Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
1~ ~7340
This invention relates to fungicidal 3-(N-acyl-N-
arylamino)- and 3-(N-thionoacyl-N-arylamino)-gamma-butyro-
lactones and gamma-thiobutyrolactones.
United States Patent No. 3,933,860, issued
~anuary 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. ~,141,989, issued
February 27, 1979, all to David Cheong King Chan, disclose the
use of a large class of 3-(N acyl-N-arylamino) lactones and
3-(N-acryl-N-arylamino) lactams as protectant fungicides.
United States Patent No. 4,03~,108 r 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-haloacetylanilines are preventive
and curative fungicides.
German Patent Publication Nos. 2,643,403 and 2,643,445,
published Aprll 7, 1977, disclose the use of N-(alkylthio-
carbonylethyl)acetanilides for controlling fungi, particularly
those of the class Ph~comycetes.
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,
discloses 3-(N-cyclopropylcarbonyl-N-arylamino)-gamma-butyro-
lactones.
Belgian Patent No. 863,615, publish~d August 3, 1978,
discloses fungicidal 3-(N-acryl-N-arylamino)-gamma-
butyrolactones.
It has been found that 3-(N-acyl-N-arylamino)- and
3-(N-thionoacyl-N- arylamino-gamma-butyrolactones and
butyrothiolactones are effective for the control of fungi,
especially for downy mildew fungal infection caused by fungal
. ' -1- ~
73~0
species of the Peronosporaceae family and late blight fungal
infection caused by Phytop_thora infest~ns. In particular,
novel fungicidal compounds have been found wherein the N-acyl
group is alkenyl carbonyl and alkenyl oxide carbonyl. Novel
fungicidal N-thionoacyl compounds have also been found. Some
of the compounds of the invention are effective 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 preferred for the control of grape
downy mildew.
The invention provides a compound of the formula
W
C R
Ar-N
CH fH2 (I)
X= ~CH-R
wherein Ar is phenyl, naphthyl, or phenyl or naphthyl substituted
with 1 to 4 of the same or di~ferent substituents selected from
fluoro, chloro, bromo, alkyl of 1 to 4 carbon atoms or alkoxy
of 1 to 4 carbon atoms; Rl is alkenyl of 2 to 6 carbon atoms,
opcionally substituted by halogen or alkoxy of 1 to 4 carbon
atoms, alkenyl oxide of 2 to 6 carbon atoms; 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
selected from fluoro, chloro, bromo and 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; W is O or S, and X is O or S.
Representative substituted-phenyl groups which Ar may
represent are 2-fluorophenyl, 2,4-dichlorophenyl, 3,5-dibromo-
phenyl~ 4-methylphenyll 2,6-diethylphenyl, 4-methoxyphenyl,
~ -2-
~7340
4-nitrophenyl, 2,6-dimethyl-~-chlorophenyl, 2,3,6-trimethyl-
phenyl, 2,3,5,6-tetramethylphenyl. Preferred substituted-
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- dialkyl-
phenyl, especially 2,6-dim~thylphenyl.
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-
l-naphthyl, 2,4-dimethyl-1-naphthyl and 2,7-dimethyl-1-naphthyl.
Preferred substituted naphthyl Ar groups are 2-alkyl-1-naphthyl
groups, especially 2-methyl-1-naphthyl.
Representative alkenyl Rl groups are vinyl, 2-methyl-
vinyl, 2,2-dimethylvinyl, l-methylvinyl, allyl, isopropenyl,
butenyl, 3-methoxyprop-1-en-1-yl, 3-chloro-prop-1-en-1-yl.
The preferred alkenyl groups are vinyl, 2-methylvinyl and
2,2-dimethylvinyl.
Representative Rl alkenyl oxide groups are oxiranyl,
l-methyloxiran-l-yl, 2,2-dimethyloxiran-1-yl, 2-methyloxiran-
l-yl.
Representative alkyl R2 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 2,6-dimethylphenyl
or 2-methyl-1-naphthyl.
Preferably Rl i5 vinyl, allyl, 2-methylvinyl or
2,2-dimethylvinyl.
,~. .j
~ -3
734~
Representative X and W are both oxygen. Preferably R2
is hydrogen or methyl.
A preferred class of N-phenylamino- and N-substituted
phenylaminolactones is that represented by the formula (II)
R O
,~ C_Rl
~/ \ ~ N
(II)
\ R5 CH - CH2
O=C \ ~CH-R
wherein Rl is alkenyl of 2 to 6 carbon atoms or alkenyl oxide
bf 2 to 6 carbon atoms, R2 is hydrogen or methyl, and R4 and R5
individually are methyl or ethyl, and Y is O or S. Particularly
preferred compounds of formula (II) are those wherein Rl is
vinyl, 2-methylvinyl, 1,2-epoxypropyl or 2,2-dimethylvinyl,
R2 is hydrogen and R4 and R5 are methyl.
The 3-~N-thionoacyl-N-arylamino) lactones and thio-
lactones of the invention may be represented by the formula
S :
c_Rl
Ar-N
\ (III)
CH - CH2
X= ~ ~ H-R
wherein Ar is phenyl, naphthyl or substituted phenyl or naphthyl
as previously defined, and Rl, X,~Y and R2 have -the same
significance as previously defined.
-4-
73~
Representative compounds of the formula (I) are:
3-(N-acryloxy-N-2,6-dimethylphenylamino)-gamma butyrolactone,
3-(N-3-methylcrotonyl-N-2,6-dimethylphenylamino)-gamma-
butyrolactone,
3-(N-crotonyl-N-2,6-dimethylphenylamino)-gamma-butyrolactone,
3-(N-acryloyl-N-2,6-dimethylphenylamino)-gamma-thio-
butyrolactone,
3-(N-2-methylacryloyl-N-2-methyl-6-ethylphenylamino)-gamma-
butyrolactone,
3-(N-3-methyl-2,3-epoxy-butanoyl-N-2,6-dimethylphenyl-
amino)-gamma-butyrolactone,
3-(N-2~methyl-2,3-epoxy-propanoyl-N-2,6-dimethyl-phenyl-
amino)-gamma-butyrolactone.
The lactone and thiolactone compounds o~ the invention
may be prepared by alkylating an aniline (X) with an alpha-halo-
gamma-butyrolactone or alpha-halo-gamma-thiobutyrolactone (XI)
and subsequ~ntly acy~ating the alpha-(N-arylamino)-gamma-
butyrolactone or thiobutyrolactone (XII) with an acyl halide
(XIII) to give the 3-(N-acyl-N-arylamino)-gamma-butyrolactone
or thiobutyrolactone product (IA), as depicted by the following
equations;
--5~
1~473~
~3 ool G
002 ArNH ~ X-CH - CH2 base Ar-NH-CH CH
2 ~ R -HX o=l ¦EI-R2
007 \Y/ \Y/
009 (XI) (XII)
012 O O
013 Ar-NH-CH~---CH2
014 l l + X-C-R > C-R
015 l l 2 -HX
016 O=C CH-R Ar-N (2)
018 Y CH - CH
019 (XIII) I 1 2
020 (XII) ¦ 1 2
021 O=C CH-R
\ /
023 ~
025 (IA)
028 wherein Ar, Rl, R2 and Y have the same slgnificance as
029 previously defined, and X is chloro or bromo.
030 The alkylation reac~ion (1) is conducted in the
031 presence of a base. Suitable bases are inorganic alkali me~al
032 carbonates such as sodium carbonates or potassium carbonate or
033 organic amines such as~ ~rialkylamines, e.g., triethylamine, or
034 pyridine compounds, e.~., oyridine 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 aniIine 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 acetonitrile and
041 aromatic hydrocarbons such as benzene and toluene, at reaction
042 temperatures varying from 25C to 1;0C, preferably from 50C
043 to 150C. Water may be employed as a co-solvent. The reac'ion
044 ?ressure may be atmospheric, subatmospheric or superatmo-
045 spheric. However, for convenience of conducting the reaction,
046 the pressure is generally atmospheric. The reaction time will,
047 of course, vary depending upon the reactants and the reaction
734~
temperature. Generally the reaction time is from 0.25 to 24
hours. The product (XII) is generally purified by conventional
procedures, e.g., extraction, distillation or crystallization,
before use in the acylation reaction (2).
Preferred alkylation reaction conditions are given in
more detail in Applicants United States Patent 4~165,322 issued
August 21, 1979.
The acylation reaction (2) is conducted by conventional
procedures. The reactants (XII) and (XIII) are generally con-
tacted in substantially equimolar amounts in an inert organicsolvent 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 conventional procedures such as extraction, distilla-
tion, chromatography, crystallization, etc.
When preparing a butyrolactone product ~compounds of
formula (I) wherein W, 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 butyrothiolactone product
(compounds of formula tI) wherein W and X-0 and Y=S~, an organic
amlne should not be employed.
Compounds of the formula (IA) wherein Rl is alkenyl
oxide are prepared by oxidizing the corresponding compound
wherein Rl is alkenyl with an oxidizing agent such as 3-chloro-
perbenzoic acid, in the presence of an inorganic base, such as
potassium acid phosphate.
The compounds of formula (IA) wherein R2 is chloro or
bromo are generally prepared by chlorinating or brominating the
corresponding compound wherein R2 is hydrogen with a chlorinating
or brominating agent such as N-bromosuccinimide or N-chloro-
succinimide by conventional procedures, as depicted in the
following equatlon (4):
~ -7-
~734~
001
.
002 O O o o
88~ ~ ~ X-N / ¦ -> Ar-N /
007 CH ----CH2 C-C~2 CH - CH2 C-CH2
00098 ~ I I l O
010 0= C~2 O=C CH-X
012 Y
014 wherein Ar, R , Y and X are as pre~iously defined.
015 The 3-(N-thionoacyl-N-arylamino) butyrolactones and
016 tbiobutyrolactones are prepared from the corresponding
OI7 3-(N-acyl-N-arylamino) butyrolactones and thiobutyrolactones of
018 the formula (II) according to the following scheme:
S
020 ~
021 / C-R 2 5 ''
024 0 ~ ~ ~R2 \ r R2
028 Y
029 (IIA) (XIV)
.
031 The reaction (5) is carried out at the reflux
032 temperature of the solvent, preferably xylene, with molar ratio
033 of (IIA) to phosphorous pentasul~fide of about 4:1, in the
034 presence of a trace of~a base, such as pyridine. The product
035 (XIV) may be isolated by conventional chromatography.
036 The thiolactone compounds of the invention may be
037 prepared by cleaving the corresponding lactone (I) with an
038 alkyl mercaptide salt followed by formation of the thiolactone
039 employing a halogenating agent such as phosphorus trichloride,
040 phosphorus pentachloride, thionyl chloride or oxalyl chloride,
041 as depicted by the following equations:
~73~ -
001 -~-
002
8 8g/CRl l)RSNa /cRl
006 Ar-N - ~ > Ar-2~ (6)
008 ~\ 2)H+ \~\rR
010 D~ ¦ SR
011 0 C02H
012 (I) (XV)
014
OlS CR
8~5(x~) 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 infectlons. ~owever,
030 some fungicidal compositions of the invention may be more fungi-
03~ cidally active than others against particular fungi. For
032 example, the activl~y of the~ preferred compounds of the
033 invention is highly specîfic for certain fungal diseases suc~
~034 as downy mildews, e.g., ~ ~ (grapes) and
035 Peronos~ra parasitica (cabbage and collard) r late ~lights,
036 e.g., ~hytophthora infestans tomatoes and potatoes), and crown
037 and root rots, e.g., Phytophthora.
038 The compounds of the invention are particularly
039 useful fungicides ~because they cure established fungal 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 program
043 of applying fungicides against potential fungal infection is
044 not necessary.
~73~
/o
D ool ~
002 t~hen 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
OOg 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 mode 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 wettable 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 'itettable powders are in the form of finely divided
020 particles which disperse readily in water~ or other dispersant.
021 These compositions normally contain from a~out S-80~ fungicide,
022 and the rest inert material, which includes dispersing agents,
023 emulsifying agents and ~etting~agents. The powder may be
024 applied to the soil as a dry dust, or prererably ~as a suspen-
025 sion in water. Typica1 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; polyethylene oxides, sul-
03~ fonated animal and vegeta~le oils; sulfonat~d 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. ,~any other types or
03~ useful surface-acti~ve agents are available in commerce. The
037 surface-active agent, when used, normally comprises from 1~ to
038 15~ by weight of the fungicidal composition.
~4'73~ -
; D oo~
002 Dusts are freely flowing admixtures 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 useEul 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 nonvolatlle 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 simple solutions of the active fungicide in a disper-
022 sant in which it is completely soluble at the desired con-
023 centration, such as aCQtOne~ alkylated naphthalenes, xylene, or
024 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
023 wherein the active ingredient is dispersed in finely divided
029 form as a result of vaporlzation of a low-boiling dispersant
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 percentages by weight of the ungicide may vary
034 according to the manner in which the composition is to be
035 applied and the particular type of formulation, but in general
036 comprise 0.5 to 9S~ of the toxicant by weight of the fungicidal
037 composition.
~ 734~C~
The fun~icidal compositions may be formulated and
applied with other active ingredients, including other fungicides,
insecticides, ~ematocides, bactericides, plant growth regulators,
fertilizers, etc.
Examples
The preparation and fungicidal activity of the compounds
of the invention is illustrated by the following examples, some
of which are included for reference or comparison purposes only.
Example 1 - Preparation of 3-(N-methoxyacetyl-
N-2,6-dimethylphenylamino)-gamma-thiobutyrolactone
A solution of 1.46 g (0.0135 mol) methoxyacetylchloride
in 10 ml dichloromethane was added dropwise to a refluxing
solution of 3 g (0.0135 mol) 3-(N-2,~-dimethylphenylamino)-gamma-
thiobutyrolactone in 200 ml toluene. The reaction mixture was
heated at reflux for 3 hours and evaporated to give a solid. The
solid was recrystallized from a 10:1:10 solvent mixture of ether:
benzene:hexane to give 1.8 g of the product, as a tan solid, m.p.
86-87C. The infrared spectrum of the product showed two strong
carbonyl absorption bands at 5~85 microns and 6.03 microns.
Example 2 - Preparation of 3-(N-acetoxyacetyl-
N-2,6-dimethylphenylamino)-gamma-butyrolactone
A 13.7-g (0.1-mol) sample of acetoxyacetyl chloride
was added dropwise to a solutlon of 20.5 g (0.1 mol) N-2,6-
dimethylphenylamino-gamma-butyrolactone and 7.9 g (0.1 mol)
pyridine in 150 ml benzene. After completion of the addition,
the reaction mixture was stirred at about 25C for 4 hours,
then washed with water, dried over magnesium sulfate and
e~aporated under reduced pressure to give an oily residue. The
residue was crystallized from ethyl ether/hexane to give 27.3 g
of product, m.p. 90-91C.
3-(N-cyclopropylacrbonyl~N-2, 6-dimethylphenylamino)-
gamma-butyrolactone can be made in an analogous manner using
cyclopropylcarbonyl chloride and N-2, 6-dimethylphenylamino-
gamma-butyrolactone as starting materials.
- -12-
4734
~ J~
001
002 Example 3 - Preparation of N-hydroxyacetyl-
003 N-2,6-dimethy~henylamino-gamma-but~rolactone
005 A solution of 50 g (0.18 mol) 3-(N-chloroacetyl-N-2,G-
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 25 C for 16 hours. The
009 resulting reaction mixture was filtered, diluted with 500 ml
010 dichloromethane. Elydrogen 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 10% ethyl
014 ether/90~ hexane, filtered and air-dried to give 36.5 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-dimethyleheny~amino gamma-butyrolactone
020 A 6.2-g (0.05-mol~ sample of ethoxyacetyl chloride
021 was added 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 bicarbonate solution,
025 washed with water, dried over magnesium sulfate~and evaporated
027 to give 11.2 g of 3-(N-ethoxyacetyl-N-2,6-dimethylphenyl-
028 amino)-gamma-butyrolactone, m.p. 7~3-75C.
030 Example 5 - Preparation of N-methylthioacetyl-
031 ~-~amma-butyroIactone
033 A 22-g (0.3-mol) sample of sodium methylmercaptide
034 was added in small portions to a solution of 25 .3 g (0.08 mol)
035 N-bromoacetyl-N-2,6-dimethylphenylamino)-gamma-butyrolactone,
036 m.p. 116 117C, in 200 ml dimethyl sulfoxide. A mild exotherm
037 ensued. ~he reaction mixture was allowed to stir at about 25 ~C
038 for about lo hours. The reaction mixture was then heated to
039 about 1;0C under reduced water aspirator pressure to remove a
040 portion of the dimethyl sulfoxide solvent. The residue was
041 diluted with water and the aqueous layer separated. 'rhe
0~2 organic portion was dissolved in 350 ml dichloromethane,
~gL73~
~ 1~
001 -~-
002 washed with water, dried over magnesium sulfate and evaporated
003 under reduced pressure to give an oil. The oil was
004 chromatographed through a silica gel column (20~ acetone/80%
005 petroleum ether elution) to give the product (11 g), which
006 after crystallization from ethyl ether/acetone melted at
007 77-~8C.
009 Example 6 - Preparation of 3-(N-methoxyacetyl-
010 N-2~methylnaphth-1-ylamino-gamma-butyrolactone
012 A 2.4-g (0.022-mol) sample of methoxyacetyl chloride
013 was added dropwise to a solution of 5.5 g (0.022 mol) 3-(N-2-
014 methylnaphth-l-ylamino)-gamma-butyrolactone and I.7 g (0.022
015 mol) pyridine in 100 ml dichloromethane. The reaction mixture
016 was stirred one hour at about 25C and then heated under reflux
017 for 6 hours. After cooling overnight, the reaction mixture was
018 washed successively with water, saturated sodium bicarbonate '-
019 solution, water, dried over magnesium sulfate and evaporated
020 under reduced pressure. The residue was chromatographed
021 through a silica gel column. Elution with 25% acetone/75
022 petroleum ether gave 4.3 g of the~produc;t, m.p. 42-4~C.
024 Example 7 - Preparation of 3-(N-methoxythionoacetyl-
025 ~
027 A slurry of phosphorus pentasuIfide t6.0 g) in 300 ml
028 xylene was heated under a Dean Stark w~ter separa~or to
029 azeotroplcally remove any water present.
?30 After cooling to 100C pyridine (2 ml) was added
031 followed by 3-(N-methoxyacetyl~3-N-2,6-dimethylphenylamino)-
032 gamma-butyrolactone (33.3 gj. The stirred slurry was heated at
033 150. After about 45 minutes, the phosphorus pentasulfide
034 dissolved and the mixture was ke~t at 150 over a weekend.
035 The mixture was diluted with an equal volume of
036 methylene chloride and washed with saturated sodium bicarbonate
037 (200 ml), water (200 ml) and dried (~lgSO4).
038 The solution was filtered and the filtrate was
039 stripped in vacuo to yield a dark oil which was chromatographed
040 on silica gel (300 g) by elution with petroleum ether, 80~
041 petroleum ether in ethyl ether, 70~ petroleum ether in ethyl
~4~3~C~
o o 1 -~-
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 8.
010 Example 8 - Preparation of 3-(N-crotonyl-
011 N-2,6-dimethylphenylamino)-gamma-butyrolactone
013 Crotonic acid (6 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 9) 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 260 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 reporced as comound 3
023 in Table A.
025 Example 9 - Preparation of 3-(N-3~methyl-2,3-epoxy-
026 == ~==~_~
028 3-(N-3-methyl-crotonyl-N-2,6-dimethylphenylamino)-
029 gamma-butyroIactone (A) was prepared as in Example 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 dichloromechane were refluxed for 48 hours.
033 The mixture ~was~ washed with water, dried (l~gSO4),
034 stripped. The residue was cr~ystallized in ether/hexane to
035 yield 5O4 g of the title pro9duct, m.p. 100-104C. The product
036 is reported as Compoun~l 7 in Table A.
037 _
038 Compound 2 of the present inventiol~ was evaluated for
039 fungicidal effectiveness by means of a mycelial inhibition
040 test. This test is designed to measure the fungitoxic activity
041 of fungicidal chemicals in terms of their degree of inhibition
042 of mycelium growth. Compound 2 7as dissolved in acetone to 500
11~734~
.
001 -~r-
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 ~prayed 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 a~ter 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 tes,ted for
011 fungicidal activity is ioo~ 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 Blight organism Phytophthora
016 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 a
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 66-68F and lO0~
022 relative humidity for at least 16 hours. Following the incuba-
023 tionj the plants were maintained in a greenhouse at 60-80
024 relative humidity for approximately 7 days. The percent
025 disease control pxovided 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 by the figures in parentheses.
030 Example 12 - Celery Late Blight
031 The celery late blight tests were conducted using
032 celery (Utah) plants 11 weeks old. The celery late blight
033 organism was Septoria apii. The celery ~lants were sprayed
034 with solutions of the candidate toxicant mixed with acetone,
035 water and a nonionic emulsifier. The plants were then inocu-
036 lated with the organism and placed in an environmental ch~mber
037 and incubated at 66-6SF in 100% ralative humidity for an
-
~73~
~D 11 001 -~-
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.
009 Example 13 - Grape Downy Mildew Control
010 The compounds of the invention were tested for the
011 control of the grape downy mildew organism Plasmopara viticola.
012 Detached leaves, between 70 and 85 mm in diameter, of 7-week-
013 old Vitis vinifer_ 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 cha~ber and incubated at 18-22C and about 100%
018 relative humidity. Seven to nine days after inoculation, the
019 amount of disease control was determined. The percent disease
020 control provided by 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 ~
024 Compounds of the invention~were tested for the
025 control of the Tomato Early Blight organism, Alternaria solani
026 conidia. Tomato (variety Bonny~est) seedlings~of 6 to 7 weeks
02? 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 ~ith the organism,
031 dried and maintained at ~0-80% relative humidity for about 12
032 days. Percent disease control was based on the oercent disease
033 development on untreated check plants. The compounds tested
034 and the results are tabulated in Table I and II.
~7~34~3
001 -~
002 Example 15 - Powdery ~lildew
003 The powdery mildew test was made using bean seedlings
004 (var. Bountiful) with well-developed primary leaves. The
005 pathogen was Erysiphe E~ly~oni. The bean seedlings were
OOO 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 greenhouse 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 6 8-70~.
024 The plants were then removed from the chamber, allowed to dry,
025 and then maintained in a greenhouse at a ~0-80~ relative
026 humidity. The rate of infection on the leaves was made after
-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-(N-cy~lopentyl-
032 carbonyl-N-2,6-dimet.hylE~henylamino)-samma-butyr?lactone
034 A 5.7 g. (.043 mol) sample of cyclopentylcarbonyl
035 chloride was added dropwise to a solution of 8.8 9. (.043 mol)
036 ~J-2,6-dimethylphenylamino-gamma-butyrolactone in 100 ml
037 toluene. After completion of the addition, the reaction mix-
038 ture was refluxed overnight, then washed with water, saturated
~734
,q
001 ~-
002 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 9 of product, m.p. 109-113C. Thic product is tabu-
006 lated in Table C as Compound No. Cl.
008 Example 18 - Preparation of 2-(N-cyclopropylcarbonyl-
009 2,6-dimethylanilino)-4-(t-butylthio)-butanoic acid
011 To 4.2 9. t-butylmercaptan 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 tempera~ure
016 overnight and poured in~o ice water.
017 The mixture was washed with 2 x 100 ml toluene and
018 the toluene was bac3~washed with water. The aqueous phase was
019 acidified (pH 1) with 12N HCl, then extracted twice with
0~0 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 ~:
027 The acid produced in Example 18 (10.6 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.j was added
-030 dropwise. The exothermic reaction caused the mixture to warm
031 to 36 C. More 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
036 was crystallized in petroleum ether to yield the title product,
037 m.p. 145-147C.
038 The compounds tabulated in Table C were prepared bv
039 procedures similar to those of Examples 17-19. The structure
040 of each compound tabulated in the Tables was conirmed by
041 nuclear slagnetic resonance spectroscopy and/or inrared
042 spectral analysis.
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001 ' ~
002 TABLE I
004 3 Control
005 Grape Downy Tomato Late Celery Late Tomato Early
006 N Mildew Blight Bli~ht Blight
007
008
009 1 89 0 65 7
010 2 54 0 23 0
011 3 100 lO0 33 29
012 4 lO0 57 94 29
013 5 18 23 23 18
014 ~ 54 13 57 8
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016 8 -- 0 50 11
017 9 100 98 . 37 0
018 10 lO0 99 S0
019 11 100 71 23 0
020 12 lO0 84 36 0
021 13 100 96 44 0
022 14 lO0 96 : 44 0
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025 17 lO0 37 -- 0
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~7341~
001 -~-
002 I'ABLE II
004FUNGICIDAL EFFICACY
008 ~o. GDM TLB CL3 TEB BR BPM
010 Cl - 81 19 0 0 ~ 10
011 C2 - S0 19 0 0 0
012 C3 - 0 7 0 0 4
013 C4 g8 71 19 0 29 4
014 C5A 99 6 44 21 0 0
015 CSB 99 13 44 56 0 23
016 C~ 13 11 0 0 0 98
020 GD~ - Grape Downy ~ildew
021 TLB = Tomato Late Blight
022 CLB = Celery Late Blight
023 TEB = Tomato Early Blight
024 BR: a Bean Rust
025 3PM = Bean Powdery :~ildew
:
