Microwave-assisted synthesis of 3-methyl-1-phenyl-chromeno[4,3-c]pyrazol- 4(1H)-ones under solvent-free conditions

Article abstract of DOI:10.3987/COM-13-12719

A novel microwave-assisted method for the synthesis of 3-methyl-1- phenylchromeno[4,3-c]pyrazol-4(1H)-ones by the cyclization of 3-[1-(phenylhydrazono)ethyl]chromen-2-ones with CuO/SBA-15 under solvent-free conditions is described. The reaction gave the c

Full text of DOI:10.3987/COM-13-12719

HETEROCYCLES, Vol. 87, No. 6, 2013, pp. . © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 25th March, 2013, Accepted, 7th May, 2013, Published online, 13th May, 2013
DOI: 10.3987/COM-13-12719
MICROWAVE-ASSISTED SYNTHESIS OF 3-METHYL-1-PHENYL-
CHROMENO[4,3-c]PYRAZOL-4(1H)-ONES UNDER SOLVENT-FREE
CONDITIONS
Guo-Yu Yang,a Jing-Tian Yang,b Cai-Xia Wang,a Su-Fang Fan,a Pu-Hui
Xie,a and Cui-Lian Xua *
a College of Science, Henan Agricultural University, Zhengzhou 450002, China
b Ecology Security and Protection Key Laboratory of Sichuan Province,
Mianyang Normal University, 621000, China; E-mail: xucuilian666@126.com
Abstract – A novel microwave-assisted method for the synthesis of
3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones by the cyclization of
3-[1-(phenylhydrazono)ethyl]chromen-2-ones
with
CuO/SBA-15
under
solvent-free conditions is described. The reaction gave the corresponding
chromenopyrazole products in good to excellent yields and in short reaction times.
Pyrazoles are heterocyclic compounds with a five membered ring containing three carbons and two
nitrogens. Such heterocyclic systems are widely distributed in nature. Pyrazoles have a wide range of
applications as agro and pharma chemicals due to their biological activities such as antibacterial,
antidepressant, antiamoebic, anti-inflammatory and antinociceptive activities.1-4
Coumarin derivatives have been widely reported to possess various biological activities, such as
antimicrobial activity5 and antifungal activity.6 Chromenopyrazoles are heterocyclic compounds
containing a rigid six-six-five tricyclic ring system. They have found application as ligands for the central
benzodiazepine receptor (BZR). For example, 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones are
commonly used to synthesize immunomodulatory drugs which can interact with the benzodiazepine
central receptor.7
One of the early synthetic methods for chromeno-pyrazoles which has been reported utilizes the
cyclization of 1-(phenylhydrazono)chromen-2-ones 4-substituted with –OH and –Cl in xylene with
p-toluenesulfonic acid as catalyst.8 Recently, a new method was reported for the preparation of
3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones
using
the
oxidative
cyclization
of
3-[1-(phenylhydrazono)ethyl]chromen-2-ones with copper acetate as catalyst.9 However this method

suffers from drawbacks such as difficult separation and recycling of the homogeneous catalyst, low
efficiency, solvent use, etc. In order to overcome these shortcomings, we decided to explore a
catalyst-supported system, using CuO as the catalyst under solvent-free microwave-assisted conditions.
SBA-15 was chosen as the carrier because of its relatively large specific surface area and uniform pore
diameter distribution.4,10-12 The supported catalyst CuO/SBA-15 has been used in many chemical reaction
and has been found to have high activity and selectivity.13,14 With the development of green chemistry,
microwave synthesis and solventless synthesis have been attracting more and more attention in organic
chemistry.15-17
In this paper, we report on the development of a novel microwave-assisted method for the synthesis of
3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones (2) by the cyclization of 3-[1-(phenylhydrazono)-
ethyl]chromen-2-ones (1) with supported Cu(II) (CuO/SBA-15) as the catalyst under solvent-free
conditions (Scheme 1).
Ar
HN
Ar
N
N
N
R1
R1
CuO/SBA-15
C Me
C Me
solvent-free, MW
O
O
O
O
R2
R2
2
1
Scheme 1. Synthetic route of the compounds 2
Under solvent-free conditions, two controlled trials were done to determine the influence of the catalyst
and microwave. In one, an oil bath was used and compound 1a was heated for 3 hours at 120 C with
CuO/SBA-15 as the catalyst (Table 1, entry 1, Conv: 85%). The other was run without the use of the
catalyst and compound 1a was heated for half an hour under microwave irradiation of 567 W (Table 1,
entry 2, Conv: 46%). we were pleased to find that in the presence of catalyst CuO/SBA-15 the conversion
of the compound 1a was 97% when the reaction was done for half an hour under microwave irradiation of
567 W (Table 1, entry 5). These results show that the influence of the catalyst and microwave are
significant.
This reaction was investigated for various reaction parameters such as time, microwave power and
catalyst loading. The effect of time on the conversion of the reactant was monitored from 10 to 30 min
(Table 1, entries 3-5). The conversion of compound 1a reached 97% when the time was 30 min. When the
microwave power was increased from 406 to 567 W (Table 1, entries 5, 6), the conversion of compound
1a increased from 10% to 97%. When the microwave power was increased from 567 to 700 W (Table 1,

entries 5, 7), the yield of product 2a decreased from 92% to 86%. When the molar ratio of the catalyst and
the reactant 1a was varied from 0.35 to 1.4 ×10-2 (Table 1, entries 7-9), the conversion of compound 1a
increased from 52% to 100%, and the time required for completing the reaction decreased from 30 to 20
minutes. This fully indicates that microwave power and catalyst amount are the key parameters affecting
the reaction rate. We also found that when the molar ratio of the catalyst and the reactant 1a increased
from 0.7 to 1.4 ×10-2 (Table 1, entries 5, 9), there was little decrease in the selectivity of the product 2a.
In comprehensive consideration of the reaction rate and product selectivity, 0.7×10-2 molar ratio of the
catalyst and the reactant 1a was optimum formulation.
Various chromenopyrazoles were efficiently synthesized with this green method. It was observed that the
coumarin hydrazones were easily converted into the expected products in excellent yields (Table 2). We
found that compounds containing electron withdrawing groups in the coumarin ring showed lower yields
(Table 2, entries 6, 8). Similarly, compounds containing electron withdrawing groups in the N-benzene
ring also showed lower yields (Table 2, entries 13, 14). These results show that electron withdrawing
groups are unfavorable for the cyclization of 3-[1-(phenylhydrazono)ethyl]chromen-2-ones.
Table 1. Effect of microwave power, time and catalyst loading on the formation of compound 2a under
microwave conditions
Catalyst loading Microwave
Microwave
power/w
_
Entry
Conversion/%a
Yield/%b
/%mol
0.7
0
time/min
1a
2
3
4
5
6
7
8
9
_
85
46
76
40
15
61
92
7.3
86
48
93
30
10
20
30
30
30
30
20
567
0.7
0.7
0.7
0.7
0.7
0.35
1.4
567
18
567
66
567
97
406
10
700
100
52
567
567
100
Reaction conditions: At the temperature 120 C in oil bath for 3 h.
a Determined by HPLC analysis of crude reaction mixture.
b Isolated yields.
A proposed mechanism for the synthesis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones is
shown in Scheme 2, which includes the Michael addition of an amino group to the enone, and then
oxidation to give the product.

To confirm their structures, monocrystals of chromenopyrazole 2d suitable for X-ray crystal diffraction
measurements were obtained by slow evaporation in acetic acid. X-Ray data for crystals of 2d were
collected by graphite monochromatized Mo Kα radiation at 293K. Crystal data and experimental details
for compound 2d are summarized in Table 3. The crystal structure and molecular packing of compound
2d are shown in Figure 1 and Figure 2, respectively. It can be seen that the benzopyran ring and the
pyrazole ring are essentially coplanar. The other benzene ring is at an approximately 90 angle to the
plane. Molecules of compound 2d are packed through weak interaction to form layered stacks.
Table 2. Preparation of products 2 by using various compounds 1 under microwave conditions
Microwave
time/min
Entry
Ar
Ph
R1
R2
Product 2
Yield/%a
1
H
H
H
H
2a
2b
2c
2d
2e
2f
30
80
81
72
76
86
50
60
41
58
68
70
64
55
50
2
3
4
Ph
Cl
40
40
45
45
30
40
45
30
30
25
40
40
45
Ph
Br
Ph
H
H
MeO
EtO
Cl
Br
H
5
Ph
6
7
Ph
Cl
Br
NO2
H
Ph
2g
2h
2i
8
Ph
9
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
3-NO2C6H4
3,5-(Cl)2C6H3
H
10
11
12
13
14
H
H
2j
H
H
2k
2l
H
H
H
H
2m
2n
H
H
15
16
2,4-Me2C6H3
4-MeOC6H4
H
H
H
H
2o
2p
30
20
78
81
Reaction conditions: Compounds 1 (0.72 mmol), CuO/SBA-15 (0.7 mol%), microwave power (567 W).
a Isolated yields.

+
HN
..
N
N
N
N
HN
C Me
C Me
C Me
O
O
1a
O
O-
O
OH
N
N
N N
H
H
C Me
C Me
O
-H2O
O
2a
O
3a
O
Cu/SBA-15
CuO/SBA-15
O2
Scheme 2. Proposed reaction mechanism for the catalytic cyclization
Figure 1. X-Ray crystal structure of chromenopyrazole 2d

Figure 2. A view of the molecular packing of compound 2d
Table 3. Crystal data and experimental details for compound 2d.
Empirical formula
C18H14N2O3
Formula weight
306.32
Temperature
293(2) K
Wavelength
0.71073 Å
Crystal system, space group
Unit cell dimensions
Monoclinic, P 1 21/c 1 (14)
a=20.3573(13) Å, alpha = 90 deg.
b=7.1099(5) Å, beta = 107.251(7) deg.
c= 25.7968(16) Å, gamma = 90 deg.
3565.8(4) Å3
Volume
Z, Calculated density
Absorption coefficient
F(000)
1, 0.171 Mg/m3
0.012 mm-1
192
Crystal size
Theta range for data collection
Limiting indices
Reflections collected/unique
Completeness to theta =26.00
Absorption correction
Data/restraints/parameters
Goodness-of-fit on F^2
Final R indices [I>2sigma(I)]
R indices (all data)
0.24×0.22×0.20 mm
2.98 to 26.37 deg.
-17≦h≦25, -8≦k≦8, -32≦l≦32
19572 / 7269 [R(int) = 0.0507]
99.8%
None
7269 / 0 / 495
1.079
R1 = 0.0817, wR2 = 0.1853
R1 = 0.1460, wR2 = 0.2141
0.312 and -0.293 e. Å-3
Largest diff. peak and hole

Table 4. Experiment on the recycling of the CuO/SBA-15 catalyst.
Cycle
1
2
3
4
Yield/% a
90
93
83
86
Reaction conditions: Compound 1a (0.72 mmol), CuO/SBA-15 (0.7 mol%), microwave power (567 W), microwave time
(35 min).
a Isolated yield of product.
The reusability of the CuO/SBA-15 catalyst was studied under microwave conditions. After the
completion of the reaction for the first run, the reaction mixture was thoroughly washed with methylene
chloride until the products were completely removed from the catalyst. Then the catalyst was washed
with ethyl alcohol, filtered and dried in an oven at 120 C for 4 h. The dried catalyst was used for the next
runs and the same procedure was adopted for all the recyclability studies. The conversion of compound
1a for the various runs are listed in Table 4. The result shows that the catalytic activity of the
CuO/SBA-15 could be kept at a constant high level.
In conclusion, a novel green, and atom economical method was developed for the synthesis of
3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones (2) by the cyclization of 3-[1-(phenylhydrazono)-
ethyl]chromen-2-ones (1) in the presence of CuO/SBA-15 under solvent-free and microwave irradiation
conditions. Compared with existing methods, the current protocol gives the targeted products in higher
yields and in shorter reaction times owing to the use of microwave. Moreover, making use of the
recoverable Cu catalyst under solvent-free conditions rendered this protocol advantageous, although
solvents are necessary for the isolation of the products as well as catalyst recovery in the work-up step.
EXPERIMENTAL
All solvents and reagents were purchased from commercial sources and were used without additional
purification. Melting points were determined with a X-5 digital microscopic melting-point apparatus
1
(Beijing Tech Instruments Co., Beijing, China) and are uncorrected. H and 13C NMR spectra were
recorded on a Bruker DPX-400 (400MHz) instrument in CDCl3 with TMS as the internal standard.
HRMS measurements were performed on a Waters Q-Tof MicroTM instrument. HPLC analysis was
performed on an Agilent 1200 HPLC (Chromatographic Column: XDB-C18 column with MeOH–H2O as
eluent) equipped with an Agilent 1200 UV detector. ICP were measured on an inductively coupled
plasmas atomic emission spectrometer from the American Thermo Electron company.
CCDC-929647 contains the supplementary crystallographic data for this paper. These data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/data-request/cif.
The preparation of the catalyst CuO/SBA-15

0.48 g (2.4 mmol) of Cu(MeCOO)2·H2O was dissolved in 75 mL of 1.6 mol/L HCl, and 2 g of p123
(EO20PO70EO20, Aldrich) was added to the above solution with stirring. The mixture was stirred until
the p123 dissolved. Then, 5 mL of TEOS as the silica source was added dropwise to the aqueous solution
with vigorous stirring. After the mixture was stirred for 24 h at 40 C and aged for 24 h at 100 C, the
solid obtained was filtered off, dried at 120 C for 8 h, and calcined at 550 C for 4 h. The sample thus
obtained is denoted as CuO/SBA-15 (0.16% by ICP).
Typical procedure for the preparation of compounds 2a-p.
3-[1-(Phenylhydrazono)ethyl]chromen-2-ones 1 (0.72 mmol), CuO/SBA-15 (0.7 mol%) and 4 g silica as
media were thoroughly grinded in a mortar. The silica supported mixture was heated with a microwave at
567 W. The sample was monitored by HPLC. After completion of the reaction, the resulting mixture was
extracted with CH2Cl2 (20 mL×3). The solvent was removed by reduced pressure distillation. The crude
product was recrystallized from EtOH to give compounds 2.
6-Ethoxy-3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-one (2e): yield 198 mg (86%); white
1
powder; mp 204-206 °C; H NMR (400 MHz, CDCl3): δ = 1.52 (t, J = 7.2 Hz, 3H, CH3), 2.70 (s, 3H,
CH3), 4.17-7.54 (m, 2H, CH2), 6.64-6.66 (m, 1H, ArH), 6.92-6.96 (m, 1H, ArH), 6.99-7.02 (m, 1H, ArH),
6.99-7.02 (m, 1H, ArH), 7.53-7.55 (m, 2H, ArH), 7.59-7.61 (m, 3H, ArH); 13C NMR (100MHz, CDCl3):
δ = 12.93, 14.75, 65.05, 106.38, 112.61, 113.88, 114.24, 123.69, 127.01, 129.79, 130.10, 139.49, 141.94,
147.52, 150.75, 157.49 ppm; HRMS (ESI+): m/z calcd for [C19H17N2O3]+: (M + H+) 321.1239; found:
321.1238.
6,8-Dibromo-3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-one (2g): yield 188 mg (60%); yellow
powder; mp 246-250 °C; 1H NMR (400 MHz, CDCl3): δ = 2.69 (s, 3H, CH3), 7.12 (d, J = 2 Hz, 1H, ArH),
13
7.51-7.54 (m, 2H, ArH), 7.64-7.66 (m, 3H, ArH), 7.81 (d, J = 2 Hz, 1H, ArH); C NMR (100 MHz,
CDCl3): δ = 12.83, 106.68, 112.67, 114.23, 116.33, 124.21, 126.70, 130.09, 130.68, 136.68, 138.63,
139.85, 149.04, 150.97, 156.02 ppm; HRMS (ESI+): m/z calcd for [C17H11Br2N2O2]+: (M + H+) 432.9187;
found: 432.9191.
1-(4-Bromophenyl)-3-methylchromeno[4,3-c]pyrazol-4(1H)-one (2k): yield 179 mg (70%); white
1
powder; mp 225-227 °C; H NMR (400 MHz, CDCl3): δ = 2.69 (s, 3H, CH3), 7.07-7.11(m, 1H, ArH),
7.15-7.17 (m, 1H, ArH), 7.43-7.49 (m, 4H, ArH), 7.74-7.77 (m, 2H, ArH); 13C NMR (100 MHz, CDCl3):
δ = 12.86, 106.64, 111.59, 118.20, 122.26, 123.99, 124.17, 128.39, 131.29, 133.09, 138.35, 141.74,
151.16, 153.27, 157.77 ppm; HRMS (ESI+): m/z calcd for [C17H12BrN2O2]+: (M + H+) 355.0082; found:
355.0083.
1-(2,4-Dichlorophenyl)-3-methylchromeno[4,3-c]pyrazol-4(1H)-one (2n): yield 124 mg (50%); light
1
yellow powder; mp 262-264 °C; H NMR (400 MHz, CDCl3): δ = 2.68 (s, 3H, CH3), 7.15 (t, J = 7 Hz,

ArH), 7.23 (d, J = 8 Hz, 1H, ArH), 7.46 (d, J = 8 Hz, 1H, ArH), 7.50-7.54 (m, 3H, ArH), 7.61(s, 1H,
ArH). 13C NMR (100MHz, CDCl3): δ = 12.83, 106.98, 111.27, 118.34, 122.16, 124.20, 125.52, 130.33,
131.58, 136.13, 140.88, 141.88, 151.57, 153.32, 157.53 ppm. HRMS (ESI+): m/z calcd for
[C17H11Cl2N2O2]+: (M + H+) 345.0198; found: 345.0199.
1-(2,4-Dimethylphenyl)-3-methylchromeno[4,3-c]pyrazol-4(1H)-one (2o): yield 170 mg (78%);
1
yellow powder; mp 176-179 °C; H NMR (400 MHz, CDCl3): δ = 2.00 (s, 3H, CH3), 2.69 (s, 3H, CH3),
6.83 (d, J = 8 Hz, 1H, ArH), 7.00-7.04 (m, 1H, ArH), 7.20-7.29 (m, 3H, ArH), 7.42-7.44 (m, 2H, ArH);
13C NMR (100 MHz, CDCl3): δ = 13.01, 17.19, 21.40, 105.66, 112.01, 117.93, 121.83, 124.19, 127.50,
28.12, 130.99, 132.15, 135.71, 135.80, 140.84, 142.16, 150.65, 153.24, 158.11 ppm. HRMS (ESI+): m/z
calcd for [C19H17N2O2]+: (M + H+) 305.1290; found: 305.1288.
ACKNOWLEDGMENTS
This work was supported by the Education Foundation of Henan Province (2006150011), the National
Natural Science Foundation (NSFC21102037) and Key Science and Technology Foundation of Henan
Province (112101110200).
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