Design, synthesis, and insecticidal activity of novel neonicotinoid derivatives containing N-oxalyl groups

Two series of novel neonicotinoid derivatives containing N-oxalyl groups were designed and synthesized, and their structures were characterized by 1 H NMR spectroscopy, high-resolution mass spectroscopy, elemental analysis and single crystal X-ray diffraction analysis. The insecticidal activities of the new compounds were evaluated. The results of bioassays indicated that some of these title compounds exhibited excellent insecticidal activities. The insecticidal activities of compounds 13c , 13d , 13g , 13h , and 13i against bean aphids at 12.5 mg kg -1 were 100%; the insecticidal activities against bean aphids of the derivative 13 c, 13d, 13g , 13h , and 14h were comparable to imidacloprid at 6.25 mg kg -1 . Surprisingly, the results indicated that the activity of ethyl 2-(3-((6-chloropyridin-3-yl)methyl)-2-(nitroimino)imidazolidin-1-yl)- 2-oxoacetate ( 13b ) against bean aphids at 6.25 mg kg -1 was 96%, which was higher than the commercialized imidacloprid.


Introduction
Since the introduction of imidacloprid (1) in the 1980s as an insecticide for crop protection, 1 neonicotinoid insecticides have been rapidly developed worldwide for controlling insects because of their high potency, low mammalian toxicity, broad insecticidal spectra, and good systemic properties.0][11][12][13][14] These six products were developed by replacing the pyridine ring with a thiazole ring or a saturated heterocyclic ring, changing the nitroimino group to an isoelectronic nitromethylene or cyanoimine group, or reconstructing the imidazolidine ring with bioisosteric cyclic or acyclic moieties. 15[18][19] Figure 1.Seven commercialized neonicotinoid compounds and two reported N-oxalyl derivatives.
The activity spectrum of a pesticide is often determined by the physical properties of the compound, and it is possible to develop a compound of new style by attaching an appropriate functional group to a present insecticide.Moreover, the physical properties of an insecticidal compound may be manipulated to obtain products with other selected types of activity by proper selection of the derivative moiety. 20It was reported that N-oxalyl derivatives of carbofuran containing a carboxylic acid or ester substituent (8) displayed an insecticidal activity comparable or superior to that of carbofuran. 21The synthesis and insecticidal evaluation of novel N-oxalyl derivatives of tebufenozide (9) have been reported and the results of bioassay showed that they exhibit excellent larvicidal activity (Figure 1). 22ncouraged by these reports, an idea was developed that the introduction of an oxalyl substituent into some neonicotinoid molecules by substituting the hydrogen on the nitrogen atom could improve biological properties and decrease resistance.Therefore, in a search for new neonicotinoid insecticide with improved profiles, two series of neonicotinoid derivatives containing N-oxalyl groups were designed and synthesized as shown in Scheme 1.

Synthesis
In the present work, the synthesis of two series novel N-oxalyl derivatives of neonicotinoid compounds as well as their insecticidal activities against bean aphids were studied.4][25] The title compounds 13 were synthesized from imidacloprid (1) and the appropriate alkyloxyoxalyl chloride (12) (obtained from the corresponding alcohol and oxalyl chloride -see Table 1) in dry dimethylformamide using sodium hydride as base as shown in Scheme 1.The target N-oxalyl derivatives of neonicotinoid compounds 14 were synthesized by a simple and convenient four-step procedure starting from 2-chloro-5-chloromethylpyridine and ethylenediamine.The compound (10)  (11).
The reaction of 11 and 12 using the method described above for compounds 13 afforded the title compounds 14.The melting points, yields, and elemental analyses of compounds 13 and 14 are listed in Table 2.The 1 H NMR data are listed in Table 3. Scheme 1.General synthetic route of the title compounds 13 a-13 j and 14 a-14 j.

Insecticidal activity
Table 4 shows the insecticidal activities of the title compounds 13 and 14 and imidacloprid against bean aphids.The results of insecticidal activities given in Table 4 indicated that most of the title compounds exhibited excellent activity against bean aphids, comparable to the commercialized imidacloprid.For instance, the insecticidal activities of compounds 13 c, 13 d, 13 g, 13 h, and 13 i against bean aphids at 12.5 mg kg -1 were 100%.Moreover, some of them still exhibited good insecticidal activity against bean aphids when the concentration was reduced to 6.25 mg kg -1 .Surprisingly, the results indicated that the activity of compound 13 b against bean aphids at 6.25 mg kg -1 was 96%, which was higher than the commercialized imidacloprid; and the activity of compound 13 h was 81% at 6.25 mg kg -1 , which was equal to imidacloprid.
From the data presented in Table 4, we found that the bioactivities of the second series 14 were weaker than that of the first series 13.Therefore the nitroimino-substituted analogue showed a higher insecticidal activity than did the corresponding cyanoimine-substituted analogue.Among those compounds, replacing the nitroimino group with cyanoimine group resulted in decreased insecticidal activity.Compounds 13 a-13 g, 14 a, 14 b and 14 d exhibited good insecticide activity against bean aphids and had > 90% mortality at 25 mg kg -1 .The allyl esters 13 h and 14 h exhibited the highest insecticidal activity in their respective series, comparable to that of the control imidacloprid.Further studies on structural optimization and structure-activity relationships of these N-oxalyl derivatives are in progress.

Conclusions
In summary, two series of novel neonicotinoid derivatives containing N-oxalyl group were designed and synthesized with structures characterized by 1 H NMR spectroscopy, high-resolution mass spectroscopy, elemental analysis and single crystal X-ray diffraction analysis.The insecticidal activities of the new compounds were evaluated.The results of bioassays indicated that some of these title compounds exhibited good insecticidal activities, and that substitution of the hydrogen atom at N in the imidazolidine ring of the parent compounds by oxalate may be a feasible approach to improving activity profiles of neonicotinoids.Most of the new derivatives retain the insecticidal activity of the parent compounds and some, such as derivative 13 b, increase the activity.The modification of the imidazolidine ring of the parent compounds offers a promising prospect and highly active analogues are expected to be found by further work.
Synthetic procedure for alkyloxyoxalyl chlorides 12 a-12 j 26 The appropriate alcohol (0.1 mol) was added dropwise over 20 minutes to an excess of oxalyl chloride (0.2 mol) at 0 o C. When the addition was complete, the mixture was allowed to warm to room temperature for 2 hours.Excess oxalyl chloride was removed by vacuum distillation.Further distillation affords alkyloxyoxalyl chloride 12 a-12 j.The boiling points, yields of compounds 12 a-12 j were listed in Table 1.General synthetic procedure for the title compounds 13 a-13 j Imidacloprid (1) (0.01 mol) was dissolved in dry dimethylformamide (30 mL) and sodium hydride (0.011 mol) was added at 10 o C. The mixture was stirred at room temperature until the generation of hydrogen ceased.Then, alkyloxyoxalyl chloride (12) (0.011 mol) was added, and the mixture was stirred at 30 o C. for 5 hours, and poured into ice water (50 mL).The aqueous layer was extracted with dichloromethane (3×40 mL).The dichloromethane layer was washed with water (3×40 mL) and dried over anhydrous sodium sulfate.Then the dichloromethane was concentrated.The residue was purified by column chromatography over silica gel using petroleum ether (60-90 o C) and ethyl acetate as the eluent to afford the title compounds 13 a-13 j.
The melting points, yields, and elemental analyses of compounds 13 a-13 j are listed in Table 2.
The 1 H NMR data are listed in Table 3.
The title compounds 14 a-14 j can be prepared using the same method.The melting points, yields, and elemental analyses of compounds 14 a-14 j are also listed in Table 2.The 1 H NMR data are listed in Table 3.

Biological assay
All compounds were dissolved in acetone and diluted with water containing Triton X-100 (0.1 mg L -1 ) to obtain series concentrations of 200.0, 100.0, 50.0, 25.0, 12.5 and 6.25 mg kg -1 and others for bioassays.The bioassay was repeated at 25 ± 1 o C according to statistical requirements.Assessments were made on a dead/alive basis, and mortality rates were corrected using Abbott's formula. 27Evaluations are based on a percentage scale of 0-100 which 0 equals no activity and 100 equals total kill.The insecticidal activities of the title compounds 13 a-13 j, 14 a-14 j and imidacloprid against the bean aphids were evaluated.Bean aphids were dipped according to a slightly modified FAO dip test. 28The tender shoots of soybean with 40~60 healthy apterous adult aphids were dipped in the diluted solutions of the compounds for 5 s, the superfluous fluid removed, and placed in the conditioned room (25 ± 1 o C, 50% RH).Mortality were calculated 48 h after treatment.Each treatment was performed three times.Water containing Triton X-100 (0.1 mg kg -1 ) was used as control.The commercial insecticide imidacloprid was used as a standard.Mortality was calculated after 48 h, and data were corrected and subjected to probit analysis as before.The results of the insecticidal activity of the title compounds 13 a-13 j, 14 a-14 j and imidacloprid were summarized in Table 4.

Figure 2 .
Figure 2. Molecular structure of the compound 14 b.

Figure 3 .
Figure 3. Packing diagram of the compound 14 b.

Table 1 .
Boiling points, yields, of the compounds 12 a-12 j

Table 2 .
Melting points, yields, and elemental analyses of the title compounds 13