CA1193274A - Heterocyclic compounds - Google Patents

Abstract

ABSTRACT

Compounds of formula:

or wherein R1 is an alkyl group containing from 1 to 6 carbon atoms, cycloalkyl containing up to 6 carbon atoms or phenyl optionally substituted with halogen, an alkyl group containing from 1 to 5 carbon atoms, an alkoxy group containing from 1 to 4 carbon atoms, trifluoromethyl, nitro or phenoxy; and R2 is phenyl or benzyl either optionally substituted with halogen, an alkyl group containing from 1 to 5 carbon atoms, an alkoxy group containing from 1 to 4 carbon atoms, trifluoromethyl, nitro or phenoxy, or R2 is phenylphenyl when R1 is alkyl or cycloalkyl; and X is a halogen atom, especially chlorine.
The compounds are useful as intermediates in the prepar-ation of novel triazole fungicides.

Description

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TRIAZOLE COMPOUNDS, A PROCESS FOR PP~PARING THEM, THEIR
USE AS PLANT FUNGICIDES AND FUNGICIDAL COMPOSITIONS
CONTAINING THEM

This invention relates to triazole compounds userul as fungicides, to a process for pxeparing them, to fungi-cidal compositions containing them, and to a method of combating fungal infections in plants using them.
The trlazole compounds have the general formula (I):

OH

N - N - CH2 -C ~ R

~ ~ R2 wherein Rl is alkyl, cycloalkyl (e.g. cyclopentyl or cyclohexyl) or optionally substituted phenyl and R2 is optionally substituted phenyl or optionall~ substituted benzyl; or an acid addition salt or metal complex thereof.
The compounds of the invention can contain chiral centres. Such compounds are g~nerally obtained in the form of racemic mixtures. However, these and-other mixtures can be separated into the individual isomers by methods know~ in ~he art.
The alkyl g~oups can be a straight or branched chaln group having 1 to 6, e.g. 1 to 4, carbon atoms; examples are methyl, ethyl, propyl (n- or iso-propyl) and butyl (n-~ sec-, iso- or t--butyl).

2~

Examples of suitable substituents for the phenyl and for the phenyl moiety of the benzyl are ha]ogen (e.g.
~'uGrine, chlorine or bromine), Cl 5 al~yl /e.g. me~hyl, ethyl, propyl (n- or 1so-propyl) and butyl (n-, sec-, iso- or t-butyl) ~ , Cl ~ alkoxy (e.g. methoxy and ethcxy), trifluoromethyl, nitro, phenyl and phenoxy. The alkyl moiety of the benzyl can be substituted with for example one alkyl (e.g. methyl or ethyl). Suitably the phenyl and benzyl are unsubstituted or substituted with 1, 2 or

3 ring substituents as defined above. ~referably the benz~l and phenyl have a single ring substituent in the -position. Examples of these groups are phenyl, benzyl, a-methylbenzyl, o-, m- or p-chlorophenyl, 2,4- or 2,6-dichlorophenyl, o-, m- or p-fluorophenyl, ~,6~difluoro-phenyl, o-, m- or p~bromophenyl, 2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, o-, m- or p-methoxyphenyl, 2,4-dimethoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-methylphenyl, o-, m- or p-t~
butylphenyl, o-, m- or p-trifluoromethylphenyl, o-, m- or p~phenoxyphenyl, and o-, m- or p-phenylphenyl (o-, m- or p-biphenylyl), and the corresponding ring substituted benxyl and ~-methylbenzyl groups.
The salts can be salts with inorganic or organic acids e.g. hydrochloric, nitric, sulphuric, acetic, p-toluenesulphonic or oxalic acid.
Suitably the metal complex is one including, as themetal, copper, zinc, manganese or iron. It preferably has the genexal formula:

U _ _ CH -C - Rl ` ~ A~ yH o wherein Y, Rl and R2 are as defined above, M is a metal, A is an anion (e.g. a chloride, bromide, iodide, nitrate, 3~

sulphate or phosphate anion), n is 2 or 4 and y is O or an integer of 1 to 12.
Examples of the compounds of the invention a.re shown in Ta le I.

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The compounds of general formula (I) may be produced by reacting a compound of general formula (II~ or (III):
OH
CH2--C--Rl X--CH2----C---Rl R2 l2 (II) (III) in which Rl and R2 are as defined above and X is a halogen atom (preferably a chlorine or bromine atom), 5 with 1,2,4-triazole either in the presence of an acid-binding agent or in the form of one of its alkali metal salts in a convenient solvent. Suitably the compo~nd of general formula (II) or (III) is reacted at 20-100C with the sodium salt of 1,2,4-triazole (the salt can be 10 prepared by adding either sodium hydride or sodium methoxide to 1,2,4-triazole) in a convenient solvent such r as acetonitrile, methanol, ethanol or dimethylformamide.
The product can be isolated by pouring the reaction mixture into water and recrystallising the solid formed 15 from a convenient solvent.
The compounds of general formula (II) ~nd (II-L) can be prepared by reacting a compound of general formula (IVa) or (IVb):
O O
X - CH2 C ~ RX CH2 -C - R
, (IVa) (IVb~
l 2 wherein R , R and X are as de~ined above wi.th, respect-ively, a Grignard compound of general formula (Va) or (Vb):

, , 3~
-- 8 ~

Y- Mg -R Y- Mg- R

(Va) (Vb) wherein Rl and R2 are as de~ined above and Y is a halogen (preferably c~lorine, bromine or iodinej in a convenient solvent such as diethyl ether or tetrahydrofuran.
Generally a mixture of the compounds o~ general formula (II) and (~II) are obtained. For example, when a compound o~ general forrnula ~IVa) wherein R is alkyl or cycloalkyl is reacted, the compound of ~orrnula (II) generally predominates in the mixturei on the other hand, when ~1 is optionally substituted phenyl, the compound of general formula (III) gene-ally predominates in the mixture.
The compounds of general formula tIV) and (V) may be made by methods set out in the literature.
The salts znd metal cornplexes of the co~pounds of general formula (I) can be prepared from the latter in known manner. For example, the comp-lexes can be made oy reacting the uncomplexed compound with a metal salt in a suitable solvent.
The compounds, salts and metal complexes ~re acti-~e fungicides, particularly against the diseases:-Piricularia oryzae on rice _ . ~
Puccinia recondita, Puccinia striiformis and other rustson wheat, Puccinia hordei, Puccinia striiformis and other . _ rusts on barley, and rusts on other hosts e.g. co~fee, apples, vegetables and ornamental plants --- -- ~
Plasmopara viticola on vines ~y~phe graminls (powdery m.ildew) on barley and wheat and other powdery mildews on various hosts such as _haerotheca fuliginea on cucur~its (e.g. cucumber), Podosphaera leucotricha on apples and Uncinula necator on vines Helminthos~orium spp. and ~yn osporiwm spp. on cereals arachidicola on peanuts and other Cercos~ora species on for example sugar beet, bananas and soya beans Botry~is cinerea (grey mould) on tomatoes, strawberries, vines and other hosts PhYtophthora infestans (late blight) on tomatoes Venturia inaequalis (scab) on apples .
Some of the compounds ha~e also shown a broad range of activities against fungi ln vitro. They have activity against various post-harvest diseases on fruit (e.g.
Penicilli~n digatatum and italicum on oranges and -Gloeosporium musarum on bananas). Further some of the compounds are active as seed dressings against: Fusarium spp., Septoria spp., Tilletia spp. (i.e. bunt, a seed borne disease of wheat), Ustila~ spp., Helminthosporium spp. on cereals, Rhizoctonia solani on cotton and Cortici~n sasakii on rice.
The compounds can move acropetally in the plant tissue~ Moreover, the compounds can be volatile enough to be acti~e in the vapour phase against fungi on the plant.
The compounds may be used as such for fungicidal purposes but are more conveniently formulated into compositions for such usage. The invention thus provides also a fungicidal composition comprising a compound of general formula (I) or a salt or complex thereof as hereinbefore defined, and a caxrier or diluen~.
The invention also provides a method-of combating fungal diseases in a plant, which method comprises applying to the plant, to seed of the plant or to the locus of the plant or seed a compound or a salt or complex thereof as hereinbefcre defined.
The compounds, salts and complexes can be applied in a n~nber of ways, for example they can be formulated or unfo~nulated, directly to the foliage of a plant, to seeds or ~o other medium in which plants are growing or ~3~

are to be planted, or they can be sprayed on, dusted on or applied as a cream or paste formulation, or the~ can be applied as a vapour. Application can be to any part of the plant, bush or tree, for example to the foliage, stems, branches or roots, or to soil surrounding the roots, or to the seed before it is planted~
The term "plant1' as used herein includes seedlings, bushes and trees. Furthermore,-the fungicidal method of the invention includes preventative, protectant, prophylactic and eradicant treatment.
The compounds are preferably used for agricultural and horticultural purposes in the form of a composition.
The type of composition used in any instance will depend upon the particular purpose envisaged.
The compositions may be in the forrn of dusting powders or granules comprising the active ingredient and a solid diluent or carrier/ for exarnple fillers such as kaolin, bentonite, kieselguhr, dolomite, calciurn carbon-ate, talc, powdered magnesia, Fuller's earth, gypsum, ~ewitt's earth, diatomaceous earth and China clay. Such - granules can be preforrned granules suitable for application to the soil without further treatment, These granules can be made either by impregnating pellets of filler with the active ingredient or by pelleting a mixture of the active ingredient and powdered ~filler. Compositions for dressing seed, for exarnple, may comprise an agent (for exarnple a mineral oil) for assisting the adhesion of the composition to the seed; alternatively the active ingred-ient can be formulated for seed dressing purposes using an organic solvent (for example N-methylpyrrolidone or dimethylformamide).
The compositions may also be in the form OI dis-persible powders, granules or grains cornprising a we:tting agent to facilitate the dispersion in liquids of the powder or grains which may con'cain also fillers and suspending agents.

. , , . . . ~ .. . .. _ . . . . ... . . .

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The aqueous clispersions or emulsions may be prepared by dissolving the active ingredient(s) in an organic solvent optionally containing wetting, dispersing or emulsifying agent(s) and then adding the mixture to water which may also contain wetting, dispersing or emulsifying agent(s). Suitable organic solvents are ethylene dichloride, isopropyl alcohol, propylene glycol, di-acetone alcohol, toluene, kerosene, methylnaphthalene, the xylenes, trichloroethylene, furfuryl alcohol, tetra-hydrofurfuryl alcohol, and glycol ethers (e.g. 2-ethoxy-ethanol and 2~butoxyethanol).
The compositions to be used as sprays may also be in the form of aerosols wherein the formulati,on is held in a container under pressure in the presence o a propellant, e.g. fluorotrichloromethane or dichlorodifluoromethane.
The compounds can be mixed in the dry state with a pyrotechnic mixture to form a composition suitable for generating in enclosed spaces a smoke containing the compounds.
Alternatively, the compounds may be used in a micro-encapsulated form.
By including sui~able additives, for example additives for improving the distribution, adhesive power and resistance to rain on treated surfaces, the different compositions can be better adapted ior variou~ utilities.
The compounds can be us~d as mix~ures with ferti-lisers (e.g. nitrogen-, potassium- or phosphorus-containing fertilisers). Compositions comprising only granules o~
fertiliser incorporating, for example coated,with, the compound, are preerred. Such granules suitably contain up to 25~ by weight ol the compound. The invention therefore also provides a fertiliser composition comprising the compound of general Eormula (I) or a salt or--metal complex thereof.
The compositions may also be in the form of liquijd preparations for use as dips or sprays which are generally aqueous dispersions or emulsions containing the active ingredient in the presence of one or more surfactants e.g. wetting agent(s), dispersing agent(s), emulsifying agent(s) or suspending agent(s). These agents can be cationic, anionic or non-ionic agents. Suitable cationic agents are quaternary ammonium compounds, for example ce~yltrimethylammonium bromide.
Suitable anionic agents are soaps, salts of aliphatic monoesters of sulphuric acid (for example sodium lauryl sulphate), and salts of sulphonated aromatic compounds (for example sodium dodecylben2enesulphonate, sodium, calcium or ammonium lignosulphonate, butylnaphthalene sulphonate, and a mixture of sodium diisopropyl- and triisopropyl-naphthalene sulphonates).
Suitable non-ionic agents are the condensation products of ethylene oxide with ~atty alcohols such as oleyl or cetyl alcohol, or with alkyl phenols such as octyl- or nonyl-phenol and octylcresol. 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 hydrophilic colloids (for example polyvinylpyrrolidone and sodium carboxymethylcellulose), and the vegetable gums (for example gum acacia and ~um tragacanth). ' T~e compositions for use as aqueous dispersions or emulsions are generally supplied in the form of a concen-trate containing a high proportion of the active ingred-ient(s), the concentrate to be diluted with water bef~
use. These concentrates often should be able to with-stand storage for prolonged periods and after such storage be capable of dilution with water in order to orm 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 95~, suitably 10-85~, for example 25-60~, /

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by weight of the active ingredient(s). These concentrates suita~ly contain organic acids (e.g. alkaryl or aryl sulphonic acids such as xylenesulphonic acid or dodecyl-benzenesulphonic acid) since the presence of such acids can increase the solubility of the active ingredient(s) in the polar solvents often used in the concentrates.
The concentrates suitably contain also a high proportion or surfactants so that sufficiently stable emulsions in water can be obtained. After dilution to fo~n aqueous preparations, such preparations may contain varying ~nounts of the active ingredient(s) depending upon the intended purpose, but an aqueous preparation containing 0.0005~ or 0.01% to 10% by weight of active ingredient(s) may be used.
The compositions o f this invention can comprise also other compound(s) having biological activity, e.g.
compounds having similar or complementary fungicidal activity or compounds having plant.growth regulating, herbicidal or insecticidal activity.
The other fungicidal compound can be for example one which is capable of combating ear diseases of cereals (e.g. wheat) such as Septoria, Gibberella and Helmintho-spori~n spp., seed and soil borne diseases and downy and powdery mildews on grapes and powdery mildew and scab on apple etc. These mixtures of fungicides can have a broader spectrum of activity than the compound o~ general formula (I) alone; further the other fungicide can have a synergistic effect on the fungicidal activity of the compound of general ormula (I). Examples of the other_ fungicidal compound are imazalil, benomyl, carbendazim (BCM), thiophanate-methyl, captafol, captan, sulphur, dithiocarbamates, carbathiins, copper oxychloride, tri-forine, dodemorph, tridemorph, dithianon, pyrazophos, binapacryl, quinomethionate, panoctine, furalaxyl, alumini~n tris(ethylphosphonate), DPX3217, ethirimol, '7~L

dirnethirimol, bupirimate, chlorothalonil, Chevron RE 20615*, vinclozolin, procymidone, iprodione, metaxanine, dichlobutrazol and thiabendazol.
The compounds of general formula (I) can be mixed with soil, peat or other rooting media for the protection of plants against seed-borne, soil-borne or foliar fungal diseases.
Suitable insecticides are pirimor, croneton, dimethoate, metasystox and formothion.
Examples of suitable plant growth regulating compounds are the gibberellins (e.g. GA3, GA4 or GA7), the auxins (e.g.
indoleacetic acid, indolebutyric acid, naphthoxyacetic acid or naphthylacetic acid), the cytokinins (e.g. kinetin, diphenylurea, benzimidazole, benzyladenine ox B~P), phenoxyacetic acids (e.g.
2,4-D or m-chlorophenoxyacetic acid~, substituted benzoic acids (e.g. triohlobenzoic acid), morphactins (e.g. chlorfluorecol), maleic hydrazide, glyphosate, glyphosine, long chain fatty alcohols and acids (e<g~ Off Shoot O or Off Shoot T), dikegulac, Sustar, Embark, substituted quaternary ammonium and phosphonium compounds (e.g. CCC or Phos-Eon-D), Ethrel, carbetamide, Racuza, Alar, asulam, abscissic acid, isopyrimol, RH531*, hydroxy-benzonitriles (e.g. bromoxynil), Avenge, Suffix or Lontrel.
The following ~xamples illustrate the invention; the temperatures are given in degrees Centigrade (C).

* Trade Mark - -:

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1-(1,_2,4-Triazol-l-yl)-2,3-diphenyl~propan-2~ol Benzyl chloride (0.2 mol) was dissolved in dry diethyl ether (200 ml) and added dropwise to magnesium turnings (0.22 g atoms). After all the magnesium had reacted, the solution was refluxed for 1 hour and ~ooled to room temperature. Phenacyl chloride (0.1 mol) in dry diethyl ether (100 ml) was added dropwise over 1 hour at such a rate as to maintain gentle reflux. The solution was then refluxed for 2 hours, and cooled to room tem-perature; the mixture was poured into ice and the complex decomposed with ammonium chloride solution. The ethereal solution was washed several times with water ~2 x 200 ml), dried (Na2S04), and the solvent removed in vacuo to give, as a colourless oil, the crude chlorohydrin which was dissolved in dimethyl formamide (80 ml) and a solution of sodium triazole / prepared from sodium (0.1 g atoms) in methanol (40 ml) and 1,2,4-triazole (0.1 mol) ~ added dropwise at room temperature. After stirring at room temperature for 2 hours, the solution was warmed at 50 for 3 hours. The solvent was removed ln vacuo and the residue pouxed into water-to give a crys~alline solid which was recrystallised from ethanol/
petroleum ether to give the title compound, m.pO 124.5 . .

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1-~1,2,4-Triazol~ 2-phenyl-3-p-fluorophenyl-~roPan -2-ol p-Fluorobenzyl chloride (0.1 mol) in dry diethyl ether (lO0 ml) was added dropwise to magnesium turnings (0.11 g atoms) and the solution stirred vigorously until refluxing occurred. When all the magnesium had reacted, the solution was refluxed for a further l hour and then cooled to room temperature. Phenacyl-chloride (0.05 mol) in dry diethyl ether (50 ml) was added dropwise to the solution over l hour at such a rate as to maintain gentle reflux. The mixture was refluxed for 2 hours, cooled to room temperature and the mixture poured into ice/ammonium chloride solution to decompose the complex. The ethereal solution was washed several times with water (2 x 200 ml), dried (Na2S04), and the solvent removed ln vacuo to give, as a colourless oil, the crude chlorohydrin~ The latter was dissolved in dimethylformamide (40 ml) and a solution of sodium triazol~ / prepared rom sodium ~0.05 g atoms) in methanol (20 ml) and 1,2,4-triazole (0.05 mol) /
added dropwise at room temperature. Aiter stirring at room temperature for 2 hours, the solution was warmed at for 3 hours. The solvent was removed in vacuo and the mixture poured into water to give a crystalline solid which was recrystallised from petroleum ether/chloroform to give the title compound, m.p. 116-8. ~
,. , ~

EXA~LE 3 1-~1,2,4-triazol-1-yl)-2,2-diphenyl-ethan-2-ol (Compound 17) Le l. Bromobenzene (0.2 mol, 31.4 g) in sodi~m dry diethyl ether (200 ml) was added dl-opwi~e to magneslum (O.22 gram atoms, 5.3 g). After all the magnesium had reacted, phenacyl chloride (0.1 mol, 15.5 g? in diethyl ether (lO0 ml) was added dropwise and the solution stir_ed at room temperature for 1 hour. The reaction mixture was poured into satura.ed ammonillm chloride solution, washed with water (3 x lS0 ml), and dried (~a2S04!.
Removal of the ether gave a pale yellow oil which solidified on stanZing. Recrystallisation from petroleu~ ether (60-80) ~ave l,l-diphenyl-2-chlo.o ethan-l-ol (60%) as a white crystalline solid, m.p. 56-57.

Stage 2. 1,2,~-Triazole (0.03 mol, 2.07 g~ was added portionwise to a suspension of so~i~m hydride (0.03 mot, 0.72 g) in DME ~30 ml~ and the solution stirred until eflervescence ceased. l,l-Diphenyl-2-chloro-ethan-l-ol (0.015 mol, 2.94 g) in dimethylformamide (~MF; lO ml~
was added dropwise and the solution war~.ed at 100 for six hours. The reaction mixture was poured into water and a white solid crystallised out. This was filtered of, washed with water, dried, and recrystallised from ethanol to gi~e the ti~le compcund as a white crystalline solid, m.p. 178-129. ~

~ 18 - PP30692A

1-(1,2,4-triazol-1-~1)-2-phenyl-4-methyl-pentan-2-ol (Compound 31) Sta~e 1. The Grignard reagent generated from isobutyl bromide (0.1 mol, 13.7 g) in sodium dry diethyl ether (50 ml) and magnesium turnings (O.11 g atoms; 2.6 g~
was added dropwise to a solution of phenac~l chloride (0.05 mol, 7.7 g) in sodium dry diethyl ether (100 ml~
so that gentle reflux was maintained. The solution was then stirred at room temperature for 1 hour and the magnesium comple~ destroved by pouring into a saturated ammonium chloride solution ~200 ml~. The ethereal extract was washed with water (3 x 150 ml) and dried (Na2SO4~.
Removal of the solvent gave a colourless liquid which distilled at reduced pressure to give 2-methyl-4-phenyl-5-chloro-pentan-4-ol (70%), b.p. 86-88/O.Ol mm Hg.

Sta~e 2. 1,2,4-Triazole (0.03 mol, 2.07 g) was added portionwise to 100% sodium hydride (0.03 mol, 0.72 g) in dry DMF (30 ml) and stirred at room temperature until the effervescence ceased. 2-Methyl-4-phenyl-5-chloro-pentan-4-ol (O.Ol mol, 2.1 g) in dry DMF (lO ml) was added dropwise at room temperature and then the solution was ~tirred at 100 for 6 hours. On cooling to room temperature the solution was poured into water to precipitate out a solid which was recrystallised from petroleum (60-80)/chloroform giving the title compound (60%~ as a white crvstalline solid, m.p. 94 95.
~ = _ /

!~ J' '1 ' The compounds were tested against a variety of foliar fungal diseases of plants. The technique employed was as follows.
The plants were grown in John Innes Potting Compost (No 1 or 2) in 4 cm diameter minipots. A layer of fine sand was placed at the bottom of the pots containing the dicotyledonous plants to facilitate uptake of test -compound by the roots. The test compounds were formulated either by bead milling with aqueous Dispersol T or as a solution in acetone or acetone/ethanol which was diluted to the re~uired concentration immediately ~efore use.
For the foliage diseases, suspensions (100 ppm active ingredient) were sprayed on to the soil. Exceptions to this were the tests on Botrytis cinerea, Plasmopara viticola and Venturia inaequalis. The sprays were applied to maximum retention and the root drenches to a final concentration equivalent to approximately 40 ppm a.iO/
dry soil. Twe~n 20, to give a final concentration of 0.05~, was added when the sprays were applied to cereals.
For most of the tests the compound was applied to the soil (roots) and to the foliage (by spraying) one or two days before the plant was inoculated with the diseases. An exception was the test on Erysiphe ~raminis in which the plants were inoculated 24 hours before treat-ment. After inoculation, the plants were put into an appropriate environment to allow infection to take place and then incubated until the disease was ready for assessment. The period between inoculation and assess-ment varied from four to fourteen days according to the disease and environment.
The disease control was recorded by the following grading~
- ~

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4 = no disease 3 - trace - 5% of disease on untreated plants 2 = 6-25% of di.sease on untreated plants 1 - 26-59% of disease on untreated plants 0 = 60-100% of disease on untreated plants ~he results are shown in Table II. -~

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Claims (4)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows;

1. Chemical compounds of the general formula:

and wherein R1 is buty,,2-chloro-, or 2-fluorophenyl, or cycloalkyl of up to 6 carbon atoms and R2 is 2-chlorobenzyl or is wherein X is hydrogen, chlorine or fluorine and Y is chlorine or fluorine.

2. Compounds as claimed in claim 1 wherein R1 is t-butyl, 2-chlorophenyl or 2-fluorophenyl and R2 is 4-fluorophenyl or 4-chlorophenyl.

3. The compounds of formula and

4. The compounds of the formulae below wherein X is chlorine or bromine:

and