Ultrasound-promoted greener synthesis of novel trifurcate 3-substituted-chroman-2,4-dione derivatives and their drug-likeness evaluation

Article abstract of DOI:10.3390/molecules171214146

An efficient and convenient approach for one-pot synthesis of 3-substituted chroman-2,4-diones via a three-component reaction of aromatic aldehydes, 4-hydroxycoumarins and diverse pyrazolone derivatives was described. The combinatorial synthesis for this

Full text of DOI:10.3390/molecules171214146

Molecules 2012, 17, 14146-14158; doi:10.3390/molecules171214146
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Ultrasound-Promoted Greener Synthesis of Novel Trifurcate
3-Substituted-chroman-2,4-dione Derivatives and Their
Drug-Likeness Evaluation
Chengyuan Liang, Hailong Jiang, Zhiguang Zhou, Dong Lei, Yu Xue and Qizheng Yao *
School of Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu, China;
E-Mails: chengyuanliang@gmail.com (C.L.); jianghailongsj@163.com (H.J.);
zhouzhiguang0728@126.com (Z.Z.); leidong0066@126.com (D.L.); xueyu0816@126.com (Y.X.)
* Author to whom correspondence should be addressed; E-Mail: qz_yao@yahoo.com.cn;
Tel./Fax: +86-25-8663-4730.
Received: 23 October 2012; in revised form: 12 November 2012 / Accepted: 23 November 2012 /
Published: 28 November 2012
Abstract: An efficient and convenient approach for one-pot synthesis of 3-substituted
chroman-2,4-diones via a three-component reaction of aromatic aldehydes, 4-hydroxy-
coumarins and diverse pyrazolone derivatives was described. The combinatorial synthesis
for this methodology was achieved by applying ultrasound irradiation in the absence of
activator while making use of water as green solvent. Additionally, novel chroman-2,4-dione
derivatives attached to an edaravone moiety represent an exploitable source of brand new
anticancer agents. In comparison with conventional methods, experimental simplicity, good
functional group tolerance, excellent yields, short routine, and atom efficiency are prominent
features of this sonocatalyzed procedure.
Keywords: chroman-2,4-diones; multicomponent reactions (MCRs); ultrasonic irradiation;
green chemistry; coumarin; edaravone
1. Introduction
In recent years, ultrasound-assisted organic synthesis (UAOS) utilizing environmentally benign
reagents and conditions has been one of the most fascinating developments in the arena of modern
synthetic chemistry owing to its green credentials [1–5]. The notable features of the aqueous UAOS

Molecules 2012, 17
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come from its advantages such as easier manipulation, energy conservation, rate enhancement and
insolubility of the final products which facilitates their isolation by simple filtration [6,7].
Coumarins, an old class of benzopyrene compounds, are widely used in the pharmaceutical industry as
precursor molecules in the synthesis of various anticoagulant [8,9], anti-HIV [10,11], anti-tumor [12,13],
anti-hypertension drugs [14]. Among these therapeutic properties, their cytotoxic effects on tumors were
most extensively examined by a number of in vitro and in vivo experiments as well as clinical studies.
Specifically, 4-hydroxycoumarin derivatives have attracted considerable attention since this class of
compounds allows access to many demonstrated bioactive agents [15,16]. For example,
4-hydroxycoumarin offshoots (Figure 1) have recently been identified as novel HIV protease inhibitors
(compounds I,II,III)[17] and anti-tumor chemicals (compounds IV,V) [18].
Figure 1. Examples of biologically active 4-hydroxycoumarin derivatives.
Moreover, the pyrazolone moiety (Figure 2) is an important pharmacophore which exhibits
widespread pharmacological properties, such as antimicrobial (compound VI) [19], anticancer
(compound VII) [20], analgesic (compound VIII) [21], and anti-inflammatory
(compound IX) entities [22]. It is noteworthy that the free radical scavenger edaravone
(X, 3-methyl-1-phenyl-2-pyrazolin-5-one, Radicut®) [23,24] enhances the anti-tumor effects of chemo-
therapeutics in murine colon cancer by increasing apoptosis via inhibition of nuclear factor kappa B
(NF-κB) [25]. Meanwhile, renal toxicity (acute cisplatin-induced renal injury) was reversed by clinically
available edaravone [26,27]. Therefore, in addition to its usefulness in the treatment of strokes,
edaravone is expected to play an integral role in oncotherapy.
Figure 2. Examples of biologically active pyrazolone derivatives.
From the viewpoint of rational drug design, the pharmacological properties and therapeutic
applications of coumarins depend upon the pattern of substitution on the benzopyrene nucleus. Hence,
novel chroman-2,4-dione (tautomer of 4-hydroxycoumarin) derivatives attached to an edaravone moiety
represented an exploitable source of brand new anticancer agents, which might also help addressing
side-toxicity. In the present research work, the objective was to develop new chemical entities (triplet
3-substituted chroman-2,4-diones interlinking 4-hydroxycoumarins and edaravone) as basic scaffolds,
endowed with potential synergy in elevating antitumor effects as well as preventing the adverse effects
and decreasing toxicity. Herein, we are delighted to afford a convenient, practical and efficient reaction

Molecules 2012, 17
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for the synthesis of the target lead compounds via readily available building blocks under ultrasonic
irradiation in water as shown in Scheme 1. The present research would significantly widen the versatility
of the diversity-oriented aldehyde-based MCRs.
Scheme 1. Synthesis of 3-substituted chroman-2,4-diones under ultrasonic irradiation.
2. Results and Discussion
To find out the suitable conditions for the reaction, our initial experiments were demonstrated by a
series of experiments with the model reaction (Scheme 2) using different catalysts and solvents. In each
case, the substrates were mixed together with 25 mL of solvent under ultrasonic irradiation (40 kHz) or
high speed stirring with traditional heating. The screening results of the reaction are listed in Table 1.
Table 1. The effect of the reaction conditions for the synthesis of 4a under ultrasound irradiation.
With sonication a
Without sonication b
Catalyst
(mol%)
Temprature
Entry
Solvent
Time (h) Yield (%) c Time (h)
Yield (%) c
(°C)
70
80
80
60
70
80
60
60
60
60
60
60
1
2
EtOH
Acetonitrile
Toluene
Water
———
1
55
14
4
4
2
2
2
4
6
2
2
2
2
2
23
<5
—
———
1
3
———
0.5
0.5
0.5
1
—
4
———
81
67
5
EtOH
ZnCl2(5)
Et3N(5)
—
—
6
Acetonitrile
Water
Trace
36
Trace
15
7
Morpholine(5)
ZnCl2(5)
AlCl3(5)
1
8
Water
0.5
0.5
0.5
0.5
0.5
—
—
9
Water
—
—
10
11
12
Water
Morpholine(5)
Et3N(5)
51
36
Water
35
17
Water
L-proline(5)
42
30
a Ultrasonic frequencies of 40 kHz, while the ultrasonic power was kept at 250 W; b The mixture was kept silent
under high stirring condition; c Isolated yields.
2.1. Effects of the Catalysts under Ultrasound Irradiation
It was observed that when classical organic bases, such as morpholine and triethylamine, were used to
mediate the reaction, low yields were obtained (entries 6, 7 and 10, 11). Further study with varying
Lewis acids and BrØnsted acids revealed no yields of 4a compared with basic catalyst, while
simultaneously, the byproduct 5a was predominantly afforded by a side-reaction (Scheme 2, entries 5, 8
and 9).

Molecules 2012, 17
Scheme 2. Side-reaction promoted by Lewis acids or Br
14149
Ø
nsted acids.
As can be seen from Table 1, the reaction rendered moderate amounts of desired product 4a in the
presence of L-proline (entry 12). When the reaction was performed in ethanol and acetonitrile in the
absence of catalyst, 4a was obtained in 55% and 14% yield, respectively (entries 1 and 2). Specifically,
the formation of product 4a was more facile and proceeded in pure water to give not only high yield, but
also with high reaction rate (81% yield in 30 min, entry 4).
2.2. Effects of the Solvents under Ultrasound Irradiation
Polar protic solvents (ethanol and water) afforded moderate to high yields of the desired product.
When the reaction was performed in acetonitrile, the desired product 4a was only obtained in 14% yield
(entry 2) and took a comparatively longer reaction time. Disappointingly, when the reaction was
conducted in the non-polar solvent toluene, only the byproduct 5a was obtained (entry 3, yield, 83%). In
general, improvements in rates and yields of all trials are observed when reactions were carried out in
polar protic solvents compared with polar aprotic and non-polar solvents.
2.3. Comparison of Ultrasonic Irradiation and Conventional Method
As depicted in Table 1, the ultrasound-assisted technique was proven to be excellent in all cases
whereas traditional heating has low efficiency, even with prolonged reaction times. Based on the results
from this study, it was attractive that the ultrasound improved both the purity and yield of products. In
order to verify the effect of irradiation frequency, the reaction was also performed in 30, 40, and 50 kHz.
When the frequency was 40 kHz, the yield of 4a (81%, Table 2, entry 2) was higher than that with 30 kHz
irradiation within 30 min (67%, Table 2, entry 1). With an increase of irradiation frequency from 40 to
50 kHz (Table 2, entries 2, 3), the reaction yield did not change considerably (79%). The results showed
that there was an optimum frequency for effective synthesis of 4a in the frequency of 40 kHz at 60 °C.
Table 2. The synthesis of 4a under ultrasound irradiation in various frequency a.
Entry
Frequency (kHz)
Temprature (°C)
Time (h)
0.5
Yield (%) b
30
40
50
60
60
60
67
81
79
2
3
0.5
0.5
a Reaction conditions: the ultrasonic power was kept at 250 W; b Isolated yield.
2.4. High Efficiency and Generality of Synthesis by Ultrasound Irradiation
With the optimized conditions in hand, the versatility of this protocol was investigated by a library of
sixteen 3-substituted-chroman-2,4-diones combining substituted aromatic aldehydes 1, 4-hydroxy-

Molecules 2012, 17
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coumarins 2 and pyrazolones 3. According to Table 3, 4-hydroxycoumarins and pyrazolones carrying
either electron-releasing or electron-withdrawing substituents at the para-position of the aromatic ring
proved to be suitable substrates for this reaction. On the other hand, the aromatic aldehydes bearing
electron-donating groups are more reactive in this protocol, affording the desired products with
excellent yields and after shortened reaction times (Table 3, entries 3, 5 and 7). It is noteworthy that the
hydroxyl group of vanillin remains intact after the reaction, obviously, which leaves a useful handle for
further synthetic diversity.
Table 3. Synthesis of 3-substituted-chroman-2,4-diones(4a–p) via Scheme 1.
Time
(min)
Isolated
Entry
R1
R2
R3
Product
4a
Mp (°C)
logP a
Yield (%)
1
H
H
30
81
151–153 3.34 ± 0.04
2
3
H
H
H
H
30
30
4b
4c
89
83
168–170 3.60 ± 0.04
163–165 3.73 ± 0.05
O
4
H
H
30
4d
77
166–168 3.89 ± 0.04
HO
5
6
7
8
H
H
H
H
H
H
H
H
30
30
30
30
4e
4f
82
71
78
83
184–186 3.47 ± 0.04
177–179 4.17 ± 0.05
149–151 4.34 ± 0.04
133–135 3.86 ± 0.04
4g
4h
9
H
H
H
30
30
4i
4j
65
79
130–132 2.45 ± 0.06
195–197 3.90 ± 0.04
10
Cl
11
12
13
14
F
H
H
H
H
Me
F
30
30
30
30
4k
4l
58
87
73
64
189–191 3.51 ± 0.04
193–196 3.83 ± 0.05
187–189 3.50 ± 0.04
185–187 4.02 ± 0.04
4m
4n
Cl
15
16
F
F
Me
F
30
30
4o
4p
81
83
199–201 3.98 ± 0.06
162–164 4.06 ± 0.04
a Isolated yield; b Theoretical values of logP were calculated using commercially available ACD
LAB/log P release 10, product version 10.08.

Molecules 2012, 17
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The structures of isolated new products 4a-p were determined by physical and spectroscopic data
1
such as: H-NMR, 13C-NMR and ESI-HRMS analysis. Taking compound 4a as a representative
example, its 1H-NMR spectrum revealed the presence of two singlet signals at δ = 2.41 and δ = 3.62 ppm
corresponding to the -CH3 group of edaravone and the -OCH3 group adjacent to vanillin, respectively,
and another singlet signal at δ = 5.66 ppm due to the -OH of the vanillin scaffold, which underwent a
facile hydrogen exchange upon addition of deuterium oxide. In the HH-COSY spectroscopy of
compound 4a, correlations between adjacent protons from three stereogenic centres were observed
(4.05 ppm, 1.19 ppm and 1.17 ppm). This phenomenon suggested that the structure of compound 4a
was depicted accurately, which could be proved by the other 2D-NMR spectra.
2.5. the Study of Acceleration Mechanism under Irradiation of Ultrasound
A plausible mechanism is proposed and shown in Scheme 3. The process represents a typical tandem
of Knoevenagel condensation and Michael addition, which might initiate via two pathways, namely path
A and path B.
Once the three components are mixed, aldehyde 1 undergoes a Knoevenagel condensation with
edaravone (3) under ultrasonic irradiation to afford the relay moiety 5 after dehydratation, which is
subsequently attacked by 4-hydroxycoumarin 2 to furnish the central target compound 4 (path A).
Alternatively, intermediate 6’ is likely formed from initial condensation of 1 with 2 to afford 6, followed
by nucleophilic addition of edaravone 3 (path B).
Upon irradiation by high-intensity ultrasound, acoustic cavitation occurs and gives rise to the
formation, growth, and implosive collapse of bubbles in water with consequent high local temperatures
and pressures, which accelerates the mass transfer and shortens the reaction time.
Scheme 3. Plausible mechanism for the formation of product 4.

Molecules 2012, 17
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2.6. Drug-Likeness Evaluation of Obtained 3-substituted-chroman-2,4-Diones
Drug-likeness may be defined as a complex balance of intriguing insights, including various
molecular properties and structure features, which determine whether a particular molecule has
potentiality to be an orally active drug. Lipinski et al. [28,29] examined the drugs on the market and
established the so-called “Rules of Five”, which have served as a guide in drug-like analysis and as an
efficient filter in prioritizing compound libraries prior to high-throughput screening. With drug-like
criteria in mind, the molecular mass of each obtained “drug-like” compound should be less than 500
Daltons. The partition coefficient logP values of the synthesized molecules were calculated (Table 3)
and found to be between 2.45 and 4.34. This range is in agreement with estimated values for good
lipophilicity and solubility (between 2.0 and 5.0).
Aqueous solubility of a solid chemical can be also applied as a rule to define drug-likeness.
Melting point is usually an indicator of crystal lattice energy, which has a dramatic influence on
solvation free energy (aqueous solubility). The ceiling melting point of all the trifurcate
3-substituted-chroman-2,4-diones discussed above is 201 °C, in which means favorable estimated
solubility. We concluded that all the key parameters (predictors of molecular transport properties
across cell membranes and indicators of protein binding characteristics) have no violation of Lipinski’s
Rules at all.
3. Experimental
General
All reagents used in this work were obtained commercially available and were used without
1
13
purification. H- and C-NMR spectra were recorded on a BRUKER AV-300 spectrometer at 300.13
and 75.47 MHz, respectively. 1H and 13C-NMR spectra were obtained from solutions of DMSO-d6 and
are reported as parts per million (ppm) downfield from a tetramethylsilane internal standard. The
following abbreviations are used; singlet (s), doublet (d), triplet (t) and multiplet (m). The mass
spectrometric analyses (HRMS) were performed using a JMS-700 MStation High Resolution JEOL
Mass Spectrometer with a source temperature of 230 °C, an ionization energy of 70 eV and an ionization
trap current of 300 A. Melting points were measured by a differential scanning calorimeter (Shimadzu
DSC-50) and were uncorrected. The standard heating rate for all compounds was 10 °C/min. Sonication
was performed in Shanghai Branson-CQX ultrasonic cleaner. The flask was located at the maximum
energy area in the cleaner and addition or removal of water was used to control the temperature of the
water bath.
3.1. Typical Procedure for the Synthesis of Trifurcate 3-substituted-chroman-2,4-Dione (4a) in Water
A 50 mL flask was charged with vanillin (152 mg, 1 mmol), edaravone (174 mg, 1 mmol) and
4-hydroxycoumarin (162 mg, 1 mmol) in water (25 mL). The reaction conditions were adjusted
separately as indicated in Table 1. After completion of the reaction (monitored by TLC)., the solvent was
removed under reduced pressure, and the crude mixture was purified by silica gel column
chromatography (n-hexane/ethyl acetate, 20:80) to offer pure product 4a.

Molecules 2012, 17
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3.2. Ultrasound-promoted Typical Procedure for Synthesis of 3-substituted-chroman-2,4-dione (4a)
A 50 mL flask was charged with vanillin (152 mg, 1 mmol), edaravone (174 mg, mmol) and
4-hydroxycoumarin (162 mg, 1mmol) in water (25 mL). The reaction flask was placed in the ultrasonic
bath, where the surface of reactants is slightly lower than the level of the water, and irradiated separately
under 30, 40, and 50 kHz at 50 °C (bath temperature, the temperature inside the reactor was also 50 °C)
for the period of time as indicated in Tables 1–3. The reaction temperature was controlled by addition or
removal of water from ultrasonic bath. After completion of the reaction (monitored by TLC), the
crude mixture was purified by silica gel column chromatography to afford desired product 4a after
solvent evaporation.
3.3. Spectral Data for New Derivatives of Trifurcate 3-substituted-chroman-2,4-diones 4a–p
3-((4-Hydroxy-3-methoxyphenyl)(3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)methyl)chroman-
2,4-dione (4a). Pale yellow crystals; 1H-NMR (DMSO-d6)  7.84 (1H, d, J = 7.28 Hz), 7.72 (2H, d,
J = 7.28 Hz), 7.59–7.50 (3H, m), 7.38–7.31 (3H, m), 6.73–6.64 (3H, m), 5.65 (1H, s), 4.05 (1H, dd,
J = 4.30 Hz, J = 5.00 Hz), 3.62 (3H,s), 2.41 (3H,s), 1.19 (1H, d, J = 5.00 Hz), 1.17 (1H, d, J = 4.30 Hz);
13C-NMR (DMSO-d6)  164.7, 163.8, 162.7, 152.4, 147.7, 145.5, 135.7, 132.3, 130.7, 129.7, 127.0,
124.3, 121.2, 119.9, 118.5, 116.3, 115.7, 112.2, 107.5, 106.4, 60.2, 56.2, 33.7, 21.1, 14.5; HRMS (ESI)
for (M+H)+: calcd 471.1 556, found 471.1559.
3-((3,4-Dimethoxyphenyl)(3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)methyl)chroman-2,4-
dione (4b). Pale yellow crystals; 1H-NMR (DMSO-d6) : 7.84 (2H, d, J = 7.10 Hz), 7.75 (1H, d, J = 7.10
Hz), 7.57 (1H, m), 7.49–7.31 (4H, m), 7.13–6.81 (4H, m), 4.20 (1H, dd, J = 5.10 Hz, J = 4.40 Hz), 3.74 (6H,
13
s), 2.42 (3H, s), 1.20 (1H, d, J = 5.10 Hz), 1.16(1H, d, J = 4.40 Hz); C-NMR (DMSO-d6) : 169.0,
162.5, 161.2, 155.6, 152.5, 147.5, 145.0, 136.7, 133.5, 129.9, 128.0, 127.6, 124.6, 124.5, 119.4, 117.3,
112.1, 109.5, 58.6, 56.1, 34.3, 22.0, 15.7; HRMS (ESI) for (M+H)+: calcd 485.1713, found 485.1719.
3-((4-Methoxyphenyl)(3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)methyl)chroman-2,4-dione
1
(4c). Colorless crystals; H-NMR (DMSO-d6) : 7.94 (2H, d, J = 7.10 Hz ), 7.78 (2H, d, J = 7.10 Hz),
7.60–7.51 (4H, m), 7.48–7.34 (4H, m), 7.19 (1H, m), 4.15 (1H, dd, J = 4.30 Hz, J = 3.81 Hz), 3.83 (3H,
13
s), 2.44(3H, s), 1.20 (1H, d, J = 4.30 Hz), 1.17 (1H, d, J = 3.81 Hz); C-NMR (DMSO-d6) : 173.9,
169.0, 162.5, 161.2, 157.8, 155.6, 152.5, 140.7, 138.9, 133.5, 128.9, 128.0, 125.4, 124.6, 124.5, 119.4,
117.3, 115.2, 59.2, 56.1, 39.2, 21.7, 14.9; HRMS (ESI) for (M+H)+: calcd 455.1607, found 455.1611.
3-((3-Fluoro-4-methoxyphenyl)(3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)methyl)chroman-
1
2,4-dione (4d). Colorless crystals; H-NMR (DMSO-d6) : 7.88(1H, d, J = 6.82 Hz), 7.74 (2H, d,
J = 6.82 Hz), 7.58–7.34 (5H, m), 7.19–6.73 (4H, m), 4.17 (1H, dd, J = 3.95 Hz, J = 2.50 Hz), 3.83 (3H,
s), 2.43 (3H, s) 1.20 (1H, d, J = 2.50 Hz ), 1.18 (1H, d, J = 3.95 Hz); 13C-NMR (DMSO-d6) : 175.1,
169.0, 162.9, 160.3, 155.6, 152.5, 151.8, 144.9, 142.3, 138.4, 132.5, 129.4, 127.6, 126.0, 125.4, 124.7,
124.2, 119.4, 117.3, 115.1, 108.1, 58.6, 55.8, 41.2, 21.7, 14.1; HRMS (ESI) for (M+H)+: calcd 473.1513,
found 473.1518.

Molecules 2012, 17
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3-((4-Hydroxyphenyl)(3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)methyl)chroman-2,4-dione
1
(4e). Light red crystals; H-NMR (DMSO-d6) : 7.89 (1H, d, J = 7.15 Hz), 7.78 (2H, d, J = 7.15 Hz),
7.60–7.36 (5H, m), 7.29–7.03 (3H, m), 6.67 (2H, m), 5.85 (1H, s), 4.12 (1H, dd, J = 3.80 Hz, J = 2.50 Hz),
2.44 (3H, s) 1.19 (1H, d, J = 2.50 Hz), 1.16 (1H, d, J = 3.80 Hz); 13C-NMR (DMSO-d6) : 172.9, 169.0,
166.6, 162.8, 155.7, 155.6, 153.5, 140.1, 138.9, 135.6, 133.5, 128.9, 127.5, 124.6, 117.3, 115.6, 110.7,
108.6, 58.6, 43.2, 21.7, 15.7; HRMS (ESI) for (M+H)+: calcd 441.1450, found 441.1459.
3-((3-Methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)(4-nitrophenyl)methyl)chroman-2,4-dione
(4f). Brown crystals; 1H-NMR (DMSO-d6) : 8.28–7.96 (4H, m), 7.78–7.60 (2H, m), 7.55–7.03 (7H, m),
4.22 (1H, dd, J = 4.80 Hz, J = 3.70 Hz), 2.43 (3H, s), 1.19 (1H, d, J = 3.70 Hz), 1.17 (1H, d, J = 4.80 Hz);
13C-NMR (DMSO-d6) : 178.9, 169.0, 166.3, 161.8, 155.6, 152.5, 145.1, 143.2, 138.9, 133.5, 128.9,
127.6, 127.5, 125.4, 124.6, 123.6, 117.3, 109.2, 58.6 , 46.2, 21.7, 19.9; HRMS (ESI) for (M+H)+: calcd
470.1352, found 470.1356.
3-((3-Methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)(p-tolyl)methyl)chroman-2,4-dione
(4g).
Colorless crystals; 1H-NMR (DMSO-d6) : 7.98–7.70 (3H, m), 7.60–7.30 (7H, m), 7.09–6.80 (3H, m),
4.13 (1H, dd, J = 4.40 Hz, J = 3.51 Hz), 2.43 (3H, s), 1.94 (3H, s), 1.19 (1H, d, J = 3.51 Hz), 1.17 (1H, d,
13
J = 4.40 Hz); C-NMR (DMSO-d6) : 170.9, 168.0, 163.5, 160.2, 158.3, 157.8, 155.6, 152.5, 140.7,
138.9, 133.5, 128.9, 128.0, 125.4, 124.6, 124.5, 119.4, 117.3, 115.2, 58.6, 56.1, 39.2, 20.8, 14.9; HRMS
(ESI) for (M+H)+: calcd 439.1658, found 439.1655.
3-((3-Methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)(phenyl)methyl)chroman-2,4-dione
(4h).
Colorless crystals; 1H-NMR (DMSO-d6) : 7.88 (2H, d, J = 6.10 Hz), 7.73 (1H, d, J = 6.10 Hz), 7.59
(1H, t, J = 6.10 Hz), 7.48–7.30 (8H, m), 7.27–7.19 (2H, m), 4.08 (1H, dd, J = 4.60 Hz, J = 3.91 Hz), 2.40
(3H, s) 1.20 (1H, d, J = 3.91 Hz), 1.17 (1H, d, J = 4.60 Hz); 13C-NMR (DMSO-d6) : 178.9, 172.9, 169.0,
166.5, 155.6, 152.5, 148.2, 138.9, 135.6, 133.2, 129.4, 128.1, 125.4, 124.6, 122.2, 117.3, 114.0, 106.5,
56.8, 46.2, 20.7, 14.3; HRMS (ESI) for (M+H)+: calcd 424.1423, found 424.1427.
3-(Furan-2-yl(3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)methyl)chroman-2,4-dione (4i).
Colorless crystals; 1H-NMR (DMSO-d6) : 7.85 (2H, d, J = 6.96 Hz ), 7.73 (1H, d, J = 6.96 Hz), 7.58
(1H, m), 7.48–7.03 (6H, m), 6.40 (1H, t, J = 6.30 Hz), 6.08 (1H, t, J = 6.30 Hz), 4.40 (1H, dd, J = 3.90
Hz, J = 2.80 Hz), 2.42 (3H, s), 1.20 (1H, d, J = 2.80 Hz), 1.16 (1H, d, J = 3.90 Hz); 13C-NMR
(DMSO-d6) : 179.1, 174.8, 169.3, 167.5,161.3, 155.6, 152.5, 148.2, 138.9, 135.6, 133.2, 129.4, 128.0,
127.6, 125.4, 124.6, 117.3, 110.0, 107.3, 104.7, 56.8, 44.4, 22.9, 19.3; HRMS (ESI) for (M+H)+: calcd
415.1294, found 415.1293.
6-Chloro-3-((4-hydroxy-3-methoxyphenyl)(3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)met
hyl)chroman-2,4-dione (4j). Pale yellow crystals;1H-NMR (DMSO-d6) : 8.05–7.66 (4H, m), 7.43–7.05
(4H, m), 6.83–6.66 (3H, m), 5.45(1H, s), 4.05 (1H, dd, J = 4.40 Hz, J = 3.60 Hz), 3.62 (3H, s), 2.44 (3H,
13
s), 1.21 (1H, d, J = 3.60 Hz), 1.17(1H, d, J = 4.40 Hz); C-NMR (DMSO-d6) :174.7, 168.8, 165.3,
156.5, 149.7, 145.6, 135.9, 131.3, 130.7, 128.7, 127.3, 125.1, 121.7, 119.5, 118.3, 116.2, 115.1, 112.8,
107.2, 106.2, 60.9, 56.2, 34.7, 22.1, 15.3; HRMS (ESI) for (M+H)+: calcd 505.9264, found 505.9267.

Molecules 2012, 17
14155
6-Fluoro-3-((4-hydroxy-3-methoxyphenyl)(3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)meth
yl)chroman-2,4-dione (4k). Pale yellow crystals; 1H-NMR (DMSO-d6) : 7.95–7.75 (3H, m), 7.44–7.07
(5H, m), 6.84–6.68 (3H, m), 5.35 (1H, s), 4.12 (1H, dd, J = 4.10 Hz, J = 3.30 Hz), 3.65 (3H, s), 2.43 (3H,
13
s), 1.20 (1H, d, J = 4.10 Hz), 1.18 (1H, d, J = 3.30 Hz); C-NMR (DMSO-d6) :178.7, 167.7, 166.2,
158.3, 150.1, 146.2, 136.8, 133.1, 131.4, 129.2, 128.1, 126.8, 126.0, 118.8, 117.1, 116.1, 115.7, 111.9,
108.1, 107.4, 59.4, 55.5, 35.6, 23.1, 14.8; HRMS (ESI) for (M+H)+: calcd 489.1462, found 489.1466.
3-((4-Hydroxy-3-methoxyphenyl)(3-methyl-5-oxo-1-p-tolyl-4,5-dihydro-1H-pyrazol-4-yl)methyl)chroman-
2,4-dione (4l). Pale yellow crystals; 1H-NMR (DMSO-d6) : 7.79–7.64 (2H, m), 7.59–7.50 (3H, m),
7.38–7.31 (3H, m), 6.73–6.64 (3H, m), 5.65 (1H, s), 4.05 (1H, dd, J = 4.30 Hz, J = 3.81 Hz), 3.62 (3H, s),
2.41 (3H, s), 2.33 (3H, s), 1.20 (1H, d, J = 3.81 Hz), 1.18 (1H, d, J = 4.30 Hz); 13C-NMR (DMSO-d6)
:167.3, 164.2, 163.4, 152.4, 147.7, 144.1, 135.7, 132.3, 131.3, 129.7, 126.9, 123.9, 121.0, 118.8, 116.3,
115.7, 114.5, 113.2, 107.4, 105.8, 61.2, 56.2, 33.7, 23.4, 21.3, 14.6; HRMS (ESI) for (M+H)+: calcd
485.1713, found 485.1719.
3-((1-(4-Fluorophenyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)(4-hydroxy-3-methoxyphenyl)-
methyl)chroman-2,4-dione (4m). Pale yellow crystals; 1H-NMR (DMSO-d6) : 7.78–7.66 (3H, m), 7.60
(1H, m), 7.48–7.05 (4H, m), 6.78–6.69 (3H, m), 5.45 (1H, s), 4.15 (1H, dd, J = 4.50Hz, J = 3.90 Hz),
3.62 (3H, s), 2.41 (3H, s), 1.19 (1H, d, J = 3.90 Hz), 1.17(1H, d, J = 4.50 Hz); 13C-NMR (DMSO-d6)
:167.7, 164.8, 162.7, 152.4, 147.7, 145.5, 135.7, 132.3, 131.7, 129.7, 128.0, 124.3, 121.2, 120.5, 118.5,
117.3, 115.7, 112.2, 108.5, 106.4, 60.2, 58.2, 33.7, 21.1, 14.5; HRMS (ESI) for (M+H)+: calcd 489.1462,
found 489.1467.
1-(4-Chlorophenyl)-4-((4-hydroxy-3-methoxyphenyl)(4-oxochroman-3-yl)methyl)-3-methyl-1H-pyrazol
-5(4H)-one (4n). Pale brown crystals; 1H-NMR (DMSO-d6) : 7.79–7.60 (4H, m), 7.46–7.04 (4H, m),
6.80–6.71 (3H, m), 5.43 (1H, s), 4.12 (1H, dd, J = 4.30Hz, J = 3.60 Hz), 3.69 (3H, s), 2.43 (3H, s), 1.20
13
(1H, d, J = 3.60 Hz), 1.18 (1H, d, J = 4.30 Hz); C-NMR (DMSO-d6) :169.3, 166.2, 163.7, 151.4,
148.7, 145.3, 135.4, 132.7, 131.2, 129.7, 128.2, 124.4, 121.7, 120.1, 118.4, 117.2,115.6, 112.1, 108.3,
106.2, 60.1, 58.1, 33.5, 21.0, 15.4; HRMS (ESI) for (M+H)+: calcd 491.1374, found 491.1378.
6-Fluoro-3-((4-hydroxy-3-methoxyphenyl)(3-methyl-5-oxo-1-p-tolyl-4,5-dihydro-1H-pyrazol-4-yl)-
1
methyl)chroman-2,4-dione (4o). Pale yellow crystals; H-NMR (DMSO-d6) : 7.79–7.64 (2H, m),
7.69–7.49 (3H, m), 7.39–7.30 (2H, m), 6.76–6.65 (3H, m), 5.62 (1H, s), 4.09 (1H, dd, J = 5.00Hz,
J = 4.10 Hz), 3.68 (3H, s), 2.43 (3H, s), 2.31 (3H, s), 1.21 (1H, d, J = 4.10 Hz), 1.17 (1H, d, J = 5.00 Hz);
13C-NMR (DMSO-d6) :168.7, 165.1, 164.3, 151.2, 149.3, 145.9, 136.2, 135.7, 132.3, 130.7, 128.4,
126.1, 120.2, 118.3, 116.5, 115.2, 114.0, 113.1, 107.2, 105.0, 61.1, 57.6, 36.0, 22.9, 21.2, 14.5; HRMS
(ESI) for (M+H)+: calcd 503.1618, found 503.1615.
6-Fluoro-3-((1-(4-fluorophenyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)(4-methoxyphenyl)-
methyl)-chroman-2,4-dione (4p). Colorless crystals; 1H-NMR (DMSO-d6) : 7.85 (2H, d, J = 7.24 Hz ),
7.52 (1H, s), 7.40–7.22 (4H, m), 6.91 (4H, d, J = 7.24 Hz), 4.08 (1H, dd, J = 4.30 Hz, J = 3.81 Hz), 3.87
(3H, s), 2.48 (3H, s), 1.19 (1H, d, J = 3.81 Hz), 1.16 (1H, d, J = 4.30 Hz); 13C-NMR (DMSO-d6) : 173.9,
172.9, 169.0, 162.9, 159.6, 157.8, 155.6, 148.1, 147.2, 140.7, 138.9, 133.5, 128.9, 128.0, 125.1, 123.2,

Molecules 2012, 17
14156
120.2, 115.7, 114.0, 108.9, 56.3, 52.8, 39.2, 22.0, 14.9; HRMS (ESI) for (M+H)+: calcd 491.1419, found
491.1421.
4-(4-Hydroxy-3-methoxybenzylidene)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (5a). Colorless crystals;
Mp, 131–133°C ; 1H-NMR (DMSO-d6) : 9.17 (1H, s), 7.95 (1H, d, J = 6.80 Hz ), 7.82 (1H, d, J = 7.10 Hz),
7.52 (1H, t, J = 7.10 Hz), 7.43–7.33 (3H, m), 7.26 (1H, d, J = 6.80 Hz), 7.17 (1H, s), 7.01 (1H, s), 4.03
13
(3H, s), 2.32 (3H, s); C-NMR (DMSO-d6) : 190.8, 162.4, 151.0, 147.4, 146.4, 138.5, 131.1, 128.7,
127.4, 126.5, 124.8, 124.5, 119.4, 115.3, 114.4, 108.8, 77.4, 77.0, 76.6, 56.5, 56.1, 29.6, 13.3; HRMS
(ESI) for (M+H)+: calcd 309.1239, found 309.1245.
4. Conclusions
In summary, an expeditious, greener and atom economic methodology for the synthesis of novel
3-substituted-chroman-2,4-diones has been reported. Compared with traditional synthetic methods, the
application of water as a promising solvent without any harmful catalysts has received considerable
attention owing to its green credentials. The aqueous ultrasound promoted synthetic approach revealed
in our research was in line with the trend of developing green chemistry using environmentally benign
reagents and energy economical conditions. Further biological evaluation of these modified coumarin
candidates with promising improved therapeutic activity and reduced toxicity is ongoing in our
laboratory. The present work could find extensive applications in view of the power of the
diversity-oriented multicomponent reactions as a valid and green alternative which would widen
significantly the versatility and scope of the aldehyde-based MCRs.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/17/12/14146/s1.
Acknowledgments
This work was supported by National Science and Technology Major Project of the Ministry
of Science and Technology of China (No. 2009ZX09301-006). We appreciate the support from
Center for Instrumental Analysis, China Pharmaceutical University, for their contribution to the
structural confirmation.
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Sample Availability: Samples of the compounds 4a–p and 5a are available from the authors.
© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).