AU663691B2 - Tri thiabicyclo {2.2.2.}octane derivatives as pesticides - Google Patents

Description

PESTICIDAL COMPOUNDS

The present invention relates to novel chemical compounds having pesticidal activity to methods for their preparation, to compositions containing them and to their use in the control of pests. More particularly, the invention relates to a class of sulphur containing heterocycles.

European Patent Applications Nos. 216625, 216624, 300797 disclose 2,6,7-trithiabicyclo[2-2.2]octanes; the main difference in the applications residing in the nature of the substituent at the 1-position.

European Patent Applications Nos. 0294229, 0294228, 0372816 disclose 1,3-dithiane pesticides having a fairly narrow range of alkyl substituents of the 5-position.

It has now been discovered that a novel group of compounds within the general scope of these earlier disclosures have advantageous insecticidal activity, for example against flies and/or cockroaches, combined with low mammalian toxicity and/or good stability.

Accordingly, the present invention provides a compound of the formula (I):

wherein n and n' are the same or different and are each 0, 1 or 2; R

1 2 3 is hydrogen or methyl, R is methyl, ethyl or cyclopropyl, R and R are the same or different and are each hydrogen or methyl; R is hydrogen or methyl, R is cyano or R and R are linked to form a group CH„S(0)m where m is 0, 1 or 2.

Preferably R is hydrogen. a b When R and R are linked to form a group CH„S(0)

1 Preferably R is ethyl,

2 3 Preferably R and R are hydrogen.

Preferably m, n and n' are 0. a b

When R is a hydrogen or methyl and R is cyano:

1 ^* 2 3 Preferably R , R and R are all methyl.

One preferred group of compounds of the formula (I) is that of the formula (II):

wherein R, m, n and n' are as hereinbefore defined and R is as hereinbefore defined and preferably is ethyl.

A further preferred group of compounds of the formula (I) is that of the formula (III):

(III)

wherein R, R , R , R , R , n and n' are as hereinbefore defined.

The compounds of the formula (III) may exist as a number of stereoisomers; the present invention relates to mixtures of isomers and the individual isomers themselves. The present invention also encompasses radiolabelled compounds of the formula (I) , particularly

14 those in which one carbon atom is C or one or more hydrogen atoms are replaced by tritium.

Preferred compounds of the formula (I) include: -

1-(3,3-dimethylbutyl)-4-n-propyl-2,6,7-trithiabicyclo[2.2.2]octane 1-(3,3-dimethylbutyl)-4-n-propyl-2,6,7-trithiabicyclo[2.2.2]octane- 2-oxide

5-t-butyl-2-cyano-2-(3,3-dimethylbutyl)-l,3-dithiane l-(3,3-dimethylbutyl)-4-ethyl-2,6,7-trithiabicyclo[2.2.2]octane

The compounds of the formula (I) may be prepared

(i) by the reaction of the anion from a compound of the formula (IV) :

with an alkylating agent. Suitable alkylating agents include 3,3-dimethylbutyl halides, for example the iodide. The anion of the compound of the formula (IV) is suitably generated from the compound of the formula (IV) in-situ. The reaction is suitably carried out in the presence of a strong base, for example butyllithium, in an inert solvent, for example an ether such as tetrahydrofuran, at a temperature between -100 and 20 C, suitably between -80 and -20 C.

a b The compounds of the formula (IV) wherein R and R are linked to form a group CH„S(0) may be prepared as described in European Patent

Application No. 300797.

The compounds of the formula (IV) wherein R is cyano may be prepared by conversion of the corresponding compound containing an aldehyde function instead of a nitrile group. This conversion may be carried out by the reaction of the aldehyde with a suitable reagent such as 0,N-bis(trifluoroacetyl)-hydroxylamine. This aldehyde is prepared in turn from the 2-unsubstituted dithiane by reaction with a formylating agent, such as dimethylformamide in the presence of a strong base, for example butyllithium.

(ii) when it is required to prepare a compound of the formula (II) , by the reaction of a compound of the formula (V) :

a) with a compound tBuCH„C_ X wherein X is an activated car¬ boxylic acid group eg carboxylic acid halide in the presence of a Lewis acid, con- veniently aluminium trichloride or boron trifluoride etherate. The reaction suitably takes place in an inert solvent, such as a halogenated hydrocarbon, for example dichloromethane, at a non-extreme temperature, e.g. between -100 and 50 C and conveniently at -60 C, in an inert atmos- phere, e.g. nitrogen. b) with a compound tBuCH„CH_CN in the presence of a suitable acid, e.g. hydrogen chloride gas. The reaction is suitably carried out in an inert solvent, for example an aromatic hydrocarbon, chlorinated hydrocarbon or an ether and conveniently toluene, dichloromethane or tetrahydrofuran, at a non-extreme temperature, i.e. -70 to 70 C and conveniently at 0°C.

The compounds of the formula (V) may be prepared from the corresponding compound of the formula (VI):

where R is a Q. , alkylsulphonyl or arylsulphonyl group, for example a me hanesulphonyl or paratoluenesulphonyl group.

a) by reaction with sodium trithionocarbonate followed by sequential acid hydrolysis and reduction. The reaction with sodium trithionocarbonate may be carried out in a solvent, for example a dipolar aprotic solvent such as dimethylformamide at a non-extreme temperature, for example between 10 and 150 C and conveniently between 20 and 130 C. The acid hydrolysis is conveniently carried out using a dilute mineral acid, for example dilute sulphuric or hydrochloric acid at a non-extreme temperature, for example 0 to 100 C and conveniently 20 to 30 C. The reduction is conveniently carried out using a reducing agent such as a metal hydride, for example lithium aluminium hydride, in a non-reactive solvent, for example an ether such as diethyl ether, at a non-extreme temperature, for example between 0 and 100 C and conveniently between 30 and 60 C. b) by reaction with potassium thiocyanate to give a trithiocyanato intermediate which is then sequentially subjected to alkaline hydrolysis and reduction. The thiocyanation reaction is conveniently carried out in a non-reactive solvent, for example dipolar apro ic solvent, such as dimethylformamide at an elevated temperature, for example between 50 and 180 C and conveniently between 120 and 170 C. The alkaline hydrolysis is conveniently carried out with an alkali hydroxide such as sodium hydroxide in an aqueous solvent system suitably containing a miscible solvent such as ethanol at a non-extreme temperature, conveniently 0 to 70 C, for example 20 to 30 C. The reduction is suitably carried out using a reducing agent, such as zinc, conveniently zinc powder and hydrochloric acid, conveniently concentrated hydrochloric acid, in a hydrocarbon solvent such as toluene at a non-extreme temperature, conveniently an elevated temperature, for example between 70 C and 120 C.

c) by reaction with sodium sulphide and sulphur to give a bisdithiolanedisulphide which is then reduced to the compound of formula (VI) by reaction with a reducing agent such as zinc and hydrochloric acid. The first reaction is conveniently carried out in a protic solvent, for example a C. , alkanol such as ethanol, at a non extreme temperature, for example between 0 C and 100 C and suitably between 60 C and 85 C. The reduction is conveniently carried out with zinc dust and concentrated hydrochloric acid in a hydrocarbon solvent such as toluene at a non-extreme temperature, conveniently an elevated temperature, for example between 70 C and 120 C.

The compounds of the formula (I) wherein one or more of m, n and n' is other than 0 may be prepared by oxidation of the corresponding compound of a lower oxidation state.

This oxidation is usually carried out in an inert solvent such as acetonitrile or a halogenated hydrocarbon such as chloroform at a non-extreme temperature, for example between 0 and 100 C and preferably between 20 and 30 C. Suitable oxidising agents include peracids such as metachloroperbenzoic acid. The oxidation is conveniently carried out in the presence of a buffer such as anhydrous sodium acetate. Compounds where m is 2 and n and n' are 0 may be prepared from compounds of the formula (I) where m is 0 or 1, using potassium permanganate in a ketone, for example, acetone, at a non extreme temperature for example -30 C to 100 C and conveniently between -10° and 30°C.

The compounds of formula (I) may be used to control pests such as arthropods e.g. insect and acarine pests, helminths, i.e. nematodes, and molluscs e.g. slugs. Thus, the present invention provides a method for the control of arthropods, helminths and/or molluscs which comprises administering to the arthropod, helminth and/or mollusc or to their environment an effective amount of a compound of the formula (I) . The present invention also provides a method for the control and/or eradication of arthropod, helminth and/or mollusc infestations of animals (including humans) and/or of plants, (including trees) and/or stored products which comprises administering to the animal or locus an effective amount of a compound of the formula (I). The present invention further provides for the compounds of the formula (I) for use in human and veterinary medicine, in public health control and in agriculture for the control of arthropod, helminth and/or mollusc pests.

The compounds of formula (I) are of particular value in the protection of field, forage, plantation, glasshouse, orchard and vineyard crops, of ornamentals and of plantation and forest trees, for example, cereals (such as maize, wheat, rice, sorghum), cotton, tobacco, vegetables and salads (such as beans, cole crops, curcurbits, lettuce, onions, tomatoes and peppers), field crops (such as potato, sugar beet, ground nuts, soyabean, oil seed rape), sugar cane, grassland and forage (such as maize, sorghum, lucerne), plantations (such as of tea, coffee, cocoa, banana, oil palm, coconut, rubber, spices), orchards and groves (such as of stone and pip fruit, citrus, kiwifruit, avocado, mango, olives and walnuts), vineyards, ornamental plants, flowers and shrubs under glass and in gardens and parks, forest trees (both deciduous and evergreen) in forests, plantations and nurseries.

They are also valuable in the protection of timber (standing, felled, converted, stored or structural) from attack by sawflies (e.g. Urocerus) or beetles (e.g. scolytids, platypodids, lyctids, bostrychids, cerambycids, anobiids) .

They have applications in the protection of stored products such as grains, fruits, nuts, spices and tobacco, whether whole, milled or compounded into products, from moth, beetle and mite attack. Also protected are stored animal products such as skins, hair, wool and feathers in natural or converted form (e.g. as carpets or textiles) from moth and beetle attack; also stored meat and fish from beetle, mite and fly attack.

The compounds of general formula I are of particular value in the control of arthropods, helminths or molluscs which are injurious to, or spread or act as vectors of diseases in man and domestic animals, for example those hereinbefore mentioned, and more especially in the control of ticks, mites, lice, fleas, midges, biting, nuisance and myiasis flies and snails.

The compounds of Formula (I) may be used for such purposes by application of the compounds themselves or in diluted form in known fashion as a dip, spray, fog, lacquer, foam, dust, powder, aqueous suspension, paste, gel, cream, shampoo, grease, combustible solid, vapourising mat, combustible coil, bait, dietary supplement, wettable powder, granule, aerosol, emulsifiable concentrate, oil suspensions, oil solutions, pressure-pack, impregnated article, pour on formulation or other standard formulations well known to those skilled in the art. Dip concentrates are not applied per se. but diluted with water and the animals immersed in a dipping bath containing the dip wash. Sprays may be applied by hand or by means of a spray race or arch. The animal, soil, plant or surface being treated may be saturated with the spray by means of high volume application or superficially coated with the spray by means of light or ultra low volume application. Aqueous suspensions may be applied in the same manner as sprays or dips. Dusts may be distributed by means of a powder applicator or, in the case of animals, incorporated in perforated bags attached to trees or rubbing bars. Pastes, shampoos and greases may be applied manually or distributed over the surface of an inert material, such as that against which animals rub and transfer the material to their skins. Pour-on formulations are dispensed as a unit of liquid of small volume on to the backs of animals such that all or most of the liquid is retained on the animals.

The compounds of Formula (I) may be prepared either as formulations ready for use on the animals, plants or surface or as formulations requiring dilution prior to application, but both types of formulation comprise a compound of Formula (I) in intimate admixture with one or more carriers or diluents. The carriers may be liquid, solid or gaseous or comprise mixtures of such substances, and the compound of Formula (I) may be present in a concentration of from 0.025 to 99% w/v depending upon whether the formulation requires further dilution.

Dusts, powders and granules and other solid formulations comprise the compound of Formula (I) in intimate admixture with a powdered solid inert carrier for example suitable clays, kaolin, bentonite, attapulgite, adsorbent carbon black, talc, mica, chalk, gypsum, tricalcium phosphate, powdered cork, magnesium siliate, vegetable carriers, starch and diatomaceous earths. Such solid formulations are generally prepared by impregnating the solid diluents with solutions of the compound of formula (I) in volatile solvents, evaporating the solvents and, if desired grinding the products so as to obtain powders and, if desired, granulating, compacting or encapsulating the products. Sprays of a compound of Formula (I) may comprise a solution in an organic solvent (e.g. those listed below) or an emulsion in water (dip wash or spray wash) prepared in the field from an emulsifiable concentrate (otherwise known as a water miscible oil) which may also be used for dipping purposes. The concentrate preferably comprises a mixture of the active ingredient, with or without an organic solvent and one or more emulsifiers. Solvents may be present within wide limits but preferably in an amount of from 0 to 90% w/v of the composition and may be selected from kerosene, ketones, alcohols, xylene, aromatic naphtha, and other solvents known in the formulating art. The concentration of emulsifiers may be varied within wide limits but is preferably in the range of 5 to 25% w/v and the emulsifiers are conveniently non-ionic surface active agents including polyoxyalkylene esters of alkyl phenols and polyoxyethylene derivatives of hexitol anhydrides and anionic surface active agents including Na lauryl sulphate, fatty alcohol ether sulphates, Na and Ca salts of alkyl aryl sulphonates and alkyl sulphosuccinates. Cationic emulsifiers include benzalkoniu chloride and quaternary ammonium ethosuphates.

Amphoteric emulsifiers include carboxymethylated oleic imidazoline and alkyl dimethyl betain.

Vaporising mats normally comprise cotton and cellulose mix compressed into a board of approximately 35 x 22 x 3mm dimensions, treated with up to 0.3ml of concentrate comprising the active ingredient in an organic solvent and optionally an antioxidant, dye and perfume. The insecticide is vaporised using a heat source such as an electrically operated mat heater.

Combustible solids normally comprise of wood powder and binder mixed with the active ingredient and formed into shaped (usually coiled) strips. Dye and fungicide may also be added.

Wettable powders comprise an inert solid carrier, one or more surface active agents, and optionally stabilisers and/or anti-oxidants. 253 ' "

Emulsifiable concentrates comprise emulsifying agents, and often an organic solvent, such as kerosene, ketones, alcohols, xylenes, aromatic naphtha, and other solvents known in the art.

Wettable powders and emulsifiable concentrates will normally contain from 5 to 95% by weight of the active ingredient, and are diluted, for example with water, before use.

Lacquers comprise a solution of the active ingredient in an organic solvent, together with a resin, and optionally a plasticiser.

Dip washes may be prepared not only from emulsifiable concentrates but also from wettable powders, soap based dips and aqueous suspensions comprising a compound of Formula (I) in intimate admixture with a dispersing agent and one or more surface active agents.

Aqueous suspensions of a compound of Formula (I) may comprise a suspension in water together with suspending, stabilizing or other agents. The suspensions or solutions may be applied per se or in a diluted form in known fashion.

Greases (or ointments) may be prepared from vegetable oils, synthetic esters of fatty acids or wool fat together with an inert base such as soft paraffin. A compound of Formula (I) is preferably distributed uniformly through the mixture in solution or suspension. Greases may also be made from emulsifiable concentrates by diluting them with an ointment base.

Pastes and shampoos are also semi-solid preparations in which a compound of Formula (I) may be present as an uniform dispersion in a suitable base such as soft or liquid paraffin or made on a non-greasy basis with glycerin, mucilage or a suitable soap. As greases, shampoos and pastes are usually applied without further dilution they should contain the appropriate percentage of the compound of Formula (I) required for treatment. Aerosol sprays may be prepared as a simple solution of the active ingredient in the aerosol propellant and co-solvent such as halogenated alkanes and the solvents referred to above, respectively. Pour-on formulations may be made as a solution or suspension of a compound of Formula (I) in a liquid medium. An avian or mammal host may also be protected against infestation of acarine ectoparasites by means of carrying a suitabl -moulded, shaped plastics article impregnated with a compound of Formula (I) . Such articles include impregnated collars, tags, bands, sheets and strips suitably attached to appropriate parts of the body. Suitably the plastics material is a polyvinyl chloride (PVC) .

The concentration of the compound of Formula (I) to be applied to an animal, premises or outdoor areas will vary according to the compound chosen, the interval between treatments, the nature of the formulation and the likely infestation, but in general 0.001 to 20.0% w/v and preferably 0.01 to 10% of the compound should be present in the applied formulation. The amount of the compound deposited on an animal will vary according to the method of application, size of the animal, concentration of the compound in the applied formulation, factor by which the formulation is diluted and the nature of the formulation but in general will lie in the range of from 0.0001% to 0.5% w/w except for undiluted formulations such as pour-on formulations which in general will be deposited at a concentration in the range from 0.1 to 20.0% and preferably 0.1 to 10%. The amount of compound to be applied to stored products in general will lie in the range of from 0.1 to 20ppm. Space sprays may be applied to give an average initial concentration of 0.001 to Img of compound of formula (I) per cubic metre of treated space.

The compounds of formula (I) are also of use in the protection and treatment of plant species, in which case an effective insecticidal, acaricidal, nematocidal or molluscicidal amount of the active ingredient is applied. The application rate will vary according to the compound chosen, the nature of the formulation, the mode of application, the plant species, the planting density and likely infestation and other like factors but in general, a suitable use rate for agricultural crops is in the range 0.001 to 3kg/Ha and preferably between 0.01 and lkg/Ha. Typical formulations for agricultural use contain between 0.0001% and 50% of a compound of formula (I) and conveniently between 0.1 and 15% by weight of a compound of the formula (I) .

Dusts, greases, pastes and aerosol formulations are usually applied in a random fashion as described above and concentrations of 0.001 to 20% w/v of a compound of Formula (I) in the applied formulation may be used.

The compounds of formula (I) have been found to have activity against the common housefly (Musca domestica) . In addition, certain compounds of formula (I) have activity against other arthropod pests including Mvzus persicae. Tetranychus urticae. Plutella xylostella. Culex spp. Tribolium castaneum. Sitonhilus pranarius. Periplaneta americana and Blattella germanica. The compounds of formula (I) are thus useful in the control of arthropods e.g. insects and acarines in any environment where these constitute pests, e.g. in agriculture, in animal husbandry, in public health control and in domestic situations.

Insect pests include members of the orders Coleoptera (e.g. Anobium. Ceutorhvnchus. Rhvnchophorus. Cosmopolites. Lissorhontrus. Meliεethes. Hvpothenemus. Hylesinus. Acalvmma. Lema. Psylliodes. Leptinotarsa. Gonocephalum. Agriotes. Dermolepida. He eronvchus. Phaedon. Tribolium. Sitonhilus. Diabrotica. Anthonomus or Anthrenus spp.), Lepidoptera (e.g. Ephestia. Mamestra. Earias. Pectinonhora. Ostrinia. Trichoplusia. Pieris. Laphvpna. Agrotis. Amathes. Wiseana. Tryporvsa. Diatraea. Sporganothis. Cvdia. Archins. Plutella. Chilo. Heliothis. Spodoptera or Tineola spp.), Diptera (e.g. Musca. Aedes. Anopheles. Culex. Glossina. Simulium. Stomoxys. Haematobia. Tabanus. Hydrotaea. Lucilia. Chrvsomia. Callitroga. Dermatobia. Gasterophilus. Hypoderma. Hylemvia. Atheri ona. Chlorops. Ph tomvza. Ceratitis. Liriomyza and Meloohagus spp.), Phthiraptera (Malophaga e.g. Damalina spp. and Anoplur e.g. Linognathus and Haematoninus spp.), Hemiptera (e.g. Aphis. Bemisia.Phorodon. Aeneolamia. Empoasca. Parkinsiella. Pyrilla. Aonidiella. Coccus. Pseudococus. Helopeltis. Lv us. Dvsdercus. Oxycarenus. Nezara. Aleurodes. Triatoma. Psylla. Mvzus. Me oura. Phylloxera. Adelves. Niloparvata. Nephrotetix or Cimex spp.), Orthoptera (e.g. Locusta. Gryllus. Schistocerca or Acheta spp.), Dictyoptera (e.g. Blattella. Periplaneta or Blatta spp.), Hymenoptera (e.g. Athalia. Cephus. Atta. Solenopsis or Monomorium spp.), Isoptera (e.g. Odontotermes and Reticulitermes spp.), Siphonaptera (e.g. Ctβπocephalides or Pulex spp.), Thysanura (e.g. Lepisma spp.), Dermaptera (e.g. Forficula spp.), Pscoptera (e.g. Peripsocus spp.) and Thysanoptera (e.g. Thrips tabaci) ..

Acarine pests include ticks, e.g. members of the genera Boophilus. Ornithodorus. Rhipicephalus. Amblvomma. Hvalomma. Ixodes. Haemaphvsalis. Dermacentor and Anocentor. and mites and manges such as Acarus. Tetranychus. Psoroptes. Notoednes. Sarcoptes. Psorergates. Chorioptes. Eutrombicula. Demodex. Panonvchus. Brvobia. Eriophves. Blaniulus. Polyphagotarsonemus. Scutieerella. and Oniscus spp.

Nematodes which attack plants and trees of importance to agriculture, forestry, horticulture either directly or by spreading bacterial, viral, mycoplasma or, fungal diseases of the plants, include root-knot nematodes such as Meloidogvne spp. (e.g. M. incognita); cyst nematodes such as Globodera spp. (e.g. G. rostochiensis) : Heterodera spp. (e.g. H. avenae) : Radopholus spp. (e.g. R. similis) : lesion nematodes such as Pratylenchus spp. (e.g. P. pratensis) : Belonolaimus spp. (e.g. B. gracilis) : Tylenchulus spp. (e.g. T. semipenetrans) : Rotv1enchulus spp. (e.g.R. reniformis) : Rotylenchus spp. (e.g. R. robustus) : Helicotylenchus spp. (e.g. H. multicinctus)iHemicycliophora spp. (e.g. H. gracilis) : Criconemoides spp. (e.g. C . similis) : Trichodorus spp. (e.g. T primitivus) : dagger nematodes such as Xiphinema spp. (e.g. X. diversicaudaturn) . Loπgidorus spp (e.g. L. elongatus) ; Hoplolaimus spp. (e.g. H. coronatus) ; Aphelenchoides spp. (e.g. A. ritzema-bosi. A. bessevi) : stem and bulb eelwor s such as Ditylenchus spp. (e.g. D. dipsaci) .

Mollusc pests which attack plants and trees of importance to agriculture, forestry and horticulture include slugs such as Deroceras spp. (eg. D. reticulatum - the grey field slug); the Arion group; Milax spp; land snails such as Helix spp. , and aquatic snails such as Planorbis spp. Mollusc pests which act as vectors of diseases in man and domestic animals include Buiinus spp., Phvsopsis spp., Planorbis spp. , and Oricomelania spp.

Compounds of the invention may be combined with one or more other pesticidally active ingredients (for example pyrethroids, carbamates and organophosphates) and/or with attractants, repellents, bacteriocides, fungicides, nematocides, anthelmintics and the like. Furthermore, it has been found that the activity of the compounds of the invention may be enhanced by the addition of a synergist or potentiator, for example: one of the oxidase inhibitor class of synergists, such as piperonyl butoxide or propyl 2-propynylphenylphos- phonate; a second compound of the invention; or a pyrethroid pesticidal compound. When an oxidase inhibitor synergist is present in a formula of the invention, the ratio of synergist to compound of Formula (I) will be in the range 25:1-1:25 eg about 10:1.

Stabilisers for preventing any chemical degradation which may occur with the compounds of the invention include, for example, antioxidants (such as tocopherols, butylhydroxyanisole and butylhydroxytoluene) and scavengers (such as epichlorhydrin) and organic or inorganic bases e.g. trialkylamines such as triethylamine which can act as basic stabilises and as scavengers.

The following examples illustrate in a non-limiting manner preferred aspects of the invention. All temperatures are in degrees Celsius. Example 1.

1- (3.3-Dimethylbutyl)-4-n-propyl-2.6.7-trithiabicvclof2.2.21octane

(i) Methanesulphonyl chloride (74.Og) was added dropwise over 30 minutes to a solution of 2-hydroxymethyl-2-n-propylpropan-l,3- diol (28.Og) (European Application No. 216624) in dry pyridine (200ml) under nitrogen at 0 C. The mixture was allowed to warm to room temperature. After stirring for 18 hours the mixture was poured into water (200ml) and extracted with chloroform (2x200ml) . The chloroform extracts were washed with water (2x100ml) , dried over anhydrous magnesium sulphate and evaporated .in vacuo to give a brown solid. This was stirred in dry diethyl ether (200ml) to give 2-hydroxymethyl-2-n-propyl- propan-l,3-diol trimethanesulphonate as a white solid. (70.Og) (m.pt.l03-6°C).

(ii) Sodium trithiocarbonate (18.Og) [see J.Org.Chem. 1968, 33, 1275] in water (25ml) was added to a solution of 2-hydroxymeth- yl-2-n-propylpropan-l,3-diol trimethanesulphonate (12.Og) in dimethyl-formamide (100ml) . The mixture was heated to reflux (130 C) for 4 hours then allowed to cool to room temperature. After a further 18 hours stirring, dilute sulphuric acid solution (50ml) was added slowly over 30 minutes. The mixture was extracted with chloroform. The extracts were dried over anhydrous magnesium sulphate and evaporated .in vacuo to give a brown liquid. Hexane (200ml) was added and the mixture washed with water (3x50ml) . Drying over anhydrous magnesium sulphate and evaporation gave an amber oil (6.8g). The crude oil (6.4g) in diethyl ether (10ml) was added dropwise to a suspension of lithium aluminium hydride (3.0g) in dry diethyl ether (100ml) at a rate sufficient to maintain reflux. The mixture was stirred for a further hour after addition was complete, then water (3ml) was added carefully. Dilute sulphuric acid (3ml) was added and was followed by water (3ml) . The mixture was filtered, the solid washed with diethyl ether (50ml) and the combined filtrates dried over anhydrous magnesium sulphate and evaporated .in vacuo to give 2-mercaptomethyl-2-n-propylpropan- 1,3-dithiol as a pale yellow oil (5.3g).

(iii) 2-Mercaptomethyl-2-n-propylpropan-l,3-dithiol (4.0g) and tri- ethyl orthoformate (3.6g) were refluxed, with stirring, in dry toluene (120ml) containing Amberlyst "15" (l.Og). The mixture was cooled and filtered. The filtrates were evaporated in vacuo and the residue was purified by chromatography on alumina eluting with dichloromethane: hexane; 1:10. 4-n-Propyl-2,6,7- trithia-bicyclo[2.2.2]octane was obtained as a colourless solid (3.1g, .pt. 139°C).

(iv) Starting from 3,3-dimethylbutan-l-ol (Aldrich) and 1 equivalent of methanesulphonyl chloride and using methodology outlined in stage (i), 3,3-dimethylbutyl methanesulphonate was prepared.

(v) A mixture of 3,3-dimethylbutyl methanesulphonate (13.6g) and sodium iodide (50g) in butanone (175ml) was heated at reflux, with stirring, for 1 hour. After this time the solvent was removed in vacuo and the residue partitioned between diethyl ether and water. The organic phase was separated, washed with water and brine before drying over anhydrous magnesium sulphate. The solvent was removed under reduced pressure to leave 3,3-dimethylbutyl iodide (10.7g) as a yellow liquid.

(vi) n-Butyllithium (8.0ml, 1.6M solution in hexane) was added dropwise to a stirred solution of 4-n-propyl-2,6,7-trithiabi- cyclo[2.2.2]octane (2.2g) in dry tetrahydrofuran (75ml) at -70 C, under a - rrent of nitrogen. The resulting solution was stirred at -70 C for 45 minutes and 3,3-dimethylbutyl iodide (2.72g) was added. The reaction mixture was stirred at -70 C for 2 hours, allowed to warm up to 20 C and stirred at 20 for eighteen hours. Water was added carefully and the aqueous 253

mixture was extracted into diethyl ether. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by chromatography on silica, eluting with dichloromethane: hexane; 1:10. 1-(3,3-Dimethylbut-yl)-4-n-propyl-2,6,7-trithiabicyclo [2.2.2]octane was obtained as a colourless solid (2.0g).

Using similar methodology 1-(3,3-dimethylbutyl)-4-ethyl-2,6,7- trithiabicyclo[2.2.2]octane was prepared.

Steps (vii) , (viii) and (ix) below describe an improved synthesis of 2-mercaptomethyl-2-n-propylpropan-l,3-dithiol.

(vii) To a stirred suspension of 2-hydroxymethyl-2-n-propylpropan-

1,3-diol trimethanesulphonate (300g) in dry dimethylformamide (2000ml) was added potassium thiocyanate (900g) . The stirred mixture was maintained at 140 C for 16 hours. The mixture was cooled and the volume was reduced to about one third by distilling off some dimethylformamide (stillhead temperature 50 C, 15mm Hg) . The residue was cooled and water (2000ml) and toluene (2000ml) were added. The mixture was stirred vigorously. The layers were separated. The aqueous layer was extracted with further portions of toluene (3x1000ml) . The combined toluene extracts were washed with water and brine and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. 2-n-Propyl-2-thiocyanatomethyl-l,3-dithio- cyanatopropane was obtained as a dark oil (140.0g).

(viii) 2-n-Propyl-2-thiocyan tomethyl-l,3-dithiocyanatopropane (20g) was dissolved in toluene (100ml) and water (800ml) was added. The aqueous mixture was stirred and sodium hydroxide (20g) was added. The mixture was refluxed for 8 hours. The mixture was left overnight and the toluene layer was separated and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. 4-Mercaptomethyl-4-n-propyl-l,2-dithiolane was obtained as a dark oil (17.Og).

(ix) A solution of 4-mercaptomethyl-4-n-propyl-l,2-dithiolane (36.Og) in toluene (200ml) was stirred vigorously. Zinc powder (60g) was added and hydrochloric acid solution (1000ml. 1:1 concentrated hydrochloric acid: water) was added over a period of 3 hours, under a current of nitrogen. The mixture was refluxed for 3 hours. The mixture was cooled and extracted with toluene (500ml) . The toluene layer was dried over anhydrous magnesium sulphate and the solvent was removed in vacuo. 2-Mercaptomethyl-2-n-propylpropan-l,3-dithiol was obtained as a pale yellow oil (36.Og).

Stages (x) and (xi) describe alternative routes to 1-(3,3-dime¬ thylbutyl)-4-n-propyl 2,6,7-trithiabicyclo[2.2.2] -octane.

(x) A slow current of dry hydrogen chloride gas was passed through dry toluene (100ml) at 0 C for 5 minutes. A solution of 2-mercaptomethyl-2-n-propylpropan-l,3-dithiol (1.8g) in dry toluene (20ml) was added and was followed immediately by a solution of 4,4-dimethylvaleronitrile (l.lg) (G.M. Whitesides, J.P. Sevenair and R.W. Goetz J.Amer.Chem.Soc. 1967, 89, 1135) in dry toluene (20ml) . Hydrogen chloride gas was passed into the stirred solution at 0 C for 1 hour. The mixture was kept at 0 C for 3 days. The mixture was poured into water and the aqueous mixture was extracted with toluene. The toluene extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was removed .in vacuo. The solid was washed with methanol and air dried. l-(3,3-Dimethyl- tyl)-4-n-propyl-2,6,7-trithiabicyclo[2.2.2]octane was obtain¬ ed as a colourless solid (0.7g).

(xi) A solution of 2-mercaptomethyl-2-n-propylpropan-l,3-dithiol (0.84g) in dichloromethane (5ml) was added to a stirred suspension of aluminium chloride (0.57g) in dichloromethane (10ml) at -70 C under nitrogen. After 5 minutes a solution of 4,4-dimethylpentanoyl chloride (0.7g) (G.M. Whitesides, J.P. Sevenair and R.W. Goetz J.Amer.Chem.Soc. 1967, ££, 1135) in dichloromethane (10ml) was added dropwise over a period of 20 minutes. The reaction mixture was allowed to warm to -20 C over 2 hours. The reaction mixture was allowed to warm to 20 C overnight. Diethyl ether (100ml) was added and the mixture was extracted with further portions of diethyl ether. The combined ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated .in vacuo. Recrystallisation from acetone gave 1-(3,3-dimethylbutyl)-4-n-propyl-2,6,7-tri- thiabicyclo[2.2.2]-octane as a colourless solid.

Steps (xii) , (xiii) and (xiv) below describe a further improved synthesis of 2-mercaptomethyl-2-proρan-l,3-dithiol

(xii) 2-Hydroxymethyl-2-n-propylpropan-l,3-diol (12kg) in pyridine

(30 litres) was added to a stirred solution of p_-toluenesulphonyl chloride (51kg) in pyridine (60 litres) in a 410 litre reactor over a period of 2 hours whilst maintaining the internal temperature at 40-45 C. After completing the addition, the mixture was cooled to 20 C and was stirred overnight at 20 C. The mixture was cooled to 5-10 C prior to addition of hydrochloric acid solution (901 of concentrated hydrochloric acid and 901 of water) over a period of 60 minutes whilst maintaining the internal temperature below 30 C. After stirring for 30 minutes, the batch was centrifuged. The damp solid was then re-slurried with water (120 litres) and re-centrifuged. The solid was washed with further water until neutral and then dried (40 C in vacuo) until a moisture content of <1% was achieved. A yield of 47.0kg of colourless 2-hydro- xymethyl-2-n-propylpropan-l,3-diol tri-p-toluenesulphonate was obtained. (Melting point 170-171°C) . (xiii) Sodium sulphide trihydrate (21.6kg) was added to a stirred suspension of sulphur (10.5kg) in ethanol (150 litres) in a 410 litre reactor. After addition of 2-hydroxymethyl-2-n-propyl- propan 1,3-diol tri-p-toluenesulphonate (25kg) the mixture was warmed slowly to reflux. After refluxing for 6 hours the mixture was cooled to 20-25 C and water added (120 litres). Toluene was then added (80 litres) and the mixture stirred rapidly for 15 minutes. After allowing to stand overnight the lower aqueous layer was transferred into an adjacent 410 litre reactor. This aqueous layer was extracted with toluene (2x80 litres) prior to discharging the aqueous layer to waste. The toluene extracts were combined in a 410 litre reactor and washed with water (3x50 litres) . Toluene was then removed from the organic layer by vacuum distillation (55-60 C, 150m bars, 120 litres). The residual solution of bis(4-propyl-l,2- dithiolane-4-ylmethyl)disulphide was used without further purification.

(xiv) Bis(4-propyl-l,2-dithiolane-4-ylmethyl)disulphide (1.2kg) in toluene (1.2 litres) (from previous stage), was added to zinc dust, under nitrogen with vigorous stirring. The mixture was heated to 85 C and concentrated hydrochloric acid (3.1 litres) added dropwise over 3-4 hours to maintain a gentle reflux. On completion of the addition the reaction mixture was stirred at 90 C for 1-2 hours. After cooling the reaction mixture was filtered to remove residual zinc. The organic layer was washed twice with water prior to removal of toluene under vacuum. 2-Mercaptomethyl-2-n-propylpropan-l,3-dithiol was obtained as a pale yellow oil, in quantitative yield.

Stages (xv) and (xvi) describe an alternative route to 4,4-dimethyl- pentanenitrile.

(xv) Hydrogen bromide was bubbled over a period of 3.75 hours into cooled (<40°C) and stirred 3,3-dimethyl-l-butene (1547g) to 1253

which a catalytic quantity of AIBN (~0.5g) had been added. The orange coloured reaction mixture was then allowed to cool and then to stand overnight. Water (600ml) was added and the mixture stirred for 15 minutes. The layers were separated and the organic layer washed with water (2x600ml) and then stirred with saturated sodium bicarbonate solution (600ml) for 15 minutes. The layers were separated and the organic layer washed with water (600ml) and brine (500ml) to give 1-bromo- 3,3-dimethylbutane (2580g) as an almost colourless liquid.

(xvi) Tetrabutylphosphonium bromide (210g) , toluene (1.5 litres) and l-bromo-3,3-dimethylbutane (1023g) was added to a stirred solution of sodium cyanide (456g) in water (1 litres) under a blanket of nitrogen. The stirred emulsion was heated to 50 C and then with caution (exotherm from 50 C to 63 C) to 85-88 C. After heating at this temperature for 6.5 hours the reaction mixture was cooled and stirred overnight. The organic layer was washed with water (3x700ml) , sodium hydroxide solution (2M,2x500ml), water (2x500ml) and brine (500ml) to give an amber coloured toluene solution of 4,4-dimeth lpentanenitrile (1952g) . The toluene was removed by distillation at atmospheric pressure and the product purified by distillation at reduced pressure (bp 80-82 C, 15mmHg) to give 4,4-dimethylpentanenitrile (Yield 75%).

Example 2.

1- (3.3-Dimethylbutyl)-4-n-propyl-2.6.7-trithiabicvcloT2.2.21octane- 2-oxide

A mixture of 1-(3,3-dimethylbutyl)-4-n-propyl-2,6,7-trithiabicyclo- [2.2.2]octane (0.6g), 3-chloroperbenzoic acid (0.45g, 80-90% supplied by Aldrich), and anhydrous sodium acetate (0.8g) in anhydrous acetonitrile (30ml) was stirred at 20 C from 24 hours. The solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. The organic phase was separated, washed with sodium hydrogen carbonate solution and brine before drying over anhydrous magnesium sulphate. The solvent was removed .in vacuo and the residue was chromatographed on silica. Elution with hexane: ethyl acetate; 1:1 gave 1-(3,3-dimethylbutyl)-4-n-propyl-2,6,7-trithiabicyclo[2.2.2]- octane-2-oxide as a colourless solid (0.23g).

Example 3.

5-t-Butyl-2-cvano-2-(3.3-dimethylbutyl)-1.3-dithiane

(i) A solution of n-butyllithium in hexane (1.6M; 17.75ml) was added to a stirred solution of 5-t-butyl-l,3-dithiane (5g) (E.L. Eliel et al. J. A er. Chem. Soc. 1976, ££, 3583) in tetrahydrofuran (50mls) at -30 C under a nitrogen atmosphere. After 1 hour of additional stirring, the mixture was transfer¬ red by syringe and added, dropwise, to neat dimethylformamide (lOmls) cooled to -10 C. The mixture was stirred for 1 hour at -10 C and then stored overnight at 0 C. The reaction mixture was then poured into ice-water (lOOmls) and extracted with hexane. The aqueous layer was neutralised with dilute hydro¬ chloric acid and then re-extracted with diethyl ether. The ethereal extracts were dried over anhydrous magnesium sulphate and then evaporated .in vacuo to leave a white solid residue (3.1g). 5-£-Butyl-2-formyl-l,3-dithiane, thus obtained, is present to a large extent as a dimer.

(ii) 5-t-Butyl-2-formyl-l,3-dithiane (lg) was heated to melting, under a nitrogen atmosphere, and then allowed to cool. The viscous oil thus obtained was taken up in dry benzene (lOOmls) containing pyridine (0.78g). 0,N-Bis-(trifluoroacetyl)hydro- xylamine (l.lg) (J.H. Pomeroyn et al J. Amer. Chem. Soc. 1959, 81 6340) was added and the resulting mixture was heated to reflux for two hours. After cooling, ether and water were added and the organic layer separated. The aqueous layer was 1253

further extracted with fresh ether and the combined organic extracts were dried over anhydrous magnesium sulphate and then evaporated .in vacuo to leave a yellow solid, which was purified by column chromatography on silica. Gradient elution with hexane/dichloromethane mixtures gave 5-£-butyl-l-cyano-l,3- dithiane as a white solid (0.38g).

(iii) A solution of 5-t:-butyl-2-cyano-l,3-dithiane (0.5g) in tetrahy- drofuran (15ml) was cooled to -50 C under a nitrogen atmosphere. n-Butyllithium (2.0ml, 1.6M solution in hexane) was added and the resulting mixture maintained at -40 C for 2 hours when 3,3-dime hylbutyl iodide (1.6g) was added. The reaction mixture was allowed to warm to room temperature overnight. After this time diethyl ether and water were added. The organic phase was separated and the aqueous layer extracted with fresh ether. The combined organic extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by column chromatography on silica, eluting with ethyl acetate: hexane; 1:6. Recrystallisation from hexane gave 5-t-butyl-2-cyano-2-(3,3-dimethylbutyl)-1,3- dithiane as a white solid (0.33g).

Biological Activities

The following examples illustrate, in a non-limiting manner, the pesticidal activity of compounds of formula (I)

Sprav Tests

The compounds of the invention were tested by dissolving the compounds in acetone (5%) and then diluting in water: 'Synperonic' (94.5%: 0.5%) to give an aqueous emulsion. The solution was then used to treat the following insects. Musca domestica:

20 female Musca were contained in a cardboard cylinder with gauze over either end. Solution containing the compound was sprayed onto the insects so enclosed and mortality assessed after 48 hours at 25 C.

Compounds active at less than 200 p.p.m. were:-

1, 2, 3, 4

Plutella xylostella:

7 Plutella larvae were put onto leaf discs and sprayed with the solution containing the compound. Mortality was assessed after 2 days at 25°C.

Compounds active at less than 1000 p.p.m. were:-

1,

Mvzus persicae:

10 adult Mvzus were placed on a leaf disc of Chinese cabbage. 24 hours later the disc was sprayed with the solution containing the compound. Mortality was assessed after 2 days at 20 C.

Compounds active at less than 1000 p.p.m. were:-

1, 3

Compounds active at less than 200 p.p.m. were:- Diabrotica Undecimpunctata

Filter paper and food were sprayed and subsequently infested with 10 second instar larvae. Mortality was assessed after 48 hours.

Compounds active at less than 1000 p.p.m. were:-

1, 2, 3, 4

Topical Application

The activity of compounds of the invention against male Periplaneta americana was demonstrated by the topical application to anaesthetised test insects of a solution of the compound under test in butanone. Mortality was assessed after 6 days.

Compounds active at less than 50μg per insect were:-

1, 3, 4

The activity of compounds of the invention against female Musca domestica (WRL strain) , was demonstrated by the topical application to the test insect of a solution of the compound under test in butanone. Mortality was assessed at 48 hours.

The following compounds were active at less than Iμg per insect:-

1, 2, 3, 4

The activity of compounds of the invention against male Blattella germanica was demonstrated by the topical application to anaesthetised test insects of a solution of the compound under test in butanone. Mortality was assessed at 6 days. Compounds active at less than lμg/cockroach were : -

1 , 2 , 3 , 4

Mouse Toxicitv

The following compounds were non-toxic to mice at an oral dose of 200mg/kg in DMSO:-

1, 2.

Slugs of species Deroceras and Arion

30 Deroceras and Arion were exposed to treated filter paper in "vented" petri dishes. Mortality was assessed after 72 hours.

3 The following compound was active at less than 6% ai 2cm : -

TABLE 1,

COMPOUNDS AND CHARACTERISING DATA

Compound Compound Mpt Mass Spectrum Nuclear Magnetic Resonance No. Chemical Ionisation Spectrum

H, CDC1-, p. .m. downfield from TMS, number of protons, multiplicity, J Hz.

(3, 3-Dimethylbutyl)- 144°C 291 0.90, 9H, s; 0.95, 3H, t, J6 n-propyl-2, 6,7-trithia- 1.20-1.55, 6H, m; 2.00, 2H, cyclo[2.2.2]octane 3.00, 6H, s.

(3,3-Dimethylbutyl)- 167°C 307 0.90, 9H, s; 0.95, 3H, t, J6 n-propyl-2, 6,7-trithia- 1.2-1.6, m, 7H; 1.90, 2H, m; cyclo[2.2.2]octane-2-oxide 2.35, IH, dd, J 13.2 and 1.6 2.40, IH, dd, J 13.1 and 2.3 2.63, IH, dd, J 11.3 and 1.6 2.95, IH, dd, J 11.7 and 1.6 3.10, IH, dd, J 11.3 and 2.3 3.30, IH, dd, J 12.9 and 2.6

Compound Compound Mpt Mass Spectrum Nuclear Magnetic Resonance No. Chemical Ionisation Spectrum

t-Butyl-2-cyano-2-(3,3- 159.6 C 286 0.95, 9H, s; 1.00, 9H, s; methylbutyl) -1, 3-dithiane 1.55, 2H, m; 1.65, IH, tt, J 11 and 2; 2.00, 2H, m; 2.92, 2H, dd, J 13 and 2; 3.05, 2H, dd, J 13 and 11

(3,3-Dimethylbutyl) -4- 133 4°C 277 0.90, 9H, s; 0.95, 3H, t, hy1-2,6,7-trithia- J7; 1.50, 4H, m; 2.05, 2H, cyclo[2.2.2]octane ; 3.00, 6H, s.

Claims (18)

125330 -CLAIMS
1. A compound of formula (I) :

   wherein each of n and n' is 0, 1 or 2;

   R is hydrogen or methyl, R is methyl, ethyl or cyclopropyl, each

   2 3 of R and R are the same or different and are each hydrogen or methyl; R is hydrogen or methyl, R is cyano or R and R are linked to form a group CH„S(0) where m is 0, 1 or 2.
2. 2. A compound according to claim 1 wherein R is hydrogen.

   a b
3. 3. A compound according to claim 1 or claim 2 wherein R and R are linked to form a group CH„S(0) and R is ethyl.

   2 3
4. 4. A compound according to claim 3 wherein R and R are hydrogen.
5. 5. A compound according to claim 3 or claim 4 wherein, m, n and n' are 0.
6. 6. A compound according to claim 1 or claim 2 wherein R is hydrogen or methyl and R is cyano.
7. 1 2 3 7. A compound according to claim 6 wherein R , R and R are all methyl.
8. 8. A compound according to claim 1 selected from:-

   1-(3,3-dimethylbutyl)-4-n-propyl-2,6,7-trithiabicyclo-

   [2.2.2]octane

   1-(3,3-dimethylbutyl)-4-n-propyl-2,6,7-trithiabicyclo-

   [2.2.2]octane-2-oxide

   5-1-butyl-2-cyano-2-(3,3-dimethylbuty1)-1,3-dithiane

   1-(3,3-dimethylbutyl)-4-ethyl-2,6,7-trithiabicyclo[2.2.2]- octane
9. 9. A process for the preparation of a compound of the formula (I)

   wherein each of n and n' is 0, 1 or 2;

   R is hydrogen or methyl; R is methyl, ethyl or cyclopropyl, each

   2 3 of R and R are the same or different and are each hydrogen or methyl; R is hydrogen or methyl, R is cyano or R and R are linked to form a group CH„S(0) where is 0, 1 or 2 which process comprises:

   (i) the reaction of the anion from a compound of formula (IV)

   with an alkylating agent; or

   a b (ii) when R and R are linked to form a group CH„S(0) the reaction of a compound of formula (V) :

   a) with a compound tBuCH„CH_X wherein X is an activated carboxylic acid group in the presence of a Lewis acid

   b) with a compound tBuCH_CH_CN in the presence of a suitable acid.
10. 10. A pesticidal formulation comprising a compound of the formula (I) as defined in any one of claims 1 to 8 in admixture with one or more carriers or diluents.
11. 11. A pesticidal formulation according to claim 10 which additionally contains a synergist or potentiator.
12. 12. A pesticidal formulation according to either claim 10 or claim 11 which additionally contains one or more pesticidally active ingredients, attractants, repellents, bacteriocides, fungicides and/or anthelmintics.
13. 13. A method for the control of arthropod, helminth or mollusc pests which comprises administering to the arthropod, helminth or mollusc, or their environment an effective amount of a compound according to any of claims 1 to 8.
14. 14. A method for the control of pest infestations of plants which comprises administering to the plant an effective amount of a compound of formula (I) as defined according to any of claims 1 to 8.
15. 15. A method for the control of pest infestations of stored products which comprises administering to the stored products an effective amount of a compound of formula (I) as defined according to any of claims 1 to 8.
16. 16. A method for the control of pest infestations of animals which comprises administering to the animal an effective amount of a compound of the formula (I) as defined according to any of claims 1 to 8.
17. 17. A compound of the formula (I) as defined according to any of claims 1 to 8 for use in the control of a pest infestation of an animal.
18. 18. The use according to claim 17 wherein said animal is a human.