Alkyl aryl oxime ethers

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). 

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. 

Table II. Foliar Activity of Alkyl Aryl Oxime Ethers...

Next, the effect on activity with respect to the size of the alkyl group in our series compared to that disclosed in the literature (2,4) was of interest. The effectiveness of alkyl groups is reported to be cyclopropyl > isopropyl > ethyl > methyl. In fact, this trend was followed in the [1,1 -biphenyl]-2-methyl-3-methanol derived alkyl aryl oxime ethers. This is illustrated with the (E,Z)-4-trifluoromethoxyphenyl(alkyl)methanone oxime ethers, Compounds 14, 16, 19 (Table V). The activity of this series increases with increasing size of the alkyl group. However, when cyclobutyl was incorporated, activity was lost. The cyclopropyl was the most effective while the isopropyl group was somewhat less effective. Other alkyl changes resulted in a rapid loss of activity. 

The activity of the 3-phenoxybenzyl alkyl aryl oxime ethers is reported to reside in the E-isomer. The activity of the E-isomer was compared with the activity of the E,Z alkyl aryl oxime ethers for this new series. This trend also occurs in the biphenylmethyl-methyl alkyl aryl oxime ethers (Table VI). 

Toxicology. The mammalian toxicity of the alkyl aryl oxime ethers was unknown. Compound 15, which had good foliar and soil insecticidal activity, was chosen for an acute toxicological study. 

The replacement of the 3-phenoxybenzyl alcohol fragment by 2-methyl[1,1 -biphenyl]-3-yl leads to an increase in initial and residual foliar activity in the alkyl aryl oxime ethers. An unanticipated result was the activity of these oxime ethers as soil insecticides. The corresponding 3-phenoxybenzyl alcohol oxime ethers were inactive as soil insecticides. The results of a structure activity relationship study revealed biological activity is enhanced by electron withdrawing substituents. 

E,Z-Alkyl aryl methanone oximes, 176 Alkyl aryl methanones, 176 Alkyl aryl oxime ethers combined with alcohols, 182... 

Now where does the discrepancy lie An acyclic paradigm was used for the oxi-mate/imidate interconversion. Had we used the plausibly aromatic paradigm of isoxa-zole/oxazole, the isomerization enthalpy would have been 95 kJ moR where the requisite enthalpies of formation are from References 76 and 1, respectively. This difference is meaningfully distinct from that of the acyclic paradigm but still does not particularly ameliorate the difference. Is it possible that the N—O bond in aryl and alkyl oxime ethers are profoundly different Could it be that we have neglected any antiaromaticity in the 8 n... 

An interesting preparation of 128 involves the cycloaddition of carbon suboxide to the anil of cyclopentanone (129).87 Compound 129 also reacts with monosubstituted malonyl chlorides to give iV-aryl-2-oxo-3-alkyl-4-hydroxy-6,7-dihydro-5ff-1 -pyrindines (131) in fair yields.88 Similarly, the oxime ether of cyclopentanone (132) reacts to give the cyclic hydroxamic acid derivative (133),89 and benzylmalonyl chloride reacts with the A,A-dimethylhydrazone of cyclopentanone (134a) to give 134b in 90% yield.90... 

Oximes react very smoothly with the chloro compound 6 to form crystalline (benz d] isothiazolyl - 3 - oximino) alkane -1,1- dioxides ( pseudosaccharin oxime ethers ) (89 R = alkyl, aryl, R = H, alkyl, aryl).20, 28, 43,254 Since 6 reacts preferably with the oxime, the reaction is carried out in the presence of water.43... 

R = alkyl or aryl imine R = NR2 hydrazone R = OH oxime R = OR oxime ether... 

Chemistry. The majority of the alkyl aryl methanone oxime ethers were synthesized as shown in Figure 1. The alkyl aryl methanones were prepared by either of two methods. In the first method, the appropriately-substituted benzonitrile was treated with the desired alkylmagnesium halide to give the desired ketone(8). 

The alkyl aryl methanone oximes can be converted to oxime ethers by several methods. The usual alkylation procedure utilized was a phase transfer catalyzed alkylation wherein the E-alkyl aryl... 

Figure 1. Synthesis of Alkyl Aryl Methanone Oxime Ethers.

Alkyl aryl methanone oxime ethers QSAR analysis, 183 insecticidal activity, 175-176 structure-activity relationships, 183-185 synthesis, 174-178... 

Ph R= alkyl or aryl imine R= NR2 hydrazone R= OH oxime R=OR oxime ether... 

The addition of alkyl radicals to vinyl sulfones to give functionalized alkenes via an addition-elimination sequence has been investigated by Russell and coworkers in some details [132, 147]. This reaction has recently been extended to unsaturated sulfimides, allowing the synthesis of styryl tetrahydrofurans and tetrahydropyrans [148]. The extension of this approach to phenylsulfonyl oxime ethers and heteroaromatic aryl sulfones (/p o-substitution) has recently been obtained with success [149, 150]. An example which comes from the work of Kim et al. is reported in equation (76) [149]. In this radical sequence, the alkyl radical generated photochemically from an alkyl iodide, in the presence of 1.2 equivalent of hexabutylditin, adds readily to the C=N bond of the oxime ether to... 

In the asymmetric reduction of ketones, stereodifferentiation has been explained in terms of the steric recognition of two substituents on the prochiral carbon by chirally modified reducing agents40. Enantiomeric excesses for the reduction of dialkyl ketones, therefore, are low because of the little differences in the bulkiness of the two alkyl groups40. In the reduction of ketoxime ethers, however, the prochiral carbon atom does not play a central role for the stereoselectivity, and dialkyl ketoxime ethers are reduced in the same enantiomeric excess as are aryl alkyl ketoxime ethers. Reduction of the oxime benzyl ethers of (E)- and (Z)-2-octanone with borane in THF and the chiral auxiliary (1 R,2S) 26 gave (S)- and (R)-2-aminooctane in 80 and 79% ee, respectively39. 

The lower members of the homologous series of 1. Alcohols 2. Aldehydes 3. Ketones 4. Acids 5. Esters 6. Phenols 7. Anhydrides 8. Amines 9. Nitriles 10. Polyhydroxy phenols 1. Polybasic acids and hydro-oxy acids. 2. Glycols, poly-hydric alcohols, polyhydroxy aldehydes and ketones (sugars) 3. Some amides, ammo acids, di-and polyamino compounds, amino alcohols 4. Sulphonic acids 5. Sulphinic acids 6. Salts 1. Acids 2. Phenols 3. Imides 4. Some primary and secondary nitro compounds oximes 5. Mercaptans and thiophenols 6. Sulphonic acids, sulphinic acids, sulphuric acids, and sul-phonamides 7. Some diketones and (3-keto esters 1. Primary amines 2. Secondary aliphatic and aryl-alkyl amines 3. Aliphatic and some aryl-alkyl tertiary amines 4. Hydrazines 1. Unsaturated hydrocarbons 2. Some poly-alkylated aromatic hydrocarbons 3. Alcohols 4. Aldehydes 5. Ketones 6. Esters 7. Anhydrides 8. Ethers and acetals 9. Lactones 10. Acyl halides 1. Saturated aliphatic hydrocarbons Cyclic paraffin hydrocarbons 3. Aromatic hydrocarbons 4. Halogen derivatives of 1, 2 and 3 5. Diaryl ethers 1. Nitro compounds (tertiary) 2. Amides and derivatives of aldehydes and ketones 3. Nitriles 4. Negatively substituted amines 5. Nitroso, azo, hy-drazo, and other intermediate reduction products of nitro com-pounds 6. Sulphones, sul-phonamides of secondary amines, sulphides, sulphates and other Sulphur compounds... 

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