Successful Exploitation of 2-Cyano Arylethyltriazoles as Agricultural

Chapter 28 Successful Exploitation of 2-Cyano Arylethyltriazoles as Agricultural Fungicides T. T. Fujimoto, S. H. Shaber, H. F. Chan, J. A. Quinn, and G. R. Carlson

Downloaded by UNIV LAVAL on May 9, 2016 | http://pubs.acs.org Publication Date: November 3, 1987 | doi: 10.1021/bk-1987-0355.ch028

Rohm and Haas Company, 727 Norristown Road, Spring House, PA 19477

The utilization of phenylacetonitriles as a starting point for the preparation of 2-substirated-2-cyano-phenethylazoles, led to the discovery of a class of compounds with high antifungal activity. Through systematic structure-activity investigations, the antifungal activity of α-butyl-α-(4-chlorophenyl)-1H-1,2,4triazole-1-propanenitrile was discovered. This compound, whose common name is myclobutanil, has been successfully introduced as an agricultural fungicide by Rohm and Haas Co., under the trademark Systhane. The first strongly active, broad spectrum, ergosterol biosynthesis inhibiting fungicide we prepared was 2-(2,4-dichlorophenyl)-l-(l-imidazolyl) hexane, 1, and we began a synthesis program in this area of chemistry in an attempt to obtain an

agricultural fungicide. A related series, the α-alkoxyalkyl phenethyl imidazoles was patented by Janssen Pharmaceuticals (1)» who, subsequently, also reported its preparation (2). However, for an agricultural chemical, structures which are more synthetically accessible are desirable, and alternative structures were sought Conceptually, it appeared that a small biologically neutral, chemical activating group which allowed either nucleophilic or electrophilic attachment of substituents would be an ideal substituent to have on the benzylic carbon. The cyano moiety seemed to have the best potential and it was found that phenylacetonitrile was 0097-6156/87/0355-0318$06.00/0 © 1987 American Chemical Society

Baker et al.; Synthesis and Chemistry of Agrochemicals ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

28. FUJIMOTO ET AL.

2-Cyano Arylethyltriazoles as Fungicides

319

readily alkylated in a sequential manner to introduce an alkyl fragment, and a methylene bromide fragment, which could subsequently be converted to a methylene imidazole. This series of compounds turned out to be highly active, and RH-2161, 2butyl-2-cyano-phenethylimidazole, 2, was selected to undergo field evaluation. RH-2161 was superceded by the triazole counterpart, RH-5781F, 3, which had better residual activity in the field. However, the efficacious rate of RH-5781F was found to be too high for cost-effective use.


X

2 C (RH-2161) 2 Ν (RH-5781F) Butyl Though the literature (3) claimed that o, p-dichloro subsitution on phenyl is optimum in the phenethylazoles and our own experiences had supported this claim, the QSAR study of the 2-cyano-phenethyltriazoles we conducted indicated otherwise. The QSAR analysis of the arylringsubstitution in conjunction with modifications of the alkyl substituent in the 2-position indicated that the best compound should have only a p-chloro as the aryl substituent; the o-chloro being detrimental to activity. The best 2-alkyl substituent was predicted to be a 4 to 5 carbon alkyl chain. ( T.T. Fujimoto, J.A. Quinn, A.R. Egan, S.H. Shaber and R.R. Ross, to be published). The compound with the alkyl group equal to butyl was made, and had superior activity over the corresponding unsubstituted, and o,pdichloro substituted phenyl, phenethyltriazoles. Further structure-activity studies on the alkyl group as well as investigation of aryl substitution showed this compound to have the best overall level of activity, and in 1986, a-butyl-a-(4chlorophenyl)-lH-1,2,4-triazole- l-propanenitrile was introduced as a commercial product in France under the trademark Systhane.

Systhane (myclobutanil) Chemical Synthesis The synthesis of phenethylimidazole 1 proceeded by alkylation of ethyl 2,4dichlorophenylacetate with η-butyl chloride under basic conditions to give the ethyl ester 4, which was reduced to 5, and activated as the mesylate 6. Treatment with imidazole gave the desired final product as shown in Figure 1. The 2-substituted-2-cyano-arylethyltriazoles were prepared by sequential alkylation of substituted phenylacetonitriles (4) as shown in Figure 2. The alkylation of phenylacetonitriles were performed under a variety of basic


SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS

320

conditions. Alkylation by phase transfer catalysis, (PTC), (5) using NaOH, catalyst and toluene or with NaOH in DMSO, proceeded smoothly at room temperature with alkyl chlorides. For less reactive phenylacetonitriles and for NaOH sensitive alkylating reagents, NaH or KH was utilized. The methylene fragment was appended by using CH C1 or CH Br in NaOH/DMSO or via PTC conditions and gave 9 in high yield. Completion of the synthesis proceeded by displacement of the neopentyl halide with imidazole or potassium triazole at elevated temperatures. In the displacement using imidazole, the reaction proceeded cleanly without preparation of the salt An alternative and more efficient preparation of 10a involves the reaction of the intermediate 8 with chloromethyltriazole hydrochloride or its corresponding free base as shown in Figure 3. Chloromethyltriazole hydrochloride (6) was prepared in a two step sequence from triazole via paraformaldehyde followed by treatment with SOCl . The coupling with chloromethyltriazole and 8 proceeded by using hydride bases in DMF or by using NaOH in DMSO. The alkylation of phenylacetonitriles can result in significant quantities of dialkylated products, especially with reactive alkylating reagents CD. Therefore, for the preparation of α-benzyl substituents, the facile two step procedure shown in Figure 4 was employed, which eliminated the dialkylation problem. Reaction of phenylacetonitriles with benzaldehydes in MeOH with NaOH as the base gives the acrylonitriles, Π , in quantitative yield. Reduction with NaBH^tOH then gives pure monoalkylated α-benzyl intermediates 12, which are subjected to the sequences described in Figures 2 and 3. Two procedures have been utilized for attaching α-alkoxy functionality at the 2-position affording the desired intermediate 14. Both involve the acetals of substituted benzaldehydes as a starting point. As shown in Figure 5, reaction of acetal 13 with trimethylsilyl cyanide and SnCl gave the alkoxy nitrile directly (9), while a two step procedure with pyridine/ acetyl chloride (α-chloro ether formation) followed by NaCN (10) displacement also afforded 14. Again, completion of the synthesis to the desired triazoles proceeded as described in Figures 2 and 3. In the preparation of 2-cyano-2-(fluoroalkyl) phenethyltriazole derivatives the fluorinated alkyl halides, e.g. 4,4,4-trifluorobutyl bromide, were employed, whenever possible, in alkylations with phenylacetonitriles. The desired triazoles were obtained by continuing the synthesis as described above. Other fluorinated and chlorinated side chains were prepared by incorporating the halogens to complete the synthesis. In these cases, alkylation using an alkyl halide containing a protected carbonyl or hydroxyl group was used. This functionality was then unprotected and converted to the appropriate fluorinated material. For terminal halogen substituents, the terminal protecting group differed between the propyl and butyl series. The compounds in the following discussion are shown in Table I. In the propyl series, the diethyl acetal was the protecting group with 3chloropropionaldehyde diethyl acetal serving as the alkylating reagent for 4chlorophenylacetonitrile. After conversion to triazole 15, the acetal was removed with 33% H S04/EtOAc giving the aldehyde 16, which gave 17 after treatment with diethylaminosulfur trifluoride (DAST/CT^CL^). Reduction of the aldehyde to the terminal alcohol 18 proceeded smoothly and was followed by conversion to thefluoro(DAST) and chloropropyl (SOCl /py) analogs 19 and 20, respectively. For the butyl series, 4-chlorophenylacetonitrile was alkylated with 1-chloro4-acetoxybutane using NaH in DMF, followed by homologation and treatment with potassium triazole (re-acetylating when necessary). Removal of the acetoxy group with NaOH/MeOH gave the 4-butanol intermediate 25. The 4-fluorobutyl 2

2

2

2


2

2

2

2


28. FUJIMOTO ET AL.


4. 4 c

R

5

R

> v

/ R

6

1

X-2,4di-CI

a«base; b«LAH,Et 0; c-MsCl.TEA; base«NaH,KH


2

Figure 1. Synthesis of 2-substituted-2-(2,4-dichlorophenyl) ethylimidazole.

7

8 C

1

JL

χ

CN

Y

s

1

-

a-base,RCI; b-base,DMSO,CH Br or CH 2 a 2 ; c-DMSO base-NaOH ;NaH ;KH 2

2

Figure 2. Three step synthesis of 2-substituted-2-cyano-phenethylazoles.

Base/DMF

R

«jQ

a

Base - NaOH, NaH, KH

Figure 3. Two step synthesis of 2-substituted-2-cyano-phenethyltriazole. CN

CN

V

U>C

C

H

11

0

C

V>*

v

N

12

I'NaOH.MeOH; b=NaBH ,THF,EtOH 4

Figure 4. Preparation of a-benzyl-phenylacetonitriles.


321


322

x

^-cHo^ ^y^

x

O R

13

°

j ^ R

x

f \ _ / W

C

1 4

N

°

R

a«ROH,H*; b-TMSCN.SnCI* c«aCOCH ,py; NaCN.DMSO


3

Figure 5. Preparation of a-alkoxy-phenylacetonitriles.

Table I. Halogenated 2-alkyl products and intermediates

»

-ν

τ

Ν" Ν

°0 W

η

η = 2

η - 3

compound 15 16 17 18 19 20 21 22 23

R

compound 24 25 26 27 28 29

C(OEt), CHO CHF, CH OH CH F 2

2

CH a 2

C((OŒ2) )CH COCH CF,CH, 2

CH OAc CH OH CH F 2

2

2

CH a 2

CHO CHF

2

3

3


28. FUJIMOTO ET AL.

2-Cyano Arylethyltriazolcs as Fungicides

323

and 4-chlorobutyl derivatives 26 and 27, respectively, were prepared in the usual manner. The alcohol was oxidized to aldehyde 28 via QO^py, and then fluorinated (DAST/CH2CI2) to give the 4,4-difluorobutyl derivative 29. Internally halogenated, 3-halobutyl derivatives, were prepared by alkylation with the ethylene glycol ketal of l-chloro-3-butanone, which was converted to the triazole adduct 21. Removal of the ketal provided the 3-oxobutyl analog 22 which gave the difluorobutyl product 23 upon treatment with DAST.


Greenhouse Evaluations In general, potted plants are treated with technical compound dissolved in 1:1:2, methanol:acetone:water, by spraying the seedling foliage past run-off. Inoculum is applied within 24 hrs. of spraying and the plants incubated 5 to 8 days before disease pressure is evaluated. Detailed test procedures are given in reference 11. Structure Activity Studies After extensively surveying major modifications of the structure attached to triazole, a systematic structure-activity study was begun on the phenethyltriazole structure. For this study, the molecule was dissected, as shown below, i n t o 4 quadrants: I) the aryl ring, Π) the hydrophobic group, ΙΠ) the cyano group, and IV) the triazole. Theresultsfrominvestigation of quadrants I, the aryl ring, and Π, the

hydrophobic sidechain are presented here. Using unsubstituted phenyl as the base, a series of quadrant Π changes were made. Arepresentativecompound list is given in Table IL From these compounds, the following structure-activity profile based on in-vivo greenhouse testing can be ascertained. There is a large species to species variation on the effect of the substitution on activity, but, in general, the activity peaks at substituents whose chain length is four to five atoms. Non-carbon atoms in the chain, especially oxygen have a negative effect on the activity, and from examining the observed biological activity of η-propyl and butyl vs. i-propyl and i-butyl, and of allyl vs. 2-methallyl, it appears that chain branching has a negative effect on activity. These results are similar to those obtained for miconazole analogues (4) on human fungi, indicating some conservation of the site of action between organisms. Once the optimum sidechain characteristics had been investigated, aryl substitution (quadrant I) of the cyanophenylethyltriazole was examined. Using butyl as the reference substituent, several mono- and di-substituted phenethyltriazoles were prepared (Table IH).£xcept for the activity of 2-methoxy, 2 and 3 substitution, led to a large loss in activity. Halogen substituents in the 4 position were better than hydrogen, with other substituents whose steric bulk is linear along the attachment bond axis also being active. Though the substitutent effect varies somewhat with the organism, the substituent effect at the three aryl positions can be generally described as follows:


324


Table Π. Control of diseases in greenhouse pot tests of compounds with an unsubstituted phenyl ring

Λ N-N J


rate giving 90% disease control(ug/ml) wheat powdery mildew

substituent n-propyl i-propyl n-butyl i-butyl n-pentyl i-pentyl n-hexyl cyclohexyl 1-methylbutyl methoxy ethoxy propoxy butoxy

CHoCH^OCHoCHa ally!

2

3

2-methylallyl 2,3-butenyl phenyl benzyl p-Cl-benzyl

leaf rust

17 50 25 29 13 7 1 9 9 300 60 5 10 120 19 82 10 25 15 5

220 >500 95 400 76 61 220 200 70 >500 >500 400 100 400 >500 >500 120 75 75 5

a) wheat powdery mildew is caused by Erysiphegraminis tritici, wheat leaf Puccinia

barley spot blotch 20 >500 25 25 10 25 7 300 >500 >500 75 10 75 19 60 150 60 200 150 >500 f.sp.

recondite f.sp. tritici and

barley spot blotch by Cochliobolus

sativus.


28.

FUJIMOTO E T AL.


Table ΠΙ. Control of wheat powdery mildew and stem rust in foliar greenhouse tests for phenyl substituted 2-butyl-2-cyano-phenethyltriazoles

X

/

ν

ι

N-N


Butyl rate giving 90% disease control (ug/ml) phenyl (X) Η 2-C1 2-CN 2-F 2-OCH 3-CF,

3

3-Cl 3-OŒ3 4-Br 4-CHj 4-Cl(myclobutanil) 4-CN 4-F

4-OC H 4-C H 2,4-Cl 2-OCH ,4-Cl 2,5-OCH 3,4-Cl 3,4-OŒ 6

6

5

5

3

3

3

3,5-CF

3

powdery mildew

60 90 400 300 500 200 150 450 33 33 2 25 5 500+ 500 15 >500 200

25 60 134 300 3 150 19 25 20 150 2 10 5 25 7 1 4 2 19 300 150

a) powdery mildew is caused by Erysiphe graminisfsp. and stem rust by Puccinia

graminisf.sp.

stem rust

tritici

triticL


325


326

ortho Η » α > CN > F; OCH varies with organism meta H » Cl > OCH > C F para Cl > F > C H > CN > Br > H > C H » O C H 3

3


6

3

5

3

6

5

The direction of activity for disubstituted aryl ring compounds was reasonably predicted by averaging the there is no large interactions between the ring substitutents. With the optimum aryl substituent in hand, the hydrophobic sidechain (quadrant Π) was re-investigated. Table IV lists the results which verified that the para-chlorophenyl, butyl substituted compound was one of the best. Some further verification of the substituent scheme was conducted by preparing other mixed quadrant I, quadrant Π variants. The best compounds were subjected to additional studies, including systemic and curative tests, and within the scope of alkyl and alkenyl sidechains, myclobutanil, was determined to be the best compound, overall.

Table IV. Control of wheat powdery mildew and leaf rust with para-chloro substitution on the phenyl ring

rate giving 90% disease control (ug/ml) R substituent

powdery mildew

n-propyl n-butyl(myclobutanil) 2- methylbutyl n-pentyl i-pentyl n-hexyl 4,5-pentenyl 3- flouropropyl 3-chloropropyl CH CH CHF C^CH^dHs 4- fluorobutyl 4-chlorobutyl CH CH CH CHF CH CH CH CF 4-methoxybutyl CH CH CH CHO CH CH CH(OCH CH ) 2

2

2

2

2

2

2

2

2

2

2

2

2

2

2

3

2

3

2

1 2 50 2 1 7 25 20 4 4 10 15 2 07 0.4 50 300 10

leaf rust 1

6

7 75 4 1

5

1 0 0

20 50 >150 >

1

5

0

125 75 150 150 80 300 300 >150


28. FUJIMOTO ET AL.



Literature Cited 1.

Janssen Pharmaceutics, Ger Offen. DE 1940 388, February 26,1970.

2.

Heeres, J; Backx, L.J.J.; Van Cutsem, J.M. J. Med. Chem. 1976, 19, 1148.

3.

Ellames,G. J. Modem Synthetic Antifungal Agents; Halsted Press: New York, 1982; pp 49-54

4.

Miller, G.A.; Chan Hak Foon. U.S. Patent 4 366 165, December 18, 1982.

5.

Weber, W.P.; Gokel G.W. Phase Transfer Catalysis in Organic Synthesis: Reactivity and Structure in Organic Chemistry 4; Springer Verlag: New York, 1977; Chapter 10.

6.

Ciba Geigy, European Patent 63 099, April 4, 1982.

7.

Makosza, M.; Serafinowa, B. Rocz. Chem. 1965, 39, 1401.

8.

Kulp, S.S.; Caldwell, C.B. J. Org. Chem. 1980, 45 171-173.

9.

Utimoto, K.; Wakabashyi, Y.; Shishiyama, Y.; Inoue, K.; Nozaki, H. Tett. Lett. 1981, 21 4279-4280.

10.

Sterling Drug, U.S. Patent 3 607 942, September 21, 1971.

11.

Quinn, J.Α.; Fujimoto, T.T.; Egan, A.R.; Shaber, S.H. Pestic. Sci. 1986, 17,357-362.

RECEIVED July 2 1 , 1987


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Successful Exploitation of 2-Cyano Arylethyltriazoles as Agricultural

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