Montmorillonite-KSF mediated one step synthesis of pyranochromene derivatives

Article abstract of DOI:10.1016/j.molstruc.2018.06.052

One-pot three-component reaction of substituted aromatic aldehydes, 2-cyanoacetamide and 4-hydroxycoumarin in the presence of Montmorillonite-KSF (MKSF) in ethanol results in the formation of pyrano[3,2-c]chromene-3-carboxylates (5a-m) has been described. The reaction was tested in different alcohols, afforded pyrano [3,2-c] chromene-3-carboxylates (5a-m) of the corresponding alcohols in good yield. The mechanism reveals that the alcohol (as solvent) plays a major role in the inter conversion of amide to the corresponding esters with Montmorillonite KSF (M-KSF) as a catalyst. Excellent yields, inexpensive and readily available substrates, environmentally benign reaction condition, shorter reaction time, and easy workup are the major advantageous features of this protocol.

Full text of DOI:10.1016/j.molstruc.2018.06.052

Accepted Manuscript
Montmorillonite-KSF mediated one step synthesis of pyranochromene derivatives
Chitreddy V. Subbareddy, Radhakrishnan Subashini, Shanmugam Sumathi
PII:
S0022-2860(18)30753-1
10.1016/j.molstruc.2018.06.052
MOLSTR 25339
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 7 March 2018
Revised Date: 10 June 2018
Accepted Date: 11 June 2018
Please cite this article as: C.V. Subbareddy, R. Subashini, S. Sumathi, Montmorillonite-KSF mediated
one step synthesis of pyranochromene derivatives, Journal of Molecular Structure (2018), doi: 10.1016/
j.molstruc.2018.06.052.
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ACCEPTED MANUSCRIPT

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Montmorillonite-KSF Mediated One Step Synthesis of Pyranochromene
Derivatives
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Chitreddy V Subbareddya, Radhakrishnan Subashinib and Shanmugam Sumathi*a
aDepartment of Chemistry, VIT, Vellore 632014, Tamilnadu, Vellore, India
bDepartment of Chemistry, Arignar Anna Govt. Arts College for women, Walajapet, Vellore
*Corresponding author: sumathishanmugam2003@gmail.com
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Abstract: One-pot three-component reaction of substituted aromatic aldehydes, 2-
cyanoacetamide and 4-hydroxycoumarin in the presence of Montmorillonite-KSF (MKSF) in
ethanol results in the formation of pyrano[3,2-c]chromene-3-carboxylates (5a-m) has been
described. The reaction was tested in different alcohols, afforded pyrano [3,2-c] chromene-3-
carboxylates (5a-m) of the corresponding alcohols in good yield. The mechanism reveals that the
alcohol (as solvent) plays a major role in the inter conversion of amide to the corresponding
esters with Montmorillonite KSF (M-KSF) as a catalyst. Excellent yields, inexpensive and
readily available substrates, environmentally benign reaction condition, shorter reaction time,
and easy workup are the major advantageous features of this protocol.
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Keywords:
Multicomponent
reaction,
Aromatic
aldehydes,
4-Hydroxycoumarin,
Montmorillonite KSF (MKSF), Pyrano[3,2-c]chromene, Heterogeneous catalyst.
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1. Introduction
Nowadays multi component reactions (MCRs) have been designed to produce
biologically active compounds and has become an important class of research in organic,
medicinal and combinatorial chemistry [1]. The selection of the catalyst and the solvent also has
a vital role in the formation of the product and selectivity [2-4]. Generally, researchers are
interested and focused on the use of MCRs to synthesize a broad range of products [5]. Recently
researcher’s focused on the synthesis of pyrano[3,2-c]chromene derivatives, which can
participate a significant role in pharmaceutical and biologically active compounds [6]. The
compounds of pyrano system were found to have various biological activities such as anti-
oxidant [7], antibacterial [8], antifungal [9], anti-inflammatory [10], anti-coagulant [11],
anticancer [12, 13] and anti-HIV [14]. Generally, the biological and pharmaceutical activities of
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chromenes depends on the nature of substituents (like Cl, F, OH, Br) being either on the pyrano
system or on the adjacent rings.
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The heterocyclic pyranochromenes are attractive targets in organic synthesis due to their
biological activities as good as synthetic intermediates for alkaloids, drug candidates, and clinical
pharmaceuticals [15]. Therefore, searching efficient methods for the synthesis of these chromene
compounds is interesting in organic synthesis and a few synthetic approaches have been reported
to exploit three-component reaction of 1,3-diketones, aldehydes, malononitriles using DBU [16],
DMAP [17], TBAB [18],ionic liquids [19], K2CO3 [20], Et3N [21], piperidine [22], nano
particles [23] and heteropoly acids [24]. Although, multicomponent reactions of aldehydes,
malononitrile or cyanoacetic esters and 4-hydroxycoumarin is the one of the powerful methods
for the synthesis of pyranochromenes as we discussed in the aforementioned section, usage of 2‐
cyanoacetamide has not been reported yet. The literature reports have their assets, but are often
useful for the synthesis of only a narrow range of pyranochromenes and may necessitate using an
expensive catalyst, longer reaction time, low yield and poor selectivity. Heterogeneous catalysts
play a major role in numerous organic transformations.
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Montmorillonite KSFis a well-known and widely used solid acid catalyst in synthetic
organic chemistry because of much importance in later years [25-27]. It has received
considerable attention because of its ease of handling, good reactivity, recyclability,
experimental simplicity, commercial availability, non-toxicity and cost effectiveness and air and
water compatibility. Owing to strong catalytic activity as Bronsted acid, Montmorillonite clay
has been used extensively as a catalyst in Diels Alder reaction [28], Friedlander synthesis [29]
and Knoevenagel condensation [30]. In this report, we have demonstrated a new, handy,
environmental protocol for the synthesis 2-amino-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-
c]chromene-3-carboxylates 5(a-m) from aromatic aldehydes 1(a-e), 2-cyanoacetamide 2 and 4-
hydroxycoumarin 3 in the presence of M-KSF catalyst in the different alcoholic media.
Meanwhile the three reactants were subjected to condensation with M-KSF in water medium
affording 2-amino-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-c]chromene-3-carboxamide, 4. To the
best of our knowledge this is the first time, one-pot multicomponent reaction of pyrano [3,2-
c]chromene derivatives with MKSF attempted and to be reported.
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2. Experimental Section
2.1. Materials and Methods
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All the commercially available materials were purchased from suppliers and were used
without further purification and the reactions were monitored by TLC. All the reactions were
performed using oven dried glassware. Elchem digital melting point apparatus was used for
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recording melting points in open capillaries and are uncorrected. The H NMR and 13C NMR
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values were obtained using a Bruker Avance-400 MHz spectrometer in CDCl3 and DMSO-d6
solvent with TMS as the internal standard. Chemical shift values (ƍ) were expressed in parts per
million (ppm). Couplingconstants (J) are reported in Hertz (Hz). Abbreviations are as follows: s
= singlet, d = doublet, t = triplet, q = quartet, m = multiplet and dd = doublet of doublets.
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2.1.1. General procedure for the synthesis of 2-amino-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-
c]chromene-3-carboxylate derivatives (5a-m)
An equimolar mixture of substituted benzaldehydes (1 mmol) and 2-cyanoacetamide (1
mmol) in alcohols with a catalytic amount of M-KSF (100 mg) was refluxed at 80 ºC for 30 min.
After consumption of aldehydes, 4-hydroxycoumarin (1 mmol) was added and kept for stirring
under reflux conditions. After the addition of 4-hydroxy coumarin, the completion of the reaction
was monitored by TLC and the reaction mixture was cooled to room temperature, solid obtained
was filtered off and washed with ethanol to obtain the desired product in good yield and
characterized by spectral analysis.
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2.1.2. General procedure for the synthesis of 2-amino-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-
c]chromene-3- carboxamide (4)
Benzaldehyde (1 mmol) 2-cyanoacetamide (1 mmol) Montmorillonite KSF (100 mg) and
5 mL of water were placed in a 50 mL round bottomed flask and stirred. The reaction was
continued to 1 h at reflux temperature. After the completion of aldehyde consumption, 4-
hydroxycoumarin was added. The reaction was refluxed for 2 h, the progress of the reaction was
monitored by TLC, for the disappearance of intermediate (E)-2-cyano-3-phenylacrylamide. After
the completion of reaction mixture was allowed to cool at room temperature and water was
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discarded. The solid was collected by simple filtration and washed with cold ethanol and
recrystallized from hot ethanol to obtain pure products for spectral analysis.
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2.2. Biological Evaluation
2.2.1. General procedure for the radical scavenging activity by DPPH method
The DPPH radical scavenging activity was carried out by the reported method [29]. In the
DPPH assay, the antioxidants are able to donate a hydrogen to reduce the stable radical DPPH to
the yellow-coloured non-radical diphenyl-picrylhydrazine (DPPH-H).The changes in the colour
(from deep violet to light yellow) of the standard and compounds 5(a-m)were measured at 517
nm on a UV-Vis light spectrophotometer.
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Stock solutions were prepared by dissolving 1 mg of the compounds 5(a-m) in 1 mL of
methanol. Then, different concentrations of the sample, 50, 75, 100, and 125 µg, were prepared
by dissolving in 3 mL methanol. The DPPH solution was prepared just before the UV
measurements. Then, 3 mL of the test sample and 1 mL of the DPPH solution were mixed and
placed for incubation for 30 min at room temperature. The absorbance of incubated test solutions
and control (without sample) were measured at 517 nm. Ascorbic acid was used as the standard.
The experiment was carried out in triplicate. The IC50 values were calculated for each sample as
well as standard is represented in Table 5.
The radical scavenging activity was calculated by following formula
% Inhibition = [AB – AA/AB] × 100
Where AB is the absorption of blank solution and AA is the absorption of the test sample
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2.2.2. General procedure for the in-vitro antibacterial studies
All the newly synthesized compounds were executed for their in vitro antibacterial
studies against Gram-positive organisms such as Staphylococcus aureus ATCC 700699, B.
subtilis MTCC 430 Micrococcus luteus MTCC 2470 and Gram negative organisms such as
Klebsiella ATCC 10273, Escherichia coli ATCC 11105 and Pseudomonas aeruginosa MTCC
2453 by the agar well technique [31]. All the compounds were dissolved in DMSO and different
concentrations were made. After inoculation, wells were scooped out with 3 mm, sterile cork
borer and the caps of the dishes were replaced. To every well different concentrations of test
solutions were added. All the plates and controls were kept at 37 ºC for 24 h incubation. Standard
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antibacterial ampicillin was used as reference antibacterial substances, respectively for
comparison.
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For MIC determination, all the compounds were dissolved in DMSO to get the
concentrations of 4.6, 9.3, 18.75, 37.50, 75.0, 150, 300, 600 and 1200 µg/mL. Standard
antibacterial ampicillin (standard) was also tested for the comparison. Serial dilutions of all the
synthesized compounds were performed by the modified agar well diffusion method. Test
organisms were lawn cultured on the MHA plates. The agar surface was bored by using a
sterilize cork borer. The concentrations of the test cultures were seeded with a 100 µL microbial
suspension of 0.5 MacFarland density. The test plates were incubated at 37 ºC for 24 h. The
lowest concentration which showed a clear zone of inhibition considered as the MIC value of
each compound. The experiments were repeated thrice and the minimum inhibitory values are
represented in Table 6.
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2.3. Spectral data of the synthesized compounds 5(a-m) & 4
2.3.1. Ethyl-2-amino-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-c]chromene-3-carboxylate (5a)
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White solid: Mp: 187-189 ºC; H NMR (400 MHz,CDCl3): δ1.18 (t, J = 7.2 Hz, 3H), 4.09-4.12
(m, 2H), 4.96 (s, 1H), 6.44 (s, 2H), 7.16-7.28 (m, 4H), 7.33-7.39 (m, 4H), 7.56 (t, J = 8.0 Hz,
1H), 7.85 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.1, 35.5, 60.0, 80.0, 100.0,
116.9, 122.1, 124.2, 126.7, 128.0,128.4, 132.1, 144.2, 152.6, 153.1, 157.9, 160.7, 168.7; Anal.
Calcd for C21H17NO5 363.3690 found 363.3688.
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carboxylate (5b)
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White solid: Mp: 190-191 ºC; H NMR (400 MHz,CDCl3): δ 1.08 (t, J = 6.8 Hz, 3H), 3.96-4.01
(m, 2H), 4.67 (s, 1H), 7.23 (s, 2H), 7.24-7.30 (m, 2H), 7.43-7.50 (m, 2H), 7.67-7.71 (m, 1H),
7.95 (d, J = 1,2 Hz, 1H), 7.97 (d, J = 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.1, 34.8,
59.0, 76.5, 106.2, 113.0, 116.5, 122.5, 124.6, 127.8, 129.9, 130.9, 132.7, 143.9, 152.1, 153.2,
158.4, 159.8, 167.4; Anal. Calcd for C21H16ClNO5 397.8110 found 397.8109.
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2.3.3. Ethyl-2-amino-4-(4-fluorophenyl)-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-c]chromene-3-
carboxylate (5c)
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White solid: Mp: 221-223 ºC; H NMR (400 MHz,CDCl3): δ 1.17 (t, J = 7.2 Hz, 3H), 4.08-4.13
(m, 2H), 4.93 (s, 1H), 6.47 (s, 2H), 6.92 (t, J = 8.8 Hz, 2H), 7.28-7.38 (m, 4H), 7.56 (t, 7.6 Hz,
1H), 7.84 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.1, 34.9,60.0, 80.1, 107.7,
113.4, 114.7, 114.9, 116.9, 122.2, 124.3, 129.9, 130.0, 132.2, 140.0, 140.1, 152.6, 153.1, 157.8,
160.4, 160.7, 162.8, 168.6; Anal. Calcd for C21H16FNO5 381.3594 found 381.3592.
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2.3.4. Ethyl-2-amino4-(4-methoxyphenyl)-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-c]chromene-3-
carboxylate (5d)
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White solid: Mp: 160-162 ºC; H NMR (400 MHz,CDCl3): δ 1.19 (t, J = 6.8 Hz, 3H), 3.76 (s,
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3H), 4.04-4.15 (m, 2H), 4.90 (s, 1H), 6.44 (s, 2H), 6.79 (d, J = 8.4 Hz, 2H), 7.28-7.34 (m, 4H),
7.36 (m, 1H), 7.83 (d, J = 8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.2, 34.6, 55.2, 60.0,
80.4, 108.1, 113.4, 113.5, 116.8, 122.1, 124.2, 129.4, 132.0, 136.6, 152.5, 152.9, 157.8, 158.3,
160.8, 168.8; Anal. Calcd for C22H16NO6 393.3950 found 393.3948.
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2.3.5. Ethyl-2-amino-4-(2,6-dichlorophenyl)-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-
c]chromene-3-carboxylate (5e)
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White solid: Mp: 197-199 ºC; H NMR (400 MHz,CDCl3): δ 0.95 (t, J = 7.2 Hz, 3H), 3.90-3.94
(m, 2H), 5.59 (s, 1H), 7.18-7.26 (m, 2H), 7.41-7.49 (m, 3H), 7.67-7.72 (m, 1H), 7.94 (t, J = 1.2
Hz, 1H), 7.96 (d, 2H); 13C NMR (100 MHz, CDCl3): δ 14.0, 32.2, 58.8, 73.2, 102.5, 112.5,
116.4, 122.5, 124.6, 128.3, 129.8, 132.9, 134.0, 136.9, 137.9, 152.1, 154.0, 159.2, 167.7; Anal.
Calcd for C21H15Cl2NO5 432.2530 found 432.2529.
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2.3.6. Methyl-2-amino-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-c]chromene-3-carboxylate (5f)
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White solid: Mp: 164-166 ºC; H NMR (400 MHz,CDCl3) δ 3.67 (s, 3H), 4.96 (s, 1H), 6.47 (s,
2H), 7.17 (t, J = 7.2 Hz, 1H), 7.27 (d, J = 5.6 Hz, 2H), 7.32-7.35 (m, 2H), 7.38 (d, J = 8 Hz, 2H),
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7.55-7,59 (m, 1H), 7.84 (t, J = 8.0 Hz, 1H); C NMR (100 MHz, CDCl3): δ 35.3, 51.2, 80.1,
108.1, 113.5, 116.9, 122.1, 124.2, 126.8, 128.1, 128.2, 132.1, 144.1, 152.6, 153.1, 158.1, 160.6,
169.1; Anal. Calcd for C20H15NO5 349.3420 found 349.3418.
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2.3.7. Methyl-2-amino-4-(4-chlorophenyl)-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-c]chromene-
3-carboxylate (5g)
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White solid: Mp: 226-227 ºC; H NMR (400 MHz,CDCl3): δ 3.66 (s, 3H), 4.92 (s, 1H), 6.49 (s,
2H), 7.22-7.25 (m, 2H), 7.28-7.35 (m, 4H), 7.56-7.60 (m, 1H), 7.83-7.85 (m, 1H); 13C NMR
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(100 MHz, CDCl3): δ 34.9, 51.3, 79.6, 107.5, 113.3, 116.9, 122.2, 124.3, 128.3, 129.7, 132.3,
132.5, 142.7, 152.6, 153.2, 158.1, 160.6, 168.9; Anal. Calcd for C20H14ClNO5 383.7840 found
383.7838.
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2.3.8. Methyl-2-amino-4-(4-fluorophenyl)-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-c]chromene-3-
carboxylate (5h)
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White solid: Mp: 220-221 ºC; H NMR (400 MHz,CDCl3): δ 3.66 (s, 3H), 4.93 (s, 1H), 6.49 (s,
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2H), 6.92 (t, J = 8.4 Hz, 2H), 7.33-7.37 (m, 4H), 7.56-7.60 (m, 1H), 7.84-7.86 (m, 1H); 13C NMR
(100 MHz, CDCl3): δ 34.7, 51.3, 79.9, 107.8, 113.4, 114.8, 115.0, 116.9, 122.1, 124.3, 129.7,
129.8, 132.3, 139.9, 139.9, 152.6, 153.1, 158.0, 160.6, 169.0; Anal. Calcd for C20H14FNO5
367.3324 found 367.3322.
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2.3.9. Methyl-2-amino-4-(4-methoxyphenyl)-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-c]chromene-
3-carboxylate (5i)
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White solid: Mp: 202-204 ºC; H NMR (400 MHz,CDCl3): δ 3.67 (s, 3H), 3.76 (s, 3H), 4.91 (s,
1H), 6.47 (s, 2H), 6.79 (d, J = 8.8 Hz, 2H), 7.89-7.35 (m, 4H), 7.54-7,58 (m, 1H), 7.82 (d, J = 7.6
Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 34.4, 51.2, 55.2, 80.2, 108.2, 113.5, 116.8, 122.1,
124.2, 127.9, 129.2, 132.1, 136.4, 152.5, 152.9, 15.81, 158.3, 160.7, 169.1; Anal. Calcd for
C21H17NO6 379.3680 found 379.3679.
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2.3.10. Methyl-2-amino-4-(4-bromophenyl)-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-c]chromene-
3-carboxylate (5j)
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White solid: Mp: 194-195 ºC; H NMR (400 MHz,CDCl3): δ 3.66 (s, 3H), 4.91 (s, 1H), 6.50 (s,
2H), 7.25 (t, J = 8.4 Hz, 2H), 7.33-7.39 (m, 4H), 7.57 (t, J = 6.8 Hz, 1H), 7.83 (d, J = 8.0 Hz,
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1H); C NMR (100 MHz, CDCl3): δ 35.0, 51.3, 79.5, 107.4, 113.3, 116.9, 120.6, 122.2, 124.3,
130.1, 131.2, 132.3, 143.2, 152.6, 153.2, 158.1, 160.6, 168.9; ; Anal. Calcd for C20H14BrNO5
428.2380 found 428.2378.
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2.3.11. Butyl-2-amino-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-c]chromene-3-carboxylate (5k)
Yellow solid: Mp: 178-180 ºC; 1H NMR (400 MHz,CDCl3): δ 0.75 (t, J = 7.6 Hz, 3H), 1.08-1.16
(m, 2H), 1.39-1.46 (m, 2H), 3.91-3.98 (m, 2H), 4.84 (s, 1H), 7.05 (s, 2H), 7.05-7.14 (m, 2H),
7.14-7.18 (m, 2H), 7.21-7.24 (m, 2H), 7.28-7.46 (m, 1H), 7.73 (d, J = 7.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3): δ 13.6, 19.0, 30.7, 35.5, 63.9, 76.7, 77.0, 77.3, 80.2, 80.2, 108.0, 113.5,
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116.8, 122.1, 124.2, 126.7, 128.0, 128.4, 132.1, 144.2, 152.6, 153.0, 158.0, 160.7, 168.8; Anal.
Calcd for C23H21NO5 391.4230 found 391.4228.
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2.3.12. Butyl-2-amino-4(4-fluorophenyl)-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-c]chromene-3-
carboxylate (5l)
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Yellow solid: Mp: 197-198 ºC; 1H NMR (400 MHz,DMSO-d6): δ 0.76 (t, J = 7.2 Hz, 3H), 1.08-
1.18 (m, 2H), 1.39-1.45 (m, 2H), 3.92-3.99 (m, 2H), 4.82 (s, 1H), 6.38 (s, 2H), 6.82 (t, J = 8 Hz,
2H), 7.23 (m, 3H), 7.46 (t, J = 7.6 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H);13C NMR (100 MHz,
DMSO-d6): δ 13.7, 19.1, 30.6, 34.6, 64.0, 105.7, 113.2, 116.8, 122.3, 124.2, 126.2, 128.0, 130.0,
132.2, 133.9, 140.2, 152.7, 153.6, 158.1, 160.4, 168.9; Anal. Calcd for C23H20NO5 409.4134
found 409.4130.
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2.3.13. Butyl-2-amino-4(2,6-dichlorophenyl)-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-
c]chromene-3-carboxylate (5m)
Yellow solid: Mp: 218-219 ºC; 1H NMR (400 MHz,DMSO-d6): δ 0.73 (t, J = 7.2 Hz, 3H), 0.86-
0.98 (m, 2H), 1.36-1.41 (m, 2H), 3.80-3.86 (m, 1H), 3.99-4.05 (m, 1H), 5.60 (s, 1H), 7.19-7.27
(m, 2H), 7.42-7.50 (m, 3H), 7.68-7.73 (m, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.97 (t, J = 1.2 Hz, 2H);
13C NMR (100 MHz, DMSO-d6): δ 13.5, 18.3, 30.2, 32.1, 62.6, 73.1, 102.5, 112.5, 116.4, 122.5,
124.6, 128.4, 128.5, 129.8, 132.9, 134.0, 136.8, 137.9, 152.1, 154.0, 159.2, 159.2, 167.8; Anal.
Calcd for C23H20Cl2NO5 460.3070 found 460.3066.
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2.3.14. 2-amino-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-c]chromene-3-carboxamide (4)
White solid: Mp: 283-285 ºC; 1H NMR (400 MHz,DMSO-d6); δ 6.28 (s, 1H), 7.08 (t, J = 7.2 Hz,
3H), 7.15 (t, J = 7.2 Hz, 2H), 7.22-7.28 (m, 4H), 7.49-7.81 (m, 2H), 7.81 (d, J = 6.8 Hz, 2H); 13C
NMR (100 MHz, DMSO-d6): δ 36.0, 63.9, 103.4, 115.4, 119.8, 122.9, 124.0, 124.8, 126.6,
127.6, 130.9, 142.2, 152.4, 164.6, 167.6; Anal. Calcd for C19H14N2O4 334.3310 found 334.3308.
24
25
26
27
28
29
3. Results and Discussion
For the synthesis of highly functionalized pyrano[3,2-c]chromene derivatives such as
ethyl
2-amino-4,5-dihydropyrano[3,2-c]chromenes,
5(a-e)
methyl
2-amino-4,5-
dihydropyrano[3,2-c]chromenes, 5(f-j) butyl 2-amino-4,5-dihydropyrano[3,2-c]chromenes 5(k-
m) and M-KSF was used as the catalyst in different alcoholic medium (Scheme 1). To optimize
the conditions, systematic study of different solvents that influencing the reaction yields was
8

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1
2
3
4
performed with an equimolar mixture of 4-chlorobenzaldehyde 1b, 2-cyanoacetamide 2, 4-
hydroxy coumarin 3 (Scheme 1) and the results has been summarized in Table 1. Only a trace
amount of the desired product 5b was obtained under reflux conditions with different base
catalysts except piperidine.
5
6
Scheme 1. Synthesis of pyrano[3,2-c]chromene-carboxylate derivatives
7
8
Then the 30 mol % of piperidine was found to afford 65% yield of the desired product 5b. The
same reaction when tried with M-KSF the desired product5b are precipitated out from the
reaction mixture, which was essentially pure and was used without any further
purification.Compared to the all employed catalysts, M-KSF afforded the compound 5b in good
yield, among them M-KSF gave a very high yield with lesser time. The products 5(a-m) were
9
10
11
12
13
14
15
16
17
18
19
20
1
1
fully characterized by H NMR and 13C NMR and Mass analysis. In H NMR spectrum the
aromatic signals appear in the range of 7.97-6.47 ppm. The NH2 proton signals in the ranges of
7.23-6.39 ppm. The methane proton (CH) appear as a singlet in the range of 5.60-4.67 ppm, the
methoxy (OCH3) proton peaks appear in the range of 3.76 ppm, the methylene (CH2) protons
appear as multiplet in the range of 4.12-3.90 ppm, and methyl (CH3) protons appear as a triplet
in the range of 1.22-0.73 ppm. The 13C NMR supports the formation of pyranochromenes.
Initially aldehydes 1(a-f) and cyanoacetamide, 2 reacts in the presence of M-KSF readily form
an intermediate (E)-2-cyano-3-phenylacrylamide, 6(a-m) and the addition of 4-hydroxy
coumarin yields the compound 4.
9

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1
2
Entry
Catalyst
Catalyst loading (mol%)
Time(h)
Yieldb(%)
1
2
3
-
-
-
-
24
24
10
-
-
DMAP
30
20
4
5
piperidine
piperidine
piperidine
Morpholine
Pyrrolidine
NaOH
10
20
30
30
30
30
30
30
10
10
8
50
58
65
40
35
50
30
23
6
7
8
8
8
9
10
10
10
10
11
KOH
DBU
3
4
Table 1.Optimization of the three-component reaction under various conditionsa
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12
13
imidazole
MKSF
20
10
20
85
(100 mg)
5
1
2
3
4
aReaction Conditions: 4-Chlorobenzaldehyde (1 mmol), 2-Cyanoacetamide (1 mmol),
4-Hydroxycoumarin (1 mmol), Ethanol (5 mL) in the presence of different catalysts at 80
bIsolated Yields.
ºC.
5
6
7
The carboxamide moieties in the 3-positions of the pyran ring were highly active and these
functional groups react with alcohols for further synthetic transformations. In this study, we
expected 2-amino-4,5-dihydropyrano[3,2-c]chromene-3-carboxamide, 4 from the aromatic
aldehydes 1(a-f), 2-cyanoaceamide 2, and 4-hydroxycoumarin 3, but the product we obtained
was pyrano[3,2-c]chromene carboxylates, 5. In the present work alcoholic functional groups are
regarded as one of the stimulant and the corresponding functional group inter conversion from
carboxamide to carboxylate was either occurring in the intermediate itself or during the final
conversion (Scheme 2). To confirm that the intermediate, 6bhas been isolated and
characterization was carried out and found thatconversion was happening towards the end. A
possible mechanism of these reactions is given in Scheme 4.
8
9
10
11
12
13
14
15
16
17
18
Scheme 2.Synthesis of pyrano[3,2-c]chromene derivatives
19
Table 2.Optimization of the three-component reaction under various loading of catalysta
Entry
Catalyst (mg) MKSF
Time(h)
10
Yieldb (%)
1
2
10
20
20
35
10
11

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3
4
5
6
7
8
40
60
10
43
50
72
85
84
85
8
8
5
5
5
80
100
110
120
1
2
aReaction Conditions: 4-Chlorobenzaldehyde (1 mmol), 2-Cyanoacetamide (1 mmol),
4-Hydroxycoumarin (1 mmol), Ethanol (10 mL) and M-KSF at 80
C. bIsolated Yields.
º
3
4
In order to generalize the optimized conditions, different derivatives of 2-amino-4,5-
dihydropyrano[3,2-c]chromene-carboxylates 5(a-m) were synthesized from the one-pot reaction
of substituted aldehydes 1(a-f), 2-cyanoacetamide 2, 4-hydroxycoumarin 3 in the presence of M-
KSF (100 mg) in different alcohols (Ethanol, Methanol, n-Butanol) under reflux conditions
(Scheme 1). Optimization of the catalyst M-KSF was carried out from 10 mg to 120 mg (Table
2). With 100 mg the yield was high and it has been arbitrarily fixed. The results of the
synthesized compounds has been tabulated in Table 3.As we know that in multicomponent
reactions solvent and catalyst plays a major role which may be attributed to the capability of the
alcoholic functional groups.
5
6
7
8
9
10
11
12
13
14
Scheme 3.One-pot Three-component reaction of pyrano[3,2-c]chromene derivatives
15
16
17
18
19
The synthesis of pyrano chromenes was performed in different protic and aprotic solvents with
M-KSF to check the formation of the compound 2-amino-5-oxo-4-phenyl-4,5-
dihydropyrano[3,2-c]chromene-3-carboxylate, 5b. Interestingly, with water as solvent the
compound 2-amino-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-c]chromene-3-carboxamide, 4 was
formed with good yield.The same reaction when tried under solvent less condition, pyrano
12

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1
2
chromene-3-carboxamide, 4 was found with a lesser yield. This created an interest to check for
various solvents and with water the expected compound, 4 was formed in high yield (Scheme 3).
3
4
Scheme 4. Plausible Mechanism for the Synthesis of 2-Amino-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-
c]chromene-3-carboxylates
5
6
7
8
3.1. Reusability of Catalyst
The recyclability of the M-KSF is one of the most important advantages of this protocol
that makes it useful for commercial applications. The reaction mixture was allowed to cool and
catalyst was filtered off from the reaction mixture at the end of the reaction. It was washed with
ethanol and water, dried and activated at hot air oven for 5h. The catalyst was reused for further
cycles. The reaction proceeded efficiently even after five cycles. The use of a catalyst for the first
time offered a yield of 85%, and although the same catalyst repeatedly reused up to four times
under similar conditions, the yields obtained were 85%, 82% and 78% and 75% respectively
(Table 4). The experimental results reveal that the catalyst showed good recyclability in all these
reactions.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Table 3. Synthesis of Pyrano[3,2-c]chromene Derivatives 5(a-m)a,b
14

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NH2
O
O
OH
O
O
O
OEt
M-KSF
N
NH2
R-OH, 80 °C
R
R
O
O
O
O
1(a-f)
NH2
2
3
5(a-m)
O
NH2
O
NH2
NH2
O
O
OEt
O
O
OEt
O
O
OEt
O
O
OEt
O
O
O
Cl
O
OMe
O
F
5b (84%)
5c (85%)
5a (88%)
5d (82%)
NH2
NH2
O
O
NH2
O
NH2
O
O
O
OMe
O
OMe
O
OMe
O
O
OEt
Cl
O
Cl
O
O
F
O
O
O
Cl
5h (80%)
NH2
5f (87%)
5g (84%)
5e (80%)
O
NH2
O
O
NH2
O
O
NH2
O
O
OBu
OBu
OMe
O
O
OMe
O
O
F
O
O
O
O
Br
O
OMe
5l (84%)
5k (84%)
5j (79%)
5i (80%)
NH2
O
O
NH2
O
O
NH2
OBu
Cl
O
O
O
O
Cl
5m (78%)
4a (86%)
1
2
aReaction Conditions: Substituted Benzaldehydes (1 mmol), 2-Cyanoacetamide (1 mmol),
4-Hydroxycoumarin (1 mmol), Alcohol (10 mL), (R = Ethyl, Methyl, n-Butyl ) and 100 mg of
M-KSF. bIsolated Yields.
3
4
5
6
7
8
9
Table 4. Recyclability of Montmorillonite KSFa
15

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Cycles
Catalyst recovered (%)
Product yieldb (%)
Initial
94
92
89
86
85
85
85
82
78
75
1
2
3
4
1
2
aReaction Conditions: 4-Chlorobenzaldehyde (1 mmol), 2-Cyanoacetamide (1 mmol),
4-Hydroxycoumarin (1 mmol), Ethanol (10 mL) and M-KSF. bIsolated Yields.
3
4
3.2. Antioxidant Activity
The DPPH values of methanolic solutions of pyrano[3,2-c]chromene derivatives 5(a-m)
were examined and compared (Table 5).Then the absorbance was measured at 517 nm using a
UV-VIS spectrophotometer. From examination of Table 5, we can conclude that the pyrano[3,2-
c]chromene derivatives 5(a-m) scavenging effects of DPPH radicals increase in the
concentration. We have measured the percentage inhibition at different concentrations of all the
synthesized compounds, 5(a-m)and calculated its corresponding IC50 values, which are given in
Table 5. The results revealed that all the synthesized compounds, 5(a-m) showed the moderate
scavenging property when compared with Ascorbic acid, a standard antioxidant agent.The
presence of substitutions on the benzaldehydes like Cl, dichloro, and Br (5b, 5e, 5g, 5j and 5m)
groups shown significant antioxidant activity compared to other functional groups like
unsubstituted, fluoro and methoxy.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
3.3. In Vitro Antibacterial Activity
The compounds 5(a-m) were screened for their in vitro antibacterial activity. The results
of antibacterial activity indicated a variable degree of efficacy of the compounds against
different strains of bacteria. Compound 5m exhibited very strong activity (9.375 µg/mL), against
S. aureus, Bacillus subtilis and K. pneumoniae. Whereas compounds 5b, 5e, 5g and 5j displayed
significant activity against S. aureus, Bacillus subtilis, Micrococcus luteus and P. aeruginosa
(18.75 µg/mL). The compounds 5c, 5k and 5l presented significant activity against S. aureus,
Bacillus subtilis and K. pneumoniae (37.50 µg/mL). The results of this study as indicated in
Table 6. The substitutions present on the phenyl rings of pyranochromene moiety with Cl, Br and
16

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1
2
3
4
dichloro have shown more activity, when compared to fluoro and methoxy
substitutions.Pyranochromenes without any substitution did not show any activity and the
pyranochromene system containing dichloro substitution on the phenyl ring with butyl ester have
revealed more activity when compared to ethyl and methyl esters.
5
Table 5. Antioxidant activity of pyrano[3,2-c]chromene derivatives 5(a-m)
Entry Compound
% of inhibition at different concentrations (mM)
IC50
50
70
100
125
1
2
5a
5b
51.27
53.79
53.81
51.20
54.73
50.41
51.90
50.73
51.28
53.62
52.29
51.45
55.92
56.81
63.08
61.22
62.17
61.50
65.37
63.36
63.58
62.89
60.72
62.46
64.19
64.90
66.37
67.91
70.14
69.35
71.29
71.15
72.12
69.54
72.40
71.46
72.67
72.04
70.43
71.65
72.50
72.29
81.02
80.47
84.58
80.60
83.94
81.29
81.93
82.71
82.33
83.67
82.73
80.54
84.65
85.58
0.813
0.678
0.751
0.854
0.502
0.891
0.741
0.884
0.909
0.707
0.740
0.714
0.378
0.265
3
5c
4
5d
5
5e
6
5f
7
5g
8
5h
9
5i
10
11
12
13
14
5j
5k
5l
5m
Ascorbic
acid
6
7
8
9
10
17

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1
Table 6. Antibacterial activity of pyrano[3,2-c]chromene derivatives 5(a-m)
Minimum inhibitory concentration (MIC) (in µg/mL)
Compound Staphylococcus Bacillus M. luteus
aureus
>150
E.coli k.
P.
subtilis
>150
18.75
37.50
>18.75
18.75
>150
18.75
>75.0
>150
18.75
37.50
37.50
9.3
pneumoniae aeruginosa
5a
>150
18.75
>37.50
>75.0
18.75
>150
>37.50
>75.0
>300
18.75
>150
>75.0
>75
>150
>75.0
>150
>150
>75.0
>150
>150
>300
>150
>75.0
>300
>75.0
>150
9.3
>150
>150
>150
>75.0
>300
>150
>37.50
>300
>150
>75.0
>300
>75.0
9.3
>150
18.75
>150
>75.0
18.75
>150
>37.50
>300
>300
>150
>75.0
>150
>75
5b
18.75
>75.0
>18.75
18.75
>75.0
18.75
>150
>75.0
18.75
>75.0
75.0
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
9.3
Ampicillin
4.6
4.6
4.6
4.6
9.3
2
3
4. Conclusions
In conclusion, the synthesis of 2-amino-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-
c]chromene-3-carboxylate derivatives 5(a-m) were reported by one-pot three component
reaction between substituted aldehydes, 2-cyanoacetamide and 4-hydroxycoumarin in the
presence of MKSF an efficient catalyst to predict the pyranochromene derivatives. Particularly,
this method includes excellent yields, cost effective and readily available substrates, mild
reaction conditions, reduced environmental impact and simple straightforwardness of procedure
which make attractive process these useful important compounds. In addition to this we have
studied the antioxidant and antibacterial properties of all the synthesized pyranochromene
derivatives 5(a-m). Among all the compounds 5m was showing excellent antibacterial as well as
antioxidant activity.
4
5
6
7
8
9
10
11
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13
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2
3
Acknowledgement
The authors thank Vellore Institute of Technology, Vellore for providing research facilities and
acknowledges VIT-SIF for providing NMR facilities to carry out this work.
4
5
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[31] L.C. Rao, N.S. Kumar, V. Dileepkumar, U.S.N. Murthy, and H.M. Meshram, “On water”
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28964.
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Highlights of work
ꢀ Montmorillonite-KSF is an effective heterogeneous catalyst.
ꢀ Easy to handle and simple reaction procedure.
ꢀ Cost effective and high yields were observed in shorter reaction time.
ꢀ Reusability of catalyst.