Synthesis and Chemistry of Agrochemicals IV - ACS Publications

Chapter 18

Oxazine Ether Herbicides Novel Grass-Selective Compounds Thomas M. Stevenson, Kanu M. Patel, Brett A. Crouse, Milagro P. Folgar, Charles D. Hutchison, and Kara K. Pine

Downloaded by MONASH UNIV on August 26, 2015 | http://pubs.acs.org Publication Date: May 5, 1995 | doi: 10.1021/bk-1995-0584.ch018

DuPont Agricultural Products, Stine-Haskell Research Center, Chemical Discovery, Levitt Laboratories, Newark, DE 19714

Benzylic ethers of oxazine-6-methanols are very effective grass herbicides which show safety to a number of major crops. We have found 2 different synthetic routes to these compounds. The first route is based on the reaction of nitroso-olefins with allylic alcohols. The second route relies on a novel reaction of oxime dianions with chloro-epoxides. We will describe our studies on the discovery and optimization of these syntheses and the biology of the oxazine ethers. Over the past 2 decades chemists from a number of companies have explored benzylic ethers as herbicides. This area began with the discovery that monocyclic oxygen heterocycles substituted with benzylic ethers had good herbicidal activity (1). Optimization of the chemistry at Shell provided the only commercial product in the area, the bicyclic ether Cinmethylin (2). The common key structural feature of active compounds was the 1,4-relationship of the oxygen of the heterocycle and the oxygen of the benzylic ether. More recently, scientists at BASF showed that nitrogen could also be present in the heterocycle with isoxazoline ethers (3).

Cinmethylin Shell

Bayer

BASF 0097-6156/95/0584-0197$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.

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SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS TV

Synthesis


We wanted to explore the synthesis of 6-membered nitrogen heterocycles since work by Bayer and Shell indicated that 6-membered oxygen heterocycles were at least as active as 5-membered ones (4). As shown in figure 1 Gilchrist and others have reported that 1,2-oxazines can be readily prepared by the reaction of nitrosoalkenes with alkenes (5). This reaction works best with electron rich alkenes. The target structures for benzylic ethers of oxazines would require fairly electron rich allylic alcohols as starting materials so we felt confident that this approach would be successful

Figure 1. Nitroso-olefin route to 1,2-oxazines. Monocyclic Oxazine Ethers. We began with the most studied nitrosoalkene system derivedfromthe oxime of 2-chloroacetophenone. Gilchrist has reported that the optimal reaction conditions for producing nitrosoalkenes from halooximes is with sodium carbonate in dichloromethane(5). Use of these heterogeneous conditions ensures a slow generation of the reactive intermediate. When we treated the oxime under those conditions in the presence of methallyl alcohol we were able to isolate the desired alcohol in moderate yield (Figure 2). We were able to readily benzylate the alcohol with a variety of benzylic bromides and chlorides using sodium hydride as base. The compounds showed good herbicidal activity especially on grasses at 100 to 400 g/Ha. and we began to explore this area further.

Figure 2. First synthesis of a substituted 1,2-oxazine benzylic ether. We studied the reaction of a variety of different substituted arylnitrosoalkenes with methallyl alcohol. The commercially available arylketones were brominated with triethyl-benzylammonium bromide perbromide. Treatment of the bromides with hydroxylamine hydrochloride in


18. STEVENSON ET AL.

Oxazine Ether Herbicides

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TriethylAmmonium

Bromide Figure 3. Synthesis of substituted 3-aryl- 1,2-oxazines. methanol led to the oximes. These were then converted as before to the desired oxazine ethers (Figure 3). Based on our knowledge of cyclic ether herbicides we were interested in increasing bulk at the 3-position of the oxazine. Cinmethylin has an isopropyl group in die same relative position of space as our 3-position. Our initial attempt to increase bulk was with a t-butyl group through the oxime of commercially available bromopinacolone. When we treated this bromooxime with an excess of methallyl alcohol under our standard conditions the desired product was produced in greater than 90 % yield (Figure 4). This was again benzylated with a variety of benzylic halides. These compounds proved to be severaltimesmore active as herbicides than the 3-aryloxazines.

Figure 4. Synthesis of 3-t-butyl-1,2-oxazines. After observing the high herbicidal activity of the 3-t-butyloxazines we used this system in our optimization work. Of the allylic alcohols we needed to explore the structure activity trends in the 6-position only allyl and methallyl alcohol were commercially available. Longer chain alcohols were synthesized by hydride reduction of the unsaturated aldehyde. If these aldehydes were not In Synthesis and Chemistry of Agrochemicals IV; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

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available they could be made by Mannich reaction of the parent aldehyde as shown in Figure 5 (6). Similarly reactions of secondary allylic alcohols were also studied.

I

I

CHO

Acetic Anhydride

x

NaBH

4

CHO

R = ethyl, n-propyl, i-propyl, n-butyl Figure 5. Variation of the 6-substituent Ring Constrained Alcohols. Next, we turned to conformationally restricted molecules. The first class was exemplified by using cyclic allylic alcohols. Formally this restrains the alcohol in a ring. The requisite alcohols were made by borohydride reduction of the 5- and 6-membered cyclic enones. These underwent smooth cycloaddition with the t-butyl nitrosoalkene (Figure 6). An alternative conformationally restrained system in which the other 6-substituent forms the ring was also prepared. Methyl cyclohexenecarboxylate was cleanly reduced to the allylic alcohol by lithium aluminum hydride. Cycloaddition with the nitrosoolefin and benzylation completed the sequence(Figure 7). These conformationally restricted compounds showed little herbicidal activity.

Na C0 2

X

OH

3

OH

NaH, PhCH Br 2

Figure 6. 1,2-Oxazines derived from cyclic allylic alcohols.





201

Figure 7. An alternative conformationally restrained 1,2-oxazine system. Ring Constrained Benzylic Ethers. Compounds in which the benzylic halide is constrained in a ring were also investigated. In our initial attempts we treated our oxazine alcohol with sodium hydride and indanyl chloride. No benzylation occurred and indene was produced. In order to circumvent this elimination reaction we decided to use a preformed benzylic allylic ether as the dienophile. This could be preparedfromindan-l-ol by reaction with commercially available methallyl chloride. The ether gave the desired herbicidally active product from reaction with the t-butyl nitrosoolelin (Figure 8). This technique was used to prepare a variety of different constrained benzylic groups including compounds from both antipodes of optically active indan-l-ol.

Figure 8. Synthesis of 1,2-oxazines with ring constrained benzylic ethers. Bi- and Tricyclic Oxazine Ethers. We also explored the use of cyclic nitrosoolefms as shown in Figure 9. A constrained 3-aryl system was derived


202


from 2-bromotetralone oxime and methallyl alcohol. The product was produced as a separable mixture of diastereomers. A cyclic version of the 3-t-butyloxazines was produced in modest yieldfromthe bromo oxime of commercially available 2,2-dimethyleyclopentanone. The benzyl ethers of both classes of compounds showed good herbicidal activity at 200 g/ha.


BenzylTriethylAmmonium Bromide Perbromide

Na CQ 2

3

1:1 mix of diastereomers

X?OH

Na C0 2

3

X^N^OH

*OH

2,6-diFBenzyl Br NaH

Figure 9. 1,2-Oxazines derivedfromcyclic nitroso-olefins. The cycloaddition route was very successful in the cases where there is no opportunity for isomerization of the nitrosoolefin from the reactive s-cis conformation. The optimal yields are produced from compounds lacking a hydrogen alpha to the oxime. However, no cycloadduct is isolated from the reaction of 2-chlorocyclohexanone oxime with methallyl alcohol. The nitrosoolefin is apparently produced as evidenced by a transient blue color, but probably adopts the s-trans conformation (Figure 10). It appears that nitrosoolefins which can isomerize to the s-trans conformation will not react with methallyl alcohol.





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Figure 10. Possible isomerization of cyclic nitroso-olefins. Dianion Route to Oxazines. In order to synthesize compounds which had alpha hydrogens at the 3-position of the oxazine we needed another route. In 1990 Jordanian workers reported that they could make isoxazolines through oxime dianions probably via an epoxide intermediate (7). Treatment of die acetophenone oxime dianion with phenacyl bromide gave 3,5diphenylisoxazoline-5-methanol in good yield. Figure 11 shows our modification of this sequence with chloroacetone and cyclohexanone oxime to give the cyclic product in 70 % yield.

70-80% Figure 11. Synthesis of bicyclic isoxazolines via a dianion approach. For this approach to be a viable one to oxazines we needed to make an epoxide intermediate which would be one carbon further removedfromthe oxime. We found that Maybridge sold 1-cWoromethyl-l-methyloxirane which appeared to be a good precursor to a homologated epoxide intermediate. We treated cyclopentanone oxime with 2 equivalents of n-butyl lithium and quenched with the oxirane. On acidic or basic workup we isolated the desired oxazine in moderate yield (Figure 12). This route was used with a variety of cyclic ketones and also for 3-methyl, 3-ethyl, and 3-isopropyl oxazines.



204


F

Separable Diastereomer Mix Figure 12. Synthesis of 1,2-oxazines via a dianion approach. Biology The oxazine ethers, represented by the structure in Figure 13, show high herbicidal activity on a wide variety of grasses and significant safety to cereals, rice, soybeans, and corn in preemergence tests (8). The activity in postemergence testing is substantially lower. However, the activity under paddy type conditions on barnyardgrass is generally higher than the postemergence activity would predict. Results of the preemergence herbicidal screening of some representative compounds are shown in Table I.

Figure 13. Generic structure of herbicidal 1,2-oxazines. Table I: Preemergence Control of Grass Weeds at 50 g/Ha (Rl = Me, R2 = R3=F) R= t-Bu i-Pr Ph 1-(1-Mec-Pr)

BKG 90 30 20 0 (90)

BYG 100 90 90 0 (100)

CBG 90 70 60 0 (100)

Wheat 0 0 0 0 (0)

Rice 0 20 0 0 (10)

BKG = blackgrass, B YG = barnyardgrass, CBG = crabgrass. Numbers in parentheses were obtained at 200 g/Ha.


18. STEVENSON ETAL.


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Structure-Activity Trends. Structure-activity trends for the 3-position emphasize the importance of bulk. However, very large groups such as adamantyl decreased herbicidal activity. R a t-Bu > i-Pr > Ph > l-(l-Me-Cyclopropyl) > Dimethylbenzyl > 4-F-Ph > Me > C F 3 > C O C H 3 > Adamantyl Substitution at the 6 position was straightforward. Any additional substitution on the ether carbon decreased activity. For the second substituent ethyl was optimal.


Rl =Et>Me>n-Pr>i-Pr>H>n-Bu The benzyl substituents were optimally either 2- or 2,6-substituted. The optimal substitution pattern for activity was 2, 6-difluoro. Substituents alpha to the phenyl ring decreased activity unless they were constrained in a ring. R2, R3 = 2,6-di-F > 2-F > 2-Cl,6-F > 2-H > 2,6-di-Cl > 2-C1 > 2-Me In conclusion, oxazine ethers are active and selective herbicides. They are readily synthesized in high yield via a hetero Diels-Alder reaction or via the reaction of oxime dianions with functionalized epoxides. The ease of synthesis, simplicity of structure, and high activity against important weeds combine to make oxazine ethers an interesting new class of herbicides. Acknowledgments We would like to thank all of the biologists who evaluated the compounds discussed above especially, Dave Fitzgerald who collated all of the biological data for these compounds. We would also like to thank Onorato Campopiano, Paul Iiang, Jim Powell, and Jim Hay for technical advice and suggestions. Literature Cited 1. 2. 3. 4. 5. 6. 7.

U. S. Patent, 3,919,251 (to Shell) U. S. Patent, 4,670,041 (to Shell) U. S. Patent, 4,954,633 (to BASF) European Patent Application, 206,005 (to Bayer) Gilchrist, T. L., Chem. Soc. Rev. 1983,12,53. DeSolms, S. J.,J.Org. Chem. 1976, 41, 2650. Jarrar, A. A.; Hussein, A. Q.; Madi, A. S. J. Heterocyclic Chem. 1990, 27, 275. 8. World Patent Publication, WO 92/09587 (to DuPont)

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Synthesis and Chemistry of Agrochemicals IV - ACS Publications

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