Synthesis of N‐Difluoromethyl Carbonyl Compounds from N‐Difluoromethylcarbamoyl Fluorides

Abstract

AbstractFluorinated small molecules are commonly used in functional small‐molecule chemistry, and N‐difluoromethyl (N‐CF2H) compounds are particularly intriguing due to their unique and unexplored physiochemical properties. However, despite limited progress, a general methodological approach to the synthesis of N‐CF2H compounds remains elusive. Here, guided by computation, we present a simple and practical protocol to access N‐CF2H amides and related carbonyl derivatives. The protocol involves a one‐pot conversion of thioformamides through desulfurization‐fluorination and acylation, providing N‐difluoromethylcarbamoyl fluoride building blocks that can be further diversified to a variety of unexplored N‐CF2H carbonyl compounds with rich functionality. Additionally, preliminary studies on their properties and stability showcased their potential application in pharmaceuticals and agrochemicals.