IE44819B1 - Isoxazoline derivatives and their use as fungicides - Google Patents

Abstract

The fungicide contains, besides a phytologically acceptable inert carrier, at least one new active substance of the formula in which the substituents are defined in claim 1. The fungicide can be used for controlling fungal phytopathogens which attack the leaves.

Description

This invention provides a class of novel 2-isoxa44819 ! ·.' zolines bearing an aryl substituent at the 3-position and· a substituted methyl or ethyl group at the 5-position, which ; , - I effectively control microorganisms, particularly fungal 5 foliar phytopathogens.

Related isoxazolines were shown by D'Alcontres,, Gazz. Chim. Ital. 80, 741-44 (1950), who made compounds having 3-phenyl groups and substituted methyl groups at the -position.. Kano, J. Med. Chem. 10, 411-18 (1967) and Japanese Patent 42-9146, disclose isoxazoles having 3-phenyl and 5-aminomethyl substituents. .

U.S, Patent 3,629,474 shows isoxazolyl carbamates said to have fungicidal efficacy, and French Patent :^,215,219 claims ths same efficacy forthiooarbamoyl isoxazolidines. .

. The present invention provides new microbioeides df the formula wherein R represents • -NCS, - :.. qyano, .1 .-. .. amino, ... amino hydrohalide, / ...' -NHCSN (R1R2) , -NHCOjtCj^-Cj alkyl) or -244819 0CH3 s_c_ch 4--a „ 3 N-N n represents 1 or 2; 2 R and R independently represent hydrogen or C^C3 alkyl, or 2 R represents hydrogen and R represents amino, or 1 2 R and R combine with the nitrogen atom to which they are attached to form morpholino, piperidino or piperazin-l-yl R represents hydrogen or phenyl; R represents naphthyl, 2-pyridyl or 6 7 R , R and R' independently represent chloro, bromo, fluoro, nitro, trifluoromethyl, Cl“C2 alkoxy, C±~C2 alkylthio, C1-C4 alkyl, hydroxy, phenyl, benzyloxy or hydrogen, -3481© provided that no more than one of R5, R6 and R7 represents phenyl or benzyloxy; ar|d further 5 6 7 provided that when one of R , R and R represents hydroxy, alkoxy or benzyloxy, 6 7 1) no more than one of R , R and R represents t-butyl; and 5 6 7 2) if one of R , R and R represents chloto, it is ortho to the hydroxy, alkoxy or benzyloxy group.

A further part of this invehtion is a process for preparing the compounds of Formula I which comprises reacting a chlorinated oxime of the formula Cl R4-C=NOH Ii wherein R^ is as defined above, with a compound of the formula , Η H R3-C=C-(CRO) -R III n » wherein R and n are as defined above, and R represents -NCS, cyano or -NHCC>2 (C^-Cj alkyl), to produce a compound of Formula I whefeinR represents -NCS, cyano or -NHC02(C^-C^ alkyl); and optionally further 1) reacting a compound of Formula I wherein R represents -NCS with an amine of the formula • MN(R1R2) IV Ϊ 2 wherein R and R are as defined above, feo produce a dom1 2 pound of Formula I wherein R represents -NHCSN(R R ); or 2) hydrolyzing a compound of Formula I wherein R represents -NHCO2(C1-C3 alkyl) to produce a compound of Formula I 4<4813 wherein R represents amino or amino hydrohalide; or 3) reacting a compound of Formula I wherein R represents 1' 2 -N1ICSN(R R ), R represents hydrogen and R represents amino, with acetic anhydride, an acetyl halide or a mixture thereof, to produce a compound of Formula I wherein R represents —Ki- ,S - C - CH „ a ll ;N - N The invention also provides a method of reducing the adverse effects of fungal foliar phytopathogens which comprises contacting the phytopathogens on the foliage of host plants with an effective amount of a compound described above. Fungicidal compositions containing the compounds are also provided.

Xn the above formula, the terms C|-C3 alkyl, C^alkyl, alkoxy and C^“C2 alkylthio refer to groups such as methyl, ethyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, methylthio and ethylthio. The term hydrohalide refers to hydrobromide, hydrochloride, hydrofluoride and hydriodide.

Throughout this document all temperatures are on the Celsius scale.

The compounds of Formula I wherein R represents which have particularly good microbiocidal activity.

Further contemplated classes of compounds of Formula I are those comprising the compounds wherein: 1. R represents -NCS; 2 2. R represents -NCS, cyano, NHCSN(R R ), or NHCC>2 (C^-C-j alkyl), wherein A. R1 and R2 represent hydrogen or C.,-^ alkyl or 2 R represents hydrogen and R represents amino, 2 B. R and R combine to form morpholino, piperidino or piperazin -1 .yl 3. R represents NHCSN(R^R2) or NHCOj (Cj-Cj alkyl), wherein A, R and R represent hydrogen or C^-C3 alkyl or 2 \ R represents hydrogen and R represents amino, , B. R and R combine to form morpholino, piperidino or piperazin-1 yl 4. R represents cyano; . R represents -NCS, amino, amino hydrohalide, NHCSN(R1R2) or NHCO2(C1-C3 alkyl), wherein A. R1 and R2 represent hydrogen or C^-C3 alkyl or 2 R represents hydrogen and R represents amino, 12' B. R and R combine to form morpholino, piperidino or piperazin >1 -v] 6. R represents hydrogen; 7. RJ represents phenyl; 8. R4 represents 2-pyridyl; 9. R4 represents naphthyl or •r . R4 represents /-J?5 -/,5 i : '•^R° 11. RJ is as defined in subparagraph 6 above, and A. R and R4 are as defined in subparagraphs and 8 above; -64481s B. R and „4 R ar,; as defined in subparaqraphs 1 and 9 above; C. R and 4 R aro as defined in subparagraphs 1 and 10 above; * 5 D. R and 4 R are as defined in subparagfaphs 2A and 8 above; E. R and R4 are as defined in subparagraphs 2A . and 9 above; F. R and R4 are as defined in subparagraphs 10 2A . and 10 above: 0. R and R4 are as defined in subparagraphs 2B and 8 above; H. R and R4 are as defined in subparagraphs 15 1. 2B and 9 above; 4 R and R are as defined in subparagraphs ’ J. 2B and 10 above; 4 R and R are as defined in subparagraphs K. 3 and 8 above; 4 R and R are as defined in subparagraphs 20 L. 3 and 9 above; 4 R and R are as defined in subparagraphs M. 3 and 10 above; 4 R and R are as defined in subparagraphs 25 N. 4 and 8 above; R and R4 are as defined in subparagraphs 0. 4 and 9 above; 4 R and R are as defined in subparagraphs 4 and 10 above; P. R and R4 are as defined in subparagraphs 5A and 8 above; Q. R and R4 are as defined in subparagraphs 5A and 9 above; R. R and R4 are as defined in subparagraphs 5A and 10 above; S. 4 R and R are as.defined in 5B and 8 above; subparagraphs T. R and R4 are as defined in subparagraphs 5B and 9 above; U. R and R4 are as defined in subparagraphs 5B and 10 above.

R3 is as defined in subparagraph 7 above, and A. 4 R and R are as 1 and 8 above; defined in subparagraphs B. 4 R and R are as 1 and 9 above; defined in subparagraphs c. 4 R and R are as 1 and 10 above; defined in subparagraphs □ . R and R4 are as 2A and 8 above; defined in subparagraphs E. 4 R and R are as 2A and 9 above; defined in subparagraphs ’ F. 4 R and R are as defined in subparagraphs 2A and 10 above; G. R and R4 are as 2B and 8 above; defined in subparagraphs H. 4 R and R are as 2B and 9 above; defined in subparagraphs I. R and 4 R are as defined in subparagraphs 2B and 10 above f J. R and 4 R are as defined in subparagraphs 3 and 8 above; 5 K. R and 4 R are as defined in subparagraphs 3 and 9 above; L. R and 4 R are as defined in subparagraphs 3 and 10 above; M. R and 4 R are as defined in subparagraphs 10 4 and 8 above; N. R and 4 R are as defined in subparagraphs 4 and 9 above; ’ 0. R and R^ are as defined in subparagraphs i 4 and 10 above; 15 • P. R and _4 R are as defined in subparagraphs 5A . and 8 above; Q. R and 4 R are as defined in subparagraphs 5A . and 9 above; R. R and 4 R are as defined in subparagraphs 20 5A . and 10 above; S. R and 4 R are as defined in subparagraphs J 5B and 8 above; T. R and 4 R are as defined in subparagraphs 5B and 9 above; 25 u. R and 4 R are as defined in subparagraphs 5B and 10 above.

The compounds below are typical of the isoxazolines of Formula I. It will-be understood that the named compounds -94481© do not bound the scope of the invention, but are named merely to help agricultural chemists to understand the invention. - (2-cyanoethyl)-3- (1-naphthyl)-2-isoxazOline -aminomethyl-3-(2-naphthyl)-2-isoxazoline -(2-aminoethyl)-4-phenyl-3-(2-pyridyl)-2-isoxazoline, hydrobromide -(2-ethoxycarbonylaminoethyl)-3-(2,4,6-trichlorophenyl)-2-isoxazolinb 3-(3-bromo-5-chlorophenyl)-5-propoxycarbonylaminomethyl-2-isoxazoline N-t[3-(2,4-difluorophenyl)-2-isoxazolin-5-yl]“ methyl]-N-(5-methyl-l,3,4-thiadiazol-2-yl)acetamide' N-[2-[3-(2-hydroxy-S-nittophenyl)-2-isoxazolin5-yl] ethyl j-N-'(5-methyl-l, 3,4-thiadiazol-2-yl) acetamide -(2-isothiocyanatoethyl)-3-(2-triflUoromethylphenyl)-4-phenyl-2-isoxazoline l-ethyl-3-[2-(3-(2,6-dinitro-4-trifluoromethylphenyl)-4-phenyl-2-isoxazolin-5-yl]ethylJthiourea l-propyl-3-,[2~[3-(3-benzyloxy-5-methoxyphenyl)2-isoxazolin-5-yl]ethyl]thiourea l-ethyl-l-methyl-3-[2-[3-(3-chloro-2-ethoxyphenyl)2-isoxazolin-5-yl]ethyl]thiourea 1,1-diethy1-3-([3-(3,4-bis(methyIthio)phenyl)-2isoxazolin-5-yl]methyl]thiourea 1-isopropyl-1-methyl-3-[[3-(3-nitro~5-phenylphenyl)-2-isoxazolin-5-yl]mefchyljthiourea l-ethyl-3-[(3-(3-bromo-2,5-dihydroxyphenyl)-4phenyl-2-isoxazolin-5-yl]methyl]thiourea -1044819 Ν- [ [3-(3-chloro-5-ethyl-4-hydroxyphenyl)-2I isoxazolin-5-yl]methyl]-4-morpholinethiocarboxamide N- [2- [3- (2,4-diisopropylphenyl)-2-isoxazolin-5y1]ethyl]-1-pipcridinethiocarboxamide N-[[3-(2,4,6-trimethylphenyl)-2-isoxazolin-5yl]methyl]-1-piperazinethiocarboxamide 3-(4-benzyloxy-3-propylphenyl)-5-isothiocyanatomethyl-4-phenyl-2-isoxazoline -aminomethyl-3-[3-(t-butyl)-5-nitrophenyl]-2isoxazoline, hydrofluoride l-methyl-3-[2-[3-(2,5-diethylphenyl)-2-isoxazolin5-y1]ethy1]thiourea 3-(2-chloro-6-ni tropheny1)-5-ethoxyoarbonylaminomethyl-4-phenyl-2-isoxazoline ' 3- (3-chloro-5-nitrophenyl)-5-(2-isothiocyanatoethyl)-2-isoxazoline 1.- [2- [3-(3,5-bis(trifluoromethyl)phenyl)-2-isoxazolin-5-yl]ethyl]thiourea 1-[[3-(2-hydroxy-4-trifluoromethylphenyl)-2isoxazolin-5-ylf^taethyl] thiourea -dminomethyl-3-(2-chloro-5-ethylthio-3-phenylphenyl)-4-phenyl-2-isoxazoline -isothiocyanatomethyl-3-(3-methylthio-6-nitro5-phenylpheny1)-2-isoxazoline The preferred compounds are 5-isothiocyanatomethyl-3-(4-chlorophenyl)-2-isoxazoline, 5-isothiocyanatomethyl-3-(4-tfifluoromethylphenyl)-2-isoxazoline, 3- (2,6dichlorophenyl) -5-isothiocyanatoraethyl-2-isoxazoline, 5isothiocyanatomethyl-3- (4-methylphenyl)-2-isoxazoline, and 5-isothiocyanatomethyl-3-(2-pyridyl)-2-isoxazoline. -11&4819 The compounds of Formula I are prepared by processes which start from readily obtainable compounds. The preparation of all of the compounds starts with an appropriately substituted arylaldehyde, a benzaldehyde when R^ represents phenyl or substituted phenyl, a naphthaldehyde when R^ represents naphthyl, or a pyridylaldehyde when R^ represents 2-pyridyl.

The aldehyde is first reacted with hydroxylamine, preferably in the form of a hydrohalide salt, to form the corresponding aldehyde oxime. An acid scavenger, such as a tertiary amine, an alkali metal alkoXide, or an inorganic base such as sodium carbonate, sodiurti bicarbonate and potassium hydroxide should be used when the hydroxylamine is used in the form of the hydrohalide. The preferred solvent is an aqueous alkanol, but other solvents, such as diethyl ether and chloroform are also satisfactory. Reflux temperature is preferred.

The α-carbon of the aldehyde oxime is then chlorinated, as by simple contact with free chlorine in a solvent such as chloroform, tow temperatures from 0° to 10° are preferred.

The chlorination step also frequently chlorinates the phenyl ring of a benzaldoxime to Some degree, particularly when hydroxy, alkoxy or benzyloxy substituents are present. Some poly-substituted intermediates are most readily prepared by making use of such chlorihation, as illustrated in the examples below.

The chlorinated oximes of Formula Ii are the immediate precursors of all. the compounds of this invention. -1244819 They are unstable in the pure form and are used without purification.

The isothiocyanates, the preferred compounds of the invention, are prepared by contact of the chlorinated oxime at low temperature with allyl- or 3-butenylisothiocyanate of Formula III in the presence of a strong base, preferably triethylamine. When the desired product has a 4-phenyl 3 (R ) substituent, the starting isothiocyanate is cmnamylisothiocyanate or 4-phenyl-3-butenylisothiocyanate of Formula III. The preferred reaction solvent is diethyl ether, although other typical inert reaction solvents may be used, such as tetrahydrofuran, benzene and the alkanes. Triethylamine is the preferred strong base for reasons of convenience, but other typical strong bases, such as pyridine, sodium hydroxide, alkali metal alkoxides and lithium carbonate may also be used effectively if desired.

The reaction temperature should be in the range of 0-15° although lower temperatures may be used.· As usual in such reactions, the preferred sequence of addition is to combine the isothiocyanate and the oxime in the solvent, lower the temperature, and then add the base very slowly while stirring.

The same process is used to prepare the products of Formula I where R represents cyano or alkyl carbamate by substituting an appropriate 3-butenyl or allyl cyanide or carbamate of Formula III for the isothiocyanate reactant.

The thioureas of Formula I are prepared by simple reaction of the Corresponding isothiocyanate of Formula I with an appropriate amine of Formula IV. Reaction at tem-13pcratures from room temperature to reflux in reaction solvents such as diethyl ether or alkanols is satisfactory.

The products of Formula>1 wherein R represents an amino group are prepared by hydrolyzing the corresponding carbamate of Formula I, as with a strong mineral acid. The aminohydrohalides result when the mineral acid is a halogen acid, such as hydrochloric acid. The free amino compounds are prepared by neutralizing the hydrohalides with bases. z The methylthiadiazole products of Formula I are prepared from the corresponding thioureas of Formula I where R represents amino by reaction with acetic anhydride, an acetyl halide or a mixture of both acetic anhydride and an acetyl halide. The preferred reaction conditions are reflux temperature in dioxane.

The following specific preparative examples are presented to ensure that organic chemists can prepare any desired compound of Formula Ϊ. The products of the following examples were identified by nuclear magnetic resonance analysis, elemental microanalysis, and in appropriate cases, infrared analysis and mass spectroscopy.

The first example illustrates a typical preparation of an isoxazolinyl isothiocyanate.

Example 1 -isothiocyanatomethy1-3-(4-chlorophenyl)-2-isoxazoline One mole, 70 g.> of hydroxylamine hydrochloride and 54 g. of sodium methoxide were added to 500 ml. of isopropanol and 250 ml. of water. A 130 g. portion of 4-chlorobenzaldehyde was added, and the reaction mixture was stirred overnight at room temperature. A large amount of -1444819 water was then added, the resulting white precipitate was separated by filtration, and the filtrate was extracted with chloroform. The organic layer was dried over sodium sulfate and evaporated to one-half its volume. Three volumes of hexane was then added, and the product, 4-chlorobenzaldoxime, was recovered by filtration. The yield was 101 g.

The benzaldoxime was dissolved in one liter of chloroform and cooled to 5-10°, and dry chlorine gas was bubbled through the solution. The resulting yellow solution was evaporated to dryness and was washed with hexane to produce 123 g. of a,4-dichlorobenzaldoxime.

A 20 g. portion of the above intermediate was dissolved in 750 ml. of anhydrous diethyl ether and 15 g. of allylisothiocyanate was added. The reaction mixture was cooled to 5°, and 15 g. of triethylamine in 125 ml. of anhydrous diethyl ether was added dropwise over 1 hour with stirring, while the temperature was held at 5°. The mixture was then stirred overnight and allowed to warm to room temperature. The reaction mixture was then filtered and the filtrate was evaporated under vacuum to a thick yellow oil * which partially crystallized. The precipitate from the filtration was first washed with acetone, then with water, then with chloroform and finally extracted with chloroform: water. All of the chloroform portions were combined with the acetone wash and the residue from evaporation of the filtrate, and the mixture was concentrated under vacuum and diluted with hexane. Approximately 12 g. of 5-isothiocyanatomethy1-3-(4-chlorophenyl)-2-isoxazoline, m.p, 118-120°, crystallized and was recovered by filtration. -154481® The following example illustrates the preparation of an isothiooyanatoethyl compound, wherein n represents 2. Example 2 -(2-isothiocyanatoethyl)-3-phenyl-2-isoxazollne 5 A 23 g. portion of α-chlorobenzaldoxime, prepared as in Example 1 above, was combined with 17 g. of 3-butenylisothiocyanate in 300 ml. of diethyl ether. The solution was cooled to 15° and 40 ml. of triethylamine in 100 ml. of tetrahydrofuran was added dropwise. The mixture was stirred for 24 hours at 15°, and was then filtered. The filtrate was washed with water, and evaporated to dryness. The residue was dissolved in chloroform, and chromatographed over a column (2.5 cm. diameter by 8 meters long) of polystyrene gel beads. The eluate was evaporated to dryness, and the residue was recrystallized from diisopropyl etherhexane. The product was identified as 10 g. of 5-(2-isothiocyanatoethyi)-3-pheny1-2-isoxazoline, m.p. 54-56°. The microanalytical results were as follows: Theoretical Found C 62.04% 61.77% H 5.21 5.021 N 12.06 11.93 S 13.80 14.03 The following isothiocyanates were all produced by 25 processes essentially similar to those just described. Only the amounts of reactants and identifying characteristics of the following compounds will be indicated. -1644819 Example 3 - isothiocyanat-ometiiyl- 3-pheny1-2- isoxazo line Λ 156 g. portion of α-ehlorobenzaldoxime was reacted with 125 g. of allylisothiocyanate to produce 110, g. of product, m.p. 61-63°. Theoretical Found C 60.53% 60.81% H 4.62 4.69 N 12.83 12.69 10 S 14.69 14.79 Example 4 -isothiocyanatomethyl-3-(2,4-dichlorophenyl)-2-isoxazoline A 34 g· portion of 2,4-dichlorobenzaldoxime was chlorinated as in Example 1 and reacted with 20 g. of allyl· 15 isothiocyanate to produce 6 g. of product, an oily liquid. Theoretical Found C 46.01% 46.24% H 2.81 2.72 N 9.76 9.85 20 S 11.17 11.06 Example 5 5-isothiocyanatomethy1-3- (3-trifluoromethylphenyl)-2-isoxa- zoline A chlorinated benzaldoxime was prepared from 18 g. 25 of 3-trifluoromethylbenzaldehyde and was reacted with 15 g. of allylisothiocyanate to produce 7 g. of product, m.p. 47-49°.

Theoretical Found C 50.35% 50.23% H 3.17 3.13 N 9.79 9.74 5 S 11.20 11.05 Example 6 3-(3-chloro-4-methoxy-5-methylphenyl)-5-isothiocyanatOmethyl 2-isoxaaoline A 40 g. portion of a,3-dichloro-4-methoxy-5-methyl benzaldoxime was reacted with 25 g. Of allylisothiocyanate to produce 100 mg. of product, m.p. 108 -108.5°. Theoretical Pound C 52.61% · 52.39% H 4.42 4.25 15 N 9.44 9.41 Cl 11.95 12.26 Example 7 -isothiocyanatomethy1-3-(2-naphthyl)-2-isoxazoline A 21 g. portion of α-chloro-p-naphthaldoxime was reacted with 25 g. of allylisothiocyanate to produce 1 g. of product, an oily liquid, NMR multiplets at 3.28-4.15, 4.835.28 and 7.5-8.42 ppm.

Example £ 3-(2-chlorophenyl)-5-iSothiocyanatomethyl-2-isoxazoline A 19 g. portion of a,2-dichlotoben2aldoxime was reacted with 15 g. of allylisothiocyanate to produce 9.5 g. of product, an oily liquid. -18' 448 2S Theoretical Found C 52.23% 52.56% H 3.59 3.37 N 11.08 10.35 5 S 12.69 12.97 Example 9 3- Q-ohlorophenyD-S-isothiocyanatomethyl-Z-isozKizoline A 40 g. portion of a,3“dichlorobensaldo-xime was reacted with 10 g. of allylisothioeyanate to produce, 5 g. 10 product, an oily liquid. Theoretical Found C 52.2-3% 52.43% H 3.59 3.72 N 11.08 10.S7 15 Cl 14.02 14.6G s 12.69 12.58 Example 10 5-isothiocyanatomethyl -3-(4-nitrophenyl) “2-isoxazoline A 12.5 g. portion of 4-nitrobenzaldehyde was con· 20 verted to the chlorine: ted oxime, and reacted with .15 g. of allylisothioeyanate to produce 1 g. of product, m.p. 13S- 138°. Theoretical Found C 50.13% 50.47% 25 H 3.45 3.52 N 15.96 15.59 3 12.18 11.98 -19Example 11 -isothiocyanatomethyl-3-(t-trifluoromethylphenyl)-2-i; oxazoline A 175 g. portion of 4-trifluoromethylbenzaldehyde 5 was converted to the chlorinated oxime, and reacted with 200 g. of allylisothiooyanate to produce 199 g. of product, m.p. 124-126°.

Theoretical Found. c 50.35% 50.55% 10 H 3.17 3.27 N 9.79 9.54 S 11.20 11.23 Example 12 3-(2,6-dlchlOrophenyl)-5-isothiocyanatomethyl-2-isoxazoiine A 35 g. portion of 2,6-dichlorobenzaldoxime was chlorinated on the ct-carbon, and reacted with 25 g. of allylisothiocyanate to produce 7 g. of product, m.p. 64- 66°. Theoretical Found 20 C 46.01% 45.82% H 2.81 2.80 N 9.76 9.97 S 11.17 11.01 Example 13 3-(3-chloro-4-methoxyphenyl)-5-isoth.iooyanatomethyl-2isoxazoline Example 14 -isothiocyanatomethyl-3-(4-methoxyphenyl)-2-isoxazoline A 28 g. portion of 4-methoxybenzaldoxime was 30 chlorinated, and reacted with 25 g. Of allylisothiocyanate -20- . as in Example 1.' Chromatography of the product mixture isolated 9 g. of 3-(3-chloro-4-niethoxyphi'iiy 1,-’i-isothiocyanatr»- mcthyl-2-isoxazoline, m.p. 92-94° and 90 mg. of S-isothio· cyanatomethyl-3-(4-methoxyphenyl)-2-iSoxazoline, an oily liquid. (Example- 13)' Theoretical Pound C 50.98% 51.25% H 3.92 4.00 N 9.91 9.67 S 11.34 11.33 (Example 14) Theoretical Pound C 46.01% 46.24% H 2.81 2.72 N 9.76 9.85 S 11.17 11.06 Example 15 -isothiocyanatomethyl-3-(4-methylphenyl)-2-isoxazoline A 29 g. portion of 4-methylbenzaldoxime was chlorinated and reacted with 25 g. of allylisothiocyanate produce 4.1 g. of product, m.p. 80.5- 81°. Theoretical Pound C 62.04% 61.76% H 5.21 5.18 N 12.06 11.96 S 13.80 14.05 Example 16 3-(4-bromophenyl)-5-isothiocyanatOmethyl-2-isoxazoline A 10 g. portion of 4-bromobenzaldoxime was chlorinated and reacted with 10 g. of allylisothiocyanate to prepare 15 g. of product, m.p. 123-125°. -21 Theoretical Found C 44.46% 44.21% H 3.05 3.15 N 9.43 9.20 5 S 10.79 10.80 Example 17 3-(4-fluorophenyl)-5-isothiocyanatomethyl-2-isoxazoline A 12.5 g. portion of 4-fluorobenzaldoxime was chlorinated and reacted with 50 ml. of allylisothiocyanate 10 to prepare 3.4 g. of product, m.p. 59- -61°. Theoretical Found C 55.92% 56,08% H 3.84 3.95 N 11.86 12.25 15 S 13.59 13.92 Example 18 3-(2-isopropylphenyl)- 5-isothiocyanatomethyl-2-isoxazoline One g. of 2- isopropylbenzaldehyde was eohverted to the oxime and chlorinated, and then reacted with 20 g. of 20 allylisothiocyanate to produce 100 mg. of product, an oily liquid. • Theoretical Pound C 64.59% 64.36% H 6.19 5.92 25 N 10.76 10.43 S 12.32 12.62 Example 19 3-(4-isopropylphenyl)-5-i5othiocyanatomethyl-2-isoxazoline Fifteen g. of 4-isopropylbenzaldehyde was con30 verted to the oxime, chlorinated and reacted with 20 g. of -2244819 allylisothiocyanate to produce 2 g. of product, m.p. 6870°.

Theoretical Found c 64.59% 64.31% H 6.19 6.00 N 10.76 10.45 S 12.32 12.38 Example 20 -isothiocyanatomethyl-3-(2-pyridyl)-2-isoxazoline Twelve g. of 2-pyridinaldoxime was chlorinated and reacted with 25 ml. of allylisothiocyanate to produce 14 g. of product, a liquid.

Theoretical Found C 54.78% 54.70% H 4.14 4.09 N 19.16 18.94 Example 2.1 -isothiocyanatomethy1-3-(4-phenylphenyl)-2-isoxazoline A 17 g. portion of 4-phenylbenzaldehyde was converted to the oxime, chlorinated and reacted with 25 ml. of allylisothiocyanate to produce 6 g. of product, m.p. 162- 164°. Theoretical Found C 69.36% 69.65% H 4.79 4.75 N 9.52 9.39 S 10.89 11.11 -23Example 22 3-[3-chloro-4-hydroxy-5-(t-butyl)phenyl]-5-isothiocyanatomethyl-2-isoxazoline A 25 g. portion of 4-hydroxy-3,5-bis(t-butyl)5 benzaldoxime was chlorinated as in Example 1 to produce 1 g. of a,3-dichloro-4-hydroxy-5-(t-butyl)benzaldoxime by chlorination and rearrangement. The intermediate was reacted with an excess of allylisothiocyanate to produce 1 g. of product, an oily liquid, NMR singlets at 1.41 and 6.18 ppm., multiplets at 2.92-3.93, 4.68-5.23 and 7.5-7.63 ppm.

Example 23 -isothioeyanatomethyl-3,4-diphenyl-2-isoxazoline A 3.5 g. portion of cinnamylisothiocyanate was reacted with 5 g. of α-chlorobenzaldoxime as in Example 1 to produce 1 g. of the product, m.p. 94-96°, NMR multiplets at 3.62-4.12, 5.65-5.78 and 7.22-7.83 ppm.

Example 24 3-(3-chloro-4-ben2yloxyphenyl)-5-isothiocyanatomethyl-2isoxazoline Example 25 3-(3,5-dichloro-4-benzyloxyphenyl)-5-isothiOCyanatomethyl-2isoxazoline A 21 g. portion of 4-benzyloxybetiZaldehyde was converted to the oxime, and chlotihated. Two chlorinated products were obtained, a,3-dichlo'ro-4-benzyloxybenzaldOxime and a,3,5“triohloro-4-benzyloxybenzaldOxime.· The reaction of the intermediate mixture withi20 g. of allylisothiocyanate produced 5.4 g. of 3-(3-chloro-4-benzyloxyphenyl)5-isothiocyanatomethyl-2-isoxazoline and 1.38 g. Of 3-244*8i9 (3,5-dichloro-4-benzyloxyphenyl) -5-isothiocyanatomethyl-2isoxazoline, both oily liquids, showing the following NMR features.

Example 25 2.77-3.83 ppm. 4.60-5.28 .05 7.20-7.78 illustrates the synthesis of nitrile substituent.

Example 24 2.83-3.82 ppm. 4.63-5.20 .17 6.96 7.25-7.78 The following example compounds of Formula I having a Example 26 -cyanomethyl-3-phenyl-2-isoxazoline A 60 g. portion of benzaldoxime was chlorinated in chloroform at 10° with dry gaseous chlorine, and the reaction mixture was evaporated to dryness. The residue was taken up in tetrahydrofuran:ether and combined with 100 g. of allyl cyanide. The reaction mixture was cooled to 10°C., and 100 g. of triethylamine was added dropwise, keeping the temperature below 20° at all times. The mixture was stirred overnight. A large amount of water was added, and the organic layer was separated. The water layer was extracted with diethyl ether and the ether layer was combined with the organic layer from the reaction mixture. The combined organics were evaporated to a thick oil which was crystallized from chloroform to yield 62 g. of 5-cyanomethyl-3phenyl-2-isoxazoline, m.p. 79-80.5°C. -251© Theoretical Found C 70.95% 70.56% H 5.41 5.55 N 15.04 14.77 The following examples illustrate the synthesis of typical thiourea compounds of Formula I.

Example 27 4-[[3-(4-chlorophenyl)-2-isoxazolin-5-yl]methyl]-3-thlosemicarbazide A 25 g. portion of the product of Example 1 was reacted with excess hydrazine in 200 ml. of ethanol for 2 hours, allowing the reaction to heat to reflux temperature. The solids which precipitated upon cooling were separated by filtration and identified as 27 g. of product, m.p. 115-117°, NMR singlets at 4.48, 7.4, 7.63, 7.97 and 8.73 ppm,, and multiplots at 3.05-4,12 and 4.67-5.28 ppm.

Example 28 l,l-diisopropyl-3-[[3-(4-methylphenyl-2-isoxazolin-5-yl]me thyl]thiourea Five g. of the product of Example 15 Was reacted with excess diisopropylamine neat at room temperature for 7 days. The reaction mixture was chromatographed over a 12meter silica gel column with methyl ethyl ketone as the eluting solvent. The desired product was in the first fraction off the column. The solvents were evaporated and the product obtained was 1 g. ofl,l-diisopropyl-3-[[3(4-methylphehyl-2-isoxazolin-5-yl]methyl]thiourea, an oily liquid, NMR singlets at 2.37; 5.82, 7.15 and 7.52 ppm,, and multiplets at 1.15-1,37, 2.87-3.72, 3.98-4.2·and 4.37-5.25 ppm. 4481 Example 29 Ν-[[3-(3-trifluoromethylphenyl)-2-isoxazolin-5-yl]methyl]4-morpholinethiocarboxamide One hundred mg. of the product of Example 5 was reacted with excess morpholine to produce 100 mg. of product, m.p. 118-120°.

Theoretical Pound c 51.47% 51.54% II 4.83 4.44 N 11.26 11.03 S 8.58 8.41 Example 30 N-[2-(3-phenyl-2-isoxazolin-5-yl)ethyl]-4-morpholinethiocar- boxamide One hundred mg. of the product of Example 2 was reacted with · excess morpholine to produce 100 mg. of product m.p. 128-130°. Theoretical Found C 60.19% 60.19% H 6.58 5.30 N 13.17 12.97 0 10.03 11.09 S 10.03 10.07 Example 31 1-[[3-(4-chlorophenyl)-2-isoxazolin-5-yl]methyl]-3-methylthiourea To 3 g. of the product of Example 1 was added 5 ml. of 40 percent methylamine in aqueous ethanol. The mixture was stirred for 1 hour, and was then allowed to -2744819 stand overnight, The product separated as a precipitate, which was collected and recrystallized from methanol-water, and recrystallized a second time from chloroform to produce 0.8 g. of product, m.p. 131-133°. Found - Theoretical C 50.79% 50.92% H 4.97 4.86 N 14.81 14.68 Cl 12.49 12.74 s 11.30 11.29 Example 32 5-methoxycarbonylaminomethyl-3-phenyl- 2-isoxazoline A 24 g. portion of benzaldoxime was chlorinated, isolated and dissolved in diethyl ether. The solution Was cooled to 15°c., and 46 g. of methyl allylearbamate was added. Sixty ml. of triethylamine was then added dropwise, keeping the temperature below 20°C. The mixture was stirred for 3 hours, and filtered. The filtrate was evaporated to dryness, and the residue was washed with water and filtered again. The solids were identified as 32 g. of product, m.p. 102-103°, NMR singlets at 3,63 and 5.48 ppm,, multiplets at 2.82-3.80, 4.57-5.08, 7.13-7.50 and 7.45-7.77 ppm.

The following example illustrates the preparation of amino compounds of Formula I.

Example 33 -aminomethyl-3-pheny1-2-isoxazoline A 5 g. portion of the product Of Example 32 Was slurried in 50 percent aqueous hydrochloric acid and refluxed overnight. The mixture was then cooled and neutralized -28*4819 with potassium hydroxide, and extracted with chloroform.

The chloroform layer was concentrated to 10 ml., and eluted through a 12-meter column of polystyrene gel beads with chloroform as the eluting solvent. The desired product was the second fraction off the column. The yield was 2 g. of -aminomethyl-3-phenyl-2-isoxazoline, an oily liquid, NMR t multiplets at 2.57-3.83, 4.43-4.98, 7.08-7.60 and 7.42-7.80 ppm., and a singlet at 1.38 ppm.

The next example illustrates the preparation of the thiadia2oles of Formula I, Example 34 N-[[3-(4-chlorophenyl)-2-isoxazolin-5-yl]methyl]-N-(5methy1-1,3,4-thiadiazol-2-yl)acetamide A 5 g. portion of the product of Example 27 was treated with 100 ml. of acetic anhydride and 50 ml. of acetyl chloride at reflux temperature in 100 ml. of dioxane until the mixture became clear. The reaction mixture was then evaporated under vacuum to a thick slurry. Fifty ml. of chloroform was added, and the mixture was filtered. The filtrate was evaporated to dryness and dissolved in 25 ml. of concentrated ^ulfuric acid, and stirred overnight at room temperature. The acid suspension was then poured into water, and the agueous suspension was filtered to produce 5 g, of N-t[3-U-chlorophenyl)-2-isoxazolin-5-yl]methyl]-N25 (5-methyl-l,3,4-thiadiazol-2-yl)acetamide, m.p. 195-197°, NMR singlets at £.43) 2.63, 7.55 and 7.78 ppm., and multiplets at 3.00-^.92, 4.23-4.53 and 4.88-5.50 ppm.

The compounds of Formula I have been tested to evaluate their ability to protect plants from the adverse effects of fungal foliar phytopathogens. The following examples illustrate the tests employed and the results produced by representative compounds.

In most of the tests, each compound was formulated for testing by dissolving or suspending about 3.5 weight percent of it in 50:50 acetone:ethanol containing about 10 g./ΙΟΟ ml. of a nonionic surfactant. The solution was then dispersed in deionized water in a quantity such that the water dispersion contained the various compound concentrations indicated in the specific test methods and the table below. Concentrations ape measured in parts per million, by weight (ppm.).

In most of the tests, the compound dispersions were applied to the test plants by spraying them with an air atomizer, using sufficient dispersion to wet the plants thoroughly. Othpr methods of formulation and application were used in a few tests, as described in the Specific test methods which follow.

Untreated, infected controls and untreated, normal controls were included in each test. The results are reported on a 1-5 rating scale where 1 indicates severe disease and 5 indicates complete control of the disease. An empty space in the table below shows that the indicated compound was not tested at the indicated rate. In some cases, more than one test was performed against a given phytopathogen, and the results in such cases are reported as averages. Compounds are identified by the example numbers used above. -3044819 Test 1 late blight of tomato Four-week-old tomato seedlings were sprayed with aqueous dispersions containing test compounds at compound concentrations indicated in the table below. The following day, the foliage was inoculated with an aqueous suspension of propagules of Phytophthora infestans. The inoculum had been reared on infected wheat seed. The plants were held for two days in a moist chamber, and were then transferred to the greenhouse. The plants were observed and rated for disease control about one week after application of the test compounds.

Test 2 powdery mildew of bean The host plants were 10-day-old bean seedlings. After aqueous dispersions containing test compounds at compound concentrations indicated in the table below had been sprayed on the foliage of the beans and allowed to dry, the plants were placed in the greenhouse and inoculated by storing them under other bean plants which were heavily infected with·, powdery mildew (Erysiphe polygoni). After about 10 days, the plants were observed and the results recorded as usual.

Test £ anthracnose of cucumber Aqueous dispersions containing test compounds at compound concentrations indicated in the table below were applied to healthy cucumber seedlings grown in sterilized greenhouse soil. The following day/ the plants were ino-3144S1S culated with Colletotrichum lagenarium conidia as an aqueous suspension. The fungus had been grown on potato dextrose agar in petri dishes. The plants were held in a moist chamber for two days and transferred to the greenhouse, and the disease was observed and rated approximately 12 days after application of the test compounds.

Test 4 rice blast of rice The test compound dispersions, at compound con10 centrations indicated in the table below, were applied to ·* V healthy rice seedlings growing thickly in plastic pots. The plants were inoculated on the next day with Piricularia oryzae (grown on rice polish agar) and the plants were held in a moist 'chamber for two days. The plants were then held in the greenhouse for 5-7 days and observed.

Test 5 helminthosporium leaf spot of wheat Healthy wheat seed was planted in sterile greenhouse soil. When the seedlings were 4-5 inches tall, they 20 were sprayed with test compound dispersions at compound concentrations indicated in the table below. The day after treatment, the plants were inoculated with a spore suspension of Helminthosporium sativum which had been grown on V potato dextrose agar. The plants were placed in a moist 25 growth chamber for two days to start disease growth, and were then transferred to the greenhouse. About a week after treatment, the plants were observed and the results were recorded. -324481s Test 6_ botrytis of grape Sound grape berries were sterilized by immersion in diluted sodium hypochlorite and thoroughly rinsed, The 2 berries were placed on wire screen Shelves in compartmented Pyrex (Registered Trade Mark)plates. The berries were then flamed and sprayed with test chemical dispersions. The following day, the berries were inoculated by spraying 5 ml. of a conidial suspension of Botrytis cinerea over each plate containing 12 berries.

The inoculum had been grown on frozen lima bean agar. A small amount of water was added to each plate and a cover was sealed over each plate. After 48 hours at 25°C., the berries were observed and disease ratings recorded.

Test 2 apple scab of apple Apple seedlings at the 4-6 leaf stage were sprayed with aqueous dispersions of the test compounds. The following day, the plants were sprayed with a suspension of fresh conidia oil Venturia inaegualis obtained from infected apple seedlings kept as a source pf inoculum. The plants were held for two days in a 20° moist chamber to start disease growth and were then transferred to the greenhouse. About two weeks after application of the compounds, the plants were observed and the results were recorded.

Test 2 downy mildew of grape Young expanding grape leaves were detached from healthy vines on the day of the test. Leaves were placed individually in plastic petri dishes, bottom side up, on top -3344S19 of an expanded plastic mat. Water was added.to each petri dish, and the petiole of each leaf was wrapped with a watersoaked wad of cotton. Each leaf was sprayed with an aqueous dispersion of the compound to be tested.

After the test compound dispersions had dried, the leaves were,ihoculated by atomizing a conidial suspension of Plasmopara viticola (grown on infected leaf tissue) evenly over the leaf surface. The plates were then covered and were stored in a growth room at about 18° and 100% relative - humidity where they were exposed to 8 hours a day of artificial light. After about a week of storage, all the leaves were observed and the signs of disease were evaluated.

Test 9^ cercospora leaf spot Of sugar beet Sugar beet seedlings were transplanted into square plastic pots and allowed to grow for three weeks. Aqueous dispersions containing 400 ppm. of the compounds to be tested were sprayed on the leaf surfaces. After the dispersions dried, but within 24 hours, the plants were inocu20 lated with a conidial suspension of Cercospora beticola which had been grown on sugar beet leaf decoction agar.

After the plants were held in a moist chamber for two days, they were transferred to the greenhouse and observed 2-3 weeks later. -34<4613 ι ω ο rtf υ Μ Μ ο φ a υ ί >ι α c Ttf > η Ο rt α £ ty rt fi Cu rtf a o fi ω I u rtf ty fc tn fi 0 fi β c fi >1 fc £ ty ty *o ·ϋ 5 rt 0 rt a £ fi ty fi fi Cp CQ fi ty · rt fi g a itf a ao: a fi Π3 ty fi rt β a · o »w g o a 0 rtf 53 e tt o w u Ν* Ν' Ν’ rt rt Ν' Ν' rt rt m «J* rt rt rt m CN σ o Ν’ in CN -3544818 ι ω nJ υ μ u ο φ α ο >1 Φ G Ό 3 ι—( Ο·Η Ω 53 cn η Μ* Η 0) ι—I Λ CL ίβ Οι □ < W Φ UJ » ρ ΰ ν> Ό (0 •Η Η a <η I ο π) 0 >1 Μ 5 0) Ρ α) ϋ ρ σι id ·Η Ρ Η Μ (J 0) · ΗΡΕ a ίο a a« a P a op S ο a o Ss g x o W CJ ι—I Η (ή Η o o in © O o m © o o o in o o 04. O o CJ o o © © 04 rd i—l «Φ • *4» <· rM -3644819 I ω Ο «ΰ ϋ Μ Μ Ο ο α υ a >1 Φ β τί £ Η Ο ·Η α a 0) Η Λ & β ti ϋ «ί W I Ο X § μ 3 β·Η •Η Η Ε 0 η a Φ w Β μ Φ ω ϋ «ΰ •Η η & Β □ Π3 0) rt w X ο •μ β β tf >1 rt £ φ φ Ό τ) 5 Η ο ·Η ti a μ φ χ* μ CP flj Ή X γΗ Β G φ . Η μ Ε ti fti ti titi ti tf 0 Φ β j—1 9 a · 0 4-t e o ti 0 rt Z ε X 0 a U tf ΓΟ Κ Η CM Η «Η ιηιηιηιη^ΗίπΗΗ •tf ·*τ η η •tf η η Η o o •tf o in O CM H O ’tf m CM o in O CM rH o o ttf CM trt ’tf H -374481S OT O TO ϋ μ Μ Ο Φ 3 U >1 Φ β τι 3 η Ο -Η α 2 Η Λ a to a υ < w ΐε -Ρ 3 β·Η •η μ £ Ο η a Φ OT « •μ φ OT □ TO I TO Φ μ ot £3 0 £> C s M 3 Φ Φ Ό Ό 3 H Ο -«M Q.S P Φ Λ 4J CP to ·μ Hl r-i a fi Φ · Γ-l 4J S a to a a« a Ό Φ § 3..

Q 'it £ o a O TO 2 e x o w a ι—I M* r-i Μ in Η ΠΗΗ<*)γΗγΜ γΜγ4 ΓΠ Π pH rM CM rM Μ4 Η rl rM r-l rd C*1rHr-ir-lr-irMrMrM CMrMrH r-i H rM CO r-l rM ' H rM rM rM rM r-l ι-i· rM rM © o in o © © © © © © O o © o © o CM © o © © © O © o © © o M4 r-l M4 M4 M4 M4 M4 M4 M4 tJ4 M4 ι—I CJ CM CM CO CM M4 CM m CM -3844819 ι in ti υ m ti o φ a u © ti Ό 3 H O rt a s v rt A Qi (0 fi 0 < W; 0 A £ A p ti rt rt ti ε 0 rt a Φ ω fi A 0 tn 0 ti rt rt if fi I ti Φ ti ω A 0 A fi >1 ti 3 Φ φ Ό Ό 5 rt 0 rt fi g A 0) A A Cr ti rt rt rt fi fid), rt A g & ti fi fifi (X < Ό φ ti rt ti & 0 A g 0« 0 (3 g X 0 M a > cn © O •Q* © O TT oo CN σι CN © © tf © o •vr in CM -3944819 ο α ο t s RO 5 H 0-H Q S Η Λ ft (S ft 0 lfi Ul ι o E fi 3 fi -H •Η H ' Ε 0 H ft 0) VT E fi O Ifl O 18 H rH ft « t O iti *i fi S Cd). rH fi E ft Ifl ft ftft ft ft o o 3· o in o 0*0)0 Η T (U § t. 0>w 6 0 fto fl2 S X 4030 44818 Many of the compounds have beenretested in replicated special tests against downy mildew and botrytis rot of grape. The test methods were the same as those described above, except that multiple replicates were used at the various rates. In many cases, the tests reported \ below have been repeated several times, and the results thereof have been averaged.

Appln.

Compound of Rate Example No. ppm.

Downy Mildew Botrytis 800 400 200 100 12.5 800 400 200 100 800 400 200 100 4’ 400 200 100 -4144819 Compound of Example No. -Appln. Rate .P.Pm- Downy Mildew Botrytis 5 800 5' . 2 . 400 5 1 200 5 1 100 1-. 6 400 5 ' 2 200 5 2 100 4 · 1 50 4 . 1 7 800 5 1 400 5 1 200 4 1 100 1 50 1 8 400 5 200 1 100 2 . 50 2 9 400 '5 - 200 2 ‘ 100 1 50 1 10 800 1 400 4 1 200 2 ' 1 100 3 ; 1 50 2 1 -42-.

...- * ? * Compound of Example No. Appln. Rate ppm. Downy Mildew Botrytis 11 800 1 400 5 1 200 5 1 100 4 1 50 4 1 25 5 12 800 5 3 400 5 1 200 4 1 100 4 50 4 25 1 13 800 5 2 400 5 2 200 5 2 100 4 50 3 25 3 14 800 5 1 400 5 1 200 5 1 100 3 50 3 15 800 5 3 400 5 4 200 5 1 100 5 50 4 25 2 -4344819 Compound of Example No. Appln. Rate ppm. Downy Mildew Botrytis 19 800 1 - 400 5 \ 1 200 5' 1 100 - 5. . 50 3 25 ' 4 12.5 1 .20 800 s... · 400 4 200 . 4 100 4 50 4 25 I 21 800 5 400 4 -. 200 4 . 100 4 50 1 ·. . 25 1.-, 26 800 ' 4 1 . 400 3 1. 200 2 j*· 1 27 800 4 1 400 4 1 200 3 1 100 2 ; · 503 25 1 . -4444819 Compound of Example No. Appln. Rate PE. Downy Mildew Botrytis 28 800 4 1 400 3 1 5 200 4 1 2'9 800 5 1 400 5 1 200 3 1 30 800 3 1 10 400 4 1 200 2 1 31 400 5 200 3 100 1 15 50 2 32 800 4 1 400 2 1 200 2 1 33,' 800 5 1 20 400 5 1 200 4 1 100 2 50 2 25 2 25 34 800 4 1 400 4 2 200 3 1 The compound of Example 1 was tested against a heavy infestation of downy mildew of grapes growing in field -45442iS plots. The compound was appliedas 600 and 1200 ppm. aqueous suspensions of a wettable powder formulation. Applications were made on a 7-10 day spray schedule throughout the do'wny mildew season. When the grapes were under extremely heavy disease pressure, with 82 percent disease involvement in untreated control plots, the 600 ppm. treatment gave 46 percent control, and the 1200 ppm. treatment gave 87 percent control.

While the efficacy of the compounds against fungal foliar phytopathqgens is their most important property, they have other significant utilities..as well. For example, they control a number of other harmful pathogens, as well as those affecting plants. The following results were obtained when representative compounds were tested in a system to determine their ability to inhibit the growth of microorganisms in vitro. The organisms named below were grown in culture media, appropriate for the growth of the various organisms, containing the compounds at various concentrations, in meg./ml. The table below lists the lowest Concentration at which each compound inhibited the growth of the microorganism.

A. Staphylococcus aureus 3055 B. Staphylococcus aureus 3074 Ci Klebsiella pneumoniae KL14 D. Streptococcus faecalis X66 E. Proteus morganii PR15 F. Salmonella typhosa SA12 G. Bordetella bronchiseptlca' 16 -464 4819 H. Escherichia coli EC14 I. Pasteurella multocida (bovine) J. Pasteurella multocida (avian) K. Mycoplasma gallisepticum 38502 L. Mycoplasma synoviae M. Mycoplasma hyorhinis N. Mycoplasma hyopneumoniae O. Pseudomonas sp.

P. Aeromonas liguefaciens Q. Erwinia amylovora R. Candida tropicalis A17 S. Trichophyton mentagrophytes T. Aspergillus flavus U. Ceratocystis ulmi -4744819 a I sj ►4 m · 0 Z Ό fi 0) fi rt 0 ft ft £ tt O tt o O o O O O O O ©: O o o rt rt rt rt rt rt ‘ O rt· rt o rt rt V V V V V V rt · V • · - V rt V V o o O o O O • '· ©J :© © © o rt O rt O © . irt . rt rt: © rt V rt V rt - rt. ·: v :.v . V rt o O O o O O ..©. - O ci ci ..: © O. © rt rt i—1 rt rt rt .© rt • © © rt rt V V V V V V .rt . V ; · rt V V o O © © O © © . © • .© ©,.. O © .© rt rt rt rt rt © O rt. : ; rt •rt © © rt V V V V V rt . , rt V v V - rt .rt V © O O o O o © · ©; o rt © rt o © -./ if © rt rt V s rt V rt rt ;.rt· V in inIN rt O rt V o © rt © rt V © . rt V O © rt © o rt O O O O o o © o rt rt rt rt © © © O o © O ' ©J rt rt rt .. rt © © O © .© : © © O O © © ';©’-. .. cr © rt rt rt rt ---:. H ··. rt rt O ' /:- O rt © © © © © o © ©. \© .-ο O O © rt rt rt O rt © © © · .rt · . rt rt © rt' V V V rt V rt rt rt v. V -'V ·. rt V O O o Q © O © © o ·,-© o. © O © rt rt rt rt rt rt © rt.. rt rt: rt . rt rt rt V V V V V V rt v -- V y V V.’ V V o rt V o rt «I . CJ t '--rt'; <*) 'rt.'· N· . rt·. Γ* rt CO rt <10 <10 <10 <10 100 <10 σ> rt -4810 •Η c flj Οι Μ Ο ο ο ι—ί 44818 1« * Ο 0 V2 ti Φ 3 r-i ο α α s £ « ο χ υ Μ ο Η 05 OJ co • ζ 4481 Many of the compounds have also been found to be effective against aquatic weeds. For example, the compounds of Examples 2, 3, 5, 7, 8, 9, 12, 13, 14, 16, 17, 18, 19 and 20 have been found to be effective against eoontail, Ceratophyllum demersum L., hydrilla, Hydrilla verticillata, and duckweed, Lenina minor L., at concentrations of 10 ppm. or less. Further, the compound of Example 9 has been found to he active against the above weeds, and also against naiad, Najas marina L., and cabomba. Cabomba caroliniana, at concentrations as low με 2 ppm.

The test data reported above show that the compounds of this invention are useful for the protection of plants from the adverse effects of a variety of fungal foliar phytopathogens. Accordingly, aii important aspect of the invention is a new method of reducing the adverse effects of fungal foliar phytopathogens which comprises contacting the phytopathogens on the. foliage of host plants with an effective phytopathogen-inhibiting amount of one of the compounds described above. The method is carried out by applying a compound of the invention to the plants to be protected.

Practice of the method does not necessarily kill the phytopathogens. As the data above show, application of the phytopathogen-inhibiting. amount of a compound reduces'the adverse effects of the disease, even though only a part of the phytopathogen population may be killed by the compound. The term phytopathogen-inhibiting amount is used here to describe an amount which is sufficient to reduce the adverse effects of a phytopathogen. The ;term reducing the adverse 50-. 44810 effects refers to weakening the pathogen sufficiently that its reproduction rate and its vigor are decreased, with the result that the express signs of the disease, and the concomitant injury to the host plant, are decreased as compared with phytopathogens growing on untreated plants.

As is usual in the plant protection art, best results are obtained by applying the compound several times during the growing season at intervals of from one to a few weeks, depending on the weather and the severity of the disease.

The methods of formulating the compounds and preparing dispersions of the formulations, and the methods of applying dispersions of the compounds to the plants to be protected, are entirely conventional in the plant protection art. Some explanation of the methods of application will be given merely to ensure that those skilled in the art can carry out the invention without undue experimentation.

• It is usual in describing foliar applications of plant protectants to measure the application rate by the concentration of the dispersion in which i’t is applied. The application rate is measured in this way because it is customary to apply a sufficient amount of the dispersion to cover the foliage with a thin film. The amount of dispersion applied is thus dependent on the foliar area of the plants being treated, and the quantity of plant protecting compound is dependent upon its concentration in the dispersion. In general, compound concentrations in the range of from 50 to 1500 parts of compound per million parts by weight of dispersion are used in the practice of this invention. -5144819 The compounds of this invention are usually applied in the form of fungicidal compositions which are important embodiments of the invention. Such compositions comprise a compound of this invention and a phytologicallyacceptable inert carrier, and are either concentrated formulations which are dispersed in water for application, or are dust formulations. The compositions are prepared according to procedures and formulae which are conventional in the agricultural chemical art, but which are novel and important because of the presence therein of the compounds of this invention. Some description of the formulation of the fungicidal compositions will be given, to ensure that agricultural chemists can readily prepare any desired fungicidal composition.

The dispersions in which the compounds are applied . are most often aqueous suspensions or emulsions prepared from concentrated compositions of the compounds. Such water-suspendible or emulsifiable formulations are either solids usually known as wettable powders or liquids usually known as emulsifiable concentrates. Wettable powders comprise an intimate mixture of the active compound, an inert carrier and surfactants. The concentration of the active compound is usually from 10 percent to 90 percent by weight. The inert carrier is usually chosen from among the attapulgite clays, the montmorillonite clays, the diatomaceous earths, or the purified silicates. Effective surfactants, comprising from 0.5 percent to 10 percent of the wettable powder, are found among the sulfonated lignins, the condensed naphthalenesulfonates, the naphthalenesulfonates, the -524*819 alkylbenzenesulfonates, the alkyl sulfates, and nonionic surfactants such as ethylene oxide adducts of alkyl phenol.

Typical emulsifiable concentrates of the compounds comprise a convenient concentration of the compound, such as from 100 to 500 g. per liter of liquid, dissolved in an inert carrier which is a mixture of water-immiscible organic solvent and emulsifiers. Useful organic solvents include the aromatics, especially the xylenes, and the petroleum fractions, especially the high-boiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha. Other organic solvents may also be used, such as terpenic solvents including rosin derivatives, and complex alcohols suqh as 2-ethoxyethanol. Suitable emulsifiers for emulsifiable concentrates are chosen from the same types of surfactants used for wettable powders.

Adjuvants are frequently used to improve the ability of the aqueous dispersion to coat and adhere to foliage. Such adjuvants as gums, emulsified polybutenes, cationic surfactants and lignin derivatives can often increase the potency of the method in a specific use.

Less frequently, the compounds are applied to foliage in the form of dusts. Agricultural chemical dusts typically comprise the compound in a finely powdered form, dispersed in a powdered inert carrier. Most often, the carrier is a powdered clay, such as pyrophyllite, bentonite, a volcanic deposit, or montmorillonite. Dusts are usually prepared to contain concentrations of the compound at the highest part of the concentration range, such as 1500 ppm., and may contain even more active ingredient. -5344819 Dispersions of the compounds are applied in the usual manners. Low-pressure sprayers, high-pressure sprayers and low-volume air blast equipment are all effective for the application of water-dispersed compounds of the invention.

Dust dispersions are readily applied by means of the usual equipment which blows the dust into intimate contact with the foliage. -54*4819

Claims (26)

1. CLAIMS :1. An isoxazoline compound of tho formula R >3 :H- (CHs) n -R wherein R represents -NCS, cyano, amino, amino hydrohalide, -NHCSN(R 1 R 2 ), -NHCO 2 (C 1 -C 3 alkyl) or COCH, | J .S - C - CH -4-II 3 4 X N - N n represents 1 or 2; 1 2 R and R independently represent hydrogen or C^Cg alkyl, or 1 o R represents hydrogen and R represents amino, or R 1 and R 2 combine with the nitrogen atom to which they are attached to form morpholino, piperidino or piperazin-1 -yl R 3 represents hydrogen or phenyl; R represents naphthyl, 2-pyridyl or t S ,5 -5544819 e zr 7 R , R and R independently represent chloro, bromo, fluoro, nitro, trifluoromethyl, C l -C 2 alkoxy, C^-Cg alkylthio, C 1 -C 4 alkyl, hydroxy, phenyl, benzyloxy or · hydrogen, provided that no more than one of R^, R® and R represents phenyl or benzyloxy;-and further provided that when one of R , R° and R' represents hydroxy, alkoxy or benzyloxy, e zr 7 1) no more than one of R r R and R' represents t-butyl; and c £ 7 2. ) if one of R , R and R' represents chloro, it is ortho to the hydroxy, alkoxy or benzyloxy group.

2. A compound of claim 1 wherein R represents hydrogen.

3. -NCS, cyano,

4. -NCS, cyano, A compound of claim 2 wherein R represents -NHCSN(R^R 2 ) or -NHCO 2 (C 1 -C 3 alkyl). A compound of claim 3 wherein R represents or -NHCO 2 (C 1 -C 3 alkyl). -564481g

5. A compound of claim 4 wherein R represents -NCS.

6. Λ compound of any onp of claims 1, 2, 3, 4 or 5 wherein R^ represents 2-pyridyl or c a 7 where R , R and R are as defined in claim 1.

7. The compound of any of claims 1-6 which is 5-isothiocyanatomethyl-3-(2-pyridyl)-2-isoxazoline.

8. The compound of any of claims 1-6 wherein 4 R represents' c g 7 where R , R and R are as defined in claim 1.

9. The compound of claim 8 which is 5-isothiocyanatomethyl-3-(4-chlorophenyl)-2-isoxazoline.

10. The compound of claim 8 which is 5-isothiocyanatomethyl-3-(4-trifluoromethylphenyl)-2-isoxazoline.

11. The compound of claim 8 which is 3-(2,6dichlorophenyl)-5-isothiocyanatomethyl-2-isoxazoline.

12. The compound of claim 8 which is 5-isothiocyanatomethyl-3-(4-methylphenyl)-2-isoxazoline.

13. A fungicidal composition comprising a compound of Formula I as claimed in any one of claims 1-12 and a phytologically-acceptable inert -carrier.

14. A composition of claim 13 wherein the concentration of the compound of Formula I is from 50 ppm. to 90 percent by weight. 44® i9

15. A composition of claim 13 which is a wettable powder wherein the concentration of the compound of Formula I is from 10 percent to 90 percent by weight. .

16. A composition of claim 13 which is an emulsifiable concentrate wherein the concentration of the compound of Formula I is from 100 to 500 g. per liter.

17. A composition of claim 13 which is a dust wherein the concentration of the compound of Formula 1 is from 50 to 1500 ppm. by weight.

18. A method of reducing the adverse effects of fungal foliar phytopathpgens which comprises contacting the phytopathogens on the foliage of host plants with an effective phytopathogen-inhibiting amount of a compound of Formula I as claimed in any one of claims 1-12.

19. A method of claim 18 wherein the host plants \ are grapes.

20. A method of claim 18 or 19 wherein the amount of the compound of claim 1 is from 50 to 1500 ppm. by weight.

21. A process for preparing a oompound of Formula I, wherein the symbols are as defined in claim 1, which comprises reacting a chlorinated oxime of the formula C1 4 I II R -C=NOH wherein is as defined above, with a compound of the formula R -C=C-(CH 2 ) n -R 3 wherein R and n are as defined above, III and R represents - 58 44819 -NCS, cyano or -NHCC> 2 (C^-C^ alkyl), to produce a compound of Formula I wherein R represents -NCS, cyano or -NHCC> 2 (C^-C 3 alkyl) ,- and optionally further 1) reacting a compound of Formula I wherein R represents -NCS with an amine of the formula HN(R 1 R 2 ) IV 1 2 wherein R and R are as defined above, to produce a 1 2 compound of Formula I wherein R represents -NHCSN(R R ) 1 2 wherein R and R are as defined in claim 1; or 2) hydrolyzing a compound of Formula I wherein R represents -NHCO 2 (C^-C 3 alkyl) to produce a compound of Formula I wherein R represents amino or amino hydrohalide; or 3. ) reacting a compound of Formula I wherein R represents 12 1 2 -NHCSN(R R ), R represents hydrogen and R represents amino, with acetic anhydride, an acetyl halide or a mixture thereof, to produce a compound of Formula I wherein R represents COCH, | 3 I S - C - CH_N-< II 3 ; X N - N

22. A compound as claimed in claim 1 substantially as hereinbefore described with particular reference to any one of the Examples.

23. A fungicidal composition as claimed in claim 13 substantially as hereinbefore described with particular reference to any one of the Examples.

24. A fungicidal method as claimed in claim 18 substantially as hereinbefore described with particular reference to any one of the Examples. • 44819

25. A process as claimed in claim 21 · substantially as hereinbefore described with particular reference to any one of the Examples.

26. A compound of formula I whenever prepared 5 by a process according to claim 21 or 25. F.R. KELLY & CO.,