Ultrasonics Sonochemistry 16 (2009) 304–307

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Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch

Short Communication

Efficient epoxidation of chalcones with urea-hydrogen peroxide under

ultrasound irradiation
Hong Jin a, Haoyu Zhao b, Feihu Zhao a, Shihong Li a, Wei Liu c, Guoping Zhou c, Ke Tao b, Taiping Hou b,*
a
Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, PR China
b
Key Laboratory of Bio-Resource and Eco-environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, PR China
c
Department of Medicinal Chemistry West China School of Pharmacy, Sichuan University, Chengdu 610064, PR China

a r t i c l e i n f o a b s t r a c t

Article history: An efficient epoxidation of chalcones with urea-hydrogen peroxide (UHP) under ultrasound irradiation
Received 21 July 2008 was carried out in 78–93% yields. Compared with the classical method, the advantages of protocol are
Received in revised form 8 October 2008 to use a safer oxidant, mild conditions, no toxic solvent and shorter reaction time.
Accepted 31 October 2008
Ó 2008 Elsevier B.V. All rights reserved.
Available online 7 November 2008

Keywords:
Epoxidation
Chalcones
Urea-hydrogen peroxide
Ultrasound irradiation

1. Introduction et al. [23] investigated epoxidation of chalcones with H2O2 in a

Epoxides are very important chemicals in organic synthetic
chemistry [1–5] and can serve as versatile precursor in synthesis
of many natural products and drug molecules [6,7]. Great attention
has been dedicated on the development of methodologies allowing
the epoxidation of carbon–carbon double bonds. Epoxidation of
chalcones is a most efficient method for epoxidation of a,b-unsat-
urated ketones [8]. Some oxidants, including sodium hypochlorite
[9], sodium peroxide [10], m-chloroperbenzoicacid [11], sodium
chlorite [12], sodium perborate tetrahydrate [13], oxone [14],
cyclohexylidenebishydroperoxide [15], trichloroisocyanuric acid
[16], hydrogen peroxide [17] and dimethyldioxirane [18], have
been used in epoxidation of chalcones. However, there were al-
ways some problems due to long reaction time, the cost of expen-
sive catalyst, the hindrance of space, involving toxic solvents or
difficult experiment operation.
A survey of literatures showed that ultrasound irradiation has
been considered as a clean and useful protocol in organic syn-
thesis and many organic reactions can be accelerated by ultra-
sonic irradiation [19–21]. For example, 10 years ago Sazivky
et al. [22] reported epoxidation of chalcones with sodium perbo-
rate tetrahydrate under sonication. Subsequently, in 2002 Boyer
* Corresponding author. Tel.: +86 28 8541 0992.
E-mail address: taipinghou@tom.com (T. Hou).
water–heptane two phase system in the presence of a surfactant
(dodecyltrimethylammonium bromide) by sonication. Recently,
Li and Liu [24] reported that epoxidation of chalcones with
aqueous sodium hypochlorite using benzyldimethyltetradecyl
ammonium chloride as phase transfer catalyst under ultrasound
irradiation gave 62–92% of 2,3-epoxyl-1,3-diaryl-1-propanone in
2–4 h.
UHP, a white crystalline solid, is formed when urea is recrystal-
lized from aqueous hydrogen peroxide [25]. The material that has
been employed as a solid substitute for liquid hydrogen peroxide
and is relatively stable at room temperature [26], has a high hydro-
gen peroxide content and the potential to release it in a controlled
manner [27]. Also it has the advantage of generating innocuous by-
products and is soluble in organic solvents. These characteristics
make it a good and safe alternative for the generation of anhydrous
hydrogen peroxide in most epoxidation reactions. Bentley et al.
[28] reported epoxidation of chalcone with UHP in an organic sol-
vent in the presence of DBU and poly-(L)-leucine in 1997. Recently,
dos Santos et al. [29] reported epoxidation of chalcone with UHP in
1,4-dioxane by means of microwave irradiation at 25 °C for 45 s in
95% yield.
All of the results stated above prompted us to study the possi-
bility of epoxidation of chalcones with urea-hydrogen peroxide
(UHP) under ultrasound irradiation. Here we report an efficient
epoxidation of chalcones with urea-hydrogen peroxide (UHP) un-
der ultrasound irradiation.

1350-4177/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2008.10.013
 H. Jin et al. / Ultrasonics Sonochemistry 16 (2009) 304–307 305

2. Method 2j: White crystal; dH (400 MHz): 3.83 (3H, s), 4.03 (1H, d,
J = 1.6 Hz), 4.13 (1H, d, J = 1.6 Hz), 6.92 (2H, d, J = 8.8 Hz), 7.27
2.1. Apparatus and analysis (2H, d, J = 8.8 Hz), 7.36 (1H, dd, J = 8.4, 2.0 Hz), 7.45 (1H, d,
J = 2.0 Hz), 7.60 (1H, d, J = 8.4 Hz) ppm.
Chalcones were prepared according to the literature [30]. Melt- 2k: White crystal; dH (400 MHz): 4.17 (1H, d, J = 2.0 Hz), 4.21
ing point were recorded on XRC-1 apparatus and were uncor- (1H, d, J = 1.6 Hz), 7.40 (1H, dd, J = 8.4, 2.0 Hz), 7.47 (1H, d,
rected. 1H NMR spectra were measured on Bruker (400 or J = 2.0 Hz), 7.60 (1H, t, J = 8.0 Hz), 7.64 (1H, d, J = 8.4 Hz), 7.69–
600 MHz) spectrometer using TMS as internal standard and CDCl3 7.72 (1H, m), 8.22–8.26 (2H, m) ppm.
as solvent. The progress of the reaction was monitored by thin-
layer chromatography on commercial Merck precoated TLC plates 3. Results and discussion
(silica gel 60 F254). Sonication was performed in a KQ-100E ultra-
sonic cleaner (with a frequency of 40 kHz, and a nominal power The effect of reaction conditions on epoxidation of benzalace-
100 W) and a KQ-100VDB ultrasonic cleaner (with a frequency of tophenone with UHP under ultrasound irradiation is summarized
28 and 100 kHz, and a nominal power 100 W). The reaction flask in Table 1.
was placed with the maximum energy area in the cleaner and reac- Firstly, as shown in Table 1, we investigated the influence of the
tion temperature was controlled by water-bath. molar of substrate to oxidant on the reaction under ultrasound
irradiation. The results showed the molar ratio of benzalacetophe-
none to UHP had significant effect on the epoxidation reaction.
2.2. Preparation of urea-hydrogen peroxide (UHP) [25]
When the molar ratio of benzalacetophenone (1a) to UHP was
2:2, the 2,3-epoxyl-1,3-diphenyl-1-propanone (2a) was obtained
In a 100 ml Pyrex flask 12 g urea and 34 ml hydrogen peroxide
in 78% yield (Entry 1). Increasing the molar ratio to 2:2.4 and
(30%) were added together. The reaction mixture was stirred at
2:3.2, the yield of 2a increased to 82% and 91%, respectively (Entry
60 °C for 10 min. When cool it was transferred to a crystallizing
2, 3), when the ratio was increased to 2:5, the yield was 91% which
dish for slow evaporation and crystallization.
was not increased (Entry 4).
Secondly, the effect of frequency of ultrasound irradiation on
2.3. General procedure the reaction was also observed. When the frequency was 28 kHz,
the molar ratio of benzalacetophenone (1a) to UHP was 2:3.2,
In a 50 ml Pyrex flask containing benzalacetophenone (1a, the epoxidation of 1a resulted in the product 2a in 88% yield within
0.416 g, 2 mmol) and UHP (0.300 g, 3.2 mmol) dissolved in a mix- 15 minutes (Entry 5). While under 100 kHz irradiation in the same
ture of ethanol (20 mL) and water (8 mL), was added an aqueous conditions, the epoxidation of benzalacetophenone (1a) was com-
solution of NaOH (4%, 0.40 mL). The mixture was irradiated in pleted in 90% yield (Entry 6). It was shown that irradiation fre-
the water-bath of an ultrasonic cleaner at room temperature for quency had minor effect on the reaction.
15 min (sonication was continued until benzalacetophenone had Subsequently, we investigated the effect of the solvent on the
disappeared as indicated by TLC). Then the mixture was extracted epoxidation reaction. Considering to the benefit of homogeneous
with diethyl ether, washed with water and dried over anhydrous reaction, we used the mixture solvent as the reaction solvent.
sodium sulfate. The solvent was evaporated under reduced pres- When we used CH3CH2OH–H2O, CH3COCH3–H2O, 1,4-dioxane–
sure and the residue was crystallized with ethanol to give the H2O or THF–H2O as the solvent respectively, in the same conditions
product 2a. the reaction yields of benzalacetophenone (1a) were 91%, 89%, 92%
The authenticity of the products 2a–c, 2e–k was established by and 93% (Entry 2, 7, 8 and 9). We could see that the effect of the
comparing their melting points with the literature as well as the several solvents was little. Considering the effect of the solvent
spectra data of 1H NMR. toxicity, we used CH3CH2OH–H2O that nearly had no toxicity as
2a: Colorless crystal; dH (400 MHz): 4.05 (1H, d, J = 1.0 Hz), 4.22 the solvent of the next experiments.
(1H, d, J = 1.2 Hz), 7.34–7.74 (10 H, m) ppm. From the results above, the reaction conditions we chose were
2b: White crystal; dH (400 MHz): 4.08 (1H, d, J = 1.2 Hz), 4.24 as follows: chalcone (1, 2 mmol), UHP (0.300 g, 3.2 mmol), NaOH
(1H, d, J = 1.6 Hz), 7.17 (2H, d, J = 8.8 Hz), 7.36–7.43 (5H, m), 8.06 (4%, 0.4 mL), ethanol (20 mL) and water (8 mL), room temperature.
(2H, d, J = 8.8 Hz) ppm. Using this reaction system, we did a series of experiments for the
2c: White solid; dH (400 MHz): 4.22 (1H, d, J = 1.6 Hz), 4.26 (1H, epoxidation of chalcones under 40 kHz ultrasound irradiation.
d, J = 2.0 Hz), 7.20 (2H, t, J = 8.4 Hz), 7.62 (1H, t, J = 8.0 Hz), 7.72 The results were summarized in Table 2.
(1H, d, J = 8.0 Hz), 8.07–8.10 (2H, m), 8.25 (2H, d, J = 8.0 Hz) ppm.
2e: White crystal; dH (400 MHz): 4.11 (1H, d, J = 1.6 Hz), 4.37
(1H, d, J = 2.0 Hz), 7.21 (2H, d, J = 8.8 Hz), 7.32 (1H, d, J = 8.0 Hz),
7.34 (1H, d, J = 8.4, 2.0 Hz), 7.45 (1H, d, J = 1.6 Hz), 8.11 (2H, d, Table 1
J = 8.8 Hz) ppm. The effect of reaction condition on epoxidation of benzalacetophenone with UHP
2f: White crystal; dH (400 MHz): 4.07 (1H, d, J = 1.6 Hz), 4.23 under ultrasound irradiation.
(1H, d, J = 1.6 Hz), 7.36–7.43 (5H, m), 7.47 (2H, d, J = 8.4 Hz), 7.97 Entry Substrate/UHP (mmol) Frequency (kHz) Solvent Yield (%)a
(2H, d, J = 8.4 Hz) ppm.
1 2:2 40 CH3CH2OH–H2O 78
2g: White crystal; dH (400 MHz): 4.09 (1H, d, J = 1.2 Hz), 4.25 2 2:2.4 40 CH3CH2OH–H2O 82
(1H, d, J = 1.2 Hz), 7.36–7.46 (5H, m), 7.66 (2H, d, J = 8.4 Hz), 7.91 3 2:3.2 40 CH3CH2OH–H2O 91
(2H, d, J = 8.4 Hz) ppm. 4 2:5 40 CH3CH2OH–H2O 91
5 2:3.2 28 CH3CH2OH–H2O 88
2h: White crystal; dH (400 MHz): 3.88 (3H, s), 4.07 (1H, d,
6 2:3.2 100 CH3CH2OH–H2O 90
J = 2.0 Hz), 4.26 (1H, d, J = 2.0 Hz), 6.95 (2H, d, J = 8.8 Hz), 7.35– 7 2:3.2 40 CH3COCH3–H2O 89
7.44 (5H, m), 8.02 (2H, d, J = 8.8 Hz) ppm. 8 2:3.2 40 1,4-Dioxane–H2O 92
2i: White solid; dH (600 MHz): 3.89 (3H, s), 4.21 (1H, d, 9 2:3.2 40 THF–H2O 93
J = 1.6 Hz), 4.27 (1H, d, J = 2.0 Hz), 6.98 (2H, d, J = 8.4 Hz), 7.32 10 2:3.2 40 CH2CH3OH–H2O 0b
(1H, t, J = 8.4 Hz), 7.22 (1H, d, J = 8.0 Hz), 8.02 (2H, d, J = 8.4 Hz), a
Isolated yield based on benzalacetophenone.
b
8.24 (2H, s) ppm. Stirred without NaOH (4%) with UHP and ultrasound.
306 H. Jin et al. / Ultrasonics Sonochemistry 16 (2009) 304–307

Table 2
Epoxidation of chalcones with UHP under ultrasound irradiation.

Entry R1 R2 t (min) Yield (%)a M.P. (°C) (lit.)

a H H 15 91 85–86 (82–85) [31]
50 83b
b 4-F H 20 87 83–84 (83–84) [16]
75 78b
c 4-F 3-NO2 35 86 150–151
240 71b
d 4-F 4-OCH3,3-NO2 60 0
600 0b
e 4-F 2,4-Cl2 35 89 89-92
360 73b
f 4-Cl H 25 90 123–126 (118–120) [32]
85 60b
g 4-Br H 30 85 126–127 (127–128) [33]
100 70b
h 4-OCH3 H 45 93 77–79 (79–80) [16]
900 65b
i 4-OCH3 3-NO2 40 84 142–145
150 70b
j 2,4-Cl2 4-OCH3 25 78 110–113
85 45b
k 2,4-Cl2 3-NO2 20 85 130–132
80 75b
l 2,4-Cl2 4-OCH3, 3-NO2 60 0
600 0b
a
Isolated yield based on chalcones.
b
Stirred with UHP without ultrasound.

As shown in Table 2 and Scheme 1, epoxidation of chalcones
was carried out at room temperature in better yields (78–93%)
and shorter reaction time (15–45 min) with urea-hydrogen perox-
ide (UHP) as an oxidant under ultrasound irradiation. In the ab-
sence of ultrasound, time of the epoxidation reaction was within
50–900 min. For example, the mixture of benzalacetophenone
(1a), UHP and NaOH (4%) was stirred at room temperature for
50 min to produce 2,3-epoxyl-1,3-diphenyl-1-propanone (2a) in
83% yield. While, the reaction was carried out in 91% yield at room
temperature just for 15 min under ultrasonication. Therefore, with
treatment of ultrasonication, results show that the yields of epox-
idation reaction are similar or even higher than those without such
treatments as described in the literatures [28], as well as short
reaction time. The reason may be the phenomenon of cavitation
produced by ultrasound [20,21].
We observed that without adding NaOH the reaction stopped
(Table 1). For example, In the absence of NaOH benzalacetophe-
none was converted to 2,3-epoxyl-1,3-diphenyl-1-propanone in
zero yield in 600 min under ultrasound.
According to mechanism of the known Weitz–Scheffer reaction
[34] and original study by Apeloig et al. [35], treatment of a,b-
unsaturated ketone with hydrogen peroxide under basic condi-
tions yields epoxy ketones via an oxidation, a plausible mechanism
for the reaction is proposed as shown in Scheme 2. It firstly in-
volved reaction of UHP and OH under ultrasound irradiation
and quickly formed HOO . And secondly, the HOO was added to

O O

UHP
R1 R2 R1 O R2
u. s.
1 2
Scheme 1.

O O
u. s.
H 2N N HO-OH + OH- H2 N NH2 + HOO - + H 2 O
H

HOO - HO
O O O- O
O
Ar 1 Ar 2 Ar 1 Ar 2 Ar 1 Ar 2

1 3 OH- 2

Scheme 2.
 H. Jin et al. / Ultrasonics Sonochemistry 16 (2009) 304–307
the enone unit (1) to form a hydroperoxide enolate (3). Finally, the
hydroperoxide enolate (3) lost the OH with concomitant ring clo-
sure and formed the epoxide (2).
In the present procedure, we found that the epoxidation of chal-
cones carrying either electron-donating or electron-withdrawing
substituents reacted very well except for 1 d and 1 m. The epoxida-
tion could not be carried out for the two chalcones under ultra-
sound irradiation. As they all have the bulky substituents (R = 4-
OCH3, 3-NO2), it may be that the steric hindrance around the dou-
ble bond inhibited the attack of UHP to double bond.
4. Conclusion
In conclusion, we have found an efficient epoxidation of chal-
cones with urea-hydrogen peroxide (UHP) by ultrasound irradia-
tion. Compared with the classical method, the main advantages
of the procedure are to use a safer oxidant, mild conditions, no
toxic solvent, especially; the reaction time is much shorter than
classical methods.
Acknowledgements
This project was supported by the Hi-Tech Research and Devel-
opment of China (No. 2006AA10A209) and the National Natural
Science Foundation of China (Grant No. 20572076).
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