Flupyradifurone

{{chembox }} Flupyradifurone is a systemic butenolide insecticide developed by Bayer CropScience under the name Sivanto. Flupyradifurone protects crops from sap-feeding pests such as aphids and is safer for non-target organisms compared to other insecticides. Sivanto was launched in 2014 since it obtained its first commercial registration in central America (Guatemala and Honduras). Insecticide Resistance Action Committee (IRAC) classified Flupyradifurone as 4D subset (butenolide) and it is the first pesticide in the butenolide category. It was approved by European Union in 2015.
 * Name=Flupyradifurone
 * ImageFile=Flupyradifuron.svg
 * ImageName=Flupyradifurone
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 * OtherNames=Flupyradifurone, Sivanto
 * IUPACName=4-[(6-Chloropyridine-3-yl)methyl](2,2-difluoroethyl)amino}furan-2(5H)-one
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Characteristics
Sap-feeding insects have developed resistance to nearly all other kinds of insecticides but flupyradifurone is effective at controlling aphids and whitefly, thereby maintaining yields of crops such as vegetables, fruits, cotton, and coffee. It also demonstrated positive toxicological and ecotoxicological safety.

According to a study by Bayer, who developed the compound, flupyradifurone has a high rate of uptake by plants and crops. The authors used phosphor imaging analysis to monitor the uptake and translocation of [pyridinylmethyl-14C]-labeled flupyradifurone by tomato plants. The result revealed fast root uptake and the even distribution of labeled flupyradifurone in the entire plant. Flupyradifurone is delivered via xylem translocation in the plants. The concentration in the plants reached the highest point in 7 and 14 days. After 24 days of the application, a significant decline is observed. Flupyradifurone also featured excellent speed of action. The speed of action can be observed by the prohibition of honeydew excretion. After applying the flupyradifurone to the plant by spraying, the honeydew excretion is inhibited within 2 hours and all the aphids die after 48 hours. The result demonstrated that flupyradifurone has an exceptional speed of action compared to other insecticides.

Flupyradifurone presented potent efficacy in controlling aphids and whiteflies. According to bioassays research, the flupyradifurone has lower LC50 numbers of aphid and whitefly compared to imidacloprid. In the field trial, flupyradifurone controlled the lettuce aphid at a favorable rate via foliar applying. It had the highest efficiency (96%) of controlling lettuce aphid after 6–10 days of the application.

Mode of action
Flupyradifurone is an agonist of insect nicotinic acetylcholine receptors, causing depolarization of nerve cells membranes. Insects cannot detoxify flupyradifurone according to the research of CYP6CM1-mediated metabolism. Since flupyradifurone cannot be inactivated by acetylcholinesterase, it will lead to the failure of nerve system of insects and end up with the death of insects.

Synthesis
Flupyradifurone is structurally related to the natural insecticide, stemofoline which occurs in the plant species Stemona japonica. Stemofoline has some advantageous features, such as being fast-acting and an effective antifeedant, but does not efficiently bind to insect nicotinic acetylcholine receptors.

There are two ways to synthesis flupyradifurone. First, flupyradifurone can be synthesized from reacting tetronic acid with 2,2-difluoroethylamine to produce the intermediate, 4-[(2-fluoroethyl)amino]furane-2(5H)-one. Heating the reaction intermediate with 2-chloro-5-(chloromethyl)pyridine in THF under reflux yields flupyradifurone. In the second method, tetronic acid, 4-touluenesulfonic acid, and N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethane-1-amine in toluene are heated under reflux for 2 hours to produce flupyradifurone.

Toxicological and ecotoxicological safety
Using the U.S. Environmental Protection Agency guidelines to classify carcinogenic effects, flupyradifurone is categorized as "not likely to be carcinogenic to humans." It is not irritant to humans' eyes and skin, and the EPA is not concerned about occupational exposure.

For the non-target species, flupyradifurone also presents toxicological safety at low concentration. Flupyradifurone will still bind to the nicotinic acetylcholine receptors of honey bees, however, it will only affect the taste and appetitive learning performance at the highest labeled concentration. The LD50 of honey bee acute contact is >100 μg/bee and acute oral is 1200 ng/bee. For bumblebee, the acute contact LD50 is >100 μg/bee.