Processes and composition for combating fungi

Anti-fungal compositions for combating plant and seed fungi comprise (a) a triazole derivative of formula: ##STR1## or a salt, or isomer, or metal complex thereof where R is--COX, --CH(OH)X, or --C(R.sup.3) (OH)X where X is iso-propyl or tertiary-butyl or phenyl optionally substituted with halogen and R.sup.3 is C.sub.1 to C.sub.4 alkyl; R.sup.1 is H, OH or C.sub.1 to C.sub.4 alkyl; R.sup.2 is phenyl optionally substituted with halogen, NO.sub.2 or halo-alkyl; and (b) gibberellic acid, or other gibberellin.

This invention relates to anti-fungal compositions and to processes for 
combating fungi; more particularly the invention relates to compositions 
for, and processes of, treating plants and seeds. 
There has long existed a need to protect plants and seeds from the adverse 
effects upon them of foliage-, seed- and soil-borne fungal diseases. Fungi 
infecting seed may often cause it to fail to germinate, or to give rise to 
diseased seedling plants, the ability of which to survive is considerably 
diminished as a result. Plants infected by fungi often fail to yield a 
good crop upon harvesting. 
To alleviate these adverse affects, plants and seeds have, for many years, 
been treated with chemical substances which have anti-fungal activity and 
therefore combat the fungal disease. 
Many such chemical substances, however, have limitations upon the extent to 
which they can be used, and one particular restriction is the tendency of 
some of them to give rise to undesirable side-effects upon the plants 
counterbalancing, at least to some extent, the beneficial effects stemming 
from a combating of the fungal disease. 
The undesirable side-effects include the following: 
(a) Hindrance of seed germination. 
(b) Stunting of the growth of the plants. 
(c) Phytotoxic effects of varying degree. 
We have now found a way in which these undesirable effects can be reduced 
for certain specified chemical substances, as hereinafter described, which 
are otherwise excellent fungicides, so that they may be more safely 
deployed with respect to any adverse effects upon plants and seeds and 
without diminishment of their fungicidal activity. 
The invention provides a composition for combating fungi comprising (a) an 
anti-fungal chemical substance and having the formula: 
##STR2## 
or salt, or isomer, or metal complex thereof, wherein R is a group --COX, 
--CH(OH)X or --C(R.sup.3)(OH)X where X is iso-propyl or tertiary-butyl or 
phenyl optionally substituted with one or more halogen atoms and R.sup.3 
is a lower alkyl group having up to 4 carbon atoms, R.sup.1 is hydrogen, 
hydroxyl, or alkyl having up to 4 carbon atoms, R.sup.2 is phenyl 
optionally substituted with one or more halogen atoms or nitro- or 
haloalkyl-groups; and (b) gibberellic acid, or other gibberellin. 
Preferred haloalkyl groups are trifluoromethyl groups. 
R is preferably the group --CH(OH)C(CH.sub.3).sub.3. R.sup.1 is preferably 
hydrogen or methyl, especially hydrogen. R.sup.3 when not hydrogen is 
preferably methyl. R.sup.2 is preferably phenyl substituted with one or 
two chlorine or fluorine atoms, especially chlorine atoms; more 
specifically R.sup.2 is preferably 4-chlorophenyl, 2-chlorophenyl or 
2,4-dichlorophenyl. 
Preferred compositions according to the invention are those wherein the 
anti-fungal chemical substance corresponds to the general formula shown 
above but has the preferred substitution as set out in the preceding 
paragraph. 
Particularly preferred compositions contain any of the specific substances 
listed, by way of exemplification only, in Table I hereinbelow, especially 
compound No. 1 thereof. 
TABLE I 
______________________________________ 
COMPOUND NO STRUCTURAL FORMULA 
______________________________________ 
##STR3## 
2 
##STR4## 
3 
##STR5## 
4 
##STR6## 
5 
##STR7## 
6 
##STR8## 
7 
##STR9## 
8 
##STR10## 
9 
##STR11## 
10 
##STR12## 
11 
##STR13## 
12 
##STR14## 
13 
##STR15## 
14 
##STR16## 
15 
##STR17## 
16 
##STR18## 
17 
##STR19## 
18 
##STR20## 
19 
##STR21## 
20 
##STR22## 
21 
##STR23## 
22 
##STR24## 
23 
##STR25## 
24 
##STR26## 
25 
##STR27## 
26 
##STR28## 
______________________________________ 
These substances, their preparation, and their deployment as, for example, 
fungicides and for plant growth regulation, are described and claimed in 
copending British patent applications Nos. 31650/76, 34590/76, 42667/76 
and 5139/77. 
Thus the compounds of the general formula: 
##STR29## 
or a salt thereof, can be prepared by reducing a compound of general 
formula (II): 
##STR30## 
wherein R.sub.1 is optionally substituted benzyl and X is as defined 
above, or a salt thereof. Suitable reducing agents are sodium borohydride 
or lithium aluminium hydride. If desired, catalytic hydrogenation using a 
suitable metal catalyst can be used. When the compound of general formula 
(II) is a sterically hindered ketone, a Grignard reagent, for example 
butylmagnesium halide (e.g. bromide or iodide) can be used as the reducing 
agent. 
The reduction can be performed by dissolving the reactants in a solvent 
such as diethyl ether or tetrahydrofuran (for lithium aluminium hydride 
reduction) or water (for sodium borohydride reduction). The reaction 
temperature will depend on the reactants and solvent; but generally the 
reaction mixture is heated under reflux. After the reaction, the product 
can be isolated by extraction into a convenient solvent after 
acidification with dilute mineral acid. On removal of the solvent in 
vacuo, the product may be crystallised from a convenient solvent. 
The compounds of general formula (I) wherein R.sub.3 is alkyl, or a salt 
thereof, can be prepared by reacting a compound of general formula (II) or 
a salt thereof with the appropriate Grignard reagent e.g. an alkyl 
magnesium halide such as methyl magnesium bromide or iodide. This reaction 
can be performed by methods known in the art. 
The starting compound of general formula (II) may be made by reacting 
1,2,4-triazole, or a salt thereof, with a .alpha.-haloketone of general 
formula (III): 
##STR31## 
wherein X is halogen, preferably bromine or chlorine, and R.sub.1 and 
R.sub.2 are as defined above. This process may be carried out by heating 
the reactants together in the absence of a solvent or diluent, but 
preferably a solvent is present. 
Suitable solvents are non-hydroxylic solvents such as acetonitrile, 
dimethylformamide, dimethyl sulfoxide, sulpholane and tetrahydrofuran. 
Hydroxylated solvents, for example, methanol and ethanol, may be used in 
certain circumstances when the presence of the hydroxyl group does not 
interfere with the reaction. The process can be carried out in the 
presence of a base such as sodium hydride, sodium ethoxide, excess 
triazole, or an alkali metal carbonate (e.g. potassium carbonate). The 
reaction temperature will depend upon the choice of reactants, solvents 
and base, but generally the reaction mixture is heated under reflux. The 
process generally consists of dissolving the reactants in a solvent and 
then isolating the product by removal of the reactant solvent in vacuo. 
Unreacted triazole can be removed by extraction of the product with a 
suitable solvent which is then washed with water. A crystallisation or 
other purification procedure may then be carried out if desired. 
The .alpha.-halo ketones may be made by known methods. 
The compound of general formula (II) may also be made by alkenylating, 
alkynylating or aralkylating a compound of general formula: 
##STR32## 
wherein X is as defined above. Further details of this reaction can be 
found in German Offenlegungsschrift No. 2610022, the disclosure of which 
document is incorporated herein by reference. 
By way of example only the preparation of Compound no. 1 of Table I is 
hereinafter described in detail. 
1-t-Butyl-2-(1,2,4-triazol-1-yl)-2-p-chlorobenzylethanol (Compound 1) 
Stage I. 1,2,4-Triazole (33.4 g) and sodium ethoxide [from sodium (11.6 g) 
and ethanol (250 ml)] were refluxed for 1 hour. To this solution at the 
reflux temperature was added bromopinacolone (87 g), and heating was 
continued for a further 2 hours. The mixture was then cooled to ambient 
temperature, filtered to remove the precipitated sodium bromide and the 
solvent removed in vacuo. The residue was extracted with chloroform (100 
ml). The solvent was washed with water (4.times.15 ml), dried (sodium 
sulphate) and filtered. Petroleum ether (50 ml; b.p. 
60.degree.-80.degree.) was added and the solution concentrated to yield 
.alpha.-1,2,4-triazol-4-yl-pinacolone, m.p. 176.degree.. Further 
concentration of the solution gave .alpha.-1,2,4-triazol-1-yl-pinacolone, 
m.p. 63.degree.-65.degree.. 
Stage II. .alpha.-1,2,4-Triazol-1-yl-pinacolone (3.3 g) in dimethyl 
formamide (20 ml) was added dropwise to a suspension of sodium hydride 
(0.48 g; 100%) in dimethyl formamide (10 ml) at room temperature with 
stirring. After stirring for two hours, p-chlorobenzyl chloride (3.2 g) in 
dimethyl formamide (2-3 ml) was added dropwise and the reaction mixture 
was kept at 5.degree.-10.degree. for two hours. The solvent was removed in 
vacuo and water was added to the residue. The aqueous solution was 
extracted with methylene chloride, the organic layer was washed with water 
and dried (magnesium sulphate), and the solvent was removed. 
Crystallisation of the yellow solid gave 
.alpha.-p-chlorobenzyl-.alpha.-1,2,4-triazol-1-yl-pinacolone, m.p. 
122.degree.-123.degree. as a white crystalline solid. 
Stage III. A solution of the product (2.0 g) of Stage II in methanol (20 
ml) was treated portionwise with sodium borohydride (0.26 g). The reaction 
mixture was then refluxed for one hour. The solvent was removed in vacuo 
and the hydrochloric acid (1 N; 40 ml) was added to the residue. The white 
precipitate was filtered off, washed with water, dried and crystallised 
from aqueous ethanol to give the title compound as a white crystalline 
solid, m.p. 162.degree.-164.degree.. 
The antifungal substances Nos. 23 and 24 and others of this type may be 
made by reacting 1,2,4-triazole or a salt thereof with the appropriate 
.alpha.-halo ketone by any of the methods set out in the literature. Thus 
for example 1,2,4-triazole can be reacted with a .alpha.-halo ketone of 
general formula: 
##STR33## 
wherein Q is halogen (preferably bromine or chlorine) and X, R.sup.1 and 
R.sup.2 are as defined above. 
This process may in some cases be carried out by merely heating the 
reactants together in the absence of a solvent or diluent, but preferably 
a solvent is present. 
Suitable solvents are non-hydroxylic solvents such as acetonitrile (which 
is preferred), dimethylformamide, dimethyl sulphoxide, sulpholane and 
tetrahydrofuran. Hydroxylated solvents (e.g. methanol and ethanol) may be 
used in certain circumstances when the presence of the hydroxyl group does 
not interfere with the progress of the reaction. 
The process may also be carried out in the presence of a base, but 
preferably excess triazole is present to remove liberated HX from the 
reaction. Other suitable bases include sodium hydride (although not when a 
hydroxylated solvent or diluent is used), alkali metal carbonates (such as 
potassium carbonate) and alkali metal hydroxides (such as potassium 
hydroxide). The temperature at which the reaction may be carried out will 
depend upon the choice of reactants, solvent and base, but generally the 
reaction mixture is heated under reflux. 
The process generally involves dissolving the reactants in a solvent and, 
after allowing reaction to occur, isolating the product by removal of the 
reactant solvent in vacuo. Unreacted triazole is removed by extraction 
with a suitable solvent which is then washed with water. Crystallisation 
or other purification procedures may then be carried out, if desired. 
The .alpha.-haloketone starting material may be made by any of the methods 
set out in the literature. 
The compounds may also be made by aralkylating the corresponding compound 
of general formula (III): 
##STR34## 
wherein X is as defined above, e.g. by first reacting it with an alkali 
metal hydride (e.g. sodium hydride) in a convenient solvent (such as 
dimethylformamide or tetrahydrofuran) to produce the alkali metal salt 
which is reacted with for example an .alpha.-alkylaralkyl halide e.g. a 
bromide (which is preferred) or a chloride. 
This process generally involves dissolving the compound of general formula 
(III) in the solvent and adding an equivalent amount of the alkali metal 
hydride, and then, after allowing the reaction to occur, the 
.alpha.-alkylaralkyl halide is added dropwise. After the reaction, the 
product can be isolated by pouring into water and recrystallising the 
solid formed from a convenient solvent, or purifying the resultant oil by 
column chromatography or another convenient technique. 
The anti-fungal chemical substances used in the compositions and processes 
of the invention contain chiral centres. The compounds are generally 
obtained in the form of racemic mixtures or diastereoisomeric mixtures. 
However, these mixtures can be separated, if desired, into the individual 
isomers by methods known in the art. The scope of the invention is to be 
understood as including not only the racemic and diastereoisomeric 
mixtures, but also other mixtures of the isomers, and each of the 
individual isomers in isolation, as anti-fungal chemical substances useful 
for the compositions and processes of the invention. 
Suitable salts are salts with inorganic or organic acids, for example 
hydrochloric, nitric, sulphuric, acetic and oxalic acids, of the 
anti-fungal chemical substances may be used in the invention compositions. 
The metal complex is suitably one including copper, zinc, manganese or 
iron. It preferably has the general formula: 
##STR35## 
wherein R, R.sub.1, and R.sub.2 are as defined above, M is a metal, A is 
an anion (e.g. a chloride, bromide, iodide, nitrate, sulphate or phosphate 
anion), n is 2 or 4, and y is zero or an integer of 1 to 12. 
The salts and metal complexes of the compounds of general formula (I) can 
be prepared in known manner. For example, the complexes can be made by 
reacting the uncomplexed compound with a metal salt in a suitable solvent. 
The anti-fungal chemical substances used in the compositions and processes 
of this invention are active fungicides, particularly against the 
diseases: Piricularia oryzae on rice Puccinia recondita, Puccinia 
striiformis and other rusts on wheat, Puccinia hordei, Puccinia 
striiformic and other rusts on barley, and rusts on other hosts e.g. 
coffee, apples, vegetables and ornamental plants Plasmopara viticola on 
vines Erysiphe graminis (powdery mildew) on barley and wheat and other 
powdery mildews on various hosts such as Sphaerotheca fuliginea on 
cucurbits (e.g. cucumber), Podosphaera leucotricha on apples and Uncinula 
necator on vines Botrytis cinerea (grey mould) on tomatoes, strawberries, 
vines and other hosts Phytophthora infestans (blight) on tomatoes Venturia 
inaequalis (scab) on apples Rhynchosporium secalis 
The anti-fungal substances have also shown a broad range of activities 
against fungi in vitro. They are also active as seed dressings against: 
Fusarium spp. Septoria spp., Tilletia spp., Ustilago spp., 
Helminthosporium spp., and Pyrenophora spp. on cereals. 
The anti-fungal chemical substances of the present invention have plant 
growth regulating activities. 
The plant growth regulating effects of the substances are manifested as for 
example as stunting or dwarfing effect on the vegetative growth of mono- 
and di-cotyledonous plants. Such stunting or dwarfing may be useful, for 
example, in cereals and soya bean where reduction in stem growth may 
reduce the risk of lodging. Substances which induce stunting or dwarfing 
may also be useful in stunting the growth of sugar in the cane at harvest. 
Stunting of peanuts can assist in harvesting. Growth retardation of 
grasses can help maintenance of grass swards. 
Other plant growth regulating effects caused by the substances include 
alteration of leaf angle and promotion of tillering in monocotyledonous 
plants. The former effect may be useful for example in altering the leaf 
orientation of, for example, potato crops thereby letting more light into 
the crops and inducing an increase in phytosynthesis and tuber weight. By 
increasing tillering in monocotyledonous crops (e.g. rice), the number of 
flowering shoots per unit area may be increased thereby increasing the 
overall grain yield of such crops. The treatment of plants with the 
substances can lead to the leaves developing a darker green colour. 
The foregoing plant growth regulating effects of the active anti-fungal 
chemical substances are controlled, as desired, for example compensated 
for (i.e. reduced or modified) to the desired extent by the use of the 
compositions of the present invention, or by the use of the plant or seed 
treatment processes of the invention. 
The substances which may be used as constituent (b) of the invention 
compositions include the substances known as gibberellic acid and the 
gibberellins generally. These are well known in the plant-growth promotion 
art, and are widely documented and referenced. Some of these references 
are listed in the Merck Index (ninth edition) under the headings 
"Gibberellic Acid" and "Gibberellins" (see pp. 4250 and 4251 of the ninth 
edition). The structures of gibberellic acid (also known as Gibberellin 
A.sub.3 or GA.sub.3) and the other particularly useful, commercially 
available, gibberellins GA.sub.4 and GA.sub.7 (the latter are usually 
commercially available as a mixture) are, however, represented below. It 
is to be understood that the compositions of this invention may include a 
salt or derivative of gibberellic acid or other gibberellin. Mixtures of 
gibberellins are also embraced as constituents of the invention 
compositions. 
##STR36## 
(U.K. Pat. No. 783611) (Gibberellic acid is also known as Gibberellin 
A.sub.3 or GA.sub.3). 
##STR37## 
##STR38## 
The invention compositions may contain varying proportions of the active 
fungicidal chemical and the gibberellic acid or other gibberellin, but a 
ratio, by weight, of from 1;5 to 1;50 of Gibberellic Acid or other 
Gibberellin to anti-fungal chemical is preferred. The preferred ratio is 
1:5. 
The invention compositions may contain, in addition to the usual adjuvants 
and fillers deployed in pesticidal compositions, in inorganic or organic 
acid to enhance the activity of the gibberellic acid or other gibberellin. 
Suitable acids are, for example, phosphoric acid and hydrochloric acid and 
various sulphonic-, hydroxy-, carboxylic- and dicarboxylic-acids. Citric 
acid and tartaric acids are preferred organic acids. The amount of acid by 
weight in the compositions may be up to ten times the amount of 
anti-fungal chemical substance. 
The compositions may also contain alkali metal, alkaline earth metal, 
metal, or ammonium, salts to reduce the phytotoxicity or growth regulatory 
effects of the anti-fungal chemical substance and/or enhance the effect of 
the gibberellic acid or other gibberellin (or derivative or salt thereof). 
Zinc chloride and alkali metal, alkaline earth metal or ammonium salts of 
mineral acids, especially the nitrates, phosphates, sulphates, chlorides 
and carbonates of sodium, potassium, ammonium, magnesium and calcium are 
preferred. 
The compositions of the invention may be in the form of dusting powders 
wherein the active substances are mixed with a solid diluent or carrier. 
Suitable diluents or carriers may be, for example, kaolin, bentonite, 
kieselguhr, dolomite, calcium carbonate, talc, powdered magnesia, Fuller's 
earth, gypsum, Hewitt's earth, diatomaceous earth and china clay. 
Compositions for dressing seed, for example, may comprise an agent 
assisting the adhesion of the composition to the seed, for example, a 
mineral oil. 
The compositions may also be in the form of dispersible powders or grains 
comprising, in addition to the active substances, a wetting agent to 
facilitate the dispersion of the powder or grains in liquids. Such powders 
or grains may include fillers, suspending agents and the like. 
The compositions may also be in the form of liquid preparations containing 
the active substances. Such liquid preparations for the invention process 
are generally solutions, aqueous dispersions or emulsions containing the 
active substances in the presence of one or more wetting (i.e. surface 
active) agents, dispersing agents, emulsifying agents or suspending 
agents. The amount, by weight of such surface active agents may be up to 
ten times the amount of anti-fungal chemical substance in any compositions 
according to the invention. 
Wetting agents, dispersing agents and emulsifying agents may be of the 
cationic, anionic or non-ionic type. Suitable agents of the cationic type 
include, for example, quaternary ammonium compounds, for example, 
cetyltrimethyl ammonium bromide. Suitable agents of the anionic type 
include, for example, soaps, salts of aliphatic monoesters or sulphuric 
acid, for example sodium lauryl sulphate, salts of sulphonated aromatic 
compounds, for example sodium dodecylbenzenesulphonate, sodium, calcium or 
ammonium lignosulphonate, butylnaphthalene sulphonate, and a mixture of 
the sodium salts of diisopropyl- and triisopropylnaphthalene include, for 
example, the condensation products of ethylene oxide with fatty alcohols 
such as oleyl alcohol or cetyl alcohol, or with alkyl phenols such as 
octyl phenol, nonyl phenol and octyl cresol. 
Other non-ionic agents are the partial esters derived from long chain fatty 
acids and hexitol anhydrides, the condensation products of the said 
partial esters with ethylene oxide, and the lecithins. Suitable suspending 
agents are, for example, hydrophilic colloids, for example, 
polyvinylpyrrolidone and sodium carboxymethylcellulose, and the vegetable 
gums, for example, gum acacia and gum tragacanth. 
The aqueous solutions, dispersions or emulsions may be prepared by 
dissolving, dispersing or emulsifying the active substances in an organic 
solvent which may contain one or more wetting, dispersing or emulsifying 
agents. Suitable organic solvents are dimethyl formamide, ethylene 
dichloride, isopropyl alcohol, propylene glycol and other glycols, 
diacetone alcohol, toluene, kerosene, methylnaphthalene, xylenes and 
trichloroethylene, N-methyl-2-pyrrolidone and tetrahydro furfuryl alcohol 
(THFA). 
The compositions to be used as sprays may also be in the form of aerosols 
wherein the formulation is held in a container under pressure in the 
presence of a propellant such as fluorotrichloromethane or 
dichlorodifluoromethane. 
By the inclusion of suitable additives, for example, for improving the 
distribution, adhesive power and resistance to rain on treated surfaces, 
the different compositions can be better adapted for the various uses for 
which they are intended. 
The compositions may also be conveniently formulated by admixing them with 
fertilisers. A preferred composition of this type comprises granules of 
fertiliser material incorporating an invention compound. The fertiliser 
material may, for example, comprise nitrogen, or phosphate-containing 
substances. 
The compositions which are to be used in the form of aqueous dispersions or 
emulsions are generally supplied in the form of a concentrate containing a 
high proportion of the active substances, the said concentrate to be 
diluted with water before use. 
The concentrates are often required to withstand storage for prolonged 
periods and after such storage, to be capable of dilution with water in 
order to form aqueous preparations which remain homogeneous for a 
sufficient time to enable them to be applied by conventional spray 
equipment. 
The concentrates may conveniently contain up to 50% and generally from 10 
to 20% by weight of the active substances. 
When diluted to form aqueous preparations, such preparations may contain 
varying amounts of the active ingredient depending upon the purpose for 
which they are to be used, but an aqueous preparation containing between 
0.002% and 0.2% by weight, and preferably 0.01 to 0.05% by weight of 
active ingredient may be used. 
It is understood that the compositions of this invention may comprise, in 
addition to one or more active compounds according to the invention, one 
or more other substances having biological activity, for example, 
insecticidal, fungicidal, or bactericidal activity. 
In certain aspects of this invention, and more particularly where the 
treatment, or dressing, of seed is concerned, it may be equally, or more, 
advantageous to apply the anti-fungal substance to the seed, either 
before, but preferably after, applying the gibberellic acid or other 
gibberellin. Simultaneous application to seed of both substances in the 
form of a composition according to the invention may also be used. A 
seed-dressing process, and apparatus therefore, may therefore be used in 
which, as consecutive steps, or simultaneously, the aforementioned 
substances are applied to the seed as a "dressing" or impregnation. Either 
one of, or both of, the substances may be admixed with a solid or liquid 
carrier substance for this purpose. Water or polar liquids of an organic 
character are preferred liquid carriers, especially dimethylformamide, 
N-methyl-2-pyrrolidone, tetrahydrofurfuryl alcohol, and glycols for their 
seed-penetrating ability. Non-aromatic hydrocarbons such as isoparaffins 
may be used, but, for example, lower-boiling dichloromethane and acetone 
may also be employed. Encapsulated formulations in which either, or both, 
substances are in the encapsulated form, may also be deployed. 
In a further aspect, therefore, the invention provides a process for 
combating fungal diseases of plants and seeds (especially powdery mildews) 
which comprises treating the plants or seeds (especially cereals) with a 
composition as hereinbefore defined or with the constituents (a) and (b) 
of such a composition applied sequentially in any order. 
The invention is illustrated, by way of example only, by the following 
examples, in which percentage amounts are on a weight basis. Examples 1, 2 
and 3 illustrate compositions according to the invention and their use to 
combat fungal disease. Examples 4 to 16 illustrate compositions according 
to the invention.