Design, synthesis and insecticidal activities of novel acetamido derivatives containing N-pyridylpyrazole carboxamides

Article abstract of DOI:10.1016/j.ejmech.2013.06.023

A series of novel acetamido derivatives containing N-pyridylpyrazole carboxamides was designed and synthesized by increasing the amide bridge of chlorantraniliprole using acetamido moieties and introducing different aryl substitutions. The target compounds were characterized by ¹H NMR, ¹³C NMR, IR, and elemental analysis. Bioassays indicated that some of the synthesized compounds exhibited strong insecticidal activity against Plutella xylostella . Compounds 5-, 5g and 5v were the most potent, with LC ₅₀ values of 23.72, 2.04, and 20.01 mg/L, respectively. The insecticidal activity of compound 5g was higher than that of chlorpyrifos (LC₅₀ = 7.25 mg/L), a commonly used insecticide. These results indicate that novel acetamido derivatives containing N-pyridylpyrazole carboxamides can effectively control P. xylostella.

Full text of DOI:10.1016/j.ejmech.2013.06.023

European Journal of Medicinal Chemistry 67 (2013) 14e18
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design, synthesis and insecticidal activities of novel acetamido
derivatives containing N-pyridylpyrazole carboxamides
*
Shenghong Kang, Baoan Song , Jian Wu, Ming He, Deyu Hu, Linhong Jin, Song Zeng,
*
Wei Xue, Song Yang
State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering,
Ministry of Education, Research and Development Center for Fine Chemicals, Guizhou University, Guiyang 550025, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel acetamido derivatives containing N-pyridylpyrazole carboxamides was designed and
synthesized by increasing the amide bridge of chlorantraniliprole using acetamido moieties and intro-
ducing different aryl substitutions. The target compounds were characterized by 1H NMR, 13C NMR, IR,
and elemental analysis. Bioassays indicated that some of the synthesized compounds exhibited strong
insecticidal activity against Plutella xylostella. Compounds 5e, 5g and 5v were the most potent, with LC50
values of 23.72, 2.04, and 20.01 mg/L, respectively. The insecticidal activity of compound 5g was higher
than that of chlorpyrifos (LC50 ¼ 7.25 mg/L), a commonly used insecticide. These results indicate that
novel acetamido derivatives containing N-pyridylpyrazole carboxamides can effectively control P.
xylostella.
Received 6 April 2013
Received in revised form
5 June 2013
Accepted 7 June 2013
Available online 19 June 2013
Keywords:
Acetamido derivatives
N-pyridylpyrazole carboxamides
Synthesis
Ó 2013 Elsevier Masson SAS. All rights reserved.
Insecticidal activity
1. Introduction
pyrazole moiety (I), substituted phenyl moiety (II), aliphatic amide
moiety (III) and the amide bridge (IV) [9]. For instance, the bromine
Plutella xylostella, one of the most widespread and harmful
Lepidoptera pests, poses significant threats to cruciferous vegeta-
bles, such as cabbage, cauliflower and turnip, in many parts of the
world. It has been causing an estimated annual loss of US $1 billion
in economic crops throughout the world since the early 1990s [1,2].
A significant challenge faced by farmers is that P. xylostella is
difficult to prevent and control due to its strong resistance to
currently available pesticides [3e6].
Chlorantraniliprole (Fig. 1), a novel insecticide that acts on
ryanodine receptors, was discovered and commercialized by
DuPont Ltd [7]. It shows excellent insecticidal activity against P.
xylostella and has low toxicity to mammals [8]. In recent years, the
chemical structure of chlorantraniliprole has received considerable
attention, and a large number of active compounds have been ob-
tained by modifying chlorantraniliprole at its 1-(3-chloropyridyl)
atom on the pyrazole ring (I) can be replaced by cyano, tri-
fluoromethyl, methoxy, perfluoroethoxy and ethynyloxy moieties
[10e13], while the benzene ring can be replaced by benzofuran,
quinoline and naphthalene [14,15]. Cyantraniliprole (Fig. 1),
another anthranilic diamide insecticide, was discovered by chang-
ing the chlorine at position 5 of the substituted phenyl moiety (II)
to a cyano group [16]. Moreover, cyano group [17], oxadiazoles,
thiadiazoles [18], and substituted hydrazinecarbonyl (or carba-
moyl) have been used to replace the methylcarbamoyl group in the
aliphatic amide moiety (III) of chlorantraniliprole [19e26]. More
recently, several compounds with high insecticidal activities have
been obtained by changing the amide bridge (IV) to acylthiourea
and acylurea moieties [9,27]. Thus, the sub-structure of N-pyr-
idylpyrazole carboxamide is an important factor in our search for
anthranilic diamide insecticides.
Acetamido derivatives have been reported to possess good
flexibility due to the presence of eCH2- groups [28]. They have also
been paid close attention due to their antimicrobial [29], anticon-
vulsant [30], antitumor [31], anticancer [32], insecticidal [33], and
antifungal activities [34]. Among agrochemicals, sub-structures of
acetamido groups can be found in the structure of several in-
secticides (e.g., dimethoate and omethoate) and herbicides (e.g.,
Abbreviations: P. xylostella, Plutella xylostella; mp, melting point; IR, infrared; 1
H
NMR, proton nuclear magnetic resonance; 13C NMR, carbon nuclear magnetic
resonance; LC50, median lethal concentration; SAR, structureeactivity relationship.
* Corresponding authors. Tel.: þ86 (851) 362 0521; fax: þ86 (851) 362 2211.
E-mail addresses: songbaoan22@yahoo.com (B. Song), fcc.syang@gzu.edu.cn
(S. Yang).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.06.023

S. Kang et al. / European Journal of Medicinal Chemistry 67 (2013) 14e18
15
Fig. 1. Design of the title compound 5.
propanil). Thus, widespread use of acetamido as a scaffold in
pesticide and medicinal chemistry establishes this moiety as an
important structural class.
was prepared using intermediates 2 and glycine ethyl ester hy-
drochloride in dry dichloromethane. Compound 3 was hydro-
lyzed in aqueous sodium hydroxide and the pH was adjusted to 3
using 5% hydrochloric acid to obtain compound 4. The title
compounds (5ae5w) were finally prepared in a single step by
treatment of compound 4 with different substituted amines in
the presence of triethylamine and phosphorus oxychloride for
30 min in refluxing acetonitrile. As reported previously, amides
can be prepared via reaction of chloride (prepared first from
acids) with amines [36] or condensation of acid with amines in
the presence of a condensing agent (such as DCC, EDC, and DIC)
[37e39]. However, these methods usually involve long reaction
steps and reaction time, and require difficult post-processing
steps. In the present work, the amides were prepared in a sin-
gle step as described previously [40]. This method offered several
advantages, such as short reaction time, relatively high yield and
simple post-processing. Moreover, yields of amide preparation
could be enhanced by aromatic amines containing electron
donating groups (such as, eOCF3, eSCF3, and eOCH2CH3 groups)
likely due to the strong alkaline system provided by these amines
(e.g., yields for 5a, 5b and 5m were 90.8%, 90.1% and 90.3%,
respectively). Consistent with this idea, amines that exhibited
lower yields contained electron withdrawing groups (such as, e
NO2, eCl) and possessed weaker alkaline properties.
In order to obtain novel acetamido derivatives (Scheme 1) with
potential insecticidal activity, we sought to retain the sub-
structure of N-pyridylpyrazole carboxamides, increase the amide
bridge by introducing an acetamido moiety, then introduce
different substituted aryls. A series of novel acetamido derivatives
containing N-pyridylpyrazole carboxamides (5) was designed
(Fig. 1) and synthesized. Structures of all synthesized compounds
were characterized by 1H NMR and 13C NMR, infrared spectros-
copy, and elemental analysis. Results of bioassays indicate that
most synthesized compounds exhibit strong insecticidal activities
against P. xylostella. In particular, the compounds 5e, 5g, and 5v
exhibited 100% insecticidal activity at 250 mg/L. Compound 5g
showed >60% insecticidal activity at 6.25 mg/L with an LC50 value
of 2.04 mg/L, indicating that its insecticidal activity was much
higher than that of chlorpyrifos (LC50 ¼ 7.25 mg/L), a commonly
used pesticide.
2. Results and discussion
2.1. Chemistry
All synthesized compounds (5ae5w) were characterized based
on their spectroscopic data. IR absorption bands near 3329e
3300 cmꢀ1 and 3255e3245 cmꢀ1 confirmed the presence of NeH
The synthesis protocol for obtaining the title compounds is
depicted in Scheme 1. Intermediates 1 and 2 were prepared ac-
cording to previously reported methods [35]. Firstly, compound 3
Scheme 1. General synthetic route for title compounds 5ae5w.

16
S. Kang et al. / European Journal of Medicinal Chemistry 67 (2013) 14e18
Table 1
Insecticidal activities of compounds 3, 5ae5w, chlorantraniliprole, chlorpyrifos and avermectin against Plutella xylostella.
Compound
R1
Insecticidal activity (%) at indicated concentrations (mg/L)
500
250
100
50
25
12.5
6.25
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
4-OCF3-Ph
4-SCF3-Ph
100
53.3
86.7
100
100
86.7
100
86.7
43.3
63.3
86.7
40
76.7
30
60
83.3
100
56.7
100
66.7
40
/
/
46.7
100
/
93.3
36.7
/
/
53.3
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
70
/
/
/
/
/
/
/
/
3,5-dieCF3ePh
4-Cl-Ph
2,6-di-Cl-4-CF3-Ph
2-Cl-4-CH3-Ph
2-NO2-Ph
83.3
/
86.7
/
/
/
/
/
50.0
/
76.7
/
/
/
/
/
66.7
/
/
/
/
/
4-NO2-Ph
2-CH3-5-Cl-Ph
3-CF3-4-Cl-Ph
2-CN-Ph
/
33.3
76.7
/
/
/
/
4-CH3-Ph
5m
5n
5o
5p
4-OCH2CH3-Ph
3,4-di-Cl-Ph
3,4-di-CH3-Ph
3-F-Ph
30
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
26.7
26.7
23.3
6.7
5q
3-Cl-Ph
/
/
/
/
/
/
5r
5s
5t
5u
5v
5w
3
3-Cl-4-F-Ph
16.7
23.3
90.0
100
100
100
90
/
/
/
0
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
3-CF3-4-F-Ph
2,5-di-Cl-Ph
5-CH3-1H-Pyrazol-3-yl
2-Cl-4-CH3-Pyridin-3-yl
2-Cl-Pyridin-3-yl
76.7
73.3
100
83.3
60
/
/
/
0
56.7
56.7
73.3
53.3
/
100
100
100
0
/
63.3
/
/
100
90
100
0
56.7
/
/
100
83.3
100
0
46.7
/
/
100
66.7
100
0
Chlorantraniliprole
Chlorpyrifos
Avermectin
CK
100
43.3
100
0
in two amides. AreH appeared in the range of 3100e2920 cmꢀ1
.
2.2. Insecticidal activity
Presence of two amide functional groups [41] in their structures
was noted based on appearance of bands at 1720e1690 cmꢀ1 and
1670e1650 cmꢀ1. For the compound 5k, absorption peak of the
cyano group appeared at 2225 cmꢀ1. In the 1H NMR spectra of the
title compounds, a broad signal peak that appeared at the lowest
field of 10.83e9.24 ppm corresponded with the eCH2CONHAre
proton influenced by the aromatic ring. Hence, the chemical shift of
eCONHCH2e appeared as a triplet at 9.35e9.15 ppm, and the
pyrazole-H proton mainly appeared as a doublet at 7.34e7.30 ppm.
The chemical shift of eNHCH2COe was influenced by its carbonyl
group and nitrogen atoms, and it appeared as a doublet at 4.10e
3.90 ppm. Moreover, in the 13C NMR spectra, the carbon resonance
frequencies of the two C¼O were at 168.73e166.38 ppm (adjacent
to pyrazole) and at 157.71e157.47 ppm (near the “eCH2e” group).
Finally, the eCH2e group appeared at 43.38e42.50 ppm.
Insecticidal activities of compounds 5ae5w against P. xylostella
are shown in Table 1. The commercial insecticides chloran-
traniliprole, chlorpyrifos, and avermectins were used as standards.
In general, most of the compounds (i.e., 5a, 5d, 5e, 5g, 5u, 5v, and
5w) showed 100% insecticidal activity at 500 mg/L. The insecticidal
activities of compounds 5e, 5g, and 5v were still 100% at 250 mg/L,
while compounds 5e and 5g displayed >90% insecticidal activity at
100 mg/L. The insecticidal activity of compound 5g was over 65% at
6.25 mg/L. For comparison, the LC50 value of chlorpyrifos (a
commonly used insecticide) and some title compounds were also
determined. The results are listed in Table 2.
The LC50 values of compounds 5d, 5e, 5g, 5k, 5t, 5u, 5v and 5w
were less than 100 mg/L (Table 2). In particular, the compounds 5e,
5g and 5v exhibited excellent insecticidal activities, with LC50
values of 23.72, 2.04, and 20.01 mg/L, respectively. The compound
5g showed much higher insecticidal activity than commercial
chlorpyrifos (LC50 ¼ 7.25 mg/L). As revealed by data in Tables 1 and
2, when R was substituted with a benzene ring, the insecticidal
activity of the title compounds could be enhanced by the groups 2-
nitro, 2,6-dichloro-4-trifluoromethyl and 4-chloro. In addition,
introduction of heterocyclic rings (i.e., pyridine and pyrazole)
increased its insecticidal activity against P. xylostella. Interestingly, a
compound containing an ester group (3) was found to have 90%
insecticidal activity against P. xylostella at 500 mg/L.
Table 2
LC50 values for insecticidal activity against Plutella xylostella.
Compound
y ¼ a þ b x
LC50 (mg/L)
R
5a
5b
5c
5d
5e
5f
5g
5h
5j
5k
5t
5u
5v
5w
y ¼ 0.39 þ 2.21 x
y ¼ 1.36 þ 1.33 x
y ¼ 0.16 þ 2.15 x
y ¼ 1.07 þ 2.01 x
y ¼ 0.82 þ 3.03 x
y ¼ 1.65 þ 1.50 x
y ¼ 4.77 þ 0.75 x
y ¼ 0.96 þ 1.87 x
y ¼ 1.14 þ 1.49 x
y ¼ 3.07 þ 1.07 x
y ¼ 1.53 þ 1.90 x
y ¼ 1.91 þ 1.64 x
y ¼ 4.01 þ 0.76 x
y ¼ 0.82 þ 2.09 x
y ¼ 3.60 þ 1.62 x
121.60
539.22
180.90
90.27
23.72
168.52
2.04
144.43
395.61
63.48
65.90
76.76
20.01
99.34
7.25
0.99
0.98
0.99
0.99
0.99
0.98
0.96
0.99
0.97
0.97
0.97
0.99
0.99
0.99
0.99
3. Conclusion
Twenty-three novel acetamido derivatives (5ae5w) containing
N-pyridylpyrazole carboxamides were designed and synthesized
based on the sub-structure of chlorantraniliprole. These com-
pounds were characterized and confirmed by 1H NMR, 13C NMR, IR,
and elemental analysis. A preliminary evaluation of the insecticidal
Chlorpyrifos

S. Kang et al. / European Journal of Medicinal Chemistry 67 (2013) 14e18
17
activities of the synthesized compounds was conducted. Most
compounds exhibited excellent toxic effects against P. xylostella. In
particular, the LC50 values of compounds 5e, 5g, and 5v were 23.72,
2.04, and 20.01 mg/L, respectively. Notably, compound 5g showed
much higher insecticidal activity than chlorpyrifos (LC50 ¼ 7.25 mg/
L). Preliminary SAR analysis indicated that the 2-nitro, 2,6-
dichloro-4-trifluoromethyl, and 4-chloro groups on the benzene
ring (in the R group) had positive influence on the insecticidal ac-
tivity of synthesized compounds. Moreover, introduction of a het-
erocyclic ring (pyridine and pyrazole) could enhance their
insecticidal effects against P. xylostella.
225 ꢁC; yield, 94%; 1H NMR (500 MHz, DMSO-d6, ppm): 12.69 (br,
1H, eCOOH), 9.17 (t, 1H, J ¼ 5.75 Hz, eCONHCH2e), 8.50 (dd,
3
4JHH ¼ 1.15 Hz, JHH ¼ 4.55 Hz, 1H, 6-Pyridine-H), 8.19 (dd,
3
4JHH ¼ 1.15 Hz, JHH ¼ 8.05 Hz, 1H, 4-Pyridine-H), 7.64 (dd,
3
4JHH ¼ 4.50 Hz, JHH ¼ 8.05 Hz, 1H, 5-Pyridine-H), 7.27 (s, 1H, 4-
Pyrazole-H), 3.83 (d, J ¼ 5.70 Hz, 2H, eNHeCH2e); Anal. calcd for
C11H8BrClN4O3 (358): C, 36.57%; H, 2.43%; N, 15.65%. Found: C,
36.74%; H, 2.24%; N, 15.58%.
4.2.3. General synthetic procedure for obtaining compounds 5ae
5w
Compound
4
(0.1 mmol), 4-(trifluoromethoxy) aniline
4. Materials and methods
(0.1 mmol), and triethylamine (0.1 mmol) were dissolved in CH3CN
(15 mL) with stirring, and POCl3 (0.1 mmol) was dissolved in CH3CN
(5 mL) and then added dropwise. After stirring and refluxing for
2 h, CH3CN was removed in vacuo. The mixture was washed with
saturated sodium bicarbonate solution. The solution was filtered to
obtain a crude product, which was recrystallized with ethanol to
obtain the title compound 5a.
Target compounds 5be5w were prepared using similar pro-
cedures as those described above for compound 5a. The melting
point, yield, IR, 1H NMR, 13C NMR and elemental analyses data for
5a are shown below, and those for compounds 5be5w can be found
in the Supporting Information.
4.1. Instruments
Unless otherwise stated, all reagents and reactants (analytically or
chemically pure) were purchased from commercial suppliers.
Melting points were uncorrected and determined using an XT-4
binocular microscope (Beijing Tech Instrument Co., China). 1H NMR
and 13C NMR spectra were recorded at room temperature on a JEOL
ECX 500 NMR spectrometer (JEOL Ltd., Japan) operating at 500 MHz
for 1H NMR and 125 MHz for 13C NMR using CDCl3 or dimethyl
sulfoxide (DMSO) as a solvent and tetramethylsilane as an internal
standard. IR spectra were recorded in KBr on an IR Prestige-21
spectrometer (Shimadzu Corporation, Japan). Elemental analysis
was performed on an Elemental Vario-III CHN analyzer (Elementar,
Germany). The reactions were monitored by thin liquid chromatog-
raphy (TLC). Analytical TLC was performed on silica gel GF 254. All
solvents were dried by standard methods and distilled before use.
Data for 3-bromo-1-(3-chloropyridin-2-yl)-N-(2-oxo-2-((4-(tri-
fluoromethoxy)phenyl)amino)ethyl)-1H-pyrazole-5-carboxamide
(5a). Phase, white solid; mp, 212e214 ꢁC; yield, 90.1%; IR (KBr,
cmꢀ1
)
n
: 3309.8, 3251.9, 3107.3, 3076.4, 2927.9, 1714.7, 1664.5,
1543.0, 1506.3, 1467.8, 1294.2; 1H NMR (500 MHz, DMSO-d6, ppm)
d
: 10.24 (s, 1H, eCONHe), 9.18 (t, 1H, J ¼ 5.75 Hz, eCONHCH2e),
8.50 (dd, 4JHH ¼ 1.15 Hz, 3JHH ¼ 4.60 Hz, 1H, 6-Pyridine-H), 8.19 (dd,
4.2. General procedure
4JHH ¼ 1.15 Hz, 3JHH ¼ 8.00 Hz, 1H, 4-Pyridine-H), 7.67 (s, 1H, Ph-H),
4
3
7.65 (s, 1H, Ph-H), 7.63 (dd, JHH ¼ 4.60 Hz, JHH ¼ 8.05 Hz, 1H, 5-
Ethyl 2-(3-substituted-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-
carboxamido) acetate (intermediates 1) and 3-bromo-1-(3-
chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride (interme
diates 2) were synthesized as previously described [35]. The title
compounds were prepared as shown in Scheme 1.
Pyridine-H), 7.33 (s, 1H, Ph-H), 7.32 (s, 1H, Ph-H), 7.30 (s, 1H, 4-
Pyrazole-H), 3.98 (d,
(125 MHz, DMSO-d6, ppm)
J
¼
5.70 Hz, 2H, eCH2e); 13C NMR
: 167.71, 157.61, 149.26, 147.58, 144.09,
d
139.71, 139.61, 138.50, 128.64, 127.21, 127.16, 122.20, 120.95, 119.62,
110.67, 43.14; Anal. calcd for C18H12BrClF3N5O3 (517): C, 41.50%; H,
2.47%; N, 13.77%. Found: C, 41.68%; H, 2.33%; N, 13.50%.
4.2.1. General procedure for the preparation of compound 3
To a mixture of glycine ethyl ester hydrochloride (3.35 g,
24.0 mmol) in dry dichloromethane (50 mL), triethylamine (2.43 g,
24.0 mmol) was added. The resulting mixture was stirred at 0 ꢁC for
5 min. Then, intermediate 2 (6.42 g, 20 mmol) in dry dichloro-
methane (20 mL) was added. After stirring at room temperature for
30 min, the mixture was concentrated and filtered to obtain 6.30 g of
compound 3. The physical and chemical properties of compound 3
are as follows: Phase, white solid; mp, 126e127 ꢁC; yield, 81.3%; 1H
NMR (500 MHz, CDCl3, ppm): 8.49 (dd, 4JHH ¼ 1.15 Hz, 3JHH ¼ 4.60 Hz,
4.3. Insecticidal activity
Insecticidal activities were measured on representative test or-
ganisms reared in the laboratory. According to statistical re-
quirements, the bioassay was repeated at 25 ꢂ 1 ꢁC [42].
Assessments were made on a dead/alive basis, and mortality rates
were corrected using Abbott’s formula [43]. Evaluations were based
on a percentage scale of 0e100, inwhich 0 corresponds to no activity
and 100 corresponds to total mortality. The insecticidal activities of
compounds 5ae5w against third instar larvae of P. xylostella were
evaluated according to a previously reported procedure [44,45].
Fresh cabbage discs (diameter: 2 cm) were dipped into the prepared
solutions containing compounds 5ae5w for 10 s, air-dried, and then
placed in a Petri dish (diameter: 9 cm) lined with filter paper. Then,
ten third instar larvae of P. xylostella were carefully transferred to the
Petri dish. Each assay was conducted in triplicate. Mortality was
calculated 72 h after treatment. The control groups were treated
with distilled water containing TW-80 (0.1 mL/L). Commercial in-
secticides (i.e., chlorantraniliprole, chlorpyrifos, and avermectins)
were tested and compared under the same conditions.
4
3
1H, 6-Pyridine-H), 7.91 (dd, JHH ¼ 1.15 Hz, JHH ¼ 8.00 Hz, 1H, 4-
4
3
Pyridine-H), 7.42 (dd, JHH ¼ 4.60 Hz, JHH ¼ 8.00 Hz, 1H, 5-
Pyridine-H), 6.83 (s, 1H, 4-Pyrazole-H), 6.81 (t, J ¼ 5.75 Hz, 1H, e
CONHCH2e), 4.24 (q, J ¼ 6.85 Hz, 2H, eCH2eCH3), 4.07 (d, J ¼ 5.45 Hz,
2H, eNHeCH2e), 1.29 (t, J ¼ 6.85 Hz, 3H, eCH3); Anal. calcd for
C13H12BrClN4O3 (386): C, 40.33%; H, 3.23%; N, 14.39%. Found: C,
40.28%; H, 3.12%; N, 14.45%.
4.2.2. General procedure for the preparation of compound 4
To a solution of compound 3 (6.00 g, 15.5 mmol) in 30 mL of
methanol, sodium hydroxide (0.74 g, 18.6 mmol) in water (5.0 mL)
was added, and the mixture was stirred at room temperature for 3 h
and concentrated. The resulting mixture was diluted with 30 mL
water, and acidified to pH 3 using 5% hydrochloric acid to obtain
4.6 g of compound 4. The physical and chemical properties of
compound 4 are as follows: Phase, light yellow solid; mp, 223e
Acknowledgements
This work was supported by the National Key Program for Basic
Research (No. 2010CB126105), Key Technologies R&D Program (No.

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Appendix A. Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.ejmech.2013.06.
023. These data include MOL files and InChiKeys of the most
important compounds described in this article.
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