Development of new multicomponent reactions in eco-friendly media-greener reaction and expeditious synthesis of novel bioactive benzylpyranocoumarins

Article abstract of DOI:10.1155/2019/8693614

Multicomponent cyclocondensation of hydrazine derivatives, ethyl acetoacetate, aromatic aldehydes, and 4-hydroxycoumarin has been reported. The optimization details of the developed novel protocol are recorded. The novel procedure features short reaction

Full text of DOI:10.1155/2019/8693614

Hindawi
Journal of Chemistry
Volume 2019, Article ID 8693614, 10 pages
https://doi.org/10.1155/2019/8693614
Research Article
Development of New Multicomponent Reactions in Eco-Friendly
Media-Greener Reaction and Expeditious Synthesis of Novel
Bioactive Benzylpyranocoumarins
Hamida Jelali,1 A. Chakchouk-Mtibaa,2 Lasaad Baklouti,3 Hallouma Bilel,1 Yaser Bathich,3
1,3
L. Mellouli,2 and Naceur Hamdi
1Research Laboratory of Environmental Sciences and Technologies (LR16ES09),
Higher Institute of Environmental Sciences and Technology, University of Carthage, Hammam-Lif, Tunisia
2Laboratory of Microorganisms and Biomolecules, Center of Biotechnology of Sfax, Road of Sidi Mansour, Km 6 B.P. 1117,
3018 Sfax, Tunisia
3Chemistry Department, College of Science and Arts, Qassim University, Al-Rass, Saudi Arabia
Correspondence should be addressed to Naceur Hamdi; naceur.hamdi@isste.rnu.tn
Received 21 February 2019; Revised 2 April 2019; Accepted 11 July 2019; Published 21 August 2019
Academic Editor: Alessandro Volonterio
Copyright © 2019 Hamida Jelali et al. &is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Multicomponent cyclocondensation of hydrazine derivatives, ethyl acetoacetate, aromatic aldehydes, and 4-hydroxycoumarin has
been reported. &e optimization details of the developed novel protocol are recorded. &e novel procedure features short reaction
time, moderate yields, and simple workup. In addition, BMIM[triflate] was chosen as a green solvent. &e structures of the
obtained benzylpyrazolyl coumarins were determined and confirmed by 1H NMR, 13C NMR, IR, and elemental analysis. &e MIC
values of benzylpyrazolyl coumarin derivatives were determined by the microbroth dilution method using 96-well plates.
However, the derivatives 5a, 5b, 5d, and 5g possess the strongest activities. Compound 5b was the most active derivative against
Candida albicans. Moreover, the antioxidant activity determination of these coumarins derivatives 5(a–g)–6(a–g) were studied
with the DPPH and compared with gallic acid (GA)and butylated hydroxytoluene (BHT). Molecular modelling studies using DFT
(density functional theory) calculations showed that there two tautomers A and B in which A is more stable than B. &e
benzylpyrazolyl coumarin derivatives 5e and 6f exhibited the most cytotoxic effect on the promising cytotoxic activity with IC50
values 4.45 μg/mL against MDA-MB-231 and 4.85 μg/mL against MCF7, respectively.
solvents. Compared with traditional catalysts, these ionic liq-
uids have shown special advantages and potential due to their
ideal catalytic performance and the unusual characteristics.
Here, we report the synthesis of pyrazolone-linked
coumarin derivatives which were obtained via the four-
component domino reaction of 4-hydroxycoumarin, hy-
drazine derivatives, ethyl acetoacetate, and arylaldehydes;
then, the structures of these new coumarin derivatives were
characterized by spectroscopic methods (1H and 13C NMR,
FT-IR, and elemental analysis). In addition, the benzyl-
pyrazolyl coumarin derivatives were tested for their anti-
microbial and antioxidant activities, which have not been
studied in the past.
1. Introduction
Coumarin scaffolds are commonly bioactive compounds
[1–23]. Pyrazolone derivatives also exhibit a broad spectrum
of biological activities [24–26] and are also important
structural moieties in many drug substances of medicinal
applications [22, 27, 28], such as phenazone, propyphena-
zone, ampyrone, and metamizole sodium (Figure 1).
Multicomponent reactions convert three or more
starting materials in one pot to a highly functionalized
product displaying maximum molecular diversity [29–35].
At present, ionic liquids (ILs) are playing a more and more
important role in organic synthesis as green catalysts and

2
Journal of Chemistry
–
+
SO3 Na
NH2
N
N
N
N
N
O
O
O
O
N
N
N
N
D
E
F
G
Figure 1: Structures of (D) phenazone, (E) propyphenazone, (F) ampyrone, and (G) metamizole.
singlet at about 4.17 ppm in accordance with the literature
data for other 4-hydroxycoumarin derivatives [36, 37]. 13
NMR showed the C2′ signal at δ � 168.06 ppm, the C4 signal
had a chemical shift of δ � 164.90 ppm, while the C2, C3, Ca,
Cc, Cb,d, C1, and C5 signals were assigned at δ � 162.87,
103.59, 13.66, 36.34, 40.01, 128.53, and 152.9 ppm,
respectively.
2. Results and Discussion
C
&e cyclocondensation of hydrazine derivatives, ethyl ace-
toacetate, and arylaldehydes with 4-hydroxycoumarins to
generate benzylpyrazolyl coumarin derivatives was in-
vestigated under a variety of conditions (solvents, reaction
time, temperature, and catalysts) (Scheme 1).
Initially, for examination of the catalytic activity, dif-
ferent catalysts such as TFA, HCOOH, Cu(OAc)2, ZnO, and
glacial acetic acid were selected. &en, a model study was
carried out by the condensation reaction of hydrazine
derivatives, ethyl acetoacetate, aromatic aldehydes, and 4-
hydroxycoumarin under conventional conditions at dif-
ferent temperatures in the presence of each catalyst, sep-
arately. &e corresponding results are summarized in
Table 1.
Several catalysts were tested to check their effects such as
TFA, HCOOH, Cu(OAc)2, ZnO, and glacial acetic acid
(Table 1, entries 10–15). &e obtained results indicated that
glacial AcOH is the best catalyst for this reaction. &en,
several amounts of this catalyst were evaluated: It was found
that 5 mol% of the catalyst gave 65% of yield. When we
increased the amounts of the catalyst to 10 mol%, 15 mol%,
and 20 mol%, the yields were also found to be increased up to
95%, 94%, and 85%, respectively. After 20 mol%, there is no
significant improvement of the yield of the reaction; con-
sequently, 10 mol% of the catalyst was chosen as the max-
imum quantity of the catalyst for the reaction. &e reaction
was also performed at different reaction times, and the
obtained results showed that the best reaction time was
30 min (Table 1, entries 1 and 15–17). Based on all of these
experiments, the optimum reaction conditions were iden-
tified as [BMIM][CF3SO3] for 30 min using 10 mmol% of
glacial acetic acid. &e reaction was then carried out with
different series of substituted aromatic aldehydes in order to
check the limitations of this methodology. &e results are
summarized in Table 2.
&e compound 5 thus obtained can exist in the form of
two tautomers A and B. &eoretical calculations with the
Gaussian program 09 carried out with the DFT (density
functional theory) level with the base 6-31G + (d) and the
functional B3LYP confirm the stability of the structure A
with respect to that of B (ΔE � 2 kcal). Optimized geometries
for compounds A and B are shown in Figure 2.
Encouraged by the obtained results, we tried to ex-
trapolate our method to the condensation with hydrazine.
&e reaction seemed to be tolerant with different aromatic
aldehydes. Overall, yields in the range of 75%–95% were
obtained (Table 3).
&e structure of the benzylpyrazolyl coumarin 6 de-
rivatives has been confirmed by their spectroscopic data, and
their melting points are compared with literature reports.
−1
&e presence of signal at 3425 cm in IR spectra was
assigned to NH.
3. Antimicrobial Activity
&e in vitro antimicrobial activity of the novel benzylpyr-
azolyl coumarin derivatives 5(a–g)–6(a–g) were evaluated
for in vitro antimicrobial activity by the well diffusion
method. All products were screened for activity against
Gram-positive bacteria (Micrococcus luteus, Listeria mono-
cytogenes, and Staphylococcus aureus), Gram-negative bac-
teria (Pseudomonas aeruginosa and Escherichia coli), and
fungi (Candida albicans). &e minimum inhibitory con-
centrations (MICs) were determined and are given in
Table 4.
As can be seen, most of the benzylpyrazolyl coumarin
derivatives exhibit considerable activity against the tested
microorganisms. &e results obtained by these tests showed
that our different molecules have antimicrobial activity. In
fact, regarding the activity against Gram-negative bacteria
(Pseudomonas aeruginosa), 5a showed excellent activity and
compounds 5b–5g showed good activity. On the contrary,
compound 5b was the most active against Candida albicans.
&e aromatic aldehydes carrying both electron-with-
drawing and electron-donating functional groups (Table 2,
entries 2–7) underwent successful condensation with ethyl
acetoacetate and hydrazines derivatives. &e structures of
compound 5 were confirmed from their spectroscopic data
including 1H NMR, 13C NMR spectra, and elemental analysis.
1
In the H NMR of compound 5c, two characteristic
singlets at 3.34 and 3.55 ppm were assigned to the methyl
protons (a) and (b, d), whereas the proton Hc appears as a

Journal of Chemistry
3
R′
R = H, Ph
RNHNH2
2a, 2b
OH
O
O
OH
O
+
O
Solvent
+
O
O
OEt
N
N
R
Catalyst
Temperature
O
1
4
OHC
H3C
H
R′
6 (R=H)
5 (R=Ph)
5 (a-g)–6 (a-g)
3a–3g
2a, R/= H, and 2b, R/= Ph
3a–3g where a = H, b = p-CH3, c = p-N(CH3)2, d = p-NO2, e = m-Br, f = m-OCH3, g = m-OH
Scheme 1: Synthesis of benzylpyrazolyl coumarin derivatives 5(a–g)–6(a–g).
Table 1: Optimization of the conditions’ reaction using diŠerent solvents.
OH
O
PhNHNH2
OH
+
O
2
+
+
O
Solvent
Catalyst
O
O
OEt
N
NH
Ph
Ph-CHO
O
O
1
3
4
H3C
5a
Entry
Catalysts (mmol%)
Solvent
Time (h)
Temperature (°C)
Yielda,b,c (%)
1
No
No
([BMIM][CF3SO3])
DMC
24
24
210
90
—
—
2
3
No
H2O
24
100
78
—
4
No
EtOH
24
—
5
No
CH3CN
24
82
—
6
No
THF
24
66
—
7
No
CH2Cl2
24
40
—
8
No
Toluene
24
110
119
210
210
210
210
210
210
210
210
210
210
210
210
210
—
9
No
Glacial AcOH
([BMIM][CF3SO3])
([BMIM][CF3SO3])
([BMIM][CF3SO3])
([BMIM][CF3SO3])
([BMIM][CF3SO3])
([BMIM][CF3SO3])
([BMIM][CF3SO3])
([BMIM][CF3SO3])
([BMIM][CF3SO3])
([BMIM][CF3SO3])
([BMIM][CF3SO3])
([BMIM][CF3SO3])
([BMIM][CF3SO3])
24
—
10
11
12
13
14
15
16
17
18
19
20
21
22
TFA (10)
HCOOH (10)
Cu(OAc)2 (10)
ZnO (10)
Gl. AcOH (5)
Gl. AcOH (10)
Gl. AcOH (15)
Gl. AcOH (20)
Gl. AcOH (10)
Gl. AcOH (10)
Gl. AcOH (10)
Gl. AcOH (10)
Gl. AcOH (10)
24
40
45
—
24
24
24
Trace
65
95
94
85
95
85
76
72
75
24
24
24
24
30 min
40 min
1
1 : 5 h
2
aAll reactions were carried with hydrazine (0.005 mol), ethyl acetoacetate (0.005 mol), benzaldehyde (0.005 mol), and 4-hydroxycoumarin (0.005 mol). bYield
of the isolated product. e reaction failed to provide a product. [BMIM][CF3SO3], 1-butyl-3-methylimidazolium tri¡uoromethanesulfonate.
c
In addition, we evaluated the antimicrobial activity of
four synthetic products (5a, 5b, 5d, and 5g) possessing
the strongest activities against two Gram-positive bacteria
(S. aureus) and Gram-negative bacteria (P. aeruginosa)
against a fungus (Candida albicans) by the determination
of the MIC in a liquid medium.
inhibitory concentration (MIC) values of benzylpyrazolyl
coumarin derivatives were determined against Staphylo-
coccus aureus ATCC 6538, Pseudomonas aeruginosa ATCC
49189, and Candida albicans. e obtained results are given
in Table 5.
We have noticed that the compounds 6a, 6b, and 6g are
very active by comparing with ampicillin used as a control
antibiotic against the strain Staphylococcus aureus. ese
We determined the MIC values of the products tested
against two bacteria and a fungus. en, the minimal

4
Journal of Chemistry
Table 2: Chemical yields and physical properties of coumarins derivatives 5a–5g.
R
OH
O
OH
O
O
O
PhNHNH2
+
O
BMIM [trifate]
+
+
N Ph
NH
Glacial acetic acid
OEt
O
O
OHC
H3C
R
5
Melting
Entry
R
Compoundb
Yielda (%)
point (°C)
1
2
3
4
5
6
7
H
5a
5b
5c
5d
5e
5f
60
70
75
80
75
85
90
204
221
176
138
242
138
174
p-CH3
p-N(CH3)2
p-NO2
m-Br
m-OCH3
m-OH
5g
aAll reactions were carried with hydrazine (0.005 mol), ethyl acetoacetate (0.005 mol), benzaldehyde (0.005 mol), and 4-hydroxycoumarin (0.005 mol). bYield
of the isolated product. [BMIM][CF3SO3], 1-butyl-3-methylimidazolium trifluoromethanesulfonate.
(a)
(b)
Figure 2: Optimized 3D geometrical structures for compounds (a) A and (b) B.
same results showed that the compounds 6a and 5a are very
the product 5e has a radical activity lower than gallic acid
and BHT (butylated hydroxytoluene). Of the same way, the
compound 5b for a concentration equal to 0.01575 mg/ml
has a lower radical activity than gallic acid and BHT (bu-
tylated hydroxytoluene). At a concentration of 1 mg/ml,
these products revealed a very interesting activity of DPPH
in comparison with the activity of the synthetic antioxidants
used.
active against the fungus Candida albicans by comparing
with a standard antifungal “fluconazole.”
4. Antioxidant Activities
&e scavenging activity of the synthesized benzylpyrazolyl
coumarin derivatives 5 with DPPH (1,1-diphenyl-2-pic-
rylhydrazyl) was investigated (Figure 3).
&e analysis of the results showed that the profiles of the
antiradical activity obtained reveal that the synthetic
products tested compound 5 have a very important anti-
radical activity. For a used concentration (0.0625 mg/ml),
5. Conclusion
In this study, the synthesis of pyrazolone-linked coumarin
derivatives
through
a
four-component,
one-pot

Journal of Chemistry
5
Table 3: Chemical yields and physical properties of coumarins derivatives 6a–6g.
R
OH
O
2
OH
[BMIM][CF3SO3]
Glacial acetic acid
OEt
+
NHNH2
+
CHO+
NH
NH
O
O
H3C
O
O
O
4
O
R
1
3
6
Entry
R
Compound
Yield (%)
Melting point (°C)
1
2
3
4
5
6
7
H
6a
6b
6c
6d
6e
6f
95
75
80
85
87
90
95
120
142
160
210
160
236
240
p-CH3
p-N(CH3)2
p-NO2
m-Br
m-OCH3
m-OH
6g
Table 4: Antibacterial activity of the prepared compounds 5(a–g)–6(a–g).
Microorganisms
Compounds
Micrococcus luteus
Listeria monocytogenes
Staphylococcus aureus
Pseudomonas aeruginosa
Candida
albicans
E. coli
LB 14110
ATCC 19117
ATCC 6538
ATCC 49189
5a
5b
5c
5d
5e
5f
—
—
—
12 0.2
—
—
24 0.1
18 0.4
16 0.1
15 0.1
20 0.6
20 0.3
16 0.4
30 0.1
28 0.2
24 0.12
24 0.3
22 0.5
24 0.4
22 0.3
—
—
—
—
—
—
—
—
—
—
—
—
25 0.1
26 0.5
20 0.2
18 0.3
20 0.6
22 0.2
18 0.2
28 0.4
28 0.5
20 0.6
26 0.3
12 0.3
16 0.5
20 0.1
12 0.5
12 0.5
14 0.2
14 0.5
15 0.4
15 0.2
14 0.2
15 0.2
—
—
—
—
—
10 0.2
10 0.2
—
—
—
10 0.2
—
—
—
16 0.5
—
5g
6a
6b
6c
6d
6e
6f
—
—
—
—
—
—
—
14 0.3
20 0.2
15 0.2 28 0.1
24 0.3 28 0.2
6g
18 0.3
Table 5: Determination of the minimum inhibitory concentrations (MICs) expressed in mg/ml.
Compounds
Microorganisms
6a
6b
6g
5a
Ampicillin
Fluconazole
Staphylococcus aureus ATCC 6538
Pseudomonas aeruginosa ATCC 49189
Candida albicans
0.3125
0.1562
0.00975
0.3125
0.3125
0.039
0.1562
0.625
0.0781
0.625
0.625
0.00975
0.04
0.04
—
—
—
0.00125
condensation of ethyl acetoacetate, aromatic aldehydes,
hydrazines, and 4-hydroxycoumarin using ([BMIM]
[CF3SO3]) as a green solvent was described. In addition,
their structures were confirmed by elemental and spectral
analyses. &e antibacterial and antioxidant property of the
synthesized compounds were assessed against Gram-posi-
tive and Gram-negative bacteria. Some of the compounds
were very effective as antimicrobial agents. &e results of the
research were promising, and some of the synthesized
derivatives represent good candidates for MIC
determination during future studies. &is study further
presents benzylpyrazolyl coumarin derivatives as a new
class of antioxidant agents, and it may serve as a model
compound for design and development of therapeutic-
based anticancer inhibitors.
6. Experimental
6.1.GeneralInformation. All manipulations were performed
using Standard Schlenk techniques under the Argon

6
Journal of Chemistry
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
Concentration (mg/mL)
Concentration (mg/mL)
5a
5b
Gallic acid
BHT
Gallic acid
BHT
(a)
(b)
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
Concentration (mg/mL)
Concentration (mg/mL)
5e
5d
Gallic acid
BHT
Gallic acid
BHT
(c)
(d)
120
100
80
60
40
20
0
100
90
80
70
60
50
40
30
20
10
0
Concentration (mg/mL)
Concentration (mg/mL)
5g
5f
Gallic acid
BHT
Gallic acid
BHT
(e)
(f)
Figure 3: Scavenging activity of benzylpyrazolyl coumarin derivatives 5 on DPPH radicals.
atmosphere. Chemicals were purchased from Sigma-Aldrich
and were used without further purification. All solvents were
purified and dried by the MBRAUN SPS 800 solvent pu-
analyses were performed with the GC-2010 Plus gas chro-
matography (SHIMADZU). &e NMR studies were carried
out in high-quality 5 mm NMR tubes. Signals are quoted in
parts per million as δ downfield from tetramethylsilane
(δ � 0.00) as an internal standard. NMR multiplicities are
abbreviated as follows: s � singlet, d � doublet, t � triplet, and
m � multiplet signals. IR spectra were recorded on a 398
spectrophotometer.
1
rification system. H NMR and 13C NMR spectra were
recorded at 400 MHz and 100 MHz, respectively. Chemical
shifts, δ, are reported in ppm relative to the internal standard
1
TMS for both H and 13C NMR. &e products were char-
acterized by GC (gas chromatography). Quantitative GC

Journal of Chemistry
7
Elemental microanalysis was performed on an Ele-
mentar Vario El III Carlo Erba 1108 elemental analyzer, and
the values found were within 0.4% of the theoretical values.
Melting points were determined with the Kofler bench. &e
biological analysis was done regarding our previous work
[36, 37].
6.2.3. 1,2-Dihydro-4-((4-hydroxy-2-oxo-2H-chromen-3-yl)-(p-
N,N-dimethyl phenyl)methyl)-5-methyl-2-phenylpyrazol-3-one
−1
(5c). Yield: 75 g (75%); m.p. 176°C–178°C; IR (cm ) 3585
(O-H), 3425 (NH), 1542 (C�C), 1715 (CO lactone), 1745
(CO amide); 1H NMR (DMSO-d6, 400 MHz): δ 3.34 (s, 3H,
Ha), 3.55 (s, 6H, Hb,d), 4.17 (s, 1H, Hc), 7.32 (s, 1H, H3″), 7.88
(d, 1H, H5″), 8.20 (t, 2H, H2″,6″), 8.33 (m, 2H, H6,8), 8.46 (t,
1H, H9′), 8.56 (t, 2H, H8′,10′), 8.62 (s, 2H, H7′,11′), 8.86 (dd,
1H, H7), 9.00 (dd, 1H, H5), 9.68 (s, 1H, H4); 13C NMR
(DMSO-d6, 100 MHz): δ 36.34 (Ca), 39.59 (Cb,), 103.59 (C3),
111.80 (C1′), 116.0 (C2″), 118.58 (C8), 120.2 (C7′), 121.68
(C9′), 123.42 (C5), 124.56 (C6), 128.53 (C3″), 129.15 (C5″),
131.53 (C7), 137.89 (C8′), 139.36 (C1″), 148.61 (C6′), 152.0
(C4″), 152.99 (C5′), 154.28 (C10), 162.87 (C2), 164.90 (C4),
168.06 (C2′); Anal. Calc. for C28H25N3O4: C, 71.93%; H,
5.39%; N, 8.9%; Found: C, 71.7%; H, 5.4%; N, 8.7%.
6.2. General Procedure for the Synthesis of Coumarin De-
rivatives 5(a–g)–6(a–g). A mixture of hydrazine (5 mmol,
0.157 mL) or phenylhydrazine 1 (5 mmol, 0.491 mL), ethyl
acetoacetate 2 (5 mmol, 0.6 mL), aromatic aldehyde 3
(benzaldehyde (5 mmol, 0.510 mL), para tolyl benzaldehyde
(5 mmol,
0.589 mL),
4-(dimethylamino)benzaldehyde
(5 mmol, 0.745 g), 4-nitrobenzaldehyde (5 mmol, 0.755 g), 3-
bromobenzaldehyde (5 mmol, 0.582 mL), m-anisaldehyde
(5 mmol, 0.609 mL), 3-hydroxybenzaldehyde (5 mmol,
0.610 g)), 4-hydroxycoumarin 4 (5 mmol, 0.810 g), and
glacial acetic acid (10 mmol%, 0.02 mL) in 5 ml of ionic
liquid [BMIM][CF3SO3] was stirred at 210°C. After com-
pletion of the reaction (indicated by TLC), the reaction
mixture was then cooled to the room temperature to give a
precipitate, and the free-flowing solid was filtered and
washed with water. &e precipitated crude product was
purified by recrystallization from hot ethanol. &e isolated
6.2.4. 1,2-Dihydro-4-((4-hydroxy-2-oxo-2H-chromen-3-yl)-
(4-nitrophenyl)methyl)-5-methyl-2-phenylpyrazol-3-one (5d).
−1
Yield: 1.87 g (80%); m.p. 138°C–140°C. IR (cm ) 3585 (O-
H), 3425 (NH), 1540 (C�C), 1715 (CO lactone), 1742 (CO
amide); 1H NMR (DMSO-d6, 400 MHz): δ 1.06 (s, 3H, Ha),
3.44 (s, 1H, H4′), 6.35 (s, 1H, Hc), 6.84 (s, 1H, H9′), 7.16 (d,
2H, H6,8), 7.27 (m, 1H, H8′), 7.37 (m, 1H, H10′), 7.53 (m, 1H,
H2″), 7.69 (d, 1H, H6″), 7.82 (d, 1H, H7′), 7.89 (d, 1H, H11′),
7.94 (s, 1H, H7), 8.05 (d, 1H, H5), 8.13 (d, 1H, H3″), 8.22 (m,
1H, H5″), 10.89 (s, 1H, H4); 13C NMR δ (DMSO-d6,
100 MHz): δ 34.87 (Ca), 39.82 (Cc), 103.60 (C3), 105.00 (C1′),
106.78 (C8), 113.03 (C7′), 116.22 (C11′), 120.37 (C9′), 121.46
(C5), 124.48 (C7), 126.43 (C3″), 129.67 (C6), 134.05 (C2″),
143.07 (C6″), 144.90 (C7), 146.44 (C8′), 147.30 (C10′), 148.46
(C6′), 151.05 (C4″), 152.55 (C5′), 152.95 (C10), 162.24 (C2),
164.89 (C4), 167.42 (C2′); Anal. Calc. for C26H19N3O6: C,
66.5%; H, 4.0%, N, 8.9%; Found C, 66.4%; H, 4.2%; N, 8.8%.
1
compounds were well characterized by IR, H NMR, 13C
NMR, and elemental analysis.
6.2.1.
1,2-Dihydro-4-((4-hydroxy-2-oxo-2H-chromen-3-
yl)(phenyl)methyl)-5-methyl-l-2-phenylpyrazol-3-one (5a).
Yield: 1.72 g (60%); m.p. 204°C–206°C; 1H NMR (DMSO-d6,
400 MHz): δ 2.42 (s, 3H, Ha), 5.74 (s, 1H, H4′), 6.38 (s, 1H,
Hc), 7.21 (s, 1H, H9′), 7.31 (m, 2H, H2”,6″), 7.35 (m, 3H,
H
3″,4″,5″), 7.43 (d, 2H, H6,8), 7.51 (m, 2H, H8′,10′), 7.62 (m,
2H, H7′,11′), 7.87 (d, 1H, H7), 7.89 (d, 1H, H5); 13C NMR
(DMSO-d6, 100 MHz,): δ 34.14 (Ca), 39.60 (Cc), 104.46 (C3),
105.95 (C1′), 107.18 (C8), 116.36 (C7′), 118.50 (C11′), 121.29
(C9′), 124.31 (C5), 126.48 (C6), 127.26 (C4″), 128.68 (C2″),
129.73 (C3″), 132.42 (C7), 135.59 (C8′), 139.93 (C10′), 147.44
(C6′), 152.45 (C1″), 162.69 (C10), 163.98 (C2), 164.74 (C4),
165.31 (C2′); Anal. Calc. C26H20N2O4: C, 73.573%; H,
4.749%; N, 6.600%; Found: C, 73.9; H, 4.5; N, 6.8%.
6.2.5. 4-((3-Bromo-phenyl)-(4-hydroxy-2-oxo-2H-chromen-3-
yl)methyl)-5-methyl-1,2-dihydro-5-methyl-2-phenylpyrazol-3-
1
one (5e). Yield: 88 g (75%); m.p. 242°C–244°C. H NMR
(DMSO-d6, 400 MHz): δ 240 (s, 3H, Ha), 3.43 (s, 1H, H4′),
5.71 (s, 1H, Hc), 7.22–7.80 (m, 13H, Harom); 13C NMR δ
(DMSO-d6, 100 MHz): δ 34.03 (Ca), 39.72 (Cc), 105.10 (C3),
106.75 (C1′), 116.41 (C8), 121.38 (C7′), 122.14 (C9′), 124.35
(C6), 126.62 (C6″), 127.24 (C7), 129.75 (C8′), 130.86 (C5″),
132.52 (C2″), 135.59 (C6′), 143.16 (C1″), 147.38 (C5′), 152.50
(C10), 162.12 (C2), 164.61 (C4), 166.12 (C2′); Anal. Calc. for
C26H19BrN2O4: C, 62.04%; H, 3.805%; N, 5.565%; Found: C,
62.1; H, 3.9; N, 5.6%.
6.2.2.
1,2-Dihydro-4-((4-hydroxy-2-oxo-2H-chromen-3-
yl)-(p-tolyl)methyl)-5-methyl-2-phenylpyrazol-3-one (5b).
−1
Yield: 1.53 g (70%); m.p. 221°C–223°C; IR (cm ) 3585 (O-
H), 3425 (NH), 1542 (C�C), 1715 (CO lactone), 1742 (CO
ketone); δ 2.24 (s, 3H, Ha), 2.40 (s, 3H, Hb), 3.17 (s, 1H, H4′),
5.67 (s, 1H, Hc), 7.01 (s, 2H, H3″,5″), 7.06 (s, 2H, H2″,6″), 7.30
(m, 3H, H6,8′,10′), 7.52 (t, 1H, H8), 7.58 (m, 2H, H7′,9′), 7.68
(d, 1H, H11′), 7.79 (dd, 1H, H7), 7.86 (dd, 1H, H5); 13C NMR
(DMSO-d6, 100 MHz): δ 20.91 (Cb), 33.81 (Ca), 39.72 (Cc),
104.73 (C3), 106.16 (C1′), 107.3 (C8), 116.3 (C11′), 121.19
(C9′), 124.25 (C5), 127.16 (C6), 129.24 (C7), 129.70 (C3″),
6.2.6. 1,2-Dihydro-4-((4-hydroxy-2-oxo-2H-chromen-3-yl)(3-
methoxyphenyl)methyl)-5-methyl-2-phenylpyrazol-3-one (5f).
Yield: 1.92 g (85%); m.p. 138°C–140°C: 1H NMR (DMSO-d6,
400 MHz): δ 2.39 (s, 3H, Ha), 3.66 (s, 3H, Hb), 5.68 (s, 1H,
Hc), 6.71 (s, 1H, H4′), 6.78 (d, 2H, H2″,6″), 7.26 (m, 5H,
132.29 (C2″), 135.39 (C8′), 136.80 (C4″), 147.39 (C1″), 152.42
(C6′), 162.74 (C5′), 163.84 (C10), 164.70 (C2), 165.33 (C4),
165.72 (C2′); Anal. Calc. for C27H22N2O4: C, 73.9%; H, 5.0%;
N, 6.3%; Found: C, 73.5; H, 6.1; N, 6.2%.
H6,8,9′,5″,4″), 7.51 (m, 2H, H8′,10′), 7.59 (t, 1H, H7), 7.71 (d,
2H, H7′,11′), 7.83 (t, 1H, H5); 13C NMR δ (DMSO-d6,
100 MHz): δ 33.66 (Ca), 39.86 (Cc), 54.83 (Cb), 105.21 (C3),
106.43 (C1′), 110.42 (C4″), 113.48 (C2″), 115.85 (C8), 118.19

8
Journal of Chemistry
(C6″), 119.23 (C7′), 120.75 (C9′), 123.76 (C5), 126.55 (C6),
129.71 (C7), 131.86 (C8′), 135.35 (C5″), 141.42 (C6′), 146.94
(d, 1H, H5), 8.56 (s, 1H, H3′); 13C NMR (DMSO-d6, 100 MHz):
δ 26.91 (Ca), 36.38 (Cb), 45.69 (Cc), 103.56 (C3), 112.37 (C1″),
116.02 (C2″), 120.17 (C8), 123.45 (C5), 124.57 (C7), 128.59
(C1″), 131.57 (C4″), 152.99 (C10), 159.56 (C4′), 164.91 (C2),
168.07 (C4); Anal. Calc. for C22H21N3O4: C, 67.5%; H, 5.4%; N,
10.7%; Found: C, 67.5%, H, 5.4%; N, 10.7%.
(C1″), 151.98 (C10,), 159.20 (C3″), 161.76 (C2), 163.83 (C4),
−1
164.25 (C2′); IR (cm ) 3588 (O-H), 3425 (NH), 1542 (C�C),
1715 (CO lactone), 1742 (CO amide); Anal. Calc. for
C27H22N2O5: C, 71.3%; H, 4.8%; N, 6.1%; Found: C, 71.5; H,
5.1; N, 5.8%.
6.2.11. 1,2-Dihydro-4-((4-hydroxy-2-oxo-2H-chromen-3-yl)(4-
6.2.7. 1,2-Dihydro-4-((4-hydroxy-2-oxo-2H-chromen-3-yl)-(3-
nitrophenyl)methyl)-5-methyl-pyrazol-3-one (6d). Yield: 85%;
−1
hydroxyphenyl)methyl)-5-methyl-2-phenylpyrazol-3-one (5g).
m.p. 210°C–212°C; IR (cm ) 3585 (O-H), 3425 (NH), 1545
−1
1
Yield: 1.98 g (90%); m.p. 174°C–176°C; IR (cm ) 3585 (O-
(C�C), 1712 (CO lactone), 1745 (CO amide); H NMR
H), 3425 (NH), 1535 (C�C), 1710 (CO lactone), 1745 (CO
(DMSO-d6, 400 MHz): δ 2.50 (s, 3H, Ha), 3.43 (s, 1H, H4′),
amide); 1H NMR (DMSO-d6, 400 MHz): δ 22.41 (s, 3H, Ha),
3.44 (s, 1H, H4′), 5.66 (s, 1H, Hc); 6.57 (s, 1H, H9′), 6.76 (m,
2H, H4″,5″), 6.97 (d, 2H, H2″,6″), 7.30 (m, 2H, H6,8), 7.37 (m,
6.36 (s, 1H, Hc), 7.29 (m, 4H, H6,8,2″,6″), 7.39 (d, 1H, H7), 7.54
(t, 1H, H5), 7.82 (d, 2H, H3″,5″), 8.06 (d, 1H, HH3′); 13C NMR
(DMSO-d6, 100 MHz): δ 37.20 (Ca), 40.00 (Cc), 103.46 (C3),
2H, H8′,10′), 7.68 (d, 2H, H7′,11′), 7.79 (d, 1H, H7), 7.84 (t, 1H,
H5);13C NMR (DMSO-d6, 100 MHz): δ 33.61 (Ca), 39.56
(Cc), 33.61 (C3), 105.65 (C1′), 112.9 (C4″), 114.7 (C2″), 116.4
(C8), 120.3 (C6″), 121.1 (C7′), 122.8 (C9′), 123.3 (C5), 125.4
(C6), 130.1 (C5″), 137.3 (C6′), 143.7 (C1″), 152.3 (C5′), 157.35
(C3″), 162.7 (C2), 163.57 (C4), 164.34 (C2′); Anal. Calc. for
C26H20N2O5: C, 70.9%; H, 4.5%; N, 6.3%; Found: C, 71.8%,
H, 4.6%; N, 6.4%.
116.17 (C1′), 119.64 (C8), 123.70 (C5), 124.58 (C2″), 128.41
(C6), 131.91 (C4″), 145.86 (C1″), 151.35 (C10), 152.96 (C2′),
164.49 (C1′), 167.68 (C4); Anal. Calc. for C20H15N3O6: C,
61.0%; H, 3.8%; N, 10.6%; Found: C, 61.0%, H, 3.8%; N,
10.6%.
6.2.12. 4-((3-Bromo-phenyl)-(4-hydroxy-2-oxo-2H-chromen-
3-yl)methyl)-5-methyl-1,2-dihydro-5-methyl-pyrazol-3-one
−1
(6e). Yield: 87%; m.p. 160°C–162°C; IR (cm ) 3592 (O-H),
6.2.8. 1,2-Dihydro-4-((4-hydroxy-2-oxo-2H-chromen-3-yl)phe-
3425 (NH), 1543 (C�C), 1715 (CO lactone), 1745 (CO
amide); 1H NMR (DMSO-d6, 400 MHz): δ 2.53 (s, 3H, Ha),
5.52 (s, 1H, H3′), 6.42 (s, 1H, Hc), 7.50(m, 4H, H6,8,5″,6″),
7.79(m, 3H, H7,2″,4″), 7.92(d, 1H, H5), 8.00 (d, 1H, H3′);
13C NMR (DMSO-d6, 100 MHz): δ 22.30 (Ca), 40.01 (Cc),
nyl)methyl)-5-methyl-pyrazol-3-one (6a). Yield: 95%; m.p.
−1
120°C–122°C; IR (cm ) 3589 (O-H), 3423 (NH), 1539
1
(C�C), 1705 (CO lactone), 1741 (CO amide); H NMR
(DMSO-d6, 400 MHz): δ 2.50 (s, 3H, Ha), 6.32 (s, 1H, Hc),
7.14 (d, 3H, H3″,4″,5″), 7.18 (d, 2H, H2″,6″), 7.31 (m, 2H, H6,8),
7.56 (t, 2H, H5,7), 7.85 (d, 2H, H3′,4′); 13C NMR (DMSO-d6,
100 MHz): δ 36.42 (Ca); 39.96 (Cc), 104.74 (C3), 116.51 (C1′),
117.99 (C8), 124.34 (C5), 126.19 (C6), 127.18 (C2″), 128.61
(C3″), 132.55 (C1″), 139.86 (C10), 152.62 (C2′), 165.31 (C2),
165.39 (C4); Anal. Calc. for C20H16N2O4: C, 68.9%; H, 4.6%;
N, 8.0%; Found: C, 68.9%, H, 4.6%; N, 8.0%.
91.46 (C3), 114.28 (C1′), 116.84 (C9), 117.1 (C8), 123.65
(C3″), 125.63 (C5), 128.73 (C6), 131.37 (C6″), 132.19 (C7),
153.07 (C2″), 153.98 (C1″), 156.13 (C10), 158.05 (C2′),
162.31 (C2), 166.0824 (C4); Anal. Calc. for C20H15N2O4Br:
C, 56.2%; H, 3.5%; N, 6.5%; Found: C, 56.2%, H, 3.5%; N,
6.5%.
6.2.13. 1,2-Dihydro-4-((4-hydroxy-2-oxo-2H-chromen-3-yl)(3-
6.2.9. 1,2-Dihydro-4-((4-hydroxy-2-oxo-2H-chromen-3-yl)(p-
methoxyphenyl)methyl)-5-methyl-pyrazol-3-one (6f). Yield:
−1
tolyl)methyl)-5-methyl-pyrazol-3-one (6b). Yield: 75%; m.p.
90%; m.p. 236°C–238°C; IR (cm ) 3585 (O-H), 3425 (NH),
−1
142°C–144°C; IR (cm ) 3440 (O-H), 3423 (NH), 1539
1535 (C�C), 1710 (CO lactone), 1735 (CO amide); δ 2.51 (s,
1
(C�C), 1741 (CO lactone), 1797 (CO amide); H NMR
3H, Ha), 3.64 (s, 3H, Hb), 6.31 (s, 1H, Hc), 6.66 (d, 2H,
(DMSO-d6, 400 MHz): δ 2.76 (s, 6H, Ha,b), 6.55 (s, 1H, Hc),
H4″,6″), 7.14 (t, 1H, H2″), 7.35 (m, 3H, H6,8,5″), 7.58 (t, 2H,
7.27 (s, 4H, H2′,3′,5′,6′), 7.59 (m, 4H, H5,6,7,8), 7.84 (t, 1H, H4′),
8.13 (d, 1H, H3′); 13C NMR (DMSO-d6, 100 MHz): δ 20.53
(Ca); 35.61 (Cb); 39.52 (Cc); 104.44 (C3), 116.07 (C1′), 117.46
(C8), 123.85 (C5), 126.64 (C6), 128.78 (C2″), 132.11 (C1″),
134.69 (C4″), 136.10 (C10), 152.13 (C2′), 164.66 (C2), 164.94
(C4); Anal. Calc. for C21H18N2O4: C, 69.6%; H, 5.0%; N,
7.7%; Found: C, 69.9%, H, 5.0%; N, 7.7%.
H
5,7), 7.88 (d, 2H, H3′,4′); 13C NMR (DMSO-d6, 100 MHz): δ
36.42 (Ca), 39.97 (Cc), 55.33 (Cb), 104.62 (C3), 110.74 (C1′),
113.73 (C2″), 116.46 (C8), 118.2 (C6″), 119.63 (C5), 124.27
(C6), 124.35 (C7), 129.57 (C5″), 132.43 (C1″), 141.96 (C10),
152.65 (C2′), 159.73 (C3′), 165.29 (C2), 165.60 (C4); Anal.
Calc. for C21H18N2O5: C, 66.6%; H, 4.7%; N, 7.4%; Found: C,
66.5%, H, 4.8%; N, 7.5%.
6.2.10. 1,2-Dihydro-4-((4-hydroxy-2-oxo-2H-chromen-3-yl)-
6.2.14. 1,2-Dihydro-4-((4-hydroxy-2-oxo-2H-chromen-3-
(4-N,N-dimethylphenyl)methyl)-5-methyl-pyrazol-3-one (6c).
yl)(3-hydroxyphenyl)methyl)-5-methyl-pyrazol-3-one (6g).
−1
−1
Yield: 80%; m.p. 160°C–162°C; IR (cm ) 3584 (O-H), 3420
Yield: 95%; m.p. 204°C–206°C; IR (cm ) 3588 (O-H), 3425
(NH), 1545 (C�C), 1715 (CO lactone), 1735 (CO amide), 1H
(NH), 1545 (C�C), 1715 (CO lactone), 1742 (CO amide); δ
NMR (DMSO-d6, 400 MHz): δ 3.03 (s, 3H, Ha), 3.11 (s, 6H,
2.51 (s, 3H, Ha), 6.31 (s, 1H, Hc), 6.66 (d, 2H, H4″,6″), 7.14 (t,
Hb,d), 6.28 (s, 1H, Hc), 6.82 (s, 1H, H4′), 6.82 (s, 1H, H4′),
1H, H2″), 7.35 (m, 3H, H6,8,5″), 7.58 (t, 2H, H5,7),7.88 (d, 2H,
7.29(m, 4H, H2″,3″,5″,6″), 7.52 (t, 2H, H6,8), 7.71 (d, 1H, H7), 7.80
H3′,4′); 13C NMR (DMSO-d6, 100 MHz): δ 36.4 (Ca), 39.9

Journal of Chemistry
9
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(Cc), 104.6 (C3), 110.7 (C1′), 113.7 (C4″), 114.3 (C2″), 116.4
(C8), 120.3 (C6″), 123.7 (C5), 128.3 (C7), 152.1 (C5′), 156.9
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C20H16N2O5: C, 65.9%; H, 4.4%; N, 7.6%; Found: C, 65.9%,
H, 4.4%; N, 7.6%.
Data Availability
Data are available on request to the corresponding author.
Conflicts of Interest
&e authors declare that there are no conflicts of interest.
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Acknowledgments
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represented by the Deanship of Scientific Research, on the
material support for this research under the number 3387-
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