Pestic. Sci. 1981, 12, 503-508

The Pyrethrins and Related Compounds. Part XXV": Synthesis and Insecticidal Activity of Conformationally Restrained Compounds Related to 3-Phenoxybenzyl Esters

Michael Elliott, Andrew W. Farnham, Norman F. Janes and Bhupinder P. S. Khambay

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

(Manuscript received 17 June 1980)

Derivatives of 3-phenoxybenzyl pyrethroidal esters were synthesised in which rotation about the benzylic C-1-C-a bond was restricted by an additional bridging ring. The insecticidal activities of these compounds to houseflies (Musca dornestica) and mustard beetles (Phaedon cochLeariue) depended on the size of the bridging unit and on whether it joined C-a to C-2 or C-6 of the benzyl nucleus. The results obtained are considered in relation to current correlations of the structures with the activities of pyrethroids.

1. Introduction

Structure-activity relationships in the present broad range of synthetic pyrethroids indicate that molecular shape is particularly important in determining p~ tency . l -~ However, this conclusion is generally based on a series of compounds in which a subunit of the molecule with fixed stereochem- istry, is replaced by another of comparable structure (for example, 5-benzyl-3-furylmethyl or 3- phenoxybenzyl) so that groups round it are necessarily disposed similarly and the capability of the molecule to adopt different conformations is little changed. A wide range of structural types is now available for consideration, but because these are still flexible molecules, knowledge of the ideal overall shape for activity in any of the series is still limited.5 Compounds related to those with free rotation, but locked in a particular conformation by additional substituents, should give relevant evidence. Provided the modification does not alter the activity in other ways (for example, by a gross change in polarity) the potency of the more rigid molecule should indicate how well the opti- mum conformation about the bond in question has been simulated. Some compounds, in which the CHz-aryl bond of simple benzyl esters is constrained in this way, are known192 but in the present study the corresponding bond in the more active 3-phenoxybenzyl series is examined.

2. Experimental

2.1. General Mass spectra, and 1H- and W-nuclear magnetic resonance (n.m.r.) spectra were determined as described previously.6 Thin-layer chromatography (t.1.c.) on plates, 20 x 20 cm, of GF silica (Anachem) 1 mm layer thickness was used to analyse and to purify samples. Esters were made from alcohols and acyl chlorides by the usual method.6 Their structures were confirmed and their purities assessed from lH-n.m.r. spectra which were as expected from the spectra of their constituents; 13C-n.m.r. spectra (Table 1) confirmed the absence of significant impurities. Insecticidal activities

a Part XXIV: Pestic. Sci. 1980, 11, 513-525.

0031-613X/Sl/l00&0503 $02.00 0 1981 Society of Chemical Industry

503

504

Table 1. 13C-n.m.r. shifts of aIcoholic component of esters synthesisedn

0-CO-R

M. Elliott et a/.

Assignments6

Compound C=O C-1 C-2 C - 3 C - 4 C-5 C-6 C-7

IIB IIC IID IIiB IIiC VB vc VIIB VIIC VIIIB VIIIC

172.2 170.1 173.2 172.0 170.0 172.2 170. I 172.7 170.7 169.9 167.2

78.1 27.2 1 8 . 3 27.2 78 .5 27.2 77.8 29.5 78.2 29.5 69.5 23.1 69 8 23.1 77.5 133.2 17.7 132.7

148.8 114.2 149.1 114 2

32.2 32.0 31.9 33.0 32.8 18.3 18 2

130.6 130.9 32 .6 32 .6

28.9 28 .8 -

135.4 135.0 135.1 138.9 138.6 130.0 130. I 133.5 133.5 131.7 131.7

152.8 152 8 152.9 125.6 125.6 154.0 154. I 149.8 149 9 152.3 152.3

118.8 118.8 118.9 116.2 115.9 126.6 126.7 120.0 120.0 116.7 116.7

C-11: 157.1-157.9; C-12: 117.9-118.4; C-13: 129.5-129.8; C 14: 122.6-123.0

C-8 c - 9 c- 10

128.4 128.4 128.5 156.1 156.1 118.5 118.6 127.8 128.0 128.3 128.2

120.9 120.7 120.5 120.1 120. I 124.8 124.7 119.8 120.0 116.1 115.7

144.4 143.9 143.7 137.1 136.7 143.2 142.7 145.1 144.6 144.7 142.1

a Shifts for the acid components fell within the ranges quoted for other pyrethroidal esters of these acids.6912 b Shifts differing by < 1 part per million may have transposed assignments.

against susceptible strains of houseflies (Musca domestica L.) and mustard beetles (Phaedon coch- leariae Fab.) were assessed as described previ~usly.~

2.2. 4-Phenoxyindan-1-yl esters 4-Hydroxyindan-1-ones (I; Figure 1) (5.0 g) and potassium methoxide (2.6 g) in benzene (70 ml) were stirred together for 1.5 h; the benzene was then removed in vacuo, and the resulting solid potassium salt heated with bromobenzene (12.0 g), pyridine (67 ml) and copper(1) chloride (1.0 g) at reflux temperature for 3 h. After cooling, the addition of petroleum spirit (boiling range 6Cr8OoC), filtration and evaporation gave 4-phenoxyindan-1-one (1.8 g, 24%), m.p. 81-82°C; n.m.r. peaks at 6 2.4-2.8 (m,2H,CHz), 2.9-3.3 (m,2H,CHz), 6.9-7.9 (m,8H, aromatic H's). Reduction of this compound (0.7 g) with sodium borohydride (0.2 g) in ethanol (20 ml) at 20°C, followed by purifi- cation of the product by t.1.c. with diethyl ether+ hexane (1 + 9 by volume) gave 4-phenoxyindan-l- 01 (IIA; 0.63 g, 90%), n.m.r. peaks at 6 1.8-3.3 (m,4H, 2xCH2), 3.14 (s,lH,OH), 5.18 (t,lH, CHOH, 6 Hz), 6.8-7.7 (m,8H, aromatic H's).

Esterification gave 4-phenoxyindan-1-yl (1R)-trans-chrysanthemate (IIB), ~ Z D ~ O 1.5600, M+ 376; and the (1 R)-cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxy~ate (LIC), ~ D Z O 1.5858, M+ 504.

2.3. 5-Phenoxy-l,2,3,4-tetrahydro-l-naphthyl esters The monopotassium salt, prepared similarly from 5-hydroxy-1,2,3,4-tetrahydro-l-naphthol (6.5 g) and potassium methoxide (2.5 g), pyridine (50 ml), bromobenzene (6 g) and copper(1) chloride (0.5 g) were heated at reflux temperature for 4 h, cooled and then diluted with diethyl ether. Washing the product successively with dilute sulphuric acid, aqueous potassium hydroxide, more acid, and saturated aqueous sodium chloride, followed by drying and evaporation, eventually at 5OoC/0.l mmHg to remove bromobenzene, gave a residue of 5-phenoxy-l,2,3,4-tetrahydro-l- naphthol (IIIA; 1.3 g, 12%), m.p. 52-53°C; single spot on t.1.c. analysis; n.m.r. peaks at 6 1.6-2.1

The pyrethrins and related compounds 505

0 0-R 0

0-R 0

I 0 Ph-0

W) A : R = H B: R = (lR)-trans-chrysanthemate

0-R I

Ph-0 010

0-R

@ \

Ph-0 (vn)

Ph-0 I

C: R = (1R)-cis-3-(2,2dibromovinyl)-2,2-dimethylcyclopropanecarboxylate D: R = (RS)-2-(4-chlorophenyl)-3-methylbutyrate

Figure 1. Structures of the compounds I-VIII referred to in the text, with the codes A, B, C and D for the identity of R in the structures; for example, compound VB is 6-phenoxyindan-1-yl (1R)-trans-chrysanthemate.

(m,4H, 2xCH2), 2.11 (s,lH,OH), 2.62.9 (m,2H,CHz), 2.87 (m,lH,CHOH), 6.6-7.5 (m,8H, aromatic H's).

Esterification gave the (1R)-trans-chrysanthemate (IIIB), nD20 1.5580, M+ 390; and the (lR)-cis- 3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate (IILC), nDZo 1 S940, M+ 518.

2.4. 6-Phenoxyindan-1-yl esters The potassium salt of 6-hydroxyindan-1-one9 (IV; 1.48 g) and potassium methoxide (0.68 g) were heated in refluxing pyridine (20 ml) with bromobenzene (1.8 g) and copper (I) chloride (0.3 g) for 48 h, then processed as in section 2.3, except that the residue was, in addition, dissolved in hexane to remove some insoluble material.

The resulting 6-phenoxyindan-1-one (0.6 g; 27 %), n.m.r. peaks at 6 2.4-2.7 (m,2H,CHz), 2.9- 3.2 (m,2H,CHz), 6.9-7.6 (m, 8H, aromatic H's), was reduced with sodium borohydride (0.15 g) in ethanol (30 ml) to give an almost quantitative yield of 6-phenoxyindan-1-01 (VA), n.m.r. peaks at 6 1.8-3.1 (m,4H, 2xCH2), 1.94 (s,IH,OH), 5.15 (t,lH,CHOH, 6 H 4 , 6.8-7.3 (m,8H, aromatic HS).

Esterification gave the (1R)-trans-chrysanthemate (VB), n ~ 2 0 1.5518, M+ 376, and the (lR)-cis-3- (2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate (VC), 1 S610, M+ 504.

2.5. 7-Phenoxyinden-3-yl and 4-phenoxyinden-1-yl esters 4-Phenoxyindan-1-one (4.5 g, see section 2.2), N-bromosuccinimide (3.4 g), benzoyl peroxide (0.08 g) and dry carbon tetrachloride (150 ml) were heated together at reflux temperature for 6 h, cooled, filtered free from succinimide, and evaporated at reduced pressure to a residue of 3-bromo-4- phenoxyindan-1-one (containing no detectable starting material), n.m.r. peaks at 6 2.6-3.7 (rn, 2H,CH2), 5.70 (dd,lH,CHBr, 2, 6 Hz), 7.0-7.8 (m,8H, aromatic H's). This bromide, dissolved immediately in diethyl ether (3.0 ml) at O"C, was treated gradually with triethylamine (4.5 g) in diethyl ether (20 ml). After 2 h at O'C, the mixture was filtered, evaporated to dryness, finally at 0.1 mmHg to remove any residual amine and the residue purified by t.1.c. to yield 4-phenoxyinden- 1-one (VI; 0.6 g) H D ~ O 1.626; n.m.r. peaks at 6 5.92 (d,lH,CH=, 6 Hz), 6.9-7.8 (m,8H, aromatic

506 M. Elliott ef ai.

H's), 7.74 (d,lH,CH = , 6 Hz). The indenone (VI; 0.3 g) in tetrahydrofuran (9 ml) and water (1 ml) was reduced with sodium borohydride (0.01 g; excess of reagent led to the formation of the corres- ponding indanol) for 1 h at 20°C; the product was diluted with water and extracted with ethyl acetate (4 x 25 ml; use of diethyl ether gave poorer results). The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous sodium sulphate, and evaporated to a residue which was purified by t.l.c., eluting with acetone+ hexane (8 + 92 by volume), to give 4- phenoxyinden-1-01 (VIIA; 0.18 g, 60%), 31~20 1.623; n.m.r. peaks at 6 2.28 (s,lH,OH), 5.17 (broad s,lH,CHOH), 6.35 (dd,lH,2-H, 2, 6 Hz), 6.7-7.6 (m,9H, aromatic H's+3-H).

Esterification was by the usual procedure but when complete, instead of chromatographing on alumina, the benzene was removed under reduced pressure, and the residue purified by t.l.c., eluting with acetone+ hexane (2+ 98 by volume). This procedure avoided structural rearrangement, and gave 4-phenoxyinden-1-yl (1R)-trans-chrysanthemate (VIIB), M+ 374, and (lR)-cis-3-(2,2- dibromnvinyl)-2,2-dimethylcyclopropanecarboxylate (VIIC), M+ 502, both with diagnostic lH- n.m.r. peaks at 6 6.50 (m,lH,2-H), and characteristic 13C-n.m.r. spectra (see Table 1).

Treatment of these esters with alumina, either after isolation, or by following the usual esterifi- cation procedure in full, induced rearrangement, and gave 7-phenoxyinden-3-yl(l R)-trans-chrysan- themate (VIIIB), Mf 374, and (1 R)-cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropan~arboxylate (VIIIC), M+ 502, both with diagnostic lH-n.m.r. peaks at 6 3.37 (d,2H,CHz, 2 Hz) and 6.42 (t,lH,CH=, 2 Hz), and characteristic 13C-spectra (see Table 1).

3. Discussion

3.1. Synthesis Two phenoxyindan-1-01s (IIA and VA) were made by similar routes: the Ullman reaction to convert the hydroxyindan-1-one (I or IV) to the phenoxy derivative, then reduction of the ketone to the alcohol with sodium borohydride. Yields were always low in the first step, but the conditions de- scribed were the most reliable of those examined. 1,2,3,4-Tetrahydronaphthalene-1,5-diol gave the corresponding phenoxy derivative (IIIA) with a fused cyclohexyl system in one step.

4-Phenoxyindan-1 -one (I) with molecular bromine gave the 2-bromo compound which did not eliminate hydrogen bromide as required. However, N-bromosuccinimide gave the 3-bromo deriva- tive which lost hydrogen bromide smoothly with triethylamine to yield VI (see discussions in references 10 and 11). Sodium borohydride gave the 4-phenoxyinden-1-01 (VIIA) in good yield, if an excess of reducing agent was not used and the unstable product was isolated under mild condi- tions. Esterification gave the 4-phenoxyinden-I-yl esters, but these also rearranged readily, for instance when chromatographed on alumina; so, depending on whether normal, or milder, pro- cessing was used, both the 4-phenoxyinden-1 -yl (VII) and the 7-phenoxyinden-3-yl (VIII) esters were available. N.m.r. spectra gave evidence for this unusual, yet rapid, rearrangement under such relatively mild conditions. In the lH-spectra, the esters VII showed only downfield peaks from the --CH=CH-CHO- system, but esters VIII had an upfield peak from the CH2- group. In the I3C-n.m.r. spectra, peaks were at 77, 133 and 131 parts per million for VII and at 33, 114 and 149 parts per million for VIII.

3.2. Insecticidal activity The results of the toxicity testing of the synthesised compounds against M . dornestica and P. coch- leariae are presented in Table 2 in terms of their relative potency to that of bioresmethrin (= 100). Two other known pyrethroids were included in the testing for comparison purposes,

The two ways of constraining the C atom a to the A ring bond (Figure 2) correspond to two rota- mers differing by a full 180" of rotation; both have been investigated in the 4-phenoxy- and 6- phenoxy-indan-1-yl esters, respectively. The 4-phenoxyindan-1-yl compounds (11) are significantly more active than the 6-phenoxy isomers (V) and although less potent than many pyrethroids see potencies relative to bioresmethrin in Table 2), such activity is significant, because it suggests that the active conformation may be closer to that necessarily adopted in 11. Further compounds

The pyrethins and related compounds 507

.-. . . . . ... . . . .

Ph O\

Figure 2. Alternatives for closure of the constrained ring.

Table 2. Relative toxicities of the compounds synthesised to houseflies (Musca domestica L.) and mustard beetles (Phaedon cochleariae Fab.)

Relative toxicitya

Compound Musca domestica Phaedon cochleariae

Bioresmethrin ‘Biophenothrin’b NRDC 157C IIB IIC IID LIIB IIIC VB vc VIIB VIIC MIIB VIIIC

100 90

180 0.7 0.3

<0.1 <0.1 <0.1 <0.1

1 0 . 6 1.2 0.1

<0.1

100 43

360 0.8 3.2 0.2

t 0 . 1 < O . 1 10.1 1 0 . 1

1 2.8

<0.1 <0.1

(LD50 of bioresmethrin)IOO/(LDso of compound). b 3-Phenoxybenzyl (1 R)-trans-chrysanthemate [( 1 R)-trans-phenothrin]. c 3-Phenox ybenzyl ( 1 R)-cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane-

carboxylate.

examined therefore contained this relative orientation of substituents. Extending the linking ring to cyclohexyl (111) apparently causes only a slight change in conformation, but greatly diminishes the activity; the larger ring might, however, interfere with the insecticidal action. Introducing un- saturation into the 5-membered ring produced little change in activity when it was in the 2,3- position (indane numbering) and the acyloxy carbon retained its sp3 hybridisation. However, with a 1,Zolefinic bond, C-1 is now sp2 hybridised and the acyloxy group is necessarily carried at a’ different angle to the rest of the molecule, so it is not surprising that activity is much lower.

It is therefore clear that although the conformational requirements for activity may be strict, leading to contrasting properties for positional isomers such as II and V, in other comparisons, subtle and less well understood effects are operating.

Acknowledgements The authors thank Dr I. J. Graham-Bryce for help and encouragement, Mrs Kate E. O’Dell, Mrs Stephanie C. Jenkinson and Mrs Janet Sandison for assistance with bioassays, and the National Research Development Corporation for support.

References 1. Elliott, M.; Janes, N. F. Chem. SOC. Rev. 1978,7,473-505. 2. Nakada, Y.; Muramat, S.; Asai, M.; Ohno, S.; Yura, Y. Agric. Biol. Chem. 1978, 42, 1357-1364.

34

508 M. Elliott ct al.

3. Elliott, M. In Synthetic Pyrethroids (Elliott, M., Ed.), ACS Symposium Series No. 42, American Chemical Society, Washington, 1977, pp. 1-28.

4. Elliott, M.; Farnham, A. W.; Janes, N. F.; Needham, P. H.; Pulman, D. A. In Mechanism ofPesticide Action (Kohn, G.K., Ed.), ACS Symposium Series No. 2, American Chemical Society, Washington, 1974, pp. 80-91.

5. Elliott, M.; Janes, N. F. In Synthetic Pyrethroids (Elliott, M., Ed.), ACS Symposium Series No. 42, American Chemical Society, Washington, 1977, pp. 29-36.

6. Elliott, M.; Farnham, A. W.; Janes, N. F.; Johnson, D. M.; Pulman, D. A. Pestic. Sci. 1980, 11, 513-525. 7. Elliott, M.; Farnham, A. W.; Ford, M. G.; Janes, N. F.; Needham, P. H. Pestic. Sci. 1972, 3.25-28. 8. Domingues, A.; Zavala, J. S. L. J. Rev. Soc. Quint. Mex. 1967,11, (2), 39-42. 9. Ingold, C. K.; Piggott, H. A.J. Chem. SOC. 1923, 1469-1509.

10. Treibs, v.W.; Schroth, W. Justus Liebigs Ann. Chem. 1961, 639,204-213. 11. Hansen, P. E.; Undheim, K. J. Chem. Soc. Perkin Trans. I 1975, 305-308. 12. Janes, N. F. J. Chem. SOC. Perkin Trans. 1 1977, 1878-1881.