WO1999038865A1 - 8-azabicyclo(3.2.1)oct-2-ene derivatives as pesticides - Google Patents

8-azabicyclo(3.2.1)oct-2-ene derivatives as pesticides Download PDF

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Publication number
WO1999038865A1
WO1999038865A1 PCT/GB1999/000225 GB9900225W WO9938865A1 WO 1999038865 A1 WO1999038865 A1 WO 1999038865A1 GB 9900225 W GB9900225 W GB 9900225W WO 9938865 A1 WO9938865 A1 WO 9938865A1
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Prior art keywords
alkyl
optionally substituted
halogen
compound
hydrogen
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PCT/GB1999/000225
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French (fr)
Inventor
Roger Salmon
Stephen Christopher Smith
Christopher Ian Brightwell
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Zeneca Limited
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Application filed by Zeneca Limited filed Critical Zeneca Limited
Priority to AU21782/99A priority Critical patent/AU2178299A/en
Publication of WO1999038865A1 publication Critical patent/WO1999038865A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system

Definitions

  • the present invention relates to 8-azabicyclo[3.2.1]oct-2-ene derivatives, to processes for preparing them, to insecticidal, acaricidal, molluscicidal and nematicidal compositions comprising them and to methods of using them to combat or control insect, acarine, mollusc or nematode pests.
  • Insecticidal l-azabicyclo[3.2.1]oct-2-enes are disclosed in WO93/14636 and insecticidal 3-cyano-3-substituted-8-azabicyclo[3.2.1]octanes are described in WO96/37494.
  • Certain 2-pyridyl-8-azabicyclo[3.2.1]oct-2-enes are disclosed in ret. Eett. 38(32) 5619-22 as intermediates for the synthesis of epibatidine analogues.
  • Certain 8-azabicyclo[3.2.1]oct-2-enes are disclosed as intermediates in EP0604352.
  • the present invention provides a compound of formula (I), wherein one of R 1 and R 2 is hydrogen and the other is a phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, benzoxazol-2-one or benzimidazolin-2-one ring, said ring being optionally substituted with halogen, C, ⁇ alkyl, C,. 6 haloalkyl, C, ⁇ alkoxy, C, ⁇ haloalkoxy, C 2 ⁇ alkenyl, C 2 .
  • R is hydrogen, formyl, C, ⁇ alkyl (optionally substituted with cyano, CO 2 (C w alkyl) or phenyl (itself optionally substituted with halogen, C M alkyl, C M alkoxy, C w haloalkyl or C M haloalkoxy)), CH ⁇ C, ⁇ haloalkyl), CO 2 (C M alkyl), CO 2 (C 2 ⁇ alkenyl), CH 2 (C 2 ⁇ alkenyl), CH 2 (C M alkynyl), benzyl (wherein the phenyl ring is optionally substituted with halogen or C M alkyl) or XR 3 ; X is O or NR 4 ; R 3 and R 4 are, independently, hydrogen, cyano, C w alkyl (optionally substituted with halogen, cyano, CO 2 (C ⁇ alkyl) or
  • R 2 is not a pyridyl, pyrimidinyl, pyrazinyl, thienyl or thiazolyl ring (said ring being unsubstituted or substituted by unsubstituted alkyl only).
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • Alkyl moieties preferably contain from 1 to 6, more preferably from 1 to 4, carbon atoms. They can be in the form of straight or branched chains, for example methyl, ethyl, n- or iso-propyl, or n-, sec-, iso- or tert-butyl.
  • Alkenyl and alkynyl moieties can be in the form of straight or branched chains, and alkenyl moieties can be of either (E)- or (Z)-conf ⁇ guration. Examples are vinyl, allyl and propargyl.
  • R is CH 2 (C W haloalkyl) it is preferred that it is CH 2 (C ⁇ fluoroalkyl) (for example, 2,2-difluoroethyl or 2,2,2-trifluoroethyl).
  • Suitable acid addition salts include those with an inorganic acid such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, or an organic carboxylic acid such as oxalic, tartaric, lactic, butyric, toluic, hexanoic and phthalic acids, or sulphonic acids such as methane, benzene and toluene sulphonic acids.
  • organic carboxylic acids include haloacids such as trifluoroacetic acid.
  • the present invention provides a compound of formula (I), wherein one of R 1 and R 2 is hydrogen and the other is a phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl or thiazolyl ring, said ring being optionally substituted with halogen, C w alkyl, C w haloalkyl, C w alkoxy, C,_ 6 haloalkoxy, C M alkenyl, C 2 ⁇ alkynyl or cyano;
  • R is hydrogen, formyl, C w alkyl (optionally substituted with cyano, CO 2 (C w alkyl) or phenyl (itself optionally substituted with halogen, C w alkyl, C w alkoxy, C, ⁇ haloalkyl or C, ⁇ haloalkoxy)), CH ⁇ C.
  • haloalkyl CO 2 (C w alkyl), CH 2 (C 2 ⁇ )alkenyl, CH 2 (C 2 alkynyl or XR 3 ;
  • X is O or NR 4 ;
  • R 3 and R 4 are, independently, hydrogen, cyano, C, ⁇ alkyl (optionally substituted with halogen, cyano, CO 2 (C,.
  • R 2 is not a pyridyl, pyrimidinyl, pyrazinyl, thienyl or thiazolyl ring (said ring being unsubstituted or substituted by unsubstituted alkyl only).
  • the present invention provides a compound of formula (I), wherein one of R 1 and R 2 is hydrogen and the other is a phenyl, pyrid-2-yl, pyrid-3-yl, pyrimidin-5-yl, pyrazin-2-yl, thien-2-yl, thiazol-5-yl, (benzoxazol-2-one)-5-yl, (benzoxazol-2-one)-6-yl or (benzimidazolin-2-one)-5-yl ring, said ring being optionally substituted with halogen (especially chlorine or bromine), C M alkyl (especially methyl), C M alkoxy (especially methoxy), C 2 alkenyl, C 2 ⁇ , alkynyl, hydroxy, nitro or methylenedioxy.
  • halogen especially chlorine or bromine
  • C M alkyl especially methyl
  • C M alkoxy especially methoxy
  • the present invention provides a compound of formula (I), wherein R is hydrogen, formyl (CHO), C alkyl (especially methyl), CO 2 (C, ⁇ alkyl) (especially CO 2 methyl or CO 2 ethyl), CO 2 (C 2 ⁇ alkenyl) (especially CO 2 ethenyl), CH 2 (C ⁇ haloalkyl) (especially CH 2 CF 3 ), benzyl (wherein the phenyl ring is optionally substituted with halogen or C M alkyl), CH 2 (C 2 ⁇ alkenyl) (especially allyl) or CH 2 (C 2 ⁇ alkynyl) (especially propargyl or but-2-ynyl).
  • R 2 is hydrogen.
  • the present invention provides a compound of formula (I), wherein R is hydrogen, formyl (CHO), C alkyl (especially methyl), CO 2 (C, ⁇ alkyl) (especially CO 2 methyl or CO 2 ethyl), CO 2 (C M alkenyl) (especially CO 2 ethenyl), CH 2 (C, ⁇ haloalkyl) (especially CH 2 CF 3 ), CH 2 (C 2 .
  • R is hydrogen, formyl (CHO), C alkyl (especially methyl), CO 2 (C, ⁇ alkyl) (especially CO 2 methyl or CO 2 ethyl), CO 2 (C M alkenyl) (especially CO 2 ethenyl), CH 2 (C, ⁇ haloalkyl) (especially CH 2 CF 3 ), CH 2 (C 2 .
  • R 1 is phenyl (optionally substituted with halogen (especially chlorine), C alkoxy (especially methoxy, hydroxy, nitro or methylenedioxy), pyrid-2-yl (optionally substituted with halogen (especially chlorine or bromine)), pyrid-3-yl (optionally substituted with halogen (especially chlorine or bromine)), pyrimid-5-yl, thien-2-yl
  • the present invention provides a compound of formula (I), wherein R is hydrogen, formyl (CHO), C M alkyl (especially methyl), CO 2 (C alkyl) (especially CO 2 methyl or CO 2 ethyl), CO 2 (C M alkenyl) (especially CO 2 ethenyl), CH 2 (C W haloalkyl) (especially CH 2 CF 3 ), CH 2 (C 2 ⁇ alkenyl) (especially allyl), CH 2 (C M alkynyl) (especially propargyl or but-2-ynyl) or benzyl (wherein the phenyl ring is optionally substituted with halogen (especially fluorine)); R 1 is hydrogen; and R 2 is phenyl (optionally substituted with halogen (especially fluorine or chlorine), C M alkoxy (especially methoxy), nitro or methylenedioxy), pyrid-2-yl (optionally substituted with halogen (especially chlorine or bromine)),
  • Table II shows selected melting point and selected NMR data, all with CDC1 3 as the solvent (unless otherwise stated), (no attempt is made to list every absorption in all cases) for compounds of Table I.
  • the compounds of formula (I) can be made by adaptation of methods described in the art (such as methods described in Pharm. Res. 1992, 9(11), 1474-9, WO97/13770, WO93/14636 and WO96/37494).
  • a compound of formula (I) can be prepared by coupling a compound of formula (II) with a compound of formula R*Hal wherein R* is a phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, benzoxazol-2-one, benzimidazolin-2-one or thiazolyl ring substituted as above and Hal is a halide (particularly a bromide or iodide) in the presence of one or more catalysts (such as palladium acetate, tetrakis-(triphenylphosphine)- palladium(O) or nickel(O) or tr ⁇ s-di( ⁇ -acetato)-bis[o-(di-o-tolyl)benzyl]dipalladium(II), preferably together with copper (I) halide (such as a bromide or chloride) or triphenyl borane under Heck conditions
  • the reaction is carried out with or without a suitable solvent (such as N,N- dimethylformamide) under an inert atmosphere (for example nitrogen) in the presence of a suitable base ⁇ such as N. N-diisopropy lethy lamine (which may also be used as solvent for the reaction), triethylamine, silver carbonate, sodium acetate or potassium acetate in the presence of a quaternary ammonium salt (such as tetra-n-butylammonium bromide) ⁇ .
  • a suitable solvent such as N,N- dimethylformamide
  • a suitable base such as N. N-diisopropy lethy lamine (which may also be used as solvent for the reaction)
  • triethylamine silver carbonate
  • sodium acetate or potassium acetate in the presence of a quaternary ammonium salt (such as tetra-n-butylammonium bromide) ⁇ .
  • a compound of formula (II) can be prepared by dehydrating a compound of formula (N), preferably wherein the hydroxy group is axial, under suitable conditions.
  • a compound of formula (N) preferably wherein the hydroxy group is axial, under suitable conditions.
  • a compound of formula (II) can be prepared by reacting a compound of formula (NI) with benzenesulfonyl hydrazide and reacting the product so formed with n-butyl lithium.
  • a compound of formula (N) wherein the hydroxy group is axial can be made by reducing a compound of formula (NI) with, for example, sodium borohydride, Raney Nickel or diisobutylaluminium hydride (DIBAL-H).
  • DIBAL-H diisobutylaluminium hydride
  • the preparation of compounds of formulae (N) and (VI) is disclosed in the literature (see, for example, WO96/37494, Y. Hayakawa et al J Am. Chem. Soc. 100 1786 (1978) or K. ⁇ ador et al Arzneim-Forsch V2 305 (1962)).
  • a compound of formula (I) wherein R 1 is hydrogen can be prepared by dehydrating a compound of formula (IN) with a suitable dehydrating reagent, such as an acid, acid anhydride or acid chloride (such as thionyl chloride).
  • a suitable dehydrating reagent such as an acid, acid anhydride or acid chloride (such as thionyl chloride).
  • a compound of formula (IN) can be prepared by reacting a compound of formula (III) with a suitable organometallic reagent R 2 M (wherein R 2 is as defined above but is not hydrogen, and M is a suitable metal residue, such as lithium or a Grignard residue (for example MgCl, MgBr or Mgl)).
  • R 2 M can be prepared by reacting compounds R 2 Hal (wherein Hal is a halogen) with a suitable organometallic reagent, such as magnesium, or an organolithium or organomagnesium reagent.
  • a compound of formula (III) can be prepared by methods analogous to those described in, for example, EP-A2-0076089, US5306718, Tetrahedron 18 405-412 (1962) and J. Am. Chem. Soc. 82 4642 (1960).
  • a compound of formula (I) wherein R and R 2 are both hydrogen can be made by treating a compound of formula (I) wherein R 2 is hydrogen and R is alkyl with either an azodicarboxylate (such as diethyl azodicarboxylate) at an elevated temperature and acidifying (with a mineral acid, such as hydrochloric acid) the product so formed; or an alkyl-, alkenyl- or haloalkyl-chloroformate (such as vinylchloroformate or 1- chloroethylchloroformate) and hydrolysing the carbamate so formed.
  • an azodicarboxylate such as diethyl azodicarboxylate
  • acidifying with a mineral acid, such as hydrochloric acid
  • alkyl-, alkenyl- or haloalkyl-chloroformate such as vinylchloroformate or 1- chloroethylchloroformate
  • a compound of formula (I) wherein R is not hydrogen and R 2 is hydrogen can be made by treating a compound of formula (I) wherein R and R 2 are both hydrogen with a compound RL (wherein L is a suitable leaving group, such as halogen or mesylate) preferably in the presence of a base.
  • a compound RL wherein L is a suitable leaving group, such as halogen or mesylate
  • Compounds of formula RL are commercially available or can be prepared by literature methods. - 18 -
  • Scheme I refers to a process for isomer conversion, in which a compound of formula (I), wherein R 2 is hydrogen, is reacted with a strong base (such as potassium tert-butoxide) in a polar solvent (such as tetrahydrofuran) at a temperature in the range 60 to 80°C.
  • a strong base such as potassium tert-butoxide
  • a polar solvent such as tetrahydrofuran
  • the present invention provides processes for preparing compounds of formula (I) as hereinbefore described.
  • the compounds of formula (I) can be used to combat and control infestations of insect pests such as Lepidoptera, Diptera, Homoptera and Coleoptera and also other invertebrate pests, for example, acarine, nematode and mollusc pests. Insects, acarines, nematodes and molluscs are hereinafter collectively referred to as pests.
  • the pests which may be combated and controlled by the use of the invention compounds include those pests associated with agriculture (which term includes the growing of crops for food and fibre products), horticulture and animal husbandry, companion animals, forestry and the storage of products of vegetable origin (such as fruit, grain and timber) and also those pests associated with the transmission of diseases of man and animals.
  • pest species which may be controlled by the compounds of formula (I) include: Myzus persicae (aphid), Aphis gossvpii (aphid), Aphis fabae (aphid), Lygus spp. (capsids), Dvsdercus spp. (capsids), Nilaparvata lugens (planthopper), Nephotettix cincticeps (leafhopper), Nezara spp. (stinkbug), Euschistus spp. (stinkbugs), Leptocorisa spp. (stinkbugs), Frankliniella occidentalis (thrip), Thrips spp.
  • insects which adversely affect the health of the public or of animals.
  • the compound In order to apply a compound of formula (I) to a pest, a locus of pest, or to a plant susceptible to attack by a pest, the compound is usually formulated into a composition which includes, in addition to the compound of formula (I), a suitable inert diluent or carrier and, optionally, a surface active agent. It is preferred that all compositions (both solid and liquid formulations) comprise, by weight, 0.0001 to 95%, more preferably 1 to 85%, for example 5 to 60%, of a compound of formula (I).
  • the composition is generally used for the control of pests such that a compound of formula (I) is applied at a rate of from 0.1 g to 10kg per hectare, preferably from lg to 6kg per hectare.
  • the present invention provides an insecticidal, acaricidal, nematicidal or molluscicidal composition
  • an insecticidally, acaricidally, nematicidally or molluscicidal composition comprising an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I), wherein one of R 1 and R 2 is hydrogen and the other is a phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, benzoxazol-2-one or benzimidazolin-2-one ring, said ring being optionally substituted with halogen, C, ⁇ alkyl, C, ⁇ haloalkyl, C, ⁇ alkoxy, C w haloalkoxy, C 2 ⁇ alkenyl, C 2 ⁇ alkynyl, hydroxy, nitro,
  • the composition is preferably an insecticidal, acaricidal or nematicidal composition.
  • the present invention provides an insecticidal, acaricidal, nematicidal or molluscicidal composition comprising an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I), wherein one - 20 -
  • R 1 and R 2 is hydrogen and the other is a phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl or thiazolyl ring, said ring being optionally substituted with halogen, C, ⁇ alkyl, C, ⁇ haloalkyl, C w alkoxy, C, ⁇ haloalkoxy, C ⁇ alkenyl, C 2 ⁇ alkynyl or cyano;
  • R is hydrogen, formyl, C, ⁇ alkyl (optionally substituted with cyano, CO 2 (C w alkyl) or phenyl (itself optionally substituted with halogen, C w alkyl, C w alkoxy, C, ⁇ haloalkyl or C, ⁇ haloalkoxy)), CH 2 (C, ⁇ ) haloalkyl, CO 2 (C alkyl), CH 2 (C 2 ⁇ )alkenyl, CH 2 (C 2 alkynyl
  • the invention provides a method of combating and controlling pests at a locus which comprises treating the pests or the locus of the pests with an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I), wherein one of R 1 and R 2 is hydrogen and the other is a phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, benzoxazol-2-one or benzimidazolin-2-one ring, said ring being optionally substituted with halogen, C M alkyl, C ⁇ haloalkyl, C, ⁇ alkoxy, C ⁇ haloalkoxy, C 2J6 alkenyl, C w alkynyl, hydroxy, nitro, cyano or methylenedioxy; R is hydrogen, formyl, C, ⁇ alkyl (optionally substituted with cyano
  • the invention provides a method of combating and controlling pests at a locus which comprises treating the pests or the locus of the pests with an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I), wherein one of R 1 and R 2 is hydrogen and the other is a phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl or thiazolyl ring, said ring being optionally substituted with halogen, C w alkyl, C haloalkyl, C w alkoxy, C w haloalkoxy, C w alkenyl, C M alkynyl or cyano; R is hydrogen, formyl, C M alkyl (optionally substituted with cyano, CO 2 (C w alkyl) or phenyl (itself optionally substituted with halogen, C w alky
  • compositions can be chosen from a number of formulation types, including dustable powders (DP), soluble powders (SP), water soluble granules (SG), water dispersible granules (WG), wettable powders (WP), granules (GR) (slow or fast release), soluble concentrates (SL), oil miscible liquids (OL), ultra low volume liquids (UL), emulsifiable concentrates (EC), emulsions (both oil in water (EW) and water in oil (EO)), suspension concentrates (SC), aerosols, fogging/smoke formulations, capsule suspensions (CS) and seed dressings.
  • the formulation type chosen in any instance will depend upon the particular purpose envisaged and the physical, chemical and biological properties of the compound of formula (I).
  • Dustable powders (DP) may be prepared by mixing a compound of formula (I) with one or more solid diluents (for example natural clays, kaolin, pyrophyllite, bentonite, alumina, montmorillonite, kieselguhr, chalk, diatomaceous earths, calcium phosphates, - 22 -
  • solid diluents for example natural clays, kaolin, pyrophyllite, bentonite, alumina, montmorillonite, kieselguhr, chalk, diatomaceous earths, calcium phosphates, - 22 -
  • Soluble powders can be prepared by mixing a compound of formula (I) with one or more water-soluble inorganic salts (such as sodium bicarbonate, sodium carbonate or magnesium sulphate) or one or more water-soluble organic solids (such as a polysaccharide) and, optionally, one or more wetting agents, one or more dispersing agents or a mixture of said agents to improve water dispersibility/solubility. The mixture is then ground to a fine powder. Similar compositions may also be granulated to form water soluble granules (SG).
  • water-soluble inorganic salts such as sodium bicarbonate, sodium carbonate or magnesium sulphate
  • water-soluble organic solids such as a polysaccharide
  • WP Wettable powders
  • WG Water dispersible granules
  • Granules may be formed either by granulating a mixture of a compound of formula (I) and one or more powdered solid diluents or carriers, or from pre-formed blank granules by absorbing a compound of formula (I) (or a solution thereof, in a suitable agent) in a porous granular material (such as pumice, attapulgite clays, fuller's earth, kieselguhr, diatomaceous earths or ground corn cobs) or by adsorbing a compound of formula (I) (or a solution thereof, in a suitable agent) on to a hard core material (such as sands, silicates, mineral carbonates, sulphates or phosphates) and drying if necessary.
  • a hard core material such as sands, silicates, mineral carbonates, sulphates or phosphates
  • Agents which are commonly used to aid absorption or adsorption include aliphatic and aromatic petroleum solvents, alcohols, polyvinyl acetates, polyvinyl alcohols, ethers, ketones, esters, dextrins, sugars and vegetable oils.
  • One or more other additives may also be included in granules (for example an emulsifying agent, wetting agent or dispersing agent).
  • Soluble concentrates (SL) can be prepared by dissolving a compound of formula (I) in water or an organic solvent, such as a ketone, alcohol or glycol ether. These solutions may contain a surface active agent (for example to improve water dilution or prevent crystallisation in a spray tank).
  • Emulsifiable concentrates (EC) or oil in water emulsions (EW) may be prepared by dissolving a compound of formula (I) in an organic solvent (optionally containing one or more wetting agents, one or more emulsifying agents or a mixture of said agents) and, for an - 23 -
  • Suitable organic solvents for use in ECs include ketones (such as cyclohexanone or methy ley clohexanone) and alcohols (such as benzyl alcohol, furfuryl alcohol or butanol).
  • Suitable organic solvents for use in ECs or EWs include vegetable oils, N-substituted pyrrolidones, glycol ethers, chlorinated hydrocarbons (such as chlorobenzenes) and aromatic solvents (such as alkylbenzenes or alkylnaphthalenes).
  • SC Suspension concentrates
  • SCs may comprise aqueous or non-aqueous suspensions of finely divided insoluble solid particles of a compound of formula (I).
  • SCs may be prepared by ball or bead milling the solid compound of formula (I) in a suitable medium with one or more dispersing agents, to produce a fine particle suspension of the compound.
  • One or more wetting agents may be included in the composition and a suspending agent may be included to reduce the rate at which the particles settle.
  • Aerosol formulations comprise a compound of formula (I) and a suitable propellant (for example n-butane).
  • a compound of formula (I) may also be dissolved or dispersed in a suitable medium (for example water or a water miscible liquid, such as n-propanol) to provide compositions for use in non-pressurised, hand-actuated spray pumps.
  • a compound of formula (I) can be mixed in the dry state with a pyrotechnic mixture to form a composition suitable for generating, in an enclosed space, a smoke containing the compound.
  • Capsule suspensions can be prepared in a manner similar to the preparation of EW formulations but with an additional polymerisation stage such that an aqueous dispersion of oil droplets is obtained, in which each oil droplet is encapsulated by a polymeric shell and contains a compound of formula (I) and, optionally, a carrier or diluent therefor.
  • the compositions may provide for controlled release of the compound of formula (I) and they can be used for seed treatment.
  • a compound of formula (I) may also be formulated in a biodegradable polymeric matrix to provide a slow, controlled release of the compound.
  • a composition may include one or more additives to improve the biological performance of the composition (for example by improving wetting, retention or distribution on surfaces; resistance to rain on treated surfaces; or uptake or mobility of a compound of formula (I)).
  • additives include surface active agents, spray additives based on oils, for - 24 -
  • mineral oils or natural plant oils such as soya bean and rape seed oil
  • blends of these with other bio-enhancing adjuvants for example certain mineral oils or natural plant oils (such as soya bean and rape seed oil), and blends of these with other bio-enhancing adjuvants.
  • a compound of formula (I) may also be formulated for use as a seed treatment, for example as a powder composition, including a powder for dry seed treatment (DS), a water soluble powder (SS) or a water dispersible powder for slurry treatment (WS), or as a liquid composition, including a flowable concentrate (FS), a solution (LS) or a capsule suspension (CS).
  • DS powder for dry seed treatment
  • SS water soluble powder
  • WS water dispersible powder for slurry treatment
  • CS capsule suspension
  • the preparations of DS, SS, WS, FS and LS compositions are very similar to those of, respectively, DP, SP, WP, SC and SL compositions described above.
  • Compositions for treating seed may include an agent for assisting the adhesion of the composition to the seed (for example a mineral oil).
  • Wetting agents, dispersing agents and emulsifying agents may be of the cationic, anionic, amphoteric or non-ionic type.
  • Suitable agents of the cationic type include quaternary ammonium compounds (for example cetyltrimethyl ammonium bromide), imidazolines and amine salts.
  • Suitable anionic agents include alkali metals salts of fatty acids, salts of aliphatic monoesters of sulphuric acid (for example sodium lauryl sulphate), salts of sulphonated aromatic compounds (for example sodium dodecylbenzenesulphonate, butylnaphthalene sulphonate and mixtures of sodium diisopropyl- and triisopropyl-naphthalene sulphonates), ether sulphates, alcohol ether sulphates (for example sodium laureth-3-sulphate), ether carboxy lates (for example sodium laureth-3 -carboxy late), phosphate esters (products from the reaction between one or more fatty alcohols and phosphoric acid (predominately mono- esters) or phosphorus pentoxide (
  • Suitable agents of the non-ionic type include condensation products of ethylene oxide with fatty alcohols (such as oleyl alcohol or cetyl alcohol) or with alkylphenols (such as octylphenol, nonylphenol or octylcresol); partial esters derived from long chain fatty acids or hexitol anhydrides; condensation products of said partial esters with ethylene oxide; block polymers (comprising ethylene oxide and propylene oxide); alkanolamides; simple esters (for - 25 -
  • fatty acid polyethylene glycol esters or their ethoxylated derivatives
  • amine oxides for example lauryl dimethyl amine oxide
  • lecithins for example fatty acid polyethylene glycol esters
  • Suitable suspending agents include hydrophilic colloids (such as polysaccharides, polyvinylpyrrolidone or sodium carboxymethylcellulose) and swelling clays (such as bentonite or attapulgite).
  • hydrophilic colloids such as polysaccharides, polyvinylpyrrolidone or sodium carboxymethylcellulose
  • swelling clays such as bentonite or attapulgite
  • compositions for use as aqueous preparations are generally supplied in the form of a concentrate containing a high proportion of the active ingredient, the concentrate being added to water before use.
  • These concentrates which may include SLs, SCs, ECs, EWs, SGs, SPs, WPs, WGs and CSs, are often required to withstand storage for prolonged periods and, after such storage, to be capable of addition to water to form aqueous preparations which remain homogeneous for a sufficient time to enable them to be applied by conventional spray equipment.
  • Such aqueous preparations may contain varying amounts of a compound of formula (I) (for example 0.0001 to 10%, by weight) depending upon the purpose for which they are to be used.
  • a compound of formula (I) can be used in mixtures with fertilisers (for example nitrogen-, potassium- or phosphorus-containing fertilisers).
  • fertilisers for example nitrogen-, potassium- or phosphorus-containing fertilisers.
  • Suitable formulation types include granules of fertiliser.
  • the mixtures suitably contain up to 25% by weight of the compound of formula (I).
  • the invention therefore also provides a fertiliser composition comprising a fertiliser and a compound of formula (I).
  • compositions are applied to the pests or to a locus of the pests (such as a habitat of the pests, or a growing plant liable to infestation by the pests) by any of the known means of applying pesticidal compositions, for example by dusting, dipping, spraying or injecting or by irrigation, distribution or inco ⁇ oration of a composition (such as a granular composition or a composition packed in a water-soluble bag) in soil or an aqueous environment.
  • a composition such as a granular composition or a composition packed in a water-soluble bag
  • the compound of formula (I) may be the sole active ingredient of the composition or it may be admixed with one or more additional active ingredients such as a pesticide, synergist, herbicide, fungicide or plant growth regulator where appropriate.
  • An additional active ingredient may: provide a composition having a broader spectrum of activity or increased persistence at a locus; synergise the activity or complement the activity (for - 26 -
  • suitable pesticides include the following: a) Pyrethroids, such as permethrin, cypermethrin, fenvalerate, esfenvalerate, deltamethrin, cyhalothrin (in particular lambda-cyhalothrin), bifenthrin, fenpropathrin, cyfluthrin, tefluthrin, fish safe pyrethroids (for example ethofenprox), natural pyrethrin, tetramethrin, s-bioallethrin, fenfluthrin, prallethrin or 5-benzyl-3-furylmethyl-(E)-(lR,3S)-2,2-dimethyl- 3-(2-ox)
  • Chloronicotinyl compounds such as imidacloprid, acetamiprid, nitenpyram or thiomethoxam; m) Diacylhydrazines, such as tebufenozide; - 27 -
  • Diphenyl ethers such as diofenolan or pyriproxifen; o) Indoxacarb; p) Chlorfenapyr; or q) Pymetrozine.
  • other pesticides having particular targets may be employed in the composition, if appropriate for the intended utility of the composition.
  • selective insecticides for particular crops for example stemborer specific insecticides for use in rice (such as cartap or buprofezin) can be employed.
  • insecticides or acaricides specific for particular insect species/stages may also be included in the compositions (for example acaricidal ovo-larvicides, such as clofentezine, flubenzimine, hexythiazox or tetradifon; acaricidal motilicides, such as dicofol or propargite; acaricides, such as bromopropylate or chlorobenzilate; or growth regulators, such as hydramethylnon, cyromazine, methoprene, chlorfluazuron or diflubenzuron).
  • suitable synergists for use in the compositions include piperonyl butoxide, sesamex, safroxan and dodecyl imidazole.
  • Suitable herbicides, fungicides and plant-growth regulators for inclusion in the compositions will depend upon the intended target and the effect required.
  • a rice selective herbicide which can be included is propanil.
  • An example of a plant growth regulator for use in cotton is PIXTM.
  • Examples of fungicides for use in rice include blasticides, such as blasticidin-S.
  • Some mixtures may comprise active ingredients which have significantly different physical, chemical or biological properties such that they do not easily lend themselves to the same conventional formulation type.
  • other formulation types may be prepared.
  • one active ingredient is a water insoluble solid and the other a water insoluble liquid
  • the resultant composition is a suspoemulsion (SE) formulation.
  • EXAMPLE 1 This Example illustrates the preparation of 4-(5-bromopyrid-3-yl)-8-methyl-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 1 Table I) and 2-(5-bromopyrid-3-yl)-8-methyl- 8-azabicyclo[3.2.1]oct-2-ene (Compound No. 2 Table I).
  • the gum was dissolved in ethyl acetate (25ml), extracted into aqueous hydrochloric acid (2M, 2x20ml) and the acidic fractions combined.
  • the aqueous, acidic solution was made basic with excess sodium carbonate, extracted with ethyl acetate (2x20ml), dried ( magnesium sulfate) and evaporated under reduced pressure to give a gum, 0.24g.
  • the gum was fractionated using preparative thick layer chromatography (silica; eluent methanol [20% by volume] in ethyl acetate) to give: 4-(5-bromopyrid-3-yl)-8- methyl-8-azabicyclo[3.2.1]oct-2-ene, gum, (0.085g) and 2-(5-bromopyrid-3-yl)-8-methyl-8- azabicyclo[3.2.1]oct-2-ene, gum, (0.085g).
  • Stage 1 Preparation of 8-carboethoxy-8-azabicyclo[3.2.1]oct-2-ene.
  • Stage 2 using the appropriately substituted phenyl iodide and 8-methyl-8- azabicyclo[3.2. l]oct-2-ene.
  • the products were purified by preparative thick layer chromatography (basic alumina; hexane:ethyl acetate, 4:1 by volume).
  • 3,5-Dibromopyridine (12g) was dissolved in diethyl ether (250ml,dry) with stirring under an atmosphere of nitrogen and cooled to -78 °C.
  • a solution of n-butyl lithium (20ml of a hexane solution, 2.5M) was added dropwise maintaining the reaction temperature below -70°C, producing a thick yellow suspension.
  • the mixture was stirred for 0.25hour at -78°C then a solution of iodine (15g) in diethyl ether (100ml, dry) was added dropwise over lhour. On complete addition the reaction was allowed to warm to -30°C, water (10ml) was added and the cold mixture was dissolved in 50% aqueous hydrochloric acid.
  • the reaction solution was decanted leaving a residual black gum which was extracted with a mixture of aqueous ammonia (25ml, density 0.88) and toluene (50ml).
  • the toluene extract was combined with the decanted solution, further toluene (25ml) added and the mixture washed with further aqueous ammonia (25ml).
  • the organic phase was separated, dried(magnesium sulfate) then evaporated under reduced pressure to give a brown oil.
  • the oil was fractionated by thick layer chromatography (silica; dichloromethane / methanol, 9:1 by volume) to give 4-(5- chloropyrid-3-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (0.041g, oil) and 2-(5-chloropyrid- 3-yl)-8-methyl-8-azabicyclo [3.2.1]oct-2-ene (0.018g, oil).
  • the aqueous acidic phase was then basified with sodium carbonate and extracted with ethyl acetate (three times). The extracts were combined, dried (magnesium sulfate) and evaporated under reduced pressure to give an orange oil.
  • the oil was fractionated by preparative thick layer chromatography (silica, dichloromethane / methanol, 4: 1 by volume) to give 4-(5-bromopyrid-3-yl)-8- azabicyclo[3.2.1]oct-2-ene, 0.10g, as an orange oil.
  • the basic mixture was extracted with diethyl ether (100ml) and the organic phase separated then washed with water, dried (magnesium sulfate) and evaporated under reduced pressure to give a brown liquid.
  • the liquid was heated at 100°C under vacuum (20mm Hg) to leave a brown oil.
  • the oil was fractionated by chromatography (silica; dichloromethane then 5% methanol in dichloromethane) to give the required product, 0.042g, as an orange oil.
  • EXAMPLE 8 This Example illustrates the preparation of 4-(5,6-dichloropyrid-3-yl)-8-methyl-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 57 Table I). 8-Methyl-8-azabicyclo[3.2. l]oct-2-ene (1.50g) and 2,3-dichloro-5-iodopyridine
  • the mixture was poured into aqueous ammonia solution and extracted with ethyl acetate (three times).
  • the organic extracts were combined and extracted twice with aqueous hydrochloric acid (2M) and the organic phase discarded.
  • the aqueous acidic extracts were combined then treated with sodium carbonate until basic.
  • the aqueous mixture was extracted three times with ethyl acetate and the organic extracts were combined and then dried (magnesium sulfate).
  • the solvent was evaporated under - 37 -
  • the aqueous mixture was extracted with ethyl acetate (three times) and the organic extracts were combined and then washed with an aqueous solution of ammonium chloride.
  • the organic phase was dried (magnesium sulfate) and evaporated under reduced pressure to give a yellow oil which was fractionated by chromatography (silica; 10% ethyl acetate in hexane ). The fractions containing the required product were evaporated under reduced pressure (O.lmmHg, 50°C) to give a yellow gum (0.485g).
  • EXAMPLE 11 This Example illustrates the preparation of 4-(6-chloropyrid-3-yl)-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 99 Table I). 4-(6-Chloropyrid-3-yl)-8-vinyloxycarbonyl-8-azabicyclo[3.2.1 ]oct-2-ene (Compound No. 99 Table I). 4-(6-Chloropyrid-3-yl)-8-vinyloxycarbonyl-8-azabicyclo[3.2.1 ]oct-2-ene (Compound No. 99 Table I). 4-(6-Chloropyrid-3-yl)-8-vinyloxycarbonyl-8-azabicyclo[3.2.1 ]oct-2-ene (Compound No. 99 Table I). 4-(6-Chloropyrid-3-yl)-8-vinyloxycarbonyl-8-azabicyclo[3.2.1 ]oct-2-ene (Compound No.
  • EXAMPLE 12 This Example illustrates the preparation of 4-(5-bromopyrid-3-yl)-8-(but-2-ynyl)-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 40 Table I).
  • EXAMPLE 14 This Example illustrates the preparation of 8-allyl-4-(6-chloropyrid-3-yl)-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 101 Table I).
  • EXAMPLE 15 This Example illustrates the preparation of 2-(3-nitro-4-methoxyphenyl)-8-methyl-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 126 Table I) and 4-(3-nitro-4-methoxyphenyl)-8- methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 127 Table I).
  • the aqueous layer was separated and basified with aqueous sodium hydroxide and extracted with ethyl acetate.
  • the ethyl acetate layer was dried (magnesium sulfate) and the solvent evaporated to leave a mixture of the 2- and 4- substituted products.
  • This mixture was purified by chromatography on silica eluting with methanol : dichloromethane : triethylamine (in the ratio 5:94: 1) and then on a preparative - 40 -
  • the ethyl acetate layer was then extracted with dilute aqueous hydrochloric acid.
  • the aqueous layer was separated and basified with aqueous NaOH and extracted with ethyl acetate.
  • the ethyl acetate layer was dried (magnesium sulfate) and the solvent evaporated to leave the crude product. This was purified by chromatographing twice on silica, eluting with methanol : dichloromethane : triethylamine (in the ratio 5:93:2) to give the product as a gum (0.012g).
  • EXAMPLE 17 This Example illustrates the preparation of 4-ex ⁇ -[(l,3-dimethylbenzimidazolin-2- one)-5-yl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 136 Table I). - 41 -
  • EXAMPLE 18 This Example illustrates the preparation of 4-exo-[(6-methoxybenzoxazol-2-one)-5- yl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 133 Table I). Stage 1 : Preparation of 5-bromo-6-methoxybenzoxazol-2-one.
  • 6-Methoxybenzoxazol-2-one (0.774g, 4.7mmol) was dissolved in dichloromethane (15ml) and the solution cooled to 0°C (ice bath). Bromine (0.24ml, 4.7mmol) in dichloromethane (5ml) was added dropwise and the mixture was left to warm to room temperature overnight, during which time a precipitate formed. This was filtered to give the crude product. Recrystallisation from ethyl acetate/hexane gave the pure product as a pink solid (0.59g). Stage 2:
  • Example 133 Table I was prepared by a similar method to that described in Example 16. The product was obtained as a white solid.
  • EXAMPLE 23 This Example illustrates the preparation of 4-ex ⁇ -[(3-methylbenzoxazol-2-one)-6-yl]- 8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2. l]oct-2-ene (Compound No. 139 Table I).
  • a solution of trifluoroethanol (13 ⁇ l) and diisopropylethylamine (30 ⁇ l) in dichloromethane (1ml) was added slowly to a solution of triflic anhydride (30 ⁇ l) in dichloromethane (4ml) at -50°C under a nitrogen atmosphere.
  • reaction mixture was sti ⁇ ed at -50°C for lhour and then allowed to warm to room temperature and sti ⁇ ed for a further lhour.
  • the mixture was then added to 4-eJ ⁇ -[(3-methylbenzoxazol-2-one)-6-yl]-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 131 Table I) (0.022g, prepared as described in Example 21, Method 2) and diisopropylethylamine (30 ⁇ l).
  • Stage 2 Preparation of 4-exo-(5-chloro-3 ,4-methylenedioxyphenyl)-8-methyl-8- azabicyclo[3.2.1 ]oct-2-ene.
  • EXAMPLE 26 This Example illustrates an emulsifiable concentrate composition which is readily convertible, by addition to water, into a preparation suitable for spraying purposes.
  • the emulsifiable concentrate has the following composition:
  • EXAMPLE 27 This Example illustrates a wettable powder composition which is readily convertible, by addition to water, into a preparation suitable for spraying purposes.
  • the wettable powder has the following composition:
  • EXAMPLE 28 This Example illustrates a dustable powder which may be applied directly to plants or other surfaces.
  • the dustable powder has the following composition:
  • This Example illustrates an oil miscible liquid formulation suitable for application by ultra low volume techniques after mixing with an organic diluent.
  • the formulation has the following composition:
  • This Example illustrates a capsule suspension concentrate which is readily convertible, by addition to water, into a preparation suitable for application as an aqueous spray.
  • the capsule suspension concentrate has the following composition:
  • EXAMPLE 31 This Example illustrates a ready for use granular formulation that is prepared from a pre-formed granular carrier.
  • the granular formulation has the following composition:
  • This Example illustrates a ready for use granular formulation that is prepared by granulation of the powdered components.
  • the granular formulation has the following composition:
  • This Example illustrates an aqueous suspension concentrate composition which is readily convertible, by addition to water, into a preparation suitable for spraying purposes.
  • the suspension concentrate has the following composition:
  • EXAMPLE 34 This Example illustrates a water dispersible granule formulation which is readily convertible, by addition to water, into a preparation suitable for spraying purposes.
  • the water dispersible granule has the following composition:
  • EXAMPLE 35 This Example illustrates the pesticidal properties of compounds of formula (I).
  • the activities of individual compounds of formula (I) were determined using a variety of pests. With the exception of nematodes, the pests were treated with a liquid composition containing 500 parts per million (ppm) by weight of a compound unless otherwise stated. Each composition was made by dissolving the compound in an acetone and ethanol (50:50 by volume) mixture and diluting the solution with water containing 0.05% by volume of a wetting agent, SYNPERONIC NP8, until the liquid composition contained the required concentration of the compound.
  • a wetting agent SYNPERONIC NP8
  • test procedure adopted with regard to each pest was essentially the same and comprised supporting a number of the pests on a medium which was usually a substrate, a host plant or a foodstuff on which the pests feed, and treating either or both the medium and the pests with a composition.
  • Pest mortality was assessed usually between two and five days after treatment.
  • Knockdown of housefly was assessed 15 minutes after treatment.
  • results of the tests against peach aphid are presented below.
  • the results indicate a grading of mortality (score) designated as A, B or C wherein C indicates less than 40% mortality, B indicates 40-79% mortality and A indicates 80-100%) 50
  • the test procedure for nematodes involved dissolving the compound in an acetone and ethanol (50:50 by volume) mixture and diluting the solution with water to obtain a final concentration of the compound of 12.5ppm.
  • J2 infective juveniles of Meloidogyne incognita were suspended in the solution in a glass vial and mortality assessed after a period of three days; Compound No. 112 of Table I gave a mortality score of A whilst Compound Nos. 3, 35 and 105 of Table I each gave a mortality score of B.

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Abstract

A compound of formula (I), wherein one of R?1 and R2¿ is hydrogen and the other is a phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, benzoxazol-2-one or benzimidazolin-2-one ring, said ring being optionally substituted with halogen, C¿1-6? alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, hydroxy, nitro, cyano or methylenedioxy; R is hydrogen, formyl, C1-6 alkyl (optionally substituted with cyano, CO2(C1-6 alkyl) or phenyl (itself optionally substituted with halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl or C1-6 haloalkoxy)), CH2(C1-6 haloalkyl), CO2(C1-6 alkyl), CO2(C2-6 alkenyl), CH2(C2-6 alkenyl), CH2(C2-6 alkynyl), benzyl (wherein the phenyl ring is optionally substituted with halogen or C1-4 alkyl) or XR?3¿; X is O or NR?4; R3 and R4¿ are, independently, hydrogen, cyano, C¿1-6? alkyl (optionally substituted with halogen, cyano, CO2(C1-6 alkyl) or phenyl (itself optionally substituted with halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl or C1-6 haloalkoxy)), phenyl (itself optionally substituted with halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl or C1-6 haloalkoxy), C2-6 alkenyl or C2-6 alkynyl; or an acid addition salt or N-oxide thereof, processes for preparing these compounds, compositions comprising them and methods of using them to combat or control insects, acarines, nematodes or molluscs.

Description

8-AZABICYCL0(3.2.1)0CT-2-ENE DERIVATIVES AS PESTICIDES
The present invention relates to 8-azabicyclo[3.2.1]oct-2-ene derivatives, to processes for preparing them, to insecticidal, acaricidal, molluscicidal and nematicidal compositions comprising them and to methods of using them to combat or control insect, acarine, mollusc or nematode pests.
Certain 2-[3-substituted-l,2,4-oxadiazol-5-yl]-8-azabicyclo[3.2. l]oct-2-enes are disclosed in Pharm. Res. 1992, 9(11), 1474-9 as potential mammalian muscarinic acetyl choline receptor agonists. Pharmaceutical 3-substituted-8-azabicyclo[3.2.1]oct-2-enes are disclosed in WO97/ 13770. Insecticidal l-azabicyclo[3.2.1]oct-2-enes are disclosed in WO93/14636 and insecticidal 3-cyano-3-substituted-8-azabicyclo[3.2.1]octanes are described in WO96/37494. Certain 2-pyridyl-8-azabicyclo[3.2.1]oct-2-enes are disclosed in ret. Eett. 38(32) 5619-22 as intermediates for the synthesis of epibatidine analogues. Certain 8-azabicyclo[3.2.1]oct-2-enes are disclosed as intermediates in EP0604352. The present invention provides a compound of formula (I), wherein one of R1 and R2 is hydrogen and the other is a phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, benzoxazol-2-one or benzimidazolin-2-one ring, said ring being optionally substituted with halogen, C,^ alkyl, C,.6 haloalkyl, C,^ alkoxy, C,^ haloalkoxy, C2^ alkenyl, C2.6 alkynyl, hydroxy, nitro, cyano or methylenedioxy; R is hydrogen, formyl, C,^ alkyl (optionally substituted with cyano, CO2(Cw alkyl) or phenyl (itself optionally substituted with halogen, CM alkyl, CM alkoxy, Cw haloalkyl or CM haloalkoxy)), CH^C,^ haloalkyl), CO2(CM alkyl), CO2(C2^ alkenyl), CH2(C2^ alkenyl), CH2(CM alkynyl), benzyl (wherein the phenyl ring is optionally substituted with halogen or CM alkyl) or XR3; X is O or NR4; R3 and R4 are, independently, hydrogen, cyano, Cw alkyl (optionally substituted with halogen, cyano, CO2(C^ alkyl) or phenyl (itself optionally substituted with halogen, C,^ alkyl, C,^ alkoxy, Cw haloalkyl or C 6 haloalkoxy)), phenyl (itself optionally substituted with halogen, C1-6 alkyl, C1-6 alkoxy, Cw haloalkyl or Cw haloalkoxy), C2^ alkenyl or CM alkynyl; or an acid addition salt or N-oxide thereof; provided that when R is methyl, CO2CH3 or CO2CH2CH3 then R2 is not a 6-substituted pyrid-3-yl; that when R is other than hydrogen or CH2(CW) haloalkyl then R2 is not phenyl substituted with hydroxy or alkoxy; and that when R1 is hydrogen and R is hydrogen, unsubstituted Cl 6 alkyl, CH2(CW alkenyl) or CH2(C2^ alkynyl) - 2 -
then R2 is not a pyridyl, pyrimidinyl, pyrazinyl, thienyl or thiazolyl ring (said ring being unsubstituted or substituted by unsubstituted alkyl only).
Halogen includes fluorine, chlorine, bromine and iodine.
Alkyl moieties preferably contain from 1 to 6, more preferably from 1 to 4, carbon atoms. They can be in the form of straight or branched chains, for example methyl, ethyl, n- or iso-propyl, or n-, sec-, iso- or tert-butyl.
Alkenyl and alkynyl moieties can be in the form of straight or branched chains, and alkenyl moieties can be of either (E)- or (Z)-confιguration. Examples are vinyl, allyl and propargyl. When R is CH2(CW haloalkyl) it is preferred that it is CH2(C^ fluoroalkyl) (for example, 2,2-difluoroethyl or 2,2,2-trifluoroethyl).
Suitable acid addition salts include those with an inorganic acid such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, or an organic carboxylic acid such as oxalic, tartaric, lactic, butyric, toluic, hexanoic and phthalic acids, or sulphonic acids such as methane, benzene and toluene sulphonic acids. Other examples of organic carboxylic acids include haloacids such as trifluoroacetic acid.
In one aspect the present invention provides a compound of formula (I), wherein one of R1 and R2 is hydrogen and the other is a phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl or thiazolyl ring, said ring being optionally substituted with halogen, Cw alkyl, Cw haloalkyl, Cw alkoxy, C,_6 haloalkoxy, CM alkenyl, C2^ alkynyl or cyano; R is hydrogen, formyl, Cw alkyl (optionally substituted with cyano, CO2(Cw alkyl) or phenyl (itself optionally substituted with halogen, Cw alkyl, Cw alkoxy, C,^ haloalkyl or C,^ haloalkoxy)), CH^C. haloalkyl, CO2(Cw alkyl), CH2(C2^)alkenyl, CH2(C2 alkynyl or XR3; X is O or NR4; R3 and R4 are, independently, hydrogen, cyano, C,^ alkyl (optionally substituted with halogen, cyano, CO2(C,.6 alkyl) or phenyl (itself optionally substituted with halogen, C,^ alkyl, C,^ alkoxy, C,^ haloalkyl or C,^ haloalkoxy)), phenyl (itself optionally substituted with halogen, C,^ alkyl, C alkoxy, C,^ haloalkyl or C,.6 haloalkoxy), CM alkenyl or C2^ alkynyl; or an acid addition salt or N-oxide thereof; provided that when R is methyl, CO2CH3 or CO2CH2CH3 then R2 is not a 6-substituted pyrid-3-yl; that when R is other than CH2(C^) haloalkyl then R2 is not phenyl substituted with hydroxy or alkoxy; and that when R1 is hydrogen and R is hydrogen, unsubstituted C,^ alkyl, CH2(C2^ alkenyl) or CH2(C2^ alkynyl) - 3 -
then R2 is not a pyridyl, pyrimidinyl, pyrazinyl, thienyl or thiazolyl ring (said ring being unsubstituted or substituted by unsubstituted alkyl only).
In another aspect the present invention provides a compound of formula (I), wherein one of R1 and R2 is hydrogen and the other is a phenyl, pyrid-2-yl, pyrid-3-yl, pyrimidin-5-yl, pyrazin-2-yl, thien-2-yl, thiazol-5-yl, (benzoxazol-2-one)-5-yl, (benzoxazol-2-one)-6-yl or (benzimidazolin-2-one)-5-yl ring, said ring being optionally substituted with halogen (especially chlorine or bromine), CM alkyl (especially methyl), CM alkoxy (especially methoxy), C2 alkenyl, C2^, alkynyl, hydroxy, nitro or methylenedioxy.
In another aspect the present invention provides a compound of formula (I), wherein R is hydrogen, formyl (CHO), C alkyl (especially methyl), CO2(C,^ alkyl) (especially CO2methyl or CO2ethyl), CO2(C2^ alkenyl) (especially CO2ethenyl), CH2(C^ haloalkyl) (especially CH2CF3), benzyl (wherein the phenyl ring is optionally substituted with halogen or CM alkyl), CH2(C2^ alkenyl) (especially allyl) or CH2(C2^ alkynyl) (especially propargyl or but-2-ynyl). In yet another aspect the present invention provides a compound of formula (I), wherein R2 is hydrogen.
In a further aspect the present invention provides a compound of formula (I), wherein R is hydrogen, formyl (CHO), C alkyl (especially methyl), CO2(C,^ alkyl) (especially CO2methyl or CO2ethyl), CO2(CM alkenyl) (especially CO2ethenyl), CH2(C,^ haloalkyl) (especially CH2CF3), CH2(C2.6 alkenyl) (especially allyl), CH2(C2^ alkynyl) (especially propargyl or but-2-ynyl) or benzyl (wherein the phenyl ring is optionally substituted with halogen (especially fluorine)); R1 is phenyl (optionally substituted with halogen (especially chlorine), C alkoxy (especially methoxy, hydroxy, nitro or methylenedioxy), pyrid-2-yl (optionally substituted with halogen (especially chlorine or bromine)), pyrid-3-yl (optionally substituted with halogen (especially chlorine or bromine)), pyrimid-5-yl, thien-2-yl
(optionally substituted by C alkyl (especially methyl)), thiazol-5-yl (optionally substituted by CM alkyl (especially methyl) or halogen (especially chlorine)), pyrazin-2-yl (optionally substituted by halogen (especially chlorine)), (benzoxazol-2-one)-5-yl (optionally substituted by C,_4 alkoxy (especially methoxy)), (benzoxazol-2-one)-6-yl (optionally substituted by CM alkyl (especially methyl)) or (benzimidazolin-2-one)-5-yl (optionally substituted by CM alkyl (especially methyl)); and R2 is hydrogen. - 4 -
In a still further aspect the present invention provides a compound of formula (I), wherein R is hydrogen, formyl (CHO), CM alkyl (especially methyl), CO2(C alkyl) (especially CO2methyl or CO2ethyl), CO2(CM alkenyl) (especially CO2ethenyl), CH2(CW haloalkyl) (especially CH2CF3), CH2(C2^ alkenyl) (especially allyl), CH2(CM alkynyl) (especially propargyl or but-2-ynyl) or benzyl (wherein the phenyl ring is optionally substituted with halogen (especially fluorine)); R1 is hydrogen; and R2 is phenyl (optionally substituted with halogen (especially fluorine or chlorine), CM alkoxy (especially methoxy), nitro or methylenedioxy), pyrid-2-yl (optionally substituted with halogen (especially chlorine or bromine)), pyrid-3-yl (optionally substituted with halogen (especially chlorine or bromine)) or (benzimidazolin-2-one)-5-yl (optionally substituted with CM alkyl (especially methyl)).
Specific compounds of formula (I) are set out in Table I. Throughout Table I R1 is on the β-face of the molecule (that is R1 is on the opposite side of the molecule to the dimethylene bridge, ie it is axial or exo). Table I
Compound R El E!
No.
1 CH3 5 -bromopyrid-3 -yl H
2 CH3 H 5-bromopyrid-3-yl
3 CO2CH2CH3 6-chloropyrid-3 -y 1 H
4 CH3 phenyl H
5 CH3 2-chlorophenyl H
6 CH3 3-chlorophenyl H
7 CH3 4-chlorophenyl H
8 CH3 4-fluorophenyl H
9 CH3 2-methylphenyl H
10 CH3 3-methylphenyl H
11 CH3 4-methylphenyl H
12 CO2CH2CH3 5-bromopyrid-3-yl H
13 H pyrid-3-yl H
Figure imgf000006_0001
14 CH2CF3 pyrid-3-yl H - 5 -
CH2CH— CH2 pyrid-3-yl H
CH2C=CCH3 pyrid-3-yl H
CHO pyrid-3-yl H
CO2CH3 pyrid-3-yl H
CH3 pyrid-3-yl H
CO2CH2CH3 pyrid-3-yl H
H 5-methylthien-2-yl H
CH2CF3 5-methylthien-2-yl H
CH2CH=:CH2 5-methylthien-2-yl H
CH2C=CCH3 5-methylthien-2-yl H
CHO 5-methylthien-2-yl H
CO2CH3 5-methylthien-2-yl H
CH3 5-methylthien-2-yl H
CO2CH2CH3 5-methylthien-2-yl H
H 5-chloropyrid-3-yl H
CH2CF3 5-chloropyrid-3-yl H
CH^H^C^ 5-chloropyrid-3-yl H H2 "*= H3 5-chloropyrid-3-yl H
CHO 5 -chloropyrid-3 -yl H
CO2CH3 5 -chloropyrid-3 -yl H
CH3 5-chloropyrid-3-yl H
CO2CH2CH3 5 -chloropyrid-3 -yl H
H 5-bromopyrid-3-yl H
CH2CF3 5-bromopyrid-3-yl H
CH2CH— CH2 5-bromopyrid-3-yl H
CH2C=CCH3 5-bromopyrid-3-yl H
CHO 5-bromopyrid-3-yl H
CO2CH3 5-bromopyrid-3-yl H
H 2-chloropyrid-3 -yl H
CH2CF3 2-chloropyrid-3 -y 1 H
Figure imgf000007_0001
CH2CH=:CH2 2-chloropyrid-3-yl H - 6 -
CH2C=CCH3 2-chloropyrid-3 -yl H
CHO 2-chloropyrid-3 -yl H
CO2CH3 2-chloropyrid-3 -yl H
CH3 2-chloropyrid-3 -yl H
CO2CH2CH3 2-chloropyrid-3 -yl H
H 5 ,6-dichloropyrid-3 -yl H
CH2CF3 5 ,6-dichloropyrid-3 -yl H
CH2CH=CH 5 ,6-dichloropyrid-3 -yl H
CH2 =CCH3 5,6-dichloropyrid-3-yl H
CHO 5,6-dichloropyrid-3-yl H
CO2CH3 5,6-dichloropyrid-3-yl H
CH3 5,6-dichloropyrid-3-yl H
CO2CH2CH3 5,6-dichloropyrid-3 -yl H
H pyrimid-5-yl H
CH2CF3 pyrimid-5-yl H
CH2CH=CH2 pyrimid-5-yl H
CH2C=CCH3 pyrimid-5-yl H
CHO pyrimid-5-yl H
CO2CH3 pyrimid-5-yl H
CH3 pyrimid-5-yl H
CO2CH2CH3 pyrimid-5-yl H
H 6-chloropyrazin-2-yl H
CH2CF3 6-chloropyrazin-2-yl H
CH2CH*=CH2 6-chloropyrazin-2-yl H
CH2C=CCH3 6-chloropyrazin-2-yl H
CHO 6-chloropyrazin-2-yl H
CO2CH3 6-chloropyrazin-2-yl H
CH3 6-chloropyrazin-2-yl H
CO2CH2CH 6-chloropyrazin-2-yl H
H 2-chlorothiazol-5 -yl H
Figure imgf000008_0001
CH2CF3 2-chlorothiazol-5-yl H - 7 -
77 CHjCH— CH2 2-chlorothiazol-5-yl H
78 CH2C=CCH3 2-chlorothiazol-5-yl H
79 CHO 2-chlorothiazol-5 -yl H
80 CO2CH3 2-chlorothiazol-5-yl H
81 CH3 2-chlorothiazol-5-yl H
82 CO2CH2CH3 2-chlorothiazol-5-yl H
83 H 2-methylthiazol-5-yl H
84 CH2CF3 2-methylthiazol-5-yl H
85 CH2CH=CH2 2-methylthiazol-5-yl H
86 CH2C≡CCH3 2-methy lthiazol-5 -yl H
87 CHO 2-methylthiazol-5-yl H
88 CO2CH3 2-methylthiazol-5-yl H
89 CH3 2-methylthiazol-5-yl H
90 CO2CH2CH3 2-methylthiazol-5-yl H
91 H thien-2-yl H
92 CH2CF3 thien-2-yl H
93 CH2CH*=CH2 thien-2-yl H
94 CH2C=CCH3 thien-2-yl H
95 CHO thien-2-yl H
96 CO2CH3 thien-2-yl H
97 CH3 thien-2-yl H
98 CO2CH2CH3 thien-2-yl H
99 H 6-chloropyrid-3 -yl H
100 CH2CF3 6-chloropyrid-3 -y 1 H
101 CH2CH=CH2 6-chloropyrid-3 -yl H
102 CH2C= CH 6-chloropyrid-3 -yl H
103 CHO 6-chloropyrid-3 -yl H
104 CO2CH3 6-chloropyrid-3 -yl H
105 CH3 6-chloropyrid-3 -y 1 H
106 H H 6-chloropyrid-3 -yl
Figure imgf000009_0001
107 CH2CF3 H 6-chloropyrid-3 -yl - 8 -
108 CH2CH— H2 H 6-chloropyrid-3 -yl
109 CH2C=CCH3 H 6-chloropyrid-3 -yl
110 CHO H 6-chloropyrid-3 -yl
111 CO2CH3 H 6-chloropyrid-3 -y 1
112 CH3 H 6-chloropyrid-3 -yl
113 CO2CH2CH3 H 6-chloropyrid-3 -yl
114 H H 5-chloropyrid-3-yl
115 CH2CF3 H 5-chloropyrid-3-yl
116 CH2CH=CH2 H 5-chloropyrid-3-yl
117 CH2C≡CCH3 H 5 -chloropyrid-3 -y 1
118 CHO H 5 -chloropyrid-3 -y 1
119 CO2CH3 H 5 -chloropyrid-3 -y 1
120 CH3 H 5 -chloropyrid-3 -y 1
121 CO2CH2CH3 H 5 -chloropyrid-3 -yl
122 CO2CH=CH2 6-chloropyrid-3 -yl H
123 CO2CH=CH2 5-chloropyrid-3-yl H
124 4-fluorobenzyl 6-chloropyrid-3 -yl H
125 CH3 2-hydroxy-5 -chlorophenyl H
126 CH3 H 3 -nitro-4-methoxyphenyl
127 CH3 3 -nitro-4-methoxyphenyl H
128 CH3 2,4-(dimethoxy)phenyl H
129 CH3 H 2-fluoro-4-chlorophenyl
130 CH3 H pyrid-2-yl
131 H (3 -methy lbenzoxazol-2- H one)-6-yl
132 benzyl (3 -methy lbenzoxazol-2- H one)-6-yl
133 CH3 (6-methoxybenzoxazol-2- H one)-5-yl
134 CO2CH3 (3 -methy lbenzoxazol-2- H
Figure imgf000010_0001
one)-6-yl - 9 -
135 CH3 H (1,3- dimethylbenzimidazolin-
2-one)-5-yl
136 CH3 (1,3- H dimethylbenzimidazolin-2- one)-5-yl
137 CH3 (3 -methy lbenzoxazol-2- H one)-6-yl
138 CH3 (1 -methy lbenzimidazolin-2- H one)-5-yl
139 CH2CF3 (3 -methy lbenzoxazol-2- H one)-6-yl
140 CH3 3 ,4-methy lenedioxyphenyl H
141 benzyl 3 ,4-methylenedioxyphenyl H
142 H 3 ,4-methylenedioxyphenyl H
143 CO2CH3 3 ,4-methylenedioxyphenyl H
144 CH3 H 2-chloro-4,5- methylenedioxyphenyl
145 H 5-bromo-6-chloropyrid-3 -yl H
146 H 5-chloro-6-bromopyrid-3-yl H
147 H 5-fluoro-6-chloropyrid-3-yl H
148 H 5-chloro-6-fluoropyrid-3-yl H
149 CH2CF3 5-bromo-6-chloropyrid-3-yl H
150 CH2CF3 5-chloro-6-bromopyrid-3-yl H
151 CH2CF3 5 -fluoro-6-chloropyrid-3 -yl H
152 CH2CF3 5 -chloro-6-fluoropyrid-3 -yl H
153 CH CH=CH2 5-bromo-6-chloropyrid-3-yl H
154 CH2CH=CH2 5 -chloro-6-bromopyrid-3 -yl H
155 CH CH=CH2 5-fluoro-6-chloropyrid-3-yl H
156 CH CH=CH2 5-chloro-6-fluoropyrid-3-yl H
Figure imgf000011_0001
157 CH2C=CCH3 5-bromo-6-chloropyrid-3 -yl H - 10 -
158 CH2C=CCH3 5-chloro-6-bromopyrid-3-yl H
159 CH2C=CCH3 5-fluoro-6-chloropyrid-3-yl H
160 CH2C**=CCH3 5-chloro-6-fluoropyrid-3-yl H
161 CHO 5-bromo-6-chloropyrid-3-yl H
162 CHO 5-chloro-6-bromopyrid-3-yl H
163 CHO 5-fluoro-6-chloropyrid-3-yl H
164 CHO 5-chloro-6-fluoropyrid-3-yl H
165 CO2CH3 5-bromo-6-chloropyrid-3-yl H
166 CO2CH3 5-chloro-6-bromopyrid-3-yl H
167 CO2CH3 5-fluoro-6-chloropyrid-3-yl H
168 CO2CH3 5-chloro-6-fluoropyrid-3-yl H
169 CH3 5-bromo-6-chloropyrid-3-yl H
170 CH3 5-chloro-6-bromopyrid-3-yl H
171 CH3 5-fluoro-6-chloropyrid-3-yl H
172 CH3 5-chloro-6-fluoropyrid-3-yl H
173 CO2CH2CH3 5-bromo-6-chloropyrid-3-yl H
174 CO2CH2CH3 5-chloro-6-bromopyrid-3-yl H
175 CO2CH2CH3 5-fluoro-6-chloropyrid-3-yl H
Figure imgf000012_0001
176 CO2CH2CH3 5-chloro-6-fluoropyrid-3-yl H
The following abbreviations are used throughout this description: mp = melting point (uncorrected) ppm = parts per million bp = boiling point (uncorrected) br = broad s = singlet 2br = two broad signals d = doublet dd = doublet of doublets t = triplet 2dd = two doublets of doublets q = quartet dt = doublet of triplets m = multiplet 11
Table II shows selected melting point and selected NMR data, all with CDC13 as the solvent (unless otherwise stated), (no attempt is made to list every absorption in all cases) for compounds of Table I.
Table II
Compound Melting NMR proton shifts (/ppm). Comments No. point (/°C)
1 1.60-2.30(4H,br.signals); 2.15(3H,s); 3.05(lH,br.d); 3.15(1H, br.d); 3.40(1H, br.t); 5.45(1H, 2dd); 6.15(1H, 2dd); 8.00(lH,t); 8.45(lH,d); 8.50(lH,d).
2 1.60-2.30(5H,br.signals); 2.40(3H,s); 2.70(lH,br.d); 3.30(1H, br.t); 3.65(1H, br.d); 6.00(1H, br.t); 7.85(lH,t); 8.50(lH,d); 8.55(lH,d).
3 0.85 and 1.25(3H,br.signals); 1.75- Mixture of 2.00(3H,m); 2.20-2.35(lH,m); 3.28(lH,m); rotational 3.75 and 4.05(2H, br.signals); 4.32 and isomers. 4.45(1H, br.signals); 4.65(lH,m); 5.54(1 H,m); 6.28(1 H,br.signal); 7.25(1 H,d); 7.50(lH,br.signal); 8.25(lH,d).
4 1.55-1.70(lH,m); 1.80-1.90(lH,m); 2.00- 2.30(5H,m); 3.08(lH,m); 3.25(lH,dd); 3.35(lH,t); 5.55(lH,m); 6.12(lH,m); 7.10- 7.40(5H,m).
5 1.60-1.72(lH,m); 1.82-1.92(lH,m); 2.00- 2.30(5H,m); 3.24(lH,dd); 3.38(lH,t); 3.50(lH,m); 5.48(lH,m); 6.18(lH,m); 7.10- 7.26(2H,m); 7.35(lH,dd); 7.48(lH,dd).
6 1.50-1.65(lH,m); 1.82-1.92(lH,m); 2.00- 2.30(5H,m); 3.05(lH,m); 3.20(lH,dd); 3.35(lH,t); 5.48(lH,m); 6.14(lH,m); 7.10- 7.26(3H,m); 7.40(lH,m).
7 1.54-1.66(lH,m); 1.82-1.92(lH,m); 2.00- 2.30(5H,m); 3.04(lH,m); 3.18(lH,dd); 3.35(lH,t); 5.48(lH,m); 6.12(lH,m); 7.20- 7.35(4H,m).
8 1.54-1.66(lH,m); 1.80-1.92(lH,m); 2.00- 2.30(5H,m); 3.04(lH,m); 3.18(lH,dd); 3.35(lH,t); 5.50(lH,m); 6.12(lH,m); 6.92- 7.00(2H,m); 7.28-7.38(2H,m).
9 1.58-1.70(lH,m); 1.84-1.94(lH,m); 2.02- 2.30(5H,m); 2.35(3H,s); 3.12(lH,dd); 3.25(lH,m); 3.38(lH,t); 5.48(lH,m);
Figure imgf000013_0001
6.18(lH,m); 7.087.20(3H,m); 7.45(lH,dd). 12
10 1.54-1.67(lH,m); 1.82-1.92(lH,m); 2.00- 2.30(5H,m); 2.35(3H,s); 3.04(lH,m); 3.26(lH,dd); 3.35(lH,t); 5.55(lH,m); 6.12(lH,m); 6.98-7.04(1 H,m); 7.12- 7.20(3H,m).
11 1.54-1.67(1 H,m); 1.82-1.92(lH,m); 2.00- 2.30(5H,m); 2.32(3H,s); 3.04(lH,m); 3.22(lH,dd); 3.35(lH,t); 5.54(lH,m); 6.10(lH,m); 7.10(2H,d); 7.26(2H,d).
12 0.85 and 1.25(3H, br.signals); 1.75 - Mixture of 2.00(3H,m); 2.20-2.35(lH,br.signal); rotational 3.28(lH,d); 3.70-4.20(2H,2br. signals); 4.3- isomers. 4.5(lH,br.signal); 4.60-4.75(lH,br.signal); 5.55(lH,m); 6.20-6.40(lH, br.signal); 7.68(lH,t); 8.40(lH,d); 8.57(lH,d).
19 1.60-1.70(lH,m); 1.90(lH,m); 2.00- 2.30(5H,m); 3.00-3.20(2H,m); 3.35(lH,m); 5.45(lH,m); 6.15(lH,m); 7.10-7.30(lH,m); 7.75(lH,d); 8.30-8.80(2H,br.signal).
30 1.75-2.20(4H,m); 2.55-2.95(2H,m); 3.10(lH,m); 3.20(lH,d); 3.50(lH,t); 5.40(lH,m); 6.10(lH,m); 7.95(lH,t); 8.0(lH,d); 8.45(lH,d).
32 1.65(lH,m); 1.85-2.05(2H,m); 2.10- 2.25(4H,m); 2.90-3.15(3H,m); 3.45(lH,dd); 3.55(lH,t); 5.45(lH,m); 6.15(lH,m); 8.05(lH,t); 8.40(2H, br. signal).
33 1.80-2.10(m) and 2.20-2.40(m) total of 4H; Mixture of 3.35-3.45(lH,m); 3.95(m) and 4.70(m) total rotational of IH; 4.30(m) and 4.90(m) total of IH; 5.55- isomers. 5.65(lH,m); 6.25-6.35(lH,m); 7.45- 7.55(lH,m); 7.50(s) and 8.15(s) total of IH; 8.35-8.50(2H,m).
35 1.55-2.20 (4H,m); 2.15(3H,s); 3.05(lH,d); 3.10(lH,m); 3.35(lH,t); 5.54(lH,m); 6.15(lH,m); 7.85(lH,t); 8.40(2H,m).
37 1.70-2.00(4H,m); 2.10-2.30(lH,m); 3.10(lH,m); 3.55(lH,d); 3.75 (lH,t); 5.50(lH,m); 6.30(lH,m); 7.80(lH,t); 8.45(lH,d); 8.55(lH,d).
40 1.60-1.75(4H,m); 1.90-2.10(2H,m); 2.15- 2.30(lH,m); 2.90-3.10(3H,m); 3.45(lH,d); 3.60(lH,t); 5.50(lH,m); 6.15(lH,m);
Figure imgf000014_0001
8.20(lH,t); 8.40-8.60(2H,m). - 13
1.65-2.30(7H,m); 3.30(lH,dd); 3.40(lH,t); 3.50(lH,d); 5.40(lH,m); 6.35(lH,m); 7.20(lH,dd); 7.85(lh,dd); 8.25(lH,dd).
1.60(lH,m); 2.05-2.30(5H,m); 3.05(2H,d); 3.35(lH,t); 5.85(lH,m); 6.15(lH,m); 7.95(lH,d); 8.20(lH,d).
1.65(lH,m); 1.90(lH,m); 2.00-2.25(5H,m); 3.05(2H,m); 3.40(lH,t); 5.40(lH,m); 6.20(lH,m); 8.80(2H,s); 9.10(lH,s).
1.55-2.20(5H,m); 2.25(3H,s); 3.35(2H,m); 5.60(lH,m); 6.05(lH,m); 6.85(lH,m); 6.90(lH,m); 7.15(lH,d).
76-78 1.50-2.20(5H,m); 3.10(lH,m); 3.50(lH,d); 3.70(lH,t); 5.45(lH,m); 6.25(lH,m); 7.25(lH,m); 7.60(lH,dd); 8.30(lH,d).
1.65-2.20(4H,m); 2.55-2.95(2H,m); 3.10(lH,d); 3.20(lH,d); 3.55(lH,t); 5.40(lH,2dd); 6.10(lH,2dd); 7.25(lH,dd); 7.90(lH,dd); 8.25(lH,d).
1.65(lH,m); 1.80-2.20(3H,m); 2.75(lH,m); 2.95(lH,m); 3.10(lH,m); 3.20(lH,dd); 3.50(lH,t); 4.95(lH,s); 5.00(lH,m); 5.40(lH,m); 5.50-5.70(lH,m); 6.15(lH,m); 7.30(lH,d); 7.85(lH,dd); 8.35(lH,d).
1.80-2.20(m) and 2.20-2.40(m) total of 4H; Mixture of 3.30-3.45(lH,m); 3.90(m) and 4.65(m) total rotational of IH; 4.30(m) and 4.90(m) total of IH; 5.55- isomers. 5.65(lH,m); 6.20-6.35(lH,m); 7.20- 7.30(lH,m); 7.40-7.55(lH, m);7.50(s) and 8.15(s) total of IH; 8.20-8.30(lH,m).
1.65(lH,m); 1.90(lH,m); 2.05-2.30(5H,m); 3.10(2H,m); 3.35(lH,t); 5.40(lH,m); 6.15(lH,m); 7.25(lH,d); 7.80(lH,dd); 8.30(lH,d).
1.65(lH,m); 1.70-1.95(2H,m); 2.25(2H,m); 2.40(3H,s); 2.70(lH,m); 3.30(lH,dd); 3.60(lH,d); 5.95(lH,m); 7.30(lH,d); 7.55(lH,dd); 8.30(lH,d).
1.55-2.30(5H,m); 2.45(3H,s); 2.65(lH,m); 3.30(lH,m); 3.65(lH,d); 6.00(lH,m); 7.60(lH,t); 8.45(2H,m).
1.75-2.05(3H,m); 2.20-2.40(1 H,m); Mixture of 3.30(lH,m); 4.10-4.80(4H,m); 5.55- rotational 5.60(lH,m); 6.20-6.40(1 H,m); 6.80- isomers
Figure imgf000015_0001
7.55(3H,m); 8.20-8.30(lH,m). 14
123 1.80-2.05(3 H,m); 2.30(lH,m); 3.35(lH,d); Mixture of 4.15-4.70(4H,m); 5.60(lH,m); 6.20- rotational 6.40(lH,m); 6.90-7.10(lH,m); 7.50(1H, isomers br.signal); 8.55(2H, br.signal).
124 62-64 1.70(lH,m); 1.95(lH,m); 2.05-2.30(2H,m); 3.05(2H,m); 3.20(lH,d); 3.40(2H,m); 5.45(lH,m); 6.15(lH,m); 6.85(2H,m); 7.05(2H,m); 7.20(lH,d); 7.70(1H, dd); 8.30(1 H,d).
125 1.70(lH,m); 1.92-2.32(3H,m); 2.29(3H,s); 2.98(lH,br.d); 3.33(lH,dd); 3.45(lH,t); 5.40(lH,m); 6.04(lH,m); 6.74(lH,d); 6.91(lH,d); 7.05(lH,dd); 14.50(lH,s).
126 1.55-2.30(5H,m); 2.46(3H,s); 2.65(lH,m); 3.30(lH,br.t); 3.64(lH,br.d); 3.97(3H,s); 5.88(lH,br.t); 7.03(lH,br.t); 7.50(lH,dd); 7.80(lH,d).
127 1.60 (lH,m); 1.87 (lH,dt); 2.01-2.25(2H,m); 2.14(3H,s); 3.04(1H br.d); 3.12(lH,d); 3.35(lH,t); 3.93(3H,s); 5.43(lH,m); 6.12(lH,m); 7.00 (IH, d); 7.58(lH,dd); 7.88(lH,d).
128 1.61(lH,m); 1.85(lH,dt); 1.98-2.25(2H,m); 2.12(lH,m); 3.15(lH,d); 3.32(lH,t); 3.36(lH,m); 3.78(3H,s); 3.81(3H,s); 5.46(lH,m); 6.12(lH,m); 6.42-6.48(2H,m); 7.26(lH,m).
129 1.65-2.73(6H,m); 2.54(3H,s); 3.36(lH,br.t); 3.63(lH,d); 5.81(lH,br.t); 7.02-7.15(3H,m).
130 1.70-1.95(4H,m); 2.10(2H,br.m); 2.35(3H,s); 3.30(lH,br.signal); 3.50(lH,br. signal); 5.00(lH,br.d); 6.80(lH,dd); 6.95(lH,d); 7.55(lH,2dd); 8.10(lH,dd).
131 1.75(lH,m); 1.85-1.97(2H,m); 2.20(lH,m); 2.32(lH,br.s); 3.12(lH,m); 3.39(3H,s); 3.52(lH,d); 3.69(lH,t); 5.52(lH,m); 6.25(lH,m); 6.92(lH,d); 7.01(lH,s); 7.08(lH,dd).
132 1.69(lH,m); 1.92(lH,dt); 2.05-2.25(2H,m); 3.10(lH,m); 3.17(lH,br.d); 3.35(2H,q); 3.39(lH,m); 3.40(3H,s); 5.47(lH,m); 6.12(lH,m); 6.82(lH,d); 7.10(5H,s);
Figure imgf000016_0001
7.12(lH,dd); 7.37(lH,d). 15
133 1.70(lH,m); 1.95(lH,dt); 2.05-2.32(2H,m); 2.25(3H,s); 3.32(lH,d); 3.40-3.52(2H,m); 3.82(2H,s); 5.47(lH,m); 6.19(lH,m); 6.75(lH,s); 7.09(lH,s).
134 1.80-2.00(3H,m); 2.20(lH,m); 3.25(3H,br.s); 3.39(3H,br.s); 3.60(lH,m); 4.35(lH,m); 4.60(lH,m); 5.55(lH,m); 6.20(lH,m); 6.89(lH,d); 7.00-7.10(2H,m).
135 1.65(lH,m); 1.85(lH,dd); 1.95(lH,t); 2.20- 2.28(2H,m); 2.65(lH,m); 3.30(lH,m); 3.40(3H,s); 3.42(3H,s); 3.72(lH,d); 5.82(lH,t); 6.92(2H,s); 7.07(lH,dd).
136 1.65(lH,m); 1.92(lH,dt); 2.10(lH,m); 2.18(3H,s); 2.25(lH,m); 3.14(lH,m); 3.27 (lH,br.d); 3.39(3H,s); 3.42(3H,s); 3.42(lH,m); 5.57(lH,m); 6.14(lH,m); 6.88(lH,d); 7.05-7.09(2H,m).
137 1.60(lH,m); 1.85(lH,m); 2.05-2.20(2H,m); 2.12(3H,s); 3.09(lH,m); 3.15(lH,d); 3.32(lH,m); 3.35(3H,s); 5.48(lH,m); 6.12(lH,m); 6.85(lH,d); 7.26(lH,dd); 7.33(lH,d).
138 1.60(lH,m); 1.82-1.92(2H,m); 2.10(lH,m); 2.15(3H,s); 3.10(lH,m); 3.22(lH,br.d); 3.35(lH,t); 3.39(3H,s): 5.51(lH,m); 6.12(lH,m); 6.88(lH,d); 7.05(lH,dd); 7.19(lH,d).
139 1.70(lH,m); 1.80-1.98(2H,m); 2.65(lH,m); 2.80(lH,m); 3.10(lH,m); 3.27(lH,dd); 3.42(3H,s); 3.52(lH,t); 5.48(lH,m); 6.08(lH,m); 6.87(lH,d); 7.22(lH,dd); 7.35(lH,d).
140 1.55(lH,m); 1.85 lH,dt); 2.05(lH,m); 2.12(3H,s); 2.20(lH,m); 2.98(lH,m); 3.15(lH,m); 3.32(1H, t); 5.90(2H, s); 6.05 (lH,m); 6.70-6.80 (2H,m); 6.98 (lH,d).
141 1.62(lH,m); 1.90(lH,dt); 2.05-2.22(2H,m); 3.00(lH,m); 3.15(lH,br.d); 3.37(lH,t); 3.39(2H,q); 5.47(lH,m); 5.92(2H,d); 6.09(lH,m); 6.70-6.80(2H,m); 6.97(lH,d); 7.07-7.20(5H,m).
142 1.70(lH,m); 1.82-1.97(2H,m); 2.05- 2.25(2H,m); 2.99(lH,m); 3.49(lH,d); 3.65(lH,m); 5.50(lH,m); 5.92(2H,d); 6.22(lH,m); 6.65(lH,dd); 6.75(lH,d);
Figure imgf000017_0001
6.79(lH,d). 16 -
143 1.62-2.10(2H,m); 2.20(lH,m); 3.12(lH,m); 3.30(3H,br.s); 4.35(lH,m); 4.59(lH,m); 5.53(lH,m); 5.90(2H,s); 6.15(lH,m); 6.58- 6.80(3H,m).
144 1.65(lH,m); 1.80(lH,dd); 1.92-2.30(3H,m); 2.60(3H,s); 2.65(lH,m); 3.32(lH,br.t); 3.60(lH,d); 5.55(lH,m); 5.97(2H,s);
Figure imgf000018_0001
6.60(lH,s); 6.82(lH,s).
Throughout this description, compounds are named according to the IUPAC system.
The compounds of formula (I) can be made by adaptation of methods described in the art (such as methods described in Pharm. Res. 1992, 9(11), 1474-9, WO97/13770, WO93/14636 and WO96/37494).
Alternatively, a compound of formula (I) can be prepared by coupling a compound of formula (II) with a compound of formula R*Hal wherein R* is a phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, benzoxazol-2-one, benzimidazolin-2-one or thiazolyl ring substituted as above and Hal is a halide (particularly a bromide or iodide) in the presence of one or more catalysts (such as palladium acetate, tetrakis-(triphenylphosphine)- palladium(O) or nickel(O) or tr ιs-di(μ-acetato)-bis[o-(di-o-tolyl)benzyl]dipalladium(II), preferably together with copper (I) halide (such as a bromide or chloride) or triphenyl borane under Heck conditions. (Examples of Heck conditions include those disclosed in: Angew. Chem. Int. Ed. Engl. (1994) 33 2379-2411; R F Heck Accounts of Chemical Research (1979) \2 146; R F Heck Palladium Reactions in Organic Synthesis, Academic Press, New York, (1985); R C Larock, B E Baker Tetrahedron Letters (1988), 29, No 8, 905; W A Herrmann et al Angew. Chem. Int. Ed. Engl. (1995) 34 1844; and Singh, Just, J Org. Chem., (1989), 54, 4453.) Typically, the reaction is carried out with or without a suitable solvent (such as N,N- dimethylformamide) under an inert atmosphere (for example nitrogen) in the presence of a suitable base {such as N. N-diisopropy lethy lamine (which may also be used as solvent for the reaction), triethylamine, silver carbonate, sodium acetate or potassium acetate in the presence of a quaternary ammonium salt (such as tetra-n-butylammonium bromide)}.
A compound of formula (II) can be prepared by dehydrating a compound of formula (N), preferably wherein the hydroxy group is axial, under suitable conditions. Alternatively, - 17 -
a compound of formula (II) can be prepared by reacting a compound of formula (NI) with benzenesulfonyl hydrazide and reacting the product so formed with n-butyl lithium.
A compound of formula (N) wherein the hydroxy group is axial, can be made by reducing a compound of formula (NI) with, for example, sodium borohydride, Raney Nickel or diisobutylaluminium hydride (DIBAL-H). The preparation of compounds of formulae (N) and (VI) is disclosed in the literature (see, for example, WO96/37494, Y. Hayakawa et al J Am. Chem. Soc. 100 1786 (1978) or K. Νador et al Arzneim-Forsch V2 305 (1962)).
Alternatively, a compound of formula (I) wherein R1 is hydrogen can be prepared by dehydrating a compound of formula (IN) with a suitable dehydrating reagent, such as an acid, acid anhydride or acid chloride (such as thionyl chloride).
A compound of formula (IN) can be prepared by reacting a compound of formula (III) with a suitable organometallic reagent R2M (wherein R2 is as defined above but is not hydrogen, and M is a suitable metal residue, such as lithium or a Grignard residue (for example MgCl, MgBr or Mgl)). [Compounds R2M can be prepared by reacting compounds R2Hal (wherein Hal is a halogen) with a suitable organometallic reagent, such as magnesium, or an organolithium or organomagnesium reagent.]
A compound of formula (III) can be prepared by methods analogous to those described in, for example, EP-A2-0076089, US5306718, Tetrahedron 18 405-412 (1962) and J. Am. Chem. Soc. 82 4642 (1960). A compound of formula (I) wherein R and R2 are both hydrogen can be made by treating a compound of formula (I) wherein R2 is hydrogen and R is alkyl with either an azodicarboxylate (such as diethyl azodicarboxylate) at an elevated temperature and acidifying (with a mineral acid, such as hydrochloric acid) the product so formed; or an alkyl-, alkenyl- or haloalkyl-chloroformate (such as vinylchloroformate or 1- chloroethylchloroformate) and hydrolysing the carbamate so formed.
A compound of formula (I) wherein R is not hydrogen and R2 is hydrogen can be made by treating a compound of formula (I) wherein R and R2 are both hydrogen with a compound RL (wherein L is a suitable leaving group, such as halogen or mesylate) preferably in the presence of a base. Compounds of formula RL are commercially available or can be prepared by literature methods. - 18 -
Scheme I refers to a process for isomer conversion, in which a compound of formula (I), wherein R2 is hydrogen, is reacted with a strong base (such as potassium tert-butoxide) in a polar solvent (such as tetrahydrofuran) at a temperature in the range 60 to 80°C.
In further aspects the present invention provides processes for preparing compounds of formula (I) as hereinbefore described.
The compounds of formula (I) can be used to combat and control infestations of insect pests such as Lepidoptera, Diptera, Homoptera and Coleoptera and also other invertebrate pests, for example, acarine, nematode and mollusc pests. Insects, acarines, nematodes and molluscs are hereinafter collectively referred to as pests. The pests which may be combated and controlled by the use of the invention compounds include those pests associated with agriculture (which term includes the growing of crops for food and fibre products), horticulture and animal husbandry, companion animals, forestry and the storage of products of vegetable origin (such as fruit, grain and timber) and also those pests associated with the transmission of diseases of man and animals. Examples of pest species which may be controlled by the compounds of formula (I) include: Myzus persicae (aphid), Aphis gossvpii (aphid), Aphis fabae (aphid), Lygus spp. (capsids), Dvsdercus spp. (capsids), Nilaparvata lugens (planthopper), Nephotettix cincticeps (leafhopper), Nezara spp. (stinkbug), Euschistus spp. (stinkbugs), Leptocorisa spp. (stinkbugs), Frankliniella occidentalis (thrip), Thrips spp. (thrips), Leptinotarsa decemlineata (Colorado potato beetle), Anthonomus grandis (boll weevil), Aonidiella spp. (scale insects), Trialeurodes spp. (white flies), Bemisia tabaci (white fly), Spodoptera littoralis (cotton leafworm), Heliothis virescens (tobacco budworm), Helicoverpa armigera (cotton bollworm), Pieris brassicae (white butterfly), Plutella xylostella (diamond back moth), Agrotis spp. (cutworms), Chilo suppressalis (rice stem borer), Chortiocetes terminifera (locust), Diabrotica spp. (rootworms), Panonvchus ulmi (European red mite), Panonvchus citri (citrus red mite), Tetranvchus urticae (two-spotted spider mite), Tetranvchus cinnabarinus (carmine spider mite), Phyllocoptruta oleivora (citrus rust mite), Polyphagotarsonemus latus (broad mite), Brevipalpus spp. (flat mites), Liriomyza spp. (leafminers), Musca domestica (housefly), Aedes aegypti (mosquito), Anopheles spp. (mosquitoes), Culex spp. (mosquitoes), Blattella germanica (cockroach), Periplaneta americana (cockroach), Blatta orientalis (cockroach), Ostrinia nubilalis (European corn borer), Meloidogvne spp. (root knot - 19 -
nematodes), Globodera spp. and Heterodera spp. (cyst nematodes), Pratylenchus spp. (lesion nematodes) and Deroceras reticulatum (slug). Further examples include insects which adversely affect the health of the public or of animals.
In order to apply a compound of formula (I) to a pest, a locus of pest, or to a plant susceptible to attack by a pest, the compound is usually formulated into a composition which includes, in addition to the compound of formula (I), a suitable inert diluent or carrier and, optionally, a surface active agent. It is preferred that all compositions (both solid and liquid formulations) comprise, by weight, 0.0001 to 95%, more preferably 1 to 85%, for example 5 to 60%, of a compound of formula (I). The composition is generally used for the control of pests such that a compound of formula (I) is applied at a rate of from 0.1 g to 10kg per hectare, preferably from lg to 6kg per hectare.
In another aspect the present invention provides an insecticidal, acaricidal, nematicidal or molluscicidal composition comprising an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I), wherein one of R1 and R2 is hydrogen and the other is a phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, benzoxazol-2-one or benzimidazolin-2-one ring, said ring being optionally substituted with halogen, C,^ alkyl, C,^ haloalkyl, C,^ alkoxy, Cw haloalkoxy, C2^ alkenyl, C2^ alkynyl, hydroxy, nitro, cyano or methylenedioxy; R is hydrogen, formyl, C 6 alkyl (optionally substituted with cyano, CO2(C,^ alkyl) or phenyl (itself optionally substituted with halogen, C,^ alkyl, C,^ alkoxy, C,^ haloalkyl or Cw haloalkoxy)), CH2(CW haloalkyl), CO2(Cw alkyl), C02(CM alkenyl), CH2(C2^ alkenyl), CH2(C2^ alkynyl), benzyl (wherein the phenyl ring is optionally substituted with halogen or CM alkyl) or XR3; X is O or NR4; R3 and R4 are, independently, hydrogen, cyano, C,^ alkyl (optionally substituted with halogen, cyano, CO2(C alkyl) or phenyl (itself optionally substituted with halogen, C,^ alkyl, C,^ alkoxy, C,^ haloalkyl or C haloalkoxy)), phenyl (itself optionally substituted with halogen, C^ alkyl, C,^ alkoxy, C,^ haloalkyl or C,^ haloalkoxy), CM alkenyl or C2* alkynyl; or an acid addition salt or N-oxide thereof; and a suitable carrier or diluent therefor. The composition is preferably an insecticidal, acaricidal or nematicidal composition. In another aspect the present invention provides an insecticidal, acaricidal, nematicidal or molluscicidal composition comprising an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I), wherein one - 20 -
of R1 and R2 is hydrogen and the other is a phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl or thiazolyl ring, said ring being optionally substituted with halogen, C,^ alkyl, C,^ haloalkyl, Cw alkoxy, C,^ haloalkoxy, C^ alkenyl, C2^ alkynyl or cyano; R is hydrogen, formyl, C,^ alkyl (optionally substituted with cyano, CO2(Cw alkyl) or phenyl (itself optionally substituted with halogen, Cw alkyl, Cw alkoxy, C,^ haloalkyl or C,^ haloalkoxy)), CH2(C,^) haloalkyl, CO2(C alkyl), CH2(C2^)alkenyl, CH2(C2 alkynyl or XR3; X is O or NR4; R3 and R4 are, independently, hydrogen, cyano, Cw alkyl (optionally substituted with halogen, cyano, CO2(C,^ alkyl) or phenyl (itself optionally substituted with halogen, Cw alkyl, Cw alkoxy, C haloalkyl or Cw haloalkoxy)), phenyl (itself optionally substituted with halogen, Cw alkyl, Cw alkoxy, CM haloalkyl or C haloalkoxy), C2^ alkenyl or CM alkynyl; or an acid addition salt or N-oxide thereof; and a suitable carrier or diluent therefor. The composition is preferably an insecticidal, acaricidal or nematicidal composition.
In a further aspect the invention provides a method of combating and controlling pests at a locus which comprises treating the pests or the locus of the pests with an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I), wherein one of R1 and R2 is hydrogen and the other is a phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, benzoxazol-2-one or benzimidazolin-2-one ring, said ring being optionally substituted with halogen, CM alkyl, C^ haloalkyl, C,^ alkoxy, C^ haloalkoxy, C2J6 alkenyl, Cw alkynyl, hydroxy, nitro, cyano or methylenedioxy; R is hydrogen, formyl, C,^ alkyl (optionally substituted with cyano, CO2(Cw alkyl) or phenyl (itself optionally substituted with halogen, C,^ alkyl, C,^ alkoxy, C,^ haloalkyl or C,^ haloalkoxy)), CH2(CW haloalkyl), CO2(Cw alkyl), CO2(C2^ alkenyl), CH2(C2^ alkenyl), CH2(CW alkynyl), benzyl (wherein the phenyl ring is optionally substituted with halogen or CM alkyl) or XR3; X is O or NR4; R3 and R4 are, independently, hydrogen, cyano, C,^ alkyl (optionally substituted with halogen, cyano, CO2(C alkyl) or phenyl (itself optionally substituted with halogen, C,^ alkyl, C,^ alkoxy, Cw haloalkyl or C,^ haloalkoxy)), phenyl (itself optionally substituted with halogen, C,^ alkyl, C,^ alkoxy, C,^ haloalkyl or C,^ haloalkoxy), C2^ alkenyl or CM alkynyl; or an acid addition salt or N-oxide thereof; or with an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a composition comprising a compound of formula (I) as hereinbefore defined. The compounds of formula (I) are preferably used against insects, acarines or nematodes. - 21 -
In a still further aspect the invention provides a method of combating and controlling pests at a locus which comprises treating the pests or the locus of the pests with an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I), wherein one of R1 and R2 is hydrogen and the other is a phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl or thiazolyl ring, said ring being optionally substituted with halogen, Cw alkyl, C haloalkyl, Cw alkoxy, Cw haloalkoxy, Cw alkenyl, CM alkynyl or cyano; R is hydrogen, formyl, CM alkyl (optionally substituted with cyano, CO2(Cw alkyl) or phenyl (itself optionally substituted with halogen, Cw alkyl, Cw alkoxy, Cw haloalkyl or Cw haloalkoxy)), CH2(C, Jhaloalkyl, CO2(C,^ alkyl), CH2(C^)alkenyl, CH2(C2^)alkynyl or XR3; X is O or NR4; R3 and R4 are, independently, hydrogen, cyano, C,^ alkyl (optionally substituted with halogen, cyano, CO2(C,^ alkyl) or phenyl (itself optionally substituted with halogen, C,^ alkyl, Cw alkoxy, Cw haloalkyl or C,^ haloalkoxy)), phenyl (itself optionally substituted with halogen, C,^ alkyl, Cw alkoxy, Cw haloalkyl or Cw haloalkoxy), Cw alkenyl or C2^ alkynyl; or an acid addition salt or N-oxide thereof; or with an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a composition comprising a compound of formula (I) as hereinbefore defined. The compounds of formula (I) are preferably used against insects, acarines or nematodes.
In a still further aspect the invention provides a method as hereinbefore described wherein R2 is hydrogen. The compositions can be chosen from a number of formulation types, including dustable powders (DP), soluble powders (SP), water soluble granules (SG), water dispersible granules (WG), wettable powders (WP), granules (GR) (slow or fast release), soluble concentrates (SL), oil miscible liquids (OL), ultra low volume liquids (UL), emulsifiable concentrates (EC), emulsions (both oil in water (EW) and water in oil (EO)), suspension concentrates (SC), aerosols, fogging/smoke formulations, capsule suspensions (CS) and seed dressings. The formulation type chosen in any instance will depend upon the particular purpose envisaged and the physical, chemical and biological properties of the compound of formula (I).
Dustable powders (DP) may be prepared by mixing a compound of formula (I) with one or more solid diluents (for example natural clays, kaolin, pyrophyllite, bentonite, alumina, montmorillonite, kieselguhr, chalk, diatomaceous earths, calcium phosphates, - 22 -
calcium and magnesium carbonates, sulphur, lime, flours, talc and other organic and inorganic solid carriers) and mechanically grinding the mixture to a fine powder.
Soluble powders (SP) can be prepared by mixing a compound of formula (I) with one or more water-soluble inorganic salts (such as sodium bicarbonate, sodium carbonate or magnesium sulphate) or one or more water-soluble organic solids (such as a polysaccharide) and, optionally, one or more wetting agents, one or more dispersing agents or a mixture of said agents to improve water dispersibility/solubility. The mixture is then ground to a fine powder. Similar compositions may also be granulated to form water soluble granules (SG). Wettable powders (WP) can be prepared by mixing a compound of formula (I) with one or more solid diluents or carriers, one or more wetting agents and, preferably, one or more dispersing agents and, optionally, one or more suspending agents to facilitate the dispersion in liquids. The mixture is then ground to a fine powder. Similar compositions may also be granulated to form water dispersible granules (WG).
Granules (GR) may be formed either by granulating a mixture of a compound of formula (I) and one or more powdered solid diluents or carriers, or from pre-formed blank granules by absorbing a compound of formula (I) (or a solution thereof, in a suitable agent) in a porous granular material (such as pumice, attapulgite clays, fuller's earth, kieselguhr, diatomaceous earths or ground corn cobs) or by adsorbing a compound of formula (I) (or a solution thereof, in a suitable agent) on to a hard core material (such as sands, silicates, mineral carbonates, sulphates or phosphates) and drying if necessary. Agents which are commonly used to aid absorption or adsorption include aliphatic and aromatic petroleum solvents, alcohols, polyvinyl acetates, polyvinyl alcohols, ethers, ketones, esters, dextrins, sugars and vegetable oils. One or more other additives may also be included in granules (for example an emulsifying agent, wetting agent or dispersing agent). Soluble concentrates (SL) can be prepared by dissolving a compound of formula (I) in water or an organic solvent, such as a ketone, alcohol or glycol ether. These solutions may contain a surface active agent (for example to improve water dilution or prevent crystallisation in a spray tank).
Emulsifiable concentrates (EC) or oil in water emulsions (EW) may be prepared by dissolving a compound of formula (I) in an organic solvent (optionally containing one or more wetting agents, one or more emulsifying agents or a mixture of said agents) and, for an - 23 -
emulsion, subsequently adding, under high shear agitation, the mixture to water (which may contain one or more wetting agents, one or more emulsifying agents or a mixture of said agents). Suitable organic solvents for use in ECs include ketones (such as cyclohexanone or methy ley clohexanone) and alcohols (such as benzyl alcohol, furfuryl alcohol or butanol). Suitable organic solvents for use in ECs or EWs include vegetable oils, N-substituted pyrrolidones, glycol ethers, chlorinated hydrocarbons (such as chlorobenzenes) and aromatic solvents (such as alkylbenzenes or alkylnaphthalenes).
Suspension concentrates (SC) may comprise aqueous or non-aqueous suspensions of finely divided insoluble solid particles of a compound of formula (I). SCs may be prepared by ball or bead milling the solid compound of formula (I) in a suitable medium with one or more dispersing agents, to produce a fine particle suspension of the compound. One or more wetting agents may be included in the composition and a suspending agent may be included to reduce the rate at which the particles settle.
Aerosol formulations comprise a compound of formula (I) and a suitable propellant (for example n-butane). A compound of formula (I) may also be dissolved or dispersed in a suitable medium (for example water or a water miscible liquid, such as n-propanol) to provide compositions for use in non-pressurised, hand-actuated spray pumps.
A compound of formula (I) can be mixed in the dry state with a pyrotechnic mixture to form a composition suitable for generating, in an enclosed space, a smoke containing the compound.
Capsule suspensions (CS) can be prepared in a manner similar to the preparation of EW formulations but with an additional polymerisation stage such that an aqueous dispersion of oil droplets is obtained, in which each oil droplet is encapsulated by a polymeric shell and contains a compound of formula (I) and, optionally, a carrier or diluent therefor. The compositions may provide for controlled release of the compound of formula (I) and they can be used for seed treatment. A compound of formula (I) may also be formulated in a biodegradable polymeric matrix to provide a slow, controlled release of the compound.
A composition may include one or more additives to improve the biological performance of the composition (for example by improving wetting, retention or distribution on surfaces; resistance to rain on treated surfaces; or uptake or mobility of a compound of formula (I)). Such additives include surface active agents, spray additives based on oils, for - 24 -
example certain mineral oils or natural plant oils (such as soya bean and rape seed oil), and blends of these with other bio-enhancing adjuvants.
A compound of formula (I) may also be formulated for use as a seed treatment, for example as a powder composition, including a powder for dry seed treatment (DS), a water soluble powder (SS) or a water dispersible powder for slurry treatment (WS), or as a liquid composition, including a flowable concentrate (FS), a solution (LS) or a capsule suspension (CS). The preparations of DS, SS, WS, FS and LS compositions are very similar to those of, respectively, DP, SP, WP, SC and SL compositions described above. Compositions for treating seed may include an agent for assisting the adhesion of the composition to the seed (for example a mineral oil).
Wetting agents, dispersing agents and emulsifying agents may be of the cationic, anionic, amphoteric or non-ionic type.
Suitable agents of the cationic type include quaternary ammonium compounds (for example cetyltrimethyl ammonium bromide), imidazolines and amine salts. Suitable anionic agents include alkali metals salts of fatty acids, salts of aliphatic monoesters of sulphuric acid (for example sodium lauryl sulphate), salts of sulphonated aromatic compounds (for example sodium dodecylbenzenesulphonate, butylnaphthalene sulphonate and mixtures of sodium diisopropyl- and triisopropyl-naphthalene sulphonates), ether sulphates, alcohol ether sulphates (for example sodium laureth-3-sulphate), ether carboxy lates (for example sodium laureth-3 -carboxy late), phosphate esters (products from the reaction between one or more fatty alcohols and phosphoric acid (predominately mono- esters) or phosphorus pentoxide (predominately di-esters), for example the reaction between lauryl alcohol and tetraphosphoric acid, additionally these products may be ethoxylated), sulphosuccinamates, paraffin or olefine sulphonates, taurates and lignosulphonates. Suitable agents of the amphoteric type include betaines, propionates and glycinates.
Suitable agents of the non-ionic type include condensation products of ethylene oxide with fatty alcohols (such as oleyl alcohol or cetyl alcohol) or with alkylphenols (such as octylphenol, nonylphenol or octylcresol); partial esters derived from long chain fatty acids or hexitol anhydrides; condensation products of said partial esters with ethylene oxide; block polymers (comprising ethylene oxide and propylene oxide); alkanolamides; simple esters (for - 25 -
example fatty acid polyethylene glycol esters) or their ethoxylated derivatives; amine oxides (for example lauryl dimethyl amine oxide); and lecithins.
Suitable suspending agents include hydrophilic colloids (such as polysaccharides, polyvinylpyrrolidone or sodium carboxymethylcellulose) and swelling clays (such as bentonite or attapulgite).
Compositions for use as aqueous preparations (aqueous solutions or dispersions) are generally supplied in the form of a concentrate containing a high proportion of the active ingredient, the concentrate being added to water before use. These concentrates, which may include SLs, SCs, ECs, EWs, SGs, SPs, WPs, WGs and CSs, are often required to withstand storage for prolonged periods and, after such storage, to be capable of addition to water to form aqueous preparations which remain homogeneous for a sufficient time to enable them to be applied by conventional spray equipment. Such aqueous preparations may contain varying amounts of a compound of formula (I) (for example 0.0001 to 10%, by weight) depending upon the purpose for which they are to be used. A compound of formula (I) can be used in mixtures with fertilisers (for example nitrogen-, potassium- or phosphorus-containing fertilisers). Suitable formulation types include granules of fertiliser. The mixtures suitably contain up to 25% by weight of the compound of formula (I).
The invention therefore also provides a fertiliser composition comprising a fertiliser and a compound of formula (I).
In use the compositions are applied to the pests or to a locus of the pests (such as a habitat of the pests, or a growing plant liable to infestation by the pests) by any of the known means of applying pesticidal compositions, for example by dusting, dipping, spraying or injecting or by irrigation, distribution or incoφoration of a composition (such as a granular composition or a composition packed in a water-soluble bag) in soil or an aqueous environment.
The compound of formula (I) may be the sole active ingredient of the composition or it may be admixed with one or more additional active ingredients such as a pesticide, synergist, herbicide, fungicide or plant growth regulator where appropriate. An additional active ingredient may: provide a composition having a broader spectrum of activity or increased persistence at a locus; synergise the activity or complement the activity (for - 26 -
example by increasing the speed of effect or overcoming repellency) of the compound of formula (I); or help to overcome or prevent the development of resistance to individual components. The particular additional active ingredient will depend upon the intended utility of the composition. Examples of suitable pesticides include the following: a) Pyrethroids, such as permethrin, cypermethrin, fenvalerate, esfenvalerate, deltamethrin, cyhalothrin (in particular lambda-cyhalothrin), bifenthrin, fenpropathrin, cyfluthrin, tefluthrin, fish safe pyrethroids (for example ethofenprox), natural pyrethrin, tetramethrin, s-bioallethrin, fenfluthrin, prallethrin or 5-benzyl-3-furylmethyl-(E)-(lR,3S)-2,2-dimethyl- 3-(2-oxothiolan-3-ylidenemethyl)cyclopropane carboxylate; b) Organophosphates, such as profenofos, sulprofos, acephate, methyl parathion, azinphos-methyl, demeton-s-methyl, heptenophos, thiometon, fenamiphos, monocrotophos, profenofos, triazophos, methamidophos, dimethoate, phosphamidon, malathion, chlorpyrifos, phosalone, terbufos, fensulfothion, fonofos, phorate, phoxim, pirimiphos-methyl, pirimiphos-ethyl, fenitrothion, fosthiazate or diazinon; c) Carbamates (including aryl carbamates), such as pirimicarb, triazamate, cloethocarb, carbofuran, furathiocarb, ethiofencarb, aldicarb, thiofurox, carbosulfan, bendiocarb, fenobucarb, propoxur, methomyl or oxamyl; d) Benzoyl ureas, such as diflubenzuron, triflumuron, hexaflumuron, flufenoxuron or chlorfluazuron; e) Organic tin compounds, such as cyhexatin, fenbutatin oxide or azocyclotin; f) Pyrazoles, such as tebufenpyrad and fenpyroximate; g) Macrolides, such as avermectins or milbemycins, for example abamectin, emamectin benzoate, ivermectin, milbemycin, spinosad or azadirachtin; h) Hormones or pheromones; i) Organochlorine compounds such as endosulfan, benzene hexachloride, DDT, chlordane or dieldrin; j) Amidines, such as chlordimeform or amitraz; k) Fumigant agents, such as chloropicrin, dichloropropane, methyl bromide or metam;
1) Chloronicotinyl compounds such as imidacloprid, acetamiprid, nitenpyram or thiomethoxam; m) Diacylhydrazines, such as tebufenozide; - 27 -
n) Diphenyl ethers, such as diofenolan or pyriproxifen; o) Indoxacarb; p) Chlorfenapyr; or q) Pymetrozine. In addition to the major chemical classes of pesticide listed above, other pesticides having particular targets may be employed in the composition, if appropriate for the intended utility of the composition. For instance, selective insecticides for particular crops, for example stemborer specific insecticides for use in rice (such as cartap or buprofezin) can be employed. Alternatively insecticides or acaricides specific for particular insect species/stages may also be included in the compositions (for example acaricidal ovo-larvicides, such as clofentezine, flubenzimine, hexythiazox or tetradifon; acaricidal motilicides, such as dicofol or propargite; acaricides, such as bromopropylate or chlorobenzilate; or growth regulators, such as hydramethylnon, cyromazine, methoprene, chlorfluazuron or diflubenzuron). Examples of suitable synergists for use in the compositions include piperonyl butoxide, sesamex, safroxan and dodecyl imidazole.
Suitable herbicides, fungicides and plant-growth regulators for inclusion in the compositions will depend upon the intended target and the effect required.
An example of a rice selective herbicide which can be included is propanil. An example of a plant growth regulator for use in cotton is PIX™. Examples of fungicides for use in rice include blasticides, such as blasticidin-S.
Some mixtures may comprise active ingredients which have significantly different physical, chemical or biological properties such that they do not easily lend themselves to the same conventional formulation type. In these circumstances other formulation types may be prepared. For example, where one active ingredient is a water insoluble solid and the other a water insoluble liquid, it may nevertheless be possible to disperse each active ingredient in the same continuous aqueous phase by dispersing the solid active ingredient as a suspension (using a preparation analogous to that of an SC) but dispersing the liquid active ingredient as an emulsion (using a preparation analogous to that of an EW). The resultant composition is a suspoemulsion (SE) formulation. 28
The invention is illustrated by the following Examples, in which the ingredients below are referred to by their Registered Trade Marks and have the following compositions.
Registered Trade Mark Composition
SYNPERONIC NP8 }
Νonylphenol-ethylene oxide condensate SYNPERONIC NP13 }
SYNPERONIC A7 Synthetic primary alcohol-ethylene oxide condensate
AROMASOL H Alkylbenzene solvent
SOLNESSO 200 Inert organic diluent
KELTROL Polysaccharide
PROXEL Bactericide
Figure imgf000030_0001
EXAMPLE 1 This Example illustrates the preparation of 4-(5-bromopyrid-3-yl)-8-methyl-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 1 Table I) and 2-(5-bromopyrid-3-yl)-8-methyl- 8-azabicyclo[3.2.1]oct-2-ene (Compound No. 2 Table I).
3,5-Dibromopyridine (7.1g), 8-methyl-8-azabicyclo[3.2.1]oct-2-ene [1.16g; Liebigs Ann. Chem. (1883) 217, 118], copper (I) bromide (0.5g), palladium acetate (0.5g) and tri- ortho-tolylphosphine (0.5g) in NN-diisopropylethylamine (10ml) was stirred under an atmosphere of nitrogen and heated to reflux for 21 hours. The mixture was cooled to ambient temperature, the solution decanted from the insoluble solids and evaporated under reduced pressure to give a green- brown gum. The gum was dissolved in ethyl acetate (25ml), extracted into aqueous hydrochloric acid (2M, 2x20ml) and the acidic fractions combined. The aqueous, acidic solution was made basic with excess sodium carbonate, extracted with ethyl acetate (2x20ml), dried ( magnesium sulfate) and evaporated under reduced pressure to give a gum, 0.24g. The gum was fractionated using preparative thick layer chromatography (silica; eluent methanol [20% by volume] in ethyl acetate) to give: 4-(5-bromopyrid-3-yl)-8- methyl-8-azabicyclo[3.2.1]oct-2-ene, gum, (0.085g) and 2-(5-bromopyrid-3-yl)-8-methyl-8- azabicyclo[3.2.1]oct-2-ene, gum, (0.085g).
EXAMPLE 2 This Example illustrates the preparation of 4-(6-chloropyrid-3-yl)-8-carboethoxy-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 3 Table I). - 29 -
Stage 1 : Preparation of 8-carboethoxy-8-azabicyclo[3.2.1]oct-2-ene.
8-Methyl-8-azabicyclo[3.2.1]oct-2-ene (12.3g) was dissolved in fluorobenzene (200ml, dry) and cooled to 0°C under an atmosphere of dry nitrogen. Ethyl chloroformate (32.4g, freshly distilled) in fluorobenzene (100ml,dry) was added slowly to the stirred solution whilst maintaining the reaction temperature below 10°C. On complete addition the mixture was heated to reflux for 3hours then allowed to cool to ambient temperature. Further ethyl chloroformate (25ml) was added to the stirred mixture at ambient temperature allowing the reaction temperature to rise gradually to 40°C. The reaction was stirred for 2hours then heated to reflux for 2.5hours, cooled to ambient temperature then stored for lδhours. The mixture was diluted with hexane (500ml), filtered to remove the insoluble material and the filtrate evaporated under reduced pressure to give a brown liquid which was distilled to give 8-carboethoxy-8-azabicyclo[3.2.1]oct-2-ene (lOg) as a colourless liquid, bp 72-74°C (0.7mmHg). Stage 2: 2-Chloro-5-iodoρyridine [0.47g, S C Clayton, A C Regan Tet Lett (1993), 34, 7493],
8-carboethoxy-8-azabicyclo[3.2.1]oct-2-ene (0.18g), palladium acetate (0.060g), tri-ortho- tolylphosphine (0.1 Og) and silver carbonate (0.080g) in acetonitrile (3ml) were stirred under an atmosphere of dry nitrogen and heated to reflux for 2.5hours. The reaction mixture was cooled to ambient temperature, poured into a mixture of ethyl acetate (20ml) and aqueous sodium carbonate (20ml) then filtered through a pad of kieselguhr. The organic portion of the filtrate was separated, dried (magnesium sulfate) and evaporated under reduced pressure to give a brown residue. The residue was fractionated by chromatography (silica; hexane: ethyl acetate, 2:1 by volume) to give 4-(6-chloropyrid-3-yl)-8-carboethoxy-8- azabicyclo[3.2.1]oct-2-ene, 0.043g, as a colourless oil. The following compounds were prepared using a similar procedure to Example 2,
Stage 2 using the appropriately substituted phenyl iodide and 8-methyl-8- azabicyclo[3.2. l]oct-2-ene. The products were purified by preparative thick layer chromatography (basic alumina; hexane:ethyl acetate, 4:1 by volume).
8-Methyl-4-phenyl-8-azabicyclo[3.2.1]oct-2-ene, (Compound No. 4 Table I), colourless oil. - 30 -
4-(2-Chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 5 Table I), pale brown oil.
4-(3-Chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 6 Table I), pale brown oil. 4-(4-Chlorophenyl)-8-methyl-8-azabicyclo[3.2.1 ]oct-2-ene (Compound No. 7 Table
I), pale brown oil.
4-(4-Fluorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 8 Table I), pale brown oil.
4-(2-Methylphenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 9 Table I), colourless oil.
4-(3-Methylphenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 10 Table I),colourless oil.
4-(4-Methylphenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 11 Table I), colourless oil. EXAMPLE 3
This Example illustrates the preparation of 4-(5-bromopyrid-3-yl)-8-carboethoxy-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 12 Table I). Stage 1 : Preparation of 3-bromo-5-iodopyridine.
3,5-Dibromopyridine (12g) was dissolved in diethyl ether (250ml,dry) with stirring under an atmosphere of nitrogen and cooled to -78 °C. A solution of n-butyl lithium (20ml of a hexane solution, 2.5M) was added dropwise maintaining the reaction temperature below -70°C, producing a thick yellow suspension. The mixture was stirred for 0.25hour at -78°C then a solution of iodine (15g) in diethyl ether (100ml, dry) was added dropwise over lhour. On complete addition the reaction was allowed to warm to -30°C, water (10ml) was added and the cold mixture was dissolved in 50% aqueous hydrochloric acid. Sodium metabisulfite was added until the mixture was colourless and the diethyl ether fraction separated. The aqueous acidic phase was made basic with sodium carbonate and the solid which had precipitated was filtered from solution, washed with water, sucked to dryness and dissolved in dichloromethane (250ml). The dichloromethane solution was dried (magnesium sulfate) and evaporated under reduced pressure to give a colourless solid, 12g. Analysis by NMR and GC-MS indicated the mixture to contain 3-bromo-5-iodopyridine and 3,5- - 31 -
dibromopyridine (ratio 7:3). The material from this Stage was used in Stage 2 without further purification. Stage 2:
8-Carboethoxy-8-azabicyclo[3.2.1]oct-2-ene (8.9g), 3-bromo-5-iodopyridine (5.6g, 70% pure), palladium acetate (2.4g), anhydrous sodium acetate (5.0g) and tetra-n- butylammonium bromide in NN-dimethylformamide (80ml, dry) were stirred under an atmosphere of nitrogen at 95-100°C for 40hours. The solvent was evaporated under reduced pressure and the brown residue treated with ethyl acetate (150ml) and aqueous sodium carbonate (150ml). The mixture was filtered through a pad of kieselguhr, the organic phase was separated, dried (magnesium sulfate) and evaporated under reduced pressure to give a brown oil. The oil was fractionated by chromatography (silica, hexane:ethyl acetate, 8:1 to 1:1 by volume) to give 4-(5-bromopyrid-3-yl)-8-carboethoxy-8-azabicyclo[3.2.1]oct-2-ene, 0.32g, as a colourless oil.
2-(6-Chloropyrid-3-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 112 Table I), oil, was prepared from 2-chloro-5-iodopyridine using a similar procedure.
EXAMPLE 4 This Example illustrates the preparation of 4-(5-chloropyrid-3-yl)-8-methyl-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 35 Table I) and 2-(5-chloropyrid-3-yl)-8-methyl- 8-azabicyclo [3.2.1]oct-2-ene (Compound No. 120 Table I). Stage 1 : Preparation of 3 -chloro-2-hydrazino-5-iodopyridine.
2,3-Dichloro-5-iodopyridine (EP-A-0136593, 2.0g) was dissolved in propan-2-ol (15ml) and treated with hydrazine hydrate (5.0ml). The mixture was stirred and heated to reflux for 7hours, cooled to ambient temperature and evaporated under reduced pressure to give a yellow solid. The solid was dissolved in ethyl acetate, washed with water, dried (magnesium sulfate) and evaporated under reduced pressure to give the required product as a fawn solid (1. lg). A portion of this material was washed with diethyl ether to provide an analytical sample, mp 168.5-170.5°C, off-white solid.
Η NMR (D6 DMSO): δ 4.20(2H,br.s); 7.78(lH,d); 7.80(lH,br.s); 8.15(lH,d)ppm. Stage 2: Preparation of 3-Chloro-5-iodopyridine. 3-Chloro-2-hydrazino-5-iodopyridine (2.00g) was dissolved in dimethyl sulfoxide
(50ml) and the stirred solution treated with 50% aqueous sodium hydroxide solution (20ml) - 32 -
at ambient temperature. The brown solution was rapidly stirred for 5hours to assist the aerial oxidation, kept at ambient temperature for lδhours then water (500ml) added. The solid which had precipitated from solution was extracted with hexane (three times) and the combined hexane extract was washed with water, dried (magnesium sulfate) and the solvent evaporated under reduced pressure to give 3-chloro-5-iodo-pyridine (1.56g) as a colourless solid, mp 84-85°C.
Η NMR (CDC13): δ 8.05(lH,t); 8.55(lH,d ); 8.72(lH,d)ppm. Stage 3:
3-Chloro-5-iodopyridine (0.23g), 8-methyl-8-azabicyclo[3.2.1]oct-2-ene (0.75g) and copper (I) bromide (0. lg) were stirred in triethylamine (1ml) and a stream of nitrogen bubbled into the mixture for 5 minutes to remove residual oxygen. tans-Di(μ-acetato)-bis[o- (di-o-tolyl)benzyl]dipalladium(II) (0.050g) was added and the reaction heated to 110°C for 9hours, cooled to ambient temperature and stored for lδhours. The reaction was re-heated to 110°C for an additional 4hours and cooled to ambient temperature. The reaction solution was decanted leaving a residual black gum which was extracted with a mixture of aqueous ammonia (25ml, density 0.88) and toluene (50ml). The toluene extract was combined with the decanted solution, further toluene (25ml) added and the mixture washed with further aqueous ammonia (25ml). The organic phase was separated, dried(magnesium sulfate) then evaporated under reduced pressure to give a brown oil. The oil was fractionated by thick layer chromatography (silica; dichloromethane / methanol, 9:1 by volume) to give 4-(5- chloropyrid-3-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (0.041g, oil) and 2-(5-chloropyrid- 3-yl)-8-methyl-8-azabicyclo [3.2.1]oct-2-ene (0.018g, oil).
Preparation of tr ιs-di(μ-acetato)-bis[o-(di-o-tolyl)benzyl]dipalladium(II) see W A Herrmann, C Brossmer, K Ofele, C-P Reisinger, T Priermeier, M Beller, H Fischer Angew. Chem Int.Ed. Engl. 1995, 34(17) 1844.
The following compounds were prepared using a similar procedure:
4-(Thien-2-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 97 Table I), oil, from 2-iodothiophene.
4-(2-Chloropyrid-3-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 49 Table I), oil, from 2-chloro-3-iodopyridine (reaction conditions 2hours at 110°C). - 33 -
EXAMPLE 5 This Example illustrates the preparation of 4-(5-chloropyrid-3-yl)-8-(2,2,2- trifluoroethyl)-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 30 Table I). Stage 1 : Preparation of 8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1 ]oct-2-ene. 8-(2,2,2-Trifluoroethyl)-8-azabicyclo[3.2. l]-octan-3-one (WO96/37494, 2.07g) was dissolved in toluene (30ml) containing p-toluene sulfonic acid (0.05g, catalyst) and treated with benzene sulfonyl hydrazide (1.72g). The mixture was stirred and heated to reflux and the water collected using a Dean Stark apparatus. After 4hours the reaction mixture was cooled to ambient temperature then stored for lδhours. The solvent was evaporated under reduced pressure to yield a brown solid. The solid was fractionated by chromatography
(silica; eluent hexane/ ethyl acetate 2:1 by volume) to give the required hydrazone, 1.76g, as a buff coloured solid, mp 107-108°C.
Η NMR (CDC13): δ 1.30(lH,m); 1.50(lH,m); 1.85(2H,m); 2.20(2H,m); 2.50(2H,m); 2.95(2H,q); 3.40(2H,m); 7.50(2H,m); 7.60(lH,m); 7.95(3H,m)ppm. Hydrazone (7.5g), prepared according to the above method, was partially dissolved in dry diethyl ether (150ml) and cooled to -78°C with stirring under an atmosphere of nitrogen. n-Butyl lithium (21ml of a solution in hexane, 2.5M) was added dropwise and on complete addition the mixture was allowed to warm to ambient temperature. The reaction was stirred for lhour at ambient temperature, water (200ml) was added then the organic layer separated. The aqueous phase was extracted with diethyl ether (200ml) and the combined ether extracts were dried (magnesium sulfate) then evaporated under reduced pressure to give an oil. The oil was fractionally distilled to give 8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]oct-2-ene as a colourless liquid (0.50g, bp 55°C at 15mm Hg).
'H NMR (CDC13): δ 1.60-2.25(5H,m); 2.40(lH,m); 3.15(2H,m); 3.35(2H,m); 5.60(lH,m); 5.80(lH,m)ppm. Stage 2:
3-Chloro-5-iodopyridine (0.24g), 8-(2,2,2-trifluoromethyl)-8-azabicyclo[3.2.1]oct-2- ene (0.50g), copper (I) bromide (0.1 Og), and triethylamine (2ml) were stirred and nitrogen bubbled into the mixture for 5 minutes to remove residual oxygen. trans-Di(μ-acetato)-bis[o- (di-o-tolyl)benzyl]dipalladium(II) (0.050g) was added and the mixture heated with stirring to 110°C in a sealed reaction vessel for 26hours then cooled to ambient temperature and stored - 34 -
for 2days. The reaction was heated to 110°C for a further 9hours, cooled to ambient temperature and stored for lδhours. The solution was decanted from the black, insoluble material, which was washed with toluene (2x5ml) and the toluene extract combined with the decanted fraction. The combined extract was evaporated under reduced pressure to give a brown oil, which was dissolved in ethyl acetate (20ml) then washed with aqueous ammonia (20ml,density 0.88), water(20ml) and dried(magnesium sulfate). The solvent was evaporated under reduced pressure to give an oil which was fractionated by preparative thick layer chromatography {[silica, hexane/ ethyl acetate 4:1 by volume] then [ basic alumina, diethyl ether]} to give 4-(5-chloropyrid-3-yl)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]oct-2-ene, 0.013g, as an oil.
EXAMPLE 6 This Example illustrates the preparation of 4-(5-bromopyrid-3-yl)-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 37 Table I).
4-(5-Bromopyrid-3-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (0.53g) was dissolved in fluorobenzene (7ml) with stirring under an atmosphere of nitrogen and diethyl azodicarboxylate (0.48ml) was added. The mixture was heated to reflux for lδhours then evaporated under reduced pressure to give a yellow oil. The oil was dissolved in ethanol (10ml) and aqueous hydrochloric acid (10ml, 2M) was added. The mixture was stirred and heated to reflux for 4hours and cooled to ambient temperature. The solution was diluted with water and extracted with ethyl acetate (twice). The aqueous acidic phase was then basified with sodium carbonate and extracted with ethyl acetate (three times). The extracts were combined, dried (magnesium sulfate) and evaporated under reduced pressure to give an orange oil. The oil was fractionated by preparative thick layer chromatography (silica, dichloromethane / methanol, 4: 1 by volume) to give 4-(5-bromopyrid-3-yl)-8- azabicyclo[3.2.1]oct-2-ene, 0.10g, as an orange oil.
EXAMPLE 7 This Example illustrates the preparation of 8-methyl-4-(pyrid-3-yl)-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 19 Table I).
8-Methyl-8-azabicyclo[3.2.1]oct-2-ene (1.23g), 3-bromopyridine (1.80g) in dusopropylethylamine (10ml) and N,N-dimethylformamide (5ml) were stirred and nitrogen bubbled into the mixture for 5minutes to remove residual oxygen. Copper (I) bromide (0.2g) - 35 -
and tetrakis(triphenylphosphine) palladium(O) (0.45g) were added then the mixture heated to 110°C for 48hours under an atmosphere of nitrogen. The reaction was cooled to ambient temperature then poured into a mixture of ethyl acetate (200ml) and aqueous ammonia (20ml, density 0.88). The organic phase was separated, extracted with aqueous hydrochloric acid (2x50ml, 2M) and the aqueous acidic fractions combined and made basic with aqueous sodium hydroxide. The basic mixture was extracted with diethyl ether (100ml) and the organic phase separated then washed with water, dried (magnesium sulfate) and evaporated under reduced pressure to give a brown liquid. The liquid was heated at 100°C under vacuum (20mm Hg) to leave a brown oil. The oil was fractionated by chromatography (silica; dichloromethane then 5% methanol in dichloromethane) to give the required product, 0.042g, as an orange oil.
EXAMPLE 8 This Example illustrates the preparation of 4-(5,6-dichloropyrid-3-yl)-8-methyl-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 57 Table I). 8-Methyl-8-azabicyclo[3.2. l]oct-2-ene (1.50g) and 2,3-dichloro-5-iodopyridine
(0.55g) in triethylamine (2ml) were stirred and nitrogen bubbled into the mixture for 5minutes to remove residual oxygen. Copper(I) bromide (0.20g) and trans-di(μ-acetato)- bis[o-(di-o-tolyl)benzyl]dipalladium(II) (0.1 Og) were added then the mixture was heated in a sealed reaction vessel at 110°C for 2hours, cooled to ambient temperature and stored for lδhours. The reaction was re-heated to 110°C for a further 5hours and cooled to ambient temperature.
The above reaction was repeated and the contents of the two reaction vessels were diluted with toluene and combined. The resulting mixture was heated to 90°C at 50mmHg to remove the volatile materials and the residue dissolved in diethyl ether (20ml). The ether solution was extracted with aqueous hydrochloric acid (2x20ml, 2M) and the aqueous fractions were filtered and the filtrates combined. The combined acidic phase was made basic with sodium carbonate and extracted with ethyl acetate (2x20ml). The extracts were combined, dried (magnesium sulfate) and evaporated under reduced pressure to give a brown oil. The oil was fractionated by preparative thick layer chromatography (basic alumina; hexane/ethyl acetate, 4:1 by volume) to give 4-(5,6-dichloropyrid-3-yl)- 8-(methyl)-8- azabicyclo[3.2.1]oct-2-ene, 0.24g, as a colourless oil. - 36 -
4-(6-Chloropyrid-3-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound 105 Table I) was prepared as a colourless oil using a similar procedure (reaction heated for 2hours at 110°C).
EXAMPLE 9 This Example illustrates the preparation of 8-methyl-4-(pyrimidin-5-yl)-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 65 Table I). Stage 1: Preparation of 5-iodopyrimidine.
A solution of nickel bromide (12ml of a 0.16M solution in N,N-dimethylformamide) was purged with nitrogen and tributyl phosphine (1ml) was added with stirring. Potassium iodide (30g) and 5-bromopyrimidine (6g) were then added and the mixture was heated to 145-150°C for 22 hours under an atmosphere of nitrogen. The reaction mixture was cooled to ambient temperature, poured into water (800ml) and extracted with diethyl ether (2x400ml). The extracts were combined, washed with water (200ml), washed with aqueous sodium chloride solution (200ml) and then dried (magnesium sulfate). The solvent was evaporated under reduced pressure and the product obtained sublimed at 120- 160°C at lOOmmHg to give a solid (3.4g). This material was triturated with hexane to give a colourless solid (0.9g) which was used in the next Stage without further purification. GC analysis indicated that the solid contained 5-iodopyrimidine (80%) and 5-bromopyrimidine (20%). Stage 2:
The product from Stage 1 (0.9g) was dissolved in triethylamine (2ml, dry) containing 8-methyl-8-azabicyclo[3.2.1]oct-2-ene (1.3g) and copper (I) bromide (0.20g). The mixture was stirred under an atmosphere of nitrogen, trans-di(μ-acetato)-bis[o (di- otolyDbenzyl] dipalladium(II) (0.1 OOg) was added and the mixture was heated to 110°C for lhour. Further N,N-dimethylformamide (0.5ml) was added and the reaction mixture was heated for a further όhours then cooled to ambient temperature. The mixture was poured into aqueous ammonia solution and extracted with ethyl acetate (three times). The organic extracts were combined and extracted twice with aqueous hydrochloric acid (2M) and the organic phase discarded. The aqueous acidic extracts were combined then treated with sodium carbonate until basic. The aqueous mixture was extracted three times with ethyl acetate and the organic extracts were combined and then dried (magnesium sulfate). The solvent was evaporated under - 37 -
reduced pressure to give a brown solid which was fractionated by preparative thick layer chromatography (silica; 10% methanol in dichloromethane) to give the required product as an orange oil (0.012g).
EXAMPLE 10 This Example illustrates the preparation of 4-(6-chloropyrid-3-yl)-8- vinyloxycarbonyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 122 Table I).
4-(6-Chloropyrid-3-yl)-8-methyl-8-azabicyclo[3.2. l]oct-2-ene (Compound 105, Table I) (0.90g) was dissolved in dry tetrahydrofuran (10ml) containing anhydrous potassium carbonate (2.12g) and the mixture stirred under an atmosphere of nitrogen at ambient temperature. Vinyl chloroformate (1.3ml) was added to the mixture which was then stiπed for 3hours and stored at ambient temperature for 1 δhours. The mixture was heated to reflux for όhours, cooled to ambient temperature and then poured into water. The aqueous mixture was extracted with ethyl acetate (three times) and the organic extracts were combined and then washed with an aqueous solution of ammonium chloride. The organic phase was dried (magnesium sulfate) and evaporated under reduced pressure to give a yellow oil which was fractionated by chromatography (silica; 10% ethyl acetate in hexane ). The fractions containing the required product were evaporated under reduced pressure (O.lmmHg, 50°C) to give a yellow gum (0.485g).
In a similar procedure, 4-(5-chloropyrid-3-yl)-8-vinyloxycarbonyl-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 123 Table I) was prepared from 4-(5- chloropyrid-3-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 35 Table I).
EXAMPLE 11 This Example illustrates the preparation of 4-(6-chloropyrid-3-yl)-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 99 Table I). 4-(6-Chloropyrid-3-yl)-8-vinyloxycarbonyl-8-azabicyclo[3.2.1 ]oct-2-ene (Compound
No. 122 Table I) (0.435g) was dissolved in methanol (5ml) and treated with aqueous hydrochloric acid (5ml). The mixture was stiπed and heated to reflux for 3hours then cooled to ambient temperature. The mixture was poured into water, extracted with ethyl acetate (twice) and the organic extracts discarded. The aqueous acidic fraction was treated with sodium carbonate until basic and then extracted with ethyl acetate (three times). The extracts - 38 -
were combined, dried (magnesium sulfate) and evaporated under reduced pressure to give the required product as a pink solid (0.25g).
In a similar procedure, 4-(5-chloropyrid-3-yl)-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 29 Table I) was prepared from 4-(5-chloropyrid-3-yl)- 8-vinyloxycarbonyl- 8-azabicyclo[3.2.1]oct-2-ene (Compound No. 123 Table I).
EXAMPLE 12 This Example illustrates the preparation of 4-(5-bromopyrid-3-yl)-8-(but-2-ynyl)-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 40 Table I).
4-(5-Bromopyrid-3-yl)-8-azabicyclo[3.2.1]oct-2-ene (0.070g) was dissolved in tetrahydrofuran (1ml) with stirring then diisopropylethylamine (0.046ml) and 2-butynyl p- toluenesulfonate (0.059g) were added. The mixture was heated to reflux under an atmosphere of nitrogen for 2hours then cooled to ambient temperature. The mixture was diluted with water and extracted with ethyl acetate (three times). The extracts were combined, dried (magnesium sulfate) and evaporated under reduced pressure to give an orange oil. The oil was fractionated by preparative thick layer chromatography (silica; ethyl acetate) to give the required product, 0.040g, as an orange oil.
In a similar manner, 8-(but-2-ynyl)-4-(5-chloropyrid-3-yl)-8-azabicyclo[3.2.1]oct-2- ene (Compound No. 32 Table I) was prepared, as a colourless oil, from 4-(5-chloropyrid-3- yl)-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 29 Table I). EXAMPLE 13
This Example illustrates the preparation of 4-(6-chloropyrid-3-yl)- 8-formyl-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 103 Table I).
4-(6-Chloropyrid-3-yl)-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 99 Table I) (0.070g) was dissolved in dry dichloromethane (1ml) and was treated with diisopropylethylamine (0.1ml) followed by formyl acetic anhydride (0.36ml). The mixture was stiπed at ambient temperature for 2hours and the solvent then evaporated under reduced pressure to give a brown gum. The gum was dissolved in diethyl ether (5ml), washed with aqueous sodium carbonate solution and then dried (magnesium sulfate). The solvent was evaporated under reduced pressure to give the required product as a gum (0.065g). - 39 -
In a similar procedure, 4-(5-chloropyrid-3-yl)- 8-formyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 33 Table I) was prepared from 4-(5-chloropyrid-3-yl)-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 29 Table I).
EXAMPLE 14 This Example illustrates the preparation of 8-allyl-4-(6-chloropyrid-3-yl)-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 101 Table I).
4-(6-Chloropyrid-3-yl)-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 99 Table I) (0.070g), allyl bromide (0.038g) and anhydrous potassium carbonate (0.43g) in tetrahydrofuran (dry, 1ml) were stiπed and heated to reflux for 5hours under an atmosphere of nitrogen. The mixture was cooled to ambient temperature, poured into water and then extracted with ethyl acetate (three times). The organic fractions were combined, dried (magnesium sulfate) and the solvent was then evaporated under reduced pressure to give a brown oil. The oil was fractionated by preparative thick layer chromatography (silica; 50% ethyl acetate in hexane) to give the required product as a pale yellow oil (0.050g). In a similar manner, 4-(6-chloropyrid-3-yl)-8-(4-fluorobenzyl)-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 124 Table I) was prepared, as a colourless solid, using 4-fluorobenzyl bromide.
EXAMPLE 15 This Example illustrates the preparation of 2-(3-nitro-4-methoxyphenyl)-8-methyl-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 126 Table I) and 4-(3-nitro-4-methoxyphenyl)-8- methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 127 Table I).
4-Bromo-2-nitroanisole (0.50g), 8-methyl-8-azabicyclo[3.2.1]oct-2-ene (0.5ml), palladium acetate (0.25g), copper (I) bromide (0.25g), tri-ortho-tolylphosphine (0.25g), diisopropylethylamine (2ml) and DMF (1.5ml) were heated together in a sealed Wheaton vial to 105°C (heater block temperature) for 96hours. After cooling, aqueous ammonia was added and the mixture extracted with ethyl acetate. The ethyl acetate layer was then extracted with dilute aqueous hydrochloric acid. The aqueous layer was separated and basified with aqueous sodium hydroxide and extracted with ethyl acetate. The ethyl acetate layer was dried (magnesium sulfate) and the solvent evaporated to leave a mixture of the 2- and 4- substituted products. This mixture was purified by chromatography on silica eluting with methanol : dichloromethane : triethylamine (in the ratio 5:94: 1) and then on a preparative - 40 -
silica plate eluting with 10% methanol in dichloromethane, to give, in order of elution, 4-(3-nitro-4-methoxyphenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene as a gum (0.058g) and 2-(3-nitro-4-methoxyphenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene as a gum (0.017g). 4-(2,4-Dimethoxyphenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 128 Table I) was prepared by a similar procedure.
4-(5-Chloro-2-hydroxyphenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 125 Table I) was prepared by a similar procedure.
4-e o-(3,4-Methylenedioxyphenyl)-8-methyl-8-azabicyclo[3.2.1 ]oct-2-ene (Compound No. 140 Table I) was prepared, as a yellow gum, by a similar procedure. EXAMPLE 16
This Example illustrates the preparation of 2-(4-chloro-2-fluorophenyl)-8-methyl-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 128 Table I).
4-Chloro-2-fluorobromobenzene (0.60g), 8-methyl-8-azabicyclo[3.2.1 ]oct-2-ene (0.672g), frm s-di(μ-acetato)-bis[o-(di-o-tolyl)benzyl]dipalladium(II) (0.20g), triphenyl borane (0. Ig), triethylamine (1ml) and dimethylformamide (4ml) were heated together in a sealed Wheaton vial to 105°C (heater block temperature) for 72hours. After cooling, water was added and the mixture extracted with ethyl acetate. The ethyl acetate layer was then extracted with dilute aqueous hydrochloric acid. The aqueous layer was separated and basified with aqueous NaOH and extracted with ethyl acetate. The ethyl acetate layer was dried (magnesium sulfate) and the solvent evaporated to leave the crude product. This was purified by chromatographing twice on silica, eluting with methanol : dichloromethane : triethylamine (in the ratio 5:93:2) to give the product as a gum (0.012g). 4-ej o-[(3-Methylbenzoxazol-2-one)-6-yl]-8-methoxycarbonyl-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 134 Table I) was prepared, as a yellow gum, by a similar procedure.
4-exo-(3 ,4-Methylenedioxyphenyl)-8-methoxycarbonyl-8-azabicyclo [3.2.1 ]oct-2-ene (Compound No. 143 Table I) was prepared by a similar method.
EXAMPLE 17 This Example illustrates the preparation of 4-exø-[(l,3-dimethylbenzimidazolin-2- one)-5-yl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 136 Table I). - 41 -
Stage 1: Preparation of l,3-dimethylbenzimidazolin-2-one.
To a solution of l-methylbenzimidiazolin-2-one (l.Og) in tetrahydrofuran was added NaH (0.28g of a 60% oil dispersion) portionwise. After the effervescence had subsided, iodomethane (0.42ml) was added and the mixture was stiπed at room temperature overnight. Water was added with caution and the mixture was extracted with ethyl acetate, dried (MgSO4) and evaporated to give the crude product (0.32g) which was used directly in Stage 2. Stage 2: Preparation of 5-bromo-l,3-dimethylbenzimidazolin-2-one. l,3-Dimethylbenzimidazolin-2-one (0.32g) was dissolved in chloroform (15ml). A solution of bromine (0.10ml) in chloroform (5ml) was added dropwise. The mixture was left at room temperature overnight and then washed with water (three times), dried (MgSO4) and evaporated to give the crude product (0.30g) which was used directly in Stage 3. Stage 3:
Using 5-bromo-l,3-dimethylbenzimidazolin-2-one prepared in Stage 2, 4-exo-[(l,3- dimethylbenzimidazolin-2-one)-5-yl]-8-methyl-8-azabicyclo[3.2. l]oct-2-ene (Compound No. 136 Table I) was prepared by a similar method to that described in Example 16. The product was obtained as a yellow gum.
EXAMPLE 18 This Example illustrates the preparation of 4-exo-[(6-methoxybenzoxazol-2-one)-5- yl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 133 Table I). Stage 1 : Preparation of 5-bromo-6-methoxybenzoxazol-2-one.
6-Methoxybenzoxazol-2-one (0.774g, 4.7mmol) was dissolved in dichloromethane (15ml) and the solution cooled to 0°C (ice bath). Bromine (0.24ml, 4.7mmol) in dichloromethane (5ml) was added dropwise and the mixture was left to warm to room temperature overnight, during which time a precipitate formed. This was filtered to give the crude product. Recrystallisation from ethyl acetate/hexane gave the pure product as a pink solid (0.59g). Stage 2:
Using 5-bromo-6-methoxybenzoxazol-2-one prepared as in Stage 2, A-exo-[{6- methoxybenzoxazol-2-one)-5-yl]-8-methyl-8-azabicyclo[3.2.1 ]oct-2-ene (Compound No. - 42 -
133 Table I) was prepared by a similar method to that described in Example 16. The product was obtained as a white solid.
EXAMPLE 19 This Example illustrates the preparation of 4-exø-[(3-methylbenzoxazol-2-one)-6-yl]- 8-methyl-8-azabicyclo[3.2.1 ]oct-2-ene (Compound No. 137 Table I). Stage 1 : Preparation of 6-bromo-3-methylbenzoxazol-2-one.
3-Methylbenzoxazol-2-one (l.Og) was dissolved in CC14 (50ml). A solution of bromine (0.346ml) in CC14 (5ml) was added dropwise. The mixture was left at room temperature overnight, washed with a saturated aqueous solution of NaHCO3, dried (MgSO4) and the solvent evaporated to give the crude product (l.lg) which was used directly in Stage 2. Stage 2:
Using 6-bromo-3-methylbenzoxazol-2-one prepared in Stage 1, 4-ej o-[(3- methylbenzoxazol-2-one)-6-yl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 137 Table I) was prepared by a similar method to that described in Example 16. The product was obtained as a brown solid.
EXAMPLE 20 This Example illustrates the preparation of 4-exo-[(l-methylbenzimidazolin-2-one)-5- yl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 138 Table I). Stage 1: Preparation of 5-bromo-l-methylbenzimidazolin-2-one.
A solution of bromine (0.346ml, 70mmol) in CHC13 (5ml) was added dropwise to a solution of l-methylbenzimidazolin-2-one in CHC13 (100ml). A precipitate formed immediately. The reaction mixture was left at room temperature overnight and the solid was collected by filtration to give a mixture of the possible mono-brominated regioisomers. Crystallisation from CHC13 gave the desired pure 5-bromo-l-methylbenzimidazolin-2-one isomer (0.52g). Stage 2:
Using 5-bromo-l-methylbenzimidazolin-2-one prepared in Stage 1, A-exo-[{\- methylbenzimidazolin-2-one)-5-yl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 138 Table I) was prepared by a similar method to that described in Example 16, except that - 43 -
copper (I) bromide was used in place of triphenyl borane. The product was obtained as a yellow gum.
EXAMPLE 21 This Example illustrates the preparation of 4-exø-[(3-methylbenzoxazol-2-one)-6-yl]- 8-azabicyclo[3.2.1 ]oct-2-ene (Compound No. 131 Table I).
Method 1 : Preparation from 4-exo-[(3-methylbenzoxazol-2-one)-6-yl]-8-methyl-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 137 Table I).
To a solution of 4-e o-[(3-methylbenzoxazol-2-one)-6-yl]-8-methyl-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 137 Table I) (0.136g) in 1,2-dichloroethane (5ml) was added chloroethyl chloroformate (66μl). The reaction mixture was heated to reflux overnight and then evaporated to dryness. The residue was partitioned between ethyl acetate and a saturated aqueous solution of NaHCO3. The organic layer was dried (MgSO4) and any remaining solvent was removed by evaporation. *H NMR analysis revealed a 2: 1 mixture of starting material to the desired product. The mixture was redissolved in 1,2- dichloroethane and further chloroethyl chloroformate (150μl) was added. The mixture was refluxed overnight, washed with a saturated aqueous solution of NaHCO3, dried (MgSO4) and then the solvent was evaporated. The residue was stiπed in methanol for 72hours and evaporated to dryness. Purification by flash chromatography on silica, eluting with dichloromethane/methanol/triethylamine (in the ratio 97:2:1) gave a mixture of starting material and the desired 8-demethylated product in a 1 : 1 ratio (0.063 g).
Method 2: Preparation from 4-exo-[(3-methylbenzoxazol-2-one)-6-yl]-8-methoxycarbonyl- 8-azabicyclo[3.2.1]oct-2-ene (Compound No. 134 Table I).
4-exø-[(3-methylbenzoxazol-2-one)-6-yl]-8-methoxycarbonyl-8-azabicyclo[3.2.1]oct- 2-ene (Compound No. 134 Table I) (0.055g, prepared as described in Example 16) was dissolved in CHC13 (3ml) under a nitrogen atmosphere. Trimethylsilyliodide (30μl) was added and the mixture was heated to reflux. After 2hours, a precipitate had formed. Dilute aqueous HC1 was added and the mixture stiπed for 5minutes. The aqueous layer was separated, basified with IN NaOH (aq) and extratcted with ethyl acetate. The organic layer was dried (MgSO4) and solvent was evaporated to give 4-exo-[(3-methylbenzoxazol-2-one)- 6-yl]-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 131 Table I) as a colourless solid (0.040g). - 44 -
4-exø-(3,4-Methylenedioxyphenyl)-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 142 Table I) was prepared by a similar procedure to that described in Method 2.
EXAMPLE 22 This Example illustrates the preparation of 4-exø-[(3-methylbenzoxazol-2-one)-6-yl]- 8-benzyl-8-azabicyclo[3.2.1 ]oct-2-ene (Compound No. 132 Table I).
A 1:1 mixture of 4-exo-[(3-methylbenzoxazol-2-one)-6-yl]-8-methyl-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 137 Table I) and 4-ejcø-[(3-methylbenzoxazol-2- one)-6-yl]-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 131 Table I) (0.063g, prepared as described in Example 21, Method 1) was dissolved in tetrahydrofuran (5ml). Benzyl bromide (12μl) and potassium carbonate (0.014g) were added and the mixture was stiπed under a nitrogen atmosphere for 48hours. The mixture was filtered and the filtrate evaporated to dryness. The residue was purified by flash chromatography on silica, eluting with ethyl acetate/hexane (1:3), to give the pure product (0.018g), leaving the unreacted 4- exø-[(3-methylbenzoxazol-2-one)-6-yl]-8-methyl-8-azabicyclo[3.2.1 ]oct-2-ene (Compound No. 137 Table I) on the baseline. The product was obtained as a white solid.
8-Benzyl-4-exø-(3,4-methylenedioxyphenyl)-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 141 Table I) was prepared by a similar procedure.
EXAMPLE 23 This Example illustrates the preparation of 4-exø-[(3-methylbenzoxazol-2-one)-6-yl]- 8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2. l]oct-2-ene (Compound No. 139 Table I). A solution of trifluoroethanol (13μl) and diisopropylethylamine (30μl) in dichloromethane (1ml) was added slowly to a solution of triflic anhydride (30μl) in dichloromethane (4ml) at -50°C under a nitrogen atmosphere. The reaction mixture was stiπed at -50°C for lhour and then allowed to warm to room temperature and stiπed for a further lhour. The mixture was then added to 4-eJ ø-[(3-methylbenzoxazol-2-one)-6-yl]-8- azabicyclo[3.2.1]oct-2-ene (Compound No. 131 Table I) (0.022g, prepared as described in Example 21, Method 2) and diisopropylethylamine (30μl). This mixture was left to stand for 72hours, evaporated to dryness and the residue purified by flash chromatography on silica, eluting with ethyl acetate/hexane (1 : 1), to give the product (0.01 lg) as a yellow gum. - 45 -
EXAMPLE 24 This Example illustrates the preparation of 2-[(l,3-dimethylbenzimidazolin-2-one)-5- yl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 135 Table I).
4-eJ ø-[(l,3-dimethylbenzimidazolin-2-one)-5-yl]-8-methyl-8-azabicyclo[3.2.1]oct-2- ene (Compound No. 136 Table I) (0.1 Og, prepared as described in Example 17) and potassium tert-butoxide (0.039g) in tetrahydrofuran (5ml) were heated in a sealed Wheaton vial at 70°C for 16hours. After cooling, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried (MgSO4) and evaporated to give the pure product (0.1 Og) as a yellow gum. EXAMPLE 25
This Example illustrates the preparation of 2-(5-Chloro-3,4-methylenedioxyphenyl)- 8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Compound No. 144 Table I). Stage 1 : Preparation of 4-bromo-5-chloro-l,2-methylenedioxybenzene.
4-Bromo-l,2-methylenedioxybenzene (l.Og, 50mmol) was dissolved in dimethylformamide (10ml). N-chloro succinimide (0.67g, 50mmol) was added and the mixture left to stand for 48hours at room temperature. Water was added and the mixture extracted with ether. The organic layer was washed with water (three times), dried (MgSO4) and the solvent evaporated. The crude product was recrystallised from hexane to give the desired 5-chloro derivative contaminated with the 3,5-dichloro derivative in a 2: 1 ratio (0.82g).
Stage 2: Preparation of 4-exo-(5-chloro-3 ,4-methylenedioxyphenyl)-8-methyl-8- azabicyclo[3.2.1 ]oct-2-ene.
Using the 4-bromo-5-chloro-l,2-methylenedioxybenzene from Stage 1, 4-exo-(5- chloro-3,4-methylenedioxyphenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene was prepared by a similar method to that described in Example 16. The 4-bromo-3,5-dichloro-l,2- methylenedioxybenzene present in the starting material did not react under these conditions.
The product was obtained as a gum, 'H NMR (CDC13) δ: 1.65(lH,m); 1.85(lH,dt); 2.05(lH,m); 2.15(3H,s); 2.20(lH,m); 3.15(lH,br.d); 3.32(lH,t); 3.42(lH,m); 5.40(lH,m); 5.92(2H,s); 6.15(lH,m); 6.82(lH,s); 7.09(1 H,s)ppm. - 46 -
Stage 3:
Using the 4-e ø-(5-chloro-3,4-methylenedioxyphenyl)-8-methyl-8- azabicyclo[3.2.1]oct-2-ene from Stage 2, 2-(5-chloro-3,4-methylenedioxyphenyl)-8-methyl- 8-azabicyclo[3.2.1]oct-2-ene was prepared using a similar procedure to that described in Example 24, except that the reaction was carried out in refluxing tetrahydrofuran. The product was obtained as a yellow gum.
EXAMPLE 26 This Example illustrates an emulsifiable concentrate composition which is readily convertible, by addition to water, into a preparation suitable for spraying purposes. The emulsifiable concentrate has the following composition:
% by weight Compound No. 1 25.0
SYNPERONIC NP13 2.5
Calcium dodecylbenzenesulphonate 2.5
AROMASOL H 70.0
EXAMPLE 27 This Example illustrates a wettable powder composition which is readily convertible, by addition to water, into a preparation suitable for spraying purposes. The wettable powder has the following composition:
% by weight Compound No. 1 25.0
Silica 25.0
Sodium lignosulphonate 5.0
Sodium lauryl sulphate 2.0
Kaolin 43.0 - 47 -
EXAMPLE 28 This Example illustrates a dustable powder which may be applied directly to plants or other surfaces. The dustable powder has the following composition:
% by weight Compound No. 1 1.0
Talc 99.0
EXAMPLE 29
This Example illustrates an oil miscible liquid formulation suitable for application by ultra low volume techniques after mixing with an organic diluent. The formulation has the following composition:
% by weight Compound No. 1 10.0
SOLVESSO 200 90.0
EXAMPLE 30
This Example illustrates a capsule suspension concentrate which is readily convertible, by addition to water, into a preparation suitable for application as an aqueous spray. The capsule suspension concentrate has the following composition:
% by weight Compound No. 1 10.0
AROMASOL H 10.0
Toluene di-isocyanate 3.0
SYNPERONIC A7 1.0
Polyvinyl alcohol 2.0
Bentonite 1.5
KELTROL 0.1
Water 72.4 - 48 -
EXAMPLE 31 This Example illustrates a ready for use granular formulation that is prepared from a pre-formed granular carrier. The granular formulation has the following composition:
% by weight Compound No. 1 0.5
SOLNESSO 200 0.2
SYNPERONIC A7 0.1
Calcium carbonate granules (diameter 0.3-0.7mm) 99.2
EXAMPLE 32
This Example illustrates a ready for use granular formulation that is prepared by granulation of the powdered components. The granular formulation has the following composition:
% by weight Compound No. 1 0.5
Sodium lignosulphonate 5.0
Kaolin 94.5
EXAMPLE 33
This Example illustrates an aqueous suspension concentrate composition which is readily convertible, by addition to water, into a preparation suitable for spraying purposes. The suspension concentrate has the following composition:
% by weight Compound No. 1 25.0
Sodium lignosulphonate 3.0
Propylene glycol 10.0
Bentonite 2.0
KELTROL 0.1
PROXEL 0.1
Water 59.8 - 49 -
EXAMPLE 34 This Example illustrates a water dispersible granule formulation which is readily convertible, by addition to water, into a preparation suitable for spraying purposes. The water dispersible granule has the following composition:
% by weight Compound No. 1 25.0
Silica 5.0
Sodium lignosulphonate 10.0
Sodium lauryl sulphate 5.0
Sodium acetate 10.0
Montmorillonite powder 45.0
EXAMPLE 35 This Example illustrates the pesticidal properties of compounds of formula (I). The activities of individual compounds of formula (I) were determined using a variety of pests. With the exception of nematodes, the pests were treated with a liquid composition containing 500 parts per million (ppm) by weight of a compound unless otherwise stated. Each composition was made by dissolving the compound in an acetone and ethanol (50:50 by volume) mixture and diluting the solution with water containing 0.05% by volume of a wetting agent, SYNPERONIC NP8, until the liquid composition contained the required concentration of the compound. The test procedure adopted with regard to each pest, except nematodes, was essentially the same and comprised supporting a number of the pests on a medium which was usually a substrate, a host plant or a foodstuff on which the pests feed, and treating either or both the medium and the pests with a composition. Pest mortality was assessed usually between two and five days after treatment. Knockdown of housefly (Musca domestica) was assessed 15 minutes after treatment.
The results of the tests against peach aphid (Mvzus persicae are presented below. The results indicate a grading of mortality (score) designated as A, B or C wherein C indicates less than 40% mortality, B indicates 40-79% mortality and A indicates 80-100%) 50
mortality. In this test Chinese cabbage leaves were infested with aphids, the infested leaves were sprayed with the test composition, and the mortality assessed after 3 days.
Compound Nos. 1, 2, 8, 19, 30, 32, 33, 35, 37, 40, 57, 65, 99, 100, 101, 103, 105, 112, 120, 122, 123, 124 and 140 of Table I each gave a mortality score of A; Compound Nos. 5, 6, 7, 10, 49, 97, 130, 132, 133, 134 and 137 of Table I each gave a score of B; and Compound Nos. 3, 4, 9, 11, 12, 125, 126, 127, 128, 129, 131, 135, 136, 138, 139 and 144 of Table I each gave a score of C.
In addition, in a similar test against two-spotted spider mites (Tetranvchus urticae) Compound Nos. 120 and 140 of Table I gave a mortality score of A whilst Compound Nos. 2, 112 and 144 of Table I each gave a mortality score of B.
The test procedure for nematodes involved dissolving the compound in an acetone and ethanol (50:50 by volume) mixture and diluting the solution with water to obtain a final concentration of the compound of 12.5ppm. J2 infective juveniles of Meloidogyne incognita were suspended in the solution in a glass vial and mortality assessed after a period of three days; Compound No. 112 of Table I gave a mortality score of A whilst Compound Nos. 3, 35 and 105 of Table I each gave a mortality score of B.
The formulae refeπed to hereinabove are set out as follows.
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000052_0003
(I) (II) (III)
ώ FT OH
(IV)
Figure imgf000052_0004
Figure imgf000052_0005
-51
Scheme 1
R
R^
Figure imgf000053_0001
(I)

Claims

- 52 - CLAIMS
1. A compound of formula (I):
Figure imgf000054_0001
(I) wherein one of R1 and R2 is hydrogen and the other is a phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, benzoxazol-2-one or benzimidazolin-2-one ring, said ring being optionally substituted with halogen, Cw alkyl, C,^ haloalkyl, C,^ alkoxy, Cw haloalkoxy, CM alkenyl, C2^ alkynyl, hydroxy, nitro, cyano or methylenedioxy; R is hydrogen, formyl, C,^ alkyl (optionally substituted with cyano, CO2(C,^ alkyl) or phenyl (itself optionally substituted with halogen, C,^ alkyl, C,^ alkoxy, C,^ haloalkyl or CM haloalkoxy)), CH2(CW haloalkyl), CO2(C,^ alkyl), CO2(C2^ alkenyl), CH2(C2^ alkenyl), CH2(C2^ alkynyl), benzyl (wherein the phenyl ring is optionally substituted with halogen or CM alkyl) or XR3; X is O or NR4; R3 and R4 are, independently, hydrogen, cyano, Cw alkyl (optionally substituted with halogen, cyano, CO2(Cw alkyl) or phenyl (itself optionally substituted with halogen, C,^ alkyl, .6 alkoxy, Cw haloalkyl or CM haloalkoxy)), phenyl (itself optionally substituted with halogen, Cw alkyl, C,^ alkoxy, Cw haloalkyl or Cw haloalkoxy), C2^ alkenyl or CM alkynyl; or an acid addition salt or N-oxide thereof; provided that when R is methyl, CO2CH3 or CO2CH2CH3 then R2 is not a 6-substituted pyrid-3-yl; that when R is other than hydrogen or CH2(C,^)haloalkyl then R2 is not phenyl substituted with hydroxy or alkoxy; and that when R1 is hydrogen and R is hydrogen, unsubstituted CM alkyl, CH2(CM alkenyl) or CH2(CM alkynyl) then R2 is not a pyridyl, pyrimidinyl, pyrazinyl, thienyl or thiazolyl ring (said ring being unsubstituted or substituted by unsubstituted alkyl only).
A compound of formula (I) as claimed in claim 1, wherein one of R1 and R2 is hydrogen and the other is a phenyl, pyrid-2-yl, pyrid-3-yl, pyrimidin-5-yl, pyrazin-2- yl, thien-2-yl, thiazol-5-yl, (benzoxazol-2-one)-5-yl, (benzoxazol-2-one)-6-yl or - 53 -
(benzimidazolin-2-one)-5-yl ring, said ring being optionally substituted with halogen, C alkyl, C alkoxy, C2^ alkenyl, Cw alkynyl, hydroxy, nitro or methylenedioxy.
3. A compound of formula (I) as claimed in claim 1, wherein R is hydrogen, formyl (CHO), CM alkyl, CO2(C^ alkyl), CO2(Cw alkenyl), CH2(C,^ haloalkyl), benzyl
(wherein the phenyl ring is optionally substituted with halogen or CM alkyl, CH2(C2_6 alkenyl) or CH2(CW alkynyl)).
4. A compound of formula (I) as claimed in claim 1 , wherein R2 is hydrogen.
5. A compound of formula (I) as claimed in claim 1, wherein R is hydrogen, formyl (CHO), CM alkyl, CO2(C,^ alkyl), CO2(CM alkenyl), CH2(CW haloalkyl), CH2(CM alkenyl), CH2(CW alkynyl) or benzyl (wherein the phenyl ring is optionally substituted with halogen); R1 is phenyl (optionally substituted with halogen, CM alkoxy, hydroxy, nitro or methylenedioxy), pyrid-2-yl (optionally substituted with halogen), pyrid-3-yl (optionally substituted with halogen), pyrimid-5-yl, thien-2-yl (optionally substituted by CM alkyl), thiazol-5-yl (optionally substituted by CM alkyl or halogen), pyrazin-2-yl (optionally substituted by halogen), (benzoxazol-2-one)-5- yl (optionally substituted by CM alkoxy), (benzoxazol-2-one)-6-yl (optionally substituted by CM alkyl) or (benzimidazolin-2-one)-5-yl (optionally substituted by
CM alkyl); and R2 is hydrogen.
6. A compound of formula (I) as claimed in claim 1, wherein R is hydrogen, formyl (CHO), C alkyl, CO2(Cw alkyl), C02(CM alkenyl), CH2(CW haloalkyl) (especially CH2CF3), CH2(CW alkenyl), CH2(C2^ alkynyl) or benzyl (wherein the phenyl ring is optionally substituted with halogen); R1 is hydrogen; and R2 is phenyl (optionally substituted with halogen, C alkoxy, nitro or methylenedioxy), pyrid-2-yl (optionally substituted with halogen), pyrid-3-yl (optionally substituted with halogen) or (benzimidazolin-2-one)-5-yl (optionally substituted with CM alkyl). - 54 -
7. Processes for preparing the compounds of formula (I) as claimed in claim 1, comprising: (i) coupling a compound of formula (II), wherein R is as described in claim 1,
(ll)
with a compound of formula R*Hal, wherein R* is a phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, benzoxazol-2-one, benzimidazolin-2-one or thiazolyl ring substituted as described in claim 1 and Hal is a halide, in the presence of a catalyst;
(ii) to form a compound wherein R1 is hydrogen, dehydrating a compound of formula (IN):
Figure imgf000056_0001
OH (IV) wherein R and R2 are as described in claim 1, with a dehydrating reagent;
(iii) to form a compound wherein R and R2 are both hydrogen, treating a compound of formula (I), wherein R2 is hydrogen and R is alkyl, with either an azodicarboxylate at an elevated temperature and acidifying the product so formed; or an alkyl-, alkenyl- or haloalkyl-chloroformate and hydrolysing the carbamate so formed; - 55 -
(iv) to form a compound wherein R is not hydrogen and R2 is hydrogen by reacting a compound RL (wherein L is a leaving group) with a compound of formula (I) wherein R and R2 are both hydrogen; or
(v) isomer conversion:
Figure imgf000057_0001
Figure imgf000057_0002
(0 in which a compound of formula (I), wherein R2 is hydrogen and R and R1 are as described in claim 1, is reacted with a base in a solvent at a temperature in the range 60 to 80°C.
8. An insecticidal, acaricidal, nematicidal or molluscicidal composition comprising an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I):
Figure imgf000057_0003
(I) wherein one of R1 and R2 is hydrogen and the other is a phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, benzoxazol-2-one or benzimidazolin-2-one ring, said ring being optionally substituted with halogen, Cw alkyl, C,^ haloalkyl, C,^ alkoxy, C,^ haloalkoxy, C2 > alkenyl, C2^ alkynyl, hydroxy, nitro, cyano or methylenedioxy;
R is hydrogen, formyl, C,^ alkyl (optionally substituted with cyano, CO2(Cw alkyl) or phenyl (itself optionally substituted with halogen, C,^ alkyl, Cw alkoxy, C,^ haloalkyl or CM haloalkoxy)), CH2(CW haloalkyl), CO2(C^ alkyl), CO2(CM alkenyl), CH2(CM alkenyl), CH2(C2^ alkynyl), benzyl (wherein the phenyl ring is optionally - 56 -
substituted with halogen or CM alkyl) or XR3; X is O or NR4; R3 and R4 are, independently, hydrogen, cyano, C,^ alkyl (optionally substituted with halogen, cyano, CO2(C,^ alkyl) or phenyl (itself optionally substituted with halogen, Cw alkyl, Cw alkoxy, C^ haloalkyl or C,^ haloalkoxy)), phenyl (itself optionally substituted with halogen, Cw alkyl, Cw alkoxy, C,^ haloalkyl or Cw haloalkoxy), C2^ alkenyl or
CM alkynyl; or an acid addition salt or N-oxide thereof; and a suitable carrier or diluent therefor.
9. A method of combating and controlling pests at a locus which comprises treating the pests or the locus of the pests with an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I):
Figure imgf000058_0001
(I) wherein one of R1 and R2 is hydrogen and the other is a phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, benzoxazol-2-one or benzimidazolin-2-one ring, said ring being optionally substituted with halogen, C,^ alkyl, Cw haloalkyl, C,^ alkoxy, Cw haloalkoxy, Cw alkenyl, C2^ alkynyl, hydroxy, nitro, cyano or methylenedioxy; R is hydrogen, formyl, Cw alkyl (optionally substituted with cyano, CO2(Cw alkyl) or phenyl (itself optionally substituted with halogen, Cw alkyl, Cw alkoxy, C,^ haloalkyl or C w haloalkoxy)), CH2(CW haloalkyl), CO2(C,^ alkyl), CO2(CM alkenyl),
CH2(C2^ alkenyl), CH2(C2^ alkynyl), benzyl (wherein the phenyl ring is optionally substituted with halogen or CM alkyl) or XR3; X is O or NR4; R3 and R4 are, independently, hydrogen, cyano, Cw alkyl (optionally substituted with halogen, cyano, CO2(Cw alkyl) or phenyl (itself optionally substituted with halogen, C^ alkyl, Cw alkoxy, Cw haloalkyl or CM haloalkoxy)), phenyl (itself optionally substituted with halogen, Cw alkyl, Cw alkoxy, Cw haloalkyl or Cw haloalkoxy), CM alkenyl or Cw alkynyl; or an acid addition salt or N-oxide thereof; or with an insecticidally, - 57 -
acaricidally, nematicidally or molluscicidally effective amount of a composition as claimed in claim 8.
10. A method according to claim 9 wherein the pests are insect pests of plants.
PCT/GB1999/000225 1998-01-29 1999-01-22 8-azabicyclo(3.2.1)oct-2-ene derivatives as pesticides WO1999038865A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993014636A1 (en) * 1992-01-23 1993-08-05 Dowelanco Insect control with substituted oxadiazole and thiadiazole compounds
WO1995003306A1 (en) * 1993-07-22 1995-02-02 E.I. Du Pont De Nemours And Company Arthropodicidal azacyclic heterocycles
WO1996008968A1 (en) * 1993-08-26 1996-03-28 Dowelanco Insect control with substituted triazole and tetrazole compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993014636A1 (en) * 1992-01-23 1993-08-05 Dowelanco Insect control with substituted oxadiazole and thiadiazole compounds
WO1995003306A1 (en) * 1993-07-22 1995-02-02 E.I. Du Pont De Nemours And Company Arthropodicidal azacyclic heterocycles
WO1996008968A1 (en) * 1993-08-26 1996-03-28 Dowelanco Insect control with substituted triazole and tetrazole compounds

Non-Patent Citations (1)

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Title
CHUNMING ZHANG ET AL.: "Synthesis of optically pure epibatidine analogs: (1R, 2R, 5S)-2 beta-(2-chloro-5-pyridinyl)-8-azabicyclo(3.2.1)octane and (1R,2S, 5S)-2 alpha-(2-chloro-5-pyridinyl)-8-azabicyclo(3.2.1)octane from (-)-cocaine", TETRAHEDRON LETTERS., vol. 38, - 11 August 1997 (1997-08-11), OXFORD GB, pages 5619 - 5622, XP002100760 *

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