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1. (WO1980000563) ESTERS D"ACIDE ACETIQUE SUBSTITUE
Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

SUBSTITUTED ACETIC ACID ESTERS

This invention relates to pesticides and in particular to certain substituted acetic acid esters as compounds, to pesticidal compositions containing them and to methods of killing pests especially insects and ara chnids using the compounds of the invention or compositions containing them.
It is well known that certain esters of chrysan themumic and related acids have potent insecticidal properties. Such insecticides are known as pyrethroid insecticides. The naturally occurring pyrethroid insecticides are esters of derivatives of cyclopropane-carboxylic acid. Attention in recent years has been focussed on this general class of pesticides because they do not suffer from the disadvantages which have become increasingly associated with the use of organo halogen and organophosphorus pesticides.
Apart from the development of closely similar analogues to the naturally occurring pyrethroids and in particular to compounds based on cyclopropane-carboxylic acid, compounds not containing a cyclopropane ring have been investigated and it has been found that certain classes of substituted acetic acid esters and in particular substituted phenylacetic acid esters have insecticidal properties similar to those of the naturally occurring pyrethroids. Such materials are conventionally included under the classification of "synthetic pyrethroids". British Patent Specification No. 1439615, for example, describes certain classes of substituted acetic acid esters having pesticidal pro perties. Of the compounds within the claims of this Sumitomo patent we are aware that 3'-phenoxy-α-cyano-benzyl-α-isopropyl—4-chlorophenylacetate, known by the common name fenvalerate has come into commercial use.
The present invention is based on the discovery that certain classes of fused bicyclic derivatives of substituted acetic acid form esters which have marked insecticidal properties.
The present invention accordingly provides compou of the general formula:



where G is a group of the formulae



where X is an oxygen or a sulphur atom, or a NH or CH2 group; and W is an oxygen atom or a CH2 group;
R1 and R2 are each independently a hydrogen or halogen (preferably chlorine or bromine) atom, or a lower alkyl aralkyl, aryl, lower alkoxy, or lower alkenyl group, or R1 and R2 may together be a methlenedioxy group; R3 is a hydrogen, or halogen (preferably chlorine, bromine or fluorine) atom, or a lower alkyl or lower alkoxy group;
R4 is a lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, cyano, halogen-substituted lower alkyl, halogen-substituted lower alkenyl group, or a C3 to C5 alicyclic group;
and R5 is a group of one of the following formulae:



where A is a hydrogen atom, or a cyano group, or a -C≡CH group, or group;


R6 and R7 are each independently a hydrogen atom, or a lower alkyl or lower alkenyl group;
Z is an oxygen or a sulphur atom, or a -CH2- or -CO-group; and
Y is a hydrogen atom, or a lower alkyl, lower alkenyl, lower alkynyl or an aryl or furyl group which is either unsubstitύted, or is substituted by one or more lower alkyl, lower alkenyl or lower alkoxy groups or halogen atoms;



where R8 is a hydrogen atom, or a methyl group; and R9 and R10 are each independently a hydrogen atom, or a lower alkyl group;

where dihydro- or


tetrahydro-benzene ring; and B1, B2, B3, B4 are each independently a hydrogen, or halogen atom, or a methyl group;



D1 and D2 are each independently a halogen atom (preferably fluorine or chlorine) or a methyl group, and each n may be independently 0, 1 or 2;


or

The invention particularly includes compounds of the formu



where R1, R2, R3, R4, R5 and X are as defined above.

Specifically the invention includes compounds of each of the following forumlae:




where R 1 R2 R3 R4 and R5 are as defined above .

Alcohols of the formula R50H, where R5 is as defined above, are generally known and have been suggested or used as the alcohol radical in synthetic pyrethroids and substituted acetate esters having pesticidal activity. In the compounds of the present invention we have found that particularly good results are obtained when R5 is a group of one of the formulae:


or



Where, in the definitions above reference is made to "lower alkyl", "lower alkoxy", "lower alkenyl" and "lower alkynyl" groups these terms refer to such groups having up to 4 carbon atoms. Those groups with 3 or 4 carbon atoms can be straight or branched chain groups. We prefer among "lower alkyl" and "lower alkoxy" groups to use methyl, ethyl, iso-propyl, iso-butyl or tert-butyl and the corresponding alkoxy groups. The lower alkenyl groups can be primary, or secondary and the double bond may be in any position in the chain. We prefer to use vinyl, allyl, propenyl and iso-propenyl groups. The lower alkynyl groups are preferably
ethynyl or 3-propynyl groups. Among halogen substituted groups we particularly prefer dihalo, especially di chloro or difluoro, vinyl groups

i.e where Hal is halogen.


Among aryl groups we prefer phenyl groups and by the term "aralkyl group" we mean one based on a C1 to C4 alkyl chain and prefer the aralkyl group to be benzyl.
The compounds of the present invention contain an asymmetric centre at the α-carbon atom of the carboxylic acid moiety. They may include other asymmetric centres elsewhere in the molecule. The pesticidal activity of the various possible isomers including enantiomers epimers and diastereoisomers will be different. It is not generally possible to predict which isomers are likely to be most active or by how much. The present invention includes the racemic and other mixtures that will usually be obtained by non-stereospecific syn thesis as well as particular isomers or mixtures having an artificially enhanced proportion of a particular isomer(s) obtained by separation or stereospecific synthesis
The pesticidal activity of the compounds of the invention which we have tested is such that we infer that they generally have activities at least comparable with those described in Sumitomo's U.K. Patent No.
1439615. The best results we have obtained, to date, represent a p esticidal potency greater than that of fenvalerate when tested comparatively.
The compounds of the invention can be made by conventional synthetic routes. It is generally
convenient to conduct the synthesis so as to produce the acid and alcohol corresponding to the ester, or reactive derivatives of the acid and/or alcohol, and to react these together to form the ester. For
convenience in the reaction schemes outlined below the acid of the formula Ila or lIb:


where X, W, R1, R2, R3, R4 are as defined, above are represented by the following abbreviated formulae, respectively:
represents formula Ila and

represents formula lIb



and F1 and F2 are to be understood accordingly. Further, the reaction schemes do not set out detailed reaction conditions, although specific exemplification is given in the Examples, because these are reckoned to be
within the knowledge and skill of a competent synthetic chemist experienced in this general field. Some of the sequences suggested will be specifically appropriate to the synthesis of particular compounds whilst others are of more general applicability. The synthetic
routes outlined are not intended to provide a fully comprehensive account of the synthesis of the compounds of the invention; other routes are no doubt possible.
The esters of general formula (I) may be prepared by any of the following esterification methods:- (a) reaction of an acid halide with an alcohol
(b) reaction of an acid with an alcohol
(c) reaction of an acid anhydride with an alcohol

(d) reaction of an ester with an alcohol
(e) reaction of an acid salt (alkali metal, silver or organic tertiary base salt) with an alkyl
halide or alkyl sulphoxylate
(f) reaction of an ester with an alkyl halide or
alkyl sulphoxylate
Reaction (a) The acid halide is allowed to react with the alcohol at 0ºC to 40ºC using an acid acceptor, for example, an organic tertiary amine base such as pyridine or triethylamine. The acid halide may be any type of acid halide but the acid chloride is generally preferred. The presence of an inert solvent (one which is inert to the reactants and the ester product) is not essential but is generally preferred in order to ensure smooth reaction, and preferred inert solvents includes benzene, toluene and petroleum ether.
Reaction (b) The acid is allowed to react with the alcohol using an appropriate dehydrating agent, for example dicyclohexylcarbodiimide, in an appropriate inert solvent, such as toluene, benzene or petroleum ether, at temperatures from 0°C to the boiling point of the solvent used.
Reaction (c) An appropriate acid anhydride is allowed to react with the alcohol at room or elevated temperature without using specific aids. In this case it is preferred to heat the reaction system and to use an inert solvent such as toluene, xylene in order to ensure smooth reaction.
Reaction (d) The so-called ester exchange reaction is carried out between an ester of an appropriate acid and a low boiling point alcohol, e.g. methanol, or ethanol, with an appropriate alcohol by means of heating the ester and the alcohol in the presence of an acidic catalyst such as P-toluene sulphonic acid, or in the presence of a basic catalyst such as an alkali metal alkoxide corresponding to the low boiling alcohol of the ester used, or sodium hydride in an inert solvent such as toluene, while removing the low boiling alcohol liberated during the reaction from the reaction system by a fractional distillation column.
Reaction (e) The halide or sulphoxylate derivative of the alcohol and an appropriate salt of an appropriate acid, usually an alkali metal salt, a silver salt or an organic tertiary base salt are allowed to react.
The salts may be formed in situ by adding simultaneously the acid and the corresponding base to the re action system. In this case a solvent such as benzene, acetone or dimethylformaraide is preferably used, and the reaction is preferably carried out by heating the reaction system at or below the boiling point of the solvent used. Preferred halides of the alcohol are the chlorides and the bromides.
Reaction (f) An appropriate ester is allowed to react with an alkyl halide or sulphoxylate in the presence of a basic catalyst for example sodium amide in an inert solvent, or in the presence of alkali hydroxide in the presence of a phase transfer catalyst for example a quaternary ammonium salt, a phosphonium salt or a crown ether.
The acids of general formula (Ila) may be prepared by one or more of the following routes. In these synthetic routes F1, R1, R2, R3, and R4 are as defined above, Et means ethyl and R means alkyl such as ethyl, Hal means halogen such as bromine or chlorine.


The substituted acetonitrile starting materials may be made by one or more of the following subsidiary routes:





The substituted ketones used as starting materials in routes (ii), (iii), (iv) and (v) may be made by conventional methods, or, in the case of substituted or unsubstituted benzofuran-2-yl ketones by the following subsidiary route:



The acids of general formula lIb may be prepared by one of more of the following routes:
(xi) By substituting ketones of the formula F2C0R4 for ketones of formula F 1C0R4 and using one of the above methods (ii), (iii), (iv) or (v).
The ketones of formula F2COR4 may be made by one or more of the following subsidiary routes:

The steps involved in the reaction routes may be carried out by the methods given below under the appropriate step number.
Route (i)
Step 1
The appropriate nitrile may be alkylated with an appropriate halide or sulphoxylate of formula R4-J (J being a halide or sulphoxylate radical) in an inert solvent (for example, an ether, tetrahydrofuran, benzene, toluene or liquid ammonia when sodamide or the like is used as base as described below) in the
presence of a base such as an alkali metal, alkali metal hydride, alkali metal amide or the like, at room temperature or elevated temperature; or the appropriate nitrile may be alkylated with an appropriate halide or sulphoxylate (R4-J) using aqueous alkali (for example, an alkali metal hydroxide) and an inert solvent (for example, an ether, tetrahydrofuran, benzene, toluene, or a chlorinated solvent such as dichloromethane, carbon tetrachloride) in the presence of a phase transfer catalyst (for example, a quaternary ammonium salt, a quaternary phosphonium salt or a crown ether).
Subsidiary Routes
(a) Reduction of the carboxylic acid to the primary alcohol e.g. with LiAlH4 in diethyl ether, followed by halogenation e.g. with S0Cl2 or PBr3 in inert solvent, followed by substitution of the halogen with a cyano-group by reaction with an alkali metal cyanide e.g.
NaCN in ethanolic solution or with aqueous alkaline (NaOH) NaCN in the presence of an immiscible solvent e.g. CH2Cl2 or CHCl3 and a phase transfer catalyst such as a quaternary ammonium salt, a quaternary phosphonium salt or a crown ether.
(b) The benzofuranone starting compound (substituted or unsubstituted) can be made by conventional synthetic methods e.g. those described in "The Chemistry of
Heterocyclic Compounds" edited by A. Weisberger and E. C. Taylor Volume 29 "Benzofurans" by Ahmed Mustafa (published by J. Wiley and Sons, Wiley Interscience, 1974) chapter 5; Benzofuranones.
The benzofuranone is converted to the acetonitrile by the method described for this class of compound in the Australian Journal of Chemistry 1975, 28, 1097.

(c) α-Halogenation of the methyl group e.g. with N-bromo succinimide in CCl4, followed by cyano-substitution as in (a).
Step 2
The appropriate nitrile may be hydrolyzed by one of the well-known methods for such reactions for
example by heating the nitrile with a mineral acid, or by heating the nitrile with an alkali metal hydroxide solution or by treating with hydrogen peroxide, fol lowed by reaction with nitrous acid, or by treating with sulphuric acid.
Route (ii)
Step 3
Darzens condensation with ethyl chloroacetate in the presence of base.
Step 4
Alcoholic alkaline hydrolysis followed by acid catalyzed rearrangement.
Step 5
Oxidation by silver hydroxide, prepared in
situ, in water.
Route (iii)
Step 6
By reaction with trimethyloxosulphonium iodide in dimethylsulphoxide under nitrogen.
Step 7
Rearrangement catalyzed by acid such as p-toluene sulphonic acid or by Lewis acid such as boron trifluoride etherate.
Step 5
Oxidation by silver hydroxide, prepared in situ, in water.
Route (iv)
Step 8
Ethoxymethylenetriphenylphospohorane generated in situ from the triphenylphosphonium halide by base such as butyl lithium in ether, phenyl lithium in tetrahydrofuran or sodium ethoxide in ethanol. The phosphonium salt may be prepared from triphenylphos phine and the appropriate aldehyde.
Step 9
Treatment with mineral acid.
Step 5
Oxidation by silver hydroxide, prepared in situ, in water.
Route (v)
Step 10
Reaction with chloroacetonitrile in the pre sence of alkoxide.
Step 11
Treatment with a catlytic amount of potassium hydrogen sulphide, lithium trifluoroacetate or lithium perchlorate in refluxing toluene.
Step 12
Hydrolysis with aqueous base.
Subsidiary Route
(d) Reaction of the (substituted or unsubstituted

2-bromobenzofuran with butyl lithium in diethyl ether to give the 2-lithium compound followed by reaction with the carboxylic acid R4CO2H in diethyl ether at -40°C.

Route (vi)
Step 13
Alkylation by alkyl halide or sulphoxylate in the presence or base, or by phase transfer catalyzed alkylation with aqueous base and alkyl halide or sulphoxylate.
Step 14
Acid or alkaline hydrolysis.
Route (vii)
Step 15
Heating with alkali in tetrahydronaphthalene at 250º in an autoclave.
Route (viii)
Step 16
Normal procedure for Grignard reagent formation, Magnesium in anhydrous diethyl ether.
Step 17
Carbonation of Grignard reagent by C02 - either with solid CO2 or with C02 gas under pressure.
Route (ix)
Step 18
Carbethoxylation using diethyl carbonate and sodium hydride under high dilution conditions.
Step 19
Reaction with α-bromo ester in the presence of base in a mixture of benzene and dimethylformamide as the solvent.
Step 20
Reduction with sodium borohydride in aqueous alkali followed by treatment with hydrochloric acid.

Acid catalysed methanolysis.
Route (x)
Step 22
Condensation with ethyl cyanoacetate in the presence of ammonium acetate and acetic acid in a solvent such as benzene.
Step 23
Alkylation using sodium alkoxide and alkyl halide. Step 24
Hydrolysis by alcoholic alkali.
Route (xi)
Subsidiary Routes
(e) Reaction of the acid chloride with R4MgBr (i.e. the Grignard of R4Br) indiethy l ether in the presence of CdBr2 (to inhibit further reaction of the product ketone.with the Grignard).
(f) Reaction of the acid chloride with N-methylaniline to give the tertiary amide followed by reduction with LiAlH4 in diethyl ether to give the aldehyde which is reacted with the Grignard R4MgBr followed by oxidation of the secondary alcohol produced, to the ketone with pyridinium chlorochromate in CH2C12.
Route (xii)
Step 25
Hydrogenation over a catalyst, for example
palladium on charcoal, in a solvent such as acetic acid, at elevated temperature and pressure.
Route (xiii)
Step 22
Condensation with ethyl cyanoacetate in the presence of ammonium acetate and acetic acid in a solvent such as benzene.
Step 23
Alkylation using sodium alkoxide and alkyl halide. Step 26
Hydrogenation at atmospheric pressure over a catalyst, for example, palladium on charcoal in a solvent such as acetic acid, or dioxan.
Step 24
Alkaline hydrolysis.
Route (xiv)
Reduction, for example, using zinc and concentrated hydrochloric acid.
The acids produced by routes (i) to (xiv) can be converted to reactive derivatives for esterification by known methods. It will be appreciated that the products of some intermediate stages in these routes can be converted into suitable reactive derivatives without intermediate formation or isolation of the free acid. Also some intermediates, notably the
product of step 13, are esters of the acid typically ethyl esters and can, accordingly, be used as reactive derivatives of the acid e.g. by ester exchange.
In common with most insecticides and similar pesticides the compounds of this invention in practice are used as compositions comprising the active ingredient in combination with a diluent and commonly
including other additives. The invention accordingly includes an insecticidal composition comprising an insecticidal concentration or quantity of a compound of the invention in combination with a diluent. Most commonly the diluent will be a physical carrier to facilitate delivery of the pesticide to its site of action. Thus the diluent can be a solvent, a liquid in which the pesticide is dispersible, an aerosol medium or a solid carrier. Dissolved in a suitable solvent such as a volatile organic solvent or an oil the composition can be used as a spray, especially a low volume spray. Such a solution can be used in the formulation of emulsions or dispersions as can the compounds themselves. Such emulsions are as used in both low and high volume sprays. In making emulsions or dispersions surface active agents such as disper sants and emulsion (and dispersion) stabilizers will usually be included. It is thus possible to formulate emulsifiable concentrates in which the insecticidal compound is in combination with a surface active agent and usually in solution in a suitable solvent such that an emulsion for use can be obtained by adding the emulsion continuous phase e.g. water, and, if necessary mixing. Solid carriers include dusts and powders e.g. wettable powders and moulded or mouldable particulate solids. The preparation of insecticidal compositions from their active constituents is understood by those skilled in the art and the brief account given above is not intended to be detailed or exhaustive.
The insecticidal compositions of the invention include compositions containing active ingredients other than the compound(s) of this invention. Thus, one or more compounds of the invention can be combined with other insecticides or other pesticides. This can be done to combine the pesticidal effects to obtain a broader spectrum of effectiveness, to take advantage of different modes of pesticidal action, to provide greater specificity, or to achieve enhanced activity. The composition may include a synergist to enhance the pesticidal activity of the composition. Typically, in insecticides, such synergists act to inhibit metabolic deactivation of the insecticidal component(s) of the composition. Piperonyl butoxide is a widely used synergist in insecticidal compositions and can be used in the compositions of the present invention.
Typical pesticidal formulations of compositions containing the compounds of the invention as an active ingredient include (all percentages by weight on the total composition unless otherwise specified):
Aerosol
Compound of invention 0.02 to 2%
Synergist (e.g. piperonyl butoxide)
0.1 to 5%
These components are typically dissolved in a suitable solvent such as an aromatic hydrocarbon and combined with an aerosol propellant e.g. liquefied petroleum gas(L.P.G.) such as butane or halogenated e.g. fluorinated or fluorinated and chlorinated, hydrocarbons such as CCl2F2, CHCl2F, CCl3F and CH3.CClF2 (these and similar materials are readily available commercially e.g. under the Trade Marks Freon, Frigen and Arcton among others).
Where LPG is used as propellant, the proportion of propellant in the composition will typically be: 10 to 40%
The solution of the compound of the active ingredients may therefore comprise:
90 to 60%
Alternatively the active ingredients as a solution e.g. in an aromatic hydrocarbon may be dispersed as an emulsion in a medium such as water prior to inclusion in the aerosol with the propellant. A small amount of emulsifier e.g. a non ionic surfactant in a concentra tion of up to 1% by weight on the emulsion, will usually be included in such an emulsion. The emulsion will typically be used in proportions similar to that of the solution.
The concentration of the active ingredients in the solution will typically be from 0.12 to 10% by weight on the solution where the solution is used directly. Where the solution is incorporated in the aerosol as an emulsion the concentration may be higher than 10% e.g. up to about 35% by weight on the solution (or saturation).
Where halogenated hydrocarbons are used as
propellant the proportion of propeleant in the composition will typically be:
60 to 80%
The solution of the active ingredients may therefore comprise:
40 to 20%
The concentration of the active ingredients in the solution will typically be in the range 0.3 to 20% by weight on the solution, but where relatively large proportions of propellant are used the upper limit of concentration may be as high as 35% by weight on the solution (or saturation).
Emulsiflable Concentrate
Compound of invention 1 to 95%
Surfactant (preferably non-ionic 0.5 to 10%
e.g. of the "Tween" type)
Optionally
Synergist 2.5 to 95%
Hydrocarbon oil to 100%
As is common practice other insecticides (or pesticide) can be included if desired. The amount used will depend on the nature of the insecticide.
Wettable Powder
Compound of invention 1 to 95%
Suspending and wetting agents 0.5 to 15%
Optionally
Synergist 2.5 to 95%
Made up to a powder with a
mineral clay e.g. talc. to 100%
The suspending and wetting agents can be those used conventionally. Typical wetting agents include
sodium dodecylbenzene sulphonate and suspending
agents include methyl cellulose.
Oil Base Compositions
Compound of invention 1 to 95%
Oil e.g. petroleum oil 99 to 5%
The nature of the oil will depend on the particular end use envisaged. Thus, for ultra low volume spraying the oil will be a heavy petroleum oil e.g. of the "Rissella" type, but for end uses involving higher volumes the oil will typically be a medium or light petroleum oil. Mixtures of oils can be used if desire Conventional other ingredients of oil base composition can be included e.g. synergists, other insecticides an surfactants.

The following Examples illustrate the invention. (All temperatures are in degrees Centigrade.)
EXAMPLE 1
m-Phenoxybenzyl α-isopropyl-2-benzofurylacetate
(a) α-Isopropylbenzofuran-2-acetonitrile
2-Iodopropane (12.6 g., 0.074 mol) was added to a well stirred mixture of benzofuran-2-acetonitrile
(5.82 g., 0.037 mol), benzyltriethylammonium chloride

(8.42 g., 0.037 mol), sodium hydroxide solution (47% w/w, 3.92 cm3, 0.07 mol) and dichloromethane (90 cm3), and the mixture was refluxed for 3.0 hr with good stirring. Water was added and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried (Na2SO4), filtered and the solvent was removed. The residue was chromatographed on silica using toluene as eluant and the component with Rf 0.55 was isolated. This was recrystallised from petroleum ether (b.p. 60-80º to give α-isopropylbenzofuran-2-acetonitrile (4.4 g., 0.022 mol, 59.8%) as an oil.
(Found: C, 78.21; H, 6.74; N, 6.93. C13H13N O requires C, 78.36; H, 6.58; N, 7.03%.)
(b) α-Isopropylbenzofuran-2-acetic acid
A mixture of α-isopropylbenzofuran-2-acetonitrile

(4.8 g., 0.024 mol), potassium hydroxide (6.8 g.,
0.12 mol), water (6.8 cm3) and ethylene glycol (85 cm3) was refluxed for 18 hr at 148° with stirring. The mixture was cooled, poured into water and extracted with diethyl ether. The aqueous solution was acidified with hydrochloric acid and the mixture was extracted with diethyl ether. The ether extract was washed with water, dried (Na2SO4), filtered and the solvent was removed to give α- isoproρylbenzofuran-2-acetic acid (5.2 g. ,
0.024 mol, 100%). Recrystallised from petroleum ether (b.p. 60-80°) m.p. 70.0-71.0°C., (Found C, 71.43;
H, 6.48, C13H1403 requires C, 71.54; H, 6.47%), tlc/ Silica/ethylacetate- Rf 0.53.
(c) α-Isopropylbenzofuran-2-acetyl chloride
Thionyl chloride (0.60 g., 0.005 mol) was added to a solution of α-isopropylbenzofuran-2-acetic acid
(1.0 g., 0.005 mol), dimethylformamide (1 drop) in dry toluene (10 cm ) and the mixture was heated at 80º for 2.5 hr. Unchanged thionylchloride and toluene were removed under reduced pressure to leave a residue of α-isopropylbenzofuran-2-acetyl chloride which was used in the next stage without further purification.
(d) m-Phenoxybenzyl ester
α-Isopropylbenzofuran-2-acetyl chloride (1.09 g., 0.005 mol) was added dropwise to a stirred solution of m-phenoxybenzyl alcohol (0.92 g. , 0.005 mol), pyridine (0.37 cm3, 0.005 mol) in toluene (10 cm ) at below 5º, and the mixture was stirred at room temperature for
2.0 hr. Dilute hydrochloric acid was added and the mixture was extracted with toluene. The toluene extract was washed with dilute hydrochloric acid, water, dried (Na2SO4), filtered and the solvent was removed. Col umn chromatography of the residue on silica using toluene as the eluant was carried out and the component with
Rf 0.64 was isolated as m-phenoxybenzyl α-isopropyl-benzofuran-2-acetate. (0.75 g., 0.0019 mol, 40.8%).
(Found C, 77.99; H, 6.23; C26K24O4 requires C, 77.98; H, 6.04%).

EXAMPLE 2
α-Cyano-m-phenoxybenzyl α-isopropylbenzo
furan-2-acetate
0.91 g
A mixture of m-phenoxybenzaldehyde (0r/{9 .
0.005 mol), and α-isopropylbenzofuran-2-acetyl chloride

(1.09 g., 0.005 mol) was added dropwise to a stirred solution of sodium cyanide (0.25 g., 0.005 mol) in water (10 cm3) at 0ºC. The mixture was stirred for

5.0 hr and allowed to stand overnight. The mixture was extracted with diethyl ether. The organic extract was washed with dilute hydrochloric acid, water and sodium bicarbonate solution, dried (Na2SO4), filtered and the solvent was removed. The residue was chromatographed on silica using toluene as eluant, and the component with Rf 0.56 was isolated as α-cyano-m-phenoxybenzyl α-isopropylbenzofuran-2-acetate (0.20 g., 0.0005 mol, 10.0%). (Found: C, 76.06; H, 5.60; N, 3.07.

C27H23N04 requires C, 76- 22; H, 5.45; N, 3.29%) .
EXAMPLE 3
m-Phenoxybenzyl α—isopropyl-lH-indole-3-acetate
(a) α-Isopropyl-lH-indole-3-acetyl chloride
Thionyl chloride (0.21 cm3, 0.003 mol) was added dropwise to a solution of α-isopropyl-lH-Indole-3-acetic acid (0.63 g., 0.003 mol), dimethylformamide (1 drop) and toluene (20 cm3) at 0°C. The mixture was stirred at room temperature for 18 hr. Unchanged thionyl chloride and toluene were removed under reduced pressure to give a residue of α-isopropyl-lH-indole-3-acetyl chloride (0.68 g., 0.003 mol, 100%) which was used in the next stage without further purification.

(b) m-Phenoxybenzyl ester
A solution of α-isopropyl lH-indole-3-acetyle chloride (0.68 g., 0.003 mol) in toluene (5 cm3) was added dropwise to a stirred solution of m-phenoxybenzy alcohol (0.58 g., 0.003 mol), pyridine (0.23 cm3,
0.003 mol) in toluene (15 cm3) at 0°C, and the mixture was stirred for 2.0 hr. Dilute hydrochloric acid was added and the mixture was extracted with toluene. The extract was washed with water, dried (Na2S04) filtered and the solvent was removed. The residue was chromatographed on silica using toluene as the eluant and the compound with Rf 0.69 was isolated as m-phenoxybenzyl α-isopropyl-lH-indole-3-acetate (0.90g., 0.0023 mol, 77%) (Found C, 78.06; H, 6.62; N, 3.12. C26H2 5N03 requires C, 78.17; H, 6.31; N, 3.51%).
EXAMPLE 4
m-Phenoxybenzyl α-isopropylbenzotblthiophene-3-aceta (a) α-Isopropylbenzo[b]thiophene-3-acetonitrile
A solution of sodium hydroxide (1.50 g., 0.037 mol) and tetrabutylammonium bisulphate (6.40 g., 0.018 mol) and water (19.0 cm3) was added to a vigorously stirred solution of 2-iodopropane (6.43 g. , 0.038 mol) and benzo[b] thiophene-3-acetonitrile (3.27 g., 0.018 mol) in dichloromethane (19.0 cm3). The mixture was reflux with vigorous stirring for 18 hr, when the organic lay was separated and the solvent was removed. Diethyl ether was added to the residue and the mixture was fil tered. The solvent was removed from the filtrate to give α-isopropylbenzo [b]thiophene-3-acetonitrile (2.11 0.0093 mol, 52%). (Found: C, 72.36; H, 6.00; N, 6.29;

S, 14.97; C1 3H13NS requires C, 72.52; H, 6.09; N, 6.52; S, 14.89%) TLC/Silica/Toluene, Rf = 0.52.
(b) α-Isopropylbenzo [b]thiophene-3-acetic acid
A solution of α-isopropylbenzo[b] thiophene-3-acetonitrile (1.0 g., 0.0046 mol) in acetic acid
(12 cm3), water (1.6 cm3) and cone, sulphuric acid
(1.6 cm3) was refluxed for 18 hr. The mixture was added and the mixture was extracted with diethyl ether.

The extract was washed with saturated sodium bicarbon ate solution and the aqueous solution was acidified with dilute hydrochloric acid. The aqueous mixture was extracted with diethyl ether and this extract was washed with water, dried (Na2SO4) , filtered and the solvent was removed to give α-isopropylbenzo[b]thiophene-3-acetic acid (0.84 g., 0.0036 mol, 77.2%) Found: C, 66.68; H, 6.01; S, 12.97, C H O2S requires C, 66.64; H, 6.02; S, 13.68%) m.p. 118-119°.
(c) α-Isopropylbenzo[b]thiophene-3-acetyl chloride
A solution of α-isopropylbenzo[b] thiophene-3-acetic acid (0.25 g., 0.001 mol), thionyl chloride
(0.2 cm3), 0.001 mol), dimethylformamide (trace) and toluene (10 cm3) was stirred at room temperature for

18 hr. Unchanged thionyl chloride and toluene were removed under reduced pressure to give a residue of α-isopropylbenzo[b] thiophene-3-acetyl chloride which was used in the next stage without further purification.
(d) m-Phenoxybenzyl ester
α-Isopropylbenzo[b]thiophene-3-acetyl chloride
(from above) in toluene (10 cm3) was added dropwise to a stirred solution of m-phenoxybenzyl alcohol (0.24 g., -0.001 mol), pyridine (0.19 g., 0.0024 mol) in toluene (10 cm3), and the mixture was stirred for 2 hr. Dilute hydrochloric acid was added to the mixture and the mixture was extracted with toluene. The extract was washed with dilute hydrochloric acid, water, dried (Na2SO4), filtered and the solvent was removed. Column chromatography of the residue on. silica using toluene as the eluant was carried out and the component with Rf 0.51 was isolated as m-phenoxybenzyl α-isopropylbenzo[b] thiophene-3-acetate (0.41 g., 0.00093 mol, 93.2%).
EXAMPLE 5
α-Cyano-m-phenoxybenzyl α-isopropylbenzo[b]
thiophene-3-acetate
A solution of α-isopropylbenzo[b]thiophene-3-acetyl chloride prepared from α,-isopropylbenzo[b] thiophene-3-acetic acid (0.20 g., 0.855 m mol) in toluene (10 cm3) was added dropwise to a stirred solution of α-cyano m-phenoxybenzyl alcohol (0.20 g., 0.89 m mol) and pyridine (0.1 cm3., 1.24 m mol) in toluene (5 cm3) at below 10ºC, and the mixture was stirred at room temperature for 2.0 hr. Dilute hydrochloric acid was added and the mixture was extracted with toluene. The extract was washed with water, dried (Na2SO4), filtered, and the solvent was removed. Column chromatography of the residue on silica using toluene as the eluant was carried out, and the component with Rf 0.68 was isolated as α- cyano-m-phenoxybenzyl α-isopropylbenzo[b] thiophene-3-acetate (0.10 g., 0.226 m mol, 26.5%). (Found: C, 73. 26 ; H, 5.43 ; N, 2. 87 C27H23NO3S requires C , 73.44; H, 5. 25 ; N, 3. 17%) .

EXAMPLE 6
m-phenoxybenzyl 5-chloro-α-isopropylbenzo[b]thiophene- 3-acetate
The title compound was made by the method of
Example 4 by substituting 5-chlorobenzo[b]thiophene-3-acetonitrile, for the benzo[b]thiophene-3-acetonitrile used in Example 4.
EXAMPLE 7
α-Cyano-m-phenoxyphenyl 5-chloro-α-isopropylbenzo[b]
thiophene-3-acetate
The title compound was made by the method of
Example 5 by substituting 5-chloro-α-isopropylbenzo[b] thiophene-3-acetyl chloride obtained as an intermediate in Example 6 , for the α-isopropylbenzo hiophene-3-acetyl chloride used in Example 5.
EXAMPLE 8
m-Phenoxybenzyl 5-chloro-α-isopropylbenzofuran-2- acetate
The title compound was made by the method of
Example 1 by substituting 5-chlorobenzofuran-2-aceto nitrile for the benzofuran-2-acetonitrile used in
Example 1.
EXAMPLE 9
α-Cyano-m-phenoxybenzyl 5-chloro-α-isopropylbenzofuran- 2-acetate
The title compound was made by the method of
Example 5 by substituting 5-chloro-α-isopropylbenzo furan-2-acetyl chloride, obtained as an intermediate in Example 8, for the α-isopropylbenzo [b] thiophene-3-acetyl chloride used in Example 5.

EXAMPLE 10
m-Phenoxybenzyl α-isopropylbenzofuran-3-acetate
The title compound was made by the method of
Example 1 by substituting benzofuran-3-acetonitrile for the benzofuran-2-acetonitrile used in Example 1.
EXAMPLE 11
α-Cyano-m-phenoxybenzyl α-isopropylbenzofuran-3- acetate
The title compound was made by the method of Exampl 5 by substituting α-isopropylbenzofuran-3-acetyl chloride, obtained as an intermediate in Example 10, for the α-isopropylbenzo[b]thiophene-3-acetyl chloride used in Example 5.
EXAMPLE 12
m-Phenoxybenzyl 5-chloro-α-isopropylbenzofuran- 3-acetate
The title compound was prepared by the method of Example 1 by substituting 5-chlorobenzofuran-3-aceto nitrile (prepared by the same method as described in Aust. J. Chem. 1975, 28, 1097 for the preparation of benzofuran-3-acetonitrile) for the benzofuran-2-aceto-nitrile used in Example 1.
EXAMPLE 13
α-Cyano-m-phenoxybenzyl 5-chloro-α-isopropylbenzo
furan-3-acetate
The title compound was made by the method of
Example 5 by substituting 5-chloro-α-isopropylbenzo furan-3-acetyl chloride, obtained as an intermediate in Example 12, for the α-isopropylbenzo[b]thiophene-3-acetyl chloride used in Example 5.

EXAMPLE 14
α-Cyano-m-phenoxybenzyl α-isopropyl-7-methyl
benzofuran-3-acetate
The title compound was made by the method of
Example 5 by substituting α-isopropyl-7-methylbenzo furan-3-acetylchloride (prepared by the method of
Example 12 by substituting 7-methylbenzofuran-3-aceto nitrile for the 5-chloro benzofuran-3-acetonitrile used in Example 12) for the α-isopropylbenzo[b] thiophene-3-acetyl chloride used in Example 5.
EXAMPLE 15
α-Cyano-m-phenoxybenzyl α-t-butylbenzofuran-2- acetate
(a) t-Butyl benzofuran-2-yl ketone
A solution of 2-bromobenzofuran (23.48 g., 0.118 mol.) in ether (40 cm3) was added to a solution of n butyl lithium (71.3 g., 15% w/w in hexane, 0.166 mol.) in ether (300 cm3) at -60ºC over 45 mins. The temperature was allowed to rise to 0ºC over 1.0 hr. and the mixture was then cooled to -40ºC. A solution of pivalic acid (17.03 g., 0.166 mol.) in ether (80 cm3) was added at -40ºC over 0.5 hr. and the temperature was allowed to rise to ambient and maintained at this for 18 hrs.
Water (200 cm3) was added and the organic layer was separated. The organic layer was washed with sodium bi carbonate solution, dried (Mg.SO4), filtered and the sol vent was removed. The residue was subjected to column chromatography on silica using toluene as the eluant and the fraction having Rf 0.35 was isolated. The frac tion was distilled at 74 - 80º/0.05 mn.Hg. to give t- butyl benzofuran-2-yl ketone (6.0 g., 0.03 mol: 19.9%).

(b) Ethyl α-tert-butyl-β-benzofuran-2-yl glycidate
A solution of potassium t-butoxide in t-butanol

(prepared from potassium (2.02 g., 0.05 mol.) in t-butanol (47 cm3) was added to a solution of t-butyl benzofuran-2-yl ketone (6.0 g., 0.03 mol.), ethyl 2-chloroacetate (5.8 g., 0.48 mol) in toluene (15 cm3) and t-butanol (6 cm3) at 5 to 10ºC under nitrogen, and the mixture was allowed to stand at room temperature for 24 hours. Water was added, the organic layer was separated, washed with water, dried (MgSO4), filtered, and the solvent was removed. The residue was subjected to column chromatography on silica using toluene: carbo tetrachloride, (1:1), as the eluant and the fraction with Rf 0.09 was isolated to give ethyl α-tert-butyl-β-benzofuran-2-yl glycidate (5.17 g., 0.0179 mol;
59.8%).
(c) α-t-butyl-benzofuran-2-acetaldehyde
A solution of ethyl α-t-butyl-β-benzofuran-2-yl glycidate (3.17 g., 0.011 mol), potassium hydroxide (3.16 g., 0.11 mol) in ethanol (100 cm3) was allowed to stand at room temperature for 18 hours. The solvent was removed, the residue was acidified and extracted with ether. The extract was washed, dried (MgS04), fil tered and the solvent was removed to give α-t-butyl-benzofuran-2-acetaldehyde (2.31 g., 0.0107 mol; 97.16%)

(d) α-t-butylbenzofuran-2-acetic acid
A solution of sodium hydroxide (2.32 g., 0.058 mol) in water (12 cm3) was added dropwise to a mixture of α-t-butylbenzofuran-2-acetaldehyde (3.67 g., 0.017 mol), silver nitrate (3.97 g., 0.20 mol), water (12 cm3) and ethanol (5 cm3) at room temperature and the mixture was stirred for 18 hours.
The mixture was filtered and the filtrate was ex tracted with ether. The aqueous solution was acidified and extracted with ether. The extract was washed, and extracted with sodium carbonate solution. The aqueous extract was acidified and extracted with ether. The ether extract was dried (MgSO4), and the solvent was removed to give α-t-butyl benzofuran-2-acetic acid
(0.4275 g., 0.0018 mol., 10.8%).
Recrystallised from petroleum ether (b.p. 60-80º), m.p. 119-120°C, (Found: C, 72.48; H, 6.93. C14H16O3 requires C, 72.39; H, 6,94%).
(e) α-Cyano-m-phenoxybenzyl α-t-butylbenzofuran-2- acetate
The ester was prepared in 50.1% yield using the same method as Example 1(d), TLC/silica/toluene, Rf

0.56.
(Found: C, 75.99; H, 6.05; N, 2.94. C28H25O4N requires

C, 76.52; H, 5.73; N, 3.1%).
EXAMPLE 16
m-Phenoxybenzyl α-t-butylbenzofuran-2-acetate
The title compound was prepared by the method of Example 1(d) by substituting α-t-butylbenzofuran-2-acetyl chloride, obtained as an intermediate in Example

15, for the α-isopropylbenzofuran-2-acetyl chloride used in Ex-ample 1.

EXAMPLE 17
α-Cyano-m-phenoxybenzyl 5-bromo-α-isopropyl- benzofuran-3-acetate
The tile compound was prepared by the method of Example 13 by substituting 5-bromo-α-isopropylbenzo furan-3-acetontrile for the 5-chloro-α-isopropylbenzo furan-3-acetonitrile used in Example 13.
EXAMPLE 18
α-Cyano-m-phenoxybenzyl α-isopropyl-7-methoxy
benzofuran-2-acetate
(a) 2-Carbethoxy-7-methoxybenzofuran was prepared in 57% yield from 7-methoxybenzofuran-2-carboxylic acid by heating under reflux with ethanol and a trace of sulphuric acid.
(m.p. 88 - 89° (from aqueous ethanol)
TLC/silica/dichloromethane, Rf 0.23.)
(b) 2-Hydroxymethyl-7-methoxybenzofuran was prepared in 50% yield by reduction of 2-carbethoxy-7-methoxy benzofuran with lithium aluminium hydride in anhydrous diethyl ether.
(b.p. 116 - 120°/0.1 mm.Hg.)
(c) 2-Chloromethyl-7-methoxybenzofuran was prepared in 52.9% yield from 2-hydroxymethyl-7-methoxybenzofuran using thionyl chloride and pyridine In dichloromethane. TLC/silica/dichloromethane, Rf 0.67.
(d) 7-Methoxybenzofuran-2-acetonitrile was prepared in 66% yield from 2-chloromethyl-7-methoxybenzofuran using sodium cyanide, tetrabutylammonium bromide in water and dichloromethane. M.pt. 82 - 83° (from
petroleum ether, b.p. 60 - 80º).

TLC/silica/toluene-dichloromethane, 1:1), Rf 0.22.
(Found: C, 70.85; H, 4.93; N, 7.37. C11H9N02
requires: C, 70.58; H, 4.85; N, 7.48%).
(e) α-Cyano-m-phenoxybenzyl α-isopropyl-7-methoxy
benzofuran-2-acetate
The title compound was made by the method of
Example 5 by substituting α-isopropyl-7-methoxybenzo furan-2-acetyl chloride (made by the method of Example 1 by substituting α-isopropyl-7-methoxybenzofuran-2-acetonitrile for the α-isopropylbenzofuran-2-acetonitrile of Example l) for the α-isopropylbenzo[b]thiophene-3-acetyl chloride used in Example 5.
EXAMPLE 19
5-Benzyl-3-furylmethyl α-isopropyl-7-methoxy
benzofuran-2-acetate
The title compound was made by the method of
Example 18(e) substituting 5-benzyl-3-furylmethanol for the α-cyano-m-phenoxybenzyl alcohol used in Example 18(e).
EXAMPLE 20
α-Cyano-m-phenoxybenzyl α-ethyl-7-methoxy
benzofuran-2-acetate
The title compound was made by the method of
Example 5 by substituting α-ethyl-7-methoxybenzofuran-2-acetyl chloride (prepared by the method of Example 1 substituting f7-methoxybenzofuran-2-acetonitrile and iodoethane for the benzofuran-2-acetonitrile and 2-iodopropane, respectively used in Example 1) for the α-isopropylbenzofbj thiophene-3-acetyl chloride used in Example 5.

EXAMPLE 21
α-Cyano-m-phenoxybenzyl 2 , 3-dihydro-g-ethyl-7- methoxybenzofuran-2-acetate
The title compound was made by the method of Example 5 by substituting 2,3-dihydro-α-ethyl-7-methoxy benzofuran-2-acetyl chloride- (prepared from the acid in the usual manner). The acid was made by catalytic hydrogenation of α-ethyl-7-methoxybenzofuran-2-acetic acid, an intermediate from Example 20), for the α-iso propylbenzo[b]thiophene-3-acetyl chloride used in
Example 5.
EXAMPLE 22
α-Cyano-m-phenoxybenzyl 5-chloro-σ-isopropyl-7- methylbenzofuran-3-acetate
The title compound was made by the method of

Example 5 by substituting 5-chloro-α-isopropyl-7-methyl benzofuran-3-acetyl chloride [prepared by the method of Example 1 by substituting 5-chloro-7-methylbenzo furan-3-acetonitrile (itself prepared by the method described for this class of compound in J. Aust. Chem. 1975, 28, 1097, c.f. Example 12) for the benzofuran-2-acetonitrile used in Example I] for the α-isopropyl benzo[b]thiophene-3-acetyl chloride used in Example 5.

TESTS OF ACTIVITY
The insecticidal activities of the compounds of the Examples has been shown by the following tests in three species of insects, namely Aedes aegypti,
Musca domestica, and Blattella germanica.
(a) Aedes aegypti
A 0.2 cm3 sample of a solution of test compound in AR acetone was applied to water (200 cm3) containing 20

(3 day old) larvae. Kill was recorded after 24 hours. Solutions of different concentration were tested from which the concentration of solution which gives 50% kill (LC50) was determined.
(b) Blattella germnanica
A 2 μl drop of a solution of the test compound in AR acetone was applied between the rear coxae of 1-4 week old adult males. Knockdown was recorded after 24 hours. Solutions of different concentration were tested from which the concentration of solution which gives 50% kill (LC50) was determined.
(c) Musca domestica
(1) A 1 μl drop of a solution of test compound in AR acetone (high purity acetone) was applied to the dorsal thorax of 3-day old adult females. Knockdown was recorded after 24 hours. Solutions of different concen tration were tested from which the concentration of solution and therefore the amount of compound which gives 50% kill (LC50) was determined.
(ii) Similar tests were carried out with the amendment that to each test solution, 0.5% w/v of commercial insecticide synergist, piperonyl butoxide, was added.

(d) Tribolium castaneum
A 1 μl drop of a solution of test compound in AR acetone was applied topically to adult insects. Knockdown was recorded after 48 hours. Solutions of dif ferent concentrations were tested from which the concentration of solution which gives 50% knockdown (LD50) was determined.
Table 1 shows the results obtained for compounds of the Examples. The results are all expressed as activities relative to the activity of Resmethfin
(assigned activity = 100) , determined by the methods described


These results indicate that the Examples shown have a high insecticidal potency and that this may be considerably increased when the compounds are applied in combination with a known synergist, viz., piperonyl butoxide.
Resmethrin is 5-benzyl-3-furylmethylchrysanthemum ate and is a synthetic pyrethoid insecticide developed by the N.R.D.C. see e.g. U.K. Patent Specification No. 1,168,797. It has an activity about 20 times that of natural pyrethrum and has been used as an insecticide and as a reference substance in assessing the insecticidal activity of other compounds.
The activities of some of the compounds of the Examples has been shown in the following tests in three species of phytophagous arthropods namely Megoura vicae, Plutella xylostella, Tetranychus cinnabarinus.

Aqueous suspensions of test compound were made by adding a solution of test compound in AR acetone to a solution of TWEEN 80 (200 p.p.m.) in water.
(a) Megoura vicae
Adult insects were dipped individually for 4 seconds in the aqueous suspension of test compound and then placed on a filter paper in a Petri dish (9.0 cm. diameter) with a p.t.f.e. rim. A 5.0 cm. long piece of broad bean stem was added and the lid was put on. Knock down was recorded after 24 hours.
(b) Plutella xylostella
A 9.0 cm. square of cabbage leaf was dipped for 4 seconds in the aqueous suspension of the test compound, and allowed to dry. The leaf was placed on filter paper in a Petri dish (9.0 cm). Five 3rd instar larvae were placed on the leaf, and the dish was placed in a polythene bag containing a wet cotton-wool pad. Knockdown was recorded after 24 hours.
(c) Tetranychus cinnabarinus
The two primary leaves of dwarf French beans were reduced to 2.5 cm. squares, and they were infested with ca. 20 adult mites. The leaves were then dipped for 4 seconds in the aqueous suspension of the test compound and allowed to dry. Adult mortality was recorded after 48 hours.
Table 2 shows the results obtained for some of the compounds of the Examples.
Phytotoxicity
Phytotoxicity is an important feature when the insecticide is applied to foliage. On application of 100 ppm of fenvalerate to lettuce, cucumber and dwarf French beans, phytotoxicity was observed.
Application of compounds of this invention in an identical regime at 100 ppm showed no phytotoxic
effects in lettuce, cucumber, dwarf French beans, tomato or broad bean.
Photostability
Photostability is an important feature when the insecticide is applied to foliage. Natural pyrethrum and many synthetic pyrethroids have low photostability, and hence have restricted use as plant protection agents The compounds of this invention exhibit considerably greater photostability than many other pyrethroids, for example, resmethrin. A deposit of selected Examples and resmethrin was exposed to a light source and tested at increasing time intervals. Example number 1 had a half-life 5 times greater than resmethrin, and Example number 11 had a half-life 14.5 times greater than resmethrin.

B