Pyrethroid esters

Pyrethroid Esters of Benzene Acetate. These insecticides have more extensive stmctural optimization in both acid and alcohol moieties. Fenvalerate [51630-58-17, a-cyano-(3-phenoxyphenyl)methyl (+)-(2R,5)"Ct"isoprop5i-4-chlorophenylacetate (24) d 1.17, vp 1.4 p.Pa at 25°C), a mixture of four isomers, is soluble in water to 0.3 mg/L The rat oral LD q is 450 mg/kg. Esfenvalerate [66230-04-4] is the (+)-2-(i, 5)-isomer (mp 59°C). The rat LD qS are 75, 458 (oral), and the rabbit dermal LD q is 2000 mg/kg. These pyrethroids are widely used general-purpose insecticides for field, vegetable, and fmit crops. 

Figure 8b shows pyrethroid esters composed of an acid moiety without a cyclopropane ring and a phenoxybenzyl alcohol group. While a cyclopropane ring had long been considered an indispensable acid component constituting a pyrethroid skeleton, Ohno et al. [41] in 1974 developed fenvalerate (32), a-isopropylphenyl acetate derivative, with no cyclopropane ring in its acid moiety. This compound exhibits... 

Fujimoto K, Itaya N, Okuno Y, Kadota T, Yamaguchi T (1973) A new insecticidal pyrethroid ester. Agric Biol Chem 37 2681-2682... 

Our search for a new lead in the pyrethroid area started with a simple proposition It has been suggested that for a pyrethroid ester to be active it must have an alcohol with the specific feature of two centers of unsaturation separated by a bridging group (1, ) (Figure 4). In the case of allethrin and res-methrin the bridging atom is a methylene group. In permethrin it is an oxygen atom. If this is a requirement, one should be able to express it with some physicochemical parameter or set of parameters. 

The oxidation of 3-carene to 3-caren-5-one (Figure 3.46) is a key step in the synthesis of the pyrethroid ester insecticide Deltamethrin [162,163]. This reaction is performed with air as the oxidant, catalyzed by 2 mol% of a Cr-pyridine complex (the catalyst precursors are CrCl3 and pyridine). Table 3.1 shows the turnover frequencies obtained using various Cr/pyridine ratios. 

Replacement of the normal pyrethroid ester by alternative linkages usually leads to diminution of biological activity. One important exception to this general phenomena is several oxime ether derivatives, in particular, 3-phenoxybenzyl derivatives of various alkyl aryl ketones. Pyrethroid esters derived from certain 2-substituted-[1,1 -biphenyl]-3-methanols have been shown to possess initial and residual activity surpassing that of esters derived from 3-phenoxybenzyl alcohol. Now it has been demonstrated that the same enhancement of activity was observed for alkyl aryl oxime ethers of certain [1,1 -biphenyl]-3-methanols compared to the corresponding 3-phenoxybenzyl alcohol derived oximes. The synthesis, biological activity, including soil activity, structure-activity relationships and toxicity of several of these biphenylmethyl oxime ethers are described. 

Many synthetic pyrethroids with excellent insecticidal activity have been discovered through modification of the acid and alcohol moieties of the natural pyrethrins. However, replacement of the pyrethroid ester linkage with an alternative linkage usually leads to compounds of diminished biological activity(D. One exception to this trend of lower activity is the class of compounds wherein the oxime linkage is introduced in place of the ester linkage in the fenvalerate series. Additionally, only the E-isomer of the alkyl aryl oxime ethers is reported to be insecticidal< 2-4). 

Pyrethroid esters derived from [1,1 -biphenyl]-3-methanol have been of interest at FMC(5-7). It has been reported that [1,1 -biphenyl]-3-methanol esterified with both cis-3-(2-chloro-3,3,3-trifluoro-l-propenyl)-2,2-dimethylcyclopropanecarboxylic acid and cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid produced esters which have initial and residual activity surpassing that of permethrin against a number of insects. It occurred to us that this same enhancement of activity might be observed with alkyl... 

The replacement of the ester linkage of pyrethroids by alternatives was known to lead to compounds of diminished biological activity. Thiol esters and amides are two such isosteric replacements that lead to a loss in biological activitv(13.14). The exception to this trend was the replacement by the oxime function-alitv(2.3). The alkyl aryl oxime ethers are not susceptible to alkaline hydrolysis and esteric attack as are the pyrethroid esters(15). The present study details our investigation of the biological activity of [1,1 -biphenyl]-3-methanols when combined with alkyl aryl methanone oximes. 

The results show that 2-methyl[1,1 -biphenyl]-3-methanol is an effective pyrethroid alcohol. It has been shown that this is true not only for pyrethroid esters but also for their isosteric replacements such as oxime ethers. 

Towards an Identification of the Pyrethroid Pharmacophore. A Molecular Modeling Study of Some Pyrethroid Esters. 

The breakthrough for pyrethroids as agricultural insecticides became possible when the high activity of its pyrethroid ester in connection with the photostabihty of 3-dichlorovinyl-2,2-dimethyl cyclopropane carboxyhc acid 91 was found. This acid, synthesized first by Farkas, Sorm and Kurim in 1957 [127], was rediscovered during a straight forward search for higher stabihty by Elhott and Janes in 1969 and tested as the photostable ester permethrin. 

The stereospecific synthesis of the cis-norisopyrethrinic acid 231 deserves particular interest. This is an acid component for highly active pyrethroid esters with a very interesting biological spectrum (Reaction scheme 156). Usually the Horner olefmation gives Z/E-mixtures [455], but by applying cyclic phosphonic esters 232, one obtains only the Z-isomers [456, 922]. 

Resolution of 262, using phenethyl amine [532], phenyl-tolyl-ethylamin [534] or cinchonidin [535] produces the S-enantiomer [529, 530, 533], essential for insecticidal activity of its pyrethroid ester esfenvalerate. Flucythrinate acid is resolved by phenethyl amine [531]. 

One fluorine atom in position 4 of 3-phenoxy benzaldehyde improves the insecticidal activity of its ensuing pyrethroid esters (cyfluthrin and flumethrin) and nonesters by a factor of at least two (see p. 42, Vol. 4 of this series). Production of this aldehyde 288 certainly is more expensive. An essential step is also the Ullmann-reaction with a fluorine atom in the nucleus of one component 289 (Reaction scheme 206) [599-604]. 

This alcohol 312 was the first one conveying very high insecticidal activity to its pyrethroid esters, and must be regarded as the direct forerunner of modem pyrethroid alcohols. The technical process for resmethrin 315 (Reaction scheme 219) builds up a furane ring in a classical manner [676, 677]. 

In view of the diversity in the synthesis of pyrethroid ester components it is small wonder, that the final step of formation of the actual insecticidal ester may be accomphshed in many ways. Often, novel methods were needed to make it possible on a larger technical scale. Classical methods like azeotropic esterification of free acid [767] or reaction of acid chloride with simple alcohols, in many cases preferably in the absence of any auxiliary additional reagent or solvent [768], mostly proceeds in a textbook-like manner. 

Formation of Pyrethroid-Ester Components in the Final Step... 

The formation of the proper acid or alcohol component for a pyrethroid-ester insecticide may occur as a binary or ternary reaction as the very last step in the course of the usually lengthy process. On the one side this is of particular interest for circumvention of patent protection for any existing precursor. On the other hand it... 

---