Pestic. Sci. 1986, 37, 691-700

The Pyrethrins and Related Compounds. Part XXVIII‘: Alkenyl- and Alkynyl-substituted Benzyl Esters

Michael Elliottb, Richard L. Elliott‘, Norman F. Janes, Bhupinder P. S. Khambay and David A. Pulman

Department of Insecticides and Fungicides, Rotharnsted Experimental Station, Harpenden, Hertfordshire AL5 2JQ

(Revised manuscript received 4 December 1985)

Over 100 benzyl esters of pyrethroidal acids were synthesised and tested for insectici- dal activity to establish detailed structure-activity relationships in compounds with side-chains similar to those in the natural pyrethrins. Alkenyl, and corresponding alkynyl, side-chains were effective, both at the 3- and 4-positions, as were side-chains with extended substitution in either E or Z forms. A cyano group at the a-position increases activity if the side-chain is at C-3, but lowers it drastically if the substituent is at C-4. Similarly, methyl groups at C-2 and/or C-6 may increase activity whether the unsaturated side-chain is at C-3 or (2-4, but only in the absence of an a-cyano group.

1. Introduction

The present range of powerful, photostable synthetic pyrethroidsl,2 can be considered to have evolved from the discovery, in 1965, of the insecticidal activity of allylbenzyl chrysanthemate (Figure lb; R = 4 - a l l ~ l ) , ~ . ~ and the concept5 that the benzyl unit in this compound could serve as a spacer unit, replacing the cyclopentenone system of allethrin. At that time, the effects of a few variants of the ally1 group and of some additional substituents in the ring were examined. However, no subsequent studies have been published even on the effect of introducing side-chains analogous to those present in the natural products (pyrethrins, cinerins and jasmolins).I Further, the optimum position (3- or 4-) for side-chains on structures based on Figure lb , and whether a substituents are advantageous has not been examined. The present paper seeks to examine the effects of such substitutions which are directly relevant to establishing the principles of structure-activity relationships in pyrethroids.

2. Experimental methods

2.1. General Methods for determining the ‘Hand I3C nuclear magnetic resonance (n.m.r.) spectra of synthesised compounds have been described previously.6 The term ‘processed’ in descriptions of syntheses implies extraction with ether, washing the organic layer with saturated sodium hydrogen carbonate solution, followed by saturated sodium chloride solution, drying over sodium sulphate and removing solvent using a rotary evaporator, to yield a residue of product.

2.2 Synthesis (general procedures) Syntheses of the compounds tested are summarised in Table 1 by a series of letters indicating the procedures described below. Biological and some physical properties are reported in this paper, but

“Part XXVII Pesric. Sci. 1983, 14, 9-16. Present address: Pesticide Chemistry and Toxicology Laboratory, Department of Entomological Sciences, 115, Wellman

Present address: Beecham Pharmaceutical Research Division, Animal Health Research Centre, Walton Oaks, Dorking Hall, University of California, Berkeley, California, 94720, USA

Road, Tadworth, Surrey, K R O 7NT.

69 1

M. Elliott ef ul. 692

Figure 1. Structures of previously examined compounds.

Table 1. Synthesis and insecticidal activities of esters prepared

Structure of alcohol component (Figure 2a)

Relative biological activity

( l R ) - t r ~ . ~ - (lR)-cis chrysanthemate DBDCCb

Compound Alkenyl At Substituent Y Methodsofsynthesis" HFc MB' HF MB

I n

Ill N V

v1 w VIII M X XI

XI1 xm XIV xv XVI XVU

X V m XIX xx XXI X W XXilI XXIV XXV m XXMI

XXvllI

Allyl 3 Allyl 3 Allyl 4 Allyl 4 Allyl 3 Ally1 3 Allyl 3 Allyl 3 Ally1 4 Allyl 4 2-Methylprop-2-enyl 3 2-Methylprop-2-enyl 3 2-Methylprop-2-enyl 4 2-Methylprop-2-enyl 4 (Z)-But-2-enyl 3 (Z)-But-Z-enyl 3 (Z)-But-Z-enyl 4 (Z)-But-2-enyl 4 (Z)-Pent-Z-enyl 3 (Z)-Pent-Z-enyl 3 (Z)-Pent-Z-enyl 4 (Z)-Pent-Z-enyl 4 (Z)-Pent-2-enyl 3 (Z)-Pent-Z-enyl 3 (E)-Penta-2,4-dienyl 3 (E)-Penta-2,4-dienyl 3 (E)-Penta-2,4-dienyl 4 (Z)-Penta-2,4-dienyl 3

H CN H CN H CN H CN H CN H CN H CN H CN H CN H CN H CN H CN H CN H H

Reference 4 m. A, B Reference 4 m, J 3BrMBK. A, B 3BrMBK, A, B 3BrDMBK. A, B 3BrDMBK. A, B Reference 4 4BrDMBK. A, B w, A, B u, A, B G, A, B 4-, A, B 3PJ, H, I, B 3PK, H, I, B

4 m , H, I , B 3BrBK. BrPYN, A, I. B 3BrBK. BrPYN, A, I, B 4BrBK, BrPYN, A, I , B 4BrBK, BrPYN, A, I , B 3BrMBK, BrPYN, A, I, B 3BrMBK. BrPYN, A, I , B 3BrBK, BrPEN, A , B 3BrBK. BrPEN, A, B 4BrBK. BrPEN, A, B 3PJ, M, K, B

E, H. I, B

2.5 c.1 18 18 19 0.3 0.6 n.t.d

15 3.9 n.t. n.t. 8.5 5.2 n.t. n.t.

19 5 n.t . n.t. 5.1 0.8

33 6.6 11 1.6

c.2 n.t. 2.4 1.5

26 17 6.1 0.8 0.4 n.t. 0.5 c.O.2 3.4 12

c.1 n.t. n.t. n.t. 1.4 0.7 n.t. n.t. 4.8 0.3

22 6.5 1.9 n.t. 2.4 25

1.5 5.3 33 44 20 5.9 0.5 0.7

120 43 1.6 1.1

45 23 13 0.6

1x0 95 n.t. n.t. 90 7.1 98 29 96 6.2 c.3 c.0.5 56 10 61 52 30 3.0 0.9 1.1

12 3.6 110 12 34 2.9 c.0.5 n.t.

9.6 9.1 0.5 0.6

70 4.8 45 14 51 1.0 87 7.2

Pyrethrins and related compounds 693

Table 1. Conrinued

Structure of alcohol component (Figure 2a)

Relative biological activity

I1 R)-rrum- (lR)-cis , I

chrysanthemate DBDCCb

Compound Alkenyl At Substituent Y Methods of synthesis‘ HF‘ MB‘ HF MB

xxrx xxx

XXXI XXXII

XXXIII XXXIV xxxv

XXXVI XXXvn

XXXVIII XXXIX

XL XLI

XLII

XLIII

XLIV XLV

XLVI XLVII

XLVIII XLIX

L LI

LIII L N LV

L n

(Z)-Penta-Z,Cdienyl (Z)-Penta-2,4-dienyl (Z)-Penta-2,4-dienyl (E)-Penta-Z,Cdienyl (E)-Penta-2,4-dienyl (E)-Penta-2,4-dienyl 1-Vinyl-prop-2-enyl Prop-2-ynyl Prop-2-ynyl Prop-2-ynyl Prop-2-ynyl But-2-ynyl But-2-ynyl But-2-ynyl

But-2-ynyl

Pent-2-ynyl Pent-2-ynyl Pent-2-ynyl Pent-Cen-2-ynyl Vinyl Vinyl Allenyl Allenyl (Z)-Buta-l,3-dienyl (Z)-Buta-1,3-dienyl (E)-Buta-l,3-dienyl (E)-Buta-1,3-dienyl

3 4 4 3 3 4 3 3 3 4 4 3 3 4

4

3 3 4 3 3 4 3 4 3 4 3 4

CN H CN

2-Me H 2-Me CN 2,6-Me2 H

H H

- - -

9.1 3PK, M, K, B - E, M, K, B 7.0 n.t. 4PK, M, K, B c.0.3 n.t. 3BrMBK. BrPEN, A, B 1.8 0.6 ___- 3BrMBK, BrPEN, A, B c.0.3 n.t. ~- 4BrDMBK, BrPEN, A, B c.1 0.2 ~- 3BrBK. BrPEN, A, B 0.8 c.0.5 K K , B 8.2 1.5

170 14 170 9.4 c.0.3 c.0.2

4.5 7.7 c.0.5 0.5 11 4.3 24 1.4 13 7.8

CN = , B 5.4 8.5 11 17 H 4PK, B 15 0.6 38 4.1 CN E , B 2.8 0.6 2.0 1.3 H K K , H , B c.0.5 0.8 3.2 8.0 CN K K , H , B 11 15 11 40 H C K , H , B

or4BrBK,BrBYN, A, B 15 2.7 120 29 CN - ,H,B

or4BrBK,BrPYN,A,B c.0.5 c.O.1 2.6 c.1 H 3BrBK, BrPYN, A, B c.0.3 n.t. 1.4 3.1 CN 3BrBK, BrPYN, A, B 5.9 6.7 4.6 c.6

21 4.6 H 4BrBK, BrPYN, A, B - - H = , M , B 0.3 3.7 0.9 1.8 H m , G , D 11.4 n.t. 3.4 0.6 H m , G , D - n.t. 7.7 0.8 H = , L , B 4.2 0.4 10 3.3 H 4PJ,L,B 4.4 0.2 2.2 1.6 H m, G , C , D 1.1 0.7 1.8 1.6 H e , G , C , D 2.1 n.t. 5.3 0.9 H w , G , C , D 0.5 n.t. 1.2 1.5 H m , G , C , D n.t. n.t. n.t. n.t.

~~~

“Underlined symbols refer to intermediates described in section 2.3., letters to the procedures described in sections 2.2.1 to 2.2.13. Except for compounds IV, XLVIII, XLIX, LII-LV, the route summarised leads to the aldehyde which was purified by h.p.1.c. (procedure C) then reduced to the alcohol (Y=H) (procedure D) and usually alsoconverted tothecyanohydrin (Y=CN) (procedure E). Both products were esterified (procedure F) with the two acids.

( 1R)-cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate. ‘HF=housefly (Muscu domestica L.), MB=mustard beetle. Activities (relative to bioresmethrin=lW) were determined by

topical application.I6 an. t. =non-toxic.

further details of physical properties (n2, some n.m.r. assignments) are given for each individual compound in the supplementary materia1.O

2.2.1. Procedure A: bromobenzaldehyde ketals to alkenyl/alkynyl benzaldehyde ketals A flask containing magnesium (0.23 g, 9.5 mmol) under nitrogen was dried using a hot-air blower, cooled, and sufficient tetrahydrofuran was added to cover the magnesium. After stirring with a crystal of iodine for 5 min, a small portion of a solution of the bromoketal (8.23 mmol) in tetra- hydrofuran (10 ml) was added and stirring continued until the Grignard reaction started (loss of iodine colour), then while the remainder of the ketal was added, and for a further 1 h. This Grignard mixture was transferred by syringe to a mixture of copper (11) bromide (0.12 g, 0.84 mEq) (or equivalent amounts of copper (11) chloride and lithium chloride)’ in tetrahydrofuran (15 ml) containing the alkenyl bromide (12.3 mmol) at -20°C with rapid stirring, which was continued while

Yorkshire, UK, as Supplementary Publication No. SUP 11001 (7 pages). “The supplementary material (3 tables) has been deposited with the British Lending Library at Boston Spa, Wetherby. West

694 M. Elliott er al.

the mixture was allowed to warm to 20°C during 1 h. Saturated aqueous ammonium chloride (20 ml) was added, the tetrahydrofuran layer and diethyl ether extracts (2x40 ml) of the inorganic layer were combined and evaporated on a rotary evaporator to leave a residue of the product.

2.2.2. Procedure B: benzaldehyde ketals to benzaldehydes The residue from procedure A was dissolved in tetrahydrofuran (50 ml), cooled to 0°C and treated with hydrochloric acid (3 M, 5 ml) with stirring. After 30 min at 20"C, the tetrahydrofuran was removed using a rotary evaporator and the residue processed.

2.2.3. Procedure C: preparative high-performance liquid chromatography (h.p.1.c.) purification The mixture (0.1-0.5 g) in light petroleum was injected on to acolumn (3.5x20 cm) of silica (100 g, compressed at up to 1 MPa) (Merck 60H, 15 pm, or Lichroprep Si 60,15-25 pm) in a Chromatospec Prep apparatus (Jobin Yvon), operating at 400 kPa, and eluted with light petroleum containing a small proportion of diethyl ether through a Cecil variable wavelength ultraviolet (u.v.) detector (CCE 212A).

2.2.4. Procedure D: reduction of benzaldehydes and benzoates to benzyl alcohols The aldehyde or ester as a 10% solution in diethyl ether was added dropwise to a suspension of lithium aluminium hydride (0.4 or 0.6 molar equivalents respectively) in diethyl ether with stirring, and the mixture was then boiled under reflux for 1 h. After cautious addition of water (1 ml g-' of hydride) followed by aqueous sodium hydroxide (15%; same volume), and then more water (three times this volume), the mixture was processed.

2.2.5. Procedure E: benzaldehydes to cyanohydrins To a solution of potassium cyanide (2.4 g) in water (4 ml) containing tetrahydrofuran (10 ml) cooled to 0°C was added a solution of the benzaldehyde (1.5 g) in tetrahydrofuran (15 ml). The tempera- ture was kept below 5°C while sulphuric acid (40%; 5.2 ml) was added with stirring, then allowed to rise to 20°C during 1 h. N.m.r. monitoring of the aldehyde peak in the organic layer showed whether addition of further cyanide and acid was necessary. When the reaction was complete, water was added, followed by dichloromethane, and the organic layer was washed with water, dried, and the solvent evaporated.

2.2.6. Procedure F: esterification This has been fully described previously.'j

2.2.7. Procedure G: Wittig reaction of benzaldehydes Butyl-lithium (2.09 g, 32 mmol, as a 15% solution in hexane) was added under anhydrous conditions to a suspension of the phosphonium bromide (32 mmol) in ether (500 ml) and stirred for 30 min at 20°C. The 3- or 4-methoxycarbonylbenzaldehyde (30 mmol) in ether (250 ml) was added gradually, the mixture was kept at 20°C for 1 h, and then refluxed for 30 min. After cooling, water was added, and the mixture was processed.

2.2.8 Procedure H: alkylation of prop-2-ynyl compounds The prop-2-ynyl ketal (intermediate 3PK or 4PK) (1.5 g, 8.0 mmol) in tetrahydrofuran (10 ml) was cooled to -78°C under dry nitrogen, and a solution of butyl-lithium (8.0 mmol, concentration 1.55 M) in tetrahydrofuran ( 5 ml) added dropwise from a syringe during 30 min, when the mixture became dark red. The cooling was maintained while a solution of methyl iodide (2.27 g, 16 mmol) in tetrahydrofuran (4 ml) was added dropwise from a syringe. After the mixture had warmed to 20°C over 1 h it was poured into saturated aqueous ammonium chloride and processed.

2.2.9. Procedure I: acetylene to (2)-olefin The acetylene (1 part) in pyridine (30 parts) containing palladium on barium sulphate (10%; 0.2 parts) was shaken at 20°C in a conventional hydrogenation apparatus (pressure= 100 kPa) until the

Pyrethrins and related compounds 695

theoretical amount of hydrogen had been absorbed ( 1 molar equivalent; typically 30 min). The mixture was filtered, and concentrated on a rotary evaporator.

2.2.10. Procedure J: alcohol to aldehyde The alcohol (0.5 g) in dichloromethane (15 ml) was treated with pyridinium dichromate (1.92 g) and progress of the reaction followed by thin layer chromatography (t.1.c.). After 4 h, light petroleum (30 ml) was added and the mixture was filtered through a bed of charcoal and celite. The colourless solution was concentrated on a rotary evaporator.

2.2.11. Procedure K: reduction of acetylene with zinc The enyne (1.3 g) in propanol (90 ml) and water (90 ml) containing zinc powder (87 g) and potassium cyanide (4.55 g) was stirred for 16 h at 20°C, then filtered through celite. The filtrate and washings were diluted with ether, then processed. The residue, containing mainly (Z)-diene, but with some (E)-isomer, was dissolved in benzene and tetracyanoethylene (0.3 g) added. After 30 min at 20°C, the mixture was passed through a florisil column and the unreacted (Z)-diene eluted with 10% diethyl ether in light petroleum.

2.2.12. Procedure L: rearrangement of prop-2-ynyl to allenyl A solution of the prop-2-ynyl compound (intermediate 3PK or 4PK; 0.7 g) in dry carbon tetra- chloride (15 ml) containing potassium tert-butoxide (0.2 g) was refluxed for 3 h, then cooled and shaken with water. The residue obtained from the organic layer was only partially converted to the allene, so it was subjected to the same treatment again, when conversion was complete.

2.2.13. Procedure M: vinylation of prop-2-ynyl group A solution of the acetylene (intermediate 3PK) (2.0 g, 10.6 mmol) in benzene (50 mi) was treated with copper (11) iodide (0.1 g), tetrakis (triphenylphosphine) palladium (0.6 g, 0.5 mmol) and n-butylamine (1.6 ml, 21.9 mmol) (compare reference 8) cooled to 10°C, and vinyl bromide (5 ml) distilled from phosphorus pentoxide into the flask via a pipette below the surface of the stirred liquid. After 16 h at 20°C, the mixture was concentrated, dissolved in carbon tetrachloride and chromato- graphed on florisil. 10% diethyl ether in light petroleum eluted the 3-(pent-2-yn-4-enyl)- benzaldehyde ketal.

2.3. Synthesis (intermediates) Application of the above procedures to the particular cases listed in Table 1 often involved less accessible intermediates for which either a reference to the previous synthesis or a description of the method used is appropriate.

2.3.1. Previously synthesised intermediates 4-Allylbenzyl alcohol4 (ABA); 3- and 4-bromobenzaldehyde ethylene ketalsY (3BrBK, 4BrBK); 3- and 4-methoxycarbonylbenzaldehydes (method as in reference 9, data as listed in Table 2 of the supplementary material) (3MB, 4MB); 1-bromobut-2-yne and 1-bromopent-2-yne'" (BrBYN and BrPYN); l-bromopenta-2(E), 4-diene" (BrPEN).

2.3.2. 3-Bromo-2methylbenzaldehyde ethylene ketal (3BrMBK) 3-Brom0-2-methylaniline~~ was converted to 3-bromo-2methylbenzaldehyde via the diazonium salt, which was reacted with formaldoxime following the method describedI3 for a closely related compound. The isolated aldehyde, b.p. 6674°C at 0.03 mm, (other properties are listed in Table 1 of the supplementary material) (9.3 g, 49.7 mmol) in dichloromethane (50 ml) was treated with 1,2- di(trimethylsily1oxy)ethane (11.3 g, 54.9 mmol) followed by a catalytic amount (6 drops) of tri- methylsilyl trifluoromethanesulphonate at -78"C, then allowed to warm to room temperature. After adding pyridine (10 drops), saturated sodium hydrogen carbonate solution (100 ml) and diethyl ether (80 ml), the mixture was processed and then distilled to give the product (11.1 g, 97%) b.p. 86-103"C/0.02 mm, (other properties are listed in Table 1 of the supplementary material).

6% M. Elliott er 01.

2.3.3. 3- and 4-Bromo-2,h-dimethylbenzaldehyde ethylene ketals (3BrDMBK, 4BrDMBK) 3-Bromo-2,6-dimethylanilineL4 or its 4-bromo a n a l o g ~ e ' ~ were converted by the methods described in section 2.3.2. to 3-bromo-2,B-dimethylbenzaldehyde, b.p. 70-74"C/0.03 mm, and thence its ketal, b.p. 99-103"C/0.04 mm, or to 4-bromo-2,6-dimethylbenzaldehyde, m.p. 62-64"C, and its ketal b.p. 108-118"C/0.05 mm, m.p. 99-1Ol0C, (other properties for all compounds in Table 1 of the supplementary material).

2.3.4. 3- and 4-(Prop-2-ynyl)benzaldehyde ethylene ketals (3PK, 4PK) These compounds were made by a variation of procedure A, in which the alkenyl bromide was replaced by metho~ypropa-1,2-diene.'~ The 3-bromobenzaldehyde ketal gave 3-(prop- 2-yny1)benzaldehyde ethylene ketal, b.p. 80-90"C/0.05 mm, n@ 1.5422, n.m.r. peaks at 2.2 (1 H. t,

m, aromatics). The 4-(prop-2-ynyl) compound was synthesised similarly and had n.m.r. peaks at 2.1

(4 H, m, aromatics).

2.4. Biossay Insecticidal activities against adult Musca dornestica L. (housefly) and Phaedon cochleariae Fab. (mustard beetle) were assessed by topical application of measured drops of solutions of the com- pounds in acetone as described.I6 Results (Table 1) are reported as relative activities, using bioresmethrin (= 100) as standard.

J=~Hz,=CH)~.~(~H,~,J=~HZ,CH,C=),~.~ (~H,s,~XCH,O),~.~(~H,S,CHO),~.~(~H,

(1 H, t, J=2Hz,=CH),3.6(2H,d, J=~Hz,CH~C=),~.O(~H,S,~XCH~O),~.~(~ H, S , CHO)7.4

sub

Mg, HalCH2CRl=CHRz

sub C H r O C H r O

H' fl; kenyl - HO - Esters HCN or LiAIH,

Y (3)

Y=H or CN

)@Br Diazotisation

then CH2=NOH

sub NH2

)@Br Diazotisation

then CH2=NOH

sub NH2

Figure 2. General routes used to synthesise required compounds.

Pyrethrins and related compounds 697

3. Results and discussion

3.1. Synthesis The key intermediates for synthesis of many of the compounds listed in Table 1 were the bro- mobenzaldehyde ketals, which, as their Grignard reagents, were converted to the corresponding alkenylbenzaldehyde ketals. Thence, hydrolysis, purification of the aldehyde by h.p.1.c. and reduc- tion (Y=H) or reaction with cyanide (Y=CN) gave the alcohol which was esterified with (lR)-truns chrysanthemic acid or (1R)-cis-3(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylic acid (Figure 2a). The intermediates used were either known compounds synthesised by standard routes (Br at 3- or 4-, ~ u b = H ) ~ , or were synthesised (Br at 3- or 4-, sub=2-Me or 2,6-Me2) from the

aniline (Figure 2b). Alkenyl halides used were ally1 bromide, 3-chloro-2-methylprop- 1-ene and l-bromopenta-2(E),4-diene, but the penta-2(Z),4-dienyl derivative was not accessible by this route. In the pentadienyl case, the 1-vinylallyl derivative was isolated as a valuable second product. Alkynyl groups were introduced using 1-bromobut-2-yne or l-bromopent-2-yne, or, for the simple prop-2-ynyl substituent, methoxypropa-l,2-diene. (Figure 2c). These products, referred to as intermediates 3PK and 4PK in the experimental methods section, proved important because they offered routes to side chains otherwise inaccessible. Thus, simple isomerisation in a strong base gave the allenyl compounds, and replacement of the acetylenic hydrogen by alkyl or vinyl using copper- catalysed coupling, followed by controlled hydrogenation gave the less easily synthesised ( Z ) - olefinic derivatives.

For the vinyl and butadienyl side chains, Wittig reactions on 3- or 4-methoxycar- bonylbenzaldehyde followed by h.p.1.c. separation of Z and E isomers in the latter case, gave compounds XLVIII, XLIX, LII-LV.

3.2. Confirmation of structures by n.m.r. spectroscopy IH n.m.r. spectra were recorded for all intermediates and final esters and 13C n.m.r. spectra were recorded for intermediates, as appropriate, and for all final esters, and these were used to confirm structures and purities. The chemical shifts and intensities of peaks in the final ester spectra (both IH and I3C) were as predicted from the spectra of their component alcohols and The complete data and assignments for all these spectra are reported in the supplementary material for this paper, and fully support the assumed structures.

Such spectra were particularly powerful in distinguishing between compounds in which side-

Table 2. 'H and "C partial n.m.r. spectra for m- and p - side-chains in benzyl alcohols and esters:

Side chain" 'H Spectrumb "C Spectrumb

8 9 10 11 12 8 9 10 11 12 8 9 10 11 12

-CHIC CH J ( H 4

J(Hz)

J W )

-CH = C = CH,

--CH = CH-CH = CH Z

E -CH+H = CH-CH = CH2 Z

E J(W

3.7 - 2.2 - - 24.6 81.7 70.6 - -

L 6.2 - 5.2 - - 93.7 209.9 78.9 - -

7

6.4 6.8 (m) 7.1 5.3,5.5 130.0 131.2 133.0 119.8 -

6.6 7.0 (m) 5.2 5.7 (m) - 130.0 132.3 137.1 117.8 - 10 10, 15

3.6 5.6 6.2 6.9 5.2, 5.3 33.7 130.2 130.2 131.8 118.1

3.6 5.0 to 6.9 (m) 38.7 133.1 132.3 136.8 115.8 7 11 11 11, 15

"Spectra from side chains in m- and p-compounds differed insignificantly. bShifts in ppm from tetramethylsilane.

M. Elliott el QI. 698

chains had rearranged or differed in stereochemistry. For instance, allenyl compounds were first detected as impurities in preparations of prop-2-ynyl compounds, but the process was subsequently exploited to produce a further structural variation (see section 2.2.12). Table 2 illustrates the diagnostic and contrasting shifts for the peaks from these isomeric side-chains. Similarly, Z and E isomers of buta-l,3-dienyl and penta-2,4-dienyl groups both differed distinctively. In those com- pounds where the IH coupling constant across the first double bond could be measured it was small (10-11 Hz), characterising these compounds as Z (in the E compounds, these spectra were too complex for analysis). Chemical shifts for carbons experiencing steric compression across this bond in the 2 isomer are typically 5 ppm less, so unequivocal assignment of stereochemistry to the two forms synthesised was possible in all cases.

Although many of the peaks in the 13C spectra of the final esters had closely similar chemical shifts, previous work in this areal8 allowed complete assignment of all the peaks with no remaining ambiguities. Peaks from the acidic components of the esters were readily recognised and assigned. Where assignment of the aromatic signals from the alcoholic component was not immediately obvious, the effect previously n ~ t e d , I ~ , ' ~ that introduction of cyano at C-a produces a consistent pattern of small, but significant changes in the shifts of all peaks from the alcohol part of the molecule, resolved the difficulty. The results for all 106 spectra are presented in Table 2 of the supplementary material. From these data, it is now apparent that the pattern of changes on

Table 3. Effect of introducing a-cyano on "C chemical shifts

1' 2 3 4 5 6 7 8 9 10

C,H--O-CbH-CH-'* -3.4 -4.2 -0.6 +0.8 +1.8 +1.1 -0.6 - -1.2 +0.3 bC,,HFX46H4-CHI'U -4.1 -0.5 +0.8 +2.0 +1.0 -0.5 - -0.5 +0.1 Present work -3.5 -4.0 -0.4 +0.9 +2.0 +0.7 -0.5 -0.1 -0.7 +0.5

Standard errors for the present work were all <+0.08 ppm (n=20 for all entries except 6 and 7, which are degenerate with 3

"Numbering as in Table 2. and 4 forp-compounds, then n=13).

X=CHz, CO, -.

introducing a-cyano [b(CN)] applies to compounds with p-side-chains as well as to those with rn-substituents studied previously. Similar 6(CN) values are observed for all side-chains, whether they are rn orp and whether they are the phenyl-X substituents studied earlier (X= 0,CH2,C0,-), or the ally1 substituents which are the subject of the present paper. The conclusions, summarised in Table 3, may be useful for further assignments in this area, but they can have little fundamental connection with biological activity, since the influence on activity of introducing a-cyano depends completely on whether the side-chain is rn orp, but the effect on C-13 shifts is almost independent of this factor.

3.3. Insecticidal activities The results of bioassays against houseflies and mustard beetles recorded in Table 1 can be used in the same way as previous data (e.g. reference 20), to give an overall assessment of the effectiveness of each side-chain in conferring activity against each species of insect. For this, recognition of other factors contributing to the obvious variation is necessary. As previously, esters of the dibromo acid are in almost every case markedly more active against both insects than those from (1R)-tram-chrysanthemic acid. With this consistent effect, both sets of results can be used in assessing other factors.

For six substituents all the eight possible esters with no other ring substituents were made. In all cases, another consistent pattern was observed: whereas introduction of an a-cyano group enhanced activity for compounds with the substituent at the 3-position, the same introduction almost com- pletely destroyed activity for 4-substituted analogues. The effect persists for the compounds reported in the following paper,*' where it is analysed quantitatively. For the present purpose it is

Pyrethrins and related compounds 699

therefore preferable to omit 4-substituted a-cyano compounds, but to weigh the contributions of the other results equally (on a logarithmic scale) in assessing the relative effectiveness of the particular side-chain.

On this basis, substituted-ally1 side chains (as in I-XLVII) are generally more effective than substituted-vinyl side chains (as in XLVIIELV). Compounds with an additional unsaturated group carried by the vinyl group (LII-LV) are only weakly insecticidal. Apart from XXXV and XLVII, which became available incidentally during the synthetic work, and represent less active compounds, all the remaining variations were sufficiently active to justify fuller examinations. The assessment based on the approach described above is summarised in Table 4 for each species of insect.

Table4. Substituentsexamined, inordepof effectiveness against the two species of insect

Houseflies Mustard beetles

2-Methylprop-Zenyl (Z)-Penta-2.4-dienyl (Z)-But-Z-enyl (E)-Penta-2,4-dienyl Prop-Zynyl

But-2-ynyl (Z)-Pent-2-enyl Pent-2-ynyl

Allyl

But-2-ynyl (Z)-But-2-enyl (Z)-Penta-Z,Cdienyl 2-Methylprop-2-en yl Allyl Prop-Zynyl Pent-2-ynyl (Z)-Pent-2-enyl (E)-Penta-2,4-dienyl

“Order computed from A log(relative toxicity) for the appropri- ate six esters (see section 3.3).

The results in Table 4 show that requirements in the side-chain for activity against the two species differ widely. As in many other types of pyrethroid, opportunities exist for optimising activity against one species to achieve a degree of selectivity. When applied to a pest and its predator or parasite, such an approach has practical significance.22 A feature common to both columns in Table 4 is the high position for the side-chains corresponding to those in pyrethrin I ((Z)-penta-2,4-dienyI) and cinerin I ((Z)-but-2-enyl), but the lower position of (Z)-pent-2-enyl, the side-chain of jasmolin I , the third type present in the natural pyrethrins. The remaining substituents show large differences in activity against the two species, but a tendency for the shorter substituents to be more effective is detectable whether the unsaturation is present as a double or triple bond. Stereochemistry in the substituent appears to be as important here as elsewhere in the molecule.

The introduction of methyl groups on to the ring of these benzyl esters enhanced weakly, if at all, the activity of compounds with less effective substituents (XXI, XXII, XXX-XXXII), but had a greater influence on some allyl-substituted compounds. Neither the 3-allyl- nor the 4-allylbenzyl esters could be beneficially substituted by 2-Me, or 2,6-Me2 if an a-cyano group was also present, but in the a -H compounds, marked increases in activity were observed for both 3- and 4-ally1 compounds against both species and for both 2-Me and 2,6-Me2 substitution patterns.

Acknowledgements The authors thank the British Technology Group for financial support, and the bioassay team ( S . Jenkinson and K. O’Dell under the supervision of A. W. Farnham) for sustained enthusiasm in obtaining essential results. Some of the compounds described are the subject of British Patent Application No. 8319930 and foreign counterparts.

References 1. 2. 3. 4.

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