Pyrimidine Derivatives

This invention relates to pyrimidine compounds useful as plant growth regulating agents and fungicides, to processes for preparing them, to compositions containing them and to methods of regulating plant growth and combating fungal diseases in plants using them.

According to the present invention there is provided a pyrimidine compound having the formula (I): ##STR2## and stereoisomers thereof, wherein

Y is an optionally substituted secondary or tertiary alkyl group containing from 3 to 7 carbon atoms or an optionally substituted cycloalkyl or alkylcycloalkyl group containing from 3 to 7 carbon atoms;

R.sup.1 and R.sup.2, which may be the same or different are hydrogen or a lower alkyl group;

A is an optionally substituted heterocyclic group;

n is an integer which may be from 0 to 2; and

R.sup.3 is hydrogen, an alkyl group containing from 1 to 4 carbon atoms, an alkenyl group containing from 2 to 4 carbon atoms or an alkynyl group containing from 2 to 4 carbon atoms; and agrochemcially acceptable salts and metal complexes of the compounds of formula (I) and esters (acylates) of compounds of formula (I) wherein R.sup.3 is hydrogen.

The compounds of the invention contain one or more chiral centres. 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 art, and this invention embraces such isomers.

Preferred optional substituents in the group Y are halogen, especially chlorine or fluorine.

Y is preferably a group which in its unsubstituted form has the structure: ##STR3## wherein R.sup.4, R.sup.5 and R.sup.6, which may be the same or different, are separately hydrogen or an alkyl group, provided that no more than one of R.sup.4, R.sup.5 and R.sup.6 is hydrogen, or wherein R.sup.4 and R.sup.5, together with the carbon atom joining them, form a cycloalkyl ring and R.sup.6 is hydrogen or an alkyl group, the total number of carbon atoms in the group (II) being from 3 to 7.

Especially preferred groups Y are optionally halo-substituted isopropyl, t-butyl, 1,1-dimethylpropyl (t-pentyl), cyclopropyl or 1-methylcyclopropyl.

It is preferred that Y is unsubstituted.

R.sup.1 is preferably hydrogen. R.sup.2 is preferably hydrogen or methyl. Preferrably both R.sup.1 and R.sup.2 are hydrogen. The integer n is preferably 1 or 0, and especially 0.

R.sup.3 is preferably methyl or hydrogen. Hydrogen is especially preferred.

As examples of optional substituents which may be present in the group A there may be mentioned one or more substituents selected from halogen, for example chlorine, bromine or fluorine; alkyl, for example lower alkyl and especially methyl; alkoxy, for example lower alkoxy and especially methoxy; haloalkyl, for example lower haloalkyl and especially trifluoromethyl; lower alkoxycarbonyl (for example --CO.CH.sub.3); nitro; amino; formamido, acetamido, dialkylsulphamoyl and cyano. The term "lower" as applied to the above groups indicates that the group contains from 1 to 6, and preferably from 1 to 4 carbon atoms.

The group, A may for example be a single heterocyclic ring system having for example 5 or 6 ring atoms and containing one or more heteroatoms which may for example be one or more of oxygen, sulphur or nitrogen. Alternatively, the group A may be a fused ring system having one or more heteroatoms in one or more of the fused rings. For example the group, A may be a fused ring system based on the fusion of two or more 4, 5 or 6 membered rings, for example the fusion of a 5 or 6 membered heterocyclic ring with a benzene ring.

The group, A is preferably an optionally substituted aromatic heterocyclic group or an optionally substituted fully hydrogenated derivative of an aromatic heterocyclic group.

As specific examples of the group A there may be mentioned the following groups each of which may be optionally substituted:

tetrazol-1-yl; tetrazol-5-yl; 1,2,4-thiadiazol-3-yl; 1,2,4-thiadiazol-5-yl; 1,3,4-thiadiazol-2-yl; 1,3,4-thiadiazol-5-yl; 1,2,3-triazol-1-yl; 1,2,3-triazol-4-yl; 1,2,3-triazol-5-yl; 1,2,4-triazol-1-yl; 1,2,4-triazol-3-yl; 1,2,4-triazol-5-yl; isoxazol-3-yl; isoxazol-4-yl; isoxazol-5-yl; oxazol-2-yl; oxazol-4-yl; oxazol-5-yl; isothiazol-3-yl; isothiazol-4-yl; isothiazol-5-yl; thiazol-2-yl; thiazol-4-yl; thiazol-5-yl; imidazol-1-yl; imidazol-2-yl; imidazol-4-yl; imidazol-5-yl; pyrazol-1-yl; pyrazol-3-yl; pyrazol-5-yl; pyrazol-5-yl; 1,3-dioxol-2-yl; 1,3-dioxol-4-yl; 1,3-dithiol-2-yl; 1,3-dithiol-4-yl; pyrrol-1-yl; pyrrol-2-yl; pyrrol-3-yl; fur-2-yl; fur-3-yl; thien-2-yl; thien-3-yl; 1,3,5-thiadiazin-2-yl; 1,3,5-thiadiazin-4-yl; 1,3,5-thiadiazin-6-yl; 1,2,4-triazin-3-yl; 1,2,4-triazin-5-yl; 1,2,4-triazin-6-yl; 1,3,5-triazinyl; 1,3,5-trioxanyl; 1,3,5-trithianyl; 1,4-oxazin-2-yl; 1,4-oxazin-3-yl; 1,4-oxazin-5-yl; 1,4-oxazin-6-yl; 1,4-thiazin-2-yl; 1,4-thiazin-3-yl; pyrazinyl; pyridazin-3-yl; pyridazin-4-yl; pyrimidin-2-yl; pyrimidin-4-yl; pyrimidin-5-yl; 1,4-oxathiin-2-yl; 1,4-oxathiin-3-yl; 1,3-dithiin-2-yl; 1,3-dithiin-4-yl; 1,3-dithiin-5-yl; 1,3-dithiin-6-yl; 1,3-dithian-2-yl; 1,3-dithian-4-yl; 1,3-dithian-5-yl; pyrid-2-yl; pyrid-3-yl; pyrid-4-yl; pyran-2-yl; pyran-3-yl; pyran-4-yl; pyran-6-yl; pyran-6-yl;

The following further examples of the group A may be attached to the group --C.tbd.C-- at any of the available points of attachment:

7-oxabicyclo[2.2.1]heptanyl; 1,2,4-triazolo[4,3-a]pyridinyl; 1H-benzotriazolyl; benzothiazolyl; 7H-purinyl; 1H-benzimidazolyl; 1H-indazolyl; 1,3-benzodioxolyl; benzofuranyl; 1H-indolyl; 2H-isoindolyl; 1-benzothienyl; pteridinyl; quinoxalinyl; quinazolinyl; isoquinolinyl; or quinolinyl.

A may also be a fully or partially hydrogenated derivative of any of the above groups which are aromatic heterocyclic groups. Thus A may for example be tetrahydrthien-2-yl; tetrahydrothien-3-yl; tetrahydrofur-2-yl or tetrahydrofur-3-yl; tetrahydropyrrol-2-yl; tetrahydropyrrol-3-yl; piperidin-1-yl; piperidin-2-yl; piperidin-3-yl; piperidin-4-yl; piperazin-1-yl; piperazin-2-yl; morpholinyl; tetrahydropyranyl; tetrahydrothiopyranyl; dioxanyl.

The present invention includes salts and metal complexes of the compounds of formula (I) and esters (acylates) of compounds of formula (I) wherein R.sup.3 is hydrogen. As examples of esters there may be mentioned for example acetates or benzoates. As examples of salts there may be mentioned for example toluene sulphonate salts, dodecylbenzene sulphonate salts, hydrochloride salts, hydrobromide salts and orthophosphate salts. Without limitation of the generality of the above statement, the present invention also includes any compound which breaks down in agrochemical use to a compound of formula (I).

Examples of the compounds of the invention are presented in Table 1 in which the values for A and R.sup.6, in the formula (III) below are as indicated.

Compounds of general formula (I) above wherein R.sup.3 is hydrogen and Y, A, R.sup.1, R.sup.2, and n are as defined may be prepared by reacting a compound of general formula (IV): ##STR5## with an organometallic compound which may be represented by the indicative formula (V):

where M indicates that the organometallic compound is based on a suitable metal, M, for example lithium, magnesium, titanium or zirconium.

The reaction conveniently takes place in a solvent such as diethylether, tetrahydrofuran or dichloromethane at --80.degree. C. to +80.degree. C. in an inert atmosphere. The product is obtained by quenching with a proton donor. When M is magnesium, the organometallic compound is more specifically:

When M is titanium, the organometallic compound is more specifically:

and is conveniently prepared by the reaction of the compound of formula (V) wherein M is lithium with chlorotitanium triisopropoxide.

When M is zirconium, the organometallic compound is more specifically:

and is conveniently prepared by the reaction of the compound of formula (V) wherein M is lithium with chlorozirconium tributoxide.

The compounds of general formula (I) wherein R.sup.3 is hydrogen may also be prepared by reacting a ketone of general formula (VI), wherein A, Y, R.sup.1, R.sup.2, and n are as defined with an organometallic compound which may be represented by the indicative formula (VII) where M indicates that the organometallic compound is based on a suitable metal, M, for example lithium: ##STR6##

The reaction preferably takes place in a suitable solvent such as diethyl ether or tetrahydrofuran at a temperature of from -120.degree. C. to +80.degree. C. and in an inert atmosphere. The product is obtained by quenching with a suitable proton donor.

A third alternative method of preparing a compound of general formula (I) wherein R.sup.3 is hydrogen and n is 0, consists of the following stages:

Stage 1

A compound of general formula (VIII) ##STR7## is prepared by reacting the ketone of general formula (IV): ##STR8## with the reaction product of

(a) a compound of formula (IX):

wherein Z is hydrogen or a protective group, and

(b) an organometallic compound; and

subsequently removing the protective group, Z, where it is present.

Stage 2

The intermedate of formula (VIII) is then converted into a compound of formula (I) (wherein R.sup.3 is hydrogen and n is 0) by reaction with the appropriate optionally substituted heterocyclic halide, A-hal, where -hal represents halogen.

The organometallic compound used in Stage (1b) is suitably based on magnesium, lithium, titanium or zirconium, and may be for example ethyl magnesium bromide or n-butyl lithium. The titanium organometallic reagent is conveniently prepared by reaction of n-butyl lithium followed by chlorotitanium triisopropoxide. The zirconium organometallic compound is conveniently prepared by reaction of n-butyl lithium followed by chlorozirconium tributoxide.

The reaction of the compound of general formula (IV) in Stage (1) above preferably takes place in the substantial absence of oxygen, for example in a nitrogen atmosphere.

The reaction preferably takes place in a suitable solvent, preferably an ether solvent, for example tetrahydrofuran, diethyl ether, dimethoxyethane, bis(2-methoxyethyl)ether or dimethoxymethane.

The reaction temperature is not critical, but is preferably in the range from --20.degree. C. to 40.degree. C., for example from 0.degree. C. to ambient temperature. Super-atmospheric or sub-atmospheric pressures may be used if desired, but the reaction preferably takes place at ambient pressure.

It is preferred that Z is a protective group. Suitable protective groups will occur to those skilled in the art as will the associated method of removing the protective group. Thus the protective group, Z, may for example be an organosilyl group. Suitable organosilyl protective groups include trialkyl silyl groups, for example the trimethylsilyl group. As a further example of a suitable protective group there may be mentioned a formaldehyde protective group such as that described by Bumagin, Ponomaryov and Beletskaya in USSR Synthesis (9), 728-9 (1984).

The compound of formula (IX) may be prepared by methods known in the art, for example by the reaction of an acetylene derivative, for example an acetylene salt, with the corresponding halosilane or with a source of formaldehyde respectively.

The subsequent removal of the protective group, Z, may be accomplished by methods well known in the art for that protective group. For example a silyl protective group, Z, may be removed under the action of potassium carbonate in a suitable solvent such as methanol. Other suitable methods are described in "Silicon in Organic Synthesis" by Ernest W. Colvin, Butterworths 1981, ISBN 0 408 10831 at page 165 and in the references cited therein. A formaldehyde protective group may be removed by oxidation as described in the USSR Synthesis publication noted above.

Preferably the heterocyclic halide, A-hal, used in Stage (2) is an iodide. Preferably the reaction takes place according to the known Heck reaction or a variant thereof (as described for example in Chemistry and Industry, 1987, (17), p 612; H M Colquhoun).

The ketones of the general formula (IV) may be prepared by the method described in U.S. Pat. No. 4,713,456 or by alkylation of a lower alkyl ketone homologue.

The ketones of general formula (VI) may be prepared using standard methods set out in the literature.

The ethers (wherein R.sup.3 is alkyl) and esters (acylates) of the invention may be made from the corresponding hydroxy compound by reaction with the appropriate halide, acid chloride or acid anhydride in the presence of a suitable base.

The plant growth regulating effects of the compounds are manifested as, for example, by a stunting or dwarfing effect on the vegetative growth of woody and herbaceous mono- and di-cotyledonous plants. Such stunting or dwarfing may be useful, for example, in peanuts, cereals such as rice, wheat and barley, oil seed rape, field beans, sunflowers, potatoes and soya bean where reduction in stem height, with or without further advantageous effects such as stem strengthening, thickening and shortening, internode shortening, increased buttress root formation and more erect stem and leaf orientation, may reduce the risk of lodging and may also permit increased amounts of fertiliser to be applied. The stunting of woody species is useful in controlling the growth of undergrowth under power lines etc. Compounds which induce stunting or dwarfing may also be useful in modifying the stem growth of sugar cane thereby increasing the concentration of sugar in the cane at harvest; in sugar cane, the flowering and ripening may be controllable by applying the compounds. Stunting of peanuts can assist in harvesting. Growth retardation of grasses can help maintenance of grass swards. Examples of suitable grasses are Stenotaphrum secundatum (St. Augustine grass), Cynosurus cristatus, Lolium multiflorum and perenne, Agrostis tenuis, Cynodon dactylon (Bermuda grass), Dactylis glomerata, Festuca spp. (e.g., Festuca rubra) and Poa spp. (e.g., Poa pratense). The compounds may stunt grasses without significant phytotoxic effects and without deleteriously affecting the appearance (particularly the colour) of the grass; this makes such compounds attractive for use on ornamental lawns and on grass verges. They may also have an effect on flower head emergence in, for example, grasses. The compounds can also stunt weed species present in the grasses; examples of such weed species are sedges (e.g., Cyperus spp.) and dicotyledonous weeds (e.g., daisy, plantain, knotweed, speedwell, thistle, docks and ragwort). The growth of non-crop vegetation (e.g., weeds or cover vegetation) can be retarded thus assisting in the maintenance of plantation and field crops. In fruit orchards, particularly orchards subject to soil erosion, the presence of grass cover is important. However excessive grass growth requires substantial maintenance. The compounds of the invention could be useful in this situation as they could restrict growth without killing the plants which would lead to soil erosion; at the same time the degree of competition for nutrients and water by the grass would be reduced and this could result in an increased yield of fruit. In some cases, one grass species may be stunted more than another grass species; this selectivity could be useful, for example, for improving the quality of a sward by preferential suppression of the growth of undesirable species. The dwarfing may also be useful in miniaturising ornamental, household, garden and nursery plants (e.g., poinsettias, chrysanthemums, carnations, tulips and daffodils).

As indicated above, the compounds can also be used to stunt woody species. This property can be used to control hedgerows or to shape or reduce the need for pruning, of fruit trees (e.g., apples, pears, cherries, peaches, vines etc).

The plant growth regulating effect may (as implied above) manifest itself in an increase in crop yield; or in an ability in orchards and other crops to increase fruit set, pod set and grain set. Some coniferous trees are not significantly stunted by the compounds so the compounds could be useful in controlling undesirable vegetation in conifer nurseries.

In the potato, vine control in the field and inhibition of sprouting in the store may be possible.

In addition the compounds may be useful as absicision agents resulting in thinning of fruit on the tree and an increase in fruit quality.

Other plant growth regulating effects caused by the compounds include alteration of leaf angle and changes in leaf morphology (both of which may permit increased light interception and utilization) and promotion of tillering in monocotyledonous plants. Improved light interception is of value in all major world crops, e.g., wheat, barley, rice, maize, soya, sugarbeet, potatoes, plantation crops and orchard crops. The leaf angle effect may be useful for example in altering the leaf orientation of, for example, potato crops thereby letting more light into the crops and inducing an increase in photosynthesis and tuber weight. By increasing tillering in monocotyledonous crops (e.g., rice), the number of flowering shoots per unit area may be increased thereby increasing the overall grain yield of such crops. In addition better control and modification of hierarchical relationships is possible both in vegetative and reproductive stages of monocotyledonous and dicotyledenous plant growth, especially in cereals such as wheat, barley, rice and maize, whereby the number of flowering shoots per unit area may be increased and the size distribution of grains within the ear may be modified in such a way as to increase yield. In the treatment of rice plants, or rice crops the invention compounds can be applied, e.g., as granules or a granular formulation, for example as slow release granules, to nursery boxes, paddy water and other like cultivation loci and media. In grass swards, especially amenity grass, an increase in tillering could Alead to a denser sward which may result in increased resilience in wear; and to increased yields and better quality of forage grass, e.g., improved digestability and palatability.

The treatment of plants with the compounds can lead to the leaves developing a darker green colour. In dicotyledonous plants such as soyabean and cotton, there may be promotion of sideshooting.

The compounds may inhibit, or at least delay, the flowering of sugar beet (and thereby may increase sugar yield) or otherwise modify the flowering patterns in many other crops. They may also reduce the size of sugar beet without reducing significantly the sugar yield thereby enabling an increase in planting density to be made. Similarly in other root crops (e.g., turnip, swede, mangold, parsnip, beetroot, yam and cassava) it may be possible to increase the planting density. The compounds could be useful in restricting the vegetative growth of cotton thereby leading to an increase in cotton yield. Crop yields may also be increased by improvement of the harvest index (i.e. the harvested yield as a proportion of the total dry matter produced) by altering dry matter partitioning. This applies to all the aforementioned root, pod, cereal, tree, plantation and orchard crops.

The compounds may be useful in rendering plants resistant to stress since the compounds can delay the emergence of plants grown from seed, shorten stem height and delay flowering; these properties could be useful in preventing frost damage in countries where there is significant snow cover in the winter since then the treated plants would remain below snow cover during the cold weather. Further the compounds may cause drought or cold resistance in certain plants.

When applied as seed treatments at low rates the compounds can have a growth stimulating effect on plants.

It is to be understood that not all the compounds of the present invention will necessarily show all the above mentioned plant growth regulating effects. Thus whilst there may be advantages in compounds which have a broad spectrum of plant growth regulating effects against a wide range of species, compounds having a high specific activity with respect to a particular species and/or plant growth regulating effect may also be of great benefit.

In carrying out the plant growth regulating method of the invention, the amount of compound to be applied to regulate the growth of plants will depend upon a number of factors, for example the particular compound selected for use, and the identity of the plant species whose growth is to be regulated. However, in general an application rate of 0.1 to 15, preferably 0.1 to 5, kg per hectare is used. With the use of biodegradable polymeric slow release granules rates of 1 to 10g per hectare are feasible; whilst electrodynamic spraying techniques may also deploy lower rates of application. However, on certain plants even application rates within these ranges may give undesired phytotoxic effects. Routine tests may be necessary to determine the best rate of application of a specific compound for any specific purpose for which it is suitable.

The compounds may also be active fungicides and may be used to control one or more of the following pathogens:

Pyricularia oryzae on rice.

Puccinia recondita, Puccinia striiformis and other rust on wheat, Puccinia hordei, Puccinia striiformis and other rusts on barley, and rusts on other hosts, e.g. coffee, pears, apples, peanuts, vegetables and ornamental plants.

Erysiphe graminis (powdery mildew) on barley and wheat and other powdery mildews on various hosts such as Sphaerotheca macularis on hops, Sphaerotheca fuliginea on cucurbits (e.g. cucumber), Podosphaera leucotricha on Aapple and Uncinula necator on vines.

Helminthosporium spp., Rhynchosporium spp., Septoria spp., Pseudocercosporella herepotrichoides and Gaeumannomyces graminis on cereals.

Cercospora arachidicola and Cercosporidium personata on peantus and other Cercospora species on other hosts, for example, sugar beet, bananas, soya beans and rice.

Botrytis cinerea (grey mould) on tomatoes, strawberries, vegetables, vines and other hosts.

Alternaria species on vegetables (e.g. cucumber), oil seed rape, apples, tomatoes and other hosts.

Venturia inaequalis (scab) on apples.

plasmopara viticola on vines.

Other downy mildews such as Bremia lactucae on lettuce, Peronospora spp. on soya beans, tobacco, onions and other hosts and Pseudoperonospora humuli on hops and Pseudoperonospora cubensis on cucurbits Phytophthora infestans on potatoes and tomatoes and other Phytophthora spp. on vegetables, strawberries, avocado, pepper, ornamentals, tobacco, cocoa and other hosts.

Thanaterphorus cucumeris on rice and other Rhizoctonia species on various host such as wheat and barley, vegetables, cotton and turf.

Some of the compounds show a broad range of activities against fungi in vitro. They may also have activity against various post-harvest diseases on fruit (e.g. Penicillium digitatum and Italicum and Trichoderma viride on oranges, Gloesporium musarum and bananas and Botrytis cinerea on grapes).

Further some of the compounds may be active as seed dressings against Fusarium spp., Septoria spp., Tilletia spp., (bunt, a seed borne disease of wheat), Ustilago spp., Helminthosporium spp. on cereals, Rhizoctonia solani on cotton and Pyricularia oryzae on rice.

The compounds may be used as such for plant growth regulating purposes or as fungicides but are more conveniently formulated into compositions for such usage. The invention thus provides a plant growth regulating or fungicidal composition comprising a compound of general formula (I) as hereinbefore defined, or a salt or metal complex thereof; and, optionally, a carrier or diluent.

The invention also provides a method of regulating plant growth or of fungicidal treatment, which comprises applying to the plant, to seed of a plant or to the locus of a plant or seed, a compound, or a salt or metal complex thereof, as hereinbefore defined, or a composition combining the same.

The compounds, salts, metal complexes, ethers and esters can be applied in a number of ways, for example they can be applied, formulated or unformulated, directly to the foliage 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; or as slow release granules. Application can be to any part of the plant, 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; or to the soil generally, to paddy water or to hydroponic culture systems. The invention compounds may also be injected into plants or trees and they may also be sprayed onto vegetation using electrodynamic spraying techniques.

The term "plant" as used herein includes seedlings, bushes and trees.

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 treatement. 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 micro-encapsulated form. They may also be formulated in biodegradable polymeric formulations to obtain a slow, controlled release of the active substance.

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); or which are spray formulations of the kind suitable for use in electrodynamic spraying techniques. The foregoing 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 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 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), and the concentrate is 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 and electrodynamic 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% to 10%, or 0.01% to 10%, by weight of active ingredient(s) may be used.

The compositions of this invention can comprise also one or more additional compound(s) having biological activity, e.g., compounds having similar or complementary fungicidal or plant growth activity or compounds having plant growth regulating, herbicidal or insecticidal activity.

The additional fungicidal compound can be, for example, one which is capable of combating ear diseases ofcereals (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. Examples of suitable additional fungicidal compound are imazalil, benomyl, carbendazim, thiophanate-methyl, captafol, captan, sulphur, triforine, dodemorph, tridemorph, pyrazophos, furalaxyl, ethirimol, tecnazene, dimethirimol, bupirimate, chlorothalonil, vinclozolin, procymidone, iprodione, metalaxyl, forsetylaluminium, carboxin, oxycarboxin, fenarimol, nuarimol, fenfuram, methfuroxan, nitrotal-isopropyl, triadimefon, thiabendazole, etridiazole, triadimenol, biloxazol, dithianon, binapacryl, quinomethionate, guazatine, dodine fentin acetate, fentin hydroxide, dinocap, folpet, dichlofluanid, ditalimphos, kitazin, cycloheximide, dichlobutrazol, a dithiocarbamate, a copper compound, a mercury compound, 1-(2-cyano-2-methoxyiminoacetyl)-3-ethyl urea, fenaponil, ofurace, propiconazole, etaconazole and fenpropemorph and fenpropidine.

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 additional insecticides are Pirimor, Croneton, dimeth- oate, Metasystox, pyrethroid insecticides and formothion. The other, additional, plant growth regulating compound can be one which controls weeds or seedhead formation, improves the level or longevity of the plant growth regulating activity of the compounds of general formula (I), selectively controls the growth of the less desirable plants (e.g., grasses) or causes the compound of general formula (I) to act faster or slower as a plant growth regulating agent. Some of these other agents will alsobe herbicides.

Examples of suitable plant growth regulating compounds, which can display synergy in admixture, or use, with the invention compounds are the gibberellins (e.g., GA.sub.3, GA.sub.4 or GA.sub.7), the auxins (e.g., indoleacetic acid, indolebutyric acid, naphthoxyacetic acid or naphthylacetic acid), the cytokinins (e.g., kinetin, diphenylurea, benzimidazole, benzyladenine or benzylaminopurine), phenoxyacetic acids (e.g., 2,4-D or MCPA), substituted benzoic acids (e.g., triiodobenzoic acid), morphactins (e.g., chlorfluorecol), maleic hydrazide, glyphosate, glyphosine, long chain fatty alcohols and acids, dikegulac, fluoridamid, mefluidide, substituted quaternary ammonium and phosphonium compounds (e.g., chlormequat* chlorphonium or mepiquat chloride*), ethephon, carbetamide, methyl-3,6-dichloroanisate, daminozide*, asulam, abscisic acid, isopyrimol, 1-(4-chlorophenyl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid, hydroxybenzonitriles (e.g., bromoxynil), difenzoquat*, benzoylprop-ethyl 3,6-dichloropicolinic acid, fenpentezol, triapenthanol, flurpirimidol, paclobutrazol, tetcyclacis and tecnazene. Synergy will be most likely to occur with those of the foregoing which are quaternary ammonium compounds and with those marked with an asterisk.

For certain applications, for example in the injection of the compounds of the invention into trees or plants, it is desirable that the compounds have a relatively high solubility in water, for example a solubility in excess of 30 parts per million. The compounds may alternatively be injected into the tree in the form of an organic solution, for example a solution in a lower alcohol.

For certain applications it is also desirable that the compound has a low persistancy in soil to prevent carry-over to adjacent crops or even crops planted subsequently in the same soil. Preferably the compound for use in such applications has a half life in the soil of less than 20 weeks.

The invention is illustrated by the following Examples in which all parts and percentages are by weight unless otherwise stated.

This Example illustrates the preparation of 3-hydroxy-4-methyl-3-pyrimidin-5-yl-1-thien-3-yl-pent-1-yne, Compound No 1 of Table 1.

Stage 1

Preparation of 3-(2,2-Dibromoethenyl)thiophene

To a stirred, cooled solution of 3-thiophenecarboxaldehyde (5 g, 44.6 mmol) and triphenylphosphine (23.38 g, 89.2 mmol) in dichloromethane (80 ml) was added tetrabromomethane (17 g, 51.3 mmol) in dichloromethane (40 ml) at such a rate as to keep the temperature below 5.degree. C. After the addition was complete, the reaction mixture was stirred for a further 40 minutes at room temperature before filtration and concentration under reduced pressure. The residue was repeatedly extracted with hexane and the combined extracts concentrated under reduced pressure to give an oil (10.3 g). Chromatography on silica eluting with hexane gave the desired product as a yellow oil.

Stage 2

Preparation of 3-hydroxy-4-methyl-3-pyrimidin-5-yl-1-thien-3-ylpent-1-yne

To a stirred solution of the product of Stage (1) (0.22 g, 0.82 mmol) in dry tetrahydrofuran (15 ml) at --78.degree. C. under nitrogen was slowly added n-butyl lithium (2.5 M in hexane; 0.8 ml, 2 mmol). After stirring for one hour at --78.degree. C., the reaction mixture was allowed to warm to room temperature before 2-methyl-1-pyrimidin-5-ylpropan-1-one (0.2 g, 1.3 mmol) was added. After 20 minutes, the reaction was quenched by addition of water, and the product was extracted with ether (2.times.20ml). The combined organic extracts were washed with water, dried over sodium sulphate, filtered, and concentrated under reduced pressure to give an oil which was chromatographed on silica. Elution with ethyl acetate - hexane (1:1) gave the desired product as a yellow oil which solidified slowly on standing to give a solid of melting point 102-105.degree. C.

This Example illustrates the preparation of 3-hydroxy-4-methyl-3-pyrimidin-5-yl-1-thien-2-yl-pent-1-yne, Compound No 2 of Table 1.

Stage 1

Preparation of 3-hydroxy-4-methyl-3-pyrimidin-5-yl-1-trimethylsilylpent-1-yne.

A solution of ethyl magnesium bromide (33 ml of a solution which was 3M in tetrahydrofuran; 0.1 mol) was added to a stirred, cooled solution of ethynyltrimethylsilane (9.8 g,0.1 mol) in dry tetrahydrofuran (150 ml) under nitrogen. The rate of addition was adjusted so as to maintain the reaction temperature below 30.degree. C. After stirring for 45 minutes, 2-methyl-1-pyrimidin-5-ylpropan-1-one (15 g, 0.1 mol) in dry tetrahydrofuran (30 ml) was slowly added. The mixture was allowed to react for 2.8 hours before quenching with dilute aqueous HCl. Extraction with ethyl acetate, drying (over sodium sulphate) and concentration under reduced pressure gave the title compound as white crystals (20.3 g). The product was further purified by recrystallisation from hexane to give a solid of melting point 116.6.degree. C.

Stage 2

Preparation of 3-hydroxy-4-methyl-3-pyrimidin-5-yl-pent-1-yne.

Potassium carbonate (4 g) was added to the product of stage 1 (19.5 g, 0.11 mol) in methanol (100 ml) and the mixture was stirred for 3.3 hours. The mixture was then partitioned between ether and water. The ether layer was separated, dried over sodium sulphate, and concentrated under reduced pressure to give the title compound as an almost colourless solid (11.2 g). The product was further purified by recrystallisation from hexane to give a solid of melting point 112.4.degree. C.

Stage 3

Preparation of 3-hydroxy-4-methyl-3-pyrimidin-5-yl-1-thien-2-ylpent-1-yne.

3-Hydroxy-4-methyl-3-pyrimidin-5-ylpent-1-yne (1 g, 5.7 mmol), prepared as in Stage (2), 2-iodothiophene (1.2 g, 5.7 mmol), triethylamine (2 ml, 14.5 mmol), copper-I-iodide (mg), and bis(triphenylphosphine)palladium-II-chloride (200 mg) were brought together in dry acetonitrile (55 ml) and the mixture was heated at 65.degree. C. under nitrogen. After 1 hour, the mixture was cooled, quenched in dilute aqueous HCl, neutralised with dilute aqueous ammonia and extracted with ether (3.times.15 ml). The combined organic extracts were washed with dilute aqueous ammonia, water, and brine before being dried over magnesium sulphate and concentrated under reduced pressure to give an oil. Flash chromatography on silica eluting with hexane-ethyl acetate (1:3) gave the title compound as a solid of melting point 113.degree.-14.5.degree. C.

This example illustrates the preparation of 3-hydroxy-1-pyrid-3-yl-3-pyrimidin-5-yl-4,4-dimethylhex-1-yne (Compound No 5 of Table 1)

Stage 1

Preparation of 2,2-dimethyl-1-pyrimidin-5-yl-butan-1-one

To a stirred solution of lithium hexamethyldisilazide (22 ml of a 1 M solution in tetrahydrofuran; 22 mmol) at --78.degree. C. under nitrogen was slowly added 2-methyl-1-pyrimidin-5-ylpropan-1-one (3.04 g, 20 mmol) in dry tetrahydrofuran (5 ml). After stirring for 30 minutes, iodoethane (1 76 ml, 22 mmol) was added in one portion. The mixture was allowed to warm to room temperature then heated under reflux for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (2.times.50 ml). The combined organic extracts were washed with dilute aqueous HCl, saturated aqueous bicarbonate, and brine, before being dried over magnesium sulphate and concentrated under reduced pressure to give a red oil (2.5 g). Flash chromatography eluting with hexane/ethyl acetate (2:1) gave the desired product (1.65g) as a yellow oil contaminated with 30% 2-methyl-1-ethoxy-1-pyrimidin-5-ylprop-1-ene. This mixture was used without further purification in Stage 2.

Stage 2

Preparation of 4,4-dimethyl-3-hydroxy-3-pyrimidin-5-ylhex-1-yne

To a stirred solution of ethynyltrimethylsilane (1.24 ml, 8.8 mmol) in dry tetrahydrofuran (10 ml) at 0.degree. C. under nitrogen was added ethyl magnesium bromide (2.9 ml of a solution 3 M in tetrahydrofuran; 8.8 mmol). When effervescence had ceased (40 minutes) crude 2,2-dimethyl-1-pyrimidin-5-ylbutan-1-one (prepared in stage 1) (1.5 g, 8 mmol) in dry tetrahydrofuran (5 ml) was added. After 90 minutes, gas/liquid chromatography indicated complete consumption of starting material and the reaction was quenched with saturated aqueous ammonium chloride. The product was extracted with ethyl acetate (3.times.20 ml) and the organic layers were combined, washed with dilute aqueous HCl, saturated aqueous sodium bicarbonate, and brine before being dried over magnesium sulphate and concentrated under reduced pressure to give a yellow oil (1.98 g). A portion of this product (1.8 g) was dissolved in methanol (10 ml) and treated with anhydrous potassium carbonate (400 mg). After stirring for 48 hours, the mixture was diluted with ethyl acetate, washed twice with water and brine before being dried over magnesium sulphate and concentrated under reduced pressure to give an oil (1.3 g). Flash chromatography eluting with hexane/ethyl acetate (2:1) gave the title compound (950 mg) as white crystals, melting point 99.degree.-101.degree. C. The impurity, 2-methyl-1-ethoxy-1-pyrimidin-5-ylprop-1-ene (370 mg) was retrieved as an oil.

Stage 3

Preparation of 3-hydroxy-1-pyrid-3-yl-3-pyrimidin-5-yl- 4,4-dimethylhex-1-yne.

A stirred mixture of 4,4-dimethyl-3-hydroxy-3-pyrimidin-5-ylhex-1-yne (412 mg, 2 mmol), 3-iodopyridine (412 mg, 2 mmol), triethylamine (300 .mu.l, 2.2 mmol), copper-I-iodide (20 mg), and bis(triphenylphosphine) palladium-II-chloride (20 mg) in dry acetonitrile (5 ml) under nitrogen was heated at 65.degree. C. After 40 minutes, the reaction was cooled and quenched with dilute aqueous hydrochloric acid. The mixture was neutralised with ammonia, extracted with ethyl acetate (3.times.20 ml), and the organic extracts were combined. Washing with ammonia, water, and brine, drying over magnesium sulphate and concentration under reduced pressure gave yellow crystals (720 mg). Recrystallisation from ethyl acetate gave the desired product of melting point 170.5.degree.-171.5.degree. C.

Compounds of Table I were tested for plant growth regulator activity against two species for various growth effects relevant to plant growth regulation.

Methodology

The plant species used in this screen are presented in Table II with the leaf stage at which they were sprayed. Each chemical was applied at 4000 ppm (4 kg/ha in a 1000 1/ha field volume) using a tracksprayer and a SS8004E (Teejet) nozzle. After spray the plants were grown in a glasshouse with 25.degree. C. day/22.degree. C. night temperatures and supplementary lighting was supplied when necessary (from mercury vapour lamps), to provide a 16 hour photoperiod. The exception to this was the temperate cereal, wheat, which was grown in 16.degree. C. day/13.degree. C. night temperatures.

After 2-6 weeks in the glasshouse, depending on the time of year, the plants were visually assessed for morphological characteristics. Formulation blanks were used as controls to assess the plants. The results are in Table III.

The manner in which the compounds of the present invention may be formulated into compositions suitable for is shown generally in the following indicative illustrations numbered as Examples 5 to 14.

An emulsifiable concentrate is made up by mixing the following ingredients, and stirring the mixture until all the constituents are dissolved.

A composition in the form of grains readily dispersible in a liquid, e.g.. water, is prepared by grinding together the first three ingredients in the presence of added water and then mixing in the sodium acetate. The resultant mixture is dried and passed through a British Standard mesh sieve, size 44-100, to obtain the desired size of grains.

The following ingredients are ground together to produce a powder formulation readily dispersible in liquids.

The active ingredient is dissolved in acetone and the resultant liquid is sprayed on to the granules of attapulgite clay. The solvent is then allowed to evaporate to produce a granular composition.

A composition suitable for use as a seed dressing is prepared by mixing the three ingredients.

A dusting powder is prepared by mixing the active ingredient with talc.

A flowable formulation is prepared by bead-milling the constituents set out below and then forming an aqueous suspension of the ground mixture with water.

A dispersible powder formulation is made by mixing together the ingredients set out below and then grinding the mixture until all are thoroughly mixed.

This Example illustrates the preparation of a dispersible powder formulation. The ingredients are mixed and the mixture then ground in a comminution mill.

The ingredients set out below are formulated into dispersible powder by mixing then grinding the ingredients.

There now follows an explanation of the compositions or substances represented by the various Trade Marks and Trade Names mentioned above.