Synthesis and Chemistry of Agrochemicals II - American Chemical

Chapter 45

Synthesis and Fungicidal Activity of 1H-Inden-1-ones Glen P. Jourdan, Barry A. Dreikorn, Ronald E. Hackler, Harold R. Hall, and Wendell R. Arnold

Downloaded by UNIV LAVAL on September 17, 2015 | http://pubs.acs.org Publication Date: December 7, 1991 | doi: 10.1021/bk-1991-0443.ch045

Lilly Research Laboratories, Eli Lilly and Company, Box 708, Greenfield, IN 46140

A novel series of protectant fungicides, derivatives of 1-H-inden-1 -one, has been prepared. These compounds are readily accessible from the reaction of Grignard reagents on 2-substituted-1,3-indandiones. The chemistry and structure-activity relationship of these broad -spectrum fungicides will be discussed. The application of chemicals to the surfaces of plants for protection against fungal organisms is among the oldest of crop protection practices. The earliest successful fungicides included sulfur and inorganic copper compounds which remained on the leaf surfaces. These agents served as protectants, penetrating poorly into plant tissue and thus were ineffective in eradicating fungi within the hosttissueφ . With the discovery of systemic chemicals the need for surface protection chemicals diminished. However, these chemicals act at a single or limited number of sites, permitting development of significant populations of resistant fungi. In order to avoid or delay resistance problems many of the systemic compounds are used in combination with protectant fungicides. The recent environmental and toxicological concerns over the use of commercial protectant fungicides has caused us to reexamine the role of protectant fungicides in disease prevention and control, either alone or in combination. Through random screening and using a criterion of activity of compounds against one or more major plant pathogens, we have discovered the broad spectrum fungicidal activity of a series of 2-substituted-l-indenones. The lead compound 1, was originally synthesized by Campaigne (2).

Ο CN CH

3

1 Compound 1 was shown in our screens to have significant fungicidal activity 0097-6156/91/0443-0566506.00/0 © 1991 American Chemical Society

In Synthesis and Chemistry of Agrochemicals II; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.

567

45. JOURDAN ET AL. lR-Inden-l-ones

against a wide range of foliar plant pathogens including apple scab, rice blast and powdery and downy mildews. Our overall structure-activity relationship (SAR) approach was to divide the molecule into three portions and, by making changes stepwise, determine what effect these changes had on fungicidal activity. The main objectives of the SAR were: A) modification of the cycloikylsubstituent at the 3position, B) replacement of the cyano group at the 2-position, C) substitution of the phenyl portion of the molecule. Ο


Β

Chemical Synthesis Modifications of the 3-Position. The chemical synthesis program was directed towards answering three questions about the nature of the alkyl group (R) in the 3position and its effect on fungicidal activity: 1. The importance of the size of the alkyl group 2. The importance of branching on activity 3. The importance of cyclic vs. acyclic alkyl groups Two general approaches were used to synthesize 2-cyano-l-indenones with different alkyl groups at the 3-position. The first was an expansion of the Campaigne synthesis (Figure 1, Scheme A), which required the synthesis of substituted ylidenemalononitriles, 2, and their subsequent cyclization in concentrated sulfuric acid. One limitation of this procedure in the expansion of the SAR was that for small R groups (i.e. lower alkyl), the cyclization did not occur. The second approach was based on earlier work by Koelsch (3), who reported the addition of aryl Grignard reagents to 2-aryl-l,3-indandiones to give 3-substituted indenones. Although nitriles are known to undergo a variety of reactions with Grignard reagents (4), treatment of the 2-cyano-l,3-indandione, 3, with excess Grignard reagent (Figure 1, Scheme B) gave addition exclusively at the indandione carrxmyl. During acidic work-up, the alcohol that formed spontaneously dehydrated to give 3-substituted-2-cyano-l-indenones. Organolithiums reacted equally well but, in either case, two equivalents of the organometallic reagent were required; one to deprotonate die indandione and the second to react with the carbonyl. The deprotonation step could be avoided by utilizing the sodium salt of 2-cyano-l,3-indandione, 27a, as it was obtainedfromthe cyclization of diethyl phthalate, sodium methylate and acetonitrile (5). This sodium salt, in THF, reacted equally well with heterocyclic lithiums such as 2-lithiothiophene and 5-litWopyrimidine. Modifications of the 2-Position. One of the primary objectives of the SAR at the 2position was to prepare ester, amide, alkyl, aryl and halogen derivatives in place of the cyano functionality. A seemingly obvious route to the carboxylate compounds was through the hydrolysis of the 2-cyano of compound 1, but it was found to be unreactive toward hydration, which has been attributed to steric hindrance (6). To synthesize other carboxylate entities at the 2-position, we utilized a reaction analogous to that for the preparation of the carbonitrile, 27a by reacting an alkyl acetate or dimethyl acetamide with molten sodium in diethyl phthalate, to give the sodium salts of



SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS II

Figure 1. Reaction schemes for the preparation of 2-cyano-l-indenones



45. JOURDAN ET AL lU-Inden-l-ones

569

the 1,3-indandiones (Figure 2). The crude sodium salts, in cooled THF, were treated with the organometallic reagents and addition again occurred exclusively at the indanone carbonyl An acidic workup with IN HCl for the esters, methyl and phenyl gave the alcohol or hydrated indenones, 28. The dimethylacetamide derivative dehydrated spontaneously. Partial dehydration was observed for some reactions, but for a complete reaction, refluxing in an aromatic solvent using an acid catalyst was necessary. The hydrated indenones were useful intermediates for the preparation of secondary amides, 30 by displacement of the ester with an appropriate amine in refluxing alcohol When the esters 29b,d were hydrolyzed under basic conditions and acidified, the resulting carboxylic acid spontaneously decarboxylated to give the 2-unsubstituted compound, 31 (Figure 3). This compound was brominated in CH2CI2 using equimolar amounts of bromine at room temperature to give the 2,3-dibromo-1indanone, 32a. Dehydrohalogenation to 33a was accomplished by treatment with sodium hydride. The chlorine analog, 33b was prepared in a like manner using IN NaOH to dehydrohalogenate. Nitration of the 2-position of 31 was achieved by fuming nitric acid. Aromatic Substitutions. The third objective of our SAR study was to synthesize and test compounds which had electron withdrawing and donating groups substituted on the phenylringwhile holding the 2- and 3-substituents constant. The route to these derivatives was through cyclization of substituted phthalic acid esters according to the previously described procedures for 27a. Many of the substituted phthalic acids were commercially available and the esterification was done with a vigorous stream of dry HCl gas while stirring under reflux in ethanol. The substituted diethyl phthalates were then washed with bicarbonate and cyclized to the substituted 1,3-indandiones, sodium salt. Suspension of the salt in dry THF, followed by treatment with organometallic reagents gave the substituted indenones as listed in Table Π. The unsymmetrical nature of the mono-substituted indandiones to the reacting organometallic reagent gave mixtures of the indenones which were separated by chromatography with the exception of the 5 and 6-CH3,35a&b and 5 and 6-CF3,37a&b. Structure-activity Relationship Greenhouse Results. After extensively modifying the substituents at the 3-position of the indenering,we systematically evaluated each compound in a primary foliage disease screen, the results for which are given in Table I. The broadest spectrum of activity was found with compounds having branched acyclic or cyclic alkyl groups. The next step in our SAR was to utilize special greenhouse studies to determine the relative activity of acyclic and cyclic structures as well as the optimum size and configuration of these groups. In studies involving the acyclic structures, the relative fungicidal activity was t-butyl > i-propyl > 1-methylpropyl, suggesting that branching at the alpha carbon was satisfying some spatial requirement. Two higher homologs of 7,1,1-dimethylpropyl, 9, and 1-ethyl- 1-methylpropyl, 10, demonstrated a significant increase in fungicidal control. Compound 10 was slightly more active than 9 but had increased phytotoxicity. Finally, a comparison of the size of the cycloalkyl ring found that the cyclohexyl 17 was generally less active than the cyclopentyl 1. Branching or tertiary substitution of the alpha-carbon was determined to be necessary as 16 and 19 were found less efficacious than 1. Invitro tests comparing 1 and 9 showed that 9 was generally more active. Both compounds were compared with maneb (£) for the control of downy mildew (Pseudoperonospora cubensis^ of squash. The ED90S were < 25 ppm for both test compounds, each giving superior control to the reference. In other side-by-side


570

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS II

OM

a

C0 Et

Na

2

R' C H

C0 Et 2

R

* '

E.' 27 a. b. c. d. e. f.


26

RMgX or R L i THF

M

-CN Na -C0 Me Na -C0 Et Na - C O N M e Na -CH * H -C H H * see reference 7 commercially available 2

2

2

3

b

6

5

b

Ο

(

—R' 1

29 R El 29 a . -C0 Me b. -C0 Me c. -C0 Et d. -C0 Et e. -C0 Et f. -CH g. -CH h. C H i. -C H 2 2

2 2 2

3

3

6

5

6

5

& t-Bu 1,1-dimethylpropyl n-Bu t-Bu 1,1-dimethylpropyl n-Bu t-Bu n-Bu t-Bu

R'=C0 Et 2

2

3

CONR R 30 30

R

R R t-Bu H b. t-Bu CH c . 1,1-dimethyIypropyl C H

R

a.

CH CH

3

d. t-Bu

3 3

CH

3

C H

3

e. 1,1-dimethylypropyl

H H

4-CI-C6H5

f. 1,1-dimethylypropyl g . 1,1-dimethylypropyl h. 1,1-dimethylypropyl

H H .

4-MeO-C H cyclohexyl -(CH CH ) 0

6

Figure 2. Modifications of the 2-position


5

6

2

2

5

2


45. JOURDAN ET AL

lYL-Inden-l-ones

OH* 29b,d

-co

2

R=l,l-dimethyl propyl

Figure 3. Modifications of the 2-position continued


572

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS H

Table I. Methods of synthesis and ED90 (ppm) for foliage disease screening of 3-position derivatives of 2-cyano-l-indenones


Ο

R Εβ9α

Compound R i t 1-methylcyclopentyl methyl 4 i-propyl 5 n-butyl 6 t-butyl 7 8 1-methylpropyl 9t 1,1-dimethylpropyl 1-ethyl- 1-methylpropyl 10 14,2-trimethylpropyl 11 1,1-dimethylbutyl 12 1-ethyl- 1-methylpentyl 13 -C(CH ) CN 14 l-methylcyclopropyl 15 cyclohexyl 16 1-methylcyclohexyl 17 1-ethylcyclohexyl 18 cycloheptyl 19 3

2

20

l

21 22 23 24 25

Synthesis A Β Β Β A&B Β A&B A&B Β Β Β Β Α Α Α Α Α Α

PM 75

a

RB 400 400

450 75 75

500 300 400 400

400

LR

DM 80

400 300

400 100 400 75

400 300 300 400

100 400 25 20 400 20 90 400 100 75 400 100 400 350

J

o cyclohexylmethyl 1-adamantyl phenyl 2-thienyl 5-pyrimidinyl

Β Α Α Β Β

a

where PM = wheat powdery mildew, RB =riceblast, LR = wheat leaf rust and DM = squash downy mildew t tested underfieldconditions


400 400 100


45. JOURDAN ET AL

573

ΙΈί-Inden-l-ones

comparisons their spectrum and level of activity were nearly identical so that synthetic factors made 1,1-dimethylpropyl the substitution of choice at the 3-position. Compounds generated by die modification of the 2-position (Figures 2 and 3) provided fungicidal control but the ED90S were generally 400 ppm or greater, with increased phytotoxicity and narrower in the spectrum of diseases controlled. The order of activity roughly followed cyano » amide > ester > phenyl with methyl, hydrogen and halogen being inactive. The hydrated intermediates 28 were weakly fungicidal. Substitutions of the aromatic ring, while keeping the other parameters constant (Table II), provided the greatest improvement in biological activity. Compound 42 offered excellent broad spectrum activity at a more efficacious level than any earlier analog. The synthesis of 42 was complicated by the unsymmetrical nature of the indandione and the presence of the 5-isomer. Synthesis and testing of the 5,6dichloro, 44, provided nearly equal control of downy mildew and was selected to undergo field evaluations. Foliar and soil drench experiments were utilized to determine the ability of selected compoundsfromTables I and Π to transport into planttissue.In a leaf band experiment, test compounds were applied in a band to the middle of squash leaves and evaluated for apical and translaminar disease control. All compounds tested failed to Table Π. Effect of aromatic substitutions on fungicidal activity

ED90 (ppm)

X Compound 34 4-CH3 35a •5-CH3 35b •6-CH3 36 7-CH3 37a •5-CF3 37b •6-CF3 38 4-OCH3 39 7-OCH3 4-CI 40 41 5-C1 42 6-C1 43 7-C1 5,6-di-Cl 44t 45 6-C1, 5-OCH3

PM* >400 100

RB 400 >400

LR

>400 300*

300

400 100*

>400

50 100 300 350 25 300 25

400 350 50 400 >400

400 400*

DM 12.5

100 200

50 40 5 300* 6.25 25

a

where PM = wheat powdery mildew, RB =riceblast, LR = wheat leaf rust and DM = squash downy mildew * denotes phytotoxicity • tested as a mixture of isomers t tested under field conditions


574

S Y N T H E S I S A N D C H E M I S T R Y O F A G R O C H E M I C A L S II

demonstrate any systemic activity. Soil drench applications of the chemicals provided no evidence of disease control through root uptake. Curative tests with these chemicals in which plants were inoculated with the disease organism, incubated and then treated were not effective for controlling the established disease. The conclusion of these studies was that these chemicals were strictly protectant fungicides. Field Results. Three compounds from the SAR (Tables I and Π) were tested under field conditions in Europe and the U.S. as broad spectrum fungicides. This series was most effective for the control of apple scab and grape downy and powdery mildew in the range of 750 to 1000 ppm.


Acknowledgments The authors wish to thank Mr. L. N. Davis for his synthetic contributions, Mrs. Anita Alexander for greenhouse evaluations and Dr. Joe Winkle for formulations research on this series. Literature Cited 1. Sisler, H. D.; Ragsdale, Ν. N. Agricultural Chemicals of the Future; Rowman & Allanheld: New Jersey, 1985; Chapter 15, 175. 2. Campaigne, E.; Forsch, R. A. J. Org. Chem. 1978, 43, 1044-50. 3. Koelsch, C . F . J. Am. Chem. Soc. 1936, 58, 1331-33. 4. Kharasch, M. S.; Reinmuth, O. Grignard Reactions of Nonmetallic Substances; Prentice-Hall: New York, 1954; Chapter 10, 767. 5. Horton, R. L.: Murdock. K. C. J. Org. Chem. 1960, 25, 938-41. 6. Campaigne, E.; Bulbenko, G. F.; Kreighbaum, W. E.; Maulding, D. R. J. Org. Chem. 1962, 27, 4428-31. 7. Koelsch, C. F.; Byers, D. J. J. Amer. Chem. Soc., 1940, 62, 560 8. Farm Chemicals Handbook; Meister Publishing Co., Willoughby, OH., 1987. RECEIVED

February 9, 1990


Synthesis and Chemistry of Agrochemicals II - American Chemical

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