CA1158654A

CA1158654A - Fungicidal 3-(n-thionoacyl-n-arylamino) lactones and thiolactones

Info

Publication number: CA1158654A
Application number: CA000415235A
Authority: CA
Inventors: David C. K. Chan
Original assignee: Chevron Research and Technology Co
Current assignee: Chevron USA Inc
Priority date: 1979-06-01
Filing date: 1982-11-09
Publication date: 1983-12-13
Also published as: AT376427B; PL126303B1; DK230880A; HU184777B; PT71339B; ES8105281A1; SE8004056L; ATA289980A; BG36195A3; IL60158A0; GR68379B; IT8022452A0; YU145580A; CA1147340A; AU5884480A; ES492022A0; PT71339A; AU543718B2; CA1154783A; YU62783A

Abstract

ABSTRACT OF THE DISCLOSURE
3-(N-thionoacyl-N-arylamino)-gamma-butyrolactones and thiobutyrolactones have fungicidal activity.

Description

~ls86s4 This invention relates to fungicidal 3-~N-thionoacyl-N-arylamino)-gamma-butyrolactones and thiobutyrolactones.
United States Patent No. 3,933,860, issued January 26, 1976, United States Patent No. 4,012,519, issued March 15, 1977, United States Patent No. 4,107,323, issued August 15, 1978, and United States Patent No.
4,141,989, issued Febr~ary 27, 1979, all to David Cheong King Chan, dis-close the use of a large class of 3-~N-acyl-N-arylamino) lactones and 3-~N-acyl-N-arylamino) lactams as protectant fungicides.
United States Patent No. 4,034,108, issued July 5, 1977, to H. Moser, and United States Patent No. 4,015,648, issued May 24, 1977 to H. Moser, disclose the use of N-~methoxycarbonylethyl~-N-halo-acetylanilines as preventive and curative fungicides.
German Patent Publication Nos. 2,643,403 and 2,643,445, published April 7, 1977, disclose the use of N-~alkylthiocarbonylethyl)acetanilides for controlling fungi, particularly those of the class Phycomycetes.
Netherlands Patent Publication No. 152,849, published April 15, 1977, discloses the use of N-~alkoxymethyl)acetanilides as fungicides.
Belgian Patent No. 867,556, published November 27, 1978, dis-closes 3-~N-cyclopropylcarbonyl-N-arylamino)-gamma-butyrolactones.
Belgian Patent No. 863,615, published August 3, 1978, discloses fungicidal 3-~N-acyl-N-arylamino)-gamma-butyrolactones.
It has been found that 3-~N-thionoacyl-N-arylamino-gamma-butyrolac-tones and butyrothiolactones are effective for the control of fungi, espe-cially for downy mildew fungal infection caused by fungal species of the Peronosporaceae family and late blight fungal infection caused by Phytophthora infestans. Some of the compounds of the invention are effec-tive both as protectant fungicides, i.e., they prevent or protect against fungal infections, and as eradicant fungicides, i.e., they eliminate and cure established infections. The compounds of the invention are especially l~S8~;S4 preferred for the control of grape downy mildew.

The invention provides a compound of the formula C - Rl Ar-N (III) \ CH - CH2 X=C CH-R
\ y/

wherein Ar is phenyl, naphthyl, or phenyl or naphthyl substituted with 1 to 4 of the same or different substituents selected from fluoro, chloro, bromo alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; R is hydroxymethyl, halomethyl of 1 to 3 of the same or different halogens select-ed from fluoro, chloro or bromo, alkoxyalkyl of 2 to 6 carbon atoms, alkyl-thioalkyl of 2 to 6 carbon atoms, phenylthioalkyl of 7 to 10 carbon atoms, phenoxyalkyl of 7 to 10 carbon atoms, phenylthioalkyl or phenoxyalkyl of 7 to 10 carbon atoms substituted on the phenyl ring with 1 to 2 of the same or different substituents selected from fluoro, chloro, bromo, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 car-bon atoms, or cycloalkyl of 3 to 6 carbon atoms substituted with 1 to 4 of the same or different substituents selected from alkyl of 1 to 4 carbon atoms, fluoro, chloro, bromo, hydroxy or alkoxy of 1 to 4 carbon atoms;
and R is hydrogen, chloro, bromo, alkyl of 1 to 6 carbon atoms, phenyl or phenyl substituted with 1 to 2 of the same or different substituents select-ed from fluoro, chloro, bromo or alkyl of 1 to 6 carbon atoms; Y is 0, S or -NR- wherein R is hydrogen or alkyl of 1 to 4 carbon atoms; and X is O or S.
Representative substituted-phenyl groups which Ar may represent are 2-fluorophenyl, 2,4-dichlorophenyl, 3,5-dibromophenyl, 4-methylphenyl,

2,6-diethylphenyl, 4-methoxyphenyl, 4-nitrophenyl, 2,6-dimethyl-4-chloro-phenyl, 213,6-trimethylphenyl, 2,3,5,6-tetramethylphenyl. Preferred substi-tuted-phenyl Ar groups are phenyl substituted with 1 to 2 of the same or different substituents selected from chloro, bromo, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms. Most preferred substituted-phenyl Ar groups are 2,6-dialkylphenyl, especially 2,6-dimethylphenyl.
Representative substituted-naphthyl Ar groups are l-naphthyl, 2-naphthyl, 1-methyl-2-naphthyl, 4-methyl-2-naphthyl, 4-methyl-1-naphthyl, 2-chloro-1-naphthyl, 2-methoxy-1-naphthyl, 2,4-dimethyl-1-naphthyl and 2,7-dimethyl-l-naphthyl. Preferred substituted naphthyl Ar groups are 2-alkyl-l-naphthyl groups, especially 2-methyl-1-naphthyl.
Representative halomethyl groups which Rl may represent include fluoromethyl, chloromethyl, bromomethyl, dichloromethyl, tribromomethyl and fluorodichloromethyl. The preferred halomethyl Rl group is chloromethyl.
Representative cycloalkyl of Rl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and 4-methylcyclohexyl.
Representative alkoxyalkyl Rl groups are methoxymethyl, ethoxy-methyl~ isopropoxymethyl and n-pentoxymethyl. The preferred alkoxyalkyl group is methoxymethyl.
Representative alkylthioalkyl Rl groups are methylthiomethyl, n-propylthiomethyl and n-pentylthiomethyl.
Representative substituted-phenylthioalkyl and substituted-phenoxy-alkyl Rl groups are 4-chlorophenylthiomethyl, 4-methylphenoxymethyl, 2,4-dichlorophenoxymethyl, 3,5-dimethylphenylthiomethyl and 2-chloro-4-methyl-phenoxymethyl.
Representative alkyl R groups are methyl, ethyl, isopropyl and n-hexyl. Representative substituted-phenyl R2 groups are 2-chlorophenyl, 2,4-dichlorophenyl, 4-methylphenyl and 2,3-dimethylphenyl.
Preferably Ar is phenyl substituted with 1 to 2 of the same or different substituents selected from fluoro, chloro, bromo or alkyl of 1 to 2 carbon atoms, or 2-alkyl-1-naphthyl. The most preferred Ar groups are ~1586~i4 -2,6-dimethylphenyl or 2-methyl-1-naphthyl.
Preferably Rl is alkoxymethyl of 1 to 6 carbon atoms, chloro-methyl or bromomethyl. Most preferably Rl is methoxymethyl or chloromethyl.
When Rl is cycloalkyl of 3 to 6 carbon atoms, then preferably is cyclopropyl when Y=S and cyclopentyl when Y=0.
Preferably R is hydrogen or methyl and X is oxygen.
A preferred class of 3-(N-thionoacyl-N-arylamino) lactones is that represented by the formula '~ 1 (IV) \ CH CH2 R5 0=C CH_R2 \ /

wherein Rl is alkoxyalkyl of 2 to 6 carbon atoms, R2 is hydrogen or methyl, and R4 and R5 individually are methyl or ethyl. Preferred compounds of formula (IV) are those wherein Rl methoxymethyl, R is hydrogen, and R4 and R are methyl.
Representative compounds of the formula (I) are:

3-(N-methoxythionoacetyl-N-2,6-dimethylphenylamino)-gamma-butyrolactone, 3-~N-methoxythionoacetyl-N-2,6-dimethylphenylamino)-gamma-thiobutyrolactone.
The lactone and thiolactone compounds of the invention may be prepared by first alkylating an aniline (X) with an alpha-halo-gamma-butyrolactone or alpha-halo-gamma-thiobutyrolactone (XI) and subsequently acylating the alpha-(N-arylamino)-gamma-butyrolactone or thiobutyrolactone (XII) with an acyl halide ~XIII) to give the intermediate 3-(N-acyl-N-aryl-amino)-gamma-butyrolactone or thiobutyrolactone product (IA), as depicted by the following equations;

~L~L586~4 002 ArNH + X-C~ CH2 base Ar-N~-CH CH
003 2 ~ 2 (1) 005 O-C C~_R2 -~IX O=C l H_R2 007 \ y/ \ y/
009 (XI) (XII) 012 o 013 Ar-NH-C~----CH2 014 + X-C-R -> C-R

015 O=C C H-R Ar-N (2) 018 Y C~ - CH2 019 (XIII) 020 (XII) 1 2 021 O=C CH-R
023 \
025 (IA) 028 wherein Ar, Rl, R2 and Y have the same significance as 029 previously defined, and X is chloro or bromo.
030 The alkylation reaction (1) is conducted in the 031 presence of a base. Suitable bases are inorganic alkali metal 032 carbonates such as sodium carbonates or potassium carbonate or 033 organic amines such as trialkylamines, e.g., triethylamine, or 034 pyridine compounds, e.g., ~yridine or 2,6-dimethylpyridine.
035 Generally, substantially equimolar amounts of reactants (X) and 036 (XI) and the base are employed. In one modification of the 037 reaction, a molar excess of the aniline reactant (X) is used as 038 the base, and no additional base is employed. The reaction is 039 conducted in inert organic solvents, e.g., apolar diprotic 040 solvents such as dimethylformamide and acetoni.rile and 041 aromatic hydrocarbons such as benæene and toluene, at reaction 042 temperatures varying from 25C to 150C, preferably from 50C
043 to 150C. Water may be employed as a co-solvent. The réaction 044 pressure may be atmospheric, subatmospheric or superatmo-045 spheric. ~owever, for convenience of conducting the reaction, 046 the pressure is generally atmos?heric. The reaction time will, 047 of course, vary depending upon the reactants and the re~ction ._ 5_ ~S86S4 temperature. Generally the reaction time is from 0.25 to 24 hours. The product (XII) is generally purified by conventional procedures, e.g., ex-traction, distillation or crystallization, before use in the acylation re-action (2).
Preferred alkylation reaction conditions are given in more detail in Applicants United States Patent 4,165,322 issued ~ugust 21, 1979.
The acylation reaction (2) is conducted by conventional procedures.
The reactants (XII) and (XIII) are generally contacted in substantially equi-molar amounts in an inert organic solvent at a temperature of 0 to 100C.
Suitable inert organic solvents include ethyl acetate, methylene dichloride, dimethoxyethane, benzene, etc. The product is isolated and purified by con-ventional procedures such as extraction, distillation, chromatography, crystallization, etc.
When preparing a butyrolactone product, i.e. a compound in which X and Y=0, an organic amine such as a trialkylamine or a pyridine compound may be employed as an acid acceptor. However, when preparing a butyrothio-lactone product (a compound wherein X=0 and Y=S), an organic amine should not be employed.
The compounds of formula (IA) wherein Rl is alkylthioalkyl, phenylthioalkyl or substituted-phenylthioalkyl may be prepared from the corresponding compound wherein R is haloalkyl by reacting the corresponding haloalkyl compound with an alkali metal mercaptide by conventional procedures as depicted in the following equation (3) in the case where Rl is alkyl-thiomethyl:

o o Il . "

Ar-N + RSM --* Ar-N ~ MX (3) \ CH CH2 \ CH CH

X=C CH-R O=C CH-R
\ y/ \ /

wherein Ar, R2, X and Y are as previously defined, M is alkali metal, R is alkyl, phenyl or substituted phenyl. In reaction (3), Y preferably is oxygen.
The compounds of formula (IA) wherein Rl is hydroxymethyl and Y is oxygen may be prepared by treatment of the corresponding compound wherein is halomethyl with an inorganic alkali metal hydroxide, such as aqueous sodium hydroxide. The compounds of Formula ~IA) wherein Rl is hydroxy-methyl and Y is oxygen or sulfur may be prepared by hydrolysis of the corresponding compound wherein Rl is alkanoylmethyl.
The compounds of formula ~IA) wherein R2 is chloro or bromo are generally prepared by chlorinating or brominating the corresponding compound wherein R is hydrogen with a chlorinating or brominating agent such as N-bromosuccinimide or N-chlorosuccinimide by conventional procedures, as depicted in the following equation (4):

~3~S8654 o o o o !l 1 h 1 1 Ar-N + X-N ¦ ~ Ar-N + HN
CH - CH2 lCo-cH2 CH CH2 "Co-cH2 O=C CH O=C CH-X
/ 2 \ y / ~4) wherein Ar, Rl, Y and X are as previously defined.
The 3-(N-thionoacyl-N-arylamino) butyrolactones and thiobutyro-lactones of the invention are prepared from the corresponding 3-(N-acyl-N-arylamino) butyrolactones and thiobutyrolactones of the formula (II) according to the following scheme:

O S
c_Rl p2s5 c_Rl Ar-N ~ Ar-N
\ Heat o ~ Y / ~ R2 ~ ~ R

(IIA) (XIV) The reaction (5) is carried out at the reflux temperature of the solvent, preferably xylene, with molar ratio of (IIA) to phosphorous penta-sulfide of about 4:1, in the presence of a trace of a base, such as pyridine.
The product (XIV) may be isolated by conventional chromatography.
The thiolactone compounds of the invention may be prepared bycleaving the corresponding lactone (I) with an alkyl mercaptide salt followed by formation of the thiolactone employing a halogenating agent such as phosphorus trichloride, phosphorus pentachloride, thionyl chloride or oxalyl chloride, as depicted by the following equations:

~58654 0~2 O O
88g / CRl l)RSNa / CRl ~ Ar-N > Ar-N (6) 008 ~ 2)H+ ~ \ R
009 ~ R I r 010 ~ O I SR

012 (I) (XV) 8~5 (xv) PC13 018 > Ar-N
019 Heat ~ ~. 2 020 ~ ~ R (7) 024 (IA) 026 wherein Rl, R2 and Ar are as previously defined.

028 The compounds of the invention are useful for control-029 ling fungi, particularly plant fungal infections. However, 030 some fungicidal compositions of the invention may be more fungi-031 cidally active than others against particular fungi. For 032 example, the activity of the preferred compounds of the 033 invention is highly specific for certain fungal diseases such 034 as downy mildews, e.g., Plasmopara viticola (grapes) and 035 Peronospora parasitica (cabbage and collard), late blights, 03~ e.g., Phytophthora inestans tomatoes and potatoes), and crown 037 and root rots, e.g., Phytopbthora.
038 The compounds of the invention are particularly oig useful fungicides because they cure established ungal infec-040 tions. This permits economical use of the fungicides of the in-041 vention, because they need not be applied to plants unless 042 fungal infection actually occurs. Thus, a preventative progr~m 043 of apolying fungicides against potential fungal infection is 044 not necessary.

r~

002 When used as fungicides, the compounds of the inven-003 tion are applied in fungicidally effective amounts to fungi 004 and/or their habitats, such as vegetative hosts and nonvegeta-005 tive hosts, e.g., animal products. The amount used will, of 006 course, depend on several factors such as the host, the type of 007 fungus and the particular compound of the invention. As with 008 most pesticidal compounds, the fungicides of the invention are 009 not usually applied full strength, but are generally incorpo-010 rated with conventional, biologically inert extenders or 011 carriers normally employed for facilitating dispersion of 012 active fungicidal compounds, recognizing that the formulation 013 and ~,ode of application may affect the activity of the fungi-014 cide. Thus, the fungicides of the invention may be formulated 015 and applied as granules, as powdery dusts, as ~ettable powders, 016 as emulsifiable concentrates, as solutions, or as any of 017 several other known types of formulations, depending on the 018 desired mode of application.
019 ~Jettable powders are in the form of finely divided 020 particles which disperse readily in water or other dispersant.
021 These compositions normally contain from about 5-80% fungicide, 022 and the rest inert material, which includes dispersing agents, 023 emulsifying agents and wetting agents. The powder may be 024 applied to the soil as a dry dust, or preferably as a suspen-025 sion in water. Typical carriers include fuller's earth, kaolin 026 clays, silicas, and other highly absorbent, wettable, inorganic 027 diluents. Typical wetting, dispersing or emulsifying agents 028 include, for example: the aryl and alkylaryl sulfonates and 029 their sodium salts, alkylamide sulfonates, including fatty 030 methyl taurides; alkylaryl polyether alcohols, sulfated higher 031 alcohols and polyvinyl alcohols; 2olyethylene oxides, sul-032 fonated animal and vegetable oils; sulfonated petroleum oils, 033 fatty acid esters of polyhydric alcohols and the ethylene oxide 034 addition products of such esters; and the addition products of 035 long-chain mercaptans and ethylene oxide. ilany other ty~es of 03~ useful surface-active agents are available in commer~e. The 037 surface-active agent, when used, normally comprises from l~ to 038 l~ by weight of the fungicidal composition.

~586S4 002 Dusts are freely flowing admi~tures of the active 003 fungicide with finely divided solids such as talc, natural 004 clays, kieselguhr, pyrophyllite, chalk, diatomaceous earths, 005 calcium phosphates, calcium and magnesium carbonates, sulfur, 006 lime, flours, and other organic and inorganic solids which act 007 as dispersants and carriers for the toxicant. These finely 008 divided solids have an average particle size of less than about - 009 50 microns. A typical dust formulation useful herein contains 010 75~ silica and 25% of the toxicant.
011 Useful liquid concentrates include the emulsifiable 012 concentrates, which are homogeneous liquid or paste composi-013 tions which are readily dispersed in water or other dispersant, 014 and may consist entirely of the fungicide with a liquid or 015 solid emulsifying agent, or may also contain a liquid carrier 016 such as xylene, heavy aromatic naphthas, isophorone, and other 017 nonvolatile organic solvents. For application, these concen-018 trates are dispersed in water or other liquid carrier, and are 019 normally applied as a spray to the area to be treated.
020 Other useful formulations for fungicidal applications 021 include si~ple solutions of the active fungicide in a disper-022 sant in which it is completely soluble at the desired con-023 centration, such as acetone, alkylated naphthalenes, xylene, or 02~ other organic solvents. Granular formulations, wherein the 025 fungicide is carried on relatively coarse particles, are of 026 particular utility for aerial distribution or for penetration 027 of cover-crop canopy. Pressurized sprays, typically aerosols 028 wherein the active ingredient is dispersed in finely divided 029 form as a result of vapori~ation of a low-boiling disoer~ant 030 solvent carrier, such as the Freons, may also be used. All of 031 those techniques for formulatIng and applying fungicides are 032 well known in the art.
033 The percentases by weight of the fungicide may vary 034 according to the manner in which the composition is to be 035 applied and the particular type of for~ulation, but in general 036 comprise 0.5 to 95~ of the toxicant by weight of the fungicidal 037 composition.

_ / /

002 The fungicidal compositions may be formulated and 003 applied with other active ingredients, including other fungi-004 cides, insecticides, nematocides, bactericides, plant growth OOS regulators, fertilizers, etc.
00~ Examples 007 The preparation and fungicidal activity of the 008 compounds of the invention is illustrated by the following 009 examples.
010 Example 1 - Preparation of 3-(N-methoxyacetyl-011 N-2,6-dimethylphenylamino)-gamma-thiobutyrolactone 012 A solution of 1.46 g (0.0135 mol) methoxyacetyl-013 chloride in 10 ml dichloromethane was added dropwise to a 014 refluxing solution of 3 g (0.0135 mol) 3-(N-2,6-dimethyl-015 phenylamino)-gamma-thiobutyrolactone in 200 ml toluene. The 015 reaction mixture was heated at reflux for 3 hours and 017 evaporated to give a solid. The solid was recrystallized from 018 a 10:1:10 solvent mixture of ether:benzene:hexane to give 1.8 g 019 of the product, as a tan solid, m.p. 86-87C. The infrared 020 spectrum of the product showed two strong carbonyl absorption 021 bands at 5.85 microns and 6.03 microns.
022 Example 2 - Preparation of 3-(N-acetoxyacetyl-023 N-2,6-dimethylphenylamino)-gamma-butyrolactone 025 A 13.7-g (0.1-mol) sample of acetoxyacetyl chloride 025 was added drop~ise to a solution of 20.5 g (0.1 mol) N-2,6-027 dimethylphenylamino-gamma-butyrolactone and 7.9 g (0.1 mol) 028 pyridine in 150 ml benzene. After completion of the addition, 029 the reaction mixture was stirred at about 25C for 4 hours, 030 then washed with water, dried over magnesium sulfate and 031 evaporated under reduced pressure to give an oily residue. The 032 residue was crystallized from ethyl ether/hexane to give 27.3 g 033 of product, m.p. 90-91C.
034 3-(~-cyclopropylcarbonyl-i~-2, 6-dimethylphenylamino)-035 gamma-butyrolactone can be made in an analogous manner using 03~ cyclopropylcarbonyl chloride and N-2, o-dimethylphenylamino-037 gamma-butryolactone as starting materials.

~.r~t365i4 002 Example 3 - Preparation of N-hydroxyacetyl-003 N-2,6-dimethylphenylamino-gamma-butyrolactone 005 A solution of 50 g (0.18 mol) 3-(N-chloroacetyl-N-2,6-006 dimethylphenylamino)-gamma-butyrolactone, 14.5 g (0.36 mol) 007 sodium hydroxide dissolved in 50 ml water, and 450 ml 008 dimethoxyethane was stirred at about 25C for 16 hours. The 009 resulting reaction mixture was filtered, diluted with 500 ml 010 dichloromethane. Hydrogen chloride gas was bubbled into the 011 reaction mixture for 1 hour. The reaction mixture was 012 filtered, dried over magnesium sulfate, and evaporated under 013 reduced pressure. The residue was washed with 109~ ethyl 014 ether/90% hexane, filtered and air-dried to give 30.5 g of the 015 product as a white crystalline solid, m.p. 173-174C.
017 Example 4 - Preparation of N-ethoxyacetyl-018 N-2 6-dimeth l~henvlamino-aamma-butYrolactone Y .~
020 A 6.2-9 (0.05-mol~ sample of ethoxyacetyl chloride 021 wasadded dropwise to a refluxing solution of 10.3 (0.05 mol) 022 3-(N-2,6-dimethylphenylamino)-gamma-butyrolactone in 150 ml 023 toluene. The reaction mixture was then heated under reflux for 024 2 hours. After cooling, the reaction mixture was washed with 025 water, washed with saturated sodium bicar~onate solution, 026 washed with water, dried over magnesium sulfate and evaporated 027 to give 11.2 5 of 3~ ethoxyacetyl-N-2,6-dimethylphenyl-028 amino)-gamma-butyrolactone, m.p. 73-75 C.
030 Example S - Preparation of N-methylthioacetyl-031 N-2,6-dimethylphenylamino)-gamma-butyrolactone 033 A 22-g (0.3-mol) sample of sodium methylmercaptide 934 was added in small portions to a solution of 25.3 g (0.08 mol) 035 N-~romoacetyl-N-2,6-dimethylphenylamino)-gamma-butyrolactone, 036 m.p. 11~-117C, in 200 ml dimethyl sulfoxide. A mild exotherm 037 ensued. The reaction mixture was allowed to stir at about 25 C
038 for about lo hours. The reaction mixture was then heated to 039 about liOC under reduced water aspirator pressure to remove a 040 portion of the dimethyl sulfoxide solvent. The residue was 041 dlluted with -Yater and the aqueous layer separated. The 042 organic portion was dissolved in 350 ml dichloromethane, _ l3 --115~654 washed with water, dried over magnesium sulfate and evaporated under reduoe d pressure to give an oil. The oil was chromatographed through a silica gel column (20% acetone/80% petrole~m ether elution) to give the product (11 g), which after crystallization from ethyl ether/aoe tone melted at 77-78& .
Example 6 - Preparation of 3-(N-methoxyacetyl-N-2-m.ethylnaphth-l-ylamLno-gamma-butyrolactone A 2.4-g (0.022-mol) sa~ple of methoxyacetyl chloride was added drop-wise to a solution of 5.5 g (0.022 mol) 3-(N-2-methylnaphth-1-ylamino)-gamma-butyrolactone and 1.7 g (0.022 mol) pyridine in 100 ml dichloromethane. The reaction mixture was stirred one hour at about 25 & and then heated under re-flux for 6 hours. After cooling overnight, the reaction mixture was washed suc oessively with water, saturated sodium bi OE bonate solution, water, dried over magnesium sulfate and evaporated under reduoed pressure. m e residue was chromatographed through a silica gel column. Elution with 25% aoetone/
75% petroleum ether gave 4.3 g of the product, m.p. 42-46 &.
Example 7 - Preparation of 3-(Nimethoxythionoacetyl-N-2,6-dimethylphenylamino)-gamma-thiobutyrolactone A slurry of phosphorus pentasulfide (6.0 g) in 300 ml xylene was heated under a Dean Stark water separator to azeotropically remDve any water present.
After cooling to 100C pyridine (2 ml) was added followed by 3-(N-methoxyaoetyl-3-N-2,6-dimethylphenylamino)-gamma-butyrolactone (33.3 g). The stirred slurry was heated at 150. After about 45 minutes, the phosphorus pentasulfide dissolved and the mixture was kept at 150 over a weekend.
The mLxture was diluted with an equal volume of methylene chloride and washed with saturated sodium bicarbonate (200 ml), water (200 ml) and dried (MgSO4).
The solution was filtered and the filtrate was stripped in vacuo to yield a dark oil which was chromatographed on silica gel (300 g) by elution with petroleum ether, 80~ petroleum ether in ethyl ether, 70% petroleum ether in ethyl ~' ~158654 002 ether, 60% petroleum ether in ethyl ether, 40~ petroleum ether 003 in ethyl ether and 25~ petroleum ether in ethyl ether.
004 The oil isolated from the petroleum ether: ethyl 005 ether elutions were dissolved in methylene chloride and treated 006 with charcoal and MgSO4, filtered and stripped to yield the 007 title product as an oil (1.8 g). The product is reported as 008 compound 10 in Table B.
010 Example 8 - Preparation of 3-(N-crotonyl-011 N-2,6-dimethylphenylamino)-gamma-butyrolactone 013 Crotonic acid (~ g) and thionyl chloride (12 g) were 014 refluxed for one hour and the excess thionyl chloride was 015 removed in vacuo. 3-(N-2,6-dimethylphenylamino)-gamma-butyro-015 lactone (14 g) was added with 150 ml toluene and refluxed for 2 017 hours.
018 The mixture was washed with water, saturated sodium 019 bicarbonate, dried (;~gSO4), filtered and stripped of solvent.
020 The product was chromatographed on 2~0 g silica gel; elution 021 with acetone/ether/petroleum ether to yield 3.1 g of the title 022 product, m.p. 122-123C. The product is reported as comound 3 023 in Table A.
025 Example 9 - Preparation of 3-(U-3-methyl-2,3-epoxy-026 butanoyl-N-2,6-dimethylphenylamino)-gamma-butyrolactone 028 3-(~1-3-methyl-crotonyl-N-2,6-dimethylphenylamino)-029 gamma-butyrolactone (A) was prepared as in E~ample 8 using 030 3-methyl-crotonic acid as a starting material. Product A
031 (9 g), 3-chloro-perbenzoic acid (6 g) and KH2PO4 (4.7 g) in 032 75 ml dichloromethane were refluxed for 48 hours.
033 The mixture was washed with water, dried (lSgSO4), 034 stripped. The residue was crystallized in ether/hexane to 035 yield 5.4 g of the title pro9duct, m.p. 100-104C. The product 036 is reported as Compoun~ 7 in Table A.
037 ~xample 10 -- E1ycelial Inhibition 038 Compound 2 of the present invention was evaluate~ for 039 fungicidal effectiveness by means of a mycelial inhi~ition 040 test. This test is designed to measure the fungitoxic activity 041 of fungicidal chemicals in terms of their degree of in~ibition 042 of mycelium growth. Compound 2 was dissolved in acetone to 50G

15 _ r ,~

~LS86S4 .

002 ppm concentration. Paper strips were inoculated with Pythium 003 ultimum mycelium growth by covering the paper with a potato 004 dextrose broth culture of mycelial suspension. The inoculated 005 papers were then placed on potato dextrose agar plates and 006 sprayed by means of a micro sprayer with the fungicidal solu-007 tion. The treated paper strips were incubated at 25C and data 008 is taken after 24 hours. Fungicidal activities are measured by 009 a zone of inhibited mycelial growth from the center of the 010 paper strip. The effectiveness of Compound 2 tested for 011 fungicidal activity is lO0~ in terms of percent inhibition 012 relative to Difolatan.
013 Example 11 - Tomato Late Blight 014 Compounds of the invention were tested for the preven-015 tative control of the Tomato Late ~light organism Phytophthora 01~ infestans. Five- to six-week-old tomato (cultivar Bonny Best) 017 seedlings were used. The tomato plants were sprayed with a 250-018 ppm suspension of the test compound in acetone, water and 2 019 small amount of a nonionic emulsifier. The sprayed plants were 020 then inoculated one day later with the organism, placed in an 021 environmental chamber and incubated at 6~-68F and 100~
022 relative humidity for at least 16 hours. Following the incuba-023 tion, the plants were maintained in a greenhouse at 60-80%
024 relative humidity for approximately 7 days. The percent 025 disease control provided by a given test compound was based on 025 the percent disease reduction relative to untreated check 027 plants. The results are tabulated in Tables I and II. In the 028 Tables, the test concentration is 250 ppm unless otherwise 029 indicated ~y the figures in parentheses.
030 Example 12 - Celery Late Blight 031 The celery late blight tests were conduct2d using 032 celery (Utah) plants 11 weeks old. The celery late blight 033 organism was Septoria a~ii. The celery plants were sprayed 03~ with solutions of the candidate toxicant mixed with acetone, 035 water and a nonionic emulsifier. The plants were then inocu-03~ lated with the organism and placed in an environmental chamber 037 and incubated at 66-o8F in lO0~ relative humi~ity for an _ /6 -?. ' ` j ~

11586~i4 002 extended period of time (approximately 48 hours). Following 003 the incubation the plants were allowed to dry and then were 004 maintained at a 60-80% relative humidity for approximately 14 005 days. The percent disease control provided by a given candi-006 date toxicant is based on the percent disease reduction 007 relative to untreated check plants. The results are reported 008 in Tables I and II.
ûO9 Example 13 - Grape Downy .~lildew Control 010 The compounds of the invention were tested for the Oll control of the grape downy mildew organism Plasmopara viticola.
012 Detached leaves, between 70 and 85 mm in diameter, of 7-wee.~-013 old Vitis vinifera cultivar Emperor grape seedlings were used 014 as hosts. The leaves were sprayed with a solution of the test 015 compound in acetone. The sprayed leaves were dried, inoculated 016 with a spore suspension of the organism, placed in a humid envi-017 ronmental chamber and incubated at 18-22C and about 100%
018 relative humidity. Seven to nine days after inoculation, the Ol9 amount of disease control was determined. The percent disease 020 control provided ~y a given test compound was based on the 021 percent disease reduction relative to untreated check plants.
022 The results are tabulated in Tables I and II.
023 Exam~le 14 - Tomato Early 31i~ht 024 Compounds of the invention were tested for the 025 control of the Tomato Early Blight organism, Alternaria solani 02~ conidia. Tomato (variety Bonny Best) seedlings of 6 to 7 wee3cs 027 old were used. The tomato plants were sprayed with a 250-ppm 028 solution of the test compound in an acetone-and-water solution 029 containing a small amount of a nonionic emulsifier. The 030 sprayed plants were inoculated one day later with the organism, 031 dried and maintained at oO-80~s rslative humidity for about 12 032 days. Percent disease control was based on the percent dise2se 033 development on untreated checlc plants. Ths compounds tested 034 and the results are tabulated in Table I and II.

. ~586~4 002 Example 15 - Powdery ~ildew 003 The powdery mildew test was made using bean seedlings 004 (var. Bountiful) with well-developed primary leaves. The 005 pathogen was Erysiph_ poly~oni. The bean seedlings were 00~ sprayed with a 250-ppm solution of the test compound in an 007 acetone-water mixture containing a nonionic emulsifier. The 008 treated plants were inoculated one day after spray application 009 of the test compound with the pathogen. The plants were then 010 maintained in a qreenhouse at a 60-80% relative humidity and at 011 a temperature of 68-70~. The rate of infection on the leaves 012 was made after about 10 days. The percent disease control pro-013 vided by a given test compound was based on the disease reduc-014 tion relative to untreated check plants. The results are 015 reported in Table II.
016 Example 16 - Leaf Rust 017 The leaf-rust was made using pinto beans. The 018 pathogen was Uronyces phaseoli tipica. The pinto-bean plants 019 were sprayed with a 250-ppm solution of the test compound in an 020 acetone-water mixture containing a nonionic emulsifier. The 021 treated plants were inoculated thereafter with the pathogen and 022 then incubated in an environmental chamber for approximately 20 023 hours at 100~ relative humidity and a temperature of 68-70F.
024 The plants were then removed from the chamber, allowed to dry, 025 and then maintained in a-greenhouse at a oO-80~ relative 0~6 humidity. The rate of infection on the leaves was made a~ter 027 about 14 days. The percent disease control provided by a given 028 test compound was based on the disease reduction relative to 029 untreated check plants. The results are reported in Table II.
031 Example 17 - Preparation of 3-(~1-cyclopentyl-032 carbonvl-N-2,6-di~ethvlPhenYlamino)-qamma-butvrolactone 034 A 5.7 g. (.043 mol) sample of cyclopentylcar~onyl 035 chloride was added dropwise to a solution of 8.8 g. (.043 mol) 03~ 2~-2,6-dimethylphenylamino-ga~ma-butyrolactone in 100 ml 037 toluene. After completion of the addition, the reaction mix-038 ture was refluxed overnight, then washed with water, saturated ~SB6Si4 00~ sodium carbonate solution and again with water, dried over 003 magnesium sulfate and evaporated under reduced pressure to give 004 an oily residue. The residue was crystallized from ethyl ether 005 to give 6.1 g of product, m.p. 109-113C. This product is tabu-006 lated in Table C as Compound No. Cl.
008 Example 18 - Preparation of 2-(~-cyclopropylcarbonyl-009 2,6-dimethylanilino)-4-(t-butylthio)-butanoic acid 011 To 4.2 g. t-bùtylmercaptan in 100 ml 1,2-dimethoxy 012 ethane was added 2.5 g. sodium methoxide with stirring.
013 A sample of 3-(cyclopropylcarbonyl-2,6-dimethyl-014 anilino)-butryolactone (11.6 g., made as in Example 1) was 015 added to the reaction mixture and stirred at room temperature Olo overnight and poured into ice water.
017 The mixture w~s washed with 2 x 100 ml toluene and 018 the toluene was backwashed with water. The aqueous phase was 019 acidified (p~ 1) with 12N HCl, then extracted twice with 020 methylene chloride. The methylene chloride extracts were 021 washed with water, dried (MgSO4), filtered and stripped to 022 yield the title product, 10.6 g. (oil).
024 Example 19 - Preparation of 3-(N-cyclopropylcarbonyl 025 2,6-dimethylanilino)-butyrothiolactone 027 The acid produced in Example 18 (10.~ g.) was 028 dissolved in 200 ml methylene chloride in a flask equipped with 029 a condensor, cooled to -20C then PC13 (6.0 g.) was added 030 dropwise. The exothermic reaction caused the mixture to warm 031 to 36C. t~ore methylene chloride was added and the mixture was 032 allowed to stand overnight at room temperature, whereupon two 033 phases formed.
034 The methylene chloride layer was collected, dried 035 (~gSO4, Silica gel), filtered and stripped. The resultant oil 03~ was crystallized in petroleum ether to yield the title product, 037 m.p. 145-147C.
038 The compounds tabulated in Table C were prepared oy 039 procedures similar to those of Examples 17-19. The structure 040 of each compound tabulated in tAe Tables was confir~ed oy 041 nuclear magnetic resonance spectroscopy and/or infrared 042 spectral analysis.

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020 GD-I = Grape Downy ~ildew 021 TLB = To~ato Late Blight 022 CLB = Celery Late Blight 023 TEB = Tomato Early Blight 024 BR = Bean Rust 025 BP.~ = Bean Powdery Mildew - ~ S _

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A compound of the formula (III) wherein Ar is phenyl, naphthyl, or phenyl or naphthyl substituted with 1 to 4 of the same or different substituents selected from fluoro, chloro, bromo alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; R1 is hydroxymethyl, halomethyl of 1 to 3 of the same or different halogens select-ed from fluoro, chloro or bromo, alkoxyalkyl of 2 to 6 carbon atoms, alkyl-thioalkyl of 2 to 6 carbon atoms, phenylthioalkyl of 7 to 10 carbon atoms, phenoxyalkyl of 7 to 10 carbon atoms, phenylthioalkyl or phenoxyalkyl of 7 to 10 carbon atoms substituted on the phenyl ring with 1 to 2 of the same or different substituents selected from fluoro, chloro, bromo, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 car-bon atoms, or cycloalkyl of 3 to 6 carbon atoms substituted with 1 to 4 of the same or different substituents selected from alkyl of 1 to 4 carbon atoms, fluoro, chloro, bromo, hydroxy or alkoxy of 1 to 4 carbon atoms;
and R2 is hydrogen, chloro, bromo, alkyl of 1 to 6 carbon atoms, phenyl or phenyl substituted with 1 to 2 of the same or different substituents select-ed from fluoro, chloro, bromo or alkyl of 1 to 6 carbon atoms; Y is O, S or -NR- wherein R is hydrogen or alkyl of 1 to 4 carbon atoms; and X is O or S.

2. A compound according to Claim 1 wherein Ar is 2,6-dialkylphenyl, Y is oxygen or sulfur, and R2 is hydrogen.

3. A compound according to Claim 1 wherein X is oxygen and Ar is 2,6-dialkylphenyl.

4. A compound according to Claim 3 wherein Ar is 2,6-dimethylphenyl, R2 is hydrogen, R1 is methoxymethyl and Y is oxygen or sulfur.

5. A compound according to Claim 4 wherein Y is sulfur.

6. A method for the control of fungi which comprises contacting said fungi or their habitats with a fungicidally effective amount of a compound as defined in Claim 1, 2 or 3.

7. A method for controlling the growth of Phytophthora infestans fungi which comprises applying to said fungi or their habitats a fungicidal-ly effective amount of a compound as defined in Claim 1, 2 or 3.

8. A method for controlling the growth of Plasmopara viticola fungi which comprises applying to said fungi or their habitats a fungicidally effective amount of a compound as defined in Claim 1, 2 or 3.