Synthesis and Chemistry of Agrochemicals VI - American Chemical

Chapter 10

Synthesis and Structure-Activity of Novel 3-(4,6substituted benzoheterocyclyl)uracil Herbicides Downloaded by PENNSYLVANIA STATE UNIV on June 16, 2012 | http://pubs.acs.org Publication Date: July 29, 2001 | doi: 10.1021/bk-2002-0800.ch010

George Theodoridis, James T . Bahr, Scott Crawford, Benjamin Dugan, Frederick W . Hotzman, Lester L. Maravetz, Saroj Sehgel, and Dominic P. Suarez Agriculture Products Group, F M C Corporation, P.O. Box 8, Princeton,NJ08543

3-(4,6-Substituted benzoheterocycl-7-yl)-1-substituted-6-trifluoromethyl uracils 1 represent a novel class of highly active pre- and postemergent herbicides, which act by inhibition of the plant enzyme protoporphyrinogen oxidase (Protox). The synthesis, biological activity, and structure-activityof these new herbicides will be discussed.

1 Research directed towards the discovery of molecules that inhibit the plant enzyme protoporphyrinogen oxidase (Protox) has resulted in a wide variety of 96

© 2002 American Chemical Society In Synthesis and Chemistry of Agrochemicals VI; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2001.

97

Downloaded by PENNSYLVANIA STATE UNIV on June 16, 2012 | http://pubs.acs.org Publication Date: July 29, 2001 | doi: 10.1021/bk-2002-0800.ch010

highly potent pre- and postemergent herbicides (1). A striking feature of Protox herbicides is the large number of different families of chemistries, each with its unique set of structure-activity rules, that can act by this mode of action (2,3,4). Here, we wish to report on a new chemistry class of Protox herbicides, 3(4,6-substituted benzoheterocyclyl)uracils, structure 2, where positions 5 and 6 of the aromatic ring are tied together to form a new ring, Figure 1. The resulting benzoheteroaryl compounds are highly potent pre- and postemergent herbicides.

2 Figure 1. Fused Benzoheterocyclic Ring Systems.

In general, the chemical structure of Protox herbicides consists of a substituted aromatic ring attached to a heterocyclic ring (J). A wide range of substituted heterocycles, attached to aromatic rings having specific substitution patterns, are known to provide good biological activity. Unlike previous Protox herbicide chemistries, the nature of the heterocyclic ring A , shown in Figure 1, plays a crucial role in the biological activity of compounds with structure 2. We will be discussing the structure-activity requirements for this new class of herbicides.

Biological Testing

The compounds described were tested pre- and postemergence on various weeds and crops in the greenhouse. The seeds of the plant test species were planted in furrows in steam-sterilized sandy loam soil contained in disposable fiber flats. A topping soil of equal portions of sand and sandy loam soil was placed uniformly on top of each flat to a depth of approximately 0.5 cm. The flats were placed in a greenhouse and watered for 8-10 days, then the foliage of the emerged test plants was sprayed with a solution of the test compound in acetone-water containing up to 5 ml liter sorbitan monolaurate emulsifier/solubilizer. The concentration of the test compound in solution was varied to give a range of application rates. Phytotoxicity data were taken as percentage control, determined by a method similar to the 0-100 rating system

In Synthesis and Chemistry of Agrochemicals VI; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2001.

98 described previously (5), with 0% control of crops or weeds showing no effect relative to controls, and 100% control indicating complete crop or weed destruction. Biological data in Tables 1-4 are presented as the preemergence and postemergence application rates required to give 85% control as compared with untreated plants.


Synthesis of benzoheterocyclyluracil Herbicides

Uracil Ring Synthesis

The uracil portion of the molecule was prepared in good yields from the corresponding aryl isocynate 3, obtained from the reaction of the aryl amine 2 and phosgene, or a phosgene substitute, and ethyl trifluoromethylaminocrotonate in the presence of a base. Addition of an alkyl halide gave the corresponding N-alkyl product 4, Figure 2.

Figure 2. General Synthesis of the Uracil Ring.

Fused Ring Synthesis

A complete review of the synthesis of each of the many hetererocycles prepared for this project is beyond the scope of this work. We will only highlight the synthesis of several of the most significant benzoheterocycles.


99 7-Amino-2,3-Dihydrobenzofuran Derivatives

The various 7-amino-2,3-dihydrobenzofuran intermediates were prepared in several steps from 5-chloro-2-nitrophenol. Claisen rearrangement of 4-chloro2-(2-methyl-2-propen-l-yloxy)nitrobenzene 5, followed by ring formation in the presence of catalytic amounts of M g C l gave 4-chloro-7-nitro-2,3dihydrobenzofuran 6. Oxidation of the 4-methylene group of compound 6 with potassium persulfate in the presence of copper sulfate in acetonitrile/water, gave compound 7. Reduction of the nitro group with iron/acetic acid gave the desired 7-amino-4-chloro-2,3-dihydrobenzofuran 8 (6), Figure 3.


2

K S 0g CH CN / H 0 CuS0 . 5H 0 80°C 2

2

3

2

4

2

Figure 3. Synthesis of7-amino-4-choro-2,3-dihydrobenzofuran.

7-Amino Benzodioxolane Derivatives The desired 7-amino benzodioxolane compounds were prepared from the reaction of 5-fluoro-2,2-dimethyl-l,3-benzodioxole, obtained from the reaction of l-fluoro-3,4-dihydroxybenzene 10 and acetone in the presence of P 0 , and η-butyl lithium followed by addition of carbon dioxide to give the corresponding carboxylic acid derivative 12. Curtius rearrangement of 2


5

100 compound 12 with diphenylphosphoryl azide resulted in 7-amino-6-fluoro-2,2dimethyl-l,3-benzodioxole 13. Chlorination of compound 13 with N chlorosuccinimide in D M F gave the corresponding 7-amino-4-chloro-6-fluoro2,2-dimethyl-l,3-benzodioxole 14 (7), Figure 4.

:

^

n

M

f

CH C1 2

2

ν

Λ ^ Κ

ο

η

CH2CI2


10

11 1) n-BuLi THF / -75°C 2) C 0 2

l)(Ph ) PON Toluene 0°C-reflux 3

2

^

3

rT^>r l| I

F ^ S ^

2) t-BuOH 14

\

"

/

0

I

1

2

Figure 4. Synthesis of 7-Amino-4-chloro-6-fluoro-l,3-benzodioxolane.

Amino Benzoisoxazole Derivatives

Treatment of 2-chloro-3-nitrobenzoic acid with thionyl chloride in toluene gave the corresponding acid chloride 15. Reaction of 2-chloro-3-nitrobenzoyl chloride with N-substituted hydroxy lamine gave compound 16, which was cyclized to 7-nitrobenzoisoxazole 17 with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetonitrile. Reduction of 17 with iron in acetic acid at 50°C, followed by chlorination with N-chlorosuccinimide gave the desired 7-amino-4-chloroisoxazol-3-one 19 (8), Figure 5.

Structure-Activity Relationships Effect of Heterocyclic Ring on Biological Activity Unlike other Protox chemistries, in the benzoheterocyclic chemistry discussed in this chapter, only certain heterocyclic rings resulted in highly active molecules. As shown below, replacement of the triazolinone ring in compound 20 with a uracil ring, compound 21, resulted in a dramatic increase in biological activity,



101

Figure 5. Synthesis ofl-Amino-4-chloro-benzoisoxazole.

Figure 6. The triazolinone ring has previously resulted in highly active molecules, including several commercial herbicides (9).

CHK

Preemergence Biological Activity ED Morningglory 395 Johnson grass 300

85

g/ha 22 10

Figure 6. Comparison of Triazolinone and Uracil Rings.


102 Effect of the Fused Benzoheterocyclic Ring System on Biological Activity


Though a large number of fused benzoheterocyclic rings were investigated, we will be presenting the results of only six different heterocycles. A l l these compounds have a uracil ring attached to the benzoheterocyclic ring. As shown in Table 1, although both five and six membered fused rings were biologically active, compounds having a five membered ring, such as 2,3 dihydrofuran-4one 22, isoxazol-4-one 23, and dioxolane 24, provided the highest biological activity. In general broadleaf weed control was greater than grass control when compounds 22-27 were applied preemergence.

Table 1. Effect of Fused Benzoheterocyclic rings on Preemergence Biological Activity Compound

Preemergence Biological Activity ED g/ha 85

Momingglory

Velvetleaf

22

23

24

25

26

27

20

58

14

100

19

643

84


103 Effect of the Substituents in Position 4 of the Fused Benzoheterocyclic Ring on Biological Activity


Several chemical groups were introduced at position 4 of the 2,3dihydrobenzofuran ring. In general, electron withdrawing lipophilic groups such as compounds 22 (R= CI) and 28 (R= Br), provided the best activity (Table 2). Electron donating groups such as methoxy, compound 32, and dimethylamine, compound 33, resulted in less active molecules.

Table 2. Effect of Substituents at Position 4 of the Benzofuran ring on Preemergence Biological Activity

Ο Preemergence Biological Activity

£ A § 5 grams/ha

Compound

R

Velvetleaf

Momingglory

22 28 29 30 31 32 33

CI Br Η CH F OCH N(CH )

2 6 10 26 24 74 233

6 16 46 26 57 91 >1000

3

3

3

2


104


Effect of Substituents at Position 6 of the Fused Benzoheterocyclic Ring on Biological Activity

Substituents at position 6 of the fused benzoheterocyclic ring had a dramatic effect on the weed spectrum and crop selectivity of these molecules when applied preemergence. This is clearly exemplified by the three 2,3dihydrobenzofuran examples shown in Figure 7. Introduction of a fluorine at position six of the aromatic ring resulted in compound 34 which has excellent corn selectivity and control of broadleaf weeds at 10-30 grams/hectare. Next, replacing the 6-fluoro group with a chlorine group resulted in a molecule, compound 35, which has good grass control at 10-30 grams/hectare. Finally, compound 22, with a hydrogen substituent at the 6-position resulted in broad spectrum control of both broadleaf and grass weeds at 10 grams/hectare. Preemergence application of compounds 22 and 35 resulted in corn injury at application rates that provided weed control. The weeds discussed in Figure 7 are velvetleaf, wildmustard and pigweed for the broadleaf weeds, and barnyardgrass, green foxtail, and Johnson grass for the grass weeds.

22

Broad Spectrum Weed Control Pre- Broadleaf and Grass Control at 10 g/ha Figure 7. Effect of Substituents at Position 6 of the 2,3~Dihydrobenzofuran ring on Biological Activity.

It is important to point out that structure-activity relationships for position 6 of the benzoheterocycle are highly dependant on the nature of the heterocycle attached to the aromatic ring as shown below. Replacement of the carbonyl in


105 compound 34 with oxygen, to give compound 36, resulted in loss of corn selectivity but increased weed spectrum and biological activity, Table 3.


Table 3. Effect of Benzohetero Ring on Preemergence Biological Activity

34 Greenhouse Preemergence Biological Activity (% control) Applied Rate (g / ha) Corn Pigweed Wild Mustard Velvetleaf Green foxtail Johnson grass

30

10

30

10

5 100 100 100 95 30

0 100 100 100 25 5

90 100 100 100 100 100

80 100 100 100 100 100

Effect of Substituents at Position 1 of the Uracil Ring on Biological Activity

A variety of substituents at position 1 of the uracil ring were investigated with a number of different benzoheterocyclic rings. The structure-activity relationship developed for the 3-benzodioxolane-1 -substituted uracil ring shown in Table 4 applied to the other rings investigated. In general, it was found that small R groups resulted in the most active compounds. It is interesting to notice that both a lipophilic (R= C H , compound 36) and a hydrophilic group (R= N H , compound 37) had comparable biological activity, Table 4. 3

2

Finally, opening of the benzoheterocyclic ring resulted in significant loss of biological activity as shown in Figure 9. Compound 42, were the two adjacent oxygens of the dioxolane ring are no longer tied together, is more than 10 times less active than its closed ring analog 36, Figure 8.


106


Table 4. Effect of Substituents at Position 1 of the Uracil Ring on Biological Activity

F

Ο

Preemergence Biological Activity EDg§ grams/ha Compound

R

36 37 38 39 40 41

CH NH CH CH CH OCH CH C H 3

2

2

3

2

2

6

3

5

CH2CH2CH3

Velvetleaf

Momingglory

Green foxtail

3 3 8 18 958 >1000

3 3 17 52 >1000 >10000

3 3 3 44 307 >1000

Pre-emergence Biological Activity ED g/ha S5

Velvetleaf Green foxtail

3 4

32 143

Figure 8. Comparison of Biological Activity of Ring Close vs. Ring Open Heterocycles.


107


Summary The 3-(4,6-Substituted benzoheterocyclyl)uracils 1 described in this chapter are highly active pre- and postemergence herbicides, with a broad spectrum of weed control. This highly versatile class of chemistry offers the potential for a variety of uses, such as preemergence control of broadleaf weeds and corn tolerance, compound 34, or broad spectrum weed control at very low rates, compound 36. The mechanism of action involves the inhibition of the plant enzyme protoporphyrinogen oxidase, which results in the buildup of high levels of protoporphyrin IX, a photodynamic toxicant.

References

1.

2. 3. 4.

5. 6. 7. 8. 9.

Duke, S.O. and Rebeiz, C.A. Porphyric Pesticides, Chemistry, Toxicology, and Pharmaceutical Applications, American Chemical Society Symposium Series 559, Washington, D.C. 1994. Theodoridis, G.; Hotzman, F.W.; Scherer, L . W . ; Smith, B . A . ; Tymonko, J.M.; Wyle, M. J. Pestic. Sci., 1990, 30, pp 259-274. Theodoridis, G . J. Pestic. Sci., 1997, 50, pp 283-290. Theodoridis,G.; Baum, J.S.; Chang, J.H.; Crawford, S.D.; Hotzman, F.W.; Lyga, J.W.; Maravetz, L . L . ; Suarez, D.P.; Valenti, H . H . ; Synthesis and Chemistry of Agrochemicals V , edited by Baker, D.R.; Fenyes, J.G.; Basarak, G.S.; Hunt, D . A . ; A C S Symposium Series No.686; American Chemical Society; Washington, D.C. 1998, pp 55-66. Frans, R.E.; Talbert, R.E.; Research Methods in Weed Science, 2 edn, ed. Truelove, B.; Auburn, AL, 1997, pp 15-23. Theodoridis, G . U.S. Patent 5,521,147 (1996). Theodoridis, G . U.S. Patent 5,346,881 (1994). Theodoridis, G . U.S. Patent 6,080,702 (2000). Theodoridis, G.; Baum, J.S.; Hotzman, F.W.; Manfredi, M . C . ; Maravetz, L . L . ; Lyga, J.W.; Tymonko, J . M ; Wilson. K.R.; Poss, K.M.; Wyle, M . J . In Synthesis and Chemistry of Agrochemicals III, edited by Baker, D.R.; Fenyes, J.G.; Steffens, J.J.; A C S Symposium Series No. 504; American Chemical Society; Washington, D.C. 1992, pp 134-146. nd


Synthesis and Chemistry of Agrochemicals VI - American Chemical

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