An SiO2/ZnBr2 mediated expeditious approach to 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one derivatives in water under microwave irradiation

Article abstract of DOI:10.1039/c5ra21146h

A new one-pot three-component green approach has been developed for the synthesis of a series of pyrazolone derivatives 2(a-s) from differently substituted aromatic aldehydes, ethylacetoacetate and phenylhydrazine/2,4-dinitrophenylhydrazine in excellent y

Full text of DOI:10.1039/c5ra21146h

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SiO2/ZnBr2 mediated expeditious approach to 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one
derivatives in water under microwave irradiation
Mehtab Parveen,*a Shaista Azaz,a Ali Mohammed Malla,a Faheem Ahmad,a Musheer Ahmadb,c,
Mayank Guptab
aDivision of Organic Synthesis, Department of Chemistry, Aligarh Muslim University, Aligarh,
202002, India
bDepartment of Chemistry, Indian Institute of Technology Kanpur, 208016, India.
cDepartment of Applied Chemistry, Aligarh Muslim University, Aligarh 202002, India.
Abstract
A new one-pot three-component green approach has been developed for the synthesis of a series
of pyrazolone derivatives 2 (a-s) from differently substituted aldehydes, ethylacetoacetate and
phenylhydrazine/2,4-Dinitrophenylhydrazine in excellent yields (94-98%), employing
SiO2/ZnBr2 as a recyclable Lewis acid catalyst in water under microwave heating. The molecular
structure of compounds 2a and 2d were well supported by single crystal X-ray crystallographic
analysis. The present protocol bears wide substrate tolerance and is believed to be more practical,
efficient, eco-friendly and compatible as compare to existing methods.
Keywords: SiO2/ZnBr2, Pyrazolone, Microwave, X-ray analysis, Eco-friendly.
*Corresponding author (Mehtab Parveen), E-mail: mehtab.organic2009@gmail.com; Tel: +91-
9897179498
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Introduction
In the last few decades application of clean technologies in chemical synthesis has turn out to be
the major area of research in green chemistry.1 The eco-friendly and reusable heterogeneous
catalysts have been the major constituent for providing such clean technologies. Due to rapid
advances in medicinal chemistry, great attention has been paid towards the development of novel
clean processes employing nontoxic reagents, catalysts and solvents.2
Pyrazolone derivatives are an important class of heterocyclic compounds as they play a
vital role both in medicinal chemistry and in organic synthesis.3 These compounds exhibit
remarkable pharmaceutical properties such as analgesic, antitubercular, antimicrobial, anti-
inflammatory and antioxidant.4-8 Moreover compounds possessing pyrazolones moiety are
gaining much importance especially in drug discovery programs9 and have been used as
cardiotonics,10,11 anticancer (TELIN)12 and as potent inhibitors of the enzyme GSK3b.13
Pyrazolones are traditionally synthesized by treatment of δ-keto esters with hydrazine substrates
under acidic conditions.14 A number of alternative methods have been documented in the
literature for the synthesis of pyrazolone derivatives such as solid-state condensation,15
electrocatalytic procedure16 and ultrasonic irradiation technique17 for this synthesis. Moreover,
Rajeev and co-workers reported its synthesis under microwave irradiation18 (Scheme 1). Various
catalysts have also been used for the preparation of these compounds via the condensation
reaction. These catalysts include acetic acid or piperidine,19 silica-bonded S-sulfonic acid,20
sodium dodecyl sulfate,21 CAN,22 and ETBA.23 Now a day’s a great deal of interest has been
placed towards the reactions in presence of water.24 Breslow and Lindstrom reported that
hydrophobic effect of water is responsible for the organic reaction.25,26
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Scheme 1 Synthetic route for pyrazolone using microwave
Although the reported protocol has lots of significance in advance chemistry due to cheap,
nontoxic and nonflammable nature of water, serves as environmentally benign solvent and good
yields of the products, but long reaction time and solubility of the substrate makes it less
applicable. Moreover the combination of water with microwaves has lead to the development of
rapid, effective and environmentally benign synthetic methodologies.27 To the best of our
knowledge silica supported zinc bromide (SiO2/ZnBr2) has not been used as a catalyst for the
synthesis of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one derivatives. As a part of our research
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program on the development of new synthetic methods28-30 under the aspects of green chemistry,
herein, we report for the first time the development of an efficient, economical and recyclable
silica supported ZnBr2 promoted synthesis of pyrazolone derivatives in excellent yields via three
component reaction of aromatic aldehydes, ethylacetoacetate and phenylhydrazine/2,4-
Dinitrophenylhydrazine (2,4-DNP) in water under microwave heating.
The SiO2/ZnBr2 catalyst has emerged as a promising heterogeneous solid catalyst for various
organic transformations. Keivanloo et.al exploited SiO2/ZnBr2 for the synthesis of ynones31 by
cross-coupling of acid chloride with terminal alkynes and synthesis of 4,5-disubstituted 1,2,3-
(NH)- triazoles.32 Moreover, Kodomari and co-workers33 also reported the synthesis of
triarylmethanes and 9,10-diarylanthracenes and Clark et al34 reported bromination of aromatic
substrate using SiO2/ZnBr2 catalyst. The catalyst possesses inherent environmentally benevolent
properties such as non-toxicity, biocompatibility, physiological inertness, recyclability,
inexpensiveness and thermal stability. The catalyst was prepared by employing standard
procedures depicted in the literature31 and recycled up to six runs. The formation of SiO2/ZnBr2
system was evaluated by FT-IR, powder XRD and SEM-EDX analysis. The stability of the
catalyst was shown by TGA/DTA analysis.
Results and discussion
Characterization of catalyst (SiO2/ZnBr2)
The FT-IR spectrum of the catalyst (SiO2/ZnBr2) is depicted in Fig. 1. The FT-IR spectrum of
the catalytic system displayed a symmetrical stretching band at 3483.37 cm-1 for hydroxyl group
and the band resonating at 1632 cm-1 was attributed to the bending vibration of adsorbed water.35
Moreover, asymmetric and symmetric stretching vibration band for Si-O-Si appeared at 1093.14
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Fig. 1 FT-IR Spectrum of catalyst (SiO2/ZnBr2)
cm-1 and 797.12 cm-1, respectively. In addition the peak resonating at 910 and 467.53 cm-1 has
been assigned for the stretching vibration of Si-OH35 and Zn-Br, respectively. Thus, FT-IR
spectrum of the catalytic system authenticates the coating of ZnBr2 on the SiO2 surface as all the
characteristic peaks related to silica and ZnBr2 has been present in the spectrum of SiO2/ZnBr2.
Formation of the catalytic system (SiO2/ZnBr2) was further confirmed by powder XRD
analysis (Fig. 2). X-ray diffractograms (XRD) of the catalyst were recorded in the 2θ range of
20-80o. A single broad peak in the range of 2θ = 20-30o ascribed to the amorphous nature of
silica. The characteristic diffraction peaks of pure ZnBr2 were reported to appear at 13.7o, 21.1o,
27.5o, 46.1o and 53.4o.36 The XRD analysis of SiO2/ZnBr2 exhibited diffraction peak for ZnBr2
only at 46.2o and 53.4o. However, the other characteristic peaks (21.1o and 27.5o) were merged
with the broad peak of SiO2 (2θ = 20-30o). The appearance of these characteristics peaks
indicating the dispersion of ZnBr2 on the silica material and thus confirming the formation of
SiO2/ZnBr2 matrix.
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350
300
250
200
150
100
50
20
30
40
50
60
70
2 (degree)
Fig. 2 Powder XRD pattern of catalyst (SiO2/ZnBr2)
SEM analysis was employed to study the surface morphology of the catalytic system
(Fig. 3). SEM micrographs of the catalyst showed that the particles of ZnBr2 were well dispersed
on silica surface. The 3D surface plot (Fig. S1) (ESI†) of pure silica and SiO2/ZnBr2 were
provided to further verify the adsorption of ZnBr2 on silica surface. The white area of plot in
figure S1(b) confirmed the successful adsorption of ZnBr2 on the silica surface. The successful
incorporation of zinc bromide was also confirmed by EDX analysis (Fig. 4). EDX spectrum
showed the presence of Zn and Br in addition to O and Si elements.
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(a)
(b)
Fig. 3 SEM micrograph of (a) pure SiO2 (b) SiO2/ZnBr2 catalyst
Fig. 4 EDX analysis of the catalyst (SiO2/ZnBr2)
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The thermal stability of the catalyst was determined by TGA analysis (Fig. 5). The only
weight loss of 16.94% in the range of 40-120 °C was attributed to loss of physically adsorbed
water molecules in the silica gel framework. TGA is further supported by DTA analysis in which
a prominent peak at 93.04 °C showed endothermic reaction which help in the removal of water
molecule (Fig. 5). Further there is no weight loss upto 800 °C. Therefore it can be concluded that
physiosorbed and chemisorbed ZnBr2 on silica surfaces is stable upto 800 °C.37
Fig. 5 TGA/DTA of catalyst (SiO2/ZnBr2)
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Optimization of reaction condition
In the present study a series of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one derivatives 2 (a-s) have
been synthesized (Scheme 2), via a facile environmentally benign cyclization reaction, involving
various aromatic aldehydes with ethylacetoacetate and phenylhydrazine to yield target 3-methyl-
1-phenyl-1H-pyrazol-5(4H)-one derivatives in excellent yields (94-98%) with high purity.
To optimize the best reaction condition for these transformations, we investigate the
solvent effect, catalyst loading, effect of temperature and recyclability of the catalyst on the
model reaction. Initially, indole-3-carbaldehyde (1a, 2 mmol), phenylhydrazine (2 mmol) and
o
ethylacetoacetate (2 mmol) were refluxed in water (10 mL) at 60 C without any catalyst. The
reaction took a longer time period of 24 h to complete and afforded desired product 2a in less
yield (Table 1, entry 1), signifying the need of a catalyst. The reaction was then studied in the
presence of different catalysts such as AlCl3, ZnBr2, FeCl3, SiO2-Cl, SiO2/ZnBr2. Our analysis
o
revealed that the catalytic activity of various catalysts in water at 60 C was found to be in the
order of SiO2/ZnBr2 > AlCl3> FeCl3 > ZnBr2 > SiO2-Cl (Table 1, entries 2-6). To compare the
efficiency as well as competence of the reactions under aqueous condition, the model reaction
was also examined in the presence of SiO2/ZnBr2 in different solvents like MeOH, EtOH,
CH3COOH, CH2Cl2, DMF and THF. The use of relatively less polar aprotic solvents CH2Cl2,
DMF and THF yielded the product 2a in moderate yield (58-62 %), after extended reaction time
(Table 1, entries 10-12). However, in polar protic solvents MeOH, EtOH, and AcOH relatively
high yield (65-70%) of the product 2a was obtained with dip in reaction time (Table 1, entries 7-
9), whereas when reaction was performed in water in the presence of SiO2/ZnBr2, there was
remarkable increase in the yield (86%) of the product 2a with prominent fall in reaction time
(Table 1, entry 6).
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Scheme 2 Synthetic scheme for the synthesis of pyrazolone derivatives 2 (a-s)
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Table 1 Effect of different reaction media on model reaction (2a)a
S.No.
Solvent
Condition
Time (h)b
Yield (%)c
Water
Water
Water
Water
Water
Water
MeOH
EtOH
60 °C, without catalyst
60 °C, AlCl3
24h
8h
10h
12h
16h
4h
6h
8h
6h
10h
14h
18h
10 min
46
56
52
53
51
86
65
70
68
62
60
58
98
1
2
3
4
5
6
7
8
9
10
11
12
13
60 °C, ZnBr2
60 °C, FeCl3
60 °C, SiO2-Cl
60 °C, SiO2/ZnBr2
60 °C, SiO2/ZnBr2
60 °C, SiO2/ZnBr2
60 °C, SiO2/ZnBr2
60 °C, SiO2/ZnBr2
60 °C, SiO2/ZnBr2
60 °C, SiO2/ZnBr2
60 °C, SiO2/ZnBr2, MW
CH3COOH
CH2Cl2
DMF
THF
Water
aReaction condition: indole-3-carbaldehyde (1a, 2 mmol), phenylhydrazine (2 mmol), and
ethylacetoacetate (2 mmol), different solvent (10 mL), different catalyst (0.10 g)
bReaction progress monitored by TLC
cIsolated yield of products
In order to further improve the protocol to make it more energy efficient we introduced
microwaves. The use of microwaves (Anton Paar, Monowave 300) enhanced the protocol
remarkably with high yield of the product 2a (98%) and short reaction period (10 min) (Table 1,
entry 13).
To achieve the optimum concentration of the catalyst, the model reaction (2a) was
investigated at different concentrations 0.02-0.12 g (Table 2, entries 1-6) of the catalyst
SiO2/ZnBr2 at 60 oC in water under MW. The best results were obtained with the use of 0.10 g of
catalyst. Using less than 0.10 g of catalyst, moderate yields of the product 2a (66-83%) were
obtained with extended reaction times, while increasing catalyst amount 0.10-0.12 g, there was
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no further increase in the yield of the product 2a, possibly due to the saturation of the catalyst.
The above results signify that 0.10 g of SiO2/ZnBr2 is optimum dose in terms of efficient yield
and reduced reaction time.
Table 2 Effect of catalyst loading on the yield and reaction time of model reaction (2a)a
Entry
Catalyst (g)
Time (min)b
Yield (%)c
0.02
0.04
0.06
0.08
0.10
0.12
35
30
28
25
10
10
60
68
75
83
98
98
1
2
3
4
5
6
aReaction condition: indole-3-carbaldehyde (1a, 2 mmol), phenylhydrazine (2 mmol), and
ethylacetoacetate (2 mmol), water (10 mL), SiO2/ZnBr2 (0.02-0.12 g), MW-60 °C
bReaction progress monitored by TLC
cIsolated yield of products
To optimize the reaction temperature, the model reaction was carried out at different
temperatures in water under microwave heating (Table 3, entries 1-7). It was observed that
o
o
increase in temperature from 25 C to 60 C, has a noteworthy effect on the model reaction in
terms of yield and reaction time (Table 3, entries 1-6). However, no further enhancement in the
yield of product 2a was observed when the reaction temperature was raised from 60 oC to 65 oC
(Table 3, entry 7).
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Table 3 Effect of reaction temperature on the model reaction (2a)a
Entry
Temperature (oC)
Time (min)b
Yield (%)c
25
40
45
50
55
60
65
75
50
35
30
25
10
10
72
74
78
84
88
98
98
1
2
3
4
5
6
7
aReaction condition: indole-3-carbaldehyde (1a, 2 mmol), phenylhydrazine (2 mmol), and
ethylacetoacetate (2 mmol), water (10 mL), SiO2/ZnBr2 (0.10 g), MW, different temperature (25-
65 °C)
bReaction progress monitored by TLC
cIsolated yield of products
After optimization of the reaction conditions, the catalyst SiO2/ZnBr2 was examined under
the optimized reaction conditions using both conventional and microwave heating. A wide range
of aromatic aldehydes reacted with ethylacetoacetate and phenylhydrazine to afford the target
pyrazolone in excellent yields. We Further explored this devised protocol using 2,4-
Dinitrophenylhydrazine (2,4-DNP) to expand its product diversity and scope (Table 4). The
catalyst showed good efficiency under conventional heating giving the products in 4-6 h.
However, microwave induction produced excellent yields (94-98%) of products in 10-15 min.
The above results demonstrate that SiO2/ZnBr2 is an efficient catalyst for the synthesis of wide
range of pyrazolones in high yields under mild aqueous conditions.
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Table 4 Synthesis of pyrazolones derivatives 2 (a-s)
S.
Products
Conventional Methoda
Microwave irradiationb
No.
Time (h)c Yield (%)d Time (min)c Yield (%)d
4
81
77
80
84
10
10
15
10
98
95
98
98
2a
2b
2c
2d
4.5
4.5
4
5
78
82
15
15
95
96
2e
2f
4.5
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2g
2h
6
79
76
81
15
15
10
94
95
97
5.0
5.5
2i
2j
6.0
74
83
15
10
94
97
2k
4
4.5
5.5
75
84
10
10
94
98
2l
2m39
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2n39
5
76
15
96
2o40
6
74
78
15
10
94
97
2p41
4.5
2q40
5
76
15
95
2r40
4
82
75
10
15
98
94
2s41
5.5
aReaction condition: indole-3-carbaldehyde (1a, 2 mmol), phenylhydrazine (2 mmol), and
ethylacetoacetate (2 mmol), water (10 mL), SiO2/ZnBr2 (0.10 g), 60 °C
bReaction condition: indole-3-carbaldehyde (1a, 2 mmol), phenylhydrazine (2 mmol), and
ethylacetoacetate (2 mmol), water (10 mL), SiO2/ZnBr2 (0.10 g), MW-60 °C
cReaction progress monitored by TLC.
dIsolated yield of the products
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Chemistry
The structural elucidation of the synthesized compounds 2 (a-s) was established on the basis of
elemental analysis (IR, 1H NMR, 13C NMR) and mass spectral studies. The analytical results for
C, H and N were within ±0.3% of the theoretical values. The absence of peak for aldehydic
carbonyl in IR spectrum, confirmed the reaction at the carbonyl moiety. Moreover, all the
compounds displayed a characteristic peak for C=N and C=O groups, resonating at around 1578-
1603 cm-1 and 1680-1700 cm-1, respectively, which signifies the formation of a pyrazolone ring.
Characteristic peaks for the different functional groups such as methoxy, nitro and hydroxyl etc.
have been discussed in experimental section. In 1H NMR spectrum, each compound displayed a
sharp singlet at around δ 7.32-7.99 ascribed to the olefinic proton, a broad singlet at around
12.02-12.46 (D2O exchangeable) has been ascribed to –NH proton of indole ring. Similarly, a
sharp singlet at around 9.32-9.82 corresponds to the H-2 proton of indole ring (2a-2c).
Furthermore, sharp singlets resonating at around δ 10.64, 10.04, 10.12, 10.10 each integrating for
one proton, has been attributed to H-2 protons of γ-pyrone ring of chromones 2d, 2e, 2f and 2g
13
respectively. C NMR spectra, showed a series of signals resonating at around δ 105.13-162.18
which have been assigned to aromatic carbons, peaks resonating at around δ 137.31-153.80 and δ
163.05-170.16 corresponds to -C=N and -C=O moiety of pyrazolone ring, respectively. Similarly
signals at δ 174.19-174.69 have been attributed to carbonyl group (C=Oγ-pyrone) of compounds
(2d-2h). The mass spectral analysis of the synthesized compounds was also in good conformity
with the proposed structures. The selective Z-geometry across C=C was authenticated by single
crystal X-ray crystallographic analysis of compound 2a and 2d (Fig. 6), which was found to be
stabilized by an intricate array of H-bonding (Fig. 7) and π…π interactions (Fig. 8). The
crystallographic data of compound 2a and 2d have been presented in Table 5. Moreover, the
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selected bond distances (Å), bond angles (°) and packing diagram of compound 2a and 2d are
shown in Table S1-S2 and Fig. S2-S4 (ESI†).
(a)
(b)
Fig. 6 Asymmetric unit showing thermal ellipsoids (50% probability level) of (a) compound 2a
(b) compound 2d
(a)
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(b)
Fig. 7 2D view showing intricate H-bonding interactions in (a) compound 2a (b) compound 2d
(a)
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(b)
Fig. 8 Diagrammatic representation of π…π interactions in (a) compound 2a, π…π and –CH …π
interactions in (b) compound 2d
Reusability of the catalyst
The reusability of the catalyst (SiO2/ZnBr2) was also explored for the selected model reaction in
order to reduce the cost of the process (Fig. 9). After the first fresh run with 98% yield, the
o
catalyst was removed by simple filtration, washed with ethylacetate and dried at 160 C for 10
hrs. The recovered catalyst was further tested up to five more reaction cycles. The results
revealed that there is little drop in the yield of the product after every successive run of the
catalyst. This little drop in the catalytic activity is believed to be due to the leaching of ZnBr2.
SEM and EDX analysis of the recovered catalyst was also performed to ascertain its morphology
and composition (Fig. S4). It was observed that the composition of the catalytic system was
almost consistent with the fresh catalyst (Fig. 3) and there have been no significant changes in
the morphology of the catalyst.
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98
100
90
80
70
60
50
40
30
20
10
0
96
93
90
88
82
Time (min)
Yield (%)
10
10
10
10
10
10
1
2
3
4
5
6
No. of Cycles
Fig. 9 Recycling data of the catalyst (SiO2/ZnBr2) for the model reaction
Experimental
Materials and general methods
All the chemicals and reagents were purchased from Merck and Sigma-Aldrich (India) as
‘synthesis grade’ and used without further purification. The microwave synthesis was performed
in Anton Paar, Monowave 300 microwave synthesizer. Melting points were determined on a
Kofler apparatus and are uncorrected. Elemental analysis (C, H, N) was conducted using Carlo
Erba analyzer model 1108. The IR spectra were recorded with a Shimadzu IR-408 Perkin-
1
13
Elmer1800 instrument (FTIR) and the values are given in cm-1. H NMR and C NMR spectra
were run in DMSO-d6 /CDCl3 on a Bruker Avance-II 400 MHz instrument with TMS as an
internal standard and J values were measured in Hertz (Hz). Chemical shifts are reported in ppm
(δ) relative to TMS. Mass spectra were recorded on a JEOL D-300 mass spectrometer. X-ray
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diffractograms (XRD) of the catalyst were recorded in the 2θ range of 20-80o with a scan rate of
41 min-1 on a Shimadzu-6100 X-ray diffractometer with Ni-filtered Cu Kα radiation at a
wavelength of 1.54060 Å. The scanning electron microscope (SEM-EDX) analysis was obtained
using a JEOL (JSM-6510) equipped with an energy dispersive X-ray spectrometer at different
magnification. TGA has been carried out with DTG-60H (Simultaneous DTA-TG Apparatus),
Shimadzu instrument. Thin layer chromatography (TLC) glass plates (20×5 cm) were coated
with silica gel G (Merck) using benzene-acetone (8:2) mixture as mobile phase and exposed to
iodine vapors to check the homogeneity as well as the progress of the reaction.
Preparation of the silica-supported zinc bromide (SiO2/ZnBr2) catalyst
Silica gel (70-230 mesh) (10g) was added to a solution of ZnBr2 (12 mmol, 2.7 g) in EtOH (50
ml), and the mixture was heated at reflux for 1 h. The solvent was removed using rotary
o
evaporator, and the product was dried under vacuum at 160 C for 10 h.31 The other catalyst i.e.
SiO2-Cl used for the comparative study has been synthesized according to the previously
published standard procedures.38
General procedure for the synthesis of pyrazolones under microwave irradiation
A mixture of substituted aromatic aldehyde (2 mmol), ethylacetoacetate (2 mmol),
phenylhydrazine/2,4-Dinitrophenylhydrazine (2 mmol) and catalyst (0.10 g) in 10 mL water was
taken in a G30 vial and irradiated using microwaves with continuous stirring at 60 °C for 10-15
min. After completion of reaction (monitored by TLC), the reaction mixture was allowed to cool
at room temperature and diluted with cold water (5 mL). The catalyst was separated by filtration
and the resulting solution was extracted with ethyl acetate (3×10 mL). The combined organic
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layers were washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced
pressure. The crude product was crystallized with chloroform-methanol to afford the pure
product. The recovered catalyst was reused for subsequent cycles without a significant loss in
yield.
Spectral characterization
(Z)-4-((1H-indol-3-yl)methylene)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2a)
o
Orange crystalline solid, yield 98%, m.p. 245-250 C. IR (KBr, cm-1): 1157, 1456 (C=Caromatic),
1
1594 (C=N), 1680 (C=O). H NMR (400 MHz, DMSO-d6, δ, ppm): 7.19-7.96 (m, 5H, phenyl
ring), 7.9 (s, 1H, -C=H), 12.46 (brs, 1H, -NH, D2O exchangeable), 7.14-7.67 (m, 4H, indole
ring), 2.39 (s, 3H, -CH3), 9.82 (s, 1H, indole ring). 13C NMR (100 MHz, DMSO-d6, δ, ppm):
165.65 (C=O), 133.44 (C=C), 147.89 (-C=N), 143.23 (-C=H), 118.24-140.54 (phenyl ring),
111.64-137.65 (indole ring), 12.93 (CH3). Analytical cal. C19H15N3O: C, 75.73; H, 5.02; N,
13.94; found: C, 75.70; H, 5.03; N, 13.96. MS (EI): (m/z) [M+•] 301.12
(Z)-4-((5-hydroxy-1H-indol-3-yl)methylene)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2b)
Yellow crystalline solid, yield 95%, m.p. 256 °C. IR (KBr, cm-1): 1150, 1450 (C=Caromatic), 1578
1
(C=N), 1685 (C=O). H NMR (400 MHz, DMSO-d6, δ, ppm): 7.23-7.98 (m, 5H, phenyl ring),
7.83 (s, 1H, -C=H), 11.22 (brs, 1H, -NH, D2O exchangeable), 6.86-7.17 (m, 3H, indole ring),
13
2.31 (s, 3H, -CH3), 9.70 (s, 1H, indole ring), 10.20 (s, 1H, -OH, D2O exchangeable). C NMR
(100 MHz, DMSO-d6, δ, ppm): 165.63 (C=O), 133.44 (C=C), 147.89 (-C=N), 143.23 (-C=H),
118.20-140.51 (phenyl ring), 111.64-137.65 (indole ring), 13.15 (CH3). Analytical cal.
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C19H15N3O2: C, 71.91; H, 4.76; N, 13.24; found: C, 71.90; H, 4.79; N, 13.22.MS (EI): (m/z)
[M+•] 317.12
(Z)-3-methyl-4-((5-methyl-1H-indol-3-yl)methylene)-1-phenyl-1H-pyrazol-5(4H)-one (2c)
°
Yellow solid, yield 98%, m.p. 248 C. IR (KBr, cm-1): 1152, 1452 (C=Caromatic), 1603 (C=N),
1
1688 (C=O). H NMR (400 MHz, DMSO-d6, δ, ppm): 7.26-7.91 (m, 5H, phenyl ring), 7.71 (s,
1H, -C=H), 12.02 (brs, 1H, -NH, D2O exchangeable), 6.89-7.27 (m, 3H, indole ring), 2.31 (s,
13
1H, -CH3), 9.32 (s, 1H, indole ring). C NMR (100 MHz, DMSO-d6, δ, ppm): 164.55 (C=O),
133.04 (C=C), 146.87 (-C=N), 142.13 (-C=H), 116.24-142.54 (phenyl ring), 112.64-135.65
(indole ring), 14.23 (CH3). Analytical cal. C20H17N3O: C, 76.17; H, 5.43; N, 13.32; found: C,
76.18; H, 5.40; N, 13.34. MS (EI): (m/z) [M+•] 317.12
(Z)-3-methyl-4-((4-oxo-4H-chromen-3-yl)methylene)-1-phenyl-1H-pyrazol-5(4H)-one (2d)
°
Red crystalline solid, yield 98%, m.p. 222 C. IR (KBr, cm-1): 1153, 1452 (C=Caromatic), 1600
1
(C=N), 1692 (C=O). H NMR (400 MHz, DMSO-d6, δ, ppm): 7.12-7.34 (m, 5H, phenyl ring),
7.99 (s, 1H, -C=H), 10.64 (s, 1H, γ-pyrone ring), 8.19-7.27 (m, 4H, chromone ring), 2.33 (s, 1H,
13
-CH3). C NMR (100 MHz, DMSO-d6, δ, ppm): 163.35 (C=O), 134.67 (C=C, C-1ʹ), 137.81 (-
C=N), 155.47 (-C=H, C-2ʹ), 118.38-142.54 (phenyl ring), 150.67 (C-2,γ-pyrone ring), 118.54 (C-
3), 174.29 (C-4, C=O, γ- pyrone ring) 14.23 (CH3), 123.10 (C-4a), 125.75 (C-5), 124.56 (C-6),
135.92 (C-7), 117.59 (C-8), 161.83 (C-8b). Analytical cal. C20H14N2O3: C, 72.72; H, 4.27; N,
8.48; found: C, 72.70; H, 4.30; N, 8.47. MS (EI): (m/z) [M+•] 330.10
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(Z)-3-methyl-4-((6-methyl-4-oxo-4H-chromen-3-yl)methylene)-1-phenyl-1H-pyrazol-5(4H)-
one (2e)
°
Orange solid, yield 95%, m.p. 230 C. IR (KBr, cm-1): 1156, 1456 (C=Caromatic), 1598 (C=N),
1
1699 (C=O). H NMR (400 MHz, DMSO-d6, δ, ppm): 7.10-7.31 (m, 5H, phenyl ring), 7.69 (s,
1H, -C=H), 10.04 (s, 1H, γ-pyrone ring), 8.09-7.20 (m, 3H, chromone ring), 2.30 (s, 1H, -CH3).
13C NMR (100 MHz, DMSO-d6, δ, ppm): 163.05 (C=O), 134.17 (C=C, C-1ʹ), 137.61 (-C=N),
155.27 (-C=H, C-2ʹ), 118.21-142.24 (phenyl ring), 150.22 (C-2,γ-pyrone ring), 118.74 (C-3),
174.19 (C-4, C=O, γ- pyrone ring), 14.13 (CH3), 123.18 (C-4a), 125.32 (C-5), 124.56 (C-6),
135.52 (C-7), 117.49 (C-8), 161.53 (C-8b). Analytical cal. C21H16N2O3: C, 73.24; H, 4.68; N,
8.13; found: C, 73.26; H, 4.69; N, 8.10. MS (EI): (m/z) [M+•] 344.12
(Z)-4-((6-fluoro-4-oxo-4H-chromen-3-yl)methylene)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one
(2f)
°
Red solid, yield 96%, m.p. 214 C. IR (KBr, cm-1): 1157, 1455 (C=Caromatic), 1599 (C=N), 1696
1
(C=O). H NMR (400 MHz, DMSO-d6, δ, ppm): 7.02-7.11 (m, 5H, phenyl ring), 7.72 (s, 1H, -
13
C=H), 10.12 (s, 1H, γ-pyrone ring), 8.07-7.23 (m, 3H, chromone ring), 2.31 (s, 1H, -CH3). C
NMR (100 MHz, DMSO-d6, δ, ppm): 163.25 (C=O), 134.19 (C=C, C-1ʹ), 137.41 (-C=N), 155.23
(-C=H, C-2ʹ), 118.27-142.21 (phenyl ring), 150.29 (C-2,γ-pyrone ring), 118.64 (C-3), 174.69 (C-
4, C=O, γ- pyrone ring), 14.18 (CH3), 123.38 (C-4a), 125.30 (C-5), 124.52 (C-6), 135.56 (C-7),
117.41 (C-8), 161.50 (C-8b). Analytical cal. C20H13FN2O3: C, 68.96; H, 3.76; N, 8.04; found: C,
68.97; H, 3.78; N, 8.01. MS (EI): (m/z) [M+•] 348.09
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(Z)-4-((6-bromo-4-oxo-4H-chromen-3-yl)methylene)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-
one (2g)
°
Brown solid, yield 94%, m.p. 248 C. IR (KBr, cm-1): 1158, 1451 (C=Caromatic), 1580 (C=N),
1
1699 (C=O). H NMR (400 MHz, DMSO-d6, δ, ppm): 7.42-7.18 (m, 5H, phenyl ring), 7.76 (s,
1H, -C=H), 10.10 (s, 1H, γ-pyrone ring), 8.03-7.21 (m, 3H, chromone ring), 2.35 (s, 1H, -CH3).
13C NMR (100 MHz, DMSO-d6, δ, ppm): 163.23 (C=O), 133.19 (C=C, C-1ʹ), 137.31 (-C=N),
155.54 (-C=H, C-2ʹ), 118.19-142.29 (phenyl ring), 150.24 (C-2,γ-pyrone ring), 118.64 (C-3),
174.47 (C-4, C=O, γ- pyrone ring), 14.22 (CH3), 123.34 (C-4a), 125.39 (C-5), 120.41(C-6),
135.36 (C-7), 117.46 (C-8), 161.76 (C-8b). Analytical cal. C20H13BrN2O3: C, 58.70; H, 3.20; N,
6.85; found: C, 58.71; H, 3.22; N, 6.82. MS (EI): (m/z) [M+•] 408.01
(Z)-4-((2-amino-4-oxo-4H-chromen-3-yl)methylene)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-
one (2h)
°
Brown solid, yield 95%, m.p. 240 C. IR (KBr, cm-1): 1157, 1450 (C=Caromatic), 1580 (C=N),
1
1681 (C=O). H NMR (400 MHz, DMSO-d6, δ, ppm): 7.32-7.17 (m, 5H, phenyl ring), 7.72 (s,
1H, -C=H), 8.57 (s, 2H, -NH, D2O exchangeable), 8.08-7.27 (m, 4H, chromone ring), 2.33 (s,
1H, -CH3). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 163.28 (C=O), 133.29 (C=C, C-1ʹ), 137.38
(-C=N), 155.34 (-C=H, C-2ʹ), 118.25-142.37 (phenyl ring), 170.24 (C-2,γ-pyrone ring), 118.61
(C-3), 174.41 (C-4, C=O, γ- pyrone ring), 14.22 (CH3), 123.28 (C-4a), 125.33 (C-5), 123.41(C-
6), 135.16 (C-7), 117.26 (C-8), 161.66 (C-8b). Analytical cal. C20H15N3O3: C, 69.56; H, 4.38; N,
12.17; found: C, 69.53; H, 4.39; N, 12.19. MS (EI): (m/z) [M+•] 345.11.
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(Z)-4-(3,4-dimethoxybenzylidene)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2i)
°
Yellow solid, yield 97%, m.p. 208 C. IR (KBr, cm-1): 1157, 1450 (C=Caromatic), 1578 (C=N),
1
1700 (C=O). H NMR (400 MHz, DMSO-d6, δ, ppm): 7.19-7.97 (m, 5H, phenyl ring), 7.32 (s,
1H, -C=H), 7.28-7.32 (m, 3H, phenyl ring), 2.31 (s, 1H, -CH3), 3.38 (s, 6H, 2×-OCH3). 13C NMR
(100 MHz, DMSO-d6, δ, ppm): 163.26 (C=O), 133.22 (C=C, C-1ʹ), 155.14 (-C=H, C-2ʹ), 137.32
(-C=N), 118.21-142.39 (phenyl ring), 128.24 (C-1), 115.23 (C-2), 148.61 (C-3), 149.41 (C-4),
111.74 (C-5), 122.25 (C-6), 14.62 (CH3), 56.06 (O-CH3). Analytical cal. C19H18N2O3: C, 70.79;
H, 5.63; N, 8.69; found: C, 70.71; H, 5.60; N, 8.71. MS (EI): (m/z) [M+•] 322.13.
(Z)-3-methyl-1-phenyl-4-(3,4,5-trimethoxybenzylidene)-1H-pyrazol-5(4H)-one (2j)
Yellow crystalline solid, yield 94%, m.p. 214 °C. IR (KBr, cm-1): 1150, 1456 (C=Caromatic), 1600
1
(C=N), 1691 (C=O). H NMR (400 MHz, DMSO-d6, δ, ppm): 7.19-7.97 (m, 5H, phenyl ring),
13
7.35 (s, 1H, -C=H), 7.12 (s, 2H, phenyl ring), 2.32 (s, 1H, -CH3), 3.34 (s, 9H, 3×-OCH3). C
NMR (100 MHz, DMSO-d6, δ, ppm): 163.28 (C=O), 133.29 (C=C, C-1ʹ), 155.39 (-C=H, C-2ʹ),
137.38 (-C=N), 118.52-142.29 (phenyl ring), 129.24 (C-1), 105.13 (C-2 and C-6), 154.11 (C-3
and C-4), 134.34 (C-5), 14.89 (CH3), 56.36 (O-CH3). Analytical cal. C20H20N2O4: C, 68.17; H,
5.72; N, 7.95; found: C, 68.20; H, 5.70; N, 7.94. MS (EI): (m/z) [M+•] 352.14.
(Z)-3-methyl-4-(4-nitrobenzylidene)-1-phenyl-1H-pyrazol-5(4H)-one (2k)
Orange crystalline solid, yield 97%, m.p. 210 °C. IR (KBr, cm-1): 1157, 1456 (C=Caromatic), 1578
1
(C=N), 1687 (C=O), 1522, 1365 (NO2). H NMR (400 MHz, DMSO-d6, δ, ppm): 7.20-7.99 (m,
5H, phenyl ring), 7.49 (s, 1H, -C=H), 8.12 (d, 2H, C-2 and C-6), 8.18 (d, 2H, C-3 and C-5), 2.36
(s, 1H, -CH3). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 163.25 (C=O), 128.21 (C=C, C-1ʹ),
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145.69 (-C=H, C-2ʹ), 145.88 (-C=N), 118.12-142.22 (phenyl ring), 139.24 (C-1), 132.17 (C-2
and C-6), 124.18 (C-3 and C-4), 148.14 (C-5), 15.09 (CH3). Analytical cal. C17H13N3O3: C,
66.44; H, 4.26; N, 13.67; found: C, 66.41; H, 4.28; N, 13.68. MS (EI): (m/z) [M+•] 307.10.
(Z)-3-methyl-4-(3-nitrobenzylidene)-1-phenyl-1H-pyrazol-5(4H)-one (2l)
°
Yellow solid, yield 94%, m.p. 202 C. IR (KBr, cm-1): 1152, 1454 (C=Caromatic), 1579 (C=N),
1
1693 (C=O), 1520, 1360 (NO2). H NMR (400 MHz, DMSO-d6, δ, ppm): 7.22-7.95 (m, 5H,
13
phenyl ring), 7.47 (s, 1H, -C=H), 7.67-8.42 (m, 4H, phenyl ring), 2.32 (s, 1H, -CH3). C NMR
(100 MHz, DMSO-d6, δ, ppm): 163.29 (C=O), 127.23 (C=C, C-1ʹ), 144.63 (-C=H, C-2ʹ), 146.98
(-C=N), 118.15-142.32 (phenyl ring), 133.34 (C-1), 125.17 (C-2), 147.08 (C-3), 123.08 (C-4),
128.18 (C-5), 123.36 (C-6), 15.19 (CH3). Analytical cal. C17H13N3O3: C, 66.44; H, 4.26; N,
13.67; found: C, C, 66.41; H, 4.27; N, 13.69. MS (EI): (m/z) [M+•] 307.10.
(Z)-4-(4-(dimethylamino)benzylidene)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2m)
°
o
Orange crystalline solid, yield 98%, m.p. 194 C, reported 188-192 C.39 IR (KBr, cm-1): 1154,
1452 (C=Caromatic), 1591 (C=N), 1689 (C=O). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 7.13-7.97
(m, 5H, phenyl ring), 7.58 (s, 1H, -C=H), 2.30 (s, 1H, -CH3), 6.84-8.66 (m, 4H, phenyl ring),
3.13 (s, 1H, 2×CH3). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 170.16 (C=O), 128.69 (C=C, C-
1ʹ), 151.56 (-C=H, C-2ʹ), 153.80. (-C=N), 118.09-138.84 (phenyl ring), 123.92 (C-1), 137.43 (C-
2 and C-6), 111.32 (C-3 and C-5), 148.18 (C-4), 15.19 (CH3), 41.28 (N-CH3). Analytical cal.
C19H19N3O: C, 74.73; H, 6.27; N, 13.76; found: C, 74.70; H, 6.28; N, 13.78. MS (EI): (m/z)
[M+•] 305.15.
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(Z)-4-(4-fluorobenzylidene)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2n)
°
°
Yellow solid, yield 96%, m.p. 104 C, reported 98-102 C.39 IR (KBr, cm-1): 1156, 1455
1
(C=Caromatic), 1593 (C=N), 1697 (C=O). H NMR (400 MHz, DMSO-d6, δ, ppm): 7.19-7.97 (m,
13
5H, phenyl ring), 7.42 (s, 1H, -C=H), 2.34 (s, 1H, -CH3), 7.14-7.86 (m, 4H, phenyl ring). C
NMR (100 MHz, DMSO-d6, δ, ppm): 168.12 (C=O), 127.60 (C=C, C-1ʹ), 145.50 (-C=H, C-2ʹ),
148.85. (-C=N), 118.02-139.81 (phenyl ring), 128.91 (C-1), 132.03 (C-2 and C-6), 115.36 (C-3
and C-5), 162.18 (C-4), 15.02 (CH3). Analytical cal. C17H13FN2O: C, 72.85; H, 4.67; N, 9.99;
found: C, 72.82; H, 4.69; N, 10.00. MS (EI): (m/z) [M+•] 280.10.
(Z)-4-benzylidene-1-(2,4-dinitrophenyl)-3-methyl-1H-pyrazol-5(4H)-one (2o)
Yellow solid, yield 94%, m.p. 194 °C.40 IR (KBr, cm-1): 1152, 1450 (C=Caromatic), 1597 (C=N),
1
1686 (C=O), 1528, 1368 (NO2). H NMR (400 MHz, DMSO-d6, δ, ppm): 8.20-9.08 (m, 3H,
13
phenyl ring), 7.42 (s, 1H, -C=H), 2.36 (s, 1H, -CH3), 7.40-7.66 (m, 5H, phenyl ring). C NMR
(100 MHz, DMSO-d6, δ, ppm): 170.12 (C=O), 126.69 (C=C, C-1ʹ), 150.56 (-C=H, C-2ʹ), 150.80.
(-C=N), 120.14-144.09 (phenyl ring), 123.02 (C-1), 136.43 (C-2 and C-6), 111.48 (C-3 and C-5),
148.88 (C-4), 15.20 (CH3). Analytical cal. C17H12N4O5: C, 57.96; H, 3.43; N, 15.90; found: C,
57.93; H, 3.45; N, 15.91. MS (EI): (m/z) [M+•] 352.08.
(Z)-1-(2,4-dinitrophenyl)-3-methyl-4-(3-nitrobenzylidene)-1H-pyrazol-5(4H)-one (2p)
Yellow crystalline solid, yield 95%, m.p. 274 °C, reported 272-274 °C.41 IR (KBr, cm-1): 1152,
1454 (C=Caromatic), 1593 (C=N), 1700 (C=O), 1520, 1360 (NO2). 1H NMR (400 MHz, DMSO-d6,
δ, ppm): 8.22-9.02 (m, 3H, phenyl ring), 7.54 (s, 1H, -C=H), 7.68-8.30 (m, 4H, phenyl ring),
2.34 (s, 1H, -CH3). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 164.20 (C=O), 127.10 (C=C, C-1ʹ),
29