Method for controlling acarina

This invention relates to the use of m-phenoxy-benzyl esters of spirocarboxylic acids as acaricidal agents.

The invention is further demonstrated by the nonlimiting examples provided 
below. 
EXAMPLE 1 
Preparation of 3,3'-dimethylspiro[cyclopropane-1,1'-indene]-2-carboxylic 
acid, m-phenoxybenzyl ester 
##STR4## 
To 4.3 g (0.02 mol) of 
3,3-dimethylspiro[cyclopropane-1,1'-indene]-2-carboxylic acid in either 
hexane/benzene or benzene is added 8 ml of thionyl chloride. The solution 
is then stirred for 12 hours at room temperature. The solvent is then 
removed in vacuo leaving 4.7 g of an orange liquid (theoretical yield). 
Infrared indicates an acid chloride carbonyl at 1790 cm.sup.-1. 
The acid chloride and 4.0 g (0.02 mol) of m-phenoxy benzyl alcohol are 
dissolved in 20 ml. of ether, and 2.1 g (0.02 mol) of triethylamine 
dissolved in 8 ml. of ether is added dropwise at 20.degree. C. Solids 
precipitate from solution immediately. The resulting mixture is stirred 
for 12 hours at room temperature. The crude product is partitioned in an 
ether/water mixture, and the ether layer is dried over magnesium sulfate 
and concentrated in vacuo in yield 7.7 g. (96% theory) of a brown liquid. 
The crude product is purified by dry-column chromatography on silica gel 
using 25% methylene chloride in hexane as a solvent. 4.4 Grams of a pale 
yellow liquid is obtained. The infrared spectrum shows an ester carbonyl 
band at 1720 cm.sup.-1. The nuclear magnetic resonance spectrum 
(CCl.sub.4) shows the following: .sigma. = 1.41, 1.45, 1.58, 1.66 (4S, 6H, 
methyls) 2.61 (S, 1H, cyclopropane H), 4.85-5.10 (m, 2H, O--CH.sub.2), 
6.12 (d, 0.5H, J = 5.5 Hz, vinyl), 6.66-7.76 (m, 14.5H aromatic and 
vinyl). 
Analyses: Calculated for C.sub.27 H.sub.24 0.sub.3 : C, 81,83: H, 6.06. 
Found: C, 82.14; H, 6.29. 
EXAMPLE 2 
Preparation of 3,3-dimethylspiro[cyclopropane-1,1'-indene]2-carboxylic 
acid, .alpha.-cyano-m-phenoxybenzyl ester 
##STR5## 
3,3-Dimethylspiro[cyclopropane-1,1'-indene]-2-carboxylic acid, 3.4 g, is 
dissolved in 100 ml of a hexane/benzene (4:1) solution. Thionyl chloride, 
15.0 g, is then added and the solution is stirred for 12 hours. Refluxing 
is carried out for 20 minutes, and the volume is reduced in vacuo to 
remove solvents and excess thionyl chloride. The acid chloride is used 
directly without further purification. The acid chloride is taken up in 20 
ml. of benzene and is added dropwise to a solution of 3.1 g of 
.alpha.-cyano-m-phenoxybenzyl alcohol and 1.0 g of pyridine in 100 ml of 
benzene. After 4 hours, the precipitate is filtered, and the filtrate 
reduced in vacuo to give a viscous oil. Purification by column 
chromatography on silica gel with elution by chloroform/hexane (1:2) gives 
1.3 g of pale yellow oil which exhibits the following spectral properties: 
infrared spectrum (neat film) 1730 cm.sup.-1 ; nuclear magnetic resonance 
spectrum (CDCl.sub.3) .delta. = 6.8=7.6 (m, 14.5H, aromatic and vinyl), 
6.37 (m, 1H, 
##STR6## 
6.22 (d, 0.5H, vinyl), 2.73 (m, 1H, 
##STR7## 
1.72-1.43 (m, 6H, methyls). 
EXAMPLE 3 
Preparation of 3,3-dimethylspiro[cyclopropane-1,1'-indane]-2-carboxylic 
acid, m-phenoxybenzyl ester. 
##STR8## 
The procedure of Example 1 is followed using 
3,3-dimethylspiro[cyclopropane-1,1'-indane]-2-carboxylic acid in place of 
3,3-dimethylspiro[cyclopropane-1,1'-indene]-2-carboxylic acid to give the 
crude product as an oil. The pure ester obtained by chromatography had the 
following spectral properties: Infrared spectrum (neat film) 1720 
cm.sup.-1 ; nuclear magnetic resonance spectrum (CCl.sub.4) .delta. = 
6.7-7.6 (m, 13H, aromatic), 4.8-5.1 (m, 2H, O--CH.sub.2), 1.1-3.2 (m, 11H, 
CH.sub.3, indane CH.sub.2, and cyclopropane H). 
EXAMPLE 4 
Preparation of 3,3-dimethylspiro[cyclopropane-1,1'-indane]2-carboxylic 
acid, .alpha.-cyano-m-phenoxybenzyl ester. 
##STR9## 
The procedure of Example 2 is followed using 
3,3-dimethylspiro[cyclopropane-1,1'-indane]-2-carboxylic acid in place of 
3,3-dimethylspiro[cyclopropane-1,1'-indene]-2-carboxylic acid to give the 
crude product. 
EXAMPLE 5 
Preparation of 3,3-dimethylspiro[cyclopropane-1,1'-indene]-2-carboxylic 
acid, m-phenoxybenzyl ester. 
##STR10## 
STEP I 
To 4.3 g of 3,3-dimethylspiro[cyclopropane-1,1'-indane]-2-carboxylic acid 
in 75 ml of n-hexane is added 10 ml of thionyl chloride. The solution is 
then stirred at room temperature for 2 days. 
The clear pale orange solution is concentrated under vacuum to yield 4.7 g 
(100% theory) of an orange liquid. IR shows a carbonyl stretch at 1780 
cm.sup.-1, typical for an acid chloride. 
STEP II 
To 4.7 g of the above acid chloride and 4.0 g of m-phenoxybenzyl alcohol in 
50 ml of ether is added 2.1 of triethylamine in 8.0 ml of ether, dropwise, 
with cooling. Solids begin to precipitate immediately. After 3 hours at 
room temperature, the crude product is worked up in ether and then H.sub.2 
O. 
The resulting crude product is then purified by dry-column chromatography 
using a silica gel packing and 25% CH.sub.2 Cl.sub.2 /hexane as a solvent 
for development. There is obtained 3.9 g (49% theory) of a pale yellow 
viscous liquid. IR shows a carbonyl stretch at 1720 cm.sup.-1, NM 
R[.delta.= 1.1-3.2 (11 H, (CH.sub.3).sub.2, 
##STR11## 
cyclopropane H), 4.8-5.1 (2H, --OCH.sub.2 --), 6.7-7.6 (13 H, aromatic)] 
confirms the assigned structure. 
Analysis calculated for O.sub.3 C.sub.27 H.sub.26 : C, 81.42; H, 6.53. 
Found: C, 81.57; H, 6.97. 
EXAMPLE 6 
Preparation of 3,3-dimethylspiro[cyclopropane-1,1'-indane]-2-carboxylic 
acid, .alpha.-cyano-m-phenoxybenzyl ester. 
##STR12## 
3,3'-Dimethylspiro[cyclopropane-1,1'-indane]-2-carboxylic acid, 4.1 g, is 
refluxed in 20 ml of thionyl chloride for 1 hour and then stripped at 
50.degree. C. using water aspirator pressure to remove excess thionyl 
chloride. 
The acid chloride thus formed is taken up in 50 ml of benzene and added to 
a 50 ml benzene solution of 3.1 g of .alpha.-cyano-m-phenoxybenzyl alcohol 
and 1.5 g of pyridine. Stirring of the solution is then continued for 18 
hours. The reaction is worked up by filtration of the precipitate and 
removal of the solvent in vacuo to give a light yellow oil. Purification 
by dry column chromatography on silica gel with elution by ethyl 
acetate:hexane (1:9) gives 4.1 g of pale yellow viscous oil. 
##STR13## 
.delta.6.36; aromatic .delta.6.8-7.6 IR carbonyl 1725 cm.sup.-1. 
Analysis calculated for C.sub.28 H.sub.25 NO.sub.3 ; C, 79.41; H, 5.95; N, 
3.31. Found: C, 78.22; H, 6.06; N, 3.15. 
EXAMPLE 7 
3,3'-Dimethylspiro[cyclopropane-1,1'-indene]-2-carboxylic acid, 
.alpha.-ethynyl-m-phenoxybenzyl ester. 
##STR14## 
The procedure of Example 1 is followed using 
.alpha.-ethynyl-m-phenoxybenzyl alcohol in place of m-phenoxybenzyl 
alcohol to give the product as an oil. 
EXAMPLE 8 
3,3-Dimethylspiro[cyclopropane-1,1'-indane]-2-carboxylic acid, 
.alpha.-ethynyl-m-phenoxybenzyl ester. 
##STR15## 
The procedure of Example 1 is followed using 
2,2-dimethylspiro[cyclopropane-1,1'-indane]-2-carboxylic acid in place of 
2,2-dimethylspiro[cyclopropane-1,1'-indene]-2-carboxylic acid and 
.alpha.-ethynyl-m-phenoxybenzyl alcohol in place of m-phenoxybenzyl 
alcohol to give the product as an oil. 
EXAMPLE 9 
Insecticidal Activity 
The unique insecticidal activity of the compounds of the present invention, 
over a variety of pyrethroid type insecticides, is further demonstrated by 
the following tests. 
The test procedures employed for evaluation against Boll weevills, Southern 
Armyworms and Tobacco Budworms are described in the preceeding examples. 
The procedures employed for evaluation against mosquito larvae and Mexican 
Bean Beetles as follows. 
Malaria Mosquito -- Anopheles quodrimaculatus Say 
1 Milliter of a 35% water/65% acetone solution containing 300 ppm of test 
compound is pipetted in a 400 ml beaker containing 250 ml of deionized 
water and stirred with the pipette, giving a concentration of 1.2 ppm. A 
wax paper ring 1/4 inch wide to fit inside the beaker is floated on the 
surface of the test solution to keep the eggs from floating up the 
meniscus curve and drying out on the side of the glass. A spoon made of 
screen is used to scoop up and transfer about 100 eggs (0-24 hours old) 
into the test beaker. After 2 days at 80.degree. F., 50% r.h., 
observations of hatching are made. Mexican Bean Beetle -- Epilachna 
varivestis Mulsant 
Sieva lima bean plants (2 per pot) with primary leaves 3 to 4 inches long, 
are dipped in the 300 ppm test solution and set in the hood to dry. One 
leaf is removed from a plant and placed in a 4 inch petri dish containing 
a moist filter paper on the bottom and 10 last-instar larvae (13 days from 
hatching). The day after treatment, another leaf is removed from the plant 
and fed to the larvae after removing the remains of the original leaf. Two 
days after treatment, the third leaf is fed to the larvae, this usually 
being the last needed. The fourth leaf is used on the third day after 
treatment if the larvae have not finished feeding. The test is now set 
aside and held until adults have emerged, usually in about 9 days after 
treatment began. After emergence is complete, each dish is examined for 
dead larvae, pupae or adults; deformed pupae or adults; larval-pupal 
intermediates or pupal-adult intermediates; or any other interference with 
normal molting, transformation and emergence of pupae or adults. 
Data obtained are reported in the table below. 
Southern Armyworm -- Spodoptera eridania (Cramer) Methods: 
Sieva lima bean plants pruned back to two expanded 3 to 4 inches primary 
leaves are dipped three seconds with agitation in the treatment solutions 
and then set in a hood to dry. After the leaves are dry they are excised 
and each excised leaf is placed in a 4 inch petri dish containing a piece 
of moist filter paper and ten third-instar southern armyworm larvae 
approximately 3/8 of an inch long. The petri dishes are covered and placed 
in a holding room for 2 days at a temperature of 80.degree. F. and 50% 
relative humidity. 
Mortality counts are made after 2 days. Compounds which produce a larval 
kill are held for an extra day and counted again. 
__________________________________________________________________________ 
Insecticidal Activity 
Mosquito Boll Southern Mexican Tobacco 
Larvae Weevil 
Armyworms 
Bean Beetles 
Budworm 
ppm ppm ppm ppm ppm 
Compound 1.2 
.4 .04 
.004 
1000 1000 
100 
10 300 100 1000 100 
__________________________________________________________________________ 
##STR16## 100 
100 
100 
100 
100 100 
100 
100 
100 100 100 100 
##STR17## -- 100 
100 
-- 30 100 
100 
0 -- -- 100 80 
##STR18## 100 
100 
100 
50 100 100 
100 
90 100 90 100 100 
##STR19## -- 100 
100 
50 100 100 
100 
0 100 70 100 80 
__________________________________________________________________________ 
-- =No Test 
EXAMPLE 10 
Residual Insecticial Activity 
Leaf Dip Test 
Young cotton plants with 2 or 3 expanded true leaves are dipped into 65% 
acetone/water solutions to thoroughly wet the leaves. The leaves are 
allowed to dry before the initial leaf samples are removed for bioassay 
with southern armyworm, Prodenia eridania (Cramer), tobacco budworm, 
Heliothis virescens (Fabricius) or cabbage looper, Trichoplusia ni 
(Hubner). Leaf samples are placed in a standard glass petri dish 
containing moist filter paper and 10 third instar southern armyworm or 
cabbage loopers. For the tobacco budworm assay, a single leaf is cut into 
sections of about 1/2 square inch and placed in individual medicine cups 
with a moist dental wick and one tobacco budworm larvae. The assay samples 
are held at a constant temperature of 80.degree. F. for 72 hours when 
mortality counts are made and the corrected percent mortality determined. 
The treatment solutions are prepared by dissolving 100 mg of test compound 
in 65 ml of acetone then making the solution to 100 ml with deionized 
water to give a 1000 ppm concentration of the compound. Ten fold dilutions 
are prepared by taking 10 ml of the 1000 ppm solution and diluting to 100 
ml with 65% acetone and water for 100 ppm. Then 10 ml of the 100 ppm 
solution is diluted the same way to give a 10 ppm solution. 
After the leaves have dried the plants are removed to the greenhouse 
section fitted with polymethyl methacrylate panels which permit the 
penetration of ultra-violet light for determination of the residual 
insecticidal persistance of the compound. Leaf samples are removed for 
bioassay over a 9 to 10 day period. 
Data obtained are reported in the table below where it can be seen that the 
compounds of the present invention are highly effective as insecticidal 
agents for an extended period of time when applied to plants as a liquid 
formulation containing from about 100 ppm to 1000 ppm of active compound. 
__________________________________________________________________________ 
Residual Insecticidal Activity 
Percent Corrected Mortality 
0 Days 7 Days 9 Days 10 Days 
Cab- Cab- Cab- Cab- 
Conc. 
bage bage bage bage 
Compound (ppm) 
Looper 
SAW TBW Looper 
SAW TBW Looper 
SAW TBW Looper 
SAW TBW 
__________________________________________________________________________ 
3,3'-Dimethylspiro- 
1000 100 100 100 100 100 100 100 80 
[cyclopropane-1,1'- 
100 100 100 60 50 20 75 38 40 
indene]-2-carboxylic 
acid, m phenoxybenzyl 
ester 
3,3'-Dimethylspiro- 
1000 100 100 100 100 100 80 
[cyclopropane-1,1'- 
100 100 80 70 80 90 20 
indene]-2-carboxylic- 
acid, .alpha.cyano-m-phen- 
oxybenzyl ester 
__________________________________________________________________________ 
SAW = Southern Armyworm 
TBW = Tobacco Budworm 
EXAMPLE 11 
Suppression of Fecundity and Chemosterilant Effect in Ixodidae 
The efficacy of the compounds of the present invention for suppression of 
fecundity in ticks is demonstrated in the following tests wherein engorged 
adult female Boophilus microplus ticks which have dropped from cattle are 
collected and used for testing. 
The compound to be tested is dissolved in a 35% acetone/65% water mixture 
in sufficient amount to provide 15.62, 31.25, 62.5, 125 and 250 ppm; of 
compound in the test solution. Fifteen ticks per treatment are used and 
they are immersed in test solution for 3 to 5 minutes, then removed and 
placed in dishes and held in incubators for 2 to 3 weeks 28.degree. C. 
Counts of ticks laying eggs are then made and recorded. Eggs which were 
laid are weighed and placed in containers and kept for one month to 
observe hatching and to determine chemosterilant effect. For each test, 
fifteen ethion-resistant ticks are used since they are the most difficult 
of their kind to control. Results of these tests are given in the tables 
below. 
Efficacy is determined on the percent reduction in weight of egg masses 
over controls and is reported for each concentration of chemical applied. 
The effectiveness of test chemicals for suppressing the fecundity of ixodid 
ticks is also determined on the basis of the 3 highest rates of 
application, e.g 62.5 ppm; 125 ppm and 250 ppm, employing the rating 
system given below. 
______________________________________ 
RATING SYSTEM 
Result Score 
______________________________________ 
No oviposition 4 
Partial ovipositions, no hatch 
3 
Total oviposition, no hatch 
2 
Partial oviposition, viable eggs 
1 
Normal oviposition and hatch 
0 
______________________________________ 
The rating system is based on the summation of scores from all ticks in the 
above-said tests. Using this rating system the best score possible would 
be 180 or 45 (the total number of ticks used) .times. 4 (the highest 
score). The efficacy is reported as percent of the best possible score. 
__________________________________________________________________________ 
Percent Reduction in Weight of Egg Masses Over Controls 
% Reduction in Weight of Egg Masses 
PPM 
Compound 250 125 62.5 
31.25 
15.62 
__________________________________________________________________________ 
3,3-Dimethylspiro[cyclopropane-1,1'- 
95.93 
97.96 
92.37 
50.64 
50.13 
indene]-2-carboxylic acid, m-phenoxy- 
benzyl ester 
3,3-Dimethylspiro[cyclopropane-1,1'- 
99.49 
96.95 
88.30 
68.96 
34.86 
indene]-2-carboxylic acid, .alpha.-cyano-m- 
phenoxybenzyl ester 
3,3-Dimethylspiro[cyclopropane-1,1'- 
89.31 
49.11 
28.24 
18.58 
0 
indane]-2-carboxylic acid, m-phenoxy- 
benzyl ester 
3,3-Dimethylspiro[cyclopropane-1,1'- 
100 83.21 
97.96 
44.53 
13.99 
indane]-2-carboxylic acid, .alpha.-cyano-m- 
phenoxybenzyl ester 
__________________________________________________________________________ 
From these data it can be seen that the spirocarboxylic acid compounds 
provided excellent ixodid control through the suppression of fecundity of 
ixodid ticks when, applied at dose levels of 62.5 ppm or higher. It can 
also be seen that ixodid tick control is virtually complete when the 
compounds of the invention are applied at the 250 ppm dose level. 
__________________________________________________________________________ 
Chemosterilant Efficacy of Spirocarboxylic Acids 
Ethion Resistant Ticks 
Oviposition 
Rate 
Partial Total % 
Compound PPM No. No. Steril 
No. No. Steril 
Efficacy 
__________________________________________________________________________ 
3,3'-Dimethylspiro[cyclopropane-1,1'- 
250 0 0 0 0 0 1 0 0 90 
indene]-2-carboxylic acid, m-phenoxy- 
125 0 2 0 1 0 0 0 0 
benzyl ester 62.5 
0 2 0 2 0 1 0 0 
3,3'-Dimethylspiro[cyclopropane-1,1'- 
250 0 1 0 0 0 0 0 0 92.2 
indene]-2-carboxylic acid, .alpha.-cyano-m- 
125 0 1 0 0 0 0 0 0 
phenoxybenzyl ester 62.5 
0 2 0 1 0 1 0 0 
3,3'-Dimethylspiro[cyclopropane-1,1'- 
250 0 3 0 1 0 2 0 0 48.3 
indane]-2-carboxylic acid, m-phenoxy- 
125 0 2 0 0 0 7 0 1 
benxyl ester 62.5 
0 1 0 1 1 1 0 1 
3,3'-Dimethylspiro[cyclopropane-1,1'- 
250 0 0 0 0 0 0 0 0 90.5 
indane]-2-carboxylic acid, .alpha.-cyano- 
125 0 2 0 1 0 3 0 0 
m-phenoxybenzyl ester 
62.5 
0 1 0 1 0 0 0 0 
__________________________________________________________________________ 
It can be seen from the above-data that from about 90% to 100% control of 
ixodid ticks can be achieved with the compounds of this invention applied 
at the 250 ppm concentration.