EP0191847A1

EP0191847A1 - Arthropodicides

Info

Publication number: EP0191847A1
Application number: EP85904398A
Authority: EP
Inventors: George Holan; Karen Elizabeth Jarvis; Wynona Marguerite Phillips Johnson
Original assignee: Commonwealth Scientific and Industrial Research Organization CSIRO
Current assignee: Commonwealth Scientific and Industrial Research Organization CSIRO
Priority date: 1984-08-30
Filing date: 1985-08-27
Publication date: 1986-08-27
Also published as: EP0191847A4; JPS62500238A; PH20900A; BR8506904A; IL76207A0; WO1986001501A1; ZA856615B; HUT41589A

Abstract

Composés à action arthropodicide, de formule générale (I), ainsi que leurs formes isomères, où R1 est un groupe halo, ou un groupe alkyle inférieur, alkoxy inférieur ou alkylthio inférieur, dans chacun desquels le groupe alkyle peut être substitué par un ou plusieurs groupes halo; R2 est hydrogène ou un groupe halo ou halométhyle; ou alors R1 et R2 forment ensemble un groupe méthylénedioxy ou un groupe difluoro-méthylènedioxy, ou alors R1 et R2, avec les atomes de carbone auxquels ils sont liés forment un anneau aromatique; X est un groupe fluoro, chloro ou bromo; A' est O, S, NH ou NZ où Z est un groupe cyano, alkyle inférieur ou haloalkyle; R3 est 3-phénoxyphényle, 2-phénoxy-6-pyridyle, 4-fluoro-3-phénoxyphényle ou 2-phénoxy-3-fluoro-6-pyridyle; R4 est hydrogène ou cyano.Compounds with arthropodicidal action, of general formula (I), as well as their isomeric forms, where R1 is a halo group, or a lower alkyl, lower alkoxy or lower alkylthio group, in each of which the alkyl group may be substituted by one or more halo groups; R2 is hydrogen or a halo or halomethyl group; or then R1 and R2 together form a methylenedioxy group or a difluoro-methylenedioxy group, or else R1 and R2, with the carbon atoms to which they are attached form an aromatic ring; X is a fluoro, chloro or bromo group; A 'is O, S, NH or NZ where Z is cyano, lower alkyl or haloalkyl; R3 is 3-phenoxyphenyl, 2-phenoxy-6-pyridyl, 4-fluoro-3-phenoxyphenyl or 2-phenoxy-3-fluoro-6-pyridyl; R4 is hydrogen or cyano.

Description

"ARTHROPODICIDES"

This invention relates to new compounds having arthropodicidal activity, to methods of preparing these compounds and to the use of the compounds afs arthropodicides, especially -as insecticides and acaricides.

The compounds provided by this invention have the general formula (I) :

X

wherein

R is a halo group; or a lower alkyl, lower alkoxy or lower alkylthio group, in each of which the alkyl group may be substituted with one or more halo groups; R2 is hydrogen or a halo or halomethyl grou'p; or R1

2 and R together form a methylenedioxy, or a difluoro-methylenedioxy group or, R 1 and R2 together with the carbon atoms to which they are attached, form an aromatic ring;

X is a fluoro, chloro or bromo group;

A' is 0, S, NH, or NZ where Z is lower alkyl or haloalkyl or cyano group;

3 R is 3-phenoxyphenyl, 2-phenoxy-6-pyrιdyl, 4-f luoro-3- henoxyphenyl , or 2-phenoxy-3- fluoro-β-pyridyl;

4 R is hydrogen or cyano.

As used herein "halo" means fluoro, chloro or bromo; "lower" implies alkyl groups having from 1 to 4 carbon atoms. Alkyl groups having more than 2 carbon atoms may -be straight or branched.

Related prior art compounds disclosed in our Australian Patents Nos. 502,950 and 525,002 are esters of dihalocyclopropane acids of the general formula (II)

wherein R 1 and R2 are essentially as defined above and X 1, X2 are the same or different and each is fluorine, chlorine or bromine, with one of the following alcohols:- 3-phenoxybenzyl alcohol 2-benzyl-4-furylmethanol α-cyano-3-phenσxybenzyl alcohol 3 ,4-methylenedioxybenzyl alcohol -ethynyl-3-phenoxybenzyl alcohol

Our International Patent Application PCT/AU83/00130 claims inter alia dihalocyclopropane compounds of the structure of Formula Ila:-

where R 1 , R2 , X1 , X2 and A1- are as previously defined,

R⁴ , R are independently hydrogen, chlorine, or fluorine

A 5 ^" 6 or R^" and R together form =0 when A is CH_; R is hydrogen, deuterium, CN or C=CH; R 7 is

3-phenoxyphenyl,2-phenoxy-6-pyridyl, 2-phenoxy-3-fluoro-6-pyridyl, pentafluorophenyl,

4-fluoro-3-phenoxyphenyl, N pyrollyl-3-benzyl,

3 ,4-methylenedioxy phenyl; or 3- (4-methoxyphenoxy) g phenyl; and R is hydrogen or deuterium.

These prior art compounds are particularly effective against flies and other insects of the order Diptera. In contrast we have discovered that the compounds of the present invention are not especially active against flies but are particularly active against larvae of -Insects of the order Lepidoptera, which order includes many important agricultural pests.

The compounds of the invention (formula (I)) are optically active and can be resolved into their optical isomers by conventional methods. The invention thus includes the individual optical isomers of the compounds as well as the racemic forms.

The compounds of formula (I) may be prepared by the conventional methods of synthetic organic chemistry.

In general, the compounds are formed by reacting together compounds of the formulae (III) and ( IV)

(III) (IV)

R 1, R2, R3 and R4 are as defined above and wherein P and

Q are reactive atoms or groups, often referred to as

"leaving groups", selected so that on reaction they give rriissee ttoo tthhee ddeessiirreedd ggrroouupp AA oorr ttoo aamnother group which is convertible to that desired group.

By way of illustration, the compounds (I) having the A groups listed below may be formed from the compounds (III) and (IV) having the indicated substituents P and Q. The groups indicated for P and Q could equally well be interchanged i.e. P = Br, Q = OH to give A¹ = -0-.

A¹ P Q -

^■0- -OH Br-

^■s - ) -SH Br-

- ^•NNHH-- ) ) ( (22)) - -NNHH,. Br-

^•NZ- )

(2) Compounds wherein A is NZ are produced by reacting the amine with the halogen ZHal, where Hal is Cl, Br or I.

Compounds of- formula (I) where the group A is -NH- or -NZ- can also be made by reacting a compound of formula (III) wherein P is NH„ with a compound of formula (V)

O = C - R³

3 ^ wherein R and R^" are as defined above, and then, if required converting the resulting amine (A = -NH-) to the compound wherein A is -NZ- as described above.

The active compounds of the invention are well tolerated by plants, have a favourable level of toxicity to warm-blooded animals, and can be used for combating arthropod pests, especially insects or acarids, which are encountered in agriculture, in veterinary practice, in forestry, in the protection of stored products and of materials, and in the hygiene field. They are active against normally sensitive and resistant species and against all or some stages of development. The abovementioned pests include Blatella germanica (German cockroach) , and Heliothis punctigera (cotton budworm) .

The present invention also provides arthropodicial compositions containing as active ingredients a compound of the present invention.

The present invention also provides a method of combating arthropods (especially insects or acarids) which comprises applying- to the arthropods, or to a habitat .thereof, a compound of the present invention alone or in the form of a composition containing as active ingredient a compound of the present invention.

The present invention also provides a method of freeing or protecting domesticated animals from parasitical insects or acarids which comprises applying to said animals a compound according to the present invention, or a composition containing such a compound as the active ingredient. s •

In the compositions of this invention, the active compounds are converted into such customary formulations as solutions, emulsions, wettable powders, suspensions, powders, dusting agents, foams, pastes, soluble powders, granules, aerosols, suspension-emulsion concentrates, seed-treatment powders, natural and synthetic materials impregnated with active compound, very fine capsules in polymeric substances, and coating compositions for use on seed, as well as ULV cold mist and warm mist formulations.

These formulations may be produced in known manner, for example by mixing the active compounds with extenders, i.e., liquid or liquefied gaseous or solid diluents or carriers, optionally with the use of surface-active agents, i.e., emulsifying agents and/or dispersing agents and/or foam-forming agents. Where water is used as an extender, auxiliary solvents, such as for example, organic solvents, can also be used.

Examples of suitable liquid diluents or carriers, especially solvents, are aromatic hydrocarbons, such as xylene, toluene or alkyl naphthalenes, chlorinated aromatic or chlorinated aliphatic hydrocarbons, such as chlorobenzenes, chloroethylenes or methylene chloride; aliphatic or alicyclic hydrocarbons, such as cyclohexane or paraffins, for example mineral oil fractions; alcohols, such as butanol or glycol, as well as their ethers; and esters, ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclσhexanone; and strongly polar solvents, such as dimethylformamide and dimethyl sulphoxide, as well as water.

By liquefied gaseous diluents or carriers are meant liquids which would be gaseous at normal temperature and under normal pressure, for example aerosol propellants, such as halogenated hydrocarbons as well as butane, propane, nitrogen and carbon dioxide. Examples of solid carriers are ground natural minerals, such as kaolins, clays, talc, chalk, quartz, attapulgite, montmorillonite or diatomaceous earth; and ground synthetic minerals, such as highly-dispersed silicic acid, alumina and silicates. As solid carriers for granules there may be used crushed and fractionated natural rocks such as calcite, marble, pumice, sepiolite and dolomite; as well as synthetic granules of inorganic and organic meals, and granules of organic material such as sawdust, coconut shells, maize cobs and tobacco stalks.

Examples of emulsifying and/or foam-forming agents are non-ionic and anionic emulsifiers, such as polyoxyethylene-fatty acid esters, polyoxy ethylene-fatty alcohol ethers, for example alkylaryl polyglycol ethers, alkyl sulphonates, alkyl sulphates, aryl sulphonates,^" as well as albumin hydrolysis products. Dispersing agents include, for example, lignin sulphite waste liquors and methylcellulose,.

Adhesives such as carboxymethylcellulose and natural and synthetic polymers in the form of powders, granules or latices, such as gum arabic, polyvinyl alcohol and polyvinyl acetate, can be used in the formulations. s

It is also possible to use colorants such as inorganic pigments, for example iron oxide, titanium oxide and Prussian Blue, and organic dyestuffs, such as alizarin^" dyestuffs, azo dyestuffs or metal phthalocyanine dyestuffs. The formulations in general will contain from 0.1 to 95 per cent by weight of active compound, preferably from 0.5 to 90 per cent by weight.

The active compounds according to the invention may be used in the form of formulations of the types that are commercially available or in the use forms prepared from these formulations.

The active compound content of the use forms prepared from the formulations of the types that are commercially available can vary within wide ranges. The active compound concentration of the use forms can be from 0.0000001 to 100% by weight of active compound, preferably from 0.0001 to 10% by weight.

The compounds may be employed in a customary manner appropriate for the particular use forms.

The active compounds according to the invention are also suitable for combating ectoparasites and endoparasites in the field of veterinary medicine. The compounds may be used in a known manner, such as orally in the form of, for example, tablets, capsules, drenches and granules; dermally by means of, for example, dipping, spraying, pouring-on, spotting-on and powdering.

The compounds may be employed either as the sole toxic agent in compositions such as those described above, or in combination with other insecticides such as pyrethrum, rotenone, or with fungicidal or bactericidal agents, to provide compositions useful for household and * agricultural dusts and sprays, textile coating and impregnation, and the like.

In particular, the compounds of the invention may be advantageously combined with other substances which have a synergistic or potentiating action. Generally such substances are of the class of microsomal oxidase inhibitors, i-.e. , they inhibit the detoxification of insecticides in insects produced by the action of oxidative enzymes. Typical substances of this type are the pyrethrin synergists of which the following are examples:-

[2-(2-butoxyethoxy) ethoxy] -4,5-methylenediσxy-2- propyltoluene (Piperonyl butoxide) , 3-hexyl-5 (3,4- methylenedioxyphenyl)-2-cyclohexanone (Piperonyl cyclonene) , 2-(3,4-methylenedioxy-phenoxy)-3,6 ,9- trioxaundecane (Sesoxane or. Sesamex), 1,2-(methylene¬ dioxy) -4-[2-(octylsulfinyl)propyl]benzene (Sulfoxide) , dipropyl-5,6,7,8-tetrahyd o-7-methylnaphtho-[2,3-d] ,

3-dioxole-5,β-dicarboxylate (n-Propyl isome), as well as propynyl ethers and propynyl oximes.

("Sesoxane", "Sesamex" and "Sulphoxide" are Registered Trade Marks) .

Piperonyl butoxide is particularly us_eful as a potentiator. The amount of piperonyl butoxide use^'d may vary from 1/lOOth to fifty times the weight of the compound I the preferred range being from about l/100th to five parts by weight. 'Sesamex' also is a useful potentiator in similar amounts. Examples of formulations in accordance with the invention are as follows: (parts are by weight) :

Dusts

The following substances are used to produce (a) a 5% dust and (b) a 2% dust:

(a) 5 parts of active substance, 95 parts of talcum;

(b) 2 parts of active substance,

1 part of highly dispersed silicic acid, 97 parts of talcum.

The active substance is mixed and ground with the carriers.

Granulates

- The following ingredients are used to produce a 5% granulate:

5 parts of active substance, 0.25 part of epichlorohydrin, 0.25 parts of cetyl polyglycol ether, 3.50 parts of polyethylene glycol, 91 parts of kaolin

The active substance is mixed with epichlorohydrin and dissolved with 6 parts of acetone, the polyethylene glycol and cetyl polyglycol ether are then added. The solution obtained is sprayed onto kaolin and the acetone is evaporated off in vacuo. Wettable powders

The following constituents are used to .produce (a) a 40%, (b) and (c) a 25%, and (d) a 10% wettable powder;

(a) 40 parts of active substance,

5 parts of sodium lignin sulphonate, 1 part of sodium dibutyl-naphthalene sulphonate, 54 parts of silicic acid;

(b) 25 parts of active substance,

4.5 parts of calcium lignin sulphonate,

1.9 parts of chalk/hydroxyethyl cellulose mixture (1:1) ,

1.5 parts- of sodium dibutyl-naphthalene sulphonate,

19.5 parts of silicic acid,

19.5 parts of chalk, 28.1 parts of kaolin;

(c) 25 parts of active substance,

2.5 parts of isooctylphenoxy-polyoxyethylene ethanol, 1.7 parts of chalk/hydroxyethyl cellulose mixture (1:1) , 8.3 parts of sodium aluminium silicate, 16.5 parts of keiselguhr, 46 parts of kaolin;

(d) 10 parts of active substance,

3 parts of a mixture of the sodium salts saturated fatty alcohol sulphates , 5 parts of naphthalenesulphonic acid/formaldehyde condensate, 82 parts of kaolin.

The active substance is intimately mixed in suitable mixers with the additives, and the mixture is then ground in the appropriate mills and rollers to obtain wettable powders which can be diluted with water to give suspensions of the desired concentration.

Emulsifiable Concentrates

The following substances are used to produce (a) a 10%, (b) a 25%, and (c) a 50% emulsifiable concentrate:

(a) 10 parts of active substance,

3.4 parts of epoxidised vegetable oil,

3.4 parts of a combination emulsifier consisting of fatty alcohol polyglycol ether and alkylarylsulphonate calcium salt, 40 parts of dimethylformamide, 43.2 parts of xyler.e;

(b) 25 parts of active substance,

2.5 parts of epoxidised vegetable oil,

10 parts of alkylarylsulphonate .fatty alcohol polyglycol ether mixture, 5 parts of dimethylformamide, 57.5 parts of xylene;

(c) 50 parts of active substance,

4.2 parts of tributylphenol-polyglycol ether, 5.8 parts of calcium-dodecylbenzenesulphonate, 20 parts of cyclohexanone, , 20 parts of xylene.

Emulsions of the required concentration can be prepared from these concentrates by dilution with water.

Sprays

The following constituents are used to produce

(a) a 5% spray, (b) a 95% spray, and (c) a synergised 4% spray.

(a) 5 parts of active substance,

1 part of epichlorohydrin, 94 parts of ligroin (boiling limits

160°-190°C) ;

(b) 95 parts of active substance, ^'•

5 parts of epichlorohydrin-;

(c) 4 parts of active substance,

1 part of piperonyl butoxide, 79 parts of deodorised kerosene, 16 parts of alkylated naphthalene.

The general method of the invention as stated above is illustrated by the following embodiments, which are representative of the methods which may be used for preparation of the compounds of the invention. It will be appreciated that the solvents, reagents, reaction conditions, work-up procedures and other reaction parameters specifically mentioned may be replaced by their known equivalents. General Method A

Preparation of ethers and sulphides ,(A = -0- or -S-)

To a suspension of sodium hydride (1 mmol) in anhydrous dimethoxyethane (DME) (1 ml) was added dropwise a solution of 1 mmol of the required 1-aryl-cycloalkyl-l-methyl carbinol or mercaptan (Formula III; P = -OH or -SH) in anhydrous DME (1 ml) . This reaction mixture was stirred at room temperature for 0.75 hours. At the end of this time, a solution of 1 mmol of the required bromide (Formula IV; Q = Br) in anhydrous DME (0.5 ml) was added. The reaction was stirred at room temperature until thin layer chromatography indicated no starting material remained. The reaction mixture was then filtered, the filtrate concentrated and the residue chromatographed on silica gel using petroleum spirit (40-60°) /ethyl acetate mixtures as the eluting solvents.

The compounds of following Examples 1 to 3 were prepared by this method.

General Method B

Preparation of araikyl (1-aryl-halocycloalkyl) methyl amines (A = -NH-)

To a cold (0°C) , stirred solution of diborane (2 mmol) in dry tetrahydrofuran (2 ml) , under dry nitrogen, araikyl 1-aryl-halocycloalkyl) -1-carboxamide (0.5 mmol) was added. The mixture was heated and stirred under reflux for 1 hour and at room temperature . for an additional 16 hours. To the reaction mixture aqueous hydrochloric acid (2 ml) was added and most of the tetrahydrofuran removed by distillation. The residue was quenched with ice (50 g) and made basic with sodium hydroxide. After extraction with diethyl ether the combined ether extracts were washed with distilled water and NaCl solution. After separation the solvent layer was dried over anhydrous Na-SO^. Filtration and removal of the solvent in vacuo gave the product as^' an oil in >90% yield.

The compound of following Example 4 was prepared by this method.

The preparation and properties of the compounds of the invention are illustrated by the following specific examples. It should be noted, of course, that these examples are intended to be illustrative of the methods and procedures utilized in preparing the compounds and that the^'y are not intended to be restrictive or to be regarded as embodying the only way in which the compounds can be formed and recovered.

EXAMPLES

Preparation of Compounds

The compounds shown in Table 1 were prepared using the appropriate General Method as described above.

Example 1

(a) Ethyl 1-(4-ethoxyphenyl)-2-fluorocyclopropane- 1-carboxv —late

Ethyl 1-(4-ethoxyphenyl)-2-chloro-2-fluorocyclo- propane-1-carboxylate (lg, 3.5 mmol) was dissolved in dry xylene (2 ml) and placed under an argon atmosphere. Tri-n-butyltin hydride (lg, 3.6 mmol) and a catalyst amount of azobisisobutyronitrile (9 mg) were added to the solution. The solution was refluxed for 3 hours. At the end of this time the solution was cooled, dissolved in ether and the ether layer thoroughly washed with water. The ether layer was filtered through a short alumina (5% H_0) column and concentrated in vacuo. The residue was fractionally distilled. The fraction boiling between 110°-130° at 0.1 ^'mm was collected. This material was further purified by high performance liquid chromatography using multiple recycles on a DuPont Zorbax SIL (12.2mm x 25cm) column and 2% ethyl acetate/petroleum spirit (40-60°) as eluting solvent to afford 200 mg of each of the diastereoisomeric pairs.

First eluting diastereomer gave: IR (film) λ max 1725 (s) , 1610 (m) , 1580(a) cm^"1

Second eluting diastereomer gave: IR (film) λ max 1710 (s) , 1610 (m) 1580 (w) cm^"1

(b) 1- (4-ethoxyphenyl) -2-fluorocyclopropyl-methanol

The two diastereomers of ethyl 1- (4-ethoxyphenyl) 2-fluorocyclopropane-1-carboxylate were reduced separately using the following general procedure.

Lithium aluminium hydride (3 mmol) was refluxed for 1 hour in anhydrous ether (1 ml) under a nitrogen atmosphere and then cooled to room temperature. Ethyl 1-(4-ethoxyphenyl) -2-fluorocyclopropane-1- carboxylate (1.5 mmol) in dry ether (0.3 ml) was added dropwise. The reaction mixture was then refluxed for 3-4 hours (until thin layer chromatography showed the reduction was complete). Ethyl acetate (0.7 ml) was added dropwise to the cooled reaction mixture. The slurry was poured onto 4N HCl, thoroughly extracted with ether. The combined ether layer was washed with water and saturated NaCl solution dried over anhydrous Na^SO. and concentrated in vacuo. Recrystallization of the products from methylene chloride/petroleum spirit (40-60°) gave:

Diastereomer #1 in 63% yield m.p. 56.9°C. Analysis: Found: C, 68.5; H, 6.9; F, 9.2; ^C ₁₂ ^H15^F02 requires C, 68.6; H, 7.2; F, 9.0%.

Diastereomer #2 in 70% yield m.p. 79.3°C. Analysis: Found: C, 68.7; H, 7.4; F, 8.9.; C₂H₁₅F0₂ requires C, 68.6; H, 7.2; F, 9.0%.

(c) 3 '-Phenoxybenzyl 1-(4-ethoxyphenyl)-2-fluoro- cyclopropyl-1-methyl ether

The two diastereomers were reacted separately by the following procedure: To a stirred suspension of sodium hydride (17 mg, 0.7 mmol) in dry dimethoxyethane (2 ml) was added 1-(4-ethoxyphenyl)-2-fluorocyclopropyl methanol (140 mg, 0.7 mmol). After 30 minutes at room temperature m-phenoxybenzyl bromide (184 mg, 0.7 mmol)- was added. The resulting reaction mixture was stirred at room temperature for 24 hours. At the end of this time the solution was filtered, concentrated and chromatographed on silica gel (60-230 mesh) using 3% ethyl acetate/petroleum spirit (40-60°) as the eluting solvent, to afford 220 mg (85%) of the desired m-phenoxybenzyl ether as a colourless oil.

Diastereomer #1

IR (film)λ max 1610, 1580 cm^-1

NMR 1.0-1.4 (m, 2H, CH CHF) ; 1.37 (t, 3H CH₃) ; 3.73 (m, 2H CH₂-cyclopropyl) ; 3.96 (q, 2H, CH₂CH₃) ; 4.43 (s, 2H, CH₂ so) ; 4.67 (m, 1H, CHF) ; 6.67-7.33 (m, 13H, aromatic H's.)

Analysis: Found: C, 76.4; H, 6.4; F, 5.2%. ^C25^H25^F03 requires C, 76.5; H, 6.4; F, 4.8%.

Diastereomer #2 IR (film)λ max 1610, 1580 cm¹

NMR 1.03-1.6 (m, 2H, CH_₂CHF) ; 1.37 (t,3H, CH₃); 3.4 (bs, 2H, CH₂-cyclopropyl) ; 3.97 (q, 2H, CH-CH..) ; 4.37 (s,2H, CH- so) ; 4.63 (m, 1H, CHF) ; 6.7-7.37 ( , 13H, aromatic H's) Analysis: Found: C, 76.5; H, 6.6; F, 4.7%; C--.H_-.F0, requires C, 76.5; H, 6.4; F, 4.8%.

Example 2

(a) 1- (4-Ethoxyphenyl) -2-chlorocyclopropane- 1-carboxylic acid

1-(4-Ethoxyρhenyl) -2 ,2-dichlorocyclopropane- 1-carboxylic acid (2.75 g, 0.01 mol) was dissolved in 3M sodium hydroxide solution (10 ml) and a 50/50 nickel-aluminium alloy was .added (5.4 g) . The temperature was maintained below 90°C for 1 hour. At the end of this time, the reaction mixture was filtered through celite. The aqueous solution was acidified with cone. HCl and extracted with methyl^ne chloride/ether. The organic layer was dried over anhydrous sodium sulphate and concentrated. The residue was recrystallized from petroleum spirit (60-80°) to afford 1.8 g (75%) of white crystals, m.p. 103.8°C.

IR ^'(film) λ max 3220-2311, 1691, 1606, 1575 cm^"1.^'

(k) Ethyl 1-(4-ethoxyphenyl) -2-chlorocyclopropane-- 1-carboxvlate

1-(4-Ethoxyphenyl)-2-chlorocyclopropane-l-carbox lic acid (2 g, 8.3 mmol) was dissolved in ethanol (100 ml) to which acetyl chloride (4.6 ml) had been added. The reagents were refluxed together for 6 hours. At the end of this time the ethanol was removed in vacuo. and ether . and water added. The layers were separated and the ether layer was washed successively with saturated

NaHCO-. solution, water and saturated NaCl solution and dried over anhydrous Na-SO.. The concentrated residue was distilled to afford 1.7g (77%) of the desired ethyl ester, bp. 150°/0.1 mm Hg. Analysis: Found: C, 62.7; H, 6.4; Cl, 13.5; C₁₄K₁ CIO- requires C, 62.6; H, 6.4; Cl, 13.2%.

, s

(c) 1-(4-Ethoxyphenyl) -2-chlorocyclopropyl-l-meth^'anol

Under a dry nitrogen atmosphere lithium aluminium hydride (153 mg, 16 mmol) in anhydrous ether (2 ml) was refluxed for 1 hour. The suspension was cooled to room temperature and ethyl 1-(4-ethoxyphenyl) -2-chlorocyclo- propane-1-carbox late (500 mg, 1.9 mmol) in dry ether (1 ml) was added. After 15 minutes ethyl acetate (0.79 ml) in dry ether (5 ml) was added dropwise. The reaction mixture was then poured onto ice cold 4M HCl (5 ml) . The acidic aqueous layer was extracted thoroughly with ether. The combined ether extracts, were washed with water, saturated NaCl solution, and dried over anhydrous Na-SO.. The concentrated extract was recrystallized from methylene chloride/petroleum spirit (40-60°) to afford 310 mg (73%) of a white crystalline alcohol, mp. 62.3°C. Analysis: Found: C, 63.4; H, 6.7; Cl, 15.4%; ^C12^H15^C102 ^re<3^{uires c}' 63.6^; H, 6.7^; Cl, 15.6%.

(d) 3'-Phenoxybenzyl 1-(4-ethoxyphenyl)-2-chlorocyclo- propylmethyl ether

To a stirred suspension of sodium hydride (33 mg, 1.4 mmol) in dry dimethoxyethane (2 ml) was.added 1-(4-ethoxyphenyl)-2-chlorocyclopropylmethanol (304 mg, 1.4 mmol). After 30 minutes at room temperature

3-phenoxybenzyl bromide (368 mg, 1.4 mmol) was added. The resulting reaction mixture was stirred at room temperature for 24 hours. At the end of this time the solution was filtered, concentrated and chromatographed on silica gel (60-230 mesh) using 3% ethyl acetate/petroleum spirit (40-60°) as the eluting solvent to afford 460 mg (84%) of the mixture of diastereoisomers. These isomers were separated using preparative high-performance liquid chromatography [μ-porasil column, 3% ethyl acetate/petroleum spirit (40-60°) ] .

• Diastereomer B (340 mg. formed) Analysis Found: C, 73.4; H, 6.1; Cl, 8.5%; C₂₅H₂₅C10₃ requires:

C, 73.4; H, 6.2; Cl, 8.8%.

Diastereomer A (120 mg formed)

Analysis Found: C, 73.7; H, 6.0; Cl, 9.1.; C₂₅H₂₅C10₃ requires: C, 73.4; H, 6.2; Cl, 8.8%.

The arthropodicidal activities of the compounds were determined according to the following Examples 3 to 5.

EXAMPLE 3

(a) [1-(4-ethoxyphenyl) -2-chlorocycloρropyl]bromethane

To a solution of [1-(4-ethoxyphenyl)-2 chlorocyclopropyl] methanol (965 mg, 4.26 mmol) in dry dimethylformamide (7 ml) under argon at 0°C was added triphenylphosphine (1.23g, 4.69mmol). Bromine (720 mg, 4.51 mmol) was added over 1 hour maintaining the reaction temperature between 0 - 2°C. The reaction mixture was allowed to warm to 20°C, and stirred for 3 hours then added to ice water. After extraction with 5 diethyl ether, the extracts were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulphate and evaporated -ξo yield a mixture of oil and crystals (2.9g). The crystals ^"were filtered off, washed with ice cold anhydrous diethyl _Q ether and discarded. The oil and washings were combined and evaporated yielding_an' oil (1.6g). The oil was chromatographed over silica gel eluting with 1:1 benzene/petroleum ether (40° - 60°) to yield the product as a light yellow oil 1.12g (91% yield) .

Analysis: Found C 49.65, H 4.88, Br 27.7, Cl 12.0%

^C12^H14^{Br Cl}° ^rec3^{uires c} 49.77, H 4.87, Br 27.59, Cl 12.24%.

(b) [1- (4-ethoxyphenyl) -2-chlorolmethyl thiocyanate

To a solution of [1- (4-ethoxyphenyl) -2-chloro] bromethane (1.05g, 3.63 mmol) in anhydrous ethanol (1.25 ml) under argon at 20°C was added powdered potassium thiocyanate (5.30 mg, 5.45 mmol) and the mixture heated with vigorous stirring to 65-70°C for 5 hours. After cooling, the reaction mixture was diluted with anhydrous diethyl ether (60 ml) filtered and evaporated yielding a tan solid (1.09g) . After chromatography on silica gel eluting with benzene the product was obtained as a white solid 940 mg (97% yield) mp 76-93°C. The molecule contains 2 assymmetric centres and thus consists of 4 diastereoisomers accounting for the broad melting point range.

Analysis: Found C 58.63, H 5.29, Cl 13.4, N 5.09, S 11.9% C₁₃H₁₄C1 NOS requires C 58.31, H 5.27,. Cl 13.24, N 5.23, S 11.97%.

(c) [1- (4-ethoxyphenyl) -2-chlorocyclopropyl) methane thiol

To a solution of [1-(4-ethoxyphenyl) -2- chlorocyclopropyl] methyl thiocyanate (700 mg, 2.61 mmol) in methanol (20 ml) under argon was added water (6 ml) , sodium carbonate (310 mg, 3.3 mmol) and zinc powder

(850 mg, 13mmol) and the mixture stirred at 20°C for 17 hours. A further amount of zinc powder (400 mg, 6.12 mmol) was added, the mixture cooled to 0°C and glacial acetic acid (6g, lOOmmol) added. The mixture was allowed to warm to 20°C and stirred at this temperature for 1 hour. The mixture was filtered and methanol removed in vacuo. The residue was extracted with diethyl ether and the extract washed with water, dried over magnesium sulphate and the solvent evaporated affording a colourless oil (510 mg) . Filtration over a short column of .silica gel eluting with benzene gave the product as a colourless oil 480 mg (76% yield) .

(d) 3-phenoxy-4-fluorobenzyl [1-(4-ethoxyphenyl)-2- chlorocyclopropyl] _^methyl sulphide

To a suspension of sodium hydride (33 mg, 1.35 mmol) in anhydrous 1,2-dimethoxyethane (1 ml) under argon at 20° was added a solution of [1-(4-ethoxyphenyl) -2-chlorocyclopropyl] methane thio (225 mg, 0.93 mmol) in anhydrous 1,2 dimethoxyethane (2 ml) . A vigorous evolution of .hydrogen resulted. After stirring at 20°C for 10 minutes a solution of 3 phenoxy-4-fluorobenz l bromide (275 mg, 0.98 mmol) in 1,2 dimethoxyethane (1 ml) was added. The mixture was stirred at 20°C for 17 hours then diluted with diethyl ether (30 ml) filtered and evaporated to afford an oil (460 mg) . This was chromatographed on silica gel eluting with 2% ethyl acetate in petroleum ether (40°-60°) to give the product as a colourless oil 275 mg (67% yield) . The product could be further separated by high performance liquid chromatography into two peaks each containing one pair of diastereoisomers. EXAMPLE 4

3-phenoxybenzyl [1- (4-ethoxyphenyl)-2-chlorocyclopropyl] methyl sulphide

To a suspension of sodium hydride (33 mg, 1.38 mmol) in anhydrous 1,2-dimethoxyethane (1 ml) under argon at 20°C was added a solution of [1- (4-ethoxyρhenyl) -2-chlorocyclopropyl] methane thiol (225 mg, 0.93 mmol) in anhydrous 1,2 dimethoxyethane (2 ml) . A vigorous evolution of hydrogen resulted. After stirring at 20°C for 10 minutes a solution of 3-phenoxybenzyl bromide (270mg 1.03mmol) in 1 ,2-dimethoxyethane (1 ml) was added. The mixture was stirred at 20°C for 17 hours then diluted with diethyl ether (30 ml) filtered and evaporated to give an oil (450 mg) . This was chromatographed on silica gel eluting with 1.8% ethyl acetate in petroleum ether (40°-60°) to give the product as a colourless oil 170 mg (72% yield) . The product could be further separated by high performance liquid chromatography into two peaks each containing one pair of diastereoisomers.

EXAMPLE 5 (a) [1- (4-ethoxyphenyl) -2-chlorocyclopropyl] carboxylic acid amide

1-(4-ethoxyphenyl) -2-chlorocyclopropyl carboxylic acid (lg, 4.18mmol) , freshly distilled thionyl chloride (3 ml) and anhydrous pyridine (1 drop) were stirred together under argon at reflux for 1 hour. The thionyl chloride was removed in vacuo at 50°C to afford the desired acid chloride as a yellow oil, (1.02 g, 94%) . To a stirred 0.880 aqueous ammonia solution (3 ml) at 0°C was added dropwise 1-(4-ethoxyphenyl)-2- chlorocyclopropyl carboxylic acid chloride (1 g, 3.89 mmol) in diethyl ether (2 ml) at such a rate that the temperature did not rise above 15°C. The reaction mixture was stirred for 1 hour, during which time a white precipitate formed. The precipitate was filtered off and washed with water. The solid was taken up in 50% diethyl ether dichloromethane and washed with water and brine, dried over anhydrous sodium sulphate, filtered and concentrated to afford the desired amide as a mixture of diastereoisomers, (900 mg, 97%). The two diastereoisomeric pairs were separated by preparative high performance liquid chromatography and then recrystallized from dichloromethane and petroleum spirit (40°-60°) .

(b) . [1-(4-ethoxyphenyl) -2-chlorocyclopropyllmethyl amine

The two diastereoisomeric pairs were reacted separately as follows. To a stirred solution of 1-(4-ethoxyphenyl)-2-chlorocyclopropyl carboxylic acid amide (400 mg, 0.00167 mmol) in anhydrous tetrahydrofuran (5 ml) under argon at 20°C was added dropwise borane dimethyl sulphide complex (10M in BH-.) (0.334 mis). The reaction mixture was refluxed for 18 hours, cooled to 0°C and 10% HCl solution (3 ml) was added dropwise. The reaction mixture was allowed to warm up to 20°C and the aqueous phase was basified with NaOH pellets. The aqueous phase was extracted with diethyl ether (3 x 10 ml) . The combined organic layers were washed with water and brine, dried over anhdryous sodium sulphate and concentrated. The crude concentrate was then distilled ( ugelrohr) to afford a colourless oil. bp. 110°C @ 0.2 Torr (270 mg, 72%).

(c) 3-Phenoxy-4-fluoro-α-cyanobenzyl [1-(4-ethoxy- phenyl) -2-chlorocyclopropyl] ethyl amine

The two diastereoisomeric pairs prepared above were reacted separately as follows. To a solution of [1-(4-ethoxyphenyl) -2-chlorocyclopropyl]methyl amine (250 mg, 1.11 mmol) in anhydrous methanol (2 ml) under argon at 20°C was added potassium cyanide (110 mg, 1.69 mmol) , gladial acetic acid (65 μl) and 3-phenoxy-4- fluorobenzaldehyde (240 mg, 1.11 mmol) in anhydrous methanol (1 ml) in that order. The reaction mixture was stirred at 20°C for 3 days. The methanol was removed in vacuo at 50°C. The residue was taken up in 10% NaOH solution (20 ml) and extracted .with, dichloromethane (4 x 20ml) . The combined organic layers were washed with water and brine, dried over Na_oS0. and concentrated.

Volatile impurities were removed by distillation (Kugel rohr) at 110°C at 5 x 10 Torr to afford a yellow oil. I.R. λ (film) cm^"1 3325 (NH) , 2250 (CEN) . NMR δ ppm - s, IH, 1.67, width (6 Hz), NH-; d, IH, 4.65, J - 20Hz CH-CEN; m, IH, 3.10-3.43, cyclopropyl CHC1; t, 1.37, J = 7Hz - CH CH₂0-; q, 3.94 J = 7Hz CH-CH 0-; v

Example 6

Insecticidal activity was investigated against blowfly, Lucilia cuprina. The method used was as follows:- (a) The compounds were tested for activity against a dieldrin susceptible strain (BLL) which had been collected before dieldrin usage in the field.

The test compound was applied in acetone solution, 0.5 μl dispensed with a Drummond micropipette to the dorsum of the thorax of 2-3 day old females. Adult flies were fed on water and sugar-only and maintained at 25°C and 60-70% RH. The mortalities were determined after 24 hours.. Moribund.flies were regarded as dead. The LD_c- values, in terms of concentration, were interpolated from the probit/log dose, relation using a computer program.

The results given in Table 2 are expressed in terms of the Potency Index which is the ratio (LD_cn Permethrin/LD-.- Test Compound) x 100.

(b) Potentiation

The compound was also tested on the insects described above in conjunction with the potentiator piperonyl butoxide by pretreating each insect with 1 μl of a 2% solution of the potentiator in acetone.

The mortalities were counted at 48 hours after treatment and compared with acetone and acetone/potentiator controls.

The LD-.- values were determined as described above and converted to Potency Index values. About the same levels of potentiation were obtained when piperonyl butoxide was replaced, by an equal amount of "Sesoxane"..

The results are shown in Table 1.

Example 7

Insecticidal activity against the German cockroach (Blatella germanica) was determined using the following method:

The compound under test was applied in acetone solution at a range of concentrations. 0.5 μl was dispensed with a Drummond micropipette to the ventral thorax of adult cockroaches. The mortalities were determined after 48 hours. Moribund cockroaches were regarded as dead. The D^. values in terms of concentration were determined by probit analysis of the mortality/concentration data and converted to Potency Index values.

The results are shown in Table 1.

Example 8

Insecticidal activity against the cotton pest Heliothis punctigera was determined using the following method:

The compound under test was applied in acetone solution at a range of concentrations. 0.5 μl was dispensed with a Drummond micropipette to the dorsal surface of 3rd instar larvae. Each larva was held in a separate container and was fed on spinach and maintained at 25°C and 60-70% RH. The mortalities were determined after 48 hours. Moribund larvae were regarded as dead. The LD.-_n values in terms of concentration were determined by a probit analysis of the mortality/concentration data and converted to Potency Index values.

The results, are given in Table 1.

TABLE 1 -

Arthropodicidal Activities

Compound of Potency Index

Example

Number

- Lucillia cuprina Blatella Heliothis σermanica punctigera

(cpd I (+potent- alone) 1 iator)

!

1 (c) -isomer 1 14 ! 44 60 8

-isomer 2 22 j 88 173 31

2 (d) -isomer B 14 23 50 240

-isomer A 8 1 17 7 10

3 (d) -isomer A 3 ! 6 16 -

-isomer 2 ⁶ 1 18 31 83

4 -isomer 1 3 6. 17 5

-isomer 2 2 6 14 24

5(c) -isomer 1 1 4 - -

-isomer 2 3 8 - 3

Permethrin 100 100 100 100 standard

Claims

CLAIMS :

1. Compounds of the general formula (I) and their isomeric forms:

X

wherein

R is a halo group; or a lower alkyl, lov/er alkoxy or lower alkylthio group, in each of which the alkyl group may be substituted with one or more halo groups;

R ~"> is hydrogen or a halo or halomethyl group; or R1

X is a fluoro, chloro or bromo group;

A' is 0, S, NH, or NZ where Z is a lower alkyl or haloalkyl or cyano group; R 3 is 3-phenoxyphenyl, 2-phenoxy-6-pyridyl,

4-fluoro-3-phenoxyphenyl, or

2-phenoxy-3-fluoro-6-pyridyl.

2. 3 '-Phenoxybenxyl 1-(4-ethoxyphenyl) -2-fluoro- cyclopropyl-1-methyl ether;

3 ' -Phenoxybenzyl 1-(4-ethoxyphenyl) -2-chloro- cyclopropyl-1-methyl ether;

3 '-Phenoxy-4-fluorobenzyl[-(4-ethoxyphenyl) - 2-chlorocyclopropylmethy1 sulphide;

3 'Phenoxybenzyl-[1-(4-ethoxyphenyl) -2-chlorocyclo- propylmethyl sulphide;

or

3 ' -Phenoxy-4 ' -fluoro- -cyclobenzyl [1- (4-ethoxy- phenyl) -2-chlorocyclopropyl] methyl amine.

3. A method for the production of the compounds of the formula I as stated and defined in Claim 1 , which is characterized in that compounds of the formulae (III)- and (IV) are reacted together

(III) . (IV)

wherein R 1 , R2 , R3 and R4 are as defined in Claim 1 and wherein P and Q are leaving groups selected so that on reaction they give rise to the desired group A or to another group which is convertible to the desired group

A¹.

4. A method as claimed in Claim 3, for the production of a compound of formula I in which he group A is -0-, characterized in that one of the groups P and Q is -OH and the other of said groups is -Br.

5. A method as claimed in Claim 3 , for the production of a compound of formula I in which the group A is -S-, characterized in that one of the groups is -SH and the other of said groups is -Br.

6. A method as claimed in Claim 3, for the production of a compound of formula I in which the group A is -NH- or -NZ-, characterized in that one of the groups P and Q is -NH- and the other is Br, and when it is desired to i form the compound where A is -NZ- a compound of formula

I wherein A is -NH- is reacted with the halogen ZHal where Hal is Cl, Br or I.

7. A method for the production of a compound of formula -I in which the group A is -NH- or -NZ-, characterized in that a compound of formula (III) wherein P is -NH- is reacted with a compound of formula (V)

0 = C - R³

wherein R 3 and R4 are as defined in Claim 1, to produce a compound of formula (I) wherein A is -NH- and when it is desired to form the compound where A is -NZ-, the compound of formula I wherein A is -NH- is reacted with a halogen ZHal where Hal is Cl, Br or I.

8. An arthropodicidal composition, characterized in that it comprises as an active ingredient a compound of the formula (I) in admixture with a diluent or carrier.

9. A composition as claimed in Claim 8, characterized in that it includes at least one substance which has a synergistic or intensifying effect on pyrethroids.

10. A composition as claimed in Claim 9, wherein the substance is selected from propynyl ethers, propynyl oxi es, propynyl σarbamates,propynyl phosphonates,

S,S,S-tributylphosphorσtrithionates,

[2-(2-butoxyethoxy)ethoxy] - 4,5-methylenedioxy-2- propyltoluene (Piperonyl butoxide) ,

3-hexyl-5 (3 ,4-methylenedioxyphenyl)-2-cyclohexanone

(Piperonyl cyclonene) ,

2-(3.,4-methylenedioxy-phenoxy)-3,6,9-trioxaundecane

(Sesoxane or Sesamex) ,

1,2-(methylenedioxy)-4-[2-(octylsulfinyl)propyl] benzene (Sulfoxide) , and dipropyl-5,6,7,8-tetrahydro-7-methylnaphtho-

[2,3-d] 3-dioxole-5,6-dicarbσxylate (n-Propyl isome).

11. A composition as claimed in Claim 10, characterized in that the substance is present in the composition in an amount of from 1/100th to fifty times the weight of the compound of formula (I) .

12. A composition as claimed in Claim 10, characterized in that the amount is from 1/100th to five times the weight of the compound of formila (I) .

13. A method of combating arthropods, characterized in that a compound of the formula (I) alone or in the form of a composition as claimed in any one of Claims 8 to 12, is applied to the arthropods, or to a habitat thereof.

14. A method of freeing or protecting domesticated animals from parasitical insects or acarids, characterized in that a compound of the formula (I) alone or in the .form of a_composition ^'as claimed in any one of Claims 8 to 12 is applied to said animals.