylquinolin-2(1H)-one (2) to give
the intermediate 8, which is followed by the cycloaddition and loss of acetone and carbon dioxide to
form the desired products 4.
Scheme 3. Proposed mechanism for the formation of pyrano[3,2-c]quinoline-2,5-diones 4.
O
O
O
O
O
O
O
H N
N
H
COOH
COO-
O
N+
COO-
3
H
Ar
H
Ar
6
H
Ar
O
5
1
CH3
N
O
O
O
O
O
N
O
O
O
O
N
COOH
O
H
OH
O
2
Ar
H
Ar
O
7
CH3
O
O
O
HO
O
O
O
HO
N
O
O
CH3COCH3
CO2
O
Ar
Ar
Ar
N
O
O
N
O
CH3
CH3
CH3
8
4
3. Experimental
General
All reagents were purchased from commercial sources and used without further purification.
Melting points were measured on an Electrothermal XT-5 apparatus. IR spectra were recorded on a Varian
1
F-1000 spectrometer in KBr with absorptions given in cm−1. H-NMR spectra were determined on a
Varian Invoa-400 MHz spectrometer in DMSO-d6 solutions. J values are in Hz. Chemical shifts are
expressed in ppm downfield from internal standard TMS. HRMS data were obtained using a TOF-MS
instrument (Micromass Inc., Manchester, UK).
General Procedure for the Synthesis of 4-Aryl-6-methyl-3,4-dihydro-2H-pyrano[3,2-c]quinolin-2,5(6H)-
diones 4
A mixture of aromatic aldehyde 1 (1 mmol), 4-hydroxy-1-methylquinolin-2(1H)-one (2, 0.175 g,
1 mmol), Meldrum’s acid (3, 1 mmol), L-proline (0.0115 g, 0.1 mmol) and ethanol (2 mL) in a 50 mL

Molecules 2012, 17
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round bottom flask was stirred at 80 °C for 1–2.5 h. At the end of the reaction, the mixture was cooled
to room temperature. The precipitate was collected by filtration and purified by recrystallization from
EtOH and DMF to give products 4.
4-(4-Methoxyphenyl)-6-methyl-3,4-dihydro-2H-pyrano[3,2-c]quinoline-2,5(6H)-dione (4a). White
solid; m.p. 192–194 °C. IR: 3041 (C-H Ar), 2924 (C-H aliph), 1782 (C=O), 1654 (C=O), 1600 (C=C),
1514 (ArC=C), 1380 (C-H CH3), 1252 (C-O); 1H-NMR: δ (ppm) 2.92 (d, J = 16.0 Hz, 1H, CH2), 3.46
(dd, J1 = 7.6 Hz, J2 = 16.0 Hz, 1H, CH2), 3.64 (s, 3H, CH3), 3.69 (s, 3H, OCH3), 4.51 (d, J = 7.2 Hz,
1H, CH), 6.86 (d, J = 8.4 Hz, 2H, ArH), 7.09 (d, J = 8.8 Hz, 2H, ArH), 7.40 (t, J1 = 8.0 Hz, J2 = 7.2
Hz, 1H, ArH), 7.64 (d, J = 8.8 Hz, 1H, ArH), 7.75 (t, J1 = 7.6 Hz, J2 = 7.2 Hz, 1H, ArH), 7.93 (d,
J = 8.0 Hz, 1H, ArH); HRMS calculated for C20H17NO4 [M]+: 335.1158, Found 335.1158.
4-(4-Bromophenyl)-6-methyl-3,4-dihydro-2H-pyrano[3,2-c]quinoline-2,5(6H)-dione (4b). White solid;
m.p. 239–241 °C. IR: 3024 (C-H Ar), 2928 (C-H aliph), 1778 (C=O), 1655 (C=O), 1596 (C=C), 1503
1
(ArC=C), 1384 (C-H CH3), 1209 (C-O); H-NMR: δ (ppm) 2.96 (d, J = 16.0 Hz, 1H, CH2), 3.52
(dd, J1 = 7.6 Hz, J2 = 16.0 Hz, 1H, CH2), 3.65 (s, 3H, CH3), 4.56 (d, J = 7.2 Hz, 1H, CH), 7.16 (d,
J = 8.4 Hz, 2H, ArH), 7.41 (t, J1 = 7.6 Hz, J2 = 7.2 Hz, 1H, ArH), 7.51 (d, J = 8.4 Hz, 2H, ArH), 7.66
(d, J = 8.8 Hz, 1H, ArH), 7.76 (t, J1 = 7.6 Hz, J2 = 8.4 Hz, 1H, ArH), 7.95 (d, J = 8.0 Hz, 1H, ArH);
79
HRMS calculated for C19H14NO3 Br [M]+: 383.0157, Found 383.0148.
4-(4-Hydroxyphenyl)-6-methyl-3,4-dihydro-2H-pyrano[3,2-c]quinoline-2,5(6H)-dione (4c). White solid;
m.p. > 300 °C. IR: 3282 (O-H), 3013 (C-H Ar), 1781 (C=O), 1653 (C=O), 1600 (C=C), 1517
1
(ArC=C), 1385 (C-H CH3), 1202 (C-O); H-NMR: δ (ppm) 2.90 (d, J = 16.0 Hz, 1H, CH2), 3.43 (dd,
J1 = 7.2 Hz, J2 = 15.6 Hz, 1H, CH2), 3.65 (s, 3H, CH3), 4.56 (d, J = 6.8 Hz, 1H, CH), 6.69 (d, J = 8.4
Hz, 2H, ArH), 6.97 (d, J = 8.4 Hz, 2H, ArH), 7.40 (t, J1 = 7.6 Hz, J2 = 7.6 Hz, 1H, ArH), 7.64 (d,
J = 8.8 Hz, 1H, ArH), 7.75 (t, J1 = 8.4 Hz, J2 = 7.6 Hz, 1H, ArH), 7.93 (d, J = 8.0 Hz, 1H, ArH), 9.37
(s, 1H, OH); HRMS calculated for C19H15NO4 [M]+: 321.1001, Found 321.1001.
4-(4-Dimethylaminophenyl)-6-methyl-3,4-dihydro-2H-pyrano[3,2-c]quinoline-2,5(6H)-dione (4d). White
solid; m.p. 220–222 °C. IR: 2981 (C-H aliph), 2798 (C-H aliph), 1773 (C=O), 1654 (C=O), 1598
1
(C=C), 1519 (ArC=C), 1382 (C-H CH3), 1208 (C-O); H-NMR: δ (ppm) 2.83 (s, 6H, 2 × CH3), 2.90
(d, J = 16.0 Hz, 1H, CH2), 3.42 (dd, J1 = 7.6 Hz, J2 = 16.0 Hz, 1H, CH2), 3.65 (s, 3H, CH3), 4.44 (d,
J = 6.8 Hz, 1H, CH), 6.64 (d, J = 8.0 Hz, 2H, ArH), 6.98 (d, J = 8.4 Hz, 2H, ArH), 7.40 (t, J1 = 8.0 Hz,
J2 = 7.2 Hz, 1H, ArH), 7.64 (d, J = 8.8 Hz, 1H, ArH), 7.73 (t, J1 = 7.6 Hz, J2 = 8.0 Hz, 1H, ArH), 7.93
(d, J = 8.0 Hz, 1H, ArH); HRMS calculated for C21H20N2O3 [M]+: 348.1474, Found 348.1478.
6-Methyl-4-(thiophen-2-yl)-3,4-dihydro-2H-pyrano[3,2-c]quinoline-2,5(6H)-dione (4e). White solid;
m.p. 243–244 °C. IR: 3040 (C-H Ar), 2947 (C-H aliph), 1774 (C=O), 1658 (C=O), 1596 (C=C), 1587
1
(ArC=C), 1213 (C-O); H-NMR: δ (ppm) 3.11 (d, J = 15.2 Hz, 1H, CH2), 3.51–3.55 (m, 1H, CH2),
3.69 (s, 3H, CH3), 4.81 (d, J = 1.2 Hz, 1H, CH), 6.93 (d, J = 18.0 Hz, 2H, ArH), 7.39 (d, J = 5.6 Hz,
2H, ArH), 7.67 (s, 1H, ArH), 7.76 (s, 1H, ArH), 7.92 (s, 1H, ArH); HRMS calculated for C17H13NO3S
[M]+: 311.0616, Found 311.0612.

Molecules 2012, 17
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4-(3-Chlorophenyl)-6-methyl-3,4-dihydro-2H-pyrano[3,2-c]quinoline-2,5(6H)-dione (4f). White solid;
m.p. 232–233 °C. IR: 3054 (C-H Ar), 2939 (C-H aliph), 1783 (C=O), 1654 (C=O), 1594 (C=C), 1387
1
(C-H CH3), 1205 (C-O); H-NMR: δ (ppm) 2.99 (d, J = 16.0 Hz, 1H, CH2), 3.52 (dd, J1 = 7.6 Hz,
J2 = 16.4 Hz, 1H, CH2), 3.65 (s, 3H, CH3), 4.59 (d, J = 6.8 Hz, 1H, CH), 7.11 (d, J = 5.6 Hz, 1H, ArH),
7.30–7.36 (m, 3H, ArH), 7.41 (t, J1 = 7.6 Hz, J2 = 7.6 Hz, 1H, ArH), 7.65 (d, J = 8.4 Hz, 1H, ArH),
7.76 (t, J1 = 7.2 Hz, J2 = 7.6 Hz, 1H, ArH), 7.94 (d, J = 8.0 Hz, 1H, ArH); HRMS calculated for
35
C19H14NO3 Cl [M]+: 339.0662, found 339.0648.
4-(4-Chlorophenyl)-6-methyl-3,4-dihydro-2H-pyrano[3,2-c]quinoline-2,5(6H)-dione (4g). White solid;
m.p. 227–228 °C. IR: 3083 (C-H Ar), 2935 (C-H aliph), 1779 (C=O), 1657 (C=O), 1593 (C=C), 1385
1
(C-H CH3), 1207 (C-O); H-NMR: δ (ppm) 2.97 (d, J = 16.0 Hz, 1H, CH2), 3.52 (dd, J1 = 7.6 Hz,
J2 = 16.0 Hz, 1H, CH2), 3.65 (s, 3H, CH3), 4.58 (d, J = 7.2 Hz, 1H, CH), 7.22 (d, J = 8.4 Hz, 2H, ArH),
7.37 (d, J = 8.4 Hz, 2H, ArH), 7.42 (d, J = 7.6 Hz, 1H, ArH), 7.66 (d, J = 8.8 Hz, 1H, ArH), 7.76
(t, J1 = 7.2 Hz, J2 = 8.4 Hz, 1H, ArH), 7.95 (d, J = 8.0 Hz, 1H, ArH); HRMS calculated for
35
C19H14NO3 Cl [M]+: 339.0662, Found 339.0654.
4-(4-Fluorophenyl)-6-methyl-3,4-dihydro-2H-pyrano[3,2-c]quinoline-2,5(6H)-dione (4h). White solid;
m.p. 230–231 °C. IR: 3076 (C-H Ar), 2923 (C-H aliph), 1777 (C=O), 1656 (C=O), 1598 (C=C), 1506
1
(ArC=C), 1386 (C-H CH3), 1214 (C-O); H-NMR: δ (ppm) 2.96 (d, J = 16.0 Hz, 1H, CH2), 3.50 (dd,
J1 = 7.6 Hz, J2 = 16.0 Hz, 1H, CH2), 3.64 (s, 3H, CH3), 4.58 (d, J = 7.2 Hz, 1H, CH), 7.13 (t, J1 = 8.4 Hz,
J2 = 8.8 Hz, 2H, ArH), 7.23 (t, J1 = 7.6 Hz, J2 = 8.4 Hz, 2H, ArH), 7.40 (t, J1 = 7.6 Hz, J2 = 7.6 Hz,
1H, ArH), 7.64 (d, J = 8.4 Hz, 1H, ArH), 7.75 (t, J1 = 7.2 Hz, J2 = 8.4 Hz, 1H, ArH), 7.93 (d, J = 8.0 Hz,
1H, ArH); HRMS calculated for C19H14NO3F [M]+: 323.0958, Found 323.0961.
4-(3,4-Dimethylphenyl)-6-methyl-3,4-dihydro-2H-pyrano[3,2-c]quinoline-2,5(6H)-dione (4i). White solid;
m.p. 170–171 °C. IR: 3010 (C-H Ar), 2939 (C-H aliph), 1777 (C=O), 1654 (C=O), 1596 (C=C), 1462
(ArC=C), 1382 (C-H CH3), 1215 (C-O); 1H-NMR: δ (ppm) 2.15 (s, 6H, 2 × CH3 ), 2.89 (d, J = 16.0 Hz,
1H, CH2), 3.46 (dd, J1 = 8.0 Hz, J2 = 15.6 Hz, 1H, CH2), 3.64 (s, 3H, CH3), 4.48 (d, J = 6.4 Hz, 1H,
CH), 6.84 (d, J = 7.6 Hz, 1H, ArH), 6.96 (s, 1H, ArH), 7.04 (d, J = 7.6 Hz, 1H, ArH), 7.41 (t,
J1 = 8.0 Hz, J2 = 7.2 Hz, 1H, ArH), 7.64 (d, J = 8.4 Hz, 1H, ArH), 7.75 (t, J1 = 7.2 Hz, J2 = 8.4 Hz, 1H,
ArH), 7.94 (d, J = 8.0 Hz, 1H, ArH); HRMS calculated for C21H19NO3 [M]+: 333.1365, Found 333.1367.
4. Conclusions
In summary, we have developed an efficient synthesis of 4-aryl-6-methyl-3,4-dihydro-2H-pyrano
[3,2-c]quinolin-2,5(6H)-diones via the three-component reactions of aromatic aldehydes, 4-hydroxy-1-
methylquinolin-2(1H)-one, and Meldrum’s acid catalyzed by L-proline. This protocol has the advantages
of easy work up, mild reaction conditions, and high yields. In view of the potential biological activities
of these molecules, further biomedical screening work is in progress in our laboratories.
Acknowledgments
We gratefully acknowledge the Natural Science Foundation of Higher Education Institutions of
Jiangsu Province (No.09KJB150012), the Key Laboratory of Cancer Biotherapy of Xuzhou Medical

Molecules 2012, 17
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College (grant No. C0901), the Key Laboratory of Organic Synthesis of Jiangsu Province (No. KJS1010)
and the Special Presidential Foundation of Xuzhou Medical College (No. 2010KJZ20) for support of
this research.
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Sample Availability: Samples of the compounds 4 are available from the authors.
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