Pseudo Multicomponent Reaction: Synthesis of Fused Pyrano Biscoumarin Analogs from 1,2-diols

Article abstract of DOI:10.1002/jhet.2742

A simple and efficient method has been developed for the synthesis of fused pyrano biscoumarins using lead tetraacetate as an oxidizing agent by the condensation of one equivalent of 1,2-diols and four equivalent of 4-hydroxy coumarin in acetonitrile as solvent at 80°C with good to excellent yields.

Full text of DOI:10.1002/jhet.2742

Month 2016 Pseudo Multicomponent Reaction: Synthesis of Fused Pyrano Biscoumarin
Analogs from 1,2-diols
*
Narasashetty Jagadishbabu and Kalegowda Shivashankar
P. G. Department of Chemistry, Central College Campus, Bangalore University, Bangalore 560 001, Karnataka, India
*
E-mail: shivashankark@gmail.com
Received May 20, 2016
DOI 10.1002/jhet.2742
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
A simple and efficient method has been developed for the synthesis of fused pyrano biscoumarins using
lead tetraacetate as an oxidizing agent by the condensation of one equivalent of 1,2-diols and four equivalent
of 4-hydroxy coumarin in acetonitrile as solvent at 80°C with good to excellent yields.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
However, they are, in general, toxic, or unstable, especially
because of aerial oxidation than their corresponding alco-
hols and prone to polymerization or hydrolysis. Thus, in
many cases, aldehydes must be purified just before their
use because the presence of other products affects not only
the concentration of the active aldehyde but also the impu-
rities often interfere with chemical reactions involving the
aldehyde [18]. Therefore, exploring new convenient ways
for efficient synthesis of fused pyrano biscoumarin scaf-
folds are still necessary.
In continuation of our work on the development of use-
ful synthetic methodologies [19,20], in this study, we re-
port the use of lead tetraacetate as an oxidizing agent for
the synthesis of fused pyrano biscoumarin analogs under
mild conditions. Lead tetraacetate functions as an oxidizing
agent offering several advantages such as high yields and
purity, broad functional group tolerance, and easy work
up when compared with traditional reagents. Although,
lead tetraacetate has been identified as an oxidizing agent,
the wider scope and synthetic utility of this reagent for
the synthesis of fused pyrano biscoumarin analogs in one
pot has not been explored. Herein, we report a novel direct
approach for synthesis of fused pyrano biscoumarin ana-
logs starting from various 1,2-diols and 4-hydroxy couma-
rin without the need for an additional catalyst. The tandem
process involves oxidation, condensation, cyclisation, and
dehydration under mild condition at 80°C.
Multicomponent reactions (MCRs) have been utilized
for the construction of complex and diverse molecules
through the sequential combination of three or more simple
substrates in single synthetic operations. When two of the
three or more components are identical, the reaction is bet-
ter designated as pseudo-MCRs [1–4]. The synthesis of
fused pyrano biscoumarin analogs, which contain pyran
parent nucleus, is an interesting heterocyclic scaffolds, be-
coming particularly useful for the construction of diverse
array of drug-like molecules in medicinal chemistry [5,6].
A large number of compounds bearing pyran nucleus have
entered preclinical and clinical trials over the last few
years. Many commercially available drugs (Fig. 1) includ-
ing erysenegalensein C (used in the treatment of stomach
pain, female infertility and gonorrhea), uvafzlelin (antimi-
crobial), cromakalim (antihypertensive), vitamin E (antiox-
idant), kojic acid (antibiotic), and tephrosin (anticancer) are
derived from pyran core entities [7].
Pyran moieties are also important as antimicrobial, anti-
oxidant [8], antitumor [9], antagonism of L-type Ca2+
channels [10], anticancer [11], antimycobacterial [12],
and antileishmanial agents [13]. Some of the protocols
have been developed for the synthesis of fused pyrano
biscoumarin analogs via the condensation of aldehydes
and 4-hydroxy coumarins with the use of various catalysts
such as P2O5/SiO2 [14], sulfonic acid functionalized ionic
liquid [15], ZnFe2O4 [16], TEBAC-H2O, KF-Al2O3-EtOH,
and ionic liquid [17]. However, these operations are com-
plicated in terms of the use of excess amounts of expensive
catalyst, product diversity, and low yields of target. Alde-
hydes are ubiquitous substrates in many powerful MCRs.
RESULTS AND DISCUSSION
Our study commenced by optimizing the reaction
conditions in order to achieve the skeleton 3 using
© 2016 Wiley Periodicals, Inc.

N. Jagadishbabu and K. Shivashankar
Vol 000
Figure 1. Commercial drugs with pyran nucleus.
Scheme 1. Synthesis of fused pyrano biscoumarin analogs. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
1,2-diphenyl-1,2-ethanediol and 4-hydroxy coumarin
in the presence of lead tetraacetate as model substrates
(Scheme 1). To our delight, product 3a was provided
in 42% yield in refluxing dichloromethane. As control
experiment, when the reaction was performed in the
absence of lead tetraacetate, it gave no yield. Solvent
screening for a model reaction (Table 1) revealed
acetonitrile as the solvent of choice and yielded the
product in 96%. It is noteworthy that rise in the
temperature from 50 to 80°C temperature resulted in
increased yield. Therefore, the optimal reaction
conditions are heating the mixture of 1,2-diphenyl-
1,2-ethanediol (1 equiv), 4-hydroxy coumarin
(4 equiv), and lead tetraacetate (1 equiv) in acetoni-
trile for 3 h.
benzylidene-chroman-2,4-dione. The benzylidene-chro-
man-2,4-dione undergoes micheal addition with 4-hydroxy
coumarin that yields the corresponding fused pyrano
biscoumarin via the cyclisation followed by the
dehydration.
CONCLUSION
In summary, we have developed a facile and efficient
procedure for the one pot synthesis of fused pyrano
biscoumarins from a pseudo MCR of 1,2-diols and
4-hydroxy coumarin using lead tetraacetate. The notable
Table 1
The strategy was further employed to create a diverse
series of fused pyrano biscoumarins (Table 2) synthe-
sized via 4-hydroxy coumarin and different 1,2-diols.
The reaction smoothly furnished 3a-o in 82–96% yield
by combining this reagent in three component fashion.
A probable mechanistic pathway (Fig. 2) for the forma-
tion of fused pyrano biscoumarin analogs is similar to
established mechanism [21]. The lead tetraacetate oxidizes
1,2-diol into benzaldehyde giving acetic acid which in turn
would able to acid catalyze condensation between
benzaldehyde and 4-hydroxy coumarin gives the
Optimization of solvents for the synthesis (3a).
Entry
Solvents (dry)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
Dioxane
Acetonitrile
Ethanol
Acetone
THF
Methanol
DMF
DMSO
6.5
5
3
4.5
6
5.5
5.5
6.5
7
42
70
96
90
72
76
80
45
52
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Synthesis of Fused Pyrano Biscoumarin Analogs from 1,2-diols
Table 2
Synthesis of fused pyrano biscoumarin analogs (3a–o).
Entry
1
1,2-diols
Products
Time (h)
3
Yield (%)
96
2
3.5
91
3
3.5
90
4
3
92
5
3.5
93
6
3
92
(Continued)
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N. Jagadishbabu and K. Shivashankar
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Table 2
(Continued)
Entry
7
1,2-diols
Products
Time (h)
4
Yield (%)
89
8
3.5
86
9
3
91
10
3
90
11
4
88
12
3
94
(Continued)
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Month 2016
Synthesis of Fused Pyrano Biscoumarin Analogs from 1,2-diols
Table 2
(Continued)
Entry
13
1,2-diols
Products
Time (h)
3.5
Yield (%)
89
14
3
96
15
4
82
Figure 2. Plausible mechanism for the formation of fused pyrano biscoumarin.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. Jagadishbabu and K. Shivashankar
Vol 000
advantages of this method are short reaction time,
excellent yields, simple workup, and mild reaction
conditions.
7-(3-Ethoxy-phenyl)-7H-pyrano[3,2-c;5,6-c’]dichromene-6,
8-dione (3d).
A white solid, 402mg (92% yield). IR
(ATR, cmÀ1): 1740 (C=O), 1734 (C=O); mp>310°C.
1H-NMR (DMSO-d6, 400MHz): δ 8.07–7.21 (m, 12H,
Ar-H), 6.10 (s, 1H, CH), 3.50–3.48 (m, 2H, CH2), 1.27–
1.20 (m, 3H, CH3) ppm. 13C-NMR (DMSO-d6, 100MHz):
δ 165.1, 164.7, 156.5, 152.1, 131.7, 131.3, 127.7, 123.8,
123.6(2C), 117.9, 115.8, 113.9, 62.8, 35.2, 14.6ppm. ESI-
MS: [M+H]+ 439.05. Anal. Calcd for C27H18O6: C,
73.97; H, 4.14; found: C, 73.94; H, 4.12%.
EXPERIMENTAL
General information.
The melting points were
determined by the open capillary method using an
electric melting point apparatus without correction. The
IR spectra were recorded on an Agilent Cary 630 FT-IR
Spectrophotometer. 1H-NMR (400 MHz) and 13C-NMR
7-(3-Bromo-4-methoxy-phenyl)-7H-pyrano[3,2-c;5,6-c’]
dichromene-6,8-dione (3e).
A brown solid, 466 mg
(100 MHz) spectra were recorded on
a
Bruker
(93% yield). IR (ATR, cmÀ1): 1742 (C = O), 1738
1
spectrometer using CDCl3 and DMSO-d6 as a solvents
and TMS as an internal standard. The chemical shifts are
reported in parts per million (δ ppm). The mass spectrum
was recorded on Thermo LCQ Fleet. The elemental
analyses were carried out using an Elemental Vario
Micro Cube Rapid Analyzer.
(C = O); mp >310°C. H-NMR (CDCl3, 400 MHz): δ
8.04–6.70 (m, 11H, Ar-H), 6.02 (s, 1H, CH), 3.87 (s,
3H, OCH3) ppm. Anal. Calcd for C26H15BrO6: C,
62.05; H, 3.00; found: C, 62.02; H, 2.97%.
7-(2-Chlorophenyl)-7H-pyrano[3,2-c;5,6-c’]dichromene-6,8-
dione (3f). A pale brown solid, 393mg (92% yield). IR
(ATR, cmÀ1): 1746 (C = O), 1735 (C =O); mp >310°C.
1H-NMR (CDCl3, 400 MHz): δ 8.20–7.26 (m, 12H, Ar-
H), 6.12 (s, 1H, CH) ppm. Anal. Calcd for C25H13ClO5:
C, 70.02; H, 3.06; found: C, 70.00; H, 3.03%.
7-(3-Bromo-4-fluoro-phenyl)-7H-pyrano[3,2-c;5,6-c’]
dichromene-6,8-dione (3g). A white solid, 435mg (89%
yield). IR (ATR, cmÀ1): 1745 (C =O), 1740 (C = O);
mp > 310°C. 1H-NMR (DMSO-d6, 400MHz): δ 7.84–
6.95 (m, 11H, Ar-H), 6.26 (s, 1H, CH) ppm. 13C-NMR
(DMSO-d6, 100MHz): δ 171.9, 170.2, 167.4, 165.5,
164.4, 161.8, 157.3, 154.9, 153.4, 152.4, 140.2 (2C),
132.6, 131.2, 131.0, 128.0, 127.9, 124.0, 123.8, 123.1,
123.0, 119.4, 116.2, 116.0, 59.6 ppm. Anal. Calcd for
C25H12BrFO5: C, 61.12; H, 2.46; found: C, 61.10; H,
2.44%.
7-p-Tolyl-7H-pyrano[3,2-c;5,6-c’]dichromene-6,8-dione (3h).
A pale brown solid, 350 mg (86% yield). IR (ATR, cmÀ1):
1748 (C = O), 1734 (C =O); mp 170°C. 1H-NMR (CDCl3,
400 MHz): δ 8.06–7.11 (m, 12H, Ar-H), 6.06 (s, 1H, CH),
2.33 (s, 3H, CH3) ppm. Anal. Calcd for C26H16O5: C,
76.46; H, 3.95; found: C, 76.43; H, 3.93%.
7-(4-Bromo-phenyl)-7H-pyrano[3,2-c;5,6-c’]dichromene-6,
8-dione (3i). A white solid, 430mg (91% yield). IR (ATR,
cmÀ1): 1742 (C=O), 1738 (C=O); mp>300°C. 1H-NMR
(DMSO-d6, 400MHz): δ 7.81–7.02 (m, 12H, Ar-H), 6.02
(s, 1H, CH) ppm. Anal. Calcd for C25H13BrO5: C, 63.45;
H, 2.77; found: C, 63.42; H, 2.76%.
7-(4-Fluoro-phenyl)-7H-pyrano[3,2-c;5,6-c’]dichromene-6,
8-dione (3j). A pale brown solid, 370mg (90% yield). IR
(ATR, cmÀ1): 1744 (C=O), 1736 (C=O); mp>310°C.
1H-NMR (DMSO-d6, 400MHz): δ 7.88–6.95 (m, 12H,
Ar-H), 6.30 (s, 1H, CH) ppm. Anal. Calcd for C25H13FO5:
C, 72.82; H, 3.18; found: C, 72.80; H, 3.15%.
Typical procedure for the synthesis of 7-phenyl-7H-pyrano
[3,2-c;5,6-c’]dichromene-6,8-dione (3a). Lead tetraacetate
(0.44 g, 1 mmol) was added to a solution of 1,2-
diphenylethane-1,2-diol (0.21 g, 1 mmol) and 4-hydroxy
coumarin (0.64 g, 4 mmol) in acetonitrile (10 mL) in a
round-bottomed flask fitted with a reflux condenser and a
guard tube. The resulting reaction mixture was stirred at
room temperature for 5 min and heated at 80°C in an oil
bath for 3 h. TLC was performed to observe the complete
consumption of starting material in the reaction mixture.
After completion of the reaction, the reaction mixture
was allowed to cool to room temperature, and 10mL of
water was added. A crude product was obtained upon
filtering the reaction mixture and subsequent evaporation
under reduced pressure. Further, this crude product was
recrystallised by ethanol to obtain pure product.
Spectral data of compounds
7-Phenyl-7H-pyrano[3,2-c;5,6-c’]dichromene-6,8-dione (3a).
A pale brown solid, 378mg (96% yield). IR (ATR, cmÀ1):
1742 (C = O), 1735 (C = O); mp >310°C. 1H-NMR
(CDCl3, 400MHz): δ 8.05–6.83 (m, 13H, Ar-H), 6.04 (s,
1H, CH) ppm. Anal. Calcd for C25H14O5: C, 76.14; H,
3.58; found: C, 76.12; H, 3.55%.
7-(4-Chloro-phenyl)-7H-pyrano[3,2-c;5,6-c’]dichromene-6,
8-dione (3b). A white solid, 389mg (91% yield). IR (ATR,
cmÀ1): 1745 (C=O), 1732 (C=O); mp> 310°C. 1H-NMR
(DMSO-d6, 400MHz): δ 7.82–7.09 (m, 12H, Ar-H), 6.24
(s, 1H, CH) ppm. Anal. Calcd for C25H13ClO5: C, 70.02;
H, 3.06; found: C, 70.00; H, 3.03%.
7-(3-Chloro-phenyl)-7H-pyrano[3,2-c;5,6-c’]dichromene-6,
8-dione (3c). A pale brown solid, 385mg (90% yield). IR
(ATR, cmÀ1): 1748 (C=O), 1736 (C=O); mp>310°C.
1H-NMR (DMSO-d6, 400MHz): δ 7.83–7.05 (m, 12H,
Ar-H), 6.27 (s, 1H, CH) ppm. Anal. Calcd for C25H13ClO5:
C, 70.02; H, 3.06; found: C, 69.99; H, 3.04%.
7-(3-Chloro-4-fluoro-phenyl)-7H-pyrano[3,2-c;5,6-c’]
dichromene-6,8-dione (3k).
A white solid, 392mg
Journal of Heterocyclic Chemistry
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Month 2016
Synthesis of Fused Pyrano Biscoumarin Analogs from 1,2-diols
(88% yield). IR (ATR, cmÀ1): 1735 (C =O), 1722 (C = O);
mp >300°C. 1H-NMR (DMSO-d6, 400MHz): δ 8.08–6.95
(m, 11H, Ar-H), 6.25 (s, 1H, CH) ppm. 13C-NMR (DMSO-
d6, 100MHz): δ 172.4, 167.7, 165.8, 164.9, 156.8, 154.4,
152.9, 140.3, 140.2, 132.1, 131.8, 131.0, 130.9, 129.1,
128.8, 127.8 (2C), 124.5, 123.6, 119.7, 119.1, 119.0,
117.8, 117.6, 62.8ppm. Anal. Calcd for C25H12ClFO5: C,
67.20; H, 2.71; found: C, 67.18; H, 2.70%.
134.6, 132.5, 130.7, 130.4, 129.5, 129.4, 127.2, 127.1,
125.1 (2C), 123.9, 123.7, 123.2, 122.8, 122.6, 119.9,
116.2, 115.4, 59.7 ppm. Anal. Calcd for C25H12ClFO5: C,
67.20; H, 2.71; found: C, 67.18; H, 2.68%.
Acknowledgments. This work was supported from the Council
of Scientific and Industrial Research (CSIR), New Delhi, India
(Grant No. 02(0172)/13/EMR-II dated: 21/10/2013).
7-(4-Hydroxy-phenyl)-7H-pyrano[3,2-c;5,6-c’]dichromene-
6,8-dione (3l).
A white solid, 385mg (94% yield). IR
(ATR, cmÀ1): 1742 (C = O), 1732 (C =O); mp >310°C.
1H-NMR (DMSO-d6, 400MHz): δ 10.02 (s, 1H, OH),
7.84–6.94 (m, 12H, Ar-H), 6.29 (s, 1H, CH) ppm. 13C-
NMR (DMSO-d6, 100MHz): δ 167.0, 164.6, 152.4,
141.6, 131.0, 129.4, 129.2, 129.0, 128.4(2C), 127.7,
126.6, 124.9, 59.6 ppm. Anal. Calcd for C25H14O6: C,
73.17; H, 3.44; found: C, 73.14; H, 3.41%.
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7-(3-Bromo-phenyl)-7H-pyrano[3,2-c;5,6-c’]dichromene-
6,8-dione (3m). A white solid, 419 mg (89% yield). IR
(ATR, cmÀ1): 1746 (C = O), 1738 (C = O); mp > 310°C.
1H-NMR (DMSO-d6, 400 MHz): δ 7.83–6.95 (m, 12H,
Ar-H), 6.03 (s, 1H, CH) ppm. 13C-NMR (DMSO-d6,
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7-(3,4-Dimethoxy-phenyl)-7H-pyrano[3,2-c;5,6-c’]dichrome
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7-(2-Chloro-6-fluoro-phenyl)-7H-pyrano[3,2-c;5,6-c’]dichro
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IR (ATR, cmÀ1): 1745 (C = O), 1738 (C =O); mp >310°C.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet