Improved synthesis of 2,2′-arylmethylene bis(3-hydroxy-5,5-dimethyl- 2-cyclohexene-1-one) derivatives catalyzed by urea under ultrasound

Article abstract of DOI:10.1016/j.ultsonch.2011.05.001

Synthesis of 2,2′-arylmethylene bis(3-hydroxy-5,5-dimethyl-2- cyclohexene-1-one) derivatives catalyzed by urea via the condensation of aromatic aldehydes and 5,5-dimethyl-1,3-cyclohexanedione was carried out in 80-98% yields at 50 °C in aqueous media unde

Full text of DOI:10.1016/j.ultsonch.2011.05.001

Ultrasonics Sonochemistry 19 (2012) 1–4
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Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch
Short Communication
Improved synthesis of 2,20-arylmethylene bis(3-hydroxy-5,5-dimethyl-2-
cyclohexene-1-one) derivatives catalyzed by urea under ultrasound
Ji-Tai Li a, , Yan-Wei Li a, Ya-Li Song b, Guo-Feng Chen a,
⇑
⇑
a College of Chemistry and Environmental Science, Hebei University, Baoding 071002, PR China
b College of Pharmaceutical, Hebei University, Baoding 071002, PR China
a r t i c l e i n f o
a b s t r a c t
Synthesis of 2,20-arylmethylene bis(3-hydroxy-5,5-dimethyl-2-cyclohexene-1-one) derivatives catalyzed
by urea via the condensation of aromatic aldehydes and 5,5-dimethyl-1,3-cyclohexanedione was carried
out in 80–98% yields at 50 °C in aqueous media under ultrasound. This method provides several advan-
tages such as environment friendliness, high yields and simple work-up procedure.
Ó 2011 Elsevier B.V. All rights reserved.
Article history:
Received 27 March 2011
Received in revised form 25 April 2011
Accepted 4 May 2011
Available online 8 May 2011
Keywords:
2,20-Arylmethylene bis(3-hydroxy-5,5-
dimethyl-2-cyclohexene-1-one)
Synthesis
Condensation
Ultrasound
Catalysis
1. Introduction
furnish the desired product in 44.5–91% and 41.1–78.1% yields
respectively [7]. Bayat et al. reported that the condensation can
be finished within 20–60 min using stirring alone at room temper-
2,20-Arylmethylene
bis(3-hydroxy-5,5-dimethyl-2-cyclohex-
ene-1-one) derivatives are important biologically active com-
pounds, which can be evaluated as tyrosinase inhibitors [1]. They
are also important synthetic intermediates and can serve as versa-
tile precursors in the synthesis of xanthenes that display biological
and therapeutic role such as antioxidants, lipoxygenase inhibitors
[2a], antibacterial and antiviral activities [2b], besides they are also
used in laser technology [3].
ature to provide the product in 96–99% yield [8,9]. In the presence
of triethylbenzylammonium chloride (TEBA), the reactions were
stirred at 90 °C in water for 6–8 h to result the product in 84–
97% yields [10]. Yu et al. carried out the reaction of benzaldehyde
and 5,5-dimethyl-1,3-cyclohexanedione by stirring in water at cat-
alyst-free condition to give 3a in 96% yield within 30 min [11]. Fan
et al. synthesized the title compounds in 80–91% yield under the
catalysis of TMSCl/FeCl3ꢀ6H2O using [bmim]+[BF4]ꢁ as the reaction
medium at 80 °C for 4–6 h [12]. Recently, Jung et al. described the
condensation catalyzed by ethylenediamine diacetate (EDDA),
dimedone reacted with aromatic aldehydes in refluxing THF for
4–6 h, 2,20-arylmethylene bis(3-hydroxy-2-cyclohexene-1-one)
was obtained in 70–97% yields [13]. However, in spite of their
potential utility, some of the reported methods suffer from draw-
backs such as longer reaction times and lower yields. There still
appears a need either to improve the yield or to reduce reaction
time.
Ultrasound has been considered as a useful protocol in organic
synthesis in the last three decades [14–16]. Compared with tradi-
tional methods, this procedure is more convenient. A large number
of organic reactions can be carried out in higher yield, shorter reac-
tion time or mild condition under ultrasound [17,18]. Jin et al.
reported that in the presence of TBABr (tetrabutylammonium
bromide) or CTABr (cetyltrimethylammonium bromide) under
2,20-Arylmethylene
bis(3-hydroxy-5,5-dimethyl-2-cyclohex-
ene-1-one) is usually prepared via condensation of aromatic alde-
hydes and 5,5-dimethyl-1,3-cyclohexanedione under different
conditions. Jin et al. reported that the condensation can be cata-
lyzed by KF/Al2O3 [4] or catalyst-free [5] to give the title com-
pounds in good yields using grinding method. But the reactants
were first ground for a period of time (20–40 min) and then needed
to be kept for 24 h. In the presence of sodium dodecyl sulfate (SDS),
the reaction was stirred at refluxing temperature in water for 3 h,
2,20-arylmethylene bis(3-hydroxy-2-cyclohexene-1-one) could be
obtained in 67–92% yield [6]. Kantevari et al. used HClO4ꢀSiO2 or
PPA-SiO2 as catalyst in aqueous media at 100 °C for 30–60 min to
⇑
Corresponding authors. Address: College of Chemistry and Environmental
Science, Hebei University, Wusi East Road No. 180, Baoding 071002, PR China. Tel.:
+86 312 5079361; fax: +86 312 5079628.
E-mail addresses: lijitai@hbu.cn (J.-T. Li), gfchen2007@yahoo.cn (G.-F. Chen).
1350-4177/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2011.05.001

2
J.-T. Li et al. / Ultrasonics Sonochemistry 19 (2012) 1–4
ultrasound, the reaction of 4-chlorobenzaldehyde and
5,5-dimethyl-1,3-cyclohexanedione was completed within 60 or
90 min to result 2,20-(4-chlorophenyl)methylene bis(3-hydroxy-
5,5-dimethyl-2-cyclohexene-1-one) in 92% and 95% yield, respec-
tively [19].
Organic reactions catalyzed by small organic molecules have
drawn much attention recently [20]. Urea group is known to coor-
dinate to a carbonyl group, and to activate it by hydrogen bond.
Computational studies also indicated that hydrogen bond donors
are able to provide two or more hydrogen bonds to bind to oxygen
atoms in carbonyl groups [21]. Thus, various carbonyl group reac-
tions catalyzed by urea have been developed [22]. In this paper we
wish to report an efficient synthesis of 2,20-arylmethylene bis(3-
hydroxy-5,5-dimethyl-2-cyclohexene-1-one) derivatives catalyzed
by urea from aromatic aldehydes and 5,5-dimethyl-1,3-cyclohex-
anedione in water under ultrasound irradiation (Scheme 1).
6H, CH3), 2.30–2.47 (m, 8H, CH2), 5.54 (s, 1H, CH), 7.10 (d,
J = 8.4 Hz, 2H, Ph-H), 7.16 (t, J = 7.2 Hz, 1H, Ph-H), 7.27 (t,
J = 7.8 Hz, 2H, Ph-H), 11.51 (brs, 1H, OH), 11.89 (s, 1H, OH).
2.2.2. Compound 3b
2,20-(2-Nitrophenyl)methylene bis(3-hydroxy-5,5-dimethyl-2-
cyclohexene-1-one): white solid; 1H NMR: dH 1.01 (s, 6H, CH3),
1.12 (s, 6H, CH3), 2.20–2.51 (m, 8H, CH2), 6.04 (s, 1H, CH), 7.24
(d, J = 7.8 Hz, 1H, Ph-H), 7.33 (t, J = 7.8 Hz, 1H, Ph-H), 7.47 (t,
J = 7.8 Hz, 1H, Ph-H), 7.52 (d, J = 7.8 Hz, 1H, Ph-H), 11.16 (brs, 1H,
OH), 11.59 (s, 1H, OH).
2.2.3. Compound 3c
2,20-(3-Nitrophenyl)methylene bis(3-hydroxy-5,5-dimethyl-2-
cyclohexene-1-one): white solid; 1H NMR: dH 1.12 (s, 6H, CH3),
1.28 (s, 6H, CH3), 2.33–2.52 (m, 8H, CH2), 5.54 (s, 1H, CH), 7.41–
7.46 (m, 2H, Ph-H), 8.01 (s, 1H, Ph-H), 8.05 (d, J = 8.4 Hz, 1H, Ph-
H), 11.58 (brs, 1H, OH), 11.86 (s, 1H, OH).
2. Methods
2.2.4. Compound 3d
2.1. Apparatus and analysis
2,20-(4-Nitrophenyl)methylene bis(3-hydroxy-5,5-dimethyl-2-
cyclohexene-1-one): white solid; 1H NMR: dH 1.12 (s, 6H, CH3),
1.24 (s, 6H, CH3), 2.32–2.51 (m, 8H, CH2), 5.55 (s, 1H, CH), 7.25
(d, J = 8.4 Hz, 2H, Ph-H), 8.13 (t, J = 9.0 Hz, 2H, Ph-H), 11.53 (brs,
1H, OH), 11.80 (s, 1H, OH).
Melting points were uncorrected. The 1H NMR and 13C NMR
spectra were recorded on Bruker AVANCE III 600 (600 MHz) spec-
trometer using TMS as internal standard and CDCl3 as solvent. MS
were determined on Agilent Technologies 6310 Lon Trap LC/MS.
Sonication was performed in Shanghai Branson-BUG40-06 ultra-
sonic cleaner (with a frequency of 40 kHz and a nominal power
250 W).
2.2.5. Compound 3e
2,20-(2-Chlorophenyl)methylene bis(3-hydroxy-5,5-dimethyl-
2-cyclohexene-1-one): white solid; 1H NMR: dH 1.06 (s, 6H, CH3),
1.15 (s, 6H, CH3), 2.25–2.46 (m, 8H, CH2), 5.62 (s, 1H, CH), 7.14
(td, J = 7.8 Hz, J = 1.2 Hz, 1H, Ph-H), 7.21 (td, J = 7.8 Hz, J = 1.2 Hz,
1H, Ph-H), 7.29 (d, J = 7.8 Hz, 1H, Ph-H), 7.38 (d, J = 7.8 Hz, 1H,
Ph-H), 10.84 (brs, 1H, OH), 11.89 (s, 1H, OH).
2.2. General procedure
A 25 mL Erlenmeyer flask was charged with aromatic aldehydes
(1,1 mmol), 5,5-dimethyl-1,3-cyclohexanedione (2,2 mmol), urea
(15 mg, 0.25 mmol) and water (2 mL). The reaction flask was lo-
cated in the ultrasonic bath, where the surface of reactants is
slightly lower than the level of the water, and irradiated at 50 °C
(bath temperature, the temperature inside the reactor was also
50 °C) for the period of time (The reaction was monitored by
TLC) as indicated in Table 2. The reaction temperature was con-
trolled by addition or removal of water from ultrasonic bath. After
completion of the reaction, the mixture was diluted with water
(10 mL), the solid was filtered, washed with water and dried to give
crude product, which was further purified by column chromatog-
raphy on silica gel (200–300 mesh) eluted with petroleum ether
(b.p. 60–90 °C) or a mixture of petroleum ether and ethyl acetate
(petroleum ether/ethyl acetate = 3/1, V/V) or recrystallization from
ethanol to offer pure product. The products (3a–k) were known
compounds, their authenticity was established by 1H NMR and
their melting point compared with that reported in literatures. 3l
was unknown and established by 1H NMR, 13C NMR and MS.
2.2.6. Compound 3f
2,20-(3-Chlorophenyl)methylene bis(3-hydroxy-5,5-dimethyl-
2-cyclohexene-1-one): white solid: 1H NMR: dH 1.10 (s, 6H, CH3),
1.23 (s, 6H, CH3), 2.30–2.48 (m, 8H, CH2), 5.48 (s, 1H, CH), 6.97
(d, J = 7.8 Hz, 1H, Ph-H), 7.06 (s, 1H, Ph-H), 7.14–7.21 (m, 2H, Ph-
H), 11.50 (brs, 1H, OH), 11.90 (s, 1H, OH).
2.2.7. Compound 3g
2,20-(4-Chlorophenyl)methylene bis(3-hydroxy-5,5-dimethyl-
2-cyclohexene-1-one): white solid; 1H NMR: dH 1.10 (s, 6H, CH3),
1.22 (s, 6H, CH3), 2.30–2.47 (m, 8H, CH2), 5.47 (s, 1H, CH), 7.01
(d, J = 8.4 Hz, 2H, Ph-H), 7.23 (d, J = 8.4 Hz, 2H, Ph-H), 11.56 (brs,
1H, OH), 11.87 (s, 1H, OH).
2.2.8. Compound 3h
2,20-(2,4-Dichlorophenyl)methylene
bis(3-hydroxy-5,5-di-
methyl-2-cyclohexene-1-one): white solid; 1H NMR: dH 1.06 (s,
6H, CH3), 1.13 (s, 6H, CH3), 2.26–2.44 (m, 8H, CH2), 5.56 (s, 1H,
CH), 7.18–7.19 (dd, J = 7.8 Hz, J = 2.4 Hz, 1H, Ph-H), 7.30–7.32
(m,2H, Ph-H), 10.88 (brs, 1H, OH), 11.88 (s, 1H, OH).
2.2.1. Compound 3a
2,20-Phenylmethylene bis(3-hydroxy-5,5-dimethyl-2-cyclohex-
ene-1-one): white solid; 1H NMR: dH 1.10 (s, 6H, CH3), 1.23 (s,
2.2.9. Compound 3i
2,20-(4-Methylphenyl)methylene bis(3-hydroxy-5,5-dimethyl-
2-cyclohexene-1-one): white solid; 1H NMR: dH 1.09 (s, 6H, CH3),
1.23 (s, 6H, CH3), 2.29 (s, 3H, CH3), 2.32–2.46 (m, 8H, CH2), 5.50
(s, 1H, CH), 6.97 (d, J = 7.8 Hz, 2H, Ph-H), 7.07 (d, J = 7.8 Hz, 2H,
Ph-H), 11.58 (brs, 1H, OH), 11.91 (s, 1H, OH).
R
O
O
O
O
urea, H2O
u.s., 50 oC
CHO
R
OH OH
3a-l
2.2.10. Compound 3j
1a-l
2
2,20-(4-Methoxylphenyl)methylene
bis(3-hydroxy-5,5-di-
methyl-2-cyclohexene-1-one): white solid; 1H NMR: dH 1.10 (s,
Scheme 1. Synthesis of 2,20-arylmethylene bis(3-hydroxy-5,5-dimethyl-2-cyclo-
hexene-1-one).
6H, CH3), 1.22 (s, 6H, CH3), 2.29–2.46 (m, 8H, CH2), 3.79 (s, 3H,

J.-T. Li et al. / Ultrasonics Sonochemistry 19 (2012) 1–4
3
Table 1
dimethyl-1,3-cyclohexanedione was selected as the model under
ultrasound irradiation. The results are summarized in Table 1.
As shown in Table 1, increasing the amount of urea can improve
the reaction yield. In the absence of urea, 3a was obtained in 64%
yield only (Table 1, Entry 1). Whereas using 10 mg (17 mol%) urea,
the yield of 3a was 81% (Table 1, Entry 2). With the increasing of
amount of urea from 10 mg to 15 mg, the yield increased from
81% to 94% (Table 1, Entry 3). Further increase of the amount of
urea to 20 mg or 30 mg, does not modify the yield (Table 1, Entries
4 and 5).
The effect of reaction temperature on the yield was observed.
With the increasing of temperature from 30 °C to 50 °C (Entries
9, 4 and 3), the higher yield (94%) was obtained in later case within
the shorter time (60 min), and we choose 50 °C as the appropriate
temperature.
The effect of irradiation frequency on the reaction was also
examined. When the frequency was 40 kHz, the yield of 3a (94%)
(Table 1, Entry 3) was better than that with 25 kHz irradiation
within 60 min (89%, Table 1, Entry 7). The result showed that
40 kHz was the appropriate frequency for this reaction.
In order to verify the effect of ultrasound irradiation, the reac-
tion was also performed by stirring alone under silent condition
at 50 °C, the yield of 3a was 73% (Entry 6). While under ultrasound
the reaction can be completed in 94% yield (Entry 3) within the
same reaction time. It’s clear that ultrasound can accelerate the
reaction and improve the result.
Cavitation is the origin of sonochemistry. Liquids irradiated
with ultrasound can produce bubbles. Under the proper conditions
these bubbles undergo a violent collapse, which generates local-
ized ‘‘hot spot’’ with a transient high temperature and pressures,
inducing molecular fragmentation, and highly reactive species
are locally produced. In the heterogeneous reactions involving
immiscible liquid, the reaction between these species can only oc-
cur in the interfacial region between the liquids. Sonication can be
used to produce very fine emulsions from immiscible liquids. This
is possible because cavitational collapse at or near the interface
disrupts it and imples jets of one liquid into the other to form
the emulsion [23]. These can cause the reaction to take place
rapidly.
The effect of reaction condition on the synthesis of 3a under ultrasound irradiation.a
Entry Amount of
urea (mg)
Frequency
(kHz)
Temperature Time
Isolated
yield (%)
(°C)
(min)
1
2
3
4
5
6
7
8
9
0
40
40
40
40
40
–
25
40
40
–
50
50
50
50
50
50
50
40
30
r.t.
60
60
60
60
60
60
60
150
240
60
64
81
94
93
93
73b
89
91
91
17c
10
15
20
30
15
15
15
15
0
10
a
Substrate:
benzaldehyde,
1 mmol;
5,5-dimethyl-1,3-cyclohexanedione,
2 mmol; water 2 mL.
b
Stirring alone without ultrasound.
Repeated the reported method [8,9,11].
c
Table 2
Synthesis of 3a–l catalyzed by urea in water at 50 °C with ultrasound or without
ultrasound.a
Entry
R
Time (min) Isolated
yield (%)
m.p., °C (Lit.)
A
B
a
b
c
d
e
f
g
h
i
H
60
40
20
30
90
70
120
100
90
94
94
95
98
80
92
91
95
94
93
91
93
73
75
80
83
70
71
74
88
69
78
71
80
189–190 (190–191) [10]
188–189 (188–190) [8]
190–191 (193–195) [10]
188–189 (188–190) [10]
199–200 (197–199) [10]
189–190 (188–190) [5]
137–138 (138–141) [12]
185–186 (188–189) [10]
142–143 (141–143) [4]
140–141 (142–143) [24]
194–195 (196–197) [5]
163–164
2-NO2
3-NO2
4-NO2
2-Cl
3-Cl
4-Cl
2,4-Cl2
4-CH3
4-CH3O
4-OH-3-CH3O 40
3,4-Cl2 100
j
k
l
100
a
Substrate: aryl aldehyde, 1 mmol; 5,5-dimethyl-1,3-cyclohexanedione,
2 mmol; urea, 15 mg; H2O, 2 mL. Condition: A, ultrasound; B, stir without
ultrasound.
From the above results, the optimum reaction conditions were
chosen: aromatic aldehyde (1,1 mmol), 5,5-dimethyl-1,3-cyclo-
hexanedione (2,2 mmol), urea (15 mg, 0.25 mmol), water (2 mL),
irradiation frequency 40 kHz, temperature 50 °C. Using this reac-
tion system, we did a series of experiments to prepare 2,20-arylm-
ethylene bis(3-hydroxy-5,5-dimethyl-2-cyclohexene-1-one). The
results are summarized in Table 2.
CH3O), 5.48 (s, 1H, CH), 6.81 (d, J = 8.4 Hz, 2H, Ph-H), 7.00 (d,
J = 8.4 Hz, 2H, Ph-H), 11.57 (brs, 1H, OH), 11.92 (s, 1H, OH).
2.2.11. Compound 3k
2,20-(4-Hydroxy-3-methoxyphenyl)methylene bis(3-hydroxy-
5,5-dimethyl-2-cyclohexene-1-one): white solid; 1H NMR: dH
1.11 (s, 6H, CH3), 1.23 (s, 6H, CH3), 2.31–2.46 (m, 8H, CH2), 3.77
(s, 3H, CH3O), 5.47 (s, 1H, CH), 5.49 (s, 1H, OH), 6.58 (d,
J = 8.4 Hz, 1H, Ph-H), 6.62 (s, 1H, Ph-H), 6.81 (d, J = 8.4 Hz, 1H,
Ph-H), 11.61 (brs, 1H, OH), 11.97 (s, 1H, OH).
In preliminary experiment, we tried to prepare 3a according to
the reported method in the literatures [8,9,11], but the result was
poor, 3a was afforded in 17% yield only (Table 1, Entry 10). Then
we decided to investigate the reaction catalyzed by urea under
ultrasound. As shown in Table 2, in the presence of urea, excellent
yields were achieved in shorter reaction time under ultrasound.
From these results, we can deduce that the yields are in general,
similar or higher than those described in literatures [4–13,19].
For example, in the previous report [7], the condensation of 2-
nitrobenzaldhyde or 4-nitrobenzaldhyde with 5,5-dimethyl-1,3-
cyclohexanedione catalyzed by HClO4/SiO2 in refluxing water for
1 h offered corresponding product in 61.1% and 68.2% yield respec-
tively. Whereas present procedure needed only 40 min and 30 min
to result 3e and 3g in 94% and 98% yield respectively. In the reac-
tion catalyzed by TEBA in water at 90 °C for 6–8 h, the yield of 3e,
3g and 3i was 84%, 90% and 85% respectively [10], while present
procedure needed 70–100 min to offer 3e, 3g, 3i in 90%, 91% and
95% yield, respectively.
2.2.12. Compound 3l
2,20-(3,4-Dichlorophenyl)methylene
bis(3-hydroxy-5,5-di-
methyl-2-cyclohexene-1-one): white solid; 1H NMR: dH 1.10 (s,
6H, CH3), 1.22 (s, 6H, CH3), 2.30–2.48 (m, 8H, CH2), 5.44 (s, 1H,
CH), 6.91 (d, J = 8.4 Hz, 1H, Ph-H), 7.15 (s, 1H, Ph-H), 7.32 (d,
J = 8.4 Hz, 1H, Ph-H), 11.55 (brs, 1H, OH), 11.88 (s, 1H, OH); 13C
NMR: dC 190.8, 189.5, 138.8, 132.3, 130.1, 129.8, 129.1, 126.3,
114.9, 47.0, 46.4, 32.4, 31.5, 29.6, 27.4; m/z (ESI): 437.4 [M + H]+.
3. Results and discussion
To examine the effect of reaction conditions on the synthesis of
title compounds, the condensation of benzaldehyde (1a) and 5,5-
Phase transfer catalyst (PTC) can prompt the heterogeneous
reaction involving immiscible liquid to give a good result [19].

4
J.-T. Li et al. / Ultrasonics Sonochemistry 19 (2012) 1–4
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synthesis of arylmethylene bis(3-hydroxy-2-cyclohexene-1-ones) and
xanthenediones by EDDA and In(OTf)3-catalyzed one-pot domino
Knoevenagel/Michael or Koevenagel/Michael/Cyclodehydration reactions,
Bull. Korean Chem. Soc. 30 (2009) 1989–1995.
4. Conclusion
In conclusion, we have found an efficient procedure for the syn-
thesis of 2,20-arylmethylene bis(3-hydroxy-5,5-dimethyl-2-cyclo-
hexene-1-one) derivatives via the condensation of aromatic
aldehyde and 5,5-dimethyl-1,3-cyclohexanedione catalyzed by
urea in water under ultrasound irradiation. Compared with some
other reported methods the main advantages of this procedure
are shorter reaction time, simple work-up and environmental
friendly.
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Acknowledgement
We thank the Natural Science Foundation of Hebei Province
(B2006000969), China, for financial support.
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