Diphenylamines I - American Chemical Society

Chapter 30

Diphenylamines I Synthesis and Structure—Activity Relationship Development of Novel N-(Substituted-phenyl)-N-alkyl-2-(trifluoromethyl)-4,6dinitrobenzenamines Leading to a Potent Miticide (El-462) 1

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B. A. Dreikorn , Κ. Ε. Kramer , D. F. Berard , R. W. Harper , Ε. Tao , L. G. Thompson , and J. A. Mollet Downloaded by CORNELL UNIV on October 5, 2016 | http://pubs.acs.org Publication Date: September 22, 1992 | doi: 10.1021/bk-1992-0504.ch030

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DowElanco Research Laboratories, P.O. Box 708, Greenfield, IN 46140 Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285 2

A series of N-alkyl-2-(trifluoromethyl)-4,6-dinitrodiphenylamines was prepared for evaluation as agricultural miticides. This work led to the discovery and development of EL-462, a miticide highly active against two-spotted spider mites (Tetranychus urticae). The synthesis, structure-activity-relationship, and efficacy of these diphenylamines will be discussed. For a number of years, the agricultural component of Lilly Research Laboratories, now a part of DowElanco, has been interested in diphenylamines because of their fungicidal^-3) and rodenticidal activity (4-7). In the course of this work EL-462, N-methyl^^-difluoro^'^'-dinitro-ô'-itrifluoromethyl)- diphenylamine, was pre pared and broadly screened. Although it possessed little or no fungicidal activity, it

EL-462 was found to control two-spotted spider mites in our screen at levels below 10 ppm and yet exhibited relatively low acute mammalian toxicity and low phytotoxicity. Although similar diphenylamines are known to be miticidal(S-9), this activity is usually accompanied by mammilian toxicity and phytotoxicity. Based on this lead, an SAR approach was developed.

0097-6156/92A)504-0336$06.00/0 © 1992 American Chemical Society

Baker et al.; Synthesis and Chemistry of Agrochemicals III ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

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STRUCTURE-ACTIVITY-RELATIONSHIP APPROACH

Downloaded by CORNELL UNIV on October 5, 2016 | http://pubs.acs.org Publication Date: September 22, 1992 | doi: 10.1021/bk-1992-0504.ch030

The SAR approach that we followed was to hold ring "A" constant (since, in our screens, only diphenlamines with this substitution pattern in ring A were miticidally active), and substitute both ring "B" and the nitrogen between the rings.

SYNTHESIS OF ANALOGS Three approaches were used in synthesizing all of the analogs of EL-462 outlined in the SAR(i0) (see Synthetic Schemes below); (A) the formation of the diphenylamine followed by the N-alkylation, (B) the N-alkylation of the aniline followed by the formation of the diphenyl amine,and (C) substitution of the phenyl group after formation of the N-alkylated diphenylamine. SYNTHETIC SCHEMES A p p r o a c h "A" N0

2

1) Triethylamine: /EtOH

NH

NO-2 y CI

2

CF

or 3

2) NaH / D M F

1) (CH ) S0 / Na C0 (Acetone) 3

2

4

2

3

or 2) R-I / Na C0 (Acetone) (R = Methyl, Ethyl, Propyl) 2

3

R

CF,

NOV^ ^N0

A p p r o a c h "B" CF H

N

+

3

I II CH

NH N0 4

2

CF

3

3

CF C0 H 3

3

NO-

NO,


2

338

SYNTHESIS AND CHEMISTRY O F A G R O C H E M I C A L S III

A p p r o a c h "C It CH

3

CF

Cl Br or

3

2

H N 0 N0

N0

2

2

3

(X)N

CH

3

N0

2

CF

3

•

2

N0

2

N = 1-3 X = CI, Br, or Ν Ο

2


SCREENING METHODS: Initial screening against two-spotted spider mite was performed on Kentucky Wonder beans in the greenhouse. Ten-day old plants were placed in contact with mite-infested leaves for two days and then three rates of a formulated solution of each compound was sprayed to runoff on the infected leaves, with four replicates. After two days an actual count of the mites surviving on 6.28 cm of leaf surface was made and the concentration that controlled 50% of mites (LC ) was determined (Table I). 2

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SAR TRENDS The best miticidal activity was observed in those compounds where the phenyl ring "B" is either mono- or poly-substituted with halogens, especially chlorine and fluorine. With the exception of the CF substituted compounds, those substituted in the phenyl ring with other electron-withdrawing groups were for the most part less active than the halogen compounds. In the case of electron-withdrawing groups, the "3" substitution gives the best activity while, in the case of halogens, the "4" position must be substituted for maximum activity. After the completion of the SAR, the best candidate for potential commercialization, based on efficacy, cost and degree of mammalian toxicity was EL-462, our lead compound. After completion of the screening SAR, the most active compounds were further compared from the standpoints of miticidal efficacy, phytotoxicity and acute L D in mice. As a result of these studies, the best candidate for potential commercialization, based on efficacy, cost and the degree of mammalian toxicity and phytotoxicity was EL-462, our lead compound. In addition to the mite activity seen with EL-462, a wide spectrum of insect pests in our screens were also controlled but required higher rates. 3

50

COMPARATIVE PHYTOTOXICITY OF THE N-H COMPOUNDS WITH N-ALKYL ANALOGS In our screens, the diphenylamines without the N-alkyl groups, although miticidal, tended to be very phytotoxic. We. postulated that this phytotoxicity was associated with the acidic proton on the amine "tether". To determine how general this phenomenon was we compared the relative phytotoxicity of a number of miticidally active diphenylamines, both with and without alkyl groups on the amine "tether". This was accomplished by spraying ten-day-old soybean plants with varying rates of formulated material, up to 4000 ppm, and, after 7 days the plants were examined for signs of chlorosis or burning (Table II). Without exception, the N-alkylated diphenylamines were from 16 to 500 times less phytotoxic than their N-H counterparts.


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TABLEI ACTIVITY OF DIPHENYLAMINES AGAINST TWO-SPOTTED SPIDER MITES

R

R2

LC

H 2-Fluoro 3-Fluoro 4-Fluoro 2-Chloro 3-Chloro 4-Chloro 3-Bromo 4-Bromo 4-Bromo 4-Iodo

Methyl Methyl Methyl Methyl Methyl Methyl Methyl Methyl Methyl Ethyl Methyl Methyl Methyl Ethyl Methyl Methyl Methyl Methyl Ethyl Methyl Methyl Methyl Methyl Ethyl Methyl Methyl Methyl Methyl Methyl Methyl Methyl Methyl Methyl Methyl Methyl Methyl Methyl Ethyl Propyl Methyl Methyl Methyl Methyl

> > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > >


x

2-CF3 3-CF3 3-CF3 4-CF3 2-Cyano 3-Cyano 4-Cyano 4-Cyano 3-Nitro 4-Nitro 3-Methyl 2,4-Difluoro 2,4-Difluoro 2,5-Difluoro 3,4-Difluoro 2,6-Difluoro 2,4-Dichloro 3,4-Dichloro 3,5-Dichloro 2,4-Dibromo 3,4-Dibromo 2,4-Dinitro 2-Chloro-5-CF 2-Methyl-4-Chloro 2,4,6-Trifluoro 2,4,6-Trichloro 2,4,6-Trichloro 2,4,6-Trichloro 2,4-Difluoro-6-Nitro 2,4,6-Tribromo 2,3,5,6-Tetrafluoro 2,3,4,5,6-Pentafluoro 3

5 0

RANGE (PPM)

1000 1000 100 10 1000 10 10 100 10 10 10 100 1 1000 10 1000 100 1000 10 100 1000 1000 10 10 1000 1 100 10 10 50 10 100 1000 50 1000 1 10 10 10 50 1000 100 100

< 1000 < 50 < < < < < < <
4000 31 < > 4000 31 < > 4000 31 < > 4000 31 < > 4000 8 > 4000 8 < 1000 16 > 4000 31 < > 4000 31 < 2000 31 < > 4000 31 < 1000 31 < > 4000 31 < > 4000 31 < > 4000 31 < 1000 31 < 1000 31 < 1000 31 < > 4000

Η CH3 Η CH

31 < > 4000 62 > 4000

3

4-Fluoro 2-Chloro

3

3-Chloro

3

4-Chloro 3-Bromo 4-Bromo 4-Iodo 3-CF

3

4-CF3 2,4-Difluoro 2,4-Difluoro 2,5-Difluoro

3

2,6-Difluoro

3

3,4-Difluoro 3,5-Dichloro

3

2,4-Dibromo

3

2,4,6-Trifluoro

3

2,4,6-Trichloro

3

2,4,6-Trichloro

2

2,4,6-Trichloro

2

2,3,5,6-Tetrafluoro Pentafluoro Pentachloro

3

3

2


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FIELD ACTIVITY EL-462 was field-tested against two-spotted spider mite infestations of soybeans, cotton, mung beans, eggplant, marigolds, almond trees, and peach trees. The compound was typically applied as an emulsifiable concentrate or wettable powder at rates between 0.25 and 2 lb/acre at 1-2-week intervals. Over 90% control was observed at rates of 0.5-1 lb/acre with no phytotoxicity. It was also tested against citrus red mite (Panonychus citri) and citrus rust mite (Phyllocoptruta oleivora) infestations of orange trees. In the case of the citrus red mite, between 60-80% control was obtained depending on the rates used (1 to 4 lb/acre). In the case of citrus rust mite, 81% control was observed at 2.0 lb/acre. We also tested EL-462 against European red mite (Panonychus ulmi) on apples. Between 85-90% control was obtained at rates between 1 to 2 lb/acre. In addition to the mite activity seen with EL-462, a wide spectrum of insect pests were also controlled but at higher rates. CONCLUSION From the initial observation that EL-462 controlled two-spotted spider mites in the greenhouse, we were able to carry out an SAR to further define the structural requirements for both miticidal activity and low phytotoxicity. The SAR led to the conclusions that the N-alkyl group on the diphenylamine was essential to reduce phytotoxicity and also that of all the compounds screened, EL-462 had the greatest promise for commercialization since it is both highly active against mites while exhibiting very low phytotoxicity. Field studies confirmed that EL-462 indeed possessed good miticidal activity and low phytotoxicity, however the rates that were required for activity proved to be unacceptable for further development because of cost and potential residue considerations. ACKNOWLEDGMENTS We would especially like to thank Dr. James Froyd, formerly of Lilly Research Laboratories, for conducting all the comparative phytotoxicity tests and Dr. Pierre Daniau of our European affiliate for his contributions. LITERATURE CITED 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Dreikorn, B.A., U.S. Patent 4,152,460, 1979. Dreikorn, B.A.; Kramer, K . E . , U.S. Patent 4,381,312, 1983. Dreikorn, B.A., U.S. Patent 4,187,318, 1980. Dreikorn, B.A., U.S. Patent 4,084,004, 1978. Dreikorn, Β.Α., U.S. Patent 4,140,778, 1979. Dreikorn, B.A., O'Doherty, G.O.P.; Clinton, A.J.; Kramer, K . E . Proceedings 1979 British Crop Protection Conference. 1979, pp. 491-498 Dreikorn, B.A.; O'Doherty, G.O.P.; A.C.S. Symposium series 255, Pesticide Synthesis Through Rational Approaches, Chapter 4, 1984. Barlow, C.B.et.al.,U.S. Patent 4,117,167, 1978 Grantham, G.D., U.S. Patents 4,215,145, 1980 and 4,341,772, 1982 Dreikorn, B.A.; Kramer, K . E . , U.S. Patent 4,407,820, 1983

RECEIVED June 16, 1992


Diphenylamines I - American Chemical Society

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