Advantages of Flow Chemistry in the Electrochemical Tri‐ and Difluoromethylation of Purines and Pyrimidines

Trifluoromethyl (–CF 3 ) and difluoromethyl (–CF 2 H) substituents are key structural motifs in modern pharmaceuticals due to their ability to enhance lipophilicity, metabolic stability, and introduce unique electronic properties. Here, we report a sustainable and operationally facile electrochemical method to introduce these groups directly onto purine and pyrimidine scaffolds, heterocycles central to nucleobase chemistry and drug design, without the need for stoichiometric oxidants, transition‐metal catalysts, or photocatalysts. Using commercially available sodium trifluoromethanesulfinate and sodium difluoromethanesulfinate under mild conditions in an undivided IKA ElectraSyn 2.0 cell, the reaction proceeds efficiently across more than 15 substrates, affording up to 80% yield. The difluoromethylation process was further translated into a microflow electrolysis platform from Analytical Sales & Services, enhancing scalability and throughput with an average 1.5‐fold increase in product generation rate relative to batch. This process is the first demonstration of electrochemical difluoromethylation of heterocycles in flow and establishes a versatile, green synthetic platform for accessing fluorinated nucleobase derivatives and other bioactive small molecules.