Preparation cyano substituted cyclopropane

A process for the preparation of cyclopropane compounds which comprises reacting a compound of formula: EQU Y--CH.sub.2 --CN with a diene of formula: EQU CX.sub.2 =CH--CH=C(CH.sub.3).sub.2 in the presence of at least one reducible copper salt, X being chlorine or bromine and Y being cyano, alkoxycarbonyl containing up to four carbon atoms in the alkoxy moiety, benzyloxycarbonyl, phenoxybenzyloxycarbonyl or 2,2-dichlorovinyloxybenzyloxycarbonyl.

The present invention relates to a process for the preparation of 
cyclopropane derivatives which are valuable chemical intermediates. 
3-(2,2-Dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid is an 
important intermediate in the production of insecticides, including, for 
example, 3-phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane 
carboxylate. The preparation of 
3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid has been 
described by Farkas et al (Collection Czechoslov. Chem. Commun., (1959), 
24, pp 2230-2236) by the reaction of ethyl diazoacetate with 
1,1-dichloro-4-methyl-1,3-pentadiene followed by hydrolysis of the 
resultant ethyl ester. This process is not suitable for large scale 
preparation of the acid because of the difficulties of working with ethyl 
diazoacetate, which is a substance which can explosively decompose unless 
the conditions are rigorously controlled, and which is believed to be a 
potent carcinogen. 
We have now discovered a process for the preparation of cyclopropane 
derivatives which avoids the use of diazoacetic esters. 
Accordingly the present invention provides a process for the preparation of 
a compound of formula: 
##STR1## 
wherein X is chlorine or bromine and Y is either cyano or alkoxycarbonyl 
containing up to four carbon atoms in the alkoxy moiety, or 
benzyloxycarbonyl or substituted benzyloxycarbonyl which comprises the 
step of reacting a compound of formula: 
EQU Y--CH.sub.2 --CN (II) 
with a diene of formula: 
EQU CX.sub.2 .dbd.CH--CH.dbd.C(CH.sub.3).sub.2 (III) 
the reaction taking place in the presence of at least one reducible copper 
salt. 
When Y represents substituted benzyloxycarbonyl it preferebly represents 
phenoxybenzyloxycarbonyl or dichlorovinyloxybenzyloxycarbonyl, especially 
3-phenoxybenzyloxycarbonyl or 3-(2,-dichlorovinyloxy)benzyloxycarbonyl. 
Cupric salts are preferred copper salts for use in the process and examples 
of cupric salts which are particularly preferred include the cupric salts 
of carboxylic acids, for example cupric acetate, and the salts with 
hydrohalic acids, for example cupric chloride. However other reducible 
copper salts may also be used, for example cupric sulphate. 
In a preferred form the process is conducted in the presence of at least 
one alkali or alkaline earth metal salt, for example a lithium, calcium or 
magnesium salt, in addition to the reducible copper salt. Halides of 
lithium, calcium or magnesium are especially preferred, although other 
salts of these metals may also be used. Particularly useful salts of 
lithium, calcium and magnesium are the chlorides. Optionally a quaternary 
ammonium salt, for example a tetra-alkyl ammonium halide such as methyl 
triethyl ammonium chloride, may be used in the place of or additional to 
the lithium, calcium or magnesium salt. 
It is also possible to conduct the process in the presence of a base which 
is preferably the alkali or alkaline earth metal salt of a weak acid such 
as carbonic acid, boric acid or a carboxylic acid (for example acetic 
acid). Specific examples of such bases includes potassium carbonate, borax 
(sodium borate), potassium acetate and calcium carbonate. 
The copper, lithium and calcium salts may be used in the process of the 
invention in anhydrous form or they may be employed as the hydrates. Thus, 
for example, it is convenient to employ cupric acetate as the monohydrate 
and lithium chloride as the monohydrate. Calcium halides are best employed 
in anhydrous form. 
A preferred combination of salts for use in the reaction is a mixture of 
cupric acetate monohydrate and lithium chloride monohydrate. Other useful 
combinations include cupric chloride with lithium chloride in the presence 
of potasium carbonate, and cupric acetate with calcium chloride. 
The copper salts may be used in molar proportions with respect to the cyano 
derivative of formula: 
EQU Y--CH.sub.2 --CN 
a preferred proportion being two moles of copper salt per mole of the cyano 
derivative. 
Since the copper salts are reduced in the course of the reaction, it will 
be appreciated that it may be possible to use a suitable redox system to 
regenerate some or all of the reduced copper species, thus enabling the 
copper reagent to be used catalytically. The regeneration may be carried 
out in situ or in a separate stage. 
The reaction may be conducted under an inert atmosphere, which may 
conveniently be nitrogen or argon. Alternatively, if the copper reagents 
are to be employed catalytically and regenerated in situ, it may be 
convenient to use an oxygen-containing atmosphere. 
The process of the invention may optionally be carried out in the presence 
of a solvent or diluent for the reactants, although it may also be 
conducted in the absence of a solvent or diluent, the reactants themselves 
being nonviscous liquids although they are not necessarily good solvent 
for the copper and other salts employed in the process. When a solvent or 
diluent is used it may be for example a polar aprotic solvent or diluent 
of the type exemplified by dimethylformamide, dimethylsulphoxide 
N,N-dimethylacetamide, or an ester such as ethyl acetate or butyl acetate, 
or a halogenated hydrocarbon such as ethylene dichloride or methylene 
dichloride. Particularly preferred solvents are saturated aliphatic 
alcohols containing up to six carbon atoms, such as methanol, ethanol, 
isopropanol and t-butanol. An especially preferred solvent is ethanol, 
optionally denatured with small amounts of methanol as in industrial 
methylated spirit. Water may be used as a diluent for the reaction, 
particularly when a phase-transfer catalyst such as a quaternary ammonium 
salt is present. Examples of quaternary ammonium salts particularly useful 
for this purpose are tetraalkyl ammonium halides such as tetramethyl 
ammonium chloride, tetrabutyl ammonium chloride, ethyl trimethyl ammonium 
bromide, and benzyltrialkyl ammonium halides such as benzyltrimethyl 
ammonium chloride. 
Water may also be used as a diluent in admixture with water-miscible 
solvents such as methanol or ethanol. 
Certain combinations of solvent and copper and other salts are particularly 
useful in performing the invention process. These include (a) cupric 
acetate monohydrate, and lithium chloride monohydrate with butyl acetate, 
(b) cupric acetate monohydrate, and calcium chloride with ethanol, (c) 
cupric chloride, lithium chloride monohydrate and potassium carbonate with 
butyl acetate, and (d) cupric acetate with methyltriethyl ammonium 
chloride in butyl acetate. 
It will be appreciated that the cyclopropane derivatives of formula I 
(where Y is not cyano) can exist in cis and trans isomeric forms. The 
proportion of each form present in the product appears to be dependent to 
some extent on the choice of solvent or diluent and the salt or salts 
used. Thus a particularly useful combination for yielding a product with 
an excess of cis - isomer present is cupric acetate and calcium chloride 
with ethanol. 
The process may be conducted at any temperature within the range 0.degree. 
C. to the reflux temperature of the reactants and solvent or diluent (when 
used). However it has been found that the reactions are accelerated by the 
application of heat and a preferred temperature range for conducting the 
process is from about 50.degree. C. to about 105.degree. C. 
The process may be conducted over a time period of from several minutes to 
several hours, for example from 30 minutes to 30 hours. A time of about 5 
hours is normally sufficient to provide a reasonable yield of product when 
a temperature in excess of 75.degree. C. is employed. 
The direct products of the process are compounds of Formula I as defined 
hereinabove. Of particular interest are compounds of Formula I wherein X 
is chlorine, and Y is lower alkoxycarbonyl, for example the following: 
methyl 1-cyano-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylate, 
and 
ethyl 1-cyano-3-(2,2-dichlorovinyl)-2,2-dimethyl cyclopropane carboxylate. 
Preferred compounds of Formula II for use in the process of the invention 
are lower alkyl esters of cyanoacetic acid, for example methyl 
cyanoacetate and ethylcyanoacetate. 
If the process is conducted with a lower alkyl ester of cyanoacetic acid in 
the presence of a polar aprotic solvent or diluent such as 
dimethylformamide or dimethylacetamide, and the reaction mixture is 
maintained at a temperature in excess of 120.degree. C. for a period in 
excess of about 24 hours there may be formed in addition to the compound 
of Formula I, an amount of the compound derived by decarbalkoxylation of 
the compound of Formula I, for example the compound 
1-cyano-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane. 
The compounds of Formula I obtained by the invention process may be readily 
converted by hydrolysis and decarboxylation to the corresponding 
carboxylic acids.

The invention is illustrated by the following Examples, wherein all parts 
are by weight. 
EXAMPLE 1 
151 Parts of 1,1-dichloro-4-methylpenta-1,3-diene, 226 parts of ethyl 
cyanoacetate, 200 parts of cupric acetate monohydrate, 148 parts of cupric 
chloride, 62.6 parts of lithium chloride monohydrate and 1884 parts of 
dimethylformamide are stirred under an atmosphere of nitrogen. The 
temperature is raised to 100.degree. C. and maintained at 
100.degree.-105.degree. C. for 40 minutes. After cooling, the low-boiling 
components of the mixture are removed by heating to 80.degree. C. at a 
pressure of 12 mm Hg to leave 806.6 parts of residue. The residue, 1740 
parts of toluene, 2360 parts of hydrochloric acid (s.g. 1.18) and 3000 
parts of water are stirred at ambient temperature for 30 minutes. The 
organic layer is separated and extracted twice with 590 parts of 
hydrochloric acid (s.g. 1.18) in 500 parts of water and finally four times 
with 500 parts of water. The toluene solution is evaporated by heating to 
85.degree. C. at a pressure of 17 mm Hg to yield 183.2 parts of ethyl 
1-cyano-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate 
(yield 49.1% based on a strength of 69.9%). 
EXAMPLE 2 
A similar reaction but omitting the dimethylformamide yielded 248.4 parts 
of ethyl 
1-cyano-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate 
(estimated strength 63.5% equivalent to 60.6% yield). 
EXAMPLE 3 
151 Parts of 1,1-dichloro-4-methylpenta-1,3-diene, 113 parts of ethyl 
cyanoacetate, 200 parts of cupric acetate monohydrate, 148 parts of cupric 
chloride, 62.6 parts of lithium chloride monohydrate and 900 parts of 
ethyl acetate are stirred in an atmosphere of nitrogen. The temperature is 
raised to 80.degree. C. and maintained at 80.degree.-81.degree. C. for 5 
hours. After cooling, the reaction mixture was stirred with 1180 parts of 
hydrochloric acid (s.g. 1.18) and 1500 parts of water for 10 minutes. The 
organic layer was separated and extracted twice with 590 parts of 
hydrochloric acid (s.g. 1.18) in 500 parts of water. The ethyl acetate 
solution was diluted with 900 parts of ethyl acetate and the solution 
washed four times with 500 parts of water. The ethyl acetate solution is 
evaporated by heating to 87.degree. C. at 20 mm Hg pressure to yield 201 
parts of ethyl 1-cyano- 
3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate (estimated 
strength 82.7% equivalent to 63.4% yield). 
EXAMPLE 4 
A similar reaction to Example 2 but reducing the ethyl cyanoacetate charge 
to 113 parts gave 232 parts of ethyl 
1-cyano-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate of 
lower strength (estimated strenght 57.6% equivalent to 51.0% yield). 
EXAMPLE 5 
A similar reaction to Example 2 but reacting at 20.degree.-25.degree. C. 
for 26 hours gave 201 parts of ethyl 
1-cyano-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate of 
low strength (estimated strength 20.5%). 
EXAMPLE 6 
A mixture of 1,1-dichloro-4-methyl-1,3-pentadiene (7.55g), ethyl 
cyanoacetate (11.3g), anhydrous cupric sulphate (15.96g), lithium chloride 
monohydrate (3.13g) and dimethylformamide (50 ml) was heated with stirring 
under a nitrogen atmosphere at 99.degree. to 106.degree. C. for 5 hours 
and 20 minutes. After cooling to the ambient temperature the insoluble 
material was removed by filtration. The filtrate was heated under reduced 
pressure and the more volatile portion boiling at up to 106.degree. C./13 
mm.Hg distilled off. The residue was partitioned between toluene (50 ml) 
and a water (75 ml) and concentrated (s.g. 1.18) hydrochloric acid (50 ml) 
mixture. The organic layer was separated, washed twice with a water (50 
ml) and concentrated hydrochloric acid (50 ml) mixture, and then four 
times with water (25 ml). After removal of the more volatile portion 
boiling up to 111.degree. C./21 mm. Hg, the residual oil (3.187 g) was 
analysed by gas liquid chromatography and shown to contain 76% of ethyl 
1-cyano-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylate. 
EXAMPLE 7 
The procedure of Example 3 was followed except that an equivalent amount of 
benzyl cyanoacetate was used in place of ethylcyanoacetate. The product 
was benzyl 1-cyano-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane 
carboxylate. 
EXAMPLE 8 
The procedure of Example 3 was repeated except that an equivalent amount of 
3-phenoxybenzyl cyanoacetate was employed. The crude product contained 71% 
of 3-phenoxybenzyl 1-cyano-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane 
carboxylate, equivalent to a yield of 77.7%. 
EXAMPLE 9 
The procedure of Example 3 was repeated except that ethanol was used as a 
diluent in place of ethyl acetate. The crude product contained 75.6% of 
ethyl 1-cyano -3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylate 
equivalent to a yield of 62.6%. 
EXAMPLE 10 
The procedure of Example 9 was followed in a series of experiments except 
that in each case a different diluent was used. Satisfactory yields of 
product were obtained when the diluent was selected from the following 
list: 
80% aqueous acetonitrile 
t-butanol 
diethylene glycol dimethyl ether (diglyme) 
tetrahydrofuran 
dimethyl sulphoxide 
acetonitrile 
cyclohexanol 
isopropanol 
dimethoxyethane 
N-methyl-2-pyrrolidone 
methanol 
dimethylformamide 
methyl chloride 
ethylene dichloride 
chlorobenzene 
toluene 
Lower yields (18 to 25%) were obtained when water, glacial acetic acid or 
tetrachloroethylene were used as diluents. 
EXAMPLE 11 
The procedure of Example 3 was followed except that butyl acetate was used 
in place of ethyl acetate. A satisfactory yield of product was obtained 
when the lithium chloride was replaced by a molar equivalent of methyl 
triethyl ammonium chloride. 
EXAMPLE 12 
The procedure of Example 9 was followed in a series of experiments except 
that in each case the molar equivalent of lithium chloride was replaced by 
one of: 
(a) a 0.1 molar equivalent of lithium chloride 
(b) a molar equivalent of calcium chloride 
(c) a molar equivalent of magnesium chloride 
(d) a molar equivalent of potassium chloride. 
Satisfactory yields of product were obtained in each experiment. In a 
similar experiment where the lithium chloride was simply omitted, a 
slightly lower yield resulted. 
EXAMPLE 13 
The procedure of Example 1 was followed except that a molar equivalent of 
cupric chloride was used in place of the cupric acetate (that is two molar 
equivalents of of cupric chloride in all) and a molar equivalent of 
potassium acetate or potassium carbonate or borax was present. In each 
case a satisfactory yield was obtained.