Design, Synthesis,and Herbicidal Activities Of Novel Hexahydropyridazine And Tetrehydroisoindoline-1,3-dione Derivatives

Chemical herbicides have been used successfully to achieve convenient and economical weed control in agricultural practices. Unfortunately, the evolution of herbicide-resistant weeds has inevitably decreased the efficiency of many herbicides. To satisfy the need of increasing crop yields, it is necessary to find alternative herbicides with novel scaffolds. As a key enzyme in the biosynthetic pathway leading to heme and chlorophyll, protoporphyrinogen oxidase (PPO) is an ideal target for herbicide development. Compared with other herbicides, PPO inhibitors have several advantages, such as high efficiency, low toxicity, broad herbicidal spectrum, quick onset of action, long-lasting effect and environmental friendly. Moreover, PPO-inhibiting herbicides was considered to have low resistance risk, which is an outstanding property. For example, only six weed species among452unique cases have been reported to be resistant to PPO-inhibiting herbicides till now. The widespread appearance of glyphosate-resistant weeds present a major risk in crop protection, and it is found in practice that some PPO-inhibiting herbicides are effective to control resistant biotypes, which, in turn, has stimulated new interest in novel PPO-inhibiting herbicides.This dissertation summarized the structural evolution of the PPO-inhibiting herbicides and the latest research progress in this field. Unfortunately, this kind of herbicide usually has some shortages like poor crop selectivity, and little or no phloem movement. To overcome those disadvantages, six series of tetrahydroisoindoline-1,3-dione and hexahydropyridazine derivatives (Figure1) were designed by introducing2-benzoxazolinone, pyridine and phenoxy carboxylic ester moieties into the commercial skeleton of cyclic imides. Based on the results of bioassay and structure-activity relationship, three potential molecules were found to be worth further developing as new commercial herbicide candidates. The following are the specific obtained research results.1. Pyridyl isothiocyanates(ITCs) are key intermediates for the synthesis of some target compounds. A one-pot preparation of pyridyl ITCs from their corresponding amines has been developed. This new approach works well for a wide range of pyridyl ITCs, in particular, some highly electron-deficient pyridyl and aryl ITCs are obtained in good yields.2. One hundred and nineteen novel compounds were designed and synthesized via the strategy of linking active sub-structures. They were all confirmed by1H NMR,13C NMR and HRMS spectra, and two representative compounds (Ⅱ-14f and Ⅲ-li) were further characterised by X-ray diffraction analysis.3. The laboratory bioassay results indicated that hexahydropyridazine derivatives Ⅱ-10displayed good herbicidal activity. With Ⅱ-10as leading compound, a series of ring-closing analoges Ⅱ-14were further designed and sysnthesized, which exhibited much better herbicidal activity than open-chain Ⅱ-10. Among them, compound Ⅱ-14f displayed the best effect against Abutilon theophrasti with ED50values of9.0g-ha-1, which are superior to that of acifluorfen (44.3g-ha-1). Field trials showed that Ⅱ-14f was found to be effective against broadleaf weeds at the rate of300g-ha-1for post-emergent applications in maize fields.4. The bioassay results indicated that some compounds belonging Ⅲ-1exhibited excellent herbicidal activity at the rate of375g-ha-1. Among them, compounds Ⅲ-1h, Ⅲ-1i, Ⅲ-1k, Ⅲ-11controlled Abutilon theophrasti with ED50values of3.0g-ha-1,1.8g-ha-1,5.3g·ha-1and1.4g·ha-1, respectively. Meanwhile it was found that Ⅲ-1i and Ⅲ-1k possess a broad spectrum against the24test weeds, with comparable activities to sulfentrazone. Further field trials indicated that Ⅲ-1i exhibited similar herbicidal activity to high concentration atrazine, and found to be safer for maize than atrazine. The bioassay results of several highly active compounds were further verified by a third test institution.5. The preliminary structure-activity relationships of target compounds were summarized, which is helpful to conduct further optimization of cyclic imide-type PPO inhibitors.