Phenylamidines having a high fungicidal activity and use thereof

The present invention relates to phenylamidines having a high fungicidal activity and their relative use, in particular substituted phenylamidines having a high fungicidal activity and their use for the control of phytopathogenic fungi of important agricultural crops.

Phenylamidines having a high fungicidal activity are described in international patent applications WO 2000/46184, WO 2003/093224, WO 2007/031508, WO 2007/031512, WO 2007/031513, WO 2007/031523, WO 2007/031524, WO 2008/110279.

The products described in these documents, however, are often unsatisfactory from the point of view of both the level of activity with respect to phytopathogenic fungi and also, or alternatively, from the point of view of phytotoxicity with respect to important agricultural crops.

In particular, for example, the compounds N-ethyl-N-methyl-N′-[4-(3-trifluoromethylphenoxy)-2,5-xilyl]-formamidine, N,N-dimethyl-N′-[4-(3-trifluoromethylphenoxy)-2,5-xilyl]formamidine, N,N-dimethyl-N′-[4-(3-trifluoromethoxyphenoxy)-2,5-xilyl]formamidine, N,N-dimethyl-N′-[4-(3-trifluoroethoxyphenoxy)-2,5-xilyl]-formamidine, described in international patent application WO 00/46184, at the doses which allow a good fungicidal activity to be obtained, show a marked leaf necrosis on cereals, cucumbers, tomatoes and other important crops: this effect makes their use as fungicides practically unacceptable. On the other hand, the compound N,N-dimethyl-N′-[4-(3-trifluoromethylphenylthio)-2,5-xilyl]formamidine, also described in international patent application WO 00/46184, proves to be insufficient from the point of view of fungicidal activity, which is only exerted satisfactorily in excessively high dosages.

International patent application WO 2008/110278 describes a whole series of (hetero)aryloxy- and (hetero)arylthio N,N-dialkyl-N′-phenyl-formamidines with a herbicidal activity, variously substituted on the (hetero)aryloxy and (hetero)arylthio rings.

The Applicant has now surprisingly found that new phenylamidines characterized by a (hetero)arylthio group in position 4 of the phenyl, and by particular combinations of substituents on the (hetero)arylthio ring and on the nitrogen atom, not only exert an excellent fungicidal activity at low doses, but are also well tolerated by many vegetable species, thus allowing the practical use of these compounds for the control of phytopathogenic microorganisms of important agricultural crops.

An object of the present invention therefore relates to new phenylamidines having general formula (I):

wherein

R represents a phenyl, pyridyl, pyrimidyl, pyrazyl or pyridazyl group, all groups substituted by at least a substituent selected from C 1 -C 6 polyfluoroalkoxy containing at least one hydrogen atom, C 1 -C 6 polyfluoroalkylthio containing at least one hydrogen atom, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 3 -C 6 cycloalkoxy, C 3 -C 6 halocycloalkoxy, C 4 -C 8 cycloalkylalkoxy, C 4 -C 8 halocycloalkylalkoxy; said groups phenyl, pyridyl, pyrimidyl, pyrazyl or pyridazyl being optionally substituted by one or two further substituents, equal to or different from each other, selected from halogen atom, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl;

R 1 represents C 2 -C 6 alkyl;

R 2 represents C 1 -C 6 alkyl; or R 1 and R 2 , together with the N atom to which they are bound, form a heterocyclic ring containing from 4 to 7 atoms, optionally substituted by halogen atoms;

R 3 and R 4 , equal to or different from each other, represent a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl, a C 1 -C 6 alkoxy, a C 1 -C 6 haloalkoxy, a CF 3 group, a CF 2 H group, a CFH 2 group, a cyano group.

Examples of halogen are fluorine, chlorine, bromine, iodine.

Examples of C 1 -C 6 alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tertbutyl, n-pentyl, 3-methylbutyl, n-hexyl, 3,3-dimethylbutyl.

Examples of C 1 -C 6 haloalkyl are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloro-methyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, heptafluoropropyl, 4,4,4-trichloro-butyl, 4,4-difluoropentyl, 5,5-difluorohexyl.

Examples of C 1 -C 6 polyfluoroalkoxy group containing at least one hydrogen atom are difluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, 1,1,2,3,3,3-hexafluoropropoxy, 2,2,3,4,4,4-hexafluorobutoxy, 4,4-difluoropentoxy, 4,4,5,5,5-pentafluoropentoxy, 2,2,3,3,4,4,5,5-octafluoropentoxy, 5,5-difluorohexyloxy.

Examples of C 1 -C 6 polyfluoroalkylthio group containing at least one hydrogen atom are difluoromethylthio, 2,2,2-trifluoroethylthio, 1,1,2,2-tetrafluoroethylthio, 2,2,3,3-tetrafluoropropylthio, 2,2,3,3,3-pentafluoropropylthio, 1,1,2,3,3,3-hexafluoropropylthio, 2,2,3,4,4,4-hexafluorobutylthio, 4,4-difluoropentylthio, 4,4,5,5,5-pentafluoropentylthio, 2,2,3,3,-4,4,5,5-octafluoropentylthio, 5,5-difluorohexylthio.

Examples of C 3 -C 6 cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

Examples of a C 3 -C 6 halocycloalkyl are 2,2-dichlorocyclopropyl, 2,2-difluorocyclopropyl, 2,2,3,3-tetrafluorocyclobutyl, 3,3-difluorocyclopentyl, 2-fluorocyclohexyl.

Examples of C 3 -C 6 cycloalkoxy are cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy.

Examples of C 3 -C 6 halocycloalkoxy are 2,2-dichlorocyclopropoxy, 2,2-difluorocyclopropoxy, 2,2,-3,3-tetrafluorocyclobutoxy, 3,3-difluorocyclopentoxy, 2-fluorocyclohexyloxy.

Examples of C 4 -C 8 cycloalkylalkoxy are cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, cyclohexylethoxy.

Examples of C 4 -C 8 halocycloalkylalkoxy are 2,2-dichlorocyclopropylmethoxy, 2,2-difluorocyclopropylmethoxy, 2,2,3,3-tetrafluorocyclobutylmethoxy, 3,3-difluorocyclopentylmethoxy, 4,4-difluorocyclohexylmethoxy, 4,4-difluorocyclohexylethoxy.

Examples of heterocyclic rings with from 4 to 7 atoms optionally halogenated are: azetidine, 3,3-difluoroazetidine, pyrrolidine, piperidine, 4-fluoropiperidine, morpholine.

Representative examples of compounds having general formula (I) are those wherein R, R 1 , R 2 , R 3 and R 4 have the meanings indicated in Table 1.

Preferred compounds of general formula (I) are those wherein:

R represents a phenyl, pyridyl, pyrimidyl, pyrazyl or pyridazyl group, all groups substituted by at least a substituent selected from difluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, 2,2,3,4,4,4-hexafluorobutoxy, 2,2,3,3,4,4,5,5-octafluoropentoxy, cyclopentoxy, cyclohexyloxy, cyclopropylmethoxy or cyclohexylmethoxy; said phenyl, pyridyl, pyrimidyl, pyrazyl or pyridazyl group being optionally substituted by one or two further substituents, equal to or different from each other, selected from a fluorine atom, a chlorine atom, methyl or trifluoromethyl;

R 1 represents ethyl, n-propyl, isopropyl;

R 2 represents methyl;

or R 1 and R 2 , together with the N atom to which they are bound, represent a pyrrolidyl, piperidyl or morpholyl group;

R 3 and R 4 represent methyl.

More preferred compounds of general formula (I) are those wherein:

R represents a phenyl group substituted by at least a substituent selected from difluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, 2,2,3,4,4,4-hexafluorobutoxy, 2,2,3,3,4,4,5,5-octa-fluoropentoxy, cyclopentoxy, cyclohexyloxy, cyclopropylmethoxy or cyclohexylmethoxy; said phenyl group being optionally substituted by one or two further substituents, equal to or different from each other, selected from a fluorine atom, a chorine atom, methyl or trifluoromethyl;

R 1 represents ethyl, n-propyl, isopropyl;

R 2 represents a methyl;

or R 1 and R 2 , together with the N atom to which they are bound, represent a pyrrolidyl, piperidyl or morpholylgroup;

R 3 and R 4 represent methyl.

The compounds having general formula (I) are prepared from the corresponding aniline having formula (II), according to the following reaction scheme 1:

Various methods for effecting this transformation are known in literature; the most widely used methods are the following:

a) treatment of aniline having formula (II) with an acetal having the formula R 1 R 2 NC(OR 5 ), wherein R 5 represents an alkyl, according to what is described in “Synthetic Communications”, 24 (1994), pages 1617-1624;

b) treatment of aniline having formula (II) with an amide having the formula HCONR 1 R 2 in the presence of POCl 3 or SOCl 2 , according to what is described in “Tetrahedron”, 46 (1990), pages 6058-6112;

c) treatment of aniline having formula (II) with an ortho-ester having the formula HC(OR 5 ), wherein R 5 represents an alkyl, to form the corresponding imino-ether followed by heating of the same in the presence of an amine having the formula HNR 1 R 2 , according to what is described in U.S. Pat. No. 4,209,319;

d) treatment of aniline having formula (II) with phosgene to form the corresponding isocyanate followed by reaction with an amide having the formula HCONR 1 R 2 , according to what is described in WO 00/46184;

e) treatment of aniline having formula (II) with C 2 H 5 OCH═NCN to form an N-cyanoamidine followed by reaction with an amine having the formula HNR 1 R 2 , according to what is described in WO 00/46184;

f) treatment of aniline having formula (II) with N,N-dimethylformamide in the presence of a sulfonyl-chloride, such as for example, 2-pyridylsulfonyl-chloride or phenylsulfonylchloride, to form the corresponding dimethylamidine (R 1 ═R 2 =Me) followed by reaction with an amine having the formula HNR 1 R 2 , according to what is described in “Tetrahedron”, 56 (2000), pages 8253-8262 and in “Journal Combinatorial Chemistry”, 11 (2009), pages 126-130.

The compound having formula (II) can be prepared by reduction of the corresponding nitro-derivative having formula (III), as indicated in reaction scheme 2, according to methods well-known in organic chemistry, as described for example in “Advanced Organic Chemistry”, Jerry March, 4 a Edition, 1992, John Wiley & Sons Pub., pages 1216-1217 and references cited therein.

The preferred reaction conditions for these substrates envisage the use of tin chloride in concentrated hydrochloric acid, according to what is described in detail in international patent application WO 00/46184.

The compound having formula (III) can be prepared by reaction of the compound having formula (IV) with a compound having formula RX, wherein X is a leaving group such as, for example, a halogen atom, a mesylate or a tosylate group, in the presence of a base, preferably potassium carbonate or sodium hydride, according to reaction scheme 3:

Alternatively, the compound having formula (III) can also be obtained by reaction of the compound having formula (V), wherein Y represents a halogen atom, with a compound having the formula RSH, in the presence of a base, preferably potassium carbonate or sodium hydride, according to reaction scheme 4.

The compounds having formula (IV) are prepared by reacting, in the presence of a palladium catalyst, a compound having formula (V) with potassium thioacetate and subsequently saponifying the thioester thus obtained, according to what is described in “Tetrahedron Letters”, 48 (2007), pages 3033-3037.

The compounds having general formula (I) containing polyfluoroalkoxy, (halo)cycloalkoxy or (halo)cycloalkylalkoxy groups on the ring R can also be obtained, by means of known techniques, starting from hydroxy-[(hetero)arylthio]phenylformamidines (obtainable as described in examples 4, 5 and 6) by addition to fluorinated olefins, as described in more detail in example 7, or by etherification with the corresponding halides or tosylates.

As already mentioned, the compounds having general formula (I) have an extremely high fungicidal activity which is exerted with respect to numerous phytopathogenic fungi which attack important agricultural crops.

Examples of phytopathogenic fungi which can be effectively treated and fought with the compounds having general formula (I) are those belonging to the groups of Basidiomycetes, Ascomycetes, Deuteromycetes or imperfect fungi, Oomycetes: Puccinia spp., Ustilago spp., Tilletia spp., Uromyces spp., Phakopsora spp., Rhizoctonia spp., Erysiphe spp., Sphaerotheca spp., Podosphaera spp., Uncinula spp., Helminthosporium spp., Rhynchosporium spp., Pyrenophora spp., Monilinia spp., Sclerotinia spp., Septoria spp. ( Mycosphaerella spp.), Venturia spp., Botrytis spp., Alternaria spp., Fusarium spp., Cercospora spp., Cercosporella herpotrichoides, Colletotrichum spp., Pyricularia oryzae, Sclerotium spp., Phytophtora spp., Pythium spp., Plasmopara viticola, Peronospora spp., Pseudoperonospora cubensis, Bremia lactucae.

The main crops which can be protected with the compounds according to the present invention comprise cereals (corn, barley, rye, oats, rice, maize, sorghum, etc.), fruit trees (apples, pears, plums, peaches, almonds, cherries, bananas, vines, strawberries, raspberries, blackberries, etc.), citrus trees (oranges, lemons, mandarin oranges, grapefruits, etc.), leguminous plants (beans, peas, lentils, soybean, etc.), horticultural plants (spinach, lettuce, asparagus, cabbages, carrots, onions, tomatoes, potatoes, aubergines, peppers, etc.), cucurbitaceae (pumpkins, courgettes, cucumbers, melons, water-melons, etc.), oleaginous plants (sunflower, rape, peanut, castor oil plant, coconut, etc.), tobacco, coffee, tea, cacao, sugar beet, sugar cane, cotton.

In particular, the compounds having formula (I) have proved to be extremely effective in the control of Phytophtora infestans and Botrytis Cinerea on tomatoes; Puccinia recondita, Erisiphae graminis, Helminthosporium teres, Septoria nodorum and Fusarium spp. on cereals, in the control of Phakopsora pachyrhizi on soybean, in the control of Uromyces Appendiculatus on beans, in the control of Venturia inaequalis on apple trees, in the control of Sphaerotheca fuliginea on cucumbers.

Furthermore, the compounds having formula (I) are also effective in the control of bacteria and phytopathogenic viruses, such as for example Xanthomonas spp., Pseudomonas spp., Erwinia amylovora , tobacco mosaic virus.

The compounds having formula (I) are capable of exerting a fungicidal action of both a curative and preventive nature and have an extremely low or zero phytotoxicity on the crops treated.

A further object of the present invention therefore relates to the use of the compounds having formula (I) for the control of phytopathogenic fungi of agricultural crops.

For practical uses in agriculture, it is often preferable to use fungicidal compositions containing the compounds of the present invention suitably formulated.

A further object of the present invention relates to fungicidal compositions comprising one or more compounds having formula (I), a solvent and/or solid or liquid diluent, optionally a surface-active agent.

The above fungicidal compositions can be in the form of dry powders, wettable powders, emulsifying concentrates, emulsions, microemulsions, pastes, granulates, water dispersible granules, solutions, suspensions, etc.: the choice of the type of composition will depend on the specific use.

The fungicidal compositions are prepared in the known way, for example by diluting or dissolving the active substance with a solvent medium and/or a solid or liquid diluent, optionally in the presence of surfactants.

Solid diluents or supports which can be used for example are: silica, kaolin, bentonite, talc, infusorial earth, dolomite, calcium carbonate, magnesia, gypsum, clays, synthetic silicates, attapulgite, sepiolite.

Liquid solvents or diluents which can be used, are for example, in addition to water, aromatic organic solvents (xylols or blends of alkylbenzols, chlorobenzene, etc.), paraffins (petroleum fractions), alcohols (methanol, propanol, butanol, octanol, glycerine, etc.), esters (ethyl acetate, isobutyl acetate, alkyl carbonates, alkyl esters of adipic acid, alkyl esters of glutaric acid, alkyl esters of succinic acid, alkyl esters of lactic acid, etc.), vegetable oils (rape oil, sunflower oil, soybean oil, castor oil, corn oil, peanut oil, and their alkyl esters), ketones (cyclohexanone, acetone, acetophenone, isophorone, ethylamylketone, etc.), amides (N,N-dimethylformamide, N-methylpyrrolidone, etc.), sulfoxides and sulfones (dimethylsulfoxide, dimethylsulfone, etc.), and mixtures thereof.

Sodium salts, calcium salts, potassium salts, salts of triethylamine or triethanolamine of alkylnaphthalenesulfonates, polynaphthalenesulfonates, alkyl sulfonates, aryl sulfonates, alkylaryl sulfonates, polycarboxylates, sulfosuccinates, alkyl sulfosuccinates, ligninsulfonates, alkyl sulfates, can be used as surfactants; as also polyethoxylated fatty alcohols, polyethoxylated alkylphenols, polyethoxylated esters of sorbitol, polypropoxy polyethoxylates (block polymers).

The fungicidal compositions can also contain special additives for particular purposes, such as for example, antifreeze agents such as propylene glycol, or adhesive agents, such as Arabic rubber, polyvinyl alcohol, polyvinyl pyrrolidone, etc.

When desired, other compatible active principles can be added to the fungicidal compositions containing the compounds of general formula (I), such as, for example, fungicides different from those having general formula (I), phytoregulators, antibiotics, herbicides, insecticides, fertilizers and/or mixtures thereof.

Examples of fungicides different from those having general formula (I) which can be included in the fungicidal compositions of the present invention are: acibenzolar, ametoctradin, amisulbrom, ampropylfos, anilazine, azaconazole, azoxystrobin, benalaxyl, benalaxyl-M, benomyl, benthiavalicarb, bitertanol, bixafen, blasticidin-S, boscalid, bromuconazole, bupirimate, buthiobate, captafol, captan, carbendazim, carboxin, carpropamid, chinomethionat, chloroneb, chlorothalonil, chlozolinate, cyazofamid, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, debacarb, dichlofluanid, dichlone, diclobutrazol, diclomezine, dicloran, diclocymet, diethofencarb, difenoconazole, diflumetorim, dimethirimol, dimethomorph, dimoxystrobin, diniconazole, dinocap, dipyrithione, ditalimfos, dithianon, dodemorph, dodine, edifenphos, epoxiconazole, etaconazole, ethaboxam, ethirimol, ethoxyquin, etridiazole, famoxadone, fenamidone, fenaminosulf, fenapanil, fenarimol, fenbuconazole, fenfuram, fenhexamid, fenoxanil, fenpiclonil, fenpropidin, fenpropimorph, fenpyrazamine, fentin, ferbam, ferimzone, fluazinam, fludioxonil, flumetover, flumorph, fluopicolide, fluopyram, fluoroimide, fluotrimazole, fluoxastrobin, fluquinconazole, flusilazole, flusulfamide, flutianil, flutolanil, flutriafol, fluxapyroxad, folpet, fosetylaluminium, fuberidazole, furalaxyl, furametpyr, furconazole, furconazole-cis, guazatine, hexaconazole, hymexazol, hydroxyquinoline sulfate, imazalil, imibenconazole, iminoctadine, ipconazole, iprobenfos, iprodione, isoprothiolane, iprovalicarb, isopyrazam, isotianil, kasugamycin, kresoxim-methyl, mancopper, mancozeb, mandipropamid, maneb, mebenil, mepanipyrim, mepronil, meptyldinocap, metalaxyl, metalaxyl-M, metconazole, methfuroxam, metiram, metominostrobin, metrafenone, metsulfovax, myclobutanil, natamycin, nicobifen, nitrothal-isopropyl, nuarimol, ofurace, orysastrobin, oxadixyl, oxpoconazole, oxycarboxin, pefurazoate, penconazole, pencycuron, penflufen, pentachlorofenol e suoi sali, penthiopyrad, phthalide, picoxystrobin, piperalin, Bordeaux mixture, polyoxins, probenazole, prochloraz, procymidone, propamocarb, propiconazole, propineb, proquinazid, prothiocarb, prothioconazole, pyracarbolid, pyraclostrobin, pyrametostrobin, pyraoxystrobin, pyrazophos, pyribencarb, pyrifenox, pyrimethanil, pyriofenone, pyroquilon, pyroxyfur, quinacetol, quinazamid, quinconazole, quinoxyfen, quintozene, rabenzazole, copper hydroxide, copper oxychloride, copper (I) oxide, copper sulfate, sedaxane, silthiofam, simeconazole, spiroxamine, streptomycin, tebuconazole, tebufloquin, tetra-conazole, thiabendazole, thiadifluor, thicyofen, thifluzamide, thiophanate, thiophanate-methyl, thiram, tiadinil, tioxymid, tolclofosmethyl, tolylfluanid, triadimefon, triadimenol, triarimol, triazbutil, triazoxide, tricyclazole, tridemorf, trifloxystrobin, triflumizole, triforine, triticonazole, uniconazole, uniconazole-P, validamycin, valifenalate, vinclozolin, zineb, ziram, sulfur, zoxamide.

The concentration of phenylamidine compounds having general formula (I) in the above compositions can vary within a wide range; it generally ranges from 1% to 90% by weight with respect to the total weight of the composition, preferably from 5% to 50% by weight with respect to the total weight of the composition.

The application of these compositions can be effected on all parts of the plant, for example on the leaves, stems, branches and roots, or on the seeds themselves before sowing, or on the ground in which the plant grows.

A further object of the present invention therefore relates to a method for the control of phytopathogenic fungi in agricultural crops, which consists in the application of effective dosages of the compounds of formula (I), used as such or formulated in fungicidal compositions as described above.

The quantity of compound to be applied for obtaining the desired effect can vary in relation to different factors, such as, for example, the compound used, the crop to be preserved, the type of pathogen, the degree of infection, the climatic conditions, the application method, the formulation adopted.

Doses of compound ranging from 10 g to 5 kg per hectare of agricultural crop generally provide a sufficient control.

The following examples are provided for a better understanding of the invention for illustrative and non-limiting purposes of the same.