Highly Efficacious Non-ester Pyrethroid Insecticides with Low Toxicity

Chapter 23

Highly Efficacious Non-ester Pyrethroid Insecticides with Low Toxicity to Fish 1

Gary A. Meier, Thomas G. Cullen, Saroj Sehgel, John F. Engel , Susan E. Burkart , Scott M. Sieburth , and Charles M. Langevine Downloaded by PENNSYLVANIA STATE UNIV on June 22, 2012 | http://pubs.acs.org Publication Date: September 22, 1992 | doi: 10.1021/bk-1992-0504.ch023

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Agricultural Chemical Group, FMC Corporation, P.O. Box 8, Princeton, NJ 08543

Studies directed towards the discovery of insecticides with improved safety to fish have resulted in the identification of 2-cyclopropyl2-arylethyl (3-phenoxyaryl)methyl ethers and thioethers. These non-ester pyrethroid analogs show potent activity as broad-spectrum insecticides and, in some cases, acaracides. In addition, these com pounds are generally safe to fish and aquatic invertebrates. The chemistry and biological activity of these compounds will be dis cussed and compared to relevant commercial standards. The pyrethroids possess a number of attributes that make them nearly ideal insecticides. Low mammalian toxicity, high intrinsic activity against a broad spectrum of insect pests, and generally low environmental mobility and persistence all contribute to the tremendous success of this class of chemistry. Pyrethroids, however, are usually quite toxic to fish. For example, cypermethrin has an LC50 of only 1 ppb vs. bluegills. This toxicity has limited the use of pyrethroid insecticides near aquatic environments and, until recently, has effectively excluded the pyrethroids from use in the paddy rice market Clearly, development of a pyrethroid thatretainsthe favorable characteristics of other pyrethroids while exhibitingreducedtoxicity to fish would gready expand the utility of this class of chemistry. Studies have demonstrated that the ester linkage once thought to be necessary for pyrethroid activity can be replaced with certain bioisosteric groups without loss of insecticidal properties. For example, the ester linkage of fenvalerate (1) has been successfullyreplacedwith an oxime ether to give compounds typified by (2) (7,2). The oxime ether (2) had an LC50 of 19 ppm vs. Southern armyworm in our testing, compared to fenvalerate's value of 40 ppm. The compounds ΜΉ-500 (ethofenprox, Current address: Lithium Chemicals Division, F M C Corporation, P.O. Box 795, Highway 161, Bessemer City, N C 28016 Current address: Agricultural Research Division, American Cyanamid Company, P.O. Box 400, Princeton, NJ 08540-0400 Current address: Department of Chemistry, State University of New York at Stony Brook, Stony Brook, N Y 11794

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0097-6156/92/0504-0258$06.00/0 © 1992 American Chemical Society

In Synthesis and Chemistry of Agrochemicals III; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

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Non-ester Pyrethroid Insecticides with Low Toxicity to Fish 259

Downloaded by PENNSYLVANIA STATE UNIV on June 22, 2012 | http://pubs.acs.org Publication Date: September 22, 1992 | doi: 10.1021/bk-1992-0504.ch023

(3)) and ΜΤΊ-800 (4) are further examples of successful bioisosteric replacement of the ester linkage, with Southern armyworm LC50 values of 16 and 7 ppm, respectively. These compounds also exhibit reduced toxicity to fish, with LDso's against carp of 5 ppm for ethofenprox and >40 ppm for MTI-800 (3). We wished to further explore the utility of ether and alkane bioisosteres in reducing the fish toxicity of pyrethroid insecticides. Elliott and Janes had previously reported that the cyclopropyl isostere of fenvalerate was less toxic than fenvalerate to rats and zebrafish (4). This observation lead us to propose structures generically represented by (5) as potential pyrethroid insecticides. The present chapter explores the structure-activity relationships of the ethers (Y = O) and thioethers (Y = S). The following chapter addresses the structure-activity relationships of the corresponding alkanes (Y = CH2) (Cullen, T. G.; et al. in this volume).

Synthesis Schemes Racemic ether synthesis. The general synthesis scheme for the racemic ethers is shown in Scheme 1. Synthesis details have previously been reported in greater detail, and will only be outlined here (5). Treatment of the appropriately substituted carboxylic acid with oxalyl chloride in dichloromethane in the presence of a catalytic amount of DMF gave the acid chloride. This was added at 0° to Ν,Ο-dimethylhydroxylamine hydrochloride in THF containing two equivalents of pyridine to give the amide, typically in greater than 90% yield. Treatment of the amide with cyclopropyl magnesium bromide in THF gave the aryl cyclopropyl ketone in good yield. The methylene phosphorane was generated from methyltriphenylphosphonium bromide using NaH in DMSO. Addition of the ketone to the phosphorane gave the olefin in greater than 90% yield after workup. Addition of BH3 -THF complex to the olefin stirring at 0° in dry THF gave 90 to 95% yield of the alcohol after standard oxidative quenching with methanol, aqueous NaOH, and hydrogen peroxide. Thefinalstep of the scheme, a Williamson ether synthesis, can be carried out either by deprotonating the alcohol with NaH in THF followed by addition of the appropriate benzyl halide, or under phase-transfer conditions, stirring the alcohol


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SYNTHESIS A N D CHEMISTRY O F A G R O C H E M I C A L S III

and benzyl halide neat in the presence of 5 mol % tetrabutylammonium bromide and 50% aqueous NaOH. These methods routinely produce yields of greater than 90%. Ο


Ο

Scheme 1: Synthesis of Arylmethyl 2-Cyclopropyl-2-(aryl)ethyl Ethers Thioether synthesis. Scheme 2. Triphenylphosphine was dissolved in THF and treated with one equivalent diisopropyl azodicarboxylate at 0°, warming gradually to room temperature. To this mixture, one equivalent thiolacetic acid and one-half equivalent of the 2-aryl-2-cyclopropyl ethanol intermediate prepared in Scheme 1 was added, yielding 80% of the desired thioester after workup and chromatography. The thioester was reduced with lithium aluminum hydride in THF to give the thiol in nearly quantitative yield. The thiol reacted under the Williamson conditions described above (NaH, THF) with the appropriate benzyl halide to give the thioether in 80% yield.



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Scheme 2: Synthesis of Arylmethyl 2-Cyclopropyl-2-(aryl)ethyl Thioethers Resolved ether synthesis. The resolved (4-fluoro-3-phenoxy)methyl 2cyclopropyl-2-(4-chlorophenyl)ethyl ether was synthesized from 4-chlorophenyl cyclopropyl ketone as shown in Scheme 3. Deprotonating 2-trimethylsily-l,3-dithiane at 5° with n-BuLi in THF followed by addition of cyclopropyl 4-chlorophenyl ketone gave the tetrasubstituted alkene in nearly quantitative yield. Treatment with mercuric chloride in a refluxing solution of aqueous methanol yielded the methyl ester in modest yield. Hydrolysis of the ester with aqueous NaOH gave the carboxylic acid in greater than 90% yield. Conversion of the acid to the acid chloride using oxalyl chloride, followed by reaction with (4S)-(-)-4-isopropyl-2-oxazolidinone gave a diastereomeric mixture of amides,readilyseparable by silica gel chromatography. Isolated yield of the levorotatory diastereomer was 27%. Reduction of this material with L1AIH4 in THF at 0° gave theresolvedalcohol in 88% yield. Reacting a small sample of the alcohol with the acid chloride derived from (R)-(+)-a~methoxy-a-trifluoromethyl)phenylacetic acid (Mosher's acid) gave the corresponding (a-methoxy-a-trifluoromethyl)phenylacetic ester. 19F NMR analysis of the trifluoromethyl signal showed the alcohol to have an enantiomeric excess of > 90%. Reacting theresolvedalcohol with 4-fluoro-3phenoxyphenyl benzyl chloride under Williamson conditions gave the resolved ether in 75% yield, [cc] = -23.62°. D

Biological Testing The compounds were screened for insecticidal and acaricidal activity against the following species: cabbage looper (Trichoplusia ni), southern armyworm (Spodoptera



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SYNTHESIS A N D CHEMISTRY O F A G R O C H E M I C A L S III

target Scheme 3: Synthesis of Resolved Arylmethyl 2-Cyclopropyl-2-(aryl)ethyl Ethers eridania), tobacco budworm (Heliothis virescens), Mexican bean beede (Epilachna varivestis), pea aphid (Acyrthosiphon pisum), potato leafhopper (Empoascafabae), brown planthopper (Nilaparvata lugeus), and twospotted spider mite (Tetranychus urticae). The activity of the test compounds against cabbage looper, tobacco budworm and Mexican bean beede was determined by spraying the upper and lower surfaces of the leaves of pinto bean plants with test solution until run-off and infesting with second instar larvae after the foliage had dried (ten larvae for each of two replicates for each compound). The test solutions were prepared by appropriate dilutionfroma stock solution of experimental compound in 10% acetone/water. The activity against pea aphid was determined in similar fashion, except that fava bean plants were used and the leaves were infested with adult aphids. The activity against potato leafhopper was determined in a similar fashion except that the treated fava bean plants were removedfromtheir pots by cutting the stem just above the soil line. The excised leaves and stems were placed in petri plates and infested with two-to-three-day-old potato leafhopper adults. The activity against mites was determined on pinto bean plants. The bean leaves were pre-infested with adult mites (about 75 mites for each of two replicates for each compound), then sprayed until run-off with test solution.



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To prevent escape of the insects from the test site, the treated plant or excised leaves were placed in capped cups or other appropriate containers. The tests were transferred to a holding room at 25°C and 50% relative humidity for an exposure period of 48 hours. At the end of the exposure period, percent mortality was determined and LC50 values were determined by probit analysis. The activity against brown planthopper was determined using TNI rice plants that were 35-50 days old. The plants were trimmed to 1.0 feet and to contain four tillers. The plants were sprayed to run-off and allowed to dry. Twenty brown planthopper nymphs (2nd-3rd instar) were introduced per pot and covered with a mylar cage. Mortality readings were taken 24 hours after infestation; the LC50 values were determined by probit analysis. Efficacy in residual testing was determined by spraying the test plants to run-off with aqueous dilutions of the compounds. The treated plants were held under greenhouse conditions for the appropriate period of time before infestation with insects. The test was then completed as described for the initial evaluations. The fish toxicity was determined by testing against fathead minnows (Pimephales promelas) and bluegill (Lepomis macrochirus). Fish testingrequiredthe test materials to be prepared as acetone (l%)/water solutions diluted to the appropriate volume and allowed to equilibrate for five to six hours in one-quart Mason jars before being infested with three minnows or bluegills (25-35 mm). Mortality counts were taken 24 hours after infestation. Testing for toxicity to water flea (Daphnia magna) was performed by the I.T. Corporation Laboratories. Test compound dilutions were prepared in water/acetone to a final acetone concentration of 0.1 mL/L. Tworeplicatesof ten Dûp/w/û/replicate were run at each concentration, ranging from 7.6 to 9.5 χ \0 mg/L. Mortality was recorded after 48 hours. Water-quality parameters, such as temperature, pH and dissolved oxygen were monitored andremainedwithin acceptable limits for the duration of the test. A

Results and Discussion An abbreviated chlorine probe set was synthesized on the phenyl ring of the 2-phenethyl moiety to determine which position(s) were most sensitive to substitution. The results are shown in Table I, for a series of analogs employing 4-fluoro-3-phenoxyphenyl as the pyrethroid alcohol fragment. Substitution in the 4-position of the phenyl ring gaveriseto the most active compounds against most foliar feeding pests, with the Table I: Effects of Varying the Substitution Position on the Phenethyl Phenyl Ring

Foliar L C Cabbage Looper 4-chloro 3-chloro 2-chloro 3,4-dichloro

1 17 250 11

5 0

(ppm) Mexican Bean Beede 4 6 36 1


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SYNTHESIS AND CHEMISTRY O F A G R O C H E M I C A L S III

3-substituted and 3,4-disubstituted compounds slightly less active. Substitution in the 2-position greatly reduced the activity of compounds in this class. The 4-position was selected for further optimization. A series of compounds to determine the most effective pyrethroid alcohol fragment was next synthesized. The results are shown in Table Π. The 4-fluoro3-phenoxyphenyl group gaveriseto the best foliar activity. The 3-phenoxyphenyl and 6-phenoxy-2-pyridyl groups were also quite active, though significandy less so than the 4-fluoro-3-phenoxyphenyl group. The 2-methyl[l,r-biphenyl]-3-yl and 2-benzyl4-furanyl (Elliott's alcohol) groups showed only modest activity.


Table Π: Pyrethroid Alcohol Selection

Foliar LC50 >50

not tested not tested >300 >300

α α


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Table X: Aquatic Testing Data

X


χ CF α α

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Vertebrate Toxicity

Invertebrate Toxicity

Y

Bluegill % kill (rate)

Water flea LQ50

H F H

not tested 50% (3 ppm) 83% (3 ppm)

< 1 ppm not tested 4 ppm

83% (6 ppm) 50% (0.001 ppm)

< 1 ppm 2 ppm

ethofenprox cypermethrin

Conclusions The non-ester pyrethroids described here are potent, broad-spectrum insecticides, and compared to typical ester pyrethroids, are generally quite safe to fish and, in some cases, to aquatic invertebrates. The most active compounds described here are considerably more active than the commercialriceinsecticide ethofenprox on the species in our screen, and several are equivalent or superior to cypermethrin. The limited field test datareportedhere supports the conclusion that these compounds have commercial-level activity. The 4-fluoro-3-phenoxybenzyl moiety is the most effective pyrethroid alcohol equivalent in this series. The ethers analogs are more active against insect pests than the thioethers. Configuration at the molecule's one chiral center is important; theresolvedenantiomers of 2-cyclopropyl-2-(4-chlorophenyl)ethyl (4fluoro-3-phenoxyphenyl)methyl ether demonstrated that the levorotatory isomer was approximately twice as active as the racemic material. Substitution at the 4position of the phenethyl phenyl ring was most important for biological activity. The compounds tolerated a variety of substituents in this position; however introduction of C F 3 or C F 3 O not only boosted the compound's activity against lepidopteran and coleopteran species, but also gaveriseto potent activity against mites and aphids. Acknowledgments The authors would like to thank Larry Marek and George Meindl for carrying out the insect bioevaluations at FMC, as well as E.D. Magallona for the testing he carried out againstricepests in the Philippines. Annette Slaney conducted most of the fish toxicity testing. Finally, the authors acknowledge the support of FMC Corporation.


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SYNTHESIS AND CHEMISTRY O F A G R O C H E M I C A L S III

Literature Cited 1.

2.


3.

4. 5.

Holan, G.; Johnson, W. M . P.; O'Keefe, D . F.; Quin, G . L.; Rihs, K; Spurling, T. H.; Wolser, R.; Virgona, C. T.; Frelin, C.; Lazdunski, M . ; Johnston, G . A . R.; ChenChow, So. Recent Advances in the Chemistry of Insect Control, James, N . F., Ed.; The Royal Society of Chemistry: London, 1985; pp 114-132. Cullen, T. G.; Manly, C. J.; Cruickshank, P. Α.; Kellar, S. M . Synthesis and Chemistry of Agrochemicals; Baker, D. R.; Fenyes, J. G.; Moberg, W. K.; Cross, B., Eds.; American Chemical Society: Washington, D.C., 1987; pp 173-188. Udagawa, T.; Numata, S.; Oda, K.; Shiraishi, S.; Kodaka, K.; Nakatani, K. Recent Advances in the Chemistry of Insect Control, James, N.F. Ed.; The Royal Society of Chemistry: London, 1985; pp 192-204. Elliott, M . ; Janes, N. F. Advances in Pesticide Science , Part 2, Geissbuhler, H . Ed.; Pergamon Press: New York, 1979; pp 166-173. Meier, G . Α.; Sieburth, S. M . ; Cullen, T. G . ; Engel, J. F., U.S. Patent 4,808,762, 1989.

RECEIVED July 6, 1992


Highly Efficacious Non-ester Pyrethroid Insecticides with Low Toxicity

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