Tioxazafen | Nematicides | Treatment of Seeds

Tioxazafen [3-phenyl-5-(thiophen- 2-yl)-1,2,4-oxadiazole] is a new broad-spectrum seed treatment nematicide that is designed to provide consistent broad-spectrum control of nematodes in corn, soy, and cotton [1].

Tioxazafen exhibits excellent activity against soybean cyst, root knot, and reniform nematodes in soy; lesion, root knot, and needle nematodes in corn; as well as reniform and root knot nematodes in cotton.

Tioxazafen: 2D and 3D Structure

Tioxazafen is a disubstituted oxadiazole, which represents a new class of nematicidal chemistry demonstrating equal or better performance in greenhouse and field trial evaluations when compared with commercial treatments.

Mechanism for Activity

The exact moleculer targets for Tioxazafen are unknown but phenotypic characterization of plant-parasitic and the free-living nematode Caenorhabditis elegans in the presence of Tioxazafen indicate a mode of action that is distinct from other commercial nematicides.

Nematodes (roundworms) are ubiquitous and important pathogens of plants. Plant nematodes globally cause significant crop injury and yield loss for growers. Among nematode-infested crops with major economic losses are soybeans, potatoes, cotton, corn, citrus, strawberries, tomatoes, carrots, peppers, and sugar beets. Plant parasitic nematodes including root knot, cyst, reniform, lesion, and others infest all parts of plants, especially the roots. The most economically damaging are sedentary endoparasitic nematodes (e.g., root knot and cyst) which establish root feeding sites. Roots suffer from nutrient loss and diminished capacity to survive drought and stress.

In the broader context, achieving safe and effective nematode control is a key part of the move toward environmentally sustainable agriculture. Therefore, chemical seed treatments are gaining traction in the marketplace because of their reduced environmental footprint, economical advantage due to lower use rates, and ease of use for the farmer. Seed treatment applications reduce the chances for off-target movement and reduce the amount of product required because of specific placement.

Nematode invasion also facilitates secondary infection with fungal pathogens. For example sudden death syndrome (SDS) is more severe when the soybean cyst nematode (SCN) is also present in a field and invasion of the roots by root knot nematode (RKN) enhanced infection by Fusarium oxysporum. For tuber crops, nematodes cause loss of harvest quality as well as yields [1].

 Developer

It is developed by Monsanto and it is one of the success stories where cheminformatics based designing produced safer, faster and efficient result.

Reported Activities for Tioxazafen

% Mortality (M. incognita @ 0.1 ppm Tioxazafen) = 46%

% Mortality (M. incognita @ 1 ppm Tioxazafen) = 86%

% Mortality (M. incognita @ 10 ppm Tioxazafen) = 95%

% Mortality (H. glycines @ 0.1 ppm Tioxazafen) = 55%

% Mortality (H. glycines @ 5 ppm Tioxazafen) = 75%

% Mortality (H. glycines @ 10 ppm Tioxazafen) = 87%

*  M. incognita = Root Knot Nematode

H. glycines = Soybean Cyst Nematode

Summary

Common name: Tioxazafen

Trademarks: -

Molecular Formula: C12H8N2OS

CAS Registry Number: 330459-31-9

CAS Name: 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole

Molecular Weight: 228.27

SMILES: C1(C2=CC=CS2)=NC(C3=CC=CC=C3)=NO1

InChI Key: IHNSIFFSNUQGQN-UHFFFAOYSA-N

InChI: InChI=1S/C12H8N2OS/c1-2-5-9(6-3-1)11-13-12(15-14-11)10-7-4-8-16-10/h1-8H

Mechanism of Action: Unknown

Activity: Nematicide; Treatment of Seeds

Status: -

Chemical Class: Sulphur containing; Thio containing; Thiophene containing; Small-molecules; Benzene containing; 5-member Heterocyles; Oxadiazoles

Originator: Monsanto Corporation

Tioxazafen Synthesis

WO2014008257A2: The patent reports synthesis for Tioxazafen and derivatives. The process appears to be an industrial one and provides yields upto 95%.

Benzonitrile (25.0 g, 242 mmol) was added to a 250 mL flask and heated to 50°C. Aqueous hydroxylamine (50%, 20.4 g, 309 mmol) was added via a syringe pump at 0.17 ml/min (2 hours addition time). Upon completion of the addition of the 50% aqueous hydroxylamine solution, the reaction was stirred an additional 1 hour 30 minutes at 50°C. The reaction was complete and 80 ml of 2-methyltetrahydrofuran and 25 ml of water were added. The solution was mixed for 10 minutes and the layers were separated. The water white organic layer (96.3 g) was collected. Upon analysis, the organic layer contained 29.48 w/w % of the benzamide oxime product (28.4 g, 208 mmol). The yield was 86 %.

A solution of benzamide oxime (24.92%) in 2-methyl THF (67.53g, 124 mmoles) was charged to a 500 ml flask, followed by DI water (20.0g), 55% aqueous tetrabutylammonium hydroxide (0.94g), and 50% sodium hydroxide (0.96g, 12 mmoles). To this mixture was added 2-thiophenecarbonyl chloride (17.77g, 120 mmoles) and 50% sodium hydroxide (9.60g, 120 mmoles) simultaneously over 30 minutes while heating to about 70°C. The reaction was complete is less than one hour. The temperature was reduced to 60°C, and the pH of the aqueous phase was neutralized to 7.61, and was drained off to waste. A hot solution of 1.25 g of Morwet D-425 in 100 ml DI water was added to the mixture and the 2-phase mixture was heated to distill off the 2-methyltetrahydrofuran /water azeotrope (boiling point 71°C). Additional water (150 ml) was pumped into the reactor flask over about 15 minutes, once the 2-methyltetrahydrofuran began to distill out. While maintaining good agitation, the pot temperature reached 100.5°C (vapor temperature 97°C). The slurry was cooled and filtered using a coarse glass frit. The scale was scraped off the agitator and combined with the wet cake; the scale was only about 3% of total product. The combined wet cake was washed with hot DI water (3 x 50 ml) and suction-dried for 5 minutes to give a 3-phenyl-5-(thiophen-2-yl)-1,2,4- oxadiazole wet cake, 34.80 g. The loss on drying of the wet cake was 20.13%. The assay of the dried 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole was 96.12%, and the residual chloride was less than200 ppm.

 Tetrahedron Lett. 2006, 47, 3629-3631: Another strategy with one-step ring closure procedure involves an acylation of benzamidoxime with methyl thiophene-2-carboxylate followed by instant cyclodehydration at 140 °C in xylene in the presence of potassium carbonate and features easy final product isolation. The benzaminodoxime was prepared from benzonitrile and hydroxyl amine (release in situ from its salt by sodium hydroxide) in methanol. This method was used for production of larger quantities of Tioxazafen in high yields (in a range of 85-87%) and high purity.

Identifications:

1H NMR (Estimated) for Tioxazafen

Adverse Reports:

Nothing available.

Others:

Tioxazafen formulations were incorporated into Acceleron, a fungicide/insecticide seed treatment package available from Monsanto Company [1].

An uptake study with soybean seed treated with radiolabeled Tioxazafen indicates that the compound is predominantly distributed to the root zone and is not upwardly mobile to the vegetative tissue. Retention within the root zone is ideal for nematode management. Extensive growth chamber and green house studies demonstrate excellent Tioxazafen efficacy as a seed treatment against several key nematodes (soy cyst nematode, root knot nematode and lesion) in common row crops.

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References:

1. Slomczynska, U.; et. al. Tioxazafen: A New Broad-Spectrum Seed Treatment Nematicide. Chap 10: In Discovery and Synthesis of Crop Protection Products; ACS Symposium Series; American Chemical Society: Washington, DC, 2015. (FMO only)

2. Miller, W. H.; et. al. Processes for the preparation of 3,5-disubstituted-1,2,4-oxadiazoles. WO2014008257A2

3. Amarasinghe, K. K. D.; et. al. One-pot synthesis of 1,2,4-oxadiazoles from carboxylic acid esters and amidoximes using potassium carbonate. Tetrahedron Lett 2006, 47, 3629-3631. (FMO only)

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