Note: Descriptions are shown in the official language in which they were submitted.
~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
-- 1 --
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
I 1 2
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-
1158654
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
001
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 2 -HX
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:
1158654
o o
Il . "
C-CH2X C-CH2SR
Ar-N + RSM --* Ar-N ~ MX (3)
\ CH CH2 \ CH CH
I 1 2 1 1 2
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
C-R C-CH2 C-R C-CH2
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:
8 -
~58654
001
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
011 0 C02H
012 (I) (XV)
014
015 CR
8~5 (xv) PC13
018 > Ar-N
019 Heat ~ ~. 2
020 ~ ~ R (7)
022 D S
023 O
024 (IA)
026 wherein Rl, R2 and Ar are as previously defined.
027 UTILITY
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~
11S86S4
001
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.
/0 --
~586S4
001
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.
_ / /
1158654
001
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
001
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
- 14 -
~'
~158654
001
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
.
001
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
001
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.
/ 1 -
. ~586~4
001
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
001
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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001
002 TABLE I
004 ~ Control
005Grape Downy Tomato Late Celery Late Tomato Early
--006 No. ~ildew Blight BlightBlight
007
008
009 1 89 0 65 7
010 2 54 0 23 0
011 3 100 100 33 29
012 4 100 57 94 29
013 5 18 23 23 18
014 o 54 13 57 8
015 7 -- 14 11 11
016 8 -- 0 50 11
017 9 100 98 37 0
018 10 100 99 50
019 11 100 71 23 0
020 12 100 84 36 0
021 13 100 96 44 0
022 14 100 96 44 0
023 15 100 89 11 0
024 16 100 84 37 0
025 17 100 37 -- o
026 18 83 0 -- 0
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001 1~5i8~:iS~L
002 TABLE II
004 FUNGICIDAL EFFICACY
008 No. GDM TLB CLB TEB RR BPM
010 C1 - 81 19 0 0 ~ 10
011 C2 - 50 19 0 0 0
012 C3 - 0 7 0 0 4
013 C4 98 71 19 0 29 4
014 CSA 99 6 44 21 0 0
015 CSB 99 13 44 55 0 23
016 C6 13 11 0 0 0 98
.
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 _
