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.

The title compounds have been determined by melting point, ¹H NMR, HRMS and optical polarimeter. The ¹H 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 × 0.18 mm × 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 R_int = 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 leastsquares 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) ų, 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 1.172 Å is intermediate between C=N(1.34–1.38 Å) and C≡N(1.14–1.16 Å) 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 Tables 1 and 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 5 g 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 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 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 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 resultsof 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, China) and uncorrected. ¹H 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 ℃. 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

5a-j were synthesized in moderate yields by the method previously published in the literature [18]. The melting point and ¹H 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 ℃; 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 ℃; 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 ℃; 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 ℃; 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, ArH), 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).

(S)-N²-(1-(Methylthio)propan-2-yl)-3-nitro-N¹-(2, 3, 4-trifluorophenyl)phthalamide 5j: White solid; yield 67.52%; mp >300 ℃; ¹H 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 ℃; 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, 13.2 Hz, 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]_D²⁰ = -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 ℃; 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]_D²⁰ = -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 ℃; 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]_D²⁰ = -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 ℃; 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]_D²⁰ = -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 ℃; 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]_D²⁰ = -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 ℃; 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, ArH), 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]_D²⁰ = -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 ℃; 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]_D²⁰ = -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 63.84%; mp 184–185 ℃; ¹H 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, ArH), 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]_D²⁰ = -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 71.09%; mp 159–162 ℃; ¹H 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, ArH), 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]_D²⁰ = +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 63.48%; mp 160–163 ℃; ¹H 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, ArH), 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]_D²⁰ = +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 ℃; 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]²⁰ _D = +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 ℃; ¹H NMR (400 MHz, DMSOd₆): 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]_D²⁰ = +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 ℃; 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]_D²⁰ = -+ 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 ℃; 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]_D²⁰ = +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 ℃; 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]_D²⁰ = +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 ℃; 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]_D²⁰ = +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 ℃; 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, ArH), 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]_D²⁰ = +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 ℃; 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]_D²⁰ = +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 ℃; 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]_D²⁰ = -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 298 K 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 repeated at 25 ±1 ℃ 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.

Acknowledgments

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).