Oxadiazole Derivatives as Novel Insect-Growth Regulators: Synthesis

Chapter 26

Oxadiazole Derivatives as Novel Insect-Growth Regulators: Synthesis and Structure-Bioactivity Relationship Downloaded by UNIV OF GUELPH LIBRARY on September 7, 2012 | http://pubs.acs.org Publication Date: November 23, 2004 | doi: 10.1021/bk-2005-0892.ch026

1

2

2

Xuhong Qian , Song Cao , Zhong Li Gonghua Song , and Qingchun Huang 2,

2

1

State Key Laboratory of Fine Chemistry, Dalian University of Technology, Dalian 116012, China East China University of Science and Technology, Shanghai 200237, China

2

Eco-friendly insect-growth regulators, 2,4-dichloro-5fluorophenyl-oxadiazoles, phenoxymethyl oxadiazoles and oxadiazolyl pyridazinones were designed and synthesized. Some efficient and novel synthetic routes were provided for their intermediates. The target compounds showed effective chronic growth inhibition activities against Pseudaletia separata Walker and the antifeedent activities against Asiatic corn borer. QSAR study suggested that the lowest unoccupied orbital energies of these compounds were very important for bioactivities.

© 2005 American Chemical Society In New Discoveries in Agrochemicals; Clark, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2004.

273

Downloaded by UNIV OF GUELPH LIBRARY on September 7, 2012 | http://pubs.acs.org Publication Date: November 23, 2004 | doi: 10.1021/bk-2005-0892.ch026

274 Recently, heterocyclic compounds have taken more important role in pesticide chemistry. The number of pesticides derived from five- or sixmembered aromatic heterocycles has increased dramatically. Therefore, the use of aromatic heterocycles to design insecticides and insect-growth regulators is the focus of our research. Eco-friendly insect-growth regulators are a great breakthrough in the research and development of low use rate, highly effective, generally selective insecticides. The typical heterocycles used for insect-growth regulators include pyridine, oxazole, pyridazinone, furan, diazole, thiazole, thiadiazole, pyrimidinone, trazine and tetraazines, etc. However, few are reported using oxadiazoles as insect-growth regulators or insecticide, except closely related thiadiazolesLY-13125. Benzoylphenylureas as the first generation IGR are inhibitor of insect's chitin synthesis. Dibenzoylhydrazines, as the second generation IGR, are mimics of ecdysone to control insect's molting. The reason for which we concentrate on the oxadiazoles is that there seems to be some correlations in chemical structure among oxadiazoles, benzoylphenylureas, and dibenzoylhydrazines.

Scheme 1. The evolution of the core structures for benzoylphenylurea, dibenzoylhydrazine and oxadiazole.

2, 5-Bis(2, 4-dichlorophenyl)- 1, 3, 4-oxadiazole (DCPO) and analogs are broad-spectrum and effective insecticides or acaricides with potential agricultural uses toward houseflies, faceflies and hornflies(7, 2). In contrast to traditional pesticides, DCPO and analogs mainly control the growth and development process of insects by interfering with chitin biosynthesis. Such a process is very similar to the characters of benzoylphenylureas as the inhibitors of chitin synthesis. Their mode of action can be explained as interference with

In New Discoveries in Agrochemicals; Clark, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2004.

275 l4


incorporation of [ C] labeled N-acetyl glucosamine active in chitin synthesis^/, 2). In addition, DCPO and its analogs also inhibit the synthesis of DNA and protein of insects. However, their limited solubilities in polar solvents make them commercially unattractive, and they tend to have a non-optimal use rate and formulation difficulties. With this in mind, our attention is drawn to changing the physical properties associated with oxadiazoles, while attempting to retain or increase their biological efficacies and promote their solubilities through the modification of substituted oxadiazoles.

1. Novel Oxadiazoles: CI

N-N

Scheme 2. The target structures A and Β for oxadiazoles

It seems that 2-(2, 4-dichlorophenyl)-l, 3, 4-oxadiazole moiety is an essential part for biological activity. However, the planarities and rigidities of 2-(2, 4-dichlorophenyl)- 5-aryl-l, 3, 4-oxadiazoles, might be a main cause for their low solubilities in polar solvents. Therefore, we adopt a strategy by increasing polarity and potential ability for non-bonded interactions in the molecular design. Because electron-negative fluorine atoms have strong hydrogen-bonding capability which has potential to promote bioactivity, the modification of 2,4-dichlorophenyl-l, 3, 4-oxadiazole by introducing fluorine atoms has become our choice to give structure A. Previously, we had found that 2-(2,4-dichlorophenyl)-5-6«fy/-1,3,4-oxadiazole also has promising bioactivity(7,), implying that one of 2- or 5-position on this oxadiazole ring can be substituted by a flexible alkyl group. Therefore, the introduction of aroxylmethyl group to 2- or 5-position to give structure Β is an alternative way to improve their bioactivities and polar solubilities. In fact, the ether linkage is frequently used in the structures of some juvenile mimics as insect-growth regulators and pyrethroids as insecticides. Based on the above findings, we design and synthesize two novel types of oxadiazoles A and B(J-6). The symmetrical 2F-DCPO, synthesized from the condensation between 4fluoro-phenoxyacetic acid hydrazide and 2,4-dichloro-5-fluoro-benzonic acid, is of particular interest, although the expected final product is asymmetrical 2-(2, 4-dichloro-5-fluoro-phenyl)-5-(4-fluoro-phenoxymethyl)-l, 3, 4-oxadiazole. It is believed that an exchange reaction occurs between the acid and the diacylhydrazine, in this case it might be more difficult to transform the


276


asymmetrical hydrazine into the corresponding oxadiazole compared to transform symmetrical hydrazine into 2F-DCPO (Scheme 3)(4).

Scheme 3. Unusual synthesis of symmetrical 2F-DCPO from an asymmetrical dibenzoylhydrazine 2-(2, 4-dichloro-5-fluorophenyl)- 5-disubstituted-l, 3, 4-oxadiazoles (A), show an enhanced biological activities against Pseudaletia separata Walker and favorable polar solubilities. The presence of the 5-fluoro group is important to increase bioactivity. It is observed that the introduction of one or two fluoro groups to DCPO would enhance the bioactivity while more than two fluoro groups would decrease the bioactivity. The data also show that when logP increases bioactivity increases: 2FDCPO (LC , 1.77 ppm; logP: 4.76); F-DCPO (LC , 5.22 ppm; logP: 4.62); DCPO (LC , 10.13 ppm; logP: 4.58). When log Ρ is less than 3.5, only lower or no bioactivity is observed. The presence of o-chloro and -bromo groups contributes to higher activity, while that of o-fluoro group decreases the activity. The activities of 2F-DCPO against other insects are also determined: Nilaparvata lugens Stal in 3 instar (LC o=25.16ppm), Chilo suppressalis Walker (250ppm, 72h, lethal rate 60%), Lipaphis erysimi Kaltenbach (125ppm, 8d, lethal rate 60%), Plutella xylostella Linnaeus and Prodenia litura Fabricius 2 instar (125ppm, lethal rate 46%). 2-( Substituted phenyl)-5-(substituted phenoxymethyl)-l, 3, 4-oxadiazole (B) also shows insect-growth regulator's activity against 2 instar larvae of Pseudaletia separata Walker. 50

50

50

rd

5

nd

nd


277 Based on Cerius2 program, the QSAR study for 9 compounds with L C values suggests that there is a good correlation among their bioactivities against Pseudaletia separata Walker, hydrophilicities and the lowest unoccupied orbital ennergies. 50

L C = 1799.44 - 309.865 logP- 344.139 E


50

* ύ

* ô

125ppm, 58.62%

1 2 5

* ά m

PP '

3 1 %

2

n=9 r = 0.9749

L U M 0

' χ χ / χ χ « / ψ :

lOOOppm 13.79% 1000ppm,0%

F lOOOppm: 0%

JP

ajy^xi N-N

CI

Ρ

N-N

« - p - ^ o .

α

F

Ν-Ν

^

ο

lOOOppm: 0%

^

-

η m

Scheme 4. The structures and bioactivities of some oxadiazoles against 2 instar larvae of P. separata

2. Oxadiazolyl Pyridazinones and Analogs: The above results also suggest that 2-aryl-5-aroxymethyl-l, 3, 4-oxadiazole has very good bioaetivityf¥-$ worth further investigating. We think that the introduction of a heterocycle containing two heteroatoms, such as pyridazinone


278


moiety, might increase their bioactivities and change their insecticidal spectra. It has been previously well-known that 2-ieri-butyl-4-chloro-5-(arylmethoxyl)3(2//)-pyridazinone derivatives, the juvenoids such as dihydropyridazinones, norflurazon, pyridaben, NC-170, NC-184 and NC-196, possess considerable bioactivities to nematodes, acarid, fungi and insect^. Therefore, asymmetrical oxadiazoles containing pyridazinone group are synthesized and evaluated for their toxic and antifeedant activities against insects of different orders, especially diptera, lepidoptera and homopterafS, 9).

XH

40-90°C,2-3h

N-N

x, Y=O, s

ι 1

Scheme 5. The synthetic route for oxadiazolyl pyridazinones Besides compounds I, some other similar oxadiazoles are designed and prepared for comparison, namely (II) containing pyridazinone moiety with "SCH -'\ (III) containing pyridyl with "-OCH -" and (IV) containing guanidinium with "-CH -" as molecular linkage. 2

2

2

Scheme 6. The target structures of oxadiazolyl pyridazinones

During the synthesis of oxadiazolyl pyridazinones, by treating 2-teri-butyl4-chloro-5-(ethoxycarbonylmethoxy) -3(2H)-pyridazinone (Cj) with hydrazine hydrate in ethanol at reflux for 6-8 hours (Scheme 7), we obtain an unexpected product Ei in good yield, instead of the anticipated product of the corresponding acetylhydrazine. Alazawe had previously reported that methoxyl group at 6position of the pyridazinone could be replaced by the hydrazino group. For this reason, we assume that the key step of this reaction is the formation of intermediate D. In fact, we also found that 2-(un)substituted-4, 5-


279 dichloropyridazinones (C ) can also give 2-(un)substituted-4-amino-3pyridazinones (E ) under the similar conditionsf/φ. The known methods lead to amino pyridazinones, which are useful intermediates for making agricultural and pharmaceutical chemicals, involving Raney-Ni cleavage of the hydrazino pyridazinonef//^, direct animation of the pyridazinones^-/^, substitution of chloropyridazinone with ammonia at enhanced pressuref/5^, and the dechlorination of chloropyridazinone performed in the presence of palladium on charcoal(7^/. Therefore, we believe that a novel and convenient synthetic route is provided for the synthesis of aminopyridazinones, which are not easily accessible by traditional methods. 2


2

Ι

Ο

NHJN^.HJO

,

Γ

Ο

I

Ο

ΝΗΝΗ. HP 2

0CH C0NHNH2

OCH COOEt

2

2

EtOH, ref 6-8 h

NHNH2

2

V ί N^/k

£1

Dl

Cl

α

NH,

+ΝΗ ΝΗ .Η 0, EtOH, ref Cl 6-8 h R= H, t-butyi, phenyl 2 1

2

2

1

N

^ N H N H

2

E2

C2

Scheme 7. A novel synthetic route for aminopyridazinones

All final compounds are evaluated for their chronic growth inhibition activities against second-instar armyworm larvae of Pseudaletia separata (Lepidoptera: Noctuidae). Type I compounds possess considerable inhibition activity to its weight gain, especially 1-2 and 1-3 with the mean effective concentration ( E C ) of 14 μΜ and 22 μΜ, respectively. The electron-donating groups, e.g. - C H , -C H , and -OCH , decrease the bioactivities of 1-7,I-8-I-11. For type II, their data of E C (>lmM) and E C (>10mM) show that they are not satisfactory agents for inhibiting the weight gain of the armyworm larvae. Type III also show some inhibitory activity, although they are inferior to that of type I. However, IV, of which the guanidinium moiety is connected with oxadiazole by a " - C H - " linkage, is almost ineffective agent against the armyworm larvae even used with high concentration up to 1000 μΜ. The QSAR analysis shows that their energies E M O of the lowest molecular orbit are important to improve their bioactivities. The multiple regression analysis clearly reveals that the inhibitory activity is positively correlated with E L U M O , but negatively with Ε Μ Ο · 5 0

3

2

5

3

5 0

9 0

2

L U

Η Ο

pEC = 7.7104 (±0.0605) + 0.5370 (±0.0700) 50

E

L U

MO


280 2

n=ll, R =0.8672, SD = 0.1029, F = 58.7918 pEC o = ~11.5831(± 12.4628) +0.3922( ± 0.1140)E 5

LUMO

-2.0733(± 1.3392)

EHOMO 2


n=ll, R = 0.8978, SD = 0.0958, F = 35.1558 Moreover, their mode of action is confirmed as novel insect-growth regulators with ecdysonergic activity according to the symptoms of larval poisoning. The experiments also indicate that I does not result in the larvicidal activity, but mainly the inhibition of larval weight gain

Table 1 Chronic growth inhibitory activity of oxadiazolyl pyridazinones and analogs on the weight gain of 2 instars larvae of P. separata. nd

Compds

EC (mM)

R

50

Compds

R

EC (mM) 50

I-l

H

0.065

II-3

p-F

2.057

1-2

p-ei

0.014

II-4

m-F, o,p-2Cl

2.837

1-3

p-F

0.022

II-5

P-C2H5

4.313

M

m-F

0.029

IIM

H

2.236

1-5

o-F

0.061

III-2

p-CI

0.478

1-6

m-F, o,p-2Cl

0.039

III-3

p-F

0.581

1-7

P-C2H5

0.059

III-4

m-F, o,p-2Cl

0.729

1-8

m-CH

0.574

III-5

P-C2H5

1.396

1-9

P-CH

0.076

IV-1

H

>10

1-10

m,m-2CH

0.785

IV-2

p-Cl

>10

M l

P-CH3O

0.085

IV-3

p-F

>10

M2

p-NOa

1.053

IV-4

m-F, o,p-2Cl

>10

IM

H

2.238

IV-5

P-C2H5

>10

II-2

p-Cl

1.066

o,p-2Cl

0.029

3

3

3

DCPO

I, II and III are consist of planar oxadiazole moiety and planar pyridazinone or pyridyl moiety through a molecular linkage "-OCH -" or "-SCH -", except unplanar guanidinium moiety (IV, no bioactivity). The positive torsion angle 2


2


281 between oxadiazole and pyridazinone moieties of type II might be the main reason for causing its bioactivity much lower than that of type I which has negative torsion angle because of its contrary configuration. I also shows antifeedent activities against Asiatic corn borer. For the rest of compounds, the deterrency indexs are not determined as their bioactivities are weak at concentrations as high as 500 mg/kg. 1-1 and 1-9 are the most and least active compounds, respectively, and 1-1 is almost as active as Azadirachtin at 500 mg/kg. 1-1, 1-4 and Azadirachtin (> 10 mg/kg) significantly reduce the weight gain in choice-diet bioassays. The substituent effects are not generalized except for the following aspects: halogens are more favorable for bioactivity than electron-donating alkyl and alkoxyl groups. For example, a m-methyl (1-8) or 3,5-dimethyl (1-10) group shows reduced bioactivities at 500 mg/kg, whereas 1-4 (m-F) is more active; Bulky electron-withdrawing groups, such as N 0 displays unfavorable bioactivity. The replacement of the oxo by mercapto bridge (II), also leads to a loss of bioactivity, which suggests that the oxo bridge is critical. 2

Conclusion 2-(2,4-Dichloro-5-fluorophenyl)-oxadiazoles and phenoxymethyl derivatives show enhanced biological activity against Pseudaletia separata Walker and favorable polar solubility. Oxadiazolyl pyridazinones show effective chronic growth inhibition activities against the second-instars armyworm larvae of Pseudaletia separata (Lepidoptera: Noctuidae) and the antifeedent activities against Asiatic corn borer.

Acknowledgements National Natural Science Foundation of China, the National Key Project for Basic Research (2003CB114400) and National 863 High-tech Project partially support this research.

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282 3. Zhang, R.; Qian, X . J. Fluorine Chem., 1998, 93, 39. 4. Shi, W.; Qian, X . ; Song, G.; Zhang, R.; L i , R. J. Fluorine Chem. 2000, 106, 173. 5. Shi, W.; Qian, X . ; Zhang, R.; Song, G. J. Agri. Food Chem. 2001, 49, 124,. 6. Cao, S. ; Qian, X.; Song, G.; Huang, Q. J. Fluorine Chem. 2002, 117, 63. 7. Miyake, T.; Haruyama, H.; Ogura, T.; Mitsui, T.; Sakurai, A. J. Pestic. Sci. (Int. Ed.), 1992, 17, 75. 8. Cao, S.; Qian, X.; Song, G.; Cai, B.; Jiang, Z. J. Agri. Food Chem., 2003, 51, 152. 9. Huang, Q.; Qian, X . ; Song, G.; Cao, S. Pest. Management Sci. 2003, 59, 933-939,. 10. Cao, S.; Qian, X . ; Song, G. etc., Chemitry Letters, 2001, 54. 11. Osner, W. M . ; Castle, R. N . J. Pharm. Sci., 1963, 52, 539. 12. Singh, B. Heterocycles, 1984, 22, 1801. 13. Coates, W. J.; McKillop, A. Heterocycles, 1989, 29, 1077. 14. Coates, W. J.; McKillop, A. Heterocycles, 1993, 35, 1313. 15. Konecny, V.; Kovac, S.; Varkonda, S. Collect. Czech. Chem. Commun., 1985, 50, 493.


Oxadiazole Derivatives as Novel Insect-Growth Regulators: Synthesis

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