pyrimidine-2-sulfonanilide Herbicides - ACS Publications - American

Chapter 2

1,2,4-Triazolo[1,5-a]pyrimidine-2-sulfonanilide Herbicides

Downloaded by UNIV OF MISSOURI COLUMBIA on March 25, 2013 | http://pubs.acs.org Publication Date: September 22, 1992 | doi: 10.1021/bk-1992-0504.ch002

Influence of Alkyl, Haloalkyl, and Halogen Heterocyclic Substitution on In Vitro and In Vivo Biological Activity 1

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William A. Kleschick , Mark J. Costales , B. Clifford Gerwick , J. B. Holtwick , R. W. Meikle , W. T. Monte , N. R. Pearson , S. W. Snider , M . V. Subramanian , J . C. VanHeertum , and A. P. Vinogradoff 2

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Discovery Research, DowElanco Research Laboratories, P.O. Box 708, Greenfield, IN 46140 Discovery Research, DowElanco Research Laboratories, P.O. Box 9002, Walnut Creek, CA 94598

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An outline of the synthetic routes used to prepare a series of alkyl, halo and haloalkyl substituted 1,2,4-triazolo[1,5a]-pyrimidine-2sulfonanilides is presented. The in vitro activity against acetolactate synthase and the herbicidal activity of these analogs is discussed. The evaluation of these activities led to the selection of DE-498 as a candidate for development as a broadleaf herbicide for soybeans, corn and other crops.

The discoveries of the sulfonylurea and the imidazolinone classes of herbicides represent important advances in technology for weed control (7,2). The attributes of the high levels of herbicidal activity, application flexibility, excellent margins of crop tolerance and low levels of toxicity to mammals exhibited by these compounds are important characteristics for modem agrochemicals. The performance characteristics of these materials are linked in part to the mechanism of action of the disruption of the biosynthesis of amino acids in plants (5). The site of action, the enzyme acetolactate synthase (ALS, EC 4.1.3.18) in the pathway to the branched chain amino acids, displays a sensitivity to a number of structural classes of compounds (4). The l,2,4-triazolo[l,5-a]pyrimidine-2-sulfonanilides (1, Figure 1) are a new class of highly active herbicides (5,6). These compounds also act by disrupting the biosynthesis of branched chain amino acids in plants through the inhibition of ALS (7). One member of this class, DE-498 (2), has been advanced to the final stages of development This report details the structure activity studies on the triazolopyrirnidineringin 1 leading to the selection of DE-498 as a development candidate. Results and Discussion Synthetic Routes. An outline of the general synthetic route to triazolopyrirnidine sulfonamides applicable to the synthesis of many compounds is illustrated in Figure 2 (8). 3-Amino-5-mercapto-l,2,4-triazole (3) or the corresponding benzylthioether (4) (9) is condensed with a 1,3-dicarbonyl compound or operational equivalent of a 1,3-dicarbonyl compound to afford triazolopyrimidines 5 or 6 respectively. Oxidative chlorination of 5 or 6 in aqueous acid media produces the sulfonyl 0097-6156/92/0504-0010$06.00/0 © 1992 American Chemical Society In Synthesis and Chemistry of Agrochemicals III; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

2. KLESCHICK ET AL. Pyrimidinesulfonanilides: Alkyl & Haloalkyl Substitution


chloride (7) which is reacted with the appropriate aniline in the presence of an acid scavenger (e.g. pyridine) to give 1.

Figure 1. l,2,4-Triazolo[l,5-a]pyrimidine-2-sulfonanilides 1 and 2. X N-NH R ' S - ^

N

XCOCH(Y)COZ"

^ - N H

2

R

solvent reflux

\

S

3: R' = H 4: R' = Bn

5—(

I

"

A. z

n + H

3°

5: R' = H 6: R' = Bn

•

I

N ^ N ^ Z

7

°\

M

pyridine

R ^V^NH0 S—( 5

I

2

^6

N ^

I N

< ^

;

1

Figure 2. General synthetic route to l,2,4-triazolo[l,5-a]pyrimidine -2sulfonanilides. The method outlined in Figure 2 can be employed to prepare a wide variety of compounds derived from symmetrically substituted 1,3-dicarbonyl compounds. However, the outcome of the first step in the reaction sequence may not be straightforward in reactions with unsymmetrically substituted 1,3-dicarbonyl compounds. Figure 3 illustrates our results in condensation reactions of 4 with a variety of unsymmetrically substituted 1,3-diketones (10). In all of these instances some measure of regiochemical control was observed in the reactions. Compounds 8 and 12 were isolated in good yield through one recrystallization of the crude product. Compounds 10 and 11 were isolated by chromatography. The structures of 8 and 10 were established by single crystal X-ray analysis. The structures of 12 and 13 were established by a synthesis of 13 by an unambiguous route as illustrated in Figure 4 (10). Reaction of 4 with ethyl cyclopentanone-2-carboxylate gave triazolopyrirnidine 14 which was converted to the chloro substituted compound 15

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

In Synthesis and Chemistry of Agrochemicals III; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1992. 2

I

8(84%)

BnS—f

3

97 : 3

+

BnS—f

Figure 3. Reaction of 4 with unsymmetrical 1,3-diketones.

AcOH, reflux

3

CF COCH COMe

CF

9

I


Me

2. KLESCHICK ET AL. Pyrimidinesulfonanilides: Alkyl & Haloalkyl Substitution with POCI3. Reaction of 15 with methyl magnesium bromide gave 13 in good overall yield. 0 OH

^COOEt N-NH

//

\

\—/


BnS

f~V

AcOH,

reflux

N

T " \

^ reflux

^ N ' ^ ^ '

14 CI

Me

ui

me

BnS ^N N ^ N ^ - ^

Et 0 -THF

U ^ ^ y 13

2

"

U

15

3

9

%

Figure 4. Unambiguous synthesis of 13, The reaction of 4 with ketoaldehyde derivatives is more complex (77). Reaction of 4 with acetylacetaldehyde dimethyl acetal under conventional reaction conditions leads to 2:1 mixture of 16 and 17 (Figure 5). If 4 is added slowly to the reaction mixture regiochemical control is achieved and 17 is isolated in good yield. The regioselection of the reaction can be reversed by conducting the reaction under basic conditions. In this instance 16 is produced as the sole product of the reaction in good yield (Figure 6). The structure of 16 was confirmed by single crystal X-ray Me

MeCOCH CH(OMe) 2

^

BnS—i

I

+

BnS-
2000 >2000 >2000

CF H H Me -CH C H C H H Me Me CI H CF H H H H 3

2

2

3

2

3

Iso (HM) 0.060 0.11 1.8 0.48 0.23 6.6 0.19 0.41 0.044 0.24 1.0 8.6 0.27 0.25

Table II. Crop tolerance to foliar and soil applications of DE-498 in greenhouse bioassays

Crop

Foliar Application GR10 Value (g/ha)

Soil Application GR10 Value (g/ha)

Corn Wheat Barley Soybeans Rice Sunflower Cotton Sugarbeet Rape

>70 >70 >70 20 15 12 7 3 3

50 >70 >70 >70 22 11 4 5 4


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SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS III


spectrum activity of DE-498 in combination with selectivity to a variety of major agronomic crops offers a multitude of opportunities for selective weed control. The basis of selectivity of DE-498 to com and soybeans is metabolic detoxification (75). In soybean the detoxification is initiated by a process which results in disruption of the pyrirnidine portion of the triazolopyrirnidine ring. In corn the process involves an initial hydroxylation of the methyl group at the 5-position on the triazolopyrirnidine ring. DE-498 possesses a favorable toxicological profile. The acute toxicity of DE498 is very low. No dermal sensitization and only slight eye irritation has been observed. No mutagenic or teratogenic effects have been found with DE-498. Conclusion DE-498 combines broad spectrum herbicidal activity with selectivity to multiple major crops. In addition it possesses low toxicity to mammals, safety to key rotational crops and favorable environmental behavior (14). The combination of these attributes render DE-498 a useful, new tool for selective weed control in a variety of major crops. Literature Cited 1.

2. 3. 4. 5.

6.

7. 8.

9. 10. 11. 12. 13. 14.

Sauers, R. F.; Levitt, G., In Pesticide Synthesis through Rational Approaches, Magee, P. S.; Kohn, G . K.; Menn, J. J., Eds.; A C S Symposium Series 255, American Chemical Society: Washington, D.C., 1984, p. 21-28. Los, M . , In Pesticide Science and Biotechnology, Greenhalgh, R.; Roberts, T. R., Eds.; Blackwell Scientific Publications: Oxford, 1987, p. 35-42. LaRossa, R. A . ; Falco, S. C. Trends in Biotechnology 1984, 2, 158-161. Schloss, J. V.; Ciskanik, L. M . ; VanDyk, D. E . Nature 1988, 331, 360-362. Kleschick, W. A . ; Gerwick, B. C., In Prospects for Amino Acid Biosynthesis Inhibitors in Crop Protection and Pharmaceutical Chemistry, Copping, L . G.; Dodge, A . D.; Dalziel, J., Eds.; British Crop Protection Council Monograph No. 42, Lavenham Press Limited: Lavenham, Suffolk, 1989, p. 139-146. Kleschick, W. A.; Costales, M . J.; Dunbar, J. E.; Meikle, R. W.; Monte, W. T.; Pearson, N. R.; Snider, S. W.; Vinogradoff, S. W. Pestic. Sci. 1990, 29, 341-355. Gerwick, B. C.; Subramanian, M . V.; Loney-Gallant, V . I.; Chandler, D. P. Pestic. Sci. 1990, 29, 357-364. For the first example of the use of this route to prepare 5,7-dimethyl-1,2,4triazolo[1,5-a]pyrimidine-2-sulfonanilide, see: Broadbent, W; Miller, G. W.; Rose, L . British Patent 951,652, 1964. O'Brien, D. E.; Novinson, T.; Springer, R. H . U.S. Patent 4,036,840, 1977. Kleschick, W. A . ; Bordner, J. J. Heterocycl. Chem. 1989, 26, 1489-1493. Monte, W. T.; Kleschick, W. A . ; Meikle, R. W.; Snider, S. W.; Bordner, J. J. Heterocycl. Chem. 1989, 26, 1393-1396. Monte, W. T.; Kleschick, W. A.; Bordner, J. unpublished results. Swisher, B. A.; Gerwick, B. C.; Cheng, M . ; Miner, V . W.; deBoer, G . J. Abstr. Meet. Weed Sci. Soc. Am. 1991, 31, 50. For a detailed discussion of the soil behavior of DE-498, see: Fontaine, D. D.; Lehmann, R. G.; Miller, J. R. J. Environ. Qual. 1991, 20, 759-762.

RECEIVED June 30, 1992


pyrimidine-2-sulfonanilide Herbicides - ACS Publications - American

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