Synthesis, crystal structure, and insecticidal activity of (Z)-nitenpyram derivatives with optical activity

Article abstract of DOI:10.1002/jhet.1660

Fourteen novel nitenpyram derivatives (Z)-4-substituted-3-acetyl-6- methylamino -6-[N-(6-chloro-3-pyridinylmethyl)-N-ethyl]amino-5-nitno-2-oxa-5- hexene 4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4j, 4k, 4l, 4m, 4n were synthesized, and their structures were confirmed by ¹H NMR, IR, and elemental analysis. The stereostructure of 4h was determined by the single-crystal X-ray analysis. The preliminary bioassay tests showed that most of the title compounds exhibited good insecticide activities against Nilaparvata lugens as well as Aphis medicaginis at 500 mg/L, whereas compound 4h afforded the best activity, with 100% mortality against A. medicaginis at 100 mg/L.

Full text of DOI:10.1002/jhet.1660

Month 2013
Synthesis, Crystal Structure, and Insecticidal Activity of (Z)-Nitenpyram
Derivatives with Optical Activity
a
a
b
a
a
*
Ying Wu, Chuan-Wen Sun, Wang-Geng Zhang, Jing Wang, and Yan-Xia Chen
aCollege of Life and Environment Sciences, Shanghai Normal University, Shanghai 200234, China
bJiangsu Institute of Ecomones Co., Ltd., JiangsuJintan 213200, China
*
E-mail: sjxue@sohu.com
Received November 27, 2011
DOI 10.1002/jhet.1660
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
Ar
O N
2
COCH
NO
NH
3
2
*
COCH
3
0
O
O
piperidine, 78 C
N
NH
N
+
+
Cl
Ar CHO
EtOH
H C
CH
3
3
Cl
N
N
4a-4n
4d Ar = 4-F-C H
6 4
4a Ar = 2,4-DiCl-C H
4b Ar = 3,4-DiCl-C H
4c Ar = C H
6 5
6
3
6
3
4e Ar = 4-Cl-C H
4f Ar = 4-CN-C H
4g Ar = 4-Br-C H
4h Ar = 3-F-C H
6 4
6
4
6
4
6
4
4i Ar = 4-CH -C H
4j Ar = 4-CF -C H
4n Ar = 4-CH O-C H
3 6 4
4k Ar = 4-NO -C H 4l Ar = 2-CH O-C H
2 6 4 3 6 4
3
6
4
4
3
6
4
4m Ar = 2-F-C H
6
Fourteen novel nitenpyram derivatives (Z)-4-substituted-3-acetyl-6-methylamino ꢀ6-[N-(6-chloro-3-
pyridinylmethyl)-N-ethyl]amino-5-nitno-2-oxa-5-hexene 4a–4n were synthesized, and their structures were
confirmed by 1H NMR, IR, and elemental analysis. The stereostructure of 4h was determined by the single-
crystal X-ray analysis. The preliminary bioassay tests showed that most of the title compounds exhibited
good insecticide activities against Nilaparvata lugens as well as Aphis medicaginis at 500 mg/L, whereas
compound 4h afforded the best activity, with 100% mortality against A. medicaginis at 100 mg/L.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
Lightened by the aforementioned views, in our previous
work [11–13] (Fig. 1), we have focused on designing novel
cis-configuration nitenpyram analogues by forming a
tetrahydropyrimidine ring, and these analogues exhibited
good insecticide activities against Nilaparvata lugens. To
search for more neonicotinoid compounds with novel
structural features and broad insecticidal spectrum, on the
basis of the aforementioned reports, using nitenpyram 1
as the leading compound, we synthesized a series of novel
nitenpyram derivatives 4a–4n possessing a chiral center
adjacent to the aryl group (Ar) by introducing bulky
substituent-fixed (Z)-configuration (Scheme 1). To confirm
the structure with precise three-dimensional information,
the single-crystal structure of compound 4h was deter-
mined by X-ray diffraction (Fig. 2). Compared with the
(E)-configuration of the structure of nitenpyram [14],
compound 4h obviously adopts a (Z)-configuration. The
preliminary insecticidal activity tests indicated that most
of title compounds 4a–4n exhibited good activities against
N. lugens as well as Aphis medicaginis at 500 mg/L.
Recently, neonicotinoid insecticides have gained worldwide
attention for being the fastest growing class of insecticides in
modern crop protection, with widespread use against most of
the sucking and certain chewing pests. Because imidacloprid
[1] was first introduced to the market in 1991, many new
neonicotinoid insecticides are now on the market with their
own prominence. As the second of the chloronicotinyl
subclass, nitenpyram [2], which was brought to the market
in 1995, was characterized with a somewhat lower toxicity
against the mammals than imidacloprid [3]. However, during
the past decades, frequent field applications have inevitably
led to insect resistance to the major class of neonicotinoid
insecticides [4–6]. Besides, the situation of bee pesticide
poisoning had become worse [7]. Hence, the development
of novel neonicotinoids with both good insecticidal activities
and less resistance is highly desirable.
It is well known that the structure optimization of
commercial neonicotinoids is one of the resistance manage-
ment tactics [4,5,8]. The electron-withdrawing group
of -NO2 in neonicotinoids plays an important role in their
activities [9], and according to X-ray analysis and 1H NMR
measurements at ambient temperature, the -NO2 group in all
commercialized neonicotinoids is in (E)-configuration. How-
ever, some neonicotinoid analogues with (Z)-configuration
have been described to possess high insecticidal activity
[8,10], and it was speculated that neonicotinoids in the (Z)-
configuration might bind to the receptor in a different way.
RESULTS AND DISCUSSION
Synthesis of compounds. Target compounds 4a–4n were
prepared in multicomponent reactions, by treating compounds
nitenpyram 1 with acetylacetone 2 and appropriate aromatic
aldehydes 3a–3n in ethanol at 78ꢁC (Scheme 1). In addition,
the products were purified by chromatography on silica gel
by using ethyl acetate: petroleum ether (1:1) as eluent.
© 2013 HeteroCorporation

Y. Wu, C.-W. Sun, W.-G. Zhang, J. Wang, and Y-X. Chen
Vol 000
group from the data in Table 1, for example, 4-NO2 (4k) >
H (4c) > 2-CH3O (4l), 4-CH3O (4n) > 4-CH3 (4i), whereas
disubstituents (e.g., 4a and 4b) on the benzene ring are
unfavorable to activities. Further studies of the insecticidal
activity test at various dosages and structure–activity
relationships are on the way.
NO
NH
2
O N
2
R
N
N
N
N
Cl
N
Cl
N
Nitenpyram
Nitenpyram analogues
X-ray crystal structure of 4h discussion. The molecular
view of 4h with atomic numbering scheme and packing
diagram is shown in Figures 2 and 3.
As expected, the structure of compound 4h adopts a (Z)-
configuration obviously (Fig. 2). Interestingly, because of
the transfer of lone-pair electrons on the amine (N(2), N(3))
to C(9)═C(13), the C(9)-N(3) and C(9)-N(2) bonds (1.412(2)
and 1.341(2) Å) are remarkably shorter than the C-N single
bond (1.50Å) but close to C═N (1.33 Å) [15].
Figure 1. Nitenpyram analogues with tetrahydropyrimidine fixed cis-
configuration in our group. [Color figure can be viewed in the online is-
sue, which is available at wileyonlinelibrary.com.]
Scheme 1. Structures and synthesis of 4a–4n.
In the crystal structure, a five-membered ring (C(14),
H(14), N(3), C(9), and C(13)), a six-membered ring (C(15),
H(15B), O(2), N(4), C(13), and C(14)), and a seven-
membered ring (C(6), H(6A), O(1), N(4), C(13) C(9),
and N(2)) are established by intramolecular hydrogen
bonds of C(14)-H(14)ꢂꢂꢂN(3), C(15)-H(15B)ꢂꢂꢂO(2), and
C(6)-H(6A)ꢂꢂꢂO(1), respectively. Intermolecular hydrogen
bonds are found between adjacent molecules, forming a
three-dimensional interaction network, which may help
stabilize the crystal structure.
Insecticidal activity. Compounds 4a–4n were tested for
insecticidal activities against N. lugens as well as A.
medicaginis at different concentrations. As indicated in
Table 1, compounds 4a–4n exhibited good insecticidal
activities against N. lugens as well as A. medicaginis at
500 mg/L. Among these compounds, 4e, 4f, and 4h had 100%
mortality against A. medicaginis at 500 mg/L, especially
compound 4h, which afforded the best in vitro activity and
had 100% mortality against A. medicaginis at 100 mg/L.
For the effect of monosubstituent at the phenyl group, it
is observed that an electron-withdrawing group showed
better potency compared with that of an electron-donating
EXPERIMENTAL
All chemical reagents and solvents were purchased and used as
1
received without further purification. H NMR spectra (CDCl3)
were recorded on a Bruker AVANCE 400 MHz with TMS as an
internal standard. Elemental analyses were performed with a
Perkin-Elmer 2400 instrument, and melting points were deter-
mined by an RK1 microscopic melting apparatus. IR spectra were
obtained from KBr disks in the range of 4000–400 cmꢀ1 on a
Nicolet 5DX FTIR spectrophotometer.
Figure 2. Molecular structure of compound 4h. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Synthesis, Crystal Structure, and Insecticidal Activity of
(Z)-Nitenpyram Derivatives with Optical Activity
Table 1
Insecticidal activities of target compounds 4a–4n against Nilaparvata lugens as well as Aphis medicaginis.
Mortality (%) at different concentrations (mg/L)
Nilaparvata lugens
Aphis medicaginis
Compound
Ar
500
100
20
40
50
20
nt
50
40
20
40
55
nt
20
10
60
10
100
500
100
20
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
2,4-diCl-C6H3
3,4-diCl-C6H3
C6H5
70
75
75
85
90
85
80
95
70
90
90
75
90
70
100
65
75
65
80
80
70
70
80
65
80
80
70
70
60
100
70
70
80
70
65
70
85
85
80
70
100
60
70
80
50
70
60
100
40
25
nt
4-F-C6H4
95
60
50
65
55
75
50
60
60
30
45
nt
4-Cl-C6H4
4-CN-C6H4
4-Br-C6H4
3-F-C6H4
4-CH3-C6H4
4-CF3-C6H4
4-NO2-C6H4
2-CH3O-C6H4
2-F-C6H4
100
100
90
100
70
95
90
70
80
4m
4n
Nitenpyram
4-CH3O-C6H4
70
100
100
nt, not tested.
The analytical data for compounds 4a–4n were summarized
as follows.
(+)-(5Z)-4-(2,4-Dichlorophenyl)-3-acetyl-6-methylamino-
6-[N-(6-chloro-3-pyridinylmethyl)-N-ethyl]amino-5-nitno-2-
oxa-5-hexene (4a).
Yield: 82%, yellow crystal, mp
25
152–153ꢁC; ½aꢃD + 6.752 (c 1.00, C2H5OH); IR (KBr) n: 2890,
2846, 3384, 1660, 1638, 1325, 1435, 1480, 1480, 950 cmꢀ1
.
1H NMR (CDCl3, 400 MHz) d: 8.42 (d, J= 31.9Hz, 1H), 7.83 (d,
J = 7.0 Hz, 1H), 7.44 (d, J =8.4Hz, 1H), 7.38 (dd, J= 13.4,
7.9 Hz, 2H), 7.22–7.16 (m, 1H), 4.26 (d, J= 14.6 Hz, 1H), 4.17
(d, J= 17.6 Hz, 1H), 3.96 (dd, J= 18.3, 9.9 Hz, 1H), 3.82 (d,
J= 15.1 Hz, 1H), 3.21 (s, 3H), 3.05 (dd, J= 13.3, 6.0 Hz, 1H), 2.79
(d, J= 4.7 Hz, 1H), 2.25 (s, 1H), 2.14 (s, 3H), 1.58 (d, J=7.1Hz,
3H), 1.17 (t, J= 7.2 Hz, 3H); Anal. Calcd for C23H25Cl3N4O4: C,
52.34; H, 4.77; N, 10.61. Found: C, 52.35; H, 4.78; N, 10.62.
(+)-(5Z)-4-(3,4-Dichlorophenyl)-3-acetyl-6-methylamino-6-
[N-(6-chloro-3-pyridinylmethyl)-N-ethyl]amino-5-nitno-2-oxa-5-
25
hexene (4b). Yield: 76%, yellow solid, mp 163–164ꢁC; ½aꢃD
+ 8.772 (c 1.00, C2H5OH); IR (KBr) n: 2968, 2910, 3220, 1660;
1335, 1545, 1500, 1458, 980cmꢀ1. H NMR (CDCl3, 400 MHz)
1
d: 8.40 (d, J = 32.8 Hz, 1H), 7.80 (d, J = 7.0 Hz, 1H), 7.42
(d, J = 8.3 Hz, 1H), 7.38 (dd, J = 13.4, 7.9 Hz, 2H), 7.22–7.16
(m, 1H), 4.23 (d, J = 14.6Hz, 1H), 4.21 (d, J = 17.6 Hz, 1H), 3.96
(dd, J = 18.3, 9.9 Hz, 1H), 3.80 (d, J = 17.1 Hz, 1H), 3.21 (s, 3H),
3.05 (dd, J = 13.7, 6.0 Hz, 1H), 2.77 (d, J = 4.7 Hz, 1H), 2.25
(s, 1H), 2.12 (s, 3H), 1.58 (d, J =7.1 Hz, 3H), 1.22 (t, J = 7.2 Hz,
3H); Anal. Calcd for C23H25Cl3N4O4: C, 52.34; H, 4.77; N,
10.61. Found: C, 52.34; H, 4.76; N, 10.63.
Figure 3. Packing diagram of compound 4h. [Color figure can be viewed
in the online issue, which is available at wileyonlinelibrary.com.]
General synthetic procedure for synthesis of 4a–4n.
A
mixture of nitenpyram 1 (10 mmol), acetylacetone 2 (15 mmol),
appropriate aromatic aldehydes 3a–3n (15 mmol), and piperidine
(catalytic amount) in ethanol (30 mL) was heated to 78ꢁC and
stirred for 6 h at the same temperature. The reaction mixture was
concentrated under reduced pressure and treated with 20mL of
water. Then, the solution was extracted three times with ethyl
acetate, and the combined extracts were dried over Na2SO4. The
organic phase was evaporated under reduced pressure, and crude
product was subjected to flash chromatography on silica gel,
eluting with ethyl acetate/petroleum ether to afford pure products.
(+)-(5Z)-4-(1-Phenyl)-3-acetyl-6-methylamino-6-[N-(6-
chloro-3-pyridinylmethyl)-N-ethyl]amino-5-nitno-2-oxa-5-
25
hexene (4c).
Yield: 79%, yellow solid, mp 132–134ꢁC; ½aꢃD
+ 10.961 (c 1.00, C2H5OH); IR (KBr) n: 2928, 2890, 3500, 1680,
1652, 1380, 1530, 1400, 1458, 980 cmꢀ1 1H NMR (CDCl3,
.
400 MHz) d: 8.45 (d, J= 2.1 Hz, 1H), 7.83 (dd, J=8.2, 2.5Hz, 1H),
7.41 (d, J= 8.2 Hz, 1H), 7.16 (dd, J= 18.4, 8.3 Hz, 5H), 4.24
(d, J= 14.7 Hz, 1H), 4.11 (d, J= 7.4 Hz, 1H), 3.97 (dd, J=10.9,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Y. Wu, C.-W. Sun, W.-G. Zhang, J. Wang, and Y-X. Chen
Vol 000
4.0 Hz, 1H), 3.78 (d, J= 14.6 Hz, 1H), 3.29 (s, 3H), 3.06 (dd, J= 14.3,
7.2 Hz, 1H), 2.89 (d, J= 5.9 Hz, 1H), 2.26 (s, 1H), 2.12 (s, 3H), 1.62 (s,
3H), 1.15 (t, J= 7.2 Hz, 3H); Anal. Calcd for C23H27ClN4O4: C, 60.19;
H, 5.93; N, 12.21. Found: C, 60.18; H, 5.94; N, 12.20.
7.2 Hz, 1H), 2.89 (d, J= 3.9 Hz, 1H), 2.26 (s, 1H), 2.13 (s, 3H),
1.67 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H); Anal. Calcd for
C23H26ClFN4O4: C, 57.92; H, 5.49; N, 11.75. Found: C, 57.94;
H, 5.50; N, 11.73.
(+)-(5Z)-4-(4-Fluorophenyl)-3-acetyl-6-methylamino-6-
[N-(6-chloro-3-pyridinylmethyl)-N-ethyl]amino-5-nitno-2-
oxa-5-hexene (4d). Yield: 79%, yellow solid, mp 114–116ꢁC;
(+)-(5Z)-4-(4-Methylphenyl)-3-acetyl-6-methylamino-6-[N-
(6-chloro-3-pyridinylmethyl)-N-ethyl]amino-5-nitno-2-oxa-5-
25
hexene (4i).
Yield: 75%, yellow solid, mp 122–123ꢁC; ½aꢃD
25
½aꢃD + 4.877 (c 1.00, C2H5OH); IR (KBr) n: 2938, 2856, 3228,
+ 21.627 (c 1.00, C2H5OH); IR (KBr) n: 2962, 2682, 3390, 1710,
1660, 1638, 1342, 1545, 1490, 1480, 950 cmꢀ1 1H NMR
.
1658, 1378, 1465, 1540, 1454, 1136 cmꢀ1 1H NMR (CDCl3,
.
(CDCl3, 400 MHz) d: 8.46 (d, J = 1.8 Hz, 1H), 8.33 (d, J = 1.7 Hz,
1H), 7.83 (dd, J = 8.2, 2.3 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.30–
7.27 (m, 1H), 7.01–6.94 (m, 2H), 4.27 (d, J = 14.7 Hz, 1H), 4.12
(dd, J = 18.6, 10.8 Hz,1H), 3.98 (dd, J = 10.9, 3.9 Hz, 1H), 3.78
(d, J = 14.7Hz, 1H), 3.32 (s, 3H), 3.09 (dd, J = 14.3, 7.1 Hz, 1H),
2.88–2.84 (m, 1H), 2.26 (s, 1H), 2.12 (s, 3H), 1.65 (s, 3H), 1.16
(t, J = 7.2 Hz, 3H); Anal. Calcd for C23H26ClFN4O4: C, 57.92; H,
5.49; N, 11.75. Found: C, 57.91; H, 5.50; N, 11.76.
400 MHz) d: 8.44 (d, J = 1.8 Hz,1H), 7.82 (dd, J= 8.2, 2.4 Hz, 1H),
7.40 (d, J= 8.2 Hz, 1H), 7.11 (dd, J = 25.9, 7.7 Hz, 2H), 7.08
(d, J= 7.4Hz, 2H), 4.23 (d, J= 14.7 Hz, 1H), 4.11 (d, J=7.1 Hz,
1H), 3.96 (dd, J= 10.8, 4.1 Hz, 1H), 3.77 (d, J= 14.7 Hz, 1H), 3.28
(s, 3H), 3.06 (dd, J= 14.2, 7.3 Hz, 1H), 2.86 (d, J= 4.3 Hz,1H),
2.29 (s, 3H), 2.23 (s, 1H), 2.11 (s, 3H), 1.63 (s, 3H), 1.14
(t, J = 7.1 Hz, 3H); Anal. Calcd for C24H29ClN4O4: C, 60.95; H,
6.18; N, 11.85. Found: C, 60.92; H, 6.19; N, 11.84.
(+)-(5Z)-4-(4-Chlorophenyl)-3-acetyl-6-methylamino-6-[N-
(+)-(5Z)-4-(4-Trifluorophenyl)-3-acetyl-6-methylamino-6-
(6-chloro-3-pyridinylmethyl)-N-ethyl]amino-5-nitno-2-oxa-5-
[N-(6-chloro-3-pyridinylmethyl)-N-ethyl]amino-5-nitno-2-
25
hexene (4e). Yield: 88%, yellow crystal, mp 152–153ꢁC; ½aꢃD
oxa-5-hexene (4j).
Yield: 77%, yellow solid, mp 180–181ꢁC;
+ 15.426 (c 1.00, C2H5OH); IR (KBr) n: 2890, 2846, 3384, 1660,
25
½aꢃD + 5.695 (c 1.00, C2H5OH); IR (KBr) n: 2892, 2882, 3295,
1728, 1658, 1378, 1465, 1470, 1394, 1236 cmꢀ1. 1H NMR (CDCl3,
400 MHz) d: 8.47 (d, J=1.3Hz, 1H), 7.83 (dd, J= 8.2, 2.4 Hz, 1H),
7.55 (d, J= 8.1 Hz, 2H), 7.42 (d, J= 8.2 Hz, 2H), 7.34 (d,
J= 8.2 Hz, 1H), 4.28 (d, J= 14.7 Hz, 1H), 4.17–4.10 (m, 1H), 4.05
(dd, J= 10.6, 3.5 Hz, 1H), 3.77 (d, J= 15.3 Hz, 1H), 3.33 (s, 3H),
3.10 (dd, J= 14.0, 6.8 Hz, 1H), 2.91–2.85 (m, 1H), 2.25 (s, 1H), 2.13
(s, 3H), 1.64 (s, 3H), 1.22–1.16 (m, 3H); Anal. Calcd for
C24H26ClF3N4O4: C, 54.70; H, 4.97; N, 10.63. Found: C, 54.69; H,
4.98; N, 10.64.
1638, 1325, 1435, 1480, 1480, 950 cmꢀ1 1H NMR (CDCl3,
.
400 MHz) d: 8.45 (s, 2H), 7.82 (d, J = 7.0Hz, 1H), 7.40
(d, J = 8.1 Hz, 1H), 7.23 (s, 4H), 4.26 (d, J = 14.6 Hz, 1H), 4.09
(dd, J = 18.8, 11.4 Hz, 1H), 3.95 (dd, J = 10.8, 3.5 Hz, 1H), 3.76
(d, J = 14.7Hz, 1H), 3.30 (s, 3H), 3.08 (dt, J = 14.6, 8.0 Hz, 1H),
2.85 (d, J= 4.3 Hz,1H), 2.25 (s, 1H), 2.11 (s, 3H), 1.65 (s, 3H),
1.15 (t, J= 7.1 Hz, 3H); Anal. Calcd for C23H26Cl2N2O4: C, 59.36;
H, 5.63; N, 6.02. Found: C, 59.38; H, 5.61; N, 6.03.
(+)-(5Z)-4-(4-Cyanophenyl)-3-acetyl-6-methylamino-6-[N-
(6-chloro-3-pyridinylmethyl)-N-ethyl]amino-5-nitno-2-oxa-
25
5-hexene (4f). Yield: 84%, yellow solid, mp 175–176ꢁC;½aꢃD
+
(+)-(5Z)-4-(4-Nitrophenyl)-3-acetyl-6-methylamino-6-[N-
(6-chloro-3-pyridinylmethyl)-N-ethyl]amino-5-nitno-2-oxa-
18.973 (c 1.00, C2H5OH); IR (KBr) n: 2898, 2886, 3320, 1680,
25
5-hexene (4k). Yield: 68%, yellow solid, mp 178–180ꢁC; ½aꢃD
1668, 1355, 1460, 1480, 1284, 972 cmꢀ1 1H NMR (CDCl3,
.
+ 11.574 (c 1.00, C2H5OH); IR (KBr) n: 2991, 2798, 3328, 1756,
400 MHz) d: 8.47 (s, 1H), 7.81 (d, J = 7.0Hz, 1H), 7.43
(d, J = 7.5 Hz,4H), 7.33 (d, J = 7.9 Hz, 1H), 4.29 (d, J = 15.1Hz,
2H), 4.02 (d, J = 11.1Hz, 1H), 3.77 (d, J = 14.6Hz, 1H), 3.33
(s, 3H), 3.11 (dd, J = 12.9, 8.6 Hz, 1H), 2.89 (d, J = 7.9 Hz, 1H),
2.25 (s, 1H), 2.13 (s, 3H), 1.65 (s, 3H), 1.17 (d, J = 7.2Hz, 3H);
Anal. Calcd for C24H26ClN5O4: C, 59.56; H, 5.42; N, 14.47.
Found: C, 59.55; H, 5.44; N, 14.46.
1598, 1365, 1585, 1570, 1394, 1236 cmꢀ1 1H NMR (CDCl3,
.
400 MHz) d: 8.40 (d, J= 52.9 Hz, 1H), 8.19–8.09 (m, 2H), 7.82
(d, J= 8.2 Hz,1H), 7.49 (d, J= 8.3 Hz, 2H), 7.42 (d, J= 8.1 Hz, 1H),
4.31 (d, J= 14.9 Hz, 1H), 4.16 (d, J= 12.9 Hz, 1H), 4.10 (s, 1H),
3.78 (d, J= 14.6 Hz, 1H), 3.34 (s, 3H), 3.12 (dd, J= 14.3,
7.0 Hz, 1H), 2.90 (d, J= 5.4 Hz, 1H), 2.26 (s, 1H), 2.14 (s, 3H),
1.66 (s, 3H), 1.18 (t, J= 7.2 Hz, 3H); Anal. Calcd for
C23H26ClN5O6: C, 54.82; H, 5.20; N, 13.93. Found: C, 54.81; H,
5.22; N, 13.94.
(+)-(5Z)-4-(4-Bromophenyl)-3-acetyl-6-methylamino-6-[N-
(6-chloro-3-pyridinylmethyl)-N-ethyl]amino-5-nitno-2-oxa-
25
5-hexene (4g).
Yield: 78%, yellow solid, mp 159–161ꢁC; ½aꢃD
(+)-(5Z)-4-(2-Methoxylphenyl)-3-acetyl-6-methylamino-6-
[N-(6-chloro-3-pyridinylmethyl)-N-ethyl]amino-5-nitno-2-oxa-5-
+ 14.158 (c 1.00, C2H5OH); IR (KBr) n: 2968, 2686, 3480, 1690,
1598, 1390, 1485, 1370, 1484, 1026 cmꢀ1 1H NMR (CDCl3,
.
25
hexene (4l). Yield: 82%, yellow solid, mp 112–113ꢁC; ½aꢃD
400 MHz) d: 8.45 (d, J= 1.7 Hz, 1H), 7.82 (dd, J= 8.2, 2.3 Hz, 1H),
7.42 (s, 1H), 7.39 (d, J= 5.4 Hz, 2H), 7.17 (d, J= 8.4 Hz, 2H), 4.26
(d, J= 14.7 Hz, 1H), 4.12 (d, J= 10.6 Hz, 1H), 3.94 (dd, J= 10.8,
3.8 Hz, 1H), 3.76 (d, J= 14.6 Hz, 1H), 3.30 (s, 3H), 3.13–3.04 (m,
1H), 2.80 (d, J= 4.1 Hz, 1H), 2.11 (s, 3H), 2.25 (s, 1H), 1.66 (s, 3H),
1.16 (t, J = 7.1 Hz, 3H); Anal. Calcd for C23H26BrClN4O4: C,
51.36; H, 4.87; N, 10.42. Found: C, 51.34; H, 4.88; N, 10.43.
(+)-(5Z)-4-(3-Fluorophenyl)-3-acetyl-6-methylamino-6-[N-
(6-chloro-3-pyridinylmethyl)-N-ethyl]amino-5-nitno-2-oxa-
+ 19.674 (c 1.00, C2H5OH); IR (KBr) n: 2987, 2795, 3187,
1739, 1468, 1348, 1565, 1580, 1420, 1310cmꢀ1 1H NMR
.
(CDCl3, 400MHz) d: 8.43 (d, J = 1.9 Hz, 1H), 7.82 (dd, J = 8.1,
2.2 Hz, 1H), 7.44 (dd, J = 7.6, 1.1 Hz, 1H), 7.40 (d, J = 8.2 Hz,
1H), 7.24–7.17 (m, 2H), 6.83 (d, J = 8.2 Hz, 1H), 4.21
(d, J = 14.7 Hz, 1H), 4.11 (d, J = 7.1 Hz, 1H), 3.96 (dd, J = 18.3,
10.8Hz, 1H), 3.82 (d, J = 11.8Hz, 1H), 3.75 (s, 3H), 3.20 (s, 3H),
3.02 (dd, J = 14.2, 7.2 Hz, 1H), 2.82 (d, J = 4.6 Hz, 1H), 2.26
(s, 1H),2.12 (s, 3H), 1.53 (s, 4H), 1.13 (t, J = 7.1 Hz, 3H); Anal.
Calcd for C24H29ClN4O5: C, 58.95; H, 5.98; N, 11.47. Found: C,
58.97; H, 5.97; N, 11.49.
25
5-hexene (4h). Yield: 80%, yellow crystal, mp 130–131ꢁC; ½aꢃD
+ 17.841 (c 1.00, C2H5OH); IR (KBr) n: 2945, 2785, 3320, 1710, 1658,
1378, 1465, 1390, 1324, 1238 cmꢀ1. 1H NMR (CDCl3, 400 MHz) d:
8.47 (d, J= 1.9 Hz, 1H), 7.83 (dd, J= 8.2, 2.4 Hz,1H), 7.42
(d, J= 8.2 Hz, 1H), 7.12 (d, J= 10.2 Hz, 1H), 7.01–6.91 (m, 3H),
4.27 (d, J= 14.7 Hz, 1H), 4.12 (d, J= 7.7 Hz,1H), 4.00 (dd, J= 10.8,
3.8 Hz, 1H), 3.78 (d, J= 14.8 Hz, 1H), 3.31 (s, 3H), 3.09 (dd, J= 14.4,
(+)-(5Z)-4-(2-Fluorophenyl)-3-acetyl-6-methylamino-6-[N-
(6-chloro-3-pyridinylmethyl)-N-ethyl]amino-5-nitno-2-oxa-
5-hexene (4m).
½aꢃD + 3.241 (c 1.00, C2H5OH); IR (KBr) n: 2968, 2686, 3480,
Yield: 80%, yellow solid, mp 134–135ꢁC;
25
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Synthesis, Crystal Structure, and Insecticidal Activity of
(Z)-Nitenpyram Derivatives with Optical Activity
1690, 1598, 1390, 1485, 1370, 1484, 1026 cmꢀ1 1H NMR
.
Table 2
(CDCl3, 400 MHz) d: 8.45 (d, J= 2.0 Hz, 1H), 7.83 (dd, J=8.2,
2.4 Hz, 1H), 7.41 (d, J= 8.2 Hz, 1H), 7.17–7.10 (m, 4H), 4.23
(d, J= 14.7 Hz, 1H), 4.11 (d, J= 7.4 Hz, 1H), 3.97 (dd,
J= 10.9,4.1 Hz, 1H), 3.77 (d, J= 14.7 Hz, 1H), 3.29 (s, 3H), 3.06
(dd, J= 14.3, 7.3 Hz, 1H), 2.88 (d, J= 4.5 Hz, 1H), 2.26 (s, 1H),
2.12 (s, 3H), 1.62 (s, 3H), 1.15 (t, J= 7.2 Hz, 3H); Anal. Calcd for
C23H26ClFN4O4: C, 57.92; H, 5.49; N, 11.75. Found: C, 57.94; H,
5.50; N, 11.76.
Crystal data and structure refinement parameters for C23H26ClFN4O4 (4h).
4h
Empirical formula
Formula weight
C23H26ClFN4O4
476.93
Temperature (K)
Wavelength (Å)
Crystal system, space group
a, b, c (Å)
298 (2)
0.71073
Triclinic, P-1
7.9732 (8), 12.2451 (12),
12.9624 (13)
94.231, 97.266, 107.781
1186.9 (2)
(+)-(5Z)-4-(4-Methoxylphenyl)-3-acetyl-6-methylamino-6-
[N-(6-chloro-3-pyridinylmethyl)-N-ethyl]amino-5-nitno-2-oxa-5-
25
hexene (4n). Yield: 88%, yellow solid, mp 129–130ꢁC; ½aꢃD
a, b, g (ꢁ)
Volume (Å3)
+ 21.135 (c 1.00, C2H5OH); IR (KBr) n: 2980, 2789, 3167, 1730,
1458, 1340, 1560, 1600, 1470, 1330 cmꢀ1
.
1H NMR (CDCl3,
Z
2
Density (calcd) (Mg/m3)
Absorption coefficient (mmꢀ1
F(000)
1.334
0.205
500
400MHz) d: 8.45 (d, J = 2.2 Hz, 1H), 7.83 (dd, J = 8.2, 2.5 Hz,
1H), 7.41 (d, J = 8.2Hz, 1H), 7.20 (d, J = 8.7 Hz, 2H), 6.81 (dd,
J = 8.9, 2.6 Hz, 2H), 4.24 (d, J = 14.7 Hz, 1H), 4.10 (d, J = 7.5 Hz,
1H), 3.94 (dd, J = 10.9, 4.1Hz, 1H), 3.78–3.75 (m, 4H), 3.30 (s,
3H), 3.07 (dd, J = 14.3, 7.1Hz, 1H), 2.85 (d, J = 4.4 Hz, 1H), 2.26
(s, 1H), 2.11 (s, 3H), 1.65 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H); Anal.
Calcd for C24H29ClN4O5: C, 58.95; H, 5.98; N, 11.46. Found: C,
58.97; H, 5.97; N, 11.47.
)
Crystal size (mm3)
Index ranges
0.20 ꢅ 0.10 ꢅ 0.10
ꢀ9 ≤ h ≤ 9, ꢀ14 ≤ k ≤ 14,
ꢀ15 ≤ l ≤ 15
12094/4416 [R(int) = 0.0351]
Full-matrix least squares
on F2
Flections collected/unigue
Refinement method
Insecticidal activity assay.
The insecticidal activities of
Completeness to theta (%)
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices
99.7
4416/2/312
1.111
compounds 4a–4n were measured against A. medicaginis
according to the standard test [16] with a slight modification. The
test analogues were dissolved in DMF and serially diluted with
water containing Triton X-80 (0.1 mg/L) to obtain the required
concentrations. The insects were reared at 25ꢁ(ꢄ1)ꢁC, and groups
of 10 were transferred to glass Petri dishes and sprayed with the
aforementioned solutions by using a Potter sprayer. Assessments
were made after 72 h by the number and size of live insects
relative to that in the negative control, and evaluations are
based on a percentage scale of 0–100, in which 100 the total kill
and 0 no activity. The mortality rates were subjected to probit
analysis. The reference compounds were nitenpyram, whereas
water containing Triton X-80 (0.1mg/L) was used as a negative
control. All experiments were carried out in three replicates
according to statistical requirements, and the results were shown
in Table 1.
R1 = 0.0549, wR2 = 0.1603
[I > 2sigma(I)]
R indices (all data)
R1 = 0.0689, wR2 = 0.1698
0.458 and ꢀ0.428
Largest diff peak and hole (Åꢀ3
)
CONCLUSION
In summary, a novel series of optical active (Z)-nitenpyram
derivatives 4a–4n possessing a chiral center adjacent to the
aryl group (Ar) by introducing bulky group into nitenpyram
was synthesized, and the (Z)-configuration was confirmed
by X-ray diffraction. The structures of title compounds were
characterized by IR, 1H NMR, and elementary analysis. Bio-
assay against N. lugens and A. medicaginis at 500 mg/L shows
that compounds 4a–4h exhibit good insecticide activities, es-
pecially compound 4h, which afforded the best activity, with
100% mortality against Aphis medicaginis at 100 mg/L.
X-ray crystallography.
The yellow crystal of compound
4h having approximate dimensions of 0.20 ꢅ 0.10 ꢅ 0.10 mm3
was mounted on a glass fiber in a random orientation. The
data were collected by
a
Bruker Smart Apex CCD
diffractometer with a graphite-monochromated MoKa radiation
(l = 0.71073 Å) by using a j–o scan mode in the range of
2.23ꢁ ≤ θ ≤ 24.75ꢁ at 298(2) K. Empirical absorption correction
was applied. A total of 12,094 reflections including 4416 unique
ones [R(int) = 0.0351] were measured. The intensity data were
corrected for Lp factors and empirical absorption. The structure
was solved by direct methods and expanded by using Fourier
difference techniques with SHELXS-97 [17] program package.
All the nonhydrogen atoms were refined anisotropically,
and hydrogen atoms were located at their idealized positions.
The final R = 0.0549, wR = 0.1603 (w = 1/[s2(Fo2) + (0.0964P)2 +
0.0770P], where P = (Fo2 + 2Fc2)/3), S = 1.111, (Δ/s)max=
0.000, (Δr)max = 0.458, and (Δr)min = ꢀ0.428 e/Å3. The structural
plots were drawn with SHELXTL-97 software package. The
details of the data collection and refinement parameters are
given in Table 2. Other details of the structure have been
deposited with the Cambridge Crystallographic Data Centre No.
CCDC 835027.
Acknowledgments. This work was supported by the National
Natural Science Foundation of China (21042010, 21102092,
and 30870560), the Key Scientific “Twelfth Five-Year”
National Technology Support Program (2011BAE06B01-17), the
Key Project of Science and Technology Commission of Shanghai
(09391912100 and 105405503400), the Leading Academic
Discipline Project of Shanghai Normal University (DZL808), and
the Shanghai Key Laboratory of Rare Earth Functional Materials,
Shanghai Normal University (07dz22303). We are also grateful for
the support from the Branch of National Pesticide R&D South Center.
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