Design, Synthesis, and Biological Activities of Novel 2-Cyanoacrylate Compounds Containing Substituted Pyrazolyl or 1,2,3-Triazolyl Moiety

To develop novel 2-cyanoacrylate derivatives with potential bioactivity, a number of 2-cyanoacrylate compounds, including substituted pyrazole or 1,2,3-triazole ring, were designed, prepared, and structurally detected by 1H NMR, 13C NMR, and elemental analysis. The biological assessment displayed that some designed compounds had significant herbicidal activities against Brassica juncea, Chenopodium serotinum, Rumex acetosa, Alopecurus aequalis, Polypogon fugax, and Poa annua at a dosage of 1500 g/ha. Furthermore, some derivatives still expressed satisfactory herbicidal activities against Brassica juncea, Chenopodium serotinum, and Rumex acetosa when the dosage was lowered to 150 g/ha, especially the inhibitory effects of compounds 9a, 9d, 9f, 9i, 10a, 10b, 10e, and 10n against Brassica juncea were all over 80%, compounds 9d, 9f, 9g, 9h, 9i, 10h, 10i, 10m, 10n, and 10o possessed more than 70% inhibition rates against Chenopodium serotinum, and compound 9d indicated 70% herbicidal activity against Rumex acetosa. These results provided an important basis for further design and discovery of biologically active 2-cyanoacrylate compounds.


Chemistry
In this paper, in order to search for novel 2-cyanoacrylates with wonderful bioactivities, NK-9717 was chosen as the pesticide precursor, and the active pyrazolyl and 1,2,3triazolyl units were introduced to replace the pyridyl ring to design and prepare new 2-

Chemistry
In this paper, in order to search for novel 2-cyanoacrylates with wonderful bioactivities, NK-9717 was chosen as the pesticide precursor, and the active pyrazolyl and 1,2,3-triazolyl units were introduced to replace the pyridyl ring to design and prepare new 2-cyanoacrylate compounds 9 and 10 ( Figure 2). The synthesis process of the title compounds 9 and 10 was depicted in Scheme 1. The condensation of 4-fluorobenzaldehyde with 1H-pyrazole or 1H-1,2,3-triazole under alkaline conditions offered compounds 1, which were conveniently reduced to compounds 2 by treatment with NaBH 4 . Furthermore, intermediates 2 reacted with thionyl chloride to produce compounds 3 successfully. Intermediates 3 were easily converted into compounds 4 by the reaction with potassium phthalimide, which were further transformed into compounds 5 by the treatment with hydrazine hydrate. The key intermediates 8 were easily synthesized in two steps from compounds 6. Cyanoacetic acid was treated with 2-alkoxy or 2-aryloxy alcohols 6 to generate intermediates 7, which were reacted with carbon disulfide and dimethyl sulfate to obtain compounds 8 directly. Subsequently, the significant intermediates 5 were mixed with 2-cyanoacrylates 8 in ethanol to obtain the target compounds 9a-9i in satisfactory yields. At the same time, compounds 9 reacted with sodium alcoholate to form the aimed compounds 10a-10o successfully. Finally, the structures of compounds 9a-9i and 10a-10o were determined through 1 H NMR, 13 C NMR, and elemental analysis. Compounds 9a and 10b were selected as the typical examples to illustrate. In 1 H NMR of 9a, the proton signal peak of the NH group was displayed at δ 10.36, a doublet signal at δ 4.80 was due to two protons of methylene group that attached to a nitrogen atom, and three protons of methylthio unit were detected as a singlet signal at δ 2.68. In 13 C NMR of 9a, the carbon atom of the C=O group was noticed at δ 168.26, the carbon atom of the methylene group that attached to nitrogen was recognized at δ 48.95, and the carbon atom of methylthio moiety was shown at δ 18.33. In 1 H NMR of 10b, one proton of NH moiety was detected at δ 9.78, a quartet signal at δ 4.61 belongs to two protons of methyleneoxy moiety adjacent to C=C group, and two protons of the methylene unit linked to nitrogen atom was exhibited as a singlet signal at δ 4.53. In 13 C NMR of 10b, the C=O group was shown at δ 169.63, the carbon atom of methyleneoxy unit adjacent to the C=C skeleton was noticed at δ 59.86, and the carbon atom of methylene moiety attached to nitrogen was seen at δ 44.53.

General Approach to Preparation of 4
Compounds 3 (5 mmol) were dissolved in 30 mL of DMF, and potassium phthalimide (6 mmol) was directly added thereto at room temperature. Next, the mixture was maintained at 50 • C for another 9 h. After cooling, the solution was dumped into 50 mL of ice water. Finally, the precipitates were filtered to get intermediates 4.

General Approach to Preparation of Title Compounds 9a-9i
Compounds 8 (2 mmol) were dissolved in anhydrous ethanol (35 mL), and intermediate 5 (2 mmol) was put in the above solution. Next, the mixture was maintained at reflux for 4-6 h. When the reaction was finished, the resulting solution was condensed to form crude products, which were further refined through column chromatography and washed by ethyl acetate/petroleum ether (1:4, v/v) to obtain compounds 9a-9i, and the spectral data of compounds 9a-9i are depicted below. 1 H NMR and 13 172.76, 168.26, 141.32, 139.97, 134.52, 128.36, 126.73, 119.66, 118.

Biological Activity Test
All bioassays were accomplished on six kinds of typical weeds cultured in the laboratory. The herbicidal activities against Brassica juncea, Chenopodium serotinum, Rumex acetosa, Alopecurus aequalis, Polypogon fugax, and Poa annua of designed compounds were measured using a pot culture method [33]. First, tested compounds were dissolved with DMF, including 0.1% Tween-80 emulsifying agent, which was subsequently diluted by water to the required doses of 1500 and 150 g/ha. Flowerpots with a diameter of 7.5 cm were plated with composite soil, and then the seeds of six weeds were sowed at 25 • C in the greenhouse. When the weeds grew to their three-leaf stage, each title compound was sprayed by post-emergence application. After air-drying, the weeds were kept in the greenhouse for normal cultivation at 25 • C. A mixture of an equivalent quantity of DMF, Tween-80, and water was sprayed as a negative contrast. Additionally, NK-9717 was used as a positive control. The fresh weight of the aforementioned ground tissues was surveyed 25 days after post-emergence treatment. The inhibition effect of each compound on the growth of the above weeds was assessed by the percentage change in the weed weight compared to that of the control, as 0% (no effect) and 100% (complete death). Each assessment was repeated in triplicate, and the results were averaged.

Conclusions
In summary, twenty-four 2-cyanoacrylate derivatives, including pyrazolyl or 1,2,3triazolyl unit, were synthesized and screened the herbicidal properties against six weeds. Bioassay results demonstrated that some target compounds showed wonderful herbicidal activities against Brassica juncea and Chenopodium serotinum at dosages of 1500 and 150 g/ha, and some title compounds expressed moderate to satisfactory herbicidal activities towards Rumex acetosa, Alopecurus aequalis, Polypogon fugax, and Poa annua at 1500 g/ha. Among them, compounds 9g, 10i, and 10n presented a wide range of herbicidal activities towards all six weeds. These compounds can be selected as lead pesticides for further structural improvement and bioactivity optimization.

Conflicts of Interest:
The authors declare no conflict of interest.