Efficient Access to Functionalized N‑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 N-difluoromethylpyrazoles,
remains challenging. Here, selective oxidation of the methyl group
in 1-(difluoromethyl)-3-methyl-1H-pyrazole and 1-(difluoromethyl)-5-methyl-1H-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···NPz.