A Novel Class of Benzamide Fungicides - ACS Symposium Series

Chapter 40

A Novel Class of Benzamide Fungicides David Bartholomew, Patrick J. Crowley, and I. Trevor Kay

Downloaded by PURDUE UNIV on September 16, 2017 | http://pubs.acs.org Publication Date: September 22, 1992 | doi: 10.1021/bk-1992-0504.ch040

ICI Agrochemicals, Jealott's Hill Research Station, Bracknell, Berkshire RG12 6EY, United Kingdom

A new class of fungicides was discovered as a result of speculative chemistry carried out in an attempt to make novel cyano imines. The products of trapping these imines with alcohols turned out to have interesting fungicidal and herbicidal activity. After a careful study of the structure activity relationships (SAR), highly active fungicides were found for the control of Oomycete fungi, and the compound 4-chloro-N[cyano(ethoxy)methyl]benzamide was chosen as a development candidate. The origins of the work, the synthetic chemistry, SAR, and physical properties of the compounds are described and, the mode of action and resistance properties of the compounds are briefly discussed.

There are a number of approaches to the discovery of agrochemicals. Those usually discussed include random screening, patent following, using natural products as the basis for invention, and biochemically oriented rational design. One approach often omitted however, is the use of blue-sky or speculative chemistry, probably because it has connotations of randomness or lack of design. Although this may be the case, blue-sky research does enable the chemist to break free from the restrictions of imitative chemistry and can lead to the generation of truly novel classes of biologically active molecule. The invention of the benzamide fungicides described in this paper provides an example of the successful application of this approach. There are perhaps two ways of using speculative chemistry in the inventive process. One is the exploration of a piece of chemistry for its intrinsic interest, perhaps to provide examples of a novel type of compound for testing. The other is the deliberate investigation of a chemical idea that the chemist believes may lead to some biological activity. The benzamide fungicides described here are a product of a combination of both approaches. The original idea was stimulated by a piece of pure chemical exploration, while the exploitation of that idea was planned to search for biological activity.

0097-6156/92/0504-0443$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.

444

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


Origins of the Work In the late 1970's, Drs. I. T. Kay and D. Bartholomew, working at ICI Agrochemicals, were exploring the chemistry of chlorocarbonyl sulfamoyl chlorides, a novel class of heterocyclic precursor which they had developed earlier (/). Using the sulfamoyl chloride 1 (Figure 1), they had built up the new ring system 2 and in turn were exploring the chemistry of this heterocycle. Attempts to alkylate 2 with chloroacetonitrile to give 3, gave instead thiatriazinone 6 (2). The reaction was postulated to involveringopening to generate the reactive cyano imine 4, which was then trapped intramolecularly to give 5. Elimination of cyanide then gave 6. On consideration of the mechanism they wondered whether cyano imines of this type (or compounds which could generate them), could be isolated, and whether they might show biological activity. As amide groups and benzene rings are frequently found in biologically active molecules they chose to make some simple model compounds incorporating both these functionalities and the cyano imine. The first target was 9. Treatment of benzoylaminoacetonitrile with t-butyl hypochlorite gave the N chloro amide 7. It was hoped that on irradiation 7 would rearrange to the C-chloro amide 8, which would in turn eliminate hydrogen chloride to give the imine 9. The reaction was carried out and worked up by treatment with aqueous methanol. Instead of chloride 8, the methoxy compound 10 was obtained, albeit in low yield (Figure 2). Biological testing of 10 gave a weak herbicidal signal. This was encouraging enough to carry out further work, to produce more material and to develop a better route for the synthesis of analogues. Herbicide and Fungicide Structure Activity Relationships Early Work. The first set of analogues exhibited both herbicidal and fungicidal activity. The fungicidal activity was interesting principally because of the activity on the Oomycete pathogens, Plasmovara viticola and Phytophthora infestans. but the high phytotoxicity of the compounds seemed to rule out their use as fungicides. Attention was therefore concentrated on optimising the promising herbicidal activity. Quite quickly the herbicidal symptomology was recognised as being similar to that of the Rohm and Haas herbicide propyzamide 11. A search of the literature revealed that the SAR for propyzamide and analogues had been published (3), and that 3,5-disubstitution in the benzene ring was optimum for herbicidal activity. Using this information it was quickly demonstrated that the same substitution pattern held in the new series with 12 having interesting herbicidal activity (Figure 3). There were, however, significant differences between the new series and the Rohm and Haas amides, (see Table I for a summary of the structure activity relationships). Most important was the presence of the cyano group, which gave greatly enhanced herbicidal activity over the acetylene in propyzamide, and was found to be essential for fungicidal activity. The corresponding amides and esters were poor as herbicides and inactive as fungicides, although most of the activity was retained with the thioamides. Highest activity was obtained with short saturated or unsaturated alkoxy groups, with ethoxy being optimal. Interestingly the analogue of propyzamide with the acetylene replaced by a nitrile was very poorly active. The analogous sulfides Baker et al.; Synthesis and Chemistry of Agrochemicals III ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

B A R T H O L O M E W E T AL.

A Novel Class of Benzamide Fungicides


40.

Figure 2


445


446

SYNTHESIS A N D CHEMISTRY O F A G R O C H E M I C A L S ΠΙ

Table I Activity of Ethers, Sulfides, and Amines on Plasmopara

HIGH (50 ppm)

2-

3,5- > 3- > 4-

CF » 3

Cl > Me , Br

PhO,

NO2 ,

F > MeO NH

OEt > OMe , SMe >

viticola *

2

O-n-Pr > O-a-Bu,

NHAr , S(0)!_ M e ,

O-i-Bu > OPh

NHAc , Me

2

X** 0-propargyl>0-allyl

* = foliar spray or root drench on vines ; lowest rate giving 100% control '* = order of activity generally independent of other variables



40.

BARTHOLOMEW ET A L


447

were quite active, but the simple alkylamino analogues were too unstable to be isolated. The corresponding anilines were isolable but had very poor activity. It was found that the order of activity for any individual variable (the side chain substituent X , the substituent R, or its position in the benzene ring) in the general structure in Table 1, was usually independent of the other variables. Attempts were made to broaden the range of active structural types, but herbicidal and particularly fungicidal activity was limited to a narrow group of structures. For example, replacement of the benzene ring with heterocycles such as substituted pyridine reduced activity markedly, while replacement with alkyl groups removed activity completely. Insertion of additional atoms between the aromatic ring and the amide carbonyl led to completely inactive compounds, while other variations such as the reversal of linkages and replacement of heteroatoms by carbons, met with a similar lack of success (Figure 4). Variations in the Amide Side Chain. At the time we were very actively researching the azole sterol inhibitors, and it was interesting to see if activity on Oomycete and cereal pathogens could be combined in one molecule. Attempts were made to replace the alkoxy group by imidazole, but the compounds were too unstable to isolate. The 1,2,4-triazoles were more stable, but unfortunately suffered the usual fate of hybrid toxophores, being poorly active on all fungi. However, as an extension of this work some pyrazoles were made. These turned out to have the highest herbicidal and fungicidal activity of all of the series (see Table II). However, following the outstanding activity of the pyrazoles, further 5membered heterocycles were tried. Activity was well down for other nitrogen rings such as 1,2,3-triazole (symmetrical isomer) or tetrazole (2-isomer). Interestingly however, good activity was maintained, although at a slightly lower level, when furan or thiophene linked either in the 2- or 3-position were used, with the furans usually being slightly more active than the corresponding thiophenes. Later work by other companies showed that high activity could also be achieved with thiophenes of this type when the benzene ring was replaced by a substituted pyrazole (72). Other Clinked heterocycles such as the 2-pyrrolyl, or 2-thiazolyl analogues were inactive. The activity of all the five-membered ring compounds was very sensitive to substitution. Even a methyl group reduced activity significantly, while the presence of more, or larger groups destroyed it. Replacement of five-membered rings by sixmembered rings such as phenyl or pyridyl led to complete inactivity. A summary is given in Table II. Fungicidal Activity and Phytotoxicity. Although the best compounds had high levels of intrinsic herbicidal activity, their lack of selectivity and relatively poor stability in soil prevented their development as herbicides. However, there was considerable interest in the high systemic fungicidal activity some of these compounds exhibited on the Oomycete pathogens Plasmovara viticola and Phytophthora infestans. despite the evident phytotoxicity. This interest was boosted by an early field test of 12 on Plasmovara viticola, which showed that promising control of disease could be obtained, although the trial was stopped early to prevent damage to the vines. Baker et al.; Synthesis and Chemistry of Agrochemicals III ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

448

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

STRUCTURAL ÇHANQES LEADING TQ LQW ACTIVITY

Ο

Ar^ ArX

Λ ^. NΛ^ ^,

OEt

O

OEt "CN Η

A

C N

r

A

A

N

x

Η

Η X = Ο , NH , S , CO :

C O N H , COOEt, CC1 2

Cl ,


IV

O

%

Ο

OEt Ν Η

A r ^ N ^ C N Η

A r ^ N ^ C N Η

CN

α

R = C N , COOEt

X

x«NHAr,CH OMe, 2

S 0 M e , P(0)(OEt) 2

ÇEt

O

HetAT

Κ Η

Ο O

XN

ϊ

HetAr = subst. furyl, pyridyl

Alkyl

ArN^V

OEt

χ

Ν Η

„OEt C

L

H

CN

Figure 4

Table II: Activity of Side Chain Λ

CI

Ο

v

ΓΥΚ.Χ

Ring

Ν Η

HIGH (

Ring Compounds*

"CN

LOW (>50

ppm)

Ù

>

>

ppm)

X = Ν , CH

Me

-

ό

-

ο

-Ο Ό ' as foliar spray or root drench on Plasmopara viticola

on vines


2

3

40.

BARTHOLOMEW ET A L


449


It was clearly critical to the success of these compounds as fungicides for their phytotoxicity to be reduced. It was found that the presence of a single substituent in the 4-position of the benzene ring preserved very good levels of fungicidal activity, and greatly reduced herbicidal effects, depending on the identity of X (see Table I). However, this was only the case with small, relatively non-polar and linear substituents such as halogen, short alkyl, ethynyl, methoxyimino and methoxymethyl groups. Polar (eg. nitro or hydroxy), or bulky (eg. phenyl, phenoxy) groups reduced activity markedly, while the presence of a sustituent in the 3-position brought back herbicidal activity. Interestingly the 4-formyl and 4-hydroxymethyl analogues were the only compounds to show reasonable activity on the soil-borne pathogen Pvthium ultimwn. A summary is provided in Table III. ICIA0001 The pyrazoles, although highly active, were generally too phytotoxic to use, while the furans were not active enough to be cost effective. However, the combination of the ethoxy side chain and 4-substitution in the ring gave a small group of compounds which had both high fungicidal activity and good crop safety. Of these, 4-chloro-N[cyano(ethoxy)methyl] benzamide 13, was chosen as a development candidate with the code number ICIA0001, and subsequently given the common name zarilamide (Figure 5). Despite the possible lability of the hydrogen adjacent to the cyano and ethoxy groups, separation of the R- and S- enantiomers of ICIA0001 was achieved by chiral chromatography, on a preparative scale. It was found that virtually all the biological activity resided in a single enantiomer, but it was not known which. Biological Activity. Details of the biological activity of ICIA0001 have been published previously (4), and so a brief summary only is provided here. Excellent activity was obtained in field trials on a range of Oomycete fungi, particularly Plasmovara viticola on both berries and foliage. The compound was usually mixed with a protectant standard such as folpet to enhance persistence of control and to reduce the risk of resistance developing. Good control was also achieved on Phytovhthora infestans on potatoes and tomatoes, Pseudoveronosvora humuli on hops, Pseudoveronosvora cubensis on cucurbits, and Phytovhthora yalmivora on cocoa. Under a wide range of conditions a good margin between fungicidal activity and phytotoxicity was found. ICIA0001 also had excellent environmental properties. Residues on grapes were exceptionally low and degradation in soils was rapid and total. The compound had little soil mobility. Physical Properties and Plant Movement. Systemic movement is a very desirable property for compounds active on the Oomycete fungi, as it enables control of disease in new growth. Some of these compounds showed good plant mobility, but only where the log Ρ was below about 2.8. This is shown in Table III, where, for example, changing from mono- to dichlorosubstitution in the benzene ring tips the balance from activity by root drench application, to activity by foliar spray only. Baker et al.; Synthesis and Chemistry of Agrochemicals III ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

450


Table III: Activity and Phytotoxicity of Leading Compounds *

Η X


R

PLASVI ** Foliar

3,5-di-Cl

1-Pyrazolyl

3,5-di-Cl 4-CI

Root Drench

PHYTIN ** P H Y T O . * * *

LOGP

Foliar

25

1

10

3.28

OEt

5

>25

2.5

25

2.90

1-Pyrazolyl

3

1

30

2.51

100

2.6

4-CI

2-Furyl

10

10

>25

>500

2.8

4-Ethynyl

OEt

10

5

10

100

2.4

e

* lowest rate (ppm) giving 100% control *** Lowest rate (ppm) where symptoms noted * ^Plasmopara e

viticola on vines, Phytophthora iitfestans on potatoes

estimated value

13

Figure 5


40.

BARTHOLOMEW ET A L


451


Pro-pesticides. Thioamide was the only functional group apart from nitrile that gave rise to good activity. The equivalence of nitriles and their corresponding thioamides has frequently been observed in biological chemistry, and is thought to be due to chemical or metabolic conversion of the thioamide to the nitrile. Some supporting evidence for this was provided in this series by the fact that significant amounts of nitrile 14 were produced when a dilute aqueous solution of thioamide 15 was heated at pH 7. It was hoped that differential metabolism of 15 between the fungus and the plant might maintain fungicidal activity and lower phytotoxicity. This would allow the use of the more active but more phytotoxic pyrazoles, as their thioamides. However, this was not the case, and both control of disease and plant damage were equally reduced. Another approach to reducing phytotoxicity was to use lipophilic protecting groups, which might be selectively cleaved in the fungus to liberate the active fungicide. Accordingly some N-benzenesulphenyl compounds 16 were made (Figure 6), but again crop safety was only achieved at the expense of fungicidal activity. Involvement of Reactive Intermediates. Since this project had arisen from ideas about reactive imines, it was of interest to see whether evidence could be found to support their existence, or their possible role in the activity of these fungicides. Information came from two sources. Firstly, analysis of the structure activity relationships showed that only compounds which were capable of producing potentially reactive imines had significant activity, (figure 7). Those which could not eliminate a leaving group to give a reactive imine, for example the N-methyl analogues 20, were inactive. The fact that 17, where X=furan, can only eliminate cyanide, suggests that only imine 19, could play a part, at least in the case of the furans. However, the inactivity of the sulphide 23, which had the potential to generate 19, showed that imine formation might not be involved in the activity. A possible alternative explanation was that cyanide, released in the elimination process, might be the ultimate toxic agent. However, evidence from biochemical experiments suggested that cyanosis was not involved in the mode of action. Secondly, results from studies on the hydrolytic breakdown of 17 suggested that imines 18 and 19 could be formed chemically. Over a range of pH, 17 (X=ethoxy, furan or pyrazole) was shown to break down to the simple benzamide 22 with the formamide 21 as an intermediate. Formamide 21 could arise from addition of water to either 18 or 19, followed by elimination of X or CN. Compounds 17 where X=OEt were found to be the least stable, particularly at high pH where the amide anion would be expected to be formed. The presence of electron-withdrawing groups in the benzene ring of 17 accelerated breakdown, supporting formation of the amide anion as the ratedetermining step. Compounds 17 where X=pyrazole were of intermediate stability, but underwent acid catalysed breakdown at low pH, when protonation of the pyrazole could occur. Compounds 17 with X=furan were the most stable, at all pH values, showing that chemical loss of cyanide was slow. From the information available it was not possible to come to a conclusion about the role of imine intermediates. The stability studies may be relevant to the persistence of the compounds rather than their mode of action. Baker et al.; Synthesis and Chemistry of Agrochemicals III ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

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

Ο

OEt

O H S / toluene 2

CN

pyridine

Η

o-sv

R chemical or metabolic

14

15

chemical or metabolic

ArSCl / Et N 3


OEt

. O ^ N ^I C N SAr 16

Ar = subst. phenyl

Figure 6

Figure 7


40. B A R T H O L O M E W E T AL.


453


Synthetic Routes The original route using photochlorination of the benzoylaminoacetonitrile 24 was not found to be generally useful, and alternative approaches were sought. Initially, attempts at direct bromintion of 24, and reaction with nucleophiles to give 28 gave only intractable mixtures. However, it was found that in acetic acid, bromination of 24 gave the isolable bromoamides 26, formed by in situ hydration, possibly of an oxazole intermediate 25. Displacement of the bromine with nucleophiles gave amides 27, which were dehydrated to give good yields of the nitriles 28, (5). This proved a versatile, if slightly lengthy route by which many analogues were made, (Figure 8). Later it was shown that direct bromination of 24 to give bromonitrile 29 could be achieved (6), but only under highly specific conditions, whereby the bromine was added very rapidly. Due to its high reactivity it was necessary to treat 29 with ethanol in situ, to obtain 31. Although not high yielding, this direct route enabled rapid synthesis of further analogues. On a large scale, where rapid bromination was a problem, development work showed that on treatment of 29 with pyridine in situ, the reasonably stable pyridinium salt 30 could be isolated (7), which could then be treated with ethanol in a separate step to give 31, (figure 9). Synthesis of the furans and thiophenes 33, was straightforward from the corresponding amino nitriles, which were readily available using the Strecker reaction on the aldehydes. An alternative route was developed to the 2-linked furans and thiophenes (5), whereby acetoxy ester 34 was treated with a Lewis acid and furan or thiophene to give the ester 35, in an amido-alkylation reaction. 35 was then converted to nitrile 37 after conversion to the amide 36, (Figure 10). During the synthesis of analogues, a wide variety of substituted benzenes were required. Most of these were obtained straightforwardly. Of note, however, was the synthesis of the acetylenic analogues 39, which were made in good yieldfromthe iodo compounds 38, by palladium-catalysed coupling with the corresponding acetylenes (8). It was necessary to carry out the reaction in triethylamine as solvent, to avoid reaction with the more usually used diethylamine, (figure 11). Mode of Action ICIA0001 showed no effects in a range of standard biochemical tests such as respiration, or DNA and RNA synthesis assays. Later studies (9, 10) showed that ICIA0001 affects microtubules in tobacco cells, and in zoospores of Phytovhthora cavsicL with consequent inhibition of mitosis. Propyzamide showed similar effects in tobacco cells, which is consistent with the similarity in herbicide symptomologies between the two compounds. Resistance Properties It is currently essential to the development of any new Oomycete fungicide that it should be able to control disease that is resistant to the phenyl amide fungicides (for example metalaxyl). It is also desirable to estimate the potential for the development of resistance in any new molecule. Detailed studies (77) carried out with ICI0001 on Phytovhthora spp. showed Baker et al.; Synthesis and Chemistry of Agrochemicals III ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

454

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

Ο

A

Ar

Br

Br

2

-Br

Ν Η

S

CN

Η 26

25

O ϊί

XH/Base^ M

X

O ï

H

CONH

'N'

AcOH

24


Ο

H 0

2

TFAA C

0

N

H

2

Pyridine

27

X Ï

ÏÏ

A r ^ N ^ C N 28

X = OR ( R = alkyl, alkenyl, alkynyl), SR , 1-pyrazolyl, etc.

Figure 8


2

40.

j?

Et N,CH Cl 3

^

+

Cl

H

2

N ^ C N 3

2

NaOH, H 0 2

V

9

2

^


Q

2

0

Reflux, EtO Ac

0

H

( 2 ) Dissolve in S O C l

NH2

X

BF .Et 0 3

Ar"

2

C

O

O

E

t

34

X (1) N H

Τ Ν

c

g

J

o il

A

I

^

2

(3) NaOAc , AcOH

Furan or Thiophene

N

33 "

(l)OCHCOOEt

II

C

^ H

X = OorS

^

455


BARTHOLOMEW ET A L

COOEt

(

2

)

RT

ο II

3

TFAA

Ar^

Ν

R

pyridine 35 X = Ο or S

36

R = CONH

37

R = CN

2

Figure 10

,

,

Ο

X

Pd(PPh ) ,

'-Ο^Λ™ ~

3

Ο

4

»—ΟΛΑ»

Et N 3

3

8

X

R = Me , η-Bu , Ph , Me Si

3

3

^ = — Η

X = O E t , 1-pyrazolyl

Figure 11


9

456


that there was no cross resistance to the phenyl amides. Attempts to generate resistant mutants by either adaptation or mutagenesis failed. Consequently it was believed that the likelihood of resistance developing was relatively small.


Conclusion Speculative chemistry around a novel heterocyclic intermediate led to the discovery of a new class of fungicidal structure with high activity on Oomycete pathogens. From this work ICIA0001 was chosen for commercial develoment, due to its excellent control of Plasmopara viticola and other Oomycetes in the field, and its very safe environmental profile. Unfortunately, the commercialisation of ICIA0001 was halted when unexpected toxicity occurred very late in two year feeding trials. No effects had been seen in any of the early in vitro and in vivo tests. Notwithstanding this result, the discovery of this new type of benzamide fungicide provides an interesting example of the successful application of a speculative chemical approach to the invention of agrochemicals. Acknowledgments The authors are indebted to the following colleagues for their work on this project: Dr. S. P. Heaney and Dr. M. C. Shepherd for biological screening; Dr. B. C. Baldwin for biochemical studies; T. E. M. Fraser for physical chemistry studies; R. Cheetham, S. E. Evans, S. E. Glue, L. G. Reynolds, I. T. Streeting, E. G. Williams and J. Williams for experimental assistance; Dr. A. T. Costello and Dr. J. D. Jones for process chemistry; and P. K. Carpenter for chiral chromatography. Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Bartholomew, D.; Kay, I. T. J. Chem. Research. 1977, 237. Bartholomew, D.; Kay, I. T. J. Chem. Research. 1977, 239. McNulty, P. J.; Swithenbank, C.; Viste, K. L . J. Agr. Food Chem. 1971, 417-421. Crowley, P. J.; Heaney, S. P.; Shearing, S. J.; Shephard, M . C. Proc. Br. Crop Prot. Conf. Pest Dis. 1988, 551-558. Bartholomew, D.; Kay, I. K.; Noon, R. Α.; Williams, E . G . European Patent 59536, 1982. Jones, J. D.; Schofield, D. European Patent 135304, 1984. Costello, A. T.; Jones, J. D. European Patent 260801, 1987. Crowley, P. J.; Heaney, S. P.; Reynolds, L . G.; British Patent 2183639, 1987. Young, D.H. Pestic. Biochem. and Physiol. 1991, 149-161. Droughot, V.; Gredt, M . ; Leroux, P. Pestic. Sci. 1990, 348. Eacott, C.J.P. Ph.D. Thesis, University of London 1986. Hanaue, M . ; Mita, T.; Nishikubo, M . ; Ochciai, Y.; Suzuki, H.; Takeyama, T.; Yamagishi, Κ. European Patent 268892, 1988.

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1992


A Novel Class of Benzamide Fungicides - ACS Symposium Series

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