Synthesis and Chemistry of Agrochemicals III - American Chemical

Chapter 24

1,4-Diaryl-1-cyclopropylbutanes Highly Efficacious Insecticides with Low Fish Toxicity 1

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Thomas G. Cullen, Scott M. Sieburth , John F. Engel , Gary A. Meier, Albert C. Lew , Susan E. Burkart , Francis L. Marek, and James H. Strickland 3

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Downloaded by CORNELL UNIV on June 22, 2012 | http://pubs.acs.org Publication Date: September 22, 1992 | doi: 10.1021/bk-1992-0504.ch024

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Agricultural Chemical Group, FMC Corporation, P.O. Box 8, Princeton, NJ 08543 1,4-Diaryl-1-cyclopropylbutanes are potent broad spectrum foliar insecticides and, in some cases, acaricides. These highly lipophilic non-ester pyrethroids are relatively safe to fish as well as mammals. The cyclopropyl group is found to be essential; replacement by an isopropyl group results in a dramatic loss in activity. The insecticidal activity, fish safety and mammalian safety are equivalent to relevant standards. A goal of our research program was to develop an insecticide that had foliar activity against cotton pests (e.g., worms) and rice pests (e.g., hoppers). In addition, we set the criteria that our compounds possess fish and mammalian safety minimally equivalent to ethofenprox, 1, and MTI-800,2. The structures of the compounds referred to in this chapter are in Figure 1. One part of that program was the preparation of 1-cyclopropyl-1-(4substituted phenyl)-4-(4-fluoro-3-phenoxyphenyl)butane, 3. In that instance, we replaced the ester linkage of fenvalerate, 4, by an ethylene linkage. Furthermore, the isopropyl group of fenvalerate was replaced by the isosteric cyclopropyl group. In our case, this was found to lead to increased insecticidal activity. Compounds in which the cyano group of fenvalerate is retained will be discussed at a future date. These changes resulted in compounds in which the insecticidal activity was maintained ( 1,2). It is well known that replacement of the carboxyl group in fenvalerate by an oxime ether linkage maintains insecticidal activity (3, 4.). Yet not all replacements of the ester linkage were successful. An amide or a thioester linkage

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3

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Current address: Department of Chemistry, State Universty of New York at Stony Brook, Stony Brook, N Y 11794 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, N J 08540-0400 Current address: Van De Mark Chemical Company Inc., 1 North Transit Street, Lockport, N Y 14094

0097-6156/92/0504-O271$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.


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

Figure 1. Structures of C o m p o u n d s Discussed



24. C U L L E N E T A L .

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shows diminished biological activity (5). Enhanced fish safety as well as good insecticidal activity is shown when the ester group is replaced with an ether linkage and the isopropyl group is replaced by a dimethyl group, resulting in ethofenprox, (6) Furthermore, replacement of the ether linkage by an alkylene linkage results in MTI-800 that is more active than ethofenprox and safer to fish (7). The transformation from ethofenprox to MTI-800 also included the addition of a 4-fluoro group. That change can contribute significantly to increased insecticidal activity, but the effect on safety to fish is not known by us. For our purposes, Figure 2 represents those portions of the 1,4-diaryl1-cyclopropylbutanes that were examined for their effect on biological activity and that will be covered in this chapter. One of our interests was to determine whether the cyclopropyl group is essential for good foliar activity. Our work in the alkyl aryl oxime ether area has shown that cyclopropyl and isopropyl groups are both active in foliar testing (5). We predicted that when Y is equal to fluorine this would be more active than the hydrogen compounds. This is the case in a direct analogy to the pyrethroid esters.

x R = cyclopropyl, isopropyl, normal propyl Y = hydrogen or fluorine Ζ = carbon or nitrogen X = Cl, C F , OC2H5, OCF3 3

Figure 2. Structure Changes Synthesis The original synthesis employed for the preparation of 1-(4-chlorophenyl)-1cyclopropyl-4-(3-phenoxyphenyl)butane (6) is shown in Figure 3. This scheme starts with 3-phenoxybenzaldehyde which is treated with commercially available ethoxycarboxylmethylene triphenylphosphorane in one portion to give ethyl 3-(3phenoxyphenyl)acrylate in 75% yield. This material is reduced to 3-(3-phenoxyphenyl)propanol in 90% using lithium aluminum hydride, and converted to the corresponding 3-(3-phenoxyphenyl)propyl bromide in 7 0 % yield using phosphorus tribromide. Refluxing this bromide and triphenylphosphine in acetonitrile gave the desired 3-(3-phenoxyphenyl) propyltriphenylphosphonium bromide, 7. Under a nitrogen atmosphere, compound 7 is treated with η-butyl lithium, followed by 4chlorophenyl cyclopropyl ketone, 8, to give 1-(4-chlorophenyl)-1-cyclopropyl-4-(3phenoxyphenyl)-1-butene, 9, in 4 5 % yield. Compound 9 is reduced to 6 in 90% yield using hydrogen with Raney nickel as the catalyst. This is found to be the catalyst of choice for this hydrogénation as other catalysts such as platinum or palladium open the cyclopropane ring to give the η-propyl derivative as well as reducing the double bond. We desired a more efficient synthesis of 6. Figure 3 required two Wittig reactions, a lithium aluminum hydride reduction and a bromination with phosphorus



Figure 3. Synthesis of 1-(4-chlorophenyl)-1-cyclopropyl-4-(4-fluoro-3-phenoxyphenyl butane, 6.



24. C U L L E N E T A L


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tribromide. In Figure 4, our alternative synthesis starts with elaboration of 8 by treatment with vinyl magnesium bromide to give 1-cyclopropyl-1-(4-chlorophenyl)2- propen-1-ol, 10, in 9 6 % yield. Compound 10 is oxidized to 3-cyclopropyl3- (4-chlorophenyl)propenal in 2 5 % yield using either pyridinum chlorochromate or dichromate. This material is added to the Wittig reagent derived from (3-phenoxybenzyl)triphenylphosphonium chloride to give 1,3-butadiene, 1 1 , in 3 2 % yield. Compound 11 is reduced to 6 in 9 2 % yield using Raney nickel. While this results in a more efficient and less time consuming synthesis, the low yields require still further improvement. Figure 5 details several improvements. This synthesis starts with 10, which is treated with thionyl chloride to give 1-cyclopropyl-1-(4-chlorophenyl )-3-chloro-1-prope ne in 9 0 % yield. Treatment with triphenyl phosphine gave the phosphonium salt, 12, in 87% yield. Compound 12, as a solid salt, is washed with toluene to remove many impurities, thereby allowing an easier purification of 11 when the Wittig reaction is performed (90% yield). The hydrogénation to 6 proceeds as described above. Biological Testing The compounds were screened for insecticidal and acaricidal activity against the following species: cabbage looper (Trichoplusia ni), tobacco budworm (Heliothis virescens), Mexican bean beetle (Epilachna varivestis), pea aphid (Acyrthosiphon pisum), potato leafhopper (Empoasca fabae), brown planthopper (Nilaparvata lugeus), twospotted spider mite (Tetranychus urticae). The activity against cabbage looper (CL), tobacco budworm (TBW) and Mexican bean beetle (MBB) 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 (ten larvae for each of two replicates for each compound) after the foliage had dried. The activity against pea aphid (PA) was determined in a similar fashion, except that fava bean plants were used and the leaves were infested with adult aphids. The activity against potato leafhopper (PLH) was determined in a similar fashion except that the treated fava bean plants were removed from their 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 (TSM) 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. 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 this time, percent mortality was determined and LC50 values were determined by probit analysis. The activity against brown planthopper (BPH) was determined using TN1 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 runoff 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.




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Figure 4. Improved synthesis of 1-(4-chlorophenyl)-1-cyclopropyl-4(4-fluoro-3-phenoxyphenyl)butane, 6.


CULLEN ET A L


(C H ) P 5

3


6

Figure 5. Final synthesis route to 1-(4-Chlorophenyl)-1-cyclopropyl-4(4-fluoro-3-phenoxyphenyl)butane, 6.


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The fish toxicity was determined by testing against fathead minnows (Pimephales promotes) and common carp (Cyprinus carpio). Minnow testing required the test materials to be prepared as acetone (1%)/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 fathead minnows (25-35 mm). Mortality counts were taken 24 hours after infestation. The toxicity to carp was determined by Analytical Bio-Chemistry Laboratories Inc., Columbia, Missouri. The acute toxicity was assessed using the methods outlined by the Committee on Methods for Toxicity Tests with Aquatic Organisms. The test was conducted with duplicate 40 liter aquaria containing 30 liters of water with five fish per replicate chamber. A total of ten fish with a mean weight of 1.7 grams and a mean standard length of 39 millimeters were exposed to each test concentration and control. The 96 hour LC50 values were determined. Results and D i s c u s s i o n The efficacy of the 1-cyclopropyl-1-(4-substituted phenyl)-4-(3-phenoxyphenyl) butanes and 1-cyclopropyl-1-(4-substituted phenyl)-4-(4-fluoro-3-phenoxyphenyl) butanes as foliar insecticides is shown in Table I. This data shows that when Y is fluorine, the compound is consistently more active than when Y is hydrogen. However, such differences are not dramatic. Compound 3, (X=CI; Y=H or F)), Table I. Foliar Activity of 1 -Cyclopropyl- 1-(4-X-phenyl-4-(4-Y-3-phenoxyphenyl) butanes

LC50 (ppm) X

Y Cabbage Tobacco Pea Looper Budworm Aphid

CI CI OCF3 OCF3 CF CF OC2H5 OC2H5 ethofenprox MTI-800 3

3

H F H F H F H F

3 1 19 5 13 10 97 51 97 16

15 8 -

14 33 9 190 86 7 15

450 36 301 24 17 3 830 173 51 33

TwoMexican spotted Spider Bean Beetle Mte 17 6 5 2 23 8 12 2 14 2

344 225 53 13 123 16 500 390 310

Potato Leafhopper

Brown Plant Hopper

14 4 2 4 9 4

12 9 -

3 5

-

-

6

31

-

I = Inactive



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provides a good illustration of this conclusion. In testing versus tobacco budworm, cabbage looper, and Mexican bean beetle, the fluoro analog is more active than the hydrogen analog but not to any great extent. Pea aphid and potato leaf hopper are more susceptible to the fluoro analog, but control of brown plant hopper is equivalent. Neither analog is effective against mites. Compounds 3, where X is equal to chloro, trifluoromethyl or trifluoromethoxy and Y is equal to fluorine, are judged by us to be the best overall insecticidal compounds in these tests. They are more active against cabbage looper than ethofenprox, and when X is chloro, more active than MTI-800. The tobacco budworm activity of these three compounds is equivalent to ethofenprox and MTI800. In examining potato leaf hopper biological activity, these three compounds are equivalent to ethofenprox. Ethofenprox is less active against brown plant hopper (foliar LC5o=31 ppm) when compared to compounds 3, where X is chloro and trifluoromethyl. The latter two compounds are active against brown plant hopper at LC50 rates of 9 ppm and 5 ppm, respectively. None of these compounds is particularly effective against mites. Further differentiation of these three compounds was not based on insecticidal activity, but upon other criteria, such as, aquatic testing data (vide infra). In addition to good initial activity, it is necessary for a foliar insecticide to possess residual activity. Compound 6 has at least seven days residual activity against lepidoptera and that result is shown in Table II.

Table II. Residual Activity of 6 LC50

Species

1 Day

CL TBW

1 2

(PPM)

3 Days 1 9

7 Days 5 17

In Figure 2, it is shown that Ζ could either be nitrogen or carbon. An examination of the data in Table III shows that nitrogen does not contribute significantly to activity in the case of cabbage looper, pea aphid, Mexican bean beetle or potato leaf hopper. From this biological data we conclude that the pyridyl analogs do not offer any advantage relative to the corresponding phenyl analogs. In our earlier work on cyclopropyl aryl oxime ethers, we showed 13, which contained the 2-methyl-1,1 -biphenyl fragment, was more active than 5, which contained 3-phenoxyphenyl fragment (5). In this project we wished to determine whether the 2-methyl-1,1'-biphenyl fragment contributed to activity to a greater extent than the corresponding 3-phenoxyphenyl and the 4-fluoro-3-phenoxyphenyl fragments. The insecticidal data for these 2-methyl-1,1'-biphenyl compounds, 14, is in Table IV. When these compounds are compared with the corresponding 3phenoxyphenyl and the 4-fluoro-3-phenoxyphenyl analogs shown in Table I, it is evident that the 3-phenoxyphenyl and the 4-fluoro-3-phenoxyphenyl fragments are more active as foliar insecticides than the compounds containing the 2-methyl-1 , 1 ' biphenyl fragment. Table V illustrates that conclusion with a series of analogs where X is chloro. In general, the compounds 6 and 3 (X=CI, Y=H or F) are more active than 14, except in foliar testing against pea aphids, where 3 (X=CI, Y=H) is less active than 14. ,


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Table III. Pyridyl Analog Insecticidal Activity ( L C 5 0 ppm)


.X) χ CI CI CF CF ethofenprox MTI-800

Cabbage Looper 3 3 13 14 97 16

ζ C Ν C Ν

3 3

Mexican Bean Beetle 17 11 23 4 14 2

Pea Aphid 450 26 17 28 51 33

Potato Leaf hopper 14 11 9 6 6

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Table IV. Insecticidal Activity of Derivatives of 14 ( L C 5 0 ppm)

Cabbage Looper 15 42 270

ν Λ

CI CF

3

OCPHR

Tobacco Budworm 114 287 150

Mexican Bean Beetle 185 72 81

Pea Aphid 92 22 475

Table V. Comparison of Foliar Activity of Analogs of 3 and 14 ( L C 5 0 ppm)

Compound 3 6 14

X CI CI CI

Cabbage Looper 3 1 15

Y H F

Tobacco Budworm 15 8 114

Mexican Bean Beetle 17 6 185

Pea Aphid 450 36 95

Table VI shows that the cyclopropyl group is essential for topical and foliar activity on our compounds. In topical testing, the cyclopropyl analog where X is chloro has a topical L D 5 0 of 55 μς g ' whereas the isopropyl analog has no control at 1000 pg g - 1 . The foliar activity shows the same relationship, as the cyclopropyl analog has a foliar L C 5 0 of 1 ppm and the isopropyl analog has a foliar L C 5 0 of 180 ppm. In this area as in the cyclopropyl aryl oxime ethers, it has been shown that the cyclopropyl group is essential for good topical and foliar activity. Surprisingly, the cyclopropyl compounds where X is equal to chloro and ethoxy are equivalent in topical activity (Table VI), but are different in foliar activity (Table I and Table VI). The foliar L C 5 0 «s 1 ppm for the chloro analog and 51 ppm for the ethoxy analog against cabbage looper. In this test, MTI-800 had the best topical activity 1


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(LD5o=19 μρ g " ) , yet the foliar L C 5 0 was 16 ppm. This suggested that good topical activity contributes to foliar control of cabbage looper, but it is not the only factor involved. 1


Table VI. Comparison of Cyclopropyl Versus Isopropyl

Cabbage Looper Topical R Cyclopropyl Isopropyl Cyclopropyl MTI-800

X CI CI

LDRO ( u a c r ) 1

OC2H5

55 0%@ 1000pgg50 19

1

Foliar LCsn (ppm) 1 180 51 16

Fish T o x i c i t y To assess safety to fish, we determined the static toxicity of two compounds to fathead minnows. On the basis of their broad spectrum foliar activity, two compounds were selected: 6 and 3, where X = C F . The results are reported in Table VII. Compound 3, where X=CF3, is relatively less safe than 1 and was dropped from further consideration. Further testing of compound 6 against carp shows it to have fish safety equivalent to ethofenprox and MTI-800 in this test as seen in Table VIII. 3

Table VII. Aquatic Testing with Fathead Minnow compound 3 (X=CF ) 6 ethofenprox cypermethrin 3

Static L C 5 0 (ppb) 5 >50 38 1 Table VIII. Aquatic Testing with Carp

compound ethofenprox MTI-800 6

static L C 5 0 ( p p 5 T 5 >40* >30

•Reference (1)


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Mammalian Toxicity With good insecticidal activity and relative safety to fish, an additional parameter to evaluate was acute toxicity. Our criteria for acceptable toxicity were acute oral and dermal toxicity comparable to or better than ethofenprox and MTI-800. The results in Table IX show the relative safety to mice by 6 desired at the outset of the project. Table IX. Results of Mammalian Toxicity Testing


Compounds 1 2 6

Acute Oral LD50 (mq/kq) >300* >300* 50-500

Acute Dermal LD50 (mq/kq) >2100** 200-2000

•Reference 1 Conclusions The 1 -cyclopropyl-1 -(4-substituted phenyl)-4-(4-fluoro-3-phenoxyphenyl)butanes are effective foliar insecticides with good initial and residual activity against worms. These compounds are also effective against hoppers and can be considered potential rice insecticides. Finally, these compounds as illustrated by 6 are equivalent to ethofenprox and MTI-800 in their relative safety to fish and mammals. Acknowledgments The authors acknowledge the contributions of our many co-workers in this program. Charles M. Langevine prepared several compounds; Kathleen A. Boyler, Michael A. Walsh, Mina Reed, Carmela E. Williams, George L. Meindl, and Lisa A. Schultz were responsible for the insecticide data; Annette C. Slaney helped perform the fathead minnow evaluation; Susan A. Meissner aided in manuscript preparation. Finally, the authors acknowledge the support of FMC Corporation. L i t e r a t u r e Cited 1. 2. 3.

4.

5. 6. 7.

Meier, G. Α.; Sieburth, S. M.; Cullen, T. G.; Engel, J. F. (FMC Corporation) U.S. Patent 4,808,762, 1989. Sieburth, S. M.; Lin, S. Y.; Cullen, T. G. Pestic. Sci. 1990, 29, 215. 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, S.; In Recent Advances in the Chemistry of Insect Control, Edited by James, N. F.; The Royal Society of Chemistry: London, 1985. Cullen, T. G.; Manly, C. J.; Cruickshank, P. Α.; Kellar, S. M.; In Synthesis and Chemistry of Agrochemicals; Edited by Baker, D. R.; Fenyes, J. G.; Moberg, W. K.; Cross, B.; American Chemical Society: Washington, D.C., 1987 Elliot, M.; Farnham, A. W.; James, N. F.; Johnson, D. M.; Pilman, D. Α.; Pestic. Sci. 1980, 11, 513. Udagawa, T.; Nakatani, K.; Inoue, T.; Numata, S.; Oda, K.; Gohbana, M.; The Fifth International Conference of Pesticide Chemistry: Kyoto Japan, 1982. Udagawa, T.; Numata, S.; Oda, K.; Shiraishi, S.; Kodaka, K.; Nakatani, K.; In Recent Advances in the Chemistry of Insect Control, Edited by James, N.F.; The Royal Society of Chemistry: London, 1985.

R E C E I V E D July 6,

1992


Synthesis and Chemistry of Agrochemicals III - American Chemical

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