DD261601A5 - PROCESS FOR THE PREPARATION OF 2,3-DIHYDROFURAN COMPOUNDS - Google Patents

Abstract

The invention relates to a process for the preparation of 2,3-dihydrofuran compounds of the formula (I) in which X is a halogen atom, preferably fluorine, bromine or chlorine, or an alkyl or alkoxy group having 1 to 12 carbon atoms, preferably 1 to 4 carbon atoms which is optionally mono- or polyhalogenated, in particular the CF 3 group, or a cyano group, when R 3 and / or R 4 represent a hydrogen atom, an integer 6 or 0, preferably 2, where - if n 1 - the substituents X may be identical or different, m is 0 or 1, Y is an atom or group which may be eliminated by nucleophilic substitution, optionally after appropriate intermediate conversion, and their agriculturally acceptable salts. These compounds are useful as intermediates for the preparation of tetrahydrofuran compounds having imidiazole or triazole groups which are useful as fungicides. Formula (I)

Description

For this 2 pages formulas

Field of application of the invention

The invention relates to a process for the preparation of 2,3-dihydrofuran compounds. These compounds are useful for preparing tetrahydrofuran compounds having a triazole group which are useful as fungicides.

Characteristic of the known state of the art

Tetrahydrofuran compounds having a triazole group are known fungicidal compounds. They are described above all in EP-A 0121979 and / or 0151084.

Object of the invention

An object of the invention is to provide a process for the preparation of novel tetrahydrofuran compounds having triazole or imidazole group, which leads to improved yields and can be carried out under improved reaction conditions.

Explanation of the essence of the invention

The invention relates to a process for the preparation of compounds of the formula (I) in the list at the end of the description, in which:

R ² , R ³ and R ^{4 are the} same or different and each represents a hydrogen atom or a lower alkyl group, lower cycloalkyl group or an aryl group, especially the phenyl group, optionally substituted by one or more atoms or groups such as halogen atoms, lower alkoxy groups , Aryl groups, in particular phenyl groups, lower alkyl groups, lower haloalkyl groups, lower haloalkoxy groups, aryloxy groups, in particular phenoxy groups, or hydroxy groups, may be substituted,

X represents a halogen atom, preferably a fluorine, bromine or chlorine atom, or an alkyl or alkoxy group having 1 to 12 carbon atoms, preferably having 1 to 4 carbon atoms, which is optionally mono or polyhalogenated, especially the CF ₃ group, or a cyano group then when R ³ and / or R ^{4 is} a hydrogen atom, η is an integer, positive or zero, and> 6, preferably = 2, where, when n> 1, the substituents X are either

may be the same or different, m is 0 or 1, Y is an atom or a group which can be removed by nucleophilic substitution, optionally after appropriate intermediate transformation,

and their agriculturally acceptable salts, characterized in that a compound of the formula (II) in which R ² , R ³ , R ⁴ , X, n, m and Y have the same meaning as for the compounds of the formula (II) I), in the presence of a catalyst, isomerized in a homogeneous or heterogeneous phase.

The agriculturally acceptable salts of the compounds of this invention include the chlorohydrates (hydrochlorides), sulfates, oxalates, nitrates, alkyl sulfonates, or alkyl sulfonates, as well as the addition complexes of these compounds with metal salts, especially iron, chromium, copper, manganese, zinc, Cobalt, tin, magnesium and aluminum salts. By way of example, complexes with zinc can be obtained by reacting the compounds of formula (I) with zinc chloride.

The term "lower" refers to an organic group of at most six carbon atoms, which may be straight chain or branched.

As an atom or group which can be removed by means of a nucleophilic substitution, especially the halogen atoms, preferably the chlorine or bromine atom, as well as hydroxyl or thiol groups. However, since these latter are not sufficiently mobile, they must be transferred to (intermediate) leaving groups. These include the tosylate, mesylate, triflate or group of formula [Ph ₃ P ⁺ -O-].

The conversion into a leaving group is carried out in a conventional manner by the action of the corresponding acid chlorides, such as tosyl chloride or mesyl chloride, or by the action of trifluoromethanesulfonic anhydride in the presence of a tertiary amine, or of pyridine, for example, or in neutral medium by the action of ethyl diazodicarboxylate and triphenylphosphine ,

The catalysts useful for the isomerization advantageously include the following transition metals: ruthenium, cobalt, palladium, nickel, rhodium, iridium, platinum and iron.

These catalysts may be effective in the metallic state in heterogeneous catalysis; in this case they are deposited on a suitable inert support, for example activated carbon. Preferably, they also function in homogeneous catalysis in the form of complexes which, in addition to the transition metal, have one or more suitable ligands, e.g. As phosphine or carbonyl, and one or more molecules contain hydrides (hydrogen). The reaction may be carried out in bulk or in the presence of a protic or aprotic solvent. Among the aprotic solvents may be mentioned: the saturated aliphatic hydrocarbons such as n-pentane, isopentane, 2-methylhexane, 2,2,5-trimethylhexane; aromatic hydrocarbons, such as benzene, toluene, ethylbenzene; saturated aliphatic ethers such as tetrahydrofuran and isopentyl ether; aromatic ethers, such as benzyl ethyl ether; saturated aliphatic or aromatic ketones, such as methyl ethyl ketone and acetophenone; saturated aliphatic or aromatic halohydrocarbons, such as fluorobenzene, 1-chloro-2-methylpropane and isobutyl chloride; saturated aliphatic or aromatic esters such as isobutyl isobutyrate, ethyl acetate and methyl benzoate. All of these solvents may be present individually or as a mixture.

As protic solvents may be mentioned: the saturated aliphatic or aromatic alcohols, such as methanol, isopropanol and phenol; the saturated aliphatic or aromatic acids, such as the propionic acids and benzoic acid. It is also possible to use a mineral acid in admixture with one of said organic solvents with which the mineral acid is miscible, for example hydrogen chloride in methanol. In this case, one directly obtains the compounds of formula (V) described below, in which R ¹ = CH ₃ . All of these solvents can be present individually or in a mixture. Among these solvents, the aromatic hydrocarbons or the lower saturated aliphatic alcohols which are optionally halogenated, such as trifluoroethanol, are preferred. If the reaction is carried out in the presence of a solvent, the dilution (concentration) of the reaction product is above all in the range from 0.5 to 99% by weight, based on the total weight of the solution, preferably from 5 to 50%.

The amount of the catalyst used is preferably 0.00005 to 0.1 mol per mole of the compound of the formula (II). The isomerization temperature may vary within a wide range, for example from -20 ° C to the decomposition temperature of the catalyst. In order to achieve a good compromise between reaction time and the commercial operating conditions, a temperature range of O to 100 ⁰ C, advantageously from 10 to 80 ° C is preferred. The pressure is generally in the range of 1 to 10 atm (0.1 to 1 MPa).

An advantageous but not mandatory method of synthesizing compounds of formula (II) wherein Y represents a hydrogen atom is by cyclizing the compound of formula (VI) in cis form, wherein X, n, m, R ² , R ³ and R ^{4 have} the same meaning as for the compounds of formula (I) and Hal is a halogen atom either in acidic medium when Z is a hydrogen atom or in basic medium when Z is an leaving group such as a mesylate tosylate triflate group or a group of the formula [Ph ₃ P ⁺ -O-].

These leaving groups are bound to the OH group as before and selectively, without touching the tertiary OH group.

For this cyclization, the organic or inorganic acid catalysts are suitable. They may be soluble or insoluble in the reaction medium as well as protic or aprotic. As protic acids can be mentioned hydrochloric or hydrochloric acid, sulfuric acid, trifluoroacetic acid, perchloroacetic acid, benzenesulfonic acid, toluenesulfonic acid and methanesulfonic acid.

Examples of aprotic acids are Lewis acids, such as BF ₃ , AICI ₃ and SnCl ₄ .

Preferably, from 0.1 to 2 molar equivalents of acid are used.

It is also possible to carry out this cyclization with the aid of catalysts bound to inert supports, for example sulfone resins or sulfonic acid-containing resins.

The cyclization is usually carried out by simply heating the indicated reactants. The temperature is generally in the range of 10 to 100 ° C or, when a solvent is present, in the range of 1O ⁰ C to the boiling temperature of the solvent used.

As examples of the many useful solvents, mention may be made of the aliphatic and aromatic solvents, such as toluene, ethers and ketones.

In the case of cyclization in basic medium, there may be exemplified inorganic bases such as sodium hydroxide or potassium hydroxide, alkali or alkaline earth carbonates, nitrogen bases such as triethylamine, quaternary amines such as tetrabutylammonium hydroxide or phosphonium hydroxides. Preferably, 0.01 to 2 molar equivalents of base are used. It is also possible to carry out this cyclization with the aid of catalysts bound to inert supports, such as resins. The reaction is usually carried out at a temperature in the range of 10 to 100 ° C and optionally in the presence of a solvent, such as the aliphatic and aromatic solvents, ethers and ketones.

The compounds of the formula (II) in which Y is an OH group can be obtained by basic treatment of compounds of the general formula (VI) in which Z = H.

In this case, the reaction proceeds via the corresponding epoxides as intermediates which are obtained from the compounds of the general formula (VI). It is then necessary after isomerization to convert the group Y = OH to an leaving group such as the mesylate, tosylate or triflate group or Ph ₃ P ⁺ -O, before the substitution reaction with the triazole takes place as described below can.

When both substituents R ³ and R ^{4 represent} a hydrogen atom, the compounds of the formula (VI) are preferably obtained by hydrogenation of compounds of the formula (VII) in which X, n, m, R ² and Y have the same meaning as for the compounds of the formula (II) and in which Pr is a protective group, such as the 1-ethoxyethyl group or a hydrogen atom, with the aid of an equimolar amount of hydrogen in the presence of a suitable catalyst, optionally (partially) poisoned, and selected from the following catalysts: palladium, Ruthenium, Raney nickel, platinum and rhodium; preferably palladium, optionally (partially) poisoned (pyridine, quinoline, tetrahydrothiophene) which specifically gives the cis-olefin.

As before, this reaction can be carried out in homogeneous or heterogeneous phase.

Preferably, one selects metallic palladium deposited on an inert support such as activated carbon, calcium carbonate or barium sulfate.

While not necessarily required, the reaction may optionally be carried out in a polar protic solvent, for example in a lower alcohol such as methanol, or aprotic solvents such as in toluene.

The dilution of the compound of the formula (VII) is preferably from 1 to 80% by weight or, more preferably, from 5 to 40% by weight, based on the total solution.

Although the molar ratio of catalyst to compound of formula (VII) may vary considerably; however, for obvious technical reasons, the catalyst is preferably used in a molar ratio of 0.01 to 0.5%, based on the compound of the formula (VII).

The reaction is carried out at temperatures in the range of -20 ⁰ C to +150 ⁰ C, preferably in the range of 10 to 80 ⁰ C, and under a pressure of 1 to 10 atm (corresponding to 0.1 to 1 MPa).

The compounds of the formula (VII) can be obtained by means of generally known processes, for example by addition of the organomagnesium compound of the formula:

R ² HOPr) CH-C = C-Mg-Br to an acetophenone of the formula:

(X) _n Ph (CH ₂ Jm-COCH ₂ Hal.

If Pr is a protecting group, it must be removed before the cyclization. The reaction can take place, for example, in a manner known per se in tetrahydrofuran.

If at least one of the substituents R ³ or R ^{4 is} not a hydrogen atom, the following synthesis or preparation route can be used: addition of an organomagnesium compound of the formula R ⁴ MgX to compounds of the general formula (VII), if appropriate in the presence of copper iodide and optionally subsequently Addition of an alkyl halide R ³ X in a solvent such as tetrahydrofuran. If the reaction is interrupted in the addition of R ⁴ MgX, of course, this addition must be followed by hydrolysis.

The compounds of formula (I) obtained according to the invention can be used as intermediates for the preparation of compounds of formula (III) in which W represents a trivalent group, either the group = CH- or a nitrogen atom = N-; R ^{1 represents} a hydrogen atom or a lower alkyl group, lower cycloalkyl group, aryl group, especially a phenyl group, aralkyl group, especially the benzyl group; these various groups may optionally be substituted with one or more atoms or groups, for example with halogen atoms, lower alkoxy groups, aryloxy or hydroxy groups; and R ² , R ³ , R ⁴ , X, η and m have the same meaning as in the case of the compounds of formula (I); the use is characterized in that it consists either in the grafting of an imidazole or triazole ring on a compound of formula (I) such that a compound of formula (IV) is obtained with subsequent addition of a compound of formula R ¹ OH in acid Medium; or addition of a compound of the formula R ¹ OH in acidic medium to a compound of the formula (I), so that a compound of the formula (V) is obtained, and subsequent grafting of an imidazole or triazole ring.

The grafting may be carried out with the aid of an imidazole or triazole, which has been converted to its salt form, optionally in situ.

The grafting is advantageously carried out in the presence of an acid acceptor, in an anhydrous or non-anhydrous medium, in a solvent inert under the reaction conditions, and generally at a temperature between 50 and 180 ° C, preferably at a temperature close to the boiling temperature of the solvent. Suitable acid acceptors are inorganic bases, such as sodium hydroxide or potassium hydroxide, alkali metal or alkaline earth metal carbonates, nitrogen bases, such as triethylamine, quaternary amines, such as tetrabutylammonium hydroxide, or the phosphonium hydroxides. The solvents used are advantageously aprotic polar solvents, for example dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetone, methyl ethyl ketone, acetonitrile, N-methylpyrrolidone or protic polar solvents, such as methanol or propanol. If desired, this reaction can be carried out in the presence of a suitable catalyst. As useful catalysts may be mentioned phase transfer catalysts, such as quaternary ammonium compounds, eg. For example, tetrabutylammonium chloride.

The reaction is preferably carried out with a molar excess of triazole or imidazole compound of preferably 1.05 to 1.5.

If a solvent is also used, preference is given to working in a dilute medium containing 1 to 70% by weight of compound of the formula (I) or (V), based on the total solution.

The acid acceptor is present in at least a stoichiometric amount based on equivalents of the mobile hydrogen of the triazole or imidazole compounds. Generally, a ratio of 1 to 2.5 molar equivalents is satisfactory. The salt compound of triazole or imidazole can be prepared independently, and in this case, the presence of an acid acceptor in the grafting reaction is not required. This preparation is carried out in anhydrous or non-anhydrous medium in a solvent under the same operating conditions as described for the in situ formation of the triazole or imidazole in its salt form

 The addition reaction is carried out in acidic medium.

The acid catalyst used in this reaction may be a protic or aprotic, soluble or insoluble acid. Suitable protic acids are, for example, hydrochloric acid, sulfuric acid, trifluoroacetic acid, perchloric acid, benzenesulfonic acid, toluenesulfonic acid and methanesulfonic acid. As aprotic acids, the Lewis acids such as BF ₃ , AICI ₃ and SnCl _{4 may} be mentioned. It is also possible to use solid resins, for example sulfone resins or sulfonic acid group-bearing resins. Preferably, 0.1 to 2 molar equivalent of acid per mole of compound of the formula (I) or (IV) (or [II]) are used. The reaction is usually carried out by simply heating the indicated reactants. The temperature is generally in the range of 10 to 100 ° C or, if a solvent is present, in the range of 10 ⁰ C and the boiling temperature of the solvent used. Suitable solvents are, in particular, aliphatic, alicyclic or aromatic solvents which are optionally halogenated. Ethers or alcohols, for example of the formula R ¹ OH.

The molar ratio R ¹ OH to compound of the formula (I) or (IV) is preferably greater than 1, advantageously in the range from 1 to 100.

If a solvent is used, the dilution (concentration) of the compound of the formula (II), based on the total solution, should advantageously amount to 5 to 70% by weight.

After completion of the reaction, regardless of the chosen method, the resulting compound of formula (III) from the reaction medium by any means known, isolated, for example by distilling off the solvent or by crystallization of the product from the reaction medium or by filtration and - if necessary - is this compound purified by conventional methods, for example by recrystallization from a suitable solvent. An imidazole or triazole ring can also be grafted onto the compound of formula (II) according to the grafting step described above or introduced into this compound and then isomerize the double bond in the presence of a catalyst in homogeneous phase or in heterogeneous phase, as described above. In this case, the reaction proceeds via a compound of formula (VIII).

The compounds of formula (IV) and their agriculturally acceptable salts are also useful as fungicides. Namely, these compounds have excellent properties, in particular for the control of mildew, the congestion disease and generally other fungal diseases of the crop.

It is known that ethers of the formula XCH2-O-CRR'-C = CH in which X is CH ₂ OH, CF ₃ or-C = CH and R and R 'are a hydrogen atom or a lower alkyl group, by Effect of a bromide of the formula BrCH ₂ -C = CH can be prepared on the corresponding sodium ethoxide in the presence of an aprotic polar solvent at room temperature. This process is described in U.S. Patent 3,077,501.

A disadvantage of this process, however, is that one must work with propargyl bromide, an unstable and difficult to handle on an industrial scale compound.

Moreover, if the bromide is replaced by the chloride, the prior art process does not result in the expected propargyl ether

 Propargyl ethers of the formula (IX)

R ¹ O-CHR ² -C =CH,

in which R ¹ and R ^{2 have} the same meaning as before, can be prepared by reacting a compound of the formula (X) R ¹ OM (M = alkali metal) with a propargyl chloride of the formula (XI)

CI-CH-C = CH (XI)

R ²

in which R ^{2 has} the same meaning as in the formula (IX), in the presence of an alkali metal halides.

In this specification, "lower / lower" means an organic group containing at most 6 carbon atoms, which may be linear or branched.

The process is of particular interest when R ^{1 is} a group substituted with one or more halogen atoms, especially -CH ₂ CF ₃ , -CH ₂ CH ₂ Cl, -CH ₂ CH ₂ F, CH ₂ OCH ₃ , CH ₂ OC ₂ H ₅ , furthermore, R ¹ can denote a C ₁ to C ₄ alkyl group.

Among the alkali halides, the alkali iodides are preferred, especially sodium iodide or potassium iodide.

Preferably, the reaction is carried out in the presence of a solvent, which is advantageously an aprotic polar solvent such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile or N-methylpyrrolidone. If necessary, a mixture of two phases, namely water + solvent as mentioned above, may be used in the presence, if appropriate, of a phase transfer catalyst, such as a quaternary ammonium compound, for example tetrabutylammonium chloride.

The reaction temperature is advantageously in the range of from room temperature to the reflux temperature of the solvent, if used.

When a solvent is used, it is preferable to work in a dilute medium containing 1 to 70% by weight of compound of formula (X) and (XI), based on the total solution.

Preferably, the molar ratio (X) :( XI) is in the range of 0.5 to 2, preferably about 1.

The molar amount of alkali halide can be much lower than that of the compound of formula (X). Advantageously, it is 2 to 100 times less.

embodiments example 1

Preparation of 2-chloromethyl-2- (2,4-dichloro-1-phenyl) -2,3-dihydrofuran.

A solution of 3.95 g (15 mmol) of 2-chloromethyl-2- (2,4-dichloro-1-phenyl) -2,5-dihydrofuran in 7.5 ml of methanol was introduced into a 25 ml flask under inert atmosphere. 144mg (0.15mmol) of RuH ₂ (PPh ₃ I _{4 was} added and the whole heated to reflux The reaction was complete after 12 hours, the methanol was removed under reduced pressure and purified to yield 3.817g (14.48mmol ) of a colorless oil; Yield: 96.5% based on the starting compound.

Preparation of 2-chloromethyl-2- (2,4-dichloro-1-phenyl) -2,5-dihydrofuran.

In a 100 ml flask under inert atmosphere, 10 g (35.5 mmol) of 1-chloro-2- (2,4-dichloro-1-phenyl) -3-pentene-2,5-diol (cis-isomer) in 60 ml of toluene submitted. Then, 0.5 g of p-toluenesulfonic acid was added and the whole was heated to reflux. After completion of the reaction was washed and separated. This gave 9.36 g (35.5 mmol) of a brown oily residue; Yield 100%, based on the starting compound.

Preparation of 1-chloro-2- (2,4-dichloro-1-phenyl) -3-pentene-2,5-diol (cis isomer). Method A:

54.5 g (0.5 mol) of bromoethane dissolved in 225 ml of THF at T = 30 ° C. were introduced into a 500 ml flask under an inert atmosphere containing 13.37 g of magnesium and 30 ml of tetrahydrofuran over the course of 2 hours , The resulting solution was then added dropwise over 1 hour at room temperature to a solution of 64.09 g (0.5 mol) of 2-ethoxyethyl-propargyl ether in 40 ml of THF. To this solution was then added at 0 ° C over 2 hours a solution of 89.4 g (0.4 mol) of 2,4,2'-trichloroacetophenone in 100 ml of THF. The whole was kept for 6 hours at 2O ⁰ C. It was then cooled to ⁰ ° C. and 28.6 ml (0.5 mol) of acetic acid were added thereto over 15 minutes at 5 ° C., then 150 ml of water and then 100 ml of ethyl ether were added. The organic phase or layer was washed twice with 50 ml of water and once with 50 ml of brine; then the solvents were removed under reduced pressure. This gave 136.6 g of a viscous yellow oil. Yield: 97.2%, based on the starting compound.

The compound was identified as 1-chloro-2- (2,4-dichloro-1-phenyl) -5- (1-ethoxyethoxy) -3-pentyne-2-ol. In a 500 ml flask under an inert atmosphere, a solution of 24 g of the just-obtained compound in 150 ml of toluene and 0.613 g of palladium - 5% were submitted to coal. Then, hydrogen was introduced under atmospheric pressure at 25 ° C. After 2 hours, filtered and the solvent removed under reduced pressure.

The oily residue was taken up in 200 ml of methanol and treated with 50 ml of 0.5 N hydrochloric acid. Then, the methanol was removed under reduced pressure to obtain 19.36 g of an oily orange residue. By adding 10 ml of ethyl acetate and then 35 ml of pentane, 5.35 g (19.3 mmol) of the desired diol were precipitated. Method B :,

In an 11 flask containing 36.5 g (1.5 mol) of magnesium and 216 g of THF and 75 ml of toluene under inert atmosphere was allowed to run at 30 ° C in the course of VAStunden 163,45g of bromoethane in 250ml of toluene. The whole was allowed to rest for 15 minutes at 24 ⁰ C. Then, a solution of 42.15 g (0.75 mol) of propargyl alcohol in 50 ml of toluene was added dropwise over 1 2 hours. Then a solution of 111.7 g (0.5 moles) of 2,4,2'-trichloroacetophenone in 100 ml of toluene was added dropwise at 44 ° C. The whole was allowed to rest at room temperature. It was then cooled to 0 ° C and treated dropwise with 90g (1.5 mol) of acetic acid. It was then evaporated, 250 ml of toluene was added and washed with dilute sulfuric acid and then with water. The organic layer was then concentrated, cooled, precipitated, filtered and dried. This gave 1-chloro-2- (2,4-dichloro-1-phenyl) -3-pentyne-2,5-diol, m.p. = 9O ⁰ C. The hydrogenation was carried in the same manner as in Method A, but at 5O ⁰ C, made. The desired diol was obtained.

Example 2

Preparation of 2- (2,4-dichloro-1-phenyl) -2-methyl- (1-triazole) -5-trifluoroethoxy-tetrahydrofuran.

Preparation of 2- (2,4-dichloro-1-phenyl) -2-methyl- (1-triazolyl) -2,3-dihydrofuran.

In a 50 ml flask under an inert atmosphere, a solution of 1,000 g (3.80 mmol) of the compound prepared according to Example 1 in 1.00 g of N-methylpyrrolidone (NMP) was submitted. Then, 314.8 mg (4.56 mmol) of 1,2,4-triazole and 630.2 mg (4.56 mmol) of potassium carbonate were added. The reaction mixture was heated to 17O ⁰ C for 14 hours and then cooled to about 2O ⁰ C. Then 10 ml of toluene and then water saturated with ammonium chloride were added. The toluene phase was separated and the aqueous phase was extracted twice more with 10 ml of toluene. The combined organic extracts were dried over sodium sulfate. Filtration and concentration under reduced pressure gave a semi-crystalline residue which was purified.

This gave 673 mg (2.28 mmol); Mp (Kofier) 100 ⁰ C.

Yield: 60%, based on the 2,3-dihydrofuran compound used.

Preparation of 2-chloromethyl-2- (2,4-dichloro-1-phenyl) -5-trifluoroethoxy-tetrahydrofuran.

Into a 10 ml flask under inert atmosphere was added 0.528 g (2 mmol) of 2- (2,4-dichloro-1-phenyl) -2-chloromethyl-2,3-dihydrofuran, 1 ml (13 mmol of trifluoroethanol, 0.5 ml of methylene chloride and some . incorporated grains p-toluenesulfonic this mixture was heated to 40 to 50 ⁰ C for 1 hour, after which time the reaction was complete, the solvents were then under reduced pressure (30 mm Hg and 40 mbar - 40 ⁰ C) is subtracted, and the like. 0.713 g (1.96 mmol) of a 60/40 mixture of the two diastereoisomers was obtained

 Yield: 98%, based on the starting compound.

Preparation of 2- (2,4-dichloro-1-phenyl) -2-methyl- (1-triazole) -5-trifluoroethoxy-tetrahydrofuran. Method A

Into a 10 ml flask under inert atmosphere were charged 600 mg (1.65 mmol) of the previously prepared tetrahydrofuran compound and 1.7 ml of N-methylpyrrolidone (NMP). Then, 0.180 g (1.98 mmol) of sodium triazolate was added. The mixture was heated to 160 ⁰ C. After 5 hours, the yield was 15% as determined by liquid chromatography. Method B

In a 25 ml flask, 0.6 g (2 mmol) of 2- (2,4-dichloro-1-phenyl) -2-methyl- (1-triazolyl-2,3-dihydrofuran in toluene solution and 1 ml (13.7 mmol) were added. The mixture was then refluxed and a dry HCl stream passed, after which the reaction was stopped, the reaction mixture was taken up in methylene chloride, washed with saturated sodium carbonate then with water and dried over sodium sulfate. Concentration and purification gave 0.440 g (1.1 mmol) of a white solid, which melted at 168 ° C

 Yield: 80.7%, based on the starting compound.

Preparation of 2- (2,4-dichloro-1-phenyl) -2-methyl- (1-triazolyl) -2,5-dihydrofuran.

In a 50 ml flask under inert atmosphere was added a solution of 1,000 g (3.80 mmol) of 2-chloromethyl-2- (2,4-dichloro-1-phenyl) -2,5-dihydrofuran in 1.00 g of N-methylpyrrolidone (NMP). Then 314.8 mg (4.56 mmol) of 1,2,4-triazole and 630.2 mg (4.56 mmol) of potassium carbonate were added. The reaction mixture was heated at 170 ^° C. for 14 hours and then cooled to about 20 ^° C. Then 10 ml of toluene and then water saturated with ammonium chloride were added. The toluene phase was separated and the aqueous phase was extracted twice more with 10 ml of toluene. The combined organic extracts were dried over sodium sulfate. Filtration and concentration under reduced pressure gave a semi-crystalline residue which was purified.

This compound was then isomerized under the conditions given in Example 1 to give a compound of formula (IV), to which trifluoroethanol was subsequently added.

Example 3

Preparation of 2,3-ditrifluoroethoxy-propene.

To the trifluoroethano-sodium salt prepared by reacting 4.8 g (0.2 mol) of NaH with 20 g (0.2 mol) of alcohol dissolved in 20 mMITHF was added 0.05 g of NaI and 14.9 g (0.2 mol) of propargyl chloride.

After stirring for 24 hours under reflux of the solvent, the reaction mixture was filtered, the precipitate was washed with 40 ml of THF and then the filtrate was distilled.

In this way, 11.44 g (0.063 mol) of a compound, which at 70 to 80 ⁰ C under 96 mm Hg / 128 mbar passed.

Yield / TFE = 63%.

Example 4

Preparation of 3-trifluoromethoxy-propyne-i.

Into a 250 ml four-necked flask with mechanical stirrer, thermometer, inlet funnel and condenser under stirring and under inert atmosphere, 150 ml of dry Ν, Ν-dimethylformamide, 60.02 g (0.6 mol) of trifluoroethanol, 82.9 g (0.6 mol) of potassium carbonate and 4 , 49g (0.03mol) sodium iodide introduced.

49.17 g (0.66 mol) of propargyl chloride were added to the resulting suspension. The reaction mixture was then heated at 85 ° C for 18 hours.

After cooling, the reaction mixture was filtered, and the resulting precipitate was washed with 40 ml of DMF. The filtrate was distilled to give 52.2 g (0.38 mol) of the compound as a colorless liquid which was passed at 81 to 82 ° C under atmospheric pressure.

Yield = 63%.

Example 5

Preparation of 5-chloro-4- (2 ', 4'-dichlorophenyl) -4-hydroxy-1-trifluoroethoxy-2-pentyne.

First, bromethane-Grignard compound starting from 6.74 g (0.27 mol) of magnesium, 27.46 g (0.25 mol) of the halide and 180 ml of anhydrous THF was conventionally prepared. It was filtered to remove excess magnesium and the filtrate was then poured slowly onto a solution of 34.8 g (0.252 mol) of the compound of Example 4 in 60 ml of anhydrous THF. The exothermic reaction caused the release of ethane; this stopped shortly after the end of the encore.

A solution of 31.3 g (0.14 mol) trichloroacetophenone in 35 mL anhydrous THF was then added slowly (exothermic reaction) to the reaction mixture.

After completion of the addition and after cooling, the reaction mixture was poured onto an ice-cold solution of 21 ml of 12N HCl in 100 ml H ₂ O.

After decantation, extraction with 2 × 100 ml Et ₂ O, washing to neutral, drying with sodium sulfate and concentration gave 49 g of an orange liquid, purity 93%; Yield = 90%.

This crude reaction compound was used as such in the next step.

Example 6

Preparation of 5-chloro-4- (2 ', 4'-dichlorophenyl) -4-hydroxy-1-trifluoroethoxy-2-pentene.

A solution of 34 g (0.094 mol) of the acetylene compound in 120 ml of toluene was hydrogenated in the presence of 1 g of palladium on carbon, 5%, under atmospheric pressure and at 65 ° C.

After consumption of one equivalent of hydrogen, stirring was stopped. After cooling, the reaction mixture was filtered and the filtrate was concentrated. This gave 34.2 g of a crude reaction product containing 90% ethylenic compound; Yield = 90%.

The ethylenic compound was predominantly in cis configuration and could be isolated from the crude product by chromatography on a silica column; Eluent: pentane / CH ₂ Cl ₂ = 60/40.

Example 7

Preparation of 5-chloro-4- (2 ', 4'-dichlorophenyl) -4-hydroxy-1-trifluoroethoxy-pentene.

A solution of 2,24g (6.16 x 10 ^"3 mol) of the ethylenic compound in 2.2 ml of toluene was in the presence of 0.07 g (6 χ 10" ⁵ mol) RuH ₂ (PPh ₃ I ₄ to reflux After 1 hour of reaction, the mixture was allowed to cool to room temperature, then diluted with 5 mL of toluene and filtered over 5 g of silica After concentrating, 1.8 g (4.9 × 10 ^-3 mol) of a 58% cis mixture were obtained Compound and 42% trans compound of the vinyl ether.

Yield = 80%.

Example 8

Preparation of 4- (2 ', 4'-dichlorophenyl) -4-hydroxy-5-triazolyl-1-trifluoroethoxy-pentene.

A suspension of 6.54 g (0.018 mol) of the ether obtained in the previous example, 1.35 g (0.019 mol) of triazole and 5.39 g (0.039 mol) of potassium carbonate in 25 mL of dry DMF was heated to 11O ⁰ C for 2 hours.

The mixture was cooled to room temperature and then diluted with 40 mL toluene and 40 mL H ₂ O. After decantation, neutral washing, drying and concentration, 7.1 g of crude reaction product containing 85% of the triazole enol ether were obtained.

After purification on a silica column - eluent: AcOEtZCH ₂ CI = 50/60 -, 4.98 g (0.0126 mol) of the enol ether, cis / trans = 56/44, were obtained. Yield of isolated compound = 70%.

Example 9

Preparation of 2- (2 ', 4'-dichlorophenyl) -2-triazolylmethyl-5-trifluoroethoxy-tetrahydrofuran, A solution of 0.476 g (1.2 × 10 ^-3 mol) of compound (V) in 3 ml of toluene and 0.722 g ( 7.2.times.10.sup.- ³ mol) trifluoroethanol was stirred in the presence of a slight flow of HCl (exothermic reaction) for 2 hours.

After treatment with sodium carbonate, neutral washing, drying and concentration, 0.485 g of crude reaction compound containing 0.404 g (1.02 = 10 ^-3 mol) of Compound A was obtained; Yield = 85%.

Claims (7)

1. A process for the preparation of 2,3-dihydrofuran compounds of the formula (I), in which: R ² , R ³ and R ^{4 are the} same or different and each represents a hydrogen atom or a lower alkyl group, lower cycloalkyl group or an aryl group, especially the phenyl group, optionally substituted by one or more atoms or groups such as halogen atoms Alkoxy groups, aryl groups, in particular phenyl groups, lower alkyl groups, lower haloalkyl groups, lower haloalkoxy groups, aryloxy groups, in particular phenoxy groups, or hydroxy groups, may be substituted, X is a halogen atom, preferably a fluorine, bromine or chlorine atom, or an alkyl or alkoxy group having 1 to 12 carbon atoms, preferably having 1 to 4 carbon atoms, which is optionally mono- or polyhalogenated, especially the CF ₃ group, or a cyano group if R ³ and / or R ^{4 are} a hydrogen atom, η is an integer, positive or zero and <6, preferably = 2, where, when n> 1, the substituents X may be either the same or different, m = 0 or 1, Y represents an atom or a group that can be removed by nucleophilic substitution, optionally after appropriate intermediate transformation, and their agriculturally acceptable salts, characterized in that a compound of formula (II) in which R ² , R ³ , R ⁴ , X, Y, n, m have the same meaning as in claim 1, in the presence of a catalyst isomerized in homogeneous or heterogeneous phase. 2. The method according to claim 1, characterized in that the isomerization catalyst is selected from the group consisting of: ruthenium, cobalt, palladium, nickel, rhodium, iridium, platinum and iron. 3. The method according to claim 1, characterized in that the M ο! Ratio of catalyst to compound of formula (II) is 0.00005 to 0.1. 4. The method according to claim 1, characterized in that the isomerization reaction is carried out in the presence of a solvent and that preferably the amount of the compound of formula (II), based on the total weight of the solution, 5 to 50 wt .-%. 5. The method according to claim 1, characterized in that the temperature of the isomerization reaction is 10 to 80 ° C. 6. The method according to claim 1, characterized in that starting from a compound of formula (II), in which Y is a halogen atom and R ² , R ³ , R ⁴ , X, m and η have the same meaning as in claim 1 which has been obtained by cyclization a compound of formula (VI) either in acidic medium when Z is a hydrogen atom or in basic medium when Z is an leaving group. 7. The method according to claim 6, characterized in that starting from a compound of formula (Vl), in which R ³ and R ^{4 are} a hydrogen atom, and which has been obtained by means of homogeneous or heterogeneous catalysis, a compound of formula (VII) hydrogenated in which Hal is a halogen atom and R ¹ , R ² , m, η and Z have the meaning given above.