2,2-Difluoro-1,3-benzodioxole-5-(.alpha.-alkyl)-acetic acids, and their use for the preparation of insecticides and acaricides

The invention is 2,2-difluoro-1,3-benzodioxole-5-(.alpha.-alkyl)acetic acids, the preparation thereof and the use of the acids for the preparation of insecticidal and acaricidal compounds.

The prior art is replete with references to various esters of substituted 
phenylacetic acids as pesticidal agents useful for the control of a 
variety of insects and mites, for instance Sumitomo Chemical Company 
Limited discloses in South African Patent Application No. 73/4462 
generically a large number of these pheylacetic acid esters. However, none 
of the art references anticipate, nor is it predictable therefrom that the 
novel acids of the present invention, when esterified with a suitable 
alcohol, would yield highly effective insecticidal and acaricidal agents. 
Surprisingly we have found that the novel acids of the invention 
represented by formula: 
##STR1## 
wherein R.sub.1 is lower alkyl and preferably, ethyl, n-propyl or i-propyl 
and the optical isomers thereof, when esterified with m-phenoxybenzyl 
alcohol or .alpha.-cyano-m-phenoxybenzyl alcohol, yield highly effective 
insecticidal and acaricidal agents. 
Advantageously, 2,2-difluoro-1,3-benzodioxole-5-(.alpha.-alkyl)acetic acids 
of the invention can be prepared by using 5-methyl-1,3-benzodioxole (VII) 
as a starting material. The process for the preparation involves 6 steps, 
the first of which is the halogenation of the 5-methyl-1,3-benzodioxole 
(VII) with a halogenating agent, such as phosphorus pentachloride in the 
presence of an inert solvent such as toluene to yield the corresponding 
2,2-dichloro-5-methyl-1,3-benzodioxole (VI). This compound (VI) is then 
converted to the corresponding 2,2-difluoro-5-methyl-1,3-benzodioxole (V) 
with antimony trifluoride in an inert solvent such as dioxane. Next, the 
thus obtained 2,2-difluoro-5-methyl-1,3-benzodioxole (V) is converted to 
the corresponding 5-halomethyl derivative by halogenation with bromine, 
chlorine, N-bromosuccinimide (NBS) and the like. This reaction is 
preferably conducted in the presence of an inert solvent such as carbon 
tetrachloride, and a radical initiator such as light, benzoyl peroxide, or 
azo-bis-isobutyronitrile, to yield 
2,2-difluoro-5-halomethyl-1,3-benzodioxole (VI). The formula (IV) compound 
is then readily converted to the corresponding acetonitrile (III) by 
reaction with sodium or potassium cyanide in the presence of 
dimethylsulfoxide (DMSO), ethanol or the like at an elevated temperature. 
This acetonitrile (III) is readily alkylated when treated with an alkyl 
halide in the presence of a base and an inert solvent. Crown ethers have 
been found to be useful catalysts in this reaction. The 
.alpha.-alkylacetonitrile formed in the above reaction is depicted by 
formula (II), and hydrolysis of this formula (II) 
.alpha.-alkylacetonitrile, using an alkali metal hydroxide in the presence 
of an alkylene glycol and water, yields the novel formula (I) 
2,2-difluoro-1,3-benzodioxole-5-(.alpha.-alkyl)acetic acids. 
With regard to the compounds of the present invention as depicted by 
formula (I), it should also be understood that various optical isomers do 
result from the preparations described, since a chiral center is present 
at the .alpha.-carbon atom and d and l isomeric pairs are formed. 
The above reactions are graphically illustrated in Flow Diagram I below. 
##STR2## 
Advantageously, the insecticidal-acaricidal m-phenoxybenzyl esters of the 
novel formula (I) 2,2-difluoro-1,3-benzodioxole-5-(.alpha.-alkyl)acetic 
acids can be prepared by reacting a formula (I) acid halide, preferably 
chloride, with m-phenoxybenzyl alcohol or a substituted m-phenoxybenzyl 
alcohol. The reaction is generally conducted in the presence of an inert 
solvent such as diethyl ether, benzene, toluene and the like, at a 
temperature between about 10.degree. and 30.degree. C in the presence of 
an acid acceptor. Among the acid acceptors that can be employed are the 
tertiary organic amines, trimethylamine, triethylamine and pyridine. This 
reaction can be illustrated as follows: 
##STR3## 
wherein R.sub.1 is C.sub.1 -C.sub.3 alkyl; R.sub.2 is hydrogen or cyano, 
and X is halogen, preferably chlorine. The above depicted acid halide is 
conveniently prepared from the corresponding formula (I) 
2,2-difluoro-1,3-benzodioxole-5-(.alpha.-alkyl)acetic acid by treating 
same with thionyl chloride, thionyl bromide or the like, preferably in the 
presence of an aromatic solvent such as benzene or toluene at elevated 
temperatures. 
The m-phenoxybenzyl esters and .alpha.-cyano-m-phenoxybenzyl esters of 
formula (I) 2,2-difluoro-1,3-benzodioxole-5-(.alpha.-alkyl)acetic acids 
represented by formula (A) below wherein R.sub.1 and R.sub.2 are as 
described. 
##STR4## 
are highly effective as contact and stomach poisons for ixodid ticks and 
for a variety of insects, particularly Dipterous, Lepidopterous, 
Coleopterous and Homopterous insects. They are unusual among pyrethroids, 
in that they exhibit an extended residual insecticidal activity on plant 
tissue, they are effective in the soil, and are surprisingly effective for 
the control of ixodidae and the protection of animals against attack by 
insects and ixodidae when administered to the animals orally or 
parenterally or applied thereto as a topical insecticidal or acaricidal 
formulation. 
The insecticidal and acaricidal compounds of formula (A) prepared from the 
novel 2,2-difluoro-1,3-benzodioxole-5-(.alpha.-alkyl)acetic acids (I) of 
the present invention may also be used in combination with other 
biological chemicals, for example pyrethroid synergists such as piperonyl 
butoxide, sesamex or n-octyl sulfoxide of isosafrole. Alternatively, they 
may also be used in combination with conventional insecticides such as the 
phosphates, carbamates, halobenzoylureas and the like. 
To achieve control of insects, including soil insects, which attack growing 
plants and/or harvested crops, the insecticidal compounds prepared from 
the above novel acids of formula (I), may be applied to the foliage of 
plants, the insect's habitat and/or the insect's food supply. 
The above insecticides may be formulated as liquid concentrates, 
emulsifiable concentrates, dusts, granulates, wettable powders and the 
like, by conventional methods. 
For use as animal systemic insecticidal and acaricidal agents, formula (A) 
compounds may be administered to the animal host either orally or 
parenterally. For such use, the compounds may be formulated as feed 
additives, pills, boluses, tablets, oral drenches, implants, injectables 
and the like, using pharmaceutically acceptable carriers, diluents, 
solvents and the like.

The invention is further described by the examples set forth below. 
EXAMPLE 1 
Preparation of 2,2-Dichloro-5-methyl-1,3-benzodioxole 
A slurry of 5-methyl-1,3-benzodioxole (52.6 g, 0.387 mole) and phosphorus 
pentachloride (162.4 g) in toluene is stirred and heated at 70.degree. C 
for 2 hours. The temperature is then raised to 90.degree. C over 30 
minutes and held for 4 hours. Phosphorus trichloride is distilled off at 
atmospheric pressure. Vacuum distillation yields 73.4 g (92% yield) of 
title product: 2,2-dichloro-5-methyl-1,3-benzodioxole; n.sub.D.sup.24 
1.5325; b.p. 78.degree. C to 82.degree. C (at 0.4 mm); nmr (CDCl.sub.3) 
.delta. 2.28 (S 3H), 6.8 (m 3H). 
EXAMPLE 2 
Preparation of 2,2-Difluoro-5-methyl-1,3-benzodioxole 
Dry dioxane (172 ml) and antimony (III) fluoride are mixed and a part of 
the solvent is distilled off (57 ml). The mixture is cooled to room 
temperature and a solution of 2,2-dichloro-5-methyl-1,3-benzodioxole (65.0 
g, 0.317 mole) in dioxane (68 ml) is added dropwise over 30 minutes. 
During the addition the temperature of the reaction mixture rises to 
42.degree. C. The solution is refluxed for 7 hours, poured into a mixture 
of concentrated hydrochloric acid (100 ml) and water (100 ml), and 
extracted with ether (3.times.100 ml). The ether extracts are combined, 
washed with water, dried over sodium sulfate and evaporated. The residual 
oil is distilled under reduced pressure (obtained by using a 
water-aspirator) to yield 29.3 g (53% yield) of title product: 
2,2-difluoro-5-methyl-1,3-benzodioxole; nmr (CDCl.sub.3) .delta. 2.28 (S, 
3H), 6.8-6.8 (m, 3H). 
EXAMPLE 3 
Preparation of 2,2-Difluoro-5-bromomethyl-1,3-benzodioxole 
A mixture of 2,2-difluoro-5-methyl-1,3-benzodioxole (29.0 g, 0.169 mole), 
N-bromosuccinimide (30.1 g, 0.169 mole), benzoyl peroxide (0.5 g) and 
carbon tetrachloride (50 ml) is refluxed for 2.5 hours. Carbon 
tetrachloride (50 ml) is then added to the hot reaction mixture and the 
solids are filtered off. The filtrate and washings are evaporated to yield 
41.0 g of title product, a brown oil; nmr (CCl.sub.4) .delta. 4.38 (S, 
2H), 6.8-7.4 (m, 3H). The product is used without further purification in 
the next step. 
EXAMPLE 4 
Preparation of 2,2-Difluoro-1,3-benzodioxole-5-acetonitrile 
To a solution of 2,2-difluoro-5-bromomethyl-1,3-benzodioxole (41.0 g) in 
absolute alcohol (160 ml) at 60.degree. to 70.degree. C a hot solution of 
potassium cyanide (22.1 g, 0.34 mole) in water (30 ml) is added. There is 
a slight exotherm and within 5 minutes potassium bromide separates out of 
the reaction mixture. The reaction mixture is refluxed for 1.5 hours, 
cooled and added to ice-water. The mixture is extracted with ether 
(3.times.100 ml), the combined extracts are washed with water (2.times.50 
ml), dried over sodium sulfate and evaporated to afford a dark oil. Vacuum 
distillation yields 21.2 g of title product; b.p. 64.degree. to 67.degree. 
C (at 0.03 mm); i.r. (neat) 2255 cm.sup.-1 ; nmr (CCl.sub.4) .delta. 3.68 
(S, 2H), 7.00 (S, 3H). 
EXAMPLE 5 
Preparation of 
2,2-Difluoro-1,3-benzodioxole-5-(.alpha.-isopropyl)acetonitrile 
A solution of 50% sodium hydroxide (25 ml) is added to a solution of 
2,2-difluoro-1,3-benzodioxole-5-acetonitrile (18.0 g, 0.0913 mole), 
2-bromopropane (11.23 g, 0.0913 mole), and dicyclohexyl-18-crown-6* (1.7 
g, 5 mole percent) in benzene (10 ml). The reaction temperature rises to 
44.degree. to 45.degree. C over 15 minutes. The reaction mixture is then 
stirred at room temperature for 5 hours. More 2-bromopropane (2.8 g, 25 
mole percent excess) is added, and the reaction mixture stirred for 3 
days. The organic layer is separated, the aqueous layer is extracted with 
ether (2.times.50 ml) and the extracts combined with the organic layer. 
The combined organic solution is washed with water (2.times.50 ml), dilute 
hydrochloric acid (50 ml) and water (2.times.50 ml) and is dried over 
sodium sulfate. The dry solution is evaporated to afford an oil. Vacuum 
distillation of this oil yields 16.35 g (75%) of product; b.p. 67.degree. 
to 69.degree. C (at 0.03 mm); i.r. (neat) 2250 cm.sup.-1 ; nmr (CCl.sub.4) 
.delta. 1.05 and 1.08 (each d, J=7Hz, 6H), 2.1 (m, 1H), 3.68 (d, J=Hz, 
1H), 7.05 (S, 3H). 
FNT *The structure of dicyclohexyl-18-crown-6 is: 
##STR5## 
By the above procedure, but substituting 1-iodopropane or iodoethane for 
2-bromopropane, 
2,2-difluoro-1,3-benzodioxole-5-(.alpha.-propyl)acetonitrile and 
2,2-difluoro-1,3-benzodioxole-5-(.alpha.-ethyl)acetonitrile can be 
prepared, respectively. 
EXAMPLE 6 
Preparation of 2,2-Difluoro-1,3-benzodioxole-5-(.alpha.-isopropyl)acetic 
acid 
A mixture of 
2,2-difluoro-1,3-benzodioxole-5-(.alpha.-isopropyl)acetonitrile (13.5 g), 
potassium hydroxide pellets (20.0 g) in ethylene glycol (100 ml) and water 
(20 ml) is heated at 140.degree. C with stirring for 14 hours. After 
cooling, the reaction mixture is poured into water and extracted with 
ether (2.times.50 ml). The aqueous portion is cautiously acidified with 
hydrochloric acid and extracted with ether (3.times.50 ml). The combined 
extracts are washed with water (2.times.50 ml), dried over sodium sulfate 
and evaporated to dryness. Recrystallization of the solid residue for 
heptane affords 9.4 g (64%) of product; m.p. 98.degree. to 101.degree. C; 
i.r. (Nujol mull) 1700 cm.sup.-1 ; nmr (CDCl.sub.3) .delta. 0.75 (d, J=8 
Hz, 3H), 1.10 (d, J=8Hz, 3H), 2.3 (m, 1H), 3.16 (d, J=10Hz, 1H), 7.0-7.2 
(m, 3H). 
By the above procedure, but substituting 
2,2-difluoro-1,3-benzodioxole-5-(.alpha.-propyl)acetonitrile or 
2,2-difluoro-1,3-benzodioxole-5-(.alpha.-ethyl)acetonitrile for 
2,2-difluoro-1,3-benzodioxole-5-(.alpha.-isopropyl)acetonitrile, 
2,2-difluoro-1,3-benzodioxole-5-(.alpha.-propyl)acetic acid and 
2,2-difluoro-1,3-benzodioxole-5-(.alpha.-ethyl)acetic acid can be 
prepared, respectively. 
EXAMPLE 7 
Preparation of 2,2-Difluoro-1,3-benzodioxole-5-(.alpha.-isopropyl)-acetyl 
chloride 
A solution of 2,2-difluoro-1,3-benzodioxole-5-(.alpha.-isopropyl)acetic 
acid (5.16 g, 0.02 mole) and thionyl chloride (2.0 ml) in benzene (10 ml) 
is refluxed for 4 hours. Evaporation of the solvent and excess thionyl 
chloride affords the product, which can be used without further 
purification in the subsequent steps. 
By the above procedure, using the appropriate 
2,2-difluoro-1,3-benzodioxole-5-(.alpha.-alkyl)acetic acids, 
2,2-difluoro-1,3-benzodioxole-5-(.alpha.-propyl)acetyl chloride and 
2,2-difluoro-1,3-benzodioxole-5-(.alpha.-ethyl)acetyl chloride can be 
prepared, respectively. 
EXAMPLE 8 
Preparation of .alpha.-Cyano-m-phenoxybenzyl ester of 
2,2-difluoro-1,3-benzodioxole-5-(.alpha.-isopropyl)acetic acid 
A solution of 2,2-difluoro-1,3-benzodioxole-5-(.alpha.-isopropyl)acetyl 
chloride (0.01 mole) in ether (10 ml) is added to a solution of 
.alpha.-cyano-m-phenoxybenzyl alcohol (2.03 g, 90 mole percent) and 
pyridine (0.8 g) in ether (25 ml) at room temperature. The reaction 
mixture is stirred overnight at room temperature. The solids are filtered 
off and washed with ether. The filtrate and washings are combined and 
evaporated to yield an oil. The oil is purified by dry column 
chromatography on silica gel using 1:1 methylene chloride-hexane as eluent 
to afford 3.40 g (73%) of product; nmr (CDCl.sub.3) 0.6-1.1 (set of d, 
6H), 2.3 (m, 1H), 3.2 (d, J=10Hz, 1H), 6.30 and 6.35 (S, 1H), 6.8-7.5 (m, 
12H). 
The .alpha.-propyl and .alpha.-ethyl analogs are made in similar fashion 
starting with the corresponding .alpha.-propyl and .alpha.-ethylacetyl 
chlorides of Example 7. 
EXAMPLE 9 
Residual insecticidal activity obtained with foliar treatment of cotton 
plants 
Young cotton plants with at least two expanded true leaves growing in 10 cm 
plastic pots were dipped, usually one leaf at a time in a 65% acetone-35% 
water solution of test compound with agitation for three seconds. The 
concentration of the compound in the solutions was 30 ppm, 100 ppm, 300 
ppm or 900 ppm of active ingredient. 
After the leaves had dried, two leaves from each of two plants were excised 
and placed in petri dishes (90 mm .times. 100 mm) on moist filter paper (9 
cm Whatman No. 1). Five third-instar tobacco budworm larvae were placed on 
each leaf and the petri dish capped. The infested dishes were than placed 
in a holding room with continuous light, ambient temperature of 80.degree. 
F and 50% r.h. Larval counts were made after 72 hours. 
The remaining plants were placed under high intensity lights in the 
greenhouse adjusted to provide 14 hours of light per day. Leaf samples 
were assayed with third instar tobacco budworm larvae after 3, 7, 10 and 
14 days exposure in the greenhouse. 
The data obtained are summarized in Table I. 
Table I 
__________________________________________________________________________ 
Residual Insecticidal Activity of a Test Compound on Cotton Plants Using 
Third-Instar Tobacco Budworm Larvae for Bioassay 
Rate 
Days Residual Activity 
Compound ppm 
0* 3 7 10 14 
__________________________________________________________________________ 
##STR6## 30 100 300 900 
45 90 95 100 
0 55 90 100 
10 55 100 100 
10 65 90 100 
10 10 95 100 
Control -- 0 0 5 0 13 
__________________________________________________________________________ 
* = Average % Mortality 20 TBW/Point 
EXAMPLE 10 
The effectiveness of an acaricide prepared from the novel 
2,2-difluoro-1,3-dioxole-5-(.alpha.-alkyl)acetic acids of the present 
invention for the control of adult Boophilus microplus ticks is determined 
in the following test wherein the test compound is dissolved in 10% 
acetone-90% water mixture in sufficient amounts to give solutions 
containing 125, 52.6, 31.2, 15.6 or 7.3 ppm of test compound. 
Adult engorged female ticks are dipped in the test solutions for 3 seconds 
and placed in individual containers and held for 48 hours in a room 
maintained at 80.degree. F and 50% r.h. At the end of the holding period 
the ticks are examined and egg deposits counted. Engorged females that do 
not deposit eggs are considered dead. Data obtained are reported below in 
Table II. 
Table II 
__________________________________________________________________________ 
Percent Adult Tick Mortality 
at Concentration (ppm) 
Compound 125 
62.5 
31.2 
15.6 
7.3 
__________________________________________________________________________ 
##STR7## 98.3 
99.7 
88.4 
85.8 
80.2 
__________________________________________________________________________