The pyrethrins and related compounds. Part XXII. Preparation of isomeric cyano-substituted 3-phenoxybenzyl esters

Preparation of 3-phenoxybenzyl chrysanthemates and their dihalovinyl analogues substituted with a cyano group at the 2-, 6-, (R)-α-, or (S)-α- positions is described. The (R)- and (S)- isomers of α-cyano-3-phenoxybenzyl esters of 2,2-difluoro-, -dichloro-, and -dibromo-vinyl analogues of cis- and trans- chrysanthemic acid are separated chromatographically, as are the separate pairs of enantiomers of fenvalerate, (RS)-α- cyano-3-phenoxybenzyl (RS)-2-(4-chlorophenyl)-3-methylbutyrate. An optically active ester of α-cyano-3-phenoxybenzyl alcohol (obtained using D -oxynitrilase) with 2,2,3,3-tetramethylcyclopropanecarboxylic acid is synthesised.     

The metabolism of the pyrethroid insecticide (±)-α-cyano-3-phenoxybenzyl 2,2,3,3-tetramethyl-cyclopropanecarboxylate,WL 41706, in the rat

The metabolism of the pyrethroid insecticide α-cyano-3-phenoxybenzyl 2,2,3,3-tetramethylcyclopropanecarboxylate (WL 41706) has been studied in rats using two forms of ¹⁴C-labelling (benzyl- and cyclopropyl-). Excretion of benzyl^?14C was rapid, 57% of the administered dose being eliminated in the urine 48 h after treatment and 40% in the faeces. No significant sex difference was observed. The amount of radioactivity excreted via expired gases was 0.005% of the administered dose and less than 1.5% of the dose remained in the animals 8 days after treatment. The mean percentage recovery of administered dose was 104% for male rats and 97% for female rats. Urinary and faecal metabolites from these rats, and from rats dosed similarly with [cyclopropyl^?14C]-WL 41706 were studied. The rapid metabolism of WL 41706 is due to efficient cleavage of the ester bond by rats in vivo to afford 2,2,3,3-tetramethylcyclopropanecarboxylic acid (partly as glucuronide) and the 3-phenoxybenzyl moiety. Before this cleavage occurs, however, about half of the intake suffers aryl hydroxylation giving the α-cyano-3-(4-hydroxyphenoxy)benzyl ester, part of which is excreted in the bile as a conjugate(s) and part of which is cleaved and eliminated as the O-sulphate of 3-(4-hydroxyphenoxy)benzoic acid and the glucuronide of 2,2,3,3-tetramethylcyclopropanecarboxylic acid. A minor amount of hydroxylation occurs at a trans-methyl group on the cyclopropane acid moiety. The metabolism of WL 41706 by rat liver occurs mainly in the microsomes and mainly via oxidative processes.     

The pyrethrins and related compounds; Part XXIV: synthesis, 13C-nuclear magnetic resonance spectra and insecticidal activity of cycloalkyl analogues of fenvalerate

Close isosteres of fenvalerate [(RS)-α-cyano-3-phenoxybenzyl (RS)-2-(4-chlorophenyl)-3-methylbutyrate], in which cyclopropyl groups replace isopropyl have insecticidal activity close to or greater than the parent compounds, and diminished intravenous toxicity to rats. A direct toxicological relationship of these compounds to fenvalerate itself and to chrysanthemate esters is indicated by the consistently greater activity of esters from one of an enantiomeric pair of acids. Other esters with larger alkyl or cycloalkyl groups, or spiropentane analogues of chrysanthemates are less active insecticides. ¹³C-Nuclear magnetic resonance spectra suggest that in the α-cyanobenzyl esters there is an intramolecular through-space interaction in solution. The relationships between the chemical structures of the compounds synthesised and their relative activities to different insect species and toxicity to rats are discussed.     

Effects of pyrethroid structure on rates of hydrolysis and oxidation by mouse liver microsomal enzymes

Studies on the metabolism rates of 44 pyrethroids and 24 model compounds in mouse liver microsomal systems serve to divide the substrates into three groups based on their ease of hydrolysis and oxidation. Primary alcohol esters of trans-substituted cyclopropanecarboxylic acids are most rapidly metabolized with hydrolysis generally serving as the major component of the total metabolism rate. Although hydrolyzed slowly or not at detectable rates, the primary alcohol cis-substituted cyclopropanecarboxylates, tetramethylcyclopropanecarboxylates, and p-chlorophenyl-α-isopropylacetates are rapidly oxidized. The highly insecticidal α-cyano-3-phenoxybenzyl esters are least susceptible to metabolic attack due to both reduced esterase rates attributable to α substitution in the alcohol moiety and reduced oxidase rates for which no adequate explanation is currently available. Other structural modifications in the acid and alcohol moieties are less important in determining the metabolism rates. The substrate specificities of the microsomal esterases and oxidases are compared with in vivo pyrethroid structure-biodegradability relationships.     

The action of pyrethroids in the insect central nervous system. I. Features of molecular structure associated with toxicity to cockroaches and to their giant fibre axons

To investigate relationships between the molecular structure of pyrethroids and their mode of action, toxicities to adult male Periplaneta americana by topical application and injection were compared with toxicities to their giant fibre nerve axons. From the tests against intact insects it was concluded that: (i) although ED₅₀S ranged from 0.04 to 65 μg/insect, each compound was equally toxic, with one exception, when administered by either route; (ii) esters of (1 R)-cis- were more toxic than esters of the corresponding (1 R)-trans-3-substituted-2, 2-dimethylcyclopropanecarboxylic acids; (iii) α-cyano-3-phenoxybenzyl esters were more toxic than the corresponding 3-phenoxybenzyl esters; (iv) changes in the alcoholic component of some compounds (particularly trans-isomers of esters of 5-benzyl-3-furylmethanol and esters of α-cyano-3-phenoxybenzyl alcohol) affected a recovery phase in their ED₅₀/time curves more than changes in the acid component; (v) the amount of recovery was positively correlated with molecular polarity. The concentration required to decrease the amplitude of the action potential of giant fibres by 30% in 1 h ranged from 0.26 μM for the most active compound to 100 μM for the least active. There was no clear relationship between neurotoxicity and toxicity to whole insects and little association between neurotoxicity and features of molecular structure. Neurotoxicity was, however, positively correlated with polarity. Giant fibre axons seem unlikely to be critical sites of action of pyrethroids.     

The pyrethrins and related compounds. Part XXXVIII—optimisation of insecticidal activity in 3-[(alkoxyimino)methyl]-4-fluorobenzyl esters

Optimisation of activity in 3-[(alkoxyimino)methylbenzyl] esters has been investigated by introducing an α-cyano group and a fluorine atom in position 4 of the benzylic moiety in conjunction with varying the length and nature of the side chain. Of the five side-chain variations investigated, the 3-methoxyiminomethyl was more effective than others. Introduction of fluorine in position 4 of the benzylic moiety generally increased activity, particularly against mustard beetles, as in previous instances. Surprisingly, the effect on insecticidal activity of introducing an α-CN group ranged from positive to negative depending upon the nature of the alkoxyimino substituent, an effect not observed previously. The most effective esters were derived from α-cyano-4-fluoro-3-[(methoxyimino)methyl]benzyl alcohol, which was synthesised from 2-{4-fluoro-3-[(hydroxyimino)methyl]phenyl}-1,3-dioxolane.     

Synthesis and insecticidal activity of 3-(haloalkyl-1,3-dienyl)-2,2-dimethylcyclopropanecarboxylates

New 2,2-dimethylcyclopropanecarboxylic acids bearing halogenated 1,3-alkadienyl substituents at position 3 of the cyclopropane ring were synthesised and the insecticidial activities of their 3-phenoxybenzyl and α-cyano-3-phenoxybenzyl esters against housefly (Musca domestica), Colorado potato beetle (Leptinotarsa decemlineata) and Egyptian cotton leafworm (Spodoptera littoralis) were determined. The activity of these compounds varied according to the relative position of the halogen substituents on the diene chain. The observed changes of activity with the structure of the side chain are discussed in terms of the coplanarity of the conjugated double bonds.     

Insecticidal activity of the pyrethrins and related compounds. VII. Insecticidal dihalovinyl analogues of cis and trans chrysanthemates

Eighteen esters of resolved cis- and trans-3-(2,2-difluoro, -dichloro or -dibromovinyl)-2,2-dimethylcyclopropanecarboxylic acids with 5-benzyl-3-furylmethyl, 3-phenoxybenzyl and α-cyano-3-phenoxybenzyl alcohols were prepared and evaluated for insecticidal activity against Musca domestica L. and Phaedon cochleariae Fab. Chlorine and bromine substituted esters are more active, in general, than those with fluorine, and in the most active esters, the cis isomer is more effective than the trans.     

Metabolism of the cis- and trans-isomers of cypermethrin in mice

Metabolism in mice of the separated cis- and trans-isomers of the pyrethroid insecticide cypermethrin (NRDC 149), (RS)-α-cyano-3-phenoxybenzyl (1RS)-cis, trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate, was investigated in each case with preparations that were ¹⁴C-labelled in the benzyl and cyclopropyl moieties. Radioactivity from the trans-isomer was mainly excreted in the urine and that from the cis-isomer in the faeces. Elimination of both isomers was rapid except for a small portion (approximately 2%) of the cis-isomer which was released from the fat with a half-life of approximately 13 days. Metabolism of cypermethrin occurred mainly by ester cleavage and elimination of the cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethyl- cyclopropanecarboxylic acid moieties as glucuronide conjugates. The α-cyano-3-phenoxybenzyl alcohol released by ester cleavage was mainly converted to 3-phenoxy-benzoic acid which was partly eliminated unchanged, partly conjugated with aminoacids (mainly taurine) and glucuronic acid, and partly oxidised to 3-(4-hydroxyphenoxy) benzoic acid which was excreted as the sulphate conjugate. Metabolites retaining the ester linkage were formed by hydroxylation at various sites in the molecule with more hydroxylation of the cis- than of the trans-isomer occurring.     

The pyrethrins and related compounds. Part XXX: Esters from acids with mono-halovinyl side chains

Esters of 3-phenoxybenzyl alcohol and its α-cyano derivative with 2,2-dimethylcyclopropanecarboxylic acids bearing (E)- or (Z)-3-monohalovinyl side chains (haloiodo, bromo, chloro or fluoro) were synthesised and had moderate to high insecticidal activities, but these were generally lower than those of established pyrethroids with the corresponding 3-(dihalovinyl) side chains. Compounds with 3-(2-chloroprop-1-enyl) side chains were intermediate in potency between the related chrysanthemates and 3-(dichlorovinyl) esters.     

Separation and identification of short-lived free radicals formed by photolysis of the pyrethroid insecticide fenvalerate

Using a spin-trap reagent 3-nitrosodurene (1,2,4,5-tetramethyl-3-nitrosobenzene), the short-lived free radicals generated by ultraviolet irradiation of fenvalerate [(RS)-α-cyano-3-phenoxybenzyl (RS)-2-(4-chlorophenyl)-3-methylbutyrate] in degassed benzene or dichloromethane, were scavenged as the more stable nitroxide radicals. These radicals were separated by high-performance liquid chromatography and identified individually by electron-spin resonance spectroscopy, as well as by gas chromatography/mass spectrometry. As a result, they were found to be the spin adduct mixtures of the 4-chloro-α-isopropylbenzyl and α-cyano-3-phenoxybenzyl radicals, which are involved in the photo-induced decarboxylation process of fenvalerate. Discrimination of the radicals was also performed by the isotope-labelling method whereby the benzylic proton in the acid moiety was deuteriated. The spin numbers of the nitroxides decreased by about five-fold when photolysis was carried out in oxygenated benzene solution. N-Benzylidene-tert-butylamine N-oxide trapped both radicals but much less efficiently. The nitroxide of the 4-chloro-α-isopropylbenzyl radical was predominant at 25°C or –40°C, but the proportion of the α-cyano-3-phenoxybenzyl nitroxide radical increased at the lower temperature.     

The vinylogous relationship in some pyrethroids

Attention is drawn to a vinylogous relationship between the structure of certain biologically-active pyrethroids. A series of racemic α-cyano-3-phenoxybenzyl 2-(2,2-dichlorovinyl)-1-phenylcyclopropanecarboxylates, based on this relationship, were synthesised and were found to be only moderately toxic to Musca domestica, Spodoptera littoralis and Leptinotarsa decemlineata.     

α-氰基-3-苯氧基苄醇乙酸酯立体选择性水解酯酶产生菌的筛选及酶学特性初探

经过酵母菌富集培养,以α-氰基-3-苯氧基苄醇乙酸酯为唯一碳源培养和分离,并进一步用手性HPLC法复筛,得到了两株优先立体选择性水解(S)-α-氰基-3-苯氧基苄醇乙酸酯的酵母菌菌株S11和S25。两株酵母菌均能产生耐酸酯酶,在pH 3.0时对α-氰基-3-苯氧基苄醇乙酸酯进行立体选择性水解,产物对映体过量值(ee/em>p)均在95％以上,转化率(C)分别达50％和46％。测定了菌株S11的生长曲线,并对其产酶特性进行了初探,发现其所产酶为生长偶联型的胞内酶。     

2-anilino-3-methylbutyrates and 2-(isoindolin-2-yl)-3-methylbutyrates,two novel groups of synthetic pyrethroid esters not containing a cyclopropane ring

A new series of substituted 2-anilino-3-methylbutyrates has been prepared; bioassay data for these compounds on Heliothis virescens, Musca domestica, Aphis fabae and Tetranychus urticae are presented and discussed. Some unexpected relationships were observed between the nature of the substituents and the biological activity. Increases in foliar stability were noted with certain substitution patterns. Both α-cyano-3-phenoxybenzyl 3-methyl-2-(α, α, α,2-tetrafluoro-p-toluidino)butyrate and the corresponding 2-(2-chloro-α, α, α-trifluoro-p-toluidino)-3-methylbutyrate showed good stability in air and light, and exhibited biological activities of a similar nature and potency to those of previously known synthetic pyrethroids. Esters of the (R)-2- anilino-3-methylbutyric acids are far more active than those prepared from the (S)-enantiomers. The (R)-configuration at C-2 in these acids is sterically equivalent to the active absolute configuration at the chiral carbon α to the carboxylate group in both the permethrin and the fenvalerate types of pyrethroids. A new class of insecticidal 2-(isoindolin-2-yl)alkanoates is also reported. In this series the most biologically active analogue was α-cyano-3-phenoxybenzyl 3-methyl-2-(4,5,6,7-tetrafluoroisoindolin-2-yl)butyrate. These esters were considerably less stable than the anilino analogues on exposure to air and light.     

The metabolism of fenvalerate in plants: The conjugation of the acid moiety

The metabolism of the pyrethroid insecticide fenvalerate [(RS)-α-cyano-3-phenoxybenzyl (RS)-2-(4-chlorophenyl)-3-methylbutyrate] ( I ), and of its most insecticidal (αS,2S) isomer ( II ), has been examined in cabbage plants grown and treated under laboratory conditions with [¹⁴C]chlorophenyl- and [ring-¹⁴C]benzyllabelled preparations of the two compounds. Both insecticides disappeared from the treated leaves with similar half-lives of approximately 12–14 days; they underwent ester cleavage to a significant extent, together with some hydroxylation at the 2- or 4-position of the phenoxy ring, and hydrolysis of the nitrile group to amide and carboxyl groups. Most of the carboxylic acids and phenols thus produced occurred as glycoside conjugates. In separate experiments, the uptake and metabolism of 2-(4-chlorophenyl)-3-methylbutyric acid ( X ), the acidic half of the molecule, were examined in the laboratory, using abscised leaves of kidney bean, cabbage, cotton, cucumber and tomato plants. The acid X was found to be readily converted, mainly into glucose and 6-O-malonylglucose esters in kidney bean, cabbage and cucumber plants, into glucosylxylose, sophorose and gentiobiose esters in cotton, and into two types of triglucose esters with differing isomerism in tomato. One of the acetyl derivatives of the trisaccharide conjugates was identical with the synthetic deca-acetyl derivative of the [1 → 6]-triglucose ester.     

Pyrethroid toxicology in the frog

Adult Rana pipiens pipiens (Shreber) are highly sensitive to insecticidal α-cyano-3-phenoxybenzyl esters administered subcutaneously, i.e., LD₅₀ 0.13–0.35 mg/kg for deltamethrin and the most potent isomer of each of cis-cypermethrin, fenpropathrin, and fenvalerate and 0.65 mg/kg for (1R,αS)-trans-cypermethrin. Pyrethroids lacking the α-cyano substituent [pyrethrins, S-bioallethrin, kadethrin, and the Cis- and trans-isomers of (1R)-tetramethrin, (1RS)-resmethrin, (1R)-phenothrin, and (1R)-permethrin] vary greatly in their toxicity (LD₅₀ 0.14 to > 60 mg/kg) and the trans isomers are much less toxic than the corresponding cis isomers. The trans/cis specificity is due in large part to relative detoxification rates based on synergism studies with the resmethrin and permèthrin isomers and liver pyrethroid esterase assays with the permethrin and cypermethrin isomers. Poisoning by the noncyano compounds involves hyperactivity and tremors whereas by the cyanophenoxybenzyl esters involves tonic seizures and choreoathetosis, i.e., types I and II syndromes, respectively. Picrotoxinin, t-butylbicyclophosphate, and five other small cage compounds give a third type of syndrome with clonic seizures. Diazepam and its 2′-fluoro-4-methyl-4,5-dihydro analog (RO 5-3636) are more effective than 23 other compounds tested in protecting against deltamethrin toxicity. Diazepam is most effective in alleviating the Type II syndrome, intermediate with the type I syndrome, and is not active with picrotoxinin.     

Interception and persistence of parathion and fenvalerate on cotton plants as a function of application method

Parathion (O,O-diethyl O-4-nitrophenyl phosphorothioate) and fenvalerate [(RS)-α-cyano-3-phenoxybenzyl (RS)-2-(4-chlorophenyl)-3-methylbutyrate] were applied by controlled droplet applicators (CDAs) and conventional hydraulic nozzles in refined soybean oil, soybean oil + water, or water, to mature cotton plants (Gossypium hirsutum L.) as ULV (ultra-low volume, < 5 litre ha^?1), VLV(very low volume, 5-50 litre ha^?1), or LV(low volume, 50–200 litre ha^?1) carrier rates. The use of CDA or soybean oil applied as ULV and VLV sprays did not produce greater deposition or persistence for either insecticide during the 49-h test period following application. In general, insecticide persistence was greatest when applied with water or soybean oil + water as LV sprays using the conventional TX8 hydraulic nozzle.     

Research into fluorinated pyrethroid alcohols—an episode in the history of pyrethroid discovery

An account of pyrethroid research from 1975 to 1985 at Bayer AG is given. The exploitation of fluorine chemistry for this purpose led to increased activity of known 3-phenoxybenzyl pyrethroid esters and to the commercialisation of the broad-spectrum insecticide cyfluthrin, the particularly tick-toxic flumethrin and the rapid-acting household insecticides fenfluthrin and transfluthrin. The last two constituted in 1976 a novel type of pyrethroid, based on polyfluorinated benzyl alcohols, off the mainstream of published pyrethroid research. Transfluthrin, the single isomer (1R)trans-permethric acid ester of 2,3,5,6-tetrafluorobenzyl alcohol has just been introduced to the market. The history of its discovery and structure–activity data as well as resistance considerations regarding cyfluthrin, are presented. © 1998 SCI.     

Comparative fungitoxicity of the insecticide permethrin and ten degradation products

The toxic effects of permethrin and ten of its degradation products on the growth of ten fungi were determined. Permethrin was relativelynon-toxic, with an EC₅₀ of > 100 mg litre^?1 but six of the degradation products were significantly (P= 0.05) more inhibitory. The ester hydrolysis products, 3-phenoxybenzyl alcohol and 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid, had EC₅₀ values ranging from 8 to > 100 and 20 to > 50 mg litre^?1, respectively. Other degradation products that were more toxic than permethrin included 3-phenoxybenzaldehyde and 3-phenoxybenzoic acid, with EC₅₀ values as low as < 1 mg lite^?1. Hydroxylated and substituted-benzene metabolites were non-toxic. Combinations of selected test compounds yielded both synergistic, antagonistic and additive interaction responses, depending upon the test system employed.