Synthesis and herbicidal activity of N-oxide derivatives

As part of an ongoing program on the chemistry and biological activity of N-oxide-containing molecules, a number of novel 1,2, 5-oxadiazole N-oxide, benzo[1,2-c]1,2,5-oxadiazole N-oxide, and quinoxaline N,N'-dioxide derivatives were synthesized and evaluated for their herbicidal activity. Many of these compounds exhibited moderate to good herbicidal pre-emergence activity against Triticum aestivum. Dose-response studies were done on the more representative compounds (12, 20, and 26). The most active compound, butylcarbamoylbenzo[1,2-c]1,2,5-oxadiazole N-oxide, 26, displayed herbicidal activity at concentrations as low as 24 g/ha.     

Synthesis and herbicidal activity of 2-cyano-3-substituted-pyridinemethylaminoacrylates

Two series of 2-cyano-3-substituted-pyridinemethylaminoacrylates, namely 12 new (Z)-2-cyano-3-methylthio-3-substituted-pyridinemethaneaminoacrylates and 10 new (Z)-2-cyano-3-alkyl-3-substituted-pyridinemethaneaminoacrylates, were synthesized as herbicidal inhibitors of photosystem II (PSII) electron transport. All of these compounds were confirmed by (1)H NMR, elemental, IR, and mass spectrum analyses. Their herbicidal activities were evaluated. Some compounds exhibited excellent herbicidal activities, even at a dose of 75 g/ha. A suitable substituent at the 2-position of the pyridine ring and the well-fit group at the 3-position of acrylate were essential for high herbicidal activity. 2-Cyanoacrylates containing a substituted pyridine ring provide higher herbicidal activities than parent compounds containing phenyl. These PSII inhibitor herbicides are safe to corn, which is a major crop in China.     

Synthesis and herbicidal activity of diphenyl ether derivatives containing unsaturated carboxylates

A series of novel diphenyl ether derivatives containing unsaturated carboxylates were designed and synthesized. Their structures were identified by (1)H nuclear magnetic resonance and elemental analyses. The bioassays indicated that the compounds 5b and 5c exhibited good herbicidal activities against velvetleaf at a concentration of 30-40 g/hm(2). The relationship between structure and herbicidal activity was also discussed. Among unsaturated carboxylates group, butenoate is the most promising one. Amonst them, 4-ethoxy-4-oxobutenyl 5-(2-chloro-4-(trifluoromethyl)phenoxy)-2-nitrobenzoate 5b was identified as the most promising candidate due to its high protoporphyrinogen IX oxidase inhibition effect (pI(50) = 6.64) and good herbicidal activity against broadleaf weeds with selectivity to soybean and low toxicity to mammals.     

Synthesis, herbicidal activity, and mode of action of IR 5790

IR 5790, an arylthiadiazolone herbicide structurally related to oxadiargyl and oxadiazon, was synthesized. The herbicidal activity and mode of action of IR 5790 were investigated. This herbicide has broad-spectrum pre-emergence activity against both dicotyledonous and monocotyledonous weeds. The phenotypic responses of susceptible plants, such as interruption of growth and light-dependent development of necrotic areas on the foliage, are consistent with those observed with protoporphyrinogen oxidase-inhibiting herbicides. Tissues exposed to IR 5790 in darkness accumulated protoporphyrin IX, which led to a photodynamic loss of membrane integrity upon exposure to light. Consistent with these physiological symptoms, IR 5790 strongly inhibited protoporphyrinogen oxidase, with an I(50) value of 3 nM. The presence of a sulfur atom did not significantly alter the molecular properties of the thiadiazolone ring, relative to the oxadiazolone ring of oxadiargyl, which explains why IR 5790 has the same mode of action as this herbicide.     

Synthesis and herbicidal activity of novel 3-aminocarbonyl-2-oxazolidinethione derivatives containing a substituted pyridine ring

A series of 3-aminocarbonyl-2-oxazolidinethione derivatives containing a substituted pyridine ring were designed and synthesized. The structures of all of the title compounds were characterized by 1H NMR, 13C NMR, IR, and HRMS. Their agricultural bioactivities were evaluated, and some of these compounds exhibited good herbicidal activities against Echinochloa crusgalli, Sorghum vulgare, Digitaria sanguinalis, Eclipta prostrasta, Cucumis sativus, and Brassica campestris, which were associated mainly with their steric properties and lipophilicities based on the structure-activity relationship discussion.     

Synthesis and herbicidal activity of 2-cyano-3-(2-chlorothiazol-5-yl)methylaminoacrylates

A series of 2-cyano-3-(2-chlorothiazol-5-yl)methylaminoacrylates were synthesized as herbicidal inhibitors of PSII electron transport. All of these compounds exhibited good herbicidal activities. In particular, (Z)-ethoxyethyl 2-cyano-3-isopropyl-3-(2-chlorothiazol-5-yl)methylaminoacrylate showed excellent herbicidal activities even at a dose of 75 g/ha. A suitable group at the 3-position of acrylate was essential for high herbicidal activity. 2-Cyanoacrylates containing a 2-chloro-5-thiazolyl group are a novel class of herbicides and display herbicidal activities comparable to existing analogues bearing chloropyridyl or chlorophenyl.     

Synthesis and herbicidal activity of N,N-diethyl-3-(arylselenonyl)-1H-1,2,4-triazole-1-carboxamide

Based on the carbamoyl triazole herbicide Cafenstrole, 12 novel selenium-containing compounds were designed and synthesized. All of the compounds were characterized and confirmed by IR, 1H NMR, and high-resolution mass spectroscopy. The bioassay tests showed that some of the compounds (C2, C4, C(7-8), and C12) exhibited good inhibitory activity against cucumber (Cucumis sativus L.) and semen euphorbiae (Leptochloa chinensis N.). Especially, compound C6 inhibited the growth of cucumber and semen euphorbiae by >90% at a concentration of 1.875 microg/mL, and the inhibition of the compound on the rice (Oryza sativa L.) was only 8.3% at a concentration of 7.5 microg/mL, which indicated a higher selectivity between weed and rice than that shown by Cafenstrole.     

Synthesis and herbicidal activity of 2alpha, 4alpha-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one derivatives.

The catalytic oxidation of 2alpha,4alpha-dimethyl-8-oxabicyclo[3.2. 1]oct-6-en-3-one with osmium tetraoxide and excess hydrogen peroxide resulted in the formation of 2alpha,4alpha-dimethyl-6, 7-exo-isopropylidenedioxy-8-oxabicyclo[3.2.1]octan-3-one (2), with 91% yield. Addition of aryllithium reagents to this compound resulted in the formation of the aromatic alcohols (6a-h) with 48-76% yield. These alcohols were treated with thionyl chloride in pyridine, and the corresponding alkenes (7a-h) were obtained with 46-80% yield. The effect of compounds 6a-h and 7a-h on the root growth of Sorghum bicolor was evaluated at a concentration of 6.6 microg g(-)(1). The alcohols 6a-h caused an inhibitory effect (8-100%) on the S. bicolor radicle growth. The three most active compounds were 6e (aryl = p-methylphenyl), 6g (aryl = p-chlorophenyl), and 6h (aryl = p-fluorophenyl) and caused 100% inhibition. The effect of alkenes 7a-h was less pronounced and varied from 15% to 46% inhibition. Another experiment was carried out in a greenhouse to evaluate the effect of alcohols 6e, 6g, and 6h, at a 6.6 microg g(-)(1) dose, against Cucumis sativus, S. bicolor and the weeds Bidens pilosa, Desmodiumtortuosum, and Pennisetum setosum. All three compounds showed an inhibitory effect on the development of the aerial parts (26-73%) and roots (13-79%) of the weeds and crops.     

Interference with soil phosphatase activity by maize herbicidal treatment and incorporation of maize residues

Summary This study is concerned with the way alachlor, atrazine and metolachlor interfered with phosphatase activity in a clay loam soil unenriched and enriched with maize residues. Enrichment caused an increase in all phosphatase activities (acid and alkaline phosphomonoesterase, phosphodiesterase, phosphotriesterase) tested. Interference with phosphatase activity following herbicidal treatment was found in both unenriched and enriched soil samples. Statistically significant interference was dependent on soil enrichment, the type of herbicide and its rate of application and the time elapsed since the herbicidal treatment. The observed changes in phosphatase activities are attributed to herbicidal action on phosphatase-producing microorganisms. Among the herbicides tested, the acetanilide derivatives exerted a lesser inhibiting effect than atrazine. Nevertheless, all the altered phosphatase activities showed a tendency, more or less rapid, to reach the levels in the corresponding untreated soil samples.     

Synthesis, herbicidal activities, and 3D-QSAR of 2-cyanoacrylates containing aromatic methylamine moieties

A series of novel 2-cyanoacrylates containing different aromatic rings were synthesized, and their structures were characterized by (1)H NMR, elemental analysis, and single-crystal X-ray diffraction analysis. Their herbicidal activities against four weeds and inhibition of photosynthetic electron transport against isolated chloroplasts (the Hill reaction) were evaluated. Both in vivo and in vitro data showed that the compounds containing benzene, pyridine, and thiazole moieties gave higher activities than those containing pyrimidine, pyridazine, furan, and tetrahedronfuran moieties. To further explore the comprehensive structure-activity relationship on the basis of in vitro data, comparative molecular field analysis (CoMFA) was performed, and the results showed that a bulky and electronegative group around the para-position of the aromatic rings would have the potential for higher activity, which offered important structural insights into designing highly active compounds prior to the next synthesis.     

Synthesis and herbicidal evaluation of novel 3-[(alpha-hydroxy-substituted)benzylidene]pyrrolidine-2,4-diones

A series of 3-[(alpha-hydroxy-substituted) benzylidene]pyrrolidine-2,4-dione derivatives were synthesized as candidate herbicides by reacting different aroyl acetates with N-substituted glycine esters. The new compounds were identified by 1H NMR spectroscopy and elemental analyses. Their herbicidal activities were evaluated. Some compounds exhibited excellent herbicidal activities at a dose of 187.5 g/ha. A suitable electron-donating substituent at the 2- and/or 4-position of the phenyl ring was essential for high herbicidal activity, a result that has not been reported before. It was also found that the title compound's structure-activity relationships were different from those of other similar kinds of earlier compounds, a result that may depend on the enol structure difference.     

Syntheses and herbicidal activities of novel triazolinone derivatives

Protoporphyrinogen oxidase (Protox, EC 1.3.3.4) has been identified as one of the most important action targets of herbicides. To search for novel Protox inhibitors, a series of title compounds 1, 2, and 3 were designed and synthesized by introducing three types of pharmacophores, cyclic imide, phenylurea, and ( E)-methyl 2-methoxyimino-2- o-tolylacetate, into the scaffold of triazolinone. The bioassay results indicated that the resulting cyclic imide-type triazolinones 1 displayed much better herbicidal activities than phenylurea-type triazolinones 2. Most fortunately, compound 3, methyl 2-[3-methyl-(2-fluoro-4-chloro-5-ethylsulfonamidephenyl)-4,5-dihydro-5-oxo-1 H-1,2,4-triazol-4-yl]methylenephenyl-2-( E)-methoxyiminoacetate, was found to be the most promising candidate due to its comparable herbicidal activity at 75-150 g of active ingredient/ha with the commercial product sulfentrazone. On the basis of test results of herbicidal spectrum and crop selectivity, compound 3 could be developed as a postemergent herbicide used for the control of broadleaf weeds in rice fields.     

Synthesis and herbicidal activity of 2-(7-fluoro-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)isoindoline-1,3-diones

The mode of action of 2-(7-fluoro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-4,5,6,7-tetrahydro-2H-isoindoline-1,3-diones, including the commercial herbicide flumioxazin, had been identified as inhibition of protoporphyrinogen oxidase (protox). As part of continuous efforts to search for new herbicides with high efficacy, broad-spectrum activity, and safety to crops, flumioxazin and its iodo analogue (B2055) were used as lead compounds for further optimization. Series of novel compounds were prepared by multistep synthetic procedures starting from 5-fluoro-2-nitrophenol. All of the test compounds were structurally confirmed by 1H NMR, IR, mass spectroscopy, and elemental analysis. Preliminary bioassay data showed that some of them possess commercial levels of herbicidal activity comparable to those of other protox-inhibiting herbicides. One of the best compounds, 5-fluoro-2-(7-fluoro-3-oxo-4-(prop-2-ynyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)isoindoline-1,3-dione (8e), has IC50 values for velvetleaf (Abutilon theophrasti Medic) and crabgrass (Digitaria sanguinalis) comparable to thos of B2055. With respect to crop selectivity, compound 8e is similar to flumioxazin. Compound 8e is safe to cotton and maize at a rate of 150 g of active ingredient (ai)/ha or less when applied at pre-emergent stage, and it has the best safety to wheat among the tested crops, showing no injury after post-emergent application at 7.5-30 g of ai/ha.     

Synthesis and herbicidal activities of novel 3-N-substituted amino-6-methyl-4-(3-trifluoromethylphenyl)pyridazine derivatives

4-(3-Trifluoromethylphenyl)pyridazine is a new series of compounds with bleaching and herbicidal activities. Starting from ethyl 2-(3-trifluoromethylphenyl)acetate, an important intermediate 7 was synthesized in five steps with a moderate total yield of 51.5% in a safe and practical way. Twenty-six novel 3-N-substituted amino-6-methyl-4-(3-trifluoromethylphenyl)pyridazine derivatives were synthesized and evaluated through a Spirodela polyrrhiza test and greenhouse test. Some compounds can completely inhibit Chl at 1 microg/mL and exhibit equal or higher herbicidal activities with the commercial bleaching herbicide diflufenican against dicotyledonous plants at a rate of 75 g/ha.     

Synthesis and phytotoxic activity of ozonides

The [4 + 3] cycloaddition of the proper furans with the oxyallyl cation, generated in situ from 2,4-dibromopentan-3-one, produced a series of 8-oxabicyclo [3.2.1]oct-6-en-3-ones. Exposure of the oxabicycles to ozone afforded the corresponding 8,9,10,11-tetraoxatricyclo[5.2.1.1 (2,6)]undecan-4-ones in variable yields (7-100%). The phytotoxic properties of these ozonides (or 1,2,4-trioxolanes) and their oxabicycle precursors were evaluated as the ability to interfere with the growth of Sorghum bicolor and Cucumis sativus seedlings. Among oxabicycles, the highest inhibitory activity was shown by compounds possessing a alpha,beta-unsaturated carbonyl moiety. A differential sensitivity of the two crops was evident with ozonides. The most active compounds were also tested against the weed species Ipomoea grandifolia and Brachiaria decumbens. To the best of our knowledge, this is the first article describing ozonides as potential herbicides.     

Chemical synthesis, in vitro acetohydroxyacid synthase (AHAS) inhibition, herbicidal activity, and computational studies of isatin derivatives

Acetohydroxyacid synthase (AHAS) catalyzes the first common step in the biosynthesis of the branched-chain amino acids. As a result of its metabolic importance in plants, it is a target for many commercial herbicides. Virtual screening analysis inspired the evaluation of 19 commercially available isatin analogues and 13 newly synthesized isatin derivatives as novel AHAS inhibitors and for their herbicidal activity. The best compound demonstrated 95% inhibition of the activity of Arabidopsis thaliana AHAS at a concentration of 100 mg L(-1), whereas the herbicidal activities of three compounds reached 50% inhibition at a concentration of 10 mg L(-1) using the rape root growth test. CoMFA contour models were established to understand the structure-activity relationships for this class of AHAS inhibitor. The compounds were docked to the active site cavity of A. thaliana AHAS using FlexX, and the dominant binding mode was consistent with frontier molecular orbital from DFT calculations. This is the first comprehensive study of isatin derivatives as AHAS inhibitors and provides a valuable starting point for the design of new herbicides.     

Synthesis and fungicidal activity of novel 2-oxocycloalkylsulfonylureas

A series of 2-oxocycloalkylsulfonylureas (2) have been synthesized in a six-step, three-pot reaction sequence from readily available cyclododecanone, cycloheptanone, and cyclohexanone. Their structures were confirmed by IR, 1H NMR, and elemental analysis. The bioassay indicated that some of them possess certain fungicidal activity against Gibberella zeae Petch. In general, compounds containing a 12-membered ring (2A) are more active than those containing a 6- or 7-membered ring (2B, 2C). In the series 2A, the compounds in which R is a disubstituted phenyl or pyrimidyl showed better activity than those in which R is a monosubstituted phenyl or pyrimidyl, and aryl-substituted compounds have somewhat higher activity than those substituted by pyrimidyl. The further bioassay showed that the representative of 2A, 2A15, has good fungicidal activities against not only G. zeae Petch but also Botrytis cinerea Pers, Colletotrichum orbiculare Arx, Pythium aphanidermatum Fitzp, Fusarium oxysporum Schl. f. sp. Vasinfectum, etc.     

Synthesis and antifungal activity of novel sclerotiorin analogues

Sclerotiorin 1, first isolated from Penicillium sclerotiorum, has weak antifungal activity and belongs to the azaphilone-type family of natural products. Several series of sclerotiorin analogues were designed and synthesized with the aim of discovering novel fungicides with improved activity. The syntheses involved two key steps, cycloisomerization and then oxidation, and used a simple and efficient Sonogashira cross-coupling reaction to construct the required functionalized precursor. With sclerotiorin as a control, the activities of the newly synthesized analogues were evaluated against seven fungal pathogens, and several promising candidates (compounds 3a?, 3d?, 3e?, 3f? and 3k?) with greater activity and simpler structures than sclerotiorin were discovered. In addition, preliminary structure-activity relationships were studied, which revealed that not only the chlorine or bromine substituent at the 5-position of the nucleus but also the phenyl group at the 3-position and the substituent pattern on it contributed crucially to the observed antifungal activity. Analogues with a methyl substituent at the 1-position have reduced levels of activity, while those with a free hydroxyl group in place of acetoxy at the quaternary center of the bicyclic ring system retain activity.