Azine Derivatives As a New Generation of Insect Growth Regulators

CROP PROTECTION RESEARCH 705 CHIMIA 2003, 57, No.11

Chimia 57 (2003) 705–709 © Schweizerische Chemische Gesellschaft ISSN 0009–4293

Azine Derivatives as a New Generation of Insect Growth Regulators

Martin Eberlea, Saleem Farooqa, André Jeanguenata*, Deborah Mousseta, Arthur Steigera, Stephan Traha, Werner Zambacha, and Alfred Rindlisbacherb

Abstract: A new generation of insect-growth-regulator insecticides, the azines, are presented. They inhibit the chitin biosynthesis process and are active against lepidopteran pests. Their synthesis and a structure–activity relationship will be discussed.

Keywords: Chitin biosynthesis · Insecticide · 1,2,4-Triazines

Introduction Chitin is a highly organized polymer of urea group of the BPUs could be replaced N-acetylglucosamine and is a major con- by a number of 6-membered ring hetero- The mode of action of many modern syn- stituent of the cell wall of most fungal cycles, leading to extremely potent lepi- thetic insecticides is linked to ubiquitous species as well as insects. It is rarely found doptericides (e.g. 6). Comparing the X-ray targets such as the nervous system or the in vertebrates and plants, where the analo- structure of teflubenzuron (1a) [8] with respiration chain [1]. Although excellent gous structural polymers are collagen and oxazolines and our heterocyclic derivatives selectivities for the target insects have been cellulose, respectively. During the insect allows us to conclude that the new genera- achieved with many insecticides, undesir- molting process, a cocktail of chitin-related tion IGRs are possibly mimics of the best able effects on non-target organisms (toxic- enzymes work towards the degradation of conformation of the BPUs (Fig.). We pres- ity) and on the environment remain a recur- the old cuticle and the synthesis of the new ent here the synthesis of a range of hetero- rent problem. Specific insect targets, which one [3]. Inhibition of these processes has cyclic derivatives. are not found in other organisms have been been a very successful approach towards previously recognized to play a prominent the development of new classes of insecti- role for the discovery of safe new insecticides or fungicides [4]. The biosynthesis of Chemistry cides. Insect growth regulators (IGR) such chitin was targeted as early as 1972 at the as molting hormones (ecdysones, juvenile Phillips-Duphar company, where the insec- Synthesis of 1,2,4-Triazines A and B hormones, [2]) and chitin metabolism regu- ticidal benzoylphenylurea family (BPU, We were interested in the synthesis of lators are particularly attractive in this re- e.g. teflubenzuron (1a) and lufenuron (1b) 1,2,4-triazines of type A and B (Scheme 1). spect (see [1a], chap. 20). Fig.) [5] was discovered. The BPUs disrupt There are numerous ways to synthesize the the formation of chitin; the exact site of ac- 1,2,4-triazine core structure [9]. However tion has still not been elucidated. These selective methods for 3,5- or 3,6-disubsti- compounds have a relatively limited insec- tuted 1,2,4-triazines (A or B) are rare. In a ticidal spectrum (lepidoptera) and are slow first approach, we decided to use a non- acting, as the insects will die only after the selective synthesis and separate both next regular molt. Closely related are the isomers by flash-chromatography. Cou- tetrazole acaricide clofentezine (2) [6a] pling of the α-keto-oxime 7 with the BOC- and the experimental triazole insecticides amidrazone 8 delivered a 3:2 mixture of

*Correspondence: Dr. A. Jeanguenata (e.g. 3) [6b]. Ethoxazole 4 is a new genera- isomers 9 and 10. Both isomers were easily Tel.: +41 61 323 36 42 tion acaricidal IGR with an oxazoline ring separated by flash-chromatography and Fax: +41 61 323 85 29 [6c]. Broad-spectrum insecticide-accari- elaborated to the final compounds via a E-Mail: [email protected] aSyngenta Crop Protection AG cides with an oxazoline moiety (e.g. 5a) Suzuki coupling (Scheme 1). Research Chemistry: Optimization were recently discovered [6d]. Their syn- As the linear isomers of type B turned WRO-1060.2.10 thesis was possible by taking advantage of out to be much more potent than the iso- Schwarzwaldallee 215 CH-4002 Basel modern Pd-catalyzed aryl-aryl coupling re- mers A in the insecticidal screening, a se- bSyngenta Crop Protection AG actions [7]. Pyrrolines 5b and imidazolines lective method for B was investigated. The Research Biology 5c represent the latest developments de- cyclization of amidoximes 11 with α-keto- Insect Control Schaffhauserstr. 101 scribed in recent patent literature [6e][6f]. oximes 12 was already published (Scheme CH-4332 Stein We discovered by serendipity that the acyl- 2, path a: [10] in collaboration with re- CROP PROTECTION RESEARCH 706 CHIMIA 2003, 57, No.11

Cl Cl

F F CF2CFHCF3 Cl N H Cl N F N F O N Cl F O HN N N Cl N Cl N N O N O F C H H F 3 F F 1a Teflubenzuron 1b Lufenuron 2 Clofentezine 3 triazoles (acaricide) (acaricides)

CF3

F O F X

N N CF N 3 F N O F F N

F 4 Ethoxazole 5a X = O: Oxazolines 6 Triazines (acaricide) 5b X = CH : Pyrrolines 2 5c X = NH: Dihydroimidazoles

Fig. Insecticidal and acaricidal IGRs: from the BPUs to the triazines

searchers of Polyphor, Allschwil, CH). Un- der optimized conditions, linear triazines BOC F such as 13 were obtained in 75–85% yield F S NH CN 1) Na2S, NEt3 F HN with only minor formation of triazines of BOC-NHNH 2) MeI NH.HI 2 type A. Another selective approach is the NH.HI F 61% F quant. condensation of a thioimidate 14 with a hy- F drazino-oxime 15 [11]. We obtained the lin- 8 ear triazine exclusively in 40% yield. Suzu- ki coupling with arylboronic acids gave the final compounds B in high yields (85–97%, O O iPent-ONO N 1) NaOAc, AcOH Scheme 2, path b). OH 2) Flash-chrom. separation Compound 16 is a very versatile inter- Br Br mediate. While a bromine–metal exchange 7 was not possible, Pd-mediated reactions proved to be very valuable (Scheme 3, [7]). Suzuki arylation (route a and b/c), Heck Br coupling (route d), Sonogashira coupling N N F N (route e) and Buchwald-Hartwig amination F N (route f) delivered a set of compounds with N + N a high diversity in physico-chemical prop- F Br F erties. In each case the conditions had to be 30% 9 10 21% optimized (catalyst, ligands, solvent, base).

The reported conditions are valid for a very Ar-B(OH)2 diverse set of coupling partners. PdCl2(PPh3)2 Na2CO3, H2O, DME 85 - 98% Ar

Synthesis of Pyridines C N N F N F N Pyridine analogues of B were easily prepared via cyclocondensation of triazines N + N B with bicyclo[2.2.1]hepta-2,5-diene, fol- F Ar F lowed by molecular nitrogen extrusion and A B a retro-Diels-Alder reaction [12]. Pyridines C were obtained in 30 to 75% yield (Scheme 4). Scheme 1. Synthesis of 3,5- and 3,6-disubstituted 1,2,4-triazines A and B CROP PROTECTION RESEARCH 707 CHIMIA 2003, 57, No.11

Synthesis of Tetrazines D and Pyridazines E Tetrazine analogues of B were prepared Br Br by chlorination of a diacyl-hydrazine 22 NH2 F N dioxane, HCl 4N N followed by cyclization with hydrazine. O n-BuOH, 80oC F N Aromatization of the obtained dihydro- NH2 OMe a) + OMe N N 82% tetrazines 23 (NaNO , AcOH) and Suzuki F 2 OH 11 12 F 13 coupling yielded tetrazines D in good yields (Scheme 5). Pyridazine 25 was read- ily made by condensation of the tetrazine Br Br intermediate 24 with acetaldehyde enolate F NH.HI N N (two steps or concerted cycloaddition) fol- H N nPrOH, reflux F N SMe + 2 lowed by nitrogen extrusion and water b) N N elimination [13]. Suzuki coupling gave the F 40% OH F final pyridazines E in high yield. 14 15 16 Synthesis of Pyrimidines F and Tetrahydropyrimidines G Subst. Pyrimidine analogues of B were pre- Ar-B(OH) 2 pared by condensation of an amidine 26 PdCl (PPh ) N 2 3 2 F N with a vinamidinium salt 27 [14]. The con- Na2CO3, H2O, DME N ditions of the final Suzuki coupling were 85-98% B critical, as the chlorine substituents in the F vicinity of the pyrimidine nucleus are acti- vated for cross coupling (Scheme 6). Cat- Scheme 2. Selective synthesis of 3, 6-disubstituted 1,2,4-triazines B alytic reduction of the pyrimidines F gave the tetrahydropyrimidines G, which are close analogues of the imidazolines 5c (Fig.). Halogen substituents (Cl or Br) did not survive these conditions and were re- duced.

N F N

N 16 F f) a)

OCF3 b) H e) N d) N N F N F N CF3

N N O 6 21 B O F O F N F N

N 17 N F N F N 19 F F c) N F N

N 20 O F F O F

N F N Conditions: a) Suzuki: ArB(OH)2, PdCl2(PPh3)2, Na2CO3, DME: H2O; b) Bis(pinacolato)diboran, o o PdCl232 (PPh ) , KOAc, DMF, 80 C, 97%; c) Suzuki: Ar-X, PdCl2232 dppf, Na CO , DMF: H O, 80 C; N d) Heck: olefin, Pd(OAc) , P(o-Tol) , iPr NEt, DMF, 100o C; e) Sonogashira: alkyne-H, 18 232 PdCl232 (PPh ) , CuI, NEt 3 , reflux; f) Buchwald-Hartwig: R-NH2 , Pd 2 dba 3 , dppf, CsCO 3 , THF, reflux. F

Scheme 3. Pd-mediated derivatisation of 16 CROP PROTECTION RESEARCH 708 CHIMIA 2003, 57, No.11

Biological Activity

These new azines turned out to be ex- Subst. Subst. tremely potent in greenhouse assays against key lepidopteran pests. Activity against cot- N F N dichlorobenzene, 145 oC F ton leaf worm (Spodoptera littoralis), to- N N bacco budworm (Heliothis virescens) and B 28 - 76% C diamondback moth (Plutella xylostella) for F F typical compounds are listed in the Tables 1 and 2. Especially remarkable is the com- Scheme 4. Synthesis of pyridine analogues C plete control of Spodoptera larvae at concentration as low as 0.05 ppm! Some interesting activity was also found against mites (Tetranychus urticae), white flies (Bemisia tabaci), thrips (Frankliniella occidentalis), and scales (Aonidiella aurantii), demon- strating the potential of this new class of insecticides. O NH N 2 Br H H 1) PCl F O Br Br 5 N Variation of the Heterocycle F O 2) NH NH F HN H 2 2 Cl N N For each variation except the pyri- N N H 62% F 88% O dazines (Table 1, entries 7 and 8), the activ- F F ity against Spodoptera was outstanding and 22 23 comparable or even better than that of the most efficient commercial standards (data Br Ar ArB(OH) , N 2 of the BPU lufenuron are shown for com- F N CsF, DME/MeOH, rt N Pd(OAc) , P(oTol) F N NaNO2, HOAc 23 parison). The triazines displayed a broad N N N N spectrum of activity (entries 1 and 2), which 77% F 50 - 80% included sucking insects (data not shown). 24 F D

MeCHO, KOH Variation of the Substituents 84% on the Triazine Analogues Ar Br ArB(OH) , 1 2 3 2 The best substituents X , X , and X on CsF, DME/MeOH, rt Pd(OAc) , P(oTol) the phenyl ring in the position 3 of the tri- F 23 F N N N N azines are listed in Table 2 (entries 1 to 4). 70- 90% 25 E They are reminiscent of the best sub- F F stituents of the BPUs or of the triazoles (see Fig., 1 and 3). Ortho substituents on the Scheme 5. Synthesis of tetrazine and pyridazine analogues D and E phenyl ring in the position 6 of the triazine are tolerated (R, entries 5 and 6). This indi- cates that the rings are probably not copla- nar but rather perpendicular as confirmed by a conformation analysis (data not shown). Substituents S1, S2, and S3 on the last phenyl group (entries 7 to 10) dramati- X NH NOH 1) tBuOCl, NH cally influence the spectrum of activity. X 3 2) H , RaNi, EtOH, HCl 1 2 NH .HCl Substituents in position 4 (S ≠ H) or 2 Br 2 ≠ 70% F 3 (S H) are tolerated. F 26 NaOMe, X N X = F, Cl + MeOH N In conclusion we have found a new gen- N > 90% F eration of IGRs with outstanding activity in 1) POCl3, DMF COOH 2) HClO4 ClO - the greenhouse against commercially im- + 4 Br N portant lepidopteran pests and interesting 75% Br ArB(OH)2 glyme, H O properties against some sucking pests. The 27 2 Na2CO3, Pd(OAc)2 activity of the triazines was confirmed in 88 -96% worldwide field trials in cotton and vege- tables. Subst. Subst.

F HN X N H , Pd/C Received: September 15, 2003 2 N G N F X = F F 75% F X = F, Cl

Scheme 6. Synthesis of pyrimidine and tetrahydropyrimidine analogues F and G CROP PROTECTION RESEARCH 709 CHIMIA 2003, 57, No.11

Table 1. Structure–activity relationship of the azines B–G Table 2. Structure–activity relationship of the triazine analogues B

R S3

S2 F N Het. X1 N R N F X3 X2 a Entry Het. R EC80 values [ppm] 1 2 3 1 2 3 a Entry X X X R S S S EC80 values [ppm] Spodoptera Heliothis Plutella Spodoptera Heliothis Plutella littoralis virescens xylostella littoralis virescens xylostella b c b (Fcon L3) (ovol La) (Fcon L3) (Fcon L3)b (ovol La)c (Fcon L3)b

Lufenuron (BPU) 0.2 md 0.2 m 0.8 m Lufenuron (PBU) 0.2 md 0.2 m 0.8 m e e 1 N CF 0.05 gr 3 gr 3 m 1 F F H H CF3 H H 0.05 gr 3 gr 3 m N 3 2 OCF 0.2 m 3 gr 50 m 2 Cl H F H CF3 H H 0.8 m 0.2 m 3 m N 3 3 Cl H H H CF3 H H 0.05 m 3 m 0.8 m 3 CF3 3 m 25 gr >100 4 Me H H H CF3 H H 3 m >100 50 4 OCF 3 m >100 >100 N 3 5 F F H Me CF3 H H 0.05 m 3 m 12.5 m 6 F F H OMe CF H H 0.8 m >100 >100 5 N CF 3 m >100 >100 3 N 3 7 F F H H H Cl Cl 0.2 m 3 gr 3 m 6 N OCF 3 m >100 > 100 N 3 8 F F H H SCF3 H H 0.2 m 3 m 3 m f 7 CF3 >100 >100 nd 9 F F H H H CF3 H 0.05 gr 12.5 >100 8 N OCF >100 >100 nd 10 F F H H Cl Cl H 3 m >100 >100 N 3 9 CF 0.05 gr >100 >100 N 3 a EC80 value: concentration in ppm for which the tested compound shows at least 80% ac- b c 10 OCF3 12.5 m >100 >100 tivity (greenhouse trials); Fcon L3: feeding/contact activity against l3 larvae; ovol La: ovolar- N vicide test, effect on larvae; dM: mortality effect; egr: growth inhibition. 11 CF 3 m >100 >100 N 3

N H

a EC80 value: concentration in ppm for which the tested compound shows at least 80% activity (greenhouse trials); bFcon L3: feeding/contact activity against l3 larvae; covol La: ovolar- vicide test, effect on larvae; dM: mortality effect; egr: growth inhibition; fnot determined.

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