Microwave-promoted efficient synthesis of pyrano[3,2-c]chromen-5(4H)-ones under catalyst and solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2015.12.061

An efficient and rapid synthesis of a new class of diversely functionalized pyrano[3,2-c]chromen-5(4H)-ones has been achieved via one-pot three-component reaction of 4-hydroxy-2H-chromen-2-one, aldehydes, and acetophenones under microwave irradiation in c

Full text of DOI:10.1016/j.tetlet.2015.12.061

Accepted Manuscript
Microwave- promoted efficient synthesis of pyrano[3,2-c]chromen-5(4H)-ones
under catalyst and solvent-free conditions
Mudumala Veeranarayana Reddy, Badur Siva Kumar, Kwon Taek Lim, Byung
Gwon Cho, Yeon Tae Jeong
PII:
S0040-4039(15)30476-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.061
TETL 47108
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 November 2015
10 December 2015
15 December 2015
Please cite this article as: Reddy, M.V., Kumar, B.S., Lim, K.T., Cho, B.G., Jeong, Y.T., Microwave- promoted
efficient synthesis of pyrano[3,2-c]chromen-5(4H)-ones under catalyst and solvent-free conditions, Tetrahedron
Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.12.061
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Microwave- promoted efficient synthesis of
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pyrano[3,2-c]chromen-5(4H)-ones under catalyst and
solvent-free conditions.
MudumalaVeeranarayanaReddy,a Badur Siva Kumar,b Kwon Taek Lim,a Byung Gwon Cho,a Yeon Tae Jeonga*

2
Tetrahedron Letters
Microwave- promoted efficient synthesis of pyrano[3,2-c]chromen-5(4H)-ones under
catalyst and solvent-free conditions.
MudumalaVeeranarayanaReddy,a Badur Siva Kumar,b Kwon Taek Lim,a Byung Gwon Cho,a Yeon Tae
Jeonga*
a Department of Image Science and Engineering, Pukyong National University, Busan, Korea, 608-737
bDepartment of Chemistry, SRM University, Kattankulathur, Kanchipuram (Dt), TamilNadu, India-603203
ARTICLE INFO
ABSTRACT
An efficient and rapid synthesis of a new class of diversely functionalized pyrano[3,2-
c]chromen-5(4H)-ones has been achieved via one-pot three-component reaction of 4-hydroxy-
2H-chromen-2-one, aldehydes, and acetophenones under microwave irradiation in catalyst and
solvent-free conditions. The present methodology offers several advantages such as short
reaction time, simple operational procedure, avoid toxic solvent and catalyst, high yield of
product and endures the substrate diversity.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Pyrano[3,2-c]chromen-5(4H)-ones; Microwave
irradiation; Catalyst and solvent-free conditions; 4-
hydroxy-2H-chromen-2-one.
Multi-component reactions (MCRs) have been
recognized as an important device for the expedient creation of
various chemical libraries of ‘drug like’ heterocyclic compounds
with high levels of molecular diversity and complexity.1
Microwave irradiation (MWI), which has proved to be clean,
increased selectivity, easier experimental procedures, fast and
convenient energy source, improved yields and high purity of
compounds, has taken an undeniable role in chemical laboratory
practice.2 Moreover microwave promoted solvent-free reactions
are particularly welcome due to their essential advantages such as
minimize reaction time, energy consumption, manipulative
simplicity, and to maximize synthetic efficiency and
environmental benefits. Currently, multi-component procedures
employing MWI under solvent-free conditions are particularly
welcome due to their vital advantages, mainly under the present
paradigm shift to green methodologies.3
However, these methods suffered with one or more drawbacks
such as relatively long reaction time, harsh reaction conditions,
high reaction temperature, require stoichiometric amounts of
toxic catalysts and the use of an organic solvent. Consequently,
there is a need to develop a new and efficient, environmentally
benign practical procedure and operational simplicity method for
the synthesis of heterocycles containing pyrano[3,2-c]chromen-
5(4H)-ones.
As part of our continuing research to be develop a green
reaction methodology by MWI under solvent-free conditions.7
Herein, we report a facile catalyst and solvent-free one-pot
synthesis of pyrano[3,2-c]chromen-5(4H)-ones via three-
component reaction of 4-hydroxy-2H-chromen-2-one, aldehydes,
and acetophenones under microwave irradiation at 60 ºC
(Scheme 1).8
Chemistry of heterocyclic compounds has been
ubiquitous in natural products, biologically active agrochemicals,
pharmaceutical agents, organic materials, and several well-
designed molecules.4 Hence, the attention for developing new,
versatile, and efficient synthesis of heterocyclic compounds has
always been a thread in the synthetic organic and bio-organic
chemistry. Pyrano[3,2-c]chromen-5(4H)-ones are the promising
class of oxygen containing heterocyclic compounds which are
ubiquitous to a diversity of biologically active products and have
been shown to a broad series of biological activities.5 Therefore,
the synthesis of the pyrano[3,2-c]chromen-5(4H)-ones has
fascinated much noticed in organic synthesis. So far, only few
methods have been reported for the synthesis of pyrano[3,2-
c]chromen-5(4H)-ones.6
Scheme 1: Synthesis of pyrano[3,2-c]chromen-5(4H)-ones under
MWI.
To develop optimal reaction conditions, we carried out
the reaction between 4-hydroxy-2H-chromen-2-one (1, 1.0
mmol), 4-ethoxybenzaldehyde (2a, 1.0 mmol) and 4-
bromoacetophenone (3a, 1.0 mmol) as a model. It was
investigated under conventional and microwave conditions under
without catalyst in ethanol solvent at room temperature. Desired
product, 4a, could not obtain even after 18 h stirring under
conventional method (Table 1, entry 1). Only a trace amount of



this product was formed even after 5 h under MWI (Table 1,
entry 2). We next examined the model reaction using different
temperature ranging from 50 to 80 ºC under both conditions. It
was found that at 50 ºC and 120 min of time, the yield of the
product was low (Table 1, entry 3). Only at 60 ºC and with 60
min of reaction time, the highest product yield of 75% was
observed (Table 1, entry 4). Further increase in the temperature
did not affect the product yield. Thus it was proved that 60 ºC is
the optimized temperature required for effecting this reaction by
MWI (Table 1, entry 5). Obtained the desired product, 4a, in
low yield at long reaction time and the majority of un-reacted
starting materials were recovered under conventional method at
50 to 80 ºC (Table 1, entries 6-8).
3
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Methanol
Acetonitrile
Methanol
Toluene
DMF
MWI
MWI
MWI
CTH
CTH
CTH
MWI
MWI
MWI
MWI
MWI
MWI
MWI
MWI
MWI
CTH
CTH
CTH
CTH
CTH
CTH
50
60
2
40
75
75
0
4
1
5
80
1
15
6
50
7
60
15
10
15
15
52
60
45
70
46
95
95
96
25
15
10
35
18
8
80
15
9
RT
60
6
With this observation, we have subsequently studied the
effect of various solvents and temperatures under MWI.
Methanol was used as a solvent for this reaction at room
temperature and desired product obtained low yield (Table 1,
entry 9). The yield of product 4a could be improved to 52%
when the reaction was performed in acetonitrile at 60 ºC
temperature (Table 1, entry 10). The yield of the products was
improved to 60% (Table 1, entry 11), when the temperature of
the reaction was increased to 60 ºC in methanol. We became
interested to study the progress of the reaction under the
influence of different organic solvents. In our observation at most
of the solvent conditions the reaction did not proceed effectively
and even though ethanol and DMF more polar solvent medium
shown moderate product yields even at higher temperature and
reaction times (Table1 entries 4 & 13). When the reaction was
carried out under solvent-free conditions at 60 ºC, the expected
product was obtained in high yield and short reaction time (Table
1, entry 15). After finding the solvent-free condition as best one
at 60 °C, we are also performed the reaction at various
temperatures between 60-80 ºC and find that no more
enhancement in the product yields appreciably (Table 1, entries
15- 17).The better yield in solvent-free conditions could be
explained by a uniform distribution of the eutectic mixture of
reactants, being in closer proximity to react than in conditions
using ethanol as the solvent.
10
11
12
13
14
15
16
17
18
19
20
21
22
3
60
3
100
120
60
6
4
Acetone
Neat
4
60
15 min
15 min
15min
20
Neat
70
Neat
80
Acetonitrile
Methanol
Toluene
DMF
80
60
22
100
120
55
25
15
Acetone
Neat
20
23
80
10
40
We also investigated effect of solvents under CTH at different
temperature. But, to our surprise, we observed that the reaction
did not proceed efficiently (Table 1, entries 18-22) in any
solvent. In absence of the solvent, the model reaction could be
carried out but the product was obtained in very low yield after
prolonged reaction time (Table1, entry 23).
aReaction
of
4-hydroxy-2H-chromen-2-one
(1,
1
mmol),
4-
bromoacetophenone (2a, 1 mmol), 1-(4-bromophenyl)ethanone (3a, 1 mmol);
bIsolated yield; cConventional thermal heating (CTH); dMicrowave irradiation
(MWI).
Encouraged by this initial success, we next designed to
perform the generalized the applicability of this method for the
synthesis of pyrano[3,2-c]chromen-5(4H)-ones from various
aromatic aldehydes and acetophenones (Table 2). In all the cases
the reaction worked efficiently and we found that phenyl groups
bearing electron-withdrawing, as well as electron-donating, groups
gave the corresponding products were obtained in excellent yield as
well as in high purity. It is noteworthy that the reaction worked also
with heterocyclic acetophenone provided good yield.
Table 1. Optimization of reaction conditions for the synthesis
of 4aa
Br
Upon these the results a reasonable reaction mechanism
has been proposed in Scheme 2. Initially aldehyde (2a-t) reacts
with the enolic form of the ketone (3a-t) to give achalcone (4) by
removal of H2O. Michael addition of 4-hydroxycoumarin (1) to
the chalcone gave the intermediate 5 which on intramolecular
cyclisation gave the desired pyrano[3,2-c]chromen-5(4H)-ones
(4a-t) by removal of H2O.
O
CHO
OEt
OH
O
O
O
+
+
O
O
OEt
Br
(3)
(1)
(4a)
(2a)
Entry
Solvent
(3mL)
Methods Tem(°C)
Time
Yieldb
(h)
18
5
1
2
Ethanol
Ethanol
cCTH
dMWI
RT
RT
0
20

4
Tetrahedron Letters
Scheme 2. The possible pathway of mechanism of formation of
titled compounds (4a-t)
In summary, A highly sustainable and efficient multi-
component reaction of readily available 4-hydroxy-2H-chromen-
2-one, aldehydes, and acetophenones was developed for the
synthesis of pyrano[3,2-c]chromen-5(4H)-ones under solvent-
catalyst free condition in microwave irradiation. The notable
features of this methodology are eco-friendly reaction conditions,
no side product, avoidance of toxic catalysts and solvents,
column chromatography purification is not required to obtain the
pure products and products are obtained in excellent yields.
Table 2. Synthesis of pyrano[3,2-c]chromen-5(4H)-ones (4a-t)a
Yieldb (%)
Entry
R
R1
Product
4a
Time (min)
95
90
91
90
89
91
92
91
93
92
93
1
2
4-OEt
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
C6H5
15
16
22
18
14
19
20
21
20
21
24
3-4-5-OMe
3-NO2
4b
3
4c
4
3-OMe
2-Cl-6-F
2-NO2
4d
5
4e
6
4f
7
3-OMe
3-NO2
4g
8
4h
9
4-OEt
4i
10
11
3-4-5-OMe
4-OMe
4j
4k
89
90
90
91
90
90
91
92
91
12
13
14
15
16
17
18
19
20
4-Br
H
4-Cl-C6H4
2-OMe-C6H4
C5H4OS
4l
4m
4n
4o
4p
4q
4r
18
23
19
17
15
19
21
15
17
H
4-NO2
4-Cl
H
4-Me-C6H4
4-OMe-C6H4
2-Br-C6H4
4-Me-C6H4
C6H5
4-Cl
H
4s
4-OMe
4-Br-C6H4
4t
aReaction of 4-hydroxy-2H-chromen-2-one (1, 1 mmol), aldehydes (2a-t, 1 mmol), acetophenones (3a-t, 1 mmol) under catalyst and solvent-free conditions in
MWI at 60 ºC; bIsolated yield.
Supporting Information
All new compounds data and NMR spectra were provided as Supplementary data.

References and notes
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7.
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8.
2-(4-bromophenyl)-4-(4-ethoxyphenyl)pyrano[3,2-c]chromen-
5(4H)-one (4a).
A mixture of 4-hydroxy-2H-chromen-2-one (1, 1 mmol), ), 4-
bromoacetophenone (2a, 1 mmol), 1-(4-bromophenyl)ethanone
(3a, 1 mmol) was taken in an open vessel in CATA-4R Scientific
Microwave oven and irradiated at 60 °C in catalyst and solvent-
free condition for 15 min. The progress of the reaction was
monitored by TLC. After completion of the reaction (TLC), the
resulting solid obtained was recrystallized from ethanol to obtain a
1
pure white product. Yield 95%; white solid; mp 153-155 °C. H-
NMR (400 MHz, CDCl3): δ 7.96 (dd, J = 1.4, 8.0 Hz, 1H), 7.59-
7.54 (m, 5H), 7.38-7.28 (m, 4H), 6.83 (d, J = 8.4 Hz, 2H), 5.82
(d, J = 4.7 Hz, 1H), 4.62 (d, J = 4.7 Hz, 1H), 3.98-3.95 (q, 2H),
1.37 (t, J = 6.9 Hz, 3H) ppm. 13C-NMR (100 MHz, CDCl3):
161.5, 158.3, 155.4, 152.8, 145.9, 135.4, 132.1, 131.9, 131.7,
129.6, 126.2, 124.3, 123.4, 122.6, 116.9, 114.7, 144.5, 104.5,
104.0, 63.5, 35.8, 14.9 ppm. HRMS (ESI, m/z): calcd for
C26H19BrO4 (M+H+) 475.331; found: 475.325.