Preparation of phenoxybenzyl esters

Phenoxybenzyl esters are prepared by neutralizing an aqueous solution of a carboxylic acid and contacting the neutralized solution with a solution of phenoxybenzyl halide in a water-immiscible base in the presence of a phase transfer catalyst.

FIELD OF THE INVENTION 
This invention relates to an improved process for preparing phenoxybenzyl 
esters of cyclopropane carboxylic acids or phenylacetic acids, these 
compounds being very active as pesticides and forming part of the group of 
compounds known as "synthetic pyrethroids". 
SUMMARY OF THE INVENTION 
Accordingly the present invention provides a process for the preparation of 
a phenoxybenzyl ester of formula (I) 
##STR1## 
wherein an acid of formula R - COOH in which R represents an optionally 
substituted cyclopropyl group or an optionally substituted benzyl group is 
neutralized with a water-soluble base, and then contacted with a solution 
in a substantially water-immiscible organic solvent of a benzyl halide of 
formula 
##STR2## 
in which X represents a halogen, preferably chlorine or bromine, atom; and 
Q represents a hydrogen atom or cyano group in the presence of a 
phase-transfer catalyst. 
The neutralisation of the aqueous acid solution can be effected by the use 
of any water-soluble base, but for reasons of convenience and economics it 
is usually preferred to use an inorganic base such as potassium carbonate 
or hydroxide or sodium hydroxide. 
Although any substantially water-immiscible organic liquid may 
theoretically be used as solvent for the benzyl halide, it is generally 
preferable to use an organic liquid in which the benzyl halide is at least 
moderately soluble. Futhermore, eventual recovery of the ester product is 
often simplified if the organic liquid solvent is lighter than water. 
Suitable solvents include aromatic hydrocarbons such as benzene and 
toluene or petroleum ether, and it may be convenient to use mixed with 
hydrocarbons such as xylenes, trimethylbenzene or kerosene as the benzyl 
halide solvent since the resulting solution of ester can then be employed 
directly, without isolation of the ester, in the production of a 
pesticidal emulsifiable concentrate. The reactant solutions are contacted 
with each other as by agitating, stirring or the like. 
The phase-transfer catalyst may be any reagent which will accelerate 
interphase reactions in aqueous/organic two-phase systems, the most 
convenient such catalysts including quaternary ammonium and phosphonium 
salts. Generally economic considerations make it preferable to use 
quaternary ammonium salts. The quaternary ammonium salts have four 
hydrocarbyl groups - which optionally may be substituted - attached to the 
nitrogen atom, for example, aromatic, aliphatic, cycloaliphatic or 
unsaturated groups or combinations of any of these groups, for example an 
aromatic-aliphatic group. The cation of the tetrahydrocarbylammonium salt 
may contain one or more quaternary bound nitrogen atoms. The salt may have 
any anion; chlorides and bromides are preferred. The total number of 
carbon atoms in the four hydrocarbyl groups is preferably from 12 to 70. 
Examples of suitable tetrahydrocarbylammonium salts are tetraalkylammonium 
halides such as tetra-n-butylammonium chloride, tetra-n-pentylammonium 
chloride, ethyl-tri-sec-otylammonium chloride, ethyl-tri-n-hexylammonium 
chloride, n-hexadecyltri-n-hexylammonium chloride, 
di-n-undecyldiethylammonium chloride and tetra-n-octylammonium chloride, 
or aryltrialkylammonium halides such as benxyltri-n-butylammonium chloride 
and the corresponding bromides. The corresponding phosphonium compounds 
are also useful. Tetra-alkyl ammonium halides are particularly preferred. 
Alternatively, the macrocyclic polyethers known as "crown ethers" may be 
utilized as phase transfer catalyst. These compounds, together with their 
preparation, are described in the literature, for example in Tetrahedron 
Letters No. 18 (1972) pp. 1793-1796, and are commonly designated by 
reference to the total number of atoms forming the macrocyclic ring 
together with the number of oxygen atoms in that ring. Thus the 
macrocyclic polyether whose formal chemical name is 
1,4,7,10,13,16-hexaoxacyclooctadecane is designated as "18-crown-6". 
Further suitable macrocylic polyethers are described in U.S. Pat. No. 
3,562,295 British Pat. No. 1,108,921 and in co-pending British patent 
application 10,744/75. Other types of compound which may be used as the 
phase-transfer catalyst include quaternary ammonium anion exchange resins 
(suitably in the hydroxyl form) as shown for example in U.S. Pat. No. 
3,917,667. 
The concentration of catalyst used may widely, but at low concentrations 
(e.g. 1mole % or less) a higher reaction temperature is required to 
complete the esterification reaction within an acceptible period of time, 
whilst the use of higher concentrations (e.g. above 10 mole %) naturally 
increases the cost of the catalyst required to produce a given quantity of 
ester. For example, the use of 5 mole % of catalyst at 
65.degree.-70.degree. C will lead to a 20-30 fold reaction in reaction 
time as compared with the same reagent concentrations at room temperature, 
and reduction of the catalyst concentration to 1 mole % increases the 
reaction time 2-3 fold. Thus, the choice of reaction temperature and 
catalyst concentration are mutually interdependent, and in any individual 
instance will depend on the local economic factors. 
In the phenoxybenzyl esters of formula (I), R is preferably 
i. a cyclopropyl group of formula (III) 
##STR3## 
wherein R.sub.a and R.sub.b each represent an alkyl group having from 1 to 
6 carbon atoms, especially methyl, or a halogen atom of atomic number 
9-35, inclusive, especially a chlorine atom; or R.sub.a and R.sub.b 
together represent an alkylene group having from 2 to 6, especially 3, 
carbon atoms; or R.sub.a represents a hydrogen atom and R.sub.b represents 
an alkenyl group having from 2 to 6 carbon atoms, especially an isobutenyl 
group, or an haloakenyl group having from 2 to 6 carbon atoms and from 1 
to 3 chlorine or bromine atoms, especially a mono- or dichlorovinyl group; 
R.sub.c and R.sub.d each represent an alkyl group having 1 to 6 carbon 
atoms, especially methyl, or R.sub.c is hydrogen and R.sub.d is an alkenyl 
group having from 2 to 6 carbon atoms, especially an isobutenyl group, or 
an haloalkenyl group having from 2 to 6 carbon atoms and from 1 to 3 
chlorine or bromine atoms, especially a mono- or dichlorovinyl group; or 
R.sub.c and R.sub.d together represent an alkylene group having from 2 to 
6, especially 3 carbon atoms; or (ii) a benzyl group of formula (IV) 
##STR4## 
wherein Z represents a halogen atom of atomic number 9-35, inclusive, 
preferably a chlorine atom, or an alkoxy group of 1 to 4 carbon atoms, 
e.g. methoxy, and Y represents an alkyl group of 1 to 6 carbon atoms, 
especially a branched chain group such as in isopropyl group. The phenoxy 
substituent in the phenoxybenzyl esters of general formula (I) is 
preferably in the 3-position. 
It will be appreciated that as a result of the asymmetric carbon atoms and 
double bonds which may be present in the phenoxybenzyl esters prepared by 
the process according to the present invention, the esters can exist in a 
number of stereoisomeric forms and therefore the present invention also 
extends to the production of any one or a mixture of such stereoisomers. 
The required stereoisomer or mixture of stereoisomers may be obtained by 
using as starting material the appropriate stereoisomeric carboxylic acid 
and/or the appropriate stereoisomeric phenoxybenzyl halide. 
The process of this invention is of particular value in its application to 
the preparation of alpha-cyano-3-phenoxybenzyl esters of 
tetramethylcyclopropane carboxylic acid, 
dimethyl-dichlorovinyl-cyclopropane carboxylic acid, 
dimethyl-dibromovinyl-cyclopropane carboxylic acid and 
2-(4-chlorophenyl)-3-methylbutyric acid, because these esters have 
interesting pesticidal, especially insecticidal, activity. 
In this application the process offers certain advantages over a 
conventional esterification process using no phase-transfer catalyst. 
Thus, for example, a conventional process normally produces significant 
amounts of impurities (such as the olefin formed by hydrogen halide 
elimination between 2 molecules of benzyl halide) whose removal requires 
an expensive crystallisation procedure. Use of the phase-transfer catalyst 
according to the present invention yields a product less contaminated with 
these impurities. Furthermore, use of the phase-transfer catalyst also 
facilitates operation of the process at higher reactant concentrations and 
because the organic solvent used for the benzyl halide can be the same as 
that required in a pesticidal emulsifiable concentrate, it is possible, 
using the process of this invention, to produce the final ester as an 
organic solution which can be transformed directly (i.e. without any 
further work-up) into a pesticidal emulsifiable concentrate by the 
addition of appropriate surfactants.

The invention is illustrated in the following Examples. 
EXAMPLE 1 
A solution of 2,2,3,3-tetramethylcyclopropane carboxylic acid (470g; 3.3M) 
in water (1200 ml) and potassium carbonate (228g; 1.65M) was treated with 
a solution of alpha-cyano-3-phenoxybenzyl bromide (864g; 3.0M) in toluene 
(1500 ml) and the phase-transfer catalyst, tetrabutylammonium bromide, 
(48g; 5 mole %). The mixture was vigorously stirred and heated to 
30.degree. C. The rate of reaction and the completion was determined by 
thin layer chromatography using Merck pre-coated plates (silica-gel 
60F-254), developed in the following solvent mixture: - ethyl acetate 1 
vol, chloroform 2 vols. and hexane 7 vols. The reaction was continued 
until no benzyl bromide could be detected by U.V. light. 
When the reaction was complete (after about 24 hours), the aqueous phase 
was separated and the toluene solution washed with 5% aqueous potassium 
carbonate solution (2 .times. 1 liter portions), water (2 .times. 1 liter 
portions), and then filtered through a pad of silica-gel (100g). The 
solution was evaporated under reduced pressure and degassed under high 
vacuum (0.1mm Hg at 50.degree. C) to give the crude product (1070g, purity 
92%). The crude product was up-graded by dissolving in methanol (2 liters) 
and crystallised with stirring and cooling. A filter-stick was then 
inserted and the mother-liquors (1230 ml) removed by suction. The residual 
solid in the reactor was melted, evaporated, and finally degassed under 
high vacuum to give alpha-cyano-3-phenoxybenzyl 
2,2,3,3-tetramethylcyclopropane carboxylate (953g, purity = 95%). 
Yield purified product was 86.4% based on starting benzyl bromide. 
EXAMPLE 2 
A mixture of 2,2,3,3-tetramethylcyclopropane carboxylic acid (7.8g, 
0.055M), potassium carbonate (3.8g, 0.0275M) water (40 mls), 
tetrabutylammonium bromide (1.5g, 10 mole %), alpha-cyano-3-phenoxybenzyl 
bromide (14.4g, 0.05 mole) and toluene (50 ml) was stirred at 25.degree. C 
for 5 hours. The aqueous phase was separated and the toluene layer washed 
twice with 5% potassium carbonate solution and twice with water. The 
solution was filtered through a pad of silica-gel (3g) and evaporated to 
leave a pale-yellow oil (17.4g; purity = 92%). Recrystallisation of this 
material from hexane gave pure alpha-cyano-3-phenoxybenzyl 
2,2,3,3-tetramethylcyclopropane carboxylate, melting point 
50.degree.-51.degree. C. 
Similar experiments carried out at different temperatures and using 
different concentrations of phase-transfer catalyst showed that complete 
reaction required 1 hour at 65.degree. C for a 5 mole % catalyst or 3 
hours at 70.degree. C for 1 mole % catalyst. 
EXAMPLE 3 
A mixture of 2-(4-chlorophenyl)-3-methylbutyric acid (703g, 3.3M), water 
(1500 ml), potassium carbonate (228g, 1.65M) and tetrabutylammonium 
bromide (48g, 5 mole %) was treated with a solution of 
alpha-cyano-3-phenoxybenzyl bromide (864g, 3.0M) in toluene (1500 ml). The 
mixture was vigorously stirred and heated to 35.degree. C. The rate of 
reaction was followed and completion determined by thin layer 
chromatography using Merck pre-coated plates (silica-gel 60 F-254), 
developed in a solvent mixture of ethyl acetate 1 vol., chloroform 2 
vols., hexane 7 vols. The reaction was continued until no bromonitrile 
could be detected by U.V. light. 
When the reaction was complete (about 60 hours), the aqueous phase was 
separated and the toluene layer washed with 5% aqueous potassium carbonate 
(2 .times. 1 liter portions), water (2 .times. 1 liter portions) and then 
filtered through a pad of silica-gel (100g). 
The resulting solution was evaporated under reduced pressure and finally 
degassed under high vacuum (0.1 mm Hg at 50.degree. C) to give 
alpha-cyano-3-phenoxybenzyl-2-(4-chlorophenyl)-3-methyl butyrate (1258g; 
purity = 98%). 
Yield based on benzyl bromide was 98%. 
EXAMPLE 4 
A mixture of 2-(4-chlorophenyl)-3-methylbutyric acid (11.68g, 0.055M), 
potassium carbonate (3.79g, 0.0275M), water (50 ml), 
alpha-cyano-3-phenoxybenzyl bromide (14.4g, 0.05M), toluene (50 ml), and 
tetrabutylammonium bromide (1.5g, 10 mole %) was stirred for 24 hours at 
25.degree. C and worked up as for Example 3. 
The desired product was isolated as a bottom oil in yield of 97% and purity 
of 96%. 
EXAMPLE 5 
Example 4 was repeated using the same reactants in the same quantities, 
except that only 0.15g (1 mole %) of tetrabutylammonium bromide was used. 
Essentially quantitative yield of the desired product was obtained after 5 
hours at 70.degree. C. 
EXAMPLE 6 
Example 4 was repeated using the same reactants in the same quantities 
except that 0.75g (5 mole %) of tetrabutylammonium bromide was used. 
Essentially quantitative yield of the desired product was obtained after 2 
hours at 65.degree. C. 
EXAMPLE 7 
A mixture of 2,2-dimethyl-3-(2',2'-dichlorovinyl)cyclopropane carboxylic 
acid (11.55g, 0.055M), water (50 mls), potassium carbonate, (3.7g, 
0.0275M), 3-phenoxybenzyl bromide (13.15g, 0.05M), toluene (50 mls), and 
tetrabutylammonium bromide (0.75g, 5 mole %), was stirred at 65.degree. C 
and yielded close to quantitative yield of the desired product after about 
48 hours reaction time. 
EXAMPLE 8 
A mixture of 2,2-dimethyl-3-(2',2'-dichlorovinyl)cyclopropane carboxylic 
acid (311g, 1.49M), water (700 mls), potassium carbonate (104g, 0.75M), 
alpha-cyano-3-phenoxybenzyl bromide (395g, 1.37M) toluene (700 mls) and 
tetrabutylammonium bromide (4.4g, 1 mole %) was stirred at 65.degree. C 
for 10 hours. The product was worked-up as described in Example 3 to give 
alpha-cyano-3-phenoxybenzyl-2,2-dimethyl-3-(2',2'-dichlorovinyl)cyclopropa 
ne carboxylate (550g). Yield based on alpha-cyano-3-phenoxybenzyl bromide 
was 96.5%. 
EXAMPLE 9 
A mixture of 2,2,3,3-tetramethylcyclopropane carboxylic acid (4.7kg,33M), 
water (12 liters), potassium carbonate (2.28kg, 16.5M), 
alpha-cyano-3-phenoxybenzyl bromide (8.64kg, 30M), toluene (15 liters) and 
tetrabutylammonium bromide (96g, 1 mole %) was stirred at 60.degree. C for 
5 hours. 
A working-up procedure similar to that employed in Example 1 gave 
alpha-cyano-3-phenoxybenzyl-2,2,3,3-tetramethylcyclopropane carboxylate 
(9.280g, purity .times. 97%). 
Yield based on starting benzyl bromide was 85.7%. 
EXAMPLE 10 
Example 2 was repeated using alpha-cyano-3-phenoxybenzyl chloride and 1 
mole % tetrabutylammonium bromide as catalyst. A similar yield of the 
desired product was obtained after stirring the mixture at 90.degree. C 
for 6 hours. 
EXAMPLE 11 
Example 6 was repeated using the same reactants in the same quantities 
except that 0.65g (5 mole %) of 1,4,7,10,13,16-hexaoxacyclooctadecane was 
used as catalyst. The mixture was stirred at 65.degree. C for 20 hours and 
then worked-up as previously to give the desired product in 98.2% yield. 
EXAMPLE 12 
Example 6 was repeated except that no catalyst was added. After 120 hours 
at 65.degree. C approximately 40% of the bromide had been converted to the 
desired product. 
EXAMPLE 13 
A mixture of cis-2,2-dimethyl-3-(2',2'-dibromovinyl)cyclopropane carboxylic 
acid (2.2g, 0.0074M), water (5 mls), potassium carbonate (0.5g, 0.0037M), 
alpha-cyano-3-phenoxybenzyl bromide (1.94g, 0.00674M), methylene chloride 
(35 mls), and tetrabutylammonium bromide (0.1g, 4.6 mole %) was stirred at 
40.degree. C for 10 hours. The product was worked-up as described in 
Example 3 to give 
cis-alpha-cyano-3-phenoxybenzyl-2,2-dimethyl-3-(2',2'-dibromovinyl)cyclopr 
opane carboxylate (3.4g, 0.00673M). Yield based on 
alpha-cyano-3-phenoxybenzyl bromide was 99.9%. 
EXAMPLE 14 
Example 13 was repeated using trans-2,2-dimethyl-3-(2',2'-dibromovinyl) 
cyclopropanecarboxylic acid under the same reaction conditions and with 
the same quantities. Yield of the trans-ester based on 
alpha-cyano-3-phenoxybenzyl bromide was 100%. 
EXAMPLE 15 
Example 13 was repeated using (-) 
cis-2,2-dimethyl-3-(2',2'-dibromovinyl)cyclopropane carboxylic acid under 
the same reaction conditions and the same quantities. Yield based on 
alpha-cyano-3-phenoxybenzyl bromide was 100%; [.alpha.].sub.D = 
-11.1.degree.. 
EXAMPLE 16 
A mixture of (-) 2-(4-chlorophenyl)-3-methylbutyric acid (46.75g, 0.22M), 
potassium carbonate (15.2g, 0.11M), water (100ml), 
alpha-cyano-3-phenoxybenzyl bromide (57.6g, 0.2M), methylene chloride (150 
ml) and tetrabutylammonium bromide (1.3g, 2 mole %) was stirred and 
refluxed for 24 hours. The desired product was isolated as a bottom oil 
(82.4g). Yield = 99.4%, purity = 97%; [.alpha.].sub.D = +7.3.degree..