Design, synthesis, and insecticidal activity of novel pyrazole derivatives containing α-hydroxymethyl-N-benzyl carboxamide, α-chloromethyl-N- benzyl carboxamide, and 4,5-dihydrooxazole moieties

Article abstract of DOI:10.1021/jf204778v

On the basis of commercial insecticides tebufenpyrad and tolfenpyrad, two series of novel pyrazole-5-carboxamides containing α-hydroxymethyl-N- benzyl or α-chloromethyl-N-benzyl and pyrazoles containing 4,5-dihydrooxazole moieties were designed and synthesized via the key intermediate 2-amino-1-(4-substituted) phenyl ethanol. The structures of target compounds were confirmed by ¹H NMR and elemental analysis or high-resolution mass spectrum (HRMS), and their activities against cotton bollworm (Helicoverpa armigera), diamondback moth (Plutella xylostella), bean aphid (Aphis craccivora), mosquito (Culex pipiens pallens), and spider mite (Tetranychus cinnabarinus) were tested. The results of bioassays indicated that compounds containing α-chloromethyl-N-benzyl and compounds containing 4,5-dihydrooxazole showed high insecticidal activity against cotton bollworm. Especially, stomach activities of compounds Ij, Il, and IIe were 60% at 5 mg kg^-1. Moreover, the target compounds exhibited high selectivity between cotton bollworm and diamondback moth, although both of them belong to the order Lepidoptera. Although the activities against diamondback moth were at a low level, some of the target compounds exhibited antifeedant activity. The compounds also had good activities against bean aphid, mosquito, and spider mite. The foliar contact activity of compounds Ic, Id, Ie, and IIf against bean aphid were 95, 95, 100, and 95%, respectively, at 200 mg kg^-1. The miticidal and ovicidal activities of compound IIi against spider mite were both 95% at 200 mg kg^-1. Furthermore, a trivial change at 4-position of pyrazole ring would lead to great changes in properties and activities, which can easily be deduced by comparing the activities of compounds in series I (4-chloro-pyrazole compounds) with corresponding compounds in series II (4-hydro-pyrazole compounds), especially from the miticidal and ovicidal activities of Ii and IIi against spider mite.

Full text of DOI:10.1021/jf204778v

Article
pubs.acs.org/JAFC
Design, Synthesis, and Insecticidal Activity of Novel Pyrazole
Derivatives Containing α-Hydroxymethyl-N-benzyl Carboxamide,
α-Chloromethyl-N-benzyl Carboxamide, and 4,5-Dihydrooxazole
Moieties
Hongjian Song, Yuxiu Liu,* Lixia Xiong, Yongqiang Li, Na Yang, and Qingmin Wang*
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, People's Republic of China
ABSTRACT: On the basis of commercial insecticides tebufenpyrad and tolfenpyrad, two series of novel pyrazole-5-carboxamides
containing α-hydroxymethyl-N-benzyl or α-chloromethyl-N-benzyl and pyrazoles containing 4,5-dihydrooxazole moieties were
designed and synthesized via the key intermediate 2-amino-1-(4-substituted) phenyl ethanol. The structures of target compounds were
confirmed by 1H NMR and elemental analysis or high-resolution mass spectrum (HRMS), and their activities against cotton bollworm
(Helicoverpa armigera), diamondback moth (Plutella xylostella), bean aphid (Aphis craccivora), mosquito (Culex pipiens pallens), and
spider mite (Tetranychus cinnabarinus) were tested. The results of bioassays indicated that compounds containing α-chloromethyl-
N-benzyl and compounds containing 4,5-dihydrooxazole showed high insecticidal activity against cotton bollworm. Especially, stomach
activities of compounds Ij, Il, and IIe were 60% at 5 mg kg−1. Moreover, the target compounds exhibited high selectivity between
cotton bollworm and diamondback moth, although both of them belong to the order Lepidoptera. Although the activities against
diamondback moth were at a low level, some of the target compounds exhibited antifeedant activity. The compounds also had good
activities against bean aphid, mosquito, and spider mite. The foliar contact activity of compounds Ic, Id, Ie, and IIf against bean aphid
were 95, 95, 100, and 95%, respectively, at 200 mg kg−1. The miticidal and ovicidal activities of compound IIi against spider mite were
both 95% at 200 mg kg−1. Furthermore, a trivial change at 4-position of pyrazole ring would lead to great changes in properties and
activities, which can easily be deduced by comparing the activities of compounds in series I (4-chloro-pyrazole compounds) with
corresponding compounds in series II (4-hydro-pyrazole compounds), especially from the miticidal and ovicidal activities of Ii and IIi
against spider mite.
KEYWORDS: pyrazole-5-carboxamide, α-hydroxymethyl-N-benzyl, α-chloromethyl-N-benzyl, 4,5-dihydrooxazole, insecticidal activity,
antifeedant activity
specific interaction between the pyrazole derivatives and the
receptor. Okada et al.2c gave a proposed model about the
interaction between tebufenpyrad and complex I, a model in
which the hydrogen of the amide in the bridge binds with the
acceptor as a hydrogen donor. In addition, some research
showed that the miticidal activity was significantly decreased
when the methylene in the bridge was substituted by a methyl
group,6 whereas the compounds still exhibited excellent
activities against a broad spectrum of insects when the cyano
group was introduced to the methylene.7 That is to say, the
substituent on the methylene also plays an important role in the
activities.
On the basis of the above consideration, hydroxymethyl and
chloromethyl were introduced to the methylene of the bridge,
which means α-hydroxymethyl-N-benzyl and α-chloromethyl-
N-benzyl pyrazole-5-carboxamides (Ia−h and IIa−h) were
designed and synthesized. To further study the role of the
bridge moiety played in the biological activities, compounds
containing 4,5-dihydrooxazole moieties (Ii−l and IIi−l) were
INTRODUCTION
■
Synthetic pyrazole-5-carboxamide derivatives such as tebufen-
pyrad and tolfenpyrad (Figure 1) belong to an important kind
mitochondrial respiration inhibitors, and they interrupt the
mitochondrial electron transport by inhibition of NADH: ubi-
quinone oxidoreductase (complex I).1 Tebufenpyrad, discovered
by Mitsubishi Kasei Co., Ltd., in 1987, shows an excellent
acaricidal activity against phytophagous mites and Homoptera
pests.2 Tolfenpyrad, discovered by Mitsubishi Chemical Corp.
(now Nihon Nohyaku Co., Ltd.), is one of the most important
insecticides for control pests that are difficult to control, such as
Hemiptera, Coleoptera, Diptera, Lepidoptera, Thysanoptera, and
Acarina. It mainly provides contact activity against target pests
on egg, larva, nymph, and adult stages.3
Because of their outstanding performance in controlling
agricultural pests, pyrazole-5-carboxamide derivatives have
attracted considerable attention for decades.4 Most of the work
was based on the structures of the two commercial varieties,
and the studies focused on two aspects: the changes of sub-
stituents on the pyrazole ring and the modification of the
benzene ring. However, there were little studies on the bridge
between the pyrazole and the benzene ring. Although there is
significant progress in the study of the mechanism of pyrazole
insecticides in recent years,5 until now, it is unknown about the
Received: November 21, 2011
Revised: January 15, 2012
Accepted: January 20, 2012
Published: February 3, 2012
© 2012 American Chemical Society
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Figure 1. Design of target compounds (Ia−l and IIa−l).
Scheme 1. General Synthetic Route for Key Intermediate 2-Amino-2-(4-substitudedphenyl) Ethanol
instrument (Ionspec 7.0 T). The melting points were determined
on an X-4 binocular microscope melting point apparatus (Beijing Tech
Instruments Co., Beijing, China) and are uncorrected. Yields were not
optimized.
also synthesized. To better compare the activities, four representa-
tive substituents (t-butyl, phenoxy, pentyloxy, and Cl) were selected
to be introduced into the para position of the benzene ring. More-
over, the changes on 4-position of pyrazoles were also reported to
have an important impact on the biological activity of the com-
pounds.8 Therefore, both of the compounds that were chlorinated
or not chlorinated at the 4-position of pyrazole were synthesized
and classified as series I and II, respectively. The insecticidal and
acaricidal activities of the target compounds (Ia−l and IIa−l)
against cotton bollworm (Helicoverpa armigera), diamondback
moth (Plutella xylostella), spider mite (Tetranychus cinnabarinus),
bean aphid (Aphis craccivora), and mosquito (Culex pipiens
pallens) were tested and discussed.
General Synthesis. All anhydrous solvents were dried and purified
by standard techniques just before use. 4-Chloro-3-ethyl-1-methyl-1H-
pyrazole-5-carboxylic acid (I) was synthesized according to reported
method.2b The synthetic route is given in Schemes 1 and 2.
Synthesis of Ethyl 2-(4-(tert-Butyl)phenyl)-2-oxoacetate (1a).
Anhydrous AlCl3 (2.67 g, 20.0 mmol) and ethyloxalyl monochloride
(2.72 g, 20.0 mmol) were added to anhydrous dichloromethane
(20 mL) under nitrogen. The mixture was stirred at room temperature
until AlCl3 was dissolved completely. After the mixture was cooled to
5 °C, tert-butyl benzene (2.24 g, 16.7 mmol) in dichloromethane
(5 mL) was added dropwise. After the mixture was stirred for 2 h at
room temperature, the mixture was poured into ice water (20 mL),
and concentrated HCl (10 mL) was added. After separation, the water
phase was extracted by dichloromethane (10 mL × 3). The combined
organic phase was washed with water (10 mL × 2) and brine
(10 mL × 2) successively, dried over anhydrous Na2SO4, and concentrated
to give 1a as a yellow liquid (3.10 g, 94%). 1H NMR (400 MHz, CDCl3): δ
MATERIALS AND METHODS
■
Instruments. 1H NMR spectra were obtained at 400 MHz using a
Bruker AV400 spectrometer in CDCl3 or DMSO-d6 solution with
tetramethylsilane as the internal standard. Chemical shift values (δ) are
given in parts per million. Elemental analyses were determined on a
Yanaca CHN Corder MT-3 elemental analyzer. High-resolution mass
spectrometry (HRMS) data were obtained on an FTICR-MS
3
3
7.95 (d, JHH = 8.0 Hz, 2H, Ar−H), 7.53 (d, JHH = 8.0 Hz, 2H, Ar−H),
3
3
4.44 (q, JHH = 7.2 Hz, 2H, CH2CH3), 1.42 (t, JHH = 7.2 Hz, 3H,
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Scheme 2. General Synthetic Route for Target Compounds
Table 1. Physical Properties and Elemental Analyses or HRMS of Compounds Ia−l and IIa−l
elemental anal (%) (calcd) or HRMS (calcd)
compd
R1
R2
mp (°C)
yield (%)
C
H
N
Ia
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
C(CH3)3
C6H5O
C5H11O
Cl
90
89
63
94
74
95
87
90
95
93
89
94
92
63
71
57
95
91
87
93
87
92
89
85
386.1601 (386.1606) (m + Na)+
Ib
Ic
122−123
98−99
124−125
62.89 (63.08)
60.90 (60.98)
52.43 (52.64)
5.85 (5.55)
10.43 (10.51)
10.61 (10.67)
12.10 (12.28)
7.31 (7.16)
5.24 (5.01)
404.1266 (404.1267) (m + Na)+
Id
Ie
C(CH3)3
C6H5O
C5H11O
Cl
If
111−112
93−94
118−119
60.15 (60.30)
57.95 (58.25)
49.66 (49.95)
5.26 (5.06)
10.01 (10.05)
9.98 (10.19)
11.48 (11.65)
Ig
6.59 (6.60)
4.58 (4.47)
Ih
Ii
C(CH3)3
C6H5O
C5H11O
Cl
346.1677 (346.1681) (m + H)+
382.1313 (382.1317) (m + H)+
376.1788 (376.1786) (m + H)+
324.0673 (324.0665) (m + H)+
Ij
Ik
26−27
49−50
147−149
120−123
73−74
171−173
147−148
115−116
92−93
145−147
61−62
Il
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIh
IIi
IIj
IIk
IIl
C(CH3)3
C6H5O
C5H11O
Cl
69.34 (69.27)
68.84 (69.02)
66.70 (66.83)
58.35 (58.54)
65.78 (65.60)
65.45 (65.71)
63.29 (63.56)
54.94 (55.23)
73.52 (73.28)
8.20 (8.26)
12.68 (12.76)
11.42 (11.50)
11.63 (11.69)
13.47 (13.65)
11.99 (12.08)
10.83 (10.95)
11.01 (11.12)
12.79 (12.88)
13.60 (13.49)
H
6.62 (6.34)
8.28 (8.13)
6.08 (5.89)
7.48 (7.53)
6.00 (5.78)
7.49 (7.47)
5.36 (5.25)
7.85 (8.09)
H
H
H
C(CH3)3
C6H5O
C5H11O
Cl
H
H
H
H
C(CH3)3
C6H5O
C5H11O
Cl
H
348.1707 (348.1707) (m + H)+
342.2176 (324.2174) (m + H)+
290.1061 (290.1055) (m + H)+
H
H
CH2CH3), 1.34 (s, 9H, t-Bu). Compounds 1b and 1c were prepared
using the same procedure as 1a.
Data for Ethyl 2-Oxo-2-(4-(pentyloxy)phenyl)acetate (1c). Pale
yellow liquid. Yield: 75%. 1H NMR (400 MHz, CDCl3): δ 7.98 (d, 3JHH
8.8 Hz, 2H, Ar−H), 6.95 (d, 3JHH = 8.8 Hz, 2H, Ar−H), 4.43 (q, 3JHH
=
=
Data for Ethyl 2-Oxo-2-(4-phenoxyphenyl)acetate (1b). Yellow
1
3
liquid. Yield: 51%. H NMR (400 MHz, CDCl3): δ 8.00 (d, JHH
=
=
=
7.2 Hz, 2H, OCH2CH3), 4.04 (t, 3JHH = 6.8 Hz, 2H, OCH2C4H9), 1.78−
1.84 (m, 2H, OCH2CH2C3H7), 1.34−1.48 (m, 7H, OCH2CH3 and
8.4 Hz, 2H, Ar−H), 7.41 (t, 3JHH = 7.6 Hz, 2H, Ar−H), 7.22 (t, 3JHH
7.6 Hz, 1H, Ar−H), 7.08 (d, 3JHH = 7.6 Hz, 2H, Ar−H), 7.01 (d, 3JHH
OCH2CH2(CH2)2CH3), 0.93 (t, JHH = 7.2 Hz, 3H, CH2CH2CH3).
3
8.0 Hz, 2H, Ar−H), 4.42 (q, JHH = 7.2 Hz, 2H, OCH2CH3), 1.40
Synthesis of Ethyl 2-(4-Chlorophenyl)-2-oxoacetate (1d).9
3
3
(t, JHH = 7.2 Hz, 3H, CH2CH3).
To magnesium (0.63 g, 26.1 mmol) in ether (15 mL) was added
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1-bromo-4-chlorobenzene (5.00 g, 26.1 mmol) in ether (30 mL), and the
mixture was stirred for 1 h at room temperature. The Grignard reagent
was added to diethyl oxalate (5.72 g, 39.2 mmol) in ether (60 mL) at
−78 °C. The reaction mixture was stirred for 5 h in the temperature range
−78 to 0 °C. The reaction was quenched with 50 mL of NH4Cl
(10%, w/w), and the aqueous layer was extracted with ether twice. The
combined organic layer was dried and concentrated to give a yellow liquid
3
(2.80 g, 51%). 1H NMR (400 MHz, CDCl3): δ 7.90 (d, JHH = 8.4 Hz,
2H, Ar−H), 7.41 (d, 3JHH = 8.4 Hz, 2H, Ar−H), 4.37 (q, 3JHH = 7.2 Hz,
3
2H, OCH2CH3), 1.34 (t, JHH = 7.2 Hz, 3H, CH2CH3).
Synthesis of Ethyl 2-(4-(tert-Butyl)phenyl)-2-(hydroxyimino)-
acetate (2a). To a solution of 1a (1.50 g, 6.41 mmol) in alcohol
was added hydroxylamine hydrochloride (0.53 g, 7.70 mmol), and
the mixture was refluxed for 5 h. After most of the alcohol was
removed in vacuo, water (20 mL) and ethyl acetate (20 mL) were
added. The separated organic layer was dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure to give crude
product 2a, which was used in the next reaction without further
purification. Compounds 2b−2d were prepared using the same
procedure as 2a.
Synthesis of 2-Amino-2-(4-(tert-butyl)phenyl)ethanol (3a).10
To a solution of 2a (0.70 g, 2.80 mmol) in tetrahydrofuran (10 mL)
was added NaBH4 (0.32 g, 8.40 mmol) in portions, then iodine
(1.07 g, 4.2 mmol) dissolved in tetrahydrofuran (10 mL) was added
slowly, and then the mixture was refluxed for 4 h. After the mixture
was cooled to room temperature, methanol (10 mL) was added
dropwise. Then, the solvent was removed in vacuo. To the residue,
NaOH solution (20 mL of 5%, w/w) was added, and then, the mixture
was heated at 100 °C for 3 h. After the mixture was cooled to room
temperature, the aqueous solution was extracted with dichloromethane
(10 mL × 3), and then, the combined organic phase was washed with
water (10 mL × 2) and brine (10 mL × 2) successively, dried over
anhydrous Na2SO4, and concentrated to give white solid (0.37 g,
69%); mp 109−110 °C. 1H NMR (400 MHz, CDCl3): δ 7.37 (d, 3JHH
=
3
7.6 Hz, 2H, Ar−H), 7.25 (d, JHH = 7.6 Hz, 2H, Ar−H), 4.00−4.01
(m, 1H, CH2OH), 3.71−3.74 (m, 1H, CH2OH), 3.54 (t, 3JHH = 9.6 Hz,
1H, CHNH2), 2.00 (br, 3H, OH and NH2), 1.31 (s, 9H, t-Bu). Com-
pounds 3b−3d were prepared using the same procedure as 3a.
Data for 2-Amino-2-(4-phenoxyphenyl)ethanol (3b). White solid.
Yield: 58%. mp: 90−92 °C. 1H NMR (400 MHz, CDCl3): δ 7.26−7.35
(m, 4H, Ar−H), 7.10 (t, 3JHH = 7.2 Hz, 1H, Ar−H), 6.97−7.01 (m, 4 H,
Ar−H), 4.04 (br, 1H, CHNH2), 3.72−3.75 (m, 1H, CH2OH), 3.55
3
(t, JHH = 9.6 Hz, 1H, CH2OH), 1.97 (br, 3H, NH2 and OH).
Data for 2-Amino-2-(4-(pentyloxy)phenyl)ethanol (3c). Cream
yellow solid. Yield: 75%. mp: 79−80 °C. 1H NMR (400 MHz,
CDCl3): δ 7.22 (d, 3JHH = 8.4 Hz, 2H, Ar−H), 6.87 (d, 3JHH = 8.4 Hz,
2H, Ar−H), 3.97−4.00 (m, 1H, CHNH2), 3.93 (t, 3JHH = 6.8 Hz, 2H,
OCH2C4H9), 3.69 (dd, 3JHH = 4.4 Hz, 2JHH = 10.4 Hz, 1H, CH2OH),
3.50−3.54 (m, 1H, CH2OH), 1.96 (br, 3H, NH2 and OH), 1.74−1.81
( m , 2 H , O C H 2 C H 2 C 3 H 7 ) , 1 . 3 5 − 1 . 4 5 ( m , 4 H ,
3
OCH2CH2(CH2)2CH3), 0.92 (t, JHH = 7.2 Hz, 3H, CH2CH2CH3).
Data for 2-Amino-2-(4-chlorophenyl)ethanol (3d). Corlorless
1
solid. Yield: 65%. mp: 86−87 °C. H NMR (400 MHz, CDCl3): δ
7.32(d, 2 H, 3JHH = 8.4 Hz, Ar−H), 7.28 (d, 2 H, 3JHH = 8.4 Hz, Ar−
3
2
H), 4.05 (dd, 1 H, JHH = 4.4 Hz, JHH = 8.0 Hz, CHNH2), 3.71 (dd,
3
2
3
1 H, JH2H = 8.8 Hz, JHH = 10.8 Hz, CH2OH), 3.52 (dd, 1 H, JHH
=
8.8 Hz, JHH = 10.8 Hz, CH2OH), 1.97 (br, 3 H, OH and NH2).
Synthesis of Ethyl 2,4-Dioxohexanoate (4).11 Metallic sodium
(1.90 g, 26.4 mmol) was dissolved in absolute alcohol (20 mL). When
the solution had been cooled to −5 °C, a mixture of 2-butanone (1.90 g,
26.4 mmol) and diethyl oxalate (3.85 g, 26.4 mmol) was added drop-
wise. The reaction mixture was stirred at −5 °C overnight and then
concentrated to dryness. The resulting residue was partitioned
between water (20 mL) and ethyl acetate (70 mL × 3). The aqueous
layer was acidified to pH 2 with dilute H2SO4 and then extracted with
ethyl acetate (50 mL × 3). The combined organic phase was dried
over anhydrous Na2SO4, concentrated in vacuo, and purified by flash
chromatography on silica gel using petroleum ether (60−90 °C) and
ethyl acetate (v/v = 10:1) as the eluent to give 4 as yellow oil (3.18 g,
1
70%). H NMR (400 MHz, CDCl3): δ 14.40 (br, 1H, OH), 6.38
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Table 3. Stomach Activities against Cotton Bollworm (H. armigera) and Diamondback Moth (P. xylostella) of Compounds Ia−l,
IIa−l, and Tolfenpyrad
larvicidal activity (%) at concn (mg kg−1)
H. armigera
P. xylostella
compd
R1
R2
110
55
22
11
5.5
0
600
200
Ia
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
C(CH3)3
C6H5O
C5H11O
Cl
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
40
70
0
80
60
90
30
90
90
90
70
50
90
70
0
40
20
30
0
Ib
Ic
40
0
30
Id
Ie
40
0
C(CH3)3
C6H5O
C5H11O
Cl
100
100
100
100
100
100
100
100
60
20
80
60
70
70
90
80
90
10
0
0
40
10
40
40
60
30
60
0
30
a
If
60
Ig
45
a
Ih
Ii
60
C(CH3)3
C6H5O
C5H11O
Cl
30
20
Ij
a
Ik
30
Il
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIh
IIi
IIj
IIk
IIl
C(CH3)3
C6H5O
C5H11O
Cl
70
90
45
100
30
45
15
30
60
70
30
60
100
60
45
30
60
15
30
0
H
30
H
60
20
0
0
H
50
H
C(CH3)3
C6H5O
C5H11O
Cl
100
40
90
0
60
H
H
40
0
H
20
0
0
a
H
C(CH3)3
C6H5O
C5H11O
Cl
40
0
45
H
40
0
45
0
H
30
0
H
70
40
100
0
15
tolfenpyrad
100
70
100
a
Compounds exhibited obvious antifeedant activities.
(s, 1H, vinyl hydrogen), 4.35 (d, 3JHH = 7.2 Hz, 2H, OCH2CH3), 2.54
Synthesis of Ethyl 4-Chloro-3-ethyl-1-methyl-1H-pyrazole-
5-carboxylate (7). To a solution of 6 (0.55 g, 3.02 mmol) in toluene
(10 mL) was added sulfonyl chloride (0.45 g, 3.32 mmol) dropwise.
After the mixture was heated at 100 °C for 2 h, the mixture was
cooled, water (20 mL) was added, and the aqueous layer was extracted
twice with dichloromethane. The combined organic phase was washed
with brine (20 mL × 2), dried over anhydrous Na2SO4, and con-
3
3
(d, JHH = 7.6 Hz, 2H, CH2CH3), 1.38 (t, JHH = 7.2 Hz, 3H,
3
OCH2CH3), 1.18 (t, JHH = 7.6 Hz, 3H, CH2CH3).
Synthesis of Ethyl 3-Ethyl-1H-pyrazole-5-carboxylate (5). To
a solution of 4 (1.17 g, 6.80 mmol) in glacial acetic acid (20 mL) was
added hydrazine hydrate (0.46 g of 80%, w/w) dropwise. The mixture
was heated at 80 °C for 5 h. After the mixture was cooled to room
temperature, water (20 mL) was then added, and the aqueous layer
was extracted with dicholoromethane (15 mL × 3). The combined
organic phase was washed with saturated Na2CO3 (10 mL × 2) and
brine (10 mL × 2) successively, dried over anhydrous Na2SO4, and
1
centrated in vacuo to give 7 as orange-yellow oil (0.58 g, 89%). H
NMR (400 MHz, CDCl3): δ 4.37 (q, 3JHH = 7.2 Hz, 2H, OCH2CH3),
3
4.07 (s, 3H, pyrazole-CH3), 2.62 (q, JHH = 7.6 Hz, 2H, CH2CH3),
3
3
1.39 (t, JHH = 7.2 Hz, 3H, OCH2CH3), 1.21 (t, JHH = 7.6 Hz, 3H,
CH2CH3).
1
concentrated to give 5 as pale yellow oil (1.00 g, 87%). H NMR
Synthesis of 4-Chloro-3-ethyl-1-methyl-1H-pyrazole-5-car-
boxylic Acid (I). NaOH (1.03 g, 5.14 mmol) was added to a solution
of 7 (0.56 g, 2.57 mmol) in absolute alcohol (30 mL) in portions, and
the mixture was heated under reflux for 3 h. The alcohol was removed
in vacuo, and the residue was acidified to pH 2 with dilute H2SO4. The
white slurry was filtered, and the cake was washed with water to afford
I as a white solid (0.45 g, 84%). mp: 133−136 °C. 1H NMR (400 MHz,
(400 MHz, CDCl3): δ 12.49 (br, 1H, NH), 6.58 (s, 1H, pyrazole-H),
3
3
4.35 (q, JHH = 7.2 Hz, 2H, OCH2CH3), 2.72 (q, JHH = 7.6 Hz, 2H,
3
3
CH2CH3), 1.33 (t, JHH = 7.2 Hz, 3H, OCH2CH3), 1.25 (t, JHH
7.6 Hz, 3H, CH2CH3).
=
Synthesis of Ethyl 3-Ethyl-1-methyl-1H-pyrazole-5-carbox-
ylate (6). To a solution of 5 (5.00 g, 30.0 mmol) in dichloromethane,
anhydrous Na2CO3 (4.42 g, 41.7 mmol) was added in portion, and
after the mixture was heated to 40 °C, dimethyl sulfate (5.25 g, 41.7
mmol) was added dropwise, and then, the mixture was heated at
80 °C for 5 h. After the mixture was cooled to room temperature,
water and dichloromethane were added, and the aqueous layer was
extracted twice with dichloromethane. The combined organic phase
was washed with brine (100 mL × 2), dried over anhydrous Na2SO4,
concentrated in vacuo, and purified by flash chromatography on silica
gel using petroleum ether (60−90 °C) and ethyl acetate (v/v = 10:1)
3
CDCl3): δ 4.13 (s, 3H, pyrazole-Me), 2.67 (q, JHH = 7.6 Hz, 2H,
3
CH2CH3), 1.25 (t, JHH = 7.6 Hz, 3H, CH2CH3).
Data for 3-Ethyl-1-methyl-1H-pyrazole-5-carboxylic Acid (II).
Compound II was prepared from 6 using the same synthetic pro-
1
cedure as I. White solid. Yield: 95%. mp: 158−159 °C. H NMR
(400 MHz, CDCl3): δ 6.77 (s, 1H, pyrazole-H), 4.15 (s, 3H, pyrazole-
3
3
Me), 2.67 (q, 2H, JHH = 7.6 Hz, CH2CH3), 1.26 (t, 3H, JHH
7.6 Hz, CH2CH3).
=
Synthesis of N-(1-(4-(tert-Butyl)phenyl)-2-hydroxyethyl)-4-
chloro-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide (Ia).
A mixture of I (0.20 g, 1.04 mmol) and thionyl chloride (15 mL)
was heated under reflux for 1 h. After the mixture had been cooled to
room temperature, the excess thionyl chloride was removed under
reduced pressure, and the residue was dissolved in toluene (10 mL).
1
as eluent to give 6 as yellow oil (3.93 g, 72%). H NMR (400 MHz,
3
CDCl3): δ 6.60 (s, 1H, pyrazole-H), 4.29 (q, JHH = 7.2 Hz, 2H,
3
OCH2CH3), 4.08 (s, 3H, pyrazole-CH3), 2.60 (q, JHH = 7.6 Hz, 2H,
CH2CH3), 1.33 (t, 3JHH = 7.2 Hz, 3H, OCH2CH3), 1.20 (t, 3JHH = 7.6
Hz, 3H, CH2CH3).
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The obtained solution was added dropwise to a toluene (15 mL)
solution of 3a (0.20 g, 1.04 mmol) and triethyamine (0.12 g,
1.14 mmol) at −5 °C. Then, the mixture was stirred at −5 °C for 8 h,
then poured into ice water (40 mL), and extracted with toluene
(20 mL × 3). The combined organic layer was washed twice with
water (40 mL) and dried over anhydrous Na2SO4. After the solvent
was removed under reduced pressure, the residue was purified by
column chromatography on silica gel and eluted with petroleum ether
(60−90 °C) and ethyl acetate (v/v = 1:1) to give Ia as yellow viscous
oil (0.34 g, 90%).
Compounds Ib−d and IIa−d were synthesized using corresponding
acid and substituted benzylamine according to the same procedure as
Ia. The physical properties and elemental analysis or HRMS of
compounds Ia−d and IIa−d are listed in Table 1, and their 1H NMR
data are listed in Table 2.
Synthesis of N-(1-(4-(tert-Butyl)phenyl)-2-chloroethyl)-4-
chloro-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide (Ie). To
the solution of Ia (0.30 g, 0.83 mmol) in toluene (10 mL), thionyl
chloride (0.30 g, 2.52 mmol) was added dropwise, and then, the
mixture was heated to 80 °C for 3 h. After it was cooled, the reaction
mixture was added a solution of Na2CO3 to make pH 8, and then, the
organic layer was separated and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel and
eluted with petroleum ether (60−90 °C) and ethyl acetate (v/v =
10:1) to give Ie as pale yellow viscous oil (0.23 g, 74%).
Table 4. LC50 Value of Ij, IIe, and Tolfenpyrad against
Cotton Bollworm
toxic
ratio
LC50
confidence interval
(95%)
compd
y = a + bx
(mg kg−1)
Ij
IIe
y = 4.15 + 1.91x
y = 4.00 + 1.90x
0.88
0.74
1
2.80
3.33
2.47
2.59−3.03
2.97−3.74
2.23−2.73
tolfenpyrad y = 4.29 + 1.81x
Acaricidal Activity against Adults, Eggs, and Larvae of
Spider Mite (T. cinnabarinus). The acaricidal activities of the target
compounds Ia−l, IIa−l, and the contrast compound tebufenpyrad
against adults, eggs, and larvae of spider mite were evaluated by the
leaf dip method using reported procedure.20
Foliar Contact Activity against Bean Aphid (A. craccivora).
The foliar contact activities of compounds Ia−l, IIa−l, tebufenpyrad,
and tolfenpyrad against bean aphid were tested by the leaf dip method
according to a reported procedure.15−17
Toxicity against Mosquito (C. pipiens pallens). The toxicities of
the target compounds Ia−l, IIa−l, and tebufenpyrad against mosquito
were evaluated according to the reported procedure.16,21
RESULTS AND DISCUSSION
■
Synthesis. Ethyl 2-oxo-2-(4-substitudedphenyl) acetate (1a−c)
was prepared from substituted benzene by Friedel−Crafts
acylation in high regioselectivity. However, ethyl 2-(4-chloro-
phenyl)-2-oxoacetate (1d) could not be obtained selectively by
Friedel−Crafts acylation, and the ortho and para acylated pro-
ducts were difficult to be separated. Then, Grignard reagent of
1-bromo-4-chlorobenzene was applied in the synthesis of 1d.
Compounds 1a−d were, respectively, reacted with hydroxyl-
amine hydrochloride and then reduced by NaBH4/iodine system
to afford the key intermediate 2-amino-2-(4-substitudedphenyl)
ethanol (3a−3d). (Scheme 1).
Compounds If−h and IIe−h were synthesized from Ib−d and
IIa−d, respectively, according to the same procedure as Ie. The
physical properties and elemental analysis or HR-MS of compounds of
1
Ie−h and IIe−h are listed in Table 1, and their H NMR data are
listed in Table 2.
Synthesis of 4-(4-(tert-Butyl)phenyl)-2-(4-chloro-3-ethyl-1-
methyl-1H-pyrazol-5-yl)-4,5-dihydrooxazole (Ii).12 Compound
Ie (0.21 g, 0.55 mmol) was dissolved in alcohol (5 mL) and treated
with NaOH (0.44 g, 1.10 mmol). After reflux at 100 °C for 1 h, the
reaction mixture was poured into water (10 mL) and extracted with
ethyl acetate (10 mL × 3). The organic layer was washed with water
and brine, dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chromato-
graphy on silica gel and eluted with petroleum ether (60−90 °C)
and ethyl acetate (v/v = 10:1) to give Ii as colorless viscous oil
(0.18 g, 95%).
Butan-2-one reacted with diethyl oxalate to give kinetic
controlled product ethyl 2,4-dioxohexanoate (4) according to
the reported method.11 Further treatment with hydrazine
hydrate provided ethyl 3-ethyl-1H-pyrazole-5-carboxylate (5),
and the methylation of 5 by dimethyl sulfate assisted with
sodium carbonate afforded N-methylated product 6. Then, the
intermediate 6 was chlorinated by sulfonyl chloride to give
intermediate 7 and then hydrolyzed by sodium hydroxide to
afford acid I. Similarly, acid II could be obtained by the
hydrolysis of intermediate 6. Both acid I and II were treated
with thionyl chloride to give corresponding carbonyl chloride
and then condensed with 2-amino-2-(4-substitudedphenyl)
ethanol (3a−d) to afford amides Ia−d and IIa−d, which were
converted to Ie−h and IIe−h by thionyl chloride. Compounds
Ie−h and IIe−h were treated with sodium hydroxide to afford
oxazoles Ii−l and IIi−l, respectively.
It is worth mentioning that when acid II was reacted with
thionyl chloride, except for the expected 3-ethyl-pyrazole-
5-carbonyl chloride, 4-chloro-3-ethyl-pyrazole-5-carbonyl chlo-
ride was also formed. To reduce the dichlorated product, the
reaction temperature must be controlled under 80 °C, and thionyl
chloride must be added no more than 1.5-fold. However, from
another aspect, the dichlorated compound could be prepared from
acid II (instead of acid I) by using excess thionyl chloride at a higher
temperature, which provided an alternative synthetic procedure.
Bioassays. Stomach Activities against Cotton Bollworm
(H. armigera) and Diamondback Moth (P. xylostella).
Table 3 shows the stomach activities of the target compounds
and the contrast tolfenpyrad against cotton bollworm and
diamondback moth. The results indicated that most of the
Compounds Ij−l and IIi−l were synthesized from If−h and IIe−h,
respectively, according to the same procedure as Ii. The physical
properties and elemental analysis or HRMS of compounds Ii−l and IIi−l
1
are listed in Table 1, and their H NMR data are listed in Table 2.
Biological Assay. All bioassays were performed on representative
test organisms reared in the laboratory. The bioassay was repeated in
triplicate at 25
1 °C. The error of the experiments was 5%.
Assessments were made on a dead/alive basis, and mortality rates were
corrected using Abbott's formula.13 Evaluations were based on a
percentage scale of 0−100, where 0 equals no activity and 100 equals
total kill. For comparative purposes, tebufenpyrad and tolfenpyrad
were tested under the same conditions.
Stomach Activities against Cotton Bollworm (H. armigera).
The stomach toxicities of the target compounds Ia−l, IIa−l, and the
contrast tolfenpyrad against cotton bollworm were tested by the diet-
corporate method.14 The test samples were dissolved in acetone in
appropriate quantities to give the desired final concentrations, and
then pipetted 3 mL of the test solution to about 27 g of configured
feed, which was mixed evenly and poured into clean 24-well plates.
After evaporation of acetone, 24 third-instars cotton bollworm larvae
were infested. The diet fed to controls contained an amount of acetone
equal to the treatment containing the maximum amount (normally not
>5% of total volume). The insects were maintained under normal
rearing conditions for development and larvae fed ad lib. Percentage
mortalities were evaluated 3 days after treatment.
Stomach Toxicity against Diamondback Moth (P. xylostella).
The stomach toxicities of the target compounds Ia−l, IIa−l, and the
contrast tolfenpyrad against diamondback moth were tested by the leaf
dip method using the reported procedure.18,19
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Table 6. Foliar Contact Activities against Bean Aphid (A.
craccivora) of Compounds Ia−l, IIa−l, and Tebufenpyrad
larvicidal activity (%) at
−1
concn (mg kg )
compd
R1
R2
600
200
Ia
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
C(CH3)3
C6H5O
C5H11O
Cl
100
100
100
100
100
100
100
80
80
50
95
95
100
80
45
50
50
60
90
35
50
70
85
75
65
95
80
0
Ib
Ic
Figure 2. Stomach activities against diamondback moth. The picture
above showed the antifeedant effect of compound Ie at 600 and 200
mg kg−1. Ie had 90% inhibitory effect against diamondback moth at
600 mg kg−1. At 200 mg kg−1, the inhibitory effect was only 30%, but
the worms were much smaller as compared with the blank test,
because the insects no longer eat after a period of time.
Id
Ie
C(CH3)3
C6H5O
C5H11O
Cl
If
Ig
Ih
Ii
C(CH3)3
C6H5O
C5H11O
Cl
90
Table 5. Acaricidal Activities against Spider Mite
(T. cinnabarinus Boisduval) Eggs, Adults, and Larvae of
Compounds Ia−l, IIa−l, and Tebufenpyrad
Ij
90
Ik
100
60
Il
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIh
IIi
IIj
IIk
IIl
C(CH3)3
C6H5O
C5H11O
Cl
70
activity (%) against
H
95
eggs
adults
larvae
H
100
98
compd R1
R2
600
200
600
200
0
600
200
H
Ia
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
C(CH3)3
C6H5O
C5H11O
Cl
40
15
30
10
34
20
40
10
20
0
0
0
10
0
25
30
20
25
30
30
30
0
H
C(CH3)3
C6H5O
C5H11O
Cl
80
Ib
Ic
0
0
H
100
100
30
20
0
15
0
0
H
Id
Ie
0
H
C(CH3)3
C6H5O
C5H11O
Cl
30
0
0
0
H
C(CH3)3
C6H5O
C5H11O
Cl
98
90
20
20
90
100
If
0
20
0
H
50
Ig
0
0
H
75
Ih
Ii
0
0
H
100
100
C(CH3)3
C6H5O
C5H11O
Cl
0
30
0
10
45
25
15
20
0
30
0
tebufenpyrad
Ij
Ik
40
40
50
20
20
0
20
0
20
10
0
15
0
0
activities of these compounds were more than those with
t-butyl or n-pentyloxy group. In series II, α-hydroxymethyl-N-
benzyl, α-chloromethyl-N-benzyl, and 4,5-dihydrooxazole com-
pounds did not have significant difference at 5.5 mg kg−1,
and the substituent on the benzene ring did not have obvious
effect on the activity either. Only compound IIe, which bears
2-chloro-1-(4-t-butylphenyl) ethyl carboxamide, exhibited 60%
at 5.5 mg kg−1, much higher than the others. The LC50 values of
compounds Ij and IIe are given in Table 4, which show
approximate concentrations as commercial tolfenpyrad.
The stomach toxicity of the target compounds against
diamondback moth formed a sharp contrast to the activities
against cotton bollworm, although both of the worms are of the
order Lepidoptera. Although the activities against diamondback
moth of the target compounds at a low level compare with
commercial insecticides tolfenpyrad, we had been pleasantly
surprised to find that Ie, If, and Ih exhibited obvious anti-
feedant activities. Figure 2 shows the antifeedant effect of
compound Ie.
Acaricidal Activities against Spider Mite (T. cinnabarinus
Boisduval) Eggs, Adults, and Larvae. Table 5 shows the
acaricidal activities against spider mite eggs, adults, and larvae.
The activities of the target compounds were lower than
tebufenpyrad, which suggested that the changes on the bridge
moiety were detrimental to the acaricidal activity. Nevertheless,
there are still some rules that could be found. Generally, the
ovicidal activities of the target compounds were a little higher
than miticidal and larvicidal activities, especially the compounds
containing 4,5-dihydrooxazole moieties in series II exhibited
excellent activities against spider mite eggs. For instance, the
ovicidal activities of IIi and IIl against spider mite were 95 and
Il
0
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIh
IIi
IIj
IIk
IIl
C(CH3)3
C6H5O
C5H11O
Cl
40
0
H
30
45
25
30
50
0
0
0
0
0
0
0
H
0
20
25
20
40
70
20
90
70
30
40
100
0
0
H
H
C(CH3)3
C6H5O
C5H11O
Cl
80
50
70
30
100
90
50
100
100
40
40
50
0
0
H
30
40
0
H
H
0
H
C(CH3)3
C6H5O
C5H11O
Cl
95
50
40
80
100
100
40
20
20
100
95
10
0
80
50
0
H
H
H
0
20
100
tebufenpyrad
100
target compounds exhibited excellent activities against cotton
bollworm, and all of the compounds had 100% inhibitory effect
at 55 mg kg−1. At reduced dosages, the compounds chlorinated
at the 4-position of pyrazole (series I) were more potent than
that of not chlorinated (series II). In series I, the compounds
containing α-chloromethyl-N-benzyl and 4,5-dihydrooxazole
moieties exhibited higher activities than the compounds
containing α-hydroxymethyl-N-benzyl moieties. For instance,
the activities of Ie−l were 100% at 22 mg kg−1, while Ia−d had
no more than 70% at the same dosage. In particular, the
activities of Ij and Il were 60% at 5.5 mg kg−1, which was near
that of tolfenpyrad. It suggested that the hydrogen donor of the
bridge was not necessary for the high activity against cotton
bollworm. Moreover, the substituent on the benzene ring of the
target compounds was also important for the activities. When
the substituent on the benzene ring was phenoxyl or chloro, the
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Journal of Agricultural and Food Chemistry
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80% at 200 mg kg−1, respectively. We also noticed that com-
pound IIi exhibited excellent activities against spider mite eggs,
adults, and larvae at 200 mg kg−1, which were 95, 95, and 80%,
respectively, whereas the corresponding compound Ii were only
0, 10, and 30%, respectively. It indicated that the 4-position in
pyrozole was a sensitive site. Therefore, a trivial change at that
site would lead to great changes in properties and activities.
The substituents on the benzene ring also have a significant
effect on acaricidal activities, and the tert-butyl substituent is
optimal.
containing α-hydroxymethyl-N-benzyl and 4,5-dihydrooxazole
moieties. The substituent R2 on the benzene ring of the target
compounds was also important for the activities against mosquito.
When the R2 group was fixed as phenoxy, the activities of the
target compounds were the highest whatever in series I or II. The
phenoxy on benzene ring of the target compounds is beneficial to
the activity against mosquito larvae. Especially, the activity of IIf
was 60% at 0.5 mg kg−1, which was higher than tebufenpyrad.
Then, their LC50 values were tested and are given in Table 8,
which showed IIf was nearly two times better than tebufenpyrad.
Foliar Contact Activities against Bean Aphid (A.
craccivora). Table 6 shows the foliar contact activities of the
target compounds and contrast tebufenpyrad. Among series I,
the compounds containing α-hydroxymethyl-N-benzyl and
α-chloromethyl-N-benzyl moieties exhibited higher activities
against bean aphid than the compounds containing 4,5-
dihydrooxazole moieties, which indicated that high polarity of
the target compounds and the hydrogen donor of the bridge
moiety might be favorable to the foliar contact activities. Series
II did not give obvious activity relationship with the bridge
moiety or the substituents on the benzene ring. Among all of
the compounds, the activities against bean aphid of Ic, Id, Ie,
and IIf were more than 95% at 200 mg kg−1.
Table 8. LC50 Value of IIf and Tebufenpyrad against
Mosquito
toxic
ratio
LC50−1
confidence interval
(95%)
compd
y = a + bx
(mg kg )
IIf
y = 5.88 + 1.91x
1.7
1
0.35
0.61
0.32−0.38
0.53−0.69
tebufenpyrad y = 5.41 + 1.87x
In summary, a series of novel pyrazoles containing α-hydro-
xymethyl-N-benzyl carboxamide, α-chloromethyl-N-benzyl
carboxamide, and 4, 5-dihydrooxazole moieties were designed
and synthesized via the key intermediate 2-amino-2-(4-
substitutedphenyl) ethanol. The results of bioassays indicated
that the target compounds possessed good to excellent
activities against a broad spectrum of insects such as cotton
bollworm (H. armigera), bean aphid (A. craccivora), mosquito
(C. pipiens pallens), and spider mite (T. cinnabarinus). Although
the acaricidal activity of these compounds was reduced
significantly as compared with commercial insecticide tebu-
fenpyrad, compounds containing α-chloromethyl-N-benzyl
carboxamide and compounds containing 4,5-dihydrooxazole
showed the high insecticidal activity against cotton bollworm.
Especially, stomach activities against cotton bollworm of
compounds Ij, Il, and IIe were 60% at 5.5 mg kg−1, which
was near to the activity of contrast tolfenpyrad. Moreover, the
target compounds exhibited high selectivity between cotton
bollworm and diamondback moth, both of which are of the
order Lepidoptera. Although the activities against diamondback
moth at a low level, it was found that compounds Ie, If, and Ih
exhibited antifeedant activities. The foliar contact activity
against bean aphid of compounds Ic, Ie, Id, Ik, IIf, IIi, and
IIl were more than 90% at 200 mg/kg. The miticidal and
ovicidal activities against spider mite of compound IIi were
both 95% at 200 mg kg−1, while compound Ii was inactive
at 600 mg kg−1. Just as we envisioned, a trivial change at
4-position of pyrazole ring would lead to great changes in
activities.
Toxicity against Mosquito (C. pipiens pallens). Table 7
showed the larvacidal activities of the target compounds and
Table 7. Larvacidal Activities against Mosquito (C. pipiens
pallens) of Compounds Ia−l, IIa−l, and Tebufenpyrad
larvicidal activity (%) at concn
(mg kg−1)
compd
R1
R2
5
2
1
0.5
Ia
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
C(CH3)3
C6H5O
C5H11O
Cl
20
100
20
0
Ib
Ic
100
0
40
0
Id
Ie
30
0
C(CH3)3
C6H5O
C5H11O
Cl
100
100
100
100
100
100
100
100
10
100
100
70
100
100
60
50
50
0
40
60
0
0
0
If
Ig
Ih
Ii
50
50
0
0
0
C(CH3)3
C6H5O
C5H11O
Cl
Ij
Ik
0
Il
0
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIh
IIi
IIj
IIk
IIl
C(CH3)3
C6H5O
C5H11O
Cl
H
30
0
H
20
0
H
20
0
H
C(CH3)3
C6H5O
C5H11O
Cl
60
0
H
100
100
10
100
60
0
100
0
60
AUTHOR INFORMATION
■
H
Corresponding Author
H
*Tel: +86-(0)22-23503952; Fax: +86-(0)22-23503952; E-mail:
liuyuxiu@nankai.edu.cn. (Y.L.). Tel: +86-(0)22-23503952; Fax:
+86-(0)22-23503952; E-mail: wang98h@263.net; wangqm@
nankai.edu.cn. (Q.W.).
H
C(CH3)3
C6H5O
C5H11O
Cl
100
30
60
0
0
H
H
30
0
H
10
0
tebufenpyrad
100
100
70
0
Funding
This work was supported by the National Key Project for Basic
Research (2010CB126106), the National Natural Science Founda-
tion of China (21072109), and the National Key Technology
Research and Development Program (2011BAE06B05).
the contrast tebufenpyrad against mosquito. Overall, the
compounds chlorinated in 4-position of pyrazole (series I)
were more potent than that of not chlorinated (series II), and
the compounds containing α-chloromethyl-N-benzyl moieties
exhibited a little higher activities than most of the compounds
Notes
The authors declare no competing financial interest.
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Journal of Agricultural and Food Chemistry
Article
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