Cycloalkyl-Substituted Amidrazones - American Chemical Society

Chapter 19

Downloaded by OHIO STATE UNIV LIBRARIES on June 19, 2012 | http://pubs.acs.org Publication Date: May 14, 1998 | doi: 10.1021/bk-1998-0686.ch019

Cycloalkyl-Substituted Amidrazones: A Novel Class of Insect Control Agents D.G.Kuhn,J.A.Furch, DavidA.Hunt,M.Asselin,S.P.Baffic, R. E. Diehl, T.P.Miller,Y.L.Palmer,M.F.Treacy, andS.H.Trotto Cyanamid Agricultural Research Center, American Cyanamid Corporation, P.O. Box 400, Princeton,NJ08543-0400

A series of cycloalkyl-substituted amidrazones has been prepared. Certain members of this series have shown activity against coleopteran pests such as Southern corn rootworms and boll weevils. Activity against certain lepidopterous species including southern armyworms and tobacco budworms has also been observed. This report details the synthesis and insecticidal activity of these compounds. Preliminary structure-activity relationships are also presented. The discovery of new chemical moieties possessing insecticidal activity remains one of the most challenging endeavors facing scientists today. In addition, the study of how chemical modification of molecules affects biological activity allows one to define and expand the spectrum of activity within a lead series. Recent workfromour laboratories (i) led to the identification of a novel class of amidrazones possessing high coleopteran activity and good eco-toxicological properties. However, these compounds had little or no activity on other insect species. These observations prompted us to undertake a synthesis program aimed at expanding the spectrum of insecticidal activity while maintaining the good ecotoxicity profile. We observed, in our initial work, that a tertiary carbon center attached to the central carbon atom of the amidrazone framework was necessary for high coleopteran activity. Using this structural requirement, our synthesis efforts turned to the preparation of analogs with cycloalkyl groups attached to the amidiazoneframeworkthrough a tertiary center as shown in Figure 1.

Figure 1. General Structures of the Open-Chain and Cycloalkylamidrazones ©1998 American Chemical Society

In Synthesis and Chemistry of Agrochemicals V; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

185

186 Chemistry


Cycloalkyl-Substituted Amidrazones. The synthesis of simple cycloalkyl substituted amidrazones, as exemplified by the 1-substituted cyclopropyl analogs, is shown in Figure 2.

Figure 2. Synthesis of Cyclopropyl Substituted Amidrazones Coupling of a substituted cyclopropane carboxylic acid 1 with 2,6-dichloro-4trifluoromethylphenyl hydrazine 2 using a water soluble carbodiimide gave the hydrazide 3 in moderate yield. Treatment of 3 with excess thionyl chloride in warm toluene gave the hydrazonoyl chloride 4. Reaction of 4 with ethylamine gave the desired amidrazone 5 in good yield. This sequence allowed us to vary, by use of the appropriate amine, carboxylic acid and hydrazine, substitution on the terminal nitrogen of the amidrazone, the one-position of the cycloalkyl substituent or the substitution partem on the aromaticringrespectively. Dihalosubstituted cyclopropyl amidrazones. The preparation of amidrazone analogs having substitution on the cyclopropane ring at other than the one position, in particular gem dihalo substitution, was accomplished as shown in Figures 3 and 4.

'

C

0

2

C

H

3

™

NaOH , 50-70%

6 l.NaOH/H 0

'Ί6 -

Χ

C

0

*

C

H

3

Χ 7

ΧΟοΗ

2

χ

χ 8

Figure 3. Synthesis of 2,2-Dihalocyclopropane Carboxylic acids



187

π Figure 4. Synthesis of Dihalocyclopropyl Substituted Amidrazones Treatment of an α,β-saturated ester 6 with chloroform (or bromoform) under basic conditions in the presence of benzyl triethylammonium chloride (BTEAC) gave moderate to good yields of the 2,2-dihaloesters 7 (X=C1, Br) (3). Mild base hydrolysis followed by acidic work-up gave the desired carboxylic acids 8 in 8090% yield. The final products (11) were prepared via the sequence analogous to the simple analogs (Figure 4). Insecticidal Activity All compounds prepared in this work were screened against Southern com rootworm larve (SCR) Diabrotica undecimpunctata in a soil assay and third instar southern armyworms (SAW), Spodoptera eridania (Cramer) using a standard leaf dip bioassay with technical material. Selected analogs were tested on adult boll weevils, Anthonomus grandis, third instar tobacco budworms (TBW), Heliothis virescens (F), and adultricewater weevils, Lissorhoptrus oryzophilus, all by leaf application of technical or formulated material as indicated. Cycloalkyl-Substituted Amidrazones. Figure 5 compares the activity of two cyclopropyl analogs.

% CONTROL R

SCR (10 PPM)

SAW (100 PPM)

12

CH

3

50

0

13

C H

5

0

80

6

Figure 5. Insecticidal Activity of Cyclopropylamidrazones The 1-methyl analog 12 was found to have selectivity on Coleopteran species similar to that of the open chain analogs described previously (7). No activity was


188


found on SAW. Replacement of the methyl group at the 1-position of the cyclopropane ring with a phenyl group to give 13 resulted in a loss of SCR activity. However, 13 was found to give 80% control of SAW at 100 ppm. Introduction of one (14) or two chlorine atoms (15) onto the aromatic ring did increase SAW activity. Both 14 and 15 gave complete control of SAW at 100 ppm. However, none of these compounds showed activity against SCR at 10 ppm (see Figure 6).

% CONTROL

13 14 15

H 4-C1 2.4-C1

SCR (10 PPM)

SAW (100 PPM)

0 0 0

80 100 100

Figure 6. Insecticidal Activity of 1 -Arylcyclopropylamidrazones The appearance of activity against lepidoperous insects (i.e. SAW) seen with the 1-aryl analogs prompted us to investigate this series in more detail. Ring size was found to be crucial, as shown in Figure 7. While the cyclopropyl analog 14 gave complete control of SAW at 100 ppm, the cyclobutyl analog was inactive on all species tested.

CI % CONTROL

14 16

η

SCR (10 PPM)

SAW (100 PPM)

1 2

0 0

100 0

Figure 7. Effect of Ring Size on Insecticidal Activity The position of the aromatic ring on the cyclopropane ring was also important (Figure 8). The 1-phenyl isomer (13) gave complete control of SAW at 100 ppm and moderate control of TBW (-30%). The 2-phenyl compound, as a mixture of cis and trans isomers, (17) was totally inactive.


189 % CONTROL


SAW (100 PPM)

TBW (100 PPM)

Figure 8. Comparison of the Activity of 1- and 2-arylcyclopropylamidrazones In an effort to improve activity in this series, further substitution on the cycloalkyl ring was studied.

% CONTROL R 12 13 18

CH

3

C H CH 6

3

5

X

SCR (10 PPM)

SAW (100 PPM)

H

100

H

0

0 80

Cl

100

80

Figure 9. Insecticidal Activity of 1-Substituted Dihalocyclopropyl Amidrazones Figure 9 compares the activity of three of these analogs. As was seen earlier, the 1-methyl compound 12 gave moderate control of SCR while the 1-phenyl analog 13 was active on SAW. Replacement of the hydrogens at the 2-position of the cyclopropane ring with chlorine atoms gave a compound (18) that was active on both SCR and SAW. Figure 10 summarizes the activity for a series of cyclopropylamidrazones in which the substitution on the terminal nitrogen has been varied. The unsubstituted analog 19 gave good control of SAW but SCR activity was reduced relative to the N-ethyl compound 18. Branching at the α-carbon of the nitrogen substitutuent (20) or replacement of the methyl group with a phenyl (21) resulted in a loss of activity. However addition of a phenyl group to the terminal carbon of 18 to give the phenethyl derivative 22 resulted in high SAW activity but little or no control of SCR. The allyl analog 23 was only moderately active on both species.


190


% CONTROL

E2

SCRflOPPM)

SAW Π 00 PPM)

_

19 18

H Et

H H

100

100 80

20 21 22

(CH )2CH

H H

100 0

40 0

C6H5CH2CH2

H

100

100

23

CH2 CHC H2

H

100

60

3

==

Figure 10. Effect of N-Substitution on Insecticidal Activity In the dichlorocyclopropane series, as in the alkyl series (i) disubstitution on the terminal nitrogen resulted in a loss of activity on both species tested (Figure 11).

% CONTROL SCRO0PPM)

Ei

SAW Π 00 PPM)

18 24

Et Et

H Et

100 100

80 0

25

Et

Me

0

0

Figure 11. Insecticidal Activity of Ν,Ν-disubstituted Amidrazone

While halogen substitution on the cyclopropane ring was necessary for broad spectrum activity, both the dichloro (18) or dibromo (26) analogs were active on the SCR and SAW (Figure 12.) Alkyl substitution at the remaining position of the cyclopropaneringin the dihalo series resulted in a loss of activity against SCR as the size of the alkyl group increased (Figure 13). The same structural changes did not result in a similar decrease in activity against SAW (18 vs 27 or 28). However, branching at the α-carbon (29) or replacement of the alkyl group with an aryl group (27 vs 30) did decrease SAW activity.


191

% CONTROL


X

SCR (10 PPM)

SAW (100 PPM)

12

Η

100

0

18

Cl

100

80

26

Br

30

100

Figure 12. Insecticidal Activity of 2,2-Dmalocycloalkylamidrazones

% CONTROL X 18 27

SCR (10 PPM)

R

CI

H

CI

CH

3

SAW (100 PPM)

100

80

30

100

28

CI

40

90

29

CI

(CH )2CH

10

60

30

CI

4-ClC H

40

60

31

Br

CH

0

100

CH CH 3

2

3

6

3

4

Figure 13. Insecticidal Activity of Dihalocyclopropylamidrazones

Attempts to combine the good lepidopteran activity seen in the 1arylcyclopropane series with the broad spectrum activity observed with the dihalo series were unsuccessful as shown in Figure 14. While the l-methyl-2,2dichlorocyclopropyl amidrazone, 18, was active on both SCR and SAW, the l-(4chlorophenyl)-2,2-dichlorocyclopropyl amidrazone, 32, was only weakly active on SCR and totally inactive on SAW. The activity seen in the dihalo series prompted us to investigate the activity of these compounds on other coleopteran species. Figure 15 shows the results of a field simulation study using the lead compound, CL 341436, 18, as an EC formulation, on boll weevils. The activity seen was superior to the standard, Vydate® at the same rate. Against adult rice water weevil, CL 341436, formulated as a 20% EC, gave control comparable to the standard, ethofenprox, at the same dose rate (Figure 16).


192


C l

FC

H

^

CI

3

CI CI % CONTROL

18 32

CH 4-ClC H 3

6

4

SCR (10 PPM)

SAW (100 PPM)

100 20

80 0

Figure 14. Activity Comparison of 1-Methyl vs. 1-Arylcyclopropyl Amidrazones

AC 341436,18

TREATMENT (LB Al/A)

% CONTROL (0 DAT)

AC 341436 1.67EC (0.125) AC 341436 1.67EC(0.25) AC 341436 1.67EC(0.35) V Y D A T E 2 E C (0.25)

70 92 100 62

Figure 15. Activity of AC 341436 on Adult Boll Weevils, Anthonomus Grandis


193

FC 3

AC 341436,18 %CONTROL


TREATMENT (G AUA)

A C 341436 20%EC (200) ETHOFENPROX 20% EC (200)

3 PAT

96 92

SPAT

100 92

Figure 16. Activity of AC 341436 on Rice Water Weevil, Lissorhoptrus Oryzophilus Conclusion In conclusion, synthetic modification of the alkyl amidrazones, compounds with high coleopteran activity, has resulted in a series of cycloalkyl-substituted amidrazones with a broader spectrum of insecticidal activity including lepidopterous insects. One compound, CL 341436, in limited trials, demonstrated levels of activity comparable to commercial standards on adult boll weevils and adultricewater weevils at both 3 and 5 days after treatment (DAT). Acknowledgments The authors wish to express their appreciation to the members of the Insecticide Discovery group for obtaining the biological results presented in this work. Literature Cited 1. Furch,J.A.;Kuhn,D.G.;Hunt,D.A.;Asselin, M.; Baffic,S.P.;Diehl, R.E.; Pamer,YL.;Trotto,S.H.companion chapter in this volume. 2. Nelson,D.G.;Roger,R.;Heatles, J.W.M.; Newlands,L.R.;Chem. Rev. 1970, 70, 151. 3. For a review of the preparation of 2,2-dihalocyclopropane carboxylic ester, see: Dehmlow,E.;Angew. Chem. Internat.Edit. 1974, 13, 170.


Cycloalkyl-Substituted Amidrazones - American Chemical Society

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