1,2,4-Oxadiazole and thiadiazole esters and compositions containing same
United States Patent Hagarty Apr. 22, 1975 [54] 1,2,4-OXADIAZOLE AND THIADIAZOLE [56] References Cited ESTERS AND COMPOSITIONS UNITED STATES PATENTS CONTAINING SAME 3.270.028 8/1966 Pulazzo 260/307 0 [75] Inventor: John Hagan) Sturtevam Wis 3.432.519 3/1969 Mctivler ct ul. 260/307 G [73] Assignee: S. C. Johnson &amp; Son. Inc., Racine. OTHER PUBLICATIONS w Wagner et ul.. Synthetic Organic Chemistry, N.Y.C., [22] Fi ed Feb 9 1973 John Wiley &amp; Sons. 1953. p. 484.  
  2 App] 331,1 4 Primary E.\&#39;aminerR. J. Gallagher [52] US. Cl 260/302 D; 260/307 G; 424/200; [57] ABSTRACT 424/270; 424/277 Novel l. ,4-oxad|a z( le and thiadlozole esters and [51] Int. CL I and 91/60; and 85/52 compositions containing same are described. The es- [581 Field of Search 260/307 G, 302 D are useful as 11 Claims, No Drawings 1 1,2,4-OXADIAZOLE AND THIADIAZOLE ESTERS AND COMPOSITIONS CONTAINING SAME The present invention relates to new and useful esters of 1,2,4-oxadiazoles or thiadiazoles having intesecticidal activity.  
  Current trends in the chemical control of insects call for inherently safer materials with low mammalian toxicity. Accordingly, there is a great demand for broad spectrum insecticides which are suitable for the high volume usage entailed in household, garden and agricultural applications. Of the several insecticide classes which demonstrate low mammalian toxicity and good biodegradability, pyrethrum, a naturally occurring insecticide mixture, has found widest use. Pyrethrin, the most active component of pyrethrum, is a widely used insecticide which has a high order of insecticidal activity and a low mammalian toxicity. Due to the high cost of pyrethrin and its related compounds, however, synthetic products have been prepared which have a similar structure and exhibit significant insecticidal activity.  
  The novel esters of the present invention can be described as pyrethroid esters which contain a 1,2,4- oxadiazole or thiadiazole ring as the planar group of the alcohol portion of the molecule.  
  The 1,2,4-oxadiazole or thiadiazole esters which are the subject of this invention may be represented by the formulas wherein A is oxygen or sulfur; R, is lower alkyl having 1-6 carbon atoms, benzyl, substituted benzyl (wherein the substituent is, for example, nitro, halo or lower alkyl having l-6 carbon atoms), lower alkenyl having 1-6 carbon atoms, furylmethyl, cyclopentylmethyl, cyclopentenylmethyl, cyclohexenylmethyl and cyclohexylmethyl; and R is the residue of a carboxylic acid wherein the carboxylic acid is selected from transchrysanthemumic acid, (i)- cis, transchrysanthemumic acid, dimethyland tetramethylcyclopropanecarboxylic acid, dihalocyclopropanecarboxylic acid, tetrahalocyclopropanecarboxylic acid and fenethric acid. It should be understood that the substituents on the cyclopropanecarboxylic acid are in the 2,2- or 2,2,3,3-position lt should also be understood that the scope of the invention is intended to include those isomeric compounds wherein the groups R, and CH R are in either the 3 or 5 positions of the ring. Either isomer can be prepared, as desired, from the appropriate starting materials, as will be apparent from the following disclosure and examples.  
  The novel 1,2,4-oxadiazole or thiadiazole esters of the present invention can be prepared by reacting the appropriate halomethyl-l ,2,4-oxadiazole or thiadiazole with a carboxylic acid in the presence of a base. The halomethyl oxadiazoles and thiadiazoles may be depicted by the formulas wherein X is a halogen such as chloro or bromo, and R is as defined above.  
  The reaction is generally carried out at a temperature between room temperature and about C. It is convenient, however, to carry out the reaction at the reflux temperature of the solvent. Solvents which are suitable for the reaction include acetone, ether, tetrahydrofuran, benzene and the like. The reaction is carried out from 1 to several hours depending upon the temperature employed. Generally, a reaction time of 6-l2 hours is sufficient to complete the reaction. After the reaction is complete, the product is isolated by techniques known in the art. For example, the residue can be taken up in a suitable water immiscible solvent such as benzene, for example, and the solution washed with water, dilute acid, such as dilute hydrochloric acid and a basic solution such as a sodium bicarbonate solution. The 1,2,4-oxadiazole or thiadiazole ester is obtained on removal of the solvent and can be further purified by techniques known in the art.  
  The carboxylic acids, include acids such as -trans-chrysanthemumic acid, (i)-cis, transchrysanthemumic acid, 2,2-dimethylcyclopropanecarboxylic acid, 2,2,3,3-tetramethylcyclopropanecarbox&#39;ylic acid, 2,Z-dihalocyclopropanecarboxylic acid, 2,2.3,- 3-tetrahalocyclopropanecarboxylic acid wherein the halogen is chloro or bromo, and fenethric acid.  
  As the basic reactant, generally an organic basic amine such as triethylamine is employed. Other amines which are suitable for the reaction include pyridine and tri-n-propylamine. The relative amounts of the reactants employed are not critical, although it is desirable that excesses of either reactant be avoided to prevent undue amounts of side reactions. It is preferred that the two reactants be present in the reaction mixture in about stoichiometric proportions, i.e., about 1 mole of the halomethyl compound per mole of the carboxylic acid.  
  The halomethyl-l ,2,4-oxadiazoles and thiadiazoles which are the starting materials for the esters are themselves novel compounds except for those compounds where A is oxygen and R is methyl or benzyl.  
  Those compounds wherein the halomethyl group is in the 5-position can be prepared by reacting a substituted acetonitrile with hydroxylamine hydrochloride in aqueous alcohol in the presence of a base such as sodium carbonate, for example. The reaction is generally carried out at about 50C. and the acetamide oxime intermediate is obtained upon removal of the solvent. The oxime intermediate is then reacted with a haloacetic anhydride in a suitable solvent such as toluene, for example. The product is generally obtained by distillation after removal of the solvent.  
  Those compounds wherein the halomethyl group is in the 3-position can be prepared by reacting a haloacetonitrile with hydroxylamine in the presence of a base such as sodium carbonate. The haloacetamide oxime which forms is then reacted with the appropriate substituted iminoacetate hydrochloride to obtain the corresponding 3-halomethyl compound.  
 The novel insecticidally active compounds provided by the present invention may be employed in combating a variety of crop pests and household pests. They are particularly useful in the eontrolof houseflies and roaches.  
 In applying the products of this invention as insecticides, conventional techniques may be used. Good results are obtained when the compounds are applied as aerosol sprays, for example, or are formulated into any of the diluted and extended types of formulations commonly used in insecticidal practice, including dusts, wettable powders, emulsifiable concentrates, solutions, granulars, baits, and the like, for application to foliage, within closed areas. to surfaces. and wherever insect control is desired.  
  The compositions may be made into liquid concentrates by solution or emulsiflcation in suitable liquids, and into solid concentrates by admixing with talc, clays. and other known solid carriers used in the insecticide art. These concentrates are compositions which normally contain about -507e of the toxicant with the remainder being inert materials such as dispersing agents, emulsifying agents and wetting agents. Minor amounts of other substances may be added to the compositions in order to obtain particular functional or esthetic effects. Substances such as perfumes, corrosion inhibitors. buffering agents, fillers, flame retardants, antioxidants, ultraviolet radiation absorbers, disinfectants and the like, are examples of such additives. The concentrates are diluted for practical application, with water or other liquids for liquid sprays or with additional solid carrier for application as a dust or granular formulation. Baits are usually prepared by mixing such concentrates with a suitable food, such as a mixture of cornmeal and sugar. The concentration of the toxicant in the diluted formulations, as generally applied for insect control, is normally in the range of about 2% to about 0.001%.  
 preferred ratio is from about 1:3 to 1:5. Even larger proportions of synergist may be employed without detriment, whether or not the optimum synergistic proportions have been achieved. It is clear that effective amounts of synergist should be employed in the composition and that the components should be present in synergistic proportions.  
  Although this invention has been described in detail with particular reference to preferred embodiments thereof, it will be understood that variations and modifications can be effected within the spirit and scope of I this invention as described hereinabove and as defined in the appended claims.  
 EXAMPLEI A solution of 3-benzyl-5-chloromethyl-1,2,4- oxadiazole 20.8 g. (0.1 mole), transchrysanthemumic acid, 16.8 g. (0.1 mole) and 10 g. (0.1 mole) of triethylamine is prepared in 120 ml. of dry acetone. The resultant mixture is refluxed for 6-12 hours after which the solvent is removed in vacuo and the residue taken up in 150 ml. of benzene. The benzene solution is washed with 100 ml. of water, 100 ml. of dilute hydrochloric acid and 100 ml. of sodium bicarbonate solution and then dried over magnesium sulfate. Upon removal of the solvent transchrysanthemumoxymethyl 3-benzyl-1,2,4-oxadiazole is obtained as a viscous oil having an index of refraction of N l.5256.  
  The following compounds were prepared in accordance with the procedure outlined in Example 1.  
 TABLE I Example No. R, R n  
 2 2,2,3,3-tetramethylcyclopropanecarboxylic acid 3-benzy1 1.5310 3 fenethric acid 3-benzyl 1.5413 4 cis, trans-chrysanthemumic acid 3-benzyl 1.5154 5 trans-chrysanthemumic acid S-benzyl 1.5288 6 2,2,3,3-tetramethylcyclopropanecarboxylic acid S-benzyl 1.5209 7 trans-chrysanthemumic acid 3-al1y1 1.4886 8 2,2,3,3-tetramethylcyclopropanecarboxylic acid 3-allyl 1.4786 9 trans-chrysanthemumic acid 3-furylmethyl 1.4921 10 trans-chrysanthemumic acid 3-(1,2-cyelopentenylmethyl) 1.4996 1 1 trans-chrysanthemumic acid 3-( l,2,-cyclohexenylmethyl) 1.5031 12 trans-chrysanthemumic acid 3-isopropyl 1.4769 13 trans-chrysanthemumic acid 3-methyl 1.4818 14 trans-chrysanthemumic acid 3-(p-nitrobenzyl) 1.5414  
  such as piperonyl butoxide, dipropargyl phenyl phosphonate, sesamex and tropital, for example, may be employed. The preferred synergists are piperonyl butoxide and dipropargyl phenyl phosphonat&#39;e.  
  The relative amounts of synergist and toxicant employed are not critical in that a relatively minor amount of synergist is effective in imparting a beneficial effect to the combination. The synergistic insecticidal compositions of this invention generally contain a ratio of ester to synergist from about 1:1 to about 1:10. The  
  The 3,5-disubstituted-1,2,4-oxadiazo1es which are the starting materials for the present invention are prepared as follows:  
 EXAMPLE 15 3-benzyl-5-chloromethyl-1,2,4-oxadiazole A. A solution of 1 17.2 g. (1 mole) of phenylacetonitrile and 69.5 g. 1 mole) of hydroxylamine hydrochloride in 500 ml. of aqueous ethanol is treated with 106 g. of sodium carbonate. The mixture is then heated to 50C. and held at this temperature for two days. After cooling, the sodium chloride which forms is filtered off and the solvent is removed in vacuo. Upon recrystallization of the crystalline residue from aqueous methanol, colorless needles of phenylacetamide oxime having a m.p. of 55-60C. are obtained.  
 B. A solution of 40 g. (0.27 mole) of crude phenylacetamide oxime in 200 ml. of dry toluene is treated with 45.9 g. (0.27 mole) of chloroacetic anhyin 250 ml. of water is prepared. The solution is then carefully treated with 53 g. of sodium carbonate while dride in 100 ml. of toluene. The resultant mixture is R1 XCH2 then refluxed and the water formed is removed by I means of a Dean. Stark trap. The mixture is refluxed for /l \o q L 3-4 hours after which it is cooled and extracted once XCH2 l \Q I R with 150 ml. of water and 4 times with 100 ml. of a sat- 5 1 Example No. X R b.p. n&#34;  
 17 C1 3-allyl 1.4826 18 Cl 3-furylmethyl 96-10lC (0.12 mm) 1.5036 19 C l 3-cyclopentenyl- 88-94C methyl (0.12 mm) 1.5034 20 Cl 3-cyclohexenyl- 96-99C methyl (0.07 mm) l.5094 21 Cl 3-isopropyl 7679C I mm) 1.4576 22 Cl 3-ethyl 8889C (35 mm) 1.4619 23 Cl 3-p-nitrobenzyl m.p. 50 52C.  
 urated sodium bicarbonate solution. The toluene solu- The following examples illustrate the insecticidal action is then dried over magnesium sulfate and the soltivity of the compounds of this invention. They also ilvent is removed in vacuo. Upon distillation of the resilustrate the unexpectedly high order of synergism obdue, 3-benzyl-5-chloromethyl-1,2.4-oxadiazole, 19.8 g. taincd when these compounds are combined with dihaving a b.p. of 100-108 (0.04 mm) is obtained. 25 propargyl phenylphosphonate. In each case where a EXAMPLE l6 synergist was employed, it was used at the ratio of 4 parts by weight of synergist per part by weight of toxiy cant. The numerical results reported in the table are A. A solution of chloroacetonitrile. 75 g. 1.0 mole) the ratio of the activity of the&#39;test toxicant to the activand hydroxylamine hydrochloride, 69.5 g. (0.1 mole), 3O ity of a combination of 4 parts of piperonylbutoxide with one part of pyrethrin, a commercially employed. potent toxicant formulation.  
 OXADIAZOLE ESTERS TOXICANT RATIO Topical Application Feet-Grady Knockdown Synergist I-Iousefly Gennan Roach 3&#34; 5&#34; Example Oxadiazole 2 Number Ester None PB DPPP None PB DPPP None PB None PB None PB 24 3-benzy1 12:01 .91:09 1.44: 08:01 08:01 .94: I 4 .27 .38 .55 .79 .71 .95 25 3-benzy1 .06:006 .40:04 .73:08 NIL NIL :05 .16 .24 .24 .30 .19 .29 26 3-a11y1 .025:003 26:02 39:04 NIL NIL 08:01 .13 .16 .16 .16 .30 .30 27 3-furylmethyl .041:005 .34:04 68:06 .04:01 .05:01 .l8:03 .19 .22 .34 .47 .58 .65 28 S-benzyl .044:O06 .45-.05 .66:07 NIL NIL .30-205 .13 .17 .12 .18 .46 .42  
 9 In Examples 25-27. the compound tested corresponded to the eneric formula ivcn above wherein R, is (:t) cis, trans chrysanthcmumic acid. In Examples 24 and 28.  
 R, is trans chrysanthemumic acid. PB piperonyl butoxidc DPPP dipropargyl phenylphosphonate.  
 keeping the temperature below-30C. The mixture is held at 30C. for 15 minutes after which it is extracted with ether several times. Sodium chloride is added to facilitate extraction. The ether extracts are combined and dried over magnesium sulfate. The solvent is removed in vacuo and crude crystalline oxime is obtained. Upon recrystallization from benzene, 56 g. of chloroacetamide oxime is obtained having a m.p. of  
  B. A mixture of chloroacetamide oxime, 11.0 g. (0.10 mole), and ethyl phenyliminoacetate hydrochloride, 22 g. (0.11 mole), in 80 ml. of absolute ethanol is refluxed for one hour. After cooling, the ammonium chloride which precipitates is filtered off and the alcohol is removed in vacuo. Upon steam distillation of the residue, 7.0 gm. of 3-chloromethyl-5-benzyl-l,2,4- oxadiazole is obtained, n 1.5386.  
  The following compounds were prepared in accordance with the procedure outlined in Example 16 above.  
 What is claimed: 1. A-compound of the formula wherein A is oxygen or sulfur, R, is lower alkyl having 7 chrysanthemumic acid, methylcyclopropanecarboxylic tetramethylcyclopropanecarbox&#39;ylic acid, dihalocyclopropanecarboxylic acid, and tetrahalocyclopropanecarboxylic acid. r  
 --2. The compound of claim 1 wherein R, is benzyl and R is the residue of (+)-trans-chrysanthemumic acid or (:)-cis, traris-chrysanth&#39;emumic &#39;acid.  
  &#39;3. The compound of claim 1 wherein A is sulfur. 4. The compound of claim I wherein&#39;A is oxygen. 5. The compound of claim 4 wherein R, is benzyl and R isithe residue of chrysanthemumic acid. cyclopropanecarboxylic acid, dimethylcyclopropanecarboxylic acid, tetramethylcyclopropanecarboxylic acid, dihalocyclopropaanecarboxylic acid and tetrahalocyclopropanecarboxylic acid.  
 &#34; 6. The compound of claim 4 wherein R, is benzyl, R  
 is the residue of (+)-trans-chrysanthemumic acid or (i)-cis, transchrysanthemumic acid and A is oxygen.  
 7. A compound of the formula R c -O-CHZ 8. The compound of claim 7 wherein R, is benzyl and R is the residue of (+)-trans-chrysanthemumic acid or (t)cis, transchrysanthemumic acid.  
 9. The compound of claim 7 wherein A is oxygen.  
 10. The compound of claim 9 wherein R, is benzyl and R is the residue of (+)-trans-chrysanthemumic acid, (i)-cis, trans-chrysanthemumic acid, dimethylcy-v tetramethylcyclo ciopropanecarboxylic acid, propanecarboxylic acid, dihalocyclopropanecarboxylic acid and, tetrahalocyclopropanecarboxylic acid.  
  11. The compound of claim 7 wherein R, is benzyl, R is the residue of (+)-trans-chrysanthemumic acid or (i)-cis, transchrysanthemumic acid and A is oxygen.  
 Patent No.  
 Inventor(s) UNITED STATES PATENT OFFICE Dated April 22,  
 John D) Hagarty It is certified that error appearsin the above-identified patent and that said Letters Patent are hereby corrected as shown below:  
 Column 1, line Column 1, line Column 4, line Table bridging 5, &#34;intesecti&#34; 49, insert a period after &#34;position&#34;. 18, delete the comma after columns 5 should be -insecti and 6, line 38, delete &#34;2&#34; under &#34;Housefly&#34; Table bridging columns 5 and 6, lines 40-44, delete .l2+, Ol .9l+09 l.44+l5 .08i.0l .08+0l .94il4 061 006 40104 73+0 8 NIL NIL 35+o5 .o2&#39;5&#39;+003 .26102 .39I.04 NIL NIL .osfol 0415005 .34504 .68506 .04i.0l .05+0l .18103 .044+006 .45.05 .66+.07 NIL NIL .30+05&#34; and insert --.,l2+.0l .9l+.09 l.44+.l5 .08+.0l .08+.0l .94+.l4 .065006 #10 304 .73-I T08 NIL NIL .35505 .025i.003 .26i.02 .39i.04 NIL NIL .O8i.0l 041-3005 .34j- .O4 .68i.06 .04 -l;.0l .05i.0l .l8i.03 Q .044+.006 .45+.05 .66+.07 NIL NIL .30j- .05  
 Claim 1, Formulation, delete &#34;[2]&#34;.  
 Claim 6, line 3, &#34;transchrysanthemumic&#34; should be transchrysanthemumic--.  
 Claim 7, formulation, delete [2] Claim 8, line 3, -l;)cis,&#34; should be (-l cis,-. Q Claim ll, line 3, &#34;transchrysanthemumic&#34; should be transchrysanthemumic.  
 Signed and gcalzd this twenty-first Day Of October 1975 [SEAL] Arrest:  
  RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner of Patents and Trademarks