Development of potential manufacturing routes for substituted thiophenes--preparation of halogenated 2-thiophenecarboxylic acid derivatives as building blocks for a new family of 2,6-dihaloaryl 1,2,4-triazole insecticides.

Dow AgroSciences has been investigating a new family of functionalized 2,6-dihaloaryl 1,2,4-triazole insecticides featuring specifically targeted insecticidal activities coupled with low mammalian toxicity. With broad spectrum control of both chewing and sap-feeding pests in mind, this family of compounds has been under investigation for aphid, mite, and whitefly control in food crop protection as well as ornamental applications. Two specific targets for development have been the 2,6-dihalo 1,2,4-triazoles XR-693 and XR-906, which require a supply of the halogenated 2-thiophenecarboxylic acid derivatives 1, 2, and 3 for assembly of the C-ring portion of the triazole products. Potential manufacturing routes to three halogenated 2-thiophenecarboxylic acid derivatives 4-bromo-3-methyl-2-thiophenecarbonyl chloride 1, 3,4,5-trichloro-2-thiophenecarbonyl chloride 2, and 3,4,5-trichloro-2-thiophenecarbonitrile 3 from commercially available thiophene raw materials have been developed and demonstrated on a laboratory scale. A one-pot bromination/debromination procedure developed for 3-methylthiophene gave 2,4-dibromo-3-methylthiophene. Carboxylic acid functionality was then introduced either by a Grignard metallation followed by carbonation with CO2, or by a palladium catalyzed carbonylation procedure under CO pressure. The vapor phase chlorination of 2-thiophenecarbonitrile with chlorine gas at 500 degrees C with an average residence time of 6 seconds gave 3,4,5-trichloro-2-thiophenenitrile 3 in a 69% distilled yield, a process that was carried out on a multi-kilogram scale in the laboratory. Finally, a route for the preparation of 3,4,5-trichloro-2-thiophenecarbonyl chloride 2 was developed from tetrachlorothiophene via either a lithiation reaction with n-butyllithium in MTBE solvent, or by a previously reported Grignard method using 1,2-dibromoethane as activator, followed by carbonation of the anion with CO2 to give the trichloro-2-thiophenecarboxylic acid, which was readily converted to the acid chloride 2 with SOCl2. The successful development of efficient synthetic routes to the halogenated thiophene building blocks 4-bromo-3-methyl-2-thiophenecarbonyl chloride 1, 3,4,5-trichloro-2-thiophenecarbonyl chloride 2, and 3,4,5-trichloro-2-thiophenecarbonitrile 3 paved the way for the development of viable commercial processes for XR-693 and XR-906, members of a new class of 2,6-dihaloaryl 1,2,4-triazole insecticides that exhibit selective activity against aphids, mites, and whiteflies coupled with low mammalian toxicity. The process development work for the experimental insecticide target molecules XR-693 and XR-906 will be the topic of a forthcoming paper.