GB2075005A - Fungicidal Imidazole and Triazole Derivatives - Google Patents

Abstract

Compounds of the formula: <IMAGE> wherein R<1> is alkyl, alkenyl, alkynyl or optionally substituted aralkyl; R<2> is hydrogen or alkyl; R<3> and R<4> are each alkyl and Y is =N or =CH- and their salts and metal complexes, have fungicidal activity.

Description

SPECIFICATION Heterocyclic Compounds This invention relates to imidazole and triazole compounds useful as fungicides, to a process for preparing them, to fungicidal compositions containing them, and to a method of combating fungal infections using them.

The compounds have the general formula (I)

wherein R1 is alkyl, alkenyl, alkynyl or optionally substituted aralkyl; R2 is hydrogen or alkyl and each of R3 and R4, which may be the same or different, is alkyl; and Y is =N- or =CH--; or an acid addition salt or metal complex of such compounds.

The compounds of the invention can contain chiral centres. The compounds are generally obtained in the form of racemic mixtures. However, these and other mixtures can be separated into the individual isomers by methods known in the art e.g. chromatography. In some cases, the compounds can be prepared stereospecifically in the form of a single diastereoisomer.

The alkyl, alkenyl and alkynyl groups, which can be straight or branched chain, preferably have 1 to 5 carbon atoms; examples are methyl, ethyl, propyl (n- or i-propyl), butyl (n-, i-, sec- or t-butyl), allyl and propargyl.

The aralkyl group can have more than one ring substituent; examples of polysubstituted groups are those substituted with up to the maximum possible number (especially 1, 2 or 3) of for example halogen (particularly chlorine) atoms and/or nitro, methyl and/or methoxy groups. The aralkyl can also be substituted on to alkyl moiety with for example one C alkyl (e.g. methyl or ethyl), phenyl or benzyl.

Examples of suitable aralkyl groups are benzyl itself, naphthyl methyl (- or ,B-naphthyl methyl), chlorobenzyl (for example o-, m- or p-chlorobenzyl), dichlorobenzyl (e.g. 3,4-, 2,4-, 3,5- or 2,6dichlorobenzyl), trichlorobenzyl (e.g. 2,3,6- or 2,4,5-trichlorobenzyl), tetrachlorobenzyl, pentachlorobenzyl, bromobenzyl (e.g. o-, m- or p-bromobenzyl), dibromobenzyl (e.g. 2,4-dibromobenzyl), fluorobenzyl (e.g. o-, m- or p-fluorobenzyl), difluorobenzyl (e.g. 2,4- or 3,4-difluorobenzyl), pentafluorobenzyl, iodobenzyl (e.g. o-iodobenzyl), methylbenzyl (e.g. o-, m- or p-methylbenzyl), ethylbenzyl (e.g. p-ethylphenyl), propylbenzyl (e.g. p-i-propybenzyl), butylbenzyl (e.g. p-tbutylbenzyl), nitrobenzyl (e.g. o-, m- or p-nitrobenzyl), dinitrobenzyl (e.g. 2,4-dinitrobenzyl), (trifluoromethyl)benzyl [e.g. o-, m- or p-(trifluoromethyl)benzyl], methoxybenzyl (e.g. o-, m- or p-methoxybenzyl), dimethoxybenzyl (e.g. 2,4-, 3,4- or 3,5-dimethoxybenzyl), ethoxybenzyl (e.g.

o-, m- or p-ethoxybenzyl), propoxybenzyl (e.g. p-i-propoxybenzyl or p-n-propoxybenzyl), butoxybenzyl (e.g. o-, m- or p-i-butoxybenzyl), chloronitrobenzyl (e.g. 3-nitro-4-chlorobenzyl), fluoronitrobenzyl (e.g.

2-nitro-4-fluorobenzyl), chlorofluorobenzyl (e.g. 2-fluoro-4-chlorobenzyl, 2-chloro-6-fluorobenzyl or 2 chloro-4-fluorobenzyl), fluorobromobenzyl (e.g. 2- fluoro-4-bromobenzyl), methoxychlorobenzyl (e.g. 3chloro-4-methoxybenzyl), methoxybromobenzyl (e.g. 2-methoxy-5-bromobenzyl or 3-bromo-4methoxybenzyl), methoxynitrobenzyl (e.g. 2-methoxy-5-nitrobenzyl or 4-methoxy-3-nitrobenzyl), ethoxynitrobenzyl (e.g. 4-ethoxy-3-nitrnbenzyl), ethoxychlorobenzyl (e.g. 4-ethoxy-3-chlorobenzyl) and ethoxybromobenzyl (e.g. 4-ethoxy-3-bromobenzyl), and the corresponding groups wherein the methylene moiety of the benzyl group is substituted with methyl or ethyl.

The halogen can be fluorine, chlorine, bromine or iodine.

Suitable salts are salts with inorganic or organic acids, e.g. hydrochloric, nitric, sulphuric, toluenesulphonic, acetic or oxalic acid.

The metal complex is suitably one including copper, zinc, manganese or iron. It preferably has the general formula

wherein Y, R', R2, R2, R3 and R4 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, and y is O or an integer of 1 to 12.

Specific examples of the compounds are given in Table Table I

R1 R R3 R4 V Melting Point (0C) 1 p-Cl6H4CH2- Me Me Me 143--145 2 p-F6H4CH2- Me Me Me =N 123125 3 2,4diCl-C6H3CH2- Me Me Me =N-- 103104 4 C8H6CH2- Me Me 1 Me =N-- 98--99 The compounds of general formula (I) or a salt thereof can be prepared by reducing a compound of general formula (Il) :-

wherein Y, R', R2, R3 and R4 are as defined above, or a salt thereof. The reduction can be performed using a dissolving metal hydride reducing agent (e.g. lithium aluminium hydride, sodium borohydride or aluminium isopropoxide) in an inert polar solvent (e.g. water, methanol or ethanol). The product can be isolated from the reaction mixture by pouring into water, neutralising with concentrated hydrochloric acid and recrystallising the solid formed from a convenient solvent.

The compounds of general formula (II) may be made by reacting a compound of general formula (Ill):-

wherein Y, R2, R3 and R4 are as defined above, or a salt thereof, with an halide or general formula (lV):- R1-X wherein X is halogen (e.g. chlorine or bromine) and R' is as defined above. This process is suitably carried out by dissolving the compound of general formula (III) in a convenient solvent (such as dimethyl formamide or tetrahydrofuran) and adding an equivalent amount of an alkali metal hydride (e.g. sodium hydride) to produce the alkali metal salt which is then reacted with the halide.The product can be isolated from the reaction mixture by pouring into water and recrystallising the solid formed from a convenient solvent, or by purifying the resultant oil by column chromatography or another convenient technique.

The compounds of general formula (II) may also be made by reacting imidazole or 1 ,2,4-triazole, or a salt thereof, with the appropriate halo ketone of general formula (V):-

wherein X, R', R2, R3 and R4 are as defined above. This reaction is suitably carried out by stirring the reactants together in a suitable solvent (such as acetonitrile, methanol, ethanol, tetrahydrofuran, or dimethylformamide); preferably it is performed by reacting the sodium salt of triazole with an a- bromoketone in ethanol at room temperature. The product can be isolated by pouring the reaction mixture into water and recrystallising the solid from a convenient solvent, or by distilling the product if a liquid. The halo ketones can be prepared by bromination of the corresponding ketones using the normal brominating agents (e.g. bromine or pyrrolidone hydrotribromide).

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 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 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 Kelminthosporium spp. on cereals Cercospora arachidicola 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 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., Tllletia spp. (i.e. bunt, a seed borne disease of wheat), Ustilago spp., Helminthosporium spp. on cereals, Rhizoctonia solani on cotton and Corticium sasakii on rice. They may also show antiviral activity.

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, complex, ether or ester 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 plant or to the locus of the plant or seed a compound or 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 foilage of a plant, or they can be applied also to bushes and trees, to seeds or to other medium in which plants, bushes or trees 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 plant, bush or tree, for example to the foilage, 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 of 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 N-methylpyrrolidone 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 the 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 phosphorus-containing 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 comprising 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 cetyltrimethylammonium 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 triisopropylnaphthalene 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 carboxymethylcellulose), 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 homogenous 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 2560%, 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 dodecylbenzenesulphonic 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, ethridiazole, 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, OGA 64250, CGA 64251 and RO 14-3169.

The compounds of general formula (I) can be mixed with soil, peat or other rooting media for the protection of 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 GA), the auxins (e.g. indoleacetic acid, indolebutyric acid, naphthoxyacetic acid or naphthylacetic acid), the cytokinins (e.g. kinetin, diphenylurea, benzimidazole, benzyladenine or BAP), phenoxyacetic acids (e.g. 2,4-Dor MCPA), substituted benzoic acids (e.g. TIBA), morphactins (e.g. chlorfluorecol), maleic hydrazide, glyphosate, glyphosine, long chain fatty alcohols and acids (e.g. Off Shoot O 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, RH53 1, hydroxybenzonitriles (e.g. bromoxynil), Avenge, Suffix or Lontrel.

The following Examples illustrate the invention; the temperatures are given in degrees Centigrade ( C).

Example 1 2-methoxy-2-methyl-4( 1 ,2,4-triazol-1 -yl)-5-(p-chlorophenyl)pentan-3-ol Stage 1:A solution of 3-methoxy-3-methyl-butan-2-one (0.5 mol) in dry methanol (1000 ml) was treated dropwise with bromine (0.5 mol) at room temperature and then stirred for 4 hours at 200.

The methanol was removed in vacuo and the residue distilled at reduced pressure to give 1-bromo-3methoxy-3-methyl-butan-2-one (yield 80%) as a colourless liquid, b.p. 96--1000/24 mm Hg.

Stage 2: 1-Bromo-3-methoxy-3-methyl-butan-2-one (0.15 mol) was added dropwise to sodium triazole (prepared) from metallic sodium (0.165 mol) and 1,2,4-triazole (0.165 mol) dissolved in ethanol (250 ml) and the solution stirred at 200 for 10 hours. The ethanol was removed at the pump and the residue dissolved in chloroform (250 ml), washed with water (3x200 ml), and dried (Na2S04).

Removal of the solvent gave an orange oil which was distilled in vacuo to give 1 -(1 ,2,4-triazol-1 -yl)-3- methoxy-3-methyl-butan-2-one (yield 60%) as a pale yellow oil, b.p. 110-115V0.1 mm Hg.

Stage3 Sodium hydride (1.5 g) (50% dispersion in oil) was added to dimethylformamide (DMF, 30 ml) and the solution cooled to 5 .1-(1,2,4-Triazol-1-yl)-3-methoxy-3-methyl-butan-2-one (5.5 g) was dissolved in DMF (5 ml) and added dropwise to the above solution at 5 . After stirring at 200 for 1 hour a solution of p-chlorobenzyl chloride (4.8 g) in DMF (5 ml) was added dropwise and the solution stirred at 200 for 10 hours. The solution was poured into water (100 ml), extracted with diethyl ether (100 ml), washed with water (2x 100 ml), and dried (Na 804). Removal of the solvent gave a solid which was recrystallised from petroleum ether/chloroform to give the title compound, m.p. 44--60.

Stage 4 2-Methoxy-2-methyl-4-(1 ,2,4-triazol-1-yl)-5-(p-chlorophenyl)-pentan-3-one (2.0 g) was dissolved in methanol (25 ml) and the sodium borohydride (200 mg) added portionwise. The solution was then refluxed for one hour, cooled to room temperature and the methanol removed in vacuo. The residue on treatment with water gave a solid which was recrystallised from petroleum ether/chloroform to give as white fluffy needles, the title compound, m.p. 1 4350 Example 2 2-Hydroxy-2-methyl-4-( 1 .2,4-triazo I-1 -yl)-5-(p-chlorophenyl)-pentan-3-ol Stage 1 Pyrrolidone hydrotribromide (25 g) was added to a solution of 3-hydroxy-3-methylbutan-2-one (5.0 g) in tetrahydrofuran (200 ml) and the mixture stirred at reflux for 30 minutes.After cooling to room temperature, the solid was filtered off and the filtrate concentrated in vacuo to give an orange oil which was distilled at reduced pressure to give 1-bromo-3-hydroxy-3-methyl-butan-2-one as a colourless liquid, b.p. 50--20/0.1 mm Hg.

Stage 2 1-Bromo-3-hydroxy-3-methyl-butan-2-one (5.4 g), 1,2,4-triazole (2.1 g) were dissolved in acetonitrile (5.4 g), 1,2,4-triazole (2.1 g) were dissolved in acetonitrile (50 ml) and triethylamine (3.0 g) added dropwise. The solution was stirred at 5060 for 2 hours, cooled to room temperature, and the solvent removed in vacuo. The mixture was extracted with ethyl acetate (50 ml) washed with water (3x20 ml) and dried (NaSO4). Removal of the solvent gave an oil which solidified on standing to give 1 (1 ,2,4-triazol-1 yl)-3-hydroxy-3-methyl-butan-2-one, m.p. 110120.

Stage 3 To a suspension of sodium hydride (0.5 g) in DMF (20 ml) was added a solution of 1 (1 ,2,4-triazol-1-yl)-3-hydroxy-3-methyl-butan-2-one (1.5 g) dissolved in DMF (20 ml) and the solution was stirred at 600 for 2-3 hours. p-Chlorobenzyl chloride (1.5 g) in DMF (10 ml) was added dropwise to the dark brown solution and the solution heated at 500 for 6 hours. The solution was poured into water, extracted with methylene chloride (40 ml), washed with water (2x30 ml) and dried (NaSO4).

Removal of the solvent gave a dark brown oil which solidified on standing and was recrystallized from ethyl acetate/petroleum ether to give 2-hydroxy-2-methyl-4(1,2,4-triazol-1-yl)-5-(p-chlorophenyl)- pentan-3-one m.p. 138--90.

Stage 4 Using the technique used in Stage 4 of Example 1, the product of Stage 3 can be converted to the title compound.

Example 3 The compounds were tested against a variety of foliar fungal deseases of plants. The techniques employed were 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 dicotyledenous 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 foliage and applied to the roots of the same plant via the soil.

Exceptions to this were the tests on Botrytis cinerea, Plasmopara viticola and Venturia inaequalis, in which the compound was sprayed on to the foliage only. 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 desease 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=trace5% of disease on untreated plants 2=625% of disease on untreated plants 1=2659% of disease on untreated plants 0=60100% of disease on untreated plants The results are shown in Table II.

Table II

Puccinia Erysiphe Piricularia Plasmopara Phytophtora Botrytis Cercospora Venturia Compound Recondita Graminis Oryzae Viticola Infestans Cinerea Arachidicola Inequalls Number (Wheat) (Barley) (Rice) (Vine) (Tomato) (Tomato) (Peanut) (Apple) 1 0 4 1 0 0 0 0 0 2 4 4 0 0 0 3 2 3 4 4 0 0 0 3 3 3 4 4 4 2 0 1 4 2

Claims (1)

1. Claim A compound of general formula (I)

   wherein R1 is alkyl, alkenyl, alkynyl or optionally substituted aralkyl; R2 is hydrogen or alkyl and each of R3 and R4, which may be the same or different, is alkyl; and Y is =N- or =CH-; or an acid addition salt or metal complex of such a compound.