Synthetic Pyrethroids -A New Class of Insecticide By M. Elliott and N. F. Janes DEPARTMENT OF INSECTICIDES AND FUNGICIDES, ROTHAMSTED EXPERIMENTAL STATION, HARPENDEN, HERTS., AL5 254 1 Introduction Pyrethroid insecticides have evolved in a classical sequence: activity observed in a natural extract, compounds responsible isolated and identified, increasingly active analogues synthesized. Recent synthetic pyrethroids are among the most potent pesticides known, and at present are being evaluated for many applications and as possible replacements for some of the organophosphate, carbamate, or organochlorine insecticides now considered unacceptable. Few classes of bio- logically active compound have such great potential for structural variation with retention or enhancement of potency.The insecticidal properties of the powder from pyrethrum flowers (Chrysan-themum cinerariaefulium)were being exploited in Europe by the 19th century’ when few effective insecticides were available. Therefore as soon as the nature of the active constituents was known2 synthetic analogues were investigated2 in attempts to elucidate the principles governing their activity and to discover simpler or more potent insecticides. New compounds have been discovered with greater insecticidal activity or faster knockdown than the natural esters and, in some cases, enhanced photostability and diminished mammalian toxicity. This survey traces the development of the present wide range of synthetic compounds, and the growing comprehension of the principles which govern their activity.It reviews most relevant publications up to Spring 1978; the profusion of information, especially in patents published in the past three years, has made detailed coverage of all topics impracticable. Previously, the chemistry of the natural estersY3s4 the relationship between structure and activity5-8 and the C. B. Gnadinger, ‘Pyrethrum Flowers’. McLaughlin Gormley King Co., Minneapolis, ’H. 1936. Staudinger and L. Ruzicka, Helv. Chim. Ada, 1924, 7, 177, 201, 212, 236, 245, 390, 448. a L. Crombie and M. Elliott, Fortsrhr. Chem. org. Nafursfofle, 1961, 19, 120. M. Elliott and N. F. Janes, in ‘Pyrethrum-the Natural Insecticide’, ed. J. E. Casida, Academic Press, New York, 1973, p. 56.ti M. Elliott, Pyrethrum Post, 1951, 2 (3), 18. M. Elliott, Chem. and Ind., 1969, 776. M. Elliott, Bull. World Health Organ., 1971, 44, 315. M. Elliott, A. W. Farnham, N. F. Janes, P. H. Needham, and D. A. Pulman, in ‘Mechanism of Pesticide Action’, ed. G. C. Kohn, ACS Symposium Series No. 2, Americ’an Chemical Society, Washington, DC., 1974, p. 80. Synthetic Pyrethroids-A New Class of Insecticitte potential of pyrethroids as economic insecticidesg-11 have been reviewed. Proceedings of recent symposia on ‘Synthetic Pyrethroids’ and ‘Newer Appli- cations of Pyrethroids’ have been published.12J3 Two valuable alerting services cover the subject.14~15 Large areas of pyrethrum are cultivated in high altitude regions of Kenya, Tanzania, and Ecuador, for commercial extraction of the natural insecticide.The structures and absolute configurations (Figure 1a) of the six insecticidal esters in the extract have been fully confirmed by physical techniques.16-19 R‘ R’ CHa=CH- -CHI PyrethrinI CH,- -CHI CincrinI CHs-CHa- -CHI JasmolinI CHa=CH- --COSCH, Pyrethrin I1 CH,- -CO,CHs Cinerin I1 CHs-CHa- -COpCHa Jasmolin I1 (a) natural esters (b) most active isomer in fenvalerate Figure 1 (a) TIte six natural esters; (6) a recent synthetic pyrethroid 2 Definition Although it is accepted that pyrethroids interfere with nerve action, the precise M. Elliott, in ‘The Future for Insecticides: Needs and Prospects’, ed. R. L. Metcalf and J. J. McKelvey, jun., Wiley, New York, 1976, p.163. lo M. Elliott, N.F. Janes, and C. Potter, Ann. Rev.Ent., 1978,23,443. l1 M. Elliott, Env. Health Persp., 1976, 14, 3. l* ‘Synthetic Pyrethroids’, ACS Symposium Series No. 42, ed. M. Elliott, American Chemical Society, Washington, DC., 1977. la Pesticide Sci., 1977, 8, 236-330. (sX~L\ l4 Bibliography of Insecticide Materials of Vegetable Origin, Tropical Products Institute, London. Is Research Service Bibliographies, Series 4, ‘Pyrethrins and Pyrethrum Insecticides’, Public Library of South Australia, Adelaide. l6 A. F.Bramwell, L. Crombie, P. Hemesley, G. Pattenden, M.Elliott, and N. F. Janes, Tetrahedron, 1969, 25, 1727. l7 L. Crombie, G. Pattenden, and D. J. Simmonds, J.C.S. Perkin I, 1975, 1500. G. Pattenden, L.Crombie, and P.Hemesley, Org. Mass Spectrometry, 1973, 7, 719. l* M. J. Begley, L. Crombie, D. J. Simmonds, and D. A. Whiting, J.C.S. Perkin I, 1974, 1230. Elliott and Janes system attacked in insects is not known,neither is their mode of action well enough understood to provide a basis for recognising an insecticide as a pyre-throid. When developments since 1974are considered, basing a definition on structural affinities is also problematical, for, with the exception that they are both esters, little superficial connection is apparent between pyrethrin I and a recent important active compound, fenvalerate20I2l (Figure 1). However, strong evidence for a definite relationship (to be discussed) suggests that fenvalerate and pyrethrin I should both be considered members of the same class.3 Structural Variations and Insecticidal Activity Almost all active pyrethroids are esters. The constituent acids and alcohols, and simple derivatives of them, are practically inactive, as Staudinger and Ruzicka2 demonstrated in their remarkable pioneering work. Much evidence suggests that high insecticidal activity depends on the overall shape of the molecule,22 with certain key structural features appropriately disposed; other properties such as electron density and polarizability are of secondary importance. Almost every part of the parent molecule has now been replaced by a unit of analogous struc- ture without losing insecticidal activity; yet other changes, apparently no more drastic, produce inactive compounds.Because of this strong dependence of the activity of pyrethroids on structural shape, the effects of structural variation are analysed in relation to the segmented structure ofpyrethrin I as shown in Figure 2. In the following sections different structures are represented as combinations Figure 2 Segmentation scheme for pyrethrin I of units directly comparable to those in pyrethrin I, and the most active natural ester, and the importance of each unit is indicated approximately by a one- to three-star rating of its overall performance. This modular approach to systematize the discussion of structural variations reflects a practical basis for designing 2o N. Ohno, K. Fujimoto, Y.Okuno, T. Mizutani, M. Hirano, N. Itaya, T.Honda, and H. Yoshioka, Pesticide Sci., 1976,7,24I ;Jap. P. 73 06 528. 21 A. N. Clements and T. E. May, Pesticide Sci., 1977, 8, 661. 22 M. Elliott, in ref. 12. 475 Synthetic Pyrethroids-A New Class of Insecticide synthetic pyrethroids which has led to a succession of potent in~ecticides~3-~7 and helped to establish the principles, reviewed here, underlying activity.28 As in other applications of additivity principles to interpret the results of variations assumed to be independent, conclusions must be qualified by recog- nizing that effects of altering one segment of the molecule may be influenced by the nature of the other groups present and may differ markedly between species of insect. Relative activities are often difficult to assess because many bioassay procedures emphasize knockdown rather than kill, and many patents lack data useful for external comparisons.Segment A.-A centre of unsaturation at this site in the molecule is essential for high activity, but the structures of the natural esters (I-111), all active insecticides, show that variation is possible. Synthetic analogues with vinyl (IV) or ethynyl (VI) groups here have extended the range, but substituents on them (V, VI) do not improve activity. Rating' Ref: Variation Rating Ref: V1"I111 ,111, 111 * 30, 32-34 natural IN***Iesters (Fig. la) ** * * 23, 29 * 30,31 23 M.Elliott, N. F. Janes, K. A. Jeffs, P. H. Needham, and R. M. Sawicki, Nature, 1965,207, 938. M. Elliott, A.W. Farnham, N. F. Janes, P. H. Needham, and B. C. Pearson, Nature, 1967, 213, 493. p5 M. Elliott, A. W. Farnham, N. F. Janes, P. H. Needham, and D. A. Pulman, Nature, 1973, 244,456. a6 (a) M. Elliott, A. W. Farnham, N. F. Janes, P. H. Needham, D. A. Pulman, and J. H. Stevenson, Nature, 1973, 246, 169; (6) 'Proceedings of the seventh British Insecticide and Fungicide Conference (Brighton)', 1973, p. 721. M. Elliott, A. W. Farnham, N. F. Janes, P. H. Needham, and D. A. Pulman, Nature, 1974, 248, 7 10. M. Elliott, N. F. Janes, and I. J. Graham-Bryce, 'Proceedings of the eighth British Insecticide and Fungicide Conference (Brighton)', 1975, p. 373. M. S. Schechter, N. Oreen, and F. B. LaForge, J. Amer. Chem. Soc., 1949, 71, 3165. *O W.A. Gersdorff and N. Mitlin,J. Econ. Entomol., 1951,44, 70. 31 P. D. Bentley and N. Punja, in ref. 12. 32 M. Nakanishi, T. Mukai, S. Inamasu, T. Yamanaka, H. Matsuo, S. Taira, and M. Tsurada, Butyu-Kngaku, 1970, 35, 87. a3 H. Ogami, Y.Yoshida, Y. Katsuda, J. Miyamoto, and T. Kadota, Bcfyu-Kagaku, 1970, 35,45. J4 C. Corral and M. Elliott, J. Sci. Food Agric., 1965, 16, 514. 35 M. Elliott, N. F. Janes, and B. C. Pearson, J. Sci. Food Agric., 1967, 18, 325, 476 Elliott and Janes The most important unsaturated unit identified so far is phenyl (VII), present in all recently discovered potent pyrethroids (see Table 1 in Section 4) as a phenoxy or benzyl group (0or CH2 in segment B); substitution on ~henyl~~-~* or its replacement by a hetero-aromatic rings9 usually diminishes activity.Segment B.-This unit is methylene in the natural esters and in many active synthetic compounds (see Table 1). Its function is steric rather than chemical, for replacement by 0 generally produces a favourable change of properties of great practical importance when segment A is pheny1.7~40 Other replacements 011-VI) usually diminish activity. Segment B Variation Rating Ref. Variation Rating Ref. I I * * see text IV *y ** 7 I1 y’ * * * see text v 0 * 37,41 I11 7’ * 40 * 42,43 e-g-J ,o When segments A and B are combined as a cyclopentenyl (~yclethrin,~~) or a penta-lY3-dienyl (isopyrethrin I,45) side-chain, activity is also less. Segment C.-Recognition of the significance of this structural unit has been very important in the discovery of the newer synthetic pyrethroids. The methyl group on C-3 of the cyclopentenone ring (a consequence of the biosynthetic route, which may involve acetate46) apparently affects activity little, for one normethyl compound was more potent than the parent (benzyl sub- stituted in segments A and B).Apart from this variation, no pyrethroids in which segment D is incorporated in the same ring as segment c show significant activity. However, with segment D outside the ring, there are many effective variations (III-WII) with planar or near planar aromatic heteroaromatic rings or acyclic M. Elliott, N. F. Janes, and M. C. Payne, J. Chem. SOC. (0,1971,2548. M. Elliott, A. W. Farnham, N. F. Janes, and P.H. Needham, Pesticide Sci., 1974, 5, 491. T. Matsuo, N. Itaya, T. Mizutani, N. Ohno, K. Fujimoto, Y. Okuno, and H. Yoshioka, Agric. Biol. Chem., 1976, 40,247. M. Matsui, F. B. LaForge, N. Green, and M. S. Schechter, J. Amer. Chem. SOC., 1952,74, 2181. I0 K. Fujimoto, N. Itaya, Y. Okuno, T. Kadota, and Y. Yamaguchi, Agric. Biol. Chem., 1973,37,268 1. W. A. Gersdorf€ and N. Mitlin, J. Econ. Entomol., 1954, 47, 888. Fr. P. 2043019/1971.M. Elliott, A. W. Farnham, N. F. Janes, M. M. Petersen, and P. H. Needham, unpublished results. I4 H. L. Haynes, H. R. Guest, H. A. Stansbury, A. A. Sousa, and A. J. Borash, Contrib.. Boyce Thompson Inst., 1954, 18, 1. M. Elliott, J. Chem. SOC.,1964, 888. Ref. 4 p. 108. 477 Synthetic Pyrethroids-A New Class of Insecticide units.By finding that an ester of piperonyl alcohol had insecticidal activity, Staudinger and Ruzicka2 established a precedent for replacing cyclopentenonyl by benzyl. An increase in activity when an unsaturated substituent was placed at position 4 3923 confirmed the structural analogy. Later, some 3-substituted benzenes (IV)were shown to be even more acti~e.~~~~ Heteroaromatic replace- ments, especially furan, close in size and shape to cyclopentenone, also have activity, which is greatest when 3,5-subst i t uted.5~240ther heterocyclic variations such as thiophene,47 and rings with two heteroatoms, are generally less insecticidal. Segment C Variation Rating Ref. Variation Rating Ref. **. natural esters *** see text x=o,s ** 36 VI ,&’ ** 48 ** see text VII 4@0 * 49, 50 *** see text esp.R1 =H Ra =C1,CHS Many acyclic compounds have been investigated (VI-VIII) but, although relatively easily synthesized, in general they are less active insecticides than the cyclic compounds. Segments A +B +C.-Some insecticidal esters are derived from alcohols which are not obvious combinations of the segments discussed, yet are clearly pyre- 47 B.P. 1265437/1972. 48 B.P. 1226788/1971. 49 B.P. 1313554/1973.RothamstedAnn. Rep. 1971, Pt. I, p. 188. 61 K.Sota, T.Amano, M. Aida, K. Noda, A. Hayashi, and I. Tanaka, Agric. Biol. Chem., 1971,35,968; 37,1019. aa RothamstedAnn. Rep. 1973, Pt. I, p. 169. Elliott and Janes SegmentsA + B + C Variation Rating Ref.Variation Rating Ref. 0 esp. R1 + R* = (CHJ. throids because they are only active when they incorporate pyrethroid acids. Tetramethrin, the prototype, is a strong knockdown agent, and many alternatives for R1 and Rz are patented, Other variations in this category are based on benzo- furans54 and dihydrofurans.65 SegmentD.-All active pyrethroids reported so far are esters in which the carbon atom joined to the ester oxygen is sp3 hybridized; it is either incorporated in a cyclopentenone ring (variation I) or connects, for example, a benzene ring to the ester oxygen, when it is either primary (11) or secondary (JY-V). Phenyl estm (III) where it is spz hybridized are much less active. Segment D Variation Rating Ref: Variation Rating Ref.* natural esters IV y-= **R =N * * *R 56 27,38 other * 38,57 11 w *** see text 111 -* 6, 23 In the benzene and furan series, esters with an unsubstituted CHz group (variation II) are effective, but especially in 3-phenoxyhnzyl compounds, introduction of cyan0 produces dramatic changes in activity. When the absolute configuration of the -CH(CN)-group is S, activity is increased up to 15-foId2' over the unsubstituted compound (depending on the acid component present), whereas in the opposite configuration activity is depressed by as much as eight times;5* the pure esters required for this study were separated from diastereo- 68 T. Kato, K. Ueda,and K. Fujimoto, Agric. Biol. Chem., 1964,243,914.64 B.P. 1271 771/1972; U.S.P. 3816469/1974. so Ger. Offen. 2108932/1972; 2555581/1974. s* B.P. 1270315/1972. ST Ger. Offen. 2407024/1974; 2609704/1976. M. Elliott, N. F. Janes, D. A. Pulman, and D. M. Soderlund, Pesticide Sci.,1978,9, 105; M. Elliott, A. W. Farnham, N. F. Janes, and D. M. Soderlund, Pesticide Sci., 1978, 9, 112. 479 Synthetic Pyrethroids-A New Class of Insecticide isomeric pairs chromatographically. The C-4 epimers of cyclopentenolone esters apparently differ less in activity (see discussion58). The a-ethynyl compounds (IV) are also active. SegmentsC + D.-If appropriate sectors of the flexible pyrethroid structure could be maintained by suitable additional connections in the conformation adopted at Segments C + D Variation Rating Ref.Variation Rating Ref. X = 0,S, CHI, CO the site of action, particularly active compounds might be produced. In variation (11), several alternative extra connecting units have been examined. Activity was generally small, comparable to that of esters of most other benzyl alcohols with a-substituents (above); the most interesting compound (11, X = 0, R = 7-Me) has moderate activity.sO Segment E.-Even small alterations in this unit at the centre of the molecule would be expected to produce large overall stereochemical differences with consequent effects on potency; the variations listed (11-VIII) do indeed diminish or remove activity. In addition, there is evidence from physical properties such as dipole momentss7 that in esters one of the two conformations in which all four bonds are coplanar is strongly preferred.X-ray analytical evidence for all pyrethroids e~aminedlS,6*,6~ shows this to be a consistent feature, therefore the ester unit in pyrethroids may have properties not reproduced by alternative structures. The relative ease of ester cleavage also exerts an important influence on mammalian toxicity (see below). 6* B.P. 1274595/1972; U.S.P. 3647857/1972; Jap. Kokai, 74 26421-2; M. Elliott, A. W. Farnham, N. F. Janes, P. H. Needham, and B. C. Pearson, unpublished results. O0 Y. Inoue, S. Ohono, T. Mimno, Y. Yura, and K. Murayama, in ref. 12. 61 P. E. Berteau and J. E. Casida, J. Agric. Food Chem., 1969, 17, 931. 6a M. R. Altamura, L.Long, and T. Hasselstrom, J. Org. Chem., 1962, 27, 594. ea M. H. Black, in ref. 12. e* M. Matsui, K. Yamashita, M. Miyano, S. Kitamuka, Y. Suzuki, and M. Hamuro, Bull. Agric. Chem. SOC. Japan, 1956,20, 89; Belg. P. 852082. O6 Jap. P. 61 8498. J. R. Reid and R. S. Marmor, J. Org. Chem., 1978, 43, 999. O7 L. E. Sutton, in 'Determination of Organic Structures by Physical Methods', ed. E. A. Braude and F. Nachod, Academic Press, New York, 1955, Vol. I. p. 405. J. D. Owen, J.C.S. Perkin I, 1975, 1865. J. D. Owen, J.C.S. Perkin I, 1976, 1231. Elliott and Janes Segment E Variation Rating Ref. Variation Rating Ref. I /O>f0 *** esters NH 0 I1 'Ir * 22, 23, 61 VI JL0, * 63 0 * 61 VII Hob *64 IV * 0 OH 0 It IX *66AOCI OMe Segmq@D + E.-As in the previous section, the evidence available indicates that compounds in which the central ester link is reversed show little or no activity.Segments D + E Variation Rating Ref. Variation Rating Ref. Segment F.-Both methyl groups (I) are present in the most active compounds72 but that cis to segment E has been shown,?* in some cases, to be the more important ;all known cyclopropyl esters with no substituents here are inactive. The function of the methyl groups in the active molecules is probably related more to their steric than to their chemical characteristics, because dichloro-01) 70J. J. K. Novak, J. Farkas, and F. Sorm, Coll. Czech. Chem. Comm.,1961,26,2090. 71 Ger. Offen. 255399111976; 271233311977.70 F. Barlow, M. Elliott, A. W. Farnham, A. B. Hadaway, N. F. Janes, P. H. Needham, and J. C. Wickham, Pesticide Sci., 1971, 2, 115. 7s P. E. Burt, M. Elliott, A. W. Farnham, N. F. Janes, P. H. Needham, and D. A. Pulman, Pesticide Sci., 1974, 5, 791. 74 T. Sugiyama, A. Kobayashi, and K. Yamashita, Agric. Biol.Chem., 1974, 38, 979. Synthetic Pyrethroids-A New Class of Insecticide Segment F Variation Rating Ref. Variation Rating Ref. y *** '7estersnatural 111 ** 71 and spiro-(111) substituted cyclopropanes show significant insecticidal activity, but esters with larger groups are less active. Inversion of stereochemistry at C-1 (IV) eliminates or greatly diminishes insecticidal activity in all dimethylcyclo- propane esters, except when there is no substituent at C-3.Cyclopropanes with an additional group at C-l,75 dimethyl a~iridines,~~ ~yclopropenes,~7and cyclob~tanes~~have little activity. Segment G.-Many compounds with diverse substituents in this segment are active, showing considerable latitude in requirements; however, certain small changes here can influence activity profoundly. Activity increases with the num- ber of C-3 methyl groups. As with segment F, alternative groups (111, IV) with steric properties similar to (11) are effective. However, only compounds with unsaturation in the substituent at C-3 are highly active. In the homologous series (VI) the but-l-enyl analogue (R1 =H, R2 =Et) with the same number of carbon atoms as the parent chrysanthemate (I), and possibly optimum polarity,85 is most active.Ethano-bridged compounds (VI; R1 +R2=(CH2)4) are also more potent than the corresponding chrysan- themates.86 3-Dienyl substituents (VI; R1 or R2 =alkenyl) give outstandingly active esters,25 the most effective being buta-l,3-dienyl and penta-l,3-dienyl, without a 1'-methyl Compounds with substituents containing hetero- 76 R. G. Bolton, Pesticide Sci., 1976,7,251. 76 M. P. Sammes and A. Rahman, J.C.S. Perkin I, 1972, 344. Jap. P. 71 21373 78 P. J. Crowley, Ph.D. Thesis, University of Manchester, 1974. 'Is M. Matsui and T. Kitahara, Agric. Biol. Chem., 1967, 31, 1143. 8o R. H. Davis and R. J. G. Searle, in ref. 12; U.S.P.3823177/1974. U.S.P. 3962458/1976. 8a M. Elliott, A. W. Farnham, N.F. Janes, P. H. Needham, and D. A. Pulman,Pesticide Sci., 1976,7,492. 83 J. Farkas, P. Kourim, and F. Sorm, Chem. Listy, 1958,52,695. 84 J. Lhoste and F. Rauch, Pesticide Sci., 1976, 7, 247. G. G. Briggs, M. Elliott, A. W. Farnham, N. F. Janes, P. H. Needham, D. A. Pulman, and S. R. Young, Pesticide Sci., 1976, 7, 236. L. Velluz, J. Martel, and G. Nomind, Compt. rend., 1969, 268,2199. 87 Ger. Offen. 2231436/1973; M. Elliott, A. W. Farnham, N. F. Janes, P. H. Needham, and D. A. Pulman, Pesticide Sci., 1976, 7, 499. 482 Elliott and Jms Segment G Rating Ref. Rating Re$ *** naturalI ‘I‘ esters VI *** see text I1 *** 61, 72, 79 VII *.+ see text I11 ** 72 VIII ** 84 IV ** 7, 80, 81 Ix ** 82 V ** 81 X Y0 ** 838-” atoms (VI;R1 =CH20Me, COzMe, etc; R2 =Me, halogen) are more polar, and especially active as knockdown agents.88 The activity of both cis-(VII; R1 =R2 = Me) and trans-chrysanthemates indicates the broad steric latitude within which unsaturated groups on C-3 confer activity.Replacing the methyl groups in either isomer with halogens (VIor VII; R1 = R2 = halogen) gives a considerable increase in insecticidal activify25-27,*9,90 and, with appropriate alcohols, the very valuable property of photostability (see Section 6). Variation (VIII) is present in the most powerful known knockdown agent. Of other variations reported, only the methoxyimino ether 0is more active than isobutenyl (I). Substituted ethynylgl and alkenylidene92 groups give esters of low activity.Substitution of methyl groups into otherwise active compounds greatly diminishes potency, a result ascribed to disturbance of the optimum conformation for activity.93 88 Ger. Offen. 2 109010/1971; 2449643/1975. M. Elliott, A. W. Farnham, N. F. Janes, P. H. Needham, and D. A. Pulman,PesticideSci., 1975,6,537. -> D. G. Brown: 0. F. Bodenstein, and S. J. Norton, J. Agric. Food Chem., 1973,21, 767; 1975,23, 1 15; Botyu-Kagaku, 1976,41, I. M. Yoshimoto, N. Ishida, and Y. Kishida, Chem. Pharm. Bull., 1972,20,2593; Rothamsted Ann. Rep. 1976, Pt. I, p. 163. g* Jap. Kokai 74 80242. 9s M. Elliott and N. F Janes, in ref. 12. Synthetic Pyrethroids-A New Class of Insecticide .~~Segments F +G.-Ohno et ~ 1 recently made the important discovery that acyclic units (11) can function as acidic components of esters with typical pyre- throid alcohols. The most effective compounds were p-substituted 3-methyl-2- phenylbutyric acids (11, R1 = R2 = Me, R3 = H, R4 =p-CI, p-CH3, or 3,4-methylenedioxy). Of the two optical forms of each of these acids, that related Segments F +G Variation Rating Ref.Variation Rating Ref. * * 20,94 II sterically to the (more active) (1R)-chrysanthemate gives the more active esters. The discovery of this variation not only provides significant evidence of the features essential for activity in this group of insecticides, but also considerably increases the potential range of practical insecticides; numerous replacements for the substituted phenyl group have already been described in patents.Variation (111) is particularly interesting because it may indicate a structural connection between DDT-type compounds and pyrethroids. Summary of structure-activity relationships.-The relative insecticidal activities of the many structures summarized in the previous sections are most straight- forwardly interpreted by assuming that the action of pyrethroids involves approach of an intact molecule to a site in the nervous system of the insect; a metabolic activation (comparable to the thion oxon transformation of organo- phosphates) is probably not involved. Greatest potency depends on at least two centres having appropriate chirality. For example, in chrysanthemates the configuration at C-1 must be [R], in 3-methylbutyrates the sterically equivalent [S]and in alcohols, for cyclopentenolones [S]at C-4,and for a-cyano-3-phenoxy-benzyl alcohol [S] at C-a.These conditions imply chirality in the interacting system at an important stage in the process of poisoning. Two centres of un- saturation at the extremities of the molecule (segments A and o) and a gem-@* N. Ohno, K. Fujimoto, Y. Okuno, T. Mizutani, M. Hirano, N. Itaya, T.Honda, and H. Yoshioka, Agric. Biol. Chem., 1974, 38, 881; M. Miyakado, N. Ohno, Y.Okuno, M. Hirano, K. Fujimoto, and H. Yoshioka, Agric. Biol. Chem., 1975, 39, 267; Ger. Offen. 2335 34711974. B5 G. Holan, D. F. O’Keefe, C. Virgona, and R. Walser, Nature, 1978,272, 735. 484 Elliott and Janes dimethyl group or its steric equivalent /?to the ester group are features of all potent pyrethroids so far described.Other segments of the molecule can be replaced by a wide range of sterically equivalent groups whose function may be to influence preferences for the relative conformations between segments, whilst maintaining suitable molecular polarity. 4 Chronological Survey of Effective Combinations The sequence of compounds in Table 1 reflects the progressive advance in under- standing structure-activity relationships and the associated development of commercially important insecticides. Although some compounds may be especially active against one particular pest at one stage in the life cycle (e.g. the 3-methyl-2-phenylbutyratesagainst lepidopterous larvae),20 experience has shown that the levels of activity against the two chosen species of insect in the Table provide a useful general indication of the practical value, where appro- priate, of the compound. By the compounds they synthesized and tested for insecticidal activity, Staudinger and Ruzicka2 showed remarkable insight into the structure-activity relationships of pyrethroids, and provided the foundation for modern concepts of the essential requirements for activity.However, the first major advance towards a commercially important synthetic pyrethroid was the versatile synthesis of cyclopentenolones by Schechter et al.29 who developed allethrin (4J),contain-ing all eight possible stereoisomers. Later one- and two-isomer preparations (3B, 4B) were developed commercially.Combining Chen and Barthel’s observationlOl of activity in various benzyl chrysanthemates with the need for unsaturation in segment A led to 4-ally1 and 4-allyl-2,6-dimethylbenzylchrysanthemates (65 and 75). This investigation was pursued by showing that benzene could be replaced by furan when benzyl was substituted for allyl, the optimum orientation found being in 5-benzyl-3-furylmethyl esters (9). In a parallel development, the chrysanthemate (85) of N-hydroxymethyl-tetrahydrophthalimide, a relatively inexpensive alcohol, was shown to have excellent knockdown action against flying insects, though relatively low insecti- cidal toxicity. 5-Benzyl-3-furylmethyl alcohol was then used to examine the relative activities of esters of novel acids.The tetramethylcyclopropane carboxylate (NRDC 108, 9L) is the most effective pyrethroid with no chiral centre. Ethanochrysanthemates (e.g. 9N) are generally somewhat more active than the corresponding chrysanthe- mates. Inverting stereochemistry at C-3, as in the cis-chrysanthemate (9F), increases activity to some species. The cis thiolactone compound, RU 15525 (9M) 96 L. Crombie, S. H. Harper, and F. C. Newman, J. Chem. SOC.,1956, 3963. g7 W. A. Gersdorff and N. Mitlin, J. Econ. Entomol., 1953, 46, 999. W. F. Barthel, Adv. Pest Control Res., 1961, 4, 33. gs B.P. 1223217/1971. loo M. Elliott, A. W. Farnham, M. G. Ford, N. F. Janes, and P. H. Needham, Pesticide Sci., 1972, 3,25. lol Y.L. Chen and W. F. Barthel, U.S.Dept. Agric. ARS, 33-23/1956. 485 Synthetic Pyrethroids-A New Class of Insecticide Table 1 Relative toxicities of pyrethroids to two insect species Name* Formula? First Pyrethrin I Allethrin ‘Bioallethrin’ ‘S-Bioallethrin’ Dimethrin Tetramethrin ‘ABC’ ‘DMABC’ Resmethrin Bioresmethrin ‘NRDC 108’ Prothrin ‘Ethanoresmethrin’ Proparthr in Cismethrin ‘3BBC‘ Phenothrin ‘Benzylnorthrin’ Bu tethrin ‘Cyan0 pheno thrin’ ‘NRDC 134’ Permethrin Biopermethrin ‘RU 15525’ Fenvalera t e ‘NRDC 167’ Decame t hr in ‘NRDC 173’ Cypermethrin Ref. Syn-thesized 1956 96 1949 29 1949 29 1953 97 1958 98 1964 53 1965 23 1965 23 1967 24 1967 24 1968 61,72 1967 33 1969 86 1970 32 1971 72 1971 7,99 1971 7940 1971 36 1971 51 1973 38 1973 25 1973 26 1973 26 1973 81 1973 20 1974 72 1974 27 1975 92,93 1975 92 Relative Toxicity (Bioresmethrin=100) to Houseflies Mustard beetles 2(+KD) 150 3(+KD) 1 5(+KD) 2 9(+KD) 4 0.3 0.2 2(+KD) 2 7 0.1 7 2 42 37 100 100 74 30 7 1.2 150 180 -6 42 52 15 53 31 72 7 17 14 -180 110 240 280 69 140 86 240 39(+KD) 52 47 100 200 160 2800 5500 390(+KD) 180 260 430 *The name by which the compound is referred to in at least one publication.If not in quotes, it is a proposed or accepted common name; ?Esters are designated by a number-letter combination to indicate the alcohol [formulae (1-12)] and acid [formulae (A-Q)] compo-nents, respectively; $Measured by topical application and probit analysis as described;loO molar basis a-e( f)-cis,frans-chrysanthemates of the following alcohols: a3,4-dimethyl-benzyl ; b5-propargylfurfuryl ; C2-methyl-5-propargy1-3 furylmethyl ; d3-benzylbenzyl ; e3-chloro-4-phenylbut-2-enyl is the most powerful knockdown agent yet described, but the trans isomer, and the corresponding 3-phenoxybenzyl esters, are not comparably active.Of the many mono- and poly-heterocyclic alcohols with a structural similarity Elliott and Janes (4) (RSat (2-4) // y&\ (6)R=H (7) R = CH, 0. R 0 (8) (B)X = Me px(F)X = Mep /wx(C)X = F (G)X=F'* '1 X (D) X = C1 7 (H)X = C1 (A) 0 (lR, trans) (E) X = Br 0 (I R, cis) (I)X = Br (J) X = Me ,p(K)X = CI 'I 0 0 (N)R' + R' = (CHJ,pOyR'(0)R1 = H,R2= MeI Ra (P) R' = H, R2= Et 0 3' 487 Synthetic Pyrethroids-A New Class of Insecticide to 5-benzyl-3-furylmethyl alcohol, only the propargyl compounds are significantly active, especially against flying insects. Butethrin with an acyclic unit for segment c shows useful activity to a limited number of species.In 1969, two research groups independently recognized the significance of the structural similarity between 5-benzyl-3-furylmethyl alcohol and benzyl alcohols with m-substituents such as benzyl and phenoxy. Esters from 3-phenoxybenzyl alcohol (10) were generally less active than those from 5-benzyl-3-furylmethyl alcohol (9) but activity in esters of a-ethynyl alcohols having been detected, a-cyano-3-benzylbenzyl and -3-phenoxybenzyl esters, e.g.(11B) were examined and found to have increased insecticidal activity. Initial indications of the valuable influence of changing the 3-substituent in dimethylcyclopropanechrboxylates(variations in segment G) stimulated synthesis and examination of analogues with a diverse range of groups at this position. Acids with dichloro- and dibromo-vinyl side chains formed exceptionally effective combinations with the three most powerful alcohols, (9A), (lOA), and (11A). The last two were not photolabile, so combining them with the com- parably stable dihalovinyl acids produced the first group of synthetic pyre- throids sufficiently persistent to control insect pests of agricultural and horti- cultural crops in sunlight.Of all the possible combinations in this group, the diasteremisomeric pair of esters (111) from the racemic cyanohydrin of 3-phenoxybenzaldehyde and [1 R,cis]-3-(2,2-di bromovinyl)-2,2-dimethylcyclopro-panecarboxylic acid was exceptionally active insecticidally, due almost entirely to one isomer (decamethrin; NRDC 161 ;121) which was separated by crystal- lization.2'958 Further, decamethrin is one of the few biologically active com- pounds suitable without modification for heavy atom X-ray analysis to establish absolute configuration.s8 Other combinations being developed for practical applications are the (k)-cis-,trans-dichlorovinyl esters of 3-phenoxybenzyl alcohol (permethrin; NRDC 143 ;10K) and of a-cyano-3-phenoxybenzyl alcohol (cypermethrin; NRDC 149; 11K).The [l R, trans]-difluorovinyl ester of 5-benzyl- 3-furylmethyl alcohol (9C)has a unique combination of rapid knockdown action against houseflies and killing power greater than bioresmethrin. The ester of a-cyano-3-phenoxybenzyl alcohol with 2-(4-chlorophenyl)-3- methylbutyric acid (fenvalerate; S-5602; 1 1Q) now being introduced also has valuable potential as an insecticide for agricultural use. The four named com- pounds (lOK, 11K, 121, and llQ), after extensive field trials throughout the world, are at present considered to have the most favourable combination of properties and prospects for practical application.5 Synthesis of Components of Pyrethroid Esters A. Alcohols.-Cyclopentenolones. The original route29 (or a variationlo2) to (f)-allethrolone (4A) is still used commercially, despite numerous published alter- lo*Fr. P. 1434224/1966. Elliott and Janes natives, some originating in the prostaglandin field; for reviews, see ref. 103. (S)-allethrolone(3A),obtained by resolving the hemi-succinate104 or -phthalatelo5 is necessary for the manufacture of S-bioallethrin (3B). The (R)-allethrolone can be rccycled by racemization of a derivative,Io6 or more directly, the R alcohol, as its mesyl derivative, undergoes an SN2 reaction with sodium chrysanthemate with inversion to give the required (4s) ester.lo7 N-hydroxyrnethyl Imides. The alcoholic component (8A) of tetramethrin (85) is readily accessible at low cost from condensation of maleic anhydride and butadiene, followed by rearrangement, imide formation with urea, and hydroxy- methylat ion with formaldehyde. lo* Substituted Benzyl Alcohols.The alcoholic components of the benzyl chrysanthe- mates needed for structure-activity investigations were made by reaction of aryl Grignard reagents with formaldehyde, by reducing appropriate aldehydes or acids, or by the sequence -CH3 --CHzhal ---CHZOH.~~The alcoholic function was protected when necessary as the tetrahydropyranyl derivative whilst a bromo substituent was converted into allyl, benzyl, etc. 2,6-Dimethyl-4-allylbenzyl alcohol was also made by a special route109 in which N-allyl-2,6- xylidine was rearranged in xylene in the presence of zinc chloride to 2,6-dirnethyl- 4allylaniline, and then converted into the alcohol by conventional reactions.5-Benzyl-3-furylrnethyl alcohol. Furans with functional groups at the 3-position are relatively inaccessible110 but an established synthesis of 3-furoic acid111 gave the starting material for the route112 to the alcohol (9A)shown in Scheme 1. The second route shown in Scheme 1 was developed later and adapted for commercial production;112 alternatives for reagents iv-vii have been patented.113 The importance of this alcohol (9A) has stimulated development of several altcrnative syntheses114 one of which (Scheme 2) was subsequently adapted to form the insecticidal ester (R = chrysanthemoyl) directly.3-Phenoxybenzyl Alcohols. These are the most important alcoholic components of lo) R. A. Ellison, Synthesis, 1973,7, 397; G. Pattenden, in 'Aliphatic Chemistry', ed. A. McKillop (Specialist Periodical Reports), The Chemical Society, London, 1977,vol. 5, p.231. lo' Ger. OlTen. 2 263 8801 1973. loo Ger. Offen. 2414794/1974. lo' Ger. Offen. 2535766/1976;B.P. 148S082/1977. lo' Ger. Offen. 2740701/1978. loo Jap. P. 65 22658; M. E. Bailey and E. D. Amstutz, J. Amer. Chem. Soc., 1956,78, 3828. loo M.Elliott and N. F. Janes, J. Chem. SOC. (C), 1967, 1780. P. Bosshard and C. H. Eugster, Adv. Heterocyclic Chem., 1966,7, 377. 111 E. Sherman and E. D. Amstutz, J. Amer. Chem. SOC., 1MO,72,219S;F.Kone, R.Heinz, and D.Scharf, Chem.Ber., 1961,94,825. 11' M. Elliott, N. F. Janes, and B. C. Pearson, J. Chem. SOC.(C), 1971,2551; Anon, Chem. Eng. News, 1971 (2), 32. '13 B.P. 1 178897/1970;B.P. 1 196202/1970;U.S.P. 3755368/1973. 11* B.P. 1213850/1970;G. R. Treves and P. A. Cruickshank, Chem. andlnd., 1971,544;Ger. Offen. 1935OO9/1971; 2122661/1972; 2122822-3/1972; U.S. 3781 308/1973; Y. Naoi,T.Nakano, K. Sakai, K. Fujii, and M. Wakaomi, Nippon Kuguku Kaai, 1977.9, 1365. Synthetic Pyrethroids-A New Class of Insecticide ixtiii vii+ Vlll0"'"iv, v vi-o/-eC0,Et Reagents:i, CHaO, HCl; ii, Benzene, AICl,; iii, LAH; iv, NaOEt + (CH,CO,Et),; v, H,O+; vi, EtOH-HCI; vii, H+, (CHaOH),; viii, NaH, HC0,Et; ix, aq, HCl Scheme 1 the recent generation of synthetic pyrethroids.Although esters from 3-phenoxy- benzyl alcohol (1OA) are less active than those from 5-benzyl-3-furylmethyl alcohol (9A)many are photostable and being more readily synthesized, are less expensive. Esters from a-cyano-3-phenoxybenzyl alrahol (1 1A) are among the most powerful insecticides known. Scheme 2 3-Phenoxybenzyl alcohol (10A) is made by several routes (Scheme 3), most of which involve the intermediate, 3-phenoxytoluene (13) originally made115 by condensing potassium cresate with bromobenzene, but more recently by a process116 more suitable for an industrial plant. Oxidation of the methyl group in (13) with either permanganatel15 or oxygen and catalyst1f7 gives 3-phenoxy- benzoic acid, which can then be reduced to the alcohol (1OA).In a more direct route118 the methyl group is halogenated and the monohalide, with the appro- priate acid in the presence of a tertiary amine, gives the insecticidal ester, e.g. pheno thrin. 11* Fr. P. 1394557-8/1965. 11' B.P. 1496821/1975. 11' Jap. Kokai 73 61450; B.P. 1489325/1977. 118 Ger. Offen. 240245711974; 243788211975 Elliott and Janes Jiii viii esters Reagents: i, Cu; ii, thoria (450°C); iii, fractionate; iv, oxidant; v, reductant;vi, halogen; vii, RCOCl; viii, RCOzH + NR', Scheme3 a-Cyano-3-phenoxybenzyl alcohol (1 1A) is made from 3-phenoxybenzaldehyde Reaction(14) available by oxidation of the or by an Ullman reacti011.l~~ of (14) with HCN gives the racemic alcohol; in the presence of D-oxynitrilase one epimer is preferentially destroyed producing predominantly the less active R-form (Scheme 4).27,58 The problem of isolating esters of this alcohol with the more active S-configuration (12) at this centre was first soIved27,5* using the IR,cis-dibromovinyl acid (11) as resolving agent; the required insecticidal enantiomer [(121); NRDC 161; decamethrin] crystallized from hexane leaving the other diastereoisomer in solution (Scheme 4).The configuration at C-ais epimerizedby base120so the inactive diastereoisomer can be inverted to provide more deca- methrin, without cleaving the ester. a-Cyano-3-phenoxybenenzylbromide is a *I* Belg. P. 842 I77/1976; see also A. Bader, Afdrichirnico Acta, 1976, 9,49. la0Belg. P.853 866-7/1977; Ger. Offen.2718038-9/1977. Synthetic Pyrethroids-A New Class of Insecticide potentially useful intermediate for preparing esters of labile acids via their sodium or amine salts.121 Reagents: i, HCN; ii, D-oxynitrilase; iii, acid chloride of (11); iv, crystallization from hexane Scheme 4 B. Acids.-Chrysanthemic Acid and Analogues. Recent elegant syntheses122 have not signifiwntly influenced the commercial production of ( f)cis,rrans-chrysan-themic acid (lC), the most direct route to which remains the addition of ethyl diazoacetate to 2,5-dimethyl-hexa-2,4-diene(for a review of many routes, see ref. 4). The established route to (& )-trans acid by addition of the methyl-propenyl unit (presented as a sulphone) to seneceoic ester has been modified.123 An efficient asymmetric addition of ethyl diazoacetate to the diene in the presence of a chiral copper catalyst gives a product 80:20 truns:cisand predominantly (80%) lx1Ger.Offen. 2619321/1976. lX*B.P.1416804/1975;H.Hirai, K.Ueda, and M. Matsui, Agric. Biol. Chem., 1976,40,153, 161,169;M.J. Devos L. Htvesi, P. Bayet, and A. Krief, Tetrahedron Letters, 1976,3911 ; A. S. Khanra and R. B. Mitra, Indian J. Chem., 1976,14B, 716; A. J. Ficini and J. d'Angelo, Tetrahedron Letters, 1976,2441 ; S. C. Welch and T. A. Valdes, J. Org. Chem., 1977,42, 2108. I** J. Martel and C. Huynh, Bull. SOC.chim. France, 1967, 985; Hung. Teljes 8014f1974. Elliott and Janes 1R.124 Chirality in the alkyl diazoacetate has less influence.125 New procedures separate optical and geometrical isomers126 and racemize less active for recycling.Many of the structural variations for segment G were first introduced128 (cf. ref. 129) by Wittig synthesis with an aldehydoester. A simple ester (e.g. R = Me) is normally the best intermediate but for side chains labile in base, the acid (15, R = H) is obtained easily by using the t-butyl ester and pyrolysing the Wittig product (15, R = But) (Scheme 5). Thence, many analogues with well-defined stereochemistry could be synthesized. Reagents: i, 0,;ii, RIR*C=PPhs Scheme 5 Commercial resolution of (k)-trans-chrysanthemic acid130 gives the (1 R,trans) acid, and thence by ozonolysis the trans aldehyde. The (lS,trans) acid, which gives esters of much diminished potency, can be converted via the (1 R,cis) acid to the cis aldehyde as shown in Scheme 6.13l As discussed below, this aldehyde is very significant commercially in addition to providing variations for structure- activity studies.HO (lS, tram) 0-0 0 (lR, cis) Reagents: i, H,O+;ii, KOBut; iii, MgBr,,6HsO; pyridine; iv, Os Scheme 6 T. Aratani, Y.Yoneyoshi, and T. Nagase, Tetrahedron Letfers, 1975, 1707; Jap. Kokai 74 14448, 102650. 75 137955. T.Aratani, Y Yoneyoshi, and T. Nagase, Tetrahedron Letters, 1977, 2599. Ia6 B.P. 1359968/1972; 1369519/1972; 1369730/1972; F. Horiuchi and M. Matsui, Agric. Biol. Chem., 1973,37, 1713: Ger. Offen. 2356702/1974; Jap. P. 75 34019. I*' Ger. Offen. 2453639/1975. 11* M. Elliott, N. F. Janes, and D.A. Pulman, J.C.S. Perkin I, 1974, 2470. 119 (a) L. Crombie, C. F. Doherty, and G. Pattenden, J. Chem. Soc. (C), 1970, 1076; (b) Fr. P. 1580474-6/1969; Jap. P. 75 33050. Ia0 F. P. 1536458/1966. Belg. P. 746726/1969. Synthetic Pyrethroids-A New Class of Insecticide Dihnlovinyl Acids. The (& )-cis,trans-dichlorovinylanalogue (1 K) of chrysanthe- mic acid, esterified in permethrin (10K)and cypermethrin (1 1K)was synthesized following Farkas et ~1.132 The potential commercial importance of these products has stimulated the search for alternative syntheses. The dichlorodiene (17) can be made by electro- lytic reduction of the acetate of (16),133 by dehydrocoupling of isobutylene and vinylidene chloride with palladous acetate,134 or by dehydration of hydroxy intermediates (Scheme 7).135 The final stage can be operated continuously136 or alternatively the 2-carbon unit is added using manganic acetatels' and the lac- i - If+ CI OH c1 (16) I A-\ /c' -CI Reagents: i, AlCI,; ii, Ac20; iii, Et,O; iv, toluene-4-sulphonic acid; v, CHN2C0,Et + Cu; vi, Mn(OAc),; vii, S0Cl2, EtOH; viii, base Scheme 7 la*J.Farkas, P. Kourim, and F. Sorm, Coll. Czech. Chem. Cumm., 1959,24,2230; J. Collongeand A. Perrot, Bull. SOC. chim. France, 1957, 204. lJSM. Alvarez and M. L Fishman, in ref. 12. la' D. Holland, D. J. Milner, and H. W. B. Reed, J. Organometallic Chem., 1977, 136, 111. la6B.P. 1493228; 1494817/1977. lJ' B.P. 1459285/1976. la' Fr. Demande 36424-5/1976; cf. Ger.Offen. 2707 104/1977. Elliott and Janes tonic product (19) converted with thionyl chloride into the required acid derivative.138 The synthesis Kondo developed from an earlier routel39 and later modified140 uses the simple, though not readily accessible, starting materials dimethylallyl alcohol and ethyl orthoacetate, and proceeds via a Claisen rearrangement, which is also an essential step in a related route141 from the trichloroethane derived from (16) as shown in Scheme 8.yL 'fj=4iii -% (18) EtO EtOOH ro iv1 it OH Reagents: i, CH,C(OEt)3; ii, heat; iii, CCI,, hv; iv, base Scheme 8 Another approach is based on 4,4-dimethylhex-5-en-2-one,available from a variety of reactions including catalysed addition of vinyl magnesium chloride to mesityl oxide.Thence, carbon tetrachloride addition, cyclization, and dehydro- halogenation give the required product (Scheme 9).13* The sequence of the two last steps determines the cisltrans ratio of the product. The cis and trans isomers of the acid (1K) give insecticidal esters of different potency, species specificity, and mammalian toxicity; controlling their ratio in lSEN. Itaya, T. Matsuo, N. Ohno, T. Mizutani, F. Fujita, and H. Yoshoika, in ref. 12. 13$ K. Kondo, K. Matsui, and Y. Takahatake, Tetrahedron Letters, 1976, 4359; Belg. P. 833 27811976. 140 Ger. Offen. 2547510/1976. Ger. Offen. 2542377/1976. 495 Synthetic Pyrethroids-A New Class of Insecticide iii or iv or 9:l Reagents: i, CH,=CHMgCl; ii, CC14, hw; iii, NaOH, then NaOCl; iv, NaOCl, then NaOH Scheme 9 the product is therefore valuable.The cis-rich products from any synthesis can be equilibrated at the acid chloride stage of ester preparation to a 22:78 niixture.142 Although under practical conditions the ethyl diazoacetate route gives a con- stant 45 55 cis:trans ratio, that from the Kondo139 and Kuraray141 routes can be adjusted within limits; the Sumitomo synthesis138 is even more flexible. The biologically active 1R,trans esters are available by resolution of the ( k)-trans acid.73 The outstanding insecticidal activity (see Table 1) of decamethrin (NRDC 161; 121) stimulated interest in commercial production of this single stereoisomer (of eight possible).This is feasible using a practical and extremely elegant route developed by Martel and shown in Scheme 10.131 The (lS,trans) chrysanthemic (2 isomers) 1or + 0 mother (12 1)liquors decamethrin $.OR 0 Reagents: i, PPh,, CBr,; ii, base; iii, acid chloride; iv. hexane Scheme 10 acid available after resolution of the (+)-trans form to provide the 1R acidic component for bioallethrin, S-bioallethrin, and bioresmethrin is used as a 14* M. Elliott. N. F. Janes. D. A. Pulman, L. C. Gaughan, T. Unai, and J. E. Casida, J. Agric.Food Chem., 1976,24,270. Ger. Offen. 2621 83011976. cf. Jap. Kokai. 75 160242. Elliott and Jones convenient source of the required (1R,cis)-caronaldehyde as described above. This, or a bicyclic equivalent12Qb gives with carbon tetrabromide in a Wittig reaction the (lR,cis)-dibromovinyl acid (11) used as summarized above to synthesize the insecticidal ester.2-(4-Chforophenyf)-3-methylbutyricAcid. Isopropyl halides a1 kylatep-chlorobenzyl cyanide in dimethyl formamide or in a phase transfer system,143 then hydrolysis provides the acidic component of fenvalerate. 6 Photochemistry A. Introduction.-The stability of pyrethroids in the presence of air and light has profoundly influenced their development as commercially important insecticides. Rapid decomposition after application of the natural pyrethrins and all com- mercial synthetic analogues developed before 1973 limited them to situations where only immediate kill is necessary. The recent more stable pyrethroids represent a major advance in insect control because their favourable combination of properties renders them appropriate for a much wider range of uses, especially in agriculture.Consequently, interest in synthetic pyrethroids has greatly increased, and the photochemistry of both unstable and stable compounds has been studied intensively (for a recent detailed review see ref. 144). B. Unstable Compounds.-Both oxygen and light are necessary for rapid poly- merization of the natural pyrethrins;* pyrethrins I and I1 (and pyrethrolone acetate) with dienic side chains polymerize more rapidly than the mono-enic constituents.145 The intractibility of the photodecomposition products formed by attack on the alcoholic components of the natural pyrethrins has obstructed detailed study of the rapid reactions by which they are f~rmed.~J~~ Photo-oxidative attack on the acid (chrysanthemate) component involves step- wise oxidation at the trans-methyl group in the side chain [compounds (20)-(22) isolated] for pyrethrin I, allethrin, and tetramethrin, and epoxidation of the olefinic group for re~methrin.l~~J~~ The products of photo-oxidative attack on the alcohol component of resme- thrin146 suggest an intermediate cyclic peroxide (23) (Scheme 11).The bicyclic products decompose further to simple benzene derivatives, including phenyl- acetic acid. The above reactions are rapid, and predominate when both air and light are present, but if oxygen is excluded, as in many laboratory U.V.irradiation studies, other reactions of these unstable compounds are observed.148 149 Jap. Kokai 76 63 145. 144 R L Holmstead, J. E. Casida, and L. 0 RUZO, in ref. 12. 146 M. Elliott, J. Chem. SOC.,1964, 5225; Y. Abe, K. Tsuda, and Y. Fujita, Botyu-Kagaku, 1972.37, 102. Id' Y.-L Chen and J. E. Casida, J. Agric. Food Chem., 1969, 17,208. 14' K. Ueda, L. C. Gaughan, and J. E. Casida, J. Agric. Food Chem., 1974,22,212. M. J. Bullivant and G. Pattenden, Pesticide Sci.,1976, 7, 231. Synthetic Pyrethroids-A New Class oj.Insecticide 0 (20) R = CHBOH (21) R = CHO (22) R = COaH 0-0 -[-0COR mOCOR' Scheme 11 C. Stable Compounds.-In the synthetic pyrethroids developed since 1973, with properties suitable for outdoor applications, the major photo-oxidative routes described above cannot occur.On the acid side, the isobutenyl side chain in chrysanthemates is replaced; similarly, no sites equivalent to those in rethrolones or furan alcohols, vulnerable to oxidative attack, are present in the benzenoid alcohols on which these important esters are based. Even one photosensitive component, in either part of the molecule, induces fast photodecomposition, but if both alcohol and acid are photostable, deposits persist substantially longer.266 Consequently, the photoproducts formed from the more stable compounds are not analogous to those from photolabile esters. The pattern for permethrin in solvents (and incidentally in soiI)149 involves (see Scheme 12) (a) a diradical intermediate similar to that proposed for chrysanthemates,148 leading to epimers, or by decomposition to 3-phenoxybenzyl dimethylacrylate, (b) loss of halogen from the dichlorovinyl side chain, and hydrogen capture to form the mono- 14' R.L Holmstead, J. E. Casida, L. 0.RUZO,and D. G. Fullmer,J. Agric. Food Chem., 1976 26, 590. + monobenzenoid products Scheme 12 chlorovinyl analogue (a minor metabolite), and (c) hydrolysis, followed by further oxidation or decomposition of the alcohol components. Photolysis produ~tsl~~J~0 from two stable a-cyano-substituted pyrethroids, decamethrin and fenvalerate, suggest that reaction pathways for permethrin (especially rnonodehalogenation) apply also to decamethrin, but that the major breakdown pathways on irradiation in solution involve cleavage of bonds at the ester group (Scheme 13).Although much work remains to be done, the important principlc is already established that the photolabile pyrethroids decompose in light by pathways which involve oxygen, whereas the more stable compounds undergo alternative types of reaction. Q loo R. L. Holmstead and D. G. Fullmer,J. Agric. Food Chem., 1977,25,56; L.0.Ruzo, R. L. Holmstead, and J. E. Casida, ibid., p. 1385: R. L. Holmstead, D. G. Fullmer, and L. 0. RUZO,ibid., 1978, 26, 954. Synthetic Pyrethroids-A New Class of Insecticide CN -co, CNI IArCHOCOR ArCHR 69%with fenvalerate 4 %with decamethrin CN CNI IArCH. + -0COR ArCHO. + COR ArCHaCN ArCOCN RH (10% with ArCH(0H)CN RCHO(ArcH--cN), fenvalerate) ArCHOArCH(CN)CH& Scheme 13 7 Structure-Toxicity Relationships of Pyrethroids in Vertebrates In practice, insecticides can at present be applied only relatively inefficiently;151 much of the dose does not reach the target and is potentially available to con- taminate the environment or affect unintended recipients.An important property of the new compounds is therefore their selectivity between target and non-target organisms, the distinction between insect and mammal being especially important. Averaged selectivity factors (Table 2) for four groups of insecticides indicate the relative safety of pyrethroids. Within this class, relative toxicities (see Table 3) are Table 2 Comparison of toxicities of classes of insecticidesa Insectslmg kg-l Ratslmg kg-l Selectivity factor Carbamates 2.8 45 16 Organophosphates 2.0 67 33 Organochlorines 2.6 230 91 Pyrethroids 0.45 2000 4500 Walues given are geometric means of LD,,’s obtained for a series of representative members of each class, against four species of insect, and against rats.Condensed with permission from a table published in ‘Synthetic Pyrethroids’, see ref. 12) related to the ease with which the compounds are metabolized in mammals. The reactions involved, classified as ester-cleavage, oxidation (mostly hydroxylation), and conjugation, are described be10w.l~~ I. J. Graham-Bryce, Chem. and Ind., 1976, 545. J5* For more extensive information, see: J.E. Casida, K. Ueda, L. C. Gaughan, L. T. Jao, and D. M.Soderlund, Arch. Environ. Contam. Toxicol., 197516, 3, 491 ;J. Miyamoto, Env. Health Persp., 1976, 14, 15; L. 0.Ruzo and J. E. Casida, Env. Health Persp., 1977, 21, 285; L.0. RUZO,T. Unai, and J. E. Casida, J. Agric. Food Chem., 1978,26, 918. Elliott and Jan Microsomal esterases, predominantly in the liver, cleave a wide range of pyrethroids at rates153 related to the degree of hindrance at the ester link. Studies with an isolated enzyme system indicate that esters of secondary alcohols (24;A, B # H) (cyclopentenolones; a-cyanobenzyl alcohols) are cleaved more slowly than those of primary alcohols, and 2,2-dimethyl-cyclopropanecarboxylateswith a substituent at C-3 cis to the ester group (24; C # H) [e.g. cismethrin (9F); NRDC 108 (9L)] are hydrolysed less readily than tram-only substituted com- pounds.2-Methyl-3-phenylbutyrates (M) react at rates intermediate between those of the cis and trans cyclopropane analogues. Oxidation at the trans methyl group (cf. photochemical reaction Section 6) of the isobutenyl side chain (CH3 -CHzOH -CHO -C02H) dominates other mechanisms in all chrysanthemates; epimerization at C-3 in some compounds during this process probably involves the aldehyde intermediate.154 The cyclo-propyl methyl groups are attacked (CH3 -CH20H) when pathways to alter- native products are suppressed (for example in the dichlorovinyl analogues of chrysanthemates). Furylmethyl and benzyl alcohols liberated by hydrolysis are oxidized to the corresponding acids (CH20H -COZH).5-Benzoyl-3-furoic acid is formed from resmethrin (CH2 -CHOH ---t CO)l55 and a secondary alcohol derivative [CH2=CHCH2 -CH2-CHCH(OH)-] produced by attack on the side chain of a1letl~in.l~~ The double bonds in the side chains of allethrin and pyrethrins I and I1 give di~ls,*~~ probably via epoxide intermediates.Phenoxy rings are hydroxylated at the 4', and less at the 2', positions. The alcohols, phenols, and carboxylic acids formed by these hydrolyses and oxidations may be conjugated with glycine, glucuronic acid, sulphate, and other groups. The water solubilities of pyrethroid metabolities are thereby increased, facilitating their excretion. The low mammalian toxicity traditionally associated with the natural pyre- thrins extends to some, but by no means to all, synthetic pyrethroids, as indicated by oral toxicities (Table 3).The ease with which pyrethrins 1 and II are oxidized on the diene side chain and pyrethrin II is cleaved at the methoxy-carbonyl group is associated with their low oral toxicities. S-Bioallethcin, with a less reactive monoene side chain, is more toxic. The central ester bond is not hydrolyscd D. M. Soderlund and J. E. Casida. in ref. 12, p. 162. 154 K. Ueda, L. C. Gaughan, and J. E. Casida, J. Agric. Food Chem., 1975. 23, 106. Is5 J. Miyamoto, T. Nishida, and K. Ueda, Prstic,icko Biocheni. Physiol., 1971, 1, 293. IS6 M. Elliott, N. F. Janes, E. C. Kimrnel, and J. E. Casida, J. Agric. Food Cheiir., 1972, 20, 300.Synthetic Pyrethroids-A New Class of Insecticide Table 3 Mammalian toxicities of synthetic pyrethroidsa Compound LD5o to ratslmg kg-1 Selectivity Oral Intravenous factor d Pyrethrin I 2-5 Pyrethrin I1 900b 0.4-1 72 S-Bioallethrin 680 4c 270 Bioresmethrin 8000 340 30000 Biophenothrin 10000 -24000 Cismethrin 100 6-7 NRDC 108 140 4-5 410 RU 11 679 63 5-10 400 NRDC 132 900 11 1-1 30 5400 NRDC 133 800 90-1 30 5000 NRDC 140 400 26-33 1600 NRDC 141 18 1 A-2.8 68 NRDC 173 130 2.0 2000 NRDC 174 14 0.5 150 permet hrin 2000 450 4800 cy per me t hr in 500 50 4200 decamethrin 70-140 2-3 -6OOo fenvalerate 450 75 900 aMuch of this table reproduced, with permission, from the ‘Annual Review of Entomology’, Volume 23, 01978 by Annual Reviews Inc.The remainder is from results (some previously unpublished) by Dr. J. M. Barnes and colleagues, Medical Research Council, Carshalton, Surrey. The data have been collected and averaged for these comparative purposes only, and should not be quoted out of context; bNatural pyrethrins; Cbioallethrin; dcalculated as LD,, to rats (oral)/LD,, to houseflies (topical), each in mg kg-l significantly in these three compounds, but bioresmethrin and phenothrin, easily cleaved primary esters of a trans-substituted cyclopropane acid with an iso- butenyl side chain also susceptible to attack are outstanding in their low toxicity; they are among the safest known insecticides. NRDC 108 and cismethrin, esters of acids with cis-substituents, are more toxic.In NRDC 132 and 133, absence of the trans-methyl group of the chrysanthemates leads to moderate toxicity, not so great, however, as that of RU 11679, where extreme lipophilicity may be sig- nificant. Transition from isobutenyl to dihalovinyl at C-3 increases toxicity to mammals (NRDC 140 and 141 compared with bioresmethrin and cismethrin) especially with the difluoro compounds NRDC 173 and 174, but these changes are offset by replacing 5-benzyl-3-furylmethyl(9)by 3-phenoxybenzyl (lo), giving esters somewhat less active as insecticides but also more susceptible to mam- malian detoxification by hydroxylation. The greater insecticidal activity pro- duced by introducing the a-cyano group (cypermethrin and decamethrin) amply compensates for the increased mammalian toxicity of the compounds associated with hindrance of esterase activity and diminished rate of oxidation.153 Although intravenous toxicities (Table 3) bear little relation to the practical Elliott and Janes application of pyrethroids they provide valuable information for correlation of structure with activity especially where the toxicities per 0s found for many pyrethroids are too low to permit significant deductions.They may provide evidence of intrinsic toxicity at the site of action in mammalian nervous systems, where few comparisons are yet reported. In one study, White et ~1.l~’measured a six-fold difference in brain levels of cismethrin and bioresmethrin in rats just showing lethal symptoms.The pyrethroids so far examined have very low toxicities to birds, but are lethal to fish at low concentrations (for a discussion and references see ref. 10). 8 Other Aspects of Biological Activity A. The Influence of Polarity.-Correlation of biological activity with measured or estimated polarity (expressed, in the Hansch approach158 as P,the octanol/ water partition coefficient) has been attempted in many systems. With pyre- throids, only a broad generalization that potent compounds have log P values near 6 was possible; the measured activity of pyrethroids is necessarily influenced by many factors, such as rate of penetration, detoxification, and potency at the site of action, dependent upon the chemical and physical properties of the compounds.Pyrethroidal activity depends closely on the overall shape of the molecule22 and may respond to small changes in conformational ~reference,~~ properties which are not easily expressed quantitatively; no useful correlations with other parameters have been reported. Nevertheless, typical log P values of pyrethroids and of other insecticides relate well with many aspects of their behaviour.85 Like the organochlorine compounds, e.g.dieldrin and DDT(1ogP also ca. 6) they partition preferentially into the lipoid rather than the aqueous tissues of complex organisms. However, unlike the organochlorine compounds, pyrethroids are readily metabolized (see above) and do not accumulate. Many organophosphate and carbamate insecticides have log P values below 4 and act systemically in plants, which implies some affinity for the moving aqueous phase.In contrast, the known pyrethroids, being extremely lipophilic, show no systemic, nor even translaminar, action. B. Knockdown.-Some pyrethroids paralyse insects remarkably rapidly. If fol- lowed by recovery, the effect is recognized as knockdown rather than kill.159 The two actions appear to be associated with different properties :160 knockdown with the more polar pyrethroids, perhaps because they penetrate more rapidly (but see also ref. 21) and the more prolonged effects that eventually kill the insect85 with greater lipophilicity. Those pyrethroids with more powerful knockdown action 15’ I. N. H. White, R. D. Verschoyle, M.H. Moradian, and J. M. Barnes, Pesticide Biochem. Physiol., 1976, 6, 49 I. C. Hansch, in ‘Drug Design’, ed. E. J. Ariens, Academic Press, New York, 1971, vol. I, p. 271. 15B R. M. Sawicki, J. Sci. Food Agric., 1962, 13, 283. lE0G. G. Briggs, M. Elliott, A. W. Farnham, and N. F. Janes, Pesticide Sci., 1974, 5, 643. 503 Synthetic Pyrethroids-A New Class of Insecticide (indicated by ‘KD’ in Table 1) are mostly less effective killing agents; of the compounds listed, only NRDC 173 (9C)combines the two actions strongly. Knockdown agents are incorporated in many domestic aerosol insect sprays and are therefore significant commercially; they are less important for agricultural applications, where formulations for residual contact are most appropriate. C.Synergism.-Most commercial formulations of the natural pyrethrins include a synergist (usually piperonyl butoxide in 8-10-fold excess). Potency is thereby increased up to 10-fold, despite the inactivity of the additive alone. In such preparations, the natural compounds, though expensive, compete with less well synergized synthetic a1 ter na t ives. For research, synergism is most rationally investigated by applying a constant largo dose of synergist (e.g., 2 pg per housefly) before the insecticide; otherwise, at fixed toxicant :synergist ratios, relatively little additive would be administered with the more potent compounds. Few formulations with synergists are therefore anticipated for the more stable, active compounds suitable for agricultural applications.The mode of action of synergists is not yet adequately understood, but may involve suppression of oxidative and esteratic detoxificationI61 or other mechanisms.162 Methylenedioxyphenyl synergists, such as piperonyl butoxide, are thought to suppress primarily oxidative detoxification within the insect; the high factor of 300 with pyrethrin 1163 is consistent with the many biologically oxidizable sites recognized in this c0mpound.1~~ However, synergists do not appreciably increase the activities of pyrethroids in all insects. Later synthetic pyrethroids, not well synergized even in the ho~sefly,l~~may be less susceptible to detoxification by insects, especially by oxidative routes. 9 Summary and Conclusions: The Present and Future Importance of Synthetic Pyrethroids This survey has indicated the diverse range of insecticidally active compounds related to the prototype, pyrethrin I.Pyrethroids are lipophilic compounds, very active as contact insecticides and possibly as stomach poisons against a wide range of insect species; some members of the group also have useful repellent action. The exceptional potency of some of the compounds discovered shows how well an active natural product (particularly a chiral one) can serve as the parent structure for examining the relationship between biological activity and chemical structure. The first synthetic compounds, although very active and relatively safe, were too unstable for many applications, but development of more persistent com- pounds with many of the favourable characteristics of the earlier esters greatly increased the scope of the group.In addition to understanding of insecticidal 16’ J. E. Casida, Ann. Rev. Biochemistry. 1973, 42, 259. lea A. W. Farnham and R. M.Sawicki, unpublished results. 163 P. E. Burt, M. Elliott, A. W. Farnham, N. F. Janes, P. H. Needham, and J. H. Stevenson, in ‘Crop Protection Agents-Their Biological Evaluation’, ed. N. R. McFarlane, Academic Press, London, 1977, p. 384. 504 Elliott and Janes activity, knowledge is now accumulating of the influence of structure on toxicity to mammals, birds, and fish and on stability in light and in soils. All implications of the anticipated widespread use of the more stable synthetic pyrethroids must be considered.In many respects they have more favourable properties than other groups of lipophilic insecticides such as the organochlorine compounds because, although they persist adequately on crop surfaces, their physical properties restrict migration in solution and as vapour, and they are rapidly decomposed when exposed to metabolizing systems, such as soil micro-organisms. The potential for developing new compounds with properties especially appropriate for many different individual applications or specifically active against particular pests is great. The many types of biological activity against invertebrates (for example repellency and antifeeding action in addition to kill) latent in the structures of the natural compounds have almost certainly not yet been fully exploited.The further development of synthetic pesticides related to the natural pyrethrins is therefore a challenging area for practical application of many aspects of organic chemistry. We acknowledge help, discussion, and disclosure of unpublished results from colleagues at Rothamsted Experimental Station, Harpenden ;Medical Research Council Toxicology Unit, Carshalton; and numerous industrial organizations, and support from the National Research Development Corporation.