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Fluoroalkyl groups profoundly affect the physical properties of pharmaceuticals and influence virtually all metrics associated with their pharmacokinetic and pharmacodynamic profile.^1-4 Drug candidates increasingly contain CF₃ and CF₂H groups, and the same trend in agrochemical development shows that the effect of fluoroalkylation translates across human, insect, and plant life.^5,6 New fluoroalkylation reactions have undoubtedly stimulated this uptake; however, methods that directly convert C–H bonds into C–CF₂X (X = F or H) groups in complex drug-like molecules are rare.^7-13 For pyridine, the most common aromatic heterocycle in pharmaceuticals,¹⁴ only one approach, via fluoroalkyl radicals, is viable for pyridyl C–H fluoroalkylation in the elaborate structures encountered during drug development.^15-17 Here, we have developed a new set of bench-stable fluoroalkylphosphines that directly convert the C–H bonds in pyridine building blocks, drug-like fragments, and pharmaceuticals into fluoroalkyl derivatives. No pre-installed functional groups or directing groups are required; the reaction tolerates a variety of sterically and electronically distinct pyridines and is exclusively selective for the 4-position in most cases. The reaction proceeds via initial phosphonium salt formation followed by <i>sp</i>²-<i>sp</i>³ phosphorus ligand-coupling, an underdeveloped manifold for C–C bond formation.

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