The article presents a novel method for the direct conversion of aliphatic alcohols into their corresponding difluoromethylated analogues, a process known as bioisostere replacement. This approach aims to overcome the challenges of traditional de novo synthesis of bioisosteres, which can be time-consuming and resource-intensive. The method combines benzoxazolium-mediated deoxygenation and copper-mediated C(sp³)–CF₂H bond formation, facilitated by metallaphotoredox catalysis. The versatility of this method is demonstrated through its application to a wide range of substrates, including primary and secondary alcohols, as well as complex drug-like compounds. The authors also extend the method to include difluoroalkylation, further expanding its utility in medicinal chemistry. The overall reaction design and optimized conditions are detailed, along with a comprehensive evaluation of the reaction scope and selectivity. This work provides a valuable tool for the rapid and efficient synthesis of difluoromethylated and difluoroalkylated compounds, which are important for improving the pharmacokinetic properties and clinical success of drug candidates.The article presents a novel method for the direct conversion of aliphatic alcohols into their corresponding difluoromethylated analogues, a process known as bioisostere replacement. This approach aims to overcome the challenges of traditional de novo synthesis of bioisosteres, which can be time-consuming and resource-intensive. The method combines benzoxazolium-mediated deoxygenation and copper-mediated C(sp³)–CF₂H bond formation, facilitated by metallaphotoredox catalysis. The versatility of this method is demonstrated through its application to a wide range of substrates, including primary and secondary alcohols, as well as complex drug-like compounds. The authors also extend the method to include difluoroalkylation, further expanding its utility in medicinal chemistry. The overall reaction design and optimized conditions are detailed, along with a comprehensive evaluation of the reaction scope and selectivity. This work provides a valuable tool for the rapid and efficient synthesis of difluoromethylated and difluoroalkylated compounds, which are important for improving the pharmacokinetic properties and clinical success of drug candidates.