Pestic. Sci. 1974,5,491-496

Insecticidal Activity of the Pyrethrins and Related Compounds

VI. Methyl-, Alkenyl-, and Benzyl-furfuryl and -3-furylmethyl Chrysanthemates" Michael Elliott, Andrew W. Farnham, Norman F. Janes and Paul H. Needham

Department of Insecticides and Fun*qicides, Rothamsted Experimental Station, Harpenden, Herts AL5 2JQ

(hfanuscr@t receiced 27 February I974 and accepted I I March 1974)

The influence of the nature, number and relative dispositions of substituents on the furan ring of furfuryl and 3-furylmethyl chrysanthemates on insecticidal activity to two insect species is described. 5-Benzyl-3-Furylmethyl chrysanthemate was the most active compound developed in the investigation.

1. Introduction

The natural "pyrethrins I"',' and allethrin3s4 (the first synthetic pyrethrojd to be manufactured) are chrysanthemates of cyclopentenolones, but Staudinger and Ruzicka as early as 1924s and Synerholm in 19496 detected insecticidal activity in non-ketonic esters such as piperonyl chrysanthemate. Greater activity was later demonstrated by Barthe17 for 6-chloro- and 6-bromo-piperonyl chrysanthemates, and for the 2,4- dimethylbenzyl ester. When all 19 methylbenzyl chrysanthemates had been synthesised,8 it was found that the most active compounds to houseflies and mustard beetles were the polymethylated compound^.^ However, even greater activity in non-ketonic esters was obtained when an unsaturated side-chain, considered to simulate the function of the pentadienyl group of pyrethrins I and TI or the ally1 group in allethrin,'o*" was attached to the benzyl nucleus, as in 4-allylbenzyl chrysanthemate (ABC) and 2,6- dimethyl-4-allylbenzyl chrysanthemate (DMABC). The insecticidal activity of ABC and DMABC12 suggested the present study, to determine whether unsaturated side- chains, attached to alternative aromatic nuclei giving similar overall spatial character- istics, could produce insecticidal chrysanthemates. This paper complements one in which the syntheses of most of the compounds used are de~cribed. '~ A direct outcome of the work was the discovery of 5-benzyl-3-furylmethyl alcohol, which gives some of the most potent esters with pyrethrin-like activity. A brief summary of this work was published previou~ly.'~

a Part V: Pestic. Sri. 1972,3, 25. 49 I

492 M. Elliott, A. W. Farnham, N. F. Janes and P. H. Needham

2. Experimental

2.1. Materials

The syntheses of most of the compounds have already been described.', 5-Benzyl-l,2,4-oxadiazol-3-ylmethyl (+)-trans-chrysanthemate.-5-Benzyl-3 - methoxy- carbonyl - 1,2,4 - oxadiazole,15 m.p. 79" (lit. 82-83") (peaks at z 2.7 (m, phenyl) 5.78 (s, CH2) and 6.07 (s, OMe)), M = 218 (mass spectrum) was reduced by a described procedure13 to 5-benzyl-3-hydroxymethyl-1,2,4-oxadiazole, n g 1.5470, peaks at z 2.8 (m, phenyl) 5.45 (s, CH,O) 5.90 (s, CH,Ph) and 8.75 (s, OH), M = 190(mass spectrum), which was esterified with (+)-trans-chrysanthemic acid chloride to give the ester, n'," 1.5235, peaks at z 2.7 (m, phenyl) 4.90 (s, CH20) 5.82 (s, CH,Ph) and peaks from chrysanthemate (cf.9. 5-Buta-l,3-dienyl-2-methyl-3-furylmethyl (+)-trans-chrysanthemate (with D. A. Pulman).-Ethyl 5-chloromethyl-2-methyl-3-furoate16 (5.05 g), triphenylphosphine (6.55 g) and benzene (50 ml) were heated to reflux for 24 h, after which thephosphonium salt (9.55 g), m.p. 235", was collected by filtration. The phosphorane generated from this salt (4.8 g) with sodamide in liquid ammonia (cf.17) was reacted with acrolein (1.5 g) in benzene (100 ml) at 20" for 30 min, then processed as in similar cases.l7 Distillation gave ethyl 5-buta-1,3-dienyl-2-methyl-3-furoate (0.5 g), b.p. 84-SS"jO. 1 mm, n'," 1.5532, peaks at z 3.1-4.1 (m, 3 x = CH) 4.6-5.0 (m, = CH,) 5.76 (9, 7 Hz, CH2CH3) 7.43 (s, CH,) and 8.68 (t, 7 Hz, CH2CH3) with small impurity peaks in the z 7-8 region. Reduction by the general methodI3 gave 5-buta-I,3-dienyl-2-methyl-3-furylmethyl alcohol, ng 1.5678, peaks at z 3.3-4.3 (m, 3x =CH) 4.6-5.1 (rn,=CH2) 5.8 (s, CH,O) 6.0 (s, OH) and 7.8 (2 x s, CH,) (2 isomers) also with impurity peaks at z 7-9. Reaction with (+)-trans-chrysanthemic acid chloride gave the ester, nZ,O 1.5341, peaks at z 5.2 (CH,O) and as anticipated for rest of molecule. Prothrin, a gift of Professor Y. Katsuda, Dainippon Jotyugiku Co. Ltd, Osaka, was identical in biological and chemical properties with the compound (entry 15 in Table 1) synthesized by us.',

2.2. Methods

Insecticidal activities were determined as LD,, values from probit analysis of mortality counts after topical application, as described previo~sly.~ In many of the tests, 5- benzyl-3-furylmethyl (+)-cis,trans-chrysanthemate (35 % cis) (resmethrin) was included as standard.

3. Results

The results are summarised in Table 1 which shows LD50 values for houseflies, Musca domestica L. (HF) and mustard beetles, Phaedon cochzeariae Fab. (MB). For those tests where resmethrin was included as a standard, relative toxicities are also givcn (based on resmethrin = 100). For other tests, relative toxicities (usually accurate within a factor of 2) can be estimated from the LD,, values in separate tests.

Insecticidal activity of the pyrethrins and related compounds 493

TABLE 1, Toxicities of chrysanthernates to houseflies, Musca domestica L. (HF) and mustard beetles, Phaedon cochleariae Fab. (MB) by topical application

U CH20*CO*CH--CH.CH=C(CHS)2

\ /

CHj CH3 CH20.COCH-CH'CH=C(CHJX :Q!2

:lQ3 \ /

CH3 CH3 /"\

Furfuryl chrysanthemates (I) 3-Furylmethyl chrysanthemates (X)

Relative toxicity Substituents (resmethrin =

3-Furvlrnethvl & & 7 ? LD&g/insect) 100)

Compound Furfuryl number" series (I)

1 2 3 4 5 6 7 8 9

10 11 12 13* 1 4 ' ~ ~ 15" 16 17' 18' 19' 20' 21' 32 23 24 25' 26 27 28 29

30' 31 32' 33' 34 35

series (11) . H F MB

None

3-Me 5-Me

3,5-Me 4,5-Me

5-Benzyl

5-Propargyl 5-AIlyl

5-Benzyl-3-Me 4-Benzyl-5-Me

5-(p-tolyl)

None

2-Me 5-Me

2,5-Me 2,4,5-Me 5-Phenyl

5-Benzyl 5-Benzyl

5-AIlyl 5-(2-Methallyl) 5-AIlyl-2-Me 5-(2-MethaIlyI)-2-Me 5 4 I ,3-Butadienyl)-2-Me

5-Benzyl-2-Me 5-Benzyl-a-Me

5-(p-tolyl) 5-(p-chlorobenzyl) 5-(p-methoxybenzyl)

>2 &20 >10 -20 >10 -10

7.6 3.6 >10 2.5

8.6 3.6 -10 -0.3

1.3 0.75 5.6 1.4 3.3 1.4 4.7 $10 0.09 0.20 0.012 0.011 0.005 0.005 0.23 0.16

-0.08 1.2 0.11 1.5 0.085 2.2 0.066 0.44 0.085 0.33 1.7 >2 0.72 1.1 0.64 0.71 0.033 0.049 1.3 10 I .o 0.70 0.068 0.063 0.033 0.022 0.085 0.013

HF ~-

1.4

0.17 12

100 240

-20 7 .O

6.0

1 . 1 4.6 3.0

0.8 2.4

42

24 46 19

MB __ -

0.15

4.8 100 270

5 .O 0.7 0.87 0.6 3 .O 3.9

0.53 9.6 0.17

23 43 30

Miscellaneous compounds 5-Benzyl-3-thenyl 0.054 0.069 13 15 2-Benzyl-4-oxazolylrnethyl 0.77 -0.8 1.4 5-Benzyl- 1,2,4-oxadiazol-3-ylmethyl 0.28 0.28 Pyrethrin I 0.30 0.003 3.0 420 Allethrin 0.20 0.18 6.0 2.3 Tetramethrin 0.12 0.10 10 8.5

I ) Unless stated otherwise, compounds are (l)-cis,truns esters. I, NRDC 104 (resrnethrin). (+) -trans ester. ' NRDC 107 (bioresmethrin). Prothrin."'

494 M. Elliott, A. W. Farnham, N. F. Jane and P. H. Needham

4. Discussion

Pyrethrin I is less active than many synthetic pyrethroids to houseflies, but is superior to most insecticides, including other pyrethroids, to mustard Therefore, to detect useful trends in structure-activity relationships, activities against both insect species were evaluated. Initially, (5)-cis,frans esters, more easily synthesised, were compared; later, appropriate (+)-trans-chrysanthemates were made.

The structural features considered necessary for activity in the compounds tested are discussed in the paper13 describing the syntheses of the compounds. Both the unsubstituted compounds (entries 1 and 2 in Table I), like benzyl chrysanthemate,' had very little insecticidal activity. Although there was some increase in activity when a methyl group was introduced (compounds 3 4 , of the same order as for methylbenzyl chrysanthemate,' there was no clear distinction between the two series (I and 11). The polymethyl compounds (7-10) gave similar results. Therefore, because greater insecti- cidal activity had been found in 4-alkenyl- and 4-benzylbenzyl chry~anthemates, '~, '~ the effect ofintroducingunsaturated substituents into the furan nucleus was investigated.

To both HF and MB, a benzyl side-chain greatly increases insecticidal activity. The 5-benzylfurfuryl compound (12) was fairly readily synthesised and its promising activity stimulated development of synthetic methodsz0 (on which commercial produc- tion was later based) for the 5-benzyl-3-furylmethyl esters (13 and 14). Allyl-substituted compounds (16, 17 and 19) were moderately active to HF, of the same order as ABC, but not to MB. A 2'-methyl group on the allyl side-chain (compounds 18 and 20) gave little or no increase in activity with or without a methyl substituent on the nucleus.

Although not all possible methylated furfuryl and 3-furylmethyl chrysanthemates and related alkenyl compounds were synthesized, the great increase in activity obtained with the benzyl substituent suggested that active compounds had not been overlooked in the simpler series. Compound 21 was prepared because molecular models indicated that the butadienyl side-chain could adopt a steric position relative to the carboxyl group identical with that attainable in pyrethrin I, but it was inactive. The propargyl ester (15) was more active than the allyl compound (16) to MB, but not to HF, and the 5-propargyl-2-methyl compound from the 3-furylmethyl series (proparthrin, kikuthrin) is sufficiently active to have been investigated commercially.21

The results with alkenyl substituents suggest no clear structure-activity relationships, but definite conclusions were possible for variations in the most active series (compounds related to 13). Most benzyl-3-furylmethyl compounds were more active than the benzylfurfurql esters (22 and 23). Substitution by a methyl group in the furan nucleus (24) or by a methyl, chloro or methoxyl group in the aromatic nucleus (27-29) dim- inished activity. The a-methyl compound (25) had very much lower activity than the parent compound (13); such great diminution suggested steric interference with insecticidal action because elsewhere (e.g. 24 v. 27) methyl substitution produced much less difference in activity. Replacing the benzyl group by phenyl also decreased toxicity considerably to both HF and MB; in this compound (1 l), the axis of the phenyl group is coplanar with the furan nucleus, unlike the situation in the benzyl CompGund, so that here also, low activity may be caused by steric inaccessibility. Replacing the furan

Insecticidal activity of the pyrethrins and related compounds 495

oxygen by sulphur (30) or one or two of the CH groups by nitrogen to give oxazole (31) or oxadiazole (32) also diminished toxicity.

The unsubstituted 5-benzyl-3-furylmethyl group therefore gives insecticides almost as active to MB as the (S)-pyrethronyl unit (as in pyrethrin I), and considerably more active to HF. In spite of the striking differences between the two units, e.g. one is

derived from a primary alcohol, the other from a secondary, all modifications to the ester (13) that were investigated decreased activity by at least half. 5-Benzyl-3- furylmethyl alcohol is now used commercially in esters with (_+)-cis,trans-chrysanthemic acid (NRDC 104, resmethrin), with the (+)-trans-acid (NRDC 107, bioresmethrin) and with the (+)-cis-acid (NRDC 119, cismethrin, RU 12,06322). Its esters withcyclopropane acids bearing other 3-substituents are even more potent i n s e c t i ~ i d e s . ~ ~ . ~ ~

Acknowledgements

We thank the National Research Development Corporation for interest and financial support, and Professor Y. Katsuda for a commercial sample of prothrin.

The compounds described are protected by British Patents 1,168,797-1,186,799 and corresponding Foreign Applications.

References

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Academic Press. 1973, pp. 56-100. 3. Schechter, M. S . ; Green, N.; LaForge, F. B. 1. Amer. Chem. Soc. 1949,71. 3165. 4. Roark, R. C. U S . Depf Agr., Bur. Entomol. Plant Quarantine E-846 1952. Roark, R. C.; Nelson,

R. H. US. Dept Agr., ARS3.7-12, 1955. 5. Staudinger, H.; Ruzicka, L. Helo. Chim. Acta, 1924, 7,448. 6. Synerholm, M. E. US. Pafent 2,458,656. 1949. 7. Barthel, W. F. Wld Rev. Pest Control 1964,3,97. 8. Elliott, M.; Janes, N. F.; Jeffs, K. A. Pesric. Sci. 1970,1,49. 9. Elliott, M.; Farnham, A. W.; Ford, M. G.: Janes, N. F.; Needham, P. H. Pestic. Sci. 1972,3,25.

10. Elliott, M. Chemy Ind. 1969, p. 776. 11. Elliott, M. Bull. WldHlth Org. 1971,44.315. 12. Elliott, M.; Janes, N. F.; Jeffs, K . A.; Needham, P. H.; Sawicki, R. M. Nature, Lond. 1965,207,

938. 13. Elliott, M.; Janes, N. F.; Pearson, 8. C. Pestic. Sci. 1971,2,243. 14. Elliott, M.; Farnham, A. W.; Janes, N. F. : Needham, P. H.; Pearson, B. C. Nature, Lond. 1967,

213,493. 15. Hellrnan, H.; Piechota, H.; Schwierisch, W. Chem. Ber. 1961, 94, 757. 16. Winberg, H. E.; Fawcett, F. S.; Mochel, W. E.; Theobald, C. W. J. Amer. Chem. Soc. 1960,82,

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496 M. Elliott, A. W. Farnham, N. F. Janes and P. H. Needham

19. Elliott, M.; Janes, N. F.; Jeffs, K. A.; Needham, P. H.; Sawicki, R. M.; Stevenson, J. H. Proc. 3rd Br. Insectic. Fungic. Conf. Brighton 1965, p. 432.

20. Elliott, M.; Janes, N. F.; Pearson, B. C . J. chem. Soc. C. 1971, p. 2551. 21. Nakanishi, M.; Mukai, T.; Inamasu, S.; Yamanaka, T.; Matsuo, H.; Taira, S.; Tsuruda, M.

Botyu-Kagaku 1970,35, 87. 22. Lhoste, J.; Martel, J.; Rauch, F. Meded. Fac. Landbouwwetensch Rijksuniv. Gent 1971,36, 978. 23. Elliott, M.; Farnham, A. W.; Janes, N. F.; Needham, P. H.; Pulman, D. A. Nafure, Land. 1973,

244,456. 24. Velluz, L.; Martel, J.; Nomine, G. C.r. hebd. SCanc. Acad. Sci. Paris 1969, 268, 2199.