AU597413B2

AU597413B2 - 2,3-dihydrofuran derivatives, process for preparing them, and their use as an intermediate for the preparation of tetrahydrofuran derivatives

Info

Publication number: AU597413B2
Application number: AU77261/87A
Authority: AU
Inventors: Jean-Pierre Corbet; Jean Manuel Mas
Original assignee: Rhone Poulenc Agrochimie SA
Current assignee: Bayer CropScience SA
Priority date: 1986-08-22
Filing date: 1987-08-20
Publication date: 1990-05-31
Anticipated expiration: 2007-08-20
Also published as: CN87105818A; FI873625A0; KR880002852A; PL267418A1; FR2603036A1; DK437287D0; PT85570A; EP0258160A2; HUT45040A; AU7726187A; PT85570B; DD261601A5; FI873625A; DK437287A; EP0258160A3; JPS6357580A; BR8704325A; ZA876182B; FR2603036B1

Description

F'

a- 1 597413 A US TRA LI A CO0M MON WEBA LT H O F PATENT ACT 1952 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE CLASS INT. CLASS Application ,Number: Lodged:

I

i

I

j

I

~t~i Complete Specif icationi Lopcjed: Accepted: Published,, S Priority: *"'Rlated Art:: This doQcuinen! contains the] aimrnnts made undert Sjdon A9 and is correct for f~ill ting **NAME rOF APPLICANT: 4 #9 9 9 4 4 #4 4 44

I

44 ADDRESS 'OF APPLICANT:- NAME(S) OF INVENTOR(S1: ADDRESS FOR SERVICE: RHONE-.POULENC AGROCHIMIE 1.4-20 Rue Piekrre Baizetpr Lyon 9a, Jean Pierre 'CORBET Jean Manuel MAS DE5 IV. COJ Patent Atticrneys 1 Little 'Ci~ling Stt~iet, 'Melbourne, 3,00,01.

COMPLETE SPECIFICATION FOR THE fNVZNT1ON ENTITLED:, '12,3-DIHYDROFURAN DERIVATIVES, PROCESS FOR PREPARING THEM, ANb THEIR USE AS AN INtERMEDIATE F0R, THE PREPARATION OF TETRAHYDROFURA4N

DERIVATIVES"

The following statement is a full desci-iption of this. invention, including the best method of performing it known to us The invention relates to 2,3-dihydrofuran derivatives, a process for their preparation and their use in a process for preparing teti~hydirofuran derivatives containing a triazole or imidazole group.

Tetrahydrofuran compounds containing a triazole 16 group are known funigieridal produjcts. They are dazcribed in prticular in Eutopean Patent Application NOS. 0,2,7 and, ,,151 ,oal4'.

4 4 4* 4 4 4#4* 4.

4 .4 I t~* It (iC I C C C'

C

C~rc (C I C IC C CI "The invention seeks to provide new compounds which ifak~e it posible, in particular, to carry out a process to r the preparation of tetrahydrofurans containing a tr$.azole or imidazole group in an improved yield and under imuproved reaction conditions.

Accordingly, the invention relates to the Compo~unds of forpiula I (formulat I and other formnulae referred to hereinafter are depicted at the end of the ,dsription) in which: ItR ancd R. which are identical or different, eacb represent the hydrogen atomn or a lower alkyl4, 1wer cycloalkyl or aryl (pefev'atly ,pheriyll radiCal, each such radical being opt rxiay Substituted fdr example by one or iftore atoms or radical~s selected fr -halogert ,ato lowtr al-koxy, aryl, (prefera-bly, phenyl), lower alkyl, lower halealIkyl, lower hacalkQxy, Acyoxy ,referablyl jhenoxy. or hycjQwxy radi.cals, X repr~sgntg A h~f1ogen 'aa, p~efer~by fluorine, -2bromine or chlorine, or an alkyl or alkoxy group containing from 1 to 12 carbon atoms, preferably from 1 to 4 carbon atoms and optionall~y mono- or polyhalogenated (preferably a CF 3 group), or when R 3 and/or R 4 represent a hydrogen atom X may also represent a cyano group, n is zero or a positive integer which is less than 6 and is preferably equal to 2, it being understood that when n is greater than 1, the substituents X may be identical or different, m, :d 0 o r 1,, )C represents an atom or group which is susceptible to removal by a nucleophilic substitution, or which can be converted into such an atom or group their Zat and complexes thereof with~ metal salts. The s4t and itfetal complexes are preferably agriculturally Acttptable and include hydrochlorides, sulphates, oxalates, nitrates or arylsulphonates, or aral1,ylsulphonates or 2G alkyl~ulphonates, and addition complexces of the compounds of 'formula I with metal. salts and particuIarly iron, chromium, coppter, manganese, zinc, cobal.t, tin, magnesiu~m and aluminiunt salts.

To give an example, complexes with zin'c can be produced by reacting :he compound of formula I with zinc C I SThe term "'lower" refers to an organi, radical by a nucleophilic substitution is preferably a halogen atom, most preferably chlorine or bromine, or a hydroxy or thiol group. However, as the latter are not sufficiently labile, they must be converted to a labile intermediate groups, for example a tosylate, mesylate, triflate or a group of formula [Ph P I, The conversion to a labile group is carried out by methods known per se, eg by treatment with the corresponding, acid chloride such as tosyl chloride or mesyl chloride,or by reaction with trifluoromethanesulphonic anhydride in the presence of a tertiary amine or pyridine, or in a neutral S medium by reaction with ethyl diazodicarboxylate and S triphenylphosphine.

c I The invention also provides ,a process for preparing the compounds of formula I which pomprises the Sisomeization of a compound of formula II, in which R 2

R

3

R

4 R n, m and Y are as hereinbefore defined, in the presence of a catalyst, in homogeneous, or heterogenebus, phase.

The following transitian metals a;e preferred catalysts: ruthenium, cobalt, palladium, nickel, rhodium, iridium, platinum and iron.

These catalysts can function in heterogeneous form in the metallic state, and in this case they are deposited onto a suitable inert support such as carbon black. They are preferably employed in homogeneous catalysis in the form of complexes which, in addition to the transition metal, contain one or more ligands (eg phosphine or carbonyl) and one or more hydride groups.

The reaction may be carried out in the presence of a protic or aprotic solvent or without a solvent. Aprotic solvents include s4turated aliphatic hydrocarbons such as n-pentane, isopentane, 2-methylhexaie and TO 2,2,5-trimethylhexane, aromatic hydrocarbons such as benzene, toluene and thylbenzene, 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 halogenated hydrocarbons such as fluorobenzene, l-chloro-2-methylpropane e a and isobutyl chloride, and saturated aliphatic or aromatic o. esters such as isobutyl isobutyrate, ethyl acetate and .o methyl benzoate. All these solvents may be used alone or as e *«e mixtures.

4. Protic solvents include saturated aliphatic or 4 4 S ,t aromatic alcohols such as methanol, isopropanol and phenol, and saturated aliphatic or aromatic acids such as propanoic J4 acid and benzoic acid. It is also possible to employ an inorganic acid mixed with an organic solvent with which it ,0 is miscible, for example hydrochloric acid in methanol. In o o this case, the compound of formula V, descibed hereinafter, in which R 1 =CH is produced directly. All these solvents 5 may be used alone or as mixtures.

Preferred solvents are the aromatic hydrocarbons or lower saturated aliphatic alcohols, optionally halogenated such as trifluoroethanol. The reaction is preferably carried out in the presence of a solvent: the concentration of the reaction product is preferably from to 99% by weight relative to the total weight of the solution, and preferably from 5 to The quantity of catalyst employed is preferably from 0.00005 to 0.1 mole per mole of compound of formula II.

The isomerization temperature may vary within a wide range, for example between -200C and the decomposition temperature of the catalyst. Nevertheless, a satisfactory compromise between the reaction time and industrial ii 15 operating conditions results in preference being given to a temperature range from 0 C to 100 0 C, advantageously from 41* 10° C to 800C.

The pressure is generally from 1 to 10 atmospheres S' (le 0.1 to 1 MPa).

A preferred prpcess for the preparation of compounds of formula II in which Y represents a halogen atom ,y ll comprises cyclizing a compound of formula VI (preferably in the cis form), in which X, n, m, R R 3 and R are as hereinbefore defined, Hal represents a halogen atom, and Z represents a hydrogef atom or OZ is a leaving group, either in an acidic imedium when Z is a hydrogen atom, or in a basic medium if Z is a leaving group such as a mesylate, tosylate, t 6 triflate or a group of formula [Ph These labile groups are selectively attached to a hydroxy group represented by Y by methods known per se without affecting the tertiary hydroxy group.

Organic or inorganic acidic catalysts are suitable for the cyclization. These may be soluble in the reaction medium, or may be insoluble, protic or aprotic.

Protic acids include hydrochloric, sulphuric, trifluoroacetic, perchloric, benzenesulphonic, toluenesulphonic and methanesulphonic acids. Aprotic acids include Lewis acids such as BF 3 AlCl and SnC1.

From 0.1 to 2 molar equivalents of acid per mole of compound of formula VI will preferably be employed.

The cyclization may also be carried out by means of catalysts fixed on inert supports such as sulphonic resins.

The cyclization is normally performed by merely heating the reactants shown. The temperature is generally I j t from 100C to 1000C or, when a solvent is present, from to the boiling point of the solvent.

Aliphatic and aromatic solvents such as toluene, Sethers and ketones may be mentioned among the many solvents which can be employed.

SIn the case of cyclization in a basic medium, inorganic bases such as, for example, sodium hydroxide or potassium hydroxide, alkali metal or alkaline-earth metal S carbonates, nitrogenous bases such as triethylamine, 7 quaternary amines such as tetrabutylammonium hydroxide, or phosphonium hydroxides may be used. 0.01 to 2 molar equivalents of base per mol of compound of formula VI are preferably employed. It is also possible to carry out the cyclization using catalysts fixed on inert supports such as resins. The reaction is usually carried out at a temperature of from 10°C to 1000C and, if desired, in the presence of a solvent such as aliphatic or aromatic solvents, ethers and ketones.

The compounds of formula II in which Y represents a hydroxy group may be obtained by treating a compound of general formula VI in which Z=H with a base In a preferred feature of the invention a compound of formula II in which Y is a hydroxy group or a leaving group, OZ, is prepared by treating with a base a compound of formula VI in which Z is a hydrogen atom, and R R R, X m and n are as hereinbefore defined and wherein the hydroxy group Y in the compound of formula II thus obtained is optionally converted into a leaving group OZ.

The resulting epoxide generated from the compound of general formula VI is then involved as intermediate.

After the isomerization the group Y hydroxy must generally be converted into a labile group (eg mesylate, tosylate, triflate or Ph 3 P-0) before the reaction of substitution with an imidazole or triazole, as desribed hereinafter.

C The compounds of formula VI in which R 3 and R 4 f i 11 8 both represent hydrogen are preferably obtained by hydrogenating a compound of formula VII, in which X, n, m, Hal and R 2 are as hereinbefore defined and in which Pr denotes a protective group, such as l-ethoxyethyl, or the hydrogen atom, in the presence of a catalyst in homogeneous or heterogeneous phase. The reaction is generally carried out using an equimolar quantity of hydrogen in the presence of a catalyst, which may be poisoned; the catalyst is preferably palladium, ruthenium, Raney nickel, platinum or rhodium preferably deposited on an inert support and most preferably palladium, optionally poisoned (eg by pyridine, quinoline or tetrahydrothiophene), which yields the cis olefin specifically. The reaction may be performed in homogeneous or heterogeneous phase.

Palladium in the metallic state deposited on an inert support such as carbon black, calcium carbonate or barium sulphate is preferred.

Although it is not essential, the reaction is advantageously carried out in a protic polar solvent, for example in a lower alcohol such as methanol, or an aprotic solvent, for example in toluene.

St' The concentration of the compound of formula VII 7 is preferably from 1 to 80% by weight or, more preferably, relative to the total solution.

Although the molar proportion of catalyst relative c'c to the compound of formula VII may vary considerably, it is :preferably to employ the catalyst in a molar proportion of from 0.01 to 0.5% relative to the compound of formula VII.

L,

9 The hydrogenation is generally carried out at temperatures of from 20 0 C to +1500C, preferably from 10 to C, and under a pressure of 1 to 10 atmospheres.(ie 0.1 to 1 MPa).

The compound of formula VII may be obtained by methods known per se, for example by addition of an organomagnesium derivative of formula:

R

2 -(OPr)CH-C C-Mg-Br in which R 2 and Pr are as hereinbefore defined with an acetophenone of formula: Ph(CH )m COCH 2 Hal O in which X, n, Pr, m and hal are as hereinbefore defined and o° Ph represents an optionally subtituted phenyl ring. When Pr is a protective group this must be removed from the alcohol before the cycliz4tion.

The preparation bf the compound of formula VII may S- be carried out, for example, in tetrahydrofuran, in a known manner.

S. When at least one of R and R4 does not represent a hydrogen atom, the following synthetic route may be Semployed: reaction of as organomagnesium derivative of 5 Thformula R 4 MgX with a compound of ~eneral formula VII, in the presence or absence of copper iodide,, followed, if R is other than hydrogen, by the addition of an alkyl halide RX generally in a solvent such as tetrthydrofuran. When an alkyl halide is not used it will be understood that the addition of R 4 MgX is followed by a hydrolysis.

The invention also relates to a process in which 10 the compounds of formula I are used as intermediates for the preparation of compounds of formula III, in which Tr represents a 1,3,4-triazol-lyl group, Im represents a 1,3-imidazole-l-yl group, R represents the hydrogen atom or a lower alkyl, lower cycloalkyl, aryl (preferably phenyl) or aralkyl (preferably benzyl) radical, each such radical being optionally substituted for example by one or more atoms or radicals selected from halogen atoms, lower alkoxy, aryloxy and hydroxy radicals, and R 2 R R 4 X; n and m are as hereinbefore defined which process comprises either the introduction of an imidazole or triazole ring into a compound of the formula I to produce a compound of formula IV, in which the symbols are. a hereinbefore 0 0o o defined followed by the addition of a.

.o o off compound of formula R OH in an acidic medium to produce a compound of formula III or the addition of a compound of formula R OH to a compound of formula I in an acidic medium, o 09 to produce a compound of formula V, in which the S.o, symbols are as hereinbefore defined, followed by the introduction of an imidazole or triazole ring.

The introduction of the imidazole or triazole ring St is advantageously performed in the presence of an acid-acceptor, in an anhydrous or nonanhydrous medium, in a solvent which is inert under the reaction conditions, generally fron 50 to 1800C and preferably at a temperature Sclose to the boiling point of the solvent. Acid acceptors include inorganic bases such as, for example, sodium I 11 hydroxide or potassium hydroxide, alkali metal or alkaline-earth metal carbonates, nitrogenous bases such as triethylamine, quaternary amines such as tetrabutylammonium hydroxide or phosphonium hydroxides. Solvents which are advantageously employed are polar aprotic solvents such as, for example, dimethylformamide, dimethylacetamide, dimethyl sulphoxide, acetone, methyl ethyl ketone, acetonitrile, N-methyl-pyrrolidone or polar protic solvents such as methanol or propanol. If desired, the reaction may be carried out in the presence of a suitable catalyst. Phase transfer catalysts, such as, for example, quaternary ammonium derivatives such as tetrabutylammonium chloride, may be employed.

The reaction is preferably carried out by means of tt 15 a salt derivative of an imidazole or triazole which is optionally formed in situ; a molar excess of triazole or imidazole derivative is preferably used; the molar ratio of t t the salt derivative relative to the compound of formula I or V is preferably from 1.05 to 1.5. The reaction is 'preferably carried out in a solvent wherein the quantity of compound of formula I or V relative to the total weight of Ssolution is from 1% to 70% by weight.

The acid acceptor is generally present in a quantity which is at least stoichiometrically equal on an equivalent bas-is to the labile hydrogen atom of the triazole or imidazole. A molar equivalent ratio of from 1 to 2.5 is generally satisfactory.

1 L i i•i ~I i i 12 It will be understood that a triazole or imidazole salt derivative may be prepared separately; there is then no need for an acid acceptor to be present for the reaction to introduce the imidazole or triazole ring. This preparation is performed in an anhydrous or nonanhydrous medium, in a solvent, under the same operating conditions as those described for the formation in situ of the triazole or imidazole salt derivative.

The addition reaction is performed in an acidic medium. The catalyst acid employed in this reaction may be a protic or aprotic acid which is soluble or insoluble in the reaction medium. Hydrochloric, sulphuric, trifluoroacetic, perchloric, benzenesulphonic, S toluenesulphonic and methanesulphonic acids may be mentioned i 15 as protic acids. Aprotic acids include Lewis acids such as .c BF,, AlCl and SnCl It is also possible to employ solid 4 resins such as sulphonic resins.

From 0.1 to 2 molar equivalents of acid will preferably be employed per mole of compound of formula I or

IV-

The reaction is normally carried out merely by heating the reactants. The temperature is generally from 'c 1000C to 1000C or, if a solvent is present, from 100C to the boiling point of the solvent. The solvent employed may be, in particular, an optionally halogenated aliphatic, alicyclic or aromatic hydrocarbon, an ether, or an alcohol such as that of formula R OH in which R is as hereinbefore ,1 I or IV is preferably greater than 1, adv'ntageously from 1 to 100.

When a solvent is employed; the concentration by weight of the compound of formula I or IV relative to the total solution is advantageously from 5 to 70% by weight.

The compound of formula III which is formed is isolated from the reaction medium by methods known per se such as, for example, by solvent distillation, or by crystallization of the product from the reaction medium, or by filtration, and then, if need be, this compound is purified by conventional methods such as recrystallization 1 from a suitable solvent.

*1 It is also possible to introduce an imidazole or triazole ring into the compound of formula II under the conditions hereinbefore described to obtain a compound of formula VIII, in which the symbols are as hereinbefore defined and then to iso.erize the double.bod in the presence ot a catalyst, in horiogeneous or heterogeneous phase as hereinbefore described.

The inventidn also relates to the compounds of t'4c formula II, III, IV, VI and VII in which X, R 1 to R 4 m, n, Y,1 and Hal are as hereinbefore (defined.

The invention also relates to the use of the compounds of formula IV and Of their &agriculturally a cceptable salts omplexes thereof with metal salts as fungicides. In factq thes'e c~gpound -display excellent 0 properties, especially atainat Mildews, root rot and, in general, other fungal diseases of cereals.

The invention provides a fungicidal composition which comprises, as active ingredient, a compound of formula IV or an agriculturally acceptable salt or complex thereof with a metal salt, in association with an agriculturally acceptable carrier. The cc~mpositions preferably comprise from 0.5 to 95% by weight anid preferably also comprise an agriculturally acceptable surfactant.

The invention also provides a method for the control of fungal diseases of crops at a locus which comprises applying thereto a compound of formula IV or an agriculturally acceptable salt or complex thereof with a metSl talt.

The invention also relates to a process for the preparation of a propargyl ether of formula: in which~ R. and It, are aa hereinbefore defined.

It is known in the art to produce ethers of formula: X' CH 2 O-CV' -C _CH wherein X'is CH OH, CF 3 or -C _CR and R and R' are H or lower -zalkyl, by reacting propargyl bromide of formula BrCH 2

-C-:CH

with the corresponding sodium ethanolate in the presence of a polar aprotic solvent at ambient temperature. This process is described in US patent 3,007,501.

However, this process h'at the disadvantage of i.

Ir: t 1 i_ ~III( IV1~ li- L~ial iS involving propargyl bromide, an unstable material which is difficult to employ under industrial conditions.

Furthermore, when the bromide is replaced with the chloride, the process of the prior act does not lead to the expected propargyl ether.

Thus, one purpose of the present invention is to provide an industrial process enabling the propargyl ether of formula (IX) to be produced.

Another purpose of the invention is to provide a process for the preparation of propargyl ether in an improved yield and under improved operating conditions.

The invention provides a process for the preparation of a propargyl ether which comprises reacting a compound of formula RIOM (in which M represents an alkali metal) with a propargyl chloride of the formula: C1-CH-CMCH ~cc t tc Li 4* 4t *4i 4* £4 i

(XI)

in which R 2 is as hereinbefore defined, in the presence of an alkali metal halide.

This process is of particular interest in the case 20 where R i is a radical substituted by one or more halogen atoms, especially -CH 2

CF

3

-CH

2

CH

2 Cl, -CH 2

CH

2 F, or represents CH2OCH 3 or CH 2

OC

2

H.

The process in which R, is a C 1

-C

4 alkyl radical is also of especial interest.

Preferred alkali metal halides are the alkali i 4. t *tt 04 4*1 *e 16 ,metal iodides, most preferably sodium iodide or potassium iodide.

The reaction is preferably carried out in the presence of a solvent, which is advantageously a polar ajrotic solvent such as, for example, dimethylformamide, dimethylacetamide, dimethyl sulphoxide, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile or N-methylpyrrolidone. If need be, a two-phase mixture of water and an abovementioned solvent may be employed in the presence, if desired, of a phase transfer catalyst such as a quaternary ammonium derivative (for example tetrabutylammonium chloride).

The reaction temperature is advantageously from ambient temperature to the reflux temperature of the solvent 15 when one is present.

When a solvent is employed, it is preferable to operate at a concentration of 1% to 70% by weight of compound of formula and relative to the total solution.

The molar ratio X: XI is preferably from 0.5 to 2, and advantageously about 1.

The molar quantity of alkali metal halide may be much smaller than that of the compound of formula X and is advantageously 2 to 100 times smaller.

The following Examples illustrate the invention.

Example 1: Preparation of 2-chloromethyl-2-(2,4-dichlorophenyl)-2,3-dihydrofuran A solution of 2-chloromethyl-2-(2,4-dichloroj 1 St 17 (3.95 g; 15 mmol) in methanol ml) is introduced into a 25-mi round flask under an inert atmosphere. RuH 2 (PPh 3 4 (144 mg; 0.15 mmol) is added and the mixture is refluxed. The reaction is finished after 12 h. Methanol is removed under reduced pressure.

18 After purification, a colourless oil (3.817 g; 14.48 mmol) is obtained yield 96.5%, based on the starting material.

Preparation of 2-ch LoromethyL (2,4-dichloroTenyl1)- 1-Chloro-2-(2,4-dichLorophenyl)-3-pentene-2,5dioL (cis isomer) (10 g; 35.5 mmoCL) in toluene (60 mL) is introduced into a 100-mi round flask under an inert atmosphere. Para-toluenesuiphonic acid (0.5 g) is added and the mixture is refluxed. When the reaction is finished' the product is washed and separated off. A brown oily residue (9.36 g; 35.5 mmol) is obtained. Yield 100%, based on the starting material.

9 00 Preparation of 1-chloro-2-(2,4-dichlorophenyl)- 3-pentene-2,5-dio1 (cis isomer) Method A: Bromoethane (54.5 g; 0.5 mel) dissolved in THF (225 ml) is added over 2 h 30 min to a 500 mL round flask containing magnesium (13.37 g) and tetrahydrofuran (30 mL) at T=30 0 C under an inert atmosphere. The solution obtained is run in dropwise over 1 hour at ambient temperature into a solution of 2-ethoxyethyl propargyl ether (64.09 g; moL) in THF (40 A solution of 2,4,21-acetophenone (89.4 g; 0.4 moCL) in THF (100 ml) is run in over 2 hoursinto the preceding solution at OOC. The mixture is kept at 20 0 C for 6 h. It is cooled -to 0 0 C and acetic acid (28.6 ml; mo) is added over 15 min at 5 0 C, followed by water (150 mtl) and then ethyl ether (100 ml). The organic phase 2 S19 is washed with water (2 x 50 ml) and once with brine ml) and the solvents are then removed under reduced pressure, A viscous yellow oil (136.6 g) is obtained.

Yield: 97.2%, based on the starting material.

The product is identified as 1-chloro-2-(2,4-dichlorophlenyl) -5-(1-ethoxyethoxy)-3-pentyn-2-ol.

The latter (24 g) is dissolved in toluene (150 ml) and is introduced, together with 5% palladium on charcoal (0.613 g) into a 500-ml round flask under an inert atmosphere. Hydrogen is fed in at atmospheric pressure and 0 C. After 2 hours the mixture i.s filtered and then the solvent is removed under reduced pressure.

The oily residue is taken up with methanol (200 ml) and 0.5 N hydrochloric acid (50 ml) is added. Methanol is then removed under reduced pressure and an orangecoloured oily residue (19.36 g) is obtained.

The addition of ethyl acetate (10 ml) followed by pentane (35 ml) permits the desired diol to precipitate (5.35 g; 19.3 mmol).

Method 8: Bromoethane (163.45 g) in toluene (250 ml) is run in over 1 h 15 min into a 1-1 round flask containing magnesium (36.5 g; 1.5 mol) and a solution of THF (216 g) and toluene (75 ml) at 30 0 C under an inert atmosphere.

The mixture is allowed to stand for 15 min at 24 0 C. A solution of propargyl alcohol (42.15 g; 0.75 mol) in toluene (50 ml) is added dropwise over 1 h 30 min. A solution .i I- I of 2,4,2'-trichoroacetophenone (111.7 g; 0.5 mot) in toLuene (100 mL) is added dropwise :t 44 0 C. The mixture is left to stand at ambient temperature. The mixture is then cooled to OOC and acetic acid (90 g; 1.5 mot) is added dropwise. The mixture is evaporated down; toluene (250 ml) is added, and the mixture is washed with dilute sulphuric acid and then with water. The organic phase is then concentrated, cooled, precipitated, filtered and dried. 1-Chloro-2-(2,4-dichLorophenyl)-3-pentyn-2,5dioL is obtained. M.p. 900C. Hydrogenation is carried out in the same way as in method A, but at 50 0

C.

The desired diot is obtained.

SExample 2: Preparation of 2-(2,4-dichorophenyl)-2methyL-( 1-triazotLyL Preparation nf 2-(2,4-dichLorophenyl)-2-methyl- .4 (1-triazoyl)-2,3-dihydrofuran: A solution of the compound prepared in Example 1 S(1.000 g; 3.80 mmol) in N-methylpyrrotidone (NMP) (1.00 g)

A

is introduced into a 50-mL round flask under an inert 20 atmosphere. 1,2,4-TriazoLe (314.8 mg; 4.56 mmol) and potassium carbonate (630.2 mg; 4.56 mmol) are then added.

The reaction mixture is heated to a temperature of 170 0

C

Ot( 4. C~ 0C oun Q for 14 hours and is then cooled to about 20 0 C. ToLuene m) is then added, followed by water saturated with ammonium chloride. The toluene phase is collected, the aqueous phase is again extracted with toluene (2 x 10 mi) and the combined organic extracts are dried over sodium -i 21sulphate. After filtration and concentration under reduced pressure, a semicrystaLine residue is obtained and is purified. Weight obtained: 673 mg (2.28 mmoL); m.p. (Kofter): 100 0

C.

Yield 60%, based on the starting 2,3-dihydrofuran.

Preparation of 2-chLoromethy-2-(2,4-dichLoro- 2-Chloromethyl-2-(2,4-dichLorophenyl)-2,3dihydrofuran (0.528 g; 2 mmol), trifluoroethanol (1 mL; 13 mmol), methylene chloride (0.5 ml) and a few particles of para-toluenesuLphonic acid are introduced into a round flask under an inert atmosphere. This mixture is 4 *1 heated to a temperature of between 40 and 50 0 C for one hour; after which time the reaction is complete. The solvents are then removed under reduced pressure (30 mm Hg 0 a 60/40 mixture of both diastereoisomers is obtained (0.713 g; 1.96 mmol).

4t titr Yield 98%, based on the starting material.

Preparation of 2-(2,4-dichLorophenyl)-2-methyl- 0 (1-triazoLyL Method A The tetrahydrofuran prepared earlier (600 mg; 1.65 mmol) and N-methylpyrroLidone (NMP) (1.7 mL) are introduced into a 10-mi round flask under an inert atmosphere. Sodium triazolate (0.180 g; 1.98 mmol) is then added. The mixture is heated to 160 0 C. After 5 hours the yield is 15% by Liquid chromatography.

-22 Method B 2-(2,4-Dichlorophenyl)-2-methyl-(1-triazolyl)- 2,3-dihydrofuran (0.6 g; 2 mmol in toluene solution and trifluoroethanol (1 ml; 13.7 mmol) are introduced into a 25-ml round flask. The mixture is then hea;ted to reflux and a stream of dry HCL gas is passed through. After one hour's heating the reaction is finished. The mixture is then taken up with methylene chloride, is washed with a saturated solution of sodium carbonate and then with water and is dried over sodium sulphate. After filtration, Sconcentration and purification, a white solid (0.440 g; S 1.1 mmol) melting at 168°C is recovered. Yield 80.7% based on the starting material.

Preparation of 2-(2,4-dichlorophenyl)-2-methyl- (1-triazolyl)-2,5-dihydrofuran: r. A solution of 2-chloromethyL-2-(2,4-dichlorophenyl)-2,5-dihydrofuran (1.000 g; 3.80 mmol) in N-methylpyrrolidone (NMP) (1.00 g) is introduced into a t round flask under an inert atmosphere. 1,2,4-Triazole (314.8 mg; 4.56 mmol) and potassium carbonate (630.2 mg; 4.56 mmol) are then added. The reacticin mixture is heated to a temperature of 170°C for 14 hours and is then cooled to about 20 0 C. Toluene (10 ml) is then added, followed with water saturated with ammonium chloride. The toluene phase is collected, the aqueous phase is extracted again with toluene (2 x 10 ml). The combined organic extracts are dried over sodium sulphate. After filtration and ~~-23 concentration under reduced pressure, a samiirystaL L ine residue is obtained and is purified.

This product is thten isomerized according to the conditions of ExampLe 1 to pr'oduce a comnpound of formuta IV to whith trifLuoroethanoL is then~ added.

(20 g; 0.2 mole), in solution in THF (2 ml).

After 24 hours' stirring the reflux temperature the soLvent, the reaction ixture is filt ered, the Sprecipitate is washed th THF (40 mL) and the filtrate A c pound which distils over between 70 and C 96 mm Hg (11.44 g; 0.063 mole) is recovered in mannpr (Y4ipl elTEP 63) a ExampLex.*: Preparation of 3-trifLuoroethoxy-l-piopyne Dry N,N-dimethyLformamide (150 mL), trifLuoroethanol (60.02 g; 0.6 mole), potassium carbonate (82.9 g; 0.6 mole) and sodium iodide (4.49 g; 0.03 mole) are introduced with stirring and under an inert atmosphere into a four-necked 250 ml flask fitted with a mechanical stirrer, a thermometer, a dropping funnel and a condenser.

PropargyL chloride (49.1.7 g; 0.66 mole) is run into the suspension obtained. The reaction mixture is heated to 85 0 C for 18 hours.

CQ b: <c I.

-24' After ;aoing, the imixture is f iLtered and the pret fpitat-e obtained is washed with Off~ (40 mL. The f.ittate is then distitted to produce. the compnound (52.2 9; 0.38 mole); cot.ourtess tiq4Jid, b.P. z 8I-82*Ci Satm. Yield =63%.

Examptej;* Preparation of S-chtoro-4-(Q ,4'-dichLorophenyt.)-4-hydroxy-l-trifLuoroethoxy-2-peltyfe The G; ignard reagent derived from bromoethane is prepared in a traditional manner from magnesium (6.74 g; 0.27 moLe), halide (27.46 g; 0.25 mole) and anhydrous THF (180 ml. This reactant, fiLtered to remove excess magnesium, is then poured slowLy into a solution of the compound of Example 4 (34.8 g; 0.252 mote) in anhydrous THF 4s (60 Wl. The exothermic reaction produces a release of ethane, which ceases shortly after the addition is complete.

A solution of trichLoroacetophenone (31.3 g; 0. 14 mole) in anhydrous THF (35 is then added slowly (exothermic reaction) to the reaction medium.

When the addition is finished and after cooling, the mixture is poured onto an ice-cold soLution of 12 N HCI (21 mL) in H 2 0 (100 ml.

After phase separation, extraction with Et2O (2 x 100 ml), washing until neutral, drying over sodium sulphate and concentration, an orange-coloured Liquid (49 g) is recovered, which assays at 93% (yield The crude reaction product is employed as such C~ in the following stage.

25 Example Preparation of 5-chloro-4-(2',4'-dichlorophenyL)- 4-hydroxy-1-trif uoroethoxy-2-pentene A solution of acetylenic compound (34 g; 0.094 mote) in totuene (120 mL) is hydrogenated in the presence of 5% pattadium on charcoal (1 g) at atmospheric pressure and 65 0

C.

After one equivalent of hydrogen has been consumed, the stirring is stopped. After cooling, the mixture is filtered and the filtrate is concentrated. A .10 crude reaction product (34.2 estimated to contain 1 90% of ethylenic compound, is thus obtained (yield i* The ethylenic compound is obtained predominantly 0 in its cis configuration. It may be isolated from the *o crude reaction product by chromatography on a silica column (eluent: pentane/CH 2

CL

2 60/40).

Example S: Preparation of 5-chloro-4-(2',4'-dichlorophenyl)-4-hydroxy-1-trifluoroethoxypentene.

A solution of ethylenic derivative (2.24 g; 6.16 x 33 3 mole) in toluene (2.2 ml) is heated to reflux in th" presence of RuH2(PPh3) 4 (0.07 g; 6 x 10 5 mole). After one hour's reaction, the mixture is allowed to return to room temperature. The mixture is diluted with toluene ml) and filtered through silica (5 After concentration, a cis and trans mixture of the vinyl ether (1.8 g; 4.9 x 10 mole) is recovered.

Yield 26 Example Preparation of 4-(2',4'-dichLorophenyl)- cly-l-trifluoroethoxypentene A suspension of the above ether (6.54 g; 0.018 mole), triazole (1.35 g; 0.019 mole) and potassium carbonate (5.39 g; 0.039 mole) in dry DMF (25 ml) is heated for 2 hours at 110oC.

The mixture is brought back to room temperature and is then diluted with toluene (40 ml) and H 2 0 (40 ml).

After phase separation, washing until neutral, drying and concentration, a crude reaction product (7.1 g) is obtained, which titration shows to contain 85% of the triazole enol ether.

t. After purification by chromatography on a silica at column (eluent: AcOEt/CH 2 CL 50/60), the enol ether (cis/trans 56/44) (4.98 g; 0.0126 mole) is obtained.

(Yield of ;solated product Example Preparation of 2-(2',4'-dichlorophenyl)-2- S. i \e ove.

A solutione-a. compoundl* (0.476 g; 1.2: x 10 mole) 20 in toluene (3 ml) and trifluoroethanol (0.722 g; 7.2 x 10- mole) is stirred in the presence of a very slow stream of HCL gas (exothermic reaction) for 2 hours., After treatment with sodium carbonate, washing until neutral, drying and concentration, a crude reaction product (0.485 g) is recovered, which contains compound (0.404 g; 1.02 x 10 3 mole) (yield

(VI)

(VII)

(I)

I Tr 1,2,4-triazoL-I-yt rin~g In 1,3-imidazoL-1-yL ring r (X)R R 3 0 R2(v MX)R R 3 o r

R

2 2

Claims

1. A compound of the formula: R 2 (CE 2 )H /1) y o R n R4 R3 in which R, and R 4 which ae 3 identical or different, represent a hydrogen atom or a lower alkyl lower cycloalkyl or aryl radical, each such radical being optionally substituted by one or more atoms or radicals selected from halogen atoms, lower alkoxy, aryl, lower alkyl, lower haloalkyl, lower haloalkoxy, aryloxy or hydroxy radicals, X represents a halogen atom, or an alkyl or alkoxy group containing from 1 to 12 carbon atoms, and, *LV ~optionally mono- or polyhalogenated or, when R, and/or R represents a hydrogen atom, X may also represent cyano, n is zero or a positive integer which is lower than 6, it being understood that when n is greater than 1, the substituents X may be either identical or different, m 0 or 1, Y represents an atom or group which is susceptible SAL to removal by a nucleophilic substitution, or which can be converted into such an atom or groupand I! -o their salts and complexes thereof with metal salts.

2. A compound according to claim 1 in which aryl radicals within the definition of R 2 R 3 and R, are phenyl, and, within the definition of X, the halogen atom is fluorine, chlorine or bromine and alkyl and alkoxy groups contain from 1 to 4 carbon atoms, and n is 2. within the definition of X, the halogen atom is fluorine, chlorine or bromine and alkyl and alkoxy groups contain from 1 to 4 carbon atoms, and n is 2.

3. A compound according to claim 1 or 2 in which Y represents a halogen atom, a hydroxy or thiol group or a tosylate, mesylate or triflate group or a group of the o formula [PhP 3 0 *too

4. A compound according to claim 1 which is o *o 9 2-chloromethyl-2-(2,4-dichlorophenyl)-2,3-dihydrofurah. 0*

5. A process for the preparation of a compound of the formula I by isomerisation of a compound of the Y formula: 0 V (X)n 4 R3 in which R 2 R 3 R4, X, Y, n and m are as defined in claim 1 in the presence of a catalyst, in homogeneous or heterogeneous phase.

6. A process according to claim 5, wherein the isomerizationcatalyst is ruthenium, cobalt, palladium, nickel, rhodium, iridium, platinum or iron. r 31

7. A process according to claim 5 or 6, wherein the quantity of catalyst is from 0.00005 to 0.1 mole per mole of compound or formula II.

8. A process according to claim 5, 6 or 7, wherein the isomerization reaction is carried out in the presence of a solvent.

9. A process according to claim 8 wherein the concentration of compound of formula II relative to the total weight of solution is from 5 to 50% by weight. A process according to any one of claims 5 to 9, wherein the isomerization reaction temperature is from to

11. A process according to claim 5 substantially as hereinbefore described.

12. A compound according to claim 1 when prepared by a process according to any one of claims 5 to 11.

13. A process for the preparation of a compound of the formula: 00 0 TO *or 1 (i I) (CH OR 1 n (X)n 4 in which Tr represents a 1,2,4-triazol-1-yl group, Im represents a 1,3-imidazol-l-yl group, R 1 represents the hydrogen atom or a lower alkyl lower cycloalkyl, aryl or aralkyl radical, each such radical being optionally substituted by one or more atoms or radicals selected from 32 halogen atoms, lower alkoxy, aryl, lower alkyl, lower haloalkyl, lower haloalkoxy, aryloxy or hydroxy radicals, and R 3 R 4 D, n and m are as defined in claim 1, which comprises either the introduction of an imidazole or triazole ring nto a compound according to claim 1 to produce a compound of the formula: Tr or (C 2 )Im O M R2 n R 4 in which Tr and Im are as hereinbefore defined and the other symbols are as defined in claim 1, followed by the addition of a compound of formula R OH in an acidic medium to produce a compound of formula III, or the addition of a compound of formula RiOH to a compound according to claim 1 in an acidic medium to produce a compound of the formula: R2 I °OR I 3 (C H 2 m OR( (X)n 3 in which RI is as hereinbefore defined and the other symbols are as defined in claim 1, followed by the introduction of an imidazole or triazole ring to produce a compound of formula III.

14. A process according to claim 13, wherein the introduction of an imidazole or triazole ring is carried out ?AL/~ IF 0/ n ~I 33 by means of a salt derivative of an imidazole or triazole which is optionally formed in situ. A process according to claim 14 wherein the molar ratio of the salt derivative relative to the compound of formula I or V is from 1.05 to

16. A process acording to claims 13, 14 or wherein the rea p e ion in the grafting stagis carried out in the presence of a solvent and wherein the quantity of compound of formula I or V relative to the total weight of solution is from 1 to 70% by weight.

17. A process according to any one of claims 13 to 16 wherein the introduction of the imidazole or triazole o ring is carried out in a solvent at a temperature close to 0 P the boiling point of the solvent. s, 15 18. A process according to any one of claims 13 to 17, wherein the addition reaction is carried out in "the presence of 0.1 to 2 equivalents of acid per mole of compound of formula I or IV. 0 00

19. A process according to any one of claims 13 BO S 20 to 18, wherein 1 to 100 moles of compound of formula ROH are employed per 1 mole of compound of formula I or IV.

20. A process according to any one of claims 13 0 to 19, wherein the addition reaction temperature is from 100C to 1000C.

21. A process according to claim 13 substantially as hereinbefore described.

22. A compound of formula III wherein Tr, Im and R are as Ir. i" ~-0 34 defined in claim 13 and the other symbols are as defined in claim 1 when prepared by a process claimed in any one of claims 13 to 21.

23. A process for preparing a compound of formula II depicted in claim 5 in which Y is a halogen atom and R 2 R 3 R X, m and n are as defined in claim 1, which comprises cyclizing a compound of the formula: OH R 4 R 3 R 2 I I I I (CH 2 )m C C C CH OZ (VI) ()n in which Hal represents a halogen atom, Z represents a TO hydrogen atom or OZ represents a leaving group and the other symbols are as defined in claim 1, either in an acidic medium when Z is a hydrogen atom or in a basic medium when Z is a leaving group.

24. A process according to claim 23, wherein the I 15 cyclization reaction is carried out in the presence of 0.1 to 2 molar equivalents of acid per mole of compound of formula VI. A process according to claim 23, wherein the cyclization reaction is carried out in the presence of 0.01 to 2 molar equivalents of base per mole of compound of formula VI.

26. A process according to claim 23, 24 or wherein the reaction temperature is from 100C to 1000C or, L i i; 35 when a solvent is present, from 100C to the boiling point of the solvent.

27. A process for the preparation of a compound of formula II depicted in claim 5 in which Y is a hydroxy group or a leaving group OZ, which comprises treating with a base a compound of the formula VI in which Z is a hydrogen atom, and R 2 R 3 R 4 X, m and n are as defined in claim 1, and wherein the hydroxy group Y in the compound of formula II thus obtained is optionally converted into a leaving group OZ. o 6I

28. A process according to claim 23 or 27 r substantially as hereinbefore described.

29. A compound of formula II depicted in claim 3 0 a a* in which the various symbols are as defined in claim 1, when prepared by a process according to any one of claims 23 to 28. O a 6 0 Dated this 5th day of March, 1990 £4 At 6 RHONE-POULENC AGROCHIMIE By its Patent Attorneys, 6 46 DAVIES COLLISON 0 L! Nw