GB2102421A - Process for the preparation of cyclopropane derivatives - Google Patents

Abstract

An ester of a substituted cyclopropane carboxylic acid may be prepared by reacting a compound of formula <IMAGE> where A is a direct C-C bond, a -CH2- group, a sulphur atom or an oxygen atom, with a compound X- CH2-CO2H where X is a leaving group; converting the resulting compound into an ester, reacting the resulting compound with a base to form the corresponding ylid; and reacting the ylid with an appropriately substituted olefin. The compounds prepared are useful as pyrethroid insecticides or as intermediates in the preparation of pyrethroid insecticides.

Description

SPECIFICATION Process for the preparation of cyclopropane derivatives This invention relates to a process for the preparation of cyclopropane derivatives.

Certain cyclopropane derivatives have extremely potent insecticidal properties.

Accordingly, much research has been directed to the synthesis of compounds containing an appropriately substituted cyclopropyl group.

Many workers have described the reaction of sulphur ylids with olefins as the means of forming the cyclopropane ring. For example, G.B. Payne, in the Journal of Organic Chemistry 32 3351 (1967) describes the use of ylids derived from dimethyl sulphide, and other workers have used the same or similar ylids. These ylids are indeed useful for laboratory scale preparations but their use is in general not feasible on an industrial scale due to the poor thermal stability of the ylids themselves and of their precursor sulphonium salts. In addition, dimethylsulphide itself is a very volatile material and therefore presents handling problems when used on a large scale.

UK Patent Specification No. 1 5531 53 describes an attempt to solve these problems, and discloses that certain cyclopropane derivatives can be prepared by reacting thiolane with the m-phenoxybenzyl or a C(1-4)alkyl ester of chloro- or bromoacetic acid, converting the resulting sulphonium salt into the corresponding ylid by reaction with a base, and reacting the ylid with an olefin having the desired substitution pattern. This process does indeed show some advantages over the method originally proposed by Payne. Severe problems still remain however.

Data are given to show that the thermal decomposition of the sulphonium salt derived from thiolane is reversible; however, close inspection of the data (Example 2 of said specification) reveals that only half of the original material is retained after heating in acetone for 1 hour.

One problem with the reaction of thiolane with a haloacetate ester is that ring opening always occurs to give compound I. In addition, compound II is formed, especially in the presence of excess thiolane.

Here, Hal is a chlorine or bromine atom and R is m-phenoxybenzyl or C(1-4) alkyl.

Further it is found that when the olefin reactant is mesityl oxide, chosen in order to prepare an ester of 2 ,2-dimethyl-3-acetylcyclopropane carboxylic acid (a precursor of pyrethroid-type insecticides containing a 2,2-dimethyl-3-(2,2dihalovinyl)cyclopropyl moiety, see for example German Offenlegungsschrift 2639777), severe practical difficulties arise when trying to operate the process economically on a large scale.

Thiolane is regenerated during reaction of the ylid with the mesityl oxide and since it is an expensive chemical economic considerations dictate that it must be recycled to the reaction with the haloacetate. It is also desirable to recycle unreacted mesityl oxide. It is in practice not possible to separate the regenerated thiolane from unreacted mesityl oxide (boiling points 1 200C and 1 290C respectively) and thus a mixture of thiolane and mesityl oxide must be recycled. However, it is found that when mesityl oxide is present, the rate of the reaction of the thiolane with haloacetate decreases markedly and in addition the selectivity to the desired product decreases. This problem occurs, of course, when using any olefin which is difficult to separate from thiolane.

The Applicants have now found a process which can be conducted at a resonable rate to give reasonable selectivities to the desired products, and which can be carried out using economical recycle of reactants.

The present invention provides a process for the preparation of an ester of an acid of the general formula

in which each of R1 and R2 independently represents hydrogen, C(1-8) alkyl, benzyl, phenyl, alkylphenyl or halophenyl, or R' and R2 together represent a C(2-7) alkylene group; each of Za and Z2 independently represents- CO,R3, --COR4, -CO --CN, --NO, or - SO2R5, or one of Z1 and Z2 has this meaning and one represents R6, or ZX and Z2 together with the interjacent carbon atom represent a cyclo pentadienyl or benzocyclopentadienyl group; each of R3, R4 and R5 independently represents C(1-8) alkyl, phenyl, alkylphenyl or halophenyl; and Rs represents hydrogen C(1-8) alkyl, phenyl, alkylphenyl or halophenyl; which comprises: a) reacting a cyclic sulphide of the general formula

in which A represents a direct C-C bond, a -CH2-group, sulphur atom or an oxygen atom, with an a-substituted acetic acid of the general formula XCH2C 2H (V) in which X represents a leaving group; b) converting the resulting compound into an ester; c) reacting the resulting compound with a base to produce the corresponding ylid; and d) reacting the ylid with an olefin of the general formula

in which Rr, R2, Z' arid Z2 have the meanings given for the general formula ill.

Any suitable ester group may be present in the compound prepared by the process according to the invention; for example the compound may be an optionally-substituted alkyl ester, such as the benzyl or m-phenoxybenzyl ester. Preferably, however, an unsubstituted lower alkyl ester is prepared.

Preferably each of R' and R2 independently represents a hydrogen atom or a lower alkyl group. Most preferably, each of R' and R2 represents a methyl group.

Preferably with Z and Z2 together with the interjacent carbon atom represent a cyclopentadienyl or benzocyclopentadienyl group, or Z1 represents a hydrogen atom and Z2 represents a QO2R3 or -COR4 group, where R3 and R4 have the meanings given above and preferably represent lower alkyl groups. Most preferably, Z' represents a hydrogen atom and Z2 represents an acetyl group.

Thus an especially preferred olefin of formula (VI) for use in the process according to the invention, is mesityl oxide, i.e. R1 and R2 represent methyl groups, Z1 represents a hydrogen atom and Z2 represents an acetyl group.

Preferably A in the compound of formula IV represents a direct C-C bond or an oxygen atom.

The direct product of reaction (a) may be a sulphonium salt (VII) of a zwitterionic compound (VIII) plus HX, depending, of course, on the basicity of the the anion X and the pH of the reaction mixture.

X may represent any group capable of being displaced by the sulphide under the reaction conditions. Suitable leaving groups X are organic suiphonyl groups such as the methyl sulphonyl, pnenyl, sulphonyl orp-toluene sulphonyl groups; hydroxyl groups; and, especially, chlorine and bromine atoms.

Throughout this specification and claims, the term "lower" applied to an alkyl group or an alkanol should be understood to mean having up to 6, preferably up to 4, carbon atoms. Especially preferred lower alkyl groups are the methyl and ethyl groups.

The displacement reaction (a) is suitably carried out at a temperature in the range of from 0 to 1 000C, especially 30 to 800C. The molar ratio of the reactants is not crucial; in order to increase the rate of reaction, it is usually preferred to operate with an excess of one of the reactants. An excess of from 0.1 to 3 moles per mole is suitable.

Either reactant can be used in excesss, but preferably the a-substituted acetic acid is used in excess.

The reaction is suitably carried out at an acidic pH in the presence of a solvent, especially a highly-polar solvent, for example water, a carboxylic acid such as acetic acid, an alcohol such as methanol, or a cyanide such as acetonitrile. Aqueous reaction media are especially suitable, and the water may be used alone or in admixture with a water-miscible cosolvent, for example a lower alkanol such as methanol. It may be convenient to use an excess of one of the reactants as solvent.

The esterification reaction (b) may be carried out by any suitable method, for example by direct reaction with an alcohol or an olefin, or transesterification with an ester, in the presence of an acidic catalyst. A sulphonium salt VII prepared by reaction (a) is of course an acid, and may itself act as the acidic cataiyst; however as this acid is removed during the course of the reaction, an additional acid is preferably used.

Suitable acids include organic acids such asp- toluene sulphonic acid, mineral acids such as the hydrogen halides and sulphuric acid, and solid acidic ion exchange resins and molecular sieves.

Lower alkanols, especially methanol, are preferred esterifying agents. The reaction is preferably carried out in the absence of substantial quantities of water, since the presence of water pushes the equilibrium away from the ester and towards the free acid. Water is of course generated by the esterification reaction if an alcohol is used as reactant, and it may be desirable to remove this water during the reaction.

The reaction is preferably conducted in the presence of a suitable solvent, for example a lower alkanol. Where appropriate, it may be convenient to conduct the reaction in the presence of an excess of the esterifying agent as solvent or co-solvent, methanol being especially suitable. Reaction temperatures in the range from O to 1000C, especially 30 to 800C, are generally suitable.

Any suitable base may be used in reaction (c) to convert the sulphonium salt into the corresponding ylid. The base may be organic, for example a tertiary amine such as triethylamine or an alkali metal alkoxide such as sodium or potassium t-butoxide, or inorganic, for example an alkali metal hydroxide or carbonate. Basic ion exchange resins may be used. Alkali metal hydroxides, lower alkoxides and carbonates are especially suitable. At least an equivalent amount of base relative to the sulphonium salt is preferably used, the number of equivalents of base per mole of sulphonium salt preferably being in the range of from 1 to 5, especially 1.2 to 3.

Temperatures in the range of from 0 to 1 000 C, especially 0 to 400C, are suitable. The reaction is conveniently carried out in the presence of an inert solvent, for example a hydrocarbon, such as toluene, a halogenated hydrocarbon, such as dichloromethane, an ether such as diethyl ether or dimethoxyethane, or an alcohol, especially a lower alkanol such as methanol. The base may be soluble in the reaction medium, or it may be used as a solid. Water may be present in the reaction mixture if desired, but in general it is preferred that the reaction takes place in a non-aqueous phase. The use of alcoholic solvents is especially preferred.It should be noted that in some cases when using an alcohol as solvent and/or an alkoxide as base, transesterification of the ester group present in the starting sulphonium salt may occur, so that the ester group in the product resulting from the process according to the invention is not necessarily the same as that introduced in reaction (b) of the process.

Reaction (c) is preferably carried out under an atmosphere of an inert gas, for example nitrogen.

In reaction (d), the ylid resulting from reaction (c) is reacted with an olefin VI. The molar ratio of olefine to ylid is not critical, and if the olefine is a liquid, it may be used in excess as a solvent for the reaction. Preferably, however, the molar ratio of olefin to ylid is in the range of from 1:1 to 6:1, especially 1.05:1 to 2:1. Preferred solvents are the same as those described above for reaction (c). The reaction temperature is suitably in the range of from 0 to 1 000C, especially 30 to 900C, and the reaction is preferably carried out under an atmosphere of an inert gas.

The ylid resulting from reaction (c) may if desired be subjected to a work-up procedure before reaction (d) is carried out, but preferably the ylid is produced and reacted in sits with the olefin VI. This may be accomplished by reacting the sulphonium salt with a base for a period of time adequate to convert all or a large proportion of the salt to the ylid, and then adding olefin to the reaction mixture; alternatively and preferably, olefin may be added to the sulphonium salt at the same time as or before base is added, thus enabling it to react with the ylid immediately the ylid is formed.

In an especially preferred embodiment of the process according to the invention, reactions (b), (c) and (d) are all carried out in the presence of the same solvent, without any intermediate isolation of products between the reactions. Lower alkanols are especially suitable solvents for use in this embodiment.

After the reaction of the ylid with the olefin is complete, the reaction mixture may be worked up in any appropriate manner. The regenerated cyclic sulphide is suitably recycled back for use in reaction (a) of the process. When using a sulphide and an olefin with similar boiling points, such as thiolane and mesityl oxide, it is most convenient not to attempt any separation of the two compounds, but to recycle both back to reaction (a). When using a sulphide and an olefin with dissimilar boiling points, a separation at this stage may be preferred, but is in general not essential.

In contrast to the reaction of thiolane with a haloacetate ester, the presence of olefin in stage (a) of the reaction has no severe detrimental effects. After reaction (a) is completed, any cyclic sulphide and olefin remaining may be evaporated off or extracted from the reaction mixture, recovered, and wholly or partially recycled for use in reaction (d) if olefin is present. Unreacted asubstituted acetic acid and the sulphonium salt product may then be separated from each other, for example by precipitation of the sulphonium salt from solution.

The following Examples illustrate the invention.

Example 1.

Step (a) of the process according to the invention.

A mixture of chloracetic acid (295 g, 3.12 mol), thiolane (90 g, 1.02 mol) and water (100 ml) was stirred at 500C for 2 hours, after which time water was evaporated off under reduced pressure.

Acetone was added, and the resulting precipitate was shown by NMR to be the desired compound, hydroxycarbonylmethyltetramethylene- sulphonium chloride, isolated in 81% yield. Its formula is shown below.

When the thiolane was replaced by 1,4oxathiane, and the reaction mixture stirred overnight at 550C, the corresponding sulphonium salt was obtained in 95% yield.

Repetition of this general method using thiolane in the presence of an amount of mesityl oxide equimolar with that of thiolane, gave the desired reaction product in 82% yield after a 4 hour reaction time.

Analogous procedures can be applied to the preparation of the corresponding bromide salts.

Example 2.

Step (b) of the process according to the invention A solution of hydroxycarbonylmethyl tetramethylenesulphonium chloride (5.0 g, 28 mmol) in 20 ml methanol was saturated with dry HCI at room temperature and the resultant solution was stirred at 500C for 45 minutes. The volatiles were evaporated under reduced pressure leaving an oily residue. NMR showed that the product was methoxycarbonylmethyltetramethylenesulphonium chloride, obtained in 87% yield.

By a similar procedure, the corresponding 1,4oxathiane sulphonium salt was converted into its methyl ester in 75% yield.

Analogous procedures can be applied to the preparation of the corresponding ethyl esters, and to the preparation of bromide salts.

Example 3 Steps (c) and (d) of the process according to the invention A mixture of ethoxycarbonylmethyltetramethylenesulphonium bromide (7.7 g, 30 mmol), chloroform (25 ml) and saturated aqueous potassium carbonate (18 ml) was stirred at O- 50C while a 50% aqueous sodium hydroxide solution (2.4 ml, 30 mmol) was added dropwise.

The temperature was then allowed to rise to 200C and stirring was continued for 1 5 minutes.

The mixture was filtered, and the upper chloroform layer was dried over potassium carbonate and evaporated down under reduced pressure. The residue was shown by NMR to be the ylid:

obtained in 67% yield.

A mixture of this ylid (1.20 g, 5.2 mmol), mesityl oxide (1.0 g 10.3 mmol) and toluene (2.5 ml) was stirred at 800C for 6 hours. Quantitative gas chromatographic analysis of the reaction mixture indicated an 83% yield of ethyl 2,2dimethyl-3-acetylcyclopropanecarboxylate, almost entirely in trans isomeric form. Repeating this procedure using chloroform and t-butanol as solvents instead of toluene gave yields of 69% and 60% respectively.

Repetition of the above two reactions using the corresponding 1,4-oxathiane compound as starting material gave the corresponding ylid in 85% yield, and the cyclopropane compound in 71% yield.

Analogous procedures can be applied to the corresponding chloride salts and to the methyl esters.

A mixture of ethoxycarbonylmethyltetramethylenesulphonium chloride (1.05 g, 5 mmol), mesityl oxide (1.45 g, 15 mmol) and t-butanol (1.3 ml) was stirred on an ice/water bath while potassium t-butoxide (0.56 g) was added over 4 minutes. Stirring was was continued for 1 5 minutes, after which the temperature was raised to 500C over a period of one hour. The mixture was then stirred at 500C for 12 hours. After cooling, toluene was added and the mixture was filtered. Quantitative gas chromatographic analysis showed that the filtrate contained a 60% yield of ethyl 2,2-dimethyl-3-acetylcyclopropanecarboxylate.

Claims (8)

Claims

1. A process for the preparation of an ester of an acid of the general formula

in which each of R' and R2 independently represents hydrogen, C(1-8) alkyl, benzyl, phenyl, alkylphenyl or halophenyl, or R1 and R2 together represent a C(2-7) alkylene group: each of Zi and Z2 independently represents C02R3, -C OR4, -CHO, -CN, -NO2 or SO2R5, or one of Z1 and Z2 has this meaning and one represents R6, or Z1 and Z2 together with the interjacent carbon atom represent a cyclopentadienyl or benzocyclopentadienyl group; each of R3, R4 and R5 independently represents C(1-8) alkyl, phenyl, alkylphenyl or halophenyl; and R6 represents hydrogen, C(1-8) alkyl, phenyl, alkylphenyl or halophenyl; which comprises: a) reacting a cyclic sulphide of the general formula

in which A represents a direct C-C bond, a CH2- group, a sulphur atom or an oxygen atom, with an a-substituted acetic acid of the general formula X-CH2-CO2H (V) in which X represents a leaving group; b) converting the resulting compound into an ester; c) reacting the resulting compound with a base to produce the corresponding ylid; and d) reacting the ylid with an olefin of the general formula

in which R1, R2, Z' and Z2 have the meanings given for the general formula Ill.

2. A process as claimed in claim 1, in which X represents an organic sulphonyl group, a hydroxyl group, or a chlorine or bromine atom.

3. A process as claimed in claim 1 or 2 in which each of R' and R2 represents a methyl group; Z1 and Z2 together with the interjacent carbon atom represent a cyclopentadienyl or benzocyclopentadienyl group, or Z1 represents a hydrogen atom and Z2 represents a -CO2R3 or COR4 group.

4. A process as claimed in claim 3, in which the olefin of formula VI is mesityl oxide.

5. A process as claimed in claim 4, in which the compound of formula IV is thiolane, and the thiolane regenerated in reaction (d) is recycled back for use in reaction (a) in admixture with unreacted mesityl oxide.

6. A process as claimed in claim 5, in which, after reaction (a) is completed any thiolane and mesityl oxide are evaporated off or extracted from the reaction mixture and unreacted compound of formula V and the sulphonium sult product are separated from each other by precipitation of the sulphonium salt from solution.

7. A process as claimed in any one of claims 1 to 6 in which there is no work-up procedure between reactions (c) and (d), and the olefin is added to the sulphonium salt resulting from reaction (b) at the same time as or before base is added.

8. An ester of an acid of the general formula Ill given in claim 1 whenever prepared by a process as claimed in any one of claims 1 to 7.