Novel ether-functional spiro-tetronic acid derivatives: Molecule design, convenient synthesis and biological evaluation

Article abstract of DOI:10.1007/s11164-012-0506-0

A novel series of ether functionalization of spiro-tetronic acid derivatives have been designed and conveniently synthesized via three steps, including esterification, one-pot heterocyclization, and etherification reactions. The target molecules have been identified on the basis of analytical spectra data. All newly synthesized compounds have been screened for their potential insecticidal activity against Heliothis armigera and Plutella xylostella compared with spirodiclofen by standard method. Springer Science+Business Media B.V. 2012.

Full text of DOI:10.1007/s11164-012-0506-0

Res Chem Intermed (2012) 38:1827–1837
DOI 10.1007/s11164-012-0506-0
Novel ether-functional spiro-tetronic acid derivatives:
molecule design, convenient synthesis and biological
evaluation
Shaoyong Ke
Liqiao Shi Ronghua Zhou
Ying Liang Ziwen Yang
•
Zhigang Zhang
•
Ya-Ni Zhang
•
•
•
•
Aibing Jiang
•
Received: 25 January 2012 / Accepted: 7 February 2012 / Published online: 22 February 2012
Ó Springer Science+Business Media B.V. 2012
Abstract A novel series of ether functionalization of spiro-tetronic acid deriva-
tives have been designed and conveniently synthesized via three steps, including
esterification, one-pot heterocyclization, and etherification reactions. The target
molecules have been identified on the basis of analytical spectra data. All newly
synthesized compounds have been screened for their potential insecticidal activity
against Heliothis armigera and Plutella xylostella compared with spirodiclofen by
standard method.
Keywords Ether functionalization Á Spiro-tetronic acid Á Synthesis Á
Insecticidal activity
Introduction
Tetronic acids derivatives comprise a subclass of 4-hydroxy-[5H]furan-2-one with
the generic structure A or B (Fig. 1), which have been isolated from a variety of
marine and terrestrial organisms such as bacteria, molds, fungi, and sponges, as well
as some higher plants [1, 2]. Up to now, a large number of natural products
containing a tetronic acid core have been isolated (Fig. 2), many of which exhibit a
widespread profile of biological properties such as antibiotic, antitumor, anticoag-
ulant, insecticidal, herbicidal, antifungal, and anti-inflammatory activity, etc. [3–6].
Because of the aforementioned importance for this novel scaffold, the research
on structural modification of 4-hydroxy-[5H]furan-2-one has thus been fruitful in
Shaoyong Ke and Zhigang Zhang contributed equally to this work.
S. Ke (&) Á Z. Zhang Á Y.-N. Zhang Á L. Shi Á R. Zhou Á A. Jiang Á Y. Liang Á Z. Yang
Hubei Biopesticide Engineering Research Center, Hubei Academy of Agricultural Sciences,
Wuhan 430064, People’s Republic of China
e-mail: keshaoyong@163.com
123

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S. Ke et al.
Fig. 1 Generic structures of a
tetronic acid
O
O
R1
R1
O
O
HO
R3
O
R3
R2
R2
A
B
O
OH
H
O
O
O
O
O
OH
OH
O
HO
OH
HO
COOH
Ascorbic acid
Pulvinic acid
Penicillic acid
Fig. 2 Representative structures of natural tetronic acid derivatives
O
O
O
O
O
O
O
O
Cl
O
O
HN
O
O
O
Cl
Spirodiclofen
Spiromesifen
Spirotetramat
Fig. 3 Novel insecticides derived from natural tetronic acid
the field of agrochemicals. Recently, one of the successful tactics in the design of
agrochemicals is the introduction of spiral cycle tetronic acid into the molecule for
better biological behaviors. Bayer CropScience have already developed three new
chemical classes of spirocyclic phenyl-substituted tetronic acid derivatives named
spirodiclofen [7, 8], spiromesifen [9–11], and spirotetramat [12–14] (Fig. 3),
respectively. All three are active in applications such as acaricides and insecticides,
which act as lipid biosynthesis inhibitors.
On the other hand, neonicotinoid insecticides have attracted considerable
attention for decades and represent a new generation of synthetic insecticides as
they combine unique properties allowing them to be the fastest growing synthetic
insecticides on the market [15, 16]. According to the chemical structures of
neonicotinoids developed in the past several decades (Fig. 4), the special molecular
structural features of these neonicotinoids consist of the important aromatic
heterocycle such as chloropyridine and chlorothiazole moiety, so we have reason to
believe that the two heterocycle skeleton can be used as an important pharmaco-
phore in exploring novel bioactive molecules.
Furthermore, spirocyclic tetronic acid insecticides act as lipid biosynthesis
inhibitors, which were relatively slow-acting on the target insects; however,
neonicotinoid insecticides are fast action and strongly systemic insecticides.
Inspired by the aforementioned findings, we conceived that a combination of the
1
23

Novel ether-functional spiro-tetronic acid derivatives
1829
Cl
Cl
Cl
Cl
C H
2
5
CH3
N
H
N
N
N
NH
N
N
S
N
N
N
CH3
NNO2
NCN
NCN
CHNO2
Nitenpyram
Imidacloprid
Thiacloprid
Acetamiprid
O
N
N
Cl
CN
N
N
N
H
H
Cl
NH
Cl
CH3
N
Cl
N
N
CH3
N
N
S
S
S
S
O
NNO2
N
NNO2
NO
2
Sulfoxaflor
Thiamethoxam
Clothianidin
Imidaclothiz
Fig. 4 Representative structures of neonicotinoid insecticides
Incorporate with
Ar
O
Neonicotinoid
Cl
O
Pharmacophore
O
O
R
O
Cl
O
O
Spirodiclofen
TM
Fig. 5 Design strategy for spirocycle derivatives containing an ether-functional group
tetronic acid scaffold with the chloropyridine and chlorothiazole units into one
molecule might result in new compounds with good biological activities. As part of
our agrochemistry program aimed at the search for novel heterocycle-based
bioactive molecules, we wish to describe here the molecule design, convenient
synthesis, and biological evaluation of a novel series of ether-functional spirocycle
derivatives as shown in Fig. 5.
Results and discussion
Synthesis of ether-functional spiro-tetronic acid derivatives
The general synthetic route for the preparation of ether-functional spirocycle
derivatives 6a–p are outlined in Scheme 1. Furthermore, for a few comparative
activity measurements of compounds without neonicotinoids pharmacophore
moiety, some spiro-tetronic acid derivatives containing 4-fluorophenyl and
4
-bromophenyl as shown in Scheme 1 were also synthesized.
As shown in Scheme 1, the target compounds were conveniently obtained via
three steps including esterification, heterocyclization, and etherification reactions.
The key intermediate phenyl-substituted tetronic acids 5 was conveniently obtained
by the modified one-pot heterocyclization reaction [17, 18] from various substituted
methyl 2-phenylacetate 2 and methyl 1-hydroxycyclohexanecarboxylate 4 in good
yield, which involve a transesterification step, followed by a Dieckmann
123

1830
S. Ke et al.
HO
O
COOH
HO
COOMe
OH
O
a
a
R
R
O
O
1
2
3
4
O
O
O
R: 2,4-Cl , 2-Me,4-F,H
b
c
2
2
4
Ar: 2-Chloro-5-thiazolyl
2-Chloro-5-pyridyl
R
R
OH
O
4
4
-Fluorophenyl
-Bromophenyl
Ar
5
6a-p
Scheme 1 Synthesis of ether-functional spiro-tetronic acid derivatives. Reagents and conditions:
t
a MeOH, concentration H
NaH/DMF, r.t. for 4–8 h
2
SO
4
2
, reflux 6–8 h; b BuOK or EtONa, THF, reflux for 8–10 h; c ArCH X,
t
condensation. After the Dieckmann condensation treated with BuOK base, the
intermediate 5 is formed and is finally etherified with various halides to yield target
compounds 6a–p in normal process. The structures of all the newly synthesized
compounds were characterized as 4-(arylmethoxy)-3-(substituted-phenyl)-1-oxaspi-
ro[4.5]dec-3-en-2-one 6a–p on the basis of satisfactory analytical and spectral data
1
1
including H NMR, ESI–MS and element analyses. The H NMR spectra of spiro-
tetronic acid derivatives 6a–p show signals in the range 3.30–5.20 ppm assigned to
the methylene group proton, 7.00–8.30 ppm for the protons of the (hetero)aromatic
ring, and at 1.30–2.05 ppm for the aliphatic cyclohexyl protons.
Biological activity evaluation
The bioactivity of synthesized ether-functional spiro-tetronic acid derivatives 6a–
p against Heliothis armigera and Plutella xylostella were evaluated according to the
standard method [19], which are listed in Tables 1 and 2, respectively.
Table 1 Insecticidal activities of some active compounds against Heliothis armigera
O
O
R
O
Ar
a
Entry
Compd. no.
Substituents
Insecticidal activity (lg/mL)
Heliothis armigera
R
Ar
1,000
500
250
125
1
2
3
4
a
Spirodiclofen
7
9
5
3
5
5
3
1
3
3
0
0
0
0
0
0
6g
6i
6l
4-F
4-Fluorophenyl
o-Me
o-Me
2-Chloro-5-thiazolyl
4-Bromophenyl
Scale: 0 (0–10% mortality); 1 (11–20% mortality); 3 (21–40% mortality); 5 (41–60% mortality); 7
61–80% mortality); 9 (81–99% mortality); 10 (100% mortality)
(
1
23

Novel ether-functional spiro-tetronic acid derivatives
1831
Table 2 Insecticidal activities of target compounds 6a–p against Plutella xylostella
O
O
R
O
Ar
a
Entry
Compd. no.
Substituents
R
Insecticidal activity (lg/mL)
Plutella xylostella
Ar
1,000
500
250
125
1
2
3
4
5
6
7
8
9
Spirodiclofen
10
10
5
5
5
0
6a
6b
6c
6d
6e
6f
H
2-Chloro-5-thiazolyl
10
10
10
0
5
5
H
2-Chloro-5-pyridinyl
4-Fluorophenyl
0
0
H
10
0
10
0
0
H
4-Bromophenyl
0
4-F
2-Chloro-5-thiazolyl
2-Chloro-5-pyridinyl
4-Fluorophenyl
ND
ND
10
ND
10
10
10
10
10
5
ND
ND
5
ND
ND
5
ND
ND
0
4-F
6g
6h
6i
4-F
4-F
4-Bromophenyl
ND
10
10
5
ND
10
10
0
ND
10
10
0
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
2-Me
2-Me
2-Me
2-Me
2,4-Cl
2,4-Cl
2,4-Cl
2,4-Cl
2-Chloro-5-thiazolyl
2-Chloro-5-pyridinyl
4-Fluorophenyl
6j
6k
6l
4-Bromophenyl
5
0
0
6m
6n
6o
6p
2
2
2
2
2-Chloro-5-thiazolyl
2-Chloro-5-pyridinyl
4-Fluorophenyl
5
5
5
5
5
5
10
5
10
5
10
0
10
0
4-Bromophenyl
Good selective insecticidal activity indicated in bold
ND not determined
a
Scale: 0 (0–10% mortality); 1 (11–20% mortality); 3 (21–40% mortality); 5 (41–60% mortality); 7
61–80% mortality); 9 (81–99% mortality); 10 (100% mortality)
(
The insecticidal activities of target compounds 6a–p were confirmed by control
with spirodiclofen, the first commercial insecticide derived from tetronic acid.
However, for test species Heliothis armigera, the present compounds’ biological
active unit of tetronic acid core and neonicotinoids pharmacophore does not present
good activity. The preliminary results showed that just a few compounds exhibited
obvious insecticidal activity against H. armigera compared with spirodiclofen.
Compound 6g bearing a 4-fluorophenyl gave an obviously higher inhibition rate
against test species than the spirodiclofen at the concentration of 1,000 lg/mL
(
Table 1).
As we can see from Table 2, the preliminary assay showed that some of the target
molecules (such as compounds 6a, 6c, 6i, 6j, and 6o) displayed obvious good and
123

1832
S. Ke et al.
selective insecticidal activity against Plutella xylostella compared with spirodiclo-
fen (Entries 2, 4, 10, 11, and 16, Table 2), but presented low activity against
H. armigera. Generally, compounds containing hydrogen and 4-fluoro substituents
6
a–h and compounds bearing ortho-methyl and 2,4-dichloro substituents 6i–p show
some contrast, the former present relative low activities at the same concentration
level, which may indicate position changes of the substituent within the aromatic
ring dramatically affecting the activity, suggesting that the presence of a group in
the ortho-position of the aromatic ring could introduce important steric and
electronic effects. As shown in Table 2, the compounds 6i, 6j, and 6o exhibited
particularly excellent insecticidal activities up to 100% inhibition under tested
concentrations, which might be used as lead molecules for further optimization.
Conclusion
In summary, we have described the molecular design, synthesis, and biological
activities of a series of novel spiro-tetronic acid derivatives and have developed a
practical and efficient procedure for the synthesis of ether-functionalization of spiro-
tetronic acid derivatives. Sixteen novel ether-functional spiro-tetronic acid deriv-
1
atives have been conveniently synthesized, and characterized by H NMR, MS
spectra and elemental analyses. The preliminary bioassay results indicated that
some of compounds exhibited obviously insecticidal activity compared with
commercial spirodiclofen. To the best of our knowledge, this is the first effort on the
syntheses and insecticidal activity of ether-functional tetronic acid derivatives
bearing neonicotinoid pharmacophore. Further structural optimization and activity
profiles concerning the designed ether-functional tetronic acid derivatives are well
under way.
Experimental
Instrumentation and chemicals
All melting points (m.p.) were obtained using a digital model X-5 apparatus and are
1
uncorrected. H NMR spectra were recorded on a Brucker AM-400 (400 MHz)
spectrometer with CDCl and DMSO-d as the solvent and TMS as the internal
3
6
standard. Chemical shifts are reported in d (parts/million) values. Coupling
constants J are reported in Hz. Mass spectra were performed on a MicroMass
n
Quattro microTM API instrument. Elemental analyses were performed on a Vario
EL III elemental analysis instrument. Analytical thin-layer chromatography (TLC)
was carried out on precoated plates (silica gel 60 F254), and spots were visualized
with ultraviolet light. All chemicals or reagents were purchased from standard
commercial supplies. Anhydrous CH Cl , THF and DMF were dried according to
2
2
standard methods [20]. All other solvents and reagents were analytical reagent and
used directly without purification.
1
23

Novel ether-functional spiro-tetronic acid derivatives
1833
General synthetic procedure for the intermediates 2, 4 and 5
The key synthetic intermediates 2, 4 and 5 were prepared following the literature
methods [21] and their spectral and analytical data were also the same as given in
the literature.
General synthetic procedure for the target compounds 4-(arylmethoxy)-3-
(
substituted-phenyl)-1-oxaspiro[4.5]dec-3-en-2-one 6a–p
The typical process of synthesis of novel ether functionalization of spiro-tetronic
acid derivatives 6a–p is shown as follows. To a stirred solution of sodium hydride
(
2.5 mmol) in 10 mL dry dimethylformamide (DMF) at 0 °C, compound
-hydroxy-3-(substituted phenyl)-1-oxaspiro[4.5]dec-3-en-2-one 5a–d (2 mmol)
was added slowly. After the hydrogen gas ceased, the mixture was kept at room
4
temperature for 0.5 h. Then, ArCH X (2.2 mmol) was added dropwise slowly. The
2
reaction mixture was stirred for 6–8 h at room temperature, which was detected by
TLC. Then, it was quenched with 1% HCl aqueous, and extracted three times with
ethyl acetate. The organic layer is washed to neutral with water and dried via
Na SO . After filtered and concentrated, the organic residue is purified by silica gel
2
4
column-chromatography (ethyl acetate/petroleum ether) to give white solid or
crystal (in 80–90% yield). Their physico–chemical properties and the spectra data
are as follows.
4
-((2-Chlorothiazol-5-yl)methoxy)-3-phenyl-1-oxaspiro[4.5]dec-3-en-2-one (6a)
This compound was obtained as white powder following the above-mentioned, yield
1
8
4%, m.p. 92–93 °C; H NMR (400 MHz, CDCl ): d = 7.37–7.52 (m, 5H, Ph–H),
3
7
J = 14.8 Hz, 1H, Thiazole–CH ), 1.39–1.69 (m, 10H, Cyclohexyl–H); ESI–MS:
?
calcd for C H ClNO S ([M ? 1] ), 376.9; found, 376.9; Anal. Calcd for
.31 (s, 1H, Thiazole–H), 3.54 (d, J = 14.8 Hz, 1H, Thiazole–CH ), 3.45 (d,
2
2
1
9
18
3
C H ClNO S: C, 60.71; H, 4.83; N, 3.73. Found: C, 60.65; H, 4.86; N, 3.79.
1
9
18
3
4
-((6-Chloropyridin-3-yl)methoxy)-3-phenyl-1-oxaspiro[4.5]dec-3-en-2-one (6b)
This compound was obtained as colorless crystal following the above-mentioned,
4
1
yield 64%, m.p. 117.5–119 °C; H NMR (400 MHz, CDCl ): d = 8.19 (d, J = 2 Hz,
3
1
H, Py–H), 7.23–7.56 (m, 7H, Ph–H and Py–H), 3.39 (d, J = 13.6 Hz, 1H, Py–CH ),
2
3
calcd for C H ClNO ([M ? 1] ), 370.8; found, 371.1; Anal. Calcd for
.30 (d, J = 14 Hz, 1H, Py–CH ), 1.35–1.60 (m, 10H, Cyclohexyl–H); ESI–MS:
?
2
2
1
20
3
C H ClNO : C, 68.20; H, 5.45; N, 3.79. Found: C, 68.24; H, 5.38; N, 3.73.
20
2
1
3
4
-(4-Fluorobenzyloxy)-3-phenyl-1-oxaspiro[4.5]dec-3-en-2-one (6c)
This compound was obtained as white powder following the above-mentioned, yield
1
6
7%, m.p. 126–127 °C; H NMR (400 MHz, CDCl ): d = 7.32–7.41 (m, 5H,
3
123

1834
S. Ke et al.
Ph–H), 6.96–7.05 (m, 4H, Ph–H), 4.90 (s, 2H, Ph–CH ), 1.66–1.82 (m, 10H,
2
?
Cyclohexyl–H); ESI–MS: calcd for C H FO ([M ? 1] ), 353.4; found, 354.0.
2
2
21
3
4
-(4-Bromobenzyloxy)-3-phenyl-1-oxaspiro[4.5]dec-3-en-2-one (6d)
This compound was obtained as light yellow powder following the above-mentioned,
1
yield 62%, m.p. 137.6–139.3 °C; H NMR (400 MHz, CDCl ): d = 7.31–7.44 (m,
3
7
Cyclohexyl–H); ESI–MS: calcd for C H BrO ([M ? 1] ), 414.3; found, 414.9.
H, Ph–H), 6.92 (d, J = 8.4 Hz, 2H, Ph–H), 4.89 (s, 2H, Ph–CH ), 1.25–1.81 (m, 10H,
2
?
2
2
21
3
4-((2-Chlorothiazol-5-yl)methoxy)-3-(4-fluorophenyl)-1-oxaspiro[4.5]dec-3-en-2-
one (6e)
This compound was obtained as white solid following the above-mentioned, yield
1
6
H), 7.12–7.17 (m, 3H, Ph–H and Thiazole–H), 5.06 (s, 2H, Thiazole–CH ),
8%, m.p. 120–122 °C; H NMR (400 MHz, CDCl ): d = 7.35–7.38 (m, 2H, Ph–
3
2
1
.25–1.79 (m, 10H, Cyclohexyl–H); ESI–MS: calcd for C H ClFNO S
19 17 3
?
[M ? 1] ), 394.9; found, 394.9.
(
4-((6-Chloropyridin-3-yl)methoxy)-3-(4-fluorophenyl)-1-oxaspiro[4.5]dec-3-en-2-
one (6f)
This compound was obtained as pale yellow crystal following the above-mentioned,
4
1
yield 73%, m.p. 73–74 °C; H NMR (400 MHz, CDCl ): d = 8.12 (d, J = 2.4 Hz,
3
4
H, Py–H), 7.40 (d, J = 2.4 Hz, 1H, Py–H), 7.29–7.39 (m, 3H, Ph–H and Py–H),
1
7
Cyclohexyl–H); ESI–MS: calcd for C H ClFNO ([M ? 1] ), 388.8; found,
.12 (t, J = 8.8 Hz, 2H, Ph–H), 4.94 (s, 2H, Py–CH ), 1.25–1.81 (m, 10H,
?
2
2
1
19
3
388.8; Anal. Calcd for C H ClFNO : C, 65.03; H, 4.94; N, 3.61. Found: C, 64.96;
21 19 3
H, 4.88; N, 3.65.
4
-(4-Fluorobenzyloxy)-3-(4-fluorophenyl)-1-oxaspiro[4.5]dec-3-en-2-one (6g)
This compound was obtained as white crystal following the above-mentioned, yield
1
6
H), 7.00–7.11 (m, 6H, Ph–H), 4.89 (s, 1H, Ph–CH ), 4.51 (s, 1H, Ph–CH ),
5%, m.p. 122–124 °C; H NMR (400 MHz, CDCl ): d = 7.29–7.33 (m, 2H, Ph–
3
2
2
?
1
3
.26–1.80 (m, 10H, Cyclohexyl–H); ESI–MS: calcd for C H F O ([M ? 1] ),
22 20 2 3
71.4; found, 372.0.
-(4-Bromobenzyloxy)-3-(4-fluorophenyl)-1-oxaspiro[4.5]dec-3-en-2-one (6h)
4
This compound was obtained as pale yellow gum following the above-mentioned,
1
yield 46%, m.p. 96–98 °C; H NMR (400 MHz, CDCl ): d = 6.93–7.49 (m, 8H,
3
Ph–H), 4.88 (s, 1H, Ph–CH ), 4.49 (s, 1H, Ph–CH ), 1.26–1.81 (m, 10H,
2
2
?
Cyclohexyl–H); ESI–MS: calcd for C H BrFO ([M ? 1] ), 432.3; found,
2
2
20
3
4
32.9; Anal. Calcd for C H BrFO : C, 61.27; H, 4.67. Found: C, 61.35; H, 4.72.
22 20 3
1
23

Novel ether-functional spiro-tetronic acid derivatives
1835
4
-((2-Chlorothiazol-5-yl)methoxy)-3-o-tolyl-1-oxaspiro[4.5]dec-3-en-2-one (6i)
This compound was obtained as light yellow powder following the above-
1
mentioned, yield 72%, m.p. 97.3–98.1 °C; H NMR (400 MHz, CDCl3):
d = 7.23–7.32 (m, 4H, Ph–H), 7.02 (s, 1H, Thiazole–H), 4.95 (dd, J = 12.4 Hz,
2
ESI–MS: calcd for C H ClNO S ([M ? 1] ), 390.9; found, 391.0.
H, Thiazole–CH ), 2.20 (s, 3H, Ph–CH ), 1.65–1.82 (m, 10H, Cyclohexyl–H);
2 3
?
2
0
20
3
4
-((6-Chloropyridin-3-yl)methoxy)-3-o-tolyl-1-oxaspiro[4.5]dec-3-en-2-one (6j)
This compound was obtained as white powder following the above-mentioned, yield
1
7
6%, m.p. 83.7–85 °C; H NMR (400 MHz, CDCl ): d = 7.97 (s, 1H, Py–H),
3
7
J = 12.4 Hz, 1H, Py–CH ), 2.12 (s, 3H, Ph–CH ), 1.69–1.88 (m, 10H, Cyclohexyl–
?
H); ESI–MS: calcd for C H ClNO ([M ? 1] ), 384.9; found, 385.0; Anal.
.17–7.30 (m, 6H, Ph–H and Py–H), 4.89 (d, J = 12.4 Hz, 1H, Py–CH ), 4.81 (d,
2
2
3
2
2
22
3
Calcd for C H ClNO : C, 68.83; H, 5.78; N, 3.65. Found: C, 68.78; H, 5.73; N,
3
2
2
22
3
.71.
4
-(4-Fluorobenzyloxy)-3-o-tolyl-1-oxaspiro[4.5]dec-3-en-2-one (6k)
This compound was obtained as white powder following the above-mentioned, yield
1
8
6
1
0%, m.p. 89–90 °C; H NMR (400 MHz, CDCl ): d = 7.19–7.28 (m, 4H, Ph–H),
3
.95–6.97 (m, 4H, Ph–H), 4.83 (d, J = 12 Hz, 1H, Ph–CH2), 4.75 (d, J = 12 Hz,
H, Ph–CH ), 2.12 (s, 3H, Ph–CH ), 1.72–1.86 (m, 10H, Cyclohexyl–H); ESI–MS:
2
3
?
calcd for C H FO ([M ? 1] ), 367.4; found, 368.1; Anal. Calcd for C H FO :
2
3
23
3
23 23
3
C, 75.39; H, 6.33. Found: C, 75.46; H, 6.28.
4
-(4-Bromobenzyloxy)-3-o-tolyl-1-oxaspiro[4.5]dec-3-en-2-one (6l)
This compound was obtained as white powder following the above-mentioned, yield
1
7
4
8%, m.p. 79–81 °C; H NMR (400 MHz, CDCl ): d = 6.83–7.49 (m, 8H, Ph–H),
3
.82 (d, J = 12 Hz, 1H, Ph–CH ), 4.74 (d, J = 12 Hz, 1H, Ph–CH ), 2.11 (s, 3H,
2
2
Ph–CH ), 1.75–1.89 (m, 10H, Cyclohexyl–H); ESI–MS: calcd for C H BrO
3
3
23 23
?
[M ? 1] ), 428.3; found, 428.9.
(
4-((2-Chlorothiazol-5-yl)methoxy)-3-(2,4-dichlorophenyl)-1-oxaspiro[4.5]dec-3-
en-2-one (6m)
This compound was obtained as light yellow solid following the above-mentioned,
1
yield 78%, m.p. 97–99.6 °C; H NMR (400 MHz, CDCl ): d = 7.51 (s, 1H, Ph–H),
3
4
7
.34 (dd, J = 2.4 Hz, 2H, Ph–H), 7.23 (s, 1H, Thiazole–H), 5.09 (d, J = 12.8 Hz,
H, Thiazole–CH ), 4.93 (d, J = 12.8 Hz, 1H, Thiazole–CH ), 1.61–1.83 (m, 10H,
1
Cyclohexyl–H); ESI–MS: calcd for C H Cl NO S (M ), 444.8; found, 444.7.
2
2
?
1
9
16
3
3
123

1836
S. Ke et al.
4-((6-Chloropyridin-3-yl)methoxy)-3-(2,4-dichlorophenyl)-1-oxaspiro[4.5]dec-3-
en-2-one (6n)
This compound was obtained as colorless gum following the above-mentioned,
1
yield 84%, m.p. 99–101 °C; H NMR (400 MHz, CDCl ): d = 8.14 (d,
3
4
4
J = 1.6 Hz, 1H, Py–H), 7.50 (s, 1H, Ph–H), 7.44 (dd, J = 8 Hz, J = 2.4 Hz,
1
CH ), 4.81 (d, J = 12.0 Hz, 1H, Py–CH ), 1.71–2.05 (m, 10H, Cyclohexyl–H);
H, Py–H), 7.28–7.34 (m, 3H, Ph–H and Py–H), 4.97 (d, J = 12.0 Hz, 1H, Py–
2
2
?
ESI–MS: calcd for C H C NO ([M ? 1] ), 439.7; found, 440.2; Anal. Calcd for
2
1
18 l3
3
C H C NO : C, 57.49; H, 4.14; N, 3.19. Found: C, 57.41; H, 4.18; N, 3.15.
2
1
18 l3
3
3
-(2,4-Dichlorophenyl)-4-(4-fluorobenzyloxy)-1-oxaspiro[4.5]dec-3-en-2-one (6o)
This compound was obtained as white powder following the above-mentioned, yield
1
4
7
6%, m.p. 120–121.4 °C; H NMR (400 MHz, CDCl ): d = 7.47 (d, J = 2 Hz,
3
1
J = 12 Hz, 1H, Ph–CH ), 4.75 (d, J = 12 Hz, 1H, Ph–CH ), 1.68–1.89 (m, 10H,
H, Ph–H), 7.23–7.30 (m, 2H, Ph–H), 6.99–7.10 (m, 4H, Ph–H), 4.93 (d,
2
2
?
Cyclohexyl–H); ESI–MS: calcd for C H Cl FO ([M ? 1] ), 422.3; found, 422.0.
2
2
19
2
3
4
-(4-Bromobenzyloxy)-3-(2,4-dichlorophenyl)-1-oxaspiro[4.5]dec-3-en-2-one (6p)
This compound was obtained as white powder following the above-mentioned, yield
1
8
H), 7.23 (d, J = 8 Hz, 2H, Ph–H), 6.97 (d, J = 8 Hz, 2H, Ph–H), 4.92 (d,
2%, m.p. 117–118 °C; H NMR (400 MHz, CDCl ): d = 7.45–7.49 (m, 3H, Ph–
3
J = 11.6 Hz, 1H, Ph–CH ), 4.75 (d, J = 11.6 Hz, 1H, Ph–CH ), 1.26–1.88 (m,
2
2
?
1
4
0H, Cyclohexyl–H); ESI–MS: calcd for C H BrCl O ([M ? 1] ), 483.2; found,
22 19 2 3
83.9; Anal. Calcd for C H BrCl O : C, 54.80; H, 3.97. Found: C, 54.71; H, 4.01.
2
2
19
2 3
Biology assays
All bioassays were performed on representative test organisms reared in the
laboratory. The bioassay was repeated at 25 ± 1 °C according to statistical
requirements. All compounds were dissolved in anhydrous ethanol (AP; Shanghai
Chemical Reagent, Shanghai, China) and diluted with distilled water containing
Triton X-100 (0.1 lg/mL) to obtain series concentrations of 1,000, 500, 250, and
125 lg/mL, and others for bioassays. For comparative purposes, spirodiclofen was
tested under the same conditions.
Acknowledgment This work was financially supported by the Projects in the Youth Science
Foundation of Hubei Academy of Agricultural Sciences (2011NKYJJ19) and the Special Fund for Agro-
Scientific Research in the Public Interest (200903052).
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