Abstract
Pyroxasulfone, which was discovered and developed by K-I Chemical Research Institute Co., Ltd.; Kumiai Chemical Industry Co., Ltd.; and Ihara Chemical Industry Co., Ltd., is a novel pre-emergence herbicide for wheat, corn, and soybean. Pyroxasulfone inhibits the biosynthesis of very-long-chain fatty acids in plants and has shown excellent herbicidal activity against grass and broadleaf weeds at lower application rates compared with other commercial herbicides. This pesticide has been registered in Japan, Australia, the USA, Canada, Saudi Arabia, and South Africa, and we sell pyroxasulfone products through domestic partner companies in each of these countries. With its high efficacy and relatively low application rates, we believe that pyroxasulfone will contribute to efficient global food production in the future.
Keywords: pyroxasulfone; 4,5-dihydro-1,2-oxazole; 2-isoxazoline; pre-emergence; herbicide; very-long-chain fatty acid elongase
Introduction
Pyroxasulfone (Fig. 1) was discovered by K-I Chemical Research Institute Co., Ltd. and developed by Kumiai Chemical Industry Co., Ltd. and Ihara Chemical Industry Co., Ltd. It was developed as a pre-emergence herbicide to control grass and small-seeded broadleaf weeds. A dose of 100–250 g a.i./ha of pyroxasulfone was sufficient to control these weeds. In fields of genetically modified crops, pyroxasulfone controlled weeds that were resistant to non-selective herbicides.1–4)
Fig. 1. Chemical structure of pyroxasulfone.
Pyroxasulfone has been classified in the Herbicide Resistance Action Committee Group K3,5) and inhibits the biosynthesis of very-long-chain fatty acids in plants.2,6)
In this paper, we describe the discovery, physicochemical properties, biological activity and development status of pyroxasulfone.
1. Discovery of pyroxasulfone
Thiobencarb was used as a basis for our research to develop a novel pre-emergence herbicide for uplands. Thiobencarb is a rice herbicide (developed by the Kumiai Chemical Industry Co., Ltd.) with pre-emergence herbicidal activity against Echinochloa spp., Digitaria ciliaris (southern crabgrass), and several other annual weeds in both uplands and paddy fields.7) A dose of 1,500–7,500 g a.i./ha of thiobencarb was required to control these weeds. However, thiobencarb sulfoxide, the active form of thiobencarb, decomposes easily under many environmental conditions.8–11) We therefore proposed the development of a novel pre-emergence herbicide with high and stable herbicidal activity.
To achieve this, we designed a compound without a carbonyl moiety by replacing the amide group with a heterocyclic ring (Fig. 2; I). For the heterocyclic ring, we used 4,5-dihydro-1,2-oxazole, which is easily synthesized using a 1,3-dipolar cycloaddition reaction between a nitrile oxide and an olefin. The 4,5-dihydro-1,2-oxazole ring is a novel chemical structure for pre-emergence herbicides, though many pesticides with this ring have been patented.12–15)
Fig. 2. Compound design and structural modifications.
After optimizing the substituents on the 4- or 5-position of the 4,5-dihydro-1,2-oxazole ring (II), we found a 5,5-dimethyl derivative that had sufficient pre-emergence herbicidal activity against Echinochloa crus-galli (barnyardgrass) and Setaria viridis (green foxtail) under upland conditions. Compound III, which was synthesized based on the result of a structure-activity relationship study between the substituents on the benzene ring and their pre-emergence herbicidal activities, had excellent pre-emergence herbicidal activity against these weeds with minimal effects on corn and soybean. However, the physicochemical properties of this compound, especially the soil adsorption coefficient, were not suitable for its use as a pre-emergence herbicide in uplands.
To improve the physicochemical properties, hetero-aromatic derivatives (IV) were designed and synthesized to replace the benzene ring. The pyrazol-4-yl derivative had stronger herbicidal activity against grasses than benzene derivatives and also showed herbicidal activities against Chenopodium album (common lambsquarters) and Abutilon theophrasti (velvetleaf). Pyroxasulfone was discovered by optimizing the substituents in the 1- and 5-positions of the pyrazole ring. This compound has excellent herbicidal activities against the grasses and broadleaf weeds mentioned above, and minimal effects on corn and soybean (Fig. 3).
Fig. 3. Herbicidal efficacy and crop injury by pre-emergence application of pyroxasulfone in a greenhouse pot trial. Herbicidal efficacy and crop injury were evaluated by visual observation of symptoms of treated plants compared with untreated controls at 21 days after application. ZEAMX: Zea mays, GLYMA: Glycine max, ECHCG: Echinochloa crus-galli, SETVI: Setaria viridis, CHEAL: Chenopodium album, ABUTH: Abutilon theophrasti.
2. Physicochemical properties
Pyroxasulfone has unique physicochemical properties that are optimal for its use as an herbicide (Table 1),16) particularly its relatively low log P value and solubility in water compared with those of chloroacetanilide herbicides such as alachlor, acetochlor and metolachlor. Pyroxasulfone is also hydrolytically stable at all pH values at 25°C, and is therefore less susceptible to decomposition.
Table 1. Physical and chemical properties of pyroxasulfone3,16).
| ISO common name | Pyroxasulfone |
| Developmental code | KIH-485 |
| Preferred IUPAC name | 3-{[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methanesulfonyl}-5,5-dimethyl-4,5-dihydro-1,2-oxazole |
| General IUPAC name | 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-ylmethylsulfonyl]-4,5-dihydro-5,5-dimethyl-1,2-oxazole, or 5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-ylmethyl 4,5-dihydro-5,5-dimethyl-1,2-oxazol-3-yl sulfone |
| CAS name | 3-[[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]sulfonyl]-4,5-dihydro-5,5-dimethylisoxazole |
| CAS registry number | 447399-55-5 |
| Molecular formula | C12H14F5N3O4S |
| Molecular weight | 391.316 |
| Appearance | White crystalline solid |
| Odor | Slight characteristic odor |
| Melting point | 130.7°C |
| Relative density | 1.60 g/cm3 |
| Log Pow | 2.39 (25°C) |
| Vapor pressure | 2.4×10-6 Pa (25°C) |
| Water solubility | 3.49 mg/L (20°C) |
| Hydrolysis (half-life) | >1 year (pH 5, 7 or 9; 25°C) |
| Adsorption in soil | KFadsOC=38–66 (25°C; in Japan) |
| KFadsOC=57–110 (25°C; in United States of America) |
3. Biological activity
3.1. Field trials in the USA
In preliminary greenhouse trials using pots of coarse soil (sandy loam) we found that 16 g a.i./ha of pyroxasulfone controlled Echinochloa crus-galli and Setaria viridis, and 63 g a.i./ha of pyroxasulfone controlled Chenopodium album and Abutilon theophrasti. Field trials were used to determine the field application rates. From 2003 through 2006 (Fig. 4), a total of 370 trials were conducted in the USA following one of four protocols, depending on soil texture (Table 2).17) Pyroxasulfone was effective against several grasses (e.g., Setaria viridis, Echinochloa crus-gall, Digitaria sanguinalis (large crabgrass)) and broadleaves (e.g., Amaranthus spp., Chenopodium album). Finer soils required greater application rates (Fig. 5). Pyroxasulfone also had good selectivity for corn and soybeans, using a lower dose than current standards (Table 3).
Fig. 4. Field trials in the USA from 2003 to 2006.
Table 2. Test protocols for the U.S. field trials17).
| Protocol | A | B | C | D |
|---|---|---|---|---|
| Soil particle size | Coarse | Medium | Medium | Fine |
| Representative soil texture | Sandy loam | Loam | Clay loam | Clay |
| Pyroxasulfone (g a.i./ha) | 100 | |||
| 125 | 125 | 125 | 125 | |
| 166 | 166 | 166 | ||
| 209 | 209 | 209 | ||
| 250 | 250 | 250 | 250 | |
| 300 |
Bold type: Assumed practical application dose at each protocol.
Fig. 5. Herbicidal efficacies by soil texture. Grass weeds: Setaria viridis, Echinochloa crus-galli, Digitaria ciliaris, etc. Broadleaf weeds: Amaranthus spp., Chenopodium album, etc.
Table 3. Effective pre-emergence application rates of pyroxasulfone and S-metolachor by soil texture17).
| Soil particle size | Coarse | Medium | Fine | |
|---|---|---|---|---|
| Soil texture | Sand Loamy sand Sandy loam | Loam Silt loam Silt | Sandy clay loam Silt clay loam Clay loam | Sandy clay Silt clay Clay |
| Pyroxasulfone (g a.i./ha) | 125 | 166 | 209 | 250 |
| S-metolachlor (g a.i./ha) | 1070 | 1423 | 1787 | 2140 |
3.2. Features
These are three favorable features of pyroxasulfone: 1) Pyroxasulfone can control a large number of annual weeds, particularly grasses (Table 4); this also includes herbicide-resistant weeds such as Lolium multiflorum (Italian ryegrass) and Alopecurus aequalis (water foxtail) (grasses) and Amaranthus spp. (broadleaf weeds). 2) Pyroxasulfone has high pre-emergence activity and longer residual activity than similar products, with residual activity still high 2 months after application (Fig. 6).18) 3) Pyroxasulfone shows good selectivity for corn, soybeans, wheat, turf, cotton, potato and onion, and we intend to extend its use to other crops in future.
Table 4. Weeds controlled by pre-emergence application of pyroxasulfone16).
| Grass weed | Broadleaf weed | Sedge |
|---|---|---|
| Alopecurus myosuroides | Abutilon theophrasti* | Cyperus esculentus |
| Avena fatua* | Amaranthus albus | |
| Bromus tectorum* | Amaranthus hybridus | |
| Cenchrus longispinus* | Amaranthus palmeri | |
| Digitaria ischaemum | Amaranthus powellii | |
| Digitaria sanguinalis | Amaranthus retroflexus | |
| Echinochloa crus-galli | Amaranthus rudis | |
| Eriochloa gracilis | Amaranthus tuberculatus | |
| Eriochloa villosa* | Ambrosia artemisiifolia* | |
| Hordeum leporinum | Chenopodium album* | |
| Lolium multiflorum | Datura stramonium | |
| Lolium rigidum | Ipomoea hederacea* | |
| Oryza punctata | Ipomoea lacunosa* | |
| Panicum dichotomiflorum | Kochia scoparia* | |
| Panicum miliaceum* | Mollugo verticillata | |
| Panicum texanum* | Polygonum convolvulus* | |
| Phalaris minor | Portulaca oleracea | |
| Poa annua | Richardia scabra | |
| Setaria faberi | Solanum ptychanthum | |
| Setaria glauca | Solanum sarrachoides | |
| Setaria viridis | Sida spinosa | |
| Sorghum halepense | Stellaria media | |
| Sorghum vulgare* | ||
| Urochloa platyphylla | ||
| (Brachiaria platyphylla) |
* Reduced competition
Fig. 6. Residual control on Urochloa platyphylla (broadleaf signal grass) at pre-emergence. Test weed: Urochloa platyphylla (broadleaf signal grass: indigenous weed), Soil texture: Silt loam; Organic matter content: 0.81%; pH: 6.45, Application date: Mar 28, 2008, Location: Mississippi, USA.
4. Mode of action
To elucidate the mode of action of pyroxasulfone, we first observed injury symptoms of pyroxasulfone-treated weeds. Pyroxasulfone has little effect on germination of Lolium multiflorum and Echinochloa spp. but greatly inhibits shoot elongation of germinated seeds. These injury symptoms are very similar to those of the very-long-chain fatty acid elongase (VLCFAE)-inhibiting herbicides. Based on these observations, we estimated the VLCFAE inhibition activity of pyroxasulfone. Our tests showed that pyroxasulfone inhibited the VLCFAEs of Oryza sativa (rice) and Lolium multiflorum, an action similar to that of chloroacetoamide herbicides such as metolachlor. Furthermore, pyroxasulfone inhibited six successive elongase reactions of very-long-chain fatty acids that catalyze the elongation steps from C16:0 to C18:0, from C18:0 to C20:0, from C20:0 to C22:0, from C22:0 to C24:0, from C24:0 to C26:0, and from C26:0 to C28:0, and also reduced unsaturated very-long-chain fatty acids (C18:1, C20:1, C22:1) (Fig. 7).2,3,6)
Fig. 7. Biosynthetic pathway of very-long-chain fatty acids in plants. Cα:β indicates a fatty acid with α carbon atoms and β carbon double bonds.
5. Sales and development updates
Pyroxasulfone has been registered as a pesticide in Japan, Australia, the USA, Canada, Saudi Arabia, and South Africa, and we sell products that include pyroxasulfone as one of the active ingredients through domestic partner companies in each of these countries (Table 5). We are actively pursuing registrations in New Zealand, Chile, and Brazil.
Table 5. Registered products of pyroxasulfone as of February 2016.
| Country | Active ingredient | Crop |
|---|---|---|
| Australia | Pyroxasulfone | Wheat, Triticale |
| United States of America | Pyroxasulfone | Corn, Soybean, Wheat, Cotton |
| Pyroxasulfone+Flumioxazin | Corn, Soybean, Wheat, Cotton, IVM* | |
| Pyroxasulfone+Flumioxazin+Chlorimuron-ethyl | Soybean | |
| Pyroxasulfone+Fluthiacet-methyl | Corn, Soybean | |
| Pyroxasulfone+Fluthiacet-methyl+Atrazine | Corn | |
| Pyroxasulfone+Carfentrazone-ethyl | Cotton, Wheat | |
| Canada | Pyroxasulfone+Flumioxazin | Soybean, IVM* |
| Pyroxasulfone+Carfentrazone-ethyl | Corn, Soybean | |
| South Africa | Pyroxasulfone | Wheat |
| Saudi Arabia | Pyroxasulfone | Wheat |
| Japan | Pyroxasulfone | Turf |
* Industrial Vegetation Management
We have recently registered AXEEV® as the original brand name of pyroxasulfone. We intend to continue selling pyroxasulfone so that we can contribute to global food production.
Conclusion
Pyroxasulfone has been used as a pre-emergence herbicide in uplands for the cultivation of wheat, corn and soybean in Australia, the USA and Canada. Crops protected by pyroxasulfone covered 3 million ha in Australia and 3 million ha in the USA in 2015.
Acknowledgments
The authors thank the staff members of the K-I Chemical Research Institute Co., Ltd., the Kumiai Chemical Industry Co., Ltd., and the Ihara Chemical Industry Co., Ltd.
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