Fungicidal agents

There are provided hydroxamic acids, and the esters and chelates thereof having the structure ##STR1## and their use for the prevention, control or amelioration of diseases caused by phytopathogenic fungi. Further provided are compositions and methods comprising those compounds for the protection of plants from fungal infestation and disease.

BACKGROUND OF THE INVENTION 
Phytopathogenic fungi are the causal agents for many diseases that infect 
and destroy crops. In particular, the diseases sugar beet cercospora leaf 
spot, apple scab, tomato early blight, banana black sigatoka, peanut leaf 
spot, and grape and pepper botrytis are especially devastating. 
Sugar beet is susceptible to many foliar diseases caused by phytopathogenic 
fungi. One of the most frequently encountered and destructive foliar 
diseases occurring on sugar beet is sugar beet cercospora leaf spot, 
caused by the fungus, Cercospora beticola. Sugar beet cercospora leaf spot 
is common to sugar beet plants throughout the world, and is particularly 
destructive in regions with wet, warm growing seasons, such as Western and 
Southern Europe, and the Midwestern United States. During periods of high 
temperature and wetness, sugar beet cercospora leaf spot spreads rapidly 
in the field. Ultimately, the disease kills sugar beet leaf tissue, 
resulting in reduced sugar beet weight and sugar content. 
The leaves and fruit of apple trees are susceptible to attack by a fungus, 
Venturia inaequalis, resulting in a disease called apple scab. The disease 
occurs wherever apples are grown, but is most common in the United States 
and Europe. Uncontrolled, apple scab results in deformed, low quality 
fruit. 
Tomatoes are also susceptible to diseases caused by fungi. For example, the 
foliage, stem and fruit of the tomato plant may be attacked by a fungus, 
Alternaria solani, resulting in a disease called tomato early blight. 
Tomato early blight occurs wherever tomatoes are grown, but is 
particularly destructive in regions with wet or humid climates. 
Uncontrolled, tomato early blight causes the defoliation of the tomato 
plant, resulting in reduced fruit number and size. 
The leaves of the banana plant are also subject to attack by fungi, for 
example, Mycosphaerella fijiensis, which causes a disease called banana 
black sigatoka. Uncontrolled, banana black sigatoka kills the leaves of 
the banana plant, resulting in small, poor quality fruit. Because bananas 
are a major export for many Latin American and other tropical countries, 
the control of banana black sigatoka is critical to those countries' 
economies. 
Currently, only five fungicide classes are used to treat banana black 
sigatoka. In some areas, the offending fungus has become resistant to the 
two most effective of those fungicide classes. The result has been more 
intensive spraying with the less effective fungicides. Therefore, there is 
a need for new fungicides with other modes of action for the continued 
protection of bananas. 
Peanut leaf spot, caused by fungi of the Mycosphaerella genus, such as 
Mycosphaerella arachidis, but more importantly fungi such as Cercospora 
arachidicola and Cercosporidium personatum, is the most destructive foliar 
disease of peanut plants in the southeastern United States. Uncontrolled, 
peanut leaf spot causes the rapid defoliation of entire fields, resulting 
in reduced pod size and number. To date, management of peanut leaf spot 
has been difficult. Because of the development of resistance to certain 
fungicides, and the repeal of regulatory approval for other fungicides, 
ninety-nine percent of the peanuts grown in this region are sprayed with a 
single fungicide. 
Grapes and peppers are susceptible to attack by the fungus, Botrytis 
cinerea, causing grape botryitis and pepper botrytis, respectively. Grape 
botrytis, for example, is an especially destructive disease that destroys 
the cell walls of the fruit, resulting in bunch rot. Grape botrytis occurs 
wherever grapes are grown, but is most common in Europe. 
In spite of the commercial fungicides available today, diseases caused by 
fungi still abound. Accordingly, there is ongoing research to create new 
and more effective fungicides for controlling or preventing diseases 
caused by phytopathic fungi. 
It is therefore an object of the present invention to provide compounds 
which are highly effective for controlling or preventing phytopathogenic 
fungal infestations in agronomic crops, both growing and harvested. 
It is also an object of the present invention to provide a method for the 
prevention, control or amelioration of a disease caused by a 
phytopathogenic fungus by contacting said fungus with a fungicidally 
effective amount of a compound. 
These and other objects of the present invention will become more apparent 
from the detailed description thereof set forth below. 
SUMMARY OF THE INVENTION 
The present invention describes hydroxamic compounds, the esters and 
chelates thereof, and their use as fungicidal agents. 
The hydroxamic compounds of the present invention have the following 
structural formula 
##STR2## 
wherein X and X.sub.1 are each independently O or S; 
R is C.sub.1 -C.sub.6 alkyl optionally substituted with one or more halogen 
atoms, or 
C.sub.3 -C.sub.12 cycloalkyl or polycycloalkyl optionally substituted with 
one or more C.sub.1 -C.sub.4 alkyl groups; 
R.sub.1 is C.sub.3 -C.sub.8 cycloalkyl, 
C.sub.1 -C.sub.8 alkyl optionally substituted with one or more halogen 
atoms, 
benzyl optionally substituted with one or more halogen, CN, NO.sub.2, 
C.sub.1 -C.sub.4 alkyl C.sub.1 -C.sub.4 haloalkyl groups, or 
phenyl optionally substituted with one or more halogen, CN, NO.sub.2, 
C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 haloalkyl groups; 
R.sub.2 is hydrogen or 
##STR3## 
R.sub.3 is hydrogen, OR.sub.4, 
NR.sub.5 R.sub.6, 
C.sub.1 -C.sub.6 alkyl optionally substituted with one or more halogen 
atoms, 
C.sub.3 -C.sub.8 cycloalkyl optionally substituted with one or more halogen 
atoms, 
C.sub.2 -C.sub.6 alkenyl optionally substituted with one or more halogen 
atoms, or 
phenyl optionally substituted with one or more halogen, CN, NO.sub.2, 
C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy or C.sub.1 -C.sub.4 
haloalkyl groups; 
R.sub.4 is C.sub.1 -C.sub.6 alkyl; 
R.sub.5 and R.sub.6 are each independently hydrogen, C.sub.1 -C.sub.6 
alkyl, or 
phenyl optionally substituted with one or more halogen, CN, NO.sub.2, 
C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 haloalkyl groups; 
n is an integer of 1, 2, 3 or 4; and 
M is an alkali metal, an alkaline earth metal, a transition metal, boron or 
aluminum. 
This invention also relates to compositions and methods comprising those 
compounds for the prevention, control or amelioration of diseases caused 
by phytopathogenic fungi. 
DETAILED DESCRIPTION OF THE INVENTION 
Phytopathogenic fungi are the causal agents for many diseases that infect 
and destroy agronomic crops, both growing and harvested. In the United 
States alone, agronomic crops must compete with about 18,000 species of 
fungi. Especially devastating are diseases such as sugar beet cercospora 
leaf spot, apple scab, tomato early blight, banana black sigatoka, peanut 
leaf spot, grape or pepper botrytis and the like. Accordingly, there is 
ongoing research to create new and more effective fungicides for 
preventing or controlling the vast array of fungal infestations of crops. 
Advantageously, the present invention provides a method for the prevention, 
control or amelioration of a disease caused by a phytopathogenic fungus by 
contacting said fungus with a fungicidally effective amount of a 
hydroxamic compound of the invention. 
The present invention also provides a method for the protection of a plant, 
plant seed or tuber from fungal infestation and disease by applying to the 
plant, plant seed or tuber, or to the soil or water in which it is 
growing, a fungicidally effective amount of a hydroxamic compound of the 
invention. 
Further, the present invention provides hydroxamic compounds which have the 
following structural formula: 
##STR4## 
wherein X and X.sub.1 are each independently O or S; 
R is C.sub.1 -C.sub.6 alkyl optionally substituted with one or more halogen 
atoms, or 
C.sub.3 -C12 cycloalkyl or polycycloalkyl optionally substituted with one 
or more C.sub.1 -C.sub.4 alkyl groups; 
R.sub.1 is C.sub.3 -C.sub.8 cycloalkyl, 
C.sub.1 -C.sub.8 alkyl optionally substituted with one or more halogen 
atoms, 
benzyl optionally substituted with one or more halogen, CN, NO.sub.2, 
C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 haloalkyl groups, or 
phenyl optionally substituted with one or more halogen, CN, NO.sub.2, 
C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 haloalkyl groups; 
R.sub.2 is hydrogen or 
##STR5## 
R.sub.3 is hydrogen, OR.sub.4, 
NR.sub.5 R.sub.6, 
C.sub.1 -C.sub.6 alkyl optionally substituted with one or more halogen 
atoms, 
C.sub.3 -C.sub.8 cycloalkyl optionally substituted with one or more halogen 
atoms, 
C.sub.2 -C.sub.6 alkenyl optionally substituted with one or more halogen 
atoms, or 
phenyl optionally substituted with one or more halogen, CN, NO.sub.2, 
C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy or C.sub.1 -C.sub.4 
haloalkyl groups; 
R.sub.4 is C.sub.1 -C.sub.6 alkyl; 
R.sub.5 and R.sub.6 are each independently hydrogen, C.sub.1 -C.sub.6 
alkyl, or 
phenyl optionally substituted with one or more halogen, CN, NO.sub.2, 
C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 haloalkyl groups; 
n is an integer of 1, 2, 3 or 4, up to the maximum valence of M; and 
M is an alkali metal, an alkaline earth metal, a transition metal, boron or 
aluminum. 
Preferred fungicidal agents of the present invention are oxo- and 
thiohydroxamic compounds of formula Ia or Ib wherein 
X is O; 
X.sub.1 is S; 
R is C.sub.1 -C.sub.6 alkyl; 
R.sub.1 is C.sub.1 -C.sub.8 alkyl; 
R.sub.2 is hydrogen or 
##STR6## 
R.sub.3 is phenyl optionally substituted with one or more halogen, CN, 
NO.sub.2, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy or C.sub.1 
-C.sub.4 haloalkyl groups; 
n is an integer of 2 or 3; and 
M is iron, zinc or copper. 
Most preferred fungicidal agents of the present invention are those 
represented by formula Ib, substituted as described above for the 
preferred fungicidal agents. 
Hydroxamic compounds of the present invention which are particularly 
effective as fungicidal agents include 
N,3,3-trimethyl-2-oxo-1-thiobutyrohydroxamic acid iron(+3) chelate; 
N,3,3-trimethyl-2-oxo-1-thiobutyrohydroxamic acid copper(+2) chelate; 
N,3,3-trimethyl-2-oxo-1-thiobutyrohydroxamic acid zinc(+2) chelate; and 
p-chlorobenzoate ester of N,3,3-trimethyl-2-oxo-1-thiobutyrohydroxamate, 
among others. 
The term halogen used herein includes fluorine, chlorine, bromine and 
iodine. The terms alkali metal includes lithium, sodium and potassium, 
alkaline earth metal includes magnesium, calcium and barium, and 
transition metal includes iron, zinc, copper, manganese, cobalt, silver, 
nickel, and the like, preferably iron, zinc and copper. In addition, other 
elements conventionally understood to be encompassed by the terms halogen, 
alkali metal, alkaline earth metal and transition metal, are contemplated 
to be useful in the compounds of the invention. The term polycycloalkyl 
designates a bicyclic or tricyclic ring system. 
The hydroxamic compounds of the present invention are useful in the 
prevention, control or amelioration of diseases such as sugar beet 
cercospora leaf spot, apple scab, tomato early blight, banana black 
sigatoka, peanut leaf spot, and grape or pepper botrytis. Such diseases 
are caused by, inter alia, the phytopathogenic fungi Cercospora beticola, 
Venturia inaequalis, Alternaria solani, Mycosphaerella fijiensis, 
Cercospora arachidicola and Botrytis cinerea, respectively. The compounds 
of the present invention are especially effective in the prevention, 
control or amelioration of sugar beet cercospora leaf spot, which can be 
caused by the fungus, Cercospora beticola. 
Thiohydroxamic compounds of formula Ia and Ib wherein R.sub.2 is hydrogen 
or COR.sub.3 may be prepared as shown in Flow Diagram I. 
##STR7## 
In Flow Diagram I, Y is OC(O)CH.sub.3 or Cl and R, R.sub.1, R.sub.3, M and 
n as are described above. 
As illustrated in Flow Diagram I, the appropriately substituted formula II 
ketone may be reacted with thionyl chloride in the presence of an organic 
base such as pyridine to form an intermediate compound which is then 
reacted with a formula III hydroxylamine (or hydroxylamine hydrohalide 
salt) in the presence of pyridine to yield the formula Ia compound wherein 
R.sub.2 is hydrogen. The formula Ia compound may then be reacted with an 
appropriate formula IV acid chloride to obtain those formula Ia compounds 
wherein R.sub.2 is COR.sub.3. Alternatively, the formula Ia compound 
wherein R.sub.2 is hydrogen may be reacted with a formula V metal complex 
to give a chelate of formula Ib. 
Compounds of formula Ia and Ib wherein X and X.sub.1 are S and R.sub.2 is 
hydrogen or COR.sub.3 may be prepared as shown in Flow Diagram II. 
##STR8## 
In Flow Diagram II, Y is OC(O)CH.sub.3 or Cl and R, R.sub.1, R.sub.3, M 
and n are as described above. 
As illustrated in Flow Diagram II, the appropriately substituted formula Ia 
compound wherein X is O, X.sub.1 is S and R.sub.2 is hydrogen may be 
reacted with 
[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] to 
form the formula Ia compound wherein X and X.sub.1 are S and R.sub.2 is 
hydrogen. The formula Ia compound wherein X and X.sub.1 are S and R.sub.2 
is hydrogen may then be reacted with an appropriate formula IV acid 
chloride to obtain those formula Ia compounds wherein R.sub.2 is 
COR.sub.3. Alternatively, the formula Ia compound wherein X and X.sub.1 
are S and R.sub.2 is hydrogen may be reacted with a formula V metal 
complex to give a chelate of formula Ib. 
Hydroxamic compounds of formula Ia and Ib wherein X and X.sub.1 are O and 
R.sub.2 is hydrogen or COR.sub.3 may be prepared as shown in Flow Diagram 
III. 
##STR9## 
In Flow Diagram III, Y is OC(O)CH.sub.3 or Cl and R, R.sub.1, R.sub.3, M 
and n are as described above. 
As illustrated in Flow Diagram III, the appropriately substituted formula 
VI oxalic chloride may be reacted with a formula III hydroxylamine (or 
hydroxylamine hydrohalide salt) in the presence of pyridine to yield the 
formula Ia compound wherein R.sub.2 is hydrogen. The formula Ia compound 
may then be reacted with an appropriate formula IV acid chloride to obtain 
those formula Ia compounds wherein R.sub.2 is COR.sub.3. Alternatively, 
the formula Ia compound wherein R.sub.2 is hydrogen may be reacted with a 
formula V metal complex to give a chelate of formula Ib. 
The hydroxamic compounds of the present invention are useful for 
controlling or preventing the growth of phytopathogenic fungi such as 
Cercospora beticola, Venturia inaequalis, Alternaria solani, 
Mycosphaerella fijiensis, Cercospora arachidicola and Botrytis cinerea. 
Therefore, harmful diseases such as sugar beet cercospora leaf spot, apple 
scab, tomato early blight, banana black sigatoka, peanut leaf spot, and 
grape and pepper botrytis may be prevented or controlled. 
The compounds of the present invention are also useful for the protection 
of growing or harvested plants from the damage caused by phytopathogenic 
fungal disease when applied to said plants at a fungicidally effective 
rate. The effective rate will vary depending upon factors such as the 
virulence of the target fungus, the environment of the treatment and other 
ambient conditions. In practice, generally about 20 ppm to 1,000 ppm, 
preferably about 50 ppm to 500 ppm of the formula Ia or Ib compound may be 
dispersed in a liquid or solid carrier and applied to the plant, seed or 
tuber, or to the soil or water in which the plant, seed or tuber is 
growing. 
The compounds of the invention may be formulated as concentrated solutions, 
emulsifiable concentrates, flowable concentrates, microemulsions and the 
like. Said compounds may also be formulated as dry compacted granules, 
granular compositions, dusts, dust concentrates, suspension concentrates, 
wettable powders, and the like. Those formulations which lend themselves 
to seed, tuber, soil, water and/or foliage applications to provide the 
requisite plant protection are suitable. Such formulations include the 
compounds of the invention admixed with an inert solid or liquid carrier. 
It is contemplated that the compounds of the invention may be used in 
conjunction with, or in combination with, a pesticidally effective amount 
of one or more other pesticides, including but not limited to, anilazine, 
benalaxyl, benomyl, bitertanol, bordeaux mixture, carbendazim, carboxin, 
captafol, captan, chlorothalonil, cyproconazole, dichloran, diethofencarb, 
diniconazole, dithianon, dodine, edifenphos, fenarimol, fenbuconazole, 
fenfuram, fenpropidin, fenpropimorph, fentin hydroxide, ferbam, 
flusilazole, flusulfamide, flutriafol, folpet, fosetyl, fuberidazole, 
guazatine, hexaconazole, imazalil, iprobenfos, iprodione, mancozeb, maneb, 
metalaxyl, metiram, myclobutanil, nuarimol, ofurace, oxadixyl, 
oxycarboxin, penconazole, probenazole, prochloraz, propiconazole, 
pyrazophos, tebuconazole, thiabendazole, thiophanate, thiophanate-methyl, 
triadimefon, triadimenol, triarimol, tricyclazole, tridemorph, 
triflumizole, triforine, vinclozolin, zineb, and the like. 
Where compositions of the invention are to be employed in combination 
treatments with other pesticidal agents, the composition may be applied 
concurrently as an admixture of the components as described above, or may 
be applied sequentially. 
In order to facilitate a further understanding of the invention, the 
following examples are presented primarily for the purpose of illustrating 
more specific details thereof. The invention should not be deemed limited 
thereby except as defined in the appended claims. 
EXAMPLE 1 
Preparation of N-methyl-.alpha.-thio-1-adamantaneglyoxylohydroxamic acid 
##STR10## 
A mixture of 1-adamantyl methyl ketone (12.5 g, 0.07 mol), thionyl chloride 
and pyridine is refluxed for 21/2 hours and concentrated with toluene in 
vacuo, to give a residue. The residue is dissolved in methylene chloride, 
filtered through a silica gel plug and concentrated in vacuo to give a red 
oil residue. The red oil is diluted with tetrahydrofuran and added to a 
mixture of N-methylhydroxylamine hydrochloride (12.5 g, 0.15 mol) and 
pyridine which has been heated at reflux temperature for 5 minutes and 
cooled. The resultant reaction mixture is stirred at 20.degree. C. for 5 
minutes, heated at reflux temperature for 45 minutes, cooled to room 
temperature and concentrated in vacuo to give a residue. The residue is 
dispersed in a mixture of ether and aqueous 10% hydrochloric acid. The 
phases are separated and the organic phase is extracted with 5% sodium 
carbonate. The carbonate extracts are combined and acidified with 10% 
hydrochloric acid to about pH 1, stirred for 1 hour and filtered. The 
filtercake is dried and recrystallized from heptane/ethyl acetate to give 
the title product as a white solid, mp 127.degree.-141.degree. C., 
identified by .sup.1 HNMR analysis. 
Using essentially the same procedure, but employing the appropriately 
substituted methyl ketone substrate and a suitable hydroxylamine 
hydrochloride, the following compounds are obtained: 
______________________________________ 
##STR11## 
R R.sub.1 mp .degree.C. 
______________________________________ 
C(CH.sub.3).sub.3 
CH.sub.3 76-79 
C(CH.sub.3).sub.3 
cyclopentyl red oil 
C(CH.sub.3).sub.3 
CH(CH.sub.3).sub.2 
1-methylcyclopropane 
CH.sub.3 brown solid 
C(CH.sub.3).sub.3 
CH.sub.2 C.sub.6 H.sub.5 
red oil 
______________________________________ 
EXAMPLE 2 
Preparation of N-isopropyl-3,3-dimethyl-2-oxo-1-thiobutyrohydroxamic acid 
zinc (+2) chelate 
##STR12## 
A mixture of N-isopropyl-3,3-dimethyl-2-oxo-1-thiobutyrohydroxamic acid 
(0.5 g, 2.5 mmol) and zinc diacetate dihydrate (0.25 g, 1.1 mmol) in 
acetic acid is heated at reflux temperature for 1 hour and concentrated in 
vacuo to give a residue. The residue is diluted with ether, washed 
sequentially with dilute sodium bicarbonate and brine. The organic phase 
is dried over MgSO.sub.4 and concentrated in vacuo to give the title 
product as an off-white solid, mp 133.degree.-140.degree. C. 
Using essentially the same procedure, and employing the appropriately 
substituted hydroxamic acid and metal diacetate, the following compounds 
are obtained: 
______________________________________ 
##STR13## 
R R.sub.1 M mp .degree.C. 
______________________________________ 
C(CH.sub.3).sub.3 
CH.sub.2 C.sub.6 H.sub.5 
Zn 200-203 
C(CH.sub.3).sub.3 
cyclopentyl Zn 140-146 
1-adamantyl CH.sub.3 Zn 225 
C(CH.sub.3).sub.3 
CH.sub.3 Zn 158-159 
C(CH.sub.3).sub.3 
CH.sub.2 C.sub.6 H.sub.5 
Cu red solid 
C(CH.sub.3).sub.3 
cyclopentyl Cu &gt;225 
1-adamantyl CH.sub.3 Cu &gt;230 
C(CH.sub.3).sub.3 
CH.sub.3 Cu 153 dec. 
C(CH.sub.3).sub.3 
CH.sub.3 Mn &gt;255 
______________________________________ 
EXAMPLE 3 
Preparation of N, 3,3-trimethyl-2-oxo-1-thiobutyrohydroxamic acid iron (+3) 
chelate 
##STR14## 
A solution of ferric chloride hexahydrate (376.4 mg, 1.39 mmol) in water is 
added to a solution of N,3,3-trimethyl-2-oxo-1-thiobutyrohydroxamic acid 
(750 mg, 4.22 mmol) in acetic acid. After the addition is complete, the 
reaction mixture is concentrated in vacuo and chased with toluene to give 
a black oil. The oil is crystallized from heptane to give the title 
product as a red-black solid (0.7 g, mp 144.degree. C. dec.). 
Using essentially the same procedure, but employing 
N-cyclopentyl-3,3-dimethyl-2-oxo-1-thiobutyrohydroxamic acid as the 
starting material, N-cyclopentyl-3,3-dimethyl-2-oxo-1-thiobutyrohydroxamic 
acid iron(+3) chelate is obtained as a dark red solid, mp 
140.degree.-146.degree. C. 
EXAMPLE 4 
Preparation of p-Chlorobenzoate ester of 
N,3,3-trimethyl-2-oxo-1-thiobutyrohydroxamate 
##STR15## 
A mixture of triethylamine (1.6 mL) in methylene chloride is added dropwise 
to a mixture of N,3,3-trimethyl-2-oxo-1-thiobutyrohydroxamic acid (1.6 g, 
9.13 mmol) and p-chlorobenzoyl chloride (1.3 mL, 10.04 mmol) in methylene 
chloride at about 5.degree. C. When the addition is complete, the reaction 
mixture is diluted with methylene chloride, washed sequentially with 2% 
hydrochloric acid, 5% sodium carbonate solution and brine, dried over 
Na.sub.2 SO.sub.4 and concentrated in vacuo to obtain a yellow oil. The 
oil is chromatographed using silica gel and a (10:1) hexane/ether as 
eluent to give the title product as a yellow solid, 2.4 g, mp 
154.degree.-162.degree. C. 
Using essentially the same procedure, but substituting acryloyl chloride 
and methyl chloroformate for p-chlorobenzoyl chloride, the acrylate ester 
of N,3,3-trimethyl-2-oxo-1-thiobutyrohydroxamate and methylcarbonate ester 
of N,3,3-trimethyl-2-oxo-1thiobutyrohydroxamate are obtained.