Study on the cyclization methods of 3-[1-(phenyl-hydrazono)ethyl]-chromen- 2-ones

Article abstract of DOI:10.1080/00397911.2011.630772

Some new methods, such as air oxidation, catalytic oxidation, and solvent-free synthesis, are developed for the synthesis of 3-methyl-1- phenylchromeno[4,3-c]pyrazol-4(1H)-ones(2) from the cyclization of 3-[1-(phenyl-hydrazono)ethyl]-chromen-2-ones(1). Co

Full text of DOI:10.1080/00397911.2011.630772

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Study on the Cyclization Methods of 3-
[1-(Phenyl-hydrazono)ethyl]-chromen-2-
ones
Guo-Yu Yang a , Cai-Xia Wang a , Su-Fang Fan a , Long-Jie Zhao a ,
Dan Wang a & Cui-Lian Xu a
a College of Science, Henan Agricultural University, Zhengzhou,
China
Accepted author version posted online: 14 Mar 2012.Version of
record first published: 21 Feb 2013.
To cite this article: Guo-Yu Yang , Cai-Xia Wang , Su-Fang Fan , Long-Jie Zhao , Dan Wang & Cui-
Lian Xu (2013): Study on the Cyclization Methods of 3-[1-(Phenyl-hydrazono)ethyl]-chromen-2-ones,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 43:9, 1263-1269
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Synthetic Communications1, 43: 1263–1269, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.630772
STUDY ON THE CYCLIZATION METHODS OF 3-[1-
(PHENYL-HYDRAZONO)ETHYL]-CHROMEN-2-ONES
Guo-Yu Yang, Cai-Xia Wang, Su-Fang Fan, Long-Jie Zhao,
Dan Wang, and Cui-Lian Xu
College of Science, Henan Agricultural University, Zhengzhou, China
GRAPHICAL ABSTRACT
Abstract Some new methods, such as air oxidation, catalytic oxidation, and solvent-free
synthesis, are developed for the synthesis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-
ones(2) from the cyclization of 3-[1-(phenyl-hydrazono)ethyl]-chromen-2-ones(1).
Compared with air oxidation, catalytic oxidation can increase the rate of the cyclization of
compound 1, and the solvent-free synthesis showed advantages of no organic solvent pollution,
elevated reaction rate, and higher selectivity.
Keywords Benzopyrano-arylhydrazone; benzopyrano-pyrazol; coumarin derivatives;
oxidative cyclization
INTRODUCTION
Recently, coumarin derivatives have received much attention in organic hetero-
cyclic compounds, with powerful biological activities including antibacterial,[1,2]
[4]
antiviral,[3] and anti-inflammatory
activities. Because of the structural features
of larger conjugated system, coumarin derivatives are also used as fluorescent mate-
rials.[5,6] Pyrazole derivatives are known to exhibit impressive antibacterial, antide-
pressant, antiamoebic, anti-inflammatory, and antinociceptive[7–10] activities. The
incorporation of a heterocyclic ring into the coumarin and pyrazole ring would make
them more potent than coumarin and pyrazole alone.[11,12]
Received August 25, 2011.
Address correspondence to Cui-Lian Xu, College of Science, Henan Agricultural University,
Zhengzhou 450002, China. E-mail: xucuilian666@126.com
1263

1264
G.-Y. YANG ET AL.
3-Methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones commonly are used for
synthesis of inmunomodulatory drugs, which can interact with the benzodiazepine
central receptor.[13] The synthesized methods of these compounds mostly use
3-acetyl-4-hydroxycoumarins [14] or 3-acetyl-4-chlorocoumarins [15] as row materials.
In contrast, the use of 3-acyl-coumarins, which are easier to obtain, as reactants has
been less studied because of their low reactivity. Recently, Padilla-Martinez et al.[16]
reported 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones were obtained by the
oxidative cyclization of 3-[1-(phenyl-hydrazono)ethyl]-chromen-2-ones with copper
acetate as catalyst, which prompted us to study the cyclization methods of 3-[1-
(phenyl-hydrazono)ethyl]-chromen-2-ones.
In this contribution, some new methods, including air oxidation, catalytic
oxidation, and solvent-free synthesis, are developed for the synthesis of 3-methyl-1-
phenylchromeno[4,3-c]pyrazol-4(1H)-ones(2) from the cyclization of coumarin
hydrazones (Scheme 1).
In one recrystallization experiment, compound 1a was unexpectedly converted
to compound 2a, whose crystal structure was determined by x-ray monocrystal
diffraction (see Fig. 1) in the ethyl acetate. The crystal structure of compound 2a
is already deposited at the Cambridge Crystallographic Data Center (CCDC) and
is available as a private communication.
Through many trials, it was found that the compound 1a can spontaneously
cyclize to form the compound 2a in the ethyl acetate by slow oxidation in the air,
and the conversion increased as the time lengthened. The yield of 2a was up to
88% after 8 days (Table 1, entries 1–4). Padilla-Martinez et al.[16] also reported that
compound 2a was spontaneously formed in chloroform solution at room tempera-
ture, but the yield of 2a was only 30%, and other 3-(phenyl-hydrazono)-chromen-
2-ones 1b–1e did not proceed under the same conditions as 1a. In our experiments
1b–1e could cyclize smoothly, and the results are shown in Table 1 (entries 5–8).
The overall yield of product 2 was more than 75% under air oxidation and the
activity order of the compounds (2a–2e) is 2a > 2b > 2c > 2d > 2e. This suggests that
the introduction of the bulky groups was not propitious for cyclization, especially for
those electron-donating groups.
To accelerate the reaction rate, copper acetate was used as the catalyst in the
cyclization reaction.[16] To expand the scope of catalyst, we tested many substances,
and the results are shown in Table 2. Most of the substances could promote the cycli-
zation of coumarin hydrazones 1 effectively. The conversion of compound 1c was up
Scheme 1. Synthetic route to the compounds 2a–2e.

3-[1-(PHENYL-HYDRAZONO)ETHYL]-CHROMEN-2-ONES
1265
Figure 1. Molecular structure of compound 2a. (Figure is provided in color online.)
Table 1. Synthesis of compounds 2a–2e with air oxidation
Entry
Compound
Time (d)
Conversion (%)
Selectivity (%)
Yield (%)
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2b
2c
2d
2e
8
6
100
65
88
95
88
62
51
33
75
94
75
92
4
51
33
100
100
75
2
12
12
15
25
100
100
99
94
76
99
93
Table 2. Synthesis of compound 2c with catalytical oxidation
Entry
Catalyst
Time (h)
Conversion (%)
Selectivity (%)
Yield (%)
TOF
1
2
3
4
5
6
7
8
9
Cu
CuCl
CuO
40
0.5
13
1
76
97
53
52
96
88
89
22
47
24
36
40
50
85
88
80
22
47
24
36
0.0034
0.54
92
0.016
0.56
1.5
Cu(CH3COO)2 ꢀ H2O
Cu (SO3)2 CF3
FeCl3
100
90
0.5
6
100
100
100
100
0.076
0.080
0.134
0.092
AgNO3
Mn(CH3COO)2 ꢀ H2O
Co(CH3COO)2 ꢀ H2O
6
4
6

1266
G.-Y. YANG ET AL.
Table 3. Synthesis of compound 2a with solvent-free synthesis
Temperature (ꢁC)
Time (h)
Conversion (%)
Selectivity (%)
Yield (%)
110
120
130
140
150
34
33
4
69
99
96
96
66
95
91
96
87
2
0.5
100
97
100
95
100
92
to 90% in the presence of different catalysts within shorter time compared with air
oxidation except for Cu. The catalyst Cu (SO3)2CF3 has greater activity and the cata-
lyst CuO showed greater selectivity than the other catalysts. As for the reason,
further research is needed.
It is considered that organic solvents are harmful to the environment, so
solvent-free synthesis was adopted to prepare the product 2a, and the experimental
data are listed in Table 3. From the results, we conclude that the reactive rate
increased as the temperature increased. The conversion of 1a was 100% and the
selectivity of product 2a was 100% at 140ꢁC for 2 h. Compared with air oxidation,
solvent-free synthesis showed advantages of no organic solvent pollution, elevated
reaction rate, and higher selevtivity.
According to experimental results, we presume the mechanism for the cycliza-
tion of 3-(phenyl-hydrazono)-chromen-2-ones is shown in Scheme 2. Take the
reactant 1a as an illustration; First, reactant 1a was changed into intermediate 3a
by intramolecular Michael addition. Then intermediate 3a was oxidized to product
2a by oxygen in the air. The first step is a reversible reaction and the second step is an
irreversible reaction. When 95% ethyl alcohol was used as the solvent in the cataly-
tical oxidation, the cyclization of the reactant 1a cannot occur, which may prove that
there is a dehydration reaction in the second step.
Scheme 2. Possible mechanism for the formation of compound 2a.

3-[1-(PHENYL-HYDRAZONO)ETHYL]-CHROMEN-2-ONES
1267
CONCLUSION
In summary, we have developed some new methods, including air
oxidation, catalytic oxidation, and solvent-free synthesis, for the synthesis of
3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones (2) from the cyclization of
3-[1-(phenyl-hydrazono)ethyl]-chromen-2-ones (1). Under air oxidation, the overall
yield of the products 2 was up to 85–90%. Some catalysts, especially Cu (SO3)2CF3,
increased the rate of the cyclization of compound 1. Compared with air oxidation,
solvent-free synthesis showed advantages of no organic solvent pollution, elevated
reaction rate, and higher selectivity.
EXPERIMENTAL
Melting points were determined on a X4 digital microscopic melting-point
apparatus and are uncorrected. Infrared (IR) spectra were recorded using a Nicolet
IS10 Fourier transform IR spectrophotometer (4000–400 cmꢂ1) with a crystalline
1
sample spread on KBr pellets. H NMR spectra of compound 2a was obtained by
a Brucker 300-MHz spectrometer with tetramethylsilane (TMS) as an internal stan-
1
dard. H NMR spectra of compounds 2b–2e were obtained by a Bruker Advance
DPX 400-MHz spectrometer with TMS as an internal standard. ESIþ (electrospray
ionization) mass spectra were obtained on a liquid chromatography (LC)–mass spec-
trometry (MS) system, Agilent MSD-Trap-SL. X-ray diffraction data were collected
on a Rigaku RAXIAS-IV type diffractometer. All chemicals and reagents were of
analytical reagent grade and were used as received without further purification.
The compounds 1a–1e were synthesized according to the standard procedures from
phenyl hydrazine and 3-acyl-coumarins. The high-performance liquid chromato-
graphic (HPLC) instrument from Agilent Company was used for the qualitative
and quantitative analyses of the products.
Synthesis of Compounds 2a–2e by Air Oxidation
In a round-bottom flask, 3-[1-(phenyl-hydrazono)ethyl]-chromen-2-one (1)
(0.1 g) was dissolved in ethyl acetate solution (20 mL) by refluxing for 10 min. Then
the round-bottom flask was covered with a plastic membrane except for one small
hole at the top and placed for some time in the air. The reaction was monitored
by HPLC at intervals. After the completion of the reaction, the resulting mixture
was removed from the bulk solvent by reduced pressure distillation, filtered, washed
with cold ethyl alcohol (3 mL ꢃ 2), air dried, and recrystallized from ethyl acetate to
obtain the compounds 2a–2e.
Compound 2a. White powder, mp : 235–236 ꢁC; IR (KBr pellets, n=cmꢂ1):
3091, 2929, 1735, 1623, 1597, 1550, 1525, 1489, 1455, 1431, 1273, 1210, 1048,
1
1027, 970, 778, 756, 703. H NMR data (300 MHz, CDCl3, ppm): 7.64–7.54 (m,
5H, benzene-H), 7.48–7.39 (m, 2H, benzene-H), 7.13–7.01 (m, 2H, benzene-H),
2.68 (s, 3H, -CH3).
Compound 2b. Pale yellow powder, mp : 280–281ꢁC; IR (KBr pellets, n=cmꢂ1):
3473, 3092, 1751, 1544, 1522, 1444, 1207, 1129, 1002, 981, 832, 770, 720, 687. 1H NMR

1268
G.-Y. YANG ET AL.
data (400 MHz, CDCl3, ppm): 7.66–7.53 (m, 5H, benzene-H), 7.39–7.27 (m, 2H,
benzene-H), 7.04–7.03 (d, 1H, benzene-H), 2.69 (s, 3H, -CH3).
Compound 2c. White powder, mp : 287–288 ꢁC; IR (KBr pellets, n=cmꢂ1
)
3434, 3088, 1758, 1542, 1521, 1267, 1206, 1085, 1001, 999, 829, 776, 703. 1H
NMR data (400 MHz, CDCl3, ppm): 7.66–7.64 (m, 3H, benzene-H), 7.56–7.53 (m,
3H, benzene-H), 7.32–7.27 (m, 1H, benzene-H), 7.19–7.18 (d, 1H, benzene-H),
2.69 (s, 3H, -CH3).
Compound 2d. White powder, mp: 235–236 ꢁC; IR (KBr pellets, n=cmꢂ1):
3443, 3056, 2977, 2929, 1532, 1454, 1241, 1208, 1104, 1018, 761, 726, 700. 1H
NMR data (400 MHz, CDCl3, ppm): 7.62–7.53 (m, 5H, benzene-H), 7.02–6.95 (m,
2H, benzene-H), 6.67–6.65 (m, 1H, benzene-H), 3.97 (s, 3H, -CH3), 2.70 (s, 3H, -
CH3).
Compound 2e. White powder, mp: 203–204 ꢁC; IR (KBr pellets, n=cmꢂ1):
3435, 1735, 1550, 1525, 1455, 1273, 1070, 1048, 1027, 778, 756, 703. H NMR data
1
(400 MHz, CDCl3, ppm): 7.62–7.53 (m, 5H, benzene-H), 7.01–6.91 (m, 2H,
benzene-H), 6.66–6.64 (m, 1H, benzene-H), 4.22–4.16 (m, 2H, -CH2), 2.70 (s, 3H,
-CH3), 1.53–1.50 (m, 3H, -CH3). LC=MS (ESIþ) calcd. for C19H16N2O3, m=z:
321.1 (M þ H)þ.
Procedure for the Synthesis of Compound 2c by the
Catalytical Oxidation
The compound 1c (0.1 g) was dissolved in ethyl alcohol (20 ml), and the metal
catalyst (0.1 g) was added to the solution. The mixture was refluxed for some time
and monitored at intervals. After the completion of reaction, as indicated by HPLC,
the resulting mixture was removed from the bulk solvent by reduced pressure distil-
lation, filtered, washed with cold ethyl alcohol (3 mL ꢃ 2), and distilled water
(3 mL ꢃ 3), air dried, and recrystallized from ethyl acetate to obtain compound 2c.
Procedure for the Synthesis of Compound 2a by the
Solvent-Free Synthesis
The compound 1a (0.1 g) was thoroughly mixed with silicon dioxide (2 g). The
silicon dioxide–supported mixture was heated on an oil bath and monitored at inter-
vals. After the completion of reaction, as indicated by HPLC, the resulting mixture
was washed with ethyl acetate. The bulk solvent was removed by reduced pressure
distillation, filtered, washed with cold ethyl alcohol (3 mL ꢃ 2), air dried, and recrys-
tallized from ethyl acetate to obtain compound 2a.
ACKNOWLEDGMENT
The authors are grateful to the Education Foundation of Henan Province
(2006150011) for its financial support.

3-[1-(PHENYL-HYDRAZONO)ETHYL]-CHROMEN-2-ONES
1269
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