CA2117503A1 - Azoxycyanobenzodioxane derivatives - Google Patents

Abstract

This invention relates to certain azoxycyanobenzodioxane derivatives of the general formula (see fig. I) in which n is 0, 1 or 2; each R, if present, independently represents a halogen atom or an optionally substituted alkyl or alkoxy group; R1 represents a hydrogen atom or a haloalkyl group;
and R2 and R3 independently represent a hydrogen atom or an alkyl or haloalkyl group; processes for their preparation, compositions containing such compounds and their use as fungicides.

Description

CA~ 1 J503 330~6-00 AZOXYCYANn~N7nnIOXANE DERIVATIVES

This invention relates to certain ~ y-.~~h~ o~ioxane derivatives, processes for their preparation, compositions cont~;ning such compounds and their use as fungicides.
EP-A-0371560 discloses a method of ~ t;ng a fungus, and/or bacterium, and/or yeast, and/or nematode, at a locus which comprises treating the locus with a compound of the general formula R4 ~ 2 (A) Rs ~ = NX
(o) n in which R2 and R3 together, or R3 and R4 together, represent an optionally substituted hydrocarbyloxy chain; the ring is optionally substituted at any or each of the 1. in;ng sites R5, R6 and R2 or R ; n le~leSe~ O or l; and X represents a cyano group, a group -COOH or a salt, ester or amido derivative thereof. The term "hydrocarbyloxy chain" is used to denote a carbon atom chain interrupted within the chain by one or more (but preferably one only) oxygen atom. In each of the examples, the hydrocarbyloxy chain contains only one oxygen atom and this is located at one end of the chain.
EP-A-0518436 discloses compounds of the general formula ~1 ~ R1 RZ (B

( ) n~ I ~R3 R4 XN=~ ~/ O

CA27 175~3 in which m is 0 or 1; each of R and R , and R and R if preSent, independently represents a hydrogen or halogen atom or an optionally substituted alkyl, cycloalkyl or aryl group, or Rl and R together or R and R together represent an optionally substituted alkylene chain; X represents a cyano group, a group -COOH or a salt, ester or amido derivative thereof; Y represents an alkyl group or a halogen atom; and n represents 0, 1, 2 or 3; and their use as fungicides.
It has now been discovered that certain ~u~y~ -1,3-benzo-dioxane derivatives exhibit good activity against certain --phytopathogenic fungi.
According to the present invention there is therefore provided a compound of general formula in which n is 0, 1 or 2; each R, if present, inA~ ..lly represents a halogen atom or an optionally substituted alkyl or alkoxy group; R represents a hydrogen atom or a haloalkyl group;
Z5 and R2 and R3 in.~e~_n.~..tly represent a hydrogen atom or an alkyl or haloalkyl group.
When the compounds of this invention contain an alkyl group, this may be linear or branched and may contain up to 12, preferably up to 6 and especially up to 4, carbon atoms.
~hen any of the foregoing substituents are designated as being optionally substituted, the substituent groups which are optionally present may be any one or more of those customarily employed in the development of pesticidal compounds, and/or the 'ificAtion of such compounds to influence their structure/ activity, persistence, penetration or other property. Specific examples of such ' CA2~ 1 -i7 5 ~ ~

substituents include, for example, halogen atoms, nitro, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, carbamoyl and alkylamido groups. When any of the foregoing substituents represents or contains an alkyl substituent group, this may be linear or branched and may contain up to 12, preferably up to 6, and especially up to 4, carbon atoms. Typically, 0-3 substituents may be present, most commonly 0 or 1.
Preferably, each R, if present, indep~-ld~ ly represen,ts a halogen atom or a Cl 6 alkyl or Cl 6 alkoxy group, each group being optionally substituted by one or more substituents selected from halogen atoms, nitro, cyano, hydroxyl and amino groups. It is also preferred that n is 0 or 1. When n is 1, R is preferably located lS at the 8-position of the 1,3-benzodioxane ring.
More preferably, R represents a halogen (especially chlorine or bromine) atom or a Cl 4 alkyl (especially methyl) or Cl 4 alkoxy (especially methoxy) group, each group being optionally substituted by one or more substituents selected from halogen atoms and hydroxyl groups.
It is preferred that R represents a hydrogen atom or a Cl 6 haloalkyl group.
More preferably, R represents a hydrogen atom or a Cl 4 halo-alkyl group, the or each halogen atom in the haloalkyl group preferably being a fluorine or chlorine atom.
It is also preferred that R2 and R3 jn~ y represent a hydrogen atom or a Cl 6 alkyl or Cl 6 haloalkyl group.
More preferably, R2 and R3 1n~pppn~en~ly represent a hydrogen atom, Cl 4 alkyl or Cl 4 haloalkyl group, the or each halogen atom in the haloalkyl group preferably being a fluorine or chlorine atom.
Preferably, the a~ ..o group -~I-N-CN is located at the o ~ 5-; 6- or 7-position of the 1~3-hpn7oAiny~np ring, the 6-position being especially preferred.

CA2i i 750~

A particularly preferred sub-group of compounds of formula I
is that in which n is 0 or 1; R represents a chlorine or bromine atom or a hydroxymethyl or methoxy group; each of R and R
in~p~n~ently represents a hydrogen atom or a trichloromethyl S group; and R3 represents a hydrogen atom.
It should also be noted that compounds of general formula I
could be in any of the following isoelectronic forms:-Ar-~T=N - CN ; Ar 1: ~T CN ; Ar N\ ~ CN ,~ "

where Ar represents R y O ~ ) n R3 ~

, and the scope of the present invention covers all such forms. In addition, it should be appreciated that the compounds of formula I
have chiral centres and are therefore capable of existing as different optical isomers. The present invention thus includes both the individual isomers and mixtures of such isomers.
The present invention also provides a process for the preparation of a compound of formula I as defined above which comprises treating a compound of general formula ~ ~ (II) in which n, R, R1, R2 and R3 are as defined above, with a mixture comprising hydrogen peroxide and methanoic acid and/or with - C~2i 1 7503 peroxymethanoic acid.
~ here a mixture of hydrogen peroxide and methanoic acid is used, the concentration of the hydrogen peroxide is suitably less than about 75wt%, preferably less than about 50wt~ and, more S preferably, less than 40wt~. In a preferred ~ the concentration of hydrogen peroxide is about 30wt~, The process is preferably carried out at or above, more preferably, above, ambient temperature. The process may be carried out at a temperature in the range from 25~C to 75~C, preferably in the range from 30~C to 50~C.
Preferably, the compound of general formula II is mixed with methanoic acid and hydrogen peroxide at ambient temperature. The mixture is preferably then heated, suitably at about 60~C, for a number of hours. The mixture may then be cooled, for instance, in an ice bath. The desired product may then be isolated by standard techniques.
A general process for the preparation of compounds of formula II is provided by R.J.W. LeFevre and H. Vine, J. Chem. Soc., (1938), 431.
The present invention further provides an alternative process for the preparation of a compound of formula I as defined above which comprises reacting a compound of general formula R~3 ~ n (III) in which n, R, Rl, R2 and R3 are as defined above, with cyanamide or a metal salt thereof and an oxidising agent.
The oxidising agent may be any compound which, in conjunction with cyanamide or a metal salt thereof, generates a cyanonitrene.
Preferred examples include in~oben7Gn~ diacetate, dibromoisocyanuric acid and cyclic or linear N-halogen or pse~-~Ah~l~gen amides or imides, especially N-bromosuccinimide.
If a metal salt of cyanamide is used in the process of the invention, it is preferred that the metal salt is an alkali metal salt or an alkaline earth metal salt. Alternatively, such metal salts can be generated in situ by reacting cyanamide with an alkali metal hydroxide or an alkaline earth metal hydroxide. The use of monosodium cyanamide is especially preferred. Alternatively, this may be replaced by a concentrated aqueous solution of cyanamide with sodium hydroxide which effectively generates monosodium cyanamide in situ.
Suitably, the reaction takes place in the presence of an organic solvent, preferably dimethylformamide or a halogenated hydrocarbon, for example, dichloromethane. The reaction is preferably effected at a temperature in the range from -20~C to 50~C.
A compound of formula III may be prepared as follows, where Ar is as defined above:-(A) (B) Ar - NOz >Ar - NHOH >Ar - N = O
V IV I-I
A

(C) Reaction A may, for example, be effected by reaction of the nitro compound with hydrazine hydrate, in the presence of a hydrogen transfer catalyst, for example rhodium on carbon, suitably in the presence of an inert polar organic solvent, for example, tetrahydrofuran, preferably with cooling; or be effected using water, stannous chloride as reducing agent, an inert, polar organic solvent, for example tetrahydrofuran, under an inert atmosphere, for example nitrogen, in the presence of sodium acetate, suitably at ambient temperature.

i~2 i 1 750 ~

Reaction B may suitably be effected by treatment of the hydroxylamine derivative with an oxidising agent, for example an Fe compound, suitably ferric chloride. The reaction may be effected in a mixed water/polar organic solvent, preferably with cooling.
Reaction C may be effected by irradiating the nitro compound, which is preferably dissolved in an inert organic solvent, for example benzene. The irradiation may be effected using a medium pressure mercury lamp.
Details of the above processes may be found in applicants' co-pending European patent applications nos. 92120580.3 and TS 8009 EPC. Other methods suitable for preparing compounds of formula I, and further descriptions of the methods described herein, may be found in The Journal of Antibiotics, Jan. 1975, p.87-90 and June 1986, p.864-868; in Eur,J.Med.Chem.-Chim.Ther., 1982, 17, No. 5, p.482 -484, and 1980, 15, No.5, p.475-478, and 1977, 12, No.l, p.59-62; in J.Chem.Soc.,Chem.Commun., 1984, p.323-324; in Chem.Ind. (Milan), 1977, 59(5), p.385; in Gaaetta Chimica Italiana, 106, 1976, p.ll07-1110; in Tetrahedron Letters, No. 38, 1974, p. 3431-3432; and in U.S. Patents Nos. 4558040 and 4550121.
The compounds of general formula I have been found to have fungicidal activity. Accordingly, the invention further provides a fungicidal composition which comprises a carrier and, as active ingredient, a compound of formula I as defined above. A method of making such a composition is also provided which comprises bringing a compound of formula I as defined above into ~CSOriAtiOn with at least one carrier. Such a composition may contain a single compound or a mixture of several compounds of the present invention. It is also envisaged that different isomers or mixtures of isomers may have different levels or spectra of activity and thus compositions may comprise individual isomers or mixtures of isomers.
- - A composition according to the invention preferably contains from 0.5 to 9s% by weight of active ingredient.

CA ~ l ~ 7~D~

A carrier in a composition according to the invention is any material with which the active ingredient is formulated to facilitate application to the locus to be treated, which may for example be a plant, seed or soil, or to facilitate storage, transport or handling. A carrier may be a solid or a liquid, including a material which is normally gaseous but which has been compressed to form a liquid, and any of the carriers normally used in formulating fungicidal compositions may be used.
Suitable solid carriers include natural and synthetic clays and silicates, for example natural silicas such as diatomaceous earths; magnesium silicates, for example talcs; magnesium aluminium silicates, for example attapulgites and vermiculites; ~1 'ni silicates, for example kaolinites, montmorillonites and micas;
calcium carbonate; calcium sulphate; ammonium sulphate; synthetic hydrated silicon oxides and synthetic calcium or ~1 ~ni silicates; elements, for example carbon and sulphur; natural and synthetic resins, for example coumarone resins, polyvinyl chloride, and styrene polymers and copolymers; solid polychlorophenols;
bitumen; waxes, for example beeswax, paraffin wax, and chlorinated mineral waxes; and solid fertilisers, for example superphosphates.
Suitable liquid carriers include water; alcohols, for example isopropanol and glycols; ketones, for example acetone, methyl ethyl ketone, methyl isobutyl ketone and cy~loh~Y~n~n~; ethers; aromatic or araliphatic hydrocarbons, for example benzene, toluene and xylene; petroleum fractions, for example, kerosine and light mineral oils; chlorinated hydrocarbons, for example carbon tetrachloride, perchloroethylene and trichloroethane. Mixtures of different liquids are often suitable.
Fungicidal compositions are often formulated and transported in a concentrated form which is all-se~.-..lly diluted by the user before application. The presence of small amounts of a carrier which is a surface-active agent facilitates this process of dilution. Thus preferably at least one carrier in a composition - according to the invention is a surface-active agent. For example -CA 2 i 1 7503 the composition may contain at least two carriers, at least one of which is a surface-active agent.
A surface-active agent may be an emulsifying agent, a dispersing agent or a wetting agent; it may be nonionic or ionic.
Examples of suitable surface-active agents include the sodium or calcium salts of polyacrylic acids and lignin sulphonic acids; the r~n~ncAtion products of fatty acids or aliphatic amines or amides containing at least 12 carbon atoms in the molecule with ethylene oxide and/or propylene oxide; fatty acid esters of glycerol, sorbitol, sucrose or pentaerythritol; r~n~GneAt~e of these with ethylene oxide and/or propylene oxide; con~nQAti~n products of fatty alcohol or alkyl phenols, for example ~-octylphenol or p-octylcresol, with ethylene oxide and/or propylene oxide;
sulphates or s~lrh~nAt c of these con~n~Ation products; alkali or alkaline earth metal salts, preferably sodium salts, of sulphuric or sulphonic acid esters contAining at least 10 carbon atoms in the molecule, for example sodium lauryl sulphate, sodium secondary alkyl sulphates, sodium salts of snlrh~nAt~d castor oil, and sodium alkylaryl c~lrh~nAt~s such as dodecylbenzene sulphonate; and polymers of ethylene oxide and copolymers of ethylene oxide and propylene oxide.
The compositions of the invention may for example be formulated as wettable powders, dusts, granules, solutions, leifiAhle concentrates, emulsions, sl~ep~nei~n conr~ntrAtes and 25 aerosols. Wettable powders usually contain 25, 50 or 75% w of active ingredient and usually contain in addition to solid inert carrier, 3-10~ w of a dispersing agent and, where necessary, 0-10 w of stabiliser(s) and/or other additives such as penetrants or stickers. Dusts are usually formulated as a dust concentrate having a similar composition to that of a wettable powder but without a dispersant, and may be diluted in the field with further solid carrier to give a composition usually ~ontl1n1ne ~-10~ w of active ingredient. Granules are usually prepared to have a size - between 10 and 100 BS mesh (1.676 - 0.152 mm), and may be manufactured by A~g1~ ~Lion or impregnation techniques.

Generally, granules will contain ~-7s% w active ingredient and 0-10% w of additives such as stabilisers, surfactants, slow release modifiers and binding agents. The so-called "dry flowable powders"
consist of relatively small granules having a relatively high concentration of active ingredient. Emulsifiable concentrates usually contain, in addition to a solvent and, when necessary, co-solvent, 1-50% w/v active ingredient, 2-20% w/v emulsifiers and 0-20% w/v of other additives such as stabilisers, penetrants and corrosion inhibitors. Suspension concentrates are usually c , ' d so as to obtain a stable, non-s~ ne flowable product and usually contain 10-75% w active ingredient, 0.5-15% w of dispersing agents, 0.1-10% w of 5-lcp~n~ine agents such as protective colloids and thixotropic agents, 0-10% w of other additives such as defoamers, corrosion inhibitors, stabilisers, penetrants and stickers, and water or an organic liquid in which the active ingredient is substantially insoluble; certain organic solids or inorganic salts may be present dissolved in the fn lAtin~ to assist in preventing sedimentation or as anti-freeze agents for water.
Aqueous dispersions and emulsions, for example compositions obtained by diluting a wettable powder or a c~.,c~..L~a~e according to the invention with water, also lie within the scope of the invention. The said emulsions may be of the water-in-oil or of the oil-in-water type, and may have a thick 'mayonnaise' like consistency.
The composition of the invention may also contain other ingredients, for example other compounds possessing herbicidal, insecticidal or fnngiri~Al properties.
Of particular interest in enhancing the duration of the protective activity of the compounds of this invention is the use of a carrier which will provide a slow release of the fungicidal compounds into the environment of the plant which is to be protected. Such slow-release fn lAtions could, for example, be - inserted in the soil adjacent to the roots of a vine plant, or ~ ~ 2 ~

could include an adhesive component enabling them to be applied directly to the stem of a vine plant.
The invention still further provides the use as a fungicide of a compound of the general formula I as defined above or a composition as defined above, and a method for combating fungus at a locus, which comprises treating the locus, which may be for example plants subject to or subjected to fungal attack, seeds of such plants or the medium in which such plants are growing or are to be grown, with such a compound or composition. A locus as described above may suitably be treated with a compound I at an application rate in the range O.OS to 4 kg/ha, preferably 0.1 to 1 kg/ha.
The present invention is of wide applicability in the protection of crop plants against fungal attack. Typical crops which may be protected include vines, grain crops such as wheat and barley, apples and tomatoes. The duration of protection is normally dependent on the individual compound selected, and also a variety of external factors, such as climate, whose impact is normally mitigated by the use of a suitable formulation.
The invention is further illustrated by the following examples.
Example lA
Preparation of 6~ y~lo-1,3-benzodioxane (n=0;Rl=R2=R3=
(a) Preparation of 6-azocyano-l~3-b~n7oainy~n~
6-Amino-1,3-benzodioxane (4 g, 26.5 mmol) was dissolved in a mixture of water (6.5 ml) and hydrochloric acid (7.5 ml, 35~ w/w).
After the addition of crushed ice (30 g), the solution was diazotised by addition of sodium nitrite (1.87 g, 27 mmol). The chilled solution was then neutralised with sodium hydroxide (10~ w/w). Trichloromethane (50 ml) was added and the reaction mixture was cooled to about 0~C. After the addition of potassium cyanide (1.84 g, 28.3 mmol) dissolved in water (14 ml), the organic - layer was separated, dried over sodium sulphate, evaporated to CA 2 i 1 7503 dryness and the resulting orange crystals were filtered to give 2.52 g crude 6-azocyano-1,3-benzodioxane.
(b) Preparation of 6-~Gu~y~y~l.u-1,3-benzoxdioxane The crude 6-azocyano-1,3-benzodioxane (1.5 g, 7.9 mmol) obtained in (a) above was suspended in a mixture of methanoic acid (3û ml) and hydrogen peroxide (10 ml, 30% /w). The mixture was heated to 6û~C for 24 hours and then cooled in an ice bath. The resulting crystals were then collected and washed with water to give 0.62 g (38% yield) 6-azoxycyano-1,3-benzodioxane as orange lû crystals, m.pt : 157~C, m/e (M ) : 205.
H-NMR(CDC13): S(ppm) e 4.92 (s;ArCH20); 5.35 (s;OCH20);
6.88, 7.95, 8.08 (m;Ar-H) Example lB
lS Preparation of 6-a~u~y~y~llo-1,3-benzodioxane (n=O;Rl=R2-R3=H) 6-Nitroso-1,3-benzodioxane (2.5 g, 15.0 mmol) and cyanamide (0.94 g, 21.7 mmol) were dissolved in dichloromethane (190 ml). Under nitrogen, a solution of inAobPn7pnp diacetate (5.34 g, 16.6 mmol) 2û in dichloromethane (190 ml) was added drop by drop at 0~C. The mixture was stirred overnight at ambient ~ , ~LUL~, filtered and evaporated to dryness. Column chromatography on silica using 1:1 petroleum ether: ethyl acetate as eluant yielded 2.3 g (75% yield) 6-azoxycyano-1,3-benzodioxane as a yellow powder, m.pt : 156-158~C, m/e(M ) : 205.
H-NMR(CDC13): ~ (ppm) - 4.92 (s;ArCH20); 5.35 (s;OCH20);
6.88,7.95,8.08 (m;Ar-H) Example lC
Preparation of 6~ Ay.y~.~o-1~3-bPn7od1nYanP
3û n=0; Rl-R2-R3-H) 6-Nitroso-1,3-bPn7odi~Y~nP (1.0 g, 6.1 mmol) and N-bromosuccinimide (1.1 g, 6.2 mmol) were dissolved in dimethyl-formamide (20 ml). MnnncoAi cyanamide (0.61 g, 9.5 mmol) was - added. The mixture was stirred for 1 hour at ambient I , ~Lu.
and poured on ice-water (80 ml), filtered, washed with water and dried to give 0.9 g (71.9% yield) 6-azoxycyano-1,3-benzodioxane as a yellow powder, m.pt. 156-158~C.
Example 2 Preparation of 6-azoxycyano-8-chloro-l~3-bpn7oaioypnp (n-l; R-8-Cl; Rl=R2=R3=H) 6-Nitroso-8-chloro-1,3-benzodioxane (3.4g, 17.0 mmol) was dissolved in dichloromethane (75 ml)., Cyanamide (0.67 g, 16.0 mml) and io~ohPn7PnP diacetate (6.2 g, 19.5 mmol) were then added. The mixture was stirred for 1 hour at 0~C and 1 hour at ambient temperature and the resulting yellow suspension was then filtered and evaporated to dryness. Column chromatography on silica using toluene as eluant gave 2.7 g (66% yield) 6-azoxycyano-8-chloro-1,3-benzodioxane as a yellow solid, m.pt : 158-160~C, m/e (M ) : 239/241 H-NMR (CDC13) : ~ (ppm) = 4.91 (s;ArCH20); 5.40 (s;OCH2O);
7.85, 8.20 (m;Ar-H) Example 3 Preparation of 6-azoxycyano-8-methoxy-1~3-hPn7nAinYAnP
(n=l;R=8 0CH~, RleR2_R3=H) 6-Nitroso-8-methoxy-1,3-benzodioxane (2.3 g, 11.8 mmol) was dissolved in dichloromethane (70 ml). Cyanamide (0.5 g, 11.9 mmol) and dibromoisocyanuric acid (1,3-dibromo-1,3,5-triazin-2,4,6(1H,3H,5H)-trione; 3.4 g, 11.8 mmol) were then added at 0~C
under nitrogen. The mixture was stirred for 2 hours at ambient - -rAt..re and the resulting suspension then filtered and evaporated to dryness. Column chromatography on silica using 2:1 petroleum ether : ethyl acetate as eluant gave 0.8 g (29% yield) 6~ y~ lo-8-methoxy-1,3-bPn7o~ioYAnp as a yellow solid, m.pt :
188-190~C, m/e (M ) :235.
H-NMR (CDC13): S (ppm) - 3.95 (s;OCH3); 4.93 (s;Ar-CH2O);
5.25 (s;OCH20); 7.62 (m;Ar-H) Examples 4 to 9 By process similar to those described in Examples 1 to 3 above, - further compounds according to the invention were prepared as detailed in Table I below. In this table the compounds are C~ 2 i 1 7503 identified by reference to formula I. Melting point, mass spectroscopy and H-NMR data for the compounds of Examples 4 to 9 are given in Table lA below.
TABLE I
s Ex n R Rl R2 R3Position of No. -N(O)=N-CN group 4 l 8-OCH3 H H H S

8 l 8-CH2OH H H H 6 9 1 8-Br H H H 6 TABLE IA

Example M.pt. m/e lH-NMR(CDC13) :~ (ppm) No. (~C) (M ) 4 191 3.99 (s;OCH3); 5.12 (s;ArCH2O); 5.33 (s;OCH2O); 6.85, 7.99 (m;Ar-H) 155 437-449 5.38 (s;ArCHO); 5.72 (s;OCHO); 7.30, 8.32, 8.77 (m;Ar-H) 6 90-93 205 5.10 (s;ArCH2O), 5.25 (s;OCH2O);
7.34, 7.73 (m;Ar-H) 7 145-147 205 4.92 (s;ArCH2O); 5.30 (s;OCH2O);
7.12, 7.73 (m; Ar-H) -TABLE IA (continued) Example M.pt, m/e lH-NMR(cDcl3) : ~ (ppm) No. (~C) (M ) s 8 235 2.50 (t;OH); 4.72 (d;ArCH2OH); 4.96 (s;ArCH20); 5.35 (OCH20); 7.90, 8.22 (m;Ar-H) 9 150-152 283/285 4.92 (s;ArCH20); 5.43 (s;OCH2O);

7.90, 8.37 (m;Ar-H) Example 10 The fungicidal activity of compounds of the invention was investigated by menas of the following eests.

(a) Direct protectant activity against tomato late blight (Phytophthora infestans; PIP) The test is a direct protectant one using a foliar spray. The upper leaf surfaces of tomato plants with two expanded leaves (cv.

First in the field) are sprayed with a solution of active material in 1:1 water/acetone c~tAinine 0.04~ "TWEEN 20" (Trade Mark; a polyoxyethylene sorbitan ester surfactant). Plants are treated using an automated sprayline with an atomising nozzle. The concentration of the compound is 1000 ppm, and the spray volume is 700 l/ha. After a y~hcc~ ..t period of 24 hours under normal glAcchn..ce conditions, the upper surfaces of the leaves are ;nACI~1At~d by spraying with an aqueous suspension ~ontAin1ne 2 x 105 zoospores/ml. The inoculated plants are kept for 24 hours in a high humidity cabinet and 5 days under growth chamber conditions.

The ACC~C is based on the percentage of diseased leaf area compared with that on control leaves.

(b) Direct protectant activity against broad bean ~rey mould - - (Botrytis cinerea; BCB) The test is a direct protectant one using a foliar spray. The upper surfaces of leaves of broad bean plants (cv The Sutton) are sprayed with the test compound at a dosage of 1000 ppm using a Antl t~ sprayline as described under (a). 24 hours after spraying the leaves are inoculated with an aqueous suspension conrAinine lO conidia/ml. For 4 days after inoculation plants are kept moist in a humidity cabinet at 21~C. Disease is assessed 4 days after in~cnlAtion, based on the percentage of leaf surface area convered by lesions.
(c) Activity against wheat leafspot (Leptosphaeria nodorum;
LN.) The test is a direct therapeutic one, using a foliar spray.
Leaves of wheat plants (cv Norman), at the single leaf stage, are inoculated by spraying with an aqueous suspension ~ntAinine l x 106 spores/ml. The inoculated plants are kept for 24 hours in a high humidity compartment prior to treatment. The plants are sprayed with a solution of the test compound at a dosage of lO00 ppm using an automated sprayline as described under (a). After drying, the plants are kept for 6-8 days at 22~C and moderate humidity, followed by Ae5~ . Aec~c ~ is based on the density of lesions per leaf compared with that on leaves of control plants.
(d) Activity a~ainst barley powdery mildew (Erysiphe graminis f.sp. hordei; EG) The test is a direct therapeutic one, using a foliar spray.
Leaves of barley seedlings, (cv. Golden Promise) are inoculated by dusting with mildew conidia one day prior to treatment with the test compound. The in~cnlAt~d plants are kept overnight at elAeeh~lee ambient ; .-rAt~.re and humidity prior to treatment.
The plants are sprayed with the test compound at a dosage of 1000 ppm using an ~ ~ t~d sprayline as described under (a). After drying, plants are returned to a compartment at 20-25~C and moderate humidity for up to 7 days, followed by A-- -Aee~c ~ is based on the percentage of leaf area covered by - sporulation compared with that on leaves of control plants.

(e) Activity a~ainst tomato early blight (Alternaria solani; AS) This test measures the contact prophylactic activity of test compounds applied as a foliar spray. Tomato seedlings (cv Outdoor Girl) are grown to the stage at which the second true leaf is expanded, The plants are treated using an automated sprayline as described under (a), Test compounds are applied as solutions or suspensions in a mixture of acetone and water (50:50 v/v) cont~inine 0.04% surfactant ("T~EEN 20" - Trade Mark), One day after treatment the seedlings are innrul~t~d by spraying the leaf upper surfaces with a suspension of A, solani conidia containing 104 spores/ml, For 4 days after inoculation plants are kept moist in a humidity compartment at 21~C. Disease is assessed 4 days after inoculation, based on the percentage of leaf surface area covered by lesions.
(f) Activity a~ainst wheat eyespot in-vitro (Pseudocercosporella herpotrichoides; PHI) This test measures the in vitro activity of compounds against the fungus causing wheat eyespot. The test compound is dissovled or 5~lqp~n~d in acetone and is added into 4 ml aliquots of half strength Potato Dextrose Broth dispensed in 25-compartment petri dishes to give a final concentration of 50 ppm compound and 2.5~
acetone. Each compartment is inncnl~te~ with a 6 mm diameter plug of agar/mycelium taken from a 14 day old culture of P.
herpotrichoides, Plates are incubated at 20~C for 12 days until the ~cc~- t of mycelial growth, (g) Activity a~ainst Fusarium in-vitro (Fusarium culmorum; FSI) This test measures the in vitro activity of compounds against a species of Fusarium that causes stem and root rots. The test compound is dissolved or suspended in acetone and added to molten half strength Potato Dextrose Agar to give a final r.."~ rn of 50 ppm compound and 3.5~ acetone, After the agar has set, plates are innc..l~trd with 6 mm diameter plugs of agar and mycelium taken from a 7 day old culture of Fusarium sp,, Plates are inrl~h~ted at - 20~C for 5 days and radial growth from the plug is measured.

The extent of disease control in all the above tests is expressed as a rating compared with either an untreated control or a diluent-sprayed-control, according to the criteria:-0 - less than 50% disease control 1 - about 50-80~ disease control 2 - greater than 80~ disease control The results of these tests are set out in Table II below:-TABLE II

Example Fungicidal Activity No. PIP ~CB LN EG AS PhI FSI

Example 11 The fungicidal activity of compounds of the invention was further investigated by means of the following tests.
(a) Antisporulant activity aRainst vine downy mildew (Plasmopara viticola; PVA) The test is a direct antisporulant one using a foliar spray. The lower surface of leaves of vine plants (cv. Cabernet Sauvignon), approximately 8cm high, are inrcl~lAtpd with an aqueous suspension rrntAining 5 x 104 zoosporangia/ml. The inoculated plants are kept for 24 hours at 21~C in a high humidity cabinet, then for 24 hours in a glAcchr~lce at 20~C and 40~ relative humidity. Infected leaves are- sprayed on their lower surfaces with a solution of the test compound in 1:1 water/acetone contAinine 0.04~ "TWEEN 20~ (Trade Mark; a polyoxyethylene sorbitan ester surfactant). Plants are sprayed using a track sprayer equipped with 2 air- ' ~.cine - no~zles. The co~r~ntrAtirn of the compound is 600 ppm and the spray volume is 750 l/ha. After drying, the plants are returned to ~ - 19 -the glasshouse at 20~C and 40% relative humidity cabinet for 24 hours to induce sporulation. Assessment is based on the percentage of the leaf area covered by sporulation compared with that on control leaves.
(b) Direct protectant activity apainst tomato late blipht (Phytophthora infestans; PIP) The test is a direct protectant one using a foliar spray. Tomato plants with two expanded leaves (cv. First in the Field) are sprayed with the test compound at a dosage of 600 ppm as described under (a). After drying, the plants are kept for 24 hours in a elAc~h~qe at 20'C and 40% relative humidity. The upper surfaces of the leaves are then inoculated with an aqueous suspension containing 2 x 10 zoosporangia/ml. The in~c~lat~d plants are kept for 24 hours at 18~C in a high humidity cabinet and then for 5 days in a growth chamber at 15~C and 80% relative humidity with 14 hours light/day, The acc~ is based on the percentage of diseased leaf area compared with that on control leaves.
(c) Activity apainst tomato early blipht (Alternaria solani;
AS) The test is a direct prophylactic one using a foliar spray.
Tomato seedlings (cv Outdoor Girl), at the stage at which the second leaf is expanded, are sprayed with the test compound at a dosage of 600 ppm as described under (a). After drying, the plants are kept for 24 hours in a glasshouse at 20~C and 40% relative humidity followed by inoculation of the leaf upper surfaces with an aqueous suspension of A. solani conidia c~nt~ininp 1 x 10 conidia/ml. After 4 days in a high humidity cabinet at 21~C, disease is assessed based on the percentage of leaf surface area covered by lesions when compared with control plants.
(d)- Direct protectant activity against broad bean prey mould (Botrytis cinerea; BCB) The test is a direct protectant one using a foliar spray. Broad bean plants (cv The Sutton) with two leaf pairs are sprayed with - the test compound at a dosage of 600 ppm as described under (a).
After drying, the plants are kept for 24 hours in a gl~cch~--c~ at 20~C and 40% relative humidity. The upper surfaces of the leaves are then inoculated with an aqueous suspension containing 1 x 10 conidia/ml. Plants are kept for 4 days at 22~C in a high humidity cabinet. The assessment is based on the percentage of diseased S leaf area compared with chat on control leaves.
(e) Activity against wheat leafspot (Leptosphaeria nodorum; LN) The test is a direct LII~Ld~ iC one using a foliar spray. ~heat seedlings (cv Norman), at the single leaf stage, are inoculated with an aqueous suspension cnntaining 1.5 x 10 conidia/ml. The inoculated plants are kept for 24 hours at 20~C in a high humidity cabinet followed by spraying with the test compound at a dosage of 600 ppm as described under (a). After drying, the plants are kept for 6-8 days in a gl~chn~c~ at 22~C and 70% relative humidity.
Acs~s t is based on the density of lesions per leaf compared with that on leaves of control plants.
(f) Activity a~ainst wheat eyespot in-vitro (Pseudocercosporella herpotrichoides; PHI) This test measures the in-vitro activity of compounds against the fungus causing wheat eyespot. The test compound is dissolved or Z0 suspended in acetone and is added into 4 ml aliquots of half strength Potato Dextrose Broth dispensed in 25-compartment petri dishes to give a final c~nce,~LLaLion of 30 ppm test compound and 0.825% acetone. The fungal inoculum consists of mycelial fragments of P. herpotrichoides grown in half strength Potato Dextrose Broth in shaken flasks and added to the broth to provide S x 10 mycelial fragments/ml broth. Petri dishes are incubated at 20~C for 10 days until the ~cs~c t of mycelial growth.
(h) Activity against apple scab in-vitro ~Venturia inaequalis;
VII) This test measures the in-vitro activity of compounds against Venturia inaequalis that causes apple scab. The test compound is dissolved or s~cp~nAed in acetone and added into 4 ml aliquots of half strength Potato Dextrose Broth dispensed in 25-compartment petri dishes to give a final concentration of 30 ppm compound and 0.825% acetone. The fungal inoculum consists of mycelial fragments CA2i 17503 and spores of V. in~q~-~l i.s grown on malt agar and added to the broth to provide 5 x 10 propagules/ml broth. Petri dishes are incubated at 20~C for 10 days until the ~cq~c~ ~. of mycelial growth.
The extent of disease control in all the above tests is expressed as a rating compared with either an untreated control or a diluent-sprayed-control, according to the criteria:-O e less than 50~ disease control 1 e 50~ 80~ disease control 2 - greater than 80~ disease control The results of these tests are set out in Table III below:-TABLE III

Example Fungicidal Activity No. PVA PIP AS BCB LN PHI RSI VII

6 1 l 2 2 9 l l l 2 2 2 * signifies concentration of test compound e 10 ppm

Claims (15)

1. A compound of general formula in which n is 0, 1 or 2; each R, if present, independently represents a halogen atom or an optionally substituted alkyl or alkoxy group; R1 represents a hydrogen atom or a haloalkyl group; and R2 and R3 independently represent a hydrogen atom or an alkyl or haloalkyl group.

2. A compound according to claim 1 in which each R, if present, independently represents a halogen atom or a C1-6 alkyl or C1-6 alkoxy group, each group being optionally substituted by one or more substituents selected from halogen atoms, nitro, cyano, hydroxyl and amino groups.

3. A compound according to claim 1 in which R1 represents a hydrogen atom or a C1-6 haloalkyl group.

4. A compound according to claim 1 in which R2 and R3 independently represent a hydrogen atom or a C1-6 alkyl or C1-6 haloalkyl group.

5. A compound according to claim 1 in which n is 0 or 1;
R represents a chlorine or bromine atom or a hydroxymethyl or methoxy group; each of R1 and R2 independently represents a hydrogen atom or a trichloromethyl group; and R3 represents a hydrogen atom.

6. A compound according to claim 1 wherein n is 0 or 1; R
represents 8-chloro, 8-bromo, 8-hydroxymethyl or 8-methoxy; each of R1 and R2 represents hydrogen or trichloromethyl; and R3 represents hydrogen.

7. A process for the preparation of a compound of general formula I according to any one of claims 1 to 6 which comprises treating a compound of general formula, in which n, R, R1, R2 and R3 are as defined in any one of claims 1 to 6, with a mixture comprising hydrogen peroxide and methanoic acid or with peroxymethanoic acid.

8. A process for the preparation of a compound of general formula I according to any one of claims 1 to 6 which comprises reacting a compound of general formula in which n, R, R1, R2 and R3 are as defined in any one of claims 1 to 6, with cyanamide or a metal salt thereof and an oxidising agent.

9. A fungicidal composition which comprises a carrier and, as active ingredient, a compound of general formula I as defined in any one of claims 1 to 6.

10. A composition according to claim 9 which comprises at least two carriers, at least one of which is a surface active agent.

11. A method of combating fungus at a locus which comprises treating the locus with a compound of general formula I as defined in any one of claims 1 to 6.

12. A method of combating fungus at a locus which comprises treating the locus with a composition as defined in claim 9.

13. A method of combating fungus at a locus which comprises treating the locus with a composition as defined in claim 10.

14. A method according to claim 11 in which the locus comprises plants subject to or subjected to fungal attack, seeds of such plants or the medium in which the plants are growing or are to be grown.

15. A method according to claim 12 or claim 13 in which the locus comprises plants subject to or subjected to fungal attack, seeds of such plants or the medium in which the plants are growing or are to be grown.