Synthesis and Chemistry of Agrochemicals IV - American Chemical

Chapter 14

5-Aryloxybenzisoxazole Esters Synthesis and Herbicidal Activity 1

1

1,2

1

Peter Wepplo , Jeffrey H. Birk , Jerome M. Lavanish , Mark Manfredi , and Donald R. Nielsen 2

1

Agrieultural Research Division, American Cyanamid Company, P.O. Box 400, Princeton, NJ 08543-0400 Barberton Technical Center, PPG Industries, P.O. Box 31, Barberton, OH 44203

Downloaded by CORNELL UNIV on June 19, 2012 | http://pubs.acs.org Publication Date: May 5, 1995 | doi: 10.1021/bk-1995-0584.ch014

2

A series of benzisoxazole glycolate and acetate ester diphenyl ethers were prepared. The preparation of intermediate 5-hydroxybenzisox -azoleacetic acid from 4,6-dihydroxycoumarin was improved by reaction in the presence of excess hydroxylamine hydrochloride. The resultant diphenyl ether herbicides were potent total vegetation control pre- and postemergence herbicides. The benzisoxazole diphenyl ethers are part of a third generation series of membrane disrupter herbicides. They share a common mode of action and bear a structural similarity to nitrofen and acifluorfen, the first and second generation herbicides of this class. Each succeeding generation has an increasing amount of structural complexity. The bicyclic series of diphenyl ether herbicides was discovered by chemists at PPG Industries. They were looking for ways to improve the activity of diphenyl ether herbicides such as acifluorfen. Acifluorfen and its esters were gaining prominence at the same time as herbicides such as diclofop methyl, Figure 1. As these classes of herbicides shared a diphenyl ether backbone, the chemists at PPG Industries reasoned that the propionate group present in diclofop methyl might be appended to acifluorfen to improve its activity. The resultant combination afforded the commercial product lactofen. With this change, they began to investigate other methods of incorporating a propionate unit with the diphenyl ether nucleus. Another herbicide candidate meeting those requirements was PPG 1013. It was synthesized by alkylation of its oxime precursor with an oc-bromopropionate. It was during oxime alkylation that some of the oxime anion cyclized with displacement of the nitro group to form the methyl benzisoxazole 1. The herbicidal activity of this simple derivative started a new search for novel bicyclic diphenyl ethers. PPG Industries has successfully identified several related herbicidal bicyclic diphenyl ethers including benzotriazoles (2), benzoxazolones (2), benzisoxazoles (3), benzisoxazole ethers (3), indolinones (5), and tetralones and indanones (6). The acquisition of a package of herbicide lead areas from PPG Industries by American Cyanamid Company allowed Cyanamid to continue to explore this area of chemistry. Thus, using acifluorfen (as well as other diphenyl ether herbicides) as a model for protoporphyrinogen oxidase inhibitors, there are several patterns which one can observe that result in good herbicidal activity, Figure 2. Our objective was to 0097-6156/95/0584-0149$12.00/0 © 1995 American Chemical Society

In Synthesis and Chemistry of Agrochemicals IV; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

150

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS TV

CT Lactofen (PPG Industries)

Acifluorfen (Rohm & Haas) (US Pat 1975)

ci

CI


COOEt

^

I

JL O

CI

COOMe

COOMe

PPG 1013 (PPG Industies)

Diclofop Methyl (Hoechst) (US Pat 1976)

CF

j

3

(PPG Industries)

Figure 1. Discovery of Bicyclic Diphenyl Ether Herbicides

O" Na

B ring •The substitution pattern of acifluorfen is either optimal or very nearly optimal, i.e. groups in those positions result in higher activity than any other groups or arrangements •Fluoro containing diphenyl ether is more active than des fluoro

+

A ring •Maintain regiochemistry •Nitro or halogen para to ether linkage •Three substituents maximum •Carboxy one of several groups that can be placed in the meta position •Addition/replacement of a propionate substituent preferred in a meta position, but not a set distance from the remaining structure

Figure 2. Conventional Wisdom for Diphenyl Ether Substituents


14. WEPPLOETAL.

5-Aryloxybenzisoxazole Esters

151

prepare new bicyclic diphenyl ether herbicides that could maintain these patterns, and determine if incorporation of an acetate or propionate unit into these analogs would further improve the activity. The route we chose to follow was to further elaborate simple bicyclic diphenyl ether herbicides by incorporating an acetate or propionate unit. This chapter will discuss the synthesis of benzisoxazole glycolate ether and acetate ester diphenyl ethers as well as their herbicidal activity. Several of the compounds reported herein have also been reported in patents (4, 7).


Synthetic Methods Preparation of Ethers of 5-Aryloxy-3-hydroxybenzisoxazole. A 3-hydroxybenz isoxazole 5 can incorporate a propionate group in a manner very similar to that found in lactofen. It was prepared by coupling of 2,5-dihydroxybenzoic acid with aryl halide 2, Figure 3. The reaction afforded a high yield with no evidence of formation of the regioisomer. The resultant acid 3 was esterified, converted to the hydroxamic acid 4, and cyclized to the desired hydroxybenzisoxazole 5 as shown. The key mechanistic step was the reaction of the intermediate hydroxamic acid cyclic carbonate A (8). This cyclization has also been demonstrated by Kinstle and Darlage (9), who isolated a hydroxamic acid cyclic carbonate intermediate and treated it with triethylamine in a separate step to form a benzisoxazole. Small amounts of the benzoxazolone 6 were also formed from a competing Curtius reaction.

Figure 3. Preparation of 3-Hydroxybenzisoxazole Diphenyl Ethers. Alkylation of 3-hydroxybenzisoxazole 5 with an cc-bromopropionate occurs on the oxygen and nitrogen atoms, with the 0-alkylation product 7 predominating. The iV-alkylation product B reacts further resulting in cleavage of the benzisoxazole ring and recyclization to give the product 8 shown (10). This N-alkylation product has very weak herbicidal properties. (See Figure 4.)


152


K2C0 (1.5 eq) DMF 18 hrs/RT 3

RX or

Br—>s_^\

15

R=CH CH=CH 2

2. Reflux/toluene

2

CI

^Ss,/

0

21

Figure 14. Preparation of Butenylbenzisoxazole via Decarboxylation.


156


Lithium aluminum hydride reduction of the ester group of 11 gave the hydroxy ethyl benzisoxazole 22 in low yield, Figure 15. The low yield may reflect the instability of the benzisoxazole ring to lithium aluminum hydride although no ring cleaved products were isolated.

Figure 15. Lithium Aluminum Hydride Reduction of Benzisoxazole Ester


Herbicidal Activity Mechanism of Action. The mechanism of action of the diphenyl ether herbicides is thought to be inhibition of protoporphyrinogen IX oxidase (14, 15), Figure 16. An unusual aspect of this mechanism is that the inhibition results in a buildup of protoporphyrin IX, the product of the oxidase enzyme. This occurs because the protoporphyrinogen diffuses from the chloroplast, where it is produced and consumed under normal conditions, and becomes oxidized to protoporphyrin IX in the cytosol. The membrane disruption that results is a consequence of protoporphyrin IX catalyzing production of singlet oxygen in the presence of light. Thus, the plant produces the toxicant itself. An additional interesting factor in the biosynthesis is that porphyrin biosynthesis is regulated by heme. Heme, in turn, is co-produced with chlorophyll. Blockage of protoporphyrin IX biosynthesis blocks the biosynthesis of chlorophyll and heme and results in a deficiency in heme levels. The porphyrin biosynthesis is no longer feedback regulated by heme and porphyrins are overproduced, thus furthering the phytotoxic effects. COOH

Glutamate semialdehyde reductase

COOH

COOH

H N—( 2

COO - phosphate

CHO

Glutamate 1-phosphate

Glutamate semialdehyde

ff

-NH

2

Aminolevulinic Acid (ALA)

Protoporphyrinogen oxidase "Protox"

Heme feedback regulation

k

x HEME ^

k

Held in * X steady state

Chlorophyll

COOH

Protoporphyrinogen IX

COOH

Protoporphyrin EX (phototoxic)

Figure 16. Mechanism of Protophorphyrinogen Oxidase Inhibition.


14. WEPPLOETAL.


157


Structure-Activity Relationships. The structure-activity data was gathered from greenhouse application of the title compounds to a variety of weed and crop species in pre- and post-emergence tests. In general, the benzisoxazole diphenyl ether herbicides were more effective against broadleaf ed species, but data on grasses has been included to give a broader scale upon which to gauge the potency of a compound. The broadleafed species reported in the tables were velvetleaf (Abutilon theophrasti), ragweed (Ambrosia artemisiifolia), and morning glory (Ipomoea spp.), while the grasses were crabgrass (Digitaria sanguinalis) and green foxtail (Setaria viridis). The crop species soybean (Glycine max), corn (Zea mays), and winter wheat (Triticum aestivum) were tested, but because no crop selectivity was found, that data is not included in the tables. The lack of success in finding crop selectivity from changes in the basic structure may be due to the rapid onset of toxicity in a post-emergence herbicide test. It is thought that the onset of symptoms occurs much faster than the combined factors required to detoxify a compound. Although the result of protoporphyrinogen oxidase inhibition is light induced membrane disruption, the herbicidal activity of this class was not limited to post-emergence applications. Table I shows comparative pre- and postemergence activity for two benzisoxazole diphenyl ether herbicides. Although the R-groups are quite different, a significant level of activity is noted for each compound in each application. The superior post-emergence potency is most evident for the ester. Table I. Pre- Versus Postemergence Herbicide Activity of Benzisoxazole Diphenyl Ether Candidates

Control Rates in grams/hectare Application timing

R

Pre Post Pre Post

COOMe

Velvetleaf

COOMe CH CH=CH

2

CH CH=CH

2

2

2

250 1 250 125

Ragweed 125 1 >500 250

Morning glory 250 250 250 4000

»4000

»4000

CHC=CH 2

2

2

3

3

(The '' marks indicate lowest and highest rates tested, respectively. A '»' indicates these was very little or no activity at the highest tested rate.)


14. WEPPLOETAL.


159

In contrast, the herbicidal activity of the C-linked series was less sensitive to the changes in the ester functionality. This may indicate improved binding of the benzisoxazole or that biological oxidation or hydrolysis is a facile process and thus diminishes the expected differences. It was also noteworthy that the enhancement in activity of the propionate was much less than expected compared to the activity of the acetate, see Table 4. This result was not expected based upon the benzotriazole diphenyl ether precedents, see Condon, et al. (16), reported earlier in this symposium.


Table IV. Benzisoxazole Alkyl Substitution Effect on Post-emergence Herbicidal Activity

Control Rates in grams/hectare R

Velvetleaf

CH COOMe 2

CH(CH )COOMe 3

CHCOOH 2

CH COOiPr 2

CHCOOCH2CH=CH 2

2

CHCOOEt

Ragweed

32 1 3642 32 64

1 32

Synthesis and Chemistry of Agrochemicals IV - American Chemical

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