3-Sulfonylisoxazoline Derivatives as Novel Herbicides - American

Chapter 19

Downloaded by CENTRAL MICHIGAN UNIV on December 8, 2015 | http://pubs.acs.org Publication Date (Web): November 4, 2015 | doi: 10.1021/bk-2015-1204.ch019

3-Sulfonylisoxazoline Derivatives as Novel Herbicides Minoru Ito,1 Masao Nakatani,1,* Makoto Fujinami,2,* and Ryo Hanai2,* 1K-I

Chemical Research Institute Co., Ltd., 408-1 Shioshinden, Iwata, Shizuoka 437-1213, Japan 2Kumiai Chemical Industry Co., Ltd., 4-26 Ikenohata, Taitoh-ku, Tokyo 110-8782, Japan *E-mail: [email protected]; [email protected]; [email protected]

A series of novel 3-sulfonylisoxazoline derivertives show good herbicidal activity against annual weeds. 3-sulfonylisoxazoline derivatives, consisting of isoxazoline and benzene rings, have unique physicochemical properties that enable them to provide stable efficacy under flooded rice culture systems and to prevent the risk of leaching into groundwater. Optimization of these compounds as a new herbicide for use in rice culture has led to the discovery of Fenoxasulfone. In this chapter, the structure–activity relationship, influence of physicochemical properties and biological activities of Fenoxasulfone are reported.

Introduction A series of novel 3-sulfonylisoxazoline derivatives (Figure 1) were found to show good herbicidal activity against annual weeds, especially grasses, when applied pre-emergence (1). Structure modifications of the skeletal structure of 3sulfonylisoxazolines were made at the substituents R1–R4 and the aromatic ring Ar, including heterocyclic groups. As a result, the substituents and aromatic moiety were optimized, and some compounds showed enhanced herbicidal activity with improved crop safety. Ultimately, Pyroxasulfone (Figure 1) was selected as a promising compound for development as a pre-emergence herbicide in corn (2, 3). © 2015 American Chemical Society In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 1. 3-sulfonylisoxazoline derivatives

On the other hand, compounds that had a benzene ring showed unique physicochemical properties (low solubility in water and strong adsorption on soil), enabling them to provide stable efficacy under flooded rice culture systems and to prevent the risk of runoff from a rice paddy field. We therefore focused on substituents on the benzene ring and evaluated the herbicidal performance of the resulting compounds. (Figure 2) In this chapter, we describe the process of optimizing the benzene ring to obtain Fenoxasulfone, as well as the herbicidal activity of this compound.

Figure 2. Compounds that had a benzene ring

Discovery of Fenoxasulfone (4) Effects of Substituents on the Benzene Ring – Mono-Substituted Ring We understood that compounds with a benzene ring had unique physical properties, which would not be suitable for use as a corn herbicide. However, we considered that their low solubility in water and strong adsorption on soil would be suitable for use in paddy field rice cultivation. Therefore, we started to optimize the benzene ring from another point of view. Initially, substituent positions on the benzene ring were replaced with an Methyl group ( Figure 3). Table 1 shows the effects of Methyl substituents on every position. The orthosubstituent derivative expressed stronger herbicidal activity as compared with the others.

262 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 3. Substituent positions on the benzene ring

Table 1. Effect of substituent position (g a.i./ha)a ED20

ED90

R

ORYSA

ECHOR

MOOVA

SCPJO

2-Me

63

32

250

250

3-Me

250

63

1,000

250

4-me

250

63

1,000

250

a

Abbreviations: ORYSA, Oryza sativa (Transplanted rice; cv. Kinmaze, 2-leaf stage); ECHOR, Echinochloa oryzoides; MOOVA, Monochoria vaginalis; SCPJP, Scripus juncoides. Treatment: A drop of diluted solution was applied directly into paddy water. Evaluation: 30 days after application (herbicidal activity and crop injury were visually evaluated on the basis of percentage of the growth relative to that of untreated control). ED20: the dosage of 20% crop inhibition by visual assessment. ED90: the dosage of 90% weed control by visual assessment.

Next, substituent groups other than Methyl were examined and the results showed the same tendency. These findings indicated that introduction of a functional group at the ortho position was necessary to express stronger herbicidal activity. The effect of the substituent group at the ortho position was then examined. The size, electronic properties and stability were evaluated, and the results are shown in Table 2. Ethoxy and chlorine substituents showed good efficacy against weeds and some safety toward rice. However, these mono-substituted derivatives did not exhibit sufficient efficacy for use as a herbicide in paddy field rice cultivation. Under the supposition that ethoxy and chlorine were effective substituents for this structure, we further investigated the effect of substituents on the benzene ring by introducing a second substituent.



Table 2. Effect of different ortho substituents (g a.i./ha)a

a

ED20

ED90

Orth position

ORYSA

ECHOR

MOOVA

SCPJO

OMe

250

63

1,000

250

OEt

250

16

250

63

OCF2H

32

16

125

32

Cl

250

16

500

500

CF3

63

16

250

125

CN

63

63

500

125

COOMe

>1,000

250

>1,000

>1,000

MeSO2

250

250

>1,000

250

See Table 1 for abbreviations and conditions.

Effects of Substituents on the Benzene Ring – Di-Substituted Ring Ethoxy and chlorine seemed to be favorable substituents of this structure for use in rice cultivation. Therefore, di-substituted benzene rings (a combination of ethoxy and chlorine) were investigated next. The results are shown in Table 3.

Table 3. Effect of di-substituent positions (g a.i./10a)a ED20

a

ED90

R

ORYSA

ECHOR

MOOVA

SCPJO

2-OEt-3-Cl

250

32

250

63

2-OEt-4-Cl

250

16

250

250

2-OEt-5-Cl

63

4

63

63

2-OEt-6-Cl

250

16

250

63

4-OEt-2-Cl

500

16

125

63

5-OEt-2-Cl

250

63

500

125


The 2-OEt-5-Cl derivative (Figure 4) showed excellent efficacy against weeds and had some safety toward rice. The 4-OEt-2-Cl derivative also showed good efficacy and better selectivity as compared with the others.



Figure 4. Lead Compound

Unlike when used as a pre-emergence herbicide for corn, 2,5-“di-substituted” derivatives exhibited stronger efficacy as a rice herbicide than the commercial standards. On the basis of these results, the 2-EtO-5-Cl derivative (Figure 4) was selected as a lead compound. Next, to improve crop safety, the effect of functional groups other than Ethoxy and chlorine at the 2- and 5-positions was investigated. As shown in Tables 4 and 5, the introduction of other functional groups only reduced herbicidal activity, and an improvement in selectivity was not observed.

Table 4. Effect of substituent at the 2-position (g a.i./ha)



Table 5. Effect of substituent at the 5-position (g a.i./ha)

We therefore compared the physical properties (logP, Soil Adsorption) of the 2-OEt-5-Cl derivative with those of commercial products to decide how to proceed with this project (Figure 5).

Figure 5. Correlation diagram of Soil adsorption and logP The logP of the lead compound was lower and the soil adsorption was lower than that of commercial products such as Fentrazamide and Cafenstrole. It was assumed that weaker soil adsorption leads to less residual activity. It was clear that an improvement of physicochemical properties was necessary for further 266 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.

development of a rice herbicide. To improve crop safety and physicochemical properties, we therefore aimed to introduce further functional groups onto the benzene ring.

Effects of Substituents on the Benzene Ring – Multi-Substituted Ring


On the basis of the results obtained so far, multi-substituted compounds with EtO and Cl were synthesized and examined. The results are shown in Table 6.

Table 6. Effect of tri-substituents (g a.i./ha)a ED20

a

ED90

R

ORYSA

ECHOR

MOOVA

SCPJO

2-OEt-3,4-Cl2

500

16

500

500

2-OEt-3,5-Cl2

1,000

16

125

125

2-OEt-3,6-Cl2

63

63

63

250

2-OEt-4,5-Cl2

1,000

16

250

250

2-OEt-4,6-Cl2

63

63

125

125

2-OEt-5,6-Cl2

1,000

16

125

125

4-OEt-2,3-Cl2

250

16

63

250

4-OEt-2,5-Cl2

>1,000

16

63

63

4-OEt-2,6-Cl2

16

16

32

63


The compound with the 4-ethoxy-2,5-dichloro benzene ring (Fig. 6), termed Fenoxasulfone, exhibited excellent herbicidal activity and was found to be very safe.

Figure 6. Structure of Fenoxasulfone

The performance of multi-substituted derivatives with other functional groups was not sufficient (data not shown). 267 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


The physicochemical properties of Fenoxasulfone (Figure 7) were also measured and compared with those of commercial products.

Figure 7. Correlation diagram of Soil adsorption and logP

The physicochemical properties of Fenoxasulfone were improved as expected with appropriate values for use in paddy field rice cultivation. For example, Fenoxasulfone exhibited excellent herbicidal activity and sufficient selectivity. In addition, Fenoxasulfone had appropriate physicochemical properties for use in paddy fields. Therefore, Fenoxasulfone was selected as an agrochemical candidate with excellent efficacy and high safety. The physical properties of Fenoxasulfone are summarized below. ◆ ◆ ◆ ◆ ◆

Water solubility LogP Adsorption/desorption in soil Koc Vapor pressure Hydrolysis

0.17 mg/L 3.30 (25°C 436-3295 2.9×10-7Pa (25°C Stable (pH=5,7,9; 25°C 30d)

Synthesis The isoxazoline and Fenoxasulfone were synthesized in the laboratory as illustrated in Figure 8. The isoxazoline moiety was prepared in five steps and the benzyl moiety was prepared in three steps. Next, the isoxazoline and benzyl moieties were reacted and oxidized, giving Fenoxasulfone as a white solid. When the hydroxymethylation of 2,5-dichlorophenol was carried out in this reaction, 2,5-dichloro-4-hydroxymethlphenol alone was obtained selectively. This is a huge advantage of Fenoxasulfone synthesis. In the following section, we present the biological data of Fenoxasulfone. 268 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 8. Synthetic route

Biological Aspects of Fenoxasulfone (5) Greenhouse tests and a field trial were conducted to evaluate the herbicidal efficacy of Fenoxasulfone. The compound exhibited excellent herbicidal efficacy at a lower application rate (200g a.i./ha) as compared with standards and also showed sufficient residual activity.

Effects on Weeds Fenoxasulfone is absorbed mainly by the shoots and roots of germinating weeds. In the case of Echinochloa oryzoides, symptoms of wilting and growth inhibition symptoms begin to appear within a week of application and death occurs in approximately 2 weeks (Figure 9). 269 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 9. Symptoms of Fenoxasulfone

Efficacy Greenhouse experiments were conducted at the Kumiai Chemical Life Science Research Institute in Shizuoka, Japan, to evaluate the herbicidal efficacy of Fenoxasulfone against E. oryzicola and Echinochloa crus-galli. As shown in Figure 10, Fenoxasulfone exhibited excellent herbicidal activity against Echinochloa oryzicola and Echinochloa crus-galli at 100g a.i./ha. The spectrum of Fenoxasulfone activity was also evaluated by greenhouse experiments. The results are shown in Figure 11. Fenoxasulfone provided more than 90% control of weed species at 200g a.i./ha when applied pre-emergence until the 2.5 leaf stage (LS) of Echinochloa spp.

Figure 10. Herbicidal efficacy of Fenoxasulfone



Figure 11. Spectrum of Fenoxasulfone

Residual Activity of Fenoxasulfone The residual activity is one of the key factors required in a herbicide for paddy field rice cultivation. As shown above, the physicochemical properties of Fenoxasulfone were favorable for use in paddy fields. To confirm the residual activity, a greenhouse experience was conducted at the Kumiai Chemical Life Science Research Institute in Shizuoka, Japan. Fenoxasulfone applied at 200ga.i./ha provided excellent residual activity against E. oryzoides and Monochoria vaginalis. The length of activity was superior to both compound A at 300 ga.i/ha and compound B at 300 ga.i./ha (Figure 12). During the normal period of rice cultivation in Japan, there is frequent heavy rainfall. An effective herbicide will be required to exhibit enough activity even under such circumstances. Therefore, under an assumption of heavy rain, the residual activity of Fenoxasulfone in overflow conditions was examined. In general, Overflow conditions did reduce the residual activity somewhat; however, the reduction in residual activity was not as significant for Fenoxasulfone as it was for the standards (Figure 13). This is due to the strong soil adsorption and low water solubility of Fenoxasulfone, which was adsorbed into the soil quickly and was not moved much in a vertical or horizontal direction by the movement of water. Thus, Fenoxasulfone exhibited stable herbicidal activity even in conditions of overflow.



Figure 12. Residual activity of Fenoxasulfone

Figure 13. Residual activity of Fenoxasulfone in overflow conditions


Crop Safety


The phytotoxicity of Fenoxasulfone was compared to that of commercial standards which have been used for rice cultivation. Greenhouse experiments were conducted at the Kumiai Chemical Life Science Research Institute in Shizuoka, Japan. Transplanted rice shows good tolerance to Fenoxasulfone when applied 0~10 days after transplanting and a planting depth of 2 cm or over. Shallow planting depth (less than 2 cm) may cause injury such as rice growth reduction (Figure 14).

Figure 14. Phytotoxicity of Fenoxasulfone

Field Trials Next, a large number of trials were conducted on transplanted rice grown under flood culture in Japan. The application rate of Fenoxasulfone was 200 g a.i./ha. Fenoxasulfone exhibited excellent control of Echinochloa spp., Monochoria spp., and Lindernia spp at the application range and provided better control of Scirpus spp. as compared with commercial standards. It also exhibited a wide range of application timings (Figure 15). Thus, the applicability of Fenoxasulfone for use in paddy fields was proven in the field trials.



Figure 15. Results of field trials

Mode of Action (6) The mechanism of Fenoxasulfone activity was studied by examining the inhibitory effects of this herbicide on the biosynthesis of very-long-chain fatty acids (VLCFAs) (Figure 16).

Figure 16. Biosynthesis of very-long-chain fatty acids (VLCFAs) 274 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Fenoxasulfone treatment decreased the proportion of VLCFAs, such as C20:0, C20:1, C22:0, C24:0, C24:1 and C26:0 fatty acids, in barnyard millet cultured cells, and increased that of long-chain-fatty acids and medium-chain-fatty acids, such as C18:0 and C15:0, which are precursors of VLCFAs. Fenoxasulfone potently inhibited the activity of VLCFA elongase (VLCFAE) in the microsomal fraction of etiolated barnyard millet seedlings, which catalyzes the elongation steps from C22:0 to C24:0 and C24:0 to C26:0, respectively. These results strongly suggest that fenoxasulfone is a potent inhibitor of plant VLCFAEs and should be categorized within the K3 group of the Herbicide Resistance Action Committee. The VLCFAE activity of recombinant Fatty acid elongation 1 (FAE1) of Arabidopsis, which catalyzes the elongation step from C18:1 to C20:1, was inhibited by Fenoxasulfone in a time-dependent manner, a feature that has been observed in the inhibition of VLCFAEs by other well-known VLCFAE-inhibiting herbicides. In addition, the VLCFAE activity of the microsomal fraction of etiolated barnyard millet seedlings, which catalyzes the elongation step from C24:0 to C26:0, was inhibited by Fenoxasulfone in a time-independent manner. This time-independent inhibition indicates a new inhibitory mechanism of VLCFAE by Fenoxasulfone, possibly similar to that of Pyroxasulfone, which is classified in the same chemical class as Fenoxasulfone.

Conclusion This chapter has described the discovery and biological aspects of Fenoxasulfone (Figure 17). Fenoxasulfone exhibits excellent efficacy against grass weeds in paddy field rice cultivation and broad-spectrum weed control. In addition, Fenoxaslfone shows outstanding residual activity on Echinochloa spp. and Monochoria spp. Fenoxasulfone also has favorable toxicological, environmental, and ecotoxicological properties.

Figure 17. Fenoxasulfone

In Japan, Fenoxasulfone was registered for use on turf on May 16th, 2014, and for use on rice on October 3rd, 2014. 275 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.

Acknowledgments The authors thank the people who engaged in research and development in KI Chemical Research Institute Co., Ltd, Kumiai Chemical Industry Co., Ltd and Ihara Chemical Industry Co., Ltd.

References


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Nakatani, M.; Yoshimura, T.; Hanai, R.; Tanetani, Y.; Shimizu, T. Modern Crop Protection Compounds, 2nd, Revised and Enlarged Edition, WileyVCH: 2011; Vol. 1, pp 326−337. Nakatani, M.; Ito, M.; Kaku, K; Ueno, R; Kawasaki, H.; Takahashi, S. J. Pestic.. Sci. 2005, 30, 74. Nakatani, M.; Ito, M.; Miyazaki, M.; Ueno, R.; Takahashi, S. J. Pestic.. Sci. 2005, 30, 75. Ito, M.; Nakatani, M.; Takahashi, Y.; Fujinami, M.; Hanai, R. J. Pestic.. Sci. 2010, 35, 52. Takahashi, Y.; Fujinami, M.; Hanai, R.; Ito, M.; Nakatani, M. J. Pestic.. Sci. 2010, 35, 88. Tanetani, Y.; Fujioka, T.; Horita, J.; Kaku, K.; Shimizu, T. J. Pestic.. Sci. 2011, 36, 357.


3-Sulfonylisoxazoline Derivatives as Novel Herbicides - American

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