United States Patent 3853958

Aliphatic 4-thia esters and acids, and derivatives thereof, useful for the control of insects.

Application Number:
Publication Date:
Filing Date:
Primary Class:
Other Classes:
554/101, 556/49, 556/50, 556/114, 556/116, 556/131, 556/134, 560/1, 560/10, 560/15, 560/20, 560/61, 560/64, 560/103, 560/105, 560/106, 560/113, 560/117, 560/121, 560/122, 560/123, 560/125, 560/139, 560/145, 560/147, 560/153, 562/426, 562/507, 562/581
International Classes:
C07C43/13; C07C309/66; C07C323/54; (IPC1-7): C07C149/20
Field of Search:
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US Patent References:
3755411N/A1973-08-28Henrick et al.
3712913N/A1973-01-23Chadnekar et al.
3097998Haloacrylate pesticides1963-07-16Miller
2556134Preparation of thioether esters1951-06-05Croxall et al.

Foreign References:
Other References:

Burger, "Medicinal Chemistry," Wiley Interscience, pp. 64, 71, 72, (1970). .
Mitra, C. A. 28, 13308 (1934)..
Primary Examiner:
Weinberger, Lorraine A.
Assistant Examiner:
Terapane, John F.
Attorney, Agent or Firm:
Priest, Lee-louise Erickson Donald H. W.
What is claimed is

1. A compound selected from those of the formula: ##SPC4##

2. A compound of claim 1 wherein R1 is methyl; each of R2, R4 and R5 is methyl or ethyl and R is hydrogen or lower alkyl.

3. A compound of claim 2 wherein Z' is hydrogen and Z is hydrogen, methyl, chloro or --OR6 in which R6 is lower alkyl of one to four carbon atoms.

4. A compound of claim 3 wherein m is one; n is two and R is hydrogen, methyl, ethyl, isopropyl or t-butyl.

5. A compound of claim 4 wherein Z is hydrogen, methyl, chloro, methoxy, ethoxy or isopropoxy.

6. A compound of claim 4 wherein R3 is hydrogen.

7. A compound of claim 4 wherein each of R2, R4 and R5 is methyl; R3 is hydrogen and Z is hydrogen, methyl, chloro or methoxy.

8. A compound of claim 3 wherein each of m and n is one and Z is hydrogen, methyl, chloro or methoxy.

9. A compound of claim 8 wherein each of R2, R4 and R5 is methyl; R3 is hydrogen and R is hydrogen, methyl, ethyl or isopropyl.

10. The compound, ethyl 4-thia-3,6,10-trimethylundec-2-enoate, according to claim 1.

11. The compound, ethyl 4-thia-3,7,11-trimethyldodec-2-enoate, according to claim 1.

12. The compound, ethyl 4-thia-11-methoxy-3,7,11-trimethyldodec-2-enoate, according to claim 1.

13. The compound, ethyl 4-thia-3,7,11-trimethyldodeca-2,10-dienoate, according to claim 1.

This invention relates to novel 4-thia aliphatic unsaturated esters and acids, derivatives thereof, syntheses thereof and the control of insects.

More particularly, the novel 4-thia compounds of the present invention are represented by the following formula A: ##SPC1##


R is hydrogen, lower alkyl, cycloalkyl, aryl, aralkyl or a metal cation;

Each of R1, R2, R4 and R5 is lower alkyl;

R3 is hydrogen or methyl;

Each of m and n is 1 or 2;

Z is hydrogen, lower alkyl, chloro, fluoro, bromo, or the group --OR6 in which R6 is hydrogen, lower alkyl, cycloalkyl, aralkyl, aryl or carboxylic acyl; and

Z' is hydrogen or taken with Z, a carbon-carbon bond, and the acid halides of formula A.

The compounds of formula A are useful for the control of insects. The utility of these compounds as insect control agents is believed to be attributable to their juvenile hormone activity. They ae preferably applied to the immature insect, namely -- during the embryo, larvae or pupae stage, in view of their effect on metamorphosis and otherwise cause abnormal development leading to death or inability to reproduce. These compounds are effective control agents for Hemipteran, such as Lygaeidae, Miridae and Pyrrhocoridae; Lepidopteran, such as Pyralidae, Noctuidae and Gelechiidae; Coleopteran, such as Tenebrionidae, Crysomelidae and Dermestidae; Dipteran, such as mosquitos, flies; Homopteran, such as aphids and other insects. The compounds can be applied at low dosage levels of the order of 0.01 μg. to 25.0 μg. per insect. Suitable carrier substances include liquid or solid carriers, such as water, acetone, xylene, mineral or vegetable oils, talc, vermiculite, natural and synthetic resins and silica. Treatment of insects in accordance with the present invention is accomplished by spraying, dusting or exposing the insects to vapor of the compounds of formula A. Generally, a concentration of less than 25 percent of the active compound is employed. The formulations can include insect attractants, emulsifying agents or wetting agents to assist in the application and effectiveness of the active ingredient. In the application of the compounds, there is generally employed a mixture of the C-2,3 trans and cis isomers.

In the description hereinafter, each of m, n, R-R6, Z and Z' is as defined hereinabove unless otherwise specified.

The compounds of formula A can be prepared according to the following outlined syntheses: ##SPC2##

In the above formulas, X is a leaving group, such as menthanesulfonyloxy, p-toluenesulfonyloxy, bromo or chloro; R' is lower alkyl; Z" is hydrogen, lower alkyl or --OR6 and Z' is hydrogen or taken with Z" is a carbon-carbon bond.

In the practice of the above-outlined syntheses, an alkylating agent of formula I is reacted with the mercapto compound of formula II in the presence of a base, such as sodium hydride, potassium hydride, and the like, in an organic solvent inert to the reaction, such as tetrahydrofuran, dimethylformamide and the like. The compounds of formula I and II are reacted in a mole for mole level and the reaction can be carried out from about room temperature or above, such as reflux temperature.

The esters of formula III are converted into the corresponding free acid by hydrolysis with base, such as potassium carbonate, sodium carbonate, sodium hydroxide, and the like, in an organic solvent, such as a lower alcohol. Other esters of the present invention can be prepared by transesterification or conversion of the acid into the acid halide by treatment with thionyl chloride, oxalyl chloride, phosphorus pentabromide, or the like, and then reacting the acid halide with the alcohol corresponding to the ester moiety desired.

Compounds of formula A, in which Z is halogen, can be prepared from a compound of formula A having a terminal double bond (Z' taken with Z is a carbon-carbon bond) by treatment with a hydrogen halide or acetyl halide in an organic solvent, such as a lower alcohol or halogenated hydrocarbon.

An alkylating agent of formula I can be prepared from the corresponding C-1 alcohol using conventional methods. Thus, the respective alcohol is converted into a compound of formula I by treatment with phosphorus trihalide, phosphorus pentahalide, or the like. The mesylates and tosylates of formula I can be prepared from the alcohol precursor according to the procedure Crossland et al., J. Org. Chem. 35, 3195 (1970). The alkylating agents of formula I can be prepared also according to the procedures of copending applications Ser. No. 38,503, filed May 18, 1970, now U.S. Pat. No. 3,637,752 Ser. No. 100,787, filed Dec. 22, 1970 and Ser. No. 119,041, filed Feb. 25, 1971, the disclosures of which are incorporated by reference.

A mercapto-ester of formula II is prepared from a carbonyl compound of formula IV by treatment with hydrogen sulfide in the presence of HC1 in an organic solvent inert to the reaction at low temperature. ##SPC3##

The term "lower alkyl," as used herein, refers to a alkyl group having a chain length of one to six carbon atoms.

The term "cycloalkyl," as used herein, refers to an cyclic alkyl group of four to eight carbon atoms. The term "aralkyl" refers to a monovalent hydrocarbon group in which an aryl group is substituted for a hydrogen atom of an alkyl group such as benzyl, xylyl, mesityl, phenylethyl, methylbenzyl, naphthylmethyl and naphthylethyl containing up to 12 carbon atoms. The term "aryl," as used herein, refers to an aromatic group of up to 12 carbon atoms. Typical aromatic groups include phenyl, naphthyl, lower alkylphenyl, such as methylphenyl, ethylphenyl, t-butylphenyl and isopropylphenyl.

The term "carboxylic acyl," as used herein, refers to the acyl group of a carboxylic acid, anhydride or halide. The acyl group is determined by the particular carboxylic acid halide or carboxylic acid anhydride employed in the esterification. Although no upper limitation need be placed on the number of carbon atoms contained in the acyl group within the scope of the present invention, generally it contains from one to 18 carbon atoms. Typical esters of the present invention include formate, acetate, propionate, enanthate, benzoate, trimethylacetate, trichloroacetate, trifluoroacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate, β-chloropropionate, adamantoate, octadec-9-enoate, dichloroacetate, butyrate, pentanoate, hexanoate, phenylacetate, p-methylbenzoate, β-phenylpropionate, 3,4-dimethyl-benzoate, p-isopropylbenzoate, cyclohexylacetate, stearate, methacrylate, p-chloromethylbenzoate, p-methoxybenzoate and p-nitrobenzoate.

The term "metal", as used herein, refers to lithium, sodium, potassium, calcium, strontium, copper, manganese and zinc.

The following examples are provided to illustrate the practice of the present invention. Temperature is given in degrees Centigrade.


A. To a mixture of 10.75 g. of 2,6-dimethylheptan-1-ol in 400 ml. of methylene chloride, cooled in ice-bath, is added 8.9 g. of triethylamine, with stirring. After about 15 minutes, 12.7 g. of methanesulfonyl chloride is added, followed by stirring for about one hour. The reaction is worked up by washing with ice water, cold 10% HCl, sodium bicarbonate and saturated sodium chloride, drying over calcium sulfate and evaporation of solvent to yield the mesylate of 2,6-dimethyl-heptan-1-ol.

B. 1.29 Grams of sodium hydride (57% in mineral oil) is washed with hexane and then 100 ml. of dimethylformamide added. After cooling in ice-bath, 4.02 g. of ethyl 3-mercapto-3-methylbut-2-enoate is added slowly. After addition is complete, 4 g. of the mesylate of part A in 20 ml. of dimethylformamide is added over about 15 minutes. The reaction is stirred for about 24 hours at room temperature and then poured into ice water and 100 ml. of ether added. The mixture is washed with water and brine, dried over calcium sulfate and solvent evaporated to give crude ethyl 4-thia-3,6,10-trimethylundec-2-enoate (mostly trans) which is further purified by thin-layer chromatography eluting with ether/hexane.


A. A mixture of 70 g. of ethyl acetoacetate and 240 ml. of acetonitrile is cooled to about -40°. Hydrogen sulfide is bubbled through for 1 hour with stirring and at about -50° and dry HCl is passed through for one hour. Then hydrogen sulfide is bubbled through for two hours. The mixture is warmed to about 0°, poured carefully into 600 ml. of water/hexane (1:1), washed with water until wash is neutral, dried over sodium sulfate and concentrated under reduced pressure. The concentrate is distilled to give ethyl 3-mercapto-3-methylbut-2-enoate.

B. 300 Mg. of sodium hydride (57% dispersion in mineral oil) is washed with hexane and then slurried in 30 ml. of tetrahydrofuran, under nitrogen. Then 0.96 g. of ethyl 3-mercapto-3-methylbut-2-enoate (from part A) is added dropwise, at 0°. A solution of 1.5 g. of the mesylate of 3,7-dimethyloctan-1-ol in 10 ml. of tetrahydrofuran is added dropwise, at 0°. The mixture is warmed to 25° and 18 ml. of hexamethylphosphoramide added. The reaction mixture is refluxed for about 40 hours and then allowed to cool to room temperature. The mixture is poured into ice water, diluted with ether, washed with water and brine, dried and evaporated under reduced pressure to give crude ethyl 4-thia-3,7,11-trimethyldodec-2-enoate (trans/cis -- mostly trans) which is purified by thin-layer chromatography eluting with ether/hexane followed by distillation.


Following the procedure of Example 1, the mesylate of each of the alcohols under Column I is reacted with ethyl 3-mercaptocrotonate to prepare the respective ester under Column II.












5-methoxy-2,4,5-trimethylhexan-1-ol, and



ethyl 4-thia-3,6,10-trimethylundeca-2,9-dienoate,

ethyl 4-thia-3,6,10,10-tetramethylundec-2-enoate,

ethyl 4-thia-10-methoxy-3,6,10-trimethylundec-2-enoate,

ethyl 4-thia-3,6,10-trimethyldodeca-2,9-dienoate,

ethyl 4-thia-3,6,10,10-tetramethyldodec-2-enoate,

ethyl 4-thia-3,7,11-trimethyldodeca-2,10-dienoate,

ethyl 4-thia-11-methoxy-3,7,11-trimethyldodec-2-enoate,

ethyl 4-thia-3,6,9,10-tetramethylundeca-2,9-dienoate,

ethyl 4-thia-3,6,8,9-tetramethyldeca-2,8-dienoate,

ethyl 4-thia-3,6,8,9-tetramethyldec-2-enoate,

ethyl 4-thia-9-methoxy-3,6,8,9-tetramethyldec-2-enoate, and

ethyl 4-thia-3,6,9,10-tetramethylundec-2-enoate.


A mixture of 14.0 g. of 2,6-dimethylhept-5-en-1-al, 1.9 g. of sodium borohydride and 110 ml. of ethanol is stirred overnight at room temperature. The mixture is poured into water, saturated with sodium chloride and extracted with ether. The ether extract is dried over calcium sulfate, concentrated under reduced pressure and distilled to yield 2,6-dimethylhept-5-en-1-ol, which is hydrogenated using 0.5 g. of 10% palladium-on-carbon in ethanol at room temperature to give 2,6-dimethylheptan-1-ol.

To a solution of 2,6-dimethylheptan-1-ol (2.5 g.) and 40 ml. of ether, cooled to -50°, is added 2.4 g. of phosphorus tribromide in 5 ml. of ether, slowly. The reaction mixture is stirred for two hours, poured onto ice and extracted with ether. The ethereal extracts are combined, washed with 10% sodium carbonate, water and brine, dried and evaporated to give 2,6-dimethylheptanyl bromide, which is used in the process of Example 1(B) to prepare ethyl 4-thia-3,6,10-trimethylundec-2-enoate.


A. 50 Grams of 3,7-dimethyloct-6-en-1-ol is dissolved in 75 ml. of pyridine and 50 ml. of acetic anhydride and left at room temperature for about 48 hours. Then the mixture is extracted with ether and the ethereal extracts washed with water, 10% aqueous HCl and brine to yield 1-acetoxy-3,7-dimethyloct-6-ene, which is purified by distillation.

B. 75 Grams of mercuric acetate in 200 ml. of dry ethanol is added to 50 g. of 1-acetoxy-3,7-dimethyloct-6-ene (citronellol acetate) in 100 ml. of dry ethanol cooled in an ice-bath. The temperature is allowed to come to room temperature by standing overnight. Then the mixture is cooled to 0°, 50 g. of potassium hydroxide in 750 ml. of ethanol is added, followed by addition of 5 g. of sodium borohydride in small portions. After about 30 minutes at 0°, water (50 ml.) is added and the mixture left at room temperature for 2 hours. The mixture is filtered, filtrate concentrated and extracted with ether. The ethereal extract is washed, dried and evaporated to yield 7-ethoxy-3,7-dimethyloctan-1-ol, which is purified by distillation or chromatography.

By using each of methanol and isopropanol in the foregoing process in place of ethanol, there is obtained 7-methoxy-3,7-dimethyloctan-1-ol and 7-isopropoxy-3,7-dimethyloctan-1-ol, respectively.

C. To 10 g. of 7-ethoxy-3,7-dimethyloctan-1-ol in 250 ml. of methylene chloride and 10 ml. of triethylamine at -5° to 0° is added slowly 6.5 ml. of mesyl chloride. About 15 minutes after addition is complete, the reaction is worked up by pouring onto ice, addition of more methylene dichloride, extraction with ice water, washing with 10% HCl, saturated sodium bicarbonate and brine and drying to yield the mesylate.

By use of the foregoing process, the mesylate of each of 6-methoxy-2,6-dimethylheptan-1-ol and 5-methoxy-2,4,5-trimethyl-hexan-1-ol is prepared from 2,6-dimethylhept-5-en-1-ol and 2,4,5-trimethylhex-4-en-1-ol.


A. A mixture of 1 g. of ethyl 4-thia-3,6,10-trimethyl-undec-2-enoate, 60 ml. of ethanol, 0.5 g. of potassium hydroxide and 6 ml. of water is heated at reflux for about eight hours. The mixture is then diluted with water, neutralized and extracted with ether. The organic phase is washed with water, dried over sodium sulfate and evaporated to yield 4-thia-3,6,10-trimethylundec-2-enoic acid.

B. Using each of the esters under Column II as the starting material in the process of this example, there is prepared the respective free acids.


To 0.5 g. of the acid of Example 6A in 10 ml. of benzene, under nitrogen, is added 0.30 ml. of oxalyl chloride, which is separated for about 45 minutes and then allowed to stand two hours. Two ml. of isopropanol is added. After three hours, ether is added and organic layer separated. The organic layer is washed with aqueous sodium bicarbonate and brine, dried over calcium sulfate and concentrated under reduced pressure to yield isopropyl 4-thia-3,6,10-trimethylundec-2-enoate.

By using each of methanol and t-butanol in the process of this example, there is prepared methyl 4-thia-3,6,10-trimethylundec-2-enoate and t-butyl 4-thia-3,6,10-trimethylundec-2-enoate.


To 30 ml. of ice cold isopropanol is added 1.0 g. of acetyl chloride. The resulting solution is stirred at 0° for 15 minutes and 1.0 g. of isopropyl 4-thia-3,6,10-trimethylundeca-2,9-dienoate added. The solution is stirred for one hour at 0° and for 24 hours at 25°. Solvent is removed under reduced pressure and the concentrate taken up in hexane. The hexane solution is washed with water until the aqueous wash is neutral and then with brine. The solution is dried over calcium sulfate and solvent evaporated to yield isopropyl 4-thia-10-chloro-3,6,10-trimethylundec-2-enoate.

Three groups of 30 each of Aedes aegypti, fourth instar larvae, in 50 ml. of tapwater containing a few drops of liver powder suspension, room temperature of 28° and photoperiod of 18 hours, are treated with ethyl 4-thia-3,7,11-trimethyldodec-2-enoate (primarily trans) using 50 microliters of acetone as the carrier at three different dosage levels. A fourth group is maintained under identical conditions. Each group is scored after 7 days by the following system: 0 = normal adult, completely emerged (free or floating); 1 = abnormal adult, non-viable; 2 = incompletely emerged adult; 3 = dead pupa; and 4 = dead larvae. For each group the total number of animals in classes 1-4 is divided by 30 to determine the percentage result. The ID50 is computed by plotting on semi-logarithmic paper, the dose on the horizontal axis and the percentage response on the verticle axis. The ID50 was determined to be less than 1.0 ppm. Each of the larvae of the control group developed into normal adults.