Design, synthesis, insecticidal, and acaricidal activities of novel pyrimidinamine derivatives containing a biphenyl ether

Article abstract of DOI:10.1002/jhet.3710

A series of original pyrimidinamine derivatives containing a biphenyl ether moiety were designed and synthesized. Their structures were confirmed by ¹H NMR, MS, and elemental analyses. Their insecticidal activities against lepidopteran and hemiptera insects and acaricidal activities were tested. The results of bioassay demonstrated that 9k showed the best activity (LC₅₀ = 2.08 mg/L) against Tetranychus urticae, which is comparable with the positive control, spirotetramat (LC₅₀ = 2.27 mg/L), and 9g showed better activity (LC₅₀ = 0.52 mg/L) against Aphis fabae than the positive control, imidacloprid (LC₅₀ = 1.02 mg/L), and relatively good activity (LC₅₀ = 2.49 mg/L) against T urticae. Their structure-activity relationships indicated that both an ethyl group on the 4-position of the pyrimidine ring and alkyl chain as a para-substituent group of the benzene ring showed good biological activity.

Full text of DOI:10.1002/jhet.3710

Received: 26 March 2019
DOI: 10.1002/jhet.3710
Revised: 14 August 2019
Accepted: 18 August 2019
A R T I C L E
Design, synthesis, insecticidal, and acaricidal activities of
novel pyrimidinamine derivatives containing a biphenyl
ether
Lizhong Li1,3
| Chunge Zhou1,3
| Minhua Liu2,3
| Ping Zhang2,3 | Ning Zhang1,3
|
Jianming Li2,3 | Tao Li2,4 | Xingping Liu2,3 | Shufen Cheng2,3 | Qianhe Li1
Aiping Liu2,3
|
1 College of Chemistry and Chemical
Abstract
Engineering, Hunan Normal University,
A series of original pyrimidinamine derivatives containing a biphenyl ether moi-
ety were designed and synthesized. Their structures were confirmed by 1H NMR,
MS, and elemental analyses. Their insecticidal activities against lepidopteran and
hemiptera insects and acaricidal activities were tested. The results of bioassay
demonstrated that 9k showed the best activity (LC50 = 2.08 mg/L) against
Tetranychus urticae, which is comparable with the positive control, spirotetramat
(LC50 = 2.27 mg/L), and 9g showed better activity (LC50 = 0.52 mg/L) against
Aphis fabae than the positive control, imidacloprid (LC50 = 1.02 mg/L), and rel-
atively good activity (LC50 = 2.49 mg/L) against T urticae. Their structure‐
activity relationships indicated that both an ethyl group on the 4‐position of the
pyrimidine ring and alkyl chain as a para‐substituent group of the benzene ring
showed good biological activity.
Changsha 410081, China
2 National Engineering Research Center
for Agrochemicals, Hunan Research
Institute of Chemical Industry, Changsha
410007, China
3 Hunan Province Key Laboratory for
Agrochemicals, Changsha 410014, China
4 Hunan Haili Chemical Industry Co., Ltd,
Changsha 410007, China
Correspondence
Tao Li, National Engineering Research
Center for Agrochemicals, Hunan
Research Institute of Chemical Industry,
Changsha 410007, China.
Email: litao@hnhlc.com
Qianhe Li, College of Chemistry and
Chemical Engineering, Hunan Normal
University, Changsha 410081, Hunan
Province, China.
Email: liqianhe@hunnu.edu.cn
Aiping Liu, National Engineering
Research Center for Agrochemicals,
Hunan Research Institute of Chemical
Industry, Changsha 410007, China.
Email: lapliu@yahoo.com
Funding information
National Natural Science Foundation of
China, Grant/Award Number: 21572050;
National Key Research & Development
Pillar Program of China during the 13th
Five‐Year Plan Period, Grant/Award
Number: 2016YFD0300708
Lizhong Li and Chunge Zhou contributed equally to this work.
All the authors declare no competing financial interest.
J Heterocyclic Chem. 2019;1–9.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

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LI ET AL.
out. This study reported the synthesis, structure‐activity,
and bioactivities of target compounds.
1 | INTRODUCTION
The outbreak of pests in crops leads to considerable dam-
age and reduce crop yields. Among these pests, Mythimna
separata, Aphis fabae, and Tetranychus urticae are
destructive pests in modern agriculture.[1–5] Moreover, at
present, there are simply few commercial pesticides that
are left in use, and their repeated and long‐term applica-
tions have led to the enhancement of biodegradation
mechanisms in soil and the development of pest resis-
tance.[6–13] Therefore, the development of new insecti-
cides and acaricides with new modes of action, low
toxicity to mammals, and environmental friendliness
becomes increasingly urgent.
Heterocyclic compounds, especially pyrimidine hetero-
cyclic compounds, play a vital role in the field of pesti-
cides because of their broad spectrum of biological
activity, such as insecticidal, acaricidal, bactericidal, and
herbicidal.[14–20] Moreover, the biphenyl ether moiety is
another important structure with remarkable bioactivity
as well and has emerged in some pesticide structures up
to now, such as permethrin, etofenprox, and phenothrin.
Therefore, target compounds including pyrimidine ring
and biphenyl ether moiety may be promising templates
for the discovery of new insecticide and acaricide
candidates.
2 | RESULTS AND DISCUSSION
2.1 | Synthesis
The general synthetic routes for compounds 9a‐p are
shown in Scheme 1. The target compounds were obtained
by the reactions of a~g, and yields of reactions were not
optimized. Compound 10g was synthesized as a case,
and every other compounds were synthesized in the sim-
1
ilar manner. The data of MS, H NMR, and elemental
analysis were applied to identify the structures of target
compounds.
2.2 | Insecticidal and acaricidal activities
The insecticidal activities of compounds 9a‐p against
M separata and A fabae and the acaricidal activities
against mite—T urticae—were tested at the concentration
of 500 mg/L. The results of bioassay were shown in
Table 1.
The insecticidal activities of compounds 9a‐p against
M separata and A fabae were tested at 500 mg/L by typi-
cal assay.[23,24] The mortality rates (MRs) of the target
compounds were shown in Table 1, and the results dem-
onstrated that there were no compounds that showed
good activities against M separata. However, compounds
9a‐p showed distinct activities against A fabae, and the
MRs at 48 hours were more than 90%. So the insecticidal
activity of compounds 9a‐p against A fabae was further
tested at 200 and 50 mg/L, and imidacloprid was used
Encouraged by these experience, a series of novel
pyrimidinamine derivatives containing a biphenyl ether
moiety 9a‐p as shown in Figure 1 were designed and syn-
thesized on the base of active group splicing principle and
intermediate derivatization method, a recently reported
approach to discover agrochemical candidates more effi-
ciently.[21,22] And an optimization program modifying
parts of A and B as shown in Figure 1 was also carried
FIGURE 1 Design strategy for the target compounds [Color figure can be viewed at wileyonlinelibrary.com]

LI ET AL.
3
SCHEME 1 Synthetic routes for compounds 9a‐q
TABLE 1 Insecticidal and acaricidal activities of compounds 9a‐q
A fabae
T urticae
M separata
Compound
500 mg/L
–
200 mg/L
100
50 mg/L
93.4
75.7
46.8
50.2
84.5
11.8
96.9
97.9
90.5
97.1
84.2
12.8
62.1
29.2
56.2
500 mg/L
500 mg/L
61.8
100
200 mg/L
–
50 mg/L
–
9a
9b
9c
9d
9e
9f
0
94.8
100
–
0
96.2
97.9
100.0
100
35
92.3
89.4
56.5
99
54.6
89.5
92.7
37.8
100
0
100
93.1
100
16.7
26.5
54.2
0
85.9
100
100
86.9
95.2
100
30
9g
9h
9i
100
97.9
95.4
95.4
96.5
100
–
96.4
97.6
86.0
55
100
100
90.1
26.9
61.4
33.3
0
100
100
99.3
96.9
100
9j
100
100
9k
9l
100
100
100
–
96.9
98.9
96.7
93.4
17.4
73.7
39.6
–
54.4
89.1
13.3
33.2
9m
9n
9o
0
81.2
–
7.5
0
–
0
–
–
(Continues)

4
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TABLE 1 (Continued)
A fabae
T urticae
M separata
500 mg/L
19.2
Compound
9p
500 mg/L
200 mg/L
50 mg/L
500 mg/L
200 mg/L
50 mg/L
91.0
45.1
22.7
49.6
–
–
Imidacloprid
Spirotetramat
–
–
–
–
100.0b
–
–
–
–
–
–
82.9a
71.1b
Note. −, no test.
a20 mg/L.
b10 mg/L.
as a positive control. The MRs of compounds 9a, 9e, 9g,
9h, 9i, 9j, and 9k were still more than 90% at the concen-
tration of 200 mg/L. In particular, the MRs of compounds
9a, 9e, 9g, 9h, 9i, and 9j were more than 85% at the con-
centration of 50 mg/L.
The LC50 values at 72 hours of four promising com-
pounds were calculated, and spirotetramat was used as a
positive control. The methods of tests and data processing
were same as above. The results were shown in Table 3.
Compounds 9k (LC50
=
2.08 mg/L) and 9g
The acaricidal activities of compounds 9a‐p against mite
—T urticae—were tested by slide‐dipping method.[25–27]
Spirotetramat was used as a positive control. The MRs at
72 hours of the target compounds at the concentration of
500, 200, and then 50 mg/L were shown in Table 1. The
MRs at the concentration of 500 mg/L of compounds 9b,
9c, 9e, 9g, 9h, 9i, 9j, and 9k are more than 95%. In particu-
lar, the MRs of compounds 9e, 9g, 9h, and 9k are still more
than 95% at the concentration of 50 mg/L.
As described in Table 2, the LC50 values at 72 hours of
six potent derivatives against A fabae were evaluated by
further assay using five to six different concentrations.
Imidacloprid was still used as a positive control, which
was tested with the solvent only. All trials were run three
times, and their results were averaged. Data were dealt
with probit analysis, and the medium lethal concentration
(LC50) value of tested compounds was calculated (95% FL).
The LC50 values of 9a, 9e, 9g, 9h, 9i, and 9j were 19.23,
26.55, 0.58, 4.03, 6.31, and 3.62 mg/L, respectively. In par-
ticular, compound 9g (LC50 = 0.58 mg/L) showed best
insecticidal activity, which was better than the commercial
insecticide, imidacloprid (LC50 = 1.02 mg/L).
(LC50 = 2.49 mg/L) showed potent acaricidal activities,
which were comparable with the commercial acaricidal,
spirotetramat (LC50 = 2.27 mg/L).
2.3 | Apparent structure‐activity
relationship
Owing to the variances of R, R1, R2, R3, and R4 in the for-
mula for compounds 9a‐q as shown in Figure 1, there were
different biological activities. Structural optimization was
implemented by changing five primary substructures: the
R, R1, R2, R3, and R4.When R1, R2, R3, and R4 remained
unchanged, the R group effected the insecticidal and acar-
icidal activities of target compounds. And the insecticidal
and acaricidal activities increased when R group was from
a hydrogen atom to methyl group (eg, 9g demonstrated the
higher insecticidal and acaricidal activities than 9b). This
suggests that the alkylation of 2‐position of pyrimidine ring
could be a direction to discover promising insecticidal and
acaricidal compounds.
(1) When R, R2, R3, and R4 remained constant and R1
was changed from Et to Me, Pr, i‐Pr, n‐Bu, i‐Bu,
TABLE 2 Median lethal concentration LC50 of the target com-
pounds against A fabae at 72 h
Regression
Equation
LC50,
mg/L
TABLE 3 Median lethal concentration (LC50) of target com-
pounds against T urticae at 72 h
Compound
Correlation
9a
y = 3.0947 + 1.4839x
y = 0.7326 + 2.9967x
y = 5.2489 + 1.0641x
y = 3.8346 + 1.9241x
y = 3.8915 + 1.3861x
y = 3.0217 + 3.5400x
y = 4.9477 + 5.3370x
0.9804
0.9297
0.9384
0.9577
0.9927
0.9157
0.9338
19.23
26.55
0.58
4.03
6.31
3.62
1.02
Regression
Equation
LC50,
mg/L
Compound
Correlation
9e
9g
9e
y = 2.1676 + 4.1874x
y = 4.1326 + 2.1921x
y = 2.1696 + 3.3574x
y = 4.4539 + 1.7151x
y = 4.6328 + 1.034x
0.9321
0.9955
0.8908
0.9818
0.9594
4.75
2.49
6.97
2.08
2.27
9h
9g
9i
9h
9j
9k
Imidacloprid
Spirotetramat

LI ET AL.
5
and Tf, the insecticidal and acaricidal activities of
the compounds decreased; such as 9g, 9i, and 9j
showed higher activity than the rests.
4.1.1 | Intermediate 2
The starting material 1 (100 mmol, 10.8 g) was dissolved
in toluene with stirring, and then potassium hydroxide
(100 mmol, 5.6 g) was added, after which the mixture
was heated to reflux for about 6 hours until the raw
material was almost consumed (monitored by HPLC).
The reaction was cooled to room temperature and
then filtered to give the solid intermediate 2, yield
88% to 91%.
(2) When R, R1, R3, and R4 were kept invariable and R2
was from H to CH3, the insecticidal and acaricidal
activities of compounds reduced; for example, 9g
showed higher insecticidal and acaricidal activities
than 9i.
(3) Similarly, when R, R1, R2, and R3 were held steady
and R4 varies from CH3 to Cl and C (CH3)3, the insec-
ticidal activity of the relative compounds reduced;
such as their insecticidal activities are correlated as
follows: 9k < 9h < 9g. However, acaricidal activity
of these compounds increased when R4 was from Cl
to CH3 and C (CH3)3; for example, acaricidal activity
of these compounds is correlated as follows:
9k > 9g > 9h. Further studies on the structure‐
activity relationships of these pyrimidinamine deriva-
tives are in progress.
4.1.2 | Intermediate 3
The mixture of intermediate 2 (70 mmol, 10.2 g) and p‐
chlorobenzonitrile (70 mmol, 9.6 g) was dissolved in
DMF, after that, the mixture was heated to reflux for
about 7 hours. And then the reacting mixture was poured
into water with stirring and then was filtered to give the
solid intermediate 3, yield 76% to 80%.
3 | CONCLUSIONS
4.1.3 | Intermediate 4
In conclusion, a series of original pyrimidinamine deriva-
tives containing a biphenyl ether moiety were designed
and synthesized. Their insecticidal and acaricidal activities
were tested. Most of compounds exhibited remarkable
activities against T urticae and A fabae. The potency of
compound 9g against A fabae was higher than that of
imidacloprid, and its potency against T urticae was compa-
rable with spirotetramat. The potency of compound 9k
against T urticae was a little better than spirotetramat.
Given their higher potency, 9g is a promising insecticide
candidate and 9k is a promising acaricide candidate, which
were worth a further development and optimization.
Intermediate 3 (40 mmol, 8.4 g), ethanol (100 mL),
ammonia water (25%) (120 mmol, 8.2 g), and Raney
nickel catalyst (1.5 g) were put in a 200‐mL autoclave,
and then the gas in the autoclave was replaced with
hydrogen; after that, the temperature of this mixture
was raised to 60°C to 70°C with stirring, and then the
hydrogen pressure was adjusted to 1 MPa; then the reac-
tion was stirred for about 7 hours, after which the
reacting mixture was filtered to remove the catalyst, and
then the solution was extracted with ethyl acetate three
times. The organic layer was combined and dried over
anhydrous sodium sulfate, and then the ethyl acetate
was rid off to give intermediate 4, yield 81% to 86%.
4 | EXPERIMENTAL
4.1 | Materials and methods
4.1.4 | Ethyl 2‐chloro‐3‐oxopentanoate 6
Unless special mention, reagents and solvents used were
received from commercial suppliers. Melting points were
tested on WPS‐1B melting point apparatus made in
shanghai physical optics instrument plant. 1H NMR spec-
tra were obtained with a Varian INOVA‐300, and TMS
was used as the internal standard. The mass of com-
pounds were confirmed by Agilent 5973‐6890 gas
chromatography–mass spectrometer (GC‐MS) or Agilent
1100 series liquid chromatography–mass spectrometer
(LC‐MS). Elemental analyses of target compounds were
carried out with a PECHNS/O 2400 II elemental analyzer.
And the purification of compounds was carried out with
column chromatography using 200 to 300 mesh silica gel.
The starting material ethyl 3‐oxopentanoate (100 mmol,
14.4 g) was placed in a three‐mouth flask and dissolved
in dichloromethane, and then the mixture of sulfonyl
chloride (110 mmol, 18.1 g) and dichloromethane was
slowly added by a dropping funnel under stirring at −5°
C to 0°C. After that, the reaction was stirred for about
10 hours. After which the mixture was poured into ice
water and then extracted with dichloromethane twice.
The organic layer was combined and dried with anhy-
drous sodium sulfate, and then the dichloromethane
was rid off to give ethyl 2‐chloro‐3‐oxopentanoate 6 as
pale yellow liquid, yield 81% to 85%.

6
LI ET AL.
2H), 6.957 (d, J = 6.6 Hz, 2H), 7.139 (d, J = 8.1 Hz, 2H),
7.283 (d, J = 8.4 Hz, 2H), 8.411 (s, 1H); GC‐MS M+ = 339.
Anal. calcd. for C19H18ClN3O: C, 67.16; H, 5.34; N, 12.37;
Found: C, 67.10; H, 5.40; N, 12.30.
4.1.5 | 5‐Chloro‐6‐ethyl‐2‐
methylpyrimidin‐4‐ol 7
The acetamidine hydrochloride (70 mmol, 6.6 g) was dis-
solved with methanol, and then sodium methylate solu-
tion (30%) (70 mmol, 12.6 g) was added by a dropping
funnel, which was stirred for 30 minutes. And then ethyl
2‐chloro‐3‐oxopentanoate (70 mmol, 12.5 g) was added by
a dropping funnel under −5°C to 0°C. The mixture was
heated slowly to reflux for 3 hours. Then the reaction
was cooled to room temperature and filtrated. Finally,
the filtrate was concentrated to give 5‐chloro‐6‐ethyl‐2‐
methylpyrimidin‐4‐ol, yield 65% to 72%.
4.1.9 | 5‐Chloro‐6‐ethyl‐N‐(4‐(p‐tolyloxy)
benzyl)pyrimidin‐4‐amine (9b)
Yield, 79%; yellow solid; mp: 107.5‐109.8°C; 1H NMR
(CDCl3) δ: 1.275 (t, J = 7.8 Hz, 3H), 2.336 (s, 3H), 2.813
(q, J = 7.5 Hz, 2H), 4.673 (d, J = 5.4 Hz, 2H), 5.672 (br,
1H), 6.905 (d, J = 7.2 Hz, 2H), 6.961 (d, J = 6.6 Hz, 2H),
7.142 (d, J = 8.1 Hz, 2H), 7.290 (d, J = 8.7 Hz, 2H),
8.465 (s, 1H); GC‐MS M+ = 353. Anal. calcd. for
C20H20ClN3O: C, 67.89; H, 5.70; N, 11.88; Found: C,
67.80; H, 5.66; N, 11.90.
4.1.6 | 4,5‐Dichloro‐6‐ethyl‐2‐
methylpyrimidine 8
The 5‐chloro‐6‐ethyl‐2‐methylpyrimidin‐4‐ol 7 (30 mmol,
5.2 g) was dissolved in toluene (15 mL), phosphorus
oxychloride (90 mmol, 13.8 g) was added by a dropping
funnel under −5°C to 0°C, and then TEA (60 mmol,
6.1 g) was added by other dropping funnel. The mixture
was stirred for about 12 hours, after which the reaction
was put into crushed ice by dropwise under stirring.
And then potassium carbonate was added to adjust pH
to weak alkalinity and then extracted with ethyl acetate
twice. The organic layer was combined and dried with
anhydrous sodium sulfate, and ethyl acetate was rid off
to give 4,5‐dichloro‐6‐ethyl‐2‐methylpyrimidine 8 as red‐
brown liquid, yield 56% to 63%.
4.1.10 | Chloro‐N‐(4‐(4‐chlorophenoxy)
benzyl)‐2,6‐dimethylpyrimidin‐4‐amine (9c)
1
Yield, 81%; light yellow solid; mp: 61.2‐61.6°C; H NMR
(CDCl3) δ: 2.429 (s, 3H), 2.495 (s, 3H), 4.672 (d,
J = 5.7 Hz, 2H), 5.577 (br, 1H), 6.930 (d, J = 6.9 Hz,
2H), 6.970 (d, J = 6.3 Hz, 2H), 7.284 (d, J = 6.9 Hz, 2H),
7.315 (d, J = 6.6 Hz, 2H); GC‐MS M+ = 373. Anal. calcd.
for C19H17Cl2N3O: C, 60.98; H, 4.58; N, 11.23; Found: C,
60.96; H, 4.52; N, 11.26.
4.1.11 | 5‐Chloro‐N‐(4‐(2,4‐
dimethylphenoxy)benzyl)‐2,6‐
dimethylpyrimidin‐4‐amine (9d)
4.1.7 | 5‐Chloro‐6‐ethyl‐2‐methyl‐N‐(4‐(p‐
tolyloxy)benzyl)pyrimidin‐4‐amin (10g)
Yield, 79%; light solid; mp: 60.5‐63.0°C; 1H NMR (CDCl3)
δ: 2.176 (s, 3H), 2.318 (s, 3H), 2.430 (s, 3H), 2.499 (s, 3H),
4.630 (d, J = 5.4 Hz, 2H), 5.298 (br, 1H), 6.809‐6.870 (m,
3H), 6.978 (d, J = 8.1 Hz, 1H), 7.065 (s, 1H), 7.255 (d,
J = 8.7 Hz, 1H); GC‐MS M+ = 367. Anal. calcd. for
C21H22ClN3O: C, 68.56; H, 6.03; N, 11.42; Found: C,
68.50; H, 5.98; N, 11.36.
(4‐(p‐Tolyloxy)phenyl)methanamine (3 mmol, 0.64 g) was
dissolved in DMF with stirring, and then 4,5‐dichloro‐6‐
ethyl‐2‐methyl pyrimidine (3 mmol, 0.57 g) was added;
after that, potassium carbonate (4.5 mmol, 0.62 g) was
added. Then reaction lasted for about 8 hours. Then the
mixture was extracted with saline solution ethyl acetate
and twice. The organic layer was combined and dried
with anhydrous sodium sulfate, and then ethyl acetate
was rid off. Residue materials were separated by silica
gel column chromatography to give the target compound,
yield 72% to 85%.
4.1.12 | N‐(4‐(4‐(tert‐Butyl)phenoxy)ben-
zyl)‐5‐chloro‐2,6‐dimethylpyrimidin‐4‐
amine (9e)
1
Yield, 83%; light yellow oil; H NMR (CDCl3) δ: 1.321 (s,
9H), 2.467 (s, 3H), 2.534 (s, 3H), 4.678 (d, J = 5.7 Hz,
2H), 5.631 (br, 1H), 6.922 (d, J = 8.7 Hz, 2H), 6.977 (d,
J = 8.7 Hz, 2H), 7.295 (d, J = 9.0 Hz, 2H), 7.348 (d,
J = 8.7 Hz, 2H); GC‐MS M+ = 395. Anal. calcd. for
C23H26ClN3O: C, 69.77; H, 6.62; N, 10.61; Found: C,
69.72; H, 6.57; N, 10.54.
4.1.8 | 5‐Chloro‐6‐methyl‐N‐(4‐(p‐tolyloxy)
benzyl)pyrimidin‐4‐amine (9a)
Yield, 76%; yellow solid; mp: 135.4‐136.6°C; 1H NMR
(CDCl3) δ: 2.333 (s, 3H), 2.473 (s, 3H), 4.668 (d,
J = 5.7 Hz, 2H), 5.636 (br, 1H, NH), 6.917 (d, J = 6.8 Hz,

LI ET AL.
7
(s, 3H), 2.760 (q, J = 7.5 Hz, 2H), 4.648 (d, J = 5.7 Hz,
2H), 5.553 (br, 1H), 6.755 (dd, J1 = 2.7 J2 = 5.7 Hz, 1H),
6.825 (d, J = 2.7 Hz, 1H, Ph H), 6.948 (d, J = 8.7 Hz,
2H), 7.084 (d, J = 8.4 Hz, 1H), 7.292 (d, J = 6.6 Hz,
2H); GC‐MS M+ = 381. Anal. calcd. for C22H24ClN3O:
C, 69.19; H, 6.33; N, 11.00; Found: C, 69.15; H, 6.29;
N, 10.97.
4.1.13 | 5‐Chloro‐N‐(4‐(3,4‐
dimethylphenoxy)benzyl)‐2,6‐
dimethylpyrimidin‐4‐amine (9f)
Yield, 85%; light yellow solid; mp: 100.1‐101.8°C; 1H NMR
(CDCl3) δ: 2.234 (s, 6H), 2.434 (s, 3H), 2.504 (s, 3H), 4.659
(d, J = 5.4 Hz, 2H), 5.547 (br, 1H), 6.742 (dd, J = 7.8,
2.7 Hz, 1H), 6.825 (d, J = 2.7 Hz, 1H, Ph H), 6.951 (d,
J = 6.6 Hz, 2H), 7.084 (d, J = 8.4 Hz,1H), 7.288 (d,
J = 6.6 Hz, 2H); GC‐MS M+ = 367; Anal. calcd. for
C21H22ClN3O: C, 68.56; H, 6.03; N, 11.42; Found: C,
68.52; H, 6.06; N, 11.37.
4.1.18 | N‐(4‐(4‐(tert‐Butyl)phenoxy)ben-
zyl)‐5‐chloro‐6‐ethyl‐2‐methylpyrimidin‐4‐
amine (9k)
1
Yield, 78%; light yellow oil; H NMR (CDCl3) δ: 1.247 (t,
4.1.14 | 5‐Chloro‐6‐ethyl‐2‐methyl‐N‐(4‐(p‐
tolyloxy)benzyl)pyrimidin‐4‐amine (9g)
J = 7.5 Hz, 3H), 1.319 (s, 9H), 2.521 (s, 3H), 2.772 (q,
J = 7.5 Hz, 2H), 4.668 (d, J = 5.4 Hz, 2H), 5.578 (br,
1H), 6.943 (d, J = 8.7 Hz, 2H), 6.975 (d, J = 8.7 Hz,
2H), 7.301 (d, J = 8.4 Hz, 2H), 7.347 (d, J = 8.7 Hz,
2H); GC‐MS M+ = 409. Anal. calcd. for C24H28ClN3O:
C, 70.32; H, 6.88; N, 10.25; Found: C, 70.30; H, 6.86;
N,10.30.
1
5‐Yield, 82%; yellow oil; H NMR (CDCl3) δ: 1.253 (t,
J = 7.5 Hz, 3H), 2.337 (s, 3H), 2.535 (s, 3H), 2.750 (q,
J = 7.5 Hz, 2H), 4.668 (d, J = 5.7 Hz, 2H), 5.610 (br,
1H), 6.915 (d, J = 6.6 Hz, 2H), 6.958 (d, J = 6.6 Hz, 2H),
7.133 (d, J = 6.6 Hz, 2H), 7.290 (d, J = 6.6 Hz, 2H); GC‐
MS M+ = 367. Anal. calcd. for C21H22ClN3O: C, 68.56;
H, 6.03; N, 11.42; Found: C, 68.53; H, 6.06; N, 11.37.
4.1.19 | 5‐Chloro‐2‐methyl‐6‐propyl‐N‐(4‐
(p‐tolyloxy)benzyl)pyrimidin‐4‐amine (9l)
4.1.15 | 5‐Chloro‐N‐(4‐(4‐chlorophenoxy)
benzyl)‐6‐ethyl‐2‐methylpyrimidin‐4‐amine
(9h)
1
Yield, 72%; light yellow oil; H NMR (CDCl3) δ: 1.001 (t,
J = 7.2 Hz, 3H), 1.679‐1.756 (m, 2H), 2.377 (s, 3H),
2.536 (s, 3H), 2.742 (t, J = 7.8 Hz, 2H), 4.667 (d,
J = 5.7 Hz, 2H), 5.608 (br, 1H), 6.924 (d, J = 6.3 Hz,
2H), 6.960 (d, J = 6.6 Hz, 2H), 7.134 (d, J = 8.7 Hz, 2H),
7.290 (d, J = 8.7 Hz, 2H); GC‐MS M+ = 381. Anal. calcd.
for C22H24ClN3O: C, 69.19; H, 6.33; N, 11.00; Found: C,
69.20; H, 6.31; N,11.06.
1
Yield, 79%; light yellow solid; mp: 61.7‐62.1°C; H NMR
(CDCl3) δ: 1.256 (t, J = 7.5 Hz, 3H), 2.510 (s, 3H), 2.724
(q, J = 7.5 Hz, 2H), 4.670 (d, J = 6.0 Hz, 2H), 5.600 (br,
1H), 6.945 (d, J = 6.6 Hz, 2H), 6.975 (d, J = 6.6 Hz, 2H),
7.284 (d, J = 6.9 Hz, 2H), 7.325 (d, J = 6.6 Hz, 2H); GC‐
MS M+ = 387. Anal. calcd. for C20H19Cl2N3O: C, 61.87;
H, 4.93; N, 10.82; Found: C, 61.82; H, 4.90; N,10.79.
4.1.20 | 5‐Chloro‐6‐isopropyl‐2‐methyl‐N‐
(4‐(p‐tolyloxy)benzyl)pyrimidin‐4‐amine
(9m)
4.1.16 | 5‐Chloro‐N‐(4‐(2,4‐
dimethylphenoxy)benzyl)‐6‐ethyl‐2‐
methylpyrimidin‐4‐amine (9i)
1
1
Yield, 73%; light yellow oil; H NMR (CDCl3) δ: 1.275 (d,
Yield, 78%; light yellow solid; mp: 70.8‐71.2°C; H NMR
J = 6.6 Hz, 6H), 2.337 (s, 3H), 2.458 (s, 3H), 3.352‐3.398
(m, 1H), 4.659 (d, J = 5.4 Hz, 2H), 5.525 (br, 1H), 6.916
(d, J = 6.6 Hz, 2H), 6.957 (d, J = 6.6 Hz, 2H), 7.146 (d,
J = 6.6 Hz, 2H), 7.295 (d, J = 6.6 Hz, 2H); GC‐MS
M+ = 381. Anal. calcd. for C22H24ClN3O: C, 69.19; H,
6.33; N, 11.00; Found: C, 69.18; H, 6.31; N, 11.05.
(CDCl3) δ: 1.240 (t, J = 7.5 Hz, 3H), 2.176 (s, 3H), 2.317
(s, 3H), 2.512 (s, 3H), 4.629 (d, J = 6.0 Hz, 2H), 5.580
(br, 1H), 6.809‐6.872 (m, 3H), 6.977 (d, J = 8.1 Hz, 1H),
7.059 (s, 1H), 7.264 (d, J = 6.6 Hz, 2H); GC‐MS
M+ = 381. Anal. calcd. for C22H24ClN3O: C, 69.19; H,
6.33; N, 11.00; Found: C, 69.16; H, 6.30; N,10.96.
4.1.21 | 6‐Butyl‐5‐chloro‐2‐methyl‐N‐(4‐(p‐
tolyloxy)benzyl)pyrimidin‐4‐amine (9n)
4.1.17 | 5‐Chloro‐N‐(4‐(2,3‐
dimethylphenoxy)benzyl)‐6‐ethyl‐2‐
methylpyrimidin‐4‐amine (9j)
1
Yield, 76%; light yellow oil; H NMR (CDCl3) δ: 0.941 (t,
1
Yield, 75%; light yellow solid; mp: 60.0‐60.1°C; H NMR
(CDCl3) δ: 1.242 (t, J = 7.5 Hz, 3H), 2.234 (s, 6H), 2.512
J = 7.5 Hz, 3H), 1.399‐1.474 (m, 2H), 1.596‐1.699 (m,
2H), 2.337 (s, 3H), 2.512 (s, 3H), 2.735 (t, J = 8.1 Hz,

8
LI ET AL.
2H), 4.657 (d, J = 5.7 Hz, 2H), 5.556 (br, 1H), 6.923 (d,
J = 6.6 Hz, 2H), 6.953 (d, J = 6.6 Hz, 2H), 7.143 (d,
J = 8.1 Hz, 2H), 7.296 (d, J = 8.4 Hz, 2H); LC‐MS Pos
[M+1]+ = 396. Anal. calcd. for C23H26ClN3O: C, 69.77;
H, 6.62; N, 10.61; Found: C, 69.78; H, 6.61; N, 11.65.
4.2.2 | Insecticidal activity against
M separata[24]
Ten third‐instar of M separata and five pieces of corn
fragments were placed in a Petri dish and sprayed with
test solutions using a potter sprayer. After air‐drying, kept
in a room for normal cultivation. Mortality was calculated
after 72 hours. Control groups were tested with the sol-
vent only. Tests were run three times, and then results
were averaged. Data were dealt with probit analysis.
4.1.22 | 5‐Chloro‐2‐methyl‐N‐(4‐(p‐
tolyloxy)benzyl)‐6‐(trifluoromethyl)
pyrimidin‐4‐amine (9o)
1
Yield, 76%; light yellow oil; H NMR (CDCl3) δ: 2.344 (s,
4.2.3 | Acaricidal activity against
3H), 2.594 (s, 3H), 4.703 (d, J = 5.7 Hz, 2H), 5.942 (br,
1H), 6.931 (d, J = 6.6 Hz, 2H), 6.972 (d, J = 6.6 Hz, 2H),
7.155 (d, J = 8.7 Hz, 2H), 7.299 (d, J = 6.6 Hz, 2H); GC‐
MS M+ = 407; LC‐MS Pos [M+1]+ = 408. Anal. calcd.
for C20H17ClF3N3O: C, 58.90; H, 4.20; N, 10.30; Found:
C, 58.89; H, 4.21; N, 10.28.
T urticae[27]
Fifty adults of T urticae were transferred to three horse
bean seedlings, and 24 hours later, the horse bean seed-
lings with acarids were dipped in the test solutions for
10 seconds, then allowed to dry with filter papers, trans-
ferred to a beaker (100 mL) containing water (10 mL),
and kept at 25°C. Each assay contained three replications.
Mortality was assessed 72 hours after the treatment. Con-
trol groups were tested with solvent on. Tests were run
three times, and results were averaged. Data were sub-
jected to probit analysis.
4.1.23 | 5‐Chloro‐6‐isobutyl‐2‐methyl‐N‐(4‐
(p‐tolyloxy)benzyl)pyrimidin‐4‐amine (9p)
1
Yield, 75%; light yellow oil; H NMR (CDCl3) δ: 0.977 (d,
J = 6.9 Hz, 6H), 2.048‐2.193 (m, 1H), 2.337 (s, 3H), 2.515
(s, 3H), 2.635 (d, J = 7.5 Hz, 2H), 4.659 (d, J = 5.4 Hz, 2H),
5.565 (br, 1H), 6.924 (d, J = 6.6 Hz, 2H), 6.959 (d,
J = 6.6 Hz, 2H), 7.143 (d, J = 8.7 Hz, 2H), 7.303 (d,
J = 6.6 Hz, 2H); LC‐MS Pos [M+1]+ = 396. Anal. calcd.
for C23H26ClN3O: C, 69.77; H, 6.62; N, 10.61; Found: C,
69.89; H, 6.51; N, 10.28.
ACKNOWLEDGMENTS
This work was financially supported by the National Nat-
ural Science Foundation of China (no. 21572050) and
Hunan University 2011 Collaborative Innovation Center
of New Chemical Technologies for Environmental Benig-
nity and Efficient Resource Utilization, the National Key
Research & Development Pillar Program of China during
the 13th Five‐Year Plan Period (no. 2016YFD0300708).
4.2 | Biological assay
The bioactivities test of the target compounds was con-
ducted according to our previous studies. All insects were
reared in a room, whose conditions were maintained at
25°C, 65( 5)% relative humidity, and 12:12 h light/dark.
Stock solutions of each test compound were prepared in
DMF at a concentration of 1.0 g/L and then diluted to the
required concentration with water containing Tween 80
(0.4 mg/L).
ORCID
Lizhong Li https://orcid.org/0000-0002-0225-4093
Chunge Zhou https://orcid.org/0000-0001-5594-7080
Minhua Liu https://orcid.org/0000-0002-0238-0030
Qianhe Li https://orcid.org/0000-0003-3487-9829
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