Three-component, one-pot synthesis of pyrano[3,2-c]chromene derivatives catalyzed by ammonium acetate: Synthesis, characterization, cation binding, and biological determination

Article abstract of DOI:10.1002/jhet.3776

Three-component reaction of arylaldehydes with malononitrile and 4-hydroxycoumarine using CH₃COONH₄ as a catalyst at reflux was used for the synthesis of novel substituted pyrano[3,2-c]chromene derivatives. The structure of these com

Full text of DOI:10.1002/jhet.3776

Received: 9 January 2019
DOI: 10.1002/jhet.3776
Revised: 5 September 2019
Accepted: 26 September 2019
A R T I C L E
Three‐component, one‐pot synthesis of pyrano[3,2‐c]
chromene derivatives catalyzed by ammonium acetate:
Synthesis, characterization, cation binding, and biological
determination
Chiheb Mhiri1 | Lamia Boubakri2 | Riadh Ternane1 | Lamjed Mansour3 |
Abdel Halim Harrath3 | J. Al‐Tamimi3 | Lassaad Baklouti1 | Naceur Hamdi2
1 Laboratory of Applied Chemistry and
Abstract
Natural Substances Resources and
Three‐component reaction of arylaldehydes with malononitrile and 4‐
Environment, Faculty of Sciences,
University of Carthage, Zarzouna, Tunisia
2 Research Laboratory of Environmental
hydroxycoumarine using CH3COONH4 as a catalyst at reflux was used for
the synthesis of novel substituted pyrano[3,2‐c]chromene derivatives. The
Sciences and Technologies (LR16ES09),
structure of these compounds was assigned by spectroscopic data such as (IR,
1HNMR, 13CNMR, and mass spectral data). The cation binding properties of
chromene derivatives 4a‐c towards Cu2+, Ni2+, and Zn2+ were studied in meth-
anol. The results showed that Zn2+ is the most complexed in this series of cat-
Higher Institute of Environmental
Sciences and Technology, University of
Carthage, Hammam‐Lif, Tunisia
3 Zoology Department, College of Science,
King Saud University, Riyadh, Saudi
ions, and 4c is best complexed with either Ni2+ and Zn2+. Antimicrobial
Arabia
properties of new pyrano[3,2‐c]chromene derivatives are investigated, the com-
Correspondence
Naceur Hamdi, Research Laboratory of
pound 4c presents against Micrococcus luteus LB 14110 an MIC value of
Environmental Sciences and Technologies
(LR16ES09), Higher Institute of
Environmental Sciences and Technology,
University of Carthage, Hammam‐Lif,
Tunisia.
0.0185 mg/mL quite better to that of ampicillin (0.0195 mg/mL) used as stan-
dard. Concerning acetylcholinesterase inhibition activity (AChEI), compound
4c presents an interesting AChEI activity with an inhibition of 52%.
Email: hamdi_naceur@yahoo.fr
Funding information
Research Supporting Project, Grant/
Award Number: RSP‐2019/75
1 | INTRODUCTION
derivatives have been recognized to possess a wide range
of medicinal benefits.[8–15]
Multicomponent reactions (MCRs) have emerged as
There has been a growing interest to use the 4‐
hydroxycoumarin as a heterocyclic motif to generate
molecular structures possessing a multitude of biological
activities such as anti‐HIV, antifungal, phytotoxic, anti-
microbial, cytotoxic, and neurotoxic activities.[1–7] The
incorporation of other heterocyclic moieties into pyran‐
2‐ones either in the form of an extra cyclic substituent
or as a fused structure has often led to enhanced biologi-
cal effects. For instance, furo[3,2‐c]pyran‐4‐ones and their
useful tools for exploring chemical space. They involve
domino processes in which at least three different reac-
tants are directly converted into products in a one‐pot fash-
ion.[16–20] Compared with classical multistep synthesis,
MCRs offer higher atom economy and selectivity and give
easy access to molecular complexity and diversity while
generating fewer by‐products. As a result, the importance
of MCRs in modern organic chemistry is growing,[21–23]
and MCRs are being developed for the efficient production
J Heterocyclic Chem. 2019;1–8.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

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MHIRI ET AL.
TABLE 2 Effect of catalyst amount on the condensation of
benzaldehyde 1, malononitrile 2, and 4‐hydroxycoumarin 3 in
Bmim[triflate]
of medicinally relevant scaffolds. In the course of our con-
tinuing interest in the synthesis of condensed coumarin
derivatives with anti‐inflammatory and antioxidant activi-
ties,[24,25] we have extended our research to the synthesis,
characterization, and biological evaluation of novel bioac-
tive new substituted pyrano[3,2‐c]chromene derivatives
via an environmentally friendly reaction condition. In
addition, their biological activities were studied.
Entry
Catalyst
Mole, %
Yield, %a
1
2
3
4
5
6
7
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
5
10
15
20
30
35
40
55
90
92
94
92
90
88
2 | RESULTS AND DISCUSSIONS
The reaction of an equimolecular amounts of 4‐
Note. Reaction conditions: 4‐hydroxycomarine (1 mmol), malononitrile
(1 mmol), benzaldehyde (1 mmol), Bmim[triflate] (5 ml), t (2 h).
hydroxycoumarine
1
with
malononitrile
and
arylaldehydes using different solvents such as DMC,
DEC, ethanol, tetrahydrofuran (THF), dichloromethane,
and toluene (Table 1, entries 1‐7) was investigated in
the presence of a catalytic amount of ammonium acetate.
The results are presented in Table 1.
The results indicated that solvents also affected the yield
of compounds (Table 1, entries 1‐7). In the organic solvents
such as dichloromethane, THF, ethanol, or toluene, the
yields of 3 were lower, and longer reaction times were
required, the best result was obtained when using DMC.
The reaction was also performed with different
amounts of catalyst at ambient temperature. The results
are summarized in Table 2
A total of 20 mol% of catalyst was found more suitable
for this reaction. In addition, when we increase the
percentage of the catalyst to 10, 15, and 20 mol%, the yields
were found to be increased up to 85%, 82%, and 95%,
respectively.
Table 3 shows that 30 minutes are not enough for the
reaction to be complete. On the other hand, beyond
120 minutes, we have no improvement in the reaction
aIsolated yields after purification.
yield. With the optimized reaction conditions in hand,
we then investigated the scope of this reaction with
substituted aromatic aldehydes as substrates. The results
are summarized in Scheme 1 and Table 4.
All the aromatic aldehydes afforded the corresponding
products 4 in good yields.
The structure of the new compounds 4 was identified
1
by their H‐NMR and 13C‐NMR data as well as by their
1
mass spectra and their elemental analysis. In H‐NMR
of compound 4a, a characteristic singlet at about
3.07 ppm is assigned to the methyl protons (a,b), whereas
the proton NH appears as a singlet at about 9.98 ppm in
accordance with the previous data (Figure 1).[26–33]
13C‐NMR showed the amide (NH–C) signal at δ
177.8 ppm, the C1′ signal had a chemical shift of
δ = 61.9, while the C4 signal was assigned further upfield
at δ = 96.1. However, the C2 signal was further upfield,
δ = 180.1, than was the C4′ signal was assigned as
δ = 134.4 ppm (Figure 2).
The MS spectrum of complex 4a is given in Figure 3.
The fragmentation leading to m/z = 79 can occur via
the mechanism fragmentation given in Scheme 2.
The formation of compound 4 could be explained by
the reaction sequence in Scheme 3. First, condensation
of ammonium acetate with malonitrile is proposed to give
intermediate (i), The Michael addition of 4‐
hydroxycoumarine to the intermediate (ii) occur to
TABLE 1 Synthesis of pyrano[3,2‐c]chromene derivatives in the
presence of different solvents
Entry
Solvent
T, °C
Yield, %a
1
2
3
4
5
6
7
8
DMC
90
128
78
85
75
72
60
90
65
60
62
DEC
EtOH
CHCl3
Bmin[triflate]
THF
61
>100
66
TABLE 3 Effect of reaction time on the yield of compounds
Toluene
CH2Cl2
110
40
t, min
30
68
40
75
60
76
90
72
120
95
130
80
Yield, %
Note. Reaction conditions: 4‐hydroxycomarine (1 mmol), malononitrile
(1 mmol), benzaldehyde (1 mmol), NH4OAc (2,5 mol%), solvant (5 ml), t (2 h).
aIsolated yield of product.
Note. Reaction conditions: 4‐hydroxycomarine (1 mmol), malononitrile
(1 mmol), benzaldehyde (1 mmol), NH4OAc (15 mol%), Bmim[triflate]
(5 mL).

MHIRI ET AL.
3
SCHEME 1 Synthesis of pyrano[3,2‐c]
chromene derivatives 4 catalyzed by
NH4OAc
0.1, 0.3, and 0.5 mg/mL. The obtained results of the syn-
thesized coumarins are shown in Table 5.
TABLE 4 Physico‐chemical characteristics of pyrano[3,2‐c]
chromene derivatives 4
Compound 4a showed activity against Micrococcus
luteus LB 14110 at three different concentrations 0.1,
0.3, and 0.5 mg/mL. We found also that if we increase
the concentration of compound 3a, the diameter of inhi-
bition zone will not increase as we have expected. Com-
pound 4b showed activity against bacteria M. luteus LB
14110 and Agrobacterium tumifaciens only in concentra-
tion of 0.5 mg/mL. Compound 4c did not show activity
against Listeria monocytogenes ATCC 19117. In the case
of L. monocytogenes ATCC 19117, by increasing the con-
centration of compound 4c, the activity will not change.
The Minimal Inhibitory Concentrations (MICs) values
of pyrano[3,2‐c]chromene derivatives 4 were determined.
The most active compound was 4c, which presents
against M. luteus LB 14110 the same MIC value of
0.0195 mg/mL than the used standard (ampicillin)
(Table 6).
t,
Yield, %a mp, °
Entry R
Product min
C
1
2
3
4
5
3,5‐OCH3‐4‐COOCH3 4a
180 92
240
258
250
260
325
2,3‐OH
2‐OH‐5‐NO2
H
4b
4c
4d
4e
100 90
120 85
50 94
45 90
m‐OCH3
Note. Reaction conditions: Aromatic aldehyde 1a (1 mmol), malononitrile 2
(1 mmol), and 4‐hydroxycoumarin 3 (1 mmol), Bmim[triflate] (5 mL)
NH4OAc (15 mol%).
aIsolated yields after purification.
provide the intermediate (iii), which undergoes isomeri-
zation to form the target 4.
3.2 | Acetylcholinesterase inhibition
3 | BIOLOGICAL ACTIVITIES
3.1 | Antibacterial activity
The acetylcholinesterase enzyme (AChE) was done using
some previously reported methods.[34–37]
The results of AChEI of the synthesized compounds 4
are presented in Table 8. Three compounds (4a, 4b, and
4c) exhibited moderate AChEI activity at 100 μg/mL. As
The antimicrobial activity of the pyrano[3,2‐c]chromene
derivatives 4 was tested at three different concentrations:
FIGURE 1 1H NMR spectra of
compound 4a (400 MHz, DMSO‐d6) [Color
figure can be viewed at wileyonlinelibrary.
com]

4
MHIRI ET AL.
FIGURE 2 13C NMR spectra of compound 4a (100 MHz, DMSO‐d6) [Color figure can be viewed at wileyonlinelibrary.com]
FIGURE 3 DART MS spectrum (DART‐TOF‐MS) of compound 4a [Color figure can be viewed at wileyonlinelibrary.com]
SCHEME 2 Mechanism of the
fragmentation leading to the m/z = 79
peak [Color figure can be viewed at
wileyonlinelibrary.com]

MHIRI ET AL.
5
SCHEME 3 A proposed mechanism for
the three‐component synthesis of
pyrano[3,2‐c]chromene derivatives 4
TABLE 5 Antibacterial activity of the synthesized pyrano[3,2‐c]chromene derivatives 4 against the tested indicator microorganisms
Bacteria
Conc, mg/mL
4a
4b
4c
4d
4e
AMC
Micrococcus luteus
LB 14110
0.1
0.3
0.5
19
23
23
0
0
24
16
16
16
15
13
14
14
12
13
25
Staphylococcus aureus
ATCC 6538
0.1
0.3
0.5
24
24
33
0
0
0
40
36
33
36
35
34
28
23
29
Listeria monocytogenes
ATCC 19117
0.1
0.3
0.5
0
0
22
0
0
0
0
0
0
0
0
0
0
0
0
Salmonella Typhimurium
ATCC 14028
0.1
0.3
0.5
0
0
16
0
0
0
0
0
22
0
0
0
0
0
0
Agrobacterium tumifaciens
0.1
0.3
0.5
21
20
21
21
19
18
0
16
0
0
0
0
0
0
0
the antibacterial and antioxidant activities, the compound
4b possesses the most active AChEI activity (Table 7).
solution. Generally, a decrease of absorbances was
observed as shown in Figure 4, which corresponds to the
complexation of Ni2+ by ligand 4c.
The interpretation of these spectrophotometric data by
means of the Letagrop calculation program made it possi-
ble to determine the stoichiometries of the species formed
and to calculate their stability constants.[37] These species
are of stoichiometry ML for the two series of ligands. All
these results are presented in Table 8.
4 | CATION BINDING PROPERTIES
4.1 | Complexation of heavy metals
cations by compounds 4a‐c
The stability constants of the ML complexes vary
between 2.92 and 3.58 logarithmic units. Small spectral
variations with Cu2+ prevented the formation of the com-
plex.[38] The stability profiles of the three ligands 4a‐c are
shown in Figure 5.
4.1.1 | Spectrophotometric study
The complexation of divalent metal cations (Cu2+, Ni2+
,
and Zn2+) by ligands 4a‐c was interpreted by spectral var-
iations throughout the titration of ligand by metal

6
MHIRI ET AL.
TABLE 6 Determination of the Minimum Inhibitory Concen-
trations (MICs) expressed in mg/ml of compounds 4
TABLE 8 Stability constants log βxy of complexes of Cu2+, Ni2+
and Zn2+ in MeOH at 25°C, I = 10−2 M, (0.01 ≤ σn−1 ≤ 0.16)
,
Microorganism Indicator
Compounds
MIC, mg/mL
M:L
Cu2+
Ni2+
Zn2+
Micrococcus luteus
LB 14110
Ampicillin
0.0195
0.02
0.025
0.0185
0.0196
0.197
4a
4b
4c
1:1
1:1
1:1
a
a
a
2.92
3.01
3.07
3.27
3.38
3.58
4a
4b
4c
4d
4e
Note. a: Absorbance changes too small to enable satisfactory fitting.
Figure 5 depicts the increase of complexes stabilities in
favor of Zn2+
Listeria monocytogenes
ATCC 19117
Ampicillin
0.039
0.040
0.042
0.032
0.041
0.042
.
4a
4b
4c
4d
4e
Zn2+ is the most complex in the series of cations con-
sidered, but its constants of stabilities are of the same
order of magnitude as those with Ni2+. However, the
absence of complexation affinity of Cu2+ suggests a prob-
able application for the separation of Ni2+ and Zn2+ in
Salmonella Typhimurium
ATCC 14028
Ampicillin
0.625
0.650
0.635
0.621
0.626
0.627
solution with Cu2+
.
4a
4b
4c
4d
4e
It is noted that chromene 4c is the best complexant for
either Ni2+ and Zn2+. In comparison with the results of
the biological activities, we can suggest this phenomenon
can be in agreement with its answer towards
S. Typhimurium at high concentration (0.5 mg/mL) and
with staphylococcus aureus in all studied concentrations
(0.1‐0.5 mg/mL).
TABLE 7 Acetylcholinesterase inhibitory activity (AChEI) (%) of
pyrano[3,2‐c]chromene derivatives 4
5 | CONCLUSION
Compound
(AChEI) (%)
4a
4b
4c
4d
4e
‐
In summary, we presented an efficient, mild, and rapid
approach for the synthesis of pyrano[3,2‐c]chromene
derivatives via three component reaction of aromatic alde-
hydes, ethyl cyanoacetoacetate, and 4‐hydroxycumarine
using cheap and readily available low toxic organocatalyst
48.5
52
47.5
49.1
FIGURE 4 UV absorption spectra on complexation of Ni2+ with 4c, in MeOH, (0 ≤ RM/L ≤ 2) at 25°C

MHIRI ET AL.
7
FIGURE 5 Stability constants log β11 (determined in MeOH) for Cu2+, Ni2+, and Zn2+ with 4a‐c [Color figure can be viewed at
wileyonlinelibrary.com]
ammonium acetate. The advantages of this procedure are
clean. The structure of the new compounds 4 was identi-
fied by their 1H‐NMR and 13C‐NMR data as well as by their
mass spectra and their elemental analysis. The complexa-
159.68 (‐C2OOC‐, ester); 158.07 (C4); 153.73 (C11); 152.24
(C9); 151.61 (C3′, 5′); 141.74 (C4′); 132.91 (C7); 127.13
(C1′); 124.59 (C6); 122.59 (C5); 119.22 (CN); 116.58 (C8);
113.13 (C10); 104.38 (C2′, 6′); 103.42 (C3); 57.77 (C12);
55.99 (Ca, c); 37.38 (C13); 20.18 (Cb). DART‐TOF‐MS: m/
z = 403, 297, 223, 157 et 79.
tion properties of the derivatives prepared towards Cu2+
,
Ni2+ and Zn2+ show that Zn2+ is the most complex in this
series of cations, and 4c is best complexant with either Ni2+
or Zn2+. The obtained products were tested for their anti-
bacterial and acetylcholinesterase activities. Most of the
synthesized compounds are more active against
Escherichia coli and Staphylococcus aureus than standard
references.
6.2 | 2‐Amino‐4‐(2,3‐dihydroxyphenyl)‐5‐
oxo‐4,5‐dihydropyrano [3,2‐c]
chromene‐3‐carbonitrile (4b)
Yield: 90%, mp = 258°C, C19H12N2O5, FT‐IR (KBr) ν,
cm−1: 3443 et 3380 (NH2), 3274 (C─H)arom, 2221 (CN),
1
1714 (C═O) cm−1. H NMR. (DMSO‐d6, 400 MHz) (δ :
6 | EXPERIMENTAL SECTION
ppm): 9.85 (s, 1H, OH); 9.56 (s, 1H, OH); 7.90 (m, 1H,
Ar─H); 7.77 (m, 1H, Ar─H); 7.57 (m, 1H, Ar─H); 7.43
(m, 1H, Ar─H); 7.30 (m, 1H, Ar─H); 7.18 (m, 2H, Ar─H);
7.00 (s, 2H, NH2); 4.66 (s, 1H, C─H). 13C NMR. (DMSO‐
d6, 100 MHz) (δ: ppm): 160.6 (C2OOC‐, ester); 158.2 (C2′);
155.1 (C3′); 152.4 (C4); 151.1 (C11); 146.8 (C9); 134.2 (C7);
129.8(C6); 129.4(C1′); 125.4 (C5); 124.6 (C6′); 124.6 (C5′);
123.9 (C8); 123.1 (C4′); 119.7 (CN); 117.8 (C10); 113.6
(C3); 103.8 (C12); 57.3 (C13).
General Procedures were done regarding our previous
work.[24]
The synthesis and characterization of compounds 4d
and 4e were done regarding our previous work.[24]
The synthesis of 3,4‐dihydropyrano[3,2‐c]chromenes 4
was done as our previous reports.[24]
6.1 | 2‐Amino‐4‐(4‐acetoxy‐3,5‐
dimethoxyphenyl)‐5‐oxo‐4,5‐dihydropyrano
[3,2‐c] chromene‐3‐carbonitrile (4a)
6.3 | 2‐Amino‐4‐(2‐hydroxy‐5‐
nitrophenyl)‐5‐oxo‐4,5‐dihydropyrano [3,2‐
c] chromene‐3‐carbonitrile (4c)
Yield: 92%, mp = 240°C, C23H18N2O7, FT‐IR (KBr) ν,
cm−1: 3326 (NH2), 3175 (C─H)arom, 2196 (CN), 1710
1
(C═O) . H NMR. (DMSO‐d6, 400 MHz) (δ : ppm):7.91
Yield: 85%, mp = 250°C, C19H11N3O6 FT‐IR (KBr) ν, cm−1
:
(d, 1H, H5, arom CH); 7.71 (m, 1H, H7, arom CH); 7.48
(m, 2H, H6, 8, arom CH); 7.41(s, 2H, H2′, 6′, arom CH);
6.60 (s, 2H, NH2); 4.49 (s, 1H, H13, arom CH); 3.70 (s,
6H, Ha,c, OCH3); 2.23 (s, 3H, Hb, OCOCH3). 13C NMR.
(DMSO‐d6, 100 MHz) (δ: ppm):168.11 (COOCH3, ester);
3435 and 3375 (NH2), 3275 (C─H)arom, 2215 (CN), 1709
1
(C═O) cm−1. H NMR. (DMSO‐d6, 400 MHz) (δ : ppm):
9.91 (s, 1H, OH); 8.04 (m, 1H, H5, arom CH); 782 (m, 2H,
H
4′,6′, arom CH); 7.48 (m, 1H, H7, arom CH); 6.79 (m,
2H, H6, 8, arom CH); 6.72 (d, 1H, H3′, arom CH); 6.20 (s,

8
MHIRI ET AL.
2H, NH2); 5.43 (s, 1H, H13, C─H). 13C NMR. (DMSO‐d6,
100 MHz) (δ: ppm): 160.7 (C2OOC‐, ester); 158.3 (C2′);
(−155.0 (C4); 152.6 (C11); 150.8 (C9); 147.2 (C5′); 134.3
(C7); 129.9 (C4′); 129.2 (C6′); 125.2 (C6); 125.2 (C1′); 124.8
(C5); 124.5 (C8); 122.8 (C3′); 119.6 (CN); 117.6 (C10); 113.8
(C3); 104.0 (C12); 57.1 (C13).
[17] A. Dömling, Curr. Opin. Chem. Biol. 2002, 6, 306.
[18] A. Dömling, I. Ugi, Angew. Chem. Int. Ed. 2000, 39, 3168.
[19] C. J. Li, T. H. Chan, Organic reactions in aqueous media, Wiley,
New York, NY, USA 1997.
[20] P. A. Grieco, Organic synthesis in water, Blackie Academic and
Professional, London 1998.
[21] K. Kandhasamy, V. Gnanasambandam, Curr. Organic Chem
2009, 13, 1820.
Stability Constant Measurements were determined
regarding our previous work.[25]
[22] H. Bienaymé, C. Hulme, G. Oddon, P. Schmitt, Chem. A Eur. J.
2000, 6, 3321.
ACKNOWLEDGMENTS
[23] T. J. J. Müller (Ed), Science of synthesis, multicomponent reac-
tions I, Georg Thieme Verlag KG, Stuttgart, New York 2014.
This work was supported by the Research Supporting
Project (RSP‐2019/75), King Saud University, Riyadh
Saudi Arabia.
[24] L. Boubakri, H. Bilel, L. Baklouti, L. Mansour, N. Hamdi,
Mediterr. J. Chem. 2016, 5, 387.
[25] R. Medyouni, W. Elgabsi, O. Naouali, A. Romerosa, A. S. Al‐
Ayed, L. Baklouti, N. Hamdi, Spectrochim. Acta A Mol. Biomol.
Spectrosc. 2016, 167, 165.
ORCID
Naceur Hamdi https://orcid.org/0000-0003-0110-9588
[26] G. Melagraki, H. Chatzidakis, A. Afantitis, O. Igglessi‐
Markopoulou, A. Detsi, M. Koufaki, C. Kontogiorgis, D. J.
Hadjipavlou‐Litina, J. Eur. J. Med. Chem 2009, 44, 3020.
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