AU4272378A

AU4272378A - Cyclobutane carboxylic acids and esters ald insecticides

Info

Publication number: AU4272378A
Application number: AU42723/78A
Authority: AU
Inventors: Holan And David Francis Okeefe George
Original assignee: Commonwealth Scient And Industrial Research Organization Ip; Commonwealth Scientific and Industrial Research Organisation
Current assignee: Commonwealth Scientific and Industrial Research Organisation
Priority date: 1978-12-19
Filing date: 1978-12-19
Publication date: 1979-06-28
Also published as: AU530169B2

Description

(DIVISIONAL)

AUSTRALIA, I PATENTS ACT 1952

APPLICATION FOR A PATENT (CONVENTION OR NON CONVENTION)

A 9 7 9 '1 no xpc We COMMONWEALTH SCIENTIFIC AND INDUSTRIAL RESEARCH ORGANIZATION, a body corporate established under the Science and Industry Research Act, 1949- 1973, carrying on scientific and industrial research, of Limestone Avenue, Campbell, Australian Capital Territory, Commonwealth of Australia PATENT FFICE PA OFFICE

LODGE hereby apply for the grant of a Patent for an invention entitled

"NEW INSECTICIDES"

which is described in the accompanying specification. XTY LLARS DOLLA gqmplete.

or similar protection made in

09 This application is a further application made by virtue of sub-section of Section 51 of the Patents Act 1952 in respect 9* of an invention disclosed in the provisional/complete specification lodged in respect of Application No. PD2818/77.

Our address for service is care of DAVIES COLLISON, Patent Attorneys, of 1 Little Collins Street, Melbourne, in the State of Victoria, Commonwealth of Australia.

9 Dated this 18th day of December, 1978 9 ee

0* 9 9 9 .9

9999.. 9

(A member of the firm of DAVIES 9* S. COLLISON) for and on behalf of 99099* COMMONWEALTH SCIENTSgC AND INDUSTRIAL 0 RESEARCH ORGAN;ZATION e Lt

To: THE COMMISSIONER OF PATENTS Davies Collison, Melbourne and Canberra.

(11) AU-A 42723/78

(12) PATENT SPECIFICATION ABSTRACT (19) AU

(21) 42723/78 (22) 19.12.78 (23) 19.12.78 (24) 19.12.77 (43) 28.6.79 (51) CO0'( 61/04 0070 69/74 C07C 121/75 C07D 317/60 C07D 317/54 C07D 407/12 C07D 307/42 A0!N 9/02 A01N 9/24 A01N 9/28 A01N 9/12 (54) CYCLOBUTANE CARBOXYLIC ACIDS AND ESTERS AND INSECTICIDES 42444/78 162) C(MMONVEALTH SCIENTIFIC AND INDUSTRIAL RESEARCH ORGANIZATION (72) HOLAN G. AND O'KEEFE D.F.

(74) DM (57) CLAIMS

1. The and forms of the compounds of the general formula I

COOR 3

C C Y

Y Y3

-I

wherein R l is hydrogen or a methoxy, ethoxy, propoxy, butoxy, tetrafluoroethoxy, methylthio, ethylthio, p-opylthio, fluoro, chloro, bromo, methyl, ethyl, or nitro group, and R2 is hydrogen or a methyl group, or R and R together form a methylenedioxy group; R is hydrogen, or a lower alkyl group, or one of the following groups to

2

271 280 351 349 120

(11) AU-A -12723/78- 2

-C2 0>

0 -0

CH 2 C2 0

CH 2 1 CH2

CH-

C=ECH 0 0

.3

3 (11) AU-A 42723/78

(f)

-CH

CN 0 Q c1

and Y y Y, Y y5 and Y6 are the same or different groups and each is hydrogen or a fluoro, bromo or chloro group, with the prov.is i th at when R s flunrn, chlonrn, bromo or methyl and R 2 is hydrogen, then one of Y to Y6 is other than hydrogen. 18. Insecticidal compositions comprising one or more of the compounds of formula I, as stated in Claim 1, where R is one of the groups to incorporated in a suitable inert liquid or solid carrier.

23-8

COMMONWEALTH OF AUSTRALIA

PATENTS ACT 1952

COMPLETE SPECIFICATION

(Original)

FOR OFFICE USE AXI9 7 93 mv-- /7 I ow

Class Int. Class

Application Number: Lodged:

Complete Specification Lodged: Accepted: Published:

Priority:

Related Art: 0e S. S 5

@0

*.Name of Applicant: COMMONWEALTH SCIENTIFIC AND INDUSTRIAL RESEARCH S ORGANIZATION

Address of Applicant: Limestone Avenue, Campbell, Australian Capital Territory, Commonwealth of Australia

Actual Inventor(s) GEORGE HOLAN DAVID FRANCIS O'KEEFE

•in o• Address for Service: DAVIES COLLISON, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000.

Complete specification for the invention entitled:

"NEW INSECTICIDES"

The following statement is a full description of this invention, including the best method of performing it known.to us

This invention relates to new insecticidal Scompounds, methods of preparing these compounds and to new insecticidal compositions containing the compounds. Throughout this specification, where the context 0* 5 permits, the word "insect" is used in its broad common

0 usage and includes spiders, mites, nematodes and other pests which are not classed as insects in the strict biological sense. Thus the term implies reference not .only to those small invertebrate animals belonging mostly 10 to the class Insecta, comprising six-legged, usually winged forms, such as beetles, bugs, flies and the like, but also to other allied classes of arthropods whose members are wingless and usually have more than six legs, such as spiders, wood lice and the like, and especially 15 to the order Acaridae which includes the mites and ticks. The words "insecticide" and "insecticidal" are similarly used. The compounds provided by this invention have the general formula I *o

R .3 1 20 COOR Y

R O c C Y I 6 3 Y 4 Y Y wherein R 1is hydrogen or a methoxy, sthoxy, propoxy, butoxy, tetrafluoroethoxy, methylthio, ethylthio, propy LLhioI fluoro, chiloro, broino, methyl, ethyl, or nitro 2group, and R2is hydrogen or a methyl group, orR and R together form a methylenedioxy group; R 3is hydrogen, or a lower alkyl group, or one of the followil grus 1- to (f)

CH 2 ~44

S. 5 *S 0 00-,@ 0 *5 S SO S.

0 gee S S. S C S5 0

5500 S 5055 -CH 2 H2

*.s3

-CH--/0

CN 0 0 cH 2

H 2- J 0

C%4 CCH-

0O So S S 0 *5 S S S S. 0

S. 0

*S S S S *5

5555

5550

CN 0 0 Cl *0 C *0

0@ S @55 and Y1, Y 2, Y 3, Y4, Y5 mad Y6are the same or different 0 55 S 5 arou~s and each is hvdrocaen or'~ fluorb,' !'roivo Or chioro S S *5 S group, with the proviso that when R 1 s fluoro, chioro, **SSSS S bronio or methylI and R is hydrogen, then one of Y 1to Y S

55.5 is other than hydrogen. S S *5 S Known compounds which can be regarded as related to the compounds of formula I are those in which the groups to are present as esterifying groups with chrysanthemic acid in commercial or experimental pyreth- roids. our copending Australian Patent application No. 19829/76 describes-and claims a similar class of esters. West German Patent Specification DT-OS 27 33 740 describes compounds of the formula I7 in which all of the groups Y to Y6 are hydrogen, R 1 and R 2 are each hydrogen, or a fluoro, chloro, bromo or methyl group and R 3 is one of the groups and above. Such compounds are excluded from the present invention. Cj The acid of the present invention (formula I, R CT H) and its esters are novel. *Preferably, R is methoxy, ethoxy or propoxy 2 1 2 O group and R is hydrogen. Compounds in which R and R K form the methylenedioxy group are also preferred. Preferably also, R3 is one of groups (c) and as defined above. It is also preferred that from one to all six of a the groups yl to Y is a fluoro group, the remainder (if any) being hydrogen. Tetrafluoro-substitution 15 Y2, Y3, Y F; Y, Y6 H) is especially preferred. Specifically preferred compounds in accordance with the invention are as follows:- 3'-phenoxybenzyl 1-(3,4-methylenedioxyphenyl)- 2,2,3,3-tetrafluorocyclobutanecarboxylate, and its a-cyano and a-ethynyl derivatives 3'-phenoxybenzyl 1-(4--ethoxyphenyl)-2,2,3,3-tetrafluoro- cyclobutane carboxylate, and its a-cyano and a-ethynyl S" derivatives. 2 a to

4'

The compounds of formula I in which R 3 is one of groups to are extremely active as insecticides, having an insecticidal activity an order of magnitude greater than most known insecticides. These compounds galso possess the property of contact repellency to insects. The compounds of the present invention are CN generally more active against flies than the compounds of Sour aforementioned copending application. 3 SThe compounds of formula I in which R H or lower alkyl are useful as intermediates in the preparation of the other esters with R to as shown below. The compounds of formula I are optically active and can be resolved into their optical isomers by convent- ional methods. The invention thus includes the S* 15 individual and optical isomers of the compounds as well as the racemic forms. It should also be noted that the insecticidal activities of the optical isomers of the compounds I with R 33 to may differ by an order of magnitude or more. The invention also includes methods for the synthesis of the compounds I. The compounds I in which R is one of the groups to may be prepared by esterification of the free *3 25 acid (formula I, R 3 H) with the appropriate alcohol *3 3 R OH, where R is One of the groups to Such esterification may be carried out by any suitable known method, by direct reaction or b prior conversion of the azid and/or the alcohol to a suitable reactive derivative, or by an ester interchange reaction between the alcohol R3OH (R to (f))and a lower alkyl ester of the acid. The acid (formula I, R H) is prepared by the reaction of an appropriately substituted benzyl compound with an appropriately substituted 1,3-dihalopropane to form a 1-phenylcyclobutane compound which -an be

-6-

hydrolysed to the acid. T7his reaction scheme is as follows: R2

Ph Rl

-C-Y 2 CJPh-CH2 Z X-C-C-C-X -4 Ph -C 21~ 2 14 16 6'1 3 pp hydrolysis

COOHY

Ph-C C

0 @0 0 0 ~6 1 3 S

00 0 0@ 5 4 00 0 y y 0S 0 000

@0 0 where Z represenits a group which activates the benzylic 00 @0 0 methylene and is itself later hydrolysable to a carboxyl 0000 0 group, -C=N or -COOEt; X represents a chioro, romQ or iodo group;1 R ,R 2 ,Y1 ,Y2 ,Y 3 ,Y,Y 4 5 and Y 6 0000

are as defined above. @0 An alternative method of preparation of the acid 0 0 00 (formula I, R= H) as its lower alkyl ester is by *0 S *0@ addition of the ole fin Y 1lY2 C -cy3 4 to the substituted @0 0 15 phenylacrylic ester of formula II OS *0

0

0000 S. COOR 09 0

S 0S0500 0 C where R is a lower alkyl group and R R2 Y Y Y -4 5 6 Y, Y and Y are as defined above. Esters of formula I (R lower alkyl) wherein Y Y4= F and Y1 2 5 6 H can be made by O first preparing the compounds wherein Y3 4 F, 1 2 Cl according to the preceding method (using dichloro- CI difluoroethylene) and then hydrogenating the product to t- replace the chlorine groups by hydrogen. The esters II wherein Y5 6 .4 H may be obtained 10 according to the following general procedure: A lower alkyl ester of the appropriately substituted phenylacetic acid is condensed with a di(lower alkyl) oxalate in the presence of a basic catalyst, to produce an enolate salt (IV). The solution of the enolate salt is acidified to give the corresponding phenyloxaloacetate (III). The compound III is reacted with formaldehyde under alkaline conditions to give the phenyl hydroxymethyl 2 acetate which on dehydration (sometimes spontaneously) 20 yields the phenylacrylic ester (II). This reaction sequence is illustrated in the following overall reaction scheme. It will be appreciated that the specific acids and bases indicated may be replaced by other suitable compounds. Also lower see: alkyl esters, other than the ethyl esters shown may be employed. e s

*So

Ph-CH 2 E tO-CO-CO-Et Ph-CH-COOEt NaQET CE (V (IV) ~ONa COQEt

CH 3 COOH

Ph-CH-COOEt Ph-CH-COaE t

HCHO/K 2 CO0 3 CH2

COOEt OH

0

064

Ph-C-COOEt 0@

00

CH 2 (II R=Et, Y= H)

When Y5= 6= F, the esters II can be made 0 0 according to the method described by D.G. Naae. and D.J. 0 0so Burton, Synthetic Communications, 3, 197-200 (1973) S0. 000 In this method the appropriate phenyl keto ester of 00

0 formula VI is reacted with di4bromodifluoromethane 00 (CBr F2 in the presence of 2 moles of tris S0* (dimethylamino)phosphine and a suitable solvent such as 00 diglyme or triglyme

Ph C COOR CF2Br Ph C COOR /I 2 0 CF 2

6 VI II (Y F)

Swhere Ph is as defined above and R is a lower alkyl group. C The general approach to formation of the esters of the invention is as follows:- A COOEt A COOH A COOH A COC1 A COC1 R3OH--- A COOR 3 where A is

R2

o6 3

5 4 Y Y

1 SR R 22 y1 2 Y2, Y33 Y4 Y5 and Y6 are as defined 3- above and R is one of the groups to defined above. Alternatively the ethyl ester can be directly 15 converted as follows:-- A COOEt R3 A COOR EtOH The new compounds described herein may be dissolved in a suitable organic solvent, or mixture of solvents, to form solutions or brought into aqueous 0 S 20 suspension by dispersing organic solvent solutions of *o the compounds in water, to provide useful liquid compositions, which may be incorporated, for example, into aerosol-type dispersions with the usual propellants.

The compounds may also be incorporated in solid compositions which may include inert solid diluents or carriers, to form useful solid compositions. Such f compositions may also include other substances such as wetting, dispersing or sticking agents, and nay be C' prepared in granular or other forms to provide slow release of the compounds over an extended period of C4 time. The compounds may be employed in such compositions either as the sole toxic agent 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. 4r 'r 6 Generally such substances are of the class of microsomal 4 04 4 ai 4 oxidase inhibitors they inhibit the detoxification a 20 of insecticides in insects produced by the action of 4 oxidatiNe enzymes. Typical substances of this type are *i A

the pyrethrin synergists of which the following are 6 examples:- 4

Common Name Chemical Name Piperonyl butoxide a[2-(2-butoxyethoxy)ethoxv]- 4,5-methylenedioxy-2-propyl- toluene Piperonyl cyclonene 3-hexyl-5(3,4-methylenedioxy- ai phenyl)-2-cyclohexanone 0*

"Sesoxane" (Sesamex) 2-(3,4-methylenedioxy-phenoxy)- 3,6,9-trioxaundecane "Sulfoxide" 1,2-(methylenedioxy)-4-[2- ai (octylsulfinyl)propyl]-benz- a ene 405 SO n-Propyl isome dipropyl-5,6,7,8-tetrahydro- 7-methylnaphtho-[2,3-d]-, 3-dioxole-5,6-dicarboxylate

("Sesoxane", "Sesamex" and "Sulphoxide" are Registered Trade Marks). We have found that 'Sesoxane' (made by Shulton Inc., Clifton, is particularly useful as a potentiator. The amount of 'Sesoxane' used may vary from 1/1000th to five times the weight of the compound I the preferred range being from about 1/100th to an Cl equal part by weight. Piperonyl butoxide also is a useful potentiator in similar amounts. The preparation and properties of the compounds of the invention are illustrated by the following specific exmaples. 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 they are not intended to be restrictive or to be regarded as embodying the only way in which the compounds can be formed and recovered. EXAMPLE 1 (Prior Art Compound)

2 1-(4-chlorophenyl)cyclobutane nitrile 20 4-Chlorobenzyl cyanide (10 g) in dry DMSO (20 ml) was added over 5 min to a stirred suspension of sodium S. hydride (4.4 g) in DMSO at 25°C under argon. The mixture was stirred for 30 minutes then a solution of 1,3-dibromopropane (27 g) in dry DMSO (50 ml) was added over 30 minutes while maintaining the temperature of the reaction mixture at 25-30 0 C. After stirring an additional 40 minutes at this temperature the reaction mixture was added to ice water (500 ml) and extracted with dichloromethane (3 x 75 ml). The extracts were S 30 evaporated and the residue extracted with diethyl ether (4 x 50 ml). The ether extracts were washed with water, dried over anhydrous sodium sulphate and evaporated to yield an oil (10.8 g) which on distillation gave the nitrile [bp 900/10 6 Torr.] yield 5.4 g

Analysis: C 68.48% H 5.49% Cl 18.3%. C 1 1 HIC1 N requires: C 68.93% H 5.26% Cl 18.5%.

S 1-(4-chlorophenyl)cyclobutane carboxylic acid

1-(4-chlorophenyl)cyclobutane nitrile (5 g) was mixed with ethylene glycol (60 ml) and 40% w/w aqueous potassium t- hydroxide solution (80 ml) and refluxed under argon for Cl 18 hours. The mixture was cooled, added to ice water and extracted with diethyl ether. The aqueous layer was acidified and the precipitate was filtered off, washed with water, dried and recrystallised from petroleum ether 40 600) to give the acid as white needles mp 88 90, yield 4.5 g Analysis: C 62.70% H 5.14% C3 16.5% 0 15.2%. C11H CIO 2 requires: C 62.72% H 5.26% Cl 16.83% 0 15.2%.

3'-phenoxybenzyl 1-(.4-chlorophenyl)cyclobutane- carboxylate l1-(4-Chlorophenyl)cyclobutane carboxylic acid (1 g) was dissolved in thionyl chloride (1 ml) and heated at reflux for 40 minutes. Excess thionyl chloride was removed in vacuo and the residue was taken up in petroleum ether 600 (40 ml) and added over 15 minutes to a stirred mixture of 3-phenoxybenzyl alcohol (1.1 pyridine (1 ml), benzene (50 ml) and petroleum ether 40 600 0 ml) maintained at 10 C. The mixture was stirred at 20 25 0 C for 3 hours then added to ice water, washed with 0.5M hydrochloric acid, water, dilute sodium bicarbonate solution and dried over anhydrous sodium sulphate. The solvent was evaporated to give an oil (2.3 g) which after chromatograpn on silica gel, eluting with benzene/petroleum ether, gave the ester 1.52 g Analysis: C 72.87% H 5.30% Cl 9.2% O 12.1% C 2 4 H 2 1 C10 3 requires: C 73.37% H 5.39% Cl 9.0% O 12.2%.

EXAMPLE 2 1- (4-e thoxyphenyl) cyclobutane c arboxyli c acid

Ethyl 4-ethoxyphenylacetate (14 g) in anhydrous diethyl Sether (20 ml) was added to a stirred suspension of sodamide (5.3 g) in liquid ammonia (400 ml) over 3 G minutes and the mixture stirred for an additional t' minutes. 1,3-dibromopropane (14 g) in diethyl ether ml) was added over 20 minutes and the mixture stirred for 17 hours. 50 ml of saturated ammonium chloride solution was added and the reaction mixture extracted with diethyl ether. Evaporation of the solvent gave a residue (17.4 g) which after chromatography on silica gel by eluting with benzene/chloroform gave an oil (7.2 The oil was dissolved in ethanol (50 ml) and 10% sodium hydroxide solution (50 ml) was added. The mixture was refluxed for 3 hours, cooled, added to ice water and extracted with diethyl ether. The aqueous layer was acidified and the precipitate was filtered off, washed with water, dried and recrystallised from petroleum 20 ether 40 600 to give the acid 5.2g mp 90-1 0 C. 0 Analysis: C 71.04%, H 7.23% 0 22.0% C13H 1603 requires C 70.89% H 7.32% 0 21.8%. 0

3'-phenoxybenzyl 1-(4-ethoxyphenyl)cyclobutane carboxylate S 25 1-(4-ethoxyphenyl)cyclobutane carboxylic acid (1 g) was refluxed in thionyl chloride (1 ml) for 30 minutes and the excess thionyl chloride removed in vacuo. The residue was taken up in petroleum ether 40-600 (25 ml) and added over 5 minutes to a stirred mixture of 00066:

30 3-phenoxybenzyl alcohol (l.lg) pyridine (1 ml) benzene 0,00 (25 ml) and petroleum ether 40-600 (25 ml) at 15°C. The 0 mixture was stirred at 150C for 3 hours, then added to 0ice water and extracted with diethyl ether. The extract was washed with water, 0.5M hydrochloric acid, and sodium bicarbonate solution then dried over anhydrous sodium sulphate and the solvent removed to give an oil (2.1 g). Chromatography on silica gel, eluting with benzene, gave f~ the ester 1.5g SAnalysis: C 77.55% H 6.65% O 16.0% C 2 6 H 2 6 04 requires C C 77.59% H 6.51% O 15.9%. t- Csl EXAMPLE 3 2-(4-ethoxyphenyl)propenoic acid ethyl ester. This part of the example shows the general method of forming the 2-aryl-acrylic acid esters. (Formula II) Alcohol-free sodium ethoxide freshly prepared from sodium (13.9g) and excess ethanol was slurried in dry benzene (200 ml). To this suspension diethyl oxalate (88.5g) was added over 15 minutes. Ethyl-p- ethoxyphenylacetate (114.2g) was added to the resulting clear yellow solution over 30 minutes at room temperature. After a further 1 hour period the reaction mixture solidified. The solid, sodium diethyl-2-p- 20 ethoxyphenyl-3-ethoxy-3-oxido-oxaloacetate (IV) was triturated and washed well with ether. The combined ether washings were evaporated to a small volume to/obtain a second crop of the salt. The combined yield was 227.4g. The sodium salt was acidified by adding it in portions to a well stirred emulsion of equal parts of 0* diethyl ether and dilute acetic acid (approximately

After separation the ether layer was washed with water and dilute sodium bicarbonate solution, and dried with 30 anhydrous sodium sulphate. After evaporation of the ether, the resulting oil was crystallized from petroleum ether 600 800), to yield diethyl-2-p-ethoxyphenyl- oxaloacetate (III) 1 4 3.8g m.p. 59 The keto-ester III (143.8g) was stirred in dilute formaldehyde solution (62 ml 37% formaldehyde water

220 ml) and to the suspension potassium carbonate solution (54.5g, in water 280 ml) was added dropwise. At the end of the addition, ether was added to the stirred suspension to dissolve the gummy precipitate which formed and after an additional 15 minutes, gas evolution Scommenced. When this gas evolution ceased (after about S2 hours) the reaction mixture was extracted with C additional ether and the combined ether extracts were Swashed with water and evaporated after drying with Na 2 SO 4 The yield of the ethyl 2-(4-ethoxyphenyl) propenoate (ii) (isolated as a yellow oil) was 97.8g

Ethyl 1-(4-ethoxyphenyl)-2,2,3,3-tetrafluorocyclo- butane carboxylate

2-(4-ethoxyphenyl)propenoic acid ethyl ester (13.2 g) was mixed with benzene (7.5 ml), a-piiene (2 drops) N-ethyldiisopropyl amine (2 drops) and tetrafluoroethylene (15.5 ml) and heated to 150-1550 for 24 hours then 155-60 C for 17 hours. After evaporation of volatile materials the residue (16.6 g) was dissolved in dichloro- methane and chromatographed on a column of silica gel to give the ester as a colourless oil 14.5g Analysis: C 56.47%, H 5.24%, F 23.4%. C 5H16F403 requires C 56.25%, H 5.04%, r. 23.7%.

1-(4-ethoxypheny)-2,2,3,3-tetrafluorocyclobutane carboxylic acid

Ethyl 1-(4-ethoxyphenyl)-2,2,3,3-tetrafluorocyclobutane carboxylate (14.5 g) was dissolved in ethanol (100 ml) and a 10% w/w solution of sodium hydroxide in water (100 ml) was added and the mixture refluxed for hours. The mixture was cooled, added to ice water and exwith die l ether. The aqueous layer was extracted with diethyl ether. The aqueous layer was acidified and the precipitate was filtered off, washed with water, dried and crystallised from 60 800 petroleum ether to give the acid mp 112-3 0 C. Yield 11. 2g Analysis: C 53,20% H 4.22%, F 25.9%. C13H12F403 requires C 53.43% H 4.14% F 26.0%. CO S(d) 3 -phenoxybenzyl 1- 4 -ethoxyphenyl) -2,2,3,3-tetra- C fluorocyclobutane-carboxylate

1-(4-ethoxyphenyl)-2,2,3,3-tetrafluorocyclobutane carboxylic acid (0.9 g) was refluxed with thionyl chloride (1 ml) for 45 minutes and the excess thionyl chloride was removed in vacuo. The residue was dissolved in petroleum ether 40-600 (40 ml) and added over minutes to a mixture of 3-phenoxybenzyl alcohol (1 g), pyridine (1 ml), benzene (25 ml), and petroleum ether 40 600 (25 ml) maintained at 200 C. The mixture was stirred for 3 hours then added to ice water and extracted with diethyl ether. The extract was washed with water, 0.5M hydrochloric acid, and sodium bicarbonate solution, dried over anhydrous sodium sulphate and the solvent 20 evaporated to give an oil (2 Chromatography on i silica gel by eluting with benzene gave the ester 1.2 g Analysis. C 65.45%, H 4.84% F 16.0%. C2 6 H2 2 F4 0 4 requires C 65.82%, H 4.67%, F 16.0%.

EXAMPLE 4 25 Enantiomer of l-(4-ethoxyphenyl)-2,2,3,3- tetrafluorocyclobutane carboxylic acid

a(+)-(l-naphthyl)ethylamine was added to a solution of the racemic acid (2g) (prepared as in Example in 30 ethyl acetate (75 ml) and n-hexane. The salt which formed was crystallized four times from ethyl acetate at room temperature. The salt was decomposed with hydrochloric acid (1M) and the residue recrystallized twice from ethanol. The acid which had a2 =-118.2 20 and m.p. 194 C was obtained in 15% yield.

3'-Phenoxybenzyl 1- 4-ethoxyphenyl) O tetrafluorocyclobutane carboxylate

The resolved acid, 0.2 was refluxed in thionyl- chloride (1 ml) for one hour. After evaporation of Sexcess thionyl chloride, the residue was dissolved in petroleum ether 60 800) and added to 3-phenoxy- benzyl alcohol (0.139g) and pyridine (0.238g) in benzene (3 ml) and petroleum ether (3 ml). The reaction mixture was stirred overnight, quenched with ice-water, washed with water and the solvent layer separated and dried over molecular sieve. After evaporation of the solvent the pure ester was obtained as a viscous liquid by chromato- graphy in silica gel using methylene chloride as the eluent. Yield 99.1%, a D -58.2. .2 20

EXAMPLE 1-(3,4-methylenedioxyphenyl)-2,2,3,3-tetrafluoro- cyclobutane carboxylic acid

20 A mixture of ethyl 2-(3,4-methylene dioxyphenyl) propenoate (2.2 tetrafluoroethylene (5 a-pinene (1 drop), N-ethyldiisopropylamine (1 drop) and benzene (10 ml), was heated at 150° 155 C for 24 hours then at 1600 165 0 C for 16 hours, then cooled. The solvent was evaporated 25 to leave an oil (3.0 This oil was purified by a chromatography on silica gel using benzene as eluent to give 1.4 g of ethyl l-(3,4-methylene dioxyphenyl)- 2,2,3,3-tetrafluorocyclobutane carboxylate.

The ethyl ester was hydrolysed by refluxing for 2 hours 30 with a mixture of potassium hydroxide (5 water (50 ml) and ethanol (50 ml). The ethanol was removed by evaporation and the aqueous residue extracted with diethyl ether. The aqueous layer was acidified and the precipitate filtered off, dried and recrystallized from petroleum spirit 600 80 diethyl ether to E yield 0.9 g of the aci.d as white crystals m.p. 1 6 8 C. SAnalysis: C 49.62%, H 2.72%, F 25.8%.

C12 F404 requires 49.33%, H 2.76%, F 26.0%. C4 S(b) 3'phenoxybenzyl 1-(3,4-methylenedioxyphenyl)-2,2,3,3- tetrafluorocyclobutane carboxylate.

The acid prepared in Example 5(a) (0.5g) was mixed with thionyl chloride (1 ml) and refluxed for 45 minutes. Excess thionylchloride was removed under vacuum. The residue was dissolved in petroleum spirit 40-600) ml), and added over 5 minutes to a stirred mixture of 3-phenoxybenzylalcohol (0.4 pyridine (0.5 ml),

0 benzene (15 ml) and petroleum spirit 40 600) 0 ml). After overnight stirring at room temperature the mixture was added to ice water and extracted with 0

00 diethyl ether. The ether extract was washed with dilute hydrochloric acid, water, sodium bicarbonate solution and

0 dried over anhydrous sodium sulphate. Evaporation of 0005 the ether left an oily residue (0.78 g) which was purified 0r

by chromatography on silica gel with benzene as eluent to yield 0.7 g of the 3-phenoxy benzyl ester as a clear 25 yellow oil. 0 0 O Analysis: C 63.54%, H 4.01%, F 35-9%. 0* Re C 2 5 H 1 8F 4 0 5 requires C 63.30%, H 3.82%, F 16.0%. 00

0O EXAMPLES 6 to

0 Using the general method set out in Example 3, s *000 the compounds listed in Table 1.were obtained from the appropriate starting materials.

19.

Analysis,spectra and other characterising data 1were consistent with the stated structures. Table 1 includes the compounds of*Examples 1, 2, S3, 4 and 5 for ease of reference.

a. .9 S. 0 S 6

S. S .0 0i 0

a. S p~ *ee

.9 6 a 00 0

a. 9

0. a

0S 0 *0 00

0

6 0

*00*a

S

TABLE 1 Example R2 y1 v2 V3 V4 5 6 D3 No. 1 Cl H H H 2 C2 H5 0 H H H ~Z3 F H C":D 4* C 2 H 50 H F H Cq 5 ,-O-CH2 .O- F H C4 6 CHF 2 CF 2 H F H qm4 7 C2 H 5 0 H F H 8 Cl H F H F H C 2 H5 0 H F H 11 Cl H F H 12 CH 3 O0 H F H 13 -0-CH 2 -0- F H 14 F H CHO H C2 H50 H F H a. a 0 0 16 V~ H 0 Cl H 0 17 F H SO 60 0 18 F H Cl H 6 *00 19 F H 0~

00 S 20 F H 0* S. U 21 F H F H 0 we.. a 22 C2 H 5 0 H F F Note* The compound of Example 4 is the optical isomer of the compound of Example 3. 0* 0 OS @6 a 050

S

00 S

0~

B

0

0 *000 p 00 00 0

0 o. a

EXAMPLE 21 The biological activity of the new cyclobutane esters was examined in a series of tests, the results of which are collected in Table 2. oo tz Insecticidal activity was investigated against the common housefly, Musca domestica, and the sheep p, blowfly, Lucilia cuprina. The methods used were as C4 follows:- "d Housefly Compound alone Tests were carried out using a standard DDT- susceptible strain (WHO/IN/1) of M. domestica. The compound was applied in an acetone solution by micro- syringe to the dorsum of the thorax of two day old female flies reared from pupae of average weight 2.2 gm/100 pupae. The adult flies were fed on water and sugar-only diet and maintained at 26°C and 70% RH. The mortalities were counted at 48 hours after treatment and compared with acetone-treated controls. Flies unable 20 to move or stand normally were considered dead. The value was obtained from a logit computer programme based on three replicates of 10 flies at each dose level. The LD50 value for DDT determined under the same 50 conditions was 0.26 pg/fly.

Potentiation

S The compound was also tested on the insects described above in conjunction with the potentiator "Sesoxane" by pretreating the insect with 1 pg of the potentiator in acetone. 30 The mortalities were counted at 48 hours after treatment and compared with acetone and acetone/ potentiator controls. The TeL LD 55 00 value was determined as described above.

For DDT, with the same potentiator the LD 5 0 value was 0.24 Pg/fly. About the same levels of potentiation were obtained when "Sesoxane" were replaced by an equal amount of piperonyl butoxide. Insect Repellency t Repellency tests were carried out on the same C4 strain of housefly as in the mortality tests. Female flies at least two days old, not previously fed protein, were taken the day before the test, anaesthetized with CO 2 and counted into holding containers of twenty flies each. These were supplied with water and solid sucrose. On the day of the tests the food and water were removed Ln the morning (0900 hr). As the tests were performed only between 1200 hr and 1730 hr, the flies were therefore starved for a minimum of three hours before testing. The test involved the use of attractant baits 0 @0 0 to which the candidate compound was applied. These S 20 were exposed to the flies and the number of flies 0 landing on each bait counted. The baits consisted of aluminium caps of area 5.94 cm 2 filled with bakers 0 yeast mixed with water and slightly heated to form a 0 0@*0 solid surface film. 25 Eight lots of 20 flies were used in a run in S 0SS0 which seven discus were treated with a graded dilution 0O series of the test chemical using acetone as solvent, 0 S together with one disc treated with acetone as a .5. control. The concentrations of the compound ranged from 0.031 pg/pl doubling at each level up to 2.0 vg/pl. One hundred microlitres of each solution was pipetted 0 evenly over the surface of each disc and left until the acetone had evaported. S* 0 The flies to be used were released into standard 205 mm x 205 mm x 255 mm mesh cages and left to

22a

c,-climatize in the test room maintained at a temperature of 26 C 10 C and humidity approximately 60%, for ten minutes before introducing the treated discs into each cage. Before use the discs were marked on the reverse 0 sides and then randomly mixed to avoid bias in counting. In the thirty minute period of the test the number of Sflies on the surface of each disc was counted in the C first and second minute after introducing the baits and thereafter every two minutes. In this way sixteen counts were obtained for each concentration, the totals of which were then used for a regression analysis of the concentration effect. Also a total number of landings for each concentration was obtained and used for calculation of the Index of Repellency All replicate tests were carried out with fresh flies and baits, and the compounds were tested in three replicate runs. 0* Se The total number of flies counted on each 0 disc for the seven concentration levels was summed and see averaged. In the following formula this figure is 0 designated where equals the number of flies *a counted on the control:- 0

0000

C N x 100 Index of Repellency (IR) S. C +N

(ii) Sheep Blowfly 0*

25 Insecticidal Activity C

The compounds were tested for activity against a dieldrin susceptible strain (.LBB) which had

0 been collected before dieldrin usage in the field. The test compound was applied in acetone solution, 0.5 pl dispensed with a Drummond midropipette to the dorsum of the thorax of 2-3 day old females. 0 Adult flies were fed on water and sugar-only and

22b

maintained at 250 C and 60 70% RH. The mortalities were determined after 24 hours. Moribund flies were regarded as dead. The LD 5 0 values, in terms of concentration, were interpolated from a probit/log dose graph using a computer program. Comparative LD 5 0 figures for DDT and dieldrin are 0.17 and 0.025 pg/insect. Potentiation SPotentiation with "Sesoxane" was investigated as described above in the housefly tests. Repellency Repellency was determined as described above in the housefly tests, except that the baits consisted of an agar gel containing fresh beef blood.

0 S

o e S*

*S

*S 4

S

TABLE 2 INSECTICIDAL ACTIVITY

Compound of Sheep Blowfly Example No. (Lucilia cuprina) LD 5 0 LD5 0 with synergist Repellency CO pg insect vg insect Index tZ 1 1.78 0.04 36 2 0.77 0.06 61 3 0.05 0.001 79 4 0.024 0.00026 73 0,04 0.003 66 6 0.40 0.04 7 0.02 0.0004 62 8 0.023 0.0023 77 9 0.11 0.03 88 0.03 0.003 78 11 0.05 0.007 *O S 12 17 0 13 0.03 0.001 68 S. S S S S. 14 0.14 0.009 42 S

S. S 15 0.18 0.006 @5@ S 16 0.10 0_00Q1 55 5 5* 55 S 17 0.14 0.002 18 0.14 0.001 S 19 0.028 0.002 0.22 Q.002

55 5 S*

S 555

55 *5

S S S

5.55 *5 S. S

S 55.5.. S S

-24. TABLE 2 INSECTICIDAL ACTIVITY (Continued) Compound Example o House fly No.f- (Musca -domestica) LD 5 0 with synergist Repellency' pg/9 insect Index

11.8 0.2 49 Cq t- 2 .1.32 0.22 81 3 0.13 0.003 81 4 0.10 0.005 86 50.26 0.017 6 0.6 0.036 12 7 0.18 0.065 89 8 0.55 0.01 9 0.58 0.05 0.13 0.005 84 11 0.34 0.018 12 >32 0.24 18 13 0.12 0.018 78 06 0S 6 S 14 0.07 0.005 S. 0@ 15 0.26 0.6 0S 0 S. 16

@06 17 00 0 S S 18 S. S

S 19 0@SS S 6500

*0@

0:9

*0 0

EXAMPLE 22 oThe following are examples of insecticidal compositions in accordance with the invention. All C parts are by weight. t-

Spray formulation The following composition is adapted for spray application. Compound of formula I "Sesoxane" or Piperonyl butoxide Deodorized kerosene 79.4 Alkylated naphthalene 16.0

Aerosol The following materials are metered into a suitable 'bomb' container sealed and equipped with a 15 valve in the usual way. S, Compound of formula I Potentiator Methylene chloride 10.0 'Freon 12' 43.0 20 'Freon 11' 43.0

Water dispersable powder The following powdered composition is intended for dispersing in water for application as a spray. Compound of formula I 50.0 o 25 Synthetic fine silica 30.0 S, Alkyl aryl sodium sulphonate Methyl cellulose (15 cp.) Attapulgite 8.25

Claims

,THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:-

1. The ()forms of the compounds Of ~the general formula I

COOR 3 Y1

R0 C Y Y -C -C 3

y 15 14 y

wherein Ris hydrogen or a methoxy, ethoxy, propoxy, butoxy, tetrafluoroethoxy, methylthio, ethylthio, propylthio, fluoro, chloro, bromo, methyl, ethyl, or nitro group, and R 2is hydrogen or a methyl group, or Rand R2together form a methylenedioxy group; *R 3is hydrogen, or a lower alkyl group, or one of the following groups to

(a) CH 2 0

0 00

see 2

S 0

(c)

00-lU C~4

/0

CH2

CH

CECH 6*

Se 0 0 0 0 00 0 00 00 0 *0

000

*0 0 0O 0O 0 0 *000

0000 CH

CN 0 00 0 0 Qo Cl 0O 0O

0~a 0 and Y 1,Y2,Y3 and Y6 are the same or different 0* 0 0e 00 groups and each is hydrogen or a fluoro, bromo or chioro *.0006 0 groun, with the proviso th,at whnn R.1:- isflunrn, chioro, 0 0 bromo or methyl and R 2is hydrogen, then one of Yl to Y6 0~00 0* 00 0 is other than hydrogen. 0 000.0~0 0. 0 -compounds*as claimed in Claim 1, wherein lis,a.

methoxy, ethoxy or propoxy group and R 2is hydrogen, or Rand R 2together form a methylenedioxy group.

co 3. Compor Js as claimed in Claim 1,

Cq wherein R is one of the groups and as t* defined in Claim 1.

4. Compounds as claimed in Claim 1,

wherein from one to all six of the groups Y 1to Y 6 is a fluoro group, the remainder (if any) being hydrogen.

Compounds as claimed in Claim 4, wherein Y 1l Y 2 and Y4are all fluoro and Y5adY6

are hydrogen.

6. The and forms of 3'-phenoxybenzyi

1- 4-methylenedioxyphenyl) 3-tetrafluorocyclo- butane-carboxylate.

00:7. The forms of a-cyano-3'-phenoxy- 0* benzyl l-(3,4-methylenedioxyphenyl) 3-tetrafluoro- cyclobutane-carboxylate.

00

0000

00

0*000:

000

9. The and forms of 3'-phenoxybenzyl 1- (4-ethoxyphenyl)-2z,2,3, 3-tetrafluorocyciLobutene- carboxylate.

The (+,C)and +)forms of c-cyano-31-phenoxy- benzyl 1- (4-ethoxyphenyl) -2,2,3 ,3-tetrafluorocyclo- Sbutane-carboxylate.

11. The (.)forms of c-ethynyl-3'- phenoxybenzyl 1(4-ethoxyphenyl) 3-tetrafluoro- cyclobutane-carboxyl ate.

00 00*00

*0 0

12. A method for preparing a compound of Formula I 1 2 1 2 3 4 as stated in Claim 1, wherein R R Y Y Y Y and Y6 are as defined in Claim 1 and R is one of the groups to as stated in Claim 1, which comprises esterifying the free acid of formula I wherein R is hydrogen,or a reactive derivative or ester thereof,with 3 3 t. an alcohol of the formula R OH, wherein R is one of Cs the said groups to

13. A method as claimed in Claim 12.,wherein the said acid (formula I, R H) is prepared by the reaction of the appropriately substituted reactive benzyl compound with an appropriately substituted 1,3-dihalopropane to form a 1-phenylcyclobutane compound which is then hydrolysed to the acid.

14. A method as claimed in Claim 12,wherein the said acid (formula I, R3 H) is prepared as its lower 1 2 3 4 alkyl ester by addition of the olefin Y1Y CY Y to the substituted phenylacrylic ester of formula II

R 9 0 *0 R1 C COOR II II 2 c

6

where R is a lower alkyl group and R R2 2, y

Y Y and Y are as defined in Claim 1. 0

1 5. A method as claimed in Claim 14, for preparing 3 eeO a compound of formula I, wherein Y =4=F and y 1 2= 5= 6=

H, which method .comprises reacting a compound of formula

5 6 II, stated in Claim 11, wherein Y Y H with dichlorodifluoroethylene to produce a compound of 3 1 2 3 formula I wherein R is lower alkyl and Y Y C1,Y S 4 and Y 5 6 H, hydrogenating this compound to y replace the chloro groups by hydrogen and then reacting Sthe resulting ester with the alcohol R OH as defined in Claim 1.

16. A method as claimed in Claim 14, wherein the Sphenylacrylic ester of formula II, wherein Y Y H, is obtained by condensing the appropriately substituted phenyl acetic ester of formula V

2

R1 0 CH 2 COOR V

*e 0

with a di(lower alkyl) oxalate in the presence of a ee basic catalyst, to produce a solution of an enolate salt Sof formula IV

R

R 0 CH-COOR

I OM

Ss. COOR

acidifying the solution of the salt IV to give the corresponding phenyloxaloacetate III e S *j

R1i CH-COOR CO III

COOR

reacting the compound III with formaldehyde under alkaline conditions to give the corresponding phenyl hydroxymethyl acetate which is then dehydrated to the ester II; wherein in the above formulae R 1 and R 2 are as defined in Claim 1, the groups R are lower alkyl groups, which may be the same or different, and M is an alkali metal.

17. A method as claimed in Claim 14, wherein the phenylacrylic ester of formula II, wherein Y F 0. do is obtained by reacting a phenyl ketoester of formula VI S 0 C R2 2O

1 SR C COOR VI 0 0:0, 0 000 wherein R is a lower alkyl group, with dibromodifluoro- methane in the presence of tris(dimethylamino)phosphine in a suitable solvent. O

I*

18. Insecticidal compositions comprising one or more of the compounds of formula I, as stated in Claim 1, where R is one of the groups to incorporated 'o in a suitable inert liquid or solid carrier.

C, 19. Insecticidal compositions as claimed in Claim 18, t" additionally containing at least one synergistic or Spotentiating agent of the class of microsomal oxidase inhibitors.

Insecticidal compositions as claimed in Claim 19, wherein the synergist or potentiator is a pyrethrin synergist.

21. Insecticidal compositions as claimed in Claim 19, wherein the synergist is one of the following:-

a-[2-(2-butoxyethoxy)ethoxy]-4,5-methylenedioxy-2- propyltoluene; 3-hexyl-5(3,4-methylenedioxyphenyl)-2-cyclohexanone; 2-(3,4-methylenedioxy-phenoxy)-3,6,9-trioxaundecane; 1,2-(methylenedioxy)-4-[2-(octylsulfinyl)propyl]- benzene; dipropyl-5,6,7,8-tetrahydro-7-methylnaphtho-[2,3-d]- 1,3-dioxole-5,6-dicarboxylate.

22. Insecticidal compositions as claimed in Claim 19, wherein the synergist is "Sesoxane" or piperonyl butoxide used in an amount from 1/1000th to 5 times the weight of the compound I. ee

23. Insecticidal compositions as claimed in Claim 19, wherein the amount of Sesoxane or piperonyl butoxide used is from about 1/100th to an equal part by weight per part of the compound I. C. o 'e

24. The steps, features,.cdxnpositions and compounds referred to or indicated in tl'e-specification and/or claims of this application, individually or collectively, and any and all combinations of any two or more of said M~ steps or features.

Dated the 11th day of December, 1978

COMNMONWE&IJTH SCIENTIFIC AND INDUSTRIAL RESEARCH ORGANI ZATION By its Patent Attorneys DAVIES COLLISON

SO SO 0 0 S S S. S S 05 S 6* S 550

S0 S 0e 55 0 0 0050 0 0056

SO 6 0 55

0 500 S

05 0 00

0 500555

S *050 9 *5 ~g

0 *00005 0

A