CA1122609A - Preparation of alpha-cyano-esters of cyclopropane carboxylic acids - Google Patents

Abstract

A B S T R A C T

A process for the preparation of a cyclopropane carboxylic acid ester of the general formula:
(I) wherein R1, R2, R3, R4 and R5 each represents a substituted or unsubstituted hydrocarbyl group or a hydrogen atom, which comprises reacting:
(a) an aldehyde of the general formula:
R5 - C(O)H (II) wherein R has the same meaning as in the general formula I, with (b) a salt of hydrocyanic acid, and (c) a 2-halocyclobutanone of the general formula:

Description

The invention relates to a process for the preparation of an ester of cycloprop3ne carboxylic acid esters.
~ccording to Ge~nall Auslegesc~ ift 2,231,312, addition Or substituted cyclopropanecarbonyl halides and m-substituted benzaldehydes, if uecessary dissolved in an aprotic solvent, to an aqueous solution of sodium cyunide or potassium cyanide and stirring of the rnixture obtained until no more conversion takes place, affords alpha-cyano-m-substituted benzyl esters of substituted cyclopropane carboxylic acids. The cyclopropane carboxylic acids can be prepared and converted in a known manner to the corresponding cyclopropanecarbonyl halides.
Such a process has the disadvantages that the cyclopropane-carboxylic acids and their carbonyl halides must be prepared in separate stages.
The present invention obviates this di,sadvantage.
The invention provides a process for the preparation of an ester of the general formula:

R R
\C/
/ \ 0 H
RJ - C - C - C - 0 - C - R' (I) wherein R , R , R3, R and R5 each represents a substituted or unsubstituted hydrocarbyl group or a hydrogen atom, which comprises reacting:
(a) an aldehyde of the general formula:
R5 - C(O)H (II) wherein R5 has the same meaning as in the general formula I, with (b) a salt of hydrocyanic acid, and {)9 (c) a 2-halocyclobutanone o~ the general formula:

R - C - C = 0 (III) R - C - C - ~lal wherein R1, R , R3 and R4 have the same meaning as in the general formula I and Hal represents a halogen atom.
The present invention enables a three-step process comprisine ring contraction of the 2-halocyclobutanone of the gen0ral ~ormula III to a cyclopropanecarboxylic acid, conversion of this acid into its carbonyl halide and reaction of this carbonyl halide with an aldehyde and a cyanide, to be replaced by a one-step process.
~he one-step process according to the invention is pre~er-ably carried out in the presence of an aprotic solvent which may be water-miscible or water-immiscible, e.g., an alkane, cyclo-alkane, aromatic hydrocarbon, ether halogenated hydrocarbon, N,N-disubstituted carboxylic acid amide, nitrogen-oxygen or sulphur heterocycle, acetonitrile or nitromethane. Substantially water-immiscible aprotic solvents are preferably used in the presence of water, because this promotes the formation o~ the esters o~ the general formula I. ~he ~ormation o~ these esters is most promoted in solvents comprising one or more alkanes.
Ex~mples of suitable alkanes are n-hexane, n-heptane, n-octane, n-nonane, n-decane and their isomers, for example 2-methyl-pentane, 3-methylpentane, 2-methylhexane, 3-methylhexane and

2,4,4-trimethylpentane. Gasolines rich in alkanes, such as gasolines with a boiling range at atmospheric pressure between, for example, 60 and 80 C are also very suitable. Very good results have been obtained with n-heptane.

(3 Exa~nples of other substantially water-immiscible solvents are cycloalkanes, for example cyclohexane and methylcyclohexarle, and aromatic hydrocarbons, such as benzene, toluene, o-, m- and p-xylene and the trime-thyl benzenes, ethers, such as die-thyl ether and di-isopropyl ether, alkanones, such as di-isobutyl ketone and halogenated hydrocarbons, such as carbon tetrachloride.
The amount of water is not critical and may vary within wide limits. On the one hand, it i5 preferably less than -the amount required to obtain a 25%w and particularly 40%w a~ueous solution with the starting amount of a water-soluble salt of hydrocyanic acid so as to reduce the possibility of reaction of the 2-halocyclobutanone of the general formula III, with water with formation of cyclopropane carboxylic acid, and on the other hand, it is preferably sufficiently large to dissolve all of this cyanide at the temperature at which the process is conducted so as to reduce the reaction time. However, the presence of solid water-soluble salt of hydrocyanic acid is not excluded.
The temperature at which the process is suitably conducted is usually in the range of from 20 to 100C and is preferably in the range of from 50 to ôO C. The esters of the general formula I
are usually obtained in the highest yield in the range of from 60 to 70C.
Water-miscible aprotic solvents are preferably used in the absence of water. Examples of such solvents are N,N-dimethyl-formamide, N,N-dimethylacetamide, dimethyl sulphoxide, N-methyl-pyrrolidone, acetonitrile, tetrahydrothiophene, 1,1-dioxide, nitromethane and tetrahydrofuran. Very good results have been obtained with N,N-dimethylformamide.
Mixtures of solvents, for example of alkanes and aromatic hydrocarbons, may be used, for instance n-heptane containing up to 10%w of benzene and/or toluene.

The sal-t o~ hydrocyanic acid is soluble in wa-ter when a substantially water-immiscible aprotic solvent is used in the presence of water and soluble in ~he aprotic solvent when -the aprotic solvent is substantially water-miscible~ Examples of suitable salts of hydrocyanic acid are alkali metal cyanides, alkaline earth metal cyanides and -tetrahydrocarbyl ammonium cyanides. Alkali metal cyanides are preferred. Potassium cyanide is particularly preferred, because it a~ords the esters of the general formula I in a shorter reaction time and in a higher yield than sodium cyanide.
The molar ratios of the aldehyde of the general formula II
to the 2-halocyclobutanone of the general formula III and of the salt of hydrocyanic acid to the aldehyde of the general formula II are not critical and may vary within wide limits.
The former molar ratio is preferably equal to one and the latter is preferably in the range of from 1.0 to 1.5 and particularly from 1.1 to 1.3.
The hydrocarbyl groups represented by R1, R2, R3 and R4 in the general formula III and by R5 in the general formula II
may be, for example, alkyl, cycloa~kyl, aryl, or ethylenically unsaturated groupsO These groups may be substituted with, for example, hydrocarbyloxy groups or halogen atoms. R5 preferably represents a substituted or unsubstituted aryl group. These aryl groups may be carbocyclic or heterocyclic. Examples of carbocyclic groups are phenyl, 1-naphthyl, 2-naphthyl and 2-anthryl groups. Heterocyclic aromatic groups are deri~ed from hetero-aromatic compounds which, according to Kirk-Othmer, "Encyclopedia o~ C'hemical Technology", Second Edition, Volume 2 (1963), page 702, are defined ae being obtained by replacement of one or more carbon atoms of a carbocyclic aromatic compound by a hetero atom, for example, pyridine, pyrimidine, pyrazine, quinoline and isoquinoline; the hetero-aromatic compounds include heterocyclic compounds having five-membered rings which show aromatic characteristics and are mentioned on page 703 of said volume, for example, -thiophene, pyrrole, furan, indole and benzothiophene. As an aromatic group a substi-tuted or un-substituted phenyl group is very suitable. Very good results have been obtained with m-phenoxyb~nzaldehyde.
R , R , R3 and R in the general formula In preferably represent alkyl groups, particularly alkyl groups with one to six carbon atoms. The alkyl groups may be linear or branched.
Methyl groups are most preferred.
The Hal atom in the general formula I~ preferably re-presents a chlorine or a bromine atom, in particular a chlorine atom.
The process according to the invention may be carried out lS by mixing the total amounts of the starting compounds with vigorous stirring. If desired, the aldehyde of the general formula II, the salt of hydrocyanic acid, the aprotic solvent and water, if any, may be mixed, followed by gradual addition of the cyclobutanone of the general formula III, but this method generally offers no advantages over the other procedure.
Esters of the general formula I, for example, alpha-cyano-

3-phenoxy-benzyl-2,2,3,3-tetramethylcyclopropane carboxylate, are valuable insecticides.
The Examples further illustrate the invention.
EXAMPLES I-VII
A 50-ml round-bottomed flask provided with a magnetic stirrer was charged with 10 mmol. of 3-p~noxybenzaldehyde, 10 mmol. of 2-chloro-3,3,4,4-tetramethylcyclobutanone, 12 mmol. of a cyanide, 20 ml of n-heptane and water. The reaction mixture was stirred vigorously and analysed by gas-liquid chromatogr~phy to determine the yield of the alpha-cyano-3-phenoxybenzyl-2,2,3,3-tetramethylcyclopropane carboxylate formed. Se~en experiments were conducted ;n this manner, except where indicated otherwise. The cyanide used, the amount o~ water added, the reaction -temperature and the time of stirring are stated in Table I. The starting ~mount of 12 mmol. of KCN in Examples I, III and IV formed a 4ll%w aqueous solution, in Examples II and V a 28~w aqueous solution. The starting amount of 12 mmol. of NaCN in Examples VI and VII formed a 37%w aqueous solution. Table I also presents the yield of the desired ester, calculated on starting 3-phenoxybenzaldehyde.

ABLE I
.. __ Ex- Cyanide Water, Temper- Time, Yield of ample - _ _ _ _ nl a~ re h ester, %

I KCN 1 65 6 ~1 II KCN 2 65 6 81 1) III KCN 1 93 3 79 1) IV KCN2) 1 25 20 46 VI NaCN 1 65 20 55 VII NaCN 1 25 24 42 1) the 2-chloro-3,3,4,4-tetramethylcyclobutanone was fully converted; the conversion of 3-phenoxybenzaldehyde was 85%, 2) the 2-chloro-3,3,4,4-tetramethylcyclo butanone was added to the reaction mixture over a period of 1~ hours.
The reaction mixture of Example I was cooled to 25C, 10 ml of water were added to dissolve precipitated potassium chloride, the water layer was separated, the heptane layer was washed with 10 ml of water, dried over anhydrous calcium chloride and the n-heptane was flashed off in a film evaporator to yield a pale yellow oil which, according to quantitative gas-liquid chromatography, contained the desired ester in an amount corre-sponding to a yield of 88%.

0~3 - o -EXAMPLE VIII
The experiment of Example I was repeated, but this time with 20 ml of cyclohexane instead Or 20 ml o~ n-hcptane and the re-action mixture was kept at re~lux temperature (about 81 C).
After 6 hours' stirring the yield of the desired es-ter was 45%.
EXAMPL S IX and X
A 50 ml round-bottomed ~lask provided with a magne-tic stirrer was charged with 10 mmol. o~-benzaldehyde, 10 mmol. of 2-chloro-3,3,4,4-tetramethylcyclobutanone, 12 mmol. of sodium cyanide, 20 ml of a solvent and 1 ml of water. The reaction mixture was stirred vigorously at a temperature of 23 C. Two experiments were carried out in this manner. Table II states the solvents used and presents the yields of the alpha-cyanoben%yl-2,2,3,3-tetramethylcyclopropane carboxylate ~ormed.

TABLE II
. ~
Example Solvent Time, ¦ Yield of ~o. hI ester, %
. __ __ IX n-heptane 493 5 29 toluene 17 15 15E-XAMPLES XI and XII
A 50-ml round-bottomed ~lask provided with a magnetic stirrer was charged with 10 mmol. of benzaldehyde9 10 mmol. of 2-chloro-3,3,4,4-tetramethylcyclobutanone, 12 mmol. of a cyanide, 20 ml of n-heptane and 1 ml of water. The reaction mixture was stirred vigorously at a temperature of 70C. Two experiments were carried out in this manner. Table III states the cyanides used and presents the yields of the alpha-cyanobenzyl-2,2,3,3-tetramethylcyclopropane-carboxylate formed.

_9_ ~ 9 TABLE II-[

Example Cyanide Time, Yield of No. h ester, %
. _ . _ _ . __ . .. _ _ XI KCN 22-5 o12 XII NaCN ~ 61 EXAMPLE XIII
A mixture of 100 mmol. of benzaldehyde, 100 mmol. of sodium cyanide and 50 ~1 of N7N-dimethylformamide was stirred at a temper-ature of ôOC for 30 min. Then, an amount of 100 mmol. of 2-chloro-3,3,4,4-tetramethylcyclobutanone was added over a period of 30 min. and stirring was continued for six hours. At the end of this period the reactants ~ere fully converted and alpha-cyanobenzyl-2,2,3,3-tetramethylcyclopropane carboxylate was obtained in a yield of 65%.
EXAMPLE XIV
~ = .
A mixture of 100 mmol. of ~enzaldehyde, 100 mmol. o~ sodium cyanide and 50 ml of di-isobutyl ketone was stirred at a temperature of 60C for 30 minutes. Then, an amount of 100 mmol.
of 2-chloro-3,3,4,4-tetramethylcyclobutanone was added over a period of 30 min. and stirring was continued for 100 hours.
The conversion of benzaldehyde was 75% and the yield of alpha-cyanobenzyl-2,2,3,3-tetramethylcyclopropane carboxylate 52%, calculated on starting benzaldehyde.

Claims (9)

C L A I M S

1. A process for the preparation of a cyclopropane carboxylic acid ester of the general formula:
(I) wherein R1, R2, R3, R4 and R5 each represents a substituted or unsubstituted hydrocarbyl group or a hydrogen atom, which comprises reacting:
(a) an aldehyde of the general formula:
R5 - C(O)H (II) wherein R5 has the same meaning as in the general formula I, with (b) a salt of hydrocyanic acid, and (c) a 2-halocyclobutanone of the general formula:

(III) wherein R1, R2, R3 and R4 have the same meaning as in the general formula I and Hal represents a halogen atom.

2. A process according to claim 1, wherein the process is conducted at a temperature in the range of from 20° to 100°C.

3. A process according to claim 1, wherein the salt of hydrocyanic acid is an alkali metal cyanide, alkaline earth metal cyanide or a tetrahydrocarbylammonium cyanide.

4. A process according to claim 1, 2 or 3, wherein the aldehyde is a substituted or unsubsituted benzaldehyde.

5. A process according to claim 1, 2 or 3, wherein the 2-halocyclobutanone has the general formula III, wherein R1, R2, R3 and R4 represent alkyl groups containing 1 to 6 carbon atoms.

6. A process according to claim 1, 2 or 3, wherein the aldehyde is 3-phenoxybenzaldehyde or benzaldehyde, the salt of hydrocyanic acid is sodium or potassium cyanide and the 2-halo-cyclobutanone is 2-bromo- or 2-chloro-3,3,4,4-tetramethylcyclobutanone.

7. A process according to claim 1, wherein the process is carried out in the presence of an aprotic solvent.

8. A process according to claim 7, wherein the aprotic solvent is an alkane, cycloalkane, aromatic hydrocarbon, ether, halogenated hydrocarbon, n,n-disubstituted carboxylic acid amide, nitrogen-, oxygen- or sulphur-heterocycles, acetonitrile or nitromethane.

9. A process according to claim 7 or 8, where water is additionally present with a water-immiscible aprotic solvent.