The exploration of chiral N-cyano sulfiliminyl dicarboxamides on insecticidal activities

Article abstract of DOI:10.1016/j.cclet.2017.02.021

Due to new mechanism of action and ecofriendly characteristics, dicarboxamide insecticides have attracted more and more attentions in modern pest management. A series of 20 dual chiral N-cyano sulfilimines containing two centers (carbon and sulfur) were designed and synthesized. All title compounds were determined by ¹H NMR, high-resolution mass spectrometry (HRMS) and optical polarimeter. The preliminary results indicated that some of them exhibited favourable insecticidal activities against oriental armyworm (Pseudaletia separata Walker). These isomers exhibited different impact on activity following the sequence as (Sc, Ss)?≥?(Sc, Rs), and the rule of title compounds’ activity against oriental armyworm was 3-CF₃?≥?2–CH₃–4–Cl >2, 3, 4-trifluro in the anilide moiety. The results indicated that these groups such as 3-CF₃, 2–CH₃–4–Cl or 2, 3, 4-trifluro were inefficient to replace heptafluoroisopropyl group for high larvicidal activity, which provided some guidance for the further modifications of sulfiliminyl dicarboxamides.

Full text of DOI:10.1016/j.cclet.2017.02.021

Accepted Manuscript
Title: The exploration of chiral N-cyano sulfiliminyl
dicarboxamides on insecticidal activities
Authors: Sha Zhou, Shaa Zhou, Yong-Tao Xie, Ru-Yi Jin,
Xiang-De Meng, Dong-Kai Zhang, Xue-Wen Hua, Ming Liu,
Chang-Chun Wu, Li-Xia Xiong, Yu Zhao, Zheng-Ming Li
PII:
S1001-8417(17)30078-5
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2017.02.021
CCLET 3994
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
10-11-2016
23-12-2016
28-2-2017
Please cite this article as: Sha Zhou, Shaa Zhou, Yong-Tao Xie, Ru-Yi Jin,
Xiang-De Meng, Dong-Kai Zhang, Xue-Wen Hua, Ming Liu, Chang-Chun Wu,
Li-Xia Xiong, Yu Zhao, Zheng-Ming Li, The exploration of chiral N-cyano
sulfiliminyl dicarboxamides on insecticidal activities, Chinese Chemical Letters
http://dx.doi.org/10.1016/j.cclet.2017.02.021
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Original article
The exploration of chiral N-cyano sulfiliminyl dicarboxamides on insecticidal
activities
Sha Zhoua,*, Shaa Zhou†a, Yong-Tao Xie†a, Ru-Yi Jinb, Xiang-De Menga, Dong-Kai Zhanga, Xue-Wen Huaa,
Ming Liua, Chang-Chun Wua, Li-Xia Xionga, Yu Zhaoa, Zheng-Ming Lia,*
a National Pesticidal Engineering Centre (Tianjin), State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical
Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China
b Shenzhen Neptunus Bioengineering Co. Ltd, Shenzhen 518057, China
 Corresponding authors.
E-mail addresses: zhousha@nankai.edu.cn (S. Zhou), nkzml@vip.163.com (Z.-M. Li)
†These authors contributed equally to this work.
Graphical Abstract
The results indicated that these groups such as 3-CF3, 2-CH3-4-Cl or 2, 3, 4-trifluro were inefficient to replace
heptafluoroisopropyl group for high larvicidal activity, which provided some guidance for the further modifications of
sulfiliminyl dicarboxamides.
ABSTRACT
Due to new mechanism of action and ecofriendly characteristics, dicarboxamide insecticides have attracted more and more attentions in modern pest
management. A series of 20 dual chiral N-cyano sulfilimines containing two centers (carbon and sulfur) were designed and synthesized. All title compounds
were determined by 1H NMR, high-resolution mass spectrometry (HRMS) and optical polarimeter. The preliminary results indicated that some of them
exhibited favourable insecticidal activities against oriental armyworm (Pseudaletia separata Walker). These isomers exhibited different impact on activity
following the sequence as (Sc, Ss) ≥ (Sc, Rs), and the rule of title compounds’ activity against oriental armyworm was 3-CF3 ≥ 2-CH3-4-Cl > 2, 3, 4-trifluro in
the anilide moiety. The results indicated that these groups such as 3-CF3，2-CH3-4-Cl or 2, 3, 4-trifluro were inefficient to replace heptafluoroisopropyl group
for high larvicidal activity, which provided some guidance for the further modifications of sulfiliminyl dicarboxamides.
Keywords:
Dual chiral
Sulfilimines
Insecticidal activity
Ryanodine receptor
Dicarboxamides
1. Introduction
With the modern agro-chemical means for pest control, crop production has made considerable progress. During the last century, a
large number of insecticides including the organochlorines, organophosphates, carbamates, pyrethroids and neonicotinoids have been
introduced to the market. However, some of these chemicals have brought undesired environmental and health problems [1]. Persistent

application of the insecticides with the same mode of action induced insecticide resistance has become a problem. Therefore, it is
necessary to discover new insecticides with novel mechanisms of action [2]. As an ideal biological target for insecticide research,
ryanodine receptor (RyR) has aroused considerable interests in integrated strategies for the development of agro-chemistry. Recently,
the first commercial RyR insecticide, flubendiamide [3-4] (Fig. 1), was developed by Nihon Nohyaku jointly with Bayer and was
brought to the market in 2007 [5-6]. In particular, flubendiamide [7-8] has been developed as a highly potent insecticide against
lepidopteran insects [9-10].
In our previous work [11-12], dual chiral scaffolds containing sulfiliminyl substituents and their larvacidal activities were reported.
For oriental armyworm, some compounds reached the same high level as flubendiamide, with LC50 values 0.0504 (B) and 0.0699 (C)
mg/L, lower than that of flubendiamide (0.1230 mg/L) [13]. Other sulfilimine derivatives exhibited higher activity against
diamondback moths than flubendiamide [14]. The previous results implied that the introduction of the dual chiral N-cyano sulfiliminyl
substituent was favorable for the larvacidal activity. The results prompted us to explore the further structural modifications. It is well-
known that heptafluoroisopropyl iodide is an expensive material for the synthesis of flubendiamide. To reduce production costs, it is
necessary to identify cheaper replacement of heptafluoroisopropyl iodide. What is more, the new structure also maintains excellent
insecticidal activity after the replacement of heptafluoroisopropyl group.
Enlightened by the above research, 20 novel dual chiral N-cyano sulfiliminyl phthalamide derivatives with these groups including 3-
CF3, 2-CH3-4-Cl or 2, 3, 4-trifluro in the anilide moiety were designed and synthesized. All title compounds were determined by 1H
NMR, high-resolution mass spectrometry and optical polarimeter. The preliminary structure-activity relationship (SAR) was discussed
as well.
2. Results and discussion
2.1 Synthesis
N-cyano sulfilimines can be easily obtained by sulfides in 95% ~ 99% yield with the ratio of diastereoselectivity 6:4. The synthetic
method of these title compounds were shown in Scheme 1.
1
1
The title compounds have been determined by melting point, H NMR, HRMS and optical polarimeter. The H NMR data of N-
cyano sulfilimines were characteristic between two diastereoisomers. The active proton signals of –NHCO- in the anilide moiety were
observed at 9.83-10.88 ppm in DMSO-d6. However, the chemical shifts of the active proton signals on the amide bridge in the aliphatic
amide moiety were at δ 8.76-9.02 and δ 8.58-8.87 ppm in DMSO-d6, respectively.
2.2 Crystal structure analysis
The crystal structure of If had been shown in the literature previously reported [13]. The crystal structure (0.20 mm x 0.18 mm x
0.12 mm) of compound Ih was cultivated from the solvent DMSO, which was selected and mounted on Rigaku Saturn 724 CCD
diffractometer equipped with a graphite-monochromatic MoKá radiation (ë = 0.71073 Å). The data were collected at 293(2) K to a
maximum θ value of 25.02 with the following index ranges: –4 ≤ h ≤ 5, –26 ≤ k ≤ 26 and –27 ≤ l ≤ 27. A total of 21057 integrated
reflections were collected and 4473 with Rint = 0.0638 were independent, of which 3581 with I > 2ó (I) were observed. The structure
was resolved by direct methods with the SHELXL-97 program [14]. Refinements were done by the full-matrix least-squares on F2 with
SHELXL-97. The crystal is of orthorhombic system with P2(1)2(1)2(1) space group. X-ray single crystal diffraction was shown in Fig.
2 with the following crystallographic parameters: a = 4.8338(10) Å, b = 22.320 (5) Å, c = 23.512(5) Å, α = 90 °, β = 90 °, γ = 90°, V =
2536.8(9) Å3, Z = 4, Dc =1.414 mg/m3, µ = 0.358 mm-1, F (000) = 1128, R = 0.0797, wR = 0.1802, final R factor = 6.29%, final wR
factor = 16.27%, absolute structure parameter = 0.06 (11). All the bond length and bond angle were in normal range, the N(5)-C(20)
bond length of 1.172Å is intermediate between C=N(1.34-1.38 Å) and C≡N(1.14-1.16Å) may be due to the conjugation effect of
S(1)=N(4). The torsion angles of S(1)-N(4)-C(20)-N(5) is 172.6 °, which indicates that the S(1)=N(4) and N(5)≡C(20) are not coplanar
in the molecular structure.
2.3 Structure-activity relationship (SAR)
2.3.1 Larvicidal activity against oriental armyworm.
The larvicidal activities of compounds 5f-5j, Ia-Ij, IIa-IIj and flubendiamide against oriental armyworm were shown in Table 1
and Table 2. Most title compounds showed moderate larvicidal activity against oriental armyworm. In general, the sequence of these
isomers’ activity is (Sc, Ss) ≥ (Sc, Rs), which is consistent with SARs described in our previous report ((Sc, Ss) ≥ (Sc, Rs) >> (Rc, Ss)
> (Rc, Rs)) [13]. As shown in Table 1, IIk (Sc, Ss) exhibited 50% insecticidal activity at 10 mg/L, while Ik (Sc, Rs) gave a mortality
rate of 30% at 50 mg/L. At concentration of 50 mg/L, IIq (Sc, Ss) (100%) possessed better insecticidal activity than Iq (Rc, Rs) (0%).
These observations indicated that the influence of sulfur chirality on biological activities is self-evident.
From Table 1, we could find that compounds 5g, IIa and IIg exhibited 100%, 80% and 60% activities at 25 mg/L, respectively. It
was worth noting that 5g gave the mortality of 40% at 5 mg/L. Furthermore, the iodine substituents (5g, IIa and IIg) showed the best
larvicidal activity. For compounds with CF3 group in the anilide moiety, I showed the best activity, Br as well as Cl, and F substituent
possessed similar biological activity against oriental armyworm. As shown in Table 1, these title compounds exerted the sequence of
biological activity as 3-CF3 ≥ 2-CH3-4-Cl > 2, 3, 4-trifluro in the anilide moiety. From Table 2, it was found that the LC50 value of IIa
was 12.8448 mg/L, higher than that of Flubendiamide (0.1230 mg/L).

2.3.2 CoMFA analysis by SYBYL
With the purpose of increasing the calculated sample, the published compounds (Ia, Ib, IIa, IIb, IId) [13] and the novel compounds
Ia, Ig, Ij, IIa, IIg, IIj were selected for 3D-QSAR model. The above compounds were prepared with SYBYL program, the
conformations with minimum energy were evaluated by Tripos force field and Gasteiger-Hükel charges in advance. The most active
molecule published Ia was used as a template to align the training samples by align database, the common skeleton was overlapped
very well. The pIC50 was the activity data, and the negative logarithms of LC50 data were shown in Table 2. Then the 3D-QSAR model
CoMFA was developed successfully. The Fig. 3 showed the CoMFA steric and electrostatic contour map. Partial least-squares analysis
gives a satisfactory R2 value of 0.952 and Q2 value of 0.867 with 2 components, which indicates a valid and stable CoMFA model.
The left of the Fig. 3 is the steric field, the green regions mean that bulky substituents can increase the insecticidal activity, while
yellow regions mean that the bulky substituents reduce the activity. From the Fig. 3, a large green region is found surrounding the
CF(CF3)2 group, indicating that bulky substituents are preferred here. For instance, insecticidal activity of published compounds Ia, Ib,
IIa, IIb and IId [13] with CF(CF3)2 group are higher than compounds Ia, Ig, Ij, IIa, IIg, IIj with other less bulky substituents. The
right of the Fig. 3 is the electrostatic field, the red regions indicate that electronegative substituents will increase the insecticidal
activity, while blue regions mean that electropositive substituents will increase the insecticidal activity. Here, red area near the CF3
group, indicating a electronegative substituent will increase the activity, such as compound IIa has higher activities than compound Ig,
Ij, IIg and IIj.
3. Conclusion
In conclusion, 20 novel optically active N-cyano sulfilimines were designed, synthesized and evaluated against oriental armyworm
(Pseudaletia separata Walker) for their insecticidal activities. The results of bioassay indicated that most target compounds possessed
favorable activities against oriental armyworm. For oriental armyworm, these isomers exhibited different impact on biological activity
following the sequence as (Sc, Ss) ≥ (Sc, Rs), which was in accordance with SARs described in our previous report [13]. And the rule
of activity against oriental armyworm was 3-CF3 ≥ 2-CH3-4-Cl > 2, 3, 4-trifluro in the anilide moiety. The results indicated that these
groups including 3-CF3, 2-CH3-4-Cl or 2, 3, 4-trifluro in the anilide moiety might not be essential for favorable larvicidal activity,
which provided some guidance for the further modifications of sulfiliminyl dicarboxamides.
4. Experimental
4.1 Instruments and materials
The melting points were determined on an X-4 binocular microscope melting point apparatus (Beijing Tech Instrument Co., Beijing,
1
China) and uncorrected. H NMR and 13C NMR spectra were recorded at 300 MHz (Bruker AC-P 300 spectrometer) or 400 MHz
(Bruker AV 400 spectrometer) in CDCl3 or DMSO-d6 solution with tetramethylsilane as internal standard, and chemical shift (δ) in
(ppm) (s = singlet, d = doublet, t = triplet, m = multiplet ). Elemental analyses were performed on a Vario EL elemental analyzer.
HRMS data were obtained on a Varian QFT-ESI. Optical rotations were measured with Perkin-Elmer 341 polarimeter at 20 °C. GC-
MS were recorded on HP 5973 MSD with 6890 GC Flash chromatography with silica gel (200-300 mesh). Reagents were all
analytically pure. All solvents and liquid reagents were dried by standard methods and distilled before use. Insecticide Flubendiamide
was used only as a control, synthesized according to the literature [2]. Compounds 3-substituented anhydride 1 [15-16], (S)-1-
(methylthio)propan -2- amine 2 [17] were synthesized according to the methods reported in the literatures.
4.2 General synthetic procedure for compounds 5a-j
1
5a-j were synthesized in moderate yields by the method previously published in the literature [18]. The melting point and H NMR
data were consistent with the literature.
(S)-N1-(1-(Methylthio)propan-2-yl)-N2-(3-(trifluoromethyl)phenyl)phthalamide 5f: White solid; yield 72.91%; mp 178-180 °C; 1H
NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H, Ar-NH), 8.36 (d, 1H, J = 7.7 Hz, -CNH), 8.22 (s, 1H, Ar-H), 7.90 (d, 1H, J = 7.1 Hz, Ar-
H), 7.58 (m, 5H, Ar-H), 7.44 (d, 1H, J = 7.0 Hz, Ar-H), 4.08 – 3.98 (m, 1H, -NCH), 2.66 (dd, 1H, J = 13.0, 6.3 Hz, -SCH2), 2.54-2.53
(m, 1H, -SCH2), 2.05 (s, 3H, -SCH3), 1.19 (d, 3H, J = 6.3 Hz, -CCH3).
(S)-N1-(4-Chloro-2-methylphenyl)-3-iodo-N2-(1-(methylthio)propan-2-yl)phthalamide 5g: White solid; yield 61.74%; mp 209-210
°C; 1H NMR (400 MHz, CDCl3): δ 8.33 (s, 1H, Ar-NH), 8.01 (d, 1H, J = 9.3 Hz, Ar-H), 7.94 (d, 1H, J = 7.9 Hz, Ar-H), 7.73 (d, 1H, J
= 7.7 Hz, Ar-H), 7.18 (t, 3H, J = 8.0 Hz, Ar-H), 6.38 (d, 1H, J = 8.1 Hz, -CNH), 4.35 – 4.27 (m, 1H, -NCH), 2.63 (dd, 1H, J = 13.5, 6.0
Hz, -SCH2), 2.56 (dd, 1H, J = 13.5, 6.3 Hz, -SCH2), 2.29 (s, 3H, -SCH3), 1.97 (s, 3H, ArCH3), 1.25 (d, 3H, J = 6.6 Hz, -CCH3).
(S)-N1-(4-Chloro-2-methylphenyl)-N2-(1-(methylthio)propan-2-yl)-3-nitrophthalamide 5h: White solid; yield 55.23%%; mp 224-226
°C; 1H NMR (400 MHz, DMSO-d6): δ 9.87 (s, 1H, Ar-NH), 8.63 (d, 1H, J = 7.6 Hz, -CNH), 8.20 (d, 1H, J = 7.9 Hz, Ar-H), 8.04 (d,
1H, J = 7.3 Hz, Ar-H), 7.78 (t, 1H, J = 7.8 Hz, Ar-H), 7.54 (d, 1H, J = 8.4 Hz, Ar-H), 7.36 (s, 1H, Ar-H), 7.30 (d, 1H, J = 7.9 Hz, Ar-
H), 3.97 (m, 1H, -NCH), 2.63 (dd, 1H, J = 12.9, 4.3 Hz, -SCH2), 2.37 – 2.32 (m, 1H, -SCH2), 2.28 (s, 3H, -SCH3), 2.02 (s, 3H, ArCH3),
1.11 (d, 3H, J = 6.3 Hz, -CCH3).
(S)-3-Iodo-N2-(1-(methylthio)propan-2-yl)-N1-(2,3,4-trifluorophenyl)phthalamide 5i: White solid; yield 61.48%; mp 160-162 °C; 1H
NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H, Ar-NH), 8.44 (d, 1H, J = 7.8 Hz, -CNH), 8.02 (d, 1H, J = 7.8 Hz, Ar-H), 7.69 (d, 1H, J =

7.4 Hz, Ar-H), 7.51 (s, 1H, Ar-H), 7.39 – 7.32 (m, 1H, Ar-H), 7.26 (t, 1H, J = 7.7 Hz, Ar-H), 3.99 (dd, 1H, J = 12.7, 6.5 Hz, -NCH),
2.69 (dd, 1H, J = 13.2, 4.8 Hz, -SCH2), 2.37 (dd, 1H, J = 13.1, 8.7 Hz, -SCH2), 2.02 (s, 3H, -SCH3), 1.15 (d, 3H, J = 6.5 Hz, -CCH3).
1
(S)-N2-(1-(Methylthio)propan-2-yl)-3-nitro-N1-(2,3,4-trifluorophenyl)phthalamide 5j: White solid; yield 67.52%; mp > 300 °C; H
NMR (400 MHz, DMSO-d6): δ 10.46 (s, 1H, Ar-NH), 8.63 (d, 1H, J = 7.7 Hz, -CNH), 8.22 (d, 1H, J = 8.1 Hz, Ar-H), 8.02 (d, 1H, J =
7.4 Hz, Ar-H), 7.79 (s, 1H, Ar-H), 7.58 (s, 1H, Ar-H), 7.39 (d, 1H, J = 9.0 Hz, Ar-H), 3.95 (d, 1H, J = 6.2 Hz, -NCH), 2.65 (dd, 1H, J
= 13.1, 4.6 Hz, -SCH2), 2.35 (dd, 1H, J = 13.0, 8.5 Hz, -SCH2), 2.04 (s, 3H, -SCH3), 1.12 (d, 3H, J = 6.5 Hz, -CCH3).
4.3 General synthetic procedure for title compounds
These phthalamide derivatives were synthesized in moderate yield by the method reported in the literature [13].
(S,R)-3-Iodo-N2-(1-(N-cyano-S-methylsulfinimidoyl)-propan-2-yl)-N1-(3-(trifluoromethyl)phenyl)p-thalamide Ia: White solid; yield
73.41%; mp 194-195 °C; 1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H, Ar-NH), 8.81 (d, 1H, J = 6.9 Hz, -CNH), 8.15 (s, 1H, Ar-H),
8.05 (d, 1H, J = 6.8 Hz, Ar-H), 7.93 (d, 1H, J = 7.4 Hz, Ar-H), 7.75 (d, 1H, J = 6.3 Hz, Ar-H), 7.59 (d, 1H, J = 6.7 ,13.2Hz, Ar-H),
7.46 (d, 1H, J = 6.6 Hz, Ar-H), 7.32 (d, 1H, J = 5.9, 12.4 Hz, Ar-H), 4.25 (m, 1H, -NCH), 3.26 – 3.17 (m, 2H, -SCH2), 2.81 (s, 3H, -
SCH3), 1.27 (d, 3H, J = 4.4 Hz, -CCH3). HRMS calcd. for C20H18F3IN4O2S ([M + H]+), 563.0220; found, 563.0216. [α]20D= -
86.4(c=0.5, DMF).
(S,R)-3-Nitro-N2-(1-(N-cyano-S-methylsulfinimidoyl)-propan-2-yl)-N1-(3-(trifluoromethyl)phenyl)phthalamide Ib: White solid;
yield 69.94%; mp 108-110 °C; 1H NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1H, Ar-NH), 9.02 (d, 1H, J = 7.9 Hz, -CNH), 8.25 (d, 1H, J
= 8.2 Hz, Ar-H), 8.15 (s, 1H, Ar-H), 8.09 (d, 1H, J = 7.6 Hz, Ar-H), 7.93 (d, 1H, J = 8.3 Hz, Ar-H), 7.83 (t, 1H, J = 8.0 Hz, Ar-H),
7.62 (t, 1H, J = 7.9 Hz, Ar-H), 7.49 (d, 1H, J = 7.6 Hz, Ar-H), 4.22 (dt, 1H, J = 13.5, 6.7 Hz, -NCH), 3.30 (dd, 1H, J = 12.7, 6.1 Hz, -
SCH2), 3.17 (dd, 1H, J = 12.7, 7.3 Hz, -SCH2), 2.81 (s, 3H, -SCH3), 1.22 (d, 3H, J = 6.6 Hz, -CCH3). HRMS calcd. for C20H18F3N5O4S
([M + H]+), 482.1105; found, 482.1103. [α]20D=-12.0(c=0.07, (CH3)2CO).
(S,R)-3-Chloro-N2-(1-(N-cyano-S-methylsulfinimidoyl)-propan-2-yl)-N1-(3-(trifluoromethyl)phenyl)phthalamide Ic: White solid;
yield 68.43%; mp 178-180 °C; 1H NMR (400 MHz, DMSO-d6): δ 10.71 (s, 1H, Ar-NH), 8.91 (d, 1H, J = 8.1 Hz, -CNH), 8.14 (s, 1H,
Ar-H), 7.94 (d, 1H, J = 8.2 Hz, Ar-H), 7.72 (dd, 2H, J = 10.9, 7.9 Hz, Ar-H), 7.59 (dd, 2H, J = 12.9, 5.0 Hz, Ar-H), 7.47 (d, 1H, J = 7.7
Hz, Ar-H), 4.27 (dt, 1H, J = 14.5, 7.4 Hz, -NCH), 3.34 – 3.31 (m, 1H, -SCH2), 3.21 (dd, 1H, J = 12.6, 7.7 Hz, -SCH2), 2.83 (s, 3H, -
SCH3), 1.25 (d, 3H, J = 6.7 Hz, -CCH3). HRMS calcd. for C20H18ClF3N4O2S ([M + H]+), 417.0864; found, 471.0868. [α]20D=-
1.0(c=0.33, (CH3)2CO)
(S,R)-3-Fluoro-N2-(1-(N-cyano-S-methyl-sulfinimidoyl)-propan-2-yl)-N1-(3-(trifluoromethyl)phenyl)phthalamide Id: White solid;
yield 70.62%; mp 179-181 °C; 1H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H, Ar-NH), 8.97 (d, 1H, J = 8.1 Hz, -CNH), 8.15 (s, 1H,
Ar-H), 7.95 (d, 1H, J = 8.5 Hz, Ar-H), 7.64 – 7.59 (m, 3H, Ar-H), 7.49 (dd, 2H, J = 11.4, 8.6 Hz, Ar-H), 4.34 – 4.25 (m, 1H, -NCH),
3.35 (m, 1H, -SCH2), 3.22 (dd, 1H, J = 12.7, 7.4 Hz, -SCH2), 2.85 (s, 3H, -SCH3), 1.28 (d, 3H, J = 6.7 Hz, -CCH3). HRMS calcd. for
C20H18F4N4O2S ([M + H]+), 455.1160; found, 455.1162. [α]20D= -61.2(c=0.5, (CH3)2CO).
(S,R)-3-Bromo-N2-(1-(N-cyano-S-methylsulfinimidoyl)-propan-2-yl)-N1-(3-(trifluoromethyl)phenyl)phthalamide Ie: White solid;
yield 71.25%; mp 182-183 °C; 1H NMR (400 MHz, DMSO-d6): δ 10.71 (s, 1H, Ar-NH), 8.90 (d, 1H, J = 8.2 Hz, -CNH), 8.14 (s, 1H,
Ar-H), 7.94 (d, 1H, J = 7.9 Hz, Ar-H), 7.72 (ddd, 2H, J = 9.6, 9.0, 4.2 Hz, Ar-H), 7.59 (dt, 2H, J = 9.8, 8.0 Hz, Ar-H), 7.49 (dd, 1H, J =
15.1, 7.5 Hz, Ar-H), 4.31 – 4.22 (m, 1H, -NCH), 3.33 – 3.31 (m, 1H, -SCH2), 3.20 (dd, 1H, J = 12.6, 7.7 Hz, -SCH2), 2.82 (s, 3H, -
SCH3), 1.25 (d, 3H, J = 6.7 Hz, -CCH3). HRMS calcd. for C20H18BrF3N4O2S ([M + H]+), 515.0359; found, 515.0356. [α]20D= -
0.6(c=0.18, DMF).
(S,R)-N2-(1-(N-Cyano-S-methylsulfinimidoyl)-propan-2-yl)-N1-(3-(trifluoromethyl)phenyl)phthalamide If: White solid; yield
59.86%; mp 74-78 °C; 1H NMR (400 MHz, DMSO-d6): δ 10.69 (s, 1H, Ar-NH), 8.76 (d, 1H, J = 7.6 Hz, -CNH), 8.21 (s, 1H, Ar-H),
7.91 (d, 1H, J = 7.8 Hz, Ar-H), 7.66 – 7.57 (m, 5H, Ar-H), 7.44 (d, 1H, J = 7.4 Hz, Ar-H), 4.35 – 4.25 (m, 1H, -NCH), 3.38-3.36 (m,
1H, -SCH2), 3.29 – 3.21 (m, 1H, -SCH2), 2.83 (s, 3H, -SCH3), 1.29 (d, 3H, J = 5.6 Hz, -CCH3). HRMS calcd. for C20H19F3N4O2S ([M +
H]+), 437.1254; found, 437.1252. [α]20D= -29.8(c=1, MeOH)
(S,R)-3-Iodo-N2-(1-(N-cyano-S-methylsulfinimidoyl)-propan-2-yl)-N1-(4-chloro-2-methylphenyl)phthalamide Ig: White solid; yield
64.24%; mp 133-134 °C;1H NMR (400 MHz, DMSO-d6): δ 9.83 (s, 1H, Ar-NH), 8.80 (d, 1H, J = 7.2 Hz, -CNH), 8.03 (d, 1H, J = 7.4
Hz, Ar-H), 7.77 (d, 1H, J = 6.6 Hz, Ar-H), 7.44 (d, 1H, J = 8.2 Hz, Ar-H), 7.35 (s, 1H, Ar-H), 7.29 (m, 2H, Ar-H), 4.25 (m, 1H, -
NCH), 3.29 (m, 1H, -SCH2), 3.20 (d, 1H, J = 6.5 Hz, -SCH2), 2.71 (s, 3H, -SCH3), 2.25 (s, 3H, ArCH3), 1.26 (d, 3H, J = 5.8 Hz, -
CCH3). HRMS calcd. for C20H20ClIN4O2S ([M + H]+), 543.0113; found, 543.0107. [α]20D= -32.2(c=1, MeOH).
(S,R)-3-Nitro-N2-(1-(N-cyano-S-methylsulfinimidoyl)-propan-2-yl)-N1-(4-chloro-2-methylphenyl)phthalamide Ih: White solid; yield
1
63.84%; mp 184-185 °C; H NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1H, Ar-NH), 9.02 (d, 1H, J = 7.6 Hz, -CNH), 8.25 (d, 1H, J =
8.1 Hz, Ar-H), 8.11 (d, 1H, J = 7.5 Hz, Ar-H), 7.83 (t, 1H, J = 7.9 Hz, Ar-H), 7.48 (d, 1H, J = 8.4 Hz, Ar-H), 7.38 (s, 1H, Ar-H), 7.32
(d, 1H, J = 8.2 Hz, Ar-H), 4.24 (dt, 1H, J = 13.1, 6.5 Hz, -NCH), 3.28 (dd, 1H, J = 12.7, 5.8 Hz, -SCH2), 3.17 (dd, 1H, J = 12.7, 6.7
Hz, -SCH2), 2.74 (s, 3H, -SCH3), 2.30 (s, 3H, ArCH3), 1.23 (d, 3H, J = 6.6 Hz, -CCH3). HRMS calcd. for C20H20ClN5O4S ([M + H]+),
462.0998; found, 462.0994. [α]20D= -44.8(c=0.5, MeOH).
(S,R)-3-Iodo-N2-(1-(N-cyano-S-methylsulfinimidoyl)-propan-2-yl)-N1-(2,3,4-trifluorophenyl)phthalamide Ii: White solid; yield
1
71.09%; mp 159-162 °C; H NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H, Ar-NH), 8.78 (d, 1H, J = 6.7 Hz, -CNH), 8.05 (d, 1H, J =
7.2 Hz, Ar-H), 7.75 (s, 1H, Ar-H), 7.45 (s, 1H, Ar-H), 7.39 – 7.26 (m, 3H, Ar-H), 4.24 (m, 1H, -NCH), 3.32 – 3.28 (m, 1H, -SCH2),

3.23-3.18 (m, 1H, -SCH2), 2.78 (s, 3H, -SCH3), 1.27 (d, 3H, J = 5.7 Hz, -CCH3). HRMS calcd. for C19H16F3IN4O2S ([M + H]+),
549.0064; found, 549.0067. [α]20D =+1.2(c=1, DMF).
(S,R)-3-Nitro-N2-(1-(N-cyano-S-methylsulfinimidoyl)-propan-2-yl)-N1-(2,3,4-trifluorophenyl)phthalamide, Ij: White solid; yield
1
63.48%; mp 160-163 °C; H NMR (400 MHz, DMSO-d6): δ 10.63 (s, 1H, Ar-NH), 9.00 (d, 1H, J = 7.7 Hz, -CNH), 8.26 (d, 1H, J =
8.1 Hz, Ar-H), 8.08 (d, 1H, J = 7.5 Hz, Ar-H), 7.82 (t, 1H, J = 7.9 Hz, Ar-H), 7.54 (s, 1H, Ar-H), 7.41 – 7.34 (m, 1H, Ar-H), 4.25 –
4.17 (m, 1H, -NCH), 3.29 (dd, 1H, J = 12.7, 5.9 Hz, -SCH2), 3.17 (dd, 1H, J = 12.6, 7.0 Hz, -SCH2), 2.80 (s, 3H, -SCH3), 1.23 (d, 3H, J
= 6.6 Hz, -CCH3). HRMS calcd. for C19H16F3N5O4S ([M + H]+), 468.0948; found, 468.0946. [α]20D= +10.0(c=1, DMF).
(S,S)-3-Iodo-N2-(1-(N-cyano-S-methylsulfinimidoyl)-propan-2-yl)-N1-(3-(trifluoromethyl)phenyl)phthalamide, IIa: White solid;
yield 26.59%; mp 147-149 °C; 1H NMR (400 MHz, DMSO) δ 10.63 (s, 1H, Ar-NH), 8.64 (d, J = 7.1 Hz, 1H, -CNH), 8.15 (s, 1H, Ar-
H), 8.04 (d, J = 7.5 Hz, 1H, Ar-H), 7.93 (d, J = 7.2 Hz, 1H, Ar-H), 7.73 (d, J = 7.2 Hz, 1H, Ar-H), 7.59 (t, J = 7.3 Hz, 1H, Ar-H), 7.46
(d, J = 7.0 Hz, 1H, Ar-H), 7.30 (t, J = 7.3 Hz, 1H, Ar-H), 4.23 (m, 1H, -NCH), 3.31 – 3.16 (m, 2H, -SCH2), 2.76 (s, 3H, -SCH3), 1.26
(d, J = 5.8 Hz, 3H, -CCH3). HRMS calcd for C20H18F3IN4O2S ([M + H]+), 563.0220; found, 563.0216. [α]20D= +28.6(c=0.2, MeOH).
(S,S)-3-Nitro-N2-(1-(N-cyano-S-methylsulfinimidoyl)-propan-2-yl)-N1-(3-(trifluoromethyl)phenyl)phthalamide, IIb: White solid;
yield 30.06%; mp 105-107 °C; 1H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H, Ar-NH), 8.87 (d, 1H, J = 7.7 Hz, -CNH), 8.25 (d, 1H, J
= 8.2 Hz, Ar-H), 8.17 (s, 1H, Ar-H), 8.08 (d, 1H, J = 7.6 Hz, Ar-H), 7.94 (d, 1H, J = 8.1 Hz, Ar-H), 7.83 (t, 1H, J = 8.0 Hz, Ar-H),
7.62 (t, 1H, J = 8.0 Hz, Ar-H), 7.49 (d, 1H, J = 7.7 Hz, Ar-H), 4.21 (m, 1H, -NCH), 3.25 (dd, 1H, J = 13.2, 9.4 Hz, -SCH2), 3.16 (dd,
1H, J = 13.3, 4.4 Hz, -SCH2), 2.77 (s, 3H, -SCH3), 1.23 (d, 3H, J = 6.7 Hz, -CCH3). HRMS calcd. for C20H18F3N5O4S ([M + H]+),
482.1105; found, 482.1103. [α]20D= +8.0(c=0.1, MeOH).
(S,S)-3-Chloro-N2-(1-(N-cyano-S-methylsulfinimidoyl)-propan-2-yl)-N1-(3-(trifluoromethyl)phenyl)phthalamide, IIc: White solid;
yield 31.57%; mp 148-150 °C; 1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H, Ar-NH), 8.72 (d, J = 4.2 Hz, 1H, -CNH), 8.15 (s, 1H,
Ar-H), 7.89 (d, J = 7.9 Hz, 1H, Ar-H), 7.71 – 7.66 (m, 2H, Ar-H), 7.62 – 7.54 (m, 2H, Ar-H), 7.46 (d, J = 7.7 Hz, 1H, Ar-H), 4.24-4.21
(m, 1H, -NCH), 3.29 – 3.17 (m, 2H, -SCH2), 2.78 (s, 3H, -SCH3), 1.22 (d, J = 6.7 Hz, 3H, -CCH3). HRMS calcd. for C20H18ClF3N4O2S
([M + H]+), 471.0864; found, 471.0868. [α]20D= -+51.6(c=0.5, (CH3)2CO).
(S,S)-3-Fluoro-N2-(1-(N-cyano-S-methylsulfinimidoyl)-propan-2-yl)-N1-(3-(trifluoromethyl)phenyl)phthalamide, IId: White solid;
yield 29.38%; mp 110-112 °C; 1H NMR (400 MHz, DMSO-d6): δ 10.74 (s, 1H, Ar-NH), 8.76 (d, 1H, J = 7.9 Hz, -CNH), 8.15 (s, 1H,
Ar-H), 7.94 (d, 1H, J = 8.0 Hz, Ar-H), 7.60 (dd, 3H, J = 10.5, 6.0 Hz, Ar-H), 7.47 (t, 2H, J = 8.9 Hz, Ar-H), 4.29-4.22 (m, 1H, -NCH),
3.28 (dd, 1H, J = 13.2, 9.5 Hz, -SCH2), 3.21 (dd, 1H, J = 13.2, 4.5 Hz, -SCH2), 2.80 (s, 3H, -SCH3), 1.26 (d, 3H, J = 6.7 Hz, -CCH3).
HRMS calcd. for C20H18F4N4O2S ([M + H]+), 455.1160; found, 455.1162. [α]20D= +76.8(c=0.5, (CH3)2CO).
(S,S)-3-Bromo-N2-(1-(N-cyano-S-methylsulfinimidoyl)-propan-2-yl)-N1-(3-(trifluoromethyl)phenyl)phthalamide, IIe: White solid;
yield 28.75%; mp 201-203 °C;1H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H, Ar-NH), 8.73 (s, 1H, -CNH), 8.15 (s, 1H, Ar-H), 7.93
(d, 1H, J = 8.9 Hz, Ar-H), 7.73 – 7.66 (m, 2H, Ar-H), 7.63 – 7.54 (m, 2H, Ar-H), 7.46 (d, 1H, J = 7.7 Hz, Ar-H), 4.29 – 4.20 (m, 1H, -
NCH), 3.32 – 3.30 (m, 1H, -SCH2), 3.23 (dd, 1H, J = 13.4, 7.1 Hz, -SCH2), 2.78 (s, 3H, -SCH3), 1.24 (d, 3H, J = 6.7 Hz, -CCH3).
HRMS calcd. for C20H18BrF3N4O2S ([M + H]+), 515.0359; found, 515.0356. [α]20D= +59.2(c=0.29, DMF).
(S,S)-N2-(1-(N-Cyano-S-methylsulfinimidoyl)-propan-2-yl)-N1-(3-(trifluoromethyl)phenyl)phthalamide, IIf: White solid; yield
40.14%; mp 85-87 °C; 1H NMR (400 MHz, DMSO-d6): δ 10.68 (s, 1H, Ar-NH), 8.58 (d, 1H, J = 7.2 Hz, -CNH), 8.20 (s, 1H, Ar-H),
7.89 (s, 1H, Ar-H), 7.59 (d, 5H, J = 5.9 Hz, Ar-H), 7.44 (d, 1H, J = 7.2 Hz, Ar-H), 4.27 (m, 1H, -NCH), 3.29 (d, 2H, J = 9.6 Hz, -
SCH2), 2.81 (s, 3H, -SCH3), 1.27 (d, 3H, J = 6.6 Hz, -CCH3). C20H19F3N4O2S. HRMS calcd. for C20H19F3N4O2S ([M + H]+), 437.1254;
found, 437.1252. [α]20D= +45.1(c=1, MeOH).
(S,S)-3-Iodo-N2-(1-(N-cyano-S-methylsulfinimidoyl)-propan-2-yl)-N1-(4-chloro-2-methylphenyl)phthalamide, IIg: White solid; yield
35.76%; mp 109-111 °C; 1H NMR (400 MHz, DMSO-d6): δ 9.81 (s, 1H, Ar-NH), 8.64 (d, 1H, J = 6.3 Hz, -CNH), 8.02 (d, 1H, J = 6.3
Hz, Ar-H), 7.74 (s, 1H, Ar-H), 7.47 (d, 1H, J = 7.7 Hz, Ar-H), 7.35 (s, 1H, Ar-H), 7.29 (m, 2H, Ar-H), 4.22 (m, 1H, -NCH), 3.29 –
3.22 (m, 1H, -SCH2), 3.16 (d, 1H, J = 11.9 Hz, -SCH2), 2.71 (s, 3H, -SCH3), 2.26 (s, 3H, ArCH3), 1.27 (d, 3H, J = 4.1 Hz, -CCH3).
HRMS calcd. for C20H20ClIN4O2S ([M + H]+), 543.0113; found, 543.0107. [α]20D= +115.6(c=1, MeOH)
(S,S)-3-Nitro-N2-(1-(N-cyano-S-methylsulfinimidoyl)-propan-2-yl)-N1-(4-chloro-2-methylphenyl)phthalamide, IIh: White solid;
yield 36.16%; mp 129-130 °C; 1H NMR (400 MHz, DMSO-d6): δ 10.06 (s, 1H, Ar-NH), 8.84 (d, 1H, J = 7.5 Hz, -CNH), 8.23 (d, 1H, J
= 8.1 Hz, Ar-H), 8.08 (d, 1H, J = 7.5 Hz, Ar-H), 7.82 (d, 1H, J = 7.9 Hz, Ar-H), 7.50 (d, 1H, J = 8.4 Hz, Ar-H), 7.36 (s, 1H, Ar-H),
7.30 (d, 1H, J = 8.3 Hz, Ar-H), 4.18 (m, 1H, -NCH), 3.26 – 3.18 (m, 1H, -SCH2), 3.13 (dd, 1H, J = 13.2, 4.1 Hz, -SCH2), 2.71 (s, 3H, -
SCH3), 2.28 (s, 3H, ArCH3), 1.24 (d, 3H, J = 6.6 Hz, -CCH3). HRMS calcd. for C20H20ClN5O4S ([M + H]+), 462.0998; found,
462.0994. [α]20D= +24.0(c=0.2, MeOH).
(S,S)-3-Nitro-N2-(1-(N-cyano-S-methylsulfinimidoyl)-propan-2-yl)-N1-(2,3,4-trifluorophenyl)phthalamide, IIj: White solid; yield
36.52%; mp 168-170 °C;1H NMR (400 MHz, DMSO-d6): δ 10.60 (s, 1H, Ar-NH), 8.85 (d, 1H, J = 7.5 Hz, -CNH), 8.25 (d, 1H, J = 8.1
Hz, Ar-H), 8.06 (d, 1H, J = 7.5 Hz, Ar-H), 7.81 (t, 1H, J = 7.9 Hz, Ar-H), 7.58 (s, 1H, Ar-H), 7.37 (dd, 1H, J = 17.7, 8.7 Hz, Ar-H),
4.18 (m, 1H, -NCH), 3.27 – 3.20 (m, 2H, -SCH2), 3.15 (dd, 1H, J = 13.2, 4.3 Hz, -SCH2), 2.77 (s, 3H, -SCH3), 1.24 (d, 3H, J = 6.6 Hz,
-CCH3). HRMS calcd for C19H16F3N5O4S ([M + H]+), 468.0948; found, 468.0946. [α]20D= -86.4(c=0.5, DMF).
4.4 X-ray diffraction

The crystals of compound If and Ih were established, and X-ray intensity data were measured at 298K on a Bruker SMART 1000
CCD area detector diffraction meter with graphite monochromated Mo Kα radiation (λ=0.71073 Å). All hydrogen atoms were
observed and placed at their calculated positions with a fixed value of their isotropic displacement parameters.
4.5 Biological assay
All biological assays were carried out on representative test organisms prepared in the laboratory. The bioassay experiments were
o
repeated at 25 ± 1 C according to statistical needs. Assessments were conducted on the basis of dead/alive, and mortality rates were
corrected applying Abbott’s formula [19]. Percentage mortalities were evaluated based on a percentage scale of 0-100, in which 0
indicates no activity and 100 indicates total kill. Error of the bioassay experiments was 5%. LC50 values were calculated by probit
analysis [20].
4.5.1 Larvicidal activity against oriental armyworm (Mythimna separate Walker)
The insecticidal activity of compounds 5f-5j, Ia-Ij, IIa-IIj and Flubendiamide were evaluated using the reported procedure [21].
The insecticidal activity is outlined in Table 1. LC50 Values of Compounds Ia, Ig, Ij, IIa, IIg, IIj and Flubendiamide are shown in
Table 2.
Acknowledgment
This work was supported by National Natural Science Foundation of China (No. 21602118), Innovation Center of Chemical Science
and Engineering (Tianjin) and the National Natural Science Foundation of China (No. 21302104).
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Fig. 1. The structures of Flubendiamide (A) and N-cyano sulfilimine (B)
Fig. 2. Crystal structure of compound Ih
Fig. 3. The CoMFA results of compound Ia

Scheme 1 The synthetic procedure of Title Compounds

Table 1
Insecticidal activities of compounds 5f-5j, Ia-Ij, IIa-IIj and flubendiamide against oriental armyworm
Larvicidal activity (%) at conc. (mg/L)
Compd.
200
100
50
25
10
5
5f
5g
5h
5i
10
100
100
75
100
60
100
100
100
40
5j
20
Ia
Ib
Ic
Id
Ie
If
100
10
100
50
100
35
100
100
100
30
40
40
15
Ig
Ih
Ii
100
100
50
40
20
Ij
25
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIi
IIj
100
10
100
40
100
35
100
30
100
100
100
100
100
60
80
50
60
10
60
100
30
flubendiamide
100
100
100
100
100
100
Table 2.
LC50 values of compounds ia, ig, ij, iia, iig, iij and flubendiamide against oriental armyworm
y=a+bx
R
LC50 (mg·L-1)
LC95 (mg·L-1)
Compd.
Ia
y=1.2188+1.8661x
y=-12.2716+8.0423x
y=-3.8711+3.4239x
y=3.4424+1.4049x
y=-3.6189+3.3477x
y=0.1006+2.0568x
y=7.4237+2.6428x
0.9809
106.2315
140.4774
389.8511
12.8448
375.4853
241.0443
0.1230
808.5173
224.9744
1178.4100
190.3473
1163.9502
1519.9492
0.5160
Ig
0.9747
0.9527
0.9761
0.9115
0.9521
0.9945
Ij
IIa
IIg
IIj
flubendiamide