Insecticidal activity of the pyrethrins and related compounds. Part XI. Relative potencies of isomeric cyano-substituted 3-phenoxybenzyl esters

The insecticidal activities to Musca domestica L. and Phaedon cochleariae Fab. of a series of 3-phenoxybenzyl pyrethroid esters with a cyano substituent at the 2-, 6-. (R)-α-, or (S)-α-position are compared with those of the unsubstituted analogues. Only an (S)-α-substituent enhances activity; others diminish or almost eliminate it. (RS)-α-mixtures are generally less active than would be predicted from the potencies of their separate constituents.     

Insecticidal activity of the pyrethrins and related compounds. Part XII: α-substituted-3-phenoxybenzyl esters

Seventy-three α-substituted 3-phenoxybenzyl esters were synthesised, mostly using one of two general routes, based on the Grignard and related reactions. Esters with simpler (smaller and more polar) α-substituents were generally more insecticidally active; correlations based on substituent volume and substituent polarity parameters were about equally significant.     

The pyrethrins and related compounds. Part xxxi: Alkoxyimino-substituted esters

Esters derived from pyrethroidal acids and benzyl and furylmethyl alcohols bearing a wide range of side-chains each containing at least one oxime ether group, and related derivatives of allethrin and benzylnorthrin, were synthesised and tested for insecticidal activity. Of the benzyl esters, the most insecticidal were those with the methoxyimino-methyl or -ethyl side-chains at C-3 or C-4, and with E configuration. Changing the alkoxy group, the configuration or the chain length resulted in lower activity. Introducing an occyano group increased activity if the side-chain was at C-3, but lowered it drastically if the substituent was at C-4. In the case of allethrin, the methoxime derivative was less active than the parent ketone, but with benzylnorthrin conversion to the methoxime markedly increased activity against one of the test species.     

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.     

Insecticidal activity of the pyrethrins and related compounds IV.—Essential features for insecticidal activity in chrysanthemates and related cyclopropane esters

A range of 5-benzyl-3-furylmethyl cyclopropane carboxylates and other esters are evaluated against house-flies, mustard beetles and two mosquito species. The results show the importance for activity of a gem-dimethyl group on the cyclopropane ring and that substitutions at C₃ give wide variations in insecticidal activity and marked species specificity. Some of the compounds had considerable knockdown activity against houseflies, but the structural requirements for this type of action differ markedly from those for kill.     

The pyrethrins and related compounds. Part XXVIII: Alkenyl- and alkynyl-substituted benzyl esters

Over 100 benzyl esters of pyrethroidal acids were synthesised and tested for insecticidal activity to establish detailed structure–activity relationships in compounds with side-chains similar to those in the natural pyrethrins. Alkenyl, and corresponding alkynyl, side-chains were effective, both at the 3- and 4-positions, as were side-chains with extended substitution in either E or Z forms. A cyano group at the α-position increases activity if the side-chain is at C-3, but lowers it drastically if the substituent is at C-4. Similarly, methyl groups at C-2 and/or C-6 may increase activity whether the unsaturated side-chain is at C-3 or C-4, but only in the absence of an α-cyano group.     

The pyrethrins and related compounds. Part XXV: Synthesis and insecticidal activity of conformationally restrained compounds related to 3-phenoxybenzyl esters

Derivatives of 3-phenoxybenzyl pyrethroidal esters were synthesised in which rotation about the benzylic C-1–C-α bond was restricted by an additional bridging ring. The insecticidal activities of these compounds to houseflies (Musca dornestica) and mustard beetles (Phaedon cochleariae) depended on the size of the bridging unit and on whether it joined C-α to C-2 or C-6 of the benzyl nucleus. The results obtained are considered in relation to current correlations of the structures with the activities of pyrethroids.     

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.     

Insecticidal activity of the pyrethrins and related compounds VIII. Relation of polarity with activity in pyrethroids

Comparing insecticidal activities of a wide range of pyrethroids with polarities measured by reversed phase, thin-layer chromatography suggests that there are optimum polarities for potency in both Musca domestica and Phaedon cochleariae, and that these optima have closely similar values. The significance of these conclusions is discussed.     

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.     

Insecticidal activity of the pyrethrins and related compounds. Part XIV: Selectivity of pyrethroid insecticides between Ephestia kuhniella and its parasite Venturia canescens

Relative potencies for 20 pyrethroids against the Mediterranean flour moth Ephestia kuhniella, and its hymenopterous parasite Venturia canescens, show a wide range of selectivity factors (2-140), indicating the possibility of identifying compounds with selectivity favouring the survival of beneficial parasites rather than pest hosts.     

The pyrethrins and related compounds. Part XXXIV. Optimisation of insecticidal activity in non-esters

Optimisation of activity within the structural constraints defined by the preceding work, by varying the substituents on phenyl in the acid fragment (10 variations), the nature of the group fulfilling the dimethyl function (three variations), the central linking group (four variations) and the presence or absence of a 4-fluoro substituent in the alcohol fragment, has led to achiral compounds as active as bioresmethrin against houseflies and mustard beetles. Statistical analysis of the effects has shown that particular combinations, for instance the cyclopropyl form of dimethyl with a central E-alkene group (but not a central ether group), lead to higher activity than expected. 4-Fluoro substitution enhances activity more strongly against mustard beetles. Difluorocyclopropyl compounds are on average slightly more active than cyclopropyl analogues.     

The pyrethrins and related compounds. Part XXVII. Esters of pulegenic and related acids

A report by Staudinger and Ruzicka of the insecticidal activity of an ester of pulegenic acid with mixed naturally derived alcohols had not been examined further, and had been misinterpreted in a review. Therefore, two isomeric pulegenic and nine related acids were synthesised, characterised and esterified with modern, more effective, pyrethroidal alcohols. The pulegenic esters were inactive, but low activity was found in esters of acids in which the 5-membered ring was additional to, rather than a replacement for, the cyclopropane ring.     

The pyrethrins and related compounds. Part XLII:Structure–activity relationships in fluoro-olefin non-ester pyrethroids

A series of compounds containing fluorine atoms in place of hydrogen in olefinic non-ester pyrethroids has been synthesised using a route based on novel intermediates, ie 2-fluoroallyl acetates, which are coupled with aryl Grignard reagents, and tested against several insect species. In most cases, after introduction of fluorine at the olefinic position, the activity remains high in both the 1-aryl-1-(3-arylprop-2-enyl)cyclopropane and the (1-aryl-4-arylbut-2-enyl)cyclopropane series. In particular, the former series have potential as soil insecticides, because in tests against Diabrotica balteata, activities were high, and dose-transferability factors were increased by the introduction of fluorine. © 1999 Society of Chemical Industry     

The pyrethrins and related compounds. Part XXXII. Replacement of the central ester link

This paper, and the two following, report a detailed examination of the effect of replacement of the central link in pyrethroids by isosteric or isoelectronic groups, and how the resulting change in insecticidal activity depends on the particular groups present in the other parts of the molecule. In this first paper, a wide range (42 variations) of central groups in different combinations are synthesised and tested. Results indicate that with conventionally pyrethroidal acid and alcohol fragments in the molecule, some isosteric replacements are tolerated, but most other variations are unsuccessful, Particularly interesting central groups are ? COCH₂? and ? CH?CH? CH₂? (E).     

The pyrethrins and related compounds. XIII. Insecticidal methyl-, alkenyl and benzyl-substituted furfuryl and furylmethyl chrysanthemates

3-Furylmethyl and furfuryl chrysanthemates with methyl, benzyl, substituted benzyl and alkenyl substituents, and other heterocyclic analogues of these compounds, are synthesised for structure-insecticidal activity investigations.     

Insecticidal activity of the pyrethrins and related compounds. VI. Methyl-, alkenyl-, and Benzyl-furfuryl and −3-furylmethyl chrysanthemates

The influence of the nature, number and relative dispositions of substituents on the furan ring of furfuryl and 3-furylmethy chrysanthemates on insecticidal activity to two insect species is described. 5-Benzyl-3-furylmethyl chrysanthemate was the most active compound developed in the investigation.     

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.     

Insecticidal activity of the pyrethrins and related compounds: III.—Penetration of pyrethroid insecticides into mustard beetles (Phaedon cochleariae)

Substituted benzyl chrysanthemates are lost from the surface of Phaedon cochleariae Fab. at rates correlated with their toxicities to this insect, less toxic compounds in general being lost faster. The forms of the penetration curves are explained by a model system in which movement into the insect is eventually balanced by detoxification, and relative detoxification rates for the members of the series of compounds are deduced from this model. Such values assist interpretation of relations between structure and activity by indicating to what extent susceptibility to detoxification limits the potency of the less toxic compounds.     

The pyrethrins and related compounds. Part XXXV. Esters of aryl-substituted cyclopentane alcohols and analogues

Synthesis of a range of 1-, 2-and 3-phenyl, benzyl and phenethyl substituted cyclopentanols and cyclopentylmethyl alcohols and related unsaturated compounds is reported. Results of bioassays of their esters with known pyrethroidal acids against two species of insect lead to recognition of some structure-activity relationships in this series. The distance and relative orientation between the alcoholic and aryl functions appears crucial, but in other respects the nature of the spacer group between them is less important. The most effective alcoholic components are based on cyclopentenes.