Pestic. Sci. 1986,17,459-463

A Note on the Synthesis and Biological Activity of Polyfluorobenzyl Pyrethroid Esters“

Edward McDonald, and Nazim Punja

ICI Plant Protection Division, Jealott’s Hill Research Station, Bracknell

(Revised manuscript received 27 February 1986)

The pentaflurobenzyl esters of acids related to chrysanthemic acid are active insecticides. Formal substitution of one or more of the fluorines in pentafluoro- benzyl alcohol has led to a new series of insecticidal compounds. The synthesis of these esters has some novel aspects. Key factors contributing to the insecticidal activity of these esters in soil, particularly against corn root w o w , are discussed, including rates of degradation and vapour pressure.

1. Introduction

Biological activity has traditionally been sought by screening large numbers of assorted chemicals including natural products. This approach has provided relatively few classes of insecticide (organochlorines, organophosphates, carbamates) but within each class a variety of products has been invented and commercialised.

In the early 1970s M. Elliott and co-workers at ARC Rothamsted, England, discovered the first photostable synthetic pyrethroids. The compounds of his invention, particularly permethrin, cypermethrin and deltamethrin were licensed to several companies, and their products have now achieved registration and substantial sales throughout the world. Elliott’s achievements’ paved the way for the invention and commercialisation of further compounds, e.g. fenvalerate by Sumitomo, and cyhalothrin (Figure 1) by ICI. All these pyrethroids have a broad spectrum of activity and their major agrochemical use is as foliar contact insecticides especially to control lepidopterous pests in cotton.

Figure 1. Chemical structures of cyhalothrin and the pentafluorobenzyl ester of cyhalothrin acid (I).

“An extended summary of the paper presented at the ACS Agrochemical Symposium ‘Insecticidal Activity of the Pyrethroids’ at Chicago, 11 September 1985, and at the Pesticides Group, Society of Chemical Industry, meeting in London, 21 October 1985.

459

E. McDonald and N. Pun@

0 /

CH2 I

0 /

OC2H5 CH, OC2HJ CH,

Figure 2. Nucleophilic substitution of protected pentafluorobenzyl alcohol.

Polyfluombenzyl pyrethoid esters 461

0 /

F \ F6: E

F \ '0: 111

Figure 3. Electrophilic substitution of 1,2,4,5-tetrafluorobenzene (m) and the preparation of III from hexduorobenzene. E=alkyl, allyl, benzyl, CH(OH)R, COR, COOH (here R=alkyl);

0 0 0

SCH3 [-tS-CHr)SCH,]; NOz, Si(CH3)3, P(OC2H&. I1 II I1

I I 0

When the carboxylic acid moiety of cyhalothrin was esterified with a range of alcohols the pentafluorobenzyl ester (I, Figure 1) was found to have excellent activity against Diubrotica balteutub larvae (ca 30 times more active than cyhalothrin after one week in soil). This raised the possibility that a new pyrethroid might be developed for use as a soil insecticide.

2. Synthesis of analogues

In order to optimise the biological effect, a range of fluorobenzyl alcohols was required. Initially esters of tetrafluorobenzyl alcohols with substituents (alkyl, haloalkyl, phenyl, phenoxy), at C-2, 3 and 4 were prepared but it was soon established that biological activity was associated mainly with 4-substitution. Methods had to be found for synthesising a wide range of analogues and the principal ones, nucleophilic substitution, electrophilic substitution and secondary transformations are summarised here (Figures 2, 3 and 4).

Reaction of protected pentafluorobenzyl alcohol (Figure 2, II) with nucleophiles led predominantly to 4-substitution. The site of substitution was easily proved by "F-n.m.r. spectroscopy. The reaction worked well with a wide range of 0, N, S and C-nucleophiles.' (Figure 2a).

With an excess of nucleophile and longer reaction time a second substituent was introduced, usually at C-2 (Figure 2b) but ethyl acetoacetate reacted in a special way to give a bicyclic product (Figure 2c).

bThis species was used as an indicator for D. undecirnpunctata (corn root-worm), the major pest of maize in mid-westem USA.

462 E. McDonald and N. Punja

C02Me I

COzMe I

CH7OH I -

F \ F<>; + '\ 'Q' 4 '\ 'Q' ' <:H2Br CHZX CHZX

(V)

Figure 4. Secondary transformation reactions from V; where X=OR (OMe, OEt, OPr, OPh), SR (SEt+SO,Et) and NRz (NHMe, Me2, NEt,).

For electrophilic substitution 1, 2, 4, 5-tetrafluorobenzene (Figure 3, 111) was a useful starting material. It could be lithiated, then reacted with an electrophile, and these steps could then be repeated with a second electrophile. These reactions gave access to an extended range of 4-substituents,2 as well as affording an alternative route to some of the alcohols shown in Figure 2a.

It is interesting to note the simple route by which the starting material could be ~ repa red .~ Hexafluorobenzene (IV) reacts with hydrazine/KOH with steady evolution of nitrogen to give the required product, III. The reaction presumably proceeds via the mechanism shown in Figure 3.

For the method involving secondary transformations the benzyl bromide intermediate V was reacted with 0, N, and S nucleophiles4 to give a further set of examples (Figure 4).

3. Discussion

After removal of protecting groups the alcohols from the foregoing examples were esterified with pyrethroid acids. Structure-activity trends for the esters prepared from 'cyhalothrin-acid' were as follows.

Stereochemistry: (lR)cis>(lR)trans>(lS); a-substituent: H>CN>Me; 4-substituent: (a) alkyl, allybaryl, benzyl (b) 0-alkyl, CH20-alkyl>S-alkyl, S-aryb NOz, CH2-N(alkyl)* (c) F>Cl>Br.

It is interesting to note that the stereochemical trends were the same in this series as in earlier ones but unexpectedly, introduction of an a-cyano substituent led to a significant drop in biological activity. Attempts to correlate activity with various physical parameters did not generate any useful QSAR.

Table 1. Some comparative electrophysiological, degradation and vapour pressure results of pyrethroids

Property Permethrin Cypermethrin Cyhalothrin I VI VII

EC, (M) H. vircscenr 8x10-" 6.8x10-" l. lxlO-" 5 . 0 ~ 1 0 - ' ~ - - ECso (M) D. Balrearu 1 x 10-16 5x10-17 1~10-18 10-14-10-15 - - Soil half-life (days)b - 14 27 - 40

In-vitro potency"

- - Hydrolytic half-life (days)c - 1 7 - 30

Vawur pressure (20°C Nm-*) 2.7x10-' 1.9x10-' 5 . 3 ~ 1 0 - ~ - - 6.7x10-' ~~~ ~

'Miniature excitatory post-synaptic potential assay. *Sandy loam, 20". aerobic. 'Aqueous buffer pH9,25"C, 0.1 gml-I). The structure for compounds I, VI and M is:

Polyfluorobenzyl pyrethroid esters 463

To explain why this new series of pyrethroids is so much more effective in soil than the phenoxybenzyl esters three main factors were considered, namely: intrinsic potency rates of breakdown in soil, and availability to the pest in soil. Using an electrophysiological assay which recorded the increase in ‘miniatures’ (miniature excitatory post-synaptic potentials) as a function of pyrethroid concentration, fluorobenzyl esters were found to have similar symptomology but lower potency against both Heliothis and Diabrotica larvae than standard phenoxybenzyl esters (Table 1).

Hydrolysis rates favoured the tetrafluorobenzyl esters but were not markedly different from those found for conventional phenoxybenzyl type!; and the rates of soil metabolism were even closer.

Vapour pressure determinations showed that 2onventional pyrethroids with the ‘heavy’ phenoxy substituent have a significantly lower volatility than the simple fluorobenzyl series. This seems to be the key factor in the control of soil pests by the new series of tetrafluorobenzyl esters, which probably act via a vapour action rather than a contact effect.

Acknowledgements The work described here has been a team effort involving a variety of specialists in chemistry and biology, including P. Bentley and E. Savins (Synthesis), Dr A. R. Jutsum (Entomology), Dr S. N. Irving (Electrophysiology), Dr D. Worthington, Dr N. H. Anderson and T. E. M. Fraser (Physical Chemistry), Dr J. Leahey and D. W. Bewick (Stability Studies).

References 1. Elliott, M.; Janes, N. Chem. SOC. Rev. 1979, 7 , 473. 2. Punja, N. US Potent 4405610, 1983. 3. Punja, N. US Parent 4370346, 1983. 4. Birchall, J. M.; Hazeldine, R. N.; Parkinson, A. R. J . Chem. SOC. 1962, 4966.