An efficient green protocol for the synthesis of coumarin fused highly decorated indenodihydropyridyl and dihydropyridyl derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.02.077

A simple, convenient, environmentally benign, and mild synthetic method has been established to afford highly decorated indenodihydropyridine and dihydropyridine derivatives employing a green solvent ethyl-l-lactate and an organo-catalyst (±)lactic acid. A wide range of functional groups were tolerated in the developed protocol. The target molecules were obtained in moderate to good yields applying the current method.

Full text of DOI:10.1016/j.tetlet.2012.02.077

Tetrahedron Letters 53 (2012) 2206–2210
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An efficient green protocol for the synthesis of coumarin fused highly decorated
indenodihydropyridyl and dihydropyridyl derivatives
⇑
Sanjay Paul, Asish R. Das
Department of Chemistry, University of Calcutta, Kolkata 700009, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple, convenient, environmentally benign, and mild synthetic method has been established to afford
highly decorated indenodihydropyridine and dihydropyridine derivatives employing a green solvent
ethyl-L-lactate and an organo-catalyst ( )lactic acid. A wide range of functional groups were tolerated
in the developed protocol. The target molecules were obtained in moderate to good yields applying
the current method.
Received 8 December 2011
Revised 15 February 2012
Accepted 16 February 2012
Available online 25 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Indenodihydropyridine
Dihydropyridine
Organocatalyst
Green protocol
In recent years, much attention has been directed toward the
synthesis of dihydropyridyl and indeno dihydropyridyl compounds
owing to their tremendous application in various research fields
including biological science and medicinal chemistry. Dihydropyr-
idyl core containing compounds are acknowledged as calcium
channel modulators and have emerged as one of the most impor-
tant classes of drugs for the treatment of cardiovascular diseases.1
Cardiovascular agents such as nifedipine, nicardipine, amlodipine,
and other related derivatives are dihydropyridyl nucleus containing
compounds, effective in the treatment of hypertension.2 Moreover
dihydropyridine derivatives possess a variety of biological activities
such as vasodilator, bronchodilator, antiatherosclerotic, antitumor,
geroprotective, hepatoprotective, and antidiabetic activities.3
Widespread studies have uncovered that dihydropyridyl unit con-
taining compounds exhibit various medicinal functions such as
neuroprotectant, platelet anti-aggregatory activity, cerebral anti
ischemic activity in the treatment of Alzheimer’s disease, and
chemosensitizer in tumor therapy.4
OMe
OMe
O
O
O
X
Y
O
N
N
O
N
Me
O
Onychnine
A
NSC 314622
Figure 1. Structures of alkaloids containing indenopyridine framework.
indenopyridone NSC 314622 (Fig. 1) is serving as a lead compound
for the development of anticancer agents targeting topoisomerase
I. Analogous to the polycyclic natural product camptothecin, iso-
lated from the extracts of Camptotheca acuminata and its clinically
useful derivative topotecan, the polycyclic planar structure of
indenopyridones allows for DNA intercalation and inhibition of
DNA relegation by topoisomerase I.14 Again coumarin and its
derivatives represent one of the most active classes of compounds
possessing a wide spectrum of biological activities.15
The vast biological importance16 of indenopyridines inspired us
to develop a novel protocol for the efficient synthesis of new inden-
odihydropyridines which are analogous to prodrugs of indenopyri-
dine motif containing drugs and can be transformed to
indenopyridine by single oxidation step. Environmental aspects
triggered organic and medicinal chemists to focus on the develop-
ment of a greener, milder, and more sustainable chemical process.
Successful catalytic versions of organic reactions have mostly em-
ployed transition-metal, metaloxide, complexes and may require
toxic, rare, and expensive metals, and suffer from possible contam-
ination of the products by metal. The concept of organocatalysis17
has been uncovered during the last decade with a considerable
Moreover, 4-azafluorenone group of alkaloids contain indeno-
pyridine framework, represented by their simplest member Ony-
chnine ( Fig. 1).5 Further, indenopyridines A ( Fig. 1) exhibit
cytotoxic,6 phosphodiesterase inhibitory,7 adenosine A2a receptor
antagonistic,8 antiinflammatory/antiallergic,9 coronary dilating,10
and calcium modulating activities.11 These compounds have also
been investigated for the treatment of hyperlipoproteinemia and
arteriosclerosis12 as well as neurodegenerative diseases.13 Lastly,
⇑
Corresponding author. Tel.: +91 3323501014/9433120265; fax: +91
3323519754.
E-mail addresses: ardchem@caluniv.ac.in, ardas66@rediffmail.com (A.R. Das).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.077

S. Paul, A. R. Das / Tetrahedron Letters 53 (2012) 2206–2210
2207
Table 1
number of synthetic applications. The special features for the choice
Influence of different catalysts for the synthesis of 3ba
of organocatalyst were that the catalyst should be easily handled
without the need for extraordinary precautions with regard to
atmosphere, humidity or equipment and that the catalyst has no
toxicity in general and preferably a natural product with no neces-
sity to remove catalyst remnants after the completion of reaction.
Literatures are available for the synthesis of coumarin fused
pyridines and dihydropyridine.18 But there is a maiden report for
the synthesis of coumarin fused indenodihydropyridines. As a part
of our ongoing research on environment friendly organic reactions
toward the synthesis of biologically active molecules,19 herein we
like to demonstrate a very efficient green synthetic protocol20 for
the synthesis of coumarin fused indenodihydropyridines and dihy-
dropyridines introducing a one pot three-component coupling of
4-aminocoumarin, aromatic aldehyde, and indane-1,3-dione or
dimedone by the installation of organocatalyst.21,22
Entry
Catalyst
Time (h)
Yieldb (%)
1
2
3
4
5
6
—
36
6
6
6
6
10
15
20
10
15
—
FeCl3
InCl3
Alumina
SiO2
6
L
-Proline
7
8
9
Citric acid
Oxalic acid
( )Lactic acid
5
5
2.5
50
15
85
a
The reaction was carried out using 4-nitrobenzaldehyde (1 mmol), 4-amino-
coumarin (1 mmol), and indane-1,3-dione (1 mmol) in the presence of ( )lactic acid
(2 mmol) at 100 °C in ethyl- -lactate.
Isolated yield of the pure compound.
L
b
At the commencement of our work, 4-aminocoumarin (1 mmol),
4-nitrobenzaldehyde (1 mmol), and indane-1,3-dione (1 mmol)
were employed as reactants for the model reaction (Scheme 1) to
synthesize indenodihydropyridine in presence of various catalysts
(Table 1). Lewis acid catalysts like FeCl3, InCl3, alumina, SiO2 and
Table 2
Influence of solvents and catalyst concentration on the synthesis of 3ba
Entry
Catalyst loading (equiv)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
0.25
0.5
1
2
3
2
2
2
2
Ethyl-
Ethyl-
Ethyl-
Ethyl-
Ethyl-
H2O
Acetonitrile
DMF
Ethanol
L
L
L
L
L
-lactate
-lactate
-lactate
-lactate
-lactate
40
50
70
85
85
—
organocatalysts like citric acid,
L-proline, ( )lactic acid were
screened to test their efficiency at 100 °C for the synthesis of inden-
odihydropyridine. In the preliminary experiment, the above men-
tioned reaction was performed in the absence of any catalyst
employing ethyl-L-lactate as the solvent. It was evident that the
—
15
30
40
reaction proceeded very slowly in the absence of catalyst and the
expected product was isolated in a very small quantity after heating
the reaction mixture for about 36 h at 100 °C (Table 1, entry 1) indi-
cating also the non-catalytic nature of the solvent. The influence of
Lewis acids in the above reaction was not very much pronounced.
2
Ethylene glycol
a
The reaction was carried out using 4-nitrobenzaldehyde (1 mmol), 4-amino-
coumarin (1 mmol), and indane-1,3-dione (1 mmol) in the presence of ( )lactic acid
(2 mmol) at 100 °C.
Organocatalysts, specifically
a-hydroxy carboxylic acids seemed
b
Isolated yield of the pure compound.
to be the most effective catalysts for the above transformation.
( )Lactic acid dramatically accelerated this reaction and gave good
yield of the desired product. The results are summarized in Table 1.
Various solvents were also screened to test their efficiency at
100 °C and the results are summarized in Table 2. The results
Table 3
Substrate scopea for the synthesis of coumarin fused indenodihydropyridines
Entry
R
Time (h)
Product
Yieldb (%)
clearly indicate that ethyl-L-lactate showed superiority over the
1
2
3
4
5
6
7
8
C6H5
3.0
2.5
3.0
2.5
3.0
2.5
2.0
2.5
3a
3b
3c
3d
3e
3f
77
85
78
79
73
78
80
75
other solvents. An increase in the amount of ( )lactic acid from
0.25 to 3.0 equiv increased the yield of the desired product to a
great extent (40–85%, Table 2).
Encouraged by the efficiency of the above reaction protocol, we
then devised a novel three-component one pot synthesis of func-
tionalized indenodihydropyridine derivatives under thermal con-
ditions. To scrutinize the scope, limitations, and generality of this
protocol, we have advocated a series of aromatic aldehydes bearing
electron-donating as well as electron-withdrawing functionalities
with 4-aminocoumarin and indane-1,3-dione (Table 3).
4-NO2–C6H4
4-CN–C6H4
2-Cl–C6H4
4-OCH3–C6H4
Naphthalene-2-yl
4-F–C6H4
3g
3h
4-OH–C6H4
a
Reactions were carried out using aromatic aldehyde (1.0 mmol), 4-amino-
coumarin (1.0 mmol), and indane-1,3-dione (1.0 mmol) in the presence of lactic
acid (2.0 mmol) at 100 °C in ethyl- -lactate.
L
b
Isolated yield of the pure compound.
O
O
R
O
O
O
NH2
O
O
O
O
O
( ) lactic acid
Ethyl-L-lactate, 1000 C
+
+
+
+
N
H
H
H
R
R
O
O
3a-3h
R
O
O
O
NH2
O
( ) lactic acid
Ethyl-L-lactate, 1000
N
H
C
R=Aryl group
4a-4h
Scheme 1. Synthesis of indenodihydropyridyl and dihydropyridyl derivatives.

2208
S. Paul, A. R. Das / Tetrahedron Letters 53 (2012) 2206–2210
Table 4
Substrate scopea for the synthesis of coumarin fused dihydropyridines
Entry
R
Time (h)
Product
Yieldb (%)
1
2
3
4
5
6
7
8
C6H5
3.0
2.5
3
2.5
3.0
2.5
2.0
2.5
4a
4b
4c
4d
4e
4f
87
91
78
89
83
89
90
90
4-NO2–C6H4
4-OCH3–C6H4
2-Cl–C6H4
4-CH3–C6H4
Naphthalene-2-yl
4-F–C6H4
4g
4h
4-OH–C6H4
a
Reactions were carried out using aromatic aldehyde (1.0 mmol), 4-amino-
coumarin (1.0 mmol), and dimedone (1.0 mmol) in the presence of lactic acid
(2.0 mmol) at 100 °C in ethyl- -lactate.
L
b
Isolated yield of the pure compound.
Subsequently, we tried to extend the capacity of the present
protocol, for the condensation of aromatic aldehydes, 4-amino-
coumarin, and dimedone to synthesize highly substituted couma-
rin fused dihydropyridine derivatives. The reactions occurred
smoothly with unsubstituted as well as substituted benzalde-
hydes. The results are summarized in Table 4.
Figure 2. X-ray crystal structure of 4a.
As anticipated, the results (presented in the Tables 3 and 4)
clearly indicate that these reactions proceeded cleanly under mild
thermal conditions and no undesirable products were obtained. In
both cases the reactions proceeded smoothly with unsubstituted
benzaldehyde, electron-withdrawing, and also with electron-
releasing para-substituted benzaldehydes with moderate to good
yields.
With these outstanding results in hand, we are now in a position
to propose the mechanism of the reaction which involves mild or-
ganic acid catalyzed Knoevenagel condensation,23 Michael addition,
and then intra molecular cyclization as presented in Scheme 2. The
Knoevenagel condensation product as an intermediate in the above
reaction was confirmed by performing two different sets of two
component reactions.24 Carrying out the reaction in the presence
of homochiral solvent, no potential asymmetric induction has been
detected though the proposed reaction gave rise to a chiral center.
This is due to the racemic nature of the catalyst.
It is noteworthy to mention that coumarin fused indenodihy-
dropyridines are quite stable and not at all prone to aerial oxida-
tion. These can be oxidized to the corresponding indenopyridines
derivative by using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in
DMF under refluxing condition.25 Furthermore, to take advantage
of the elaborated green protocol, the reaction was scaled up to
10 mmol scale; excellent results were obtained in 3 h. Solid prod-
uct was precipitated on cooling the reaction mixture to room tem-
perature (indenodihydropyridine) or by pouring the cold reaction
mixture into 100 ml of water (dihydropyridine). The solid thus
appeared was collected by filtration, washed with ethanol, and
a-hydroxy carboxylic acid showed most pronounced catalytic activ-
ity. The -hydroxy carboxylic acid may increase the electrophilicity
a
of both the carbonyl groups (forming H-bond from above or below
the plane of the 1,3-indanedione and dimedone ring) (Scheme 2)
of the Knoevenagel condensation product which in turn accelerate
the Michael addition step (II). But the influence of citric acid in the
above reaction was not so prominent due to the steric factor for
which it cannot approach the reaction center. The formation of
NH2
R
O
O
H
R
O
H
O
HO
H
O
O
Lactic acid
(I)
H
R
O
+
O
O
(II)
H N
O 2
-H2O
O
O
H
O
(III)
O
R
O
O
H
O
O
R
O
O
(IV)
-H2O
H2N
O
O
H
N
O
H
Scheme 2. Proposed mechanism for the formation of coumarin fused indenodihydropyridyl and dihydropyridyl derivatives.

S. Paul, A. R. Das / Tetrahedron Letters 53 (2012) 2206–2210
2209
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scale preparation. After completion of the reaction the solvent cat-
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used for four times with almost the same catalytic activity. After
the removal of the solvent–catalyst mixture, water was added to
the residual mass and the generated solid was filtered to obtain
the crude product.
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20. General procedure for the synthesis of indenodihydropyridine and dihydropyridine:
A mixture of an aromatic aldehyde (1.0 mmol), 4-aminocoumarin (1.0 mmol),
1,3-indanedione (1.0 mmol) or dimedone (1.0 mmol), and ( )lactic acid
In summary, we have successfully developed a simple, conve-
nient, environmentally benign, mild, and safe synthetic method
to afford coumarin fused highly decorated indenodihydropyridine
and dihydropyridine derivatives using a green solvent ethyl-L-lac-
tate and an organo-catalyst lactic acid in nearly quantitative yields.
To the best of our knowledge, it is probably the first example of
synthesizing coumarin fused indenodihydropyridine and dihydro-
pyridine scaffolds using ( )lactic acid as the catalyst in ethyl-L-lac-
tate media. This process provides an opportunity to use
environmentally secure green organic solvent. The simplicity of
the method, the ease of product isolation, and mild reaction condi-
tions will make this synthetic method attractive and useful on an
industrial scale. Most important of all, the purification procedure
is just followed by filtration, washing, and drying.
(2 mmol) was taken in 4 ml of ethyl-L-lactate. The mixture was stirred at
100 °C for a required period of time (TLC). After completion of the reaction, the
solid product was obtained by cooling the reaction mixture to room
temperature (indenodihydropyridine) or by pouring the cold reaction
mixture into water (dihydropyridine). The solid was collected by filtration,
washed with ethanol, and finally recrystallized from DMF–water to get pure
product.
Acknowledgements
7-Phenyl-7,13-dihydro-5-oxa-13-aza-indeno[2,1-b]phenanthrene-6,8-
dione (3a): Yield: 77%; Characteristic: Red powder; Mp: 285 °C (dec); IR (KBr):
We gratefully acknowledge the financial support from U.G.C.
and Calcutta University. S.P. thanks U.G.C., New Delhi, India for
the grant of Junior Research fellowship.
3272, 1683, 1612, 1506, 1454, 1351, 1179 cmÀ1 1H NMR (DMSO-d6):
; d
4.81(1H, s), 7.07–7.49 (10H, m), 7.65 (1H, t, J = 7.6 Hz), 7.96 (1H, d, J = 7.2 Hz),
8.49 (1H, d, J = 7.2 Hz), 10.36 (1H, s); 13C NMR (75 MHz, DMSO-d6):
d
35.3,103.9, 110.0, 113.5, 116.9, 120.7, 120.9, 123.6, 124.1, 126.6, 127.9,
128.3, 130.3, 132.3, 132.4, 132.5, 136.5, 143.2, 144.9, 152.0, 160.3, 161.9,
191.3; Anal. Calcd for C25H15NO3: C 79.56, H 4.01, N 3.71. Found: C 79.61, H
3.99, N 3.78.
10,10-Dimethyl-7-phenyl-7,10,11,12-tetrahydro-9H-chromeno[4,3-
b]quinoline-6,8-dione (4a):
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.02.077.
Yield: 87%, Characteristic: White powder; Mp: 272 °C; IR (KBr): 3338, 2951,
1672, 1641, 1506, 1466, 1364 cmÀ1 1H NMR (DMSO-d6): d 0.89 (3H, s), 1.03
;
References and notes
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8. Heintzelman, G. R.; Averill, K. M.; Dodd, J. H.; Demarest, K. T.; Tang, Y.; Jackson,
P. F. Pat. Appl. Publ. US 2004082578 A1 20040429, 2004.
9. Cooper, K.; Fray, M. J.; Cross, P. E.; Richardson, K. Eur. Pat. Appl. EP 299727 A1
19890118, 1989.
4 ml of ethyl-
When two-component coupling reaction between the Knoevenagel
condensation product of 1,3-indanedione or dimedone (B or C) and 4-
aminocoumarin was performed in 4 ml of ethyl- -lactate and ( )lactic acid
(2 mmol) at 100 °C temperature, 80% of 3a or 90% of 4a was isolated after 2 h.
L-lactate for 30 min at 100 °C.
a
L

2210
S. Paul, A. R. Das / Tetrahedron Letters 53 (2012) 2206–2210
NH2
O
O
O
O
O
( )
lactic acid
O
+
Ethyl-L-lactate, 1000 C
O
N
H
B
3a
O
O
NH2
O
O
O
( )
lactic acid
+
Ethyl-L-lactate, 1000 C
N
H
O
4a
O
C
25. To the solution of dihydro compound (3g) (1.0 mmol) in hot DMF (10 ml) was
added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.2 mmol). Then the
reaction mixture was heated at reflux for 30 min, and 1 ml of water was
added to the mixture. Heating was continued for additional 2 minutes and then
the mixture was cooled to room temperature. The yellow precipitate formed
J = 7.2 Hz), 8.56 (1H, d, J = 7.8 Hz) 13C NMR (DMSO-d6): d 116.8, 120.7, 123.8,
124.2, 127.3, 128.2, 129.5, 130.5, 131.7, 132.4, 132.7, 136.3, 142.2, 145.7, 152.2,
154.9, 159.9, 161.9, 164.9, 188.8; Anal. Calcd for C25H12FNO3: C 76.33; H 3.07;
N 3.56 Found: C 76.61, H 3.09, N 3.68.
26. Crystallographic data for the structure 4a has been deposited with Cambridge
Crystallographic Data Center as supplementary publication No. CCDC 842689.
Copies of the data can be obtained, free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: +44 01223 336033 or e-mail:
deposit@ccdc.cam.ac.uk).
was filtered on
a glass filter and washed successively with ethanol and
ethylacetate to get pure 7-(4-fluoro-phenyl)-5-oxa-13-aza-indeno[2,1-
b]phenanthrene-6,8-dione. Yield: 95%; Characteristic: yellow powder; Mp:
295 °C (dec); IR (KBr): 1735, 1558, 1493, 1365 cmÀ1 1H NMR (DMSO-d6): 6.88
;
(2H, t, J = 7.6 Hz), 7.23–7.47 (7H, m), 7.62 (1H, t, J = 7.8 Hz), 8.171 (1H, d,