Microwave-assisted one-pot synthesis of pyrazolone derivatives under solvent-free conditions

Article abstract of DOI:10.3390/molecules15053593

An efficient one-pot method to generate structurally diverse and medicinally interesting pyrazolone derivatives in good to excellent yields of 51-98% under microwave irradiation and solvent-free conditions has been developed.

Full text of DOI:10.3390/molecules15053593

Molecules 2010, 15, 3593-3601; doi:10.3390/molecules15053593
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Microwave-Assisted One-Pot Synthesis of Pyrazolone
Derivatives under Solvent-Free Conditions
Ruoqun Ma 1, Jin Zhu 1, Jie Liu 1, Lili Chen 2,*, Xu Shen 1,2, Hualiang Jiang 1,2,3 and Jian Li 1,2,
*
1
School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road,
Shanghai 200237, China
2
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy
of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
3
Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of
Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
∗ Author to whom correspondence should be addressed. E-Mails: jianli@ecust.edu.cn (J.L.);
lilichen@mail.shcnc.ac.cn (L.L.C.)
Received: 23 April 2010; in revised form: 10 May 2010 / Accepted: 13 May 2010 /
Published: 17 May 2010
Abstract: An efficient one-pot method to generate structurally diverse and medicinally
interesting pyrazolone derivatives in good to excellent yields of 51–98% under microwave
irradiation and solvent-free conditions has been developed.
Keywords: microwave-assisted reactions; one-pot; pyrazolones
1. Introduction
Pyrazolone derivatives are an important class of heterocyclic compounds that occur in many drugs
and synthetic products [1]. These compounds exhibit remarkable antitubercular [2,3], antifungal [4,5],
antibacterial [6], anti-inflammatory [7], and antitumor activities [8]. In our effort to identify new
farnesoid X receptor (FXR) ligands [9], we recently found by virtual screening that a 4-arylidene-
pyrazolone derivative 1a (Figure 1) was a FXR antagonist (unpublished data). Consequently, to
explore the structure activity relationships (SAR) for this family of compounds, a facile and practical
approach for synthesizing 4-arylidenepyrazolone-containing derivatives 1 (Figure 1) became desirable.

Molecules 2010, 15
Figure 1. The structures of 4-arylidenepyrazolone derivatives 1 and FXR antagonist 1a.
3594
R1
N
N
N
N
HOOC
Ar
O
R2
O
O
O
1
1a
Generally, 4-arylidenepyrazolone derivatives 1 are synthesized using as starting materials
substituted aldehydes 5 [10–12] (or their their acetal [13,14] or imine [15,16] precursors) and 2-
pyrazolin-5-ones 4, the latter generally being obtained by the Knorr condensation [17,18] of β-
ketoesters 2 with substituted hydrazines 3 (Scheme 1). It is obvious that all described methods involve
multiple step reactions and most of them produce equimolar amounts of unwanted by-products. In this
respect, the development of a one-pot reaction using readily available chemicals would be of
considerable significance due to its synthetic efficiency and atom economy.
Scheme 1. The synthetic routes to 4-arylidenepyrazolone derivatives 1 by classical two
step or the proposed one-pot method.
R1
N
N
O
R2
O
4
Ar
R1
5
O
N
N
H
O
O
N
NH2
Ar
5
+
OEt
Ar
R2
R2
R1
O
Microwave-assisted
one-pot reaction
1
2
3
Microwave-assisted organic reactions have been applied to a wide range of reaction types [19–25],
especially cycloaddition reactions. Microwaves accelerate a variety of synthetic transformations
providing time- and energy-saving protocols [19–25]. Recently, Botta et al. [26]. reported a
microwave-assisted three-component Knoevenagel/hetero Diels–Alder reaction, which suggested that
2-pyrazolin-5-ones 4 might react well with aldehydes 5 under microwave irradiation conditions.
Inspired by this reaction, we envisioned that a new three-component (compounds 2, 3, and 5) one-pot
reaction might take place using a microwave-assisted approach and would directly create the target 4-
arylidene-pyrazolone scaffolds 1 (Scheme 1).
2. Results and Discussion
2.1. Optimization of the reaction conditions
Initially we selected ethyl acetoacetate (2a), 3-nitrophenylhydrazine (3b) and 3-methoxy-4-ethoxy-
benzaldehyde (5a) as the model substrates for the optimization of the reaction conditions, which
included microwave oven power, time of irradiation, solid supports and reactant ratios. The results are
summarized in Tables 1-2. The preliminary investigations revealed that the one-pot reaction occurred,

Molecules 2010, 15
3595
as designed. Nevertheless, the reaction efficiency was highly microwave oven power dependent
(entries 1-3, Table 1), with a good yield being achieved at 420 W. We then compared the synthesis of
1b with irradiation times of 5 min, 10 min, and 15 min at 420 W, and the corresponding yields were
54%, 71%, and 62%, respectively (entries 2 and 4,5, Table 1).
Table 1. Optimization of the power of microwave oven and time of irradiation.a
N
NH2
O
O
O
O2N
N
O2N
NH
+
MeO
EtO
MWI
+
OEt
O
OMe
OEt
3b
1b
5a
2a
Entry
Power (W)
280
Time (min)
Yield (%)b
1
2
3
4
5
5
5
20
67
54
71
62
420
560
5
420
10
15
420
a
the reaction was carried out with 2a, 3b and 5a in equimolar ratio (0.3 mmol); for the detailed
reaction conditions see the Experimental section; b Isolated yields.
Table 2. Optimization of the reactant’s equivalence ratio and solid support.a
Reagent Ratio
Entry
Solid support
Yield (%)b
2a
1
3b
1.2
1
5a
1
1
2
3
4
5
6
7
8
9
-
60
78
63
83
73
79
81
81
80
-
1.2
1
1
-
1
1.2
1
-
1.5
2
1
-
1
1
-
-
2.5
3
1
1
1
1
SiO2
Al2O3
1.5
1.5
1
1
1
1
a
The reaction was carried out under microwave radiation 420 W for 10 min; for detailed reaction
conditions see the Experimental section; b Isolated yields.
Encouraged by the promising results, we further optimized the reactant ratio (entries 1–7, Table 2)
and solid support (entries 8,9, Table 2). The optimum results were obtained when the reactants were
mixed is a ratio of 2a/3b/5a = 1.5/1/1 without solid support and irradiated at 420 W for 10 min (entry
4, Table 2). Solid supports such as aluminium oxides and silica gel have been widely used in
microwave-assisted organic synthesis to enhance substrates absorption of microwave energy.
However, solid supports appeared to offer no advantages in our one-pot reaction (entries 4, and 8,9,
Table 2).

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2.2. Scope of microwave-assisted one-pot synthesis of 4-arylidenepyrazolone derivatives
Having established the optimal reaction conditions, we subjected a series of β-ketoesters,
hydrazines, and aldehydes to them to explore the generality and scope of the one-pot process. As
shown in Table 3, we were pleased to find that this method was applicable to a broad range substrate
of substituted β-ketoester (2a-b), hydrazine (3a-j), and aldehyde (5a-h) substrates.
Table 3. Scope of microwave-assisted one-pot synthesis of 4-arylidenepyrazolone derivatives.a
R1
H
N
N
O
O
N
O
MWI, 420 W
10 min
NH2
+
+
Ar
R2
Ar
OEt
R1
R2
O
2a-b
5a-h
3a-j
1a-r
Yield
Compd.
R1
R2
Ar
(%)b
98
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
Me, 2a
Me, 2a
Me, 2a
Me, 2a
Me, 2a
Me, 2a
Me, 2a
Me, 2a
Me, 2a
Me, 2a
Me, 2a
Me, 2a
Me, 2a
Me, 2a
Ph, 2b
Me, 2a
Me, 2a
Me, 2a
3-CO2H, 3a
3-NO2, 3b
4-NO2, 3c
4-CF3, 3d
3-CF3, 3e
3-MeO-4-EtO-Ph, 5a
3-MeO-4-EtO-Ph, 5a
3-MeO-4-EtO-Ph, 5a
3-MeO-4-EtO-Ph, 5a
3-MeO-4-EtO-Ph, 5a
3-MeO-4-EtO-Ph, 5a
3-MeO-4-EtO-Ph, 5a
3-MeO-4-EtO-Ph, 5a
3-MeO-4-EtO-Ph, 5a
3-MeO-4-OH-Ph, 5b
3,4-di-OH-Ph, 5c
83
78
53
67c
54c
51
3,5-di-CF3, 3f
2-F, 3g
3,4-di-Cl, 3h
3,5-di-Cl, 3i
3-CO2H, 3a
3-CO2H, 3a
3-NO2, 3b
H, 3j
86
73c
68
73
53
5-Me-thiophen-2-yl, 5d
3-MeO-4-EtO-Ph, 5a
4-Br-Ph, 5e
63
H, 3j
53c
61
3-NO2, 3b
3-CO2H, 3a
3-CO2H, 3a
3-CO2H, 3a
3-MeO-4-OH-Ph, 5c
3-MeO-4-PhCH2O-Ph, 5f
3-MeO-4-Me(CH2)4O-Ph, 5g
3-MeO-4-Me2CHO-Ph, 5h
84
83
76
a Unless stated otherwise, the reaction was carried out with 2 (0.45 mmol), 3 (0.3 mmol) and 5
(0.3 mmol) under microwave radiation 420 W for 10 min; for the detailed reaction conditions see
the Experimental section; b Isolated yields; c These reactions were carried out with 2 (0.36 mmol), 3
(0.3 mmol) and 5 (0.3 mmol).
The target products 1a-r were prepared in good to excellent yields (51–98%). A variety of
substituents on the aryl ring including halogens, -CO2H, -NO2, -CF3, alkoxy, etc. were well tolerated.
These outcomes imply that electronic features have a marginal effect on the process. Examination of
the results also revealed that the steric effects also play a minimal role in governing the reaction
efficiency, as all para- (such as compound 1c), meta- (such as compound 1e), and ortho- (such as
compound 1g) substituted substrates were smoothly transformed into the desired products.
Heterocycles (compound 1l) could efficiently participate in the one-pot reaction as well. Finally, it is
noteworthy that the process features simple operation and purification, and all target products could be
directly obtained by simple suction filtration and washing with ethyl acetate.

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With regard to the stereochemistry of the 4-arylidenepyrazolone products 1a-r, they were all
exclusively assigned the Z-configuration based on NOE spectroscopy of compound 1b. NOE was
observed between H-13 (δ 7.37) and H-12 (δ 2.38), suggesting a Z configuration at △[4,13] (Figure 2).
Figure 2. NOE correlation (double-headed arrows) established the stereochemistry of the
double bond in 1b.
12
3
H
13
N
1 N
7
4
O2N
O
O
O
1b
3. Experimental
3.1. General
The reagents were purchased from Shanghai Chemical Reagent Company, Lancaster, and Acros,
and used without further purification. Yields were not optimized. Nuclear magnetic resonance (NMR)
spectra were recorded on a Brucker AMX-400 NMR instrument (1H at 400 MHz and 13C at 100 MHz,
respectively). Chemical shifts are reported in parts per million (ppm, δ) downfield from
tetramethylsilane (TMS) used as internal standard. Proton coupling patterns were described as singlet
(s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). Low- and high-resolution mass
spectra (LRMS and HRMS) were obtained by electron ionization (EI) on a Finnigan MAT-95
instrument. Microwave experiments were carried out in a domestic microwave oven (Midea
MM721AAU-PW).
3.2. General Procedure for the Preparation of 1a-r: Preparation of 1b
(Z)-4-(4-Ethoxy-3-methoxybenzylidene)-3-methyl-1-(3-nitrophenyl)-pyrazolone (1b).
A
one-neck
50-mL flask containing ethyl acetoacetate (2a, 0.45 mmol), 3-nitrophenylhydrazine (3b, 0.3 mmol)
and 3-methoxy-4-ethoxy-benzaldehyde (5a, 0.3 mmol) was placed in a domestic microwave oven and
irradiated at a power of 420 W for 10 min. The solid obtained after cooling was triturated with ethyl
acetate and collected by suction filtration, to afford product 1b (95 mg, yield 83%) as an orange solid.
1
m.p. 212–213 ºC. H-NMR (CDCl3): δ 1.55 (t, 3H), 2.38 (s, 3H), 4.07 (s, 3H), 4.27 (q, 2H), 6.98 (d,
1H), 7.37 (s, 1H), 7.59 (t, 1H), 7.75 (d, 1H), 8.03 (d, 1H), 8.47 (d, 1H), 8.93 (d, 2H); 13C-NMR
(CDCl3): δ 162.7, 153.6, 152.1, 149.0, 148.6, 148.3, 139.6, 130.9, 129.6, 126.5, 124.0, 123.9, 118.8,
115.8, 113.5, 111.4, 64.7, 56.4, 14.6, 13.5; EI-MS m/z 381 (M+, 100%); HRMS (EI) m/z calcd.
C20H19N3O5 (M+) 381.1325, found 381.1321.
(Z)-3-(4-(4-Ethoxy-3-methoxybenzylidene)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzoic acid
1
(1a). Solid. m.p. 276–278 ºC. H-NMR (DMSO): δ 1.38 (t, 3H), 2.34 (s, 3H), 3.88 (s, 3H), 4.17 (q,
2H), 7.16 (d, 1H), 7.56 (t, 1H), 7.77 (s, 2H), 8.12 (d, 1H), 8.21 (d, 1H), 8.51 (s, 1H), 8.75 (s, 1H),

Molecules 2010, 15
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13.05 (s, 1H); EI-MS m/z 380 (M+, 100%); HRMS (EI) m/z calcd. C21H20N2O5 (M+) 380.1372, found
380.1371.
(Z)-4-(4-Ethoxy-3-methoxybenzylidene)-3-methyl-1-(4-nitrophenyl)-1H-pyrazol-5(4H)-one (1c). Solid.
1
m.p. 213–215 ºC. H-NMR (CDCl3): δ 1.55 (t, 3H), 2.38 (s, 3H), 4.06 (s, 3H), 4.25 (q, 2H), 6.97 (d,
1H), 7.37 (s, 1H), 7.73 (d, 1H), 8.29 (s, 4H), 8.90 (s, 1H); EI-MS m/z 381 (M+, 100%); HRMS (EI)
m/z calcd. C20H19N3O5 (M+) 381.1325, found 381.1323.
(Z)-4-(4-Ethoxy-3-methoxybenzylidene)-3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5(4H)-one
1
(1d). Solid. m.p. 144–147 ºC. H-NMR (CDCl3): δ 1.54 (t, 3H), 2.37 (s, 3H), 4.05 (s, 3H), 4.25 (q,
2H), 6.96 (d, 1H), 7.35 (s, 1H), 7.66 (d, 2H), 7.72 (d, 1H), 8.18 (d, 2H), 8.93 (s, 1H); EI-MS m/z 404
(M+, 100%); HRMS (EI) m/z calcd. C21H19F3N2O3 (M+) 404.1348, found 404.1349.
(Z)-4-(4-Ethoxy-3-methoxybenzylidene)-3-methyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5(4H)-one
(1e). Solid. m.p. 147–151 ºC. 1H-NMR (CDCl3): δ 1.54 (t, 3H), 2.37 (s, 3H), 4.06 (s, 3H), 4.24 (q, 2H),
6.97 (d, 1H), 7.35 (s, 1H), 7.42 (d, 1H), 7.53 (t, 1H), 7.75 (d, 1H), 8.28 (d, 1H), 8.31 (s, 1H), 8.91 (s,
1H); EI-MS m/z 404 (M+, 100%); HRMS (EI) m/z calcd. C21H19F3N2O3 (M+) 404.1348, found
404.1349.
(Z)-1-(3,5-bis(Trifluoromethyl)phenyl)-4-(4-ethoxy-3-methoxybenzylidene)-3-methyl-1H-pyrazol-
1
5(4H)-one (1f). Solid. m.p. 198–200 ºC. H-NMR (CDCl3): δ 1.54 (t, 3H), 2.38 (s, 3H), 4.07 (s, 3H),
4.25 (q, 2H), 6.98 (d, 1H), 7.37 (s, 1H), 7.65 (s, 1H), 7.77 (d, 1H), 8.61 (s, 2H), 8.84 (s, 1H); EI-MS
m/z 472 (M+, 100%); HRMS (EI) m/z calcd. C22H18F6N2O3 (M+) 472.1222, found 472.1223.
(Z)-4-(4-Ethoxy-3-methoxybenzylidene)-1-(2-fluorophenyl)-3-methyl-1H-pyrazol-5(4H)-one
(1g).
Solid. m.p. 153–155 ºC. 1H-NMR (CDCl3): δ 1.52 (t, 3H), 2.34 (s, 3H), 4.00 (s, 3H), 4.22 (q, 2H), 6.93
(d, 1H), 7.22 (q, 2H), 7.32 (t, 1H), 7.36 (s, 1H), 7.52 (t, 1H), 7.67 (d, 1H); EI-MS m/z 354 (M+, 100%);
HRMS (EI) m/z calcd. C20H19FN2O3 (M+) 354.1380, found 354.1377.
(Z)-1-(3,4-Dichlorophenyl)-4-(4-ethoxy-3-methoxybenzylidene)-3-methyl-1H-pyrazol-5(4H)-one (1h).
Solid. m.p. 164–166 ºC. 1H-NMR (CDCl3): δ 1.53 (t, 3H), 2.34 (s, 3H), 4.05 (s, 3H), 4.23 (q, 2H), 6.95
(d, 1H), 7.32 (s, 1H), 7.44 (s, 1H), 7.71 (d, 1H), 7.94 (d, 1H), 8.21 (s, 1H), 8.90 (s, 1H); EI-MS m/z
404 (M+, 100%); HRMS (EI) m/z calcd. C22H18F6N2O3 (M+) 404.0694, found 404.0695.
(Z)-1-(3,5-Dichlorophenyl)-4-(4-ethoxy-3-methoxybenzylidene)-3-methyl-1H-pyrazol-5(4H)-one (1i).
Solid. m.p. 182–185 ºC. 1H-NMR (CDCl3): δ 1.54 (t, 3H), 2.35 (s, 3H), 4.06 (s, 3H), 4.23 (q, 2H), 6.96
(d, 1H), 7.15 (s, 1H), 7.33 (s, 1H), 7.72 (d, 1H), 8.04 (s, 2H), 8.89 (s, 1H); EI-MS m/z 404 (M+,
100%); HRMS (EI) m/z calcd. C22H18F6N2O3 (M+) 404.0694, found 404.0697.
(Z)-3-(4-(4-Hydroxy-3-methoxybenzylidene)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzoic acid
1
(1j). Solid. m.p. 255–257 ºC. H-NMR (DMSO): δ 2.33 (s, 3H), 3.90 (s, 3H), 6.96 (d, 1H), 7.56
(t, 1H), 7.70 (s, 1H), 7.75 (d, 1H), 8.04 (d, 1H), 8.21 (d, 1H), 8.53 (s, 1H), 8.76 (s, 1H); EI-MS m/z
352 (M+, 100%); HRMS (EI) m/z calcd. C19H16N2O5 (M+) 352.1059, found 352.1057.

Molecules 2010, 15
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(Z)-3-(4-(3,4-Dihydroxybenzylidene)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl) benzoic acid (1k).
1
Solid. m.p. 278–280 ºC. H-NMR (DMSO): δ 2.34 (s, 3H), 6.93 (d, 1H), 7.57 (t, 1H), 7.65 (s, 1H),
7.76 (d, 1H), 7.92 (d, 1H), 8.18 (d, 1H), 8.52 (s, 1H), 8.63 (s, 1H), 10.45(s,1H); EI-MS m/z 338 (M+,
100%); HRMS (EI) m/z calcd. C19H16N2O5 (M+) 338.0903, found 338.0782.
(Z)-3-Methyl-4-((5-methylthiophen-2-yl)methylene)-1-(3-nitrophenyl)-1H-pyrazol-5(4H)-one (1l). Solid.
1
m.p. 199–201 ºC. H-NMR (CDCl3): δ 2.39 (s, 1H), 2.67 (s, 3H), 7.00 (s, 1H), 7.58 (t, 2H), 7.85 (s,
1H), 8.02 (d, 1H), 8.53 (d, 1H), 8.92 (s, 1H); EI-MS m/z 327 (M+, 100%); HRMS (EI) m/z calcd.
C16H13N3O3S (M+) 327.0678, found 327.0675.
(Z)-4-(4-Ethoxy-3-methoxybenzylidene)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (1m). Solid. m.p.
1
134–139 ºC. H-NMR (CDCl3): δ 1.54 (t,3H), 2.36 (s, 3H), 4.05 (s, 3H), 4.23 (q, 2H), 6.95 (d, 1H),
7.19 (t, 1H), 7.32 (s, 1H), 7.42 (t, 2H), 7.72 (d, 1H), 7.97 (d, 2H), 8.98 (s, 1H); EI-MS m/z 336 (M+,
100%); HRMS (EI) m/z calcd. C20H20N2O3 (M+) 336.1474, found 336.1475.
(Z)-4-(4-Bromobenzylidene)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (1n). Solid. m.p. 117–120 ºC.
1H-NMR (CDCl3): δ 2.36 (s, 3H), 7.21 (t, 1H), 7.32 (s, 1H), 7.43 (t, 2H), 7.65 (d, 2H), 7.95 (d, 2H),
8.39 (d, 2H); EI-MS m/z 340 (M+, 100%); HRMS (EI) m/z calcd. C17H13BrN2O (M+) 340.0211, found
340.0212.
(Z)-4-(4-Hydroxy-3-methoxybenzylidene)-1-(3-nitrophenyl)-3-phenyl-1H-pyrazol-5(4H)-one (1o). Solid.
m.p. 199–202 ºC. 1H-NMR (CDCl3): δ 4.14 (s, 3H), 6.38 (s, 1H), 7.03 (d, 1H), 7.53 (d, 1H), 7.56 (m,
4H), 7.69 (d, 1H), 7.71 (d, 1H), 8.07 (d, 1H), 8.54 (d, 1H), 9.06 (s, 1H), 9.15 (s, 1H); EI-MS m/z 415
(M+, 100%); HRMS (EI) m/z calcd. C23H17N3O5 (M+) 415.1168, found 415.1159.
(Z)-3-(4-(4-(Benzyloxy)-3-methoxybenzylidene)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzoic
acid (1p). Solid. m.p. 249–252 ºC. 1H-NMR (DMSO): δ 2.35 (s, 3H), 3.89 (s, 3H), 5.26 (s,2H), 7.28–
7.50 (m, 7H), 7.57 (t, 1H), 7.77 (d, 2H), 8.14 (d, 1H), 8.22 (d, 1H), 8.52 (s, 1H), 8.77 (s, 1H); EI-MS
m/z 442 (M+, 100%); HRMS (EI) m/z calcd C26H22N2O5 (M+) 442.1529, found 442.1530.
(Z)-3-(4-(3-Methoxy-4-(pentyloxy)benzylidene)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzoic
acid (1q). Solid. m.p. 224–226 ºC. 1H-NMR (DMSO): δ 0.91 (t, 3H), 1.32–1.43 (m, 4H), 1.77 (m, 2H),
2.35 (s, 3H), 3.88 (s, 3H), 4.11 (t, 2H), 7.18 (d,1H), 7.57 (t, 1H), 7.77 (d, 2H), 8.13 (d, 1H), 8.22 (d,
1H), 8.52 (s, 1H), 8.77 (s, 1H); EI-MS m/z 422 (M+, 100%); HRMS (EI) m/z calcd. C24H26N2O5 (M+)
422.1842, found 422.1840.
(Z)-3-(4-(4-Isopropoxy-3-methoxybenzylidene)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzoic
1
acid (1r). Solid. m.p. 206–208 ºC. H-NMR (DMSO): δ 1.33 (s, 6H), 2.36 (s, 3H), 3.87 (s, 3H), 4.83
(m, 1H), 7,21 (d, 1H), 7.57 (t,1H), 7.76 (d, 1H), 7.79 (s, 1H), 8.15 (d, 1H), 8.22 (d, 1H), 8.53 (s, 1H),
8.75 (s, 1H); EI-MS m/z 394 (M+, 100%); HRMS (EI) m/z calcd. C24H26N2O5 (M+) 394.1529, found
394.1528.

Molecules 2010, 15
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4. Conclusions
We have developed a simple, rapid, and efficient one-pot protocol for the preparation of the
4-arylidenepyrazolone derivatives by a solvent-free, microwave-assisted reaction. Furthermore, the
procedure used commercially available reagents, giving the desired compounds in good to excellent
yields (51–98%). The versatility of this methodology makes it suitable for library synthesis in drug
discovery efforts.
Acknowledgements
We gratefully acknowledge the financial support from the National Natural Science Foundation of
China (Grants 90813005, 20902022, 30801415 and 30890044), the Open Project Program of State Key
Laboratory of Drug Research (Grant SIMM0901KF-03) and Shanghai Rising-Star Program (Grant
09QA1406800).
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Sample Availability: Samples of the compounds reported in this paper are available from the authors.
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