TRIAZOLE COMPOUNDS, A PROCESS FOR PREPARING THEM, THEIR USE AS PLANT FUNGICIDES AND FUNGICIDAL COMPOSITIONS CONTAINING THEM

Abstract: Compounds of formula: which are cis- and trans-isomers, and mixtures thereof, wherein R¹ and R² which may be the same or different are alkyl, cycloalkyl or optionally substituted phenyl and their acid addition salts and metal complexes. The compounds have fungicidal activity useful in the agricultural and phar­ maceutical fields. They are also capable of regulating plant growth.

Description: TRIAZOLE COMPOUNDS, A PROCESS FOR PREPARING THEM, THEIR USE AS PLANT FUNGICIDES AND FUNGICIDAL COMPOSITIONS CONTAINING THEM This invention relates to triazole compounds useful as fungicides, to a process for preparing them, to fungicidal compositions containing them, and to processEs using them to combat fungal infections in plants,. The invention also relates to pharmaceutical and veterinary compositions comprising triazole compounds, and in particular to such compositions which are orally or topically active against fungus diseases of humans and other animals. These compositions of the invention are especially useful for treatment of candidiasis and human dermatophyte infections. The invention provides a compound having the formula EMI1.1 formula (I) which is the cis- or trans- isomer, or a mixture thereof, wherein R1 and R2, which may be the same or different, are alkyl, cycloalkyl (e.g. cyclopropyl, cyclopentyl, or cyclohexyl) or optionally substituted phenyl; and acid addition salts and metal complexes thereof. The compounds of the invention are generally obtained in the form of isomeric mixtures which can be separated into the individual isomers by methods known the art. The alkyl groups can be a straight or branched chain group having 1 to 6, e.g. 1 to 4, carbon atoms; examples are methyl, ethyl, propyl (n- or iso-proyl) and butyl (n-, sec-, iso- or t-butyl). Examples of suitable substituents for the phenyl are halogen (e.g. fluorine, chlorine or bromine), C15 alkyl Ce.g. methyl, ethyl, propyl (n- or iso-propyl) and butyl (n-, sec-, iso-or t-butyl)], C14 alkoxy (e.g. methoxy and ethoxy), C14 halo-alkoxy (e.g. trifluoromethoxy), C15 halo-alkyl (e.g. trifluoromethyl), nitro, phenyl and phenoxy. Either R1 or R2, but preferably both R1 and R21 are phenyl, unsubstituted or substituted with 1, 2 or3 ring substituents as defined above. Preferably the phenyl has one or two ring substituents in the 2- or 4positions. Examples of these groups are phenyl, 2-, 3- or 4-chlorophenyl, 2,4- or 2,6-dichlorophenyl, 2-, 3 or 4fluorophenyl, 2,6-difluorophenyl, 2-, 3- or 4-bromophenyl, 2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 2-, 3- or 4-methoxyphenyl, 2,4-dimethoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 2-, 3- or 4-nitrophenyl, 2-, 3- or 4-methylphenyl, 2-, 3- or 4-t-butylphenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4-phenoxyphenyl, and 2-, 3- or 4-phenylphenyl (2-, 3- or 4-biphenylyl). In a further aspect, therefore, the invention provides a triazole compound as defined above wherein R1 and R2, which may be the same or different are straight or branched chain alkyl groups having from 1 to 6 carbon atoms, or are phenyl optionally substituted with halogen, alkyl or halo-alkyl having from 1 to 5 carbon atoms, alkoxy or halo-alkoxy having from 1 to 4 carbon atoms, nitro, phenyl or phenoxy. In a still further aspect the invention provides a triazole compound as defined above wherein R1 and R2 are alkyl having from 1 to 4 carbon atoms, phenyl or halophenyl. In a preferred aspect the invention provides a triazole compound as defined above wherein R1 and R2 are both phenyl, 2-, 3- or 4-chlorophenyl, 2, 4- or 2, 6dichlorophenyl, 2-, 3- or 4-fluorophenyl, 2,6difluorophenyl, 2-, 3- or 4-bromophenyl, 2-chloro-4 fluorophenyl, 2-chloro-6-fluorophenyl, 2-, 3- or 4methoxyphenyl, 2,4-dimethoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 2-, 3- or 4-nitrophenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4-phenoxyphenyl or 2-, 3- or 4phenylphenyl (2-, 3- or 4-biphenyl). The salts can be salts with inorganic or organic acids e.g. hydrochloric, nitric, sulphuric, acetic, 4-toluenesulphonic or oxalic acid. Suitably the metal complex is one including, as the metal, copper, zinc, manganese or iron. It preferably has the general formula: EMI3.1 wherein R1 and R2 are as defined above, M is a metal, A is an anion (e.g. a chloride, bromide, iodide, nitrate sulphate or phosphate anion), n is 2 or 4, y is 0 or an integer of 1 to 12, and m is an integer consistent with valency. Examples of the compounds of the invention are shown in Table I. TABLE I EMI4.1 COMPOUND <SEP> RÚ <SEP> Rê <SEP> MELTING <tb> NO <SEP> POINT <SEP> ( C) <tb> 1 <SEP> 2-chlorophenyl <SEP> 4-fluorophenyl <SEP> Oil <tb> 2 <SEP> 2-chlorophenyl <SEP> 4-fluorophenyl <SEP> (nitrate <SEP> salt <tb> of <SEP> 1) <SEP> 124 <tb> 3 <SEP> phenyl <SEP> phenyl <tb> 4 <SEP> 4-chlorophenyl <SEP> 4-chlorophenyl <tb> 5 <SEP> 2,4-dichlorophenyl <SEP> phenyl <tb> 6 <SEP> 2-fluorophenyl <SEP> 4-chlorophenyl <tb> 7 <SEP> 2-fluorophenyl <SEP> 4-fluorophenyl <tb> 8 <SEP> 2-chlorophenyl <SEP> 4-chlorophenyl <tb> 9 <SEP> t-butyl <SEP> 4-chlorophenyl <tb> 10 <SEP> t-butyl <SEP> t-butyl <tb> 11 <SEP> 2-bromophenyl <SEP> 4-chlorophenyl <SEP> nitrate <SEP> salt <tb> 140-1 <tb> TABLE I CONTINUED EMI5.1 COMPOUND <SEP> MELTING <tb> NO <SEP> RÚ <SEP> Rê <SEP> POINT <SEP> ( C) <tb> 12 <SEP> 2-bromophenyl <SEP> 4-fluorophenyl <SEP> nitrate <SEP> salt <tb> 124-5 <tb> 13 <SEP> 4-chlorophenyl <SEP> 4-fluorophenyl <SEP> 101-2 <tb> 14 <SEP> 4-fluorophenyl <SEP> 4-fluorophenyl <tb> methoxyphenyl <tb> 15 <SEP> 2-chloro-4- <SEP> 4-fluorophenyl <tb> methoxyphenyl <tb> 16 <SEP> 4-(4-chloro- <SEP> phenyl <tb> phenyl) <SEP> phenyl <tb> 17 <SEP> 4-(4-chloro- <SEP> 4-chlorophenyl <tb> phenyl)phenyl <tb> 18 <SEP> 2,4-dichloro- <SEP> 4-fluorophenyl <tb> phenyl <tb> 19 <SEP> 2-chloro-4- <SEP> 4-fluorophenyl <tb> methylphenyl <tb> 20 <SEP> t-Butyl <SEP> 2,4-dichlorophenyl <tb> 21 <SEP> 2-(5-chloro- <SEP> 2,4-dichlorophenyl <tb> thienyl) <tb> The compounds of general formula (I) may be produced by dehydrating a compound of general formula (II): : EMI6.1 in which R1 and R2 are as defined above, under acidic conditions by refluxing in a suitable solvent. Suitably the compound of general formula (II) is reacted with phosphoric acid or trifluoroacetic acid by reflux in toluene or other suitable solvent. The product can be isolated by pouring the reaction mixture into water and purification by column chromatography. The compounds are usually produced as oils which readily form salts, e.g. nitrate salts. The compounds of general formula (II) may be produced by reacting a. compound of general formula (III) or (IV): EMI6.2 in which R1 and R2 are as defined above and Y is a halogen atom (preferably a chlorine or bromine atom), with 1,2,4-triazole either in the presence of an acidbinding agent or in the form of one of its alkali metal salts in a convenient solvent. Suitably the compound of general formula (III) or (IV) is reacted at 20-1000C with the sodium salt of 1,2,4-triazole (the salt Tan be prepared by adding either sodium hydride or sodium methoxide to 1,2,4-triazole) in a convenient solvent such as acetonitrile, methanol, ethanol or dimethylformamide. The product can be isolated by pouring the reaction mixture into water and recrystallising the solid formed from a convenient solvent. The compounds of general formula (III) and (IV) can be prepared by reacting a ketone of general formula (Va) or (Vb): EMI7.1 wherein R1, R2 and Y are as defined above with, respectively, a Grignard compound of general formula (VIa) or (VIb): Z- Mg- R2 Z -- Mg-- R1 (VIa) (VIb) wherein R1 and R2 are as defined above and Z is a halogen (preferably chlorine, bromine or iodine) in a convenient solvent such as diethyl ether or tetrahydrofuran. Generally a mixture of the compounds of general formula (III) and (IV) are obtained. For example. when a compound of general formula (Va) wherein R1 is alkyl or cycloalkyl is reacted, the compound of formula (III) generally predominates in the mixture; on the other hand, when R1 is optionally substituted phenyl, the compound of general formula (IV) generally predominates in the mixture. The compounds (III) and (IV) are valuable intermediates and form part of the present invention. The compounds of general formula (V) and (VI) may be made by methods set out in the literature. The compounds of general formula (III) wherein each of R1 and R2, which may be the same or different, is substituted phenyl may also be prepared by reacting the appropriate ketone of general formula (VII) R1¯ CO R2 (VII) wherein R1 and R2 are as defined above, with dimethyl oxosulphonium methylide (Corey and Chaykovsky, JACS, 1965, 87, 1353-1364) or dimethyl sulphonium methylide (Corey and Chaykovsky, JACS, 1962, 84, 3782) using methods set out in the literature. The ketones of general formula (VII) can be prepared,' using the Friedel-Crafts reaction, by methods set out in the literature. These ketones are valuable intermediates and as such form part of the invention. The compounds of general formula (III) wherein each of R1 is alkyl, cycloalkyl or optionally substituted phenyl and R2 is optionally substituted phenyl or optionally substituted benzyl can also be produced by reacting a /-hydroxy selenide compound of general formula (VIII) EMI8.1 wherein R1 and R2 are as defined above, with methyl iodide in potassium t-butoxide according to the method of Van Ende, Dumont alld Krief, Angew. Chem. Int. Ed., 1975, 14, 700. The g-hydroxy selenide compound can be prepared by treating the diselenide with the appropriate ketone in the presence of butyl lithium. The salts and metal complexes of the compounds of general formula (I) can be prepared from the latter in known manner. For example, the complexes can be made by reacting the uncomplexed compound with a metal salt in a suitable solvent. The compounds, salts and metal complexes are active fungicides, particularly against the diseases: Piricularia oryzae on rice Puccinia recondita, Puccinia striiformis and other rusts on wheat, Puccinia hordei, Puccinia striiformis and other rusts on barley, and rusts on other hosts e.g. coffee, apples, vegetables and ornamental plants Plasmopara viticola on vines Erysiphe graminis (powdery mildew) on barley and wheat and other powdery mildews on various hosts such as Sphaerotheca fuliginea on cucurbits (e.g. cucumber), Podosphaera leucotricha on apples and Uncinula necator on vines Helminthosporium spp. and Rhynchosporium spp. on cereals Cercospora arachi di cola on peanuts and other Cercospora species on for example sugar beet, bananas and soya beans Botrytis cinerea (grey mould) on tomatoes, strawberries, vines and other hosts Phytophthora infestans (late blight) on tomatoes Venturia inaequalis (scab) on apples Some of the compounds have also shown a broad range of activities against fungi in vitro. They have activity against various post-harvest diseases on fruit (e.g. Penicillium digatatum and italicum on oranges and Gloeosporium musarum on bananas). Further some of the compounds are active as seed dressings against: Fusarium spp., Septoria spp., Tilletia spp. (i.e. bunt, a seed borne disease of wheat)1 Ustilago spp., Helminthosporium spp. on cereals, Rhizoctonia solani on cotton and Corticium sasakii on rice. The compounds can move acropetally in the plant tissue. Moreover, the compounds can be volatile enough to be active in the vapour phase against fungi on the plant. The compounds are also useful for the treatment of candidiasis and human dermatophyte infections. The compounds may be used as such for fungicidal purposes but are more conveniently formulated into compositions for such usage. The invention thus provides also a fungicidal composition comprising a compound of general formula (I) or a salt or complex thereof as hereinbefore defined, and a carrier or diluent. The invention also provides a method of combating fungal diseases in a plant, which method comprises applying to the plant, to seed of the pant or to the locus of the plant or seed a compound or a salt or complex thereof as hereinbefore defined. The compounds, salts and complexes can be applied in a number of ways, for example they can be formulated or unformulated, directly to the foliage of a plant, to seeds or to other medium in which plants are growing or are to be planted, or they can be sprayed on, dusted on or applied as a cream or paste formulation, or they can be applied as a vapour. Application can be to any part of the plant1 bush or tree, for example to the foliage, stems, branches or roots, or to soil surrounding the roots, or to the seed before it is planted. The term "plant" as used herein includes seedlings, bushes and trees. Furthermore, the fungicidal method of the invention includes preventative, protectant, prophylactic and eradicant treatment. The compounds are preferably used for agricultural and horticultural purposes in the form of a composition. The type c,f composition used in any instance will depend upon the particular purpose envisaged. The compositions may be in the form of dusting powders or granules comprising the active ingredient and a solid diluent or carrier, for example fillers such as kaolin, bentonite, kieselguhr, dolomite, calcium carbonate, talc, powdered magnesia, Fuller's earth, gypsum, Hewitt's earth, diatomaceous earth and China clay. Such granules can be preformed granules suitable for application to the soil without further treatment. These granules can be made either by impregnating pellets of filler with the active ingredient or by pelleting a mixture of the active ingredient and powdered filler. Compositions for dressing seed, for example, may comprise an agent (for example a mineral oil) for assisting the adhesion of the composition to the seed; alternatively the active ingredient can be formulated for seed dressing purposes using an organic solvent (for example Nmethylpyrrolidone or dimethylformamide). The compositions may also be in the form of dispersible powders, granules or grains comprising a wetting agent to facilitate the dispersion in liquids of he powder or grains which may contain also fillers and suspending agents. The aqueous dispersions or emulsions may be prepared by dissolving the active ingredient(s) in an organic solvent optionally containing wetting, dispersing or emulsifying agent(s) and then adding the mixture to water which may also contain wetting, dispersing or emulsifying agent(s). Suitable organic solvents are ethylene dichloride, isopropyl alcohol, propylene glycol, diacetone alcohol, toluene, kerosene, methylnaphthalene, the xylenes, trichloroethylene, furfuryl alcohol, tetrahydrofurfuryl alcohol, and glycol ethers (e.g. 2-ethoxyethanol and 2-butoxyethanol). The compositions to be used as sprays may also be in the form of aerosols wherein the formulation is held in a container under pressure in the presence of a propellant, e.g. fluorotrichloromethane or dichlorodifluoromethane. The compounds can be mixed in the dry state with a pyrotechnic mixture to form a composition suitable for generating in enclosed spaces a smoke containing the compounds. Alternatively, the compounds may be used in a microencapsulated form. By including suitable additives, for example additives for improving the distribution, adhesive power and resistance to rain on treated surfaces, the different compositions can be better adapted for various utilities. The compounds can be used as mixtures with fertilisers (e.g. nitrogen-, potassium- or phosphoruscontaining fertilisers). Compositions comprising only granules of fertiliser incorporating, for example coated with, the compound are preferred. Such granules suitably contain up to 25% by weight of the compound. The invention therefore also provides a fertiliser composition comprisijlg the compound of general formula (I) or a salt or metal complex thereof. The compositions may also be in the form of liquid preparations for use as dips or sprays which are generally aqueous dispersions or emulsions containing the active ingredient in the presence of one or more surfactants e.g. wetting agent(s), dispersing agent(s), emulsifying agent(s) or suspending agent(s). These agents can be cationic, anionic or non-ionic agents. Suitable cationic agents are quaternary ammonium compounds, for example cetyltrimethyl'ammonium bromide. Suitable anionic agents are soaps, salts of aliphatic monoesters of sulphuric acid (for example sodium lauryl sulphate), and salts of sulphonated aromatic compounds (for example sodium dodecylbenzenesulphonate, sodium, calcium or ammonium lignosulphonate, butylnaphthalene sulphonate, and a mixture of sodium diisopropyl- and triisopropyl-naphthalene sulphonates). Suitable non-ionic agents are the condensation products of ethylene oxide with fatty alcohols such as oleyl or cetyl alcohol, or with alkyl phenols such as octyl- or nonyl-phenol and octylcresol. Other non-ionic agents are the partial esters derived from long chain fatty acids and hexitol anhydrides, the condensation products of the said partial esters with ethylene oxide, and the lecithins. Suitable suspending agents are hydrophilic colloids (for example polyvinylpyrrolidone and sodium crboxymethylcellulose), and the vegetable gums (for example gum acacia and gum tragacanth). The compositions for use as aqueous dispersions or emulsions are generally supplied in the form of a concentrate containing a high proportion of the active ingredient(s), the concentrate to be diluted with water before use. These concentrates often should be able to withstand storage for prolonged periods and after such storage be capable of dilution with water in order to form aqueous preparations which remain homogeneous for a sufficient time to enable them to be applied by conventional spray equipment. The concentrates may conveniently contain up to 95%, suitably 10-85%, for example 25-60%, by weight of the active ingredient(s). These concentrates suitably contain organic acids (e.g. alkaryl or aryl sulphonic acids such as xylenesulphonic acid or dodecyl benzenesulphonic acid) since the presence of such acids can increase the solubility of the active ingredient(s) in the polar solvents often used in the concentrates. The concentrates suitably contain also a high proportion of surfactants so that sufficiently stable emulsions in water can be obtained. After dilution to form aqueous preparations, such preparations may contain varying amounts of the active ingredient(s) depending upon the intended purpose, but an aqueous preparation containing 0.0005% or 0.01% to 10% by weight of active ingredient(s) may be used. The compositions of this invention can comprise also other compound(s) having biological activity, e.g. compounds having similar or complementary fungicidal activity or compounds having plant growth regulating, herbicidal or insecticidal activity. The other fungicidal compound can be for example one which is capable of combating ear diseases of cereals (e.g. wheat) such as Septoria, Gibberella and Helminthosporium spp., seed and soil borne diseases and downy and powdery mildews on grapes and powdery mildew and scab on apple etc. These mixtures of fungicides can have a broader spectrum of activity than the compound of general formula (I) alone; further the other fungicide can have a synergistic effect on the fungicidal activity of the compound of general formula (I). Examples of the other fungicidal compound are imazalil, benomyl, carbendazim, thiophanate-methyl, captafol, captan, sulphur, triforine, dodemorph, tridemorph, pyrazophos, furalaxyl, ethirimol, dimethirimol, bupirimate, chlorothalonil, vinclozolin, procymidone, iprodione, metalaxyl, forsetyl-aluminium, carboxin, oxycarboxin, fenarimol, nuarimol, fenfuram, methfuroxan, nitrotal-isopropyl, triadimefon, thiabendazole, etridiazole, triadimenol, biloxazol, dithianon, binapacryl, quinomethionate, guazitine, dodine, fentin acetate, fentin hydroxide, dinocap, folpet, dichlofluanid, ditalimphos, kitazin, cycloheximide, dichlobutrazol, a dithiocarbamate, a copper compound, a mercury compound, DPX 3217, RH 2161, Chevron RE 20615, CGA 64250, CGA 54251, RO 14-3169 and fenpropemorph. The compounds of general formula (I) can be mixed with soil, peat or other rooting media for the protection oç plants against seed-borne, soil-borne or foliar fungal diseases. Suitable insecticides are Pirimor, Croneton, dimethoate, Metasystox and formothion. Examples of suitable plant growth regulating compounds are the gibberellins (e.g. GA3, GA4 or GA7, the auxins (e.g. indoleacetic acid, indole-butyric acid, naphthoxyacetic acid or naphthylacetic acid), the cytokinins (e.g. kinetin, diphenylurea, benzimidazole, benzyladenine or BAP), phenoxyacetic acids (e.g. 2,4-D or MCPA), substituted benzoic acids (e.g. TIBA), morphactins (e.g. chlorfluorecol), maleic hydrazide, glyphosate, glyphosine, long chain fatty alcohols and acids (e.g. dff Shoot 0 or Off Shoot T), dikegulac, Sustar, Embark, substituted quaternary ammonium and phosphonium compounds (e.g. CCC or Phosfon-D), Ethrel, carbetamide, Racuza, Alar, asulam, abscissic acid, isopyrimol, RH531, hydroxybenzonitriles (e.g. bromoxynil), Avenge, Suffix or Lontrel. As indicated above the compounds of the invention possess antifungal properties which are useful in the treatment of candidiasis and human dermatophyte infections. For this purpose they are conveniently formulated into pharmaceutical and veterinary compositions. The pharmaceutical and veterinary compositions of the invention may be in a conventional pharmaceutical form suitable for oral administration, for example a tablet, a capsule, an emulsion or an aqueous or oily solution or suspension, or suitable for topical application, for example a cream, ointment or gel. The composition may contain conventional pharmaceutical excipients, and may be manufactured by conventional pharmaceutical techniques. Preferred pharmaceutical or veterinary compositions of the invention are compositions suitable for oral administration, and particularly tablets and capsules. Thus according to a further feature of the invention there is provided a pharmaceutical or veterinary fungicidal composition which comprises a compound of formula I as defined above, or a salt, metal complex, ether or ester thereof, together with a pharmaceutically or veterinary acceptable diluent or carrier. The following Examples illustrate the invention; the temperatures are given in degrees Centigrade ("C). EXAMPLE 1 This Example illustrates the preparation of 1-(1,2,4-Triazol-l-yl)-2-(2-chlorophenyl)-2-(4-fluorophenyl)- ethylene (Compound No 1 of Table I) and its nitrate salt (Compound No 2 of Table I) A solution of dimethyl oxosulphonium methylide was prepared under nitrogen from sodium hydride (0.03 mol) and powdered trimethyl oxosulphonium iodide (0.03 mol) in dry dimethylsulphoxide (DMSO; 30 ml). A solution of 2chlorophenyl-4-fluorophenyl ketone (0.025 mol)-in DMSO (10 ml) was added dropwise at room temperature. The solution was then heated at 50" for 1.5 hours, cooled to room temperature and poured into water. The solution was extracted with diethyl ether (100 ml), washed with water (3 x 100 ml), and dried over anhydrous sodium sulphate. Removal of the solvent gave 1-(2-chlorophenyl)-1-(4-fluorophenyl)ethylene oxide (9096) as a colourless liquid. 1,2,4-Triazole (0.04 mol) was added portionwise to sodium hydride (0.04 mol) in dimethylformamide (DMF) (40 ml) and the solution stirred at room temperature until effervescence ceased. 1-( 2-Chlorophenyl) -1-(4-fluorophenyl) ethylene oxide (0.02 mol) in DMF (10 ml) was added dropwise and the solution stirred at 80" for 4 hours. The solution was poured into water and triturated with petroleum ether to give a white crystalline solid which was filtered off and dried. Recrystallisation from petroleum ether (60 80")/methylene chloride gave 1-(1,2,4-Triazol'-l-yl)-2-(2- chlorophenyl)-2-(4-fluorophenyl)-ethan-2-ol (70%) as a white crystalline solid m.p. 115-6 . A mixture of 1-(1,2,4-Triazol-l-yl)-2-(2-chlorophenyl)- 2-(4-fludrophenyl)ethan-2-ol (0.01 mol) and orthophosphoric acid (30 ml) were stirred at room temperature for 30 minutes and then warmed at 500 for 1 hour. After standing overnight at room temperature the mixture was poured into water (200 ml) and extracted with diethyl ether (150 ml). The ether solution was washed with water (3 x 100 ml) and dried over anhydrous sodium sulphate. Removal of the solvent gave a yellow oil which was purified by medium pressure column chromatography (silica gel eluted with ethyl acetate/petrol 1:1) to give the title compound as a light brown oil (80%). The oil was dissolved in diethyl ether (30 ml) and concentrated HNO3 (6 drops) added to precipitate out the title compounds as the nitrate salt m.p. 124 . EXAMPLE 2 This Example illustrates the preparation of l-(l,2,4-Trjazol-l-yl)-2-(4-chlorophenyl)-2-(4- fluorophenyl)ethylene (Compound No 13 of Table I) A solution of dimethyl oxosulphonium methylide was prepared under nitrogen from sodium hydride (0.03 mol) and powdered trimethyl oxosulphonium iodide (0.03 mol) in dry dimethyl sulphoxide (DMSO; 30 ml). A solution of dr¯ chlorophenyl-4-fluorophenyl ketone (0.025 mol) in DD5SO (10 ml) was added dropwise at room temperature. The solution was then heated at 500 for 1.5 hours, cooled to room temperature and poured into water. The solution was extracted with diethyl ether (100 ml), washed with water (3 x 100 ml), and dried over anhydrous sodium sulphate. Removal of the solvent gave 1-(4-chlorophenyl)-1-(4fluorophenyl)ethylene oxide (90%) as a colourless oil. 1,2,4-Triazole (0.04 mol) was added portionwise to sodium hydride (0.04 mol) in DMF (40 ml) and the solution stirred at room temperature until effervescence ceased. 1 (4-chlorophenyl) -l-( 4-fluorophenyl) ethylene oxide (0.02 mol) in DMF (10 ml) was added dropwise and the solution stirred at 800 for 4 hours. The solution was poured into water and triturated with petroleum ether to give a white crystalline solid which was filtered off and dried. Recrystallisation from petroleum ether (60-80 )/chloroform gave l-(1,2,4-Triazol-l-yl)-2-(4-chlorophenyl)-2-(4- fluorophenyl)ethan-2-ol (75%) as a white crystalline solid m.p. 154-50. A mixture of 1-(l,2,4-Triazol-1-yl)-2-(4- chlorophenyl)-2-(4-fluorophenyl)ethan-2-ol (0.007 mol) and orthophosphoric acid (30 ml) were stirred at room temperature for 30 minutes and warmed to 50 for 1 hour. After standing overnight at room temperature the mixture was poured into water (200 ml), extracted with ether (150 ml) and washed with saturated sodium bicarbonate solution. The ether solution was washed with water (2 x 100 ml)- and dried over anhydrous sodium sulphate. Removal of the solvent gave a solid which recrystallised from petroleum ether (60-800)/chlorofor= as the title compound (50%) m.p. 10l20. EXAMPLE 3 An emulsifiable concentrate was made up by mixing the ingredients, and stirring the mixture until all the constituents were dissolved. Compound No 1 of Table I 10% Ethylene dichloride 40% Calcium dodecylbenzenesulphate 5% "Lubrol" L 10% "Aromasol " H 358 EXAMPLE 4 A composition in the form of grains readily dispersible in a liquid, e.g. water, was prepared by grinding together the first three ingredients in the presence of added water and then mixing in the sodium acetate. The resultant mixture was dried and passed through a British Standard mesh sieve, size 44-100, to obtain the desired size of grains. Compound No 2 of Table I 50% "Dispersol" T 25% "Lubrol" APN5 1.5% Sodium acetate 23.5% EXAMPLE 5 The ingredients were all ground together to producc a powder formulation readily dispersible in liquids. Compound No 11 of Table I 45% "Dispersol" T 5% "Lissapol" NX 0,5% "Cellofas" B600 2% Sodium acetate 47.5% EXAMPLE 6 The active ingredient was dissolved in a solvent and the resultant liquid was sprayed on to the granules of China clay. The solvent was then allowed to evaporate to produce a granular composition. Compound No 12 of Table I 5% China clay granules 95% EXAMPLE 7 A composition suitable for use as a seed dressing was prepared by mixing the three ingredients. Compound No 13 of Table I 50% Mineral oil 2% China clay 48% EXAMPLE 8 A dusting powder was prepared by mixing the active ingredient with talc. Compound No 1 of Table I 5% Talc 95% EXAMPLE 9 A Col formulation was prepared by ball-milling the constituents set out below and then forming an aqueous suspension of the ground mixture with water. Compound No 2 of Table I 40% "Dispersol" T 10% "Lubrol" APN5 1% Water EXAMPLE 10 A dispersible powder formulation was made by mixing together the ingredients set out below and then grinding the mixture until all were thoroughly mixed. Compound No 11 of Table I 255, "Aerosol" OT/B 2% "Dispersol" A.C. 5% China clay 28% Silica 40% EXAMPLE 11 This Example illustrates the preparation of a dispersible powder formulation. The ingredients were mixed and the mixture then ground in a comminution mill. Compound No 12 of Table I 25% "terminal" BX "Dispersol" T 5% Polyvinylpyrrolidone 10% Silica 25% China clay 34% EXAMPLE 12 The ingredients set out below were formulated into a dispersible powder by mixing then grinding the ingredients. Compound No 13 of Table I 25% "Aerosol" OT/B 2% "Dispersol" A 5 China clay 68% In Examples 3 to 12 the proportions of the ingredients given are by weight. There now follows an explanation of the compositions or substances represented by the various Trade Marks and Trade Names mentioned above. LUBROL L : a condensate of nonyl phenol 1 mole) with ethylene oxide (13 molesj AROMASOL H : a solvent mixture of alkylbenzenes DISPERSOL T & AC : a mixture of sodium sulphate and a condensate of formaldehyde with sodium naphthalene sulphonate LUBROL APNS : a-condensate of nonyl phenol (1 mole) with naphthalene oxide (5.5 moles) CELLOFAS B600 : a sodium carboxymethyl cellulose thickened LISSAPOL NX : a condensate of nonyl phenol (1 mole) with ethylene oxide (8 moles) AEROSOL OT/B : dioctyl sodium sulphosuccinate PERMINAL BX : a sodium alkyl naphthalene sulphonate EXAMPLE 13 The compounds were tested against a variety of foliar fungal diseases of plants. The technique employed was as follows. The plants were grown in John Innes Potting Compost (No 1 or 2) in 4 cm diameter minipots. A layer of fine sand was placed at the bottom of the pots containing the dicotyledonous plants to facilitate uptake of test compound by the roots. The test compounds were formulated either by bead milling with aqueous Dispersol T or as a solution in acetone or acetone/ethanol which was diluted to the required concentration immediately before use. For the foliage diseases, suspensions (100 ppm active ingredient) were sprayed on to the soil. Exceptions to this were the tests on Botrytis cinerea, Plasmopara viticola and Venturia inaequalis. The sprays were applied to maximum retention and the root drenches to a final concentration equivalent to approximately 40 ppm a.i./dry soil. Tween 20, to give a final concentration of 0.05%, was added when the sprays were applied to cereals. For most of the tests the compound was applied to the soil (roots) and to the foliage (by spraying) one or two days before the plant was inoculated with the diseases. An exception was the test on Erysiphe graminis in which the plants were inoculated 24 hours before treatment. After inoculation, the plants were put into an appropriate environment to allow infection to take place and then incubated until the disease was ready for assessment. The period between inoculation and assessment varied from four to fourteen days according to the disease and environment. The disease control was recorded by the following grading: 4 = no disease 3 = trace - 5% of disease on untreated plants 2 = 6-258 of disease on untreated plants 1 = 26-59% of disease on untreated plants 0 = 60-100% of disease on untreated plants The results are shown in Table II. TABLE II EMI25.1 COMPOUND <SEP> PUCCINIA <SEP> ERYSIPHE <SEP> PIRICULARIA <SEP> PLASMOPARA <SEP> PHYTOPHTHORA <SEP> BOTRYTIS <SEP> CERCOSPORA <SEP> VENTURIA <tb> NUMBER <SEP> RECONDITA <SEP> GRAMINIS <SEP> ORYZAE <SEP> VITICOLA <SEP> INFESTANS <SEP> CINEREA <SEP> ARACHIDICOLA <SEP> INAE@UALIS <tb> (WHEAT) <SEP> (BARLEY) <SEP> (RICE) <SEP> (VINE) <SEP> (TOMATO) <SEP> (TOMATO) <SEP> (PEANUT) <SEP> (APPLE) <tb> 1 <SEP> 4 <SEP> 4 <SEP> - <SEP> 0 <SEP> 0 <SEP> 3 <SEP> 4 <SEP> 4 <tb> 11 <SEP> 2 <SEP> 4 <SEP> - <SEP> 3 <SEP> 0 <SEP> 0 <SEP> 3 <SEP> 3 <tb> 12 <SEP> 4 <SEP> 4 <SEP> - <SEP> 4 <SEP> 0 <SEP> 2 <SEP> 4 <SEP> 4 <tb> 13 <SEP> 2 <SEP> 4 <SEP> - <SEP> 0 <SEP> 0 <SEP> 0 <SEP> 1 <SEP> 1 <tb> "-" means not tested. HGHA/aj@/SPECl45 16 June 1981

Claims: 1. A triazole compound having the general formula (I): EMI26.1 formula (I) which is the cis- or trans-isomer, or a mixture thereof, wherein R1 and R2, which may be the same or different, are alkyl, cycloalkyl (e.g. cyclopropyl, cyclopentyl, or cyclohexyl) or optionally substituted phenyl; and acid addition salts and metal complexes thereof. 2. A triazole compound according to claim 1 wherein R1 and R2, which may be the same or different are a straight or branched chain alkyl groups having from 1 to 6 carbon atoms, or are phenyl optionally substituted with halogen, alkyl or halo-alkyl having from 1 to 5 carbon atoms, alkoxy or halo-alkoxy having from 1 to 4 carbon atoms, nitro, phenyl or phenoxy. 3. A triazole compound according to claim 1 or 2 wherein R1 and R2 are alkyl having from 1 to 4 carbon atoms, phenyl or halo-phenyl. 4. A triazole compound according to claim 1 or 2 wherein R1 and R2 are both phenyl, 2-, 3- or 4-chlorophenyl, 2,4 or 2,6-dichlorophenyl, 2-, 3- or 4-fluorophenyl, 2,6 difluorophenyl, 2-, 3- or 4-bromophenyl, 2-chloro-4 fluorophenyl, 2-chloro-6-fluorophenyl, 2-, 3- or 4 methoxyphenyl, 2,4-dimethoxyphenyl, 2-, 3- or 4-ethoxy phenyl, 2-, 3- or 4-nitrophenyl, 2-, 3- or 4 trifluoromethylphenyl, 2-, 3- or 4-phenoxyphenyl, or 2-, 3- or 4-phenylphenyl (2-, 3- or 4-biphenyl). 5. A process for preparing a compound as defined in any of claims 1 to 4 which comprises dehydrating a compound of general formula (II) EMI27.1 formula (11) in which R1 and R2 are as defined in any of claims 1 to 4 under acidic conditions by refluxing in a solvent. 6. A process according to claim 5 wherein compounds of general formula (II) are produced by reacting a compound of general formula (III) or (IV): EMI27.2 formula (III) formula (IV) in which R1 and R2 re as defined in any of claims 1 to 4 and Y is a halogen atom (preferably a chlorine or bromine atom), with 1,2,4-triazole either in the presence of an acid-binding agent or in the form of one of its alkali metal salts in a solvent. 7. A process according to claim 6 wherein the compound of general formula (III) or (IV) is reacted at 20-1000C with the sodium salt of 1,2,4-triazole (the salt can be prepared by adding either sodium hydride or sodium methoxide to 1,2,4-triazole) in a solvent such as acetonitrile, methanol, ethanol or dimethylformamide and isolating the product by pouring the reaction mixture into water and recrystallising. 8. A process according to claim 6 wherein the compounds of general formula (III) and (IV) are prepared by reacting a compound of general formula (Va) or (Vb): EMI28.1 formula (Va) formula (Vb) wherein R11 R2 and Y are as defined with, respectively, a Grignard compound of general formula (VIa) or (VIb): Z Mg R2 Z- Mg R1 formula (VIa) formula (VIb) wherein R1 and R2 are as defined above and Z is a halogen (preferably chlorine, bromine or iodine) in a convenient solvent such as diethyl ether or tetrahydrofuran. 9. A process according to claim 6 wherein the compounds of general formula (III) wherein each of R1 and 2, which may be the same or different, is substituted phenyl are prepared by reacting the appropriate benzophenone compound of general formula (VII) R1----CO R2 formula (VII) wherein R1 and R2 are as defined above, with dimethyl oxosulphonium methylide or dimethyl sulphonium methylide. 10. As novel intermediates : epoxides and halohydrins as defined in claim 6; and ketones as defined in claim 9. 11. A fungicidal composition comprising as an active ingredient, a compound as claimed in any of claims 1 to 4, or a salt or metal complex thereof; and a carrier or diluent therefor. 12. A method of combating fungal diseases in a plant, which method comprises applying to the plant1 to seed of the plant, or to the locus of the plant or seed, a compound, or a salt or metal complex thereof, as claimed in any of claims 1 to 4 or a composition according to claim 11. 13. A pharmaceutical or veterinary fungicidal composition which comprises a compound, or a salt, metal complex, ether or ester thereof, as defined '? any of claims 1 to 4 together with a pharmaceutically or veterinary-acceptable diluent or carrier. 14. A method of treatment of candidiasis or human dermatophyte infections which comprises administering to a human or animal an effective amount of a compound as claimed in any of claims 1 to 4 or a composition as claimed in claim 11.

Inventors: DE FRAINE, PAUL, RATHMELL, WILLIAM GEORGE, WORTHINGTON, PAUL ANTHONY
Applicants: IMPERIAL CHEMICAL INDUSTRIES PLC
Application year: 1981
Main classification: C07D249
IPC codes: C07D303, C07D249, C07D521, A01N43