Synthesis And Bioactivities Of Novel Diacylhydrazine And Aryl-Pyrrole Derivatives

The diacylhydrazines are a promising class of insect growth regulators, with target pest selectivity, novel mode of action and ecotoxicological safety. While they act slowly and most of them have not systemic action and have low solubility in water and limited solubility in common organic solvents, and these disadvantages impede their field application. Therefore, in a search for new insect growth regulators with improved profiles, we designed and synthesized five series of 70 novel diacylhydrazines. 2-Aryl-pyrrole derivative, Chlorfenapyr is a broad spectrum insecticide and acaricide. The compound is a pro-pesticide, and the active compound is generated via oxidative N-dealkylation to the NH derivative. We designed and synthesized two series of 8 novel Aryl-pyrrole derivatives by derivativing of the active compound of Chlorfenapyr. The structures of new compounds were confirmed by 1H NMR, IR, MS, Elemental Analyses and X-ray diffraction. The idea of bioisosterism is one of the most successful techniques of bioactive compound design. For the chloride and the methyl are bioisosterism, we designed and synthesized a series of 31 novel N′-tert-butyl-N′-substitutedbenzoyl-N-5-chloro-6-chromanecarbohydrazide derivatives by displacement of the methyl on the benzene ring of 5-methyl-6-chromane of ANS-118 with the chloride. Their larvicidal activities against Oriental armyworm were evaluated. In addition, the results of bioassays indicated that most of them exhibit higher larvicidal activities than RH-5849, and several of them somewhat lower than the commercial insecticide tebufenozide. The larvicidal activities are strongly associated with the types and patterns of substitution on the benzene. Among mono-substituted derivatives, compared to non-substituent compound, substituents are unfavorable to activity except for methyl at meta or halogen at para. In addition, the bulkier substituent, such as C2H5O, I and NO2 (except for NO2 at ortho), drastically decreased activity. Among multi-substituted compounds, 3,5-dimethyl and 2-nitro-4-chloro derivatives are most prominent in increasing activity, 2,4-dichloro and 3,5-dichloro derivatives slightly increase activity. Introduction of tri-substituted groups results in rapidity decreasing activity. 3D-QSAR analyses were first performed on diacylhydrazins containing heterocyclic and the QSAR model gave good correlation between the variations on the percent inhibition and the steric-electrostatic properties. Moreover, the CoMFA results suggested that electron-withdrawing inductive of 2-, 3-, or 4-substituents and bulkiness of 3-substiuents were favourable to larvicidal activity, while the bulkiness of 4-substiuents were unfavourable to activity. For diacylhydrazines act slow, we designed and synthesized a series of 4 novel N-oxalyl derivatives of diacylhydrazines containing methylcarbamate moieties by introduction of N-methylcarbamates into N-tert-butyl-N,N′-diacylhydrazines through oxalyl group in order to retain insecticidal activities of the two parent insecticides, and reduce the toxicity of the parent methylcarbamates to mammals at the same time. The results of bioassay showed that the compounds exhibit much lower larvalicdal activities than the parent compounds, diacylhydrazines, and did not exhibit the activities of the other parent compounds, N-methylcarbamates. Tebufenozide does not have systemic action and has low solubility in water and limited solubility in common organic solvents. It was believed that the derivatives containing a carboxylate moiety may result in compounds that possibly have unusual systemic activity because carboxylic acid groups are phloem mobile and may move downward as well as upward in plants. We designed and synthesized a series of 19 novel N-oxalylderivatives of Tebufenozide by introduction of an alkyloxyoxalyl or aryloxyoxalyl containing carboxylic acid or ester substituent on the aryl group into N-tert-butyl-N′-4-ethylbenzoyl-N-3,5-dimethyl benzoylhydrazide. The results of bioassays showed that those derivatives containing carboxylic acid at the meta or para on the aryl are almost comparable to the patent compound tebufenozide. Moreover, the larvicidal activities of N-aryloxyoxalyl derivatives appeared to be strongly associated with the substituent and its position on the benzene. The derivatives with substituent at meta or para are obviously superior to those with substituent at ortho position. The derivatives containing carboxylic acid are much better than that containing carboxylate ester. While those containing carboxylic acid at ortho position displayed abnormal reduced larvicidal activity. In addition, those derivatives containing carboxylic acid at the meta or para on the aryl are much better than non-substituent N-aryloxyoxalyl derivative, also superior to N-alkyloxyoxalyl derivatives. Moreover, the non-substituent N-aryloxyoxalyl derivative issuperior to N-benzyloxyoxalyl derivative. However, these compounds have no systemic activity. It is an effective method to find novel pesticides by combining the bioactive units of different pesticides, we designed and synthesized a series of 16 novel diacylhydrazine derivatives containing the urea linkage by introduction the urea linkage to the benzene ring of diacyhydrazines or assembling the bioactive units of diacyhydrazines and benzoylphenylureas. The results of bioassay showed that some of these compounds exhibit good larvicidal activities. Moreover, the acyl urea linkage on the benzene is essential for larvicidal activities, and the larvicidal activities are strongly associated with the position of the acyl urea linkage on the benzene, only when it is on the para of phenyl ring far away N-tert-butyl, the compound can display larvicidal activities. At the same time, the substituents on the phenyl ring near to N-tert-butyl affect larvicidal activities too. A series of 4 N-alkyloxyoxalyl derivatives of 2-aryl-pyrrole were synthesized by derivativing of the active compound of Chlorfenapyr. The results of bioassay indicated that their larvicidal activities against Oriental armyworm are comparable to Chlorfenapyr and its active compound. 5-chlorochromane-6-carboxylic acid was first synthesized from 2-tert-butyl-4-methylphenol as start compound via 7 steps reactions. The reaction of 2-tert-butyl-4-methylphenol with 3-bromoprop-1-yne was studied in some details, and it was found that high temperature would result in 7-tert-butyl-3,5-dimethyl benzofuran as byproduct. Oxidation of the aromatic ring with alkyl side chain was also studied, and it was first found that the aromatic ring was partially oxidized by chromium (VI). The reaction of oxalyl chloride with N-tert-butyl-N,N′-diacylhydrazines to yield 1,3,4-oxadiazole and 4-tert-butyl-2-substituted-phenyl-4H-1,3,4-oxadiazine-5,6-dione was first found and the reaction was studied in some detail. Substituted aryloxyoxalyl chlorides were first prepared by the reaction of different hydroxybenzonate esters with oxalyl chloride in dichloromethane using pyridine as the acid acceptor. N-tert-Buty-N-substituted benzoylhydrazines were synthesized by different methods, when the substituted groups on benzene ring are halogens or nitro, Boc-Protection was adopted, andthe other substituted groups except halogens or nitro on benzene ring, Cbz-Protection were applied.