Pyrethroid insecticides derived from substituted biphenyl-3-ylmethanols

The synthesis of a series of mono- and disubstituted biphenyl-3-ylmethyl esters of 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid is described. The bioactivity of these compounds against Spodoptera eridania, Epilachna varivestis, Oncopeltus fasciatus, Acrythosiphon pisum and Tetranychus urticae is presented and discussed. Substitution of fluorine, chlorine and methyl groups in the 2-position of the biphenyl ring generally led to an increase in activity over the unsubstituted parent biphenyl ester. In addition, pyrethroid esters derived from these 2-substituted biphenyl-3-ylmethanols appeared to have a broader spectrum of activity than ‘classical’ pyrethroids. For example, the (1RS)-cis-3-(2,2-dichlorovinyl)-2, 2-dimethylcyclopro-panecarboxylic acid ester of 2-methylbiphenyl-3-ylmethanol was acaricidal, while maintaining a level of activity against other insects that was equal to or greater than cis-permethiin. Biological data on other esters of this novel alcohol are also presented.     

The uptake of metabolites of permethrin by plants grown in soil treated with [14C]permethrin

Sugar beet, wheat, lettuce and cotton were grown in soil treated with [¹⁴C]permethrin, the crops being sown at intervals of 30, 60 and 120 days after treatment of the soil. The uptake of radioactive residues into these crops was measured. Low radioactive residues (up to 0.86 μg g^?1) were detected in the mature plants sown 30 days after soil treatment, and this uptake declined significantly as the interval between soil treatment and sowing increased. Metabolites derived from the acid moiety of the permethrin molecule were shown to constitute the greater part of the residue transferring from the soil to the crops. (1RS)-cis- and (1RS)-trans-3-(2,2-dichlorovinyl)- 2,2-dimethylcyclopropanecarboxylic acid and 3-(2,2-dichlorovinyl)-1-methylcyclopropane-1,2-dicarboxylic acid were identified as the major acidic metabolites. The latter compound is a metabolite of permethrin which has not previously been identified in soil or plants.     

The pyrethrins and related compounds. XIX Geometrical and optical isomers of 2,2-dimethyl-3-(2,2-dichlorovinyl)-cyclopropanecarboxylic acid and insecticidal esters with 5-benzyi-3-furylmethyi and 3-phenoxybenzyl alcohols

Esters of 2,2-dimethyl-3-(2,2-dichlorovinyl)-cyclopropanecarboxylic acid with appropriate alcohols are more active insecticides than the corresponding 3-isobutenyl compounds (chrysanthemates). (±)-Cis and (±)-trans forms of the dichloro acid are obtained by fractional crystallisation of the mixed acids or by hydrolysis of the ethyl esters separated by fractional distillation. The (±)-cis and (±)-trans acids are resolved into their (+)- and (-)-forms with α-methyl-benzylamine and threo-l-p-nitrophenyl-2-N,N-dimethyiamino-propane-1,3-diol respectively. As for the corresponding chrysanthemates, the (+)-cis and (+)-trans acids give esters more active as insecticides than their enantiomers.     

The optical isomers of α-cyano-3-phenoxybenzyl 3-(1,2-dibromo-2,2-dichloroethyl)-2,2-dimethylcyclo-propanecarboxylate and their insecticidal activities

Bromination of the dichlorovinyl group of cypermethrin yielded a new compound which is a highly potent insecticide. This dibromo adduct has four asymmetric centres and therefore can exist as a mixture of 16 stereoisomers. To establish the influence of the absolute configuration at the chiral centres on the biological activities of these isomers, each of the isomers was isolated; their insecticidal activities against larvae of Heliothis virescens, and adult Calliphora erythrocephala and Blattella germanica were then determined and compared with those of (S)-α-cyano-3-phenoxybenzyl (1R)-cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate (deltamethrin NRDC 161), of fenvalerate, and of the eight stereoisomers of cyper methrin.     

A stereoselective versatile synthesis of 3-(2,2- dihalovinyl)-2,2-dimethylcyclopropanecarboxylic acids

A straightforward high-yield synthesis of cis-3-(2,2-dihalovinyl)-2,2-dimethylcyclo-propanecarboxylic acids is described which uses only inexpensive starting materials and reagents. The synthesis of these acids, involving a [2+2]-cyclo-addition of halogenated ketenes with 2-methylpropene and two rearrangements (the ?cine’? and the Favorskii rearrangements) as the key steps, exemplifies the conceptually new synthesis.     

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.     

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.     

1(R)-(2,6-cis-dimethylmorpholino)- 3(S)-(p-tert-butylphenyl)cyclopentane: A representative of a novel,potent class of bio-rationally designed fungicides

Inhibition of the Δ⁸-Δ⁷ sterol isomerase in the ergosterol biosynthesis pathway is known to lead to fungistatic or even fungicidal effects. Our approach to the rational design of new putative inhibitors of the enzyme was based on the assumed mechanism of the enzymic transformation and in particular on the structure of the unstable carbocationic intermediate, i.e. the ‘transition-state-analogue’ principle. The synthesis and the biological properties of 1(R)-(2,6-cis- dimethylmorpholino)-3(S)-(p-tert-butylphenyl)cyclopentane, a representative of a novel, potent class of rationally designed fungicides, as well as the synthesis and biological activities of several other related compounds are described and discussed.     

Actions of pyrethroid insecticides on insect axonal sodium channels

The actions of pyrethroid insecticides were tested on isolated giant axons of the cockroach Periplaneta americana, using oil-gap, single-fibre recording techniques. Current-clamp and voltage-clamp experiments were used to determine the actions of pyrethroids on axonal membrane potentials and ionic currents. Treatment with deltamethrin at micromolar concentrations caused gradual depolarisation of the axon accompanied by a reduction in amplitude of the action potential. This depolarisation was enhanced by an increase in stimulation frequency. Other synthetic pyrethroids: 3,4,5,6-tetrahydrophthalimidomethyl (1RS)-cis-3-[(RS)-2,2-dimethylcyclopropyl]-2,2-dimethylcyclopropanecarboxylate, biopermethrin and its (1S)-enantiomer, (1R)-tetramethrin, S-bioallethrin, bioresmethrin and its (1S)-enantiomer, cismethrin, and 5-benzyl-3-furylmethyl (E)-(1R)-cis-2,2-dimethyl-3-(2-oxothiolan-3-ylidenemethyl)cyclopropanecarboxylate (RU-15525, ‘Kadethrin’) were investigated. The (1S)-enantiomers were inactive, but all the other pyrethroids tested, apart from deltamethrin, induced prolonged negative (depolarising) after-potentials. All the treatments with the active pyrethroids resulted in the appearance of a voltage and time-dependent ‘maintained’ sodium conductance. The duration of this ‘slow’ conductance varied considerably depending on the pyrethroid under test. Clearly, the effectiveness of pyrethroids on whole insects is not determined only by the degree to which they directly modify the properties of sodium channels. Nevertheless, voltage-clamp experiments on isolated axons readily permit direct comparison of the actions of different pyrethroids on the sodium channels of insect neurones.     

Chemistry and biosynthesis of natural pyrethrins

A short account is given of the occurrence, separation, and properties of the insecticidal ester pyrethrins from Chrysanthemum cinerariaefolium. Methods for the synthesis of the two component acids, chrysanthemic and 'chrysanthemumdicarboxylic acid' [3-(2-carboxyprop-1-enyl)-2,2-dimethylcyclopropanecarboxylic acid], and the alcohols (rethrolones) are surveyed, and brief consideration is given to the limited knowledge of the biosynthesis of this group of compounds.     

The activity of some pyrethroids against Periplaneta americana and Blattella germanica

The knockdown and contact killing actions of various pyrethroids were compared using Blattella germanica and Periplaneta americana. A wide range of knockdown activity was found; 5-benzyl-3-furylmethyl (1R)-cis-3-(dihydro-2-oxo-3-thienylidenemethyl)-2,2-dimethylcyclopropanecarboxylate (RU 15525) acted fastest, more rapidly than pyrethrins, against B. germanica as well as having a low LD₅₀ value. Topical application and direct spray tests showed that (S)-α-cyano-3-phenoxybenzyl (1R)-cir-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate (NRDC 161) was more active as a killing agent, by an order of magnitude, than cismethrin, the next most active compound, and also had considerable knockdown activity. Piperonyl butoxide generally had little synergist effect. Female P. americana were over three times more tolerant than males to a range of insecticides applied topically. Residual knockdown action in the WHO resistance test was observed to provide baseline data. There was little overlap in speed of action between pyrethroids and other insecticides among the compounds tested.     

The bromination of highly halogenated chrysanthemic acid analogues

(Z)-cis- and (Z)-trans-3-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethylcyclo-propanecarboxylic acids react with bromine under radical conditions predominantly to open the cyclopropane ring; the stereochemistry and reactions of the dibromides thus formed are described.     

Degradation of the pyrethroid cypermethrin NRDC 149 (±)-α-cyano-3-phenoxybenzyl (±)-cis,trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate and the respective cis-(NRDC 160) and trans- (NRDC 159) isomers in soils

The degradation of the pyrethroid insecticide cypermethrin and the geometric isomers NRDC 160 (cis-) and NRDC 159 (trans-) in three soils has been studied under laboratory conditions. Samples of the insecticides labelled separately with ¹⁴C in the cyclopropyl and benzyl rings were used. The rate of degradation was most rapid on sandy clay and sandy loam soils, 50% of the NRDC 160 and NRDC 159 applied to both soils being decomposed in 4 weeks and 2 weeks respectively. The major degradative route in all soils was hydrolysis of the ester linkage leading to the formation of 3-phenoxybenzoic acid and 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid; soil treated with the cis-isomer (NRDC 160) was found to contain both cis- and trans-isomer forms of the cyclopropanecarboxylic acid. Further degradation of these carboxylic acids was evident since ¹⁴CO₂ was released from cyclopropyl- and benzyllabelled cypermethrin in amounts equivalent to 24 and 38% of the applied radioactivity over a 22 week period. A minor degradative route was ring-hydroxylation of the insecticide to give an α-cyano-3-(4-hydroxyphenoxy)benzyl ester followed by hydrolysis of the ester bond. Under waterlogged conditions the rate of hydrolysis of cypermethrin on sandy loam soil was slower than under aerobic conditions and 3-phenoxybenzoic acid accumulated in the anaerobic soil.     

The pyrethrins and related compounds. Part XXIX: Haloallylbenzyl esters

Synthesis and bioassay of a series of esters based on pyrethroidal acids established that the activity of halosubstituted allylbenzyl esters depends on the position and stereochemistry of substitution in the allyl side-chain, on the substitution pattern on benzyl, on the esterifying acid, and, to a lesser extent, on the nature of the halogen substituent itself. The most powerful combination of the first four parameters for activity against houseflies is in (Z)-3-haloallylbenzyl esters of the (1R)-cis 3-(2,2-dibromovinyl) acid. Other combinations have moderate to low activity. Some aspects of the variation conform to previously recognised patterns, others define more precisely the requirements for the side-chain to confer activity. The pattern of response of activity to cyano-substitution at the α-position, noted earlier, persists in the current compounds, and is here analysed quantitatively.     

Structure and insecticidal activities of pyrethroids available through new methods of synthesis

Starting from derivatives of cyclobutanone the synthesis is described of α-cyano-3-phenoxybenzyl esters of 2,2-dimethylcyclopropanecarboxylic acid, substituted in the 3-position of the cyclopropane ring by an alkoxy, alkylthio, phenoxy or phenylthio group. The insecticidal activities of these synthetic pyrethroids towards adult Musca domestica, and larvae of Aedes aegypti, Spodoptera littoralis and Heliothis virescens are reported and compared with known pyrethroids.     

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.     

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 conjugation and accumulation of metabolites of cypermethrin by earthworms

When earthworms are maintained in soil containing [¹⁴C]cypermethrin they accumulate radioactive residues. These residues are not eliminated when the worms are transferred to untreated soil. The accumulated radioactive residue is a complex mixture of conjugates of two metabolites of cypermethrin (3-phenoxybenzoic acid and (1RS)-cis, trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid). One major constituent of this mixture of conjugates has been identified as N¹, N¹²-di-(3-phenoxybenzoyl)spermine. Feeding studies with quail and rats have established that the residues accumulated by the earthworms are not further bioaccumulated by earthworm predators.     

Synthetic pyrethroids containing a C–C triple bond

The three commercial synthetic pyrethroids containing a carbon–carbon triple bond, α-ethynyl-2-methylpent-2-enyl (1R)-trans-chrysanthemate, (S)-2-methyl-4-oxo-3-(2-propynyl)cyclopent-2-enyl (1R)-trans,cis-chrysanthemate and [2,5-dioxo-3-(2-propynyl)-1-imidazolidinyl]methyl (1R)-trans-chrysanthemate are reviewed with emphasis on their inventive histories. Their chemistry and efficacy are described briefly. The relationship between stereochemistry and the biological activity is also discussed. © 1998 SCI.