Synthesis of 2-(1,5-diaryl-1,4-pentadien-3-ylidene)- hydrazinecarboximidamide hydrochloride catalyzed by p-dodecylbenzenesulfonic acid in aqueous media under ultrasound irradiation

Article abstract of DOI:10.1016/j.ultsonch.2012.02.009

Amidinohydrazone compounds are very important synthetic intermediates and can serve as versatile precursors in synthesis of many natural products and drug molecules. The use of ultrasound, p-dodecylbenzenesulfonic acid (DBSA) and water as solvent improved the synthesis of different 2-(1,5-diaryl-1,4- pentadien-3-ylidene)-hydrazinecarboximidamide hydrochlorides. The best reaction conditions for the condensation of 1,5-diphenyl-1,4-pentadien-3-one with aminoguanidine hydrochloride were as follows: 1,5-diphenyl-1,4-pentadiene-3-one (1, 1 mmol), aminoguanidine hydrochloride (1.1 mmol), DBSA (0.5 mmol), water 10 mL, reaction temperature 25-27°C, irradiation frequency 25 kHz. 2a was achieved in 94% yield within 2 h. The other seven amidinohydrazones were obtained in 84-94% yield within 2-3 h under the same conditions. Compared to the method involving catalysis by hydrochloric acid in refluxing EtOH, the advantages of present procedure are milder conditions, shorter reaction times, higher yields, and environmental friendly conditions, which make it a useful strategy for the synthesis of analogues.

Full text of DOI:10.1016/j.ultsonch.2012.02.009

Ultrasonics Sonochemistry 19 (2012) 1033–1038
Contents lists available at SciVerse ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch
Synthesis of 2-(1,5-diaryl-1,4-pentadien-3-ylidene)-hydrazinecarboximidamide
hydrochloride catalyzed by p-dodecylbenzenesulfonic acid in aqueous media
under ultrasound irradiation
⇑
⇑
Ji-Tai Li , Chao Du, Xiao-Ya Xu, Guo-Fen Chen
Key Laboratory of Analytical Science and Technology of Hebei Province, Key Laboratory of Medical Chemistry and Molecular Diagnosis, Ministry of Education,
College of Chemistry and Environmental Science, 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
Article history:
Received 31 August 2011
Received in revised form 8 February 2012
Accepted 24 February 2012
Available online 3 March 2012
Amidinohydrazone compounds are very important synthetic intermediates and can serve as
versatile precursors in synthesis of many natural products and drug molecules. The use of ultrasound,
p-dodecylbenzenesulfonic acid (DBSA) and water as solvent improved the synthesis of different
2-(1,5-diaryl-1,4-pentadien-3-ylidene)-hydrazinecarboximidamide hydrochlorides. The best reaction
conditions for the condensation of 1,5-diphenyl-1,4-pentadien-3-one with aminoguanidine hydrochlo-
ride were as follows: 1,5-diphenyl-1,4-pentadiene-3-one (1, 1 mmol), aminoguanidine hydrochloride
(1.1 mmol), DBSA (0.5 mmol), water 10 mL, reaction temperature 25–27 °C, irradiation frequency
25 kHz. 2a was achieved in 94% yield within 2 h. The other seven amidinohydrazones were obtained in
84–94% yield within 2–3 h under the same conditions. Compared to the method involving catalysis by
hydrochloric acid in refluxing EtOH, the advantages of present procedure are milder conditions, shorter
reaction times, higher yields, and environmental friendly conditions, which make it a useful strategy for
the synthesis of analogues.
Keywords:
1,5-Diaryl-1,4-pentadien-3-one
amidinohydrazone hydrochloride
Synthesis
Ultrasound irradiation
Condensation
Aqueous media
Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction
Organic reactions in aqueous media have currently attracted
increasing interest because of environmental issues and the under-
Amidinohydrazone compounds are very important synthetic
intermediates and can serve as versatile precursors in synthesis
of many natural products and drug molecules [1–5]. These com-
pounds are useful as insecticidal agents [6,7], and anti-tubercular
and anti-malarial agents in warm-blooded animals [8,9].
standing of biochemical processes. Water is an inexpensive, abun-
dant, non-toxic, and environmentally friendly solvent. It exhibits
unique reactivity and selectivity, which is different from those in
conventional organic solvents [11]. In this respect, the develop-
ment of water-tolerant catalysts has rapidly become an area of
intense research [12]. Also, most organic reactants including
catalysts are insoluble in water, and the surfactants, due to their
hydrophobic and hydrophilic nature, form micelles and promote
the reaction in water. p-Dodecylbenzenesulfonic acid (DBSA) as a
Brønsted acid-surfactant combined catalyst acts both as an acid
catalyst to activate a substrate and as a surfactant to form stable
colloidal dispersion with water-insoluble substrates, and thus
can facilitate the reaction [13]. DBSA has been successfully used
in many organic reactions [14].
Ultrasound irradiation has been considered as a clean and use-
ful protocol and widely used in organic synthesis in the recent two
decades. The most important effect of ultrasound passing through
a liquid medium is the generation of cavities. This leads to the
development of high temperatures and high pressures within the
cavities during their collapse [15]. A large number of organic reac-
tions can be carried out in higher yields, shorter reaction times and
milder conditions under ultrasound irradiation [15,16]. Ultrasound
has been previously used for the acceleration of condensation, such
In general, amidinohydrazones are synthesized via the conden-
sation of 1,5-diaryl-1,4-pentadien-3-one with aminoguanidine
hydrochloride, with water as a by product. The reaction involves
nucleophilic addition of aminoguanidine to the carbonyl, followed
by elimination of water. Acid catalysis can aid the reaction [10].
Tomcufcik et al. reported that the synthesis of the title compound
was carried out in 40–70% yield under refluxing EtOH via the
condensation of bischalcone with aminoguanidine hydrochloride
catalyzed by hydrochloric acid (classical method) [6]. The method
suffers from drawbacks such as a longer reaction time (4–16 h),
lower yields, and the use of organic solvent. Therefore, the devel-
opment of simple, efficient and green methodology for the prepa-
ration of amidinohydrazone is still desirable.
⇑
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 address: lijitai@hbu.cn (J.-T. Li).
1350-4177/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2012.02.009

1034
J.-T. Li et al. / Ultrasonics Sonochemistry 19 (2012) 1033–1038
NH
O
N
NH
NH2 HCl
NH HCl
DBSA, u. s.
H2O, 25-27 oC
C
NH
2
R1
R2
+
NH NH2
R2
R1
1a-l
2a-l
Scheme 1. Synthesis of 2-(1,5-diaryl-1,4-pentadien-3-ylidene)-hydrazinecarboximidamide hydrochloride.
as the condensation of carbonyl compounds and hydroxylamine
hydrochloride [17], the Knoevenagel condensation of malononitrile
with aromatic aldehydes to form arylmethylenemalononitriles
[18], the condensation of aromatic aldehydes and barbituric acid
[19] and Claisen–Schmidt condensation of acetophenone with
aromatic aldehydes [20]. These reactions all involve nucleophilic
addition followed by elimination of water. Recently, our laboratory
has described the preparation of bis(indolyl)methanes [14b] and
12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one derivatives
catalyzed by DBSA in aqueous media under ultrasound irradiation
[21]. To the best of our knowledge, however, there are no reports
on the synthesis of the title compound catalyzed by DBSA under
ultrasound irradiation. The aims of this study are to improve the
syntheses of amidinohydrazone by the use of ultrasonic irradiation
(u.s.) and DBSA (Scheme 1).
The reaction was monitored by TLC (silica, CH3OH:CH2Cl2 = 1:4,
V/V), and the reaction temperature was controlled by removal or
addition of water from ultrasonic bath. After the completion of
the reaction, the reaction mixture was extracted with CH2Cl2
(3 Â 10 mL), the combined organic layer was dried over anhydrous
Na2SO4 and filtered. The solvent was removed by evaporation un-
der reduced pressure to give the crude product, which was further
purified by column chromatography on silica (200–300 mesh) and
eluted with petroleum ether (b.p. 60–90 °C) or a mixture of CH3OH
and CH2Cl2 (1:20, V:V). The authenticity of the products (2b–e) was
established by comparing their melting points and 1H NMR with
data reported in the literatures [6]. The authenticity of the other
samples (2a, 2f–l) was established by their 1H NMR, 13C NMR
and MS.
2.2.1. Compound 2a
2. Experimental
2-[3-phenyl-1-(2-phenylethenyl)-2-propen-1-ylidene]-hydra-
zinecarboximidamide hydrochloride: yellow solid, m.p. 223–
224 °C (223–225 °C) [6]. 1H NMR: dH 7.25 (d, J = 16 Hz, 1H, CH),
7.34–7.43 (m, 6H, Ph-H), 7.45 (d, J = 16 Hz, 1H, CH), 7.54 (d,
J = 16 Hz, 1H, CH), 7.62 (d, J = 16 Hz, 1H, CH), 7.70 (d, J = 7.4 Hz,
2H, NH2), 7.90–7.92 (m, 4H, Ph-H), 7.96 (brs, 1H, NH), 12.11 (s,
1H, NH); 13C NMR: dC 156.4, 149.1, 139.3, 136.8, 135.4, 130.0,
129.3, 129.2, 129.1, 128.7, 127.8, 122.9, 119.2; HRMS m/z (ESI):
calcd for C18H19N4 [M + H]+ 291.1604, found 291.1605.
2.1. Apparatus, materials and measurements
All reagents were purchased from Tianjin Reagent Co. (Tianjin,
China). Liquid aldehydes and ketones were purified by distillation
prior to use. The melting points of the products were uncorrected.
1,5-Diaryl-1,4-pentadien-3-ones were prepared according to
reported method in the literature [22]. To a Pyrex flask (50 mL)
were added 95% ethanol (4 mL), acetone (2 mmol), aromatic alde-
hyde (4 mmol) and 1.25 mol/L aqueous potassium hydroxide
(4 mL). The mixture was irradiated in the water bath of an ultra-
sonic cleaner until the aromatic aldehyde disappeared, as indicated
by TLC (Thin Layer Chromatography). After completion of the reac-
tion, the mixture was chilled in an ice-water bath. The precipitate
was isolated by suction filtration, washed to neutral with cool 95%
ethanol and water successively.
MS were determined on Agilent Technologies 6310 Lon Trap LC/
MS (the accuracy is the percent) or Bruker apex ultra 7.0 T spec-
trometer (the accuracy is one ppm). The 1H NMR (600 MHz) and
13C NMR (150 MHz) spectra were recorded on a Bruker AVANCE
III 600 spectrometer using TMS as internal standard and DMSO-
d6 as solvent. Chemical shifts are expressed in parts per million
(ppm), and J values are given in hertz (Hz). Sonication was per-
formed using a Shanghai Branson BUG 25-06 ultrasonic cleaner
(Branson Ultrasonics (Shanghai) Co., Ltd, with a frequency of 25
or 40 kHz and a nominal power 250 W. The total acoustic power
injected into the sample solution was found to be 0.63 and
1.53 W by calorimetry, respectively [23]).
2.2.2. Compound 2b
2-{3-(2-chlorophenyl)-1-[2-(2-chlorophenyl)ethenyl]-2-propen-
1-ylidene}-hydrazinecarboximidamide hydrochloride: yellow so-
lid, m.p. 243–244 °C (243–244 °C) [6]. 1H NMR: dH 7.16 (d,
J = 16 Hz, 1H, CH), 7.34–7.54 (m, 6H, Ph-H), 7.44 (d, J = 8 Hz, 1H,
CH), 7.49 (d, J = 8 Hz, 1H, CH), 7.59 (d, J = 16 Hz, 1H, CH), 7.83
(brs, 2H, NH2), 7.87–7.88 (m, 2H, Ph-H), 8.29 (s, 1H, NH), 11.83
(s, 1H, NH).
2.2.3. Compound 2c
2-{3-(3-chlorophenyl)-1-[2-(3-chlorophenyl)ethenyl]-2-pro-
pen-1-ylidene}-hydrazinecarboximidamide hydrochloride: yellow
solid, m.p. 217–219 °C (217–220 °C) [6]. 1H NMR: dH 7.29 (d,
J = 16 Hz, 1H, CH), 7.36–7.47 (m, 4H, Ph-H), 7.48 (d, J = 16 Hz, 1H,
CH), 7.55 (d, J = 16 Hz, 1H, CH), 7.65 (d, J = 16 Hz, 1H, CH), 7.80
(s, 2H, NH2), 7.86–7.92 (m, 4H, Ph-H), 7.98 (brs, 1H, NH), 12.21
(s, 1H, NH).
2.2. General procedure for the synthesis of the title compounds
2.2.4. Compound 2d
1,5-Diaryl-1,4-pentadiene-3-one (1, 1 mmol), aminoguanidine
hydrochloride (121 mg, 1.1 mmol), DBSA (164 mg, 50% mmol)
and H2O (10 mL) were added into a 25 mL round bottomed flask.
The reaction flask was placed in the cleaner bath, where the surface
of reactants was slightly lower than the level of the water. In the
water bath of the ultrasonic cleaner, the reaction mixture was irra-
diated at 25–27 °C for the period of time as indicated in Table 2.
2-{3-(4-chlorophenyl)-1-[2-(4-chlorophenyl)ethenyl]-2-pro-
pen-1-ylidene}-hydrazinecarboximidamide hydrochloride: yellow
solid, 233–234 °C (233–234 °C) [6]. 1H NMR: dH 7.24 (d, J = 16 Hz,
1H, CH), 7.45 (d, J = 16 Hz, 1H, CH), 7.46–7.50 (m, 4H, Ph-H), 7.52
(d, J = 16 Hz, 1H, CH), 7.55 (d, J = 16 Hz, 1H, CH), 7.71 (d, J = 8 Hz,
2H, NH2), 7.78 (brs, 1H, NH), 7.82–7.91 (m, 4H, Ph-H), 11.94 (s,
1H, NH).

J.-T. Li et al. / Ultrasonics Sonochemistry 19 (2012) 1033–1038
1035
Table 1
The effect of reaction conditions on the yield of 2a under ultrasound irradiation.a
Entry
Frequency, kHz
Substrate/regent, molar ratio
DBSA, mmol
T, °C
Isolated yield, %
1
2
3
4
5
6
7
8
25
25
25
25
25
25
25
25
25
25
40
25
–
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1
1:1.2
1:1.1
1:1.1
1:1.1
0.1
0.2
0.3
0.4
0.5
0.6
0.5
0.5
0.5
0.5
0.5
–
25–27
25–27
25–27
25–27
25–27
25–27
35–37
45–47
25–27
25–27
25–27
25–27
25–27
26
41
58
75
94
96
90
93
91
95
92
–
9
10
11
12
13
0.5
75
a
Reaction time: 2 h.
2.2.5. Compound 2e
CH2), 6.08 (s, 2H, CH2), 6.95 (d, J = 8 Hz, 1H, CH), 6.98–7.07 (m,
2H, Ph-H), 7.08 (d, J = 8 Hz, 1H, CH), 7.25 (d, J = 8 Hz, 1H, CH),
7.31 (d, J = 8 Hz, 1H, CH), 7.38 (s, 2H, NH2), 7.42–7.70 (m, 4H, Ph-
H), 7.75 (brs, 1H, NH), 11.67 (s, 1H, NH); 13C NMR: dC 156.4,
149.1, 148.4, 148.3, 148.2, 139.9, 135.4, 131.2, 130.6, 125.2,
123.5, 121.0, 116.2, 108.9, 106.9, 106.3, 101.9, 101.5; HRMS m/z
(ESI): calcd for C20H19N4O4 [M + H]+ 379.1401, found 379.1401.
2-{3-(4-methylphenyl)-1-[2-(4-methylphenyl)ethenyl]-2-
propen-1-ylidene}hydrazinecarboximidamide hydrochloride: yel-
low solid, m.p. 179–180 °C (179.5–180.5 °C) [6]. 1H NMR: dH 2.33
(s, 3H, CH3), 2.35 (s, 3H, CH3), 7.17 (d, J = 16 Hz, 1H, CH), 7.22–
7.28 (m, 4H, Ph-H), 7.29 (d, J = 16 Hz, 1H, CH), 7.40 (d, J = 16 Hz,
1H, CH), 7.49 (d, J = 16 Hz, 1H, CH), 7.57 (d, J = 8 Hz, 2H, NH2),
7.710–7.75 (m, 4H, Ph-H), 7.85 (brs, 1H, NH), 11.85 (s, 1H, NH).
2.2.10. Compound 2j
2-{3-(2,4-dichlorophenyl)-1-[2-(2,4-dichlorophenyl)ethenyl]-
2-propen-1-ylidene}-hydrazinecarboximidamide hydrochloride:
yellow solid, m.p. 187–188 °C. 1H NMR: dH 7.17 (d, J = 16 Hz, 1H,
CH), 7.42 (d, J = 16 Hz, 1H, CH), 7.46–7.53 (m, 4H, PH-h), 7.66 (s,
2H, NH2), 7.75–7.81(m, 2H, PH-h), 7.83 (brs, 1H, NH), 7.87 (d,
J = 8 Hz, 1H, CH), 8.29 (d, J = 8 Hz, 1H, CH), 11.97 (s, 1H, NH); 13C
NMR: dC 134.6, 133.9, 133.8, 133.5, 132.9, 132.5, 129.6, 129.3,
129.2, 128.0, 127.9, 127.9, 121.3. m/z (EI): 429.1 [M + H]+.
2.2.6. Compound 2f
2-{3-phenyl-1-[2-(4-methylphenyl)ethenyl]-2-propen-1-yli-
dene}-hydrazinecarboximidamide hydrochloride: yellow solid,
m.p. 183–184 °C. 1H NMR: dH 2.33 (s, 3H, CH3), 7.12 (d, J = 16 Hz,
1H, CH), 7.16–7.26 (m, 5H, Ph-H), 7.28 (d, J = 16 Hz, 1H, CH), 7.32
(d, J = 16 Hz, 1H, CH), 7.37 (d, J = 16 Hz, 1H, CH), 7.40 (d, J = 8 Hz,
2H, NH2), 7.50–7.62 (m, 4H, Ph-H), 7.65 (brs, 1H, NH), 11.62 (s,
1H, NH). 13C NMR: dC 153.4, 147.1, 139.2, 135.8, 129.8, 129.7,
129.1, 129.0, 127.6, 127.5, 127.1, 22.1; HRMS m/z (ESI): calcd for
C
19H21N4 [M + H]+ 305.1761, found 305.1764.
2.2.11. Compound 2k
2-{3-(3,4-dichlorophenyl)-1-[2-(3,4-dichlorophenyl)ethenyl]-
2-propen-1-ylidene}-hydrazinecarboximidamide hydrochloride:
yellow solid, m.p. 237–239 °C. 1H NMR: dH 7.33 (d, J = 16 Hz, 1H,
CH), 7.50 (d, J = 16 Hz, 1H, CH), 7.57 (d, J = 16 Hz, 1H, CH), 7.67–
7.70 (m, 3H, Ph-H), 7.72 (d, J = 16 Hz, 1H, CH), 7.88 (d, J = 8 Hz,
2H, NH2), 7.92 (brs, 1H, NH), 8.0–8.2 (m, 3H, Ph-H), 10.48 (s, 1H,
NH); 13C NMR: dC 137.8, 137.2, 132.3, 132.2, 131.1, 130.2, 129.3,
129.2, 128.4, 127.8, 120.3; m/z (EI): 429.1 [M + H]+.
2.2.7. Compound 2g
2-{3-phenyl-1-[2-(4-methoxylphenyl)ethenyl]-2-propen-1-yli-
dene}-hydrazinecarboximidamide hydrochloride: yellow solid;
m.p. 146–148 °C. 1H NMR: dH 3.80 (s, 3H, CH3), 7.24 (d, J = 16 Hz,
1H, CH), 7.31–7.44 (m, 6H, Ph-H), 7.45 (d, J = 16 Hz, 1H, CH), 7.52
(d, J = 8.4 Hz, 1H, CH), 7.63 (d, J = 8.4 Hz, 1H, CH), 7.68 (d,
J = 7.5 Hz, 2H, NH2), 7.78–7.84 (m, 3H, Ph-H), 7.87 (brs, 1H, NH),
11.97 (s, 1H, NH). 13C NMR: dC 160.9, 160.2, 156.5, 136.8, 130.2,
129.8, 129.1, 129.0, 128.5, 127.7, 123.1, 114.7, 55.8; HRMS m/z
(ESI): calcd for C19H21N4O [M + H]+ 321.1710, found 321.1712.
2.2.12. Compound 2l
2-{3-phenyl-1-[2-(4-chlorophenyl)ethenyl]-2-propen-1-yli-
dene}-hydrazinecarboximidamide hydrochloride: yellow solid,
m.p. 209–210 °C. 1H NMR: dH 7.27 (d, J = 16 Hz, 1H, CH), 7.33–
7.45 (m, 5H, Ph-H), 7.48 (d, J = 16 Hz, 1H, CH), 7.54 (d, J = 16 Hz,
1H, CH), 7.68 (d, J = 16 Hz, 1H, CH), 7.72 (d, J = 8 Hz, 2H, NH2),
7.81 (brs, 1H, NH), 7.86–7.92 (m, 4H, Ph-H), 11.95 (s, 1H, NH).
13C NMR: dC 156.3, 139.2, 136.8, 136.4, 135.7, 135.4, 134.5, 133.5,
130.5, 130.1, 129.5, 129.2, 128.5, 127.7, 119.0, 118.0; HRMS m/z
(ESI): calcd for C18H18ClN4 [M + H]+ 325.1214, found 325.1217.
2.2.8. Compound 2h
2-{3-(4-methoxyphenyl)-1-[2-(4-methoxyphenyl)ethenyl]-
2-propen-1-ylidene}-hydrazinecarboximidamide hydrochloride:
yellow solid, m.p. 208–209 °C. 1H NMR: dH 3.81 (s, 6H, CH3),
6.96–7.01 (m, 4H, Ph-H), 7.08 (d, J = 16 Hz, 1H, CH), 7.38 (d,
J = 16 Hz, 1H, CH), 7.42 (d, J = 16 Hz, 1H, CH), 7.46 (d, J = 16 Hz,
1H, CH), 7.63 (d, J = 8.6 Hz, 2H, NH2), 7.70 (brs, 1H, NH), 7.76–
7.86 (m, 4H, Ph-H), 11.83 (s, 1H, NH); 13C NMR: dC 160.9, 160.2,
156.0, 150.7, 139.2, 134.9, 130.2, 129.5, 129.2, 128.9, 120.6,
116.9, 114.6, 55.7, 55.8; HRMS m/z (ESI): calcd for C20H23N4O2
[M + H]+ 351.1816, found 351.1818.
3. Results and discussion
To optimize the reaction conditions, the condensation of 1,5-di-
phenyl-1,4-pentadien-3-one (1a) and aminoguanidine hydrochlo-
ride was selected as the model under ultrasound irradiation
(Table 1).
The effect of the amount of DBSA on the reaction was observed.
When the amount of DBSA was 0.1 mmol, 0.2 mmol, 0.3 mmol,
2.2.9. Compound 2i
2-{3-(3,4-dioxanemethylphenyl)-1-[2-(3,4-dioxanemethylphenyl)
ethenyl]-2-propen-1-ylidene}-hydrazinecarboximidamide hydro-
chloride: yellow solid, m.p. 234–235 °C. 1H NMR: dH 6.06 (s, 2H,

1036
J.-T. Li et al. / Ultrasonics Sonochemistry 19 (2012) 1033–1038
Table 2
Synthesis of 2a–l in aqueous media with or without ultrasound irradiation.
Entry
R1
R2
Product
Ultrasound
Time (h)
Stir.a (Lit.)
Time (h)
Isolated yield (%)
Isolated yield (%)
a
b
c
d
e
f
g
h
i
H
2-Cl
3-Cl
4-Cl
4-CH3
H
H
4-OCH3
3,4-(OCH2O)
2,4-Cl2
3,4-Cl2
H
H
2-Cl
3-Cl
4-Cl
4-CH3
4-CH3
4-OCH3
4-OCH3
3,4-(OCH2O)
2,4-Cl2
3,4-Cl2
4-Cl
2a
2b
2c
2d
2e
2f
2 g
2 h
2i
2
2
2
2
2
2.5
2
2
2.5
3
94
87
84
85
87
95
90
91
92
88
89
94
8 (16)
2 (6.5)
2 (7)
2 (4)
6
8
2
5
2.5
3
91 (69) [6]
55 (70) [6]
72 (40) [6]
51 (58) [6]
65
72
45
80
63
75
78
67
j
k
l
2j
2 k
2 l
3
2.5
3
2.5
a
Stirring alone without ultrasound, reaction temperature 25–27 °C.
OH
O
1
O
2
Ar1
Ar2
Ar1
Ar2
Ar1
NH HCl
NH
Ar2
NH HCl
NH
NH
NH HCl
NHNH2
NH2
H2N
H2N
H2N
3
H
H
OH
OH
NH
Ar1
Ar2
4
5
Ar1
Ar2
Ar1
Ar2
NH HCl
NH
NH HCl
NH
N
NH HCl
NH
NH
H2N
H
H2N
H2N
O
H
H
6
NH HCl
H2N
N
H3O
+
NH
Ar1
Ar2
Scheme 2. Formation of 2a–l.
0.4 mmol and 0.5 mmol, the yield of 2a was 26%, 41%, 58%, 75% and
94%, respectively (Entries 1–5). When the amount of DBSA was
0.6 mmol, the yield of 2a increased to 96%, but the improvement
from entry 5 is slight (Entry 6). In the absence of DBSA, we also
did the experiment for the reaction of 1a with aminoguanidine
hydrochloride, the reaction was not taken place at all (Entry 12).
It seems that DBSA plays an important catalytic role in the reaction.
The following sequence of reactions appears to afford a satisfac-
tory explanation of the mode of formation of products 2a–l for the
condensation of 1,5-diary-1,4-pentadien-3-one with aminoguani-
dine hydrochloride [10] (Scheme 2).
As shown in Scheme 2, the reaction involves nucleophilic addi-
tion of the amino group followed by elimination of water. The
nitrogen, with a lone pair electron, is a good nucleophile. It is suf-
ficiently nucleophilic to attach the carbonyl group without the
need for acid catalysis. DBSA catalysis is important in creating a
good leaving group (Scheme 2, step 4). If protonation did not occur,
the leaving group would have to be the hydroxide ion, which is a
more reactive molecule and a poorer leaving group. In addition,
the condensation of 1a and aminoguanidine hydrochloride was
performed in a solid–liquid system in which the emulsification of
BDSA could also facilitate the reaction.

J.-T. Li et al. / Ultrasonics Sonochemistry 19 (2012) 1033–1038
1037
As shown in Table 1, we also examined the effect of reaction
4. Conclusion
temperature. When the temperature was 25–27 °C, 35–37 °C and
45–47 °C, the yield was 94% (Entry 5), 90% (Entry 7) and 93% (Entry
8), respectively. Consequently, the reaction temperature had little
effect on the reaction.
The influence of the molar ratio of 1a to aminoguanidine hydro-
chloride on the reaction was investigated. When the molar ratio
was 1:1, 2a was obtained in 91% yield (Entry 9). Increasing the
molar ratio to 1:1.1 and 1:1.2, the yield of 2a was 94% (Entry 5)
and 95% (Entry 10) respectively.
In conclusion, we have found an efficient and practical
procedure for the synthesis of the title compound via the conden-
sation of 1,5-diaryl-1,4-pentadiene-3-one with aminoguanidine
hydrochloride catalyzed by DBSA under ultrasound irradiation in
the presence of water. Compared to the classical method, the
advantages of present procedure are milder conditions, shorter
reaction times, higher yields and environmental friendly reaction
conditions.
The effect of frequency of ultrasound irradiation on the reaction
was also observed. When the frequency was 25 kHz, the molar
ratio of substrate to aminoguanidine hydrochloride was 1:1.1,
the condensation of 1a and aminoguanidine hydrochloride cata-
lyzed by DBSA (0.5 mmol) at 25–27 °C resulted in the desired prod-
uct in 94% yield within 2 h, while with 40 kHz irradiation under
otherwise the same reaction conditions, the yield was 92%. Thus,
the irradiation frequency had little effect on the reaction.
We also did the experiments using stirring without ultrasound
irradiation. Compound 2a was obtained in 75% (Entry 13) yield in
2 h, whereas under ultrasound irradiation the yield of 2a was
94% (Entry 5). It is apparent that ultrasound irradiation can accel-
erate the reaction significantly to give better yield. The reason may
be the phenomenon of cavitation produced by ultrasound. The ef-
fects of ultrasound observed during organic reactions are due to
cavitation which can induce instantaneous high local temperatures
and pressures. In addition, ultrasound is known to generate extre-
mely fine emulsions from mixtures of immiscible phases. On closer
inspection this disturbance can be seen as a large number of tiny
‘explosions’ at the interface, effectively sending small jets of liquid
from one phase into the other. One of the main consequences of
these emulsions is the dramatic increase in the interfacial contact
area between the immiscible phases, i.e. an increase in the region
over which any reaction between species dissolved in the different
phases can take place [24,15a,16a].
From the results above, the reaction conditions we chose were
as follows: 1,5-diaryl-1,4-pentadiene-3-one (1, 1 mmol), amino-
guanidine hydrochloride (1.1 mmol), DBSA (0.5 mmol), water
10 mL, reaction temperature 25–27 °C, irradiation frequency
25 kHz. Using this reaction system, a series of experiments for
the condensation of 1,5-diaryl-1,4-pentadien-3-one and amino-
guanidine hydrochloride were completed under ultrasound irradi-
ation or silent conditions. The results are summarized in Table 2.
As shown in Table 2, the condensation of various 1,5-diaryl-1,4-
pentadiene-3-one and aminoguanidine hydrochloride was carried
out in good yields catalyzed by DBSA in aqueous media under
ultrasound irradiation. From these results, we can deduce that
the yields are, in general, similar or higher than those described
in literatures. The dramatic improvements were the short reaction
times and high yields. According to the method catalyzed by
hydrochloric acid in the literature [6], the time and yield of 2a were
16 h and 69% respectively under refluxing EtOH, for the condensa-
tion of 1,5-diphenyl-1,4-pentadiene-3-one and aminoguanidine
hydrochloride. The present procedure gave a 94% yield within 2 h
(Table 2, Entry a) at 25–27 °C. Other reactions can be completed
in 2–3 h instead of 4–16 h to give the products in 84–94% instead
of 40–70% yields (Table 2 2a–d) with no requirement of an organic
solvent.
References
[1] A.L. LaFrate, J.R. Gunther, K.E. Carlson, J.A. Katzenellenbogen, Synthesis and
biological evaluation of guanylhydrazone coactivator binding inhibitors for the
estrogen receptor, Bioorg. Med. Chem. 16 (2008) 10075–10084.
[2] F. Sielaff, M.E. Than, D. Bevec, I. Lindberg, T. Steinmetzer, New furin inhibitors
based on weakly basic amidinohydrazones, Bioorg. Med. Chem. Lett. 21 (2011)
836–840.
[3] W.B. Wright Jr., A.S. Tomcufcik, Derivatives of p-formylbenzamide
amidinohydrazone and use thereof, United States Patent 4289,769, Sep. 15,
1981.
[4] D.G. Brown, Spiro-cyclopropyl amidinohydrazones, and use as insect and fire
ant control agents, United States Patent 4349,553, Sep. 14, 1982.
[5] H. Stegelmeier, F.J. Morich, A. Knorr, Amidinohydrazones of derivatives of
tetraline, chromone, thiachromone, and tetrahydroquinoline, process for their
preparation, and their use in medicaments, European Patent 0163888, Dec. 11,
1985.
[6] A.S. Tomcufcik, 1,5-Bissubstituted-1,4-pentadien-3-one substituted amidino-
hydrazone salts and method of preparing the same, United States Patent
3878,201, April 15, 1975.
[7] J.B. Lovell, Pentadienone hydrazones as insecticides, United States Patent
4087,525, May 2, 1978.
[8] A. Takai, I. Saikawa, Studies on nitrofuran and related compounds for
medicinal purpose. I. Cyclization of 1,5-bis(5-nitor-2-furyl)-1,4-penatdien-3-
one amidinohydrazone and related compounds, J. Pharm. Soc. Japan. 84 (1964)
1–9.
[9] A. Takai, I. Saikawa, Studies on nitrofuran and related compounds for
medicinal purpose. III. Synthesis and antibacterial activity of 3-amino-1,2,4-
triazine derivatives, J. Pharm. Soc. Japan. 84 (1964) 16–23.
[10] G. Patrick, Organic Chemistry, Bios Scientific Publishers Limited, 2000.
[11] (a) C.J. Li, T.H. Chan, Organic Reactions in Aqueous Media, 2nd ed., Wiley,
Hoboken, NJ, 2007;
(b) J.J.V. Eynde, K. Mutonkole, Y.V. Haverbeke, Surfactant-assisted organic
reactions in water. Effect of ultrasound on condensation reactions between
active methylene compounds arylaldehydes, Ultrason. Sonochem. 8 (2001)
35–39;
(c) I.L. Odinets, E.V. Matveeva, Ionic liquids and water as ‘‘green’’ solvents in
organophosphorus synthesis, Curr. Org. Chem. 14 (2010) 1171–1184;
(d) J.T. Li, X.T. Meng, B. Bai, M.X. Sun, An efficient deprotection of oximes to
carbonyls catalyzed by silica sulfuric acid in water under ultrasound
irradiation, Ultrason. Sonochem. 17 (2010) 14–16.
[12] B.R. Madje, K.F. Shelke, S.B. Sapkal, G.K. Kakade, M.S. Shingare, An efficient one-
pot synthesis of anthraquinone derivatives catalyzed by alum in aqueous
media, Green Chem. Lett. Rev. 3 (2010) 269–273.
[13] K. Manabe, S. Kobayashi, Mannich-type reactions of aldehydes, amines, and
ketones in a colloidal dispersion system created by a Brønsted acid-surfactant-
combined catalyst in water, Org. Lett. 1 (1999) 1965–1967.
[14] (a) K. Manabe, Y. Mori, S. Kobayashi, Three-component carbon–carbon bond-
forming reactions catalyzed by a Brønsted acid-surfactant-combined catalyst
in water, Tetrahedron 57 (2001) 2537–2544;
(b) J.T. Li, M.X. Sun, G.Y. He, X.Y. Xu, Efficient and green synthesis of
bis(indolyl)methanes catalyzed by ABS in aqueous media under ultrasound
irradiation, Ultrason. Sonochem. 18 (2011) 412–414.
[15] (a) T.J. Mason, D. Peters, Practical Sonochemistry, second ed., Power
ultrasound uses and applications, Ellis Horwood, New York, 2002;
(b) T.J. Mason, Sonochemistry and the environment – Providing a ‘‘green’’ link
between chemistry, physics and engineering, Ultrason. Sonochem. 14 (2007)
476–483.
[16] (a) J.L. Luche, Synthetic Organic Sonochemistry, Plenum Press, New York,
1998;
In the presence procedure, 1,5-diaryl-1,4-pentadiene-3-ones
carrying either electron-donating or electron-withdrawing substit-
uents on the benzene ring all reacted very well. It seems that the
effect of electronic factors on the yield was not obvious. The con-
densation of 1a and aminoguanidine hydrochloride was slightly
easier and the yield was slightly higher than that of others. It
may be that the steric hindrance around the carbonyl inhibited
the attack of aminoguanidine hydrochloride to carbonyl.
(b) J.T. Li, S.X. Wang, G.F. Chen, T.S. Li, Some applications of ultrasound
irradiation in organic synthesis, Curr. Org. Synth. 2 (2005) 415–436.
[17] (a) J.T. Li, X.L. Li, T.S. Li, Synthesis of oximes under ultrasound irradiation,
Ultrason. Sonochem. 13 (2006) 200–202;
(b) J.T. Li, X. Li Zhai, B. Bai, Y.H. Liang, An efficient synthesis of 1,5-diaryl-1,4-
pentadien-3-one oxime in the presence of anhydrous sodium sulfate, Lett. Org.
Chem. 7 (2010) 323–326.
[18] J.T. Li, G.F. Chen, S.X. Wang, L. He, T.S. Li, Synthesis of arylmethylene-
malononitriles catalyzed by KF–Al2O3 under ultrasound, Aust. J. Chem. 58
(2005) 231–233.

1038
J.-T. Li et al. / Ultrasonics Sonochemistry 19 (2012) 1033–1038
a highly efficient catalyst for the [22] G.F. Chen, J.T. Li, H.Y. Duan, T.S. Li, Improved ultrasound-induced synthesis 1,5-
[19] J.T. Li, M.X. Sun, SiO2Á12WO3Á24H2O:
synthesis of 5-arylidene barbituric acid in the presence of water, Aust. J.
Chem. 62 (2009) 353–355.
diaryl-1,4-pentadien-3-ones, Chem. J. Int. 6 (2004) 7–10.
[23] T. Kimura, T. Sakamoto, J.M. Leveque, H. Sohmiya, M. Fujita, S. Ikeda, T. Ando,
Standardization of ultrasonic power for sonochemical reaction, Ultrason.
Sonochem. 3 (1996) 157–161.
[20] J.T. Li, W.Z. Yang, S.X. Wang, S.H. Li, T.S. Li, Improved synthesis of chalcones
under ultrasound irradiation, Ultrason. Sonochem. 9 (2002) 237–239.
[21] J.T. Li, Y.W. Li, Y.L. Song, Efficient synthesis of 12-aryl -8,9,10,12- tetrahydro-
benzo[a]xanthen-11-one derivatives catalyzed by p-dodecylbenzenesulfonic
acid in aqueous media under ultrasound, Synth. Commun. 42 (2012) 2161–
2170.
[24] J. Lindley, P.J. Lorimer, T.J. Mason, Enhancement of an Ullmann coupling
reaction induced by ultrasound, Ultrasonics 24 (1986) 292–293.