Oxime Fungicides: Highly Active Broad-Spectrum Protectants

Chapter 34 Oxime Fungicides Highly Active Broad-Spectrum Protectants

Downloaded by UNIV OF GUELPH LIBRARY on June 19, 2012 | http://pubs.acs.org Publication Date: May 5, 1995 | doi: 10.1021/bk-1995-0584.ch034

Joseph E. Drumm, John B. Adams, Jr., Richard J. Brown, Carlton L. Campbell, David L. Erbes, William T. Hall, Stephen L. Hartzell, Mark J. Holliday, Daniel A. Kleier, Marsha J. Martin, Stephen O. Pember, and George R. Ramsey DuPont Agricultural Products, Stine-Haskell Research Center, Newark, DE 19714

Broad spectrum contact fungicide activity was demonstrated by several oxime classes of chemistry. Biological data, chemistry, structure activity trends and the importance of hydrolysis to the effectiveness of the oxime fungicides are discussed. The discovery of the fungicidal activity of compound 1 led to a major analog program in order to explore the range of biological activity possible for this class of chemistry (Figure 1). Control at 200 ppm of several of the economically important diseases (apple scab, peanut early leaf spot, rice blast, tomato late blight, wheat leaf rust, grape downy mildew, and cucumber botrytis) provided results similar to commercial contact standards such as mancozeb, chlorothalonil, and captan.

Amide Region

N-O-Q

Capping Group

X Leaving Group Figure 1. Lead and Generic Structures 0097-6156/95/0584-0396$12.00/0 © 1995 American Chemical Society

In Synthesis and Chemistry of Agrochemicals IV; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

34.

Oxime Fungicides

D R U M M E T A L .

397

As shown in Figure 1, we have divided the molecule into three regions and will refer to them as the amide region (G-group), leaving group (X-group) and the capping group (Q-group). A discussion of some of the chemistry of the area will be followed by a presentation of some of the biological data. Structure activity relationships will be discussed, as will some of the hydrolysis (degradation) trends.


Synthesis In many cases, it is preferable to start the synthesisfromhydroximidoyl chlorides. The hydroximidoyl chlorides where G = amide or ester were readily made using Scheme 1 shown below (7-5). Compounds where G = phosphonate were made similarly, starting with the required p-keto-phosphonate. This method was used to generate the majority of the hydroximidoyl chlorides. 2

HNR*R

NaN0

n

O

2

O

£*2 HOAc

H

Q

O

Scheme 1 Compounds where G = CN were made according to the method of Adamczyk and Kozikowski (6) (Scheme 2). H

H N-OH 2

CC-CHO

0

\

,OH

sOCl

H 2

^ JUL —

0

\

JL =N C

Scheme 2 Thioamide G-groups were made by reacting the appropriate carbamyl or esteramides with Lawesson's reagent, with high selectivity for the amide carbonyl (Scheme 3).

j? \i AN(CH ) 1—C-0-N=* b

3 2 3 2

Lawesson's Reagent ^ CH C1 2

2

% „ >-N(CH ) R—C-0-N=^ b Q

3

R = Ar NH-Ar Scheme 3


2

398

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS IV

Scheme 4 shows a method adapted from Shimizu et al (7) that incorporates the X-group and Q-group in one step, for cases where G = sulfonyl. The nitronate anion, generated by deprotonation, is O-acylated. Elimination of an equivalent of the acid (corresponding to the acid chloride) provides the sulfonyl nitrile oxide, which adds across a second acid chloride equivalent. O


JJ

2 eq R-COC1

Scheme 4 Capping methods are shown below in Scheme 5. Aliphatic isocyanates (except methyl isocyanate) failed to react under a variety of conditions. With aryl isocyanates, the use of a catalytic amount of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was essential to the formation of the product. Other bases failed to produce the carbamates cleanly, or at all. The reaction of the hydroximidoyl chlorides with other acylating groups proceeds through the reactive nitrile oxides following well-precedented pathways (8). Acetonitrile was the preferred solvent, although THF was frequently used; triethylamine was most frequently used as the base. u O-C—NH-Ar

Me. Me

Me,

Cl

ArNCO DBU CH CN

ArCOCl Et N CH CN or THF 3

3

Me

3

-OH Me

Cl ROCOCI, Base OR COCl , then ROH Pyridine

ArS0 Cl DBU THF 2

2

O

II

-O-S-Ar

Me,

II

Me

Cl

II

-O-C—OR

Me.

O Me

Cl

Scheme 5


34. DRUMMETAL.

Oxime Fungicides

399

O-Alkyl Derivatives


Two strategies were employed to make O-alkylated hydroximidoyl chloride derivatives (9-11). First, N-alkoxyoxamides were chlorinated with phosphorous pentachloride as shown in Scheme 6. The other strategy employed chlorination of the oxime with N-cWorosuccinimide to give the hydroximidoyl chloride as shown below in Scheme 7.

5

°

C

„ , I n-BuLi - 78 ^ | HN(Me) THF

2

O O

H //-O^Y^

Mex

PCls

M e

^

N

H II N H - O ^ V ^

Me'

Scheme 6 j?

P *

EtO-L( O-Et

n-BuLi ^ HN(Meb THF m

O

O-Et H N-OH Me j? | j ' N-"—"k^ Me'' £x o J»

\.J-/

" ,"

0 H

2

\

K C0 2

C l 3

D M F

RT

f ^f H

^-C

D M F

M

1

E

\a

Cl

Scheme 7 When different X-groups were required, they were formed prior to acylation by reaction of the nitrile oxide (7) with nucleophiles such as mercaptans (12) or heterocycles. The nitrile oxide can also be trapped with acyl halide derivatives as shown below in Scheme 8. Sulfide oxidations were carried out using either MCPBA or peroxyacetic acid.


400

SYNTHESIS 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 IV


O

Scheme 8 Biology - Greenhouse The broad spectrum of activity demonstrated by these compounds is shown in Table I. This activity was limited to preventative control for most of the diseases. These compounds were equivalent to the commercial standards such as mancozeb, chlorothalonil and captan, when compared in the greenhouse. The O-alkylated oximes, by contrast, were not active. The greenhouse disease control data were used to develop the structure activity relationships. Structure-Activity Relationships Several elements of SAR were evident for this class of compounds (Figure 2). The criteria used for the ranking were based on the spectrum of diseases controlled, followed by the rates that disease control began to diminish (break-rate). The most consistent diseases controlled were grape downy mildew and late blight on tomatoes or potatoes. N

—

N — O — Q

X

Figure 2. Generic Oxime Structure G-group. The G-group substituents are ranked in descending order of their biological activity as shown below. The G-group was also believed to be important


34. DRUMMETAL.

Oxime Fungicides

401

Table I. Biological data


N-O-COZ-R

#

G

X

Z

1 2 3

Me2NCO Me2NCO

Cl Cl Cl

NH -

4

OO

Cl

-

Cl

NH

Cl Br

-

5 6 7 8 9 10 11 12 13 14 15 16 17 18

f^N-CO c0

c o

Me2NCO Me2NCO Me2NCO Me2NCO Et02C NC Ph-S02 Me2N-S02 Me2NCO CH3CO Me2NCO Me2NCS (CH3Q)2PO

\n S02-Ph Cl Cl Cl Cl Cl Cl Cl Cl Cl

-

-

-

R

3,5-Cl-Ph 96 29 43 3,5-Cl-Ph 100 NT 90* 2-Naphthyl 100 72 86

95 100 99

21 0 99 NT NT NT 100 8 20

2-Naphthyl 100 82

78

99

100 0

100 NT 94

99

98

2,6-Cl-Ph

100 99 100 99 NT 100 90* 100 100 NT

97 52 70 0 NT 88 NT 92 80 NT

97 63 NT 0 91 97 92 85 NT 23

100 97 68 95 100* 100 90 100 0 25

-

88 49

100* 53 NT 99* 0 82 99 0 0 70* 0 0 100* 0 91 100 93 99 94* NT 0 100 96 99 48* 0 0 80 0 0

* indicates disease control at 40 ppm; NT indicates compound not tested APS PCS WLR TLB GDM RCB CBT

18

2-Naphthyl 100 99 85 100 100 NT 59 2-Naphthyl 97* 94 72 100 99* 21 0 2-Naphthyl NT NT NT 55 100* 0 0

3-CF3-Ph 2-Naphthyl 2-Naphthyl 4-Cl-Ph Ph NH 3,4-Cl-Ph 2-Naphthyl OCH2 2-Naphthyl NH 3,5-Cl-Ph 3-CF3-Ph -

Percent Disease Control at 200 ppm APS PCS WLR TLB GDM RCB CBT

Apple Scab (Venturia inequalis ) Peanut Early Leaf spot (Cercospora arachidicola) Wheat Leaf Rust (Puccinia recondita) Tomato Late Blight (Phytophthora infestans) Grape Downy Mildew (Plasmoparaviticola) Rice Blast (Pyricularia oryzae) Cucumber Botrytis (Botrytis cinerea)


402


in controlling the solubilization of the compounds in water. Dissolution of the compounds in the water containing either fungal spores or actual growing fungi was found to be important for expression of disease control. A more detailed discussion will follow later. Optimal disease control was seen when the number of carbons on the amide nitrogen substituents totaled five, with the exception of the dimethylamide which provided the highest level of control.


-CO-NR1R2 > -S02NMe2 > -S02-Ar > -CN > -PO3R2 > -S-R > -CO2R

X-group. The X-group substituents demonstrated that a good leaving group is required. Table H shows the relationship of p K to biological activity; halogens as the X-group gave the most active compounds. a

-Br, -Cl > -SO2R > -NO2 »-imidazole, -tetrazole > -CN > -S-R, -H, - C O C H 3 Q-group. The Q-group must be hydrolyzable. The carbamates were the most active of the sub-classes, while the carbonates and benzoates (and naphthoates) were also highly active. The sulfonates were much less active, and the O-alkyl derivatives, like the uncapped hydroximidoyl chlorides themselves, were not fungicidal. -CO-NH-R > -CO-Ar, -CO2R > SO2R » H, alkyl Biology - Field The lead compound 1 showed poor performance in early field trials due, we believe, to hydrolytic instability. Several other carbamate analogs along with an ester and carbonate were also tested, but their performance was also erratic (potato late blight, grape downy mildew and apple scab). The field results even for a given compound were not consistent, one test giving significantly more control than another, against the same disease. The results for several years of field testing for all of these compounds were much below the standards. Hydrolysis Many of the structural modifications reported in the synthesis section and summarized in the SAR were made in an attempt to retain the fungicidal activity while lengthening the hydrolytic stability. Investigations revealed that each of the sub-classes of capping groups fell within very specific hydrolysis ranges. The carbamates had half-lives as low as 10 minutes provided the material was completely dissolved. In most cases, an inverse relationship existed between the hydrolysis stability and the fungicidal activity in the greenhouse (Table HI). The best balance between disease control and hydrolytic stability arose from the O-acyl capping group (oxime esters). We initially viewed the proclivity toward aqueous hydrolysis of the carbonyl linkage between the oxime and the capping group as an attractive feature, offering a ready mechanism for environmental degradation of these compounds. It now appears that the length of the dew periods and amounts of rainfall experienced by these hydrolytically unstable compounds greatly influences the field activity and accounts for the erratic field performance noted above.


34. DRUMMETAL.

403

Oxime Fungicides


Table II. Leaving group effects on biological activity X

pK ofHX

Plant Disease Control

-Br

-8

++

-Cl

-7

++-

-S02-R

2

++

-NO2

3.5

+

Imidazole

7

-/+

-CN

9.3

-

-S-R

10

-

Acetyl

>30

-

-H, -alkyl

>40

-

a

Table III. Comparison of solution hydrolysis rates and biological activity Capping group

Class

Half-life (hrs.)

Activity

R-S02 R-CO R-O-CO R-NH-CO

sulfonate ester carbonate carbamate

12 2-10 2.5-3.5 0-2

+ ++ +++ +++

Nitrile Oxide Hypothesis The hydrolytic instability of the O-acylated hydroximidoyl chlorides led us to speculate that they might be acting as profungicides. Greenhouse testing showed that the compounds with the fastest hydrolysis rates (carbamates) provided the highest levels of disease control when the plants were inoculated 24 hours after treatment with the chemical. Hydrolysis degradation products of 1 were isolated and identified using LC-MS. Examination of these degradation products in greenhouse testing failed to identify any active materials, including the uncapped hydroximidoyl chloride. In vitro studies of the hydroximidoyl chlorides, however, showed that they caused lysis of Plasmopara zoospores within minutes. Hydrolytic stability studies within the physiological pH range on these hy(koximidoyl chlorides noted a steady decomposition to other products, with an estimated half-life of several hours. Since hydroximidoyl chlorides are known to generate nitrile oxides, this led us to speculate that the nitrile oxides might be acting as the fungicidal agents (Figure 3). Zoospore lysis was observed on treatment with nitrile oxides or else, on generation of the nitrile oxides in situ from hydroximidoyl chlorides and base. Uncapped oximes in which the chlorine was replaced by a hydrogen or 3,5-dichloroaniline failed to cause any zoospore lysis. Thus, for in vitro activity, the need for a good leaving group was demonstrated. These results led us to propose the model


404


O

I,

^ N| ' ^ ^S ^ I

Undissolved oxime carbamate

j-Cl

O N %

O ^ N H^- / / S/ =

I

Dissolution


o

' o

Pi

Dissolved oxime carbamate

Hydrolysis

".I Free Oxime

%

OH

I.

I

Deprotonation O

|

Free oxime anion Elimination

N

cr

O

Nitrile oxide Interaction with leaf surface

\ \

Reaction with criti critical cell com component(s)

/

„ _ Loss of fungicidal activity

Inhibition of pathogen

Figure 3. HYDROLYTIC CASCADE AND THE GENERATION OF NITRILE OXIDE



34. DRUMMETAL.

Oxime Fungicides

405

describing a hydrolytic cascade which generates a nitrile oxidefrom1 (Figure 3). We used this as our working model to guide subsequent investigations. We believe that the decomposition of 1 occurs on solubilization releasing first the hydroximidoyl chloride and then the nitrile oxide, the active fungicide. In the presence of a pathogen, the nitrile oxide can react with some critical cell component to inhibit its growth. In the absence of fungi, the nitrile oxide reacts mdiscriminately to yield materials no longer fungicidal. Greenhouse testing with simulated dew periods showed decreased effectiveness for the capped compounds as the number and duration of die dew periods between spraying of the compound and inoculation with a pathogen were increased. These results suggested hydrolysis of the compounds was occurring on the leaf surface, followed by decomposition of the nitrile oxide prior to encountering the pathogen. This would explain the lack of residual activity that was observed. Conclusions The hydroximidoyl chloride derivatives discussed display broad spectrum fungicidal activity in greenhouse testing. The molecules can be divided into three portions, each of which plays a key role in the resulting biological activity. The data suggest that these compounds are profungicides, which release a reactive nitrile oxide in a hydrolytic cascade. This hydrolytic cascade, although essential to the fungicidal activity of the compounds, limits their effectiveness under field conditions where hydrolysis is influenced by uncontrollable factors such as rainfall, dew periods or other moisture. Since the hydrolysis occurs whether or not the pathogen is present, the amount of nitrile oxide available for disease control (hminishes too rapidly for a standard commercial spray interval. Acknowledgments The authors would like to thank the many people who assisted in this work, in particular, E.A. Steel, C. Happersett, T. Tran, B. Atkins, A.E. Trivellas, F.T. Coppo and C.G. Sternberg. Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

WO 9012784 (DuPont, 1990) WO 9202491 (DuPont, 1991) WO 9203050 (DuPont, 1991) WO 9204318 (DuPont, 1991) Rave, T.W.; Breslow, D.S.J.Org. Chem. 1971, 36, 3813. Kozikowski, A.P.; Adamczyk, M.J.Org. Chem. 1983, 48, 366. Shimizu, T.; Hayashi, Y.; Shibafuchi, H.; Teramura, K. Bull. Chem. Soc. Japan 1986, 59, 2827. Torssell, K.B.G., Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis; VCH Publishers, Inc.: NY, 1988. Grundmann,C.;Richter, R.J.Org. Chem. 1968, 33, 476. Johnson, J.E.; Springfield, J.R.; Hwang, J.S.; Hayes, L.J.; Cunningham, W.C.; McClaugherty J. Org. Chem. 1971, 36, 284. Johnson, J.E.; Nalley, E.A.; Kunz, Y.K.; Springfield, J.R.J.Org. Chem. 1976, 41, 252. Benn,M.H. Can. J. Chem. 1964, 42, 2393.

RECEIVED September 16, 1994


Oxime Fungicides: Highly Active Broad-Spectrum Protectants

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