NO157122B - USE OF 1,2,4-TRIAZOLD DERIVATIVES AS PLANT FUNGICIDES. - Google Patents

Description

The present invention relates to the use of triazole compounds as fungicides and plant growth regulators.

The triazole compounds have the general formula (I):

where R1 is an alkyl group with from 1 to 6 carbon atoms, cyclo-

alkyl with from 3 to 6 carbon atoms or phenyl which is optionally substituted with 1-2 substituents selected from halogen, alkyl with 1

to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, nitro, trifluoromethyl or behzyloxy optionally substituted with a halogen, and R 2 is phenyl or benzyl both of which are optionally substituted with 1-2 substituents selected from halogen, alkyl mod from 1 to 4 carbon atoms' , alkoxy having from 1 to 4 carbon atoms,

nitro, phenyl or phenoxy; and acid addition salts and metal complexes thereof.

The compounds used may contain chirality-

centers. Such 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 state of the art.

The salts can be inorganic or organic salts

acids, e.g. hydrochloric acid, nitric acid, sulfuric acid, acetic acid, p-toluenesulfonic acid or oxalic acid.

The metal complex appropriately includes such as metal, copper,

zinc, manganese or iron. It preferably has the general formula:

where .R. 1 and R 2 are as 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 0 or an integer from 1 to 12.

x Includes 1 mol of ethanol occluded in the crystal network.

xx Compounds 8 and 18 were obtained as polymorphic compounds, and this explains their different melting points.

C-jH;- = cyclopropyl

C^Hg cyclopentyl

CgH^ = cyclohexyl

The compounds with the general formula (I) can be prepared by reacting a compound with the general formula (II) or (III):

1 2

where R and R are as above and X is a halogen atom (preferably a chlorine or bromine atom), with 1,2,4-triazole either in the presence of ct acid binding agent, or when it is in the form of one of the alkali metal salts , in ct appropriate solvent. Appropriately, the compound is reacted with the general formula

(II) or (III) at 20-100°C 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 suitable solvent so such as acetonitrile, methanol, ethanol or dimethylformamide. The product can be isolated by pouring the reaction mixture into water

and the solid formed is recrystallized from a suitable solvent.

The compounds of the general formula (II) and (III) can be prepared by reacting a compound of the general formula (IVa) or (IVb): where R 1 , R 2 and X are as indicated above, respectively, with a Grignard compound with the general formula (Va) or (Vb):

1 2

where R and R are as indicated above and Y is halogen (preferably chlorine, bromine or iodine) in a suitable solvent then

such as diethyl ether or tetrahydrofuran. In general, a mixture of the compounds of the general formulas (II) and (III) is obtained. When a compound with the general formula (IVa) where K1 is alkyl or C3_6 cycloalkyl is reacted, e.g. the compound of formula (II) will normally be dominant in the mixture, and on the other hand, when R is optionally substituted phenyl, the compound of general formula (III) will normally be dominant in the mixture.

The compounds with the general formulas (IV) and (V) can

produced by methods known from the literature.

The compounds of the general formula (II) where each

R 1 and R 2 , which may be the same or different, are substituted phenyl, may also be prepared by reacting the appropriate benzophenone compound of the general formula (VI)

where R 1 and R 2 are as above, with dimethyloxosulfonium methylide (Corey and Chaykovsky JACS, 1965, 87, 1353-1364) or with dimethylsulfonium methylide (Corey and Chaykovsky, JACS, 1962, 84, 3782) using methods described in the literature.

The benzophenone compounds of the general formula (VI)

can be prepared using the Friedel-Crafts reaction, by reacting a substituted benzoyl chloride with an appropriately substituted benzene in the presence of a Lewis acid, e.g. aluminum chloride.

The compounds of the general formula (II) where each

R is alkyl, C3-6cycloalkyl or optionally (as indicated above) substituted phenyl, and R<2> is phenyl or benzyl both of which are optionally substituted as indicated above, can also be prepared by reacting a B-hydroxy-selenide compound with the general formula (VII)

wherein R 1 and R 2 are as indicated above, with methyl iodide in potassium t-butoxide according to the method of Van Ende, Dumont and Krief, Angew. Chem. Int. Ed., 1975 , 1_4, 700. (The 3-hydroxy-selenide compound can be prepared by treating the diselenide with an appropriate ketone in the presence of butyllithium. The compounds of the general formula (III) where R 1 is alkyl or cycloalkyl and R 2 is optionally substituted benzyl (especially benzyl substituted on the ring with alkoxy) can also be prepared by reacting a compound with the general formula (VIII)

where R 1 ■ and R 2 are as indicated above and Ar is aryl (e.g. phenyl), with an alkylating agent to give the corresponding sulfonium salt which is then reacted with 1,2,4-triazole in the form of an alkali metal salt ( eg the sodium or potassium salt). The compound with the general formula (VIII) can be prepared by methods known in the art.

The salts and metal complexes of the compounds of the general formula (I) can be prepared from these in a known manner. E.g. the complexes can be formed by reacting the uncomplexed compound with a metal salt in a suitable solvent.

The compounds with the general formula (I) are usually prepared by the above reactions in the form of racemic mixtures. Splitting these mixtures into the individual ones

enantiomers can be carried out by known methods. Examples of

such methods are

(1) formation of the diastereoisomeric salts or esters of

the compound of the general formula (I) with an optically active acid (e.g. camphor sulphonic acid), separation of the isomeric salts or esters and conversion of the separated isomeric salts or esters into the enantiomers of the compound of the general formula (I) :,

(2) formation of the diastereoisomeric carbamates of the compound

with the general formula (I) by reacting a halogen-

formate (e.g. chloroformate) thereof with an optically active amine (e.g. 2-methylbenzylamine), separating the isomeric carbamates, and converting the separated isomeric carbamates to the enantiomers of the compound of general formula (I); (3) forming the hemiphtate of the compound of general formula (I), reacting the hemiphtate with an optically active amine (e.g. α-methylbenzylamine) to obtain the salt of the hemiphtate, separating the isomeric salts and converting the separated salts of the enantiomers of the compound of general formula (I); or

(4) cleavage of the mixtures using enantio-

selective crystallization techniques (Leigh, Chemistry and Industry, 1970, pages 1016-1017, and ibid, 1977, page 36).

Separation of the diastereoisomeric salts, esters and

the carbamates can be obtained by e.g. crystallization techniques or by high-pressure liquid chromatography (IIPLC). Alternatively, the enantiomers can be prepared directly from the compounds of the general formula (II) by stereospecific reduction, e.g.

by biochemical reduction (using e.g. yeast or Aspergillus niger) or by hydrogen ringing using chiral catalysts (e.g. a Wilkinson catalyst) or by reduction with borohydride/amino acid complexes.

The compounds, salts and metal complexes are active fungicides, particularly against the following diseases:

Piricularia oryzae on rice,

Puccinia recondifca, Puccinia striiformis and other rust fungi

on wheat, Puccinia hordei, Puccinia striiformis and other rust fungi on barley, and rust fungi on other host plants,

like for example. coffee, apple, vegetables and ornamental plants,

Plasmopara viticola on vines

Erysiphe graminis (powdery mildew) on barley and wheat and other powdery mildews

on different host plants such as Sphaerotheca fuliginea on cucumber plants (e.g. cucumber), Podosphaera Leucotricha on

apples and Uncinula necator on vines,

Helminthosporium spp. and Rhynchosporium spp. on cereals,

Cercospora arachidicola on peanuts and other Cercospora species on e.g. sugar beets, bananas and soybeans,

Botrytis cinerea (gray mold) on tomatoes, strawberries, wine and

other host plants,

Phytophthora infestans (dry rot) on tomatoes

Venturia inaequalis (scab) on apples.

Some of the compounds have also shown a broad spectrum of activity against fungi in vitro. They are effective against various post-harvest fruit diseases (e.g. Penicillium digatatum and italicum on oranges and Gloeosporium musarum on bananas). Furthermore, some of the compounds are active as seed dressings

against: Fusarium spp., Septoria spp., Tilletia spp. (i.e. stink blight, a seed-borne disease of wheat), Ustilago spp., Helminthosporium spp. on cereals, Rhizoctonia solani on cotton and Corticium sasakii on rice.

The compounds can be taken up from below in the plant tissue. Further

may the compounds be volatile enough to be active in vapor form against fungi on the plant. They may also be useful as fungicides for industrial (as opposed to agricultural) applications, e.g. to prevent fungal attacks on wood, skin, leather and especially on paint film.

The compounds can also have a plant growth-regulating effect.

The plant growth-regulating effect of the compounds can e.g. result in a crippling and growth-inhibiting effect on the vegetative growth of woody and herbaceous one- and two-seeded plants. Such stunting or growth retardation can e.g. be useful for peanuts, cereals and soybeans where reducing the growth of the stem can reduce the risk of leggy,

and can also allow larger amounts of fertilizer to be added. Growth inhibition of woody species is useful in controlling the growth of bottom vegetation under power lines etc. Compounds which produce stunting or growth inhibition may also be useful in limiting the growth of the stem of sugarcane for

thereby increasing the sugar concentration in the tube before harvesting;

for cane sugar, flowering and ripening can be controlled by adding the compounds. Growth inhibition on peanuts can be useful at harvest. Growth inhibition of grass can be useful for the maintenance of grass carpets. Examples of suitable grass types are Stenotaphrura secundatum (St. Augustine grass), Cynosurus cristatus, Lolium multiflorum and perennial, Agrostis tenuis, Cynodon dactylon (Bermuda grass), Dactylis glomerata, Festuca spp (eg Festuca rubra) and Poa spp. (e.g.

Poa pratense). The compounds can inhibit grass growth without it

some significant phytotoxic effect, and without damaging the appearance (especially the colour) of the grass. This makes the compounds attractive for use on ornamental lawns and on grass strips. They can also work against the appearance of flower heads in e.g. grass. The compounds may also inhibit weed species that may be present in the grass; examples of such weed species are tall grass (e.g. Cyperus spp.) and dicotyledonous weeds (e.g. daisy, giant, knotweed, veronica, thistle, haymole and pigweed). The growth of non-cultivated vegetation (e.g. weeds or cover vegetation) can be set back to preserve crops on plantations and fields. In orchards, especially gardens that are exposed to soil erosion, the presence of a grass cover is important. However, extensive grass growth requires a lot of maintenance. The compounds of the invention can be useful in this situation, as they can limit growth without killing the plants, which would lead to soil erosion. At the same time, the competition from the grass for nutrients and water could be reduced, which in turn could result in an increased yield of fruit. In some cases, one type of grass can be inhibited to a greater extent than another type of grass. This selectivity can be useful for e.g. to improve the quality of a turf by preferentially suppressing the growth of undesirable species.

Dwarfing can also be useful for producing miniature types of ornamental plants, of plants for the household, for gardens and in nurseries (eg poinsettias, chrysanthemums, carnations, tulips and daffodils).

As indicated above, the compounds can also be used to inhibit woody species. This property can be used to control the growth of hedges or to shape fruit trees

(e.g. apple trees). Some conifers are not inhibited to a great extent by the compounds, so the compounds may be useful in controlling unwanted vegetation in planting fields with conifers.

The plant growth-regulating effect can (as indicated above) provide sec; resulting in an increased supply of crops.

Potato plants can be controlled in the field, and inhibition of potato germination during storage may be possible.

Other plant growth-regulating effects that can be produced with the help of the compounds include changing the leaf angle as well as promoting root shoot shooting in monocot plants. The former can be useful for e.g. to change the blade orientation in e.g. potato plants thereby letting more light in to the plants and causing an increase in phytosynthesis and in the weight of the root tubers. By increasing root shoot shooting in monocots (e.g. rice), the number of flower shoots per unit area is increased, thereby increasing the overall grain yield from such plants. In grass carpets, an increase in root shoots can lead to a denser carpet, which in turn can lead to the grass having a better ability to recover after wear.

Treatment of plants with the compounds may cause the leaves to develop a darker green colour.

The compounds can inhibit, or at least delay, flowering in sugar beet and thus increase the yield of sugar.

They can also reduce the size of sugar beet without significantly reducing the yield of sugar, thereby making it possible to increase plant density. Similarly, for other root crops (e.g. turnips, turnips, beetroot, parsnips, beetroot, yams and cassava) it may be possible to increase plant density.

The compounds may be useful in limiting the vegetative growth of cotton and thus lead to an increase in the yield of cotton.

The compounds may be useful in making plants resistant to stresses, as the compounds may delay emergence of plants grown from seed, reduce stem length and delay flowering. These properties can be useful to prevent frost damage to the plants in countries where there is a significant snow cover in winter, since the treated plants will then remain under the snow cover in the cold weather. Furthermore, the compounds can make certain plants more resistant to cold and drought.

When used for seed treatment in small quantities, the compounds can have a growth-stimulating effect on plants.

When using the compounds for plant growth regulation, the amount of the compound to be applied to regulate the growth of the plants will depend on several factors, such as e.g. the particular compound chosen and the species of plant whose growth is to be regulated. Usually, however, an application rate of 0.1 to 15, preferably 0.1 to 5 kg/hectare is used. For certain plants, however, even quantities of this order of magnitude can produce undesirable phytotoxic effects. Routine investigations may be necessary to determine the best application rate of a particular compound for the particular purpose for which it is suitable.

The compounds can be used as such for fungicidal or plant growth-regulating purposes, but are more suitably prepared in preparations for such use. It is thus possible to prepare a fungicide or plant growth-regulating preparation comprising a compound which is an enantiomer of formula I or an ester, a salt or a complex thereof, as well as a carrier or a diluent.

A method of combating fungal diseases on plants comprises applying a compound which is an enantiomer of formula I, or an ester, salt or complex thereof, to the plant, to seeds from the plant or to the site around the plant or seed.

A method for regulating the growth of a plant comprises applying a compound which is an enantiomer of formula I, or an ester, salt or complex thereof as set forth above, to the plant, to seeds from the plant or to the site around the plant or seed.

The compounds can be added in different ways, e.g. they can be used as such, or they can be prepared in preparations and applied directly to the foliage of a plant, to seeds or to the medium in which the plant grows or is to be planted, or they can be applied as a spray, dust, in cream or paste form, or as steam. The application can take place on any part of the plant, bush or tree, e.g. on the foliage, trunk, branches or roots, on the soil around the roots, or on the seeds before they are planted.

The term "plant" as used herein includes small

seedlings, shrubs and trees. Furthermore, the fungicidal methods according to the invention include preventive, protective, prophylactic and removal treatment.

The compounds are preferably used for agricultural and horticultural purposes in the form of a preparation. The type of preparation used in each case will depend on the intended purpose.

The preparations can be in the form of dusty powders or granules comprising the active ingredient and a solid diluent or carrier, e.g. fillers such as kaolin, bentonite, diatomaceous earth, dolomite, calcium carbonate, talc, powdered magnesium oxide, Fuller's earth, gypsum, Hewitt's earth, diatomaceous earth and porcelain earth. Granules can be pre-made granules suitable for application to the soil without further treatment.

These granules can be produced either by impregnating filler pellets with the active ingredient, or by producing pellets from a mixture of the active ingredient and powdered filler. Preparations for seed dressing can e.g. contain an agent (eg a mineral oil) to improve the adhesion of the preparation to the seeds, and alternatively the active ingredient can be prepared for seed treatment purposes using an organic solvent (eg N-methylpyrrolidone or dimethylformamide).

The preparations can also be in the form of dispersible powders, granules or grains, and include a wetting agent to facilitate the dispersion in liquids of powders or grains which may also contain fillers and suspending agents.

Aqueous dispersions or emulsions can be prepared by dissolving the active ingredients in an organic solvent which may possibly contain wetting agents, dispersing agents or emulsifying agents, and then adding the mixture to water which may also contain wetting, dispersing or emulsifying agents. Suitable organic solvents are ethylene dichloride, isopropyl alcohol, propylene glycol, diacetone alcohol, toluene, kerosene, methyl naphthalene, xylenes, trichlorethylene, furfuryl alcohol, tetrahydrofurfuryl alcohol and glycol ethers (e.g. 2-ethoxyethanol and 2-butoxyethanol).

The preparations to be used in spray form can be i

form of aerosols where the preparation is kept in a container under pressure in the presence of a propellant, e.g. fluorotrichloromethane

or dichlorodifluoromethane.

The compounds can be mixed in a dry state with a pyro-

technical mixture to form a preparation which in a closed space can develop a smoke containing the compounds.

Alternatively, the compounds can be used in the microencapsulation

shape.

By introducing suitable additives, e.g. additives to improve spreading, adhesion and resistance

the rain resistance of treated surfaces, the different preparations can be better adapted to different purposes.

The compounds can be used as a mixture with fertilizer

substances (e.g. nitrogen, potassium or phosphorus-containing fertilisers). Preparations consisting only of granules of fertilizer and comprising the compound, e.g. as coating, is preferred. Such granules conveniently contain up to 25% by weight of the compound. A fertilizer preparation comprising one of the compounds indicated above is thus provided.

The preparations can also be in the form of liquid preparations

for use as agents for dipping or as spray preparations which are generally aqueous dispersions or emulsions containing the active ingredient in the presence of one or more surfactants, such as e.g. wetting agents, dispersants

agents, emulsifiers or suspending agents. These are ionic, anionic or non-ionic agents. .* a nmon Linn-compounds, ;e.g.ce Ly triniel.y .linmone iur.brom i d.;Suitable anionicc agents are soaps, salts of aliphatic monoesters of sulfuric acid (e.g. sodium lauryl sulfate), and salts of sulphonatesc aromatic compounds (eg sodium dodecylbenzene sulphonate, sodium, calcium or ammonium lignosulphonate, butyl naphthalene sulphonate and a mixture of sodium diisopropyl and -triisopropyl naphthalene sulphonates). ;Suitable nonionic agents are condensation products of ethylene oxide and fatty alcohols such as oleyl or cetyl alcohol, ;or alkylphenols such as octyl or nonyl phenol and octylcresol. Other nonionic agents are partial esters derived from ;.long-chain fatty acids and hexitol.l-anhydrides, ;the condensation products of said partial esters and ethylene oxide, and lecithins. Suitable suspending agents are hydrophilic colloids (e.g. polyvinylpyrrolidone and sodium carboxymethyl cellulose) and vegetable gums (eg gum acacia and gum tragacanth). ;Preparations to be used as aqueous dispersions or emulsions are usually produced in the form of a concentrate that contains a high proportion of the active ingredients, so that the concentrate must be diluted with water before use. These concentrates often have to withstand storage for longer periods and after such storage could be diluted with water to form an aqueous preparation which remains homogeneous for a sufficiently long time to be applied using conventional spray equipment. The concentrates can conveniently contain up to 95%, preferably 10-85%, e.g. 25-60% based on weight, of the active ingredient. These concentrates can conveniently contain organic acids (e.g. alkaryl or arylsulphonic acids such as xylenesulphonic acid or dodecylbenzenesulphonic acid) since the presence of such acids can increase the solubility of the active ingredients in the polar solvents that are often used in the concentrates. The concentrates can also appropriately contain 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 ingredients, depending on the intended purpose, but aqueous preparations containing 0.0005% by weight or 0.01 to 10% by weight of the active ingredients may be used . The preparations may also include other compounds with a biological effect, e.g. compounds with similar or supplementary fungicidal or plant growth-regulating action, or compounds with herbicidal or insecticidal action. Other fungicidal compounds can e.g. be such as can combat diseases on grain (e.g. wheat) such as Septoria, Gibberella and Helminthosporium spp, diseases that are transmitted through seeds or through the soil and down or powdery mildew on grapes, as well as powdery mildew and scab on apples etc. These mixtures of fungicides can. have one. wider spectrum of activity than the compounds of the general formula (I) alone, and furthermore the second fungicide can have a synergistic effect on the fungicidal activity of the compounds of the general formula (I). Examples of other fungicidal compounds are imazalil, benomyl, carbendazim, thiophanate-methyl, captafol, captan, sulphur, triforin, dodemorph, tridemorph, pyrazofos, furalaxyl, etirimol, dimethirimol, bupirimate, chlorthalonil, vinclozolin, procymidon, iprodione, metalaxyl, forsetyl- aluminium, carboxin, oxycarboxin, fenarimol, nuarimol, fenfuram, metfuroxan, nitrothal-isopropy1, triadimefon, thiabendazole, etridiazole, triadimenol, biloxazole, dithianone, binapacryl, kino-methionate, guazitin, dodine, fentin acetate, fentin hydroxide, ;dinocap, folpet, diclofluanid , ditalymphos, kitazine, cycloheximide, diclobutrazole, a dithiocarbamate, a copper compound, a mercury compound, "DPX 3217", "RH 2161", "Chevron RE 20615", "CGA 64250", "CGA 64251" and "RO 14-3169". ;The compounds of the general formula (I) can be mixed with soil, peat or another medium in which the plants take root, ;for the protection of the plants against fungal diseases transmitted through seeds, soil or foliage. Suitable insecticides are pirimor, croneton, dimethoate, metasystox and formotion. Another plant growth-regulating compound may be one that controls weed or seed head formation, improves the level or duration of action of the plant growth-regulating compound of the general formula (I), selectively regulates the growth of less desirable plants (e.g. grass) or causes the compound of the general formula (I) to act sooner or later as a plant growth regulator. Some of these other agents will be herbicides. Examples of suitable agents are gibberellins (e.g. GA^, GA^ or GA7), auxins (e.g. indoleacetic acid, indolebutyric acid, naphthoxyacetic acid or naphthylacetic acid), cytokinins (e.g. kinetin, diphenylurea, benzimidazole, benzyladenine or BAP), phenoxy-acetic acids (e.g. 2,4-D or MCPA), pyridyloxyphenoxy-propionic acids, substituted benzoic acids (e.g. TIBA), morphactins (e.g. chloro-fluorecol), maleic hydrazide, glyphosate, glyphosine, long chain fatty alcohols and acids (eg "Off Shoot 0" or "Off Shoot T"), dikegulac, "Sustar", "Embark", substituted quaternary ammonium and phosphonium compounds (eg CCC, mepiquat chloride (or Phosphon-D) , "Ethrel", carbetarlide, "Racuza", "Alar", ;asulam, abscisic acid, ancymidol (and its analogues eg isopyrimol) , RH531, hydroxybenzonitriles (eg bromoxynil ), "Avenge", "Suffix", "Lontrel", or Ithiocarbamates (eg "Eptam"). The following examples illustrate the invention. The temperatures are indicated in °C (°). ;E xample 1 ;( l-(l,2,4-triazol-l-yl)-2,3-diphenyl-propan-2-ol;Benzyl chloride (0.2 mol) was charged in dry diethyl ether (200 ml) and added dropwise to magnesium shavings (0.22 g.atom). After all the magnesium had reacted, the solution was heated under reflux for 1 hour and cooled to room temperature. Phenacyl chloride (0.1 mol) in dry diethyl ether (Joo ml) was added dropwise over 1 hour at such a rate that gentle reflux was maintained. The solution was then refluxed for 2 hours and cooled to room temperature; the mixture was poured onto ice and the complex was cleaved with ammonium chloride solution. The ethereal solution was washed several times with water; (2 x 200 mL), dried (Na 2 SO 4 ), and the solvent was removed in vacuo to give, as a colorless oil, the crude chlorohydrin which was dissolved in dimethylformamide (80 mL), and a solution of sodium triazole [prepared from sodium (0.1 g.atom) in methanol (40 mL) and 1,2,4-triazole (0.1 mol)] was added dropwise at room temperature. After stirring at room temperature for 2 hours, the solution was heated to 50° for 3 hours. The solvent was removed in vacuo and the residue poured into water to give a crystalline solid which was recrystallized from ethanol/petroleum ether to give the title compound, m.p. 124.5°. Example 2 1-(1,2,4-triazol-1-yl)-2-phenyl-3-p-fluorophenyl-propan-2-ol;p-fluorobenzyl chloride (0.1 mol) in dry diethyl ether (100 ml) was added dropwise to magnesium shavings (0 in 11 g.atom), and the solution was vigorously stirred until reflux occurred. When all the magnesium had reacted, the solution was heated under reflux for an additional 1 hour and then cooled to room temperature. Phenacyl chloride (0.05 mol) in dry diethyl ether (50 ml) was added dropwise to the solution over 1 hour at such a rate that slight reflux was maintained. The mixture was refluxed for 2 hours, cooled to room temperature and the mixture was poured into ice/ammonium chloride solution to cleave the complex. The ethereal solution was washed several times with water (2 x 200 mL), dried (Na 2 SO 4 ), and the solvent was removed in vacuo to give, as a colored oil, the crude chlorohydrin. This was dissolved in dimethylformamide (40 mL) and a solution of sodium triazole [prepared from sodium (0.05 g.atom) in methanol (20 mL) and 1,2,4-triazole (0.05 mol)] was added dropwise at room temperature. After stirring at room temperature for 2 hours, the solution was heated to 50° for 3 hours. The solvent was removed in vacuo and the mixture was poured into water to give a crystalline solid which was recrystallized from petroleum ether/chloroform to give the title compound, m.p. 116-8°. ;Example 3 ;1,l-diphenyl-2-(1,2,4-triazol-l-yl)-ethan-l-ol ;(Compound 17) ;Step 1 ;Bromobenzene (0.2 mol, 31.4 g) in sodium-dry diethyl ether; (200 ml) was added dropwise to magnesium (0.22 g.atom, 5.3 g). After all the magnesium had reacted, phenacyl chloride (0.1 mol, 15.5 g) in diethyl ether (100 ml) was added dropwise, and the solution was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated ammonium chloride solution, washed with water (3 x 150 mL) and dried (Na 2 SO 4 ). Removal of ether gave a pale yellow oil which solidified on standing. Recrystallization from petroleum ether (60-80°) gave 1,1-diphenyl-2-chloro-ethan-1-ol (60%) as a white, crystalline solid, m.p. 56-57°. ;Step 2 ;1,2,4-triazole (0.03 mol, 2.07 g) was added portionwise to a suspension of sodium hydride (0.03 mol, 0.72 g) in DMF (30 mL), and the solution was stirred until effervescence ceased. 1,1-Diphenyl-2-chloroethan-1-ol (0.015 mol, 2.94 g) in dimethylformamide (DMF, 10 mL) was added dropwise, and the solution was heated at 100° for 6 hours. The reaction mixture was poured into water, and a white phase crystallized out. This was filtered off, washed with water, dried and recrystallized from ethanol to give the title compound as a white crystalline solid, m.p. 128-129°. ;Example 4 ;2-methyl-4-phenyl-5-(1,2,4-triazol-1-yl)-pentan-4-ol;(compound 31) ;Step 1 ;The Grignard reagent formed from isobutyl bromide (0 ,1 mol, ;13.7 g) in sodium-dry diethyl ether (50 ml) and magnesium shavings (0.11 g.atom; 2.6 g) were added dropwise to a solution of phenacyl chloride (0.05 mol, 7, 7 g) in sodium dry diethyl ether (100 ml) so that gentle reflux was maintained. The solution was then stirred at room temperature for 1 hour, and the magnesium complex was cleaved by pouring the mixture into a saturated ammonium chloride solution (200 mL). The ether extract was washed with water (3 x 150 mL) and dried (Na 2 SO 4 ). Removal of the solvent gave a colorless liquid which, distilled under reduced pressure, gave 2-methyl~4-phenyl-5-chloro-pentan-4-ol (70%), m.p. 86-88°/Of01 mm Hg. ;Step 2 ;1,2,4-triazole (0.03 mol, 2.07 | q) was added portionwise to 100% sodium hydride (0PO3 mol, 0.72 g) in dry DMF (30 mL) and stirred at room temperature until the effervescence ceased. 2-Methyl-4-phenyl-5-chloro-pentan-4-ol (0.01 mol, 2.1 q) in dry DMF (10 mL) was added dropwise at room temperature, and the solution was then stirred at 100° in 6 hours. On cooling to room temperature, the solution was poured into water to precipitate a solid which was recrystallized from gasoline (60-80°)/chloroform to give the title compound (60%) as a white crystalline solid, m.p. . 94-95°, ;Example 5 ;1-(1,2,4-triazol-1-yl)-2-o-chlorophenyl-2-p-fluorophenylethan-2-ol;A solution of dimethyl-oxdsulfonium-methylide was prepared under nitrogen from sodium hydride (0.03 mol) and powdered trimethyloxosulfonium iodide (0.03 moi) in dry dimethylsulfoxide (OMSO, 30 mL). A solution of o-chlorophenyl-p-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 sulfate. Removal of the solvent gave 1-o-chlorophenyl-1-p-fluorophenyl-ethylene oxide (90%) as a colorless liquid. ;1,2,4-triazole (0.04 mol) was added portionwise to sodium hydride (0.04 mol) in DMF (40 mL), and the solution was stirred at room temperature until effervescence ceased. 1-o-Chlorophenyl-1-p-fluorophenyl 1-ethylene oxide (0.02 mol) in DMF (10 mL) was added dropwise and the solution was 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. Recrystallization from petroleum ether (60-80°)/methylene chloride gave the title compound (70%) as a white crystalline solid, m.p. 115-116°. ;Example 6 ;2,2-Dimethyl-3-(o-methoxybenzyl)-3-(1,2,4-triazol-1-yl)-butan-3-ol;(Compound 130) ;Step 1: ;Potassium -t-butoxide (19 g) was dissolved in dimethyl sulfoxide (200 mL; dried by distillation from calcium hydride and sodium hydride), and pinacolon (15 g, freshly distilled from calcium hydride) was added under argon to give a yellow solution, o-methoxyphenyl iodide (10 g) was then added, and a brown color rapidly developed. The solution was stirred for 1.5 hours before being poured into water (1 liter). The mixture was acidified with 2M hydrochloric acid and extracted with diethyl ether. Evaporation of the dried (MgSO 4 ) ethereal solution gave a yellow liquid (11.8 g), m.p. 88-93 /0.9 mm. The distillate solidified to give 2,2-dimethyl-4-(o-methoxyphenyl)-butan-3-one (6 g). Step 2: Thioanisole (3.3 g) was added to diazobicyclooctane (3.5 g) in dry tetrahydrofuran (THF) under argon, and the colorless solution was cooled in an ice/salt bath. 1.6M butyllithium solution (20 mL) in hexane was then added over 10 minutes at 0 to 2°C. After stirring the yellow up-. ;. the solution for 15 minutes, a solid was ut.fe.lt. The mixture was stirred for a further 45 minutes in the ice bath, and then allowed to warm to room temperature. The mixture was then cooled in an ice bath, and a solution of the product (5 g) from step 1 in dry THF (25 mL) was added at 0 to 5°C. When the addition was complete, the resulting yellow solution was allowed to stand overnight, poured into water, acidified with 2M hydrochloric acid and extracted with diethyl ether. The ether solution was washed well with water, dried (MgSO 4 ) and evaporated to give a yellow liquid (8.8 g) which solidified on standing. Recrystallization from petroleum ether (60-80°) gave 2,2-dimethyl-3-hydroxy-3-(o-methoxy-benzyl)-4-thiophenylbutane (3.1 g), m.p. 74-75°C. Step 3: The product (2.5 g) from step 2 was added to a stirred suspension of trimethy1-oxonium tetrafluoroborate (1.3 g) in methylene chloride (25 ml). After approx. 1 hour a clear solution was obtained. The solvent was then removed on a rotary evaporator to give a pale orange gum, which was dissolved in dry DMF (10 mL). The solution was added to a solution of 1,2,4-triazole sodium salt (1.2 g) in DMF (15 mL). [The solution was prepared by washing sodium hydride with dry diethyl ether, suspending in dry DMF and adding the triazole]. The reaction mixture was then stirred at 120°C for 2.5 hours. The reaction mixture was then quenched by pouring into water (100 mL) and the emulsion was extracted with diethyl ether (3 x 50 mL). The ether solution was washed well with water, dried (MgSO 4 ) and evaporated to give a pale yellow liquid. The mixture was subjected to dry column chromatography on silica gel eluting with diethyl ether to give a colorless liquid which solidified by trituration with diethyl ether. Recrystallization from petroleum ether (60-80°) gave the title compound (0.5 g, 23%), m.p. p. 113-116°. ;EXAMPLE 7 ;This example illustrates the preparation of a compound of the formula ;;(Compound No. 99 in Table I) ;1-(1,2,4-triazol-1-yl)-2-(2,4-dichlorophenyl) hexan-2-ol. ;The epoxide (1 mol) with the formula ;;and dimethylformamide (DMF) (0.5 1) are introduced into a reaction vessel and stirred. ;Potassium carbonate (4 mol), as an acid-binding agent, is added and the mixture is heated to approx. -125°C. ;The heat is then turned off and the mixture is cooled. At approx. At 80°C, the remainder of DMF (0.5 1) and 1,2,4-triazole (2 mol) are added. The mixture is heated, and the temperature is maintained at 80-90°C until the reaction is complete. Vacuum is then carefully applied and heating is maintained to distill the solvent from the mixture. ;When the distillation is complete, the vacuum is released with nitrogen and the mixture is cooled. At approx. At 45°C, water (2 liters) is added, followed by hexane (1 liter) and the mixture is further cooled to room temperature and stirred until a solid product is formed. The product is filtered and blown free of aqueous solvent with nitrogen. The product is then washed with hexane, blown solvent free with nitrogen, washed again with water and air blown to give a moist product (crude). The product is taken out and dried. ;Description of the product ;White, (whitish) solid, m.p. 112-114°C. ;EXAMPLE 8 ;This example illustrates the preparation of: 1- ( 1, 2, 4- triazol-l- yl)- 2-( 2- chloro- 4- methoxy- phenyl)- 2-( 4- fluorophenyl)- ethane- 2-ol (Compound No. 156 in Table I). Step 1. 3-Chloronisole (0.1 mol) was added dropwise to a suspension of aluminum chloride (0.11 mol) in carbon disulfide (40 mL) at room temperature and stirred for 30 minutes until dissolved. The mixture was cooled in ice and 4-fluorobenzoyl chloride (0.1 mol) was added dropwise. After the addition was complete, the solution was stirred for 1 hour at room temperature and refluxed for 1 hour. The solution was poured into ice (200 mL) containing CHCl 3 (20 mL), extracted with ether (200 mL), washed with water (3 x 150 mL) and dried over anhydrous sodium sulfonate. Removal of the solvent gave an oil which was purified by column chromatography and silica gel "K60" eluting with toluene/gasoline 1:1 to give (2-chloro-4-methoxy-phenyl)-4-fluorophenyl-ketone (40%) as a colorless, crystalline, solid, m.p. 31°C. ;Step 2. A solution of dimethylsulfonium methylide was prepared under nitrogen at 0°C from sodium hydride (0.3 mol using 80% suspension in oil), trimethylsulfonium iodide (0.03 mol) in dry dimethylsulfoxide (30 mL) and dry tetrahydrofuran (30 ml). A solution of (2-chloro-4-methoxyphenyl)-4-fluorophenyl ketone (0.02 mol) in tetrahydrofuran (20 mL) was added at 0°C, stirred for 30 minutes at 0°C and allowed to warm to room temperature . The solution was poured into water, extracted with diethyl ether (150 mL), washed with water (3 x 100 mL) and dried over anhydrous magnesium sulfate. Removal of the solvent gave 1-(2-chloro-4-methoxy-phenyl)-1-(4-fluorophenyl)-ethylene oxide (90%) as a colorless oil. Step 3. 1,2,4-triazole (0.03 mol) was added portionwise to sodium hydride (0.03 mol) in dimethylformamide (30 ml) and the solution was stirred at room temperature until effervescence ceased. 1-(2-Chloro-4-methoxy-phenyl)-1-(4-fluorophenyl)-ethylene oxide (0.015 mol) in diethylformamide (10 ml) was added dropwise, and the solution was stirred at 80°C for 4 hours. The solution was poured into water and triturated with petroleum ether to give a whitish solid which was filtered off and dried. Recrystallization from petroleum ether/chloroform gave the title compound (65%) as a white crystalline solid, mp 138 ~140OC ; EXAMPLE 9 ; This example illustrates the preparation of: 1- ( 1, 2, 4- triazol-l- yl)- 2-( 4- chlorophenyl)- 3, 3- dimethyl- butan-2-ol ; ( Compound No. 109 in Table I) Step 1. Trimethylacetonitrile (0.1 mol) in dry tetrahydrofuran (50 ml) was added dropwise with stirring to a Grignard reaction prepared from 4-chloro-iodobenzene (0.11 mol ) and magnesium filings (0.11 g atoms) in sodium dry ether (50 mL) at such a rate that slight reflux was maintained. The solution was refluxed. for 4 hours, cooled to room temperature, and water (40 mL f was added cautiously ig. 2N H 2 SO 4 (50 mL) was added and the ether solution was washed with water (3 x 1.00 mL) and dried over anhydrous magnesium sulfate. Removal of the solvent gave a yellow oil which was distilled under water pump vacuum to give tertiary butyl-4-chlorophenyl ketone (40%) as a colorless liquid b.p. 116-128°C/15 mm Hg.

Step 2. A solution of dimethyloxosulfonium methylide was prepared under nitrogen from sodium hydride (0.03 mol) and powdered trimethyloxosulfonium iodide (0.03 mol) in dry dimefyl sulfoxide (40 mL). A solution of 4-chlorophenyl-tert .butyl ketone (0.025 mol) in dry dimethyl sulfoxide (10 ml) was added dropwise at room temperature and the solution was heated at 50° C. for 2.5 hours. After cooling to room temperature the solution was extracted with ether (150 ml) , washed with water and dried over anhydrous sodium sulfate Removal of the solvent gave 1-(4-chlorophenyl}-1-t-butyl-ethylene oxide (95%) as a colorless liquid.

Step 3. 1,2,4-triazole (0.04 mol) was added portionwise to sodium hydride (0.04 mol) in dimethylformamide (40 ml) and the solution was stirred at room temperature until effervescence ceased. 1-(4-Chlorophenyl)-1-t-butyl-ethylene oxide (0.02 mol) in dimethylformamide (10 ml) was added dropwise, and the solution was stirred at 60°C for 3 hours. The solution was poured into water and triturated with petroleum ether to give a white solid which, after recrystallization from 60/80 petroleum ether, gave the title compound (65%) m.p. 70-73°C.

EXAMPLE 10

This example illustrates the preparation of: 1-(1,2,4-triazol-1-yl)-bis-2-(4-fluorophenyl)-2-methoxy-ethane

(Compound No. 169 in Table I)

Step 1. A solution of dimethyloxosulfonium methylide was prepared under nitrogen from sodium hydride (0.1 mol) and powdered trimethyloxosulfonium iodide (0.1 mol) in dry dimethyl sulfoxide (100 mL). A solution of 4,4'-difluorobenzophenone (0.08 mol) in dimethylsulfoxide (40ml) was added dropwise at room temperature, and the solution was heated at 50°C for 2 hours. After cooling to room temperature, the solution was extracted with diethyl ether (400 mL), washed with water (3 x 250 mL), and dried over anhydrous sodium sulfate. Removal of the solvent gave 1,1-bis-(4-fluorophenyl)-ethylene oxide (95%) as a colorless oil.

Step 2. 1,2,4-triazole (0.1 mol) was added portionwise to sodium hydride (0.1 mol) in dimethylformamide (100 mL) and the solution was stirred at room temperature until effervescence ceased. 1,1-bis-(4-fluorophenyl)-ethylene oxide (0.05 mol) in dimethylformamide (25 ml) was added dropwise, and the solution was stirred at 80°C 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. Recrystallization from petroleum ether (60-80°C)/chloroform gave 1-(1,2,4-triazol-1-yl)-bis-2-(4-fluorophenyl)ethan-2-ol (70%) as a white , crystalline, solid

J

fabric, m.p. 17 0~171°C.

Step 3. Sodium hydride (0.02 mol) was suspended in dry tetrahydrofuran (50 ml), and 1-(1,2,4-triazol-1-yl)-bis-2-(4-fluorophenyl)-ethane-2 -ol (0.02 mol) was added portionwise at room temperature. The solution was heated to 50°C to complete the reaction. After cooling to room temperature, methyl iodide (0.04 mol) was added dropwise at 20°C, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into water (100 mL), extracted with diethyl ether (150 mL), washed with water (2 x 100 mL) and dried over anhydrous sodium sulfate. Removal of the solvent gave an oil which solidified on standing. Recrystallization from petroleum ether/chloroform gave the title compound (90%) as a white crystalline solid,

sm.p. 100°C.

EXAMPLE 11

This example illustrates the production of

2-(1,2,4-triazol-1-yl)-1-cyclopentyl-1-(2,4-dichlorophenyl)-ethanol.

(Connection 121).

Cyclohexene oxide (19.6 g, 0.2 mol) in sodium dried ether (45 mm) was added dropwise to the Grignard reagent prepared from 2f4~dichloroiodobenzene (54.6 gf0.2 mol) and magnesium filings (5.0 gF 0.2 g atoms) in sodium-dried ether (100 mL) under cooling

at 0-10°C« After completion of the addition, the solution was warmed to room temperature. Toluene (100 mL) was added and the ether was removed at 70°C. The solution was stirred at 70-80°C for 2 hours, cooled to room temperature and acidified with 2N H 2 SO 4 (300 mL).

The ether layer was washed with 2N H 2 SO 4 (2 x 200 ml), water (2 x 250 ml) and dried over anhydrous sodium sulfate. Removal of the solvent gave a dark orange oil which on purification (flash chromatography on silica gel and elution with hexane r toluene 1:1) gave cyclopentyl-2,. '1-dichloroenyl-methanol (24.5 g) as an orange oil'

Cyclopentyl-2,4-dichlorophenylmethanol (8.5 g, 0.035 mol) was stirred in acetic acid (85 mL), and a solution of chromium trioxide (10.6 g, 0.1 mol) in water (40 mL) was added dropwise at room temperature. After addition was complete, the reaction mixture was heated to 50°C for 2 hours, cooled to room temperature, poured into water (100 w) and extracted with ether (2 x 200 mL). The ether extracts were washed with 2N NaOH (2 x 200 ml), water (2 x 200 ml) and dried over anhydrous sodium sulfate. Removal of the solvent gave a yellow liquid which on purification (flash chromatography on silica gel eluting with hexane:toluene = 7:3) gave cyclopentyl-2,4-dichlorophenylketone (5.1 g).

Sodium hydride (0.48 g, 0.02 mol) was suspended in dry DMSO (20 mL) and heated at 70°C for 2 h under nitrogen. After cooling to 0 °C, dry THF (20 mL) was added, followed by trimethylsulfonium iodide (4.08 g, 0.02 mol) in dry DMSO (20 mL) and the solution was stirred at 0 °C for 2 minutes. Cyclopentyl-2,4-di-chloro phenyl ketone (2.43 g, 0.01 mol) in dry DMSO (10 mL) and dry THF (10 mL) was added to this mixture at 0 °C and the solution was allowed to warm to room temperature over 2 hours. The reaction mixture was then poured into water (200 mL) and extracted with ether (3 x 150 mL). The ether extracts were washed with water (5 x 200 mL), dried over anhydrous sodium sulfate, and the solvent removed to give 1-cyclopentyl-1-(2,4-dichlorophenyl)ethylene oxide (2.57 g) as a yellow oil. -

To a stirred solution of sodium triazole [from 1.2, 4-triazole (1.38 g, 0.02 mol) and sodium hydride (0.48 g, 0.02 mol)] in dry DMF (20 mL) at room temperature. The reaction mixture was heated at 90°C for 5 hours, then allowed to cool, poured into water and extracted with diethyl ether. The ether extract was washed with water and then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a white solid which was purified (flash chromatography on silica gel eluting with ethyl acetate : gasoline = 1:1) to give the title compound (1, 1 g) m.p. 157°C.

EXAMPLE 12

This example describes the production of

1-(1,2,4-triazol-1-yl)-2-(4-chlorophenyl)-propan-2-ol, by the method described above.

The Grignard reagent prepared from methyl iodide (0.02 mol, 2.84g) and magnesium filings (0.02 g atom, 0.5 g) in sodium dried diethyl ether (20 ml) was added dropwise to a solution of a-(1,2,4 -triazol-1-yl)-4-chloroacetophenone (0.01 mol, 2.21 g) in sodium-dried tetrahydrofuran (20 mL). After complete addition, the solution was refluxed for 4 hours. The reaction mixture was cooled to room temperature, neutralized with saturated NH 2 Cl solution and extracted with diethyl ether. The ether extracts were washed with water (x4), dried over anhydrous sodium sulfate and concentrated to give a white crystalline solid. GC/MS of this solid showed that it contained

1-(1,2,4-triazol-1-yl)-2-(4-chlorophenyl)-propan-2-ol (25%, M<+> 237) and unreacted

α-(1,2,4-triazol-1-yl)-4-chloroacetophenone (75%).

Purification by hplc (silica gel eluted with ethyl acetate : petroleum ether = 1:1) gave the title compound as a white crystalline solid m.p. 88-90°C.

EXAMPLE 13

The compounds were tested against various fungal diseases on the foliage of plants. The technique used was as follows.

The plants were grown in John Innes Potting Compost (No. 1 or 2) in mini pots with a diameter of 4 cm. A layer of fine sand was placed at the bottom of the pots containing the dicot plants to facilitate uptake of the test compound by the roots. The test compounds were prepared either by ball milling

with aqueous "Disoersol T" or as a solution in acetone or acetone/ethanol which was diluted to the desired concentration immediately before use. For foliar diseases, suspensions (100 ppm active ingredient) were sprayed

On earth. Exceptions to this were the trials against Botrytis cinerea, Plasmopara viticola and Venturia inaequalis. The spray preparations were applied to maximum absorption, and the liquid for

uptake through the roots to a final concentration corresponding to

about. 40 ppm active ingredient/dry soil. "Tween 20" was added to give a final concentration of 0.05% when the spray preparation was applied to grain.

In most experiments, the test compound was applied to the soil (roots) and to the foliage (by spraying) one or two days before the disease was inoculated into the plant. An exception was the experiment on Erysiphe graminis, where the plant was infected 24 hours before treatment. After inoculation, the plants were placed in suitable environments for the infection to develop, and then incubated until the degree of the disease could be assessed. The period between inoculation and assessment varied from 4 to 14 days depending on the disease and the environment.

The disease control was recorded according to the following grading:

4 = no disease

3 = trace - 51 disease on untreated plants

2=6- 25% disease on untreated plants

1 = 26 - 59% disease on untreated plants

0 = 60 - 100% disease on untreated plants.

The results are shown in Table II-

Example 14

This example illustrates the plant growth-regulating properties of the compounds. The compounds were applied in the form of a 40cc ppm solution in distilled water to the foliage of newly sown plants of various species. The experiment was repeated twice, 12 or 13 days after the treatment, the plant growth-regulating and phytotoxic effect on the plants was assessed.

Table III shows the compounds' inhibitory effect on

the vegetative growth, according to the following grading:

1 - 0-30% retardation

2 = 31-75% retardation

3 = 75% retardation.

If no figure is given, the compound was mainly without inhibitory effect. Additional growth regulating properties are listed as follows:

G darker green leaf colour

A = effect on the leaf tips

T = root shoot promoting effect.

Claims (3)

1. Use of a 1,2,4-triazole derivative of the general formula where is an alkyl group with from 1 to 6 carbon atoms, cycloalkyl with from 3 to 6 carbon atoms or phenyl which is optionally substituted with 1-2 substituents selected from halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1.' to. 4 carbon atoms, nitro, trifluoromethyl or benzyloxy optionally substituted with a halogen, and R <2> is phenyl or benzyl which are both optionally substituted with 1-2 substituents selected from halogen, alkyl with from 1 to. 4 carbon atoms, alkoxy having from 1 to 4 carbon atoms, nitro phenyl or phenoxy; and acid addition salts and metal complexes thereof; as plant fungicide. 2. Use as stated in claim 1 of 1-(1(2,4-triazol-1-yl)}-2=(2-fluorophenyl)-2-(4-fluorophenyl)ethan-2-ol - 3 c Use as stated in claim 1 of 1-(1 e 2 , 4-triazol-1-yl) 2-(2 0 4-dichlorophenyl)-hexan-2-ol. 4, Use as stated in claim I of ,2,4-triazol-1-yl)-2-(2-chlorobenzyl)-3,3-dimethyl-butan-2-ol.