aminocarbonyl - American Chemical Society

Chapter 19

Downloaded by UNIV OF MICHIGAN ANN ARBOR on February 18, 2015 | http://pubs.acs.org Publication Date: September 22, 1992 | doi: 10.1021/bk-1992-0504.ch019

Synthesis and Gametocidal Activity of 1-Aryl-5-(aminocarbonyl)-1H-pyrazole4-carboxylic Acids 1

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Michael P. Lynch , Stephen A. Ackmann , Dale R. Heim , George E. Davis , Michael A. Staszak , James R. Beck , Edward E. Tschabold , and Fred L. Wright 1

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Discovery Research, DowElanco Research Laboratories, 2001 West Main Street, Greenfield, IN 46140 Lilly Research Laboratories, Eli Lilly and Company, Lilly Industrial Center, Indianapolis, IN 46285 2

A series of1-aryl-5-(aminocarbonyl)-1H-pyrazole-4-carboxylicacids were serendipitously discovered to be chemical hybridizing agents. Different synthetic routes were developed for the active analogs depending on whether an electron withdrawing group or electron donating group was present on the phenyl ring. Development of the "second generation gametocides" produced analogs which were 5-6 times more active than the original lead.

Hybridization of plants has long been known to be a desirable means of increasing the physical and productive qualities of crops. Seed hybrids are available on a commercial scale for only a few crops: corn, sorghum and some vegetables. For many years breeders have utilized a number of techniques to create a mass hybridization system for a variety of crops (7). The key to hybridization is achieving male sterility. Over the years a number of techniques have been utilized to achieve male sterility. The first method developed was the mechanical or manual method of sterilization. This method simply involved the removal of the plants' anthers. Depending on the species this method can be extremely difficult. Since in most crops the anthers and pistils are in close proximity of each other, manual removal can be extremely time consuming and cosdy. More recendy, breeders have used such techniques as cytoplasmic male sterilization and a newer technique called nuclear male sterilization. Of course, a number of companies have been involved in the synthesis and development of chemical hybridizing agents (2-9). In the early 1980's the Plant Science Discovery Group initiated a screen for chemical hybridizing agents. The target crop was spring wheat since it could be grown to flowering and seed set under greenhouse conditions. The pyrazole carboxamide chemical hybridizing agents 4a were discovered during an investigation of pyrazole derivatives which had herbicidal properties (Figure 1). Treatment of the common intermediate cyano ester 1 with methylamine led to 2 , which exhibited preemergent control of Alopecurus in European cereals (10,11). This research eventually led to the synthesis of 3 which was evaluated as a pre- and postemergent herbicide in cereals and corn (10,12). Saponification of the common intermediate la with potassium hydroxide resulted in the discovery of the gametocides (13). 0097-6156/92A)504-0200$06.00A) © 1992 American Chemical Society In Synthesis and Chemistry of Agrochemicals III; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1992.


19.

LYNCH ETAL. l-Aryl-5-(aminocarbonyl)-l\i-pyrazole-4-carboxylic Acids

Figure 1. Synthesis of pyrazole herbicides and gametocides from intermediate 1. Method of Preparation The discovery of the gametocides was a result of the synthesis of a series of l-aryl-5chloro-lH-pyrazole-4-carboxamides (Figure 2). The synthesis was initiated by reacting phenylhydrazine with ethyl (ethoxymethylene)cyanoacetate to produce the pyrazole amino ester 5. Treatment of 5 with excess nitrosyl chloride in chloroform at room temperature gave the chloro ester 6. Nitrosyl chloride is no longer commercially available, but can be synthesized in the laboratory (14). The chloro ester 6 was saponified with potassium hydroxide to produce the carboxylic acid 7 in quantitative yield. Finally, treatment of 7 with carbonyldiimidazole (CDI) and aqueous methylamine in DMF produced the pyrazole carboxamide 8, which was found to exhibit preemergent herbicidal activity at 4 lb/acre against crabgrass, pigweed, foxtail and velvetleaf.

80%

99%

80%

Figure 2. Synthesis of 5-chloro-1 -aryl-N-methyl- lH-pyrazole-4-carboxamides.

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

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SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS III


This research led to the development of novel pyrazole chemistry which provided a new series of herbicidally active compounds. As depicted in Figure 3 a number of herbicidal 1 -aryl-5-chloro-lH-pyrazole-4-carbonitriles 10 were prepared (75). A cyano group was introduced in the 5-position of the pyrazole ring via a nucleophilic displacement reaction, using sodium cyanide in DMF, but the resultant bis cyano pyrazoles 11 lacked herbicidal activity at 8 lbs/acre.

Figure 3. Synthesis of l-aryl-lH-pyrazole-4,5-dicarbonitriles. When 6 was treated with two equivalents of sodium cyanide in DMF and heated to 100°C for two hours the 5-cyano pyrazole ester la was produced. Saponification of la produced the cyano acid 12. Finally, treatment of 12 with CDI and aqueous methylamine produced the pyrazole cyano carboxamide 2 (Figure 4). It was also discovered that a direct aminolysis of la using aqueous methylamine in methanol could produce 2 in 90% yield. Compound 2 was active at 0.5 lb/acre in the greenhouse, and this derivative was pursued as a preemergent cereal herbicide (10,16). The key step in the reaction sequence in Figure 4 was the saponification of la to the cyano acid 12. Reaction conditions had to be monitored carefully because there was the possibility that the nitrile could be hydrolyzed. The cyano ester la was taken up in ethanol, potassium hydroxide was added and the solution was heated on the steam bath for five minutes. The solution was then cooled, poured over ice water and acidified with concentrated hydrochloric acid to produce 12a. However, when a solution of lb and potassium hydroxide in ethanol was heated for an hour on the steam bath the nitrile was indeed hydrolyzed. Figure 5 shows the products that were formed in these two reactions. The first analog synthesized in the serendipitous discovery of the pyrazole amide acids was the 3-chlorophenyl analog 4b. The initial greenhouse testing indicated that this analog inhibited anther formation. A structure activity relationship (SAR) was initiated and three parameters were investigated. The first parameter studied was the phenylringmonosubstitution (Figure 6). The 3-CI and 3-Me derivatives were found to be the most active, with the 3-Me being slighdy more active. Substitution in the ortho position resulted in inactivity, and substitution in the para position resulted in reduced activity.



19. LYNCH ETAL. 1-Aryl-5-(aminocarbonyl)-lH-pyrazole-4-carboxylic Acids

2

12

Figure 4. Synthesis of 5-cyancHl-aryl-N-memyl-lH-pyrazole-4-carboxarnides. CI

4b Figure 5. Treatment of the pyrazole cyano ester with potassium hydroxide under various refluxing conditions.


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4c H 3-CI 4-C1 2-C1 2-Br 3-Br 4-Br 3-Cl,4-Me 2,4-diCl

X 2,3-diCl 3-CF3 3-OMe 4-OMe 3-Me 4-Me 3,4-diMe 4-F 2-CF ,4-Cl

3,4-diCl 4-CF3 4-OCF3 3-OCF2CHF2 4-OCHF2 4-OCF2CHF2 3-F 3-Et

3

Figure 6. Phenylringsubstituents in the pyrazole amide acid series.

The next parameter investigated was the substitution at the carboxamide position. A new synthetic scheme was developed in order to achieve substitution at the carboxamide nitrogen (Figure 7). The amide acid 4b was hydrolyzed with 48% hydrobromic acid to give the corresponding bis acid 13. Treatment of the bis acid 13 with methanolic hydrogen chloride gave the bis methyl ester 14. Treatment of this bis ester with hydroxide ion under mild conditions selectively yielded the half acid ester 15 (77). Treatment of the acid ester 15 with CDI followed by the appropriate amine resulted in the production of the amide ester 16. Finally, treatment with sodium hydroxide in methanol produced the amide acid 17 (Figure 8). All analogs except for the primary carboxamide were inactive. The third parameter investigated was alteration at the carboxylate functionality. The esters and salts 18 were prepared using standard reaction conditions (Figure 9) (77). The rationale for preparing die long chain aliphatic esters and Kemamine Salts was to enhance the lipophilicity of these analogs and hopefully have better penetration in the plant Whole plant data (not listed) indicated that all analogs were inactive. Finally, analogs isomeric with 4c which had the acid and amide functionalities reversed were investigated. Reaction of 4c with GDI produced the imide 19 which ring opened to give 20, and all analogs were found to be inactive (Figure 10). Kilogram quantity samples of the 3-CI and 3-Me derivatives were required for field experiments. However, upon scale-up, a major problem developed with the synthesis of the 3-methylphenyl analog of 4c. Treatment of the amino ester 5a with nitrosyl chloride in chloroform resulted in the formation of significant amounts (30-40%) of the desamino ester 21 in addition to the expected chloro ester 6a (Figure 11).


LYNCH ET AL. l-Aryl-5-(aminocarbonyl)-lYl'pyrazole'4'Carboxylic Acids

CI


CI

(63%)

(60%)

Figure 7. Synthesis of the pyrazole N-substituted carboxamide acids.



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NR R 1

2

COOH

Ri H H Me H H H H H H

R2 H Ms Me Et isoPr CycloPr CycloHex AUyl Ph

Figure 8. 3-Chlorophenyl-4-carboxylic acid-lH-pyrazole-5-carboxamides.

COR

OMe OisoPr 0(CH )3 e 0(CH2)7Me OAUyl 0'K M

2

+

OEt OCH2Ph 0(CH2)5Me 0(CH2)9 e ONa+ Kemamine Salts M

Figure 9. Functionalization at the 4-position of the pyrazole ring.



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LYNCH ETAL. 1 •Aryl-5-(aminocarbonyl)-lYl-pyrazole-4-carboxylic Acids

Figure 11. Synthesis of the chloro ester 6a and the desamino ester 21.


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Alternatively, thefieldtrial sample was prepared by the route illustrated in Figure 12. The pyrazole amino ester 5a was converted to the methylthio ester 22 utilizing nonaqueous diazotization conditions. The yield of 22 was increased to 85% by carefully controlling the rate of addition of t-butyl nitrite to a solution of 5a and dimethyl disulfide in chloroform. The yield of desamino product 21 in this case was only 1-2%. Oxidation of 22 with hydrogen peroxide in acetic acid produced the methyl sulfone 23 in 90% yield. Treatment of 23 with sodium cyanide (2.2 equivalents) in DMF at 80°C for 35 minutes yielded the cyano ester lb in 96% yield. Finally, saponification of lc gave the desired product 4c. As a consequence of the synthetic investigations a number of conclusions have been reached: 1) the nitrosyl chloride process was found to be superior with electronwithdrawing groups on the arylring,and the methylthio route was found to be superior with electron-donating groups present, 2) the nitrosyl chloride process gives higher yields in the presence of hydrogen chloride and 3) cyanide displacement of methylsulfonyl is faster than chloro (77). Biological Testing In the field results with 4c (X=3-Me) (Table 1) each multiple treatment resulted in at least 95% male sterility. Seed set compared to untreated controls rangedfrom61% at the lowest treatment of 2.24 Kg ha" to 1% at the highest rate of 33.6 Kg ha- . As rates increased, total seed set decreased. The 3-Me analog of 4c applied in single treatments also produced high levels of sterility, although the efficacy depended on treatment timing. When applied at the second date, 3.36 Kg ha" produced 98% sterility. The 11.2 Kg ha" rate at either of thefirsttwo treatment dates produced plots that were totally sterile. At each treatment date, the main shoots of several plants were harvested and were dissected to determine the size of the flowering spike. The most effective application was when the average main shoot spike was about 5 mm long. High application rate of 4c (X=3-Me) prevented anther development (Figure 13). Lower doses resulted in progressively less inhibition, but still caused an abnormal morphology characterized by smaller, twisted and more intensely pigmented locules (79). No biochemical mechanism has been suggested. Recent structure activity studies on bis phenyl substitution resulted in the synthesis of the "second generation gametocides", namely 4c (X=3,5-diMe and X=3,5-diCl) which were 5-6timesmore active than the original lead compound 4c (X=3-Me) (no data shown). Other multiply substituted analogs prepared during the second phase of synthesis were all found to be inactive (Figure 14) (20). 1

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Summary The l-(3-chlorophenyl) and l-(3-methylphenyl)-5-(aminocarbonyl)-lH-pyrazole-4carboxylic acids 4b and 4c are a new class of chemical hybridizing agents. The large scale synthesis of these analogs was achieved by two different routes depending on whether an electron donating group or electron withdrawing group was present on the phenyl ring. A split foliar application of the active analogs appeared to provide the best percentage of sterility. The "second generation gametocides" provided an enhanced sterilizing capacity and were 5-6timesmore active than the original lead in greenhouse testing.



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LYNCH ETAL. 1-Aryl-5-(aminocarbonyl)-l¥i-pyrazol€-4-carboxylic Acids

Table 1 Male sterilizing activity of 4c (X=3-Me) on Caldwell Wheat t Treatment regime

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1 2 3 4 5

20.0 55.1 13.9 98.4 98.3

Compound Rate Kg ha 3^4 -% Sterility91.0 99.8 70.3 100.0 99.9

-1

11.2 100.0 100.0 94.3 100.0 100.0

tFoliar applications were made on three different dates. Experimental plots for Regimes 1,2 and 3 received single treatments on dates 1,2 and 3, respectively. Regime 4 consisted of duplicate treatments to specified plots on dates 1 and 2, and the plots of Regime 5 received three similar applications, one on each treatment date. Treatment intervals in all cases were 7 days.


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Figure 13. Excisedfloretsfromwheat heads of a control plot (top) andfroma plot treated with 7.73 Kg ha of the 3-methylphenyl analog 4c with split foliar application. Reproduced with permissionfromref. 19. Copyright 1988 Crop Science Society of America, Inc.. -1

4c X 3,5-dlMe 3,5-diCl 2,3,4,5-tetraCl 3,5-diF 2,4,5-triCl

2,5-diCl 3,5-diCF3 3,4,4-triCl 3,4,5-triMe

Figure 14. List of "second generation gametocides."


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LYNCH ETAL.

1 -Aryl-5-(aminocarbonyl)-lE-pyrazole-4-carboxylic Acids 21


Literature Cited 1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) 12)

13) 14) 15) 16) 17) 18) 19) 20)

Agrichemical Age, Oct. 1990, p.20. Searle, R. J. G.; Day, J. A., U.S. Patent 4,249,936, 1981. Searle, R. J. G.; Day, J. A., U.S. Patent 4,288,367, 1981. Devlin, B. J. R., U.S. Patent 4,560,401,1986. Fujimoto, T. T., U.S. Patent 4,661,145, 1987. Carlson, G. R., U.S. Patent 4,714,492, 1988. Labovitz, J. N.; Fang, L., U.S. Patent 4,729,782, 1988. McDaniel, R. G., U.S. Patent 4,925,477, 1990. Carlson, G. R., U.S. Patent 4,964,896, 1990. Beck, J. R., U.S. Patent 4,589,905, 1986.; see also Chem. Abstr., 1985,103. Beck, J. R.; Lynch, M. P.; Wright, F. L., J. Heterocyclic Chem., 1988,25,555. Michael P. Lynch, James R. Beck, Eddie V. P. Tao, James Akins, George Babbitt, John R. Rizzo, and T. William Waldrep, Synthesis and Chemistry of Agrochemicals II; Don R. Baker, Joseph G. Fenyes and William K. Mosberg, ACS Symposium Series No. 443; Washington D.C., 1991, pp. 144-157. Beck, J. R.; Price, C. W., European Pat. Appl.:177242,1986. Ratcliffe, Charles, T.; Shreeve, Jean'ne, M., Inorg. Syn.,1968,11,194. Beck, J. R.; Lynch, M. P., U.S. Patent 4,563,210, 1986.; see also Chem. Abstr., 1986, 105, 42791. Beck, J. R.; Gajewski, R. P.; Lynch, M. P.; Wright, F. L.,J.Heterocyclic Chem.,1987,24,267. R. G. Jones and C. W. Whitehead, J. Org. Chem.,1955,20,1342. James R. Beck, Stephen A. Ackmann, Michael A. Staszak and Fred L. Wright, J. Heterocyclic Chem.,1988,25,955. E. E. Tschabold, D. R. Heim, J. R. Beck, F. L. Wright, D. P. Rainey, N. H. Terando and J. F. Schwer, Crop Science,1988,28(4), 583. Stephen A. Ackmann, James R. Beck and Fred L. Wright, U.S. Patent 4,801,326, 1988.

R E C E I V E D June1,1992


aminocarbonyl - American Chemical Society

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