Efficient Access to Functionalized <i>N</i> -Difluoromethylpyrazoles

Fluorinated pyrazoles play important roles in medicinal chemistry, drug discovery, agrochemistry, and coordination chemistry. Although fluorinated compounds have many benefits, the preparation of functionalized fluorinated pyrazoles, partly <i>N</i>-difluoromethylpyrazoles, remains challenging. Here, selective oxidation of the methyl group in 1-(difluoromethyl)-3-methyl-1<i>H</i>-pyrazole and 1-(difluoromethyl)-5-methyl-1<i>H</i>-pyrazoles to prepare the corresponding pyrazole-3- and pyrazole-5-carboxylic acids was described. The carboxylic acids were transformed into a broad range of new functionalized derivatives: esters, alcohols, aldehydes, amines, amides, nitriles, and chloro derivatives. The crystal structure of the initial carboxylic acid derivatives has been determined from single-crystal X-ray analysis, which provided unambiguous proof of the regiochemistry of all prepared 1-difluoromethyl-pyrazoles. Note, in the crystalline structure of substituted pyrazole-3-carboxylic acid, the formation of dimers via double hydrogen bonds of O-H···O between molecules was observed, while the pyrazole-5-carboxylic acid derivative forms chains via hydrogen bonds of O-H···N_Pz.