REVIEW OF LITERATURE

2.1. Origin of synthetic pyrethroids:

Natural products can be used 8s model canpounds lor reaearch and

developnent progrcmnes to produce analogues with favourable econanics

and enhanced potency and utility. 'Ihis approach involves

identification of the active ctrrponents followed by synthesis and

Structure optimization. 'Ihe most important and significant

application of a natural M e 1 f m n botanical origin centers on the

insecticidal properties of the @er f m pyrethrun f lowers, Recent

synthetic pyrethroids are m n g the moet potent pesticides known, and

at present are being evaluated for many applications and as possible

replacements lor sane of the organophosphorus, carbanlato and

organochlorine insecticides now considered unacceptable due to

developnent of resistance in insects and undue persistence in the

envirormmt.

Pyrethm f l w r s are of the genus Chrysanthemm and the most

important cmmrcial species is cinerariaefoliun. llu production of

insect povder from flowers of Chrysanthm cinerariaefolim started

in 1840 (MLaughlin, 1973; Casida, 1980). ?he extract f r m wretkun

flowers grown in Kenya replaced the Japanese product because it

aWt#lmd Dlarr Pvrrthrln prr unlt bry wnuht,

Lar photoatabili ty and high biodegradabili ty caPbined with high

prcductim costs precluded the general Use of pyrethrins in the open

field. Because of the low maaaelian taxicity thy were, howver,

preferentially used over the synthetic insecticides for ths control

of houseflies, mosquitoes and other indoor pests for the protection

of stored food products and for the direct application on man and

livestock (Gillenwater and Burden, 1973; Smith, 1973 ) .

Early in the history of chemical investigation of pyrethrun

axtract, the insecticidal const itwnte were recognized as esters

(Fujitani, 1909). T h y were formed by the esterification of two

different acid moieties - chrysanthemic acid and pyrethric acid with three alcohol moieties - Wrethmlone, cinerolone and jamlone. Ihe

structures of the six insecticidal esters in the extract have been

proposed based on the work of Staudinger and Ruzicka (1924) end the

structures and absolute conflguratione of the esters (fig. 11 by

various physical techniques were later fully confirmed. (Brawl 1

al., 1969: Cranbie g., 1975; Pattenden 2 g., 1973; Begley 2 - &. , 19741. Pyrethrins I and I1 were more potent insecticides than

the cinerins and jamline. ohrysanthemates were more potent for

kill and the Wrethrates for knockdown. Hence pyrethnm extract has a

h d epectnm of activity (Winney, 1973).

Fig. 1 - Structures of natural ~rethrins

1 2 R R Name

ai- - Cinerin I 3

M - J a m l i n I 3

M -COD. Pyrethrin I1 3

(31 -033- Cinerin I1 R

al -mO. J a m l i n I1 3

A large mrnber of ~ r e t h m i d 8 haw been developed by modificetlon

of the structure of t h ~ natural pyrethrl~.

2.2. Structural variatione and tneecticid81 activity.

AlBDIC all ctctiw, pyrethrolds em &tern with the comititUUnt

Page. .8

alcohDl and acid mietiea. 'Ihs high insecticidal activity i s

geumrally dependent on the wsrill ahnpe of the mlecule (Elliott,

1977) by appropriately disposing certain key structural features.

2.3.1. Modifications in the alcohol moiety with chrysanthemic

acid: -

The first synthetic ncdifications of the structure of pyrethrins

mainly involved the changes of the alcohol moiety. Allethrin 1, the

first crrrmercially available pyrethroid was derived fran pyrethrin I

by ahortening the pentadienyl side chain of the pyrethrolone moiety

Replacement of the double bond in the side chain of allethrin by

a triple bond resulted in 2-propynylrethrin 2 which retained the imacticidal activity of allethrin (Ger$dorf f g., 1961).

t h a y a l ~ t m o l o m ring of pyrothrin I to trans-2,I-hgudisn-1-Yl

Page. .9

and its 2- or 3- -thy1 eubstituted hamlogues 3, 4 and 5 (Sota,

Many aranatic analogues of allethrin were synthesized by

replacing the allylic moiety with a benzyl group (with methyl group 6 and without the methyl group 1 in the cyclopentenolone ring) and a phergrlethyl group 8 but none was significantly better than allethrin itself. The absence of methyl group was found to increase the

activity to a slight extent whereas the additional methylens link

with phenylethyl group was found to make the resulting compound

totally inactive (Gersdorff and Mitlin, 1954; Elliott, 2 s., 1971al.

l b insecticidal ectivi ty of pyrethrin I could be improved by

-it@ the alcohol moiety into a substituted benzyl alcohol

Page. .10

9 L..

Barthel further examined the activity of benzyl chrysanthemates,

2,4-dlmethylbenzyl chrysanthemate 10 and 2,s-analog 2. He found that 2,4-analog, dimethrln 2 was an active insecticide but the

related 2,s-canpound was not active (Barthel , 1961).

?he activity was further found to be enhanced by substituting the

2,3,6-, 2,4,6- and 2,3,4,6- positions of the benzyl ring with methyl

group resul ting in the esters 12, 2 6 14, (Elllott g g., 1972)

12 U

13 m

14 - r-allylbenzyl chrysanthemate (ABC) 15 was found to have

Sufficient activity and the syntbsis of 4-allyl-2,6-dimethyl benzyl

chrysmthemate (l%WX) 16 was proved to be the most effective in this

series (Elliott etg., 1965; ~lliott a Janes, 1967).

Page. .ll

IS - Js 4-Benzylbenzyl chrysanthemate 2 was more potent than the 4-ally1

benzyl canpound 2. (Elliott fi g., 1967)

Sufficient insecticidal activity of 5-benzylfuryl ester

encouraged the investigation of other variations of this conbinat ion.

hhanomrent in the insecticidal actlvi ty was observed when the point

of attachnent of the alcohol was shifted fran the 2- (2) to the 3-position (19) [Elliott fi g., 1971b: Elliott fi g, , 1974).

18 - ry 19

Ihe product 2, resmethrin, was the first synthetic pyrethroid

with activity against a range of insect species of the sane order as

py'rethrin I. Acetylenic unsaturation, as in the carpound prothrin

20, produced a volatile hockdown agent more effective than ally1 - derivative, furanethrin, 21 for flying insects (Katsuta, Gel. , 19691. Wrefore, aranatic unsaturation was as effective as the

Page. -12

cis-dienyl system on the C ring of pyrethrin I, but as in 5

allethrln, the simpler ally1 side chain was not adequate.

The xanthenylmethyl chrysanthemate 22 was synthesised because it

rescanbled the furan superficially and was also related to 4-benzyl-

benzyl chrysanthemate, but it had no insecticidal activity (~lliot t,

1970).

M r e ccmpounds related to resmethrin were synthesised; among them

3-benzylbenzyl c h r y s a n t h t e 2 was selected becauk the angle

betwen the bonds at the m-posi tion was very similar to that betwen

the 3- and 5- position of the furan ring (Elliott, 1970; Elliott 6

Janes, 1978a). The higher activity of this canpound than that of the

4-benzylbenzyl ester 17 suggested that this was an important feature.

23 hr

The chrysanthemate type esters of 2-methyl-3-phenylbsnzyl alcohol

Page. .l3

24 and 2-1 luoro-3-phenylbenzyl alcohol 25 s b d enhanced insec ti- - tidal and miticidal activity (Pngel g., 1983; P l m r fi &,

1984).

Introduction of a tetrahydrophthalimidwthl alcohol (neo-

pynaninol) as an alternative alcohol resulted in the fast knockdown

agent tetrmnethrin (neopynamin] 26 (Kato g g., 1964).

Sota g., (19721 modified the Puran ring of regnethrin by

substituting with other heteroatons and found that only 4,5,6,7-

tetrahydrobenzothiazolylmethyl chrysanthemate 2 possessed about the smne order of activity as allethrin.

27 A.1

Studies with various substituted i-1 chryeantbtes resulted

in esters with improved insecticidal activity of which 4-allyl-1-

indmyl eater 28 was more potent than allethrin (Naked &. 9

Page. .l4

Extensive studies were carried out to exploit synthetic

pyrethroids, which are superior to natural pyrethrins in insecticidal

activity by changing the alcohol moiety leading to thiophenylmthyl

chrysanthemate 2 (Matsui gal., 1971).

29 N

Nakada et al., (1978b) found that the esters of 2,3-dihydro-

benzofuranyl alcohols having substitutions, 7-methyl 30, 7-chloro 2, and 5-chloro-4,6-dimethyl 2 were much more effective than a1 lethrin.

insecticidal activity of methyl substituted cyclohaxenyl-

methyl and cyclohaxadienylmethyl chrysanthemate against houseflies

was investigated and found that 4-methyl-I-cyclohexenylmthyl- 33 and

4,5-dimethyl-l,4-~yclohexadienylmethyl 34 chrysanthemates were

equally effective as pyrethrins and allethrins (Sugawara st fi.,

%? ?? The chrysanthemete ester of 3-chloro-4-phenyl-2-buten-1-01 35 was

tested for insecticidal activity and found to be effective than

allethrin against houseflies. (Hayashi fi z., 19721

Isobutenyl, cis-pentadienyl, ally], furylmthyl and

tetrahydrophthalimidyl groupings were identified as strongly

photosensitive sites in pyrethroid molecules. These pyrethroids were

still subject to rapid photodegradation, especially by W light

(Leahey, 1979: Elliott g g . , 1973 a,b).

During the early 1970s, further modifications were carried out

with 3-phenaxybenzyl alcohol to develop photostable and effective

pyrethroid esters than the earlier ccmpounds. [Elliott, 19701;

Fujbto 2.. 1973). he chrysanthmic ester. phenothrin 36

obtained with 3-phenaxy benzyl almhol was found to be less effective

than the Corresponding ester 19 with a 5-benZyl-3-fur~l-

Page. .l6

methyl alcohol (Elliott g. , 1974a).

*4q % -Q

Cevelopnent of chrysanthemates of sane d-acetylenic alcohols

(BASF, 19681 yielded sane novel structured esters but none of the

caqmunds was sufficiently active to excite much interest.

An improved pyrethroid activity was noticed in the resulting

ester, cyphenothrin 37 after the incorporation of a cyano group on

the ol -carbon atan of 3-phenwybenzyl alcohol. (Matsuo, fi g. ,

2.3.2. Modifications in the alcohol moiety with dihalovinyl-

2,2-dimthyl cyclopropane carbaxylic acid:

3-Phenaxybenzyl alcohol was proved to be an effective alcohol

moiety in enhancing the photostability and insecticidal activity. 'Ihe

first photos table pyrethroid, pemthrin g, was reported after the

replac€€nBnt of ieobutenyl side chain by a dichlorovinyl group.

(Elliott a fi., 1973b).

Page. .l7

A dramatic enhancement of the insecticidal activity ccmpared to

penmthrin was observed in the resulting ester, cypemthrin, 2 by

incorporating a cyano group on the a-carbon atan of 3-phenoxy benzyl

alcohol (Elliott g g., 197@.

Pyrethroid ester 40 with a strong knockdown activity was

developed by incorporating a carboximidanethyl group in the alcohol

moiety [Hirano etg. , 1979).

O 0 59 m u n i &. , (1981. 1987) synthesised esters with different

heterocyclic rings in the alcohol moiety and reported that the esters

41 6 2 with 3-benzyl~razol-1-ylmethyl and 3-benzylpyrrol-1-ylmthyl - alcohols were found to be effective. The ester g was found to be Kn-0 effective than pemthrin 2 against houseflies. Selby and

Thomas (1987) reported the insecticidal activity of pyrethroids

Page. . l 8

derived lran methyl and phenyl substituted pyrazolylmethanols with

permethric acid.

k! &2

A high level of insecticidal activity and decrease in niamlian

toxicity was reported with the esters derived from a-cyano-6-

phenoxy-2-pyridinylmethyl alcohol 43. (Malhotra 2 g. , 19811.

The introduction of an PC-methyl group in the alcohol moiety of

43 gave the canpound fi and the corresponding g-alkyl thioester 5 which were found to have good insecticidal activity (Henrick, 1982).

?he introduction of an &-methyl group in pemthrin was found to

retain the activity in the resulting ester 46 against houseflies (Henrick &., 1984) whereas other reports showed a reduction in

Page. -19

activity (Mtsuo g z., 1976; Elliott g G., 1982)

Behrenz and Naunann [I9821 reported a volatile and fast acting

pyrethroid, fenfluthrin 7, effective against all public health and stored product pests, by esterifying the acid moiety of penmthrin

with a pentaf luorobenzyl alcohol.

fs Hamnann and Fuchs (1981) reported the broad spectrun insecticidal

activity of cyfluthrin (Eaythroid) 2 by using a-cyano-4-fluoro-

3-phanaxybenzyl alcohol for esterification with permethric acid. ?he

same alcohol moiety, with one of the chlorine a t m in the pemthric

acid replaced by a 4-chlorophenyl group gave rise to a pyrethroid

f lunethrin 49 effective against cattle ticks [Hopkins and Woodley,

1982).

?he insecticidal activities of the esters of 2,3,4,5-tetrafluoro-

Page. .20

6-methyl benzylalcohol 50 (Elushell and Jone, 1987) and 3-benzyl-

4-rluorobendyl alcohol 1 (Whittle, 1988) with pelnwlhrlc iiclll wl lh

one chlorine replaced by a trifluoranethyl group were studied. ?he

same acid moiety with different alcohols such as biphenylmethanol

with a methyl group in the 2-position of the benzyl ring and

2,3,5,6-tetrafluoro-4-rnethylbenzyl alcohol resulted in the effective

pyrethroids bifenthrin 52 and tefluthrin 53. (Plumner g. , 1983;

The dihalovinylcyclopropane carboxylate esters derived frcm

biphenyl-3-yl methanols showed that the esters 2 a-c substituted with F, C 1 and methyl groups in the 2-position of the biphenyl ring

generally led to an increase in activity (Plumr s., 1983) and the esters of 2,Z1-bridged biphenyl-3-yl rnethanols 2 (when n = 1-4)

were useful as insecticides and acaricides (Plurmer, 19841.

Page. .21

a, R = F i b. 4=c1: c, R= cn3.

55 (n= 1-4) N

'Ihe esters produced from 6,7-dihydro-5H-dibenzo[a,c] cyclo-

hepten-4-yl methanol 56 were found to be highly active (Plurmer g

el., 19841. -

A fluorescent analogue of pyrethroid ester 51 was reported using pyrene-1-methanol with pemthric acid with activity caiparable to

permethin. (Jones 5 g., 1985).

Insecticidal activities of d-cya~-subSti tuted 3-quinolylmethyl

esters 2 of dihalovinyl substituted chrysanthmic acids were

reported (8aiicki g G., 1 ~ 8 6 )

Page. .22

28 X = F . G L o r B r

Bingfang and Yuan (1987) studied the insecticidal activities of

sane pyrethroids 59 and 60 with trichlorunethyl group on the 01 -carbon atan of the alcohol moiety.

5 9 60 H

N

Philip (1987) reported the insecticidal activity of

[1-(6-plenaxy-2-~ridinyl)2,2,2-trifluoroethyl]3-(2,2-dichloro-

ethe~1)-2,2-dimethyl cyclopropane carbylate 61 and related

canpounds.

?he insecticidal and acaricidal activities of dihydrobenzof uranyl

cyclapsopane carboxylates of type 62 and related campounds were

reported. (Katsuta g., 1987a).

Page. -23

62 rCI

?he insecticidal activity and the vapour pressure studies of the

pyrethroids containing acyclic alcohol moieties resulted in &-

ethynyl-2-1mthyl-2-hexenyl and I% -ethynyl-2-methyl-2-pentenyl-

3[ 2,2-dichloroetheny1)-2,2-dimethyl cyclopropans carboxylates 63 and 64 (Hirano g g., 1978, 1983). -

R = w 63

'Ihe dihalovinylchrysantmte trstars j of substituted 06-

cya~-2-mthyl-2-pentenols were studied for their insecticidal

activity. [ Jap. Pat., 1981a)

R1 : atkyl, alkenyl.

+$,+. a l k y n y l

ci - p R' 2 z H,CH3,C2H9

C t 0 CN

s5 ?he dihalovinylcyclopropane carbaxylate derivatives 66 have been

prepared by varying the substitutions in the lactol alcohol rmiety

snd tested for insecticidal activity against houseflies. [Szekely

Page. .24

66 N

Farnham g &, , (1989) reported the insecticidal activities of

esters of a range of I-, 2-, and 3-phenyl, benzyl and phenethyl

substituted cyclopentanola and cyclopentylmethyl alcohols and related

unsaturated canpounds. The distance and relative orientation between

the alcohol and aryl functions appears crucial, but in other respects

the nature of the spacer group between them is less important.

l l ~ insecticidal and acaricidal activi t ies of cyclopropane

carboxylate esters 61 with different substituted 3-anilino-benzyl alcohols have been reported. [Jap. Pat. , 1981b)

'Ihe activity of halosubstituted allylbenzyl esters depends on the

POSitim and btereochtn~~istry of substitution in the ally1 side chain,

the substitution pattern on benzyl, the esterifying acid and to a

lesser extent on the nature of the halogen substituent itself

(Elliott gal., 1986).

Page. .25

2.3.3. Mifications in the acid miety.

'Ihe search for an ideal pyrethroid insecticide untivated many

researchers which resulted in the structural modifications of the

natural pyrethrin I starting with the alcohol miety followed by the

acid moiety. Recently, many studies on structure modification of the

acid misty have disclosed a nunber of useful synthetic pyrethroids.

LaForge et al., (19521 proposed that the presence of the

unsaturated sidechain on the cyclopropane ring was indispensible for

biological activity. Matsui gal.. (1967) contradicted this theory by inlr'uJuc111g uy111w ll*luul Lul~'w~w Ll~yluyulupt'upu~lu cor'lwxyl l c ould

which retained the biological activity in the resulting ester.

?he esters 68, 69 (Y-40421, (fenpropathsin) of tetramethyl-

cyclopropanecarbaxylic acid with the respective alcohols. 5-benzyl-

3-furylrmthyl alcohol. [Z-methyl-5-(2-pro~ny1)- 3-furanyl]methyl

alcohol and with cC -cyano-3-phenaxybenzyl alcohol were found to be

effective for insecticidal activity (Berteau 6 Casida. 1969: Barlow

cg., 1971; Inamasu ets., 1977: Ger. Off,, 19731.

Page. .26

Farkas (1959) reported that the allethronyl ester 2 of

2,2-dimethyl-3-dichlorovinyl cyclopropane carbaxylic acid had almost

t h suw ec tlvl ty ua u l l u l l i ~ ~ i n . Mittree8 ttm dlclilurocli~uuthyl iaostttrw

72 was less potent. (Barlow, g g., 1971). -

CIS;, ct

0

72 O+ :@yo* 72 0 Anong the 3-(3,s-dihalo-2-propnyl) analogues of allethrin, the

dif luoro analogue 73 was more active (Ando g g., 1983)

F

The two methyl groups at the C position of the cyclopropane 2

ring were present in most active cyclopropane carboxylates; a1 1 known

cyclopropyl esters with no substi tuent a t this pasit ion were inactive

(Earlow g., 1971). Introduction of dichloro (Novak g g. , 19611

and spiro (Ger, Off,, 1973) substitutions at C position resulted 2

in ineecticidally active esters. This explains the function of the

mthyl groups at C in the active molecules as related more to 2

their steric than their chemical characteristics as esters with

larger group were inactive (Elliott and Jams, 1978b).

Page. .27

Cyclopropane esters with an additional group at C , aziridine 1

analogues (Sheppard and Norton, 1980), cyclopropenes (Jap. Pat.,

1971) cyclobutanes (Crowley, 1974) showed little activity.

Even a very small change in the vinyl side chain of the

chrysanthanic acid resulted in canpounds with varying insecticidal

activity. 'Ihe ester 2 of 5-benzyl-3-furylmethyl alcohol with

2,2-dimethyl-3-cyclopentylidenemet~l cyclopropane carbaxylic acid

[ethanochrysanthemate) was more potent than the corresponding ester

with chrysanthmic acid (Velluz et 'al., 1969; Lhoste and Rauch,

1969).

?2 ?he insecticidal activity of dibrunovinyl chrysanthmic ester 2

of 5-benzyl-3-f urylmethyl alcohol had been reported by Brown g 2..

( 1973).

~lliott st g., (1975) synthesized, resolved cis- and trans-

esters of 3-[2,2-dif luoro, dichloro or dibram-vinyl] cyclopropane

Carbaxylic acids with 5-benzyl-3-furylme thyl, 3-phenoxybenzyl and

oC -cyano-3-phenmcybenzyl alcohols and tested the insecticidal

Page, -28

activities. He found that trans isamrs of chloro and bmm,

substituted esters were effective. brig than, the well known

carpounds were 2 (pemthrin) with 3-phenaxy benzyl alcohol,

(cypenmthrin) and 2 (Del temsthrin) with a-cyano-3-phenawybenzyl

alcohol.

Substitution of one of the chlorine atam in the isobutenyl side

chain of cypemthrin by a trifluoranethyl group resulted in

cytialothrin with enhanced insecticidal activity. (Bentley &. ,

Branination of the unsaturated dihalovinyl side chain of

cypemthrin and deltamethin resulted in the proinsecticides,

tralocythrin 3 and tralanethrin, 2 [ G m n and Ruzo, 1984). ?he

acid moiety of 78 with OL-cyano-3-(4-brornoplenauyl-benzyl

alcohol was f ound to yield an effective ester 2 (Hirano g g., 1980).

Page. .29

?he OL-cyano (3-phenaxy-4-f luorophenyl )methyl ester 81 of

3-(2,2-diiodoethenyl I-2,Z-dimethylcyclopropane carbaxylic acid

showed insecticidal activity (Jap. Pat., 1987).

Hydrogenation of the isobutenyl side chain of the chrysanthemic

acid esters, 82 of allethrolone (LaForge g &, , 1952) and 83 of

5-benzyl-3-Purylmethyl alcohol (Sugiyema d., 1974) resulted in a reduction of the toxicity against the houseflies.

Elliott et al., (1973a) modified the chrysanthic acid side

Chin in biorevnethrin by which the four carbon a t m in the

isobutenyl group were redisposed to a but-1-enyl subst i twnt

resulting in the ester 8Q which showed greater insecticidal activity

than pyrethrin I. Further changes of the acid side chain with

butadiewl Rroup resulted in canpound 85 with more insecticidal

Page.. 30

activity than bioresmethrin,

Elliott g &. , (1976al studied the insecticidal activities of

5-benzyl-3-furylmethyl-2,2-dimethylcyclopropane carboxylates with

non-ethylenic substituents at position 3 on the cyclopropane ring and

found that 3-methoxyiminanethyl group in the ester 3 enhanced the activity.

Lhoste and Rauch (1976) reported a new pyrethroid ester kadethrin

87 (RU-155251, 5-benzyl-3-furylmethyl-2,2-dimethyl-3(2,3,4,5-tetra- - bdro-2-0x0-thien-3-ylidenemethyl )cyclopropane carbaxyla te.

E The pyrethmidal esters with thiocyanato group substituted at

C of the cyclopropane carbaxylic acid were synthesized and it was 3

Page. .31

reported that the esters fi and 2 were effective against houseflies than allethrin. (Jap. Pat., 1981~).

Mttra g g., (1983) reported the insecticidal activity of

3-phenoxybenzy1-2,2-dime thyl-3-( 2-cyanopropny 1) -cyclopropane

carbaxylate 90 against housellles.

cN)J-+qa CH3 90 - N

Tessier g g., (1984) prepared the Scyam-3-phenawy-benzyl

esters of the type with 2-[2-(alkylthiocarbony1)-2-halovinyl]-

cyclopropane carbaxylic acids and tested the canpounds for both

insecticidal and acaricidal activities.

R = halo

CH > H SC(0) ')aa - cn3 91

rU

Katsuta &. , (1987bl studied the insecticidal and acaricidal

activities of cyclopropane carbaxylic acid ester containing a

carbaaate side chain in the acid moiety and found that 2 is an

active canpound.

Wilkerson and Norton (19811 investigated the insecticidal

activity of a series of 3-phenauybenzyl esters of the type 93 with

2,2-dicyam cyclopropanecarbaxylic acid and showed that the

structural parmeters influencing the activity were different f ran

the gem-dimethylcyclopropane carbaxylates.

Recently synthesis of trifluoranethyl substituted pyrethroid

esters of the type 2 has been reported (Nagele and Hanack, 1989).

Ide fi G., (1983) reported that the 3-phenoxybenzyl ester 95 of 3-[2-ct1luro-l-pruplly l j-L,1-dl11wll1yl cycluprop~~u crrl'buy llr: uuid

which is a hybrid of naturally occurring chrysanthmic acid and

dichlorovinyl cyclopropane carboxylic acid was having both insecti-

cidal activity and reduced fish toxicity.

Elliott g &. , (1976b) studied a nunber of different 3-substi-

tuents such as alkoxy, aryloxy and aryl on the cyclopropane ring of

the resnethrin type of pyrethroid and showd that the insecticidal

activity of these analogues 96 depended on the nature and stereo-

c W s t r y of the C substituent. 3

Greuter 5 G., (1980) studied the insecticidal activities of d -Cyano-3-phenoxybenzyl esters of the type 2 with alkoxy, alkyl-

thi0, phenwy, and phenylthio groups substituted at the C of the 3

2,2,dlmethyl cyclopropane carboxylic acid.

Page. .34

4 : - 0 C H 3

- OPh

- 5 P h

Chloro, f luoro or trifluoranethyl groups, when present in the

terminal carbon of the dienyl sidechain in 3-(alka-1,3-dienyll-

2,2-dime thylcyclopropanecarboxylates provided good insecticidal

pyrethroid esters 2, 99 6 100 with CL-cyano-3-phenoxybenzyl

alcohol. (8osone g g., 19861

c F;

Ccmbining the molecular features of DDT in the acid moiety a

series of pyrethroidal esters of type 101 were developed by Holan g

s., (1978).

In 1977, Davis and Searle prepared 2,2-dichlorovinyl-substi-

tuted spiro-hexane and spiro-octane-carbaxylates 102 6 103 with 4-

and 6-mEmbered rings instead of the dimethyl-substituents which were

relatively less active insecticides.

Brown and Addor (1978) studied the insecticidal activities of the

esters generated frm different substituted 3,3-dimethyl spiro[cyclo-

propane-l,l'-indene]-2-~arboxylic acid 104, its dihydro isomer g with 3-phenaxybenzyl and a-cyano-3-phenaxybenzyl alcohols.

104 N

105 N

Attmts to substitute at C of the 2,Z-dimethylcyclo 3

propanecarboxylic acid with spiro fused ring (Tsushima g., 1983)

afforded good perspectives which resulted in the disclosure of the

novel acid canponent 106 (a-b) .

Page. ,36

2.4. Non-Cyclopropane pyrethroid esters

[nno g G., 1974 discovered a new class of substituted

2-phenylalkanoates that are unique in lacking the cyclopropane ring

hitherto appeared to be essential for insecticidal activity. ?he

discovery of fenvalerate 107 (Chno fi z., 19761, a pyrethroid without a cyclopropane ring, made a new lamhark in the chemistry of

synthetic pyrethroids. lXey reported that replacsment of the

isoprowl group by an ethyl, isopropenyl ,or a tert .butyl group gave

active analogues.

Ihe 4-chlorophenylisovalerate esters 108 of a-cyano-3-(4-halo-

~~enaxy1 benzyl alcohols were reported with f luoro, chloro and bram

substitutions as useful insecticides and acaricides. (Suzuki g @. ,

1980)

108 x = F, ct o r 5 r N

SYnthesis and insecticidal activities of pyrethroid esters

derived f r m 3~t~l-2-[3,4-dihy&onBplthyl) butanoic acid 2 with

Page. .37

pyrethroid alcohols were reported. (Hhieeler, 19841.

129

Nakagawa 5 &., (1987) studied the esters derived frm both the

exo- and endo-isomers of 2,3-trimethylenenorbornane- 2-carbmcylic

acids with pyrethroid alcohols and reported that the esters and

111 exhibited a high level of activity when esterified with 3-phenaxy - mndeloni trile.

10

The esters of the type 112 with bicyclo [Z,Z,llhe~tene carbox~lic acid were prepared and tested for insecticidal activity considering

the Steric resanblance to that of Z,2,3,3-tetrmthyl cyclopropane

carboxylic acid esters. (Furuhata and Matsui, 19871.

Page. .38

Esters of cerboxylic acids (a-8) with a cleaved type of

cyclopropane ring betwen the C-2 and C-3 bond in tetrarathyl-

cyclopropane carbaxylic acid with pyrethmidal alcohols showed less

insecticidal activity than fenpropathein 2 (Furuhata i., 1987).

Various acyclic carbaxylic acid esters with 3-phenoxybnzyl

alcohol were developed and tested for insecticidal activity, Amng

than, two conpounds 114 and 115 were found to have significant

insecticidal activity (Ckada g g. , 19801.

Ayad and Wheeler (1984) reported the synthesis and biological

activities of pyrethroid esters derived f ron different hal0-4-

alkenoic acids. ?he 3-phenoxybenzyl ester of 5,5-dichloro-2-

isopropyl-4-pentenoic acid known as secopemthrin 116 has been

reported. (Taylor and Shmanchuk, 19841

Page. -39

Henrick g g., (1980s) found that substi tuted 2-amino-3-methyl-

butanoatee showed prcanising insecticidal activity. In particular,

substi tutsd 2-anilino-3-methyl-butanoates were active insecticides

which showed considerable activity against houseflies than the

corresponding phenoxy, phenyl thio, benzyl, anilinanethyl, benzylamino

or benzmnido analogues. The most promising ester fran 2-anilino-

3-methyl-butyrates, from the standpoints of both biological activity

and stability was fluvanilate 117.

117 rCI

The aromatic ring of the acid part of fenvalerate was replaced by

6 heterocyclic ring containing nitrogen (Henrick &. , 1980bl. A

nunber of ring substituted 3-methyl-2-(3-pyrrolin-1-yl)butanoates,

3-mthyl-2-( 1-pyrrolyl)butanoates and related structures showed some

activity. They reported a new class of insecticidal 2-[isoind~lin-

2-yllalkanoates of hich the mat biologically active carpound was

oL -~yano-3-phe~~zyl-3-met&l-2-(4,5,6,7-tetrafl~0r0i~0ind0lin

-2-~llbutyrate 118.

Page. .40

Wiittle Gal., ( 1 Y B 7 1 reported the insecticidal activity dguinst

houseflies of 3-phenaxybenzyl-3-methyl-2-[2-(l-methyl-cyclopro~1]-

5-pyrimidlnyl lbutyrate 119 and related caqmunds.

Close isosteres of fenvalerate in which isopropyl was replaced by

cycloalkyl groups were studied for insecticidal activity and It was

reported that the ester 120 in which the isopropyl group was replaced by cyclopropyl group showed insecticidal activity as that of the

parent canpound. (Elliott g g.. 1980).

1 2

Elliott fi &., (1983) also prepared a nunber of analogues of

fenvalerate in which non-aryl suhstituents replaced the 4-chloro-

Fbnyl group. In particular, esters of 3-methylbutanoic and 3-

methyl-3-butenoic acids were prepared, but very little activity was

found.

Page. .41

Henrick g., [1983) described a series of vinylogous analogues

of 3-phenoxybenzyl-3-methyl-2-phenyl-butanoate and found that the

4-(4-f luorophenyl)-2-isopropy1-3-but0noate 121 exhibited higher

sctivi ty as that of fenvalerate. Substitution at C or C in the 3 4

2-isopropyl-4-phenyl-3-butenoates with a chloro or methyl group

resulted in lowering of activity.

In the same study, they found that the 3-phenoxybenzyl esters of

2-I 2-indeny1)- 122, 2-(2- naphthy1)- 2, 2-(2-benzo[b] thieny1)- 124 and 2-(2-benzo[blfuranyl)- 125 3-methylbutanoic acids also showed

high insecticidal activity.

Randad and Kulkarni (1984) reported the larvicidal activity of

the type g.

Wification of the phenyl ring in the acid moiety of fenvalerate

by substituting a difluormthoxy group in the para position resulted

in flucythrinate 127, an affective insecticide (Whitney and

Wet tstein, 1979).

The replacement of isopropylrnethyl groups by trif luormthyl

groups in fenvalerate resulted in a novel pyrethroid ester (Mack

and Hanack, 1989) .

Page. .43

2.5 hbdilications in the central ester linkage.

So far, many synthetic pyrethroids with remarkable insecticidal

potency have been discovered through malif ication of the acid and

alcohol moieties in the natural pyrethrin. But all the canpounds are

known t o contain the central ester linkage. When the ester linkage

in the non-cyano analogue of fenvalerate was replaced by an mime-

ether, the activity was retained in the resulting non-ester

pyrethroid 129. (Bull Bt g., 1980; Nanjyo 5 g . , 1980)

Svendsen and Pedersen (1987) studied the insecticidal activities

of oxime ethers and sane unsaturated canpounds of tta type 130 6 131. -

I L O , X = NOR

131, w s CR'R' - Eventhough the non-ester pyrethruids with oxime ethers were

showing pmmising insecticidal potential, their persistence under

field conditions was too low. 'Iherefore a new group of ether

Page. .44

pyrethroids was s tuciiod and one canpound, etofenprox 132 (MTI-500) effective against agricultural pests was reported (Nakatani g.,

1962)

Svendsen 2 &. , (1986) reported the insecticidal activities of

bis aralkylketones of the type 133. Several structural variations, including substituent exchange in the aryl mieties, the position of

the ketone function and increase or decrease of the length of the

carbon chain connecting the two aryl moieties, were studied.

'IT@ synthesis of non-ester pyrethroids with central alkene

linkage was studied by Elliott (1985) who reported that the ccmpound

134 was effective, Elliott and co-workers (1988) studied the effect - Of replacement of the central linkage in pyrethroids by isostoric Or

isoelectronic group on insecticidal activity. Particularly

interesting central groups are -a3M -and -(91=CH-M -. 2 2

Page. .45

Baydar 2 &. , (1988) studied the insecticidal activity of a wide

range of canbinat ions representing simultaneous variation in

different f rapnts of non-ester pyrethroids to understand the

optimal interaction between the canponents for designing canpounds

with higher insecticidal activity.

Yanada g g., (1987) reported the insecticidal activities of

organosila pyrethroids of the type 135. R'= OEt. OMe,

E L . F . C t

X = C U P 0' 0

135 Cy

Tshushino g g., (1989) studied the insecticidal activities of a

novel range of trimethylsta~ianethyl ethers 136 of pyrethroidal

alcohols.

Page. . 4 6

2.6. Structure activity relationships.

?he biological activities of pyrethroids are intimately related

with their chemical structure (Elliott, 1970). In the developnent of

new chanical control agents, it is necessary to understand the

relationship betwen the structure of the canpound in relation to

various physicochemical properties like lipophilicity, steric and

electronic factors and the biological activity.

Elliott g., (1974b) reported the need for two centres of

unsaturation in the alcohol unit and the two centres should not be

coplanar for potent activity. Miyakado g., (1975) studied the modified phanylacetates of optically active d -isopropyl-

4-substituted phenylacetic acids with 5-benzyl-3-furylmethanol and

reported that the esters of the optically active ( S ) - ( + I - acids were

nearly twice toxic to houseflies than the racemic esters. Elliott 6

Janes (1978b) reported that the potencies of synthetic pyrethroid

esters were sensitive to the structure and chirality of the acidic

and alcoholic components.

The pyrethroid esters with dihalovinyl side chain in the acid

WJiety were shown to have high potency against houseflies in the

0-r with respect to different halo groups as F > C 1 > Br > 1.

(Norton g.. 1976)

Page. .47

'me toxicity of various isameric mixtures of allethrins against

houseflies sholhgd that the activity was fully' realized in the

optically pure form and considerable masking of activity occurred in

the racemic form (Wickhmn, 1976). The structure activity relationship

in pyrethrin and related pyrethroid esters showed that an optim

value for lipaphilicity was essential in influencing the insecticidal

activity against houseflies. (Briggs fi &. , 1976)

'h structure-act ivi ty relationship in a nunber of stereoisomers

of fenvalerate esters showed that the ester with S-acid and R-alcohol

was more effective than S-acid and S-alcohol against mosquitoes

[Nakayama st g. . 1978). The structure activity relationship in

phenothrin analogs for insecticidal activity against houseflies

shaved that confomtional as well as partition coefficients played a

role in determining the activity. [Hopfinger and Bettershell, 1978)

Ford, (1979) studied the structure-activi ty relationships of two

congeneric series of pyrethroid insecticides against houseflies using

multiple regression analysis and substitwnt constants.

Wntitative Structure-Activity Relationship (QSAR) of pyrethroid

esters synthesized with a series of 3-substituted benzyl alcohols has

Bhm that the bridging atan betneen the two centres of unsaturation

not essential for g& activity (hgel st g., 1983). study

with a nudmr of substituted benzyl chrysanth-tSS for neui-0-

Page. -48

physiological activities against cockroaches showed that both

position and optimun van der waal's volune (steric factor) wore found

to influence the activity. (Nakagawa 2 g. , 1982a)

' he QSAR studies of substituted benzyl chrysanthemates for

knockdown activity against houseflies indicated that the rate

constant was correlated with the hydrophobicity (Nishimura etg., 1982a). Another study with substituted benzyl chrysanthemates for

neuroevcitatory activity on the crayfish showed that the rate of

penetration into the nerve tissue was found to be enhanced by the

hydroNilicity as well as the electron-withdrawing substituents.

(Nishimura g g . , 198213)

h n g the benzyl chrysanthemates studied for convulsive and

lethal activities against cockroaches the steric effects and position

of the substituents played an important role for causing variation in

the activity, (Fujita etg., 1983)

The influence of physicochdcal parameters on the insecticidal

activities of pyrethroid esters, their mime ether, thiol ester and

amide analogs against houseflies showed that the activity was found

to be associated with the dipole m n t and polarisability of the

central linkage (Brown and Casida, 1984).

Page. .49

studies of substituted benzyl chrysanthemates for calciun

uptake inhibition in crayfish demonstrated a parabclic relationship

betwen the inhibition of calci~ uptake and lipophilicity (Doherty

u l u l . , 19UG). '111~ t ~ u l u l lu~lbl t lp b u l w u n Llla ) I l ~ y a l ~ u u l w r ~ ~ i c u l - - properties and the speed for neurotavicity for a series of knzyl

cyclopropane carbaxylates dmnstrated a relationship between the

activity and size and electron donating ability of the substituents

at C and C of the benzyl ring. (Ford &. , 19851 3 4

The structure-activi ty relationship of a -cyanobenzyl chrysanthe-

mates was studied for knockdown activities against houseflies with

respect to hydrophobicity, steric factor and stereoelectronic

properties (Hatakoshi et al.. 1985). Nishimura et al.. (1985)

reported that in determining the knockdown activities against

houseflies with meta and para substituted benzyl chrysanthemates, the

steric factor played the most significant role.

Studies M the neurophysiological effects of substituted

benzylchrysanthemates against cray fish in relation to physico-

chemical properties showed that the activity was influenced by the

electron releasing substitusnts on the armtic ring. (Qnatsu g..

1985).

Elliott g. , (19861 reported that the activity of

blOS~bstituted allylbenzyl esters depended on the position and

stereochistry of substitution in the ally1 ulda-chain,

substitution pattern on benzyl, esterifying acid, and to a lesser

extent, on the nature of the halogen subtituent itself. GSM studies

with IDT-pyrethroid esters for insecticidal activity against

cockroaches showed that the variations in the activity were

parabolically correlated with the van der waal's volune of armtic

substituents (Nishimura fi g. , 1986)

The structure activity relationships by the use of

physicochsmical paraneters and regression analysis showed the

importance of molecular shape and hydrophobicity to the insecticidal

activity in pyrethroids containing a heterocycle in their alcohol

moiety (Ohsuni fi g., 1987). Nishimura etg., 1987 reported that the most important parameters influencing the activities of a series

of benzyl pyrethrates were hydrophobicity and the steric factors.

Yang fi &., (1987) studied the physicochsmical substituent

effects in different pyrethroid esters for insecticidal activity

against cockroaches and reported that the variations in the activity

were related parabolically to both hydrophobicity and the length of

the substituent.

'l?m QSAR studies with tetremethrin and related canpounds with

imide and lac tam s tructures for knockdown act ivi ty against

houseflies showed that the -t significant pareneters correlated

Page. - 5 1

with the activity were hydro@bici ty and steric factors. (Nishimura

et al., 1988) --

Winkler e t g . , ( 1 9 8 8 ) studied the quantitative structure activity

relationships in pyrethroidal ethers and reported that the molecular

size and polarisability should not be too large for insecticidal

activity with an optimun lipophilicity of 5.5. ACjSM study of

pyrethroids with respect to the physicochical properties and the

rate of developnent of residual and tail sodiun currents in crayfish

giant axons showed that the rate constants varied parabolically with

hydrophobicity of the molecule. [Kobayashi &. , 19881,

Livingstone g., (1988) reported a multivariate @.Q study.of

pyrethroid neurotaxicity basd upon molecular paraneters like

hydrophobic, steric and electronic properties derived by canputer

chemistry.

The use of multivariate QSAR studies in different substituted

bnzyl chrysanthemetes for biological activity against houseflies

revealed that the activity was influenced by the presence of a

partial positive charge at a meta carbon in the benzyl ring of the

alcohol moiety, small nucleophilic superdelocalisabili t ies on the

carbonyl carbon and oxygen atans of the ester linkage and chl01-0

substitwnts in the terminal carbon atom of the vinyl side chain in

the acid miety. (~ord &. , 1989)

Page. .52

With this background information, the synthesis of 2-(subst i tuted

phennxyl-3-mthylbutanoates was undertaken. These esters were tested

for both larvicidal and adulticidal activities against Culex quinque-

fasciatus, the filariasis vector to study the structure-activity

relationship with respect to the nature and position of the

substituents in the acid moiety, three different alcohols and

physicochemical substituent parmeters.